Gallstone disease pathophysiology

Studies have shown that gallstone formation is mostly due to bile supersaturation. In the United States, patients that present with gallbladder stones mostly have cholesterol stones. Cholesterol stones form when the concentration of cholesterol in the bile is much higher than the concentration of cholesterol that can be dissolved in the bile. Normally cholesterol is metabolized in the body and excess cholesterol is disposed of in the bile. There is a balance between pronucleating (crystallization-promoting) and antinucleating (crystallization-inhibiting) forces, so that gallstones don’t form. When pronucleating forces take the upper hand, gallstones will form. On the other hand, moderate intake of wine and the consumption of whole grain bread may decrease the risk of developing gallstones.

• The most common type of gallstone is a cholesterol stone.^{[1][2][3][4][5]}
• When pronucleating proteins are present, such as mucin, the bile becomes hypersaturated with cholesterol and cholesterol stones form.
• Gallstone disease can also be caused by a lack of motility in the muscular wall of the gallbladder or excessive sphincter contraction, that prevents bile secretion.
• In this way the bile stagnates within the gallbladder and promotes the formation of stones.

• Cholesterol stones are the most common type of gallstone.
• The quantity of cholesterol is balanced within the body.
• Cholesterol is an important organic molecule that is needed for incorporation within cell membranes and to produce steroid hormones in the body.

• Less commonly, gallstones can be composed of bilirubin and are sometimes referred to as “pigment stones”.^[8]
• Bilirubin is a byproduct of red blood cell breakdown and so are usually found in patients with hemoglobin disorders.
• Pigment stones are formed via two main pathways:
  • Infection of the biliary tree with bacteria that can release hydrolytic enzymes and form insoluble calcium salts.
  • Non-bacterial, non-enzymatic hydrolysis of bilirubin conjugates such as what may happen in patients with Gilbert’s syndrome and chronic hemolysis.

• There is a lack of evidence that supports a true pathology to explain how mixed stones are formed.^[2]
• However, there have been theories that include a combination of several mechanisms including supersaturation, infection and hypomotility of the gall bladder.

The conditions associated with gallstone disease include:^[9][10]

• Diabetes mellitus type 2
• Obesity
• Pregnancy
• Gallbladder cancer
• Gallbladder polyps
• Primary sclerosing cholangitis
• Porcelain gallbladder
• Rapid weight loss
• Constipation
• Eating fewer meals
• Low intake of:
  • Fish
  • Magnesium
  • Folate
  • Whole grain bread
  • Fiber
  • Vitamin C

• On gross pathology, commonly multiple small stones are found and less commonly a solitary stone is seen.^[11]

• On microscopic analysis, characteristic findings include:^[12]
  • Transmural thickening of the gall bladder wall
  • Neutrophilia

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