Cirrhosis of the liver is the fifth ranked cause of lost years of life in Americans. Hepatic encephalopathy (HE) is an important contributor to mobidity and mortality in this population. In this application we propose positron-emission tomographic studies to evaluate basic disease mechanisms in HE. Two protocols will be followed. In the first group of patients with active or controlled HE and normal controls, we will measure cerebral blood flow (CBF) with 15-O-water and regional glucose metabolism with 18-F-fluorodeoxyglucose. We believe that we will observe a distinctive pattern of altered glucose metabolism, perhaps similar to that seen in rats with chronic portacaval shunts, and that there may be regions where blood flow and glucose metabolism are uncoupled, indications of regional differences and susceptibilities to effects of neurotoxins causing HE. We will attempt to correlate glucose metabolism in the region of the hypothalamus with the degree of cachexia when our next generation PET camera is available to test the hypothesis that hypothalamic stimulation, shown by increased glucose metabolism, is correlated with appetite supression and cachexia. In a second group of patients and controls, we will measure CBF and regional ammonia metabolic rates and use these data to calculate ammonia extraction and permeability-surface area (PS) products to evaluate the effects of HE or prior hyperammonemia on the uptake and metabolism of this neurotoxin in order to improve our understanding of factors relevant to the cerebral uptake of ammonia. Preliminary animal studies have shown that PS is increased in chronically hyperammonemic rats. Confirmation in humans would strengthen the hypothesis that ammonia is important in the pathogenesis of HE, explain the development of toxin hypersensitivity observed in patients and animals, and findings of normal arterial ammonia levels in HE patients.
