What Causes Gallstones?
Gallstones form when there is an imbalance in the composition of bile, resulting in precipitation of one or more of its components—primarily cholesterol supersaturation, but also bilirubin and other bile constituents. 1
Primary Mechanisms of Gallstone Formation
Cholesterol Gallstones (Most Common Type)
Cholesterol gallstones develop when bile becomes supersaturated with cholesterol due to increased hepatic cholesterol synthesis and secretion into bile. 2 This represents 37-86% of all gallstones and is the predominant type in Europe and North America. 1
The key pathophysiologic mechanisms include:
- Increased cholesterol secretion by the liver into bile, exceeding the solubilizing capacity of bile acids and phospholipids 2
- Decreased bile acid synthesis or secretion, reducing the ability to keep cholesterol in solution 2
- Impaired gallbladder motility, allowing cholesterol crystals to nucleate and grow rather than being expelled 3
Pigment Stones (Less Common)
Black pigment stones form due to chronic hemolysis, which increases unconjugated bilirubin in bile that precipitates as calcium bilirubinate. 4
Brown pigment stones typically develop in obstructed and infected bile ducts, where bacterial enzymes deconjugate bilirubin. 4
Major Risk Factors
Non-Modifiable Risk Factors
- Female sex: Women have higher prevalence due to estrogen and progesterone exposure, which increases cholesterol secretion and decreases gallbladder motility 1, 3
- Age: Gallstone disease increases progressively with age 3, 1
- Genetics: Common mutations in the hepatic cholesterol transporter ABCG8 (particularly the p.D19H variant) confer approximately 25% of total gallstone risk 4, 5
- Pregnancy: Hormonal changes lead to decreased gallbladder motility and lithogenic bile 3
Modifiable Risk Factors
Obesity is a major risk factor, with those having the highest body mass index showing 5-6 times increased relative risk. 6 This is attributed to:
- Increased hepatic cholesterol synthesis and secretion 6
- Diets high in refined carbohydrates and saturated fat 1, 7
Rapid weight loss paradoxically increases gallstone risk, with new stone formation occurring in 10-12% after 8-16 weeks of low-calorie diet and >30% within 12-18 months after gastric bypass surgery. 6 Risk factors during weight loss include:
- Weight loss >24% of initial body weight 6
- Rate of weight loss >1.5 kg per week 6
- Very low-calorie diets with no fat 6
- Long overnight fasting periods 6
Physical inactivity and metabolic syndrome components increase gallstone risk. 4
Specific Medical Conditions
- Chronic liver disease and cirrhosis are associated with pigment stone formation 3
- Chronic hemolytic conditions (e.g., sickle cell disease) cause black pigment stones 4
- Primary sclerosing cholangitis increases risk of cholangiocarcinoma and gallbladder cancer 3
- Inflammatory bowel disease is associated with increased gallstone risk 3
Genetic Disorders
Low phospholipid-associated cholelithiasis syndrome results from loss-of-function mutations in the ABCB4 transporter, causing low phosphatidylcholine concentrations in bile. 5 This represents a smaller subset of patients with primarily genetic gallstone disease. 5
ABCB11 (BSEP) mutations can cause progressive familial intrahepatic cholestasis with associated gallstone formation. 3
Clinical Implications
Approximately 80% of patients with gallstones remain asymptomatic throughout their lifetime, with only 1-4% developing symptoms annually. 1, 8 The likelihood of developing symptoms actually diminishes over time in those who remain asymptomatic. 1
Common Pitfalls to Avoid
- Do not attribute non-specific symptoms like belching, bloating, fatty food intolerance, or chronic pain to gallstones—these are NOT caused by gallstone disease itself 9
- Recognize that stone recurrence is common: Up to 50% of patients experience stone recurrence within 5 years after medical dissolution therapy with ursodiol 2
- Understand that calcified stones and stones >20 mm rarely dissolve with medical therapy and require surgical management 2