What is the pathophysiology of Refeeding Syndrome?

From the Guidelines

Refeeding syndrome is a potentially fatal metabolic complication that occurs when nutritional support is reintroduced to severely malnourished patients, characterized by dramatic shifts in electrolytes and fluid balance triggered by the sudden transition from a catabolic to an anabolic state, as described in the ESPEN guidelines 1. The pathophysiology of refeeding syndrome centers on the sudden increase in carbohydrate intake, which stimulates insulin release and drives glucose, phosphate, potassium, and magnesium into cells for glycolysis and protein synthesis, depleting serum levels of these electrolytes, particularly phosphate, which is essential for ATP production, as noted in the study by 1. During prolonged starvation, the body adapts by decreasing insulin secretion and increasing glucagon, leading to the breakdown of fat and protein for energy while conserving intracellular minerals like phosphate, potassium, and magnesium, as explained in the guidelines by 1. When refeeding begins, the sudden increase in carbohydrate intake stimulates insulin release, which drives glucose, phosphate, potassium, and magnesium into cells for glycolysis and protein synthesis, causing widespread cellular dysfunction affecting cardiac, respiratory, neurological, hematological, and musculoskeletal systems, as highlighted in the study by 1. The most recent and highest quality study, published in 2024, recommends initiating nutrition support slowly, with 5–10 kcal/kg for the first 24 h, and monitoring serum electrolytes (potassium, magnesium, and phosphorous) both before the initiation of nutrition and at least every frequently for the first 3 days thereafter, as stated in the guidance by 1. Key points to consider in the pathophysiology of refeeding syndrome include:

• Dramatic shifts in electrolytes and fluid balance triggered by the sudden transition from a catabolic to an anabolic state
• Depletion of serum levels of phosphate, potassium, and magnesium due to increased insulin release and cellular uptake
• Widespread cellular dysfunction affecting cardiac, respiratory, neurological, hematological, and musculoskeletal systems
• Importance of identifying at-risk patients and starting nutritional rehabilitation at approximately 25% of caloric needs, gradually increasing over 3-5 days, and closely monitoring and repleting electrolytes, particularly phosphate, potassium, magnesium, and thiamine, as recommended by 1 and 1.

From the Research

Pathophysiology of Refeeding Syndrome

The pathophysiology of refeeding syndrome is characterized by a constellation of metabolic disturbances that occur as a result of reinstitution of nutrition to patients who are starved or severely malnourished 2, 3, 4, 5, 6.

• Key features of the syndrome include:
  • Fluid and electrolyte disorders, particularly hypophosphatemia, hypokaliemia, and hypomagnesemia 3, 4, 5, 6
  • Neurologic, pulmonary, cardiac, neuromuscular, and hematologic complications 2, 3, 5
  • Abnormal glucose metabolism and vitamin deficiencies 5, 6
• The syndrome is thought to occur due to compensatory metabolic alterations secondary to chronic starvation, which predispose malnourished patients to refeeding syndrome 4
• Providing nutritional support initiates an intracellular shift of potassium, magnesium, and phosphate, resulting in adverse effects 4

Clinical Manifestations

The clinical manifestations of refeeding syndrome can be severe and potentially life-threatening 3, 5.

• Patients can develop:
  • Cardiorespiratory failure 3
  • Sodium and fluid retention 3
  • Abnormalities affecting multiple organ systems, including neurological, pulmonary, cardiac, neuromuscular, and hematological functions 2, 5
• The incidence of refeeding syndrome is unknown, but it is frequently underdiagnosed 6

Prevention and Treatment

Prevention and treatment of refeeding syndrome involve identifying patients at risk, reintroducing nutrition cautiously, and correcting electrolyte and vitamin deficiencies properly 2, 3, 5, 6.

• Key steps include:
  • Identifying patients at risk for developing refeeding syndrome 2, 3, 5
  • Instituting nutrition support cautiously 2, 5
  • Correcting and supplementing electrolyte and vitamin deficiencies to avoid refeeding syndrome 2, 5