Liver Failure and Transplantation - Amino Acid Metabolism

Clowes, George

Abstract

The central plasma clearance rate of amino acids (CPCR-AA), a recently developed hepatocyte function test, is to be evaluated as a method for assessing the severity of hepatic failure in patients who are candidates for liver transplantation. In the post transplant period it will also be studied as a means for determining the presence any degree of damage to the transplanted liver caused by anoxia, rejection or infection, and thus, its usefullness as a guide to immunological management, and ultimately, as an indicator for the need for retransplant another liver. CPCR-AA is a measure of the quantity of plasma cleared of amino acids per unit of time by the liver and other central tissues for snythesis of proteins essential to immunological defense against bacterial or viral invasion and for survival. It is the ratio of the rate of entry into plasma or amino acids from degradation of muscle protein plus the rate of infused amino acids divided by the arterial plasma amino acid concentration. CPCR-AA is expressed as ml/M2/min. Recent results from study of non-infected cirrhotic patients have shown a response similar to septic patients with normal liver function. Cirrhotics whose CPCR-AA values exceeded 180 ml/M2/min survived major surgery while those with lesser values died. CPCR-AA will be correlated with the advent of serious infection and other complications in preoperative and postoperative patients who undergo liver transplantation. Slices of the resected liver will be incubated to determine the in vitro rate of hepatic synthesis of complement, fibrinogen and other acute phase proteins, a function which correlates with CPCR-AA in other types of patients (r=0.65, p less than 0.01). The accelerated muscle protein net degradation and hepatic protein synthesis of acute phase proteins required for survival are mediated by interleukin-1 (IL-1) and its stable circulating cleavage product """"""""proteolysis inducing factor"""""""" (PIF) which are produced by activated macrophages. Patients with liver failure also have been found to have high PIF activity in their plasma. Measurement of PIF titres in plasma, ascitic fluid, and the incubating medium will be directed toward ascertaining the source of IL-1 and PIF in liver failure. Controlled experiments in pigs and rats will be conducted to supplement the clinical observations on liver injury and transplantation of amino acid and protein metabolism. It is anticipated that information will be obtained on the causes of the metabolic defects in liver failure and in their correction by transplantation.