Functional hyperactivity of hepatic glutamate dehydrogenase as a cause of the hyperinsulinism/hyperammonemia syndrome: Effect of treatment

Objective. The combination of persistent hyperammonemia and hypoketotic hyp oglycemia in infancy presents a diagnostic challenge. Investigation of the possible causes and regulators of the ammonia and glucose disposal may resu lt in a true diagnosis and predict an optimum treatment. Patient. Since the neonatal period, a white girl had been treated for hyper ammonemia and postprandial hypoglycemia with intermittent hyperinsulinism. Her blood level of ammonia varied from 100 to 300 mu mol/L and was independ ent of the protein intake. Methods. Enzymes of the urea cycle as well as glutamine synthetase and glut amate dehydrogenase (GDH) were assayed in liver tissue and/or lymphocytes. Results. The activity of hepatic GDH was 874 nmol/ (min.mg protein) (contro ls: 472-938). Half-maximum inhibition by guanosine triphosphate was reached at a concentration of 3.9 mu mol/L (mean control values: .32). The ratio o f plasma glutamine/blood ammonia was unusually low. Oral supplements with N -carbamylglutamate resulted in a moderate decrease of the blood level of am monia. The hyperinsulinism was successfully treated with diazoxide. Conclusion. A continuous conversion of glutamate to 2-oxoglutarate causes a depletion of glutamate needed for the synthesis of N-acetylglutamate, the catalyst of the urea synthesis starting with ammonia. In addition, the shor tage of glutamate may lead to an insufficient formation of glutamine by glu tamine synthetase. As GDH stimulates the release of insulin, the concomitan t hyperinsulinism can be explained. This disorder should be considered in e very patient with postprandial hypoglycemia and diet-independent hyperammon emia.