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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

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2023. | This topic last updated: Feb 15, 2023.

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
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 [2]. 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 [3].

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 [6].

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".)

DEFINITIONS

Anorexia nervosa — The core features of anorexia nervosa ( table 1) are [7]:

● 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 [8]. 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:

● Hypophosphatemia
● Hypokalemia
● Congestive heart failure
● Peripheral edema
● Rhabdomyolysis
● Seizures
● Hemolysis
● Respiratory insufficiency

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 [14]. 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 [17]. 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 [12]. 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 [11]. 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 [11]. 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 [10].

Hypophosphatemia may also cause rhabdomyolysis, which is suggested by an abnormally high
creatine kinase [11]. (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 [11]. 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
[11]. Thiamine should be given at least 30 minutes before starting nutritional replenishment at
a dose of 100 to 200 mg once daily for three to five days [22,23]. 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 [24].
(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 [10]. 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 [4]. 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
[25,26].

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".)

SUMMARY

● 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.)

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GRAPHICS

DSM-5 diagnostic criteria for anorexia nervosa

A. Restriction of energy intake relative to requirements, leading to a significantly low body weight in
the context of age, sex, developmental trajectory, and physical health. Significantly low weight is
defined as a weight that is less than minimally normal or, for children and adolescents, less than that
minimally expected.

B. Intense fear of gaining weight or of becoming fat or persistent behavior that interferes with weight
gain, even though at a significantly low weight.

C. Disturbance in the way in which one's body weight or shape is experienced, undue influence of
body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the
current low body weight.

Specify whether:

Restricting type: During the last three months, the individual has not engaged in recurrent
episodes of binge eating or purging behavior (ie, self-induced vomiting or the misuse of laxatives,
diuretics, or enemas). This subtype describes presentations in which weight loss is accomplished
primarily through dieting, fasting, and/or excessive exercise.

Binge eating/purging type: During the last 3 months, the individual has engaged in recurrent
episodes of binge eating or purging behavior (ie, self-induced vomiting or the misuse of laxatives,
diuretics, or enemas).

Specify if:

In partial remission: After full criteria for anorexia nervosa were previously met, criterion A (low
body weight) has not been met for a sustained period, but either criterion B (intense fear of
gaining weight or becoming fat or behavior that interferes with weight gain) or criterion C
(disturbances in self-perception of weight and shape) is still met.

In full remission: After full criteria for anorexia nervosa were previously met, none of the criteria
have been met for a sustained period of time.

Specify current severity:

The minimum level of severity is based, for adults, on current BMI (see below) or, for children and
adolescents, on BMI percentile*. The ranges below were derived from World Health Organization
categories for thinness in adults; for children and adolescents, corresponding BMI percentiles
should be used. The level of severity may be increased to reflect clinical symptoms, the degree of
functional disability, and the need for supervision.

Mild: BMI ≥17 kg/m2¶

Moderate: BMI 16 to 16.99 kg/m2

Severe: BMI 15 to 15.99 kg/m2

Extreme: BMI <15 kg/m2

DSM-5: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; BMI: body mass index.
* See "Calculator: Body mass index (BMI; Quetelet's index)".

¶ UpToDate defines mild severity as BMI 17 to 18.4 kg/m2 ; BMI ≥18.5 kg/m2 and <25 kg/m2 is a
healthy weight.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright © 2013).
American Psychiatric Association. All Rights Reserved.

Graphic 91103 Version 7.0