From the Guidelines
Gallstones form due to imbalances in bile composition, leading to stone formation in the gallbladder, primarily through cholesterol supersaturation, gallbladder hypomotility, and accelerated nucleation. The pathophysiology of cholelithiasis involves several key mechanisms. Most gallstones are cholesterol stones that form when the liver secretes bile containing more cholesterol than can be dissolved by bile salts and phospholipids, creating a supersaturated solution. This excess cholesterol precipitates as crystals. Gallbladder hypomotility, often seen during pregnancy, rapid weight loss, or with certain medications, allows these crystals to remain in the gallbladder longer, promoting stone growth. Nucleation accelerators, such as mucin glycoproteins and calcium bilirubinate, facilitate crystal aggregation.
Some studies suggest that genetic disorders, such as those discussed in the EASL clinical practice guidelines 1, may also play a role in gallstone formation, particularly in individuals with a predisposition for elevated serum liver tests and increased risk of hepatobiliary malignancies. However, the exact mechanisms by which these genetic disorders contribute to gallstone formation are not fully understood.
Key factors that contribute to gallstone formation include:
- Cholesterol supersaturation
- Gallbladder hypomotility
- Accelerated nucleation
- Genetic predisposition
- Demographic associations, such as female gender, obesity, and rapid weight loss. Understanding the pathophysiology of cholelithiasis is crucial for developing effective prevention and treatment strategies, such as the use of ursodeoxycholic acid to increase cholesterol solubility and prevent stone formation in high-risk patients.
From the Research
Pathophysiology of Cholelithiasis (Gallstone) Formation
The formation of gallstones, also known as cholelithiasis, is a complex process involving multiple factors. The key factors include:
- Supersaturation of bile with cholesterol 2, 3, 4
- Rapid nucleation of cholesterol crystals 2, 5
- Incomplete emptying of the gallbladder 2, 6
- Imbalance between pro-nucleating and nucleation inhibiting proteins 3, 4
- Hypersecretion of gallbladder mucin 5, 4
- Gallbladder dysmotility 6, 4
Role of Bile Supersaturation
Bile supersaturation is the principal pathophysiological defect and is hepatic in origin 4. It results from excessive secretion of cholesterol or bilirubin conjugates, and/or deficient secretion of bile salt and lecithin, the solubilizers of these otherwise insoluble lipids 4.
Nucleation of Cholesterol Crystals
The nucleation of cholesterol crystals is accelerated by human gallbladder mucin 5. The concentration of human gallbladder mucin and the time of incubation affect the number of cholesterol crystals formed 5. An imbalance in pro- and antinucleating biliary proteins also promotes nucleation 3, 4.
Gallbladder Motility and Function
Gallbladder motility and function play a crucial role in the formation of gallstones 2, 6. Incomplete emptying of the gallbladder and gallbladder dysmotility can lead to the retention of microstones, which then grow to macroscopic gallstones 6. The odds for stone recurrence are increased in the presence of excessive deoxycholic acid or incomplete emptying of the gallbladder 2.