INTRODUCTION — Weight gain is the cornerstone of treatment for patients with anorexia nervosa . However, restoring weight by refeeding patients can lead to the refeeding syndrome, which is potentially but rarely 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 . The definition of the refeeding syndrome, promulgated by the American Society for Parenteral and Enteral Nutrition in 2020, may increase the incidence of the syndrome .
Patients other than those with anorexia nervosa are at risk for the refeeding syndrome if they are fed without monitoring their electrolytes, phosphorous levels, and other parameters as indicated [4,5]. These include oncology patients undergoing chemotherapy, malnourished older adult patients, certain postoperative patients, and homeless patients or patients with alcohol use disorder who have not eaten for many days. One of the earliest reports of the refeeding syndrome involved severely malnourished prisoners of war who died in the first few days after liberation .
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 prevention and treatment", section on 'Anorexia nervosa'.)
●(See "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management".)
Anorexia nervosa — The core features of anorexia nervosa (table 1) are :
●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 . These complications are potentially fatal when not detected or treated early during nutritional rehabilitation.
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 [3,8-13]. The refeeding syndrome is marked by:
●Congestive heart failure
Hypophosphatemia is the hallmark of the syndrome and predominant cause of the refeeding syndrome [10,11]. 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 . The risk of hypophosphatemia during refeeding appears to be greater in patients who are more severely malnourished and at lower percent of ideal body weight [14-16]. 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 . Conversely, in that same study, a higher body mass index (BMI; 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 serum phosphorous nadir generally first manifests during the first week of refeeding [2,16].
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) and a decrease in serum phosphorous levels. Insulin also causes cells to produce a variety of molecules that require phosphate (eg, adenosine triphosphate and 2,3-diphosphoglycerate), which further depletes the body’s stores of phosphate . The subsequent lack of phosphorylated intermediates causes tissue hypoxia, myocardial dysfunction, respiratory failure due to an inability of the diaphragm to contract, hemolysis, rhabdomyolysis, and seizures.
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 [3,10,11,18]. Patients who weigh less than 70 percent of ideal body weight (calculator 1) or rapidly lose large amounts of weight are at greatest risk for the syndrome, even if their BMI following the rapid weight loss is not abnormal. Thus, patients who weigh less than 70 percent of their ideal body weight, or have a BMI (calculator 2) <14 kg/m2, generally require hospitalization for the initial stage of nutritional replenishment and medical stabilization. Other risk factors for the refeeding syndrome include low baseline levels of phosphate, potassium, or magnesium prior to refeeding the patient; and little or no nutritional intake for the previous 5 to 10 days. Criteria for hospitalization of 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'.)
Patients are at the highest risk for the refeeding syndrome in the first one to two weeks of nutritional replenishment and weight gain . Generally, the risk progressively dissipates over the next few weeks if there has been consistent intake and weight gain and normalization of serum phosphorus levels.
MEDICAL COMPLICATIONS — Medical complications that occur as a result of fluid and electrolyte shifts during nutritional rehabilitation of malnourished patients involve multiple organ systems [1,9-12]. Management of these complications may include reducing the rate of nutritional support and always involves proactively screening for and correcting hypophosphatemia, hypokalemia, and hypomagnesemia. (See 'Prevention and management' below.)
Cardiovascular — Most fatalities that occur because of the refeeding syndrome are due to cardiac complications, including impaired myocardial contractility, decreased stroke volume, heart failure, and arrhythmias [10,12]. Atrophy of the heart during starvation renders the patient more vulnerable to fluid overload and heart failure. Sodium and fluid retention can also increase circulatory volume and lead to volume overload in patients with cardiac atrophy, and thiamine (vitamin B1) deficiency may also contribute to heart failure . Electrocardiograms, echocardiograms, and consultation with the cardiology service should be obtained as indicated by the patient’s clinical status. Heart failure is discussed separately. (See "Treatment of acute decompensated heart failure: General considerations".)
Bradycardia is expected with anorexia nervosa [1,19,20]. A “normal” heart rate may in fact be a harbinger of cardiac compromise in these patients. During the early stages of refeeding, a resting heart rate >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 [10,12]. 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, impaired respiratory function, and respiratory failure. However, respiratory failure and the need for mechanical ventilation are rare [10,12]. Heart failure may secondarily lead to respiratory symptoms and failure. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation", section on 'Diagnostic evaluation'.)
Muscular — Impaired contractility, weakness, myalgia, and tetany may occur . Hypophosphatemia may also cause rhabdomyolysis, which is suggested by an abnormally high creatine kinase . (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)
Gastrointestinal — Liver function tests may be elevated and several gastrointestinal symptoms may develop early in refeeding.
Liver function tests, including aspartate aminotransferase and alanine aminotransferase, are often mildly elevated during the first few weeks of refeeding the patient due to either excessive calories and fat deposition (steatosis) or due to cell death-apoptosis from malnutrition [11,21]. These elevations are usually not clinically significant and resolve by reducing the rate and type of nutritional replenishment or by continuing nutritional rehabilitation if thought to be apoptosis. If due to steatosis, more calories may be reintroduced at a later date once the liver tests have normalized. Hepatic apoptosis will also 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 . 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 provide calories via a more elemental diet may help, as well as providing smaller, more frequent meals.
Neurologic — Patients may develop tremors, paresthesias, delirium, and seizures as a result of electrolyte abnormalities (severe hypophosphatemia) during the early stages of refeeding [10,12]. (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 encephalopathy may occur, with signs that include encephalopathy, oculomotor dysfunction, and gait ataxia . 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 . The clinical manifestations, diagnosis, and treatment of Wernicke encephalopathy are discussed separately. (See "Wernicke encephalopathy".)
PREVENTION AND MANAGEMENT — The refeeding syndrome can be completely avoided by restoring weight with an initial amount of calories that is close to 1400 to 1600 kcals/day, avoiding very rapid increases in the daily caloric intake, and closely monitoring the patient clinically and biochemically (eg, on a daily basis) during the early stages of the refeeding process. Complications of the syndrome may be reduced by proactively and frequently checking electrolyte and phosphorous levels along with correcting electrolyte abnormalities, especially phosphorous levels, and by monitoring for and treating cardiovascular and pulmonary complications. Nevertheless, refeeding patients with anorexia nervosa has justifiably become more aggressive for inpatients and patients treated at residential care facilities, with the desired weekly weight gain in the range of 3 to 4 pounds . (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 . Although one clinical guideline states that clinicians may correct electrolyte imbalances during the feeding process rather than beforehand [8,13,18], we suggest that nutritional replenishment not commence until baseline electrolyte levels are normal, based upon multiple reviews [3,4,10,12]. Treating electrolyte abnormalities usually requires no more than 12 to 24 hours . No randomized trials have studied this issue.
Although administering prophylactic phosphorous supplements to prevent refeeding hypophosphatemia is a widening practice, it remains controversial and seems unjustified [23,24].
Treatment — If the refeeding syndrome occurs, clinicians should reduce nutritional support and aggressively correct hypophosphatemia, hypokalemia, and hypomagnesemia [10,11] while managing other related abnormalities. Moderately to severely ill patients with seizures, marked edema, or a serum phosphorous <2 mg/dL should be hospitalized to intravenously correct electrolyte deficiencies and for close monitoring. Continuous telemetry may be needed to monitor cardiopulmonary physiology. Management of electrolyte abnormalities is discussed separately:
●(See "Hypophosphatemia: Evaluation and treatment".)
●(See "Clinical manifestations and treatment of hypokalemia in adults".)
●(See "Hypomagnesemia: Evaluation and treatment".)
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".)
●Definition – The refeeding syndrome is defined as the typical clinical complications that occur due to fluid and electrolyte shifts during nutritional rehabilitation of significantly malnourished patients. (See 'Refeeding syndrome' above.)
●Pathogenesis and clinical features – The refeeding syndrome is marked by hypophosphatemia and volume overload. (See 'Pathogenesis and clinical features' above.)
●Medical complications – Multiple organ systems can be affected as part of the refeeding syndrome. Most fatalities that occur because of the syndrome are due to cardiac complications (induced by hypophosphatemia), including impaired contractility, decreased stroke volume, heart failure, and arrhythmias. Seizures can also occur. (See 'Medical complications' above and 'Cardiovascular' above and 'Neurologic' above.)
●Prevention and management – The refeeding syndrome can nearly always be avoided by judiciously avoiding very rapid increases in the amount of daily calories ingested and closely monitoring patients and their laboratory tests during the first few weeks of refeeding. If the refeeding syndrome occurs, clinicians should immediately slow nutritional replenishment and aggressively correct hypophosphatemia and other electrolyte abnormalities, while evaluating the cardiovascular system. Moderately to severely ill patients with marked edema or a serum phosphorous <2 mg/dL should be hospitalized to intravenously correct electrolyte deficiencies. (See 'Prevention and management' above.)
1 : Eating Disorders: Core Interventions in the Treatment of and Management of Anorexia Nervosa, Bulimia Nervosa and Related Eating Disorders. National Institute for Clinical Excellence, Clinical Guideline 9. http://guidance.nice.org.uk (Accessed on December 22, 2010).
2 : Hypophosphatemia during nutritional rehabilitation in anorexia nervosa: implications for refeeding and monitoring.
12 : Refeeding syndrome: treatment considerations based on collective analysis of literature case reports.
15 : Refeeding hypophosphatemia in hospitalized adolescents with anorexia nervosa: a position statement of the Society for Adolescent Health and Medicine.
23 : Prophylactic Phosphate Supplementation for the Inpatient Treatment of Restrictive Eating Disorders.
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