In alcoholic cirrhosis, malnutrition is a ubiquitous finding which results from, as yet, incompletely defined abnormalities in protein and energy metabolism. Because this malnutrition is an independent and unfavorable risk factor for both long term survival and successful liver transplantation in patients with this disease, empiric nutritional therapies have been instituted without sound scientific rationale and with only marginal benefits obtained. Therefore, the major objectives of this proposal are twofold. The first is to study the normal response of protein metabolism during feeding and how the presence of cirrhosis effects that response. The second is to further delineate the causes of altered protein metabolism in alcoholic cirrhosis; while testing specific nutritional and pharmacologic therapies in vivo to correct these abnormalities. Using a combination of stable and radioactive isotope tracers along with kinetic modeling, the effects of feeding, beta-adrenergic blockade, exercise, insulin resistance and endotoxemia on phenylalanine, leucine, leucine's ketoacid (keto-isocaproic acid), and glycine kinetics will be examined. Based on the kinetics of these amino and keto acids, estimates of whole body protein degradation and hepatic synthesis will be made. Furthermore by measuring blood flow and arterial-venous gradients of amino acids across the human forearm, protein turnover in the skeletal muscle compartment (based on the human forearm model) will be calculated and compared to whole body protein turnover. The need to use protein for energy as an alternative to glucose in these patients with 'accelerated starvation' will also be assessed by measuring leucine oxidation and gluconeogenesis using a novel new technique based on the incorporation of hydrogen molecules of water into different carbons of glucose. In addition, the efficacy of specific nutritional therapies designed to improve protein metabolism by decreasing endotoxemia (glutamine supplements), by increasing protein while decreasing urea synthesis (BCKA supplements), and by improving insulin sensitivity and nitrogen balance (complex carbohydrate, low fat diet) will be studied. In addition, the importance of the route (intestinal vs intravenous) of nutrient administration in determining postprandial protein metabolism will be investigated. Finally, absolute rates of protein turnover will be normalized for body cell mass (based on intracellular water determinations); thereby allowing for the first time a valid comparison of these processes between normal controls and patients with cirrhosis; a disease associated with abnormalities in extracellular compartmentation. It is anticipated that by measuring outcomes from specific nutritional interventions designed to correct abnormalities in protein metabolism, the nutritional management of alcoholic cirrhosis will be optimized and its prognosis improved.
