Pathogenesis of cholesterol stones in the gallbladder

Abstract

SummaryThe secretion by the liver of bile saturated with cholesterol is the first stage in the development of cholesterol stones in the gallbladder. Biliary cholesterol is derived mainly from lipoprotein cholesterol, which is transported to the liver by chylomicron remnants, low-density and high-density lipoproteins. Oestrogens stimulate the uptake and catabolism of low-density lipoproteins in the liver.Newly synthetized cholesterol contributes less to biliary excretion. Insulin may increase gallstone formation by increasing the activity of the rate-limiting enzyme in the synthesis of cholesterol in the liver.Cholesterol is virtually insoluble in water and is held in solution in bile by its association with bile salts and phospholipids. An increased cholesterol secretion into bile can predispose to saturation and gallstone formation in obesity, on high-caloric diet, on weightreduction diet, in hypcrtriglyceridaemia, and by the effects of insulin, oestrogens and clofibrate therapy.Plasma low-density lipoprotein cholesterol is positively correlated with bile cholesterol saturation whereas high-density lipoprotein cholesterol shows an inverse relation.A reduced total body pool and biliary secretion of bile salts may also be responsible for gallstone formation. A low bile salt secretion may result from an excessive intestinal loss of bile salts, from an impaired hepatic bile acid synthesis or from a rapid bile salt circulation within the enterohepatic circulation with normal feedback inhibition of synthesis.Supersaturation of bile with cholesterol not only occurs in patients with cholesterol gallstones but is also quite common in normal individuals. Gallstone patients and normal persons can be discriminated by the presence of cholesterol crystals in bile and by a difference of the in vitro nucleation time. The in vitro nucleation time of gallbladder bile of gallstone patients is more rapid than that of controls. A potent nucleating factor may be added to gallbladder bile in patients with cholesterol gallstones or an inhibitor of cholesterol crystal nucleation might be present in bile from normal persons.An impaired gallbladder emptying with stasis of bile may contribute to gallstone formation in patients on total parenteral nutrition, in pregnancy and during oral contraceptive therapy.