Intestinal absorption, hepatic synthesis, and biliary secretion of cholesterol: Where are we for cholesterol gallstone formation?

With a 10%-15% prevalence, gallstone disease is one of the most prevalent and costly digestive diseases in Western countries. About two-thirds of gallstones are cholesterol gallstones, while the remaining are pigment stones that contain less than 30% cholesterol. The prevalence of gallstones increases with age and is associated with a number of major risk factors. Overall, cholesterol gallstone disease is deemed as the gallbladder/bile expression of the metabolic syndrome, as it is often associated with obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia. The combination of multiple disturbances affecting cholesterol homeostasis in bile is essential for cholesterol gallstone formation. The interactions of five primary defects result in rapid cholesterol nucleation and crystallization in bile, the key step for gallstone formation1,5: (1) LITH genes and genetic defects; (2) unphysiological sustained supersaturation of bile with cholesterol due to hepatic hypersecretion; (3) enhanced intestinal cholesterol absorption; (4) accelerated phase transitions of cholesterol; and (5) prolonged gallbladder stasis due to disrupted gallbladder motility accompanied with immunomediated gallbladder inflammation, as well as hypersecretion of mucins and accumulation of mucin gel in the gallbladder lumen.1,6,7 Growth of solid, platelikecholesterol monohydrate crystals to form gallstones. is a consequence of persistent hepatic hypersecretion of biliary cholesterol together with enhanced gallbladder mucin secretion and incomplete evacuation by the gallbladder due to its impaired motility function