SIMULTANEOUS DETERMINATION OF PLASMA MEVALONATE AND 7-ALPHA-HYDROXY-4-CHOLESTEN-3-ONE LEVELS IN HYPERLIPOPROTEINEMIA - CONVENIENT INDEXES FOR ESTIMATING HEPATIC DEFECTS OF CHOLESTEROL AND BILE-ACID SYNTHESES AND BILIARY CHOLESTEROL SUPERSATURATION

The high prevalence of cholesterol gallstone disease in hypertriglycer idemic patients may be associated with frequent metabolic defects in c holesterol and bile acid syntheses and in the concomitant formation of bile supersaturated with cholesterol, This study had the two aims: 1) to assess whether the defects as well as the degree of biliary choles terol supersaturation in patients with hyperlipoproteinemia (HLP) can be estimated by the simultaneous determination of plasma mevalonate (M VL) and 7 alpha-hydroxy-4-cholesten-3-one (C4); and 2) to assess the p ossible application of an estimated cholesterol saturation index ([CSI ](E)) as a means of evaluating the clinical effects of simvastatin on biliary lipid composition, Biliary cholesterol supersaturation was obs erved in patients with both IIa and IV HLP types, Consistent with the high activity and steady-state messenger RNA level of 3-hydroxy-3 meth ylglutaryl coenzyme A (HMG-CoA) reductase, plasma MVL was significantl y higher in 86 patients with HLP (38 type IIa, 44.1 +/- 2.4 nmol/L and 48 type IV, 56.7 +/- 2.3; P < .01) than in 41 normolipidemic subjects (34.2 +/- 1.5), closely correlating with the molar percentage of chol esterol in bile (r = .61, P = .0001; n = 86), On the other hand, consi stent with the high activity and messenger RNA level of cholesterol 7 alpha-hydroxylase, plasma C4 was significantly higher in patients with HLP (type IIa, 28.8 +/- 2.3 nmol/L and type IV, 38.3 +/- 2.7; P < .01 ) than in normolipidemic subjects (17.4 +/- 1.5), Plasma C4 was closel y correlated with plasma MVL (r = .40, P = .0001; n = 86), but was inv ersely correlated with the molar percentage of bile acids in bile (r = .49, P = .0001; n = 86), Assuming that cholesterol supersaturation in patients with HLP may be governed by both an enhanced cholesterol sec retion (closely reflected by plasma MVL) and a decreased secretion of bile acids (closely reflected by plasma C4), the multivariate linear r egression-analyses revealed that an index defined as estimated CSI ([C SI](E)) (%) in patients with HLP was given by the following equation u sing plasma MVL and C4 (nmol/L): [CSI](E) = 1[MVL] + 0.7[C4] + 44.4, B iliary cholesterol supersaturation in patients treated with simvastati n improved in a manner parallel to the time course of decreases in pla sma MVL and C4, The [CST](E) before and at the end of treatment were c orrelated with biliary CSI. These results indicate that defects of hep atic cholesterogenesis, and bile acid synthesis, and the degree of bil iary cholesterol supersaturation in patients with HLP can be estimated exactly by the simultaneous determination of plasma MVL and C4; furth ermore [CSI](E) may be adopted for clinical use as a convenient index of biliary CSI.