Main Cause of Gallbladder Stones
The primary mechanism underlying gallstone formation is supersaturation of bile with cholesterol (for cholesterol stones) or unconjugated bilirubin (for pigment stones), resulting from an imbalance between excessive secretion of these insoluble lipids and deficient secretion of their solubilizers (bile salts and lecithin). 1, 2
Pathophysiologic Mechanisms by Stone Type
Cholesterol Stones (Most Common)
Cholesterol stones develop through a three-stage process:
- Hepatic oversecretion of cholesterol into bile creates supersaturation, which is the fundamental metabolic defect originating in the liver 1, 3
- Deficient bile salt and lecithin secretion reduces the solubilizing capacity needed to keep cholesterol in solution 1, 4
- Gallbladder dysfunction including hypomotility and hypersecretion of mucin glycoprotein promotes nucleation and crystal aggregation 1, 2
The progression requires an imbalance between pro-nucleating and anti-nucleating biliary proteins, with gallbladder mucin gel trapping cholesterol crystals to form "biliary sludge"—an essential precursor stage before macroscopic stone formation 1, 2
Pigment Stones (Two Subtypes)
Black pigment stones:
- Form in sterile gallbladder bile from polymerized and oxidatively degraded calcium bilirubinate 1, 2
- Result from increased unconjugated bilirubin concentrations due to altered heme metabolism or enhanced bilirubin absorption 4
Brown pigment stones:
- Form in infected bile, primarily in bile ducts rather than the gallbladder 1, 2
- Contain unpolymerized calcium bilirubinate plus calcium fatty acid soaps from bacterial phospholipase degradation of lecithin 1
- Most commonly develop secondary to biliary obstruction from migrating gallbladder stones, accounting for 10-20% of symptomatic gallstone cases in European populations 5
Contributing Risk Factors
Metabolic factors that increase cholesterol secretion:
- Obesity and dietary factors leading to absolute increases in biliary cholesterol 3, 6
- Medications including corticosteroids and oral contraceptives containing steroid hormones 6
Disrupted enterohepatic circulation:
- Ileal disease or resection (particularly with intestinal remnant <180 cm or absent ileocecal junction) impairs bile salt reabsorption 5
- Excessive bile salt pool loss decreases cholesterol solubilization capacity 3
Gallbladder factors:
- Stasis and hypomotility, possibly from cholesterol "toxicity" to sarcolemma 1
- Increased fluid absorption and mucus glycoprotein secretion (potentially mediated by prostaglandin production) 2, 3
Parenteral nutrition:
- Nil or negligible oral intake is the most attributable risk factor for biliary sludge and stone formation, with duration of parenteral nutrition, Crohn's disease, and narcotics/anticholinergics further increasing risk 5
Clinical Implications
Biliary sludge represents the critical intermediate stage between supersaturated bile and macroscopic stones, comprising cholesterol monohydrate crystals, glycoproteins, and calcium bilirubinate granules suspended in mucin gel 1, 2
Even small stones (<4 mm) pose serious risks, with 15.9% of conservatively managed patients experiencing adverse outcomes including pancreatitis, cholangitis, and biliary obstruction 5
Migration of gallbladder stones into the common bile duct causes up to 50% of acute biliary pancreatitis cases through pancreatic duct obstruction, with particularly high migration risk during acute episodes 5