INTRODUCTION — Anorexia nervosa is associated with numerous general medical complications that are directly attributable to weight loss and malnutrition [1,2]. The complications affect most major organ systems and often include physiologic disturbances such as hypotension, bradycardia, hypothermia, and amenorrhea.
Medical complications account for approximately half of all deaths in anorexia nervosa, which has one of the highest mortality rates of any mental illness . A meta-analysis of 25 studies, which included more than 12,000 patients with anorexia nervosa who were followed on average for 14 years, estimated that the rate of death was six times greater in patients than the general population (standardized mortality ratio 6) .
The medical complications of low weight in anorexia nervosa and the management of these complications are reviewed here. The evaluation for medical complications and criteria for hospitalizing patients with anorexia nervosa; epidemiology, clinical features, diagnosis, and treatment of anorexia nervosa; and the refeeding syndrome are discussed separately. In addition, the medical complications of binge eating and purging (which can occur in anorexia nervosa) are discussed in the context of the topic that reviews the medical complications of bulimia nervosa and binge eating disorder:
DIAGNOSIS OF ANOREXIA NERVOSA — According to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the diagnosis of anorexia nervosa requires each of the following criteria (table 1) :
●Restriction of energy intake that leads to a low body weight, given the patient’s age, sex, developmental trajectory, and physical health. A low body weight is defined as a body mass index (ratio of weight in kg divided by height in m2) <18.5 (calculator 1).
●Intense fear of gaining weight or becoming fat, or persistent behavior that prevents weight gain, despite being underweight.
●Distorted perception of body weight and shape, undue influence of weight and shape on self-worth, or denial of the medical seriousness of one’s low body weight.
There are two subtypes of anorexia nervosa, based upon symptoms during the past three months :
●Restricting – Marked by weight loss through dieting, fasting, and excessive exercise. In addition, the patient has not engaged in recurrent episodes of binge eating (eating an amount of food that is definitely larger than most people would eat under similar circumstances) or purging (self-induced vomiting and misuse of laxatives, diuretics, or enemas).
●Binge eating and purging – Marked by episodes of binge eating and purging.
This topic reviews the medical complications of the restricting type of anorexia nervosa. Complications due to bingeing and purging are discussed separately within the context of the medical complications that occur in patients with bulimia nervosa and binge eating disorder. (See "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management".)
The clinical features and diagnosis of anorexia nervosa are discussed separately. (See "Anorexia nervosa in adults: Clinical features, course of illness, assessment, and diagnosis".)
MEDICAL EVALUATION — Patients with the food-restricting subtype of anorexia nervosa should be evaluated for general medical complications, which can occur in many organ systems (table 2) [2,3,6]. The evaluation should include a history, physical examination, and laboratory testing, and is discussed separately. (See "Anorexia nervosa in adults: Evaluation for medical complications and criteria for hospitalization to manage these complications".)
GENERAL PRINCIPLES — The general medical complications of anorexia nervosa are a direct result of weight loss and malnutrition [7,8]. Starvation induces protein and fat catabolism that leads to loss of cellular volume and atrophy of the heart, brain, liver, intestines, kidneys, and muscles. As an example, muscle wasting, including the myocardium, occurs during starvation in order to provide amino acids for production of glucose. The number of organ systems adversely affected increases with the severity of weight loss (table 2).
The reported incidence of these medical complications varies, depending upon individual predispositions and severity of the current episode of anorexia nervosa, as reported in cross-sectional studies and case series [9,10]. The primary risk factors for developing medical complications in anorexia nervosa are the degree of weight loss and the chronicity of the illness . There are no known sociodemographic risk factors for developing complications.
Treatment for each complication includes nutritional replenishment. Although many complications are reversible with weight gain , some complications (eg, loss of bone mineral density) may not completely resolve after nutritional rehabilitation . There are no randomized trials that have evaluated the management of medical complications from anorexia nervosa.
Hospitalizing patients — Criteria for hospitalizing patients with anorexia nervosa for management of the illness and its medical complications are discussed separately. (See "Anorexia nervosa in adults: Evaluation for medical complications and criteria for hospitalization to manage these complications", section on 'Inpatient hospitalization'.)
Structural changes — Structural changes can include decreased cardiac mass, reduced cardiac chamber volumes, mitral valve prolapse, myocardial fibrosis, and pericardial effusion .
Substantial weight loss in anorexia nervosa is accompanied by atrophy of cardiac muscle, decreased cardiac mass, reduced ventricular wall thickness, and reduced cardiac chamber volumes, which are often visualized on imaging (image 1) [11,15-17]. This leads to decreased cardiac output, reduced exercise capacity, an attenuated blood pressure response to exercise, and subjective fatigue . Some individuals may also display decreased contractility. Most cardiac changes become clinically significant only when the patient is below 80 percent of ideal body weight (calculator 2). The weakened heart muscle generally improves with weight gain, and heart size normalizes with clinical recovery over weeks to months .
Patients with anorexia nervosa may complain of chest pain or palpitations, which are often due to mitral valve prolapse. The valve prolapses as the patient loses weight because the heart muscle decreases in size while the structural tissue that comprises the mitral valve remains the same size . One echocardiography study of patients with anorexia nervosa (n = 40) found mitral valve prolapse in 20 percent . By contrast, the Framingham Heart Study found an overall prevalence of 2.4 percent in the general population . Another observational study compared patients (n = 40) with healthy controls (n = 28) and found that mitral valve prolapse was more common in patients (23 versus 4 percent) . Physical examination in patients with the mitral valve prolapse syndrome often reveals a systolic murmur and “click,” but there are no associated electrocardiogram (ECG) findings. Clinically significant regurgitation is rare, and there are no known cases that required mitral valve surgery . The prolapse generally recedes with weight gain. The mitral valve prolapse syndrome is discussed separately. (See "Mitral valve prolapse syndrome" and "Mitral valve prolapse: Clinical manifestations and diagnosis".)
Myocardial fibrosis can also occur in anorexia nervosa. An observational study performed cardiac magnetic resonance imaging in patients (n = 40) as well as healthy controls (n = 28), and found that myocardial fibrosis was more common in patients (23 versus 0 percent) .
There is no evidence of increased anginal pain in young patients with anorexia nervosa, and autopsy studies do not reveal evidence of obstructive coronary disease . Total levels of cholesterol may be elevated in as many as 50 percent of patients; this is due to a high level of cardioprotective high-density lipoprotein (HDL) and insignificant elevations in low-density lipoprotein (LDL) . Statin therapy is not needed. The presumptive cause of elevated HDL is excessive exercise and weight loss. An overview of risk factors for cardiovascular disease and management of cardiovascular risk in women are discussed separately. (See "Overview of established risk factors for cardiovascular disease" and "Overview of atherosclerotic cardiovascular risk factors in females".)
Pericardial effusion — Pericardial effusion has been reported in patients with anorexia nervosa, but the prevalence and etiology are not clear [14,16,24]. The effusions generally appear to remit with weight restoration :
●One prospective study compared young adult patients (n = 40) with healthy controls (n = 28) and found that pericardial effusion was more common in patients (30 versus 4 percent) .
●A prospective study of 128 female adolescents with anorexia nervosa revealed a pericardial effusion in 23 percent (29 patients), using two-dimensional Doppler echocardiography . None of the patients with an effusion had a friction murmur and none had clinical or echocardiographic signs of cardiac tamponade. Among the 29 patients with an effusion at baseline, the effusion disappeared within three months of refeeding in 18 (62 percent).
●Another prospective study of female adolescents with anorexia nervosa (n = 173) and healthy controls (n = 40) found that pericardial effusion was more common in patients (35 versus 0 percent) . The effusions were clinically silent, including no cases of cardiac tamponade. Among the 50 patients with a follow-up echocardiogram after refeeding, remission of the effusion was observed in 88 percent.
Diagnosis and treatment of pericardial effusion are discussed separately. (See "Diagnosis and treatment of pericardial effusion".)
Functional changes — Functional cardiovascular changes include bradycardia, hypotension, decreased diastolic ventricular function, and diminished heart rate variability [12,13,17,26]. In addition, QT interval prolongation may be seen in some patients, but it is unlikely that anorexia nervosa directly causes prolongation of the corrected QT (QTc) interval .
There are no ECG findings specific to anorexia nervosa . Aside from bradycardia, the ECG is often normal. As an example, one retrospective study found that among 673 patients with anorexia nervosa who were admitted to a facility at the inpatient or residential level of care, all but two percent were in cardiac sinus rhythm . Of the patients not in cardiac sinus rhythm, the majority were in slow junctional rhythm.
Case reports describe ST and T-wave changes, atrioventricular block, or ventricular arrhythmia, particularly in patients with hypokalemia or hypomagnesemia [27-31]. The QRS axis is generally normal and when abnormal it is almost always right axis deviation . Diminished R-wave amplitude has also been observed in anorexia nervosa. An ECG at baseline will screen for these potential abnormalities. ECG abnormalities should dissipate with weight restoration and correction of any underlying electrolyte abnormality. An overview of management of arrhythmias is discussed separately. (See "Arrhythmia management for the primary care clinician".)
Concerns have been raised that anorexia nervosa causes QT interval prolongation, which predisposes patients to life-threatening ventricular arrhythmias such as torsade de pointes [3,32]. Some studies have documented QT interval prolongation in severe anorexia nervosa , which normalized after weight gain [11,33]. However, other studies have found that the QT interval is usually normal . As an example, one retrospective study found that among 673 patients with anorexia nervosa who were admitted to a facility at the inpatient or residential level of care, the corrected QT interval was prolonged in only 1.5 percent . Many authorities think that the QT interval is not inherently prolonged in anorexia nervosa, and that QT prolongation does not independently cause sudden death in patients with anorexia nervosa . Thus, the presence of a long QT interval in a patient with anorexia nervosa should not be summarily dismissed as being secondary to anorexia nervosa; rather, it should prompt a search for an electrolyte disturbance, the presence of the congenital long QT syndrome, or the use of medications known to prolong the QTc. The long QT syndrome is discussed separately. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Congenital long QT syndrome: Epidemiology and clinical manifestations".)
Myocardial repolarization reserve may be impaired in anorexia nervosa. A prospective study of adolescents with anorexia nervosa (n = 61) and healthy controls matched on age and sex (n = 45) found that in the absence of QT prolongation, patients had impaired repolarization reserve .
In patients with anorexia nervosa, abnormal autonomic nervous system function appears to diminish heart rate variability . Normally, moment-to-moment fluctuations in heart rate reflect the underlying stability of the autonomic nervous system and integration of sympathetic and parasympathetic function. Reduced heart rate variability predicts sudden death in patients with heart failure, and may also be correlated with an increased incidence of sudden death in anorexia nervosa, especially in patients who weigh less than 80 percent of ideal body weight. A decreased rate of variability suggests that the patient needs a more comprehensive cardiac evaluation. Heart rate variability is discussed separately. (See "Evaluation of heart rate variability".)
Hypotension (systolic blood pressure <90 mmHg and/or a diastolic blood pressure <50 mmHg) can often occur in patients with anorexia nervosa . One study of patients found hypotension in 16 percent . Symptoms include fatigue and weakness. In addition, there may be orthostatic hypotension (within two to five minutes of moving from a supine position to standing, a decrease in systolic blood pressure of ≥20 mmHg, decrease in diastolic blood pressure of ≥10 mmHg, or symptoms of cerebral hypoperfusion). Symptoms of orthostasis include lightheadedness upon standing, weakness, and cognitive impairment. Orthostasis may also indicate the need for hospitalization, depending upon the severity . Orthostasis in anorexia nervosa indicates that the patient’s cardiac status has been affected by malnutrition. Weight restoration seems to resolve hypotension and orthostasis, albeit slowly over weeks to months [14,37]. Thus, it is generally not prudent to invoke a new diagnosis such as postural orthostatic tachycardia syndrome in more severely ill patients with anorexia nervosa to explain dizziness. Rather, exuberant rises in heart rate with falls in blood pressure are inherent to the more severe stages of anorexia nervosa. Evaluation and treatment of orthostatic hypotension are discussed separately. (See "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Treatment of orthostatic and postprandial hypotension".)
Bradycardia — Bradycardia (<60 beats per minute) is often found in anorexia nervosa, with heart rates as low as 25 beats per minute [9,14]:
●A study of 214 women with anorexia nervosa found that the average mean heart rate was 62 beats per minute, and that bradycardia was present in 41 percent (and hypotension in 16 percent) .
●In a retrospective study of 673 patients with anorexia nervosa, who were admitted to a facility at the inpatient or residential level of care, bradycardia was present in approximately 44 percent .
The cause of bradycardia appears to be increased parasympathetic (vagal) activity with unchanged sympathetic tone [37,38].
Patients typically describe nonspecific symptoms related to bradycardia, such as fatigue, weakness, and lightheadedness. Bradycardia is expected with anorexia nervosa, and should not, in and of itself, result in therapy directed to increase the heart rate. Inserting a pacemaker is almost never indicated, even with heart rates as low as the low 30s.
Although clinicians might find comfort in a normal heart rate, “relative tachycardia” (pulse of 70 to 100) in patients with moderate to severe anorexia nervosa may have more sinister implications . A normal heart rate, even if not strictly in the elevated range (pulse >100), is probably due to a medication side effect, anxiety, or an impending medical complication, and should be viewed as a warning sign in need of medical evaluation . This is especially germane during the early stages of refeeding, in which a normal heart rate may be a harbinger of heart failure and the refeeding syndrome. (See "Anorexia nervosa in adults and adolescents: The refeeding syndrome", section on 'Pathogenesis and clinical features'.)
One clinical judgement is deciding what degree of bradycardia requires hospitalization for continuous monitoring of cardiac function with telemetry or treatment in an intensive-care unit. There are no studies that have directly addressed this question in patients with anorexia nervosa. Nearly all authorities agree on the need for hospitalization and telemetry for any adult patient with a heart rate less than 30 beats per minute. Whether the patient is admitted to an intensive care unit depends upon the presence of other clinical problems and availability of resources. The American Psychiatric Association practice guideline suggests hospitalization for a heart rate of less than 35 to 40 beats per minute . Based upon our clinical experience, we suggest telemetry if the patient has a cardiac rhythm other than sinus bradycardia, or a heart rate of less than 40 beats per minute and hypotension or symptoms of lightheadedness. Bradyarrhythmias can lead to dangerous sinus pauses and thus need initial telemetry monitoring . Criteria for hospitalizing patients with anorexia nervosa are discussed separately. (See "Anorexia nervosa in adults: Evaluation for medical complications and criteria for hospitalization to manage these complications", section on 'Inpatient hospitalization'.)
Bradycardia in patients with anorexia nervosa generally resolves as weight is restored to a level greater than 80 percent of ideal body weight (calculator 2) or when the body mass index (calculator 1) is greater than 17 to 18 kg/m2, or even earlier once a stable pattern of nutritional replenishment and progressive weight gain ensues [14,42].
An overview of bradycardia is discussed separately. (See "Sinus bradycardia".)
GYNECOLOGIC AND REPRODUCTIVE — The reproductive system is altered in anorexia nervosa, causing a cascade of events that typically result in secondary amenorrhea [5,43]. By contrast, an epidemiologic study of 403 healthy, premenopausal women aged 18 to 39 years found that 5 percent had anovulatory menstrual cycles .
Central nervous system reproductive functions are disrupted in anorexia nervosa [45,46]. Normally, nerve impulses within the hypothalamus trigger the pulsatile secretion of gonadotropin releasing hormone, which acts upon the pituitary. This initiates the release of luteinizing hormone and follicle-stimulating hormone, which in turn determine the onset of normal menstrual function. In patients with anorexia nervosa, secretion of gonadotropin releasing hormone is reduced, which ultimately prevents ovulation and causes a functional hypothalamic amenorrhea and reversion to a prepubertal state. (See "Epidemiology and causes of secondary amenorrhea", section on 'Functional hypothalamic amenorrhea'.)
Weight loss of between 10 to 15 percent of normal weight disrupts the menstrual cycle in most women . However, amenorrhea may precede weight loss in up to 20 percent of women with anorexia nervosa. In addition, rigorous exercise in patients with anorexia nervosa contributes to the secondary amenorrhea [47,48]. Although a minority of women with anorexia nervosa maintain some menstrual activity even at significantly low weights, this should not falsely reassure clinicians or patients that weight restoration is not necessary.
Weight gain usually restores normal menstrual cycles . The time course and amount of weight required for resumption of menses has varied among different studies. A two-year study of 100 adolescent females with anorexia nervosa found that resumption of menses occurred in a mean average of nine months and required a weight of 4.5 pounds (2 kg) more than the weight at which menses were lost and that 86 percent resumed their menses within six months of achieving a weight approximately 90 to 95 percent of ideal body weight (calculator 2) . Other studies support a goal of attaining 90 percent of ideal body weight in order to restore normal menses . In a study that followed 56 adolescent females with anorexia nervosa for up to one year, a return of menses occurred in 64 percent . One study found the weight requirement for resumption of menses varied considerably and was predicted by the weight at which menstruation ceased .
Amenorrhea persists in about 10 to 30 percent of patients with anorexia nervosa despite weight gain, because of ongoing abnormal eating behaviors (binge eating and purging), exercise, or stress [43,52]. For patients distressed by persistent amenorrhea, eventual recovery of menstrual periods may occur following psychotherapy. We do not suggest the early use of sex hormones for the purpose of treating amenorrhea in patients with anorexia nervosa. The etiology, diagnosis, and treatment of secondary amenorrhea are discussed separately. (See "Evaluation and management of secondary amenorrhea".)
In adult patients with anorexia nervosa and secondary amenorrhea, the uterus regresses to its prepubertal length of 2 to 3 cm, the endometrium becomes thin or undetectable, and the ovaries decrease to a volume <2 cm3 . In adolescents, the uterus and ovaries are smaller than expected for the patient’s age. These findings in adults and adolescents can be visualized on pelvic ultrasound.
Fertility — Patients with anorexia nervosa may become pregnant despite their amenorrheic state  and should be encouraged to use contraception. Following stable recovery from anorexia nervosa, fertility is usually restored, although not completely in some cases [54,55].
Infertility is expected in anorexia nervosa due to amenorrhea and decreased libido; nevertheless, patients may ovulate and become pregnant [43,53]. Many patients want to avoid pregnancy, and some of the pregnancies that occur are not planned. In one study, an unplanned pregnancy occurred in more patients with anorexia nervosa (n = 62), compared to women with no eating disorder (n = 61,998; 50 versus 19 percent). More patients also had a history of induced abortion (24 versus 15 percent). The choice of birth control is based upon patient preference. (See "Contraception: Counseling and selection".)
Patients with anorexia nervosa may conceal their eating disorder when seeking treatment for infertility . One study of 66 women treated in an infertility clinic found covert anorexia nervosa in 8 percent . Although it is possible for amenorrheic women to conceive by inducing ovulation using pulsatile gonadotrophin-releasing hormone or gonadotrophins, the presence of active anorexia nervosa is commonly felt to be a contraindication for this type of infertility treatment.
If pregnancy does occur while the patient has anorexia nervosa, both pregnancy and lactation stress the maternal skeleton for mineralization of the fetus and newborn. Based upon clinical experience, clinicians should provide vitamin D and calcium supplementation and suggest a diet enriched in protein and phosphate. Nutrition during pregnancy is discussed separately. (See "Nutrition in pregnancy: Dietary requirements and supplements".)
In addition, pregnancy in anorexia nervosa is associated with a greater incidence of complications and warrants referral for high-risk pregnancy. Potential complications include miscarriages, premature birth, smaller head circumference, and low-birth-weight infants, especially if the disease is active . (See "Eating disorders in pregnancy".)
ENDOCRINE — Anorexia nervosa causes multiple endocrine complications, including hypothalamic-pituitary abnormalities that contribute to severe bone loss. The pathophysiology, clinical manifestations, evaluation, and management of endocrine complications in anorexia nervosa are discussed separately. (See "Anorexia nervosa: Endocrine complications and their management".)
GASTROINTESTINAL — A review of 123 publications found that gastrointestinal complications of anorexia nervosa may occur at any point in the gastrointestinal tract . However, most complications remit with refeeding. Thus, laboratory studies and symptom specific treatments are used in a limited manner.
Moderate to severe anorexia nervosa consistently causes gastroparesis (delayed emptying of the stomach) and constipation , and there may be mild elevation of liver function tests . Acute pancreatitis in patients with anorexia nervosa has been described in case reports . In addition, the superior mesenteric artery syndrome is an increasingly frequent complication of anorexia nervosa , which can interfere with eating.
Gastroparesis — Gastroparesis (delayed gastric emptying) frequently develops with food restriction and a weight loss of approximately 10 to 20 pounds (4.5 to 9.1 kg) [37,59,62]. It seems to be more common as weight loss becomes more severe. The main symptom is bloating (gas and distension), which often occurs after eating and may be severe. Bloating is worsened by a high-fiber diet or by fiber-based laxatives. Other symptoms of gastroparesis include early satiety, fullness, nausea, and vomiting (not self-induced). Heartburn may also occur as a result of acidic, vomitus-induced esophagitis from food remaining in the stomach for prolonged periods of time. In some cases it may be difficult to tell whether vomiting is spontaneous and/or self-induced. The symptoms of gastroparesis may inhibit the patient from eating and hamper attempts at weight restoration.
Case reports describe acute gastric dilatation in anorexia nervosa that is thought to be due to gastroparesis and may appear on radiographs or computed tomography as gross distension [15,61]. Treatment of gastric dilatation includes a brief course (eg, one to three days) of nasogastric suction followed by liquid food for a few days . The decision to discontinue suction is based upon radiographic confirmation that the dilatation has resolved.
Gastroparesis in anorexia nervosa should be managed with the following conservative measures [21,32,54]:
●Reassure patients that eating is not causing gastroparesis, which will eventually resolve with weight restoration over four to six weeks
●Liquid food supplements may need to comprise half of the daily calories for the first week or two of refeeding
●Ingest liquid components as opposed to solids earlier in the meal
●Divide the daily calorie intake into three small meals and two to three snacks per day
●Avoid legume-type foods, excessive fiber, and bran products, which promote gas and distention
For patients not responding to these measures, many clinicians use metoclopramide, an oral medication that stimulates stomach contraction and hastens emptying of the stomach . Based upon our clinical experience, a dose of 2.5 mg, 30 minutes before meals and at bedtime, is useful to treat bloating and early satiety secondary to weight loss in anorexia nervosa. It also acts as an antiemetic medication. Although metoclopramide increases the risk for tardive dyskinesia with long-term use, the risk is mitigated by using a relatively small dose of 2.5 mg.
Gastroparesis induced by weight loss generally improves with partial weight restoration [32,58]. A significant improvement often occurs with a 10 pound (4.5 kg) weight gain and the disorder largely resolves with weight gain back to 80 to 90 percent of ideal body weight (calculator 2) or if the body mass index (calculator 1) reaches 17 to 18 kg/m2. However, symptoms of bloating and early satiety may persist despite weight gain. A macrolide (eg, erythromycin 250 to 500 mg every 6 to 12 hours or azithromycin 250 mg daily) may be added to the metoclopramide to further improve the slowed gastric emptying  if 7 to 10 days of metoclopramide does not demonstrate improvement in these symptoms. An electrocardiogram should be obtained while using macrolide antibiotics due to their propensity to cause QTc prolongation. In rare cases it may be necessary to obtain a nuclear medicine gastric emptying study to investigate persistent symptoms of early satiety after refeeding and weight restoration.
Additional information on gastroparesis is discussed separately. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Treatment of gastroparesis".)
Constipation — Constipation frequently accompanies weight loss in anorexia nervosa even when laxatives were never used in the past . Symptoms include infrequent and small bowel movements and abdominal pain. Patients may incorrectly respond to their constipation or pain by starting treatment with bulking, fiber-containing laxatives or stimulant laxatives. These may worsen constipation. It is helpful to reassure patients that bowel patterns in healthy ambulatory patients normally vary from two or three times per day to three times per week, that patients with extensive weight loss have even fewer bowel movements, and that there is nothing fundamentally wrong with their bowels other than a need for weight gain. With weight restoration, the patient’s prior bowel pattern should return over a few weeks.
Additional conservative measures to manage constipation in anorexia nervosa include [21,32]:
●Water (six to eight glasses per day)
●Avoiding high doses of fiber, which can cause bloating
●Polyethylene glycol powder (one to three tablespoons per day)
Lactulose, 30 to 60 mL one to two times per day, may be used as a last resort along with judicious use of stimulant laxatives if the other measures have failed [21,32]. Additional information about the treatment of constipation is discussed separately. (See "Management of chronic constipation in adults".)
Other — Anorexia nervosa can lead to other gastrointestinal complications, including elevated liver function tests, the superior mesenteric artery syndrome, acute pancreatitis, gastroesophageal reflux disease, dysphagia, and diarrhea due to villous atrophy.
Weight loss and fasting can elevate liver function tests (aspartate aminotransferase and alanine aminotransferase) in anorexia nervosa [58,63]. A prospective study of 214 women with anorexia nervosa found that alanine aminotransferase was elevated in 12 percent ; a retrospective study adolescents (n = 356) found elevated alanine aminotransferase in 41 percent  and a retrospective study of adults (n = 181) found aspartate aminotransferase and alanine aminotransferase were each elevated in more than 50 percent of patients . Liver wasting may also cause decreased protein synthesis and programmed hepatocyte cell death . This is referred to as autophagy. Rarely, transaminases may be markedly elevated with severe anorexia nervosa and a sign of serious multiorgan failure . Nutritional rehabilitation is then required . However, liver function tests may also increase during refeeding; a liver ultrasound may help distinguish starvation-induced enzyme elevations from refeeding-induced elevations . During starvation, the ultrasound typically reveals that the liver is normal or small in size, whereas the ultrasound in refeeding hepatitis may show an enlarging (fatty) liver. Gastrointestinal complications that can occur as part of the refeeding syndrome, as well as an overview of evaluating patients with elevated liver functions tests are discussed separately. (See "Anorexia nervosa in adults and adolescents: The refeeding syndrome", section on 'Gastrointestinal' and "Approach to the patient with abnormal liver biochemical and function tests".)
Acute pancreatitis in patients with anorexia nervosa has been rarely described in case reports [58,60]. The inflammation is usually marked by acute upper abdominal pain and elevated serum levels of pancreatic enzymes. The presumptive etiology is that malnutrition activates proteases, such as trypsin, which damage cells. In addition, rapid weight loss may cause retrograde pressure or reflux of duodenal contents into the pancreatic duct. The etiology, clinical manifestations and treatment of acute pancreatitis are discussed separately. (See "Clinical manifestations and diagnosis of acute pancreatitis" and "Management of acute pancreatitis" and "Etiology of acute pancreatitis".)
Multiple case reports describe gastroesophageal reflux disease and Barrett’s esophagus in patients with self-induced vomiting, including anorexia nervosa [68-70]. Other case reports describe esophageal dysphagia [37,58]. (See "Medical management of gastroesophageal reflux disease in adults" and "Barrett's esophagus: Surveillance and management" and "Approach to the evaluation of dysphagia in adults".)
Severe anorexia nervosa often causes oropharyngeal dysphagia, which refers to difficulty swallowing food or liquids from the mouth to the pharynx, and may lead to aspiration pneumonia. A retrospective study of patients hospitalized for anorexia nervosa (n = 206) found that oropharyngeal dysphagia was present in 20 percent . Compared with patients who did not have oropharyngeal dysphagia, patients with oropharyngeal dysphagia were more medically compromised at the time of admission, and were twice as likely to suffer refeeding hypophosphatemia (61 versus 30 percent). Management includes consultation with speech and language pathology and individualized interventions such as exercise for swallowing muscles, neuromuscular stimulation, and postural techniques; weigh restoration is curative.
The superior mesenteric artery syndrome is a rare complication that can occur in more severe cases of anorexia nervosa [6,37,58,72]. It results from compression of the third portion of the duodenum between the aorta posteriorly and the superior mesenteric artery anteriorly. The superior mesenteric artery is normally covered with fatty tissue; weight loss reduces the fat pad and narrows the angle between the two vessels, entrapping the duodenum and causing a small bowel obstruction. Depending upon the severity of the complication, symptoms include early satiety, abdominal epigastric pain soon after starting a meal, nausea, and vomiting. Weight gain of as little as 5 to 10 pounds (2.3 to 4.5 kg) can lead to tolerance of normal feeding. The clinical manifestations, diagnosis, and treatment are discussed separately. (See "Superior mesenteric artery syndrome".) Surgery is not indicated.
RENAL AND ELECTROLYTES — Patients with anorexia nervosa may demonstrate a reduced glomerular filtration rate and problems concentrating their urine, which leads to diuresis and hypernatremia or to hyponatremia and dehydration [73,74]. Patients with restricting anorexia nervosa typically present with a low serum creatinine due to reduced muscle mass . Renal function appears to recover with weight gain, and is usually not an issue in the restricting subtype of anorexia nervosa.
Potassium, magnesium, and phosphate are occasionally depleted  and chronic hypokalemia may induce nephropathy  (see "Hypokalemia-induced kidney dysfunction"). Electrolyte abnormalities may indicate covert purging. Although electrolytes in restricting anorexia nervosa are generally normal, this should not falsely reassure clinicians or patients that weight restoration is not necessary.
Dehydration and depletion of electrolytes should be corrected prior to refeeding the patient. Management of electrolyte abnormalities is discussed separately:
PULMONARY — Anorexia nervosa can lead to weakness and wasting of respiratory muscles, dyspnea, reduced aerobic capacity, and decreased pulmonary capacity [6,77]. Respiratory muscle weakness and diaphragmatic functioning may be slow to recover after refeeding. An overview of dyspnea and other causes and diagnosis of bilateral and unilateral diaphragmatic paralysis are discussed separately. (See "Approach to the patient with dyspnea" and "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation".)
Some studies have found abnormal results of pulmonary function tests in patients with anorexia nervosa . As an example, one study of 27 patients with anorexia nervosa and 18 healthy controls demonstrated greater functional impairment in patients, which worsened progressively with the duration of anorexia nervosa . The nature of the impairment indicated enlargement of peripheral lung units without alveolar septa destruction, consistent with changes observed in older adult patients and not in patients with classic emphysema. It is not known whether this impairment is reversible with refeeding.
Patients with the purging subtype of anorexia nervosa may aspirate regurgitated material and develop pneumonia. Chest radiographs typically reveal opacities in the dependent portion of the lung.
Aspiration may also occur due to dysphagia that is caused by pharyngeal muscle weakness resulting from protein-calorie malnutrition . Difficulty swallowing and uncoordinated transfer of the food bolus from the mouth to the stomach may lead to aspiration and then pneumonia. A bedside swallow evaluation by a speech therapist and/or a video fluoroscopic swallow study can confirm the diagnosis. If dysphagia is confirmed, modifying the consistency of foods or inserting a temporary feeding tube may be required until sufficient weight gain restores normal swallow function .
Spontaneous pneumothorax has been described in case reports, with prolonged air leak in patients with severe malnutrition  and difficulty in keeping the lung re-expanded . It is not known whether the pulmonary changes that predispose to spontaneous pneumothorax or persistent air leak are reversible with refeeding. Pneumothorax and management of prolonged air leak are discussed separately. (See "Clinical presentation and diagnosis of pneumothorax" and "Treatment of primary spontaneous pneumothorax in adults".)
Pneumomediastinum has also been reported in severe cases of anorexia nervosa, due to alveolar wall weakness and rupture, with consequent air leak into the mediastinum [15,82,83]. Symptoms include chest pain, dyspnea, and anxiety, and physical examination reveals subcutaneous crepitation. In the absence of traumatic or iatrogenic events, the complication should be managed by radiographic surveillance and resolve within a few weeks without surgical drainage.
HEMATOLOGIC — Cytopenias and bone marrow changes are commonly observed in anorexia nervosa, and are reversible with nutritional rehabilitation [37,84,85]. Weight restoration with proper nutrition leads to normalization of blood counts over weeks to months .
The bone marrow is often affected in anorexia nervosa. In a study of patients with anorexia nervosa (n = 44), bone marrow biopsies were classified as normal in 11 percent, hypoplastic or aplastic in 39 percent, and gelatinous degeneration with serous fat atrophy in 50 percent . The authors found that severity of bone marrow changes correlated with the degree of weight loss.
Patients with anorexia nervosa often present with, in order of frequency, anemia, leukopenia, or thrombocytopenia in a pattern involving one, two, or all three cell lines simultaneously . Among less severely ill patients (eg, outpatients), anemia occurs in approximately 33 percent of patients, and tends to be normocytic and normochromic [9,84,85]. Leukopenia occurs in approximately 33 percent as well, and both relative lymphopenia and neutropenia have been observed [9,84]. Thrombocytopenia occurs in 5 to 10 percent of patients with anorexia nervosa [9,84], but there are case reports describing both severe thrombocytopenia and bleeding complications .
Among severely ill patients, the frequency of hematologic abnormalities is greater . As an example, a retrospective study of 53 hospitalized patients (mean body mass index 12) found the following abnormalities :
●Anemia – 83 percent
●Leukopenia – 79 percent
●Thrombocytopenia – 25 percent
Petechiae and purpura may appear on the extremities as a result of these hematologic complications [91,92].
Clinicians should have a lower threshold for considering infectious complications because signs of infection such as fever may be absent. A retrospective study matched 23 cases of bacterial infection in patients with anorexia nervosa to cases of bacterial infection in patients without anorexia nervosa, and found that the diagnosis of the infection was often delayed and that more complications occurred in the patients with anorexia nervosa . However, the majority of outpatients with anorexia nervosa and leukopenia do not seem to have infectious complications, and population-based surveys report that infection is not a major cause of death in anorexia nervosa .
Wernicke encephalopathy — Case reports describe Wernicke encephalopathy in patients with anorexia nervosa . Wernicke encephalopathy is an acute syndrome marked by global confusion, oculomotor dysfunction, and gait ataxia. The condition is caused by thiamine (vitamin B1) deficiency and requires emergency treatment to prevent death and neurologic morbidity. (See "Wernicke encephalopathy".)
Korsakoff syndrome — Korsakoff syndrome is a late, neuropsychiatric manifestation of Wernicke encephalopathy in which there is selective anterograde and retrograde amnesia. The prognosis is poor. (See "Overview of the chronic neurologic complications of alcohol", section on 'Korsakoff syndrome'.)
Brain atrophy — Brain atrophy is a complication of anorexia nervosa that is evident on neuroimaging . Findings include reductions in gray and white matter volume, ventriculomegaly, enlarged cortical sulci and interhemispheric fissure, and cerebellar atrophy [15,95]. A meta-analysis of seven whole brain magnetic resonance imaging (MRI) studies found that the cerebral spinal fluid space was increased among patients (n = 102) compared with controls (n = 120), and the clinical difference was large . In addition, both gray and white matter were reduced in patients compared with controls; the clinical differences between patients and controls were moderate to large. As an example, one study found that compared with controls (n = 21), the mean average gray matter volume in women with anorexia nervosa (n = 32) was 5 percent less . Another study found that the right and left hippocampus were each reduced by 8 percent in the patients compared with controls . Although it remains unclear whether these brain changes are related to the loss of neurons, glia, and/or neuropil, or are merely due to fluid shifts, some degree of both white and gray matter appear to be lost as a result of anorexia nervosa .
The clinical implications of brain atrophy are not known. A prospective study found that gray matter volume was smaller in adolescents with anorexia nervosa (n = 12) compared with controls (n = 9), but that performance on neuropsychological testing was comparable on six of seven tests .
Results from MRI studies suggest that brain atrophy in anorexia nervosa is often reversible with weight restoration and that permanent scarring does not occur [94,95,97]:
●One MRI study of women with anorexia nervosa (n = 32) found that during short-term hospitalization and weight restoration to 90 percent of ideal body weight, gray matter volumes increased but remained smaller compared with control women (n = 21) .
●A second MRI study of 12 female adolescents with anorexia nervosa and 9 female controls found that gray matter volumes were smaller in the patients at the beginning of their treatment, but that after seven months, the two groups were comparable .
●An MRI study compared cortical thickness in adolescent and young adult females acutely ill with anorexia nervosa (n = 40), females remitted from anorexia nervosa for at least six months (n = 34), and female healthy controls (n = 69) . Cortical thickness was decreased in the acutely ill patients compared with controls, and thinning in patients was observed in over 85 percent of the cortical surface. By contrast, cortical thickness was comparable for the remitted patients and controls. However, this was a cross-sectional study, and a prospective longitudinal study would help confirm the findings.
Other changes in brain structure — Among patients with anorexia nervosa, specific areas of the brain may be enlarged. As an example, MRI of women with current anorexia nervosa (n = 19), women recovered from anorexia nervosa (n = 24), and healthy women (n = 24) found that both eating disorder groups manifested increased gray matter volume of the orbitofrontal cortex (gyrus rectus) .
OPHTHALMIC — Anorexia may cause ophthalmic changes. As an example, a prospective study included female patients with anorexia nervosa who had no history of vision loss or symptoms, ophthalmic disease, and ocular surgery (n = 13), and a control group of healthy females (n = 20) . Several areas of the retina (eg macula), as well as the choroid, were thinner in patients than controls. In addition, electrical activity in the macula was decreased, consistent with functional impairment.
Severe anorexia nervosa may lead to lagophthalmos, which is the inability to close the eyelids completely, and places patients at risk for corneal abrasions and permanent loss of ocular acuity. Lagophthalmos was described in a retrospective case series of five patients with anorexia nervosa, who were hospitalized with a mean body mass index 10 kg/m2 . The symptoms of lagophthalmos included dry, irritable eyes and photophobia, in the context of ptosis and enophthalmos. Lagophthalmos was managed with protective measures (topical lubrication during the day with artificial tears, and sterile ophthalmic ointment and direct taping of the eyelids during the night) and nutritional rehabilitation, and resolved in all five patients.
TASTE — Anorexia nervosa may be accompanied by abnormalities in taste, including reduced sweetness sensitivity, increased perception of food as being fatty, and overall dysgeusia . These may take time to remit after weight restoration has occurred.
DERMATOLOGIC — The cutaneous manifestations of anorexia nervosa are numerous. Symptoms of starvation include, in order of frequency [10,92]:
●Xerosis (dry, scaly skin)
●Lanugo-like body hair (fine, downy, dark hair)
●Telogen effluvium (hair loss)
●Seborrheic dermatitis (erythema and greasy scales)
●Acrocyanosis (cold, blue, and occasionally sweaty hands or feet)
●Perniosis (painful or pruritic erythema)
●Livedo reticularis (reddish-cyanotic circular patches)
●Paronychia (inflamed lateral and posterior nail folds)
●Striae distensae (erythematous or hypopigmented linear patches)
●Slower wound healing
Xerosis on the back and arms is frequently present due to reduced sebaceous gland secretion [92,105,106]. A case series of 62 patients with anorexia nervosa found xerosis in 97 percent . Moisturizing ointments and humidifying the environment can ameliorate the problem and relieve pruritus. Lanugo hair on the back, abdomen, and forearms is not a sign of virilization. Carotenoderma is due to excess ingestion of carotenoid-rich vegetables that are low in calories, and decreased hepatic catabolism of carotene. Acne can be caused by starvation, but may also be a risk factor for anorexia nervosa, in that a new dieting behavior intended to control acne may additionally lead to weight loss and then anorexia nervosa. Seborrheic dermatitis (most commonly on the scalp) should be treated with medicated shampoos. Acrocyanosis is associated with arterial vasoconstriction and secondary dilation of venules, and may represent a mechanism by which the body conserves heat. Delayed wound healing may be the result of hypothyroidism and zinc deficiency.
Self-injurious behavior is common in anorexia nervosa, and patients may show acute or chronic signs of trauma from cuts or burns (dermatitis artefacta) [3,6,106].
OTHER — Anorexia nervosa is associated with other general medical conditions beyond those described above. In a national hospital registry study that identified patients with anorexia nervosa (n = 8700) and controls with minor medical conditions (n >1,000,000), the risk of the following medical conditions was greater in patients with anorexia nervosa than controls :
●Adrenal insufficiency (Addison disease) – Relative risk (in anorexia nervosa) 10, 95% CI 5-17.
●Celiac disease – Relative risk 3, 95% CI 2-4.
●Sjögren syndrome – Relative risk 4, 95% CI 1-9.
●Vitamin B12 deficiency – Relative risk 4, 95% CI 2-7.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Eating disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Anorexia nervosa (The Basics)")
SUMMARY AND RECOMMENDATIONS
●The numerous general medical complications of anorexia nervosa are a direct result of weight loss and malnutrition. The number of organ systems adversely affected increases with the severity of weight loss (table 2). (See 'General principles' above.)
●Treatment for each medical complication of anorexia nervosa includes nutritional replenishment, and many complications resolve with weight gain. There are no randomized trials that have evaluated the management of complications from anorexia nervosa. Some patients will require hospitalization to manage the illness and its medical complications. (See 'General principles' above and "Anorexia nervosa in adults: Evaluation for medical complications and criteria for hospitalization to manage these complications", section on 'Inpatient hospitalization'.)
●Cardiovascular complications of anorexia nervosa involve structural abnormalities, including decreased cardiac mass, reduced cardiac chamber volumes, mitral valve prolapse, and pericardial effusion. In addition, functional changes include bradycardia, and hypotension. A prolonged QT interval may be seen in some patients, but anorexia nervosa does not directly cause the syndrome. (See 'Structural changes' above and 'Functional changes' above.)
●The reproductive system is altered in anorexia nervosa, causing a cascade of events resulting in secondary amenorrhea. Many patients have amenorrhea (functional hypothalamic amenorrhea). Normal menstrual cycles usually resume with weight gain. However, amenorrhea persists in about 10 to 30 percent of patients with anorexia nervosa despite weight gain. (See 'Gynecologic and reproductive' above.)
●Patients may become pregnant despite their amenorrheic state. Fertility is generally intact in patients who recover from anorexia nervosa and remain stable. However, there is a higher rate of pregnancy problems and neonatal complications in patients with anorexia nervosa who become pregnant. (See 'Fertility' above.)
●Patients with anorexia nervosa have endocrine complications, including hypothalamic-pituitary abnormalities that contribute to severe bone loss. (See "Anorexia nervosa: Endocrine complications and their management".)
●Gastroparesis consistently occurs in anorexia nervosa. For patients with anorexia nervosa and gastroparesis, we suggest using liquid food supplements to provide half of the daily calories for the first week or two of refeeding; ingesting liquid components earlier in each meal; dividing the daily calorie intake into three small meals and two snacks per day; and avoiding legume-type foods, excessive fiber, and bran products; rather than metoclopramide, to restore bowel function (Grade 2C). Unresponsive gastroparesis can be treated with metoclopramide 2.5 mg, 30 minutes before meals and at bedtime. (See 'Gastroparesis' above.)
●Constipation also occurs often in anorexia nervosa. For patients with anorexia nervosa and constipation, we suggest six to eight glasses of water per day, fiber 10 grams per day, and polyethylene glycol powder one to three tablespoons per day, rather than lactulose, to restore bowel function (Grade 2C). Unresponsive constipation can be treated with lactulose 30 to 60 mL one to two times per day. (See 'Constipation' above.)