Oxford Handbook of Clinical and Laboratory Investigation

OXFORD MEDICAL PUBLICATIONS

Oxford Handbook of

Clinical and

Laboratory

Investigation

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Oxford Handbook of

Clinical and

Laboratory

Investigation

Fourth Edition

Editedby

DrewProvan

Honorary Reader in Autoimmune Haematology,

Barts & The London School of Medicine & Dentistry

Queen Mary University ofLondon

London,UK

Great Clarendon Street, Oxford, OX26DP,

United Kingdom

Oxford University Press is a department of the University of Oxford.

It furthers the University’s objective of excellence in research, scholarship,

and education by publishing worldwide. Oxford is a registered trade markof

Oxford University Press in the UK and in certain other countries

The moral rights of the authors have been asserted

First Edition published in2002

Second Edition published in2005

Third Edition published in 2010

Fourth Edition published in 2018

Impression:1

a retrieval system, or transmitted, in any form or by any means, withoutthe

prior permission in writing of Oxford University Press, or as expressly permitted

by law, by licence or under terms agreed with the appropriate reprographics

rights organization. Enquiries concerning reproduction outside the scopeofthe

above should be sent to the Rights Department, Oxford University Press,atthe

addressabove

You must not circulate this work in any otherform

and you must impose this same condition on any acquirer

Published in the United States of America by Oxford UniversityPress

198 Madison Avenue, NewYork, NY 10016, United States of America

British Library Cataloguing in PublicationData

Data available

Library of Congress Control Number:2017942066

ISBN 978–0–19–876653–7

Printed and bound in China by

C&C Oset Printing Co., Ltd.

Oxford University Press makes no representation, express or implied, thatthe

drug dosages in this book are correct. Readers must therefore alwayscheck

the product information and clinical procedures with the most up- to- date

published product information and data sheets provided by the manufacturers

and the most recent codes of conduct and safety regulations. The authorsand

the publishers do not accept responsibility or legal liability for any errorsinthe

text or for the misuse or misapplication of material in this work. Exceptwhere

otherwise stated, drug dosages and recommendations are for the non- pregnant

adult who is not breast- feeding

Links to third party websites are provided by Oxford in good faithand

for information only. Oxford disclaims any responsibility for the materials

contained in any third party website referenced in thiswork.

To Richard and Fraser.

This book lls an important gap in the market, being a comprehensive guide

to the requesting and interpretation of a wide range of diagnostic tests. The

authors have crammed a huge amount of information into a relatively small

volume. Its size, scope, and relevance mean that it is likely to be used daily

as a quick reference and aide- memoire. This fourth edition, which has been

entirely updated, covers conditions from the very common, such as nausea

and joint pain, to those seen less often. The fact that it is written by

ex perienced clinicians, including trainees, is evident from its practical

approach and focus on the patient.

This book highlights the importance, often forgotten, of diagnostic tests

in almost all patient care pathways. Its use will ensure that the right investi-

gations are done rst time, reducing unnecessary testing and enabling faster

and more accurate diagnosis. I am particularly pleased that it contains a

section on collecting specimens and how to avoid laboratory errors.

No medical student or junior doctor should be without this book (it

is ideal for revision); in fact, any doctor at any stage of their career will

nd it useful. The appropriate requesting and interpretation of clinical and

laboratory investigations is vital for maximizing the value of healthcare and

improving the quality of care for patients.

Suzy Lishman

President of The Royal College of Pathologists

2018

Foreword

vii

Six years have elapsed since the third edition of this book was published

and during that time there have been advances in investigative techniques,

both laboratory- based and clinical. My own specialty, haematology, has seen

renements in diagnostic tests for conditions such as leukaemias and lym-

phomas, but there have also been developments in the red cell and clotting

arenas. My colleagues in other clinical specialties have also enjoyed advances

within their own disciplines, and in order to make the book truly contempor-

ary, we have had to update all sections of the book bringing in all of these

new techniques.

As before, Ihave had the privilege to work with leaders in all branches

of medicine who have given up their time to update their chapters, bringing

them right up- to- date, and Iam immensely grateful tothem.

I am also indebted to Oxford University Press for their tireless work

on this Oxford Handbook which has been used by clinicians worldwide

for 14years. It has grown from 600 pages to almost 1000 in that time! If

this small book has helped in the diagnosis of patients, then Ifeel we have

achieved our task. Special thanks go to Michael Hawkes, Elizabeth Reeve,

and many others who have helped bring this book to publication.

Being an edited text, Itake responsibility for errors or omissions in the

book and welcome any comments readers may have. As ever, this book

is meant to be used at the bedside and in the clinic, and its usability relies

on input from readers. Please contact me at drewpro[email protected] if you

have any suggestions or spot any errors in thebook.

DrewProvan

2018

Preface tothe

fourth edition

viii

With the increasing complexity of modern medicine, we now have literally

thousands of possible investigative techniques at our disposal. We are able

to examine our patient’s serum and every other body uid down to the

level of individual nucleotides, as well as being able to perform precise imag-

ing through CT, MRI, and other imaging technologies. The problem we have

all faced, especially as senior medical students or junior doctors is:Which

test should we use in a given setting? What hazards are associated with the

tests? Are there any situations where specic tests should not be used or

are likely to produce erroneous results? As medical complexity increases,

so too does cost; many assays available today are highly expensive and,

wherever possible, we would ideally like to use a test that is cheap, reliable,

reproducible, and right for a given situation.

Such knowledge takes many years to acquire and it is a fact of life that

senior doctors (who have attained such knowledge) are not usually those

who request the investigations. In this small volume, we have attempted to

distil all that is known about modern tests, from blood, urine, and other

body uids, along with imaging and molecular tests. The book is divided into

two principal parts:the rst deals with symptoms and signs in The patient

section, because that is how patients present. We have tried to cover as

many topics as possible, discussing these in some detail and have provided

dierential diagnoses where possible. We also try to suggest tests that

might be of value in determining the cause of the patient’s symptom or

sign. The second part of the book Investigations

is specialty- specic and is

more relevant once you know roughly what type of disease the patient

might have. For example, if the symptom section suggests a likely respira-

tory cause for the patient’s symptoms, then the reader should look to the

Respiratory medicine chapter in order to determine which tests to carry out

or how to interpret the results.

The entire book is written by active clinicians, rather than scientists, since

we wanted to provide a strong clinical approach to investigation. We have

tried, wherever possible, to cross- refer to the Oxford Handbook of Clinical

Medicine, Oxford University Press, which provides the clinical detail omitted

from this handbook. The symbol E

is used to highlight a cross- reference to

OHCM, in addition to cross- referencing within thisbook.

We would value feedback from readers since there will doubtless be tests

omitted, errors in the text, and many other improvements we could, and

will, make in future editions. All contributors will be acknowledged individu-

ally in the next edition. We would suggest you e- mail us directly.

DrewProvan

AndrewKrentz

2002

Preface tothe ﬁrst edition

Contributors x

Symbols and abbreviations xii

Approach to investigations xxxiv

Laboratory errors and how to avoid them xxxvi

Part I The patient

1 Symptoms and signs 3

Part II Investigations

2 Endocrinology and metabolism

123

3 Haematology

227

4 Immunology and allergy

333

5 Infectious and tropical diseases

381

6 Cardiology

435

7 Gastroenterology

497

8 Respiratory medicine

535

9 Neurology

583

10 Renal medicine

649

11 Poisoning and overdose

699

12 Rheumatology

741

13 Radiology

765

14 Nuclear medicine

865

Index 957

Contents

BrianAngus

Director, Centre for Tropical

Medicine and Global Health,

Oxford,UK

Chapter5:Infectious and tropical

diseases

Jim Ballinger

Honorary Senior Lecturer,

Imaging Sciences, King’s College

London,UK

Chapter14:Nuclear medicine

Martyn Bracewell

Senior Lecturer in Neurology and

Neuroscience, Bangor University,

Bangor,UK

Chapter9:Neurology

JoannaBrown

Respiratory Consultant, Imperial

College Healthcare NHS

Trust, Hammersmith Hospital,

London,UK

Chapter8:Respiratory medicine

TanyaChawla

Sta Radiologist and Assistant

Professor, Joint Department of

Medical Imaging, University of

Toronto, Toronto,Canada

Chapter13:Radiology

ColinDayan

Professor of Clinical Diabetes

and Metabolism, Division of

Infection and Immunity, Cardi

University School of Medicine,

Cardi, UK

Chapter2:Endocrinology and

metabolism

VanessaFoggo

Consultant Haematologist, Royal

London Hospital, London,UK

Chapter3:Haematology

Gopinath Gnanasegaran

Consultant Physician in Nuclear

Medicine, Department of Nuclear

Medicine, Guy and St Thomas’

Hospital, London,UK

Chapter14:Nuclear medicine

EmmaGreig

Consultant Gastroenterologist,

Musgrove Park Hospital, Taunton,UK

Chapter7:Gastroenterology

Andrew R Houghton

Consultant Cardiologist

and Visiting Fellow of the

University of Lincoln, United

Lincolnshire Hospitals NHS Trust,

Lincolnshire,UK

Chapter6:Cardiology

AlisonJones

Pro Vice-Chancellor (Health

Strategy) and Executive Dean,

Faculty of Science, Medicine and

Health, University of Wollongong,

NSW, Australia

Chapter11:Poisoning and overdose

SuzanneLane

Consultant Rheumatologist, Ipswich

Hospital NHS Trust, Ipswich,UK

Chapter12:Rheumatology

Sarah McCloskey

Speciality Trainee in Nephrology,

Department of Renal Medicine,

Freeman Hospital, Newcastle

uponTyne, UK

Chapter10:Renal medicine

Gavin Spickett

Consultant Immunologist,

The Newcastle upon Tyne

Hospitals NHS Foundation Trust,

Newcastle,UK

Chapter4:Immunology and allergy

Contributors

CONTRIBUTORS

CharlesTomson

Consultant Nephrologist,

Department of Renal Medicine,

Freeman Hospital, Newcastle

uponTyne, UK

Chapter10:Renal medicine

My thanks, also, to those who contributed to the rst edition:John Axford,

Keith Dawkins, and Praful Patel. Also to those who contributed to the

second edition:James Dunbar, AFrew, Stephen T Green, Val Lewington,

Rommel Ravanan, Dr Penelope Sensky, Adrian Williams, and Lorraine

Wilson.

xii

7 approximately

α alpha

β beta

δ delta

γ gamma

κ kappa

λ lambda

l leadingto

E cross- reference

i increased

d decreased

n normal

M website

2 important

3 very important

> greaterthan

≥ equal to or greaterthan

>> much greaterthan

< lessthan

≤ equal to or lessthan

= equalto

+ve positive

−ve negative

° degree

°C degree Celsius

° primary

2° secondary

♂ male

♀ female

ii greatly increased

± plus orminus

2D two- dimensional

3D three- dimensional

β- TG beta- thromboglobulin

γGT gamma- glutamyl transpeptidase

5HIAA 5- hydroxyindole aceticacid

Symbols and abbreviations

SYMBOLS AND ABBREVIATIONS

xiii

μg microgram

μL microlitre

μmol micromole

99m

Tc technetium- 99m

AA aorticarch

AAA abdominal aortic aneurysm

AAFB acid- and alcohol- fast bacilli

ABG arterial bloodgas

ABO ABO bloodgroups

ABPA allergic bronchopulmonary aspergillosis

AC air conduction

ACD anaemia of chronic disease

ACE angiotensin- convertingenyme

ACEI angiotensin- converting enzyme inhibitor

ACh acetylcholine

AChE red cell cholinesterase

AChRAb acetylcholine receptor antibodies

ACL anticardiolipin antibody

ACPA anti- cyclic citrullinated peptide antibodies

ACR albumin:creatinineratio

ACS acute coronary syndrome

ACTH adrenocorticotrophic hormone

ADA American Diabetes Association

ADC apparent diusion coecient

ADH antidiuretic hormone

ADP adenosine 5- diphosphate

AF atrial brillation

AFP alpha- fetoprotein

AICD automatic intracardiac debrillationdevice

AIDS acquired immune deciency syndrome

AIH autoimmune hepatitis

AIHA autoimmune haemolytic anaemia

AIP autoimmune prole

AKI acute kidneyinjury

ALD adrenoleucodystrophy

ALL acute lymphoblastic leukaemia

ALP alkaline phosphatase

ALT alanine transaminase

AMA antimitochondrial antibodies

AML acute myeloid leukaemia

SYMBOLS AND ABBREVIATIONS

xiv

ANA antinuclear antibodies

ANAE alpha- naphthyl acetate esterase

ANCA antineutrophil cytoplasmic antibody

ANNA anti- neuronal nuclear antibodies

AP anteroposterior; action potential

APCR activated protein C resistance

APS antiphospholipid syndrome

APTR activated partial thromboplastin timeratio

APTT activated partial thromboplastintime

APVD anomalous pulmonary venous drainage

ARB angiotensin II receptor blocker

ARDS acute respiratory distress syndrome

ARF acute renal failure

ARMS amplication refractory mutationsystem

ASAS Assessment of SpondyloArthritis International Society

ASCA antibodies to Saccharomyces cerevisiae

ASIS anterior superior iliacspine

ASMA anti- smooth muscle antibodies

ASO anti- streptolysin

ASOT anti- streptolysin Otitre

AST aspartate transaminase

AT antithrombin

AT- II angiotensinII

ATN acute tubular necrosis

AV atrioventricular; arteriovenous

AVM arteriovenous malformation

AVN avascular necrosis

AVP arginine vasopressin

AVPD anomalous pulmonary venous drainage

AXR abdominalX- ray

AZT zidovudine

BAEP brainstem auditory evoked potential

BAER brainstem auditory evoked response

BAL bronchoalveolarlavage

BC bone conduction

BCG bacillus Calmette– Guérin

bd bis die (twicedaily)

bDNA branched- chain deoxyribonucleicacid

BIPLED bihemispheric periodic lateralized epileptiform discharge

BIRADS breast imaging and reporting datasystem

SYMBOLS AND ABBREVIATIONS

BJP Bence– Jones protein

BM bonemarrow

BMI body massindex

BMT bone marrow transplant

BOLD blood oxygenlevel

BP blood pressure

bpm beat perminute

BSAEP brainstem auditory evoked potential

BSG British Society of Gastroenterology

BSL Biosafetylevel

BW bronchial washing

C&S culture and sensitivity

calcium

Ca 19- 9 carbohydrate antigen19- 9

Ca- 125 cancer antigen125

CAD computer- assisted detection

CAH congenital adrenal hyperplasia

cAMP cyclic adenosine monophosphate

c-ANCA cytoplasmic antineutrophil cytoplasmic antibody

CaSR calcium- sensing receptor

CBC complete bloodcount

CBD common bileduct

CC craniocaudal

CCF congestive cardiac failure

CCK cholecystokinin

CCP cyclic citrullinated peptide

CCTA coronary computed tomography angiography

CCU coronary careunit

CD cluster dierentiation

CEA carcinoembryonic antigen

cf. comparewith

CF complement xation

CFA cryptogenic brosing alveolitis

CFU colony- formingunit

CGMS continuous glucose monitoring systems

CHD coronary heart disease

Cho choline

CHr reticulocyte

CINCA chronic infantite neurologic, cutaneous and articular syndrome

CJD Creutzfeldt– Jakob disease

SYMBOLS AND ABBREVIATIONS

xvi

CK creatinekinase

CKD chronic kidney disease

CKD- EPI Chronic Kidney Disease Epidemiology Collaboration

−

chloride

CLL chronic lymphocytic/ lymphatic leukaemia

CLO Campylobacter- like organism

cm centimetre

CMAP compound motor action potential

cmH

O centimetre ofwater

CML chronic myeloid leukaemia

CMR cardiovascular magnetic resonance

CMV cytomegalovirus

C3Nef C3 nephriticfactor

CNS central nervoussystem

CO carbon monoxide

carbon dioxide

COHb carboxyhaemoglobin

COPD chronic obstructive pulmonary disease

cP centipoise

CPAP continuous positive airway pressure

CPE carbapenemase- producing Enterobacteriaceae

CPK creatinine phosphokinase

CPPD calcium pyrophosphate disease

CPS complex partial seizure

Cr creatine

CrAg cryptococcal antigen

CrC creatinine clearance

CRC colorectal carcinoma

CREST calcinosis, Raynaud’s syndrome, oesophageal motility

dysfunction, sclerodactyly, and telangiectasia

CRH corticotropin- releasing hormone

CRP C- reactive protein

CSF cerebrospinaluid

CSU catheter specimen ofurine

CT computed tomography

CTC computed tomography colonography

CT- IVP computed tomography intravenous pyelography

CTLp cytotoxic T- lymphocyte precursor

CTPA computed tomography pulmonary angiography

CTU computed tomography urography

SYMBOLS AND ABBREVIATIONS

xvii

CVA cerebrovascular accident (stroke)

CVD cardiovascular disease

CVID common variable immunodeciency

CVP central venous pressure

CVS cardiovascular system; chorionic villus sampling

CW continuouswave

CXR chestX- ray

CyF cystic brosis

DAT direct antibodytest

dB decibel

DBCE double contrast bariumenema

DCCT Diabetes Control and ComplicationsTrial

DEC diethylcarbamazine

DESS dual- echo steadystate

DEXA dual- energy X- ray absorptiometry

DFa direct uorescein- labelled monoclonal antibody

DFA direct uorescent antibody

DHEAS dehydroepiandrosterone sulfate

DI diabetes insipidus

DIC disseminated intravascular coagulation

DIDMOAD diabetes insipidus, diabetes mellitus, optic atrophy, and

deafness

DIF direct immunouorescence

DIP distal interphalangealjoint

DJ duodenojejunal

DKA diabetic ketoacidosis

dL decilitre

DLCO diusing lung capacity for carbon monoxide

DM diabetes mellitus

DMSA dimercaptosuccinicacid

DNA deoxyribose nucleicacid

DOAC direct- acting anticoagulant

DPLD diuse parenchymal lung disease

dRVVT dilute Russell viper venomtest

DSA digital subtraction angiography

ds- DNA double- strandedDNA

DSI dimensionless severityindex

DTI diusion tensor imaging

DTPA diethylenetri aminepentaaceticacid

SYMBOLS AND ABBREVIATIONS

xviii

DU duodenalulcer

DVT deep vein thrombosis

DWI diusion- weighted imaging

DXA dual- energy X- ray absorptiometry

EBB endobronchialbiopsy

EBUS endobronchial ultrasound

EBV Epstein– Barrvirus

ECG electrocardiogram

EDC estimated date of connement

EDH extradural haemorrhage

EDTA ethylenediamine tetra- aceticacid

EEG electroencephalogram

EF ejection fraction

eGFR estimated glomerular ltrationrate

EGFR epidermal growth factor receptor

EGPA eosinophilic granulomatosis with polyangiitis

EIA enzyme- linkedassay

ELISA enzyme- linked immunosorbentassay

EM electron microscopy

EMA endomysial antibody

EMG electromyogram/ electromyography

EMU early morningurine

ENA extractable nuclear antigen

EOG electro- oculography

EP evoked potential

Epo erythropoietin

EQA external quality assurance

ER evoked response

ERCP endoscopic retrograde cholangiopancreatography

ERF established renal failure

ESA erythropoiesis- stimulatingagent

ESR erythrocyte sedimentationrate

ESS Epworth sleepinessscale

ETT endotrachealtube

EUS endoscopic ultrasound

Fab antibody fragment

FACS uorescence- activated cellsorter

FAP familial polyposis syndrome

FBC full bloodcount

FBHH familial benign hypocalciuric hypercalcaemia

SYMBOLS AND ABBREVIATIONS

xix

FCHL familial combined hyperlipidaemia

FDG uorodeoxyglucose

FDP brin degradation product

FeNO exhaled nitric oxide fraction

FEV forced expiratoryvolume

FEV

forced expiratory volume in 1second

FFP fresh frozenplasma

FGF broblast growthfactor

FH familial hypercholesterolaemia

FiO

inspired oxygen concentration

FISH uorescence in situ hybridization

fL femtolitre

FLAIR uid attenuation inversion recovery

fMRI functional magnetic resonance imaging

FNA ne- needle aspirate/ aspiration

FNH focal nodular hyperplasia

FOB faecal occultblood

FPG fasting plasma glucose

Fr French

FRC functional residual capacity

FSH follicle- stimulating hormone

FT4 freeT4

FTA- ABS uorescent treponemal antibody absorption

FUO fever of unknownorigin

FVC ow– volume curve; forced vital capacity

FVL factor VLeiden

g gram

GABA gamma- aminobutyricacid

GAD glutamic acid decarboxylase

GAn general anaesthetic

GBM glomerular basement membrane

GBS Guillain– Barré syndrome

GC gas chromatography

GCA giant cell arteritis

GC- MS gas chromatography mass spectrometry

GCS Glasgow ComaScale

Gd gadolinium

GFR glomerular ltrationrate

GGT gamma glutamyl transpeptidase

GH growth hormone

SYMBOLS AND ABBREVIATIONS

GHRH growth hormone- releasing hormone

GI gastrointestinal

GIT gastrointestinaltract

GLC gas– liquid chromatography

GM- CSF granulocytic macrophage colony- stimulatingfactor

GnU genitourinary

GORD gastro- oesophageal reux disease

GPA granulomatosis with polyangiitis

GPC gastric parietalcell

G6PD glucose- 6- phosphate dehydrogenase

GPI glycosyl phosphatidyl inositol

GRA glucocorticoid remediable aldosteronism

G&S group andsave

GT glucose tolerance

GTN glyceryl trinitrate

GTT glucose tolerancetest

GU gastriculcer

GvHD graft- versus- host disease

h hour

HAART highly active antiretroviral therapy

HACEK Haemophilus species, Actinobacillus actinomycetemcomitans,

Cardiobacterium hominis, Eikenella corrodens, and Kingella species

HAV hepatitis Avirus

Hb haemoglobin

HbA

haemoglobinA

HbC haemoglobinC

HbD haemoglobinD

HbE haemoglobinE

HbF fetal haemoglobin

HbH haemoglobinH

HbO oxyhaemoglobin

HbS sickle haemoglobin

HbSC haemoglobinSC

HBV hepatitis Bvirus

HC haemoglobin content

hCG human chorionic gonadotrophin

HCO

−

bicarbonate

Hct haematocrit

HCV hepatitis Cvirus

HD Hodgkin’s disease

SYMBOLS AND ABBREVIATIONS

xxi

HDFN haemolytic disease of the fetus and newborn

HDL high- density lipoprotein

HDN haemolytic disease of the newborn

HELLP haemolysis, elevated liver enzymes, and low plateletcount

HEMPAS hereditary erythroblastin multinuclearity with positive acidied

serum lysistest

HEV hepatitisE

HHT hereditary haemorrhagic telangiectasia

HHV human herpesvirus

Hib Haemophilus inuenzaetypeB

HIE hypoxic– ischaemic encephalopathy

HIV human immunodeciencyvirus

HLA human leucocyte antigen

HLH haemophagocytic lymphohistiocytosis syndrome

HMPAO hexamethyl- propylene- amine- oxime

HMSN hereditary motor sensory neuropathy

HNA heparin neutralizing activity

HNF hepatic nuclearfactor

HNPCC hereditary non- polyposis colorectal carcinoma

HNPP hereditary neuropathy with liability to pressure palsies

HONK hyperosmolar non- ketotic

Hp haptoglobin

HPA hybridization protection

HPFH hereditary persistence of fetal haemoglobin

HPLC high- performance liquid chromatography

HPOA hypertrophic pulmonary osteoarthropathy

HPV human papillomavirus

HRC hypochromic redcell

HRCT high- resolution computed tomography

HRP- 2 histidine- rich protein2

HRT hormone replacement therapy

hsTnI high- sensitivity troponinI

hsTnT high- sensitivity troponinT

HSV herpes simplexvirus

HTLV human T- lymphotropicvirus

HU Hounseldunit

HUS haemolytic uraemic syndrome

HUVS hypocomple mentaemic urticarial vasculitis syndrome

Hz hertz

IABP intra- aortic balloonpump

SYMBOLS AND ABBREVIATIONS

xxii

IAT indirect antiglobulintest

IBD inammatory bowel disease

IBS irritable bowel syndrome

ICA islet cell antibodies

ICD internal cardioverter– debrillator

ICM insertable cardiac monitor

ICP intracranial pressure

ICPMS inductively coupled plasma mass spectroscopy

ICU intensive careunit

IDA iminodiaceticacid

IDDM insulin- dependent (type 1)diabetes mellitus

IDMS isotope dilution mass spectrometry

IEF isoelectric focusing

IF intrinsicfactor

IFA intrinsic factor antibodies

IFCC International Federation of Clinical Chemistry

IFG impaired fasting glucose

IFT immunouorescencetest

Ig immunoglobulin

IgA immunoglobulinA

IgD immunoglobulinD

IgE immunoglobulinE

IGE idiopathic generalized epilepsy

IGF insulin- like growthfactor

IgG immunoglobulinG

IgM immunoglobulinM

IGRA interferon gamma releaseassays

IGT impaired glucose tolerance

IHD ischaemic heart disease

IIH intracranial hypertension

IL interleukin

ILD interstitial lung disease

ILR implantable loop recorder

IM intramuscular

IMN idiopathic membranous nephritis

INR international normalizedratio

INR/ PT international normalized ratio/ prothrombintime

IPSS inferior petrosal sinus sampling

IQ intelligence quotient

ITP idiopathic thrombocytopenic purpura

SYMBOLS AND ABBREVIATIONS

xxiii

ITT insulin tolerancetest

ITU intensive therapyunit

IU internationalunit

IUP intrauterine pregnancy

IV intravenous

IVC inferior venacava

IVI intravenous infusion

IVP intravenous pyelography

IVU intravenous urogram

JME juvenile myoclonic epilepsy

JVP jugular venous pressure; jugular venouspulse

potassium

kBq kilobecquerel

KCCT kaolin cephalin clottingtime

KCO transfer coecient for carbon monoxide

kDa kilodalton

KDIGO Kidney Disease Improving Global Outcomes

kg kilogram

kPa kilopascal

KSHV Kaposi’s sarcoma- associated herpesvirus

kU kilounit

KUB kidney, ureter, bladder (X- ray)

kV kilovoltage

L litre

LA lactic acidosis

LADA latent autoimmune diabetes ofadults

LAn local anaesthetic

LAP leucocyte alkaline phosphatase; left atrial pressure

LAt leftatrial

lb pound

LC liver cytosol

LCM left costalmargin

LC- MS/ MS liquid chromatography tandem- mass spectrometry

LC/ Q- TOF- MS liquid chromatography/ quadrupole time- of- ight mass

spectrometry

LCR ligase chain reaction

LDH lactate dehydrogenase

LDL low- density lipoprotein

LDST low- dose dexamethasone suppressiontest

LEMS Lambert– Eaton myasthenic syndrome

SYMBOLS AND ABBREVIATIONS

xxiv

LFT liver functiontest

LH luteinizing hormone

LHRH luteinizing hormone- releasing hormone

LIF left iliacfossa

LKM liver– kidney microsomal

LMN lower motor neurone

LOC loss of consciousness

LP lumbar puncture

LPL lipoproteinlipase

LSCC lateral semicircularcanal

LTOT long- term oxygen therapy

LUQ left upper quadrant

LV left ventricle

LVEDP left ventricular end- diastolic pressure

LVF left ventricular failure

m metre

MAA macroaggregated albumin

MAG myelin- associated glycoprotein

MAG3 mercaptoacetyl -triglycine

MAHA microangiopathic haemolytic anaemia

MAIPA monoclonal antibody immobilization of platelet

antigens

MALDI matrix- assisted laser desorption/ ionization

MALDI- TOF MS matrix- assisted laser desorption/ ionization time- of-

ight mass spectrometry

MALT mucosa- associated lymphoidtumour

MAOI monoamine oxidase inhibitor

MARS Molecular Absorbance RecirculatingSystem

MBq megabecquerel

MCH mean cell haemoglobin

MCHC mean corpuscular haemoglobin concentration

MCP metacarpophalangeal

M,C&S microscopy, culture, and sensitivity

MCUG micturating cystourethrogram

MCV mean cellvolume

MCVm mutated citrullinated vimentin

MD myotonic dystrophy

MDMA methylene dioxymethamphetamine or ecstasy

MDR multi- drug- resistant

MDRD Modication of Diet in Renal Disease

MDR- TB multi- drug- resistant tuberculosis

SYMBOLS AND ABBREVIATIONS

xxv

MDS myelodysplastic syndrome

MELAS mitochondrial myopathy, lactic acidosis, and stroke- like

episodes

MEN multiple endocrine neoplasia

MEP motor evoked potential

mEq milliequivalent

MERRF myoclonic epilepsy and ragged redbres

MERS- CoV Middle East respiratory syndrome coronavirus

MetHb methaemoglobin

mg milligram

magnesium

MG myastheniagravis

MGUS monoclonal gammopathy of undetermined signicance

MHC major histocompatibility complex

MHz megahertz

MI myocardial infarction

MIBG iodine- 131- meta- iodobenzylguanide

MIC minimum inhibitory concentration

min minute

m- In myo- inositol

mIU milli- internationalunit

mL millilitre

MLC mixed lymphocyte culture

MLO mediolateral oblique

mm millimetre

mmHg millimetre of mercury

M- mode motion- mode

mmol millimole

MND motor neurone disease

MoAb monoclonal antibody

MODY maturity- onset diabetes of theyoung

mOsmol milliosmole

MP metacarpophalyngeal

mPA millipascal

MPD myeloproliferative disease

MPHR max predicted heartrate

MPI myocardial perfusion imaging

MPO myeloperoxidase

MPV mean plateletvolume

MR magnetic resonance

SYMBOLS AND ABBREVIATIONS

xxvi

MRA magnetic resonance angiogram

MRC Medical Research Council

MRCP magnetic resonance cholangiopancreatography

MRD minimal residual disease

MRI magnetic resonance imaging

mRNA messenger ribonucleicacid

MRS magnetic resonance spectroscopy

MRSA meticillin- resistant Staphylococcusaureus

MRV magnetic resonance venography

ms millisecond

MS multiple sclerosis

MSD mean sac diameter

MSU midstreamurine

mSv millisievert

MTP metatarsophalangeal

mU milliunit

MUGA multigated radionuclide angiography

MUP motor unit potential

MuSK muscle- specickinase

mV millivolt

sodium

NAA N- acetyl- aspartate

NAC N- acetylcysteine

NAG N- acetyl- D- glucosaminidase

NAP neutrophil alkaline phosphatase

NASBA nucleic acid sequence- based amplication

NCS nerve conduction studies

NCSE non- convulsive status epilepticus

NEC necrotizing enterocolitis

NET neuroendocrinetumour

ng nanogram

ammonia

ammonium

NHL non- Hodgkin’s lymphoma

NHS National Health Service

NICE National Institute for Health and Care Excellence

NIDDM non- insulin- dependent diabetes mellitus

NK naturalkiller

nm nanometre

nmol nanomole

SYMBOLS AND ABBREVIATIONS

xxvii

NMS neuroleptic malignant syndrome

NO nitricoxide

NOGG National Osteoporosis GuidelineGroup

NPA nasopharyngeal aspirate

NPH normal pressure hydrocephalus

NPSA National Patient SafetyAgency

NREM non- rapid eye movement

NSAID non- steroidal anti- inammatorydrug

NSF nephrogenic systemic brosis

NSTEMI non- ST- elevation myocardial infarction

oxygen

OA osteoarthritis

Oc calculated osmolality

OCB oligoclonalband

OCP oral contraceptivepill

OGD oesophagogastroduodenoscopy

OGTT oral glucose tolerancetest

OHCM Oxford Handbook of Clinical Medicine

Om measured osmolality

OMIM Online Mendelian InheritanceinMan

OSA obstructive sleepapnoea

OTC over the counter

PA pernicious anaemia

P- A posteroanterior

PABA para- amino benzoic acid; N- benzoyl- L- tyrosol

p- aminobenzoicacid

. partial pressure of carbon dioxide in arterialblood

PACS picture archiving and communication systems

PAD peripheral arterial disease

PAN polyarteritisnodosa

p-ANCA perinuclear antineutrophil cytoplasmic antibody

arterial oxygen tension

PAS periodic acid– Schi

PB peripheralblood

PBC primary biliary cirrhosis

PC protein C; provocation concentration

PCH paroxysmal cold haemoglobinuria

PCI percutaneous coronary intervention

PCNA proliferating cell nuclear antigen

PCO

partial passure of carbon dioxide

SYMBOLS AND ABBREVIATIONS

xxviii

PCP Pneumocystis jiroveci pneumonia

PCR polymerase chain reaction

PCrR protein:creatinineratio

PCT procalcitonin

PCV packed cellvolume

PD Parkinson’s disease

PDW platelet distributionwidth

PE pulmonary embolism/ embolus

PEFR peak expiratory owrate

PEG percutaneous endoscopic gastrostomy

PET positron emission tomography

PFR peak owrate

pg picogram

PICC peripherally inserted central catheter

PIFT platelet immunouorescencetest

PIP proximal interphalangeal

PK pyruvatekinase

PkS Parkinson’s syndrome

PLA- 2 phospholipaseA2

PLED periodic lateralized epileptiform discharge

PLMD paroxysmal leg movement disorder

PmA pulmonaryartery

PMA paramethoxymethamphetamine

PMF progressive massive brosis

PMLE progressive multifocal leukoencephalopathy

PNH paroxysmal nocturnal haemoglobinuria

PNS peripheral nervoussystem

PO per os (bymouth)

partial pressure ofoxygen

3−

phosphate

POTS postural orthostatic tachycardia syndrome

PP pancreatic polypeptide

ppb parts per billion

PPD puried protein derivative

PR perrectum

PR3 proteinase3

PRA plasma renin activity

PrC provocation concentration

PRL prolactin

PRV polycythaemia rubravera

SYMBOLS AND ABBREVIATIONS

xxix

PS proteinS

PSA prostate- specic antigen

PSMA prostate- specic membrane antigen

PT prothrombintime

PTA percutaneous transluminal angioplasty

PTC percutaneous transhepatic cholangiogram

PTH parathyroid hormone

PTR prothrombinratio

PTTK partial thromboplastin time withkaolin

PUO pyrexia of unknownorigin

PV plasmavolume

PVA polyvinyl alcohol

PvC provocation concentration

PVNS pigmented villonodular synovitis

PW pulsedwave

PWI perfusion- weighted imaging

PxCT proximal convolutedtubule

qds quarter die sumendus (four timesdaily)

RA refractory anaemia

RAPA rheumatoid arthritis particle agglutinationtest

RAS renal artery stenosis

RAST radioallergosorbenttest

RAt right atrial/ atrium

RBC red bloodcell

RBP retinol- binding protein

RCC red cellcount

RDT rapid diagnostictest

RDW red cell distributionwidth

REM rapid eye movement

RES reticuloendothelialsystem

Ret- He reticulocyte haemoglobin content

RF rheumatoidfactor

RFLP restriction fragment length polymorphism

Rh rhesus

RhA rheumatoid arthritis

RhMK Rhesus monkeykidney

RIA radioimmunoassay

RiCoF Ristocetin Cofactor

RID radial immunodiusion

RIF right iliacfossa

SYMBOLS AND ABBREVIATIONS

xxx

RIPA ristocetin- induced platelet aggregation

RIS radiology informationsystem

RNP ribonucleoprotein

RNV radionuclide ventriculography

RPR rapid plasmareagin

RSV respiratory syncytialvirus

RTA renal tubular acidosis

rTMS repetitive transcranial magnetic stimulation

RUQ right upper quadrant

RV right ventricle; residualvolume

s second

SAA serum amyloidA

SAAG serum ascites albumin gradient

SAH subarachnoid haemorrhage

SaO

arterial oxygen saturation

SARS severe acute respiratory syndrome

SB Sudanblack

SBE subacute bacterial endocarditis

SBO small bowel obstruction

SBP spontaneous bacterial peritonitis

sbt serum bactericidaltest

SC subcutaneous

SCC squamous cell carcinoma

SCID severe combined immunodeciency

SCLC small- cell lungcancer

SDH subdural haemorrhage

SDS- PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis

SeHCAT

selenium homotaurocholate

SG specic gravity

SGLT2 sodium– glucose cotransporter2

SHBG sex hormone- binding globulin

SI Système International

SIADH syndrome of inappropriate antidiuretic hormone

SLA soluble liver antigen

SLE systemic lupus erythematosus

SMA smooth muscle antibody

SNAP sensory nerve action potential

–

sulfate

SOB shortness ofbreath

SOD sphincter of Oddi dysfunction

SYMBOLS AND ABBREVIATIONS

xxxi

SOL space- occupyinglesion

SPECT single photon emission computed tomography

SpO

oxygen saturation

SSFP steady- state free precession

SSP single strand polymorphism

SSPE subacute sclerosing panencephalitis

SSR somatostatin receptor

STD sexually transmitted disease

STEMI ST- elevation myocardial infarction

sTfR serum transferrin receptor

STfR soluble transferrin receptorassay

STIR short tau inversion recovery

SUV standardized uptakevalue

SVC superior venacava

SWS slow wavesleep

SXR skullX- ray

T testa

T1W T1- weighted

T2W T2- weighted

TA temporal arteritis

TACO transfusion- associated circulatory overload

TB tuberculosis

TBLB transbronchial lungbiopsy

TBNA transbronchial needle aspiration

TCR T- cell receptor

TCT thrombin clottingtime

tds ter die sumendus (three timesdaily)

TE echotime

TfR transferrin receptor

TFT thyroid functiontest

Tg thyroglobulin

TG triglyceride

THR total hip replacement

TIA transient ischaemicattack

TIBC total iron binding capacity

TIPS transjugular intrahepatic portosystemicshunt

TLC thin- layer chromatography; total lung capacity

TLCO transfer factor for carbon monoxide

TMA thrombotic microangiopathy; transcription- mediated

amplication

SYMBOLS AND ABBREVIATIONS

xxxii

TMS transcranial magnetic stimulation

TN trigeminal neuralgia

TnI troponinI

TnT troponinT

TOE transoesophageal echocardiography

tPA tissue plasminogen activator

TPHA Treponema pallidum haemagglutinationassay

TPN total parenteral nutrition

TPO thyroid peroxidase

TR repetitiontime

TRALI transfusion- related acute lunginjury

TRAP tartrate- resistant acid phosphatase

TRH thyrotropin- releasing hormone

tRNA transfer ribonucleicacid

TRP tubular reabsorption of phosphate

TSE transmissible spongiform encephalopathy

TSH thyroid- stimulating hormone

TTE transthoracic echocardiogram

tTG tissue transglutaminase

TTP thrombotic thrombocytopenic purpura

U unit

UCTD undierentiated connective tissue disease

U&E urea and electrolytes

UFC urinary free cortisol

UFE uterine broid embolization

UK United Kingdom

UMN upper motor neurone

URTI upper respiratory tract infection

US ultrasound

USA UnitedStates

USS ultrasoundscan

UTI urinary tract infection

UV ultraviolet

VATS video- assisted thoracoscopic surgery

VC vital capacity

vCJD variant Creutzfeldt– Jakob disease

VDRL Venereal Disease Research Laboratory

VEP visual evoked potential

VHF viral haemorrhagicfever

VHL von Hippel– Lindau

SYMBOLS AND ABBREVIATIONS

xxxiii

VIP vasoactive intestinal peptide

VLCFA very long- chain fattyacid

VLDL very low- density lipoprotein

VMA vanillylmandelicacid

oxygenuptake

2max

maximum oxygenuptake

VP vasoactive peptide

V/ Q ventilation/ perfusion

VRE vancomycin- resistant Enterococcus

VSD ventricular septaldefect

VTE venous thromboembolism

vWD von Willebrand disease

vWF Ag von Willebrand factor antigen

WBC white blood count/ cells

WCE wireless capsule endoscopy

WHO World Health Organization

w/ v weight byvolume

XDP cross- linked brin degradation product

XDR- TB extensively drug- resistant tuberculosis

XLA X- linked agammaglobulinaemia

ZN Ziehl– Neelsen

ZPP zinc protoporphyrin

xxxiv

Why dotests?

Patients seldom present to their doctors with diagnoses— rather, they have

symptoms or signs. The major challenge of medicine is being able to talk to

the patient and obtain a history, then carry out a physical examination look-

ing for pointers to their likely underlying problem. Our elders and, some

would argue, betters in medicine had fewer tests available to them than we

have today, and their diagnoses were often made solely from the history

and examination. Of course, they would claim that their clinical acumen

and skills were greater than ours, and that we rely too heavily on the huge

armoury of laboratory and other investigations available today. This, in part,

is probably true, but we cannot ignore the fact that advances in science and

technology have spawned a bewildering array of very useful and sophisti-

cated tests that help us to conrm our diagnostic suspicions.

By ‘test’ we mean the measurement of a component of blood, marrow,

or other body uid or physiological parameter to determine whether the

patient’s value falls within or outside the normal range, either suggesting the

diagnosis or, in some cases, actually making the diagnosis forus.

Factors aecting variable parameters inhealth

Many measurable body constituents vary throughout life. For example, a

newborn baby has an extremely high haemoglobin concentration, which

falls after delivery. This is completely normal and is physiological, rather than

pathological. Ahaemoglobin level this high in an adult would be pathological,

since it is far outside the normal range for the adult population.

Approach toinvestigations

Factors aecting measurable variables

• Age.

• Sex.

• Ethnicity.

• Altitude.

• Build.

• Physiological conditions (e.g. at rest, after exercise, standing, lying).

• Sampling methods (e.g. with or without using a tourniquet).

• Storage and age of sample.

• Container used, e.g. for blood sample, as well as anticoagulant.

• Method of analysis.

Reference ranges (normal values)

These are published for most measurable components of blood and other

tissue, and we have included the normal ranges for most blood and

cerebrospinal uid (CSF) analytes at the end of thebook.

xxxv

APPROACH TO INVESTIGATIONS

What makes a test useful?

A really good test, and one that would make us appear to be outstanding

doctors, would be one that would always be positive in the presence of a

disease and would be totally specic for that disease alone; such a test would

never be positive in patients who did not have the disorder. What we mean

is that what we are looking for are sensitive tests that are specic for a given

disease. Sadly, most tests are neither 100% sensitive nor 100% specic, but

some do come veryclose.

How touse tests and thelaboratory

Rather than request tests in a shotgun or knee- jerk fashion where every box

on a request form is ticked, it is far better to use the laboratory selectively.

Even with the major advances in automation where tests are batched and

are cheaper, the hospital budget is nite and sloppy requesting should be

discouraged.

Outline your dierential diagnoses: what are the likeliest diseases, given

the patient’s history, examination ndings, and population from which the

patientcome?

Decide which test(s) will help you make the diagnosis:request these and

review the diagnosis in the light of the test results. Review the patient and

arrange further investigations as necessary.

The downside oftests

It is important to remember that tests may often give ‘normal’ results, even

in the presence of disease. For example, a normal electrocardiogram (ECG)

in the presence of chest pain does not exclude the occurrence of myocardial

infarction with 100% certainty. Conversely, the presence of an abnormal-

ity does not necessarily imply that a disease is present. This, of course, is

where clinical experience comes into its own— the more experienced clini-

cian will be able to balance the likelihood of disease with the results avail-

able, even if some of the test results give unexpected answers.

Quick- x clinical experience

This simply does not exist. Talking to patients and examining them for physi-

cal signs and assimilating knowledge gained in medical school are absolute

requirements for attainment of sound clinical judgement. Those students

and doctors who work from books alone do not survive eectively at the

coal face! It is a constant source of irritation to medical students and junior

doctors, when a senior doctor asks for the results of an investigation on

the ward round and you nd this test is the one that clinches the diagnosis.

How do

they do it? Like appreciating good wine— they develop a nose for

it. You can learn a great deal by watching your registrar or consultant make

decisions. This forms the basis of your own clinical experience.

Sensitivity and specicity

Sensitivity % of patients with the disease and in whom the test is positive

Specicity % of people without the disease and in whom the test is negative

xxxvi

It is a fact of life that the sophisticated automated analysers in current use

are not 100% accurate 100% of the time, but they come pretty close. In

order to keep errors to a minimum, precautions need to be taken when

sampling biological material, e.g.blood.

Minimizing spurious results using blood samples

• Use correct bottle.

• Fill to line (if anticoagulant used). This is less of a worry when vacuum

sample bottles are used since these should take in exactly the correct

amount of blood, ensuring the correct blood:anticoagulant ratio. This is

critical for coagulation tests.

•

Try to get the sample to the laboratory as quickly as possible. Blood

samples left lying around on warm windowsills, or even overnight at

room temperature, will produce bizarre results, e.g. crenated red blood

cells (RBCs) and abnormal- looking white blood cells (WBCs) in old

EDTA samples.

•

Try to avoid rupturing red cells when taking the sample (e.g. using

narrow- gauge needle, prolonged time to collect whole sample);

otherwise a ‘haemolysed’ sample will be received by the laboratory.

This may cause spurious results for some parameters (e.g. [K

]).

•

Remember to mix (not shake) samples containing anticoagulant.

Variations innormal ranges inhealth

As discussed earlier, most of the normal ranges for blood parameters dis-

cussed in this book are for non- pregnant adults. The reason for this is that

blood values, e.g. haemoglobin (Hb), red cell count (RCC), are high in the

newborn and many full blood count (FBC), coagulation, and other param-

eters undergo changes in pregnancy.

Laboratory errors and

how toavoidthem

The patient

1 Symptoms and signs

PartI

Symptoms andsigns

Chapter1

Abdominal distension 4

Abdominal pain 6

Alteration of behaviour 7

Alteration in bowel habit 9

Anaemia 10

Anaphylaxis 12

Angio- oedema 12

Anorexia 13

Anuria 14

Ataxia 15

Bradycardia 17

Breathlessness 18

Bruising 20

Calf swelling 21

Chest pain 22

Clubbing 25

Coma 26

Confusion 28

Constipation 29

Cyanosis 31

Diarrhoea 32

Dizziness and syncope 34

Dysarthria and dysphasia 36

Dysphagia 37

Facial pain 38

Fever of unknown origin

(FUO or PUO) 39

Firstt 40

Galactorrhoea 42

Gout 43

Gynaecomastia 44

Haematemesis 46

Haematuria 47

Haemoptysis 48

Headache 49

Heart sounds and murmurs 51

Hepatomegaly 55

Herpes zoster 56

Hyperlipidaemia 57

Hypertension 58

Incontinence:faecal 60

Incontinence:urinary 61

Indigestion 62

Infective endocarditis signs 64

Irregular pulse 65

Jaundice 66

Joint pain/ swelling 68

Jugular venous pulse 69

Loin pain 71

Lymphadenopathy 72

Nausea 74

Neck stiness 76

Nystagmus 77

Obesity 79

Oliguria 81

Palpitations 82

Pancytopenia 83

Paraesthesiae 84

Peripheral neuropathy 86

Peripheral oedema 87

Petechiae and

thrombocytopenia 88

Plethora 89

Polyuria 90

Pruritus 91

Ptosis 92

Pulmonary embolism 93

Pulse character 94

Purpura 95

Recurrent thrombosis 96

Retinal haemorrhage 97

Rigors 97

Short stature 98

Skin pigmentation 100

Splenomegaly 102

Steatorrhoea 103

Stridor 104

Suspected bleeding disorder 105

Suspected stroke 107

Sweating 109

Tachycardia 110

Tinnitus 112

Tiredness 113

Urgency of micturition 114

Urticaria 115

Vasculitis 116

Visual loss 117

Wasting of the small hand

muscles 118

Weight loss 119

Wheeze 120

CHAPTER1 Symptoms andsigns

Abdominal distension

Patients may describe generalized abdominal swelling or localized fullness in

a specic area of the abdomen.

In thehistory enquire specicallyabout

• Change in bowelhabit.

• Weightloss.

• Associatedpain.

Generalized swelling

Consider

•

Fat.

• Fluid.

• Faeces.

• Flatus.

• Fetus.

• Full bladder.

Ascites

Fluid in the peritoneal cavity. Look for shifting dullness and uid thrill on per-

cussion, stigmata of chronic liver disease, lymphadenopathy, and oedema,

and assess the jugular venous pressure(JVP).

Causes

•

Malignancy.

• Cirrhosis/ portal hypertension.

• Hypoproteinaemia.

• Right heart failure.

Investigations

•

Urea and electrolytes (U&Es).

• Liver function tests (LFTs).

• Serum albumin.

• Ascitic tap for cytology, and microscopy, culture, and sensitivity

(M,C&S).

•

Serum- ascites albumin gradient.

• Ultrasound scan (USS) of the abdomen.

(See Fig.1.1.)

Flatus

Gaseous distension. Need to exclude bowel obstruction. Assess for colicky

abdominal pain, bowel habit, atus, and vomiting. Look for resonant disten-

sion on percussion, altered or absent bowel sounds, and focal tenderness

with rebound and guarding. Always check for herniae and perform a per

rectum (PR) examination in suspected obstruction.

Causes

•

Intraluminal:faecal impaction, gallstoneileus.

•

Luminal:inammatory stricture (e.g. Crohn’s), tumour, abscess.

•

Extraluminal:herniae, adhesions, pelvic mass, lymphadenopathy,

volvulus, intussusception.

ABDOMINAL DISTENSION

• Paralytic ileus:drug- induced, electrolyte disturbances.

• Age- related causes of obstruction.

• Neonatal:congenital atresia, imperforate anus, volvulus, Hirschsprung’s

disease, meconiumileus.

•

Infants:intussusception, Hirschsprung’s, herniae, Meckel’s diverticulum.

•

Young/ middle- aged adults:herniae, adhesions, Crohn’s.

•

Elderly:herniae, carcinoma, diverticulitis, faecal impaction.

Investigations

•

Full blood count(FBC).

• U&E.

• Abdominal X- ray (AXR) (erect and supine).

• Consider barium enema, barium follow- through, sigmoidoscopy, surgical

intervention for complete acute obstruction.

Localized swelling/ masses:common causes accordingtosite

Investigate accordingtosite

•

Consider USS abdomen and pelvis.

• Computed tomography (CT) scanning.

• Barium studies.

• Intravenous urogram(IVU).

E OHCM 10e, p.62, p.604.

RUQRUQ

LiverLiver

Gall bladde

BowelBowel

Right kidneyRight kidney

LUQLUQ

SpleenSpleen

BowelBowel

Left kidneyLeft kidney

LIFLIF

Faecal loadingFaecal loading

Colonic mass Colonic mass

—carcinoma—carcinoma

—diverticular abscess—diverticular abscess

—ovarian cyst/tumour—ovarian cyst/tumour

RIFRIF

Appendix massAppendix mass

Carcinoma of caecumCarcinoma of caecum

Ovarian cyst/tumourOvarian cyst/tumour

MidlineMidline

Gastric massGastric mass

PancreasPancreas

—cyst—cyst

—pseudotumour —pseudotumour

—carcinoma—carcinoma

Aortic aneurysm (is it pulsatile?

)

Aortic aneurysm (is it pulsatile?

)

LymphadenopathyLymphadenopathy

Urinary retention or tumourUrinary retention or tumour

Uterine massUterine mass

Fig.1.1 Main causes of abdominal swelling according tosite.

CHAPTER1 Symptoms andsigns

Abdominalpain

Abdominal pain may be acute or chronic. Severe acute pain may indicate a

surgical emergency, including perforation, peritonitis, or obstruction. Assess

nature and radiation of pain, clinical status of the patient, including fever,

tachycardia, and hypotension.

Common causes ofabdominal pain accordingtosite

Epigastricpain

Peptic ulcer disease, gastritis or duodenal erosions, cholecystitis, pancreatitis.

Periumbilicalpain

Pancreatitis, mesenteric artery ischaemia (older patient with vascular disease).

Right upper quadrant (RUQ)pain

Biliary colic, cholecystitis, hepatitis, pepticulcer.

Left upper quadrant (LUQ)pain

Splenic, pepticulcer.

Loinpain

Renal colic (colicky radiating loin l groin), pyelonephritis, renal pathology.

Left iliac fossa (LIF)pain

Constipation, diverticular disease, irritable bowel syndrome (IBS), pelvic

referred pain, inammatory bowel disease(IBD).

Right iliac fossa (RIF)pain

Appendicitis, pelvic referred pain, IBD (e.g. Crohn’s of terminal ileum).

Suprapubicpain

Urinary tract infection (UTI), cystitis, salpingitis.

Generalizedpain

Gastroenteritis, irritable bowel, constipation, generalized peritonitis.

Pitfalls

• Metabolic causes, e.g. diabetic ketoacidosis (DKA), hypercalcaemia,

Addison’s disease, porphyria, lead poisoning.

•

Atypical referred pain, e.g. myocardial infarction (MI), pneumonia.

Investigations

• FBC.

• U&E, e.g. deranged electrolytes following vomiting, diarrhoea, or bowel

obstruction.

•

Plasma glucose.

• Serum amylase (i in pancreatitis and bowel obstruction).

•

Urinalysis and midstream urine (MSU), e.g. haematuria, proteinuria, glucose.

• LFTs (consider obstructive vs hepatitic picture).

• Plain AXR (erect and supine to assess for perforation and bowel

obstruction).

•

Kidney, ureter, bladder X- ray (KUB) for renal tract calculi.

• USS abdomen, particularly for biliary tract, gall bladder, and renaltract.

• IVU to assess for renal tract calculi/ pathology.

E OHCM 10e, p.30, p. 57, p. 609.

ALTERATION OFBEHAVIOUR

Alteration ofbehaviour

This is usually reported by a relative or friend, rather than by the patient.

Often the patient will have little or no insight into the disease and taking a

history can be dicult. In addition to a full general and neurological physical

examination, a mental state examination is required.

Find out if this is the rst episode of altered behaviour or if the epi-

sodes are recurrent. Is there a gradual change in behaviour (and personal-

ity) overtime?

Acute delirium

Causes

•

Sepsis (common).

• Acute intracranial event, e.g. haemorrhage.

• Metabolic disturbance, e.g. uraemia, hypercalcaemia (common).

• Intracerebral tumour (including meningioma).

• Drugs— especially interactions in the elderly.

• Alcohol (and withdrawal syndrome).

• Hypoxia (common).

• Hypoglycaemia (iatrogenic in diabetic patients receiving insulin

treatment or oral insulin secretagogues, or insulinoma and other

causes).

Dementia

• Alzheimer’s (common), Pick’s (rare).

• Vascular, e.g. multi- infarct.

• Huntington’s chorea.

• Vitamin B

deciency (severe).

•

Hypothyroidism (severe).

• Wilson’s disease.

• Alcoholism.

• Normal pressure hydrocephalus.

Note:‘frontal lobe syndrome’ from space- occupying lesion (SOL), e.g. men-

ingioma. Presents with disinhibition, impaired social functioning, primitive

reexes, e.g. grasp reex.

Anxietystates

Usually psychogenic, but consider organic possibilities suchas

•

Phaeochromocytoma (rare).

• Hyperthyroidism (common).

• Paroxysmal atrial tachycardia (fairly common).

• Alcohol withdrawal (usually history of excessive alcohol intake).

Psychosis

• Schizophrenia.

• Bipolar disorder or pseudo- dementiain:

•

Systemic lupus erythematosus(SLE).

•

Cushing’s syndrome.

•

Multiple sclerosis(MS).

•

Thyrotoxicosis (‘apathetic’ thyrotoxicosis in the elderly).

CHAPTER1 Symptoms andsigns

Temporal lobe epilepsy

• Temporary disturbance of content of consciousness.

Investigations:guided byhistory and examination

• U&E.

• Glucose (in non- diabetics, take fasting venous plasma in a uoride

oxalate tube with simultaneous serum or plasma for insulin

concentration, e.g. suspected insulinoma).

•

Chest X- ray(CXR).

• LFTs.

• Thyroid function tests (TFTs).

• FBC.

• Erythrocyte sedimentation rate(ESR).

• Urinalysis (protein, nitrites, glucose).

• Cranial CTscan.

• Serum vitaminB

•

Arterial blood gases (ABGs) ± carboxyhaemoglobin (COHb).

• Blood cultures.

Consider

• Syphilis serology.

• Human immunodeciency virus (HIV)test.

• Urine drug screen (E Chapter11).

•

Blood ethanol level (may be low in withdrawal state).

• Electroencephalogram(EEG).

• 24h electrocardiogram(ECG).

• Sleepstudy.

ALTERATION INBOWELHABIT

Alteration inbowelhabit

A change in bowel habit in an adult should always alert you to the possibility

of bowel cancer. Ask about associated features— PR bleeding, tenesmus,

weight loss, mucus, abdominal pain, or bloating.

Has the patient started any new medications, including ‘over the coun-

ter’? Look for signs of systemic disease.

Consider

• Carcinoma of thecolon.

• Diverticular disease.

• IBS.

• Constipation with overow diarrhoea.

• All of the above may present with alternating diarrhoea and

constipation.

Investigations

• Digital rectal examination.

• Proctoscopy.

• Sigmoidoscopy (rigid/ exible).

• Colonoscopy.

• Bariumenema.

• CT colonography.

E Diarrhoea (pp. 32–3), E Constipation (pp. 29–30), E Incontinence:

faecal (p. 60).

CHAPTER1 Symptoms andsigns

Anaemia

Reduced haemoglobin (Hb), no specic cause implied (and not a diagnosis

in itself, so don’t be complacent):♂

<13.5g/ dL, ♀ <11.5g/ dL. Often associ-

ated with non- specic symptoms such as fatigue, poor concentration, short-

ness of breath, and dizziness. Older patients may experience palpitations

and exacerbation of angina, congestive cardiac failure (CCF), or claudication.

Signs

Pallor of conjunctivae and skin creases, nail pallor and koilonychia (spoon-

shaped nails, very rare nding in severe chronic iron deciency), angular

cheilitis, and glossitis. Most of these signs are unreliable and it is dicult to

gauge anaemia from skin signsalone.

Causes

(See Table1.1.)

Two common approaches to assess anaemiaare:

1. Red cell dynamics:

•

i Red blood cell (RBC) loss/ breakdown, e.g. haemolysis (congenital

or acquired) or bleeding.

•

d RBC production, e.g. vitamin/ mineral deciency, marrow suppres-

sion/ inltration, myelodysplasia, Hb disorders (e.g. thalassaemia),

chronic disease, renal failure.

2. Red cell indices:

Investigations

FBC andlm

Assessment of RBC indices helps direct investigation asabove.

Table1.1 Some causes ofanaemia based ontheMCV

Microcytic/ hypochromic d MCV, d MCHC, e.g.

Iron deciency

Thalassaemia

Anaemia of chronic disease

Macrocytic i MCV

Reticulocytosis (polychromasia on bloodlm)

or folate deciency

Chronic liver disease

Hypothyroidism

Alcohol

Myelodysplasia

Normocytic, normochromic n MCV andMCHC

Anaemia of chronic disease,e.g.

•

Chronic infection

• Inammation

Inammatory disease or malignancy

Acute bloodloss

Renal failure

Myeloma

MCHC, mean corpuscular haemoglobin concentration; MCV, mean cell volume.

ANAEMIA

Microcytic

•

Check iron stores (ferritin or soluble transferrin receptor assay).

Note:ferritin is i in acute inammation and may be misleading. Iron/

total iron binding capacity (TIBC) no longer used for assessment of iron

deciency (E Assessment of iron status, pp. 244–7).

•

Consider thalassaemia screening if not iron- decient (i.e. d MCV, n

ferritin).

•

If iron- decient, assess dietary history (vegetarians) and look for risk

factors for blood loss and i demands.

•

Premenopausal women:assess menstrual losses.

• Pregnancy/ infants/ adolescence:consider physiological (i requirements).

•

All others:look for source of blood loss. The gastrointestinal (GI) tract is

the commonest source. Consider oesophagogastroduodenoscopy (OGD)

and/ or colonoscopy if clinically indicated by symptoms and barium studies.

Macrocytic

•

Reticulocytecount.

• Serum B

and red cell folate levels.

•

If folate- decient:assess dietary history and physiological requirements.

• If B

- decient:rarely dietary cause alone, usually an associated

pathology. Pernicious anaemia (PA) is the commonest cause— check

parietal cell antibodies (90% of patients with PA are +ve, but seen in

other causes of gastric atrophy, especially in older individuals) and/

or intrinsic factor antibodies (+ve in only 50% with PA, but specic).

Consider ileal disease and malabsorption.

•

LFTs.

• Thyroid function.

Normocytic

•

Bloodlm.

• ESR.

• Renal function.

• Consider myeloma screen in older adults (immunoglobulins (Igs),

protein electrophoresis, urine Bence– Jones protein (BJP)). Skeletal

survey of value if paraprotein orBJP.

•

Autoimmune screen to exclude connective tissue disease.

Haemolysisscreen

•

FBC, mean cell volume (MCV) (i due to reticulocytosis— these are

larger thanRBCs).

•

Blood lm (spherocytes, polychromasia, bite cells, and red cell

fragmentation).

•

Reticulocytecount.

• Serum bilirubin and serum lactate dehydrogenase(LDH).

• Haptoglobins (absent in haemolysis).

• Direct antibody test (DAT) (old term is direct Coombs’test).

Consider

• Congenital haemolytic anaemias:membrane defects, enzyme deciencies

(e.g. glucose- 6- phosphate dehydrogenase (G6PD), pyruvate kinase).

• Disseminated intravascular coagulation (DIC)/ microangiopathic

haemolysis— DIC screen.

CHAPTER1 Symptoms andsigns

Anaphylaxis

Dened as a systemic reaction (local oral angio- oedema is not anaphylaxis),

with any or all of the following:

•

Stridor (laryngeal obstruction).

• Wheeze (bronchospasm).

• Generalized urticaria and/ or angio- oedema.

• Hypotension ± loss of consciousness.

• Abdominal pain/ cramps, vomiting, and diarrhoea.

Note:not all patients have urticaria or rash— only 50% willdoso.

Dierentiate IgE- mediated reactions (anaphylaxis) from non- IgE- mediated

reactions (anaphylactoid)— due to direct mast cell degranulation).

Angio- oedema

Angio- oedema is deep tissue swelling which is non- itchy. May be premoni-

tory tingling. May occur with or without urticaria. Caused by bradykinin,

not histamine.

Causes

• As for urticaria; also hereditary angioedema (rare).

• Also think of drugs— these are the commonestcause:

•

Angiotensin- converting enzyme (ACE) inhibitors (ACEIs) (elevated

bradykinin levels due to inhibition of breakdown).

•

Angiotensin II (AT- II) receptor antagonists.

•

Statins.

•

Proton pump inhibitors.

•

Non- steroidal anti- inammatory drugs (NSAIDs).

May also be seen in patients with autoimmune disease, such as lupus and

rheumatoid arthritis (RhA) (antibodies against C1q), and in older patients in

association with paraproteins (myeloma, lymphoma).

Angio- oedema with urticaria is not due to hereditary angio- oedema.

Investigations

• Check drug history rst! If suspect drugs, then stop drugs and wait! If no

drugs, then investigate.

Angio- oedema WITH urticaria

• Investigate as for urticaria.

Angio- oedema WITHOUT urticaria

• Complement C3 andC4.

• If C4 low, check C1 esterase inhibitor (immunochemical and functional).

• Serum Igs and electrophoresis.

• Autoantibody screen.

• FBC andESR.

• Thyroid function.

• Liver function.

ANOREXIA

Anorexia

This describes a loss of appetite for food and is associated with a wide range

of disorders. In fact, anorexia is a fairly common consequence of underly-

ing disease and represents general undernourishment. Anorexia per se is

associated with i morbidity, especially when present in patients undergoing

surgery; post- operative infection is commoner, as is prolongation of the

hospitalstay.

The extent to which it will be investigated depends on the general status

of the patient and the presence and duration of any symptoms or signs.

Clinical judgement willhelp!

Causes

• Anorexia nervosa.

• Depressive illness.

• Stress.

• Cancers:any, including carcinoma of the stomach or oesophagus,

metastatic, leukaemia, or lymphoma.

•

Drugs, including chemotherapy.

• Radiotherapy.

• Renal failure.

• Hypercalcaemia.

• Infections.

• Cigarette smoking.

Investigations

• Full history and examination.

• FBC— looking for anaemia or non- specic changes seen in underlying

disease.

•

ESR— may be elevated in inammatory disorders.

• U&E.

• LFTs.

• Serum calcium (Ca

•

CXR (e.g. lung cancer, tuberculosis (TB),etc.).

• Cultures of blood, sputum, urine, stool if pyrexial and/ or localizing

symptoms orsigns.

CHAPTER1 Symptoms andsigns

Anuria

Anuria denotes absent urine production. Oliguria (<400mL urine/ 24h) is

commoner than anuria. Acatheter must be passed to conrm an empty

bladder.

Causes

• Urinary retention— prostatic hypertrophy; pelvic mass; drugs, e.g.

tricyclic antidepressants; spinal cord lesions.

•

Blocked indwelling urinary catheter.

• Obstruction of the ureters— tumour, stone, sloughed papillae (bilateral).

• Intrinsic renal failure— acute glomerulonephritis, acute interstitial

nephritis, acute tubular necrosis (ATN), rhabdomyolysis.

•

Pre- renal failure— dehydration, septic shock, cardiogenicshock.

An urgent USS of the renal tract must be performed and any physical

obstruction relieved as quickly as possible, either directly (urethral cath-

eter) or indirectly (nephrostomy).

3 Renal function and serum electrolytes must be measured withoutdelay.

Further tests asclinically indicated

• FBC.

• Blood cultures.

• ABGs.

• Uricacid.

• Autoimmune prole.

• ESR.

• Creatine kinase(CK).

• Prostate- specic antigen (PSA) (prostatic carcinoma).

• Serum Ca

and phosphate (PO

3−

•

12- leadECG.

• CXR.

• Central venous pressure (CVP) measurement via central line (to guide

intravenous (IV) uids).

•

MSU(UTI).

• Urine microscopy (for casts).

• Urine osmolality, sodium, creatinine, urea concentrations.

• IVU (E Radiology of the urinary tract, pp. 808–11).

•

Urinary stone analysis, if available.

• CT pelvis.

• Renal biopsy (if intrinsic renal disease suspected, normal- sized kidneys).

E OHCM 10e, p. 81, p. 293.

ATAXIA

Ataxia

Ataxia is an impaired ability to coordinate limb movements. There must be

no motor paresis (e.g. monoparesis) or involuntary movements (e.g. the

characteristic cogwheel tremor in Parkinson’s disease (PD) is not ataxia).

Ataxiamaybe

• Cerebellar.

• Vestibular.

• Sensory.

Note:many forms of ataxia are hereditary (but are uncommon).

Hereditarycauses

• Friedreich’s ataxia.

• Ataxia telangiectasia.

• Spinocerebellar ataxia.

• Corticocerebellar atrophy.

• Olivopontocerebellar atrophy.

• Hereditary spastic paraplegia.

• Xeroderma pigmentosa.

Investigations

•

Family studies.

• Genetic analysis (discuss with the regional genetics laboratory—

counselling may be required).

Vestibularataxia

• Acute alcohol intoxication.

• Labyrinthitis.

Sensoryataxia

• Loss of proprioception— peripheral neuropathy, dorsal column disease.

• Visual disturbance.

Investigations

•

Venous plasma glucose (diabetic neuropathy).

• Serum vitamin B

(subacute combined degeneration of the cord— rare,

but serious).

•

LFTs.

• Cryoglobulins.

Cerebellarataxia

• Demyelinating diseases, e.g.MS.

• Cerebellar infarct or haemorrhage.

• Alcoholic cerebellar degeneration.

• Cerebellar tumour— ° in children, metastases in adults. Note:von

Hippel– Lindau (VHL) disease (E OHCM 10e, Chapter19).

•

Nutritional deciency:

•

VitaminB

•

Thiamine.

• Cerebellar abscess.

CHAPTER1 Symptoms andsigns

• Drugs (supratherapeutic blood levels):

•

Carbamazepine.

•

Phenytoin.

• Tuberculoma.

• Paraneoplastic syndrome.

• Developmental.

• Arnold– Chiari malformation.

• Dandy– Walker syndrome.

• Paget’s disease of theskull.

• Wilson’s disease (hepatolenticular degeneration).

• Hypothyroidism.

• Creutzfeldt– Jakob disease (CJD) and other chronic infections.

• Miller Fisher syndrome.

• Normal pressure hydrocephalus.

Ataxia should be distinguished frommovement

disorders,e.g.

• Chorea:Huntington’s, Sydenham’s, thyrotoxicosis (veryrare).

• Athetosis.

• Hemiballismus:characteristic movement disorder,rare.

• Tardive dyskinesia:chronic phenothiazine therapy.

Investigations

• CranialCT.

• Magnetic resonance imaging (MRI) brain (if demyelination suspected).

• CXR (cerebellar metastases from bronchogenic carcinoma;

paraneoplastic syndrome).

•

TFTs.

• Triple evoked potentials (demyelination).

• Lumbar puncture (LP) (E Lumbar puncture, pp. 584–9).

•

LFTs.

• Serum drug concentrations, especially anticonvulsants.

• Serum vitaminB

•

Erythrocyte transketolase (d in thiamine deciency, e.g. alcoholism).

•

Isotope bone scan (Paget’s, metastases).

• Serum alkaline phosphatase (ALP)— bone isoenzyme (Paget’s,

metastases).

•

Urine hydroxyproline (Paget’s disease— reects bone turnover).

• Caeruloplasmin (Wilson’s disease).

• Serum and urine copper (Wilson’s disease).

Consider whether the movement disorder is psychogenic (uncommon),

rather than due to neuropathology. Uncommon and should not be con-

dently assumed.

E OHCM 10e, p.467.

BRADYCARDIA

Bradycardia

Bradycardia is dened as a heart rate of <60 beats per minute. It is a normal

physiological response to tness training but should always be considered a

marker of potential cardiac disease until proved otherwise.

Causes

A comprehensive history and thorough examination are important. Atran-

sient bradycardia can cause disabling symptoms of dizziness or blackouts in

the elderly, whilst persistent bradycardia often heralds systemic disease,e.g.:

•

Iatrogenic:cardiac drugs, e.g. β- blockers (including eye drops for

glaucoma), amiodarone, and calcium channel blockers (e.g. diltiazem

and verapamil), cause sinus bradycardia; digoxin (atrioventricular (AV)

block). The likelihood of extreme bradycardia or heart block is i with

combination therapy.

•

Cardiac causes:acute MI (often transient in inferior MI); coronary artery

disease; sick sinus syndrome; myocardial disease (amyloid, Chagas’

disease, sarcoid, myocarditis).

•

i vagal tone associated with nausea and vomiting.

•

Diminished sympathetic activity.

• Physiological:bradycardia is normal in sleep and in athletes.

•

Hypothyroidism:associated with characteristic symptoms andsigns.

•

i intracranial pressure (ICP), e.g. cerebral tumour.

•

Hypothermia, e.g. myxoedemacoma.

•

Metabolic:severe hyperkalaemia, anorexia.

•

Toxic: severe jaundice.

•

Drug toxicity: opiates.

•

Infective:inappropriate bradycardia seen in diphtheria, typhoid.

Investigations

• 12- lead ECG to identify the underlying rhythm.

If there are symptoms ofchestpain

•

Serum troponin andCK.

• Bedside ECG monitoring.

• ExerciseECG.

If there is a history ofintermittent dizziness

•

24h ambulatory ECG monitoring, patient- activated event recorder, or

implantable loop recorder, depending on the frequency of symptoms.

If indicated byclinical presentation, consider

•

TFTs (hypothyroidism).

• Low reading thermometer (hypothermia— check for J waves onECG).

• CT brain scan (? intracranial pathology).

• U&E.

• LFTs (especially bilirubin).

• Toxicology screen.

E OHCM 10e, p.124, p.808.

CHAPTER1 Symptoms andsigns

Breathlessness

Breathlessness (dyspnoea) is the subjective awareness of diculty in breath-

ing. Almost universal during exercise, it is a common presenting symptom

in a broad spectrum of diseases. Acomprehensive history and a thorough

examination are therefore essential. Speed of symptom onset, the patient’s

age and occupation, and local disease prevalence are particularly helpful in

devising a dierential diagnosis and a guide to investigations.

Causes

• Acute pulmonary disease:pneumonia, acute asthma, pulmonary embolus

(PE), inhaled foreign body, pneumothorax, acute respiratory distress.

• Chronic pulmonary disease:emphysema, chronic bronchitis, ruptured

bulla; interstitial disease (sarcoid, brosing alveolitis, extrinsic alveolitis,

pneumoconiosis).

•

Carcinoma:bronchogenic carcinoma, lymphangitis carcinomatosis, 2°

carcinoma.

•

Acute cardiac disease:acute MI (and associated complications of

pulmonary oedema, ventricular septal defect (VSD), mitral valve chordal

rupture and arrhythmias).

•

Chronic cardiac disease:left ventricular dysfunction, valvular heart disease

(mitral or aortic stenosis and regurgitation), ischaemic heart disease

(IHD), pulmonary hypertension, pleural eusion, arrhythmias (especially

atrial brillation(AF)).

•

Metabolic:poisoning from salicylates, methanol, and ethylene glycol,

DKA, lactic acidosis, hepatic and renal failure.

•

Neuromuscular:intercostal muscle/ diaphragmatic weakness due to

Guillain– Barré syndrome (GBS), muscular dystrophy.

• Haematological:anaemia.

•

Anxiety and hyperventilation.

• Morphological:kyphoscoliosis, obesity.

•

Laryngeal obstruction:extrinsic compression (retrosternal goitre),

angioedema (often acute drug allergy), laryngeal spasm (hypocalcaemia).

Initial investigations

• FBC.

• U&E.

• Glucose.

• CXR.

• ABGs.

• Peak expiratory ow rate (PEFR).

• 12- leadECG.

BREATHLESSNESS

Additional investigations (as indicated)

• Transthoracic echocardiography(TTE).

• 24h ambulatory ECG monitoring.

• Pulmonary functiontests.

• CTchest.

• Bronchoscopy.

• Ventilation/ perfusion (V/ Q) scan/ computed tomography pulmonary

angiography (CTPA).

•

LFTs.

• Ca

•

ESR.

• Serum salicylate levels.

• Lactate.

• Lung biopsy.

E OHCM 10e, p.782.

CHAPTER1 Symptoms andsigns

Bruising

Easy bruising is a common complaint and warrants careful assessment of

onset and nature. Recent onset of spontaneous and unusual bruising or

bleeding may suggest a serious acquired defect. Alifelong history of bruis-

ing and bleeding (e.g. post- tonsillectomy, dental extraction, or surgery) may

imply a congenital defect. Family history may be informative.

Examine: skin, mouth, dependent areas, and fundi for mucocutaneous

bleeding and purpura (non- blanching haemorrhages into theskin).

Plateletcauses

• Thrombocytopenia or platelet dysfunction (e.g. aspirin).

• Marrow failure, inltration, immune thrombocytopenia (ITP), DIC,

hypersplenism, drugs, or alcohol.

Vascularcauses

• Congenital, e.g. Osler– Weber– Rendu syndrome.

• Acquired, e.g. senile purpura, vasculitis (Henoch– Schönlein purpura,

infection), diabetes, corticosteroid therapy, scurvy, connective tissue

diseases.

Coagulopathy

• Congenital— mucocutaneous bruising is suggestive of a platelet-

mediated defect (e.g. von Willebrand’s disease, Glanzmann’s

thrombasthenia), rather than a clotting factor deciency

(e.g. haemophilia AandB).

•

Acquired, e.g. DIC, vitamin K deciency.

Hyperviscosity

• Myeloma, Waldenström’s macroglobulinaemia (low- grade lymphoma

associated with i IgM and i plasma viscosity), ii white blood cells

(WBC) in leukaemia.

Investigations

• FBC andlm.

• Coagulation— international normalized ratio (INR) and activated partial

thromboplastin time ratio (APTR).

•

Bleeding time, measures platelet and vascularphase.

• DIC screen, including brinogen, thrombin time, D- dimers or brin

degradation products (FDPs).

Consider further tests and referral tohaematologyfor

• Factor assays.

• Platelet aggregation studies to assess platelet function.

E OHCM 10e, p.346.

CALF SWELLING

Calf swelling

Assess whether swelling is bilateral or unilateral, precipitating factors,

and duration of onset. Careful examination of the aected leg should be

extended to a full examination, particularly of the abdominal and cardio-

vascular systems.

Causes

Venous and lymphatic

•

Deep vein thrombosis(DVT).

• Supercial thrombophlebitis.

• Varicoseveins.

• Post- phlebitic limb (post- DVT).

Soft tissue/ musculoskeletal

• Calf haematoma or trauma.

• Ruptured Baker’s cyst (synovial eusion in the popliteal fossa associated

with rheumatoid disease).

•

Cellulitis (associated fever, sepsis, tachycardia).

Systemic

•

CCF (bilateral limb oedema, i JVP, and signs of left ventricular failure

(LVF)).

•

Hepatic failure.

• Hypoalbuminaemia.

• Nephrotic syndrome.

• Pregnancy:i dependent oedema, but note also i thrombotic risk, and

DVT should be excluded.

Deep vein thrombosis(DVT)

Usually aects the lower limb and can extend proximally into the iliofemoral

veins and inferior vena cava (IVC), with a higher risk of associated PE and

a higher incidence of post- phlebitic limb. Occasionally seen aecting the

upper limb, but this is atypical.

Risk factors forDVT

•

Age >60years.

• Previous DVTorPE.

• Recent major surgery, especially orthopaedic lower limb, abdominal,

and pelvic.

•

Marked immobility.

• Malignancy.

• Pregnancy and postpartum.

• High- dose oestrogen oral contraceptive pill(OCP).

• Family history of venous thromboembolism(VTE).

Investigations

USS Doppler studies, impedance plethysmography, venography, exclude PE.

If any associated symptoms, arrange V/ Q scan, multislice CT, and pulmo-

nary angiography. Thrombophilia screening for younger patients (age <55),

atypical site and extensive clots, spontaneous onset, and family history.

CHAPTER1 Symptoms andsigns

Chestpain

Acute chest pain is a common symptom. Adetailed history and a full physi-

cal examination should be performed in order to dene the most likely

cause and necessary investigation pathway.

History

Be sure to ask the following questions about thepain:

•

Site and radiation.

• Character.

• Onset and duration.

• Precipitating and relieving features.

• Associated symptoms.

• Response to pain relief, antacids, or nitrates.

Most types of chest pain fall within one of the categories in Table1.2.

Investigations

(See Table1.3.)

E OHCM 10e, p.36, p. 48, p. 94, p. 784.

Table1.2 Pain sources

Pain source Description of pain

Myocardial ischaemia Retrosternal, heavy ache, can radiate l jaw and arms,

precipitated by exertion, and relieved by rest or nitrates

Aortic dissection Severe central tearing pain, radiates to back

Gastro- oesophageal

disease

Burning central pain; can radiate to shoulders, throat, or

abdomen; exacerbated by meals, eased with antacids/ milk

Pleuritic pain Focal sharp pain, exacerbated by inspiration

Pericardial pain Sharp pain, radiates to left shoulder tip, worse on lying

at and during inspiration, eased by sitting forwards

Musculoskeletal pain Sharp focal pain exacerbated by movement and palpation

CHESTPAIN

Table1.3 Investigations forsuspected diagnoses

Cardiovascular causes:all patients should have a 12- lead ECG and CXR

Suspected diagnosis Investigations

Myocardial ischaemia/ infarction

Consider:

• Coronary artery disease

• Aortic stenosis

• Hypertrophic obstructive cardiomyopathy

Serial ECGs

Cardiac markers of necrosis

FBC

TFTs

Echocardiogram

Exercise electrocardiogram

Stress cardiac imaging

Coronary angiography

Thoracic aortic dissection

Note:myocardial ischaemia may also be

present if it involves the coronary arteries

Syphilitic aortitis

FBC, U&E, X- match

Echocardiogram (TTE orTOE)

CT,MRI

Syphilis serology

Mitral valve prolapse

Echocardiogram (TTE or TOE)

Acute pericarditis FBC, viral titres, ESR

Echocardiogram

Pulmonary causes: all patients should have CXR ± ABGs

Suspected diagnosis Investigations

Pneumonia/ pleurisy FBC, CRP

Acute bronchitis Sputum and blood cultures

Pulmonary tuberculosis (TB) Aspiration if empyema suspected

Early morning urine(TB)

Mantoux test (TB)

Pneumothorax CXR

Pulmonary embolus

D- dimers

12- lead ECG

V/ Q scan

CT pulmonary angiography

Lung carcinoma Sputum cytology

Pleural tumour, e.g. mesothelioma

High- resolution CT

Mediastinal tumour Bronchoscopy

Tissue biopsy

Gastro-oesophageal causes

Oesophageal

• Spasm

• Oesophagitis

• Candidiasis

• Reux disease

• Mallory– Weiss tear

FBC

G&S

Helicobacterpylori

Endoscopy

Oesophageal manometry

Oesophageal biopsy

(Continued)

CHAPTER1 Symptoms andsigns

Suspected diagnosis Investigations

Peptic ulcer disease

Endoscopy

Gastrogran

swallow

Barium swallow, meal, or

follow- through

Erect CXR (if perforation

suspected clinically)

Acute pancreatitis Amylase

Abdominal USS

Cholecystitis/ biliary colic FBC, CRP, LFTs

Urinalysis

AbdominalUSS

ERCP

Musculoskeletal and dermatological causes

Suspected diagnosis Investigations

Muscular

Bony structures

Chest wall bony metastases

Rib/ sternal fractures

Costochondritis (Tietze’s syndrome)

Ankylosing spondylitis

Cervical/ thoracic spine disease

Thoracic outlet syndrome

CXR

Bonescan

SpinalX- rays

CT scan

Skin/ soft tissue

Acute shingles

Post- herpetic neuralgia

Herpetic serology/ smear (rarely)

CRP, C- reactive protein; G&S, group and save; TOE, transoesophageal echocardiography; TTE,

transthoracic echocardiography.

ACC/ AHA 2002 guideline update for the management of patients with chronic stable angina.

M http:// www.onlinejacc.org/ content/ 41/ 1/ 159?_ ga=2.15239422.956431479.149977610

8- 163922176.1499776108.

Table1.3 (Contd.)

CLUBBING

Clubbing

Soft tissue hypertrophy under the nail bed distorts nger and toenail

growth.

Characteristic features

• i lateral and longitudinal nail curvature.

•

The skin at the base of the nail becomes spongy.

• The angle between the nail and skin is obliterated.

• In extreme cases, the terminal phalanx becomes bulbous like a

drumstick.

Clubbing can be an important visual indicator of major disease, although it

can also be congenital. Rarely, clubbing may accompany swollen wrists and

ankles as part of a proliferative periostitis seen in hypertrophic pulmonary

osteoarthropathy (HPOA). This is associated with squamous carcinoma of

thelung.

Majorcauses

• Lung disease:cystic brosis, bronchiectasis, empyema, lung abscess,

asbestosis, mesothelioma, pulmonary sarcoid.

•

Carcinoma:bronchogenic (especially squamous cell), mediastinal, pleural,

oesophageal, gastric, colonic, thoracic lymphoma, familial polyposiscoli.

•

Infection:infective endocarditis, colonic amoebiasis.

•

Vascular disease:cyanotic congenital heart disease, atrial myxoma,

arteriovenous malformation(AVM).

•

Liver disease:primary biliary cirrhosis (PBC), chronic active hepatitis.

•

Ulcerative colitis and Crohn’s disease, malabsorption.

• Rare causes:thyrotoxicosis, polycythaemia,SLE.

Investigations

As guided bydierential diagnosis and clinical suspicion

•

FBC.

• ESR.

• C- reactive protein(CRP).

• LFTs.

• TFTs.

• SerumACE.

• Autoantibodies.

• Blood cultures (at least three sets if infective endocarditis suspected).

• Faecal occult blood (FOB) (three samples).

• CXR.

• Echocardiography (TTE or transoesophageal echocardiography (TOE)).

• OGD and biopsy.

• Colonoscopy and biopsy.

• AbdominalUSS.

• CTchest.

• Bronchoscopy, biopsy, washings.

• Liver biopsy.

E OHCM 10e, p.40,p.77.

CHAPTER1 Symptoms andsigns

Coma

The Glasgow Coma Scale (GCS) is used to assess the level of consciousness

(see Table 1.4). The minimum score is 3; the maximum15.

Assess the level of consciousness and determine whether this is stable,

uctuating, improving, or deteriorating on serial assessments.

Cerebralcauses

• Intracranial haemorrhage (subarachnoid haemorrhage (SAH), subdural

haemorrhage (SDH), extradural haemorrhage (EDH), intracerebral

bleed).

•

Large cerebral infarct.

• Pontine haemorrhage (pinpoint pupils).

• Cerebral venous sinus thrombosis.

• Hypertensive encephalopathy.

• Cerebral tumour (associated local cerebral oedema may respond to

dexamethasone).

•

Head injury.

• Cerebral infection— encephalitis, meningitis, cerebral malaria, brain

abscess.

•

Post- ictalstate.

• Subclinical status epilepticus. (Note:this is an EEG diagnosis.)

• Cerebral vasculitis, e.g.SLE.

• End- stageMS.

• Leukodystrophy.

• CJD (including variant CJD (vCJD)).

Table1.4 Glasgow ComaScale

Eye opening 1

Nil

Topain

Tovoice

Spontaneously

Motor response 1

Nil

Extension

Flexion

Withdrawal frompain

Localizing topain

Voluntary

Vocal response 1

Nil

Groans

Inappropriatewords

Disorientatedspeech

Orientated speech

COMA

Metaboliccauses

• Drugs (usually in deliberate overdose; E Chapter11).

•

Alcohol excess. (Note:remember hypoglycaemia as a cause of coma in

alcoholics, as well as extradural haematoma.)

•

Hypoglycaemia (iatrogenic, overdose of insulin or sulfonylureas,

insulinoma, insulin- like growth factor (IGF)- 2- associated hypoglycaemia

in certain tumours).

•

DKA (coma in 710% of cases— adverse prognosticsign).

• Hyperosmolar non- ketotic coma (HONK) (may present as severe

dehydration ±coma).

•

Uraemia.

• Late stages of hepatic encephalopathy.

• Severe hyponatraemia (relatively common— especially inappropriate

antidiuretic hormone (ADH) syndrome).

•

Hypothyroidism (myxoedema coma— rare).

• Hypercalcaemia.

• Inborn error of metabolism, e.g. porphyria, urea cycle disorders.

• Type 2 respiratory failure (carbon dioxide (CO

) narcosis).

•

Hypothermia (severe).

• Hyperpyrexia (neuroleptic malignant syndrome (NMS), after

anaesthesia).

•

Severe nutritional deciency— thiamine, pyridoxine, vitaminB

Investigations

• Venous plasma glucose (exclude hypoglycaemia with a ngerstick +

reectance meter; conrm with a venous plasma uoride– oxalate

sample).

•

U&E.

• LFTs.

• SerumCa

•

Serum osmolality.

• UrineNa

•

Blood cultures.

• Clotting screen (E p. 288, p. 289, p. 290).

•

ABGs.

• Drug screen (serum, urine).

• Cranial CTscan.

• L P.

• CXR (bronchogenic carcinoma with cerebral metastases).

• 12- leadECG.

• EEG.

• Erythrocyte transketolase (d in thiamine deciency).

•

Serum ammonia (NH

) (i in urea cycle disorders).

•

Brain biopsy.

Always assess Airway, Breathing, Circulation before assessment of the

cause of d consciousness. Consider psychogenic unresponsiveness.

E OHCM 10e, p.220, pp.786–9, p.834, p. 836.

CHAPTER1 Symptoms andsigns

Confusion

A reliable witness, family member, or carer may be vital in assessing a

patient with confusion, and care must be taken to discriminate between

acute and chronic symptoms. Acute confusional states carry a very broad

dierential diagnosis and require careful initial evaluation (see Table 1.5).

Any systemic illness can precipitate a confusionalstate.

Investigations

• FBC, U&E, LFTs, serum Ca

, BM stix, and blood glucose.

•

ABGs.

• MSU, blood cultures, sputum culture.

• CXR.

• ECG.

• Thyroid function.

• Drug/ toxicology screen— blood andurine.

• CTscan.

• L P.

3 Always look for a MedicAlert

™

bracelet, necklace, orcard.

Table1.5 Causes ofconfusion

Hypoxaemia Acute infection, asthma, COPD, etc.

Head injury Cerebral trauma

Vascular CVA, TIA, intracerebral, SDH

Infection Systemic

Meningitis or encephalitis

Endocrine/ metabolic DKA, hypoglycaemia, thyrotoxicosis or

myxoedema, uraemia, hypercalcaemia,

hyponatraemia

Alcohol and drug abuse Acute intoxication and withdrawal

Also consider overdose

Iatrogenic Full and recent medication history (especially

opiates, analgesia, and sedatives)

Post- ictal state

Cerebral tumour

Psychiatric

Wernicke’s encephalopathy

E OHCM 10e, p.576.

CONSTIPATION

Constipation

Patients may use the term constipation to mean infrequent, hard, small vol-

ume, or dicult to pass faeces. Patients vary enormously in their threshold

to seek medical advice about bowelhabit.

Askabout:

•

Associatedpain.

• PR bleeding.

• Tenesmus.

• Weightloss.

Causes

• Carcinoma of thecolon.

• Diverticular disease.

• Anorectal disease— ssure or haemorrhoid.

• Benign stricture.

• Rectocele.

• Sigmoid volvulus.

• Hernia.

• Drugs, especially analgesics.

• Poor uid intake.

• Low- brediet.

• Change indiet.

• Immobility.

• IBS.

• Megarectum.

• Hirschsprung’s disease.

• Spinal cord lesion.

• Stroke.

• Jejunal diverticulosis.

• Hypothyroidism.

• Diabetic neuropathy.

• Hypercalcaemia, hyperparathyroidism, hypokalaemia.

• Uraemia.

• Porphyria.

• Pregnancy.

• MS.

• PD.

• Dermatomyositis.

• Myotonic dystrophy.

• Scleroderma.

• Psychological.

CHAPTER1 Symptoms andsigns

Investigations

• Digital rectal examination.

• Proctoscopy.

• Sigmoidoscopy.

• Colonoscopy.

• Bariumenema.

• U&E.

• Ca

•

TFTs.

• FBC.

• Bowel transit time studies.

• Anorectal manometry.

• Electrophysiological studies.

• Defecating proctography.

3 Elderly patients are more prone to constipation.

E OHCM 10e, pp.260–1, p. 534.

CYANOSIS

Cyanosis

Cyanosis is a blue/ purple dusky discoloration of tissue caused by a rise in

blood deoxygenated Hb content (>5g/ dL). Rarely it may be caused by i

sulphaemoglobin, methaemoglobin, or COHb. Cyanosis may be peripheral

aecting only cutaneous areas, or central when mucous membranes of the

mouth and tongue are also discoloured.

Causes ofperipheral cyanosis

• Central cyanosis.

• Shock.

• Hypothermia.

• Mitral stenosis.

• Raynaud’s syndrome.

• Peripheral arterial disease.

• Patent ductus arteriosus (dierential cyanosis, i.e. cyanosed toes, but

not ngers, is pathognomonic of this condition).

Causes ofcentral cyanosis

Pulmonary disease withseverely impaired oxygen transfer

•

Pneumonia.

• Asthma.

• Chronic obstructive pulmonary disease (COPD).

• PE.

• Fibrosing alveolitis.

Right- to- left shunt (Eisenmenger’s syndrome)

• Atrial septal defect.

• VSD.

• Patent ductus arteriosus.

• Partial anomalous pulmonary venous drainage (APVD).

• AVM.

Methaemoglobinaemia, sulphaemoglobinaemia, carboxyhaemoglobinaemia

•

Congenital.

• Ingestion of oxidizing agents, e.g. phenacetin, inorganic nitrates, local

anaesthetic.

Cyanosis arising from pulmonary disease can be reversed by administration

of oxygen (O

) to improve alveolar O

uptake. O

has no eect where right-

to- left shunts are the cause. Central cyanosis may be underestimated with

signicant anaemia and is more apparent in patients with polycythaemia.

In methaemoglobinaemia, the arterial concentration of O

is normal. This

condition can be treated with IV methylthioninium chloride (methylene

blue) (E Chapter11).

Investigations

• FBC.

•

ABGs.

• CXR.

• 12- leadECG.

• TTE (proceeding to TOE if shunt is suspected).

• CT chest (if AVM is suspected).

• Cardiac MRI (if APVD is suspected).

E OHCM 10e, p.34.

CHAPTER1 Symptoms andsigns

Diarrhoea

Patients may use the term diarrhoea to describe loose stools, i frequency

of defecation, i volume of stool, steatorrhoea, melaena, or faecal inconti-

nence (E Incontinence:faecal, p. 60).

Askabout

• Duration.

• Associated features (abdominal pain, vomiting, mucus, or bloodPR).

• Systemic symptoms.

• Recent foreign travel.

• Suspectfood.

• Is anyone else in the household aected?

Causes

• Infection (including ‘traveller’s diarrhoea’).

• IBD.

• Diverticular disease.

• Colonic carcinoma.

• Other tumour, especially villous adenoma.

• Coeliac disease.

• Tropicalsprue.

• IBS.

• Ischaemic colitis/ bowel infarction.

• Laxativeuse!

• Other drugs, e.g. metformin, orlistat.

• Overindulgence in fruit or vegetables.

• Overow 2° to constipation.

• Carcinoid syndrome (uncommon).

• Gastrinoma (rare).

• VIPoma (rare).

• Glucagonoma (veryrare).

• Hyperthyroidism (common).

• Medullary carcinoma of the thyroid (uncommon).

• Bile salt diarrhoea (previous ileal disease or surgery).

• Dumping syndrome (previous gastric surgery).

• Gut motility disorders.

• Malabsorption (cf. pancreatitis, lymphangiectasia, coeliac).

• Lactose intolerance.

• Scleroderma.

• Amyloidosis.

• Whipple’s disease.

Investigations

• Stool culture, hot stool for parasites.

• Clostridium dicile toxin instool.

•

High rectal swab for parasites. (Note:giardiasis is diagnosed on duodenal

biopsy.)

•

Rectal examination, proctoscopy, sigmoidoscopy ± biopsy.

• Colonoscopy.

DIARRHOEA

• AXR.

• Bariumenema.

• Small bowel follow- through contrast studies.

• Upper GI endoscopy.

• Small bowel biopsy.

• FBC and bloodlm.

• ESR.

• CRP.

• Serum ferritin and folate.

• U&E (exclude haemolytic uraemic syndrome (HUS), especially in

children).

•

Urine screen for laxatives.

• Antigliadin, antiendomysial antibodies and anti- tissue transglutaminase

(tTG) (coeliac disease).

•

TFTs.

• Serum gut hormone prole (gastrin, vasoactive intestinal peptide (VIP),

glucagon— seek expert advice).

• 24h urine for 5- hydroxyindole acetic acid (5HIAA).

• Serum calcitonin (medullary carcinoma of the thyroid).

• Lactose hydrogen breath test (for lactose intolerance).

•

C- xylose breath test (bacterial overgrowth in the small bowel).

• CT abdomen.

• Mesenteric angiography (ischaemia).

Investigations must be guided by history and examination ndings. If the

patient is an inpatient, they should be isolated until infection is excluded.

Consider HIV and other immune disorders if an unusual bowel organism

isfound.

CHAPTER1 Symptoms andsigns

Dizziness and syncope

Dizziness is a term that may be used to describe a variety of symptoms, e.g.

spinning (rotatory vertigo), light- headedness, muzzy feeling, or unsteadiness

on walking. It is therefore important to establish precisely what the patient

means by dizziness.

Loss of consciousness or ‘blackout’ may not be reported by the patient

and an eyewitness account is important. Enquire about any awareness of

abnormal heart beat (rhythm- induced syncope), chest pain (ischaemia),

neurological symptoms (cerebrovascular disease), preceding micturition,

change of posture, or unusual sensations (prodromal epileptic symptoms,

e.g. strange taste or smell) prior to the collapse.

Causes ofdizziness

• Rotatory sensation lasting >10s and precipitated by movement or

position— vestibular cause such as labyrinthitis, Ménière’s disease,

cerebello- pontine angle tumour (acoustic neuroma).

• Rotatory sensation lasting 2 or 3s and precipitated by movement—

cervical spondylosis.

•

Non- rotatory sensation lasting 2 or 3s and precipitated by movement,

position, or standing up— cervical spondylosis, cerebrovascular disease,

postural hypotension, cardiac arrhythmia (usually back to normal in

minutes), epilepsy (incontinence is common and return to normal may

take hours).

Investigations

Suspected vestibularcause

•

Hallpike manoeuvre.

• MRI or CT cerebello- pontineangle.

• Audiometry.

Suspected non- vestibularcause

• Blood glucose.

• 12- leadECG.

• 24h ambulatory ECG monitoring.

• EEG.

• MRI or CThead.

• Tilt tabletest.

Causes ofsyncope

• Vasovagal:pain, fear, prolonged standing, excess heat, alcohol, orfood.

• Micturition (often elderly men standing up during the night to urinate).

• Defecation (often elderly women with constipation).

• Coughing:chronic airways disease.

• Orthostatic hypotension:

•

Autonomic dysfunction (diabetic neuropathy, Shy– Drager

syndrome).

•

Drugs (antihypertensives, diuretics, nitrates, tricyclics; dehydration

and sodium depletion).

•

Carotid sinus syndrome.

• Epilepsy.

DIZZINESS AND SYNCOPE

• Drugs:alcohol, illicitdrugs.

• Cardiac:arrhythmias, outow obstruction (aortic stenosis, hypertrophic

obstructive cardiomyopathy, myxoma).

•

Hyperventilation and anxiety.

• Acute cerebrovascular disease:transient ischaemic attack (TIA),

stroke,SAH.

•

Acute vascular obstruction:PE,MI.

• Hypoglycaemia:poorly controlled diabetes.

Investigations

•

12- leadECG.

• 24h Holter monitoring.

• Echocardiography.

• MRI or CThead.

• Tilt tabletest.

• Blood glucose,HbA

•

U&E.

• Cardiac markers.

• ABG.

• Toxicology screen.

• V/ Qscan.

2 Driving and dizziness/ syncope

For guidance on driving in the United Kingdom (UK), see M http:// www.

dvla.gov.uk.

Further reading

Brignole M, Alboni P, Benditt DG, etal.; Task Force on Syncope, European Society of Cardiology.

Guidelines on management (diagnosis and treatment) of syncope. Eur Heart J 2004; 25:2054– 72.

CHAPTER1 Symptoms andsigns

Dysarthria and dysphasia

Dysarthria is diculty in articulating words. The patient may complain of

‘slurred speech’. Dysphasia is a diculty in the formation of speech due to

interference with higher mental function. These disturbances often occur

together, most commonly in the context of a stroke.

Damage to Wernicke’s area causes a receptive dysphasia. Speech may

be uent, but meaning is lost. Damage to Broca’s area causes an expressive

dysphasia. Speech is non- uent and the patients are aware they are not

using the rightwords.

Causes of dysphasia include stroke (usually with right hemiparesis, arm

more aected than leg) or SOL. Psychosis, especially schizophrenia, may

cause a similar picture— the so- called ‘word salad’.

Causes ofdysarthria

• Stroke (internal capsule or extensive lesion of the motor

cortex— acute).

• Motor neurone disease(MND).

• Midbrain or brainstem tumour.

• PD.

• Cerebellar disease (haemorrhage, infarct, MS, hereditary ataxia,

alcoholic or paraneoplastic degeneration).

•

Syringobulbia (chronic, progressive).

• Neuromuscular (myasthenia gravis (MG), dermatomyositis, myotonic

dystrophy).

•

Acute alcohol or drug intoxication.

Dysarthria may be more obvious when the (English- speaking!) patient is

invited to say ‘Baby hippopotamus’, ‘British constitution’,etc.

Investigations

•

Cranial CTscan.

• Venous plasma glucose.

• ESR.

• Serum lipids.

• 12- leadECG.

• Echocardiogram.

• Carotid Doppler studies (especially if bruit).

• CXR.

• LFTs.

Less commonly

•

Serum muscle enzymes (polymyositis).

• Autoimmune prole.

• Electromyogram(EMG).

• Skeletal muscle biopsy.

E OHCM 10e, pp.86–7.

DYSPHAGIA

Dysphagia

Dysphagia is diculty in swallowing. The patient may have associated

odynophagia (painful swallowing) or regurgitation of food (immediate or

delayed?). Elicit whether the dysphagia is for liquid, solids, or both. Is it inter-

mittent or progressive? Are there associated symptoms?

A careful physical examination is mandatory. Pay special attention to the

lower cranial nerves; search for lymph nodes in the supraclavicular fossae.

Palpate the thyroid and percuss for retrosternal enlargement.

Causes

• Oesophageal carcinoma.

• Benign oesophageal stricture 2° to chronic acid reux.

• Barrett’s oesophagus.

• Achalasia or diusespasm.

• Stroke (bilateral internal capsule cerebrovascular accidents (CVAs)—

pseudo- bulbar palsy).

• Oesophageal web (+ iron deciency anaemia=Plummer– Vinson

(Patterson– Kelly– Brown) syndrome).

• Pharyngealpouch.

• Muscular problem (MG, dermatomyositis, myotonic dystrophy).

• Bulbar palsy (MS, MND, poliomyelitis).

• Scleroderma (including CREST syndrome— E OHCM 10e, Chapter12).

•

Infection (usually acute pain on swallowing).

• Mediastinal mass (goitre, carcinoma of the bronchus, enlarged left

atrium, aortic aneurysm).

Investigations

• FBC.

• ESR.

• Upper GI endoscopy.

• Barium swallow.

• CXR.

• Oesophageal manometry studies (E Gastrointestinal physiology,

pp. 526–7).

•

Cranial CT or MRI (if neurological signs).

• Acetylcholine (ACh) receptor antibodies and Tensilon

(edrophonium).

test if MG is suspected (E

Edrophonium (Tensilon

) test, p. 631).

Note:consider HIV testing if there is oesophageal Candida, or herpes sim-

plex or cytomegalovirus (CMV) infection in the oesophagus.

E OHCM 10e, p.64, pp.250–1.

CHAPTER1 Symptoms andsigns

Facialpain

Is the pain unilateral or bilateral? Is it constant or intermittent? Precipitating

factors or trigger points? Afull examination of the head and neck is required

in addition to a detailed neurological and systemic examination.

Causes

• Trigeminal neuralgia(TN).

• Temporal arteritis (TA). 3 Risk of visual loss (E OHCM 10e,

Chapter11).

•

Herpes zoster (shingles or post- herpetic neuralgia).

• Dental caries, sepsis.

• Sinusitis.

• Temporomandibular joint dysfunction.

• Cluster headache.

• Glaucoma.

• Angina pectoris.

• Tonsillitis.

• Syringobulbia.

• Atypical facial neuralgia.

• Migraine.

Investigations

• ESR— urgent in suspectedTA.

• Temporal artery biopsy if TA strongly suspected. (3 Must be

performed rapidly— within days— if steroid treatment is commenced.

However, do not withhold corticosteroid therapy for this reason!)

Because of ‘skip’ lesions, false −ve biopsies may be encountered. Be

guided by the full clinical picture, rather than reliance on a singletest.

•

Plain radiographs or CT imaging of frontal or maxillary sinuses.

• MRI to exclude MS, basilar aneurysm, trigeminal schwannoma,

neurobroma as causesofTN.

•

MRI of the cervical spinal cord to exclude syringobulbia if pain is

accompanied by brainstemsigns.

E Headache, pp. 49–50 and E OHCM 10e, p. 64, pp. 456–7.

FEVER OFUNKNOWN ORIGIN (FUO ORPUO)

Fever ofunknown origin (FUO orPUO)

Dened as temperature >38.3°C on several occasions, lasting 3 weeks

or more. It is very important to take a full history and consider infectious

contacts, recent travel abroad, recent surgery and dental treatment, sexual

history, and risk factors forHIV.

Signs

Examine for heart murmurs, splinter haemorrhages, splenomegaly, lym-

phadenopathy, and rashes/ pruritus (see Table1.6).

Investigations

• Re- take the history and re- examine the patient (something might have

been missed or new symptoms/ signs may have developed).

• FBC,ESR.

• U&E, LFTs,Ca

•

CXR.

• MSU, urinalysis.

• Serology for Brucella and Toxoplasma.

•

All biopsy material should be sent for culture, includingTB.

• Blood cultures (serial may be necessary).

• Monospot/ Paul Bunnell.

• Autoimmune prole (antinuclear antibodies (ANA), rheumatoid factor

(RF), ANCA,etc.).

•

Bone marrow aspirate/ trephine/ culture for TB with Ziehl– Neelsen

(ZN)stain.

• Abdominal USS (? masses).

Extend investigations asbelow accordingtosymptoms

andsigns

• Consult microbiology or infectious disease consultant for advice.

• Stool cultures and fresh stool for ova, cysts, and parasites.

• Repeat serological investigation for changing titres (2– 3 weeks).

• Thick and thin blood lm for malaria and parasites.

• Mantoux.

• TTE or TOE to exclude endocarditic vegetations.

• CT chest, abdomen, and pelvis.

3 Always re- examine the patient for evolving new signs if the cause

remains unknown.

E OHCM 10e, pp. 442–3.

Table1.6 Causes ofFUO/ PUO

Infection Abscesses (e.g. subphrenic, pelvic, lung), osteomyelitis,

TB, endocarditis, parasites, rheumatic fever, brucellosis,

toxoplasmosis, Lyme disease, histoplasmosis, viral (especially

Epstein– Barr virus, CMV, hepatitis, and HIV)

Malignancy Lymphoma, leukaemia, hypernephroma, ovary, lung, hepatoma

Connective tissue

Polyarteritis nodosa, SLE, RhA, Still’s disease, TA

Other Sarcoidosis, atrial myxoma, drug fever, IBD, factitious

CHAPTER1 Symptoms andsigns

Firstﬁt

3 Arst t in an adult requires careful evaluation since the probability of

an underlying structural lesion i withage.

Take a careful history, preferably from a witness as well as the patient.

Most lay persons will recognize a generalized tonic– clonic t. However,

the occurrence of a few ‘epileptiform’ movements in patients with synco-

pal episodes (E Dizziness and syncope, pp. 34–5) may cause diagnostic

uncertainty.

Be sure toaskabout

• Aura preceding the episode. 2 Temporal lobe epilepsy— olfactory or

gustatory auras (not necessarily followed by convulsions).

•

Loss of consciousness— how long? Often overestimated by witnesses!

• Tongue biting.

• Focal or generalized convulsive movements. Note:a clear history of

a tonic– clonic t commencing in a limb and progressing to a more

generalized convulsion is highly suggestive of a structural intracerebral

lesion; cranial imaging is mandatory.

•

Central cyanosis (tonic phase).

• Urinary incontinence.

• Injuries.

• Post- ictal confusion.

• History of trauma.

• Alcohol intake. Remember:alcohol withdrawal ts as well as acute

intoxication.

•

Drug history— prescribed and recreational.

• History of insulin- treated diabetes or type 2 diabetes treated

with oral secretagogues, i.e. sulfonylureas, repaglinide, nateglinide.

Note:metformin and thiazolidinediones as monotherapy do not cause

signicant hypoglycaemia.

A full general and neurological examination is needed, specically including:

•

Fever.

• Meningism, i.e. nuchal rigidity, +ve Kernig’s sign (meningoencephalitis).

• Cutaneous rash or ecchymoses (? bleeding diathesis).

• Evidence of head trauma (preceding t or as a consequence).

• Signs of chronic liver disease.

• Focal neurological decit. 2 Third nerve palsy in an intracranial SOL,

including aneurysm of the posterior communicating artery. Sixth nerve

lesion may act as a ‘false localizing sign’ iniICP.

•

MedicAlert

™

bracelet (history of epilepsy or diabetes— search personal

belongings).

Bilateral extensor plantar reexes can occur after a generalized t without

a structural brain lesion and there may be transient hemiparesis (Todd’s

paresis).

FIRSTFIT

Causes

• Epilepsy (E OHCM 10e, Chapter10).

•

Hypoglycaemia (acute, severe, history of diabetes?).

• Hyponatraemia (usually <110mmol/ L or rapid development).

• Hypocalcaemia (E OHCM 10e, Chapter14).

•

Hypomagnesaemia (may accompany hypocalcaemia).

• Hypophosphataemia (rare).

• Alcohol withdrawal. 3 Risk of associated hypoglycaemia.

•

Discontinuation of anticonvulsant medication.

• Infection— viral encephalitis or bacterial meningitis. 3 Consider

intracerebral abscess, tuberculoma in predisposed patients.

•

Encephalopathy— hepatic, uraemic, hypertensive, thyrotoxic (rare—

‘thyroid storm’).

•

Eclampsia.

• Porphyria.

• CerebralSLE.

• Head injury.

• Hypoxia.

• Cerebral tumour.

• Stroke— cerebral infarct, haemorrhage.

Investigations

• Venous plasma glucose (ngerprick test at bedside useful as ‘screen’—

but can be unreliable).

•

U&E.

• Serum Ca

, magnesium (Mg

), phosphate (PO

3−

•

Cranial CT or MRIscan.

• EEG.

• LP (E Lumbar puncture, pp. 584–9).

•

CXR.

• Serum prolactin (PRL) (may be i after generalized convulsions, but not

pseudo- seizures).

• ABGs— remember transient lactic acidosis following generalized tonic–

clonic convulsions.

•

Blood ethanol (may be undetectable in withdrawal state).

• Serum or urine drug screen.

‘Pseudo- seizures’ may be encountered in patients with atypical recurrent

ts (usually long history of epilepsy) and this is unlikely in an adult presenting

with a rst t. 2 In UK, the DVLA prohibits driving for 12months following

a rstt.

E OHCM 10e, pp. 490–2.

CHAPTER1 Symptoms andsigns

Galactorrhoea

Denotes inappropriate breast milk production, i.e. in the absence of preg-

nancy. The commonest cause is hyperprolactinaemia (i PRL) due to a pitui-

tary microprolactinoma of <10mm in diameter (E Precocious puberty,

p. 179). Prolactinomas (usually macroadenomas) may cause galactorrhoea

inmen.

Note:other disease in the pituitary region, certain drugs, and several sys-

temic disorders may be associated with i PRL (E OHCM 10e, Chapter5).

Causes

Normoprolactinaemic galactorrhoea

•

This has been described in premenopausal women occurring after the

conclusionof:

•

Treatment with the combined contraceptivepill.

•

Breastfeeding (for >6months afterwards).

• i sensitivity of lactogenic tissue PRL is postulated, but the mechanism

remains uncertain. In part, this may reect diculties that can arise

in determining whether PRL is persistently elevated. Menstrual

disturbances have been described.

Hyperprolactinaemia

•

The dierential diagnosis and investigation of hyperprolactinaemia are

considered in E Galactorrhoea (hyperprolactinaemia), pp. 172–3.

Investigations

• Serum PRL (E Galactorrhoea (hyperprolactinaemia), pp. 172–3).

•

Repeated measurements under controlled conditions may be required

since PRL is a ‘stress’ hormone and may be i by venepuncture.

Note:if i PRL is conrmed, further investigations to exclude causes other

than a prolactinoma are required.

•

Pituitary imaging (CT, or preferably MRI) and visual eld testing

(Goldmann) may also be indicated if a macroprolactinoma is suspected

(PRL concentrations usually veryhigh).

Note: if there is doubt about the nature of the nipple discharge, further

specialized investigations may be required on the uid, including:

•

Casein.

• Lactose.

• Microscopy.

Clear uid may result from benign breast disease.

Note:bloody discharge should prompt urgent specialist investigations to

exclude carcinoma of the breast:

•

Mammography.

• Biopsy.

E OHCM 10e, p.237.

Further reading

Kleinberg DL, Noel GL, Frantz AG. Galactorrhoea:a study of 235 cases, including 48 with pituitary

tumors. N Engl J Med 1977; 296

:589– 600.

GOUT

Gout

Gout is a disease of deposition of monosodium urate monohydrate crys-

tals in tissues and relates to hyperuricaemia. Hyperuricaemia is due to

an imbalance between purine synthesis and uric acid excretion. Episodes

of acute gout may be precipitated by alcohol, trauma, dietary changes,

infection, chemotherapy, or surgery. Commoner in men and very rare in

premenopausalwomen.

Clinical features

• Inammatory arthritis, classically monoarthritis or oligoarthritis aecting

the rst metatarsophalangeal (MTP) joint of the foot but can aect any

joint, including thespine.

•

Tenosynovitis.

• Bursitis or cellulitis.

• Tophi— urate deposits in tendons, ear pinnae, and joints.

• Urolithiasis and renal disease.

Investigations

• ESR (maybei).

•

Urate crystals demonstrated in the synovial uid or tissues— negatively

birefringent on polarized light microscopy.

•

Serum urate (not always i in an acute episode, and a normal urate level

does not exclude the diagnosis).

•

X- ray— soft tissue swelling and punched- out bony erosions.

• Autoimmune prole (AIP) (to exclude rheumatoid).

• Microscopy of synovial uid (Gram stain and culture).

Treatment

Acute episode

•

NSAIDs, colchicine, intra- articular steroids, or oral steroids.

• Avoid precipitating factors and purine- richfoods.

• Urate- lowering therapy indicated for tophi, recurrent attacks, and

urine/ renal disease,e.g.

•

Allopurinol (xanthine oxidase inhibitor).

•

Probenecid (uricosuric).

Note: asymptomatic hyperuricaemia is commoner than gout, and a high

serum urate level with coexistent arthritis is not necessarily due to crystal

deposition. Consider important other causes, especially infective arthritis

and pseudo- gout.

Pseudo- gout

Calcium pyrophosphate crystal deposition causing acute arthritis or chon-

drocalcinosis. Crystals are weakly positively birefringent on polarized

light microscopy. Associations include old age, dehydration, hyperpar-

athyroidism, hypothyroidism, haemochromatosis, acromegaly, RhA, and

osteoarthritis(OA).

E OHCM 10e, p.548.

CHAPTER1 Symptoms andsigns

Gynaecomastia

Gynaecomastia is benign bilateral hyperplasia of glandular and fatty breast

tissue in the ♂. The balance between androgens and oestrogens is thought

to be of importance in the pathogenesis; many conditions may inuence this

ratio. Most commonly, it appears transiently during normal puberty (detect-

able at some stage in 750% of cases). Gynaecomastia may also be caused

by specic endocrine disease or be associated with certain chronic diseases.

Treatment with certain drugs is a common cause (730% of cases) and arises

via several mechanisms. Investigations will be guided by the individual cir-

cumstances. Acareful drug history and thorough physical examination are

required, particularly in the post- adolescent period.

When indicated, and after excluding causes such as congenital syndrome

and drug therapy, investigations are principally directedat:

•

Excluding endocrine carcinoma (rare).

• Identifying associated chronic diseases.

Note:

•

Simple obesity is not usually a cause of true gynaecomastia, i.e. the

glandular element isnoti.

•

i serum PRL in isolation does not cause gynaecomastia.

•

Unilateral, eccentric breast enlargement should prompt exclusion of

breast carcinoma (rare).

Causes include

• Physiological states (transient):

•

Newborn.

•

Puberty.

•

Advancedage.

• Klinefelter’s syndrome (47,XXY; mosaics).

• 2° hypogonadism, e.g. mumps orchitis.

• Androgen resistance syndromes, e.g. testicular feminization.

• i tissue aromatase activity (converts androgens to oestrogens).

•

Oestrogen- producing tumours:

•

Leydig cell tumour.

•

Sertoli cell tumour.

•

Adrenal carcinoma.

• Chronic liver disease.

• Chronic renal failure.

• Panhypopituitarism.

• Tumours producing human chorionic gonadotrophin(hCG).

• Drugs:oestrogens (prostatic carcinoma, transsexuals), spironolactone,

cimetidine, digoxin, cytotoxic agents, marijuana.

•

Hyperthyroidism (i serum sex hormone- binding globulin (SHBG)).

• ° hypothyroidism.

• Cushing’s syndrome.

• Carcinoma of the bronchus.

• Idiopathic.

GYNAECOMASTIA

Investigations

• Testosterone.

• FSH.

• LH.

• LFTs.

• TFTs.

• Oestradiol.

• β- hCG.

• PRL.

• SHBG (anity of SHBG is higher for testosterone than for oestrogens,

therefore i SHBG causes disproportionate d in free testosterone

levels).

•

Dehydroepiandrosterone sulfate (DHEAS).

• Androstenedione.

• TesticularUSS.

• CXR.

• Abdominal CT or MRI imaging (for suspected adrenal tumours).

• Pituitary imaging.

• Karyotype.

• Urinary 17- oxo- steroids.

If carcinoma ofthe breast is suspected

• Mammogram.

• Fine- needle aspiration(FNA).

E OHCM 10e, p.230.

Further reading

Braunstein GD. Gynecomastia. N Engl J Med 1994; 328:490– 5.

CHAPTER1 Symptoms andsigns

Haematemesis

This literally means vomiting blood and is often associated with melaena

(passage of black tarry stools).

Causes

• Chronic peptic ulceration (e.g. duodenal ulcer (DU) or gastric ulcer

(GU)) accounts for 50% of cases of bleeding from the upper GItract.

•

Acute GUs or gastric erosions.

• Drugs (e.g. NSAIDs) or alcohol.

• Reux oesophagitis.

• Mallory– Weisstear.

• Oesophageal varices.

• Gastric carcinoma (uncommon).

Investigations afteradmission and stabilization ofthe

patient

• Full history, including drugs, alcohol, past history, indigestion,etc.

• FBC. (Note:Hb will take 724h to fall; initially may be normal.)

•

U&E.

• Cross- matchblood.

• Urgent upper GI tract endoscopy.

• Check Helicobacter pylori serology ± urea breathtest.

E OHCM 10e, p.30, p. 256.

HAEMATURIA

Haematuria

In health, adults pass between 500,000 and 2,000,000 red cells over a 24h

period. Haematuria implies the passage of excess blood that may be detect-

able using dipsticks (microscopic haematuria) or may be obvious to the

naked eye (macroscopic haematuria).

Causes

• Many.

• Glomerular disease, e.g. ° glomerulonephritis, 2° glomerulonephritis

(SLE, vasculitis, infection).

• Vascular or interstitial disease due to hypersensitivity reactions, renal

infarction, papillary necrosis, or pyelonephritis.

•

Trauma.

• Renal epithelial or vascular tumours.

• Lower renal tract disease, e.g. tumours, stones, infection, drug toxicity

(e.g. cyclophosphamide), foreign bodies, or parasites.

•

Systemic coagulation abnormalities, e.g. platelet or coagulation factor

abnormalities such as profound thrombocytopenia orDIC.

Investigations

• Urinalysis— dipstick, microscopic examination, culture.

• Radiology,* e.g. KUB orIVU.

• Specialist investigation,* e.g. angiography, CT or MRI scanning.

• Cystoscopy.*

Note:ideally these tests (*) should be arranged after discussion with either

a nephrologist or a urologist.

E OHCM 10e, p.80, p. 294.

CHAPTER1 Symptoms andsigns

Haemoptysis

This describes coughing up blood or bloodstained sputum and can vary

from faint traces of blood to frank bleeding. Before embarking on investiga-

tion, it is essential to ensure that the blood is coughed up from the respira-

tory tract and is not that of epistaxis or haematemesis (easily confused).

Causes

• Infective, e.g. acute respiratory infection, exacerbation ofCOPD.

• Pulmonary infarction, e.g.PE.

• Lung cancer.

• TB.

• Pulmonary oedema.

• Bronchiectasis.

• Uncommon causes, e.g. idiopathic pulmonary haemosiderosis,

Goodpasture’s syndrome, microscopic vasculitis, trauma, haematological

disease (e.g. ITP orDIC).

Investigations

• Colour of blood provides clues (pink frothy in pulmonary oedema, rust-

coloured in pneumonia).

•

Check oxygen (O

) saturation.

•

FBC (? d platelets).

•

ESR.

• Coagulation screen.

• Sputum culture.

• CXR.

• Arrange bronchoscopy after discussion with the respiratoryteam.

E OHCM 10e, pp.48–9.

HEADACHE

Headache

E Facial pain,p. 38.

Headache is an extremely common complaint. Most patients self-

medicate and only a small proportion will seek medical advice. Headache

may be acute or chronic, constant, recurrent, or gradually progressive. It

may arise from structures within the cranial vault or from external causes

(E OHCM 10e, Chapter10).

Causes dier according to age; temporal arteritis is very uncommon in

patients under 755 years, for example. Migraine may be associated with

classic features (E OHCM 10e, Chapter10). Remember to enquire about

the combined OCP— may exacerbate migraine. ‘Tension’ headaches

predominate.

Causes inadults include

• ‘Tension’ headache (very common; usually recurrent and stereotyped).

• Migraine. Although common, many patients who believe they have

‘migraine’ probably have ‘tension’ headaches. Classic migraine

predominantly aects adolescents and young adults.

•

Cluster headaches.

• As part of a generalized viral illness, e.g.‘u’.

• Causes of i ICP (E OHCM 10e, Chapter10).

•

Acute infective meningitis (bacterial, viral most commonly).

• Encephalitis (most commonly viral, e.g. herpes simplex).

• Intracerebral haemorrhage.

• Post- traumatic (common).

• Intracerebral tumour (° or 2°, benign or malignant).

• AcuteSAH.

• Subdural haematoma.

• Acute glaucoma.

• Acute sinusitis.

• Rubeosis iridis (2° glaucoma in patients with advanced diabetic eye

disease).

•

TN.

• Referred pain, e.g. from dental caries or sepsis.

• Arterial hypertension; malignant or accelerated phase; essential

hypertension is rarely the cause of headache.

•

TA. 3 Visual loss preventable with prompt corticosteroid therapy

(E OHCM 10e, Chapter10).

•

Venous sinus thrombosis.

• Benign intracranial hypertension (mimics intracerebral tumour).

• Pneumonia caused by Mycoplasma pneumoniae may be associated with

headache (meningoencephalitis).

•

Nocturnal hypoglycaemia (often unrecognized) may cause morning

headaches in patients with insulin- treatedDM.

• Analgesia- withdrawal headache (E OHCM 10e, Chapter10).

•

Hangover following alcohol excess.

• Otitismedia.

• Chronic hypercalcaemia (rare).

CHAPTER1 Symptoms andsigns

Investigations

• ESR (3 TA— exclude with urgency).

• CRP.

• FBC.

• U&E.

• Throatswabs.

• Blood cultures (if febrile).

• LP (E Lumbar puncture, pp. 584–9).

•

Skull X- ray (SXR) ± cervical spineX- ray.

• Sinus X- rays (may be local tenderness in sinusitis).

• Cranial CT (E Computed tomography, pp. 598–600).

•

CXR (cerebral metastases from bronchogenic carcinoma).

• Urinalysis.

• Intraocular pressure measurement and refraction.

• Cerebral angiography (if aneurysm orAVM).

• SerumCa

E OHCM 10e, p.64, pp. 456–7.

HEART SOUNDS AND MURMURS

Heart sounds and murmurs

Auscultation of the heart should be conducted over several cardiac cycles.

Heart sounds and murmurs are traditionally assessed at the apex, lower

left sternal edge, aortic area, and pulmonary area, but they may radiate into

other regions such as the axilla or carotid arteries. The carotid pulse should

be palpated simultaneously in order to time cardiac events. The following

should be identied:

•

First (S1) and second (S2) heart sounds.

• Added heart sounds such as third (S3) or fourth (S4) heart sounds,

opening snaps, ejection clicks, and prosthetic sounds.

•

Murmurs, including location, intensity, and characteristics.

The rst heart sound is produced by closure of the mitral and tricuspid

valves. It is best heard at the apex and is timed just prior to the carotid

pulse. The second heart sound is caused by closure of the aortic (A2) and

pulmonary (P2) valves and is heard just after carotid pulsation. Closure of

the pulmonary valve is slightly delayed relative to the aortic valve and so the

second heart sound is normally split. This split is exaggerated by inspiration

(see Table1.7).

Normal and abnormal heart sounds are shown in Table1.7.

The third heart sound is heard just after S2 and arises as a consequence of

rapid ventricular lling and volume overload. The fourth heart sound occurs

just before S1 and is caused by atrial contraction against a sti ventricle

or pressure overload. Abnormal valves may cause extra heart sounds on

opening, e.g. an opening snap or ejection click. The heart sounds generated

by articial valve closure are referred to as prosthetic heart sounds. These

should be crisp, not mued (see Table1.8).

Murmurs may be graded accordingtothe following criteria

1. Very soft (just audible under optimal conditions).

2. Soft.

3. Moderate (easily heard with a stethoscope).

4. Loud ± palpable thrill.

5. Very loud/ palpable thrill.

6. Heard without a stethoscope/ palpable thrill.

Innocent murmurs are generated by turbulent ow such as in high cardiac

output states, e.g. pregnancy, fever, anaemia, and thyrotoxicosis. They have

the following characteristics:

•

No accompanying thrill.

• Never > grade3.

• Systolic.

• Maximal at the left sternaledge.

• Normal heart sounds.

• Normal pulses, ECG, andCXR.

Systolic murmurs are synchronous withthe carotid pulse and causedby

•

Abnormal regurgitation through a structure that is normally closed in

systole, e.g. AV valve, septum (pansystolic).

•

Normal systolic ow through a narrowed or stenosed valve, e.g. aortic

valve, pulmonary valve (ejection systolic).

CHAPTER1 Symptoms andsigns

HEART SOUNDS AND MURMURS

Diastolic murmurs are audible afterthe carotid pulse and arisefrom

•

Incompetence of the cardiac outow valves, e.g. aortic or pulmonary

valves.

•

Narrowing of the cardiac inow valves, e.g. mitral or tricuspid valves.

Mixed murmurs (systolic and diastolic) arisefrom

•

Mixed valvular disease (stenosis and regurgitation).

• Patent ductus arteriosus.

Murmurs arising from left heart structures are accentuated in expiration,

whereas right heart murmurs are augmented in inspiration (see Table1.9).

Table 1.8 Heart murmurs

Pansystolic

murmur

S1 S2

1 S2

S1 S2

S1 S2 S1

Mitral regurgitation

Tricuspid regurgitation

VSD

Late

systolic

murmur

Mitral valve prolapse

Hypertrophic obstructive

cardiomyopathy

Aortic coarctation

Ejection

systolic

murmur

Aortic stenosis

Pulmonary stenosis

Early

diastolic

murmur

Aortic regurgitation

Pulmonary regurgitation

Mid-

diastolic

murmur

Mitral stenosis

Tricuspid stenosis

Mixed

murmur

Mixed valvular heart

disease

Patent ductus arteriosus

AVMs

Collateral circulations

CHAPTER1 Symptoms andsigns

Table 1.9 Added heart sounds

A2 S3

S1 P2

S1 P2A2

S1 P2A2 OS

S1 P2A2EC

2P1SA2MSC

2P1SP PS2

Normal (young adult)

Left ventricular failure

Right ventricular failure

Mitral regurgitation

Constrictive pericarditis

(pericardial ‘knock’)

Normal (elderly)

Left ventricular hypertrophy

Left ventricular diastolic dysfunction

Systemic hypertension

Aortic stenosis

Acute ischaemia

Mitral stenosis

Tricuspid stenosis

Opening

snap

Aortic stenosis

Systemic hypertension

Pulmonary stenosis

Pulmonary hypertension

Ejection

click

Mitral valve prolapseMid-

systolic

click

Arti cial valve replacementProsthetic

heart

sounds

HEPATOMEGALY

Hepatomegaly

Measure the liver edge below the (right) costal margin after percussing out

the upper and lower borders. Bruits may be heard in hepatoma and a fric-

tion rub may occur with malignant deposits. Other signs may suggest the

underlying diagnosis (E Pitfalls below).

Commoncauses

• CCF.

• Malignant deposits.

• Hepatitis/ cirrhosis (usually alcoholic or infectious, e.g. Epstein– Barr

virus (EBV), viral hepatitis).

Foreign residence?

If so, consider amoebic and hydatid cysts, schistosomiasis, and malaria.

Investigations

• FBC, lm, LDH (leukaemia, lymphoma).

• ESR.

• Virology (EBV, CMV, and hepatitis A, B, and C antibody serology).

• LFTs— transaminases.

• Serum albumin.

• Prothrombin time (PT) (hepatocellular damage).

• γ- glutamyl transpeptidase (GGT), MCV (alcohol).

• ALP (obstructive causes; malignant deposits if isolatedi).

•

Serum Igs may be polyclonal i in immunoglobulin G (IgG) (autoimmune

hepatitis), immunoglobulin A(IgA) (alcoholic liver disease), or

immunoglobulin M (IgM)(PBC).

•

Serum protein electrophoresis (myeloma, amyloid).

• Reticulocytes, bilirubin (if i, suggests haemolysis).

•

Haemoglobinopathy screen (thalassaemia/ sickle disorders).

• USS to assess liver texture, splenomegaly, lymphadenopathy.

• CXR and cardiac investigations (cardiomyopathies, sarcoid).

• α- fetoprotein (AFP) (primary hepatocellular carcinoma).

• Serum ferritin, transferrin saturation, DNA analysis

(haemochromatosis).

•

Mitochondrial antibodies and autoimmune markers, e.g. ANA

(autoimmune hepatitis), ANCA (primary sclerosing cholangitis).

•

Caeruloplasmin, urinary copper (Wilson’s disease).

• α1- antitrypsin (α1- antitrypsin deciency).

• Porphyria screen.

Pitfalls

•

Hepatomegaly is a common sign but may not necessarily implicate liver

pathology.

•

End- stage cirrhosis may commonly present with a small, shrunkenliver.

E OHCM 10e, p.63, p.604.

CHAPTER1 Symptoms andsigns

Herpeszoster

The pattern of the eruption varies from mild to dense with the involvement

of several dermatomes. Complications may occur if involvement of the

eye, motor nerves, and autonomic nerves (bladder), or when the disease

presents as an encephalomyelitis or purpura fulminans.

3 In the immunocompromised host, zoster is more likely both to occur

and to disseminate.

Investigations

• Conrm the diagnosis by isolation of the virus from the vesicularuid.

• Consider underlying disorders if recurrent or severe attacks.

• Look for lymphadenopathy (Hodgkin’s or other lymphoma).

• FBC, blood lm, LDH (i in lymphoma).

•

Serum protein electrophoresis (myeloma, amyloid).

• Serology for HIV (zoster is common in adult HIV individuals).

• Immunodeciency work- up.

Pitfalls

The rash is not always unilateral— it may be bilateral.

E OHCM 10e, p.462.

HYPERLIPIDAEMIA

Hyperlipidaemia

Abnormalities of lipid metabolism are common in Western societies.

Populations with high levels of cholesterol have high rates of vascular

morbidity, especially cardiovascular disease (CVD), and premature death.

Vascular risk can be estimated from published risk tables or calculators.

Various classications of hyperlipidaemia exist, each with a characteristic

lipid prole. Many patients with lipid disorders have cutaneous markers,

which identify to a certain extent the type of lipid abnormality.

Clinical features

Lipid abnormalities may cause dermatological manifestations

•

Grey- yellow plaques or xanthomata in tendons, especially the forearm

and Achilles. Usually indicative of elevated low- density lipoprotein

(LDL) cholesterol.

•

Corneal arcus, a thin white rim around the iris— whilst this is common in

the elderly, it is not a sign of i LDL, except in the under40s.

•

Yellow, fatty deposits or xanthelasmata around the eyelids— associated

with elevated LDL, these painless, non- tender plaques are common in

the elderly.

•

Yellow streaks in palmar creases— palmar xanthomata are associated

with IDL cholesterol.

•

Plaques over tibial tuberosities and elbows— tubero- eruptive

xanthomata. Often seen with hepatosplenomegaly with elevated

triglycerides.

•

Eruptive xanthomata— in severe triglyceridaemia, associated with

pancreatitis and hepatomegaly.

Hyperlipidaemia may be 2° to drugs such as corticosteroids, oestrogens,

and progestogens, as well as a range of conditions such as hypothyroidism,

myeloma, and alcoholism, each of which may be associated with specic

clinicalsigns.

CHAPTER1 Symptoms andsigns

Hypertension

Blood pressure (BP) measurements are graded into a number of categories

by the British Hypertension Society (see Box1.1):

Optimal blood pressure

Normal blood pressure

High- normal blood pressure

Grade 1 hypertension(mild)

Grade 2 hypertension (moderate)

Grade 3 hypertension (severe)

<120/ 80

<130/ 85

130– 139/ 85– 89

140– 159/ 90– 99

160– 179/ 100– 109

≥180/ 110

Hypertension should not be diagnosed on the basis of a single BP reading.

Unless urgent treatment is required, e.g. malignant hypertension, the BP

should be rechecked over a number of weeks to conrm the presence of

sustained hypertension.

Causes

Remember that the cause of hypertension in most (95%) cases is unknown

(‘essential’ hypertension). One of the following identiable causes can be

found in the remaining5%:

•

Renal disease, e.g. polycystic kidney disease.

• Renovascular disease, e.g. renal artery stenosis(RAS).

• Endocrine disease, e.g. Cushing’s syndrome, Conn’s syndrome,

phaeochromocytoma, acromegaly.

•

Coarctation of theaorta.

• Drugs, e.g. NSAIDs, OCP, steroids, erythropoietin (Epo),

sympathomimetics, liquorice.

•

Pregnancy, e.g. pre- eclampsia, eclampsia.

Routine investigation

The investigation ofhypertensive patients has thefollowingaims

•

To conrm the presence and severity of hypertension.

• To assess overall cardiovascularrisk.

• To identify target organ damage.

• To identify 2° causes (where present).

Routine investigations should include

•

Urinalysis (protein, blood, glucose).

• U&E.

• Plasma glucose (ideally fasted).

• Lipid prole (ideally fasted).

• 12- leadECG.

Box 1.1 British Hypertension Society grading

ofhypertension

HYPERTENSION

CXR, urine microscopy and culture, and echocardiography are not required

routinely but should be considered where indicated by your initial assess-

ment and investigation of the patient. The use of 24h ambulatory BP

monitoring is often useful where clinic readings are thought to be unreliable

because of ‘white coat’ hypertension.

Further investigation

Where more detailed assessment is required (for instance, to rule out a 2°

cause or to identify end- organ damage), the following investigations may

be appropriate:

Renal investigations

•

Renal USS (to assess overall renal morphology).

• Renal artery Doppler studies (forRAS).

• Renal artery magnetic resonance (MR) imaging (forRAS).

• Captopril renogram (forRAS).

• Renal angiography (forRAS).

• Renal vein renin measurements (for Conn’s syndrome).

Endocrine investigations

•

Renin and aldosterone studies for Conn’s syndrome (consult your local

endocrine laboratory).

•

Investigations for Cushing’s syndrome.

• Investigations for acromegaly.

• Urinary catecholamine (and metabolite) excretion.

Further reading

Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of

the fourth working party of the British Hypertension Society, 2004— BHS IV. J Hum Hypertens

2004; 18

:139– 85.

CHAPTER1 Symptoms andsigns

Incontinence:faecal

E Alteration of bowel habit, p. 9; E Constipation, pp. 29–30; E Diarrhoea,

pp. 32–3.

Causes include

• Any cause of diarrhoea (E OHCM 10e, Chapter6).

•

Overow diarrhoea from severe constipation.

• IBD (acute or chronic).

• Coeliac disease (diarrhoea is a variable feature).

• Infectious diarrhoea (E OHCM 10e, Chapter1).

•

Hyperthyroidism (may cause diarrhoea; rare cause of incontinence).

• Carcinoma of the colon (stricture).

• Diverticular disease of the colon (acute attack, chronic stricture).

• Neurological (multiple CVAs, MS, spina bida, post- childbirth

neuropathy) may often be associated with sphincter disturbances.

•

Drugs, e.g. laxatives, orlistat (causes fat malabsorption).

• Causes of steatorrhoea (E OHCM 10e, Chapter6).

•

Intestinal hurry, e.g. post- gastrectomy (E OHCM 10e, Chapter6).

•

Diabetic diarrhoea (autonomic neuropathy— rare; diagnosis of exclusion

but may cause nocturnal faecal incontinence).

•

VIPoma (veryrare).

Investigations

Non- invasivetests

• Stool cultures (ova cysts, parasites). Note:Clostridium dicile— relatively

common in patients who have received recent antibiotic therapy.

•

FBC (anaemia, especially iron deciency).

• CRP.

• ESR.

• U&E.

• TFTs.

Imaging

•

Pelvic/ abdominalX- ray.

• Bariumenema.

• CT abdomen.

Procedures

•

Colonoscopy.

• Sigmoidoscopy ± biopsy.

E OHCM 10e, p.58.

INCONTINENCE:URINARY

Incontinence:urinary

E Anuria,p. 14.

Consider

• Common causes of polyuria (E OHCM 10e, Chapter7); these may

present as, or aggravate, urinary incontinence.

•

Acute or chronic confusional state (common; loss of voluntary sphincter

control).

•

UTI (very common— always exclude).

• Drug- induced, e.g. thiazide or loop diuretics; α- adrenergic blockade, e.g.

doxazosin (uncommon).

•

Psychological, e.g. severe depression.

• Immobility, e.g. PD (Shy– Drager syndrome is uncommon).

• Other causes of autonomic neuropathy (E OHCM 10e, Chapter10).

•

Detrusor muscle instability.

• Urethral incompetence.

• Stool impaction.

• Spinal cord compression.

• Tabes dorsalis.

Investigations

• U&E.

• Urinalysis for blood, protein, glucose, nitrates, and nitrites.

• MSU for culture and sensitivity(C&S).

• Plasma glucose (if glycosuria).

• SerumCa

In selected patients, consider referral to urology or gynaecology services

for considerationof:

•

Bladder manometry studies.

• Post- voiding USS of the bladder.

• Pelvic imaging, e.g. CTscan.

E OHCM 10e, pp. 648–9.

CHAPTER1 Symptoms andsigns

Indigestion

This term is often loosely used by patients to describe a variety of symp-

toms. These are often regarded as representing relatively minor, and usually

intermittent, pathology. However, serious pathology, e.g. carcinoma of the

stomach, may present as a vague complaint of ‘indigestion’. The symptoms

may be retrosternal or abdominal. Adetailed history is essential, focusing

on features that raise the probability of serious pathology, e.g. dysphagia

and weightloss.

Examination

Examination should include a search for the following signs, particularly in

the middle- aged and elderly patients:

• Anaemia (especially iron deciency— common).

• Ascites.

• Troisier’s sign (malignant involvement of the left supraclavicular lymph

nodes due to carcinoma of the stomach— rare).

Note:the presence of associated pathologies, e.g. pernicious anaemia (E

OHCM

10e, Chapter8)— i risk of stomach cancer— will alter the threshold

for more detailed expert investigation. Carcinoma of the stomach is com-

moner in Japanese.

Peptic ulceration may have classic elements that point to the diagnosis.

Non- ulcer dyspepsia is very common and is often treated empirically with

antacids, H

receptor antagonists, or H

pump inhibitor drugs. The clinical

challenge is to identify the patient for whom more detailed, and often inva-

sive, investigation is indicated.

Alternative causes, e.g. cardiac ischaemia, should be considered in the

dierential diagnosis; similarities of the symptoms between cardiac and

upper GI disorders are well recognized and sometimes pose considerable

diagnostic diculties.

Causes include

• Oesophageal acid reux.

• Hiatus hernia.

• Inammatory disease.

• Peptic ulcer disease of the duodenum or stomach.

• Biliary colic (usually distinctive clinical features).

• Malignancy of the oesophagus, stomach, or rarely small intestine.

• Cardiac symptoms, usually ischaemia.

• IBS.

• Symptoms arising from other structures within the chest or abdomen.

Investigations

• FBC.

• U&E.

• ESR.

• Upper GI endoscopy ± tissue biopsy.

• LFTs.

• CK if MI/ acute coronary syndrome (ACS) suspected.

• Troponin (T or I) if MI/ ACS suspected.

INDIGESTION

• Serum amylase (normal in chronic pancreatitis; may be i by a duodenal

ulcer eroding the posteriorwall).

•

Barium swallow and meal (for oesophageal disease).

• CLO test for Helicobacter pylori.

•

Urea

C breath test for H.pylori.

•

USS of the biliary tract (E Ultrasound, p. 802).

•

Cholecystogram.

If diagnosis remains uncertain, consider

• CT abdomen (discuss with a radiologist).

• Serum gastrin (Zollinger– Ellison syndrome, E OHCM 10e, p.716).

•

24h ambulatory oesophageal pH monitoring.

• Oesophageal manometry (oesophageal motility disorders).

CHAPTER1 Symptoms andsigns

Infective endocarditissigns

Infective endocarditis is characterized by infection of the endocardial sur-

face of the heart. The left heart valves are the most commonly aected,

but the right heart valves and congenital heart lesions, such as VSDs, may

also become infected. Vegetations (composed of the organism, white cells,

platelets, and brous tissue) are formed at the site of infection. They give

rise to periodic septicaemia and may embolize to other parts of the body.

There is gradual destruction of the valve with i valvular dysfunction, regur-

gitation, and heart failure.

Clinical features

• Pyrexia (low- grade or swinging).

• Pale conjunctivae suggestive of anaemia (of chronic disease).

• Clubbing (chronic low- grade infection).

• Cardiac murmur (new or changing).

• Left or right heart failure.

• Splenomegaly (friction rub if splenic infarction is present).

• Microscopic haematuria (on urinalysis).

Embolic phenomena

Embolic phenomena are common and produce clinical signs classically asso-

ciated with infective endocarditis:

•

Splinter haemorrhages (>5, sited in the proximal nger and

toenailbeds).

•

Janeway lesions (palmar macular spots).

• Osler’s nodes (painful nodules on the palmar surface of the ngers

ortoes).

•

Roth spots (retinal haemorrhages).

• Conjunctival haemorrhages.

• Microvascular infarction (in the distal limbs).

Further reading

Prendergast BD. Diagnostic criteria and problems in infective endocarditis. Heart 2004; 90:611– 13.

Task Force on Infective Endocarditis of the ESC. Guidelines on prevention, diagnosis and treatment

of infective endocarditis. Eur Heart J 2004; 25:267– 76.

IRREGULARPULSE

Irregularpulse

In health, the pulse is usually regular, although a minor degree of variation

in heart rate with respiration (sinus arrhythmia) is common, particularly in

children and young adults. In sinus arrhythmia, the heart rate i with inspira-

tion and d with expiration. This is a benign phenomenon.

An irregular pulse can present as a symptom (with the patient complain-

ing of an awareness of irregular or ‘missed’/ ‘extra’ heartbeats) or as a sign

(incidental nding on clinical examination).

Pulse irregularities are traditionally classied

intotwogroups

• Regular irregularities.

• Irregular irregularities.

A regularly irregularpulse

Most commonly the result of ventricular or supraventricular ectopic activ-

ity. Ectopic beats often occur after a certain number of sinus beats— thus

in ventricular bigeminy, every other beat will be a ventricular ectopic beat

and thus occur prematurely with reduced volume. In trigeminy, every third

beat will beearly.

A regularly irregularpulse

Can also be evident in second- degree AV block (Mobitz type IorII).

An irregularly irregular pulse is most commonly theresultof

•

Multiple ectopic beats (supraventricular or ventricular).

• AF.

• Atrial utter with variable AVblock.

Investigations

The key to diagnosis is to record an ECG, whilst the pulse irregularity is

present. If the paroxysmal irregularity is infrequent, this can prove challeng-

ing. A12- lead ECG is mandatory and may provide an immediate diagnosis.

If not, a number of ambulatory ECG monitoring techniques are available:

• 24h ambulatory ECG monitoring.

• Cardiac event monitoring.

• Implantable loop recorder(ILR).

The choice of technique should be guided by how frequently the irregularity

is thought tooccur.

Additional investigations depend upon the nature of the suspected

arrhythmia:

•

FBC.

• U&E.

• TFTs.

One may also consider

•

CXR (to assess heart size and valvular calcication).

• Echocardiogram (if structural heart disease suspected).

• Exercise treadmill test (if IHD suspected, or to provoke arrhythmias

thought to be exercise- related).

CHAPTER1 Symptoms andsigns

Jaundice

This denes the yellow discoloration of the sclerae, mucous membranes,

and skin that occurs when bilirubin accumulates. Bilirubin is the major bile

pigment in humans and is produced as an end- product of haem catabolism.

Jaundice usually only becomes noticeable when the serum bilirubin level

is>30– 60µmol/ L.

Causes

(See Table1.10.)

•

Can be pre- hepatic, hepatic, or post- hepatic.

• Haemolysis.

• Hepatitis (viral, drugs, alcohol).

• Pregnancy.

• Recurrent cholestasis.

• Hepatic inltration.

• Stones in the common bileduct.

• Carcinoma of the bile duct, head of the pancreas, or ampulla.

• Biliary strictures.

• Sclerosing cholangitis.

• Pancreatitis.

Investigations

(See Fig.1.2.)

•

FBC (? haemolysis).

• Clotting screen (often deranged in liver disease).

• LFTs.

• Viral serology for hepatitis Avirus (HAV), hepatitis B virus (HBV), and

hepatitis C virus(HCV).

•

USS abdomen.

• Consider endoscopic retrograde cholangiopancreatography (ERCP).

• Liver biopsy may be indicated, depending on history, examination, and

laboratory ndings. Discuss with the gastroenterology team before

embarking onthis.

E OHCM 10e, pp. 272–3.

Table1.10 Common causes ofjaundice

Cholestatic

Pre- hepatic Intra- hepatic Post- hepatic

Haemolysis

Gilbert’s syndrome

Crigler– Najjar syndrome

Dubin– Johnson syndrome

Viral hepatitis

Drugs

Alcoholic hepatitis

Cirrhosis (anytype)

Pregnancy

Recurrent idiopathic

cholestasis

Inltration (e.g.

amyloidosis, etc.)

Gallstones

Carcinoma (biliary tree,

head of pancreas, ampulla)

Biliary stricture

Sclerosing cholangitis

Pancreatic pseudocyst

JAUNDICE

Non-dilated ducts

Dilated ducts

MRCP/ERCP

Conjugated Unconjugated

Hepatocellular Cholestatic

Investigate pre-

hepatic cause

Blood tests ±

liver biopsy

Ultrasound

liver/bile ducts

iBilirubin

Fig.1.2 Investigation of jaundice.

CHAPTER1 Symptoms andsigns

Joint pain/ swelling

Covers a multitude ofdisorders including

• OA.

• RA.

• Tendinitis.

• Bursitis.

• Trigger nger.

• Mechanical low backpain.

• Fibromyalgia.

• Other arthropathies.

History and examination

• Ask about aected joints, site of origin, mono- or polyarticular, oligo-

articular (e.g. 2– 4 joints involved), migratory features, arthralgia (joint

pain without swelling).

•

Is the pain constant or intermittent?

• Aggravating or precipitating factors?

• Any associated neurological features?

• Is there swelling?

• Associated redness or excessive warmth?

• Drug history (e.g. diuretic- induced).

• Race (e.g. sickle).

• Past history.

• Family history.

• Occupational history.

• Social history.

Investigations

• FBC— a normochromic normocytic anaemia is common in chronic

inammatory disorders. May be microcytic if long- standing inammation

or associated iron deciency (e.g. induced by NSAIDs).

•

ESR— non- specic marker of inammation.

• CRP— as forESR.

• Biochemistry screen, especially looking at bone prole andLFTs.

• Consider serum Igs and protein electrophoresis (myeloma).

• Uric acid levels (gout).

• X- ray aected joint(s).

• Consider USS, especially if soft tissue swelling.

• MRI can be useful to help visualize intra- articular structures.

• CTscan.

• Bone scintigraphy (helps identify abnormal bone turnover).

• Dual X- ray absorptiometry (DEXA) scan (useful for diagnosis and

monitoring of osteoporosis).

•

Arthroscopy may help in selectedcases.

• Joint aspiration (allows culture and examination of uid for crystals).

JUGULAR VENOUSPULSE

Jugular venouspulse

The height and waveform of the internal jugular venous pulse ( JVP) reect

right atrial pressure and haemodynamics. The JVP should be inspected

with the patient positioned at 45° to the horizontal. The JVP may be distin-

guished from the carotid pulse by the following features:

•

Pulsation is not palpable.

• It may be compressed and obliterated by pressure.

• It rises on compression of the right upper quadrant (hepatojugular

reux).

•

It varies with posture.

• Height d with inspiration.

The height of the JVP is measured as the vertical distance between the

manubriosternal angle and the top of the venous pulsation. Elevation is

dened as>3cm.

There are several components of the jugular venous pulsation waveform.

The a wave is produced by atrial systole. This is followed by the x descent

at the end of atrial contraction. The x descent is interrupted by a small,

barely perceptible deection called the c wave. This deection is caused

by the rapid i in right ventricular pressure just before the tricuspid valve

closes. Asubsequent v wave results from the rise in right atrial pressure as

it lls with venous return during ventricular systole and whilst the tricuspid

valve remains closed. At the end of ventricular systole, the tricuspid valve

opens and the pressure in the right atrium falls, leading to the y descent

(see Table1.11).

CHAPTER1 Symptoms andsigns

Table 1.11 Jugular venous pulse waveforms

Description DiagramDiagnosis Comment

Normal

i JVP

Normal

waveform

Right heart

failure

Fluid overload

Pulmonary

embolus

Cardiac

tamponade

i right atrial

pressure

Absent a

wave

Atrial

 brillation

Poor atrial

contraction fails to

generate a waves

Large a

waves

Tricuspid

stenosis

Right

ventricular

hypertrophy

Resistance

to right atrial

emptying causes

i right atrial

pressure

Large ν

waves

Tricuspid

regurgitation

Re ux of blood

into the great

veins with right

ventricular

contraction

Cannon (a)

waves

Complete

heart block

Ventricular

tachycardia

Right atrium

contracts against

closed tricuspid

valves, creating a

cannon wave

Rapid y

descent

Constrictive

pericarditis

Cardiac

tamponade

Tricuspid

regurgitation

Right heart

failure

A steep y descent

is caused by right

ventricular

diastolic collapse

(Freidrich’s sign)

Absent

pulsation

i JVP

Superior

vena caval

obstruction

No right atrial

pressure can be

transmitted to

the JVP

LOINPAIN

Loinpain

Denition

Pain located in the renalangle.

Causes

• Uretericcolic.

• Renal or ureteric obstruction.

• Acute pyelonephritis.

• Renal infarction or papillary necrosis.

• Acute nephritis (uncommon).

• IgA nephropathy— pain caused by extension of the renal capsule.

• Musculoskeletal causes.

• Shingles at T10– 12 (obvious if a rash is seen on examination or

suspected if pain is in a dermatomal distribution).

•

Infection or bleeding into a cyst in polycystic kidneys.

• Vesico- ureteric reux— pain occurs when the bladder is full; this

worsens at the initiation of micturition and then is rapidly relieved on

voiding.

•

Loin pain- haematuria syndrome— this is recurrent pain which occurs in

young women. Angiography reveals tortuous vessels.

Investigations

• U&E.

• Serum creatinine.

• Creatinine clearance (CrC) (if renal impairment).

• FBC.

• ESR.

• Urine dipstick for protein, blood, nitrites, leucocytes.

• Urine microscopy (for casts).

• MSU for C&S testing.

• Blood cultures (if bacteraemia suspected).

• Plain X- ray (KUBview).

• IVU (e.g. if +ve urine dipstick for haematuria).

• Renal USS (useful for rapid, non- invasive exclusion of obstruction).

• CT of urinarytract.

• Angiogram (if suspicion of thrombus, embolus, or loin pain- haematuria

syndrome).

•

Serum IgA concentration.

• Cystoscopy (specialist procedure).

• Retrograde pyelography.

• Renal biopsy (only after specialist advice).

CHAPTER1 Symptoms andsigns

Lymphadenopathy

Lymph node enlargement may be localized or generalized (see Table1.12).

Localized cervical lymphadenopathy

• Local causes in the mouth (pharyngitis, dental abscess).

• Scalp (skin malignancies or disease).

• Nose (nasopharyngeal carcinoma).

Enlargement ofleft supraclavicularnodes

• May suggest carcinoma of the stomach.

Isolated posterior cervical node enlargement

• Is less often due to malignancy.

Othercauses

• Sometimes drugs may be associated with lymph node enlargement

(phenytoin, antithyroid).

Table1.12 Causes oflymphadenopathy

Infection

Viral

Infectious hepatitis, EBV syndromes, HIV, rubella, varicella,

herpes zoster

Bacterial Streptococcal, staphylococcal, salmonella, brucellosis,

Listeria

, cat- scratch (Bartonella)

Fungal Histoplasmosis, coccidioidomycosis

Chlamydial

Mycobacterial

Parasites Trypanosomiasis, microlaria, toxoplasmosis

Spirochaetes Syphilis, yaws, leptospirosis

Connective tissue

RA, SLE, dermatomyositis, serum sickness

Drugs e.g. phenytoin

Malignancy

Haematological

Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, acute

and chronic lymphoid malignancies (chronic lymphocytic/

lymphatic leukaema (CLL), acute lymphoblastic leukaemia

(ALL)), acute myeloid leukaemia (AML)

Non- haematological Metastases from carcinomas (breast, bowel, lung,

prostate, kidney, head and neck)

Endocrine Thyrotoxicosis

Miscellaneous Sarcoidosis, amyloidosis

LYMPHADENOPATHY

Investigations

• FBC, blood lm, LDH (leukaemia, lymphoma, Hodgkin’s).

• Serology/ virology/ microbiology/ other antigen detectiontests:

•

Viral (EBV, hepatitis, CMV,HIV).

•

Bacterial (TB, bacterial endocarditis, syphilis).

•

Fungal (histoplasmosis).

•

Protozoal (toxoplasmosis).

• ANA (collagen disorder, systemic lupus).

• TFTs (hyperthyroidism).

• CXR (sarcoid,TB).

• USS/ CT scan (to assess intra- abdominal, mediastinal/ hilar

lymphadenopathy).

•

LFTs/ hepatomegaly (i ALP suggests malignant deposits).

•

Lymph node biopsy (groin nodes should usually be avoided because

commonly enlarged due to skin and infectious disorders).

•

BM (may conrm haematological malignancy).

Note:FNA, although easier to perform, may not be diagnostic and lymph

node biopsy should be considered for microbiology and histology.

E OHCM 10e, p.35, p. 594.

Although we have provided a large list of possibilities, common sense

should be used in determining the cause. For example, an 80- year- old

woman with axillary lymphadenopathy is unlikely to have cat- scratch dis-

ease! Common things are common.

CHAPTER1 Symptoms andsigns

Nausea

The so- called vomiting centre is located in the medulla oblongata and is

stimulated by the chemoreceptor trigger zone in the fourth ventricle. There

are many causes of acute and chronic nausea. These can be divided into GI

and non- GI causes.

GI causes ofnausea

• Food poisoning (viral, bacterial— common).

• Acute and chronic gastritis (remember H.pylori).

•

Peptic ulceration.

• Biliary and renalcolic.

• IBD.

• Cholecystitis.

• Appendicitis.

• Pancreatitis.

• Gastric outow obstruction.

• Post- gastrectomy syndrome.

• Acute liver failure.

• Pseudo- obstruction of thebowel.

Investigations

•

U&E.

• LFTs.

• ESR.

• CRP.

• Serum or urinary amylase.

• AXR (erect and supine— beware perforated viscus).

•

AbdominalUSS.

Consider:

•

OGD.

• Barium swallow andmeal.

• Isotopic gastric emptying studies.

• Oesophageal manometry.

• Oesophageal muscle biopsy (rarely indicated).

Non- GIcauses

• Acute infections, e.g.UTI.

• Metabolic disorders, including:

•

Hypercalcaemia.

•

Ketoacidosis (diabetic, alcoholic).

•

Uraemia.

• Pregnancy. Note:hyperemesis gravidarum may be associated with i free

T4 (FT4), d

thyroid- stimulating hormone(TSH).

• Many drugs, notably opiates and digoxin toxicity (check serum levels).

• MI (nausea common; exacerbated by opiates).

• Acute glaucoma.

NAUSEA

Investigations

•

FBC.

• ESR.

• Venous plasma glucose.

• Urine dipstick(UTI).

• SerumCa

•

Serum drug levels, e.g. digoxin, theophylline.

• 12- leadECG.

• CK.

• TroponinI.

Neurologicalcauses

• Acute migraine.

• iICP.

•

Acute labyrinthine lesions.

• Ménière’s disease.

• Cerebellar lesions (e.g. infarct, haemorrhage, metastases,

demyelination).

Investigations

•

CranialCT.

• MRI if cerebellar lesion suspected.

• Tilt table test (E Tilt table testing, pp. 494–5).

•

Audiometry (specialist technique).

E OHCM 10e, p.70. Nystagmus.

CHAPTER1 Symptoms andsigns

Neck stiness

The main concern in a patient with neck stiness is that s/ he may have

meningitis which may result from infection or may reect inltration by a

disease such as acute leukaemia.

Causes

• Bacterial infection.

• Viral infection.

• Fungal infection.

• TB.

• Inltration by malignancy (e.g. acute lymphoblastic leukaemia (ALL),

high- grade lymphoma, or sometimes acute myeloid leukaemia (AML)).

• Drug- induced.

• Contrast media (myelogram).

• Blood (e.g. post- SAH).

• Mechanical/ trauma.

• Connective tissue disease, e.g.RhA.

Investigations

• CT scan of brain ± contrast.

• LP if noiICP:

•

Glucose.

•

Protein.

•

M,C&S ± TB culture.

•

Xanthochromia if SAH suspected.

• If patient immunocompromised, consider:

•

Polymerase chain reaction (PCR) for viruses, e.g. herpes simplex

virus(HSV).

•

Toxoplasma serology.

•

India ink stain for Cryptococcus.

•

If considering malignancy, send cerebrospinal uid (CSF) for cytospin.

E OHCM 10e, p.478.

NYSTAGMUS

Nystagmus

An involuntary oscillatory or (more commonly) rapid jerking movement

of the eyes that is rhythmic and repetitive. It results from acute or chronic

lesions of the eight cranial nerves, brainstem, or cerebellum. The ‘slow’

phase is pathological, the rapid, rhythmic jerking phase (used arbitrarily to

dene the direction of nystagmus) being a corrective response. Nystagmus

‘to the right’ describes the direction of the quick phase. Such ‘sawtooth’

nystagmus may be evident in the horizontal or vertical plane (includ-

ing ‘downbeat’ nystagmus of foramen magnum lesions) or as oscillations

around a central point (e.g. in albinism).

Jerk nystagmus

Jerk nystagmus may be graded in severity, depending on whether:

•

It occurs only in the direction of directedgaze.

• It occurs when eyes are in the midline,or

•

It is present even on looking in a direction contralateral to the rapid

movement.

Note:nystagmus (or, more correctly, nystagmoid jerks) may be induced by

inappropriate testing, often being present at the extremes of gaze. Do not

ask the patient to follow a visual target beyond 730° of the midline when

testing at the bedside.

In unilateralcauses

Cerebellar nystagmus

Greatest when gaze directed towards the side of the destructive lesion.

Vestibular nystagmus

Greatest away from the side of the lesion.

Pathological nystagmus

May be due to labyrinthine and vestibular lesions— occurs in one direction

only. If visual xation is removed, nystagmus becomesworse.

Central lesions

Including brainstem lesions caused by, e.g. tumour, MS; cerebellar lesions or

medial longitudinal fasciculus lesions leading to internuclear ophthalmople-

gia (E OHCM 10e, Chapter10) with ataxic nystagmus.

Investigations

• Positional nystagmus may be investigated by using the Hallpike

manoeuvre (E OHCM 10e, Chapter10). Abrupt alteration of the

spatial position of the head (from supine, with the head below the bed,

rapidly to a sitting position) will induce nystagmus. This will demonstrate

benign positional vertigo (common), vestibular disorders, or brainstem

lesions.

•

Audiometry (specialized investigation).

• Auditory and visual evoked potentials (VEPs) may be pathologically

reduced in MS. Examination of CSF may reveal oligoclonal bands

(OCBs).

CHAPTER1 Symptoms andsigns

• MRI to include the brainstem. (Upbeat nystagmus will suggest a midbrain

lesion and downbeat nystagmus will suggest a foramen magnum lesion.)

MRI is superior to CT for demonstrating cerebellopontine angle lesions.

Gadolinium enhancement is used to investigate acoustic neuromas.

•

Ototoxicity can be caused by some drugs such as gentamicin and

phenytoin. Acute poisoning with alcohol or barbiturates may cause

transient nystagmus. Chronic alcoholism can lead to permanent

cerebellar damage. Excessive doses of anticonvulsant drugs, e.g.

phenytoin, are a common cause— measure serum concentrations of

thedrug.

E OHCM 10e,p.70.

OBESITY

Obesity

The World Health Organization (WHO) denes obesity as a body mass

index (BMI) >30kg/ m

(Table1.13).

Note

:central (abdominal) fat distribution— commoner in men— is associ-

ated with greater health risks. The waist- to- hip ratio, or simply the waist

girth, can be used to identify levels at which long- term health risks warrant

intervention (see Box1.2):

Aetiology

The great majority of obese subjects have no identiable metabolic or

hormonal defects and detailed investigation is rarely indicated. A chronic

imbalance of the equation with energy intake (dietary calories) on the one

hand and expenditure (resting metabolic rate + physical activity) on the

other is thought to be responsible. Reduced levels of habitual activity allied

to an abundance of energy- dense foods appears to account for the current

pandemic of obesity and related disorders:

•

Impaired glucose regulation.

• Type 2 diabetes mellitus(DM).

• Dyslipidaemia.

• Hypertension.

• CVD.

• OA.

• Impaired physical functioning.

• Gout.

• i surgicalrisk.

•

Depression.

• Certain cancers, e.g. bowel, breast.

Weight gain tends to occur in middle age; ♀ are more at risk than ♂. Socio-

economic factors are also important.

Table1.13 BMI

BMI (kg/ m2)

Underweight <18.5

Normal

18.5– 24.9

Overweight >25.0– 29.9

Obesity Class I 30.0– 34.9

II 35.0– 39.3

III >40

Box 1.2 WHO BMI gradingsystem

Men

Women

>102cm

>88cm

CHAPTER1 Symptoms andsigns

Speciccauses

Genetic

•

For example, Prader– Willi syndrome, Laurence– Moon (Biedl– Bardet)

syndrome.

Single gene defects

•

For example, mutations of leptin (provides feedback from adipocytes to

the hypothalamus about body fat stores) or its hypothalamic receptor

(veryrare).

Hypothalamic lesions

•

Lesions which damage the ventromedial nucleus (the ‘satiety’ area) may

lead to obesity.

Lesions include

•

Trauma.

• Tumours— craniopharyngiomas and astrocytomas.

• Inammation— such as TB and meningitis.

• Inltration— histiocytosis and sarcoidosis.

Cushing’s syndrome

•

With ‘bualo’ hump and central obesity.

Hypothyroidism

•

Disputed, unless severe myxoedema, but hyperthyroidism is associated

with unphysiological weightloss.

Insulinoma

•

Often associated with moderate weight gain;rare.

Marked decreased motor inactivity

•

For example, severe mental retardation or physical disability.

Investigations

• Weight (calibrated scales).

• Height (stadiometer).

• Waist circumference (maximal).

• BP (large cu required).

• Venous plasma glucose (or oral glucose tolerance test (OGTT)).

• TFTs.

• LFTs (i non- alcoholic steatohepatitis in obese subjects).

• Fasting lipid prole (E Investigation of hyperlipidaemia, pp. 212–15).

•

Serumurate.

Additional investigations

These may occasionally be indicated if clinical features give cause for suspi-

cion of an organiccause:

•

Cranial CT or MRI of the pituitary and hypothalamus.

• Investigations for Cushing’s syndrome (E Obesity/ hypercortisolism,

pp. 142–6).

•

Genetic testing (seek advice of the genetics service).

Further reading

Lean MEJ, Han TS, Seidell JC. Impairment of health and quality of life in men and women with a larger

waist. Lancet 1998; 351:853– 6.

OLIGURIA

Oliguria

Causes

Acute renal failure (ARF)— distinguish pre- renal from renal and post- renal

causes.

Pre- renal

• Severe sepsis.

• Hypovolaemia, e.g. GI haemorrhage, diuretics.

• Burn injury.

• CCF.

• Addison’s disease.

• Acute pancreatitis.

Renal

• ATN (e.g. 2° to nephrotoxins such as aminoglycosides and radiological

contrast media).

•

Acute cortical necrosis.

• Renal infarction.

• Accelerated hypertension.

• Salicylate overdose.

• Hepatorenal syndrome.

Post- renal

• Renal calculi.

• Retroperitoneal calcinosis.

• Papillary necrosis.

• Bladder, prostate, and cervical tumours.

• Blocked urinary catheter (common!).

Investigations

• U&E.

• Serum creatinine.

• CrC.

• FBC.

• ESR.

• Autoimmune prole.

• LFTs.

• Urinary Na

excretion (<20 pre- renal, >40ATN).

• Urine osmolality (>500mOsmol/ L=pre- renal, <350mOsmol/

L=ATN).

•

Urine dipstick for blood, protein, nitrites, and leucocytes.

• Urine microscopy forcasts.

• Renal USS (± biopsy in selected cases).

• IVU.

• CT pelvis.

• Investigation of renal stones:

•

Serum Ca

, phosphorus.

•

24h excretion of oxalate, calcium, creatinine.

E OHCM 10e, p.81, p.293, p.576.

CHAPTER1 Symptoms andsigns

Palpitations

Patients generally use the term palpitations to refer to an awareness of

an abnormally fast, forceful, or irregular heart rhythm. Palpitations can be

physiological, as in the fast and/ or forceful heart rhythm felt with exercise

or anxiety, or pathological.

Common arrhythmias

Supraventricular arrhythmias

•

Sinus tachycardia (E Causes of sinus tachycardia, pp. 110–11).

•

AF.

• Atrial utter.

• Atrial tachycardia.

• AV re- entry tachycardias.

• Supraventricular ectopics.

Ventricular arrhythmias

•

Ventricular tachycardia.

• Torsades de pointes.

• Ventricular ectopics.

Investigations

The key to diagnosis is to record a 12- lead ECG, whilst palpitations are pre-

sent. Although simple in principle, infrequent paroxysmal palpitations can

make this very challenging. A12- lead ECG is mandatory and may provide

an immediate diagnosis if the patient is experiencing palpitations as it is per-

formed. As well as assessing the heart rhythm, it is important to inspect the

12- lead ECG for evidence of abnormal AV conduction (short PR interval,

pre- excitation) or abnormal repolarization (long QT interval). Check also

for evidence of an underlying structural heart disease, e.g. pathological Q

waves indicative of a previousMI.

If the patient’s palpitations are paroxysmal, a number of ambulatory ECG

monitoring techniques are available:

•

24h ambulatory ECG monitoring.

• Cardiac event monitoring.

• ILR.

The choice of technique should be guided by how frequently the

palpitationsoccur.

Additional investigations depend upon the nature of the suspected

arrhythmia. It is generally prudent tocheck:

•

FBC.

• U&E.

• TFTs.

One may also consider:

•

CXR (to assess heart size and valvular calcication).

• Echocardiogram (if structural heart disease suspected).

• Exercise treadmill test (if IHD suspected, or to provoke arrhythmias

thought to be exercise- related).

E OHCM 10e,pp. 36–7, p. 94.

PANCYTOPENIA

Pancytopenia

Pancytopenia (d Hb, d WBC, and d platelets) may occur because of bone

marrow failure (hypoplasia) or inecient production (myelodysplastic syn-

drome (MDS)) or peripheral destruction of cells or sequestration (spleno-

megaly/ hypersplenism).

3 Pancytopenia usually means something is seriouslywrong.

Bone marrow assessment is necessary to establish whether the mar-

row is hypocellular or hypercellular in the face of peripheral blood pan-

cytopenia. If hypercellular, the cause may be an inltrative process (due

to leukaemia/ carcinoma, granulomatous disease, brosis– myelobrosis,

osteosclerotic– osteopetrosis, increased macrophages– haemophagocytic

syndromes due to viral infections). Causes of hypoplastic bone marrow

failure may be hereditary (e.g. Fanconi’s anaemia) or acquired (e.g. drugs).

Critically ill patients may develop pancytopenia for multiple reasons (sepsis,

haemorrhage,DIC).

Investigations

• FBC, lm (aplastic anaemia usually presents with d lymphocyte count,

but minor morphological changes).

•

Reticulocytes (d if production failure).

•

Serum vitamin B

, folate (megaloblastic anaemia can be associated with

pancytopenia).

•

Serology for EBV, hepatitis A, B, and C, HIV (associated with aplastic

anaemia).

•

Serology for parvovirus infection (if pure red cell aplasia, also consider

lymphoma, thymoma).

•

ANA (lupus).

• Neutrophil alkaline phosphatase (NAP) score (i in aplastic anaemia).

•

Check for lymphadenopathy, hepatomegaly, and splenomegaly.

• CXR (bronchial carcinoma, sarcoid, TB, lymphoma).

• USS/ CT to assess lymphadenopathy/ splenomegaly (pancytopenia may

be due to hypersplenism and portal hypertension).

•

Ham’s test for paroxysmal nocturnal haemoglobinuria (PNH) or cell

marker analysis of CD55 andCD59.

•

Bone marrow (BM) aspirate and cytogenetics (myelodysplasia is a clonal

disorder).

E OHCM 10e, p.364.

CHAPTER1 Symptoms andsigns

Paraesthesiae

This may be described by the patient as an abnormal sensation of aching,

pricking, tickling, or tingling commonly in the extremities or face. Often

described as feeling like ‘pins and needles’.

The selection of investigations will be determined largely by the history

(transient? chronic?), the surface anatomical site of the abnormal sensa-

tion, and associated symptoms or precipitating factors (e.g. clear history of

hyperventilation).

The common causes include the numbness or tingling associated with

pressure on the peripheral nerves, such as caused by sleeping awkwardly on

an arm (‘Saturday night palsy’ of the radial nerve), or chronic or recurrent

pressure, e.g. on the ulnar nerve at theelbow.

If paraesthesiae is persistent, consider the following conditions, depending

on the distribution of the symptoms:

•

Carpal tunnel syndrome (with radiation proximally along the forearm;

worse at night).

•

Peripheral neuropathy (DM, alcohol, drug- induced; E OHCM 10e,

Chapter10).

•

Sciatica (reduced straight leg raising).

• Meralgia paraesthetica (lateral cutaneous nerve of the thigh).

• Lateral popliteal palsy (common peroneal nerve).

Other less common causes

Peripheral neuropathydueto

•

DM.

• Vitamin B

or B

deciencies.

•

Chronic renal failure.

• Chronic hepatic failure.

• Malignancy.

• Neurotoxicdrugs:

•

Vinca alkaloids.

•

Metronidazole.

•

Nitrofurantoin.

•

Isoniazid (pyridoxine- dependent).

• Environmental toxins.

• Hypothyroidism.

• GBS (acute).

• Certain porphyrias.

• MS.

Acute hypocalcaemia causes a characteristic perioral paraesthesiae and

can be due to many causes, including ° and 2° hypoparathyroidism and

alkalosis.

PARAESTHESIAE

General investigations

• ABGs (acute or chronic acid– base disturbances leading to alterations in

ionizedCa

•

Serum Ca

(not all laboratories measure ionizedCa

•

Serum parathyroid hormone (PTH) (uncued sample).

• Serum Mg

(see below).

•

Venous plasma glucose.

• Vitamin B

(and other investigations in suspected chronic peripheral

neuropathy).

If serum calcium or magnesium concentrationislow

Identify thecause:

•

Chronic GI loss (stula, excessive diarrhoea, bowel obstruction).

• Chronic renal loss (diuretic drugs, intrinsic renal disease).

• DKA— total body Mg

may be low, but this very rarely causes

symptoms.

Additional investigations

•

UrinaryMg

Consider

•

USS abdomen/ renal tract and subsequent GI investigations.

• U&E.

• Nerve conduction studies(NCS).

• TFTs.

• IGF- 1, growth hormone (GH) response during 75g- OGTT (if features

of acromegaly present; E Acromegaly (growth hormone excess),

p. 132).

CHAPTER1 Symptoms andsigns

Peripheral neuropathy

The patient will complain of numbness in hands and feet that progresses

proximally in a distribution classically termed ‘glove and stocking’. Dierent

aetiologies lead to a motor, sensory, or mixed sensorimotor picture.

Commoncauses

• Idiopathic (50%, commonest).

• DM.

• Vitamin B

deciency (may occur in the absence of anaemia).

•

Vitamin B deciency (e.g. alcoholics).

• Vitamin E deciency.

• Carcinomatous neuropathy.

• Drugs, e.g. isoniazid, vinca alkaloids, cisplatin, dapsone, gold,

metronidazole.

•

Paraproteinaemias (e.g. monoclonal gammopathy of undetermined

signicance (MGUS) or myeloma).

Rarercauses

• Amyloidosis.

• Uraemia.

• Collagen vascular diseases, e.g. rheumatoid, SLE, polyarteritis

nodosa(PAN).

•

Endocrine disease, e.g. myxoedema, acromegaly.

• GBS.

• Infections, e.g. tetanus, leprosy, diphtheria, botulism.

• Sarcoidosis.

• Hereditary, e.g. Charcot– Marie– Tooth disease.

• Acute intermittent porphyria.

• Toxins, e.g. lead (predominantly motor), arsenic (mixed sensory and

motor), mercury (sensory), and thallium (mixed sensory and motor).

•

Chronic inammatory demyelinating polyneuropathy.

• Hereditary motor and sensory neuropathy types IorII.

Investigations

• NCS to conrm the diagnosis.

Further investigations

• In order to determine the underlyingcause.

• Discuss with neurologysta.

E OHCM 10e, p.447.

PERIPHERALOEDEMA

Peripheraloedema

Swelling of the legs, or peripheral oedema, is a common presenting symp-

tom, which occurs when excess tissue uid is redistributed by gravity.

Severe oedema is usually pathological and swelling of the ankles may pro-

gress to ascites and even pleural and pericardial eusion.

Causes ofgeneralized swelling

• Cardiac failure:congestive heart failure, dilated cardiomyopathy,

constrictive pericarditis, cor pulmonale.

•

Hypoalbuminaemia:liver failure (hepatic cirrhosis), renal failure

(nephrotic syndrome), protein- losing enteropathy, malnutrition

(malabsorption or starvation).

Causes oflocalized swelling

• Immobility:common in old age, long- distance travel.

• Infection:cellulitis.

• DVT and/ or subsequent venous insuciency.

• Drugs:calcium channel blockers (nifedipine, amlodipine), NSAIDs.

• Malignancy:compression of deep vein, enlarged lymph nodes or

lymphatics.

•

Lymphatic obstruction:congenital, inltrative (lariasis).

• Milroy’s disease.

• Pregnancy.

• Wet beriberi.

• Idiopathic.

Patients atspecialrisk

• Pregnancy.

• Prolonged bedrest.

• Following removal of lower limb plastercast.

• Relative immobility:long- distance travel.

• CCF.

Investigations

These should be guided by the history and examination.

•

FBC.

• U&E.

• Albumin.

• ESR.

• Blood cultures.

• ECG.

• Echocardiography.

• Doppler studies of leg veins/ contrast venography (according to local

availability).

•

AbdominalUSS.

• Malignancy screen for common cancers.

• Urine dipstick for proteinuria.

• 24h urinary protein excretion or urine protein/ creatinineratio.

• Small bowel biopsy.

• Xylose breathtest.

CHAPTER1 Symptoms andsigns

Petechiae and thrombocytopenia

Spontaneous bleeding in the absence of trauma is uncommon with platelet

counts >20 × 10

/ L. However, bleeding is much more likely if thrombo-

cytopenia is not immune in origin (e.g. aplastic anaemia, acute leukaemia,

drug- induced, chemotherapy, myelodysplasia).

Thrombocytopenia may be inherited or acquired (e.g. DIC). As for pan-

cytopenia, these may be classied as due to a failure of production, or i

consumption in the peripheries (DIC, ITP), or abnormal tissue distribution

(splenomegaly).

ITP may be ° or 2° (e.g. lymphoma, lupus,HIV).

Drugs (e.g. heparin) and blood transfusion (post- transfusion purpura)

may cause severe thrombocytopenia.

Investigations

• FBC,lm:

•

Inherited causes may be associated with giant platelets.

•

Morphological abnormalities may suggestMDS.

•

Red cell fragments suggest thrombotic microangiopathies, e.g.TTP.

• LDH (i in thrombotic thrombocytopenic purpura (TTP) and

lymphoproliferative disorders).

•

Serum vitamin B

, folate (megaloblastic anaemia can be associated with

d platelets).

•

ANA, autoimmune screen, Igs (lupus, hyperthyroidism).

• Virology (HIV, EBV, viral hepatitis,CMV).

• Clotting screen(DIC).

• Lupus anticoagulant, cardiolipin antibodies (antiphospholipid antibody

syndromes).

•

Platelet serology for drug- or transfusion- related causes.

• BM assessment to establish whether thrombocytopenia is due to a BM

production problem or due to peripheral consumption (discuss with

the haematology team; depending on the degree of thrombocytopenia,

other haematological ndings, and the age of the patient, a marrow may

not be required).

Pitfalls

Thrombocytopenia due to HIV infection must be considered, especially

in all younger adults. Not worth checking platelet- associated IgG or IgM

since these are elevated in thrombocytopenia caused by immune and non-

immune mechanisms, so they add no useful information.

PLETHORA

Plethora

A plethoric appearance is typically seen in association with polycythaemia

but may also be mistaken for a normal outdoors complexion or cyanosis.

Patients with haematocrits above the normal reference range may or may

not have an i red cell mass (real or relative polycythaemia, respectively)

(see Table1.14).

Investigations

• FBC, lm (repeat FBC as sampling errors can falsely cause elevations

of Hb; polycythaemia rubra vera (PRV) may be associated with

neutrophilia, basophilia, or i platelets).

•

Measurement of red cell mass may be necessary to conrm true

polycythaemia.

•

Investigations are then aimed at establishing whether real polycythae-

mia, if documented, is due to a ° BM abnormality (PRV) or a 2°

disorder (e.g. respiratory disease).

•

NAP score (may be raised in PRV). Seldom used now (E Neutrophil

alkaline phosphatase, pp. 300–1).

•

Vitamin B

and urate (may be i inPRV).

•

ESR/ CRP (acute phase reactants may suggest 2° causes).

• Blood gas analysis, O

saturation, COHb levels (2° polycythaemia due

to respiratory disease, smoking).

•

Biochemistry (urea, creatinine; renal disease).

• Epo (i in 2° causes).

•

USS abdomen (renal cysts, liver disease, uterine broids, and other

malignancies may ‘inappropriately’ secrete Epo; also check for

splenomegaly inPRV).

•

Sleep studies (obstructive sleep apnoea (OSA), supine desaturation).

• O

dissociation studies (polycythaemia due to abnormal, high- anity Hb

variant).

•

BM aspirate and chromosomal studies/ cytogenetics (PRV is a clonal

disorder).

Table1.14 Polycythaemia

i red cell count >6.0 × 10

/ L

>5.5 × 10

/ L

♂

♀

i PCV >50%

>45%

♂

♀

i Hb

>18.0g/ dL

>16.0g/ dL

♂

♀

CHAPTER1 Symptoms andsigns

Polyuria

Polyuria (the passage of an excessive volume of urine, which may be asso-

ciated with frequency of micturition and nocturia) must be dierentiated

from urinary symptoms associated with prostatic disease and urinary infec-

tions. The latter are also characterized by frequency, urgency, and nocturia,

but usually small amounts of urine are passed at eachvoid.

Causes include

• DM.

• Cranial diabetes insipidus (DI) (E OHCM 10e, Chapter5):

•

Familial (autosomal dominant).

•

2° to posterior pituitary or hypothalamic disease, e.g. surgery,

tumours, especially metastases, neurosarcoidosis.

•

NephrogenicDI:

•

Familial (X- linked recessive).

•

Chronic intrinsic renal disease, e.g. pyelonephritis.

•

Hypokalaemia.

•

Hypercalcaemia.

•

Sickle- cell crisis.

•

Lithium, colchicine, amphotericin.

•

Post- obstructive uropathy.

• ° polydipsia (psychogenic).

Investigations

• 24h urinary volume.

• Venous plasma glucose.

• U&E.

• TFTs.

• LH.

• FSH (? panhypopituitarism).

• Serum Ca

andPTH.

•

Sickle- celltest.

• CXR (? mediastinal lymphadenopathy in TB, sarcoidosis).

If no obvious cause found, consider detailed investigations for cranial or

nephrogenic DI (E Polydipsia and polyuria:diabetes insipidus, pp. 134–6).

E OHCM 10e,p.81, p. 293.

PRURITUS

Pruritus

Implies generalized itching and may be associated with many disorders,

including:

•

Iron deciency.

• Malignant disease, e.g. lymphoma.

• DM.

• Chronic renal failure.

• Liver disease, e.g.PBC.

• Thyroid disease.

• PRV.

• HIV infection.

Investigations

• Aim to exclude the above diseases.

• FBC.

• Biochemistry screen, including LFTs and renal function.

• Glucose.

• TFTs.

E OHCM 10e, p.28, p.535.

CHAPTER1 Symptoms andsigns

Ptosis

Ptosis can be unilateral and bilateral. Bilateral ptosis can be more dicult

to recognize. Ptosis must be considered in association with other signs and

symptoms. Ptosis may be long- standing, of recent onset, progressive, or

intermittent, especially at the end of the day— myasthenia gravis(MG).

Unilateralptosis

Causes

•

Constitutional (congenital).

• Oculomotor (III) nerve palsy— levator palpebrae. ‘Down and out’ pupil

with loss of light reex (e.g. DM, SOL, demyelination).

•

Aneurysm (basilar or posterior communicating arteries).

• Cavernous sinus disease.

• Meningitis.

• Horner’s syndrome— superior tarsal muscle (brainstem infarction,

syringobulbia, SOL,MS).

•

Encephalitis.

If abnormal (reduced) sweating onipsilateral side face (damage tocervical

sympatheticchain)

•

Pancoast’s tumour.

• Aortic arch aneurysm.

• Cervical injuries.

No disorder ofsweating

•

Cluster headache.

• Parasellar tumours.

• Carotid artery aneurysm or dissection.

• Nasopharyngeal tumours.

Investigations

•

Venous plasma glucose.

• CXR (Pancoast’s syndrome).

• Cranial CT orMRI.

• Cerebral angiography (aneurysm).

Bilateralptosis

Causes

•

GBS (Miller– Fisher syndrome).

• MD.

• MG.

• Neurosyphilis (bilateral; Argyll Robertson pupils).

Investigations

•

Syphilis serology.

• EMG (‘dive- bomber’ inMD).

• Serum anti- acetylcholine receptor antibodies (AChRAb)(MG).

• IV edrophonium (Tensilon

) test (MG; E Edrophonium (Tensilon

)

test, p. 631).

E OHCM 10e,p.73.

PULMONARY EMBOLISM

Pulmonary embolism

Occurs when a thrombus in systemic veins or the right side of the heart

embolizes into the pulmonary arterial system. Impaired gas exchange

occurs because of a mismatch between ventilation and perfusion.

Investigations

• FBC (may be leucocytosis, neutrophilia most likely).

• ESR (ofteni).

•

Plasma D- dimers:i with fresh thrombus.

•

ABGs:hypoxia and hypocapnia.

• ECG:look for AF. Usually sinus tachycardia, may be evidence of right

ventricular ‘strain’. In massive PE, there may be S

•

CXR:often normal but may show signs of pulmonary infarction or

eusion.

•

V/ Q scan (may be useful for detection of areas of the lungs that are

being ventilated but not perfused).

•

Multislice CT scan:useful for detection of medium- sized PEs but does

not exclude smallPEs.

E OHCM 10e, p.98, pp. 190–1, p. 351, p. 818.

CHAPTER1 Symptoms andsigns

Pulse character

Rate and heart rhythm can be determined from palpation of the radial

pulse. The arm should then be elevated to check for a collapsing pulse.

Pulse volume and additional characteristics are assessed from palpation of

the brachial or carotid pulse (see Table1.15).

PURPURA

Purpura

Implies bleeding of varying degrees into the skin. Includes petechial haem-

orrhages (pinpoint) and ecchymoses (bruises). There are many causes,

including disorders of platelets and blood vessels.

Causes

• Congenital, e.g. Osler– Weber– Rendu syndrome (= HHT), connective

tissue (Ehlers– Danlos), osteogenesis imperfecta, Marfan’s.

• Severe infection (septic, meningococcal, measles, typhoid).

• Allergic, e.g. Henoch– Schönlein purpura.

• Drugs, e.g. steroids.

• Miscellaneous, e.g. senile purpura, scurvy, factitious.

• Thrombocytopenia— any cause (immune, marrow inltration, deciency

of vitamin B

or folate, myelobrosis, DIC, TTP/ HUS).

Investigations

• FBC (looking for platelet abnormalities and presence of leukaemic cells

or other signs of inltration).

•

Coagulation screen (looking for clotting factor deciencies, DIC,etc.).

• Bleeding time using template device (previously used as a test of platelet

function, but largely abandoned now because of poor reproducibility).

E OHCM 10e, p.311, p. 315, p. 556, p. 702.

CHAPTER1 Symptoms andsigns

Recurrent thrombosis

The pathogenesis (and hence causes) of thrombosis reect abnormalities

in the dynamics of the circulation, the blood vessel walls, or the blood con-

stituents (Virchow’s triad). Ahypercoagulable or thrombophilic risk factor

is an inherited or acquired disorder of the haemostatic mechanisms, which

may be associated with an i likelihood of a thrombotic event (venous or

arterial) or recurrent thrombosis. This concept of risk factors for throm-

bosis is analogous to that for heart disease, and similarly for most patients

multiple causal factors operate (see Table1.16).

Hereditary thrombotic disease may be suggested by a positive family his-

tory but should be tested for if the venous thrombotic events occur in the

absence of acquired causes, at a younger age, at unusual sites (e.g. mesen-

teric), or as recurrent thromboses.

Investigations inrecurrent thrombosis

Inherited thrombophilia screening

•

Deciency of factors, e.g. protein C, protein S, or antithrombin.

• Abnormal protein(FVL).

• i procoagulant (PT, VIII); others (homocysteinuria).

•

Consider occult malignancy (PSA in ♂, pelvic USSin♀).

•

FBC (myeloproliferative disorder,PNH).

• Biochemistry (cardiac disease, liver disease, nephrotic syndrome).

• ESR/ CRP (ulcerative colitis).

• ANA/ lupus anticoagulant/ cardiolipin antibodies (antiphospholipid

antibody syndromes, lupus).

Pitfalls

Thrombophilia testing may be complicated if the patient is on warfarin/

heparin; discuss with the lab before sending samples.

E OHCM 10e, p.375.

Table1.16 Thromboembolic risk factors

Acquired

Cardiac disease MI, AF, cardiomyopathy, CCF

Post- op Especially abdominal, pelvic, or orthopaedic surgery

Pregnancy

Malignancy Any

Polycythaemia

Immobilization Prolonged

Fractures

Especially hip and pelvis

Obesity

Varicose veins

Drugs

e.g. oestrogen- containing oral contraceptive

Inherited Activated protein C resistance, e.g. FVL mutation

Protein C or S deciency

Dysbrinogenaemias

RIGORS

Retinal haemorrhage

Maybe

• Flame- shaped (e.g. hypertension).

• Dot and blot (e.g. DM, vein occlusion, or haematological disease).

• Pre- retinal haemorrhage; suggests new vessel formation, e.g. DM or

post- retinal vascular occlusion.

• Hyperviscosity syndromes.

• Severe anaemia.

• Severe thrombocytopenia.

• Haemoglobinopathy, e.g.HbSC.

Investigations

• CheckBP.

• Renal function.

• FBC (ii Hb or platelets).

•

ESR or plasma viscosity (hyperviscosity syndromes such as myeloma or

Waldenström’s macroglobulinaemia).

•

Serum Igs and protein electrophoresis.

• Hb electrophoresis.

Rigors

Fever is due to a resetting of the anterior hypothalamic thermostat, is medi-

ated by prostaglandins (hence aspirin is benecial), and is most commonly

caused by infection. Large variations in temperature may be accompanied

by sweats, chills, and rigors. An undulant fever may suggest Hodgkin’s

disease or brucellosis. ‘B’ symptoms dene fever (>38°C), night sweats

(drenching), and weight loss (>10%) and suggest a diagnosis of lymphoma.

(Fever is unusual in chronic lymphocytic/ lymphatic leukaemia (CLL) in the

absence of infection.)

Investigations

• FBC, lm (Hodgkin’s disease is associated with anaemia, neutrophilia,

eosinophilia, and lymphopenia).

•

LDH (i in lymphoma, non- specictest).

• Microbiological tests, blood/ urine cultures (also consider pyogenic

infection and abscesses in more unusual sites, e.g. renal).

•

Antigen detection tests for specic pathogens.

• CXR (TB, lymphoma).

• ANA (connective tissue disease).

• BM aspirate/ trephine may be necessary as part of leukaemia and

lymphoma work- up.

Pitfalls

Not all fever is caused by infection.

E OHCM 10e, p.29.

CHAPTER1 Symptoms andsigns

Short stature

The assessment of short stature can be a long and dicult process.

Constitutional short stature is the commonest cause. Psychosocial disease

must be considered, but extensive investigation is required to rule out

organic disease. If no cause is found, a period of observation may make

the underlying cause apparent. Specialist evaluation should be undertaken

in allcases.

Causes

Endocrine

•

GH deciency.

• GH resistance (veryrare).

• Hypothyroidism (readily treatable).

• Cushing’s syndrome (rare in children). (Note:corticosteroid treatment

for chronic asthma.)

•

Rickets.

• Pseudohypoparathyroidism.

• Type 1 DM— Mauriac’s syndrome, nowrare.

Non- endocrine

• Constitutional short stature (short parents).

• Emotional deprivation.

• Intrauterine growth retardation.

• Achondroplasia.

• Mucopolysaccharidoses (rare).

• Turner’s syndrome (46 XO and variants).

• Noonan’s syndrome (46 XY, but features of Turner’s ina♂).

•

Congenital cardiac disease, e.g. left- to- right shunt, cardiac failure.

• Cystic brosis.

• Other causes of malabsorption, e.g. coeliac disease, Crohn’s colitis.

• Chronic liver disease.

• Haematological disease, e.g. sickle- cell disease.

• Chronic renal disease.

Investigations

• Current height + weight (compare to any previous data available; plot

on growth charts).

•

Growth velocity— normal if prior problem, e.g. intrauterine growth

retardation.

•

Physical stigmata of physical disease. Note:central nervous system

(CNS) examination mandatory.

•

FBC.

• ESR.

• U&E.

• LFTs.

• TFTs.

• Serum albumin (? nutritional status).

• Venous plasma glucose.

• SerumCa

SHORT STATURE

• Serum ALP (bone isoenzyme).

• Serum PO

3−

(reduced in rickets).

•

X- ray pelvis (Looser’s zones), epiphyses (wide, irregular in rickets), ribs

(multiple fractures).

•

Serum antigliadin and antiendomysial antibodies (coeliac).

• Testosterone or oestradiol, LH, FSH, PRL (if puberty

delayed— panhypopituitarism?).

• X- ray of the wrist for bone age. If delayed, measure serum IGF- 1

(if IGF- 1 normal, then GH deciency unlikely; if IGF- 1 low, consider

nutritional and general health status before diagnosing GH deciency—

stimulation tests required; E Endocrinology and metabolism, Short

stature, p. 178). If normal— constitutional short stature.

• Karyotype (Turner’s and Noonan’s syndromes).

• 24h urinary free cortisol (as screen for Cushing’s syndrome;

Obesity/ hypercortisolism, pp. 142–6).

• CT or MRI of the pituitary (if GH deciency or panhypopituitarism).

100

CHAPTER1 Symptoms andsigns

100

Skin pigmentation

Skin pigmentation can be due to i melanin deposition, e.g. racial dierences

in skin pigmentation, or due to i melanin deposition seen in sun exposure.

Lentigines and freckles are common. Haemosiderin and other substances

can i skin pigmentation. i pigmentation can be seen in various dermato-

logical conditions; chronic inammation and fungal infection can result in i

skin pigmentation. Lichen planus and xed drug eruptions are associated

with i pigmentation.

Increased pigmentation may also be found inassociation

withchronic systemic disease

• Addison’s disease (palmar creases, buccal pigmentation, recent scars).

• Porphyria cutanea tarda (especially exposed areas— dorsum of the

hands).

•

Chronic malabsorption syndromes.

• Drugs, e.g. amiodarone, psoralens, mepacrine, minocycline, chloroquine.

• Chronic uraemia.

• Haemochromatosis (so- called ‘bronzed diabetes’).

• PBC (deep green- yellow jaundice, chronic pruritus).

• Ectopic ACTH syndrome, e.g. bronchial carcinoma.

• Nelson’s syndrome (excessive adrenocorticotrophic hormone (ACTH)

secretion from pituitary basophil adenoma in Cushing’s disease treated

by bilateral adrenalectomy).

•

Carotenaemia (orange discoloration does not involve the sclerae;

E Jaundice, p. 66).

•

Chloasma (pregnancy, oestrogen- containingOCP).

• Acanthosis nigricans— most often a marker of insulin resistance in

obese patients with type 2 DM. Rarely in association with underlying

carcinoma.

•

Peutz– Jeghers syndrome (ngers, lips, in association with small intestine

polyposis).

Contrast withhypopigmentation

• Localized acquired depigmentation (vitiligo) is a marker of autoimmune

disease.

•

Oculocutaneous albinism (autosomal recessive).

• Chronic hypopituitarism (E Hypothalamus/ pituitary function,

pp. 128–30).

•

Phenylketonuria.

SKIN PIGMENTATION

101

Investigations

• FBC.

• U&E.

• Venous plasma glucose.

• Antigliadin and antiendomysial antibodies.

• Short tetracosactide (Synacthen

) test (if ° hypoadrenalism suspected;

E Short Synacthen

test, p. 225).

•

Urinary porphyrins.

• LFTs, serum albumin, and PT(INR).

• Fe/ TIBC/ ferritin + genetic markers for haemochromatosis + liver

biopsy.

•

ESR and/ orCRP.

• Autoimmune prole (E Chapter4).

•

Testosterone (or oestradiol) + LH,FSH.

• Antimitochondrial antibodies, liver biopsy(PBC).

• Investigations for Cushing’s syndrome (E Obesity/ hypercortisolism,

pp. 142–6).

•

Investigations for causes of chronic renal failure.

102

CHAPTER1 Symptoms andsigns

102

Splenomegaly

A palpable spleen is at least twice its normal size, when its length is >14cm.

Enlargement may represent changes in the white pulp (lymphoid tissue

expansion, inammation), red pulp (blood congestion, extramedullary hae-

mopoiesis), or occasionally supporting structures (cysts).

Causes inWestern societies

• Leukaemias.

• Lymphomas.

• Myeloproliferative disorders.

• Haemolytic anaemias.

• Portal hypertension.

• Infections, e.g. infective endocarditis, typhoid, TB, brucellosis, viral (EBV,

viral hepatitis).

Less commoncauses

•

Storage disorders (e.g. Gaucher’s).

• Collagen diseases.

• Sarcoid.

• Amyloid.

If foreign residence, consider infectious causes (malaria, leishmaniasis, schis-

tosomiasis) and haemoglobinopathies (HbC, HbE, thalassaemia).

Massive splenomegaly (>8cm palpable belowLCM)

• Myelobrosis.

• Chronic myeloid leukaemia(CML).

• Gaucher’s.

• Malaria.

• Leishmaniasis.

Investigations

• Thorough history and physical examination.

• FBC, blood lm, LDH (leukaemia, lymphoma, pernicious anaemia).

• Reticulocytes, bilirubin (if i, suggests haemolysis).

•

Virology/ microbiology (sepsis, bacterial endocarditis, EBV,CMV).

• Serum protein electrophoresis (myeloma, amyloid).

• Autoantibody screen, ANA (collagen disease, lupus,RhA).

• Haemoglobinopathy screen.

• LFTs (splenomegaly may be associated with hepatomegaly, or due to

portal hypertension).

•

Peripheral blood cell markers (immunophenotype— may show

leukaemia or lymphoma).

•

BM aspirate/ trephine/ cell markers/ cytogenetics.

• Leucocyte glucocerebrosidase activity (Gaucher’s disease).

• USS to assess liver texture, splenomegaly, and lymphadenopathy.

E OHCM 10e, p.63, p.373, p.604.

STEATORRHOEA

103

Steatorrhoea

Implies that the patient is passing pale, bulky stools that are oensive (con-

tain fat and tend to oat) and are dicult to ushaway.

Causes

• Any disorder that prevents absorption of micellar fat from the

smallbowel.

•

Ileal disease.

• Ileal resection.

• Parenchymal liver disease.

• Obstructive jaundice.

• Pancreatic disease, including cystic brosis.

• d bile salt concentration.

•

Bile salt deconjugation by bacteria.

• Cholestyramine.

• β- lipoprotein deciency.

• Lymphatic obstruction.

Investigations

Bloodtests

•

LFTs.

• Bone prole.

• Vitamin B

and serum (or red cell) folate.

•

Autoantibody prole.

• Serum amylase.

Pancreatic investigations

•

Pancreatic functiontests.

• CTscan.

Smallbowel

•

Small bowel follow- through.

• Jejunal biopsy (? villus atrophy).

• Bacterial overgrowth (

C glycocholate breathtest).

Parasites

•

Stool culture (e.g. Giardia).

Ileal disease

•

Consider Crohn’s.

E OHCM 10e, p.59.

104

CHAPTER1 Symptoms andsigns

104

Stridor

Stridor denotes a harsh respiratory added sound during inspiration. It may

be a high- pitched musical sound similar to wheeze but arising from constric-

tion of the larynx or trachea. Stridor may be aggravated by coughing.

3 Progressive breathlessness is accompanied by indrawing of intercos-

tal spaces and cyanosis indicates severe laryngeal obstruction with risk of

suddendeath.

In young children

Because of the smaller size of the larynx and trachea in children, stridor may

occur in a variety of conditions:

•

Postural stridor (laryngomalacia).

• Allergy, e.g. nut allergy, insect stings— common. Note:emergency

treatment with IM or subcutaneous (SC) adrenaline (epinephrine)— self-

administered or by parent, and parenteral hydrocortisone.

•

Vocal cordpalsy.

• Croup (acute laryngitis— often coryza).

• Acute epiglottitis.

• Inhaled foreign body, e.g. peanut (common— inhalation further down the

respiratory tract, usually into the right main bronchus, may produce localized

wheeze or distal collapse; E Patterns of lobar collapse, p. 780).

Investigations

•

Pulse oximetry (non- invasive measurement of partial pressure of

oxygen (PO

)).

•

Plain lateral X- ray of the neck (for radio- opaque foreignbody).

• Endoscopic nasolaryngoscopy.

Adults

• Infection, especially Haemophilus inuenzae.

•

Inammatory or allergic laryngeal oedema, e.g. penicillin allergy (see

above); may be accompanied by anaphylacticshock.

•

Pharyngeal pouch (may be recurrent lower respiratory tract infection).

• Inhaled vomitus or blood in an unconscious patient.

• Tetany (due to low serum Ca

or alkalosis; E OHCM 10e, Chapter14).

•

Large multinodular goitre, carcinoma, or lymphoma of the thyroid

(uncommon).

•

Laryngeal tumours.

• Bronchogenic tumour with bilateral cord paralysis (subcarinal and

paratracheal gland involvement. Note:‘bovine’ cough of right recurrent

laryngeal nerve palsy).

•

Shy– Drager syndrome (of autonomic neuropathy).

Investigations

•

CXR.

• Lateral X- ray of theneck.

• USS of the thyroid.

• Endoscopic nasolaryngoscopy.

• Bronchoscopy.

• Barium swallow (pharyngeal pouch).

• CT neck and mediastinum.

E OHCM 10e,p.48.

SUSPECTED BLEEDING DISORDER

105

Suspected bleeding disorder

Bleeding problems present a considerable challenge. Patients may pre- sent

with simple easy bruising— a common problem— or catastrophic post-

traumatic bleeding. The best predictors of bleeding risk are found in taking

an accurate history, focusing on past haemostatic challenges (e.g. tonsil-

lectomy, teeth extraction, menses— especially at time of menarche) and

current drug history (e.g. aspirin). The history may also help delineate the

type of defect. Platelet bleeding (e.g. thrombocytopenia) starts at the time

of the (even minor) haemostatic insult but, if controlled by local pressure,

tends not to recur. Bleeding due to coagulation factor deciency tends to be

associated with internal/ deep muscle haematomas as the bleeding typically

occurs in a delayed fashion after initial trauma and then persists.

Inappropriate bleeding or bruising may be due to a local factor or an

underlying systemic haemostatic abnormality.

2 Acquired causes of bleeding are much commoner than inherited

causes.

Causes ofbleeding include

• Surgical.

• Trauma.

• Non- accidental injury.

• Coagulation disorders.

• Platelet dysfunction.

• Vascular disorders.

Clinical features

History and presenting complaint. Is this an isolated symptom? What type

of bleeding does the patient have, e.g. mucocutaneous, easy bruising, spon-

taneous, post- traumatic. Duration and time of onset— ? recent or present

in childhood. Menstrual and obstetrical history are important.

Systemic enquiry

Do the patient’s symptoms suggest a systemic disorder, bone marrow fail-

ure, infection, liver disease, or renal disease?

Past medical history

Previous episodes of bleeding, recurrent— ? ITP, congenital disorder.

Exposure to trauma, surgery, dental extraction, or pregnancies.

Family history

First- degree relatives. Pattern of inheritance (e.g. autosomal, sex- linked). If

family history is negative, this could be a new mutation (one- third of new

haemophilia is due to new mutations).

Drugs

All drugs cause some side eects in some patients. Bleeding may result from

thrombocytopenia and platelet dysfunction. Do not forget to ask about

aspirin and warfarin.

106

CHAPTER1 Symptoms andsigns

106

Physical examination

Signs ofsystemic disease

Is there any evidence of septicaemia, anaemia, lymphadenopathy ±

hepatosplenomegaly?

Assess bleedingsite

Check the palate and fundi. Could this be self- inicted? Check size—

petechiae (pinhead); purpura (larger ≤1cm); bruises (ecchymoses;≥1cm).

Joints

Swelling or other signs of chronic arthritis.

Vascular lesions

Purpura— allergic, Henoch– Schönlein, senile, steroid- related, hypergam-

maglobulinaemic, HHT— capillary dilatations (blanches on pressure), vas-

culitic lesions, autoimmune disorders, hypersensitivity reactions.

Investigations

• FBC, lm, platelet count, biochemistry screen, ESR, coagulation screen.

• Special tests, e.g. BM for ° haematological disorders; radiology,USS.

• Family studies.

SUSPECTEDSTROKE

107

Suspectedstroke

A stroke denotes an acute neurological decit. Strokes may vary in pres-

entation, e.g. rapidly resolving neurological decit to a severe permanent

or progressive neurological defect (e.g. multi- infarct disease). Neurological

decits persisting >24h are termed ‘completed stroke’ (cf. TIA). With sus-

pected stroke, a full history and general physical examination are manda-

tory. Risk factors for cerebrovascular disease should be sought, including

a history of hypertension (common— major risk factor), DM (common—

major risk factor), and dyslipidaemia. Ask about recent falls or trauma.

Hemiparesis can occur as a post- ictal phenomenon or a result of migraine

or hypoglycaemia (see below). Hysterical or functional paralysis is also seen

but should not be condently assumed at presentation. Neuroanatomical

localization of the decit and the nature of the lesion(s) require appropri-

ate imaging. Note

: the post- ictal state may be associated with temporary

(<24h) limb paresis (Todd’s paralysis) in focal epilepsy (suggests structural

lesion— cranial imaging is mandatory).

General investigations

• FBC (polycythaemia, anaemia).

• U&E.

• ESR.

• Protein electrophoresis (if hyperviscosity syndrome suspected, e.g.

iiESR).

• ECG (AF, IHD— statins reduce the risk of stroke in patients with

previousMI).

•

CXR (cerebral metastases from bronchogenic carcinoma?).

Specic risk factors

• Venous plasma glucose. Note:severe hypoglycaemia, e.g. insulin- induced

or 2° to sulfonylureas, may mimic acute stroke. Always check the

capillary ngerprick glucose concentration to exclude this possibility—

even if there is no history of DM. Take a venous sample in a uoride–

oxalate tube (+ serum for insulin concentration) if hypoglycaemia

conrmed. (E Diabetes mellitus, pp. 194–9 for further details of

investigation and treatment.) Hyperosmolar non- ketotic diabetic coma

may also be misdiagnosed as stroke (plasma glucose usually >50mmol/ L

with pre- renal uraemia).

• Thrombophilia screen (if indicated by clinical or haematological

features).

•

Lipid prole (not an immediate investigation; 2° prevention— see

above).

•

Blood cultures (if subacute bacterial endocarditis (SBE) or other sepsis

suspected. Note:cerebral abscess).

108

CHAPTER1 Symptoms andsigns

108

Imaging

• Cranial CT scan (± IV contrast).

• Echocardiogram (if mural thrombus, endocarditis suspected).

• Carotid Doppler studies— may not be indicated if surgical intervention

(endarterectomy) is unlikely because of poor prognosis, e.g. dense

hemiplegia orcoma.

Consider alternative diagnoses including

• ° or 2° brain tumour (may present as acute stroke— search for°).

• Cerebral abscess (usually clear evidence of sepsis).

• Cerebral lupus (ESR, autoantibodies).

E OHCM 10e, p.159, pp. 470–5, p. 746.

SWEATING

109

Sweating

Fairly non- specic symptom, but one which may indicate serious underlying

disease.

Causes

• Excess heat (physiological).

• Exercise (physiological).

• Fever— anycause.

• Anxiety.

• Thyrotoxicosis.

• Acromegaly.

• DM.

• Lymphoproliferative disease, e.g. lymphomas.

• Cancer(any).

• Hypoglycaemia.

• Alcohol.

• Nausea.

• Gustatory.

• Neurological disease, e.g. lesions of the sympathetic nervous system,

cortex, basal ganglia, or spinalcord.

Investigations

• FBC.

• ESR.

• Biochemistry screen, includingLFTs.

• Glucose.

• TFTs.

• Urinalysis and culture.

• Blood cultures.

• CXR.

• Further investigations, depending on results ofabove.

110

CHAPTER1 Symptoms andsigns

110

Tachycardia

Tachycardia is arbitrarily dened as a heart rate above 100 beats per min-

ute. It is a normal physiological response to exercise and to emotional stress

but can also herald a cardiac rhythm disorder. One should always begin by

assessing the nature of the tachycardia and identifying any underlying cause

or contributing factor.

Assessment begins with a 12- lead ECG, performed whilst the patient

is tachycardic. This will enable the immediate identication of the heart

rhythm. One must then dierentiate between sinus tachycardia (which

may or may not have a pathological cause) and tachycardias due to other

(abnormal) cardiac rhythms.

Causes ofsinus tachycardia

• Sympathetic stimulation, e.g. anxiety, pain, fear, fever, exercise.

• Drugs, e.g. adrenaline, atropine, salbutamol.

• Stimulants, e.g. caeine, alcohol, amphetamines.

• Thyrotoxicosis.

• Heart failure.

• PE.

• IHD, acuteMI.

• Anaemia.

• Blood or uid loss, e.g. post- operative.

• Inappropriate sinus tachycardia (a persistent resting sinus tachycardia,

diagnosed when all other possible causes have been excluded).

In assessing abnormal heart rhythms causing tachycardia, it is helpful to

divide them into narrow- complex tachycardia (QRS duration <120ms) and

broad- complex tachycardia (QRS duration >120ms).

Narrow- complex tachycardias

• Sinus tachycardia (see above).

• Atrial tachycardia.

• Atrial utter.

• AF.

• AV re- entry tachycardias.

Broad- complex tachycardias

• Narrow- complex tachycardia with aberrant conduction.

• Ventricular tachycardia.

• Accelerated idioventricular rhythm.

• Torsades de pointes.

TACHYCARDIA

111

Investigations

• 12- lead ECG to identify the underlying rhythm.

• Consider bedside monitoring on the Coronary Care Unit (CCU),

particularly if the patient is compromised or ventricular arrhythmias are

suspected.

•

Other investigations depend upon the underlying cause but may include:

•

FBC.

•

U&E.

•

TFTs.

•

Cardiac markers.

•

CXR.

•

ABGs.

•

V/ Q scan/ CTPA.

•

Echocardiogram.

•

Exercise treadmilltest.

•

Cardiac catheter.

•

Electrophysiological studies.

It can be useful to perform carotid sinus massage (2 exclude carotid bruits

rst) or to give IV adenosine (2

do not use in asthma/ COPD), whilst the

patient is on a bedside ECG monitor. Supraventricular tachycardias will usu-

ally slow transiently, allowing clearer identication of the underlying atrial

activity, and re- entry tachycardias may terminate altogether. Ventricular

tachycardias will be unaected.

E OHCM 10e, Chapter 3.

112

CHAPTER1 Symptoms andsigns

112

Tinnitus

Tinnitus is a common symptom in which the patient perceives a sound,

often chronic and distressing, in the absence of aural stimulation. It usually

manifests as a ‘ringing’ or ‘buzzing’ in the ears. Tinnitus may occur as a symp-

tom of nearly all disorders of the auditory apparatus. Psychological stresses

may be relevant in somecases.

Causes include

• Acoustic trauma (prolonged exposure to loud noise, e.g. gunshots,

amplied music).

•

Barotrauma (blast injury, perforated tympanic membrane).

• Obstruction of the external auditory meatus (wax, foreign body,

infection).

•

Otosclerosis.

• Ménière’s disease.

• Drug- induced ototoxicity.

• Gentamicin— may be irreversible.

• Acute salicylate toxicity.

• Quinine toxicity.

• Acute alcohol poisoning.

• Hypothyroidism.

• Hypertension (rare symptom).

• Intra- or extracranial aneurysm (typically causes ‘pulsatile’ tinnitus).

• Glomus jugulare tumours.

Note: consider acoustic neuroma in unilateral tinnitus (E OHCM 10e,

Chapter10).

Investigations

• FBC.

• Serum concentrations of, e.g. salicylates, gentamicin (2 mandatory

during systemic therapy).

•

TFTs.

• B P.

Audiological assessment

Specialist investigations include

•

Assessing air and bone conduction thresholds.

• Tympanometry and acoustic reex testing.

• Speech perception thresholds.

Consider

•

CT temporal bone (acoustic neuroma).

• Cranial MRI (following specialist advice).

E OHCM 10e, p.464.

TIREDNESS

113

Tiredness

Tiredness is a common presenting complaint in the endocrine clinic.

Important diagnoses to exclude are hypo- / hyperthyroidism, hypoadrenal-

ism, hypercalcaemia, and DM. AU&E is useful to exclude hyponatraemia or

hypokalaemia (muscle weakness), as well as renal failure.

Recommended investigations fortiredness inthe absence

ofan obvious cause fromhistory and examination

• TSH.

• FT4.

• Synacthen

test.

•

SerumCa

•

Glucose.

• U&E, creatinine.

• FBC.

• ESR (orCRP).

• LFTs.

114

CHAPTER1 Symptoms andsigns

114

Urgency ofmicturition

Urgency of micturition denotes a strong desire to void and the patient

often has to rush to the toilet because of an acute call to micturate. Urinary

incontinence may result, especially if physical mobility is impaired. Urgency

forms part of a cluster of symptoms which include frequency of micturition

(E Polyuria, p. 90), nocturia, and hesitancy of micturition.

Men

• Prostatic disease.

• UTI.

• Bladder irritability.

• Urethritis.

• States of polyuria (E Polyuria, p. 90); may lead to urinary incontinence

(E Incontinence:urinary, p. 61).

Investigations toconsider

•

Urinalysis— stick test for glucose, protein, blood, and nitrites.

• MSU for microscopy and culture.

• FBC.

• U&E.

• Venous plasma glucose.

• ESR.

• SerumPSA.

• PSA is i in 30– 50% of patients with benign prostatic hyperplasia, and in

25– 92% of those with prostate cancer (depending on tumour volume),

i.e. a normal PSA does not exclude prostatic disease. Check the

reference range with the local laboratory.

•

Transrectal USS of the prostate.

• Prostatic biopsy (specialist procedure).

Women

• UTI.

• Gynaecological disease, e.g. pelvic oor instability, uterine prolapse.

• Bladder irritability.

• Urethritis.

• States of polyuria; may lead to urinary incontinence (E Incontinence:

urinary, p. 61).

Investigations toconsider

•

FBC.

• U&E.

• MSU for microscopy and culture.

• Urodynamic studies.

E OHCM 10e, p.80, p. 648.

URTICARIA

115

Urticaria

Itchy supercial wheals; may be giant. Distinguish acute from chronic—

chronic is rarely allergic in origin. If persists for >24h and fades with brown

staining, consider urticarial vasculitis (rare).

Causes

• Allergic:drugs, foods, additives, acute infection, e.g. HBV, Mycoplasma.

•

Physical:sunlight, heat, cold, pressure, vibration.

• Stress.

• Thyroid disease:hypo- or hyperthyroidism.

• Occult infection:gall bladder, dental,sinus.

• Vitamin deciency:B

, folic acid,iron.

•

Autoimmune:antibodies against IgE receptor on mast cells— veryrare.

Investigations

Based onhistory but should include asbaseline

•

FBC (with eosinophil count).

• Thyroid function.

• Infection marker(CRP).

• Liver function.

Further tests may include

•

and red cell folate.

•

Serum ferritin.

Allergy tests are of little value, unless there is a clearly identied trigger.

116

CHAPTER1 Symptoms andsigns

116

Vasculitis

Denition

Disease caused by inammatory destructive changes of blood vessel walls

(see Table1.17).

Presentation

Wide variety of clinical presentations aecting one or more organ systems:

•

Skin:splinter haemorrhages, nailfold infarcts, petechiae, purpura, livedo

reticularis.

•

Respiratory:cough, haemoptysis, breathlessness, pulmonary inltration,

sinusitis.

•

Renal:haematuria, proteinuria, hypertension,ARF.

•

Neurological:mononeuritis multiplex, sensorimotor polyneuropathy,

confusion, ts, hemiplegia, meningoencephalitis.

•

Musculoskeletal:arthralgia, arthritis, myalgia.

•

Generalized:PUO, weight loss, malaise.

Causes ofsecondary vasculitis

• Infective endocarditis.

• Meningococcal septicaemia.

• Malignancy.

• RhA.

• Henoch– Schönlein purpura.

• SLE.

• Cryoglobulinaemia.

• Drug reaction.

Investigations

• FBC.

• U&E.

• LFTs.

• ESR.

• CRP.

• Protein electrophoresis.

• ANA.

• RF.

• ANCA.

• CXR.

• Biopsy of artery and/ or skin lesions.

• Urine dipstick and microscopy.

E OHCM 10e, p.314, p.556, p.557.

Table1.17 Causes of° vasculitis

Granulomatous Non- granulomatous

Large vessel Giant cell arteritis (GCA) Takayasu’s arteritis

Medium vessel

Churg– Strauss disease Polyarteritis nodosa

Small vessel Wegener’s arteritis Microscopic arteritis

VISUALLOSS

117

Visualloss

Total loss of vision may be bilateral or unilateral. Unilateral blindness is due

to a lesion either of the eye itself or between the eye and the optic chiasm.

Determine whether the visual loss is gradual or sudden. Gradual loss of

vision occurs in conditions such as optic atrophy or glaucoma. In the elderly,

cataract and macular degeneration are common. Remember tobacco

amblyopia and methanol toxicity. Trachoma is a common cause worldwide.

Causes ofsudden blindness include

• Optic neuritis, e.g.MS.

• Central retinal artery occlusion.

• Central retinal vein occlusion.

• Vitreous haemorrhage. (Note:proliferative diabetic retinopathy.)

•

Acute glaucoma.

• Retinal detachment.

• Temporal (giant cell) cell arteritis (TA). Note:visual loss is potentially

preventable with early high- dose corticosteroid therapy (E OHCM 10e,

Chapter10).

•

Migraine (scotomata).

• Occipital cortex infarction.

• Acute severe quinine poisoning (consider stellate ganglion block).

• Hysteria (rare), e.g. is blindness:

•

Complete? No pupil response or opticokinetic nystagmus.

•

Cortical? Normal pupillary light reex, no opticokinetic nystagmus.

•

Hysterical? Normal pupillary light reex, normal opticokinetic nystagmus.

•

HELLP syndrome complicating pre- eclampsia— rare.

Investigations will be determined by the history and examination ndings; a

specialist opinion should be sought withoutdelay.

If TA suspected

• ESR/ CRP.

• Autoimmune prole, including cytoplasmic ANCA (cANCA)/

perinuclear ANCA (pANCA).

•

Temporal artery biopsy (within days; 3 do not withhold steroid therapy).

Investigations insudden onset ofvisualloss

• Visual acuity (Snellen chart).

• Goldmann perimetry.

• Intraocular pressure measurement (tonometry).

• Fluorescein angiography (specialist investigation— may delineate diabetic

retinopathy in more detail. 3 Risk of anaphylaxis).

•

Cranial CTscan.

• Cranial MRIscan.

• LP (CSF protein and OCBs if MS suspected).

Screen for risk factors and causes of cerebrovascular thromboembolic disease:

•

Venous plasma glucose.

• Serum lipid prole.

• Carotid Doppler studies.

• 12- leadECG.

• Echocardiogram.

118

CHAPTER1 Symptoms andsigns

118

Wasting ofthe small hand muscles

Wasting of the small muscles of the hand may be found in isolation or

maybe associated with other neurological signs. If found in isolation, this

suggests a spinal lesion at the level of C8/ T1 or distally in the brachial

plexus or upper limb motor nerves.

Unilateral wasting ofthe small muscles ofthe hand may

occur inassociationwith

• Cervicalrib.

• Brachial plexus trauma (Klumpke’s palsy).

• Pancoast’s tumour (may be associated with Horner’s syndrome).

• Cervical cord tumour.

• Malignant inltration of the brachial plexus.

Bilateral wasting ofthe small muscles ofthe hand occursin

• Carpal tunnel syndrome (common).

• RA (common).

• Cervical spondylosis (common).

• Bilateral cervicalribs.

• MND.

• Syringomyelia.

• Charcot– Marie– Tooth disease.

• GBS.

• Combined median and ulnar nerve lesions.

• Cachexia.

• Advancedage.

• Peripheral neuropathies.

Investigations

• ESR.

• CRP.

• RF.

• CXR.

• X- ray cervicalspine.

• NCS (E Nerve conduction studies, pp. 606–8).

•

EMG (E Electromyogram, pp. 610–11).

• LP, CSF protein, etc. (E Lumbar puncture, pp. 584–9).

•

CT thorax.

• MRI of the cervical cord/ brachial plexus.

WEIGHTLOSS

119

Weightloss

Causes

• Diet.

• Anorexia.

• DM.

• Malnutrition.

• Small intestinal disease (coeliac, bacterial overgrowth).

• Malignant disease (carcinoma and haematological malignancies).

• HIV/ AIDS.

• Chronic pancreatitis.

• Chronic respiratory failure.

• Cirrhosis.

• Diuretic therapy.

• Hyperthyroidism.

• Addison’s disease.

Investigations

May well need extensive investigation before determining the cause, but

startwith:

•

FBC.

• ESR orCRP.

• Biochemistry screen.

• TFTs.

• MSU, includingC&S.

• CXR.

• Stool culture (if appropriate).

• Blood culture.

• Other endocrine tests as appropriate.

• Consider HIV testing.

E OHCM 10e,p.35, p. 245.

120

CHAPTER1 Symptoms andsigns

120

Wheeze

Wheezes (rhonchi) are continuous high- , medium- , or low- pitched added

sounds audible during respiration. Typically they are loudest on expiration

in asthma and may on occasion be heard without a stethoscope. The impli-

cation is reversible or irreversible airway obstruction. If wheeze is audible

only during inspiration, this is termed stridor, implying an upper respiratory

obstruction. An important distinction must be made between monophonic

and polyphonic wheezes and whether wheeze is localized to a single area

or is heard throughout the thorax.

Polyphonicwheeze

Wheezes with multiple tones and pitch. The commonest causes of wheeze

(usually recurrent)are:

•

Asthma.

• COPD (often audible during both phases of respiration).

Fixed monophonicwheeze

A wheeze with a single constant pitch. Implies local bronchial obstruction,

usually dueto:

•

Bronchogenic carcinoma.

• Foreignbody.

Note:stridor is a harsh form of monophonic wheeze arising from an upper

airway obstruction (E Stridor, p. 104).

Investigations

• ABGs. (Note:inspired O

concentration should be recorded.)

•

Pulse oximetry at the bedside (does not provide information about the

partial pressure of carbon dioxide (PCO

)).

•

Spirometry (peak ow rate (PFR), pre- and post- bronchodilator

therapy).

•

Pulmonary function tests (forced expiratory volume in 1s (FEV

forced vital capacity (FVC), total lung capacity; E

Flow volume loops/

maximum expiratory ow– volume curve, p. 554).

• CXR (posteroanterior (P- A) and lateral).

• Sputum cytology (if tumour suspected).

• CT thorax.

• Bronchoscopy and biopsy (specialist procedure— especially if foreign

body or suspected tumour).

E OHCM 10e, p.52.

Investigations

2 Endocrinology and metabolism

123

3 Haematology

227

4 Immunology and allergy

333

5 Infectious and tropical diseases

381

6 Cardiology

435

7 Gastroenterology

497

8 Respiratory medicine

535

9 Neurology

583

10 Renal medicine

649

11 Poisoning and overdose

699

12 Rheumatology

741

13 Radiology

765

14 Nuclear medicine

865

PartII

122

123

Endocrinology and

metabolism

Guiding principles of endocrine investigation 124

Hypothalamus/ pituitary function 128

Acromegaly (growth hormone excess) 132

Polydipsia and polyuria:diabetes insipidus 134

Hyponatraemia (including syndrome of inappropriate

antidiuretic hormone) 138

Obesity/ hypercortisolism 142

Endocrine hypertension 148

Hypokalaemia 158

Hyperkalaemia 160

Adrenal failure 162

Amenorrhoea 166

Infertility 168

Hirsutism/ virilization (raised testosterone) 170

Galactorrhoea (hyperprolactinaemia) 172

Impotence/ loss of libido/ male hypogonadism 174

Gynaecomastia 175

Delayed puberty 176

Short stature 178

Precocious puberty 179

Thyroid function testing:general 180

Hyperthyroidism (thyrotoxicosis) 182

Hypothyroidism 186

Hypercalcaemia 188

Hypocalcaemia/ osteomalacia 190

Diabetes mellitus 194

Which type of diabetes isit? 200

Monitoring diabetic control 204

Laboratory assessment of glycaemic control 206

Diabetic emergencies:diabetic ketoacidosis, hyperosmolar

non- ketotic syndrome, and lactic acidosis 210

Investigation of hyperlipidaemia 212

Test protocols 216

Combined anterior pituitary function testing 218

Water deprivation test 220

Diagnostic trial of desamino

D- arginyl vasopressin 222

Low- dose dexamethasone suppression test 223

High- dose dexamethasone suppression test 224

Short Synacthen

test 225

Long (depot) ACTH test 225

Chapter2

124

CHAPTER2 Endocrinology and metabolism

124

Guiding principles ofendocrine

investigation

Investigations for endocrine disease have caused a lot of confusion in the

minds of clinicians (many still do!). Tests have come and gone over the years

and have been adopted with varying degrees of enthusiasm by specialist

centres. In particular, there is often confusion over which tests to do, what

procedures to follow, and how to interpret the results. In some areas (e.g.

Cushing’s syndrome), controversy persists among the experts. In others, a

clear consensus approach exists.

Some useful general principles

1. Use dynamic tests, rather than random (untimed) sampling where the

hormone under investigation is secreted in infrequent pulses (e.g. GH)

or levels are easily inuenced by other factors (e.g. cortisol varies

markedly with stress levels and has a marked circadian rhythm; see

Table2.1).

2. Use the correct collection method, e.g. ACTH or insulin levels require

rapid separation of the sample and prompt freezing (−20°C). Timing of

sampling may also be critical. Label samples carefully, including time of

collection! Check procedures with the local laboratory. Many units will

have protocols for endocrine investigations.

3. Do tests in the correct sequence, e.g. ACTH levels can only be

interpreted once the cortisol status is known. In many cases,

simultaneous samples are required for interpretation, e.g. PTH

with Ca

for hypo- / hyperparathyroidism, glucose with insulin for

insulinoma.

4. ‘Normal’ results may be ‘abnormal’, depending on the activity of the

hormone axis under investigation. Interpretation of the absolute

levels of hormones in isolation may be highly misleading. For

example, a serum PTH within the normal range in the presence of

hypocalcaemia suggests hypoparathyroidism; ‘normal’ LH and FSH

levels in the presence of a very low serum testosterone concentration

suggest pituitary failure. In both instances, the regulatory hormone

concentration is inappropriately low. Thus, the level of the regulatory

hormone (or releasing factor) must be considered in the light of the

simultaneous level of the ‘target’ hormone or metabolite.

In general

• If you are suspecting a LOW level— do a STIMULATION test (to see if

it staysLOW)

•

If you are suspecting a HIGH level— do a SUPPRESSION test (to see if

it staysHIGH)

GUIDING PRINCIPLES OFENDOCRINE INVESTIGATION

125

5. Results may vary according to the laboratory assay. Reference ranges

varybetween laboratories— it is especially important with endocrine

tests to interpret your results according to your laboratory’s ‘normal

range’. Also, interfering factors may dier between assays, e.g. dierent

PRL assays cross- react very dierently with macroprolactin

(E Galactorrhoea (hyperprolactinaemia), pp. 172–3). Some individuals

have a heterophile interfering antibody that aects the results of many

radioimmunoassays. Resist ‘discarding clinical evidence in favour of a

numerical value’.

6. Beware of interfering medication, e.g. inhaled beclomethasone can

suppress serum cortisol levels; administered hydrocortisone (cortisol)

is detected by the cortisol assay; synthetic androgens and oestrogens

can appear to cause low serum testosterone/ oestrogen (as they are

not detected in the testosterone/ oestrogen assay); some anti- emetics

and antipsychotics can raise circulating PRL levels; carbenoxolone

or liquorice may cause hypokalaemia. Always ask patients for a full

medication list (including herbal remedies and other self- medications).

7. Take a family history. Familial forms of many common endocrine

problems exist that require important changes in the management

approach, e.g. familial hypercalcaemia may suggest MEN- 1 or MEN- 2

requiring a dierent form of parathyroid surgery and a risk of

phaeochromocytoma (MEN- 2).

Endocrine tests are generally expensive and should not be performed

unnecessarily or outside standard protocols. Dynamic tests may have cau-

tions and contraindications and can be hazardous if used inappropriately

(see Table 2.1). Ahigh degree of organization and close liaison with the

laboratory are required to perform these tests in a way that can be clearly

interpreted. Dynamic tests should ideally be performed in an endocrine

investigation unit. Chemical pathologists (clinical biochemists) and other

laboratory sta generally have great experience with performing and

interpreting endocrine tests— seek their advice, wherever possible, before

embarking on tests with which you are unfamiliar. Tests in children should

be performed and interpreted under expert paediatric guidance.

126

CHAPTER2 Endocrinology and metabolism

126

Further reading

American Association of Clinical Endocrinologists Clinical Guidelines. AACE/ ACE clinical practice

guidelines. M https:// www.aace.com/ publications/ guidelines.

Endocrine Society. Endocrine Society Guidelines. M https://www.endocrine.org/guidelines-and-

clinical-practice.

Ismail AA, Barth JH. Wrong biochemistry results. BMJ 2001; 232

:705– 6.

Table2.1 Random sampling vs dynamic testing

Hormone Random or dynamic sampling?

GH Dynamic:glucose tolerance test for excess; insulin

stress test or GHRH arginine stimulation test for

deciency

IGF- 1 Random

LH, FSH Random in ♂

, post- menopausal

Timed with menstrual cycle in premenopausal♂

Random or stimulated in pre- pubertal children

Testosterone Random

Oestrogen

(oestradiol)

Random in ♂

, post- menopausal ♂

Timed with menstrual cycle in premenopausal

ACTH Random

Cortisol Dynamic:dexamethasone suppression test for excess;

Synacthen

stimulation test if suspect deciency

TSH Random

T4 and T3 Random

PRL Random

ADH/ vasopressin Do not normally measure directly

Osmolality Dynamic:water deprivation test if suspect DI

PTH Random, but need simultaneous Ca

value

Insulin Fasting, plus simultaneous glucose value

Calcitonin Random

Renin/ aldosterone Upright usually, o medication

Metanephrines Measure in urine, 24h sample or seated random

plasma sample

5HIAAs Measure in urine, 24h sample

GUIDING PRINCIPLES OFENDOCRINE INVESTIGATION

127

128

CHAPTER2 Endocrinology and metabolism

128

Hypothalamus/ pituitary function

Hypothalamic dysfunction

Causes

•

Familial syndromes (Laurence– Moon– Biedl, Prader– Willi).

• Tumours (especially craniopharyngiomas, dysgerminomas, optic gliomas,

meningioma— rarely pituitary tumours).

• Pituitary surgery.

• Inltration (histiocytosis X, sarcoidosis).

• Trauma.

• Meningitis.

• Encephalitis.

• TB.

Symptoms andsigns

•

Obesity/ hyperphagia.

• Somnolence.

• Thermodysregulation.

• DI.

• Hypogonadism.

• Precocious puberty.

Investigations

•

MRI.

• Water deprivation test for DI (E Polydipsia and polyuria:diabetes

insipidus, pp. 134–6), tests of pituitary function.

Hypopituitarism

Denition

Failure of one or more pituitary hormones (usually multiple).

Causes

•

Congenital.

• Pituitary tumour (including infarction of tumour ‘apoplexy’).

• Craniopharyngioma.

• Post- cranial irradiation.

• Following pituitary irradiation.

• Metastases to the pituitary (especially the breast).

• Post- surgery.

• Empty sella syndrome (occasionally).

• Sheehan’s syndrome (infarction with postpartum haemorrhage).

• CTLA- 4 Ig immunotherapy for malignancy.

Symptoms andsigns

Often very vague, e.g. tiredness, normocytic anaemia (easily missed).

Combined with impotence or amenorrhoea— very suggestive. Other clues

include loss of body hair (especially axillary), reduced shaving, hyponatrae-

mia, and growth failure in children. DI is not a feature (unless there is also

hypothalamic damage), as ADH can be secreted directly from the hypothal-

amus. There may also be signs of an SOL— bitemporal hemianopia (rarely

HYPOTHALAMUS/PITUITARY FUNCTION

129

optic nerve compression, homonymous hemianopia); headache (especially

following apoplexy); III, IV, V1, V2, or VI cranial nerve lesions; and CSF rhi-

norrhoea. Occasionally, galactorrhoea following pituitary stalk compression

by a tumour (‘disconnection’). Note

: generally GH is lost rst, then LH/

FSH, and ACTH/ TSH last. If multiple pituitary hormones are decient, GH

deciency can be assumed.

Investigations

(See Fig. 2.1.) Basal- free T4 (not TSH, which can be misleadingly normal),

LH, FSH, PRL, and oestrogen/ testosterone are usually sucient to test the

thyroid and gonadal axes. Adrenal and growth hormone testing requires

dynamic tests (e.g. insulin tolerance test (ITT), but see below). Severe GH

deciency = peak stimulated GH <12.3mU/ L (4.1ng/ mL) using GHRH

arginine test; <15.3mU/ L (5.1ng/ mL) using ITT testing. Note that the

short Synacthen

test (E Short Synacthen

test, p. 225) is only suitable

for testing the hypothalamopituitary– adrenal axis if pituitary failure is long-

standing (>6 weeks), allowing time for adrenal atrophy tooccur.

Basal: U&E, free T4

(not TSH), LH, FSH,

testosterone/

oestradiol, cortisol,

prolactin, IGF-1

Basal tests normal,

low level of suspicion

Stop: normal

Basal tests abnormal

or high level of

suspicion

Suggestive signs/

symptoms

• Short Synacthen

test (cortisol)

• Insulin tolerance

test* (GH, cortisol)

• MRI pituitary +

visual elds

• LHRH test

(optional)

Fig.2.1 Investigation of suspected hypopituitarism. Note:specialist paediatric advice

should be taken in children.

* E See also note under Alternative investigations, p. 130.

130

CHAPTER2 Endocrinology and metabolism

130

Alternative investigations

• GHRH arginine stimulation test. Although the ITT (E Test protocols,

pp. 216–17) is the traditional gold standard test for GH and 2° adrenal

insuciency, the GHRH arginine test has equal sensitivity and specicity

for GH deciency. It is also safer and better tolerated and is gradually

replacing theITT.

• Combined anterior pituitary testing— giving LHRH, thyrotropin-

releasing hormone (TRH), ACTH, and GHRH (E Combined anterior

pituitary function testing, p. 218)— no clear advantage of this approach

has been demonstrated and the results of the LHRH test, in particular,

are dicult to interpret in pre- pubertal children.

• Long (depot) Synacthen

test— rarely required (E Adrenal failure,

pp. 162–4; Long (depot) ACTH test, p. 225).

Further reading

Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine Society. Evaluation

and treatment of adult growth hormone deciency. J Clin Endocrinol Metab 2011; 96:1587– 609.

1 National Institute for Health and Care Excellence. UK NICE guidelines for GH replacement 2003. M

https://www.nice.org.uk/guidance/ta64.

HYPOTHALAMUS/PITUITARY FUNCTION

131

132

CHAPTER2 Endocrinology and metabolism

132

Acromegaly (growth hormone excess)

For GH deciency, see E Hypothalamus/ pituitary function, pp. 128–30.

Clinical features

• Often insidious over manyyears.

• Enlarging hands and feet with rings having to be resized.

• Increase in shoesize.

• Coarsening of facial features, especially enlargement and broadening of

thenose.

•

Sweating.

• Headache.

• Malocclusion (protuberance of the lower jaw) and splaying of theteeth.

• Skintags.

• Hypertension.

• Cardiac failure.

• Renal stones.

• Arthritis.

• Colonic polyps.

• Sleep apnoea.

• Carpal tunnel syndrome.

• DM.

• May be local symptoms from the pituitary tumour and symptoms/

signs of loss of other pituitary hormones (E Hypothalamus/ pituitary

function, pp. 128–30).

•

GH excess commencing before puberty results in gigantism (tall stature).

Investigations

• Arandom GH level is not helpful— may be high in normal people.

• Arandom IGF- 1 level should be measured and compared with

laboratory normal ranges corrected for age. This can be used as a

screening test, but IGF- 1 assays vary in reliability. IGF- 1 levels should be

raised in all cases of acromegaly, but levels can be aected (reduced) by

fasting and systemic illness.

•

Where IGF- 1 results suggest GH excess, this should be conrmed in a

standard 75g OGTT with glucose and GH measurements at 0, 30, 60,

90, and 120min.

•

If no GH values are <2mU/ L, then a diagnosis of acromegaly is

conrmed.

•

The vast majority (99%) of cases of acromegaly are due to pituitary

tumours. If a pituitary tumour is not seen on MRI scanning, yet

acromegaly is conrmed, a GHRH level should be requested to exclude

ectopic production of this polypeptide by non- pituitary tumours

stimulating the release of GH from the pituitary.

•

For follow- up of treated cases of acromegaly, IGF- 1 levels (more

sensitive) and/ or random GH levels can beused.

• Life expectancy appears to return to normality when the nadir of GH

values is <3mU/ L or IGF- 1 levels return to the referencerange.

Further reading

Katznelson L, Laws ER Jr, Melmed S, et al.; Endocrine Society. Acromegaly:an Endocrine Society

clinical practice guideline. J Clin Endocrinol Metab 2014; 99

:3933– 51.

ACROMEGALY (GROWTH HORMONE EXCESS)

133

134

CHAPTER2 Endocrinology and metabolism

134

Polydipsia and polyuria:

diabetes insipidus

‘First- linetests’

It is relatively common for patients to report excess thirst or i need to

pass urine. Figure 2.2 and Box 2.1 summarize the causes. Prostatism and

urge incontinence resulting in urinary frequency should be distinguished by

history- taking as the patients do not have thirst. Then the rst step is to

identify straightforward causes, such as drugs (diuretics), DM, hypercalcae-

mia, hypokalaemia, and chronic renal failure with U&E, creatinine, glucose,

and Ca

. Measuring 24h urine volume is also useful as volumes over 3L

are likely to be pathological and volumes under 2L do not require further

investigation. AGTT should not be required to diagnose DM as the renal

threshold for glucose needs to be exceeded (7

10mmol/ L) to cause polyuria

and there should be glucose in theurine.

‘Second- linetests’

Once other diagnoses have been excluded, subsequent tests aim to distin-

guish DI from ° polydipsia (compulsive water drinking). Acarefully super-

vised water deprivation test should be performed (E Water deprivation

test, pp. 220–1). However, it is not always easy to arrive at a conclusive diag-

nosis. Serum Na

levels are helpful, as DI is unlikely if Na

<140mmol/ L.

Morning spot urine osmolality after overnight water restriction (not shown

on chart) is occasionally useful— values >600mOsmol/ L make signicant

degrees of DI unlikely. Measuring 24h urine volume is also useful, as volumes

over 3L are likely to be pathological. However, obligate urine volumes as low

as 2L could still cause the patient to complain of polyuria. In such border-

line cases, the distinction between partial DI, normality, and ° polydipsia can

be very dicult. It has been proposed that in an adult or child over 2years

of age, a 24h urine volume of >40mL/ kg body weight, a plasma osmolarity

of <300mOsmol/ L, and a −ve test for glucose is diagnostic of DI, but this

requires conrmation.

Guidance on interpretation of second- line tests, including the water

deprivation test, is given in Table 2.2. Note that ° polydipsia may be a

psychiatric condition but can also occur in patients with a dry mouth

(e.g.Sjögren’s syndrome, anticholinergic drugs) or who have been previ-

ously encouraged to drink regularly ‘to help their kidneys’.

Box 2.1 Causes ofpolyuria/ polydipsia

Diabetes mellitus

•

DI (cranial or nephrogenic)

• HighCa

• LowK

• Chronic renal failure

• ° polydipsia (including dry mouth, e.g. Sjögren’s)

POLYDIPSIA AND POLYURIA: DIABETES INSIPIDUS

135

Distinction between partial cranial DI and habitual (psychogenic) water

drinking is complicated by the fact that drinking very high volumes over time

may ‘wash out’ the renal medullary concentrating gradient. In this situation,

a plasma vasopressin level at the end of the water deprivation test may be

very helpful to distinguish a lack of vasopressin from a lack of vasopres-

sin action. A24h urine volume is also helpful as volumes of <3L/ day are

unlikely to cause renal ‘washout’. Clues to ° polydipsia include an initial

plasma osmolality (and serum Na

) that is low, plasma osmolality rising

to >295mOsmol/ L, and thirst not abolished by desmopressin, despite a

rise in urine osmolality. Note that ‘full- blown’ cranial DI results in urine

volumes of around 500mL/ h (12L/ day).

Cause identied

•

Diabetes mellitus

•

Hypokalaemia

•

Chronic renal failure

•

Hypercalcaemia

•

Diuretics

Polydipsia/polyuria

Cause not identied

•

24h urine collection for

volume

• Morning urine

osmolality

• Review serum Na

• Water deprivation test

See text for interpretation

Distinguish remaining

causes

•

Diabetes insipidus:

cranial, partial cranial,

nephrogenic

•

Primary polydipsia:

psychogenic, dry mouth

•

Urinary frequency (e.g.

unstable bladder)

(normal ADH axis)

History: prostatism, urinary

frequency (no thirst)

Drug history: diuretics

Blood: glucose, Na

, K

creatinine, calcium

Urine: glucose, protein

Fig.2.2 Investigation of polydipsia/ polyuria. Note:once cranial DI is diagnosed,

further investigations into the underlying cause are required (E Hypothalamic

dysfunction under Hypothalamus/ pituitary function, p. 128).

136

CHAPTER2 Endocrinology and metabolism

136

Interpretation ofsecond- line tests forpolyuria/ polydipsia

‘If all elsefails’

In cases of doubt, a carefully supervised therapeutic trial of desmopressin

can be useful to distinguish DI from ° polydipsia (E Diagnostic trial of

desmopressin, p. 222). This should be done as an inpatient, as there is a risk

of signicant hyponatraemia in habitual water drinkers. The principle is that

patients able to regulate water intake according to their thirst (DI) should

not develop a hypo- osmolar plasma. In ° polydipsia, the urine volume will

fall and the urine concentrating gradient will gradually recover. However, if

the patient continues to drink due to their psychological drive, rather than

their thirst, they will become water- overloaded and hypo- osmolar.

An additional valuable test to distinguish partial DI from ° polydipsia is

hypertonic saline infusion testing, which usually requires access to a plasma

vasopressin assay but has been used with urinary vasopressin levels.

2–3

MRI

scanning typically shows an i signal in the posterior pituitary, which is lost

in cranial DI. However, this sign is not helpful in distinguishing more subtle

degrees of DI from other causes.

Table2.2 Interpretation ofsecond- line tests forpolyuria/ polydipsia

Normal Partial DI:cranial (C)

ornephrogenic (N)

Primary

polydipsia

Random serum Na

Normal >140mmol/ L <140mmol/ L

Random serum

osmolality**

Variable >290 <290

Morning urine

mOsm**

Variable Unlikely if >600 (C)

Excluded if >600 (N)

End of water

deprivation test before

desmopressin**

Urine >600

Plasma

280– 295

Urine <600

Plasma >295

Urine >600*

Plasma

280– 295

Urine osmolality after

desmopressin SC**

>600 Rises to >600 or >50%

i (C); rises to <600

or <50% i (N)

Rises to

>600* or

>50% i

Plasma vasopressin

at end of water

deprivation test

Normal

for plasma

osmolality

Low for plasma

osmolality(C); normal

forplasma osmolality (N)

Normal

for plasma

osmolality

* With long- standing large- volume polyuria (>3L/ day), these values may not be achieved due to

washout of the renal medullary concentrating gradient— if results equivocal, seetext.

** Osmolalities are all expressed in mOsmol/ L.

2 Robertson GL. Diabetes insipidus:diagnosis and management. Best Pract Res Clin Endocrinol Metab

2016; 30

:205– 18.

3 Diederich S, Eckmanns T, Exner P, Al- Saadi N, Bähr V, Oelkers W. Dierential diagnosis of poly-

uric/ polydipsic syndromes with the aid of urinary vasopressin measurements in adults. Clin Endocrinol

(Oxf ) 2001; 54

:665– 71.

POLYDIPSIA AND POLYURIA: DIABETES INSIPIDUS

137

138

CHAPTER2 Endocrinology and metabolism

138

Box 2.2 Causes ofpseudohyponatraemia

With normal serum osmolality

•

Hyperproteinaemia (e.g. myeloma)

• Hyperlipidaemia (hypertriglyceridaemia)

• Glycine or sorbitol (from bladder irrigant)

With raised osmolality

•

Hyperglycaemia

• Mannitol

• Glycerol

Box 2.3 Criteria fordiagnosingSIADH

• Hyponatraemia present

• No diuretics

• Nooedema

• Normal renal function

• Normal adrenal function

• Normal thyroid function

• Urine Na

>20mmol/ L

• Euvolaemic

Hyponatraemia (including syndrome

ofinappropriate antidiuretic hormone)

Hyponatraemia is a very common clinical problem. Figure 2.3 shows a ow

chart for investigation. If patients are on diuretics, further evaluation is usu-

ally not possible. The diuretic will need to be discontinued. If this is not

possible, hyponatraemia is likely to be attributable to an underlying condi-

tion (cardiac, renal, or liver failure). Pseudo- or dilutional hyponatraemia

is important to exclude at an early stage (see Box 2.2). Acareful clinical

assessment should be made of the volume status, including identication

of oedema, uid loss (e.g. diarrhoea, stula leakage), and signs of dehy-

dration, including postural drop in BP. Aurine Na

and TSH estimation is

useful at this stage (see Fig. 2.3). Note that the most important diagnosis

not to miss is hypoadrenalism, as this can be fatal if untreated. Clinicians

should have a low threshold for performing a short Synacthen

test

(E Short Synacthen

test, p. 225). Hypoadrenalism due to pituitary failure

may not be accompanied by hyperkalaemia, hypotension, or hyperpigmen-

tation and can easily be missed. Cerebral salt wasting occurs within days

of brain injury (e.g. SAH, neurosurgery, or stroke) and is probably due to

release of brain natriuretic peptides.

The syndrome of inappropriate antidiuretic hormone (SIADH) is a diagno-

sis of exclusion (see Box2.3).

139

HYPONATRAEMIA (INCLUDING SIADH)

All the criteria in Box 2.3 should be met. A specic cause for SIADH is

frequently not found or there may be a combination of precipitating factors

(see Table 2.3). In the elderly, a state of chronic SIADH is relatively com-

mon and usually explains hyponatraemia persisting for many years without

any other apparent cause. Aected individuals should be encouraged to

drink less than a litre a day (‘5 cups or less’), to only drink if they are thirsty,

and to avoid exacerbating factors (see Table2.3).

Features ofSIADH/ hyponatraemia that are often

underappreciated

1. Other than a CXR, there is no requirement to search for an underlying

malignant cause. If there is underlying malignancy, it is usually extensive,

very apparent, and incurable (e.g. extensive small- cell carcinoma of

thelung).

2. The urine osmolality does not have to be high. In individuals drinking

large volumes of uid, a urine osmolality as low as 250mOsmol/ L

(i.e. less than plasma) may be inappropriately concentrated, reecting

trueSIADH.

3. Conditions previously diagnosed as ‘sick cell syndrome’ are now

thought to represent SIADH in ill patients.

4. ‘Water intoxication’ is usually the combination of SIADH and excessive

uid intake. Healthy patients drinking to excess can rarely exceed

the renal capacity to excrete a water load (7

12L/ day) and hence

do not become hyponatraemic. Adegree of SIADH is required for

potomaniacs (excess water drinkers) to become hyponatraemic.

5. The post- operative state contains many precipitants to SIADH

(nausea, pain, opiates, pneumonia) and ADH secretion is promoted by

hypovolaemia from blood loss. The administration of ‘3L of IV uid a

day’ post- operatively frequently results in hyponatraemia.

Table2.3 Causes ofSIADH

Cause Examples

Drugs Carbamazepine, chlorpropamide, opiates, psychotropics,

cytotoxics

CNS disorders

Head trauma, post- pituitary surgery (transient), stroke,

cerebral haemorrhage, GBS, meningitis, encephalitis, ts

Malignancy

Small- cell lung cancer, pancreas, prostate

Chest disease Pneumonia, TB, abscess, aspergillosis

General stimuli Nausea, pain, smoking

Other Acute intermittent porphyria

140

CHAPTER2 Endocrinology and metabolism

140

Further reading

Spasovski G, Vanholder R, Allolio B, etal.; Hyponatraemia Guideline Development Group. Clinical

practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014; 170

:G1– 47.

6. Symptoms of hyponatraemia, such as drowsiness, coma, or ts, are

dependent on the rate of fall of serum Na

, not the absolute value.

Patients who are alert with Na

<125mmol/ L have clearly been

chronically hyponatraemic and their serum Na

requires only gentle

correction. However, a very rapid fall in serum Na

to <130mmol/ L

(typically due to massive infusion of hypotonic uid into the bladder)

may cause coma and needs to be corrected as a medical emergency

with hypertonic saline.

Cardiac failure

Renal failure

Hepatic failure

Pseudohyponatraemia

Oedema absent Oedema present

No Yes

Raised glucose,

triglycerides, total

protein

Normal or elevated

serum osmolality

Hypovolaemia

Urine Na

>20mmol/L

Hypoadrenalism

Diuretics

Salt-losing

nephropathy

Hypovolaemic

Urine Na

<20mmol/L

Diarrhoea

Loss of other

body uids incl.

sweat, burns,

bowel

obstruction

Euvolaemic

Urine Na

>20mmol/L

SIADH

Hypothyroidism

Fig.2.3 Investigation of hyponatraemia.

141

HYPONATRAEMIA (INCLUDING SIADH)

142

CHAPTER2 Endocrinology and metabolism

142

Obesity/ hypercortisolism

Endocrinologists are frequently asked to determine whether there is an

underlying endocrine cause in patients who are obese. 2° causes of obesity

are listed in Box 2.4. Along history of obesity, typically going back to child-

hood, is characteristic of constitutional obesity and further investigation,

other than thyroid function, is rarely necessary. However, simple obesity

may result in eects suggestive of hypercortisolism, e.g. striae, bruising,

central obesity, rounded facial features, mild hyperandrogenism in women,

bualo hump, hypertension, and hyperglycaemia. Rapidly progressive

obesity, marked hypertension, hypokalaemia, proximal muscle weakness,

poor sleep, osteoporosis/ vertebral collapse, and marked hirsutism or acne

are more suggestive of hypercortisolism and require further investigation.

Hypothalamic damage is usually apparent from the history.

The optimal approach to the diagnosis of hypercortisolism (Cushing’s

syndrome) is probably the most controversial subject in endocrinology.

Endocrinologists who have seen many cases of Cushing’s syndrome have

seen exceptions to every rule, and the episodic nature of ACTH and corti-

sol secretion means that low values can occur even in disease. True cyclical

Cushing’s disease also occurs but israre.

Diagnosis consists oftwophases

1. Does the patient have hypercortisolism ornot?

2. What is the cause of the hypercortisolism? Phase 1 must be completed

rst, as phase 2 tests can only be interpreted if hypercortisolism is

present.

Investigation ofhypercortisolism phase1

Does thepatient have hypercortisolism?

Patients being investigated for hypercortisolism should look Cushingoid.

One exception is malignant ectopic ACTH secretion (e.g. from small- cell

lung cancer) which can cause profound hypokalaemia before Cushingoid

appearance is apparent. Depression and alcoholism may cause abnormal

tests for hypercortisolism without representing a true hypercortisolae-

mic state and hence are termed ‘pseudo- Cushing’s syndrome’. Such

depressed patients often do not appear Cushingoid and alcoholism should

Box 2.4 Secondary causes ofobesity

• Constitutional

• Hypothyroidism

• Cushing’s syndrome

• Hypothalamic damage (extreme hyperphagia)

• Genetic, e.g. Prader– Willi

• GH deciency

• Drugs, e.g. antidepressants

OBESITY/HYPERCORTISOLISM

143

be identiable clinically and biochemically. If there is a high degree of sus-

picion of hypercortisolism in a depressed patient, midnight cortisol levels

<140nmol/ L or a −ve result on dexamethasone– corticotropin- releasing

hormone (CRH) testing (E Low- dose dexamethasone suppression test,

p. 223) may be helpful in excluding the diagnosis. Note that iatrogenic

or factitious Cushing’s syndrome is usually due to a steroid other than

hydrocortisone (not detected in the cortisol assay) and characteristically

results in an apparent suppression of the hypothalamopituitary– adrenal

axis on testing.

Four tests are used todetermine whether a patient does have hypercortisolism

1. 24h urinary- free cortisol (UFC) collections. Three collections with

simultaneous creatinine excretion estimation are ideal. If the creatinine

excretion varies by >10% between collections, the samples are

not true 24h collections and should be repeated. If two or more

collections have a value >3 times the laboratory upper limit of normal

(e.g.>800nmol/ 24h), then the diagnosis of hypercortisolism is secure.

Patients with intermediate values should have repeat sampling after

several weeks or additional tests. Steroids, adrenal enzyme inhibitors,

statins, and carbamazepine must be discontinued prior to testing.

False +ves can be caused by pregnancy, anorexia, exercise, psychoses,

alcohol, and alcohol withdrawal.

2. Low- dose dexamethasone suppression test (LDST). This can be

performed overnight or over 2days (E

Low- dose dexamethasone

suppression test, p. 223), the latter having less false +ves. Some

authorities believe it adds little to UFCs as when cortisol secretion is

high, the UFC is clearly raised, but in times when it is intermediate,

the LDST may be normal. It is a useful outpatient screening test

Overnight dexamethasone suppression test under Low- dose

dexamethasone suppression test, p. 223) in individuals who cannot

reliably collect 24h urine samples.

3. Late- night salivary cortisol test. High salivary cortisol levels (>4nmol/

L) measured between 11p.m. and 12 midnight indicate loss of diurnal

rhythm and are one of the best tests of hypercortisolism. Salivary

samples can be collected as an outpatient by drooling into a collection

tube or use of a cotton pledgelet. The tests should be repeated on two

occasions. An alternative is a venous sample taken via an indwelling

cannula in as relaxed a state as possible, preferably during sleep,

but this requires an inpatient admission. Values <140nmol/ L make

hypercortisolism very unlikely.

4. Dexamethasone- suppressed CRH test (E Low- dose dexamethasone

suppression test, p. 223). This is a modication of the LDST, which was

initially claimed to have a specicity of 100% for hypercortisolism, but

subsequent series suggest<80%.

Summary

In patients who appear Cushingoid, three UFCs should be performed (note

causes of false +ves). If these give equivocal results, additional tests are

required, including further UFCs, late- night salivary cortisols, and a formal

2- day LDST followed byCRH.

144

CHAPTER2 Endocrinology and metabolism

144

Investigation ofhypercortisolism phase2

What is thecause ofhypercortisolism?

The common and rare causes of hypercortisolism are summarized in

Tables2.4 and 2.5, along with useful clinical features. 765% of cases are due

to a pituitary adenoma (Cushing’s disease), 20% due to an adrenal adenoma

or carcinoma, and 10% due to ectopic ACTH production.

These are the three main causes to be distinguished using a combina-

tion of the tests shown under Investigations below. Distinction between

a pituitary adenoma (which may not be visualizable on MRI) and a small

indolent tumour (typically lung carcinoid) represents the greatest challenge.

Despite extensive investigation, the cause will remain uncertain in some of

thesecases.

Investigations

1. Plasma ACTH level (separate and freeze immediately). Undetectable

plasma ACTH levels are strongly suggestive of an adrenal tumour.

However, ACTH secretion is intermittent and two suppressed values

with simultaneous high cortisol levels (>400nmol/ L) are preferable and

should prompt adrenal CT scanning.

2. High- dose dexamethasone suppression test (E High- dose

dexamethasone suppression test, p. 224). Greater than 90%

suppression of basal UFC levels is strongly suggestive of a pituitary

adenoma. Lesser degrees of suppression are seen with ectopicACTH.

3. Inferior petrosal sinus sampling (IPSS). This is an excellent diagnostic tool

but requires expert radiological support and should only be performed

in tertiary referral centres. Atotal of 100mg IV of CRH is also given

via a peripheral vein, while sampling, to ensure active secretion of

ACTH during the test. ACTH levels are compared between the

Table2.4 Common causes ofhypercortisolism (Cushing’s syndrome)

Cause Pathology Characteristic features

ACTH- secreting

pituitary adenoma

(Cushing’s

disease)— 65%

Pituitary adenoma Typical features of hypercortisolism

with little virilization

Ectopic ACTH

secretion— 10%

Malignant:small- cell

lung cancer, thymic

carcinoid, medullary

thyroid cancer

Indolent/ benign:

bronchial/ pancreatic

carcinoids,

phaeo chromocytoma

Malignant:rapid progression, marked

hypokalaemia, proximal muscle

weakness, iBP, tumour clinically

apparent, few Cushingoid signs

Indolent:indistinguishable from

Cushing’s disease, tumour not easily

detected

Adrenal

tumour— 20%

Adrenal adenoma

Adrenal carcinoma

Adenomas:typical Cushingoid signs,

sometimes virilization

Carcinomas:rapid progression

(months) with virilization, poor

prognosis

OBESITY/HYPERCORTISOLISM

145

inferior petrosal sinus on both sides and a peripheral vein. Sampling is

performed at −15, 0, +15, and +30min after CRH injection. Ratios >2

(ideally >3) post- CRH are strongly suggestive of pituitary- dependent

disease. Risks include failure to enter the sinus and sinus thrombosis.

4. Imaging. Pituitary and adrenal imaging should not be performed without

biochemical testing, as non- functioning tumours of the pituitary and

adrenal are common (false +ves), and conversely functioning pituitary

tumours are often too small to be visualized by MRI (false – ve).

However, if the ndings are consistent with the biochemical tests, this is

useful supportive evidence. Patients with ndings suggestive of ectopic

ACTH production should have thin- slice CT of the chest looking for

a bronchial adenoma, and MRI scanning of the pancreas for an islet

tumour.

111

Indium- labelled octreotide scanning may also be useful in

locating small tumours.

5. Plasma CRH levels. Very rarely, ‘ectopic ACTH’ syndrome is actually

due to ectopic CRH production stimulating ACTH from the pituitary

(see Table 2.5). Raised plasma CRH levels may be diagnostic in this

condition.

Table2.5 Rare causes ofhypercortisolism (Cushing’s syndrome)

Cause Pathology Characteristic features

Ectopic CRH

secretion

Variety of tumours,

mostly carcinoids

Clinical features indistinguishable

from Cushing’s disease, but no

pituitary tumour, i serum CRH and

may fail to suppress with high- dose

dexamethasone

Ectopic gastrin-

releasing peptide

secretion

Medullary thyroid

cancer

Very rare, resembles ectopic CRH

Factitious ACTH

administration

Injections of ACTH Very dicult to distinguish from

ectopic CRH secretion or Cushing’s

disease but, if isolated from their

ACTH source, become adrenally

insucient in days

Cyclical Cushing’s

disease

Cyclical secretion from

pituitary adenoma

Cushing’s disease with

intermittently −ve tests

Pseudo-

Cushing’s

syndromes

Depression or

alcoholism

Clinical evidence of Cushing’s

disease may be limited; evidence of

depression or alcoholism

Bilateral

micronodular

adrenal

hyperplasia

Often associated with

Carney complex

Investigation suggestive of adrenal

tumour (ACTH suppressed), but

adrenals normal or slightly enlarged

and contain pigmented nodules

Bilateral

macronodular

adrenal

hyperplasia

Sporadic or familial Investigation suggestive of adrenal

tumour (ACTH suppressed), but

marked or very marked bilateral

nodular enlargement of adrenals on

CT scanning

146

CHAPTER2 Endocrinology and metabolism

146

Additional tests include

• Metyrapone test:here the adrenal enzyme blocker metyrapone is used

to lower cortisol levels. Pituitary adenomas respond by i ACTH

production, but ectopic sources of ACTH do not. The test can also

be used to conrm that ACTH levels are truly suppressed in adrenal

tumours (rarely necessary).

•

Peripheral CRH test:ACTH levels are measured before (−30, −15min)

and +15 and +30min after injection of 100mg IV of CRH into a

peripheral vein. Arise in ACTH levels of >34% is suggestive of a

pituitary adenoma. The addition of 5µg IV of desmopressin improves

the response rate and reduces false−ves.

Summary

(See Fig.2.4.)

Further reading

Nieman LK, Biller BM, Findling JW, etal. The diagnosis of Cushing’s syndrome:an Endocrine Society

Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93

:1526– 40.

Equivocal/suggest

ectopic cause

Suggest pituitary cause

Peripheral ACTH x2

+ cortisol

ACTH detectable ACTH undetectable

Adrenal CT/MRI

Establish hypercortisolism

Phase 1 tests – see text

• High-dose

dexamethasone

suppression test

• Inferior petrosal

sinus sampling

with CRH

• Pituitary MRI

Thin-slice CT chest

MRI pancreas

111

In-octreotide scan

Consider CRH

estimation

Fig.2.4 Hypercortisolism. Flow chart for diagnosing the cause once

hypercortisolism is established.

OBESITY/HYPERCORTISOLISM

147

148

CHAPTER2 Endocrinology and metabolism

148

Endocrine hypertension

Ninety- ve per cent of cases of hypertension are ‘essential hypertension’

with no specic underlying cause. If hypertension is very marked, occurs in

younger patients, is dicult to control with drugs, is episodic/ uctuating, is

of recent onset, is familial, is associated with recurrent hypokalaemia, or

has associated features (see Table 2.6), then an underlying cause should

be excluded.

History and examination should include features of conditions in

Table 2.6, with particular attention to paroxysmal attacks, drugs (e.g.

liquorice), and family history.

Figure 2.5 provides a ow chart for further investigations. At least three

separate BP readings should be obtained— 24h BP monitoring may be use-

ful where ‘white coat hypertension’ is suspected.

Table2.6 Secondary causes ofhypertension

Physical features Notes

Absent

Phaeochromocytoma

May be familial, e.g. in MEN- 2 (may have mucosal

neuromas), von Hippel– Lindau syndrome,

neurobromatosis; paroxysmal i BP in only 60% of

cases with headache, sweating, and palpitations

Hyperaldosteronism Multiple syndromes, including Conn’s syndrome

(see Table2.7)

Renal artery stenosis Congenital or acquired (atheroma)

Renal disease Any cause, including polycystic kidneys

Hyper- / hypothyroidism Diastolic hypertension with hypothyroidism, systolic

hypertension with hyperthyroidism

Hyperparathyroidism Does not usually improve after surgical cure

Drugs Epo, ciclosporin, cocaine, amphetamines,

steroids, liquorice, oestrogens, and androgens

Physical features present

Coarctation of the aorta

Cushing’s syndrome

Acromegaly

Pregnancy- induced

ENDOCRINE HYPERTENSION

149

The majority of 2° causes of hypertension can be rapidly excluded by the

investigations shown in the rst box of Fig. 2.5. If the results are normal or

the only abnormality is a low K

level, then the possibilities of hyperaldo-

steronism or RAS remain to be distinguished from essential hypertension.

Further investigation should be driven by the severity of the hyperten-

sion, the (young) age of the patient, and the diculty in obtaining control

withdrugs.

See Fig. 2.6

Investigate for

hyperaldosteronism

(Figs. 2.6 and 2.7)

Selective renal

angiogram

Notes:

1. Ideally, this test should be performed o all antihypertensive drugs for 2 week

(6 weeks for spironolactone) except alpha blockers.

2. Low renin and very low aldosterone should prompt, investigations for `apparent

mineralocorticoid excess'.

High renin

Equivocal results

Low renin, high

aldosterone

Upright renin/aldosterone

(Renal duplex ultrasound)

Investigate as appropriate

Results normal or low K

alone:

Hyperaldosteronism

Renal artery stenosis

Essential hypertension

Abnormal results other than

low K

U&E, creatinine

Urinalysis

TSH

24h urinary catecholamines

Renal ultrasound

If indicated: 24h urine free

cortisol, CT aorta, tests for

acromegaly

Fig.2.5 Investigation of causes of hypertension.

150

CHAPTER2 Endocrinology and metabolism

150

Investigation ofrenal artery stenosis/ high reninlevels

Selective renal angiography remains the gold standard for diagnosing RAS—

other imaging methods can miss the diagnosis. Three- dimensional (3D) MR

angiography is now considered a non- invasive alternative. High renin lev-

els associated with hypertension (o drugs) in the absence of RAS should

prompt a search for a juxtaglomerular cell tumour of one kidney. Note that

the presence of hypertension is essential, as many conditions associated

with a low or normal BP can result in ‘appropriate’ hyper- reninaemia (e.g.

diuretics; cardiac, renal, or liver failure; hypocortisolism; hypovolaemia).

High renin levels can also occur in essential hypertension.

Investigation ofhyperaldosteronism

Hypertension with persistent hypokalaemia raises the possibility of hyper-

aldosteronism which may be due to a variety of causes (see Table 2.7).

Note that investigation for hyperaldosteronism is also appropriate with K

levels in the normal range if other investigations are −ve and hypertension

is marked, dicult to control, or in a younger patient. The optimal approach

to investigation remains controversial and equivocal cases frequently occur.

If there is marked hypokalaemia of recent onset, a 24h UFC (and review of

medication) is indicated to exclude recent- onset hypercortisolism (usually

due to ectopic ACTH production) in which Cushingoid features have not

yet become apparent. True hyperaldosteronism is never due to a malignant

lesion, so that if hypertension can be medically controlled, it is not always

necessary to establish a denitive diagnosis of aetiology. Adetailed scheme

is provided in Fig.2.6.

Establishing hyperaldosteronism

The initial investigation is an upright aldosterone/ renin ratio, performed

when the patient has been upright or sitting (not lying) for at least 2h. The

sample needs to be taken to the laboratory, separated, and frozen imme-

diately. Ideally, the patient should be on no antihypertensives other than

- blockers (e.g. doxazosin), as most drugs can aect interpretation of the

test results (see Table 2.8). This is dicult to achieve in subjects with very

marked hypertension. Combination antihypertensive therapy and spironol-

actone cause the most confusion. An undetectable renin with an unequivo-

cally high aldosterone level makes the diagnosis very likely. A normal or

raised upright renin excludes hyperaldosteronism. Borderline results should

be repeated o interfering medication and after K

replacement (hypoka-

laemia can inappropriately lower aldosterone). Alow renin with a normal

aldosterone can be seen in essential (‘low renin’) hypertension. Refer to

the laboratory for normal and diagnostic ranges. Additional tests (e.g. renin

after Na

restriction/ furosemide, aldosterone after captopril, Na

loading,

or IV saline) are used in specialist centres, but their exact role in testing

remains unresolved.

ENDOCRINE HYPERTENSION

151

Table2.7 Investigating established primary hyperaldosteronism

Change in

aldosterone with

posture

CT ndings

Adrenal venous sampling

(ratio of aldosterone

between sides)

Response to

glucocorticoids*

Treatment

of choice

Notes

Adenoma (Conn’s)

None/ fall Unilateral nodule >10:1 Absent Surgery

Renin- responsive adenoma Rise Unilateral >10:1 Absent Surgery

Unilateral hyperplasia None/ fall ‘Normal’ >10:1 Absent Surgery

Bilateral hyperplasia Rise ‘Normal’ No dierence Absent Medical

Glucocorticoid remediable

aldosteronism (GRA)

None/ fall Normal No dierence Present Steroids Very raised 18- oxo

cortisols. Positive

genetic screening**

Dexamethasone 0.5mg 6- h for 2– 4days resulting in supperession of aldosterone levels to nearly undetectable levels (usually associated fall in BP also).

** Positive for chimeric CYP11B1/ CYP11B2gene.

152

CHAPTER2 Endocrinology and metabolism

152

Still non-diagnostic—

treat medically

Apparent

mineralocorticoid

excess

Primary

hyperaldosteronism:

CT adrenals

Postural studies

Adrenal vein sampling

Upright plasma renin/

aldosterone o as

many interfering drugs

as possible

Undetectable renin,

raised aldosterone

Low renin, borderline

renin/aldosterone

ratio

Repeat renin/aldo o

all interfering

medication

Low renin, low

aldosterone

Review medication,

liquorice ingestion,

family history

Exclude other causes

of hypertension

24h urinary free

cortisol normal

Fig.2.6 Investigation of hyperaldosteronism/ mineralocorticoid excess in patients

with hypertension.

Table2.8 Renin/ aldosterone testing anddrugs

Drug Eect on PRA Eect on aldosterone

Drugs that i PRA

Spironolactone

channel blockers

ACE inhibitors*

Diuretics

Vasodilators

Mayi

Variable

Drugs that d PRA

- blockers

NSAIDs

PRA, plasma renin activity.

* Angiotensin II receptor antagonists are likely to have same eects.

ENDOCRINE HYPERTENSION

153

Investigating thecause ofestablished primary

hyperaldosteronism

There are ve causes of established ° hyperaldosteronism with sup-

pressed renin and high aldosterone (see Box 2.5). Surgery (unilateral

adrenalectomy) is indicated for adenoma (65% of cases), the unusual renin-

responsive adenoma, and the rare cases of unilateral hyperplasia, but not

for bilateral hyperplasia (idiopathic hyperaldosteronism, 30% of cases) or

the rare familial glucocorticoid- remediable aldosteronism (GRA). Tests to

distinguish these are summarized in Box 2.5 and Fig.2.7.

E OHCM 10e, pp. 228–9.

Adenoma or

unilateral hyperplasia

Surgery

Bilateral

hyperplasia

Treat medically

Uncertain

Treat medically

Adrenal vein sampling

Shows lateralization

No lateralization Unsuccessful sampling

Adenoma likely

Surgery

Trial of glucocorticoid

GRA

No suppression Suppression

• Conrm with

genetic testing,

18-OH cortisols

• Screen family

• Treat with

glucocorticoid

CT/MRI adrenals

Unilateral nodule

No nodule/bilateral

nodules

Fig.2.7 Identifying the cause of established primary hyperaldosteronism.

154

CHAPTER2 Endocrinology and metabolism

154

If hyperaldosteronism is established and a nodule is visible on CT/ MRI

imaging, it is reasonable to proceed to unilateral adrenalectomy/ excision

of the nodule. If no nodule or bilateral nodules are seen, then adrenal

vein sampling is the most useful test to determine whether surgery should

be performed. Aldosterone levels after glucocorticoid administration or

genetic testing for the chimeric CYP11B1

/ CYP11B2 gene should be per-

formed beforehand to exclude GRA (see Table 2.7, p. 151— family mem-

bers may be only mildly hypertensive, making family histories unreliable).

Unfortunately, the right adrenal vein cannot be catheterized in up to 25%

of cases and there is a risk of precipitating adrenal haemorrhage. Postural

studies identifying a >50% rise in aldosterone comparing recumbent and

2– 4h of standing/ walking suggest idiopathic hyperplasia, but a small renin-

responsive adenoma not visible on CT could give similar results.

Investigating thecause ofapparent

mineralocorticoidexcess

Rarely, investigation reveals low renin and low aldosterone levels in the

presence of hypertension, hypokalaemia, and alkalosis. There are ve

causes of this (see Box 2.5). A 24h UFC estimation will rapidly exclude

recent- onset, aggressive hypercortisolism. Repeated enquiry should be

made for drug and liquorice product ingestion. The remaining causes may

be diagnosed by urinary cortisol/ cortisone ratio (11β- OH steroid dehydro-

genase deciency— often referred to alone as ‘apparent mineralocorticoid

excess’) or other appropriate changes in urinary and plasma cortisol metab-

olites (e.g. raised DOC levels— 11β- hydroxylase or 17α- hydroxylase de-

ciency) or responsiveness to amiloride (Liddle’s syndrome).

Box 2.5 Causes ofhyperaldosteronism/ apparent

mineralocorticoidexcess

Primary hyperaldosteronism (decreased renin, increased aldosterone)

•

Aldosterone- producing adenoma (Conn’s syndrome)

• Renin- responsive adenoma

• Idiopathic unilateral hyperplasia

• Idiopathic bilateral hyperplasia

• Glucocorticoid- remediable hyperaldosteronism

Apparent mineralocorticoid excess (decreased renin, increased aldosterone)

•

Liquorice ingestion, carbenoxolone, udrocortisone

• Congenital 11β- hydroxysteroid dehydrogenase deciency

• Liddle’s syndrome

• Congenital adrenal hyperplasia (11β- hydroxylase or

17α- hydroxylasedef.)

• Hypercortisolism

ENDOCRINE HYPERTENSION

155

Phaeochromocytoma

1. Clinical features. Phaeochromocytoma is rare, but an important diagnosis

not to miss— can result in fatal hypertensive crisis, especially during

surgery or after inadvertent β- adrenoreceptor blockade without α

blockade. It can be sporadic (90%) or be the rst clue to a familial

syndrome (see Table 2.6). 7

10% of cases are extra- adrenal, 10% multiple,

and 10% malignant (‘tumour of 10%’). Ninety per cent of cases have

sustained or paroxysmal hypertension, but paroxysmal attacks of some

nature are a feature of only 55% of cases. Pure adrenaline- secreting

lesions can occasionally cause hypotension. They are always intra- adrenal.

Phaeochromocytoma needs to be excluded in cases of incidentally found

adrenal masses. Paragangliomas are non- secreting phaeos.

2. Diagnostic tests. Plasma free or 24h urinary fractionated metanephrines

have replaced catecholamine estimations or catecholamine metabolites

(vanillylmandelic acids (VMAs)), as they are more sensitive and specic

and are released continuously. Asingle clearly positive estimation in the

presence of hypertension is usually sucient. If non- diagnostic, sampling

in the recumbent position may help conrm normal levels (metanephrines

are 2- fold higher in the seated position). Mild i can be seen in anxiety

states and with very small lesions detected in the follow- up of familial,

recurrent disease. Causes of false +ve results include methyldopa,

levodopa, labetalol, sotalol, tricyclic and monoamine oxidase inhibitor

(MAOI) antidepressants, paracetamol, sulfasalazine, sympathomimetics,

cocaine, clonidine withdrawal, intracranial events (e.g. SAH, posterior

fossa tumour), or metabolic stress (e.g. hypoglycaemia,MI).

3. Finding the tumour. Once the diagnosis is established, blockade (typically

with increasing twice- daily (bd) doses of phenoxybenzamine) should

be established before invasive investigation. The tumours are usually

large (>2cm) and bright on T2- weighted (T2W) images. CT/ MRI

scanning therefore identies virtually all adrenal lesions. Radionuclide

scanning with

131

I- MIBG (iodine- 131- meta- iodobenzylguanide) is useful

to conrm activity if >1 adrenal nodule is present and to identify

extra- adrenal lesions where no adrenal lesion is seen. Note that extra-

adrenal phaeochromocytomas (paragangliomas) are usually in the chest

or abdomen but can occur in the neck (including chemodoctomas

of the carotid body), pelvis, and bladder. Biopsy of suspected

phaeochromocytoma lesions is contraindicated.

4. Malignant phaeos. The only reliable indicator of malignancy in phaeos is

the presence of distant metastases or local invasion on histology. The

histological appearance of the tumour cells themselves surprisingly has

no signicance.

5. Genetic testing. Up to 30% of phaeos, especially if familial, will have a

genetic basis (see Table 2.9). Genetic testing is now recommended to

be considered in all conrmed cases, especially in familial, syndromic,

or recurrent cases. Fourteen gene loci have been associated with

phaeochromocytoma— the commonest are shown in Table 2.9.

Genetic testing can be targeted to limited loci according to the clinical

presentation, the location of the tumour, and whether it is metastatic

or not (E Further reading, p. 156).

E OHCM 10e, pp. 228–9, p. 738, p. 837.

156

CHAPTER2 Endocrinology and metabolism

156

Further reading

Lenders JW, Duh QY, Eisenhofer G, et al.; Endocrine Society. Pheochromocytoma and paragan-

glioma:an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99

:1915– 42.

Table2.9 Phaeochromocytomas:genetic mutations associated

withphaeochromocytomas or paragangliomas

Gene Syndrome Associated features Frequency

RET

MEN- 2 Medullary carcinoma

of the thyroid,

hyperparathyroidism

VHL von

Hippel– Lindau

syndrome

Haemangioblastomata,

renal, pancreatic

tumours

SDH B

Large, malignant, extra-

adrenal paragangliomas

SDH D Often head and neck

paragangliomas

SDH C Rare 0%

Neurobromatosis von

Recklinghausen’s/

disease

Skin neurobromata,

café- au- lait spots

SDH, succinate dehydrogenase.

ENDOCRINE HYPERTENSION

157

158

CHAPTER2 Endocrinology and metabolism

158

Hypokalaemia

Persistent hypokalaemia (<2.5mmol/ L) can cause muscle weakness,

cramps, tetany, and polyuria, and exacerbate digoxin toxicity and predis-

pose to cardiac arrhythmias. The majority of cases are due to the common

causes (see Box 2.6) and are relatively easy to diagnose. However, puzzling

cases where none of these features are present occur and prompt further

investigation. Aow chart is shown in Fig.2.8.

Note in Fig. 2.8 the importance of identifying the presence of acidosis and

hypertension. Occult diuretic and purgative use should always be borne

in mind. The commonest cause of persistent hypokalaemia with no other

cause presenting in adulthood is Gitelman’s syndrome (NCCT- Na- Cl

cotransporter defect), an asymptomatic congenital disorder, which can usu-

ally be separated from the rare, more severe Bartter’s syndrome (which

usually presents neonatally or in early childhood and represents gene

defects in the renal tubular proteins NKCC2, ROMK, or CLCNKB) by low

serum Mg

levels.

E OHCM 10e, p.98, p. 674.

Box 2.6 Common causes ofhypokalaemia*

• Diuretics

• Vomiting/ diarrhoea

• Intestinal stula

• Laxative or diureticabuse

• Steroids (including udrocortisone), liquorice, ACTH therapy

* See text for investigation of rare causes.

HYPOKALAEMIA

159

Further reading

Shaer AJ. Inherited primary tubular hypokalemic alkalosis: a review of Gitelman and Bartter syn-

dromes. Am J Med Sci 2001; 322

:316– 22.

Episodic/

thyrotoxic:

Periodic

paralysis

woL

Gitelman’s

syndrome

Normal Mg

Bartter’s or

other tubular

defect

High/normal bicarbo-

nate not hypertensive

Thyroid function

Episodic?

Serum Mg

Diuretic screen

Urinary K

High bicarbonate

and hypertensive

Bicarbonate

Exclude common

causes (see table)

Low bicarbonate:

• Renal tubular

acidosis

• Uretero-sigmoid

diversion

• (11-β-OHase

deciency)

Investigate as for

hyperaldosteronism

• Upright renin/aldo

ratio

• Diuretic screen

+ve: occult abuse

• Urinary K

<10mmol/day

consider occult

purgatives

Fig.2.8 Investigation of hypokalaemia.

160

CHAPTER2 Endocrinology and metabolism

160

Hyperkalaemia

Artefactual and common causes need to be excluded, of which renal failure

is the most important (see Table 2.10). If these fail to reveal a cause, then

hypoadrenalism (which can be life- threatening), isolated mineralocorticoid

deciency, and type IV renal tubular acidosis (RTA) need to be excluded.

Hypoadrenalism is suggested by concomitant hyponatraemia, hypotension

(including postural), malaise, and skin pigmentation. Diagnosis is by short

Synacthen

testing (E Adrenal failure, pp. 162–4). Note that hyperkalae-

mia is not a feature of 2° (pituitary) hypoadrenalism since aldosterone

production is maintained by the renin– angiotensin system. Type IV RTA is

common in patients with diabetes. It is associated with renal tubular dys-

function, as well as mildly impaired glomerular function. Serum creatinine

is usually at, or above, the upper limit of normal. It is a state of hyporeni-

naemic hypoaldosteronism. Renin/ aldosterone testing is suggestive, but

there is no denitive test. Isolated mineralocorticoid deciency is usually

congenital (e.g. due to aldosterone synthase deciency) but can be acquired

(e.g. HIV disease). High renin and low aldosterone levels would be expected.

Aldosterone resistance (pseudohypoaldosteronism with high aldosterone

levels, but biochemical mineralocorticoid deciency) has been described.

E OHCM 10e, p.93, p. 301, p. 674.

Table2.10 Causes ofhyperkalaemia

Artefactual Other Rare, but important

Sample left

unseparated

overnight

Excess K

replacement Hypoadrenalism

Sample haemolysed K

- sparing diuretics, ACE

inhibitors

Type IV RTA

Myeloproliferative

disease (leakage of K

from high cell counts)

Renal impairment, especially

acute and after trauma or surgery

Metabolic acidosis (especially

DKA), rhabdomyolysis, burns,

massive blood transfusion

Isolated

mineralocorticoid

deciency

HYPERKALAEMIA

161

162

CHAPTER2 Endocrinology and metabolism

162

Adrenal failure

For causes of ° adrenal failure, see Table2.11.

Hypoadrenalism is often insidious in clinical onset. However, it is an impor-

tant diagnosis to make, as it can be life- threatening, especially at times of

stress. The key is to have a high index of suspicion. ° adrenal failure is

suggested by hyperkalaemia, hyponatraemia, hypotension (including pos-

tural), malaise, weight loss, nausea, abdominal pain, and skin pigmentation.

In pituitary (2° adrenal failure, hyperkalaemia, hypotension, and pigmenta-

tion are absent, and malaise may be the only feature. Signs/ symptoms of

gonadal failure (e.g. loss of libido, reduced shaving, or amenorrhoea), if

present, mandate exclusion of pituitary failure. Random cortisol levels can

be misleading, as they may be high in the morning and low in the evening.

Nonetheless, a random cortisol level >550nmol/ L excludes the diagnosis

and is a useful test in patients undergoing severe stress/ illness (e.g. in inten-

sive therapy unit (ITU)).

2 Do not delay treatment. Where there is a strong suspicion of adre-

nal failure, treatment must not be delayed pending investigation. A short

Synacthen

test or random cortisol should be performed immediately and

treatment commenced with steroids, awaiting results. Alternatively, treat-

ment with dexamethasone 0.5mg daily (which does not cross- react in the

cortisol assay) can be used and then discontinued for the day of testing.

Patients on other forms of glucocorticoid therapy should discontinue treat-

ment on the morning of the test and ideally 24h beforehand (12h for hydro-

cortisone or cortisone acetate). Mineralocorticoid replacement need not

be discontinued.

Short ACTH (Synacthen

)test

The standard test for adrenal failure is the short ACTH test. Alow dose

of synthetic ACTH (0.5 or 1.0µg) test was previously in vogue but has not

been conrmed to be useful.

For 2° (pituitary) adrenal failure, alternative tests include the insulin toler-

ance test (E Insulin tolerance test, pp. 216–17) and the metyrapone test.

However, these tests involve applying a stress and carry a risk in patients

who are profoundly hypoadrenal. They are only indicated in patients within

6 weeks of pituitary surgery or with a pituitary insult where hypotrophy of

the adrenal cortices has yet to develop.

Test todistinguish primary vs secondary adrenal failure

In the context of known pituitary disease and with failure of other pituit-

ary hormones, adrenal failure can be assumed to be 2° (pituitary) in origin.

Where isolated adrenal failure is identied, ° adrenal failure is most likely

and suggested by i skin pigmentation and hyperkalaemia.

ADRENAL FAILURE

163

Table2.11 Causes of° adrenal failure

Cause Associated features Diagnostic tests/ notes

Autoimmune adrenalitis

(>90% of cases in

developed countries)

Autoimmune damage

may be associated with

polyglandular failure types

1 and 2

Anti- adrenal

(21- hydroxylase)

antibodies

Drugs Ketoconazole, mitotane,

etomidate, rifampicin,

phenytoin

Exacerbate pre-

existing adrenal

impairment

Extra- adrenal TB Calcied or enlarged

adrenals, extra- adrenal

TB, but may only

show shrunken glands

Other infections, e.g.

histoplasmosis, syphilis

Seen in North and South

America

Adrenal glands

enlarged

Metastatic malignancy Common with breast, lung,

melanoma, or GI cancer,

although does not always

cause adrenal failure

Enlargement/ deposits

in adrenal glands

on CT

Bilateral adrenal

haemorrhage

Anticoagulation, adrenal

vein sampling

Signs of haemorrhage

on CT

AIDS

CMV/ TB, Cryptococcus

adrenalitis

Adrenoleukodystrophy Especially in ♂ <15years,

dementia, quadriplegia

Adrenomyeloneuropathy

Neuropathy, blindness—

may appear after adrenal

failure

Familial glucocorticoid

deciency

Defective melanocortin

2 receptors, including

Allgrove’s syndrome,

hypoadrenalism associated

with seizures, achalasia, and

alacrima from childhood

Defective cholesterol

metabolism

Congenital adrenal

hypoplasia

Mutation in DAX1 or

related genes, causing

failure of adrenals

to develop. Adrenal

insuciency from birth

164

CHAPTER2 Endocrinology and metabolism

164

Three additional tests can be used toconrm thelevel ofadrenal failure

1. Basal plasma ACTH. This is usually the only additional test required.

High levels are seen in ° adrenal failure; ‘normal’ or low levels are

seen in 2° adrenal insuciency. Note that the sample must be taken

and separated immediately at least 24h after the last dose of a short-

acting glucocorticoid (e.g. hydrocortisone) to avoid pharmacological

suppression. Patients on a longer- acting steroid may have to have

the test repeated >24h after cessation of the steroid if the result is

equivocal.

2. Anti- adrenal antibodies (anti- 21 hydroxylase antibodies). These

antibodies are present in around 70% of patients with autoimmune

adrenalitis (Addison’s disease), the commonest cause of ° adrenal

insuciency. However, they can also be present without adrenal failure

in patients with other autoimmune conditions.

3. Long (depot) ACTH test. Chronic stimulation with ACTH can recover

function in adrenal glands that have failed because of lack of pituitary

ACTH, but not in ° adrenal failure. This is given in the form of ACTH

in oil on 2 consecutive days (E Long (depot) ACTH test, p. 225) or as

an infusion over 48h. With the advent of reliable ACTH assays, this test

is rarely indicated.

Additional diagnostic tests— exclude adrenoleukodystrophy

inmales

While the majority of cases of ° hypoadrenalism are due to autoimmune

disease in developed countries, there are multiple other rare causes.

These should particularly be considered where adrenal failure occurs

in childhood and/ or is associated with neurological disease or hypog-

onadism (see Table 2.11). In particular, adrenoleukodystrophy (ALD)

should be excluded. All ♂ diagnosed with ° adrenal failure should have

serum sent for very long- chain fatty acids (VLCFAs— raised in ALD), as

early bone marrow transplantation (and, to a limited extent, treatment

with ‘Lorenzo’s oil’) may prevent irreversible progressive neurological dis-

ease from developing (e.g. spastic paraparesis).

Further reading

Bornstein SR, Allolio B, Arlt W, etal. Diagnosis and treatment of primary adrenal insuciency:an

Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016; 101

:364– 89.

ADRENAL FAILURE

165

166

CHAPTER2 Endocrinology and metabolism

166

Amenorrhoea

Amenorrhoea is often separated into ° (never menstruated) and 2° (cessa-

tion of periods after menarche) amenorrhoea, but many causes are shared

between the two categories. Structural assessment of the genital tract should

be performed earlier in investigation of ° amenorrhoea. Investigation of

oligomenorrhoea is similar to 2° amenorrhoea. Menorrhagia and intermen-

strual bleeding are due to dierent causes, often gynaecological in origin.

‘Irregular periods’ can fall into either category, depending on whether it

actually refers to intermenstrual bleeding or variably spaced (anovulatory)

periods. Aplan of investigation is shown in Fig.2.9.

In 2° amenorrhoea, it is helpful early on to identify ° ovarian failure (e.g.

due to Turner’s syndrome, premature ovarian failure, radiation, mumps

orchitis, radiation, chemotherapy, or non- 45XO gonadal dysgenesis) char-

acterized by high gonadotrophins (LH, FSH). Where the gonadotrophins

are equivocal or low, amenorrhoea due to hyperprolactinaemia or thyro-

toxicosis should be excluded, but the commonest diagnosis is chronic ano-

vulation due to polycystic ovarian syndrome. In this condition, the ovaries

still produce oestrogen, resulting in a +ve progesterone withdrawal test;

10mg of medroxyprogesterone is given daily for 5days and the test is +ve

if any menstrual bleeding occurs in the following week. If the test is −ve, a

pituitary (e.g. pituitary tumour) or hypothalamic (e.g. stress, anorexia ner-

vosa, systemic illness, or weight loss) cause resulting in profound oestrogen

deciency must be considered.

Further reading

Azziz R. The evaluation and management of hirsutism. Obstet Gynecol 2003; 101:995– 1007.

AMENORRHOEA

167

(a)

(b)

No periods for > 6 months

Structural imaging of

reproductive tract

Never had periods but

some pubertal

development, age > 14y

Never had periods

(primary amenorrhoea)

and delayed puberty

Secondary

amenorrhoea:

Investigate as

shown in (b)

Structural cause

Investigate as delayed puberty

Secondary amenorrhoea

Exclude pregnancy, depot progesterone

Take history of weight loss, stress,

excessive exercise

LH, FSH, oestradiol, prolactin, TSH, FT4

LH and FSH not

markedly raised

(e.g. FSH < 20IU/L)

Raised prolactin or

abnormal thyroid

function

Raised LH, FSH,

(e.g. FSH > 20IU/L)

Progesterone

withdrawal test

(see text)

Investigate and treat

prolactin excess or

thyroid dysfunction

Bleeding occurs:

chronic

anovulation

e.g. polycystic

ovarian

syndrome

No bleeding—

hypothalamic /

pituitary failure:

MRI pituitary

Consider stress/

weight loss/anorexia

Ovarian failure

Chromosomal

analysis esp. for

Turner’s syndrome

Abnormal

Normal

Fig.2.9 Investigation of amenorrhoea:(a)° and (b)2°. See E Delayed puberty,

p. 176 for investigation of delayed puberty.

168

CHAPTER2 Endocrinology and metabolism

168

Infertility

Detailed assessment of infertility is beyond the scope of this text and is

best referred to a specialist in this area. However, the general physician can

take the following basic steps, always remembering that the couple should

be assessed together as the problem may lie with the man, the woman, or

a combination ofboth:

1. Semen analysis of the ♂ and, where possible, a post- coital test to

conrm that live semen are delivered to the vaginaltract.

2. If amenorrhoea is present in the ♀, investigate as in Fig.2.9.

3. If the ♀ is menstruating, determine if the cycles are ovulatory, e.g. by

day 21, progesterone levels, or home measurement urinary dipstick of

the LHsurge.

If live semen are delivered and ovulation is occurring, then structural dam-

age or chlamydial infection in the female genital tract is likely, and will require

gynaecological assessment.

169

INFERTILITY

170

CHAPTER2 Endocrinology and metabolism

170

Hirsutism/ virilization (raised

testosterone)

Hirsutism refers to an i in androgen- dependent terminal hairs in the ♀,

typically over the face/ chin, lower abdomen, arms and legs, and around

the areola of the breast. Virilization reects much higher androgen levels

and comprises the features shown in Box 2.7. Over 20% of women have

more androgen- dependent hair than they consider to be normal. In >95%

of cases, this is associated with androgen levels in the ♀ normal range or

slightly elevated in association with polycystic ovarian syndrome. Some

drugs, such as ciclosporin, diazoxide, minoxidil, and androgenic steroids can

also cause hirsutism. A history of recent onset (<6 months) and rapidly

progressive hirsutism, particularly when associated with features of viriliza-

tion and a testosterone level of >5nmol/ L, should prompt a search for

alternative adrenal or ovarian causes (see Fig.2.10).

E OHCM 10e, p.230.

Box 2.7 Features offemale virilization

• Clitoral enlargement

• Temporal hairloss

• Breast atrophy

• Deepening ofvoice

HIRSUTISM/VIRILIZATION (RAISED TESTOSTERONE)

171

Further reading

Martin KA, Chang RJ, Ehrmann DA, etal. Evaluation and treatment of hirsutism in premenopausal

women:an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008; 93

:1105– 20.

Speiser PW, Azziz R, Baskin LS, et al.; Endocrine Society. Congenital adrenal hyperplasia due to

steroid 21- hydroxylase deciency:an Endocrine Society clinical practice guideline. J Clin Endocrinol

Metab 2010; 95

:4133– 60.

No Yes

Benign androgen

excess

Polycystic ovarian

syndrome

Drugs

Heterozygous CAH*

Treat symptomatically

Cushing syndrome incl.

adrenal carcinoma

Congenital adrenal

hyperplasia

Ovarian tumour

Ovarian hyperthecosis

Ultrasound/CT adrenal

and ovaries

24h urine free cortisol

Urinary steroid prole

Adrenal/ovarian venous

sampling

Increased androgen-

dependent hair growth

• Virilization

• Serum testosterone

>5nmol/L

• Rapidly progressive?

Fig.2.10 Investigation of hirsutism. * CAH, congenital adrenal hyperplasia.

172

CHAPTER2 Endocrinology and metabolism

172

Galactorrhoea (hyperprolactinaemia)

Galactorrhoea is always due to PRL and should be conrmed by asking

the woman to demonstrate a secretion of milky appearance from the nip-

ple. Rarely, galactorrhoea can occur with PRL levels in the normal range

and regular menses, but usually it is associated with mildly raised levels

and amenorrhoea in ♀ or very elevated levels in ♂. There is no link with

breast size— gynaecomastia in ♂ is associated with excess oestrogen. Once

dopamine- blocking drugs (major tranquillizers and anti- emetics, but not

antidepressants), depot progesterone administration, and hypothyroidism

have been excluded, all patients should have pituitary imaging to exclude

a large tumour pressing on the pituitary stalk, especially if there are mod-

est PRL levels (<10,000IU/ L) associated with a large tumour (>2cm) (see

Fig.2.11). If the PRL levels are disproportionately low for the tumour size,

serial dilution of the sample and re- estimation should be considered to

exclude an artefactually low level due to the ‘hook eect’. Very high PRL

levels (>10,000IU/ L) are invariably associated with true prolactinomas.

Nipple manipulation (e.g. to check if galactorrhoea has ceased) and chest

wall trauma (including shingles) can also stimulate PRL levels.

Asymptomatic raised prolactin (macroprolactin)

If PRL is found (accidentally) to be persistently raised (>1000IU/ L), but

menstruation is normal and there is no galactorrhoea, consider the pos-

sibility of macroprolactin. This is a circulating complex of PRL multimers,

and sometimes PRL autoantibodies of no biological importance, but gives

a high reading in the PRL assay and the result often varies widely between

assays. If the laboratory is alerted to a mismatch between PRL levels and

the clinical picture, they can easily screen for this with polyethylene glycol

precipitation. Stress and epileptic ts can result in transiently raised PRL

levels, insucient to cause galactorrhoea.

E OHCM 10e, p.236.

GALACTORRHOEA (HYPERPROLACTINAEMIA)

173

Further reading

McKenna TJ. Should macroprolactin be measured in all hyperprolactinaemic sera? Clin Endocrinol

(Oxf ) 2009; 71

:466– 9.

Melmed S, Casanueva FF, Homan AR, etal.; Endocrine Society. Diagnosis and treatment of hyper-

prolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;

:273– 88.

Normal or

lesion < 1cm

Prolactin

microadenoma

Lesion > 1cm

Prolactin

macroadenoma or

pituitary stalk

compression

Yes No

Raised TSH

Major tranquillizers,

metoclopramide,

domperidone

Chest wall injury/

excess nipple stimulation

Dopamine-blocking

drugs

Markedly raised TSH

Chest wall stimulation

Treat cause and ensure

prolactin returns to

normal

MRI pituitary

Conrm discharge is milk

Check prolactin, TSH,

drug history

Fig.2.11 Investigation of galactorrhoea.

174

CHAPTER2 Endocrinology and metabolism

174

Impotence/ loss oflibido/ male

hypogonadism

Symptoms and signs ofhypogonadism inmen

(lowtestosterone levels)

• Reduced shaving.

• Loss of libido.

• Impotence.

• Reduced energy/ aggression levels.

• Loss of pubic, chest, and axillaryhair.

• Gynaecomastia often results due to a lower testosterone/

oestrogenratio.

Note that very low levels of testosterone (at least <5nmol/ L, typical normal

range 10– 30nmol/ L) are required to result in symptoms. Mild reductions are

common, especially in the elderly, and are rarely of importance. Impotence

alone (without loss of libido) can also be caused by neurovascular and

psychological causes (e.g. diabetes, spinal damage, urological surgery, athero-

sclerosis of the aorta, drugs, stress, and psychosexual dysfunction). Where

the testosterone level is at the lower limit of normal or SHBG abnormalities

are suspected and symptoms are present, measurement of free testoster-

one or bioavailable testosterone by an established method may be indicated.

Such methods may need referral to a reference laboratory.

After history taking forconditions described, investigation ofsuspected male

hypogonadism requires

•

PRL.

• Thyroid function.

• LH andFSH.

• Testosterone.

Hyperprolactinaemia or thyrotoxicosis, if present, need to be treated on

their own merits. If the testosterone level is clearly low, high gonadotro-

phins point to testicular failure (e.g. testicular surgery, irradiation or trauma,

chemotherapy, crypto- orchidism, previous orchitis, gonadal dysgenesis,

including Klinefelter’s syndrome XXY). Low gonadotrophin levels with a

clearly low testosterone level point to a hypothalamic or pituitary cause

(systemic illness, pituitary tumour), which requires further investigations

(E Hypopituitarism, pp. 128–30). If no cause is found for hypogonado-

trophic hypogonadism, the likely cause is Kallman’s syndrome, especially if

associated with anosmia.

E OHCM 10e, p.230.

Further reading

Bhasin S, Cunningham GR, Hayes FJ, etal.; Task Force, Endocrine Society. (2010) Testosterone ther-

apy in men with androgen deciency syndromes:an Endocrine Society clinical practice guideline. J

Clin Endocrinol Metab 2010; 95

:2536– 59.

Sato N, Katsumata N, Kagami M, etal. Clinical assessment and mutation analysis of Kallmann syn-

drome 1 (KAL1) and broblast growth factor receptor 1 (FGFR1, or KAL2) in ve families and 18

sporadic patients. J Clin Endocrinol Metab 2004; 89

:1079– 88.

GYNAECOMASTIA

175

Gynaecomastia

Gynaecomastia results from an excessive eect of oestrogens or a raised

oestrogen/ testosterone ratio. Causes are summarized in Table 2.12. True

gynaecomastia should be associated with palpable breast tissue and distin-

guished from apparent breast enlargement due to obesity. Though very

rare, the most important diagnoses to exclude are hypogonadism and tes-

ticular and lung tumours.

Investigations should include

• LFTs.

• Thyroid function.

• LH andFSH.

• Testosterone.

• Oestradiol.

• hCG.

• AFP.

• CXR.

• TesticularUSS.

• Further review of drug history.

Physiological gynaecomastia should only be diagnosed if other causes have

been excluded.

E OHCM 10e, p.230.

Table2.12 Causes ofgynaecomastia

Physiological Newborn, adolescent, elderly

Hypogonadism e.g. Klinefelter’s syndrome, testicular failure

i oestrogen Testicular tumours, lung cancer producing hCG, liver

disease, thyrotoxicosis

Drugs Including oestrogens, spironolactone, cimetidine, digoxin,

testosterone administration

176

CHAPTER2 Endocrinology and metabolism

176

Delayed puberty

Denition

Puberty is considered delayed in girls if there is no breast development by

age 13 (or menses by age 15)and in boys if there is no testicular enlargement

by age 14. Note that 3% of normal children will fall into these categories.

Clinical features and initial investigations

A detailed history and examination is required for overt systemic disease,

psychosocial stress, and anorexia nervosa, and to assess the child’s height,

pubertal features (pubic hair, testicular size, breast growth, menses), and

any dysmorphic features (e.g. features of Turner’s syndrome). Where pos-

sible, growth rate should be calculated from sequential height measure-

ments over at least 6months.

If no obvious cause is identied, baseline investigations should include:

•

LH andFSH.

• TSH, FT4,PRL.

• FBC, U&E, bicarbonate (HCO

−

), CRP, and antigliadin/ endomysial

antibodies for occult systemic disease.

•

Boneage.

This should enable the child to be placed in one of ve categories:

1. Raised LH/ FSH (° gonadal failure). Causes:Turner’s syndrome,

Klinefelter’s syndrome, ovarian/ testicular injury. Proceed to

karyotyping (should be performed in all girls with delayed puberty as

Turner’s syndrome may not be apparent).

2. Short, low LH/ FSH, overt systemic disease. Causes:asthma, anorexia

nervosa, social deprivation, generalized illness, treatment for cancer,

including cranial irradiation, dysmorphic (Noonan’s syndrome and

others).

3. Short, low LH/ FSH, occult systemic disease. Causes:hypothyroidism,

hyperprolactinaemia, renal failure, RTA, coeliac disease, Crohn’s

disease.

4. Short, low LH/ FSH, no systemic disease. Causes:constitutional delay of

puberty, hypothalamic/ pituitary disease.

5. Not short, low LH/ FSH. Causes:Kallman’s syndrome (if anosmia present)

or isolated gonadotrophin deciency. Cannot reliably distinguish from

constitutional delay of puberty. Observe.

The investigation of children who fall into the commonest category ‘short,

low LH/ FSH, no systemic disease’ is summarized in Fig. 2.12. The onset of

puberty after a period of observation is reassuring, but continued observa-

tion is required to ensure the process proceeds to completion, including a

growth spurt. If not, further investigation for disorders of steroidogenesis,

androgen insensitivity, skeletal dysplasia, premature gonadal failure, and,

in the ♀, genital tract abnormalities and polycystic ovarian syndrome are

indicated.

DELAYED PUBERTY

177

Observe

MRI pituitary/

hypothalamus

Test for growth

hormone

reserve/

LHRH test

Calculate bone age

Obtain parental heights

Observe for 6 months

• Normal height for

skeletal age/parents

• Normal growth

velocity for skeletal age

• Early signs of puberty

now appear

• Short for skeletal

age/parents

• Low growth velocity

for skeletal age

• No signs of puberty

Fig.2.12 Investigation of delayed puberty in children who are short, with no

evidence of systemic disease

and low LH/ FSH levels.

Notes:

1. Including normal thyroid function andPRL.

2. If develops headache, vomiting, or visual symptoms, proceed immediately toMRI.

3. Refer to a paediatric endocrinologist. Tests used vary, e.g. gonadotrophin response to luteinizing

hormone- releasing hormone (LHRH) after androgenic priming and ITT for GH response.

178

CHAPTER2 Endocrinology and metabolism

178

Short stature

Evaluation of children who are below the third growth centile for age or

particularly small for their family should include:

•

Height for age (percentile).

• Mid- parental height (for girls, mean of father’s height minus 12.6cm +

mother’s; for boys, add 12.6cm to mother’s height).

•

Bone age (to assess growth potential/ height prediction).

• Observation over 3– 6months to determine growth velocity.

Children of short (but normal) parents, who are growing normally, can

be observed. Dysmorphic children require further evaluation/ specialist

assessment. Children who are short for their parental heights (low pre-

dicted height), particularly if growing slowly, and short children of pubertal

age who have not entered puberty should be investigated as for ‘delayed

puberty’. Referral for paediatric endocrinological assessment is advised.

PRECOCIOUS PUBERTY

179

Precocious puberty

Denition

Puberty is considered premature if multiple signs, including accelerated

growth rate and bone age, appear by age 8 in girls or age 9 in boys. Note

that isolated breast development (premature thelarche) or pubic hair (pre-

mature adrenarche) are benign conditions if no other evidence of puberty

appears. True precocious puberty requires urgent investigation to deter-

mine the cause and avoid irreparable loss of nal adult height. In girls, it is

often idiopathic, but not in boys. The causes are given in Table2.13.

Investigations

Precocious puberty is conrmed by pubertal levels of sex steroids (oestra-

diol, testosterone). Testicular enlargement (or ovarian enlargement on

USS) and detectable LH/ FSH levels suggest central precocious puberty and

a CT/ MRI scan of the brain is indicated. Gonadal enlargement can also

be seen with testotoxicosis, hCG- producing tumours, hypothyroidism, and

McCune– Albright syndrome. Further investigation should be performed in

combination with a paediatric endocrinologist.

Table2.13 Causes ofprecocious puberty

Central Gonadotrophin- independent

Idiopathic (especially girls) Congenital adrenal hyperplasia (♂)

CNS hamartoma

(especially pinealoma)

Adrenal/ ovarian/ hCG- secreting tumour

Other CNS diseases, e.g.

hydrocephalus, trauma

McCune– Albright syndrome, hypothyroidism,

follicular cyst (♀) familial testotoxicosis (♂)

180

CHAPTER2 Endocrinology and metabolism

180

Thyroid function testing:general

In the majority of cases, thyroid function testing and interpretation are

straightforward (see Fig. 2.13). However, the following points should be

borne inmind.

1. Which rst- line test?— TSH. TSH levels are the most sensitive indicator

of thyroid dysfunction, except in patients with pituitary disease where

they are uninterpretable. TSH used alone as a rst- line test will miss

(levels ‘normal’) unsuspected cases of 2° hypothyroidism, and some

laboratories combine TSH and T4 as rst- line tests. TSH is also

unreliable in patients with recently treated hyperthyroidism, as it can

remain suppressed (undetectable) for several weeks after FT4 or FT3

levels have normalized.

2. Which tests?— T4/ T3. Free T3 and T4 tests (FT3, FT4) are now

more reliable and preferred (although more expensive) to total T3

or T4 measurements. Interference in these assays does occur but is

increasingly rare. Total thyroid hormone levels are markedly inuenced

by changes in binding proteins (e.g. due to pregnancy, oestrogen-

containing contraceptives).

3. Thyroid autoantibodies. These are markers of autoimmune thyroid

disease. Antithyroid microsomal antibodies have been identied as

antithyroid peroxidase (anti- TPO) antibodies. Anti- TPO antibodies

are more sensitive than anti- thyroglobulin (Tg) antibodies and

are present in around 45– 80% of Graves’ disease and 80– 95% of

Hashimoto’s disease/ atrophic thyroiditis. Increasingly, laboratories are

measuring anti- TPO directly as their only antibody test (sometimes just

referred to as ‘antithyroid antibodies’). Note that anti- TSH receptor

antibodies— the cause of Graves’ disease— require a specic assay

request. (For indications for testing, E Anti- TSH receptor antibody

testing, p. 184).

4. Tests should agree. To conrm thyroid dysfunction, at least two TFTs

and, in cases of doubt, all three (TSH, FT3, FT4) should be performed.

Results of the tests should be in agreement— if not, assay interference

(heterophile antibodies, anti- T4 or anti- T3 antibodies present in the

serum) or unusual causes should be suspected.

5. Avoid thyroid function testing in systemically unwell patients. In very ill

patients, especially in intensive care, a pattern of ‘sick euthyroidism’

is often seen, with low TSH levels, low FT3 levels, and sometimes

low FT4 levels. Accurate interpretation of true thyroid status is

impossible. Araised FT3 level in a very ill patient suggests signicant

hyperthyroidism, and a very raised TSH level (>20mU/ L) with

undetectable FT4 levels suggests profound hypothyroidism. Other

changes should be interpreted with extreme caution and the tests

repeated after recovery.

E OHCM 10e, pp. 216–17.

THYROID FUNCTION TESTING:GENERAL

181

Normal

FT4/FT3

Low

FT4/FT3

Raised

FT4/FT3

Thyrotoxicosis

Subclinical

thyrotoxicosis

Levothyroxine

ingestion

Steroid therapy

Non-thyroidal

illness

Dopamine

infusion

Non-thyroidal illness

Pituitary failure

Recent (excessive) treatment for

hyperthyroidism

Hypothyroidism

Subclinical

hypothyroidism

Poor compliance

with T4 therapy

Interfering

(heterophile)

antibody

Recovery from

non-thyroidal

illness

Hypoadrenalism

Normal

TSH-secreting pituitary tumour

Thyroid hormone resistance (receptor

defect)

Intermittent T4 therapy/acute

overdose

Interfering

anti-T4/T3 antibody

Familial dysalbuminaemic

hyperthyroxinaemia

Acute psychiatric illness

Note:

free thyroid hormone assays are assumed—eects of changes in binding

proteins on total thyroid hormone assays are not included.

Low TSH Normal TSH Raised TSH

Fig.2.13 Patterns of TFTs. To use this table, you need the results of both TSH

and either free T4 (FT4) or free T3 (FT3) tests. If either FT4 or FT3 are outside the

reference range, then FT4/ FT3 are considered abnormal in this table. If FT4 and

FT3 are abnormal in dierent directions (e.g. one is low and the other is high), see

point4, ‘Tests should agree’, pp. 180–1.

Reprinted from The Lancet, 357, Dayan CM ‘Interpretation of thyroid function tests’ 619– 24 (2001)

with permission from Elsevier.

Further reading

Association for Clinical Biochemistry/ British Thyroid Association (2006). UK guidelines for the use

of thyroid function tests

. London: ACB/ BTA. M http:// www.acb.org.uk/ docs/ default- source/

guidelines/ TFTguidelinenal.pdf.

National Academy of Clinical Biochemistry Practice Guidelines (2002). M

http:// www.aacc.org/

members/ nacb/ LMPG/ Pages/ default.aspx.

182

CHAPTER2 Endocrinology and metabolism

182

Hyperthyroidism (thyrotoxicosis)

Clinical features

Hyperthyroidism is rare in childhood but aects all adult age groups.

Classic features include weight loss despite i appetite, palpitations, AF,

heat intolerance, anxiety, agitation, diarrhoea, tremor, and proximal weak-

ness. Lid retraction and lid lag can be seen in any cause of hyperthyroid-

ism, but proptosis, periorbital oedema, chemosis, diplopia, and optic nerve

compression only occur in association with Graves’ disease (thyroid eye

disease) and occasionally associated with pretibial myxoedema and thyroid

acropachy. In the elderly, presentation with isolated weight loss or AF is

common. Raised ALP and SHBG, leucopenia, and rarely hypercalcaemia

are recognized associations.

Thyroid function testing

An undetectable TSH level and an i free T3 level are required to diag nose

hyperthyroidism. In milder cases, T4 levels may be in the normal range (‘T3

toxicosis’). Normal TSH levels with i

T4 and T3 are seen in TSH- secreting

pituitary tumours (very rare) or in patients with thyroid hormone resistance

(also very rare) (see Fig.2.13).

Investigation ofcause

For an overview of investigation, see Fig.2.14.

Under the age of 40, Graves’ disease is the commonest cause. After

this age, Graves’ disease, toxic nodular goitre, and toxic nodule all occur.

However, a short history (1 month) of symptoms or absence of relevant

symptoms (chance blood test nding) raises the possibility of self- resolving

(transient) thyroiditis, a diagnosis supported by neck pain and raised ESR

(viral/ subacute/ De Quervain’s) or occurrence in the rst 9months post-

partum (postpartum thyroiditis— painless). Transient thyrotoxicosis can also

occur in patients with subclinical autoimmune thyroiditis (‘silent thyroiditis’—

painless), especially during cytokine therapy (e.g. interferon for hepatitis C).

Graves’ disease or other forms of autoimmune thyroiditis are seen in >30%

of patients 2– 3years after treatment with alemtuzumab (for MS), in associa-

tion with lymphocyte repopulation. If self- resolving thyroiditis is suspected,

withhold treatment and repeat the tests after 6 weeks. When thyroid eye

disease is present, no further tests are required to diagnose Graves’ disease.

If not, antithyroid antibodies (e.g. anti- TPO antibodies) and isotope thy-

roid scanning can be useful to distinguish possible causes (see Fig. 2.14 and

E Chapter14). No uptake is seen in transient thyroiditis. Excess thyroid

hormone ingestion rarely causes very marked thyrotoxicosis, unless the

active form (T3) is taken (T3 tablets or desiccated thyroid extract).

HYPERTHYROIDISM (THYROTOXICOSIS)

183

Iodine

Iodine has multiple and conicting eects on the thyroid. Potassium iodide

inhibits release of thyroid hormones from the gland and thyroid hormone

biosynthesis (Wol– Chaiko eect), promoting hypothyroidism. However,

escape from these eects occurs in most individuals in a few weeks. In

patients with a multinodular goitre, excess iodine (e.g. in amiodarone or

radiographic contrast media) can result in thyrotoxicosis by excess provi-

sion of substrate (Jod– Basedow eect).

Amiodarone

Has three main eects on the thyroid hormoneaxis:

•

Inhibits T4 l T3 conversion, which in the pituitary can result in an

asymptomatic mild rise in TSH level (reduced thyroid hormone action)

and/ or a rise in FT4level.

• Can induce true hypothyroidism, usually in the rst year of treatment.

• Can induce true hyperthyroidism either via the Jod– Basedow eect in

patients with multinodular goitre or by destructive thyroiditis in healthy

glands.

Thyrotoxicosis can occur at any time after commencing therapy and

can be very dicult to treat. Interpretation of TFTs on amiodarone: a

raised FT3 level indicates true hyperthyroidism; a markedly raised TSH

level (e.g. >10mU/ L), especially if the FT4 level is low, indicates true

hypothyroidism.

Repeat tests in

6 weeks

Now eu-/

hypothyroid

Spontaneously

resolving

thyroiditis

Hyperthyroidism

conrmed

(suppressed TSH,

raised free T3)

Short history

(<6wks)

Neck pain,

raised ESR

Within 9 mo

post-partum

Graves’ eye

disease

Isotope thyroid

scan, antithyroid

Abs

Clear history,

no eye disease

Graves’ disease

Diuse

uptake or

Ab +ve

Irregular

uptake

Ab −ve

Toxic

nodule

Multinodular

goitre

Hot nodule

Ab −ve

Fig.2.14 Investigation of the cause of hyperthyroidism.

184

CHAPTER2 Endocrinology and metabolism

184

Hyperthyroidism inpregnancy

Signicant hyperthyroidism in pregnancy is generally due to Graves’ dis-

ease. Mild hyperthyroidism, particularly in association with hyperemesis

gravidarum in the rst trimester, is often due to a cross- reaction by very

high hCG levels with the TSH receptor (‘gestational thyrotoxicosis’). In the

postpartum period, thyrotoxicosis may be due to postpartum thyroiditis

(self- resolving) or a recurrence of Graves’ disease (requires treatment).

Measurement of anti- TSH receptor antibody levels may be indicated to

distinguish these possibilities.

Thyroidstorm

This is dened as severe thyrotoxicosis with confusion/ delirium not

explained by other factors. There is no denitive test and levels of thyroid

hormone are not higher than in other thyrotoxic individuals with no fea-

tures of storm. Severe agitation, tachycardia, and hyperpyrexia are usually

seen. Usually precipitated by infection, trauma, or surgery, especially to the

thyroid gland. Very rare but tends to occur in individuals who have been

poorly compliant in the rst few weeks of drug therapy for thyrotoxicosis.

Anti- TSH receptor antibody testing (TBII, TRAbs.TSAb)

This test is increasingly available in local and regional laboratories. In second-

or third- generation assays, especially assays for stimulatory antibodies, it is

positive in >95% of cases, save other tests, and indicated that the patient

is at risk of Graves’ eye disease. Indications for anti- TSH receptor antibody

testing include distinguishing gestational thyrotoxicosis or postpartum thy-

roiditis from Graves’ disease, indicating the risk of neonatal thyrotoxicosis

and (controversial) predicting recurrence after a course of thioamide drug

therapy.

E OHCM 10e, p.31, p. 216, p. 562.

Further reading

Barbesino G, Tomer Y. Clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013;

:2247– 55.

HYPERTHYROIDISM (THYROTOXICOSIS)

185

186

CHAPTER2 Endocrinology and metabolism

186

Hypothyroidism

Clinical features

Classic clinical features of hypothyroidism include weight gain, cold intoler-

ance, dry skin, constipation, memory loss, lethargy/ slow thought/ ‘slowing

up’, menorrhagia, periorbital/ facial oedema, loss of the outer two- thirds of

eyebrows, deafness, chest pain, and coma. These are rarely seen nowadays,

as TFTs are easy to perform and detect the disease usually at an earlier

stage. Weight gain, dry skin, and lethargy are frequently reported, but even

biochemically hypothyroid individuals can only condently be ascribed to

thyroid status if they reverse on treatment.

Biochemical diagnosis

i TSH with T4 in the normal range is referred to as subclinical hypothy-

roidism. i TSH with d T4 is overt hypothyroidism. d T4 with TSH in the

normal range may also be due to pituitary failure (2° hypothyroidism) and,

if persistent, requires pituitary function testing. See Fig. 2.13 for other pat-

terns ofTFTs.

Dierential diagnosis (causes)

In iodine- sucient countries, most spontaneous hypothyroidism is due to

autoimmune thyroiditis (Hashimoto’s disease if goitre present, atrophic thy-

roiditis if goitre absent)— antithyroid antibodies (anti- TPO, anti- Tg) present

in 80– 90% of cases. Other common causes are post- thyroidectomy, post-

radioiodine therapy, and side eects of amiodarone or lithium. Rarer causes

include treatment with cytokines or other drugs (e.g. interferons, granulo-

cytic macrophage colony- stimulating factor (GM- CSF), interleukin- 2, tyros-

ine kinase inhibitors, alemtuzumab), vast excess of iodine intake (iodine

drops, water purifying tablets), congenital hypothyroidism (caused by a

variety of genetic defects; should be detected by neonatal screening pro-

gramme), iodine deciency (urinary iodide excretion <45µg/ day, common-

est cause worldwide, especially mountainous areas, S.Germany, Greece,

Paraguay— ‘endemic goitre’), thyroid- blocking substances in the indigenous

diet (goitrogens, especially in brassicas and cassava, e.g. in Sheeld, Spain,

Bohemia, Kentucky, Virginia, Tasmania— ‘endogenous goitre’ without iodine

deciency), Pendred’s syndrome (mild hypothyroidism with sensorineural

deafness due to Mondini cochlear defect detectable on MRI, positive per-

chlorate discharge test). For further information, E Transient hypothy-

roidism, p. 187.

3 Diagnostic catches i TSH and d T4 always represents hypothyroid-

ism. If the TSH alone is i and the T4 is not even slightly low, a heterophile

antibody interfering in the TSH assay may be present in the patient’s serum.

This is especially likely if there is no change in TSH level after thyroxine

treatment, but the T4 level rises (conrming compliance with tablets). For

unusual patterns of thyroid function tests, see Fig. 2.14. Note that, within

the rst 1– 3months (or longer) after treatment of hyperthyroidism, pro-

found hypothyroidism may develop with a d T4, but the TSH may still be

suppressed or only mildly raised due to the long period of TSH suppression

prior to treatment. Raised TSH alone with disproportionate symptoms of

lethargy may be seen in hypoadrenalism.

HYPOTHYROIDISM

187

Transient hypothyroidism

Transient/ self- resolving hypothyroidism, often preceded by hyperthyroid-

ism, is seen in viral thyroiditis, after pregnancy (postpartum thyroiditis), and

in some individuals with autoimmune thyroiditis. Treatment temporarily

with levothyroxine is only required if the patient is very symptomatic.

Thyroid function should return to normal within 6months.

Subclinical hypothyroidism

A raised TSH (<20mU/ L) with normal T4/ T3 is very common and seen

in 5– 10% of women and 72% of ♂. It is usually due to subclinical autoim-

mune thyroid disease and is frequently discovered on routine testing. In ran-

domized trials, 720% of patients obtain psychological benet from beginning

T4 therapy; in many others, it is probably truly asymptomatic. If antithyroid

antibodies are detectable, the rate of progression to overt hypothyroid-

ism is 750% at 20years, but higher than this with higher initial TSH levels.

If the TSH alone is raised with −ve antibodies (or the TSH is normal with

raised antibodies alone), overt hypothyroidism develops in 25% at 20years.

Areasonable approach is a trial of levothyroxine for 6months in symp-

tomatic patients with subclinical hypothyroidism or TSH >10mU/ L, and

observing the TSH level at 6- to 12- monthly intervals in asymptomatic

patients with TSH <10mU/ L.

Hypothyroidism and pregnancy

Overt hypothyroidism is associated with poor obstetric outcomes. Recent

evidence suggests that subclinical hypothyroidism is associated with an i

miscarriage rate and a slight reduction in the baby’s intelligence quotient

(IQ) and should be treated. Some authorities advocate screening for hypo-

thyroidism in all antenatal patients as early as possible in pregnancy. Patients

on T4 need to i

their dose by 25– 50µg from the rst trimester of preg-

nancy. Maternal levothyroxine can compensate for fetal thyroid failure

inutero, but congenital hypothyroidism must be detected at birth (screen-

ing test) to avoid mental retardation developing. Where the mother and

fetus are both hypothyroid— most commonly due to iodine deciency—

mental retardation can develop in utero (cretinism). Note that mothers with

+ve antithyroid antibodies and/ or subclinical hypothyroidism have a 50%

chance of developing (transient) postpartum thyroiditis.

E OHCM 10e,p. 31, p. 149, p. 203.

Further reading

Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012; 379:1142– 54.

188

CHAPTER2 Endocrinology and metabolism

188

Hypercalcaemia

Clinical features

Usually asymptomatic if Ca

<3.0mmol/ L. Typical symptoms include poly-

dipsia/ polyuria, constipation, indigestion, pancreatitis, hypertension, tired-

ness, drowsiness/ confusion, abdominal pains, and renal colic. Renal failure

can occur due to dehydration (reversible), nephrocalcinosis, and/ or stag-

horn calculi. Osteitis brosa cystica in cases of hyperparathyroidism (with

subperiosteal resorption of bone, particularly of the distal phalanges and

bone cysts— brown tumours) is now rare, other than in renal failure, but

can be associated with bonepain.

Investigation ofthecause

Ninety- ve per cent of persistent hypercalcaemia is due to either hyperpar-

athyroidism or malignancy (see Fig. 2.15). Asymptomatic 1° hyperparathy-

roidism is common in 50- to 70- year- old women, and a PTH level (sampled

simultaneously with i Ca

and measured in a highly sensitive assay) which

is raised or in the upper normal range in the presence of hypercalcaemia

conrms the diagnosis. Low normal or low levels of PTH should prompt a

search for malignancy, especially breast, prostate, bronchus, kidney, thyroid,

or myeloma. Bone- derived ALP levels may be raised in both malignancy and

hyperparathyroidism. Bone scan may be useful in disseminated malignancy

but can be −ve in cancers releasing PTH- related peptide (NOT detected in

routine PTH assays) and in myeloma. If malignancy is not found, the condi-

tions shown in Fig. 2.15 need to be considered. Markedly abnormal renal

function is seen in milk- alkali syndrome, myeloma, and tertiary hyperpar-

athyroidism. Sarcoid may be dicult to diagnose but is suggested by a raised

serum ACE level (not invariable), a dramatic response to steroids, and a

+ve liver or other biopsy for granulomata.

Investigation ofestablished hyperparathyroidism

Familial benign hypocalciuric hypercalcaemia (FBHH) is a very rare con-

dition caused by an inactivating mutation of the calcium- sensing receptor

(CaSR). This results in stable, lifelong hypercalcaemia with a raised PTH

level, which rarely causes complications. It is inherited in an autosomal

dominant fashion.

The hallmark is hypocalciuria— denedas:

Urine [Ca

] × plasma creatinine/plasma [Ca

] × urine creat <0.01

(All in units of mmol/ L.)

Although rare, it is important to recognize, as parathyroidectomy is not

required.

Further investigation of ° hyperparathyroidism should include serum

creatinine, KUB plain abdominal X- ray to exclude renal stones, and a spot

urine Ca

/ creatinine to rule outFBHH.

HYPERCALCAEMIA

189

In >80% of cases, ° hyperparathyroidism is due to adenomatous change

in one of the four parathyroid glands. In a minority of cases and in familial

hyperparathyroidism associated with MEN- 1 (pituitary tumours, endocrine

pancreatic tumours, and hyperparathyroidism) or MEN- 2 (medullary carci-

noma of the thyroid, phaeochromocytoma, and hyperparathyroidism) four

gland hyperplasia occurs, requiring resection of at least three- and- a- half

glands for treatment. Very rarely (<1% of cases), parathyroid carcinoma is

the cause. Lithium therapy may also be associated with (mild) hyperparath-

yroidism. Once a diagnosis of ° hyperthyroidism is made,

99m

technetium-

sestamibi radionucleotide scanning is the most sensitive imaging technique

and will show the location of the parathyroid adenoma. In dicult cases,

local venous sampling may be required for localizing a parathyroid ade-

noma, especially if it is outside theneck.

Tertiary hyperparathyroidism

Refers to acquired autonomy of the parathyroid glands leading to hyper-

calcaemia following chronic vitamin D deciency, as seen in renal failure or

with malabsorption. 2° hyperparathyroidism is associated with hypocalcae-

mia and is the appropriate response to vitamin D deciency.

Hypercalcaemia

(persistent):

>2.7mmol/L

Measure PTH (sensitive

assay, while Ca

raised)

Normal or

raised PTH

Investigation of hypercalcaemia

Hyperparathyroidism

(primary or tertiary)

Exclude malignancy

inc. myeloma

Consider:

Sarcoid/granulomatous

disease

Milk alkali syndrome

Thyrotoxicosis

Acute hypoadrenalism

Immobility

Paget’s disease

Vitamin D intoxication

Thiazide diuretics

Check:

Urine Ca

/creatinine ratio

to exclude FBHH (see text)

KUB X-ray vs stones

Serum creatinine

Low or

undetectable PTH

Fig.2.15 Investigation of hypercalcaemia.

190

CHAPTER2 Endocrinology and metabolism

190

Hypocalcaemia/ osteomalacia

Clinical features

Chronic hypocalcaemia is often surprisingly asymptomatic. Symptoms

and signs, when present, include muscle spasms, paraesthesiae, especially

around the mouth and in ngers, tetany, ts, +ve Chvostek’s (VIIth nerve

hyperexcitability) and Trousseau’s signs (tetany of the hand when BP cu

inated). Chronic hypocalcaemia is also associated with papilloedema,

abnormal dentition (if begins in childhood), cataract, and intracranial cal-

cication (of no clinical consequence). Hypocalcaemia due to vitamin D

deciency is associated with muscle pains, proximal myopathy, and osteo-

malacia. In some cases of pseudohypoparathyroidism (type Ia), there are

phenotypic abnormalities (somatic features), including short fourth meta-

carpal, bone changes (Albright’s hereditary osteodystrophy), mental retar-

dation, short stature, obesity, and resistance to other hormones, e.g. TSH,

glucagon, gonadotrophins.

Investigation ofcause

Persistent hypocalcaemia (corrected for serum albumin levels) with a

normal serum creatinine level is almost always due to either hypopar-

athyroidism or vitamin D deciency (osteomalacia). Other causes and

distinguishing features are shown in Table 2.14, and a scheme for diag-

nosis is shown in Fig. 2.16. In failure of PTH action, Ca

is very low

(<1.8mmol/ L) and PO

4−

is raised, but ALP is not raised and there is no

osteomalacia. If the PTH is found to be raised, then pseudohypopar-

athyroidism can be diagnosed, which is subclassied as type Ia (paternally

inherited a Gs- α defect with somatic features), type Ib (‘renally selec-

tive’ maternally inherited Gs- α defect— no somatic features), or typeII.

The classic test is the Elsworth– Howard test— measuring urine cyclic

adenosine monophosphate (cAMP) response to infused PTH(1– 34) ana-

logue. Families with type 1a may also include patients with pseudopseu-

dohypoparathyroidism, characterized by normocalcaemia, but somatic

changes of pseudohypoparathyroidism. The mutations are in the same

gene. The aetiology of type II pseudohypoparathyroidism (normal

renalCa

excretion and no other somatic features) remains unclear.

A low or normal PTH in the presence of a Ca

level <1.8mmol/ L makes

hypoparathyroidism the likely diagnosis (see Table 2.14 for possible causes),

but an attempt to rule out an activating CaSR mutation with a urine Ca

creatinine ratio (see Fig. 2.15) should be made. In this rare genetic condition,

levels are generally higher (around 1.75mmol/ L). Importantly, Ca

or vitamin D replacement has a high likelihood of causing nephrocalcinosis

and is best avoided. Autoimmune hypoparathyroidism in children or young

people is particularly seen in association with autoimmune polyglandular

syndrome type 1 (chronic candidiasis, coeliac disease, adrenal insuciency).

In failure of vitamin D action (see Fig. 2.16, Table 2.14), there is a com-

pensatory PTH rise, which partly corrects the Ca

level but causes a raised

ALP. In addition, there is osteomalacia. In the presence of a signicantly

raised creatinine, renal osteodystrophy (impaired 25- OH vitamin D gen-

eration) is the most likely diagnosis; otherwise dietary vitamin D deciency

(low 25- OH vitamin D) or vitamin D resistance must be distinguished (see

Table2.14).

HYPOCALCAEMIA/OSTEOMALACIA

191

Osteomalacia

Osteomalacia is strictly a histological diagnosis but is suggested by Looser’s

zones and pseudo- fractures on X- ray (especially pelvis and upper femur).

If osteomalacia with muscle weakness occurs in the absence of hypocal-

caemia or a raised ALP, hypophosphataemia (‘vitamin D- resistant rickets’)

is likely. Causes of a low PO

4−

include intrinsic renal disease, congenital

4−

leak, acquired PO

4−

leak, and oncogenic osteomalacia. This last con-

dition is associated with very dicult- to- nd tumours, often benign, typi-

cally haemangiopericytomas of the naso- / oropharynx that may take years

to become manifest. It is due to secretion of the cytokine broblast growth

factor 23 (FGF23) by tumours, causing a phosphaturic eect. If suspected,

FGF23 levels can be assayed in specialized laboratories. Treatment is PO

4−

replacement until the tumour can be resected.

Investigation of hypocalcaemia

Consistently low Ca

(<2.1mmol/L)

check albumin, phosphate, creatinine, alk

phos, Mg

, PTH (while Ca

low)

Raised alk phos

and raised

PTH

Check 25-OH

vit D

X-rays for

osteomalacia

Low 25-OH

vit D

Dietary vit D

deciency/

malabsorption

Measure 1.25-OH

vit D and review creat:

Renal failure

1-OHase dec

Vit D rec defect

Low (<0.2)

Hypopara-

thyroidism

Normal

(>0.2)

Ca rec

mutation

Normal 25-OH

vit D

Urine Ca/creat

ratio (mmol/mmol)

PSEUDOHYPO-

PARATHYROIDISM

HYPOPARA-

THYROIDISM

Raised PTH

Normal alk

phos

Low or normal

PTH, normal

alk phos

Low Mg

low albumin – consider measuring

ionized Ca

– replace

Fig.2.16 Investigation of hypocalcaemia.

192

CHAPTER2 Endocrinology and metabolism

192

Further reading

Ward BK, Magno AL, Walsh JP, Ratajczak T. The role of the calcium- sensing receptor in human

disease. Clin Biochem 2012; 45:943– 53.

Table2.14 Causes ofhypocalcaemia

Cause Features

Lack of PTH action Very low Ca

, high PO

3−

, normal ALP

Hypoparathyroidism

Autoimmune, post- neck surgery (may be

transient), radioiodine, congenital (e.g. di George)

Pseudohypoparathyroidism

Type Ia (paternally inherited Gs- α mutation plus

somatic features)

Type Ib (maternally inherited, no somatic features,

‘renally selective’)

Type II (no somatic features, normal Ca

excretion

Hypomagnesaemia Inhibits PTH release

Activating CaSR mutation Indistinguishable from ° hypoparathyroidism,

except present from childhood and urinary Ca

creatinine ratio not low

Failure of vitamin D action Ca

not very low (>1.8mmol/ L), i A L P, d PO

3−

, i

PTH, osteomalacia

Vitamin D deciency Dietary/ d sunlight, malabsorption, i metabolism

(phenytoin, rifampicin)

Renal failure

Failure of 1- hydroxylation of vitamin D

Inherited failure of 1- α

hydroxylase (vitamin D-

dependent rickets type I)

Normal 25- OH vitamin D, d 1,25- OH vitamin

D levels

Vitamin D receptor defect

(vitamin D- dependent rickets

type 2*)

Normal 25- OH, normal 1,25- OH vitamin D levels

Other

Acute pancreatitis Transient

Hungry bone

syndrome— immediately

post- parathyroidectomy

Transient

Drugs, e.g. foscarnet,

bisphosphonates,

ethylenediamine tetra- acetic

acid (EDTA), citrate in blood

Transient

Neonatal (with prematurity) Transient

* ‘Vitamin D- resistant rickets’ is rickets with normal Ca

and vitamin D due to X- linked

hypophosphataemia.

HYPOCALCAEMIA/OSTEOMALACIA

193

194

CHAPTER2 Endocrinology and metabolism

194

Diabetes mellitus

Diagnosing diabetes mellitus

Diabetes is dened as a state of chronic hyperglycaemia at levels that, if

untreated, would result in microvascular complications (e.g. retinopathy).

Adverse pregnancy outcomes (and i macrovascular risk) occur at a lower

level of glucose and hence lower cut- os are used in pregnancy. However,

since blood glucose levels vary through the day following meals, physical

activity, and stress, dening these levels of glucose with a single test or a

short dynamic test has proved dicult.

Figure 2.17 provides a scheme for testing for diabetes. Table 2.15 provides

the American Diabetes Association (ADA) and WHO criteria for the diag-

nosis of diabetes, which dier slightly and have been updated since 2013.

One of four dierent criteria can now be used to diagnose diabetes. Note

that HbA

can now be used to diagnose diabetes if performed in a stand-

ardized Diabetes Control and Complications Trial (DCCT)- aligned assay

and has the advantage that a fasting sample is not required. HbA

for diabe-

tes diagnosis is not recommended using point- of- care machines (not stand-

ardized). In conditions where there is i RBC turnover, such as pregnancy

RBG > 11.1mmol/L:

Diabetes

conrmed

FBG > 7.0

Diabetes

conrmed

FBG 5.6-7.0

‘Pre-diabetes’

Consider OGTT

(See Table 2.22)

FBG < 5.6

Diabetes

excluded

Measure

random blood

glucose (RBG)

Symptoms present

(polydipsia, polyuria)

RBG < 11.1mmol/L:

Measure

fasting glucose

(FBG)

Repeat tests on

two separate

occasions

NO YES

Fig.2.17 Diagnosis of diabetes.

DIABETES MELLITUS

195

Table2.15 ADA and WHO criteria forthe diagnosis ofdiabetes

ADA (2016) WHO (2006, 2013)

Normoglycaemia Fasting plasma glucose

<5.6mmol/ L (100mg/ dL)*

Fasting plasma glucose

<6.1mmol/ L (110mg/ dL)*

OR 2h post- 75g load of

plasma glucose <7.8mmol/ L

(140mg/ dL)

OR 2h post- 75g load of

plasma glucose <7.8mmol/

L (140mg/ dL)

Diabetes Casual plasma glucose

>11.1mmol/ L (200mg/ dL)

Casual plasma glucose

>11.1mmol/ L (200mg/ dL)

OR fasting plasma glucose

>7.0mmol/ L (126mg/ dL)

OR fasting plasma glucose

7.0mmol/ L (126mg/ dL)

OR 2h post- 75g load of

plasma glucose >11.1mmol/ L

(200mg/ dL)

OR 2h post- 75g load

of plasma glucose

>11.1mmol/ L (200mg/ dL)

OR HbA

>48mmol/ mol

(6.5%)

OR HbA

>48mmol/ mol

(6.5%)

IFG Fasting plasma glucose

5.6– 6.9mmol/ L*

Fasting plasma glucose

6.1– 7.0mmol/ L (126mg/ dL)

BUT not ocially

recognized— recommend

progress to 2h 75g glucose

tolerance test (GTT)*

Impaired glucose

tolerance (IGT)

Not routinely measured

2h post- 75g load of plasma

glucose 7.8– 11.1mmol/ L

(140– 199mg/ dL)

2h post- 75g of glucose

7.8– 11.1mmol/ L (140–

199mg/ dL)

i risk of diabetes

(pre- diabetes)—

includes IFG and

IGT also

HbA

:5.7– 6.4%

(39– 46mmol/ mol)

Gestational

diabetes

Casual plasma glucose

>11.1mmol/ L (200mg/ dL)

Casual plasma glucose

11.1mmol/ L

OR fasting plasma glucose

7.0mmol/ L (126mg/ dL)*

OR fasting plasma glucose

>7.0mmol/ L

OR two or more of the

following plasma glucose

values after 75g glucose load:

fasting>5.3mmol/ L; 1h

>10mmol/ L; 2h >8.6mmol/ L

(155mg/ dL)*

OR one or more of the

following:fasting

5.1– 6.9mmol*; or following

75g glucose load:1h

post- glucose >10mmol/ L;

2h post- glucose

8.5– 11.0mmol/ L

* ADA and WHO criteria dier.

If the patient does not have classic symptoms (polyuria, polydipsia, unexplained weight loss),

then this test should be repeated on a dierentday.

Not recommended by the ADA for routine clinicaluse.

196

CHAPTER2 Endocrinology and metabolism

196

(second and third trimesters), recent blood loss or transfusion, Epo therapy,

or haemolysis, HbA

should not be used for diagnosis. HbA

may also be

problematic in the presence of haemoglobinopathies, unless specic assays

not inuenced by abnormal Hb are used. It should also be noted that the

four dierent criteria for diagnosing diabetes do not completely overlap, e.g.

a person may have fasting blood sugar of 6.8mmol/ L (= impaired fasting

glucose (IFG)/ i diabetes risk) but an HbA

of 55mmol/ mol (= diabetes).

Hence only one test should beused.

Oral glucose tolerance testing is rarely required (and only recommended

in pregnancy by the ADA) but can sometimes be useful to make the diagno-

sis of i diabetes risk in borderline cases (see Table2.15).

Notes

•

If symptoms are not present, tests must be repeated on two occasions,

ideally more than a week apart, to conrm that levels are indeed

chronically raised.

•

Values are given for venous plasma glucose. Capillary blood glucose

are71.0mmol/ L higher than venous plasma.

• If the patient has an intercurrent illness (e.g. infection or MI), tests

should be repeated once the patient has recovered.

•

Dierent criteria are used to diagnosis diabetes in pregnancy

(gestational diabetes).

Blood samples for glucose testing:in unseparated whole blood, glycolysis

by red cells reduces glucose levels by 10– 15% per h at room temperature,

leading to falsely low results. Clotted (serum) samples without preservative

can be used for glucose measurements if the sample is separated rapidly;

once separated, the glucose level is stable for 8h at room temperature and

72h at 4°C. Alternatively, a tube containing uoride oxalate to inhibit glyco-

lysis can be used if the sample is to be kept unseparated at room tempera-

ture for manyhours.

False +ve diagnoses may arise if the subject has prepared inadequately

(see Box2.8).

Box 2.8 Preparation fora fasting bloodtest

• Refrain from any food or drink from midnight before the morning of

thetest.

•

Water only is permitted.

• Regular medication can generally be deferred until a blood sample has

beentaken.

•

The appropriate sample is taken between 8 a.m. and 9 a.m. the

following morning.

This preparation is also required for a 75g oral glucose tolerance test (OGTT) or for

measurement of fasting blood lipids. Fasting blood tests should be avoided in insulin- treated

patients— risk of hypoglycaemia. Fasting is dened by the ADA as no caloric intake for at

least8h.

DIABETES MELLITUS

197

Normoglycaemia

The diagnostic criteria for normoglycaemia are given in Table 2.15 (note

the dierence between ADA and WHO for FPG cut- o). Note that there

is NO dened random plasma glucose that conrms normoglycaemia,

and this complicates the development of screening strategies for diabetes.

However, if a random value is <5.6mmol/ L, diabetes is unlikely.

Impaired glucose tolerance

This is the preferred diagnostic category for pre- diabetes used by the

WHO. The diagnosis of IGT can only be made using a 75g OGTT; a ran-

dom blood glucose measurement will often point to the diagnosis when

other results are non- diagnostic.

This category denotes a stage intermediate between normal glucose lev-

els and DM. By denition, plasma glucose levels are not raised to DM levels,

so typical osmotic symptoms are absent. Although subjects with IGT are

not at direct risk of developing chronic microvascular tissue complications,

the incidence of macrovascular complications (i.e. coronary heart disease

(CHD), cerebrovascular disease, peripheral arterial disease (PAD)) is i.

Presentation with one of these conditions should therefore alert the clini-

cian to the possibility of undiagnosed IGT (or type 2 DM). Note that up to

25% of individuals who are diagnosed with IGT by an OGTT may revert to

normal on re- testing.

Impaired fasting glucose

This is the diagnostic category for pre- diabetes preferred by the ADA

and depends on the FPG. Instructions for fasting blood test are shown in

Box2.8. The revised 2005 criteria lowered the lower limit for diagnosing

IFG, so the range according to the ADA is 5.6– 7.0mmol/ L. This category

is also usually asymptomatic. To date, cross- sectional studies suggest that

IGT and IFG may not be synonymous in terms of pathophysiology and

long- term implications, and a proportion of patients will fall into one cat-

egory, but not the other. Also some patients with fasting blood glucose

<7.0mmol/ L may have 2h blood glucose on the OGTT of >11.1mmo/

L and hence would have diabetes by the WHO criteria. If an OGTT is

performed, the 2h value takes precedence over the fasting value in the diag-

nosis of diabetes if the values do notagree.

Oral glucose tolerancetest

The OGTT (see Box 2.9) continues to be regarded as the most relevant

means for establishing the diagnosis of diabetes in equivocal cases, although

its reproducibility is poor. In borderline cases, the WHO suggests that only

when an OGTT cannot be performed does the diagnosis rely on FPG. It is

also the preferred approach in pregnancy. OGTTs should be carried out

under controlled conditions after an overnightfast.

The interpretation of the 75g GTT is shown in Table 2.16. These results

apply to venous plasma. Marked carbohydrate depletion can impair glucose

tolerance; the subject should have received adequate nutrition in the days

preceding thetest.

198

CHAPTER2 Endocrinology and metabolism

198

Eect ofintercurrent illness onglycaemia

Patients under physical stress associated with surgery, trauma, acute MI,

acute pulmonary oedema, or stroke may have transient i of plasma

glucose— often settles rapidly without antidiabetic therapy. However, the

hormonal stress response in such clinical situations is liable to unmask pre-

existing DM or to precipitate DM in predisposed individuals. Blood glucose

should be carefully monitored and the urine tested for ketones. Sustained

hyperglycaemia, particularly with ketonuria, demands vigorous treatment

with insulin in an acutely ill patient. Re- testing is usually indicated following

resolution of the acute illness— an OGTT at a 4- to 6- week interval is rec-

ommended if glucose levels are equivocal.

Box 2.9 Oral glucose tolerancetest

• Preparation: 3- day unrestricted CHO intake and activity. No

medication on day of test. 8– 14h fast. No smoking.

• 75g

of anhydrous glucose is dissolved in 250mL of water; avouring

with sugar- free lemon and chilling i palatability and may reduce

nausea. The subject sits quietly throughout thetest.

•

Blood glucose is sampled before (time 0), and at 120min after,

ingestion of the drink, which should be completed within5min.

•

Urinalysis may also be performed every 30min, although it is only

of interest if a signicant alteration in renal threshold for glucose is

suspected.

In children, 1.75g/ kg, up to75g.

Table2.16 Interpretation ofthe 75g OGTT(WHO)

Venous plasma glucose (mmol/ L)

Fasting 120min post- glucose load

Normal <6.0 <7.8

IFG

6.1– 6.9 N/ A

IGT N/ A 7.8– 11.0

DM >7.0 >11.1

1. In the absence of symptoms, a diagnosis of diabetes must be conrmed by a second diagnostic

test on a separate day.

2. For capillary whole blood, the diagnostic cut- os for diabetes are>6.1mmol/ L (fasting)

and 11.1mmol/ L (120min). The range for IFG based on capillary whole blood is >5.6 and

<6.1mmol/ L. In the diagnosis of diabetes, the 2h post- blood value predominates if values do

notagree.

DIABETES MELLITUS

199

Screening fordiabetes

This remains controversial, and universal screening is not generally advo-

cated, even though rates in the adult population exceed 5% in almost all

countries and >10% in many countries. Alow threshold for testing in those

at high risk is advocated. The ADA suggests that 3- year screening in asymp-

tomatic adults be considered over the age of 45, and especially where the

BMI is >25 and there is high- risk ethnicity (including African or South Asian

origin), a rst- degree relative with diabetes, or women who have had a large

baby (>9lb) or a previous diagnosis of gestational diabetes.

Further reading

American Diabetes Association. Diagnosis and classication of diabetes mellitus. Diabetes Care

2016;39

(Suppl 1), S13– 22.

World Health Organization 2006 Guidelines: M http:// www.who.int/ diabetes/ publications/

Denition%20and%20diagnosis%20of%20diabetes_ new.pdf

World Health Organization (2013). Diagnostic criteria and classication of hyperglycaemia rst detected

in pregnancy. Geneva: World Health Organization. M

http:// apps.who.int/ iris/ bitstream/

10665/ 85975/ 1/ WHO_ NMH_ MND_ 13.2_ eng.pdf.

WHO criteria for use ofHbA1c.

Diabetes websites

American Diabetes Association. M http:// www.diabetes.org.

Diabetes UK. M http:// www.diabetes.org.uk.

World Health Organization. Diabetes. M

http:// www.who.int/ topics/ diabetes_ mellitus/ en/ .

200

CHAPTER2 Endocrinology and metabolism

200

Which type ofdiabetesisit?

Table 2.17 shows the types and causes of diabetes. Type 2 diabetes due to

insulin resistance is by far the commonest (accounting for >90% of cases)

and is i as the prevalence of obesity and low physical activity in our society

rise. However, there are no denitive tests that can distinguish type 1 and

type 2 diabetes. Instead, a collection of clinical and laboratory parameters

are used (see Table 2.18), but many cases are hard to categorize (some-

times referred to as type 1.5 diabetes!).

Figure 2.18 (guide to the type of diabetes) provides an algorithm for diag-

nosing the type of diabetes. Although type 2 diabetes remains the com-

monest diagnosis in adults and is increasingly common in children, this is a

diagnosis for the lifetime of the individuals and care should be taken to diag-

nose any underlying conditions as accurately as possible. Note especially:

•

Unusual features:if any of the unusual features listed in Table 2.19 are

present, then the algorithm should not be pursued and an underlying

cause for the diabetes investigated.

•

Type 1 diabetes:it is important to always consider the possibility of

type 1 diabetes (see Fig. 2.18), even in older people, as early insulin

treatment is essential to avoid the risk of ketoacidosis.

•

Pregnancy:although the majority of diabetes diagnosed for the rst

time in pregnancy (gestational diabetes) is part of the spectrum of type

2 diabetes, diabetes due to other causes can occur. The algorithm in

Fig.2.18 should still be considered.

•

Latent autoimmune diabetes of adults (LADA) refers to diabetes with +ve

autoantibodies (anti- glutamic acid decarboxylase (GAD)) developing in

adults (typically over the age of 35)but not developing ketosis or with

absolute requirement for insulin within 6months of diagnosis. However,

subjects are usually not overweight and develop a need for insulin within

a few years. LADA is considered to be a ‘slow- onset’ version of type 1

diabetes, often initially misdiagnosed as type 2 diabetes.

Table2.17 Types and causes ofdiabetes

Type of diabetes* Comment

Type 1 β

- cell destruction usually leading to absolute insulin

deciency:1A— immune- mediated; 1B— idiopathic

(formerly known as juvenile- onset or IDDM)

Type 2 Predominantly insulin- resistant with relative insulin

deciency (formerly known as maturity- onset or

NIDDM)

Gestational diabetes Diabetes during pregnancy that resolves postpartum.

Often an early manifestation of type 2 diabetes

Other specic types

Includes genetic (MODY, mitochondrial, insulin

resistance syndromes), pancreatic disease, drug-

induced, occurrence in other genetic syndromes,

endocrinopathies (e.g. acromegaly)

* Abbreviated from the ADA classication.

WHICH TYPE OFDIABETESISIT?

201

• Monogenic diabetes— maturity- onset diabetes of the young

(MODY):monogenic disorders resulting in diabetes (see Tables2.19

and 2.20). Although these account for <1% of cases, they

are important to diagnose as they may be easily treated with

sulfonylureas (MODY3), associated with renal disease (MODY5),

or require no treatment (MODY 2). The diagnosis also has

important implications for other family members diagnosed with

diabetes. Note that it can be very difficult to distinguish type 2

diabetes from MODY without genetic testing, and a high level of

suspicion in young people is required (see Fig. 2.18). If suspected,

further advice from a genetic testing centre with experience in

MODY should be sought (M http:// www.diabetesgenes.org).

•

‘Flatbush’ diabetes refers to patients who present in DKA but

subsequently have a course that is more like type 2 diabetes

and are able to come o insulin. This is most commonly seen in

African- Caribbeans.

Table2.18 Clinical features and laboratory tests used todistinguish

type 1 and type 2 diabetes, and maturity- onset diabetes ofthe

young(MODY)

Type 1 Type 2 MODY

Clinical

features

Weight Slim (BMI <25)

+ weight loss at

diagnosis

Overweight

(BMI >25)

Average weight

(BMI <30)

Ketosis Occurs Rare Rare

Race Caucasian i risk in

South Asians

and Afro-

Caribbeans

Acanthosis

nigricans

Absent May be

present

Absent

Parent with

diabetes

Unusual Common Common

Laboratory

tests

Auto- antibodies Anti- GAD

antibody +ve in

around 80%*

−ve −ve

Insulin c- peptide Low (but still

present for up

to 5years from

diagnosis)

Present Present

High- density

lipoprotein

(HDL) >1.2

Usual Rare Usual

* Additional antibody tests can include anti- IA2 and anti- ZnT8 antibodies.

202

CHAPTER2 Endocrinology and metabolism

202

Diagnosis of

diabetes

conrmed

Unusual

features

present

Unusual

features

absent

Consider

specic

type of

diabetes

(Table 2.26)

BMI > 40

BMI 25-40

BMI < 25

Likely type

2 diabetes

All of:

Caucasian

Wght loss

at dx

Ketones >++

at dx

Yes—likely

Type 1

diabetes

No other

features

Family history

In two

generations

Diagnosis

< 25 yrs

Ketones > ++

at dx Or

wght

loss at dx O r

fail tablet Rx

within 1 year

Consider

Type 1

Test for auto

antibodies

Consider

MODY

Likely type

2 diabetes

(esp if

acanothosis,

Non-

caucasian)

Fig.2.18 Guide to the type of diabetes.

Table2.19 Specic features suggestive ofan unusual cause ofdiabetes

Feature Possible diagnosis

Alcohol excess, history of

pancreatic disease

Chronic pancreatitis

Painless jaundice, weight loss in

older person

Pancreatic cancer

Cystic brosis Pancreatic disease

On steroids/ Cushingoid

appearance

Steroid- induced diabetes/ Cushing’s

syndrome

Post- organ transplant Drug- induced

Specic drugs, e.g. somatostatin

analogues, diazoxide

Drug- induced

Severe hypertension Phaeochromocytoma

Acromegalic appearance Acromegaly

‘Muscular appearance’

(lipodystrophy)

Partial lipodystrophy

WHICH TYPE OFDIABETESISIT?

203

Table2.20 Genetically inherited forms ofdiabetes, includingMODY

Gene % of MODY

cases

Comments

Glucokinase 20

MODY 2 ‘mild’ complications rare

HNF- 1α 60 MODY 3 diagnosed later— 35years, progressive

β cell failure, but very sensitive to sulfonylureas

HNF- 4α 1 MODY 1

HNF- 1β 1 MODY 5 renal cysts/ abnormalities

IPF- 1 1 MODY 4

NeuroD1 ? <1 MODY 6

Unknown 15 ‘MODY X’

SUR1 <1%?? Hyperinsulinism in infancy and β cell failure as adult

Mitochondrial

Not MODY Maternally inherited. May be associated with

nerve deafness, lactic acidosis, or syndromes

such as DIDMOAD (diabetes insipidus, diabetes

mellitus, optic atrophy, and deafness)

Lipodystrophy

Not MODY,

lamin a/ c and

others

Associated with localized fat loss

Feature Possible diagnosis

Family history of diagnosis <25

in two or more generations

MODY

Renal cysts, urogenital dysplasia Hepatic nuclear factor (HNF)1β MODY

Bilateral deafness (maternal

inheritance)

Mitochondrial diabetes

Optic atrophy, DI Wolfram syndrome

Diagnosis <6months old Kir 6.2 mutation or other forms of neonatal

diabetes

Megaloblastic anaemic Roger’s syndrome (thiamine)

Short stature, severe insulin

deciency (>1000U/ day)

Insulin receptor defect (leprechaunism,

Rabson– Mendenhall syndrome)

Sti legs/ gait/ falls:−ve- GAD

antibodies

Sti person syndrome

Table 2.19 (Contd.)

Further reading

DiabetesGenes.org. M http:// www.diabetesgenes.org.

204

CHAPTER2 Endocrinology and metabolism

204

Monitoring diabetic control

Self- testing and near- patient testing

Self- testing capillary blood glucose (or urine) can be readily performed by

the majority of patients, with results available in under 20s. Measurements

of longer- term glycaemic control are typically laboratory- based, although

increasingly near- patient testing equipment is available for use in clinics that

can give results to patients within minutes.

Urine testing

Glycosuria

Semi- quantitative testing for glucose using reagent- impregnated test strips

is of limited value and although used to ‘screen’ for diabetes, it is not rec-

ommended for monitoring of glycaemic control. Urinalysis provides retro-

spective information over a limited period of time. Other limitationsare:

•

The renal threshold for the reabsorption of glucose in the proximal

convoluted tubule (PxCT) is 710mmol/ L on average but varies

between individuals. Subjects with a low threshold will tend to show

glycosuria more readily, even with normal glucose tolerance (‘renal

glycosuria’). Children are particularly liable to test +ve for glucose.

The renal threshold is eectively lowered in pregnancy. Conversely,

a high threshold, common among the elderly, may give a misleadingly

reassuring impression of satisfactory control. Fluid intake and urine

concentration may aect glycosuria. Renal impairment may elevate the

threshold for glucose reabsorption.

•

Delayed bladder emptying, e.g. due to diabetic autonomic neuropathy,

will reduce the accuracy of the measurements through dilution.

•

Hypoglycaemia cannot be detected by urinalysis.

Ketonuria, self- blood testing forketones

Semi- quantitative test strips for acetoacetate (e.g. Ketostix

) are available

for patients with type 1 DM but have largely been replaced by self- testing

of blood (capillary, ngerprick) for ketones (β- hydroxybutyrate). Useful

when intercurrent illness leads to disturbance of metabolic control. The

presence of ketonuria on dipstick testing (++ or +++) or blood ketones

(>3.0mmol/ L) in association with hyperglycaemia indicates marked insulin

deciency. The patient may be developing ketoacidosis, and i insulin doses

and urgent assessment for DKA is required (E Diabetic emergencies:dia-

betic ketoacidosis, hyperosmolar non- ketotic syndrome, and lactic acidosis,

pp. 210–11). Note that low- level ketonuria (‘+’) or blood ketones <0.6mmol/ L

can occur after a period of fasting, especially in overweight patients, and

does not necessarily indicate DKA. Occasionally, patients with type 2

DM develop ketosis during severe intercurrent illness, e.g. major sepsis.

Urine testing strips do not detect 3- hydroxybutyrate (although acetone is

detected by Acetest

). Occasional underestimation of the degree of keto-

naemia using these tests is a well- recognized, albeit uncommon, caveat of

alcoholic ketoacidosis but is no longer an issue with the use of blood ketone

testing. Blood testing is preferred, as it does not require any delay in obtain-

ing a urine sample and is more accurate. Separate testing strips from glucose

testing are required (but often the same meter can beused).

MONITORING DIABETIC CONTROL

205

Self- testing ofblood glucose

Self- testing of capillary blood glucose obtained by ngerprick has become

an established method for monitoring glycaemic control. Frequent testing is

a prerequisite for adjusting insulin doses and for safe intensive insulin ther-

apy such as that employed in the DCCT. Use in type 2 diabetes treated by

diet or tablets only is not essential. Enzyme- impregnated dry strip methods

are available, which are used in conjunction with meter devices and give

results in <20s with just 50µL of blood. Adequate training and a system of

quality control are important; even when trained health professionals use

such systems in clinics or hospitals, misleading results are possible, particu-

larly in the lower range of blood glucose results. Where there is doubt,

an appropriate sample (in a tube containing the glycolysis inhibitor uoride

oxalate) should be collected immediately for analysis by the clinical chem-

istry laboratory. However, acute treatment of hypoglycaemia, where indi-

cated, should not be delayed.

Continuous glucose monitoring systems(CGMS)

Several systems are now available using electrical conductance or microdi-

alysis to provide continuous monitoring of interstitial glucose. Sensors are

inserted SC and need to be replaced every 3– 7days. Most systems can dis-

play the results in real time (if regularly calibrated against traditional nger

stick readings), so that they can be reviewed by the patient, and linked to

alarms indicating high and low levels. While these systems, although expen-

sive, are proving increasingly valuable for patients with type 1 diabetes on

complex insulin regimes and insulin pump therapy, it must be remembered

that the interstitial glucose level is up to 30min ‘behind’ the blood level

and if glucose levels are changing rapidly, continuous monitors may ‘miss’

signicant hypoglycaemic events. Arecent development is sensors that do

not require calibration and the reading is made by ‘swiping’ the reader (or

an appropriately congured smartphone) over the sensor. These newer

sensors have signicantly reduced ‘delay’ time, claimed to be <10min vs

blood levels.

206

CHAPTER2 Endocrinology and metabolism

206

Laboratory assessment ofglycaemic

control

Glycated haemoglobin

MeasuringHbA

HbA

(comprises 60– 80% of total glycated haemoglobin HbA

) is formed

by the slow, irreversible post- translational non- enzymatic glycation of

the N- terminal valine residue of the β chain of Hb. The proportion of

HbA

:total Hb (normal non- diabetic reference range 74– 6%) provides

a useful index of average glycaemia over the preceding 6– 8 weeks. The

result is disproportionately aected by blood glucose levels during the nal

month before the test (750% of value). Laboratory values have now been

aligned to a standard from the DCCT trial (DCCT- aligned), and values are

generally consistent between laboratories. Recent recommendations sug-

gest expressing HbA

in new units (mmol/ mol) against a new International

Federation of Clinical Chemistry (IFCC) standard (see Table2.21).

Table2.21 Guide toHbA

values innew and oldunits

DCCT- aligned HbA

(%) IFCC- HbA

(nmol/ mol)

6.0 42

6.5 48

7.0 53

7.5 59

8.0 64

9.0 75

Frequency oftestingHbA

It is suggested that HbA

is measured every 6months in stable patients,

every 3 months in patients with unstable metabolic control, and every

month in pregnancy.

Interpreting HbA

levels

Average HbA

levels collected over a longer period (i.e. years) provide

an estimate of the risk of microvascular complications. Sustained high con-

centrations identify patients in whom eorts should be made to improve

long- term glycaemic control and i surveillance for long- term complications.

Table 2.22 summarizes recent recommendations for target HbA

levels

and capillary glucose measurements in adult subjects with diabetes. Targets

need to be modied in pregnancy (see footnote to Table 2.22), in children,

in patients with recurrent hypoglycaemia or diculty complying with medi-

cation, and in patients with vascular (especially coronary artery) disease in

whom hypoglycaemia may precipitate fatal arrhythmias.

LABORATORY ASSESSMENT OFGLYCAEMIC CONTROL

207

Limitations ofHbA

measurements

Although glycated Hb levels are a reliable indicator of recent average gly-

caemic control, they do not provide information about the daily pattern

of blood glucose levels or the frequency of hypoglycaemic episodes; this

supplementary information required for logical adjustment of insulin doses

is derived from frequent home blood glucose monitoring. More recent

changes in glycaemia (i.e. within the preceding 4 weeks or so) will inuence

HbA

level more than glucose levels 12 or more weeksago.

Spurious HbA

levels may arise in statesof:

•

Blood loss/ haemolysis/ reduced red cell survival (low HbA

•

Haemoglobinopathy.

•

i levels of HbS (low levels ofHbA

)

•

i levels of HbF (high HbA

Modern HbA

methods are likely to detect haemoglobinopathies with-

out specic testing. Where haemoglobinopathy is present and cannot be

adjusted for by an assay method where there is no interference, the HbA

test is uninterpretable and capillary blood glucose levels or fructosamine

must beused.

HbA

measurements are less reliable in pregnancy where rapid changes

in blood glucose levels can occur (e.g. last trimester). They are still used, as

they are more reliable than other available methods or estimating overall

control, but results should be interpreted with caution.

Uraemia due to advanced diabetic nephropathy is associated with anae-

mia and d RBC survival, thereby falsely lowering HbA

levels.

Table2.22 Target levels ofHbA

and capillary blood glucosevalues

Pre- meal (mmol/ L) Post- meal (mmol/ L) HbA

(nmol/ mol)

Non- diabetic 3.5– 5.5 <7.8 4– 6% (20– 42)

Ideal 4– 7* <10* <7%** (<53)

Suboptimal

control

7– 10%

Poor control >10%

* In pregnancy, NICE recommends 3.5– 5.9 pre- meal and <7.8 post- meal (1h) HbA

; aim

for<6.1%.

** In type 2 diabetes, NICE recommends a target of 6.5% in patients without vascular disease.

Note:lower target levels (HbA

<6.5%) have been proposed in subjects with type 2 diabetes

treated with lifestyle or metformin alone; Higher targets (e.g. HbA

<8.0% or higher) are

appropriate in subjects with frequent hypoglycaemia or hypoglycaemia unawareness, extensive

co- morbid conditions, or limited life expectancy.

208

CHAPTER2 Endocrinology and metabolism

208

Fructosamine:refers to protein– ketoamine products resulting from the

glycation of plasma proteins. The fructosamine assay measures glycated

plasma proteins (mainly albumin), reecting average glycaemia over the pre-

ceding 2– 3 weeks. This is a shorter period than that assessed using glycated

Hb measurements and may be particularly useful when rapid changes in

control need to be assessed, e.g. during pregnancy. Levels can be misleading

in hypoalbuminaemic states, e.g. nephrotic syndrome. Some fructosamine

assays are subject to interference by hyperuricaemia or hyperlipidaemia.

The main indications for fructosamine measurement are currently:(a)the

presence of haemoglobinopathy or other interference with the HbA

assay

(E Limitations of HbA

measurements, pp. 207–8) and (b)rapidly chang-

ing blood glucose levels (e.g. pregnancy).

Further reading

American Diabetes Association (ADA). Clinical guidelines on pages for health professionals.

http:// www.diabetes.org.

American Diabetes Association. 5.Glycemic targets. Diabetes Care 2016; 39

(Suppl 1), S39– 46 (ADA

standards of medicalcare).

National Institute for Health and Care Excellence. Diabetes guidelines. M

http:// www.nice.org.uk.

LABORATORY ASSESSMENT OFGLYCAEMIC CONTROL

209

210

CHAPTER2 Endocrinology and metabolism

210

Diabetic emergencies:diabetic

ketoacidosis, hyperosmolar non- ketotic

syndrome, and lactic acidosis

DKA should be considered in any unconscious or hyperventilating patient.

The hyperosmolar non- ketotic (HONK) syndrome is characterized by

marked hyperglycaemia (>30mmol/ L) and dehydration in the absence

of signicant ketosis or acidosis. Lactic acidosis (LA) associated with

metformin is uncommon. Arapid clinical examination and bedside blood

tests should allow the diagnosis to be made. Treatment (IV rehydration,

insulin, electrolyte replacement) of these metabolic emergencies should be

commenced without delay (for details, E Further reading, p. 211).

Conrm diagnosis bybedside measurementof

• Capillary blood glucose.

• Capillary blood testing for ketones (betahydroxybutyrate).

• Urine for nitrites and leucocytes(UTI).

Venous blood forurgent laboratory measurementof

• Plasma glucose (uoride oxalate; 2 true ‘euglycaemic’ DKA israre).

•

U&E (arterial potassium (K

) can be measured by some gas analysers).

Plasma Na

may be depressed as a consequence of hyperglycaemia or

marked hyperlipidaemia.

•

Plasma creatinine (2 may be falsely elevated in some assays byDKA).

•

Plasma lactate (if indicated— can also be measured by some gas

analysers). Indicated if acidosis without heavy ketonuria is present. LA is

a complication of tissue hypoxia (type A) and is a rare complication of

metformin treatment in patients with type 2 DM (typeB).

•

Plasma osmolality in HONK— either by freezing point depression or

calculated:

2 × [plasma Na

] + [plasma K

] + [plasma glucose] + [plasma urea]

•

FBC (non- specic leucocytosis is common inDKA).

• Blood cultures (signs of infection, e.g. fever, may be absent inDKA).

• ABGs (corrected for hypothermia) for arterial pH, HCO

−

, PCO

, and

(if shock or hypotension).

DKA is conrmed by blood glucose >11mmol/ L (rarely euglycaemic

ketoacidosis can occur in pregnancy or subjects on sodium– glucose

cotransporter 2 (SGLT2)- inhibiting drugs), ketonaemia >3.0mmol/ L, and

acidosis (pH <7.3 or HCO

−

<15mmol/ L). Severe DKA is considered

to be pH <7.0, HCO

−

<5mmol/ L, or ketones >6.0mmol/ L. Repeat

laboratory measurement of blood glucose, electrolytes, and urea at 2, 4,

and 6h, and as indicated thereafter. Electrolyte disturbances, renal impair-

ment, or oliguria should prompt more frequent (1– 2h) measurements

of plasma K

. Capillary blood glucose and ketone testing are monitored

hourly at the bedside. 2 Avoidance of hypokalaemia and hypoglycae-

mia is most important during therapy. Current therapy is aimed at rapid

resolution of ketosis which is considered to be ketonaemia <0.6mmol/ L

(‘normal’ <0.3mmol/ L) with pH>7.3.

211

DIABETIC EMERGENCIES

Other investigations, asindicated

• CXR.

• Microbial culture of urine, sputum,etc.

• ECG:acute MI may precipitate metabolic decompensation; note that

serum transaminases and CK may be non- specically elevated inDKA.

• Sickle- cell test (in selected patients).

• Venous plasma PO

4−

(if there is respiratory depression).

•

2 Performance of investigations should not delay initiation of treatment

and transfer to a high- dependency or intensive care unit(ICU).

Severe metabolic acidosis inthe absence ofhyperglycaemia (or other obvious

cause ofacidosis such asrenal failure) raises thepossibilityof

•

LA.

• Alcoholic ketoacidosis:this occurs in alcoholics following a binge.

Alterations in the hepatic redox state may result in a misleading

−veor‘trace’ Ketostix

reaction but detectable on blood ketone strips.

Asimilar caveat may occasionally be encountered when signicant

LAcoexists with DKA. Venous plasma glucose may be normalori.

Anion gap >15mmol/ L. Normally, the anion gap (<10mmol/ L) results

from plasma proteins, sulfate (SO

2−

), PO

3−

, and lactate ions. When the

anion gap is i, measurement of plasma ketones, lactate, etc. usually con-

rms the aetiology (see Table2.23).

Further reading

Joint British Diabetes Societies (JBDS) guidelines (2013). Available at:M http:// www.diabetologists-

abcd.org.uk.

Table2.23 Causes ofan anion gap acidosis

Ketoacidosis DKA

Alcoholic ketoacidosis

LA (2 metformin)

Chronic renal failure

Drug toxicity Methanol (metabolized l formic acid)

Ethylene glycol (metabolized l oxalic acid)

Salicylate poisoning

212

CHAPTER2 Endocrinology and metabolism

212

Investigation ofhyperlipidaemia

° dyslipidaemias are relatively common and contribute to an individual’s

risk of developing atheroma (e.g. CHD, CVD). Prominent examples include

familial combined hyperlipidaemia (FCHL; 72– 3% of UK population) and

heterozygous familial hypercholesterolaemia (FH; UK incidence 1 in 500).

Major hypertriglyceridaemia also predisposes to pancreatitis. The key fea-

tures of familial FH, FCHL, and diabetic dyslipidaemia are consideredlater.

Investigations

Although many subtle alterations in plasma lipids have been described,

therapeutic decisions rest on measurement of some or all of the following

in serum or plasma (plasma being preferred, since it can be cooled rapidly):

•

Total cholesterol (may be measured in non- fasting state in rst instance,

since levels are not greatly inuenced by meals).

•

Triglycerides (TGs) (after 12hfast).

• LDL- cholesterol (calculated using the Friedewald formula when TGs are

<4.5mmol/ L):

LDL-cholesterol = [(total cholesterol − HDL-cholesterol) − TGs]/2.19

Note that because of the unreliability of this calculation, especially at higher

TG levels, it has been recommended to report results also as ‘non- HDL-

cholesterol’, which is typically around 0.7mmol/ L higher than calculated

LDL- cholesterol.

• HDL- cholesterol (regarded as the ‘cardioprotective’ subfraction)— HDL

particles are synthesized in the gut and liver and thought to be involved

in ‘reverse transport’ of cholesterol from peripheral tissues to the liver

where it can be excreted as bilesalts.

Notes onsampling inrelation tolipoprotein metabolism

•

TGs (triacylglycerols) are measured after a 712h overnight fast in order

to clear diet- derived chylomicrons.

• Alcohol should be avoided the evening prior to measurement of TGs

(can exacerbate hypertriglyceridaemia).

•

Aweight- maintaining diet is recommended for 2– 3 weeks before

testing.

•

Lipid measurements should be deferred for 2– 3 weeks after minor

illness and 2– 3months after major illness, surgery, or trauma since

cholesterol levels may be reduced. Following acute MI, it is generally

accepted that plasma cholesterol is reliable if measured within 24h of

the onset of symptoms.

•

The eects of certain drugs on lipids should be considered (see

Box2.10).

•

Glycaemic control should be optimized wherever possible before

measuring plasma lipids in patients with diabetes.

Important additional considerationsare

•

Day- to- day variability:generally, decisions to treat hyperlipidaemia should

be based on >1 measurement over a period of 1– 2 weeks. This is

especially true for patients with mixed hyperlipidaemia (i.e. including

hypertriglyceridaemia).

INVESTIGATION OFHYPERLIPIDAEMIA

213

• Exclusion of 2° hyperlipidaemia— many common conditions, drugs, and

dietary factors can inuence plasma lipids (see Box2.10).

•

Family members should also have their plasma lipids measured if familial

hyperlipidaemia is suspected in a proband.

Both cholesterol and TGs may be aected to some degree by these fac-

tors, but one often predominates. Pre- existing ° hyperlipidaemias may be

exacerbated.

Clinical features

For example, xanthelasma, tendon xanthomas, etc. should always be

sought. Adetailed family history, drug history, and medical history (for dia-

betes and other cardiovascular risk factors such as hypertension) should

always be obtained. Certain endocrine disorders and impaired hepatic or

renal function can inuence circulating lipid composition and cardiovascu-

lar risk. Aclassication of the major familial dyslipidaemias is presented in

Table2.24.

2 Specialist advice should be sought in the management of major or

resistant hyperlipidaemias. TG levels >11mmol/ L (1000mg/ dL) are con-

sidered ‘very high’ and require therapy because of the risk of pancreatitis.

Box 2.10 Causes ofsecondary hyperlipidaemia

Hypercholesterolaemia

•

Hypothyroidism (even minor degrees of ° hypothyroidism)

• Cholestasis (raised lipoprotein X levels)

• Nephrotic syndrome

• Anorexia nervosa

• Diuretics

• Immunosuppressiveagents

• Hepatoma

• Dysglobulinaemias

Hypertriglyceridaemia

•

Obesity

• Diabetes (especially type2DM)

• Lipodystrophic syndromes (of diabetes and HIV- associated)

• Alcohol excess (note:moderate alcohol consumption may raise

HDL- cholesterol)

• Renal failure

• Antiretroviralagents

• Oestrogens (especially oral preparations in somewomen)

• Corticosteroids

• β- adrenergic blockers

• Retinoids

Recommended investigation for exclusion of 2° hyperlipidaemia: U&E,

plasma creatinine, fasting venous glucose, LFTs, and TFTs. For patients on

statins, check LFTs and CK periodically (2 measure urgently if myositis

occurs— a rare, but potentially fatal, complication).

214

CHAPTER2 Endocrinology and metabolism

214

Table2.24 Familial hyperlipoproteinaemias

Genetic disorder Defect Presentation Cholesterol Triglycerides Phenotype

Familial LPL deciency Absence of LPL activity Eruptive xanthomata;

hepatosplenomegaly

i iii I

Familial apo C- II deciency Absence of apo C- II Pancreatitis i iii I or V

Familial

hypercholesterolaemia

LDL receptor deciency Tendon xanthomata;

premature atheroma

iii i or N IIa or IIb

Familial

dysbeta- lipoproteinaemia

Abnormal apo E and

defect in TG metabolism

Tubo- eruptive and palmar

xanthoma; premature

atheroma

iii iii III

Familial combined

hyperlipidaemia

Uncertain Premature atheroma i or N i or N IIa, IIb, or IV

Familial

hypertriglyceridaemia

Uncertain; eruptive

xanthomata;

hepatosplenomegaly;

pancreatitis

i iii V

i, ii, and iii, mildly, moderately, and serverly raised; respectively cholesterol and triglycerides refer to concentrations in plasma; phenotype refers to Fredrickson classication

(I to V, see Table2.25); apo, apoprotein; LPL, lipoprotein lipase; n, normal; TG, triglycerides.

INVESTIGATION OFHYPERLIPIDAEMIA

215

Table2.25 Phenotypic (Fredrickson) classication ofhyperlipidaemias

Type Cholesterol Triglycerides Particle excess Usual underlying cause

I i iii Chylomicrons

LPL or apo C- II

deciency

IIa ii i LDL LDL receptor defect,

LDL overproduction

IIb ii ii

VLDL, LDL VLDL or LDL

overproduction or d

clearance

III ii ii

IDL— dysbetalipo-

proteinaemia

Impaired remnant

removal may be

due to certain apo E

phenotypes or apo E

deciency

IV N or i ii VLDL VLDL overproduction

or d clearance

V i iii ChylomicronsVLDL Diabetes

i, ii, and iii, mildly, moderately, and severely raised, respectively; LDL, low- density

lipoprotein; VLDL, very low- density lipoprotein; LPL, lipoprotein lipase; apo, apoprotein; IDL,

intermediate- density lipoproteins.

Further reading

JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of cardiovascular

disease (JBS3). Heart 2014; 100

Suppl 2:ii1– 67.

National Heart, Lung, and Blood Institute, National Cholesterol Education Programme Guidelines

(2013). Managing blood cholesterol in adults:systematic evidence review from the Cholesterol Expert

Panel. M

http:// www.nhlbi.nih.gov/ health- pro/ guidelines/ in- develop/ cholesterol- in- adults.

216

CHAPTER2 Endocrinology and metabolism

216

Test protocols

Insulin tolerance test (insulin stresstest)

• Indication:suspected ACTH or GH deciency.

•

Contraindications:patients with epilepsy, CHD (checkECG).

•

Children:use no more than 0.1U/ kg. Considerable care should be

exercised; the test should only be performed in a centre with expertise.

•

Alternatives:short Synacthen

test for hypocortisolism; stimulation tests

for GH deciency, e.g. growth hormone- releasing hormone (GHRH)

arginine test (E Hypothalamus/ pituitary function, see pp. 128–30).

• Preparation:patient fasting overnight. Bed required (although day- case

procedure). Patient must be accompanied home and may not drive.

OMIT morning hydrocortisone or other steroid hormone replacement

if patient is taking this and previous day’s GH. Physician must be present

throughout the test. Requires written consent.

•

Procedure:early morning outpatient test in fasting patient. Indwelling

venous cannula and constant medical supervision required throughout.

Cannula is kept patent by running a saline infusion with a three- way tap

for sampling. Discard initial 2– 3mL when each sample is taken. Label

all samples clearly with time and patient details. Near- patient testing

glucometer required.

1. Take baseline blood for glucose, cortisol, and GH. Check IV access

is working well. Review the test with the patient, and explain symp-

toms s/ he is likely to experience (see point5).

2. Draw up 25mL of 50% glucose for immediate administration IF

REQUIRED.

3. Give soluble (regular) insulin as an IV bolus in a dose of 0.15U/ kg

after an overnight fast. Consider 0.1U/ kg (lower dose) if suspected

profound hypocortisolism. 2 This appears a very small dose, e.g.

typically around 10U. CHECK DOSE CALCULATION CAREFULLY.

Usually an insulin syringe is used to draw it up and then transfer it to

a 2mL syringe containing saline.

4. Take blood at 15min intervals (0, 15, 30, 45, 60min) for glucose,

cortisol, andGH.

5. Observe for symptoms and signs of hypoglycaemia. The rst sign

is usually profuse sweating. The patient may then be aware of

symptoms such as palpitations, hunger, and paraesthesiae. This typi-

cally occurs 30– 45min into the test. Check near- patient glucose to

conrm <3.5mmol/ L. Continue to talk to, and reassure, the patient.

If the patient becomes very drowsy or unrousable, then give 25mL

of 50% glucose. This does not invalidate the test, as the hypogly-

caemic stimulus has already occurred. Continue blood sampling at

standardtimes.

6. If the patient has not experienced hypoglycaemia by 45min and near-

patient glucose is >4mmol/ L, give a further IV bolus of 0.15 or 0.3U/ kg

if the patient is known to be very insulin- resistant (e.g. acromegalic).

Repeat sampling at 15min intervals for 60min after this secondbolus.

7. At the end of procedure (usually 60min), give IV 25mL of 50%

dextrose if the patient still has symptoms of hypoglycaemia.

8. Give the patient a meal including complex carbohydrate (e.g. sand-

wiches or lunch), and observe for a minimum of 1h further before

accompanied discharge.

TEST PROTOCOLS

217

• Unwanted eects:severe hypoglycaemia with depressed level of

consciousness or convulsion requires immediate termination of the test

with 25mL of 50% glucose IV. Repeat if necessary and follow with 5%

or 10% glucose infusion. Continue to collect samples for hormone and

glucose measurements.

•

Interpretation:the test is only interpretable if adequate hypoglycaemia is

achieved (<2.2mmol/ L). Normal maximal cortisol response >550nmol/ L.

(Note:may be lower, depending on local assay range— check with the

laboratory). Normal GH response >20mU/ L. Impaired responses (if

hypoglycaemic stimulus adequate) denote corticotrophin (assuming

adrenal glands are normal) or GH deciency or both. Peak GH response

<10mU/ L is sucient to consider GH replacement; peak GH response

<5mU/ L is severe GH deciency.

Combined arginine– growth hormone- releasing

hormonetest

• Indication:GH deciency. Now preferred toITT.

•

Contraindications:previous reaction to stimulatory hormones.

Administer with caution to patients with severe liver or renal disease.

•

Alternatives:ITT. Other stimulation tests now outdated (e.g. glucagon,

exercise). Serum IGF- 1 levels give an idea of the GH status but are

unreliable at low levels.

•

Preparation:order GHRH and arginine from pharmacy. Omit GH

injections for a minimum of 24h. The patient arrives in the morning after

fasting for 10h (overnight). Water is allowed and patients should take

all their routine medications in the morning (but not GH). Informed

consent must be obtained and documented. Warn patients about

possible side eects of IV GHRH such as ushing lasting<5min.

• Procedure:

•

Weigh the patient.

•

Insert an indwelling IV cannula for blood sampling, administration

of bolus GHRH and arginine infusion (keep patent with heparinized

saline).

•

Patients should rest throughout thetest.

•

Take basal samples for GH at −30 and0min.

•

Give GHRH as an IV bolus of 1µg/ kg body weight at 0min; at the

same time, start infusing 30g of 12.5% arginine solution over 30min,

preferably using an infusion pump (children:0.5g/ kg as a 12.5% solu-

tion, to a maximum of30g).

•

Take blood samples for GH at 30, 45, 60, 75, 90, 105, and 120min.

•

Patients are allowed home after a fulllunch.

• Interpretation: the diagnosis of adult GH deciency is conrmed if the

peak GH concentration is <15mIU/ L (by ITT, <12mU/ L in GHRH

testing). Severe GH deciency (as dened by NICE)— peak <9mIU/ L.

Cut- os by BMI range have been proposed (34.5mU/ L for those with a

BMI <25kg/ m

, 24mU/ L for a BMI of 25– 30kg/ m

, and 12.6mU/ L for

those with a BMI >30kg/ m

) but are not universally accepted.

Note

:conversion factor:µg/ L × 3.0=mIU/ L.

218

CHAPTER2 Endocrinology and metabolism

218

Combined anterior pituitary function

testing

• Indication:assessment for anterior pituitary hypofunction.

•

Contraindications:previous reaction to stimulatory hormones.

•

Alternatives:ITT for GH and adrenal axis; metyrapone test for adrenal

axis. Other stimulation tests for GH, e.g. GHRH– argininetest.

• Preparation:test usually performed in morning for basal sampling.

•

Procedure:IV cannula inserted. Basal blood samples taken for cortisol,

oestradiol (♀) or testosterone (♂), FT4, and IGF- 1. Hypothalamic

hormones are given sequentially IV, each as a bolus, over around

20s:LHRH 100µg, TRH 200µg, and ACTH 250µg. Additionally, GHRH

(1µg/ kg body weight) may be given. (Reduce doses in children.)

Samples are drawn at 0, 20, 30, 60, and 120min for LH, FSH, TSH,

cortisol, and PRL. If GHRH is given, samples are drawn at the same time

points forGH.

•

Interpretation:normal values as follows:

•

TRH— suspect 2° hypothyroidism if peak response (at 20min)

<20mU/ L. (Note:low levels also seen in hyperthyroidism— ensure

FT4 or total T4 not raised.)

•

ACTH— peak cortisol response >550nmol/ L at 30 or 60min.

(Note:may be lower, depending on local assay range— check with the

laboratory.)

•

LHRH— peak LH/ FSH response 2– 5 times the basal value. LH, peak

at 20min; FSHlater.

•

GHRH— normal GH peak response >15mU/ L.

COMBINED ANTERIOR PITUITARY FUNCTION TESTING

219

220

CHAPTER2 Endocrinology and metabolism

220

Water deprivationtest

• Indication:diagnosis of DI and to distinguish cranial and nephrogenicDI.

•

Contraindications:none if carefully supervised. For correct interpretation,

thyroid and adrenal deciencies should be replaced rst. Interpretation

in the presence of DM and uraemia can be dicult.

•

Alternatives:morning urine osmolality of >600mOsmol excludes

signicant degrees of DI. No other denitive test forDI.

•

Patient preparation:usually an outpatient procedure. Correct thyroid

and adrenal insuciencies in advance. Renal function and blood glucose

should have been checked in advance. Steroid and thyroid hormone

replacement should be taken as normal on the day of the test. If the

patient is on desmopressin, omit the dose on the evening before the

test (or, if not possible, halve this dose). Free uids, but not to excess,

up to 7.30 a.m. on the day of the test. No alcohol on the night before

the test or on the morning of the test. Light breakfast, but no tea,

coee, or smoking on the morning of the test. Empty the bladder

before attending for the test. If urine volume is <3L/ day (‘mild cases’),

ask the patient to have no uids or food from 6.00p.m. on the evening

before the test (‘prolonged water deprivation test’).

•

Requirements for test:accurate weighing scales. Supervision for the whole

test (up to 8h). Desmopressin for injection (2µg). Immediate access to

serum electrolyte, plasma, and urinary osmolality assays. Access to a

plasma arginine vasopressin (AVP) (ADH) assay desirable.

• Procedure:7.30a.m.

1. Weigh the patient, and calculate 97% of the body weight.

2. Mark this target on thechart.

3. No food or uid for the next8h.

4. Insert a cannula for repeated blood sampling, andush.

• Procedure:8a.m.

5. Obtain plasma for Na

and osmolality, and urine for osmolality.

6. Then collect urine hourly for volume and osmolality, and plasma

every 2h for Na

and osmolarity.

7. Weigh the patient before and after passing urine if unobserved.

8. If patient loses 3% of the body weight, order urgent plasma osmo-

lality andNa

9. If plasma osmolality >300mOsmol (Na

>140mmol/ L), stop

the test; allow the patient to drink, and give desmopressin (see

point14).

10. If plasma osmolality <300mOsmol, the patient may have been

uid- overloaded before the test, and water deprivation can

continue.

11. Stop the test at 8h (4.00p.m.), and take nal recordings of urine

and plasma.

12. Save an aliquot of plasma for vasopressin levels in case of dicul-

ties in test interpretation.

13. Ideally urine osmolalities will have reached a plateau (<30mOsmol

rise between samples).

14. Now give 2µg of desmopressin intramuscularly (IM) (or 20µg

intranasally), and collect urine samples only for a further 2h. Allow

free uids at thisstage.

WATER DEPRIVATIONTEST

221

• Interpretation:normal response:plasma osmolality remains in the

range of 280– 295mmol; urine osmolality rises to >2 times plasma

(>600mOsmol). If urine volumes during water deprivation do not

reduce and yet the plasma does not become more concentrated (rising

osmolality) and weight does not fall, suspect surreptitious drinking

during the test. For interpretation of abnormal results, E Table 2.2,

p. 136

222

CHAPTER2 Endocrinology and metabolism

222

Diagnostic trial ofdesamino d- arginyl

vasopressin

• Indication:distinction of partial DI from ° polydipsia.

•

Contraindications:cardiac failure; current diuretic use (test

uninterpretable). Note that this test may precipitate severe

hyponatraemia in ° polydipsia and should be performed in an inpatient

unit with clinical and biochemical regular review.

•

Preparation:admission to an assessment unit. First- line tests for

polydipsia/ polyuria should have been performed (E Polydipsia and

polyuria:diabetes insipidus, pp. 134–6).

•

Procedure:

1. 24h urine volume, morning urine osmolality, weight, uid intake (as

far as possible), serum osmolality, Na

, urea, and creatinine should

all be performed daily and the results reviewed the sameday.

2. Subjects should have access to uid ad libitum but should be

reminded that they should only drink if they are thirsty.

3. After an initial 24h period of observation, desmopressin is

administered at a dose of 2µg bd SC for 3days.

4. Stop the test if serum Na

falls to <130mmol/ L.

• Interpretation:reduction in urine volume to <2L/ day and in urine

osmolality to >600mOsmol/ L without a fall in serum Na

<140mmol/ L suggests central DI. Reduction in urine volume with noi

in urine osmolality >600mOsmol/ L and without a fall in serum Na

suggests partial nephrogenic DI. Limited reduction in urine volume,

with some i in urine osmolarity, but a fall in serum Na

, suggests °

polydipsia.

LOW-DOSE DEXAMETHASONE SUPPRESSIONTEST

223

Low- dose dexamethasone

suppressiontest

• Indication:to distinguish hypercortisolism from normality. The

dexamethasone- suppressed CRH test is believed to have less false +ves

in cases of alcoholic or depressive pseudo- Cushing’s syndrome.

• Patient preparation:patients should not be on oral steroids or drugs that

i steroid metabolism.

•

Overnight dexamethasone suppression test:1mg of dexamethasone is

taken by mouth (PO) at midnight. Aserum sample for cortisol is taken

the following morning between 8 a.m. and9a.m.

•

Interpretation:serum cortisol should suppress to <140nmol/ L

(usually <50nmol/ L). Values of 140– 175nmol/ L are equivocal and

suggest a 2- day test should be performed. There is 10– 15% false

+verate.

•

Two- day low- dose dexamethasone suppression test (preferred):

dexamethasone 0.5mg is given PO every 6h for eight doses (2days),

starting in the early morning. Ideally tablets are taken strictly at 6- hourly

intervals (6 a.m., 12 noon, 6p.m., 12 midnight), which may necessitate

an inpatient stay. A24h collection for UFC is taken on the second day

of the test, and serum cortisol is measured at 6 a.m. on the third day, 6h

after the last dose. IV administration of dexamethasone can be used if

there are concerns over absorption or compliance.

•

Interpretation:serum cortisol 6h after the last dose should be

<140nmol/ L, usually <50nmol/ L. UFC on the second day should be

<70nmol/ L, normally <30nmol/ L. The 2- day test strictly performed

has less false +ves than the overnighttest.

•

Dexamethasone- suppressed CRH test:dexamethasone 0.5mg is given PO

every 6h for nine doses (2days), but starting at midnight and ending

at 6 a.m. Tablets are taken strictly at 6h intervals (12 midnight, 6 a.m.,

12 noon, 6p.m.), which may necessitate an inpatient stay. The last dose

is taken at 6 a.m., and an injection of CRH (100µg IV or 1µg/ kg) |is

given at 8 a.m. Ablood sample for cortisol is taken at 8.15 a.m. (i.e.

15min later).

•

Interpretation:serum cortisol level should be <38nmol/ L (normal).

Further reading

Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotrophin- releasing hormone stimulation

following low- dose dexamethasone administration:a new test to distinguish Cushing’s syndrome

from pseudo- Cushing’s states. JAMA 1993; 269:2232– 8.

224

CHAPTER2 Endocrinology and metabolism

224

High- dose dexamethasone

suppressiontest

• Indication:to distinguish between patients with Cushing’s disease

(ACTH- secreting pituitary tumour) and ectopic ACTH production in

patients with established hypercortisolism.

•

Patient preparation:as low- dose test, except that the test can be

performed immediately following the 2- day low- dosetest.

• Procedure:

1. 2 × 24h UFC collections are made to calculate the mean basal

24hUFC.

2. Baseline serum cortisol measurement is also taken before the

rst dexamethasone dose, ideally at 6 a.m. If the low- dose test is

performed rst, the baseline values (urine and blood) must be taken

prior to the low- dose test (i.e. any doses of dexamethasone).

3. Dexamethasone 2mg is given PO every 6h for eight doses (2days),

starting in the early morning. Ideally tablets are taken strictly at 6h

intervals (6 a.m., 12 noon, 6p.m., 12 midnight), which may neces-

sitate an inpatientstay.

4. A24h urine collection for UFC (nal) is taken on day 2, and a blood

sample is taken for (nal) cortisol 6h after the last dexamethasone

dose (6 a.m. on day 3). Creatinine excretion should be meas-

ured and compared between urine samples to conrm true 24h

collections.

•

Interpretation:the percentage suppression of basal cortisol is calculated

as follows:

(Basal cortisol – nal cortisol)/basal cortisol × 100

The same calculation is made for basal and day 2 UFC. Fifty per cent sup-

pression is suggestive of pituitary- dependent disease; 90% suppression

ithe likelihood (strict criteria). Thymic carcinoids and phaeochromocyto-

mas releasing ACTH are sources of false+ves.

LONG (DEPOT) ACTHTEST

225

Short Synacthen

test

• Indication:suspected adrenal insuciency. Will not detect recent- onset

2° adrenal insuciency.

•

Contraindication:asthma/ allergy to ACTH— risk of allergic reaction (can

be performed with careful medication supervision of the patient).

•

Preparation:the patient must not take hydrocortisone on the morning

of the test, as this will be detected in the cortisol assay. The test can be

performed on low- dose dexamethasone, but the morning dose should

be omitted until after the test. May have some value in patients on

higher- dose steroid therapy to indicate the degree of suppression of

adrenocortical function.

•

Procedure:250µg of synthetic ACTH (Synacthen

) given IM or IV. Blood

taken at times 0, 30, and 60min for serum cortisol.

•

Low- dose test:the test can be performed with a very low dose of ACTH

(e.g. 1µg). This may detect more subtle degrees of hypoadrenalism, but

the clinical signicance of these ndings remains uncertain.

•

Interpretation:a value at any time of >550nmol/ L makes the diagnosis

very unlikely. (Note:may be lower, depending on local assay range—

check with the laboratory).

Long (depot) ACTHtest

• Indication:distinguishing ° and 2° adrenal failure.

•

Patient preparation:a short Synacthen

test should be performed prior

to the test to diagnose adrenal failure. If the patient is on steroid

replacement, change to dexamethasone 0.5mg/ day.

• Procedure:blood is taken at 9 a.m. for basal cortisol; 1mg of depot

synthetic ACTH (Synacthen

) is then given IM on two consecutive days,

and blood collected 5h after each dose (2p.m.). Anal cortisol sample

is taken at 9 a.m. on the thirdday.

•

Interpretation:serum cortisol should rise to >1000nmol/ L on the last

day and, if adrenal failure previously indicated by a short Synacthen

test, such a rise indicates 2° adrenal failure (pituitary/ hypothalamic

cause, including suppressive drugs).

226

227

Chapter3

Haematology

Full blood count 228

Red cell parameters 230

White cells 232

Platelet count 233

Peripheral blood lm 234

Red cell morphology 236

Parasites on blood lm and

marrow 240

White blood cell morphology 242

Assessment of iron status 244

Assessment of vitamin B

and

folate status 248

Erythrocyte sedimentation rate 252

Plasma viscosity 253

Tests for glandular fever 254

Investigation of haemolytic

anaemia 255

General tests of haemolysis 256

Reticulocytes 258

Serum haptoglobins 260

Serum bilirubin 261

Urobilin, urobilinogen, and urinary

haemosiderin 262

Plasma haemoglobin 264

Schumm’s test 265

Hereditary haemolytic

anaemias 266

Red cell membrane disorders 268

Red cell enzyme assays 270

Haemoglobin abnormalities 271

Haemoglobin analysis 272

Investigation of possible

thalassaemia 276

Investigation of sickle

haemoglobin 278

Estimation of haemoglobin A

(α

) 280

Estimation of fetal

haemoglobin 280

Haemoglobin H bodies (β

) 280

Heinz bodies 281

Testing for unstable

haemoglobins 281

Molecular tests for diagnosis of

thalassaemia 282

Acquired haemolytic

anaemias 284

Immunophenotyping for GPI- linked

proteins 286

Bleeding time 287

Prothrombin time 288

Activated partial thromboplastin

time 289

Thrombin clotting time 290

D- dimers 290

3 Disseminated intravascular

coagulation 291

Platelet function tests 292

Thrombophilia screening 294

Antithrombin and proteins

CandS 295

Bone marrow examination 296

Cytochemistry tests (leukaemia

diagnosis) 298

Neutrophil alkaline

phosphatase 300

Blood transfusion 302

Transfusion reactions 304

Bacterial contamination of blood

products 308

Antiglobulin test 308

Kleihauer test 309

Erythropoietin assay 310

Immunohaematology 311

Immunophenotyping 312

Cytogenetics 314

Cytogenetics:prenatal

diagnosis 316

Cytogenetics:haematological

malignancies 318

Human leucocyte antigen (tissue)

typing 320

Southern blotting 322

Polymerase chain reaction

amplication ofDNA 324

In situ hybridization and

uorescence in situ

hybridization 328

Specialized haematology

assays 330

228

CHAPTER3 Haematology

228

Full bloodcount

Called complete blood count (CBC) in the United States(USA).

Before the advent of modern haematology blood analysers, the blood

count consisted of a haemoglobin (Hb) concentration (estimated using a

manual colorimetric technique), a white cell count, and a manual platelet

count. Other parameters, such as mean cell volume (MCV), had to be

mathematically calculated (derived) using the measured variables Hb, red

cell count (RCC), and packed cell volume(PCV).

Modern analysers use a variety of methods to provide a huge range of

full blood count (FBC) variables, including electronic impedance, laser light

scatter, light absorbance, and staining characteristics. The resultant FBC

provides measured variables such as Hb, PCV, and RCC, along with derived

(mathematically) MCV, mean cell Hb (MCH), and mean corpuscular Hb

concentration (MCHC). These machines also provide automated platelet

counts and a 5- part dierential white blood count(WBC).

Sample:peripheral blood ethylenediamine tetra- acetic acid (EDTA); the

sample should be analysed in the laboratory within 4h, if possible.

Main parameters measured

• Hb concentration.

• RCC.

• MCV.

• MCH.

• MCHC.

• Haematocrit (Hct) orPCV.

• Red cell distribution width(RDW).

• White cellcount.

• WBC dierential.

• Plateletcount.

Some machines are even more sophisticated and will measure reticulocyte

counts, in addition to determination of reticulocyte Hb andMCV.

Role offull bloodcount

Why ask for an FBC? How will this aid the diagnosis or management of the

patient? The FBC assesses several dierent parameters and can provide a

great deal of information. The red cell variables will determine whether or

not the patient is anaemic. If anaemia is present, the MCV is likely to pro-

vide clues as to the cause of the anaemia. The white cells are often raised

in infection— neutrophilia in bacterial infections and lymphocytosis in viral

(but not always so). Platelets (size or number) may be abnormal either as

a direct eect of an underlying blood disease or simply reecting the pres-

ence of some other underlying pathology. Most of us take a somewhat

cursory glance at the FBC when the report arrives on the ward or in clinic,

but a more detailed look may reveal a great dealmore!

Further reading

M http:// www.bbc.co.uk/ health/ talking/ tests/ blood_ full_ blood_ count.shtml.

http:// www.rcpa.edu.au/ pathman/ full_ blo.htm.

FULL BLOODCOUNT

229

230

CHAPTER3 Haematology

230

Red cell parameters

Haemoglobin concentration

Units:g/ dL or g/ L (Europe uses SI units; the USA uses g/ dL or grams%).

Denes anaemia (Hb < lower limit of normal, adjusted for age and sex).

Values dier between ♂ and ♀, since androgens drive RBC production and

hence an adult ♂ has higher Hb, PCV, and RCC than an adult♀.

Red cellcount

Unit:x 10

/ L.

Useful in the diagnosis of polycythaemic disorders (i production of

microcytic, hypochromic erythrocytes) and thalassaemias.

Causes oflow red cellcount

•

Hypoproliferative anaemias, e.g. iron, vitamin B

, and folate deciencies.

•

Aplasias, e.g. idiopathic or drug- induced (do not forget chemotherapy).

• Parvovirus B

infection- induced red cell aplasia resulting in transient

marked anaemia.

Causes ofhigh red cellcount

•

PRV.

• Thalassaemia.

Mean cellvolume

Unit:femtolitre (fL), 10

−15

Provided as part of the derived variables or, if you know the PCV and

RCC, can be calculated as (PCV/ RCC), e.g. if the PCV is 0.45 and RCC 5x

/ L, then the MCV is90fL.

This index provides a useful starting point for the evaluation of anaemia

(see Table3.1).

Table3.1 MCVindex

MCV d MCV normal MCV i

Iron deciency Blood loss B

or folate deciency

Thalassaemia homo- /

heterozygotes

Myelodysplasia Myelodysplasia

Sideroblastic anaemia Anaemia of chronic disease

RED CELL PARAMETERS

231

Mean cell haemoglobin

Unit:pg.

•

High (for range, E Normal ranges, inside front cover):macrocytosis.

•

Low:microcytosis, e.g. iron deciency anaemia.

Mean cell haemoglobin concentration

Unit:g/ dL org/ L.

• Of value in evaluation of microcytic anaemias.

• High:severe prolonged dehydration, hereditary spherocytosis, cold

agglutinin disease.

•

Low:iron deciency anaemia, thalassaemia.

Haematocrit or packed cellvolume

These are not entirely synonymous terms (but they are more or less). If

blood is placed in a microcapillary tube and centrifuged, the red cells are

spun down to the bottom, leaving the plasma above. The RBCs will occupy

about 40% of the blood in the tube— the blood will have a PCV of 0.4 (or

40%). The Hct is similar, but derived, using automated blood counters.

PCV unit

:L/ L (although the units are seldom cited in reports).

• High PCV:polycythaemia (any cause).

•

Low PCV:anaemia (any cause).

Red cell distributionwidth

Measures the range of red cell size in a sample of blood, providing informa-

tion about the degree of red cell anisocytosis, i.e. how much variation there

is between the sizes of the red cells. Of value in some anaemias,e.g.:

•

d MCV with normal RDW suggests β- thalassaemiatrait.

• d MCV with high RDW suggests iron deciency.

(Probably noticed more by haematology sta than those in general

medicine!)

Hypochromic red cells (%HRCs)

Dened as red cells with Hb <280g/ L. This is useful in identifying patients

with functional iron deciency and monitoring response to erythropoietin-

stimulating agent (ESA) Epo therapy and the requirement for IViron.

Reticulocyte mean cell haemoglobin (CHr), reticulocyte

haemoglobin content (Ret- He)

Predict iron deciency anaemia and functional iron deciency, and predict

response to IV iron in those on haemodialysis.

E Assessment of iron status, pp. 244–7.

232

CHAPTER3 Haematology

232

Whitecells

The automated dierential white cell count is provided as part of the FBC.

The RBCs in the sample are lysed before WBCs are counted. Atypical FBC

will show the total WBC and the

5- part dierential white cell count, bro-

ken down into the ve main white cell subtypes in peripheral blood which

include:

•

Neutrophils.

• Lymphocytes.

• Monocytes.

• Eosinophils.

• Basophils.

The printed FBC usually shows the % of each type of white cell, but unless

the absolute WBC (as x 10

/ L) is known, this % count is of littlevalue.

2 As a general rule, ignore the % count— you cannot detect abnormali-

ties, such as neutropenia, unless you have the absolute values.

Abnormalities of the WBC, e.g. neutrophilia, neutropenia, etc., are dis-

cussed in E OHCM 10e, p.330.

PLATELETCOUNT

233

Plateletcount

• Unit:x10

/ L.

• Normal:150– 400 x10

/ L.

Platelets (thrombocytes in the USA) are the smallest cells in peripheral blood.

Traditional counting methods with a microscope and counting chamber have

now been replaced by automated counting with haematology analysers.

Platelet distributionwidth

This is analogous to the RDW and provides information about the range of

platelet sizes in a blood sample.

•

The platelet distribution width (PDW) will be high if there are giant

platelets in the presence of normal- sized platelets, e.g. essential

thrombocythaemia (one of the myeloproliferative disorders).

•

The PDW will be normal in a reactive thrombocytosis (where the

platelet count is i, but they are all of normalsize).

Platelet clumping

This is an in vitro artefact in some individuals. Platelets clump in EDTA and

the blood analyser will report spurious thrombocytopenia. The actual

in vivo count is normal and the platelets function normally. Taking blood into

citrate or heparin will show the patient’s platelet count to be normal. The

presence of even a small blood clot in an EDTA sample may also reduce

the platelet count (the haematology technical sta will usually check to see

whether the sample contains a small clot before sending out the report).

234

CHAPTER3 Haematology

234

Peripheral bloodﬁlm

Examining a stained peripheral blood smear under the microscope allows

the examination of red cells, white cells, and platelets (see Fig. 3.1). In addi-

tion, the blood lm will help detect parasites (e.g. malaria, trypanosomes)

or abnormal cells in theblood.

When torequest a blood lm examination

The haematology laboratory will usually examine a peripheral blood lm if

the patient’s indices are abnormal (unless there has been no major change

from previous FBCs). If you suspect an underlying blood disorder, you

should request a lm. Note:the laboratory sta may not make a lm if the

indices are completely normal.

Method

A ngerprick blood sample may be spread onto a glass slide (the phleboto-

mist may do this for you), air- dried, xed, and stained. Alternatively, a drop

of EDTA blood may be treated in the same manner (the haematology labo-

ratory sta will make the lm). Beware:old EDTA samples produce strange

artefacts such as extreme red cell crenation— if a lm is required, it should

be made from a fresh blood sample.

•

Sample:EDTA (as fresh as possible).

Information frombloodlm

Redcells

•

Size.

• Shape (e.g. sickling).

• Membrane changes (e.g. oxidative membrane damage).

• Colour.

• Basophilic stippling.

• Inclusions, e.g. Howell– Jolly bodies, malarial parasites, haemoglobin C

(HbC) crystals,etc.

Neutrophi

Red cell

Platelets

Fig.3.1 Normal peripheral blood lm showing a neutrophil with its typical lobulated

nucleus, numerous red cells, and a few platelets.

PERIPHERAL BLOODFILM

235

Whitecells

•

Number.

• Morphology.

• Abnormalities such as toxic granulation, dysplastic changes.

• Presence of abnormal cells, e.g. leukaemic blasts or lymphomacells.

Platelets

•

Number.

• Size.

• Shape.

Other features onthelm

•

Parasites.

• Red cell rouleaux (stacking eect— seen, e.g. when ESRisi).

•

Nucleated redcells.

• Plasmacells.

• Occasionally see circulating carcinomacells.

E OHCM 10e, p.328.

236

CHAPTER3 Haematology

236

Red cell morphology

In health, the normal RBC is a pink, biconcave disc- shaped cell, and most

red cells are roughly the same size, shape, and colour. They should be

roughly the size of a small lymphocyte nucleus. Many diseases and de-

ciency disorders alter the RBC appearance by either reducing its Hb content

or altering the membrane such that characteristic morphological abnormali-

ties are produced. Examples include target cells, sickle cells, bite cells, burr

cells, and many others (see Table 3.2). Most of the morphological features

are not absolutely specic for one particular disorder, but rather they sug-

gest a range of conditions that may be associated with the RBC feature

(see Fig. 3.2). This should prompt you to look for conditions which might

account for the abnormality.

Table3.2 Peripheral blood lm inanaemias

Microcytic RBCs Fe deciency, thalassaemia trait and syndromes, congenital

sideroblastic anaemia, ACD (if long- standing)

Macrocytic RBCs Alcohol/ liver disease (round macrocytes), MDS,

pregnancy and newborn, compensated haemolysis, B

or folate deciency, hydroxyurea and antimetabolites

(oval macrocytes), acquired sideroblastic anaemia,

hypothyroidism, chronic respiratory failure, aplastic anaemia

Dimorphic RBCs Two populations, e.g. Fe deciency responding to

Fe, mixed Fe and B

/ folate deciencies, sideroblastic

anaemia, post- red cell transfusion

Hypochromic RBCs Reduced Hb synthesis, e.g. Fe deciency, thalassaemia,

sideroblastic anaemia

Polychromatic RBCs Blood loss or haematinic treatment, haemolysis, marrow

inltration

Spherocytes Hereditary spherocytosis, haemolysis, e.g. warm AIHA,

delayed transfusion reaction, ABO, HDN, DIC, and

MAHA, post- splenectomy

Pencil/ rod cells Fe deciency anaemia, thalassaemia trait and syndromes,

PK deciency

Elliptocytes Hereditary elliptocytosis, MPD, and MDS

Fragmented RBCs MAHA, DIC, renal failure, HUS, TTP

Teardrop RBCs Myelobrosis, metastatic marrow inltration, MDS

Sickle cells

Sickle- cell anaemia, other sickle syndromes (not sickle trait)

Target cells Liver disease, Fe deciency, thalassaemia, HbC syndromes

Crenated RBCs Usually storage or EDTA artefact. Genuine RBC

crenationmay be seen post- splenectomy and in renal

failure (lburrcells)

RED CELL MORPHOLOGY

237

2 Pay attention to the peripheral blood lm comment (inserted on the

report by the haematology laboratory sta or automated blood counter)—

it should help you decide which tests to carry out next. Conversely, cryptic

laboratory comments like ‘anisopoikilocytosis noted’ do not help the clini-

cian much. (Note:aniso=unequal; poikilo=varied.)

Burr cells Renal failure

Acanthocytes

Hereditary acanthocytosis, a- β- lipoproteinaemia, McLeod

red cell phenotype, PK deciency, chronic liver disease

(especially Zieve’s syndrome)

Bite cells G6PD deciency, oxidative haemolysis

Basophilic stippling Megaloblastic anaemia, lead poisoning, MDS, liver disease,

haemoglobinopathies, e.g. thalassaemia

Rouleaux Chronic inammation, paraproteinaemia, myeloma

i reticulocytes Bleeding, haemolysis, marrow inltration, severe hypoxia,

response to haematinic therapy

Heinz bodies Not seen in normals (removed by spleen), small numbers

seen post- splenectomy, oxidant drugs, G6PD deciency,

sulfonamides, unstable Hb (Hb Zurich, Köln)

Howell– Jolly bodies Composed of DNA, removed by the spleen, seen in

dyserythropoietic states, e.g. B

deciency, MDS, post-

splenectomy, hyposplenism

H bodies HbH inclusions, denatured HbH (β

tetramer), stain with

methylthioninium chloride (methylene blue), seen in HbH

disease (– – - / – α), less prominent in α- thalassaemia trait,

not present in normal subjects

Hyposplenic lm

Howell– Jolly bodies, target cells, occasional nucleated

RBCs, lymphocytosis, macrocytosis, acanthocytes.

Infectious mononucleosis, any viral infection,

toxoplasmosis, drug reactions

ABO, ABO blood groups; ACD, anaemia of chronic disease; AIHA, autoimmune haemolytic

anaemia; DIC, disseminated intravascular coagulation; Fe, iron; G6PD, glucose- 6- phosphate

dehydrogenase; HDN, haemolytic disease of the newborn; HUS, haemolytic uraemic syndrome;

MAHA, microangiopathic haemolytic anaemia; MPD, myeloproliferative disease; PK, pyruvate

kinase; TTP, thrombotic thrombocytopenic purpura.

Table 3.2 (Contd.)

238

CHAPTER3 Haematology

238

Stippled red cells in haemolysis.

Marked rouleaux in myeloma.

Single nucleated red cell (on left). Crenated red cells.

Fig.3.2 Red cell abnormalities in various disease states.

RED CELL MORPHOLOGY

239

240

CHAPTER3 Haematology

240

Parasites onblood ﬁlm andmarrow

Bloodlm

Although there are now highly sensitive monoclonal antibody (MoAb) kits

for the diagnosis of diseases such as malaria, a well- stained blood lm can

often make the diagnosis more easily and more cheaply. Blood lms are

useful for conrming a diagnosisof:

•

Malaria.

• Trypanosomiasis.

• Microlaria.

Parasites inbonemarrow

Some diseases, such as leishmaniasis, require bone marrow aspiration and

staining (in fact, there are many infections that can be diagnosed using bone

marrow):

•

Leishmania donovani.

•

TB.

• Tropheryma whippelii (Whipple’s disease).

•

Cryptococcus neoformans.

•

Penicillium.

•

Histoplasma capsulatum.

•

Candida albicans.

•

Toxoplasma gondii.

See Fig. 3.3 for examples.

Further reading

MedlinePlus (2016). CBC blood test. M http:// www.nlm.nih.gov/ medlineplus/ ency/ article/

003642.htm.

Thomas DW, Hinchlie RF, Briggs C, Macdougall IC, Littlewood T, Cavill I; British Committee for

Standards in Haematology. Guideline for the laboratory diagnosis of functional iron deciency.

Br J Haematol 2013; 161

:639– 48.

PARASITES ONBLOOD FILM ANDMARROW

241

Falciparum malaria (blood lm)

Loa loa (bone marrow)

Trypanosome (blood lm)

Fig.3.3 Parasites, such as malaria, loa loa, and trypanosomes, may be seen on a

stained bloodlm.

242

CHAPTER3 Haematology

242

White blood cell morphology

In much the same way as RBC morphology provides clues about underlying

disease, so too does microscopical examination of stained peripheral blood

WBCs. Modern counters enumerate WBCs, and our greater reliance on

modern technology means that visual inspection of blood lms is becoming

a dying art. Awell- stained blood lm may provide the diagnosis much more

cheaply (see Fig.3.4).

Blood lm whenWBC is decreased

• Sometimes dicult to determine the diagnosis since so fewWBCs.

• May suggest B

or folate deciency (are the RBCs normal or large?).

•

Aplastic anaemia:are the platelets and Hb normal?

•

Underlying leukaemia:are there any leukaemic blasts* present?

•

Overwhelming infection:may see toxic granulation (large, dark granules in

the cytoplasm— not diagnostic, but suggestive).

• May be immune or post- viral:atypical lymphocytes may be seen; other

indices usually normal.

Note:a blast (*) is a primitive cell seen in the marrow in large numbers in

leukaemia. We all have some blasts in our marrows, but these should be

<5% of the total nucleated bone marrow cells in health.

Blood lm whenWBC is increased

What cell predominates?

•

Lymphocytes:suggests viral, CLL, acute leukaemia (lymphoblastic).

• Granulocytic? (neutrophils, eosinophils, basophils)— may be reactive

orCML.

• Abnormal- looking WBC? Look for Auer rods (≡ AML), smear cells (CLL),

bilobed neutrophils (pseudo- Pelger cells seen inMDS).

(See Table3.3.)

Fig.3.4 Blood lm:atypical WBCs (this was from a patient with glandular fever, but

these cells may be seen in any viral illness).

WHITE BLOOD CELL MORPHOLOGY

243

Diagnosis must be made incontext

How old is thepatient?

•

Viral illnesses often produce bizarre lms in children, but beware of

complacency (acute leukaemia may be the cause).

•

MDS and malignancies like CLL and CML are diseases of older

individuals.

Is thepatientwell?

•

May be worth repeating the FBC and lm to see if abnormalities have

resolved.

•

If the patient is unwell or has lymphadenopathy or hepatosplenomegaly,

then an underlying disease must be excluded.

Table3.3 Some WBC abnormalities seen onFBC reports

Atypical

lymphocytes

Infectious mononucleosis, any viral infection, toxoplasmosis,

drug reactions

Auer rods

Seen in myeloblasts; pathognomonic of AML Prominent in AML

M3 subtype (acute promyelocytic leukaemia)

Pelger– Huët

anomaly

Bilobed neutrophils. May be hereditary (neutrophils are

functionally normal) or acquired, e.g. MDS (pseudo- Pelger cells)

Left- shifted Immature WBCs seen in peripheral blood. Seen in severe

infections, inammatory disorders, DKA, marrow ‘stress’,

MPD,CML

Right- shifted Hypermature WBCs seen in, e.g. megaloblastic anaemia and

iron deciency

Toxic

granulation

Coarse granules in neutrophils. Seen in severe infection, post-

operatively, and inammatory disorders

Smear cells

Lymphocytes in which the cell membrane has ruptured when

making the blood lm— there are no smear cells in vivo! Seen

in CLL

244

CHAPTER3 Haematology

244

Assessment ofironstatus

Anaemia of iron deciency is caused by defective synthesis of Hb, resulting

in red cells that are smaller than normal (microcytic) and contain reduced

amounts of Hb (hypochromic). The diagnosis of iron deciency anaemia is

generally straightforward, but it may be confused with anaemia of chronic

disease (ACD) or other hypochromic anaemias (see Table 3.4 and Fig.3.5).

Iron plays a pivotal role in many metabolic processes, and the average

adult contains between 3 and 5g of iron, of which two- thirds are present

in the O

- carrying molecule Hb. Somewhat surprisingly, there is no specic

excretion mechanism in humans. Iron balance is controlled at the level of

gut absorption and relies on two iron- sequestering proteins transferrin (iron

transport and recycling of iron) and ferritin (safeguards iron entry into the

body and maintains surplus iron in a safe and readily accessibleform).

Ferritin

This is the ° iron storage protein, consisting of 24 apoferritin subunits

forming a hollow sphere (each can hold up to 4500 iron atoms).

Haemosiderin

Haemosiderin, located predominantly in macrophages, is a water- soluble

protein– iron complex with an amorphous structure.

Transferrin and its receptor

Transferrin contains only 4mg of iron and is the principal iron transport

protein with >30mg of iron transported round the body daily. Synthesis of

transferrin is inversely proportional to the body iron stores, with i transfer-

rin concentration when iron stores are reduced.

The transferrin receptor (TfR) is a disulde- linked dimer, composed

of two identical 85kDa subunits. The serum TfR (sTfR) concentration is

elevated in iron deciency. However, sTfR may also i in any condition in

which there is i erythropoiesis, e.g. haemolytic anaemias, thalassaemia,

polycythaemia vera, and other myeloproliferative disorders.

Assessment ofironstatus

Several parameters are available

•

Hb concentration.

• Serum ferritin.

• Serum iron and transferrin (asTIBC).

• % hypochromic cells in peripheralblood.

• Reticulocyte MCH (CHr) and reticulocyte Hb content (Ret- He).

• Red cell protoporphyrin assay (not widely available).

• Bone marrow aspirate (stained for iron)— the ‘gold standard’.

• Soluble TfR assay (STfR).

Remember, iron deciency is not an ‘all- or- nothing’ phenomenon. In pro-

gressive deciency, there is a gradual loss of iron with subtle alterations of

iron- related parameters, during which the red cells may look entirely nor-

mal. In the initial stages of developing iron deciency, macrophages become

depleted of iron and the serum ferritin d to the lower end of the normal

ASSESSMENT OFIRONSTATUS

245

range; during this ‘latency’ period, the Hb is normal. As the deciency pro-

gresses, plasma iron levels d and TIBC i. Free RBC protoporphyrin levels i

as it accumulates, and eventually hypochromic RBCs appear in the periph-

eral blood. At this stage, an FBC will usually show d Hb, MCV, MCH, and

MCHC, and the peripheral blood lm will show microcytic hypochromic

redcells.

Table3.4 Hypochromic anaemias— may be confused withiron

deciency

Disorder Example

Disorders of iron metabolism Iron deciency anaemia:

•

Bloodloss

• Reduced ironintake

• Impaired iron transport

Anaemia of chronic disorders Chronic inammatory diseases

Malignant disease

Disorders of haem synthesis Sideroblastic anaemias:

•

Hereditary

• Idiopathic

• 2°:

•

Drugs

•

Alcohol

•

Lead poisoning

Globin synthesis disorders Thalassaemias:

•

β- thalassaemia

• α- thalassaemia

Target cells

Pencil cell

Fig.3.5 Blood lm of iron deciency anaemia. Note the variation in cell size andshape.

246

CHAPTER3 Haematology

246

Conrmation ofsimple iron deciency anaemia

(See Fig.3.6.)

•

Hbd.

•

Serum ferritin willbed.

•

Serum iron d and TIBC i (generally unhelpful and little used today).

•

STfRi.

•

MCVd.

•

MCH and MCHCd.

•

Microcytic and hypochromic RBCs on bloodlm.

• Absent marrowiron.

Functional iron deciency

This is the situation where iron is retained in body stores and, although

stores are adequate, delivery to the bone marrow is inadequate for eryth-

ropoiesis. It occurs in inammatory disease, being one component of ACD.

Functional iron deciency also occurs during the use of Epo where response

is improved with the use of IViron.

% Blasts:

% Hyper:

% Hypo:

% Macro:

% Micro:

RBC fragments:

1.2

0.0

86.8

0.0

62.9

0.09

RBC volume

Additional routine parameters

RBC V/HC

RBC HC

Fig.3.6 The % hypochromic red cells (provided by some automated counters) helps

in the diagnosis of iron deciency. Note that the RBC volume and Hb content (HC)

are both shifted to the LEFT (= small, pale red cells).

2 Beware:serum ferritin is an acute phase protein and may be normal or

even i in inammatory, malignant, or liver disease. During the inamma-

tory response, the iron/ TIBC are unlikely to be of any value (iron d and

TIBC will be d). If an inammatory process is suspected, an alternative

test is required, e.g. STfR, which is not aected by inammatory disorders.

ASSESSMENT OFIRONSTATUS

247

Iron overload

Can be iatrogenic or genetic (haemochromatosis).

Ferritin and transferrin saturation are elevated. Investigations to assess

the degree of cardiac and hepatic iron accumulation are required.

E OHCM 10e, p.326.

Further reading

Iron Disorders Institute. Iron deciency anemia. M http:// www.irondisorders.org/ iron- deciency-

anemia.

Iron Panel. M

http:// www.ironpanel.org.au/ AIS/ AISdocs/ adultdocs/ Acontents.html.

Provan D, Weatherall D. Acquired anaemias and polycythaemia. Lancet 2000; 355

:1260– 8.

248

CHAPTER3 Haematology

248

Assessment ofvitamin B

and folatestatus

Measurement of serum B

and red cell folate levels is necessary in the

investigation of macrocytic anaemia and certain other situations (see

below). Serum folate levels are an unreliable measurement of body stores

of folate— the red cell folate level is probably more meaningful.

• B

unit:ng/ L.

• Serum and red cell folate units:µg/ L.

• Sample:clotted blood sample (serum B

and folate) and peripheral

blood EDTA (red cell folate).

Deciency of either vitamin leads to megaloblastic anaemia where there

is disruption of cell division in all actively dividing cells (includes the bone

marrow and gut). In the marrow, there is nuclear:cytoplasmic asynchrony

where the nuclei are immature despite a mature, well- haemoglobinized

cytoplasm. In the peripheral blood, there may be anaemia, often with

pancytopenia; the red cells show oval macrocytic changes with basophilic

stippling and occasionally nucleated red cells. Neutrophils typically become

hypersegmented (they have >5 lobes).

Until recently, B

and folate assays were tedious microbiological assays,

but these have now been replaced by automated techniques using radio-

isotopic methods, which allow large numbers of samples to be batched and

tested fairly cheaply.

Deciencies ofB

or folate do not always cause macrocytic

anaemia

In the past, deciency of either B

or folate was synonymous with

macrocytic anaemia, but deciency of either vitamin may present with-

out anaemia or macrocytosis— remember, these are late features of the

disease. However, in most cases of deciency, the marrow will show

characteristic megaloblastic change (nuclear asynchrony with giant meta-

myelocytes). 2 Deciency of B

may cause neurological problems in the

absence of anaemia.

Whom should youtest?

• Patients with gastrointestinal tract (GIT) disease, glossitis, abnormalities

of taste, previous surgery, or radiotherapy to the stomach or

smallbowel.

•

Neurological disease, e.g. peripheral neuropathy, demyelination.

• Psychiatric disturbance, e.g. confusion, dementia.

• Malnutrition, e.g. growth impairment in children; vegans.

• Alcoholabuse.

• Autoimmune disease of the thyroid, parathyroid, or adrenals.

• Patients with a family history of pernicious anaemia.

• Others, e.g. drugs that interfere with vitamin absorption or metabolism

such as nitrous oxide, phenytoin,etc.

249

ASSESSMENT OFVITAMIN B

AND FOLATESTATUS

Look forblood lm abnormalities

2 B

and folate deciencies produce similar clinical and laboratory features:

•

Oval macrocytes.

• Hypersegmented neutrophils (also seen in renal failure, iron deciency,

andMDS).

(See Fig.3.7.)

Which testnext?

Make sure you have thefollowing

•

FBC.

• Bloodlm.

• Serum B

level.

•

Serum and red cell folate levels.

• Intrinsic factor antibodies (IFA), +ve in 50– 75% of patients withPA.

• Consider the bone marrow (helps exclude MDS, myeloma, and other

pathologies that give rise to macrocytic anaemia, but seldom performed

today since it is easy to get B

and folate results back quickly).

Interpretation ofresults:vitaminB

Normal ranges are based on two standard deviations either side of the

mean, so there will be ‘normal’ people who have ‘abnormal’ B

(or folate)

levels.

•

< normal:

•

Deciency.

•

Altered metabolism.

•

‘Normal’.

The lowest levels are seen in those most decient. What matters is whether

there is tissue deciency (leads to marrow and neurological changes).

Fig.3.7 Blood lm of megaloblastic anaemia. There are large oval macrocytes and

two hypersegmented neutrophils (the nucleus has >5 lobes).

250

CHAPTER3 Haematology

250

Mild decrease inB

level?

Dicult, but common! Probably worth repeating the test and reviewing the

patient and other results. If no evidence of tissue deciency, can probably

observe the patient. If there is evidence of tissue deciency, then the patient

will require treatment.

Detecting tissue deciency

The most reliable method is probably the measurement of serum homo-

cysteine (accumulates in vitamin B

and folate deciency).

Beware B

not associated withtissue deciency

•

Folate deciency.

• Pregnancy.

• Myeloma.

• Transcobalamin Ideciency (veryrare).

Folate

d level seen in hospitalized patients due to −ve folate balance.

The B

level is low— whatnext?

Available tests forthe cause ofB

deciency include

•

Parietal cell (+ve in serum of 90% of patients with PA, but also found

in other disorders and 15% of the normal elderly) and intrinsic factor

antibodies (IFA now preferred— if +ve, conrms diagnosis ofPA).

• Schilling test (urinary excretion method where the addition of

intrinsic factor (IF) restores B

absorption in PA, but not in intestinal,

e.g. ileal, disease), seldom performed now due to lack of required

radioisotope,or

•

Whole body B

counting.

•

Endoscopy with duodenal biopsy.

• Other gastroenterology tests for malabsorption (E Gastroenterology,

p. 522).

The folate level is low— whatnext?

• Check dietary history.

• Endoscopy with duodenal biopsy.

• Other gastroenterology tests for malabsorption (E Gastroenterology,

p. 522).

E OHCM 10e, p.266.

Further reading

Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for

the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166

:496– 513.

Guidelines and Protocols Advisory Committee (2012). Cobalamin (vitamin B12) deciency:investiga-

tion and management. M

http:// www2.gov.bc.ca/ gov/ content/ health/ practitioner- professional-

resources/ bc- guidelines/ vitamin- b12.

Hobrand AV. Megaloblastic anaemia and miscellaneous deciency anaemias. In:DA Warrell, TM

Cox, JD Firth, eds. Oxford Textbook of Medicine, 5th edn. Oxford:Oxford University Press, 2010;

pp.4402– 19.

Provan D, Weatherall D. Acquired anaemias and polycythaemia. Lancet 2000; 355:1260– 8.

251

ASSESSMENT OFVITAMIN B

AND FOLATESTATUS

252

CHAPTER3 Haematology

252

Erythrocyte sedimentationrate

This simple, but very useful, qualitative test measures how fast a patient’s

red cells fall through a column of blood. It is a sensitive, but non- specic,

index of plasma protein changes that result from inammation or tissue

damage. The ESR is aected by Hct variations, red cell abnormalities (e.g.

poikilocytosis, sickle cells), and delay in analysis, and it is therefore less reli-

able than measurement of plasma viscosity (PV). The ESR is aected by

age, sex, menstrual cycle, pregnancy, and drugs (e.g. OCP, steroids) (see

Table3.5).

The ESR is widely used in clinical medicine and, despite attempts (by hae-

matology departments) to replace the ESR with PV, the ESR has remained

in use and appears to retain a valuable place in the armoury of disease

diagnosis and monitoring.

•

Sample:peripheral blood EDTA; the sample should be analysed in the

laboratory within4h.

Many factors inuence the ESR, causing a high or low result:

•

High ESR (signicant*— look for a cause):

•

Any inammatory disorder, e.g. infection, rheumatoid,TB.

•

MI (the ESR i as an early response).

•

Anaemia.

Note:(*) depends on exactly how high. An ESR of 30 probably means little,

but >100 is highly signicant and indicates something seriouslywrong.

•

Low ESR (rarely important, but useful for exams):

•

Polycythaemia.

•

Hypobrinogenaemia.

•

CCF.

•

Poikilocytosis.

•

Spherocytosis.

•

Sickledcells.

3 Anormal ESR does not exclude organic disease.

E OHCM 10e, p.372.

Table3.5 Normal range (upper limits)

Age Men Women

17– 50years 10mm/ h 12mm/ h

51– 60 12 19

>60 14 20

Further reading

Brigden M. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician 1999; 60:1443– 50.

M http:// www.aafp.org/ afp/ 991001ap/ 1443.html.

Harris GJ. Plasma viscometry and ESR in the elderly. Med Lab Technol 1972; 29

:405– 10.

Lewis SM. Erythrocyte sedimentation rate and plasma viscosity. Ass Clin Pathol Broadsheet 1982;

:1– 6.

PLASMA VISCOSITY

253

Plasma viscosity

This test is a sensitive, but non- specic, index of plasma protein changes,

which result from inammation or tissue damage. Provides much the same

information as the ESR. The ESR and PV tend to rise in parallel, but the PV

is unaected by Hct variations (e.g. severe anaemia or polycythaemia) and

delay in analysis up to 24h, and it is therefore more reliable than the ESR.

It is not aected by sex but is aected by age, exercise, and pregnancy. It is

constant in health and shows no diurnal variation. There is a suggestion that

the PV may be a more sensitive indicator of disease severity than theESR.

•

Sample:peripheral blood EDTA. The sample is centrifuged and the

plasma removed.

•

Normal range:1.50– 1.72cP (or mPA/ s at25°C).

High and low plasma viscosity

A high PV generally signies some underlying pathology, e.g. inamma-

tory states, paraproteinaemias such as MGUS or myeloma; low PV can be

ignored.

Note:despite the advantages outlined, the PV has not been adopted by all

medical sta (who still prefer the ESR as a measure of inammation). The

PV is better for monitoring hyperviscosity syndromes, e.g. Waldenström’s

macroglobulinaemia. The fact that both tests are still used shows that there

is a role forboth.

E OHCM 10e, p.373.

Further reading

Cooke BM, Stuart J. Automated measurement of plasma viscosity by capillary viscometer. J Clin Pathol

1988; 41

:1213– 16.

254

CHAPTER3 Haematology

254

Tests forglandularfever

This infection is caused by EBV. Infected cells produce so- called hetero-

phile antibodies (these are IgM molecules that agglutinate horse and sheep

RBCs but do not agglutinate ox RBCs and do not react at all with guinea

pigRBCs).

There are various kits available that can detect the presence of hetero-

phile antibodies and, in the right clinical context, will conrm a diagnosis of

EBV infection. The Monospot test is probably the commonest in current

use. The Paul– Bunnell test was the rst to demonstrate the presence of

heterophile antibodies in patients with EBV infection.

Clinical features

Glandular fever often aects young adults (12– 25 years) and results in

malaise, fever, tonsillitis, petechial haemorrhages on the palate, and lym-

phadenopathy. Splenomegaly is fairly common. Asimilar clinical picture is

seen in CMV, Toxoplasma, and early HIV infections.

•

Sample:EDTA.

Positive Monospot

• EBV infection.

False positives

• Toxoplasmosis.

• CMV infection.

• Rheumatoid.

• Malaria.

Further reading

Ho G, Bauer S. A new rapid slide test for infectious mononucleosis. JAMA 1996; 194:351– 3.

INVESTIGATION OFHAEMOLYTIC ANAEMIA

255

Investigation ofhaemolytic anaemia

The normal red cell has a lifespan of 7120days. Anaemia resulting from d

RBC lifespan is termed haemolytic. May be inherited or acquired, and the

basic underlying mechanisms may involve abnormalities of the RBC mem-

brane, RBC enzymes,orHb.

Extravascular vs intravascular

Extravascular haemolysis implies RBC breakdown by the reticuloendothelial

system (RES) (e.g. liver, spleen, and macrophages at other sites), whilst intra-

vascular haemolysis describes RBC breakdown in the circulation itself (see

Fig. 3.8). There are many investigations available that will help determine the

predominant site of destruction, which, in turn, will help dene the underly-

ing cause of haemolysis, which is why we do the tests in the rstplace.

Detection ofhaemolysisitself

The main question is whether the patient’s anaemia is due to haemolysis or

some other underlying mechanism such as blood loss, marrow inltration,etc.

E OHCM 10e, p.336.

EXTRAVASCULAR

(e.g. spleen)

INTRAVASCULAR

HAEMOLYSIS

Kidney

Methaemalbumin

Fe recycled

Globin

Free plasma Hb

Hb–Hp complex

MetHb

Haemosideri

Amino acids

Haem

Bilirubin

(unconjugated)

Liver

Conjugated bilirubin

Gut

Urobilinogen

Faeces

Urine

Fig.3.8 Increased red cell breakdown may be extravascular (outside the circulation,

predominantly the spleen, liver, and marrow) or intravascular (within the vessels).

Modied from Lewis SM, Bain BJ & Bates I, eds. (2001) Dacie & Lewis Practical Haematology,

11th edition, Churchill Livingstone, Edinburgh.

256

CHAPTER3 Haematology

256

General tests ofhaemolysis

Is haemolysis actually occurring? Suggestive features

• Evidence of i red cell destruction.

•

Evidence of i red cell production (to compensate for red cellloss).

•

Evidence of autoantibody in the patient’sserum.

Evidence ofred blood cell destruction

• i serum bilirubin (split conjugated/ unconjugated is useful).

• i serum LDH (reecting i RBC turnover).

•

Spherocytes or other abnormal RBCs, e.g. fragments on bloodlm.

• Plasma haptoglobins may be d or absent.

•

i faecal and urinary urobilinogen (faecal not measured).

•

d RBC lifespan (seldom measured nowadays).

Evidence ofincreased red blood cell production

• i reticulocytes (on lm, manual, or automated count). Not absolutely

specic, will i in brisk acute bleed, e.g.GIT.

•

i MCV (reticulocytes are larger than mature RBCs, and do not forget

folate deciency, which occurs in haemolytic disorders).

Is it mainly intravascular?

• i plasmaHb.

•

Methaemalbuminaemia.

• Haemoglobinuria.

• Haemosiderinuria.

What is thecause?

Genetic

•

RBC morphology (e.g. spherocytes, elliptocytes).

• Hb analysis.

• RBC enzyme assays.

Acquired

•

Immune— checkDAT.

• Non- immune:check RBC morphology (e.g. TTP/ HUS).

• Is there some other underlying disease?

• Consider PNH (rare).

Further reading

Hill QA, Stamps R, Massey E, Grainger JD, Provan D, Hill A; British Society for Haematology

Guidelines. Guidelines on the management of drug- induced immune and secondary autoimmune,

haemolytic anaemia. Br J Haematol 2017; 177:208– 20.

Hill QA, Stamps R, Massey E, Grainger JD, Provan D, Hill A; British Society for Haematology. The

diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol 2017;

176

:395– 411.

Schick P (2016). Hemolytic anemia. M http:// www.emedicine.com/ med/ topic979.htm.

GENERAL TESTS OFHAEMOLYSIS

257

258

CHAPTER3 Haematology

258

Reticulocytes

These are immature RBCs formed in the marrow and found in small num-

bers in normal peripheral blood. They represent an intermediate matura-

tion stage in the marrow between the nucleated RBC and the mature RBC

(the reticulocyte lacks a nucleus but retains some nucleic acid). Measuring

the number of reticulocytes in the blood may help determine whether the

anaemia is due to d RBC production. The reticulocyte count is also a use-

ful measure of response to haematinic (iron, B

, or folate) replacement

therapy.

Detection and measurement

• Modern automated blood counters using laser technology measure the

number of reticulocytes directly.

•

Demonstrated by staining with supravital dye for the nucleicacid.

• Appear on blood lm as larger than mature RBCs with ne, lacy blue

staining strands or dots (see Fig.3.9).

•

Usually expressed as a percentage of total red cells, e.g. 5%, though

absolute numbers can be derived from this and the total red cellcount.

•

Sample:EDTA.

•

Normal range:0.5– 2.5% (50– 100 x 10

/ L).

Causes ofincreased reticulocytecounts

Marrow stimulationdueto

•

Bleeding.

• Haemolysis.

• Response to oral iron therapy.

• Infection.

• Inammation.

• Polycythaemia (any cause).

• Myeloproliferative disorders.

• Marrow recovery following chemotherapy or radiotherapy.

• Epo administration.

Spherocyte

Fig.3.9 Blood lm of numerous spherocytes (small, darker red cells) and

reticulocytes (larger red cells) in autoimmune haemolytic anaemia.

RETICULOCYTES

259

Causes ofdecreased reticulocytecounts

Marrow inltrationdueto

•

Leukaemia.

• Myeloma.

• Lymphoma.

• Other malignancy.

Marrow underactivity (hypoplasia)dueto

•

Iron, folate, or B

deciency. Note:the return of reticulocytes is the

earliest sign of response to replacement therapy.

•

Immediately post- chemotherapy or radiotherapy.

• Autoimmune disease, especially refractory anaemia(RA).

• Malnutrition.

• Uraemia.

• Drugs.

• Aplastic anaemia.

• Red cell aplasia.

Further reading

Howells MR, Jones SE, Napier JA, Saunders K, Cavill I. Erythropoiesis in pregnancy. Br J Haematol

1986; 64

:595– 9.

260

CHAPTER3 Haematology

260

Serum haptoglobins

Haptoglobins (Hps) are plasma proteins synthesized by the liver, whose

function is the removal of free plasma Hb. Hp molecules bind free Hb and

are taken up by the RES for degradation. Hp– Hb complexes do not appear

in the urine because their large size prevents them from passing through

the renal tubules.

The Hp– Hb complex is cleared by the RES at a rate of 15mg/ 100mL/ h,

which means that even very mild haemolysis will cause the disappearance

of Hps from the circulation. Serum Hps should be measured in patients with

suspected intravascular haemolysis. However, the Hp level is frequently

reduced in patients with extravascular haemolysis, and the Hp level cannot

be used to determine whether the basic haemolytic process is intra- or

extravascular. It should generally be accompanied by estimation of serum

methaemalbumin, free plasma Hb, and urinary haemosiderin.

•

Sample:clottedblood.

•

Normal range (expressed as Hb- binding capacity):30– 250mg/ dL.

Conditions withdecreased haptoglobins

Haemolysis including

•

Incompatible blood transfusion.

• AIHA.

• Sickle- cell disease.

• Thalassaemiamajor.

• PNH.

Others

•

1% of the population have a genetic lack ofHps.

• Lower levels in infancy.

Note:it takes about 1 week after haemolysis has stopped for Hp levels to

return to normal.

Conditions withincreased haptoglobins (acute phase

protein, likeferritin)

• Any disorder withiESR.

•

Carcinoma, especially if bony2°.

• Any inammatory disorder.

• Trauma.

• Surgery.

• Steroid therapy.

• Androgen therapy.

• DM.

Further reading

Rougemont A, Dumbo O, Bouvier M, etal. Hypohaptoglobinaemia as an epidemiological and clini-

cal indicator for malaria. Results of two studies in a hyperendemic region in West Africa. Lancet

1988; 2

:709– 12.

SERUM BILIRUBIN

261

Serum bilirubin

Two forms are found: pre- hepatic bilirubin (unconjugated) and bilirubin

conjugated to glucuronic acid (conjugated). Generally, serum bilirubin levels

are 17– 50µmol/ L in haemolysis (mainly unconjugated).

2 Beware: serum bilirubin levels may be normal, even if haemolysis is

present; a level of >85µmol/ L suggests liver disease.

Serum bilirubin levels may be modestly i (e.g. 20– 30µmol/ L) in dys-

erythropoietic disorders, such as vitamin B

or folate deciency, or myelo-

dysplasia, due to ineective erythropoiesis where RBCs are destroyed in

the marrow before ever being released into the circulation.

262

CHAPTER3 Haematology

262

Urobilin, urobilinogen, and urinary

haemosiderin

Urobilinogen is the reduced form of urobilin, formed by bacterial action on

bile pigments in the GIT. Faecal and urinary urobilinogen i in haemolytic

anaemias.

Urinary haemosiderin

Usage

The most widely used and reliable test for detection of chronic intravascu-

lar haemolysis. Results from the presence of Hb in the glomerular ltrate.

Principle

Free Hb is released into the plasma during intravascular haemolysis. The

Hb- binding proteins become saturated, resulting in the passage of haem-

containing compounds into the urinary tract of which haemosiderin is the

most readily detectable.

Method

1. Aclean- catch sample of urine is obtained from the patient.

2. The sample is spun down in a cytocentrifuge to obtain a cytospin

preparation of urothelialcells.

3. Staining and rinsing with Perl’s reagent (Prussian blue) are performed

on the glass slides.

4. Examine under the oil- immersion lens of a microscope.

5. Haemosiderin stains as blue dots within urothelialcells.

6. Ignore all excess stain and staining outside cells or in debris, all of which

are common.

7. True +ve only when clear detection within urothelial squames isseen.

Caution

An iron- staining +ve control sample should be run alongside the test case

to ensure the stain has worked satisfactorily. Haemosiderinuria may not be

detected for up to 72h after the initial onset of intravascular haemolysis, so

the test may miss haemolysis of very recent onset— repeat the test in 3–

7days if −ve. Conversely, haemosiderinuria may persist for some time after

the haemolytic process has stopped. Arepeat in 7days should conrm.

Causes ofhaemosiderinuria

(See Table3.6.)

UROBILIN, UROBILINOGEN, AND URINARY HAEMOSIDERIN

263

Table3.6 Causes ofhaemosiderinuria

Common causes Red cell enzymopathies, e.g. G6PD and pyruvate kinase

deciencies, but only during haemolytic episodes

Mycoplasma

pneumonia with anti- I cold haemagglutinin

Sepsis

Malaria

Cold haemagglutinin disease

TTP/ HUS

Severe extravascular haemolysis (may cause intravascular

haemolysis)

Rarer causes PNH

Prosthetic heartvalves

Red cell incompatible transfusion reactions

UnstableHb

March haemoglobinuria

264

CHAPTER3 Haematology

264

Plasma haemoglobin

In health, Hb is contained within RBCs, but during intravascular haemolysis,

excessive quantities of Hb may be released from ruptured RBCs. Normally

Hps mop up free Hb. If there are insucient Hps to cope with the free Hb,

the kidneys clear the Hb, leading to haemoglobinuria. Some Hb may be bro-

ken down in the circulation to haem and globin; haem can bind to albumin,

producing methaemalbumin (l methaemalbuminaemia).

2 The nding of free Hb in plasma is highly suggestive of intravascular

haemolysis.

•

Sample:sodium citrate (but discuss with the haematology laboratory

before sending sample).

•

Normal range:10– 40mg/ L (up to 6mg/ L).

• Pitfalls:any RBC damage occurring during blood sampling may result

in an erroneously high reading. Great care must be taken during

venepuncture.

Causes ofincreased plasma haemoglobin

(See Table3.7.)

Further reading

Crosby WH, Dameshek W. The signicance of hemoglobinemia and associated hemosiderinuria,

with particular reference to various types of hemolytic anemia. J Clin Lab Med 1951; 38

:829– 41.

Table3.7 Causes ofincreased plasma haemoglobin

Mild i (50– 100mg/ L) Moderate i (100– 250mg/ L) Severe i (>250mg/ L)

Sickle/ thalassaemia AIHA Incompatible blood

transfusion

Haemoglobin C

disease

Sickle- cell disease

Thalassaemiamajor

HaemoglobinSC

Prosthetic heartvalve

March haemoglobinuria

PNH

Paroxysmal cold

haemoglobinuria

Blackwater fever

SCHUMM’STEST

265

Schumm’stest

• Use:detection of methaemalbumin (seen after all Hps used up in

a haemolytic process; usually implies haemolysis is predominantly

intravascular).

This spectrophotometric test for methaemalbumin (which has a distinc-

tive absorption band at 558nm) should be requested in patients with

suspected intravascular haemolysis and may be abnormal in patients with

signicant extravascular (generally splenic) haemolysis. It should be accom-

panied by an estimation of the serum Hp level, free plasma Hb, and urinary

haemosiderin.

•

Sample:heparinized or clottedblood.

Positive resultin

• Intravascular haemolysis.

• Mismatched blood transfusion.

• RBC fragmentation syndromes.

• G6PD deciency with oxidative haemolysis.

• PNH.

• March haemoglobinuria.

• UnstableHb.

Further reading

Hobrand AV, Lewis SM, Tuddenham EGD (eds.). Postgraduate Haematology, 4th edn. Oxford:

Butterworth- Heinemann,2000.

Winstone NE. Methemalbumin in acute pancreatitis. Br J Surg 1965; 52:804– 8.

266

CHAPTER3 Haematology

266

Hereditary haemolytic anaemias

There are many inherited causes for haemolytic anaemia, which fall into

three major groups, shown in Table3.8.

Table3.8 Inherited causes forhaemolytic anaemiaa

Mechanism Example

Red cell membrane disorders Hereditary spherocytosis

Hereditary elliptocytosis

Red cell enzyme disorders G6PD deciency

Pyruvate kinase deciency

Hb disorders

Sickle- cell anaemia

Thalassaemia

HEREDITARY HAEMOLYTIC ANAEMIAS

267

268

CHAPTER3 Haematology

268

Red cell membrane disorders

Hereditary spherocytosis

This is the best known inherited membrane abnormality leading to a

reduced red cell lifespan and sometimes severe anaemia. Inheritance is usu-

ally autosomal dominant and there is often a +ve family history.

Hereditary elliptocytosis

Usually autosomal dominant. Rarely causes symptomatic anaemia.

Hereditary pyropoikilocytosis

Autosomal recessive, often compound heterozygotes. Often severe

haemolysis.

South East Asian ovalocytosis

Heterozygotes asymptomatic.

Hereditary stomatocytosis

Heterogeneous group with often severe haemolysis.

EMA bindingtest

Immunophenotyping using the reagent EMA to bind to red cell trans-

membrane proteins. Altered uorescence is seen with red cell membrane

disorders.

SDS- PAGE (sodium dodecyl sulfate polyacrylamide

gel electrophoresis)

Gel electrophoresis of membrane proteins. Only available in reference

laboratories.

Osmotic fragilitytest

Principle ofthetest

The test measures the ability of red cells to take up water before rupturing

(lysing). This is determined by the volume:surface area ratio. Normal red

cells can i

their volume by up to 70% before lysing (because they are disc-

shaped and have the capacity to take in extra water easily). Spherocytic red

cells have an i volume:surface area ratio and are able to take up less water

than normal red cells before lysing (they are spheres and, as such, they are

‘full’ already).

•

Sample:EDTA (need a normal control sample sent at the sametime).

(See Fig.3.10.)

Method

•

RBCs are incubated in saline at various concentrations. This results in

cell expansion and eventually rupture.

•

Normal RBCs can withstand greater volume i than spherocyticRBCs.

RED CELL MEMBRANE DISORDERS

269

• A+ve result (conrming hereditary spherocytosis) seen when RBCs

lyse in saline at near to isotonic concentration, i.e. 0.6– 0.8g/ dL (normal

RBCs will simply show swelling with little lysis).

•

Osmotic fragility is more marked in patients who have not undergone

splenectomy and if the RBCs are incubated at 37°C for 24h before

performing thetest.

Other supportivetests

• There will be a +ve family history of hereditary spherocytosis in

manycases.

•

The blood lm shows ii spherocyticRBCs.

•

Anaemia, i reticulocytes, i LDH, unconjugated bilirubin, urinary

urobilinogen withdHps.

•

DAT−ve.

2 Beware:this test is not diagnostic of hereditary spherocytosis but will be

+ve in any condition in which there are i numbers of spherocytic red cells.

Use this test in conjunction with a history, blood lm, and family studies

(hereditary spherocytosis is inherited as autosomal dominant, so one of the

parents and some siblings should be aected).

Most testing laboratories use a combination of the above tests. No one

screening test can detect all cases of hereditary spherocytosis.

Further reading

Bolton- Maggs PHB, Langer JC, Iolascon A, Tittensor P, King MJ. Guidelines for the diagnosis and

management of hereditary spherocytosis – 2011 update. Br J Haematol 2012; 156:37– 49.

Parpart AK, Lorenz PB, etal. The osmotic resistance (fragility) of human red cells. J Clin Invest 1947;

:636– 40.

Weatherall DJ, Provan AB. Red cells I:inherited anaemias. Lancet 2000; 355:1169– 75.

100

% Saline

Control

Patient

% RBC lysis

Normal

range

0.2 0.4

0.6 0.8

1.0

Fig.3.10 Test and control samples subjected to varying concentrations of saline.

The broad grey band represents the normal range. The red cells in the test sample

(from a patient with hereditary spherocytosis) lyse at higher concentrations of saline

than that seen in the normal control, which suggests that hereditary spherocytosis is

a likely diagnosis.

270

CHAPTER3 Haematology

270

Red cell enzymeassays

Numerous red cell enzymes are responsible for maintaining the integrity of

the RBC in order to allow it to function eciently in O

delivery and CO

removal. RBC enzyme defects lead to shortened RBC survival (i.e. hae-

molysis) and anaemia. Although there are numerous enzymopathies that

may cause haemolysis, the most useful starting assays are for G6PD and

pyruvate kinase(PK).

Of course, one should start by taking a detailed history from the patient,

asking about previous haemolytic episodes, family history, ethnic origin, and

possible drug toxicities.

•

Sample:fresh EDTA or heparin. The enzymes are stable for 6days at

4°C and 24h at25°C.

•

Methods:these are too numerous and complex to listhere.

Essentially there are three methods for analysis ofG6PD:

1. Brilliant cresyl blue decolorizationtest.

2. Methaemoglobin reductiontest.

3. Ultraviolet (UV) spottest.

•

Normal range:varies between laboratories (check with your local

laboratory).

•

Pitfalls:during a haemolytic episode in patients with G6PD deciency,

the oldest RBCs are destroyed rst. Younger RBCs (and especially

reticulocytes) have higher levels of the enzyme than older cells. It

follows therefore that if the enzyme level is assayed during an acute

episode, the G6PD level obtained may be falsely normal. This will

rise further as reticulocytes pour into the peripheral blood, as hap-

pens during recovery from the acute attack. It is better to wait until

the acute attack is over and the patient is in steadystate.

Further reading

Arya R, Layton DM, Bellingham AJ. Hereditary red cell enzymopathies. Blood Rev 1995; 9:165– 75.

Beutler E. The molecular biology of G6PD variants and other red cell enzyme defects. Annu Rev

Med 1992; 43

:47– 59.

World Health Organization Scientic Group (1967). Standardization of procedures for the study of

glucose- 6- phosphate dehydrogenase. Technical Report Series, No. 366. Geneva: World Health

Organization.

HAEMOGLOBIN ABNORMALITIES

271

Haemoglobin abnormalities

There are two main classes of Hb abnormalities (see Table3.9).

Table3.9 Main classes ofHb abnormalities

Abnormality Example

Structural Hb variants Sickle Hb, HbD, HbE

Imbalanced globin production Thalassaemias (α, β, etc.)

Structural haemoglobin variants

If the amino acid change results in an electrical charge dierence, this may

be detected by protein electrophoresis (separates proteins on the basis of

charge). Investigation requires a full clinical history, FBC, blood lm, and Hb

electrophoresis.

Thalassaemias

β- thalassaemia is diagnosed from the blood indices, blood lm, HbA

, and

HbF levels. For α

- thalassaemia, the investigation is more complex, requiring

DNA analysis to detect α- globin deletions. Globin chain synthesis, which

examines the ratio of α:β- globin production, is performed less with the

advent of DNA- based methods.

Further reading

Weatherall DJ, Provan AB. Red cells I:inherited anaemias. Lancet 2000; 355:1169– 75.

272

CHAPTER3 Haematology

272

Haemoglobin analysis

Haemoglobin electrophoresis

Electrophoresis is an electrical method for separating molecules on the basis

of size (for DNA fragments) or overall electrical charge (for proteins). Hb

electrophoresis allows the separation of dierent Hb, providing they have

diering charges (Hb molecules with the same charge will move together on

the gel and cannot be distinguished). The methods used take advantage of

the fact that amino acid side chains on the globin molecules can be ionized.

The net overall charge of a protein depends on the pH of the solution in

which it is and the pKs of the amino acids (the pK is the pH at which half of

the side chains are ionized).

Electrophoretic methodsused

• Cellulose acetate (at pH8.6).

• Citrate agar (at pH6.0).

• Isoelectric focusing(IEF).

• High- performance liquid chromatography (HPLC).

Due to space limitations, each of these methods will be discussed only

briey. Other texts deal with this topic in considerable detail.

•

Sample:peripheral bloodEDTA.

Cellulose acetate

This test is commonly performed in the diagnosis of abnormal Hb produc-

tion (haemoglobinopathies or thalassaemia). Because some Hb have the

same net charge, they will run together, e.g. HbS will run in the same band

as HbD and HbG, and HbC will run with HbE. To resolve these bands,

electrophoresis is next carried out at acidpH.

Citrateagar

This is similar to cellulose acetate where Hb molecules are separated at an

acid pH (pH 6.0) to separate out Hb that run together at alkalinepH.

Isoelectric focusing

This is a high- resolution method for separating dierent Hb molecules. The

basic principle of the test relies on the fact that all proteins and amino acids

have a pH at which their net charge is zero. This is termed the isoelectric

point. At this pH, there is no net movement in the presence of an externally

applied electric eld. The Hb molecules are subjected to a pH gradient. This

method has the advantage of high resolution but is more expensive than

standard electrophoresis (see Fig.3.11).

Normal adult haemoglobins

• HbA:97%total.

• HbA

:2.0– 3.2%.

• HbF:0.5%.

HAEMOGLOBIN ANALYSIS

273

High- performance liquid chromatography

This chromatographic technique has been around for 20 years or more

and is being increasingly used for analysis of Hb molecules. Hb molecules

are passed through a matrix column and eluted from the column at varying

times, during which their absorbance is measured. Detection of standard

Hb variants is simple; the advantage of HPLC is that novel Hb variants can

also be detected, and HPLC can separate proteins that cannot be resolved

using other means. HPLC is more expensive than all the techniques men-

tioned above (see Figs 3.12 and3.13).

Fig.3.11 Isoelectric focusing of haemoglobin.

Fig.3.12 HPLC analysis showing sickle trait (HbA +HbS).

274

CHAPTER3 Haematology

274

When should you request thesetests?

Haemoglobin analysis is usually carriedout

•

When the MCV is dd, but Hb normal or slightlyd.

•

In patients from ethnic groups known to be associated with high levels

of Hb disorder, e.g. sickle or thalassaemia.

Fig.3.13 HPLC analysis showing β- thalassaemia trait (elevatedHbA

HAEMOGLOBIN ANALYSIS

275

276

CHAPTER3 Haematology

276

Investigation ofpossible thalassaemia

1. Check the FBC and look at theMCV.

2. Is the MCV normal (>76fL)? If so, thalassaemia is unlikely.

3. Does the FBC show anything else? i RCC with d MCV and MCH are

likely in thalassaemia.

4. Measure the HbA

; this is generally i in β- thalassaemia trait (carrier).

5. Carry outHPLC.

6. Measure HbFlevel.

7. Look at the distribution of HbF in RBCs (HbF is present in all RBCs in

African hereditary persistence of fetal Hb (HPFH), but not present in

all cells in carriers for d β

- thalassaemia.

8. Assess the iron status (common cause of d MCV— do not miss this!).

9. Look for RBC inclusions (e.g. H bodies in α- thalassaemia or Heinz

bodies in unstable Hb disorders).

10. Carry out DNA analysis, examining both α- and β- globingenes.

Further reading

Information Center for Sickle Cell and Thalassemic Disorders. Thalassemia. M http:// sickle.bwh.

harvard.edu/ menu_ thal.html.

INVESTIGATION OFPOSSIBLE THALASSAEMIA

277

278

CHAPTER3 Haematology

278

Investigation ofsickle haemoglobin

Sickle Hb is the result of a point mutation in the β- globin gene, resulting in

a Glu l Val switch at position 6 of the β- globin protein. Sickle Hb (HbS)

forms long laments (tactoids), reducing its solubility when O

tension is

reduced. This forms the basis of the sickle solubility test (see Fig.3.14).

•

Sample:any anticoagulant.

The patient’s blood is mixed with sodium dithionite solution and left to

stand. A+ve sickle sample should be used as a control. When the tubes are

examined, a clear solution implies that there is no sickle Hb; a turbid solu-

tion conrms the presence of HbSS in the patient’s sample.

A+ve result will be obtained for sickle carriers (HbAS) and sickle- cell

homozygotes (HbSS). If a +ve result is obtained, Hb electrophoresis must

be carried out to determine whether the patient is a carrier or has homozy-

gous sickle- cell anaemia.

Molecular diagnosis ofsickle- cell disease

This is useful for prenatal diagnosis. The β- globin genes of the fetus are

amplied using PCR; cells are obtained by amniocentesis or chorionic villus

sampling (CVS) and digested with a bacterial restriction enzyme, e.g.MstII.

If the sickle mutation is present, no digestion will occur (the mutation

removes the restrictionsite).

Sickled red cells

Fig.3.14 Blood lm of homozygous sickle- cell anaemia (HbSS). Note the sickle-

shaped (crescent) redcells.

INVESTIGATION OFSICKLE HAEMOGLOBIN

279

Neonatal haemoglobin screening

• Obtain blood from the neonate (e.g. heel prick) and in babies at risk

of sickle or β- thalassaemia major (e.g. the mother has a gene for HbS,

C,D

Punjab

, E, O

Arab

, β- or d β- thalassaemia).

• Universal neonatal screening is generally used in areas where there is a

high incidence of haemoglobinopathy.

E OHCM 10e, p.340.

Further reading

Information Center for Sickle Cell and Thalassemic Disorders. Sickle cell disease. M http:// sickle.

bwh.harvard.edu/ menu_ sickle.html.

Steinberg MH, Forget BG, Higgs DR, Weatherall DJ (eds.). Disorders of Hemoglobin: Genetics,

Pathophysiology, and Clinical Management. Cambridge:Cambridge University Press,2001.

280

CHAPTER3 Haematology

280

Estimation ofhaemoglobin A

(α

)

Normal adults have three types of Hb:HbA, HbA

, and HbF. HbA (α

)

is the major Hb, and HbA

is a minor adult Hb, which is very useful for the

diagnosis of the β

- thalassaemia trait. HbA

levels are i in the heterozygote

(carrier state), and this is a specic test for this genotype. The test is carried

out using a column chromatography method.

•

Sample:EDTA.

•

Normal range:2.0– 3.2%.

Causes ofincreasedHbA

• β- thalassaemia trait (HbA

level is 73.9– 6.5%).

Causes ofdecreasedHbA

• Iron deciency.

• δ- thalassaemia.

Estimation offetal haemoglobin

Fetal Hb (HbF) makes up >50% of the total Hb at birth but d to 75% by

5months of age (as γ chain production is replaced by β chains). HbF levels

may be raised in some haemoglobinopathies.

•

Sample:EDTA.

Increased HbF foundin

•

β- thalassaemiatrait.

• β- thalassaemiamajor.

• Hereditary persistence ofHbF.

• Homozygous sickle- cell disease (HbSS).

• Sickle/ β

thalassaemia (some cases).

•

Sickle/ β

thalassaemia (some cases).

•

JuvenileCML.

• Multiple myeloma (uncommon and never measured).

• Acquired aplastic anaemia.

Haemoglobin H bodies(β

)

HbH, consisting of a tetramer of β- globins (β

), is found in α- thalassaemia.

The β chains form tetramers due to the relative lack of α- globins with

which to pair. The demonstration of HbH allows the detection of the α-

thalassaemia trait (either – α/ – α or – – / αα) and HbH disease (– – / – α).

Method

The HbH body test involves staining RBCs with brilliant cresyl blue; HbH

bodies are seen as large, dark inclusions in the redcells.

•

Sample:freshEDTA.

2 Note:the presence of HbH conrms α

- thalassaemia, but the absence of

HbH bodies does not exclude the diagnosis.

TESTING FORUNSTABLE HAEMOGLOBINS

281

Heinzbodies

These are red cell inclusions made up of insoluble denatured globin protein.

Heinz bodies are seen when RBCs are stained with methyl violet or new

methylthioninium chloride (methylene blue)stain.

•

Sample:freshEDTA.

•

Interpretation:Heinz bodies are seen close to the RBC membrane.

These are normally removed by the spleen and are therefore more

frequent following splenectomy.

Causes ofHeinzbodies

Oxidative haemolysis

•

Chlorates, phenacetin, otherdrugs.

• G6PD and PK deciencies, and other enzymopathies.

• UnstableHb.

Further reading

Sevitt S, Stone P, Jackson D, Baar S, Pollock A. Acute Heinz- body anaemia in burned patients. Lancet

1973; 2

:471– 5.

Testing forunstable haemoglobins

Globin gene mutations may lead to amino acid substitutions that render the

Hb molecule unstable, leading to haemolysis. Most mutations causing unsta-

ble Hb are autosomal dominant, and >80% aect the β chain. Aected

individuals are heterozygotes. Heinz bodies in RBCs are intracellular Hb

precipitates. Unstable Hb can be detected electrophoretically or by using

the heat precipitation test, in which lysed RBCs are heated to 50°C for1h.

•

Sample:freshEDTA.

•

Interpretation:normal fresh haemolysates should be stable for 1h at

50°C. If there is an unstable Hb, a precipitate will be seen in thetube.

Examples

• HbKöln.

• Hb GunHill.

282

CHAPTER3 Haematology

282

Molecular tests fordiagnosis

ofthalassaemia

Although most haematology laboratories can diagnose β- thalassaemia trait

and β- thalassaemia major, there are occasions when molecular tests are

required, e.g. antenatal diagnosis where a couple are at risk of having a

child with β

- thalassaemia major or hydrops fetalis (absence of α- globin,

usually lethal). In addition, the diagnosis of α- thalassaemia is dicult and

requires DNA analysis, either using Southern blotting or PCR amplication

of globingenes.

β- thalassaemia

There are >100 β- globin mutations now known, but fortunately each popu-

lation tends to have its own group of mutations (this avoids having to test

for all known mutations). It is important that you include the ethnic group

on the request form, since this will assist the laboratory who will then screen

for mutations commonly found in the ethnic group of the patient. Details of

these mutations can be found in the β

- and δ- thalassemia repository.

Methods used formolecular diagnosis ofβ- thalassaemia

The methods used are complex and outwith the scope of this small book.

–3

How theARMS PCR techniqueworks

•

This is amplication refractory mutation systemPCR.

• Specic point mutations are known for the β- globin mutations.

• PCR primers are designed to bind with the mutated sequence.

• If the patient has the mutation, there will be PCR amplication.

• If the patient lacks the mutation, there is no binding of the primers to

the patient’s DNA and no amplication.

•

So a band on the gel means the mutation is present (and the reverse is

true— if the band is absent, then that particular mutation is absent).

Other techniques, including reverse dot blots and DNA sequencing, are

sometimes needed if ARMS PCRfails.

Methods used formolecular diagnosis ofα- thalassaemia

Whereas β- thalassaemia is usually the result of point mutations (single base

changes), the α- thalassaemias are usually the result of deletions of chunks

of DNA in the region of the α- globin genes. Southern blotting is useful in

detecting deletions, since the DNA band sizes after digestion with restric-

tion enzymes will dier to the wild type (i.e. normal).

1 Bowden DK, Vickers MA, Higgs DR. A PCR- based strategy to detect the common severe deter-

minants of alpha thalassaemia. Br J Haematol 1992; 81

:104– 8.

2 Lewis SM, Bain BJ, Bates I (eds.). Dacie & Lewis Practical Haematology, 9th edn. Edinburgh:Churchill

Livingstone,2000.

3 Huisman TH, Carver MF. The beta- and delta- thalassemia repository. Hemoglobin 1988;

:169– 95.

MOLECULAR TESTS FORDIAGNOSIS OFTHALASSAEMIA

283

UK Haemoglobinopathy Reference Laboratory

This is based at the John Radcliffe Hospital in Oxford (UK). Difficult

cases (e.g. α

- thalassaemia) can be sent to this laboratory (after discuss-

ing the case first); they will perform α

- globin gene analysis and send

a detailed report containing the genotype of the patient. See end of

the chapter for contact details (E Specialized haematology assays,

pp. 330–1).

284

CHAPTER3 Haematology

284

Acquired haemolytic anaemias

Determining the cause of haemolytic anaemia can be a complex process.

Having excluded inherited disorders of Hb, RBC membrane, or enzymes,

we are left with a diverse group of disorders with a common phenotype

ofi RBC destruction (and d RBC lifespan; see Table3.10).

Immune

• Autoimmune (°, or 2° to SLE orCLL).

• Alloimmune (e.g. transfusion reactions, haemolytic disease of the

newborn (HDN)).

•

Antibody can be warm (IgG) or cold (IgM usually).

Red blood celldamage

• Drugs.

• Poisons.

• Burns.

Red blood cell fragmentation syndromes

• DIC.

• Thrombotic microangiopathies(TMAs)

• March haemoglobinuria.

Investigations

There is little point investigating the cause of haemolytic anaemia until you

have shown that haemolysis is actually occurring.

Table3.10 Acquired haemolytic anaemias:mechanisms

Mechanism Examples

Autoimmune Warm antibody (IgG mainly):

• Idiopathic haemolytic anaemia

• 2° to other autoimmune diseases (e.g. SLE), lymphoid

malignancies (e.g. CLL), infections, drugs (e.g.

penicillins, methyldopa)

Cold antibodies (IgM mainly):

• Cold agglutinin syndromes, cold haemagglutinin

disease (CHAD), 2° to infection

Alloimmune Haemolytic transfusion reactions, HDN

Infections Many, including malaria, meningococcal, pneumococcal,

viral

Chemical or physical Drugs, burns, drowning

RBC fragmentation

syndromes

Mechanical heart valves, MAHA (seen in DIC, HUS,

TTP, pre- eclampsia, SLE, carcinoma)

Membrane disorders Examples are liver disease, PNH

ACQUIRED HAEMOLYTIC ANAEMIAS

285

Look forthe acquiredcause

• FBC and peripherallm:

•

Spherocytes (suggests warm antibody; also present in hereditary

spherocytosis).

•

i WBC, e.g. might suggest an underlying lymphoproliferative disor-

der such asCLL.

•

RBC fragments (suggests physical damage to the RBC, e.g. micro-

angiopathic haemolytic anaemia (MAHA), TTP/ HUS, burns, March

haemoglobinuria, mechanical heart valves).

•

Parasites, e.g. malaria.

•

Infections, e.g. Clostridium, Bartonella, Babesia.

•

Antiglobulin test(DAT):

•

IgG or IgG + complement (C3d) onRBC.

•

DAT is usually +ve in immune- mediated haemolysis.

• Renal function (often abnormal in TTP/ HUS).

• Coagulation screen (DIC with RBC fragmentation).

• LFTs (abnormal in Zieve’s syndrome).

• USS for splenomegaly.

• Cold agglutinins:IgM, usually against Ior i proteins, RBC membrane

proteins.

•

Immunophenotype if suspectPNH.

286

CHAPTER3 Haematology

286

Immunophenotyping forGPI- linked

proteins

PNH is a rare acquired red cell membrane disorder. Loss of glycosyl

phosphatidyl inositol (GPI)- linked surface proteins make the red cells

vulnerable to complement- mediated lysis, causing episodes of marked

intravascular haemolysis, with free Hb in the urine (haemoglobinuria).

Immunophenotyping shows cells to be decient in the GPI- anchored

proteins CD55 and CD59 (erythrocytes) and CD16, CD24, and FLAER

(granulocytes),

The technique of immunophenotyping is described later in this chapter.

BLEEDINGTIME

287

Bleedingtime

This is a test of ° haemostasis, and mainly of platelet function in vivo, rather

than a laboratory test. You will generally need to arrange this test through

the haematology department who will carry out the test foryou.

Procedure

A disposable spring- loaded blade is used to make two incisions of xed

depth into the skin of the forearm, whilst a sphygmomanometer is inated

to 40mmHg. Blood from the incisions is mopped up using circular lter

paper (care needs to be taken to avoid disturbing the clot that forms on

the cut surface).

•

Normal range:up to 7min (varies, depending on the method

used;>9min is abnormal). Longerin♀.

•

Uses:previously felt to be the best screen for acquired or congenital

functional or structural platelet disorders. If bleeding time is normal and

history −ve (i.e. no major bleeding problems in the past), this excludes

an underlying platelet disorder.

Precautions

2 Do not carry out bleeding time if the platelet count is <100 x 10

/ L

(will be prolonged). Aspirin will interfere with the test— ask patients to stop

aspirin 7days before the test is carriedout.

Causes ofprolonged bleedingtime

•

Low plateletcount.

• Platelet function defect (acquired, e.g. aspirin, paraprotein,MDS).

• von Willebrand’s disease(vWD).

• Vascular abnormalities, e.g. Ehlers– Danlos.

• Occasionally low factor VorXI.

• Abrinogenaemia.

Pitfalls

Highly operator- dependent, with low reproducibility. Because of this, the

test is seldom usednow.

Further reading

Mielke CH Jr. Aspirin prolongation of the template bleeding time:inuence of venostasis and direc-

tion of incision. Blood 1982; 60

:1139– 42.

Parkin JD, Smith IL. Sex and bleeding time. Thromb Haemost 1985; 54:731.

288

CHAPTER3 Haematology

288

Prothrombintime

This tests the extrinsic coagulation pathway and is useful for detecting

coagulation deciencies, liver disease, and DIC. The prothrombin time (PT)

is also the main monitor for coumarin therapy (e.g. warfarin), expressed

as a ratio— the international normalized ratio (INR). The test measures the

clotting time of plasma in the presence of a tissue extract, e.g. brain (throm-

boplastin). The test measures prothrombin, but also factors V, VII, and X

(see Fig.3.15).

•

Sample:citrate.

Increased prothrombintime

• Oral anticoagulation therapy (vitamin K antagonists).

• Fibrinogen deciency (factorI).

• Prothrombin deciency (factorII).

• Deciency of factors V, VII, or X (in V or X deciency, the activated

partial thromboplastin time (APTT) willbei).

•

Liver disease, especially obstructive.

• Vitamin K deciency.

• DIC.

TF–VII

TF–VIIa

XXa

II Thrombin

XI XIa

Fibrinogen Fibrin

IX IXa

VIIIa

TFPI

TISSUE INJURYTEST

APTT

and

APTT

Key

Becomes active

Activates

Inhibits

Protein C

APC

Protein S

Factor V

1. Anticoagulant pathway

FDPs

Plasmin

inhibitor

TPA

2. Fibrinolytic pathway

Plasminogen

Fig.3.15 Coagulation cascade showing the factors assayed using the various clottingtests.

Modied from Provan D, etal. Oxford Handbook of Clinical Haematology, 2nd edn. Oxford:Oxford

University Press,2004.

Further reading

Provan D, Singer CRJ, Baglin T, Lilleyman J. Oxford Handbook of Clinical Haematology, 2nd edn.

Oxford:Oxford University Press,2004.

ACTIVATED PARTIAL THROMBOPLASTINTIME

289

Activated partial thromboplastintime

Other terms:somewhat confusingly, the APTT may be called kaolin cephalin

clotting time (KCCT) or partial thromboplastin time with kaolin (PTTK).

What is APTT testing?

This is a test of the intrinsic coagulation system and depends on contact

factors + factors VIII and IX, and reactions with factors X, V, II, and I.The

APTT is sensitive to circulating anticoagulants (e.g. lupus anticoagulant) and

heparin.

•

Sample:citrate.

Uses

1. Heparin monitoring.

2. Screening for haemophilia Aand B (VIII and IX deciencies,

respectively).

3. Screening for coagulation inhibitors.

• Normal range:26.0– 33.5s (often expressed as activated partial

thromboplastin time ratio (APTR)).

Increased activated partial thromboplastintime

• DIC.

• Liver disease.

• Massive blood transfusion.

• Heparin treatment.

• Circulating anticoagulant.

• Modest i in patients taking oral anticoagulants.

•

Haemophilia.

Is there aninhibitor present?

The APTT will be long if there is an inhibitor, such as the lupus anticoagu-

lant, present. This can be determined by mixing the patient’s plasma with

an equal volume of normal control plasma and repeating the APTT. This is

known as a 50:50 mix. If the APTT is long because of an inhibitor, it will not

fully correct when normal plasma is added. However, if the APTT is long

because of a deciency, it will be corrected with the normal plasma.

Further reading

Denson KW. Thromboplastin— sensitivity, precision and other characteristics. Clin Lab Haematol

1988; 10

:315– 28.

Lab Tests Online (2012). Coagulation cascase. M http:// www.labtestsonline.org/ understanding/

analytes/ coag_ cascade/ coagulation_ cascade.html.

Turi DC, Peerschke EI. Sensitivity of three activated partial thromboplastin time reagents to coagula-

tion factor deciencies. Am J Clin Pathol 1986; 85

:43– 9.

van den Besselaar AM, Meeuwisse- Braun J, Jansen- Grüter R, Bertina RM. Monitoring heparin therapy

by the activated partial thromboplastin time— the eect of pre- analytical conditions. Thromb

Haemost 1987; 57

:226– 31.

290

CHAPTER3 Haematology

290

Thrombin clottingtime

This is aected by the concentration of factor I(brinogen) and the pres-

ence of brin or brinogen degradation products and heparin.

•

Sample:citrate.

Increased thrombin clottingtime

• Low brinogen, e.g.DIC.

• i FDPs/ cross- linked brin degradation products (XDPs)/ D- dimers.

• Heparin.*

• Dysbrinogenaemia (inherited; mutation in the brinogen gene leads to

amino acid change and non- functional brinogen).

Note:(*) if suspected, check reptilase time, similar to thrombin clotting time

(TCT), but not aected by heparin.

D- dimers

D- dimers are produced during polymerization of brinogen as it forms

brin. Measurement of D- dimer levels is more specic for this process than

the older FDP test and is now being used to detect the presence of DIC

and other coagulation disorders. The test measures brin lysis by plasmin

and is a sensitive indicator of coagulation activation (e.g. such as that seen in

DIC). The assay uses an MoAb specic for D- dimers; it will not cross- react

with brinogen or brin.

•

Sample:citrate (clotting screen bottle).

Increased D- dimers seenin

• DIC.

• DVT.

• PE.

Summary ofclotting tests ina variety ofdisorders

(See Table3.11.)

Table3.11 Summary ofclotting tests ina variety ofdisorders

PT APTT TCT Platelets Diagnosis

N N N N Platelet function defect, XIII deciency, normal

i N N N VII deciency, early oral anticoagulation

N i N N

VIIIC/ IX/ XI/ XII deciencies, vWD, circulating

anticoagulant, e.g. lupus

i i N N Vitamin K deciency, oral anticoagulant,

V/ VII/ X/ II deciencies

i i i N Heparin, liver disease, brinogen deciency

N N N d Thrombocytopenia (any cause)

i i N

Low Massive transfusion, liver disease

i i i

Low DIC, acute liver disease

Modied from Dacie & Lewis Practical Haematology, 8th edn. Edinburgh:Churchill Livingstone,1995.

291

DISSEMINATED INTRAVASCULAR COAGULATION

3 Disseminated intravascular

coagulation

DIC is a medical and haematological emergency. It may be seen in a variety

of situations and is characterized by generalized bruising and bleeding, usu-

ally from venepuncture sites, post- operatively, and spontaneously.

Diagnosis requires FBC, clotting screen, and evidence of rapid consump-

tion of brinogen. Classic (acute) DIC, where the test results t the bill, is

easy to spot. The situation may be more subtle and you are strongly advised

to discuss the case with a haematology registrar or consultant if you are in

any doubt about the diagnosis ofDIC.

Conditions associated withDIC

(See Table3.12.)

Further reading

Levi MM (2016). Disseminated intravascular coagulation. M http:// www.emedicine.com/ emerg/

topic150.htm.

Table3.12 Conditions associated withDIC

Disorder Example

Infectious disease Septicaemia

Viraemia

Obstetric emergency Placental abruption

Eclampsia

Amniotic uid embolism

Placenta praevia

Septic abortion

Surgical Cardiac bypass

Malignant disease Metastatic cancer

Acute leukaemia (especially AML M3, i.e. acute

promyelocytic leukaemia)

Shock Trauma

Severe burns

Transfusion

ABO- mismatched transfusion

Miscellaneous Snake bites (some)

Liver cirrhosis

3 Laboratory diagnosis

FBC d platelets

± red cell fragments seen on blood lm

PT i in moderately severe DIC

APTT Usually i

Fibrinogen d

(falling levels signicant— but remember this is an acute phase

protein, so levels may be normal, even in orid DIC)

D- dimers i

292

CHAPTER3 Haematology

292

Platelet functiontests

These are specialized tests carried out by the coagulation laboratory for

the investigation of patients with suspected platelet dysfunction. Because of

their complexity, platelet function tests will not be described in detailhere.

Patients generally present with bleeding or bruising problems and have

had normal coagulation results. Because of the labour- intensive nature and

cost of these assays, you will need to arrange these tests after discussion

with your local haematology medicalsta.

•

Sample:blood collection needs to be optimal with non- traumatic

venepuncture, rapid transport to the laboratory with storage at room

temperature and testing within a maximum of2– 3h.

Currenttests

• Plateletcount.

• Morphology.

• Adhesion.

• Aggregation.

• Platelet release.

• Bleedingtime.

Plateletcount

Normal range 150– 400 x 10

/ L. Adequate function is maintained, even

when the count is <0.5 normal level but progressively deteriorates as it

drops. With platelet counts <20 x 10

/ L, there is usually easy bruising and

petechial haemorrhages (although more serious bleeding can occur).

Morphology

Large platelets are biochemically more active; i mean platelet volume

(MPV>6.5) is associated with less bleeding in patients with severe throm-

bocytopenia. Altered platelet size is seen in inherited platelet disorders.

Platelet adhesion

Adhesion to glass beads now rarely performed in routine laboratory prac-

tice, but potentially useful in vWD diagnosis.

Platelet aggregation

Most useful of the special tests; is performed on a fresh sample using an

aggregometer.

Aggregantsused

•

Adenosine 5- diphosphate (ADP) at low and high concentrations.

Induces two aggregation waves:the ° wave may disaggregate at low

concentrations of ADP; the second is irreversible.

•

Collagen has a short lag phase, followed by a single wave, and is

particularly aected by aspirin.

•

Ristocetin- induced platelet aggregation (RIPA) is carried out at

high (1.2mg/ mL) and lower concentrations and is mainly used to

diagnosevWD.

•

Arachidonicacid.

• Adrenaline (epinephrine), not uncommonly reduced in normal people.

PLATELET FUNCTIONTESTS

293

Platelet release

Enzyme- linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)

are used to measure the granule proteins β- thromboglobulin (β- TG) and

heparin neutralizing activity (HNA). These are sensitive markers of platelet

hyper- reactivity and beyond the scope of the routine laboratory.

Practical application oftests

Their main role is in diagnosis of inherited platelet functional defects. In

acquired platelet dysfunction 2° to causes such as renal and hepatic disease,

DIC, and macroglobulinaemia, platelet function is rarely tested.

Further reading

Yardumian DA, Mackie IJ, Machin SJ. Laboratory investigation of platelet function:a review of meth-

odology. J Clin Pathol 1986; 39

:701– 12.

294

CHAPTER3 Haematology

294

Thrombophilia screening

Thrombophilia describes acquired or inherited disorders that predispose to

arterial or venous thromboembolism (VTE). Thrombophilia should be con-

sidered in young patients who have apparent strong family history ofVTE.

•

Causes:E Recurrent thrombosis, p. 92.

Which patients should be screened forpossible

thrombophilia?

• Arterial thrombosis, consider antiphospholipid antibody and lupus

anticoagulant testing.

•

Venous thrombosis:

•

Patients <40years from thrombosis-prone families.

•

Family history of thrombosis with high-risk thrombophilia in rst-

degree relative.

•

Unusual site, e.g. mesenteric, portal vein thrombosis.

•

Children with purpura fulminans.

•

Recurrent miscarriage (three ormore).

•

VTE in pregnancy and theOCP.

Screen

• Exclude medical causes (check ESR, LFTs, AIP, fasting lipids).

• FBC (exclude thrombocytosis).

• Clotting screen for acquired defects (PT, APTT, LA/ anticardiolipin

antibody (ACL), i brinogen).

•

Screen for inherited thrombophilia:

•

First- line protein C (PC), protein S (PS), antithrombin (AT), activated

protein C resistance (APCR).

•

Check for the presence of the factor V Leiden mutation in APCR

+ve patients (DNA analysis).

•

Consider testing plasminogen, brinogen, homocysteine levels,

prothrombin variant.

•

DNA analysis for prothrombin gene mutation.

Thrombophilia investigations are time- consuming and expensive, and you

should discuss with the local haematology medical or laboratory sta

before sending samples. Note:some thrombophilia tests cannot be carried

out in the ‘acute’ phase of a VTE event or whilst the patient is taking an

anticoagulant.

Further reading

Baglin T, Gray E, Greaves M, etal. Clinical guidelines for testing for heritable thrombophilia. Br J

Haematol 2010; 149

:209– 20.

Cattaneo M, Monzani ML, Martinelli I, Falcon CR, Mannucci PM. Interrelation of hyperhomocyst(e)

inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1998; 97:295– 6.

Chong LY, Fenu E, Stansby G, Hodgkinson S. Management of venous thromboembolic diseases and

the role of thrombophilia testing:summary of NICE guidance. BMJ 2012; 344:e3979.

Dahlback B. Resistance to activated protein C as risk factor for thrombosis:molecular mechanisms,

laboratory investigation, and clinical management. Semin Hematol 1997; 34

:217– 34.

Lane DA, Mannucci PM, Bauer KA, etal. Inherited thrombophilia:Part 1. Thromb Haemost 1996;

:651– 62.

Lane DA, Mannucci PM, Bauer KA, etal. Inherited thrombophilia:Part 2. Thromb Haemost 1996;

:824– 34.

ANTITHROMBIN AND PROTEINS CANDS

295

Antithrombin and proteins CandS

These proteins are the body’s natural anticoagulants; hence, deciencies may

lead to thromboembolic disease.

Antithrombin

Used to be called ATIII, but there was never an ATI or ATII, so now abbrevi-

ated to AT. Auseful measure in thrombophilia screening since low levels of

AT are found in 4.5% of patients with unexplainedVTE.

Decreased antithrombinlevels

• Hereditary (40– 60% normal level), autosomal dominant.

• Chronic liver disease.

• Protein wasting disorders.

• Heparin therapy.

• Third trimester of pregnancy.

• Acute leukaemia.

• Burns.

• Renal disease.

• Gram −ve sepsis.

ProteinS

• Reduced levels predispose to VTE. Individuals with 30– 60% normal level

may suer recurrent thrombosis.

•

dPS.

•

Inherited (autosomal dominant).

• Pregnancy.

• Oral anticoagulants, e.g. warfarin.

• Nephrotic syndrome.

• Liver disease.

ProteinC

• Similar to PS; autosomal dominant inheritance in geneticcases.

• dPC.

•

Hereditary.

• Liver disease.

• Malignancy.

• Warfarin therapy.

• Pregnancy.

296

CHAPTER3 Haematology

296

Bone marrow examination

This is a key investigation in haematology. It may be diagnostic in the follow-

up of abnormal peripheral blood ndings and is an important staging pro-

cedure in dening the extent of disease, e.g. lymphomas. It is a helpful

investigative procedure in unexplained anaemia, splenomegaly, or selected

cases ofPUO.

•

Preferred sites:the posterior iliac crest is the usual site (allows an aspirate

and a biopsy to be obtained). The sternum is suitable only for marrow

aspiration and is not a test for the squeamish.

The marrow aspirate provides

• Cytology of nucleatedcells.

• Qualitative and semi- qualitative analysis of haematopoiesis.

• Assessment of iron stores (if Perls’ iron stainused).

• Smears for cytochemistry (helps in the diagnosis of leukaemias).

Marrow cells can also be usedfor

• Chromosomal (cytogenetic) analysis.

• Immunophenotype studies usingMoAbs.

Marrow trephine biopsy provides informationabout

• Marrow cellularity.

• Identication and classication of abnormalcells.

• Immunohistochemistry on inltrates.

Contraindications

None, other than physical limitations, e.g. pain or restricted mobility. Avoid

sites of previous radiotherapy (inevitably grossly hypocellular and not rep-

resentative). (See Table3.13.)

Table3.13 Tests carried outon bonemarrow

Test Purpose

Chromosomes Standard cytogenetic analysis, looking for

rearrangements suggestive of acute or chronic

leukaemias and myelodysplasia

Fluorescence in situ hybridization (FISH) looking for

additions or losses of chromosomes, as well as more

subtle changes seen in leukaemias and lymphomas

DNA or RNA analysis Using PCR to look for mutations or translocations that

help classify leukaemias and lymphomas; also useful for

monitoring disease levels in some disorders

Immunophenotype Cell surface marker prole helps in the diagnosis of

most leukaemias and lymphomas; may also be used to

monitor disease levels post- treatment

Microbiology For example, TB culture (not routine, but occasionally

useful in cases of PUO)

Cytochemical stains To help dene type of leukaemia

BONE MARROW EXAMINATION

297

Procedure

1. BM aspiration may be performed under local anaesthetic (LAn) alone,

but short- acting IV sedative (e.g. midazolam) is preferred when a

trephine biopsy is performed. General anaesthetic used in children.

2. Place the patient in the (left) lateral position, or use the right side if

s/ he cannot lie on the leftside.

3. Inltrate the skin and periosteum over the posterior iliac spine

withLAn.

4. Make a small cutaneous incision before introducing the aspirating

needle, which should penetrate the marrow cortex 3– 10mm before

removal of the trocar.

5. Aspirate no more than 0.5– 1mL of marrow initially (to avoid dilution

of the sample with blood).

6. Make smears promptly (2 the sample clots rapidly!).

7. If further samples are needed, e.g. for immunophenotyping,

cytogenetics, etc., these can be aspirated after making initial slides.

8. For trephine biopsy, use an Islam or Jamshidi needle.

9. Advance the needle through the same puncture site to penetrate the

cortex.

10. Remove the trocar and, using rm hand pressure, rotate the needle

clockwise and advance as far as possible.

11. Remove the needle by gentle anticlockwise rotation.

12. Following the procedure, apply simple pressure dressings.

13. Minor discomfort at the location may be dealt with by simple analgesia

such as paracetamol.

298

CHAPTER3 Haematology

298

Cytochemistry tests (leukaemia

diagnosis)

These staining methods have been around for many years (for decades,

they were all that was available) but remain extremely useful in the diag-

nosis and classication of leukaemias. Modern technologies, such as ow

cytometry and nucleic acid analysis, have rened leukaemia and lymphoma

diagnosis, but the examination of well- stained cytochemistry BM smears

remains the cornerstone of good haematology practice.

After performing a BM aspirate and spreading the material onto glass

slides, the air- dried, unxed microscope slides are passed to the cyto-

chemistry laboratory that will x and stain the slides according to the likely

diagnosis (e.g. stains for AML dier to those for ALL; see Tables 3.14

and 3.15). Positive results with particular stains will point to a specic

diagnosis. This will then be augmented by ow cytometric or molecular

assays (see Fig.3.16).

Table3.14 Cytochemicalstains

Cytochemical stain Substrate/ cell

Myeloperoxidase (MPO) Lysosomal enzyme found in neutrophils and

monocytes

Sudan black (SB) Phospholipids in neutrophil granules

Chloroacetate esterase

Stain- specic esterase in granulocytes and mast

cells. Makes it easier to diagnose AML M4 subtype

α- naphthyl acetate esterase

(ANAE)

Esterase stain, useful for diagnosis of AML

subtypes

Acid phosphatase Enzyme found in many dierent WBCs. Useful for

T- cell malignancies

Periodic acid– Schi (PAS) Detects glycogen in cells. Granulocytes have

diuse staining, whereas lymphocytes staining is

much coarser

CYTOCHEMISTRY TESTS (LEUKAEMIA DIAGNOSIS)

299

Further reading

Cytochemistry. M https:// clinicalgate.com/ cytochemistry/

Table3.15 Cytochemical stains inacute leukaemia

Acute lymphoblastic

leukaemia

Acute myeloid leukaemia

B lineage T lineage M1– 3 M4– 5 M6– 7

MPO − − +/ ++ + −

SB − −

+/ ++ + −

Chloroacetate

esterase

− −

−/ ++ − −

ANAE − − − ++ −

Acid

phosphatase

− + (focal) − + (diuse) + (focal)

PAS + (blocks) − − + (ne

granular)

+, positive; ++, strongly positive; −, negative.

From Hobrand AV, Lewis SM, Tuddenham EGD. Postgraduate haematology, fourth edition,

Oxford:Butterworth- Heinemann,2000.

myeloblast

Auer rods AML

Auer rods

Fig.3.16 AML marrow showing myeloblasts (leukaemic cells) and an Auer rod in

one cell. Auer rods are pathognomonic of AML, since they do not occur in any other

disorder.

300

CHAPTER3 Haematology

300

Neutrophil alkaline phosphatase

Uses

This is a cytochemical stain used to demonstrate the presence and quantity

of the neutrophil enzyme ALP. Historically, the NAP score was of value

in dierentiating ‘reactive’ states from myeloproliferative disorders such as

CML, PRV, etc.— now more often it features in examination multiple choice

questions! (Note:sometimes termed leucocyte alkaline phosphatase,LAP.)

Procedure

Best performed on fresh blood lms, made without the use of anticoagu-

lant. EDTA samples may be used but are less satisfactory. The lm should

be made, air- dried, xed, and then stained— all within 30min. Positive NAP

activity is indicated by the presence of bright blue granules in the neutrophil

cytoplasm (the nucleus is stained red; see Fig.3.17).

•

Scoring:lms are scored from 0 to 4 on the basis of stain intensity:

•

0:−ve, no granulesseen.

•

1:weak +ve, few granules.

•

2:+ve, few to moderate numbers of granules.

•

3:strongly+ve.

•

4:very strong.

Red cell

NAP stain

in cytoplas

Fig.3.17 NAP- stained blood lm showing positively stained neutrophils. Red cells

do not take up thestain.

NEUTROPHIL ALKALINE PHOSPHATASE

301

Interpretation and signicance

(See Table3.16.)

Table3.16 NAP

High NAP score Low NAP score

PRV

Leukaemoid reaction

Neutrophilia— anycause

Myelobrosis

Essential thrombocythaemia

Hepatic cirrhosis

Hodgkin’s disease

Aplastic anaemia

Down’s syndrome

Cushing’s disease

CML

PNH

AML

The NAP score is aected by corticosteroids, oestrogens, and pregnancy

(i NAP). In Hodgkin’s disease, the NAP score oers no advantage over

simpler tests, such as ESR, for assessment of disease activity. Occasionally

of value in a patient with aplastic anaemia who is developing PNH— the

NAP score is seen to fall (both of these are very rare disorders). NAP score

has been replaced in most hospitals by ow cytometry and other methods.

Further reading

Lewis SM, Bain BJ, Bates I (eds.). Dacie & Lewis Practical Haematology, 9th edn, Edinburgh:Churchill

Livingstone,2001.

302

CHAPTER3 Haematology

302

Blood transfusion

Due to space limitation, it is inappropriate to go into major details about the

investigations used in transfusion medicine. However, we have provided the

more important tests in current use which include:

•

Blood group and antibody screen.

• Cross- match (compatibilitytest).

• DAT.

• Antiplatelet and antineutrophil antibody testing.

Safe transfusion practice

Each year, patients are transfused with the wrong blood. In 2015, seven

patients were given ABO- incompatible blood, whilst 280 patients were

given incorrect blood components (not just ABO- incompatible) in 2015.

Note that reporting is currently voluntary and very likely underestimates

actual incidents. However, with 2.5million blood components transfused

annually, it is a small percentage overall. Pulmonary complications, particu-

larly transfusion- associated circulatory overload (TACO), are a major cause

of morbidity and death. However, it is also clear that delay in appropriate

transfusion also contributes to mortality.

A common error is clerical and generally involves the cross- matched

sample being taken from the wrong patient, and so the compatibility test

is performed on the wrong sample. Occasionally, the sta carrying out the

transfusion connect the blood up to the wrong patient. In any event, the

result varies from no symptoms to shock and possibledeath.

How tominimizeerrors

• First, ask yourself, ‘Does this patient really need to be transfused with

blood or blood products (e.g. fresh frozen plasma (FFP), platelets,

etc.)?’ For example, a post- operative patient who is asymptomatic

with Hb of 9g/ dL probably does not require red cell transfusion. Use

clinical judgement in helping decide whether or not to proceed with

transfusion.

•

Before taking the blood sample, check that you are taking blood from

the correct patient— ask for his/ her name and check the identity

bracelet.

•

Label the patient’s blood bottle at the bedside (i.e. no prelabelling of

bottles). Many transfusion laboratories insist on 1, 2, 5, 6, and 7, and

either 3 or 4from:

1. Surname and forename (correctlyspelt)

2. DoB

3. Hospital/ A&E/ new NHSnumber

4. First line of address

5. Sex

6. Time and date bloodtaken

7. Signature of person takingblood

4 Serious Hazards of Transfusion (SHOT) Steering Group (2016). The 2015 annual SHOT report.

https:// www.shotuk.org/ wp- content/ uploads/ SHOT- 2015- Annual- Report- Web- Edition- Final-

bookmarked.pdf; Annual SHOT report 2015 summary. M https:// www.shotuk.org/ wp- content/

uploads/ SHOT- Summary- Infographic_ Final.pdf.

BLOOD TRANSFUSION

303

• Ensure details on the form match those on the bottle.

• Complete the request form properly:

•

State what is required (e.g. 2U of packed cells,etc.).

•

Detail any previous transfusions, reactions, antibodies (if known).

•

Let the laboratory know when you want the blood or blood

product.

3 Adhesive patient labels are ne for forms but are not suitable for speci-

men bottles, and they are usually not accepted by transfusion laboratories.

Transfusion specimens should be labelled by hand— at the bedside.

The TACO checklist should be used to identify those at risk. Defer trans-

fusion, if safe, pending assessment or treatment of risk factor. Single unit

transfusion, followed by a review, is preferable.

The bedside checklist should be usedto:

•

Conrm +ve patient identication.

• Check identication of the component against the patient’s wristband.

• Check the prescription.

• Check the component.

• Check for specic requirements.

Further reading

Estcourt LJ, Birchall J, Allard S, etal.; British Committee for Standards in Haematology. Guidelines for

the use of platelet transfusions. Br J Haematol 2017; 176

:365– 94.

Hunt BJ, Allard S, Keeling D, Norfolk D, Stanworth SJ, Pendry K; British Committee for Standards in

Haematology. Apractical guideline for the haematological management of major haemorrhage.

Br J Haematol 2015; 170

:788– 803.

Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional

Advisory Committee ( JPAC). M

http:// www.transfusionguidelines.org.uk/ .

McClelland B (2001). Handbook of transfusion medicine

, second edition. London:HMSO.

NHS Blood and Transplant. M http:// www.blood.co.uk/ .

Scottish National Blood Transfusion Service. M

http:// www.scotblood.co.uk/ .

If this sounds cumbersome and bureaucratic

Remember many people die annually because they are transfused with

the wrong blood

. In most cases, clerical error is to blame— people have

lled out bottles in advance and failed to check patient identity.

304

CHAPTER3 Haematology

304

3 Transfusion reactions

(See Table3.17.)

Rapid fever, chill, rigor, hyper- or hypotension, collapse, ushing, urticaria,

or respiratory distress at the start of transfusion indicate transfusion should

be stopped and resuscitation initiated (suggests a severe or life- threatening

acute transfusion reaction).

If the temperature rises to above 39°C or >2°C from baseline, with

other signs/ symptoms, consider bacterial contamination and monitor the

patient carefully. Investigate as appropriate.

•

If an isolated temperature of >38°C and a 1– 2°C rise with no

symptoms, or rash only, providing the patient is not acutely unwell,

continue the infusion. Fever often due to antibodies against WBCs (or

to cytokines in platelet packs).

3 Immediate transfusion reaction

Intravascular haemolysis (l haemoglobinaemia and haemoglobinuria).

Usually due to anti- A or anti- B antibodies (in ABO- mismatched transfu-

sion). Symptoms occur in minutes/ hours. May befatal.

Immediate transfusion reaction or bacterial contamination

ofblood

If predominantly extravascular, may only suer chills/ fever 1h after starting

transfusion— commonly due to anti- D. ARF is not a feature.

Mechanism

Complement (C3a, C4a, C5a) release into recipient plasma l smooth

muscle contraction. May develop DIC or oliguria (10% of cases) due to

profound hypotension.

Initial steps inmanagement ofacute transfusion reaction

• Stop blood transfusion immediately.

• Replace the giving set; keep the IV access open with 0.9% saline.

Table3.17 Transfusion reactions

Symptoms Signs

Patient restless/ agitated Fever

Flushing Hypotension

Anxiety Oozing from wounds or venepuncture sites

Chills Haemoglobinaemia

Nausea and vomiting Haemoglobinuria

Pain at venepuncture site

Abdominal, ank, or chest pain

Diarrhoea

305

TRANSFUSION REACTIONS

• Check the patient identity against the donorunit.

• Insert a urinary catheter and monitor the urine output.

• Give uids (IV colloids) to maintain urine output >1.5mL/ kg/ h.

• If urine output <1.5mL/ kg/ h, insert a CVP line and give a uid

challenge.

•

If urine output <1.5mL/ kg/ h and CVP adequate, give furosemide

80– 120mg.

• If urine output still <1.5mL/ kg/ h, consult senior medical sta for

advice.

•

Contact the blood transfusion laboratory before sending back the blood

pack and for advice on blood samples required for further investigation

(E Urgent investigations below).

Complications

•

Overall mortality710%.

Urgent investigations

Your local blood transfusion department will have specic guidelines to help

you with the management of an acute reaction. The following guide lists

the samples commonly required to establish the cause and severity of a

transfusion reaction (see Box 3.1). If you are uncertain about the labora-

tory procedure or management of a patient who appears to have suered

a severe reaction, you must notify your hospital’s haematology medical sta

who will provide advice.

3 Delays may threaten the patient’slife.

Febrile transfusion reactions

Seen in 0.5– 1.0% of blood transfusions. Mainly due to anti- HLA (human leu-

cocyte antigen) antibodies in recipient serum or granulocyte- specic anti-

bodies (e.g. sensitization during pregnancy or previous blood transfusion).

Box 3.1 Investigation oftransfusion reaction

1. Check the compatibility label of the blood unit matches with the

patient’s identity band, forms, and casenotes.

2. If mistake found, tell the blood bank urgently— the unit of blood

intended for your patient may be transfused to another patient.

3. Take bloodfor:

•

Haematology:

—FBC.

—DAT.

—PlasmaHb.

—Repeat cross- match sample.

—Coagulation screen.

•

Chemistry:U&E.

•

Microbiology:blood cultures.

4. Check urinalysis and monitor urine output.

5. Do ECG and check for evidence of i[K

6. Arrange repeat coagulation screens and biochemistry 2- to 4- hourly.

306

CHAPTER3 Haematology

306

Delayed transfusion reaction

Occurs in patients immunized through previous pregnancies or transfu-

sions. Antibody weak (so not detected at pre- transfusion stage). 2° immune

response occurs— antibody titrei.

Symptoms andsigns

•

Occur 7– 10days after blood transfusion.

• Fever, anaemia, and jaundice.

• ± haemoglobinuria.

Management

•

Discuss with the transfusion laboratorysta.

• Check DAT and repeat compatibilitytests.

• Transfuse the patient with freshly cross- matchedblood.

Further reading

Kardon EM (2016). Transfusion reactions in emergency medicine. M http:// www.emedicine.com/

emerg/ topic603.htm.

307

TRANSFUSION REACTIONS

308

CHAPTER3 Haematology

308

Bacterial contamination

ofblood products

Uncommon, but potentially fatal, adverse eect of blood transfusion

(aects red cells and blood products, e.g. platelet concentrates). Implicated

organisms include Gram −ve bacteria, including Pseudomonas, Yersinia, and

Flavobacterium.

Features

Include fever, skin ushing, rigors, abdominal pain, DIC, ARF, shock, and

possible cardiac arrest.

Management

As per Immediate transfusion reaction (E p. 304):

•

Stop transfusion.

• Urgent resuscitation.

• IV broad- spectrum antibiotics if bacterial contamination suspected.

Antiglobulintest

The old term is Coombs’ test. DAT detects antibodies or complement, or

both, on the RBC surface, and the indirect antiglobulin test (IAT) detects

the presence of antibodies in serum. Auseful investigation when investigat-

ing haemolytic anaemia.

•

Sample:EDTA.

Interpretation

• Positive DAT in mostAIHA.

• Lymphoproliferative disorders, e.g.CLL.

• Drug- induced haemolysis (e.g. methyldopa, levodopa).

•

Haemolytic disease of the fetus and newborn (HDFN), e.g. rhesus

(Rh)HDN.

Note: as with many tests in medicine, things are never entirely black or

white— a +ve DAT does not necessarily imply that haemolysis is actively

occurring and a −ve DAT does not exclude haemolysis.

Further reading

Coombs RRA. A new test for the detection of weak and ‘incomplete’ Rh agglutinins. Br J Exp Pathol

1945; 26

:255– 66.

Kelton JG. Impaired reticuloendothelial function in patients treated with methyldopa. N Engl J Med

1985; 313

:596– 600.

KLEIHAUERTEST

309

Kleihauertest

Uses

To determine whether fetal red cells have entered the maternal circulation

and, if so, the volume of such fetalcells.

Background

If an Rh (D)−ve mother has a baby that is Rh (D)+ve, she may develop

antibodies (maternal anti- D) against fetal red cells. This may result in fetal

red cell destruction termed rhesus haemolytic disease of the newborn, a seri-

ous haemolytic disorder that is seen less today due to a greater understand-

ing of the underlying mechanism and our ability to prevent it. Sensitization

to the fetal red cells occurs when fetal RBCs enter the maternal circulation,

e.g. at birth or through obstetric manipulations, e.g. amniocentesis, previous

pregnancies,etc.

Fetal RBCs in the mother’s circulation can be detected and quantied (in

mL) using the Kleihauer test, which exploits the resistance of fetal red cells

to acid elution (acid washes adult Hb out of the mother’s red cells, but fetal

RBCs contain HbF, which is not washed out). The Kleihauer test should be

performed on all Rh (D)−ve women who deliver an Rh (D)+ve infant.

Fetal cells appear as darkly staining cells against a background of ghosts

(these are the maternal red cells). An estimate of the required dose of anti-

D can be made from the number of fetal cells in a low- powereld.

• Sample:maternal peripheral bloodEDTA.

Calculating thevolume offetal red blood cells

inmaternal circulation

Basically, a calculation is made by the laboratory sta, based on the number

of fetal RBCs seen in the Kleihauer lm. The actual calculationis:

1800* × ratio of fetal/adult RBCs × 4/3 (correction factor)

For example, if there are 1% of fetal RBCs in maternal circulation:

1800 × 1/100 × 4/3 = 24mL

(* where 1800 is the maternal red cell volume)

A 4mL bleed (i.e. 4mL of fetal RBCs) requires 500IU of anti- D given IM

to the mother, with a further 250IU of anti- D for each additional mL of

fetalRBCs.

Do notpanic!

The laboratory carrying out the Kleihauer test will tell you the volume of fetal

RBCs detected, since they will count the cells and do the calculation for you.

If the total is >2mL of fetomaternal haemorrhage, the maternal sample is sent

for FMH conrmation by ow cytometry. After this, you will need to calculate

the dose of anti- D to give the mother, but if you are unsure, either discuss with

the haematology medical sta or contact your local transfusion centre.

Further reading

Chanarin I (ed.). Laboratory Haematology:An Account of Laboratory Techniques. Edinburgh:Churchill

Livingstone,1989.

310

CHAPTER3 Haematology

310

Erythropoietinassay

Epo is the hormone produced largely by the kidney that drives red cell

production. The typical anaemia found in renal disease is a result of failure

of Epo production. Epo assays are of value in renal medicine and haematol-

ogy. For example, in the assessment of polycythaemic states, an i Epo level

may be appropriate (e.g. in hypoxia where the body is attempting to i O

availability to tissues) or inappropriate (e.g. some tumours). The Epo assay

is carried out using an RIA method and is not available in all haematology

laboratories (may need to be sent to another hospital or laboratory).

•

Normal range:35– 25mU/ mL, steady- state level, no anaemia. May rise to

10,000mU/ mL in hypoxia or anaemia.

Causes ofi Epo (appropriate)

• Anaemias.

• High altitude.

• Hypoxia:

•

Lung disease.

•

Sleep apnoea syndromes.

• Cyanotic heart disease (e.g. right l left shunts).

•

High- anityHb.

• Cigarette smoking.

• Methaemoglobinaemia.

Causes ofi Epo (inappropriate)

• Renal disease:

•

Hypernephroma.

•

Nephroblastoma.

•

Post- renal transplant.

•

Renalcysts.

•

RAS.

• Hepatoma.

• Uterine broids.

• Cerebellar haemangioblastoma.

• Phaeochromocytoma.

Other causes ofiEpo

• Androgen therapy.

• Cushing’s disease.

• Hypertransfusion.

• Neonatal polycythaemia.

Causes ofdEpo

• Renal failure.

• Polycythaemiavera.

• RhA and other chronic inammatory diseases.

• Myeloma and other cancers.

Further reading

Cotes PM, Doré CJ, Yin JA, etal. The use of immunoreactive erythropoietin in the elucidation of

polycythemia. N Engl J Med 1986; 315

:283– 7.

IMMUNOHAEMATOLOGY

311

Immunohaematology

Immunohaematology is the study of the eects of the immune system on

the blood and its components. This includes red cells, white cells, platelets,

and coagulation proteins.

Tests forantiplatelet and antineutrophil antibodies

These tests are usually requested by the haematology department for

patients with either thrombocytopenia or neutropenia, respectively. These

assays are used to detect the presence of specic antibodies against platelet

or neutrophil antigens on the cell surface.

Antibodies may be alloantibodies (e.g. antibodies produced by the mother

against fetal antigens) or autoantibodies, which are antibodies produced by

the patient against his/ her own antigens (see Table3.18).

Antiplatelet antibodytests

Generally platelet immunouorescence tests (PIFTs) or monoclonal anti-

body immobilization of platelet antigens (MAIPA) are used. These are

useful for detecting even weak antibodies or where there are only a few

antigenic sites percell.

Elegant though these tests are, they are actually not useful in clinical prac-

tice for the diagnosis of neutropenia or thrombocytopenia where the cause

is autoimmune, since these are largely clinical diagnoses. (Platelet- associated

IgG or IgM may be high in autoimmune thrombocytopenia. However, it may

also be high in non- immune causes of thrombocytopenia.) Where these

tests are of value is in the neonatal setting where the neonate has low plate-

lets or neutrophils.

Table3.18 Disorders withneutrophil- specic allo- and autoantibodies

Disorders with neutrophil- specic alloantibodies

• Neonatal alloimmune neutropenia

• Febrile transfusion reactions (HLA antibodies)

• Transfusion- related acute lung injury (TRALI)

Disorders with neutrophil- specic autoantibodies

• ° autoimmune neutropenia

• 2°:

•

SLE

•

Evans’ syndrome (AIHA + d platelets)

•

Lymphoproliferative disorders (e.g.CLL)

•

Immune dysfunction (e.g. HIV, graft- versus- host disease)

Further reading

Roitt I. Essential Immunology, 10th edn. Oxford:Blackwell Science,2001.

312

CHAPTER3 Haematology

312

Immunophenotyping

This describes the identication and counting of cell types using powerful

MoAbs specic for cell surface proteins.

Uses

(See Table3.19.)

•

Diagnosis and classication of leukaemias and lymphomas.

• Assessment of cellular DNA content and synthetic activity.

• Determination of lymphocyte subsets, e.g. CD4

T cells in HIV

infection.

•

Assessment of clonality.

• Allows identication of prognostic groups.

• Monitoring of minimal residual disease (MRD, the lowest level of

malignancy that can be detected using standard techniques).

Terminology and methodology

Cell surface proteins are denoted according to their cluster dierentia-

tion (CD) number. Most cells will express many dierent proteins, and the

pattern of expression allows cellular characterization. MoAbs recognize

specic target antigens on cells. Using a panel of dierent antibodies, an

immunophenotypic prole of a sample is determined. Immunophenotyping

is used in conjunction with standard morphological analysis of blood and

marrow cells. The antibodies are labelled with uorescent markers, and

binding to cell proteins is detected by laser. For each analysis, thousands

of cells are assessed individually and rapidly. Some antibodies can detect

antigens insidecells.

•

Sample:heparin.

Table3.19 Uses ofimmunophenotyping

Surface immunophenotyping Leukaemias

Lymphomas

CD4:CD8 ratios in HIV infection

DNA content of tumours Ploidy

S phase analysis

Proliferation markers

TdT measurement In leukaemias and lymphomas

Bone marrow transplant/ stem cell

transplantation

Antiplatelet antibody detection

Reticulocyte counts and maturation

Apoptosis

Detection of small numbers of cells For example, fetal cells in mother’s

circulation, microorganisms in blood

Data from Provan D etal. Oxford Handbook of Clinical Haematology, 2nd edn, Oxford:Oxford

University Press,2004.

IMMUNOPHENOTYPING

313

Monoclonal antibodies

These are so- called because they are derived from single B lymphocyte cell

lines and have identical antigen- binding domains (idiotypes). It is easy to

generate large quantities of MoAbs for diagnosticuse.

•

Cell populations from, e.g. peripheral blood or BM samples are

incubated with a panel of MoAbs, e.g. anti- CD4, anti- CD34, which are

directly or indirectly bound to a uorescent marker antibody.

•

Sample is passed through a uorescence- activated cell sorter (FACS)

machine.

•

FACS instruments assign cells to a graphical plot by virtue of cell size

and granularity detected as forward and side light scatter by thelaser.

•

Allows subpopulations of cells, e.g. mononuclear cells, in blood samples

to be selected.

•

The reactivity of this cell subpopulation to the MoAb panel can then be

determined by uorescence for eachMoAb.

•

Atypical result for a CD4 T- lymphocyte population is shown:CD3,

CD4 +ve; CD8, CD13, CD34, CD19−ve.

Leukaemia diagnosis:common patterns (proles)

• AML:CD13+, CD33+, ± CD34, ± CD14+ve.

•

cALL:CD10 and TdT+ve.

•

T- ALL:cCD3, CD7, TdT+ve.

•

B- ALL:CD10, CD19, surface Ig+ve.

•

CLL:CD5, CD19, CD23, weak surface Ig+ve.

Clonality assessment

Particularly useful in determining whether there is a monoclonal B- cell or

plasma cell population.

Monoclonal B cells from, e.g. non- Hodgkin’s lymphoma (NHL) will

have surface expression of κ or λ light chains, but notboth.

2 Polyclonal B cells from, e.g. a patient with infectious mononucleosis will

have both κ and λ expression.

Further reading

Clinical Flow Wiki. M http:// wiki.clinicalow.com/ .

Johansson U, Bloxham D, Couzens S, et al.; British Committee for Standards in Haematology.

Guidelines on the use of multicolour ow cytometry in the diagnosis of haematological neo-

plasms. Br J Haematol 2014; 165

:455– 88.

University of Medicine and Dentistry of New Jersey. Immunophenotyping lymphomas. M http://

pleiad.umdnj.edu/ hemepath/ immuno/ immuno.html.

314

CHAPTER3 Haematology

314

Cytogenetics

Uses

• The study of chromosomes.

• Looks at the number of chromosomes in eachcell.

• Detects structural abnormalities between chromosomepairs.

Chromosome abnormalities may be constitutional (inherited) or acquired

later in life. Cytogenetic analysis of chromosome structure and number

has been used for many years for the study of disorders such as Down’s

syndrome. Acquired chromosomal abnormalities are found in malignancies,

especially haematological tumours. The analysis and detection of cytoge-

netic abnormalities is known as karyotyping. Because of the complexity of

this subject area, we will concentrate on two main areas where chromo-

some analysis is ofvalue.

•

Prenatal diagnosis of inherited disorders:

•

Detection of common aneuploidies (gain or loss of chromosomes).

•

Detection/ exclusion of known familial chromosome abnormalities.

• Detecting acquired chromosome abnormalitiesfor:

•

Diagnosis of leukaemia subtypes, e.g. t(15;17) characteristic of AML

M3 subtype.

•

Markers of prognostic information in a variety of diseases such as

leukaemias, e.g. t(9;22) in acute leukaemias, N- myc amplication in

neuroblastoma.

•

Monitoring response to treatment (in CML, the Philadelphia chromo-

some t(9;22) should disappear if the malignant cells are killed).

Principal indications forcytogenetic analysis are therefore

• Haematological malignancies at diagnosis (assuming the BM is

inltrated).

•

Inltrated solid tumour tissue at diagnosis.

• Patients with equivocal morphology (e.g. type of leukaemia not clear

using microscopy and other markers).

•

FISH analysis when required in certain treatment protocols, e.g.MRC.

• Conrmation of disease relapse.

• Accelerated phase or blast crisis inCML.

Cytogenetic assays are expensive (around £250 for a leukaemia or lym-

phoma karyotype), and if there is any doubt as to whether the test is indi-

cated, we would suggest you discuss the case with one of your seniors or

the cytogenetics sta. Arranging karyotyping before or during pregnancy

is generally carried out by the obstetrician in charge of the woman’scare.

(See Table3.20.)

CYTOGENETICS

315

Table3.20 Cytogenetic terminology

Constitutional Present at conception or arising during embryonic life

Acquired Arise later in fetal life or after birth

Translocation Exchange of material between chromosomes

Deletion

Loss of part of a chromosome

Duplication Part of a chromosome is gained

Inversion Part of a chromosome is rotated through 180°

Diploid 46 chromosomes (somatic cell)

Haploid 23 chromosomes (germinal cell, e.g. egg or sperm)

Trisomy Extra copy of a chromosome

Monosomy

Loss of a chromosome

Aneuploidy Loss or gain of certain chromosomes, e.g. monosomy or trisomy

316

CHAPTER3 Haematology

316

Cytogenetics:prenatal diagnosis

This allows both the detection of genetic diseases associated with specic

chromosomal abnormalities, thereby oering the possible prevention of an

aected child. With the advent of CVS in the rst trimester, karyotyping

can be done at an early stage of development (see Figs 3.18 and 3.19).

Pre- implantation genetic diagnosis allows abnormalities to be detected even

before implantation has occurred.

Cervix

Sample of sac

is withdrawn

Embry

Uterus

Fig.3.18 Diagram showing method of chorionic villus sampling.

678910 11 12

13 14 15 16 17 18

19 20 21 22 XY

5432

Fig.3.19 Normal karyotype showing metaphase chromosomes (22 autosomes

1– 22, and two sex chromosomes XX or XY, depending on the sex of the patient).

CYTOGENETICS:PRENATAL DIAGNOSIS

317

• Sample:amniotic uid (15– 16 weeks’ gestation).

Tests available

• AFPlevel.

•

Chromosome analysis.

• Biochemical tests, e.g. acetylcholinesterase.

• Sample:CVS (9– 12 weeks’ gestation).

Tests available

• DNA analysis.

• Chromosome analysis.

• Biochemistrytests.

Procedure (inbrief )

1. Cells are obtained using amniocentesis, CVS, or fetal blood sampling.

2. Cells are cultured in medium.

3. Cell division is arrested at metaphase using, e.g. colchicine.

4. Chromosomes are spread onto slides and stained.

5. Chromosomes are examined directly using light microscopy or with the

aid of a computerized image analysis system.

Chromosome anatomy

Note:the banding pattern helps identify individual chromosomes, along with

the position of the centromeres (the mitotic spindle attaches to these dur-

ing cell division), the short (p) and long (q) arms, and telomeres (chromo-

some ends). (See Fig.3.20.)

Further reading

East of Scotland Regional Genetics Service. Prenatal cytogenetics. M https:// humangenetics.org.uk/

prenatal- cytogenetics/ .

Rooney DE. Human Cytogenetics, Vol 2, 2nd edn. Oxford:Oxford University Press,2001.

University of Washington, Department of Pathology. Cytogenetics gallery. M

http:// www.pathology.

washington.edu/ galleries/ Cytogallery/ .

p (short) ar

Centromere

q (long) arm

Telomere

Fig.3.20 Chromosome anatomy:note short (p) arms and long (q)arms.

318

CHAPTER3 Haematology

318

Cytogenetics:haematological

malignancies

Uses

• Aids the diagnosis and classication of haematological malignancy.

• Assessment of clonality.

• Identication of prognostic groups.

• Monitoring response to therapy.

• Determining engraftment and chimerism post- allogeneic transplant.

Terminology

• Anormal somatic cell has 46 chromosomes:22 pairs, and XXorXY.

• Numbered 1– 22 in decreasing sizeorder.

• Two arms meet at the centromere— short arm denoted p, long armisq.

•

Usually only visible during condensation at metaphase.

• Stimulants and cell culture used— colchicine disrupts the spindle

apparatus, thereby arresting cells in metaphase.

•

Chromosomes are G- banded using Giemsa or Leishman’s stain to

create characteristic banding patterns along the chromosome. The

regions and bands are numbered, e.g. p1, q3,etc.

Common abnormalities

• Whole chromosome gain:e.g. trisomy 8(+8).

•

Whole chromosome loss:e.g. monosomy 7(−7).

•

Partial gain:e.g. add9q+, or partial loss, e.g. del5q−.

•

Translocation:material exchanged with another chromosome; usually

reciprocal, e.g. t(9;22)— the Philadelphia translocation.

• Inversion:part of chromosome runs in opposite direction, e.g. inv(16)

inM4Eo.

•

Many translocations involve breakpoints around known oncogenes,

e.g.

bcr, ras, myc,bcl- 2.

(See Table3.21.)

Molecular cytogenetics

• Molecular revolution is further rening the specic abnormalities in the

genesis of haematological malignancies.

•

Techniques such as FISH and PCR can detect cryptic abnormalities.

• Bcr– abl probes are now used in diagnosis and monitoring of treatment

response inCML.

• IgH and T- cell receptor (TCR) genes are useful in determining clonality

of suspected B- and T- cell tumours, respectively.

• Specic probes may be used in diagnosis and monitoring of subtypes of

acute leukaemia, e.g. AML, e.g. PML– RARA in AML M3, t(9;22), t(12;21),

and 11q23 rearrangements in paediatricALLs.

CYTOGENETICS:HAEMATOLOGICAL MALIGNANCIES

319

Further reading

Heim S, Mitelman F. Cancer Cytogenetics, 2nd edn. NewYork:Wisley- Liss,1995.

Kingston HM. ABC of Clinical Genetics, 2nd edn. London:BMJ Books,1994.

Sandberg AA. The Chromosomes in Human Cancer and Leukemia, 2nd edn. New York: Elsevier

Science,1990.

Table3.21 Karyotypic abnormalities inleukaemia and lymphoma

CML

t(9;22) Philadelphia chromosome translocation creates bcr

– abl chimeric

gene.

AML

t(8;21)

AML M2, involves AML– ETO gene— has better prognosis

t(15;17) AML M3 involves PML– RARA gene— has better prognosis

inv(16) AML M4Eo– – has better prognosis

−5, −7 Complex abnormalities have poor prognosis

MDS

−7, +8, +11 Poor prognosis

5q− syndrome Associated with refractory anaemia and better prognosis

Myeloproliferative disease

20q− and +8 Common associations

ALL

t(9;22) Philadelphia translocation, poor prognosis

t(4;11) Poor prognosis

Hyperdiploidy i

in total chromosome number— good prognosis

Hypodiploidy d in total chromosome number— bad prognosis

T- ALL

t(1;14) Involves tal- 1 oncogene

B- ALL and Burkitt’s lymphoma

t(8;14) Involves myc and IgH genes, poor prognosis

CLL

+12, t(11;14)

NHL

t(14;18) Follicular lymphoma, involves

bcl- 2 oncogene

t(11;14) Mantle cell lymphocytic lymphoma, involves

bcl- 1 oncogene

t(8;14) Burkitt’s lymphoma, involves myc and IgH genes

320

CHAPTER3 Haematology

320

Human leucocyte antigen

(tissue)typing

The HLA system or major histocompatibility complex (MHC) is the name

given to the highly polymorphic gene cluster region on chromosome 6,

which codes for cell surface proteins involved in immune recognition.

Uses

Tissue typing patients (to ensure compatibility between donor and recipient)

who are undergoing transplantation to reduce the likelihood of rejection or

graft- versus- host disease (GvHD) in the following types of transplant:

• Heart.

• Lung.

• Liver.

• Kidney.

• BM.

• Stemcells.

The gene complex is subdivided intotwo regions

Class1

•

The A, B, and Cloci.

• These proteins are found on most nucleated cells and interact with

CD8

T lymphocytes.

Class2

•

Comprises DR, DP, and DQ loci present only on B lymphocytes,

monocytes, macrophages, and activated T lymphocytes.

•

Interact with CD4

T lymphocytes.

•

Class 1 and 2 genes are closely linked, so one set of gene loci is

usually inherited from each parent, although there is a small amount of

cross- over.

• There is 725% chance of two siblings being HLA identical.

• There are other histocompatibility loci apart from the HLA system, but

these appear less important generally, except during HLA- matched stem

cell transplantation when even dierences in these minor systems may

causeGvHD.

Typing methods

Class 1 and 2 antigens were originally dened by serological reactivity with

maternal antisera containing pregnancy- induced HLA antibodies. There are

many problems with the technique and it is too insensitive to detect many

polymorphisms. Molecular techniques are increasingly employed, such as

single strand polymorphism (SSP). Molecular characterization is detecting

enormous class 2 polymorphisms.

HUMAN LEUCOCYTE ANTIGEN (TISSUE)TYPING

321

Importance ofHLAtyping

• Matching donor/ recipient pairs for renal, cardiac, and marrow stem cell

transplantation.

•

Degree of matching more critical for stem cell than solid organ

transplants.

•

Sibling HLA- matched stem cell transplantation is now the treatment of

choice for many malignancies.

•

Unrelated donor stem cell transplants are increasingly performed,

but outcome is poorer due to HLA disparity. As molecular matching

advances, improved accuracy will enable closer matches to be found and

results should improve.

Functional tests ofdonor/ recipient compatibility

• Mixed lymphocyte culture (MLC):now rarelyused.

•

Cytotoxic T- lymphocyte precursor (CTLp) assays:determine the frequency

of cytotoxic T lymphocytes in the donor directed against the recipient.

Provides an assessment of GvHD occurring.

HLA- related transfusionissues

• HLA on WBC and platelets may cause immunization in recipients of

blood and platelet transfusions.

•

May cause refractoriness and/ or febrile reactions to platelet

transfusions.

•

Leucodepletion of products by ltration prevents this (the National

Blood Service removes the WBCs at source routinely nowadays).

•

Diagnosis of refractoriness conrmed by detection of HLA or platelet-

specic antibodies in the patient’sserum.

•

Platelet transfusions matched to recipient HLA type may improve

increments.

Further reading

BSBMT. Interpreting HLA typing and matching. M http:// bsbmt.org/ registry- help- documents/ .

Klein J, Sato A. The HLA system. N Engl J Med 2000; 343:702– 9. M http:// content.nejm.org/ cgi/

content/ full/ 343/ 10/ 702?ijkey=oOilwRsUqacag.

Naik S. The human HLA system. J Indian Rheumatol Assoc 2003; 11:79– 83. M http:// medind.nic.in/

jaa/ t03/ i3/ jaat03i3p79.pdf.

322

CHAPTER3 Haematology

322

Southern blotting

This technique has been around since the mid 1970s. It explained much

about the physical structure of genes and was a major advance in the diag-

nosis of many single gene disorders. The method is simple and elegant, but

time- consuming. Not used as much today with the advent of PCR technol-

ogy. Southern blotting relies on the physical nature of DNA whereby single

strands are able to recognize and bind to their complementary sequences

(see Fig.3.21).

•

Sample:EDTA sample (heparin can be used, but beware inhibitory eect

on PCR amplication; if any chance PCR required, sendEDTA).

−

Digestion by restriction

enzyme, e.g. Mst II

(chops the DNA up)

Digested products

separated using

agarose gel

electrophoresis

(small fragments

move furthest)

Separated fragments

exposed to

radiolabelled probe,

e.g. for β globin gene

Transferred to nylon lter

which is then placed next to X-ra

lm. A black band is seen where

the probe has bound to the

patient’s DNA fragment

DNA from blood, marrow,

fetal cells, etc.

Fig.3.21 Southern blotting method.

SOUTHERN BLOTTING

323

Procedure

1. Genomic (i.e. total) DNA is extracted from WBC in EDTA blood

sample.

2. DNA is digested with bacterial restriction endonucleases (enzymes

cleave DNA at specic sequences— each enzyme recognizes a dierent

DNA sequence).

3. After digestion of the DNA, the fragments are separated on the basis

of size using agarose gel electrophoresis (the smallest fragments travel

the farthest).

4. The fragments are transferred to a nylon membrane and xed

permanently to the membrane using ultraviolet (UV)light.

5. Membranes are ‘probed’ using specic (known) gene probes that are

radioactively labelled using

6. The location of specic binding is detected by placing the membrane

next to a radiographic lm (standard X- raylm).

7. The lm is developed using standard techniques, and the

autoradiograph generated will show bands corresponding to the

position of binding of the labelledprobe.

8. Fragment sizes are calculated, and the presence or absence of

mutations is worked out by determining whether enzyme cutting sites

have been lost through mutation.

Applications

• Historically, many diseases caused by single base changes (loss of

restriction enzyme cutting site) have been diagnosed using Southern

blotting.

•

Globin gene disorders:

• Sickle- cell anaemia (mutation in β- globingene).

• Thalassaemia (mutations or deletions in α- or β- globin genes).

• Clotting disorders:

• Haemophilia.

• Analysis of Ig or TCR genes to detect clones of cells in suspected

leukaemia or lymphoma.

•

Detection of chromosomal translocations in leukaemia and lymphoma

(e.g. t(9;22) in CML, t(14;18) in follicular lymphoma).

Further reading

Kimball’s Biology Pages. Gel blotting. M http:// www.biology- pages.info/ G/ GelBlotting.html.

Southern EM. Detection of specic sequences among DNA fragments separated by gel electro-

phoresis. J Mol Biol 1975; 98

:503– 17 (3 Southern’s classic paper and probably the most cited

molecular biology paperever).

Thermo Fisher Scientic. Southern blotting. M

https:// www.thermosher.com/ uk/ en/ home/ life-

science/ dna- rna- purication- analysis/ nucleic- acid- gel- electrophoresis/ southern- blotting.html#.

324

CHAPTER3 Haematology

324

Polymerase chain reaction

ampliﬁcationofDNA

The ability to use an enzyme to amplify specic DNA sequences has revo-

lutionized modern diagnostic pathology. Whereas Southern blotting might

take up to 1 week to produce a result, PCR can do the same thing in 2– 3h!

PCR is now in routine use in the analysis of oncogenes, haematological

malignancies, general medicine, infectious disease, and many other spe-

cialties. Because the system amplies the starting DNA up to a million-

fold, there need only be one cell as starting material; in practice, much

more DNA is required, but because of the extreme sensitivity of the

technique, PCR has been used in forensic medicine where there may be

only a few cells available for analysis (e.g. blood or semen stain).

(See Fig.3.22.)

Advantages

• Requires very littleDNA.

• DNA quality does not matter (can be highly degraded, e.g. with age and

still be amplied— DNA from Egyptian mummies has been amplied).

• Rapid results.

Disadvantages

• Expensive, but less so than it usedtobe.

• DNA sequence of the gene of interest must be known in order to

design the short PCR primers (oligos). With the near completion of the

Human Genome Project, this is less of a problemnow.

•

Highly sensitive, and contamination of samples may occur (DNA

fragments oat through the air constantly; if these drop into the reaction

tube, a false +ve result may be obtained).

Band on gel

corresponding to

PCR product

(positive result)

Patient 1 2 Control

Base pair ladder

(lets you calculat

size of PCR band

)

−603

−310

−194

−118

Origin

Fig.3.22 Detection of residual leukaemia using PCR. Patients 1 and 2 have undergone

chemotherapy, but as can be seen (arrow), there is still some leukaemia- specic DNA

sequence present, i.e. they have minimal residual disease.

POLYMERASE CHAIN REACTION AMPLIFICATIONOFDNA

325

Procedure (inbrief )

(See Fig.3.23.)

•

Two short DNA primers on either side of the gene of interest bind to

the fragment of interest.

•

The region between the primers is lled in using a heat- stable DNA

polymerase (Taq polymerase).

•

After a single round of amplication has been performed, the whole

process is repeated.

•

This takes place 30 times (i.e. through 30 cycles of amplication),

leading to a million- fold i in the amount of specic sequence.

•

After the 30 cycles are complete, a sample of the PCR reaction is run

on agarose gel and bands are visualized.

•

Information about the presence or absence of the region or mutation of

interest is obtained by assessing the size and number of dierent PCR

products obtained after 30 cycles of amplication.

Target sequence

Unamplied DNA

Denature and anneal primers

Start primer extension

Complete primer extension

Denature and anneal primers

30 or 40 cycles total

Cycle 1

Cycle 2

I I I I I I

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

I I I I I I

I I I I I I I I I I I I I I I I I I I I I I I I I I I

Fig.3.23 PCR amplication method.

326

CHAPTER3 Haematology

326

Applications

• PCR is currently used to amplify Ig genes, HIV loci, TB genes, and many

other targets that are of use in molecular medicine (cystic brosis,

haemophilia, thalassaemia, sickle- cell disease, and many others).

• PCR can be used to quantitate messenger ribonucleic acid (mRNA)

species in blood samples and tissue samples. Allows gene ‘activity’ to be

measured.

Further reading

Nobelprize.org. The PCR method—a DNA copying machine. M http:// nobelprize.org/ chemistry/

educational/ pcr/ .

Principles of the PCR. M

http:// users.ugent.be/ ~avierstr/ principles/ pcr.html.

Saiki RK. Primer- directed enzymatic amplication of DNA with a thermostable DNA polymerase.

Science 1988; 239:487– 91 (classic PCR method paper).

POLYMERASE CHAIN REACTION AMPLIFICATIONOFDNA

327

328

CHAPTER3 Haematology

328

In situ hybridization and ﬂuorescence

insitu hybridization

Like PCR and other techniques, in situ hybridization and FISH are conceptu-

ally simple techniques that rely on the ability of a DNA probe to ‘nd’ its

counterpart on a chromosome and bind, and if a uorescent tag is present,

it will light up the region of binding (this modication is termed uorescence

in situ hybridization, or FISH). These techniques have evolved from standard

cytogenetic analysis of metaphase chromosomes in which metaphase chro-

mosomes were prepared on glass slides to which specic labelled probes

were applied.

•

Sample:discuss with your local cytogenetics or haematology laboratory

(they will have specialized medium for maintaining cells from blood

or marrow, so that they will divide and be suitable for hybridization

studies).

In situ hybridization

The location of binding of the probe is detected by visualizing the signal pro-

duced after coating microscope slides with photographic emulsion, which

generates a black area around the probe which is labelled with

FISH

A further modication based on the original principles, whereby specic

gene probes are hybridized to chromosomes without the need for meta-

phase preparations (interphase cells can be used). Instead of

P, the probes

are labelled with a uorescent dye and hybridization may be detected as

red, blue, or other coloured dots over the cells (see Fig.3.24).

Applications ofFISH

• Used in the analysis of trisomies (chromosome gains) and monosomies

(chromosome losses) associated with leukaemias and lymphomas. The

presence of trisomy is detected as three uorescent dots within the cell,

whilst monosomy is seen as a single uorescent dot within thecell.

•

FISH has been used widely within paediatric leukaemias, such as ALL,

where abnormalities of chromosome number are common.

denature

Probe

Slide containing cells

hybridize

visualize

Fig.3.24 FISH analysis. Metaphase chromosomes are placed on a microscope slide,

and the probe (e.g. for the gene of interest) is applied. The chromosome region to

which the probe binds will uoresce— highlighting its exact location in the genome.

329

IN SITU HYBRIDIZATION & FISH

Further reading

Mathew P, Sanger WG, Weisenburger DD, etal. Detection of the t(2;5)(p23;q35) and NPM- ALK

fusion in non- Hodgkin’s lymphoma by two- color uorescence in situ hybridization. Blood 1997;

, 1678– 85.

O’Connor C. Fluorescence in situ hybridization (FISH). Nature Education 2008; 1:171. M https://

www.nature.com/ scitable/ topicpage/ Fluorescence- In- Situ- Hybridization- FISH- 327.

Sinclair PB, Green AR, Grace C, Nacheva EP. Improved sensitivity of BCR- ABL detection:a triple-

probe three- color uorescence in situ hybridization system. Blood 1997; 90:1395– 402.

Vaandrager JW. Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell

lymphoma by multicolor DNA ber uorescence in situ hybridization. Blood 1996; 88

:1177– 82.

330

CHAPTER3 Haematology

330

Specialized haematologyassays

The following laboratories provide specialized molecular, biochemical, and

cellular investigations for rare haematological disorders. Please contact the

laboratory before tests are requested to conrm the specimen(s) required.

Thalassaemia disorders

Dr JohnOld

National Haemoglobinopathy Reference Laboratory, Institute of Molecular

Medicine, John Radclie Hospital, Headington, Oxford OX38DU

Tel:01865- 222449; Fax:01865- 222500

E- mail:jold@hammer.imm.ox.ac.uk

Professor Swee LayThein

Haematological Medicine, King’s College Hospital, Denmark Hill, London

SES9RS

Tel:020- 7346- 1682; Fax:020- 7346- 6168

E- mail:[email protected]

Dr MaryPetrou

Perinatal Centre, University College Hospital, 84– 86 Chenies Mews,

London WC1E6HX

Tel:020- 7388- 9246; Fax:020- 7380- 9864

E- mail:[email protected]

Haemoglobin variants, unstable, and altered anity

haemoglobins

Dr JohnOld

National Haemoglobinopathy Reference Laboratory, Institute of Molecular

Medicine, John Radclie Hospital, Headington, Oxford OX38DU

Tel:01865- 222449; Fax:01865- 222500

E- mail:jold@hammer.imm.ox.ac.uk

Professor Sally Davies and Joan Henthorn

Department of Haematology, Central Middlesex Hospital, Acton Lane,

London NW107NS

Tel:020- 8453- 2112; Fax:020- 8965- 1115

E- mail:sally[email protected].gov.uk

Professor Joan Henthorn

Department of Haematology, Central Middlesex Hospital, Acton Lane,

London NW107NS

Tel:020- 8453- 2323

SPECIALIZED HAEMATOLOGYASSAYS

331

Dr BarbaraWild

Haematological Medicine, King’s College Hospital, Denmark Hill, London

SE59RS

Tel:020- 7737- 4000 Ext 2283; Fax:020- 7346- 3514

E- mail:[email protected]

Glycolytic defects, G6PD deciency, other

erythroenzymopathies

Dr MarkLayton

Haematology, ICSTM, Hammersmith Hospital, London W120HS

Tel:020- 8383- 2173; Fax:020- 8742- 9335

E- mail:[email protected]

Dr BarbaraWild

Haematological Medicine, King’s College Hospital, Denmark Hill, London

SE59RS

Tel:020- 7737- 4000 Ext 2283; Fax:020- 7346- 3514

E- mail:[email protected]

Porphyrias

Dr AllanDeacon

Clinical Biochemistry, King’s College Hospital, Denmark Hill, London

SE59RS

Tel:020- 7346- 3856; Fax:020- 737- 7434

Dr Michael Badminton

Porphyria Service, Medical Biochemistry, University Hospital of Wales,

Cardi CF144XW

Tel:02920- 748349; Fax:02920- 748383

E- mail:badminton.mn@cardi.ac.uk

Ms J Woolf/ Dr S Whatley

Porphyria Service, Medical Biochemistry, University Hospital of Wales,

Cardi CF144XW

Tel:02920- 743565

Red cell membrane defects

Dr May- JeanKing

International Blood Group Reference Laboratory, Southmead Road, Bristol

BS105ND

Tel:0117- 991- 2111; Fax:0117- 959- 1660

E- mail:may- [email protected].uk

332

333

Chapter4

Immunology and allergy

Serum immunoglobulins 334

Immunoglobulin G subclasses 336

Evaluation of specic antibody production (antibacterial and

antiviral antibodies) 338

ImmunoglobulinD 340

Electrophoresis and immunoxation 342

Serum free light chains 344

‘Bence– Jones proteins’; urine electrophoresis and

immunoxation 344

Cryoglobulins 345

- microglobulin 346

Acute phase proteins (CRP, ESR, SAA) 348

Amyloidosis 350

Measurement of serum complement components 351

C1 esterase inhibitor 352

Haemolytic complement (lytic complement function tests) 353

Factor H and factorI 354

C3 nephritic factor 354

Autoimmunity 354

Rheumatoid factor 355

Autoantibody screen 356

Double- stranded DNA antibodies 358

Antibodies to extractable nuclear antigens (ENA) 360

Antiphospholipid antibodies 362

Other patterns of autoantibodies identied on ‘autoantibody

screen’ 363

Autoantibodies in autoimmune hepatitis 364

Antibodies to gastric parietal cells and intrinsic factor 365

Thyroid disease (thyroid peroxidase antibodies) 366

Islet cell antibodies (ICA), anti- GAD antibodies, and insulin

receptor and insulin antibodies 367

Adrenal antibodies and other endocrine autoantibodies 368

Classication of autoimmune polyglandular syndromes 368

Endomysial (EMA) and tissue transglutaminase (tTG) antibodies 369

Autoimmune skin diseases 370

Autoantibodies and neurological disease 371

Vasculitic syndromes 372

Allergic disease 374

Skin prick tests 375

Specic IgE:‘RAST tests’ 376

Mast cell tryptase 377

Drug allergy testing 377

Cellular function assays 378

Lymphocyte function tests 380

Neutrophil and macrophage function 380

Natural killer cell function 380

334

CHAPTER4 Immunology and allergy

334

Serum immunoglobulins

Units:g/ L.

Normal range (adultsonly):

•

IgG:5.8– 15.4g/ L.

• IgA:0.64– 2.97g/ L.

• IgM (♂):0.24– 1.90g/ L.

• IgM (♀):0.75– 2.30g/ L.

Principles ofassay

The three main classes of Igs are measured by either rate nephelometry or

turbidimetry on automated analysers. The principles are similar, depend-

ent on immune complex formation, using antisera specic for the class of

antibody. Rarely radial immunodiusion (RID) may be used; this is slow

and less accurate. For automated analysers, coecients of variation should

be in the range of 5– 10%. Results are standardized against international

standards. In the UK, an external quality assurance (EQA) scheme operates.

Laboratories should provide normal ranges, which vary according to age

and sex. Unfortunately many laboratories do not adjust ranges for age and

sex, which may lead to confusion.

Indications fortesting

Measurement ofserum immunoglobulin is indicated inthe following conditions

•

Suspected immunodeciency (° or 2°); diagnosis and monitoring.

• Suspected myeloma, plasmacytoma; diagnosis and monitoring.

• Lymphoma.

• Liver disease (PBC, hepatitis, cirrhosis).

• Sarcoidosis; diagnosis.

• Post- BM/ stem cell transplantation; monitoring.

Interpretation

Measurement of serum Igs does not provide categorical diagnosis in any

disease. Normal serum Igs do NOT exclude immunodeciency. In all cases,

measurement of Igs MUST be accompanied by serum electrophoresis and

immunoxation to look for paraproteins (E Electrophoresis and immuno-

xation, pp. 342–3).

Causes ofhypogammaglobulinaemia

• X- linked agammaglobulinaemia (XLA) (absent B cells; all Igs low/

absent).

•

Common variable immunodeciency (CVID) (reduced T/ B cells;

lowIgs).

•

Hyper- IgM syndrome (normal/ raised IgM; low/ absent IgG,IgA).

• Selective IgA deciency (absent IgA; normal IgG,IgM).

• Severe combined immunodeciency (SCID) (mainly children; all Igs low;

absent T cells).

•

Lymphoma (reduced IgM; IgA normal; IgG normal or low; disease,

chemotherapy, or radiotherapy).

•

SLE (rare).

SERUM IMMUNOGLOBULINS

335

• Infections:

•

HIV (rare).

•

Herpesviruses (rare, EBV in X- linked lymphoproliferative disease).

•

Acute bacterial infections.

•

Measles/ rubella.

• Drugs (immunosuppressants, e.g. cyclophosphamide, azathioprine,

chemotherapy).

•

Plasmapheresis.

• Renal loss (IgM normal; IgG and IgA reduced).

• GI loss (IgM normal; IgG and IgA reduced).

Causes ofhypergammaglobulinaemia

• Chronic infection— all Igs raised:

•

Osteomyelitis.

•

Bacterial endocarditis.

•

TB.

• Chronic inammation:

•

SLE, RA— all Igs elevated.

•

Sjögren’s syndrome— raised IgG (allIgG

•

Sarcoidosis— raised IgG and IgA; IgM usually normal.

• Liver disease:

•

PBC— IgM, may be very high (>30g/ L) with small monoclonal bands

on a polyclonally raised background.

•

Alcohol- related— i IgA, polyclonal, β– γ bridging on electrophoresis.

•

Autoimmune hepatitis (i IgG, IgA; normalIgM).

•

Hodgkin’s disease— IgE raised (also eosinophilia).

• Viral infections:

•

Acute common viral infections— raised IgM, normal IgG andIgA

•

HIV— all Igs raised (IgG very high, but polyclonal).

•

EBV— all raised.

Criticalaction

ALL patients with recurrent infections* should be reviewed by an immu-

nologist or a paediatric immunologist, according to age, irrespective of age.

Any patient with recurrent infections and low serum Igs has an immunologi-

cal problem until proven otherwise.

Note:(*) recurrent infections can be pragmatically dened as two or more

major microbiologically/ virologically proven infections, requiring hospitali-

zation, within 1year. One major infection and recurrent minor infections

should also be referred where minor infections are documented infections

requiring treatment in the community.

Patients with unusual infections or with illness caused by opportunistic or

normally non- pathogenic organisms and patients with infections in unusual

sites (without good reason) should all be referred for further investigation.

336

CHAPTER4 Immunology and allergy

336

Immunoglobulin G subclasses

Units:g/ L.

Normal range (adults):

•

IgG

:2.2– 10.8g/ L.

• IgG

:0.5– 8.0g/ L.

• IgG

:0.05– 0.9g/ L.

• IgG

:0.0– 2.4g/ L.

Principles oftest

As for serum Igs, IgG subclasses are normally measured by nephelometry

or turbidimetry. RID is still occasionallyused.

Indications fortesting

There are no absolute indications for testing, as signicant immunode-

ciency can occur in the presence of normal subclasses, and conversely

complete genetic absence of a subclass may be completely asymptomatic.

Measurement is usually performed as part of the work- up of patients with

recurrent infections. IgG

disease has been described recently; this is associ-

ated with a wide range of organ- based diseases. IgG

levels are signicantly

raised.

Interpretation

Low levels may be signicant in the context of presentation with recurrent

infections. Deciency of IgG

, which is involved in immunity against viruses

and associated with asthma and intractable epilepsy. IgG

deciency may

be seen in patients with IgA deciency and may be associated with poor

responses to polysaccharide antigens such as the capsular polysaccharides

of bacteria.

Raised IgG

with normal or reduced IgG

, IgG

, and IgG

is seen in

Sjögren’s syndrome and is a specic pattern, which may occasionally be

helpful in diagnosis.

Raised IgG

suggests IgG

disease.

IMMUNOGLOBULIN G SUBCLASSES

337

338

CHAPTER4 Immunology and allergy

338

Evaluation ofspeciﬁc antibody

production (antibacterial and antiviral

antibodies)

Units:variable:u/ L, IU/ mL,μg/ mL.

Ranges:variable, check with reporting laboratory.

•

Pneumococcal antibodies:>20u/ L (asplenics>35).

• Tetanus antibodies:>0.1IU/ mL (minimum protective level).

• Haemophilus inuenzae type B:>1.0μg/ mL (full protection;

asplenics>1.5).

Principles oftest

Measurement of antibody production against dened pathogens or anti-

gens puried from pathogens plays an important role in the investigation of

suspected immunodeciency. Most assays are carried out by enzyme- linked

immunoassay, but some viral antibodies are still measured by haemaggluti-

nation or complement xation. Pre- and post- immunization samples should

be run on the same run for direct comparison, as coecients of variation

for the assays tend to be high— 15– 25%! An EQA scheme exists. Assays

have tended to focus on agents for which there are safe and eective vac-

cines. Live vaccines should NEVER be given to any patient in whom immunode-

ciency is suspected.

Antibodies normally run in immunology laboratories include pneumo-

coccal polysaccharides, which may be further dierentiated as IgG

and

IgG

, H. inuenzae type B (Hib), and tetanus. Diphtheria antibodies are

not run by many laboratories, as the assay performance has been so poor.

Meningococcal C polysaccharide antibodies are run by a few specialized

laboratories, but correspondence with known clinical status has been poor.

Anti- streptolysin O titre (ASOT) may be helpful.

Antibodies to pneumococcal serotypes are available from reference labo-

ratories and may be valuable in assessing response to the conjugated pneu-

mococcal serotype vaccine. There is debate about the protetctive levels

(0.2– 0.35).

Viral antibodies may be valuable to natural exposure and immunization

antigens such as polio, measles, mumps, rubella, chickenpox, EBV, and hepa-

titis B (if immunized).

Indications fortesting

These assays should be used in the work- up of patients with suspected

immunodeciency or in monitoring change in such patients. Responsiveness

to immunization is a helpful marker of immunological recovery post- bone

marrow transplant (BMT). Annual monitoring of levels may be valuable in

asplenic patients, as such patients lose immunity more rapidly than a eus-

plenic population.

Interpretation

The interpretation is entirely dependent on the context. Assays for pneu-

mococcal polysaccharides measure a composite of responses to the 23

strains in the Pneumovax

vaccine. This can be misleading as not all strains

339

EVALUATION OF SPECIFIC ANTIBODY PRODUCTION

represented in the vaccine are equipotent as immunostimulators. This

means that a ‘normal’ response may actually mean a good response to the

immunogenic strains, masking failure of response to the less immunogenic

strains. For this reason, evaluation of such patients should be carried out by

an immunologist with an interest in immunodeciency. More weight should

be placed on change in response to immunization than to actual values.

A ‘normal’ response to immunization has never been standardized, with

publications frequently using dierent criteria, rendering comparison impos-

sible. The following is a useful working denition:‘a 4- fold rise in titre, which

rises to well within the normal range’.

Antibody deciency inadults

This usually presents with upper and lower respiratory tract infections

(Streptococcus pneumoniae, Haemophilus, Staphylococcus, Klebsiella), leading

to chronic bronchiectasis and sinusitis; GI infections (Salmonella, Giardia,

Campylobacter); skin infections (recurrent boils); autoimmune features (ITP,

haemolytic anaemia, diabetes, thyroid disease) only in CVID, not XLA. i

incidence of lymphoma.

Normal serum Igs DO NOT EXCLUDE antibody deciency (IgG subclass

deciency, specic failure of antibody production against polysaccharides).

Use test immunization with killed or puried component vaccines to test

humoral responses.

Asplenia

Patients are at i risk of overwhelming sepsis:S.pneumoniae, H.ineunzae,

Staphylococcus aureus, Meningococcus, Klebsiella species, Capnocytophaga

canimorsus (from dog bites), fulminant malaria, and babesiosis. Risk is life-

long. Asplenia may result from trauma, involvement in malignancy, removal

for diagnosis (rare these days), coeliac disease, and sickle disease and rarely

due to congenital absence. Serum Igs and IgG subclasses are normal, but

responses to polysaccharide antigens are often poor, especially in patients

with lymphoma. Blood lm will show Howell– Jolly bodies. Absence (if not

known from records) will be shown by ultrasound(US).

340

CHAPTER4 Immunology and allergy

340

ImmunoglobulinD

IgD is rarely measured in clinical practice, as its main function is as a mem-

brane receptor. Elevated levels may be seen in periodic fever syndrome, in

hyper- IgD syndrome, due to deciency of mevalonate kinase, and in IgD-

secreting myeloma. Measurement is usually byRID.

IMMUNOGLOBULIND

341

342

CHAPTER4 Immunology and allergy

342

Electrophoresis and immunoﬁxation

Units: not applicable to electrophoresis (qualitative). Paraprotein quanti-

tated by scanning densitometry reported ing/ L.

Normal range:N/ A

Principles oftesting

In serum or urinary electrophoresis, the relevant body uid is applied to an

electrolyte- containing agarose gel. Acurrent is applied across the gel and

causes the proteins to migrate through the gel on the basis of their charge

and, to a lesser extent, their size until they reach a neutral point in the

electric eld. The proteins are then visualized with a protein- binding stain.

If the total protein is known, then the electrophoretic strip can be scanned

and the absorption by the stain measured, which will be proportional to the

amount of protein in the particular region in the gel. Thus, any monoclonal

bands can be directly measured. This is useful for patients with myeloma,

as immunochemical methods for measurement of Igs may be inaccurate in

patients with myeloma.

Immunoxation is the technique by which monoclonal Igs are identied

by overlaying the electrophoresed strips with antisera against heavy and

light chains. These precipitate with the monoclonal proteins in the gel, and

unbound antisera can be washed free prior to staining.

The same techniques can be carried out with urine, although this may

require concentration to provide the clearest results.

Indications fortesting

Electrophoresis and, if necessary, immunoxation of serum is an integral

part of measurement of serum Igs. ALL requests for serum Igs must have

electrophoresis carried out; failure to do so will lead to important abnor-

malities being missed. There is no place for carrying out electrophoresis as

a stand- alonetest.

ELECTROPHORESIS AND IMMUNOFIXATION

343

Interpretation

See Table 4.1 for interpretations of results.

Monoclonal proteins may polymerize to give >1 band. Some patients will

have >1 clone present producing dierentIgs.

Densitometry cannot be used where the monoclonal protein overlies the

- region, as the gures include non- Ig proteins.

Table4.1 Interpretation

Report Interpretation

Reduced albumin Chronic inammation, nephritic syndrome

Absent α1 band

Absent/ reduced α1- antitrypsin

i α2 band Chronic inammation/ infection; also seen

in nephrotic syndrome, due to selective

retention of α

2- macroglobulin

i β Seen in pregnancy (raised β- lipoprotein) and

iron deciency (transferrin)

– γ bridging Caused by raised polyclonal IgA, e.g. cirrhosis

i γ Caused by polyclonal i

in IgG:infection/

inammation

Faint band(s) on polyclonal

background

Caused by monoclonal escape during

polyclonal response to infection/

inammation (does NOT indicate myeloma)

Monoclonal band in γ Due to myeloma, lymphoma, and MGUS*

Absent/ reduced γ Due to inherited or acquired Ig deciency

* MGUS, monoclonal gammopathy of uncertain signicance— most evolve to myeloma, given

time (years).

344

CHAPTER4 Immunology and allergy

344

Serum free lightchains

Modications in the techniques for measurement of free, as opposed to

bound, light chains are valuable in monitoring light chain- only myelomas

and other myelomas that produce excess free light chains, in addition to

a whole paraprotein, which would previously have been monitored by

measurement of 24h urinary light chain excretion. Urinary measurement

can be problematic where there is renal impairment, and as light chains

are nephrotoxic, as the disease advances, urinary measurements become

less accurate.

‘Bence– Jones proteins’; urine

electrophoresis and immunoﬁxation

Bence– Jones proteins are urinary free light chains, i.e. unbound to heavy

chains. During normal antibody synthesis, a small excess of light chains are

produced which are excreted. Hypergammaglobulinaemic states, such as

RhA and chronic infection, may therefore be accompanied by excretion of

polyclonal free light chains. Monoclonal free light chains are seen in mye-

loma and may be the only marker in light chain- only myelomas, which do

not produce any heavy chains atall.

Testing is carried out as forserum.

CRYOGLOBULINS

345

Cryoglobulins

Units:usually reported qualitatively, but a ‘cryocrit’ can be measured in a

similar way to a manual Hct using capillarytubes.

Normal range: tiny amounts of cryoglobulins may be found in normal

individuals.

Principles oftest

Cryoglobulins are Igs that precipitate when serum is cooled. The temper-

ature at which this occurs determines whether disease will result. If the

blood circulates through a part of the body where the temperature is below

the critical temperature, then the protein will precipitate in the capillaries,

causing obstruction, vascular damage, and eventually necrosis. The tem-

perature of the hand is 728°C at ambient room temperature. To check for

the presence of cryoglobulins, take blood using a warmed syringe into a

warmed bottle and transport to the laboratory at 37°C, using a Thermos

™

ask with either pre- warmed sand or water at 37°C. The laboratory will

allow the blood to clot at 37°C and then cool the serum. Cryoglobulins will

form a precipitate as the temperature drops. The precipitate is then washed

and re- dissolved for analysis by electrophoresis and immunoxation.

Cryoglobulins are not the same as cold agglutinins (a feature of

Mycoplasma pneumoniae infection) (E Chapter3).

Indications fortesting

All patients with Raynaud’s phenomenon of new onset or with winter

onset of purpuric or vasculitic lesions on the extremities should be tested.

Chronic hepatitis C infection is often accompanied by type II cryoglobuli-

naemia and a characteristic syndrome— ‘mixed essential cryoglobulinae-

mia’ = autoimmune phenomena, arthritis, ulceration, glomerulonephritis,

neuropathy. C3 normal; C4 reduced. Patients with myeloma, SLE, Sjögren’s

syndrome, and RhA are also atrisk.

Interpretation

Interpretation of the results of testing cryoglobulins is provided in Table4.2.

Cryobrinogen

This is found less commonly than cryoglobulins. It will not be detected

unless both EDTA and heparinized blood samples are sent warm to the

laboratory. The main association is with occult malignancy (and throm-

bophlebitis migrans). Also associated with connective tissue disease,

pregnancy, OCP use, DM, and cold urticaria.

Table4.2 Interpretation

Type Nature of cryoprecipitate

Type I All monoclonal Igs; myeloma, lymphoma

Type II Monoclonal Ig with RF activity; myeloma, lymphoma, connective

tissue diseases, infections (especially HCV; SBE)

Type III Polyclonal RF:connective tissue diseases, infections

346

CHAPTER4 Immunology and allergy

346

- microglobulin

Unit:mg/ L.

Normal range: 1– 3mg/ L.

Principles oftest

The test measures free β

- microglobulin, which normally forms the light

chain of HLA class I molecules but is shed when there is i lymphocyte

turnover. It is usually rapidly cleared by the kidneys. Measurement is usually

by an automated analyser, nephelometry, or turbidimetry. RID is stillused.

Indications fortesting

The main indication is as part of routine monitoring of patients with mye-

loma and HIV. Other biomarkers are now felt to be more useful. Very high

levels are seen in renal failure and patients on dialysis, which can cause β

microglobulin amyloid.

Interpretation

Levels elevatedin:

•

HIV infection (surrogate marker of progression).

• Myeloma (marker of tumourmass).

• Lymphoma.

• CVID (correlation with severity).

• Renal dialysis (depending on type of membrane).

347

- MICROGLOBULIN

348

CHAPTER4 Immunology and allergy

348

Acute phase proteins (CRP, ESR,SAA)

Units:

•

C- reactive protein (CRP):mg/ L.

• Erythrocyte sedimentation rate (ESR):mm/ h.

• Serum amyloid A(SAA):mg/ L.

Normal ranges:

•

CRP 0– 6mg/ L.

• ESR (E Erythrocyte sedimentation rate, p. 252).

•

SAA (not measured routinely).

Principles oftest

Serum proteins CRP and SAA are amenable to measurement by nephelom-

etry or turbidimetry. Measurement of the ESR is covered in E Chapter 3.

Indications fortesting

Acute and chronic infections, vasculitis, connective tissue disease, arthritis.

Interpretation

Clinicians are usually confused by ESR and CRP— they do not give the same

information and should be used together. CRP is like blood glucose, whilst

ESR is like HbA

. CRP rises within hours of onset of inammation/ infection

and falls quickly once treatment is instituted. It is therefore useful for rapid

diagnosis and monitoring response. The ESR rises slowly, being depend-

ent, in part, on brinogen, a long- lived protein, and falls equally slowly (see

Fig.4.1). In active SLE, the ESR is high, but CRP is not elevated. CRP is

driven by interleukin (IL)- 6 and may be elevated in myeloma. See Table 4.3

for interpretation of results.

300

200

100

6–12hrs 14 days

C-reactive protein

ESR

Fig.4.1 Time course of acute phase response proteins. ESR in acute phase response

parallels brinogenlevel.

ACUTE PHASE PROTEINS (CRP, ESR,SAA)

349

Table4.3 Causes ofelevatedCRP

Level of CRP Common associations

Little or no change (<4– 100mg/ L) Most viral infections

ActiveSLE

Systemic sclerosis andCREST

InactiveRhA

Myeloma

Most tumours

Moderate elevation (100– 200mg/ L) EBV/ CMV infection

Bacterial infection

ActiveRhA

Polymyalgia rheumatica

Lymphoma

Hypernephroma

Large elevation (>200mg/ L) Severe bacterial sepsis

Legionella

Active vasculitis (Wegener’s, rheumatoid)

Huge elevation (>400mg/ L) Overwhelming sepsis (deep tissue

abscess)

Fulminant Legionella

At this level, death usually ensues!

CREST, calcinosis, Raynaud’s syndrome, oesophageal motility dysfunction, sclerodactyly, and

telangiectasia.

Levels in very young children may be much lower for a given stimulus. Avery small number of

patients do not make inammatory responses that exceed the normal range but seem to run on

a lower ‘normal’ range (10- fold less); ultra- sensitive assays for low- level CRP are available.

350

CHAPTER4 Immunology and allergy

350

Amyloidosis

Amyloid refers to the deposition of altered proteins in tissues in an insolu-

ble form. The precursor protein varies according to the cause and can often

be measured specically. Amyloid is usually conrmed by special stains on

histological examination of biopsies. Measurement of serum Igs and elec-

trophoresis, β

- microglobulin, and CRP is essential if amyloid is suspected

(see Table4.4).

Table4.4 Types ofamyloid

Amyloid protein Protein precursor Clinical syndrome

AL, AH Light or heavy chain of Ig Idiopathic, multiple myeloma,

- heavy chain disease

AA Serum amyloid A 2°, reactive:inammatory

arthritis, familial Mediterranean

fever, hyper- IgD syndrome,

TRAPS (periodic fever), Behçet’s,

Crohn’s disease

Aβ

M β

- microglobulin Dialysis amyloid

ACys Cystatin C Hereditary cerebral angiopathy

with bleeding (Iceland)

ALys, AFibA Lysozyme, brinogen Aa

Non- neuropathic hereditary

amyloid with renal disease

AIAPP Islet amyloid polypeptide DM type 2; insulinoma

AANF Atrial natriuretic peptide Senile cardiac amyloid

ACal Procalcitonin Medullary carcinoma of the

thyroid

AIns Porcine insulin Iatrogenic

ATTR Transthyretin Familial amyloid polyneuropathy,

senile cardiac amyloid

Aβ Aβ

- protein precursor Alzheimer’s disease

AprP Prion protein Spongiform encephalopathies

TRAPS, tumour necrosis factor receptor- associated periodic syndrome.

MEASUREMENT OFSERUM COMPLEMENT COMPONENTS

351

Measurement ofserum complement

components

Units:g/ L.

Normal ranges:

•

Complement C3 0.68– 1.80g/ L.

• Complement C4 0.18– 0.60g/ L.

• Factor B (rarely measured routinely).

• Other components usually reported as percentage of normal human

plasma.

Principles oftest

C3, C4, and factor B are usually measured by rate nephelometry or turbi-

dimetry. Other components are measured by RID or simply by double diu-

sion where presence or absence is the only result of interest. Complement

breakdown products are measured by RID or enzyme- linked assay(EIA).

Indications

Valuablein:

•

SLE (C3, C4,C3d).

• Suspected complement deciency (C3, C4, haemolytic complement).

• Suspected anaphylaxis (anaphylotoxins C4a,C5a).

• Suspected hereditary angioedema (C3, C4, C1q, C1 esterase inhibitor,

immunochemical AND functional).

Complement deciency is common (especially C4 and C2 deciencies);

predisposes to recurrent neisserial disease, bacterial infections (C3 de-

ciency), and immune complex disease (lupus- like). Anyone with >1 episode

of systemic neisserial disease has a complement deciency until proven

otherwise.

352

CHAPTER4 Immunology and allergy

352

C1 esterase inhibitor

Units:

•

Immunochemical:g/ L.

• Functional:reported as percentage activity, compared to normal fresh

plasma.

Normalrange:

•

Immunochemical:0.18– 0.54g/ L (paediatric ranges not well dened, but

lower than adults).

•

Functional:80– 120% of normal plasma.

Principles oftests

Immunochemical measurement carried out by RID; functional assay is usu-

ally a colorimetricassay.

Indications fortesting

Key indication is angioedema occurring WITHOUT urticaria at any age. If

urticaria is present, diagnosis is virtually never C1 esterase inhibitor de-

ciency. C4 is a useful screen; normal C4 during an attack excludes C1 ester-

ase inhibitor deciency.

Interpretation

C1 esterase inhibitor deciency causes hereditary angioedema.

Twotypes:

•

Type I(common, 80%); absence of immunochemical C1 esterase

inhibitor (C1- inh).

• Type II (rare, 20%); presence of non- functional C1- inh; immunochemical

levels normal orhigh.

Both are inherited as autosomal dominant. Present with angioedema, NO

urticaria; may involve the larynx and gut, usual onset at puberty. C4 absent

during acute attacks. Treat with puried C1- inh (FFP may be a substitute but

can make attacks worse) or icatibant; maintenance therapy with danazol,

stanozolol, or tranexamic acid to d

frequency of attacks. Pregnancy/ oral

contraceptive exacerbate.

A rare type (type III) of hereditary angioedema is also described, thought

to be due to gain- of- function mutations in clotting factor XII. Angioedema

can also be caused by deciency of ACE and C4- binding protein.

Rare acquired form due to autoantibody to C1- inh (SLE, lymphoma);

C1q levels are reduced, and paraproteins may be present.

353

HAEMOLYTIC COMPLEMENT

Haemolytic complement (lytic

complement functiontests)

Units: can be reported in arbitrary units, or as a percentage of normal

plasma, but better reported as normal reduced or absent.

Normal range

:present (80– 120% of reference plasma).

Principles oftest

Haemolytic complement assays screen for the integrity of the classical

and alternate pathways and the terminal lytic sequence, and use either

antibody- coated sheep cells (CH100, classical pathway) or guinea pig red

cells (APCH100, alternate pathway). Either a gel or liquid assay can be used,

but the gel is easier! Both tests must be performed in parallel.

Indications fortesting

Any patient in whom deciency of a complement component is suspected.

Testing is also used to monitor the eectiveness of the MoAb eculizumab,

used to treat atypicalHUS.

Interpretation

Reduced levels of haemolytic activity will be seen during infections and dur-

ing immune complex diseases such as serum sickness and SLE. Testing for

absence of a component needs to be undertaken a minimum of 4– 6 weeks

after recovery from infection. Absence in both CH100 and APCH100 indi-

cates a deciency in the terminal lytic sequence C5– C9 (C9 deciency will

give slow lysis). Absence of CH100 indicates a missing component in the

classical pathway C1– C4. Absence of APCH100 indicates deciency in the

alternate pathway (factor D, factor B,C3).

Follow- up testing to identify the missing component will be performed by

the laboratory automatically (if they are doing theirjob!).

Criticalaction

Anyone who has a single episode of neisserial meningitis with an unusual

strain or a second episode with a common strain MUST be assumed to have

a complement deciency until proven otherwise. REFER after recovery to

the immunologist for investigation.

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CHAPTER4 Immunology and allergy

354

Factor H and factorI

Deciency of either of these factors may lead to HUS. Measurement is pos-

sible in specialized centres, with follow- up genetic testing. Autoantibodies

against these proteins have been described.

C3 nephriticfactor

This is an autoantibody which reacts with a neo- antigen in the alternate

pathway convertase C3bBb to stabilize the convertase and i complement

breakdown. Typically seen in membranoproliferative glomerulonephritis

and in lipodystrophy. C3 will typically be extremelylow.

Autoimmunity

Autoantibodies are usually divided into organ- specic and organ- non-

specic, but clinical testing rarely follows this pattern. They are therefore

covered in convenient groups, associated with types of testing.

RHEUMATOIDFACTOR

355

Rheumatoidfactor

Units:

•

Titre (particle agglutination assay).

• IU/ mL (nephelometry,EIA).

Normalrange:

•

Titre <1/ 20:<16years.

•

Titre <1/ 40:16– 65years.

• Titre <1/ 80:>65years.

•

<30IU/ mL.

Principles oftest

Tests detect autoantibodies binding to human Ig; these can be of any class,

but assays commonly recognize IgG and IgM autoantibodies. Suggestions

that IgA RF may be helpful have not been widely accepted. Assays use either

agglutination of Ig- coated particles (visual assay) or latex particle- enhanced

nephelometry.

Indications fortesting

The test is only relevant in patients already diagnosed withRhA.

Interpretation

NOT a diagnostic test for RhA! Only +ve in 70– 80%. High titre in a patient

with known RhA is a risk factor for extra- articular manifestations and

poorer prognosis.

RF is also foundin:

•

Healthy elderly (asymptomatic).

• Chronic bacterial (SBE) and viral infections (HIV,HCV).

• Acute viral infections (transient; especially adenovirus).

• Myeloma (often type II cryoglobulins).

• Lymphoma.

• Connective tissue diseases (SLE, Sjögren’s, systemic sclerosis,

polymyositis, undierentiated connective tissue disease (UCTD)).

Antibodies to cyclic citrullinated peptide (anti- CCP) may be more valuable

in the diagnosis of RhA, as they are more specic.

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CHAPTER4 Immunology and allergy

356

Autoantibodyscreen

Another abused test! Usually used as an immunological shing expedition.

Multiple tissues (rodent), often with human Hep- 2 cell line; gives rapid and

semi- quantitative results for the following autoantibodies:

• ANAs (see Table 4.5 for patterns).

• Anti- ribosomal antibodies.

• Antimitochondrial antibodies(AMA).

• Anti- smooth muscle antibodies (ASMA).

• Anti- liver– kidney microsomal (LKM) antibodies.

• Anti- gastric parietal cell (GPC) antibody.

Where Hep- 2 cells are used, other patterns of nuclear and cytoplasmic

uorescence may be seen. See Fig. 4.2 for examples.

Increasingly, laboratories are using multiplex analysers (modied enzyme-

linked or ow cytometry- based testing) which allow high- throughput

screening for nuclear and related antibodies.

Table4.5 Patterns ofantinuclear antibodies(ANAs)

Homogeneous SLE, drug- induced SLE (ds- DNA or histones)

Coarse- speckled UCTD*, SLE (U1- RNP)

Fine- speckled SLE, Sjögren’s (Ro and La)

Nucleolar Systemic sclerosis, polymyositis, SLE

Centriole Commonest in Mycoplasma pneumonia, also

scleroderma

Proliferating cell nuclear

antigen (PCNA)

SLE— highly specic, but rare

Centromere ‘CREST’ syndrome, limited scleroderma,

Raynaud’s, never diuse scleroderma; may be

confused with multinuclear dot pattern, which is

seen in mitochondrial antibody- negative PBC

Nuclear matrix

Nuclear mitotic spindle

SLE and UCTD

Non- specic:SLE, RA, CREST, UCTD, and

Sjögren’s syndrome

Histones

SLE, drug- induced (>90% of patients); other

connective tissue diseases (low frequency)

* UCTD, undierentiated connective tissue disease (previously mixed connective tissue disease).

Note:ribosomal antibodies associated with SLE, especially neuro- lupus (cytoplasmic pattern, not

nuclear).

Titre of antibodies does NOT correlate with disease activity.

ANAs may be seen transiently after viral infections, especially in children. Therefore, observe

a child where low- titre antibodies occur in the absence of clinical symptoms compatible with

juvenile arthritis.

AUTOANTIBODYSCREEN

357

Principles oftest

The traditional method is to overlay suitably diluted serum into frozen sec-

tions of rodent liver, kidney, and stomach, and human Hep- 2 cells. Bound

antibody in the serum is then identied using a uoresceinated anti- human

IgG (or IgM, IgA) as the second stage. Slides are then read manually.

Enzyme- based immunoassays are being introduced for screening, including

multiplex bead- laser array systems. These can be very specic when puri-

ed or recombinant antigens are used but lose out because of their inability

to pick up unexpected patterns.

Enzyme- linked assays are used for conrming antigens such histone anti-

bodies and double- stranded (ds- )DNA antibodies.

Indications fortesting

The correct use of testing is to identify which specic autoantibody is being

sought as part of the dierential diagnosis.

Interpretation

Because of the multiple patterns detected in this system, the interpretation

for each is covered separately (see Table4.5).

Fig.4.2 ANA on Hep- 2 cells with a speckled pattern (left) and a homogeneous

pattern (right).

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CHAPTER4 Immunology and allergy

358

Double- stranded DNA antibodies

Unit:IU/ mL.

Normal range:varies according toassay:

•

<30IU/ mL:−ve.

• 30– 50IU/ mL:borderline.

• >50IU/ mL:+ve.

Principles ofassay

The original and still best assay is the Farr assay, a radioisotope- based assay.

EIA tends to be widely used but is less specic, due to frequent contamina-

tion with single- stranded DNA. Crithidia assay used only rarely, as quick

uorescent screen (kinetoplast is pure ds- DNA).

Indications fortesting

Suspected SLE or autoimmune hepatitis; used to monitor SLE, in conjunc-

tion with complement studies.

Interpretation

Sensitive and specic for SLE and autoimmune hepatitis (AIH); +ve result is

signicant (in correct clinical context).

DOUBLE-STRANDED DNA ANTIBODIES

359

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CHAPTER4 Immunology and allergy

360

Antibodies toextractable nuclear

antigens(ENA)

Units:reported qualitatively.

Normal range:dependent on antibody, normally−ve.

Principles oftest

Usually carried out by enzyme- linked immunoassay. However, counter-

current immunoelectrophoresis and western blotting are still widely used,

especially for rare antibodies. EIA is much more sensitive than other meth-

ods and has led to clinical confusion.

Indications fortesting

Should always be carried out in patients with suspected connective tissue

disease. Monitoring at yearly intervals should be carried out in diagnosed

patients, as the antibody pattern may change with time and this may cor-

relate with changes in the clinical prole.

Interpretation

Reported qualitatively; normally laboratories will carry out a 6- antigen

screen:Ro, La, ribonucleoprotein (RNP), Sm, Jo- 1, and Scl- 70 (see Table 4.6).

Awide range of other antibodies are described, some of which may be avail-

able through reference laboratories.

Diagnosis and monitoringofSLE

ANAs and ds- DNA antibodies, both +ve; low C3 and C4; raised com-

plement breakdown products in active disease (C3d); normal CRP.

ANA- negative lupus often anti- Ro positive. West Indian lupus anti- Sm+.

Always check for cardiolipin antibodies and lupus anticoagulant (dRVVT)

(E Antiphospholipid antibodies, p. 362). Ribosomal P antibodies may be a

marker for neuropsychiatriclupus.

Monitor with CRP (dierential between infection and are of disease),

C3, C4, and ds- DNA antibodies (no value from serial ANAs); rising titre of

DNA antibodies often heralds a relapse (actual titre not related to disease

activity).

ANTIBODIES TOEXTRACTABLE NUCLEAR ANTIGENS(ENA)

361

Table4.6 Antibodies toextractable nuclear antigens

Ro/ SS- A SLE, Sjögren’s, neonatal lupus, neonatal congenital complete

heart block (cause of ANA- negative lupus, as not picked up

by standard ANA screen, which does not include Hep- 2 cells).

Newer assays will distinguish Ro52 and Ro60

La/ SS- B SLE, Sjögren’s, neonatal lupus, neonatal congenital complete

heart block (rare)

(U1)- RNP Mixed (undierentiated) connective tissue disease (if present

alone); SLE (if present with ds- DNA). Other RNPs may be

reported

Sm Highly specic marker for SLE (mainly West Indians; rare in

Caucasians)

Jo- 1 Polymyositis, dermatomyositis; transferase syndrome (brosing

lung disease; 65% +ve); many other specicities are known (all

recognizing transfer RNA (tRNA)- transferases)

Scl- 70 Systemic sclerosis (diuse scleroderma); only 30% of patients

are +ve

Pm- Scl (PM1) Scleroderma– myositis overlap

Ku, Ki Rare:SLE, UCTD, Sjögren’s syndrome, polymyositis

Mi- 2 Rare:steroid- responsive polymyositis

Histones Found in connective tissue diseases, especially drug- induced lupus

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CHAPTER4 Immunology and allergy

362

Antiphospholipid antibodies

Principles oftesting

Many types of antibodies to phospholipids are recognized. However, rou-

tinely available tests are IgG and IgM anticardiolipin antibodies detected

by EIA, and the presence of a ‘lupus anticoagulant’ detected using the

dilute Russell viper venom test (dRVVT). BOTH tests must be carried out

together, as either may be +ve without the other, but the clinical signi-

cance is the same. Antibodies to β

- glycoprotein Iare also important, as the

protein is a key co- factor for pathogenic antibodies. Other specicities are

available only as researchtools.

Indications fortesting

Patients with unexplained venous or arterial thrombosis; recurrent mis-

carriage (>3); connective tissue disease; early TIAs or stroke (<60years).

Livedo reticularis is a cutaneous marker.

Interpretation

• Prolonged APTT and reduced platelet count (80– 120 × 10

/ L) are

typical features. May get false +ve VDRL (Venereal Disease Research

Laboratory).

•

Persistent +ve IgM anticardiolipin antibodies as the only marker of

syndrome unusual, but clinically signicant.

•

Hughes’ syndrome=antiphospholipid antibodies without evidence of

other connective tissue disease or vasculitis. Presents with recurrent

miscarriage, thrombosis, or strokes. Fulminant disease causes multi-

organ failure.

•

Antibodies also found in SLE, but NOT cerebral lupus, Behçet’s, and

Sneddon’s syndrome. Also seen after EBV infection (asymptomatic and

disappear).

•

Treatment is lifelong warfarinization if symptomatic (heparin in

pregnancy); aspirin may be acceptable if asymptomatic (but no

controlled studies). No indication for intensive immunosuppression.

363

OTHER PATTERNS OF AUTOANTIBODIES

Other patterns ofautoantibodies

identiﬁed on‘autoantibody screen’

Antimitochondrial antibodies (AMA) and anti- M2

antibodies

Units:reported as titre (AMA) Anti- M2 reported as +ve or−ve.

Normal range:not usually detectable.

Principles oftesting

AMA are identied on uorescent screen, and previously unknown +ves

should be followed up with EIA or blot- based test for anti- M2 antibodies.

Indications fortesting

Suspected liver disease, especially with raised ALP (and in ♀); investigation

of unexplained pruritus (early feature ofPBC).

Interpretation

Ninety- ve per cent of PBC patients +ve for AMA (anti- M2, against dihy-

drolipoamide acyltransferase, E2). The remainder may have antibodies

against S100 antigen of the nuclear membrane (Nsp- II pattern; multinuclear

dots) or gp210, another nuclear antigen. The type of antibody present has

no inuence on prognosis or response to therapy. Marked elevation inIgM.

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CHAPTER4 Immunology and allergy

364

Autoantibodies inautoimmune hepatitis

Units: reported as titres (ASMA, anti- LKM antibodies). Anti- liver cytosol

(LC- 1) and soluble liver antigen (SLA) reported as +ve or−ve.

Normal range:not usually detectable.

Principles oftesting

ASMA and LKM are identied on uorescent screen, and previously

unknown +ves should be followed up with EIA or blot- based test for anti-

LC and anti- SLA antibodies. Also do ANCA (E Vasculitic syndromes,

pp. 372–3).

Indications fortesting

Suspected autoimmune liver disease (abnormal LFTs, alcohol and viral infec-

tions excluded).

Interpretation

Antibodies to HCV or HCV PCR+=exclusion criteria forAIH.

Autoimmune hepatitis

• Type 1 (AIH- 1) is ANA +ve, smooth muscle antibody (SMA) +ve,

p- ANCA +ve, and SLA antibody +ve. Typically occurs in adults and has

a better prognosis and responds well to therapy.

•

Type 2 (AIH- 2) is typically LKM- 1 and LKM- 3 antibody +ve and LC- 1

antibody +ve. AIH- 2 is seen in children and has a worse prognosis with

poor response to therapy.

•

In serological studies, 50% of AIH- 1 are ANA +ve/ SMA +ve,

15%ANA+ve only, and 35% SMA +ve only. However, there are

biopsy- proven serologically −ve hepatitis; 8% of AIH- 1 are SLA +ve

only. 43% of AIH- 2 are LC- 1 +ve only. Therefore, necessary to do SLA

and LC- 1 tests. Prognosis is dependent on type and early diagnosis.

• LKM antibodies are also associated with drug- induced hepatitis

(especially halothane) and chronic hepatitis CorD.

•

Non- actin SMA may be seen in SLE and after viral infections (especially

adenovirus).

•

Sclerosing cholangitis may be associated with atypical p- ANCA

(EVasculitic syndromes, pp. 372–3).

365

ANTIBODIES TOGASTRIC PARIETAL CELLS & INTRINSICFACTOR

Antibodies togastric parietal cells

and intrinsicfactor

Units:GPCs may be reported as titre or simply +ve/ −ve (as titre of no

clinical value); IF antibodies reported as +ve/ −ve.

Normal range:GPC antibodies found in healthy normals without evidence

of B

deciency or gastritis— may be at risk of later PA. IF antibodies only

foundinPA.

Principles oftesting

GPC antibodies are detected as part of the ‘autoantibody screen’; IF anti-

bodies usually detected by either RIA or EIA, but assays are inconsistent.

There is a robust EQA scheme for GPC antibodies, but none currently for

IF antibodies.

Indications fortesting

GPC antibodies should be checked in all patients with thyroid disease, as

there is a close association (‘thyrogastric disease’). Also check in patients

with unexplained macrocytosis ± low B

. Positive antibodies identied inci-

dentally should be followed up with a blood count and, if the MCV is high,

a B

level. IF antibodies may help in patients with a high MCV and low B

to conrm PA. Diagnosis of PA more dicult now Schilling test withdrawn.

IF antibodies are NOT suitable for screening, as present in only 50% of

patients with PA and pre- administration of B

will interfere with detection.

Interpretation

GPC antibodies found in 90% of patients with PA and in 40% of patients

with other organ- specic autoimmune diseases; the antigen is the β subu-

nit of gastric H

/ K

ATPase. Anti- IF antibodies are of two types: those

that block B

binding to IF (70% of patients with PA) and those that block

uptake of the B

– IF complex (35% of patients withPA).

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CHAPTER4 Immunology and allergy

366

Thyroid disease (thyroid peroxidase

antibodies)

Units:variable— check with the laboratory.

Normal range:low levels of antibodies may be found in asymptomatic indi-

viduals, although higher levels may indicate a predisposition to later devel-

opment of thyroid disease.

Principles oftesting

TPO antibodies are the test of choice. Tg antibodies not monitored now,

except as part of monitoring for thyroid carcinoma (interfere with assays

for Tg, which is used as a tumour marker). Antibodies to TSH receptor may

be stimulating or blocking, but these can only be identied by bioassay or

RIA in specialized laboratories.

Indications fortesting

Suspected thyroid disease and as reex testing when thyroid function is

abnormal; often now combined with thyroid testing on same analyser. Also

check in patients with PA. Use TPO antibodies. Other antibodies are for

specialist useonly.

Interpretation

TPO (thyroid microsomal) antibodies in 95– 100% of Hashimoto’s thyroidi-

tis, 70% of Graves’ disease; highest titres seen in Hashimoto’s. Tg antibodies

add little to diagnosis (also found in other endocrinopathies and thyroid

carcinoma). Antibodies to TSH receptor (stimulating or blocking) found in

95% of Graves’ patients.

367

ISLET CELL ANTIBODIES

Islet cell antibodies (ICA), anti- GAD

antibodies, and insulin receptor and

insulin antibodies

Units:qualitative (previously measured in JDF units) for ICA; numeric values

for othertests.

Normal range:0.4% of normal population +ve forICA.

Principles oftesting

ICA can be detected by immunouorescence on pancreatic sections; other

antibodies detected byEIA.

Indications fortesting

All newly diagnosed early- onset diabetics should be tested; they should

also be tested for coeliac disease using endomysial or tTG antibodies. May

be used to screen normoglycaemic rst- degree relatives for likelihood of

developing diabetes. Also advisable to screen children with coeliac disease.

Interpretation

ICA found in 75– 86% of type 1 diabetics, but only 10% of type 2 diabet-

ics and 2– 5% of rst- degree relatives. Levels decline with time and may

disappear completely in long- standing type 1 patients. Antigen is glutamic

acid decarboxylase (GAD) (similar antibodies cause sti man (person!) syn-

drome, although a dierent epitope on the molecule is recognized); GAD65

and GAD67. Other target antigens for autoantibodies, with high specicity

for diabetes,are:

•

Insulin/ proinsulin (seen at diagnosis in 40% of type 1 diabetics).

• Insulin receptor (associated with acanthosis nigricans and insulin

resistance).

•

IA- 2 (present in 60% of newly diagnosed type1DM).

• ZnT8 (zinc transporter) found in 60– 80% of type1DM.

Monitoring is of novalue.

Note: IgE antibodies to porcine or bovine insulin may occur in insulin

allergy, due to exogenous ‘foreign’ insulin.

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CHAPTER4 Immunology and allergy

368

Adrenal antibodies and other endocrine

autoantibodies

Units:qualitative.

Normal range:not detectable.

Principles oftesting

Usually detected by immunouorescence on appropriate tissue (adre-

nal, ovary, testis, parathyroid, pituitary). EIA for 21- hydroxylase, 17-

hydroxylase, and P450 side chain cleavage enzymes (targets of adrenal

antibodies) in research centres.

Indications fortesting

Suspected autoimmune endocrinopathy (adrenal insuciency, premature

ovarian failure, hypoparathyroidism).

Interpretation

Positives indicate autoimmune disease of relevantorgan.

Classiﬁcation ofautoimmune

polyglandular syndromes

Refer to Table4.7.

Table4.7 Classication ofautoimmune polyglandular syndromes

Syndrome Major criteria Minor criteria

Type I Candidiasis

Adrenal failure

Hypoparathyroidism

Gonadal failure

Alopecia

Malabsorption

Chronic hepatitis

Type II

(Schmidt’s

syndrome)

Adrenal failure

Thyroid disease

IDDM

Gonadal failure

Vitiligo

Non- endocrine autoimmunity (myasthenia)

Type III Thyroid disease Either

IDDM

Non- endocrine autoimmunity (myasthenia)

IDDM, insulin- dependent (type 1)diabetes mellitus.

369

EMA & tTG ANTIBODIES

Endomysial (EMA) and tissue

transglutaminase (tTG) antibodies

Units:qualitative for EMA; numeric fortTG.

Normal range:not usually detected in healthy individuals. +ve IgA EMA or

tTG with normal biopsy probably indicates risk of later development of

coeliac disease.

Principles oftesting

Originally identied as anti- reticulin R1 antibodies on ‘autoimmune screen’.

Later identied as antigliadin antibodies by modied immunouorescence

or by EIA. EMA detected by immunouorescence on monkey oesophagus

(also umbilical vein, but this is dicult to read); puried recombinant human

tTG used for EIA (assays with guinea pig tTG are less sensitive).

Indications fortesting

Patients with malabsorption, wheat intolerance, ‘irritable bowel’; children

with type 1 diabetes (and suggested that they should be monitored every

year!). Suspected dermatitis herpetiformis. Unexplained hyposplenism,

small bowel lymphoma.

Interpretation

IgA EMA has nearly 100% sensitivity and specicity for coeliac disease.

Antigen is tTG. In IgA deciency (commoner in coeliac), IgG EMA is as

good a diagnostic test. Gliadin antibodies (IgG or IgA) are not sensitive and

specic and should no longer be used; they are found in a range of bowel

diseases and in healthy individuals. Reticulin R1 antibodies may be picked up

on routine autoantibody screen; these may also be found in IBD, especially

with liver involvement, and non- specic bowel disease (post- infectious,

allergic, etc.). Also found in dermatitis herpetiformis (typical rash). Strong

association with juvenile type1DM.

Antibodies disappear with strict gluten- free diet, over 6– 12 months.

Persistent positivity of IgA EMA or IgA tTG antibodies in a patient on a

gluten- free diet is an indication of incomplete/ non- compliance with the

diet. Monitoring tTG antibodies is valuable.

Gliadin antibodies and neurological disease

Gluten sensitivity enteropathy is also associated with neurological disease,

typically cerebellar ataxia. Reports have suggested that gliadin antibodies

are a marker for this syndrome; the lack of specicity of gliadin antibodies

means that it is unlikely that these antibodies can be used as an accurate

diagnostic test, and specic tests (EMA and tTG) should be used instead.

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CHAPTER4 Immunology and allergy

370

Autoimmune skin diseases

Units:normally reported qualitatively.

Normal range

:antibodies when detected are highly disease- specic.

Principles oftesting

Autoantibodies to components of the skin can be detected either by direct

immunouorescence (DIF) on a skin biopsy of aected tissue or indirectly

in the patient’s serum using monkey oesophagus as a substrate. Saline split-

ting of the skin may be used to identify the precise location of the antigenic

target to dierentiate between epidermolysis bullosa acquisita (antigen on

the dermal side) and pemphigoid (antigen on the epidermalside).

Indications fortesting

Bullous (blistering) skin diseases.

Interpretation

Bullous pemphigoid

Antibodies bind to the dermal– epidermal junction and recognize hemides-

mosome antigens (BP 230 (BPAG1) and BP 180 (BPAG2)); detect by DIF on

skin biopsies or in serum (only 70% of patients have detectable circulating

antibodies in serum). Linear basement membrane deposition of IgG and

C3 onDIF.

Herpes gestationis

Antibodies to BP 180 (BPAG2) binding to the dermal– epidermal junction

on DIF of biopsies, often −ve for serum antibodies. Linear basement mem-

brane deposition of IgG and C3 onDIF.

Pemphigus

Antibody binds to the cell surface of stratied squamous epithelium and

recognizes the desmosomal proteins desmoglein Iand III. Eighty to 90% of

patients have detectable antibody in serum. Chicken- wire pattern of immu-

nouorescence in the epidermis. May occur as a paraneoplastic phenom-

enon in patients with lymphoma, but antigenic specicity is for desmoplakin

IandII.

Dermatitis herpetiformis

Granular deposits of IgA at the dermal– epidermal junction in dermal papil-

lae on DIF; EMA and tTG antibodies will be+ve.

AUTOANTIBODIES AND NEUROLOGICAL DISEASE

371

Autoantibodies and neurological disease

Principles oftesting

Most neurological autoantibodies of interest are rare and are available from

reference laboratories. A variety of methods are used; some assays are

reported with numeric values.

Indications fortesting

These are restricted to very specic neurological syndromes.

Interpretation

• AChRAb associated with MG (90%); reported numerically as high

and low +ves to distinguish dierent clinical phenotypes. May also

be found in asymptomatic relatives. Striated muscle antibodies

(immunouorescence on striated muscle section) strongly associated

with underlying thymoma.

•

Lambert– Eaton myasthenic syndrome (LEMS), occurring with small- cell

carcinoma of the lung, associated with autoantibodies to voltage- gated

channels, α and β subunits. Same tumour also associated with

retinal autoantibodies. Antibodies to voltage- gated K

channels are

associated with neuromyotonia.

•

Anti- ganglioside antibodies associated with GBS (GM- 1, GD1a) and

variants (Miller– Fisher— GQ1b, GT1a), chronic variants (chronic

inammatory demyelinating polyneuropathy), and neuropathy

associated with paraproteins.

•

Myelin- associated glycoprotein (MAG) antibodies associated with

paraproteinaemic neuropathy, especially with Waldenström’s

macroglobulinaemia.

•

Antibodies to myelin basic protein found in MS, but not useful

diagnostically.

•

Anti- Yo (Purkinje cell antibodies) found in paraneoplastic cerebellar

degeneration (gynaecological or breast tumours associated); anti-

Hu (anti- neuronal nuclear antibodies (ANNA)) associated with

paraneoplastic neuropathies and myelopathies (small- cell carcinoma).

Anti- Ri (anti- neuronal nuclei) associated with cerebellar ataxia and

opsiclonus (small- cell carcinoma, gynaecological or breast tumours

associated). Other specicities have been dened.

•

Anti- neuronal antibodies in the CSF of 74% of patients with cerebral

lupus; also associated with anti- ribosomal P antibodies.

• Anti- GAD antibodies found in sti person syndrome; same antigen to

that found in pancreatic islets; diabetes usually occurs in sti person

syndrome. Antibodies appear to inhibit the production of

- aminobutyric acid (GABA), an inhibitory neurotransmitter.

Rasmussen’s encephalitis associated with autoantibodies to GluR3

receptor, which cause hyperexcitability of neurones.

•

Anti- aquaporin- 4 antibodies are associated with neuromyelitis optica

(Devic’s disease).

372

CHAPTER4 Immunology and allergy

372

Vasculitic syndromes

ANCA

Units:usually expressed as titre (qualitative EIAs are used in some centres).

Normal range:in adults, normal=undetectable.

Principles oftesting

Screening is usually carried out by immunouorescence on ethanol- xed

human neutrophils; rapid EIA screening tests exist for +ve/ −ve testing in

emergencies. EIA to specic antigens is an essential follow- up. Distinction

between antinuclear and perinuclear staining may require the use of

Hep- 2cells.

Indications fortesting

Suspected vasculitis; acute glomerulonephritis.

Interpretation

•

Two main patterns recognized:c- ANCA (mostly Wegener’s; 90% of

Wegener’s ANCA +ve) and p- ANCA (some Wegener’s, microscopic

polyarteritis, Churg– Strauss syndrome, glomerulonephritis, sclerosing

cholangitis, AIH, ulcerative colitis).

•

c- ANCA pattern due to antibodies against proteinase- 3; p- ANCA

pattern due to antibodies against MPO, lactoferrin, cathepsin,

and elastase. Follow- up EIA required to identify antigenic

specicity:minimum PR3 and MPO ELISA; other antigens available

through supra- regional referral laboratories.

• In Wegener’s, monitoring titre of ANCA is useful; a rising titre in a

patient in clinical remission heralds relapse.

•

ANCA may be seen as epiphenomenon in states of chronic neutrophil

activation and turnover, e.g. cystic brosis.

Anti- GBM disease (Goodpasture’s syndrome)

Units: qualitative (quantitation available through reference centres— used

only to follow patients post- plasmapheresis or transplant).

Normal range:not detectable.

Principles oftesting

Usually carried out by EIA; screening by immunouorescence is not sen-

sitive. Biopsies will show linear IgG deposition in glomeruli (and alveoli).

Antibodies recognize the NC1 region in the α3 chain of type IV collagen.

Indications fortesting

Acute glomerulonephritis, particularly if associated with pulmonary

haemorrhage.

Interpretation

Positive antibodies conrm Goodpasture’s syndrome. Urgent plasmapher-

esis is required, and monitoring reduction of antibody with treatment is

advisable. Disease may recur in transplanted kidneys, so monitoring of

antibody is advised. Some patients may be both ANCA and anti- GBM

antibody+ve.

VASCULITIC SYNDROMES

373

Anti- phospholipase A2 antibodies (anti- PLA- 2)

Units:quantitative, through reference laboratoriesonly.

Normal range:not detectable.

Principles oftesting

Usually carried out by EIA or western blot. Indirect immunouorescence

also available using a cell line expressingPLA- 2.

Indications fortesting

Marker antibody for idiopathic membranous nephritis(IMN).

Interpretation

Very high specicity for IMN but may also be found inlupus.

374

CHAPTER4 Immunology and allergy

374

Allergic disease

TotalIgE

Unit:kU/ L.

Normal range:<100kU/ L (>14yearsold).

Principles oftesting

Previously carried out by RIA, now byEIA.

Indications fortesting

There are FEW indications for testing. Screening for atopic disease;

investigation of suspected hyper- IgE syndrome (Job’s syndrome, a rare

immunodeciency), Churg– Strauss vasculitis. Gating requests for radioal-

lergosorbent tests (RASTs) on the basis of IgE is scientically unsound (see

E Interpretation below).

Interpretation

Signicant allergic disease is possible with low levels of total IgE (including

anaphylaxis). Only patients with undetectable IgE (<7) are unlikely to have

allergic disease. Conversely, levels above the normal range are compatible

with no clinical allergic disease. IgE >1000 associated with atopic eczema;

IgE >50,000 conrms hyper- IgE syndrome (although patients may have

lower levels— diagnosis is clinical). Raised levels are also seen in parasitic

infections of the bowel, lariasis, lymphoma (especially Hodgkin’s disease),

and Churg– Strauss vasculitis.

SKIN PRICKTESTS

375

Skin pricktests

Unit:mm wheal size, compared to histamine and saline controls.

Normal range:nowheal.

Principles oftesting

This remains the gold standard for allergy diagnosis. It identies IgE-

mediated reactions (type I) such as inhalant allergy, anaphylaxis, and food

allergy. It is dependent on triggering the release of histamine from cutane-

ous mast cells. Solution of allergen or controls (histamine or saline) placed

on the skin and pierced through by a lancet. After 15min, wheal will be

visible. Positive is at least 2mm greater than −ve control. Histamine control

must be +ve. Not interpretable if the patient is dermographic (−ve con-

trol gives wheal). Can use factory- prepared allergens; also use double- prick

technique with fresh foods (prick food, then the patient)— useful where

allergens are labile, e.g. fruits.

Indications fortesting

Mainstay for diagnosis of all types of allergic disease. Contraindicated when

there is signicant skin disease, previous severe allergic reactions (use RASTs

rst), patients on antihistamines (need to be o drug for a week). Other

drugs will interfere, e.g. Ca

channel blockers, tricyclic antidepressants.

Interpretation

Results can only be interpreted in the context of the clinical history. Testing

should be tailored to individual patients to answer specic questions. May

need to be followed up by open or blinded challenges where −ve results are

obtained in patients with good histories.

Good specicity for inhalant allergens and some foods (nuts, sh); results

comparable with RAST testing.

Many known families ofcross- reactivity betweenbiological families

• Latex allergy associated with food reactions:banana, avocado, kiwi fruit,

chestnut, potato, tomato, cannabis, lettuce. Also birch pollen allergy

commoner.

•

Birch pollen allergy (asthma, rhinitis) with food- related reactions to nuts,

apples, plums, cherries, carrots, and potatoes (‘oral allergy’ or ‘pollen–

fruit’ syndrome).

•

Mugwort pollen and celery.

• Ragweed pollen with melon and banana.

376

CHAPTER4 Immunology and allergy

376

Speciﬁc IgE:‘RASTtests’

Units: continuous numeric scale in IU/ mL. Also (less frequently now)

reported as grades0– 6.

Normal range:grades 0 and 1 indicate insignicant specicIgE.

For an overview of grades, see Table4.8.

Principles oftesting

Previously tested by RIA (hence the acronym RAST=radioallergosorbent

test); now identied by enzyme- linked or uorimetric assays.

Indications fortesting

‘RAST’ tests are expensive and should be reserved for cases where skin

prick testing is not possible: extensive skin disease, patient on antihista-

mines, severe reactions, small children, dermographic patients. Testing

MUST be guided by the history— do not request ‘allergen screen’.

Interpretation

Presence of specic IgE does NOT equate to allergic disease— indicates

sensitization only. Must be interpreted in the context of the clinical history.

Numerical value does NOT correlate with severity of clinical reactions.

RAST tests are of little value for identifying allergy to fruits and vegeta-

bles, as the allergens are labile, and to drugs (unreliable). False +ves possible

when total IgE is very high due to non- specic binding (less of a problem

with newer assays).

Table4.8 Grades

0 <0.35

0.35– 0.70

2 0.70– 3.50

3 3.50– 17.50

4 17.5– 50.0

5 50– 100

6 >100

DRUG ALLERGY TESTING

377

Mast cell tryptase

Unit:μg/ L.

Normal range: 2– 14μg/ L.

Principles oftesting

Measured by EIA. Analyte is stable in clottedblood.

Indications fortesting

Valuable test for the investigation of acute? allergic reactions. Released

when mast cells degranulate, and stable in serum for up to 24h. Also useful

for monitoring patients with mastocytosis.

Interpretation

Raised levels indicate mast cell degranulation and will help distinguish ana-

phylactic and anaphylactoid reactions from other causes of reactions (vas-

ovagal, hyperventilation, carcinoid, phaeochromocytoma, etc.). Persistent

elevated levels may indicate mastocytosis.

Drug allergy testing

Investigation of severe drug allergy is a specialized eld and all patients

should be referred to an appropriate expert for an opinion, usually a con-

sultant in allergy or clinical immunology in a regional centre. Testing will

usually involve skin prick testing, followed by intradermal testing and patch

testing and, if necessary, blind challenge.

Patchtests

Unit:scored qualitatively.

Normal range:−ve.

Principles oftesting

This test identies cell- mediated reactions = delayed- type hypersensitiv-

ity (type IV reactions). It should not be confused with skin prick testing.

Allergens in petrolatum jelly are placed in contact with the skin for 48h

under occlusion with aluminium cups. The test result is read at 96h, looking

for eczematous change and blistering. Usually carried out by dermatology

departments.

Indications fortesting

Investigation of contact reactions, e.g. eczema.

Interpretation

Positive results are invariably signicant. Common allergens include metals

such as nickel and chromium, dyes and chemical in leather, rubber chemicals

(accelerators), and cosmetic chemicals. Panels of allergens used, depending

on the clinical history.

378

CHAPTER4 Immunology and allergy

378

Cellular functionassays

Investigation of cellular function of lymphocytes, neutrophils, macrophages,

and natural killer (NK) cells are restricted to specialized regional immunol-

ogy laboratories. The tests are labour- intensive and dicult to standardize,

with the exception of basic lymphocyte markers. EQA schemes are avail-

able only for basic lymphocyte markers.

All tests, other than basic lymphocyte markers, should only be requested

after discussion with a consultant immunologist. Their role is in the inves-

tigation of suspected cellular immunodeciency, particularly SCID and °

disorders of neutrophils. In such cases, urgent referral of the patient to

an appropriate paediatric or adult immunologist is more appropriate than

ddling around trying to get tests done, as the immunologist will have

direct and immediate access to the appropriate tests. Lives have been lost

due to delay in transfer, whilst inexperienced clinicians have tried to make

diagnoses.

Lymphocyte surface markers

Unit:cells/ μL.

Normal range:see Table4.9.

Principles oftesting

Lymphocyte surface markers should be carried out on a single- platform

ow cytometer, which will give a direct absolute count, not requiring a total

lymphocyte count from a haematology analyser. Absolute counts are the

preferred value; percentages are not useful. Fresh samples are required for

optimum results. Many other surface markers are available to answer more

specic immunological questions, but these will usually be of interest only

to clinical immunologists. An EQA scheme operates.

Indications fortesting

There are no absolute indications. Investigation of lymphocyte subsets is

an important part of the work- up of any patients with suspected ° or

2° immunodeciency and of patients with unexpected lymphopenia.

Serial measurements are valuable in patients undergoing BMT or stem cell

transplantation, those with ° immunodeciencies, those on any immu-

nosuppressive therapy, and those with HIV on therapy with highly active

antiretroviral therapy (HAART).

Table4.9 Normal ranges forlymphocyte surface markers

CD3+ (total T cells) 690– 2540

CD19+ (total B cells; CD20 is equivalent) 90– 660

CD3+CD4+ (T helper cells) 410– 1590

CD3+CD8+ (cytotoxic T cells) 190– 1140

CD16+CD56+ (NK cells) 90– 590

CELLULAR FUNCTIONASSAYS

379

Interpretation

Results can only be interpreted in the context of the clinical question.

Lymphocyte surface marker analysis CANNOT be used as a surrogate for

HIV testing, as many acute viral and bacterial infections, as well as other

medical problems, will give rise to a reduction in CD4+ Tcells.

Criticalaction

Baby <6months with lymphocyte count <2 × 10

/ L=SCID until proven

otherwise:IMMEDIATE referral to a SCID BMT unit (in the UK, Newcastle

General Hospital, Newcastle upon Tyne, and Great Ormond Street

Hospital for Sick Children, London). Look at the dierential white count,

not just the total whitecount!

380

CHAPTER4 Immunology and allergy

380

Lymphocyte functiontests

These are highly specialized and should only be carried out on the recom-

mendation of a clinical immunologist.

Indications fortesting

There are no absolute indications for testing, but it is usually carried out as

part of the specialized work- up of patients with known or suspected SCID

and in the monitoring of immunological reconstitution post- BMT.

Interpretation

Is complex and dependent on the precise clinical circumstances.

Neutrophil and macrophage function

This is a specialized test. Samples do not transport well, and results are

often abnormal if the patient has an active infection or is on antibiotics. It

is preferable to refer patients to a clinical immunologist who will organize

testing if appropriate.

Indications fortesting

Patients with deep- seated abscesses, recurrent major abscesses (exclude

diabetes, staphylococcal carriage, and hidradenitis suppurativa rst), major

oral ulceration, and unusual fungal or bacterial infections (Pseudomonas,

Serratia, staphylococci, Aspergillus). Atypical granulomatous disease, includ-

ing atypical Crohn’s disease. Genetic defects of neutrophil function may

present at anyage.

Interpretation

Interpretation is complex; defects of oxidative metabolism may indicate

chronic granulomatous disease; defects of phagocytosis are recognized.

Also MPO deciency. Neutropenia may be chronic or cyclical. Genetic test-

ing to follow up may be required.

Natural killer cell function

Is rarely required. The main indication is in recurrent severe infection with

herpesviruses. Assays are complex and need specialist interpretation.

Always discuss cases with a clinical immunologist.

Further reading

Shoedfeld Y, Meroni PL, Gershwin ME (eds.). Autoantibodies, 3rd edn. Sand Amsterdam:Elsevier,2014.

Spickett G. Oxford Handbook of Clinical Immunology and Allergy, 3rd edn. Oxford:Oxford University

Press,2013.

381

Chapter5

Infectious and tropical

diseases

Introduction to infectious diseases 382

Investigating the infectious diseases/ tropical medicine case 388

Culture techniques 390

Immunological tests 396

Antigen tests 400

Collection of specimens 402

Molecular diagnostics 406

Haematology 408

Radiology 410

Gastrointestinal tract investigations 412

Immunology 414

Biochemical tests 416

Tissue biopsy and deep aspiration specimens 418

Other tests 422

Clinical investigation in action:pyrexia of uncertain origin 424

382

CHAPTER5 Infectious and tropical diseases

382

Introduction toinfectious diseases

Everything about microscopic life is terribly upsetting … how can

things so small be so important?

(Isaac Asimov— 1920– 1992)

An oldenemy

Infectious diseases have had a huge impact on the human species. Throughout

history, mighty armies have been humbled by microbiology. After the intro-

duction of eective antibiotics during the Second World War, there was great

optimism that the ght against infectious diseases had been won. In recent

years, this hope has been dramatically dashed. Almost all new diseases are

infections, and some of the twenty- rst century’s most pressing problems are

pathogens that have only appeared in the 30years prior to this book being

written. Globally, the most important of the newer organisms are HIV and

hepatitis C, though old enemies, such as TB, Pneumococcus, and malaria, are

still killing millions throughout the world. The dreadful epidemic of Ebola virus

disease has shaken the world’s biosecurity.

New challenges

As we proceed through the twenty- rst century, several factors are serv-

ing to i the relative importance of infection over other areas of medicine.

Infections such as Ebola, zika, and avian/ swine inuenza are continually

emerging and re- emerging. Antimicrobial resistance is increasing, meticillin-

resistant Staphylococcus aureus (MRSA), vancomycin- resistant Enterococcus

(VRE), and carbapenemase- producing Enterobacteriaceae (CPE) being the

most infamous examples. There are more immunosuppressed patients

as a result of i use of chemotherapy agents and organ transplantation.

Tourists and other travellers are making their way to ever more remote

parts of the world. Medical tourism is a cheap way of getting cosmetic sur-

gery. Migration of populations has always spread disease and this continues

today. There are concerns of wilful bioterrorism. All of these factors mean

that the infectious dierential diagnosis— even in the developed world—

grows ever longer.

It is always worth bearing in mind infection in a dierential diagnosis

is often treatable. Accordingly, it is always better not to miss treatable

options over incurable ones. Furthermore, some infectious diseases like

Ebola, multidrug- resistant tuberculosis (MDR- TB), severe acute respiratory

syndrome (SARS), Middle East respiratory syndrome coronavirus (MERS-

CoV), and avian/ swine inuenza have major public health consequences,

including for the treating physician.

A challenge tothe clinician

The same infection is often capable of causing a wide variety of clinical

pictures. HIV, for example, is a great mimicker. Acquired immune deciency

syndrome (AIDS) is dened by its consequences. This is not so surprising,

given the genetic variety of mankind, hence individual responses to a bewil-

dering variety of infecting agents. Some clinical syndromes can be caused

by many, quite dierent pathogens. Good examples include pneumonia,

hepatitis, and endocarditis.

INTRODUCTION TO INFECTIOUS DISEASES

383

Furthermore, some infectious diseases can resemble non- infectious dis-

eases. For example, amoebic colitis can resemble ulcerative colitis; syphilis

can present with serious psychiatric symptomatology; a brain abscess or a

tuberculoma can resemble a brain tumour; and TB of the vertebral column

can resemble metastatic malignancy. Getting it wrong can be catastrophic

for the patient.

Other diseases can mimic infections

Non- infectious diseases can resemble infection. Examples include gout of

the rst MTP joint, rather than cellulitis; cervical lymphadenopathy due to

lymphoma, rather than TB; familial Mediterranean fever as a cause of PUO;

SLE leading to Libman– Sachs endocarditis; adult Still’s disease as a cause of

fever and neutrophilia; and inammatory carcinoma of the ♀ breast resem-

bling a pyogenic breast abscess.

Importance ofepidemiological factors

Epidemiology is fundamental to determining which, if any, infecting agents,

and therefore investigations, are relevant in a given patient.

Geography

This is very important and needs to be specic.

Some infections are common theworld overand include

•

Staphylococcal infection.

• Salmonella infections.

•

Pneumococcal pneumonia.

• Gonorrhoea.

• Thrush (candidiasis).

• TB.

• Inuenza.

• EBV.

• HIV (although sub- Saharan Africa is still the worst aectedarea).

• HepatitisC.

• Herpes simplex.

• Threadworm (Enterobius).

•

Syphilis.

Some infectious diseases are commoner inthe tropical world,e.g.

•

Malaria.

• Diphtheria (although still common in Eastern Europe).

• Rheumaticfever.

• Enteric fever (typhoid and paratyphoid).

• Hepatitis E (although increasingly widespread).

• Poliomyelitis (very restrictednow).

• Rabies (although Eastern Europe has signicant disease).

• Viral haemorrhagic fever (VHF), including Ebola, Lassa, Marburg.

• Onchocerciasis (river blindness).

• Schistosomiasis.

• Leishmaniasis (although commonly found around the Mediterranean).

• Ascariasis.

• Cutaneous myiasis (e.g. tumbu and boty).

384

CHAPTER5 Infectious and tropical diseases

384

Some infectious diseases are common insome parts ofthe developed world,

but not inothers, including

•

Lyme disease.

• Babesiosis.

• Ehrlichiosis.

• Histoplasmosis.

• Hydatid disease.

• Anisakiasis.

In theUSA, only certain areas are endemicfor

•

Lyme disease.

• Coccidioidomycosis.

• Babesiosis.

• Histoplasmosis.

• Tick- borne diseases.

Travel and vaccination history

This is important for many reasons. Travel exposes patients to new infec-

tious agents to which they have no immunity. Immunization schedules dif-

fer throughout the world, and some groups refuse to have their children

vaccinated. Vaccination before travel does not necessarily happen as rec-

ommended. The clinician must therefore be aware of the distribution of

common infections. Great variation in antibiotic resistance patterns can be

observed in dierent parts of the world; this clearly has an impact on the

choice of empirical treatment. Finally, travel often has an impact on patterns

of sexual and risk- taking behaviour (see Fig.5.1).

Tropic of Cancer

Equator

Tropic of Capricorn

Fig.5.1 The importance of taking a geographic history. Malaria, which can be

life- threatening, is a very common disease in many parts of the world but is not

indigenous to most parts of the developed world. Making a diagnosis depends heavily

upon the clinician eliciting the clues in the patient’s history. Even if s/ he has been

taking antimalarial drugs, a patient who has been on holiday to Kenya, Thailand, or

Brazil may die if the disease is not diagnosed. Clinical suspicion should lead to blood

lms (on 3 consecutive days) and a platelet count. Bear in mind that the patient may

not have been taking adequate prophylaxis, may have been missing tablets, or may

not have been absorbingthem.

INTRODUCTION TO INFECTIOUS DISEASES

385

Sexual and drug- taking activity

Searching and personal questions may need to be asked. This is sometimes

dicult to do, even with great experience. Patients will/ may not admit to

high- risk sexual activity or the use of illegal substances and may need to be

pressed. Beware of using family members as ‘translators’. The clinician must

maintain high clinical suspicion at all times, even and especially when the

patient does not t a social stereotype. Bear in mind that any patient may

have a ‘double life’, of which even his/ her spouse is unaware. It is danger-

ous for the clinician to assume that being married equates to sexual delity

or even heterosexuality.

It may not be immediately obvious that the fever, rash, and hypotension

in a woman may be related to her tampon usage (toxic shock syndrome),

yet menstruation can be a dicult subject to discuss in some cultural set-

tings. TB of the ♀ genital tract may present as infertility or menorrhagia.

‘Lumpy semen’ may be indicative of Schistosoma haematobium infection, and

a ‘urinary tract infection’ or a septic arthritis in a 19- year- old man may be

gonorrhoea.

Social and professional

Pets, hobbies, and jobs may well be important. The patient with pneumonia

and a budgerigar could have psittacosis. The tropical sh salesman with a

chronic rash on his hand could have Mycobacterium marinum infection (aka

‘sh tank granuloma’). The jaundiced volunteer cleaning out canals at week-

ends could have leptospirosis related to contact with rats. The cat owned

by the middle- aged lady with recurrent axillary lymphadenopathy may be

the key to her problem of cat- scratch disease (Bartonella henselae).

Assessing thepatient

The recognition of an infectious disease in a patient (or the absence of

one) goes far beyond the Petri dish, the microbiology bench, and PCR test-

ing technology. The Andromeda Strain phenomenon (with all due credit to

Michael Crichton MD) should be borne in mind. The disease in front of you

might be the rst ever presentation or the rst in a new outbreak! Almost

the only signicant new human diseases that will appear in the future will be

infectious diseases and they will keep appearing till the end of the human

species (see Fig.5.2).

Assessment should include

•

Adetailed history.

• Full physical examination (including temperature).

• The generation of a dierential diagnosis.

• Specimen collection before antimicrobial therapy.

• Laboratorytests.

• Non- invasive procedures (including radiological tests where

appropriate).

•

Invasive procedures.

• The making of a denitive diagnosis (wherever possible).

386

CHAPTER5 Infectious and tropical diseases

386

When considering thepossibility ofan infective process, one should always

consider thebasic taxonomy

•

Bacteria (including primitive forms).

• Mycobacteria.

• Fungi.

• Viruses.

• Protozoa.

• Helminths.

• Prions.

• Myiasis.

Investigations available tothe infectious diseases

or general physician

Many tests will be performed with a view to making a diagnosis.

Investigation of a patient should be rational and evidence- based, wher-

ever possible. Although the interrogative armamentarium of the infec-

tious diseases and tropical medicine physician is enormous— as with any

other branch of medicine— the history and examination will point the way.

Results will emerge which, whilst not producing a diagnosis as such, will

nevertheless require following up. For example, low C5 levels in recur-

rent meningococcal septicaemia may need immunological assessment.

(Remember also that there is a new drug eculizumab which specically

inhibits C5.) IgG deciency leading to recurrent pneumonia may require

regular infusions of γ globulins. Alow CD4+ cell count, which is not due

to HIV infection, could be a feature of sarcoidosis.

Fig.5.2 Infection and history taking.

INTRODUCTION TO INFECTIOUS DISEASES

387

Making a diagnosis alone is not the only issue at stake. Some tests must be

done if a patient is going to be treated safely. Examples might include:G6PD

levels before administering primaquine for hypnozoite eradication in malaria;

TB cultures for antibiotic sensitivity prior to starting empirical therapy; and

exclusion of pregnancy before using certain antibiotics such as doxycycline

and ciprooxacin. Other tests relate to the fact that some infectious dis-

eases are dangerous to others, including the doctor! Prime examples of this

would be MDR- TB and extensively drug- resistant TB (XDR- TB), avian inu-

enza, SARS, MERS- CoV, and Ebola, all of which are potentially dangerous

for the population at large and need to be identied (or at least suspected

wherever appropriate) and treated in an isolationunit.

388

CHAPTER5 Infectious and tropical diseases

388

Investigating theinfectious diseases/

tropical medicinecase

Available diagnostic techniques

Direct detection

•

Microscopy:

•

Direct— e.g. faecal parasites (± iodine) or malarial and trypanosomal

bloodlms.

•

Special stains— these include Gram and ZN stains.

•

Electron microscopy (EM)— for viruses and other pathogens.

•

Immunouorescence— with specicsera.

• Presence of toxin:e.g. Clostridium dicile.

•

Antigen detection (E Serology, pp. 396–9).

•

Molecular assays (E Molecular diagnostics, pp. 406–7):these include

gene probes, amplication assays, e.g.PCR.

• Point- of- care tests:bedside rapid diagnostic tests (RDTs) for malaria,

inuenza, HIV, andHBV

Culture

•

All body uids and tissues can be cultured. As a general principle, the

larger the sample sent, the greater the yield. It is good practice to

forewarn the laboratory before sending any unusual samples, especially

if there is a risk to laboratory sta, and label accordingly (E Biohazards,

pp. 402–5) Laboratory preparation and specialist containers may be

required. Adequate clinical details should be written on any request

forms, including travel history. The choice of culture technique can vary

dramatically, depending on the organism that is being sought. There may

be only one chance to culture the correct organism, so it should not be

wasted.

•

Once a culture has grown, identication maybe:

•

Through special growth media, culture temperature, or atmosphere.

•

By biochemical reactions (e.g. catalase or coagulase), API strip, or

matrix- assisted laser desorption/ ionization (MALDI).

•

With specic antisera (e.g. latex agglutination or

immunouorescence).

•

Using molecular- based methods (e.g. specic probes, restriction

enzyme patterns, DNA sequencing).

•

Using antimicrobial susceptibility testing (e.g. metronidazole sensitiv-

ity for anaerobes and vancomycin for Gram+ves).

Serology

E Serology, pp. 396–9.

1 Todar’s Online Textbook of Bacteriology. M http:// textbookofbacteriology.net.

INVESTIGATING THE INFECTIOUS DISEASES

389

Other tests asappropriate

(See appropriate sections.)

•

Biochemistry.

• Haematology.

• Immunology.

• Moleculartests.

• Radiology.

• Stool and bowel contents.

• Tissue biopsy and deep aspiration specimens.

• Othertests.

390

CHAPTER5 Infectious and tropical diseases

390

Culture techniques

Microorganisms exist in nature as mixed populations. Diagnosis of an infec-

tion means identifying the relevant pathogen. Furthermore, dierent organ-

isms can cause the same disease (e.g. pneumonia), require very dierent

treatment and management, and have dierent prognoses. Whilst some

specimens (e.g. stool, sputum) contain extremely large numbers of varied

organisms, some specimens (e.g. blood, CSF, urine) should be sterile, unless

infected or contaminated during their collection.

Microbiological culture assists with the aetiological diagnosis of bacterial,

fungal, protozoal, or viral illness by enabling identication and susceptibil-

ity testing of the isolated organism(s). Bacterial culture was the rst to

evolve, but useful data on other pathogenic groups can also be obtained

through the use of culture- based methodologies (although options for

treatment are currently more limited for viruses and fungi than for bac-

teria). Furthermore, culture of mycobacteria, viruses, and fungi usually

takes longer than most bacterial cultures; therefore, the data obtained are

most valuable for late conrmation of the diagnosis or for epidemiological

purposes (e.g. for predicting the appropriate constituents for a polyvalent

inuenza vaccine).

Bacteria

Three major steps are involved in extracting pure cultures from a diverse

population of microorganisms and identifying a pathogen. Many of these

processes can now be automated (see Fig.5.3).

1. An isolation plate is created. To do this, the mixture must be diluted until

the various individual microorganisms have been dispersed far enough

apart on an agar surface, so that, after incubation, they will form visible

colonies isolated from the colonies of their neighbours. Specialized

culture media (such as selective media, dierential media, enrichment

media, and combination selective and dierential media— a great many

exist) may be used to supplement mechanical techniques of isolation.

Culture can be aerobic or anaerobic. (Note:specimens for the isolation

of anaerobic pathogens require special care, as anaerobic bacteria die

in the presence of O

. Such specimens should therefore be transported

in a reduced container.) Lastly temperature can be used to further

select for pathogenic organisms, e.g. Campylobacter jejuni is unusual as it

will grow at41°C.

2. A pure culture is created. To achieve this, an isolated colony will be

selected out and carefully ‘picked o ’ the isolation plate for transferring

to a new sterile medium. Following incubation, all the organisms in the

new culture will be descendants of the same organism.

3. The organism can then be identied through various manoeuvres:

•

Increasingly, matrix- assisted laser desorption/ ionization time- of- ight

mass spectrometry (MALDI- TOF MS) and other automated systems

(see below).

CULTURE TECHNIQUES

391

• Other techniques include:

•

The colony appearance and susceptibility to specic antibioticdiscs.

•

The microscopic appearance.

•

The staining responses (e.g. Gram +ve vs Gram−ve).

•

The use of a range of biochemical tests designed to uncover

characteristics typical of a particular organism, e.g. catalase reaction,

sugar fermentation as in the API strip. The presence of the enzyme

coagulase is useful for distinguishing Staphylococcus aureus from less

pathogenic coagulase −ve staphylococci (normal skin commensals).

Fig.5.3 Overview of new methods in the workow of clinical microbiology

laboratories.

Reproduced from Fournier, Pierre- Edouard etal, Modern clinical microbiology:new challenges and

solutions, Nature Reviews Microbiology

11, (2013) 574– 585 doi:10.1038/ nrmicro3068, with permis-

sion from Macmillan PublishersLtd.

392

CHAPTER5 Infectious and tropical diseases

392

•

Less frequently now is the use of antisera (direct serology) for

culture conrmation:

— Agglutination and latex agglutination tests can be used

on colonies to identify Escherichia coli 0157, Streptococcus

pneumoniae, serogroups of Neisseria meningitidis, Shigella, and

Salmonella, Lanceeld groups of β

- haemolytic streptococci, and

serotypes of Haemophilus inuenzae.

— Detection of specic antigens by direct uorescent antibody

(DFA) staining can be used to identify colonies of Streptococcus

pyogenes, Bordetella pertussis, and the species and serotypes of

Legionella.

Ideally, specimens for bacterial culture should be taken before antibiot-

ics are administered. This may not always be feasible, but the information

yielded may well be less thanideal.

Matrix- assisted laser desorption/ ionization time- of- ight mass spectrometry

MALDI- TOF MS is a new automated technique using mass spectrometry,

which allows the analysis of biomolecules such as DNA, proteins, peptides,

sugars, and large organic molecules, which tend to fragment when ionized.

MALDI- TOF MS is a 3- step process. Firstly, the sample is mixed with a

matrix material and applied to a metal plate. Secondly, a pulsed laser irradi-

ates the sample, triggering disintegration. Finally, the analyte molecules are

ionized in a plume of hot ablated gases, which are then accelerated into

a mass spectrometer for analysis. The resultant spectra generated can be

used for the identication of microorganisms, when compared to stored

database proles. Species diagnosis by this procedure is much faster, more

accurate, and cheaper than other techniques. MALDI/ TOF has become

the standard method for species identication in large, modern medical

microbiological laboratories. It is easy to use, robust, and rapid, allow-

ing accurate bacterial identication of a large variety of species within a

few minutes, with only a small amount of culture sample required for the

analysis (104– 106 CFU). The absence of the need to purify the suspect

colonies allows for a much faster turnaround time. There are other new

automated systems on the market such as the BD Phoenix identication

method (BD Diagnostic Systems, Sparks, MD) which uses modied con-

ventional, uorogenic, and chromogenic reactions. Similarly, the Biologue

system (Biologue, Inc.) combines up to 2000 phenotypic tests. The older

Analytical Prole Index (API, bioMérieux) system uses direct inoculation

into a strip of various reactants, manually producing a code which is then

compared to a database. (See Fig.5.4.)

Antibiotic sensitivity

Once a bacterium is isolated, it can be cultured in the presence of antibiotic(s)

to assess if it is susceptible to that agent or not. The minimum inhibitory con-

centration (MIC) is the lowest antibiotic concentration at which the micro-

organism under assessment shows no visible growth in vitro. The MIC can

provide the clinician with precise information about the infecting bacterium’s

degree of antibiotic susceptibility and enable him/ her to avoid antibiotics to

which the organism shows resistance.

CULTURE TECHNIQUES

393

Samples

Sterile

Contaminated

Media for culture Growth and subtyping Susceptibility Typing

1–3 weeks

All isolates Small subset

Blood

1–2 days 1–2 days 1–6 weeks

Body uid

Urine

Pus

Surface swabs

Sputum

Faeces

Gram stain

MALDI-TOF

Acid fast stain

and Hain test

1 weeks–3 months

All Mycobacterium

tuberculosis

Species

identication

Species

identication

Aerobic bacilli

Fastidious

organisms

Anaerobic

organisms

Miscellaneous,

e.g. Legionella spp.

Mycobacterium

spp.

Staphylococci

Streptococci

Mycobacterium

spp.

Rapid

grower

Fig.5.4 MALDI- TOFMS.

Nature Reviews Genetics 13, 601– 612 (September 2012)doi:10.1038/ nrg3226 Transforming clinical microbiology with bacterial genome sequencing Xavier Didelot,

Rory Bowden, Daniel J.Wilson, Tim E.A. Peto & Derrick W.Crook.

394

CHAPTER5 Infectious and tropical diseases

394

For organisms exhibiting unusual resistance patterns, susceptibility panels

using methodologies such as broth microdilution, gradient diusion, and/ or

disc diusion have been created to assist clinicians.

On occasions, these data will need to be linked to testing of blood levels

for some antibiotics (e.g. gentamicin, vancomycin, cycloserine). MALDI-

TOF and other automated systems can also be used to identify antimicro-

bial resistance patterns. Nowadays genome sequencing can identify genetic

mutations associated with resistance.

Viruses

Viral culture is rarely used now, but it diers signicantly from bacterial cul-

ture as viruses require a very dierent type of medium to grow. Molecular

techniques, such as PCR and antigen detection, have become more eec-

tive, can quantitate the amount of virus present, and have almost com-

pletely replaced culture.

The appropriate type of specimen to collect, the best means of trans-

port, and the most appropriate cell culture to use will vary with the particu-

lar virus suspected, the specimen site, and the time of theyear.

•

The choice of specimen is very important. Numerous viruses enter

via the mucosa of the upper respiratory tract, yet that virus may

compromise multiple or distant tissues and organs.

•

Swabs can be used to collect a variety of specimens from the body

surfaces for viral detection, e.g. nose, throat, eye, skin, and rectum.

Anasopharyngeal aspirate (NPA) may be the more appropriate

specimen if inuenza is suspected. It is important to collect mucosal

cells, as this is where the virus resides. Deeper specimens, such as blood

and CSF, will be appropriate for some viruses. Dierent viruses will

need dierent collection approaches, e.g. heparin, citrate, and EDTA are

all acceptable for the detection of CMV by PCR, antigenaemia testing,

or culture, but for some other viruses, only citrate should be used if

they are to be cultured.

•

Unlike many bacterial or fungal pathogens, the time of year is important

to keep in mind when making a diagnosis of certain viral diseases. For

example, enteroviruses circulate almost exclusively in the summer

months and inuenza likewise circulates during the winter months.

•

Timing is important when collecting specimens for viral detection. They

should be collected as early as possible after the onset of symptoms,

as once viral shedding ceases, culture will be impossible and serological

and molecular techniques may be the only way of diagnosing the viral

pathogen.

•

Some viruses cannot be cultured, e.g. viral agents of diarrhoea

(caliciviruses, astroviruses, and coronaviruses), HCV, andHBV.

Laboratory assays for antiviral susceptibility testing include phenotypic and

genotypic assays. Genotypic assays have almost completely replaced phe-

notypic testing, especially for HIV and HBV. Genotyping of HCV is criti-

cal in guiding treatment. Phenotypic assays require growth of the virus in

vitro and so present a biohazard. In these circumstances, genotypic assays

(E Molecular diagnostics, pp. 406–7) are now routinely available and very

useful.

CULTURE TECHNIQUES

395

Fungi

Unlike bacterial and viral diseases, direct microscopy can often be used to

diagnose fungal infections (based on distinctive morphological character-

istics of the invading fungi, e.g. Aspergillus

or tinea, and/ or the judicious

use of special stains such as methylthioninium chloride (methylene blue)).

However, histopathological diagnoses should be conrmed by culture,

wherever possible. Conversely, although diagnoses are usually made by iso-

lating the causative fungus from bodily samples, the presence of a fungus in

a culture from a non- sterile site does not mean that it is pathological (e.g.

Candida isolation from sputum). Fungal infection can only be denitively

established with evidence of tissue invasion histologically. There are also

a range of serological tests available for systemic mycoses (E Serology,

pp. 396–9), but few provide denitive diagnoses by themselves. Antigen

detection has been promising but generally has poor sensitivity and speci-

city, even when used in combination. For example, galactomannan and

- D- glucan can be indicative of invasive aspergillosis in combination with

PCR for Aspergillus, but the context also needs to be considered. Allergic

bronchopulmonary aspergillosis (ABPA) patients can have serum samples

tested for total IgE and aspergillus- specicIgE.

An exception is cryptococcal antigen (CrAg) which is useful in serum and

CSF samples for diagnosis of cryptococcal disease, especially meningitis in

immunocompromised HIV patients.

Fungal culture techniques are similar to bacterial ones. They are most

useful for detecting dimorphic fungi, which manifest both mycelial and

yeast forms. This group includes Candida species, Cryptococcus neoformans,

Blastomyces dermatidis, Histoplasma capsulatum, Penicillium marneei, and

Coccidioides immitis. MALDI can identify most fungal species.

Protozoa

Protozoa of the genera Acanthamoeba and Naegleria may cause fatal CNS

disease. Acanthamoeba species are free- living amoebae associated with

keratitis; they may also cause granulomatous encephalitis. Another free-

living amoeba Naegleria fowleri is able to cause acute fulminant meningoen-

cephalitis and is usually associated with a history of swimming in freshwater

lakes or brackish water. In suspected cases, CSF and other suspicious clinical

material may be cultured on a non- nutrient agar plate seeded with a ‘lawn’

of Gram −ve bacteria (such as E.coli). Pathogenic amoebae can be identi-

ed microscopically.

Worldwide the most important protozoan infection are the plasmodia

causing malaria. They can be cultured, but this is rarely of use clinically.

The mainstay of malarial identication is direct microscopy, although antigen

detection tests are now available.

396

CHAPTER5 Infectious and tropical diseases

396

Immunologicaltests

Immunological methods are in wide usage to detect many pathogens pre-

sent in clinical samples. Serology refers to the laboratory usage of antigen–

antibody reactions for such diagnostic purposes. Diagnosis is made by

detecting antibody or antigen in blood and/ or other bodily uids, or by the

identication of pathogens in culture. More recently, interferon γ release

assays (IGRA) have been developed to look for evidence of T- lymphocyte

reactivity to antigens from pathogens such as Mycobacterium tuberculosis.

Both direct and indirect serological testsexist

Indirect serological techniques

Employ antigen– antibody reactions to detect specic antibodies manufac-

tured in response to an antigen or antigens on an infecting pathogen’s sur-

face. These antibodies are found circulating in the patient’s blood or present

in other body uids.

Direct serological techniques

Employ antibodies to detect specic antigens. Because this technique can

be used to identify and type cultured organisms (E Culture techniques,

pp. 390–5), not only does it have individual clinical value, but it also has

important epidemiological applications.

HBV is a good example of an infection where both antigen and antibody

proles are diagnostically, therapeutically, prognostically, and epidemiologi-

cally important:

•

Antibody detection of a specic antibody, e.g. anti- hepatitis Be antigen

(anti- HBe antibody), anti- hepatitis B surface antigen (anti- HBs antibody).

• Antigen detection, e.g. hepatitis B ‘e’ antigen (HBeAg), hepatitis B

surface antigen (HBsAg).

•

More recently, pre- core mutants of HBV have emerged that are not

picked up by the common antigentests.

(See Fig.5.5.)

Antibodytests

A wide variety of methodologies for assessing antibody response are avail-

able such as immunouorescence, agglutination, ELISA, and complement

xation(CF).

Sub- classication of organisms, through serogrouping, can be valuable

epidemiologically, e.g. whilst investigating an outbreak of meningococcal

(N.meningitidis) disease; if the culprit is determined to be type C, vaccina-

tion can be utilized to control the outbreak. However, this is being replaced

by molecular techniques.

IMMUNOLOGICALTESTS

397

General principles

(See Fig.5.6.)

1. Specic IgM levels indicates a ‘new’ infection.

2. Specic IgG levels indicates a ‘new’ or a ‘previous’ infection, or, in some

cases, immunity generated by vaccination.

3. i IgG (‘rising titre’) when two samples (‘paired sera’) are taken with

an appropriate intervening interval between them indicates a ‘new’

infection or re- infection. Diagnosis (as indicated by seroconversion)

necessitates a diagnostic antibody titre or a 4- fold i in antibodytitre.

4. Seroconversion is said to have occurred in situations 1and3.

Viral antibodytests

These can be very useful because once viral shedding has ceased, viral cul-

ture is of no further value. They include tests for HIV- 1, HIV- 2, human T-

lymphotropic virus (HTLV)- 1, HTLV- 2, hepatitis A, hepatitis B, hepatitis C,

δ agent (hepatitis D), hepatitis E, EBV, CMV, dengue, Ebola virus disease,

Lassa fever, respiratory syncytial virus (RSV), mumps, measles, rubella,

inuenza, parainuenza, St Louis encephalitis, West Nile virus, yellow fever,

SARS, and many more (see Fig.5.7).

Fig.5.5 Antibody tests in hepatitis BandD.

398

CHAPTER5 Infectious and tropical diseases

398

0246810 12 14

LAG

phase

LOG

phase

Plateau

phase

Decline

phase

IgM

IgG

Antibody

titre

Exposure to

infecting agent

(‘antigen’)

Days

Fig.5.6 Relative rate of appearance and disappearance of IgM andIgG.

HBV

infection

Symptoms

HBcAg

HBsAg

HBeAg

DNA

polymerase

Anti-HBc

Anti-HBe

Anti-HBs

Months

‘core

window’

Fig.5.7 Hepatitis B antigens and antibodies.

IMMUNOLOGICALTESTS

399

Bacterial antibodytests

Less useful, these include anti- streptolysin (ASO) and anti- DNAse B for

streptococcal infection.

They can be useful for non- culturable or dicult- to- grow organisms in

the correct clinical context, e.g. cat- scratch fever (B.henselae), B.pertussis,

Lyme disease (Borrelia burgdorferi), Brucella species, C.jejuni, Chlamydia spe-

cies, Q fever (Coxiella burnetti), E.coli 0157, Francisella tularensis, Helicobacter

pylori, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes,

Mycoplasma pneumoniae, N. meningitidis, Neisseria gonorrhoeae, Rickettsia

prowazekii, Salmonella species, Treponema pallidum (including Treponema pal-

lidum

haemagglutination assay (TPHA), rapid plasma reagin (RPR), VDRL,

uorescent treponemal antibody absorption (FTA- ABS), IgM- FTA, IgM-

ELISA), Yersinia enterocolitica/ Y.pseudotuberculosis (Widaltest).

Protozoal antibodytests

Include tests for amoebiasis, toxoplasmosis, leishmaniasis (kala- azar),

African trypanosomiasis (sleeping sickness), American trypanosomiasis

(Chagas’ disease), babesiosis, and Toxoplasma gondii.

Helminthic antibodytests

Include tests for Echinococcus granulosus (hydatid disease), Echinococcus

multilocularis (alveolar echinococcosis), Microsporidium species, schistoso-

miasis (bilharzia), strongyloidiasis, lariasis, onchocerciasis, Trichinella spiralis,

Toxocara canis, Taenia solium (cysticercosis or pork tapeworm), paragonimi-

asis (Chinese lung uke), and gnathostomiasis.

Fungal antibodytests

See above, but include tests for Aspergillus fumigatus, Aspergillus niger,

Aspergillus nidulans, Aspergillus versicolor, B. dermatidis, Candida albicans,

C.immitis, C.neoformans, H.capsulatum, Mukorazeen.

Note:in the case of CF antibody assays for antibodies to coccidioidomy-

cosis, these are specic and do not require proof of rising levels. They can

provide indispensable conrmatory evidence for a diagnosis of coccidioi-

domycosis as well as an indication of the relative risk of extrapulmonary

dissemination. In a case of chronic meningitis, a +ve CF for anti- coccidioidal

antibodies in the CSF often provides the only denite diagnostic indication

of the need for aggressive antifungal therapy.

Further reading

British Infection Association. Infection resources. M https:// www.britishinfection.org/ guidelines-

resources/ infection- resources/ .

Public Health England (2009). Public health laboratories:general clinical laboratory tests. M https://

www.gov.uk/ guidance/ public- health- laboratories- general- clinical- laboratory- tests.

400

CHAPTER5 Infectious and tropical diseases

400

Antigentests

Antigen measurement is achieved through techniques such as CF and immu-

nodiusion. Avariety of bodily uids can yield diagnostically useful antigens,

including saliva, serum, urine, CSF, and fresh stool. The choice depends

upon the clinical context. Again many of these tests have been replaced

by PCR or, in the case of HIV, combined antigen detection with antibody

responses to improve sensitivity.

Viral antigentests

Include mumps, CMV, inuenza, HIV, hepatitis B and C, RSV, parainuenza

viruses, adenovirus, rotavirus, and varicella- zostervirus.

Bacterial antigentests

Include L.pneumophila (serotype 1)and B.burgdorferi (in urine), β- haemolytic

streptococci, Pneumococcus, C.dicile, H.inuenzae, N.meningitidis, H.pylori,

and C.jejuni.

Helminthic antigentests

Filariasis.

Protozoal antigentests

Include malaria, giardiasis, Trypanosoma cruzi (Chagas’ disease), Pneumocystis

jiroveci (formerly Pneumocystis carinii). Malaria antigen tests form the basis

for the so- called RDTs which are now the mainstay of diagnosis for malaria

in both endemic and non- endemic areas. Two main forms are available;

histidine- rich protein 2 (HRP- 2) is specic for Plasmodium falciparum, whilst

Pf LDH can distinguish between P.falciparum and P.vivax. They are rapid

and almost as sensitive as PCR and critically do not need highly trained

sta to carry out. They are not so reliable for the other species P.ovale,

P.malariae, and P.knowelsi.

Fungal antigentests

Include C.neoformans (CrAg), H.capsulatum, and mannoprotein antigen in

C.albicans.

2 Falci DR, Stadnik CMB, Pasqualotto AC. A review of diagnostic methods for invasive fungal dis-

eases:challenges and perspectives. Infect Dis Ther 2017; 6

:213– 23.

ANTIGENTESTS

401

402

CHAPTER5 Infectious and tropical diseases

402

Collection ofspecimens

Principles ofgood specimen collection

• Good- quality specimen and clinical information produce the most

valuabledata.

•

Optimal time of collection, e.g. take bacterial specimens before

administering antibiotics.

•

Collect the optimal type of specimen wherever possible, e.g. pus is

preferable to a ‘pusswab’.

•

Acquire expertise in specimen collection— ensure minimal

contamination by normal ora (e.g. MSU, use of a tongue depressor for

throat swab collection).

•

Freshness of specimens— rapid transport to the laboratory is essential

(especially for anaerobic organisms and for ‘hot stools’ for parasite

diagnosis).

•

Collect the appropriate number of specimens at the appropriate

intervals, e.g. paired antisera should be taken at least 1– 6 weeks apart if

a diagnostic rising titre is to be demonstrated.

•

Be aware of biological hazards. It is critical to categorize samples with

potential pathogens in them and label appropriately.

•

Biohazard level 1:bacteria and viruses, including Bacillus subtilis, E.coli,

and varicella, as well as some cell cultures and non- infectious bacte-

ria. Precautions against the biohazardous materials are minimal, most

likely involving gloves and some sort of facial protection.

•

Biohazard level 2:bacteria and viruses that cause only mild disease

to humans or are dicult to contract via aerosol in a laboratory

setting such as hepatitis A, B, and C, some inuenza Astrains, Lyme

disease, Salmonella, mumps, measles, scrapie, dengue fever, and HIV.

Routine diagnostic work with clinical specimens can be done safely

at Biosafety level 2 (BSL- 2), using BSL- 2 practices and procedures.

Research work (including co- cultivation, virus replication studies, or

manipulations involving concentrated virus) can be done in a BSL- 2

(P2) facility, using BSL- 3 practices and procedures.

•

Biohazard level 3:bacteria and viruses that can cause severe or fatal

disease in humans, but for which vaccines or other treatments exist

such as anthrax, West Nile virus, Venezuelan equine encephalitis,

SARS virus, MERS- Co, hantaviruses, TB, typhus, Rift Valley fever,

Rocky Mountain spotted fever, yellow fever, and malaria. The para-

sites P.falciparum, which causes malaria, and T.cruzi, which causes

trypanosomiasis, also come under thislevel.

•

Biohazard level 4:viruses and bacteria that cause severe to fatal

disease in humans and for which vaccines or other treatments are

not available such as Bolivian and Argentine haemorrhagic fevers,

Marburg virus, Ebola virus, Lassa fever virus, Crimean– Congo

haemorrhagic fever, and other haemorrhagic diseases. Variola virus

(smallpox) is an agent that is worked with at BSL- 4, despite the

existence of a vaccine, as it has been eradicated. When dealing with

biological hazards at this level, the use of a +ve pressure personnel

suit, with segregated air supply, is mandatory. The entrance and exit

COLLECTION OF SPECIMENS

403

of a Level 4 biolab will contain multiple showers, a vacuum room, a

UV light room, an autonomous detection system, and other safety

precautions designed to destroy all traces of the biohazard. Multiple

airlocks are employed and are electronically secured to prevent both

doors from opening at the same time. All air and water services

going to and coming from a BSL- 4 (P4) laboratory will undergo

similar decontamination procedures to eliminate the possibility of an

accidental release.

Surface specimens include

• Anal/ anorectal:e.g. gonococcus (N.gonorrhoeae).

•

Cervical swab:e.g. HSV, gonococcus, human papillomavirus(HPV).

• Ear swab:e.g. otitis externa, otitis media, bacterial and fungal infections.

•

Foreign bodies:almost always infected if causing trouble! (Includes

iatrogenic foreign bodies such as arthroplasties, cardiac valves,

pacemakers, ventriculo- peritoneal shunts, etc.) Foreign bodies in the ear,

nose, or vagina can lead to prolonged (and often unpleasant) discharges.

•

Genital ulcers:dark ground microscopy for syphilis organisms. Also

chancroid, Entamoeba histolytica.

•

Indwelling catheters:include urinary catheters, IV cannulae, Portacaths,

etc. If a catheter is thought to be the source of an infection, cultures

should be performed, and if the catheter or cannula is removed, this can

be sent for culture. Urinary catheters are always colonized by bacteria.

Intravascular foreign bodies such as central venous catheters and

prosthetic heart valves are often aected by bacteria which are normally

non- virulent such as coagulase −ve staphylococci.

• Laryngeal swab:can be useful forTB.

•

Nasal, pharyngeal, gingival, and throat:e.g. meningococcus, S.aureus

carriage, streptococcal infections, pertussis, adenovirus. NPAs are

useful for diagnosing upper respiratory tract infections (URTIs) such as

inuenza and RSV through DIF tests and, more commonly now, PCR. In

lepromatous leprosy, a swab from the anterior nares may reveal acid-

fast bacilli indicative of this infection.

•

Ophthalmic:e.g. bacterial conjunctivitis, adenovirus, rabies (from corneal

impressions.

For trachoma, PCR, direct uorescein- labelled monoclonal

antibody (DFA), and EIA of conjunctival smears are useful.

• Skin:

•

Abscess— culture for bacteria and other unusual organisms.

•

Dermal scrapings, nail clippings— fungal infections (tinea— includes

pedis, capitis, cruris, versicolor forms).

•

Petechial rash scrapings— meningococcus (occasionally gonococcus).

• Throat:e.g. C.albicans, diphtheria, gonococcus, croup organisms.

•

Urethral:e.g. Chlamydia, gonococcus.

•

Vagina (high vaginal swab):e.g. S.aureus in toxic shock syndrome

(including toxin testing), Gardnerella, gonococcus.

3 Zaidman GW, Billingsley A. Corneal impression test for the diagnosis of acute rabies encephalitis.

Ophthalmology 1998; 105:249– 51.

4 Rostami S (2016). Trachoma. M http:// www.emedicine.com/ OPH/ topic118.htm.

404

CHAPTER5 Infectious and tropical diseases

404

Normally sterile uids include

• Amniotic uid:bacterial infection can cause premature delivery, and

rDNA was detected by PCR (E Molecular diagnostics, pp. 406–7) in

samples from 15 (94%) of 16 patients with +ve amniotic uid cultures.

Hydrops fetalis can be caused by congenital infections (e.g. CMV,

parvovirus B19, toxoplasmosis, syphilis, and Chagas’ disease), and

making a diagnosis may involve analysis of amniotic uid with cultures,

PCR,etc.

• Ascites:consider TB (consider laparoscopy for biopsying peritoneal

lesions for culture as well as histology; E Gastrointestinal tract

investigations, pp. 412–13).

•

Blood:multiple samplings at separate times from separate body sites

may need to be taken, e.g. in endocarditis. For some organisms and

pathologies, an extended period of culture may be needed.

•

CSF:possibilities include, e.g. meningococcus, pneumococcus,

L.monocytogenes, TB, fungi (e.g. C.neoformans), and viruses (E Tissue

biopsy and deep aspiration specimens, pp. 418–21).

•

Ejaculate (semen):if the semen contains a high number of leucocytes,

this may be an indication of either infection or inammation. WBCs

are considered signicant if >1million found in each mL of ejaculate.

Sexually transmitted diseases (STDs), e.g. gonorrhoea, or urea,

plasma, and prostate infections come into the dierential diagnosis.

S.haematobium (bilharzia) may cause haemospermia and be found

in ejaculate.

Acute mumps orchitis can be associated with loss of

spermatozoa.

•

Ocular uids (intra- ):include aqueous humour and vitreous humour.

Bacterial, fungal, and parasitic problems can aect the interior of

theeye.

•

Pericardial uid:the commonest organisms will include staphylococci,

streptococci, pneumococci, H.inuenzae, meningococci, andTB.

•

Pleural uid:numerous pathologies, including underlying bacterial

pneumonia, tuberculous pleurisy, parasitic infections (such as

strongyloidiasis), and fungal diseases (such as histoplasmosis). Biopsy

of the pleura under direct visualization by video- assisted thoracoscopy

(VATS) may give a better diagnosticyield.

•

Synovial uid (joint aspirate):bacterial infections can be very destructive

and the options are legion. Staphylococcal disease is the commonest,

but TB must always be borne in mind. Viral arthritides are usually self-

limiting, and treatment is supportive.

•

Urine:standard culture and sensitivity, e.g. MSU specimen, catheter

specimen of urine (CSU)— useful for diagnosing cystitis, pyelonephritis,

prostatitis, etc. (prostatic massage may be helpful for improving

diagnosis of prostatic infections); ‘early morning urine’ (EMU) for TB,

and a terminal specimen for S.haematobium (bilharzia) best collected

around midday.

5 Hitti J, Riley DE, Krohn MA, etal. Broad- spectrum bacterial rDNA polymerase chain reaction

assay for detecting amniotic uid infection among women in premature labor. Clin Infect Dis 1997;

:1228– 32.

6 Torresi J, Yung A. Usefulness of semen microscopy in the diagnosis of a dicult case of Schistosoma

haematobium infection in a returned traveler. J Travel Med 1997; 4

:46– 7.

COLLECTION OF SPECIMENS

405

Normally infected uids include

• Pus:e.g. abscess contents, wound swab/ aspirates, drainage swabs.

Usually bacterial (consider both aerobic and anaerobic), but amoebic

and hydatid options need to be considered when the lesion is in

theliver.

•

Saliva:normally contains a wide range of commensal ora. Cannulation

of a parotid gland duct may yield a specic pathogen that is causing a

problem in thatgland.

•

Sputum:includes tracheal aspirate, induced sputum (obtained with

physiotherapy assistance), and bronchoalveolar lavage (BAL), which

may be needed in sicker patients unable to produce sputum or in

conditions where copious sputum production may not be a feature

(such as P.jiroveci

pneumonia (PCP) in HIV infection). C&S assists with

identifying a vast range of organisms, including and especially TB (always

ally sputum culture to direct microscopy).

•

Stool:vast range of uses (E Gastrointestinal tract investigations,

pp. 412–13). Includes direct microscopy for parasites, ova, and cysts,

i.e. giardia and ascariasis, culture for Salmonella, Campylobacter, Shigella,

E.coli 0157, typhoid and paratyphoid, Plesiomonas shigelloides, and

enteroviruses, and antigen detection of rotavirus. ‘Hot stools’ (from

patient to the microbiology bench in <1h) may be helpful for amoebae,

strongyloides larvae,etc.

Further reading

Health and Safety Executive. Biological agents:managing the risks in laboratories and healthcare premises.

http:// www.hse.gov.uk/ biosafety/ biologagents.pdf.

406

CHAPTER5 Infectious and tropical diseases

406

Molecular diagnostics

These tests are now the mainstay of mainstream clinical practice. HIV viral

load and antiretroviral drug resistance are considered routine tests, whilst

examination of the CSF for JC virus DNA by PCR is the method of choice

for the diagnosis of progressive multifocal leukoencephalopathy (PMLE).

Genetic testing for the rifampicin resistance mutation in RPO provides a

rapid indication of MDR- TB, e.g. Cephid GeneExpert. (See Fig. 5.8 for the

immunological prole of HIV disease.)

The areas ofgreatest value include

• Detection and quantication of viruses to monitor and guide therapy,

e.g. HCV, HIV, HBV,CMV.

•

Detection of slow- growing organisms, e.g. TB, atypical mycobacteria.

• Diagnosis of pathogens, which are potentially too dangerous for the

laboratory sta to handle, e.g. VHF, smallpox, avian/ swineu.

• Detection of organisms killed by antibiotics prior to culture samples

being taken, e.g. meningococcal sepsis.

•

Detection of organisms that cannot be cultured, e.g.HCV.

• Detection of unusual diseases, e.g. helminthic diseases,fungi.

• Detection of toxins elaborated in small quantities by bacteria, e.g. toxic

shock syndrome toxins.

•

Detection of mutations manifesting resistance to antimicrobial agents

(genotypic resistance testing), e.g. HIV, CMV,TB.

•

Elucidation of pathogens that are as yet ‘undiscovered’, e.g. 16s

ribosome testing.

01 23 45678

HIV viral load

CD4+ cell count

Anti-HIV antibody

HIV viral load

Anti-HIV antibod

CD4+ cell count

Years

‘Window period’

Symptoms likely to be present

Exposure

Fig.5.8 The immunological prole of HIV disease.

MOLECULAR DIAGNOSTICS

407

Available molecular techniques include

• PCR:this test uses probes to look for the presence of the genes of

infecting organisms (E

Polymerase chain reaction amplication of

DNA, pp. 324–6).

There are numerous PCR tests available, and it is particularly valuable for

hepatitis C (including for genotyping), HIV, and TB. Auniversal eubacterial

PCR (for genus and species identication of prokaryotes) and a universal

fungal PCR (genus and species identication of fungi) are available. HBV

DNA quantication is accomplished throughPCR.

Choosing an appropriate sample for the application of PCR testing is

important (e.g. biopsy of possible Kaposi’s sarcoma lesion and Kaposi’s

sarcoma- associated herpesvirus (KSHV) (human herpesvirus (HHV)- 8);

BAL uid and PCP; small bowel biopsy and Whipple’s disease; CSF and

meningococcal disease, HSV, or M.tuberculosis). Note:uid samples for PCR

usually have a higher yield when not spun in a centrifuge.

•

LCR (ligase chain reaction):works through specic probe amplication

through the use of DNA ligase. Greatest value in Chlamydia infection.

•

Transcription- mediated amplication (TMA):uses an isothermal

amplication system. Amplied telomerase products are rna,

detected using a non- isotopic hybridization protection (HPA) system.

Identication of HCV, TB, gonococcus, and Chlamydia are among its

potentialuses.

•

Branched- chain DNA (bDNA):a signal amplication methodology able to

quantify HIV RNA levels.

• Nucleic acid sequence- based amplication (NASBA):a quantitative test for

HIV RNA; also of value withCMV.

• Hybridization with nucleic acid probes:detects specic ribosomal RNA

and is most widely used for culture conrmation of an organism (e.g.

fungi, mycobacteria).

•

Sequencing:organisms are identied by direct sequencing of amplied

gene fragments. Has been applied to TB, H.pylori, enteroviruses, and

HIV (for assessing drug resistance). Whole genome sequencing (next-

generation sequencing) is moving forward rapidly but brings with it the

problems of bioinformatics and ‘bigdata’.

•

Restriction fragment length polymorphisms (RFLPs):restriction enzymes are

used to cut up DNA into pieces, and the fragments are then subjected

to gel electrophoresis (such as Southern blotting; E Southern blotting,

pp. 322–3). The patterns produced can be used to identify organisms.

Further reading

Shanson DC. Microbiology and Clinical Practice, 3rd edn. Oxford:Butterworth- Heinemann,1999.

408

CHAPTER5 Infectious and tropical diseases

408

Haematology

Many infectious diseases manifest haematological changes that are diagnosti-

cally valuable.

Bloodlm

Blood smear examination provides general data on the size and appearance of

cells, as well as data on particular cell segments, whilst pathogens may be seen,

e.g. malaria, African trypanosomiasis, Chagas’ disease, babesiosis, borreliosis,

bartonellosis, ehrlichiosis, laria (time of day the blood is taken may be signi-

cant in this condition), haemolysis, and evidence of hyposplenism. Thick and

thin blood lms should be considered, especially where malaria is concerned;

at least three blood lms, each taken 24h apart, should be performed. Blood

lms are also useful in assessing if a patient hasDIC.

Bone marrow examination

Culture (for, e.g. TB, brucellosis, Mycobacterium avium intracellulare,

typhoid/ paratyphoid, CMV), microscopy (for, e.g. leishmaniasis), and

establishing cell line integrity (e.g. WBC abnormalities). An aspirate is gen-

erally useful for culture purposes and for establishing what cells are present

in the marrow, but a trephine is needed if structural information is needed

(e.g. to establish if granulomata suggestive of TB are present).

Coagulation studies, brin degradation products, D- dimers

Useful where DIC is suspected. DIC is a common association of severe sep-

sis (especially meningococcal disease). Coagulation abnormalities are also

present in conditions such as VHF, P.falciparum malaria, rickettsial diseases,

etc. D- dimers may assist with the diagnosis of thrombosis but are generally

raised in infection.

Cold agglutinins

A haemagglutination- based test. Can be caused by M. pneumoniae (most

commonly), inuenza A, inuenza B, parainuenza, and adenoviruses.

Dierential white cell count in peripheral blood. Useful associations

include:

•

Eosinophilia and parasite infection.

• Neutrophilia and bacterial sepsis.

• Neutropenia and atypical pneumonias.

• Atypical lymphocytes andEBV.

• Neutropenia and pyrexia.

Erythrocyte sedimentationrate

Together with CRP (E Biochemical tests, pp. 416–17), the rate of eryth-

rocyte sedimentation is sensitive to the extent of a body’s response to a

lesion or disease. The ESR is important for pointing to the possible exist-

ence of an organic disease, but a normal result does not exclude the pres-

ence of disease. Ai

ESR points to the need for additional investigations

and, if d, is very useful in monitoring the course of a disease. Procalcitonin

(PCT) may eventually prove to have even greater value in a similarrole.

7 Meisner M, Tschaikowsky K, Palmaers T, Schmidt J. Comparison of procalcitonin (PCT) and C- reactive

protein (CRP) plasma concentrations at dierent SOFA scores during the course of sepsis and MODS. Crit

Care 1999; 3

:45– 50. M http:// www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=29013.

HAEMATOLOGY

409

Ferritinlevels

d in iron deciency, e.g. associated with hookworm infestation of the bowel

(Ancylostoma duodenale, Necator americanus) or H.pylori

- associated gastritis.

Ferritin levels are often extremely high in Still’s disease, an important non-

infective cause of pyrexia and neutrophilia. It is also markedly raised in hae-

mophagocytic lymphohistiocytosis syndrome (HLH). Serum iron and TIBC

may be helpful in a fuller evaluation (E Biochemical tests, pp. 416–17).

Glucose- 6- phosphate dehydrogenase

Useful in therapy of benign malarias, e.g. P.vivax and P.ovale (a deciency

will cause severe haemolysis when primaquine is used to kill the hypnozoite

phase to prevent relapse).

Hb concentration and red cell parameters (especially mean

cell volume)

Useful in, e.g. anaemia of chronic infection, haemolysis, iron deciency

(microcytosis) associated with hookworm infestation of the bowel or

H.pylori- associated gastritis, macrocytosis due to vitamin B

deciency with

Diphyllobothrium latum (sh tapeworm) infestation.

Hb electrophoresis

Can detect haematological conditions such as thalassaemia, sickle- cell dis-

ease, etc. These can predispose to certain infections via hyposplenism such

as salmonellosis and melioidosis.

Haemolysis screen (including reticulocytecount)

May be abnormal in, e.g. malaria, DIC, EBV, VHF, E.coli 0157 gastroenteritis

due to HUS, rickettsial infections, dengue, and gas gangrene. Hp levels can

be useful (E Biochemical tests, pp. 416–17), since they are generally d/

absent in haemolysis.

Monospot test (Paul Bunnelltest)

Diagnostic of EBV infection.

Sicklingtest

Uncovers sickle- cell disease, known to be associated with Salmonella osteo-

myelitis, chronic leg ulcers,etc.

Thrombocytopenia

Characteristic in some conditions, e.g. HIV disease, P. falciparum malaria,

and dengue.

Vitamin B

level

d in D.latum infestation, TB of the terminal ileum,etc.

410

CHAPTER5 Infectious and tropical diseases

410

Radiology

PlainX- rays

• Chest:the potential diagnoses are legion, including pneumonia, TB,

pleural eusion/ empyema, bronchiectasis, PCP, tropical eosinophilia

and other parasite- related diseases (e.g. paragonimiasis), occupational

risks for infections (e.g. silicosis and TB), and post- varicella calcication.

Also useful to exclude non- infectious causes of fever such as cancer or

sarcoidosis.

•

Plain abdominal X- ray:e.g. bowel dilatation and perforation, calcication

of adrenal glands and lymph nodes (e.g. TB, histoplasmosis), ‘babies

head’ sign of schistosomal bladder calcication.

•

Dental radiography (orthopantomogram):occult dental sepsis.

•

Elsewhere:e.g. limbs for osteomyelitis, skeletal muscles for calcied

cysticercosis lesions, joints for Charcot changes (such as in syphilis).

More sophisticated imaging

Endoscopic retrograde cholangiopancreatography

Using contrast medium and radiographs to dene the anatomy of the bil-

iary tree and pancreatic duct. Useful for HIV- associated biliary tree disease

(including porta hepatis nodal lymphoma), parasites (e.g. Clonorchis sinensis,

Ascaris lumbricoides), and pancreatic disease suchasTB.

Intravenous urogram

Denes renal anatomy. Renal infection, such as pyelonephritis, renal calculi,

malignancy, or anatomical abnormalities (including congenital) leading to

recurrent infections. Computed tomography intravenous pyelography (CT-

IVP) is generally considered superiornow.

Magnetic resonance imaging

Including with contrast enhancement using gadolinium.

•

Cranial:vCJD (exhibits bilateral pulvinar high signal), encephalitis, rabies,

sagittal sinus thrombosis, PMLE. MRI is also more sensitive than CT

when looking for infective SOLs such as tuberculoma, especially in and

around the cerebellum.

•

Bones:essential for the diagnosis of osteomyelitis.

•

Spinal cord:essential for diagnosis of spinal infections and myelitis.

•

Elsewhere in the body:dening solid lesions, uid- lled lesions,etc.

• Magnetic resonance cholangiopancreatography (MRCP):non- invasively

denes the hepatopancreatic biliary tree anatomy.

•

New techniques:e.g. as cardiac MRI imaging, show great promise in the

diagnosis of valvular disease.

Computed tomography

Including with contrast enhancement.

•

Cranial:e.g. brain abscess, paranasal sinus disease, middle ear disease,

orbital sepsis, cysticercosis, mastoid aircells.

•

Chest:e.g. cardiac lesions (possibly with associated endocarditis risk),

mediastinum (e.g. lymphadenopathy, including retrosternal), lung lesions

such as bronchiectasis, lung abscess, other non- infectious pathologies.

RADIOLOGY

411

• Abdomen:delineates intra- abdominal abscesses and abnormalities in

retroperitoneal and mesenteric lymph nodes, defects in the spleen, liver,

kidneys, adrenals, pancreas, and pelvis.

•

CT- IVP:powerful tool for dening the anatomy of the urinarytract.

•

Multislice CTPA:e.g. for dening PEs as a cause ofPUO.

• CT- guided biopsy:to specically pick out an area for sampling, e.g. liver

lesion, lymph node, mediastinalmass.

•

CT colonoscopy:helpful in diagnosing colonic disease, especially in

older patients unable to undergo invasive testing (e.g. when looking

for an associated colonic tumour in a patient with Streptococcus bovis

endocarditis).

Ultrasound

•

Abdomen:evidence of pancreatic, liver, renal, and biliary tree/ gall

bladder abnormalities (e.g. abscess, hepatic cyst, presence or absence of

spleen, ascites, gallstones,etc.).

•

Thoracic:pleural eusion, empyema (can assist with drainage).

•

Echocardiography:to help exclude cardiac vegetations of endocarditis,

TB pericarditis (with eusion), myocarditis. Note

:both TTE and TOE

approaches are available, each yielding data of diering value in dierent

situations.

•

Doppler studies of blood vessels:to exclude DVT such as in thelegs.

•

Guided biopsy:to specically pick out an area for sampling, e.g. liver

lesion, lymphnode.

•

Drainage:to specically pick out an area for draining, e.g. liver abscess,

pleural eusion.

Radionuclide scanning

•

Has limited value but can localize area of inammation for biopsy.

• Indium (

111

In)- labelled granulocyte scan:may help localize many infectious

or inammatory processes (i.e. deep sepsis).

•

99m

Technetium bone scan:bone and joint sepsis.

•

V/ Q scan:to exclude PE as a cause of PUO, to delineate consolidation,

abscess, bronchiectasis,etc.

Positron emission tomography- computed tomography (PET- CT)

Enormous potential for locating localized infective processes, especially in

the brain. Increasingly used in oncology and can be helpful inPUO.

These techniques are all described in detail in E Chapter13.

412

CHAPTER5 Infectious and tropical diseases

412

Gastrointestinal tract investigations

Biopsy- based

• Duodenal biopsy (Crosby capsule and endoscopic methods ± EM): e.g.

Whipple’s disease, giardiasis, cryptosporidium, strongyloidiasis.

•

Gastric biopsy:H.pylori.

•

Laparoscopy:useful to exclude TB and other infections in the presence

of ascites (biopsies should be sent for histology and C&S; peritoneal

biopsies have a higher yield than ascitic uid).

•

Liver biopsy:E Tissue biopsy and deep aspiration specimens, pp. 418–21.

•

Oesophageal biopsy:e.g. candidiasis, CMV (e.g. in advanced HIV disease).

•

Sigmoidoscopy and bowel biopsy:e.g. amoebiasis, pseudomembranous

colitis (C.dicile infections), exclusion of microscopic colitis andIBD.

Gastrointestinal contents- based

• These are rarely performed now, as endoscopic sampling is standard.

• Baermann concentration technique:the method of choice for the

detection of Strongyloides stercoralis.

•

Capsule endoscopy:involving the swallowing of a pill- sized capsule

containing digital video recording equipment, which broadcasts to

a receiver outside of the body. Enormous potential for diagnosing

pathology within the GIT, including small bowel infective processes such

asTB.

• Duodenal aspirate:e.g. giardiasis, cryptosporidium, strongyloidiasis.

•

Enterotest (string test):e.g. giardiasis, cryptosporidium, strongyloidiasis.

•

Hot stools:little evidence that they need to be hot! (E Culture techniques,

pp. 390–5.)

•

Stool C&S (E Culture techniques, pp. 390–5).

•

Stool microscopy:for ova, cysts, parasites (e.g. amoebae, helminths such

as A.lumbricoides).

•

Stool EM:good for viruses, e.g. rotavirus and norovirus, but rarelydone.

•

Stool chromatography:C.dicile toxin, a specic C.dicile toxin Aand B

EIA and PCR areused.

• Sellotape

(adhesive) strip test:for the threadworm Enterobius

verminformis. To perform this test, roll some clear adhesive tape around

four ngers of a hand, sticky side out, whilst an assistant spreads the

buttocks. In good lighting, identify the involved perianal area, and apply

the tape 1– 2 times to the aected perianal area. Place the tape on a

slide with the clean side downwards, trim the tape, label the slide, and

send to the laboratory.

•

Toxin tests:most widely used for C.dicile toxins Aand/ or B; the

denite diagnosis of botulism food poisoning is the examination of

faeces for Clostridium botulinum

and toxin (EMG is also helpful). In

wound botulism (e.g. in drug injectors), the organism may grow in

material taken directly from the wound(s); also used for E.coli0157.

8 Lee WK, Van Tonder F, Tartaglia CJ, etal. CT appearances of abdominal tuberculosis. Clin Radiol

2012; 67

:596– 604.

GASTROINTESTINAL TRACT INVESTIGATIONS

413

Gastrointestinal tract function

• D- xylose absorption test:for malabsorption syndromes such as Whipple’s

disease and tropicalsprue.

•

C breath test:for detection of H.pylori.

• Faecal elastase:for diagnosis of pancreatic exocrine insuciency in

conditions suchasHIV

•

Vitamin levels:diagnosis of fat- soluble vitamin malabsorption in

pancreatic or small bowel disease or of B

levels in terminal ileal

problems such as withTB.

9 Di Rienzo TA, D'Angelo G, Ojetti V, etal. 13C- urea breath test for the diagnosis of Helicobacter

pylori infection. Eur Rev Med Pharmacol Sci 2013; 17

Suppl 2:51– 8.

414

CHAPTER5 Infectious and tropical diseases

414

Immunology

Cutaneous hypersensitivity tests are discussed elsewhere (E Other tests,

pp. 422–3).

•

Complement (especially ‘terminal’ complements C5– C9):deciencies can

lead to recurrent meningococcal sepsis, pneumococcal disease,etc.

•

Cytokine studies:currently experimental, but levels of interferon can

sometimes be helpful.

•

Dierential white cell count (E Haematology, pp. 408–9):neutropenia

and lymphopenia are associated with bacterial sepsis.

•

Igs:deciencies lead to recurrent infections (some cases may be

hereditary, and family history is important). Levels may also be higher—

IgM tends to be markedly i in brucellosis, malaria, trypanosomiasis, and

toxoplasmosis.

•

Splenic dysfunction:indicated by a history of surgical removal (not

always clear!) or a condition associated with hyposplenism (e.g. coeliac

disease/ dermatitis herpetiformis, sickle- cell disease), an abnormal blood

lm, and an absent spleen on abdominal imaging. This state may be

associated with recurrent meningococcal infection and life- threatening

pneumococcal sepsis. Once diagnosed, the patient will need appropriate

vaccinations and advised to always carry a warning card and/ or wear a

MedicAlert

bracelet or similar.

•

T- cell subsets:the absolute CD4+ (T4) cell count and the CD4+/ CD8+

(T4/ T8) cell ratio is of value. HIV disease, TB, and sarcoidosis are

associated with reduced CD4+ cell levels, HIV with a reversed CD4+/

CD8+ cellratio.

•

Human pharmacogenomics:

•

HLA typing— HLA B5701 is associated with hypersensitivity (some-

times fatal) to the antiretroviral drug abacavir, and so patients should

be tested before prescribing thisdrug.

•

IL- 28R polymorphisms— these can be associated with treatment failure

in hepatitis C infection.

IMMUNOLOGY

415

416

CHAPTER5 Infectious and tropical diseases

416

Biochemicaltests

A number of biochemical tests are useful in the diagnosis and assessment of

a range of infectious illnesses.

•

AFP:i in hepatocellular carcinoma (associated with HCV and HBV).

Note

:much higher AFP than in other causes of hepatocellular damage.

• ABGs:assessment of sepsis, assessment of pneumonia.

•

Ca- 125:i false +ve in peritonealTB.

•

CRP: together with the ESR, a valuable method for monitoring infections.

CRP is an acute phase reactant, i in bacterial infections and d in viral

infections. PCT may be ofvalue.

• Creatinine phosphokinase (CPK) level:i in L.pneumophila infection.

Also

i with zidovudine (AZT) usage in HIV disease.

•

Glucose metabolism:DM is a common association of infection,

particularly TB. Consider performing a fasting glucose level, an OGTT,

or checking HbA

levels.

•

Hp levels:part of the haemolysis screen (E Haematology, pp. 408–9).

Iron levels (serum iron), TIBC:iron d (TIBC i) in iron deciency, e.g.

associated with hookworm infestation of the bowel (A.duodenale,

N.americanus) or H.pylori

- associated gastritis. Serum ferritin may be

helpful.

•

Lactate levels:may be i in HIV- associated mitochondrial toxicity

syndrome. Also high in severe sepsis syndrome.

•

Lipid abnormalities (cholesterol, TGs):HIV drug toxicity.

•

LFTs:abnormalities are present in many conditions, e.g. hepatitis,

leptospirosis, yellow fever, antimicrobial drug toxicity (e.g. inTB).

•

ALP:in the serum of healthy adults, ALP mostly originates from the

liver. Biliary obstruction, often associated with sepsis, leads to an i in

serum concentration ofALP.

•

Bilirubin:determination of bilirubin levels (conjugated and unconju-

gated) is important in the dierential diagnosis of jaundice.

•

γGT:i in serum concentration of γGT is the most sensitive indicator

of liver damage.

•

Pancreatic amylase level:i with pancreatitis in, e.g. mumps (consider

also salivary amylase), toxicity with antiretroviral drugs (e.g. didanosine

orDDI).

•

Pleural uid analysis:analysis for LDH levels is useful (as well as albumin,

total protein, and amylase). An exudate, which implies infection in

the dierential diagnosis, is dened by at least one of the following

criteria:pleural uid/ serum total protein ratio >0.5, pleural uid/ serum

LDH ratio >0.6, or pleural uid LDH > two- thirds the upper limits of

normal of serumLDH.

•

Pregnancy test:some infections, e.g. varicella, genital herpes (simplex),

and TB, are often more serious in pregnancy. The use of some

antibiotics, e.g. ciprooxacin and tetracyclines, is relatively contra-

indicated in pregnancy. There is the potential to prevent vertical

transmission of HIV if diagnosed prior to delivery.

BIOCHEMICALTESTS

417

• PCT:shows promise for detecting and following ‘inammation induced

by microbial infections’.

• Serum Na

levels:hyponatraemia associated with legionnaires’ disease

but may also be related to intracranial sepsis or hypocortisolaemia.

•

Synacthen

test:TB and histoplasmosis can damage the adrenal glands,

leading to an Addisonian state (hypocortisolaemia).

•

Vitamin D levels:if decient, may predispose to TB and may lead to

diculties with treating TB infections due to hypocalcaemia (consider

checking levels in patients with darkly pigmented skins, especially those

with a culture of wearing clothing over most of their body surface).

Deciency may be exacerbated by some anti- infective drugs, notably

rifampicin and antiretrovirals.

10 Meisner M, Tschaikowsky K, Palmaers T, Schmidt J. Comparison of procalcitonin (PCT) and

C- reactive protein (CRP) plasma concentrations at dierent SOFA scores during the course of

sepsis and MODS. Crit Care 1999; 3:45– 50. M http:// www.pubmedcentral.nih.gov/ articlerender.

fcgi?artid=29013.

Kociuba KR, Buist M, Munro R, Lee A, Cleland B. Legionnaires’ disease outbreak in south western

Sydney, 1992. Clinical aspects. Med J Aust 1994; 160:274– 7.

418

CHAPTER5 Infectious and tropical diseases

418

Tissue biopsy and deep aspiration

specimens

Whatever part of the anatomy from which they are taken, biopsy speci-

mens should be evaluated both histopathologically (with specialized stains

used, wherever appropriate) and by culture for bacteria, mycobacteria,

fungi, viruses, and prions (using specialized culture techniques, where

appropriate).

Bone marrowbiopsy

(E Haematology, pp. 408–9)

Important for TB, brucellosis, Mycobacterium avium intracellulare

typhoid/

paratyphoid, leishmaniasis.

Cerebrospinaluid

Whilst the main objective of an LP is usually to obtain uid for microscopy

and C&S, there are other useful tests that can be performed. The opening

pressure should be between 10 and 20cmH

O— infective and other pro-

cesses may alter this. Whilst the usual approach to obtaining CSF is through

an LP, if the pressure is high, a cisternal puncture can be performed instead

(normally the advice and help of a neurosurgeon would need to be sought).

In neonates, foramenal puncture is a possibility. ACT scan is usually per-

formed beforehand to assess the risk of ‘coning’, although it is by no means

a guarantee.

Along with the Gram staining process and microscopy, other tests to con-

sider include a complete blood cell count and dierential measurement of

glucose and protein levels, ZN staining for TB, and bacterial, mycobacterial,

viral, and fungal cultures. On occasions, other tests that might be consid-

ered include:

•

Wet mount (for amoebae such as Acanthamoeba; E Culture

techniques, pp. 390–5).

•

PCR for HSV, herpes varicella- zoster, enteroviruses, TB, JC virus, and

cryptococcosis (E Molecular diagnostics, pp. 406–7).

•

Antibodies to specic pathogens (e.g. arboviruses; E Serology,

pp. 396–9).

•

India ink capsule stain (for cryptococcosis).

• CrAg (E Serology, pp. 396–9).

•

VDRL, etc. for syphilis (E Serology, pp. 396–9).

•

14- 3- 3 protein— specic protein marker present in the CSF of patients

withvCJD.

•

Xanthochromia to help exclude SAH also seen in leptospirosis.

• Cytology to help exclude carcinomatous meningitis.

• Assessing comparative CSF protein– cellular levels if GBS (recognized

association of infections such as Campylobacter gastroenteritis) is being

considered.

Liverbiopsy

Indications are numerous and include assessment of viral hepatitis (espe-

cially HBV and HCV, including possible cirrhosis and/ or hepatocellu-

lar carcinoma), assessment of PUO (including TB and lymphoma), and

TISSUE BIOPSY AND DEEP ASPIRATION SPECIMENS

419

determining if the patient has a medication- induced liver disease. Only on

<1% of occasions does the liver biopsy overestimate the amount of hepatic

damage. Fibroscan is increasingly used in conjunction with blood tests to

non- invasively score liver damage, but it is not as accurate as the biopsy.

The biopsy is commonly preceded by an USS examination of the liver to

determine the best and safest biopsy site. Usually, the biopsy is conducted

under ultrasonic guidance to avoid major blood vessels. Coagulation status

should be optimized at the time of biopsying, including by the administration

of clotting factors.

The risks ofthe traditional liver biopsy (not performed underultrasound

guidance) include

•

Pain (1 in 5 patients).

• Haemorrhage (1 in 500 patients).

• Bleeding requiring transfusion or surgery (1 in 1000 patients).

• Pneumothorax and/ or puncture of the gall bladder, kidney, or bowel

(1 in 1000 patients).

•

Death (1 in 5000 patients).

Equivalent gures are not available for USS- guided liver biopsy, but the

technique is well established. Liver biopsy material should be subjected to

microbiological culture, as well as to histological assessment.

Lymph node sampling

The likely pathologies depend upon whether or not lymphadenopathy is

regional or generalized, and upon thesite.

•

Biopsy:for histology and culture, especially for TB, for tropical infections

such as chancroid, and for other relevant infections such as cat- scratch

fever (B.henselae). If regional, the dierential diagnosis varies with the

site; if intra- abdominal, for example, TB, Y.enterocolitica, and adenovirus

should be considered.

•

FNA:useful as full biopsy for culture purposes, but no structural

information available (similar to the aspirate vs trephine issue in BM

sampling), therefore dicult to exclude lymphoma from dierential.

Respiratory samples

Sputumtests

•

Microscopy:can perform direct microscopy (e.g. for Aspergillus species,

eggs of paragonimiasis), Gram stain, ZN, PCP (silver staining needed).

• Induced sputum:e.g. for TB, PCP, Aspergillus.

•

Tracheal aspirate:used in ill individuals. May produce similar material.

Bronchoscopy

•

BAL:useful for TB and other mycobacteria, PCP, fungi, melioidosis,

resistant bacteria (e.g. Pseudomonas), RSV, and paragonimiasis.

•

Lung biopsy:useful for TB and other mycobacteria, PCP (needs silver

staining, immunouorescence test (IFT), or PCR), fungi, melioidosis,

resistant bacteria (e.g. Pseudomonas), RSV, and paragonimiasis. Also for

exclusion of non- infective causes of non- resolving pneumonia.

Open lungbiopsy

When not feasible to obtain intrathoracic tissue by less invasivemeans.

420

CHAPTER5 Infectious and tropical diseases

420

Pleural disease:eusion, empyema,biopsy

Consider, e.g. TB, pneumococcal sepsis, underlying neoplasm (and rarer

conditions like strongyloidiasis). Biochemical analysis of pleural uid can

help (E Biochemical tests, pp. 416–17). An empyema will have white cell

count, protein, pH, LDH changes compatible with an exudate, and possibly

organisms visible and/ or culturable within the uid. Apleural biopsy can be

obtained blindly with an Abraham’s needle, but in recent times pleuroscopy

and VATS has developed into a better option.

Skinbiopsy

Biopsy and hair sampling

•

Useful for, e.g. TB, Kaposi’s sarcoma (caused by HHV- 8 and associated

with HIV), onchocerciasis, the aetiology of warts (common viral warts

vs molluscum contagiosum— the distinction can be important in view of

the therapeutic options and the potential for malignant change in some

sites such as the ♀ cervix).

•

The identication of pathogenic arthropod parasites, e.g. myiasis

(the invasion and feeding on living tissues of humans or animals by

dipterous larvae such as that of the tumbu y), scabies, lice, ticks, and

chigger eas, depends on the oending agent being seen and correctly

recognized or the appropriate specimen (e.g. excision biopsy) being

taken and examined histologically.

Skinsnips

•

Filarial infestations:examination of skin snips will identify microlariae

of Onchocerca volvulus and Mansonella streptocerca. Skin snips can be

obtained using a corneal– scleral punch, or more simply a scalpel and

needle. The sample must be allowed to incubate for 30min to 2h

in saline or culture medium, and then examined microscopically for

microlariae that would have migrated from the tissue to the liquid

phase of the specimen. In onchocerciasis, nodulectomy is also of value,

as is examination of the eye with a slitlamp.

•

Leprosy:acid- fast bacilli are present in theskin.

Other tissues and collections are numerous and include

•

Bone infection/ abscess/ osteomyelitis:consider, e.g. pyogenic sepsis, TB,

atypical mycobacteria, sickle- cell disease, ectopic ova of schistosomiasis.

History is important, e.g. with a history of ght trauma to a hand,

anaerobic bony infection may be more likely.

•

Brain lesions and abscesses:biopsy and drainage useful for, e.g. TB,

herpes simplex, rabies, cysticercosis, encephalitis, vCJD, JC virus, and

toxoplasmosis (in HIV infection).

•

Cervix:HPV, HSV, N.gonorrhoeae.

•

Joint infections:aspirate synovial uid and consider, e.g. pyogenic

sepsis, TB. An acute attack of gout (diagnosed through identifying the

birefringent crystals of sodium urate) can mimic an acute infective

12 Corcoran JP, Wrightson JM, Belcher E, DeCamp MM, Feller- Kopman D, Rahman NM. Pleural

infection:past, present, and future directions. Lancet Respir Med 2015; 3:563– 77.

TISSUE BIOPSY AND DEEP ASPIRATION SPECIMENS

421

arthritis (including a systemic inammatory response with neutrophilia)

and should be excluded.

• Liver abscess:consider Streptococcus milleri, hydatid disease, amoebic

dysentery, necrotic hepatocellular carcinoma in hepatitis C or hepatitis

B, obstruction of the biliary tree by A.lumbricoides or liver ukes such as

C.sinensis.

•

Muscle biopsy:

•

Cardiac— may point towards myocarditis or Chagas’ disease.

•

Skeletal— may be used to identify parasites, including, e.g. trichinosis,

cysticercosis.

•

Nerve biopsy:peripheral nerve biopsy (e.g. posterior auricular nerve)

may reveal tuberculoid leprosy.

•

Ocular:

•

Vitreous humour— e.g. intraocular infections, including fungal, HSV,

herpes varicella- zoster, pyogenic bacterial.

•

Cornea— e.g. rabies,CJD.

•

Retina— e.g. herpes varicella- zoster, toxocariasis,CMV.

• Paranasal sinus aspirates:e.g. bacteria, fungal (such as mucomycosis).

•

Pericardial biopsy:particularly important for establishing a diagnosis in

chronic pericarditis, e.g. TB, fungal.

•

Peritoneal infection:via laparoscopic tissue sampling and ascites sampling

(E Gastrointestinal tract investigations, pp. 412–13).

•

Splenic aspiration:useful in the diagnosis of visceral leishmaniasis

(kala- azar) by microscopic examination and culture and demonstration

of the organism.

• Tonsillar biopsy:of particular value for diagnosing vCJD:also consider

MRI scanning (E

Radiology, pp. 410–11), EEG, and 14- 3- 3 protein in

theCSF.

13 Singh N, Vogelgesang SA. Monoarticular arthritis. Med Clin North Am 2017; 101:607– 13.

14 Sakkas H, Gartzonika C, Levidiotou S. Laboratory diagnosis of human visceral leishmaniasis.

J Vector Borne Dis 2016; 53

:8– 16.

15 Collins S, Boyd A, Fletcher A, Gonzales MF, McLean CA, Masters CL. Recent advances in the

pre- mortem diagnosis of Creutzfeldt- Jakob disease. J Clin Neurosci 2000; 7:195– 202.

422

CHAPTER5 Infectious and tropical diseases

422

Othertests

Antibiotic plasma concentration monitoring

Some drugs are toxic if the plasma levels rise too high and their use is futile

if the levels are too low. Monitoring serum drug levels ensures that plasma

drug levels remain within the therapeutic range. Antimicrobial drugs that

may require this approach include gentamicin, vancomycin, teicoplanin, kan-

amycin, amikacin, tobramycin, chloramphenicol, streptomycin, cycloserine,

amphotericin, ucytosine, voriconazole, and itraconazole.

Cardiac

• ECG:serial ECGs can be of value in Lyme disease, rheumatic fever,

pericarditis, myocarditis, and toxic shock syndrome. Also of value in

conditions where the cardiac conduction mechanism has been damaged,

e.g. Chagas’ disease (American trypanosomiasis) and with a valve root

abscess in severe infective endocarditis. In cholera and enteric fever

(typhoid and paratyphoid), the cardiac rate will often be slower than

one might anticipate for the degree offever.

•

Echocardiography:TTE and TOE for the diagnosis of endocarditis. TOE

especially for prosthetic valves.

Dermatologicaltests

• TB skin tests:measure delayed hypersensitivity. The Mantoux test usually

involves the intradermal injection of 10 tuberculin units of puried

protein derivative (PPD), and the response is quantied. The reaction

is read at 48– 72h. Most useful epidemiologically, their individual clinical

value being relatively limited. Multiple puncture techniques (the Heaf

and Tine tests) are likely to be more convenient for large group studies.

Interpretation of these tests is more dicult in patients inoculated

with the bacillus Calmette Guérin (BCG) vaccine, and IGRAs (e.g.

QuantiFERON

) are generally more helpful as they distinguish between

T- cell responses to BCG andTB.

• Histoplasmin test:a +ve intradermal skin reaction to histoplasmin

(the histoplasmin test) may be the only sign of past infection with

H.capsulatum. Main value is epidemiological. Asimilar skin test exists for

C.immitis.

•

Mazzotti (DEC) test:for lariasis. Rarely used now, this test relied on

the intense pruritic response induced by microlariae after treatment

with the antilarial agent diethylcarbamazine* (DEC). Used in a minute

quantity, it can nevertheless be associated with side eects, ranging

from mild discomfort, fever, headaches, and intolerable pruritus to

tachypnoea, tachycardia, and even pulmonary oedema.

Note:(*) diethylcarbamazine is not licensed for use as a laricide.

•

Skin testing for antibiotic allergy:this can be performed in the same way

as for other allergens by patch testing or skin prick testing.

OTHERTESTS

423

Narcotics and anabolic steroidsscreen

If +ve, these may point towards occult drug use and a concomitant risk

of blood- borne viruses (e.g. HIV, hepatitis C, hepatitis B). vCJD has been

transmitted through anabolic steroid injecting. The antiretroviral efavirenz

interferes with these tests producing a false+ve.

Neurological

• EEG:may help with making a diagnosis of encephalitis (e.g. in patients

with HSV encephalitis, the EEG may exhibit focal unilateral or bilateral

periodic discharges localized in the temporal lobes), of brain abscess, or

of cerebral cysticercosis. It may also be of value invCJD.

•

LP:material for C&S can be obtained, but much additional information is

also gathered, e.g. the opening pressure is usually elevated in infections

(E Tissue biopsy and deep aspiration specimens, pp. 418–21).

•

EMG:oers rapid bedside conrmation of the clinical diagnosis of

botulism. It shows a pattern of brief, small, abundant motor unit

potentials. In GBS (associated with Campylobacter

gastroenteritis), EMG

may be helpful in excluding ° muscle disease.

•

NCS:helpful with diagnosing neuropathies (e.g. HIV, leprosy,GBS).

Ophthalmology

• Slit lamp examination:can help with the diagnosis of infective and

parasitic ocular problems, e.g. uveitis (syphilis, Reiter’s syndrome),

O.volvulus larvae, toxocariasis, toxoplasmosis, candidiasis.

•

Colour vision testing (Ishihara):used to assess toxicity associated with

ethambutol in treatmentofTB.

•

Direct and indirect ophthalmoscopy:essential for the diagnosis of CMV

retinitis in all HIV +ve patients with a CD4 cell count<100.

Pulmonary

• Pulmonary function tests:bronchial hyper- reactivity can be assessed for

(often provoked by infection, e.g. ABPA) and interstitial lung disease

checked for (which can include, e.g. TB, fungal infections,etc.).

424

CHAPTER5 Infectious and tropical diseases

424

Clinical investigation inaction:pyrexia

ofuncertainorigin

Common problem in hospital medicine, with huge potential dierential

diagnosis.

PUO is best dened as a body temperature of 38.3°C centrally (rectally)

for 3 weeks or longer without the cause being discovered, despite extensive

investigation for at least 1week.

Assessment should include

Observation offever pattern

Some conditions, such as VHF, typhoid, and malaria, may exhibit character-

istic fever patterns.

Complete and repeated detailed history, withemphasis onthe recognized

dierential diagnosis, including

•

Travel history.

• Antimalarialusage.

• Vaccination history.

• Past use of medical services in foreign parts may be especially important

(e.g. blood transfusions, splenectomy post- trauma, needlestick assaults).

• Drug- using history (including illicit drugs and especially injecting).

• Exposure to certain agents and/ or animals (e.g. pet ownership,

occupational risk of animal contact such as veterinary medicine, nursing,

farming, meat packing).

•

Hobbies (e.g. caving is linked to histoplasmosis and canal shing to

leptospirosis).

•

Sexual history (and risk taking).

• Menstrual history.

Complete and repeated physical examination, including re- evaluation

ofprevious ndings,e.g.

•

Check the skin, eyes, nail beds, lymph nodes, heart, and abdomen.

• Anew sign, e.g. cardiac murmur, may have developed overtime.

• The judicious use of repeated tests is also critical, depending upon the

context.

•

Laboratory and radiological tests, taking into account new data, e.g.

blood cultures, blood lms, autoantibody screen, radiological ndings.

•

Non- invasive procedures, taking into account new data, e.g. genito-

urinary assessment such as high vaginalswab.

•

Invasive procedures, e.g. liver biopsy, BM biopsy, laparoscopy,

Waldeyer’s ring assessment by an otolaryngologist.

Common groups ofcauses ofa PUO inan adultare

•

Infections.

• Connective tissue diseases.

• Occult neoplasms (especially leukaemia, lymphoma, and renal

carcinoma).

CLINICAL INVESTIGATION IN ACTION:PUO

425

A list ofrelevant pathologies might include

HIV, TB, endocarditis, osteomyelitis, malaria, syphilis, zoonoses (e.g. brucel-

losis, Lyme disease, tularaemia), viral hepatitis (especially hepatitis C and B),

typhoid/ paratyphoid, pelvic inammatory disease, chronic meningococcae-

mia, dental sepsis, tumours such as lymphoma, renal carcinoma, liver metas-

tases, familial Mediterranean fever, multiple PEs, drugs, rheumatological, e.g.

Still’s disease, TA, SLE, granulomatosis with polyangiitis (GPA, previously

known as Wegener’s granulomatosis), vasculitis, atrial myxoma, factitious

fever, Munchausen’s syndrome, Munchausen’s syndrome byproxy.

With improved non- invasive and microbiological techniques, most cases

of PUO are found not to be caused by infections, but rather by other sys-

temic diseases such as sarcoidosis, SLE, and TA. However, there are also

infectious diseases capable of causing prolonged fever that should always be

considered and factored into the assessment because they are often treat-

able and/ or transmissible to others and will have serious consequences if

missed. Adenitive diagnosis is not made in around 25% of patients; how-

ever, they tend not to come to any harm when observed over a long period.

Endocarditis

Endocarditis is a deep- seated infection that behaves like a deep- seated

abscess. Indeed, an abscess can form adjacent to an infected cardiac valve

or shunt. The diagnosis involves thoughtful clinical assessment, including

whether or not there is a history of injecting drug use, and requires multiple

blood cultures and cardiac assessment. The Duke criteria form the basis of

the diagnosis.

Assess clinically for likelihood, e.g. background of injecting

drug use, congenital heart disease, prosthetic valves, rheumatic fever, scar-

let fever. Endocarditis may manifest changing cardiac murmurs over a period

of time, as well as a number of additionalsigns.

•

Establish diagnosis:echocardiography (especially TOE)— to look at

valves, cardiac chambers, shunts,etc.

•

Establish aetiology:

•

Blood cultures (multiple)— consider culturing for unusual organ-

isms such as fungi, HACEK organisms (Haemophilus species, e.g.

H.parainuenzae, H.aphrophilus, and H.paraphrophilus, Actinobacillus

actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens,

and Kingella species), L.monocytogenes,etc.

•

Serology— Q fever (Coxiella burnetii) phase Iand II, C.albicans.

•

Assess clinical status:

•

ECG— tachycardia, conduction abnormalities.

•

CXR— cardiac size, PEs with right- sided endocarditis.

•

U&E— to assess renal compromise, ifany.

•

Haematology— WBC.

•

Inammatory markers— ESR,CRP.

•

Proteinuria— to assess renal compromise, ifany.

•

Blood- borne virus status— HIV, hepatitis C, hepatitis B if there is a his-

tory of drug injecting.

16 MedCalc. Duke criteria for infective endocarditis. M http:// www.medcalc.com/ endocarditis.html.

426

CHAPTER5 Infectious and tropical diseases

426

• Assistance with therapy:

•

Antibiotic sensitivity testing.

•

Serum antibiotic levels (e.g. gentamicin, vancomycin).

• Prevention:dental assessment— for prevention in the future. Endocarditis

warning card. MedicAlert

bracelet.

Tuberculosis

Consider pulmonary vs extrapulmonary disease and other epidemiological

parameters. (Pleural disease is by denition extrapulmonary.)

• Establish diagnosis/ aetiology:

•

Radiological evidence.

•

Bodily uids (e.g. sputum, EMUs, gastric washings, CSF) and

biopsies— always consider performing induced sputum, even with

a normal CXR; histology may show caseating granulomata (see

Fig.5.9).

•

PCR testing.

•

Mantouxtest.

•

IGRAs such as QuantiFERON

•

Ca- 125 levels— abdominal TB inwomen.

• Assess clinical status:

•

Inammatory markers— ESR,CRP.

•

T- cell subsets— low CD4+ cell count characteristic.

•

Body weight.

•

HIV testing— now essential in all patients.

•

Glucose metabolism— may be an association (fasting glucose, OGTT,

HbA

Lymphocytes

Activated macrophages

(epithelioid cells)

Caseous

necrosis (amorphous)

Langhans giant

cell (multinucleated)

Fibroblast

CASEOUS GRANULOMA

Fig.5.9 Caseating granulomata are the principal histological feature of TB, together

with acid- fast bacilli (detected using the ZN stain). In any tissue aected by TB,

caseating granulomata may be present and are accordingly of immense assistance

diagnostically.

CLINICAL INVESTIGATION IN ACTION:PUO

427

• Assistance with therapy:

•

Antibiotic sensitivity testing.

•

Serum antibiotic levels (e.g. cycloserine).

•

LFTs.

•

Skin testing.

•

Calcium and vitamin D levels.

•

Gene probes (for rifampicin resistance).

• Prevention:notify cases to public health authorities. Contact tracing.

•

TB and biopsies:when a biopsy is being obtained of any organ or

tissue, the possibility of extrapulmonary TB should be borne in mind.

If histology is performed, caseating granulomata may be seen, and

appropriate staining for acid- fast bacilli (such as the ZN stain) may reveal

the presence of TB organisms. However, because of the i risk of MDR-

TB and XDR- TB, material should always be sent to the microbiology

laboratory and appropriate cultures for TB should be set up, both for

diagnostic and for drug sensitivity purposes. Molecular techniques,

including gene probes and PCR, are now essential parts of the

diagnostic armoury for TB. In many instances, having a biopsy taken is an

unpleasant experience for a patient, and remembering to perform a TB

culture at the outset may prevent the patient from having to undergo an

unpleasant procedure more thanonce.

Malaria (fever inthe returning traveller)

Always consider malaria in the febrile individual returning from overseas.

Adetailed geographical history and malaria prophylaxis history is essential.

Always consider the possibility of a coexistent second diagnosis (especially

in P. falciparum infestation) such as Salmonella

septicaemia (the so- called

‘algid malaria’).

•

Establish diagnosis/ aetiology:

•

Thick and thin blood lms— perform three (each 24h apart).

•

Antigen tests— such as ParaSightF

and OptiMAL

•

Blood sugar— hypoglycaemia is common and needs immediate

treatment.

•

Platelet count— thrombocytopenia suggestive of P.falciparum.

•

Haematology— WBC.

•

Inammatory markers— ESR,CRP.

• Assess clinical status:

•

Blood cultures— to exclude 2° infection.

•

Haemoglobinopathy— to assess for sickle- cell disease.

•

Assess the very ill patient thoroughly for markers of severity

(includes LFTs, blood lm for haemolysis, coagulation status, CXR,

ECG, ABGs, glucose levels, lactate levels, conscious level, etc.). Note

that severe P.falciparum malaria can present as a diarrhoeal illness.

•

Assistance with therapy:

•

G6PD levels.

•

Tests of hearing— deafness can occur with quinine.

• Prevention:avoid blood donation for 18months.

428

CHAPTER5 Infectious and tropical diseases

428

Jaundice (acute)

Jaundice can be pre- or post- hepatic, or a combination of both. Epidemiological

factors are important (drug injecting, travel, unsafe food, unsafe sex, job, hob-

bies, vaccination history, alcohol, prescribed medications, herbal remedies,

etc.). The patient may have an acute exacerbation of a chronic disease, e.g.

hepatitis C.Always remember Courvoisier’s law (a distended gall bladder in a

patient with obstructive jaundice means cancer) and Charcot’s triad (the char-

acteristic presentation of acute cholangitis, with biliary colic, jaundice, and spik-

ing fevers with rigors). Haemolysis may lead to jaundice without liver disease

being present.

•

Establish diagnosis:

•

LFTs— conjugated and unconjugated bilirubin levels.

•

Urinalysis.

•

Stool examination— colour, ushability.

•

Haemolysis screen— blood lm, coagulation studies, antiglobulin

test,etc.

•

Hepatobiliary US— serial scans can assess hepatobiliary status

sequentially.

•

AFP levels— may suggest hepatocellular carcinoma associated with

hepatitis C and hepatitis B infection.

•

Establish aetiology:

•

Serology— e.g. hepatitis Athrough to E, EBV, CMV, toxoplasmosis,

leptospirosis, hantavirus, yellowfever.

•

Blood culture.

•

Stools for ova, cysts, and parasites— e.g. C.sinensis, ascariasis).

•

Monospot forEBV.

•

Hepatobiliary US— obstruction by malignancy or parasites, liver

parenchyma status, gallstones.

•

ERCP/ MRCP— may diagnose parasitic invasion of the biliary tree,

CMV/ cryptosporidial disease, porta hepatis lymphadenopathy

associated with HIV,etc.

•

Paracetamol levels.

•

Assistance with therapy:

•

HIV testing— if appropriate; co- infection with HIV, HCV, and HBV an

i problem worldwide.

•

Ethanol assessment— γGT levels,iMCV.

•

Molecular tests— PCR testing for HCV, circulating DNA levels inHBV.

•

Antigens— hepatitisB.

• Prevention:

•

Notify cases to public health authorities; safe sex education; safe

drug- injecting education possible once viral diagnosis of HCV, HBV,

and/ or HIV established.

•

Assess family, sexual partners, etc. for possible infection (HIV, HBV,

HCV) and/ or need to vaccinate(HBV).

•

Vaccination strategies:HBV, HAV as appropriate.

CLINICAL INVESTIGATION IN ACTION:PUO

429

Diarrhoea

Diarrhoea can be acute vs chronic, or acute on chronic. For example, a

gastroenteritis illness may uncover pre- existing IBD (such as Crohn’s dis-

ease) or malabsorption (such as coeliac disease or pancreatic insuciency).

Drugs such as opiates can lead to ‘overow’ diarrhoea. Also bear in mind

that where there is one bowel pathogen, another one might be present.

Antibiotic resistance is common among some bowel pathogens. Diarrhoea

can appear infective but, for example, might be endocrine in origin (e.g.

carcinoid syndrome, Zollinger– Ellison syndrome, medullary carcinoma of

the thyroid), whilst the possibility of bowel cancer must always be borne in

mind. Note that the presence of S.bovis in blood cultures may be indicative

of the presence of bowel cancer until proven otherwise. Irritable bowel

disease is being increasingly diagnosed. Malaria can present as diarrhoea.

•

Establish diagnosis:

•

Examine stools.

•

Keep a stool chart on theward.

• Establish aetiology:

•

StoolC&S.

•

Stool microscopy for ova, cysts, and parasites.

•

Faecal fat and elastase for pancreatic insuciency.

Pneumonic illness

Pneumonia is multi- aetiological. If recurrent, this throws up certain diagnos-

tic possibilities that must be considered. Many epidemiological considera-

tions are important such as travel history, occupation, pet keeping, hobbies,

sexual activity, etc. Osler’s triad of rigors, pleuritis, and rust- coloured spu-

tum is said to be characteristic of pneumococcal pneumonia.

•

Establish diagnosis/ aetiology:

•

CXR (or CT chest).

•

Serology— atypical pneumonia organisms (L.pneumophila, M.pneumo-

niae, C.burnetii, Chlamydia psittaci), hantavirus, RSV, inuenza.

•

Sputum— including induced sputum, bronchoscopy, and BAL:micros-

copy and culture.

•

Blood cultures.

•

Serum Na

level— d in Legionella.

•

Antigen— pneumococcal (blood), Legionella (urine).

•

NPA for viral culture— RSV, inuenza.

•

Cryoglobulins— e.g. M.pneumoniae.

•

Molecular— various PCR tests for viruses and Mycoplasma.

•

HIV test— essential in risk groups.

• Assess clinical status.

•

(CURB65 score):

•

ABGs.

•

Confusion, Urea, Respiratory rate, Blood pressure.

•

US of the chest— if eusion developing (drain if necessary), check pH

ofuid.

•

Pulmonary function tests if appropriate.

17 M http:// www.aafp.org/ fpm/ 20060400/ CURB65.pdf.

430

CHAPTER5 Infectious and tropical diseases

430

• Assistance with therapy:

•

Antibiotic sensitivity testing.

•

If recurrent:consider TB testing (see earlier), HIV testing, Ig levels

(to check for deciency), assessing for hyposplenism, checking termi-

nal complement levels (C5– C9).

• Prevention:

•

Notify appropriate cases to public health authorities (e.g. Legionella,

TB); isolate as necessary.

•

Vaccination strategies:inuenza, Pneumococcus,Hib.

•

Stop smoking, if relevant.

Meningitic illness (headache and photophobia)

Meningitis can be extremely serious, particularly bacterial, mycobacterial,

fungal, and protozoal forms, but viral meningitis is generally less serious.

Meningitic infection is often mimicked by much less serious infections such

as UTI (especially in women), throat infections (ASO, Monospot), atypi-

cal pneumonias, and sinusitis (especially ethmoidal, sphenoidal). Asimilar

picture can also be generated by SAH. Meningococcal infection can be

life- threatening without ever causing meningitis. If bacterial meningitis is

recurrent, certain diagnostic possibilities must be considered. Brain abscess

(consider injecting drug use, congenital heart disease, immunodeciency,

etc.) and, under certain circumstances, encephalitis can present in a similar

fashion to meningitic illnesses. Where the patient has a marked petechial

rash and a history of travel to Africa, Ukraine, or South America, even

VHF (particularly the Congo– Crimean variety) comes into the picture (see

Fig.5.10).

•

Establish diagnosis/ aetiology:

•

LP/ cisternal puncture/ foramenal puncture (in neonates)— for CSF

pressure, microscopy, bacterial and mycobacterial culture (includ-

ing special cultures, e.g. for Listeria), viral culture, biochemistry (e.g.

protein, glucose), dierential cell count, viral PCR, xanthochromia,

India ink stain, CrAg testing.

•

CT scan of head— sometimes necessary to exclude an SOL prior to

performing an LP; CT is little better than a clinical assessment in the

exclusion of raised ICP. When i ICP is found, cisternal puncture and

foramenal puncture is possible in skilledhands.

•

CXR and assessment for atypical pneumonia, if appropriate.

•

NPA (see earlier).

•

Petechial rash sampling— aspirate material from a fresh purpuric lesion

using a small- needle insulin syringe, Gram stain, and culture.

•

Molecular— meningococcal PCR (blood and CSF), pneumococcal

PCR (blood andCSF).

•

Serology— urine and blood for CrAg; blood for pneumococcal anti-

gen; urine and saliva for mumps antigen; ASO, antibodies to mumps,

EBV, Cryptococcus, N.meningitidis.

•

Nasopharyngeal swab for meningococcus.

•

Stool for enteroviral culture.

•

Monospot test forEBV.

CLINICAL INVESTIGATION IN ACTION:PUO

431

• Assess clinical status:

•

CT/ MRI scan of head— assess for raised ICP; exclude SAH

(xanthochromia), sagittal vein thrombosis; exclude skull fracture,

especially of cribriform plate or middle ear (this can lead to recur-

rent pneumococcal meningitis— if there is a nasal drip, test uid for

glucose to exclude presence of CSF as CSF contains glucose).

•

Dierential WBC inblood.

•

Inammatory markers— ESR,CRP.

•

Coagulation screen and platelet count:for meningococcal sepsis.

•

ABGs— to assess acid– base balance in severecases.

1. A detailed travel history

and a high index of suspicion

are essential in making the

diagnosis of VHF. A recent

travel history to an area

where one of these viruses

are known to be particularly

prevalent is suggestive,

particularly Africa (e.g.

Uganda and Ebola, Nigeria

and Lassa) and South

America — the incubation

period ranges from 3 to 21 days,

depending upon the variety.

Many VHF cases presenting

together may suggest a

bioterrorism attack.

2. VHFs are severe febrile

illnesses that can be

complicated by a

haemorrhagic tendency,

petechiae, hypotension

(and even shock), ushing

of the face and chest, and

oedema. Constitutional

symptoms such as

headaches, myalgia,

vomiting and diarrhoea

may occur. Some VHFs

manifest particular features

not shared by the others.

3. Once suspected, VHFs

are category 4 pathogens,

so precautions for

healthcare workers must

be instituted and the case

notied to the proper

authorities. Isolation

measures and barrier

nursing procedures are

indicated (Marburg,

Ebola, Lassa and Congo-

Crimean HF viruses may

be particularly prone to

aerosol nosocomial spread),

usually in a special infectious

diseases/tropical medicine

unit staed with clinicians

with expertise in the eld.

Intensive supportive care

may be required.

5. Almost always, the true

diagnosis will not be a VHF,

but they must be considered

where appropriate. Strict

adherence to isolation and

infection control precautions

has prevented secondary

transmission in almost all cases.

4. Diagnosis requires clinical

expertise in infectious

diseases/tropical medicine.

The dierential diagnosis

includes malaria, yellow

fever, dengue, typhoid/

paratyphoid fever,

non-typhoidal salmonellae,

typhus and other rickettsial

diseases, leptospirosis,

shigella dysentery, relapsing

fever (borreliosis), fulminant

hepatitis and meningo coccal

disease. Antigen tests,

antibody detection and

viral culture are all available

for most of the VHFs. The

patient should be fully

investigated and treated

accordingly.

Biohazard

Fig.5.10 Investigating a possible case ofVHF.

432

CHAPTER5 Infectious and tropical diseases

432

•

Synacthen

test (E Short Synacthen

test, p. 225)— adrenal

failure in severe meningococcal sepsis (Waterhouse– Friderichsen

syndrome).

•

HIV test— suggested by some pathologies and may be the overall

underlying problem.

•

TB assessment— may be the underlying pathology.

• Assistance with therapy:

•

Antibiotic sensitivity testing.

•

Serum antimicrobial levels, e.g. amphotericin, ucytosine.

• Prevention:

•

Notify relevant cases to public health authorities; isolate as

necessary.

•

Vaccination strategies— meningococcus, pneumococcus,

inuenza,Hib.

•

History of skull fracture— may need neurosurgery,etc.

Urethritis (with or withouthaematuria)

Pain on micturition can simply represent a UTI or there may be an STD, such

as gonorrhoea, present. The patient’s sexual and travel history is important.

Renal calculi can produce clinical pictures resembling an infection, as can

dermatological conditions such as Stevens– Johnson syndrome. UTIs are

commoner during pregnancy. Prostatitis can be a problem in oldermen.

• Establish diagnosis/ aetiology:

•

Urine collection (MSU)— culture (bacterial infections), microscopy

(parasites, etc., such as schistosomiasis— use terminal specimen),

molecular techniques (LCR for Chlamydia).

•

STDs and pelvic inammatory disease— perform high vaginal swab

and urethral swabs; screen for gonococcus (includes throat and anal

swabs).

•

Calcular disease— exclude with urine microscopy, radiology,etc.

•

Prostatitis— prostatic massage,CrAg.

•

TB— can present like any otherUTI.

•

Reiter’s syndrome— slit lamp examination of the eye, urine, and stool

culture/ LCR for Chlamydia.

•

Assess clinical status:

•

Biochemistry— exclude renal failure (urea, creatinine,etc.).

•

Markers of inammation— CRP,ESR.

•

White cellcount.

•

Check all other mucosal surfaces of the body (mouth, conjunctivae,

nose, etc.) to help exclude Stevens– Johnson syndrome.

• Assistance with therapy:

•

Pregnancytest.

•

PSA to exclude prostatic carcinoma (recurrent UTIs in oldermen).

•

Radiology of renal tract— US, IV pyelography (IVP) (to exclude under-

lying renal tract anatomical problems, TB involvement, calculi,etc.).

•

Prevention:

•

History of unsafe sex, recent new sexual partner, drug injecting—

consider VDRL, HIV, viral hepatitis testing.

•

TB— notify, contact trace,etc.

•

Calculi— exclude hypercalcaemia, hyperuricaemia,etc.

CLINICAL INVESTIGATION IN ACTION:PUO

433

Red, painful swollen lowerleg

One of the most dicult things in medicine is to distinguish eectively

between a distal DVT and cellulitis— and a combination of both! Less com-

monly, a ruptured Baker’s cyst of the knee can present in almost the same

way. The key is in the history. Sometimes the problem is in the tissues, and

sometimes in the joints (even gout and pseudogout can look like cellulitis)

or the bone (osteomyelitis). Ulceration may be present on the legs. Venous

and arterial insuciency may complicate the picture— infected legs in older

people can be very dicult to treat with antibiotics alone. Recent long- haul

air travel may point more towards thrombosis, but swollen legs with com-

promised veins can easily get infected. Although rare, syphilis, yaws, and

Mycobacterium ulcerans can cause leg ulcers that are potentially amenable

to treatment. Pyoderma gangrenosum can resemble infection of the leg

but is associated with non- infectious systemic diseases. Check for eschar

from tickbite.

•

Establish diagnosis/ aetiology:

•

Exclude DVT with Doppler US (and possible embolic disease on

occasions).

•

Swabs:from ulcers, between the toes usually not helpful.

•

Blood cultures.

•

RarelyVDRL.

•

Joint assessment:urate levels for gout; assess (if relevant) for pseu-

dogout, rheumatological screen, synovial uid analysis (if relevant),

Lyme disease titres (depends on the travel history,etc.).

•

Leg ulcers in the young:consider sickle- cell disease, hereditary

spherocytosis.

•

Assess clinical status:

•

White cellcount.

•

Inammatory markers— ESR,CRP.

•

Assess blood vessel integrity— e.g. compression US for venous prob-

lems, lower limb arteriography.

•

Assistance with therapy:

•

Exclude diabetes,HBA

•

X- ray, bone scanning, MRI— is osteomyelitis present?

• Prevention:

•

Treat diabetes, if present.

•

Treat other underlying conditions, if present.

•

Patient advised to take care in future (e.g. DVT avoidance whilst

travelling).

Vesicularrash

Many vesicular rashes are infective; many are not. In particular, the distri-

bution of the rash should be carefully assessed, and joint assessment and

management with a dermatologist are often valuable. If atopic, eczema

herpeticum comes into the picture. Staphylococcal impetigo can cause

vesiculation. If there is a relevant travel history, rickettsial pox and mon-

key pox come into the picture. Erythema multiforme, which often has an

infective basis but can also be produced by medications, can produce a

vesiculating rash (so check the mouth, eyes, and genitalia, and determine the

434

CHAPTER5 Infectious and tropical diseases

434

medication history). Non- infective blistering conditions include dermatitis

herpetiformis (coeliac disease), pompholyx, and pemphigus.

•

Establish diagnosis/ aetiology:

•

Vesicular uid— PCR, EM, IFT, culture,etc.

•

Serology— HSV, herpes varicella- zoster, rickettsial pox, Coxsackie

virus, ASOtitre.

•

Assess clinical status:

•

CXR— chickenpox (if compromised, ABGs will be needed).

•

EEG— if cerebral symptoms present (e.g. cerebellar encephalitis can

occur with herpes varicella- zoster).

•

Monkey pox, smallpox, rickettsial pox— the patient will be ill and will

require full assessment, even possibly intensivecare.

•

Assistance with therapy:

•

Pregnancy test:herpes varicella- zoster a bigger problem in pregnancy.

• Prevention:

•

Avoid precipitants with erythema multiforme.

•

Manage atopy optimally.

Further reading

Chin J (ed.). Control of Communicable Diseases Manual, 18th edn. Washington DC:American Public

Health Association,2004.

Cohen J, Powderly WG (eds.). Infectious Diseases, 2nd edn. St Louis:Mosby,2003.

Cook GC, Zumla AI (eds.). Manson’s Tropical Diseases

, 22nd edn. Philadelphia:WB Saunders,2008.

Mandell GL, Douglas JE, Dolin R, Bennett RE (eds.). Principles and Practice of Infectious Diseases, 7th

edn. London:Churchill Livingstone,2009.

Peters W, Pasvol G. Color Atlas of Tropical Medicine and Parasitology, 5th edn. St Louis:Mosby,2001.

Shanson DC. Microbiology and Clinical Practice

, 3rd edn. Oxford:Butterworth- Heinemann,1999.

Steen R, Dupont HL, Wilder- Smith A. Manual of Travel Medicine and Health, 3rd edn. Ontario:BC

Decker,2007.

435

Chapter6

Cardiology

Cardiac catheterization 436

Cardiac markers of myocardial necrosis 440

Cardiac volumetric imaging:magnetic resonance and computed

tomography 442

Echocardiography 450

Electrocardiogram 470

Electrocardiographic monitoring 478

Exercise testing 482

Myocardial perfusion imaging 486

Radionuclide ventriculography 490

Pulmonary artery catheterization 492

Tilt table testing 494

436

CHAPTER6 Cardiology

436

Cardiac catheterization

Principle

Cardiac catheterization is an invasive procedure during which catheters are

placed within the cardiac chambers, coronary arteries, and great vessels to

provide information on cardiac anatomy, pressures, disease states, function,

and O

saturations.

Indications

• Diagnosis of suspected coronary artery disease (after appropriate non-

invasive assessment or if results are equivocal).

•

Assessment of coronary artery disease burden and suitability for

intervention, e.g. percutaneous coronary intervention (PCI), coronary

artery bypass surgery, or cardiac transplantation.

•

Measurement of intracardiac pressures in patients with valvular heart

disease (largely superseded by non- invasive imaging).

• Detailed measurement of left and right ventricular cardiac output

and pulmonary hypertension in patients considered for cardiac

transplantation or with suspected congenital heart disease.

•

Evaluation of O

saturations in cardiac chambers to identify cardiac

shunting.

•

Myocardial biopsy in patients with cardiomyopathy of unknowncause.

• Monitoring of cardiac transplantation success/ rejection.

Contraindications

• Pregnancy is an absolute contraindication to coronary angiography.

• Relative contraindications include:

•

Severe peripheral vascular disease.

•

Aortic aneurysm.

•

Renal failure.

•

Unstable cardiac failure or arrhythmias.

•

Haemodynamic instability.

•

Sensitivity to contrast agents.

Patient preparation

The patient is fasted for 4h prior to the procedure. IV access is required,

together with haemodynamic and ECG monitoring. Sedation may be used

according to patient request or operator direction. It is important that the

patient understands the risks of the procedure and gives informed written

consent. The contrast agents used can provoke renal failure in susceptible

patients. Metformin should be withdrawn for 48h prior to the procedure. In

patients with renal impairment, pre- treatment with acetylcysteine is advised

and a less nephrotoxic contrast agent may be considered. Contrast agent

volume should be minimized.

CARDIAC CATHETERIZATION

437

Procedure

1. The patient lies at on a catheter laboratory table and appropriate

monitoring is applied.

2. LAn is used and an aseptic technique employed. For a left heart

procedure, arterial access is required. The radial artery is the most

commonly employed, but the femoral artery provides an alternative

route (unless signicant peripheral vascular disease is present).

3. The chosen artery is cannulated using the Seldinger technique, and an

access sheath inserted.

4. Fluoroscopic screening is used to monitor the passage of a guidewire

and catheter to theheart.

5. Catheters are pre- shaped according to the structure being examined.

Typically, a Judkins left 4 catheter is used for the left coronary artery,

Judkins right 4 catheter for the right coronary artery, and an angled

pigtail catheter is placed in the LV and/ or aorta for examination of

these structures.

6. Acontrast agent is injected for image acquisition. Images of the coronary

arteries are acquired in multiple planes in order to optimally identify

coronary artery stenoses. Continuous pressure transducers can be used

for dynamic left heart pressure monitoring, e.g. LV andaorta.

7. Evaluation of the right heart necessitates venous access. The

commonest access point is the femoral vein, but the central veins, e.g.

subclavian or internal jugular vein, can also beused.

8. Aright heart or Swan– Ganz catheter is passed towards the right heart.

Right- sided pressures, e.g. vena cavae, right atrium, right ventricle (RV),

pulmonary artery (PmA), and pulmonary capillary wedge pressure

(indirect left atrial (LAt) pressure), can be measured.

9. Blood samples obtained from these sites can be analysed for O

saturation and used to identify the presence and site of cardiac shunts,

e.g. atrial or ventricular septal defects. Cardiac output studies can also

be performed.

Risks

Cardiac catheterization is an invasive technique, and so there are inherent

risks to the procedure (1:200 patients). Full cardiopulmonary resuscitation

facilities should be immediately available.

These risks include

•

Trauma to arterial/ venous access sites, including haematoma, occlusion,

aneurysm, pseudo- aneurysm, nerve damage.

• Aortic/ coronary artery dissection.

• CVA (embolus).

• MI (embolus/ dissection).

• Arrhythmias.

• Pulmonary oedema (left main stem stenosis).

• Renal failure.

• Vasovagal response to arterial access/ sheath removal.

Additionally, the patient is exposed to ionizing radiation, and so screening/

image acquisition times should be reduced as much as possible. Serial stud-

ies should be avoided.

438

CHAPTER6 Cardiology

438

Possible results

Results froma left heart study can provide informationon

•

Coronary artery anatomy and distribution of disease, to aid decisions

regarding the need for revascularization (see Fig.6.1).

•

Left ventricular size and function.

• Left heart pressures.

• Aortic and mitral valve integrity.

• Aortic size and disease.

• Congenital abnormalities.

A right- sided study can provide informationon

• Right ventricular size and function.

• Tricuspid and pulmonary valve integrity.

• PmA anatomy.

• Right heart pressures.

• Congenital abnormalities, e.g. shunts.

• Myocardial histopathology where biopsy istaken.

Advantages overothertests

Invasive coronary angiography has high resolution for the evaluation of cor-

onary artery disease and is the current gold standard imaging technique for

this application. However, CT coronary angiography is rapidly becoming an

accurate alternative means of depicting coronary artery atheroma, particu-

larly in the proximal vessels. Advances in echocardiography and cardiovas-

cular MR (CMR) have reduced the need for right heart catheterization, but

the latter is still the only means with which to obtain direct histopathological

information from myocardial structures.

Fig.6.1 Coronary angiogram showing a normal left coronary artery.

CARDIAC CATHETERIZATION

439

Pitfalls

The procedure is invasive and the risks involved are not insignicant. Whilst

coronary angiography is the gold standard for the demonstration of ana-

tomical coronary arterial lesions, it provides little information regarding

their physiological signicance on the myocardium. The information should

therefore be used in conjunction with imaging techniques that can assess

the adequacy of myocardial perfusion, e.g. stress nuclear imaging, stress

echocardiography, orCMR.

Further reading

Callan P, Clark AL. Right heart catheterisation:indications and interpretation. Heart 2016; 102:1– 11.

Fihn SD, Blankenship JC, Alexander KP, etal. 2014 ACC/ AHA/ AATS/ PCNA/ SCAI/ STS Focused

update of the guideline for the diagnosis and management of patients with stable ischemic heart

disease. J Am Coll Cardiol 2014; 64

:1929– 49.

440

CHAPTER6 Cardiology

440

Cardiac markers ofmyocardial necrosis

Principle

When cardiac muscle is damaged, certain substances, e.g. troponins I(TnI)

and T (TnT), myoglobin, and creatine kinase, are released into the blood-

stream and can be measured by biochemical assays. Such assays can be

helpful in making the diagnosis of ACS or myocardial contusion. Myoglobin

and creatine kinase (CK and CK- MB) are relatively non- specic cardiac

markers of myocardial necrosis (CK is also released by skeletal muscle)

that are elevated within 2– 4h of myocyte damage. Troponins (TnT and TnI)

are cardiac muscle proteins that are released into the peripheral circulation

more slowly and are highly specic for myocardial injury. High- sensitivity

troponin assays (hsTnT and hsTnI) detect troponins at much lower con-

centrations than the standard troponin assays available previously, allowing

more rapid diagnosis in ACS. Using a high- sensitivity assay, an initial eleva-

tion of circulating troponin levels is detectable within 3h of the event, peak-

ing at around 24h (see Fig.6.2).

Patients presenting with unstable ischaemic cardiac pain are initially labelled

as having an ACS and are categorized on the basis of their initial 12- lead

ECG into ST- segment elevation ACS (which requires urgent reperfusion

via primary PCI or thrombolysis) or non- ST- segment elevation ACS (which

requires appropriate antiplatelet and antithrombotic therapy, followed by

coronary revascularization as appropriate). MI is conrmed later if there is

a rise in markers of myocardial necrosis, most commonly troponins. When

these markers are raised, those presenting with an ST- segment elevation

ACS are classied as ST- elevation myocardial infarction (STEMI) and those

with non- ST- elevation ACS are classied as non- ST- elevation MI (NSTEMI).

0 24

144

1209672

Hours from onset of symptoms

Relative enzyme activity

Troponin

Fig.6.2 Changes in levels of cardiac markers following acuteMI.

CARDIAC MARKERS OF MYOCARDIAL NECROSIS

441

Indications

Cardiac markers ofmyocardial necrosis areuseful

•

In conjunction with the clinical history and 12- lead ECG to diagnose and

categorize suspectedACS.

• To stratify risk inACS.

• To ascertain the extent of any myocardial injury following coronary

revascularization procedures.

•

To identify myocardial contusion following thoracic trauma.

Procedure

A 10mL venous blood sample is sucient. For hsTnT or hsTnI testing, this

sample is ideally taken 3– 6h after the patient’s most severe symptoms.

Repeat sampling is necessary to demonstrate a rise in cardiac markers.

Risks

In patients who have had thrombolysis for acute MI, bleeding or haema-

toma formation may occur spontaneously at venepuncturesites.

Possible results

Within the normal population, 99% of individuals will have a hsTnT <14ng/

L. In the appropriate clinical setting of chest pain typical of acute MI ± ECG

changes:

•

An elevated troponin (hsTnT >30ng/ L) is consistent with a

diagnosisofMI.

•

Acute MI (STEMI and NSTEMI) can be condently excluded if a high-

sensitivity troponin result is within normal limits 6h after the onset of

symptoms.

Pitfalls

CK may be elevated in skeletal muscle injury, as well as with MI. Direct esti-

mation of CK- MB, the isoenzyme that is more specic for cardiac muscle,

may be helpful. Troponins are more specic for cardiac injury but may also

be elevated in cardiac failure, arrhythmias, renal failure, or PE, and so the

clinical context should always be taken into account. Timing of blood sam-

ples is critical since values may be normal if blood is taken too soon after

symptom onset. Troponins may remain elevated for up to 14days following

a cardiac event, and so the diagnosis of re- infarction using troponins alone

may be unreliable.

Further reading

Shah ASV, Anand A, Sandoval Y, etal. High- sensitivity cardiac troponin Iat presentation in patients

with suspected acute coronary syndrome:a cohort study. Lancet 2015; 386:2481– 8.

Sherwood MW, Newby LK. High- sensitivity troponin assays:evidence, indications, and reasonable

use. J Am Heart Assoc 2014; 3:e000403.

Thygesen K, Alpert JS, Jae AS, et al. Third universal denition of myocardial infarction. J Am Coll

Cardiol 2012; 60

:1581– 98.

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CHAPTER6 Cardiology

442

Cardiac volumetric imaging:magnetic

resonance and computed tomography

Principle

Cardiac volumetric imaging is now established as a powerful tool to visualize

the anatomy, size, and function of cardiac structures, i.e. valves, chambers,

myocardium, pericardium, and great vessels. Advanced technology MR

imagers and multislice CT scanners are increasingly available to clinicians.

These techniques provide information regarding the aetiology and severity

of most congenital and acquired cardiac abnormalities.

Indications

The indications for CMR and CT are shown in Table 6.1. CMR is especially

useful in patients with IHD where a comprehensive assessment of left ven-

tricular function, reversible myocardial ischaemia, and myocardial viability

can be made. Cardiac CT is of particular value in screening for coronary

artery disease and for assessment of the great vessels and coronary arteries.

Contraindications

• Presence of any ferrous metal, e.g. intracranial clips, intra- ocular foreign

bodies, shrapnel(MRI).

•

Temporary or permanent pacing systems (MRI), unless MRI- conditional.

Table6.1 Indications forCMRandCT

Condition MRI CT

Congenital heart disease +++ ++

Anatomy, size, or mass of cardiac chambers (left atrium, LV,

right atrium, RV)

++++ +++

Global and regional left ventricular function ++++ +++

Screening (cardiomyopathy, including arrhythmogenic right

heart)

++++ +

Valvular heart disease (aortic, mitral, tricuspid, and pulmonary) +++ +

Prosthetic heart valves +++ +

Cardiac masses +++ ++

Pericardial disease +++ ++

Aortic disease +++ ++++

Coronary artery anatomy and patency ++ ++++

Screening for coronary artery disease + ++++

Myocardial perfusion +++

–

Stress study in IHD ++++ –

Myocardial viability ++++ +

CARDIAC VOLUMETRIC IMAGING

443

• Internal cardioverter– debrillator (ICD) systems (MRI), unless

MRI- conditional.

• Clinically dehiscing Starr– Edwards valve prostheses manufactured

between 1960 and 1964(MRI).

•

Severe claustrophobia (more of an issue withMRI).

• Allergy to non- ionic contrast agents(CT).

• Haemodynamic instability.

• Pregnancy is a relative contraindication to MRI, but an absolute

contraindicationtoCT.

Patient preparation

A patient questionnaire is performed to exclude contraindications. Patients

should be relaxed and have the procedure explained, so that they are able

to co- operate eectively. Breath- holding techniques should be practised

prior to the scan to achieve optimal image quality. Height and weight are

required for indexing cardiac measurements. Where stressors are to be

used, a 12- lead ECG should be obtained. IV access is required for contrast

agent administration.

Procedure

The patient is positioned on the imaging couch. Electrodes are attached to

allow image acquisition to be gated to the ECG. For CMR, a cardiac coil is

selected and earplugs supplied. Images are then acquired in order to evalu-

ate the clinical problem.

The following MRI sequences are commonly performed

T1- weightedimages

These are used for anatomical assessment and contribute, with optional

contrast agent enhancement, towards tissue characterization.

Cine sequences

Cine sequences are used for anatomical assessment and particularly for car-

diac function. Repetitive short- axis slices from the cardiac base to the apex

are summated to calculate left ventricular function. This is an extremely

accurate method, since it avoids geometrical assumptions created by

regional wall abnormalities. It is therefore a gold standard method for the

calculation of left ventricular ejection fraction (EF), mass, and other cardiac

volumes. The technique can be used in conjunction with pharmaceutical

stress (e.g. dobutamine) in a manner analogous to stress echocardiography

to identify regional reversible myocardial ischaemia.

First- pass contrast agent imaging

Myocardial perfusion is assessed by imaging the rst pass of a T1- shortening

contrast agent (gadolinium). The contrast agent passes through the right

heart and lungs to the left heart. It is carried into the myocardium by the

coronary circulation, giving rise to a rapid i in myocardial signal intensity.

Myocardial areas with reduced blood ow have slower and reduced signal

change. The eect is enhanced by use of pharmaceutical coronary artery

vasodilators, e.g. adenosine, and can be used for the identication of MI

and reversible ischaemia. In contrast to nuclear perfusion imaging, high

444

CHAPTER6 Cardiology

444

spatial resolution allows detection of subendocardial, as well as transmural,

ischaemia.

Delayed contrast agent imaging

Gadolinium is an interstitial contrast agent, and it accumulates within 10min

after administration in tissue where extracellular membranes are damaged.

This is a powerful tool to delineate between myocardial scar tissue (i signal

intensity) and viable or hibernating myocardium (no change in signal inten-

sity on delayed imaging).

Velocity- encoded imaging

Velocities can be encoded into grey scale to measure the motion of cardiac

structures and the ow within great vessels. This has similar applications to

echocardiographic Doppler imaging and can be used to quantify valvular

disease, e.g. stenosis or regurgitant volumes, and congenital heart disease,

e.g. cardiac shunts.

Magnetic resonance angiography

A volume (3D) image acquisition is performed after a bolus of gadolinium

reaches an area of interest within the great vessels. This technique is use-

ful for evaluating aortic disease, congenital heart disease, and the presence

ofRAS.

Cardiac computed tomography

An infusion of iodinated contrast agent is given, and a volume image acquisi-

tion is attained during a 15– 20s breath- hold. Where coronary arteries are

the area of interest, a coronary artery calcication score is performed ini-

tially, and these data can then be used to guide further imaging. Aβ- blocker

may be required to lower the heart rate to optimize the image resolution.

Images are then post- processed to reconstruct them to attain clinical infor-

mation according to scan indication.

Risks

If appropriate screening is carried out to exclude patients with contraindi-

cations, then MRI carries minimal risk. Patients who are haemodynamically

unstable, e.g. acute aortic dissection, should undergo an alternative form

of imaging. CT exposes the patient to ionizing radiation, and so this should

limit its application.

Possible results

Figures 6.3– 6.9 show the types of images that can be acquired by CMR

imaging.

Advantages overothertests

Volumetric imaging is non- invasive and facilitates excellent temporal and

spatial denition of soft tissues. It overcomes diculties of echocardiog-

raphy where acoustic window availability limits the scan. CMR uses no

ionizing radiation and so is ideal for serial imaging. Avery comprehensive

examination can be performed and allows dynamic assessment of the heart

and great vessels at a single visit. Multislice CT provides very accurate infor-

mation regarding coronary artery disease and is a non- invasive alternative

to traditional coronary angiography.

CARDIAC VOLUMETRIC IMAGING

445

Pitfalls

CMR image quality may be impaired by artefact in some patients, especially

if metal is present, e.g. non- ferrous surgical clips, spinal rods, or prosthetic

valves. Rapid heart rates degrade the image quality in multisliceCT.

Aortic coarctation

bypass graft

Fig.6.3 Examples of volumetric imaging techniques— MRI black blood sequence

illustrating aortic coarctation bypass.

Aortic stenosis

Fig.6.4 MRI cine sequence of aortic stenosis.

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CHAPTER6 Cardiology

446

Inferoposterior

left ventricular

aneurysm

Thrombus

Fig.6.5 MRI cine sequence demonstrating huge inferoposterior left ventricular

aneurysm containing a thrombus.

Anteroseptal scar

Fig.6.6 MRI delayed enhancement study delineating subendocardial scar tissue in

the anteroseptal wall followingMI.

CARDIAC VOLUMETRIC IMAGING

447

Fig.6.7 MRI rst- pass perfusion:(i)prior to contrast injection; (ii) contrast agent

appears in the RV and (iii) LV; (iv, arrow) contrast opacies normally perfused

myocardium, (v, arrow) but identies an inferoseptal subendocardial perfusion decit.

Ascending aorta

aneurysm

Fig.6.8 Magnetic resonance angiogram (MRA) of a severe ascending aortic aneurysm.

448

CHAPTER6 Cardiology

448

Further reading

Myerson SG, Francis J, Neubauer S. Cardiovascular Magnetic Resonance. Oxford:Oxford University

Press,2010.

Nicol E, Stirrup J, Kelion AD, Padley SPG. Cardiovascular Computed Tomography. Oxford: Oxford

University Press,2011.

Descending aorta

dissection

Thrombus

Fig.6.9 CT of type II aortic dissection and associated thrombus.

CARDIAC VOLUMETRIC IMAGING

449

450

CHAPTER6 Cardiology

450

Echocardiography

Principle

Echocardiography is the use of US to visualize the anatomy, size, and func-

tion of cardiac structures, i.e. valves, chambers, myocardium, pericardium,

and great vessels. The technique provides information regarding the aeti-

ology and severity of most congenital and acquired cardiac abnormalities.

Imaging modalities

Several imaging modalities are available, including 2- dimensional (2D), 3D,

motion- mode (M- mode), Doppler, and contrast agent enhancement (see

Figs 6.10– 6.15).

2D imaging

2D echocardiography allows real- time visualization of cardiac anatomy,

abnormalities of cardiac structures, and their motion. Image quality is

enhanced by use of harmonic imaging and contrast opacication. With

some systems, 3D imaging is also possible.

3D imaging

3D echocardiography is now widely available and used in both TTE and

TOE. The modality is particularly useful for the assessment of left ventricu-

lar size and function, of congenital heart disease (morphology and function),

and in the guidance of interventional procedures (e.g. percutaneous atrial

septal defect closure).

M- mode imaging

M- mode imaging samples movement of cardiac structures along a single

scan line, creating a graph of the motion of sampled structures against time.

It is useful for accurate timing of cardiac events and measurement of cardiac

dimensions.

LV aneurysm

Fig.6.10 2D TTE image of the LV demonstrating an apical aneurysm.

ECHOCARDIOGRAPHY

451

Mitral & aortic

stenosis

Fig.6.11 2D TOE image of rheumatic heart disease (mitral and aortic stenosis).

Mitral

regurgitation

Fig.6.12 Colour Doppler of eccentric jet of severe mitral regurgitation 2° to mitral

valve prolapse. (E Colour plate1.)

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CHAPTER6 Cardiology

452

Mitral stenosis

Fig.6.14 Laminar pulsed- wave Doppler ow in a patient with mitral stenosis.

(E Colour plate2.)

M-mode Mitral valve

Fig.6.13 Normal M- mode through mitral valve leaets.

ECHOCARDIOGRAPHY

453

Doppler

Doppler is the comparison of transmitted US beam frequency with received

US frequency reected from moving structures, e.g. soft tissues (Doppler

tissue imaging) or blood cells. The direction of motion and its velocity can

be assessed. When blood cells reect US as they move towards the trans-

ducer, they compress the US wavelength, whereas if they are moving away,

the US wavelength lengthens. The change in frequency between the trans-

mitted and reected wavelengths is the Doppler shift frequency.

Continuous- wave Doppler

Continuous- wave (CW) Doppler acquires velocity data along the US beam’s

entire path. Blood ow of varying strengths and velocities is demonstrated

in blood vessels and through the cardiac valves. The signal is represented

graphically on a spectral display. Flow away from the transducer is reected

below the zero line; ow towards the transducer is +ve in deection. Signal

density and shape give an indication of the severity of any abnormalities.

CW Doppler velocity data can be used to measure the pressure gradi-

ents between the cardiac chambers according to the Bernoulli equation.

The data thus obtained can be used to calculate the severity of valvular ste-

nosis, expressed in terms of mean and peak pressure gradients, and eec-

tive orice area. The pressure half- time can be used to estimate the severity

of diastolic valvular lesions, i.e. mitral stenosis and aortic regurgitation. It is

dened as the time taken for the peak gradient to fall to half of its original

value. It is inversely related to the eective oricearea.

Pulsed- wave Doppler

The velocity of blood is sampled within a small area. Since this involves only

a small sample volume, it localizes blood ow. It is particularly useful for

evaluating low velocity ow such as cardiac inow and outow tract veloci-

ties. At higher velocities, it is limited by the problem of aliasing.

Tricuspid regurgitation

Fig.6.15 Continuous- wave Doppler of tricuspid regurgitation, with PmA systolic

pressure calculated as 54mmHg (plus right atrial pressure). (E Colour plate3.)

454

CHAPTER6 Cardiology

454

Colour Doppler

Colour Doppler colour- codes the direction and velocity of blood ow

through cardiac structures. Blood ow in the direction away from the US

probe is depicted as blue, whereas blood owing towards the probe is

red.i blood ow velocity is reected by colour mixing or turbulence. This

is a useful screening tool for abnormal jets of blood and can be used to

estimate the severity of some abnormalities.

Contrast echocardiography

Microbubbles, consisting of a gas core encapsulated by a protein shell, can

be used as contrast agents to improve image quality. Typically, they are used

in conjunction with harmonic imaging to allow opacication of the left ven-

tricular volume and thereby assess wall motion. Research is continuing into

their use to assess myocardial perfusion.

Transthoracic and transoesophageal echocardiography

TTE, where the US beam is directed to the heart from outside the chest

wall, is the most commonly performed examination. In certain clinical situ-

ations, more information is obtained by directing the US beam towards

the heart from the oesophagus, and this is termed TOE. This allows image

acquisition without interference of the chest wall, i.e. ribs, soft tissues, and

lungs. US beam attenuation is small and a high- frequency transducer can be

used, giving rise to higher spatial resolution than with TTE. This facilitates

improved denition of the posterior cardiac structures, i.e. valves, atria, and

aorta. Relatively small structures, such as cardiac vegetations, may be visual-

ized with greater accuracy.

Indications

Indications for TTE and TOE are shown in Table6.2.

Contraindications

TTE is a very safe imaging technique with no known side eects.

Contraindications to TOE include:

•

Cervical spine instability, e.g. RhA, ankylosing spondylitis.

• Oesophageal disease, e.g. stricture, carcinoma, oesophageal varices.

• Haemodynamically unstable patients, including signicant hypoxia.

Patient preparation

For both procedures, the patient is made comfortable on an imaging

couch in the left lateral position with the head end raised to at least 60°.

Cardiac electrodes should be applied to obtain an ECG trace. Aqueous

gel is used on the probe to aid US beam conduction. For TOE, the patient

should be nil by mouth for at least 6h prior to the procedure and IV access

sited. Any loose teeth or dentures should be removed. The throat should

be sprayed with an LAn, e.g. lidocaine, and a bite guard inserted prior to

intubation. The patient may be sedated according to the clinical situation,

patient preference, or operator recommendation. Antibiotic prophylaxis is

not required.

ECHOCARDIOGRAPHY

455

Procedure

For TTE, the probe is applied to the chest in standard imaging positions

(parasternal, apical, subcostal, and suprasternal), and the following imaging

planes (see Fig. 6.16) are acquired with use of all available modalities:

•

Parasternal (long axis and shortaxis).

• Apical (2- , 3- , 4- , 5- chamber).

• Subcostal and suprasternal.

For TOE, the probe is passed gently over the tongue towards the cri-

copharyngeal muscles. Gentle continuous pressure is applied, and the

patient is encouraged to swallow until the probe lies within the oesophagus.

Views of the cardiac structures are acquired from varying levels within the

oesophagus, gastro- oesophageal junction, and stomach.

Risks

TTE is extremely safe. TOE is a semi- invasive procedure, and so informed

written consent should be obtained. Intubation of the oesophagus carries

a risk of 71 per 2000 of oesophageal trauma. There is a small risk of laryn-

gospasm and cardiac arrhythmia (usually supraventricular). This usually

resolves spontaneously on probe withdrawal. Neither technique should be

performed on a haemodynamically compromised patient where an inter-

ventional procedure is delayed by inappropriate image acquisition, e.g. aor-

tic dissection, cardiac tamponade.

Table6.2 Indications forTTE andTOE

Condition TTE TOE

Congenital heart disease ++ +++

Suitability for percutaneous closure of atrial septal defect − ++++

Anatomy, size, and function of the cardiac chambers (left

atrium, LV, right atrium, RV)

+++ ++++

Global and regional left ventricular function +++ +++

Valvular heart disease (aortic, mitral, tricuspid, and pulmonary) +++ ++++

Assessment for mitral valvuloplasty + ++++

Prosthetic heart valves ++ ++++

Infective endocarditis (and its complications) ++ ++++

Guide to safe cardioversion (AF) − +++

Intra- operative assessment of valve disease/ repair/ replacement − +++

Pulmonary hypertension ++ +++

Unexplained pulmonary hypertension/ right- sided dilatation + ++++

Cardiac source of embolus in TIA/ CVA/ peripheral embolism + +++

Cardiac masses ++ +++

Pericardial disease +++ ++

Aortic disease + +++

Screening (cardiomyopathy) +++ ++

456

CHAPTER6 Cardiology

456

Fig.6.16 Transthoracic imaging planes:(a)parasternal long axis, (b)parasternal short axis at level of aortic valve, (c)mitral

valve, (d)papillary muscles, (e)suprasternal notch, (f– i) apical 5- , 4- , 3- , and 2- chamber views, (j)subcostal plane. LA, left

atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; Ao, aorta; PA, pulmonary artery; AV, aortic valve; MV, mitral valve;

DAo, descendingaorta.

a) b) c) d) e)

f) g) h) i) j)

ECHOCARDIOGRAPHY

457

Advantages overothertests

TTE is cheap and non- invasive and requires no ionizing radiation, ensuring

that serial examinations are without risk. It is portable and can easily be

used at the bedside. The technique provides a comprehensive assessment

of cardiac anatomy, function, and blood ow. TOE has similar advantages to

TTE, with the dierence that it is a semi- invasive technique but oers supe-

rior spatial resolution, particularly of structures in close proximity to the

probe (e.g. left atrium, mitral valve). It is a powerful tool for intra- operative

use and in patients with limited transthoracic windows.

Pitfalls

Transthoracic image quality may be limited by inadequate acoustic windows

in patients with obesity, lung disease, and chest wall deformities, and those

undergoing articial ventilation. Structures at the posterior aspect of the

heart are not well visualized. Optimal transoesophageal image quality is

obtained at the posterior aspect of the heart, and so the apex of the heart

is less well seen. Image quality may be compromised in patients with hiatus

hernia. Not all patients tolerate the procedure, and so images relating to the

suspected pathology should be acquired rst in case the procedure has to

be abandoned prematurely.

Possible results

Anatomy and size ofcardiac chambers

Normal anatomy is demonstrated to exclude congenital heart disease. Each

cardiac chamber and its connections are systematically identied and the

presence of any shunts excluded. The size of the cardiac chambers and

walls are assessed. Normal values are shown in Table6.3.

Causes ofchamber abnormalities include

• LAt dilatation:mitral valve disease, systemic hypertension, coronary

artery disease, dilated cardiomyopathy, restrictive cardiomyopathy,

hypertrophic cardiomyopathy,AF.

• Left ventricular dilatation:mitral regurgitation, aortic regurgitation, severe

aortic stenosis, systemic hypertension, IHD, dilated cardiomyopathy.

• Left ventricular hypertrophy:systemic hypertension, left ventricular

outow obstruction (aortic stenosis, supra- aortic membrane, subaortic

membrane), hypertrophic cardiomyopathy (asymmetric), aortic

coarctation, inltrative cardiomyopathy (amyloidosis).

Table6.3 Normal values forcardiac linear dimensions

Parameter Normal range

LAt diameter ♂ 3.0– 4.0cm

♀ 2.7– 3.8cm

Left ventricular diastolic diameter ♂ 4.2– 5.9cm

♀ 3.9– 5.3cm`

Interventricular septum diastolic diameter 0.6– 1.2cm

Left ventricular posterior wall diastolic diameter 0.6– 1.2cm

458

CHAPTER6 Cardiology

458

• Aortic root dilatation:systemic hypertension, collagen disorders, e.g.

Marfan’s syndrome, syphilitic aortitis, aortic coarctation, aortic valve

disease, aortic aneurysm, aortic dissection.

•

Right atrial (RAt) dilatation:tricuspid valve disease, pulmonary valve

disease, pulmonary hypertension, dilated cardiomyopathy, restrictive

cardiomyopathy, constrictive pericarditis.

•

Right ventricular dilatation:° pulmonary hypertension, 2° pulmonary

hypertension (e.g. mitral stenosis, PEs, lung disease, left- to- right shunts),

tricuspid regurgitation, pulmonary regurgitation, right ventricular

cardiomyopathy (including arrhythmogenic), right ventricular infarction.

•

Right ventricular hypertrophy:° pulmonary hypertension, 2° pulmonary

hypertension (e.g. mitral stenosis, PEs, lung disease, left- to- right shunts),

pulmonary stenosis, right ventricular outow tract obstruction.

•

Pulmonary trunk dilatation:pulmonary hypertension, collagen disorders,

e.g. Marfan’s syndrome, pulmonary atresia, pulmonary valve disease,

idiopathic PmA dilatation.

Global and regional left ventricular systolic function

The size, shape, and function of the LV are evaluated with 2D/ 3D imaging ±

contrast opacication. Commonly measured echocardiographic parameters

of left ventricular function include EF, fractional shortening, stroke volume,

and cardiac output. It should be remembered that, when calculated from

the M- mode image, only the function of the base of the heart is assessed.

This should not be extrapolated to global left ventricular function, unless the

entire ventricle is normal. EF can also be calculated from apical diastolic and

systolic views (using the modied Simpson’s rule). This is more reective of

global left ventricular function but is still limited since it is a 2D measurement

and requires geometric assumptions. Amore subjective assessment can be

made by visually estimating left ventricular function as normal or as having

mild, moderate, or severe impairment. Causes of impaired left ventricular

systolic functionare:

•

Ischaemic cardiomyopathy.

• Hypertensive cardiomyopathy.

• Dilated cardiomyopathy.

• Valvular heart disease.

Regional wall motion abnormalities are conned to specic walls or seg-

ments of the LV. Systolic wall thickening is dened in Table6.4.

Table6.4 Categorization ofregional wallmotion

Severity Description

Normal >50% i in systolic wall thickness, compared with diastole

Hypokinetic <50% i in systolic wall thickness, compared with diastole

Akinetic Absent systolic wall thickening

Dyskinetic Outward wall motion during systole

ECHOCARDIOGRAPHY

459

Causes ofregional wall motion abnormalities are almost exclusively related

tocoronary artery disease

•

MI.

• Left ventricular aneurysm.

• Myocardial hibernation.

• Myocardial ischaemia.

• Post- cardiac surgery.

• Cardiac tumour.

Stress echocardiography

Dobutamine stress may be used in conjunction with left ventricular global

and regional wall functional assessment. As well as allowing distinction

between normal, ischaemic, and infarcted myocardium, it also permits the

assessment of myocardial viability (regional dysfunction that will improve

with revascularization) vs scar tissue (no eect on function from revasculari-

zation). It should be noted that CMR is now proven to be a superior tech-

nique for identication of myocardial scar/ viability. Resulting interpretation

with respect to regional wall motion responses to low- dose and peak- dose

dobutamine stress is shown in Table6.5.

Left ventricular diastolic function

Left ventricular lling during diastole is an important component of left

ventricular functional assessment. Normal LAt lling is passive throughout

systole (S wave) and diastole (D wave) and is assessed from pulsed- wave

(PW) Doppler sampling of pulmonary venous ow. Left ventricular lling

is assessed from diastolic mitral valve ow. It is predominantly passive and

early in diastole (E wave), with a small later contribution from atrial sys-

tole (A wave). Diastolic dysfunction results in elevated left ventricular end-

diastolic pressure (LVEDP), and ultimately left atrial pressure (LAP), and

so alters measured ow characteristics. There are three types of diastolic

dysfunction (see Table 6.6), depending on the degree of raised LAP that

occurs in order to drive ow across the mitralvalve.

Right heart function

Right heart failure is depicted by a dilated, poorly functioning RV. Raised

right- sided pressures are indicated by a dilated right atrium and IVC (seen

on subcostalview).

Table6.5 Interpretation ofcontractile responses todobutaminestress

Interpretation Rest Low dose Peak dose

Normal Normal i Hyperdynamic

Inducible

ischaemia

Normal or d No change or

d from baseline

Scar tissue

Absent Absent Absent

Viability Absent Improved Improved or d compared

with low dose (biphasic

response)

460

CHAPTER6 Cardiology

460

Table

6.6 Echo assessment of left ventricular diastolic dysfunction

Characteristics

Abnormal relaxation Pseudonormalization Restrictive

Haemodynamics

iLVEDP

Normal LAP

Loss of passive gradient LA:LV

Left ventricular lling from atrial

systole

iLVEDP

iLAP

LA:LV passive lling gradient

restored

Pulmonary vein: LA gradient lost

iLVEDP

iiiLAP

LA:LV passive lling gradient

Pulmonary vein: LA gradient lost

Mitral valve

(E:A reversal Ed Ai)

Normal

(Eii, sharp descent, Ad)

Pulmonary venous o

w redaorb repeed ,evaw S dehsinimiDNormal

A wave

Diminshed S wave, deeper broader

A wave

Doppler pattern

(mitral valve

above pulmonary vein belo

ereveSetaredoMdliMLeft ventricular impairment

Signi

cance

Slow early left ventricular relaxation

Slow early relaxation, reduced

compliance

Slow early left ventricular relaxation,

severely reduced compliance

SymptomsWell at rest, but shortness of breath if

heart rate i

Shortness of breath on exercise and

limited exercise tolerance

Shortness of breath on minimal exertion

ECHOCARDIOGRAPHY

461

Pulmonary hypertension

Systolic PmA pressure, assuming there is no pulmonary valve stenosis, can

be estimated from the pressure gradient between the right atrium and ven-

tricle. This is measured from any tricuspid regurgitant jet (Bernoulli equa-

tion) summated with the estimated RAt pressure. Diastolic PmA pressure is

measured by substituting the end- diastolic velocity of pulmonary regurgita-

tion into the Bernoulli equation, again summated with the estimated RAt

pressure. If the systolic PmA pressure is raised but the diastolic pressure

is normal, this represents i ow volume, rather than pulmonary hyperten-

sion. RAt pressure is assessed by IVC diameter evaluation and its calibre

reduction with inspiration (see Table6.7).

Valvular heart disease

Echocardiography can identify and quantify valve abnormalities to decide

whether long- term follow- up or referral for valve surgery is necessary.

Valvesmaybe

•

Stenosed (narrowed).

• Regurgitant (leaky).

• Infected (endocarditis).

• Aected by other cardiac pathological processes, e.g. cardiomyopathy,

carcinoid.

Aortic stenosis

Aortic stenosis leads to left ventricular hypertrophy, i left ventricular pres-

sures, and, if untreated, LVF and risk of sudden death (see Table6.8).

Table6.7 Estimation ofright atrial pressure

IVC size (cm) IVC change with inspiration Estimated RAt

pressure (mmHg)

<1.5 Collapse

0– 5

1.5– 2.5 d >50% 5– 10

1.5– 2.5 d <50% 10– 15

>2.5 d <50% 15– 20

2.5 No change >20

Table6.8 Parameters ofaortic stenosis severity

Mild Moderate Severe

Mean gradient (mmHg) <25 25– 40 >40

Peak gradient (mmHg) <36 36– 64 >64

Eective orice area (cm

) 1.5– 2.0 1.0– 1.4 <1.0

462

CHAPTER6 Cardiology

462

• Aetiology:congenital abnormality (bicuspid, unicuspid, or quadricuspid

valve), calcic degenerative disease, rheumatic heart disease.

•

Dierential diagnosis:hypertrophic obstructive cardiomyopathy,

subaortic membrane, supra- aortic membrane.

• 2D/ 3D ndings:thickened, calcied, and/ or fused aortic cusps with

reduced excursion, left ventricular outow tract dimension (to calculate

the aortic valve area), eects on the LV (hypertrophy/ impaired systolic/

diastolic function), post- stenotic dilatation of the ascending aorta/ aortic

coarctation.

•

Colour Doppler ndings:turbulent bright colour is seen through thevalve.

•

CW/ PW Doppler ndings:peak and mean valvular gradients; aortic

valve area; the dimensionless severity index (DSI) is a useful parameter,

particularly where left ventricular function is impaired.

Aortic regurgitation

Aortic regurgitation leads to mild left ventricular hypertrophy, left ventricu-

lar dilatation, andLVF.

•

Aetiology:congenital abnormality (bicuspid, unicuspid, or quadricuspid

valve), rheumatic heart disease, aortic leaet prolapse, calcic or

idiopathic degeneration, subaortic VSD, infective endocarditis (presence

of vegetations), aortic dissection (aortic root dissection ap), ascending

aortic dilatation (hypertension, aortic stenosis, age), aortitis (syphilis,

ankylosing spondylitis, GCA, RhA, Reiter’s syndrome), degenerative

disease, including collagen disease, e.g. Marfan’s syndrome.

•

2D/ 3D ndings:aortic valve anatomy (including calcication, prolapse,

vegetations, presence of subaortic VSD), size of aortic root/ aortic

dissection ap/ aortic coarctation, eects on the LV (hypertrophy/

impaired systolic/ diastolic function).

• Colour Doppler ndings:a diastolic regurgitant jet is seen. The width of

the jet (colour M- mode) comparative with left ventricular outow tract

diameter and its extent into the left ventricular cavity is measured.

•

CW/ PW Doppler ndings:the density of the diastolic signal is assessed,

together with the pressure half- time. Diastolic ow reversal in the aortic

arch or descending aorta is indicative of signicant aortic regurgitation,

unless the left ventricular diastolic pressure is high from a separate

aetiology, e.g. MI. It can be dicult to dierentiate between mild and

moderate aortic regurgitation, especially with transthoracic imaging (see

Table6.9).

Table6.9 Parameters ofaortic regurgitation severity

Mild Moderate Severe

Jet width (as % of left

ventricular outow tract)

<25 65

Pressure half- time (ms) >500 <250

Vena contracta width (cm) <0.3 >0.6

Diastolic ow reversal

None Aortic arch Descending aorta

ECHOCARDIOGRAPHY

463

Mitral stenosis

Mitral stenosis causes LAt dilatation, i pulmonary venous pressures, pul-

monary oedema, pulmonary hypertension, right heart failure, and func-

tional tricuspid regurgitation. TOE should be used to assess the suitability of

the patient for percutaneous mitral valvuloplasty (see Table6.10).

•

Aetiology:rheumatic heart disease/ calcication (valve leaets, chordae,

or papillary apparatus), congenital abnormality (very rare), SLE (rare).

•

Dierential diagnosis:LAt myxoma, obstruction of the valve by thrombus

or vegetations.

•

2D/ 3D ndings:anatomy and degree of any calcication/ fusion of

the mitral valve leaets and apparatus for suitability for valvuloplasty,

eective orice area (evaluated with planimetry), LAt size (dilated),

presence of LAt thrombus, right heart size (hypertrophy) and function.

• Colour Doppler ndings:turbulent ow is seen through thevalve.

•

CW/ PW Doppler ndings:peak and mean valvular gradients are

calculated, the pressure half- time is measured, and the eective orice

area calculated. Pulmonary hypertension is estimated.

Mitral regurgitation

Mitral regurgitation causes LAt dilatation, i pulmonary venous pressures,

pulmonary oedema, LVF, pulmonary hypertension, right heart failure, and

functional tricuspid regurgitation. TOE gives an optimal assessment of

severity (see Table6.11).

Table6.10 Parameters ofmitral stenosis severity

Mild Moderate Severe

Mean gradient (mmHg) <5 5– 10 >10

Pressure half- time (ms) 71– 139 140– 219 >219

Mitral orice area (cm

) 1.6– 2.0 1.0– 1.5 <1.0

Table6.11 Parameters ofmitral regurgitation severity

Mild Moderate Severe

Jet area (cm

) <4 >10

Signal density on CW Doppler + ++ +++

Vena contracta width (cm) <0.3 0.7

Pulmonary venous ow

Normal Absent systolic

component

Reversed systolic

component

464

CHAPTER6 Cardiology

464

• Aetiology:rheumatic heart disease, mitral valve prolapse/ redundant

tissue, IHD (papillary muscle rupture/ infarction/ restriction of posterior

leaet), dilated/ ischaemic cardiomyopathy (annular dilatation),

hypertrophic obstructive cardiomyopathy (systolic anterior motion),

infective endocarditis (presence of vegetations), congenital abnormality

(very rare; note the association of cleft mitral valve and primum atrial

septal defect), SLE (rare).

•

2D/ 3D ndings:mitral valve anatomy (calcication, prolapse, redundant

tissue, leaet excursion, vegetations, annular size, apparatus integrity),

left ventricular size and function (hypertrophy, dilatation), LAt size

(dilatation), right heart function (hypertrophy, dilatation), and PmA

pressures.

•

Colour Doppler ndings:an abnormal systolic jet is seen through the

mitral valve into the left atrium. The size of this is assessed. This can be

deceptive with very eccentric jets associated with mitral valve prolapse.

•

CW/ PW Doppler ndings:signal density and shape are characterized.

Analysis of pulmonary venous ow with PW Doppler can be helpful.

Tricuspid stenosis

Tricuspid stenosis causes RAt dilatation and i systemic venous pressures.

•

Aetiology:rheumatic heart disease (occurs in 10% of patients with mitral

stenosis), carcinoid disease, endomyocardial brosis,SLE.

•

2D/ 3D ndings:tricuspid valve anatomy and degree of any doming,

calcication, fusion of tricuspid valve leaets and apparatus, size of the

right atrium, and IVC (dilated).

•

Colour Doppler ndings:turbulent ow is seen through thevalve.

•

CW/ PW Doppler ndings:peak and mean valvular gradients are

calculated, the pressure half- time is estimated, and the eective orice

area calculated. Pulmonary hypertension is calculated from the velocity

of any tricuspid regurgitant jet. Peak E wave velocity is elevated (normal

peak is <0.7ms

−1

) and there is a slow deceleration time. Amean

gradient of 2– 3mmHg may be clinically signicant.

Tricuspid regurgitation

Tricuspid regurgitation leads to RAt dilatation, right ventricular hypertro-

phy, and failure (see Table6.12).

Table6.12 Parameters oftricuspid regurgitation severity

Mild Moderate Severe

Jet area (cm

) <5 5– 10 >10

Vena contracta width (cm) <0.7 >0.7

Signal density on CW Doppler + ++ +++

Shape of CW Doppler signal Pansystolic Pansystolic Triangular

Hepatic venous ow reversal None Absent systolic

component

Pansystolic ow

reversal

ECHOCARDIOGRAPHY

465

• Aetiology:rheumatic heart disease, infective endocarditis (IV drug abuse),

functional (2° to right ventricular dilatation, e.g. cardiac left- to- right

shunts, right ventricular cardiomyopathy, pulmonary hypertension,

permanent pacing system), carcinoid disease, Ebstein’s anomaly, SLE,

myxomatous degeneration, cardiac amyloidosis.

•

2D/ 3D ndings:tricuspid valve anatomy (site, calcication, prolapse,

redundant tissue, leaet excursion, vegetations, annular size, apparatus

integrity), right ventricular size (dilated) and function, size of the right

atrium, IVC (dilated), presence of pacingwires.

•

Colour Doppler ndings:abnormal systolic jet is seen through the tricuspid

valve into the right atrium. The size of this is assessed, compared with

the right atrium.

•

CW/ PW Doppler ndings:the density of the signal and shape is assessed.

Analysis of hepatic ow with PW Doppler can be helpful. Pulmonary

arterial pressure can be measured but may be underestimated if there is

severe tricuspid regurgitation.

Pulmonary stenosis

Pulmonary stenosis causes right ventricular hypertrophy and, if left

untreated, right heart failure (see Table6.13).

•

Aetiology:congenital, rheumatic heart disease, carcinoid.

•

Dierential diagnosis:right ventricular outow obstruction (infundibular

stenosis).

•

2D/ 3D ndings:pulmonary valve anatomy (calcication, leaet

thickening, doming), size of the pulmonary trunk (post- stenotic

dilatation), eects on the RV (hypertrophy/ impaired function).

• Colour Doppler ndings:turbulent systolic ow through the

pulmonaryvalve.

•

CW/ PW Doppler ndings:The maximum gradient and pulmonary valve

area are calculated.

Pulmonary regurgitation

•

Aetiology:congenital, infective endocarditis (IV drug abuse), pulmonary

hypertension, PmA dilatation, carcinoid disease, post- pulmonary

valvotomy.

•

2D/ 3D ndings:pulmonary valve anatomy (calcication, prolapse,

vegetations), size of the pulmonary trunk, eects on the RV

(hypertrophy/ impaired function).

• Colour Doppler ndings:a diastolic regurgitant jet is seen. The width of

the jet and its extent into the right ventricular outow tract and cavity

are measured.

Table6.13 Parameters ofpulmonary stenosis severity

Mild Moderate Severe

Peak gradient (mmHg) <40 40– 75 >75

466

CHAPTER6 Cardiology

466

• CW/ PW Doppler ndings:the density of the diastolic signal and its

duration are estimated. Pulmonary regurgitation is haemodynamically

signicant if the jet is broad relative to the width of the PmA, extends

>2cm into the right ventricular outow tract, and persists throughout

diastole.

Prosthetic heartvalves

Echocardiography is used for follow- up of prosthetic heart valves and

potential dysfunction. It is important to consult tables of normal ow pat-

tern values for each valve type according to its make and size. TOE is supe-

rior to TTE. The following parameters are assessed:

•

Direct 2D/ 3D imaging of the valve ring and leaets.

• Presence of any rocking motion suggestive of valvular dehiscence.

• Forward blood ow through thevalve.

• Valvular regurgitation (typical regurgitation on valve closure is normal).

• Infective endocarditis.

• Thrombus/ pannus.

Infective endocarditis

The following features are characteristic of infective endocarditis:

•

Predisposing abnormal structure (valve lesion/ congenital abnormality).

• Regurgitant lesion.

• Mobile echogenic masses (vegetations, usually in the path of

regurgitantjets).

•

Spread of infection to other valves (usually along the path of a

regurgitantjet).

•

Abscess (particularly around the aortic root, prosthetic valves).

• Embolic potential (large, mobile vegetations, especially the aortic valve).

• Valve destruction (degree of regurgitation and eect on cardiac

chamber size and function).

•

Chamber perforation and shunting.

• Prosthetic valve dehiscence.

Pericardial disease

The normal pericardium is poorly visualized with echocardiography, since it

is a very thin structure. Pericardial abnormalities that may be identiedare:

•

Pericardial eusion (uid between the pericardial layers).

• Pericardial thickening or calcication (constrictive pericarditis).

• Pericardial masses, e.g. cysts or tumour.

Pericardial eusion

A pericardial eusion gives rise to echo- free space around the heart. The

anatomical relationship of pericardial uid with the descending aorta dis-

tinguishes pericardial (anterior) and pleural (posterior) eusions. If the

eusion is organizing or contains a thrombus or tumour, then echodense

structures may be identied within it. The width of this space is measured

to give a rough guide as to the size of the eusion:

•

Small:<1cm

• Moderate1:1– 2cm.

• Large:>2cm.

ECHOCARDIOGRAPHY

467

The most important assessment is whether uid is causing any haemody-

namic compromise, i.e. cardiac tamponade. This may occur regardless of

the size of the eusion, particularly if it has accumulated rapidly. Features

suggestive of a tamponade include:

•

Dilatation of the IVC (>2.5cm), poor collapse with inspiration (<50%).

• Exaggerated reduction in transmitral velocities on inspiration (>40%).

• Right ventricular diastolic collapse.

• Low- volume, poorly lledLV.

Constrictive pericarditis

This is typically caused by TB and constrains left and right ventricular ll-

ing. On 2D imaging, the pericardium is thickened and appears bright when

calcication is present. The period of left ventricular diastolic function is

shortened. Systolic function is normal. Dopplershows:

•

Exaggerated reduction of transmitral E wave velocity with inspiration.

• Shortened transmitral E wave decelerationtime.

• Exaggerated ow reversal in the superior vena cava (SVC) on expiration.

Cardiacmasses

The commonest intra- cardiac masses are thrombi and vegetations (infective

endocarditis). Thrombus formation is i in conditions causing slow blood

ow such as mitral or tricuspid valve stenosis or cardiomyopathy. The com-

monest cardiac tumours are atrial myxomas and metastatic deposits. An

atrial myxoma is typically a pedunculated, frond- like mass that arises from

the interatrial septum. Metastatic deposits can be found anywhere within

the heart, including the pericardium. Extrinsic masses may cause compres-

sion of cardiac structures. Atrial pectinate muscles, Eustachian valve, Chiari

network, papillary muscles, brin strands, sutures on prosthetic valves, large

vascular structures, such as the aorta, coronary sinus, or left ventricular

aneurysms, may be incorrectly interpreted as cardiac masses.

•

Atrial masses:thrombus, myxoma, lipomatous hypertrophy of the

interatrial septum, ruptured mitral valve apparatus, ° benign tumour, °

malignant tumour, 2° tumour.

•

Ventricular masses:thrombus, ruptured mitral valve apparatus, ° benign

tumour (broma, lipoma, rhabdomyoma, haemangioma), ° malignant

tumour (rhabdomyosarcoma, brosarcoma, angiosarcoma), 2° tumour.

•

Valvular masses:vegetations, thrombus/ pannus, broelastoma.

Aortic disease

The aorta is a predominantly posterior structure, and so the arch and

descending aorta are best visualized byTOE.

•

2D ndings:integrity of the walls is assessed for atheroma (irregular wall

thickening), intramural haematoma, or dissection ap. The latter may be

indirectly suspected from the presence of pericardial eusion or aortic

regurgitation. Its anatomy and extent are noted to allow classication.

Presence of regional left ventricular wall motion abnormalities may

indicate coronary artery involvement. The size of the aorta is measured

at several sites to assess dilatation or coarctation (see Table 6.14). The

normal aortic wall thickness is4mm.

468

CHAPTER6 Cardiology

468

• Doppler ndings:colour, CW, and PW Doppler can all be used to

distinguish between true (normal systolic velocity ow) and false (low

or absent systolic ow) lumens in aortic dissection, to identify and

determine the severity of aortic regurgitation and aortic coarctation.

Congenital heart disease

It is important to recognize situs and connections of cardiac chambers and

great vessels.

•

The RV is recognized by the following features:

•

It is associated with the tricuspidvalve.

•

The tricuspid valve is sited more towards the apex than the

mitralvalve.

•

The tricuspid and pulmonary valves are not continuous (compare the

aortic and mitral valves).

•

It is trabeculated and contains a moderatorband.

• The ventricles should be connected to the correct outowtract:

•

The aorta is a single vessel.

•

The PmA bifurcates soon after its origin, unless hypoplasia/ atresia is

present.

•

The atria should be connected to the correct inow:

•

The pulmonary veins normally drain into the left atrium. Drainage

into alternative structures, e.g. SVC or IVC, hepatic veins, is referred

to as anomalous pulmonary venous drainage and is associated with a

left- to- rightshunt.

There should be no shunts between systemic and pulmonary systems; such

shunts include atrial septal defect (abnormal connection between the left

and right atria; see Table 6.15), VSD (abnormal connection between the LV

and RV; see Table 6.16), or patent ductus arteriosus (abnormal connection

between the aorta andPmA).

If shunts are identied, they are quantied. Pulmonary artery pressure is

assessed, together with evidence of shunt reversal (right to left), indicat-

ing Eisenmenger’s syndrome. Fallot’s tetralogy is a relatively common con-

genital condition, composed of a subaortic VSD, an overriding aorta, right

ventricular outow tract or pulmonary valve stenosis, and right ventricular

hypertrophy.

Table6.14 Normal aortic dimensions

Site Normal range (mm)

Annulus 20– 31

Sinus of Valsalva 29– 45

Sinotubular junction 22– 36

Tubular ascending aorta 22– 36

Descending 20– 30

ECHOCARDIOGRAPHY

469

Valves and outow tracts should be morphologicallynormal

•

Aortic valve:may be unicuspid, bicuspid, quadricuspid, or associated with

a subaortic or supra- aortic membrane.

• Pulmonary valve/ right ventricular outow tract:may be obstructed.

•

Mitral valve:cleft leaet associated with primum atrial septal defect,

mitral stenosis, parachutevalve.

•

Tricuspid valve:ventricularization of site=Ebstein’s anomaly.

•

Aortic and pulmonary arteries:should be normal situs, size, and anatomy,

and unobstructed:

•

Left- sided aortic arch, aortic coarctation.

•

Pulmonary hypoplasia, atresia, aecting either of the PmAs after

trunk bifurcation.

Further reading

British Society of Echocardiography. M http:// www.bsecho.org.

Houghton AR. Making Sense of Echocardiography, 2nd edn. Boca Raton:CRC Press,2014.

Leeson P, Augustine D, Mitchell ARJ, Becher H. Echocardiography, 2nd edn. Oxford: Oxford

University Press,2012.

Otto CM. Textbook of Clinical Echocardiography, 5th edn. Philadelphia:Elsevier Saunders,2013.

Table6.15 Types ofatrial septaldefect

Atrial septal defects Site Associations

Ostium secundum Fossa ovalis Mitral valve prolapse

Ostium primum Low septum

AV valve abnormalities

Sinus venosus Upper septum Anomalous pulmonary venous drainage

Table6.16 Types ofventricular septaldefect

VSD Site Associations

Membranous Infundibular septum

Subaortic Below aortic valve

Aortic regurgitation

Fallot’s tetralogy

Muscular Muscular septum

AV Posterior septum near AV valves AV valve abnormalities

470

CHAPTER6 Cardiology

470

Electrocardiogram

Principle

The ECG records the heart’s electrical activity. It can provide valuable infor-

mation about not just arrhythmias, but also a host of other disorders that

aect the electrical activity of the myocardium such as ischaemia, cardio-

myopathy, and electrolyte disturbances.

Indications

• Investigation of suspected arrhythmias, both to ‘capture’ the cardiac

rhythm, whilst the patient is experiencing symptoms, and also to look

for predisposing abnormalities, e.g. short PR interval, ventricular pre-

excitation (deltawaves), conduction abnormalities, long QT interval.

•

Investigation of chest pain, e.g. myocardial ischaemia or infarction,

pericarditis,PE.

•

Assessment of suspected cardiomyopathy and/ or LVF (a normal ECG is

unusual in the presence of left ventricular systolic dysfunction).

•

Assessment of electrolyte disturbances, particularly where these might

have pro- arrhythmic potential, e.g. hyperkalaemia.

• Assessment of drug eects on the heart, e.g. digoxin, tricyclic

antidepressants.

Contraindications

None. However, always check if the patient has a known allergy to the self-

adhesive pads used to attach the electrodes to theskin.

Patient preparation

• Explain what the procedure involves.

• Ask the patient to lie supine on a bed or examinationcouch.

• Prepare the skin by shaving, where necessary, and cleaning with

alcoholwipes.

•

Ask the patient to relax and lie still, whilst the recording is in progress.

Procedure

• Having prepared the patient for the test, attach the chest and limb

electrodes in the appropriate positions.

•

Before recording the ECG, check that the calibration settings of the

ECG machine are appropriate. Standard settings are an amplitude of

10mm/ 1mV and a paper speed of 25mm/ s. Ensure that these settings

are noted on theECG.

•

After recording the ECG, ensure that the patient’s identication details

and the time and date of the recording are notedonit.

•

It is good practice to make a record on the ECG of any symptoms (e.g.

chest pain, palpitations) that the patient was experiencing at the time of

the recording or to write ‘asymptomatic’ where appropriate.

•

Ensure that the ECG is seen and reported by an appropriate sta

member as soon as practicable.

ELECTROCARDIOGRAM

471

Reporting thendings

Always use a systematic approach to ECG reporting to ensure nothing is

overlooked.

Report theECG inthe followingorder

•

Heart rate:bradycardia vs tachycardia.

•

Rhythm:regular vs irregular, supraventricular vs ventricular, broad

complex vs narrow complex.

•

QRS axis:left or right axis deviation.

•

P wave:presence or absence, inverted, tall (peaked), or wide (bid).

•

P– R interval:long, short, or variable.

•

Q waves:are pathological Q waves present?

•

QRS complex:large, small, broad, or abnormally shaped.

•

ST- segment:elevated or depressed.

•

T wave:tall, small, or inverted.

•

QT interval:short orlong.

•

U wave:are prominent U waves present?

•

Additional waves:are delta waves or J waves present?

Possible results

Heartrate

Heart rate can be calculated inone oftwoways

•

By counting the number of large squares between two successive

QRS complexes and dividing this number into 300, e.g. four large

squares=300/ 4=75bpm. This method is preferred when the heart

rhythm is regular.

•

By counting the number of QRS complexes along a 25cm rhythm strip

(50 large squares) and multiplying this number by 6, e.g. 14 complexes

in 25cm=14 × 6=84bpm. This method is preferred when the heart

rhythm is irregular.

Bradycardia is arbitrarily dened as a heart rate <60bpm, and tachycardia as

a heart rate >100bpm.

If thepatient is bradycardic, consider

•

Sinus bradycardia.

• Sick sinus syndrome.

• Second- and third- degree AVblock.

• Escape rhythms, e.g. AV junctional escape rhythms, ventricular escape

rhythms, asystole, and drug- induced conditions.

If thepatient is tachycardic, consider

•

Narrow complex tachycardia:e.g. sinus tachycardia, atrial tachycardia,

atrial utter, AF, AV re- entry tachycardias.

• Broad complex tachycardia:e.g. narrow complex tachycardia with

aberrant conduction, ventricular tachycardia, accelerated idioventricular

rhythm, torsades de pointes.

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CHAPTER6 Cardiology

472

Cardiacrhythm

To identify thecardiac rhythm, ask thefollowing questions

•

How is the patient?

• Is ventricular activity (QRS complexes) present?

• What is the ventricularrate?

• Is the ventricular rhythm regular or irregular?

• Are the QRS complexes narrow orbroad?

• Are there P waves (atrial activity)?

• What is the correlation between P waves and QRS complexes?

Being able to describe the cardiac rhythm in these terms will narrow down

the range of possible diagnoses in most cases and you will, at least, be able

to describe the key features of the rhythm clearly over the telephone to

an expert.

Rhythms toconsider include

•

Sinoatrial nodal rhythms:

•

Sinus rhythm.

•

Sinus bradycardia.

•

Sinus tachycardia.

•

Sinus arrhythmia.

•

Sick sinus syndrome.

• Atrial rhythms:

•

Atrial tachycardia.

•

Atrial utter (see Fig.6.17).

•

AF (see Fig.6.18).

•

AV junctional rhythms.

•

AV re- entry tachycardias (see Fig.6.19).

• Ventricular rhythms:

•

Accelerated idioventricular rhythm.

•

Ventricular tachycardia (see Fig.6.20).

•

Polymorphic ventricular tachycardia (torsades de pointes;

seeFig.6.21).

•

Ventricular brillation (see Fig.6.22).

Fig.6.17 Atrial utter with 4:1 AVblock.

Fig.6.18 Atrial brillation.

ELECTROCARDIOGRAM

473

Fig.6.19 AV re- entry tachycardia.

Fig.6.20 Ventricular tachycardia.

Fig.6.21 Polymorphic ventricular tachycardia.

Fig.6.22 Ventricular brillation.

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CHAPTER6 Cardiology

474

• Conduction disturbances.

•

Escape rhythms.

•

Ectopicbeats.

QRSaxis

•

Left axis deviation:left anterior hemiblock, Wol– Parkinson– White

syndrome, inferior MI, ventricular tachycardia (with left ventricular apical

focus).

•

Right axis deviation:left posterior hemiblock, right ventricular

hypertrophy, Wol– Parkinson– White syndrome, anterolateral MI,

dextrocardia.

Pwave

•

P waves absent:AF, sinus arrest or sinoatrial block (persistent or

intermittent), hyperkalaemia.

•

P waves inverted:dextrocardia, retrograde atrial depolarization,

electrode misplacement.

•

Tall or peaked P waves:RAt enlargement.

• Wide, often bid P waves:LAt enlargement.

PR interval

•

Short PR interval (<0.12s):AV junctional rhythm,

Wol– Parkinson– White syndrome (see Fig.6.23).

• Long PR interval (>0.2s):rst- degree AV block (see Fig. 6.24),

e.g.IHD,hypokalaemia, acute rheumatic myocarditis, Lyme disease,

digoxin, β- blockers, certain calcium channel blockers.

• Variable PR interval:second- degree AV block (Mobitz type I(see Fig. 6.25),

Mobitz type II, 2:1 AV block), third- degree AV block (see Fig.6.26).

Fig.6.23 Wol– Parkinson– White syndrome.

Fig.6.24 First- degree AVblock.

Fig.6.25 Second- degree AV block (Mobitz typeI).

ELECTROCARDIOGRAM

475

Qwaves

•

Pathological Q waves:MI, left ventricular hypertrophy, bundle

branchblock.

QRS complex

•

Large R or S waves:incorrect ECG calibration, left ventricular

hypertrophy, right ventricular hypertrophy, posterior MI,

Wol– Parkinson– White syndrome (left- sided accessory pathway),

dextrocardia, bundle branchblock.

•

Small QRS complexes:incorrect ECG calibration, obesity, emphysema,

pericardial eusion.

•

Broad QRS complexes (>0.12s):bundle branch block, ventricular

rhythms, hyperkalaemia.

•

Abnormally shaped QRS complexes:incomplete bundle branch block,

fascicular block, Wol– Parkinson– White syndrome.

ST- segment

• Elevated ST- segments:acute STEMI (see Fig. 6.27), left ventricular

aneurysm, Prinzmetal’s (vasospastic) angina, pericarditis (concave

‘saddle- shaped’ appearance), high take- o.

• Depressed ST- segments:myocardial ischaemia, acute posterior MI, drugs,

e.g. digoxin (reverse tick), ventricular hypertrophy with ‘strain’.

Twave

•

Tall T waves:hyperkalaemia, acuteMI.

•

Small T waves:hypokalaemia, pericardial eusion, hypothyroidism.

•

Inverted T waves:normal (aVR, V1, sometimes V2– V3 and III),

myocardial ischaemia, MI, ventricular hypertrophy with ‘strain’, digoxin

toxicity.

Fig.6.26 Third- degree AVblock.

Fig.6.27 AnterolateralSTEMI.

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CHAPTER6 Cardiology

476

QT interval

• Short QT interval:hypercalcaemia, digoxin eect, hyperthermia.

•

Long QT interval:hypocalcaemia, drug eects, acute myocarditis,

hereditary syndromes (Jervell and Lange– Nielsen syndrome, Romano–

Ward syndrome).

Uwave

•

Prominent U waves:hypokalaemia, hypercalcaemia, hyperthyroidism.

Jwave

•

If present:hypothermia.

Pitfalls

• Acommon error is to interpret an ECG in isolation. To avoid this error,

always consider the clinical context in which it was recorded. Begin your

assessment of the ECG by asking, ‘How is the patient?’ before rushing

to conclusions about the clinical relevance of any abnormalities that may

be present.

•

Anormal ECG does not necessarily exclude a signicant cardiac

problem, particularly when recorded whilst the patient is asymptomatic.

This is particularly the case when investigating palpitations and

chestpain.

•

Technical artefacts are often mistaken for signicant abnormalities.

Ensure adequate patient preparation and correct electrode placement

to minimize the risk of artefact.

Further reading

Houghton AR, Gray D. Making Sense of the ECG, 4th edn. Boca Raton:CRC Press,2014.

ELECTROCARDIOGRAM

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478

Electrocardiographic monitoring

Principle

ECG monitoring allows continuous observation of a patient’s ECG in an

ambulatory setting over an extended period of time. This is typically from

24h all the way up to a year or more, depending upon the technique used.

There are three types of device available for ambulatory ECG monitoring:

•

24h ambulatory ECG (Holter) monitor.

• External loop recorder.

• Insertable cardiac monitor (e.g. Medtronic Reveal LINQ

™

The choice of device is largely determined by how frequently the patient

experiences symptoms, as the key to successful ECG monitoring is to maxi-

mize the chances of capturing a typical symptomatic event during the moni-

toring period. AHolter monitor is typically worn for 24– 48h but becomes

somewhat impractical over longer periods. It is therefore ideally suited to

patients with frequent (daily) symptoms. An external loop recorder (often

called an event monitor) is carried for around 7days and is therefore used

for patients with less frequent symptoms. Instead of recording a continuous

ECG, they capture brief periods of the ECG, usually when activated by

the patient. Transtelephonic monitors allow captured loops to be relayed

to a cardiac centre by telephone, allowing an immediate analysis of the

recordedECG.

An insertable cardiac monitor (ICM) is used to detect infrequent events.

It is used to monitor a patient’s cardiac rhythm over an extended period (up

to its battery life, usually around 3years). An ICM is implanted SC and con-

tains a battery, a digital memory, and diagnostic software to analyse the ECG

recording. It records the ECG on a digital ‘loop’, continuously overwriting

older ECG data with the most current data. Should a symptomatic event

occur, the patient can ‘freeze’ the loop using an external hand- held device

that is held over the ICM (‘patient- activated’ recordings). Additionally, the

device can be programmed to detect and store abnormal cardiac rhythms

automatically (‘auto- activated’ recordings). The device will usually store the

ECG leading up to an event and also a short segment of ECG following

the event. Stored ECG loops can subsequently be downloaded for further

analysis via a telemetry device at the hospital clinic or via a wireless device

in the patient’s ownhome.

Indications

Where patients have symptoms suggestive of a paroxysmal arrhythmia

(palpitation and/ or dizziness/ syncope), ECG monitoring can provide a

diagnosis by capturing the cardiac rhythm during a typical event. This allows

the underlying arrhythmia to be identied or, where the rhythm proves to

be normal, an arrhythmic aetiology to be ruled out. The choice of method

depends upon the frequency of the symptoms.

Contraindications

None. However, always check if the patient has a known allergy to the self-

adhesive pads used to attach the electrodes to theskin.

ELECTROCARDIOGRAPHIC MONITORING

479

Patient preparation

For external monitoring, no specic preparation is required, apart from

ensuring that the electrodes make good contact with the patient’s skin, so

that an ECG of diagnostic quality can be recorded. For the implantation of

anICM:

•

Explain what the procedure involves.

• Obtain written informed consent.

• Check the FBC (and clotting prole if bleedingrisk).

• LAn.

• Sedation if the patient is anxious.

The best site for the device is established by optimal ECG signal measure-

ment prior to insertion.

Procedure

External monitors are attached to the patient’s skin via electrodes, ensur-

ing good contact is maintained. The recorder itself is carried on a belt or

in a pouch. The patient should be given a diary with clear instructions on

how to operate the monitor and how to note the timing and nature of any

symptoms that occur. Some event monitors are carried by the patient and

only applied to the skin during symptomatic episodes. The patient should

be given clear instructions on how to operate such a monitor and a ‘test

run’ should be conducted.

An ICM is implanted SC under aseptic technique and using LAn. The

implantation takes around 15min and can be done as a day case procedure.

The device is self- contained since, unlike a pacemaker, there are no asso-

ciated leads. The ICM is commonly implanted near the left deltopectoral

groove or below the left breast. Once implanted, the device is interrogated

using an external programmer to ensure that a high- quality ECG is being

recorded. The incision is closed using surgical glue or buttery closures.

Risks

External monitoring carries no signicant risks. Implantation of an ICM car-

ries a riskof:

•

Infection.

• Erosion through the skin (if the patient isthin).

Possible results

Depending upon the underlying cause of the patient’s symptoms, almost

any cardiac rhythm disturbance (or indeed no rhythm disturbance whatso-

ever) may be revealed by ECG monitoring. The most important aspect of

interpreting the results is to correlate recordings with symptoms. Patient-

activated recordings are, as one might expect, usually made in relation to a

symptomatic episode. In this case, it is essential to nd out precisely what

symptoms were experienced at the time (including a witness account where

appropriate). Auto- activated recordings may be asymptomatic and made by

the device without the patient being aware of a problem. The most useful

outcome is to assess the ECG recorded during a typical symptomatic event.

It is then usually straightforward to make a diagnosis and plan further treat-

ment as appropriate.

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CHAPTER6 Cardiology

480

Advantages overothertests

Ambulatory ECG monitoring allows the chance of capturing paroxysmal

arrhythmias, an opportunity that is unlikely to arise with a 12- lead ECG

recording unless the patient happens to be symptomatic at the time. Each of

the methods of ECG monitoring has advantages over the others. External

monitoring is non- invasive but can only be performed for relatively short

periods. An ICM allows continuous ECG monitoring over a much longer

period, making it extremely useful for investigating patients with infrequent,

but nonetheless troublesome, symptoms. It does, however, involve an inva-

sive procedure (with the attendant risks) and is more expensive than other

forms of ambulatory monitoring. It can, however, prove very cost- eective

if it avoids the need for multiple short- term ambulatory recordings.

Pitfalls

As with any other form of ambulatory monitoring, failure to correlate

symptoms with recorded events can lead to inappropriate diagnoses.

Further reading

Crawford MH, Bernstein SJ, Deedwania PC, etal. ACC/ AHA guidelines for ambulatory electrocardi-

ography:executive summary and recommendations. Circulation 1999; 100

:886– 93.

National Institute for Health and Care Excellence (2010). Transient loss of consciousness (‘blackouts’) in

over 16s. Clinical guideline CG109. M

http:// www.nice.org.uk/ guidance/ cg109.

Task Force for the Diagnosis and Management of Syncope; European Society of Cardiology (ESC);

European Heart Rhythm Association (EHRA); Heart Failure Association (HFA); Heart Rhythm

Society (HRS), Moya A, Sutton R, Ammirati F, etal. Guidelines for the diagnosis and management

of syncope (version 2009). Eur Heart J 2009; 30

:2631– 71.

ELECTROCARDIOGRAPHIC MONITORING

481

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CHAPTER6 Cardiology

482

Exercise testing

Principle

Exercise testing permits the dynamic assessment of cardiac function. There

are many dierent indications for exercise testing, but the commonest is the

investigation of suspected or knownCHD.

Indications

• Assessment of likelihood of CHD in patients with chestpain.

• Risk stratication of patients with known CHD and hypertrophic

cardiomyopathy.

•

Evaluation of response to treatment or revascularization inCHD.

• Assessment of exercise- induced arrhythmias.

• Assessment of symptoms in valvular heart disease.

• Objective assessment of exercise capacity.

Contraindications

The absolute and relative contraindications to exercise testing are listed in

Box6.1.

Box 6.1 Absolute and relative contraindications

toexercise testing

Absolute contraindications

•

Recent MI (within 2days)

• Unstable angina (rest pain within previous48h)

• Uncontrolled cardiac arrhythmias (causing symptoms or

haemodynamic compromise)

•

Symptomatic severe aortic stenosis

• Uncontrolled symptomatic heart failure

• Acute PE or pulmonary infarction

• Acute myocarditis or pericarditis

• Acute aortic dissection

Relative contraindications

•

Left main stem coronary stenosis

• Moderate valvular stenosis

• Electrolyte abnormalities

• Uncontrolled hypertension (systolic >200mmHg, diastolic

>110mmHg)

• Tachyarrhythmias or bradyarrhythmias

• Outow obstruction, e.g. hypertrophic cardiomyopathy

• Inability to exercise adequately

• High- degree AVblock

EXERCISE TESTING

483

Patient preparation

Unless the exercise test is being performed to assess response to treatment,

patients should be advised to discontinue anti- anginal drugs, e.g. β- blockers,

calcium channel blockers, long- acting nitrates, nicorandil, and also digoxin 48h

prior to the test. Patients should attend for the test wearing suitable clothing

and footwear.

Procedure

The test should be carefully explained to the patient, so that they are famil-

iar with the exercise protocol being used. Aresting ECG is recorded, and

the patient’s BP measured. An appropriately trained team comprising at

least two personnel, trained in advanced life support, should supervise the

test. Full resuscitation and debrillation facilities must be readily available.

Exercise can be performed using either an exercise treadmill or an exercise

bicycle. Avariety of protocols are available, of which the commonest are

the Bruce protocol and the modied Bruce protocol (see Table 6.17). The

workload during exercise normally i at 3min intervals, with the BP and ECG

being recorded at each stage. The patient should be asked to report any

symptoms during thetest.

Exercise should be stopped ifthereis

•

Afall of >10mmHg in systolic BP from baseline associated with

ischaemia.

•

Moderate to severe angina.

• i ataxia, dizziness, or near syncope.

•

Evidence of poor perfusion.

• Diculty in monitoring the ECGorBP.

• Onset of arrhythmias (ventricular tachycardia, supraventricular

tachycardia, AF, worsening ventricular ectopics).

• 1.0mm or more ST elevation (in leads without Q waves, other than V1

oraVR).

•

Arequest from the patient to stop thetest.

One should also consider stopping theexercise ifthereis

•

Afall of >10mmHg in systolic BP from baseline, even in the absence of

ischaemia.

•

>3mm of ST- segment depression or marked axisshift.

• Development of bundle branch block that cannot be distinguished from

ventricular tachycardia.

Table6.17 Modied Bruce and Bruce protocols

Protocol Modied Bruce Standard Bruce

Stage 01 02 03 1 2 3 4 5

Speed (kph) 2.7 2.7 2.7 2.7 4.0 5.5 6.8 8.0

Slope (°) 0 1.3 2.6 4.3 5.4 6.3 7.2 8.1

484

CHAPTER6 Cardiology

484

• i chestpain.

•

Rise in BP above 250/ 115.

• Fatigue, breathlessness or wheezing, leg cramps, claudication.

At the end of the exercise, the patient may be permitted to sit. Monitoring

of the ECG and BP must continue until the heart rate and BP have returned

to baseline and any ECG changes have resolved.

Risks

Exercise testing is generally well tolerated, with a morbidity of 2.4 in 10,000

and a mortality of 1 in 10,000 (within 1 week of testing). Risks include

arrhythmias and cardiac arrest, MI, and cardiac rupture, and are more likely

in those with a recent history of ACS. Facilities for resuscitation and debril-

lation must be immediately available.

Possible results

Myocardial ischaemia is indicated by 1mm horizontal or downsloping ST-

segment depression 80ms after the J point. Some cardiologists use 2mm of

ST- segment depression as the diagnostic criterion— this i the specicity of

the test but reduces the sensitivity. Upsloping ST- segment depression and

T wave changes are not reliable indicators of ischaemia. Afall in BP (or a

failure of BP to rise) during exercise can also indicate ischaemia, particularly

if accompanied by ST- segment depression and chestpain.

Generally speaking, the earlier and the more marked the ST- segment

changes, the more severe the underlying coronary artery disease. The

prognostic value of exercise testing is well established. Patients can be risk-

stratied using the Duke treadmill score, calculated as follows:

Duke treadmill score

= Exercise time (Bruce protocol) – [5 × ST

depression (mm)] – (4 × exercise angina index)

where:0=no exercise angina; 1=exercise angina; 2=exercise angina that

led to termination of thetest.

The Duke treadmill score denes a high- risk group with a score of ≥−11,

with an annual cardiovascular mortality of 5%. Low- risk patients have a

score of ≥+5, with an annual cardiovascular mortality of0.5%.

Almost any arrhythmia or conduction disturbance can occur during exer-

cise testing. If the exercise test is being performed to investigate arrhyth-

mias, this can indicate a diagnostic result.

Advantages overothertests

Exercise testing is a relatively simple and inexpensive investigation, with a

strong evidence base that it is useful in a large number of clinical situations.

Alternative tests for myocardial ischaemia include stress echocardiography,

CMR, and myocardial perfusion imaging.

EXERCISE TESTING

485

Pitfalls

Exercise test results are commonly reported as ‘positive’ or ‘negative’,

giving the erroneous impression that the results are ‘black or white’. The

sensitivity and specicity of exercise testing vary widely between dierent

patient populations, and false −ve and false +ve results are not uncom-

mon. If the pretest probability of CHD is low, e.g. an asymptomatic young

woman, exercise testing is of little value as even a ‘positive’ result is unlikely

to be true. Similarly, if the pretest probability of CHD is high, e.g. a ♂ in his

60s with typical anginal symptoms, a ‘negative’ result is also unlikely to be

true. Guidelines from NICE state that exercise testing should not be used

for the de novo diagnosis of IHD, but only for the assessment of patients

with knownIHD.

Further reading

National Institute for Health and Care Excellence (2016). Chest pain of recent onset:assessment and

diagnosis. Clinical guideline CG95. M

http:// www.nice.org.uk/ guidance/ cg95.

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CHAPTER6 Cardiology

486

Myocardial perfusion imaging

Principle

Since myocardial perfusion abnormalities occur early following the onset

of ischaemia, evaluation of regional myocardial perfusion heterogeneity is

a sensitive marker for the presence of coronary artery disease. Myocardial

perfusion imaging is most commonly performed with radionuclide imag-

ing. Alternative modalities include contrast echocardiography and contrast

CMR imaging.

The radioisotopes thallium- 201 or technetium- 99m are taken up by the

myocardium in proportion to blood ow. Images are then acquired by a

gamma camera. The images are processed to provide colour mapping of

myocardial perfusion. Information is obtained regarding the presence of

reversible or xed myocardial ischaemia. Late repetition of image acquisi-

tion allows redistribution of the isotope in areas of slow blood ow for

assessment of myocardial viability.

As with all investigational methods for evaluation of ischaemia, perfu-

sion imaging is enhanced by the addition of cardiac stress. This may be

in the form of physical exercise, e.g. treadmill or bicycle, or with use of

pharmacological stressors. The latter are particularly useful if the patient

is physically unable to exercise suciently or has ECG abnormalities that

prohibit accurate interpretation, e.g. left bundle branch block or ventricular

pacing. The most commonly used pharmacological stressor is the vasodila-

tor adenosine, which has a very short half- life. Dobutamine can also be used

in patients with contraindications to adenosine, but it is a less eective vaso-

dilator. Adenosine gives rise to a 4- or 5- fold hyperaemia, whereas dobu-

tamine only has a 2- fold vasodilatory eect. During adenosine stress, there

is a 4- to 5- fold i in blood ow to normal myocardial territories, compared

with the basal state. In the presence of coronary artery stenosis, there is

impaired vasodilatation and a reduction in the stress:rest ratio, precipitating

a myocardial perfusion mismatch.

Indications

• To assess the presence and degree of coronary artery stenoses in

patients with suspected coronary artery disease.

•

To assist in the management of patients with known coronary artery

disease:

•

To determine the likely prognosis and probability of future cardiac

events, e.g. following MI or during proposed non- cardiac surgery.

•

To guide proposed revascularization procedures by determining the

physiological signicance of known coronary artery lesions, including

the eects of anomalous coronary arteries, muscle bridging, and

coronary artery ectasia in Kawasaki’s disease.

•

To assess the success of performed revascularization strategies.

• To dierentiate between areas of myocardial scar tissue and viable

myocardium prior to proposed revascularization.

MYOCARDIAL PERFUSION IMAGING

487

Contraindications andrisk

Pregnancy is a contraindication to nuclear imaging. Contraindications to

physical exercise testing are listed in Box6.1.

Contraindications toadenosineare

•

Known hypersensitivity to adenosine.

• Untreated second- or third- degree heart block, sick sinus syndrome,

long QT syndrome.

•

Asthma, chronic obstructive airways disease with known bronchospasm.

• Hypotension (systolic BP <90mmHg).

• ACS not successfully stabilized with medical therapy.

• Decompensated heart failure.

• Concomitant use of dipyridamole (within last 24h) or xanthines (within

last12h).

Contraindications todobutamine include those forphysical exercise testingand

•

Known hypersensitivity to dobutamine.

• Glaucoma.

• Hypokalaemia.

• Concomitant use of β- blockade.

Patient preparation

β- blockers and rate- limiting calcium antagonists should be withdrawn for

48h prior to the test if physical exercise or dobutamine stress is planned.

Xanthines and dipyridamole should be withdrawn for 24h prior to adeno-

sine stress, and any foods or drugs containing caeine should be avoided.

Peripheral IV access should besited.

Procedure

The stress study is generally performed rst, since if this is normal, there

may be no need to acquire resting images. The radioisotope is injected at

peak stress, so that myocardial uptake of the tracer reects maximal blood

ow and optimizes visualization of any perfusion decit. The protocols for

the varying forms of stress are given in Table6.18.

Table6.18 Radionuclear exercise and imaging protocols

Stress Protocol Injection time of radioisotope

Physical exercise

As directed by physician, e.g.

Bruce, Sheeld, to 85% max

predicted heart rate (MPHR)

1– 2min prior to cessation of

peak exercise

Adenosine 140µg/ kg/ min for 6min 3– 4min after start of infusion

Dipyridamole* 140µg/ kg/ min for 4min 4min after infusion completion

Dobutamine

In 3min stages:5– 10, 20, 30,

40µg/ kg/ min

When 85% MPHR and/ or

maximal dose dobutamine

* See Pellika PA, Nagueh SF, Elhendy AA, etal. American Society of Echocardiography

recommendations for performance, interpretation, and application of stress echocardiography.

JAm Soc Echocardiogr 2007; 20

:1021– 41.

488

CHAPTER6 Cardiology

488

Heart rate and BP should be measured throughout physical or pharmaco-

logical stress. A12- lead ECG should be observed continuously for evidence

of ST- segment or T wave changes suggestive of ischaemia and arrhythmias.

Redistribution imaging for assessment of myocardial viability can be

performed 3– 4h after stress imaging. To enhance redistribution imag-

ing, particularly if any perfusion decits seen with stress are severe, sub-

lingual nitrate can be given, followed by a further resting injection of the

radioisotope and image acquisition an hour later. This is known as a stress–

redistribution– reinjection protocol.

A single- or dual- head gamma camera is used for image acquisition. This

rotates 180° round the patient from 45° in the right anterior oblique posi-

tion to 45° in the left posterior oblique position. The tomographic data are

reconstructed into double oblique imaging planes. Stress and rest images

are aligned carefully with accurate image registration for comparison. Image

quality is assessed, and then the long and short axis images are evaluated for

myocardial perfusion decits.

Risks

It should be remembered that the patient is exposed to ionizing radiation,

especially if sequential studies are planned. Physical or pharmacological

stress may induce severe myocardial ischaemia, infarction, and potentially

life- threatening arrhythmias (0.01– 0.05%).

The test should be stopped ifthe patient is physically unable tocomplete

thetest or ifs/ he develops

• Severe angina.

• ST- segment elevation of >0.1mV in leads without Qwaves.

• Afall in systolic BP >10mmHg below baseline.

• Asevere hypertensive response (BP >250/ 115).

• Clinical loss of peripheral perfusion, i.e. pallor or cyanosis.

• Dizziness or near syncope.

Possible results

Perfusion decits are identied as areas of reduced tracer uptake. These

may be assessed qualitatively or semi- quantitatively. Semi- quantitative clas-

sication expresses regional myocardial uptake as a percentage of the maxi-

mal uptake seen, according to the followingscale:

•

Absent:10– 9%.

• Severely reduced:10– 29%.

• Moderately reduced:30– 49%.

• Mildly reduced:50– 69%.

• Normal:70– 100%.

Perfusion decits may be categorized as either reversible (present on

stress imaging alone) or xed (present on stress and rest imaging). When

the redistribution protocol is followed, areas of reduced perfusion can

be examined for the presence of viability (revascularization will improve

regional function) or scar tissue (revascularization is futile). The size of the

LV and RV can also be determined (see Table6.19).

MYOCARDIAL PERFUSION IMAGING

489

Advantages overothertests

Radionuclide imaging is readily available and non- invasive. It is inexpensive,

compared with coronary angiography. In contrast to MRI, where the num-

ber of imaging planes that can be acquired may be limited, radionuclide

imaging provides full myocardial coverage. There are many studies support-

ing the ability of the technique to give accurate diagnostic information and

prognosticdata.

Pitfalls

Qualitative or semi- quantitative analytical techniques, whereby signal inten-

sity is compared with the area of maximal myocardial uptake, may limit

accuracy in the presence of triple- vessel disease where there is globally

reduced myocardial perfusion. Additionally, the study may be suboptimal

if peak stress is not achieved. Radionuclide imaging has poor spatial resolu-

tion in comparison with other techniques. Perfusion defects limited to the

subendocardium may not be visualized. Image quality can be degraded by

patient movement and artefacts. Such artefacts include attenuation from

breast tissue in the anterior wall and inferior signalloss.

Further reading

Anagnostopoulos C, Harbinson M, Kelion A, etal. (2004) Procedure guidelines for radionuclide

myocardial perfusion imaging. Heart 2004; 90

(Suppl 1):i1– 10.

Bourque JM, Beller GA. Stress myocardial perfusion imaging for assessing prognosis:an update. JACC

Cardiovasc Imaging 2011; 4

:1305– 19.

Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ ASNC/ ACR/ AHA/ ASE/ SCCT/ SCMR/ SNM

2009 appropriate use criteria for cardiac radionuclide imaging. Circulation 2009; 119:e561– 87.

Table6.19 Possible results formyocardial perfusion imaging

Stress Rest Clinical conclusion

Myocardial

perfusion

Normal/ i Normal Normal

Reduced Normal Myocardial ischaemia

(reversible defect)

Reduced/ absent Reduced/ absent MI (xed defect)

Late

redistribution

Reduced i from baseline Viable myocardium

Reduced Reduced MI (scar)

490

CHAPTER6 Cardiology

490

Radionuclide ventriculography

Principle

Radionuclide ventriculography (RNV) is a technique to provide accu-

rate assessment of cardiac chamber size, morphology, and function. The

patient’s RBCs are radiolabelled with

99m

technetium pertechnate in vitro or

in vivo. The labelled blood pool within the cardiac chambers is then imaged

with a gamma camera, gated to the ECG. Multiple image acquisitions are

acquired throughout the cardiac cycle, typically over at least 16 systolic and

32 diastolic frames. These images can be assessed either based on either the

radioactive count or by geometric analysis.

Indications

• Prognostic estimation in patients with heart failure or coronary artery

disease.

•

Estimation of operative coronary risk for non- cardiac surgery.

• Diagnosis of coronary artery disease where conventional exercise

testing is inadequately performed or result equivocal.

•

Evaluation of the ecacy of revascularization or medical management

strategies in patients with coronary artery disease.

•

Monitoring of cardiac function in patients undergoing chemotherapy.

Contraindications

The technique is contraindicated in pregnant or lactatingwomen.

Patient preparation

No special preparation is required for a resting study. If an exercise study is

to be performed, the patient should fast for 3– 4h prior to the procedure. If

pharmacological stress agents are used, the same preparation as for myo-

cardial perfusion imaging should be followed. Aresting ECG is helpful to

exclude arrhythmias.

Procedure

For a resting study, the patient lies supine whilst anterior and left anterior

oblique images are acquired. Stress studies may be performed with either

physical exercise, e.g. bicycle ergometry, or pharmacological stressors, e.g.

dobutamine. Images are acquired at intervals once the heart rate has sta-

bilized at each new level of exercise or stress. The patient should have

haemodynamic and ECG monitoring throughout. Cardiopulmonary resus-

citation facilities should be available. Images are then analysed to obtain

the required morphological and functional parameters. High activity areas,

such as the spleen or aorta, may be ltered out for optimal assessment of

cardiac parameters.

Risks

Technetium has a 6h half- life. Although the heart receives the largest dose,

5% of the total radiation dose is sequestered by the BM, the most radio-

sensitive body tissue. Radiation dose is up to 1100MBq, and so a typical

examination carries a fatal cancer risk of 1 in 3300. Serial studies should be

avoided where alternative forms of imaging suce.

RADIONUCLIDE VENTRICULOGRAPHY

491

Possible results

• Dilatation or hypertrophy of the cardiac chambers and great vessels

may be identied.

•

Left and right ventricular EFs can be measured. Normal left ventricular

EF is 60– 80% at rest and slightly more during exercise. Right ventricular

EF is 46– 70%. Both values decline with age. The extent of any global left

ventricular dysfunction can therefore be identied.

•

Regional wall dysfunction at rest, at low- and peak- dose stress, and

during recovery may be described in a manner analogous to stress

echocardiography, in order to identify areas of reversible myocardial

ischaemia, myocardial hibernation, orscar.

Advantages overothertests

RNV is non- invasive and repeatable and provides serial measurements,

especially in patients who are dicult to scan echocardiographically or who

cannot tolerate MRI. It can be used in critically ill patients soon after an

acuteMI.

Pitfalls

Patients receive a signicant radiation dose. Echocardiography is safer, and

CMR is likely to replace this technique as the gold standard. Red cell labelling

may be inecient in chronic renal failure. Technical factors are important;

in particular, radioactivity in the left atrium must be separated from that in

the LV to obtain an accurate EF. Apoor ECG signal and inappropriate gat-

ing may render data uninterpretable; heart rate variability may compromise

diastolic lling indices, and inadequate frame counts d statistical reliability.

Further reading

Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ ASNC/ ACR/ AHA/ ASE/ SCCT/ SCMR/ SNM

2009 appropriate use criteria for cardiac radionuclide imaging. Circulation 2009; 119:e561– 87.

492

CHAPTER6 Cardiology

492

Pulmonary artery catheterization

Principle

A PmA (Swan– Ganz) catheter is a multi- lumen catheter that is passed

percutaneously from a central vein, e.g. femoral, subclavian, or jugular, to

the right heart structures. It can be used to measure venous, RAt, right

ventricular, PmA, and LAt (indirect) pressures to obtain blood samples for

saturation estimation, to measure cardiac output and systemic vascular

resistance, and additionally to act as a central venous infusionport.

Indications

• Aid in the diagnosis of cardiovascular shock and pulmonary oedema.

• Management of complicated acute MI, especially right ventricular

infarction, cardiogenicshock.

•

Management of patients with cardiac failure.

• Fluid therapy/ inotropic delivery in severely ill patients, e.g. sepsis, burns,

multi- organ failure, cardiac surgery, trauma.

• Diagnostic right heart catheterization, including congenital heart disease,

pulmonary hypertension, intra- cardiac shunts.

Contraindications

• Right- sided endocarditis.

• Prosthetic tricuspid or pulmonaryvalve.

• Right heart tumour or thrombus.

• Unstable ventricular arrhythmia.

Patient preparation

LAn is injected into the skin at the site of venous access. The patient is

positioned at on a couch, generally with a head- down orientation if ceph-

alad access is to be used. Pressure transducers are made ready and zeroed

for accurate measurements. Fluoroscopic screening should be available, if

required.

Procedure

An access sheath is placed in the vein using a Seldinger technique. The

PmA triple- lumen catheter is ushed with saline, and the integrity of the

otation balloon assessed by ination with air. Under uoroscopic guidance

or by observation of intra- cardiac pressure traces, the catheter is passed

through the venous system towards the right heart and into a branch of the

PmA. At each stage, pressure and O

samples can be measured. The bal-

loon can be inated to assist passage through the right heart. The balloon

is wedged briey into a PmA branch to obtain an assessment of indirect

pressure (PmA wedge pressure). Cardiac output can be calculated using

a thermodilution method. Iced saline at a known temperature is injected

through the proximal lumen and a thermistor at the catheter tip measures

the temperature rise in the blood- warmed saline as it passes through the

tricuspid valve, RV, and pulmonary valve. Systemic peripheral resistance can

also be estimated.

PULMONARY ARTERY CATHETERIZATION

493

Risks

• Arterial puncture, pneumothorax, haemothorax.

• Sepsis.

• PE or infarction (if the right heart contains masses or if the balloon

remains inated in wedge pressure position).

•

PmA rupture (balloon over- ination).

• Arrhythmia.

Possible results

PmA catheterization can be used to assess pulmonary and systemic venous

lling pressures and uid status, right and left cardiac function, and also,

where indicated, to provide information on valve dysfunction, intra- cardiac

shunts, tamponade, and pulmonary hypertension.

Advantages overothertests

This technique has traditionally been a useful adjunct to patient monitoring

in the intensive care setting, in particularly for accurate pressure evaluation

of the right heart and left atrium and for continuous cardiac output assess-

ment. However, recently several less invasive devices have been designed

for cardiac output monitoring, e.g. oesophageal Doppler.

Pitfalls

The procedure is generally well tolerated, but it is an invasive procedure not

without risk. It is essential that the PmA catheter is inserted only by suit-

ably trained individuals to assist diagnosis and monitor treatment in carefully

selected patients. If a non- invasive alternative is available, then this should

be preferentially employed. Care must be taken in data interpretation, as

misleading results may be obtained if the system is not systematically and

accurately zeroed for serial measurements. Indirect LAt pressure measure-

ments may be inaccurate in patients with pulmonary disease.

Further reading

Kelly CR, Rabbani LE. Pulmonary- artery catheterization. N Engl J Med 2013; 369:e35.

494

CHAPTER6 Cardiology

494

Tilt table testing

Principle

On standing, gravity redistributes up to 800mL of blood to the legs. The

normal compensatory response is i sympathetic and d parasympathetic

stimulation, which maintains BP with a small i

in heart rate. Head- up tilt

table testing uses gravity- induced venous pooling to assess autonomic con-

trol and to attempt to reproduce symptoms of autonomic dysfunction of

dizziness or collapse, i.e. neuro- cardiogenic (vasovagal) syncope.

Indications

Testing is appropriate in the investigation of sudden, unpredictable loss of

consciousness thought to be neurally mediated (vasovagal syncope, carotid

sinus syncope, or situational syncope) in the absence of structural heart

disease.

Contraindications

• Severe mitral stenosis.

• Severe left ventricular outow tract obstruction.

• Severe proximal cerebral or coronary artery disease.

• Testing is not appropriate for frail patients who cannot weight- bear for

up to anhour.

Patient preparation

Fasting is not required. Patients should continue all suspected culprit

medications.

Procedure

The test should take place in a quiet room at a constant temperature. The

patient is lightly strapped to a table with a weight- bearing footboard. Pulse

and beat- to- beat BP are recorded throughout the test. The patient is laid

supine for 10min (20min, if cannulated), and then the table is mechanically

tilted to 70° for 20min of passive tilt. If positivity or discontinuation criteria

have not been reached by this point, 400μg of sublingual glyceryl trinitrate

(GTN) are administered whilst upright, and the tilt is continued for a further

15min. If the patient has a history of adverse reaction to nitrates, or if a

diagnosis of psychogenic or hyperventilation syncope is suspected, then a

40min tilt protocol should be used instead with no GTN provocation.

Risks

Syncopal symptoms (or, in extreme cases, loss of consciousness), hypoten-

sion, and bradycardia may be induced, albeit transiently, so full cardiopul-

monary resuscitation facilities and an appropriately trained supervising team

should be available.

Possible results

A normal response is a <20% d in BP associated with a modest rise in pulse

rate. The test is −ve in the absence of a fall in BP, fall in heart rate, and lack

of syncopal symptoms, and +ve if syncopal symptoms are induced by hypo-

tension and/ or bradycardia. Acardio- inhibitory response is characterized

TILT TABLE TESTING

495

by a fall in heart rate (asystole in extreme cases), a vasodepressor response

by a fall in BP with no pulse change, and a mixed response by a fall in both

pulse and BP. A diagnosis of postural orthostatic tachycardia syndrome

(POTS) is indicated by a rise in heart rate of ≥30bpm and/ or to ≥120bpm,

within 10min of uprighttilt.

Advantages overothertests

Monitoring of ECG and BP during a 24h ambulatory period or during a

Valsalva manoeuvre— measurements of plasma catecholamines, miner-

alocorticoids, and glucose have a role in the investigation of autonomic

dysfunction and syncope, but only tilt table testing provides a dynamic

objective, witnessed assessment.

Pitfalls

The test is time- consuming and requires technical and medical person-

nel trained in the conduct and interpretation of the procedure and in

resuscitation.

Further reading

National Institute for Health and Care Excellence (2010). Transient loss of consciousness (‘blackouts’)

in over 16s. Clinical guideline CG109. M

www.nice.org.uk/ guidance/ cg109.

Parry SW, Reeve P, Lawson J, etal

. The Newcastle protocols 2008:an update on headup tilt table

testing and the management of vasovagal syncope and related disorders. Heart 2009; 95:416– 20.

Task Force for the Diagnosis and Management of Syncope; European Society of Cardiology (ESC);

European Heart Rhythm Association (EHRA); Heart Failure Association (HFA); Heart Rhythm

Society (HRS), Moya A, Sutton R, Ammirati F, etal. Guidelines for the diagnosis and management

of syncope (version 2009). Eur Heart J 2009; 30

:2631– 71.

496

497

Chapter7

Gastroenterology

Endoscopy 498

Oesophagogastroduodenoscopy 502

Enteroscopy 504

Flexible sigmoidoscopy and colonoscopy 506

Endoscopic retrograde cholangiopancreatography 508

Endoscopic ultrasound 509

Wireless capsule endoscopy 510

Tests for Helicobacter pylori

512

Faecal occult blood testing 514

Faecal and serological testing in inammatory bowel disease 516

Tumour markers 517

Investigations for small bowel pathology 518

Tests of small bowel absorption 522

Tests for bacterial overgrowth 523

Tests of pancreatic exocrine function 524

Testing for neuroendocrine tumours 525

Gastrointestinal physiology 526

Non- invasive liver investigations 528

Liver biopsy 532

Investigation of ascitic uid 534

498

CHAPTER7 Gastroenterology

498

Endoscopy

This allows direct visualization of the GIT mucosa and oers further diag-

nostic investigations to obtain tissue for histology, cytology, or microbiol-

ogy, as well as therapeutic possibilities.

Consent (general)

Consent is a vital component of the endoscopy process. Patients should

receive written information before attending for the procedure. This should

describe pretest preparation, the procedure itself, risks and possible compli-

cations, after- care advice (particularly for those patients requiring sedation),

and contact details in the event of problems and include the consent form

that the patient will be asked tosign. In the UK, the Montgomery v Lanarkshire

case of 2015 has established that the patient should be told whatever they

want to know rather than what the clinician thinks they should be told, so

covering issues of importance to the patient is paramount.

Sedation

Whilst the majority of OGD procedures can be performed using a local

anaesthetic spray to the oropharynx, either sedation or patient- controlled

Entonox

(an inhaled mix of medical nitrous oxide and O

) will be required

for more complex or prolonged procedures. An IV combination of a seda-

tive with amnesic eects, such as midazolam, is usually combined with an

analgesic such as fentanyl. Addition of hyoscine butylbromide may act

to reduce intestinal motility, which is useful for colonoscopy, ERCP, or

enteroscopy. An alternative to hyoscine is glucagon, which may be used for

patients with glaucoma or IHD where hyoscine is contraindicated. Rarely,

for patients who are relatively intolerant of procedures and require pro-

longed interventions at ERCP or enteroscopy, general anaesthetic (GAn) is

an option, depending on patient tness and the availability of an anaesthetist

and anaesthetic support.

Antibiotic prophylaxis pre- procedure

Pre- procedure prophylaxis is only indicated for patients undergoing:

• Percutaneous endoscopic gastrostomy or jejunostomy placement.

• ERCP where biliary drainage is unlikely to be achieved at the rst

procedure.

•

Severe neutropenia (<0.5 × 10

/ L) and/ or severe immunocompromise

undergoing procedures with a high risk of bacteraemia such as

oesophageal dilatation or variceal sclerotherapy.

ENDOSCOPY

499

Anticoagulation guidelines pre- procedure

With the advent of novel oral anticoagulants and greater use of PY212

receptor antagonists (including clopidogrel and ticagrelor). this has become

a more complex area. Please see British Society of Gastroenterology (BSG)

guidelines for further details.

In summary, procedures are dividedinto:

•

Low risk:diagnostic procedures (OGD, colonoscopy, exible

sigmoidoscopy, enteroscopy), with simple mucosal biopsies possible if

needed.

•

High risk:polypectomy, ERCP with sphincterotomy, dilatation of

strictures, variceal therapy, percutaneous endoscopic gastrostomy (PEG)

placement, endoscopic ultrasound (EUS) with FNA, stenting of theGIT.

PY212 receptor antagonists

Can be continued (± aspirin) for low- risk procedures but should be discon-

tinued 5days before high- risk cases. If there is a high thrombotic risk, con-

tinue aspirin and liaise with a cardiologist about risk/ benet of discontinuing.

Warfarin

For low- risk procedures, continue the usual dose of warfarin and go ahead

if the INR is within the normal range. For high- risk procedures, stop warfa-

rin 5days beforehand. If there is a low risk of thrombosis, then check INR

pre- procedure and go ahead if INR <1.5. If there is a high thrombosis risk,

then cover with low- molecular- weight heparin from 2days after stopping

warfarin, with the last dose ≥24h pre- procedure.

Direct- acting oral anticoagulants (DOACs)

For low- risk procedures, omit on the morning of the procedure. For high-

risk procedures, the last dose should be taken ≥48h pre- procedure. For

patients on dabigatran with an estimated glomerular ltration rate (eGFR)

of 30– 50mL/ min, the last dose should be taken 72h pre- procedure.

Specialist haematology advice should be sought if renal function is worse

thanthis.

Risks and points forconsent

Table 7.1 shows the common complications of endoscopic procedures.

500

CHAPTER7 Gastroenterology

500

Table7.1 Risks and complications ofthe most commonly performed

endoscopic procedures

Procedure

Risks

Morbidity

for each

complication

Overall

mortality

Other issues

OGD

Perforation

Haemorrhage

0.03%

0.002%

0.0001% Greatest risk

for therapeutic

procedures

Cardiorespiratory

sedation- related

complications—

0.005%

Flexible

sigmoidoscopy/

colonoscopy

Perforation

Haemorrhage

0.005%

0.001%

0.001% Cardiorespiratory

complications

related to

sedation— 0.01%

Colonic

polypectomy

Perforation

Haemorrhage

0.06%

0.26%

0.007% As above

PEG placement Perforation

Haemorrhage

Infection

Overall risk

5– 10%

1– 2% 30- day mortality

of 710% (often

resulting from

underlying

condition)

ERCP Perforation

Haemorrhage

Cholangitis

Pancreatitis

1.1%,

0.9%

3.8%

Cardio-

respirat ory

complications

related to

sedation— 2.3%

1.0% Greatest risks

overall with

dilated bileduct,

placementofstent,

and high- dose

hyoscine

butylbromide

Risk of pancreatitis

greatest with

age <40years,

placement of stent,

and dilated bile

duct

ENDOSCOPY

501

Safety considerations beforeprescribing oral bowel

cleansing pre- colonoscopy/ CT colonography/ bariumenema

In view of the risk of electrolyte disturbance and renal failure using oral

bowel- cleansing agents, the National Patient Safety Agency (NPSA) advice

from 2009 suggests the following:

•

Check U&E, creatinine, and eGFR before oral bowel cleansing. If

evidence of renal impairment (eGFR <30mL/ min), then assess risks

andbenets of procedure. Polyethylene glycol- based preparations

(Klean-Prep

or Moviprep

) are safer if eGFR 30– 50mL/ min.

• If safe to do so, omit ACE inhibitors, angiotensin- 2 inhibitors, diuretics,

and/ or NSAIDs on the day of starting oral bowel preparation for

3days. If unable to stop (e.g. heart failure), then consider the risks and

benets of the procedure and seek advice from a cardiologist.

Further reading

Allison M, Sandoe ATM, Tighe R, et al. Antibiotic prophylaxis in gastrointestinal endoscopy. Gut

2009; 58

:869– 80.

Connor A, Tolan D, Hughes S, Carr N, Tomson C (2009). Consensus guidelines for the prescription

and administration of oral bowel cleansing agents. M

http:// www.bsg.org.uk/ attachments/ 960_

obca_ draft_ 10.pdf.

Veitch AM, Vanbiervliet Gj, Gershlick AH, etal. Endoscopy in patients on antiplatelet or anticoagu-

lant therapy, including direct oral anticoagulants:British Society of Gastroenterology (BSG) and

European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Gut 2016; 65

:374– 89.

502

CHAPTER7 Gastroenterology

502

Oesophagogastroduodenoscopy

• Endoluminal visualization:oropharynx to second part of duodenum.

• Allows direct testing for Helicobacter pylori.

•

In preparation for OGD, patients should not eat for 4– 6h beforehand,

with clear uids allowed up to 2h before the procedure.

•

They should remain nil by mouth for at least 30min afterwards to allow

the LAn spray or sedation to wearo.

• Stop proton pump inhibitors 2 weeks before an elective diagnostic

OGD to prevent masking of appearances (risk of partial healing and

thus misdiagnosing malignant oesophageal or gastric ulcers).

Alternative investigations

As an alternative procedure to OGD or enteroscopy, barium swallow,

meal, or follow- through may be performed, depending upon symptoms (for

oesophageal, gastric, or duodenal pathology, respectively). Investigations

are limited by their lower sensitivity for mucosal pathology and inability to

obtain tissue for histology or undertake therapeutic procedures.

Indications

Symptoms/ signs

• Dysphagia.

• Haematemesis and melaena.

• Dyspepsia despite appropriate therapy.

• Iron deciency anaemia (see Fig.7.1a).

• Weightloss.

• Vomiting or nausea.

• Investigation of suspected giardia or bacterial overgrowth to obtain

duodenal aspirates.

•

Obtaining duodenal biopsies in suspected coeliac disease.

• Investigation to obtain histology and cultures of H.pylori.

•

Abnormal barium swallow, meal, or early follow- through.

Surveillance/ screening

• Ensures healing of oesophageal and gastric ulceration.

• Barrett’s oesophagus.

• Establishes response to a gluten- free diet in coeliac disease.

• Diagnosis of polyps in familial polyposis syndromes.

Therapeutic

•

Treatment of bleeding lesions (peptic ulceration, angiodysplasia, varices,

vascular malformations).

•

Palliation of oesophageal cancers using stent placement, argon plasma

coagulation, or Nd:Yag laser therapy.

• Placement of PEG or jejunostomy tubes (see Fig.7.1b).

• Direct placement of nasogastric or nasojejunal feedingtubes.

• Dilatation of strictures of the oesophagus or pylorus.

• Polypectomy.

OESOPHAGOGASTRODUODENOSCOPY

503

(a) (b)

Fig.7.1 (a)Endoscopic view of gastric antral vascular ectasia, one cause for blood

transfusion- dependent iron deciency anaemia, which may be treated using argon

plasma coagulation. (E Colour plate4.) (b) Endoscopic view of internal bumper

of percutaneous endoscopic gastrostomy (PEG) holding this in situ in the stomach

to allow feeding. PEG placement is a therapeutic possibility by using OGD to allow

direct visualization.

504

CHAPTER7 Gastroenterology

504

Enteroscopy

Conventional enteroscopy

• Similar to OGD, but allows views of the distal duodenum and jejunum

using a 2.4m instrument.

•

An overtube allows less looping but i complications.

•

Preparation as for OGD; usually requires sedation, analgesia, and

hyoscine butylbromide.

Single- or double- balloon enteroscopy

• Allows views of the entire small bowel from an oral or rectal approach.

• Preparation is as for OGD or colonoscopy and requires deep sedation

or GAn, with the addition of hyoscine butylbromide.

• Consists of one or two balloons, respectively. For single- and double-

balloon procedures, one is attached to a transparent overtube sliding

over the endoscope, allowing movement forward by telescoping the

small bowel by gripping and pleating it over the endoscope. For the

double balloon, the second balloon is attached to the distal endoscope

to act as an anchor.

Alternative investigations toenteroscopy

Barium investigations (follow- through or small bowel enema) are limited by

a lower sensitivity for mucosal pathology.

MRI small bowel studies are good for young patients, as these present no

radiation risk, with contrast allowing clear serosal and mucosal images and

views of the whole length of the smallbowel.

Wireless capsule endoscopy (WCE) is a more eective (but less fre-

quently available) alternative. However, each of these is limited by an inabil-

ity to obtain tissue or provide therapeutic intervention.

Which type ofenteroscopy tochoose?

Single- or double- balloon enteroscopy allows visualization and treatment

of lesions within the full length of the small bowel and may replace con-

ventional enteroscopy, although procedure length and intensity will require

deep sedation or GAn. Conventional enteroscopy will diagnose and treat

lesions within the upper small bowel (to the jejunum) but is limited by

patient tolerance as conscious sedation isused.

Indications forenteroscopy

• Investigation and/ or treatment of obscure GI bleeding or severe

anaemia (following non- diagnostic OGD and colonoscopy).

• Investigation and/ or removal of lesions found on CT scan abdomen/

MRI small bowel/ capsule endoscopy/ barium investigation (e.g.

polypectomy).

•

Treatment of bleeding lesions found at enteroscopy or byWCE.

ENTEROSCOPY

505

506

CHAPTER7 Gastroenterology

506

Flexible sigmoidoscopy and colonoscopy

• Allows examination from anus to splenic exure (exible

sigmoidoscopy) or from anus to caecum/ terminal ileum (colonoscopy).

• Preparation for exible sigmoidoscopy:phosphate enema 30– 60min

prior to the procedure.

•

Preparation for colonoscopy:oral preparation using an oral bowel-

cleansing agent. Need to bear in mind both the patient’s tness and

willingness to undergo the purgative preparation, and also the risk of

renal failure and electrolyte disturbance associated with administration

of these agents (for advice, E

Endoscopy, pp. 498–501). Ideally, a low-

residue diet should be followed for the 3days pre- procedure to obtain

the bestviews.

•

Whilst colonoscopy usually requires sedation/ analgesia, and ideally a

smooth muscle relaxant (hyoscine butylbromide), both colonoscopy

and exible sigmoidoscopy are possible using Entonox

with or without

hyoscine butylbromide. For patients who are intolerant of such

procedures, GAn may rarely be available with appropriate anaesthetic

specialist support.

Alternative investigations

Alternative procedures are radiological— mainly CT colonography, which

has largely superseded barium enema. Neither allows tissue or polypec-

tomy to be taken for histology nor other therapeutic procedures to be per-

formed. For these reasons, colonoscopy is considered the ‘gold standard’

for investigating likely colon cancer, diarrhoea, anaemia, and rectal bleed-

ing. Sensitivity is lower for detecting adenomas of ≤10mm using CT colo-

nography (90%) than colonoscopy (99%). These alternative procedures all

require the use of oral bowel- cleansing agentstoo.

For patients not t to undergo oral bowel cleansing, then an unprepared

CT abdomen and pelvis is a possibility. However, it is signicantly less sensi-

tive for lesions of <10mm; it may have a role for elderly or medically unt

patients where prognosis is important.

Indications

Symptoms andsigns

•

Rectal bleeding (bright red=exible sigmoidoscopy, and dark

red=colonoscopy), but beware as some right- sided colonic lesions do

present with bright red bleeding.

•

+ve faecal occult bloods (colonoscopy).

• Abnormal barium enema (depends upon site of pathology found).

• Iron deciency anaemia (colonoscopy).

• Diarrhoea (colonoscopy with biopsies from right and left colon).

FLEXIBLE SIGMOIDOSCOPY AND COLONOSCOPY

507

Surveillance/ screening forspecic diseasestates

• Extensive ulcerative colitis or colonic Crohn’s disease for >10years,

then ongoing follow- up determined by disease extent and severity.

• High risk of adenomatous colonic polyps or carcinoma, or previous

history of adenomatous polyps or carcinoma.

•

Familial polyposis syndrome (FAP), hereditary non- polyposis colorectal

carcinoma (HNPCC), or other family cancer syndromes.

• For further information, please see BSG guidelines.

Therapeutic

•

Treatment of bleeding lesions (angiodysplasia, vascular abnormalities,

haemorrhoids).

•

Dilatation of benign strictures.

• Palliation of malignant strictures (placement of stents, argon plasma

coagulation, or Nd:Yag laser therapy).

• Decompression of sigmoid volvulus and non- malignant toxic megacolon.

• Endoscopic mucosal resection of tumours.

National screening programmes

National Bowel Cancer Screening Programme

Oers 2- yearly screening using FOB testing (due to change to faecal immu-

nochemical testing shortly) with kits sent to everyone from 60– 74 years

of age. Face- to- face review for all patients with a +ve result allows either

colonoscopy or CT colonography to be oered, depending on patient t-

ness and wishes. Aim:to allow diagnosis and removal of polyps (adenomas)

before development of carcinoma.

Bowel Scope Screening Programme

Currently in roll- out phase across the UK to oer one- o exible

sigmoidoscopy for all 55- year- olds. Aim: to diagnose and remove polyps

(adenomas) and reduce future bowel cancer risk. Full colonoscopy is

oered to those with >3 adenomas, those with a villous component to one

or more polyps, and anyone with an adenoma of>1cm.

1 Cairns SR, Scholeeld JH, Steele R, etal. Guidelines for colorectal cancer screening and surveillance

in moderate and high risk groups (update from 2002). Gut 2010; 59

:666– 90.

508

CHAPTER7 Gastroenterology

508

Endoscopic retrograde

cholangiopancreatography

• Side- viewing endoscope used to nd the ampulla of Vater and guide

cannulation of the biliary and pancreatic ducts by injecting radio- opaque

contrast medium using uoroscopy.

•

MRCP has replaced ERCP in ° diagnosis. ERCP is used for

interventional procedures and to obtain biopsy and cytology specimens.

•

ERCP requires sedation, analgesia, and hyoscine butylbromide or GAn

(which requires anaesthetic support).

Alternative investigations

MRCP allows imaging of the biliary and pancreatic systems and is the best

(and safest) option for diagnosis, although no therapeutic procedures are

possible. Apercutaneous transhepatic cholangiogram (PTC) allows imaging,

stent placement, and drainage of a dilated biliary tree using a transabdomi-

nal approach. PTC is indicated if therapeutic ERCP fails, albeit with greater

risk of complications.

Indications

Diagnostic

•

Endoscopic diagnosis of periampullary polyps and tumours.

• Obtain bile/ brushings for cytology in suspected cholangiocarcinoma.

• Investigation of dilated biliary ducts found on USS with contraindications

toMRCP.

• Assessment of the sphincter of Oddi pressures in suspected sphincter

of Oddi dysfunction (SOD) syndromes— at specialist centres.

Therapeutic

•

Biliary stenting:

•

Palliation of pancreatic, ampullary, and cholangiocarcinomas.

•

Treatment of a biliary leak following surgery.

•

Benign biliary stricture.

• Biliary sphincterotomy:

•

Gaining access to perform diagnostic or therapeutic procedures.

•

Choledocholithiasis.

•

Ampullary carcinoma.

•

Treatment of a biliary leak following surgery.

•

Treatment of SOD (types Iand possibly IIonly)

•

Treatment of acute severe pancreatitis 2° to gallstones.

• Pancreatic stenting:

•

Drainage of pseudocysts (via the stomach).

•

Following sphincterotomy forSOD.

• Pancreatic sphincterotomy:

•

Pancreatic stone disease.

•

Gaining access prior to stent placement.

•

Minor duct papillotomy in pancreatic divisum.

ENDOSCOPIC ULTRASOUND

509

Endoscopic ultrasound

• Combines endoscopy with US imaging to allow visualization of organs,

such as the pancreas, and accurate assessment of the degree of invasion

of luminal tumours in the oesophagus, stomach, and duodenum.

•

Higher- frequency US probe allowed by proximity of the probe to the

organ results in i spatial resolution, compared with transabdominal US,

CT, or MR scanning.

• Two dierent modes of imaging are possible:radial (which allows a 360°

view around the shaft of the instrument) or linear (which is in line with

the endoscope and allows 90° and up to 270° views).

•

Pre- procedure preparation is as forOGD.

• Consent procedures dier, depending upon indications and potential

pathology.

Alternative investigations

Transabdominal US, CT, and MRI scanning allow views of the pancreas and

liver but do not allow such ne detail for diagnosis or therapy.

Indications

• Staging of oesophageal, gastric, pancreatic, and distal biliary tumours.

• Diagnosis and staging for GI stromal tumours.

• FNA of ‘Trucut’ biopsy of mediastinal or coeliac axis lymph nodes,

pancreatic lesions, or submucosal lesions.

•

Dening mucosal abnormalities such as Barrett’s oesophagus.

• Coeliac axis nerve block to treat pancreatic pain (chronic pancreatitis or

pancreatic carcinoma).

•

Evaluation and treatment of pancreatic pseudocysts.

• Detection of CBD stones.

Further reading

Allum WH, Blazeby JM, Grin SM, etal. Guidelines for the management of oesophageal and gastric

cancer. Gut 2011; 60

:1449– 72.

510

CHAPTER7 Gastroenterology

510

Wireless capsule endoscopy

• Allows imaging of the entire small bowel by using an 11 × 27mm capsule

(e.g. PillCam

SB) with up to 7.5h of batterylife.

•

When swallowed, the capsule transmits images to aerials attached by

adhesive pads to the abdominal wall and stored on a recorder attached

round thewaist.

•

Propelled by the patient’s own peristalsis, so symptom- free.

• Specialist procedure, but with a higher diagnostic yield for mucosa

pathology than other small bowel investigations (see Table7.2).

•

If there is suspicion of stricturing where WCE could precipitate

obstruction, then a dissolvable patency pill will verify adequate patency,

allowing subsequent WCE. Prior barium radiology would also rule out

stricturing.

•

New capsules for investigation of the colon and oesophagus (PillCam

COLON and PillCam

ESO) are not in widespreaduse.

Indications

• WCE has a role in visual diagnosis but is unable to obtain samples for

subsequent analysis or allow therapeutic management.

•

Occult GI bleeding undiagnosed at endoscopy.

• Possible small bowel polyposis (e.g. Peutz– Jegher syndrome).

• Unexplained diarrhoea or malabsorption undiagnosed at endoscopy.

Points forconsent

• A0.5% risk of obstruction reported, especially if stricturing (e.g. small

bowel Crohn’s disease) or previous small bowel surgery. However,

prior use of the patency pill will rule out stricturing signicant enough to

cause capsule retention.

Table7.2 Diagnostic yield ofsmall bowel investigations foroccult

bleeding lesions

Sensitivity (%) Specicity (%) Diagnostic yield (%)

Enteroscopy 37 97

30– 32

WCE 64 92 55– 68

Further reading

Mylonaki M, Fritscher- Raven A, Swain CP. Wireless capsule endoscopy: a comparison with push

enteroscopy in patients with gastroscopy and colonoscopy negative gastrointestinal bleeding. Gut

2003; 52

:1122– 6.

Swain P. Wireless capsule endoscopy. Gut 2003; 52:48– 50.

WIRELESS CAPSULE ENDOSCOPY

511

512

CHAPTER7 Gastroenterology

512

Tests forHelicobacterpylori

Indications fortesting

• ‘Test and treat’:patients <55years of age with a low probability of

signicant pathology and dyspeptic symptoms do not require OGD.

Non- invasive testing for H.pylori allows treatment of those found to

be +ve, with acid suppression using a proton pump inhibitor to assess

response for all patients.

•

Ensure eective eradication in patients with conrmed peptic ulceration

or mucosa- associated lymphoid tumour (MALT) lymphoma.

Non- invasivetests

Faecal antigentest

•

H.pylori antigens in faeces measured using an

immunochromatographictest.

•

Sensitivity exceeds 91%, and specicity exceeds92%.

• Commercially available kits make an initial diagnosis and conrm

eradication.

Urea breathtest

•

Expired air is collected after ingestion of

C- labelledurea.

• If H.pylori present, bacterial urease breaks down urea l ammonium and

bicarbonate, then l CO

and ammonia.

•

Expired

is collected into a tube 30min after ingestion, measured

by a mass spectrophotometer, and compared with one collected prior

to ingestion.

•

Test almost 100% sensitive and specic, and remains the gold standard

to conrm eradication.

Serology

•

Serum IgG antibodies to H.pylori may be detected by ELISA with

sensitivity of 90% and specicity of 70– 90%.

• IgG levels persist up to 1year, so fail to conrm eradication.

• Other organisms may cause cross- reactivity.

• False −ves occur in elderly or immunocompromised patients.

Invasive tests (performed atOGD)

• Investigations are based on biopsy samples.

• H.pylori density is usually the greatest in the antrum, but during acid

suppression, the greatest concentration is found in the corpus.

•

Colonization is patchy so may yield sampling errors.

• So for patients taking proton pump inhibitors, one biopsy should be

taken from each area (two in total) for the greatest yield for each of the

testsbelow.

Histology

•

H.pylori can be detected on routine histology using the modied

Giemsastain.

•

Sensitivity is 85%, with a specicity of almost100%.

513

TESTS FORHELICOBACTERPYLORI

Culture

•

This is useful in those few patients who have failed eradication to

establish antibiotic sensitivities.

•

Sensitivity is over 95%, with specicity of almost100%.

Rapid ureasetest

•

Biopsy is placed into a urea solution containing phenolred.

• H.pylori contains urease, releasing ammonia from urea, thus changing

the pH and detected as a colour change with phenol red dye turning

from straw to pink/ purple.

• Commercial kits, such as the Campylobacter- like organism (CLO) test,

are available.

•

Specicity is 97%, and sensitivity between 70 and95%.

Further reading

National Institute of Health and Care Excellence (2014). Gastro- oesophageal reux disease and dys-

pepsia in adults:investigation and management. Clinical guideline CG184. M

https:// www.nice.

org.uk/ guidance/ cg184.

514

CHAPTER7 Gastroenterology

514

Faecal occult blood testing

Faecal occultblood

Indications

•

Used in the current National Health Service (NHS) England National

Bowel Cancer Screening Programme as population screening for 60- to

74- year- olds every 2years.

• Early diagnosis of cancer pathway for primary care (NICE guidelines,

2015). General practitioners advised to oer testing for adults without

rectal bleedingif:

•

50years or over with unexplained abdominal pain or weightloss.

•

Under 60years with a change in bowel habit or iron deciency

anaemia.

•

Aged 60 or over with anaemia in the absence of iron deciency.

Investigation

•

Simple and inexpensive, performed by the patient in their ownhome.

• Samples taken onto a test card from three consecutive bowel motions

and card sent to a screening centre.

•

Test card uses the ‘guaiac’ reaction with pseudoperoxidase in Hb,

causing a colour change in an indicatordye.

•

Dietary changes advised to avoid red meat, horseradish, broccoli, and

turnips, as their high peroxidase activity may cause false +ve results, and

avoid vitamin C tablets (high ascorbic acid activity).

Results

•

Sensitivity of the non- hydrated test is 70%; this i to 90% with

rehydration, but at the loss of specicity. Sensitivity improves with the

number of samplestaken.

•

Individuals who are +ve require full colonoscopy.

• Multicentre UK trial invited 486,355 for screening using FOB (take up

56%), nding 2% FOB +ve, and of these, 10.9% have carcinoma, 35%

adenoma, and 54.1% normal.

Limitations

Polyps and carcinomas may bleed intermittently, but FOB are more likely to

be +ve with early- stage cancers than polyps.

False positives

Non- colorectal blood source such as the upper GIT or nosebleed; diet con-

taining red meat, broccoli, or turnips (peroxidase activity).

False negatives

‘Old’ sample with bacterial degradation of Hb, the presence of ascorbic

acid, and reduced or absent bleeding at time of testing.

FAECAL OCCULT BLOOD TESTING

515

Faecal immunochemical test(FIT)

• This will replace FOB testing used by the NHS England National Bowel

Cancer Screening Programme and has already happened in Scotland.

• Asingle sample is collected via a brush into a pot; this appears to

encourage more people to take part in screening (currently just 55% of

those invited to participate).

•

Tests for human Hb protein from the colon in stool, with less reactivity

for blood from the upper GIT ornose.

•

+ve result means that colonoscopy or CT colonography is required.

• Higher sensitivity to lower concentrations of blood thanFOB.

Further reading

Hardcastle JD, Chamberlain JO, Robinson MHE, etal. Randomised controlled trial of faecal- occult-

blood screening for colorectal cancer. Lancet 1996; 348:1472– 7.

National Institute of Health and Care Excellence (2015). Suspected cancer:recognition and referral.

NICE guideline NG12. M

http:// www.nice.org.uk/ guidance/ ng12.

Tappenden P, Chilcott J, Eggington S, Patnick J, Sakai H, Karnon J. Option appraisal of population-

based colorectal cancer screening programme in England. Gut 2007; 56:677– 84.

Valori R (2007). Bowel cancer screening. M http:// www.18weeks.co.uk..

516

CHAPTER7 Gastroenterology

516

Faecal and serological testing

ininﬂammatory bowel disease

Faecal calprotectin

• Neutrophil granulocyte cytosol protein, which acts as a marker of

intestinal inammation.

•

+ve correlation with inammation in Crohn’s disease and ulcerative

colitis.

•

Non- specically elevated in neoplasia and radiation proctitistoo.

• Sensitivity for diagnosing pathology is 93%, with specicity of 100%, with

a result of ≤50μg/ g classed as −ve, eectively excludingIBD.

• Anormal result of ≤50μg/ g reduces the need for invasive

investigations, such as colonoscopy, for patients of 16– 40years of age

with no alarm symptoms of pathology (weight loss, bleeding, anaemia,

nocturnal diarrhea, or a signicant family history of bowel cancer).

Faecal lactoferrin

• Neutrophil- derived protein; marker of intestinal inammation.

• May be used for non- invasive testing to dierentiate those who require

colonoscopy from those more likely to have functional disease such

asIBS.

•

Not as eective as calprotectin, as sensitivity for diagnosing pathology is

82% and specicity is84%.

Perinuclear antineutrophil cytoplasmic antibodies

• Occur in the serum of 50– 80% of patients with histologically conrmed

ulcerative colitis, but only 10% of those with Crohn’s disease. This is

likely to be genetically determined.

•

Antibodies are particularly associated with ° sclerosing cholangitis in

association with ulcerative colitis.

•

Overall sensitivity is 55.3%, with a specicity of88.5%.

• In a paediatric cohort with −ve antibodies to Saccharomyces cerevisiae

(ASCA), sensitivity i to 70.3%, with 93.4% sensitivity.

Antibodies toSaccharomyces cerevisiae

• Found in 60% of patients with Crohn’s disease, but only 5% of those

with ulcerative colitis.

•

In Crohn’s disease, the presence of high titres of ASCA is associated

with early age of onset, brostenosing and stulating diseasetypes.

•

Sensitivity is 54.6%, with specicity of 92.8% if pANCA is−ve.

Further reading

National Institute of Health and Care Excellence (2013). Faecal calprotectin diagnostic tests for inam-

matory disease of the bowel. Diagnostics guidance DG11. M

https:// www.nice.org.uk/ guidance/

dg11.

Reese GE, Constantinides VA, Simillis C, etal. Diagnostic precision of anti- Saccharomyces cerevisiae

antibodies and perinuclear antineutrophil cytoplasmic antibodies in inammatory bowel disease.

Am J Gastroenterol 2006; 101

:2410– 22.

TUMOUR MARKERS

517

Tumour markers

• As a result of generally low sensitivities and specicities, these should

not be rst- line investigations.

• They are best used for tracking patients following a diagnosis of

carcinoma through subsequent surgery, and chemo- radiotherapy when

levels should fall to normal unless disease recurs.

Carcinoembryonic antigen

• i in 60% of those with localized colorectal carcinoma (CRC) and 80–

100% of those with metastatic disease.

•

Non- specic and non- diagnostic— also i in bronchial carcinoma, heavy

smokers, andIBD.

•

Levels do not relate to tumour load, but rising levels, which were

previously low/ normal, may imply recurrence ofCRC.

Alpha- fetoprotein

• Normally produced by fetalliver.

• High levels in non- pregnant adults imply hepatocellular carcinoma

(raised in over 90% cases).

•

i serological concentrations in pregnancy suggest neural tube defect.

•

Blood levels may be i in hepatocyte regeneration, acute viral hepatitis,

cirrhosis, choriocarcinoma, and teratoma.

•

May be used 6- monthly (with liver USS) to screen cirrhotic patients for

development of hepatocellular carcinoma.

Carbohydrate antigen 19- 9 (CA19- 9)

• i in pancreaticobiliary obstruction, with the highest levels in pancreatic

carcinoma.

•

Levels >40IU/ L have 75– 90% sensitivity and 80– 95% specicity for

ductal pancreatic carcinoma.

•

Serum levels may be elevated in jaundice, cholangitis,

choledocholithiasis, and chronic pancreatitis.

Cancer antigen 125 (Ca- 125)

• Glycoprotein antigen to an epidermal growth factor receptor

(p110 sEGFR).

• Blood levels i with menstruation, endometriosis, pelvic inammatory

disease, pregnancy, and ascites of alltypes.

•

Highest levels with ovarian malignancy, but also i with ovarian,

pancreas, breast, lung, and colon cancers.

•

20% of ovarian cancers have little/ no expression of Ca- 125.

• Useful in monitoring response of ovarian carcinoma to treatment

(if initially +ve), as rising level of Ca- 125 precedes clinical recurrence by

up to 3months (>90% of cases).

•

As isolated values lack sensitivity and specicity, serial Ca- 125 readings

may be used to achieve specicity of 99.6%, but with a sensitivity of

only80%.

518

CHAPTER7 Gastroenterology

518

Investigations forsmall bowel pathology

General investigations

• Presenting features of small bowel pathology include diarrhoea,

steatorrhoea, abdominal pain, weight loss, and nutritional deciencies.

•

Investigation of diarrhoea is shown in Fig.7.4.

• Occasionally, occult GI bleeding may originate in the small bowel, and an

algorithm for investigation of anaemia is shown in Fig.7.5.

Serology

•

Anti- tTG antibodies have almost 100% sensitivity for coeliac disease but

may be false −ve in presence of lowIgA.

• Diagnosis should be conrmed using duodenal or jejunal biopsies taken

at OGD, which would reveal partial or total villous atrophy.

Endoscopy

•

OGD and enteroscopy allow views of the proximal small intestine to

obtain tissue and allow therapeutic possibilities.

•

WCE permits diagnosis from the whole small intestine but does not

allow therapeutic options.

Radiology

•

MRI of the small bowel has mostly replaced barium radiology,

particularly in younger patients, with a lack of radiation, greater

sensitivity for mucosal detail by using contrast, and abilities to use cine

views to determine motility.

•

Barium follow- through involves ingestion of dilute barium, with images

taken every 10– 30min until barium reaches the caecum.

• Small bowel enema (enteroclysis) uses insertion of a nasoduodenal

tube to infuse barium slowly, creating a column, which may be followed

continuously using uoroscopy. This allows focusing on areas including

the terminal ileum (see Fig.7.2).

Nuclear medicine

Radiolabelled white cell scintigraphy forinammation/ infection

• Uses

99m

technetium– hexamethyl- propylene- amine- oxime (

99m

Tc-

HMPAO) to show intensity and extent of inammation or infection 1

and 3h after injection of autologous radiolabelled leucocytes.

•

Delineates disease extent in Crohn’s disease and ulcerative colitis (see

Fig.7.3).

•

False −ve results may occur in small bowel Crohn’s disease.

• Sensitivity of 96% and specicity of 97% for IBD, and sensitivity of

85– 100% and specicity of 100% for detecting abscesses.

Radionuclide studies todetect Meckel’s diverticulum

•

99m

Tc pertechnate accumulates in gastric mucosa with a time course

of 5– 60min.

• Uptake in ectopic mucosa (e.g. Meckel’s diverticulum) occurs

simultaneously.

•

Imaging at 5– 10min intervals up to 2h after injection allows localization

of the site of ectopic mucosa.

•

False +ves are caused by early gastric emptying.

• Sensitivities vary from 90% in children to 60% in adults.

INVESTIGATIONS FORSMALL BOWEL PATHOLOGY

519

Fig.7.2 Barium follow- through image showing a terminal ileal stricture.

Fig.7.3 Radiolabelled white cell scintigraphy using

99m

Tc- HMPAO to show

inammation of the terminal ileum consistent with Crohn’s disease (taken at3h).

SeHCAT scan forbile salt malabsorption

•

The labelled bile acid

selenium homotaurocholate (SeHCAT) is

administered orally. Retention measured at 7days by whole body

counting.

•

Retention of >15% SeHCAT is normal (less indicates malabsorption).

• Commonest reason for abnormal result is post- cholecystectomy,

presence of ileal disease, or post- ileal resection.

• Useful second- line investigation in patients with diarrhoea of unknown

aetiology.

520

CHAPTER7 Gastroenterology

520

History and examination

Infection

Treat cause

No infection

apparent

Baseline investigations

Blood: FBC, ESR, albumin, U&E, LFTs,

glucose, TFT, ferritin, B

red cell folate

Stool: microscopy and culture,

Clostridium dicile toxin, faecal

calprotectin

Sigmoidoscopy: with rectal biopsy

AXR: if patient unwell

Suspected bacterial

overgrowth (blind loop,

dilatation or stasis, jejunal

diverticulosis, diabetes

mellitus, dB

with i red cell

folate)

Suspected colonic

disease (blood ± urgency

± anaemia with low ferritin)

Endoscopy: Colonoscopy

with terminal ileoscopy &

multiple biopsies

Suspected pancreatic

disease/neuroendocrine

problem (steatorrhoea, weight

loss, symptoms of vasoactive

hormone secretion)

Radiology: abdominal ultrasound,

CT scan, endoscopic ultrasound,

MRI

Blood: fasting gut hormones

Urine: laxative screen, 24 hours 5HIAA

Faeces: elastase, chymotrypsin, (3-day

faecal fat)

Faeces: amoebic antigen

testing

Blood: anti-tissue transglutaminase

antibodies, HIV, Mg

, Zn

Endoscopy: OGD, duodenal biopsies

and duodenal aspirate (for giardia),

colonoscopy and terminal ileoscopy,

wireless capsule endoscopy, enteroscopy

Radiology: MRI small bowel, CXR,

AXR, barium follow through or small

bowel enema.

Isotope scans: radiolabelled white

cell scan, SeHCAT scan

Suspected small bowel disease:

(dB

, red cell folate, dferritin,

dcalcium, dalbumin, iMCV, weight

loss, diarrhoea)

Hydrogen breath tests:

lactose, lactulose, glucose

Direct aspiration of duodenal

jejunal uid with culture

Fig.7.4 Investigation of diarrhoea with specic tests for likely sites of pathology.

INVESTIGATIONS FORSMALL BOWEL PATHOLOGY

521

If falling haemoglobin despite oral iron or

blood transfusion dependent or if patient

now symptomatic (e.g. weight loss, rectal

bleeding), consider further investigation if

not already done using wireless capsule,

enteroscopy, small bowel barium studies

or MRI small bowel as dictated by local

availability and consider repeating OGD/

colonoscopy

History and examination – investigate

in order suggested by symptoms, age

and tness of patient

All other patients require all of:

OGD and D2 + D1 biopsies; Coeliac

serology; colonoscopy/CT

colonography depending on tness.

Dipstick urine for haematuria and refer

to Urology if positive.

If no cause found and patient remains

asymptomatic, replace iron using 3 months

of high dose oral treatment then check

haemoglobin and ferrin 3 monthly for

2 years

Premenopausal women only

• Check Coeliac serology

• If serology positive or if upper GI

symptoms, then for OGD and D2 + D1

biopsies

• Only if colonic symptoms or if relevant

family history of colorectal cancer,

then for colonoscopy

• Treat conditions if found

• If Coeliac serology negative and no

symptoms, then may need

gynaecology referral as heavy menses

most likely cause

• Treat cause if found

• If Coeliac disease conrmed

(positive D2 and D1 biopsies

and positive serology) –

make dietetics referral

and ensure colonoscopy/CT

colonography is carried out

too if patient >60 years or

has symptoms of colonic

disease

No action

needed

unstable

stable

transferrin saturation

Iron deciency anaemia

ferritin,MCV,

(

)

Fig.7.5 An algorithm for investigation of iron deciency anaemia.

522

CHAPTER7 Gastroenterology

522

Tests ofsmall bowel absorption

Tests ofcarbohydrate malabsorption

D- xylose tolerancetest

Xylose is absorbed from the proximal small bowel, and urinary excretion

and blood levels reect absorption. It is used mainly in paediatric practice

and has a low sensitivity.

Lactose tolerancetest

Oral administration of 50g of lactose is followed by blood sampling every

30min for 2h. Arise in blood glucose of <1.1mmol/ L suggests deciency

of disaccharidases, especially with colicky abdominal pain and diarrhoea.

Lactose hydrogentest

This is similar to the hydrogen breath test for bacterial overgrowth. Lactase-

decient individuals fail to metabolize lactose, which then undergoes lumi-

nal metabolism by lactase- producing colonic bacteria to yield hydrogen.

Glucose and fructose may be used as alternative short- chain carbohydrates

to determine the presence of malabsorption.

Tests offat malabsorption (may occur inpancreatic

malabsorptiontoo)

Patients with fat malabsorption 2° to small bowel diseases, such as coeliac

disease or tropical sprue, may malabsorb between 10 and 20g/ day of fat,

whilst patients with pancreatic insuciency may malabsorb 30– 50g/ 24h.

Anormal faecal fat excretion is <6g/ day (17mmol/ day).

3- day faecalfat

• Unpleasant test, fallen into disuse, but remains gold standard.

• Fat content measured in a 3- day faecal collection.

• Patient takes a standard diet of 100g of fat perday.

• Does not dierentiate small bowel and pancreatic malabsorption.

TESTS FORBACTERIAL OVERGROWTH

523

Tests forbacterial overgrowth

Deep duodenal/ jejunal aspiration

• Samples may be collected through the biopsy channel atOGD.

• Scanty bacteria are present in normal upper smallbowel.

• Numbers in excess of 10

/ mL of aspirated uid are pathological.

• This technique may culture Giardia and Strongyloides species.

Hydrogen breathtests

Rationale

In mammals, the only source of breath hydrogen is bacterial fermentation

of carbohydrates. Hydrogen is absorbed from the intestinal lumen and

expired during breathing. In bacterial overgrowth, hydrogen production can

occur in the small intestine, as well as in thecolon.

Method

•

Amouthwash is given beforehand to reduce contamination by oral

bacteria.

•

Test dose of glucose/ lactose (50g of either) or lactulose (10– 15mL) and

breath hydrogen measured.

•

An early peak (e.g. 40min) suggests bacterial overgrowth.

• This test can be used for other short- chain carbohydrates, such as

fructose or lactose, to determine if a patient is malabsorbing one

ormore.

Limitations

•

Sensitivity 60– 90%, with specicity of80%.

• False −ves result from variations in microora present in the small

intestine or antibiotic administration within 3weeks.

•

False +ves occur in patients with IGT, those with rapid transit to the

colon, and smokers.

•

Patients should avoid eating pulses for 48h prior to the test (normal

digestion of pulses liberates excess hydrogen).

524

CHAPTER7 Gastroenterology

524

Tests ofpancreatic exocrine function

• Symptoms of pancreatic exocrine dysfunction include diarrhoea or

steatorrhoea and weightloss.

•

Investigations aim to determine the degree of pancreatic insuciency,

although biochemical and radiological investigations are more reliable

with greater sensitivity and specicity in advanced disease.

Faecal testing

Elastase

•

Proteinase produced by pancreatic acinar cells and remains un- degraded

during gut transit.

•

Measured using immunoassay of non- liquid faeces sample.

• Levels of >200µg/ g of faeces being normal, 100– 200 representing mild

insuciency, and <100 being diagnostic of severe disease.

•

Specicity is 93%, whilst sensitivity is 63% and 100% for mild and severe

disease, respectively.

•

False +ves may occur with high- volume watery stools.

• The result is not aected by pancreatic enzyme supplements.

Chymotrypsin

•

Less sensitive (64%) and specic (89%) than elastase.

• Used mainly in children to screen for cystic brosis.

• Result is aected by pancreatic enzyme supplements.

Direct investigations

Secretintest

•

Direct intubation of the duodenum allows collection of pancreatic

juice, following IV injection of either secretin (allowing measurement

of volume and bicarbonate content) or cholecystokinin (allowing

measurement of amylase, trypsin, and lipase).

•

Whilst highly sensitive and specic, even with mild pancreatic disease,

this is only available in specialist centres.

Indirect investigations

PABA (N- benzoyl- L- tyrosol p- aminobenzoic acid)test

• Synthetic peptide, which is given orally.

• In normal patients, pancreatic chymotrypsin hydrolyses this peptide,

yielding free PABA, which is absorbed, metabolized, and excreted

inurine.

•

In pancreatic insuciency, free PABA levels are reduced, resulting in

reduced absorption and excretion with lower urinary and serum PABA

concentrations.

Pancreolauryltest

•

Fluorescein dilaurate (an ester) is taken orally with a setdiet.

• In the presence of normal pancreatic function, aryl esterases release

uorescein, which is absorbed, partially conjugated in liver, and excreted

inurine.

•

A24h urine collection for excreted levels shows close correlation with

pancreatic exocrine function.

TESTING FORNEUROENDOCRINE TUMOURS

525

Testing forneuroendocrine tumours

• Specialist area where clinical suspicion results from baseline

investigations, and radiology should allow targeting of more specic

biochemical investigations, depending on which syndrome is suspected.

•

Histology is required to conrm the diagnosis.

Baseline biochemicaltests

Urinary 5- hydroxyindole aceticacid

• 24h collection of urine for 5- hydroxyindole acetic acid (5HIAA).

• High levels imply carcinoid syndrome.

• High specicity, but false +ves result from serotonin- rich bananas,

tomatoes, or drugs such as phenothiazines.

ChromograninA

•

Marker of neuroendocrine tumours (NETs) found in high

concentrations, regardless of presence or absence of hormone- related

clinical features.

•

May be falsely elevated in proton pump inhibitor use and atrophic

gastritis.

Baseline radiological/ endoscopic investigations

• CT or MRI of the chest, abdomen, and pelvis. The ° tumour is

identied in only 50– 70%.

• Radiolabelled somatostatin receptor scintigraphy (OctreoScan).

• Positron emission tomography (PET) using gallium- 68 with concurrent

CT (PET/ CT) if unknown ° or to look for2°.

• Endoscopy or EUS may allow tissue diagnosis.

Vasoactive peptides andamines

• Measured using fasting serum gut hormone assays:insulin (paired with a

serum glucose sample), glucagon, chromogranin Aand B, VIP, pancreatic

polypeptide (PP), gastrin, and somatostatin.

• Single tumours often secrete >1 type of hormone.

• Up to 50% of slow- growing tumours are thought to be non- functional.

• Several types of tumour occur as part ofMEN- 1.

• Concurrent therapy with a proton pump inhibitor will falsely raise serum

gastrin and chromogranin Alevels, so these should be stopped for at

least 1 week prior to measuring serum levels.

Further reading

Ramage JK, Ahmed A, Ardill J, etal. Guidelines for the management of gastroenteropancreatic neu-

roendocrine (including carcinoid) tumours (NETs). Gut 2012; 61

:6– 32.

526

CHAPTER7 Gastroenterology

526

Gastrointestinal physiology

Sphincter ofOddi (SOD) manometry

• Awater- perfused pressure catheter is used during ERCP to measure

sphincter of Oddi pressures to formally diagnoseSOD.

•

SOD is triad of abnormal liver function, biliary- type abdominal pain, and

dilatation of the biliary tree in the absence of gallstone disease.

•

Diagnosis is conrmed by high resting pressure, retrograde peristalsis,

and failure of contrast to drain from the biliary tree within45min.

•

Whilst patients with SOD have an i risk of pancreatitis post- ERCP,

biliary sphincterotomy may relieve symptoms of pain in selectedcases.

pH monitoring

Indications

•

Assessment of gastro- oesophageal reux disease (GORD).

• Atypical symptoms such as asthma or non- cardiac chestpain.

• Before consideration of anti- reux surgery.

• Poorly controlled GORD to conrm diagnosis on or o treatment.

Investigation

•

Ambulatory 24h test that places a pH electrode through the nose to sit

5cm above the lower oesophageal sphincter.

•

Connected to a portable microprocessor that records episodes where

the pH dips below4.

• Patient lls in a simultaneous event diary to correlate symptoms and

episodes of lowpH.

• For most patients, H

receptor antagonists and proton pump inhibitors

are stopped 7days beforehand. Afew patients require testing on

medication to establish treatment response.

Results

•

Measure frequency and duration of episodes ofpH<4.

• Duration of longest episode.

• Assess correlation between symptoms andpH.

• Excessive oesophageal acid reux is dened as a total duration of pH <4

of 4– 6% of recordingtime.

Oesophageal manometry

Indications

•

Diagnosis and assessment of motility disorders suggested by symptoms/

OGD/ barium swallow ndings.

• Dening the precise location of the lower oesophageal sphincter prior

to 24h pH monitoring.

• Before consideration of anti- reux surgery.

Investigation

•

Static test using a nasogastrically placed multiple channel, water-

perfused catheter, which is gradually withdrawn during a series of wet

and dry swallows.

•

Pressure is measured through the length of the oesophagus, at the

upper and lower oesophageal sphincter, and the duration and frequency

of contractions are recorded (see Table7.3).

GASTROINTESTINAL PHYSIOLOGY

527

Gastric emptying

• Scintigraphy using the radioactive tracer

99m

technetium displays gastric

movements with a range of test meals (liquid to solid) to quantify gastric

emptying and intestinal lling overtime.

•

In practice, barium and endoscopic studies often provide enough

information when investigating patients with vomiting.

Intestinal transit studies

• Intestinal transit is measured using 50 radio- opaque plastic markers

inside a pH- sensitive gel capsule, swallowed by the patient and designed

to release its contents in the terminal ileum. An abdominal radiograph at

100h should show <20% of markers present in thecolon.

•

Measures colonic transit in suspected slow transit constipation.

Anorectal manometry

• Water- perfused catheter measures anorectal pressures to assess

voluntary and involuntary sphincter squeeze pressures and reex

responses to balloon distension in the rectum.

•

Readings allow assessment of rectal sensation, spinal reexes, and

internal and external sphincter integrity.

•

Assesses symptoms of faecal soiling, incontinence, and chronic

constipation.

Table7.3 Results fromoesophageal manometry studies

Non- specic motility

disorder

Abnormal and incomplete peristalsis with normal body

contractions

Achalasia Incomplete relaxation and high pressure of lower

oesophageal sphincter with aperistalsis of the

oesophageal body

Nutcracker

oesophagus

High amplitude and duration of contractions, normal

peristalsis

Oesophageal spasm Disordered peristalsis with simultaneous prolonged

contractions throughout

528

CHAPTER7 Gastroenterology

528

Non- invasive liver investigations

Basic liver function testing

These are basic serological screening tests that establish whether liver

inammation, infection, or obstruction is present.

Alanine transaminase

Alanine transaminase (ALT:cytosol enzyme specic to the liver) and aspar-

tate transaminase (AST:mitochondrial enzyme also present in the heart,

muscle, kidney, and brain)— both enzymes are present in hepatocytes and

leak into blood with liver cell damage.

Alkaline phosphatase

Alkaline phosphatase (ALP: canalicular and sinusoidal membranes of the

liver, but also bone, intestine, placenta)— specic isoenzymes for ALP are

produced by dierent tissues, but simultaneously raised γ- glutamyl trans-

peptidase (γ

GT) and ALP implies a hepatic origin. Extra- and intra- hepatic

cholestasis may cause raised ALP and results from benign or malignant dis-

ease with or without raised bilirubin. The highest levels result from PBC and

hepatic metastases.

Gamma glutamyl transpeptidase

GT (microsomal enzyme)— activity can be induced by drugs, such as phe-

nytoin and rifampicin, and alcohol. Mild elevation of γGT is common with

even a small alcohol intake, and isolated elevation does not imply liver dis-

ease. It rises in parallel with ALP in cholestasis.

Albumin

A protein that is synthesized in the liver. Plasma concentration partially

results from functional capacity within the liver. However, it has a serum

half- life of 20days and may be normal in early phases of acute liver disease.

Hypoalbuminaemia may also arise from i volume of distribution (sepsis,

overhydration, pregnancy), i excretion or degradation (nephrotic syn-

drome, protein- losing enteropathy), haemorrhage, or catabolic states such

as malignancy orburns.

Prothrombintime

Test of plasma clotting activity and reects the activity of vitamin K-

dependent clotting factors synthesized by the liver. PT may be elevated in

acute or chronic liver disease. In vitamin K deciency with normal liver func-

tion, PT will return to normal within 18h of administration of parenteral

vitaminK.

Bilirubin

In liver disease, a raised bilirubin is usually associated with other liver

function abnormalities. There are many causes of raised serum bilirubin.

Bilirubin may be conjugated or unconjugated, although in practice, this

conjugation state only dierentiates congenital hyperbilirubinaemias. In

Gilbert’s syndrome (the commonest benign cause of an isolated raised

serum bilirubin), an elevated unconjugated bilirubin, which rises during fast-

ing and mild illness, diagnoses the condition. Haemolysis is another cause of

hyperbilirubinaemia, which is covered in E Chapter3.

NON-INVASIVE LIVER INVESTIGATIONS

529

Immunoglobulins

•

IgG i in viral hepatitis, chronic AIH, and cirrhosis.

• IgM i in PBC, non- biliary cirrhosis, and acute viral hepatitis.

• IgA is i in alcoholic liver disease, with β– γ fusion seen on

electrophoresis.

Specic biochemicaltests

These are summarized in Table 7.4, with serological tests, diagnosis, and

denitive investigations required to conrm the diagnosis. The best investi-

gations for an individual patient are established from history, examination,

and basic biochemical parameters.

Table7.4 Specic biochemicaltests

Test Condition Findings More specic tests

Serum ferritin

Serumiron

Transferrin

saturation

Haemo-

chromatosis

Serum iron

>30µmol/ L

Serum ferritin

>500µg/ L

Transferrin saturation

>60%

HFE gene testing

(83– 90% of patients

have Cys 282 Tyr

mutation; 25% have

His 63 Asp; 187G

in complete linkage

disequilibrium with Cys

282 Tyr). Liver biopsy—

with dry weight of iron

24h urinary

copper excretion

Serum copper

Caeruloplasmin

Wilson’s

disease

Serum copper and

caeruloplasmin levels

are usually reduced

but can be normal

Liver biopsy— with dry

weight of copper

- antitrypsin α

- antitrypsin

deciency

Levels of <10%

of normal in

homozygotes and

60% in heterozygotes

Liver biopsy and lung

function testing for

emphysema

AMA PBC AMA present in titres

>1/ 160

Specic M2 antibody

(possible non- specic

i ANA/ SMA)

i serum IgM and ALP

Liver biopsy

ANA/ SMA Type IAIH i ANA ± SMA

i total IgG

Liver biopsy

Anti- LKM1 or

anti- liver cytosol

antibodies

Type II AIH i antibodies titres

i total IgG

Liver biopsy

Fasting

cholesterol

and glucose,

glycosylated Hb

Non- alcoholic

fatty liver

disease/

non- alcoholic

Steatohepatitis

IGT Fibroscan

/ brosis

score/ liver biopsy

530

CHAPTER7 Gastroenterology

530

Specic virologicaltests

HepatitisA

•

Acute infection:+ve IgM antibodies toHAV.

• Chronic infection:does notoccur.

•

Markers of clearing virus:+ve IgG antibodies to HAV and anti- HAVIgM.

HepatitisB

Acute infection withsubsequent clearing ofvirus

•

HBsAg appears in blood from 6– 12 weeks after infection, then

disappears.

•

HBeAg appears early, then declines rapidly.

• Anti- HBs appears late and indicates immunity.

• Anti- HBc is the rst antibody to appear, and IgM anti- HBc may persist

for many months as the only marker of ongoing viral replication when

HBsAg has disappeared and anti- HBs is not yet detectable.

• Anti- HBe appears after anti- HBc and indicates d infectivity.

Acute infection leading tochronic hepatitisB

•

HBsAg persists and indicates chronic carrierstate.

• HBeAg persists, correlating with i severity and infectivity.

•

Anti- HBe indicates seroconversion (if this occurs) with disappearance of

HBeAg and a rise inALT.

• HBV DNA suggests continued viral replication.

HepatitisC

•

Acute infection:hepatitis C HCV RNA is +ve 1– 2 weeks after infection,

with HCV antibodies developing after 712weeks.

•

Chronic infection:>50% of patients with persistent HCV RNA, which can

be measured as viralload.

•

Hepatitis C has six genotypes that determine response to treatment.

HepatitisE

•

Similar to hepatitis Awith no chronic or carrierstate.

Investigation ofliver disease

Figure 7.6 shows an algorithm for investigation of liver disease. This dif-

ferentiates obstructive from parenchymal liver disease to suggest further

investigation and treatment.

NON-INVASIVE LIVER INVESTIGATIONS

531

Non- invasive testing ofliver brosis

Transient elastography (Fibroscan

)

•

Stages liver disease by assessing stiness using the velocity of a

vibrationwave.

•

Measures liver inammation and brosis, with i stiness correlating with

disease severity.

•

Requires a minimum of ten valid readings; results are expressed inkPa.

•

Normal result:<7.0kPa.

•

Fibrosis:>7.0kPa (with an 85% probability).

•

Cirrhosis:>14.0kPa (with a 90% probability).

• Falsely high results:liver inammation (active hepatitis), cholestasis,

mass lesion or tumour, liver congestion in heart failure.

•

Unreliable results:presence of ascites.

• Not suitable:pregnancy and patients with a pacemaker.

• Benet:avoid risks of liver biopsy.

History and examination

Basic liver function tests

ULTRASOUND

Dilated ducts

Non-dilated ducts

MRCP, ERCP, or

PTC

Therapeutic procedure

to relieve obstruction

Biliary

obstruction

Virology, autoantibodies,

caeruloplasmin, ferritin,

iron, transferrin, α

-anti-

trypsin, glucose,

cholesterol

Liver

biopsy

Fig.7.6 An algorithm for investigation of liver disease.

532

CHAPTER7 Gastroenterology

532

Liverbiopsy

• Obtains tissue for diagnosis of diuse or localized parenchymal disease.

• Severity of histological liver dysfunction cannot be predicted from

basicLFTs.

•

Consent should be obtained based onrisks.

• Transjugular liver biopsy overcomes many contraindications.

Indications

• Unexplained persistently abnormalLFTs.

• Staging of disease in hepatitis B or C infection, and prior to considering

antiviral treatment.

•

Acute hepatitis of unknown aetiology.

• Cirrhosis of unknown aetiology.

• Alcohol- related liver disease.

• PBC/ chronic active hepatitis.

• Targeted liver biopsy of lesions (not if resection/ transplant is a possibility).

• PUO.

• Haemochromatosis/ Wilson’s disease.

• Storage diseases.

• Post- liver transplant to rule out acute or chronic rejection.

Methods forobtaining tissue (risks and benets)

Percutaneous withor withoutultrasound viewing

(See Table7.5.)

•

Standard method for obtaining tissue.

• Ultrasonography of liver and biliary tree pre- procedure to identify

anatomical variations i risk and to rule out obstruction.

•

Most complications <2h but can occur up to24h.

• No evidence that direct US- guided biopsy is safer, but US should

denitely be used if a targeted biopsy is required.

Contraindications

•

An uncooperative or confused patient.

• PT prolonged by >3s, platelets <80 × 10

/ L, or bleeding diathesis.

• Ascites.

• Hydatid cysts (risks of anaphylaxis and abdominal seeding).

• Extrahepatic cholestasis.

• Higher risk of bleeding if amyloidosis present.

Minor complications

Shoulder tip pain, minor intra- abdominal bleeding, or mild abdominal pain

(up to 30%)— usually settles with analgesia.

Major complications

•

Perforation (0.01– 0.001%:pneumothorax, gall bladder puncture, kidney,

colon).

•

Intra- abdominal haemorrhage; haemobilia (0.05%:a triad of biliary colic,

jaundice, and melaena within 3days of liver biopsy).

•

Mortality varies between 0.001 and 0.0001% and results from

intraperitoneal haemorrhage or biliary peritonitis.

•

Risk of tumour seeding if a malignant lesion is biopsied; if curative

resection/ transplantation is planned, needle biopsy should be avoided.

LIVERBIOPSY

533

Transjugular

• Specialist technique carried out using uoroscopic guidance.

• Catheter passes from the right internal jugular vein, through the right

atrium and IVC, and into the hepaticveins.

•

Patient holds his/ her breath, whilst the biopsy needle is advanced

through the catheter then rapidly pushed forward by 1– 2cm into the

liver to obtain a small core of liver parenchyma.

•

Safe technique with few complications (1.3– 2% morbidity and 0.5%

mortality), usually performed in higher- risk patients.

• Complications range from neck haematoma, puncture of intrathoracic

arteries, transient Horner’s syndrome, cardiac arrhythmias, infection,

and perforation of the liver capsule.

•

Test of choice in patients excluded from percutaneous biopsy by

coagulopathy, bleeding diathesis, ascites, portal hypertension, and

amyloidosis.

•

Transjugular cannulation allows measurement of portal venous pressures.

Laparoscopic

• Allows sampling of the liver when an operation is planned.

• Allows targeted biopsies, as well as parenchymal biopsies.

• Bleeding is directly controlled and perforation is avoided.

• Risks of surgery and anaesthesia should be considered.

Further reading

Grant A, Neuberger J, Day C, Saxseena S (2004). Guidelines on the use of liver biopsy in clinical practice.

http:// www.bsg.org.uk/ images/ stories/ docs/ clinical/ guidelines/ liver/ liver_ biopsy.pdf.

Table7.5 Percutaneous liver biopsy— practical procedure

Procedure Should be carried out by an experienced doctor using aseptic

precautions

Check Clotting, FBC, and take group and save (G&S) within 24h before

procedure (cancel if platelets <80 × 10

/ L or PT prolonged >3s)

Patient Lies at on his/ her back

Liver margins Delineated using percussion and/ or US

1% lidocaine 5mL injected at the point of maximal dullness down to the liver

capsule through intercostal space in expiration

Menghini

or Trucut

needle

Used to obtain sample with patient’s breath held in expiration (up

to two passes may be used). Menghini needles use suction, have a

lower rate of complications, and allow more rapid biopsy, but they

have a lower yield for tissue than Trucut (a cutting needle)

Sample

Placed into 10% formalin (or into a dry pot to estimate dry weight

of iron or copper or for culture)

Patient Nurse in supine position or right lateral for >6h, with regular BP and

pulse measurements (every 15min for 2h, every 30min for the next 2h,

then hourly), with urgent medical review if any sign of deterioration

If stable

At 6h, the patient can be discharged home as long as s/ he can return

to hospital within 30min and have a responsible adult with him/ her

overnight

534

CHAPTER7 Gastroenterology

534

Investigation ofasciticﬂuid

(See Table7.6.)

Investigation requires diagnostic aspiration

• 10mL is sent for cell count, Gram stain, ZN stain culture (add 10mL to a

pair of blood culture bottles to i diagnostic yield).

•

10mL is sent for cytology.

• 10mL for biochemical investigation of protein, glucose, LDH, TGs

(if chylous ascites is suspected), and amylase (if pancreatic ascites is

suspected).

Results

Cellcount

•

Polymorphonuclear leucocytes (neutrophils) of >250 cells/ mm

suggest

underlying spontaneous bacterial peritonitis (SBP) (or 2° infection).

• Total leucocytes of >500 cells/ mm

imply bacterial peritonitis (SBP) if a

specic neutrophil count is not available.

•

Lymphocyte count of >500 cells/ mm

implies tuberculous peritonitis

(with raised protein, positive ZN stain/ TB culture, and low glucose).

Gram stain and culture

•

Gram staining for early identication of bacteria and bacterial culture

allow targeting of antimicrobial therapy.

Protein

•

Using ascitic uid protein levels to aid diagnosis is best achieved using

the serum ascites albumin gradient (SAAG) by subtracting ascites

albumin concentration from serum albumin concentration. Levels of

≥11g/ L suggest cardiac failure, cirrhosis, and nephrotic syndrome, whilst

levels of <11g/ L suggest malignancy, TB, or pancreatitis as causes.

• Risk of SBP is greatest if ascitic protein <10g/ L.

Cytology

May be diagnostic in cases of peritoneal malignancy.

Amylase

ascitic amylase (>2000IU/ L) is typical of pancreatic ascites.

Triglycerides

i in chylous ascites.

Table7.6 Ascitic uid aspiration— practical procedure

Patient Lies on his/ her back, tilting towards side planned for aspiration

Percussion Used to nd shifting dullness in left or right lower quadrant

Chlorhexidine Used to clean the site

Lidocaine

2– 3mL of 1% used to inltrate a site in the left or right lower

quadrant where shifting dullness is detected. It should be

possible to aspirate ascitic uid using a standard 19G needle

50mL syringe Sterile 19G needle placed through the same site to obtain the

samples required

Rare

complications

Include bowel perforation, 2° bacterial peritonitis, or

haemorrhage

535

Chapter8

Respiratory medicine

Airway hyperresponsiveness test or histamine/ methacholine

challenge test 536

Arterial blood gas sampling 538

Pleural aspiration (diagnostic) 540

Epworth test/ Epworth sleepiness scale 542

Exercise testing 544

Exhaled nitric oxide fraction 546

Fibreoptic bronchoscopy 548

‘Fitness to y’ assessment 552

Flow– volume loops/ maximum expiratory ow– volume

curve 554

Nijmegen questionnaire 556

Peak ow charts 558

Percutaneous pleural biopsy 562

Polysomnography 564

Pulse oximetry 566

Skin prick tests 567

Spirometry 568

Sputum microscopy and culture/ sputum cytology 570

Static lung volumes/ whole body plethysmography 572

Sweat test 576

Medical thoracoscopy 578

Transfer factor 582

536

CHAPTER8 Respiratory medicine

536

Airway hyperresponsiveness test or

histamine/ methacholine challengetest

Clinical indications

Suspected asthma in patients with normal spirometry.

Patient preparation

1. Explain the procedure to the patient.

2. Obtain informed consent.

3. Warn that wheezing and shortness of breath (SOB) may occur and that

a bronchodilator may begiven.

4. Baseline FEV

measured.

5. Patient breathes in a nebulized aerosol of histamine (or methacholine)

of i concentrations. This stimulates bronchoconstriction in a dose-

dependent manner.

6. The FEV

is measured after eachdose.

7. Patient must remain in the department for 30min following the

procedure to observe any delayed reactions.

Possible results

The percentage fall in FEV

from baseline is plotted against the dose of

inhaled histamine on a logarithmic scale. A dose– response curve is con-

structed, and the provocation concentration (PC) of inhaled histamine

required to reduce the FEV

by 20% (PC

) can be derived by linear extrapo-

lation. This gure has been arbitrarily chosen to assess degrees of bronchial

reactivity for ease of comparison and safety.

Interpretation

• Asthma suggested by PC

<8mg/ mL (see Fig.8.1).

• Adirect relationship exists between the severity of asthma and

requirement for medication, and the PC

value as an index of bronchial

hyperresponsiveness.

•

Non- asthmatic subjects almost always have a PC

>8mg/ mL.

Advantages overothertests

• Easytodo.

• Cheap.

• Non- invasive.

• Quick.

• Reproducible.

• Safe— bronchoconstriction may be reversed by an inhaled β- adrenergic

agonist. It is important that personnel performing the test are able to

recognize severe bronchospasm and that resuscitation equipment is

available.

Contraindications

• Documented cholinergic hypersensitivity, e.g. cholinergic urticaria or

angio- oedema, orboth.

• Allergy to histamine/ methacholine.

AIRWAY HYPERRESPONSIVENESS TEST

537

• Inability to perform acceptable- quality spirometry.

• Unstable cardiac status, e.g. recent MI, arrhythmia, or heart failure.

• Uncontrolled hypertension (systolic BP >200 or diastolic BP>100).

• Pregnancy.

• Severe baseline obstruction with FEV

<80% predicted or<1.5L.

Ancillarytests

• PEFR chart:diurnal variation.

• Sputum cytology:eosinophilia.

• Exhaled nitric oxide (NO):elevated levels.

Pitfalls

• Bronchial hyperresponsiveness in asthma is not a static phenomenon

and may vary widely from day today.

•

May change quite markedly without any change in symptoms

(and vice versa).

•

Represents only one component contributing to the symptomatology of

asthma. Others include airway oedema and mucus hypersecretion.

Further reading

Crapo RO, Casaburi R, Coates AL, etal. Guidelines for methacholine and exercise challenge testing–

1999. Am J Respir Crit Care Med 2000; 161:309– 29.

Joos GF, O’Connor B. Indirect airway challenges. Eur Respir J 2003; 21:1050– 68.

Lotvall J, Inman M, O’Byrne P. Measurement of airway hyperresponsiveness:new considerations.

Thorax 1998; 53

:419– 24.

Pratter MR, Irwin S. The clinical value of pharmacologic bronchoprovocation challenge. Chest 1984;

:260– 5.

Smith CM, Anderson SD. Inhalation provocation tests using nonisotonic aerosols. J Allergy Clin

Immunol 1989; 84

:781– 90.

Reduction in FEV

from baseline (%)

0.804.02.01.0.5.25

0.125

.062.031

Control

Histamine concentration (mg/mL)

A : Marked hyperresponsiveness

= 0.125mg/mL

Moderate hyperresponsiveness

= 8.0mg/mL

C : Not responsive

Fig.8.1 Diering responses to varying concentrations of histamine.

538

CHAPTER8 Respiratory medicine

538

Arterial blood gas sampling

Clinical indications

• Breathlessness (acute or chronic).

• Cardiorespiratory failure.

• Metabolic disturbance.

• Poisoning withdrugs.

• Acute asthma with O

saturation <92% (onair).

E OHCM 10e, p.189, p. 665.

Patient preparation

• Informed consent (verbal usually satisfactory).

• Common sites:radial/ brachial/ femoral arteries.

Contraindications toradial

•

Absent ulnar circulation (Allen’stest).

• Arteriovenous (AV) stula for dialysis.

• Fracturedwrist.

• Poor peripheral circulation.

Contraindications tobrachial

•

AV stula.

• Fracturedelbow.

• Poor peripheral circulation.

Contraindications tofemoral

•

Presence of graft/ extensive vascular disease.

Procedure

1. Identify thepulse.

2. Clean the skin with an alcoholswab.

3. Conrm the position of maximum pulsation with the

non- dominanthand.

4. LAn reducespain.

5. Insert a 23G needle attached to a heparinized 2mL syringe.

6. If using low- resistance syringe, this will ll automatically; otherwise

aspirate gently.

7. Remove the needle, and apply rm, gentle pressure with a cotton wool

ball for5min.

8. Expel air bubbles from the sample.

9. Label the specimen.

Possible results

• Hypoxaemia with normalCO

•

Hypoxaemia withiCO

•

Normoxaemia withdCO

•

Metabolic acidosis vs compensation.

E OHCM 10e, p.162, p. 189, p. 771.

Interpretation

Start by looking at the pH. Next check whether CO

ts with the pH

change; if so, the ° problem is respiratory. Then check for any metabolic

compensation or for a combined respiratory and metabolic process. If CO

is not consistent with the pH change, the ° disturbance is metabolic and

you should check whether there is any respiratory compensation. To assess

ARTERIAL BLOOD GAS SAMPLING

539

oxygenation properly, it is essential to record the patient’s inspired O

con-

centration (FiO

) at time of sampling.

Advantages overothertests

• Easy, quick,cheap.

• No real alternative for assessing CO

or acid– base balance.

• Greater precision in upper ranges of arterial O

saturation (SaO

) curve

(see Fig.8.2).

Ancillarytests

• Pulse oximetry:gives indication of oxygenation status, but not CO

levels.

•

Arterialized blood sampling.

Complications

• Haematoma.

• Nerve damage.

• Inadvertent venous sampling.

Pitfalls

• If the sample is to be analysed in a laboratory with >5min transit time, it

should be kept on melting ice to slow the metabolic activity of thecells.

•

Avoid arterial puncture, if possible, in patients on anticoagulant

therapy, those with bleeding disorders, or those who have received

thrombolytics in previous24h.

•

Failure to note the FiO

at time of sampling will lead to diculty in

interpretation and potential therapeutic errors.

12345678910 11 12 13

1002030405060708090100

Tissues Lungs

Tension of O

(mmHg)

Tension of O

(kPa)

100

Saturation (%)

Loading in lungs

Unloading in tissu

capillaries

Normal

curve

Curve shifted to right

by i temperature, d pH, i 2,3-DPG

Curve shifted to left by d temperature, i pH, d 2,3-DPG

Fig.8.2 Dissociation curve for oxyhaemoglobin.

Further reading

Carruthers DM, Harrison BD. Arterial blood gas analysis or oxygen saturation in the assessment of

acute asthma? Thorax 1995; 50:186– 8.

Syabbalo N. Measurement and interpretation of arterial blood gases. Br J Clin Pract 1977; 51:173– 6.

540

CHAPTER8 Respiratory medicine

540

Pleural aspiration (diagnostic)

Clinical indications

• Unilateral pleural eusion detected clinically and with imaging, e.g. CXR,

USS, CTchest.

•

Aspiration should not be performed routinely for bilateral pleural

eusions if a transudate is suspected.

Patient preparation

1. Informed written consent.

2. Aseptic technique.

3. Posterior or axillary approach if eusion large (be guided by

bedsideUSS).

4. Clean skin with antiseptic solution.

5. Inltrate with LAn (1% lidocaine).

6. Insert a ne- bore 21G (green) needle attached to a 50mL syringe under

USS guidance. Note:ensure the needle enters immediately above the

rib to avoid the neurovascular bundle.

7. Aspirate uid. If no uid, then try adjusting the angle of the needle with

USS guidance.

8. Remove the needle and apply a plaster.

9. Post- aspirationCXR.

Possible results

• Pleural uid is normally straw- coloured and odourless.

• Pleural uid analysed for protein, glucose, LDH, microbiology, cytology,

andpH.

• If heavily bloodstained, suspect malignancy, pulmonary infarction, or

trauma. Atraumatic tap will become progressively less bloodstained.

•

If pus present:empyema.

• If creamy, opalescent uid:chylothorax (lymphoma, trauma to the

thoracic duct, yellow nail syndrome, lymphangioleiomyomatosis) or

pseudo- chylothorax, e.g. in TB orRhA.

Interpretation

Measure blood LDH and total protein simultaneously for Light’s criteria;

satisfying any ONE criterion means it is exudative:

•

Pleural total protein/ serum total protein>0.5.

• Pleural LDH/ serum LDH>0.6.

• Pleural LDH > two- thirds of upper limit of normal for serumLDH.

(See Table8.1.)

Advantages overothertests

• Quick andeasy.

• Cheap.

• Relatively non- invasive.

• Provides cytological, microbiological, and biochemicaldata.

PLEURAL ASPIRATION (DIAGNOSTIC)

541

Ancillarytests

• Thoracoscopy (medical or surgical).

• Percutaneous pleural biopsy.

Pitfalls

• Traumatictap.

• May be dicult to locate a loculated eusion, even withUSS.

Complications

• Haemorrhage.

• Pneumothorax.

• Visceral injury (e.g. liver).

• Large volumes of pleural uid (>1000mL) should not be aspirated at

one time due to risk of inducing re- expansion pulmonary oedema.

Further reading

Hooper C, Lee G, Maskell N. Investigation of a unilateral pleural eusion in adults:British Thoracic

Society pleural disease guideline 2010. Thorax 2010; 65:ii4– 17.

Light RW. Diagnostic principles in pleural disease. Eur Respir J 1997; 10:476– 81.

Table8.1 Interpretation

Cytology +ve in 760%, especially carcinoma of lung/ breast

Immunohistochemistry should be used to dierentiate

between malignant cell types and may guide oncological

therapy

Protein

Exudate >30g/ L protein

Transudate <30g/ L protein

pH <7.0:empyema, oesophageal rupture

>7.0 and <7.3:collagen disorders, TB, malignancy, empyema

Glucose d

in RhA, TB, malignancy, infection

Microbiology Organisms, ZN stain

Eosinophilia >10% in benign asbestos eusions, parasitic

hydropneumothorax

Neutrophilia >1.0 × 10

/ L in acute inammation, e.g. pneumonia, infarction

Lymphocytosis Chronic eusions, e.g. TB, malignancy, lymphoma, or RhA

Amylase iii in pancreatitis

i in oesophageal rupture (salivary amylase)

i in malignancy

ANA >1:160 virtually diagnostic of SLE

LDH i in infection

RF +ve in RhA

Complement d in RhA, SLE, malignancy, infection

542

CHAPTER8 Respiratory medicine

542

Epworth test/ Epworth sleepinessscale

Clinical indications

Screening tool for OSA. Measures general level of daytime sleepiness.

Patient preparation

1. Ask patient to ll in questionnaire.

2. Subject rates on a scale of 0– 3 the chance that, as part of his usual life

in recent times, he would doze in each of eight dierent situations.

Use the following scale to choose the most appropriate number for each

situation:

0=Would NEVERdoze

1=SLIGHT chance ofdozing

2=MODERATE chance ofdozing

3=HIGH chance ofdozing

Situation

•

Sitting and reading.

• WatchingTV.

• Sitting inactive in a public place (e.g. theatre or a meeting).

• As a passenger in a car for an hour without abreak.

• Lying down to rest in the afternoon when circumstances permit.

• Sitting and talking to someone.

• Sitting quietly after lunch without alcohol.

• In a car, whilst stopped for a few minutes in the trac.

Possible results

Epworth sleepiness scale (ESS) score is the sum of eight item scores and

can range from 0to24.

Interpretation

Clinically normal score <10. Each ESS item gives an estimate of sleep pro-

pensity in one of eight specic situations, whereas the total ESS score gives

a measure of more general average sleep propensity. Does not measure

‘subjective’ sleepiness.

Advantages overothertests

• Cheap.

• Easily administered.

Ancillarytests

• Polysomnography/ Visi- Lab studies.

• Stanford sleepinessscale.

• Multiple sleep latencytest.

• Maintenance of wakefulnesstest.

Pitfalls

Limited by patient’s ability to read and comprehend the questionnaire and

answer questions honestly.

EPWORTH TEST/EPWORTH SLEEPINESSSCALE

543

544

CHAPTER8 Respiratory medicine

544

Exercise testing

Clinical indications

• To conrm that reduced exercise tolerance exists.

• To determine the degree of impairment and disability.

• To investigate which system appears responsible for the reduction.

• To evaluate treatment results.

• To plan rehabilitation.

Patient preparation

1. Evaluate the patient’s medical history for contraindications totest.

2. Warn the patient of cardiovascular complications (e.g. mortality

1:10,000 tests).

3. Obtain informed written consent.

4. Patient to wear comfortable clothes andshoes.

5. Monitoring:ECG, O

saturation,BP.

6. Exercise:treadmill/ bike/ free run on at surface.

7. Steady state 5– 12min walking test (usually 6min) or stepped stresstest.

8. During a maximal exercise test, the patient should be able to achieve

85– 90% of predicted maximum heartrate.

Contraindications

• Unstable myocardium (recent MI, unstable angina, arrhythmias, severe

valvular heart disease, congestive heart failure).

•

Acute asthma.

• Acute febrile illness.

• Uncontrolled diabetes.

• Systemic hypertension (systolic >200mmHg, diastolic >120mmHg).

Possible results

• Cardiac response:ECG, BP, cardiac output, and stroke volume response.

•

Ventilatory response:ventilatory limitation (reduced breathing reserve),

pattern of response, V

, minute volume, respiratoryrate.

•

Gas exchange:ABGs, A– a gradient,P

•

Ventilatory (anaerobic) threshold:normalori.

•

2max

(maximum O

uptake):normalori.

Interpretation

Useful in making the distinction between exertional dyspnoea 2° to lung dis-

ease or fatigue 2° to cardiac dysfunction. In patients known to have asthma,

exercise test is +ve in 75% of cases with a single treadmill run and 97% if

the test is repeated in −ve responders. Afall of 10% or more from baseline

in PEFR or FEV

suggests exercise- induced asthma.

Advantages overothertests

Best assessment of exercise capacity. Adds to diagnostic accuracy quantita-

tively (measurement of work capacity, VO

2max

, and sustained work capacity)

and qualitatively (identication of the cause of exercise limitation).

EXERCISE TESTING

545

Ancillarytests

• Static lung functiontests.

• For asthma:exhaled NO levels, histamine/ methacholine inhalation

challenges, and PEFRdiary.

Pitfalls

• Dependent on patient eort and compliance.

• Not suitable for patients with severe objective measurement of

respiratory impairment.

Complications

• 2 Bronchospasm:usually easily reversed with an inhaled β - adrenergic

agonist.

•

2 Cardiac arrhythmias/ arrest:appropriate equipment and drugs should

be available in the exercise testing area. Personnel should be trained in

basic and advanced cardiopulmonary resuscitation.

Further reading

Hughes JMB, Pride NB (eds.). Lung Function Tests: Physiological Principles and Clinical Applications.

Philadelphia:WB Saunders,1999.

König P. Exercise challenge:indications and techniques. Allergy Proc 1989; 10

:345– 8.

Sue DY. Exercise testing in the evaluation of impairment and disability. Clin Chest Med 1994;

:369– 87.

546

CHAPTER8 Respiratory medicine

546

Exhaled nitric oxide fraction

Clinical indications

Asthma

•

Diagnosis.

• Assessment of severity.

• Assessment of treatment response.

Patient preparation

1. Patient breathes directly into the NO analyser.

2. Perform three tests each time, and record the largestvalue.

Possible results

Exhaled nitric oxide fraction (FeNO) can be detected by chemilumines-

cence in the range of 5– 300ppb.

Interpretation

Elevated FeNO levels are associated with eosinophilic asthma:

•

<25ppb:low probability. Asthma unlikely. Consider other possible

aetiologies for symptoms.

•

25– 50ppb:intermediate probability. Based on clinical judgement, asthma

is a possible diagnosis. Consider initiating inhaled corticosteroids and

monitoring further FeNO levels.

•

>50ppb:high probability. Asthma likely in an appropriate clinical

context. Symptomatic patients are likely to benet from inhaled

corticosteroids.

Advantages overothertests

• Simple andquick.

• Non- invasive.

• Objective measure of response to treatment.

Ancillary tests fordiagnosis ofasthma

• PEFRdiary.

• Histamine/ methacholine inhalation challenges.

• Sputum cytology:eosinophilia.

Pitfalls

• A−ve FeNO does not exclude asthma; asthma may be caused by

neutrophilic airways inammation.

•

FeNO levels are reduced by smoking.

EXHALED NITRIC OXIDE FRACTION

547

Further reading

Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001;

163

:1693– 722.

Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM. Expired nitric oxide levels during treat-

ment of acute asthma. Am J Respir Crit Care Med 1995; 152

:800– 3.

National Institute for Health and Care Excellence (2012). Measuring fractional exhaled nitric oxide

concentration in asthma:NIOX MINO, NIOX VERO and NObreath. Diagnostics guidance DG12. M

http:// www.nice.org.uk/ guidance/ dg12.

Saito J1, Gibeon D, Macedo P, Menzies- Gow A, Bhavsar PK, Chung KF. Domiciliary diurnal variation

of exhaled nitric oxide fraction for asthma control. Eur Respir J 2014; 43:474– 84.

548

CHAPTER8 Respiratory medicine

548

Fibreoptic bronchoscopy

Clinical indications

• Any patient with persistent/ substantial haemoptysis.

• Suspected lung neoplasm:

•

For histology.

•

To assist with staging.

• Infection:

•

To identify organism.

•

To determine course of recurrence/ persistence.

• Interstitial lung disease(ILD):

•

To obtain BAL for cytology; useful in diagnosis of sarcoidosis and

hypersensitivity pneumonitis.

•

To obtain endobronchial biopsies (EBBs); useful in diagnosis of

sarcoidosis.

•

To obtain transbronchial lung biopsies (TBLBs); useful in diagno-

sis of sarcoidosis, hypersensitivity pneumonitis, and lymphangitis

carcinomatosa.

Pre- assessment

• CXR.

• FBC.

• Spirometry. Patients with obstruction may require nebulized

bronchodilators pre- procedure.

• Clotting.

• Pulse oximetry.

• ABGs on air if hypoxaemia suggested by O

saturation.

Patient preparation

Endoscopysuite

1. Patient informed and consented. Fasted from solids for 6h and liquids

for3h.

2. Frontal approach with patient lying on couch, trunk at45°.

3. IV access obtained.

4. Basic monitoring— pulse oximeter andBP.

5. Supplementary O

via single nasal cannula.

6. IV sedation:midazolam/ alfentanil.

7. Topical lidocaine spray to nose and pharynx.

8. Bronchoscope lubricated with 2% lidocaine gel and passed via nostril or

mouthguard.

9. Further boluses of lidocaine (1%) applied to cords and bronchialtree.

Contraindications

• Patients at risk of pulmonary and cardiovascular decompensation, e.g.

recent MI, unstable angina, arrhythmias, severe valvular heart disease,

uncontrolled congestive heart failure, pulmonary hypertension, severe

hypoxaemia.

FIBREOPTIC BRONCHOSCOPY

549

• Patients at high risk of bleeding, e.g. patients on antiplatelet or

anticoagulant therapy or patients with coagulopathies such as

thrombocytopenia.

•

Bronchoscopists should be cautious when sedating patients withCOPD.

Possible results

• Direct inspection of the nares, nasopharynx, and oropharynx.

• Assess movement of vocal cords (ask patient to say ‘eee’).

• Direct inspection of the bronchial tree down to subsegmentallevel.

• Able to take endobronchial/ transbronchial biopsies and brushings.

BAL:wedge the tip of the bronchoscope into a subsegmental bronchus

and instil aliquots of 50mL of sterile saline into the distal airway.

Aspirate immediately, aiming to obtain 750% of instilled volume.

Bronchial washings (BWs) are performed in a similar fashion with

10– 20mL of sterile saline instilled into the bronchus.

Interpretation

(See Table8.2.)

Advantages overothertests

• Well tolerated.

• Quick,cheap.

• Provides histological and immunobiological conrmation (to back up

CT/ CXR diagnosis).

• Therapeutic— removal of retained secretions, mucus plugs, bloodclots.

Table8.2 Interpretation

Histology Tumours

ILD

EBB

TBLB

Cytology Tumours

ILD

Brush/ BAL/ BW

BAL

Microbiology Gram stain

ZNstain

Stain for Pneumocystis jiroveci

Fungi

Virus

PCR for Legionella and atypical

organisms

BAL/ BW

Some appearances diagnostic.

Screening:X- ray- guided biopsy of non- visible lesions.

550

CHAPTER8 Respiratory medicine

550

Ancillarytests

• Endobronchial ultrasound- guided transbronchial needle aspiration

(EBUS- TBNA):allows assessment and biopsy of mediastinal lymph

nodes and tumours.

•

Rigid bronchoscopy:underGAn:

•

Allows therapeutic interventions, e.g. laser therapy, cryotherapy,

stent insertion, debulking of large tumours in the major airways, and

better control of haemorrhage.

•

Preferable for removal of foreignbody.

Side eects and complications

• Pneumothorax with transbronchial biopsies.

• Haemorrhage post- biopsy.

• Hypoxaemia.

• Post- bronchoscopy fever with BAL (usually resolves in a few hours with

paracetamol, but antibiotics may be necessary).

•

If performed in a day case unit with sedation, the patient will not be able

to drive home and will need a responsible adult in attendance overnight.

Pitfalls

• Only visualizes proximal airways.

• Biopsies may be inadequate or from necroticareas.

• Not easy to biopsy submucosal tumour.

• Needs good- quality cytology preparation.

Further reading

Du Rand IA, Blaikley J, Booton R, etal. British Thoracic Society guideline for diagnostic exible bron-

choscopy in adults. Thorax 2013; 68

:i1– 44.

Yasufuku K, Nakajima T, Chiyo M, Sekine Y, Shibuya K, Fujisawa T. Endobronchial ultrasonogra-

phy:current status and future directions. J Thorac Oncol 2007; 2

:970– 9.

FIBREOPTIC BRONCHOSCOPY

551

552

CHAPTER8 Respiratory medicine

552

‘Fitness toﬂy’ assessment

Clinical indications

The following groups of patients should be referred to a chest physician for

assessment before ying:

•

Severe COPD (FEV

<30%) or asthma.

•

Severe (vital capacity (VC) <1L) restrictive disease (including chest wall

and respiratory muscle disease).

•

Cystic brosis.

• Recent pneumothorax.

• Bullous lung disease.

• Pre- existing requirement for ventilator support or O

therapy.

•

Co- morbidity with conditions worsened by hypoxaemia (e.g. coronary

artery disease, pulmonary hypertension, cyanotic congenital heart

disease, cerebrovascular disease).

Patient preparation

1. Take a history and examine the patient, with particular reference to

cardiorespiratory disease and previous symptoms during ights.

2. Perform spirometry.

3. Measure SpO

by pulse oximeter. ABGs should be performed if

hypercapnia is suspected.

4. Ahypoxic challenge test (breathing 15% FiO

for 20min via a face mask,

followed by ABG sampling) may be necessary, depending on the results

of the initial assessment.

Possible results

(See Tables 8.3 and8.4.)

Table8.3 Results ofinitial assessment breathingair

Screening result Recommendation

Sea- level SpO

>95% O

not required

Sea- level SpO

92– 95% and no risk factor* O

not required

Sea- level SpO

92– 95% and additional risk factor* Perform hypoxic

challenge and ABGs

Sea- level SpO

<92% In- ight O

* Additional risk factors:hypercapnoea; FEV

<50% predicted; lung cancer; lung brosis;

kyphoscoliosis; respiratory muscle weakness; cerebrovascular or cardiac disease; within 6 weeks

of discharge for an exacerbation of chronic lung or cardiac disease; recent pneumothorax;

risk of (or previous) VTE disease; recent pneumothorax; and patients with previous signicant

respiratory symptoms associated with air travel.

‘FITNESS TO FLY’ ASSESSMENT

553

Interpretation

Identies most patients requiring in- ight O

therapy.

Ancillarytests

• Exercise testing.

• In complex cases, patients may require testing in a hypobaric chamber.

Pitfalls

• Infectious patients should noty.

• Even with in- ight O

therapy, travel cannot be guaranteed to besafe.

Further reading

Ahmedzai S, Balfour- Lynn IM, Bewick T, etal.; British Thoracic Society Standards of Care Committee.

Managing passengers with stable respiratory disease planning air travel:British Thoracic Society

recommendations Thorax 2011; 66

(Suppl 1):i1– 30.

Coker RK, Shiner RJ, Partridge MR. Is air travel safe for those with lung disease? Eur Respir J 2007;

:1057– 63.

Table8.4 Results ofhypoxic challengetest

Hypoxic challenge result Recommendation

PaO

≥6.6kPa (>50mmHg) or SpO

≥85% O

not required

<6.6kPa (<50mmHg) or SpO

<85% In- ight O

(ow rate 2L/ min)

PaO

, arterial oxygen tension; SpO

, oxygen saturation.

554

CHAPTER8 Respiratory medicine

554

Flow– volume loops/ maximum expiratory

ﬂow– volumecurve

Clinical indications

Patient in whom COPD/ small airways disease or upper airway obstruction

is suspected.

Patient preparation

• Advised to wear comfortable, loose clothing.

• Technician explains procedure to patient.

• Mouthpiece in position; patient breathes in maximally and then out as

hard and fast as possible.

•

Three acceptable manoeuvres should be performed. Patients must

perform the test with maximal eort each time, and the results should

be similar for each of the three attempts.

Interpretation

Particularly useful in recognizing patients with narrowing of the central air-

way (larynx and trachea). Narrowing at this site has the greatest eect on

maximum expiratory ow and also on maximum inspiratory ow, giving rise

to a characteristic appearance. Also identies patients with reduced elas-

tic recoil (bullae, emphysema) or reduced airway lumen (asthma, COPD,

bronchiolitis).

Oscillation of ow gives a ‘sawtooth’ pattern. This usually signies insta-

bility of the upper airway and has been observed in OSA, thermal injury to

the airway, bulbar muscle weakness, extrapyramidal neuromuscular disor-

ders, upper airway stenosis/ tracheomalacia, and snoring.

(See Fig.8.3.)

Advantages overothertests

• Allows early detection of small airway disease— more sensitive than

FEV

alone.

•

Reproducible.

Ancillarytests

• Spirometry.

• Transfer factor.

Pitfalls

• Dependent on patient understanding and maximal eort.

• Infection control necessary in patients with known or suspected

transmissible disease (e.g. active pulmonaryTB).

FLOW–VOLUME LOOPS

555

75 50 25 %

Volume

Inspiratory ow

Expiratory ow

Normal

Inspiratory ow

In emphysema

75 50 25

PIF

Expiratory ow

75 50 25

Expiratory o

PEF

FEF

FIF

In extrathoracic upper airway narrowing

Fig.8.3 Flow– volumeloops.

556

CHAPTER8 Respiratory medicine

556

Nijmegen questionnaire

Clinical indications

Hyperventilation syndrome

•

Diagnosis.

• Assessment of severity.

• Assessment of response to therapy.

Patient preparation

1. Ask patient to ll in questionnaire.

2. Subject rates on a scale of 0– 4 the frequency of 16 dierent symptoms.

Use the following scale to choose the most appropriate number for each

symptom:

0=Would NEVER experience that symptom

1=RARELY experience that symptom

2=SOMETIMES experience that symptom

3=OFTEN experience that symptom

4=VERY OFTEN experience that symptom

Symptoms

•

Chestpain.

• Feelingtense.

• Blurred vision.

• Dizzy spells.

• Feeling confused.

• Faster or deeper breathing.

• SOB.

• Tight feeling in thechest.

• Bloated feeling in the stomach.

• Tingling ngers.

• Unable to breathe deeply.

• Sti ngers orarms.

• Tight feelings around themouth.

• Cold hands orfeet.

• Heart racing (palpitations).

• Feelings of anxiety.

Possible results

Nijmegen score is the sum of 16 item scores and can range from 0to64.

Interpretation

Clinically normal score<23.

NIJMEGEN QUESTIONNAIRE

557

Advantages overothertests

• Cheap.

• Easily administered.

Ancillarytests

• ABGs to identify hypocapnia and respiratory alkalosis.

• Hyperventilation provocation test. (Ask the patient to over- breathe for

several minutes to see if it reproduces symptoms.)

Pitfalls

Limited by the patient’s ability to read and comprehend the questionnaire

and answer questions honestly.

Further reading

Van Dixhoorn J, Duivenvoorden HJ. Ecacy of Nijmegen Questionnaire in recognition of the hyper-

ventilation syndrome. J Psychosom Res 1985; 29

:199– 206.

558

CHAPTER8 Respiratory medicine

558

Peak ﬂowcharts

Clinical indications

Asthma

•

Diagnosis.

• Assessment of severity.

• Assessment of treatment response to β

- agonists.

Occupationalasthma

•

Diagnosis.

Patient preparation

Patients need to be equipped with a peak ow meter and a peak ow and

symptom diary, and have a thorough understanding of how to usethem.

Guidelines topatients should include

1. Perform the test standing (if possible).

2. Hold the meter lightly and do not interfere with the movement of the

marker.

3. Perform three tests each time and record the largestvalue.

Readings should be taken at various times throughout the day. Limiting

the patient to two readings in each day may aid compliance. In occupa-

tional asthma, 2- hourly peak ow readings are required during the day and

evening.

Possible results

• Diurnal variability:as measured by the lowest PEFR value (usually on

waking) and the highest PEFR value (usually in the afternoon/ evening).

• Patient symptoms and PEFR can be examined together.

Interpretation

Diurnal variation is i in patients with asthma, compared with normals

(amplitude >20%), i.e. peak ow falls signicantly overnight and in the early

morning (see Figs 8.4 and8.5).

Advantages overothertests

• Cheap.

• Saves time of the respiratory physician and technician.

• Reproducible.

• Objective measure of response to treatment.

Ancillary tests fordiagnosis ofasthma

• Airway hyperresponsiveness test or histamine/ methacholine

challengetest.

•

Exercisetest.

• Sputum cytology:eosinophilia.

• FeNO.

PEAK FLOWCHARTS

559

Peak Flow Meter Record

Name: J. Smith Predicted normal: 240 Personal Best: 280

DateDate

Time

6th June 7th June5th June4th June3rd June

300

100

200

Peak ow readings

l/min

Peak ow chart of an

asthmatic patient showing

diurnal variations.

indicates morning dips

612182

12 18 24612182461218246121824

Fig.8.4 An example of a patient’s peak ow record.

700

650

600

550

500

450

500

400

300

1.5 m 1.6 m 1.7 m 1.8

.9 m

SD 60 litres/min

SD 67 litres/min

Men Age (years)

20–25

SD 1 litre/s

SD 1.1 litre/s

Height (m) = metres, " = inches

Peak expiratory ow (litres/min)

Peak expiratory ow (litres/s)

Women

Age (years)

63"

59" 68"

67"

67" 71"

1.4 m 1.5 m 1.6 m 1.7

.8 m

Height (m) = metres, " = inches

Peak expiratory ow (litres/s)

Fig.8.5 Peak ow readings.

560

CHAPTER8 Respiratory medicine

560

Pitfalls

• Not all asthma exacerbations are associated with i diurnal variability.

•

Calculating diurnal variation can be complicated and tedious.

• Time of recording or recent use of β

- agonist drugs may result in minor

changes in peak ow but can cause large errors in diurnal variability.

•

Dependent on patient understanding, cooperation, and accuracy.

Further reading

Hetzel MR, Clark TJ. Comparison of normal and asthmatic circadian rhythms in peak expiratory ow

rate. Thorax 1989; 35:732– 8.

Reddel H, Jenkins C, Woolcock A. Diurnal variability— time to change asthma guidelines? BMJ 1999;

319

:45– 7.

PEAK FLOWCHARTS

561

562

CHAPTER8 Respiratory medicine

562

Percutaneous pleuralbiopsy

Clinical indications

• Pleural eusion of unknown aetiology, especially if TB or malignancy

suspected.

Note:if malignancy is suspected and areas of pleural nodularity are shown

on a contrast- enhanced CT, an image- guided cutting needle is the percuta-

neous pleural biopsy method of choice.

Abrams’ needle biopsies are only diagnostically useful in areas with a high

incidenceofTB.

Patient preparation

1. Informed written consent.

2. Aseptic technique.

3. Posterior or mid- axillary approach using USS guidance.

4. Skin cleaned with antiseptic solution.

5. Lidocaine (1%) inltrated in rib interspace. Check pleural uid

aspirated.

6. Stab incision with a narrow scalpel.

7. Insert closed Abrams’ needle (requires rm pressure to be applied until it

penetrates the parietal pleura— take care not to apply too much force).

8. Attach a 50mL syringe.

9. Twist open the Abrams’ needle.

10. Aspirate uid to ensure needle in pleuralspace.

11. Withdraw needle at angle to chest wall until side hole ‘snags’ parietal

pleura.

12. Maintain lateral pressure and rotate to close hole, thereby cutting

biopsy. Remove needle and extract biopsy tissue.

13. Repeat with samples taken from 3, 6, and 9 o’clock position (avoid the

12 o’clock position to avoid the neurovascular bundle).

14. May require suture toclose.

15. Apply dressing.

16. Obtain CXR post- procedure.

17. Place samples in formalin for histological examination, and saline for

microbiological culture.

Possible results

• Slivers of white pleural tissue.

• Examine histology and culture for acid- and alcohol- fast bacilli (AAFB).

Interpretation

• Malignant mesothelioma may be diagnosed on histology, especially

with addition of immunohistochemical methods looking at tumour cell

markers.

•

More sensitive than pleural uid aspiration in diagnosingTB.

• Carcinoma cells may arise from direct spread from lung ° or represent

2° carcinoma. In either case, management is palliative.

PERCUTANEOUS PLEURALBIOPSY

563

Advantages overothertests

• Easy, quick, cheap; more reliable than diagnostic pleural aspiration.

• Less invasive than thoracoscopy for diagnosisofTB.

Ancillarytests

• Diagnostic pleural uid aspiration.

• Thoracoscopy.

• Image- guided cutting needle pleural biopsy is more sensitive than

Abrams’ pleural biopsy at diagnosing malignancy.

Complications

• Pneumothorax.

• Haemothorax.

Pitfalls

• Skeletal muscle biopsy— inadequate specimen.

• Damage to neurovascular bundle.

• Diagnosis of mesothelioma may remain equivocal.

Further reading

Benamore RE, Scott K, Richards CJ, Entwisle JJ. Image- guided pleural biopsy:diagnostic yield and

complications. Clin Radiol 2006; 61:700– 5.

Kirsch CM, Kroe DM, Azzi RL, Jensen WA, Kagawa FT, Wehner JH. The optimal number of pleural

biopsy specimens for a diagnosis of tuberculous pleurisy. Chest 1997; 112:702– 6.

Kirsch CM, Kroe DM, Jensen WA, Kagawa FT, Wehner JH, Campagna AC. A modied Abrams

needle biopsy technique. Chest 1995; 108:982– 6.

Maskell NA, Gleeson FV, Davies RJ. Standard pleural biopsy versus CT- guided cutting- needle biopsy

for diagnosis of malignant disease in pleural eusions:a randomised controlled trial. Lancet 2003;

361

:1326– 30.

Prakash UB, Reiman HM. Comparison of needle biopsy with cytologic analysis for the evaluation of

pleural eusion:analysis of 414 cases. Mayo Clin Proc 1985; 60:158– 64.

564

CHAPTER8 Respiratory medicine

564

Polysomnography

Clinical indications

Note:symptoms alone do not help predict which patient with sleep distur-

bance hasOSA.

•

Patients with low- probability sleep disorder, e.g. snores with no other

features suggestive ofOSA.

•

Patients with high- probability sleep disorder, e.g. typical symptoms and

physiognomy. Need study for diagnosis and assessment of severity.

•

Known OSA— assessing treatment response.

• Assessment of nocturnal hypoventilation syndromes, e.g. scoliosis.

• Patients with unexplained sleep– wake disorders.

Patient preparation

The patient is admitted to the sleep laboratory in the early evening.

Monitoring is explained and attached, using some combination shown in

Table8.5.

Table8.5 Monitoring combinations

Sleep EEG

Electro- oculogram

EMG

Oxygenation O

saturation probe

(ear or nger)

Breathing pattern Airow by:

Thoracoabdominal

movement by:

Thermocouples

Thermistor

End- tidal CO

pressure

Inductance plethysmography

Impedance

Strain gauge

Miscellaneous Snoring

Leg movement by:

Microphone

EMG

Video

Movement detector

POLYSOMNOGRAPHY

565

Possible results

Original diagnosis of OSA based on polysomnography— overnight record-

ing of sleep, breathing patterns, and oxygenation. It is relatively expensive,

and most centres use a combination of video to assess the quality of sleep

and identify transient arousals and paroxysmal leg movement disorder

(PLMD), and oximetry (to detect desaturation), plus some form of meas-

uring the breathing pattern to detect hypopnoea.

Interpretation

OSA diagnosed in the context of multiple (typically >15/ h) hypopnoeic/

apnoeic events occurring throughout the night and resulting in desaturation.

Advantages overothertests

Demonstrates a number of hypopnoeic (reduction in breathing) or apnoeic

(absence of breathing) events occurring per hour. May be used to monitor

eectiveness of treatment.

Ancillarytests

• ESS.

Pitfalls

• Expensive.

• Time- consuming.

• Most sleep study systems are poorly validated; therefore, need expert

interpretation of results to consider false +ves and−ves.

•

Patients need to sleep for >3h/ night and have rapid eye movement

(REM)sleep.

Further reading

British Thoracic Society (2009). IMPRESS service specication for investigation and treatment of

obstructive sleep apnoea syndrome. M

https:// www.brit- thoracic.org.uk/ document- library/

clinical- information/ sleep- apnoea/ impress- service- specication- for- investigation- and- treatment-

of- osas/ .

566

CHAPTER8 Respiratory medicine

566

Pulse oximetry

Clinical indications

• Any acutely unwell patient:avoids repeated blood gas measurements,

provided that hypercapnia is absent.

•

Monitoring of long- term oxygen therapy (LTOT):not suitable for initial

assessment.

•

Assessment of nocturnal FiO

and screening for sleep apnoea

syndrome:identication of nocturnal desaturations.

•

Exercise walktest.

Patient preparation

1. Clean probe site (ear or nger).

2. Ensure good contact of probe with warm, well- perfusedskin.

3. Avoid nail- varnished ngers.

Possible results

• SpO

expressedas%.

Interpretation

• Respiratory failure unlikely if SpO

>92% onair.

•

Provides almost immediate arterial O

saturationdata.

•

Must know the FiO

the patient is breathing.

Advantages overothertests

• Non- invasive.

• Easy,cheap.

• Instantaneous.

• Sensitive.

• Portable.

Ancillarytests

• ABG sampling.

Pitfalls

• Does not detect CO

levels.

•

If COHb or methaemoglobin (MetHb) is present in the blood in

elevated levels, the pulse oximeter will give a falsely elevated reading for

the arterial O

saturation.

•

i in jaundice.

•

Erroneous information if patient poorly perfused.

• Excessive patient movement can give false readings.

SKIN PRICKTESTS

567

Skin pricktests

Clinical indications

• To evaluate atopy in asthmatic individuals.

• To assess the possible development of ABPA in patients with asthma/

other long- standing lung disease.

Patient preparation

1. Explain what the test involves.

2. Use a pen to label the patient’s forearm with the antigens to be tested,

including +ve and −ve controls (alternatively, numbered adhesive tape

may beused).

3. Clean the test area with an alcoholwipe.

4. Place a drop of antigen next to each correspondinglabel.

5. Use a lancet to puncture the skin. Repeat with other antigens using a

new lancet eachtime.

6. Blot o excess antigen, taking care not to contaminate other testsites.

7. After 10min, measure any resulting wheal reactions using a ruler.

Record the mean diameterinmm.

Possible results

A +ve result is indicated by a wheal and are reaction of 3mm, providing

there is no reaction at the −ve control site. −ve results are validated by a

wheal reaction at the +ve controlsite.

Interpretation

A +ve result indicates sensitization to the allergen but does not necessarily

mean that this allergen is responsible for the patient’s symptoms. All tests

should be carefully interpreted in light of the clinical history.

Advantages overothertests

• Cheap,quick.

Ancillarytests

• Specic IgE to allergens (especially where the history is not supported

by skin test results).

•

Total IgE (aects interpretation of weak +ve specic IgE results, which

are less relevant if the total IgE is veryhigh).

•

Aspergillus precipitins(IgG).

Pitfalls

• False −ve results if the patient has taken an antihistamine within 5days

of thetest.

•

False +ve results with dermatographism or inamedskin.

568

CHAPTER8 Respiratory medicine

568

Spirometry

Clinical indications

• To evaluate symptoms, signs, or abnormal test results.

• Provide objective, quantiable measures of lung function.

• Evaluate and monitor disease.

• Assess eects of environmental/ occupational/ drug exposures, both

adverse (e.g. amiodarone) and benecial (e.g. bronchodilators).

•

Preoperative assessment.

• Employment/ insurance assessment.

• Early detection of bronchiolitis obliterans in lung transplant patients.

Patient preparation

1. Explain what the test involves. Most respiratory technicians

demonstrate the technique to ensure maximal eort and co- operation

of the patient.

2. Patient must inhale fully before thetest.

3. Exhale into the breathing tube. Encourage maximal eort with no

breath- holding before the manoeuvre.

4. No cough/ glottal closure in the rst second.

5. Test should last at least 6s (may need up to 15s with obstruction).

6. No evidence of airow leak/ obstruction of mouthpiece.

Possible results

(See Table8.6.)

Interpretation

At least three acceptable tracings should be obtained. Examine each tracing

to ensure adequate eort is made by the patient, that it is reproducible, and

that there are no artefacts (see Table8.7).

Advantages overothertests

• Cheap,quick.

• Bedside/ outpatienttest.

• Reproducible.

Ancillarytests

• Total lung capacity (TLC):to conrm interstitial disease with restrictive

spirometry.

•

Pre- and post- bronchodilator studies:an i of 15% in FEV

and 20% in FVC

suggest reversibility.

Pitfalls

• Need standardization of normal data for height, weight, age, sex,

andrace.

•

Level at which a result may be considered abnormal is contentious,

usually accepted to be outside the range of 80– 120% of mean

predicted.

•

FEV

may remain relatively normal in early stages of generalized lung

disease.

SPIROMETRY

569

Normal

Obstructive

Restrictive

FEV

sec

Litres

FEV = 4.0

FEV

= 1.3

FEV

= 2.8

FVC = 5.0

FVC = 3.1

% = 80

% = 42

% = 90

FEV

FVC

FEV

FVC

Fig.8.6 Examples of spirograms.

Table8.6 Possible results

FEV

Forced expiratory volume in 1s

Test of mechanical function of thelungs

Depends on size and elastic properties of the lungs, calibre of

the bronchial tree, and collapsibility of airway walls

FVC Forced vital capacity

Table8.7 Interpretation

FEV

/ FVC ratio Index of the presence/ absence of airow limitation

Young and middle- aged healthy non- smokers rate75%

Older normal patients ratio 70– 75%

FEV/ FVC d Obstructive

Classify severity using FEV, expressed as % of predicted

value, e.g. COPD, asthma

FEV/ FVC

n or i

Restrictive, but need reduced thin- layer chromatography

(TLC) to conrm, e.g. lung brosis, chest wall problems,

pulmonary eusion and oedema

If used for monitoring purposes, need an adequate baselinestudy.

• FEV

/ FVC ratio is a good guide to the presence of signicant airway

narrowing, but as disease progresses, both will fall and correlation with

severity of disease ispoor.

•

Variability (noise) is greater in pulmonary function tests than in most

other clinical laboratory tests because of the inconsistency of eort by

patients.

For examples of spirograms, see Fig. 8.6 and E OHCM 10e, p.163.

Further reading

Crapo RO. Pulmonary- function testing. N Engl J Med 1994; 331:25– 30.

570

CHAPTER8 Respiratory medicine

570

Sputum microscopy and

culture/ sputum cytology

Clinical indications

Microbiology

•

Productive cough with sputum.

• Infective exacerbations of any chronic lung disease.

• Pneumonia.

Cytology

•

Suspected lung cancer:only in elderly/ frail patients who are not t for

invasive investigation.

•

Sputum eosinophilia in asthma.

Patient preparation

• Explain the need for a sputum sample.

• Provide suitable sputumpots.

• Early morning samples arebest.

• Consider induced sputum— use ultrasonically nebulized hypertonic

saline to facilitate sputum production, in association with chest

physiotherapy.

Possible results

Induced sputum results in successful sputum production in >70% of normal

and asthmatic subjects who cannot produce sputum spontaneously (see

Table8.8).

Interpretation

• Commensal organisms common.

• Streptococcus pneumoniae and Haemophilus inuenzae likely pathogens

inCOPD.

•

S.pneumoniae commonest organism in community- acquired °

pneumonia.

•

Staphylococcus aureus and Pseudomonas likely in bronchiectasis.

•

Nosocomial infections:

•

S.aureus.

•

Pseudomonas.

•

Klebsiella.

•

The sensitivity of sputum cytology varies by location of the lung cancer

and is greatest in central endobronchial lesions.

SPUTUM MICROSCOPY AND CULTURE/SPUTUM CYTOLOGY

571

Advantages overothertests

• Cheap,easy.

• Non- invasive.

Ancillarytests

• Bronchoscopy andBAL.

• Serum serology if atypical pneumonia suspected.

• If bronchiectasis suspected, consider high- resolution CT (HRCT) chest

± CT sinuses, and check Igs (IgG, IgA, and IgM). Other investigations

depend on the clinical scenario (RF, IgG subclasses, IgE, Aspergillus IgE

and precipitins, α

1- antitrypsin). Involve the respiratory teamearly.

• PCR for drug- resistantTB.

Pitfalls

• Sputum may be diluted by saliva.

• Diagnosis of squamous cell carcinoma is not as robust as for small- cell

lung cancer or adenocarcinoma. Needs careful cross- referencing to

radiology and should be conrmed, if possible, with biopsies.

•

−ve results should not preclude further investigations if malignancy

suspected.

Further reading

Pasteur M, Bilton D, Hill A; British Thoracic Society Bronchiectasis non- CF Guideline Group. British

Thoracic Society guideline for non- CF bronchiectasis. Thorax 2010; 65(Suppl 1):i1– 58.

Rosia E, Scano G. Association of sputum parameters with clinical and functional measurements in

asthma. Thorax 2000; 55:235– 8.

Table8.8 Possible results

Gram stain Gram +ve or −ve organisms

ZN stain AAFB

Microscopy Dierential cell count

Eosinophils in asthma

Cytology Malignant cells

Small cell, squamous cell, adenocarcinoma cells

572

CHAPTER8 Respiratory medicine

572

Static lung volumes/ whole body

plethysmography

Clinical indications

• Dierentiate between obstructive and restrictive disease patterns.

• Identify and quantify trapped air (shown by i residual volume (RV)/ TLC

ratio).

•

Assess response to therapeutic interventions (e.g. drugs, radiation,

transplantation).

•

Identify the presence and amount of unventilatedlung.

• Assess chronic lung disease (e.g. sarcoidosis, rheumatoidlung).

• Preoperative assessment.

• Assessment of pulmonary disability.

Patient preparation

1. Ask the patient to wear comfortable clothes.

2. Place the mouthpiece securely in the mouth with the lips tight

aroundit.

3. Breathe in a relaxed manner through the spirometer system (nose clips

mandatory).

4. After a total of ve tidal breaths with consistent end- expiratory levels,

patient asked to maximally inspire to TLC, followed by exhalation with

encouragement to force out the last 5– 15% ofair.

5. Aminimum of two attempts should be obtained.

6. More may be needed in the young and elderly to obtain reproducible

results.

Most accurate results are obtained with whole body plethysmography.

Possible results

• Total lung capacity:volume of air in the lungs at the end of full

inspiration.

•

Residual volume:volume of air remaining in the lungs after maximal

expiration.

•

Vital capacity:the amount of air expired (or inspired) between

maximum inspiration and maximum expiration.

•

Functional residual capacity:the amount of air in the lungs at the end- tidal

position.

•

Inspiratory capacity:the maximum amount of air that can be breathed

into the lungs from the end- tidal position.

• Tidal volume:the volume of air inspired and expired with each breath.

•

Inspiratory reserve volume:the volume between the peak inspiratory tidal

position and maximum inspiration.

(See Table 8.9 and Fig.8.7.)

STATIC LUNG VOLUMES/WHOLE BODY PLETHYSMOGRAPHY

573

Interpretation

• Only interpret if the test is reproducible, i.e. if the two largest VC values

are within 5% or 100mL (whichever is the larger).

•

VC may remain within normal range in some pulmonary disease,

e.g. emphysema.

•

d VC— restrictive pulmonary disease, neuromuscular disease,

e.g. amyotrophic lateral sclerosis.

•

During the testing process, the patient is enclosed in a chamber

equipped to measure either pressure, ow, or volume changes. Because

all the gas in the thorax is accounted for, this method is particularly

useful in patients with trapped gas, e.g. bullous emphysema.

Table8.9 Causes

Causes of i

TLC

Generalized airway obstruction, e.g. COPD

Emphysema (including bullae)

Bronchiectasis

Asthma

Other, e.g. acromegaly

Causes of d

TLC

Intrapulmonary:

•

Pneumonectomy

• Collapsedlung

• Consolidation

• Oedema

• Fibrosis

Extrapulmonary:

•

Pleural disease

• Eusion

• Thickening

• Pneumothorax

• Rib cage deformity

• Scoliosis

• Thoracoplasty

• Respiratory muscle weakness

Causes of i RV Generalized airway obstruction

Pulmonary vascular congestion, e.g. mitral stenosis, atrial

septaldefect

Expiratory muscle weakness, e.g. spinal injury, myopathies

Causes of i

FRC

Age, lung disease causing air trapping, e.g. asthma,

emphysema, COPD

Causes of d

FRC

Restrictive lung diseases, e.g. diuse interstitial pulmonary

disease of any aetiology, pneumonectomy

574

CHAPTER8 Respiratory medicine

574

Advantages overothertests

• Reproducible.

Pitfalls

• Patient co- operation is essential. They must provide maximal eort and

be capable of understanding instructions.

•

Calibration should take place on a regularbasis.

• Risk of disease transmission between patients, and between patient and

technician; therefore, avoid if pulmonary TB suspected.

TLC

FVC

FVC Forced vital capacit

TLC Total lung capacity

RV Residual volume

Normal

Obstructive

(Hyperination)

Restrictive

Fig.8.7 Lung volumes:physiological and pathological.

STATIC LUNG VOLUMES/WHOLE BODY PLETHYSMOGRAPHY

575

576

CHAPTER8 Respiratory medicine

576

Sweattest

Clinical indications

Suspected cystic brosis inthe contextof

•

Bronchiectasis/ recurrent chest infections.

• Pancreatic insuciency/ DM.

• Family history.

• Fertility problems.

Patient preparation

1. Obtain informed consent:verbal usually sucient, but important to

discuss the reasons for the test and possible implications. Perform two

sweat tests simultaneously on each arm for greater accuracy.

2. Induce sweating by pilocarpine iontophoresis. Aweak electrical current

aids penetration of pilocarpine into the skin, thus stimulating the sweat

glands of the forearm, previously washed and dried, to secretesweat.

3. Collect sweat on preweighed lter paper (>100mg), then measure

eluted Na

and chloride(Cl

−

Possible results

• 98– 99% of children homozygous for CyF have sweat Cl

−

and Na

levels

well above 70 and 60mmol/ L, respectively.

• Sweat Na

concentrations tend to i with age and show wide variability

between individuals.

•

Diagnostic accuracy is improved in borderline cases by a suppression

test using udrocortisone.

Interpretation

• A+ve test is virtually diagnostic of CyF. This should lead to counselling

and genetic testing.

•

Equivocal results are dened as Na

or Cl

−

concentrations between

50 and 70mmol/ L.

• The diagnosis should never rest on the sweat test alone and should be

considered together with the clinical ndings and laboratory evidence of

pancreatic insuciency.

Advantages overothertests

• Cheaper than genetictests.

• Assesses functional decit, therefore capable of detecting patients who

have rare variants ofCyF.

Ancillarytests

• Nasal potential dierence.

• Pancreatic function tests (3- day faecal collection).

• Genetic studies.

SWEATTEST

577

Pitfalls

• Awide discrepancy between the results from each arm suggests a

problem with the technique.

•

Accurate interpretation of sweat tests requires knowledge of the age-

related changes in sweat Na

and Cl

−

concentrations and should be

done in a specialized centre.

False negatives

• Inexperience of operator.

• Low rates of sweating.

• Poor skin preparation.

• Poor iontophoretic contact with theskin.

• Faulty chemical analysis.

False positives

• Evaporation of sweat 2° to inadequate sealing during collection.

• Untreated adrenal insuciency.

• NephrogenicDI.

• Hypothyroidism.

• Glycogen storage disease.

• Nephrotic syndrome.

• Severe malnutrition.

• AIDS (some reports of abnormal sweat electrolytes).

• Faulty chemical analysis.

Further reading

Green A, Dodds P, Pennock C. A study of sweat sodium and chloride:criteria for the diagnosis of

cystic brosis. Ann Clin Biochem 1985; 22

:171– 6.

Hall SK, Stableforth DE, Green A. Sweat sodium and chloride concentrations— essential criteria for

the diagnosis of cystic brosis in adults. Ann Clin Biochem 1990; 27:318– 20.

Heeley AF, Watson D. Cystic brosis— its biochemical detection. Clin Chem 1983; 29:2011– 18.

578

CHAPTER8 Respiratory medicine

578

Medical thoracoscopy

Clinical indications

• Pleural eusions when pleural uid analysis non- diagnostic.

• Pneumothorax.

• Staging of lung cancer.

• Diagnosis of malignant mesothelioma and other pleural abnormalities,

e.g. neurinomas, lipomas, plastocytomas.

Pre- assessment

• Arecent (<1month) CT scan of the chest is mandatory. Apre-

procedure USS is desirable.

•

FBC.

• Clotting.

• Renal function and electrolytes.

• Serum glucose.

• Spirometry.

• Pulse oximetry.

• ABGs on air if hypoxaemia suggested by SpO

or if signicant

hypercapnia is suspected.

Patient preparation

Endoscopysuite

1. Patient informed and consented. Fasted from solids for 6h and liquids

for3h.

2. IV access obtained.

3. Full aseptic technique.

4. Patient positioned in the lateral position with the side to be examined

uppermost.

5. Basic monitoring:pulse oximeter, BP, and cardiac monitor.

6. Supplementary O

given via face mask or nasal cannulae to maintain

saturations>92%.

7. IV sedation— midazolam/ alfentanil. LAn:0.5– 1% lidocaine.

8. An absolute prerequisite for thoracoscopy is the presence of an

adequate pleural space (i.e. at least 6– 10cm diameter).

9. If pleural eusion:drain using a 3- way tap. Replace with equal quantity

of atmosphericair.

10. If no eusion:create a pneumothorax. Insert a needle connected to a

manometer into the pleural space. Introduce 400– 1000mL ofair.

11. Skin incision 1cm in fth intercostal space, mid- axillary line (or guided

byUSS).

12. Insert 5– 10mm pleural trocar and cannula.

13. Introduce the thoracoscope via the trocar into the pleural cavity.

14. After inspection and biopsies, remove the trocar and insert adrain.

15. CXR post- procedure.

16. May need to apply suction to the drain:i in small increments of

5cmH

O (0.5kPa), up to a maximum of −20cmH

MEDICAL THORACOSCOPY

579

Possible results

• Direct inspection of pleural surfaces.

• Biopsy of parietal pleura— histology/ culture, especiallyAAFBs.

• Pleural uid l M,C&S l cytology.

•

Therapeutic options:pleurodesis, coagulation of blebs, resection of

brinous loculations in empyemas.

•

Drainage of large pleural eusions possible without risk of re- expansion

pulmonary oedema due to rapid equalization of pressures by entrance

of air into the pleuralspace.

Interpretation

• Macroscopic appearance of pleura may be diagnostic, e.g. metastatic

disease.

Advantages overothertests

• Better than blind pleural biopsy.

• Able to obtain diagnosis in 70– 95% ofcases.

• Especially good at diagnosingTB.

• Less invasive than thoracotomy.

• Can perform talc poudrage (pleurodesis) at the sametime.

• Less expensive than surgical VATS. Does not require a theatre or an

anaesthetist.

•

Done under sedation, unlike VATS which requires GAn and selective

one- lung ventilation.

Ancillarytests

• Diagnosis of mesothelioma improved with use of immunohistochemical

markers.

Pitfalls

• Biopsies may be inadequate or non- representative.

Contraindications

• Obliterated pleuralspace.

• Small pneumothorax.

• Patient SOB at rest, unless 2° to pneumothorax or pleural eusion,

which can be treated during the procedure.

•

Disturbed haemostasis:

•

Platelets <40 ×10

/ L.

•

APTT >50% of normal.

• Recent MI, arrhythmias, heart failure.

580

CHAPTER8 Respiratory medicine

580

Complications

• Fever 24– 36h post- procedure.

• Empyema(<1%).

• Wound infection.

• SC emphysema.

• Air embolism.

• Bronchopleural stula following lung biopsy.

• Seeding of metastases/ mesothelioma along trocar wound.

(Radiotherapy a few weeks post- thoracoscopy should be carried out to

preventthis.)

•

Haemorrhage.

• Arrhythmias.

• Mortality rate <0.01%.

Further reading

Blanc FX, Atassi K, Bignon J, Housset B. Diagnostic value of medical thoracoscopy in pleural dis-

ease:a 6- year retrospective study. Chest 2002; 5:1677– 83.

Buchanan DR, Neville E. Thoracoscopy for physicians:a practical guide. London:Arnold,2004.

Colt HG. Thoracoscopy:window to the pleural space. Chest 1999; 116:1409– 15.

Loddenkemper R. Thoracoscopy— state of the art. Eur Resp J 1998; 11:213– 21.

MEDICAL THORACOSCOPY

581

582

CHAPTER8 Respiratory medicine

582

Transferfactor

Clinical indications

• Test for abnormalities of pulmonary gas exchange.

Patient preparation

• Avoid smoking 6h prior and strenuous exercise2hprior.

• Allow 15– 30min fortest.

• Usually measured by single- breath inhalation technique.

• Patient breathes in air containing a known concentration of carbon

monoxide (CO) and holds breath for10s.

Possible results

• Transfer factor (TLCO).

• Transfer coecient(KCO).

• May need to correct for anaemia:

•

Result usually standardized to Hb 14.6g/ dL.

•

Eect of mild anaemia (Hb >10g/ dL) slight but becomes progres-

sively more marked at lower values.

Interpretation

Decrease inTLCO

•

Obstructive lung disease, e.g. COPD, emphysema.

• Diuse ILD, e.g. cryptogenic brosing alveolitis (CFA), amiodaronelung.

• Pulmonary involvement in systemic disease, e.g. SLE, RA, Wegener’s.

• Cardiovascular disease, e.g. pulmonary oedema, mitral stenosis,PE.

• Others:anaemia, cigarette smoking.

Increase inTLCO

•

Diseases associated with polycythaemia.

• Pulmonary haemorrhage.

• Diseases associated with i pulmonary blood such as left- to- right intra-

cardiac shunts.

•

Exercise.

• Asthmatics (reasons not clear).

Advantages overothertests

• Quick.

• Relatively easy to perform.

• Reproducible.

Pitfalls

• Breath- holding time may be dicult for some patients to achieve.

• Calculation of TLCO is based on assumption that ventilation and

diusion are homogeneous in the entire lung. With unequal distribution

of ventilation and diusion, the TLCO will be underestimated on the

alveolarlevel.

•

With extrapulmonary lung restriction and consequent inability to

achieve full inspiration, KCO tends to be higher than normal.

583

Chapter9

Neurology

Lumbar puncture 584

Skull radiograph 590

Ultrasound 592

Angiography 594

Myelography 595

Radionuclide scans 596

Computed tomography 598

Magnetic resonance imaging 602

Nerve conduction studies 606

Electromyogram 610

Electroencephalogram 612

Electroencephalogram:abnormalities 614

Electroencephalogram:in epilepsy 616

Electroencephalogram:how touse 618

Electroencephalogram:invasive techniques 620

Polysomnography 621

Sensory evoked potentials or responses 622

Transcranial magnetic stimulation 628

Neurological investigation of sphincter disturbance 630

Edrophonium (Tensilon

) test 631

Amobarbital (Wada) test 631

Biopsies 632

Oligoclonal bands 635

Diagnostic and prognostic antibodies, and other markers

in blood and urine 636

Biochemical markers 640

Genetic tests 642

Neuro- otology 646

584

CHAPTER9 Neurology

584

Lumbar puncture

Indications

• Meningitis.

• Encephalitis.

• Polyradiculitis, polyneuritis.

• MS.

• Myelitis.

• Vasculitis.

• SuspectedSAH.

Note:in general, a −ve CT does not exclude anSAH.

• Suspected malignancy with meningeal involvement.

• Assessment of CSF pressure:

•

High (e.g. idiopathic or ‘benign’ intracranial hypertension (IIH)).

•

Low (e.g. ‘low pressure’ headache).

• Therapeutic trials,e.g.

•

IIH.

•

Normal pressure hydrocephalus (NPH) (not particularly helpful).

• To seek specic antibodies/ markers in CSF,e.g.

•

HIV.

•

Lyme (Borrelia).

•

Syphilis.

•

ACE (for neurosarcoid).

•

Tumour markers.

•

Lactate in mitochondrial cytopathies.

Preparation

• Decide exactly what investigations you want. If necessary, alert

the appropriate laboratories and organize transport of samples. In

particular, samples for xanthochromia and cytology should be rapidly

taken to the laboratory to be spundown.

•

If the patient is also due to have a neuroradiological investigation with

contrast and an LP is not urgent, delay the LP until after the scan, as

there may be diuse meningeal enhancement after theLP.

•

If the patient is extremely anxious, he may benet from 5– 10mg of oral

diazepam prior to theLP.

Procedure

1. Explain to the patient what you are abouttodo.

2. Arrange all your equipment on a sterile tray, including assembled CSF

manometer.

3. Position the patient on his side, with the back perpendicular to the

bed, at the edge of a rm bed. Place the head on one pillow. Draw the

knees up, and place one pillow betweenthem.

4. Adjust the height of the bed, so that you are comfortable.

5. Identify the bony landmarks. L3/ L4 space is in line with the iliac crests

and is most commonly used. L2/ L3 to L5/ S1 are also used. If you like,

mark the target space with the imprint of your thumb nail. Take time

over these rst four stages.

LUMBAR PUNCTURE

585

6. The insertion of the needle should be a sterile procedure. Clean the

skin over the lower back. Don sterile gloves andmask.

7. Insert a little (0.25– 0.5mL) LAn— too much can obscure the bony

landmarks.

8. Pass the LP needle horizontally into the space, with the tip angled at

about 10– 15° (towards the umbilicus), in the midline horizontal plane.

At all times, the stylet should be fully inserted and the bevel of the

needle facingup.

9. Slight resistance should be felt as the needle passes through the

ligamentum avum and dura, and then a ‘give’ as it enters the

subarachnoidspace.

10. Slowly withdraw the stylet. CSF drops should appear.

11. If CSF does not appear, reinsert the stylet and slightly rotate the

needle— this sometimes frees it of obstructing nerve roots. Agentle

cough from the patient can alsohelp.

12. If the needle encounters bone, or the patient complains of pain

shooting down the leg, check the position of the needle (is it in the

midline? Is it angled correctly?) and then withdraw it entirely.

13. Insert a fresh needle, correcting for any error notedabove.

14. If this second pass is unsuccessful, withdraw the needle and inform

the patient. If he is happy for you to proceed, then attempt the LP in

another space, repeating all steps from 4 down. Use a fresh needle.

15. If you fail again, explain to the patient and seek a more experienced

operator to perform the LP. Multiple failed attempts are painful and

discouraging (to both you and your patient).

16. If a more experienced operator fails, ask your friendly radiologist to

do it under X- ray guidance, but give him the help he requests and

precise instructions about the samples required.

17. When CSF collection is complete, gently pull out the needle and place

a sterile dressing over the insertionsite.

18. Allow the patient to mobilize shortly after theLP.

Measuring thecerebrospinal uid pressure

As soon as the CSF starts to ow, attach the pre- assembled manometer.

Wait until the CSF stops rising. If the patient is very anxious, or uncomfort-

able, a falsely raised opening pressure may be recorded. Sometimes having

the patient slightly relax his legs will help. Using the 3- way tap, let the CSF

run into your rst prelabelled tube (do not waste the CSF!). Having col-

lected all the CSF you require, if the opening pressure was elevated, note

the closing pressure. If the opening pressure is expected to be very raised,

e.g. in suspected or conrmed idiopathic (benign) intracranial hypertension,

then two or more manometers should be pre- assembled, as the pressure

may exceed 40mmCSF.

Collecting samples

• As always, tailor your investigations to the clinical picture. If you are

just checking the CSF pressure, then no samples need necessarily be

collected. If you suspect an SAH, collect three samples in sequentially

labelled bottles and promptly hand- carry to the laboratory for

quantitative estimation of xanthochromia and Hb breakdown products.

586

CHAPTER9 Neurology

586

If you are looking for evidence of malignant cells, then at least one

sample should be sent to the laboratory promptly for cytology.

•

To avoid contamination, allow the microbiology laboratory to split

samples, rather than attempting this yourself.

•

Collect at least ten drops in each bottle. The microbiology and cytology

laboratories in particular will thank you for greater volumes.

•

As soon as the CSF is collected, a blood sample should be obtained (if

necessary) for glucose and OCB detection.

Alternative positioning ofpatient

Sometimes there is a dry tap if the CSF pressure is too low to distend

the lumbar cistern. This can sometimes be overcome by performing the

LP with the patient sitting on a rm reversed chair, leaning forward to bend

over its back. This manoeuvre maximizes the separation of the vertebrae.

Again, the needle should be angled slightly (10°) upward relative to the

spine at that point. This position does not allow accurate measurement of

CSF pressure.

Which needle touse?

A 22G needle usually appropriate. Needles with larger bores tend to cause

a greater CSF leak (and thus more headache). Some advocate even ner

needles, but these make the collection of CSF take too long. ‘Blunt’ anaes-

thetists’ needles reduce the risk of post- LP headache.

Clinical record keeping

Record what you did in the notes after the procedure (e.g. if >1 pass was

required; which space you used), the opening and closing CSF pressures,

and what investigations you have requested. Note the appearance of the

CSF (if normal, it will be clear and colourless). If the CSF appears bloody,

record this and whether the nal bottle collected is clearer than therst.

When NOT toattempt a lumbar puncture

• Risk of herniation:

•

SOLs.

•

Non- communicating hydrocephalus.

•

Cerebral oedema (if in doubt, cranial imaging should be performed

rst).

•

Uncorrected bleeding diathesis/ anticoagulantuse.

• Caution:if previous lumbar spine surgery or known anatomical

abnormalities.

•

Local skin sepsis.

Note:it is usually safe and appropriate to perform an LP in suspected menin-

gitis, unless there are specic clinical features to suggest raised ICP, in which

case cranial imaging should be performedrst.

LUMBAR PUNCTURE

587

Complications and what todo aboutthem

Headache

•

Usually starts within 24hofLP.

• May last from a few hours to 2 weeks, but typically severaldays.

• Probably related to persistent CSF leak via the dural tear; therefore,

tends to have ‘low pressure’ characteristics (frontal, worse on sitting up,

better on lying down). There may be mild meningism and nausea.

Treatment has traditionally involved bed rest, analgesia, and the encourage-

ment of plenty of uids.

•

If nausea is a major problem, the patient may require IV uids.

• Rarely, if the headache is severe and persistent, then an anaesthetist

may place an autologous blood patch to ‘plug’ the dural tear. Surgical

intervention is very rarely required.

Low backache

A variety of causes of post- LP backache exist; these may usually be treated

conservatively.

Infection

Very rare if a sterile technique is used. Occasionally may occur if the needle

passes through a region of infection. Meningitis typically develops within

12h. Very rarely, there may be an epidural abscess or vertebral osteomyeli-

tis. Treat with appropriate antibiotics and, if necessary, surgery.

Herniation

•

Uncal or cerebellar herniation may occur, particularly in the presence

of a posterior fossa mass. 3 An LP should not be performed if there is

suspicion of raised ICP without rst obtaining cranial CT orMRI.

•

Should the CSF pressure be found to be very high (300mmCSF), even

after relaxing the patient, and in the absence of idiopathic (benign)

intracranial hypertension, manage as follows:

•

Nurse the patient prone with no pillow.

•

Raise the foot of thebed.

•

Start an infusion of 20% mannitol at 1g/ kg over20min.

•

Start a neurological observationchart.

•

Arrange an urgent CT of the brain and notify the neurosurgeons.

3 Do not instil saline into the subarachnoidspace.

Haemorrhage

A ‘traumatic’ tap may cause a little local bleeding that is rarely of clinical

signicance. Patients with impaired clotting (remember warfarin) or platelet

function are at risk of more extensive bleeding, and an LP should not be

attempted unless the coagulopathy is corrected. An arachnoiditis, or spinal

subdural, or epidural haemorrhage may develop. Aspinal SDH is otherwise

rare, and an intracranial SDH veryrare.

588

CHAPTER9 Neurology

588

Cerebrospinal uid constituents:normalvalues

• White cells:0– 4/ mm

•

RBCs:ideallynone!

•

Protein:0.15– 0.45g/ L.

• Glucose:7 half to two- thirds of simultaneous blood glucose.

• Opening pressure:8– 20cmCSF.

Note:if there is a traumatic ‘bloody’ tap, there may be hundreds or thou-

sands of RBCs/ mm

. If so, then white cells should be expected in the CSF,

but in similar proportions to the peripheralblood.

Rules ofthumb

1. Pressure:

•

i by SOLs within the cranial vault such as oedema, masses, chronic

inammation.

•

i by i CVP, e.g. in the anxious patient with tensed abdominal

muscles.

•

d if the spinal subarachnoid space is obstructed, thus impeding

CSFow.

2. Cells:

•

Polymorphs (neutrophils):suggest acute bacterial infection.

•

Lymphocytes and monocytes:viral and chronic infections or tumours.

•

Eosinophils:tumours, parasites, foreign body reactions.

3. Glucose— d by non- viral processes causing meningeal inammation.

4. Total protein— i by breakdown of the blood– brain barrier.

5. Igs specic to the CSF, i.e. without matching Igs in a simultaneous

blood sample:inammation within the theca, e.g. MS, infection, tissue

damage.

Common patterns

These are shown in Table9.1.

E OHCM 10e, p.822.

LUMBAR PUNCTURE

589

Further reading

Davis A, Dobson R, Kaninia S, Giovannoni G, Schmierer K. Atraumatic needles for lumbar punc-

ture:why haven’t neurologists changed? Pract Neurol 2016; 16

:18– 22.

Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar

puncture in adults with suspected meningitis. N Engl J Med 2001; 345:1727– 33.

Thomas SR, Jamieson DR, Muir KW. Randomised controlled trial of atraumatic versus standard

needles for diagnostic lumbar puncture. BMJ 2000; 321

:986– 90.

Whiteley W, Al- Shahi R, Warlow CP, Zeidler M, Lueck CJ. CSF opening pressure:reference interval

and the eect of body mass index. Neurology 2006; 67:1690– 1.

Table9.1 Common patterns

Condition Glucose Protein Cells Comments

Acute bacterial

meningitis

d i

Often >300/ mm

Polymorphs;

lactate i

Acute viral

meningitis

N N or i <300

mononuclear

Culture, antigen

detection may be

possible

Fungal

meningitis

d i <300

mononuclear

Culture and antigen

detection

Tuberculous

meningitis

d i Mixed pleocytosis

<300

ZN stain organisms,

culture PCR

Herpes simplex

encephalitis

N Mildly i

5– 500

lymphocytes

PCR

GBS N i Normal

SAH

†

N May be i Erythrocytes Look for bilirubin

pigments on

spectrophotometry;

xanthochromia

unreliable

Malignant

meningitis

d i Mononuclear Rapid cytospin and

look for malignant

cells

HIV N N or i Mononuclear

pleocytosis

Culture, antigen

detection, antiviral

antibodies

Neurosyphilis N or d i <300

lymphocytes

VDRL

Neurosyphilis—

early

i Treponema

pallidum

Neurosyphilis—

late

Immobilization

tests

†

LP should be done >12h after onset of headache; the CSF should be spun down within 45min;

d numbers of RBCs in successive bottles are compatible withSAH.

Reprinted from Brain Res Bull, 61:287– 97 Kleine T O etal. ‘New and old diagnostic markers of

meningitis in cerebrospinal uid (CSF)’(2003) with permission from Elsevier.

590

CHAPTER9 Neurology

590

Skull radiograph

Indications

Usually more modern imaging techniques are much more informative, but

there are occasions when these may not be speedily available. However,

the plain SXR has quite low specicity and sensitivity for detecting many

abnormalities of neurological importance.

Used in(suspected) casesof

• Skull fracture.

• Pituitary fossa abnormalities.

• Tumours involvingbone.

• Bone changes related to meningiomata.

Procedure

• Lateral view in the rst instance.

Consider

• Occipitofrontal.

• Towne’s (half axial).

• Basal (submentovertical).

• Specic views (e.g. orbits).

What tolook for(what you see will depend onthe

pathology)

See E Chapter13.

•

Shape and symmetry of thevault.

• Pituitaryfossa.

• Position of calcied pineal (midline shift?).

• Bone density changes (e.g. tumour, meningioma, Paget’s).

• Fractures.

• Evidence of neurosurgical procedures.

• Intracranialair.

• Post- nasalspace.

• Craniocervical junction.

Indications forSXR afterheadinjury

(But see E Computed tomography, pp. 598–600 for cranial CT; in general,

CT is the preferred imaging modality.)

In anorientated adult patient

•

Loss of consciousness or amnesia.

• Fall of>60cm.

• Full- thickness scalp laceration.

• Scalp haematoma.

If a skull fracture is detected, proceedtoCT.

SKULL RADIOGRAPH

591

592

CHAPTER9 Neurology

592

Ultrasound

US may be used in a variety ofmodes.

Mostly commonly used inneuroradiology

• B mode:gives 2D images.

•

Doppler eect is used to assess alterations in the pattern (especially

velocity) of ow in vessels.

•

Duplex scanning combines B mode and Doppler.

Extracranial vessels

Bmode

•

Can image from the clavicle (common carotid bifurcation) and internal

and external carotids to the angle of thejaw.

•

Can image the proximal and distal subclavian and vertebral arteries.

• Supraorbital artery (anterior circulation).

• Fibrofatty plaques and thrombus on plaques not very echogenic,

therefore missable.

•

Fibrous plaques more echogenic.

• Calcication in plaques is highly echogenic.

• Can sometimes detect intraplaque haemorrhage or ulceration.

Note:requires patient co- operation and considerable operator skill. High-

grade stenosis can appear as total occlusion.

Dopplermode

•

Stenosis alters the normal pattern of velocities recorded.

Duplex

•

Combination of anatomic and ow imaging more sensitive and specic

for clinically signicant stenoses.

Carotid duplex studies incerebrovascular disease

•

Use of carotid US:most commonly in the assessment of patients with

carotid territory ischaemic strokes or TIAs, who might be candidates for

carotid endarterectomy. Such surgery should be performed as soon as

possible, so carotid Doppler studies should be arranged promptly after

the rst event. If a patient has neurological signs or symptoms suggestive

of posterior circulation events, there is little point in organizing carotid

(i.e. anterior circulation) studies. Both the degree of stenosis and the

morphology of the plaque (irregular plaques are more pathogenic) are

important.

Duplex studies insuspected giant cell arteritis

•

Making, or excluding, the diagnosis of GCA can be dicult. Most

guidelines suggest a temporal artery biopsy, but timely access to a

biopsy may be dicult, GCA may occur without temporal artery

involvement, and some patients with GCA have a −ve biopsy. Duplex

studies of the temporal arteries have been shown to have high

specicity and sensitivity.

ULTRASOUND

593

Intracranial vessels

Transcranial Doppler

•

2MHz to penetrate thinnerbone.

• Flow velocity in anterior, middle, and posterior cerebral, ophthalmic,

and basilar arteries; carotid siphon.

What itshows

•

Intracranial haemodynamics.

• Vasospasm inSAH.

• Monitoring of microemboli.

• This is an area of active research, with new clinical indications being

described frequently.

Further reading

Croft AP, Thompson N, Duddy MJ, etal. Cranial ultrasound for the diagnosis of giant cell arteritis.

Aretrospective cohort study. J R Coll Physicians Edinb 2015; 45

:268– 72.

Rothwell PM, Eliasziw M, Gutnikov SA, etal. Analysis of pooled data from the randomised controlled

trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361

:107– 16.

Tegeler CH. Ultrasound in cerebrovascular disease. In: JO Greenberg (ed.). Neuroimaging.

NewYork:McGraw- Hill, 1995; pp.577– 95.

594

CHAPTER9 Neurology

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Angiography

Indications

• Strongly suspected or conrmedSAH.

• Suspected cerebral vasculitis.

• Detection and delineation of other vascular abnormalities (e.g. AVM) of

the brain or spinalcord.

•

Delineation of tumour blood supply (occasionally).

Procedure

1. Catheter passed via the femoral artery to the carotid or vertebral

artery under image intensication.

2. Contrast isgiven.

3. In digital subtraction angiography (DSA), subtraction of pre- from post-

contrast images (pixel by pixel) is used to help remove signals from

bone density.

Arch angiography (aortography)

• Visualizes the aorta, major neck vessels, and sometimes the circle of Willis.

• No venous imaging.

Selective intra- arterial angiography

• Later images show venous system.

Carotidartery

•

Anteroposterior (AP), lateral, and oblique views— anterior and middle

cerebral, and internal carotid arteries.

Vertebralartery

•

Towne’s (half- axial) and lateral views— vertebral, basilar, posterior

cerebral arteries.

What can be demonstrated?

• Occlusion, stenosis, plaques.

• Aneurysms.

• Arteriovenous and other blood vessel abnormalities.

• Abnormal tumour circulation.*

• Displacement or compression of vessels.*

• Experimental role in acute stroke analysis.

Note:(*) although CT and MRI give ner spatial details, angiography is still

useful, e.g. delineating blood supply of a tumour.

Complications

• Sensitivity to the contrast medium.

• Cerebral ischaemia, e.g. 2° to dislodgement of embolic fragments by

catheter tip or thrombus in the catheterlumen.

•

The rate of transient or permanent neurological defect following

angiography depends on the operator.

Further reading

Larsen DW, Teitelbaum GP. Radiological angiography. In:WG Bradley, RB Daro, D Marsden, GM

Fenichel (eds.). Neurology in Clinical Practice

, 3rd edn. Boston: Butterworth- Heinemann, 2000;

pp.617– 43.

Osborne AG. Diagnostic Cerebral Angiography, 2nd edn. NewYork:Lippincott, Williams & Wilkins,1999.

MYELOGRAPHY

595

Myelography

Indications

• Largely superseded by CT and especiallyMRI.

• Still used in subjects in whom MRI is contraindicated (e.g. cardiac

pacemaker, metallic implants, claustrophobia).

•

Can screen whole spinal cord and cauda equina for compressive or

expanding lesions.

•

Can visualizeroots.

• Spinal vasculature abnormalities.

Procedure

A total of 5– 25mL of (usually water- soluble) radio- opaque contrast

medium is injected via an LP needle in the usual location (occasionally a

cisternal puncture is used). By tipping the patient on a tilt table, the whole

spinal subarachnoid space may be visualized.

Complications

• ThoseofLP.

• Spinal arachnoiditis (after months or years), now rare with water-

soluble contrast.

•

Acute deterioration if there is cord/ root compression.

• Direct neurotoxicity (3 in 10,000):

•

Seizures, encephalopathy.

•

Usually resolves in48h.

• Allergic reaction to contrast. Give dexamethasone 4mg 12 and 2h prior

to investigation if known allergy.

Note:send CSF for usual investigations (E Lumbar puncture, pp. 584–9).

596

CHAPTER9 Neurology

596

Radionuclidescans

Positron emission tomography

Unstable positron- emitting isotopes (produced locally by a cyclotron or lin-

ear accelerator) are incorporated into biologically active compounds. The

distribution of isotope shortly after IV administration is plotted. Arange of

compounds may be labelled such as ligands for specic neurotransmitter

receptors or 18F- uorodeoxyglucose (FDG). Commonly, PET is used to

determine regional cerebral bloodow.

Single photon emission computed tomography (SPECT)

• Stable radioactive isotopes are incorporated into biologically active

compounds.

•

Their distribution after IV administration is plotted.

• These images often lack ne spatial detail.

Although the range of ligands available is limited, SPECT has certain advan-

tages overPET:

•

Isotopes are stable, and therefore a cyclotron or linear accelerator need

not be onsite.

•

Alabelled ligand can be given after a clinically important event, e.g. can

give agent and scan within 20min of the occurrence of a seizure.

Uses ofPET andSPECT

PET is not widely available as a clinical tool. With the i availability of func-

tional MRI (fMRI), the uses of PET in both clinical practice and neuroscience

research have lessened. SPECT is more widely available in clinical centres.

Clinical applicationsofPET

PET is mainly used in neurological practice as whole- body FDG- PET to look

for systemic malignancy, especially in paraneoplastic syndromes.

Clinical applications ofSPECT

•

An epileptogenic focus may show interictal hypometabolism (ictal

hypermetabolism may be demonstrated with SPECT).

•

Regional hypometabolism may be seen in neurodegenerative conditions

such as Alzheimer’s disease and frontotemporal dementia. This may aid

in diagnosis and dierential diagnosis.

•

‘Pseudo- dementia’ 2° to psychiatric disease such as depression (with

normal SPECT scans) may sometimes be dierentiated from dementia

due to ‘organic’ neurological disease (with regional hypoperfusion),

although psychiatric diseases may themselves be associated with regional

hypoperfusion.

•

Assessment of Parkinsonism.

The functional integrity of the nigrostriatal system can be assessed, e.g. by

the use of SPECT ligands for the dopamine transporter (e.g. FP- CIT). Such

DAT scans can be used to dierentiate true Parkinsonism from other causes

of movement disorders.

RADIONUCLIDESCANS

597

Clinical/ research applications ofPET and SPECT include

• Determination of regional cerebral blood ow, glucose metabolism, and

oxygen utilization

•

Hypometabolism may be seen following a stroke. The aected area

may exceed that with a demonstrable lesion on conventional CT or MR

imaging.

•

In vivo pharmacology (e.g. distribution of neurotransmitter receptors).

E Positron emission tomography, pp. 894–7.

Further reading

Marshall V, Grosset D. Role of dopamine transporter imaging in routine clinical practice. Mov Disord

2003; 18

:1415– 23.

Younes- Mhenni S, Janier MF, Cinotti L, etal. FDG- PET improves tumour detection in patients with

paraneoplastic neurological syndromes. Brain 2004; 127:2331– 8.

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Computed tomography

Cranial computed tomography

Lookfor:

•

Disturbances in the normal anatomy of the ventricular system.

• Skull base andvault.

• Width of cortical ssures/ sulci.

• Midlineshift.

• Areas of abnormal tissue density.

• Opacity or lucency of sinuses.

• Normal owvoids.

High- density (‘white’)signal

• Freshblood.

• Calcication:

•

Slow- growing tumour.

•

AVM/ aneurysm.

•

Hamartoma.

•

In pineal/ choroid plexus/ basal ganglia, may be normal.

Low- density (‘black’)signal

• Infarction.

• Tumour.

• Abscess.

• Oedema.

• Encephalitis.

• Resolving haematoma.

Mixed density

•

Tumour.

• Abscess.

• AVM.

• Contusion.

• Haemorrhagic infarct.

After administration of IV contrast medium, areas with a breakdown in the

blood– brain barrier may ‘enhance’ (appear ‘white’). This may reveal pre-

viously ‘invisible’ lesions (isodense with the surrounding tissue). Especially

useful for tumour and infection.

Common patterns ofenhancement include

•

Ring enhancement of tumours and abscesses.

• Solid enhancement of meningiomas.

• Meningeal enhancement with meningeal disease involvement.

Indications forhead CT afterheadinjury

CT imaging ofthe head inadults

Request a CT brain scan immediately for adult patients with any of the fol-

lowing risk factors:

•

GCS score <13 on initial assessment in the emergency department.

• GCS <15 2h after the injury on assessment in the emergency

department.

COMPUTED TOMOGRAPHY

599

• Suspected open or depressed skull fracture.

• Any sign of basal skull fracture.

• Post- traumatic seizure.

• Focal neurological decit.

• One or more episodes of vomiting.

• Amnesia for events >30min before impact.

CT imaging ofthe head inchildren

Request CT of the brain immediately for children with any one of the fol-

lowing risk factors:

•

Age over 1year:GCS <14 on assessment in the emergency department.

•

Age under 1year:GCS paediatric <15 on assessment in the emergency

department.

•

Age under 1year and presence of bruise, swelling, or laceration (>5cm)

on thehead.

•

Dangerous mechanism of injury.

• Clinical suspicion of non- accidental injury.

• Loss of consciousness lasting >5min (witnessed).

• Post- traumatic seizure but no history of epilepsy.

• Abnormal drowsiness.

• Suspected open or depressed skull injury, or tense fontanelle.

• Any sign of basal skull fracture.

• Focal neurological decit.

• Three or more discrete episodes of vomiting.

• Amnesia (antegrade or retrograde) lasting >5 min.

1,2

CT angiography and venography

CT, especially rapid image acquisition with helical CT, can allow imaging

of the intracranial vasculature. CT angiography is particularly used in the

detection of aneurysms and is i widely available.

CT venography is impor-

tant in the assessment of possible intracerebral venous thrombosis.

CT ofspine

MRI is usually preferable, but plain CT can give information about the discs

and bony architecture. CT may be helpful in suspected bony abnormali-

ties. Some patients cannot have MRI because of, e.g. metallic implants. CT

myelography can be used to demonstrate compressive lesions.

1 National Institute for Health and Care Excellence (2014). Head injury:assessment and early manage-

ment. Clinical guideline CG176. M

https:// www.nice.org.uk/ guidance/ cg176.

Yates D, Aktar R, Hill J; Guideline Development Group. Assessment, investigation, and early man-

agement of head injury:summary of NICE guidance. BMJ

2007; 335:719– 20.

3 Karamessini MT, Kagadis GC, Petsas T, etal. CT angiography with three- dimensional techniques

for the early diagnosis of intracranial aneurysms. Comparison with intra- arterial DSA and the surgical

ndings. Eur J Radiol 2004; 49:212– 23.

4 Smith R, Hourihan MD. Investigating suspected cerebral venous thrombosis. BMJ 2007; 334:794– 5.

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CHAPTER9 Neurology

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Indications forcervical spine imaging aftertrauma

Plain radiograph is the initial investigation, but CT preferredwhen:

•

Age >9years:

•

GCS <13 on initial assessment.

•

Intubated patient.

•

Technically inadequate plain radiographs.

•

Clinical suspicion of injury despite normal radiograph.

•

Patient being scanned for multi- region trauma.

• Age <10years:

•

GCS<9.

•

Strong clinical suspicion of injury despite normal radiograph.

•

Technically inadequate plain radiographs.

1,2

E OHCM 10e, p.730, p. 746.

COMPUTED TOMOGRAPHY

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CHAPTER9 Neurology

602

Magnetic resonance imaging

For most neurological indications, MRI is preferred to CT. It gives supe-

rior anatomical detail, and the range of sequences available allows superior

determination of pathology. Unlike CT, there is no radiation exposure.

Note: MRI is not safe in the presence of ferromagnetic materials (e.g.

certain prostheses, metal lings in theeye).

Some people nd MRI dicult to tolerate because of claustrophobia.

Counselling and experience of ‘dummy’ scanners prior to MRI may be helpful.

Upright and ‘open’ scanners are increasingly available in specialist centres.

MRI sequences

There is a variety of sequences available, which oer various advantages in

delineating anatomy and pathology. This is an area of active research, with

new sequences continuing to enter clinical practice. It is important that the

requesting clinician provides appropriate clinical details, so that the radiolo-

gist may select the appropriate imaging sequences (and planes) to beused.

The commonest sequences are T1 and T2 (see Table9.2).

•

T1 CSF is hypointense (‘black’); fat and mature blood clotwhite.

• T2 CSF is hyperintense (‘white’).

MRI withenhancement

Intravenously administered gadolinium leaks through areas of damaged

blood– brain barrier to give a marked enhancement. It may be helpful in

delineating:

•

Ischaemia.

• Infection.

• Tumour (may help dierentiate from surrounding oedema).

• Active demyelination.

Table9.2 Comparison ofT1 andT2MRI

T1 T2 Tissue or lesion

Good anatomical

detail

Reveals most pathology

better than T1

Hypointense Hyperintense CSF

Hyperintense Iso- intense Fat, e.g. dermoid, lipoma,

some metastases (melanoma),

atheroma

Very hypointense Very hyperintense Cyst, hygroma

Hypointense Hyperintense Ischaemia, oedema,

demyelination, many

malignant tumours

Hyperintense Moderately

hyperintense

Subacute or chronic

haemorrhage

Iso- intense Hypointense Acute haemorrhage

Iso- intense Iso- intense Meningioma

MAGNETIC RESONANCE IMAGING

603

Magnetic resonance venography and angiography

MR may be used to obtain non- invasive images of blood vessels by using

special MRI sequences and image reconstruction. Whilst standard angiogra-

phy remains a ‘gold standard’ for many purposes, MRA has the advantage

of being non- invasive and therefore ‘safe’. MRA images ow, rather than

structure, and therefore may fail to ‘pick up’ low ow abnormalities such

as cavernous angiomas. 2 Caution:congenital abnormalities in the venous

sinuses may be misinterpreted as thrombosis on MR venography(MRV).

Uses

•

Assessment of patency of major arterial and venous vessels.

• Visualization of large (73mm diameter) aneurysms.

Functional magnetic resonance imaging

Certain (indirect) indices of neural activity (most commonly changes

reecting regional perfusion) may be imaged with sucient temporal and

spatial resolution to be useful for both research and clinical applications

(although fMRI has been largely a research tool to date). As a conventional

MRI machine, albeit with special software, is required, fMRI is being i used

in the clinical setting.

Clinical and research applications have included

•

Demonstration of the language areas prior to epilepsy surgery.

• Demonstration of the functional anatomy of cognitive, sensory, and

motor processes.

Diusion tensor imaging

Diusion tensor imaging (DTI) allows anatomical tract tracing in vivo,

using specialized software on standard MRI machines. As with fMRI, DTI

was initially a research tool but has now entered clinical practice in some

neuroscience centres. Major tracts, such as the corticospinal tract and the

optic radiation, can be identied; these can then be spared during resective

surgery.

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) can be used to measure the con-

centration of certain neurochemicals in vivo (see Fig. 9.1). Because of the

low concentrations of the neurochemicals, measurements are taken from

large volumes of interest (typically several cm

, therefore giving MRS a

much lower spatial resolution than standard structural MRI (spatial reso-

lution typically of 1– 2mm

). Metabolites commonly measured include the

following (although it is often the ratio of dierent metabolites that is par-

ticularly useful):

•

N- acetyl- aspartate (NAA) is present in high concentration in neuronEs

and axons. Areas of neuronal or axonal loss show reduced levels

ofNAA.

•

Choline (Cho) is associated with turnover in cell membranes and i

cell division. Areas of demyelination and malignant tumours can cause

raised Cho. i

Cho can help distinguish recurrent tumours from post-

radiotherapy changes (this can be a dicult distinction to make using

standardMRI).

604

CHAPTER9 Neurology

604

• Creatine (Cr) (and phosphocreatine) is a marker of metabolism.

Reduced levels may indicate celldeath.

•

Myo- inositol (m- In) may be i in certain diseases such as Alzheimer’s

dementia.

•

Lactate (Lac) is typically present in concentrations too low to be

detected, except in areas of ischaemia, hypoxia, and certain tumours.

Further reading

Faro SH, Mohamed FB (eds.). Functional Neuroradiology. NewYork:Springer,2011.

Powell HW, Koepp MJ, Richardson MP, Symms MR, Thompson PJ, Duncan JS. The application of

functional MRI of memory in temporal lobe epilepsy:a clinical review. Epilepsia 2004; 45:855– 63.

Stieltjes B, Brunner RM, Fritzsche K, Laun F. Diusion Tensor Imaging: Introduction and Atlas.

Berlin:Springer,2013.

White PM, Teasdale EM, Wardlaw JM, Easton V. Intracranial aneurysm: CT angiography and MR

angiography for detection prospective blinded comparison in a large patient cohort. Radiology

2001; 219

:739– 49.

Myo-Ins

4.0 3.0

Frequency (ppm)

2.0

Cho

Cre

Glu

NAA

Fig.9.1 The upper panels show the position of the volume of interest; the lower

panel shows the MRS spectrum from that volume.

MAGNETIC RESONANCE IMAGING

605

606

CHAPTER9 Neurology

606

Nerve conduction studies

Please give your neurophysiologists as much information as possible about

your case and, if necessary, discuss it with them. They will then be in the

position to organize the most appropriate neurophysiological investigations.

In certain circumstances, you may need to specically ask for unusual inves-

tigations such as repetitive stimulation in suspected LEMS (E Repetitive

stimulation, p. 608).

Sensory nerve action potential and sensory conduction

velocity

Procedure

•

Orthodromic conduction velocity:electrically stimulates distal sensory

branches (e.g. index nger) and records the evoked sensory nerve action

potential (SNAP) proximally (e.g. over the median nerve at the wrist).

The distance between the two sites (D)and the latency (L)of the onset

of the SNAP determine the sensory conduction velocity (D/ L).

The SNAP amplitude is also useful.

•

Antidromic conduction velocity:supramaximal electrical stimulation

proximally; records distally (e.g. by a ring electrode on the little nger).

By varying the position of the stimulating electrode, the conduction

velocity in various portions of the nerve may be ascertained.

What does itmean?

•

d SNAP amplitude, or SNAP absence altogether, implies a lesion distal

to the dorsal root ganglion.

•

d velocity/ i latency (see Table 9.3). Motor velocities are more

commonly measured.

Motor conduction velocity

Procedure

Supramaximally stimulate a peripheral nerve trunk at a proximal (p) and

a more distal (d)site. Record the time to the onset of the evoked muscle

response (compound motor action potential (CMAP)) from each (Tp and

Td) and the distance between them (D). The motor conduction velocity

between p and d is therefore D/ (Tp−Td).

Table9.3 Typicalvalues

Latency Amplitude

Median nerve (index nger to wrist)

2– 3ms 9– 40mV

Ulnar nerve (little nger to wrist) 2– 2.6ms 6– 30mV

Sural nerve (mid- calf to below med. mall) 2– 4ms 5– 40mV

med. mall, medial malleolus.

NERVE CONDUCTION STUDIES

607

Typicalvalues

•

Median nerve in forearm (to abductor pollicis brevis) >48m/ s.

• Ulnar nerve in forearm (to abductor digiti minimi) >48m/ s.

• Common peroneal nerve (to extensor digitorum brevis) >40m/ s.

What does itmean?

(See Table9.4.)

Distal motor latency

• Latency from stimulation of most distal site on nerve toCMAP.

Typicalvalues

•

Median nerve (wrist to abductor pollicis brevis) <4.1m/ s.

• Ulnar nerve (wrist to abductor digiti minimi) <3.8m/ s.

• Radial nerve (spiral groove to brachioradialis)<5m/ s.

Note:these latencies include time taken for impulses to pass along the most

distal (unmyelinated) portion of the nerve and for transmission at the neu-

romuscular junction (therefore, they may not be used to calculate nerve

conduction velocities). Compare with velocities elsewhere in the nerve

being studied.

What does itmean?

Increased distal motor latency seenin

•

Conditions in which the very distal segment of a nerve is compromised

(most commonly carpal tunnel syndrome).

•

Early demyelinating neuropathy (e.g.GBS).

• Chronic demyelinating neuropathy.

Table9.4 Typical patterns

Conduction velocity AP amplitude AP dispersion

Axonal

neuropathy

Late stage:d distally

> proximally (loss of

fastest conducting

axons)

Late stage:d Not seen

Demyelinating

neuropathy

Marked slowing Greater

dispersion,

perhaps especially

in acquired,

not inherited,

demyelination

Ganglionopathies Slowing proportional

to loss of large bres;

often not marked

d proportional

to loss of large

bres; often not

marked

Not seen

Note:limbs should be warm; look for asymmetries. What are your laboratory’s current values?

608

CHAPTER9 Neurology

608

Compound motor action potential

The waveform, amplitude, and area under the curve of the CMAP reect

the number of depolarized muscle bres (e.g. reduced in axonal neuropathy

and denervated muscle) and the temporal dispersion of conduction veloci-

ties in the motor neurones to them (e.g. i in demyelinating neuropathy).

Late responses

Fwave

•

If a motor nerve is stimulated, there are orthodromically directed action

potentials (APs) that may cause a response in the muscle (CMAP).

However, antidromically directed APs will also pass proximally towards

the cell body. If these result in sucient depolarization of the axon

hillock, then a second orthodromic volley will pass down the nerve.

This may cause a second motor AP (the F wave). Therefore, the F

wave:(i)does not involve synapses (other than the neuromuscular

junction, of course) and (ii) depends on the integrity of the wholeaxon.

•

It may be dicult to elicit.

• Delay or absence of the F wave may reect a lesion proximal to the

site of stimulation, in parts of the nerve that may be inaccessible to

electrodes, e.g. brachial plexopathy or thoracic outlet syndrome. May

also be an early feature inGBS.

Hwave

•

This is ‘an electrical ankle jerk’:submaximal stimulation of the posterior

tibial nerve in the popliteal fossa causes trans- synaptic activation of the

soleus, recorded as aCMAP.

•

Amplitude may be d by aerent or eerent problems, e.g. neuropathy

or radiculopathy.

Repetitive stimulation

• Procedure:stimulate a motor nerve with 3– 5 supramaximal stimuli at

2– 4Hz, whilst recording evokedCMAPs.

• Normal response:no change in CMAP amplitude.

•

In MG:>10% decrement in CMAP amplitude after two stimuli.

•

InLEMS:

•

After voluntary contraction or after rapid stimulation (20– 50Hz) for

2– 10s, the CMAP amplitude, often initially small, i by 25% (sugges-

tive) or 100% (diagnostic).

•

At a slow (3Hz) rate of stimulation, there is a response decrement.

NERVE CONDUCTION STUDIES

609

610

CHAPTER9 Neurology

610

Electromyogram

Procedure

• Aconcentric needle electrode is usuallyused.

• It is inserted into the muscle to be studied.

• The dierence in potential between the inner part of the electrode

and the outer core is amplied and displayed on an oscilloscope or

computer screen.

•

It is also ‘displayed’ as an auditory signal, and experienced

electromyographers as much listen to as watch the pattern of electrical

activity.

Normal muscle is ‘silent’ (electrically inactive) at rest (there is no ‘spon-

taneous activity’), although there will be a brief burst of activity when the

electrode is rst inserted (the ‘insertional activity’).

The electrode can pick up electrical activity from muscle bres within

about 0.5mm of its tip; therefore, muscle bres from several motor units

(each innervated by a dierent motor neurone) in this volume can contrib-

ute to the signal. However, with care, potentials from a single motor unit

may be recorded when a co- operative subject tries to exert the muscle

a little (the ‘motor unit potential’). With i muscular eort, more muscle

bres are recruited, giving rise to the ‘interference pattern’.

Various nerve and muscle problems cause characteristic alterations tothese

four patterns ofactivity

1. Insertional.

2. Spontaneous.

3. Motor unit potential.

4. Recruitment.

5. In addition, certain other patterns may be observed in certain diseases

(in particular, myotonia).

1. Insertional activity

•

Usually there is a brief burst of potentials which lasts<1s.

• Insertional activity is normal in upper motor neurone (UMN) lesions

and most non- inammatory myopathies.

• It may be longer- lasting in lower motor neurone (LMN) lesions,

inammatory myopathies, and acid maltase deciency.

•

In myotonia, myotonic discharges occur (E Electromyogram, p. 611).

2. Spontaneous activity

•

Normal muscles at rest are silent.

• This is also the case in UMN lesions, non- inammatory myopathies

(unless 2° denervation has set in), and myotonia.

•

Fibrillation potentials and +ve sharp waves are seen in LMN lesions

and inammatory myopathies. They occur in regular bursts of constant

amplitude (unlike activity related to voluntary contraction).

•

Fibrillation potentials are spontaneous APs in irritable, acutely

denervated muscle bres. They are low- amplitude, brief −ve potentials.

• Positive sharp waves are brief +ve potentials, followed by a −ve wave.

Typically, they can be seen for 2– 3 weeks after denervation but may

persist.

ELECTROMYOGRAM

611

3. Motor unit potentials

•

If the electrode is positioned quite close to the bres of a motor unit

which is active during slight voluntary contraction, then a motor unit

potential (MUP) may be recorded. In normal muscle (and in UMN

lesions), this waveform is triphasic, 5– 10ms, and has an amplitude of

0.5– 1mV (larger muscles have larger motor units).

• In myopathies and muscular dystrophies, the motor units are smaller

and polyphasic. They tend to be briefer but, in some cases, last longer

thanusual.

•

In denervated and then reinnervated muscles (typically LMN lesions),

the size of individual motor units i (as the surviving motor neurones

‘take over’ the muscle bres previously innervated by the now absent

other motor neurones). MUPs therefore are of greater amplitude and

duration and are polyphasic.

•

In myotonia, myotonic discharges areseen.

Note:up to 15– 20% of MUPs in ‘normal’ muscle may be polyphasic.

4. Recruitment

•

Normally, as the strength of voluntary contraction i, i numbers

of motor units are recruited, and these units tend to be larger

(Heinneman’s size principle). The potentials due to these active units

overlap and become dicult, and nally impossible, to tell apart— a

full ‘interference pattern’, usually well below the maximum voluntary

contraction.

•

In muscle diseases, a full interference pattern may be produced, but it is

of low amplitude. In weak muscles, there may be ‘early recruitment’ (i.e.

recruitment of many motor units at low levels of voluntary contraction).

•

In denervated muscles, a full interference pattern may not be achieved,

because of the d number of motorunits.

•

In UNM lesions, there is a lower frequency of ‘normal’MUPs.

5. Myotonia

•

High- frequency repetitive discharges occurring after voluntary

movement or provoked by moving the electrode. The amplitude and

frequency wax and wane, giving the auditory signature likened to the

sound of a Second World War dive bomber (or a motorcycle).

•

Note:following the onset of a neuropathy, it may take at least 10–

14days for evidence of denervation to appear in the EMG. Therefore, a

repeat study after this time is often useful.

Single- bre electromyogram

A recording electrode with a smaller recording surface than usually used

samples a few muscle bres from a single motor unit (supplied by a single

motor neurone). The variability (‘jitter’) in the timing of APs from dierent

muscles should be <20– 25ms. Conduction block during voluntary contrac-

tion may also be shown. These techniques are used to investigate neuro-

muscular disorders and reinnervation in neuropathies.

Further reading

Blum AS, Rutkove SB (eds.). The Clinical Neurophysiology Primer. Totowa:Humana Press,2007.

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Electroencephalogram

The standard EEG is non- invasive. Electrodes are attached to the scalp with

collodion adhesive. Stable recordings may be made for days. Usually they

are arranged according to the international 10– 20 system. This is a method

for positioning electrodes over the scalp in an orderly and reproducible

fashion. Additional electrodes can be applied to the scalp, depending on the

region of interest.

Standard recording conditions

• Rest.

• Hyperventilation for 3– 5min can activate generalized epileptiform

changes (and precipitate absence seizures):

•

Can i frequency of focal discharge.

•

Can i slow- wave abnormalities.

• Photic stimulation (a strobe light at 30cm with a frequency of 1– 50Hz);

this can produce several patterns of activity:

•

Photoparoxysmal response— bilateral spike or spike and wave dis-

charges not time- locked to the visual stimulus, which may outlast the

visual stimulus by hundreds of milliseconds. Generalized, but may

have frontal or occipital predominance; commonly seen in idiopathic

generalized epilepsies; high- voltage occipital spikes, time- locked to

the stimulus; weakly associated with epilepsy.

•

Photomyogenic (photomyoclonic) responses— non- specic, mostly fron-

tal spikes due to muscle activity; associated with alcohol and some

other drug withdrawal states.

•

Sleep studies:

•

Subject either stays awake the night before the recording or is given

a small dose of choral prior to the recording (sometimesboth).

•

Subjects tend to show the earlier stages of non- REMsleep.

•

These studies i the yield of EEG abnormalities, including

epileptiformones.

•

By capture of ‘natural sleep’:certain seizure types are commoner in

sleep (e.g. juvenile myoclonic epilepsy (JME)).

•

Sleep deprivation itself i the number of seizures and epileptiform

changes.

E Polysomnography, p. 621.

ELECTROENCEPHALOGRAM

613

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614

Electroencephalogram:abnormalities

The normal electroencephalogram

There is a wide range of normal EEG phenomena. Some of the common

patterns in the awake adult are listed in Table9.5.

EEG abnormalities (not peri- ictal orictal)

• Avariety of EEG abnormalities may be seen outside the peri- or per-

seizure period.

•

Abnormalities in the EEG are not restricted to the appearance of

abnormal waveforms.

•

The loss, or redistribution in the scalp location, of normal background

activities is abnormal.

The classication ofEEG abnormalities is complex. Below is a highly

simpliedguide

1. General excess of slow waves— commonly seenin:

•

Metabolic encephalopathy.

•

Encephalitis.

•

Post- ictal states.

2. Focal slow waves— commonly seenin:

•

Large cerebral lesions (e.g. tumour, haematoma).

•

Post- ictal states.

•

Migraineurs.

3. Localized, intermittent, rhythmic slow waves— may be seen in

idiopathic generalized and localization- related epilepsies.

Table9.5 EEG rhythms

Activity Frequency

(Hz)

Amplitude

(mV)

Scalp

location

Behavioural

state

Alpha

8– 12 20– 60 Usually

occipital

Maximum relaxed,

awake, eyes closed

Beta >13

10– 20 Frontocentral Wakeful, drowsy;

REM and SWS 1 and 2

Theta

4– 8 Variable

diuse

Frontocentral,

temporal

Minimally awake,

drowsy, SWS

Delta <4 Variable Diuse Awake; drowsy

8– 10 20– 60 Central Awake, suppressed in

voluntary movements

SWS, slow- wave sleep.

The terms alpha, beta, theta, and delta are often used to describe the background activity but

are also used to describe the frequency of EEG activity.

Sharp activity may be a normal phenomenon.

ELECTROENCEPHALOGRAM:ABNORMALITIES

615

4. Epileptiform abnormalities:

•

Spikes (if last <80ms) or sharp waves (80– 200ms) may be associated

with slowwaves.

•

Consistently focal spikes suggest epilepsy with a focal seizureonset.

Note:2– 4% of non- epileptics have occasional spikes or sharps.

5. Repetitive stereotyped ‘periodic’ complexes.

EEG patterns may show periodicity. These patterns may be epileptiform or

not, and may be focal or generalized. They are an abnormal EEG feature,

the interpretation of which depends on the clinical context.

Examples include

•

Burst suppression:bursts of generalized high- voltage mixed waveforms,

alternating with generalized voltage suppression:

•

Coma.

•

Late- stage status epilepticus (both convulsive and non- convulsive).

• Triphasic waves over one or both temporal lobes:common in herpes

simplex encephalitis.

•

Periodic lateralized epileptiform discharges (PLEDs) are localized sharp

or slow- wave complexes 0.2– 1s long, every1– 5s:

•

Non- specic but suggest localized cerebral insult (stroke, haema-

toma, tumour).

•

Occasionally seen in migraine and focal epilepsies.

• BIPLEDs are bihemispheric PLEDs:suggest more widespread insults, e.g.

anoxia, encephalitis.

•

Bilateral or generalized high- voltage complexes for 0.5– 2s every 4–

15s:characteristic of subacute sclerosing panencephalitis (SSPE).

•

Triangularwaves:

•

Characteristic ofCJD.

•

Not seen in vCJD (may see a ‘disorganized’ EEG without repetitive

complexes).

•

Runs of broad triphasic waves (1.5– 3Hz):severe metabolic

encephalopathy (e.g. renal or hepatic failure).

•

Periodic spikes or sharp waves:bi- or multiphasic morphology (0.5– 2Hz);

usually generalized— suggest severe encephalopathy,e.g.

•

Herpes encephalitis.

•

CJD (in the setting of rapid dementia and myoclonus).

•

Lithium intoxication.

•

Post- anoxic brain injury.

•

Tricyclic antidepressant overdose.

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CHAPTER9 Neurology

616

Electroencephalogram:inepilepsy

Idiopathic (genetic) generalized epilepsy(IGE)

• Generalized, bilaterally synchronous epileptiform discharges with

virtually normal background.

•

Absence epilepsy:3Hz spike andwave.

• JME:6Hz multiple spike andwave.

Symptomatic (secondary) generalized epilepsy

• More variable.

• Inter- ictal background activity:excessslow.

•

Inter- ictal epileptiform activity:irregular spikes or sharp and slow waves

1.5– 4Hz. Usually generalized, but may show asymmetry or (multi- ) focal

features.

Localization- related partial focal epilepsy

• Inter- ictal EEG is often normal, particularly if the focus is located deeply

(especially common with frontalfoci).

•

There may be lateralized or localized spikes or sharpwaves.

ELECTROENCEPHALOGRAM:IN EPILEPSY

617

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CHAPTER9 Neurology

618

Electroencephalogram:howtouse

In suspected epilepsy

• Routine EEG with photic stimulation and hyperventilation gives about

up to a 50% detection rate for inter- ictal epileptiform abnormalities in

a subject with epilepsy (higher ‘yield’ in ° generalized epilepsies than in

localization- related epilepsies).

• Sleep- deprived or choral- induced sleep recording may i the yield of

EEG abnormalities to up to 60– 70%.

• Consider 24h or longer ambulatory EEG, ideally with audio/ video

monitoring. Most useful in helping to determine the nature of the

seizure in a subject with frequent (e.g. daily) attacks.

In general, avoid reduction in anti- epileptic drugs or drugs such as pentyl-

enetetrazole to induce seizures, except in exceptional circumstances, e.g.

videotelemetry as part of work- up for epilepsy surgery.

Note:

•

No inter- ictal spikes does not imply no epilepsy.

• Similarly, inter- ictal spikes do not always imply epilepsy.

• A−ve ictal EEG does not necessarily imply a non- epileptic (‘pseudo-

’) seizure, especially in simple partial and some brief complex partial

seizures (CPS). Scalp electrodes may fail to record deep, especially

frontal, activity.

•

However, a tonic– clonic seizure with loss of consciousness should be

associated with an epileptiform EEG during the ictus. This EEG activity

may be obscured by muscle artefact, but post- ictal slowing may beseen.

• The EEG may be slow after a tonic– clonic seizure for many tens of minutes.

Note:the diagnosis of epilepsy is mainly clinical! Remember that most epi-

sodes of altered consciousness are not epileptic in origin. In many cases,

cardiological investigations are appropriate. Have a low threshold for order-

ing a 12- lead ECG. Ambulatory ECG monitoring, particularly with cardiac

memo devices, and ambulatory BP monitoring can be very useful.

In established epilepsy

• Classication (e.g. CPS vs absence).

• Assessment of frequency of seizures (e.g. ambulatory EEG to assess

frequency of absence seizures).

•

Reduction in inter- ictal discharges in some syndromes (e.g. absence,

photosensitive epilepsy) correlates with anti- epileptic drug ecacy.

In focal cerebral dysfunction

Often not particularly helpful. Modern imaging studies usually provide more

information.

•

Small, deep, or slow- growing lesions often cause no eects.

• Asymmetric voltage attenuation may be caused by a subdural

haematoma (or other uid collection) overlying the cortex.

•

Direct grey matter involvement may cause alteration/ loss of normal

EEG or cause epileptiform discharges.

•

Subcortical white matter changes can cause localized polymorphic

slowwaves.

•

Deeper subcortical lesions tend to produce more widespread slow-

wave disturbances.

ELECTROENCEPHALOGRAM:HOWTOUSE

619

In central nervous system infections

• CJD and SSPE have relatively characteristic EEG associations.

• Meningitis and encephalitis cases may show diuse background

disturbances and polymorphic or bilateral intermittent slow wave

abnormalities.

•

Encephalitis usually causes more changes than meningitis.

• Focal changes may be seen over abscesses and in cases of herpes

simplex encephalitis.

In dementia

• To exclude some conditions such as toxic encephalopathy, non-

convulsive status epilepticus (NCSE).

•

Afew dementing conditions have characteristic EEGs (CJD,SSPE).

• Slowing of background frequency occurs in Alzheimer’s disease, but

values may overlap with those of the normal aged, therefore not very

helpful clinically.

In confusionalstates

• Helpful in diagnosing NCSE (absence and complex partial status).

• To exclude cerebral dysfunction.

• Not very useful in psychiatric diagnosis per se, but an abnormal EEG in a

confusional state may help exclude psychogenic causes for an apparent

reduction in level of consciousness.

In toxic metabolic encephalopathies

• EEG always abnormal.

• Diuse slowing in mildcases.

• Other abnormalities may develop in later stages.

• Specic patterns may be seen in certain aetiologies.

• Excess fast activity:barbiturate and benzodiazepine toxicity.

•

Triphasic waves:hepatic and renal failure, anoxia, hypoglycaemia,

hyperosmolality, lithium toxicity.

•

Periodic spikes or sharp waves:anoxia, renal failure, lithium and tricyclic

antidepressant toxicity.

Incoma

• EEG, especially serial EEGs, provides an indication of the degree of

cerebral dysfunction.

•

In general, any ‘normal’- looking EEG, spontaneous variability, sleep–

wake changes, and reaction to external stimuli are relatively good

prognosticsigns.

•

An invariant, unreactive EEG is a poor prognostic sign; the pattern,

however, is not uniform; it may include periodic spikes of sharp waves,

episodic voltage attenuation, alpha coma, and burst suppression.

•

May give some diagnostic clues, e.g. localized abnormality—

supratentorial mass lesion; persistent epileptiform discharges— status

epilepticus.

•

‘Alpha coma’:monotonous unresponsive alpha with anterior distribution

seen after a cardio/ respiratory arrest is a poor prognostic feature.

• Monotonous, but partially reactive, alpha may follow brainstem infarcts.

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CHAPTER9 Neurology

620

Electroencephalogram:invasive

techniques

These are generally restricted to specialist centres, most commonly used in

the pre- surgical work- up of patients.

Foramen ovale electrodes, corticography (usually done by laying strips

of electrodes on the surface of the brain), and depth EEG (electrodes

implanted into the parenchyma of the brain) may be used, depending on

the region of interest. Sphenoidal electrodes are rarely used today but can

give useful EEG information about the medial temporal structures.

Further reading

Blum AS, Rutkove SB (eds.). The Clinical Neurophysiology Primer. Totowa:Humana Press,2007.

National Institute for Health and Care Excellence (2012). Epilepsies: diagnosis and management.

Clinical guideline CG137. M

https:// www.nice.org.uk/ guidance/ cg137.

POLYSOMNOGRAPHY

621

Polysomnography

• This is a multimodal recording used in the analysis of sleep- related

disorders.

•

There is concurrent recording of EMG, EEG, and electro- oculography

(EOG— eye movements), often with audiovisual channels. Other

physiological parameters may also be recorded, e.g. nasal airow, chest

expansion.

Sleep is divided into three stages (N1– N3) of progressively ‘deeper’ non-

REM (NREM) sleep and a stage of REM sleep (see Table 9.6), characterized

physiologically by bursts of rapid eye movements (saccades). NREM sleep

was previously divided into four stages:1 (now N1), 2 (now N2), and 3

and 4 (nowN3).

Multiple sleep latencytest

This is a diagnostic test for narcolepsy. Following a good night’s sleep, nor-

mal subjects typically enter REM sleep with a latency of >>10min (usually

790min). In narcolepsy, the latency is <10min.

Further reading

Abad VC, Guilleminault C. Polysomnographic evaluation of sleep disorders. In:MJ Amino (ed.).

Amino ’s Electrodiagnosis in Clinical Neurology, 6th edn. Oxford:Elsevier Saunders, 2012; p.727.

Table9.6 Sleepstages

Stage Behaviour Main EEG pattern Comments

N1 Drowsy Diuse alpha and theta Diminished EMG; rolling

eye movement

N2 Light sleep

High theta; K

complexes; sleep

spindles

Further diminished EMG;

may have rolling eye

movements

N3 Deep sleep Delta Diminished EMG; no eye

movements

REM No body

movements,

but vivid

dreams

Low amplitude, mixed

frequency

Muscular atonia; rapid eye

movements

REM:rapid eye movements.

There is progression through stages N1- N3, and several episodes of REM during a typical

night’s sleep. Polysomnography can be important in understanding the pathophysiology of the

insomnias, parasomnias and other sleep patterns.

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CHAPTER9 Neurology

622

Sensory evoked potentials or responses

Whilst many techniques and protocols have been developed in research

laboratories, there are only a few techniques in widespread clinical use.

Astimulus is delivered to the periphery, thus activating a sensory system

and evoking an electrical response over a more central, often cortical, area.

Multiple surface electrode recordings time- locked to the peripheral stimulus

are recorded and averaged, to help eliminate ongoing random background

‘noise’ from the sensory stimulus- evoked ‘signal’. Deviations of this evoked

potential (EP) or response (ER) from the norm (especially in latency and

waveform) suggest pathology in the sensory pathway tested.

Visual evoked potentials

Pattern- evoked visual evoked potentials

An alternating chequerboard pattern (temporal frequency 1– 2Hz) is pre-

sented to each eye individually (see Fig. 9.2). The EP is recorded over the

occipital (° visual) cortex. Most commonly, the rst large +ve wave, called

P1 or P100 (as it typically occurs at about 100ms), is studied.

A delayed, smaller, or dispersed VEP indicates disease in the retino-

geniculo- striate pathway (if severe refractive errors or cataracts have been

excluded), but most commonly aecting the optic nerve (a uniocular decit

implies a lesion anterior to the optic chiasm) or at the chiasm.

Flash- evoked visual evoked potentials

In subjects with very poor vision or xation and in the very young, a bright

ash may be used as the stimulus. This gives less reproducible results, par-

ticularly in the P100 latency.

Commonuses

The VEP is used in general to document intrinsic, inammatory, or com-

pressive lesions of the optic nerve (or chiasm).

1. Suspected optic or retrobulbar neuritis.

2. In a patient with suspected MS, evidence of a VEP abnormality in an

asymptomatic eye would suggest a previous episode of optic neuritis.

3. Evaluation of hysterical blindness (may need to use a strobe light

stimulus if patient non- co- operative).

4. Evaluation of optic nerve function in compressive lesions such as

dysthyroid eye disease, optic nerve glioma.

5. Follow- up after surgery to decompress the optic nerve or chiasm.

6. Assessment of poor visual acuity in patients unable to co- operate with

usual testing. Vary the size of the chequerboard squares; subjects with

poor acuity will only have a VEP to the coarser patterns.

Somatosensory evoked potentials

• Stimulation site over a peripheral nerve, e.g. ulnar or median at the

wrist, common peroneal at the knee, posterior tibial at the ankle (see

Fig.9.3).

•

Record over Erb’s point (above the medial end of the clavicle), C7 or

C2 vertebra, or the parietal cortex for arm stimulation; L1, C7, C2, or

vertex for leg stimulation.

•

Calculate absolute and interpeak latencies.

SENSORY EVOKED POTENTIALS OR RESPONSES

623

• Need to show with NCS that distal parts of the somatosensory

pathways are conducting normally.

•

Assesses the dorsal column, not anterolateral (spinothalamic) tract

pathways:

•

For example, stimulate the median nerve at the wrist; prolonged

latency to Erb’s point suggests a brachial plexus (or more distal)

lesion.

•

Prolonged Erb’s point to C2 latency suggests a spinal cord lesion.

Uses

•

Diagnosis of plexopathies.

• Evaluation of subclinical myelopathy in possibleMS.

• Evaluation of hysterical sensoryloss.

• Per- operative monitoring (e.g. during scoliosis surgery).

Right ey

Left eye

Right ey

3mV divisions

30 60 90 120 150 180 210 240 (ms)

Fig.9.2 Visual evoked potential (to chequerboard stimulus).

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CHAPTER9 Neurology

624

Brainstem auditory evoked potentials (BAEPs, BAERs,

BSAEPs)

(See Fig.9.4.)

•

Stimulus:rarefaction clicks of 50 or 100ms duration, presented mono-

aurally at 10Hz at 60– 70dB above threshold (masking the noise to the

otherear).

•

Record over the mastoid and vertex of theskull.

• Classic waveform has seven peaks, said to be generated by sequential

auditory nuclei:

Fig.9.3 Leg somatosensory potentials.

SENSORY EVOKED POTENTIALS OR RESPONSES

625

•

I:VIIIth nerve (must be present to interpret subsequent waves).

•

II:cochlear nucleus (may be absent in normals).

•

III:superiorolive.

•

IV:lateral lemniscus (may be absent in normals).

•

V:inferior colliculus (should be 50% or more of wave I’s amplitude).

•

VI:medial geniculate (too variable for regular clinicaluse).

•

VII:auditory thalamocortical radiation (too variable for regular

clinicaluse).

Latency I– V (central conduction time) should be no more than 4.75ms.

The dierence between left and right central conduction times should be

<0.4ms.

III

RIGHT EAR

LEFT EAR

III

Fig.9.4 Brainstem auditory evoked potentials.

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CHAPTER9 Neurology

626

Uses

• Hearing assessment, especially in children.

• Evaluation in suspected MS and other myelinopathies (e.g.

adrenoleukodystrophy; MRI more importantnow).

•

Evaluation and detection of posterior fossa lesions (e.g. acoustic

neuromas; MRI more importantnow).

•

Evaluation of brainstem function (e.g. tumour,CVAs).

• Evaluation of brainstem function in coma and braindeath.

• Per- operative, e.g. acoustic neuroma excision.

Use ofevoked potentials inthe diagnosis ofmultiple

sclerosis

Traditionally, trimodal EPs (VEPs, SSEPs, and BAEPs) have been requested

to look for evidence of a disturbed conduction in multiple sensory systems.

Modern practice, however, is to request only VEPs, if any at all. MRI is much

more useful in demonstrated dissemination of CNS lesions.

Further reading

Blum AS, Rutkove SB (eds.). The clinical neurophysiology primer. Totowa:Humana Press,2007.

5 Polman CH, Reingold SC, Edan G, etal. Diagnostic criteria for multiple sclerosis:revisions to the

‘McDonald criteria’. Ann Neurol 2005; 58

:840– 6.

SENSORY EVOKED POTENTIALS OR RESPONSES

627

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CHAPTER9 Neurology

628

Transcranial magnetic stimulation

• Brief, high- current pulse produced in a circular or gure- of- eight- shaped

coil held over thescalp.

•

This induces a magnetic eld with ux perpendicular to thecoil.

• This, in turn, produces an electric eld perpendicular to the

magneticeld.

The result is excitation or inhibition of the subjacent cortex (depending on

stimulus parameters).

•

Transcranial magnetic stimulation (TMS) has been used for diagnostic

purposes in a number of ways, although as yet it is not in widespread

clinicaluse.

Measurement ofcentral motor conductiontime

• TMS over the motor cortex indirectly (presumably via synaptic

activation of corticospinal neurones) causes a volley of activity in the

corticospinal tracts. The latency of the EMG in, say, the abductor digiti

minimi may be measured.

•

May be used in cervical myelopathy and MS to show i latency of EMG

in hand muscles evoked by TMS over the motor cortex. If the EMG

latency to more distal stimulation (e.g. at C7 over the spinal cord and

in the ulnar nerve) is normal, then an i central motor conduction time

may be inferred.

•

Latency may also be i in other neurodegenerative conditions.

Motor evoked potentials

Abnormalities in the amplitude of motor evoked potentials (MEP) may

reect abnormalities anywhere in the pathway from the motor cortex to

the muscles.

Silentperiod

• If a subject maintains muscle contraction and a single suprathreshold

TMS pulse is applied to the contralateral motor cortex, ongoing EMG

activity ceases for a few hundred milliseconds after the MEP (the ‘silent

period’).

•

Silent period may be long in, e.g. stroke, MS, spinal cord injury.

• Silent period may be short in, e.g. MND,PD.

Interhemispheric conduction

• Interhemispheric inhibition may be d in MS orMND.

•

It may be absent following lesions to the corpus callosum.

Motor cortex excitability

• High thresholds may be seen in strokeorMS.

• Low thresholds and i intracortical inhibition may be seen inMND.

•

d intracortical inhibition may be seeninPD.

TRANSCRANIAL MAGNETIC STIMULATION

629

Psychogenic limb weakness

Some authorities have used TMS to evoke muscle activity in ‘paralysed’

limbs in patients with psychogenic paralysis. This needs to be done in the

context of a ‘holistic’ approach to the patient, aimed at dealing with any

psychological pathology.

Potential clinical applications

There have been many TMS studies, some that may prove useful as clinical

tests,e.g.

•

Determination of lateralization of language function by repetitive TMS

(rTMS) prior to surgery for epilepsy.

•

Assessment of cortical excitability in certain epilepsy syndromes.

• Assessment of d intracortical inhibition in dystonia.

•

Assessment of recovery from stroke.

Further reading

Currà A, Modugno N, Inghilleri M, Manfredi M, Hallett M, Berardelli A. Transcranial magnetic stimula-

tion techniques in clinical investigation. Neurology 2002; 59

:1851– 9.

Kobayashi M, Pascuel- Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol 2003;

:145– 56.

6 Devlin JT, Watkins KE. Stimulating language:insights from TMS. Brain 2007; 130:610– 22.

630

CHAPTER9 Neurology

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Neurological investigation

ofsphincter disturbance

Electromyogram

• Of pelvic oor muscles may be helpful in faecal incontinence, stress

urinary incontinence, and cauda equina syndrome.

•

Pelvic oor and sphincter muscle EMGs may reect pudendal nerve

damage.

•

Anal sphincter EMG abnormalities may reect damage to Onuf ’s

nucleus, e.g. in multi- system atrophy. It is characteristically unaected

inMND.

Magnetic resonance imaging

• In suspected sacral spinal cord, conus medullaris, and equina lesions.

Urodynamics

Flowmetry

•

Measurement of rate and amount of urine ow overtime.

• Allows calculation of parameters such as time to maximal ow,

maximum and mean ow rate, and volume voided.

•

Post- micturition US can determine residual volume.

Cystometry (needs urinary catheterization)

•

Measurement of intravesicular pressure during lling (usually at 50mL/

min) or emptying. Typically, bladder lling sensation starts at about

100mL and the bladder is full at 400– 600mL (with no more than

15cmH

O rise in pressure). Detrusor instability may cause sharp rises in

pressure during lling.

•

During voiding, ow rate should be >15mL/ min (♂) or >20mL/ min

(♀) with pressures of <50cmH

O (♂) or 30cmH

O(♀).

Further reading

Fowler CJ. Investigational techniques. Eur Urol 1998; 34(Suppl):10– 12.

Panicker JN, Fowler CJ. The bare essentials:uro- neurology. Pract Neurol 2010; 10:178– 85.

AMOBARBITAL (WADA) TEST

631

Edrophonium (Tensilon

)test

Procedure

• Explain the test to the patient.

• Select weak and/ or fatiguable muscles to be assessed.

• Attach an ECG monitor.

• Draw up 0.6mg of atropine (for use if extreme bradycardia develops),

10mg of edrophonium in 5mL of normal saline (A), 5mL of normal

saline (B), and salineush.

•

Administer 1mL of the test solution (A or B, ideally patient and

administrating physician should be blinded to the nature of the solution).

•

If no adverse reaction, administer the remaining4mL.

• Repeat with the other solution (BorA).

Note: if the diagnosis of MG is clinically obvious, and the patient has

responded to pyridostigmine given empirically, there is little point in stop-

ping this and performing an edrophoniumtest.

Interpretation

• In MG, there should be a response within 30– 60s, which should wear

o in 2– 4min.

• There may be a response in LEMS, polymyositis, andMND.

Amobarbital (Wada)test

Amobarbital is injected into the right or left internal carotid artery. It is a

short- acting barbiturate that temporarily causes hemispheric dysfunction

on the injected side. If injected into the left in most right- handers, the abil-

ity to speak and continue to hold up the right arm is temporally impaired.

If speech is preserved following right- sided injection, it suggests normal

left lateralization for language function. More complex testing may also be

undertaken during the period of hemispheric dysfunction, but it is usually

used to determine language dominance prior to certain neurosurgical pro-

cedures. Increasingly, non- invasive techniques, such as fMRI, are being used

in place of the Wadatest.

Further reading

Wagner K, Hader C, Metternich B, Buschmann F, Schwarzwald R, Schulze- Bonhage A. Who needs

a Wada test? Present clinical indications for amobarbital procedures. J Neurol Neurosurg Psychiatry

2012; 83

:503– 9.

632

CHAPTER9 Neurology

632

Biopsies

• Always liaise with those taking the biopsy and those processingit!

• Abiopsy should be undertaken to answer specic questions, in light of

a dierential diagnosis formulated following history, examination, and

other investigations.

Skeletalmuscle

Indications

•

° muscle disease, e.g. metabolic myopathy, polymyositis, muscular

dystrophy.

•

Neurogenic atrophy.

• Mitochondrial cytopathies (even in the absence of clinical muscle

involvement).

•

Multi- organ disease, e.g. vasculitides.

Which muscle tobiopsy?

•

An involved, but not end- stage, muscle.

• One that has not been used for EMG recording or had an injection for

>1month.

•

Quadriceps and deltoid oftenused.

Open or needle biopsy?

Openbiopsy

•

Larger specimen.

• Can x specimen at in situ length.

•

Especially for inammatory myopathy and in vasculitis.

Needlebiopsy

•

Smallerscar.

• Multiple biopsies possible.

• However:

•

Smaller biopsies.

•

Diculties in orientating the sample.

What may be done tothe tissue?

•

Routine histology.

• Examination of small blood vessels.

• Histochemistry.

• EM.

• Tests of muscle metabolism.

• Mitochondrial DNA studies.

Nerve

Indications

•

Distinction between segmental demyelination and axonal degeneration

(if not already determined).

•

Certain neuropathies with characteristic histological features, e.g. due to

amyloid deposition, sarcoid, vasculitis, neoplastic involvement.

•

Certain myelinopathies (e.g. leukodystrophies) with peripheral nervous

system (PNS) and CNS involvement.

BIOPSIES

633

Which nerve tobiopsy?

•

The cutaneous branch of the sural nerve at the ankle (usually).

• Supercial peroneal (sometimes).

• Supercial radial (occasionally).

• Occasionally, small motor nerve twigs are obtained in muscle biopsy.

• Overlying skin may be co- biopsied.

What isdone?

•

2– 3cm of full- thickness nerve or fascicle.

What may be done tothe tissue?

•

Routine light microscopy (morphometry, structural survey; amyloidosis).

• Frozen section light microscopy (immunochemistry).

• EM (ultrastructure).

• Teased out single bres (to examine sequential myelin internodes).

Brain/ meningealbiopsy

Indications

•

Diagnosis and management of suspected ° and some metastatic brain

tumours.

•

Dierential diagnosis of other mass lesions (inammatory and infective).

• Dierentiation of radiation necrosis and tumour regrowth.

• Dierentiation of neoplastic and non- neoplastic cysts (and their

drainage).

•

Diagnostic biopsy of a suspected infectious lesion that has not

responded to a trial of therapy.

•

Diagnosis of cerebral vasculitis or vasculopathy.

What isdone?

•

High- quality cranial CT/ MRI, possibly with contrast, to delineate the

lesion.

•

If no discrete lesion, generally an area of non- dominant, non- eloquent

cerebrum istaken.

•

Stereotactic needle biopsy with image guidance:

•

Deep, small lesions in ‘eloquent’areas.

•

Multiple biopsies along the needle track (useful in heterogeneous

lesions such as some gliomas).

•

And/ or open biopsy:

•

Accessible lesions.

•

When resection considered during procedure.

• Intra- operative evaluation of frozen samples:

•

For example, can a biopsy bemade?

•

For example, is the sample adequate?

Note:caution in suspectedCJD!!

Skin

• Some storage diseases:

•

Laforabody.

•

Batten’s disease.

• Mitochondrial cytopathies.

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CHAPTER9 Neurology

634

Bonemarrow

• Niemann– Pick typeC.

• Haematological and other malignancies.

Rectal and appendicectomy

• Most neuronal storage diseases aect the autonomic nervous system, so

evidence can be sought in neurones of the gut’s intrinsicplexi.

•

Amyloid in rectal biopsy.

Tonsillarbiopsy

• Research tool invCJD.

OLIGOCLONALBANDS

635

Oligoclonalbands

• Electrophoresis of serum and CSF separates protein components by

size and charge.

•

OCBs may be present in serum and CSF. Bands in the CSF not seen in

the serum suggest intrathecal- specic synthesis ofIgs.

• This pattern is seen in most (95%) cases of established MS but may also

occur in other conditions such as chronic meningitis, neurosyphilis, SSPE,

and neurosarcoid (although uncommonly).

Further reading

Thompson EJ. Cerebrospinal uid. In:RAC Hughes (ed.). Neurological Investigations. London:BMJ

Publications, 1997; pp.443– 66.

636

CHAPTER9 Neurology

636

Diagnostic and prognostic antibodies,

and other markers inblood andurine

Multi- system disorders

PNS and CNS are aected in many multi- system disorders; markers in blood

and other uids and tissues for these are therefore commonly requested in

neurology patients.

Vasculitides,e.g.

•

ENAs inSLE.

• ANCA in Wegener’s.

• RFinRA.

Enteropathies,e.g.

•

Gliadin and endomysial antibodies in coeliac disease.

Systemic infections,e.g.

•

Serology for many diseases, e.g. Borrelia in Lyme disease,HIV.

• PCR forTB.

Disorders ofcoagulation:thrombophilia screen currently commonly includes

•

Protein S and C levels.

• Antithrombin III levels.

• Screening for the Leiden mutation in factorV.

• Lupus anticoagulant.

• Tumour markers,e.g.

•

carcinoembryonic antigen (CEA) for gut neoplasia.

•

Serum and urinary paraproteins in haematological disorders like

myeloma.

Sarcoid

•

ACE and ACE genotype.

Endocrinopathies,e.g.

•

TSH, FT4, and FT3, thyroid autoantibodies in thyroid dysfunction.

Other metabolic disorders,e.g.

•

Wilson’s disease:blood copper and caeruloplasmin; some authorities

also request 24h urinary copper excretion. Note:slit lamp examination

performed by an experienced ophthalmologist reveals Kayser– Fleischer

rings in most cases of Wilson’s disease with neurological involvement.

•

Phaeochromocytoma:catecholamine metabolites in three 24h urine

collections.

Disease- specic markers

• MG:anti- ACh receptor and muscle- specic kinase (MuSK) antibodies.

• Neuromyelitis optica:aquaporin 4 and MOG antibodies

DIAGNOSTIC & PROGNOSTIC ANTIBODIES

637

Paraneoplastic antibodies

Certain neurological syndromes are ‘paraneoplastic’, i.e. due to remote,

but non- metastatic, eects of non- nervous system cancers. These paraneo-

plastic syndromes are rare, but important to recognize. In perhaps 50% of

cases, the neurological symptoms may predate those of the cancer. This is

an area of intensive research. Antibody tests that are well described include

those in Table9.7.

Most of these paraneoplastic antibodies target intracellular antigens and

are not thought to be pathogenic in themselves. Increasingly, autoantibod-

ies to antigens on the surface of neurones or glia are being recognized and

associated with clinical syndromes (see Table 9.8). Such antibodies may

be directly pathogenic. Recognizing clinical syndromes associated with

these cell surface- directed antibodies is important, as many respond to

immunotherapies.

Table9.7 Paraneoplastic antibodies

Antibody Paraneoplastic syndrome Associated tumour

Anti- Hu (ANNA1) Encephalomyelitis

Sensory neuronopathy

Cerebellar degeneration

Chronic GI pseudo- obstruction

Limbic encephalitis

Small- cell lung cancer

(SCLC)

Anti- Yo (PCA1) Cerebellar degeneration Breast, ovary

Anti- Ri (ANNA2) Brainstem encephalitis Breast, SCLC

CV2 (CRMP5) Encephalomyelitis

Chorea

Sensory neuronopathy

Sensorimotor neuropathy

Cerebellar degeneration

Limbic encephalitis

Chronic GI pseudo- obstruction

Thymoma, SCLC

Anti- Ma2 (Ta) Limbic/ diencephalic encephalitis

Cerebellar degeneration

Brainstem encephalitis

Testis, lung

Anti- amphiphysin Sti person syndrome

Other syndromes

Breast, SCLC

CAR Retinopathy Breast, SCLC

Tr Cerebellar ataxia

Hodgkin’s

638

CHAPTER9 Neurology

638

Further reading

Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr Opin Neurol 2012; 25:795– 801.

Graus F, Delattre JY, Antoine JC, etal. Recommended diagnostic criteria for paraneoplastic neuro-

logical syndromes. J Neurol Neurosurg Psychiat 2004; 75

:1135– 40.

Honnorat J, Antoine J- C. Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2007;2:22.

Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody

associated syndromes:review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012;

:638– 45.

Table9.8 Neuronal surface antibody antibodies

Antibody Syndrome Associated tumour

NMDAR Encephalitis; dyskinesia;

psychiatric presentation;

epilepsy

Ovarian teratoma

LGI1 Limbic encephalitis Rare

CASPR2 Limbic encephalitis

Morvan’s syndrome

Lung, breast, thymus

GABA

R Limbic encephalomyelitis

Prominent seizures

SCLC

mGluR5 Limbic encephalitis

Orphelia syndrome

Hodgkin’s lymphoma

GlyR Progressive encephalomyelitis

with rigidity and myoclonus

Thymoma

VGCC Cerebellar ataxia SCLC

mGluR1 Cerebellar ataxia

Hodgkin’s lymphoma

DIAGNOSTIC & PROGNOSTIC ANTIBODIES

639

640

CHAPTER9 Neurology

640

Biochemical markers

Many ‘inborn errors of metabolism’ cause neurological disease. Avariety of

investigations, including tests on blood, urine, and CSF, biopsies, and genetic

analyses, are used in their diagnosis (E Diagnostic and prognostic antibod-

ies, and other markers in blood and urine, pp. 636–8; E Genetic tests,

pp. 642–5; for an accessible review, see Gray etal.).

Biochemicaltests

Some basic principles

Many autosomal recessive and X- linked metabolic diseases are caused by

reduced or absent activity of a specic enzyme, in turn due to a single gene

defect.

In some, there is a tissue- specic decit

For example, McArdle’s (glycogen storage disease V) demonstrates the

absence of phosphorylase activity in muscle biopsy (as only the myophos-

phorylase isozyme is aected).

In other conditions, notably thelipidoses, theenzyme is decient inmany

tissues

For example, in Niemann– Pick diseases Aand B, sphingomyelinase is de-

cient in the brain and spinal cord, but also in the GIT, liver, spleen, and BM.

Abnormal lipid metabolism can therefore be demonstrated in relatively eas-

ily accessible tissue such as broblasts.

Not only may the absence or lower activity of an enzyme reduce the

amount of product of the reaction it catalyses, but it may also lead to the

accumulation of precursors in the metabolic pathway:

A—(1) l B—(2) l C—(3) l D

If enzyme (3)is reduced, A, B, and C may accumulate, withlower levels ofD

than usual being produced

•

For example, in acute intermittent porphyria, there is i urinary

excretion of d heme aminolevulinic acid and porphobilinogen

(intermediates in the haem synthetic pathway) during an acute attack.

•

d levels of porphobilinogen deaminase may be demonstrated in

erythrocytes, leucocytes, and cultured broblasts.

7 Gray RG, Preece MA, Green SH, Whitehouse W, Winer J, Green A. Inborn errors of metabolism

as a cause of neurological disease in adults:an approach to investigation. J Neurol Neurosurg Psychiat

2000; 69

:5– 12.

BIOCHEMICAL MARKERS

641

Ischaemic forearm exercise test (ischaemic lactatetest)

Procedure

1. Rest the patient supine for30min.

2. Draw a baseline lactate sample from a catheter in an antecubitalvein.

3. Inate the sphygmomanometer cu on that arm to above arterial

pressure.

4. Subject squeezes a rubber ball in that hand until exhaustion.

5. Rapidly deate thecu.

6. Take further venous samples at 30, 60, and240s.

Results

Normally the venous lactate will rise by 2- , 3- , or even 4- fold; if it fails to rise

by 1.5- fold, then there is likely to be a glycogenolysis or glycolysis defect (or

the patient has not exercised suciently!).

642

CHAPTER9 Neurology

642

Genetictests

The list of diseases for which we have specic genetic tests grows each

month. Rather than give a necessarily incomplete compendium, we discuss

some general principles.

Several important neurological conditions may today be diagnosed by

(relatively) simple genetic tests, whereas in the past biopsy was necessary.

For example, Duchenne, Becker, and oculopharyngeal muscular dystro-

phies are associated with well- dened genetic abnormalities. Similarly, sev-

eral mitochondrial cytopathies (such as myoclonic epilepsy and ragged red

bres (MERRF) and mitochondrial myopathy, lactic acidosis, and stroke- like

episodes (MELAS)) may now often be diagnosed by nding common muta-

tions or deletions in mitochondrialDNA.

When might a neurologist refer toa clinical geneticist?

• Genetic counselling of an index patient and his family.

• Cytogenetic or molecular diagnosis.

• Long- term follow- up of family:

•

Notication of advances.

•

Counselling family members as they becomeadult.

•

Coordinating care with paediatric and adult neurologists.

Cytogenetics:whentodoit

• ♀ with an X- linked disorder.

• Unexplained developmentaldelay.

• Unexplained major CNS malformation.

• The coexistence of two genetic diseases in a patient.

What isdone?

•

Conventional karyotype.

• FISH for suspected submicroscopic chromosomal aberrations, e.g. a

p13.3 deletion may cause lissencephaly.

Molecular genetics:whentodoit

• Conrming a clinical diagnosis.

• Identify carriers in the family.

What isdone?

An ever i range of diseases may be tested for. Some of these tests may

be routinely available at your local clinical genetics laboratory, others at

regional, national, or even supranational centres. Other tests may be avail-

able on a ‘research’ basis. It is clear, however, that tests for genetic ‘lesions’

or risk factors will become increasingly available. Rather than give an, at

best, partial list of readily available tests, we give a few examples below of

the kinds of tests that are available. The astute reader will spot that dierent

mutations within a given gene can give rise to dierent clinical phenotypes.

Indeed, recent work has shown that the same mutation in some genes can

give rise to >1 phenotype— we clearly have a great deal yet to learn about

the genetics of neurological diseases!

GENETICTESTS

643

Detection ofdeletions

•

For example, in mitochondrial (mt)DNA in MELAS andMERRF.

• For example, of dystrophin gene in Duchenne and Becker muscular

dystrophies.

Detection ofDNA rearrangement

•

For example, PMP22 gene duplication in some cases of Charcot– Marie–

Tooth disease type 1 (or hereditary motor sensory neuropathy type 1

(HMSN1); deletions within this gene cause hereditary neuropathy with

liability to pressure palsies (HNPP).

Detection oftrinucleotide repeats

•

Found in >10 neurological diseases (see Table9.9).

• So far, there is no overlap in the number of repeats in controls and

aected patients (except rarely in Huntington’s, in the region of 33– 36

repeats).

•

Anticipation (more severe phenotype and earlier onset) often reects

in i number of repeats in the most recent generations (especially

myotonic dystrophy).

Detection ofsingle base mutations

This involves fragmenting the DNA of the gene into manageable pieces,

then amplifying these so that there are multiple copies. Subsequently, vari-

ous methods may be used to detect fragments with abnormal sequences,

even if only diering at a single base from the ‘wild- type’. There are sev-

eral such techniques, constantly being rened, and many are restricted to

research laboratories.

Table9.9 Some trinucleotide repeat diseases

Disease Gene Triplet repeats Transmission

Fragile X FMR1 CGG

X- linked

Myotonic dystrophy DM CTG AD

Friedreich’s ataxia FRDA GAA AR

Spinobulbar muscular

atrophy

Androgen

receptor

CAG

X- linked

Huntington’s disease IT15 CAG AD

Spinocerebellar atrophy

•

SCA1

• SCA2

• SCA3

• SCA6

• SCA 7

SCA1

SCA2

SCA3

SCA6

SCA 7

CAG

Dentarubropallidoluysian

atrophy

DRPLA CAG AD

AD, autosomal dominant; AR, autosomal recessive.

Note:SCA 6 is a CAG triplet expansion in the CACNL1A4

calcium channel gene. Other (non-

triplet repeat) mutations in the gene cause other conditions— episodic ataxia type 2 and familial

hemiplegic migraine.

644

CHAPTER9 Neurology

644

• However, molecular genetics is proceeding at a tremendous pace, both

in terms of the number of conditions with identied genetic lesions and

the laboratory techniques for analysis.

•

High- speed DNA sequencing will facilitate sequencing large pieces

ofDNA.

•

For example, point mutations in the MPZ gene, which encodes P0, a

component of the myelin sheath, have been found in some families with

Charcot– Marie– Tooth disease type1B.

Genetic risk factors

Another area of clinical genetics which is likely to become more important

is the detection of genetic ‘risk factors’ for diseases. Certain allelic variants,

whilst not ‘causing’ a disease in the traditional sense, may predispose an

individual to exhibiting a certain clinical phenotype or alter the age at which

it might become apparent.

For example, there are three allelic variants in the apolipoprotein E

(APOE4

) gene e2, e3, and e4. Homozygosity for e4 is likely to be a risk

factor for developing Alzheimer’s disease and for developing it at an earlier

age. However, the majority of e4 homozygotes do not develop the condi-

tion (therefore, it is not ‘causative’).

Detection ofthe presence ofabnormal protein or altered

levels ofnormal protein

Immunocytochemistry and immunoblotting (western blots) on tissue sam-

ples from the patient allow direct visualization of the presence of abnormal

protein or the absence or reduced levels of normal protein, in a variety of

conditions. (These techniques are not genetic in the strictest sense but are

often useful in ‘genetic’ conditions.)

For example, Duchenne and Becker muscular dystrophies have absent or

reduced levels of dystrophin in muscle biopsy samples.

Whole genome sequencing

With developments in technology and informatics, it is becoming increas-

ingly feasible (in terms of both cost and time) to sequence the entire genome

of individuals. Whole genome sequencing has resulted in the detection of

rare pathogenic mutations and the determination of genetic risk factors

The 100,000 Genomes Project was established in 2012 and aims to

sequence 100,000 whole genomes from NHS (England) patients with rare

diseases, their families, and patients with cancer (M http:// www.genomic-

sengland.co.uk/ the- 100000- genomes- project/ ).

Useful website

Online Mendelian Inheritance in Man (OMIM) is a continually updated cata-

logue of ‘genetic’ diseases in man, giving data about the genotype, mode

of inheritance, and clinical phenotype of thousands of disorders (not just

neurological).

GENETICTESTS

645

Further reading

Manolio TA. Genome- wide association studies and the risk of disease. N Engl J Med 2010;

363

:166– 76.

Online Mendelian Inheritance in Man. M https:// www.omim.org/ .

Young AB. Huntington’s disease and other trinucleotide repeat disorders. In:JB Martin (ed.). Scientic

American Molecular Neurology

. NewYork:Scientic American, 1998; pp.35– 54.

646

CHAPTER9 Neurology

646

Neuro- otology

Pure tone audiometry

• Measures the threshold for air (AC) and bone conduction (BC) at

frequencies from 250 to 8000Hz.

Typical patterns

•

Conduction deafness:BC > AC at all frequencies.

• Sensorineural deafness:AC=BC at all frequencies, but i deafness as

the frequencyrises.

More specializedtests

• Tonedecay.

• Loudness discomfort.

• Speech audiometry.

• Acoustic impedance.

Caloric testing

Procedure

1. Inspect the eardrum; if intact, proceed.

2. Place the patient supine with the neck exed 30° (on pillow).

3. Irrigate the external auditory meatus with 30°C water (ice water if

testing for brain death).

4. Observe for (or record*) nystagmus.

5. Repeat after 5min with 44°Cwater.

Note:(*) there are various techniques for recording eye movements that are

available in specialized clinical and research laboratories.

What shouldhappen

1. Cold water induces convection of uid in the ipsilateral lateral

semicircular canal (LSCC).

2. There is less output from the ipsilateralLSCC.

3. Imbalance of signals from the two LSCCs results in eye drift towards

the irrigatedear.

4. Fast- phase contraversive movements correct for eye drift (hence,

nystamus with the fast phase away from the irrigatedear).

5. This nystagmus starts in about 20s and persists for1min.

6. Warm water reverses the nystagmus.

Common pathological responses

Canal paresis

1. Reduced duration of nystagmus following irrigation on one side (with

cold or warm water).

2. Suggests ipsilateral peripheral or central lesion.

NEURO-OTOLOGY

647

Directional preponderance

1. Prolonged nystagmus in one direction.

2. Suggests a central lesion on the side of preponderance or contralateral

peripheral lesion.

Combination of clinical examination, audiometry, and caloric testing of the

vestibulo- ocular reex will help localize a lesion (peripheral vs central; left

vs right).

Brainstem auditory evoked responses

E Sensory evoked potentials or responses, Brainstem auditory evoked

potentials (BAEPs, BAERs, BSAEPs), pp. 624–6.

Further reading

Brandt T, Dieterich M, Strupp M. Vertigo and Dizziness, 2nd edn. London:Springer,2014.

648

649

Chapter10

Renal medicine

Estimation of kidney function 650

Classication of kidney disease 654

Assessment of proteinuria 658

Assessment of renal tubular function 662

Assessment of acid– base balance 664

Assessment of urinary acidication 668

Plasma potassium 670

Urine potassium, chloride, and magnesium measurements 672

Urine sodium concentration 674

Urine dipstick testing 676

Urine culture 680

Urine microscopy 684

Investigations in patients with renal or bladder stones 686

Renal biopsy 688

Renal imaging 690

Renal bone disease 694

Immunological tests in renal medicine 696

650

CHAPTER10 Renal medicine

650

Estimation ofkidney function

Estimates based onserum creatinine

Measurement of serum creatinine concentration is the most commonly

used way of assessing the excretory function of the kidneys, which is mostly

dependent on the glomerular ltration rate (GFR). Creatinine is the non-

enzymatic breakdown product of creatine and phosphocreatine (almost

exclusively found in skeletal muscle). Its production rate is proportional

to muscle mass— the average individual produces around 10mmol/ day.

Endogenous production of creatinine is usually constant, but ingestion of

cooked meat and severe exercise cause a rapid, temporary rise in produc-

tion of creatinine, and thus in creatinine concentration. It is excreted mainly

by glomerular ltration, but tubular secretion of creatinine also occurs and

contributes a signicant proportion of overall excretion when GFR falls,

resulting in overestimation of the GFR at low GFR. Drugs, e.g. cimetidine,

trimethoprim, can block the secretory component and elevate serum cre-

atinine without any change in trueGFR.

Because of the reciprocal relationship between clearance and serum cre-

atinine, serum creatinine does not rise outside the normal range until there

has been a substantial fall in GFR, particularly in patients with low muscle

mass (see Fig. 10.1). However, in an individual patient, a progressive i in

serum creatinine over time, even within the normal range, indicates declin-

ing GFR. Wide variation between individuals based on muscle mass, sex,

and age makes serum creatinine an imperfect screening test for renal failure.

Estimation of 24h urine creatinine excretion allows measurement of CrC

but is beset with diculties largely related to the timing and completeness

of urine collections. For these reasons, use of CrC in clinical practice has

been superseded by the use of prediction formulae.

The 4- variable Modication ofDiet inRenal

Disease formula

The GFR may be estimated by the 4- variable Modication of Diet in Renal

Disease (MDRD) formula. This is the simplest of several formulae derived

from the MDRD data set and gives an estimate of the GFR normalized to a

body surface area of 1.73m

eGFR (mL/min/1.73m

)

= 175 × {[serum creatinine (mmol/L)/88.4]

−1.154

} × age (years)

−0.203

× 0.742 if ♀ and

× 1.21 if Afro-Caribbean

This formula does not give an accurate estimate of the GFR at extremes of

muscle mass, including amputees, and is not validated in the paediatric pop-

ulation. Most laboratories in the UK now measure creatinine with an assay

calibrated to an isotope dilution mass spectrometry (IDMS) standard and

are able to report an eGFR, alongside creatinine results, using this formula.

2 Where the laboratory reports a value for the eGFR, this should be

used, rather than any value subsequently derived.

651

ESTIMATION OFKIDNEY FUNCTION

The formula previously used a constant of 186, rather than 175, as it was

developed using a creatinine assay that gave higher values than the IDMS

standard; it remains important to check which assay is being used before

using this or any other formula to estimate theGFR.

1300

1200

1100

1000

900

800

700

600

500

400

300

200

100

GFR

140100100 1301201109080706050403020

: daily creatinine production 15mmoL

: daily creatinine production 10mmoL

: daily creatinine production 5mmoL

Fig.10.1 Creatinine production is dependent on muscle mass, which varies widely.

Graph illustrates the theoretical relationship between the GFR and plasma creatinine,

ignoring the eects of tubular secretion of creatinine, which results in overestimation

of the GFR from plasma creatinine or measurement of CrC. Note that in a patient

with low muscle mass, creatinine does not rise outside the normal range until the

GFR has fallen to <30mL/ min, whereas a patient with higher muscle mass will reach

the same level of creatinine at a GFR of 90mL/ min.

652

CHAPTER10 Renal medicine

652

The Cockcroft and Gault formula and other estimates

ofeGFR

The Cockroft and Gault formula gives an estimate of CrC, using age,

weight, and serum creatinine as input variables. For simplicity of reporting,

because weight is not required and because the MDRD formula gives an

estimate of the GFR, which is normalized to the body surface area (and thus

gives an estimate of how well kidney function is matched to body size), the

MDRD formula is now preferred.

CrC = (({[140 – age (years)] × weight (kg)}/serum creatinine

(mmol/L)))

× 1.23 if ♂ or

× 1.04 if ♀

E See M

http:// ckdepi.org/ equations/ creatinine- based- equations/ for a

discussion of these and other formulae.

Where estimation of the GFR is made, the formula used should be

stated. There are important dierences between the two estimates, par-

ticularly as the GFR declines at extremes of body size, but either formula is

a major advance on the use of serum creatininealone.

CKD- EPI

The CKD- EPI (Chronic Kidney Disease Epidemiology Collaboration) equa-

tion gives a more accurate estimation of the GFR in patients with normal or

near- normal renal function than the MDRD. The result is that fewer peo-

ple with near- normal GFR are misclassied as having CKD and, as a result,

treated as ‘high risk’ for cardiovascular outcomes, based on theireGFR.

eGFR = 141 × min(SCr/κ, 1)

× max(SCr/κ, 1)

−1.209

× 0.993

Age

× 1.018 if ♂

× 1.159 if black

where SCr (standardized serum creatinine)=mg/ dL

κ=0.7 if ♂ or 0.9 if♀,and

α=−0.329 if ♂ or −0.411if♀

min indicates the minimum of S

/ κ or1,and

max indicates the maximum of S

/ κor1.

ESTIMATION OFKIDNEY FUNCTION

653

654

CHAPTER10 Renal medicine

654

Classiﬁcation ofkidney disease

The following classication of chronic kidney disease (CKD) is now com-

monly used in the UK and is based on the Kidney Disease Improving Global

Outcomes (KDIGO) classication.

Independently of the eGFR, the degree

of albuminuria has been shown to be a strong predictor of cardiovascular

mortality, progression of CKD, and acute kidney injury (AKI), and for these

reasons, a measure of albuminuria was added to the original CKD classica-

tion in2012.

•

CKD G1:normal GFR; GFR >90mL/ min/ 1.73m

with other evidence of

chronic kidney damage.*

•

CKD G2:mild d in GFR; GFR 60– 89mL/ min/ 1.73m

with other

evidence of chronic kidney damage.*

Note:(*) other evidence of CKD may include persistent microalbuminuria,

proteinuria, or glomerular haematuria, structural abnormalities, including

renal scarring and polycystic disease, and biopsy- proven chronic glomeru-

lonephritis. An eGFR of >60 in the absence of other evidence of kidney

damage should be considered normal.

•

CKD G3a:moderate d in GFR 45– 59mL/ min/ 1.73m

•

CKD G3b:moderate d in GFR 30– 44mL/ min/ 1.73m

•

CKD G4:severe d in GFR 15– 29mL/ min/ 1.73m

•

CKD G5:established renal failure (ERF) GFR <15mL/ min/ 1.73m

or on

dialysis.

The staging for albuminuria quantication is then added as follows:

• A1— albumin:creatinine ratio (ACR) <3mg/ mmol.

• A2— ACR 3– 30mg/ mmol.

• A3— ACR ≥30mg/ mmol.

Using this staging system, a person with an eGFR of 48mL/ min/ 1.73m

and

an ACR of 25mg/ mmol has CKD stage G3a,A2.

Classication of CKD in this way allows identication of those with

severe disease in need of specialist assessment and can be used to guide

BP targets and frequency of monitoring in those with less severe disease.

Serumurea

Urea is the product of protein catabolism in the liver. Production is i by

high protein intake, catabolic states, breakdown of blood in the gut lumen

in GI bleeding, and tetracycline treatment, and may d in liver disease. Urea

is freely ltered at the glomerulus, with variable reabsorption, which is

inuenced by extracellular volume status. Intravascular volume depletion,

diuretics, CCF, GI bleeding, tetracyclines, and renal failure cause elevated

levels. Disproportionate rise in serum urea, compared to creatinine, occurs

in hypovolaemia and GI bleeding. Reduced levels are seen in chronic liver

disease and alcohol abuse. By itself, serum urea is a very poor marker of

excretory kidney function.

1 KDIGO. Guidelines. M http:// kdigo.org/ guidelines/ .

National Institute for Health and Care Excellence (2014). Chronic kidney disease in adults:assess-

ment and management. Clinical guideline CG182. M

https:// www.nice.org.uk/ guidance/ cg182.

CLASSIFICATION OFKIDNEY DISEASE

655

CystatinC

Cystatin C, a 13kDa protein of the cystatin superfamily of cysteine protease

inhibitors, is produced by all nucleated cells at a relatively constant rate and

excreted nearly exclusively by glomerular ltration. It can be assayed using

ecient enzyme- linked immunoassays. Multiple studies have shown that

cystatin C is probably a more sensitive and specic marker than creatinine

for assessing impaired excretory renal function. Minor reductions in GFR

cause cystatin C concentrations to rise above normal, even when serum

creatinine is still within normal range. Cystatin C- based estimation of the

GFR is now recommended by NICE for conrmatory testing in patients

with an eGFR

creatinine

of 45– 59mL/ min/ 1.73/ m

with no other evidence

ofCKD.

Measurement ofglomerular ltrationrate

Occasionally, it is necessary to measure renal excretory function accurately,

e.g. in clinical research:

•

When using drugs with a narrow therapeutic index and which are

excreted by the kidney.

•

When accurate measurement of kidney function is required in patients

with abnormal muscle mass, e.g. paraplegics with bilateral lower limb

muscle wasting.

The ‘gold standard’ for measurement of the GFR is measurement of inu-

lin clearance (see Fig. 10.2); inulin is freely ltered, not protein- bound, and

not reabsorbed or secreted. However, measurement of inulin is not widely

available as a routine laboratorytest.

Radionuclide studies

Radionuclide studies are contraindicated during pregnancy; women of

childbearing age should have a −ve pregnancy test before proceeding with

thetest.

A variety of radioisotope markers are available for estimating the GFR.

An ideal marker should be safe, not be extensively protein- bound, be freely

ltered, not be secreted or reabsorbed in the renal tubule, and be excreted

only by the kidney.

•

The commonly used markers are

Cr EDTA,

99m

Tc DTPA (diethylenetri-

aminepentaacetic acid), iohexol, and

125

I iothalamate. Iothalamate is also

available without radiolabelling and can be measured by uorimetry.

•

These substances are injected IV and after allowing for equilibration,

plasma levels are measured at predetermined intervals. Plasma

clearance, and hence renal elimination, is calculated from the rate of fall

of the concentration of the substance in the bloodstream.

•

Cr EDTA has been the most extensively studied marker and is

extensively used in Europe as a single injection technique followed by

plasma sampling at 0, 90, 120, 150, and 240min.

Cr EDTA is reliable,

even at low levels of renal function. Studies in humans suggest renal

clearance estimated by this method is 710% lower than that of inulin.

656

CHAPTER10 Renal medicine

656

•

125

I iothalamate is only slightly protein- bound, and studies suggest

clearance values similar to that of inulin. Unlike other markers, it

can also be administered SC, and this allows for slow equilibration

with stable plasma concentrations. It is considered safe, but potential

problems of thyroid uptake necessitate pre- treatment with oral iodine.

•

99m

Tc DTPA is used in renal isotope scanning, which allows anatomical

correlation to renal function such as information on relative uptake by

each kidney.

99m

Tc has a very short half- life, and radiation exposure is

minimized. Protein binding can result in diminished renal clearance.

± 2 SD

100

80604020101

180

160

140

120

100

insulin

(mL/min/1.73m

)

Age (years)

Fig.10.2 GFR, measured by inulin clearance (C

inulin

), in apparently healthy individuals

according toage.

CLASSIFICATION OFKIDNEY DISEASE

657

658

CHAPTER10 Renal medicine

658

Assessment ofproteinuria

Proteinuria may result from i glomerular permeability or tubular disease,

causing d reabsorption of ltered protein or i excretion of tubular enzymes.

Glomerular proteinuria is commoner and more likely to signal potentially

progressive kidney damage. Disease states inuence the absolute amount of

protein excreted, so protein excretion should be assessed either by meas-

urement of excretion over 24h (the ‘gold standard’, but highly inconvenient)

or after correction for the degree of urine concentration. Because total daily

urine creatinine excretion is constant, the ACR ratio or protein:creatinine

ratio (PCrR) in the urine can allow correction for urine concentration.

Although dipstick tests are useful, they can be misleading, with false +ve

(concentrated urine) and false −ve (dilute urine) results. Assuming an aver-

age creatinine production of 10mmol/ day, a PCrR of mg/ mmol allows esti-

mation of the daily protein excretion as 10 × mg/ 24h. Greater precision can

be gained by the use of prediction equations for creatinine excretion (see

http:// ckdepi.org/ equations/ creatinine- excretion/ ), but this is not yet

standard practice.

Indications forquantitation ofproteinuria

Diagnosis ofnephrotic syndrome

Nephrotic syndrome is dened as triad of oedema, hypoalbuminaemia, and

proteinuria

>3g/ 24h (or urine PCrR >3mg/ mmol). Hyperlipidaemia is also

commonly present.

Prognosis ofprogressive renal disease

Proteinuria is one of the most potent risk markers for progressive loss

of renal function in renal disease, e.g. diabetic nephropathy, chronic glo-

merulonephritis, and reux nephropathy. In addition, treatments that

reduce proteinuria (e.g. antihypertensive drugs, particularly ACE inhibitors

and angiotensin II receptor blockers (ARBs)) d the rate of progression.

Presence of signicant proteinuria should result in adoption of lower BP

targets and preferential use of ACE inhibitors or ARB drugs. Because reduc-

tion of proteinuria is an important therapeutic aim, regular assessment of

the severity of proteinuria is also important in monitoring the eects of

treatment. Annual measurement of the ACR is now recommended in the

UK for all patients with CKD stages3– 5.

Diagnosis ofearly diabetic nephropathy

Diabetic nephropathy is mostly treatable in its early stages— characterized by

an i in GFR, i albumin excretion, and then hypertension. ‘Microalbuminuria’

is the term for pathologically i albumin excretion below the limit of detec-

tion of standard dipstick tests for proteinuria. Microalbuminuria without

diabetic retinopathy should raise suspicion of non- diabetic kidney disease.

ASSESSMENT OFPROTEINURIA

659

Quantitation ofproteinuria

Urine protein and creatinine concentrations should be measured in an EMU

sample (because protein excretion i with activity).

Detection of proteinuria in glomerular disease should be by ACR. This

allows for detection of proteinuria, and thus CKD, at lower levels of protein

excretion than either reagent strips or PCrR. Microalbuminuria is present if

urine ACR is 2.5mg/ mmol (in ♂) or >3.5mg/ mmol (in ♀) in repeated sam-

ples. Reagent strip testing for albuminuria is not recommended, although

strips that detect, and even quantify, microalbuminuria are now available.

Measurement of total protein in urine is cheap but does not dierentiate

between the various proteins present in urine. Proteinuria with >30mg/

mmol creatinine is usually dened as pathological, but patients with early

diabetic nephropathy have total protein excretions below this limit, hence

the preferred use of ACR in the identication of early renal disease.

Although less sensitive than ACR at detection of low levels of proteinuria

and less precise at all degrees of proteinuria, PCrR can still be used for

quantication and monitoring of established proteinuric renal disease if

ACR cannot be used for reasons ofcost.

Diagnosis ofpostural proteinuria

Protein excretion i with activity and upright posture. For reasons that are

not completely understood, this i is exaggerated in some individuals, result-

ing in +ve dipstick tests for proteinuria and even i 24h urine protein excre-

tion. This ‘postural proteinuria’ has a nearly completely benign prognosis.

In patients with proteinuria who have no other evidence of renal disease,

it is worth quantifying proteinuria separately in urine collected whilst the

patient has been recumbent overnight and in a daytime specimen. This can

be done by measuring ACR on both EMU and a sample taken after a period

of activity. Normal protein excretion during the night with i protein excre-

tion during the day indicates postural proteinuria.

Assessment oftubular proteinuria

This is occasionally of value to detect the relatively low- grade proteinuria

that results from tubular disease, e.g. Dent’s disease (a rare genetic disorder

caused by mutation in a tubular chloride channel), which causes calcium stone

formation and tubular proteinuria. Other examples include screening for gen-

eralized tubular dysfunction and for drug toxicity, e.g. during treatment with

platinum derivatives. Tubular proteinuria is best diagnosed by measurement

of specic proteins whose presence in the urine results from tubular disease,

e.g. retinol- binding protein (RBP), N- acetyl- D- glucosaminidase (NAG) or β2-

microglobulin, either in 24h urine specimens or as ratios between the protein

concentration and creatinine concentration.

3 National Institute for Health and Care Excellence (2008). Chronic kidney disease:early identication

and management of chronic kidney disease in adults in primary and secondary care. Clinical guideline

CG73. M

http:// www.nice.org.uk/ Guidance/ CG73.

660

CHAPTER10 Renal medicine

660

Assessment ofselectivity ofproteinuria

The more severe the damage to glomerular permeability, the larger the

protein molecules that pass through the glomerulus in glomerular disease.

Measurement of the ratio of clearance of transferrin or albumin (a small

molecule) to IgG (a large molecule) can therefore be used as a measure of

selectivity and is calculated as follows:

Albumin/IgG clearance = {(urine [IgG] × serum [albu-min])/

(serum IgG × urine [albumin])} × 100%

Transferrin/ IgG clearance is calculated similarly.

A ratio of <0.16 indicates highly selective proteinuria.

In children, minimal change nephropathy causes selective proteinuria.

Non- selective proteinuria raises the possibility of an alternative type of renal

disease and might lead to a recommendation of renal biopsy to avoid ster-

oid treatment when this would be unlikely to be of benet. Measurement of

selectivity in adults rarely inuences clinical decision- making.

Detection and quantitation ofurinary light chains (Bence– Jones protein)

Detection of urinary light chains (BJP) is useful in the initial diagnosis of

multiple myeloma. Quantication of Bence– Jones proteinuria as a marker

of disease activity during treatment has been superseded by measurement

of serum free light chains.

ASSESSMENT OFPROTEINURIA

661

662

CHAPTER10 Renal medicine

662

Assessment ofrenal tubular function

There are two main types of renal tubular diseases:those due to a single

defect, usually genetic, in solute secretion or reabsorption, and those due

to generalized tubular damage.

Screening tests forgeneralized tubular dysfunction:testfor

• Renal glycosuria:dipstick or laboratory test for glucose in urine plus

normal plasma glucose.

•

Hypophosphataemia:can be followed by estimation of phosphate

reabsorption (E Assessment of phosphate reabsorption, pp. 662–3).

•

Low- molecular- weight proteinuria:due to failure of tubular reabsorption

plus i release of proteins derived from tubularcells.

•

Normal anion gap metabolic acidosis:serum bicarbonate, plus sodium,

potassium, and chloride to permit calculation of the anion gap (followed

by tests to conrm RTA; E Assessment of urinary acidication,

pp. 668–9).

•

Aminoaciduria:detected by amino acid electrophoresis on a random

urine sample.

•

Hypouricaemia:plasma urate may be low due to d tubular reabsorption.

(This can be followed by measurement of fractional urate excretion;

E Assessment of renal urate handling, p. 663.)

Assessment ofphosphate reabsorption

This is occasionally useful in the dierential diagnosis of hypophosphatae-

mia, e.g. in conrming the diagnosis of X- linked hypophosphataemic rickets.

This can be calculated using a 24h urine collection for phosphate or more

easily using a spot fasting urine sample and serumtest.

Procedure

•

The patient is asked to fast overnight.

• The overnight urine is discarded.

• The next urine sample is obtained for phosphate and creatinine,

together with a blood sample for urea, creatinine, and phosphate.

•

Both are analysed for phosphate and creatinine.

Fractional phosphate excretion is calculatedas

PO4

= C

= [serum creatinine × urine phosphate]/

[urine creatinine × serum phosphate]

This is the fraction of ltered phosphate, which appears in theurine.

Fractional tubular reabsorption ofphosphate (TRP) is calculatedas

1 – FE

PO4

TmP/ GFR, the tubular maximum for phosphate reabsorption, can be read

o a nomogram

or can be calculated as follows:

4 Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration.

Lancet 1975; ii:309– 10.

ASSESSMENT OFRENAL TUBULAR FUNCTION

663

If TRP<0.86,

TmP/GFR = TRP × plasma phosphate

If TRP>0.86,

TmP = {0.3 × TRP/[1 – (0.8 × TRP)]} × plasma phosphate

Interpretation

The adult reference range for TmP/ GFR is 0.80– 1.35mmol/ L with dened

age- and sex- specic values. Higher values of normal are seen in infancy

and childhood.

Low values are seen in X- linked hypophosphataemic rick-

ets and osteogenic osteomalacia, both of which are thought to be due to

overproduction or failure of inactivation of phosphatonins (a group of

phosphaturic hormones, including FGF- 23 and FRP4). TmP/ GFR is raised

in hypoparathyroidism and reduced in hyperparathyroidism and by PTH-

related peptide secretion.

Reduced phosphate reabsorption may also be seen in hypercalciuric

stone formers, but it remains dicult to be certain whether this is the °

disorder, causing i

production of 1,25- (OH)

vitamin D, or 2° to tubular

damage as a result of renal stones.

Reduced phosphate reabsorption is also seen in a number of ° and 2°

disorders of renal tubular function.

Assessment oftubular urate handling

The relative contributions of production rate, glomerular ltration, pre-

secretory reabsorption, secretion, and post- secretory reabsorption to

control plasma urate concentration cannot be dissected out without com-

plex tests involving selective pharmacological blockade of some of these

processes. However, it is possible to determine whether an abnormal

plasma urate concentration is due to abnormal production or abnormal

renal handling.

The 24h urinary urate excretion is i in overproduction, but normal in

patients whose hyperuricaemia is due to d excretion. In the latter case,

urate excretion is normal, not d

, because in under- excretion, the steady

state is maintained at the expense of a raised plasma level. If 24h urinary

urate is raised, the collection should be repeated on a low purinediet.

Fractional excretion ofurate is calculatedas

{(urinary [urate] × plasma [creatinine])/(plasma [urate] × urinary

[creatinine])} × 100%

Normal values are dependent on age and sex, but in adults, they are of

the order of 10%. High fractional excretion is a cause of hypouricaemia in

SIADH and several other conditions; low fractional excretion occurs in °

gout, but also in a familial syndrome called uromodulin- associated kidney

disease or autosomal dominant tubulointerstitial kidney disease, comprising

hyperuricaemia with early- onset gout and progressive renal failure.

5 Payne RB. Renal tubular reabsorption of phosphate (TmP/ GFR):indications and interpretation.

Ann Clin Biochem 1998; 35:201– 6.

664

CHAPTER10 Renal medicine

664

Assessment ofacid– base balance

Plasma HCO

−

and Cl

−

are the two major anions in extracellular uid. The

major reason for measuring them is to assess acid– base status. Changes in

serum [HCO

−

] concentration reect changes in acid– base balance, with

a d in [HCO

−

] reecting metabolic acidosis and an i reecting alkalosis.

Plasma Cl

−

is helpful in assessing the cause of acidosis or alkalosis.

There is no justication at all for performing an arterial puncture to

measure arterial pH as part of the assessment of metabolic acidosis or

alkalosis— it can be adequately assessed from serum [HCO

−

]. Arterial

samples are needed when it is unclear whether the acid– base disturbance is

respiratory or metabolic in origin or in mixed disturbances.

Plasma bicarbonate

The most reliable way to interpret plasma HCO

−

is to use the acid– base

diagram (see Fig. 10.3), which allows assessment of how much the change

in [HCO

−

] concentration is due to changes in CO

excretion via the lungs

and how much to changes in [H

] or HCO

−

wasting. In the absence of sig-

nicant respiratory disease, it can often safely be assumed that any change

is due to metabolic causes, in which case low plasma HCO

−

indicates i

production (or occasionally i HCO

−

loss) and vice versa. If ABGs are

obtained, the ‘standard bicarbonate’ is a calculated value which indicates

what the plasma HCO

−

would be if CO

excretion were normal and is thus

a way of allowing assessment of whether there is a metabolic component

to an abnormal HCO

−

concentration or whether it is solely due to the

respiratory disturbance.

Remember that the kidneys compensate for respiratory disease and

the lungs for metabolic disease; for instance, metabolic acidosis causes

hyperventilation, resulting in lower P

and lessening the acidosis seen.

However, overcompensation does notoccur.

Plasma chloride

Many laboratories omit plasma Cl

−

assays from ‘routine’ serum chemistry

measurements, but this measurement is helpful if a systemic acid– base dis-

turbance is suspected. As a useful over- simplication, low HCO

−

with high

−

can be seen as accumulation of hydrochloric acid, which can only result

from altered renal handling of acid, as in RTA. If HCO

−

is low with a nor-

mal or low Cl

−

, some other acid must be accumulating. More precision in

deciding the cause of metabolic acidosis can be obtained by calculating the

aniongap.

The aniongap

The anion gap is the dierence between the sum of the concentrations of

the positively charged ions routinely measured in plasma and the negatively

chargedions:

Anion gap = ([Na

] + [K

]) – ([Cl

–

] + [HCO

–

])

Obviously, the total +ve charges in plasma must be balanced by the same

number of −ve charges. The normal anion gap is caused by the fact that

there are more unmeasured anions in plasma (mostly albumin, but including

ASSESSMENT OFACID–BASE BALANCE

665

lactate, sulfate, and others) than cations (including calcium and magnesium).

The concentrations of all of these unmeasured ions can vary, so the normal

range for the anion gap is wide, e.g. hypoalbuminaemia reduces the anion

gap by 2.5mEq per 1g/ dL fall in serum albumin.

The main use of calculation of the anion gap is in the dierential diagnosis

of metabolic acidosis.

A high anion gap acidosis is caused byan abnormally high concentration ofan

unmeasured anion, suchas

•

Acute or chronic renal dysfunction.

• L- lactate (reecting anaerobic metabolism or hepatic dysfunction).

• Salicylate (in aspirin poisoning).

• Chronic paracetamol use at therapeutic doses in malnourished

patients through the accumulation of pyroglutamic acid (also called

5- oxoproline).

• β- hydroxybutyrate (inDKA).

• Glycolate and oxalate (in methanol poisoning).

• Hippurate (in toluene poisoning, e.g. glue sning).

• D- lactate (from gut bacterial fermentation in blind loop syndrome).

Metabolic

Acute respiratory

Chronic respiratory

Arterial PCO

mmHg

]

nmol/L

08642

070605040302010

100

110

120

7.6

7.1

7.0

6.0

7.2

7.3

7.4

7.5

Fig.10.3 Acid– base diagram.

666

CHAPTER10 Renal medicine

666

A normal anion gap acidosis may be caused byloss ofbicarbonate or failure

ofrenal H

excretion, forinstance

•

RTA.

• High ileostomy losses (bicarbonate wasting).

• Carbonic anhydrase inhibitors.

• Urinary diversions, e.g. ureterosigmoidostomy (Cl

−

/ HCO

−

) exchange

and NH

reabsorption in the colonic segment).

2 Beware

:in North America, the anion gap is usually calculated as [Na

] −

{[Cl

−

] + [HCO

−

]}, not including [K

] in the measured cations. This results

in a lower reference range for the anion gap. In addition, dierent labora-

tories use dierent assays for Cl

−

. For these reasons, the local laboratory

reference range for the anion gap should beused.

In general, the anion gap is only useful when very high, conrming high

concentrations of an unmeasured anion. If the diagnosis is not already obvi-

ous, this then justies further investigation, including assay of plasma lactate

concentration.

ASSESSMENT OFACID–BASE BALANCE

667

668

CHAPTER10 Renal medicine

668

Assessment ofurinary acidiﬁcation

Indications

• Unexplained hyperchloraemic metabolic acidosis.

Defects in the kidneys’ ability to excrete acid in the urine may lead to perma-

nent systemic acidosis, or to systemic acidosis at times of i acid generation,

depending on the severity of the defect. Acidication defects may occur as

part of generalized tubular disease or as isolated, often genetically deter-

mined, alterations in function, most commonly of cell surface ionpumps.

Ammonium chloride loadingtest

This test is regarded as the ‘gold standard’ for the diagnosis of distal (‘type 1’)

RTA where there is impaired excretion of ‘xed acid’ into the distal tubule.

Procedure

•

The patient attends after an overnight fast but is allowed to drinkwater.

• At the start of the test, a urine sample is sent to the laboratory

for measurement of pH, and a plasma or serum sample is sent for

measurement of HCO

−

. Because pH changes rapidly in urine exposed

to air, the urine container should be lled to the top or the urine sent in

a stoppered syringe and sent to the laboratory without anydelay.

•

If the urine pH is <5.4, this indicates normal acidifying ability, and there

is no need to continue with thetest.

•

If the venous blood HCO

−

is low, with a urine pH of >5.4, the

diagnosis of RTA is conrmed.

• If neither of these conditions is met, then proceed to give the patient

ammonium chloride, 0.1g/ kg body weight. Ammonium chloride is given

as capsules, is unpalatable, and frequently causes nausea and vomiting,

but this can be reduced if the capsules are taken slowly or with bread

and honey. Even if the patient vomits, it is worth proceeding with the

test, as acidosis is often achieved; no more ammonium chloride should

begiven.

•

Urine samples are then collected hourly for the next 6– 8h and sent,

protected from the air (as above), for pH analysis in the laboratory. If

any sample has a pH of <5.4, the test can be stopped, as this indicates

normal acidifying ability of the distal tubule.

•

At 3h after ingestion of ammonium chloride, a venous sample should

be sent for plasma HCO

−

measurement to ensure that acidaemia has

occurred.

Alternative tests ofdistal acidication

Rationale

The distal tubule reabsorbs Na

in exchange for H

. Furosemide, by i deliv-

ery of Na

to the distal tubule, therefore causes a fall in urine pH, particu-

larly in ‘salt- avid’ states produced by Na

restriction or udrocortisone.

6 Walsh SB, Shirley DG, Wrong OM, Unwin RJ. Urinary acidication assessed by simultaneous

furosemide and udrocortisone treatment:an alternative to ammonium chloride. Kidney Int 2007;

:1310– 16.

ASSESSMENT OFURINARY ACIDIFICATION

669

Procedure

•

No need to fast or uid- restrict.

• Collect a baseline urine sample forpH.

• Administer furosemide 40mg and udrocortisone 1mg orally.

• Collect urine for pH measurement hourly for 4h or until urine pH<5.3.

• Urine pH persistently >5.3 at 4h implies distalRTA.

Bicarbonate infusiontest

This is the ‘gold standard’ for the diagnosis of proximal (‘type 2’) RTA,

which is characterized by impaired HCO

−

reabsorption. In this condition,

urine pH may be <5.5 in untreated patients, because at steady state, serum

HCO

−

levels fall to the point at which ltered HCO

−

is reabsorbed and

distal acidication mechanisms are intact.

Procedure

•

Sodium bicarbonate is infused IV at 0.5– 1.0mmol/ kg/ h. After 60min,

plasma bicarbonate is measured to conrm that this has risen to

>20mmol/ L. Urine pH is measured hourly and urine HCO

−

measured

to allow calculation of the fractional excretion ofHCO

−

HCO3

= {(urine [HCO

−]) × plasma [creatinine]}/(plasma [HCO

−]

× urine [creatinine]) ×100%

• Fractional excretion of HCO

−

is normally<15%.

•

Alevel of >20% conrms type2RTA.

670

CHAPTER10 Renal medicine

670

Plasma potassium

Although most of the body’s K

is intracellular, small changes in extracel-

lular K

concentration can cause major changes in membrane excitability.

Hypokalaemia causes i excitability, causing atrial and ventricular cardiac

arrhythmias; hyperkalaemia d excitability, causing a characteristic pattern

of ECG changes and eventually causing asystole. Both hypokalaemia and

hyperkalaemia may be associated with skeletal muscle paralysis.

Plasma K

concentration is inuenced both by distribution across cell

membranes and by the balance between intake and excretion. Renal excre-

tion is dependent on renal function, urine ow rate, and aldosterone.

Pseudohyperkalaemia

Caused by excessive release of K

from cells after venepuncture and should

be considered when hyperkalaemia ‘does not t’ with the clinical picture.

The laboratory should report the presence of visible haemolysis (usually

due to RBC trauma during dicult venepuncture), but pseudohyperkalae-

mia can also occur in the absence of visible haemolysis,e.g.:

•

Haematological malignancies causing a high white cell or platelet count,

e.g. chronic lymphatic leukaemia.

•

Other causes of leucocytosis and thrombocytosis, e.g. leukaemoid

reactions,RhA.

•

Familial pseudohyperkalaemia:rare disorder of RBC cation transport

leading to an i rate of release of K

from red cells at low temperatures,

associated with stomatocytosis.

Diagnosis can be conrmed by showing that plasma [K

] is normal in

a heparinized sample analysed immediately and then by demonstrat-

ing that delayed separation results in higher values being obtained.

Pseudohyperkalaemia with a normal WBC and platelet count can be fur-

ther investigated by measuring the rate of rise of plasma [K

] in samples

incubated at 37°C and 22°C, and studying the eects of drugs that aect

cation exchange, e.g. thiazide diuretics and quinine. Artefactual hyperkalae-

mia can be caused by st clenching plus a venous tourniquet during phle-

botomy; plasma K

can rise by as much as 2mmol/ L.

Hyperkalaemia due toredistribution acrosscell

membranes

Hyperkalaemic periodic paralysis is an autosomal dominant genetic mus-

cle disorder caused by mutations in the voltage- gated sodium channel

SCN4A. It presents in early infancy with attacks of paralysis associated with

hyperkalaemia.

Other causes ofrelease ofpotassium fromtissues (including muscle) include

•

Exercise.

• Acidosis (particularly inorganic acidosis).

• Muscle damage (rhabdomyolysis), e.g. crush injury, revascularization of

ischaemic limb, prolonged unconsciousness following drug intoxication.

•

Burns.

PLASMA POTASSIUM

671

• Tumour lysis, e.g. after initiation of chemotherapy for haematological

malignancy.

•

Drugs, e.g. digoxin, depolarizing muscle relaxants, β- blockers.

• Malignant hyperthermia.

Hyperkalaemia due toaltered external balance

• i ingestion is seldom able to cause hyperkalaemia on its own but can

contribute to hyperkalaemia when combined with impaired excretion of

a K

load.

•

d excretion may be due to d GFR, d urine ow rate, d aldosterone

production, drugs which inhibit renal tubular K

excretion, or genetic

defects in renal K

excretion (pseudohypoaldosteronism, Liddle’s

syndrome).

•

In most cases, the cause is obvious.

Investigation ofunexplained hyperkalaemia

• Serum creatinine, CK,HCO

−

•

Urine K

is of limited utility because urinary K

excretion is primarily

determined by, and roughly equal to, K

intake.

•

Tests for type IVRTA:

•

Normal Synacthen

test (to exclude Addison’s disease).

•

24h urinary aldosterone (low in type IVRTA).

•

Plasma renin and aldosterone response to upright posture and

40mg furosemide (subnormal levels of both suggest hyporeninaemic

hypoaldosteronism).

•

Correction of hyperkalaemia with oral udrocortisone 0.1mg/ day.

Pseudohypokalaemia

Can be caused by delayed separation of samples kept at warm ambient

temperatures and is caused by continued uptake of K

into cells. This occurs

more in heparinized samples than in those allowed toclot.

Hypokalaemia due toredistribution acrosscell membranes

• Alkalosis.

• Insulin treatment.

• β2- adrenergic stimulation (e.g. high- dose nebulizers).

• B

therapyofPA.

•

Rapid cell division, e.g. acute leukaemia.

• Hypokalaemic periodic paralysis. Mutations in the CANCL1A3 and

SCN4A voltage- gated ion channels can lead to this rare condition.

Carbohydrate intake or rest after exercise typically precipitates

hypokalaemia.

•

Conrm diagnosis (under strict supervision) by infusing 2g/ kg glu-

cose and 0.1U/ kg insulin; consider referral for mutation analysis of

relevant ion channels.

•

Consider thyrotoxic hypokalaemic periodic paralysis in non- familial

patients, particularly of oriental background; checkTFTs.

Hypokalaemia due toincreased renalloss

E Chapter2.

672

CHAPTER10 Renal medicine

672

Urine potassium, chloride, and

magnesium measurements

Urine potassium

Measurement of urine K

concentration is occasionally useful in the dif-

ferential diagnosis of hyperkalaemia. The proportion of K

ltered at the

glomerulus which is excreted in the urine is extremely variable and is modu-

lated by the distal tubule in response to aldosterone, plasma K

concen-

tration, acid– base balance, urine ow rate, Na

status, and other factors.

The nal concentration of K

in the urine also depends on urine dilution,

controlled independently by factors (e.g. ADH) controlling water excretion.

Low urinary K

(<20mmol/ L) withhypokalaemia is seenin

• GI K

loss, e.g. diarrhoea, laxative abuse, villous adenoma, high

ileostomy output, enterocutaneous stula, ureterosigmoidostomy.

•

Dietary deciency

• Skin losses, e.g. burns, severe eczema.

High urinary K

(>20mmol/ L) withhypokalaemia and normal blood pressure

is seenin

•

Vomiting (K

is exchanged for hydrogen ions:acid– base preservation

takes precedence). Note:urinary Cl

−

will below.

•

Diuretic use, abuse, and conditions which mimic diuretic use, e.g.

Bartter’s syndrome, Gitelman’s syndrome.

•

Tubular damage causing K

wasting, e.g. RTA types 1and2.

• DKA.

High urinary K

(>20mmol/ L) withhypokalaemia and high blood pressure is

seenin

•

Hyperaldosteronism:adrenal adenomas, bilateral adrenal hyperplasia.

•

Apparent mineralocorticoid excess.

• Liddle’s syndrome.

Urine chloride

This measurement is helpful in the dierential diagnosis of otherwise unex-

plained normotensive hypokalaemia. Urine Cl

−

is low if hypokalaemia is

being caused by extrarenal sodium chloride or hydrogen chloride losses,

as seen in diarrhoea or vomiting, respectively. In these conditions, K

exchanged in the distal tubule for Na

or hydrogen, respectively, but Cl

−

conserved. Urine Cl

−

is high when the cause of hypokalaemia is inappropri-

ate loss of potassium chloride, as in diuretic use and in Bartter’s syndrome

(the genetic equivalent of being on permanent high- dose loop diuretics)

and Gitelman’s syndrome (the genetic equivalent of being on permanent

high- dose thiazide diuretics).

The distinction between drug- induced and genetic causes can be very

dicult to make, but temporary withdrawal from diuretics causes intense

−

retention and a very low urine Cl

−

concentration, which is never seen

in Bartter’s or Gitelman’s syndromes. Repeated measurements of urine Cl

−

are therefore helpful in this situation, together with screens for the presence

of diuretics in the urine when urine Cl

−

ishigh.

673

URINE POTASSIUM, CHLORIDE, & MAGNESIUM MEASUREMENTS

Urine magnesium

This measurement can be helpful in identifying the cause of hypomagne-

saemia by distinguishing inappropriate tubular Mg

loss (e.g. from diuretics,

aminoglycosides, Gitelman’s syndrome) from GI Mg

loss (e.g. from diar-

rhoea, proton pump inhibitoruse).

= {(urine [Mg

] × plasma [creatinine])/((0.7 × (plasma [Mg

])

× urine [creatinine])} × 100%

Plasma Mg

is multiplied by 0.7, as only 70% of Mg

is non- albumin- bound

and thus freely ltered.

Fractional Mg

excretion of >2% in a subject with normal renal function

indicates renal Mg

loss.

674

CHAPTER10 Renal medicine

674

Urine sodium concentration

In health, serum electrolyte concentrations are kept constant because intake

of electrolytes is balanced by excretion in the faeces and urine. Renal excre-

tion is tightly regulated to achieve this balance. These basic principles imply

that the urinary excretion of, for instance, Na

, is nearly totally dependent

on dietary intake of Na

. Because this is very variable, there is no ‘normal

range’ of urine Na

, or any other urinary electrolyte. Measurements of uri-

nary electrolytes therefore have to be interpreted with great caution.

The 24h urine Na

excretion is a good marker at steady state for

dietary intake and has been used in epidemiological studies of the rela-

tionship of salt intake to BP. Dietary Na

intake varies from as little as

10mmol/ day in the Amazon rainforest to >400mmol/ day in Westerners

living on processed foods. Current UK advice is to restrict Na

intake to

around 100mmol/ day.

In clinical practice, there are several reasons formeasuring

output, including

• Calcium stone formers:Na

and Ca

excretion are linked, and reduction

of excessive salt intake results in a reduction in Ca

excretion.

•

Cystine stone formers:similarly, cystine excretion is reduced by reduction

of dietary salt intake.

•

During antihypertensive and antiproteinuric treatment:salt restriction

amplies the eects of ACE inhibitors in reducing not only systemic BP,

but also protein excretion in renal disease, and may be more tolerable

than diuretic treatment.

The 24h urine Na

is usually measured on a sample collected in a plain

container. However, it can also be measured, by ame photometry, in a

sample collected into an acid container, and this is useful if Ca

and oxalate

excretion are also being measured, for instance in stone formers.

Spot urine Na

concentration is of very limited value, because Na

excre-

tion varies considerably through the day and because it is normally inu-

enced by urine dilution, and hence by recent water intake. However, there

are two situations in which it may be ofvalue.

Acute kidneyinjury

The normal response of the kidneys to underperfusion from hypovolaemia

or hypotension is to retain salt avidly, urine Na

concentration dropping to

<10mmol/ L. If urinary Na

concentration is this low in AKI, this indicates

normal ability of the renal tubules to retain salt. Low urine Na

concentra-

tion is seen in ‘pre- renal’ renal failure; ATN results in loss of tubular salt

reabsorption and a higher urine Na

concentration. The problem is that

some conditions other than underperfusion can cause low urine Na

(e.g.

contrast nephropathy, rhabdomyolysis). High urine Na

does not neces-

sarily indicate ATN; indeed, it is seen in normal people. In any case, the

measurement seldom has a useful impact on management, which both in

pre- renal failure and in ATN is to restore renal perfusion by correcting

hypovolaemia, hypotension, and sepsis as quickly as possible.

URINE SODIUM CONCENTRATION

675

Syndrome ofinappropriate antidiuretic hormone

This diagnosis cannot be made in a hypovolaemic patient, because hypo-

volaemia is a physiological stimulus to ADH secretion. For this rea-

son, the diagnosis cannot be made if the urine Na

concentration is low

Hyponatraemia (including syndrome of inappropriate antidiuretic hor-

mone), pp. 139–40).

Fractional excretion ofsodium is calculatedas

{(urine [Na

] × plasma [creatinine])/(plasma [sodium] × urine

[creatinine])} × 100%

This gives an index of avidity of Na

reabsorption independent of changes

in overall renal function. An FE

of <1% is seen in pre- renal failure and of

>1% in ATN. However, this measurement is prone to some of the same

criticisms as that of urine Na

excretion.

Sodium- wasting and sodium- retainingstates

wasting is caused by diuretics, Bartter’s syndrome, Gitelman’s syn-

drome, and occasionally renal tubular disease. It cannot be diagnosed by

measurement of urine Na

excretion alone, as at steady state, this equals

intake, but is diagnosed by nding clinical evidence of hypovolaemia

without avid renal Na

retention.

retention is caused by diseases causing eective hypovolaemia (e.g.

CCF), in which case the diagnosis is suggested by oedema and the clini-

cal signs of the underlying disease. However, Na

retention can also cause

hypertension without oedema, as in hyperaldosteronism, pseudohyperal-

dosteronism, chronic renal failure, and inherited disorders of renal tubular

excretion (e.g. Liddle’s syndrome). Again, measurement of Na

excre-

tion alone is not helpful in the diagnosis of these conditions.

676

CHAPTER10 Renal medicine

676

Urine dipstick testing

Urine analysis has been used for many years for screening patients with

potential renal disease and for serial assessment of patients with known

renal pathology. However, the results of dipstick testing are dependent on

urine dilution and, for this reason, laboratory measurement of the ACR is

the preferred screening test for proteinuria. Reagent strips should only be

used for the detection of microalbuminuria if they are specically capable

of detecting low concentrations of albumin and expressing the result as

anACR.

Many commercially available dipsticks rapidly test the urine for multiple

chemical contents. The sticks use reagent strips, which change colour fol-

lowing a chemical reaction with an active constituent, depending on the

presence (or absence) of a particular component.

Depending onthe type ofdipstick used,

urine can be testedfor

• pH.

• Protein.

• Albumin.

• Hb.

• Glucose.

• Leucocyte esterases and nitrites.

• Specic gravity.

• Ketones.

• Urobilinogen.

The reagent strip is fully immersed in urine obtained by voiding or, if a 1%

risk of iatrogenic urine infection is warranted, by urethral catheterization,

and the excess shaken o. The change in colour, if any, is read after the time

specied by the manufacturer— usually30s.

Dipstick testing only gives a rough estimate of the pH, because of the

eects of storage and reaction on exposure to atmospheric air on urine

pH in vitro. The dipstick contains a polyionic polymer bound with H

, which

is released on reaction with the cations in urine. Release of H

causes a

change in colour of a pH- sensitive dye. Normal pH varies between 4.5 and

8.0, depending on the diet; vegetarians, in whom xed acid ingestion is low,

commonly have alkaline urine. Urine infection with urease- producing organ-

isms also causes alkalineurine.

Urine pH >5.5 in spite of metabolic acidosis is seen in RTA. Urine pH is

important in some recurrent stone formers. For instance, uric acid solubil-

ity in urine is critically dependent on urine pH, and many uric acid stone

formers are found to have normal 24h urinary urate, but highly acidic and

concentrated urine (e.g. as a result of high losses from an ileostomy). In

patients with triple phosphate stones, alkaline urine is commonly seen due

to infection with urea- splitting organisms.

URINE DIPSTICK TESTING

677

Protein

Binding of proteins to the dye indicators is highly pH- dependent, and the

indicators undergo a sequential colour change based on the concentra-

tion of protein in the sample. Albumin binds at a pH of 5– 8 and has the

highest anity, so most commercially available dipsticks almost exclusively

detect albumin. Dipsticks are thus cheap and reliable, and give rapid, semi-

quantitative assessment of proteinuric renal disease. However, these tests

measure the concentration of protein, rather than absolute excretion; false

−ve tests are therefore possible in dilute urine caused by a high uid intake,

and false +ve tests may be obtained in highly concentrated urine. At pH <5

or >8, results obtained by dipsticks are not accurate. Ig light chains (BJP) do

not result in +ve dipstick tests for proteinuria, even when present in high

concentrations. Sticks able to detect low concentrations of albumin and give

a ‘near patient’ quantication of ACR are available, but not in universaluse.

Haemoglobin

Reagent strips use peroxidase- like activity of Hb to induce a colour change

in a dye linked to organic peroxide. This reaction does not distinguish hae-

moglobinuria from erythrocyturia or from myoglobinuria. False +ve results

are obtained with myoglobin, contamination with menstrual blood, semen,

and iodine. Positive dipsticks for blood with absence of RBC on micros-

copy suggest lysis of RBCs due to prolonged storage, myoglobinuria, or

haemoglobinuria. False −ve results are seen with high- dose vitamin C and

captopril.

Glucose

Most strips use the glucose oxidase/ peroxidase method and can estimate

levels as low as 50mg/ dL. Ketones, salicylate, and ascorbic acid can inter-

fere with results. These strips estimate all reducing sugars, including fructose

and lactose. In the absence of concomitant hyperglycaemia, glycosuria is

suggestive of proximal tubular disorders or, rarely, reduced renal threshold

for glucose. When associated with glomerular disease, glycosuria with a

normal serum glucose may be a marker of worse prognosis. Drugs that

inhibit Na

- dependent glucose transport (the SGLT- 2 inhibitors) are now

available as novel hypoglycaemic drugs and act by causing renal glycosuria.

Leucocyte esterases and nitrites

The esterase method relies on esterases released from lysed WBCs.

Esterases release pyrroles, which react with a diazonium salt on the dip-

stick, resulting in a colour change. False +ve results are seen in vaginal con-

tamination and excessively dilute urine which favours cell lysis. Presence of

glucose, albumin, ketones, tetracyclines, and cephalosporins in the urine can

give false −ve results, along with a concentrated urine, which impedes the

release of esterases.

Most, but not all, uropathogenic bacteria convert nitrates to nitrites,

which react with a diazonium compound, resulting in a colour change. False

−ve results are due to frequent bladder emptying, prolonged external stor-

age, and ascorbic acid. Some bacteria, including Neisseria gonorrhoeae and

Mycobacterium tuberculosis, do not convert nitrates.

678

CHAPTER10 Renal medicine

678

Sensitivity and specicity of the above tests vary and are not useful for

screening low- risk populations. However, a −ve test is useful in excluding a

UTI in a patient with a high pretest probability of infection. Further guidance

on the diagnosis of UTIs is available at: M https:// www.gov.uk/ govern-

ment/ publications/ urinary- tract- infection- diagnosis.

Specic gravity

Dipstick testing for specic gravity (SG) is not accurate; non- ionic constitu-

ents, including albumin, glucose, and urea, are also estimated. Normal val-

ues are between 1003 and 1030 but vary with the patient’s hydration status,

and hence urinary concentration. SG d with age, as the kidney loses its con-

centrating ability. Fixed SG of 1010 is a variable feature of advancedCKD.

Ketones

Acetoacetic acid is detected by the nitroprusside test. Ascorbic acid results

in false +ve results. Dipsticks do not detect β

- hydroxybutyrate, which com-

prises the largest ketone fraction inblood.

URINE DIPSTICK TESTING

679

680

CHAPTER10 Renal medicine

680

Urine culture

There are numerous situations in which an accurate diagnosis of UTI is

important. ‘Sending an MSU’ is not, however, quite as simple as it sounds

and is not always the most appropriatetest.

Obtaining a midstream urinesample

The aim is to obtain a sample of bladder urine, avoiding contamination by

cells or organisms on the perineal skin. Men should retract the foreskin

prior to micturition; women should hold the labia well apart with the parted

ngers of one hand, to allow the urine to exit directly from the urethral

meatus. The patient should be asked to begin to pass urine and then, with-

out stopping passing urine, pass a sterile container into the path of the uri-

nary stream and collect a sample, before nishing passing urine normally. If

a sterile foil container has been used to catch the specimen, the specimen

is then transferred into a specimen container and sent to the laboratory.

Suprapubic aspiration ofurine

In patients suspected of having bladder infection, but in whom the results of

culture of MSUs are equivocal, it may be necessary to proceed to suprapu-

bic aspiration (widely performed in paediatrics, but not in adults). After skin

preparation, a ne needle (e.g. an LP needle) is introduced into the bladder

by direct puncture just above the symphysis pubis and urine is aspirated.

US can be used to conrm that the bladder is full prior to the procedure.

‘In– out’ catheter urine specimens

Although bladder catheterization carries a small (1– 2%) risk of introduc-

ing new infection into the bladder, this risk is sometimes justied by the

importance of obtaining urine direct from the bladder. Aurethral catheter

is passed into the bladder, the rst few millilitres discarded, and a sample

collected.

Obtaining urine specimens fromileal conduits

Urine in ileal conduit bags is always contaminated by skin organisms, and

the culture of ‘bag urine’ is not a useful way of diagnosing upper UTIs in

patients with conduits. In patients suspected of having an ascending infec-

tion, a urine specimen should be obtained by passing a catheter as far into

the conduit as it willgo.

‘Two glasstest’

This is a test for urethritis and is performed when a patient presents with

dysuria or urethral discharge and a sexual history suggesting a possible

recent infection. Culture of a urethral swab or of the urethral discharge

should also be obtained and sent for gonorrhoea testing (requires attend-

ance at a sexual health clinic). Two urine samples are collected— the rst

10mL passed and a midstream sample. Each is sent for culture; urethritis is

diagnosed when the bacterial count is highest in the rst sample. The rst

sample should also be sent for Chlamydia testing.

URINE CULTURE

681

‘Stamey– Mearestest’

This test is performed for the diagnosis of prostatitis. An MSU sample is

obtained, and then the patient is asked to stop passing urine. The pros-

tate gland is massaged per rectum, and ‘expressed prostatic secretions’

collected, followed by a nal urine sample. In prostatitis, bacterial counts

are higher in the expressed prostatic secretions or the post- massage urine

sample than in the midstream sample.

Indwelling catheter urine specimens

Colonization of the bladder is nearly inevitable within a fortnight of inser-

tion of an indwelling urethral or suprapubic catheter. Unnecessary antibiotic

treatment i

the selective pressure for the emergence of antibiotic- resistant

organisms and i the risk of antibiotic- associated diarrhoea and hospital-

acquired infection. Antibiotic therapy must therefore be reserved for symp-

tomatic infection. There is no point in sending catheter specimens, unless

there is a suspicion of symptomatic infection at the time. ‘Surveillance’ sam-

ples sent to predict which antibiotics should be used if the patient becomes

symptomatic at a later time are unjustied, because the colonizing organ-

isms may change over time. Afresh specimen of urine is obtained from the

collection port into the collection pot. Samples should NOT be collected

from the reservoir into which the catheter drains.

Localizationtests

• On rare occasions, it is justied to attempt to localize the site of

infection to the bladder or to one or other kidney.

•

The ‘gold standard’ is to obtain samples from each ureter and from the

bladder during rigid cystoscopy under general anaesthesia.

•

The ‘Fairley test’ requires passage of a urethral catheter followed by a

bladder washout with a wide- spectrum antibacterial and a brinolytic

enzyme. Sequential samples of urine are then obtained. If infection

is present in the upper tracts, this will not have been aected by the

bladder washout, and organisms will be detected in the rst specimen

obtained after the washout, whereas if infection was conned to the

bladder, subsequent samples will be sterile. This is now rarely used

in practice, as it involves inserting a catheter into an already infected

system and is labour- intensive.

• Infection may be conned to one or other kidney as a result of ureteric

obstruction or may be present within a renal cyst. In these situations,

direct aspiration of urine under US control in the radiology department

is necessary.

Microscopy and culture ofurine

Once a sample has been obtained, it is sent to a microbiology laboratory

for microscopy and culture.

Microscopy is required to assess pyuria (WBCs in the urine) and

contamination.

682

CHAPTER10 Renal medicine

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• Signicant pyuria indicates inammation within the urinary tract; if this

persists, despite −ve urine cultures, the patient has ‘sterile pyuria’,

for which there are a number of causes, including infection with an

organism which does not grow on conventional culture media, e.g.

Chlamydia.

•

Pyuria plus a +ve culture conrms the diagnosis ofUTI.

• The absence of pyuria makes a UTI less likely but can occur in the early

stages of infection or in the presence of a very high uid intake.

•

Contamination (in the ♀ ) is indicated by the presence of large numbers

of squamous cells, which usually come from the vaginal wall; however,

squamous cells can occasionally come from the bladder.

Culture and sensitivity are necessary to decide what treatment is necessary

and to dierentiate contamination of the urine sample by organisms outside

the bladder from true infection.

•

A‘pure growth’ of a single organism to >10

CFU/ mL is the

conventional criterion forUTI.

• However, low counts of 10

– 10

CFU/ mL can be associated with early

infection and should be taken seriously in the presence of suggestive

symptoms inwomen.

•

Low counts in men are likely to represent true infection, because

contamination is uncommon.

•

Genuine mixed growth may occur, in the presence of impaired urinary

drainage or a foreign body within the urinarytract.

URINE CULTURE

683

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CHAPTER10 Renal medicine

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Urine microscopy

Urine microscopy is a useful, quick, reliable, cheap, and underused

investigation— the ‘liquid renal biopsy’! Far more information can be

obtained by careful microscopy than is usually obtained in the microbiol-

ogy laboratory where the priority is detection of signicant urine infection.

Indications

• SuspectedUTI.

• Suspected acute glomerulonephritis.

• Suspected acute interstitial nephritis (requires staining for eosinophils).

• Unexplained acute or chronic renal failure.

• Haematuria (with or without proteinuria) on urine dipsticktest.

• Suspected urinary tract malignancy.

Procedure

A freshly voided, clean- catch, midstream early morning specimen is ideal.

The sample should be centrifuged and resuspended in a small volume.

Although bright eld microscopy will allow identication of most formed

elements in the urine sediment, phase contrast microscopy is useful for

detection of red cell ghosts, ‘glomerular’ red cells, and some other constitu-

ents. Staining of the urine sediment is not necessary for most purposes but

is useful for identication of eosinophils and malignant cells— this is usually

performed in the cytology laboratory.

Haematuria

RBCs appear as non- nucleated, biconcave discs. Even when urine is red

in colour or dipsticks +ve for blood, it should be examined for the pres-

ence of red cells. The dierential diagnosis of haematuria is broad, but it

is broadly classied into glomerular (renal) and infrarenal causes. Transit of

red cells through the renal tubules causes osmotic changes in their shape

and size; ‘dysmorphic’ or ‘crenated’ red cells are best seen using phase con-

trast microscopy and may be missed altogether if bright eld microscopy is

used. In experienced hands, detection of these glomerular red cells strongly

suggests a glomerular origin for haematuria, although failure to detect these

changes does not reliably indicate a lower urinary tract cause of bleeding—

heavy haematuria in IgA nephropathy, for instance, can result in large num-

bers of normal red cells in the urine. Urine pH, concentration, and storage

can aect red cell morphology.

Leukocyturia

The presence of signicant numbers of polymorphs (pyuria) in urine is

highly suggestive of UTI but can also occur in glomerulonephritis, interstitial

nephritis, and peri- ureteric inammation, for instance in acute appendicitis.

The presence of leucocyte casts is diagnostic of renal parenchymal infec-

tion (‘acute pyelonephritis’). Eosinophiluria is associated with acute allergic

interstitial nephritis and athero- embolic renal disease.

URINE MICROSCOPY

685

Othercells

Squamous epithelial cells are usually taken as indicative of vaginal contam-

ination but may also derive from the bladder and urethra. Occasionally,

malignant cells arising from the lower urinary tract are picked up on routine

microscopy. Spermatozoa are also rarelyseen.

Microorganisms

Identication of bacteriuria, in association with leukocyturia, is very sugges-

tive of an infection. Organisms may be in chains or clusters, and some are

motile. Fungi, including yeast, and protozoans, including Trichomonas, can

also be readily identied.

Casts

Casts are cylindrical bodies, which usually form in the distal tubule

and collecting duct. They consist of cells or cell debris held together by

Tamm– Horsfall protein. Staining and phase contrast microscopy improve

identication and characterization of casts, but results are operator-

dependent. Extreme shaking or agitation can disintegratecasts.

•

Hyaline casts appear translucent and homogeneous and are present in

normal urine. Number may be i in dehydration and proteinuria.

•

Cellular casts, especially red cell casts, always indicate signicant

parenchymal renal disease. Red cell casts are strongly suggestive of

acute glomerulonephritis but may occur in interstitial nephritis and ATN

aswell.

•

White cell casts are seen in acute pyelonephritis and acute interstitial

nephritis.

•

Granular casts are formed from cell debris and are seen in a wide variety

of renal diseases.

•

Waxy broad casts form in atrophic renal tubules and are seen in chronic

renal failure.

Crystals

A variety of crystals can be visualized and are of importance in stone form-

ers. Afreshly voided sample should be examined, as storage and tempera-

ture changes can aect the type and number of crystals found. Calcium

oxalate crystals may be seen in hypercalciuria, hyperoxaluria, and ethylene

glycol poisoning. Presence of even a single crystal of cystine is diagnostic

of cystinuria, as cystine is not a constituent of normal urine. Calcium phos-

phate crystals can form in normal urine as it cools and are of no pathological

signicance.

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CHAPTER10 Renal medicine

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Investigations inpatients withrenal

or bladderstones

Not all renal tract stones are formed because of abnormal urine chemistry.

They may also be formed because of stasis, e.g. in calyceal or bladder diver-

ticula. Infection (‘struvite’) stones are the result of chronic infection in the

urinary tract with urease- producing organisms, which metabolize urea to

form an alkaline urine in which struvite readily precipitates.

Indications

Although up to 75% of patients who present with renal stones eventually

form a second stone, this may not be for 20years. Most urologists there-

fore only refer patients for metabolic evaluation if there is a heightened

suspicion of an underlying metaboliccause.

Situations inwhich evaluation is denitely indicated include

•

Formation of stones in childhood or adolescence.

• Recurrent stone formation.

• Nephrocalcinosis (calcication in the renal parenchyma) as well as stone

formation in the collecting systems.

Radiology

IVU or unenhanced helical CT will usually have been performed during the

patient’s presentation with stone disease, but the lms should be reviewed

to look for evidence of any cause of stasis within the collecting systems,

and in particular for medullary sponge kidney. Radiolucent stones can be

detected using US, IVU, or CT scanning, and can be made of cystine, uric

acid, xanthine, or 2,8 dihydroxyadenine. ‘Staghorn’ calculi lling the collect-

ing systems are most often struvite (infection) stones, but not always—

calcium oxalate stones can grow to similar size and shape, particularly in

hyperoxaluria, as can cystine stones.

Stone analysis

Depending on the facilities in the laboratory, this may be qualitative or semi-

quantitative. The purpose of analysis is to distinguish calcium stones from

cystine, urate, and struvite stones, to pick up the rare types of stone, and

in addition to distinguish calcium oxalate from calcium phosphate stones.

The result of stone analysis should be used to guide further investigation.

Stones can be obtained for analysis either at surgery, including percutaneous

nephrolithotomy, or by asking a patient to pass urine through a nesieve.

‘Spot’ urinetests

Amino acid analysis on a random sample of urine shows i excretion of cys-

tine, ornithine, lysine, and arginine in cystinuria, and this nding is sucient

to conrm a suspected diagnosis. However, measurement of 24h urinary

cystine excretion is necessary for optimal management of this condition.

Random urine calcium:creatinine and oxalate:creatinine ratios are used in

children to diagnose hypercalciuria and hyperoxaluria but are not as reliable

as 24h urine collections, which are preferred in adults.

INVESTIGATIONS INPATIENTS WITHRENAL OR BLADDERSTONES

687

24h urine collections

Collections must be made into an acidied container for measurement of

calcium and oxalate, and into a plain container for measurement of urate

(because acidication is necessary to prevent calcium from binding to the

plastic surface of the urine container and to prevent in vitro generation of oxa-

late, and because acidication precipitates uric acid crystals). Measurement

of sodium and citrate excretion can be made on either type of collection.

•

Calcium excretion is not a good predictor of stone formation (calcium

activity is less than concentration due to the presence in urine of anions

that form soluble complexes with calcium). However, marked i of

urinary calcium is a risk factor for stone formation.

•

Oxalate excretion correlates well with the risk of recurrent calcium

oxalate stone formation, even within the normal range. Marked

hyperoxaluria may result from enteric hyperoxaluria (i colonic oxalate

absorption resulting from small bowel resection, jejunoileal bypass, or

malabsorption), acute ethylene glycol poisoning, excess dietary oxalate,

or as a result of ° hyperoxaluria (one of several metabolic defects

causing i endogenous oxalate production).

•

Glycolate and L- glycerate should be measured in patients suspected of

having ° hyperoxaluria to allow dierentiation between type 1 and

type 2 ° hyperoxaluria. Raised urine glycolate suggests type 1 disease,

and raised L

- glycerate suggests type 2 disease, but neither test is 100%

sensitive or specic.

•

Liver biopsy with assays to detect enzyme activity can be used to

diagnose ° hyperoxaluria

•

Genetic testing is now widely used for the diagnosis of type 1, 2, and 3

° hyperoxaluria.

•

Citrate excretion should be measured because citrate is a potent inhibitor

of calcium stone formation; correction of hypocitraturia with, for

instance, oral potassium citrate, reduces stone recurrencerate.

•

Sodium excretion (a good marker for dietary sodium intake) should

be measured in calcium stone formers and in patients with cystinuria,

because reduction of dietary sodium intake results in d excretion of

calcium and cystine, respectively.

•

Cystine excretion should be measured in cystine stone formers. The aim of

treatment is to maintain the cystine concentration well below the solubility

limit for cystine (7

1mmol/ L at urine pH of 7). Rather than a single 24h

collection, it is worth asking the patient to split the urine collection into

daytime and night- time aliquots to ensure that this target is met at night,

when urine tends to become more concentrated, as well as during theday.

•

Urinary phosphate measurement is of no proven value in the

management even of calcium phosphate stone formers.

Tests ofurinary calcium excretion

Tests performed after calcium restriction and following a high- calcium test

meal have been used widely in the USA to dierentiate ‘absorptive’ from

‘renal’ hypercalciuria. These tests are necessary to dene dierent pheno-

types associated with hypercalciuria for research studies, but there is no

evidence that management strategies based on them have any advantage

over those based on simpler tests of urine chemistry.

688

CHAPTER10 Renal medicine

688

Renalbiopsy

Percutaneous renal biopsy is a valuable tool to establish diagnosis, suggest

prognosis, and guide therapy in renal diseases. It also has a major role in the

management of a renal transplant recipient.

Denite indications (result likely tochange management)

• Nephrotic syndrome (in adults).

• Steroid- unresponsive nephrotic syndrome in children.

• Acute nephritic syndrome.

• Rapidly progressive glomerulonephritis.

• Unexplained renal failure with normal- sized kidneys relative to body size

andage.

•

Renal involvement in multi- system disorders.

• Diagnosis of renal transplant dysfunction.

Relative indications (result may change management or

help todene prognosis)

• Non- nephrotic range proteinuria with or without haematuria.

• Isolated haematuria (only rarely does biopsy change management—

sometimes justied for potential live kidney donors, or for employment

or insurance purposes).

•

UnexplainedCKD.

• Diabetic patient with renal dysfunction, particularly with features not

typical of diabetic nephropathy, or without retinopathy.

Absolute contraindications

• Uncontrolled severe hypertension.

• Bleeding diathesis, including platelets <50 × 10

/ L, uncorrected

bleeding/ clotting disorders, and patients on anticoagulation with

prolonged clottingtimes.

Relative contraindications

• Single kidney.

• Kidney size small, compared to patient’s body size andage.

• Renal tumour/ mass— risk of abdominal seeding.

• Uncooperative patient (can be done under sedation or underGAn).

• Multiple renalcysts.

Procedure

1. Recent imaging of kidneys to document the size and rule out

obstruction is mandatory. Arecent normal platelet count, clotting

prole, and informed consent are necessary.

2. The procedure is performed where proper US facilities are

available and is usually done under LAn. Sedation can be given to an

uncooperative or tense patient.

3. An attending pathologist or technician at the time of sampling to

comment on adequacy of tissue is very useful.

4. Biopsy can be performed with either a spring- loaded disposable device

or a biopsy gun, depending on local practice.

5. The patient lies prone and the kidney is identied withUS.

6. The skin over the target area is prepared and anaesthetized with lidocaine.

RENALBIOPSY

689

7. Asmall cut in the skin is made using a scalpel. The kidney is localized

with a ne- bore 21G LP needle and LAn inltrated up to the level

of the renal capsule. Either kidney can be biopsied— all parenchymal

renal diseases are bilateral. After suitably protecting the US probe,

the biopsy needle/ gun is inserted along the anaesthetized track under

real- time US guidance to the level of the renal capsule, aiming to

obtain a sample from the cortex of the lower pole. The patient is

asked to hold their breath whilst the biopsy istaken.

8. The needle/ gun is red and subsequently withdrawn. The patient is

then allowed to breathe normally.

9. Two cores of tissue are usually taken; this may require three or

four ‘passes’ with the biopsy needle. If an attending pathologist or

technician is present, they can comment on the adequacy of tissue

by examining the core for glomeruli (see Fig. 10.4) using a hand- held

magnifying glass or a simple microscope. If immunouorescence is to

be performed, part of one core is placed in saline; the remainder is

placed in formalin.

10. Following the biopsy, the patient is turned supine and strict bed rest

enforced for a minimum of 6h. Vital signs are monitored every 15min

for 2h, every 30min for 2h, and hourly thereafter. If no complications

are encountered at 6h, the patient is allowed to mobilize. Most bleeding

complications occur within the rst 8h, but bleeding can start up to 72h

after the biopsy. If macroscopic haematuria is present and does not

resolve within the observation period, discharge should be delayed.

Mesangial cells:

i number,

polymorph inltration

Bowman’s space:

cellular proliferation

(crescents)

Urinary epithelial cell:

foot proces

eacement/fusion

Brush

border

Basement membrane:

congenital thinning,

immune complex deposition

—lumpy (e.g. ‘membranous’)

—linear (e.g. Goodpasture’s)

—splitting (membranoproliferative)

Proximal

tubule

Glomerular

ltrate ow

Glomerular

capillary loops

Eerent

arteriole:

vasculitis

Aerent arteriole:

vasculitis thrombosis,

atheromatous embolism

Blood ow

Mesangial matrix:

expansion,

sclerosis, lysis

Fig.10.4 The normal glomerulus and its repertoire of response to injury.

Reproduced from Tomson CRV. Essential Medicine, 2nd edn. London:Churchill Livingstone,1998.

690

CHAPTER10 Renal medicine

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Renal imaging

Contrast nephropathy

Renal toxicity due to radiocontrast agents may cause or exacerbate renal

impairment. The risk of nephropathy i with i contrast dose and is higher

with intra- arterial injection. Nephrotoxicity is due to a combination of local

vasoconstriction and direct tubular injury. There is an i risk in patients with

pre- existing renal impairment, diabetes, myeloma, hypovolaemia, or eec-

tive hypovolaemia (e.g. CCF), and concurrent administration of medica-

tions that can reduce renal blood ow, including NSAIDs, ACE inhibitors,

and ARBs. The Royal College of Radiologists recommends discussion with

the referring clinician before contrast is given to any patient taking met-

formin, given the theoretical risk of precipitating lactic acidosis, but it is

no longer recommended that metformin is routinely discontinued in this

setting.

Although usually reversible, contrast nephropathy can precipitate the need

for dialysis in patients whose renal function is already seriously impaired.

Non- ionic media, use of the minimum possible dose, and IV pre- treatment

with saline or sodium bicarbonate reduce the risk in high- risk patients.

Details of the radiological investigation of the urinary tract appear in

E Renal imaging, pp. 690–2; E Radiology of the urinary tract, pp. 808–11;

E Static cortical renography:DMSA imaging, p. 924; E Dynamic renogra-

phy, pp. 926–7; E Captopril renography, p. 928.

Gadolinium- based contrastmedia

An association between exposure to gadolinium- based contrast media and

nephrogenic systemic brosis (NSF) was established in 2006. NSF manifests

as brosis of the skin and connective tissue, causing contractures and joint

immobility, and can cause visceral brosis, in some cases leading to a fatal

outcome. With relatively few cases reported so far, the risks are hard to

quantify, but patients with CKD stages 4– 5 can be considered high risk and

CKD stage 3 low risk. No cases have been reported with eGFR of >60mL/

min/ 1.73m

. Post- exposure dialysis is recommended for patients already

established on renal replacement therapy, but dialysis is not recommended

for those not established on renal replacement; the risks of temporary

vascular access and dialysis initiation outweigh the benets of gadolinium

removal. The risk of developing NSF seems to relate to the extent to which

the contrast medium releases free gadolinium (Gd

) ions, with cyclic agents

less likely to release Gd

than linear chelates.

7 Royal College of Radiologists (2015). Standards for intravascular contrast agent administration to

adult patients, 3rd edn. M

https:// www.rcr.ac.uk/ sites/ default/ les/ Intravasc_ contrast_ web.pdf.

Medicines and Healthcare Products Regulatory Agency (2007). Gadolinium- containing MRI contrast

agents:nephrogenic systemic brosis. M http:// www.mhra.gov.uk/ safety- public- assessment- reports/

CON081759.

RENAL IMAGING

691

Choice ofinvestigation

Unexplained renal impairment

When a patient rst presents with renal impairment it is important to

decide whether this is acute— and therefore potentially reversible— or

chronic. Although the history, examination, and blood tests may give some

clues, considerable doubt may remain.

All patients presenting withrenal impairment should therefore undergo

•

Ultrasound:

•

Hydronephrosis suggests obstructive nephropathy.

•

Small, smooth kidneys with i echogenicity and d corticomedul-

lary dierentiation suggests chronic parenchymal renal disease, e.g.

chronic glomerulonephritis.

•

Irregular cortical scarring can be caused by reux nephropathy, previ-

ous obstructive nephropathy (e.g. complicating renal stones), and

renal infarction from vascular disease or embolism.

•

Renal asymmetry, particularly in a patient with known atherosclerosis

elsewhere, suggests RAS, although this can just as commonly be

bilateral.

•

Renal enlargement can occur in ATN, renal vein thrombosis, and

renal inltration, e.g. in haematological malignancy.

•

Plain abdominal lm (KUB) if renal stones or nephrocalcinosis

suspected— nephrocalcinosis and urinary tract stones, particularly if

outside the renal pelvis, can be missedonUS.

Further radiological investigations, including renal angiography and isotope

scanning, are sometimes helpful.

Suspected nephrolithiasis

Unenhanced helical CT is increasingly the investigation of rst choice and

is more useful than IVU, particularly if the GFR is reduced or radiolucent

stones present. IVU remains readily available and may be the preferred

investigation in some centres.

Investigation ofhaematuria

In patients over 40 and possibly in some younger patients, it is important

to exclude urinary tract malignancy. US is the investigation of choice for

the detection of renal cell carcinoma but will miss some transitional cell

carcinomas of the renal pelvis, which are best detected using CT or IVU.

Cystoscopy or high- resolution US of the full bladder is required to rule out

transitional cell carcinoma of the bladder.

Investigation ofsuspected renal artery stenosis

In younger patients in whom bromuscular dysplasia is suspected, conven-

tional angiography should be performed. Atherosclerotic RAS can be rea-

sonably assessed by contrast CT angiography or by gadolinium- enhanced

MRA, with direct angiography reserved for interventional procedures.

Reux nephropathy

Conrming this diagnosis can be important in counselling patients, as reux

nephropathy is often inherited as an autosomal dominant trait. Cortical

scarring is best detected using a static DMSA (dimercaptosuccinic acid)

692

CHAPTER10 Renal medicine

692

renal scan. However, there are other causes of cortical scarring. The diag-

nosis is best conrmed by showing the combination of cortical scarring with

underlying calyceal deformity on IVU. Demonstration of vesico- ureteric

reux on direct or indirect micturating cystourethrography is useful in

infants and small children, but reux commonly resolves with growth, so

these tests are seldom used in adults.

Obstructive uropathy

Although hydronephrosis demonstrated on IVU or US is usually sucient to

conrm obstruction, it is possible to have obstruction without much dilata-

tion (e.g. complicating encasement by tumour). More commonly, there is

uncertainty over whether dilatation of the collecting system and pelvis is due

to previous obstruction, now resolved, or continuing obstruction. Diuretic

MAG3 (mercaptoacetyl triglycine) renography may be useful but gives less

reliable results as the GFR falls. Insertion of a nephrostomy to determine

whether direct drainage of urine improves renal function or retrograde

insertion of ureteric stents may be useful for both diagnosis and treatment

of obstruction. If doubt persists, a Whitaker test may be performed; this

involves infusion of saline at a constant rate through a nephrostomy tube

and measuring the relationship between pressure and ow down the ureter.

Renal transplant dysfunction

The dierential diagnosis usually lies between obstruction, ureteric leak,

rejection, ATN, nephrotoxicity, and renal vein thrombosis. Depending on

the centre, US with Doppler assessment of renal blood ow (giving resist-

ance index) or isotope renography may be the investigation of rst choice.

RENAL IMAGING

693

694

CHAPTER10 Renal medicine

694

Renal bone disease

Parathyroid hormone

Indications

Diagnosis of ° hyperparathyroidism in patients with hypercalcaemia.

Diagnosis of 2° or tertiary hyperparathyroidism in patients with stage 4

or5CKD.

Procedure

A serum sample is sent and separated within 4h of venepuncture.

Alternatively, PTH remains stable for 24h if the sample is taken into EDTA,

allowing samples to be sent from ° care. Check with the local laboratory.

Other markers ofbone biochemistry

Serum Ca

is often normal, even in patients with signicant renal disease,

because a fall in serum Ca

caused by reduced 1,25- (OH)

vitamin D pro-

duction results in an i

in PTH secretion, returning serum Ca

towards

normal. Hypocalcaemia occurs after parathyroidectomy or after treatment

with bisphosphonates. Hypercalcaemia occurs when the PTH release loses

sensitivity to serum Ca

in tertiary hyperparathyroidism.

If PTH is raised in the presence of CKD 3, check 25- (OH) vita-

min D; vitamin D deciency should be corrected before treatment of

hyperparathyroidism.

•

Serum phosphate is often i in patients with renal impairment due to

impaired renal excretion of phosphate.

•

Serum total ALP rises in severe hyperparathyroidism and osteomalacia.

•

Serum bone ALP is a more sensitive marker of bone turnover, but

quantitative measurement is not widely available. If total ALP is raised,

ALP isoenzymes can be measured as an indicator of whether the i is of

bone origin.

•

FGF- 23 (broblast growth factor) is a phosphaturic peptide

produced primarily by osteocytes. Patients with CKD have i

FGF- 23

concentrations due to phosphate retention and d clearance. FGF- 23

excess is a better predictor of adverse outcomes in CKD than serum

phosphate levels and could represent a novel early biomarker for

disordered bone mineral metabolism. However, the only current clinical

indication for FGF- 23 measurement is in the diagnosis of tumour-

induced osteomalacia.

Serum aluminium and thedesferrioxaminetest

Patients with renal disease may be exposed to aluminium from contami-

nated water used for the preparation of dialysates or by ingesting aluminium

hydroxide as an antacid or, rarely nowadays, as a phosphate binder taken

with meals. Because of the eects of aluminium on the brain, BM, and

bones, it is important to monitor patients at risk for evidence of aluminium

accumulation.

Serum aluminium

has to be taken into an aluminium- free glass tube. Serum

aluminium levels reect current exposure and do not give any informa-

tion about cumulative exposure. Serum aluminium levels may be i by iron

RENAL BONE DISEASE

695

deciency. Levels above 60µg/ L (2.2µmol/ L) are considered indicative of

a dangerous level of exposure and should lead to a review of treatment.

The increment in serum aluminium 24 or 48h after IV desferrioxamine is

a marker of aluminium ‘load’. The original protocol requires the use of

40mg/ kg desferrioxamine; a rise in serum aluminium of >200µg/ L corre-

lates well with the presence of aluminium- related bone disease on bone

biopsy. Low- dose protocols have also been described and validated.

Skeletalsurvey

Severe hyperparathyroidism causes erosion of the terminal phalanges,

subperiosteal erosions, and, in rare cases, brown tumours and pathologi-

cal fractures. Severe osteomalacia causes loss of bone density and Looser

zones (pseudo- fractures). These radiological signs are not commonly seen

in modern renal patients because biochemical monitoring allows earlier

detection and treatment of bone disease.

Transiliac bonebiopsy

This is the ‘gold standard’ for the diagnosis of renal bone disease but is not

commonly used in clinical (as opposed to research) settings. However, it can

be useful particularly for the conrmation of aluminium- related bone dis-

ease and low bone turnover states. For maximum information to be gained

from this invasive test, double tetracycline labelling should be performed,

allowing the pathologist to determine the rate of new bone formation.

Procedure

Fourteen and 13days before the procedure, the patient takes a tetracy-

cline antibiotic, e.g. oxytetracycline 250mg four times daily (qds), and 4 and

3 days before the procedure a dierent tetracycline, e.g. demeclocycline

300mg bd. Under GAn, a transiliac core of bone, including both cortical

surfaces, is taken and placed in absolute alcohol. The sample should be sent

to a laboratory specializing in the interpretation of bone biopsies in patients

with metabolic bone disease.

696

CHAPTER10 Renal medicine

696

Immunological tests inrenal medicine

Immune- mediated diseases can aect the kidney in isolation or as part of

a systemic disorder. Immunological tests commonly used to diagnose or

monitor progress of renal disease are discussedhere.

Complement

Indications

Acute nephritic syndrome, renal failure with skin ± neurological involve-

ment, and suspected SLE, endocarditis, or cryoglobulinaemia. The normal

complement system, its activation pathways, and assay methods are dis-

cussed elsewhere (E Serum complement components, p. 351). In rela-

tion to renal disease, hypocomplementaemia is important and relative

deciencies of various components can point to certain disorders. (See

Table10.1.)

Successful treatment normalizes complement levels in endocarditis and

in SLE, except when SLE results from congenital complement deciency.

C3 nephritic factor (C3Nef ) is an IgG autoantibody that binds to, and sta-

bilizes, alternative pathway C3 convertase— C3bBb. This results in continu-

ous activation of the alternative pathway with C3 depletion. It is detected

by ELISA. C3Nef is classically associated with the C3 glomerulopathies,

dense deposit disease, and C3 glomerulonephritis (previously known as

type 2 membranoproliferative glomerulonephritis).

Immunoglobulins and serum electrophoresis

forparaproteins

Indications

•

Suspected myeloma or other clonal B- cell disorders.

• Unexplained renal failure, with or without proteinuria, particularly in

patients >50years.

•

Renal failure in association with hypercalcaemia.

Serum electrophoresis to identify a monoclonal Ig band may be useful but

should always be combined with tests for urinary light chains (BJPs), as

some types of myeloma cause light chain proteinuria without a monoclo-

nal band in the serum. Serum free light chain assays are also now available

and should be used to monitor myeloma in patients with kidney disease.

Table10.1 Complement levels inselected diseases

C3 C4

Post- streptococcal GN Low Normal

SLE Low Low

Cryoglobulinaemia

Low/ normal Very low

Membranoproliferative GN Low Low/ normal

Subacute endocarditis Normal/ low Low

GN, glomerulonephritis.

IMMUNOLOGICAL TESTS INRENAL MEDICINE

697

In patients with normal renal function, κ light chains are cleared more rap-

idly than λ light chains, so the κ:λ ratio is lower than the production ratio;

as the GFR falls, this dierence becomes less. The normal range for the

κ:λ ratio is 0.26– 1.65, but a normal range of 0.37– 3.1 should be used if

eGFR <60mL/ min/ 1.73m

. Routine serum and urine electrophoresis in the

absence of clinical features to suggest a B- cell disorder will identify many

patients with MGUS incidental to their renal disease and seldom identies

treatable disease.

Measurement of serum Ig concentrations is of value in patients with

known myeloma but is otherwise not useful in the assessment of patients

with renal disease. Polyclonal hypergammaglobulinaemia is seen in chronic

infections, connective tissue disorders (e.g. RhA, Sjögren’s syndrome), neo-

plasms, and chronic liver disease. Measurement of serum IgA concentration

is of no value in the diagnosis or monitoring of IgA nephropathy, although

a raised total IgA concentration is seen in some patients with this disease.

Paraproteins are products of abnormal B- cell clones and can be detected

in serum as monoclonal bands on Ig electrophoresis or in urine as BJPs.

Paraproteins may be whole Igs or heavy or light chains in isolation.

Light chains are suciently small to be ltered at the glomerulus, are not

reabsorbed, and are not picked up on routine dipsticks. BJPs are light chains

excreted in the urine; they precipitate on heating to 45°C and re- dissolve on

boiling, but are now detected by electrophoretic techniques.

Paraproteins can cause a number ofdierent renal lesions, including

•

Myeloma cast nephropathy.

• Light chain nephropathy.

• AL amyloidosis.

• Fibrillary/ immunotactoid glomerulopathy (although this appearance is

more frequently not associated with a plasma cell dyscrasia).

Cryoglobulins

Cryoglobulins are Igs, which precipitate on cooling and re- dissolve on

warming.

Cryoglobulinaemia should be suspectedin

•

Renal failure with otherwise unexplained hypocomplementaemia or

+veRF.

•

Renal failure in association with skin and neurological involvement.

• Unexplained proteinuria/ renal failure in patients with clonal B- cell

disorders.

Meticulous attention to collection, transportation, and assessment of the

sample is required; a serum sample must be kept at 37°C and sent to

the laboratory for analysis immediately, having warned the laboratory that

the sample is on the way. False −ve results are common due to improper

handling of the specimen.

Once a cryoglobulin has been found, further electrophoresis and

immunoxation allow identication ofthree distincttypes

•

Type 1 has a single monoclonal Ig (IgG, IgA, or IgM) and is associated

with monoclonal B- cell disorders.

698

CHAPTER10 Renal medicine

698

• Type 2 has a monoclonal IgM directed against the Fc portion of IgG, and

the cryoprotein therefore consists of monoclonal IgM with polyclonal

IgG. Tests for RF (i.e. anti- IgG antibodies) are +ve. This may be

associated with haematological malignancy, chronic hepatitis C infection,

or may be unexplained (‘essential’).

•

Type 3 has polyclonal IgG and polyclonal IgM and occurs in chronic

infections (e.g. bacterial endocarditis, viral hepatitis), autoimmune

disorders (e.g. RhA, SLE), or may be unexplained (‘essential’).

Hypocomplementaemia, especially very low C4 levels due to classical com-

plement pathway activation, is characteristic and helpful in diagnosing active

cryoglobulinaemic disorder. Renal disease can present as an acute nephritic

disorder or as nephrotic syndrome, and is usually seen in association with

skin and systemic involvement.

Antineutrophil cytoplasmic antibody

These are autoantibodies directed against enzymes present in the cyto-

plasm of human neutrophils. They are present in nearly all patients with

small- vessel vasculitis (including GPA, microscopic polyangiitis, renal- limited

crescentic glomerulonephritis, and Churg– Strauss syndrome). ANCA and

its pattern of distribution are conventionally detected by indirect immuno-

uorescence, with pANCA having a characteristic perinuclear staining pat-

tern and cANCA a cytoplasmic staining pattern. Changing titres can reect

changing disease activity. ELISA is now readily available for the two com-

monest ANCA protein targets:proteinase 3 (PR3) which is the commonest

target of cANCA and MPO, the commonest target of pANCA. Low- titre

+ve ANCA is unlikely to reect an underlying disease if the ELISA is −ve.

However, a −ve ANCA does not rule out vasculitis, and false +ve tests

occur, so the test is not a substitute for renal biopsy.

Anti- glomerular basement membrane antibody

Circulating anti- glomerular basement membrane (GBM) antibodies are

present in Goodpasture’s disease and may also be +ve in ANCA +ve vas-

culitis where ‘double positivity’ may confer a worse prognosis than ANCA

positivity alone. ELISA and RIAs are available. Conrmatory renal biopsy in

Goodpasture’s disease shows linear deposition of anti- GBM IgG along the

GBM, detectable by immunouorescence or immunoperoxidase staining.

699

Chapter11

Poisoning and overdose

General principles 700

Samples of medicolegal importance 702

Methods used in analytical toxicology 704

Brainstem death testing and organ donation 706

Interpretation of arterial blood gases in poisoned patients 707

Amphetamines and derivatives 708

Anticonvulsants 710

Benzodiazepines 712

Cannabis (marijuana) 713

Carbon monoxide 714

Cocaine 716

Cyanide 717

Digoxin 718

Ethylene glycol, ethanol, and methanol poisoning 720

Iron 724

Lead exposure and poisoning 726

Lithium 728

Methaemoglobinaemia 730

Opioids 731

Paracetamol (acetaminophen) poisoning 732

Salicylate poisoning 736

Theophylline 737

Tricyclic antidepressants 738

Warfarin and superwarfarins 739

Table of conversion factors between mass and molar units 740

700

CHAPTER11 Poisoning and overdose

700

General principles

Many poisoned patients recover without specic management other than

good supportive care. Aminority have life- threatening toxicity. In assessing

the poisoned patient, it is important to ensure adequate airway, breathing,

and circulation, take a thorough history, and undertake a full clinical exami-

nation. Tablets, bottles, syringes, aerosol containers, and other items found

with or near the patient should be retained and any corroborative history

obtained. It is usually best to analyse biological specimens (usually blood

and/ or urine) if analytical conrmation of toxin exposures is required.

The role ofblood and urine tests intoxicology

Close collaboration between analytical sta and clinicians is required if any-

thing other than the simplest toxicological analysis is to be useful.

Toxicological analysis using blood or urine is used to conrm:

•

The diagnosis of poisoning, when this is in doubt or for medicolegal

purposes.

•

To help in the management, or in the diagnosis of braindeath.

• To work out the time to restart chronic drug therapy e.g.

anticonvulsants.

Few centres have full analytical toxicology services, and a ‘toxicology

screen’ rarely inuences acute inpatient management, with the exception

of paracetamol, salicylate, lithium, digoxin, and iron poisoning, and on occa-

sions a drugs of abuse screen. Toxicological analysis of blood plasma or

serum is also of value if an extracorporeal method of elimination, such as

haemodialysis or MARS

(Molecular Absorbance Recirculating Systems),

is being contemplated. Any toxicology analysis should be tailored to that

patient’s circumstances and the poisons commonly encountered in that

country. In Western Europe and North America, most patients will have

taken pharmaceutical agents (often in combination), but pesticide poison-

ing, for example, is common in less well- developed countries.

Plasma paracetamol, salicylate, lithium, digoxin, and iron measurements

in blood are usually available on an urgent basis. For other patients, particu-

larly those who present a complex clinical picture or who are unconscious,

a 50mL sample of urine and a 10mL sample of heparinized blood should

be collected on admission and stored at 4°C (refrigerated). This can be

analysed later if it is felt the result will inuence your management or if

needed for medicolegal purposes (E Samples of medicolegal importance,

p. 702). Urine is useful for screening, especially for drugs of abuse, as it is

often available in large volumes and often contains higher concentrations of

poisons and their metabolites than blood samples. The samples should be

obtained as soon as possible after admission, ideally before any therapeutic

drugs are administered. Urine samples usually provide qualitative results,

e.g. detect the presence of amphetamines or benzodiazepines. Quantitative

measurements in urine are of little use because some compounds, such as

benzodiazepines, are extensively metabolized prior to excretion inurine.

1 Wittebole X, Hantson P. Use of the molecular adsorbent recirculating system (MARS

) for the

management of acute poisoning with or without liver failure. Clin Tox 2011; 49

:782– 93.

GENERAL PRINCIPLES

701

Sample requirements

Plasma or serum is normally used for quantitative assays for drugs and drug

metabolites, and in general there are no marked dierences in concentration

between these uids. Evacuated blood tubes and containers containing gel

separators or soft rubber stoppers are not recommended if a toxicological

analysis is to be performed, as the plasticizers (phosphates and phthalates)

used in many such tubes may interfere with chromatographic methods, and

volatile compounds, such as CO or ethanol, may belost.

EDTA tubes are preferred for COHb assays and for measurement of lead

and some other metals, as these are concentrated in RBCs. Auoride/ oxa-

late tube should be used if ethanol, cocaine, or benzodiazepines are being

assayed, although special tubes containing 1% (w/ v) uoride are needed

if enzymic hydrolysis of these and other compounds is to be completely

prevented.

The use of disinfectant swabs containing alcohols should be avoided, as

should heparin, which contains phenolic preservatives (chlorbutol, cresol),

and preservatives containing mercury salts (see Table11.1).

Table11.1 Sample requirements formetals/ trace elements analysis

Metal Sample needed

Aluminium

10mL whole blood in plastic (not glass) tube— no anticoagulant/

beads*

Antimony 5mL heparinized whole blood; 20mL urine

Arsenic 5mL heparinized whole blood; 20mL urine

Bismuth 5mL heparinized whole blood

Cadmium 2mL EDTA whole blood*; 10mL urine*

Chromium 2mL heparinized whole blood*; 20mL urine*

Copper 2mL heparinized or clotted whole blood, or 1mL plasma;

10mL urine

Iron 5mL clotted blood or 2mL serum (avoid haemolysis)

Lead 2mL EDTA whole blood

Lithium 5mL clotted blood or 2mL serum (NOT lithium heparin tube!)

Manganese 1mL heparinized whole blood or 0.5mL plasma*

Mercury 5mL heparinized whole blood; 20mL urine

Selenium

2mL heparinized whole blood or 1mL plasma/ serum

Thallium 5mL heparinized whole blood; 20mL urine

Zinc

2mL whole blood (not EDTA) or 1mL plasma/ serum

* Send unused container from the same batch to check for possible contamination.

702

CHAPTER11 Poisoning and overdose

702

Samples ofmedicolegal importance

A toxicology screen is helpful if murder, assault, or child abuse is suspected.

Samples collected in such cases are often so important that they should

be kept securely at −20°C or below, until investigation of the incident is

concluded. Legal requirements mean that all specimens should be clearly

labelled with the patient’s family or last name and any forenames, the date

and time of collection, and the nature of the specimen, if this is not obvious.

Strict chain of custody procedures should be implemented, and the doctor

or nurse taking the sample should seal the bag with a tamper- proof device

and sign and date the seal. Achain of custody form must accompany the

sample and should be signed and dated by every person taking possession

of the sample. The sample should be secured in a locked container or refrig-

erator if left unattended before arrival at the laboratory.

Post- mortem concentrations of some drugs may not necessarily repre-

sent antemortem levels and should therefore be interpreted with caution,

e.g. in one case where a patient died 72h after admission to hospital, the

post- mortem serum olanzapine concentration was elevated 5- fold over the

antemortem level.

With passage of time after death, some drugs (espe-

cially basic drugs with a high volume of distribution) move along a concen-

tration gradient from areas of high concentration in solid organs into the

local blood, a phenomenon called ‘post- mortem redistribution’. Therefore,

the highest blood drug concentrations are found in central vessels such as

the pulmonary artery or vein and the lowest levels in femoral veins e.g.

morphine, amphetamines. Thus, the most appropriate post- mortem blood

sample is a femoral blood sample.

The stability of the drug in post- mortem blood samples that are stored

also needs to be considered. After a specimen has been collected, enzymes

may remain active and continue to metabolize the drug in vitro. In general,

drug instability occurs because functional groups are susceptible to transfor-

mation (e.g. 6- acetylmorphine) or readily oxidized or reduced. Olanzapine

blood concentrations d with time by 23– 84% during storage.

However,

conjugated drugs, such as the glucuronides, may deconjugate, which i

the free drug concentration. In general, drug stability should be evaluated

with consideration of long- term storage, the eect of freeze– thaw cycles,

short- term stability (e.g. refrigerated samples), and bench- top (room tem-

perature) stability. Thus, femoral blood sample drug concentrations should

be measured as soon as possible after death and samples must be stored

appropriately.

Further reading

Drummer OH. Requirements for bioanalytical procedures in post- mortem toxicology. Anal Bioanal

Chem 2007; 388

:1495– 503.

Kerrigan S. Sampling, storage and stability. In:A Negrusz, G Cooper (eds.). Clarke’s Analytical Forensic

Toxicology

, 2nd edn. London:Pharmaceutical Press, 2013; pp.335– 50.

2 Chue P, Singer P. A review of olanzapine- associated toxicity and fatality in overdose. J Psychiatr

Neurosci 2003; 28

:253– 61.

3 Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn. San

Francisco:Chemical Toxicology Institute,2011.

SAMPLES OF MEDICOLEGAL IMPORTANCE

703

704

CHAPTER11 Poisoning and overdose

704

Methods used inanalytical toxicology

Older and newer methods are discussed here to reect global use. Arange

of chromatographic and other methods, such as radioligand immunoassays,

are available for toxicological analyses. Plasma concentrations associated

with serious toxicity range from µg/ L in the case of drugs such as digoxin to

g/ L in the case of ethanol.

Specialized laboratories use a combination of solvent extraction and

thin- layer chromatography (TLC) together with gas chromatography- mass

spectrometry (GC- MS) or liquid chromatography tandem- mass spectrom-

etry (LC- MS/ MS) as the basis for a ‘toxicology screen’. It is unwise to use

TLC without corroboration of results by another method, e.g. LC- MS/ MS,

because the resolution power of TLC is limited and interpretation of

chromatograms is subjective. Acommercial kit for TLC (Toxi- lab, Marion

Laboratories) is supplied with a compendium of colour plates, but even so

problems can arise in the dierentiation of compounds with similar mobility

and colour reactions. The kit is aimed at the US market, and some common

UK drugs are not included. Spectrophotometry is commonly used to meas-

ure salicylates, iron, and COHb. However, UV spectrophotometry and

spectrophotouorimetry are often used as detectors for high- performance

liquid chromatography (HPLC) and in immunoassays. Spectrophotometric

methods and immunoassays often suer from interference from metabo-

lites or other drugs. Immunoassays have the advantage of long shelf- life

and simplicity, but all require conrmation with a chromatographic method

if the results are to stand scrutiny. This is because immunoassays for small

molecules are often not specic, e.g. some urine amphetamine immunoas-

says give +ve results with proguanil, isoxsuprine, labetalol, tranylcypromine,

and phenylethylamine. The Syva Emit antidepressant assay cross- reacts

with phenothiazines after overdose. Chromatographic methods have the

advantage of selectivity and sensitivity and the ability to perform quanti-

tative measurements, but they are more expensive. Generally, gas– liquid

chromatography (GLC) or LC- MS/ MS are used to measure basic drugs.

Acidic or neutral moieties can also be analysed by LC- MS/ MS. For screen-

ing very large numbers of compounds simultaneously or sequentially, then

the Applied Biosystems Q- Trap technology is one of the most versatile—

this is an LC- MS/ MS where one of the quadruples of the triple quadrupole

is used as an ion trap. Most laboratories that aim to be as versatile as pos-

sible have a fast GLC, in addition to the LC- MS/ MS.

Modern methods of assay for heavy metals vary enormously. Inductively

coupled plasma mass spectroscopy (ICPMS) is the most commonly used

method in the UK. Here, ICPMS is used, instead of the ame or electro-

thermal furnace for atomization of the elements and mass is the detector.

Atomic absorption spectrophotometry, with either ame or electrothermal

atomization is the older method. In the case of iron, reliable kits based on

the formation of a coloured complex are available.

METHODS USED IN ANALYTICAL TOXICOLOGY

705

There is wide variation in the units that various laboratories use to report

results. This has caused confusion and errors in treatment, and great care is

needed to ensure that clinical interpretation is undertaken in full knowledge

of the units used by the reporting laboratory. Particular care is also required

in interpretation and application of analytical techniques in post- mortem

toxicology, due to changes in concentrations of blood in storage and dif-

ferential post- mortem redistribution of drug after death (E Samples of

medicolegal importance, p. 702).

Further reading

Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn. San Francisco,

Chemical Toxicology Institute,2011.

Drummer OH. Requirements for bioanalytical procedures in post- mortem toxicology. Anal Bioanal

Chem 2007; 388

:1495– 503.

706

CHAPTER11 Poisoning and overdose

706

Brainstem death testing and organ

donation

Brain death cannot be diagnosed in the presence of drugs that mask CNS

activity, e.g. baclofen. The rule of thumb, based on the pharmacological

principle that most drugs need ve half- lives to be eectively eliminated

from the circulation, is to allow four half- lives of any drug to elapse before

declaring death, or to allow at least 2– 3days for drug eects to wear o.

Whether this is satisfactory for patients with organ failure, and hence

impaired drug elimination, is unclear. Often in patients being assessed for

organ donation, measurement of plasma concentrations of residual drugs,

with expert interpretation, is required to determine whether brainstem

death tests are valid or whether a drug could be interfering with the results.

Selected donor organs from those who have died from poisoning by tri-

cyclic antidepressants, benzodiazepines, barbiturates, insulin, CO, cocaine,

methanol, and paracetamol have been used in transplantation. It is impor-

tant to identify which organs act as reservoirs for drugs and either not con-

sider such organs, e.g. a liver from a paracetamol- poisoned patient, or take

prophylactic precautions like acetylcysteine administration in the case of

donation of a heart from a paracetamol- poisoned patient.

Further reading

Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn. San Francisco,

Chemical Toxicology Institute,2011.

Hanson P. Organ donation after fatal poisoning:an update with recent literature data. Adv Exp Med

Biol 2004; 550:207.

Wood DM, Chan WL, Dargan P. Using drug- intoxicated deaths as potential organ donors:impres-

sion of attendees at the American College of Medical Toxicology 2014 annual scientic meeting.

J Med Toxicol 2014; 10

:360– 3.

INTERPRETATION OF ABG IN POISONED PATIENTS

707

Interpretation ofarterial blood gases

inpoisoned patients

Interpretation of blood gas values may be found in E OHCM 10e, p.162,

pp. 188–9. Essentially four patterns emerge, which may occur together.

Respiratory acidosis

Hypoventilation results in retention of CO

. This can occur after an over-

dose with any drugs that depress the CNS, e.g. tricyclic antidepressants,

opioids, and ketamine.

Respiratory alkalosis

Hyperventilation with respiratory alkalosis is classically caused by aspirin

(salicylate). It can also occur in response to hypoxia, drugs, and CNS injury.

Metabolic alkalosis

Metabolic alkalosis is very uncommon in poisoning. Rarely, it may result

from excess administration of alkali, e.g. deliberate alkali ingestion.

Metabolic acidosis

This is the commonest metabolic abnormality in poisoning. If acidosis is par-

ticularly severe (e.g. pH <7.2), this should raise the question of poisoning by

ethanol, methanol, or ethylene glycol. Measuring the anion gap and osmolar

gaps are helpful in further dierentiation of the medical or toxicological

cause (E Ethylene glycol, ethanol, and methanol poisoning, pp. 720–2).

708

CHAPTER11 Poisoning and overdose

708

Amphetamines and derivatives

For example, methylene dioxymethamphetamine (MDMA) (ecstasy), MDEA,

crystal methamphetamine (‘ICE’), paramethoxymethamphetamine(PMA).

Acute amphetamine overdose may cause sympathetic hyperstimulation,

cardiovascular collapse, rhabdomyolysis, ventricular tachyarrhythmias, and

death (often trauma- related). The following investigations should be con-

sidered in patients presenting to hospital with acute amphetamine(s) intoxi-

cation. In man, the half- life of methamphetamine ranges from 10 to 20h,

depending on urine pH and the dosetaken.

Plasma urea and electrolytes and glucose

It is critical that at least one set of U&E and creatinine are checked in every

patient. Most are profoundly dehydrated and require vigorous rehydra-

tion. Some patients develop hyponatraemia, often after drinking excess

water, and ADH secretion may also be responsible for this (E OHCM 10e,

p.672). Hypoglycaemia mayoccur.

Dipstick test ofurine formyoglobin and subsequent serum

creatinekinase

Hyperthermia can develop after amphetamine exposure and may cause

rhabdomyolysis. Hyperthermia may be one of the features of serotonin

toxicity (accompanied by autonomic instability, ocular and peripheral clo-

nus. and hyper- reexia). Dipstick testing of urine is +ve for blood in rhab-

domyolysis, as myoglobin is detected by the Hb assay. This is an indication

that serum CK should then be measured. If found to be elevated, adequate

rehydration is needed to reduce deposition of myoglobin in renal tubules

and reduce the risk of ARF as a consequence. Caution in use of alkaliniza-

tion as for certain drugs, e.g. amphetamines; this potentially delays drug

excretion.

Full bloodcount

Rarely, aplastic anaemia (E OHCM 10e, p.364) has been reported after

ecstasy (MDMA) ingestion.

Clotting studies

DIC (E OHCM 10e, p.353) can occur, often in the context of hyperther-

mia. Once liver damage ensues, INR/ PT (E OHCM 10e, p.351) willrise.

Temperature

Hyperpyrexia can lead to rhabdomyolysis, DIC, and hepatocellular necrosis.

Risks relate to the time in hours spent above 39°C. Arectal thermometer

is the most accurate measure of temperature.

Blood pressure

A BP >180/ 120mmHg requires urgent medical care to reduce the risk of

stroke.

Liver functiontests

Acute liver injury can occur with a rise in AST or ALT, often of several

thousands.

AMPHETAMINES AND DERIVATIVES

709

3 Note:do not miss a hidden paracetamol overdose— check paracet-

amol levels in blood, from the earliest sample you have on that patient!

Checking an INR or prothrombin ratio (PTR) is essential in suspected late

paracetamol poisoning and is of good prognosticvalue.

ECG

An ECG should be carried out in patients with tachycardia, chest pain,

or reduced GCS. Patients should undergo cardiac monitoring. Cardiac

arrhythmias are common and deaths, which occur soon after ingestion, may

be due to these. Arrhythmias are often supraventricular, although ventricu-

lar arrhythmias also occur. Serial troponin levels are required if there has

been/ is chestpain.

Urinetests

Urine tests, e.g. EMIT dipstick system or by immunoassay in the labora-

tory, are sensitive and group- specic for amphetamines and can conrm an

amphetamine has been ingested if that is in doubt, e.g. agitated patient in

the emergency department. Note:amphetamine, MDMA, and MDA con-

centrations in blood are of no value in determining clinical management.

Newer synthetic amphetamines (cathinones) may not be detected by urine

dipstick tests but can be detected by chromatographic techniques in the

laboratory.

Imaging

A CT brain scan should be performed for patients with altered conscious

state, focal neurological signs, or severe headache.

Patients who are suspected body packers or body stuers should

undergo abdominal imaging, e.g. CTscan.

Further reading

Jones AL. Amphetamine overdose. BMJ Best Practice (online), Sept 2015. M us.bestpractice.bmj.com.

Volkow ND, Fowler JS, Wang GJ, etal. Distribution and pharmacokinetics of methamphetamine in

the human body:clinical implications. PLoS One 2010; 5:e152369.

710

CHAPTER11 Poisoning and overdose

710

Anticonvulsants

For most anticonvulsants, LC- MS/ MS will be the analytical method of

choice. However, some (e.g. valproic acid) are dicult to assay by LC- MS/

MS, and GLC may be more appropriate.

Carbamazepine toxicity

Plasma concentrations of carbamazepine and its active metabolite the

10,11- epoxide can be measured by HPLC or LC- MS/ MS but do not cor-

relate well with the degree of toxicity. They are seldom performed, unless

the diagnosis is in doubt or there is concern about a therapeutic excess.

The therapeutic range in plasma is between 8 and 12mg/ L. Toxicity has

been seen with carbamazepine concentrations above 20mg/ L (85mmol/

L). Coma, ts, respiratory failure, and conduction abnormalities have been

seen with concentrations in excess of 40mg/ L (170mmol/ L). In seven fatali-

ties due to carbamazepine overdose, femoral blood concentrations taken

post- mortem averaged 45mg/ L (range 35– 70).

An FBC should be performed. U&E and creatinine should also be

checked, as hyponatraemia and SIADH (E OHCM 10e, p. 241) have

been reported. Hypoglycaemia has also been reported. LFTs and PTR/

INR should be performed to assess hepatotoxicity. An ECG should be per-

formed in all but the most trivial carbamazepine overdosage to assess if

any conduction abnormalities or interval prolongations (e.g. QRS widening,

sinus tachycardia, AV block, or QTc prolongation) are present.

Lamotrigine toxicity

Overall, most patients exposed to lamotrigine in overdose experienced no

clinical eects.

Plasma concentrations of lamotrigine can be measured for

compliance purposes (therapeutic range 1– 4mg/ L; upper limit may be as

high as 10mg/ L) but are not of value in the overdose situation. In a fatal

case, the femoral blood concentration was 54mg/ kg.

Valproate toxicity

Plasma concentrations of sodium valproate can be measured by HPLC but

do not correlate well with either the depth of coma or risk of seizures after

overdose. The therapeutic plasma range is 40– 100mg/ L. U&E, creatinine,

and glucose should be measured, as hypernatraemia, hypoglycaemia, and

hypocalcaemia have been reported after overdosage. LFTs and PTR/ INR

should be taken to assess hepatotoxicity. Depending on the clinical need, a

CT head scan and/ or ECG may be required. Post- mortem blood concen-

tration in a 34- year- old man was 720mg/ L.

4 Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn, San Francisco,

Chemical Toxicology Institute,2011.

Lofton AL, Klein- Schwartz. Evaluation of lamotrigine toxicity reported to poison centers. Ann

Pharmacother 2004; 38

:1811– 15.

ANTICONVULSANTS

711

Phenytoin toxicity

Most patients with acute phenytoin poisoning do not require measurement

of their plasma phenytoin concentration and are treated with multi- dose

activated charcoal. Blood glucose, U&E, creatinine, LFTs, and PTR/ INR

should be checked. An ECG should be obtained. Most cardiac complica-

tions have occurred with rapid (>50mg/ min) IV administration. ACT head

scan is needed if there is focal neurology (excluding ataxia or nystagmus) or

any history of traumatic injury.

Most phenytoin toxicity is managed by repeat multi- dose activated

charcoal. Rarely, an urgent phenytoin measurement may help in severe

phenytoin poisoning where charcoal haemoperfusion or some other extra-

corporeal elimination method, such as MARS, is being considered,

e.g. if

the plasma phenytoin concentration is above 40mg/ L and rapidly rising or

is close to, or exceeding, the potential lethal level of 100mg/ L. The over-

all clinical value of such elimination methods remains to be established.

Post- mortem phenytoin concentration in femoral blood of a 4.5- year- old

child who ingested 2g was 45mg/ L.

Phenytoin undergoes post- mortem

redistribution.

Patients with suspected chronic phenytoin toxicity as a result of thera-

peutic dosing should have their plasma phenytoin concentration measured.

The ‘therapeutic range’ is 10– 20mg/ L. Routine measurements may be use-

ful to monitor anticonvulsant therapy or to time re- institution of chronic

therapy after overdose.

6 Sen S, Ratnaraj N, Davies NA, etal. Treatment of phenytoin toxicity by the Molecular Adsorbents

Recirculating System (MARS). Epilepsia 2003; 44:265– 7.

712

CHAPTER11 Poisoning and overdose

712

Benzodiazepines

Most patients who have taken an overdose with benzodiazepines just sleep

o the drug without sequelae within 24h. However, more severe eects

can occur when benzodiazepines are mixed with other drugs, especially in

patients with pre- existing cardiovascular or respiratory disease. Pulse oxi-

metry is useful for monitoring the adequacy of ventilation if signicant CNS

depression is present.

Generally, measuring benzodiazepine concentrations in blood or urine

is not of value in the management of benzodiazepine overdose patients.

Benzodiazepines can be detected in routine urine drugs screens. LC- MS/

MS is the method of choice for quantitative analysis of diazepam and its

metabolites. Liquid chromatography simultaneously assays diazepam and its

polar metabolites, and post- mortem blood concentrations of 5 and 19mg/ L

have been found in fatalities.

CANNABIS (MARIJUANA)

713

Cannabis (marijuana)

Cannabis use may be detected in routine urine drug screening. They may

be detected for up to several days after use, depending on the dose and

frequency ofuse.

Synthetic cannabinoids may be consumed in herbal mixtures for recrea-

tional use, as an alternative to cannabis. Blood glucose, U&E, creatinine,

and ECGs should be undertaken. Note that synthetic cannabinoids, e.g.

JWH018, are often not detected by standard bedside urine drug screens

(and thus are often the drugs of abuse selected by workers who undergo

regular employment screening). However, they are detected by GC- MS,

mass spectrometry, or LC- MS/ MS if the sample is sent to the laboratory.

Further reading

Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn, San Francisco,

Chemical Toxicology Institute,2011.

Hermanns- Clausen M, Kneisel S, Szabo B, Auwärter V. Acute toxicity due to the conrmed con-

sumption of synthetic cannabinoids:clinical and laboratory ndings. Addiction 2013; 108

:534– 44.

714

CHAPTER11 Poisoning and overdose

714

Carbon monoxide

CO non- re poisoning deaths have started to reduce in the UK, e.g. in

2012, compared with previous years. Incidence peaks in winter months, due

to i

use of indoor heating and fossil fuel- powered generators and reduced

external ventilation. It is highly likely that CO poisoning remains signicantly

underdiagnosed with patients presenting with ‘u- like’ illness.

Survival rates for those resuscitated post- cardiac arrest with CO poison-

ing is very low, especially if there was pre- existing cardiovascular or respira-

tory disease. Pregnant women and their fetus are particularly susceptible

to CO poisoning. Patients surviving signicant CO poisoning may develop

acute or delayed neurological sequelae leading to loss of consciousness,

coma, and death. In the recovery phase, neurological sequelae, such as poor

concentration and memory problems, may be seen. Symptoms include cog-

nitive or personality changes, incontinence, psychosis, and Parkinsonian fea-

tures such as rigidity. 7

50– 75% of people recover from their neurological

features within 1year.

A COHb concentration in blood conrms recent exposure to CO and

should be measured urgently in all patients with suspected CO poisoning,

including those with smoke inhalation. The space above the blood in the

sample tube (headspace) should be minimized prior to blood gas analysis.

Expected ‘normal’ values for COHb are up to 5% in non- smokers and up

to 10% in smokers. However, people with pre- existing cardiovascular or

respiratory disease can present with symptoms of toxicity at COHb con-

centrations in the low or normal range. ACOHb concentration, however,

does not measure severity of poisoning because COHb begins to dissociate

from the moment of removal from the source of CO, and the rate of dis-

sociation is also dependent on factors such as exogenous O

administration.

Thus, any attempt to ‘back- extrapolate’ to nd the initial highest COHb, e.g.

by using nomograms, is awed.

Management of the CO- poisoned patient is determined by the patient’s

clinical condition and also on circumstantial evidence such as the inten-

sity and duration of exposure, rather than a COHb concentration per

se, although a level of >40% has been used as one criterion to guide the

use of hyperbaric O

therapy (which is of controversial clinical value).

The CO- exposed patient should be administered high- ow O

(e.g. 12L/

min through a tight- tting non- rebreather mask) until the COHb is <5%

and clinical signs of CO poisoning, such as impaired heel– toe walking and

nger– nose incoordination, have resolved. If in doubt, O

is administered

for a minimum of 6h. It is currently unknown if hyperbaric O

is more eec-

tive than normobaric 100% O

in prevention of neurological complications

in patients with CO poisoning.

Arterial bloodgases

Any patient with suspected poisoning by CO requires ABG analysis. O

saturation monitors are misleading, as they read COHb as oxyhaemoglobin

(HbO), and the true O

saturation of the patient can only be determined

by ABG analysis.

CARBON MONOXIDE

715

Electrocardiogram

An ECG should be performed in anyone severely poisoned (e.g. drowsi-

ness or any neurological abnormality, chest pain, or breathlessness) or with

pre- existing ischaemic cardiomyopathy. ECG changes, such as ST- segment

depression, T wave abnormalities, ventricular tachycardia or brillation, and

cardiac arrest can occur. If ischaemia/ infarction is seen on the ECG or sus-

pected clinically, then serial troponins should be requested.

Further reading

Fisher DS, Leonardi G, Flanagan RJ. Fatal unintentional non- re- related carbon monoxide poison-

ing:England and Wales, 1979– 2012. Clin Toxicol 2014; 52:166– 70.

Smollin C, Olson K. Carbon monoxide poisoning (acute). BMJ Clin Evid. 2010 Oct 12; 2010– 103.

716

CHAPTER11 Poisoning and overdose

716

Cocaine

Cocaine is snorted into the nose or injectedIV.

Blood pressure monitoring

Patients with cocaine intoxication should have frequent measurements of

their BP, as hypertension is a signicant risk, and strokes and chest pain

have been widely reported. Acontinuous monitoring device for repeated

measurements is suitable.

ECG and cardiac markers

Cocaine- induced angina and MI are common. ECG monitoring is advised

for all but the most trivial exposure to cocaine.

The predominant coronary pathology of cocaine is vasoconstriction.

Thrombosis is less common, and troponin is the most sensitive indicator of

myocardial damage (MI) due to cocaine. Cardiac troponins should also be

performed in any patient with chest pain or ECG abnormalities. They are

the most sensitive and specic markers. If elevated, then coronary angiog-

raphy is usually indicated.

The ECG is of less diagnostic value. Up to 84% of patients with cocaine-

related chest pain have abnormal ECGs, even in the absence of MI. In

another study, 42% of patients with ‘MI- like’ ST elevation on their ECGs had

MI excluded by cardiac markers. In a further study, total CK was elevated in

75% of patients, including 65% withoutMI.

Urine or blood testing

The use of cocaine can be determined by self- reports from patients or urine

analysis of metabolites of cocaine (benzoylecgonine), e.g. EMIT test. This

remains +ve for 24– 48h after cocaine use. In assessing patients who may

be a body packer, a +ve urine test may indicate pre- existing cocaine use or

leaking cocaine from the packets.

GC- MS is more specic and can be carried out on blood or urine.

Cocaine is unstable in blood, and samples are best taken into 1% w/ v uo-

ride oxalate tubes if medicolegal sequelae of cocaine use are a possibility.

‘Nasal insuation of 106mg of the drug to six volunteers produced mean

peak plasma concentrations of 0.22mg/ L at 0.5h and 0.61mg/ L for the

metabolite benzoylecgonine at 3h’.

Smoking 50mg in six volunteers pro-

duced mean peak plasma concentrations of 0.2mg/ L at 0.08h and 0.15mg/

L for benzoylecgonine at 1.5h. Patients have survived plasma concentrations

of 5.2mg/ L, but usually fatalities are associated with cocaine/ benzoylecgo-

nine concentrations in excess of 5mg/ L, depending on the route of use.

The IV route is the most dangerous. Cocaine may show signicant post-

mortem redistribution.

Further reading

McCord J, Jneid H, Hollander JE, etal.; American Heart Association Acute Cardiac Care Committee

of the Council on Clinical Cardiology. Management of cocaine- associated chest pain and myocar-

dial infarction:a scientic statement from the American Heart Association Acute Care Committee

of the Council on Clinical Cardiology. Circulation 2008; 117:1897– 907.

Senthilkumaran S, David SS, Jena NN, Menezes RG, Thirumalaikolundusubramanian P.Acute myo-

cardial infarction and cocaine toxicity:One step closer. Indian J Crit Care Med 2014; 18:118.

Shields LB, Rolf CM, Hunsaker JC 3rd. Sudden death due to acute cocaine toxicity- excited delirium

in a body packer. J Forensic Sci 2015; 60:1647– 51.

7 Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn. San Francisco,

Chemical Toxicology Institute,2011.

CYANIDE

717

Cyanide

Cyanide poisoning can occur by deliberate inhalation of gas, ingestion of

cyanide salts, or exposure in industrialres.

Arterial blood gas estimation

Essential to determine the O

saturation and acid– base status of the patient.

Serum lactate

This is helpful in conrming suspected toxicity and can be used clinically as

a surrogate for the cyanide assay. It is likely to exceed 7mmol/ L in cases of

signicant exposure. Thus, a blood gas analyser in the emergency depart-

ment can give a quick (indicative) answer to the question of whether expo-

sure has takenplace.

Electrocardiogram

All patients should have an ECG. It should be examined for evidence of

ischaemic damage, e.g. ST depression, ST elevation, T wave inversion.

Cyanideassay

Blood cyanide concentrations are rarely of use in emergency management,

because they cannot be measured quickly enough. However, a sample

should be taken before antidote administration for assay at a later stage.

Cyanide concentrations of <0.2mg/ L are ‘normal’; 1.0– 2.5mg/ L causes

obtundation and coma, and >2.5mg/ L is potentiallyfatal.

3 Note:the antidote of choice for cyanide poisoning is hydroxocobala-

min, together with O

; these are antidotes that can safely be given without

certainty of cyanide ingestion. An alternative is to give sodium thiosulfate

and sodium nitrite, and dicobalt edetate. However, note that dicobalt ede-

tate should only be given if cyanide poisoning is certain, i.e. a proper history

is available; otherwise you may kill your patient with cardiotoxicity of the

antidote. Excessive administration of sodium nitrite can cause signicant

methaemoglobinaemia.

Further reading

Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for

acute cyanide poisoning in smoke inhalation. Ann Emerg Med 2007; 49

:794– 801.

Borron SW, Baud FJ, Megarbane B, Bismuth C.Hydroxocobalamin for severe acute cyanide poison-

ing by ingestion or inhalation. Am J Emerg Med 2007; 25

:551– 8.

Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol 2009; 39:541– 52.

718

CHAPTER11 Poisoning and overdose

718

Digoxin

Patients who are already taking digoxin and those with pre- existing CVD are

more susceptible to digoxin toxicity after overdosage. Digoxin toxicity can

also result from progressive renal impairment or due to interactions with

other drugs, as well as overdoses. Acute digoxin toxicity is an indication for

oral multi- dose activated charcoal and IV hydration.

Electrocardiogram

All patients with suspected digoxin poisoning should have a 12- lead ECG,

and all symptomatic patients should be attached to a cardiac monitor.

Digoxin poisoning can cause virtually any type of cardiac arrhythmia due to

i automaticity and d AV conduction. The combination of heart block with

tachyarrhythmia is very common.

Plasma digoxin concentration

Absorption of digoxin often peaks at 4– 6h after ingestion. Its half- life is in

excess of 30h. Digitoxin is a structurally related drug that has an even longer

plasma half- life (6days). Adigoxin measurement is a useful, but not absolute,

guide to toxicity, as plasma digoxin concentrations correlate poorly with the

severity of poisoning, particularly early in the course of acute poisoning.

However, it is desirable in acute poisoning (although not essential) if anti-

digoxin antibody fragments (Fab) are to be used, as it is useful in calculating

the dose of fragments required (E Digoxin, Indications for Fab fragments

and doses of Fab fragments, pp. 718–19), as well as conrming exposure.

Plasma digoxin concentrations cannot be interpreted after administration

of digoxin Fab using normal assay procedures. Samples taken to investigate

probable chronic digoxin intoxication should be taken at least 6h after dos-

ing. They are not normally analysed urgently, unless life- threatening features

of toxicity are present and use of Fab is being considered. The therapeutic

range for digoxin is 0.8– 2.0µg/ L.

Urea and electrolytes, creatinine

It is important to ascertain if the patient has any renal impairment and

plasma creatinine and urea are helpful, although of course do not exclude

renal impairment completely. Hyperkalaemia is common in acute digoxin

overdose and may be severe, e.g. >7mmol/ L.

If possible, a magnesium level is helpful to exclude hypomagnesaemia,

which contributes to risk of cardiotoxicity and is easily corrected.

Indications fordigoxin antibody (Fab) fragments inacute

toxicity and doses ofFab fragments

• Bradycardia or heart block associated with hypotension.

• Tachyarrhythmias associated with hypotension, especially ventricular

arrhythmias

Fab fragment administration should be considered in less severe stages of

poisoning in older patients and those with pre- existing CVD. At one time,

the plasma K

concentration was considered an indication for use of Fab

fragments, but this is no longer used as an indication. Previously, use of

DIGOXIN

719

Fab fragments was considered for chronic toxicity, but this tends not to be

usednow.

The dose of Fab fragments to give for an acute ingestion of digoxin can

be calculated from either the dose of digoxin ingested or the plasma digoxin

concentrations. If in doubt, ten ampoules of Digibind

can be given, fol-

lowed by an additional ten ampoules if clinically indicated.

Number of 40mg vials of Fab=plasma digoxin concentration

(ng/ mL) × body weight ×0.0084

Ingested dose (mg)×1.2

Best guess of 10– 20 vials

E OHCM 10e, p. 842. Please note that if other types of digoxin- binding

antibodies are used, then the dosage may be dierent to those indicated

above.

Further reading

BMJ Best Practice (last updated 2016). Digoxin overdose. M http:// bestpractice.bmj.com/ best-

practice/ monograph/ 338.html.

Dasgupta A. Therapeutic drug monitoring of digoxin:impact of endogenous and exogenous digoxin-

like immunoreactive substances. Toxicol Rev 2006; 25:273– 81.

Flanagan RJ, Jones AL. Fab antibody fragments:some applications in clinical toxicology. Drug Safety

2004; 27

:1115– 33.

720

CHAPTER11 Poisoning and overdose

720

Ethylene glycol, ethanol, and methanol

poisoning

A history of ingestion or the presence of a metabolic acidosis raises suspi-

cion of poisoning with these substances. Calculation of the anion gap and

osmolal gaps is helpful in the assessment of such patients.

Aniongap

The normal anion gap is 12±2.

Many toxins cause a high anion gap acidosis and these

include

• Ethanol.

• Methanol. (Note:the high anion gap is due to metabolites and may take

several hours to develop.)

•

Ethylene glycol. (Note:the high anion gap is due to the metabolites and

may take 6– 24h to develop.)

• Metformin.

• Cyanide.

• Isoniazid.

• Salicylates (aspirin).

This list can be further reduced by measuring the osmolalgap.

Osmolalgap

This is the dierence between the laboratory estimation of osmolality

(Om) and calculated osmolality(Oc).

Toxic causes ofa raised osmolal gap include

• Methanol.

• Ethylene glycol.

• Diethylene glycol.

• Isopropanol.

• Ethanol.

The acronym ‘MEDIE’ can be a helpful mnemonic.

Calculating theaniongap

Anion gap = ([Na

] + [K

] – ([Cl

–

] + [HCO3

–

])

Calculating theosmolalgap

The osmolal gap is measured osmolality (Om) minus calculated

osmolality(Oc):

Oc = 2([Na

] + [K

]) + [urea] + [glucose]

The osmolal gap is normally<10.

ETHYLENE GLYCOL, ETHANOL, AND METHANOL POISONING

721

Ethylene glycol and methanol plasma concentrations

Often the diagnosis of ethylene glycol or methanol poisoning can be dif-

cult, because assays for these substances are not widely available. If

possible, their measurement can help manage severe intoxication. Other

parameters may have to be used, i.e. anion gap, osmolal gap, and ABG

analysis. Anormal osmolal gap does not exclude poisoning with ethylene

glycol or methanol, but if the osmolal gaps and anion gaps are both nor-

mal, and the patient is not symptomatic, then signicant ingestion is unlikely

to have occurred. In general, ethylene glycol or methanol measurements

should not be carried out, unless metabolic acidosis is present and there

is an aniongap.

Ethylene glycol and methanol concentrations in blood are useful to con-

rm ingestion and indicate when to stop antidotal treatment (with ethanol

or 4- methylpyrazole) and/ or when haemodialysis is needed (>500mg/ L;

E Indications for haemodialysis in methanol or ethylene glycol poisoning

are, p. 722). However, a low concentration may just mean that most of

the parent compound has been metabolized. Formate (i.e. the methanol

metabolite) levels can also be checked in patients who may have taken

methanol.

Microscopy ofurine foroxalate crystals

In suspected ethylene glycol poisoning, microscopy can be performed to

look for oxalate crystals. However, they are only present in 50% of cases

and often only many hours after ingestion. Treatment of a patient should

not be delayed or dependent upon looking for crystals.

Plasma ethanol concentrations

Plasma ethanol concentrations are usually not needed in patients who are

drunk, unless there is doubt about the diagnosis, e.g. patients with a widen-

ing osmolal gap or the patient is so severely poisoned that haemodialysis is

being considered for the ethanol poisoning. They are, however, essential

to guide appropriate use of ethanol as an antidote in ethylene glycol or

methanol poisoning (E Ethylene glycol, ethanol, and methanol poison-

ing, Indications for haemodialysis in methanol or ethylene glycol poisoning,

p. 722). Rarely, a plasma ethanol measurement will be needed in child pro-

tection cases, and such sampling will need chain of custody and a specic

method (GLC) by a specialist laboratory. The need for frequent monitoring

of ethanol concentrations during treatment is avoided by use of the alter-

native antidote 4- methylpyrazole (a competitive alcohol dehydrogenase

antagonist).

Antidotal therapy withethanol

The dose of ethanol for treatment of ethylene glycol and methanol poison-

ing can be very dicult to predict, because ethanol metabolism is variable

and unpredictable. It is therefore important to frequently recheck blood

ethanol concentrations in patients receiving an ethanol infusion. The dose

should be adjusted to achieve a blood ethanol concentration of 1– 1.5g/ L to

achieve competitive inhibition of alcohol dehydrogenase.

722

CHAPTER11 Poisoning and overdose

722

Indications forcontinued ethanol therapyare

• Methanol or ethylene glycol poisoning with blood concentrations

>200mg/ L.

• Metabolic acidosis with pH<7.3.

• Osmolal gap >10mOsmol/ kgwater.

• Formate concentration >10mg/ L.

• Urinary oxalate crystals.

• Severe symptoms.

Indications forhaemodialysis inmethanol or ethylene glycol

poisoningare

• Methanol or ethylene glycol concentration >500mg/ L.

• Severe metabolic acidosis (pH <7.3) unresponsive to therapy, i.e. ABGs

are needed in all cases of high anion gap poisoning.

•

Renal failure— hence, it is essential to check plasma U&E in all patients.

• Presence of visual problems in methanol poisoning.

• Formate concentration >500mg/ L in methanol poisoning.

• Haemodialysis should be continued until the methanol/ ethylene glycol

concentration is well below 200mg/ L.

Further reading

Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 2009; 360:2216– 23.

McMartin K, Jacobsen D, Hovda KE. Antidotes for poisoning by alcohols that form toxic metabolites.

Br J Clin Pharmacol 2016; 81:505– 15.

Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol

poisonings. Intens Care Med 2005; 31

:189– 95.

ETHYLENE GLYCOL, ETHANOL, AND METHANOL POISONING

723

724

CHAPTER11 Poisoning and overdose

724

Iron

Serum iron concentrations

In the UK, one 200mg tablet of ferrous sulfate contains 65mg of elemental

iron. Iron is also found in varied amounts in many over- the- counter vita-

min supplements. The elemental iron content of the preparation ingested

should be checked carefully, as the important consideration is the amount

of elemental iron ingested, not the weight of iron or vitamin tablets.

Serum iron concentrations should be measured urgently in all patients

who may have ingested >30mg/ kg of elemental iron acutely, those who

have ingested an unknown quantity, or those with symptoms, e.g. GI. If a

sustained- release preparation of iron has been taken, a later serum iron

concentration should be taken. Ablood sample taken late after ingestion

may underestimate the iron, as it may have already started distributing to

tissues, i.e. in a late- presenting patient, a low concentration cannot be inter-

preted, but a high one indicates toxicity.

If the antidote desferrioxamine is given before 4h have elapsed, it inter-

feres with the colorimetric assay for iron, and so a serum sample for iron

should be taken o before it is given. If atomic absorption spectrophotom-

etry is available for measurement of serum iron, there is no interference

from desferrioxamine.

It is essential to interpret the serum iron concentration result in the

context of the clinical state of the patient. If <55µmol/ L (<300mg/ dL),

mild toxicity is expected. If above 90µmol/ L (500mg/ dL), severe toxicity is

expected and treatment with desferrioxamine is necessary. Do not wait for

an iron concentration if altered conscious state, shock, or severe acidosis

(pH <7.1) is present. Antidotal treatment is also indicated for patients with

iron concentrations of >55µmol/ L if there is additional clinical evidence

of toxicity, e.g. GI symptoms, leucocytosis, or hyperglycaemia. Antidotal

therapy with desferrioxamine is indicated without waiting for the serum

iron concentration in patients with severe features (e.g. tting, unconscious,

or hypotensive). Desferrioxamine is usually continued until the urine has

returned to a normal colour, symptoms have abated, and all radio- opacities

of iron tablets on AXR have disappeared. Urine free iron estimation is the

best test of when to stop chelation therapy with desferrioxamine but is not

widely available.

Working outif thepatient needs a serum iron level checked

If a patient has ingested <30mg/ kg body weight of elemental iron (a 200mg

ferrous sulfate tablet = 65mg of elemental iron), then no serum iron level

is required. If in doubt, a plain AXR will usually indicate if lots of tablets

are present. Aserum concentration of <55µmol/ L (<300mg/ dL) also indi-

cates low risk (E Iron, Serum iron concentrations, p. 724).

AbdominalX- ray

This is required in patients who have ingested in excess of 30mg of elemen-

tal iron/ kg body weight. The AXR determines the need for gut decontami-

nation either by gastric lavage or whole bowel irrigation with polyethylene

glycol. Undissolved tablets appear radio- opaque, but they disappear once

dissolved, so the absence of radio- opacities does not exclude the possibility

of toxicity.

IRON

725

Full bloodcount

This is needed in all cases of iron poisoning. Leucocytosis (>15 × 10

/ L) is

common with signicant toxicity. Cross- match is a wise precaution in poten-

tially serious poisoning.

Urea and electrolytes and creatinine, baseline liver function

tests, and clotting

This is needed in allcases.

Blood glucose

Hyperglycaemia is common in serious poisoning.

Arterial bloodgases

These should be checked in symptomatic or severely poisoned patients.

Metabolic acidosis canoccur.

Total iron binding capacity

This has no role in the assessment of acute iron poisoning.

What todo ifestimation ofserum iron concentration is

unavailable

If serum iron assay is not available, the presence of nausea, vomiting, leuco-

cytosis (>15 × 10

/ L), and hyperglycaemia (>8.3mmol/ L) suggests signi-

cant ingestion and the need for treatment with desferrioxamine.

E OHCM 10e, p.842.

Further reading

Chang TP, Rangan C. Iron poisoning:a literature- based review of epidemiology, diagnosis, and man-

agement. Pediatr Emerg Care 2011; 10

:978– 85.

Royal Children’s Hospital Melbourne. Iron poisoning. Clinical practice guidelines. M http:// www.rch.

org.au/ clinicalguide/ guideline_ index/ Iron_ poisoning/ .

726

CHAPTER11 Poisoning and overdose

726

Lead exposure and poisoning

Blood lead concentrations

Blood lead concentrations are used to conrm exposure and decide on

whether environmental exposure reduction measures or (rarely) iron chela-

tion therapy is required. Samples are not ‘urgent’ (except in the case of sus-

pected acute lead encephalopathy) and must be taken into an EDTAtube.

A blood lead level of 5µg/ dL or more requires further testing and moni-

toring, and the source of lead to be found and removed. Alead level of

>45µg/ dL in a child usually indicates the need for chelation treatment.

Occupational lead levels and appropriate responses for adults are enshrined

in Worker/ Occupational Health and Safety legislation.

There are two agents used for chelation therapy in lead poisoning— IV

EDTA (disodium calcium edetate) and oral DMSA (2,3- dimercaptosuccinic

acid). Before use, chelation therapy should be discussed with a toxicologist.

In general, patients with a blood lead concentration of >45µg/ dL should

be treated with chelation therapy and removal from further exposure.

Children with encephalopathy or a blood lead concentration of >75µg/ dL

require admission to hospital for urgent chelation therapy.

AbdominalX- ray

A plain AXR should be performed in all children, particularly if there is a his-

tory of pica, to exclude ingested paint or lead foreign bodies such as curtain

pulls or shing sinkers. Long bone X- rays in children may show leadlines.

Zinc protoporphyrin estimations

Zinc protoporphyrin (ZPP) estimations can be helpful in individuals with

moderate (>20µg/ dL) to high (>40µg/ dL) blood lead concentrations in

whom one is trying to determine the chronicity of exposure. There is a

poor correlation between ZPP and blood lead at lower blood lead concen-

trations. There are other conditions (e.g. iron deciency) that can i ZPP,

and there is signicant inter- individual variation. ZPP has been proposed as

a surrogate marker for blood lead, but blood lead is the best marker and

should not be replaced byZPP.

Other essential investigations

Patients should also have FBC and a blood lm (for basophilic stippling),

U&E, LFTs, and serum Ca

measured. All children should have their serum

iron measured, as iron deciency is an important diagnosis and, if corrected,

can reduce ongoing lead absorption from thegut.

Further reading

Boreland F, Lesjak MD, Lyle DM. Managing environmental lead in Broken Hill:a public health success.

NSW Public Health Bull 2008; 19:174– 9.

Gulson B, Korsch M, Matisons M, Douglas C, Gillam L, McLaughlin V. Windblown lead carbonate as

the main source of lead in the blood of children from a seaside community:an example of local

birds as “canaries in the mine”. Environ Health Perspect 2009; 117

:148– 54.

LEAD EXPOSURE AND POISONING

727

728

CHAPTER11 Poisoning and overdose

728

Lithium

Blood lithium concentration

Lithium is available as sustained- release and non- sustained- release tablets

and liquid. After ingestion of liquid preparations, plasma lithium concentra-

tions peak at 30min. With sustained- release preparations, peak concentra-

tions occur at 4– 5h. The plasma half- life of lithium is often in excess of

24h. Interpretation of plasma lithium concentrations depends on the clinical

circumstances of exposure (E

Acute overdose in lithium- naive patient,

p. 728, E Chronic excess of lithium, p. 728, E

Acute- on- chronic lith-

ium poisoning, p. 728). Do not take blood for lithium levels into a lithium

heparintube!

Acute overdose inlithium- naive patient

A single overdose in a lithium- naive patient is of low risk. However, onset of

toxicity may be delayed for as much as 24h. Plasma samples for lithium assay

should be taken at 6h post- ingestion and measured urgently. The patient

should have IV uids to facilitate lithium elimination. Consider haemodialysis

if plasma lithium concentration is >7.5mmol/ L.

Chronic excess oflithium

Lithium toxicity can occur if the patient has been taking too high a dose

or is dehydrated, or if an interaction with thiazide diuretics, NSAIDs, ACE

inhibitors, or tetracyclines has occurred. Risk of toxicity is further enhanced

by the presence of hypertension, diabetes, cardiac failure, renal failure, or

schizophrenia. Blood for plasma lithium assay should be taken at presen-

tation. Often good IV hydration suces to clear the lithium; rarely hae-

modialysis is needed. Consider haemodialysis if the plasma lithium exceeds

2.5mmol/ L.

Acute- on- chronic lithium poisoning

A patient taking lithium chronically who then takes an acute overdose is

at risk of serious toxicity, because tissue binding of lithium is already high.

The plasma lithium levels should be measured urgently at 6h post- ingestion.

Lithium measurements should be repeated 6- to 12- hourly in symptomatic

patients until clinical improvement occurs. Consider haemodialysis if plasma

concentrations exceed 4mmol/ L.

Indications forhaemodialysis or arteriovenous

haemodialtration

Lithium is eectively removed by haemodialysis (preferred) or arterio-

venous haemodialtration. It is indicated in all patients with severe lithium

poisoning, i.e. coma, convulsions, respiratory failure, or ARF. Plasma lithium

concentrations can also guide the need for haemodialysis/ haemodialtra-

tion. Each hour of dialysis will reduce the plasma lithium by 1mmol/ L, but

plasma lithium often rebounds after haemodialysis has stopped, so the assay

should be repeated at the end of dialysis and again 6– 12hlater.

LITHIUM

729

Urea and electrolytes, serum creatinine

Hyponatraemia is common in lithium toxicity. It is also important to check

the serum K

concentration and urea, as lithium is renally excreted and renal

failure delays its elimination.

ECG

Lithium poisoning may result in arrhythmias, and complete heart block has

been reported. An ECG (and sometimes monitoring) is required. Chronic

lithium toxicity frequently has non- specic and diuse depressed ST-

segments and T wave inversion, which are seldom of sinister consequence.

Further reading

Bellomo R, Kearly Y, Parkin G, etal. Treatment of life- threatening lithium toxicity with continuous

arterio- venous hemodialtration. Crit Care Med 1991; 19:836– 7.

Eyer F, Pfab R, Felgenhauer N, etal. Lithium poisoning pharmacokinetics and clearance during dier-

ent therapeutic measures. J Clin Psychopharmacol 2006; 3

:325– 30.

730

CHAPTER11 Poisoning and overdose

730

Methaemoglobinaemia

Oxidizing agents convert Hb to methaemoglobin (MetHb), and this renders

it incapable of carrying O

. Common agents causing methaemoglobinaemia

include:dapsone, sulfonamides, chlorates, nitrites, nitrates, and local anaes-

thetics including lidocaine. The onset and duration of symptoms will depend

on the agent. Nitrites cause breathlessness and ushing within minutes of

exposure, but dapsone may cause methaemoglobinaemia several hours

after ingestion and the methaemoglobinaemia may then persist fordays.

Essential investigations

Patients withsuspected methaemoglobinaemia should have thefollowing

•

ABGs.

• FBC (especially if dapsone has been taken l haemolytic anaemia).

•

Blood MetHb concentration.

MetHb can produce a normal PO

in the presence of reduced O

satura-

tion. Pulse oximetry measures both MetHb and oxygenated Hb so can give

false results.

Methaemoglobin estimation inblood

Measurement of blood MetHb is required to conrm the diagnosis and

assess the severity of poisoning. The measurement must be done urgently

when administration of the antidote methylthioninium chloride (methylene

blue) is contemplated. Samples for MetHb estimation need to be analysed

as soon as possible after collection, as if left to stand around, the MetHb will

be falsely low owing to a reduction by endogenous MetHb reductase. The

severity of symptoms correlates roughly with the measured MetHb con-

centrations. Anaemia and cardiac or pulmonary disease will lead to more

severe symptoms at a lower MetHb level (see Table11.2).

If the patient has severe clinical features of toxicity or if the blood

MetHb concentration is >30%, the patient should be given methylene blue.

Methylene blue can be given at lower blood MetHb concentrations in those

who are symptomatic.

Table11.2 Clinical eects

MetHb concentration (%) Clinical eects

0– 15 None

15– 30 Mild:cyanosis, tiredness, headache, nausea

30– 50 Moderate:marked cyanosis, tachycardia, dyspnoea

50– 70 Severe:coma, ts, respiratory depression,

metabolic acidosis, arrhythmias

>70% Potentially fatal

OPIOIDS

731

Opioids

Classic features ofopioid poisoning

• Depressed respiratory rate and volume.

• Pinpoint pupils.

• Coma

• Signs of parenteral drug use, e.g. needlemarks.

Toxicity can be prolonged for 24– 48h, particularly after ingestion of metha-

done, which has a long half- life. The lifesaving measure is prompt adminis-

tration of adequate doses of naloxone, before waiting for results of any

investigations. This often needs to be repeated or an infusion started, as the

half- life of the antidote is much shorter than opioiddrugs.

Adequacy ofventilation

saturation monitoring and/ or ABG analysis demonstrates the adequacy

of ventilation in those whose respiration is depressed, together with accu-

rately measuring the respiratoryrate.

Urine drug screening

Qualitative screening of the urine (group- specic immunoassay) conrms

recent use. This may, however, not detect fentanyl derivatives, tramadol,

and other synthetic opioids.

Measuring opioids inblood

Quantitative analysis is usually undertaken by LC/ Q- TOF- MS or GC- MS or

MS. This is often required for medicolegal purposes, particularly where a

fatality or a childcare issue is involved.

‘Plasma morphine free and total morphine concentrations were an

average of 88 and 277µg/ L in 54 people treated for heroin overdose’.

Interestingly, the degree of poisoning correlated better with total morphine

concentrations than free concentrations.

Post- mortem morphine levels in heroin overdose deaths vary, depending

on prior narcotic history, but in general exceed 0.3mg/ L.

‘Blood tramadol concentrations in 105 people arrested for impaired driv-

ing performance averaged 850µg/ L’.

Post- mortem concentrations in ve

tramadol deaths averaged 6.1mg/ L. Heroin metabolites and tramadol do

not undergo signicant post- mortem redistribution.

Paracetamol screening

Opioid tablets are frequently combined with paracetamol. All unconscious

patients should therefore have plasma paracetamol level measured.

Further reading

Jones AL. Management of opioid poisoning. In:A Webb, D Angus, S Finfer, L Gattinoni, M Singer

(eds.). Oxford Textbook of Critical Care

, 2nd edn. 2016; pp.1522– 5.

8 Baselt RC, Cravey RH. Disposition of Toxic Drugs and Chemicals in Man, 9th edn. San

Francisco:Chemical Toxicology Institute,2011.

732

CHAPTER11 Poisoning and overdose

732

Paracetamol (acetaminophen) poisoning

Overview

Paracetamol is the commonest drug taken in overdose in the UK.

Paracetamol can be measured by a variety of assay methods, but HPLC or

LC- MS is less susceptible to interference than some enzyme- based assays.

Measurement of plasma paracetamol concentration is essential for

assessing the need for antidotal treatment (NAC) in most cases of par-

acetamol poisoning. The nomogram for paracetamol concentrations and

protocols for when and how to give NAC diers between countries, and it

is important to consult your own national guidelines. If NAC is given within

12h of the overdose, it provides complete protection against liver injury

and renal failure. Beyond 12h after ingestion, the protection is less com-

plete and assessment of liver damage is required. Paracetamol poisoning

can be deceptive, as there is a latent phase of many hours where the patient

remains well before liver damage develops. The co- ingestion of opioids may

delay gastric emptying and peak plasma paracetamol concentrations.

INR/ PT

The most sensitive marker of prognosis in paracetamol poisoning is the PT

or INR. This often starts to i within 24– 36h of the overdose and peaks at

48– 72h. Once the INR/ PT starts to improve, this is a sign that hepatotoxic-

ity is starting to improve and the patient will not go on to develop acute

liver failure. Approximately half of patients with a PT of 36s at 36h post-

ingestion will develop acute liver failure.

Plasma alanine and aspartate aminotransferases

These may begin to rise as early as 12h post- ingestion but usually peak at

72– 96h. AST or ALT values in excess of 10,000IU/ L are not unusual, and

a plasma ALT of >5000IU/ L is very suggestive of paracetamol poisoning

(see Fig. 11.1). Serum bilirubin may peak after the aminotransferase, and

this should not lead to concern for patients in whom the INR or PT have

begun tofall.

Do not correct abnormalities in PT or INR with FFP or cryoprecipitate,

unless life- threatening bleeding is taking place; otherwise the most sensitive

marker of how the patient is progressing will belost.

Other blood test abnormalities inparacetamol poisoning

Hypoglycaemia and metabolic acidosis are common. Early metabolic acido-

sis is often associated with very high plasma paracetamol concentrations,

e.g. >400mg/ L. Later, development of acidosis indicates incipient acute

liver failure and the need to urgently check ABGs, LFTs, and INR/ PTR.

Pancreatitis with i serum amylase/ lipase has been reported. Several

cases of thrombocytopenia have been reported.

U&E and creatinine should be checked. Renal failure can occur in the

context of hepatic failure, but also in its absence (in 1 in 100 patients). It is

treated with NAC and supportive measures, e.g. haemodialysis, if needed.

Full recovery with supportive care is common.

PARACETAMOL (ACETAMINOPHEN) POISONING

733

Investigating thepatient who has taken a paracetamol

overdose <4hago

Ingestion of >75mg/ kg of paracetamol or a paracetamol- containing prod-

uct should be recognized as a potential hepatotoxic dose for most people. If

ingestion of this amount or more has occurred within the last 1h, activated

charcoal should be given orally (50g for an adult). Aplasma paracetamol

level should then be checked at 4h from the time of ingestion, to determine

the need for NAC treatment from the nomogram (see Fig.11.2).

Very rarely, e.g. after ingestion of 4 × 500mg tablets by an adult, a con-

rmatory plasma paracetamol level is not needed, but in general it is safer

to be certain by checking a blood concentration.

Investigating thepatient who has taken a paracetamol

overdose between4 and8hago

A plasma paracetamol level should be checked as soon as possible. If a sin-

gle acute ingestion has taken place, then the result is plotted on the relevant

national nomogram against the time since ingestion (e.g. see Fig. 11.2). This

determines the need for NAC antidote treatment (i.e. if the level is above

or very close to theline).

If the overdose is staggered or repeated, supratherapeutic, then specic

toxicology, advice is needed. If in doubt, treat the patient withNAC. Some

countries have modied this nomogram to treat patients at lower paraceta-

mol levels.

Investigating thepatient who has taken a paracetamol

overdose between8 and 24hago

Start treatment with NAC straightaway. Take blood for a paracetamol level,

INR/ PT, creatinine, and plasma venous HCO

−

(if plasma venous HCO

−

abnormal, check ABGs). Check results and refer to the graph to determine

whether treatment with NAC needs to be continued (i.e. is the plasma level

above the treatment line?) or can be stopped (below the line). 3 Beyond

7500

15,000

12,500

2500

468 14 162

5000

10 12

10,000

ALT (IU/L)

Time after ingestion (days)

Bilirubin

(µmol/L)

INR

100

ALT

Bilirubin

INR

Fig.11.1 Time course of liver function tests in paracetamol poisoning.

734

CHAPTER11 Poisoning and overdose

734

16h after ingestion, the sensitivity of the assay for paracetamol may be too

low to detect a treatable level— check and, if in doubt, treat the patient

with NAC! On completion of NAC, check blood INR/ PT, creatinine, and

plasma venous HCO

−

(if abnormal, check ABGs). If the patient is asympto-

matic and the INR or creatinine is normal or falling, discontinue NAC. If the

patient has symptoms (abdominal pain or vomiting) or the INR or creatinine

is rising, continue maintenance NAC (50mg/ kg in 500mL of glucose every

4h) until the INR improves. Contact a poisons centre/ liverunit.

Investigating thepatient who has taken a paracetamol

overdose >24h ago or thetiming is not able tobe

established

Start treatment with the antidote NAC straightaway, unless a trivial amount

has beentaken.

Take blood for baseline INR/ PT, creatinine, venous HCO

−

(if abnormal,

check ABGs), and paracetamol.

If the patient is asymptomatic and the laboratory tests normal (INR <1.3,

paracetamol concentration <5 mg/ L, and ALT <2 times the upper limit of

normal), discharge the patient and advise to return if vomiting/ abdominal

pain develops. If the blood results are abnormal, continue NAC, and phone

a liver unit/ poisons centre for advice.

120

Plasma-paracetamol concentration (mmo/litre)

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

110

100

Plasma-paracetamol concentration (mg/litre)

0246810 12

Time (hours)

14 16 18 20 22 24

Treatment lineTreatment line

Fig.11.2 An acetylcysteine treatmentgraph.

Note: The most up-to-date national nomogram should be accessed for your country.

PARACETAMOL (ACETAMINOPHEN) POISONING

735

Investigating thepatient who has taken a staggered

overdose

The Commission on Human Medicines currently recommends that a Xmg/

kg/ 24h dose ingested calculation is not used to guide therapy. Current

advice is that all staggered overdoses should be treated with NAC and dis-

cussed with a toxicologist.

Blood is taken for paracetamol level, U&E, creatinine, HCO

−

, ALT, and

INR. Hepatotoxicity is not likely if the patients is asymptomatic, the plasma

paracetamol concentration is <5 mg/ L, INR is <1.3, and ALT is <2 times

the upper limit of normal. If all of the above are found, then NAC may be

stopped and the patient discharged, with advice to return if they experience

vomiting or abdominalpain.

Investigating thepatient who has a repeated

supratherapeutic ingestion

All patients with a supratherapeutic overdose should be considered for

NAC treatment and discussed with a toxicologist. Currently, patients with

symptoms or signs of hepatotoxicity or those who have denitely ingested

75mg or less of paracetamol require no treatment.

Further reading

BMJ Best Practice. Paracetamol overdose. M http:// bestpractice.bmj.com/ best- practice/ mono-

graph/ 337.html.

TOXBASE. M

https:// www.toxbase.org/ .

UK National Poisons Information Service. M

http:// www.npis.org/ .

736

CHAPTER11 Poisoning and overdose

736

Salicylate poisoning

Features ofsevere poisoning

Ingestion of >150, 250, and 500mg/ kg body weight of aspirin, respectively,

produces mild, moderate, and severe poisoning, respectively. Aspirin poi-

soning is becoming increasingly rare in developed countries. Signs of seri-

ous salicylate* poisoning include metabolic acidosis, renal failure, and CNS

eects such as agitation, confusion, coma, and convulsions. Death may

occur as a result of CNS depression and cardiovascular collapse. The devel-

opment of metabolic acidosis is a bad prognostic sign, as it also indicates i

CSF transfer of salicylate.

Note:(*) aspirin, oil of wintergreen.

Plasma salicylate concentration

Plasma salicylate should be measured urgently in all, but the most trivial

overdose, i.e. all those thought to have ingested >150mg/ kg body weight

of aspirin or any amount of oil of wintergreen. It should be performed at

4h post- ingestion, because delayed absorption of the drug renders such

levels uninterpretable before this time. As salicylates may form concretions

in the stomach, which delay absorption, it is recommended that a salicylate

level is rechecked 3– 4h after the rst sample, to catch the peak salicylate

concentration. There is no evidence for indiscriminate requesting of salicy-

late concentrations in every unconscious patient (unlike paracetamol) or

in conscious patients who deny taking aspirin and who have no features

suggesting salicylate toxicity. The plasma salicylate concentration is not an

absolute guide to toxicity, as paracetamol levels are in paracetamol poison-

ing, but should be interpreted together with clinical features and acid– base

status of the patient.

Urinary alkalinization (E OHCM 10e, p. 844) is indicated for patients

with salicylate concentrations of 600– 800mg/ L in adults and 450– 700mg/ L

in children and the elderly. Metabolic alkalosis is not a contraindication to

bicarbonate therapy, as patients may have a high base decit in spite of an

elevated serumpH.

Haemodialysis is very eective at salicylate removal and correction of

acid– base and electrolyte abnormalities. It should be considered if the

plasma salicylate levels are >700mg/ L in children and >800mg/ L in adults.

Other indications for haemodialysis include resistant metabolic acido-

sis, severe CNS eects, such as coma, convulsions, pulmonary oedema,

andARF.

Arterial bloodgases

Acid– base problems are common in salicylate poisoning. Respiratory cen-

tre stimulation causes respiratory alkalosis. Uncoupled oxidative phospho-

rylation and interruption of glucose and fatty acid metabolism by salicylates

often cause concurrent metabolic acidosis. Serial ABGs are needed in

severe salicylate poisoning.

Further reading

Ghosh D, Williams KM, Graham CG, et al. Multiple episodes of aspirin overdose in an individual

patient:a case report. J Med Case Rep 2014; 19:374.

THEOPHYLLINE

737

Theophylline

Acute theophylline poisoning can carry a high mortality, and its manage-

ment is best guided by the Shannon severity grading scheme, bearing in

mind that delayed eects tend to occur after sustained- release formulations

have been ingested. The adult therapeutic range is 10– 20mg/ L. Serious tox-

icity occurs at >100mg/ L (770mmol/ L).

Urea and electrolytes, creatinine, glucose

It is vital to check the plasma K

concentration frequently, as hypokalaemia

is a life- threatening complication and the serum K

concentration is a use-

ful guide to severity. If >2.5mmol/ L, the patient is less severely poisoned

(grade 1) than if it falls to <2.5mmol/ L (grade 2). Check blood glucose

since hyperglycaemia is a common complication.

Arterial bloodgases

In potentially serious poisoning (e.g. ingestion of >20mg/ kg body weight),

abg analysis is helpful in optimizing the acid– base status of the patient. An

initial phase of hyperventilation with respiratory alkalosis can be followed

by a further stage of metabolic acidosis.

ECG

In potentially serious poisoning (e.g. ingestion of >20mg/ kg body weight),

an ECG is required. Cardiac monitoring is helpful for early identication of

arrhythmias in such patients.

Plasma theophylline concentrations

Measuring plasma theophylline concentrations conrms theophylline ingestion

if this is in doubt, and it is usually undertaken by HPLC or LC- MS/ MS. However,

for the vast majority of poisoned patients, obtaining a plasma theophylline con-

centration does not guide their management. Therapeutic levels rarely exceed

20mg/ L (155mmol/ L). Theophylline peak concentration in plasma may occur

at 1– 3h after ingestion of a standard- release formulation. However, overdose

is often with sustained- release products, and delayed absorption can result in

delayed peak plasma concentration and toxicity, often 12– 24hlater.

Plasma concentrations are also helpful in deciding when to employ char-

coal haemoperfusion in seriously poisoned patients (particularly if plasma

concentrations are >100mg/ L (770mmol/ L)). Charcoal haemoperfusion

can be considered at lower concentrations, e.g. 80mg/ L, in the elderly or

those with pre- existing IHD, and those with persistent seizures or hypo-

tension not responding to IV uids. Charcoal haemoperfusion can also be

decided on the basis of grade 3 or 4 severity grading alone. If charcoal hae-

moperfusion is not possible, then haemodialysis with multi- dose activated

charcoal is probably an alternative.

Urine testing formyoglobinuria and measuring serum

creatinekinase

Theophylline poisoning can be accompanied by rhabdomyolysis. Hence,

the urine should be dipstick- tested, and if found +ve for blood, a serum

CK should be obtained. This will then indicate that renal function should

be closely monitored and whether the urine should undergo alkalinization.

Further reading

Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993;

119

:1161– 7.

738

CHAPTER11 Poisoning and overdose

738

Tricyclic antidepressants

The main risks of overdose with these drugs are the cardiovascular system

(CVS) and CNS toxicity.

Electrocardiogram

An ECG should be performed in all but the most trivial cases of overdose.

ECG abnormalities are common inmoderate tosevere poisoning and include

•

QRS prolongation:>110ms in adults predicts the risk of ventricular

cardiac arrhythmias (and the need for IV sodium bicarbonate), and a

QRS >160ms predicts the risk of ts. In children, a QRS >110ms is

predictive of the risk of arrhythmias, but notts.

•

Note:ECG criteria are not the only factors assessing the risk of

arrhythmias, ts, and acidosis— electrolyte disturbances contribute.

Supraventricular, and potentially fatal ventricular, arrhythmias canoccur.

Cardiac monitoring

This is essential if ingestion of >10mg/ kg body weight has taken place. It is

seldom necessary beyond 24h after ingestion.

Arterial blood gas analyses

These should be done on all patients with marked symptoms and signs,

particularly those with a reduced GCS score. It should also be performed

on those with widened QRS or seizures, not least because such patients

are receiving IV sodium bicarbonate therapy and a pH of 7.5 should not

be exceeded.

Plasma concentrations

This is of no value, as plasma concentrations of tricyclic antidepressants

correlate poorly with clinical features of toxicity.

WARFARIN AND SUPERWARFARINS

739

Warfarin and superwarfarins

INR/ PTR

This is a key test in possible warfarin/ superwarfarin overdose. In the case

of warfarin, the INR often begins to rise from day 2 after the overdose and

settles within a week, but with superwarfarins, the time course of clotting

abnormality may stretch to weeks. Thus, repeated INR/ PTR estimations

may guide progress and the need for vitamin K1 antidote in warfarin toxicity.

Individual factor assays have been done in some cases but are not routinely

necessary.

Liver functiontests

Assessment of liver function is helpful in warfarin overdose. Acongested,

dysfunctional liver would be expected to handle the consequences of a

warfarin overdose lesswell.

740

CHAPTER11 Poisoning and overdose

740

Table ofconversion factors

betweenmass and molarunits

(See Table11.3.)

Table11.3 Conversion factors betweenmass and molecularunits

Drug Mass units Molar (SI) units Conversion factor

Carbamazepine

mg/ L µmol/ L 4.23

Digoxin

µg/ L or ng/ mL nmol/ L 1.28

Ethanol

g/ L mmol/ L 1.28

Iron

mg/ L mmol/ L 0.179

Lead

mg/ L mmol/ L 0.0048

Paracetamol

mg/ L mmol/ L 0.0066

Phenytoin

mg/ L mmol/ L 3.96

Salicylate (aspirin)

mg/ L mmol/ L 0.0072

Theophylline

mg/ L mmol/ L 7.7

741

Chapter12

Rheumatology

Rheumatological investigations 742

Inammatory markers 744

Haematology 746

Biochemistry tests 748

Autoantibodies 750

Arthrocentesis 754

Neurophysiology 755

Diagnostic imaging 756

742

CHAPTER12 Rheumatology

742

Rheumatological investigations

Investigations in rheumatology are important not only in diagnosis, but also

in assessing disease activity and monitoring treatment. They are comple-

mentary to a careful history and physical examination and should only be

requested in the correct clinical context where results are likely to aect

management. In isolation, ‘abnormal’ results can lead to unwarranted anxi-

ety, investigations, and treatment.

RHEUMATOLOGICAL INVESTIGATIONS

743

744

CHAPTER12 Rheumatology

744

Inﬂammatory markers

Inammatory rheumatic disease is usually associated with an acute

phase response. The ESR and CRP are the most commonly used to

screen for inammation. However, they are non- specic, also i in infec-

tion and malignancy. Obesity is also recognized as a cause for high CRP.

Conversely, a normal ESR or CRP does not exclude rheumatic disease, e.g.

spondyloarthropathies.

Erythrocyte sedimentationrate

ESR is measured by observing how fast RBC fall through a column of blood

in 1h. It is dependent upon many variables, including serum Igs, brinogen,

and Hct. Therefore, a raised ESR may not reect inammation, but other

factors, e.g. hypergammaglobulinaemia. Normal ESR levels also i with age.

In some centres, plasma viscosity is preferred as a screening for acute phase

response, rather than the ESR, as it is independent of age, sex, and Hb

Erythrocyte sedimentation rate, pp. 252–3).

C- reactive protein

CRP production is driven by IL- 1 and IL- 6 on hepatocytes. It generally pro-

vides a more accurate reection of inammatory or infective processes

than ESR, as it changes more rapidly and is independent of the variables

that complicate ESR interpretation.

ESR and CRP indiagnosis and monitoring

Although ESR or CRP are not specic, the degree of elevation and relation-

ship of ESR to CRP may suggest a diagnosis. For example CRP and ESR may

be very high in infection and gout but are usually only moderately raised

in RhA (see Table 12.1). Isolated elevation of CRP may also reect auto-

inammatory disorders, e.g. familial Mediterranean fever and amyloidosis

or infection.

In cases where ESR/ CRP are i in active disease, they are extremely use-

ful in monitoring disease activity and response to treatment.

Other acute phase markers

In general, it is not helpful to measure other acute phase reactants, e.g. caer-

uloplasmin, α

1- antitrypsin, brinogen, and Hp. Two exceptions are serum

ferritin and complement, which can be useful in diagnosis. Other common

biochemical and haematological tests discussed below also reect levels of

inammation, e.g. albumin and Hb fall, whilst ALP and γGTrise.

In a clinical scenario where CRP is very high and it is dicult to distinguish

between systemic infection or inammation (e.g. vasculitis), measuring PCT

might be considered. This is usually used in the ITU/ acute medicine setting.

Ahigh level suggests a high risk of progression to systemic sepsis, whilst a

low level may support an inammatory cause for the raisedCRP.

INFLAMMATORY MARKERS

745

Serum ferritin

Ferritin may be used as a surrogate marker for body iron stores but is also

an acute phase reactant. In the presence of active inammation or infection,

a normal or high serum ferritin may be found, even if the patient has true

iron deciency (E

Assessment of iron status, pp. 244–7). Serum ferritin

levels are often very high in active adult Still’s disease and fall with treatment.

Elevated ferritin associated with a transferrin saturation of over 45% is also

seen in haemochromatosis arthropathy.

Complement

Complement components C3 and C4 usually rise in the presence of active

inammation or infection. However, in SLE, they are commonly low. In

some, but not all, SLE patients, they are abnormal when disease is active and

normalize on treatment, making them useful in monitoring disease activ-

ity, especially lupus nephritis. Low levels of C1 can be associated with the

development ofSLE.

Table12.1 ESR and CRP indiagnosis

Diagnosis ESR CRP

Infection ii or iii ii or iii

Malignancy Normal to ii Normal to i

RhA ii ii

SLE* i Normal to i

SLE with serositis i Normal to ii

Gout/ CPPD** ii or iii ii or iii

Sjögren’s syndrome i or ii i

Vasculitis ii or iii ii or iii

Osteoarthritis Normal Normal

Psoriatic arthritis/ spondyloarthropathy Normal to ii Normal to ii

* Systemic lupus erythematosus.

** Calcium pyrophosphate disease.

746

CHAPTER12 Rheumatology

746

Haematology

Haemoglobin

There are three common scenarios for anaemia (d Hb) in patients with

rheumatic symptoms.

•

Related to the rheumatic disease— most commonly ‘anaemia of

chronic disease’. Rarely AIHA (associated with +ve Coombs’ test, high

reticulocytes, high bilirubin, lowHp.)

•

As a manifestation of an alternative systemic disorder that presents with

arthralgia (e.g. coeliac disease/ leukaemia).

• Related to drug side eects, e.g. GI bleeding due to NSAIDs or

pancytopenia caused by immunosuppressive agents (e.g. methotrexate).

The degree, speed of onset, and type of anaemia should be assessed, tak-

ing into account the clinical picture. Trends in Hb are useful in monitoring

disease activity and treatment.

Microcytic hypochromic anaemia

The major dierential diagnosesare:

• Chronic iron deciency anaemia.

• Thalassaemiatrait.

• Anaemia of chronic disease (typically associated with normal MCV, but

if chronic, the MCV may reduce).

Iron deciency related to acute or chronic blood loss (e.g. GI bleeding), or

nutritional or bowel disease, such as Crohn’s disease or coeliac disease,

should be considered.

Macrocytic anaemia

Vitamin B

or folate deciency related to nutritional deciency, e.g. scle-

roderma causing jejunal diverticulosis, Whipple’s disease causing malab-

sorption, or due to drug therapy such as methotrexate, sulfasalazine, and

azathioprine. Excessive alcohol consumption may also cause macrocytosis

without signicant anaemia.

Normocytic normochromic anaemia

Usually reects chronic disease, and the degree of anaemia may vary with

disease severity, e.g. RhA, crystal arthritis, vasculitis.

Dimorphic anaemia (large and small redcells)

This picture is seen in mixed deciency, e.g. iron deciency plus vitamin B

or folate deciency, post- transfusion, or during iron replacement therapy

in a patient with iron deciency. It is afeature of malabsorption associated

with coeliac- related arthritis, scleroderma of the gut, and jejunal bypass

arthritis.

White cellcount

White cell count may be helpful in diagnosis and monitoring disease activity

and is essential for monitoring immunosuppressive therapies. Diagnoses to

consider where levels are i

/ d are listed. BM biopsy may need to be consid-

ered to distinguish from ° haematological disorders.

HAEMATOLOGY

747

Increased

• Neutrophilia:septic arthritis, crystal arthropathy (gout and pseudogout),

systemic corticosteroid administration, myeloproliferative disorders.

•

Lymphocytosis:consider lymphocytic leukaemia with joint symptoms and

viral infection.

•

Eosinophilia:eosinophilic granulomatosis with polyangiitis (EGPA;

formerly known as Churg– Strauss syndrome) and other vasculitides,

hypereosinophilic syndromes, eosinophilic fasciitis, and also Addison’s

disease (can complicate rheumatological diseases). Newly raised

eosinophils should heighten awareness of potential adverse reactions to

disease- modifying drugs. Asthma and allergy.

Reduced

• Neutropenia:consider autoimmune neutropenia, e.g. associated with SLE

and Felty’s syndrome in RhA. May be drug- induced (very common with

tocilizumab and seen as adverse response to sulfasalazine, methotrexate,

azathioprine, cyclophosphamide, ciclosporin, mycophenolate, leunomide,

and other cytotoxics). Normal range for neutrophils also vary between

races, e.g. neutrophils may be lower in Afro- Caribbean populations.

• Lymphopenia:common inSLE.

Plateletcount

• Thrombocytosis:reects active inammation, e.g. RhA, but should be

distinguished from ° polycythaemia vera (JAK2 kinase and BM biopsy if

appropriate).

•

Thrombocytopenia:autoimmune thrombocytopenia, may also be related

to connective tissue disease, including SLE, RhA (Felty’s syndrome), and

antiphospholipid syndrome(APS).

• Can also reect drug toxicity, including those listed under

neutropeniaabove.

Pancytopenia may alsooccur

• As part of autoimmune disease, e.g. SLE/ Felty’s syndrome.

• As a side eect to immunosuppressive drugs previously mentioned.

• As a severe complication of disease. Macrophage activation syndrome

is a life- threatening disorder that can manifest with pancytopenia in

systemic juvenile arthritis, adult Still’s disease, lupus, and Kawasaki

disease. Pancytopenia is associated with high fever, hepatosplenomegaly,

high ferritin, and hypertriglyceridaemia and is associated with

unexpectedly lowESR.

748

CHAPTER12 Rheumatology

748

Biochemistrytests

Although biochemical tests do play a role in the diagnosis of rheumatic dis-

ease (e.g. metabolic bone disease), their major use is in the assessment of

systemic involvement of disease, e.g. renal or hepatic. In addition, they are

essential for monitoring treatment.

Renal function

Renal function is measured in the diagnosis and monitoring of systemic

disease. eGRF is widely used as a surrogate marker for the GFR. Awide

range of diseases may involve the kidney, including vasculitis, SLE, Sjögren’s

syndrome, andgout.

The dose of many drugs should be adjusted according to renal func-

tion, including immunosuppressive agents, e.g. cyclophosphamide and

methotrexate. Some drugs are contraindicated with low eGFRs, e.g. IV

zoledronate and other bisphosphonates for osteoporosis. Drug treatment

should also be considered as a cause for decline in renal function in rheuma-

tology patients, e.g. NSAIDs, sulfasalazine.

Uricacid

Ninety per cent of cases of gout will have a raised serum urate. However,

it may also be elevated in normal health and be i by diuretic treatment.

Denitive diagnosis of gout can only be made by identication of urate

crystals by polarizing light microscopy of joint uid or in biopsy.

Gamma globulins

γ- globulins are often elevated in active inammatory disease. They are usu-

ally globally i

in Sjögren’s syndrome but may also be raised in RhA, sar-

coidosis, SLE, and other connective disease.

Liver functiontests

These are measured in the monitoring of many disease- modifying agents,

e.g. methotrexate and sulfasalazine. Elevated γGT and ALP can also reect

active inammation. They may be relevant in considering underlying diagno-

ses of arthralgia, e.g. haemochromatosis.

Bone function

Serum calcium

Hypercalcaemia should raise suspicion of malignancy, metabolic bone dis-

ease, and sarcoidosis. In metabolic bone disease/ hyperparathyroidism,

is not always elevated and a ‘high normal’ result may be signicant

in the correct clinical context. Hypocalcaemia may indicate hypoparathy-

roidism (E Hypercalcaemia, pp. 190–2; E

Hypercalcaemia/ osteomalacia,

pp. 188–9).

BIOCHEMISTRYTESTS

749

Alkaline phosphatase

ALP may be elevated due to bone, liver, or GI disease. If γGT is concomi-

tantly raised, one would suspect it originates from the liver. In isolation, it

is more likely to be related to bone and further investigation, e.g. PTH,

vitamin D, urinary Ca

, should be considered. ALP is high in Paget’s disease,

hyperparathyroidism, fractures, and bony metastases. Low ALP may be the

only biochemical clue to hypophosphatasia.

Phosphate

Hypophosphataemia occurs in hyperparathyroidism and hereditary and

acquired hypophosphatasia.

Serum parathyroid

Where bone biochemistry is abnormal, PTH should be measured. It

is elevated in hyperparathyroidism and vitamin D deciency. In cases of

hypocalcaemia, low PTH suggests ° parathyroid disease, whereas normal

or raised PTH suggests PTH resistance (E Hypercalcaemia, pp. 188–9;

Hypercalcaemia/ osteomalacia, pp. 190–2).

Urinary calcium

Urinary Ca

is useful in the investigation of hypercalcaemia and elevated

PTH. In hyperparathyroidism, urinary excretion is i. If it is low, familial

hypocalciuric hypercalcaemia should be considered. Hypercalciuria may

also be associated with renal calculi.

Bone markers

Bone turnover markers are available but have limited use due to the

requirement for consistent sample collection, especially for bone resorption

markers. Serum and urinary C- terminal and N- terminal telopeptide type 1

collagen (CTX and NTX) are the most commonly used markers of bone

resorption, and procollagen type 1 N- terminal propeptide (P1NP) of bone

formation.

750

CHAPTER12 Rheumatology

750

Autoantibodies

Autoantibody tests are an integral part of rheumatological investigation.

Detection of antibodies against specic antigens is useful for both diagnostic

and prognostic purposes and less often monitoring disease activity. However,

these tests have their limitations. Most autoantibodies are not specically

associated with a single diagnosis but can occur in a range of diseases and in

healthy individuals. ELISA is often used for screening, as it is more automated

and cheaper than other methods and provide some quantitative information.

Other methods, e.g. indirect immunouorescence, are used for screening or

to detect specic antibodies, depending on the tissue substrateused.

Rheumatoidfactor

RF is an antibody to the Fc portion of IgG, forming immune complexes,

rst described in the 1940s. Although included in the American College of

Rheumatology criteria for rheumatology, RF is not specic to RhA. It can be

found in 4– 16% of healthy individuals (prevalence i with age). It may also

be +ve in other autoimmune diseases, malignancy, and chronic infection.

The rheumatoid arthritis particle agglutination (RAPA) test may still be used

to conrm a diagnosis of rheumatoid disease in the presence of an appro-

priate clinical picture of symmetrical inammatory polyarthritis. Ahigh titre,

e.g. 1:320, is of more relevance than a borderline result, e.g. 1:20. It is less

helpful in early diagnosis, compared to established disease, with RF being

+ve in around one- third of rheumatoid patients at 3months post- diagnosis

and two- thirds at 6 months. Other methods e.g. ELISA, are more com-

monly used in modern practice but risk false +ve results.

Anti- cyclic citrullinated peptide antibodies

Anti- cyclic citrullinated peptide antibodies (ACPA) may be considered more

useful in clinical practice in the diagnosis of RhA. In some centres, RF is only

checked if ACPA are −ve. First described in 1998, they are high- anity IgG

class antibodies that react with the amino acid citrulline and are measured

by ELISA. They are found in the sera of about 75% of rheumatoid patients

and are about 96% specic for RhA. They appear earlier than RF, are unaf-

fected by treatment, and predict the development of erosions. However,

they are not pathognomic.

Antinuclearfactor

ANA, commonly detected by ELISA, is often thought of as a screening test

for SLE or other connective tissue disease. Indeed, it is +ve in 90– 99% of

cases of lupus, in over 90% of cases of scleroderma, and in many cases of

Sjögren’s syndrome, mixed connective tissue disease, and myositis. ANA,

however, can be +ve in 3– 5% of healthy individuals and many diseases,

including hepatic disease, e.g. PBC, pulmonary disease, e.g. ° pulmonary

hypertension, chronic infections, malignancy, or may be drug- induced. It

should therefore be interpreted only in the context of clinical symptoms.

Indirect immunouorescence is another method of detecting ANA, and

results are presented as patterns of uorescence, e.g. homogenous, speck-

led, nucleolar. Although not specic, some clinicians may use these in deter-

mining the relevance of the test, e.g. a strong +ve homogenous ANA is

more likely to be associated with SLE than a weak speckled pattern.

AUTOANTIBODIES

751

Anti- DNA antibody

In contrast to ANA antibodies, dsDNA is less sensitive (50– 80% of cases),

but highly specic for SLE. They are seen rarely in healthy individuals and in

disorders such as chronic active hepatitis and Sjögren’s syndrome. They are

also useful in monitoring disease activity in some, but not all, individuals with

SLE. Arising titre of dsDNA may precede a are in disease.

Extractable nuclear antigen antibodies

Where ANA is +ve, ENA antibodies should be measured as their presence

can suggest a risk of certain clinical scenarios.

•

Anti- Ro and anti- La (SSB):occur in Sjögren’s syndrome and SLE, but also

other autoimmune diseases. They have been associated with fetal heart

block when they are present in the mother.

•

Anti- Sm:lupus nephritis.

•

Anti- Scl- 70 (anti- topoisomerase 1)and anti- centromere antibodies (anti- CENP A/

B/ C):these antibodies are associated with scleroderma. Anti- centromere

antibodies are particularly associated with limited cutaneous scleroderma,

and anti- Scl- 70 with diuse systemic sclerosis. They may be a marker of

pulmonary hypertension. Anti- Scl- 70 is associated with pulmonary brosis.

• A ‘myositis panel’ can be requested where polymyositis or dermatomyositis

are suspected, including Jo-1, Mi-2, PM-Scl, SRP, Ku and antisynthetase

antibodies (PL-7, PL-12, EJ, OJ).

• Presence of Mi-2 is more commonly associated with dermatomyositis

and associates with better prognosis.

•

PM-Scl suggests polymyositis/scleroderma overlap, SRP associates with

chronic progressive disease.

•

Antisynthetase antibodies suggest risk of interstitial lung disease.

• Anti- RNP antibodies:have been associated with ‘mixed connective tissue

disease’ where features of several clinical syndromes can occur in

combination.

•

Anti- histone antibodies:have been associated with drug- inducedlupus.

Antiphospholipid antibodies

° APS (thrombosis, thrombocytopenia, and fetal loss) and other connec-

tive tissue diseases are associated with antiphospholipid antibodies. They

should only be requested in the correct clinical context, as they can also be

detected in normal health and many other clinical contexts, e.g. infection.

IgG and IgM anticardiolipin antibodies (ACL) and β2- glycoprotein antibod-

ies are most commonly measured via ELISA. Asingle +ve result should be

interpreted with caution, and the test should be repeated after 6 weeks to

determine relevance. Ahigh titre and IgG- type antibody may be of greater

clinical relevance than a low titre andIgM.

Lupus anticoagulant tests are also undertaken and are +ve when an i in

clotting time is not reversible when control plasma is added invitro.

Antineutrophil cytoplasmic antibody

First described in 1982, classical ANCA (cANCA) gives a characteristic

bright central granular cytoplasmic staining of ethanol- xed human neutro-

phils by immunouorescence (IIF). pANCA was later described to give a

perinuclear IIF pattern. ELISA is used to identify antigen- specic ANCA, and

PR3 and MPO are now usually tested routinely.

752

CHAPTER12 Rheumatology

752

ANCA is often thought to be a screening test for vasculitis. Indeed, the

presence of cANCA and PR3 in combination has been reported to be

99% specic (and 755% sensitive) for granulomatous polyangiitis (formerly

known as Wegener’s granulomatosis). Similarly (790% specic), the pres-

ence of pANCA and MPO together is associated with microscopic poly-

angiitis. However, like other autoantibodies, ANCA (especially pANCA)

may be +ve in many other situations, including infection, TB, malignancy,

and IBD. Therefore, the full clinical picture must be used in making treat-

ment decisions, and reliance should not be put on ANCA alone. In par-

ticular, the absence of a +ve PR3 or MPO or a pANCA with weak +ve

MPO should raise suspicion to carefully exclude an alternative explanation

to vasculitis.

HLA- B27

HLA- B27 has been strongly associated with ankylosing spondylitis (present

in 90% of patients) and is also linked to other diseases, including reactive

arthritis, IBD, and uveitis. However, as it occurs in about 8% of the popula-

tion, it is not helpful as a screening test in such a common symptom as back

pain (approximately two- thirds of HLA- B27 +ve individuals with back pain

would not have ankylosing spondylitis).

Reactive and infection- related arthritis

Where reactive arthritis is suspected, appropriate serology and swabs

should be sent. These may include ASOT and anti- DNAse for Streptococcus,

serology for Campylobacter, Salmonella, Yersinia

, and EBV, stool samples for

culture, and urethral swab for Chlamydia. Investigations chosen and results

depend upon the clinical presentation. Where an infection- related arthritis

is suspected, specic investigations should be requested, e.g. Borrelia for

Lyme disease, leptospirosis for Weil’s disease,etc.

Urinalysis

Where systemic disease is a possibility, e.g. vasculitis and SLE, urinaly-

sis should be tested both in diagnosis and routine monitoring of disease.

The presence of RBCs and casts are early indicators of renal disease.

Proteinuria in long- standing inammatory disease should raise the suspicion

of amyloidosis.

Urinalysis is also used in monitoring of drugs, including gold, ciclosporin,

and penicillamine.

AUTOANTIBODIES

753

754

CHAPTER12 Rheumatology

754

Arthrocentesis

This refers to the aspiration of uid from a joint. Examination of the uid can

be helpful in diagnosis and is essential in septic arthritis, crystal arthropathy,

and haemarthrosis. Where infection is excluded, the joint may be therapeu-

tically injected with a steroid (e.g. methylprednisolone or triamcinolone).

Synovial uid examination

Physical characteristics

Observation of the colour and consistency of the synovial uid is helpful in

diagnosis. In general, inammatory arthritis, e.g. sepsis/ RhA/ gout, is associ-

ated with a turbid uid with low viscosity, whilst osteoarthritis or normal

joint uid is clear with higher viscosity. Crystal arthropathies are often asso-

ciated with bloodstaineduid.

Microscopy

White cell count and the percentage of polymorphonuclear cells (neutro-

phils) should be measured in synovial uid. They are higher in inamma-

tory arthritis, e.g. RhA (5000– 75,000/ mm

, >50%), and septic arthritis

(>50,000/ mm

, >75%) than normal (<200/ mm

, <25%) or osteoarthritis

(200– 10,000/ mm

, <50%). AGram stain and culture should be performed

to detect organisms in suspected septic arthritis. Culture for less common

organisms, such as TB, may also need to be considered.

Polarized light microscopy should be used to detect the presence of crys-

tals. Urate is associated with characteristic negatively birefringent crystals,

whilst calcium pyrophosphate crystals are positively birefringent. Other

crystals may also be observed, e.g. hydroxyapatite in Milwaukee shoulder.

Arthroscopy

Arthroscopy and synovial biopsy may occasionally be required for the diag-

nosis of chronic indolent infections, such as TB, or unusual slow- growing

organisms such as Coxiella (fever polyarthritis). Arthroscopy is essentially a

diagnostic procedure used by orthopaedic surgeons where direct visualiza-

tion of the aected joint is required.

1 American Academy of Orthopaedic Surgeons. M http:// www.orthoinfo.aaos.org/ .

NEUROPHYSIOLOGY

755

Neurophysiology

These are dynamic electrical nerve and muscle tests that are performed in

the context of appropriate clinical history and examination. They may be

considered in rheumatology, including:

•

Assessment of muscle disorders, e.g. to distinguish inammatory muscle

disease (polymyositis/ dermatomyositis) and other ° muscle disease,

e.g. muscular dystrophy.

•

Where mononeuritis multiplex/ peripheral neuropathy is suspected as

part of a rheumatological diagnosis, e.g. vasculitis, RhA, amyloidosis.

•

Nerve entrapment syndromes, e.g. carpal tunnel syndrome, tarsal

tunnel, or ulnar nerve compression where the clinical diagnosis is

uncertain.

•

Spinal cord/ nerve root compression.

756

CHAPTER12 Rheumatology

756

Diagnostic imaging

Imaging techniques are essential tools in the management of rheumatologi-

cal conditions and are useful if performed under appropriate indications.

It is not a substitute for clinical examination, and ndings should be inter-

preted in the context of clinical abnormalities. It is important to follow the

guidelines for radiological investigations published by the Royal College of

Radiologists.

Inammatory arthritis

It is important to diagnose inammatory arthritis as early as possible, as

timely treatment with disease- modifying anti- rheumatic drugs improves

outcomes in terms of function, joint damage, quality of life, and costs to

health service usage. Although conventional X- rays can be useful in diagno-

sis, this is generally only when disease is established and structural damage

to the joints has already occurred. The challenge to identify early arthritis

has led to widespread use of alternative imaging techniques, including mus-

culoskeletal US andMRI.

Plain radiography

Arthropathy

Hand and feet radiographs are useful in diagnosis. Soft tissue changes can

show swelling, eusions, and specic abnormalities, such as calcication,

which can be helpful even in early disease. Bony changes occur usually in

more established arthritis. The pattern and type of radiological damage can

suggest the diagnosis (see Table 12.2), and serial lms can be used to assess

disease progression. Other ndings may suggest specic diseases, e.g. cal-

cinosis in limited cutaneous scleroderma and chondrocalcinosis inCPPD.

Radiographs of the lumbar spine and sacroiliac joints may be utilized in

distinguishing mechanical and inammatory (e.g. ankylosing spondylitis/

psoriatic arthritis) back pain. Changes seen in inammatory back disease

include sacroiliitis (sclerosis and joint space loss), squaring of the vertebrae,

bony proliferation along vertebrae (syndesmophytes), and spondylodis-

citis. However, changes do not usually occur early in disease, and it can

be dicult to distinguish changes from degenerative disease (osteophytes,

loss of disc height). Evidence of bony change elsewhere, e.g. enthesitis, is

helpful in diagnosis. Isotope bone scan or MRI may be appropriate further

investigations.

Other joints should be imaged according to an individual’s clinical needs.

For example, a knee or hip would be required if joint replacement surgery

may be appropriate, or a shoulder if calcic tendinitis is considered. Plain

radiography is also useful in assessing complications of rheumatic disease,

e.g. rheumatoid lung disease. Limitations of plain lms are that only limited

information is provided about soft tissues and bone texture and early joint

damage is missed.

Bone lesions

Osteopenia should be further investigated with dual- energy X- ray absorpti-

ometry (DXA) scanning (E Nuclear medicine imaging, p. 763) and appro-

priate blood tests, e.g. PTH, Igs, and vitamin D.The underlying diagnosis

DIAGNOSTIC IMAGING

757

can be suggested by typical bony appearances, e.g. Looser’s zones are

lucent lines visualized at 90° to the bony cortex in osteomalacia (vitamin

D deciency). Periosteal reactions and, in more advanced disease, bone

resorption, can be seen in hyperparathyroidism and renal osteodystrophy.

Hypertrophic osteoarthropathy is another cause of periostitis, which can

signify underlying disease, e.g. bronchial carcinoma.

Sclerotic bone lesions (i bone density) can also be seen in renal

osteodystrophy.

Paget’s disease is characterized by focal excessive bone resorption (osteo-

lytic phase), followed by excessive bone formation (osteoblastic phase).

Radiological features are of radiolucent areas associated with bone widen-

ing, then subsequent coarsening of trabeculae and areas of i

radiodensity/

sclerosis. In advanced disease, there may be bowing of the bone, pathological

fracture, and i risk of osteosarcoma.

Other causes of sclerotic bone lesions include neoplasms (° and metas-

tases), osteomyelitis, uoride toxicity, and haemangiomas. Myeloma and

other neoplasms should be considered in osteolytic lesions.

Figures 12.1– 12.4 show the use of plain radiology in a variety of rheum-

atological disorders.

Table12.2 X- ray appearance inarthritis ofthehands

Diagnosis Pattern Joints involved Radiographic features

Osteoarthritis Asymmetrical DIPs, PIPs Joint space loss

Peri- articular sclerosis

Bonecysts

Osteophytes

RhA Symmetrical MCPs, PIPs Joint space loss

Peri- articular osteopenia

Erosions

Psoriatic

arthritis

Asymmetrical/

symmetrical

DIPs, PIPs

(MCPs)

Periostitis

Resorption of terminal

phalanx

Bony proliferation

Ivorydigit

Peripheral erosions

Pencil- in- cup deformity

Soft tissue dactylitis

Gout Asymmetrical DIPs, PIPs

(MCPs)

Juxta- articular erosions—

can be ‘punched out’

Soft tissue tophi

CPPD Asymmetrical DIPs, PIPs,

MCPs

Erosions

Chondrocalcinosis

DIP, distal interphalangeal; MCP, metacarpophalangeal; PIP, proximal interphalangeal.

758

CHAPTER12 Rheumatology

758

Fig.12.1 Hands in rheumatoid disease.

Fig.12.2 Hands showing calcinosis, especially prominent distally.

Fig.12.3 Plain CXR showing pulmonary brosis in rheumatoid disease.

Fig.12.4 X- ray of pelvis showing avascular necrosis of the femoralheads.

DIAGNOSTIC IMAGING

759

Ultrasound

USS is ideally suited to rheumatology. It is a non- invasive, ‘X- ray- free’ tech-

nique that can be used dynamically in a clinic setting as an extension to

clinical examination. Grey- scale US can be used in inammatory arthritis

to detect synovial thickening, joint eusions, and bony erosion in RhA,

entheseal changes in spondyloarthropathy, and crystal deposition in calcium

pyrophosphate.

Ultrasonography

US has an important role in the diagnosis of early arthritis, because ero-

sions can be identied before they are visible on radiographs and subclinical

synovitis can be detected. It can also be helpful in monitoring disease pro-

gression/ treatment response. Power Doppler can be used to assess joint

activity in addition to joint damage.

US is also ideal for imaging tendon pathology, including tendinitis, ten-

osynovitis, calcic tendinitis, and tears. It has been reported to be highly

sensitive and specic for rotator cu tears, and the dynamic nature of

examination means that a tendon/ joint can be examined, whilst in motion.

Bursae, uid- lled cysts, and ganglia are also readily identied.

More advanced US assessments include soft tissue and muscle disorders,

assessment of masses, and nerve entrapment. Imaging of temporal arteries

in GCA is also reported to show diagnostic changes in experienced hands,

with a hypoechoic halo being demonstrated due to artery oedema and ste-

nosis. This may potentially be used to guide biopsy. US has also been used

to assess blood ow in vasculitis, e.g. brachial and axillary arteries.

Limitations of US include diculty in imaging less accessible areas, e.g.

carpal bones, and no information beyond the bony cortex.

Figures 12.5– 12.8 show the use of US in a variety of rheumatological

disorders.

Fig.12.5 Achilles tendinosis.

760

CHAPTER12 Rheumatology

760

Fig.12.6 Erosion of MCPjoint.

Fig.12.7 Extensor tenosynovitis of thewrist.

Fig.12.8 Flexor tenosynovitis of the middle nger.

DIAGNOSTIC IMAGING

761

Magnetic resonance imaging

In contrast to plain lms and US, MRI has the strength that all components

of a joint can be visualized at once. Not only can the bony cortex be appre-

ciated, but also the composition of the bone. Use of MRI is limited by acces-

sibility, expense, duration of scans, and presence of metal implants, e.g.

pacemakers preclude its use. MRI has a role in the diagnosis of inammatory

arthritis, especially in early disease, to optimize treatment and outcomes,

but also in distinguishing alternative, often signicant, bone and joint disease,

including neoplasm.

Inammatory arthritis

In RhA, MRI detects erosions earlier than X- ray and can identify ‘pre-

erosion’— areas of bony oedema, which proceed to erosions in time. This

suggests that patients at risk of erosive arthritis could be identied prior to

permanent structural damage and treatment tailored accordingly. However,

not all such areas do progress to erosions and similar features have been

seen in bone disease (E Bony lesions, p. 761), healthy joints, bone cysts,

and ganglia.

Spondyloarthropathy can be dicult to diagnose, traditionally requir-

ing X- ray evidence of sacroiliitis. MRI can detect both active and chronic

lesions of spondyloarthritis in the spine, sacroiliac joints, and entheses.

Active inammation/ BM oedema is detected on short tau inversion recov-

ery (STIR) and fat- suppressed sequences, whereas chronic lesions are seen

best on T1- weighted (T1W) images. MRI is now included in the ASAS

(Assessment of SpondyloArthritis International Society) international clas-

sication of axial spondyloarthritis.

Muscle disease

MRI is useful in identifying abnormal areas of muscle. In the context of

myositis, an MRI scan can be used to guide a muscle biopsy to ensure sam-

pling of abnormal tissue.

Soft tissue and back disorders

MRI is able to visualize tendon and cartilage lesions and bone tumours. MRI

is particularly useful in the assessment of the back, especially in identifying

infective lesions, e.g. discitis/ abscess, in addition to identifying inammatory

lesions, sacroiliitis, spinal stenosis, myelopathy, disc prolapse disease, and

nerve compression. It is used in the assessment of orthopaedic lesions, such

as meniscal tears in the knee, especially prior to surgery.

Bony lesions

MRI is an excellent modality for investigating localized musculoskeletal

symptoms, identifying signicant lesions.

Bone oedema is also seen in a variety of bone lesions including avas-

cular necrosis and transient osteoporosis of the hip, trauma, e.g. stress

fractures, infection including osteomyelitis, metabolic bone disease, e.g.

Paget’s disease, chronic pain syndrome (‘reex sympathetic dystrophy’),

and neoplasm.

762

CHAPTER12 Rheumatology

762

Vasculitis

MRA is used in the investigation of vasculitis, including large- vessel vascu-

litides, e.g. GCA and Takayasu’s arteritis, and smaller- vessel disease, e.g.

Buerger’s disease.

Computed tomographyscans

CT scans are rarely used in imaging of the musculoskeletal system, especially

as associated radiation dose is high. CT/ HRCT does, however, have a role

in the conrmation of diagnosis in bony lesions, e.g. inltrative lesions, hae-

mangiomas, lipomas, osteoid osteomas, and other bony lesions. Sacroiliac

inammation, erosions, and calcication are also well visualized. HRCT has

been used in the assessment of osteoporosis but is largely superseded by

DXA scanning (E Nuclear medicine imaging below).

The major role for CT is in identifying complications of rheumatic dis-

ease, e.g. pulmonary brosis associated withRhA.

Nuclear medicine imaging

Bonescan

Radionuclide imaging with

99m

technetium or

gallium is relatively easy to

perform and gives information about the whole body. In rheumatology, it

is used to assess the pattern of joint involvement in arthritis and to detect

other causes of bony pain, including Paget’s disease, metastases, stress frac-

tures, and other specic diagnoses, e.g. chronic regional pain syndrome.

Although bone scans are sensitive to abnormalities, they have poor speci-

city so should be used in clinical context and may be a guide to further

additional investigation, e.g.MRI.

Positron emission tomography

(See Fig.12.9.)

18- FDG PET was originally used for tumour imaging but has gained wide

acceptance in its use in the imaging of medium- to large- vessel vasculitis. It is

(b)

(a)

(c)

Fig.12.9 Coronal images of CT (a), PET (b), FDG-PET/CT (c) of a 90-year-old

woman with bilateral axillary artery thrombosis, arthralgia, and fatigue. These

demonstrate increased FDG uptake in the carotid, subclavian and axillary vessels,

consistent with large vessel vasculitis.

Reproduced from Watts, Richard, et al., Oxford Textbook of Rheumatology, 4th edition

(2013), with permission from Oxford University Press.

DIAGNOSTIC IMAGING

763

of particular benet in the diagnosis and assessment of the extent of vessel

involvement in GCA, Takayasu’s arteritis, and aortitis. It can also be used in

the monitoring of disease activity. Other potential uses for PET- CT include

inammatory myositis and investigation for underlying malignancy associ-

ated with rheumatic disease.

Dual- energy X- ray absorptiometryscan

Osteoporosis may not be recognized clinically, unless a fracture occurs.

DXA is a non- invasive, low- radiation assessment of bone density. Potential

fracture sites (lumbar spine, hip, neck of femur, and wrist) are imaged, and

the result is compared with that expected in a standard population to give a

T- score and an age- adjusted population to give a z- score. For every stand-

ard deviation below the mean of the standard population, the fracture risk

is i

by 2– 3 times. Vertebral fracture analysis may also be oered to iden-

tify fractures at the time of the scan. DXA is oered to patients at risk

of developing osteoporosis (see Table 12.3). Online calculators have been

developed to identify those most at risk of developing fragility fractures

and to determine who needs a DXA scan and/ or treatment. The Q frac-

ture method is most suited to the elderly, and the FRAX/ NOGG (National

Osteoporosis Guideline Group) calculator is intended for 40- to 90- year-

olds and can be used with the bone mineral density of the femoral neck,

following DXA, to improve prediction of the 10- year fracture risk. Ideally,

repeat scans should be carried out on the same DXA machine, as results

cannot be reliably compared between dierent machines.

Table12.3 Risk factors inosteoporosis

Osteoporosis Diseases associated with

osteoporosis/ bone fragility

°

Menopause <45(+ <5- year HRT) RhA

2° amenorrhoea Ankylosing spondylitis

Radiological osteopenia

Lupus

History of maternal hip fracture Hyperparathyroidism

Previous fragility fracture* Hyperthyroidism

Heavy long- term smoking ♂ hypogonadism

Low BMI (kg/ m

) <19 Chronic liver disease

Prolonged immobilization, e.g. MS Chronic IBD

Excessive alcohol consumption Malabsorption

Chronic renal failure

2°

Oral steroids Hypopituitarism

Aromatase inhibitors Haemochromatosis

Androgen deprivation treatment for

prostate cancer

Organ transplant patients

Excessive thyroxine/ anticonvulsants Anorexia/ bulimia

* Fracture sustained with no trauma or fall from standing height.

764

765

Chapter13

Radiology

Radiology and the role of imaging 766

Plain X- rays 768

Digital radiology 769

Chest X- ray:useful landmarks 770

Chest radiograph 774

Patterns of lobar collapse 780

Cardiac enlargement 782

Computed tomography of the thorax 786

Abdominal X- ray:useful landmarks 788

Plain abdominal X- ray 790

Barium studies 794

Barium swallow 796

Barium meal 798

Small intestine 800

Cholangiography 802

Barium enema 806

Radiology of the urinary tract 808

Breast imaging 812

Ultrasound 816

Obstetric imaging 820

Gynaecological imaging 822

Computed tomography 824

Magnetic resonance imaging 828

Spinal imaging 836

Pelvis 838

Vascular intervention 840

Interventional radiology 844

Musculoskeletal imaging 850

Hands 852

Neuroradiology 856

Skull X- ray 860

Reference section 862

Internet resources 864

766

CHAPTER13 Radiology

766

Radiology and therole ofimaging

Eective use of the radiology department relies on good communication

between radiologists and their clinical colleagues. The overall aim must be

to target investigations eciently in order to provide answers to clinical

dilemmas at minimal cost and radiation dose (see Table 13.1). The investiga-

tion of neurological problems has been transformed by the advent of CT

and MRI. Local availability varies and CT, in particular, can add considerably

to the radiation burden. Conversely, if a CT is likely to provide the best

answer and minimize overall costs by resulting in an early discharge, then

it should be the investigation of choice. It is helpful to consider plain lms,

contrast studies, US, and then CT/ MRI as a hierarchy where plain lms are

requested as an initial investigation. This hierarchy may be circumvented

if a more expensive investigation is likely to produce the denitive result.

The following are important points to consider:

• Will the investigation alter patient management? That is, is the expected

outcome clinically relevant? Do you needit?

•

Investigating too often or repeating investigations before there has been

an adequate lapse of time to allow resolution or to allow treatment to

take eect

. Similarly, investigations performed too early may be non-

contributory. Do Ineed it now? Especially relevant when investigations

may have been performed elsewhere. Make every eort possible to

obtain prior studies. Transfer of digital data through electronic links will

assist in this process. Has it been done already?

•

Would an investigation that does not use ionizing radiation be more

appropriate

, e.g. USS/ MRI?

• Failure to provide accurate clinical information and questions that you are

hoping will be answered by the investigation may result in an unsatisfactory

outcome or an inappropriate focus in the report. Have Iexplained the

problem?

•

Would another technique be more appropriate? The advances in radiology

mean that discussion with a radiologist may be helpful in determining the

best possible test. Is this the best investigation?

•

Over- investigating. Are you taking comfort in too many tests or providing

reassurance to the patient in thisway?

RADIOLOGY AND THEROLE OFIMAGING

767

Table13.1 Typical eective doses fromdiagnostic medical exposures

Procedure

Typical eective

dose (mSv)

Equivalent

number of

CXRs

Equivalent period

background

radiation

Chest (P- A) 0.015 1 2.5days

Lumbar spine 0.6 40 3months

Abdomen 0.4 30 2months

IVU 2.1 140 11.5months

Mammography

(two views)

0.5 35 3months

Barium enema 2.2 150 1year

CT head 1.4 90 7.5months

CT chest 6.6 440 3years

CT abdomen 5.6 370 2.5years

CT colonography 10 670 4.5years

Bone scan (

99m

Tc) 3 200 1.4years

PET scan (body)

(F18- FDG)

18 1200 8.1years

UK average background radiation=2.2mSv/ year.

Table adapted from Royal College of Radiologists (2012) Guidelines for Doctors. Making the

best use of clinical radiology services. Doses for conventional X- ray examinations are based on

data compiled by the Health Protection agency (HPA) from a survey of UK hospitals in 2008.

The doses for CT examinations and radionuclide studies are compiled from surveys conducted

by the HPA and the British Nuclear Medicine Society.

Royal College of Radiologists. Making the best use of clinical radiology services, Version 7.0.2.

London:Royal College of Radiologists,2012.

768

CHAPTER13 Radiology

768

PlainX- rays

Wilhelm Roentgen discovered X- rays in 1895. X- rays form part of the elec-

tromagnetic spectrum, with microwaves and radio waves lying at the low-

energy end, visible light in the middle, and X- rays at the high- energy end.

They are energetic enough to ionize atoms and break molecular bonds as

they penetrate tissues and are therefore called ionizing radiation. Diagnostic

X- rays are produced when high- energy electrons strike a high atomic num-

ber material. This interaction is produced within an X- ray tube. A high

voltage is passed across two tungsten terminals. One terminal (cathode) is

heated until it liberates free electrons. When a high voltage is applied across

the terminals, the electrons accelerate towards the anode at high speed. On

hitting the anode target, X- rays are produced.

The X- ray picture is a result of the interaction of the ionizing radiation

with tissues as it passes through the body. Tissues of dierent densities are

displayed as distinct areas, depending on the amount of radiation absorbed.

There are four basic densities in conventional radiography: gas (air), fat,

soft tissue and uid, and calcied structures. Air absorbs the least amount

of X- rays and therefore appears black on the radiograph, whereas calcied

structures and bone absorb the most, resulting in a white density. Soft tis-

sues and uid have a similar absorptive capacity and therefore appear grey

on a radiograph.

DIGITAL RADIOLOGY

769

Digital radiology

X- ray lm is exposed by light photons emitted by intensifying screens sensi-

tive to radiation transmitted through the patient. Storage phosphor tech-

nology uses photostimulatable phosphor screens to convert X- ray energy

directly into digital signals. The i dynamic range and image contrast of

digital radiography, compared with conventional lm screen combinations,

and the facility to manipulate signal intensity after image capture reduce

the number of repeat exposures. This i eciency and minimizes patient

radiation dose. Digital images can be made available on a local network for

reporting by a radiologist or for review on a ward- based computer. Picture

archiving and communication systems (PACS) are ecient at image produc-

tion and manipulation and in the storage, retrieval, and transmission of data.

PACS facilitates remote radiology reporting and alleviates workow pres-

sures. The vast majority of imaging studies conducted in the UK are stored,

manipulated, and shared via a picture archiving and communication system.

PACS has been rolled out to all healthcare organizations over the last dec-

ade or more as local, regional, or national implementations with dierent

degrees of connectivity to radiology information systems (RIS), either via a

local RIS or shared with other organizations (domain- based). Global chal-

lenges to PACS systems include management of i volumes of imaging data

and the ability to data- share across a spectrum of healthcare communities.

Advantages include inventive ways of providing diagnostic imaging cover-

age, for instance in remote or scantily populated communities.

770

CHAPTER13 Radiology

770

Chest X- ray:useful landmarks

In order to interpret a plain P- A or lateral CXR, some knowledge of chest

anatomy and the major landmarks on the lm is required. We have high-

lighted the major bony and soft tissue structures visible on the plain lm

in order to make it easier to spot abnormalities. Patient positioning for

a P- A CXR (see Figs 13.1– 13.3) and lateral CXR (see Figs 13.4– 13.6) is

illustratedbelow.

Fig.13.1 Patient position for P- ACXR.

Fig.13.2 P- ACXR.

CHEST X-RAY:USEFUL LANDMARKS

771

Companion shadow

of left clavicle

Aortic knob

Carina

Left hilum

Border of

descending

thoracic aorta

Wall of

left ventricle

Left dome

of diaphragm

Gas bubble in

fundus of stomach

Right lateral

costophrenic angle

Right dome

of diaphragm

Inferior vena cava

Wall of right atrium

Inferior angle

of right scapula

Horizontal ssure

of right lung

superimposed on

posterior segment o

right 7th rib

Right hilum

Right 5th

interspace

Posterior segment

of right 5th rib

Right tracheal stripe

Right rst rib

Medial end of

left clavicle

Fig.13.3 P- A CXR landmarks.

Fig.13.4 Patient position for lateralCXR.

772

CHAPTER13 Radiology

772

Fig.13.5 LateralCXR.

Shadow of aortic arch

superimposed on

tracheal lumen

Lumen of

a bronchus

Bodies of lower

thoracic vertebrae

Retrocardiac area

Left dome

of diaphragm

Right dome

of diaphragm

Right posterior sulcus

Manubriosternal joint

Retrosternal area

Body of sternum

Horizontal ssure

of right lung

Oblique ssure

Gas bubble in fundus

of stomach

Fig.13.6 Lateral CXR landmarks.

CHEST X-RAY:USEFUL LANDMARKS

773

774

CHAPTER13 Radiology

774

Chest radiograph

The chest lm is the most widely requested, yet most easy to misinterpret,

investigation. Using a logical approach will avoid most pitfalls. This should be

the initial imaging modality in all patients with suspected thoracic pathology.

Points toconsider

• Always obtain prior imaging, if available; temporal changes assist greatly

in image interpretation and dierential diagnosis.

•

Standard projections of the chest are P- A (posteroanterior) vs AP

(anteroposterior). See E Projectionbelow.

•

Additional views to aid problem- solving include lordotic, oblique, and

decubitus projections (see below).

•

Initially assess the technical quality.

Projection

P- A vs AP will determine whether assessment of the cardiac size is reliable.

Potential other views include:

•

Lateral:improves visualization of the retrocardiac space and thoracic

spine; earlier and more sensitive detection of eusions.

•

Lateral decubitus:assesses for pleural eusion or pneumothorax in

immobile patients (portable US also has a utility in this setting).

•

Lordotic:angled beam allows better view of the apices which are

typically obscured by the clavicles and anteriorribs.

Posture

Erect lms enable a more accurate assessment of the mediastinum, since

the lungs are more expanded, and allow detection of air– uid levels, pleural

thickening, and comment on the size of the pulmonary vasculature.

Rotation

Look for the relationship of the medial ends of the clavicles to the spinous

process at the same level; a common cause of unilateral transradiancy is

rotation.

Degree ofinspiration

Ideally, six ribs should be seen anteriorly and ten ribs posteriorly. If more,

this suggests hyperination (does the patient have asthma or COPD?). If

less (e.g. poor inspiratory eort, obesity, or restrictive chest disorders),

there will be apparent cardiomegaly, i basal shadowing, and less commonly

tracheal deviation.

Quality of image can be assessed by the degree of penetration. The

thoracic disc spaces should be just visible through the heart. Absence of

respiratory or motion artefact.

The heart and mediastinum

Sequentially consider the heart, mediastinum, lungs, diaphragms, soft tissues

(breast shadows), and bones. Remember to assess your review areas— the

lung apices, behind the heart, under the diaphragm, and the costophrenic

angles.

CHEST RADIOGRAPH

775

Diaphragm

This should lie between the fth and seventh ribs. If attened, consider

hyperination. In 90% of cases, the right is higher than the left by 3– 4cm.

Eacement of the interface between the lung and diaphragm suggests pleu-

ral or pulmonary pathology. Loss of smooth contour suggests localized her-

niation (eventration). Peaks laterally may be due to subpulmonary eusion.

Root ofneck and trachea

The upper trachea is central with a slight displacement to the right inferiorly

due to the oesophagus. Thickening of the paratracheal line (>5mm) may

imply nodal enlargement.

CXR inthe intensive care unit patient

Look at the following parameters:

1. Patient demographics.

2. Date and time of study should be included in the report.

3. Has there been surgery?

4. If there are lines, catheters, drains, endotracheal tube (ETT), etc.,

comment on the position. If new lines, comment on changes in position

or if any removed.

5. Cardiac and mediastinal size andshape.

6. Presence of pneumothorax.

7. Lung disease. Pattern of disease as well as its evolution overtime.

8. Interval changes from one lm to the next as well as overtime.

Mediastinum

The mediastinum should be central. The heart is normally <50% of the

thoracic width. Mediastinal enlargement or widening is a non- specic nd-

ing. The silhouette sign may help, but a lateral lm is helpful for localization.

Table 13.2 gives a list of distinguishing features that enable distinction of

mediastinal masses from intra- pulmonary masses.

Normal variants mimicking a wide mediastinumare:

•

AP projection (notP- A).

• Mediastinal fat (steroids, obesity).

• Vascular tortuosity— elderly patients.

• Low inspiratory supine position.

Table13.2 Dierentiating mediastinal frompulmonarymasses

Mediastinal mass Pulmonary mass

Epicentre lies in mediastinum Epicentre in lung

Obtuse angles with lung Acute angles

No air bronchograms Air bronchograms possible

Smooth and sharp margins Irregular margins

Moves on swallowing Moves with respiration

Bilateral Unilateral

776

CHAPTER13 Radiology

776

The mediastinum is divided into three arbitrary compartments to aid in

the dierential diagnosis of a mediastinal mass (see Table 13.3). As there

are no anatomical planes separating these divisions, disease can spread from

one compartment to thenext.

Based on the location of the mediastinal abnormality, possible patholo-

gies include:

•

Superior mediastinum:thymoma, retrosternal thyroid, and lymphoma.

•

Anterior mediastinum (anterior line formed by the anterior trachea

and the posterior border of the heart and great vessels):lymphoma

(Hodgkin’s disease (HD) and non- Hodgkin’s lymphoma (NHL)),

germ cell tumours, thymoma, retrosternal goitres, and Morgagni

hernias(low).

•

Middle mediastinum (extends behind the anterior mediastinum to a

line 1cm posterior to the anterior border of the thoracic vertebral

bodies):aortic aneurysm, bronchial carcinoma, foregut duplication cysts

(including bronchogenic/ oesophageal), and hiatus hernia.

• Posterior mediastinum (posterior to line described above):neurogenic

tumours, Bochdalek hernia, dilated oesophagus, oraorta.

Pneumomediastinum

Mediastinal air may be due to a number of sources.

Intrathoracic

•

Trachea and bronchi.

• Oesophagus.

• Lung.

• Pleuralspace.

Extrathoracic

•

Head andneck.

• Intraperitoneum and retro- peritoneum.

Signs include: subcutaneous emphysema, pneumopericardium, elevated

thymus (sail sign), or air around major structures such as the PmA,

bronchialwall.

Table13.3 Radiographic localization ofa mediastinalmass

Location of mass Signs associated with mass in this compartment

Anterior mediastinum Deformation of anterior junctional line

Hilum overlay sign (hilar vessels seen through mass)

Middle mediastinum Distortion of the paratracheal stripe

Convexity of the AP window

Posterior mediastinum Distortion or displacement of the following:

•

Azygo- oesophagealrecess

• Posterior junctionline

• Paraspinal lines

CHEST RADIOGRAPH

777

Enlarged lymphnodes

May be seen in any compartment.

Pleural disease

•

Pleural and extra- pleural masses generally form obtuse angles with the

adjacent pleura.

•

Pulmonary or intra- parenchymal masses form acute angles with the

pleura.

Common pleural abnormalities

Eusion

•

The lateral view is more sensitive, as accumulation of uid occurs rst in

the posterior recess.

•

May cause mediastinal/ tracheal shift to the contralateral side or adjacent

atelectasis.

•

US invaluable (and better than plain lm) in evaluation of small eusions

and guiding thoracocentesis.

•

If blunting of the costophrenic angles is present, it indicates the

presence of uid of at least 200mL (P- A) or 75mL (lateral view) or may

be 2° to thickening of the pleura.

•

Pleural thickening most commonly a sequela of inammatory change.

• Asbestos exposure results in a spectrum of pleural abnormality, ranging

from benign plaques to brosis and malignant mesothelioma (obtain

occupational history).

•

Pleural eusion can be divided into either a transudate or an exudate.

•

Transudate:ultraltrate of plasma, low in protein, no

inammatorycells.

•

Exudate:rich in protein, cells, and debris.

Pneumothorax

•

On an erect lm, the partially collapsed lung is delineated from pleural

air as a curvilinear line (visceral pleura) paralleling the chestwall.

•

On a supine lm, the changes are more subtle; look for the deep

(costophrenic) sulcus sign, the double diaphragm sign (the dome and

anterior portions of the diaphragm outlined by the lung and pleural air,

respectively), hyperlucent thorax, and sharpening of mediastinal structures.

•

Subtle pneumothorax will be more readily apparent on an expiratory

lm or a lateral decubitus lm (accumulation of air superiorly).

•

If the air is under tension, there may be mediastinal shift (tension

pneumothorax). This can result in vascular compromise. On imaging:

•

The lung appears over- expanded.

•

Depression of the diaphragm.

•

Mediastinal shift and of the heart to contralateralside.

Thoracic intervention

Diagnostic thoracocentesis

•

Indication:exclude malignancy; obtain a sample for culture.

•

USS used to determine skin entry site:18– 22G needle advanced into

pleural uid. Angle over the superior border of the rib to avoid

inadvertent neurovascular injury.

•

Complications:pneumothorax (when blind,1– 3%).

778

CHAPTER13 Radiology

778

Therapeutic thoracocentesis

Usually if respiratory compromise from a large eusion. Similar technique

as above, but place a 7– 10Fr catheter. Potential risk of expansion pulmonary

oedema if evacuate in excess of 2– 3L or aspirate both lungs in one sitting.

Also potential for pneumothorax— always obtain post- aspirationCXR.

Percutaneous lungbiopsy

True +ve rate of 90– 95%. False +ve results usually related to malplacement

of biopsy needle, necrotic tumour. Contraindications (relative) include

severe COPD, pulmonary hypertension, coagulopathy, and contralateral

pneumonectomy. Tumour seeding is extremely rare (1:20,000).

Complications include pneumothorax (25%, of which 5– 10% need a

chest tube) and haemoptysis(3%).

Hila

Density should be equal; the left is higher than the right by 5– 15mm. If

more disparity, consider elevation due to brosis (e.g. TB, radiotherapy) or

depression by lobar or segmental collapse. Hilar enlargement may be vas-

cular (e.g. pulmonary arterial or venous hypertension) or due to lymphad-

enopathy (e.g. sarcoidosis, lymphoma, or TB). Hilar calcication is seen in

silicosis, sarcoidosis, and treated lymphoma.

Management ofpneumothorax

Indications

•

Symptomatic pneumothorax.

• Pneumothorax>20%.

• Enlarging pneumothorax on subsequentCXR.

• Tension pneumothorax.

• Poor lung function of contralateral lung disease.

Technique

Either:

1 Second to fourth anterior intercostal space, mid- clavicular line,or

2 Sixth to eighth intercostal space; mid- axillary line or posterior.

Use 8– 12Fr catheters using a trocar technique. After the lung is fully re-

expanded for 24h, the catheter is placed on a water seal for 6h and then

removed if no residual pneumothorax.

Lung disease

Lung opacities may be subdivided into several basic patterns.

Alveolar

Air space shadowing

:ill- dened, non- segmental, and with air bronchograms.

No associated volume loss. Large variety of causes:

•

Fluid l pulmonary oedema (cardiogenic and non- cardiogenic).

• Fat l fat embolism.

•

Haemorrhage l trauma, coagulopathies, pulmonary haemosiderosis.

•

Cells l pulmonary alveolar proteinosis, sarcoidosis, bronchoalveolar cell

carcinoma, lymphoma, and infection (bacterial, fungal, and viral).

CHEST RADIOGRAPH

779

Reticular

Linear opacities:associated obscuration of vessels and late appearance of

CXRsigns:

•

Collagen disorders.

• Extrinsic allergic alveolitis.

• Sarcoidosis, pneumoconiosis.

• CFA.

• EarlyLVF.

• Malignancy (lymphangitis carcinomatosis).

Nodular shadows

Characterize according to their size and distribution:

•

If solitary, exclude tumour.

• Multiple:

•

Granulomata (TB, histoplasmosis, hydatid).

•

Immunological (Wegener’s,RhA).

•

Vascular (AVMs).

•

Inhalational (progressive massive brosis (PMF), Caplan’s syndrome).

Primary signs ofa malignancy

•

Mass or nodule with spiculated or irregular borders.

• Unilateral hilar enlargement or mediastinal widening.

• Cavitating nodule with thick rind of soft tissue.

• Cavitation commonest in squamous cell carcinoma(SCC).

• Malignancy can simulate air space disease (e.g. bronchoalveolar

carcinoma, lymphoma).

Secondary signs ofmalignancy

•

Atelectasis.

• Obstructive pneumonia.

• Pleural eusion.

• Interstitial patterns (lymphangitic spread of disease).

• Hilar and mediastinal adenopathy.

• Metastatic disease (including to ipsilateral or contralateral lung

parenchyma).

Further reading

Corne J, Carroll M, Delaney D. Chest X- ray Made Easy, 2nd edn. Edinburgh:Churchill Livingstone,

2002.

Hansell DM, Lynch DA, McAdams HP, Bankier AA. Imaging of Diseases of the Chest, 5th edn.

London: Mosby,2010.

780

CHAPTER13 Radiology

780

Patterns oflobar collapse

Lobar collapse may be complete or incomplete. The commonest cause is

obstruction of a central bronchus. The ° signs are opacication due to lack

of aeration and displacement of the interlobar ssures. Typical patterns of

lobar collapse are illustrated in Fig.13.7.

Secondary signs include

• Elevation of the hemidiaphragm (more prominent in lower lobe

atelectasis than upper).

•

Mediastinal displacement (tracheal displacement with upper lobe and

cardiac displacement with lower lobe atelectasis).

•

Hilar displacement more prominent with upper lobe atelectasis

thanlower.

•

Crowded vessels in the aectedlobe.

• Compensatory hyperination of remaininglung.

Silhouettesign

• In a normal CXR, the interface between the diaphragm and the

mediastinum are visible due to a dierence in density between the lung

and these structures.

•

The silhouette sign refers to loss of normal interfaces, implying there is

opacication due to consolidation (the commonest cause), atelectasis,

or a mass in the adjacentlung.

•

Silhouetting helps to localize the site of the pathology, and both pleural

and mediastinal disease produce the silhouette sign (see Table13.4).

Table13.4 Localization using thesilhouettesign

Interface lost Location of lung pathology

SVC Right upper lobe

Right heart border Right middle lobe

Right hemidiaphragm Right lower lobe

Aortic knob/ left superior mediastinum Left upper lobe

Left heart border Lingula

Left hemidiaphragm Left lower lobe

PATTERNS OFLOBAR COLLAPSE

781

(a) Left upper-lobe collapse

(b) Left lower lobe collapse

Right upper lobe collapse

(d) Right middle lobe collapse

(e) Right lower lobe collapse

Trachea

deviated

to L

III-dened

opacity

Sharply dened

posterior border

due to anterior

displacement

of oblique

ssure

Oblique

ssure displaced

posteriorly

Triangular opacity

visible through the heart

with loss of medial end

of diaphragm

Indistinct

L heart

border

Trachea deviated to R

Horizontal

ssure and

R hilum

displaced

upwards

Horizontal ssure

displaced down

III-dened

opacity adjacent

to R heart

border

Loss of R heart

border

Horizontal

ssure

displaced

downwards

Oblique

ssure and

hilum displaced

posteriorly

Well-dened

posterior

opacity

Well-dened opacity adjacent

to R heart border

(R heart border still visible)

Triangular

opacity with

well-dened

margins

Well-dened

triangular

opacity

running from

hilum

Indistinct

elevated

L hilum

Fig.13.7 (a)Left upper lobe collapse. (b)Left lower lobe collapse. (c)Right upper

lobe collapse. (d)Right middle lobe collapse. (e)Right lower lobe collapse.

782

CHAPTER13 Radiology

782

Cardiac enlargement

i of the cardiothoracic ratio beyond 50% is considered abnormal if the P- A

lm is of good quality.

Aetiologies toconsider

• Cardiomegaly (hypertrophy or dilatation of cardiac chambers).

• Pericardial eusion (globular heart).

• Poor inspiratory eort/ d lung volumes.

•

Pectus excavatum.

The location of cardiac valves may be relevant when determining the loca-

tion of calcication. On a lateral projection, draw a line from the xiphi-

sternum to the carina and divide the heart into thirds. The location of the

cardiac valves will be as demonstrated in Fig.13.8.

Normal plain lm anatomy

Figure 13.9 shows a P- A view. The right cardiac margin comprises three

segments:

•

SVC.

• RAt.

• IVC.

The left cardiac margin comprises four segments:

• Aortic arch (AA) (becomes more prominent withage).

• Main PmA at level of the left main stem bronchus.

• Left atrial appendage (may not be visible in normal hearts).

• LV.

• RV is not usually seen in frontal projection.

Line positions

Endotrachealtube

•

Tip of the ETT should be above the carina and below the thoracicinlet.

• The inated cu should not bulge the trachealwall.

• Neck position can change the impact location of thetip.

• In neutral:the tip should be 4– 6cm above the carina.

• Flexed:moves the tip inferiorly by2cm.

•

Extended:moves the tip superiorly by2cm.

•

Complications:malpositioned results in atelectasis or collapse due to

bronchial obstruction. Tracheomalacia if over- inated cu; tracheal

rupture may result in pneumothorax.

•

Pearl:in situations where there is low pulmonary compliance (e.g. acute

respiratory distress syndrome (ARDS)), a tip position closer to the

carina may reduce barotrauma.

Nasogastrictube

•

Tip should be in the stomach.

• Tip and side port should lie distal to the oesophagogastric junction and

proximal to the gastric pylorus.

•

Potential complications include placement in airway or gastric/ duodenal

erosion.

CARDIAC ENLARGEMENT

783

Swan– Ganz catheter

• Tip should be located in the left or right PmA within 1cm from the

hilum. Loops in the RA or RV may cause arrhythmias. There are two

types of Swan– Ganz catheters:

1 Used to measure wedge pressure.

2 With an integrated pacemaker.

• Complications include pulmonary infarct, haemorrhage, PmA pseudo-

aneurysm, and infection. If the tip is distal to the proximal interlobar

PmA, there is a potential risk of PmA rupture or pseudo- aneurysm.

P = pulmonary valve Ao = aortic valv

M = mitral valve T = tricuspid valve

Fig.13.8 Schematic diagram showing the relations of the cardiac valves on a lateral

lm of thechest.

SVC

IVC

Left atrial

appendage

Fig.13.9 Schematic diagram depicting a normal cardiac silhouette as seen on a

plainCXR.

784

CHAPTER13 Radiology

784

Dialysis catheter

• Should be located in theRAt.

Epicardial pacingwire

•

Typically anchored in the anterior mediastinum. Multiple wires may be

present and usually exit through the anterior chestwall.

Automatic intracardiac debrillation device(AICD)

•

Newer systems have intraventricular electrodes with pin sensors.

Intra- aortic balloonpump

• Tip should be located just distal to the origin of the left subclavian artery

and be 2– 4cm below the aortic knuckle.

• Complications include aortic dissection, low position associated with

mesenteric or renal ischaemia, and high position withCVA.

Central venousline

•

Tip should end in the lower SVC or the cavoatrial junction below the

anterior rst rib. Azygos malposition is seen in 1% and is associated with

risk of venous perforation or catheter- associated thrombosis.

Pacemaker

•

Typical position should be in the apex of the RV. Can be located in the

atrial appendage for atrial pacing and in the coronary sinus for atrial left

ventricular pacing.

•

Complications include electrode displacement, perforation, infection, or

venous thrombosis.

Chesttube

•

Side port should lie within the thoracic cavity.

• Tip of tube should not abut the mediastinum.

CT angiography ofcoronary vessels (coronary computed

tomography angiography,CCTA)

CT is very sensitiveat:

• Detecting and quantitating calcication in coronary arteries.

• Non- invasively depicting the entire coronarytree.

• Determining the luminal diameter.

Improved hardware has resulted in less blooming artefact which could

potentially overestimate the degree of stenosis seen with calcied plaques.

It is very sensitive to haemodynamic stenosis (>50% of the luminal diam-

eter). Multiple meta- analyses have shown NPV in high90s.

For calcium scoring, the examination is performed without IV contrast and

there are various algorithms available that provide a measure of the total

coronary plaque burden. ECG gating is used to minimize cardiac motion;

the type of gating employed has signicant impact on patient radiationdose.

CARDIAC ENLARGEMENT

785

Magnetic resonance coronary angiography

Also has potential for non- invasive diagnosis of coronary artery disease.

The in- plane image resolution for current MR techniques is about 0.5mm,

sucient for assessment of large coronary vessels as well as in venous grafts

following coronary artery bypass grafting, but inadequate for detecting dis-

ease in smaller side branches.

Cardiac magnetic resonance imaging

Provides a high- resolution dynamic study using predominantly steady- state

free precession (SSFP) and/ or gradient echo cine sequences.

SSFP is a ‘white blood sequence’ that provides excellent contrast between

the myocardium and the blood pool. It is suited to cardiac imaging due to its

high temporal resolution and excellent contrast.

Cine MRI provides quantitative assessment of cardiac morphology and

function. Real- time images can be used for subjective analysis when gating

is poor. Tissue characterization is usually performed with double or triple

inversion fast spin echo sequences. These ‘black blood’ sequences null sig-

nal from owingblood.

First- pass contrast- enhanced perfusion MRI is performed pre- and

post- vasodilator stress to assess myocardial perfusion. Delayed contrast-

enhanced MRI is used to assess myocardial viability, inammation, and

brosis.

Further reading

Miller SW, Abbara S, Boxt LB. Cardiac Imaging:The Requisites, 3rd edn. Mosby,2009.

Ra GL, Abidov A, Achenbach S, etal

. SCCT guidelines for the interpretation and reporting of coro-

nary computed tomographic angiography. J Cardiovasc Comput Tomogr 2009; 3

:122– 36.

786

CHAPTER13 Radiology

786

Computed tomography ofthethorax

Indications include

• Evaluation of an abnormal nding on plainlm.

• Staging of ° or metastatic malignancies.

• Evaluation of suspected mediastinal or hilarmass.

• Detection of thromboembolic disease by CTPA (see Figs 13.10 and 13.11).

• Detection and assessment of aortic dissection.

• Distinguishing empyema from lung abscess.

• CT- guided percutaneous needle biopsy of focal lung lesion or

mediastinal abnormality.

•

CT- guided pleural biopsy.

High- resolution computed tomography (HRCT) comprises thin section images

that are reconstructed using a special algorithm.

Fig.13.10 Axial image from CTPA showing the presence of thrombus within the

lower lobePmA.

Fig.13.11 Sagittal reformatted image conrms the extent of the thrombus and its

relationship to thelumen.

COMPUTED TOMOGRAPHY OFTHETHORAX

787

Indications include

• Evaluation of a diuse lung disease (see Fig. 13.12).

• Characterization of a solitary pulmonary nodule.

• Haemoptysis.

• Lung disease in a patient with abnormal pulmonary function tests but

apparently normal CXR (see Table13.5).

• Assessment of emphysema.

Fig.13.12 HRCT image of the chest in a patient with cystic lung disease due to

tuberous sclerosis.

Table13.5 HRCT patterns ofinterstitial lung disease

Pattern Description Causes

Ground glass

opacity

i haze

Vessels can be seen

through hazing

Allergic hypersensitivity

Acute interstitial disease (DIP, active

IPF),viral

PCP, BOOP, COP, pulmonary

oedema, eosinophilic pneumonia

Reticulonodular

Peri- bronchovascular

thickening (equivalent

of cung on CXR)

Thickened interlobular

septal (Kerley) lines)

Pulmonary brosis, viral, Mycoplasma

pneumonia, PCP

Pulmonary oedema,IPF

Lymphangitic spread of tumours,

brosis due to drugs, radiation,

asbestosis, collagen vascular disease

Nodular

opacities

1– 2mm interstitial

nodules, often seen

in conjunction with

reticular opacities

Haematogenous infection,

metastases, sarcoid, pneumoconiosis,

histiocytosis, silicosis, and CWP

Cystic spaces May or may not have

walls

Lymphangioleiomyomatosis

Histiocytosis, honeycombing

IPF, LIP, cysticPCP

End- stage interstitial disease

BOOP, bronchiolitis obliterans organizing pneumonia; COP, cryptogenic organizing pneumonia;

CWP, coalworker’s pneumoconiosis; DIP, desquamative interstitial pneumonia; IPF, idiopathic

pulmonary brosis; LIP, lymphocytic interstitial pneumonitis; PCP, pneumocystis pneumonia.

788

CHAPTER13 Radiology

788

Abdominal X- ray:useful landmarks

Interpretation of the AXR, like the CXR, requires experience. In order to

make things slightly easier, we have provided a rough guide to the various

bony, soft tissue, and gas shadows seen on a ‘typical’ AXR (see Fig. 13.13).

Figure 13.14 provides a normal AXR for correlation with the diagram.

Figure 13.15 shows diuse sclerotic metastases.

Lateral border of

right psoas major

Right transverse process

of 4th lumbar vertebra

Large bowel gas

Right sacroiliac joint

Bladder

Symphysis pubis

Lower pole

of left kidney

Iliac crest

Fig.13.13 P- A AXR landmarks.

ABDOMINAL X-RAY:USEFUL LANDMARKS

789

Fig.13.14 P- AAXR.

Fig.13.15 Diuse sclerotic metastases in a patient with a prostatic carcinoma. Note

the presence of bilateral ureteric stents.

790

CHAPTER13 Radiology

790

Plain abdominalX- ray

The standard plain lm is a supine AXR. Erect views have largely been

superseded and in the acute setting have been replaced by the erect chest

to show free subphrenic air. Furthermore, chest diseases, such as MI or

pneumonia, may simulate an acute abdomen. If there is doubt regarding the

presence of a pneumoperitoneum, consider a lateral decubitus lm (dis-

plays as little as 1mL ofair).

Indications

Suspected obstruction, perforation, renal colic, and toxic megacolon and

bowel ischaemia.

Contraindications

None, but where abdominal pain is non- specic and not attributable to the

conditions listed above, an AXR is unlikely to be helpful.

Interpretation ofthe plain abdominalX- ray

A normal patient will have variable amounts of gas in the stomach, small

bowel, and colon. You can identify the stomach as it lies above the trans-

verse colon, has an air– uid level in the erect view, and has rugae in its lumen.

Large bowel calibre is variable; 5.5cm is considered the upper limit for the

transverse colon in toxic megacolon and 9cm for the caecum in obstruc-

tion. Short uid levels are normal. Fluid levels are abnormal when seen in

dilated bowel or if numerous. If the bowel is dilated, distinguish between

small and large bowel by the features listed in Table 13.6. Thickening of the

bowel wall may be seen in a variety of aetiologies, most notably ischaemia,

but also inIBD.

Causes of bowel dilatation include mechanical obstruction, paralytic ileus,

or a localized peritonitis (meteorism), e.g. adjacent to pancreatitis or appen-

dicitis (see Table13.7).

Table13.6 Distinguishing features betweensmall and largebowel

Small bowel Large bowel

Haustrae Absent Present

Valvulae conniventes Present in jejunum Absent

Number of loops Many

Few

Distribution of loops Central Peripheral

Diameter of loops

30– 50mm >50mm

Solid faeces Absent May be present

Maximum diameter 3cm 6cm (9cm in caecum)

Maximum fold thickness 3mm 5mm

PLAIN ABDOMINALX-RAY

791

Look forextraluminalgas

• Gas in the peritoneal cavity:look for air under the hemidiaphragm,

outlining the falciform ligament or both sides of the bowel wall (Rigler’s

sign). If there is any doubt, consider a lateral decubitus lm. Causes

include perforation (ulcer, neoplasm), post- operative, following

peritoneal dialysis, or tracking down from the mediastinum.

•

Air in the biliary tree:following sphincterotomy, gallstone ileus, or

following anastomosis of the CBD to the bowel. This has a linear

morphology and is seen centrally within theliver.

•

Portal vein gas:pre- morbid sign in the context of bowel infarction,

but less sinister in neonates with necrotizing enterocolitis (NEC) or

following umbilical catheterization. In contrast to air in the bile ducts, its

location is peripheral.

•

Intramural gas:linear streaks of air in the bowel wall again usually a

sinister nding implying ischaemia, but may be seen due to benign causes

such as in patients with COPD where its conguration is more rounded

and cystic (pneumatosis cystoides).

•

Air in the retroperitoneum:delineates the renal shadows and psoas

muscle; common causes are trauma, iatrogenic (e.g. after colonoscopic

perforation), and after perforation of a duodenalulcer.

•

Gas in an abscess:look for displacement of adjacent bowel and an

air– uid level. Other causes include air in the urinary tract and within

necrotic tumours. In this scenario, the gas is mottled and does not

display features consistent withbowel.

•

Look for any soft tissue masses or ascites:the latter is detectable on

plain lms if gross. There will be displacement of the ascending and

descending colon from the side walls, with loops of small bowel seen

centrally.

•

Look for abdominal or pelvic calcication:rstly, localize the site. This

may require another view. The vast majority are clinically insignicant,

i.e. vascular calcication, pelvic phleboliths, and calcied mesenteric

nodes. In the abdomen, there may be pancreatic calcication (chronic

pancreatitis) or hepatic calcication (old granulomata, abscesses, or less

commonly hepatomas and metastases from mucinous °s). Gallstones

are less commonly calcied and may contain central lucency (e.g.

Mercedes Benz sign), whilst renal and ureteric calculi commonly calcify.

Table13.7 Distinguishing mechanical obstruction froma paralyticileus

Feature Ileus Obstruction

Bowel calibre Normal or dilated Dilated

Air– uid levels Same level in a single loop Dierential levels

(stepladder)

Other

distinguishing

features

Air seen throughout the GIT

(diuse ileus) or in localized

ileus may be conned to a

short segment

Distension seen to level of

transition. Beyond this level,

no air in bowel

792

CHAPTER13 Radiology

792

Renal tumours and cysts rarely calcify, and more widespread renal

calcications may be seen in nephrocalcinosis due to a wide variety of

causes. In the pelvis, ovarian calcications (less common with malignant

masses and seen more often in association with benign pathologies such

as dermoids) is uncommon, whilst uterine calcications due to broids

commonly occur. Bladder wall calcications may be seen with bladder

tumours, TB, and schistosomiasis. Prostatic calculi and calcications are

common and of no signicance. Vas deferens calcications is seen in

patients with diabetes.

•

Soft tissues:look at renal outlines (normally smooth and parallel to the

psoas; should be between 2– 3 vertebral bodies). Absence of psoas

margins may indicate retroperitoneal disease and haemorrhage.

•

Bones of the pelvis and lumbar spine:look for OA, metabolic bone disease

(hyperparathyroidism, sickle- cell anaemia), the rugger jersey spine of

osteomalacia, and Paget’s disease (E Spinal imaging, pp. 836–7; Pelvis,

p. 838). Bony metastases may be lytic or sclerotic.

PLAIN ABDOMINALX-RAY

793

794

CHAPTER13 Radiology

794

Barium studies

Barium suspension is made up of small particles of barium sulfate in a solu-

tion. Due to its high atomic number, it is highly visible on X- rays. The con-

stituents of individual suspensions vary, depending on the part of the GIT

being examined. The particles are coated to improve ow and aid mucosal

adhesion. When made up, it comprises a chalky (sometimes unpalatable!)

suspension. Advantages include low cost, easy availability, and good assess-

ment of the mucosal surface.

Risks are commoner inthe contextof

• Perforation:if leakage occurs into the peritoneal cavity, it can produce

pain and hypovolaemic shock (50% mortality). Long- term sequelae

include peritoneal adhesions.

•

Aspiration:in small amounts, unlikely to have any clinical signicance, but

if pre- existing respiratory impairment or aspiration of larger amounts

(i.e. more than a few mouthfuls), the patient will need physiotherapy.

•

Obscuration:CT examination in the presence of a recent barium

examination will result in a poorly diagnostic study, as high- density

barium results in streak artefacts.

•

Barium impaction:rarely may exacerbate obstruction if barium collects

and is concentrated above a point of obstruction.

Water- soluble contrastmedia

These are more expensive and provide inferior coating and contrast. They

include iodinated agents such as Gastrogran

Indications fortheir use include

•

Suspected perforation, especially into the peritoneal cavity.

• Meconiumileus.

• To opacify bowel during CT examinations.

Risks include pulmonary oedema if aspirated and hypovolaemia, especially

in children. Both are a result of hyperosmolar eects. If aspiration is likely,

use water- soluble non- ionic contrast, which causes less shift of body uid

compartments. Non- ionic contrast should be used in all infants (especially

neonates) and preoperative patients requiring water- soluble contrast.

Contrastagents

(See Table13.8.)

For studies other than when barium is being utilized, the contrast media

are non- ionic iodinated agents that are given PO, endoluminally, or IV. Non-

ionic contrast agents are higher in cost than their ionic counterparts (rarely

used currently) but have a lower incidence of adverse reactions (by a fac-

tor of 9 for severe reactions). They are typically excreted by glomerular

ltration. Half- life is dependent on the dose given, distribution, and renal

function. Contrast reactions can be idiosyncratic or anaphylactoid or

non- idiosyncratic.

BARIUM STUDIES

795

High- risk patients are those with prior contrast reactions, a history of

allergy or atopy, sickle- cell disease, phaeochromocytoma, and multiple

myeloma (to name a few). Contrast- induced nephropathy is commoner if

creatinine is elevated at time of administration or if the patient has a pre-

existing renal impairment, e.g.DM.

Pre- medication can be administered to patients with prior contrast reac-

tions. Protocols vary but typically include a corticosteroid and an antihis-

tamine. Consider the use of alternate modalities if risk is high, e.g. USS or

MRI, instead of CT with contrast.

Extravasation of contrast is typically treated symptomatically with ice

pack and elevation. Plastic surgery consult should be obtained if concern

regarding compartment syndrome in patients who have in excess of 100mL

in extremity or severe pain/ discoloration or altered perfusion.

Gadolinium is an MR- based contrast agent that is paramagnetic. It is also

excreted by glomerular ltration.

Its safety prole is favourable in that it does not have any of the nephro-

toxicity associated with the iodinated contrast media and is more commonly

associated with minor reactions such as headaches. Since 2006, there is an

established association between the use of gadolinium- containing contrast

agents and NSF. NSF involves brosis of the skin, joints, eyes, and other

viscera. Subsequent to this nding, the use of gadolinium is contraindicated

in patients with an eGFR of under 60 and particularly if below30.

Table13.8 Pharmacological agents used inbarium studies

Agent Dose Advantages Disadvantages

Hyoscine

butylbromide

20mg IV Reduced bowel

peristalsis due to

smooth muscle relaxant

action

Immediateonset

Short duration of action

(15min)

Anticholinergic side

eects

Contraindicated

with CVD and

glaucoma

Glucagon 0.3mg IV

for barium

meal

1.0mg IV

for barium

enema

More potent smooth

muscle relaxant than

hyoscine butylbromide

Short duration of

action, no interference

with small bowel transit

Contraindicated

with insulinomas

or phaeo-

chromocytomas

Relatively expensive

Meto-

clopramide

20mg PO

or IV

Gastric peristalsis

enhances barium transit

during a follow- through

study

Possible

extrapyramidal side

eects

796

CHAPTER13 Radiology

796

Barium swallow

Plain lms do not usually demonstrate the oesophagus, unless it is very dis-

tended, e.g. achalasia. They may be useful in identifying an opaque foreign

body within the lumen. The barium swallow is the usual contrast examina-

tion to visualize the oesophagus (see Fig. 13.16). Rapid- sequence lms are

taken with a uoroscopy unit, whilst the patient swallows barium (usually in

an erect position). Films are taken in an AP and oblique projection (to throw

the oesophagus clear of the spine), with the oesophagus distended with

barium (to demonstrate its outline) and empty to show the mucosalfolds.

Normal anatomy

The oesophagus commences at C5/ 6. There are normal indentations

on its outline by the cricoid cartilage, aortic arch, left main bronchus, and

leftheart.

Indications

These include the assessment of dysphagia, pain, reux disease, tracheo-

oesophageal stulae (in children), and post- operative assessment where

there has been gastric or oesophageal surgery.

Contraindications

No absolute contraindications exist, but in all barium studies, the quality

of the study relies heavily on patient co- operation, and therefore immo-

bile patients who are unable to weight- bear may only be suitable for

limited studies. The post- operative oesophagus is usually assessed with

Gastromiro

or a non- ionic contrast.

Fig.13.16 Lateral oblique projection during a barium swallow series shows a feline

oesophagus. This can be a normal variant but is often associated withGORD.

BARIUM SWALLOW

797

Common disorders and patterns

• Diverticulae:these include pharyngeal pouches (a midline diverticulum),

traction diverticulae (due to adhesions), or pseudodiverticulae; dilated

mucous glands seen in reux or infective oesophagitis.

•

Luminal narrowing:strictures may be benign (e.g. oesophagitis— shown

in Fig. 13.17, scleroderma, pemphigus, corrosives, or infection) or

malignant.

•

Webs:mucosal structures, which may be seen anywhere in the

oesophagus; seen with skin lesions, e.g. epidermolysis or pemphigus,

GVHD, and Plummer– Vinson syndrome.

• Mega- oesophagus:can be with associated obstruction, as in malignant

strictures, or without as in achalasia, diabetic neuropathy, or Chagas’

disease (see Fig. 13.18a– c).

• Ulceration/ oesophagitis:may be due to GORD, infection, corrosives,

or iatrogenic. Findings include lack of distensibility, fold thickening, and

mucosal irregularity.

•

Oesophageal tears:spontaneous, neoplastic, post- traumatic, iatrogenic,

and following prolonged emesis. Look for pneumomediastinum, left

pleural eusion, and features of mediastinitis.

•

Filling defects:foreign bodies, varices (proximal due to SVC obstruction),

distal (in association with portal hypertension), neoplasms that may be

benign (as in leiomyoma) or malignant. Most commonly SCC(95%).

•

Fold thickening:may be due to oesophagitis, varices, or inltration by

lymphoma.

•

Air– uid level:commonest in hiatal hernias, but also seen with a

pharyngealpouch.

Web

Stricture

Ring

Fig.13.17 Benign strictures.

(b)

(c)

open

Moderate

dilatation

Irregularit

(a)

Bird's beak

Massive dilatation

Curves to

the right

Fig.13.18 Obstruction in: (a)achalasia,

(b)scleroderma, and (c)cancer.

798

CHAPTER13 Radiology

798

Bariummeal

About 200mL of a high- density (85% w/ v barium sulfate), low- viscosity

barium is used for a double contrast study, which gives good coating with-

out obscuration of mucosal detail. An eervescent agent is given to pro-

vide adequate luminal distension. The gastric mucosa is characterized by

rugae (parallel to the long axis, 3– 5mm thick) and area gastricae (nodular

elevations, 2– 3mm wide). The patient is fasted for about 6h to avoid food

residue, which may cause diagnostic uncertainty. The techniques for coat-

ing the stomach and projections are variable. A smooth muscle relaxant

may be given as part of the routine, particularly to assess the pylorus and

duodenum.

Indications

Dyspepsia, weight loss, abdominal masses, iron deciency anaemia of

uncertain cause, partial outlet obstruction, and previous GI haemorrhage.

Contraindications

Complete large bowel obstruction.

Abnormal ndings

• Filling defects:these may be intrinsic or extrinsic. Carcinoma remains the

commonest cause of a lling defect in an adult (irregular, shouldered

with overhanging edges). If there is antral involvement, there may be

associated outlet obstruction. Diuse mucosal thickening and failure

to distend is seen with linitis plastica. Other causes include gastric

lymphoma, polyps (histology dicult to predict), and bezoars. Smooth

lling defects are seen in conjunction with leiomyomas, lipomas, and

metastases. Extrinsic indentation by pancreatic tumours or an enlarged

spleen may cause an apparent lling defect.

•

Fold thickening (>5mm):seen in association with hypersecretion states

such as Zollinger– Ellison syndrome, gastritis, and Crohn’s disease. It may

also be 2° to inltration by carcinomas, lymphomas, or eosinophilia.

•

Outlet obstruction:may be diagnosed by failure of the stomach to empty

<50% of the barium ingested at 4h. This may be seen in carcinomas, but

also in scarring caused by chronic duodenal ulceration.

•

Hiatal hernia:herniation of the stomach into the chest occurs via

the oesophageal hiatus in the diaphragm. There are two types— in a

sliding hernia (commoner), there is incompetence of the sphincter

at the cardia, often associated with reux. Other sequelae include

oesophagitis, ulceration, or stricture. In a rolling hernia, the fundus

herniates through the diaphragm, but the gastro- oesophageal junction

remains competent and lies below the diaphragm.

•

Gastritis and ulceration:gastritis is characterized by small, shallow

barium pools with surrounding lucent rings due to oedema. There

are features that may be used to distinguish benign from malignant

ulcers on barium studies. Ulcers are seen either as a crater or as a

projection from the luminal surface (see Fig. 13.19). Benign ulcers

BARIUMMEAL

799

are commonly seen on the lesser curve with smooth radiating folds,

which reach the edge of the ulcer crater. Malignant lesions may have

an associated mass and have a shallow crater and an irregular contour.

With the ease of availability of endoscopy, the use of barium meals

in diagnosing ulceration has declined. Endoscopy has the advantage of

being able to diagnose gastritis more accurately, assess ulcer healing,

make a histological diagnosis, and more accurately assess the post-

operative stomach. However, early assessment of the post- operative

stomach is radiologically performed to exclude complications such as

anastomotic leaks. Awater- soluble contrast agent is preferred in the

early post- operativephase.

Fig.13.19 Double contrast barium meal showing an ulcer crater.

800

CHAPTER13 Radiology

800

Small intestine

Small bowel studies are performed for indications such as occult bleeding,

recurrent obstructive symptoms, and malabsorption, and to conrm and

dene the extent of small bowel disease in Crohn’s.

•

Small bowel follow- through:the patient drinks 200– 300mL of barium (with

metoclopramide to speed transit time). The single contrast column is

followed by lms at regular intervals until the barium reaches the colon.

Transit time is variable, but the entire process may take 1– 6h, depending on

the adequacy of bowel preparation. Films are taken at intervals of 720min

initially, in the prone position, which aids separation of the loops. When the

barium reaches the caecum, spot views of the terminal ileum aretaken.

•

Small bowel enema (enteroclysis):this technique provides better

demonstration of mucosal detail, as there is rapid infusion of a

continuous column of barium directly into the jejunum. Methylcellulose

is administered following the barium to provide double contrast. This is

achieved via a weighted nasogastric tube which is positioned at, or distal

to, the duodenojejunal (DJ) exure. Disadvantages include poor patient

tolerance (related to intubation) and a relatively high screeningdose.

Both techniques require the patient to be on a low- residue diet beforehand.

Indications

The indications are the same for both techniques and include pain, diar-

rhoea, bleeding, partial obstruction, malabsorption, overgrowth syn-

dromes, assessment of Crohn’s disease activity and extent, and suspected

masses. The small bowel enema may be preferred for assessment of recur-

rent Crohn’s disease or complex post- operative problems, but the small

bowel follow- through is otherwise routinelyused.

Contraindications

Complete obstruction and suspected perforation.

Normal ndings

The small intestine measures 75m and extends from the DJ exure to the ile-

ocaecal valve. The proximal two- fths is the jejunum; the distal three- fths is the

ileum. Normal calibre is 3.5cm for the jejunum and 2.5cm for the ileum (up to

1cm more on enteroclysis). The valvulae conniventes are circular in congura-

tion, and 7

2mm thick in the jejunum and 1mm thick in the ileum (see Fig. 13.20).

Abnormal ndings

• Dilatation is indicative of malabsorption, small bowel obstruction (SBO),

or paralytic ileus. There may be accompanying eacement of the mucosal

pattern. When seen with fold thickening, it may be due to Crohn’s,

ischaemia, or radiotherapy. Mucosal thickening may be due to inltration by

lymphoma or eosinophilia, adhesions, ischaemia, or radiotherapy.

•

Strictures are seen in Crohn’s disease and lymphoma. There is usually

dilatation of the bowel proximally. Crohn’s disease causes skip lesions,

ulceration, strictures of variable length, and a high incidence of terminal

ileal involvement. There may be associated ulceration, fold thickening,

and stulation (see Fig. 13.21).

• Malabsorption:radiological investigation may reveal an underlying

structural abnormality. The ndings in malabsorption include dilatation,

fold thickening, and occulation of barium.

SMALL INTESTINE

801

CT enteroclysis

This is a hybrid technique that combines uoroscopic intubation and small

bowel infusion with an abdominal CT. This can be performed with +ve

enteral contrast or neutral enteral contrast.

The advantage of this technique is that both intra- and extraluminal/

extra- enteric information is obtained, rendering it superior to many of the

per- oral small bowel studies. Disadvantages include the minimally invasive

nature and the radiation associated with a CT examination. CT enterocly-

sis is complementary to capsule endoscopy in the elective investigation of

small bowel disease and should be particularly considered in Crohn’s dis-

ease, small bowel obstruction, and unexplained GI bleeding. There has been

a paradigm shift to CT enterography for the assessment of small bowel

disease. This is most relevant in the IBD population who are on disease-

modifying drugs.

Fig.13.20 A30min lm in a small bowel follow- through series showing a normal

mucosal fold pattern.

Fig.13.21 Small bowel enema showing at least two strictures (arrows) in this patient

with Crohn’s disease. Compare the mucosal detail with the small bowel follow- through.

802

CHAPTER13 Radiology

802

Cholangiography

Ultrasound

This is the ° modality for assessment of the biliary tree and for exclusion

of pancreatic pathology. With the current scanner resolution, the sensitiv-

ity for stone disease is in the range of >95% for stones exceeding 2mm in

diameter. For choledocholithiasis (stones in the CBD), the sensitivity falls to

around 50%, and MRCP or ERCP is more helpful.

Intravenous cholangiography

This is rarely performed but may be useful in patients with biliary symptoms

post- cholecystectomy or with a non- functional gall bladder. It is contrain-

dicated in the presence of severe hepatorenal disease, as the side eects

related to the contrast media are considerable. CT cholangiography uses

a similar contrast agent but oers the advantage of cross- sectional assess-

ment of the bile ducts. It is often used when MRCP has not helped delineate

the anatomy in donors prior to liver transplantation or when MR is con-

traindicated or simply not available.

Endoscopic retrograde cholangiopancreatography

The biliary and pancreatic ducts are directly lled with contrast, following

endoscopic cannulation and during X- ray screening. This has both a diag-

nostic and therapeutic role. It is particularly of value in the demonstration

of ampullary lesions and to delineate the level of biliary tree obstruction

in patients with obstructive jaundice. It allows sphincterotomy to be per-

formed to facilitate the passage of stones lodged in theCBD.

Percutaneous transhepatic cholangiography

The biliary tree is directly injected with contrast, following percutaneous

puncture of the liver. This is both diagnostic in dening a level of obstruc-

tion and therapeutic in biliary duct obstruction, as it may be used as a

precursor to a biliary drainage procedure or prior to insertion of a stent.

Contraindications include bleeding diatheses and ascites.

Other cholangiographic techniques

• Per- operative cholangiogram:in which the CBD is lled with contrast

during cholecystectomy to exclude the presence of CBD stones.

•

T- tube cholangiogram:after operative exploration, a T- tube is left in the

CBD for a post- operative contrast study to exclude the presence of

retained stones.

•

MRCP:this is a non- invasive technique where heavily T2- weighted

(T2W) images are obtained without contrast administration. The bile

acts as an intrinsic contrast agent, and stones are visualized as lling

defects. The entire biliary and pancreatic ductal system can be visualized

(see Fig. 13.22). Common indications for this technique include

unsuccessful ERCP, a contraindication to ERCP, as well as evaluation of

the post- surgical biliarytree.

CHOLANGIOGRAPHY

803

Fig.13.22 Heavily T2- weighted slab image showing an irregular beaded pancreatic

duct in this patient with chronic pancreatitis. There is a small pseudocyst in the tail

(arrowhead).

Magnetic resonance cholangiopancreatography

•

Non- invasive.

• Cheaper.

• Uses no radiation.

• Requires no anaesthesia.

• Less operator- dependent.

• Allows better visualization of the ducts proximal to the level of

obstruction.

•

When combined with conventional sequences, allows detection of

extraductal disease.

Disadvantages

•

d spatial resolution for peripheral intra- hepatic ducts and for pancreatic

ductal side branches (e.g. as in pancreatitis).

•

Subtle ductal lesions may be dicult to appreciate, as ducts are imaged

in the non- distended physiologicalstate.

• Inability to perform therapeutic endoscopic or percutaneous

intervention of obstructing bile duct lesions.

•

MRCP is comparable with ERCP in the detection of obstruction, with a

sensitivity and specicity of 91 and 100%, respectively.

•

Causes of lling defects are usually stones, air, tumours, blood, or

sludge.

Contrast- enhanced MRCP can also be performed with fat- saturated T1-

weighted (T1W) imaging after injection of gadolinium contrast agents that

have biliary excretion. These cause TI hyperintensity with bile but require a

20– 45min delay prior to imaging to allow for biliary excretion.

804

CHAPTER13 Radiology

804

Liver disease

US is the modality of choice for initial screening, whether assessing the

parenchyma for diuse disease or trying to evaluate and/ or characterize

focal liver lesions. Although US is sensitive in depicting focal lesions, it is not

specic and there can be overlap in the imaging characteristics of benign

and malignant lesions. CT, and particularly MRI, are more tissue- specic in

characterizing liver lesions. The liver is supplied predominantly by the por-

tal venous system (80%). On CT, the diering phases of enhancement are

utilized to assess a lesion.

Arterial phase images (20– 30s after injection) i the conspicuity of lesions

that are hypervascular such as hepatocellular carcinoma or focal nodular

hyperplasia. Portal venous phase images are acquired at 50– 70s and pro-

vide maximum enhancement of background hepatic parenchyma. Lesions

that are relatively hypovascular on this phase stand out such as metastases.

Delayed imaging (equilibrium phase) minutes after contrast adminis-

tration allows lesions that demonstrate relative washout of contrast (i.e.

appear hypo- attenuating) relative to background liver, such as hepatocellu-

lar carcinomas, to stand out. Lesions that are relatively brotic (e.g. in tissue

content or scars) conversely exhibit i enhancement on delayed images.

MRI displays the same patterns of contrast enhancement but has superior

lesion- to- liver contrast and imparts no ionizing radiation. Multiple dynamic

post- contrast sequences can thus be obtained. Tissue characterization

allows for detection of intralesional lipid (as in adenomas), and advanced

techniques such as diusion- weighted imaging (DWI) improve sensitivity

for lesion detection.

Further characterization of lesions can be obtained by hepatocellular-

specic MRI contrast agents which allow denitive assessment of lesions

with hepatocytes such as focal nodular hyperplasia (FNH), precluding the

need for biopsy.

CHOLANGIOGRAPHY

805

806

CHAPTER13 Radiology

806

Bariumenema

This is used for evaluation of the large bowel. Increasingly, many institutions

are replacing this technique with CT colonography (CTC; E Virtual colo-

noscopy, p. 807) or conventional CT, depending on the clinical indication.

Barium is run into the colon under gravity via a tube inserted into the rec-

tum. The column of barium is followed by air (room air or CO

) to achieve

double contrast. The CO

is better tolerated and more readily absorbed.

Hyoscine butylbromide (a smooth muscle relaxant) may be given to mini-

mize spasm and optimize mucosal relief. Bowel preparation prior to the

examination (low- residue diet and aperients) is vital to ensure that there is

no faecal material, which may mask mucosal abnormalities or be mistaken

for small polyps. Remember the examination is uncomfortable and requires

reasonably good patient co- operation and mobility.

2 Do not request this in frail or elderly patients, unless there is a good

clinical indication.

A rectal examination or sigmoidoscopy is essential to avoid abnormalities

being missed.

Single vs double contrast

If evaluation of the colonic mucosa is not the ° aim, then a single contrast

technique will suce. This is applicable in children where the patient is unco-

operative and where gross pathology is being excluded, and in the evalua-

tion of obstruction/ volvulus or in the reduction of an intussusception.

Indications

Change in bowel habit, iron deciency anaemia, abdominal pain, palpable

mass of suspected colonic origin, and weight loss of unknowncause.

Contraindications

Suspected perforation, recent rectal biopsy, toxic megacolon, or pseudo-

membranous colitis.

Common ndings

• Solitary lling defect:polyps are classied according to histology. The

commonest are hyperplastic (no malignant potential; adenomatous

polyps are premalignant with the risk of malignancy i with size

(<5mm=0%, >2cm=20– 40%). Also found are adenocarcinoma

(i risk in ulcerative colitis, polyposis syndromes, villous adenoma) and

less commonly metastases and lymphoma.

•

Multiple lling defects:polyps (polyposis syndromes or post-

inammatory pseudopolyps), pneumatosis coli, metastases, and

lymphoma.

•

Ulceration:IBD, ischaemia, infection, radiation, and neoplasia.

•

Colonic narrowing:neoplasms (apple core lesion), metastases, lymphoma,

diverticular disease, IBD, ischaemia, and radiation.

•

Dilatation:mechanical, e.g. proximal to neoplasm, volvulus or non-

mechanical, post- operative ileus, metabolic, and toxic megacolon.

• Diminished haustration:cathartic colon, IBD, and scleroderma.

BARIUMENEMA

807

Fig.13.23 Standard supine projection

from a double contrast barium enema

(DCBE) showing a normal large bowel.

• i haustration (thumbprinting):ischaemia, haemorrhage, neoplasm,

andIBD.

•

Widening of the pre- sacral space (>1.5cm at S2):normal in up to 40%,

but also seen in association with IBD, neoplasms, infection, and sacral/

pelvic lipomatosis.

Colonoscopy

Remains a complementary technique and has the advantage of being both

therapeutic and diagnostic (e.g. biopsy, polypectomy, etc.). In elderly

patients, CT with prior bowel preparation and air insuation is less invasive

and less arduous.

Virtual colonoscopy

Helical CT images of distended colon taken during a breath- hold are used

to obtain 2D or 3D images of the colon. Images are acquired in the supine

and prone positions to assess lesional mobility (and thus distinguish stool

from polyps). No IV contrast is administered for routine screening stud-

ies, and the examination is often performed utilizing a low- dose technique.

Recent studies using ° 3D interpretation, as well as national studies, such

as the ACRIN II trial, have shown sensitivities in the range of 94% for polyps

of at least 1cm in diameter and around 88% for lesions measuring at least

6mm. Current renements in this technique include the use of computer-

assisted detection (CAD) to improve performance, as well as the use of

prepless techniques (i.e. the patient does not have to undergo prior bowel

cleansing).

(See Figs 13.23 and 13.24.)

Fig.13.24 Supine DCBE showing a tight

stricture in the transverse colon in this

patient withIBD.

Further reading

Pickhardt PJ, Choi JR, Hwang I, etal. Computed tomographic virtual colonoscopy to screen for

colorectal neoplasia in asymptomatic adults. N Engl J Med 2003; 349

:2191– 200.

808

CHAPTER13 Radiology

808

Radiology ofthe urinarytract

Plain abdominallm

• Look for any urinary tract calcication:90% of stones are radio- opaque.

Other causes include hyperparathyroidism, medullary sponge kidney,

andRTA.

• Renal outline:between T12 and L3 and 10– 15cm. Left bigger and higher

than theright.

•

Assess bones of spine and sacrum:for bony metastases or spina bida

(may be relevant in enuresis).

Intravenous urogram

This provides a good overview of the urinary tract and, in particular, the

pelvicalyceal anatomy. Fluid restriction and laxatives are no longer neces-

sary and, in particular, the former is to be avoided in diabetics, renal failure,

and myeloma. Following the preliminary plain lm, 300mg/ kg of contrast

media is injected IV. The lm sequence is varied according to the clinical

scenario. An immediate lm shows the nephrogram phase and displays the

renal outlines. An increasingly dense delayed nephrogram is seen in acute

obstruction, acute hypotension, ATN, and renal vein thrombosis. Afaint

persistent nephrogram is seen with acute glomerulonephritis and it may

be delayed in RAS. Later lms show the pelvicalyceal systems (pyelogram),

ureters, and bladder.

Common abnormalities

(See Fig. 13.25.)

• Loss of renal outline:congenital absence, ectopic kidney, tumour, abscess,

or post- nephrectomy (look for absent twelfthrib).

• Small kidney (unilateral):ischaemia (RAS), radiation, or congenital

hypoplasia.

•

Small kidney (bilateral):atheroma, papillary necrosis, or

glomerulonephritis.

•

Large kidney (unilateral):duplex, acute pyelonephritis, tumour, or

hydronephrosis.

•

Large kidney (bilateral):polycystic kidneys and inltrative disease such

as myeloma, amyloid, and lymphoma. Acute inammation such as

glomerulonephritis, ATN, and collagen vascular disease.

• Pelvicalyceal lling defect:smoothly marginated (clot, papilloma),

irregular margins (tumour, e.g. renal cell or transitional carcinoma),

intraluminal (sloughed papilla, calculus, or clot), extrinsic (vascular

impression or cyst), irregular renal outline (scarring, e.g. in ischaemia,

TB, pyelonephritis, or reux nephropathy).

• Dilated ureter:>8mm in entire length. May be due to obstruction

(functional as in ° megaureter) or mechanical stenosis as in ureteric or

urethral stricture and in reux disease.

•

Ureteric stricture:wide dierential; determine the length. Dierentials

include tumour (transitional cell carcinoma, metastatic), inammatory

(TB, schistosomiasis), congenital, trauma (radiation or iatrogenic).

RADIOLOGY OFTHE URINARYTRACT

809

• Deviated ureters:normal course of ureters in close proximity to

transverse processes of vertebral bodies.

•

Lateral deviation:seen with retroperitoneal nodes, tumours, and aortic

aneurysm.

•

Medial deviation:posterior bladder diverticulum, retroperitoneal brosis

(can be idiopathic or related to various aetologies, including malignancy.

Computed tomography ingenitourinary pathology

CT is the preferred method for assessment of many pathologies within the

genitourinary (GnU) tract, including trauma, complex infections, renal and

adrenal masses, neoplastic disease, retroperitoneal processes, renovascular

hypertension, and in renalcolic.

Computed tomography urography

In many institutions, IVU has been replaced by its CT counterpart (CT urog-

raphy (CTU)). MDCT has had an impact on slice thickness and speed of

scanning, such that the urinary tract mucosa can be assessed in exquisite

detail. Depending on institutional protocol, the examination is performed

as a 2- or 3- part study. Typically, it includes a non- contrast phase (to assess

for stones, acute blood) and then an excretory/ delayed phase to assess

Renal cyst

Multiple renal cysts

(elongation and distortion

of calyces – polycystic

disease)

Renal tumour

Duplex kidney with

hydronephrotic

upper moiety.

(‘drooping ower’)

Dilatation of a

single calyx

(may be due to

vascular compression)

Fig.13.25 Common patterns of abnormalities seen onIVU.

810

CHAPTER13 Radiology

810

the collecting systems and ureters. It has a high sensitivity (95%) in detect-

ing upper urinary tract uroepithelial malignancies. Common indications for

usage include:

•

Haematuria (with −ve cystoscopy and USS having excluded parenchymal

causes).

•

Unexplained hydronephrosis onUSS.

• Evaluation of the upper tract in patients with known lower urinary tract

transitional cell carcinoma or following trauma or iatrogenic ureteric

injury.

Ultrasound

May be used as an alternative or complementary examination with IVU and

may be usedto:

•

Demonstrate or exclude hydronephrosis, especially inARF.

• Evaluate renal tumours, cysts, and abscesses.

• Follow up transplant kidneys and chronic renal disease.

• Assess renal blood ow using Doppler.

• Perform serial scanning in children with recurrentUTIs.

• Assess bladder morphology and volume, and the prostate.

• Provide guidance for interventional techniques, e.g. renal biopsy and

nephrostomy placement.

Computed tomography and magnetic resonance imaging

CT is more accurate for staging renal tumours, assessing retroperitoneal

pathology, staging bladder and prostatic tumours, and assessing renal vascu-

lar pathology (such as RAS). In many centres, unenhanced CT is replacing

IVU as a gold standard for assessment of renal stone disease. It is more

accurate at depicting stone burden than IVU and precisely demonstrating

the level and cause of obstruction in the acute setting. Evaluation of ure-

teric pathology in the context of haematuria is also being performed with

contrast- enhancedCT.

MRI is valuable in staging vascular involvement by renal carcinomas.

Dedicated pelvic coils and endoluminal coils show excellent results in stag-

ing pelvic and gynaecological malignancies.

Micturating cystourethrogram

Following catheterization of the bladder, contrast is introduced till bladder

capacity is reached. This is the technique of choice for dening the urethral

anatomy and gauging the presence/ degree of vesicoureteric reux in chil-

dren. It is also used if there are recurrent UTIs or suspected lower urinary

tract obstruction.

Ascending urethrography

Contrast is injected directly into the urethra in ♂ in the assessment of

urethral trauma, strictures, and congenital anomalies such as hypospadias.

RADIOLOGY OFTHE URINARYTRACT

811

Retrograde pyelography

The ureters are catheterized (usually following cystoscopy in theatre) and

contrast injected under X- ray screening. Of value in urothelial tumours and

to dene the site of obstruction, e.g. non- opaque calculi. Useful if IV tech-

niques have failed to demonstrate the intra- renal collecting system or ure-

ters due to impaired renal function or a high- grade obstruction.

Angiography

A femoral approach with selective catheterization of renal vessels. Main

uses include haematuria (look for AVMs), hypertension (RAS), in transplant

donors (to dene anatomy), and in renal cell carcinoma (where emboliza-

tion is being contemplated).

Nephrostomy

E Interventional radiology, pp. 844–7.

812

CHAPTER13 Radiology

812

Breast imaging

Breast cancer is a common problem (1 in 12 women). The average ♀ has

a 1 in 8 chance of being diagnosed with breast cancer during her lifetime.

Mammography is the rst- line tool for detection of breast cancer; however,

sensitivity of screening mammogram is variable and is inuenced by vari-

ables such as density of breast tissue. Sensitivity is between 68 and 90% and

is higher if the patient is symptomatic(93%).

Screening mammography detects 2– 8 cancers per 1000 women

screened. Since 1990, mortality from breast cancer has steadily declined,

and this has been attributed to advances in adjuvant therapy as well as to

mammographic screening.

Mammography

Technical factors

Breast tissue has a narrow spectrum of inherent densities, and in order to

display these optimally, a low- kilovoltage (kV) beam is used. It enhances

the dierential absorption of fatty, glandular, and calcic tissues. Dedicated

mammographic units provide low- energy X- ray beams with short expo-

sure times. The breast is compressed to minimize motion and geometric

unsharpness. High resolution is paramount in order to detect microcalcica-

tion (as small as 0.1mm). The breast is a radiosensitive organ, so doses need

to be kept to a minimum.

Standard projections

These are the mediolateral oblique (MLO) and craniocaudal (CC) views

(see Fig. 13.26). The CC view is trans- axial. The MLO image plane is 745–

60° from the axial plane and parallels the pectoralis major. Adequacy of the

lateral oblique view may be gauged by the pectoralis major muscle, which

should be visible to the level of the nipple, inclusion of the axillary tail,

Fig.13.26 CC mammographic view of the breast. The arrows depict a stellate mass

consistent with a carcinoma.

BREAST IMAGING

813

and inclusion of the inframammary fold. The CC view detects posterome-

dial tumours that may be missed on the MLO view and is better at breast

compression. Additional projections, such as true lateral, cleavage, exag-

gerated CC, spot compression, and magnication views, may be used to

clarify abnormalities. These techniques provide better detail and disperse

any overlapping tissue to avoid obscuration of lesions.

Mammographicsigns

The breast parenchyma is made up of glandular tissue in a brofatty stroma.

Cooper’s ligaments form a connective tissue network. The amount of glan-

dular tissue d with age; as it is dense on mammography, the suitability of the

technique for detecting pathology i withage.

Systematic evaluation ofa mammogram

•

Adequacy of study; are additional views required?

• Adequate penetration of broglandular tissue.

• Skin, nipple, trabecular changes.

• Presence of masses.

• Calcications.

• Axillarynodes.

• Asymmetry (may be a normal variant).

• Architectural distortion.

Comparison with prior imaging is imperative, as changes can be subtle and

progressive.

Additional technical adequacy

•

There should be adequate tissue demonstrated on both CC and MLO

views. The posterior nipple line is a line drawn from the posterior nipple

to the pectoralis muscle. On each view, the posterior nipple line should

be within 1cm of eachother.

•

Image should be free from blur and artefacts.

• Nipple should be in prole on at least oneview.

• Blurring can cause benign calcication to look amorphous, and subtle

calcication may be missed.

Primary signs ofa malignancy

• Amass with ill- dened or spiculate borders (see Fig. 13.27).

• Clustered, linear, or irregular calcication (which may occur in the

absence of amass).

•

2° signs include distortion of adjacent stroma, skin thickening, and nipple

retraction.

Ninety- four per cent of breast carcinomas is ductal in origin.

The breast imaging and reporting data system (BIRADS) is a standardized

way of reporting mammography and includes a lexicon, a structured report,

and clear categories for follow- up and reassessment of imaging ndings.

814

CHAPTER13 Radiology

814

Breast ultrasound

This largely forms a modality for assessment, not diagnosis or detection,

and is a valuable adjunct and problem- solving tool. It can be used to evalu-

ate non- palpable masses and palpable masses not seen on mammography,

to determine the internal architecture (solid vs cystic), to assess asymmetric

density, to assess breast implants, and as a ° imaging modality in young

women (<35 years), as well as pregnant and lactating women. It is also

used as a tool to guide intervention, i.e. drainage of cysts and biopsy of

suspicious lesions.

Magnetic resonance imaging

MRI remains a problem- solving tool in breast imaging. Widespread imple-

mentation of MRI (for instance, for screening) is hampered by its low speci-

city (37– 97%). It can i the number of benign biopsies that are performed.

This clearly has resource implications, as well as generating unnecessary

patient anxiety. Both MRI and US may be used to evaluate implants and

their integrity, but MRI is the only modality that is sensitive in the evaluation

of intracapsular implant rupture. Contrast- enhanced MRI of the breast is

also a sensitive method for detection of malignancy, with reported sensitivi-

ties in the region of 93%. It is especially useful to detect recurrent breast

carcinoma and where conventional techniques are unable to help in the

distinction from more benign lesions. Breast MRI is also being advocated

for screening young patients with a family history/ genetic risk of breast

carcinoma.

Fig.13.27 Subtraction sagittal MR image of the breast following gadolinium,

showing an enhancing spiculated mass consistent with malignancy.

BREAST IMAGING

815

Breast MRI is increasingly being used for staging breast carcinomas, to

look for synchronous ° lesions, and to evaluate the breast in patients found

to have malignant nodes in the axilla. It can also be used to evaluate tumour

response to neo- adjuvant chemotherapy. In problematic mammographic

patients, it can be useful in distinguishing dense breast tissue or brosis from

malignancy. In the post- operative setting, it can be used in patients with +ve

surgical margins or to assess post- operative scar vs disease recurrence. The

selection of pulse sequences and IV contrast administration is based on the

clinical indication.

The patient lies prone on the scanner, and a specialized coil surrounds the

breast. The entire scan varies in duration from 20min to 1h. Most protocols

for exclusion of malignancy rely on a dynamic enhanced sequence. Cancers

typically enhance more rapidly than benign lesions.

816

CHAPTER13 Radiology

816

Ultrasound

US is a high- frequency mechanical vibration produced by piezoelectric

materials, which have the property of changing thickness when a voltage

is applied across them. It is an important cross- sectional modality and has

widespread applications in the abdomen, neck, pelvis, and extremities. At

diagnostic levels, there are no known damaging sequelae to tissues, and

therefore it is safe for use in obstetrics, providing invaluable imaging of the

developingfetus.

Probe selection is dependent on the area being imaged. Highe- frequency

probes provide greater resolution but have limited depth of penetration

and may therefore be suitable for assessment of supercial structures (e.g.

extremity US, thyroid, testicular US). Doppler USS is based on the principle

that sound reected by a moving target has a dierent frequency to the

incident sound wave. The frequency shift is proportional to the velocity of

the owing material. Doppler therefore not only enables detection but also

quantication of velocity.

Indications

USS is cheap, readily available, and non- invasive, and has high patient accept-

ability. It has a wide range of applications as listed below. There are also no

radiation implications. Again, advances in technology have resulted in vast

improvements in the resolution of this modality, such that subtle pathology

is more readily identiable. The portability of USS also lends itself to use in

the setting of emergency and critically ill patients, as well as providing guid-

ance for intra- operative procedures.

Contraindications

None, but remember that USS is operator- and patient- dependent and

should be used as a problem- orientated modality, not as a total body sur-

vey. It cannot be used to image air- containing structures or bone. The reso-

lution of the USS image is inversely related to the depth of penetration.

Therefore, image quality in obese patients is suboptimal.

Applications

• Head and neck:may be used for evaluation of the salivary glands,

thyroid, lymph nodes, and palpable or clinically suspected masses.

Doppler is used to assess the carotid vessels and quantify the degree of

stenosis/ occlusion.

• Chest (excluding breast):the use here is limited to palpable chest wall

lesions, assessment of pleural abnormalities, biopsy, and drainage of

pleural eusions, and is occasionally of use in directing a biopsy of

peripheral lung or mediastinal masses.

•

Abdomen and pelvis:this is the main use of USS. Useful for assessment

of solid organs, e.g. kidneys, spleen, gall bladder (see Figs 13.28

and 13.29), liver (see Fig. 13.30), pancreas, uterus/ adnexae, and

bladder. Afull bladder is used as an acoustic window in the pelvis.

Retroperitoneal masses and lymph nodes may be visible, depending on

patient habitus. USS is useful for directing biopsy of solid organs/ masses

and for drainage of ascites, abscesses, and collections.

ULTRASOUND

817

Fig.13.28 Trans- axial view of the gall bladder on US demonstrating a soft tissue

mass in the lumen, suspicious for carcinoma. There is cholelithiasis, a common

coexistent entity. The arrow shows an abnormal interface with the liver parenchyma,

suggestive of local inltration.

Fig.13.29 Colour Doppler image in the same patient showing abnormal vascularity

in the wall of the gall bladder (E Colour plate5.)

Fig.13.30 Dilated intra- hepatic ducts seen in this axial view of theliver.

818

CHAPTER13 Radiology

818

• Limbs:musculoskeletal USS has been revolutionized by advances in high-

frequency probes, which enable characterization of soft tissue masses,

tendon- related pathology, rotator cu lesions, masses, eusions, and

collections. The dynamic nature of the examination allows the diagnosis

of functional pathological conditions and is also used to guide aspiration

and lavage. Assessment of supercial lumps and masses can be

performed as a rst line before triaging to other modalities such as MRI.

It is also used for vascular assessment and the diagnosis ofDVT.

• Intracavitary transducers:these place the transducer as close as

possible to the area of interest. They include transvaginal, transrectal,

urethral, oesophageal, and intravascular probes. They are usually high-

frequency transducers that produce detailed high- resolution images.

Transvaginal USS is more invasive than transabdominal scanning but is

used in the routine assessment of gynaecological disorders. It can also

be used for infertility monitoring, egg retrieval, and the exclusion of

suspected ectopic pregnancy. Transrectal scanning is used for screening,

assessment, and biopsy of suspected prostatic pathology, as well as

rectal pathology including staging rectal cancers. Endo- anal probes

may be used to assess morphology and characterize tears of the anal

sphincter.

•

Contrast agents:US contrast agents are available as an additional tool

in diagnosis, although currently used primarily in academic centres.

These are micro- bubbles, which are stable over a period of time,

and may be used to improve anatomical detail, assess tubal patency

(hysterosalpingography), assess tumour vascularity, and characterize

focal masses (e.g. within the liver), and for contrast enhancement.

ULTRASOUND

819

820

CHAPTER13 Radiology

820

Obstetric imaging

US is the ° imaging modality in obstetric imaging, with MRI being used for

problem- solving. USS is performed via both the transabdominal and trans-

vaginal approach. Imaging is never performed in isolation and should always

be performed in conjunction with clinical information, such as the patient’s

menstrual status (including date of last menstrual period), presence/

absence of pain and vaginal bleeding, as well as knowledge of biochemical

parameters including serum β

- hCG when available.

Role ofimaging

First trimester

•

Conrm an intrauterine pregnancy(IUP).

• Conrm the presence of a gestational sac and date the pregnancy.

• Determine the fetal number and placentation.

• Exclude ectopic gestation.

• If there is bleeding, assess the viability of pregnancy (possible aetiologies

in this scenario include a normal IUP, impending abortion (missed,

incomplete, or impending), ectopic pregnancy, or a subchorionic bleed).

•

8- to 12- week gestational age dating US (most accurate form of

pregnancy dating).

•

Measurement of crown– rump length (margin of error ± 5days).

• Change the estimated date of connement (EDC) to US date if >5days

discrepancy from EDC based on last menstrual period.

• 11- to 14- week gestational age nuchal translucency US (assess uid

behind the fetal neck); early screen for trisomy21.

Second trimester

•

Determine the fetal number and viability.

• Locate and assess placental morphology.

• Estimate the volume of placentaluid.

• Assess gestational age and evaluate growth (margin of error ± 10days).

• Fetal survey.

• Assess the cervix and look at adnexae.

Third trimester

•

Fetal presentation (cephalic, breech).

• Type of placenta.

• Assess the cervix andos.

• Biophysical prole and serial growth.

Amniocentesis

Typically performed at 15– 16 weeks with US guidance. Indications include

advanced maternal age, abnormal biochemical markers (triple screen or

AFP), and a history of genetic/ chromosomal disorders. CVS typically per-

formed earlier (10– 12 weeks) and also under imaging guidance using the

transabdominal or transcervical approach.

OBSTETRIC IMAGING

821

• Gestational sac:the product of implantation and is usually visible within

the uterus at2– 3mm.

•

Normal mean sac diameter (MSD, mm) + 30=days of pregnancy.

•

Normal landmarks (transvaginal scan) (see Table13.9).

•

MSD >8mm:yolk sac should be visible.

•

MSD >16mm:heartbeat should be present (crown– rump

length>5mm).

•

Other criteria worrisome for abnormal pregnancy:

•

Irregular sac contour.

•

Crown– rump length of <7mm and no heartbeat.

•

Mean sac length of 16– 24mm and no embryo.

•

Absence of embryo ≥6 week after last menstrual period.

•

Empty amnion.

•

Enlarged yolk sac of>7mm.

• Small gestational sac also has a high risk of subsequent pregnancy loss

(>90%). MSD (mm) to crown– rump length (mm) <5mm indicates loss

of pregnancy

•

Empty sac:one without a yolk sac or embryo. May represent a very

early IUP (if MSD <8mm) or an embryonic pregnancy (if MSD >8mm),

or a pseudo- gestational sac as seen in ectopic pregnancy.

A full review of obstetric imaging is beyond the scope of this chapter.

Table13.9 Transvaginal scan landmarks (accuracy ± 0.5week)

Age β- hCG Gestational

sac

Yolk

sac

Heartbeat Embryo

(fetal pole)

5 weeks

500– 1000 + − − −

5.5 weeks >3600 + + − −

6 weeks >5400 + + + −

>6 weeks + + + +

822

CHAPTER13 Radiology

822

Gynaecological imaging

USS remains the modality of choice for initial assessment of pelvic pathol-

ogy in ♀ and can be used to assess uterine morphology and endometrial

thickness, to exclude focal uterine pathology such as leiomyomas (broids),

and for initial assessment of adnexal pathology.

Normal endometrium is echogenic with a surrounding hypo- echoic halo.

Thickness is variable, depending on the stage of the menstrual cycle and

the patient’s menstrual status (e.g. pre- or post- menopausal). Typical values

range from <4mm in the menstrual phase, 4– 8mm in the proliferative phase

(up to day 14 of the cycle) to 7– 14mm in the secretoryphase.

The post- menopausal uterus is typically atrophic and may be modied by

the administration of exogenous hormones (hormone replacement therapy

(HRT)), which will also inuence endometrial thickness. Normal thickness

<5mm if no HRTusage.

Hysterosalpingogram

• Indications:for assessment of infertility, to dene uterine anatomy, and

to evaluate tubal patency as a precursor for in vitro fertilization or for

evaluation of congenital anomalies.

•

Procedure performed at days 6– 12 of menstrual cycle. Foley catheter

inserted into the cervical canal, and contrast hand- injected to dene the

above. Complications include pain and infection. Contraindications are

active infection, pregnancy, or recent uterine surgery.

Pelvic magnetic resonance imaging

Indications

Include locating and conrming the presence of leiomyomas (often pre-

and post- uterine broid embolization (UFE); E Interventional radiology,

pp. 844–7), conrming the presence of adenomyosis, endometriosis, in the

assessment of congenital uterine anomalies, as well for the assessment of

complex pelvic or adnexal masses.

T2W imaging of the uterus denes the zonal anatomy and is invaluable in

staging neoplasms. MRI is the modality of choice for tissue characterization

and in this setting will demonstrate small quantities of blood products (as

in endometriosis plaque), as well as showing tissue content such as intra-

lesional fat (dermoids).

GYNAECOLOGICAL IMAGING

823

824

CHAPTER13 Radiology

824

Computed tomography

This technique diers from conventional radiography in that it is able to

visualize a vast spectrum of absorption values, and therefore tissue den-

sities. Furthermore, being a tomographic technique, the resultant image

is essentially 2D and overcomes the problem of confusing overlap of 3D

structures on plain lm. The image is a grey- scale representation of the

density of tissues (attenuation), as depicted by X- rays. Each image is made

up of a matrix of squares (pixels), which collectively represent the attenu-

ation values of tissues within that volume (voxel). With conventional CT,

separate exposures are made for each slice. Current scanners can acquire

data in a continuous helical or spiral fashion, shortening the acquisition time

and reducing artefacts caused by patient movement. This improves the

overall throughput and i the likelihood of a diagnostic scan, particularly

in unco- operative patients. The volumetric data that are acquired may be

manipulated by image processing and displayed in a variety of techniques,

including 3D reformats and ‘virtual’ endoscopy.

The attenuation values are expressed on an arbitrary scale (Hounseld

units), with water being 0, air being −1000 units, and bone +1000 units.

The range of densities displayed on a particular image can be manipulated

by altering the window width and level. This also allows discrimination of

tissues that dier in density by as littleas1%.

Prior to scanning the abdomen or pelvis, dilute oral contrast is given to

opacify the bowel. IV contrast is given to aid the problem- solving process

and dierentiate vascular- enhancing lesions from surrounding tissue.

Multislice CT scanners are third- generation scanners with helical capabili-

ties and low- voltage slip rings, which acquire anywhere between 64 and 320

slices (and counting!) per X- ray tube rotation.

Dose management has become more of a concern with the i utility of

CT across a spectrum of pathologies. The dose is dependent on a number

of patient- and scan- related variables, including patient habitus, the volume

(area) scanned, the number(s) of acquisitions, as well as the desired resolu-

tion and image quality.

To address this problem, there have been innovations in reconstruction

to minimize the dose without impacting on noise and including instances

where data are incomplete. These include adaptive statistical iterative

reconstruction. There is minimal, if little, impact on spatial or contrast

resolution.

Indications

There are a wide variety as detailed below. CT is often the most diagnostic

cross- sectional examination and more denitive than USS in many instances.

Contraindications

Due to the relatively high radiation dose, CT should be avoided in preg-

nancy. Artefact from indwelling, high- density foreign material, e.g. hip pros-

thesis, dental amalgam, and barium, may limit the diagnostic quality of the

examination. Claustrophobia is less of a problem, compared toMRI.

COMPUTED TOMOGRAPHY

825

Applications

• CNS/ spine:CT remains the tool for ° diagnosis, pre- surgical

assessment, treatment monitoring, and detection of relapse in many

CNS disease conditions. MRI is superior in the posterior fossa and

parasellar region and for assessment in MS, epilepsy, and tumours.

Where MRI is not available, it is useful for assessment of degenerative

spinal and disc disease. It is superior to MRI in the assessment of head

injury. In the context of trauma, MRI is only utilized when CT is −ve

despite strong clinical suspicion. CT is also used as the ° modality in the

evaluation of acute stroke and in the emergency settling prior to LP of

patients suspected of CNS infection such as meningitis.

•

Orthopaedics/ trauma:uses include diagnosis and staging of bony and

soft tissue neoplasms and assessment of vertebral, pelvic, and complex

extremity trauma (e.g. tibial plateau fractures). It is also used in the

detection of loose bodies, in the assessment of acetabular dysplasia, and

in providing an answer in joint instability (especially in shoulders, wrists,

and elbows where it may be performed as an adjunct to/ in conjunction

with conventional arthrography).

•

Oncology/ radiotherapy:staging of solid tumours, treatment planning, and

the detection of relapse. CT is of particular value in obtaining whole

body scans in oncology due to the speed and ease of use with the

advent of multislice CT. CT is used for radiotherapy treatment planning

to allow more precise targeting of treatment.

•

Chest:indications include the staging of bronchogenic carcinomas,

characterization of solitary nodules, diuse inltrative lung disease,

widened mediastinum/ mediastinal masses, and pleural abnormalities.

With multislice CT, pulmonary angiography has advanced the diagnosis

of Pes, particularly when V/ Q scanning is indeterminate or equivocal.

Helical CT is equivalent to formal angiography in the detection of

emboli within proximal arteries of < fth/ sixth generation. Sensitivity

(80– 100%, specicity 78– 100%).

• Abdomen:applications include the diagnosis of abdominal pathology,

which may be of traumatic, neoplastic, inammatory, or infective origin

(see Figs 13.31– 13.34). CT is particularly useful for masses, pancreatic

and hepatic disease, detection of the site and nature of obstructive

jaundice, and the assessment of abdominal trauma. It is also used in

the pre- surgical assessment of abdominal aneurysms (see Fig. 13.35)

and as an aid to interventional techniques (E Interventional radiology,

pp. 844–7).

826

CHAPTER13 Radiology

826

Fig.13.31 Direct coronal reformat through the liver showing ndings consistent

with ° sclerosing cholangitis. Note the markedly thickened bile duct wall (arrows).

Fig.13.32 Free intraperitoneal air 2° to perforation of a gastric ulcer. Note the

thickened antrum of the stomach.

Fig.13.33 Virtual barium enema image reconstructed from CT colonoscopy. The

arrow shows the location of the polyps.

COMPUTED TOMOGRAPHY

827

Fig.13.34 Reformatted maximum intensity projection MIP image of an abdominal

CT showing small bowel obstruction due to the presence of a caecal carcinoma

(arrows).

Fig.13.35 Reformat of a CT angiogram to assess the extent of RAS in this patient

who has bilateral common iliac stents.

828

CHAPTER13 Radiology

828

Magnetic resonance imaging

This is a non- invasive technique, which displays the internal structure, whilst

avoiding the use of ionizing radiation. The nuclei of certain elements align

with the magnetic force when placed in a strong magnetic eld. These are

usually hydrogen nuclei in water and lipid (at clinical eld strengths), which

resonate to produce a signal when a radiofrequency pulse is applied. When

the radiofrequency pulse is switched o, the protons return to their pre-

excitation axis, giving o the energy they absorbed. The energy can be

measured with a detector and used by a computer to display anatomical

information. The T1 and T2 signal characteristics of common tissue types

are seen opposite (see Table 13.10). Further discussion of the physics is

beyond the scope of this chapter. Inherent tissue T1 and T2 characteristics

depend on the longitudinal relaxation (T1) and transverse relaxation (T2)

times of the protons in that tissue. Pathologic processes alter the relaxation

times of the tissue and will produces signal abnormalities.

MR image weighting (e.g. T1W or T2W images) depends on the repeti-

tion time (TR) and echo time (TE) used to obtain images.

Table13.10 Examples ofsequences used inclinical practice

Pulse sequence Acronyms Clinical applications

Conventional

spin echo

SE Workhorse sequences. Therefore, integral to

most protocols

Multi- spin

echo

TSE,

HASTE,

RARE

Reduced scan time, but similar applications to SE

Inversion

recovery

FLAIR, STIR Used to suppress certain tissues by nulling their

signal

Therefore, high net signal results in i conspicuity

of pathology, e.g. infarcts, perilesional oedema,

MSplaque

STIR invaluable in marrow imaging to show

oedema, to assess optic nerves

Gradient echo

FLASH,

SPGR, FISP,

FIESTA,

many more

Uses gradient to rephase signal

Reduced scanningtime

Useful for showing acute blood, in cardiac

imaging with ECGgating

Can also be used in functional imaging

Blood O

level (BOLD)- dependent sequences

Echoplanar

imaging

EPI Generates multiple quantities of data (k- space)

in short time, so potential for real- time/

interventional MRIApplications include cardiac,

abdominal imaging

MAGNETIC RESONANCE IMAGING

829

T1- weightedimages

• Contrast is due to inherent T1 relaxation.

• Provides good anatomical information.

• Fat is displayed as high signal (white).

• Distinction between cystic (black) and solid structures is possible.

• Good evaluation of marrow signal.

• The sequence of choice when evaluating enhancement, as gadolinium

administration makes structures of even higher signal intensity on T1W

images (see Tables 13.10 and 13.11).

T2- weightedimages

• Technique of choice for evaluating pathology.

• Fluid is of high signal and therefore optimally displays oedema.

• Improved soft tissue contrast allows evaluation of zonal anatomy of

organs such as the uterus and prostate.

Magnetic resonance angiography

MRI principles are used to exploit the properties of owing blood. Images

generated display structures containing owing blood, with suppression of

all other structures. These principles can be further modied, so that only

vessels with ow in a specic direction (i.e. arteries vs veins are) visualized.

MRA is currently being used in the evaluation of suspected cerebrovascular

disease, renovascular disease, and peripheral vascular disease.

Functional imaging

MRI techniques have evolved, such that diusion imaging utilizes the diu-

sion of water protons in the diagnosis of evolving ischaemia. This technique

shows how movement of water molecules is impeded by cytotoxic oedema

of ischaemic cells. These are manifested by signal changes that show early

evidence of cerebral ischaemia prior to structural changes becoming

apparent.

Diusion MRI comprises two separate components— DWI and apparent

diusion coecient (ADC) which are interpreted together to evaluate the

diusion characteristics of tissue. DWI has had a profound impact in the

Table13.11 MR signal intensity ofcommon tissues

Tissue or body uid T1 signal T2 signal

Air Nil Nil

Bone or calculi Nil Nil

Fat High (bright) Medium to high

Proteinaceous uid (e.g. abscess or

complex cyst)

Medium High

Muscle Low Low to medium

CSF, urine, bile, or oedema Low High

Blood (depends on age), hyperacute

(oxyHb), chronic (haemosiderin)

Low/ low High/ low

830

CHAPTER13 Radiology

830

assessment of cerebral infarcts and is 795% sensitive and specic for infarcts

within minutes of onset of symptoms. The ADC map shows pure diusion

information without any T2 weighting. Reduction in diusion is therefore of

low signal (hypointense) on the ADC map. The b- value is an important con-

cept for impacting sensitivity for the detection of diusion abnormalities.

The higher the b- value, the more contrast the image provides for detection

of reduced diusion. DWI is also increasingly used in the oncological setting

both at the time of staging but also for evaluation of treatment response.

Similarly, early ischaemia of the myocardium is detectable on MRI. This

has great therapeutic potential, as early treatment may prevent the estab-

lishment of ischaemia and result in overall improvement of ventricular func-

tion and survival. MRA is also being used to depict coronary vessel disease

non- invasively.

Perfusion imaging

An advanced technique where the brain is repeatedly imaged as a bolus of

gadolinium (contrast) is injected. Gadolinium causes a magnetic eld dis-

turbance which results in a transient reduction in image intensity. As these

are echo- planar T2*images, they can be acquired quickly and are invalu-

able in imaging of strokes and tumours. The signal changes associated with

gadolinium can be plotted over time for a selected brain volume. The time

signal plots can be manipulated to obtain parameters related to cerebral

perfusion.

Indications

The indications are legion and continue to grow. There are a wide vari-

ety of indications, summarized below (E Applications, pp. 830–2). MR

is especially useful in imaging the brain, spine, peripheral limbs, and joints,

neck, and pelvis. Again, improvements in scanner hardware and software

have had huge impact on clinical practice. The prior limitations of long scan

times have been overcome by robust sequences that can be performed in

a breath- hold. This means that respiratory and peristaltic artefacts are no

longer an issue when imaging in the chest and abdomen.

Contraindications

These largely apply to patients with magnetically susceptible devices or

materials whose movement or loss of function can have deleterious conse-

quences. These include cardiac pacemakers, metallic fragments, and pros-

thetic heart valves. Relative contraindications include pregnancy (especially

the rst trimester) and claustrophobia. MRI magnets are relatively conned

and even those who are not normally claustrophobic may be provoked.

Applications

• The spine:MR imaging is superior to other techniques in displaying

anatomy and is the technique of choice in assessing disc disease and

the post- operative back, in evaluating neural compression (benign or

malignant), in imaging acute myelitis and infection (such as discitis or

osteomyelitis), and in excluding marrow inltration. Contrast is helpful

in assessing the post- operative back to distinguish scar from residual

herniation, as well as for conrming extruded fragments. It also helps

conrm the presence of neuritis 2° to a disc herniation.

MAGNETIC RESONANCE IMAGING

831

• CNS:imaging of the CNS is used to evaluate mass lesions,

hydrocephalus, white matter disease, leptomeningeal pathology,

cerebrovascular disease (see Figs 13.36, 13.37, 13.38,), degenerative

disorders, and visual and endocrine disorders such as pituitary

dysfunction. In trauma/ acute haemorrhage, CT is the preferred

technique (E Neuroradiology, pp. 856–9).

•

Paediatric:the uses here include assessment of perinatal trauma/ anoxic

injury, congenital anomalies, and developmental delay. Within the spine,

it is invaluable in the assessment of spinal dysraphism and progressive

scoliosis.

Fig.13.36 Axial T2W shows acute infarction in the right cerebellar hemisphere.

Fig.13.37 Coronal reformatted MRI image showing a tight stenosis of the distal

vertebral artery on theright.

832

CHAPTER13 Radiology

832

• Musculoskeletal:along with CNS disease, this is a major component

of the MRI workload. It has revolutionized musculoskeletal imaging

and is used to characterize meniscal pathology, ligamentous injury, and

degeneration and sequelae of trauma in the knee, shoulder, wrist, and

ankle. Further uses include imaging mass lesions, assessing the extent of

infection, and diagnosing early avascular necrosis(AVN).

•

Chest/ cardiac:within the thorax, MRI is useful for assessment of apical

lesions such as Pancoast’s tumours (see Fig. 13.39), chest wall and

brachial plexus lesions, and mediastinal masses. Cardiac applications

are legion and fast- evolving; they include imaging of the great vessels to

exclude congenital/ acquired aortic disease (including dissection) and the

diagnosisofPE.

• Abdominal/ pelvic MRI:within the abdomen, MR is often a problem-

solving tool and can be used to more condently characterize focal liver

and pancreatic lesions, as well as assess diuse liver disease. It is also of

use in evaluating indeterminate adrenal masses. Within the pelvis, uses

include imaging of congenital anomalies, as well as staging tumours such

as cervical (see Figs 13.40 and 13.41), prostate, and rectal tumours.

There have been rapid advances in techniques for imaging bowel- related

pathology.

•

Interventional MRI:open MRI units image patients in large- bore or

C- shaped units, rather than the closed narrow tunnel used in conventional

units. They can therefore be used for claustrophobic patients and to provide

imaging guidance for interventional procedures. Disadvantages include a

low magnetic eld strength (0.1– 0.3T vs 1.5T) and a limited anatomical and

spatial resolution due to their basic construct.

Recently, short- bore magnets have been developed that combine the accu-

racy of a tunnel scanner and the comfort of an open MRI scan. Although

they are not completely open, they are much less constrictive because of

the short- bore magnet (shorter tunnels) but can produce a higheld.

Fig.13.38 AP coronal MRA showing mild irregularity of the carotid siphon on the

left. The images are examined in multiple projections to exclude anomalies such as

stenosis or small aneurysms.

MAGNETIC RESONANCE IMAGING

833

Fig.13.39 Sagittal T2W MRI image in patient with a superior sulcus (Pancoast’s)

tumour showing invasion into the chestwall.

Fig.13.40 Axial T2W sequence showing bilateral parametrial inltration in this

patient with a cervicalmass.

834

CHAPTER13 Radiology

834

Fig.13.41 Sagittal and axial T2W images showing a large cervical carcinoma. MRI is

the modality of choice for local staging.

MAGNETIC RESONANCE IMAGING

835

836

CHAPTER13 Radiology

836

Spinal imaging

Basic principles ofbony trauma imaging

• Obtain two lms at right angles to one another (most commonly an AP

and a lateral to rule out a fracture).

•

Image proximal and distal joints.

• Bone scanning is more sensitive, but less specic, than plain lms to rule

out a fracture. (Not useful in the acute setting.)

•

CT is invaluable for complex injuries (e.g. spine, calcaneus, and sacrum).

• MRI is used to assess ligaments, tendons, joint capsules, menisci, and

cartilage.

In each case, evaluate thefollowing

• Site of fracture:assess if proximal/ distal and intra- vs extra- articular.

• Type of fracture:simple (transverse, oblique, spiral) vs comminuted.

•

Degree of displacement:usually described with reference to the distal

fragment.

•

Soft tissue involvement:exclude foreign bodies, presence of gas. Open

(compound) vs closed.

Cervicalspine

• Trauma:obtain a cross- table lateral rst (this has the highest yield),

and then perform the remainder of the cervical spine series (AP and

open mouth peg views), if patient mobility allows and a high index

of suspicion. All seven cervical vertebral bodies should be visualized

(a large number of cervicothoracic injuries are missed because of

inadequate views). If not seen, request a specialized lateral view

(swimmer’s) or a CT. Then sequentially evaluate:

•

Alignment:assess the following lines shown in Fig. 13.42. They should

be parallel with no step- os.

•

Bones:inspect C1 and C2. The anterior arch of C1 should be 3mm

from the dens in adults (5mm in children). The vertebral bodies

should be intact, and they should be uniform in size and shape.

Check disc spaces for any inordinate narrowing or widening which

may be post- traumatic.

Cartilage

• Soft tissues:look for abnormal widening or a localized bulge; 50% of

patients with a bony injury will have soft tissue thickening. The soft

tissues should be no more than one- third of a vertebral body until C4,

and a vertebral body width thereafter.

•

The peg views:do not mistake a superimposed arch of C1 or the incisors

as a fracture. Important points to rememberare:

•

The lateral margins of C1 and C2 shouldalign.

•

The spaces on either side of the peg should be equal (see Fig. 13.42).

Remember normal plain lms do not exclude ligamentousinjury

In the routine setting, cervical spine lms are taken to exclude spondylo-

sis (disc space narrowing and osteophytes) and atlantoaxial subluxation,

which results in long tract signs and cord compression (RhA, ankylosing

spondylitis, Down’s syndrome). (See Fig. 13.43 for image showing a large

osteophyte.)

SPINAL IMAGING

837

Thoracic and lumbarspine

Degenerative disease is common with disc space narrowing, end- plate scle-

rosis, and osteophyte formation. Wedge compression fractures are com-

mon in the osteoporotic spine and need to be distinguished from the more

sinister causes (absence of paraspinal mass, posterior elements spared).

Multiple collapsed vertebrae are found in osteoporosis, neoplastic disease,

trauma, and histiocytosis X.Bone density may help narrow the dierential,

which includes i (sclerotic metastases, lymphoma) and d (acute infection,

osteoporosis).

Spondylolisthesis is the subluxation of one vertebral body on another and

may be degenerative or due to bilateral pars defects (spondylosis). This is

a fracture/ defect of the posterior elements of the vertebrae. In an oblique

view, the posterior elements form a Scottie dog (with the pars making up

the collar). This may be a purely incidental nding; however, if severe, it can

result in neuroforaminal stenosis. Plain lms are insensitive in the evaluation

of disc disease. MRI is the investigation of choice for disc disease and its

neurological complications.

Fractures typically occur at the thoracolumbar junction (90% at T11– L4).

CT typically indicated other than in stable compression fractures, isolated

spinous or transverse process fractures, and spondylolysis.

Plain lm ndings include paraspinal haematoma and widened inter-

pedicular distance. An unstable injury may be accompanied by disruption

of the posterior elements and widened interlaminar space, and is seen in

the context of all fracture dislocations or if there is a compression fracture

of>50%.

—Soft tissue line closely applied to posterio

aspect of the airway widens at level of

laryngeal cartilage

2—Anterior border of vertebral bodies

3—Posterior border of vertebral bodies

4—Spino laminar line = posterior limit of

spinal canal

5—Tips of the spinous processes

Fig.13.42 Schematic diagram

depicting the lines that need to be

assessed when looking at a lateral

lm of the cervicalspine.

Fig.13.43 Sagittal T2W image showing a

large osteophyte at the C6/ 7level.

838

CHAPTER13 Radiology

838

Pelvis

Pelvic fractures are complex, and there are many classication systems

around. The pelvis should be regarded as being made up of three bony

rings. The sacroiliac joints and the pubic symphysis are part of the main

bony ring. Afracture of one ring is frequently associated with a second ring

fracture (see Fig. 13.44).

• Sacroiliac joints should be equal inwidth.

• The superior surfaces of the pubic rami should align. The joint width

should be no more than5mm.

•

The sacral foramina should form a smootharc.

• Acetabular fractures are subtle— look for symmetry.

Stable fractures (single break of the pelvic ring or peripheral fractures)

commoner. These include avulsion injuries (e.g. anterior superior iliac spine

(ASIS), pubis, and ischial tuberosity), as well as sacral fractures and those of

the ischiopubicrami.

Unstable fractures (pelvic ring interrupted in two places)— less common.

All require CT for clarication of the extent of injury, as a plain lm may

underestimate the extent of posterior ring disruption (includes Malgaigne

and bucket handle fractures).

•

Bone texture:the pelvis is a common site for metastatic involvement,

especially with urological malignancies, e.g. prostate (sclerotic

metastases) and myeloma (multiple lytic lesions). Paget’s disease of the

pelvis may mimic sclerotic metastases but tends to be conned to one

hemipelvis and may expand or thickenbone.

•

Sacroiliitis:sacroiliac joint involvement is common in seronegative

arthropathies and is usually symmetrical in conditions such as IBD,

ankylosing spondylitis, and hyperparathyroidism. More asymmetrical

change is seen in Reiter’s disease and RhA. It is characterized by initial

erosion and widening of the joint, resulting in chronic sclerosis, which

has a preferential involvement of the lower one- third of the joint (iliac >

sacralside).

•

AVN of the femoral heads:an important nding but is often advanced

when plain lm ndings are seen. Radiographically occult AVN may be

detected on MRI or a bone scan. On plain X- ray, it is characterized by

sclerosis, attening, and fragmentation of the femoral head. Subchondral

crescents are pathognomonic. AVN can also be a sequel of trauma,

but bilateral AVN is seen in conjunction with steroid therapy, sickle- cell

disease, and as part of Perthe’s disease.

PELVIS

839

Fig.13.44 The pelvis is made up of bony rings:the main pelvic ring and two smaller

rings made up of the pubic and ischialbones.

840

CHAPTER13 Radiology

840

Vascular intervention

Angiography is catheterization of a vessel followed by subsequent

opacication with a water- soluble iodine- containing contrast medium.

Catheterization is usually performed using the Seldinger technique.

An approach tointerpretation ofan angiogram

• What:is the type of study— angiogram, digital subtraction angiogram

(DSA), venogram?

•

Where is the catheter and which vessel? Is it a large vessel or a

selective/ super- selective angiogram?

• When:what phase is it (early/ late arterial, parenchymal, or venous)?

• Vessels:is there contrast in unexpected vessels (extravasation or

neovascularity)? Is the vascular contour normal (look for irregularity,

stenosis, dissection, or encasement)?

•

Intervention (previously placed stents, lters, coils, clips, or drains).

Catheter selection

Catheters are sized in French (Fr) where 1 Fr=0.33mm. Sheath vs catheter.

Asheath has a dened luminal diameter; however, the overall diameter will

generally be larger.

High- ow (ush) catheters have multiple side holes and are used for large

vessel angiography.

Selective catheters have a single hole at the end. The distal portion has

numerous shapes tailored to a specic or general purpose.

Indications include

• Demonstration of arterial anatomy prior to surgery where this is likely

to inuence surgical management.

•

To elucidate the nature of arterial disease, e.g. occlusions, stenoses,

thrombi, aneurysms, and vascular malformations in coronary, carotid,

and cerebrovascular disease. Also in the setting of endovascular

procedures (aneurysm repair, thrombolysis, stenting, and angioplasty).

•

To identify the source of bleeding in the GIT or following trauma.

• To demonstrate tumour circulation (often prior to embolization).

• Due to advances in technique, non- invasive assessment of vessels by

techniques such as colour Doppler US, CT angiography, and MRA is

often used as rstline.

Potential complications include

Puncture site haematoma, infection, pseudo- aneurysm, AV stula, dissec-

tion, thrombosis, embolic occlusion of a distal vessel.

Contrast

Volumes used are variable, depending on the area being imaged. The con-

trast agents are iodinated, non- ionic, and of low osmolarity, resulting in

reduced toxicity. Nevertheless, potential side eects include anaphylaxis,

hypotension, urticaria, and bronchospasm. Patients particularly at risk

include those with a history of a previous reaction, iodine allergy, and atopy.

Nephrotoxicity is a potential risk and may be exacerbated by dehydration.

VASCULAR INTERVENTION

841

Contrast reactions are seen in 1/ 1000 patients. Risk of anaphylaxis is 1/

400,000. Pre- medication with corticosteroids may reduce the incidence of

reactions if contrast administration is essential, but this is not universally

accepted.

Specic applications

These include pulmonary angiography (gold standard for detection of PEs),

which is highly invasive, and therefore reserved for when thrombolysis or

embolectomy are being considered. Cerebral angiography is useful in the

diagnosis of aneurysms, AVMs, tumour vascularity, and both intra- and

extracranial vascular disease. Renal angiography is selectively performed to

diagnose RAS and prior to embolization of tumours.

•

DSA:a technique whereby there is subtraction of the contrast-

containing shadows from the initial plain lms (mask), resulting in an

image containing opacied structures only. The resulting images may

be digitized and manipulated. The overall advantage is smaller doses of

contrast and smaller catheters may beused.

•

Angioplasty:percutaneous transluminal angioplasty (PTA) is a method

used to fracture the vascular intima and stretch the media of a vessel

by a balloon. Atherosclerotic plaques are very rm and are fractured

by PTA. Healing occurs by intimal hyperplasia. Indications include

claudication or rest pain. Acommon alternate to surgical bypass, with

5- year patency similar to that of surgery.

• Intravascular stents:typically, metallic stents used when there has been

unsuccessful PTA or in cases of recurrent stenosis, venous obstruction/

thrombosis or as transjugular intra- hepatic portosystemic shunt

(TIPS) shunts (E Interventional radiology, Transjugular intrahepatic

portosystemic shunt, p. 846). They can either be balloon- expandable or

self- expandable. Aortic stent grafts used to treat aortic aneurysms or

dissections are typically a combination of a metallic stent with synthetic

graft material. Stents can also be used in revascularization procedures

when there is long segment stenosis, total occlusion, or ineectivePTA.

• Therapeutic embolization:

•

Used to selectively occlude vessels by introducing a variety of

materials via a catheter. Permanent materials used include metallic

coil, balloons, and cyanoacrylate glue. Temporary embolic materials

include gel foam and autologous blood clots. This technique is used

at active bleeding sites and to reduce tumour vascularity preop-

eratively in resectable tumours. It can also be used to treat AVMs,

for symptomatic uterine broid embolization (E

Figs 13.49 and

13.50, p. 848), and in varicocele embolization for infertility. Proximal

occlusion of a vessel is equivalent to surgical ligation and does not

compromise collateralow.

•

Distal embolization usually infarcts tissue and is followed by necrosis.

•

Complications include post- embolization syndrome (fever, pain,

elevated WBC), infection of embolized area, and reux of embolic

material (non- target embolization).

842

CHAPTER13 Radiology

842

• Vascular catheterization:is also used to selectively infuse vessels, as

with thrombolytic treatment or rarely with cytotoxics. Vascular

stenting is of i use in coronary and peripheral vascular disease. IVC

lters (see Fig. 13.45) are metallic umbrellas used to mechanically

trap emboli and prevent venous thromboembolic disease. They are

percutaneously placed via the femoral, jugular, or antecubital vein. In

the treatment of patients with recurrent PEs despite anticoagulation or

where anticoagulation is contraindicated. IVC lters can be temporary

(retrievable) or permanent. They are placed infrarenally to avoid renal

vein thrombosis.

•

Thrombolytic therapy:

•

Is the infusion of a brinolytic agent (urokinase, streptokinase, TNK,

tissue plasminogen activator (tPA)) via a catheter inserted directly

into a thrombus. This can restore blood ow in a vessel obstructed

with a thrombus or embolus.

•

Indications include treatment of an ischaemic limb, early treatment

of MI or stroke to reduce end- organ damage, and treatment of

venous thrombosis (DVT) of the legorPE.

Fig.13.45 Cavogram showing infrarenal deployment of an IVC lter

(Gunther– Tulip).

VASCULAR INTERVENTION

843

•

Contraindications include active bleeding, recent intracranial event

(CVA, tumour, or recent surgery), non- viable limb, and infected

thrombus.

Central venous access

:there are a variety of devices available— peripherally

inserted central catheters (PICCs), external tunnelled catheter (Hickman),

subcutaneous port (Portacath

™

). Indications include chemotherapy, total

parenteral nutrition (TPN), long- term antibiotics, administration of u-

ids and blood products, and blood sampling. Potential complications are

venous thrombosis, infection, and pneumothorax.

844

CHAPTER13 Radiology

844

Interventional radiology

Interventional radiology is a sub- speciality where a variety of imaging

modalities are used to guide percutaneous procedures. This may obviate

alternative surgical procedures and consequently result in lower morbidity.

Interventional procedures are usually carried out under LAn or using con-

scious sedation (E Interventional radiology, Conscious sedation, p. 846),

and on an outpatient basis, thereby considerably reducing bed occupancy.

There is a huge range of procedures that are currently performed. The fol-

lowing is a limited list of some of them (see also Table 13.12).

Percutaneousbiopsy

Biopsy needle placement may be done under uoroscopy, CT, MRI, and

US. This provides a non- operative conrmation of tissue diagnosis and, in

the case of a suspected malignancy, it is possible to accurately plan treat-

ment. For histology, a 14– 18G needle is used. With a ne- aspiration needle

(20– 22G), material may be obtained for cytology. Using imaging guidance,

there is avoidance of damage to vital structures such as blood vessels, solid

organs, and bowel loops. With chest biopsy, there is a 30% risk of pneu-

mothorax. Other potential complications include false −ve samples (due

to sampling error or tissue necrosis). Bleeding is more likely to occur in

patients with underlying coagulopathies (vigorous pre- biopsy screening

important for safety) and in patients with ascites.

Percutaneous drainage

With image guidance, surgical intervention may be avoided by accurate

placement of a drainage catheter. Calibre varies from 8 to 14F, depending

on the nature of the underlying uid. Regular irrigation of the catheter may

be necessary to ensure successful drainage. Successful resolution may be

impeded in the more complex and multiloculated collections. There are

a variety of routes of access other than the conventional percutaneous,

including transvaginal, transrectal, and transgluteal. Potential complications

include injury to overlying structures and sepsis.

Drainage ofthe urinarysystem

Can be via double J stents, which are placed into an obstructed collecting

system, with the distal catheter tip lying in the bladder. More short- term

drainage is achieved via a percutaneous nephrostomy. Here, the obstructed

kidney is punctured under uoroscopic or US guidance, and a catheter

placed in the renal calyx (preferably the lower pole). This is the technique

of choice in the acutely obstructed or infected kidney. Nephrostomy inser-

tion is also performed in the setting of ureteric injury either with or without

accompanying peritonitis. Potential risks include septic shock, haematuria

(due to pseudo- aneurysm or AV stula), or injury to regional structures.

Biliary system drainage

Surgical outcome in patients with malignant bile duct obstruction is often

poor. This may be due to carcinoma of the pancreas or cholangiocarcinoma.

Biliary stenting alleviates obstruction and improves quality of life. Stenting

may be performed at ERCP or percutaneously via antegrade puncture

INTERVENTIONAL RADIOLOGY

845

Table13.12 Established and newer interventional applications

Established techniques Newer interventional applications

Arterial and venous sampling AVM embolization

Biliary drainage, stenting, angioplasty,

biopsy, and stone extraction

Chemoembolization

Diagnostic angiography Cryoablation of liver tumours

Embolization

Oesophageal dilatation Endovascular repair of abdominal

aortic aneurysms with stent grafts

Fallopian tube recanalization Radiofrequency ablation of tumours

Feeding tube placement Uterine artery embolization for

symptomatic broids

IVC lter placement Varicocele embolization

Nephrostomy placement Vertebroplasty

Pain management (e.g. coeliac ganglion block,

selective and non- selective nerve block)

Percutaneous biopsy, cholecystostomy, and

drainage of uid collections

° gastrostomy, gastrojejunostomy, or

jejunostomy tube placement

Thrombolysis

TIPS insertion

Ureteral stent placement

Vascular angioplasty and stent placement

Venous access and foreign body retrieval

through the liver (PTC to delineate the anatomy, being performed rst).

Other than alleviating biliary obstruction, PTC can provide biliary diversion

in the case of ductal injury (post- traumatic or post- surgical). Often there is

unilateral obstruction which requires only treatment of the aected side.

Hilar obstruction, however, due to a hilar (Klatskin) tumour requires two

biliary drains.

Percutaneous drainage of the gall bladder (cholecystostomy) is indicated

for the treatment of acute calculous or acalculous cholecystitis in patients

who are not surgical candidates or as a temporizing measure prior to deni-

tive surgery.

Other GI interventions include stenting/ balloon dilatation of oesophageal

strictures, stenting of obstructive colonic neoplasms (see Fig. 13.46), and

percutaneous gastrostomy or gastrojejunostomy insertion. Oesophageal,

head and neck, and neurologic disease may necessitate percutaneous gas-

trostomy. In some instances, it may be used for long- term bowel decom-

pression, for instance in a prolongedileus.

846

CHAPTER13 Radiology

846

Transjugular intra- hepatic portosystemicshunt

A procedure whereby a connection is made between the hepatic and portal

veins to reduce portal pressure in patients with portal hypertension. The mor-

tality is considerably lower than in acute shunt surgery, particularly in the con-

text of an acute variceal bleed, which has failed to respond to sclerotherapy.

Conscious sedation

Form of sedation whereby the patient is given sedation and analgesic medi-

cation but remains conscious and easily arousable. At all times, the follow-

ing are monitored— BP, pulse oximetry, ECG, and heart rate. Typical drugs

used include a short- acting benzodiazepine (e.g. midazolam) and a narcotic

analgesic (e.g. fentanyl), administered in small aliquots.

Endovascular repair ofabdominal aortic aneurysms

With stent grafts, this is a new image- guided, catheter- based approach that pro-

vides a valuable alternative to standard open surgical repair. Radiological imaging

plays an essential role in pre- procedure evaluation, the procedure itself, and

patient follow- up. The ultimate goal remains the same— complete exclusion of

the aneurysm sac to prevent rupture. Advantages include lower blood loss,

shorter ITU stay, and rapid recovery. Complications include graft thrombosis,

kinking, pseudo- aneursym caused by graft infection, and endoleak. Bifurcation

grafts are used mainly for abdominal aortic aneurysm (AAA) repair and aorto-

iliac occlusive disease. Tube grafts are used mainly for AAA repair.

Radiofrequency ablation

Not all patients with tumours are eligible for surgical intervention because

of unfavourable location of the tumour, adverse clinical conditions, or

advanced disease. In addition, the cost, morbidity, and mortality associated

with surgical resection have led to the search for other forms of therapy.

Newer, minimally invasive treatments include intra- arterial chemoem-

bolization, injection of ethanol, and radiofrequency ablation. Among the

thermal ablative procedures, radiofrequency ablation has evolved into an

established technique for non- invasive management of tumours in patients

Fig.13.46 Obstructing sigmoid carcinoma has been decompressed with a colonicstent.

INTERVENTIONAL RADIOLOGY

847

where underlying medical co- morbidities or tumour burden preclude deni-

tive surgery or as a bridge to further therapy. For this procedure, US, CT

scanning (see Figs 13.47 and 13.48), or MRI is used by the radiologist to

guide percutaneous placement of long, thin (usually <18G), insulated nee-

dles into the tumour. The distal end (1– 3cm) of each needle is not insulated

and emits radiowaves. Electrodes are attached to a generator, and the elec-

trical energy is converted to heat that kills cells through coagulation necro-

sis. The radiologist can vary the amount of current used, thereby tightly

controlling the treatment radius. The entire treatment session usually lasts

1h and can be performed in the outpatient setting. The procedure is typi-

cally performed with conscious sedation and LAn. Radiofrequency ablation

has been used to treat a variety of tumours, but the commonest utility is for

hepatocellular carcinoma, liver metastases, and renal tumours.

Fig.13.47 Contrast- enhanced CT showing several high- attenuation metastases

overlying the dome of theliver.

Fig.13.48 Radiofrequency ablation of the metastasis shows the electrode insitu.

848

CHAPTER13 Radiology

848

Fig.13.49 Pre- uterine artery embolization (UFE). Selective catheterization shows

the supply to a large left- sided broid.

Fig.13.50 Post- embolization with polyvinyl alcohol (PVA) showing no ow in the

previously demonstrated broid.

INTERVENTIONAL RADIOLOGY

849

850

CHAPTER13 Radiology

850

Musculoskeletal imaging

Fracture terminology

Anatomicalsite

•

In long bones, divide the shaft into thirds.

• Use anatomical landmarks for description.

Pattern offracture

•

Simple fracture:no fragments. Describe the orientation of the fracture

plane, e.g. transverse, spiral, and oblique.

•

Comminuted fracture:>2 fragments:T- , V- , and Y- shaped patterns,

buttery fragments.

Apposition and alignment

Dened in relation to distal fragments.

Other important descriptors include:

•

Displacement (e.g. medial, lateral, anterior, posterior).

• Angulation (direction of fracture apex, e.g. valgus or varus).

• Rotation (internal vs external).

• Overlap (of fragments).

• Distraction (refers to degree of separation of fragments).

• Impaction:fracture fragments are compressed, resulting in

shortenedbone.

Adjacent joints:are they normal? Is there dislocation, subluxation, or any

intra- articular extension of the fractureline?

Also consider thefollowing

• Soft tissue involvement (foreign body, gas, calcication).

• Type of fracture (stress vs pathological).

• Stress fractures are of twotypes:

•

Insuciency- related (if abnormal underlying architecture, as in

osteoporosis).

•

Fatigue:when abnormal stress is placed on normal bone (as in march

injuries).

•

Pathological fracture occurs when fracture occurs in the setting of

underlying bone disease or discrete lesion.

Types oforthopaedic hardware

• Intra- medullary rods:usually hollow, closed nails. Rotation and

shortening of bone fragments is avoided by distal interlocking screws.

•

Kirschner wires (K- wires):these are used to temporarily xate or treat

fractures, particularly with small fragments or paediatric metaphyseal

fractures. These are drilled into cancellous bone and can be used to

maintain rotational stability if >1 is used. The ends are typically folded

over to avoid any soft tissue or other injury.

•

Circlage wires can be used to contain bone fragments.

• Other hardware includes staples, plates, nails, and screws.

MUSCULOSKELETAL IMAGING

851

Types ofjoint replacements

• Polyethylene is a radiolucent substance used for joints with concave

articular surfaces (e.g. the hip). Typically backed with metal as a support.

Ultra- high molecular weight versions are also available.

• Silastic is also radiolucent and is used for hand and foot arthroplasty

implants.

•

Methylmethacrylate is used as a cement or can be directly injected into

the medullary space. Radio- opaque.

• Variety of metal alloys.

Constrained prostheses are intrinsically stable and are therefore more likely

to suer loosening. Unconstrained prostheses rely on extra- articular struc-

tures to provide stability and are therefore less likely to dislocate.

A discussion of the types of prostheses is beyond the scope of this chap-

ter. Potential complications of prostheses include, but are not limited to,

the following.

•

Polyethylene wear, dislocation, heterotopic bone formation, and

infection can be seen. Small particle disease is seen as areas of osteolysis

around the prosthesis due to macrophage- mediated reaction to particle

debris. Cement leakage can cause necrosis and vascular and neurological

injury, depending on location.

•

Acute loosening occurs in the setting of infection. More chronic

loosening is seen due to mechanical factors.

Magnetic resonance imaging inmusculoskeletal imaging

Musculoskeletal neoplasm imaging

Critical role in evaluating disease extent, staging, and treatment planning.

Lack of mobile protons, and an acellular matrix render cortical bone, liga-

ment, tendon, and brous signal of low signal intensity on all sequences.

Tissues like muscle, fat, osteoid, and chondroid matrix have diering signal

intensities, which can be used to dierentiate tumours. Marrow involve-

ment can be excluded by T1W and STIR sequences (E Magnetic reso-

nance imaging, pp. 828–32). The bone involved should be imaged in its

entirety to exclude skip lesions. IV contrast is mandatory to assess lesional

margin and tumour vascularity.

Joint imaging

MRI is the mainstay in assessment of joint pathology and, in particular, is

excellent in depiction of ligaments, cartilage, and joint eusions. It is there-

fore the modality of choice for infection, neoplasm, trauma, and arthritis.

STIR shows marrow oedema, uid collections, and bursal inammation.

Dual- echo steady state (DESS) is a sequence used for specic evaluation

of articular cartilage. MRI is also the gold standard for marrow imaging. It

is able to dierentiate red from yellow marrow. T1W and STIR sequences

are used for evaluating marrow pathology. Marrow oedema, as well as early

involvement of the marrow by pathologies such as infection, neoplasia, and

subtle trauma, is seen on STIR sequences when not easily evident on plain

radiographs.

852

CHAPTER13 Radiology

852

Hands

There are specic patterns that may be seen in the hand as an indicator of

the underlying disorder. Some patterns are pathognomonic, whereas oth-

ers are more non- specic.

• Generalized osteopenia:osteoporosis, multiple myeloma, andRhA.

•

Coarsening of the trabecular pattern:common in haemoglobinopathies,

especially thalassaemia and Gaucher’s disease.

•

Periosteal reaction:

•

HPOA associations include carcinoma of the bronchus, IBD, and

coeliac disease.

•

Thyroid acropachy, commonest on the radial side of the thumbs.

•

Juvenile chronic arthritis seen in about25%.

• Carpal abnormalities:include short metacarpals (Turner’s syndrome,

pseudo- and pseudopseudohypoparathyroidism), carpal fusion

(inammatory arthritis, RhA and juvenile chronic arthritis, post- trauma),

and look for syndactyly and polydactyly.

•

Soft tissue changes:e.g. i in soft tissue thickness/ size seen in acromegaly,

localized i seen in gouty tophi, nodes as in OA, soft tissue calcication

seen in CREST (calcinosis, Raynaud’s syndrome, oesophageal motility

dysfunction, sclerodactyly, and telangiectasia), and scleroderma.

•

Joint disease:the hand X- ray above all may help in sorting out the type of

arthropathy and aid rheumatological management (see Fig. 13.51). The

ABCS approach is invaluable (see Table 13.13).

Fig.13.51 Asymmetric oligoarthritis with dominant involvement of the DIP joints.

The pencil- in- cup appearance is typical.

HANDS

853

Trauma

Two views are essential for ensuring no subtle injuries are missed. On a P- A

view, the spaces between the carpal bones and the carpometacarpal articu-

lations should be roughly equal (1– 2mm). If a dislocation is present, then

there is obliteration/ overlap. Common injuries include Bennett’s fracture

and the rst metacarpal base injury extending into the joint surface with

dislocation at the carpometacarpal joint. Scaphoid fractures are the com-

monest (75– 90%) of carpal injuries. Because of the blood supply, there is a

potential risk of osteonecrosis of the proximalpole.

Table13.13 An ABCS approach tointerpretation ofthe hand

radiograph

A:Alignment Subluxation/ dislocation common in RhA and SLE

B:Bone Osteoporosis:mineralization is usually normal, except in RhA.

Juxta- articular osteopenia can be seen in any arthropathy. Diuse

osteopenia is seen inRhA.

Erosions:

•

Aggressive (i.e. no sclerosis of margins) seen in RhA and

psoriasis

•

Non- aggressive (with sclerotic margins) seen in gout;

inammatory erosions are marginal (OA erosions are central)

(Distinguish from subperiosteal resorption (radial border; seen in

hyperparathyroidism)

Bone production:periosteal new bone formation, (psoriasis)

Reiter’s syndrome:

•

Ankylosis (bony bridging) in inammatory arthropathies

• Overhanging cortex (typical ofgout)

• Osteophyte formation,OA

• Subchondral bone (reparative bone beneath cortex); typical

of OA

C:Cartilage Joint space has uniform narrowing in all arthritis, except OA

Eccentric narrowing:typically seeninOA

Wide joint space :early arthritis, gout, and pigmented

villonodular synovitis (PVNS)

S:Soft tissue Swelling:

Symmetrical:about joint seen in all inammatory arthropathies,

but most typicallyRhA

Asymmetric:typically due to osteophytes and seen withOA

Lumpy swelling of soft tissues seen in gout (due totophi)

Swelling of entire digit; psoriasis, Reiter’s

Calcication:soft tissue; gout (calcied tophus)

Cartilage:CPPD

Subcutaneous tissues:scleroderma

854

CHAPTER13 Radiology

854

Image- guided arthrography

May be performed in isolation or in conjunction with subsequent cross-

sectional imaging (CT or MRI) for the following indications:

• Ligamentous and tendinoustears.

• Cartilage injuries.

• Proliferative synovitis.

• Masses and loose bodies.

• Implant loosening.

Plain lms are obtained prior to the procedure. All joint uid that is aspi-

rated is routinely sent for culture. The contrast ows away from the needle

if the tip is intra- articular.

Single contrast studies are performed to exclude non- calcied loose bod-

ies. Double contrast studies are performed in the setting of cartilaginous

injury such as a labraltear.

•

Contraindications:allergy to contrast media, concomitant infection.

•

Complications:pain, infection, allergic reaction (to contrast), and

vasovagal reaction.

When performing MR, the examination is performed with dilute gadolinium.

Approach todiagnosis ofbonelesion

•

Single or multi- focal? Multiple lesions can be seen in benign disease such

as enchondromas, brous dysplasia, as well as malignant aetiologies such

as myeloma, metastases, and lymphoma.

•

What is the degree of aggressiveness (type of destruction, as well as

reparative pattern)? Cortical penetration implies aggressive behavior, as

does an ill- dened or wide zone of transition (area between the lesion

and normal bone). Moth- eaten and permeative patterns are also in

keeping with aggressive disease.

•

Location (within bone). Central and cortical lesions are usually benign.

° tumours occur at sites of rapid growth, for instance the distal

femur. Metastases occur at sites of high vascularity such as the spine or

iliacbone.

•

Tissue characterization by matrix. Matrix refers to the intercellular

substance produced by tumour cells (is done in conjunction with a

cross- sectional modality such as CT). Osseous matrix is seen with

osteogenic tumours, and chondrogenic tumours have a cartilaginous

matrix.

•

Age is a very helpful way of narrowing the dierential. Over 40years,

metastases are much commoner than ° bone tumours.

•

Is there a periosteal reaction? More aggressive lesions are associated

with typical patterns such as sunburst, Codman’s triangle, or an onion

peel conguration

•

Soft tissue mass:more typically seen with malignant lesions.

HANDS

855

856

CHAPTER13 Radiology

856

Neuroradiology

• CT is the initial study for evaluation of neuropathology due to its speed,

availability, and lowercost.

•

Excellent for evaluation of bony abnormality.

• Done both with and without IV contrast, depending on the clinical

indication. The use of contrast delineates vascular structures and

anomalies.

•

Visualization of the posterior fossa is inferior toMRI.

• MRI is useful in assessing diuse axonal injury and the sequelae of head

injury.

Logical approach tointerpretation

• Soft tissues (look for thickening which may suggest haematoma or

oedema):assess the ear and orbital contents.

•

Bone (use bone window):check the calvarium, mandible, and C spine

for fractures and lytic lesions. Assess sinuses and mastoid air cells for

opacity that may suggest the presence of uid, pus, blood, mass, or

fracture. If there has been facial trauma, the integrity of facial bones/

orbit best assessed on coronalview.

•

Dura and subdural space:assess symmetry of thickness (early clue to

presence of blood). Look for crescentic or lentiform density.

•

Cortical parenchyma:poor dierentiation between grey and

white matter suggestive of infarction, tumour, oedema, infection,

or contusion. Hyperdense areas may suggest enhancing lesions,

intracerebral haematoma, or calcication. If central grey matter nuclei

(globus pallidus, internal capsule) are not visible, suspect infarct, tumour,

or infection.

•

Ventricular system:assess the position for midline shift or compression.

High density suggests ventricular or subdural bleed. Enlargement is

suggestive of hydrocephalus. High density in the cisterns may suggest

blood, pus, or tumour.

•

Symmetry:asymmetry of the parenchyma suggests midlineshift.

• Falxshift.

Rule out skull fracture, extradural haematoma (lentiform shape), subdural

haematoma (crescentic shape), SAH (see Fig. 13.52), SOLs (see Fig. 13.53),

hydrocephalus, and cerebral oedema. Look for target lesions (when con-

trast given):metastases, abscesses, and fungal infections.

Cerebral angiography

Evaluation of vascular lesions, including atherosclerotic disease, aneurysms,

vascular malformations, and arterial dissection. Supplements information

obtained on CT/ MRI regarding tumour vascularity.

Conventional DSA is the gold standard for the assessment of neck and

intracranial vessels; however, it is an invasive technique requiring an arterial

(femoral) puncture. There is also potential for vessel injury at the time of

catheter manipulation (e.g. dissection, occlusion, or vasospasm). Used for

guidance of interventional procedures such as embolization.

NEURORADIOLOGY

857

Fig.13.52 Non- contrast CT head showing extensive SAH in a patient with

underlying cerebral aneurysm (not shown).

Fig.13.53 Axial T2W MRI showing multiple high signal lesions in the deep white

matter of the right frontal lobe in a patient with lung carcinoma. The anterior lesion is

cystic. These are consistent with metastases. Note the surrounding oedema.

858

CHAPTER13 Radiology

858

Cerebrovascular accident

Imaging may be −ve in the rst 6h. Thereafter, lookfor:

• Oedema (loss of grey– white dierentiation, sulcal eacement, and mass

eect). Cytotoxic oedema develops within 6h and is seen onMRI.

•

Within 24h, there will be a low- density wedge- shaped area

corresponding to the vascular territory and extending to the cortical

surface. Vasogenic oedema within 12– 24h seenonCT.

• If ischaemic stroke, may see a hyperdense (bright) artery representing

an intravascular thrombus or embolus.

•

Acute haemorrhage seen if there is haemorrhagic transformation

(white=acute blood). Density on NECT is 80– 100HU relative to

normal brain (40– 50HU). There may be surrounding oedema. Will not

be hyperdense if low Hct (<8g/ dL). Subacute haemorrhage (3– 14days)

may be hyper- , hypo- , or isointense to brain. Chronic haemorrhage (>2

weeks) is hypodense.

•

Hypertensive haemorrhage typically seen in the pons in80%.

• Prognosis depends on size, brainstem location, and intraventricular

extension.

•

Advances in MR sequences have revolutionized stroke imaging. Diusion

sequences (DWI) and perfusion- weighted imaging (PWI) demonstrate

acute infarction, even in the context of a −veCT.

• T2W and uid attenuation inversion recovery (FLAIR) images show

oedema with high signal.

•

DWI shows high signal suggestive of cytotoxic oedema.

• Gradient echo identies acute haemorrhage, whereas fast FLAIR can

show acute subarachnoid blood. Time- of- ight angiography can non-

invasively assess underlying vessels. If the infarct is thought to be venous

(e.g. peripheral or haemorrhagic), then phase contrast MRV can exclude

sinus thrombosis.

In the case of strokes in the posterior circulation, thin sectional axial images

can exclude thrombosis or dissection within the vertebral arteries.

CT is important in the early stages of stroke evaluation to facilitate

thrombolytic therapy. Highly accurate in identication of proximal occlu-

sions in the circle of Willis and therefore aids triage to facilitate thromboly-

sis. Non- contrast CT is initially performed, as haemorrhage is an absolute

contraindication to thrombolytic therapy.

Multiple sclerosis

MRI is the modality of choice and is highly sensitive (>90%), but with low

specicity (71– 74%). There can therefore be overlap with other entities,

such as ischaemia, and conuent disease may simulate neoplastic mass

lesions. T2W MRI shows ovoid high signal lesions in a periventricular dis-

tribution. Conventional T2 may underestimate the plaque size and overall

plaque burden; advanced MRI techniques, such as DTI and MR spectros-

copy, can have greater utility. FLAIR sequences show lesions in a perive-

ntricular distribution by suppressing (CSF) signal. Active lesions show

enhancement following gadolinium. The spinal cord should also be screened

to exclude involvementbyMS.

NEURORADIOLOGY

859

Magnetic resonance imaging inthe paediatricbrain

Assessing the degree of myelination is an important part of excluding struc-

tural pathology in paediatric neurological disorders. MRI is the modality of

choice in brain tumours, congenital anomalies, and hypoxic– ischaemic dis-

orders (hypoxic– ischaemic encephalopathy (HIE)). DWI is useful in acute

HIE, whilst spectroscopy is critical in metabolic disorders.

860

CHAPTER13 Radiology

860

SkullX- ray

Indications

The main indication is for penetrating acute trauma, although SXRs are of

limited use in the era of widespread CT availability. Occasionally, the SXR

is obtained as part of a skeletal survey in the evaluation of metabolic bone

disease and endocrine disorders, and in the assessment of metastatic dis-

ease. It is still used in the assessment of sinus disease and in the evaluation

of the post- operative skull or for conrmation of hardware placement (see

Fig. 13.54).

Contraindications

None, but if there is suspicion of underlying intracranial injury, plain lms

are unnecessary (E

Fractures and associated ndings, p. 861).

Normal ndings

The bones of the skull vault have an inner and outer table of compact bone,

with spongy diploe between the two. Sutures are visible, even after fusion,

and should not be mistaken for fractures. Blood vessels may cause impres-

sions, as can small lucencies in the inner table near the vertex caused by

normal arachnoid granulations which can be mistaken for small lytic lesions.

Trauma

SXRs are basic and widely available, and yet potentially yield the least

information in the context of trauma. The presence or absence of a skull

fracture does not correlate with the presence or extent of any intracranial

injury. Up to 50% of lms may be technically unsatisfactory due to factors

such as poor patient co- operation. With the advent of CT, this is the tech-

nique of choice for evaluation in acute injury and neurological decit. It

allows a rm diagnosis to be made and excludes other alternate diagnoses.

Fig.13.54 Lateral SXR showing ‘hair- on- end’ appearance in thalassaemiamajor.

SKULLX-RAY

861

Fractures and associated ndings

Basic radiographs include a lateral projection (obtained with a horizontal

beam) and a further tangential projection, depending on the site of injury.

Findings include

• A linear fracture:well- dened margins, no branching, and no sclerosis

(cf. vascular markings or sutures that have an undulating course and

sclerotic margins).

•

A depressed fracture:i density due to overlapping bone; those that are

depressed by >5mm may lacerate the dura or cause parenchymal injury,

and therefore need elevation.

•

A uid level/ pneumocephalus:implies an associated basal skull fracture or

a duraltear.

Note: pineal displacement is an inconstant nding and is not a reliable

method of assessing the presence of intracranial injury.

Abnormal ndings

Look for intracranial calcication; then examine the pituitary fossa, review

the bony density, and look for focal areas of lysis and sclerosis.

•

Intracranial calcication:the majority is normal and of no clinical

signicance. However, it may be of pathological signicance— causes

include ° tumours, such as meningiomas, craniopharyngiomas, AVMs,

and tuberous sclerosis, and infections such as toxoplasmosis.

•

Raised ICP:in practice, plain lm changes are only seen if the condition is

long- standing. These include sutural widening (diastasis) and erosion of

the lamina dura of the pituitaryfossa.

•

Enlargement of the pituitary fossa (normal dimensions:height 6– 11mm,

length 9– 16mm):expansion will result in a double oor, loss of the

lamina dura, and elevation/ destruction of the clinoid processes. The

vast majority of the lesions will be pituitary adenomas; other causes

include meningiomas and aneurysms.

•

Bone lysis:may be diuse as in metastasis or myeloma. Large areas of

bone destruction are seen in histiocytosis X and in the active phase of

Paget’s disease (osteoporosis circumscripta).

•

Bone sclerosis:may be localized as in meningiomas, depressed skull

fractures, or generalized as in Paget’s sclerotic metastases, myeloma,

and uorosis.

•

Sutural widening:may be due to raised ICP, inltration by malignancy

(neuroblastoma or lymphoma), or defective ossication as in rickets.

862

CHAPTER13 Radiology

862

Reference section

For abbreviations, see Table 13.14. For a list of adverse reactions to con-

trast agents, see Table13.15.

Table13.14 Abbreviations used inradiology

AP Anteroposterior

AXR

Abdominal X- ray

CT Computed tomography

CXR

Chest X- ray

IVU Intravenous urogram

MRI Magnetic resonance imaging

P- A Posteroanterior

USS Ultrasound scan

V/ Q Ventilation perfusion scan

Table13.15 Management ofadverse reactions tointravascular

contrastagents

Symptoms Treatment

Nausea/ vomiting Reassurance

Urticaria

Antihistamine chlorpheniamine maleate 10– 20mg by slow IV

injection (0.2mg/ kg body weight paediatric dose)

Side eects:drowsiness and/ or hypotension may occur

Angio- oedema/

laryngeal oedema

Adrenaline (epinephrine) 1– 3mL 1:10,000 IV (slowly), 0.3–

0.5mL SC or IM (1:1000) solution

Protect airway and give O

Bronchospasm O

by mask (6– 10L/ min)

β2- agonists nebulized or metered- dose inhaler

Adrenaline (epinephrine) 0.1– 0.3 mg IM (1:1000)

Hypotension If isolated, O

by mask, IV access, and rapid IV uids

If unresponsive, adrenaline 1:1,000, 0.5mL (0.5mg)

Vasovagal Hypotension and bradycardia

Elevate patient legs. O

by mask (6– 10L/ min)

Atropine 0.6– 1mg IV (up to maximum of3mg)

Normal saline 250– 500mL IV. Rapid infusion

Data sourced from Standards for intravascular contrast administration to adult patients. 3rd

edition RCR October2014.

REFERENCE SECTION

863

Order ofappearance ofossication centres oftheelbow

The order of appearance is more important than the absolute age of

appearance, which varies widely. Remember ‘CRITOE’ (see Table 13.16).

Fracture healing rapid inchildren

• Periosteal new bone:1week.

•

Loss of fracture line:2– 3weeks.

• Hard callus:2– 4weeks.

• Remodelling of bone:12months.

•

Types of paediatric fractures:torus (buckle) fractures— buckled

cortexonly.

•

Greenstick fracture:incomplete transverse fracture with intact

periosteum on concave side (ruptured on side of convexity).

•

Complete fracture.

Epiphyseal plate fractures:theSalter– Harris

classication (SALTR)

• Type I:epiphyseal slip separates it from the physis (5– 6%). S=slip of

physis.

•

Type II:fracture line extends into the metaphysis (50– 75%). A=above

physis.

•

Type III:the epiphysis is vertically split, i.e. the equivalent of an intra-

articular fracture (8%). L=lower than physis.

•

Type IV:fracture involves the metaphysis, epiphysis, and physis (8– 12%).

T=through physis.

• Type V:crush injury with vascular compromise, i.e. poor prognosis for

growth (1%). R=rammed physis.

Table13.16 Order ofappearance ofossication centres oftheelbow

Approximate average age (years)

Capitellum 1

Radial head

3– 6

Internal (medial) epicondyle 4

Trochlea 8

Olecranon 9

External (lateral) epicondyle 10

864

CHAPTER13 Radiology

864

Internet resources

National Radiological ProtectionBoard

For issues regarding radiation safety:M https:// www.gov.uk/ government/

collections/ national- radiological- protection- board- nrpb- report- series

Royal College ofRadiologists

For information relating to radiological issues, guidelines in clinical manage-

ment, training, and publications:M

http:// www.rcr.ac.uk

MRI safety and compatibility

M http:// www.mrisafety.com

Radiological Society ofNorth America

M http:// www.rsna.org

American College ofRadiology

Incorporates guidelines for use of contrast media and practice guidelines, as

well as information on technical standards (e.g. teleradiology):M

http://

www.acr.org

British Institute ofRadiology

M http:// www.bir.org.uk

American Roentgen Ray Society

M http:// www.arrs.org

Also includes an image library with peer- reviewed published images:

http:// goldminer.arrs.org/

General radiology resources

Educational website oering radiology cases, dierential diagnoses, etc.:

M Learningradiology.com

CT imaging/ protocols:M http:// www.ctisus.com

865

Chapter14

Nuclear medicine

Introduction to nuclear medicine 866

Bone scintigraphy:bone scan 868

Reticuloendothelial system:bone marrow scintigraphy 872

Cerebral blood ow imaging 874

Brain transporter imaging 876

Cerebrospinal uid shunt patency 878

Thyroid scintigraphy 880

Parathyroid scintigraphy 882

Meta- iodobenzylguanidine (MIBG) imaging 884

Somatostatin receptor scintigraphy:SPECT 886

Radioiodine thyroid cancer imaging 888

Sentinel node imaging 890

Scintimammography 892

Positron emission tomography (PET) 894

Somatostatin receptor scintigraphy:

Ga- DOTA- peptide

PET/ CT 898

Prostate- specic membrane antigen:

Ga- PSMA PET/ CT 900

C- choline/

F- uorocholine PET/ CT 902

F- uoride PET/ CT 904

Myocardial perfusion imaging 906

Radionuclide ventriculography:MUGA scan 910

Radionuclide rst- pass cardiac studies 912

Lung scan:ventilation/ perfusion imaging 914

Lung shunt studies 918

Lung permeability studies 920

Lymphoscintigraphy 922

Static cortical scintigraphy:dimercaptosuccinic acid imaging 924

Dynamic renography 926

Captopril renography 928

Gastrointestinal bleeding:labelled red cell imaging 930

Gastric emptying studies 932

SeHCAT studies 934

Meckel’s scan:ectopic gastric mucosa localization 936

Hepatobiliary scintigraphy 938

Splenunculus detection:heat- damaged red cell imaging 940

Hepatosplenic scintigraphy 942

Labelled leucocyte imaging 944

Gallium scintigraphy 946

Dacroscintigraphy 948

Salivary gland scintigraphy 950

Glomerular ltration rate measurement 952

Urea breath test 953

Red cell survival studies 954

Red cell volume/ plasma volume measurement 955

Bile salt deconjugation studies 956

866

CHAPTER14 Nuclear medicine

866

Introduction tonuclear medicine

Nuclear medicine techniques employ a carrier molecule, selected to target

the organ/ tissue of interest, tagged with a gamma- emitting radioisotope.

The labelled drug (radiopharmaceutical) is usually given PO or IV, although

it can also be administered interstitially or by inhalation. Its distribution is

mapped in vivo

using a gamma camera (scintigraphy) or, for non- imaging

tests, biological specimens are assayed in vitro using a radiation counter.

SPECT uses images collected, whilst rotating a gamma camera (usually

multi- headed) around the patient, then reconstructed mathematically to

produce 3D images. PET images are obtained from a ring of detectors fol-

lowing administration of a positron- emitting radiopharmaceutical.

Nuclear medicine procedures can detect early physiological responses

to disease processes, generally before structural changes have taken place,

and thus scintigraphy is often more sensitive than conventional radiology in

early disease. Specicity varies depending on the radiopharmaceutical used,

and characterization of abnormalities often relies upon pattern recognition

within a particular clinical setting. Anatomical detail is poor, compared with

conventional radiology, and increasingly single photon emission computed

tomography (SPECT) and positron emission tomography (PET) images are

co- registered with CT or MRI images using hybrid cameras.

Nuclear medicine procedures are non- invasive and allow the whole

body to be imaged during a single examination. Absorbed radiation doses

depend on the radiopharmaceutical used but are usually in the same range

as diagnostic radiology. Pregnancy is an absolute contraindication to nuclear

medicine examinations, except where likely clinical benet far outweighs

potential risk, e.g. lung perfusion imaging. Some radiopharmaceuticals are

excreted in breast milk, and additional precautions may be advisable for

lactatingwomen.

Diagnostic radiopharmaceuticals are used in tracer quantities and toxicity

is negligible. Individual hypersensitivity reactions are rare. The most widely

used radionuclide is technetium- 99m (

99m

Tc), which can be obtained from

an on- site generator, has a half- life of 6h, and is suitable for labelling a wide

variety of radiopharmaceuticals.

Specic information required whenrequesting nuclear

medicine tests includes

• Patient identication details.

• Examination requested.

• Relevant clinical history, including results of other investigations.

• Pregnancy/ lactation details where relevant.

• Special needs— visual/ hearing/ learning diculties; needle phobia.

• Some scanning beds have a weightlimit.

INTRODUCTION TO NUCLEAR MEDICINE

867

868

CHAPTER14 Nuclear medicine

868

Bone scintigraphy:bonescan

Background

Nuclear medicine investigations supplement the anatomical information

obtained from radiology. Bone scintigraphy is sensitive, with changes fre-

quently detected earlier than on plain lm, but non- specic. It plays a piv-

otal role in the staging of patients with malignant disease and in dicult

orthopaedic cases. May be restricted to ‘local views’ only, e.g. loose hip

prosthesis or ‘whole body imaging’ in metastatic screening. Can include a

dynamic phase image at the time of radiopharmaceutical administration, in

addition to the delayed bone phase image 2– 4h post- injection. Dynamic

phase reects blood ow to the site of interest— useful when there is con-

cern over vascularity, infection, or recent trauma. Helps to dierentiate soft

tissue from bone pathology, e.g. cellulitis vs osteomyelitis.

The

99m

Tc- bisphosphonate complex (MDP/ medronate, HDP/ oxidronate)

targets the skeleton with renal excretion of unbound activity. Patients with

poor renal function may need delayed imaging to improve the bone:soft

tissue ratio (see Fig.14.1).

Fig.14.1 Normal whole body

99m

Tc- bisphosphonate bone scan; anterior view on

left, posterior view onright.

BONE SCINTIGRAPHY:BONESCAN

869

Indications

• Tumour staging— assess skeletal metastases (see Fig.14.2).

• Bonepain.

• Trauma— when radiographs unhelpful.

• Prosthetic loosening, e.g. total hip replacement(THR).

• Infection.

• AVN.

• Paget’s disease to assess extent (monostotic or polyostotic) (see Fig.14.3).

• Sports injuries.

Patient preparation

Should be well hydrated and continent.

Procedure

Inject

99m

Tc- bisphosphonate complex IV. For suspected AVN or sepsis,

image immediately to assess vascularity. Otherwise, image 2– 4h later.

Whole body views are required for metastatic screening. Tomography

improves anatomical denition and detection of small lesions, e.g. osteoid

osteoma, and is particularly useful in back pain. Fusion with CT images is

being used increasingly.

Results

• Radiopharmaceutical uptake reects osteoblastic activity.

• Focal i uptake in sclerotic metastases, trauma, or infection.

•

Diuse i uptake associated with advanced metastases, Paget’s (local),

and metabolic bone disease.

•

Reduced tracer uptake in acute AVN and lytic bone metastases.

Interpretation

Sensitive, but non- specic. Interpretation relies on pattern recognition in

the clinical setting.

Advantages

Sensitive— detects early changes in bone physiology, often before abnormal

plain radiographs, e.g. occult trauma, metastases, and sepsis.

Pitfalls

False −ves in multiple myeloma and osteolytic bone metastases.

False +ves: artefacts due to urine contamination.

870

CHAPTER14 Nuclear medicine

870

Fig.14.3 Bone scan showing Paget’s disease aecting the right hemipelvis and left

distalfemur.

Fig.14.2 Bone scan showing extensive metastases.

BONE SCINTIGRAPHY:BONESCAN

871

872

CHAPTER14 Nuclear medicine

872

Reticuloendothelial system:bone

marrow scintigraphy

Background

Largely superseded by MRI. Colloid particles are cleared from the circulat-

ing blood pool by reticuloendothelial tissue— larger particles to the liver and

spleen, smaller particles to the BM. Abnormal uptake pattern where the BM

is replaced, e.g. by tumour inltration.

Indications

• Suspected malignant marrow inltration.

• Equivocal conventional bone imaging.

• Osteomyelitis (rarelyused).

Patient preparation

None.

Procedure

•

99m

Tc- nanocolloid injectedIV.

• Whole body gamma camera imaging at 30– 45min.

Results

Normal marrow distribution in the thoracic cage, spine, pelvis, and proximal

long bones. Homogeneous uptake in the liver and spleen.

Interpretation

• Focal or generalized d skeletal uptake indicates marrow replacement or

inltration with marrow displacement to the distal femora and humeri.

•

Heterogeneous hepatic uptake is abnormal but non- specic.

Advantages

Non- invasive. Avoids sampling errors, compared with BM biopsy.

Pitfalls

False −ves in early malignancy. Liver and spleen uptake may obscure abnor-

malities in the midspine.

RETICULOENDOTHELIAL SYSTEM:BONE MARROW SCINTIGRAPHY

873

874

CHAPTER14 Nuclear medicine

874

Cerebral blood ﬂow imaging

Background

Used to study acute and chronic cerebrovascular disease, dementias, and

epilepsy, using a neutral lipophilic

99m

Tc complex hexamethyl- propylene-

amine- oxime (exametazime, HMPAO), which crosses the blood– brain bar-

rier and xes in proportion to regional blood ow, with high accumulation

in cortical grey matter, compared with white matter. Images reported with

CT/ MRI correlation to ensure appropriate interpretation, compared with

normal variants of cerebral asymmetry).

Indications

• Dementia characterization.

• Epilepsy for localization of epileptogenicfocus.

Patient preparation

Secure venous access under resting conditions. Allow the patient to relax

before injection of the radiopharmaceutical. Ensure that the patient can co-

operate with the imaging procedure.

Procedure

•

99m

Tc- HMPAO (exametazime) injected IV in a quiet, darkened room,

with the patient’s eyes closed.

•

Tomographic brain imaging undertaken immediately and may be

repeated 4hlater.

Results

Cortical grey matter uptake is proportional to blood ow (see Fig. 14.4a).

Interpretation

• Characteristic patterns of abnormal uptake recognized in dierent

dementias (see Fig. 14.4b) and in cerebrovascular disease.

•

d uptake at epileptogenic focus on interictal scans— often changing

to i uptake on ictal imaging.

Advantages

Abnormalities on functional imaging should predate structural atrophy on

anatomical imaging.

Pitfalls

• Tomographic image analysis degraded by movement artefact and

asymmetric positioning.

•

Data processing is operator- dependent.

Further reading

Kapucu OL, Nobili F, Varrone A, etal. EANM procedure guideline for brain perfusion SPECT using

99m

Tc- labelled radiopharmaceuticals, version 2. Eur J Nucl Med Mol Imaging 2009; 36:2093– 102.

CEREBRAL BLOOD FLOW IMAGING

875

(a)

(b)

Fig.14.4

99m

Tc- HMPAO brain imaging. Trans- axial tomographic slices:(a)normal

and (b)dementia. (E Colour plate6.)

876

CHAPTER14 Nuclear medicine

876

Brain transporter imaging

Background

Reects the role of the dopaminergic system in movement disorders, e.g.

Parkinsonian syndromes, essential tremor.

123

I- ioupane is a cocaine ana-

logue, which binds to the dopamine transporter on the pre- synaptic nerve

terminal. Post- synaptic receptor imaging agents are necessary to dierenti-

ate among the various Parkinsonian syndromes (not routinely available).

Indications

• Movement disorders:distinguishes Parkinson’s syndrome (PkS) from

benign essential tremor.

Patient preparation

• Block the thyroid— potassium iodate/ iodide.

• Multiple potential drug interactions— stop:

•

Amphetamines.

•

Citalopram.

•

Cocaine.

•

Fluoxetine.

•

Fluvoxamine.

•

Mazindol.

•

Methylphenidate.

•

Orphenadrine.

•

Phentermine.

•

Procyclidine.

•

Sertraline.

Procedure

123

I- labelled radiotracer, e.g. ioupane, injected IV. Tomographic gamma

camera imaging 3– 6hlater.

Results

Intense, symmetric uptake in basal ganglia receptors— striatum, caudate,

and putamen (see Fig. 14.5a).

Interpretation

d basal ganglia uptake in PkS (see Fig. 14.5b).

Advantages

Sensitive and specic for PkS, dierentiating PkS from essential tremor. No

other imaging technique currently available to demonstrate receptor status.

Pitfalls

Drug interactions (E Patient preparation above).

BRAIN TRANSPORTER IMAGING

877

Further reading

Darcourt J, Booij J, Tatsch K, etal. EANM procedure guidelines for brain neurotransmission SPECT

using

123

I- labelled dopamine transporter ligands, version 2. Eur J Nucl Med Mol Imaging 2010;

:443– 50.

(a)

(b)

Fig.14.5

123

I- ioupane brain transporter imaging:(a)normal dopamine transporters

and (b)in Parkinson’s disease. (E Colour plate7.)

878

CHAPTER14 Nuclear medicine

878

Cerebrospinal ﬂuid shunt patency

Background

Ventricular shunts are routinely used to manage hydrocephalus. Symptoms

of shunt obstruction may be non- specic and do not indicate the level of

obstruction. Nuclear medicine oers a straightforward means of determin-

ing shunt patency.

Indications

Suspected ventriculoperitoneal shunt obstruction.

Patient preparation

None.

Procedure

Inject

111

In- DTPA into the shunt reservoir using a strict aseptic technique.

Image the head and abdomen immediately and 30– 60min post- injection.

(

99m

Tc- DTPA not recommended because dicult to ensure apyrogenicity.)

Results

Normally, rapid reservoir emptying and shunt visualization within 2– 3min of

injection. Free activity within the abdominal cavity by 30min (see Fig.14.6).

Interpretation

Delayed clearance implies obstruction— level usually at reservoir/ proximal

shunt or due to intra- abdominal kinking.

Advantages

Sensitive, simple, rapid results.

Pitfalls

Infectionrisk.

CEREBROSPINAL FLUID SHUNT PATENCY

879

Reservoir

Thorax

Free activity

in peritoneal

cavity

Fig.14.6 Patent ventriculoperitoneal shunt showing reservoir, shunt, and free

activity within the peritoneal cavity.

880

CHAPTER14 Nuclear medicine

880

Thyroid scintigraphy

Background

Used to investigate thyrotoxicosis and thyroid ectopia. Thyroid mass or

suspected malignancy should be investigated by US/ CT and FNA cytology.

Imaging is undertaken using

99m

Tc- pertechnetate, which is trapped by the

thyroid by the same transporter mechanism as iodine but, unlike iodine,

is not organied.

123

I is more sensitive and specic for the investigation of

congenital hypothyroidism.

Indications

• Characterization of thyrotoxicosis— diuse toxic goitre (Graves’

disease), toxic multinodular goitre (Plummer’s disease).

•

Solitary autonomous nodule.

• Acute thyroiditis.

Patient preparation

Levothyroxine and iodine- rich preparations (e.g. iodine supplements, con-

trast media, amiodarone) will block tracer uptake by the thyroid for up

to 9 months. T4 should be withdrawn for 4–6 weeks, T3 for 2 weeks.

Antithyroid drugs can be continued.

Procedure

Inject

99m

Tc- pertechnetate IV. Image after 15– 30min. Include anterior thorax

views if retrosternal extension is suspected. Neck palpation essential to

assess function in discrete thyroid nodules.

123

I may be administered either

PO or IV. Imaging is carried outat2h.

Results

• Uptake reects function of the thyroid iodine trap (sodium iodide

symporter).

•

Diuse i uptake in Graves’ disease (see Fig. 14.7a).

•

Heterogeneous uptake with suppressed background activity indicates

toxic multinodular change (see Fig. 14.7b).

•

Solitary autonomous nodules show intense i uptake, with complete

suppression of the remainder of the gland (see Fig. 14.7c).

•

Reduced tracer uptake in non- functioning nodules (see Fig. 14.7d).

• Acute thyroiditis is characterized by absent tracer uptake

(see Fig. 14.7e).

Interpretation

Sensitive and specic for hyperthyroidism.

Advantages

Simple, cheap, and non- invasive. Essential to planning therapy in

hyperthyroidism.

Pitfalls

Anatomical denition inferior to US, CT, etc. Superseded by US- guided

FNA for diagnosis of thyroid mass lesions.

THYROID SCINTIGRAPHY

881

(a) Grave’ disease

(e) Thyroiditi

(d) Non-functioning nodule

(b) Toxic multinodular goitre

Fig.14.7 Thyroid scintigraphy:(a)in Graves’ disease (toxic diuse hyperplasia)

and (b)in toxic multinodular goitre, (c)toxic autonomous nodule (arrow), (d)non-

functioning (cold nodule; arrow), and (e)thyroiditis (arrow).

882

CHAPTER14 Nuclear medicine

882

Parathyroid scintigraphy

Background

Hyperparathyroidism may be ° (i.e. functioning adenoma), 2° (where

there is hypocalcaemia from chronic lowering of serum Ca

, e.g. renal

insuciency), or tertiary (i.e. hypersecretion of PTH in the presence of

either normal or elevated levels of Ca

). Nuclear medicine is of value in

localizing parathyroid adenomas, particularly following previous surgery.

Indications

Localization of parathyroid adenoma in proven hyperparathyroidism.

Patient preparation

Withdraw levothyroxine or iodine- containing compounds (cf. thyroid

imaging).

Procedure

Three dierent techniques are available.

•

99m

Tc- sestamibi IV early (15 min) and delayed (2–3 h) imagesor

•

123

I- iodide IV followed by

99m

Tc- sestamibi,or

•

99m

Tc- pertechnetate followed by

201

Tl- thallous chloride.

Image the anterior neck and mediastinum after each administration.

Results

Normal thyroid concentrates

123

99m

Tc- pertechnetate,

99m

Tc- sestamibi

(initially), and

210

Tl, whereas parathyroid only concentrates

99m

Tc- sestamibi

and

201

Tl.

Computer- assisted image subtraction [(thyroid + parathyroid) − thyroid]

identies abnormal parathyroid tissue.

Interpretation

Parathyroid adenoma shown as hyperfunctioning nodule(s) (see Figs

14.8– 14.10.)

(a) (b)

Fig.14.8 Normal

99m

Tc- sestamibi dual- phase parathyroid scan; 5min image on left,

4h image onright.

PARATHYROID SCINTIGRAPHY

883

Advantages

Good when other imaging fails, particularly ectopic adenomas and after

unsuccessful neck exploration. Hybrid SPECT/ CT images particularly help-

ful to surgeons.

Pitfalls

Multinodular thyroid prevents subtraction analysis in smaller adenomas and

hyperplastic glands and thyroid nodules. Many surgeons still prefer intra-

operative bluedye.

False –ves in smaller adenomas and hyperplastic glands.

False +ves in thryoid nodules.

Further reading

Hindié E, Ugur O, Fuster D, etal. 2009 EANM parathyroid guidelines. Eur J Nucl Med Mol Imaging

2009; 36

:1201– 16.

(a) (b)

Fig.14.9

99m

Tc- sestamibi (dual- phase). Parathyroid adenoma at left lower lobe of

the thyroid (arrow) evident on delayedimage.

(a)(b) (c)

Fig.14.10 Parathyroid scintigraphy showing images obtained with both (a)

123

I- iodide,

(b)

99m

Tc- sestamibi, and (c) subtracted image showing a parathryoid adenoma.

884

CHAPTER14 Nuclear medicine

884

Meta- iodobenzylguanidine (MIBG)

imaging

Background

Neuroendocrine tumours (NETs) are rare. Symptoms reect hormone

hypersecretion, but intermittent secretory patterns can result in false −ve

screening tests, e.g. 24h urine collections. MIBG (iobenguane) is concen-

trated by adrenergic tissue via the noradrenaline reuptake mechanism.

Virtually all phaeochromocytomas and neuroblastomas will be demon-

strated using

123

I- MIBG scintigraphy. The sensitivity for other NETs is vari-

able. High- dose

131

I- MIBG therapy is a useful treatment for MIBG +veNETs.

Indications

• Localization, staging, and response monitoring of neuroectodermal

tumours.

•

Phaeochromocytoma (imaging investigation of choice).

• Neuroblastoma.

• Carcinoid tumours.

• Medullary thyroid cancer.

Patient preparation

• Multiple known and theoretical drug interactions:Stop for>48h:

•

Antidepressants— tricyclics, tetracyclics, MAOIs, serotonin reuptake

inhibitors.

•

Phenothiazines.

•

Labetalol (no interaction with any other α- or β- blocker or

antihypertensive).

•

Levodopa, dopamine agonists.

•

Sympathomimetics— including over- the- counter nasal decongestants.

• Block the thyroid:potassium iodate/ iodide; perchlorate.

Procedure

Inject

123

I- MIBG slowly IV with BP monitoring. Image the posterior abdo-

men at 5min to identify renal outlines, then whole body imaging at 18–

24h. Tomographic imaging may improve tumour localization— not always

required.

Results

Physiological uptake at 24h in the salivary glands, myocardium, liver, and

normal adrenals, with gut and renal excretion.

Interpretation

• Intense i uptake in phaeochromocytomas, with suppressed activity in

the contralateral and normal adrenal, and myocardium. Whole body

imaging identies extra- adrenal and metastatic disease (see Fig. 14.11).

• Diuse BM uptake common in stage IV neuroblastoma.

META-IODOBENZYLGUANIDINE (MIBG) IMAGING

885

Advantages

Sensitive, non- invasive tumour localization preoperatively excludes multi-

focal and extra- adrenal tumours. Non- invasive treatment response moni-

toring in neuroblastoma— avoids sampling errors, compared with BM

biopsy.

Pitfalls

Drug interactions causing false −ve results. Dilated renal pelvis sometimes

confused with tumour uptake. Check with 5min renal image if indoubt.

Fig.14.11

123

I- MIBG whole body scan.

123

I-MIBG positive left adrenal mass

(phaeochromocytoma). Excludes multi- focal, ectopic, and malignant tumour.

886

CHAPTER14 Nuclear medicine

886

Somatostatin receptor

scintigraphy:SPECT

Background

Somatostatin receptor (SSR) imaging identies NETs, including gastroenter-

opancreatic tumours, e.g. carcinoids, gastrinomas, insulinomas. Many other

common neoplasms also express surface SSRs. Somatostatin analogues,

e.g. octreotide, bind to cell surface SSRs. Radiolabelled SSR analogues

demonstrate receptor +ve disease. Sub- centimetre (i.e. below the limits

of cross- sectional radiology) hyperfunctioning ° tumours can be detected.

High- dose radiolabelled SSR therapy is used to treat multi- site disease.

Indications

Localize and stage NETs, e.g. carcinoid, insulinoma, gastrinoma, phaeochro-

mocytoma, and medullary thyroid cancer.

Patient preparation

None. Prophylactic laxatives at time of radiopharmaceutical administration

accelerate gut clearance and improve image quality.

Procedure

Inject

111

In- pentetreotide or

99m

Tc hynic- octreotide (SSR analogues) IV.

Whole body gamma camera imaging at 4 and 24h (± 48h), with SPECT if

necessary.

Results

Normal uptake in the thyroid, liver, spleen, kidneys, and RES, with gut and

renal excretion.

Interpretation

i uptake in tumours expressing surface SSRs. SPECT improves detection of

small pancreatic and intra- hepatic tumours (see Fig. 14.12).

Advantages

Tumour uptake predicts symptom response to somatostatin analogue ther-

apy. Image co- registration with CT or MRI improves localization of occult

pancreaticNETs.

Pitfalls

Interpretation often hindered by gut excretion.

Further reading

Bombardieri E, Ambrosini V, Aktolun C, etal.

111

In- pentetreotide scintigraphy:procedure guidelines

for tumour imaging. Eur J Nucl Med Mol Imaging 2010; 37:1441– 8.

SOMATOSTATIN RECEPTOR SCINTIGRAPHY:SPECT

887

Fig.14.12 Whole body

111

In- octreotide scan in a patient with a neuroendocrine

tumour showing somatostatin receptor positive hepatic and extra-hepatic

metastases.

888

CHAPTER14 Nuclear medicine

888

Radioiodine thyroid cancer imaging

Background

The treatment for thyroid carcinoma is total thyroidectomy with lymph

node dissection, depending on tumour stage. Radioactive iodine is adminis-

tered post- operatively to ablate the thyroid remnant. Tg can then be used

as a tumour marker— Tg is undetectable in the absence of functioning thy-

roid tissue. Rising Tg following

131

I ablation indicates recurrence. If Tg rises,

a diagnostic

131

I imaging study localizes the site of relapse and assesses the

feasibility of further radioiodine therapy. The sensitivity of imaging is i by

recombinant TSH stimulation.

Indications

Routine dierentiated follicular thyroid cancer follow- up, after surgery and

131

I thyroid remnant ablation.

Patient preparation

Need high TSH drive to stimulate

131

I uptake— stop T3/ T4 replacement

for a minimum of 2 (T3) or 4-6 weeks (T4), or give recombinant TSH.

Avoid cold iodine administration, IV contrast media, and amiodarone (cf.

thyroid imaging).

Procedure

Give

131

I sodium iodide PO/ IV. Obtain blood samples for Tg and TSH

at the time of

131

I administration. Whole body gamma camera imaging

2– 5dayslater.

Results

Physiological uptake in salivary glands. Occasional stomach and GI reten-

tion. Renal excretion.

Interpretation

Abnormal uptake indicates functioning thyroid metastasis. Anatomical

markers improve localization (see Fig. 14.13a andb).

Advantages

Detects residual tumour and identies patients likely to benet from

131

therapy.

Pitfalls

False −ve without signicant TSH drive— aim for TSH >50mU/ L; undif-

ferentiated and papillary tumours may be

131

I−ve.

RADIOIODINE THYROID CANCER IMAGING

889

(a) (b)

Fig.14.13 Anterior whole body

131

I image showing (a)local tumour recurrence in

the thyroid bed and physiological activity in the bowel and (b)local recurrence in the

thyroid bed with lung, mediastinal nodal, and skeletal metastases.

890

CHAPTER14 Nuclear medicine

890

Sentinel node imaging

Background

Regional lymph node dissection is performed for cancer staging to deter-

mine the need for adjuvant therapy. Lymphatic drainage can be demon-

strated by radiolabelled colloid imaging, which identies the rst or ‘sentinel’

draining node. Staging based on the excision and histological examination of

this node for evidence of metastasis is as reliable as that obtained from block

dissection and avoids the morbidity of extended lymph node dissection.

Indications

Preoperative assessment in breast cancer and melanoma. May have applica-

tions in head and neck, vulval, and penile cancer staging.

Patient preparation

None. Usually undertaken within 24h of planned surgery.

Procedure

Intradermal, subcutaneous, or intratumoural injection of

99m

Tc- labelled

nanocolloid. Gamma camera imaging of draining lymph nodes to identify

sentinel node. Where surgery is undertaken within 24h, an intra- operative

gamma probe can be used to identify the sentinel node for staging excision

biopsy.

Results

Sentinel node usually identiable 15min to 2h post- injection, depending on

the ° tumour location and injection techniqueused.

Interpretation

The sentinel node is the rst lymph node identied on gamma imaging or

the node with the highest radioactive count rate using the gamma probe

(see Fig. 14.14a andb).

Advantages

Accurate sentinel node identication avoids block node dissection where

this is undertaken solely for tumour staging.

Pitfalls

May fail if local lymphatic channels have been disrupted by previous surgery.

Further reading

Procedure guidelines for several types of cancer are available at:M http:// www.eanm.org.

SENTINEL NODE IMAGING

891

(a)

(b)

A NODE

Fig.14.14

99m

Tc- nanocolloid sentinel node study. (a) Breast cancer: left breast injection

and sentinel lymph node in left axilla (arrow). (b) Melanoma left thigh: left thigh injection

(not shown) and sentinel lymph node in left groin (arrow).

892

CHAPTER14 Nuclear medicine

892

Scintimammography

Breast cancer diagnosis relies on accurate localization (US ± mammog-

raphy) and tissue biopsy (FNA) or core biopsy. Where mammography is

non- diagnostic, MRI, CT, or

F- FDG PET/ CT are useful. Nuclear medi-

cine scintimammography is as sensitive as, but more specic than, MRI and

mammography in palpable lesions.

Indications

Investigation of suspicious breast lesions, in dicult- to- interpret mammo-

grams, e.g. dense or lumpy breast tissue, calcication, breast implants, pre-

vious surgery.

Patient preparation

None.

Procedure

99m

Tc- sestamibi administered IV ideally into the contralateral foot, with early

(5– 10min) imaging post- injection. Patient is imaged prone, with the breast

fully dependent, with prone and lateral views of each breast, to include the

axillae.

Results

Normal distribution of

99m

Tc- sestamibi is to the myocardium, the liver, and

occasionally the thyroid.

Interpretation

Focal accumulation in the breast and/ or axilla implies the presence of a

tumour. Findings should be interpreted in conjunction with othertests.

Advantages

Can demonstrate multi- focal, multicentric disease, and both ipsilateral and

contralateral axillary spread. May be used to identify the most suitable site

for guided biopsy.

Pitfalls

Not reliable in small (<1cm) lesions; extravasation of injection in upper

limbs may result in false +ve axillary uptake.

Poor injection technique will lead to errors in analysis. The camera and

supporting software require high count rate capability, and the technique

requires expertise in data analysis to ensure reliable, reproducible results.

Close liaison with the referring clinician is essential to maximize the value

of the investigation.

Further reading

Buscombe J, Hill J, Parbhoo S. Scintimammography: A Guide to Good Practice. Birmingham: Gibbs

Associates Ltd,1998.

Taillefer R. Clinical applications of

99m

Tc- sestamibi scintimammography. Semin Nucl Med 2005;

:100– 15.

SCINTIMAMMOGRAPHY

893

894

CHAPTER14 Nuclear medicine

894

Positron emission tomography (PET)

PET has expanded rapidly over the last 20years. Tomographic PET images

are acquired using a dedicated PET scanner after administration of positron-

emitting radiopharmaceuticals. Spatial resolution (75mm) is signicantly

superior to conventional nuclear medicine imaging.

PET uses biologically important molecules such as radiolabelled water,

ammonia, amino acids, or glucose derivatives— the glucose analogue

F-

uorodeoxyglucose (

F- FDG) being used for most clinical PET studies,

particularly in oncology. Malignant cells have both a higher glycolytic rate

and over- expression of membrane glucose transporters, leading to high

F- FDG uptake, compared to normal tissues.

F- FDG is trapped within

metabolically active cells, so that abnormalities are detected by metabolic

dierences, rather than anatomical size, i.e. inherently more sensitive than

structure- based imaging.

The main indications for PET imaging are in oncology where

F- FDG

PET is used for diagnosis, staging, and monitoring treatment response. Low-

grade uptake occurs in granulomatous disease, inammation, and sepsis.

PET allows radioactive concentrations within tissues to be measured

accurately, so that physiological processes can be expressed in absolute

units. The standardized uptake value (SUV) measures the concentration of

tracer within a tumour, compared to the injected activity, normalized to

body weight. Serial SUV measurements allow

F- FDG uptake to be fol-

lowed as a marker of treatment response and may be of prognosticvalue.

Other major applications include nuclear cardiology where patterns of

myocardial

F- FDG uptake are used to detect myocardial hibernation. In

neurosciences, PET remains a largely research tool for the investigation of

movement disorders, dementia, and degenerative disease.

Other oncological tracers that are available for clinical use include

C-

methionine, measuring tumour amino acid transport and protein synthesis

and H

O water for blood ow measurements.

Ga- labelled somatostatin

peptides are used to image NETs. Future developments will include labelled

thymidine analogues (e.g.

F- FLT) to measure proliferation, hypoxia mark-

ers, and tracers capable of detecting apoptosis and angiogenesis.

The main limitation of PET imaging in oncology is limited anatomical de-

nition. To improve attenuation correction and tomographic localization,

PET imaging is usually combined with CT (or MRI). The combination of

functional and anatomical data in fused images signicantly improves the

sensitivity and specicity of imaging.

Indications

• Tumour diagnosis:solitary pulmonary nodule characterization, location of

carcinoma of unknown ° origin.

•

Tumour staging:non- SCLC; lymphoma; oesophageal cancer; colorectal

cancer; head and neck cancer; melanoma.

•

Response assessment/ relapse detection:asabove.

POSITRON EMISSION TOMOGRAPHY

895

Patient preparation

• Cellular

F- FDG uptake is glucose- dependent.

•

Non- diabetic patients— 6hfast.

•

Aim for blood glucose <7mmol/ L.

•

Insulin- dependent diabetic patients— allow a normal diet and insulin.

•

Avoid hyperglycaemia— use a sliding scale if necessary or defer the

investigation.

•

Patients should be rested:to avoid skeletal muscle uptake.

•

Diazepam administration:5mg PO reduces physiological brown fat

uptake in young patients.

•

Patients with head and neck cancer should be silent during injection and

until completion of imaging to prevent vocal cord uptake.

Procedure

•

F- FDG injected IV supine in restful surroundings.

• Whole body or half- body (base of skull to proximal femora) imaging

undertaken 60– 90min post- injection.

Results

The normal distribution of

F- FDG is to the brain and myocardium, with GI

and renal excretion (see Fig. 14.15).

Interpretation

Abnormal uptake should be correlated with cross- sectional imaging for pre-

cise anatomical localization (see Figs 14.16 and 14.17). SUV (E pp. 894–7)

measurement is helpful in serial studies.

Fig.14.15 Normal

F- FDG PET scan— coronal tomogram.

896

CHAPTER14 Nuclear medicine

896

Fig.14.16

F- FDG PET scan— non- SCLC right lung (arrow). Whole body coronal.

Fig.14.17

F- FDG PET scan— trans- axial views showing CT (top left) correlation

with PET (top right). The image fusion is shown (bottom left). (E Colour plate8.)

POSITRON EMISSION TOMOGRAPHY

897

Advantages

• Discriminates between viable and necrotic/ scar tissue where a residual

mass may persist on anatomical imaging post- therapy (see Figs 14.18

and 14.19).

•

Non- invasive, whole body 3D imaging.

Pitfalls

• Sensitivity lower in more indolent tumours— lung carcinoid, alveolar cell

carcinoma, NETs, depending on proliferative index, and occasionally in

pancreatic tumours.

•

Limited availability— specialist centresonly.

• Relatively expensive.

Fig.14.18

F- FDG PET scan— non-

Hodgkin’s lymphoma. Whole body

coronal view of patient pre- treatment

showing extensive FDG- avid adenopathy.

Fig.14.19

F- FDG PET scan— non-

Hodgkin’s lymphoma. Post- treatment

showing complete metabolic response.

898

CHAPTER14 Nuclear medicine

898

Somatostatin receptor scintigraphy:

Ga- DOTA- peptidePET/ CT

Background

SSR imaging identies NETs, including gastroenteropancreatic tumours,

e.g. carcinoids, gastrinomas, insulinomas. Many other common neoplasms

also express surface SSRs. Somatostatin analogues, e.g. octreotide, bind to

cell surface SSRs. Radiolabelled SSR analogues demonstrate receptor +ve

disease. High- dose radiolabelled SSR therapy is used to treat multi- site dis-

ease. Currently, given its high accuracy, compared with conventional SPECT

imaging techniques,

Ga- DOTA- peptide PET/ CT is considered to be the

rst- line diagnostic imaging technique of choice for high SSR- expressing

tumours.

Indications

Localize and stage NETs, e.g. carcinoid, insulinoma, gastrinoma, phaeochro-

mocytoma, and medullary thyroid cancer.

Patient preparation

Best option is to perform the study after discontinuing short- acting octreo-

tide for 12– 24h and perform imaging in the week before the next dose of

long- acting octreotide.

Procedure

Inject

Ga- labelled SSR analogue (DOTA- TATE/ DOTA- NOC) IV. Whole

body (vertex to mid thigh) PET/ CT imaging SSR PET/ CT is performed

45– 60min after radiotracer injection.

Results

Normal uptake in the spleen, adrenal glands, kidneys, and pituitary gland.

Moderately intense uptake is often seen in the liver, salivary glands, and

thyroid gland (see Fig. 14.20a).

Interpretation

i uptake in tumours expressing surface SSRs (see Fig. 14.20b).

Advantages

Short half- life of 68min (compared with 2.8days for

111

In); lower radiation

dose to the patient; imaging performed 45– 60min after radiotracer injec-

tion; more accurate than conventional imaging; and allows identication of

additional sites of disease and helps identify patients who are suitable for

radiopeptide therapy (e.g.

177

Lu- DOTA- TATE).

Pitfalls

False −ve:octreotide therapy or the endogenous production of somatosta-

tin by the tumour may interfere with tumour detection. False +ve:promi-

nent pancreatic uncinate process uptake, benign meningioma inammation,

osteoblastic activity (degenerative bone disease, fracture, vertebral hae-

mangioma), splenunculi or splenosis,etc.

SOMATOSTATIN RECEPTOR SCINTIGRAPHY

899

Further reading

Virgolini I, Ambrosini V, Bomanji JB, etal. Procedure guidelines for PET/ CT tumour imaging with

Ga- DOTA- conjugated peptides:

Ga- DOTA- TOC,

Ga- DOTA- NOC,

Ga- DOTA- TATE. Eur

J Nucl Med Mol Imaging 2010; 37

:2004– 10.

(a) (b)

Fig.14.20 (a)Normal

Ga- DOTA- TATE scan; (b)abnormal

Ga- DOTA- TATE

scan showing liver metastases.

900

CHAPTER14 Nuclear medicine

900

Prostate- speciﬁc membrane

antigen:

Ga- PSMAPET/ CT

Background

Prostate- specic membrane antigen (PSMA) is a cell surface protein with

high expression in prostate cancer cells, and over- expression enables tar-

geting of prostate cancer metastases using

Ga- labelled PSMA ligands for

PET/ CT imaging.

Indications

High- risk prostate cancer prior to radical prostatectomy, patients with rising

PSA levels after radical prostatectomy, and diagnosis of recurrent prostate

cancer.

Patient preparation

None.

Procedure

Ga- PSMA is injected IV and PET/ CT performed 60min post- injection.

Results

Physiological uptake in kidneys and salivary glands. i uptake in prostate can-

cer cells expressing PSMA (see Fig. 14.21a).

Interpretation

i tracer uptake in tumours expressing PSMA (prostate and extra- prostatic)

(see Fig. 14.21b).

Advantages

Superior to choline tracers in detecting prostate cancer cells and recurrent

disease at low PSA levels.

Pitfalls

False −ve:limited detection of micrometastases. False +ve:PSMA is also

expressed in tumour- associated neovasculature of most solid tumours.

Further reading

Maurer T, Gschwend JE, Rauscher I, etal. Diagnostic ecacy of

Gallium- PSMA positron emission

tomography compared to conventional imaging in lymph node staging of 130 consecutive patients

with intermediate to high risk prostate cancer. J Urol 2016; 195

:1436– 43.

PROSTATE-SPECIFIC MEMBRANE ANTIGEN

901

(a) (b)

Fig.14.21 (a)Normal

Ga- PSMA scan; (b)abnormal scan with multiple osseous

and extra- osseous metastases.

902

CHAPTER14 Nuclear medicine

902



C- choline/

8

F- ﬂuorocholinePET/ CT

Background

Following radical prostatectomy for treatment of prostate cancer, recurrent

disease is suspected if there is rising PSA.

F- choline PET/ CT is often used

in restaging of patients with prostate cancer (

C- choline or

C- acetate PET

can also be used where available).

Indications

Prostate cancer patients with rising PSA levels after radical prostatectomy

and in patients with recurrent prostate cancer.

Patient preparation

Fasting for 6h recommended to minimize impact of dietary choline. Patient

should be well hydrated.

Procedure

C- choline (half- life 20min) is injected IV and PET images acquired

over 0– 15min.

F- choline (half- life 110min) is injected IV and scan is

performedat1h.

Results

Physiological uptake in the liver, pancreas, spleen, salivary and lacri-

mal glands, urinary tract, and less commonly in BM and intestines (see

Fig.14.22a).

Interpretation

i tracer uptake in recurrent prostate cancer and metastases (see Fig.14.22b).

Advantages

High specicity in lymph node staging, high sensitivity in recurrent disease,

and often helps in treatment planning.

Pitfalls

(a) Limited accuracy for the staging of the ° tumour; (b)often unable to

dierentiate prostate cancer from benign prostate hyperplasia, chronic

prostatitis, and high- grade intraepithelial neoplasia; and (c)high background

signal frequently hampers lesion detection.

Further reading

Schillaci O, Calabria F, Tavolozza M, etal.

F- choline PET/ CT physiological distribution and pitfalls

in image interpretation:experience in 80 patients with prostate cancer. Nucl Med Commun 2010;

:39– 45.

903

C-CHOLINE/

F-FLUOROCHOLINEPET/CT

(a) (b)

Fig.14.22 (a)Normal

F- choline scan; (b)abnormal scan with pelvic nodal

metastases (arrows).

904

CHAPTER14 Nuclear medicine

904

F- ﬂuoridePET/ CT

Background

F- uoride is a highly sensitive bone- seeking PET tracer used for detec-

tion of skeletal pathology. In general, the tracer uptake mechanism is similar

to conventional SPECT tracer. The CT component of the PET/ CT study

allows localization, characterization, and dierentiation of skeletal metasta-

ses from benign lesions.

Indications

Similar to

99m

Tc- MDP bonescan:

•

Tumour staging— assess skeletal metastases.

• Bonepain.

Patient preparation

Patients should be (a)well hydrated and (b)instructed to empty their blad-

der immediately before imaging.

Procedure

F- uoride is injected IV. The adult activity is 185– 370MBq. Paediatric activ-

ity should be weight- based (2.22MBq/ kg).

Results

• Radiopharmaceutical uptake reects osteoblastic activity (see Fig.

14.23a).

•

Focal i uptake in sclerotic metastases (see Fig. 14.23b), trauma, or

infection.

•

Diuse i uptake associated with advanced metastases, Paget’s, and

metabolic bone disease.

Interpretation

Highly sensitive, but non- specic. Interpretation relies on pattern recog-

nition in the clinical setting. The CT component of PET/ CT, even when

performed primarily for attenuation correction and anatomic registration,

also provides diagnostic information.

Advantages

Sensitive— detects early changes in bone physiology, often before abnormal

plain radiographs, e.g. occult trauma, metastases, and sepsis.

905

F-FLUORIDEPET/CT

Further reading

Segall G, Delbeke D, Stabin MG, etal. SNM practice guideline for sodium

F- uoride PET/ CT bone

scans 1.0. J Nucl Med 2010; 51:1813– 20.

(a)

(b)

Fig.14.23 (a)Normal

F- uoride scan; (b)abnormal scan with multiple skeletal

metastases in thespine.

906

CHAPTER14 Nuclear medicine

906

Myocardial perfusion imaging

Background

MPI reects regional blood ow during stress (i demand) and at rest, pro-

viding prognostically signicant information that, both in isolation and in

conjunction with coronary angiography, can be used to optimize patient

management. Originally performed using

201

Tl- thallous chloride, but now

based on

99m

Tc- labelled tracers— sestamibi (methoxy- isobutylisonitrile)

or tetrofosmin. Exercise or pharmacological stress are used to challenge

the coronary artery reserve. Exercise is performed by treadmill or bicy-

cle, whilst pharmacological stressors are either adenosine/ dipyridamole

infusion, which i coronary artery blood ow by vasodilatation, or dobu-

tamine infusion with both inotropic and chronotropic activity. Can also be

performed using PET/ CT with

Rb- rubidium chloride or

N- ammonia as

tracer.

Indications

Ischaemic heart disease.

Pre- angiography

• When conventional stress testing fails, e.g. bundle branchblock.

• Left ventricular hypertrophy.

• Atypical chestpain.

• Recurrent chest pain post- intervention. Good prognostic indicator.

Post- angiography

• Assess functional signicance of known stenoses.

• Identify critical vascular territory for intervention.

Patient preparation

• Stop β- blockers 24h prior to stressstudy.

• Sometimes helpful to withdraw all anti- anginal medication.

• Assess the optimal stress technique for individual patients, i.e. exercise

or pharmacological.

•

Attach 12- leadECG.

• Insert IV cannula.

• Check baselineBP.

Procedure

Two- part investigation comparing myocardial perfusion duringstress and

atrest

Stresstest

•

Treadmill or bicycle exercise to >85% of maximum predicted heart

rate or adenosine 140µg/ kg/ min IV infusion for 6min— sometimes with

submaximal exercise or dobutamine 5– 40µg/ kg/ min in 5µg/ kg/ min

increments over16min.

•

Inject the radiopharmaceutical (

201

Tl- thallous chloride,

99m

Tc- sestamibi,

99m

Tc- tetrofosmin) at peak stress.

• Tomographic imaging immediately (

201

Tl) or 15– 60min post- injection

(

99m

Tc compounds). Images generally acquired with ECG gating.

MYOCARDIAL PERFUSION IMAGING

907

Reststudy

•

Second

99m

Tc radiopharmaceutical injection under resting conditions.

•

Tomographic imaging as before.

• With

201

Tl, second injection not necessary, since tracer redistributes into

ischaemic areas over 4h, but top- up dose sometimesgiven.

Results

Myocardial uptake reects radiopharmaceutical delivery and myocyte func-

tion (see Fig. 14.24).

Interpretation

Infarction causes matched perfusion defects during stress and rest.

Inducible ischaemia creates a perfusion defect at stress, which reperfuses at

rest=reversible ischaemia (see Fig. 14.25). The severity, extent, and num-

ber of reversible defects are prognostically signicant. Anormal MPI study

implies risk of an adverse cardiac event of <0.5% perannum.

Advantages

Non- invasive; relatively inexpensive, compared with angiography.

tseRssertS

Short axis

Vertical

long axis

Horizontal

long axis

Fig.14.24 Normal myocardial perfusion scan. (E Colour plate9.)

908

CHAPTER14 Nuclear medicine

908

Pitfalls

Less sensitive in multiple small- vessel coronary disease, e.g. DM. Sensitivity

depends on stress test quality.

Further reading

Marcassa C, Bar JJ, Bengel F, etal. Clinical value, cost- eectiveness, and safety of myocardial perfusion

scintigraphy:a position statement. Eur Heart J 2008; 29:557– 63.

Verberne HJ, Acampa W, Anagnostopoulos C, etal. EANM procedural guidelines for radionuclide

myocardial perfusion imaging with SPECT and SPECT/ CT: 2015 revision. Eur J Nucl Med Mol

Imaging 2015; 42

:1929– 40.

(a)

(b)

Fig.14.25 Myocardial perfusion scan:(a)in xed perfusion loss (anterolateral

infarction) and (b)in inferior stress- induced (reversible) ischaemia. (E Colour

plate10.)

MYOCARDIAL PERFUSION IMAGING

909

910

CHAPTER14 Nuclear medicine

910

Radionuclide

ventriculography:MUGAscan

Background

Increasingly replaced by TTE, TOE, and contrast ventriculography at time

of cardiac catheterization. Multigated radionuclide angiography (MUGA)

scans are less operator- dependent than either TTE or TOE, which is impor-

tant in serial assessment. The cardiac blood pool is imaged dynamically after

injection of radiolabelled RBCs. Wall motion, synchronicity of ventricular

contraction, and EF are measured (see Fig. 14.26). The estimated EF unreli-

able in presence of dysrhythmias— acquisition requires a relatively regular

heartrate.

Indications

• LVEF measurement, e.g. unechogenic patients (see Fig. 14.27).

• Monitor anthracycline cardiotoxicity.

Patient preparation

None.

Procedure

Radiolabel red cells (in vivo or in vitro) using

99m

Tc- pertechnetate. Image the

patient supine in anterior and left anterior oblique projections. Camera

acquisition gated to cardiac cycle. Imaging may be combined with low-

impact exercise/ pharmacological stress to assess cardiac reserve.

Frame

100

161284

Volume curve

Norm counts

Fig.14.26 Computer- generated EF of40%.

RADIONUCLIDE VENTRICULOGRAPHY:MUGASCAN

911

Results

Visual image of 300– 400 summated cardiac cycles. Computer- generated

images used to assess regional wall motion and synchronous contraction

(see Fig. 14.27). Computer- generated EF calculation. Normal EF 60– 70%,

d withage.

Interpretation

To monitor treatment response in cardiac failure, cardiomyopathy.

Advantages

Good for serial measurements during anthracycline chemotherapy. Reliable

in unechogenic subjects.

Disadvantage

Moderately high radiation dose:echocardiography preferable in most patients.

Pitfalls

Cardiac dysrhythmias interfere with gating, e.g.AF.

Further reading

Hesse B, Lindhardt TB, Acampa W, etal. EANM/ ESC guidelines for radionuclide imaging of cardiac

function. Eur J Nucl Med Mol Imaging 2008; 35:851– 85.

(a) (b)

(c)

(d)

Fig.14.27 MUGA scan showing (a)LV regions of interest at end- diastole and

(b)end- systole for EF calculation; (c)amplitude image showing relative anteroseptal

hypokinesis, but (d)synchronous LV contraction. (E Colour plate11.)

912

CHAPTER14 Nuclear medicine

912

Radionuclide ﬁrst- pass cardiac studies

Background

Nuclear medicine can assess simple shunts, e.g. left- to- right shunts (ven-

tricular and atrial septal defects), but has no place in bidirectional shunting

or multiple sources of pulmonary blood ow (e.g. patent ductus arterio-

sus). First- pass studies quantify shunt severity both pre- and post- surgical

correction. Complementary to cardiac catheterization and Doppler colour

ow echocardiography. Dynamic imaging of a small bolus of IV radioactivity,

usually

99m

Tc- DTPA, outlines the cardiac venous return, pulmonary circula-

tion, left heart, and systemic circulation. Largely superseded by angiography

andMRI.

Indications

Measurement of simple left- to- right cardiac shunts.

Patient preparation

None.

Procedure

•

99m

Tc- DTPA administered IV as a bolus into a right antecubital vein with

the shoulder abducted.

•

Image immediately as a dynamic acquisition over60s.

Results

Normal circulation will demonstrate sequential appearance of the right

heart, pulmonary outow tract, lungs, left heart, andaorta.

Interpretation

Variation in the normal sequence implies cardiac shunting. Interpretation

must be performed in conjunction with denitive knowledge of the patient’s

anatomy, e.g. echocardiography with Doppler colourow.

Advantages

Relatively non- invasive technique for serial follow- up of congenital heart

disease. Mathematical analysis of the data allows quantication of shunt size

and is important for consideration and timing of corrective surgery.

RADIONUCLIDE FIRST-PASS CARDIAC STUDIES

913

914

CHAPTER14 Nuclear medicine

914

Lung scan:ventilation/ perfusion imaging

Background

One of the most widely requested nuclear medicine studies. Sensitivity and

specicity reduced in coexisting lung disease, when CTPA is more useful. All

patients should have had a chest radiograph within 24h to aid V/ Q inter-

pretation and exclude other causes of pleuritic chest pain and hypoxia, e.g.

pneumothorax.

Lung perfusion shown by injection of

99m

Tc particles which are trapped

by the pulmonary capillary bed. Ventilation shown using radiolabelled gases

or aerosols.

Indications

• Suspectedpulmonary embolism (PE).

• Preoperative lung function assessment.

Patient preparation

None. Relative contraindication in right- to- left intra- cardiac shunts; caution

in severe pulmonary hypertension.

Procedure

• Lie the patient supine and inject

99m

Tc- macroaggregated albumin

(MAA)IV.

•

Obtain gamma camera perfusion images in fourviews.

• Ventilation images are obtained in same projections by continuous

breathing of

81m

Kr gas or using

99m

Tc aerosol or

133

xenongas.

Results

Homogeneous, matched V/ Q patterns (see Fig. 14.28).

Interpretation

Four abnormal patterns recognized:

•

Segmental perfusion loss with preserved ventilation:PE (see Fig. 14.29).

•

Segmental matched perfusion and ventilation loss:pulmonary infarction/

infection.

•

Segmental/ subsegmental ventilation loss with preserved perfusion:infection.

•

Non- segmental, patchy, matched perfusion, and ventilation loss:COPD (see

Fig. 14.29).

Advantages

Quick, non- invasive. Normal scan virtually excludesPE.

Pitfalls

Specicity reduced in underlying lung disease— COPD, asthma giving inde-

terminate results. False +ves with tumour, bullae, vasculitides, brotic lung

disease, and old unresolvedPE.

LUNG SCAN:VENTILATION/PERFUSION IMAGING

915

Perfusion Ventilation

Right posterior

oblique

Left posterior

oblique

(b)

Perfusion Ventilation

Posterior

(a)

Fig.14.28 Normal lung V/ Q images:(a)anterior and posterior views;

(b)obliqueviews.

916

CHAPTER14 Nuclear medicine

916

Further reading

Bajc M, Neilly JB, Miniati M, etal. EANM guidelines for ventilation/ perfusion scintigraphy:Part 1.

Pulmonary imaging with ventilation/ perfusion single photon emission tomography. Eur J Nucl Med

Mol Imaging 2009; 36

:1356– 70.

(a)

(b)

Posterior perfusion

Posterior ventilation

Fig.14.29 Lung scans:(a)showing matched, non- segmental V/ Q defects in

COPD; and (b)showing segmental V/ Q mismatch– – extensive bilateral pulmonary

thromboembolism and unmatched perfusionloss.

LUNG SCAN:VENTILATION/PERFUSION IMAGING

917

918

CHAPTER14 Nuclear medicine

918

Lung shunt studies

Background

Largely research procedure.

Indications

Suspected pulmonary AV shunting.

Patient preparation

None.

Procedure

Inject

99m

Tc- MAA IV; consider manoeuvres to reduce particle number.

gamma camera lung, abdomen, and head imaging. Calculate relative uptake

in lungs, kidneys, and brain. Express as fraction of cardiac output to quantify

shunt fraction.

Results

Kidneys and brain not normally visible on lung perfusion imaging.

Interpretation

Abnormal extrapulmonary activity implies degree of shunting. Intensity of

uptake rises with shunt severity (see Fig. 14.30).

Advantages

Non- invasive, quantitative. Can be used to monitor response to

intervention.

Pitfalls

Injection extravasation invalidates shunt calculation.

LUNG SHUNT STUDIES

919

Fig.14.30 Lung shunt study showing extrapulmonary activity in the brain and

kidneys.

920

CHAPTER14 Nuclear medicine

920

Lung permeability studies

Background

Altered alveolar permeability aects gas exchange. Also shown by lung

transfer factor measurement.

Indications

• PCP infection:rapid screening in high- risk patients with normalCXR.

• Monitor treatment response inCFA.

Patient preparation

None.

Procedure

Patient breathes

99m

Tc- DTPA aerosol. Gamma camera images of the thorax

over 1h. Computer data analysis generates lung clearance curves, reecting

the integrity of the alveolar cell barrier.

Results

Clearance curves used to calculate the permeability index. Individual results,

compared with centre- dened normalrange.

Interpretation

Accelerated clearance in PCP, which d with successful treatment.

Advantages

Non- invasive. Allows rapid PCP diagnosis.

Pitfalls

Non- specic, e.g. accelerated clearance in smokers.

LUNG PERMEABILITY STUDIES

921

922

CHAPTER14 Nuclear medicine

922

Lymphoscintigraphy

Background

Lymphoedema can be congenital or acquired. The lymphatic system nor-

mally drains subcutaneous tissues l local lymphatic channels and regional

nodes. Lymphatic channels can be imaged using radiolabelled colloid parti-

cles (E Sentinel node imaging, p. 890).

Indication

Unexplained limb swelling, e.g. lymphatic hypoplasia.

Patient preparation

None.

Procedure

99m

Tc- nanocolloid injection SC into a nger or toe web space on the aected

and contralateral limbs. Regional gamma camera imaging at 10min intervals

over1h.

Results

Normally rapid clearance via lymphatic channels to regional nodes (see

Fig. 14.31a).

Interpretation

Slow clearance and failed regional node uptake in hypoplastic systems or

metastatic regional node inltration, dermal backow (see Fig. 14.31b),

depending on clinical context.

Advantages

Much easier than conventional (contrast) lymphography— avoids lymphatic

channel cannulation.

Pitfalls

Lymphatic drainage may be disrupted by surgery or radiotherapy.

LYMPHOSCINTIGRAPHY

923

(a)

(b)

Fig.14.31 (a)Normal lymphoscintograms. (b)Abnormal study: bilateral dermal

backow with non-visualization of lymphatic channels and lymph nodes.

924

CHAPTER14 Nuclear medicine

924

Static cortical scintigraphy:

dimercaptosuccinic acid imaging (DMSA)

Background

DMSA is concentrated by the proximal convoluted tubules in the renal cor-

tex.

99m

Tc- DMSA provides good denition of functioning renal parenchyma.

It should be used in conjunction with anatomical imaging, e.g. ultrasonogra-

phy, to dierentiate between scarring, cysts, or calculi.

Indications

• UTI:‘gold standard’ for renal scarring.

• Measurement of relative renal function.

• Renal duplication assessment.

• Ectopic kidney localization.

• Renal trauma.

• Renal vein thrombosis.

• Pre- biopsy.

Patient preparation

None, but avoid dehydration.

Procedure

99m

Tc- DMSA injected IV. Static anterior, posterior, and posterior oblique

images acquired 2– 4hlater.

Results

Visual image evaluation, assessing the integrity of cortical outlines for

scarring (see Fig. 14.32a). Quantitative computer image analysis is used

to measure relative renal function, i.e. the contribution of each kidney to

overallGFR.

Interpretation

Cortical scars distort the renal outline (see Fig. 14.32b). Duplication may

result in a non- functioning upper moiety, usually due to obstruction, or a

scarred lower moiety, 2° to vesico- ureteric reux. Relative renal function

is usually 50:50±5%.

Advantages

Sensitive for renal scarring. Superior to US. Non- invasive.

Pitfalls

False +ves during or immediately after acute pyelonephritis. May give corti-

cal defects that do not progress to scarring. Splenic impression at the left

upper pole may be mistaken for scarring.

STATIC CORTICAL RENOGRAPHY

925

roiretsoProiretnA

Right post oblique

Left post oblique

(a)

Right post oblique Left post oblique

(b)

Fig.14.32 DMSA static scan:(a)normal and (b)showing extensive left kidney

cortical scarring.

926

CHAPTER14 Nuclear medicine

926

Dynamic renography

Background

Nuclear medicine oers unique ‘real- time’ imaging of renal function, i.e.

visualization of uptake, drainage, and bladder emptying. Available radiop-

harmaceuticals include:

•

99m

Tc-diethylenetriaminepentacetic acid (DTPA), cleared by glomerular

ltration.

•

99m

Tc- mercaptoacetyltriglycine (MAG3), cleared by glomerular ltration

and tubular secretion.

•

99m

Tc- ethylenedicysteine (EC), cleared by glomerular ltration and

tubular secretion.

Tubular agents preferred, particularly in the presence of renal impairment

and in the immature kidney.

99m

Tc- DTPA reserved for assessment of ATN,

post- transplant viability,etc.

Indications

• Assessment of renal drainage:discrimination between renal dilatation and

outow obstruction.

•

Measurement of relative renal function.

• Loinpain.

• Post- pyeloplasty follow- up.

• RAS (E Captopril renography, p. 928).

Patient preparation

Good hydration essential. Empty the bladder immediately before undertak-

ing thestudy.

Procedure

• Position the patient supine or seated erect, with the camera behind.

• Obtain good peripheral venous access. Bolus IV radiopharmaceutical

injection

99m

Tc- MAG3 or

99m

Tc- DTPA, followed by 10– 20mL of

salineush.

•

Image immediately, acquiring real- time dynamic data for 20– 30min.

• Diuretic administration is essential to distinguish dilatation from outow

obstruction.

•

Post- voiding images are always required to assess the completeness of

bladder emptying and may improve drainage of the upper renal tracts in

high- pressure systems.

Results

Visual inspection of renal size, perfusion, function, and drainage (see

Fig. 14.33a). Quantitative computer image analysis measures relative func-

tion and transit times, and generates drainage graphs.

Interpretation

Uptake and excretion of activity normally rapid. Dilated systems show pro-

gressive pooling in the renal pelvis that empties following diuretic challenge.

Obstructed systems show progressive tracer accumulation with no diuretic

response, often associated with reduced function on the aected side (see

Fig. 14.33b).

DYNAMIC RENOGRAPHY

927

Advantages

Sensitive, non- invasive, quantitative renal function assessment. Anatomical

imaging, e.g. IVU, better for renal morphology, stones,etc.

Pitfalls

Movement artefact, chronic renal failure, and dehydration reduce data reli-

ability. Renal drainage may be gravity- dependent— always complete the

study with an erect image. Drainage curves invalidated by radiopharmaceu-

tical extravasation.

20min5min

20min

60min

(b)

(a)

Fig.14.33 Dynamic renogram posterior images:(a)normal, showing an early

parenchymal image and later symmetrical excretion with bladder lling; (b)outow

obstruction:early image shows left hydronephrosis 2° to pelviureteric junction

obstruction, with poor drainage at60min.

928

CHAPTER14 Nuclear medicine

928

Captopril renography

Background

RAS is a rare (<2%) cause of hypertension. Suspected in young adults

presenting with hypertension, usually due to bromuscular dysplasia. In

patients >50years, the commonest cause is atherosclerosis. Perfusion pres-

sure is maintained by angiotensin II in RAS. Captopril is an ACE inhibitor,

which blocks the conversion of angiotensin Ito angiotensin II. Captopril

reduces perfusion pressure, leading to a fall in the relative function and

delayed tracer uptake on the aected side. Captopril administration is con-

traindicated in the presence of a solitary kidney.

Indications

Diagnosis of RAS (especially bromuscular dysplasia) and prediction of

response to revascularization.

Patient preparation

Well- hydrated. Baseline BP. IV access. Stop ACE inhibitors for 48h prior

to thetest.

Procedure

• Perform standard dynamic renogram using

99m

Tc- MAG3.

• Repeat renogram 1h after captopril 25mg single dosePO.

• Monitor BP— beware hypotension.

Results

Quantitative evaluation of R:L renal function and time to peak activity in

each kidney.

Interpretation

RAS due to bromuscular dysplasia— fall in relative renal function and

delayed time to peak renal activity of >10min.

Advantages

Distinguishes generalized atherosclerosis (often poor BP outcome following

angioplasty) from bromuscular hyperplasia (good angioplasty response).

Pitfalls

• d reliability in the presence of renal impairment.

•

Severe hypotension.

CAPTOPRIL RENOGRAPHY

929

930

CHAPTER14 Nuclear medicine

930

Gastrointestinal bleeding:labelled red

cell imaging

Background

The source of GI blood loss is usually identied by GI endoscopy but may

be dicult to localize. Labelled red cell studies are useful when there is

evidence of ongoing bleeding (typically falling Hb of 1g/ L/ day). The patient

must be actively bleeding at the time of the study. This is a time- consuming

investigation, with serial imaging beyond 24h often performed.

Indications

Localize source of active GI haemorrhage when other techniques

(e.g. endoscopy or angiography) have failed.

Patient preparation

No recent contrast barium studies. Fasting during rst 2h of imaging.

Procedure

Label red cells (in vitro or in vivo) using

99m

Tc- pertechnetate. Abdominal

gamma camera blood pool imaging immediately and at intervals for up to

36h post- injection or until the bleeding source is identied.

Results

Activity normally restricted to vascular compartment.

Interpretation

Any activity in the gut lumen implies active haemorrhage. Serial images help-

ful (see Fig. 14.34).

Advantages

More sensitive and less invasive than angiography for intermittent bleeding.

Pitfalls

• Poor red cell label:degrades image quality, could lead to false+ve.

•

Limits of detection:0.5mL/ min bloodloss.

GASTROINTESTINAL BLEEDING:LABELLED RED CELL IMAGING

931

30min

Fig.14.34 Anterior abdominal images showing increasing red cell haemorrhage into

the distalileum.

932

CHAPTER14 Nuclear medicine

932

Gastric emptying studies

Background

The diagnosis of dysfunctional gastric emptying can be dicult. In children,

delayed gastric emptying may contribute to gastro- oesophageal reux. In

adults, both gastric stasis and ‘dumping’ syndromes occur, sometimes fol-

lowing previous surgery. Imaging following ingestion of radiolabelled solids

or liquids demonstrates the timing and pattern of gastric emptying.

Indications

Altered GI motility— delayed or accelerated gastric emptying.

Patient preparation

Fast for 4h. Stop drugs likely to inuence GI motility, e.g. domperidone,

metoclopramide.

Procedure

Milkstudy

•

Give radiolabelled (

99m

Tc- DTPA) milk drinkPO.

• Image the anterior abdomen immediately and at 10min intervals for 1h.

Generate computer- derived clearance curves to calculate the emptying

half- time.

• Delayed thoracic image helpful to exclude lung aspiration if clearance

signicantly delayed.

Dual isotopemethod

•

Give

99m

Tc- labelled standard meal (e.g. porridge, egg) with

111

In- DTPA

inwater.

•

Anterior abdomen gamma camera imaging as before using dual isotope

settings.

•

Generate solid and liquid phase clearance curves.

Results

Normal gastric emptying half- time (milk = 20min). Normal range for

solids is centre- specic, depending on the standard meal composition (see

Fig. 14.35a andb).

Interpretation

Visual image evaluation and half- time calculation.

Advantages

Non- invasive and quantitative.

Pitfalls

Vomiting during study invalidates emptying time calculations.

GASTRIC EMPTYING STUDIES

933

Counts

8,000

6,000

4,000

2,000

0102030

Time-Minutes

Time Activity Curve

40 50 60

100

(%)

Stomach: Exp: y

a: 8797

b: −0.0228634

(a)

Counts

10,000

8,000

2,000

0102030

Time-Minutes

Time Activity Curve

40 50 60

100

(%)

6,000

4,000

(b)

Stomach: Exp: y

a: 11205

b: −0.000490928

Fig.14.35 (a)Normal gastric emptying study:anterior images showing clearance of

99m

Tc- labelled semi- solid meal into the proximal small intestine; (b)abnormal gastric

emptying study:anterior images showing poor clearance of

99m

Tc- labelled semi- solid

meal into the proximal small intestine.

934

CHAPTER14 Nuclear medicine

934

SeHCAT studies

Background

The SeHCAT test is an important test for diagnosing bile acid malabsorp-

tion. SeHCAT is a taurine- conjugated bile acid analogue and it is incorpo-

rated with

Se (gamma- emitter) into the SeHCAT molecule (radiotracer)

to assess in vivo the enterohepatic circulation of bile salts. The retention of

radiotracer in the body is evaluated using a conventional gamma camera.

Indications

• Chronic diarrhoea.

• Diarrhoea- predominantIBS.

• Crohn’s disease.

• Ileal resection, cholecystectomy, radiation- induced bowel damage, or

ulcerative colitis.

Patient preparation

Colestyramine and colesevelam should be stopped for 3days prior toscan.

Procedure

A capsule containing radiolabelled SeHCAT (370kBq) capsule is taken PO

with water, and a scan is performed to measure SeHCAT activity at 1– 3h.

Patients will return on day 7 to undergo a second scan to measure the per-

centage of SeHCAT retention.

Results

The percentage of SeHCAT retention gives an indication as to whether the

patient has bile acid malabsorption ornot.

Interpretation

Retention values of <15% are considered abnormal and are suggestive of

bile acid malabsorption (<5%, severe bile acid malabsorption; 5– 10%, mod-

erate; and 10– 15%, mild). Retention values of >15% are normal.

Advantages

Easy to perform and well tolerated.

Further reading

Boyd GS, Merrick MV, Monks R, Thomas IL. Se- 75- labeled bile acid analogs, new radiopharmaceuti-

cals for investigating the enterohepatic circulation. J Nucl Med 1981; 22

:720– 5.

Jazrawi RP, Ferraris R, Bridges C, Northeld TC. Kinetics for the synthetic bile acid 75selenoho-

mocholic acid- taurine in humans: comparison with [14C]taurocholate. Gastroenterology 1988;

:164– 9.

935

SeHCAT STUDIES

936

CHAPTER14 Nuclear medicine

936

Meckel’s scan:ectopic gastric mucosa

localization

Background

Meckel’s diverticulum is the commonest congenital anomaly of the GIT,

occurring in 72% of the population. Less than 10% contain ectopic gastric

mucosa which may bleed, but diverticuli can also cause obstruction or

become inamed. Typically, childhood presentation. Nuclear medicine pro-

vides a straightforward imaging technique that targets gastric mucosal cells,

which normally take up

99m

Tc- pertechnetate.

Indications

Unexplained abdominal pain or GI haemorrhage— after endoscopy/ con-

trast radiology.

Patient preparation

• Fast for4h.

• H

antagonist administration may improve specicity.

•

No recent barium studies.

Procedure

Inject

99m

Tc- pertechnetate IV. Immediate and serial abdominal imaging

over1h.

Results

Normal uptake in gastric mucosa.

Interpretation

Focal abnormal uptake appearing at the same time as the stomach implies

ectopic gastric mucosa (Meckel’s diverticulum) (see Fig.14.36), or occasion-

ally a duplication cyst. Commonest site— right iliac fossa(RIF).

Advantages

Non- invasive.

Pitfalls

False +ves due to activity in the renal tract— lateral images usuallyhelp.

MECKEL’S SCAN:ECTOPIC GASTRIC MUCOSA LOCALIZATION

937

Fig.14.36 Ectopic gastric mucosa in the right iliac fossa towards the midline

(arrow).

938

CHAPTER14 Nuclear medicine

938

Hepatobiliary scintigraphy

Background

Iminodiacetic acid (IDA) compounds are cleared from the circulation by

hepatocytes and secreted into the bile in the same way as bilirubin.

99m

Tc-

labelled IDA compounds show biliary excretion through the biliary tree and

gall bladder l

duodenum. Useful in acute/ chronic acalculous cholecystitis

and to diagnose biliary atresia.

Indications

• Acute cholecystitis.

• Trauma.

• Post- operative leak detection.

• Bile duct/ stent patency.

• Gall bladder emptying.

• Bile reux.

• Neonatal biliary atresia.

Patient preparation

• Adults:fast for6h.

•

Neonates:phenobarbital 5mg/ kg/ day PO for 3days prior to study

(enzyme induction).

Procedure

• Adults:IV injection of

99m

Tc- labelled IDA complex (mebrofenin). Gamma

camera imaging over1h.

•

Neonates:IV injection of

99m

Tc- IDA. Immediate dynamic imaging for

5min, then serial static images for up to 24h or until activity reaches the

small bowellumen.

Results

Gall bladder and biliary tree normally shown with tracer excretion via the

CBD into the duodenum by 30min post- injection. Cholecystokinin 0.5U/

kg IV sometimes administered to stimulate gall bladder emptying (see Fig.

14.37a)

Interpretation

• Acute cholecystitis:absent gall bladder.

•

Obstruction, leak, or reux assessed visually (see Fig. 14.37b).

• Neonates:passage of activity into the gut lumen excludes biliary atresia.

•

Quantication of T0 to T10 min images improves specicity for atresia

diagnosis.

Advantages

Non- invasive. Straightforward pattern recognition.

Pitfalls

Delayed IDA excretion in severe jaundice:bilirubin >300µmol/ L.

HEPATOBILIARY SCINTIGRAPHY

939

(a)

(b)

Fig.14.37 (a)Normal hepatobiliary scan; (b)hepatobiliary scan showing leak post-

laparoscopic cholecystectomy.

940

CHAPTER14 Nuclear medicine

940

Splenunculus detection:heat- damaged

red cell imaging

Background

Splenectomy may be indicated in haemolytic syndromes and in refractory

haemorrhagic tendencies (e.g. ITP) if associated with hypersplenic throm-

bocytopenia. Remnant splenic tissue, or ‘splenunculi’, can give rise to recur-

rent thrombocytopenia— dicult to detect on anatomical imaging. As the

spleen removes abnormal red cells from the circulating blood pool, radiola-

belled heat- damaged red cells can be used to localize ectopic splenic tissue.

Indications

Recurrent thrombocytopenia post- splenectomy.

Patient preparation

None.

Procedure

• Obtain a venous blood sample.

• Radiolabel red cells in vitro using

99m

Tc- pertechnetate.

• Heat to 49.5°C for 20– 30min.

• Cool and re- injectIV.

• Image the anterior abdomen 30minlater.

Results and interpretation

Damaged red cells taken up by splenic remnants (see Fig. 14.38).

Advantages

Investigation of choice for splenunculus detection.

Pitfalls

Enlarged left lobe of the liver may obscure a small splenic remnant.

PosteriorAnterior

Fig.14.38 Post- splenectomy. Intense uptake in a splenunculus lying in the

splenicbed (arrow).

SPLENUNCULUS DETECTION:HEAT-DAMAGED RED CELL IMAGING

941

942

CHAPTER14 Nuclear medicine

942

Hepatosplenic scintigraphy

Background

Largely superseded by ultrasonography and cross- sectional imaging. Maps

reticuloendothelial tissue within the liver (Kuper cells) and spleen, to iden-

tify SOLs and conrm the presence or absence of functioning splenic tissue.

Indications

Liver SOLs— now largely replaced by US, CT, orMRI.

Patient preparation

None.

Procedure

99m

Tc- colloid injected IV. Abdominal gamma camera images 30min

post- injection.

Results

Normal, homogeneous liver and spleen uptake (see Fig. 14.39).

Interpretation

Focal d uptake in SOLs. i spleen and bone activity in portal hyperten-

sion. Focal i

uptake in the caudate lobe pathognomonic of Budd– Chiari

syndrome.

Advantages

Cheap.

Pitfalls

Non- specic. Largely superseded by anatomical imaging.

HEPATOSPLENIC SCINTIGRAPHY

943

Fig.14.39 Normal hepatosplenicstudy.

944

CHAPTER14 Nuclear medicine

944

Labelled leucocyte imaging

Background

Localization and assessment of acute or chronic infection/ inammation can

be dicult. Nuclear medicine techniques show inammation but do not

dierentiate infective from non- infective causes. Radiolabelled autologous

leucocytes are injected and imaged. The normal distribution includes the

liver and spleen, making peri- diaphragmatic collections dicult to identify.

Delayed imaging useful in chronic low- grade infection, e.g. osteomyelitis,

where cell migration to the site of inammation isslow.

Indications

• Sepsis localization.

• IBD to determine disease activity, extent, severity.

Patient preparation

None. Avoid recent barium contrast radiology.

Procedure

• Obtain 40– 60mL of blood sample.

• Separate the white cell layer, and radiolabel in vitro using

99m

Tc-

exametazime (HMPAO) or

111

In- oxine.

• Re- inject labelled cellsIV.

• Image 1 and 3h later (IBD), or 2, 4, and 24h for intra- abdominal sepsis/

osteomyelitis.

Results

Physiological uptake in the RES. Variable GI and renal excretion, depending

on the radiopharmaceutical used (see Fig. 14.40a).

Interpretation

Focal i uptake indicates sepsis. Diuse i gut uptake reects the extent and

activity of IBD (see Fig. 14.40b).

(b)

(a)

Fig.14.40 Labelled leucocyte imaging:(a)normal, and (b)acute inammatory

bowel disease— intense uptake in small and large bowel loops (Crohn’s disease).

LABELLED LEUCOCYTE IMAGING

945

Advantages

Very sensitive in IBD. Non- invasive, useful in sick patients, e.g. acute

exacerbation ofIBD.

Pitfalls

• False −ves:leucopenia and poor white cell label, perihepatic and

perisplenic collections obscured by normal liver and spleen uptake.

•

False +ves:physiological gut and renal activity.

•

Damaged white cells during labelling causing lung sequestration.

•

99m

Tc- exametazime (HMPAO) preferred for routine imaging and IBD—

lower radiation dose and earlier result than

111

In- oxinelabel.

• Reserve

111

In- oxine for low- grade bone sepsis localization.

• Requires aseptic facilities and trained personnel.

• Risk to sta (blood handling) and patient (contamination, re- injection

into wrong patient).

946

CHAPTER14 Nuclear medicine

946

Gallium scintigraphy

Background

Previously used to diagnose and monitor sarcoid and lymphoma, but

increasingly superseded by

F- FDG PET (E Labelled leucocyte imaging,

pp. 944–5) and cross- sectional imaging. Sometimes useful in ‘pyrexia of

unknown origin’ (PUO), e.g. immunocompromised patient where there is

a suspicion of Pneumocystis jiroveci infection (cf. lung permeability studies).

Indications

• PUO and infection localization, especially inAIDS.

• Lymphoma follow- up.

• Sarcoidosis follow- up.

Patient preparation

None.

Procedure

• Inject

Ga- citrate IV. Gamma camera imaging at 48– 96h with tomography.

• Non- specic gut retention reduced by laxative administration.

Results

Normal uptake in lacrimal glands, nasal mucosa, blood pool, liver, spleen,

testes, ♀ perineum, breast (see Fig. 14.41a).

Interpretation

• Focal lymph node uptake in lymphoma and sarcoid distinguishes active

disease from post- therapy scarring/ brosis (see Fig. 14.41b).

• In AIDS, i lung uptake indicates infection— PCP, CMV,

mycobacterium— chest radiograph correlation essential.

• i activity in IBD and focal sepsis; largely superseded by WBC imaging.

Advantages

Excellent, non- invasive marker of disease activity in lymphoma— but likely

to be superseded by

F- FDG.

Pitfalls

Poor specicity. High radiation dose often dicult to justify when alternative

techniques available. Prolonged test (48– 96h).

947

GALLIUM SCINTIGRAPHY

(a)

(b)

Fig.14.41 (a)Normal

Ga scan; (b)abnormal tracer uptake in the lacrimal glands,

parotid glands, mediastinum, and lungs, in keeping with known sarcoidosis.

948

CHAPTER14 Nuclear medicine

948

Dacroscintigraphy

Background

Epiphora may arise from excessive tear production or inadequate drainage

due to lower lid ectropion or nasolacrimal obstruction, i.e. nasal puncti, lac-

rimal sac, nasolacrimal ducts. Straightforward technique to assess function

of the nasolacrimal apparatus.

Indications

Epiphora.

Patient preparation

None.

Procedure

One to two drops of

99m

Tc- labelled DTPA or pertechnetate instilled into the

outer canthus of each eye. Immediate dynamic gamma camera imaging for

20min, with delayed static scans as required.

Results

Normal rapid radiopharmaceutical clearance through the nasolacrimal

apparatus.

Interpretation

Delayed clearance implies obstruction— level of dysfunction usually identi-

ed, i.e. punctum, lacrimal sac, nasolacrimal duct (see Fig. 14.42a andb).

Righ

eft

Fig.14.42 Dacroscintigram (lacrimal drainage) showing normal lacrimal drainage on

the right, and on the left obstructed drainage at the proximal nasolacrimalduct.

DACROSCINTIGRAPHY

949

Advantages

Non- invasive. Avoids nasolacrimal duct cannulation (cf. dacrocystography).

Pitfalls

Obstructed systems result in excess radiolabelled tears on the cheek, alter-

ing drainagetimes.

950

CHAPTER14 Nuclear medicine

950

Salivary gland scintigraphy

Background

99m

Tc- pertechnetate uptake in the salivary glands reects intact parenchyma.

Salivary gland scintigraphy demonstrates both parenchymal function and

excretory function. Salivary gland scintigraphy is a safe and sensitive tech-

nique to assess the function and morphology of salivary glands.

Indications

• Sjögren’s syndrome.

• Chronic sialadenitis.

• Post- multiple radioiodine therapies.

• Irradiation of the head andneck.

Patient preparation

None.

Procedure

After IV injection of

99m

Tc- pertechnetate, dynamic scintigraphy is performed

for 15– 20min, and a sialagogue (e.g. lemon juice) stimulation is delivered

and imaging is continued for further 15– 20min to access excretory function.

Time– activity curves for the four major salivary glands are generated.

Results

Normal uptake of radiopharmaceutical in parotids and submandibular

glands, with spontaneous excretion following lemon juice stimulation.

Interpretation

Delayed or reduced tracer uptake or accumulation and would be compat-

ible with salivary gland dysfunction usually identied (see Fig. 14.43).

Advantages

Easy to perform, reproducible, and well tolerated.

SALIVARY GLAND SCINTIGRAPHY

951

Fig.14.43 The left parotid and submandibular glands show prompt tracer uptake

and excretion. The right parotid gland shows poor uptake and function (arrow).

952

CHAPTER14 Nuclear medicine

952

Glomerular ﬁltration rate measurement

Background

In many instances, GFR estimation from CrC is adequate, but accurate

measurement is essential in renal impairment or to monitor nephrotoxic

drug therapy. Glomerular compensation prevents early renal damage

detection by CrC measurements— 60% of ltration activity can be lost

before CrCfalls.

Indications

Accurate GFR to monitor renal failure, cytotoxic chemotherapy, immuno-

suppression, e.g. ciclosporin.

Patient preparation

Well hydrated.

Procedure

• IV injection of

Cr- EDTA or

99m

Tc- DTPA.

• Venous sampling 2 and 4hlater.

• Count plasma sample radioactivity and known standards in gamma

counter. Correct for height and weight.

Results

Normal GFR=125mL/ min (age- dependent).

Interpretation

d values in chronic renal failure.

Advantages

More reliable and reproducible than CrC— avoids need for urine collection.

Pitfalls

Accuracy depends on accurate measurement of dose and good injection

technique— avoid any extravasation. Unreliable results in severe peripheral

oedema.

UREA BREATHTEST

953

Urea breathtest

Background

Helicobacter pylori infection is associated with duodenal ulceration.

Eradication therapy reduces ulcer recurrence. H. pylori produces urease

which converts labelled urea l labelled CO

, detected in breath samples.

Indications

H.pylori detection— diagnosis and conrmation of eradication.

Patient preparation

Stop antibiotics, H

antagonists, proton pump inhibitors for 2– 4weeks.

Procedure

• Patient swallows urea drink labelled with

C (stable isotope) or

(radioactive isotope).

•

Breath samples (CO

) collected over next30min.

•

Labelled CO

measured by mass spectroscopy (

C) or liquid scintillation

counting(

C).

Results

Normal range varies according to local protocol.

Interpretation

i exhaled CO

levels imply abnormal urea breakdown by urease- producing

bacteria in the stomach, e.g. H.pylori.

Advantages

• Very sensitive marker of active H.pylori infection (cf. serology).

•

Non- invasive (cf. endoscopy) and avoids sampling errors.

• Good for non- invasive monitoring of recurrent symptoms.

Pitfalls

Occasional false +ves in oral H.pylori infection.

954

CHAPTER14 Nuclear medicine

954

Red cell survival studies

Background

Although infrequently performed, provides evidence of abnormal red cell

survival and localizes sites of red cell destruction. The investigation is pro-

longed, with initial in vitro red cell labelling and daily activity measurements

over target organs— spleen, liver, and heart— for 14days.

Indications

• Haemolytic anaemia (to conrm d RBC survival, i.e. active haemolysis).

•

Localize abnormal red cell sequestration.

• Predict response to splenectomy.

Patient preparation

None. Avoid blood transfusion duringstudy.

Procedure

• Obtain a venous blood sample, and label the patient’s red cells with

Cr- chromate.

• Re- inject cells and measure blood activity over 14days using gamma

counter.

•

Measure activity over the liver, spleen, and heart using gamma probe

daily for 14days.

Results

• Normal red cell half- life >24days.

• Equal fall in the heart, liver, and spleen counts withtime.

Interpretation

Short red cell life conrms abnormal destruction. Ratio of counts in

liver:spleen indicates the site of red cell destruction.

Advantages

Only available technique.

Pitfalls

Lengthy and labour- intensive. Sensitivity reduced by blood transfusion dur-

ing 14days’ measurement period. Consistent probe positioning essential for

accurate organ sequestration curves.

RED CELL VOLUME/PLASMA VOLUME MEASUREMENT

955

Red cell volume/ plasma volume

measurement

Background

Polycythaemia is suspected when Hb and Hct are raised. Routine labora-

tory screening does not dierentiate true polycythaemia, i.e. elevated red

cell mass, from apparent, stress, or pseudo- polycythaemia, i.e. reduced

plasma volume. Radiolabelled red cells can be used to measure red cell

mass. Plasma volume can be calculated from the Hct or measured indepen-

dently using radiolabelled human serum albumin.

Indications

Polycythaemia, to distinguish between true polycythaemia (i RBC mass)

from apparent polycythaemia (d plasma volume).

Patient preparation

Avoid recent therapeutic venesection. Less sensitive in patients already

receiving myelosuppressive therapy.

Procedure

• Obtain 10 mL of venousblood.

• Radiolabel red cells using

99m

Tc or

Cr.

•

Re- inject radiolabelled blood and, if required,

125

I- albumin.

• Obtain venous samples at 15 and30min.

• Count activity in blood samples, compared with known standards, using

gamma counter to establish plasma and red cell volumes.

Results

Compare measured red cell mass and plasma volume with predicted values

for height and weight.

Interpretation

Distinguish relative polycythaemia (due to d plasma volume) from genuine

elevation of red cellmass.

Advantages

Only technique available.

Pitfalls

Recent venesection or myelosuppressive therapy reduces test reliability.

Plasma volume measurement unreliable in severe peripheral oedema.

956

CHAPTER14 Nuclear medicine

956

Bile salt deconjugation studies

Background

Bile salts are synthesized and stored in the liver and are essential for ade-

quate GI absorption. They are excreted into the gut as conjugated, water-

soluble bile salts and recycled by the enterohepatic circulation with terminal

ileal reabsorption. Bile salt deconjugation products are insoluble and can-

not enter the enterohepatic circulation, leading to bile salt malabsorption.

Bacterial overgrowth after small bowel surgery or terminal ileal disease can

i deconjugation.

The

C- labelled synthetic bile acid glycocholine is administered PO.

Rapid transit into the large bowel will result in breakdown of the label by

the normal large bowel ora and a rise in detected exhaled

. Small

bowel bacterial overgrowth, e.g. due to a ‘blind loop’, will also result in i

liberation of

Indications

• Bacterial overgrowth.

• Bile salt malabsorption.

Patient preparation

• Starve overnight.

• Avoid antibiotics for 1month beforestudy.

Procedure

• Give oral

C- labelled glycocholic acid inwater.

• Count

activity in breath samples over 6h using β liquid scintillation

counter.

Results

Glycocholate is deconjugated into

C glycine and cholic acid by small intes-

tine bacteria, releasing expired

. Correct result for age- related varia-

tions in endogenous

production.

Interpretation

levels imply bacterial colonization or bile salt malabsorption.

Advantages

Accurate. Only availabletest.

Pitfalls

False −ves (unusual).

957

Index

abdominal aortic aneurysm

repair 846

abdominal distension 4– 5

abdominalpain 6

abdominal ultrasound 411

abdominal X- ray 410,

788– 92,808

acanthocytes 237

acanthosis nigricans 100

acetaminophen

poisoning 732– 5

acetylcholine receptor

antibodies 371

acid– base balance 664– 6

acid phosphatase 298,299

acquired, meaning 315

acromegaly 132

ACTH, basal plasma 164

activated partial

thromboplastin time

(APTT) 289,290

acute bacterial

meningitis 589

acute bronchitis 23

acute delirium 7

acute kidney injury 674

acute lymphoblastic leukae-

mia 299, 313,319

acute myeloid leukae-

mia 299, 313,319

acute pancreatitis 24

acute pericarditis 23

acute phase

markers 348,744

acute viral meningitis 589

Addison’s disease 164

adenosine,

contraindications 487

adrenal antibodies 368

adrenal failure 162– 4

adrenoleukodystrophy 164

airway hyperresponsiveness

536– 7

alanine transaminase 528

albumin 528

alcoholic ketoacidosis

211

aldosterone/ renin

ratio 150,152

algid malaria 427

alkaline phosphatase

416– 17, 528,749

alloantibodies 311

- antitrypsin 529

alpha- fetoprotein 416– 17,

517

- naphthyl acetate

esterase 298,299

alpha rhythm 614

alpha- thalassaemia 282

aluminium 694– 5,701

ambulatory ECG 478– 80

amenorrhoea 166,167

amiodarone 183

ammonium chloride loading

test 668

amniocentesis 820– 1

amniotic uid 404

amobarbital test 631

amphetamine

overdose 708– 9

amyloid 348,350

amyloidosis 350

anabolic steroid screen 423

anaemia 10– 11

acquired

haemolytic 284– 5

dimorphic 746

haemolytic 255,

266,284– 5

hereditary haemolytic 266

hypochromic 245

investigation algorithm 521

iron deciency 244– 7

macrocytic 10, 11,746

microcytic hypochromic

10, 11,746

normocytic normochromic

10, 11,746

pernicious 11

anal specimens 403

anaphylactoid reactions 12

anaphylaxis 12

aneuploidy 315

angiography 840– 2

arch 594

cerebral 856

computed

tomography 599,784

magnetic resonance 444,

603, 785,829

neurology 594

urinary tract 811

angio- oedema 12

anion gap 664– 6,720

anion gap acidosis 211,

665– 6,720

anorectal manometry 527

anorectal specimens 403

anorexia 13

anterior pituitary function

test 218

anti- adrenal antibodies 164

anti- amphiphysin

antibodies 637

anti- aquaporin- 4

antibodies 371

antibacterial

antibodies 338– 9

antibiotic allergy 422

antibiotic plasma

concentration

monitoring 422

antibiotic sensitivity 392– 4

anti- CAR antibodies 637

anti- centromere

antibodies 751

anticonvulsant

poisoning 710– 11

anti- CRMP5 antibodies 637

anti- CV2 antibodies 637

anti- cyclic citrullinated

peptide antibodies 750

anti- DNA antibody 751

anti- GAD

antibodies 367,371

anti- ganglioside

antibodies 371

anti- GBM disease 372

antigen tests 400

antiglobulin test 308

anti- glomerular base-

ment membrane

antibodies 698

anti- histone

antibodies 361,751

anti- Hu antibodies 371,637

anti- 21 hydroxylase

antibodies 164

anti- Jo- 1 antibodies 361,751

anti- Ki antibodies 361

anti- Ku antibodies 361

anti- La antibodies 361,751

anti- LC antibodies 364,529

anti- LKM

antibodies 364,529

anti- M2 antibodies 363

Anti- Ma2 antibodies 637

anti- Mi- 2 antibodies 361

antimitochondrial

antibodies 363,529

antimony poisoning 701

anti- neuronal antibodies

371

anti- neuronal nuclear

antibodies 371

INDEX

958

antineutrophil

antibodies 311

antineutrophil cytoplas-

mic antibodies 372,

698,751– 2

antinuclear antibodies 356,

529,750– 1

anti- phospholipase A2

antibodies 373

antiphospholipid

antibodies 362,751

anti- PLA- 2 antibodies 373

antiplatelet antibodies 311

anti- Pm- Scl (PM1)

antibodies 361

anti- Ri antibodies 371,637

anti- RNP

antibodies 361,751

anti- Ro antibodies 361,751

anti- Scl- 70

antibodies 361,751

anti- SLA antibodies 364

anti- Sm antibodies 361, 364,

529,751

anti- SS- A antibodies 361

anti- SS- B antibodies 361

anti- Ta antibodies 637

antithrombin 295

antithyroid antibody 180– 1

anti- TPO

antibodies 180– 1,366

anti- Tr antibodies 637

anti- TSH receptor

antibodies 180– 1,184

anti- U1- RNP antibodies 361

antiviral antibodies 338– 9

anti- Yo antibodies 371,637

anuria 14

anxiety 7

aortic disease 467– 9

aortic dissection 22,23

aortic regurgitation 462

aortic root dilatation 458

aortic stenosis 461– 2

aortography 594

apparent mineralocorticoid

excess 154

appendicectomy 634

arch angiography 594

arginine– growth hormone-

releasing hormone

test 217

ARMS PCR 282

arrhythmias 82

arsenic poisoning 701

arterial blood gas

sampling 416– 17,

538– 9,707

arthrocentesis 754

arthrography,

image- guided 854

arthroscopy 754

ascending

urethrography 810

ascites 4,404

ascitic uid 534

aspirin poisoning 736

asplenia 339

ataxia 15– 16

atrial brillation 472

atrial utter 472

atrial masses 467

atrial myxoma 467

atrial rhythms 472– 4

atrial septal defects 469

atrioventricular block 474– 5

atrioventricular re- entry

tachycardia 473

Auer rods 243,299

autoantibodies 311,

371,750– 2

autoantibody screen 356– 7

autoimmune hepatitis 364

autoimmune polyglandular

syndromes 368

autoimmune skin

disease 370

autoimmunity 354

automatic intracardiac

debrillation device 784

avascular necrosis, femoral

head 838

axonal neuropathy 607

B- cell acute lymphoblastic

leukaemia 313,319

bacterial antibody tests 399

bacterial antigen tests 400

bacterial culture 390– 4

bacterial overgrowth 523

Baermann concentration

technique 412

barium enema 806– 7

barium meal 798– 83

barium studies 794– 5

barium swallow 796– 7

Bartter’s syndrome 158– 9

basophilic stippling 237

behavioural alteration 7– 8

Bence– Jones

proteins 344,660

benzodiazepine

overdose 712

beta- 2- microglobulin 346

beta rhythm 614

beta- thalassaemia 282

bicarbonate 664

bicarbonate infusion

test 669

bile salt deconjugation

studies 956

bile salt malabsorption 519

biliary colic 24

biliary system

drainage 844– 5

bilirubin 261, 416– 17,528

biohazard levels

(1– 4) 402– 3

biopsy

bone marrow 418,634

brain 633

GI tract 412

image- guided 411,844

liver 412, 418– 19,532– 3

lung 419,778

lymph node 419

meningeal 633

muscle 421,632

nerve 421,632– 3

ocular 421

pericardial 421

pleural 420,562– 3

rectal 634

renal 688– 9

skin 420– 1,633

TB 427

temporal artery 38

tonsillar 421,634

transiliac bone 695

BiPLEDs 615

birch pollen allergy 375

bismuth poisoning 701

bite cells 237

bladder stones 686– 7

bleeding disorders 105– 6

bleeding time 287

blindness 117

blood lm 234– 5,408

blood glucose,

self- testing 204,205

blood products, bacterial

contamination 304,308

blood specimens 404

blood toxicology 700

blood transfusion 302– 3

bacterial contamina-

tion of blood

products 304,308

HLA- related issues 321

reactions 304– 6

body mass index (BMI) 79

bone biopsy 695

bone function tests 748– 9

bone lysis 861

bone marrow

biopsy 418,634

bone marrow

examination 296– 7,408

bone marrow

scintigraphy 872

bone scintigraphy

(scan) 762,868– 70

bone sclerosis 861

bowel biopsy 412

INDEX

959

bowel cancer screening

507

bowel habit 9

Bowel Scope Screening

Programme 507

bradycardia 17,471

brain biopsy 633

brain transporter

imaging 876– 7

brainstem auditory evoked

potentials 624– 6

brainstem death 706

branched- chain DNA 407

breast imaging 812– 15

breathlessness 18– 19

broad- complex

tachycardia 110

bronchitis 23

bronchoalveolar lavage 419

Bruce protocol 483

bruising 20

bullous pemphigoid 370

Burkitt’s lymphoma 319

burr cells 237

burst suppression 615

C- choline/

F- uorocholine

PET/ CT 902,905

C- reactive protein 348, 349,

416– 17, 744,745

C1 esterase inhibitor 352

C3 nephritic factor 354

CA 19- 9 517

Ca- 125 416– 17,517

cadmium poisoning 701

caeruloplasmin 529

calcium excretion 687,749

calcium pyrophosphate

disease 43,757

calf swelling 21

caloric testing 646

cancer antigen 125

(Ca- 125) 416– 17,517

cannabis 713

cannon waves 70

capsule endoscopy 412,510

captopril renography 928

carbamazepine toxicity 710

carbohydrate antigen 19- 9

(CA 19- 9) 517

carbohydrate

malabsorption 522

carbon monoxide

poisoning 714– 15

carcinoembryonic

antigen 517

cardiac arrhythmias 82

cardiac

catheterization 436– 9

cardiac CT 442– 8

cardiac enlargement 782– 5

cardiac magnetic

resonance 442– 8,785

cardiac markers 440– 1

cardiac masses 467

cardiac rhythms 472– 4

cardiac volumetric

imaging 442– 8

carotid ultrasound 592

CASPR2 antibodies 638

casts 685

cellular casts 685

cellular function

assays 378– 9

cellulose acetate 272

central cyanosis 31

central venous access 843

central venous lines 784

cerebellar ataxia 15– 16,369

cerebellar herniation 587

cerebellar nystagmus 77

cerebral angiography 856

cerebral blood ow

imaging 874,875

cerebrospinal uid 404, 418,

585,588

cerebrospinal uid shunt

patency 878,879

cerebrovascular

accident 858

cerebrovascular disease 592

cervical

lymphadenopathy 72

cervical spinal imaging 836

cervical swab 403

chest pain 22,23

chest tubes 784

chest X- ray 410,

770– 2,774– 9

chloride

plasma 664

urine 672

chloroacetate

esterase 298,299

cholangiography 802– 4

cholecystitis 24

chorionic villus

sampling 316– 17

chromium poisoning 701

chromograninA 525

chromosome

abnormalities 314

chromosome anatomy 317

chronic kidney disease,

classication 654– 6

chronic lymphocytic

leukaemia 313

chronic myeloid

leukaemia 319

Chvostek’s sign 190

citrate agar 272

citrate excretion 687

CK- MB 441

CKD- EPI equation 652

clonality assessment 313

clubbing 25

coagulation cascade 288

coagulation studies 408

cocaine 716

Cockcroft and Gault

formula 652

cold agglutinins 408

collapsing pulse 94

colonic polypectomy 500

colonoscopy 500,

506– 7,807

colour Doppler 454

colour vision 423

coma 26– 7, 619

combined anterior pituitary

function test 218

combined arginine– growth

hormone- releasing

hormone test 217

complement 351, 414,

696,745

complete blood count 228

compound motor action

potential 608

computed tomography

(CT) 824– 6

angiography 599,784

biopsy guidance 411

cardiac 442– 8

colonoscopy 411

cranial 598– 9

enteroclysis 800– 1

infection 410– 11

intravenous

pyelogram 411

rheumatology 762

spinal 599– 600

thorax 786– 7

urinary tract 810

urography 809– 10

venography 599

confusion 28, 619

congenital heart

disease 468– 9

conscious sedation 846

constipation 29– 30

constitutional, meaning 315

constrictive pericarditis 467

continuous glucose monitor-

ing systems 205

continuous- wave

Doppler 453

contrast agents, adverse

reaction 862

contrast

echocardiography 454

contrast nephropathy 690

Coombs’ test 308

copper 529,701

INDEX

960

corneal arcus 57

coronary computed tomog-

raphy angiography 784

cranial CT 598– 9

creatine kinase 440,441

creatinine 650,651

creatinine

phosphokinase 416– 17

crenated RBCs 236,238

Crithidia assay 358

cryobrinogen 345

cryoglobulins 345,697– 8

crystals 685

CSF 404, 418, 585,588

CSF shunt patency 878,879

CT angiography 599,784

CT colonoscopy 411

CT enteroclysis 800– 1

CT- guided biopsy 411

CT intravenous

pyelogram 411

CT urography 809– 10

CT venography 599

culture 388,390– 5

Cushing’s syndrome 142– 6

cyanide poisoning 717

cyanosis 31

cystatinC 655

cystine excretion 687

cystometry 630

cytochemical stains 298– 9

cytogenetics 314,642

haematological

malignancies 318– 19

prenatal diagnosis 316– 17

cytokines 414

cytotoxic T- lymphocyte

precursor assay 321

D- dimers 290,408

D- xylose absorption

test 413,522

dacroscintigraphy 948– 9

DEC test 422

deep vein thrombosis 21

delayed transfusion

reactions 306

deletion 315

delirium 7

delta rhythm 614

dementia 7, 619

demyelinating

neuropathy 607

dental radiography 410

dentarubropallidoluysian

atrophy 643

dermatitis herpetiformis 370

desamino D - arginyl vaso-

pressin trial 222

desferrioxamine test 694– 5

Devic’s disease 371

dexamethasone- suppressed

CRH test 143,223

dexamethasone

suppressiontest

high- dose 144– 5,224

low- dose 143,223

diabetes insipidus 134– 6

diabetes mellitus

diagnosis 194– 8

emergencies 210– 11

atbush 201

genetically inherited 203

gestational 195,200

laboratory assessment of

control 206– 8

latent autoimmune diabe-

tes of adults 200– 3

maturity- onset diabetes

of the young

(MODY) 201

monitoring control 204– 5

screening 199

type 1 200,201

type 2 200,201

types 200– 3

unusual causes 202

diabetic

ketoacidosis 210– 11

diabetic nephropathy 658

dialysis catheter 784

diaphragm 775

diarrhoea 32– 3, 429,520

diethylcarbamazine 422

dierential white cell

count 232,414

diusion tensor imaging 603

digital radiology 769

digital subtraction

angiography 841– 3

digoxin poisoning 718– 19

dimercaptosuccinic acid

imaging 924,927

dimorphic RBCs 236

diploid 315

dipstick urine test 676– 8

direct antiglobulin test 308

direct ophthalmoscopy 423

disseminated intravascular

coagulation 291

distal motor latency 607

dizziness 34– 5

DMSA scan 924,927

DNA amplication 324– 6

dobutamine,

contraindications 487

dobutamine stress

echocardiography 459

donor/ recipient

compatibility 321

Doppler studies 411, 453– 4,

593,816– 18

double- stranded DNA

antibodies 358

driving

dizziness/ syncope 35

rstt 41

drug allergy testing 377

dual- energy X- ray absorpti-

ometry (DXA) 763

Duke treadmill score 484

duodenal aspirate 412,523

duodenal biopsy 412

duplication 315

dynamic renography 924– 7

dysarthria 36

dysphagia 37

dysphasia 36

dyspnoea 18– 19

ear swab 403

echocardiography 411,

422,450– 69

ectopic gastric

mucosa 936,939

edrophonium test 631

Eisenmenger’s

syndrome 31,468– 9

ejaculate 404

ejection click 54

ejection fraction 458

elbow ossication

centres 863

electrocardiogram

(ECG) 422,470– 6

ambulatory 478– 80

electroencephalogram

(EEG) 423, 612,614– 20

electromyogram

(EMG) 423, 610– 11,630

electrophoresis

haemoglobin 272– 4,409

serum 342– 3,696– 8

urine 342– 3,344

elliptocytes 236

EMA binding test 268

embolization 841– 3

empyema 420

endocarditis 64, 425– 7,466

endocrine

autoantibodies 368

endocrine tests 124– 6

endomysial antibodies 369

endoscopic retrograde

cholangiopancreatogra-

phy (ERCP) 410, 500,

508,802

endoscopic ultrasound 509

endoscopy 498– 501

endotracheal tubes 782

enteroclysis 800– 1

enteroscopy 504

INDEX

961

enterotest 412

enzyme- linked assay 358

eosinophilia 747

epicardial pacing wire 784

epigastricpain 6

epilepsy 8, 616,618

epiphyseal plate

fractures 863

Epworth sleepiness

scale 542

Epworth test 542

erythrocyte sedimentation

rate (ESR) 252, 348,

408, 744,745

erythroenzymopathies

331

erythropoietin assay 310

ethanol poisoning 720– 2

ethylene glycol

poisoning 720– 2

event monitor 478

evoked potentials 622– 6

exercise

testing 482– 5,544– 5

exhaled nitric oxide

fraction 546– 7

external loop recorder 478

extractable antinuclear

antigen antibodies 360,

361,751

extraluminal gas 791– 2

F- uoride PET/

CT 904– 5,907

F wave 608

Fab fragments 718– 19

facial pain 38

factorH 354

factorI 354

faecal antigen test 512

faecal calprotectin 516

faecal chymotrypsin 524

faecal elastase 413,524

faecal fat, 3- day 522

faecal immunochemical

test 515

faecal incontinence 60

faecal lactoferrin 516

faecal occult blood 514– 15

Fairley test 681

falciparum malaria 241

Fallot’s tetralogy 468– 9

familial apo C- II

deciency 214

familial benign hypocalciuric

hypercalcaemia 188– 9

familial combined

hyperlipidaemia 212– 15

familial dysbeta-

lipoproteinaemia 214

familial hypercholesterolae-

mia 212– 15

familial hyperlipoproteinae-

mias 214

familial hypertriglyceridae-

mia 214

familial LPL deciency 214

Farr assay 358

fasting blood test 196

fat malabsorption 522

febrile transfusion

reactions 305

femoral head, avascular

necrosis 838

ferritin 244, 409, 529,745

fertility problems 168

fetal haemoglobin 280

FEV

/ FVC ratio 569

fever of unknown

origin 39,424– 34

FGF- 23 694

breoptic

bronchoscopy 548– 50

brin degradation

products 408

broblast growth factor

(FGF- 23) 694

Fibroscan

531

rst- degree AV block 474

rst- pass cardiac studies 912

FISH 328– 9

t, rst 40– 1

tness to y 552– 3

ash- evoked visual evoked

potentials 622

atbush diabetes 201

atus 4– 5

exible sigmoidoscopy/

colonoscopy 500,506– 7

ow– volume loops 554,555

uorescent in situ

hybridization 328– 9

ying 552– 3

folate status 248– 50

foreign bodies 403

fractional excretion of

phosphate 662

fractional excretion of

sodium 675

fractional excretion of

urate 663

fractional tubular

reabsorption of

phosphate 662– 3

fracture

epiphyseal plate 863

healing in children 863

pelvis 838

skull 861

terminology 850

fragileX 643

fragmented RBCs 236

Fredrickson

classication 215

free light chains 344

free T3/ T4 180– 1

Friedreich’s ataxia 643

frontal lobe syndrome 7

fructosamine assay 208

full blood count 228

functional iron

deciency 246

functional MRI 603,829– 30

functional residual

capacity 572

fungal antibody tests 399

fungal antigen tests 400

fungal culture 395

fungal meningitis 589

Ga- DOTA- peptide PET/

CT 898– 9,901

Ga- PSMA PET/

CT 900,903

GABA

R antibodies 638

gadolinium- based contrast

media 690

galactorrhoea 42, 172– 3

gallium

scintigraphy 946,948

gamma globulins 748

gamma glutamyl transpepti-

dase 416– 17,528

ganglionopathies 607

gastric biopsy 412

gastric emptying 527,

932,937

gastric parietal cell

antibodies 365

gastric ulcers 798– 9

gastritis 798– 9

gastrointestinal

bleeding 930,933

gastrointestinal

physiology 526– 7

gastrointestinal tract

412– 13

gastro- oesophageal

disease 22

genetic risk factors 644

genetic tests 642– 5

genital ulcers 403

gestational

diabetes 195,200

gestational

thyrotoxicosis 184

giant cell arteritis 117,592

gingival specimens 403

Gitelman’s syndrome 158– 9

glandular fever 254

Glasgow Coma Score 26

gliadin antibodies 369

INDEX

962

global left ventricular systolic

function 458

glomerular ltration

rate 655, 656,952

glucagon 795

glucose dipstick testing 677

glucose metabolism 416– 17

glucose- 6- phosphate dehy-

drogenase (G6PD) 409

assays 270

deciency 331

glycaemic

control 204– 5,206– 8

glycated

haemoglobin 206– 8

L- glycerate 687

glycolate 687

glycolytic defects 331

glycosuria 204,677

GlyR antibodies 638

Goodpasture’s

syndrome 372

gout 43,757

GPI- linked proteins 286

granular casts 685

Graves’ disease 182

growth hormone

excess 132

Guillain– Barré

syndrome 371,589

gynaecological imaging 822

gynaecomastia 44– 5,175

H bodies 237,280

H wave 608

haematemesis 46

haematocrit 231

haematuria 47, 684,691

haemoglobin

280

abnormalities 271

altered anity 330– 1

concentration 230,409

electrophoresis 272– 4,

409

fetal 280

glycated (HbA

) 206– 8

H bodies 237,280

mean cell 231

mean cell

concentration 231

neonatal screen 279

normal adult 272

plasma 264

reticulocyte content 231

reticulocyte mean cell 231

rheumatology 746

sickle 278– 9

structural variants 271

unstable 281,330– 1

urine dipstick testing 677

variants 330– 1

haemolysis 256

haemolysis screen 11,409

haemolytic anaemia 255

acquired 284– 5

hereditary 266

haemolytic complement 353

haemoptysis 48

haemorrhage

lumbar puncture 587

retinal 97

splinter 64

subarachnoid 589

haemosiderin 244

haemosiderinuria 262,263

hair samples 420

hand imaging 852– 4

hand muscle wasting 118

haploid 315

haptoglobins 260,416– 17

HbA

206– 8

HDL- cholesterol 212– 13

head injury 590,598– 9

headache 49– 50

Heaf test 422

heart murmurs 51– 4

heart rate 471

heart sounds 51– 4

heat- damaged red cell

imaging 940

Heinz bodies 237,281

Helicobacter pylori 512– 13

helminthic antibody

tests 399

helminthic antigen

tests 400

hepatitis, autoimmune 364

hepatitisA 530

hepatitis B 396, 397,

398,530

hepatitisC 530

hepatitisD 397

hepatitisE 530

hepatobiliary

scintigraphy 938,940

hepatomegaly 55

hepatosplenic

scintigraphy 942,944

hereditary elliptocytosis 268

hereditary

pyropoikilocytosis 268

hereditary

spherocytosis 268

hereditary

stomatocytosis 268

hernia, hiatal 798– 9

herpes gestationis 370

herpes simplex

encephalitis 589

herpes zoster 56

heterophile antibodies 254

hiatal hernia 798– 9

high- dose dexametha-

sone suppression

test 144– 5,224

high- performance liquid

chromatography 273

high- resolution computed

tomography 786,787

high vaginal swab 403

hila 778

hirsutism 170– 1

histamine challenge 536– 7

histoplasmin test 422

HIV 406,589

HLA- B27 752

HLA typing 320– 1,414

Holter monitor 478

hot stools 412

Howell– Jolly bodies 237

Hughes’ syndrome 362

human leucocyte antigen

(HLA) typing 320– 1,414

Huntington’s disease 643

hyaline casts 685

hybridization with nuclei acid

probes 407

hydrogen breath test 523

5- hydroxyindole acetic

acid 525

hyoscine butylbromide 795

hyperaldosteronism 150,

151, 152,153– 4

hypercalcaemia 188– 9,748

hypercholesterolaemia

212– 15

hypercortisolism 142– 6

hyperemesis

gravidarum 74– 5

hypergammaglobulinae-

mia 335

hyperkalaemia 160,670– 1

hyperlipidaemia 57,212– 15

hyperosmolar non-

ketotic (HONK)

syndrome 210– 11

hyperparathyroidism 188– 9

hyperpigmentation 100– 1

hyperprolactinaemia 172– 3

hypertension 58– 9, 148– 56

hyperthyroidism 182– 4

hypertriglyceridaemia

212– 15

hypoadrenalism 162– 4

hypocalcaemia 190– 2

hypochromic red

cells 231,236

hypogammaglobulinaemia

334– 5

hypogonadism 174

hypokalaemia 158– 9, 671

hyponatraemia 138– 40

hypopigmentation 100

INDEX

963

hypopituitarism 128– 30

hyposplenic lm 237

hypothalamic

dysfunction 128

hypothyroidism 186–7

hysterosalpingogram 822

IgA 334– 5

IgD 340

IgE

specic (RAST) 376

total 374

IgG 334, 336

IgM 334– 5

IL- 28R polymorphisms 414

ileal conduit specimens 680

immunoxation 342– 3,344

immunoglobulins 334– 5,

529,696– 8

immunohaematology 311

immunology 396– 9,

414,696– 8

immunophenotyp-

ing 286,312– 13

impaired fasting

glucose 195,197

impaired glucose

tolerance 195,197

impotence 174

‘in– out’ catheter urine

specimens 680

in situ hybridization 328– 9

incontinence

faecal 60

urinary 61

indigestion 62– 3

indirect antiglobulin

test 308

indirect

ophthalmoscopy 423

indwelling

catheters 403,681

infectious

disease 382– 7,388– 9

infective endocarditis 64,

425– 7,466

inferior petrosal sinus

sampling 144– 5

infertility 168

inammatory bowel

disease 516

inammatory

markers 744– 5

INR 288

insertable cardiac

monitor 478

inspiratory capacity 572

insulin antibodies 367

insulin receptor

antibodies 367

insulin tolerance (stress)

test 216– 17

international normalized

ratio (INR) 288

interstitial lung disease 787

interventional

radiology 844– 8

intestinal transit studies 527

intra- aortic balloon

pump 784

intracranial calcication 861

intracranial pressure,

raised 861

intra- ocular uids 404

intravascular stents 841– 3

intravenous

cholangiography 802

intravenous

urogram 410,808– 10

intrinsic factor

antibodies 365

inulin clearance 655,656

inversion 315

iodine 183

iron, serum 529,724

iron deciency,

functional 246

iron deciency

anaemia 244– 7

iron overload 247

iron poisoning 701,724– 5

iron status 244– 7

ischaemic forearm exercise

test 641

ischaemic lactate test 641

islet cell antibodies 367

isoelectric focusing 272

isolation plate 390– 4

J wave 476

Janeway lesions 64

jaundice 66, 67,428

jejunal aspirate 523

jerk nystagmus 77

Jod– Basedow eect 183

joint aspirate 404,754

joint pain/ swelling 68

joint replacements 851

jugular venous pulse 69,70

kaolin cephalin clotting

time 289

karyotyping 314,316– 17

ketones 678

ketonuria 204

kidney disease,

classication 654– 6

kidney function 650– 2

Kirschner wires

(K- wires) 850

Kleihauer test 309

koilonychia 10

L- glycerate 687

labelled leucocyte

imaging 944– 5

labelled red cell

imaging 930,933

lactate 416– 17

lactic acidosis 210– 11

lactose hydrogen test 522

lactose tolerance test 522

Lambert– Eaton myasthenic

syndrome 371

lamotrigine toxicity 710

laparoscopy 412

laryngeal swab 403

late- night salivary cortisol

test 143

latent autoimmune diabetes

of adults 200– 3

latex allergy 375

LDL- cholesterol 212– 13

lead exposure and

poisoning 701,726

left atrial dilatation 457– 9

left iliac fossapain 6

left iliac fossa swelling 5

left- shifted 243

left upper quadrantpain 6

left upper quadrant

swelling 5

left ventricular diastolic

function 459,460

left ventricular

dilatation 457– 9

left ventricular

hypertrophy 457– 9

left ventricular systolic

function 458

leg swelling 21,433

leucocyte alkaline

phosphatase 300

leucocyte esterases 677– 8

leucocyte nitrites 677– 8

leukaemia

cytochemical stains 298– 9

immunophenotyping 313

karyotyping 319

leukocyturia 684

LGI1 antibodies 638

libido loss 174

ligase chain reaction 407

lipid disorders 57,416– 17

lithium

poisoning 701,728– 9

liver biopsy 412,

418– 19,532– 3

INDEX

964

liver function tests 416– 17,

528– 31,748

loa loa 241

lobar collapse 780,781

loin pain 6,71

loin pain- haematuria

syndrome 71

long (depot) ACTH

test 164,225

low- dose dexametha-

sone suppression

test 143,223

lumbar puncture 423,584– 9

lumbar spinal imaging 837

lung biopsy 419,778

lung cancer 23

lung opacities 778– 9

lung permeability

studies 920

lung scan 914– 16

lung shunt studies 918,923

lung volumes 572– 4

lymph node sampling 419

lymphadenopathy 72– 3

lymphocyte function 380

lymphocyte surface

markers 378

lymphocytes, atypical 243

lymphocytosis 747

lymphoma, karyotyping 319

lymphopenia 747

lymphoscintigraphy 922,

925

lytic complement function

tests 353

macrocytic RBCs 236

macrophage function 380

macroprolactin 172– 3

magnesium, urine 673

magnetic resonance

angiography 444, 603,

785,829

magnetic resonance

cholangiopancreatogra-

phy 410,802– 3

magnetic resonance imaging

(MRI) 828– 34

breast 814– 15

cardiac 442– 8,785

functional 603,829– 30

infection 410

musculoskeletal

system 851

neurology 602– 4,630

paediatric brain 859

pelvis 822

perfusion imaging 830

rheumatology 761– 2

urinary tract 810

magnetic resonance

spectroscopy 603– 4

magnetic resonance

venography 603

major histocompatibility

complex (MHC) 320– 1

malaria 241,427

MALDI- TOF MS 392,393

malignant meningitis 589

mammography 812– 15

manganese poisoning 701

Mantoux test 422

marijuana 713

mass units 740

mast cell tryptase 377

maturity- onset diabetes of

the young (MODY) 201

maximum expiratory ow–

volume curve 554

Mazzotti test 422

MCV index 230

MDRD formula 650– 1

mean cell haemoglobin 231

mean cell haemoglobin

concentration 231

mean cell volume 230,409

Meckel’s diverticulum 518,

936,939

mediastinal mass 23,

775,776

mediastinum 775– 6

medical

thoracoscopy 578– 80

medicolegal samples 702

mega- oesophagus 797

MEN- 1/ MEN- 2 189

meningeal biopsy 633

meningitic illness 430– 2,589

mercury poisoning 701

meta- idiobenzylguanidine

(MIBG) imaging 884– 7

metabolic acidosis 707

metabolic alkalosis 707

metabolic coma 27

metal analysis 701

methacholine

challenge 536– 7

methaemalbumin 265

methaemoglobinaemia 730

methanol poisoning 720– 2

metoclopramide 795

metyrapone test 146

mGluR1 antibodies 638

mGluR5 antibodies 638

MIBG imaging 884– 7

microcytic RBCs 236

micturating

cystourethrogram 810

micturition urgency 114

midstream urine sample 680

mid- systolic click 54

Miller– Fisher syndrome 371

mineralocorticoid

excess 152,154

minimum inhibitory

concentration 392– 4

mitral regurgitation 463– 4

mitral stenosis 463

mitral valve prolapse 23

Mobitz type I block 474

Modication of Diet in

Renal Disease (MDRD)

formula 650– 1

molar units 740

molecular

cytogenetics 318– 19

molecular diagnostics 406– 7

molecular genetics 642– 4

monoclonal antibodies 313

monoclonal antibody

immobilization of platelet

antigens 311

monosomy 315

monospot test 254,409

motor conduction

velocity 606– 7

motor unit potentials 611

MR angiography 444, 603,

785,829

MR cholangiopancreato-

graphy 410,802– 3

MR venography 603

mu rhythm 614

MUGA scan 910– 11

mugwort pollen allergy 375

multigated radionuclide

angiography (MUGA)

scan 910– 11

multiple sclerosis

autoantibodies 371

evoked potentials 626

imaging 858

multiple sleep latency

test 621

murmurs 51– 4

muscle biopsy 421,632

musculoskeletal chest

pain 22,24

musculoskeletal

imaging 850– 1

myasthenia gravis 371

myelin- associated glyco-

protein antibodies 371

myelin basic protein

antibodies 371

myelodysplastic

syndrome 319

myelography 595

myeloperoxidase 298,299

myocardial infarction 23

myocardial ischaemia 22,

23,484

myocardial necrosis

markers 440– 1

INDEX

965

myocardial perfusion

imaging 486– 9,906– 8

myoglobin 440,441

myotonia 611

myotonic dystrophy 643

NAP score 300– 1

narcotics screen 423

narrow- complex

tachycardia 110

nasal specimens 403

nasogastric tubes 782

National Bowel

Cancer Screening

Programme 507

natural killer cell

function 380

nausea 74– 5

neck stiness 76

Nelson’s syndrome 100

neonatal haemoglobin

screening 279

nephrogenic systemic

brosis 690

nephrolithiasis 691

nephrotic syndrome 658

nerve biopsy 421,632– 3

nerve conduction

studies 423,606– 8

neuroendocrine

tumours 525

neurological

autoantibodies 371

neuromyelitis optica 371

neuronal surface antibody

antibodies 638

neuro- otology 646– 7

neuroradiology 856– 9

neurosyphilis 589

neutropenia 747

neutrophil alkaline

phosphatase 300– 1

neutrophil function 380

neutrophilia 747

Nijmegen

questionnaire 556– 7

NMDAR antibodies 638

non- HDL- cholesterol 212– 13

non- Hodgkin

lymphoma 319

normoglycaemia 195,197

nuclear medicine 866

nucleic acid sequence- based

amplication 407

nystagmus 77– 8

obesity 79– 80,142– 6

obstetric imaging 820– 1

obstructive uropathy 692

ocular biopsy 421

oedema, peripheral 87

oesophageal biopsy 412

oesophageal

manometry 526,527

oesophagogastroduodenos-

copy 500,502, 503

oligoclonal bands 635

oliguria 81

opening snap 54

ophthalmic specimens 403,

404,421

ophthalmoscopy 423

opioid poisoning 731

oral allergy 375

oral bowel cleansing 501

oral glucose tolerance

test 197– 8

organ donation 706

orthopantomogram 410

orthostatic

hypotension 34– 5

Osler’s nodes 64

Osler’s triad 429– 30

osmolal gap 720

osmotic fragility test 268– 9

osteitis brosa cystica 188

osteoarthritis 757

osteomalacia 191– 2

osteoporosis 763

ostium primum ASD 469

ostium secundum ASD 469

overdose 700– 1

oxalate crystals 721

oxalate excretion 687

oxyhaemoglobin dissociation

curve 539

P wave 474

PABA test 524

pacemakers 784

packed cell volume 231

Paget’s disease 757

palpitations 82

pancreatic amylase

416– 17

pancreatic exocrine

function 524

pancreatic

malabsorption 522

pancreatitis 24

pancreolauryl test 524

pancytopenia 83,747

paracetamol

poisoning 732– 5

paraesthesiae 84– 5

paragangliomas 155– 6

paralytic ileus 791

paranasal sinus aspirates 421

paraneoplastic

antibodies 637– 8

paraproteins 696– 8

parasites 240,241

parathyroid

hormone 694,749

parathyroid

scintigraphy 882– 3

parietal cell 250

paroxysmal nocturnal

haemoglobinuria 286

partial thromboplastin time

with kaolin 289

patent ductus arteriosus 31

pattern- evoked visual

evoked potentials 622

Paul– Bunnell test 254,409

PCR 324– 6,407

peak ow charts 558– 60

PEG placement 500

Pelger– Huët anomaly 243

pelvis 838,839

pemphigus 370

pencil cells 236

Pendred’s syndrome 186– 7

peptic ulcer disease 24

percutaneous transhepatic

cholangiography 802

percutaneous transluminal

angioplasty 841– 3

perfusion imaging 830

pericardial biopsy 421

pericardial disease 466– 7

pericardial eusion 466– 7

pericardial uid 404

pericardial pain 22

pericarditis

acute 23

constrictive 467

perinuclear antineu-

trophil cytoplasmic

antibodies 516

periodic acid- Schi 298,

299

periodic lateralized

epileptiform discharges

(PLEDs) 615

peripheral blood

lm 234– 5,408

peripheral CRH test 146

peripheral cyanosis 31

peripheral neuropathy 86

peripheral oedema 87

periumbilicalpain 6

pernicious anaemia 11

PET/ CT 411

C- choline/

F-

uorocholine 902,905

F- uoride 904– 5,907

Ga- DOTA- peptide

898– 9,901

Ga- PSMA 900,903

INDEX

966

petechiae 88

Peutz– Jeghers

syndrome 100

GI monitoring 526

urine dipstick testing 676

phaeochromocytoma 155– 6

pharyngeal specimens 403

phenytoin toxicity 711

phosphate 749

phosphate

reabsorption 662– 3

picture archiving and

communication systems

(PACS) 769

pituitary fossa

enlargement 861

pituitary function 128– 30

plain X- rays 768

abdomen 410,

788– 92,808

chest 410, 770– 2,774– 9

dental 410

rheumatology 756– 8

skull 590,860– 1

plasma ACTH 164

plasma bicarbonate 664

plasma chloride 664

plasma haemoglobin 264

plasma potassium 670– 1

plasma viscosity 253

plasma volume 955

platelet adhesion 292

platelet aggregation 292

platelet clumping 233

platelet count 233, 292,747

platelet distribution

width 233

platelet function tests

292– 3

platelet immunouorescence

tests 311

platelet morphology 292

platelet release 293

plethora 89

pleural aspiration 540– 1

pleural biopsy 420,562– 3

pleural eusion 420,777

pleural uid 404,416– 17

pleural tumour 23

pleurisy 23

pleuritic pain 22

pneumococcal

pneumonia 429– 30

pneumomediastinum 776

pneumonia 23,429– 32

pneumothorax 23, 777,778

poisoning 700– 1

pollen– fruit syndrome 375

polychromatic RBCs 236

polycystic ovary

syndrome 166

polycythaemia 89

polydipsia 134– 6

polymerase chain reaction

(PCR) 324– 6,407

polymorphic ventricular

tachycardia 473

polysomnography 564– 5,

621

polyuria 90,134– 6

porphyrias 331

portal vein gas 791– 2

positron emission

tomography 596– 7,

762– 3,894– 7

post- mortem

toxicology 702

postpartum

thyroiditis 184,187

postural proteinuria 659

potassium

plasma 670– 1

urine 672

PR interval 474

precocious puberty 179

pre- diabetes 197

pregnancy

gestational

diabetes 195,200

hyperemesis

gravidarum 74– 5

hyperthyroidism 184

hypothyroidism 187

infections 416– 17

prenatal diagnosis 316– 17

procalcitonin 417

prostate- specic membrane

antigen 900,903

prosthetic heart

valves 54,466

prosthetic joints 851

protein, urine dipstick

testing 677

proteinC 295

proteinS 295

proteinuria 658– 60

prothrombin time (PT) 288,

290,528

protozoal antibody

tests 399

protozoal antigen tests 400

protozoal culture 395

pruritus 91

pseudo- Cushing’s

syndrome 142– 3

pseudo- gout 43

pseudohyperkalaemia 670

pseudohypokalaemia 671

pseudohyponatraemia 138

pseudohypoparathy-

roidism 190

pseudopseudohypoparathy-

roidism 190

pseudo- seizures 41

psoriatic arthritis 757

psychogenic limb

weakness 629

psychosis 7

ptosis 92

puberty

delayed 176,177

precocious 179

pulmonary artery

catheterization 492– 3

pulmonary embolism 23,93

pulmonary function

tests 423

pulmonary

hypertension 461

pulmonary

regurgitation 465– 6

pulmonary stenosis 465

pulmonary trunk

dilatation 458

pulmonary tuberculosis 23

pulse 65,94

pulse oximetry 566

pulsed- wave Doppler 453

pulsus alternans 94

pulsus bigeminus 94

pulsus bisferiens 94

pulsus paradoxus 94

pure culture 390– 4

pure tone audiometry 646

Purkinje cell antibodies 371

purpura 95

pus 405

pyrexia of uncertain

origin 39,424– 34

Q waves 475

QRS axis 474

QRS complex 475

QT interval 476

radiation dose 767

radiofrequency

ablation 846– 7

radiographs, see plainX- rays

radioiodine

imaging 888,891

radiology information

systems (RIS) 769

radionuclide ventriculogra-

phy 490– 1,910– 11

ragweed pollen allergy 375

rapid urease test 513

Rasmussen’s

encephalitis 371

RAST tests 376

reactive arthritis 752

INDEX

967

recruitment 611

rectal biopsy 634

recurrent infections 335

recurrent thrombosis 96

red cell count 230

red cell distribution

width 231

red cell enzyme assays 270

red cell membrane

disorders 268– 9,331

red cell morphology 236– 8

red cell

parameters 230– 1,409

red cell survival studies 954

red cell volume 955

reux nephropathy 691– 2

regional left ventricular

systolic function 458

regional wall

motion 458,459

renal artery

stenosis 150,691

renal biopsy 688– 9

renal bone disease 694– 5

renal imaging 690– 2

renal stones 686– 7

renal transplant

dysfunction 692

renal tubular function 662– 3

renin elevation 150,152

renography

captopril 928

dynamic 924– 7

static cortical 924,927

repetitive nerve

stimulation 608

residual volume 572

respiratory acidosis 707

respiratory alkalosis 707

respiratory samples 419– 21

restriction fragment length

polymorphisms 407

reticulin R1 antibodies 369

reticulocyte

count 258– 9,409

reticulocyte haemoglobin

content 231

reticulocyte mean cell

haemoglobin 231

retinal haemorrhage 97

retrograde pyelography 811

rhesus haemolytic disease of

the newborn 309

rheumatoid arthritis 757

rheumatoid factor 355,750

rhonchi 120

right atrial dilatation 458

right atrial pressure 461

right heart function 459

right iliac fossapain 6

right iliac fossa swelling 5

right- shifted 243

right- to- left shunt 31,468– 9

right upper quadrantpain 6

right upper quadrant

swelling 5

right ventricular

dilatation 458

right ventricular

hypertrophy 458

Rigler’s sign 791– 2

rigors 97

rod cells 236

Roth spots 64

rouleaux 237,238

Saccharomyces cerevisiae

antibodies 516

sacroiliitis 838

salicylate poisoning 736

saliva 405

salivary gland

scintigraphy 950, 951

Salter– Harris

classication 863

Schilling test 250

Schumm’s test 265

scintomammography 892

SDS- PAGE 268

second- degree AV

block 474

secretin test 524

SeHCAT studies 519,934

selenium poisoning 701

Sellotape

strip test 412

semen 404

sensory ataxia 15

sensory conduction

velocity 606

sensory evoked

potentials 622– 6

sensory nerve action poten-

tial (SNAP) 606

sentinel node

imaging 890,895

sequencing 407

serology 396

serum aluminium 694– 5

serum amyloidA 348

serum bilirubin 261

serum caeruloplasmin 529

serum calcium 748

serum complement

components 351

serum copper 529

serum creatinine 650,651

serum electrophoresis

342– 3,696– 8

serum ferritin 529,745

serum free light chains 344

serum haptoglobins 260

serum immunoxation 342

serum

immunoglobulins 334– 5

serum iron 529,724

serum Na

417

serum parathyroid

hormone 749

serum urea 654

short ACTH (Synacthen

)

test 162, 225,417

short stature 98– 9,178

shunt patency 878,879

sick euthyroidism 180– 1

sickle cell disease 278,409

sickle cells 236,409

sickle haemoglobin 278– 9

sigmoidoscopy 412,

500,506– 7

silent thyroiditis 182– 4

silhouette sign 780

single- bre

electromyogram 611

single photon emission

computed tomogra-

phy (SPECT) 596– 7,

886,889

sinoatrial node

rhythms 472– 4

sinus tachycardia 110

sinus venosus ASD 469

skin autoimmune

disease 370

skin biopsy 420– 1,633

skin pigmentation 100– 1

skin prick tests 375,567

skin specimens 403

skull X- ray 590,860– 1

sleep stages 621

slit lamp 423

slow rising pulse 94

small bowel absorption

522

small bowel enema 800– 1

small bowel

follow- through 800– 1

small bowel

pathology 518– 19

small bowel studies 800– 1

smear cells 243

sodium

excretion 674– 5,687

sodium- retaining states 675

sodium- wasting states 675

somatosensory evoked

potentials 622– 4

somatostatin receptor

scintigraphy

Ga- DOTA- peptide PET/

CT 898– 9,901

SPECT 886,889

South East Asian

ovalocytosis 268

Southern blotting 322– 3

INDEX

968

specic gravity 678

specimen collection 402– 5

SPECT 596– 7, 886,889

spherocytes 236,258

sphincter disturbance 630

sphincter of Oddi

manometry 526

spinal

imaging 599– 600,836– 7

spinobulbar muscular

atrophy 643

spinocerebellar atrophy 643

spiral CTPA 411

spirometry 568– 9

splenic aspiration 421

splenic dysfunction 414

splenomegaly 102

splenunculi 940

splinter haemorrhages 64

‘spot’ urine tests 686

sputum 405, 419,570– 1

ST- elevation MI

(STEMI) 475

ST- segment 475

Stamey– Meares test 681

static cortical

renography 924,927

steatorrhoea 103

STEMI 475

stents 841– 3

sti person syndrome 371

stool samples 405,412

stress

echocardiography 459

stridor 104

stroke 107– 8

subarachnoid

haemorrhage 589

Sudan black 298,299

superwarfarin

overdose 739

suprapubic aspiration of

urine 680

suprapubicpain 6

supraventricular

arrhythmias 82

surface specimens 403

sutural widening 861

swallowing problems 37

Swan– Ganz

catheter 492,783

sweat test 576– 7

sweating 109

Synacthen

test 162,

225,417

syncope 34– 5

syndrome of inappro-

priate antidiuretic

hormone 138– 40,675

synovial uid 404,754

systemic lupus

erythematosus 360

T- cell acute lymphoblastic

leukaemia 313,319

T- cell subsets 414

T- tube

cholangiogram 802– 3

T wave 475

T3 180– 1

T3 toxicosis 182

T4 180– 1

tachycardia 110– 11,471

target cells 236

teardrop RBCs 236

temporal artery biopsy 38

temporal (giant) cell

arteritis 117,592

temporal lobe epilepsy 8

Tensilon

test 631

tertiary

hyperparathyroidism 189

testosterone

low 174

raised 170– 1

tetralogy of Fallot 468– 9

thalassaemia 271, 276,

282– 3,330

thallium poisoning 701

theophylline poisoning 737

therapeutic

embolization 841– 3

thermodilution method 492

theta rhythm 614

third- degree AV block 475

thoracic aortic dissection 23

thoracic CT 786– 7

thoracic spinal imaging 837

thoracocentesis 777– 8

thoracoscopy 578– 80

3- day faecal fat 522

throat specimens 403

thrombin clotting time 290

thrombocytopenia 88,

409,747

thrombocytosis 747

thrombolytic therapy 842

thrombophilia

screen 96,294

thrombosis, recurrent 96

thyroid

autoantibodies 180– 1

thyroid cancer 888,891

thyroid function

tests 180– 1

thyroid peroxidase (TPO)

antibodies 180– 1,366

thyroid

scintigraphy 880,881

thyroid- stimulating

hormone 180– 1

thyroid storm 184

thyrotoxicosis 182– 4

tidal volume 572

tilt table testing 494– 5

Tine test 422

tinnitus 112

tiredness 113

tissue transglutaminase

antibodies 369

tissue typing 320– 1,414

Todd’s paralysis 107– 8

tonsillar biopsy 421,634

total cholesterol 212– 13

total lung capacity 572

toxic granulation 243

toxic metabolic

encephalopathies 619

toxicology 700– 1,

702,704– 5

toxin tests 412

trace element analysis 701

transcranial Doppler 593

transcranial magnetic

stimulation 628– 9

transcription- mediated

amplication 407

transfer factor 582

transferrin 244

transferrin receptor 244

transferrin saturation 529

transfusion reactions 304– 6

transient elastography 531

transient

hypothyroidism 187

transient thyroiditis 182– 4

transiliac bone biopsy 695

transjugular intra- hepatic

portosystemic shunt 846

translocation 315

transoesophageal

echocardiography 454– 7

transthoracic

echocardiography 454– 7

tricuspid

regurgitation 464– 5

tricuspid stenosis 464

tricyclic antidepressant

poisoning 738

triglycerides 212– 13

trisomy 315

Troisier’s sign 62

tropical disease

diagnosis 388– 9

troponins 440,441

Trousseau’s sign 190

trypanosome 241

tuberculosis 23,426– 7

tuberculosis skin tests 422

tuberculous meningitis 589

tubular proteinuria 659

tubular urate handling 663

tumour markers 517

24h urinary copper

excretion 529

INDEX

969

24h urinary- free cortisol

collections 143

24h urine collections 687

two glass test 680

U wave 476

UK Haemoglobinopathy

Reference

Laboratory 283

ultrasound 816– 17

abdominal 411

breast 814

cholangiography 802

endoscopic 509

gynaecology 822

neurology 592–3

obstetric 820– 1

rheumatology 759– 60

urinary tract 810

uncal herniation 587

urea 654

urea breath test 413,

512,953

urethral specimens 403

urethritis 432

urgency 114

uric acid 748

urinary acidication 668– 9

urinary calcium 687,749

urinary chloride 672

urinary citrate 687

urinary cystine 687

urinary glycolate 687

urinary

haemosiderin 262,263

urinary 5- hydroxyindole

acetic acid 525

urinary incontinence 61

urinary L- glycine 687

urinary light chains

(BJ proteins) 344,660

urinary magnesium 673

urinary oxalate 687

urinary oxalate crystals 721

urinary potassium 672

urinary sodium 674– 5,687

urinary system drainage 844

urinary tract

radiology 808– 11

urine culture 680– 2

urine dipstick testing 676– 8

urine electrophoresis

342– 3,344

urine glucose testing 204

urine

immunoxation 342,344

urine microscopy 681– 2,

684– 5

urine samples 404, 680,681

urine toxicology 700

urobilin 262

urobilinogen 262

urodynamics 630

uroowmetry 630

urticaria 115

vaginal specimens 403

valproate toxicity 710

valvular heart disease 461– 6

vascular catheterization 842

vascular interventions 840– 2

vasculitic

syndromes 116,372– 3

vasoactive peptides and

amines 525

vasovagal syncope 34– 5

vegetations 64

ventilation/ perfusion

imaging 914– 16

ventricular arrhythmias 82

ventricular brillation 473

ventricular masses 467

ventricular rhythms 472– 4

ventricular septal

defects 469

ventricular tachycardia 473

vesico- ureteric reux 71

vesicular rash 433– 4

vestibular ataxia 15

vestibular nystagmus 77

VGCC antibodies 638

viral antibody tests 397

viral antigen tests 400

viral culture 394

viral haemorrhagic fever 431

Virchow’s triad 96

virilization 170– 1,171

virtual colonoscopy 807

visual evoked potentials 622

visual loss 117

vital capacity 572

vitamin B

248– 50,409

vitaminD 417

vitiligo 100

vomiting centre 74– 5

V/ Q scan 914– 16

Wada test 631

waist girth 79

warfarin overdose 739

water deprivation

test 220– 1

water intoxication 139– 40

waxy broad casts 685

weight loss 119

wheeze 120

white cell casts 685

white cell count 232,746– 7

white cell

morphology 242– 3

whole body

plethysmography 572– 4

whole genome

sequencing 644

wireless capsule

endoscopy 412,510

Wol– Chaiko eect 183

Wol– Parkinson– White

syndrome 474

word salad 36

X- rays, see plainX- rays

xanthelasmata 57

xanthomata 57

zinc poisoning 701

zinc protoporphyrin 726

970