Eating disorders in adolescents with chronic gastrointestinal and endocrine diseases

Review

Eating disorders in adolescents with chronic gastrointestinal and endocrine diseases Jonathan T Avila, KT Park, Neville H Golden

Eating disorders are one of the most common chronic conditions in adolescents. The clinical symptoms can mimic those of other chronic diseases including gastrointestinal and endocrine disorders. However, an eating disorder can coexist with another chronic disease, making the diagnosis and management of both conditions challenging. This Review describes what is known about eating disorders in adolescents with chronic gastrointestinal and endocrine diseases, focusing on coeliac disease, inflammatory bowel disease, diabetes, and thyroid disorders. The prevalence and onset of each condition during adolescence is discussed, followed by a description of the associations among the conditions and eating disorders. We also discuss management challenges posed by the coexistence of the two conditions. When both diseases coexist, a multidisciplinary approach is often needed to address the additional complexities posed.

Introduction Eating disorders are prevalent in adolescents and young adults aged from 12 to 25 years. More than 90% of patients with eating disorders present before the age of 25 years. Some other chronic medical conditions, including coeliac disease, inflam­matory bowel disease, diabetes, and thyroid disease, can also begin during adolescence and need to be dis­tinguished from an eating disorder when evaluating an adolescent for weight loss, vomiting, abdominal dis­ comfort, dizziness, or menstrual dysfunction. However, emerging evidence shows that eating disorders and chronic diseases can coexist1 and might even share common genetic susceptibilities,2,3 suggesting common molecular pathways. Adolescents with chronic illness are at high risk for engaging in unhealthy weight control behaviours.4 Medications such as corticosteroids, used to treat some chronic medical conditions, can cause weight gain and body image dissatisfaction that can lead to disordered eating. Diabetes and coeliac disease require attention to dietary intake for appropriate treatment, but preoccupation with dietary intake can become excessively restrictive, leading to weight loss and a fully developed eating disorder. Finally, some medications such as thyroid hormone and insulin, used to treat certain chronic diseases, can be misused by an adolescent trying to lose weight, making treatment of the chronic condition more challenging. Evidence is emerging of links between eating disorders and several autoimmune diseases with different genetic backgrounds. Such diseases include coeliac disease, inflammatory bowel disease, diabetes, and thyroid disorders,1,5,6 suggesting a possible role of autoimmunity in eating disorders. Evidence is also growing implicating changes in the microbiome and gut–brain interactions in the cause and course of anorexia nervosa.7 It has been postulated that exposure to microbes can result in autoantibodies that could crossreact with neurons, possibly mediated via cytokines, and can play a role in the patho­ genesis of some neuropsychiatric illnesses.8 A meta-analysis from 20189 found elevations in the pro­­­­­­­­ inflammatory cytokines tumour necrosis factor-α and

interleukin-6 in patients with anorexia nervosa. These cytokines are known to play a role in regulation of both mood and appetite. Furthermore, auto­antibodies against neuro-peptides involved in appetite regulation and the stress response have been identified in patients with Key messages • Signs and symptoms of eating disorders can mimic those of chronic gastrointestinal and endocrine diseases. However, these diseases can also coexist. • The approach to adolescents with an eating disorder and a chronic gastrointestinal or endocrine disease should be multidisciplinary given the complexities in management of these conditions. • Adolescents with an eating disorder presenting with unexplained abdominal pain should be evaluated for coeliac disease and inflammatory bowel disease. • An elevated ESR or a low serum albumin concentration should raise suspicion of inflammatory bowel disease. • An eating disorder is one of the most common comorbidities in patients with insulin-dependent diabetes. Intentional insulin omission is a common behaviour for weight manipulation, resulting in elevated glycated haemoglobin and other complications of persistent hyperglycaemia, including diabetic ketoacidosis. • Low triiodothyronine euthyroid sick syndrome is the most common thyroid function test abnormality seen in patients with malnutrition, and resolves with nutritional rehabilitation. • Surreptitious levothyroxine use (thyroiditis factitia) might be seen in adolescents with an eating disorder who have access to levothyroxine medication. Although their thyroid function tests would be consistent with hyperthyroidism, the absence of a goiter, a decreased radioactive iodine uptake, low thyroglobulin concentrations, and high faecal thyroxine concentrations help to distinguish this condition from true hyperthyroid pathology.

www.thelancet.com/child-adolescent Published online January 9, 2019 http://dx.doi.org/10.1016/S2352-4642(18)30386-9

Lancet Child Adolesc Health 2019 Published Online January 9, 2019 http://dx.doi.org/10.1016/ S2352-4642(18)30386-9 Department of Pediatrics, Division of Adolescent Medicine (J T Avila MD, Prof N H Golden MD) and Department of Pediatrics, Division of Gastroenterology (K T Park MD), Lucile Packard Children’s Hospital, Stanford University School of Medicine, Palo Alto, CA, USA Correspondence to: Prof Neville H Golden, Department of Pediatrics, Division of Adolescent Medicine, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Palo Alto, CA 94304, USA [email protected]

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Bodyweight

Fear of weight gain

Negative feelings about shape or weight

Dietary restriction

Binge eating

Purging

Anorexia nervosa, restrictive type

Decreased

Yes

Yes

Yes

No

No

Anorexia nervosa, binge eating or purging type

Decreased

Yes

Yes

Yes

Yes

Yes

Atypical anorexia nervosa

Normal or increased

Yes

Yes

Yes

Sometimes

Sometimes

Bulimia nervosa

Normal or increased

Yes

Yes

Sometimes

Yes

Yes

Binge eating disorder

Normal or increased

No

Yes

No

Yes

No

Avoidant restrictive food intake disorder

Decreased

No

No

Yes

No

No

Rumination disorder

Normal or decreased

No

No

No

No

No

Pica

Normal or decreased

No

No

No

No

No

Table 1: Key clinical features of eating disorders per fifth edition of the Diagnostic and Statistical Manual of Mental Disorders criteria22

both anorexia nervosa and bulimia nervosa.10 Recent interest in the gut–brain axis has led to the discovery of changes in the composition and diversity of the gut microbiome (dysbiosis) in both anorexia nervosa11–15 and in inflam­matory bowel disease.16 Such alterations can cause down­stream depletion of short chain fatty acids, especially butyrate, which acts not only as a physical barrier of protection along the intestinal mucosa but also as a biochemical regulator of T-cell function. This regulation is integral for correct recognition of self and non-self in humans.17 Such a mechanism could explain the coexistence of eating disorders with not only gastrointestinal diseases but also diabetes18 and thyroid disorders.19,20 We did the search according to PRISMA guidelines.21

Diagnostic criteria for eating disorders In 2013, the diagnostic criteria for eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders were revised to improve clinical utility of the diagnostic categories. Before the revision, the majority of children and adolescents presenting to clinical eating disorder programmes did not meet diagnostic criteria for either anorexia nervosa or bulimia nervosa, and were assigned the diagnosis of eating disorder not otherwise specified.22,23 With the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5),24 diagnostic criteria for anorexia nervosa and bulimia nervosa are less stringent, and new diagnostic categories have been introduced, including avoidant restrictive food intake disorder and atypical anorexia nervosa (table 1). Furthermore, eating disorder not otherwise specified was eliminated as a diagnostic category. As a result of application of the DSM-5 criteria, there have been modest increases in the number of children, adolescents, and young adults meeting criteria for anorexia nervosa and bulimia nervosa.25,26 The key features of anorexia nervosa are persistent low bodyweight, marked fear of weight gain, and disturbance in the way that body image is experienced. Although the 2

specific cutoff for low bodyweight has been removed, guidance suggests that a body-mass index less than the fifth percentile for age indicates a low bodyweight. In DSM-5, amenorrhoea has been removed as one of the required diagnostic criteria for anorexia nervosa because it does not apply to male patients, to female patients before menarche, or to some female adolescents on hormonal contraception. Atypical ano­ rexia nervosa describes patients who meet all criteria for anorexia nervosa, but despite substantial weight loss, their weight is within or above the normal range. Key features of bulimia nervosa are recurrent episodes of binge eating and the use of inappropriate compensatory behaviours such as self-induced vomiting, excessive exercise, periods of starvation, or the use of laxatives, diuretics, or diet pills to prevent weight gain. A binge is defined as the consumption of an objectively large amount of food in a discrete period of time, accompanied by a subjective sense of loss of control over eating during the episode. Patients with bulimia nervosa are usually of normal bodyweight. Patients who binge but do not engage in inappropriate compensatory behaviours are assigned the diagnosis of binge eating disorder. Avoidant restrictive food intake disorder describes individuals who avoid some foods because of taste, texture, colour, smell, or fear of vomiting, with their reduced dietary intake leading to weight loss, failure to gain weight, or interruption of growth. No fear of weight gain and no body image concerns are present. In clinical samples, between 5% and 23% of patients referred to specialised adolescent eating disorder programmes meet criteria for avoidant restrictive food intake disorder.25,27,28 Compared with patients with anorexia nervosa or bulimia nervosa, adolescents with avoidant restrictive food intake disorder are more likely to be younger and male.27,28 In DSM-5, rumination disorder and pica are included under the broad category of feeding and eating disorders. Rumination disorder describes the repeated regurgitation of recently eaten food over a period of at least 1 month. The regurgitated food might be re-chewed, re-swallowed,

www.thelancet.com/child-adolescent Published online January 9, 2019 http://dx.doi.org/10.1016/S2352-4642(18)30386-9

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or spat out. The behaviour is not better explained by gastrointestinal disease and does not occur during an episode of anorexia nervosa, bulimia nervosa, or avoidant restrictive food intake disorder. Although these symptoms occur most commonly in infants and children with intellectual disabilities, they can occur in children and adolescents of normal intelligence. Pica describes the ingestion of one or more nonnutritive, non-food substances (such as hair, paper, paint, among others) on a persistent basis for at least 1 month. Pica can be observed with other medical and psychiatric conditions such as developmental delay, autism spectrum disorder, and schizophrenia, but is only given a separate diagnosis if the symptoms are serious enough to warrant additional clinical attention.

Epidemiology of eating disorders Eating disorders typically arise during adolescence29 and occur in all racial and ethnic groups. The highest prevalence is in adolescent females. Approximately 5–15% of patients diagnosed with an eating disorder are male, with a 9:1 female-to-male preponderance.30 The proportion of male patients is higher in individuals presenting under the age of 13 years, with a female-tomale ratio closer to 6:1.31–33 The lifetime prevalence of anorexia nervosa, bulimia nervosa, and binge eating disorder is estimated to be 0∙9%, 1∙5%, and 3∙5%, respectively for female individuals and 0∙3%, 0∙5%, and 2∙0%, respectively for male individuals.34 A large Dutch community cohort study26 found a lifetime diagnosis of any eating disorder in 5∙7% of adolescent females and 1∙2% of adolescent males. Mean age at onset was 15∙1 years (SD 2∙8) for anorexia nervosa, and 16∙0 years (1∙9) for bulimia nervosa.26 In the UK, there has been a modest increase in the incidence of eating disorders from 2000 to 2009, with the highest incidence in adolescent females aged 15–19 years.35 A study from Denmark revealed that over the observation period from 1995 to 2010, the most frequent age group at first diagnosis of anorexia nervosa decreased from 16–19 years in 1995 to 12–15 years in 2010.36 Population-based estimates of the prevalence of avoidant restrictive food intake disorder are not known, but adolescents with avoidant restrictive food intake disorder account for 12–23% of patients referred to specialised adolescent eating disorder programmes.25,27,28,37 Adolescents with avoidant restrictive food intake disorder differ from individuals with other types of eating disorders. They are more likely to be males, to be a younger age, and to have a longer duration of illness.27,28,37,38 Similar to avoidant restrictive food intake disorder, population-based estimates of prevalence of atypical anorexia nervosa are not known. Patients with atypical anorexia nervosa account for approximately 30% of patients referred to specialised adolescent eating disorder programmes28,39 and 25–50% of all patients hospitalised on adolescent eating disorder units.40,41 A study from Melbourne, Australia40 found that

the number of patients with atypical anorexia nervosa requiring hospitalisation for medical instability grew five times from 2005–10.

Specific eating disorders and chronic diseases Coeliac disease

Coeliac disease is an immune-mediated enteropathy triggered by gluten ingestion resulting in small bowel inflammation and chronic nutrient malabsorption. Approximately three million people in the USA (paediatric prevalence of 1–13 per 1000) have coeliac disease,42,43 the majority of whom are undiagnosed or untreated.44 As the vast majority of patients with coeliac disease have silent or subtle signs and symptoms, characteristic poor weight gain and failure to thrive in an adolescent or young adult might be the initial presentation. Undiagnosed and untreated coeliac disease can lead to substantial com­plications, including chronic nutritional deficiencies, progressive bone loss and derangements, increased risk of early osteoporosis and non-traumatic fractures of hip and vertebrae, and intestinal lymphoma. Given these concerns, it is important to consider serological screening for coeliac disease in any adolescent and young adult being considered for diagnosis of an eating disorder. The standard screening for coeliac disease involves a onetime serological test for IgA antibodies to tissue trans­ glutaminase and total IgA. The combination of high levels of tissue transglutaminase IgA with a normal IgA while ingesting at least 3–10 g of gluten daily is both highly sensitive and specific (>95%) for coeliac disease.45 Patients with a positive serological test often require duodenal mucosal biopsy confirmation per American consensus guidelines. A 2015 population-based study5 described the significant association between coeliac disease and anorexia nervosa, both before and after the diagnosis of coeliac disease. The investigators found the hazard ratio for later development of anorexia nervosa in individuals with biopsy-supported coeliac disease to be 1∙46 (95% CI 1∙08–1∙98), and a previous diagnosis of anorexia nervosa was also associ­ ated with coeliac disease (odds ratio [OR] 2∙18, 95% CI 1∙45–3∙29).5 In the same study, the bidirectional association of the two diseases could imply a shared genetic susceptibility or an incremental risk of developing either anorexia nervosa or coeliac disease if the other condition is present. The clinical implication of this study is that misdiagnosis or delayed treatment of coeliac disease can occur during the peak age of onset of an eating disorder. Undiagnosed or misdiagnosed coeliac disease and eating disorders can be devastating during a particularly vulnerable period of growth and develop­ ment. It is important to note that both coeliac disease and anorexia nervosa can present with non-specific gastrointestinal discomfort, disordered defecation (either constipation or diarrhoea), intestinal bloating, and failure to thrive.

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Recommended screening laboratory tests Complete blood count ESR Serum chemistry panel Liver function tests, albumin Thyroid function tests (thyroid stimulating hormone, free thyroxine, triiodothyronine) Urinalysis 25-hydroxyvitamin D If amenorrhoea test for luteinising hormone, follicle stimulating hormone, oestradiol If suspicious of gastrointestinal disease test for coeliac screen, stool calprotectin If goiter on exam test for thyroid peroxidase antibodies, thyroid-stimulating immunoglobulins, and antithyroglobulin antibodies

Expected findings in anorexia nervosa Complete blood count White blood cells: normal or decreased Haemoglobin: normal or decreased Platelets: normal or decreased Decreased ESR Chemistry panel Na+, K+, Mg, or P: normal or decreased Transaminases: normal or increased Other laboratory tests Thyroid function tests: decreased triiodothyronine Urinalysis: normal or increased ketones (starvation) 25-hydroxyvitamin D: often decreased

Findings suggestive of other gastrointestinal or endocrinological chronic diseases Complete blood count White blood cells: can be increased in untreated coeliac disease or inflammatory bowel disease, can also be normal; normal in thyroid disease and diabetes Haemoglobin: decreased in inflammatory bowel disease and coeliac disease Platelets: increased in inflammatory bowel disease and inflammatory conditions Increased ESR in inflammatory bowel disease and other inflammatory conditions Chemistry panel Decreased Na+ and increased K+ in adrenal insufficiency; increased glucose in diabetes Albumin is decreased in inflammatory bowel disease or chronic kidney disease Other laboratory tests Increased triiodothyronine in Graves’ disease Urinalysis: increased glucose and sometimes increased ketones in diabetes

Figure 1: Recommended laboratory tests in adolescents and young adults with weight loss, and expected findings in anorexia nervosa and in other chronic gastrointestinal or endocrinological medical diseases

Inflammatory bowel disease Inflammatory bowel diseases, consisting of Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract that are most commonly diagnosed between adolescence and young adulthood. Although it is common to have haematochezia as one of the initial presenting signs of inflammatory bowel disease, especially in ulcerative colitis, some phenotypes of inflammatory bowel disease are more indolent in disease progression. An elevated ESR or a low serum albumin level in an adolescent suspected of having anorexia nervosa, should raise suspicion of inflammatory bowel disease (figure 1). Similar to the subtle clinical progression of undiagnosed coeliac disease, the indolent nature of some inflammatory bowel disease presentations make co-occurrence with an eating disorder in the adolescent and young adult cohorts more probable. The clinician caring for suspected or diagnosed patients with an eating disorder should be mindful of the stool calprotectin screening test, which has a more than 90% sensitivity for underlying inflam­matory 4

bowel disease with quantitative calprotectin levels more than 50 μg/g.46 Calprotectin, a calcium-containing protein that makes up 60% of the cytosolic protein of neutrophils and monocytes, is released during acute and chronic inflammation.47 Having a low threshold for testing stool calprotectin before treatment of an eating disorder is advised as reliance on polymeric formula supplementation in patients with anorexia nervosa to achieve daily caloric needs can concomitantly treat undiagnosed small bowel Crohn’s disease. Exclusive enteral therapy with use of polymeric formulas has been shown to have a treatment effect similar to corticosteroids during treatment induction.48 The diagnosis of inflammatory bowel disease is made on the basis of a combination of history, physical, and laboratory findings, oesophagogastroduodenoscopy and ileocolonoscopy with histology, and imaging of the small bowel.49 Crohn’s disease of the duodenum, jejunum, and ileum can be elusive to diagnose because of the relapsing and remitting nature of the inflammation and the difficulty of obtaining histopathology in the small intestine. It is not uncommon for patients with isolated small bowel Crohn’s disease to have negative results in endoscopic and colonoscopic investigations. A referral to an inflammatory bowel disease specialist and a targeted evaluation of the small bowel are often necessary with use of advanced endoscopic techniques (ie, enteroscopy or wireless capsule endoscopy) or highly sensitive radiological imaging (ie, magnetic resonance enterography). In a large Finnish cohort6 of patients with anorexia nervosa, bulimia nervosa, and binge eating disorder, increased prevalence of gastrointestinal disease was largely explained by Crohn’s disease (0∙6% in patients vs 0∙2% in controls, OR 3∙1, 95% CI 1∙5–6∙3), and not by coeliac disease (OR 1∙4, 0∙7–3∙1), or ulcerative colitis (OR 1∙6, 0∙7–3∙2). This increased prevalence of gastrointestinal disease was significantly increased in patients with anorexia nervosa, but not in individuals with bulimia nervosa or binge eating disorder.6 In contrast to coeliac disease, bidirectionality of asso­ ciation between inflammatory bowel disease and eating disorders has not been shown. However, given the emerging relationship between dysbiotic gut microbiota and inflammatory bowel disease, it would be forwardthinking to consider dietary regimens that optimise microbiota health in addition to meeting caloric goals in the treatment of patients with eating disorders. Specifically, while there is ongoing debate about whether a typical diet of people in developed countries has causal links to autoimmunity triggering new-onset inflam­ matory bowel disease, it is interesting to note the evidence supporting the association of dysbiosis and inflammatory bowel disease, especially in paediatric Crohn’s disease.16 Reproducible research has shown that there is loss of microbial diversity and total abundance of commensal gut bacteria in patients with inflammatory bowel disease, specifically depletion of bacteria from the

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phyla Firmicutes and Bacteroidetes.50 Loss of bacterial species from these phyla allows increased interactions of the host immune system with the environmental antigens within the mucosal lining of the intestinal tract.17 Although the question of causality about diet and inflammatory bowel disease continues, research has shown that a diet high in animal fats and processed foods is associated with an increased risk of developing Crohn’s disease and ulcerative colitis. Conversely, regular intake of foods rich in dietary plant fibres has been shown to be protective against new-onset inflammatory bowel disease.51 Therefore, in the management and rehabilitation of patients with known eating disorders, thoughtful consideration about incorporating plantbased fibres in meals would optimise gut bacterial health in a population with known dysbiosis.

Type 1 diabetes Diabetes is one of the most common chronic conditions in youth (less than 20 years), affecting approximately 0∙2% of children and adolescents in the USA.52 Around 87% of new cases of diabetes in adolescents are classified as type 1 diabetes,52 characterised by partial or total deficiency of insulin production due to autoimmune destruction of pancreatic β cells. More than 50% of patients with type 1 diabetes present after the age of 10 years.52 Weight loss, along with polyuria and polydipsia, is one of the classic presenting symptoms, and is often followed by rapid weight gain after initiation of insulin therapy.53 Eating disorders represent one of the most common psychiatric diagnoses in adolescents with type 1 diabetes,54 with a prevalence twice as high as in individuals without diabetes.55 Although a coexisting eating disorder might be more common in female adolescents,56 in a large population-based study, adolescent males with type 1 diabetes were twice as likely to report body development concerns and unhealthy methods of weight control compared with their male peers without type 1 diabetes.4 Several factors associated with type 1 diabetes could put these adolescents at risk for developing an eating disorder, including but not limited to: disruption in typical eating patterns, including having to calculate the carbohydrate content of every meal and continually having to evaluate the effect of food and exercise on blood glucose levels; rapid weight changes at time of diagnosis and initial treatment; psychological distress at time of diagnosis and stressors of living with a chronic disease; and body image emphasis as part of typical adolescent development.57,58 Intentional omission of insulin for weight loss purposes is probably the most common unhealthy weight control method used by patients on insulin therapy.54,58,59 This behaviour has rendered the informal term diabulimia, a portmanteau of diabetes and bulimia.54,58 Without insulin, glucose cannot be metabolised, resulting in hyper­ glycaemia, glycosuria, and weight loss. The subsequent hyperglycaemic state, as evidenced by elevated glycated haemoglobin A1c (HbA1c), not only accelerates the

development of chronic complications of type 1 diabetes but also increases the risk for acute medical complications such as diabetic ketoacidosis.54 It is not surprising, therefore, that intentional insulin omission is associated with a three-times increase in mortality and a reduced mean age of death by more than 10 years.60 The opposite behaviour, intentional insulin overdose, has also been described in patients with type 1 diabetes and bulimia nervosa, done specifically to abate cravings for binge eating.61 Although excess insulin leads to hypoglycaemia, HbA1c in these patients is also typically elevated, suggesting an overall hyperglycaemic state, probably from binge eating followed by compensatory insulin omissions. Carbohydrate avoidance is commonly observed in patients with anorexia nervosa. With coexisting type 1 diabetes, carbohydrate restriction or elimination can decrease insulin needs and lower HbA1C, which in turn might be misinterpreted as an improvement in glycaemic control. This behaviour also increases the risk for starvation ketoacidosis and the rare complication of euglycaemic diabetic ketoacidosis.62 Additionally, it also impairs appropriate hepatic storage of substrates needed for gluconeogenesis, thus increasing the risk of hypo­ glycaemia during the initial nutritional rehabilitation of these patients.63 In patients with undiagnosed type 1 diabetes, the course of re-feeding could be atypical with an inappropriately slow rate of weight gain, unusual hunger or increase in appetite, or glycosuria. As carbohydrate restriction lowers HbA1c, this serological test could be unreliable in the evaluation of diabetes in these patients.64 Other screening tests, such as 2 h postprandial blood glucose levels, might be more helpful.

Type 2 diabetes Type 2 diabetes is characterised by insulin resistance and impaired glucose metabolism. Its incidence has increased in children and adolescents, especially in the USA, where it might be as frequent as type 1 in some regions of the country.65 Obesity is the most common comorbidity in youth (less than 20 years) with type 2 diabetes.65 As unhealthy weight control behaviours are more common in overweight and obese people,66 it should not be surprising that in the multicentre TODAY study67 of adolescents with recent diagnosis of type 2 diabetes, 6% of the participants met criteria for clinical binge eating, and 20% for subclinical binge eating. Binge eating was associated with higher levels and rates of extreme obesity, global eating disorder scores, depressive symptoms, and impaired quality of life.67 In a systematic review and meta-analysis of observational studies, patients with bulimia nervosa were found to have an increased risk for developing type 2 diabetes across all studies, whereas for individuals with binge eating disorder, the increased risk was seen only in crosssectional studies, but not in cohort studies.68 This finding was important as obesity is more common in binge eating disorder than in bulimia nervosa.69 The increased

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Thyroid disorders Thyroid gland

I HO I

Normal state I

I

H

NH2 C C H COOH H

O I

Malnutrition

Thyroxine

I

HO

O

I

I

R

HO

R

O

I

I Triiodothyronine

Reverse triiodothyronine (inactive)

Figure 2: Mechanism for low triiodothyronine euthyroid sick syndrome in malnutrition In the normal state, thyroxine is converted to triidonthyonine (grey arrows). In malnutrition, thyroxine is preferentially converted to reverse triiodonthyronine (red arrows). R=CH2CH(NH2)(COOH) group attached to the inner aromatic ring.

Free Total Thyroidstimulating thyroxine triiodothyronine hormone

Antibodies

Other

Hashimoto’s thyroiditis

Increased

Decreased

Decreased

Thyroid peroxidase and antithyroglobulin antibodies

Low triiodothyronine euthyroid sick syndrome

Normal or decreased

Normal or decreased

Decreased

None

Reversible with weight restoration

Graves’ disease

Decreased

Increased

Increased

Thyroidstimulating immunoglobulin

Enlarged thyroid gland (goiter), increased radioactive iodine uptake

Thyroiditis factitia

Decreased

Increased

Increased

None

Decreased thyroglobulin, increased faecal thyroxine

Table 2: Laboratory and imaging tests associated with different thyroid disturbances

risk seen in bulimia nervosa could be in part due to an association with hyperinsulinaemia or polycystic ovarian syndrome, or both,70 which were not factored into the analysis of the review. Hyper­ insulinaemic states, commonly seen in type 2 diabetes due to impaired glucose metabolism, stimulate appetite and could contribute to binge eating.70,71 These observations suggest that patients with type 2 diabetes should be screened for unhealthy methods of weight control, and that patients with binge eating disorder and bulimia nervosa should similarly be screened for type 2 diabetes. 6

Endocrinological dysfunction affecting the thyroid axis is often seen in eating disorders.70 Normally, thyroxine is metabolised into triiodothyronine by monodeiodination at its outer ring. In starvation states, however, the decreased secretion of leptin from adipose tissue mediates thyroxine monodeiodination to occur at the inner ring instead,72 resulting in the preferential formation of reverse triiodothyronine, the metabolically inactive isomer of triiodothyronine (figure 2).70 This change results in low triiodothyronine euthyroid sick syndrome, character­ ised by low triiodothyronine but usually normal thyroxine and thyroid-stimulating hormone (TSH) concentrations. Low triiodothyronine euthyroid sick syndrome is more commonly seen in anorexia nervosa than in bulimia nervosa,70 with some studies suggesting that low triiodothyronine is seen more specifically during the periods between binge eating.73 The decrease in triiodothyronine is a com­ pensatory adaptation in starvation states to lower metabolic needs and decrease energy imbalance, but it results in bradycardia, hypothermia, and delayed deep tendon reflexes.70 Following weight restoration, triiodothyronine concentrations normalise with resolution of these clinical signs.70 Thyrotoxicosis factitia is another cause of reversible abnormalities in thyroid function tests in patients with eating disorders. In thyrotoxicosis factitia, exogenous thyroid hormone is taken surreptitiously or in excess for weight control purposes.74 The resulting biochemical profile is similar to that of hyperthyroidism, with low TSH and elevated thyroxine or triiodothyronine, or both. In contrast to true hyperthyroidism, the supraphysiological thyroid hormones in thyrotoxicosis factitia lead to a hypoactive thyroid gland with decreased iodine uptake, so there is no enlargement of the thyroid gland (goiter).74 Serum thyroglobulin and faecal thyroxine concentrations might be helpful in differentiating thyrotoxicosis factitia from a true thyroid pathology.74 In thyrotoxicosis factitia, serum thyroglobulin concentrations are decreased and faecal thyroxine concentrations elevated, whereas in either silent thyroiditis or true hyperthyroidism, the reverse pattern is expected (table 2).74 Although not as commonly seen as thyrotoxicosis factitia or low triiodothyronine euthyroid sick syndrome, a true thyroid pathology could also coexist with an eating disorder, although there are no large population-based studies assessing its prevalence among patients with eating disorders. To date, there has only been a limited number of published case reports on the topic (17 on hyperthyroidism coexisting with an eating disorder, all in female patients,75–77 and two on hypothyroidism and anorexia nervosa, both in adolescents78,79). The prevalence of both disorders, however, might be higher than what is suggested by the medical literature. In a study of 50 adult women attending a thyroid clinic, three women with hypothyroidism aged 26–29 years met criteria

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for bulimia nervosa.80 However, as two of the three women also endorsed intentionally abusing their thyroid hormone for weight loss, these cases could actually represent thyrotoxicosis factitia rather than a truly shared asso­ciation between hypothyroidism and bulimia nervosa. In the case reports of hyperthyroidism,75–77 elevated triiodothyronine concentrations were associated with binge eating or purging behaviours in adults but not in adolescents. These behaviours also improved with treatment of their thyroid disorder and normalisation of triiodothyronine concentrations. Binge eating was likely the result of appetite increase caused by elevated triiodothyronine, similar to the relationship between binge eating and hyperinsulinaemia discussed earlier. In the case reports76,78,79 in which the thyroid disease and the eating disorder were both diagnosed at the time of presentation, the diagnosis of a thyroid pathology was often masked because of normal thyroxine or triiodo­ thyronine concentrations, even when a goiter was present. Yet, in all of these cases, TSH concentrations were slightly above or below normal limits. With weight restoration, thyroid function tests gradually became more consistent with the underlying thyroid pathology, whether hypothyroidism or hyperthyroidism. The initial re-feeding course in these patients was often atypical as well. For instance, in a case of undiagnosed hypo­ thyroidism, sinus bradycardia persisted despite weight gain.78 In a case of undiagnosed hyperthyroidism, the refeeding course was notable for an inappropriately slow weight gain, rise of heart rate above the normal range, and temperature reaching low-grade pyrexia.76 In another patient, the hyperthyroid-induced hypermetabolic state coupled with dietary restrictions from the eating disorder led to multivitamin deficiency with subsequent severe polyneuropathy from deficient amounts of vitamins E, B6, and folic acid,77 and could have increased the risk of electrolyte deficiencies in another patient.75 Treatment of the underlying thyroid disorder can be challenging in the setting of an eating disorder due to a patient’s desire to remain in a hypermetabolic state to facilitate weight loss, fear of weight gain with treatment, and self-induced vomiting of the thyroid medication. As a result, non-adherence was commonly observed in patients with hyperthyroidism, and thyroid medication abuse (as in thyrotoxicosis factitia) has been observed in individuals with hypothyroidism.

Conclusion Eating disorders and some chronic gastrointestinal and endocrine diseases begin during adolescence and frequent­­ ly present with similar symptoms. The conditions can be misdiagnosed inter­ changeably, but they can also coexist, making manage­ment challenging. Adolescents with a suspected eating disorder should be screened for coeliac disease, inflammatory bowel disease, diabetes, and thyroid disease, especially when symptoms

Search strategy and selection criteria We searched PubMed and MEDLINE for articles published between Jan 1, 1995, and June 30, 2018 with the terms: (“chronic disease”, “diabetes mellitus”, “celiac disease”, “inflammatory bowel diseases”, “ulcerative colitis”, “thyroid disease”) AND (“anorexia nervosa”, “binge eating disorder,” “avoidant restrictive food intake disorder” OR “bulimia nervosa”) according to PRISMA guidelines. These specific chronic medical illnesses were selected on the basis of the chronic medical diseases most frequently encountered in adolescents with eating disorders treated in a large specialised multidisciplinary adolescent eating disorder treatment programme located within a tertiary care children’s hospital. We focused on comorbid medical diseases in which the coexistence of both diseases could make management difficult. We searched only for articles published in English or those translated into English involving adolescents or young adults and excluded animal studies (appendix). Additionally, supplemental searches for the separate topics in this Review were done. We included randomised controlled trials, observational studies, retrospective studies, meta-analyses, review articles, editorials, case reports, and other relevant articles.

See Online for appendix

are not typical for the eating disorder. Similarly, adolescents with chronic gastrointestinal and endocrine diseases should be screened for unhealthy methods of weight control. When an eating disorder coexists with a chronic disease, frequent communication among healthcare professionals is advised. The con­tinued discovery of possible genetic, immunological, and environmental factors shared by eating disorders and chronic medical standing of the diseases will increase our under­ mechanisms under­ lying the shared pathogenesis of these conditions. Contributors NHG drafted the manuscript. JTA did the systematic review. NHG contributed to the introduction, search strategy and selection criteria, diagnostic criteria, epidemiology, and conclusion. JTA contributed to the sections on diabetes and thyroid disorders. KTP contributed to the sections on coeliac disease and inflammatory bowel disease. All authors reviewed and edited the manuscript and accept responsibility for the accuracy and integrity of the work. Declaration of interests KTP reports grants from the Crohn’s & Colitis Foundation, Takeda Pharmaceutical, Abbvie, Prometheus, and Inova Diagnostics, all outside the submitted work. JTA and NHG declare no competing interests. Acknowledgments Supported in part by The Mary Gallo Endowed Postdoctoral Fellowship Fund (JTA), National Institutes of Health—National Institute of Diabetes and Digestive and Kidney Diseases (DK094868), Crohn’s & Colitis Foundation (KTP), and National Institutes of Health—Eunice Kennedy Shriver National Institute of Child Health and Human Development (RO1 HD082166; NHG). References 1 Wotton CJ, James A, Goldacre MJ. Coexistence of eating disorders and autoimmune diseases: record linkage cohort study, UK. Int J Eat Disord 2016; 49: 663–72.

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