Epidemiology
Among women, the lifetime prevalence of the full syndrome of AN is approximately 0.5%. AN is much less common in males. AN is more prevalent in cultures where food is plentiful and in which being thin is associated with attractiveness. Individuals who pursue interests that place a premium on thinness, such as ballet and modeling, are at greater risk. The incidence of AN appears to have increased in recent decades.

Etiology
The etiology of AN is unknown but appears to involve a combination of psychological, biologic, and cultural risk factors. Risk factors, such as sexual or physical abuse and a family history of mood disturbance, are best viewed as nonspecific risk factors that increase vulnerability to a range of psychiatric disorders, including AN.

Patients who develop AN are inclined to be more obsessional and perfectionist than their peers. The disorder often begins as a diet not distinguishable at the outset from those undertaken by many adolescents and young women. As weight loss progresses, the fear of gaining weight grows; dieting becomes stricter; and psychological, behavioral, and medical aberrations increase.

Eating disorders, including AN, may develop among individuals with type 1 diabetes mellitus, and are associated with poorer glycemic control and an increased frequency of complications.

Numerous physiologic disturbances, including abnormalities in a variety of neurotransmitter systems, have been described in AN (see below). It is difficult to distinguish neurochemical, metabolic, and hormonal changes that may have a role in the initiation or perpetuation of the syndrome from those that are secondary to the disorder. The resolution of most of these abnormalities with weight restoration argues against their having a critical etiologic role.

Genetic factors contribute to the risk of development of AN, as its incidence is greater in families with one affected member and the concordance in monozygotic twins is greater than in dizygotic twins. However, specific genes have not been identified.

Clinical Features
See Table 65-1. AN typically begins in mid to late adolescence, sometimes in association with a stressful life event such as leaving home for school. The disorder occasionally develops in early puberty, before menarche, but seldom begins after age 40. Despite being underweight, patients with AN are irrationally afraid of gaining weight, often out of a concern that weight gain will get “out of control.” They also exhibit a distortion of body image, which may express itself in several ways. For example, despite being emaciated, patients with AN may believe that their body as a whole, or some part of their body, is too fat. Further weight loss is viewed by the patient as a fulfilling accomplishment, while weight gain is seen as a personal failure. Patients with AN rarely complain of hunger or fatigue and often exercise extensively. Despite the denial of hunger, one-quarter to one-half of patients with AN engage in eating binges. Patients tend to become socially withdrawn and increasingly committed to work or study, dieting, and exercise. As weight loss progresses, thoughts of food dominate mental life and idiosyncratic rules develop around eating. Patients with AN may obsessively collect cookbooks and recipes and be drawn to food-related occupations.

Physical Features
Patients with AN typically have few physical complaints but may note cold intolerance. Gastrointestinal motility is diminished, leading to reduced gastric emptying and constipation. Some women who develop AN after menarche report that their menses ceased before significant weight loss occurred. Weight and height should be measured to allow calculation of body mass index (BMI; kg/m2). Vital signs may reveal bradycardia, hypotension, and mild hypothermia. Soft, downy hair growth (lanugo) sometimes occurs, and alopecia may be seen. Salivary gland enlargement, which is associated with starvation as well as with binge eating and vomiting, may make the face appear surprisingly full in contrast to the marked general wasting. Acrocyanosis of the digits is common, and peripheral edema can be seen in the absence of hypoalbuminemia, particularly when the patient begins to regain weight. Some patients who consume large amounts of vegetables containing vitamin A develop a yellow tint to the skin (hypercarotenemia), which is especially notable on the palms.

Laboratory Abnormalities
Mild normochromic, normocytic anemia is frequent, as is mild to moderate leukopenia, with a disproportionate reduction of polymorphonuclear leukocytes. Dehydration may result in slightly increased levels of blood urea nitrogen and creatinine. Serum transaminase levels may increase, especially during the early phases of refeeding. The level of serum proteins is usually normal. Blood sugar is often low and serum cholesterol may be moderately elevated. Hypokalemic alkalosis suggests self-induced vomiting or the use of diuretics. Hyponatremia is common and may result from excess fluid intake and disturbances in the secretion of antidiuretic hormone.

Endocrine Abnormalities
The regulation of virtually every endocrine system is altered in AN, but the most striking changes occur in the reproductive system. Amenorrhea is hypothalamic in origin and reflects diminished production of gonadotropin-releasing hormone (GnRH). When exogenous GnRH is administered in a pulsatile manner, pituitary responses of luteinizing hormone (LH) and follicle stimulating hormone (FSH) are normalized, indicating the absence of a primary pituitary abnormality. The resulting gonadotropin deficiency causes low plasma estrogen in women and reduced testosterone in men. The hypothalamic GnRH pulse generator is exquisitely sensitive, particularly in women, to body weight, stress, and exercise, each of which may contribute to hypothalamic amenorrhea in AN. Although the mechanisms underlying these effects are unknown, the decreased adipose tissue associated with weight loss leads to a marked reduction in leptin, a hormone that plays a permissive role in GnRH production.

Serum cortisol and 24-h urine free cortisol levels are generally elevated but without characteristic clinical signs of cortisol excess. Thyroid function tests resemble the pattern seen in euthyroid sick syndrome. Thyroxine (T4) and free T4 levels are usually in the low-normal range, triiodothyronine (T3) levels are reduced, and reverse T3 (rT3) is elevated. The level of thyroid stimulating hormone (TSH) is normally or partially suppressed. Growth hormone is increased, but insulin-like growth factor 1 (IGF-1), which is produced mainly by the liver, is reduced, as in other conditions of starvation. Diminished bone density is routinely observed in AN and reflects the effects of multiple nutritional deficiencies, reduced gonadal steroids, and increased cortisol. The degree of bone density reduction is proportional to the length of the illness, and patients are at risk for the development of symptomatic fractures. The occurrence of AN during adolescence may lead to the premature cessation of linear bone growth and a failure to achieve expected adult height.

Cardiac Abnormalities
Cardiac output is reduced, and congestive heart failure occurs rarely during rapid refeeding. The electrocardiogram usually shows sinus bradycardia, reduced QRS voltage, and nonspecific ST-T-wave abnormalities. Some patients develop a prolonged QTc interval, which may predispose to serious arrhythmias, particularly when electrolyte abnormalities are also present.

Diagnosis
The diagnosis of AN is based on the presence of characteristic behavioral, psychological, and physical attributes (Table 65-2). Widely accepted diagnostic criteria are provided by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These criteria include weight <85% of that expected for age and height, which is roughly equivalent to a BMI of 18.5 kg/m2 for adult women. This weight criterion is somewhat arbitrary, so that a patient who meets all other diagnostic criteria but weighs between 85 and 90% of expected would still merit the diagnosis of AN. The current diagnostic criteria require that women with AN not have spontaneous menses, but occasional patients with the characteristics and complications of AN describe regular menstruation. Two mutually exclusive subtypes of AN are specified in DSM-IV. Patients whose weight loss is maintained primarily by caloric restriction, perhaps augmented by excessive exercise, are considered to have the “restricting” subtype of AN. The “binge eating/purging” subtype is characterized by binge eating, self-induced vomiting and/or laxative abuse. Patients with the binge/purge subtype are more prone to develop electrolyte imbalances, are more emotionally labile, and are more likely to have other problems with impulse control, such as drug abuse.

The diagnosis of AN can usually be made confidently on the basis of history when significant weight loss is accomplished by restrictive dieting and excessive exercise and is accompanied by a marked reluctance to gain weight. Patients with AN often deny that they have a serious problem and may be brought to medical attention by concerned family or friends. In atypical presentations, other causes of significant weight loss in previously healthy young people should be considered, including inflammatory bowel disease, gastric outlet obstruction, diabetes mellitus, central nervous system (CNS) tumors, and neoplasm.

Prognosis
The course and outcome of AN are highly variable. One-quarter to one-half of patients eventually recover fully, with few psychological or physical sequelae. However, many patients have persistent difficulties with weight maintenance, depression, and eating disturbances, including BN. The development of obesity following AN is rare. The long-term mortality of AN is among the highest associated with any psychiatric disorder. Approximately 5% of patients die per decade of follow-up, primarily due to the physical effects of chronic starvation or by suicide.

Virtually all of the physiologic abnormalities associated with AN are observed in other forms of starvation and markedly improve or disappear with weight gain. A worrisome exception is the reduction in bone mass, which may not recover fully, particularly when AN occurs during adolescence when peak bone mass is normally achieved.

Treatment
Because of the profound physiologic and psychological effects of starvation, there is a broad consensus that weight restoration to 90% of predicted weight is the primary goal in the treatment of AN. Unfortunately, because most patients resist this goal, the management of AN is often accompanied by frustration for the patient, the family, and the physician. Patients typically exaggerate their food intake and minimize their symptoms. Some patients resort to subterfuge to make their weights appear higher, for example, by water-loading before they are weighed. In attempting to engage the patient in treatment, it may be useful for the physician to elicit the patient’s physical concerns (e.g., about osteoporosis, weakness, or fertility) and, if possible, educate the patient regarding the importance of normalizing nutritional status in order to address those concerns. The physician should attempt to reassure the patient that weight gain will not be permitted to get “out of control” but simultaneously emphasize that weight restoration is medically and psychologically imperative.

The intensity of the initial treatment, including the need for hospitalization, is determined by the patient’s current weight, the rapidity of recent weight loss, and the severity of medical and psychological complications (Fig. 65-1). Hospitalization should be strongly considered for patients weighing <75% of expected, even if the results of routine blood studies are within normal limits. Acute medical problems, such as severe electrolyte imbalances, should be identified and addressed. Nutritional restoration can almost always be successfully accomplished by oral feeding, and parenteral methods are rarely required. For severely underweight patients, sufficient calories (approximately 1500 to 1800 kcal/d) should be provided initially in divided meals as food or liquid supplements to maintain weight and to permit stabilization of fluid and electrolyte balance. Calories can then be gradually increased to achieve a weight gain of 1 to 2 kg (2 to 4 lb) per week, typically requiring an intake of 3000 to 4000 kcal/d. Meals must be supervised, ideally by personnel who are firm regarding the necessity of food consumption, empathic regarding the challenges entailed, and reassuring regarding the patient’s eventual recovery. Patients have great psychological difficulty complying with the need for increased caloric consumption, and the assistance of psychiatrists or psychologists experienced in the treatment of AN is usually necessary.

Figure 65-1 An algorithm for basic treatment decisions regarding patients with anorexia nervosa or bulimia nervosa. Based on the American Psychiatric Association’s practice guidelines for the treatment of patients with eating disorders. *Although outpatient management may be considered for patients with anorexia nervosa weighing more than 75% of expected, there should be a low threshold for using more intensive interventions if the weight loss has been rapid or if current weight is <80% of expected.

Less severely affected patients may be treated in a partial hospitalization program where medical and psychiatric supervision is available and several meals can be monitored each day. Outpatient treatment may suffice for mildly ill patients. Weight must be monitored at frequent intervals, and explicit goals agreed on for weight gain, with the understanding that more intensive treatment will be required if the level of care initially employed is not successful. For younger patients, the active involvement of the family in treatment is crucial regardless of the treatment venue.

Psychiatric treatment focuses primarily on two issues. First, patients require much emotional support during the period of weight gain. Patients often intellectually agree with the need to gain weight, but strenuously resist increases in caloric intake, and often surreptitiously discard food that is provided. Second, patients must learn to base their self-esteem not on the achievement of an inappropriately low weight, but on the development of satisfying personal relationships and the attainment of reasonable academic and occupational goals. While this is often possible, some patients with AN develop other serious emotional and behavioral symptoms such as depression, self-mutilation, obsessive-compulsive behavior, and suicidal ideation. These symptoms may require additional therapeutic interventions, in the form of psychotherapy, medication, or hospitalization.

Medical complications occasionally occur during refeeding. As in other forms of malnutrition, fluid retention and peripheral edema may occur, but generally do not require specific treatment in the absence of cardiac, renal, or hepatic dysfunction. Acute gastric dilatation has been described when refeeding has been rapid. Transient modest elevations in serum levels of liver enzymes occasionally occur. Low levels of magnesium and phosphate should be repleted. Multivitamins should be given, and it is important to ensure adequate intake of vitamin D (400 IU/d) and calcium (1500 mg/d) to minimize bone loss.

No psychotropic medications are of established value in the treatment of AN; tricyclic antidepressants are contraindicated when there is prolongation of the QTc interval. The alterations of cortisol and thyroid hormone metabolism do not require specific treatment and are corrected by weight gain. Estrogen treatment appears to have minimal impact on bone density in underweight patients but may be helpful to relieve symptoms of estrogen deficiency.