The Diagnosis and Treatment of Anorexia Nervosa in Childhood and Adolescence

Background: Anorexia nervosa (AN) is a serious disease with a lifetime prevalence of up to 3.6% in women and 0.3% in men. Abnormally low weight and the associated starvation partly account for its somatic and mental manifestations.

Methods: This review is based on publications retrieved by a selective search concerning AN in childhood and adolescence.

Results: The peak age of onset of AN is 15.5 years. The frequency of inpatient treatment for AN rose by 40% during the COVID pandemic, indicating the importance of environmental factors; the heritability of AN is estimated at 0.5. The ICD-11 sets the threshold for AN-associated underweight at the fifth percentile for age of the body mass index, as long as the remaining diagnostic criteria are met. The main goal of the multiprofessional treatment of AN is the return to normal body weight, which is a central prerequisite for regaining somatic and mental health. The mean duration of AN is 3.4 years, and approximately two-thirds of patients recover from the disease over the long term.

Conclusion: Marked weight loss in childhood and adolescence can trigger AN in the presence of a predisposition to this disease. Patients and their families should receive psychoeducation regarding the symptoms of starvation and their overlap with those of AN. Important objectives are to shorten the duration of the illness, minimize mortality and the risk of chronic illness, and to identify pharmacological approaches to treatment.

Anorexia nervosa (AN) begins in late childhood to young adulthood. It is characterized by underweight that is not explicable by constitutional underweight, medical factors, or a lack of food. It is characterized by an exaggerated preoccupation with one‘s own figure and body weight, intense fear of gaining weight or becoming fat, and behaviors that prevent weight gain. The affected persons express little or no fear of impaired physical or mental health as a consequence of being underweight (1).

In an international, systematic epidemiological review, the lifetime prevalence of AN was up to 3.6% in women and 0.3% in men (2). A meta-analysis revealed peak onset at age 15.5 years; 18% of all patients had already received a diagnosis of AN by age 14, and 55% by 18 (3).

The sufferers’ health is usually impaired for many years, with major adverse effects on their emotional, social, and cognitive development. Body image disturbances and weight phobia are known to be risk factors for the development of AN (e1), but an adequate understanding of the early warning signs or the initial, subsyndromal signs of disease in AN is still lacking (4). AN carries a serious prognosis (e2).

Prolonged inadequate energy intake leads to starvation. Somatic and psychological adaptations occur, including behavioral changes that increase the likelihood of survival of the starved organism (5). A wide range of humoral factors are involved. A subphysiological decrease in the serum level of the hormone leptin, which is mainly produced in adipocytes, is thought to be an essential hormonal signal for the gradual somatic and psychological adaptation to starvation (5, 6). Knowledge about this adaptation is indispensable for an understanding of the manifestations, comorbidities, course, and treatment of AN. In particular, psychological manifestations are often directly attributed to AN, yet there is often an overlap (Table 1) : starvation (itself a consequence of AN) is a contributing cause of many of the psychological manifestations of AN.

Table 1

Anorexia nervosa (AN) and starvation: comparison of mental manifestations (abbreviated version)

Learning objectives

This article should enable the reader to:

• know the prevalence, risk factors, diagnostic evaluation, and common comorbidities of AN, its treatment (including with drugs), and key figures relating to the usual course of anorexia nervosa in children and adolescents;
• understand adaptation to starvation and its implications for psychological findings in patients with AN;
• be familiar with the clinical symptomatology of atypical anorexia nervosa;
• be aware of the tasks confronting physicians who care for young patients with anorexia nervosa and their relatives.

Etiology

Genetic risk factors

The relative risk of an eating disorder in first-degree female relatives of index cases, compared to normal controls, is 11 (7). Heritability, as measured in twin studies, is 0.5–0.6 (8, e3); genes thus account for 50–60% of the variance. The known genetic correlations reflect comorbidities that are evident in clinical experience (e.g., obsessive-compulsive disorder and depression). A correlation with schizophrenia and a possible link to delusional body image disturbances have also been reported (8). The polygenic predisposition to AN overlaps with underweight and low fat mass, a high level of physical activity, a high educational level, and a variety of metabolic phenotypes (e.g., low fasting insulin and leptin levels and high HDL cholesterol). These complex genetic overlaps, collectively termed a “metabopsychiatric disorder,” set AN apart from other mental disorders (8). These correlations may, however, be partly or wholly due to underweight being a criterion for the diagnosis of AN. Many premorbidly obese adolescents with AN-like manifestations whose BMI does not drop below the 5^th centile as required for the diagnosis of AN, even after they have lost a large amount of weight, are given a DSM-5 diagnosis of atypical AN and are therefore not represented in genetic studies of AN (e4, e5).

Environmental risk factors

The COVID-19 pandemic revealed the importance of environmental factors. Elevated incidence and hospitalization rates were observed in a number of countries, as was a more rapid progression of the manifestations of AN (e6, 9). In Germany, the hospitalization rate per 100 000 children and adolescents rose from 5.38 in 2019 to 7.48 in 2021 (10).

In a predisposed individual, weight loss or weight stagnation and, in particular, a decrease in fat mass must take place at a critical age in order to trigger AN (or a relapse of AN) (5). Patients may go on a diet in order to lose weight, live more healthily, or lessen their environmental impact by means of vegetarianism or veganism. Fat mass reduction can also be initiated by intense physical activity (e.g., workouts). The role of (social) media as a co-trigger, mediator and amplifier for disordered eating and excessive exercise behavior is debated (e7). Weight loss can also be induced by critical/unmanageable life events and other psychosocial or sociocultural triggers (e8). In some cases, AN may follow weight loss that has occurred, for example, because of an infection, food abstinence after surgery, or depression. Such factors are distinct from disease-intensifying or disease-maintaining factors such as positive comments from others regarding the initial weight loss, the need to remain in control, stress or the defense against stress, and dysfunctional cognition (e8).

Diagnostic evaluation

The diagnosis of AN is based, on the one hand, on the finding of underweight and, on the other hand, on the presence of specific thought patterns and behaviors (see diagnostic criteria according to DSM-5 and ICD-11, eTable 1; the tasks of the physician relating to the diagnostic evaluation are listed in Box 1 (for details, see the eBox).

eBox

The physician’s tasks in suspected anorexia nervosa and case management

eTable 1

Comparison of the ICD-11 and DSM-5 diagnostic criteria for anorexia nervosa

Weight criterion

According to the DSM-5, underweight in children and adolescents is operationalized as a body mass index (BMI; kg/m²) lying below the 5th sex-specific age percentile for BMI (1). Some patients display no clear loss of weight; rather, body weight remains fairly constant over time and the BMI gradually drops below the 5th age percentile as the individual ages and grows in height. It is pointed out in both the DSM-5 and the ICD-11 that the 5th percentile criterion is not meant to imply a sharp boundary between normal and abnormal. The ICD-11 alternatively permits a diagnosis of AN after rapid, marked weight loss (> 20% of body weight over 6 months); thus a patient who was overweight and then developed AN may, in fact, be of normal weight.

Body image disturbance/weight phobia

In addition to being underweight, most patients also have a body image disturbance and weight phobia. They consider themselves too fat overall or in certain parts of their body. The DSM-5 (1) allows a diagnosis to be made even if these cognitions are not present, provided that the eating and exercise behaviors preclude the physiological need for weight gain.

Differential diagnosis

Diagnostic difficulties may arise because of hidden abnormal eating behavior or weight loss. It is, therefore, essential that a medical history should also be taken from the patient’s parents or other people close to her or him. Other mental disorders that can cause weight loss, such as avoidant or restrictive eating disorder (e9), bulimia nervosa, emetophobia (pathological fear of vomiting), obsessive-compulsive disorder, depressive episodes, and psychoses, should be ruled out in the differential diagnosis. Infection, autoimmune disease (e.g., encephalitis), neoplasia, and endocrine disease (e.g. Addison‘s disease) can rarely simulate AN.

Constitutionally underweight healthy persons are occasionally wrongly diagnosed with AN. A detailed exploration in constitutionally thin, healthy children in the lowest percentile range will, however, reveal the following:

• a long-term weight history in the lowest percentile range,
• a relatively unremarkable food intake in quantity and quality,
• no body image disturbance or weight phobia, and
• often, first-degree relatives who were also underweight at that age.

Subclassification

Both the DSM-5 and the ICD-11 further classify AN into a restrictive type and a binge-eating/purging type. The restrictive type dominates in adolescence (> 80%) (11, 12). The DSM-5 classifies remission as either partial or total, while the ICD-11 contains a separate diagnosis of anorexia nervosa in remission. These subclassifications take into account the fact that the return of normal weight is not a sufficient criterion for recovery: amenorrhea, body image disturbances, or the desire to lose weight may persist. Atypical AN according to the DSM-5 (in which the underweight criterion is not met) has become more common in recent years.

Laboratory diagnostic testing

The blood tests listed in the eBox and eTable 3 should be carried out when AN is diagnosed and over the course of the disease. The serum leptin level informs about the patient’s fat mass and the extent of neuroendocrine starvation. Leptin measurement can also be helpful if patients deny the manifestations of the disease despite clinical evidence (AN is likely with subnormal leptin levels) (13). In severely starved individuals, serum leptin becomes undetectable with standard assays. Constitutional underweight is usually associated with a leptin level in the (low) normal range.

eTable 3

Parameters whose combined values are relevant to the assessment of somatic risk

Premorbid history and the onset of the eating disorder

Premorbid social anxiety, compulsions, perfectionism, and/or ambition are frequently found (14). These personality traits in particular contribute to the intensive and prolonged pursuit of intentional behavioral changes (e.g. dieting, increasing fitness). Major depression, anxiety and obsessive-compulsive disorders can begin before AN. According to studies, patients with AN, in contrast to those with atypical AN according to DSM-5, are more likely to be underweight from the age of 2 to 4 (15, 16). The average premorbid BMI of hospitalized patients in Germany was also below the median (eTable 2). A small subgroup of people with AN had other eating disorders before developing AN (e10).

eTable 2

Baseline data of hospitalized patients with anorexia nervosa (AN) and atypical AN (one diagnostic criterion not met) from the German Anorexia Nervosa Registry with the participation of 16 hospitals

Many patients retrospectively associate initial weight loss with improved performance and mood as well as an increased sense of control (e11). As weight loss continues, the clinical picture changes: patients are unable to gain weight on their own or can only do so with a major effort (e12). Persistent hunger becomes a chronic stressor (Tabelle 1) (5). Patients sometimes set an even lower target weight and are usually severely impaired by eating disorder-specific cognitions, including constant mental preoccupation with food and weight. Their memory and concentration may be impaired.

Comorbidities and clinically relevant accompanying manifestations

Comorbid mental disorders, in particular depression, anxiety and obsessive-compulsive disorder, are found in more than half of inpatients (11, 17). Depression can be a consequence of starvation (Table 1) and often improves after weight gain. The clinical picture of depression in AN differs from other forms of depression in adolescence. For example, suicidal ideation was three times more common in individuals with AN and comorbid depression than in persons with depression but no comorbid eating disorder (46% vs. 14%). On the other hand, depressed patients with AN attempted suicide less frequently than other depressed adolescents (1% vs. 39%; e13). The symptoms of comorbid OCD are sometimes closely interwoven with those of an eating disorder (e.g. compulsive washing due to fear/disgust of food). Some sufferers have delusional cognitions (e.g. calorie intake via ointments).

30–80% of patients display increased physical activity (18), e.g., sports and/or marked physical restlessness. Motivations for such behavior include the fear of weight gain and the mood-stabilizing effect of physical activity. Many patients experience physical hyperactivity as a compulsion. Studies in animals and human beings have found evidence that this hyperactivity is triggered by a subphysiological level of leptin secretion (18). Patients with hyperactivity nevertheless experience tiredness and exhaustion (e14).

Treatment

Essential components of the treatment of AN are psychoeducation, the initiation and monitoring of weight gain, improvement of mental and physical condition, a multidisciplinary networked approach, and involvement of the family (19). The aim is to normalize eating behavior, treat the physical consequences of disordered eating and underweight, improve the underlying difficulties on an emotional, cognitive and interactional level, and enable social integration and catching up on missed steps in development (20).

Nutritional therapy, target weight, and exercise therapy

All guidelines emphasize rapid weight restoration as a central treatment goal (19, 20, 21). Weight restoration is a prerequisite for mental and physical recovery and an improved quality of life (19). Depressiveness, preoccupation with food (22), and restrictive eating behavior all diminish during inpatient realimentation; body image disturbances, drive for thinness, and mental fixation on weight diminish to a lesser extent (11). The German guideline recommendations for weight gain are 200–500 g in the outpatient setting and 500–1000 g per week in the inpatient setting (20). In recent studies, no refeeding syndrome was observed in severely malnourished adults (BMI <13 kg/m²; [e15]) or adolescents (BMI <15 kg/m²; [23]) during realimentation with an initially higher/normocaloric calorie count (e.g., 2000 kcal/d from the start of treatment, with increasing energy intake if weight gain is insufficient) under close clinical laboratory monitoring (phosphate, calcium, potassium, magnesium) and, if necessary, phosphate and thiamine supplementation. Hypophosphatemia and other electrolyte imbalances are the most important manifestations of this severe metabolic derailment (24). At the same time, 2000 kcal/d were needed at the start of treatment in order to achieve a weight gain of 700 g/week (23). Even with constant weight gain, the improvement of starvation-related psychopathology requires an individually varying period of several weeks (Table 1). As the energy requirement for adequate weight gain can be over 3000 kcal/d in some phases, energy-dense foods are recommended. Gastrointestinal complaints (bloating, nausea, abdominal pain, flatulence, constipation) often occur before or at the beginning of refeeding but subside as weight restoration progresses (e16).

The initial weight goal for discharge from inpatient treatment is usually the 25th BMI percentile (20). In the case of habitually lower premorbid BMI percentiles, a lower weight target can also be set, but in the authors‘ opinion not below the 10th BMI percentile. The premorbid BMI percentile and, in girls, the menarche/return of menstruation in the intermediate term provide orientation for determining the individual healthy body weight. While, in some female patients, menstruation already recommences during realimentation, in others it may not do so even after the target weight has been reached. In addition to an adequate body fat percentage (e17) and sufficient leptin secretion (6), prerequisites to the resumption of menstruation also include the return of the ovaries and uterus to normal size after their starvation-induced reduction (e18).

For many years, physical exercise was not recommended for patients with AN during realimentation. Today, specialized institutions successfully integrate moderate sports and exercise interventions (Table 2 [e19, 25]), also to reduce the risk of osteoporosis. To improve bone density, calcium and vitamin D are orally substituted in patients with vitamin D deficiency up to the 10th BMI percentile, although the transdermal application of 17-beta-estradiol appears to be more effective. Supplementation of other demonstrated micronutrient deficiencies (vitamins, zinc, selenium) is advisable (20). The benefit of hormone replacement therapy with estradiol or progesterone is debated (20, 21). In older adolescents (bone age ≥ 15 years) who do not gain weight and have a bone density Z-score of 2.0 or less, a 17-beta-estradiol patch and oral progesterone can be considered, in consultation with pediatricians (26).

Table 2

Efficacy studies on the treatment of children and adolescents with anorexia nervosa

Psychotherapy and treatment settings

Aside from realimentation, psychotherapy is a further major element of treatment in the German clinical practice guidelines, which are now being updated (20). In the starvation stage, supportive psychotherapy is used to increase motivation and provide reassurance regarding the (usually unfounded) fear of excessive weight gain. After this, individual issues increasingly come to the fore. Finally, the focus is on relapse prevention.

Initially, the least restrictive setting for outpatient treatment is indicated: both the patient and her/his parents should be involved, and therapy should be provided by a psychotherapist who is experienced in the treatment of eating disorders under medical supervision. The patient should be hospitalized for treatment if not enough weight is gained, or, obviously, in case of an imminent threat to life. The length of inpatient treatment in Germany ranged from 3 to 6 months (eTable 2; [e20]). Treatment teams should be experienced in dealing with patients with AN. On the basis of evidence from 9 RCTs, Anglo-American guidelines (19, 21) recommend manual-based, eating-disorder-specific, family-centered procedures (FBT/FT-AN), with close involvement of parents in therapy carried out by specially trained therapists, as the first line of treatment. FBT/FT-AN is practically unavailable to date in Germany. Promising results were obtained in two recent pilot studies of home treatment (27) and FBT (28) as two different means of shortening the 3- to 6-month-long inpatient treatments (29) in Germany (e20). The findings of both pilot studies now need confirmation in RCTs of adequate size.

Pharmacotherapy

No drug has been approved for the treatment of AN. Antidepressants, including serotonin reuptake inhibitors, are nevertheless used clinically despite the lack of evidence for their effectiveness (30). Comorbid depression may fail to respond to antidepressant treatment because of a starvation-dependent pathogenesis. Evidence for the benefit of antipsychotic drugs in AN is largely lacking as well (31, 32), yet they are commonly used to facilitate weight gain and to reduce tension, AN-specific cognitions, and physical hyperactivity.

There have been small-scale RCTs investigating the use of cannabinoids (e21) and ghrelin agonists (e22) for appetite enhancement. A feasibility study with psilocybin (10 adults) appears promising (e23). In recent case studies, recombinant leptin (metreleptin) has been used for the off-label treatment of severe AN in adolescents and adults, under the assumption that leptin deficiency induces mental manifestations of starvation (18, 33, 34).

Medical case management and disease course

Aside from making the initial diagnosis, physicians in private practice have an important role in psychoeducation on the medical consequences of AN, motivating patients to undergo treatment, and somatic management (35), including risk assessment in children and adolescents with AN, with the involvement of their parents or legal guardians. Medical treatment and follow-up should be individually adapted to the ongoing medical assessment (Box 1, Box 2, eBox, eTable 3). Patients can be motivated to undergo treatment through repeated discussion; for some patients, the parents will need to be educated to understand that there is an urgent need for treatment. Patients often become more willing to participate in a personal discussion if they are asked to identify positive aspects of their illness. A subsequent stage of the discussion can then address its negative aspects, including the patient’s depressive mood, social withdrawal, and family disputes about eating (and, possibly, exercise) behavior. In acute, severe AN, the patient’s thoughts and feelings may be dominated by the eating disorder to such an extent that they appear delusional (e24). Discussions with medical staff then revolve exclusively around the desire to eat less and lose weight. In this situation, a persistent appeal to reason, with exhortation to eat more, is unhelpful and may well exacerbate anxiety and stress. The German clinical practice guideline (20) recommends actively calling patients in for regular follow-up under standardized conditions while remaining aware of possible weight manipulation, which should be understood as a symptom of the disease.

Box 1

The physician’s tasks in suspected anorexia nervosa and case management

Box 2

Parameters relevant for assessment of somatic risk

25% of patients were readmitted to the hospital within one year of their initial inpatient treatment (e25). Psychological problems that were already present before AN, such as anxiety disorders, depression, or an emotionally unstable personality accentuation, may re-emerge after successful realimentation. The transition from adolescence to adulthood poses potential risks because of a potentially inadequate transition to care by non-pediatric physicians, combined with the sudden attainment of legal age. The parents or guardians of a child or adolescent whose welfare is at risk can apply to the family court for a closed placement in accordance with §161b of the German Civil Code (BGB); from age 18 onward, this is only possible if the patient presents an acute danger to herself/himself, or to others (Mental Illness Act). Medicolegal guardianship should be considered in some cases and should ideally be applied for before the individual’s 18th birthday.

There are no standardized, internationally accepted criteria for remissions of AN (36). In an 18-year longitudinal outcome study including 51 adolescent patients, the duration of AN was 3.4 ± 2.4 years (mean ± standard deviation) (37). In a recent meta-analysis of 109 studies that included 10,644 adolescent and adult patients with AN, body weight normalized in 45% of over 72.8 ± 76.8 months of observation. At 10 years and beyond, 67% recovered from AN, with recovery defined as the absence of eating disorder symptoms or a “good” outcome on established scales (e.g., the Morgan-Russell scale; [38]). Subclinical abnormalities, such as mild eating disturbances, increased perfectionism and compulsiveness (e26), and an increased risk of other mental disorders, especially anxiety disorders and depression (e27), often persist after recovery. The lethality of AN is evident in long-term studies of adults: in a German 25-year longitudinal study of adults who had been hospitalized for AN, 97 (7.6%) of the 1271 study participants died (39). A meta-analysis revealed a standardized mortality ratio of 5.86 for AN, which was the highest among all mental disorders (40), with deaths rarely occurring before age 18. Common causes of death are suicide and complications of starvation. Childhood-onset AN has been reported to have both a better and a worse prognosis (e28 and e29, respectively).

Overview and perspectives

AN is among the more severe mental illnesses of childhood and adolescence; it endangers physical health through starvation. Early detection and early intervention are essential. The higher prevalence of AN in females has not yet been adequately explained. In the near future, internationally accepted remission criteria will need to be defined; if possible, the course of the disease should be shortened, the risks of chronification and of death should be reduced, and an understanding should be gained of whether and how weight loss in adolescence (be it intentional or unintentional) can transform into AN. If it is found that certain drugs can counteract the central adaptation to starvation and thereby alleviate the starvation-related manifestations of AN, their use might markedly improve the outcome of AN. The putative benefit of leptin supplementation has yet to be confirmed in randomized and controlled trials.

Patients should be taught about the complex physical and mental changes induced by starvation and their improvement once normal weight is restored; psychoeducation about these matters can strengthen their motivation to gain weight. In the hospital setting, normocaloric realimentation can be provided from the outset under close supervision. Treatment settings should be reconsidered; appropriate outpatient and day-treatment facilities should be made more widely available in accordance with best professional practice so that each patient can receive individually optimized treatment. There is a need for stronger coordination of the diagnostic procedures and treatments that are offered in pediatrics and child and adolescent psychiatry. The efficacy of FBT, FT-AN, and home treatment should be investigated in RCTs in Germany; if the findings are positive, these procedures should be recommended in the next update of the German clinical practice guidelines. Further study is needed on the benefits and risks of psychoactive drugs and the potential definability of a prognostically valid prodromal stage in which preventive treatment might be provided.

Acknowledgement

For their support in creating the manuscript, we would like to thank Magdalena Berg, Jana Thiemann, Caroline Di Maria, and Katja Wechsung.

Conflict of interest statement
JH has received lecture honoraria from Amryt Pharmaceuticals and Novo Nordisk. He is named as an inventor in three patent applications of the Universität Duisburg-Essen concerning the use of leptin analogs to treat anorexia nervosa/depression.

GGD is named as an inventor in a patent application of the Universität Duisburg-Essen concerning the use of leptin analogs to treat anorexia nervosa/depression.

CUC served as a consultant for AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He is a share option holder in Cardio Diagnostics, Mindpax, LB Pharma and Quantic.

The remaining authors declare that they have no conflicts of interest.

Manuscript received on 16 February 2023, revised version accepted on 9 October 2023.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Dr. oec. troph. Verena Haas
Klinik für Psychiatrie, Psychosomatik und Psychotherapie
des Kindes- und Jugendalters
Charité Universitätsmedizin Berlin – Campus Virchow-Klinikum
Augustenburger Platz 1, D-13353 Berlin, Germany

Cite this as:
Hebebrand J, Gradl-Dietsch G, Peters T, Correll CU, Haas V: The diagnosis and treatment of anorexia nervosa in childhood and adolescence. Dtsch Arztebl Int 2024; 121: 164–74. DOI: 10.3238/arztebl.m2023.0248

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