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 patients
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 ones 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 bodys 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) <15 to 16 kg/m2, generally require hospitalization
for the initial stage of nutritional replenishment. 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 'Hospitalization'.)

Patients are at the highest risk for the refeeding syndrome in the first two weeks of
nutritional replenishment and weight gain [9]. Generally, the risk progressively
dissipates over the next few weeks.

MEDICAL COMPLICATIONS Medical complications that occur as a result of

fluid and electrolyte shifts during nutritional rehabilitation of malnourished
patients involve multiple organ systems [1,6,7,9,10]. Management of these
complications may include reducing the rate of nutritional support and always
involves 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 [7,10]. 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 [9]. Electrocardiograms,
echocardiograms, and consultation with the cardiology service should be obtained
as indicated by the patients clinical status. Heart failure is discussed separately.
(See "Treatment of acute decompensated heart failure: General considerations".)

Bradycardia is expected with anorexia nervosa [1,17,18]. 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 [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
Wernickes 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 Wernickes 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 <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 "Evaluation and treatment of hypophosphatemia".)

(See "Clinical manifestations and treatment of hypokalemia in adults".)
(See "Evaluation and treatment of hypomagnesemia".)

SUMMARY

The refeeding syndrome is defined as the clinical complications that occur as

a result of fluid and electrolyte shifts during nutritional rehabilitation of
significantly malnourished patients. (See 'Refeeding syndrome' above.)

The refeeding syndrome is marked by hypophosphatemia and volume

overload. (See 'Pathogenesis and clinical features' above.)

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.)

The refeeding syndrome can nearly always be avoided by judiciously limiting

the amount of calories and fluid provided in the early stages of refeeding,
avoiding very rapid increases in the amount of daily calories ingested, and
closely monitoring the patient during the first few weeks of the refeeding
process. 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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