Primary dual defect of cholesterol and bile acid metabolism in liver of patients with intrahepatic calculi

Background/Aims Intrahepatic calculi, which are characterized by cholesterol-rich pigment stones, are highly prevalent in East Asia. Their pathogenesis remains unknown. To elucidate the etiological factors underlying the formation of cholesterol-supersaturated bile, which leads to the formation of cholesterol-rich pigment stones, cholesterol and bile acid de novo syntheses in the liver were studied. Methods Liver specimens were assayed for the catalytic activities and steady-state messenger RNA levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and cholesterol 7α-hydroxylase. Results The activity of HMG-CoA reductase, consistent with the messenger RNA level, was significantly higher in 13 patients with intrahepatic brown pigment stones (11.2 ± 1.3 pmol · min^-1 · mg protein^-1 [mean ± SEM; P < 0.0001] for affected hepatic lobes and 13.4 ± 1.7 [P < 0.0001] for unaffected ones [P < 0.0001]) than in 19 control subjects (6.4 ± 0.4) and in 29 patients with gallbladder cholesterol stones (2.1 ± 0.1). On the other hand, the activity of 7α-hydroxylase, consistent with the messenger RNA level, was significantly lower in patients with intrahepatic brown pigment stones (2.8 ± 0.5 pmol · min^-1 · mg protein^-1 [P < 0.0001] for affected lobes and 2.6 ± 0.5 [P < 0.0001] for unaffected ones) than in control subjects (6.0 ± 0.6) and in patients with cholesterol stones (5.1 ± 0.5). Conclusions In intrahepatic calculi, the formation of supersaturated bile and cholesterol-rich pigment stones may be attributed to the primary dual defect of up-regulated cholesterogenesis and down-regulated bile acid synthesis in the liver.