The genetic background of gallstone formation

Cholelithiasis is a common disease associated with a substantial economic burden to our health systems. Gallstones are remarkably common in Europe and America, whereas their prevalence is lowest in Africa [1]. In 1976, Brett and Barker calculated the worldwide prevalence of 4 Gallstones to be almost 16% based on data of large autopsy studies [2]. These data are confirmed by a recent meta-analysis [3] of 22 ultrasound studies published in the years 1979-1995, which demonstrated the prevalence rate of cholecystolithiasis to be 10-12% in Europe. Principally there are two major gallstone types, cholesterol and pigment stones, which are distinguished based on morphological and physical-chemical criteria. Cholesterol stones are far more common (90% of all gallstones); in contrast to pigment stones, they contain more than 50% cholesterol by weight. The biochemical and metabolic pathways of cholesterol and bile synthesis are depicted in figure 1. The current hypothesis is that the primary pathophysiological defect in cholesterol stone formation is hepatic hypersecretion of cholesterol. Biliary cholesterol is solubilised by a complex mixture of lipid aggregates (mixed micelles and vesicles), composed of bile salts and phospholipids (mainly phosphatidylcholine = lecithin). If bile contains more cholesterol than can be solubilised by mixed micelles, crystals can precipitate, grow and agglomerate to form macroscopic stones. Furthermore, additional defects have been observed, including gallbladder hypomotility, gallbladder wall inflammation, mucin hypersecretion, and an imbalance of promoter- and inhibitor proteins, all of which contribute to gallstone formation [4].