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Anorexia nervosa in adults and adolescents: The refeeding syndrome Author: Philip Mehler, MD Section Editor: Joel Yager, MD Deputy Editor: David Solomon, MD Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2017. | This topic last updated: Apr 29, 2017. INTRODUCTION — Weight gain is the cornerstone of treatment for patients with anorexia nervosa [1]. However, restoring weight by refeeding patients can lead to the refeeding syndrome, which is potentially fatal. A retrospective study of adolescents hospitalized for anorexia nervosa (n = 69) found that moderately severe cases of the refeeding syndrome occurred in 6 percent, and mild cases in 22 percent [2]. In addition, patients other than those with anorexia nervosa are at risk for the refeeding syndrome [3]. These include oncology patients undergoing chemotherapy, malnourished elderly patients, certain postoperative patients, and homeless or alcoholic patients who have not eaten for many days. The refeeding syndrome in anorexia nervosa and its management are reviewed here. Nutritional rehabilitation for anorexia nervosa; the evaluation for medical complications and criteria for hospitalizing patients with anorexia nervosa; medical complications of anorexia nervosa and their management; the epidemiology, pathogenesis, clinical features, treatment, and outcome of anorexia nervosa; and the medical complications of bulimia nervosa and binge eating disorder are discussed separately. ● (See "Anorexia nervosa in adults and adolescents: Nutritional rehabilitation (nutritional support)".) ● (See "Anorexia nervosa in adults: Evaluation for medical complications and criteria for hospitalization to manage these complications".) ● (See "Anorexia nervosa in adults and adolescents: Medical complications and their management".) ● (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".) ● (See "Eating disorders: Overview of treatment", section on 'Anorexia nervosa'.)

● (See "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management".) DEFINITIONS Anorexia nervosa — The core features of anorexia nervosa (table 1) are [4]: ● Restriction of energy intake, which leads to a significantly low body weight (defined as a weight that is less than minimally normal), given the patient’s age, sex, developmental trajectory, and physical health. ● Intense fear of gaining weight or becoming fat, or persistent behavior that interferes with weight gain, despite a weight that is significantly low. ● Disturbance in how one experiences body weight and shape, undue influence of weight or shape on self-worth, or denial of the seriousness of one’s low body weight. Additional information about the clinical features and diagnosis of anorexia nervosa are discussed separately. (See "Anorexia nervosa in adults: Clinical features, course of illness, assessment, and diagnosis".) Refeeding syndrome — The refeeding syndrome is defined as the clinical complications that can occur as a result of fluid and electrolyte shifts during aggressive nutritional rehabilitation of malnourished patients [5]. These complications are potentially fatal. PATHOGENESIS AND CLINICAL FEATURES — In significantly malnourished patients, the initial stage of oral, enteral, or parenteral nutritional replenishment causes electrolyte and fluid shifts that may precipitate disabling or fatal medical complications [5-11]. The refeeding syndrome is marked by: ● Hypophosphatemia ● Hypokalemia ● Vitamin (eg, thiamine) deficiencies ● Congestive heart failure ● Peripheral edema ● Rhabdomyolysis ● Seizures ● Hemolysis Hypophosphatemia is the hallmark of the syndrome and predominant cause of the

refeeding syndrome [7,9]. A pooled analysis of data from 17 studies (nearly all retrospective; total n = 1039 adolescent patients with anorexia nervosa) found that the average incidence of refeeding hypophosphatemia was 14 percent [12]. The risk of hypophosphatemia during refeeding appears to be greater in patients who are more severely malnourished [12-14]. In addition, a retrospective study (n = 123 patients with severe anorexia nervosa) found that one predictor of refeeding hypophosphatemia was higher hemoglobin levels, which are probably a marker for hemoconcentration due to dehydration and intravascular volume depletion [15]. Conversely, a higher body mass index (13.3 versus 12.3 kg/m2), higher potassium (3.7 versus 3.2 mmol/L), and higher prealbumin (22.6 versus 20.3 mg/dL) were each associated with a decreased risk for refeeding hypophosphatemia. Retrospective studies of patients who are hospitalized for anorexia nervosa suggest that the phosphorous nadir generally occurs during the first week of admission [2,14]. The pathogenesis of hypophosphatemia begins when stores of phosphate are depleted during episodes of anorexia nervosa and starvation. When nutritional replenishment starts and patients are fed carbohydrates, glucose causes release of insulin, which triggers cellular uptake of phosphate (and potassium and magnesium). Insulin also causes cells to produce a variety of depleted molecules that require phosphate (eg, adenosine triphosphate and 2,3-diphosphoglycerate), which further depletes the body’s stores of phosphate [10]. The lack of phosphorylated intermediates causes tissue hypoxia and resultant myocardial dysfunction and respiratory failure due to an inability of the diaphragm to contract. Vitamin and trace mineral deficiencies are due to starvation [10]. These deficiencies are exacerbated by the onset of anabolic processes that accompany refeeding the patient. Volume overload begins with an increase in insulin secretion during the early stage of refeeding the patient [9]. This eventually increases renal sodium reabsorption and retention, and then fluid retention. Risk factors — The risk of developing the refeeding syndrome is directly related to the amount of weight loss during the current episode and the rapidity of the weight restoration process [7-9,16]. Patients who weigh less than 70 percent of ideal body weight (calculator 1) or lose weight rapidly are at greatest risk for the syndrome. Thus, patients who weigh less than 70 percent of their ideal body weight, or have a body mass index (calculator 2) 70 beats per minute may suggest heart failure and the refeeding syndrome. Bradycardia in patients with anorexia nervosa is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Bradycardia'.) Hypertension, hypotension, and peripheral edema may also occur during the refeeding syndrome [7,10]. An overview of hypertension, hypotension in the context of shock, and diagnosis and treatment of edema are discussed separately. (See "Definition, classification, etiology, and pathophysiology of shock in adults"

and "General principles of the treatment of edema in adults".) Pulmonary — Impaired diaphragmatic contractility due to overall weakness or to hypophosphatemia may occur, leading to dyspnea and impaired respiratory function. Respiratory failure and the need for mechanical ventilation are rare [7,10]. Heart failure may secondarily lead to respiratory symptoms and failure. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation", section on 'Evaluation'.) Muscular — Impaired contractility, weakness, myalgia, and tetany may occur [7]. Hypophosphatemia may also cause rhabdomyolysis, which is suggested by an abnormally high creatine kinase (CK) [9]. (See "Clinical manifestations and diagnosis of rhabdomyolysis".) Gastrointestinal — Liver function tests may be elevated, and several gastrointestinal symptoms may develop. Liver function tests, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are often mildly elevated during the first few weeks of refeeding the patient due to excessive calories and fat deposition or due to cell death-apoptosis from malnutrition [9,19]. These elevations are usually not clinically significant and resolve by reducing the rate of nutritional replenishment or by continuing nutritional rehabilitation. More calories may be reintroduced at a later date once the liver tests have normalized. However, malnutrition and hepatic apoptosis can also elevate liver enzymes, which normalize with nutritional replenishment. Starvation-induced enzyme elevations, as well as an overview of evaluating patients with elevated liver functions tests, are discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Other' and "Approach to the patient with abnormal liver biochemical and function tests".) Diarrhea may occur during the early stages of refeeding, due to atrophy of the intestinal mucosa and pancreatic impairment [9]. The diarrhea generally resolves within the first few weeks of refeeding as the villous surface is reconstituted. In the interim, working with a dietician to reduce the amount of complex carbohydrates and to provide calories via a more elemental diet may help as well. Neurologic — Patients may develop tremors, paresthesias, delirium, and seizures as a result of electrolyte abnormalities during the early stages of refeeding [7,10]. (See "Evaluation and management of the first seizure in adults" and "Overview of the management of epilepsy in adults" and "Delirium and acute confusional states:

Prevention, treatment, and prognosis".) The malnourished patient may be thiamine deficient at baseline. With refeeding, intracellular uptake of electrolytes leads to increased utilization of thiamine, and Wernicke’s encephalopathy may occur, with signs that include encephalopathy, oculomotor dysfunction, and gait ataxia [9]. Thiamine at a dose of 100 mg should be given at least 30 minutes before starting nutritional replenishment and continued twice daily for 7 to 10 days [3]. The clinical manifestations, diagnosis, and treatment of Wernicke’s encephalopathy are discussed separately. (See "Wernicke encephalopathy".) Central pontine myelinolysis has also been reported as a complication of the refeeding syndrome in anorexia nervosa [20]. PREVENTION AND MANAGEMENT — The refeeding syndrome can be avoided by restoring weight with an initial amount of calories that is close to and above the resting energy expenditure, avoiding very rapid increases in the daily caloric intake, and closely monitoring the patient clinically and biochemically during the refeeding process. Complications of the syndrome may be reduced by proactively correcting electrolyte abnormalities, especially phosphorous levels, and by monitoring for and treating cardiovascular and pulmonary complications. However, nutritional refeeding practices have justifiably become more aggressive than they were previously [21]. (See "Anorexia nervosa in adults and adolescents: Nutritional rehabilitation (nutritional support)".) Electrolyte deficiencies that are present in patients with anorexia nervosa should be corrected prior to initiating the refeeding process [7]. Although one clinical guideline states that clinicians may correct electrolyte imbalances during the feeding process rather than beforehand [5,11,16], we suggest that nutritional replenishment not commence until electrolyte levels are normal, based upon multiple reviews [3,7,8,10]. Treating electrolyte abnormalities usually requires no more than 12 to 24 hours [3]. No randomized trials have studied this issue. In addition, administering prophylactic phosphorous supplements to prevent refeeding hypophosphatemia is a widening practice, but remains controversial [22,23]. Treatment — If the refeeding syndrome occurs, clinicians should reduce nutritional support and correct hypophosphatemia, hypokalemia, and hypomagnesemia [7,9]. Moderately to severely ill patients with marked edema or a serum phosphorous