In Japan the composition of
gallstones is changing rapidly from the once-predominant brown-pigment stones to
cholesterol ones. The present work was undertaken to clarify the mechanism of
cholesterol supersaturated bile production in Japanese patients with
cholesterol gallstones. In 26 non-obese and normolipidemic patients (11 with
cholesterol gallstones, 8 with black- or brown-pigment
gallstones, 7 without
gallstones) a liver biopsy and hepatic bile were surgically obtained under standardized conditions. The
cholesterol saturation of hepatic bile was significantly higher in
cholesterol gallstone patients than in
gallstone-free controls (195 +/- 10 vs. 146 +/- 8%, respectively; P < 0.01). The microsomal activities of 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG-CoA) reductase, the rate-limiting
enzyme for
cholesterol synthesis,
cholesterol 7 alpha-hydroxylase, the rate-limiting
enzyme for
bile acid synthesis, and
7 alpha-hydroxy-4-cholesten-3-one 12 alpha-hydroxylase (12 alpha-hydroxylase), the rate-limiting
enzyme for
cholic acid synthesis, were assayed simultaneously in the same subjects. There were positive correlations between
HMG-CoA reductase and
cholesterol 7 alpha-hydroxylase activities (Rs = 0.62, P < 0.005), and between
cholesterol 7 alpha-hydroxylase and
12 alpha-hydroxylase activities (Rs = 0.44, P < 0.05) in all subjects, irrespective of the existence of
gallstones. The activities of the three rate-limiting
enzymes did not differ significantly among the three groups (
cholesterol stone, pigment stone and stone-free). In conclusion, the
cholesterol supersaturation of hepatic bile in nonobese and normolipidemic Japanese patients with
cholesterol gallstones does not result from an increased hepatic
cholesterol synthesis or a decreased
bile acid synthesis.