Mechanisms for reduced hepatic clearance and elevated plasma levels of bile acids in cirrhosis: A study in patients with an end-to-side portacaval shunt

Abstract

The mechanisms for reduced hepatic clearance and for elevated levels of plasma bile acids were investigated in cirrhotic patients having an end-to-side portacaval shunt. The liver plasma flow and the concentration and relative composition of total bile acids in the systemic and hepatic venous blood were determined in the fasting state. Mean values for liver plasma flow, hepatic extraction ratio, hepatic clearance and Vmax/Km of total bile acids were respectively: 395 ± 37 ml/min (mean ± SEM), 0.48 ± 0.08, 184 ± 36 ml/min, and 287 ± 74 ml/min. These values are lower than those estimated in healthy subjects assuming a mean liver plasma flow of 600 ml/min and a mean hepatic extraction ratio of 0.80. It was shown that the hepatic clearance of bile acids depends on Vmax/Km, i.e., on the inherent ability of the liver to remove bile acids from the blood rather than on liver plasma flow. Chenodeoxycholic acid was the major bile acid in both the hepatic and systemic venous blood. The hepatic clearance of total bile acids therefore mainly reflected the hepatic clearance of chenodeoxycholic acid. The respective contribution to plasma bile acid levels of: (a) the hepatic clearance and its two biologic determinants, i.e., liver plasma flow and Vmax/Km, (b) the total extrahepatic portosystemic shunting, and (c) the intestinal absorption rate of bile acids were quantitated. A significant and hyperbolic relationship existed between bile acid levels and Vmax/Km values. The largest relative contribution to bile acid levels due to portacaval shunting was found in those subjects with the greatest hepatic clearances. The intestinal absorption rate of bile acids varied in a narrow range (5.7–9.5 μmol/min) despite wide variations in bile acid levels; no significant relationship was found between these two parameters. Finally, the results of this study show that altered hepatic elimination of bile acids and of drugs which are fully absorbed by the intestine and completely metabolized by the liver share common mechanisms in liver cirrhosis.