Journal of
Clinical Medicine
Review
A Comprehensive Review of Complications and New Findings
Associated with Anorexia Nervosa
Leah Puckett
1,2
, Daniela Grayeb
1,2
, Vishnupriya Khatri
1,2
, Kamila Cass
1,2
and Philip Mehler
1,2,3,
*
Citation: Puckett, L.; Grayeb, D.;
Khatri, V.; Cass, K.; Mehler, P. A
Comprehensive Review of
Complications and New Findings
Associated with Anorexia Nervosa. J.
Clin. Med. 2021, 10, 2555. https://
doi.org/10.3390/jcm10122555
Academic Editors: Yael Latzer,
Daniel Stein and Itay Tokatly Latzer
Received: 25 March 2021
Accepted: 6 June 2021
Published: 9 June 2021
Publisher’s Note: MDPI stays neutral
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1
ACUTE Center for Eating Disorders, Denver, CO 80204, USA; [email protected] (L.P.);
2
Department of Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USA
3
Eating Recovery Center, Denver, CO 80230, USA
* Correspondence: [email protected]; Tel.: +1-(303)-602-4972
Abstract:
Anorexia nervosa is a complex and deadly psychiatric disorder. It is characterized by a
significant degree of both co-occurring psychiatric diseases and widespread physiological changes
which affect nearly every organ system. It is important for clinicians to be aware of the varied
consequences of this disorder. Given the high rate of mortality due to AN, there is a need for
early recognition so that patients can be referred for appropriate medical and psychiatric care
early in the course of the disorder. In this study, we present a comprehensive review of the recent
literature describing medical findings commonly encountered in patients with AN. The varied
and overlapping complications of AN affect pregnancy, psychological well-being, as well as bone,
endocrine, gastrointestinal, cardiovascular, and pulmonary systems.
Keywords:
eating disorders; anorexia nervosa medical complications; medical findings in
anorexia nervosa
1. Introduction
Anorexia nervosa (AN) is a complex psychiatric disorder with a high rate of mortality
and a relatively low rate of remission [
1
]. Using DSM-V criteria, the lifetime prevalence of
AN in females is estimated to be as high as 4% [
2
]. The lifetime prevalence in males has
been estimated to be between 0.1% and 0.3%, although this is likely an underestimate [
3
].
AN has a high rate of psychiatric comorbidities including strong associations with mood
and anxiety disorders, personality disorders, self-harm and suicidality, as well as substance
use disorders [
4
,
5
]. In addition, AN leads to widespread medical complications across
virtually all organ systems, which contributes to it being one of the highest causes of
mortality among psychiatric disorders [
6
]. Complications worsen with a lower body mass
index (BMI), which indicates a greater severity of disease [
7
]. Medical complications have
been related to a plethora of complex physiological changes that lead to decreased energy
expenditure and include cardiac, bone, obstetric, and gynecological changes, as well as
endocrine, gastrointestinal, hematological, electrolyte imbalance, and skin changes [4].
2. Etiopathogenesis
The etiopathogenesis of AN is still unknown. Although progress has been made in
identifying genetic, developmental, psychological, and neurobiological factors that play
a role in the development of the disorder [
8
], it is evident that, similar to all psychiatric
disorders, its origins are multifactorial. AN is familial, with heritability estimates for AN
ranging from 0.41 to 0.74 [
9
,
10
], and higher heritability estimates have been found when
more stringent definitions of anorexia were applied [
11
]. Significant genetic correlations
have been found among AN and various anthropometric and metabolic traits, including
negative correlations with BMI, fasting insulin, and fasting glucose [
12
], and therefore
metabolic factors, including the gut microbiome, have been considered for understand-
ing the etiology of AN [
13
,
14
]. Developmentally, cesarean section, multiple births, low
J. Clin. Med. 2021, 10, 2555. https://doi.org/10.3390/jcm10122555 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2021, 10, 2555 2 of 15
gestational age, congenital malformations of the mouth or digestive system, and older
parental age are associated with increased risk of AN [
15
,
16
]. Temperamental characteris-
tics associated with lifetime prevalence of AN include perfectionism, obsessionality, reward
dependence, negative affectivity, and neuroticism [
17
–
19
]. Neurobiologically, findings of
reward processing and reward learning abnormalities indicate reward circuit dysfunction
in AN [
20
,
21
]. Neuropsychologically, impairments such as set-shifting difficulties and poor
central coherence may be related to the pathophysiology of the disorder [
22
]. Dieting is the
most common precipitating factor for the development of AN, with severe dieting being
especially implicated in triggering the onset of AN [23,24].
3. Psychiatric Treatment
There are currently no FDA approved medications for the treatment of AN [
25
]. The
most established psychological treatment for adolescents with AN is family-based therapy
(FBT) [
26
]. Randomized controlled trials have shown adolescent FBT to be superior to
individual therapy for supporting weight restoration in adolescents. Currently, there
are no therapy modalities that have achieved empirical support for adults with AN and
no evidence that a particular mode of therapy is more efficacious than another mode
of therapy [
27
]. Novel approaches are being explored, including treatments focused on
neurocognitive factors found to be impaired in individuals with AN, including problems
with set-shifting and central coherence [
28
]. Treating patients at the appropriate level of
care is important. In severe cases, initial medical stabilization, followed by inpatient and
residential treatment, is recommended [
29
]. Severe AN is defined by a BMI of <15 kg/m
2
.
For adolescents, inpatient treatment of AN has been shown to be highly effective, with
sustained increases in body weight and decreases in eating disorder symptoms found at
one-year follow-up [
30
]. Due to a lack of insight into the severity of the disease among
patients, involuntary treatment may be indicated [31].
4. Medical Complications
4.1. Endocrine System Complications
Anorexia nervosa (AN) is characterized by alterations in multiple neuroendocrine axes
and peptides that signal or regulate energy intake. Some of the endocrine and metabolic ab-
normalities in patients with AN represent physiological adaptive responses to chronic star-
vation that are reversible after weight restoration. However, other abnormalities may play
a role in disease pathophysiology and sustained neuropsychiatric symptoms. Hormonal
changes include growth hormone (GH) resistance with low insulin-like growth factor-1
(IGF-1) levels, hypothalamic hypogonadism, hypercortisolemia, and changes in appetite-
regulating hormones such as leptin, ghrelin, peptide YY, and possibly adiponectin [
32
].
Changes are seen in the hypothalamic-pituitary axis (HPA) in patients with AN which
affect both anterior and posterior derived pituitary hormones.
4.1.1. Hypothalamic-Pituitary-Adrenal Axis
The hypothalamic-pituitary-adrenal axis (HPAA) is in a chronically stimulated state
in at least one-third of patients with AN [
33
]. Elevated baseline cortisol levels are likely
observed during extreme caloric restriction in both healthy individuals and patients with
AN. However, reversibility of HPAA dysregulation, even in recovered patients with AN,
is not always observed [
34
]. Cortisol stimulates gluconeogenesis, and cortisol levels in
patients with AN have been shown to be inversely correlated to fasting glucose [
35
].
The degree of hypercortisolemia also correlates inversely with BMI and fat mass [
36
].
Furthermore, it is associated with the severity of bone loss and depression in patients with
AN [37].
4.1.2. Hypothalamic-Pituitary-Thyroid Axis
Severe weight loss in patients with AN is characterized by the nonthyroidal illness
syndrome (also known as euthyroid sick syndrome) seen in patients with systemic illnesses,
J. Clin. Med. 2021, 10, 2555 3 of 15
including chronic starvation. In women with AN, levels of total triiodothyronine (T3) are
low. The reverse T3 level is elevated due to increased peripheral deiodination of thyroxine
(T4) to reverse T3. Free T4 levels vary from normal to low normal, and TSH levels vary
from normal to low normal [
38
]. These changes are an adaptive response to a decrease
in metabolic rate and energy expenditure, and therefore require no treatment other than
weight recovery.
4.1.3. Hypothalamic-Pituitary-Gonadal Axis
Studies of adult women with AN show immature, low amplitude luteinizing hormone
(LH) pulses. The altered LH pulsatility manifests as hypothalamic amenorrhea. LH
secretory patterns may revert to prepubertal levels of low, nonpulsatile secretion or to a
pubertal pattern of entrainment of LH secretion to the sleep cycle. LH and FSH responses
to GnRH appear normal, indicating that the reduced pulse frequency is not secondary to
pituitary changes but presumably because of changes in the GnRH pulse generator. The
gonadotropin secretion is stimulated by both estradiol and leptin, which are both decreased
in patients with AN [39].
4.1.4. Growth-Hormone/Insulin-Like Growth Factor-1 Axis
Anorexia nervosa (AN) is characterized by a nutritionally acquired growth hormone
(GH) resistance leading to low concentrations of insulin-like growth factor-1 (IGF-1), which
is another essential determinant of reduced bone mineral density. High levels of GH in
individuals with AN have a gluconeogenic role in maintaining euglycemia, mediated
through increased lipolysis. Weight gain leads to a normalization of GH secretion and GH-
binding protein concentrations, which are consistent with adaptation to the individual’s
nutritional status [40].
4.1.5. Hypothalamic Neuropeptides
Hypothalamic neuropeptides such as nesfatin-1, phoenixin, spexin, and kisspeptin af-
fect energy homeostasis and eating behaviors and may also be involved in the pathogenesis
of anxiety related to eating disorders [41].
4.1.6. Vasopressin (or Antidiuretic Hormone, ADH)
Hyponatremia is very common in patients with AN and may lead to complications
such as altered levels of consciousness and seizures. Purging behaviors, as seen in the
binge eating-purging subtype, are the most common cause, although the syndrome of
inappropriate antidiuretic hormone secretion (SIADH) may also be implicated. Central
diabetes insipidus (DI), resulting in hypernatremia, has also been reported in patients with
AN due to defective vasopressin secretion [
42
]; DI can also manifest during the refeeding
period as a disorder of osmoregulation between serum osmolality and plasma vasopressin
levels [43].
4.1.7. Oxytocin
Basal levels of oxytocin, a neuropeptide normally produced in the hypothalamus and
released by the posterior pituitary, are decreased in patients with AN. Oxytocin plays a role
in social bonding, modulation of anxiety and depressive symptoms, and bone metabolism.
It is speculated that low oxytocin levels may contribute to alexithymia in women with
anorexia nervosa [44].
4.1.8. Appetite-Regulating Hormones
Gastrointestinal hormones are normal signals to modulate appetite and maintain
energy homeostasis. Ghrelin is an orexigenic hormone predominantly produced in the
stomach and is thought to act upon the HPA, affecting the secretion of gonadotropin-
releasing hormone (GnRH), adrenocorticotropic hormone (ACTH), growth hormone (GH),
follicle-stimulating hormone (FSH), and LH. Plasma ghrelin levels are elevated in both
J. Clin. Med. 2021, 10, 2555 4 of 15
AN-restricting (AN-R) and AN-binge eating/purging (AN-BP) subtypes. The increase in a
hormone with orexigenic action in patients with AN is paradoxically caused by a central
resistance to ghrelin. In patients with AN, the lack of a motivating feeding response to
ghrelin, despite hunger sensation, supports an altered reward circuit that may contribute to
the disease’s onset and maintenance [
45
]. Elevated ghrelin concentrations in patients with
AN may be necessary to modulate glucose homeostasis, serving as an adaptive mechanism
for maintaining normoglycemia in response to severe undernutrition. The secretion of
ghrelin varies with insulin levels, suggesting a reciprocal regulation of these hormones [
46
].
Peptide YY (PYY) is an anorexigenic hormone released by the L cells of the distant
intestine in response to caloric intake that acts at the hypothalamus to decrease appetite
and food ingestion. PYY correlates inversely with BMI and fat mass. Levels of PYY are
paradoxically elevated in patients with AN; this would not be adaptive to a state of chronic
malnutrition but may play a role in the disorder’s pathogenesis contributing to decreased
nutrient intake and disordered eating psychopathology [47,48].
Adipocytokines secreted by adipose tissue, such as adiponectin, leptin, and resistin,
have significant roles in regulating energy metabolism and insulin sensitivity [
49
]. Leptin,
a hormone mainly produced in white adipose tissues, is a valuable marker of long-term
energy stores. In patients with AN, there is a marked fall in leptin concentration in
proportion to fat mass [
46
]. A decrease in serum leptin levels, described in the literature,
has been postulated to lead to both amenorrhea and restlessness similar to rat-specific
semi-starvation-induced hyperactivity [
50
]. However, data concerning serum levels of
the other adipocytokines are conflicting. Serum adiponectin has been found to be either
increased, normal, or decreased in various studies in AN patients [
51
,
52
]. Likewise, serum
plasma resistin levels have been found to be either decreased or normal [
53
,
54
]. These
discrepancies suggest that confounding factors, such as eating behaviors and physical
activity level, could interfere with the results and further studies are needed.
4.1.9. Glucose Metabolism
In general, fasting levels of glucose are lower in patients with AN than in healthy
controls. Hypoglycemia has been described as one of the causes of sudden death in patients
with AN. Liver injury caused by autophagia, hypotension, ischemia, in addition to marked
glycogen depletion, seem to be the causes of hypoglycemia. To counteract the effects
of hypoglycemia, secretion of both GH and cortisol induce insulin resistance, and thus
increase glycemia. Gastrointestinal hormones such as glucagonlike peptide 1 (GLP-1) and
amylin stimulate insulin release from pancreatic cells. The plasma levels of GLP-1 and
amylin are both found to be low in patients with AN, which seems to be an appropriate
adaptive response to starvation in order to prevent further hypoglycemia [42].
4.2. Refeeding Syndrome
The term refeeding syndrome (RS) has been used to describe the adverse consequences
that can occur in all malnourished patients during the early stages of nutrition repletion,
whether the method of refeeding is oral, enteral, or parenteral. Patients with AN are at
high risk for RS. Refeeding hypophosphatemia (RH) is the most common complication
of nutritional restoration for patients with AN. The highest risk of hypophosphatemia
seems to be in patients who weigh less than 70% of their ideal body weight or lose weight
rapidly [
55
]. Other consequences of RS include acute thiamine deficiency resulting in
Wernicke’s encephalopathy and Korsakoff syndrome, with the potential for permanent
cognitive impairment, hypokalemia, hypomagnesemia, metabolic acidosis, or alkalosis,
and fluid overload resulting in cardiac failure. The American Society for Parenteral and
Enteral Nutrition (ASPEN) Parenteral Nutrition Safety Committee and the Clinical Practice
Committee have developed consensus recommendations for identifying patients with or
at risk for refeeding syndrome (RS) and for avoiding and managing the condition. RS
diagnostic criteria can be stratified as follows: a decrease in any one, two, or three of
serum phosphorus, potassium, or magnesium levels by 10–20% (mild), 20–30% (moderate),
J. Clin. Med. 2021, 10, 2555 5 of 15
or >30% and/or organ dysfunction resulting from a decrease in any of these or due to
thiamine deficiency (severe), occurring within 5 days of reintroduction of calories [
56
]. In
patients with AN, the degree of malnourishment appears to correlate with the severity of
RH [57].
The reintroduction of nutrition leads to a switch from fat to carbohydrate metabolism
and an increase in insulin concentration. Insulin stimulates the movement of potassium,
phosphate, and magnesium into cells leading to their depletion in the extracellular com-
partments. Reactivation of carbohydrate metabolism increases degradation of thiamine,
a cofactor required for cellular enzymatic reactions in Krebs cycle. Deficiency in all these
nutrients can then occur [58].
Recent studies have provided evidence to support a switch in current care practices
for refeeding from a conservative approach to higher calorie refeeding; however, caution
should still be applied for more severely malnourished, i.e., <70% average body weight,
and/or chronically ill, adult patients [59].
4.3. Bone Health in Anorexia Nervosa
Of notable concern related to AN are the effects of malnutrition on bone health.
Unfortunately, the deleterious effects on bone mineral density (BMD) are not completely
reversible despite weight restoration. These effects include decreased height, chronic pain,
and increased immediate and lifetime risk of fracture due to inadequate bone accrual and
ongoing bone loss [
60
,
61
]. A recent cohort study of 344 female patients who were being
treated for eating disorder found a significantly lower BMD at the L-spine (16%), femoral
neck (18%), and total hip (23%) in patients with active AN. Patients in remission had lower
BMD than healthy controls but higher than women with active AN at the L-spine and
hip [62].
Bone mineral density is measured by dual-energy X-ray absorptiometry (DEXA). T
scores reflect a comparison with peak bone mass of healthy adults, while Z scores reflect
age and sex-matched comparisons. Generally, in younger patients (<50 years old), Z scores
are used for reporting. Osteopenia is defined as a BMD between
−
1.5 and
−
2.5, while
osteoporosis is defined as a BMD < −2.5 [63].
Males and females with AN are both at risk of bone disease; 80% of females with AN
have BMD Z scores < 1, 44% of females have BMD Z scores < 2, and 32% of males with
AN have BMD Z scores < 2 [
64
]. A previous longitudinal study demonstrated a decrease
in BMD over time, with a large mean annual decline of 2.4% at the hip and 2.6% at the
spine. While BMD stabilized over the first year after weight restoration and continued to
increase over time, it failed to fully normalize [
64
]. A recent study that assessed long-term
outcomes of bone health in females, at 5 and 10 years after initial diagnosis of anorexia
nervosa, demonstrated decreased BMD at the femoral neck and arms and CT evidence of
cortical thinning, despite BMI being normal [65].
Factors associated with an increased risk of low BMD include lower BMI, longer
duration of illness and amenorrhea, decreased muscle mass, and lower serum vitamin
D levels [
61
,
66
]. The risk appears to be increased primarily in patients with restrictive
eating disorder patterns. One large community sample found that BN was not a risk factor
for low BMD if not associated with restriction [
67
]. An additional risk factor for bone
disease in patients with AN is adolescent age. An earlier age of onset of AN (<18 years) is
associated with a greater decrease in BMD [
64
]; 39% of bone mineral content is accrued
between ages 10–14 and 95% of peak bone mass is typically reached prior to age 19 in
healthy females, a process that is impaired in patients with AN. Adolescent females as well
as males demonstrate decreased markers of both bone formation and resorption [
64
]. Adult
women with AN demonstrate increased bone resorption and decreased bone formation [
64
].
This “uncoupling” is indeed the reason for aggressive loss of BMD in patients with AN,
notwithstanding their typically young age, in contrast to post-menopausal women with
osteoporosis where the only issue is increased resorption.
J. Clin. Med. 2021, 10, 2555 6 of 15
Bone disease in AN is caused by a complex interplay of physiological changes that
occur in the malnourished state in response to energy deprivation which are incompletely
understood. Changes in function of the hypothalamic-pituitary-adrenal axis include de-
creased GNRH leading to decreased LH and FSH and impaired ovulatory function. This
leads to decreased estrogen which results in increased bone resorption. Decreases in testos-
terone and dihydroepiandrosterone (DHEA) are also observed and can further lead to
decreased estrogen. In males with AN, low testosterone contributes to decreased BMD [
68
]
and indeed severe osteoporosis is also a major problem for these males. In addition, GH
resistance and increases in CRH, ACTH, and cortisol lead to decreased BMD. Changes in
hormones such as leptin which is stored in adipose tissue and alterations in gut hormones
further contribute. Collectively, these changes are reflective of the energy-conserving state
in AN [64].
Patients with AN demonstrate a lifetime increased risk of fracture in both males and
females. Thirty percent of women with AN report a fracture at one or more sites over
a lifetime [
67
]. Risk of fractures in females is observed at younger ages, across all sites,
whereas risk of fractures in males with AN is seen after age of 40 with an increased rate of
vertebral fractures specifically [
64
]. Cumulative incidence of any fracture persists 40 years
after diagnosis [69].
Despite the evidence of bone disease as evidenced by both decreased BMD and in-
creased fracture risk in patients with AN, it is unclear if the increased fracture risk seen in
AN can be directly associated with BMD measurement. One study, which demonstrated
60% increased fracture risk in women with AN, found fractures occurred even in women
with normal BMD. Another 18-month longitudinal study demonstrated that 12.5% of
women with AN had asymptomatic vertebral fractures not associated with illness dura-
tion, severity of malnutrition, or BMD [
64
]. A recent study that demonstrated increased
fracture risk in AN did not find a direct association with decreased BMD [
62
]. Authors
cited potential limitations of DEXA for assessing BMD in patients with AN, including
relationships between DEXA and fracture risk taken primarily from post-menopausal
populations, altered body composition arising from cycles of weight-loss and weight-gain
leading to inaccurate estimate of BMD, and difficulty estimating the cumulative effects of
AN given multiple periods of disease relapse and remission [
62
]. Further studies need to
be conducted to better elucidate how to utilize DEXA in evaluating and reducing fracture
risk in patients with AN.
Given the interplay between amenorrhea and bone disease, there has been interest in
hormonal treatment of both males and females with AN. Many studies have not demon-
strated increased BMD in females with AN who used oral contraceptive pills (OCPs), and
there has been concern regarding hormonal treatment in younger patients with AN due to
the risk of premature closure of epiphyseal plates [
64
]. However, a recent cross-sectional
study demonstrated possible benefits. Females with AN using OCPs were found to have
improved BMD at whole body, lumbar spine, as well as femoral neck, hip, and radius.
The benefits correlated with longer duration of treatment with OCPs and shorter delay in
initiating OCP treatment after AN onset. Patients with lower BMI experienced the greatest
benefit from use of OCPs [
70
]. Yet, most experts do not recommend OCPs to treat low BMD
in patients with AN. Previously, physiologic estrogen has been shown to improve BMD at
the spine and hip in adolescents with AN [
71
]. Another recent small exploratory study that
investigated the use of transdermal estrogen in adult women with AN found increased
spine BMD [
72
], and many experts have recommend transdermal estrogen for younger
patients with AN and low BMD. Testosterone therapy may be beneficial for treating males
with AN. In older men with osteoporosis, testosterone has been shown to increase BMD, as
well as in younger men with hypogonadism. However, there is a lack of data on treatment
of bone disease in males with AN [68].
The mainstay for treatment of bone disease in AN is nutrition and weight restora-
tion. In addition, patients should be instructed to take an adequate amount of calcium
and vitamin D to optimize bone health. Studies in patients with AN have demonstrated
J. Clin. Med. 2021, 10, 2555 7 of 15
an association with calcium intake <600 mg/day and lower bone mineral densities, as
well as a high prevalence of vitamin D deficiency and insufficiency [
68
]. Treatment of
bone disease in AN with prescription medication must take into account the risks and
benefits of the various potential options. Bisphosphonates, which work by inhibiting bone
resorption, are one option. Alendronate has been shown to increase BMD in adolescents
treated for one year; however, the improvement compared to controls was not statistically
significant. A randomized controlled trial demonstrated improvement in spine and hip
BMD in adult women with AN [
68
]. Possible adverse effects include congenital abnor-
malities in women of childbearing age, which are particularly concerning given the long
half-life of bisphosphonates [
68
]. Other potential side effects are osteonecrosis of the jaw
in patients undergoing extensive dental work, gastrointestinal side effects, and atypical
femur fractures [
63
]. Another treatment option is teriparatide, a recombinant parathyroid
hormone analog which improves bone formation. It is given as a daily injectable for at least
2 years which may be impractical for some women. Yet, it has demonstrated significant
improvement in BMD (10.5% at the spine) in older women with AN [
73
]. Teriparatide is
contraindicated in pregnancy and should be avoided in patients with Paget’s disease or un-
explained alterations in alkaline phosphatase given a risk of development of osteosarcoma
observed in rats [
63
,
68
]. Another option is denosumab, a human monoclonal antibody that
inhibits osteoclasts and is an injection given every 6 months. This medication has been
demonstrated to be effectiveness in post-menopausal women with osteoporosis but has
not been studied in AN. BMD decreases quickly after cessation of denosumab, therefore,
drug holidays are not recommended with its usage [63,68].
4.4. Gastrointestinal Complications in Anorexia Nervosa
Gastrointestinal (GI) symptoms are common in AN, with over 90% of patients report-
ing GI complaints. While the pathogenesis of GI complaints are attributed to sequelae of
weight loss, there is also a significant functional component to many of the GI complaints
by patients with AN [74,75].
A recent systematic literature review, from 1967 to 2019, categorized the most common
subjective GI symptoms reported by patients with AN. Among them include constipa-
tion, nausea, abdominal pain, abdominal fullness, vomiting, heartburn, epigastric pain,
decreased appetite, diarrhea, and dysphagia [
76
]. Kessler et al. found that the severity
of GI symptoms was more significantly correlated with somatization than with eating
disorder severity and did not correlate with BMI [
77
]. This supported a previous study by
Boyd et al. that also reported an association with anxiety and neuroticism and severity
of GI complaints in patients with AN [
78
]. A recent literature review (2000–2017) of the
medical causes of food-related GI symptoms in eating disorders found that AN patients
reported higher food-associated symptoms than average; however, the incidence of celiac
disease, an immune-mediated disorder to gluten, was similar among patients with AN and
the general population. On the basis of their comprehensive review, Kress et al. predicted
that the prevalence of immunological or structural GI disorders was no higher in patients
with AN than in the general population, and that GI complaints from patients with AN
were more likely to be functional. They advised that further diagnostic workup for per-
sistent symptoms was warranted only after control of purging and restrictive behaviors
and weight restoration [
75
]. More studies in patients with AN are needed to assess the
functional nature of GI complaints and to further evaluate the prevalence of food allergies
and intolerances.
Another interesting area of research is the role of intestinal microbiota, i.e., living
organisms including prokaryotes, eukaryotes, archaea, and viruses, on the gut-brain
axis [
79
]. Hata et al. found that transplanting the gut microbiome from patients with
AN into germ-free mice resulted in poor weight gain, decreased appetite, decreased food
efficiency, increased anxiety-related and compulsive behaviors, and decreased serotonin
levels as compared with healthy mice. Compulsive behavior improved after administration
of Bacteroides vulgatus (a genus found to be low in AN patients), however, it did not impact
J. Clin. Med. 2021, 10, 2555 8 of 15
weight gain [
80
]. Studies in patients with AN have shown a significant reduction in
Roseburia species, which was associated with a decreased level of butyrate, i.e., a short-
chain fatty acid, that correlated with anxiety and depression disorders. A reduction in
Roseburia inulinivorans was correlated with lower insulin levels, which may help patients
with AN to preserve euglycemia. Additionally, higher levels of Enterobacteriacee and
Methanobrevibacter smithii, an Archaeon capable of extracting more calories from food
through the transformation of hydrogen to methane, have been identified in patients with
AN as compared with healthy controls. There is experimental evidence that intestinal
methane production is linked to slower intestinal transit, predisposing to constipation [
81
].
One study showed that, while overall microbial richness increased after weight gain, gut
dysbiosis, short chain fatty acid profiles, and GI complaints remained persistent three
months after weight gain [
74
]. Whether dysbiosis is the cause or effect of AN remains to be
seen. Furthermore, fecal microbiota transplant is a promising area of research that might
provide treatment and shed more light into this complex system [74,81].
While many of the GI complaints in patients with AN may be functional, there are cer-
tain GI complaints that require further investigation. Many case reports have documented
superior mesenteric artery (SMA) syndrome (more commonly in AN-R) [
76
,
82
]; acute
gastric dilation with subsequent gastric wall ischemia, necrosis, and perforation (more
commonly in AN-BP); and duodenal dilation (more commonly in AN-R) [
76
], which further
exacerbate GI symptoms and should remain in the differential diagnosis of abdominal pain
in patients with AN.
In addition, there are numerous abnormalities in the liver that occur in AN. Starvation-
induced autophagy and apoptosis is the proposed mechanism for liver dysfunction in AN,
supported by liver biopsies in patients with AN with aminotransferase > 1900 IU/mL (typ-
ically with ALT > AST) [
83
]. Independent of body weight, the incidence of hypoglycemia
was four to five times higher with liver dysfunction, and hypophosphatemia occurred
twice as often with elevated liver function tests in patients with AN [
84
]. Severe, acute
liver failure in patients with AN is reversible with weight restoration and rarely requires
testing for secondary causes of liver dysfunction. An increase in aminotransferases also
occurs with refeeding, likely due to excessive hepatic fat and glucose deposition, and can
be managed with a reduction in daily caloric amount [83].
4.5. Cardiovascular Complications in Anorexia Nervosa
Cardiovascular complications have long been implicated in sudden death of patients
with AN, which, as previously stated, remains to be one of the deadliest psychiatric disor-
ders [
85
]. Research advances over the past few years have progressed our understanding
of the static and dynamic cardiac changes in patients with AN.
Studies of cardiac hemodynamics continue to demonstrate the near universal finding
of bradycardia, as well as decreased heart rate variability (HRV) in patients with AN [
85
,
86
].
Bradycardia is reversed with weight restoration, and permanent pacemaker placement is
unwarranted and causes procedural complications [
85
,
86
]. As Cotter et al. recommended,
society guidelines should be updated to include AN within reversible causes of bradycardia
to avoid unnecessary permanent pacemaker placement [
86
]. A meta-analysis demonstrated
a small increase in resting vagal tone, measured indirectly through HRV [
87
]. A decreased
HRV has also been seen in patients with AN who underwent continuous cardiac monitoring
for a year [
85
]. Co-morbid depression further decreased the HRV in patients with AN [
88
].
Decreased HRV has been a known independent predictor of mortality in post-myocardial
infarction patients for decades [
89
]. However, more studies are needed to understand the
clinical implication of decreased HRV in patients with AN.
Our understanding of cardiac structure and function in patients with AN continues
to progress with comprehensive, modern, and dynamic echocardiographic evaluations
and more recently cardiac MRI (CMRI) studies. A retrospective study evaluated Doppler
echocardiograms in adult patients with AN with an average BMI of 12 (N = 124) [
90
]. All
AN patients had subclinical cardiac impairments and 15% had reduced ejection fraction
J. Clin. Med. 2021, 10, 2555 9 of 15
(EF). Interestingly, AN-BP and hypertransaminasemia were independently associated with
a reduced EF. Consideration for echocardiogram should be made in patients with AN
(especially AN-BP) with hypertransaminasemia to prevent complications of heart failure
with refeeding [
90
]. Doppler echocardiography used to assess aortic stiffness by pulse
wave velocity in adolescent AN patients found increased arterial stiffness [
91
]. Whether
this portends a higher risk of cardiovascular disease, or if it is reversed with weight restora-
tion, remains to be seen. A meta-analysis of echocardiographic findings in patients with
AN revealed a reduction in left ventricular mass, a reduction in cardiac output, diastolic
dysfunction, and an association with mitral valve prolapse and pericardial effusion, with
a trend toward improvement with weight restoration [
92
]. Left ventricular mass was
increased in hyperactive patients with AN as compared with non-hyperactive patients with
AN but was still significantly lower than in the healthy controls [
93
]. Dynamic changes in
cardiac function during exercise have been evaluated using stress echocardiography [
94
].
Adolescent patients with AN had reduced exercise duration, which was independently
associated with BMI, and reduced peak cardiovascular indices as compared with healthy
controls, but a normal pattern of cardiovascular response with progressive exercise [
94
].
In a study of 40 patients with AN (average BMI 15), 23% of the patients showed evidence
of myocardial fibrosis on CMRI as evidenced by late gadolinium enhancement (LGE) as
compared with 0% in the control group [
95
]. Myocardial fibrosis has been positively corre-
lated to sudden death in the general population, likely due to propensity for arrhythmia
formation [
95
]. A more recent study did not find evidence of LGE on CMRI in patients with
AN. However, the majority of AN patients had recovered weight at the time of CMRI in
the study [
96
]. More CMRI studies in patients with AN are warranted to better understand
the prevalence of myocardial fibrosis and the clinical significance.
Previous studies have reported conflicting results on whether QTc prolongation is
inherent in AN [
97
–
100
]. Recent studies, however, have reported consistent findings of
normal QTc in patients with AN, including a meta-analysis of 964 patients and a cohort
study of 1026 patients, using a variety of QTc correcting formulas [
97
,
98
]. Furthermore,
another study found no correlation between QTc > 440 ms and increased risk of cardiac
events or all-cause mortality in patients with AN [
99
]. QTc prolongation, when present in
patients with AN, therefore, should be considered in the context of extrinsic factors such
as hypokalemia and/or known QT prolonging medications rather than being summarily
attributed to AN [
97
]. A dynamic QTc evaluation during exercise showed a longer QTc
in patients with AN than healthy controls during peak exercise, returning to normal at
rest [
100
]. More studies are needed to validate this finding and control for QTc prolonging
medications. As the focus shifts from QTc prolongation as a cause of sudden death of
patients with AN, a year-long insertable cardiac monitor study revealed bradyarrhythmia,
particularly sinus pauses, to be more common and perhaps more relevant for understanding
the etiology of sudden cardiac death than ventricular tachyarrhythmias, although more
studies are needed [85].
4.6. Pulmonary Complications in Anorexia Nervosa
Anorexia nervosa can lead to weakness and wasting of respiratory muscles, dyspnea,
reduced aerobic and pulmonary capacity, lung parenchyma alterations, and life-threatening
consequences [
101
]. In recent studies, cases of spontaneous pneumothorax and pneumo-
mediastinum related to starvation have been reported [
102
–
104
]. Different mechanisms
for this have been proposed. One proposed mechanism is a traumatic mechanism with
vomiting-induced esophageal rupture (Boerhaave syndrome), as has been described in
cases of AN. Another proposed mechanism is the Macklin effect, where alveolar rupture
may occur due to increased intra-alveolar pressure and low perivascular pressure [
105
,
106
].
Air from ruptured alveoli may migrate into the mediastinum, pericardium, peritoneal, and
retroperitoneal cavities; subcutaneous tissues; and the epidural space [107].
J. Clin. Med. 2021, 10, 2555 10 of 15
Bullae, bronchiectasis, and other structural changes of the lungs may occur as severe
complications of AN [
108
]. Emphysema-like changes have also been reported in the lungs
of chronically malnourished patients because of anorexia nervosa [109].
Lung infections due to opportunistic organisms and usually nonpathogenic mycobac-
teria have been described in patients with AN and no history of a preexisting pulmonary
disease [
110
–
112
]. However, gastroesophageal disease and other causes of chronic aspira-
tion (self-induced vomiting) may predispose patients with AN to develop bronchiectasis,
and thus increase their risk for non-tuberculous mycobacterial infections [113].
4.7. Hematologic Complications in Anorexia Nervosa
Gelatinous marrow transformation occurs as malnutrition worsens. Specifically,
serous fat atrophy in the bone marrow, and normal marrow fat is replaced by a thick
mucopolysaccharide substance that impedes the egress of precursor cells from the bone
marrow [
114
,
115
]. This leads to trilinear hypoplasia with leukemia, anemia, and thrombo-
cytopenia detected in that order of decreasing frequency [116].
Interestingly, despite frank neutropenia, patients with AN do not appear to be at an
increased risk of infection, and thus neutropenic precautions are not needed. Similarly,
the use of expensive growth factors is not indicated because the marrow reconstitutes
quickly with nutritional rehabilitation. Anemia in patients with AN is typically normocytic,
but when the red blood cells indices are abnormal, it is typically macrocytic, although
vitamin B
12
and folate levels are not low [
117
]. Microcytic anemia is rare and requires
additional evaluation.
4.8. Obstetric/Gynecologic Complications in Anorexia Nervosa
Amenorrhea occurs in up to 84% of females with AN, related to complex physiolog-
ical hormonal changes including the aforementioned drop in serum levels of leptin and
a decrease in gonadotropin-releasing hormone which leads to decreased LH, FSH, and
anovulation [
118
,
119
]. This has important consequences on fertility in women with AN,
making it more difficult to conceive and increases the likelihood of miscarriage and preg-
nancy related complications such as preterm birth, cesarean section, microcephaly, small
for gestational age, and perinatal mortality if conception does occur. These complications
persist in women with a history of AN despite recovery, albeit with overall improvement
in fertility potential [
118
,
120
]. Thus, women with AN need a higher level of surveillance
during pregnancy and delivery [120].
Despite overall difficulties with fertility in patients with AN, adolescents with AN
have a two-fold increase in unplanned pregnancy. A recent review found a lack of evidence
for a negative impact on BMD in adolescents and young women with AN treated with
combined hormonal contraceptives over a 12–18 month period [
119
]. In addition, there
may be a protective effect of prolonged usage of OCPs [
119
]; however, this remains contro-
versial. Given the high risk of unplanned pregnancies, contraception is an important issue
to consider.
5. Conclusions
In summary, the complications of AN are varied and complex, with a significant over-
lap in pathophysiological mechanisms. The devastating effects of malnutrition perpetuate
the eating disorder given exacerbation of physical and psychological discomfort during
malnutrition and refeeding. Awareness of current and real medical complications that
occur in patients with severe AN can help both clinicians and families to recognize the
complexity of the illness and underscores the need for informed care. There is significant
emerging research about the widespread medical impact of AN, the understanding of
which helps providers to best serve patients who suffer from this disorder.
J. Clin. Med. 2021, 10, 2555 11 of 15
Author Contributions: L.P., writing—original draft preparation abstract, introduction, bone health,
obstetric/gynecologic health, conclusion, writing—review and editing of entire manuscript, project
administration; D.G., writing—original draft preparation endocrine, pulmonary complications,
writing—review and editing endocrine, pulmonary complications; V.K., writing–original draft
preparation GI, cardiac complications, writing—review and editing GI, cardiac complications; K.C.,
writing—original draft preparation etiopathogenesis and psychiatric treatment, writing—review and
editing etiopathogenesis and psychiatric treatment; P.M., conceptualization of entire manuscript,
writing—original draft preparation hematologic complications, writing—review and editing entire
manuscript, supervision of entire manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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