From the Guidelines
Gallstones form when substances in bile, primarily cholesterol or bilirubin, harden into solid deposits within the gallbladder, with most gallstones (about 80%) developing from excess cholesterol in bile, as supported by the American College of Physicians guidelines 1.
Formation of Gallstones
The formation of gallstones is a complex process that involves the concentration of bile and the precipitation of cholesterol or bilirubin crystals.
- The liver produces bile, which is stored in the gallbladder and concentrated between meals.
- When the liver produces more cholesterol than the bile can dissolve, or when the gallbladder doesn't empty properly, cholesterol can crystallize and form stones.
- Pigment stones, the second type, form when there's excess bilirubin in bile, often due to liver disease, biliary tract infections, or blood disorders.
Risk Factors
Several risk factors contribute to the development of gallstones, including:
- Being female, over 40, overweight
- Having certain medical conditions like diabetes or liver disease
- Rapid weight loss, fasting, pregnancy, and genetic predisposition
Clinical Implications
The gallbladder concentrates bile between meals, creating an environment where substances can precipitate and form crystals that gradually grow into stones over months or years.
- Gallstones can range from tiny grains to golf ball-sized formations and may cause no symptoms until they block bile ducts, leading to pain, inflammation, and potential complications, as noted in the guidelines for the treatment of gallstones 1.
- The most recent and highest quality study on the management of common bile duct stones, published in 2017, provides updated guidance on the diagnosis and treatment of gallstone disease, but does not directly address the formation of gallstones 1.
- Another recent study, published in 2019, provides guidelines on the management of acute cholecystitis in the elderly population, but also does not directly address the formation of gallstones 1. Therefore, based on the strongest and most recent evidence, gallstones form through the concentration of bile and the precipitation of cholesterol or bilirubin crystals, with risk factors including being female, over 40, overweight, and having certain medical conditions.
From the FDA Drug Label
Although insoluble in aqueous media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxy bile acids. The overall effect of ursodiol is to increase the concentration level at which saturation of cholesterol occurs The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterol-solubilizing, thus resulting in bile conducive to cholesterol stone dissolution.
The formation of gallstones is related to the saturation of cholesterol in bile. Normally, bile is able to solubilize cholesterol, but when the concentration of cholesterol exceeds the capacity of bile to solubilize it, cholesterol can precipitate out of solution and form stones. Ursodiol works by increasing the concentration level at which saturation of cholesterol occurs, making it more difficult for cholesterol to precipitate out of solution and form stones. However, the exact mechanism of gallstone formation is not directly addressed in the provided text. 2 2
From the Research
Formation of Gallstones
Gallstones form when there is an imbalance in the composition of bile, resulting in the precipitation of one or more of its components 3. The main types of gallstones are:
- Cholesterol-rich stones (37-86% of cases)
- Pigment stones (2-27% of cases)
- Mixed stones (4-16% of cases)
Factors Contributing to Gallstone Formation
Several factors contribute to the formation of gallstones, including:
- Metabolic alterations in hepatic cholesterol secretion
- Changes in gallbladder motility
- Intestinal bacterial degradation of bile salts
- Imbalance in pro- and antinucleating biliary proteins
- Hypersecretion of gallbladder mucin
- Gallbladder dysmotility
Role of Diet and Nutrition
Dietary factors can influence the risk of developing cholesterol gallstones, with:
- High intake of cholesterol, saturated fat, trans fatty acids, and refined sugar increasing the risk
- High intake of polyunsaturated fat, monounsaturated fat, fiber, and caffeine potentially reducing the risk
- Obesity also being a risk factor for gallstones 4
Pathogenesis of Gallstones
The pathogenesis of gallstones involves:
- Biliary supersaturation, which is hepatic in origin
- Excessive secretion of cholesterol or bilirubin conjugates
- Deficient secretion of bile salt and lecithin
- Crystallization of cholesterol crystals or bilirubinate salts in gallbladder mucin gel, resulting in "biliary sludge" 5
- Nucleation and growth of gallstones, which can be influenced by various factors, including diet, nutrition, and gallbladder motility 6