Simultaneous Determination of Plasma Mevalonate and 7a- Hydroxy-4-Cholesten-3-one Levels in Hyperlipoproteinemia: Convenient Indices for Estimating Hepatic Defects of Cholesterol and Bile Acid Syntheses and Biliary Cholesterol Supersaturation

plasma MVL) and a decreased secretion of bile acids The high prevalence of cholesterol gallstone disease (closely reflected by plasma C4), the multivariate linear in hypertriglyceridemic patients may be associated with regression–analyses revealed that an index defined as frequent metabolic defects in cholesterol and bile acid estimated CSI ([CSI]E) (%) in patients with HLP was syntheses and in the concomitant formation of bile sugiven by the following equation using plasma MVL and persaturated with cholesterol. This study had the two C4 (nmol/L): [CSI]E Å 1[MVL] / 0.7[C4] / 44.4. Biliary aims: 1) to assess whether the defects as well as the decholesterol supersaturation in patients treated with simgree of biliary cholesterol supersaturation in patients vastatin improved in a manner parallel to the time with hyperlipoproteinemia (HLP) can be estimated by course of decreases in plasma MVL and C4. The [CSI]E the simultaneous determination of plasma mevalonate before and at the end of treatment were correlated with (MVL) and 7a-hydroxy-4-cholesten-3-one (C4); and 2) to biliary CSI. These results indicate that defects of hepatic assess the possible application of an estimated cholescholesterogenesis, and bile acid synthesis, and the deterol saturation index ([CSI]E) as a means of evaluating gree of biliary cholesterol supersaturation in patients the clinical effects of simvastatin on biliary lipid compowith HLP can be estimated exactly by the simultaneous sition. Biliary cholesterol supersaturation was observed determination of plasma MVL and C4; furthermore in patients with both IIa and IV HLP types. Consistent [CSI]E may be adopted for clinical use as a convenient with the high activity and steady-state messenger RNA index of biliary CSI. (HEPATOLOGY 1997;25:18-26.) level of 3-hydroxy-3 methylglutaryl coenzyme A (HMGCoA) reductase, plasma MVL was significantly higher in 86 patients with HLP (38 type IIa, 44.1 { 2.4 nmol/L and The prevalence of gallbladder disease, i.e., cholelithiasis 48 type IV, 56.7 { 2.3; Põ .01) than in 41 normolipidemic and cholecystitis, is abnormally high in patients with prisubjects (34.2 { 1.5), closely correlating with the molar mary type IV hyperlipoproteinemia (HLP). Current repercentage of cholesterol in bile (r Å .61, P Å .0001; n Å search suggests that the formation of cholesterol stones is 86). On the other hand, consistent with the high activity preceded by metabolic defects resulting in the formation of and messenger RNA level of cholesterol 7a-hydroxylase, bile supersaturated with cholesterol. Primary type IV HLP plasma C4 was significantly higher in patients with HLP is often associated with abnormalities in cholesterol and bile (type IIa, 28.8 { 2.3 nmol/L and type IV, 38.3 { 2.7; P õ acid metabolism, which in turn may lead to biliary choles.01) than in normolipidemic subjects (17.4 { 1.5). Plasma terol supersaturation. Cholesterol homeostasis in humans C4 was closely correlated with plasma MVL (r Å .40, P is preserved mainly through the modulation of catalytic activÅ .0001; n Å 86), but was inversely correlated with the ities of two key enzymes, 3-hydroxy-3 methylglutaryl coenmolar percentage of bile acids in bile (r Å .49, P Å .0001; zyme A (HMG-CoA) reductase (EC1.1.1.34), the rate-limiting n Å 86). Assuming that cholesterol supersaturation in enzyme for cholesterol synthesis, and cholesterol 7a-hydroxypatients with HLP may be governed by both an enlase (EC1.14.13.7), the rate-limiting enzyme for bile acid synhanced cholesterol secretion (closely reflected by thesis. From a clinical perspective, ethical issues and overly cumbersome methodologies, such as the determination of catalytic activities of the two key enzymes in liver biopsy speciAbbreviations: HLP, hyperlipoproteinemia; MVL, plasma mevalonate; C4, 7a-hydroxymens and in kinetic analysis with either radiolabeled or sta4-cholesten-3-one; [CSI]E, estimated cholesterol saturation index; HMG-CoA, 3-hydroxy-3 methylglutaryl coenzyme A. ble isotopes, have made it difficult to study the regulation of From the Department of Gastroenterology, Institute of Clinical Medicine, University cholesterol homeostasis. of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki, Japan; Miyamoto Hospital, 1247 Koda, In a recent series of experiments, we developed a method Azuma-mura, Inashiki-gun, Ibaraki, Japan; Aikawa Hospital, 232 Daihata, Senba-cho, for the simultaneous determination of mevalonate (MVL) Mito-shi, Ibaraki, Japan; and The 2nd Department of Internal Medicine, Showa University