Cholesterol gallstone formation is a complex process and involves phase separation of cholesterol crystals from supersaturated bile. In most cases, cholesterol hypersecretion is considered the primary event in gallstone formation. The sterol is transported through the hepatocytic canalicular membrane by ABCG5-G8. Expression of this transport protein is regulated by transcription factor Liver X Receptor-α, which may be responsible for biliary hypersecretion. Hydrophobic bile salt pool, bile concentration, excess pronucleating mucin, and impaired gallbladder and intestinal motility are secondary phenomena in most cases but nevertheless may contribute to gallstone formation.
Gallstone disease is very common in the Western world with an estimated prevalence of 10% to 15% in white adults, leading to significant morbidity, mortality, and considerable health care costs. In the Western world, approximately 70% of gallstone carriers exhibit cholesterol gallbladder stones (cholesterol content >50%), and 30% exhibit black pigment gallbladder stones. In East Asia, there is a high prevalence of brown pigment stones residing in the bile ducts, and causing potentially devastating cholangitis. Nevertheless, also in these countries, prevalence of cholesterol gallstones increases, supposedly caused by the introduction of Western diet. Because of increased prevalence of overweight or a higher proportion of elderly subjects in the population, the prevalence of gallstone disease may further increase in the near future. This article focuses on the pathogenesis of cholesterol gallstones. Cholesterol crystal nucleation is considered the earliest step in cholesterol gallstone formation. Various conditions affecting the crystallization process are discussed, such as biliary cholesterol supersaturation, excess pronucleating proteins, or shortage of nucleation-inhibiting proteins, and factors related to the gallbladder, such as hypomotility. Pigment gallstone pathogenesis is briefly discussed.
Physical-chemical aspects of biliary cholesterol solubilization and cholesterol crystallization
Although solubility of cholesterol in aqueous solutions is extremely limited, in gallbladder bile a relatively large amount (approximately 20 × 10 −3 M) of the sterol can be kept in solution. This significant increase in solubility is explained by incorporation of cholesterol in mixed micelles, together with bile salts and phospholipids (mainly phosphatidylcholine). Supersaturation occurs when either too much cholesterol or not enough solubilizing bile salt and phosphatidylcholine molecules are secreted to allow complete micellar solubilization of all cholesterol. Excessive cholesterol may be kept in vesicles (ie, spherical bilayers of cholesterol and phospholipids, without bile salts) or in cholesterol crystals. Cholesterol crystal nucleation is thought to occur in general from vesicles supersaturated with cholesterol (ie, vesicular cholesterol/phospholipid ratio >1). First, small unilamellar supersaturated vesicles aggregate or fuse into larger multilamellar vesicles (“liquid crystals”), with subsequent phase-separation of cholesterol crystals. Pivotal information on the process of cholesterol crystal nucleation, the earliest step in cholesterol gallstone formation, has been obtained from in vitro studies in model bile systems. Wang and Carey found that cholesterol crystallization pathways and sequences in human gallbladder biles are identical to model biles matched for all relevant physical-chemical conditions, underlining the relevance of the model bile data. Based on these model bile data, the equilibrium bile salt–phospholipid–cholesterol ternary phase diagram was constructed, which allows one to predict behavior of mixtures of the three biliary lipids when present in various proportions. As shown in Fig. 1 , the phase diagram contains a bottom one-phase zone (only micelles); a left two-phase (micelles and cholesterol crystals containing) zone; a central three-phase (micelles, vesicles, and cholesterol crystals containing) zone; and a right two-phase (micelles and vesicles containing) zone. Going from baseline to top in the phase diagram the relative percentage of cholesterol increases, with progressive tendency of cholesterol crystallization as a result. Second, a shift from left to right in the phase diagram increases relative amounts of phospholipids compared with bile salts, allowing more solubilization of cholesterol in vesicles, lower vesicular cholesterol/phospholipid ratios, and less cholesterol crystallization as a result. If gallstones are present in supersaturated bile, competition may occur between the gallstone surface (gallstone growth) and the surrounding bile for available cholesterol molecules. Three factors strongly affect the ternary equilibrium bile salt–phospholipid–cholesterol ternary phase diagram, with potential consequences for in vivo cholesterol crystallization: (1) increased bile concentration, (2) increased bile salt hydrophobicity, and (3) phospholipids containing unsaturated acyl chains all strongly promote cholesterol crystallization. Corresponding effects on the ternary equilibrium bile salt–phospholipid–cholesterol ternary phase diagram are in all three cases an increase of the bottom one-phase (micellar) zone, an expansion of the cholesterol crystal–containing zones to the right, and a decrease of the vesicles-containing zones (see Fig. 1 ).
