What Causes Gallstones
Gallstones form when there is an imbalance in bile composition, leading to precipitation of cholesterol, bilirubin, or bacterial degradation products of biliary lipids. 1, 2
Primary Mechanisms by Stone Type
Cholesterol Gallstones (Most Common)
Cholesterol stones represent the predominant entity, accounting for 37-86% of all gallstones, and result from multiple interacting factors 3, 2:
- Biliary supersaturation is the principal pathophysiological defect, originating from the liver through excessive cholesterol secretion and/or deficient secretion of bile salts and lecithin (the solubilizers) 1
- Imbalance in pro- and antinucleating biliary proteins promotes crystal formation 1
- Hypersecretion of gallbladder mucin creates a gel matrix that traps cholesterol crystals, forming "biliary sludge"—an essential stage for stone evolution 1
- Gallbladder dysmotility, possibly from cholesterol "toxicity" to the gallbladder muscle membrane, allows crystals to aggregate rather than being expelled 1, 4
Pigment Stones
Black pigment stones form in sterile gallbladder bile from 1, 4:
- Increased bilirubin concentrations due to chronic hemolysis or altered heme metabolism
- Precipitation of polymerized and oxidatively degraded calcium bilirubinate
- Often contain crystalline calcium carbonate 1
Brown pigment stones develop in infected, obstructed bile ducts from 1:
- Bacterial infection of the biliary tree (most commonly from migrating gallbladder stones)
- Bacterial phospholipase A1 hydrolysis of biliary lecithin, producing calcium fatty acid soaps
- Unpolymerized calcium bilirubinate and calcium phosphate 1
Major Risk Factors
Non-Modifiable Risk Factors
- Female sex due to estrogen and progesterone exposure 3, 2
- Age—by age 75, approximately 35% of women and 20% of men have developed gallstones 5, 6
- Genetic factors—common mutations in hepatic cholesterol transporter ABCG8 confer most genetic risk, accounting for ~25% of total risk 3
Modifiable Risk Factors
- Obesity and overnutrition are strongly associated with cholesterol stone formation 3, 2
- Physical inactivity increases risk 3
- Metabolic syndrome components form the basis for primary prevention through lifestyle changes 3
- Rapid weight loss and low-calorie diets paradoxically increase cholesterol stone formation 2
- Diets high in refined carbohydrates, saturated fat, trans fatty acids, and cholesterol promote stone formation 7, 2
Special Clinical Circumstances
Parenteral nutrition-associated stones 8, 9:
- Nil or negligible oral intake is the most attributable risk factor for biliary sludge and stone formation
- Duration of parenteral nutrition, Crohn's disease, and use of narcotics or anticholinergics further increase risk
- Prevention requires encouraging oral/enteral nutrition as soon as possible 8, 9
Ileal disease or resection 8:
- Disrupts enterohepatic circulation of bile salts
- Particularly high risk with intestinal remnant <180 cm or absent ileocecal junction
Clinical Significance
Most gallstones (approximately 80%) remain asymptomatic throughout life, with only 1-4% developing symptoms annually 6, 3, 2. However, once formed, 10-20% of patients with gallstones will develop complications including acute cholecystitis, acute pancreatitis, common duct obstruction, ascending cholangitis, and gallstone ileus 5, 6.
Critical Pitfall
Even small stones (<4 mm) can cause serious complications including pancreatitis, cholangitis, and biliary obstruction, with 15.9% of conservatively managed patients experiencing adverse outcomes 8. Most common bile duct stones in European populations are secondary stones that originate in the gallbladder and migrate through the cystic duct, accounting for 10-20% of patients with symptomatic gallstones 8.