Gallstone disease: pathogenesis
Last reviewed: 23.04.2024
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Composition of bile
In bile, cholesterol is present in a free, non-esterified form. Its concentration does not depend on the level of cholesterol in the serum. To a small extent, it is affected by a pool of bile acids and the rate of their secretion.
Phospholipids bile are insoluble in water and include lecithin (90%) and a small amount of lysolecithin (3%) and phosphatidylethanolamine (1%). Phospholipids hydrolyse in the intestine and are not involved in enterohepatic circulation. The bile acids regulate their excretion and stimulate the synthesis. Bile acids are trihydroxycholic and dihydroxychine deoxycholic acid. They bind to glycine and taurine and, under the action of the intestinal microflora, decompose to secondary bile acids - deoxycholic and lithocholic. Cholate, henocholic and desoxycholic acid are absorbed and subjected to enterohepatic circulation (up to 6-10 times a day). Lithocholic acid is not absorbed badly, therefore in bile is present in a small amount. The bile acid pool is 2.5 g in norm, and the daily production of cholic and chenodeoxycholic acids is about 330 and 280 mg, respectively.
The regulation of the synthesis of bile acids is complex and, possibly, occurs by the mechanism of negative feedback with the amount of bile salts and cholesterol that enter the liver from the intestine. The synthesis of bile acids is inhibited by the intake of their salts and is enhanced by the interruption of enterohepatic circulation.
Factors affecting the formation of cholesterol stones:
The formation of cholesterol stones is affected by three main factors: gluten cholesterol supersaturation, precipitation of cholesterol monohydrate in the form of crystals and a violation of the function of the gallbladder.
Change in the composition of the hepatic bile
The bile is 85-95% water. Cholesterol, which is insoluble in water and is normally found in bile in a dissolved state, is secreted by the tubular membrane in the form of single-layer phospholipid vesicles. In the liver bile, not saturated with cholesterol and containing a sufficient amount of bile acids, the vesicles dissolve to lipid micelles with a mixed composition. The latter have a hydrophilic outer surface and a hydrophobic inner surface containing cholesterol. With the inclusion of phospholipids in the walls of micelles, their growth occurs. These mixed micelles are able to keep cholesterol in a thermodynamically stable state. This state is characterized by a low saturation index with cholesterol, which is calculated from the molar ratio of cholesterol, bile acids and phospholipids.
With a high saturation index of cholesterol (with bile cholesterol supersaturation or a decrease in the concentration of bile acids), cholesterol can not be transported as mixed micelles. Its excess is transported in phospholipid vesicles, which are unstable and can be aggregated. In this case, large multilayer vesicles are formed, of which crystals of cholesterol monohydrate are precipitated.
The process of aggregation and fusion of bubbles and factors affecting it and the crystallization of cholesterol remain unclarified. The importance of these processes is underscored by the fact that the necessary condition for the occurrence of gallstones - glut of bile cholesterol - is not the only link in pathogenesis. Bile is often oversaturated with cholesterol and in the absence of cholesterol stones.
Nevertheless, in Western countries, almost all patients with cholelithiasis have a glut of bile cholesterol due to an increase in the ratio of cholesterol / bile acids. In most patients, the main disturbance is a decrease in the secretion of bile acids by the liver, which is caused by a decrease in their total pool. More intensive enterohepatic circulation of bile acids suppresses their synthesis.
Ursodeoxycholic acid, as well as a decrease in the saturation of bile cholesterol, also increases the deposition time, which can be used to prevent recurrence of cholelithiasis.
In the center of cholesterol stones is bilirubin, which allows us to think about the possibility of precipitation of cholesterol crystals in the gall bladder to protein-pigment complexes.
Precipitation of cholesterol
The precipitation of crystals of cholesterol monohydrate from multilayer vesicles is the key link in the formation of gallstones. In this case, the ability of bile to activate or suppress deposition plays a greater role than its oversaturation with cholesterol. The time required for precipitation (deposition time) in patients with gallstones is much less than that in the absence of gallstones, and for multiple concrements it is less than for solitary ones. Interaction of factors leading to the precipitation of cholesterol is complex. In the lithogenic bile, the concentration of protein is increased.
The proteins that accelerate precipitation (pronucleators) include mucin of the gallbladder, N-aminopeptidase, acid ot1-glycoprotein, immunoglobulin and phospholipase C. Aspirin reduces the production of mucus by the gallbladder, so it, like other non-steroidal anti-inflammatory drugs, inhibits the formation of gallstones.
Factors that slow precipitation (inhibitors) include apolipoproteins AI and A2 and a glycoprotein with a molecular weight of 120 kDa. The role of the interaction of pH and concentration of calcium ions in the formation of stones in vivo has yet to be established.
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