How Gallstones Form
Pathophysiologic Mechanisms
Gallstones form when there is an imbalance in the composition of bile, resulting in precipitation of one or more of its components. 1 This fundamental disturbance leads to two main types of stones based on their composition.
Cholesterol Gallstone Formation
The formation of cholesterol gallstones requires three key abnormalities working in concert:
Supersaturation of bile with cholesterol occurs primarily from hepatic hypersecretion of cholesterol into bile, creating an unphysiologic state where cholesterol exceeds the solubilizing capacity of bile salts and phospholipids 2
Accelerated nucleation allows cholesterol crystals to form and aggregate rather than remaining in solution 2
Impaired gallbladder motility prevents the expulsion of cholesterol crystals, allowing them to nucleate and grow into stones 3
Accumulation of mucin gel in the gallbladder provides a scaffolding matrix that traps cholesterol crystals and promotes stone growth 2
Cholesterol-rich stones represent 37-86% of all gallstones and are more common in Europe and North America, attributed to obesity and diets high in refined carbohydrates and fat 1
Pigment Stone Formation
Pigment stones form through a different mechanism involving bilirubin metabolism:
Black pigment stones develop from supersaturation of bile with calcium hydrogen bilirubinate (the acid calcium salt of unconjugated bilirubin), along with deposition of calcium carbonate and calcium phosphate 2
Black pigment stones are caused by hepatic hypersecretion of bilirubin conjugates in chronic hemolytic disorders, or possibly enterohepatic cycling of unconjugated bilirubin in nonhemolytic states 2
Brown pigment stones form in obstructed and infected bile ducts due to bacterial enzymatic hydrolysis of biliary lipids, resulting in precipitation of calcium hydrogen bilirubinate (which remains unpolymerized), calcium salts of saturated fatty acids, and free bile acids 4, 2
Bile salt deficiency from impaired synthesis or interrupted enterohepatic circulation causes incomplete solubilization of unconjugated bilirubin and impaired calcium ion binding, promoting pigment stone formation 2
Special Circumstances
Disruption of enterohepatic circulation increases stone formation risk in patients with ileal disease or resection, particularly when intestinal remnant is <180 cm or the ileocecal junction is absent 5
Parenteral nutrition-associated stones form primarily due to nil or negligible oral intake, which is the most attributable risk factor for biliary sludge and stone formation, with duration of parenteral nutrition, Crohn's disease, and use of narcotics or anticholinergics further increasing risk 5
Stone Migration and Secondary Complications
Most bile duct stones in European populations are secondary stones that originate in the gallbladder and migrate through the cystic duct into the common bile duct, accounting for 10-20% of patients with symptomatic gallstones 5
The presence of multiple small (<5 mm) gallstones in the gallbladder creates a 4-fold risk for migration into the common bile duct 6
Clinical 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 5 This underscores that stone size does not predict clinical significance.