Hyperammonemia related to urea cycle disorders is a rare cause of potentially fatal encephalopathy that is encountered in intensive care units (ICUs). Left undiagnosed, this condition may manifest irreversible neuronal damage. However, timely diagnosis and treatment initiation can be facilitated simply by increased awareness of the ICU staff. Here, we describe a patient with acute severe pancreatitis who developed hyperammonemia and encephalopathy without liver disease. Urea cycle disorder was suspected and hemodialysis was initiated. Following reduction of ammonia levels, subsequent treatment included protein restriction and administration of arginine and sodium benzoate. The patient was discharged to home after 47 days with plasma ammonia within normal range and without neurological symptoms. In clinical care settings, patients with neurological symptoms unexplained by the present illness should be assessed for serum ammonia levels to disclose any urea cycle disorders to initiate timely treatment and improve outcome.
Hyperammonemia is a frequent complication of liver failure or portal-systemic shunt implantation. In patients without liver failure or portal-systemic shunt, hyperammonemia may result from urea cycle disorders, which can disrupt the hepatic disposal process that otherwise clears the toxic ammonia by-product from protein or amino acid breakdown.
Clinical study has revealed that deficiency of any of the five primary urea cycle enzymes in infants results in ammonia accumulation that manifests as severe neurological symptoms culminating in coma and death. In adults, mild or partial deficiency of any of the urea cycle enzymes has been attributed to severe illness- or stress-induced increases in protein catabolism or protein overload [
A 49-year-old male with biliary acute pancreatitis was admitted to another hospital’s intensive care unit (ICU) for 13 days. After discharge, the patient presented to our hospital with high fever, and a large pancreatic abscess was detected by computed tomography (CT) scanning. Upon admission, the patient underwent necrosectomy, cholecystectomy, and abscess drainage in a single surgical setting. Seven days later, he required an additional surgical drainage. Parenteral nutrition was initiated, and on the 8th day the patient developed progressive lethargy, confusion, and coma requiring intubation. Laboratory tests indicated hyperammonemia (137 micromol/L) and normal liver function with enzyme levels and serum bilirubin within normal range. CT and magnetic resonance imaging (MRI) revealed no brain lesions. Lactulose treatment produced no improvement in clinical signs, and the patient remained in deep coma with ammonia elevated to 254 micromol/L. Since there was no evidence of liver disease, hyperammonemia caused by disruption of urea cycle due to an enzyme deficiency was suspected as the etiology of the patient’s mental disruption. Since there was no time to wait the results of amino acid analysis, with brain damage risk, empiric treatment was started. Accordingly, parenteral and enteral nutrition were replaced with a protein-free diet. Continuous venous hemofiltration with dialysis was initiated. Thirty-six hours later, the ammonia level had decreased to 82 micromol/L and the patient’s mental status had improved. The patient was weaned from the respirator and completely awake. However, hemofiltration discontinuation was accompanied by deterioration in mental status. Since OTC deficiency is the most common defect reported in late-onset hyperammonemia, sodium benzoate (3 g) and arginine (3 g) were administered every four hours via nasogastric tube. The mental status improved, and serum ammonia levels returned to normal. Plasma amino acid analysis showed reduced citrulline (13 micromol/L, normal: 16–51), severely reduced arginine (17 micromol/L, normal: 43–407), elevated glutamic acid (165 micromol/L, normal: 10–97), and elevated aspartic acid (8 micromol/L, normal: 1–4). Urinalysis showed elevated orotic acid (1.8 mmol/mol of creatinine, normal: 0.4–1.2). Late-onset OTC deficiency was diagnosed. The protein-free diet was gradually replaced with a protein diet, and no increase in ammonemia was detected. After 47 days, the patient was discharged to home with medication and counseling on diet. The final serum ammonia levels were within normal range (Figure
Effect of hemodialysis, arginine, and sodium benzoate on ammonia levels in late-onset OTC deficiency.
Under normal physiologic conditions, ammonia is converted to urea in the liver by five enzymes: carbamoyl phosphate synthase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (ASS1), argininosuccinic acid lyase (ASL), and arginase (ARG) [
In newborns, hyperammonemia is usually due to severe deficiency or even absence of activity of any of the five enzymes of the urea cycle or the NAGS cofactor. Urea cycle disorder affects ~1 of 8200 live births in the United States [
OTC catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine [
In general, hyperammonemia treatment is based on the following objectives: decreasing waste products from endogenous protein breakdown by reducing the nitrogen intake; minimizing protein catabolism, and providing substrates lacking in the urea cycle and substances that may facilitate ammonia removal from the blood [
Since ammonia is a gas, its rapid removal by hemodiafiltration is not associated with osmotic problems and no special care must be taken to avoid dialysis disequilibrium syndrome [
Marcel Cerqueira Cesar Machado and José Jukemura designed the study; Marcel Cerqueira Cesar Machado performed the research; Marcel Cerqueira Cesar Machado, Gilton Marques Fonseca, and José Jukemura wrote the paper; Gilton Marques Fonseca collected and analyzed data and edited the paper.