PATHOGENESIS OF HEPATIC COMA

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The underlying assumption of the proposed research is that excess ammonia is a major factor in the neurological complications arising from both acute and chronic liver disease. Failure of the diseased liver to remove ammonia from the portal circulation, and limited capacity of extrahepatic tissues to remove this ammonia, leads to an increase in ammonia entering the brain. Our hypothesis is that the increased ammonia load leads to a disruption of cerebral energy metabolism by interfering with, a) the malate-aspartate shuttle (MAS) for the transport of reducing equivalent between cytosol and mitochondria and with b) the TCA cycle (at the level of alpha-ketoglutarate dehydrogenase complex and, possibly, at other dehydrogenase steps). Prolonged exposure to excess ammonia results in increased cerebral "sensitivity" to ammonia, hypoxia, and other superimposed metabolic stresses. Astrocytes in the brains of liver diseased patients and in the brains of animals subjected to experimentally-induced metabolic impairment. To evaluate the role of ammonia in the pathogenesis of hepatic encephalopathy our goals will be multifaceted: 1) to design inhibitors of aspartate aminotransferase (an important component of the MAS) that will cross the blood-brain barrier, in order to investigate the metabolic consequences of disruption of the MAS; 2) to use [13N] leucine, [13N] tyrosine, [13N-amine'- and [13N-amide]glutamine (13N, positron emitter; t 1/2=9.96 min.) to label the astrocytic pool in vivo, to provide evidence that astrocytic glutamine is a precursor of neuronal GABA and to determine whether this pathway is disrupted in the hyperammonemic animal; 3) to elucidate the role of glutathione in the normal and hyperammonemic rat brain; 4) to determine the major source of metabolically-derived ammonia in brain (glutaminase, glutamate dehydrogenase, and/or the purine nucleotide cycle). Finally, some workers have questioned the notion that the major role of the urea cycle is to remove excess nitrogen and have suggested that the urea cycle may have evolved to regulate acid-base levels. To provide evidence for, or against, this theory we will use our recently developed tracer techniques to investigate the short-term metabolic fate of 13N labeled ammonia, alanine and glutamate in the metabolically acidotic rat. The urea cycle is compromised in liver disease. Therefore, it is important to understand how the disruption of this cycle affects both whole-body nitrogen homeostasis and acid-base balance in liver disease. It is hoped that the results of the above mentioned studies will lead to improved therapies in patients with liver disease.