Hyperammonemic encephalopathy

Hyperammonemia is most often observed in the clinical setting of liver failure. However, understanding the consequences of hyperammonemia under such conditions is hindered by the many other metabolic abnormalities associated with liver failure. To clarify the clinical picture of hyperammonemic encephalopathy, a patient with a urea cycle disorder is described, a setting in which mechanisms attributable to severe liver impairment are absent. Hyperammonemic encephalopathy in urea cycle disorders is compared with the encephalopathy of fulminant hepatic failure and hepatic encephalopathy. Such a comparison reveals that the following features are shared by all 3 conditions: hyperammonemia; respiratory alkalosis; increased levels of glutamine in plasma, cerebrospinal fluid, and brain; decreased brain levels of myo-inositol; and astrocyte swelling with few neuronal changes. These findings in patients, when added to data obtained from experimental animals made hyperammonemic but with normal liver function, support the proposal that hyperammonemic encephalopathy is a consequence of astrocyte swelling and dysfunction resulting from the osmotic effects of astrocyte glutamine synthesis (activated by ammonia) and accumulation. If this proposal is correct the physiologic changes induced by hyperammonemia should be prevented or ameliorated by inhibiting brain glutamine synthetase activity. Animal studies demonstrate that the astrocyte is the site of brain glutamine synthetase and that abnormalities induced by hyperammonemia, for example, cerebral edema, cerebral glutamine accumulation, astrocyte swelling, and brain functional changes, are prevented or ameliorated by treatment with the glutamine synthetase inhibitor, L-methionine S-sulfoximine (MSO). Therapeutic implications of MSO are discussed.