Abstract
Urea synthesis is an irreversible, essential for maintenance of health and life, and highly regulated liver function with a very high capacity for production of the end-product urea-nitrogen. The set-point of urea synthesis in relation to its overall substrate, the prevailing blood concentration of L-α-amino acids, contributes to determine whole-body nitrogen balance and the size and composition of the plasma free amino acid pool. Ammonia is definitively eliminated from the body by urea synthesis. Ammonia is released by all tissues as part of their nitrogen metabolism and accumulation of ammonia to supranormal levels is toxic, particularly to the brain where it gives rise to the devastating complication to liver diseases, hepatic encephalopathy. The first line ammonia scavenging has an efficiently high clearance several times over hepatic blood flow and close to cardiac output, under normal conditions securing rapid neutralization of ammonia by synthesis of amino acids and glutamine. This scavenging has a much lower capacity than urea synthesis. Maintenance of the scavenging system, therefore, relies on subsequent definitive depletion and elimination of amino- and amide-nitrogen to urea-nitrogen. In liver diseases, the capacity for urea synthesis is deficient due to reduced functional liver mass and dysregulation, which eventually delays the scavenging so that ammonia overflows. Considering the key role of ammonia in hepatic encephalopathy, this indirect relationship implies that deficient urea synthesis is a prerequisite for development of hyperammonemia and hepatic encephalopathy. This is in accordance with the definition of hepatic encephalopathy as being caused by liver insufficiency, where the insufficiency more specifically likely is deficiency of the urea synthesis.