title: Ammonia: key factor in the pathogenesis of hepatic encephalopathy.
abstract: There is substantial clinical and experimental evidence to suggest that ammonia toxicity is a major factor in the pathogenesis of hepatic encephalopathy associated with subacute and chronic liver disease. Ammonia levels in patients with severe liver disease are frequently found to be elevated both in blood and cerebrospinal fluid (csf). Hepatic encephalopathy results in neuropathological damage of a similar nature (Alzheimer type II astrocytosis) to that found in patients with congenital hyperammonemia resulting from inherited defects of urea cycle enzymes. Following portocaval anastomosis in the rat, blood ammonia concentration is increased 2-fold, and brain ammonia is found to be increased 2-3-fold. Administration of ammonia salts or resins to rats with a portocaval anastomosis results in coma and in Alzheimer type II astrocytosis. Since the CNS is devoid of effective urea cycle activity, ammonia removal by brain relies on glutamine formation. Cerebrospinal fluid and brain glutamine are found to be significantly elevated in cirrhotic patients with encephalopathy and in rats following portocaval anastomosis. In both cases, glutamine is found to be elevated in a region-dependent manner. Several mechanisms have been proposed to explain the neurotoxic action of ammonia. Such mechanisms include: Modification of blood-brain barrier transport; alterations of cerebral energy metabolism; direct actions on the neuronal membrane; and decreased synthesis of releasable glutamate, resulting in impaired glutamatergic neurotransmission.
authors.forename: R F
authors.initials: RF
authors.lastname: Butterworth
authors.forename: J F
authors.initials: JF
authors.lastname: Giguère
authors.forename: J
authors.initials: J
authors.lastname: Michaud
authors.forename: J
authors.initials: J
authors.lastname: Lavoie
authors.forename: G P
authors.initials: GP
authors.lastname: Layrargues
mesh_terms: D000641:Ammonia / Q000097:blood / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005973:Glutamine / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000097:blood* / Q000503:physiopathology; D006801:Humans
chemical_list: D005973:Glutamine; D000641:Ammonia