The Contribution of Various Organs to Ammonia Formation: A Review of Factors Determining the Arterial Ammonia Concentration

Abstract

Additional key phrases: hepatic encephalopathy; liver; metabolismThe arterial ammonia concentration-which is clinically regarded as the gold standard for blood ammonia determinations in hepatic encephalopathy (HE)-has narrow limits and a complex background. Several factors relating to single organs are of crucial importance, e.g. the ammonia concentration of the artery and the vein, the blood inflow and outflow, the weight of the organ and the enzymes which playa key role in the formation and metabolism of ammonia. In this review we attempt to provide a quantitative survey of the organs and mechanisms involved in maintaining ammonia uptake and release under normal physiological conditions with regard to liver failure and subsequently to other organs. METABOLISM OF AMMONIAAmmonia is derived mainly from deamination of the a-amino nitrogen of amino acids and is toxic to all animals, especiallyat elevated concentrations. Human tissue, therefore, initially detoxifies ammonia by converting it to glutamine for transport to the liver. Under normal conditions, deamination of glutamine and glutamate in the liver releases ammonia, which then is efficiently converted to the non-toxic nitrogen-rich compound urea, which is subsequently excreted into the urine. In liver failure, diminished urea synthetic capacity and portal-systemic shunting cause impairment of the physiological route of ammonia detoxification, leading to elevated arterial ammonia levels.'In mammals, ammonia is liberated by transamination followed by oxidative deamination Correspondence to: Mr J R Huizenga. of glutamate.P In this process alanine transaminase and glutamate transaminase catalyse the transfer of amino groups from most amino acids to form L-alanine from pyruvate or L-glutamate from a-ketoglutarate:Each transaminase is specific for one pair of substrates but not for the other pair. Since L-alanine is also a substrate for glutamate transaminase, all the amino nitrogen from amino acids that can undergo transamination can be concentrated in L-glutamate. In mammalian tissue L-glutamate is the only amino acid that undergoes oxidative deamination to ammonia. The reaction is catalysed by glutamate dehydrogenase and is reversible:The overall reaction of transamination followed by oxidative deamination is localized almost exclusively in the liver. Also in the liver, ammonia is fixated by carbon dioxide to form carbamoyl phosphate catalysed by carbamoyl phosphate synthetase:This is the first step in urea synthesis and takes place in liver mitochondria. The remaining main part of the urea cycle takes place in liver cytosol. The urea cycle will not be further discussed here. Ammonia generated by enteric bacteria is absorbed into the portal venous blood and transported to the liver, where it is converted into L-glutamate, L-glutamine and finally into urea. In addition to fixation of ammonia via the glutamate dehydrogenase reaction, formation of L-glutamine is catalysed by glutamine synthetase, 23

Metabolic differences in hepatocytes of obese and lean pigs

“…Urea synthesis Blood ammonia derives from tissue catabolism and intestine lumen (Huizenga et al, 1996). Most portal ammonia is removed from the blood by the liver through urea synthesis preventing hyperammonemia, which would disrupt the central nervous system.…”

Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy–therapeutic perspectives

“…Substantial activity is in the brain, heart, and perivenous hepatocytes. However, the main GLN producer in the body is skeletal muscle because of its large mass relative to other GS containing organs (Huizenga et al 1996). Appreciable GS activity and the potential to release GLN have also the lungs; however, their contribution to whole body GLN production in humans is not clear (Cooper and Freed 2005).…”

Cerebral Herniation in Patients With Acute E Liver Failure Is Correlated With Arterial Ammonia Concentration

“…Under normal conditions, quantitatively important release of ammonia arises from gut, pancreas 14,15 and kidney, 16 and removal of ammonia from circulation predominantly takes place only in the liver, 14 by synthesis of urea, and by incorporation into glutamine by the enzyme glutamine synthetase. During hyperammonemia, brain and muscle can also remove ammonia from the circulation.…”