Bile acid metabolism in cirrhosis: VI. Sites of blockage in the bile acid pathways to primary bile acids

Patients with advanced cirrhosis have been shown to have a marked reduction of cholic acid synthesis, while chenodeoxycholic acid synthesis was affected to a much lesser extent. This preferential impairment of cholic acid synthesis has been attributed to a selective defect in the 12α-hydroxylation of cholic acid precursors. In order to provide more definitive information on the nature of the defect of bile acid synthesis, several 3H-labeled bile acid intermediates were administered simultaneously with tracer doses of [14C]cholic and [14C]chenodeoxycholic acid to patients with advanced cirrhosis and to control subjects without liver disease. Bile acid kinetics and the fractional conversion of the labeled intermediates to primary bile acids were estimated from the specific activity data. The 5β-[7β-3H]cholestane 3α,7α,12α,26-tetrol and 5β-[7β-3H]cholestane 3α,7α,12α-triol tested the integrity of side-chain oxidation of cholic acid, while the 7α-hydroxy-4-[6β-3H]cholesten-3-one was administered to provide information about a possible block in the 12α-hydroxylation step. The results of the present study demonstrate that patients with advanced cirrhosis have a marked and significant reduction of cholic acid and chenodeoxycholic acid synthesis. 5β-[7β-3H]Cholestane 3α,7α,12α,26-tetrol and 5β-[7β-3H]cholestane 3α,7α,12α,-triol were efficiently converted to cholic acid in subjects without liver disease (92%–100%) and in patients with advanced cirrhosis (70%–95%). A somewhat less efficient (20%) conversion of these two intermediates may be suggestive of a slight impairment of cholic acid side-chain oxidation in advanced cirrhosis. This minor impairment, however, could not account for the profound reduction of cholic acid synthesis in these patients. The 7α-hydroxy-4-[6β-3H]cholesten-3-one was also efficiently converted (70%–100%) to primary bile acids in both groups of study subjects. In contrast to the patients without liver disease, the conversion of this labeled intermediate to cholic acid was significantly reduced in cirrhotic patients. This finding suggests that 12α-hydroxylation of this cholic acid precursor is impaired in cirrhosis and is probably the major factor contributing to the reduction of cholic acid synthesis. The observed reduction of chenodeoxycholic acid synthesis in patients with advanced cirrhosis suggests that in addition to the impairment of the 12α-hydroxylation step, other defects in the biosynthesis pathway are present in cirrhosis. As lab