Hyperammonemias and Related Disorders

Abstract

The term hyperammonemia describes a clinical situation marked by increased plasma ammonia concentration. It is generally due to decreased ammonia detoxification as urea. Patients can be of any age. Since ammonia is neurotoxic, life and mental status can be threatened within few hours of breaking the balance between ammonia production and detoxification, as in neonatal urea cycle defects patients when they stop relying on maternal ammonia detoxification upon birth. The urea cycle, fully expressed exclusively in periportal hepatocytes, is the main pathway to detoxify ammonia; it can be primarily affected by an inherited enzyme or transporter defect (primary hyperammonemia) or secondarily by toxic metabolites or substrate depletion (secondary hyperammonemia). Hyperammonemia in infants and children is mainly due to inborn metabolic errors causing primary or secondary hyperammonemia. In adults, hyperammonemia is more often due to acquired hepatic disease. The clinical manifestations of hyperammonemia are generally unspecific and are mainly neurological, gastrointestinal, or psychiatric. The hallmark of hyperammonemia is an unexplained change in consciousness; thus, in any unexplained encephalopathy hyperammonemia must be excluded without delay to avoid severe neurological sequelae. Treatment of acute hyperammonemia most urgently requires the establishment of anabolism and the avoidance of protein catabolism, with rapid initiation of parenteral glucose infusion and protein restriction. Additional urgent measures include the use of dialysis to remove ammonia and of medications that can improve residual urea cycle function (carbamylglutamate and either L-arginine or L-citrulline) and that allow circumventing the urea cycle (the nitrogen scavengers sodium benzoate and/or sodium phenylbutyrate). Liver transplantation is curative. Prognosis of acute hyperammonemia remains poor but can be improved by increasing awareness of healthcare professionals. This chapter focuses on hyperammonemia due to urea cycle defects but also deals with the very rare deficiencies of pyrroline-5-carboxylate synthetase and glutamine synthetase and with the transient hyperammonemia of the newborn.