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From Prevention to Prognosis: Clinical Research Update on Adolescent Eating Disorders

Eating disorders are complex illnesses that afflict an increasing number of children and adolescents. The widely accepted biopsychosocial model for their pathogenesis is supported by growing evidence of the biologic and environmental factors that predispose young people to develop an eating disorder. The interaction among these factors, coupled with the specific age of onset during adolescence, prompted the Society for Adolescent Medicine and the Academy for Eating Disorders to co-sponsor an institute entitled “From Prevention to Prognosis: Clinical Research Update on Adolescent Eating Disorders” at the 1999 annual meeting of the Society for Adolescent Medicine in Los Angeles. The characterization and prevention of and comprehensive multimodal interventions into these complex disorders were discussed.

GENETIC FACTORS IN EATING DISORDERS

Michael Strober

Dr. Michael Strober (University of California, Los Angeles, Neuropsychiatric Institute) described emerging evidence of the inherited determinants of the risk for eating disorders. Although well-controlled studies are still sparse, recent family, twin, and molecular studies suggest that some aspects of the causes and pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN) may be mediated by genetic factors. Moreover, several factors raise the possibility of common genetic influences across the full phenotypic expression of eating disorder pathology, including overlapping clinical descriptions of these two disorders, switching between disorders, and similar patterns of central serotonergic hyperactivity.

Of the nearly one dozen family studies of eating disorders conducted, all but one suggest that the disorders cluster in families and that the two major types coaggregate in families. Similarly, concordance rates for AN and BN are higher in monozygotic twin pairs than in dizygotic pairs.

In Strober's recent study of some 1,500 first-degree relatives of probands with AN, BN, or no psychiatric illness, the largest family transmission study of eating disorders ever conducted, his team determined whether relatives of these proband groups differed in rates or patterns of lifetime psychiatric illness. They found that whereas AN was rare in the families of normal control subjects, full and partial syndromes of the illness were 11 and 5 times higher, respectively, among female relatives of probands with AN. Rates of BN were 4 times as high among female relatives of probands with this illness than among female relatives of control subjects. The hypothesis of shared vulnerability to these two disorders was also confirmed, as cross-transmission occurred in the families studied.

Certain environmental, biologic, and genetic factors, acting with shared causative determinants, may affect the expression of eating disorder phenotypes in persons at risk. The nature of the putative disease-conferring genes underlying eating disorders remains entirely speculative. However, they may include polymorphisms influencing temperament, proneness to anxiety, response to rewarding substances, body phenotypes, and energy expenditure under conditions of caloric restriction.

STRUCTURAL BRAIN CHANGES IN ANOREXIA NERVOSA

Debra K.

Katzman

Dr. Debra Katzman (The Hospital for Sick Children, Toronto, and the University of Toronto) reviewed the evidence of structural abnormalities found in the brains of adolescents with AN and discussed the possible pathophysiologic mechanisms leading to them, the reversibility of these abnormalities, and their association with impaired cognitive function.

Studies using computed tomography and magnetic resonance imaging (MRI) demonstrated the enlargement of ventricles and sulci in the acute stages of AN. Most of these studies, however, have measured the size of cerebrospinal fluid (CSF) spaces rather than tissue volumes; none used MRI to characterize the brain tissue changes associated with the observed increase in CSF volume.

In a study by Katzman and her colleagues, MRI images were segmented into various tissues to determine whether the increased CSF volume reported in patients with acute AN resulted from differences in gray-matter or white-matter volumes. This study of 13 adolescent females with AN in a low-weight state and 8 healthy female controls found that the AN group had markedly increased ventricular and sulcal CSF volumes and significant deficits in both gray-matter and white-matter volumes. Total gray-matter volumes were correlated positively with the patients' lowest recorded body mass index (BMI) and negatively with urinary free-cortisol levels. These results suggest that AN may affect gray-matter and white-matter volumes differently: gray-matter volumes may be more closely related to the degree of weight loss and cortisol elevation.

A review of the pathophysiology of reported brain abnormalities raises the question of whether these changes were primary, causing the development of AN, or secondary, resulting from its expression. The evidence suggests they are secondary for a number of reasons. First, the ventricles were more enlarged in patients with AN than in those with other psychiatric illnesses. Second, the magnitude of brain abnormalities and degree of starvation were correlated. Third, elevated serum cortisol levels have been found to correlate with enlarged ventricles in adult patients with AN. In addition, Katzman reported that CSF volumes in acutely ill adolescents with AN were significantly correlated with 24-h urinary free-cortisol levels. Hypercortisolism may therefore contribute to the brain abnormalities found in patients with AN—a possibility supported by animal studies showing that corticosteroids may cause neuronal damage.

Finally, the abnormalities are, to some degree reversible. In Katzman's pilot MRI study, 12 weight-recovered subjects with a history of AN had significant deficits in gray-matter volume that differed from those of controls, but there were no differences in white-matter volumes. These findings were replicated in weight-recovered patients who had a history of AN. Six patients from Katzman's original study were rescanned 2 to 3 y after their initial MRI scan. These patients showed significant increases in white-matter volume and decreases in CSF volume, but continued to show significant deficits in gray-matter volume and significantly enlarged sulci.

The association of structural brain changes in patients with AN with impairments in cognitive functioning, however, remains unclear. Cognitive deficits in these patients have been described, specifically in the focusing-execution, verbal, memory, and visual-spatial domains. Some studies have documented improvement in cognitive function after weight gain. However, inconsistencies in findings underline the need for further investigation of these brain abnormalities and their association with impaired cognitive functioning.

LEPTIN IN ANOREXIA NERVOSA

Neville H.

Golden

Dr. Neville H. Golden (Schneider Children's Hospital of Long Island Jewish Medical Center, New York and Albert Einstein College of Medicine) discussed the role of leptin in regulating eating behavior, body weight, and reproductive function in patients with AN.

Leptin is a protein product of the fat cell that is coded for by the ob gene. It circulates in the blood and acts on the hypothalamic receptors to modulate food intake and energy expenditure to maintain a relatively stable weight. Leptin deficient (ob/ob) mice are obese and lose weight when administered leptin. In another genetically obese mouse model (db/db mice), leptin levels are high, presumably because of a defect in the leptin receptor, producing a state of leptin resistance. Many of the neuroendocrine responses to starvation (such as activation of the hypothalamic-pituitary-adrenal axis and suppression of the reproductive axis) can be reversed by administering leptin to experimentally starved mice. In addition to its modulation of satiety and body weight, leptin plays an important role in the regulation of reproduction in rodents. Both ob/ob and db/db mice do not mature sexually and remain sterile. Administration of leptin to the ob/ob mice triggers puberty and fertility.

The human homologue of the ob gene is 84% identical to the mouse ob gene. Cross-sectional studies have consistently demonstrated that leptin levels are high in obese children and adults suggesting leptin resistance, rather than deficiency in most instances of human obesity.

Leptin levels are low in patients with AN, probably reflecting a reduced amount of body fat. Similar to the findings in obesity, leptin levels are highly correlated with body weight, percentage of body fat, and BMI. In patients admitted to an inpatient or partial hospitalization program, leptin levels increased with refeeding and partial weight gain, but at the end of the program when subjects were still of low weight, levels remained significantly lower than those of normal controls.

In a recent study of serum leptin levels, Golden's team found that leptin levels were lower in adolescent girls with AN than in control subjects at baseline and rose slightly, but not significantly, with refeeding. Levels increased significantly from baseline to follow-up only in girls who resumed menses, not in those who remained amenorrheic, even though both groups gained weight. At follow-up, leptin levels were significantly higher in the former group than in the latter, but were still lower than those of healthy age-matched controls.

In summary, since leptin is part of a feedback loop in which the amount of energy stored is sensed by the hypothalamus, it can adjust food intake and energy expenditure to maintain a constant body weight. In patients with AN, leptin levels are low, increasing with refeeding and resumption of menses. Persistent amenorrhea, however, is associated with low leptin levels, despite weight gain, suggesting an association between reproductive function and leptin levels that is independent of weight gain.

TREATMENT OF EATING DISORDERS

Joel Yager

Dr. Joel Yager (University of New Mexico School of Medicine, Albuquerque) described the revision of the 1993 American Psychiatric Association's practice guidelines for eating disorders. The new practice guidelines contain more than 350 citations, many recently published. Like the previous version, the new guidelines rely as much as possible on evidence-based medicine. Although a large number of randomized controlled trials have been conducted for BN, such trials are still quite scarce for AN.

The guidelines stress the need for comprehensive medical, psychological, and social assessments and interventions conducted by interdisciplinary treatment teams, including psychiatrists, pediatricians, internists or family physicians, psychologists, dietitians, and social workers. Comprehensive care has several objectives: helping patients to restore healthy nutritional status and improve eating behaviors; to manage the associated distorted thoughts and feelings about weight and shape; to cope with associated emotional and psychiatric problems; and to deal with the family problems that often accompany eating disorders. The guidelines stress the importance of enhancing patients' motivation for treatment and communicating with empathic compassion while setting appropriate limits.

The new version includes specific recommendations about the levels of care required for the physiologic, behavioral, and psychological features of AN. The primary intervention is nutritional rehabilitation featuring increasingly diverse meals. Liquid supplements or nasogastric feedings may be lifesaving and are recommended when regular feedings prove unsuccessful. Education and counseling and/or therapy for patients and their families are essential components for all treatment plans. Psychiatric medications are adjunctive for treating patients with AN. In programs with appropriate nursing care, controlled trials found that selective serotonin re-uptake inhibitors (SSRIs) did not improve rates of weight gain in severely malnourished patients with AN. Psychiatric medications may help if specific mood, anxiety, or obsessive-compulsive clinical features are present, especially after a healthy weight has been restored. In addition, controlled studies have shown that SSRIs may help after weight restoration by reducing weight loss, depression, and re-admissions to hospital.

Clinicians must appreciate that recovery from AN, even under the best of circumstances, is a slow process, often requiring several years. Cognitive therapy, interpersonal therapy, and antidepressant medications, particularly SSRIs, can effectively treat BN. Family therapy is essential, particularly for younger patients.

Further critical research is required in both fundamental and clinical aspects of these conditions to improve our understanding and treatments.

PREVENTION OF EATING DISORDERS

Dianne Neumark-Sztainer

Dr. Dianne Neumark-Sztainer (Division of Epidemiology, University of Minnesota, Minneapolis) discussed the general principles of preventing eating disorders and obesity. Preventive efforts are essential because of the impact of these disorders on physical and psychosocial health, their high prevalence among youth, and the difficulties and costs of treatment. In developing preventive measures, health care workers need to consider the entire spectrum of weight-related disorders, including AN, BN, anorectic and bulimic behaviors, unhealthy dieting, binge-eating disorder, and obesity.

Although consensus exists on the importance of preventive interventions, questions have arisen about their potential impact, given the complex causes of eating disorders. Clearly, it is too early to draw conclusions about their effectiveness, since relatively few long-term interventions have been implemented or have included stringent evaluation. However, numerous interventions show strong potential for modifying media awareness, body image attitudes, and weight-control behaviors.

Schools offer an excellent, yet underused forum for prevention. Neumark-Sztainer found that a 10-week classroom intervention for high-school youth helped prevent unhealthy weight control behaviors and binge eating, but she urged a more comprehensive school-based approach to increase its impact. She conducted a needs assessment in a large urban school district and found strong staff support for school-based interventions aimed at the primary and secondary prevention of eating disorders, obesity, and other weight-related disorders.

Existing community networks can also be used for preventive purposes. Community-based programs could supplement messages given in school-based programs, in a more social and less academic environment. Neumark-Sztainer's pilot project “Free to be Me” with Girl Scout troops aims to prevent unhealthy dieting practices and improve body image and media awareness among young adolescent girls. Initial findings showed high levels of satisfaction with the program among troop leaders, parents, and girls.

The development and widespread implementation of interventions that prevent eating disorders is urgently needed. Rigorous evaluations are essential to ensure that programs are implemented as intended, have no unintended harmful effects, and effectively lead to positive changes in weight-related attitudes and behaviors. Prevention at the individual, school, community, and societal level must be a priority.

PROGNOSIS OF ADOLESCENT-ONSET ANOREXIA NERVOSA

Michael Strober

Dr. Strober then discussed the findings of a recent long-term prospective follow-up of adolescents hospitalized in the eating disorders treatment program at his center. To our knowledge, this study provides the most detailed quantitative examination of the course of recovery and relapse in the naturalistic history of AN. As background, he discussed previous efforts to assess the course of AN, pointing out the methodological shortcomings of previous studies. Specifically, in virtually all studies published to date, the course of illness was assessed only retrospectively; little attention was paid to the temporal patterns of recovery; the question of relapse after symptomatic recovery was rarely considered; surprisingly scant attention was given to the identification of patients who achieved complete clinical recovery; statistical methods inadequately identified the independence of predictors of outcome; and, in all but a few studies, the period of observation was too brief to characterize the natural history of the illness accurately.

In contrast, his UCLA study was conducted over a 15-year period, comprised serial semiannual to annual assessments of symptomatic and functional outcomes, was conducted prospectively on a large patient cohort, drew on a large database for identification of the predictor variables across the clinical and psychosocial domains of interest, had carefully defined categories of outcome, including relapse after recovery, and applied contemporary statistical methods to quantify course and outcome variables.

Nearly three quarters of the 95 patients studied fully recovered from their illness; however, their course of recovery was protracted (median time, 72 months). At the same time, no patients achieving this level of recovery relapsed into full illness, suggesting that the common impression of AN as a lifelong disease from which full recovery is rare is ill founded. Moreover, the progression from AN to BN was not uncommon: it occurred in about 30% of the cohort within 5 years of follow-up; however, the reason for this relatively early first onset of binge eating remains unknown.

Of the many variables observed for their potential to predict course and outcome, surprisingly few achieved statistical significance. In particular, early weight loss after hospital discharge, extreme premorbid social isolation, and extreme compulsivity in daily routines were significant independent predictors of chronic outcome, whereas family discord predicted increased odds of the onset of binge eating.

These findings provide evidence of the potential for full recovery in patients with AN. However, they also underline the sobering reality of the tenacious character of the illness, the need for early, very aggressive intervention, and the unpredictability of the long-term course and outcome of any individual case.

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This paper was prepared with the assistance of Editorial Services, The Hospital for Sick Children, Toronto, Ontario, Canada.

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Katzman, D., Golden, N., Neumark-Sztainer, D. et al. From Prevention to Prognosis: Clinical Research Update on Adolescent Eating Disorders. Pediatr Res 47, 709–712 (2000). https://doi.org/10.1203/00006450-200006000-00005

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