Glutamine as a pathogenic factor in hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) results from acute or chronic liver dysfunction and is associated with hyperammonemia. Ammonium ions penetrate from blood to brain, where they form glutamine (Gln) in the reaction with glutamate catalyzed by an astroglia-specific enzyme, glutamine synthetase (GS). Experimental data suggest that many manifestations of HE can be ascribed to increased Gln synthesis and accumulation in the brain. In HE resulting from acute liver failure ("fulminant hepatic failure"), the osmotic action of Gln appears to be in a large degree responsible for cerebral edema and edema-associated disturbances of cerebral blood flow and ionic homeostasis. In chronic HE not accompanied by cerebral edema, Gln contributes to impairment of cerebral energy metabolism, and its increased transport from brain to the periphery accelerates the blood-to-brain transport of aromatic amino acids, of which tryptophen (Trp) is converted to metabolites directly implicated in HE. Most of the evidence that Gln participates in pathological events has been derived from their disappearance or amelioration in HE rats in which the cerebral Gln content was reduced by treatment with a GS inhibitor, methionine sulfoximine.