Biliary lipids and cholesterol gallstone disease

Abstract

Biliary lipids are a family of four dissimilar molecular species consisting of a mixture of bile salts (substituted cholanoic acids), phospholipids, mostly (>96%) diacylphosphatidylcholines, unesterified cholesterol, and bilirubin conjugates known trivially as lipopigments. The primary pathophysiological defect in cholesterol gallstone disease is hypersecretion of hepatic cholesterol into bile with less frequent hyposecretion of bile salts and/or phospholipids. Several other gallbladder abnormalities contribute and include hypomotility, immune-mediated inflammation, hypersecretion of gelling mucins, and accelerated phase transitions; there is also reduced intestinal motility that augments "secondary" bile salt synthesis by the anaerobic microflora. Cholesterol nucleation is initiated when unilamellar vesicles of cholesterol plus biliary phospholipids fuse to form multilamellar vesicles. From these "plate-like" cholesterol monohydrate crystals, the building blocks of macroscopic stones are nucleated heterogeneously by mucin gel. Multiple Lith gene loci have been identified in inbred mice, paving the way for discovery of an ever-increasing number of LITH genes in humans. Because of the frequency of the metabolic syndrome today, insulin resistance and LITH genes all interact with a number of environmental cholelithogenic factors to cause the gallstone phenotype. This review summarizes current concepts of the physical-chemical state of biliary lipids in health and in lithogenic bile and outlines the molecular, genetic, hepatic, and cholecystic factors that underlie the pathogenesis of cholesterol gallstones.

Fig. 1.

Pie diagram representation of the relative proportions of the four biliary lipids in humans with conventional presentations of their space-filling molecular models and the three common macromolecular structures that they form in bile. Molecules of bilirubin conjugates, although highly water soluble, are bound to the hydrophilic faces of bile salt molecules in solution and on micelles and vesicles by π-orbital-OH interactions (see text for further description).

Fig. 2.

Equilibrium phase diagrams for common taurine-conjugated bile salts, lecithin (egg yolk), and cholesterol in 0.15 M NaCl as functions of hydrophilic-hydrophobic balance of the bile salt (37°C, pH 7.0, total lipid concentration 7.5 g/dl). As bile salt hydrophobicity is decreased (TDC > TCDC > TC > TUDC), the maximum micellar cholesterol solubility is reduced; concomitantly, the multiphase regions above the micellar zone are all shifted to the left, i.e., to lower phospholipids-to-bile salt ratios. Because of this, the crystallization pathways (labeled A to E) are also moved to the left. Reproduced with permission from Ref. .