Gallstone disease - Pathogenesis

Composition of bile

In bile, cholesterol is present in a free, non-esterified form. Its concentration does not depend on the serum cholesterol level. It is slightly affected by the pool of bile acids and the rate of their secretion.

Bile phospholipidsare insoluble in water and include lecithin (90%) and a small amount of lysolecithin (3%) and phosphatidylethanolamine (1%). Phospholipids are hydrolyzed in the intestine and are not involved in enterohepatic circulation. Bile acids regulate their excretion and stimulate synthesis. Bile acidsare trihydroxycholic and dihydroxychenodeoxycholic acids. They bind with glycine and taurine and, under the influence of intestinal microflora, are decomposed into secondary bile acids - deoxycholic and lithocholic. Cholic, chenocholic and deoxycholic acids are absorbed and undergo enterohepatic circulation (up to 6-10 times a day). Lithocholic acid is poorly absorbed, therefore it is present in bile in small quantities. The pool of bile acids is normally 2.5 g, and the daily production of cholic and chenodeoxycholic acids is on average about 330 and 280 mg, respectively.

Regulation of bile acid synthesis is complex and may occur via a negative feedback mechanism with the amount of bile salts and cholesterol entering the liver from the intestine. Bile acid synthesis is suppressed by the intake of their salts and is enhanced by interruption of enterohepatic circulation.

Factors influencing the formation of cholesterol stones:

The formation of cholesterol stones is influenced by three main factors: supersaturation of liver bile with cholesterol, precipitation of cholesterol monohydrate in the form of crystals and dysfunction of the gallbladder.

Changes in the composition of liver bile

Bile is 85-95% water. Cholesterol, which is insoluble in water and is normally dissolved in bile, is secreted by the canalicular membrane in the form of single-layer phospholipid vesicles. In liver bile, which is not saturated with cholesterol and contains a sufficient amount of bile acids, the vesicles dissolve to form 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 the micelles, their growth occurs. These mixed micelles are able to retain cholesterol in a thermodynamically stable state. This state is characterized by a low cholesterol saturation index, which is calculated from the molar ratio of cholesterol, bile acids and phospholipids.

At a high cholesterol saturation index (with bile oversaturation with cholesterol or a decrease in the concentration of bile acids), cholesterol cannot be transported in the form of mixed micelles. Its excess is transported in phospholipid vesicles, which are unstable and can aggregate. In this case, large multilayer vesicles are formed, from which cholesterol monohydrate crystals precipitate.

The process of aggregation and fusion of bubbles and the factors influencing it and cholesterol crystallization remain unclear. The importance of these processes is emphasized by the fact that the necessary condition for the formation of gallstones - oversaturation of bile with cholesterol - is not the only link in pathogenesis. Bile is often oversaturated with cholesterol even in the absence of cholesterol stones.

However, in Western countries, almost all patients with cholelithiasis have bile cholesterol oversaturation due to an increase in the cholesterol/bile acid ratio. In most patients, the main disorder is a decrease in bile acid secretion 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 reducing the saturation of bile with cholesterol, also increases the sedimentation time, which can be used to prevent recurrence of gallstone disease.

Bilirubin is located in the center of cholesterol stones, which allows us to think about the possibility of the deposition of cholesterol crystals in the gallbladder on protein-pigment complexes.

Precipitation of cholesterol

Precipitation of cholesterol monohydrate crystals from multilayered vesicles is a key link in the formation of gallstones. The ability of bile to activate or suppress precipitation plays a greater role than its supersaturation with cholesterol. The time required for precipitation (precipitation time) in patients with gallstones is significantly less than that in the absence of gallstones, and with multiple stones it is less than with single stones. The interaction of factors leading to cholesterol precipitation is complex. Lithogenic bile has an increased protein concentration.

Proteins that accelerate sedimentation (pronucleators) include gallbladder mucin, N-aminopeptidase, acidic ot1-glycoprotein, immunoglobulin, and phospholipase C. Aspirin reduces mucus production by the gallbladder, so it, like other nonsteroidal anti-inflammatory drugs, inhibits the formation of gallstones.

Factors that slow down 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 calcium ion concentration in stone formation in vivo remains to be established.

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