Refeeding Encephalopathy in a Patient with Severe Hypophosphataemia and Hyperammonaemia

CLINICAL CASE REPORT Refeeding encephalopathy in a patient with severe hypophosphataemia and hyperammonaemia

S Becker, G Dam and CL Hvas

The refeeding syndrome is a potentially fatal condition that affects multiple organ systems. It is the consequence of ﬂuid and electrolyte shifts that may occur in a malnourished patient following the introduction of nutrition therapy. The most prominent characteristic is hypophosphataemia. Although hyperammonaemia is usually seen in decompensated liver cirrhosis or acute liver failure, it may occur in other settings. We report a clinical case of prolonged and severe encephalopathy accompanied by hypophosphataemia and hyperammonaemia in a 59-year-old woman with no preexisting liver disease, urea cycle defects or portosystemic shunting. We suggest that these biochemical abnormalities were caused by uncontrolled refeeding and that the clinical picture was consistent with refeeding encephalopathy.

European Journal of Clinical Nutrition (2015) 69, 279–281; doi:10.1038/ejcn.2014.244; published online 12 November 2014

INTRODUCTION 252 µmol/l (o50 µmol/l). Urea excretion was 89–117 mmol/day The refeeding syndrome (RFS) is a condition of severe fluid and (300–600 mmol/day) and the glomerular filtration rate was electrolyte shifts that may occur when nutrition is reintroduced to normal. Arterial blood gas revealed an alkalosis with a pH of a malnourished patient.1 RFS is characterised by hypopho- 7.54 (7.37–7.45). sphataemia, hypokalaemia, hypomagnesaemia, fluid imbalance Two cerebral computed tomography scans and one magnetic and frequently thiamine deficiency. RFS may be caused by oral, resonance imaging (MRI) revealed no pathology, particularly no enteral or parenteral nutrition.1 Hyperammonaemia is most pontine myelinolysis. Spinal fluid had normal cell counts, commonly seen in decompensated liver cirrhosis but may occur cerebrospinal fluid/serum glucose ratio and marginally elevated in other conditions such as acute liver failure, portosystemic protein at 0.94 g/l (0.15–0.5 g/l). Neuroinfection was disproved by shunting or urea cycle defects.2 Here, we describe a case of RFS PCR, microscopy and culture. Electroencephalography was con- presenting with encephalopathy associated with both hypopho- sistent with metabolic encephalopathy and ruled out epileptic sphataemia and hyperammonaemia in a patient without liver state. An abdominal computed tomography showed no signs of disease. cirrhosis, portal hypertension or portosystemic shunting. Over 10 days, the patient’s mental status did not improve despite intravenous antibiotics, phosphate 20–80 mmol per day Case report and thiamine (Figure 1). Following normalisation of plasma A 59-year-old woman with a 30-year history of perianal Crohn’s phosphate levels, enteral tube feeding including lactulose was disease was admitted to the hospital. Two days earlier, she had re-established. Haemodialysis was carried out to lower ammonia. been discharged from a surgical department after revision of On the 12th day of hospitalisation, the patient’s cerebral state sacral ulcers. Because of poor nutritional status and a low food slowly improved. During recovery, she complained of muscle pain intake, oral thiamine supplementation and nasogastric tube and disorientation. She was discharged on day 31 on a stable tube feeding had been established at discharge with an initial dose feeding regimen. Although awake and oriented, the patient of 500 ml (625 kcal) per day. experienced cognitive deficits and muscle weakness. On admission, the patient was deeply comatose with no response to pain stimuli. She had myoclonus, spontaneous pronations of all extremities and an extensive plantar response. DISCUSSION Physical examination revealed two spider angiomas but no palmar Hypophosphataemia is a predominant feature of RFS. RFS is erythema or caput medusae. She was malnourished with a body potentially fatal and can affect any organ system.1 Phosphate is weight of 43 kg and a body mass index of 16 kg/m2. Before essential for most cellular processes and is particularly important admission, she had a daily alcohol consumption of 2–3 glasses of during the anabolic phase.1 In this patient, multiple risk factors wine. Her daily medications included morphine, acetaminophene, predisposed to RFS––that is, alcohol consumption, inflammation, magnesium, potassium and B vitamins. weight loss, low body mass index and low food intake before Blood tests showed elevated C-reactive protein 80 mg/l (o8mg/l), realimentation. The initial enteral feeding dose was low (15 kcal/kg/day leukocytosis 18.1 × 109/l (3.5–10 × 109/l), hypoalbuminaemia 13 g/l and 0.7 g protein/kg/day) but sufficient to induce a severe and (36–45 g/l), normal liver function tests, sodium, potassium and prolonged hypophosphataemia. Guidelines recommend that magnesium levels, severe hypophosphataemia o0.17 mmol/l patients at a high risk of RFS should be started at 10 kcal/kg/day (0.76–.41 mmol/l) and markedly increased arterial ammonia of or even lower in extreme cases.1 Profound hypophosphataemia

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark. Correspondence: Dr CL Hvas, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, DK-8000, Aarhus C, Denmark. E-mail: [email protected] Received 12 July 2014; revised 22 September 2014; accepted 28 September 2014; published online 12 November 2014 Refeeding encephalopathy S Becker et al 280 may explain the coma, myoclonus, respiratory insufficiency, or centropontine myelinolysis5 should be considered. In this case, neurological deficits and muscle pain. thiamine was provided orally at initiation of enteral tube feeding, Encephalopathy during refeeding may be caused by hypopho- and MRI excluded centropontine myelinolysis. sphataemia alone,3,4 but other factors such as thiamine deficiency Hyperammonaemia is usually seen in decompensated liver cirrhosis but may occur in acute liver failure, portosystemic shunting and urea cycle defects.2 Our patient had no pre-existing liver disease. No previous episodes of coma indicated primary urea cycle defects, and she received no medications that could interfere with the urea cycle—for example, valproic acid.2 In the absence of predisposing factors, we suspected a link between hyperammonaemia and hypophosphataemia. Normally, ammonia is detoxified through glutamine synthesis in liver, muscle, kidney and brain tissue or via the urea cycle in the liver. Both are ATP-demanding processes (Figure 2). In order not to underestimate plasma ammonia, arterial blood samples could therefore be preferred.6 Hyperammonaemic encephalopathy has been described in protein-deprived children7 and in adults hyperalimentated with essential amino acids.8 A suggested mechanism was limited substrate for the urea cycle.8 In protein-deprived rats,8,9 ammonia increased and urea excretion decreased during starvation, and the authors found reduced urea enzyme and glutamine synthetase (GS) activity. Although the urea cycle enzymes rapidly reversed upon realimentation, GS took 4 weeks to recover and was compensated by increased GS activity in muscle tissue.9 In the present case, we believe that the hyperammonaemia was caused by a combination of refeeding-induced nitrogen challenge and limited urea detoxification via both the urea cycle and GS. A low muscle mass may have contributed, and hypophosphataemia may have impaired the ATP-demanding steps in both processes. Hyperammonaemia was ultimately treated by haemodialysis in combination with lactulose. Other ammonia-lowering therapies such as rifaximine were omitted in the absence of chronic liver Figure 1. Plasma levels of ammonia (upper level) and phosphate disease.6 Potentially, carnithine deficiency could contribute to (lower level) during hospitalisation for refeeding encephalopathy. hyperammonaemia, but this has mainly been associated with

Figure 2. Two essential pathways for ammonia detoxiﬁcation: glutamine synthesis and the urea cycle. (a) Glutamine synthetase (GS) is present in liver, muscle, kidney and brain tissue. It catalyses the ATP-dependent condensation of glutamate with ammonia to yield glutamine. (b) The urea cycle is restricted to the liver and located in the mitochondria and cytoplasm of periportal hepatocytes. Urea is formed through ﬁve enzymatic steps, which require the cofactor N-acetylglutamate and four ATP equivalents.2

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