Metabolic Encephalopathy

Abstract

Disorders of metabolism are the most common cause of coma of unknown etiology. Hyperammonemia is important as an etiologic factor in the development of hepatic encephalopathy, operating via direct and indirect mechansims that affect the function of the limbic system. The entry of ammonia into the brain is controlled by blood-brain pH gradients, and cerebral blood flow, coupled with regional variations in the capillary surface area-permeability product. In the brain, ammonium ions may inhibit the generation of action potentials, by substituting for potassium and sodium in current generation, and interfere with the chloride pump, producing a reversible depolarizing shift of the inhibitory post synaptic equilibrium potential toward the equilibrium potential. Ammonia entering the brain is quickly trapped by the ATP-consuming glutamine synthetase reaction leading to energy depletion in the reticular activating system. Ammonia may also interfere with ATP production due to a suspected inhibition of the malate aspartate shuttle, the mechanism for moving reducing equivalents into mitochondria for oxidative phosphorylation. Ammonia also depletes glutamate, causing a potential dysruption of glutamatergic neurotransmission. We recently evaluated the effects of chronic portacaval shunts (PCS) and ammonia on regional brain glucose metabolism using the 14C-deoxyglucose technique and found important direct and indirect effects on the limbic system. After a PCS, glucose metabolism was significantly increased in all 20 brain regions that were sampled, with the smallest increase in the cortex and the greatest increase in the reticular activating system. The pattern of glucose metabolism appeared to be different in the two groups, an impression that was confirmed by multivariate statistical analytical techniques. Assuing that differences in metabolic rate are linked to differences in function, we hypothesized that the hyperammonemia associated with a PCS causes a functional reorganization of the brain that may be responsible for the development of HE. When intracarotid infusions of ammonia were given, glucose metabolism in the ventromedial nucleus of the hypothalamus was activated. Since stimulation of this nucleus inhibits feeding behaviors, we postulated that ammonia's action on satiety centers is directly responsible for appetite loss and the development of cachexia, important elements of chronic liver disease. Since skeletal muscle is an