Pathogenesis of cholesterol gallstones

Abstract

Symptomatic cholesterol gallstone disease occurs because of the combination of a number of biochemical and physiologic defects: formation of supersaturated bile, nucleation, crystal retention, stone growth, and gallbladder inflammation. There are several possible explanations for the high prevalence of supersaturated bile in the Western adult human as compared to other adult mammals. First, the human liver is defective in converting cholesterol to bile acids; the majority of cholesterol is eliminated as cholesterol. Second, the large flux of cholesterol in vesicular form is not matched by a large flux of recycling bile acids. Third, humans live sedentary lives and voluntarily reduce their caloric requirement to prevent obesity. Low caloric intake decreases the circulation of bile acids (including the flux through the hepatocyte). Fourth, the human species is a defective bile secretor in terms of biliary volume (microliter/kg-min) compared to other mammals. This is because human enterohepatic circulation of bile acids is "sluggish" and because bile acid-independent flow is also lower than in all other mammals. The accumulation of deoxycholic acid, a secondary bile acid formed in the colon, appears to cause secretion of bile that is supersaturated in cholesterol, and may also contribute. Five additional risk factors explain why cholesterol gallstone disease is so prevalent. First, the human species has a gallbladder, and the irregular meal pattern of humans may be responsible for prolonged storage of bile. Second, bile from cholesterol gallstone patients nucleates cholesterol more rapidly. Third, defective gallbladder contraction is associated with cholesterol gallstone disease in the majority of gallstone patients. Fourth, the healthy gallbladder absorbs cholesterol and desaturates bile--protective functions that may be lost with chronic cholecystitis. Finally, the presence of gallstones stimulates mucous secretion, which traps cholesterol crystals.