Refeeding Syndrome Following Exclusive Enteral Nutritional Treatment in Crohn Disease

The refeeding syndrome, first described in starved Far East prisoners of war after World War II (1), refers to a constellation of metabolic complications that can occur when nutrition is reintroduced for patients who are severely malnourished. The syndrome, characterised by severe fluid and electrolyte shifts, is potentially fatal and can occur with any form of nutrition (oral, enteral, or parenteral) in patients who are malnourished from any cause. Crohn disease (CD) is frequently associated with malnutrition, and nearly 60% of children with CD have weight loss at the time of initial diagnosis (2). For the past 2 decades, exclusive enteral nutrition has increasingly been used as primary therapy for acute CD (3), but there is little in the literature on the occurrence of the refeeding syndrome in malnourished children with CD who are treated with exclusive enteral nutrition. We report 2 children with acute CD who developed the refeeding syndrome following treatment with exclusive enteral nutrition. PATIENT 1 A white boy presented at the age of 10 years with a 7-month history of diarrhoea, abdominal pain, poor appetite, and weight loss. Laboratory investigations included haemoglobin, 8.3 g/dL (11.5–14.5); erythrocyte sedimentation rate, 35 mm in the first hour; platelet count, 675 × 109/L; albumin, 17 g/L (30–45); and orosomucoid, 4087 mg/L (300–1200). A barium contrast study showed terminal ileitis with longitudinal ulceration and bowel wall thickening. At colonoscopic examination, there was a cobblestone appearance of the mucosa of the caecum. Histological analysis of biopsy specimens showed active chronic inflammation with granulomata. The clinical, radiological, endoscopic, and histological features were consistent with a diagnosis of CD. Following the diagnosis, the patient was treated with a 6-week course of exclusive polymeric diet as primary therapy for CD. Within a few days of starting the polymeric diet, his serum phosphate concentration, which was normal initially, had dropped to 0.77 mmol/L (1.0–1.8). Oral phosphate supplements were commenced, and the serum phosphate concentration normalised within 48 hours to 1.28 mmol/L. Following the initial treatment, he remained reasonably well but required intermittent courses of polymeric diet for acute exacerbations of the disease, without any untoward events. At the age of 13 years, he was readmitted to hospital because of an acute exacerbation of disease. He complained of abdominal pain, diarrhoea, and weight loss. His admission weight was 26.5 kg and his height was 148.9 cm. Using sex- and age-related UK growth and height curves (4), weight-for-height, weight-for-age, and height-for-age were calculated to be 67%, 60%, and 94%, respectively. His body mass index (BMI), calculated as weight (kg)/height (m2), was 12 (<0.4th centile). His z scores for weight, height, and BMI were −2.9, −1.04, and −3.9, respectively. He was started on exclusive polymeric diet treatment. Two days after starting the feeds, he developed an acute episode of breathlessness and tachycardia. His pulse was 128 beats/minute and blood pressure was 87/50 mmHg. Blood tests revealed hypophosphatemia with a serum phosphate level of 0.61 mmol/L (1.0–1.8). Other results included corrected calcium, 2.2 mmol/L (2.2–2.7); magnesium, 0.75 mmol/L (0.65–1.00); sodium, 131 mmol/L (135–145); and potassium, 4.1 mmol/L (3.5–5.00). A diagnosis of refeeding syndrome was made, and he was initially treated with an intravenous phosphate infusion followed by oral phosphate supplements. When he was reviewed in the clinic about 6 weeks after commencing exclusive polymeric feeds, he was clinically improved. His weight was recorded as 32.65 kg and his height was 149.3 cm. His BMI had improved to 14.7, which was between the 0.4th and second centiles. His BMI z score was −1.1. He was put on polymeric diet supplements in addition to unrestricted normal diet. PATIENT 2 An Asian girl presented at the age of 11 years with a history of diarrhoea, abdominal pain, erythema nodosum, and weight loss. Her admission weight was 18.7 kg and her height was 134.5 cm. Using age-related UK growth and height curves (4), weight-for-height, weight-for-age, and height-for-age were calculated to be 62%, 52%, and 93%, respectively. Her BMI, calculated as weight (kg)/height (m2), was 10.3 (<0.4th centile). Using age-related UK growth and BMI curves, weight, height, and BMI standard deviation scores (z scores) were calculated. The z scores for weight, height, and BMI were −3.46, −1.45, and −4.23, respectively. Initial laboratory investigations included haemoglobin, 8.6 g/dL (11.5–14.5); erythrocyte sedimentation rate, 55 mm in the first hour; platelet count, 588 × 109/L; albumin, 21 g/L (30–45); and orosomucoid, 4158 mg/L (300–1200). At colonoscopic examination, there was evidence of patchy areas of ulceration throughout the colon. Histological analysis of mucosal biopsy specimens confirmed active inflammation throughout the colon and terminal ileum with granulomata. The clinical, endoscopic, and histological features were consistent with a diagnosis of CD. Following the diagnosis, the patient was started on a 6-week course of exclusive polymeric diet as primary therapy for CD. The aim was to provide her with about 120% of her estimated average requirement (1845 kcal) by day 3. She received the feeds orally during the first week but subsequently required a nasogastric tube. Within 4 days of starting the polymeric diet her serum phosphate level dropped to 0.63 mmol/L (1.0–1.8). Other investigations included sodium, 133 mmol/L (135–145); potassium, 4.6 mmol/L (3.5–5.00); corrected calcium, 2.25 mmol/L (2.2–2.7); and magnesium, 0.65 mmol/L (0.65–1.00). Oral phosphate supplements were commenced and the serum concentrations had normalised after 24 hours to 1.41 mmol/L. DISCUSSION In addition to the use of enteral nutritional supplements to help improve growth, exclusive enteral nutrition is being increasingly used as primary therapy for children with CD. Although the ultimate aim is to provide enough enteral nutrition to meet at least the child's estimated average requirement for energy, it is not always appreciated that the feeds should be introduced slowly for days. Considering the common association of CD with malnutrition, it is perhaps surprising that there is little in the medical literature on the occurrence of refeeding syndrome in malnourished patients with CD who are refed. To the best of our knowledge, there is only 1 case report. In 2002, Afzal et al (5) described what they stated to be the first report of refeeding syndrome in an adolescent with CD and malnutrition who received exclusive polymeric enteral nutrition. The girl, who was given exclusive polymeric enteral feeds, developed significant hypophosphatemia within 2 days. She was successfully treated with feed reduction and phosphate supplements. In this article, we report 2 further patients with CD who developed refeeding syndrome on receiving exclusive enteral nutrition. Both patients were severely malnourished and developed the complication within days of starting the feeds. The pathophysiology of the refeeding syndrome has been established. During periods of starvation, insulin secretion is reduced in response to reduced carbohydrate intake (6). The reduced insulin concentration coupled with an increase in glucagon concentration results in glycogenolysis and glycogen stores are converted into glucose (7). There is also gluconeogenesis, in which glucose synthesis occurs via fat and protein breakdown products. Thus during starvation, there is a shift from carbohydrate metabolism to fat and protein catabolism to provide energy. The breakdown of glycogen, protein, and fat results in losses of lean tissue mass, body water, and minerals such as phosphates, potassium, and magnesium. This results in a total body depletion of electrolytes, although serum levels are usually maintained by redistribution from the intracellular space. When a malnourished patient is provided with nutrition in oral, enteral, or parenteral forms, a metabolic transition from catabolism to anabolism occurs. The delivery of carbohydrates stimulates the release of insulin (8), which in turn increases the cellular uptake of glucose, phosphate, potassium, magnesium, and water, in addition to promoting protein synthesis (7). The abrupt reversal of catabolism to tissue anabolism with resynthesis of glycogen and protein create a sudden demand for inorganic phosphate for phosphorylation and adenosine triphosphate (ATP) synthesis and for potassium to balance the negative charges on protein and glycogen (9). Magnesium is also taken up by the cells because it is also involved in ATP synthesis. These effects may cause a fall in the serum concentrations of these minerals and may lead to potentially dangerous hypophosphataemia, hypokalaemia, and hypomagnesaemia. Unless the stores are rapidly restored, tissue malfunctions may soon occur leading to complications (10). It is believed that whereas increased insulin drives phosphate, potassium, and magnesium intracellularly, sodium is driven extracellularly leading to an expansion of the extracellular fluid volume, which may cause haemodilution (11). Thus, the increased insulin secretion also leads to sodium retention and fluid shifts (12). Although phosphate is not the only mineral that can be affected in the refeeding syndrome, hypophosphataemia is considered the hallmark biochemical manifestation of the condition and the primary cause of morbidity and mortality. Hypophosphataemia has far-reaching consequences on the functioning of various organ systems (9). Phosphate is required for the production of ATP, creatinine phosphokinase, 2,3-diphosphoglycerate, and glucose-6-phosphate and also plays an important role in maintaining the integrity of DNA (10). The high-energy substrate ATP is required for glycogen formation and protein synthesis, and inadequate phosphate stores lead to poor utilization of energy, resulting in abnormalities in skeletal and cardiac muscle function, neurological function, and pulmonary function (13). The clinical features of the refeeding syndrome result from the electrolyte disturbances (hypophosphataemia, hypokalaemia, and hypomagnesaemia) and from disturbed body fluid shifts. The early features of the syndrome may be nonspecific and may go unrecognised (1) because the syndrome is usually asymptomatic unless the electrolyte disturbances are severe. Deaths resulting from acute cardiopulmonary decompensation associated with severe hypophosphataemia have been reported in both adults (14) and children (15). An important aspect of the management of the refeeding syndrome is for clinicians to be aware of the condition and identify and monitor patients at risk. Although not all patients who are refed develop refeeding syndrome, the syndrome can occur in any patient with significant malnutrition regardless of the cause of the malnutrition. Refeeding syndrome should be considered as a potential complication during the first week of provision of nutritional support for these patients (5). In at-risk patients, baseline serum concentrations of electrolytes, in particular phosphate, potassium, magnesium, calcium, sodium, urea, and creatinine, should be ascertained before the initiation of nutritional support. Any preexisting electrolyte disorders should be corrected before refeeding (7). Refeeding should be started slowly and caloric intake gradually increased. Some authorities recommend starting refeeding at about 25% to 50% of the estimated energy requirement for the particular patient to reduce the risk of refeeding syndrome (1). The caloric intake should be increased slowly. The optimal period during which the energy increase should take place is not clearly established. Some authors have suggested 3 to 5 days (3), 5 to 7 days (12), and 4 to 10 days (9). Serum phosphate, magnesium, calcium, potassium, urea, and creatinine should be repeated daily for at least 4 days after feeding is started (1). Stanga et al (9) have suggested categorising refeeding syndrome into the “biochemical refeeding syndrome,” in which only biochemical abnormalities prevail, and the “symptomatic refeeding syndrome,” in which there are also clinical features. This differentiation is arbitrary, however, because the 2 aspects only represent a spectrum of the same condition and it is also not clear at what threshold level of electrolytes (particularly phosphate) clinical symptoms develop in the refeeding syndrome. The 2 patients reported on in this article exhibited the different aspects of the refeeding syndrome, although their degrees of hypophosphataemia were similar. Patient 1 developed clinical symptoms of hypophosphataemia and the symptoms settled with phosphate supplementation, whereas Patient 2 developed only biochemical hypophosphataemia without clinical symptoms. CONCLUSIONS Malnourished children with CD are at risk for developing the refeeding syndrome when they are provided with enteral nutrition. Clinicians caring for these children should be aware of the syndrome to allow the identification and monitoring of patients at risk.