Cholelithiasis (Gallstones)

Epidemiology

• Affects 10-20% of adults in high-resource countries (western Europe, North America).
• Over 20 million persons in the United States have gallstones, with more than 700,000 cholecystectomies performed annually at a cost of ~$6 billion.
• In the UK, the prevalence at the time of death is estimated at 17%.
• Prevalence among Native Americans (Pima, Hopi, Navajo) approaches 75%.
• Cholesterol stones predominate in the West (90%); pigment stones predominate in parts of Asia (80%).
• 70-80% of patients remain asymptomatic throughout their lives; symptomatic conversion occurs at ~4% per year.

Classification and Types

1. Cholesterol Stones (>50% crystalline cholesterol monohydrate)

• Composition: 50-99% cholesterol, plus calcium salts, bile acids, bile pigments, and phospholipids.
• Appearance: Pale yellow, round to ovoid, hard external surface with a radiating crystalline palisade on cross-section. Multiple stones are typical and may be faceted.
• Radiology: Mostly radiolucent (10-20% have enough calcium carbonate to be radiopaque).
• Form exclusively in the gallbladder.

Fig. Cholesterol gallstones. Note the thickened, fibrotic gallbladder wall from chronic cholecystitis. (Robbins Pathology)

2. Pigment Stones (<30% cholesterol)

• Composed of oxidized polymers of calcium salts of unconjugated bilirubin, calcium carbonate, calcium phosphate, and mucin glycoprotein.
• Found in sterile gallbladder bile.
• Associated with chronic hemolytic anemia (sickle cell disease, hereditary spherocytosis), cirrhosis, and mechanical heart valves.

• Contain calcium bilirubinate, calcium palmitate, calcium stearate, and cholesterol.
• Found in infected bile ducts.
• Related to bile stasis, infection, and deconjugation of bilirubin by bacterial beta-glucuronidase.
• Associated with biliary parasites (Clonorchis sinensis, Ascaris lumbricoides) and bile duct stents.

Fig. Black pigment gallstones from a patient with chronic intravascular hemolysis due to a mechanical mitral valve. (Robbins Pathology)

Risk Factors

Cholesterol Stones

Pigment Stones

Pathogenesis

Cholesterol Stone Formation

1. Supersaturation of bile with cholesterol - when cholesterol concentrations exceed the solubilizing capacity of bile, nucleation into solid cholesterol monohydrate crystals occurs.
2. Gallbladder hypomotility - stasis allows crystal aggregation; removing stones without removing the gallbladder invariably leads to recurrence.
3. Accelerated cholesterol crystal nucleation - from unstable unilamellar phospholipid vesicles.
4. Hypersecretion of gallbladder mucus - traps nucleated crystals, leading to progressive accretion into macroscopic stones.

Pigment Stone Formation

• Bacterial infection of the biliary tree releases microbial beta-glucuronidases, which hydrolyze bilirubin glucuronides (from E. coli, Ascaris, liver flukes).
• Chronic hemolytic anemia increases secretion of conjugated bilirubin; ~1% undergoes spontaneous deconjugation in the biliary tree - enough to precipitate pigment stones over time.

Clinical Features

• Episodic, severe, constant (not truly "colicky") pain in the right upper quadrant or epigastrium.
• Radiates to the right shoulder or back.
• Typically follows a fatty meal that triggers gallbladder contraction against an obstructing stone.
• Episodes last 30 minutes to several hours.

Note: Small stones are more dangerous than large ones because they can migrate into the cystic and common bile ducts. Large stones are more likely to remain in the gallbladder but can erode into adjacent bowel.

Diagnosis

• Ultrasound (first-line): Highly sensitive and specific for gallstones; shows acoustic shadowing. Also detects wall thickening, pericholecystic fluid, and dilated ducts. It is the investigation of choice in pregnancy.
• Plain X-ray: Only 10-20% of cholesterol stones are radiopaque; 50% of pigment stones are radiopaque.
• CT scan: Detects complications (perforation, abscess, pancreatitis) but less sensitive than US for gallstones themselves.
• MRCP (MR cholangiopancreatography): Best non-invasive modality for bile duct stones (choledocholithiasis).
• ERCP: Both diagnostic and therapeutic for common bile duct stones.
• Labs: In uncomplicated cholelithiasis, labs are normal. Elevated bilirubin, ALP, and GGT suggest ductal obstruction; elevated amylase/lipase suggest pancreatitis.

Management

Asymptomatic Cholelithiasis

• Generally watchful waiting is appropriate; prophylactic cholecystectomy is not routinely indicated.
• Exceptions: patients undergoing bariatric surgery, immunocompromised patients, or those with porcelain gallbladder.

Symptomatic Cholelithiasis

• Laparoscopic cholecystectomy is the gold standard - it definitively treats the disease and prevents recurrence.
• Removing stones alone (without the gallbladder) leads to inevitable recurrence because the underlying defect in bile composition and gallbladder motility persists.

Special Considerations

• Pregnancy: Laparoscopic cholecystectomy is preferred in the first or second trimester for symptomatic disease; associated with lower fetal and maternal complications than the open approach. Gallstone pancreatitis in pregnancy carries a maternal mortality of 15% and fetal mortality of 60%, strongly supporting surgical intervention.
• Bariatric surgery: Rapid weight loss after RYGB carries a ~30% risk of new gallstone formation. Prophylactic ursodiol 300-400 mg twice daily for 6 months reduces this to ~4%. Synchronous cholecystectomy is recommended for those with existing biliary pathology.
• Non-surgical options: Ursodeoxycholic acid (UDCA) can dissolve small cholesterol stones in selected patients but requires months of therapy and stones recur when stopped. Rarely used today given the safety of laparoscopic surgery.

Summary Table

• Cholesterol stones (left, yellow) - the dominant type in Western countries, driven by bile supersaturation, obesity, hormonal factors, and gallbladder stasis.
• Black pigment stones (center, dark) - sterile gallbladder bile, linked to hemolytic conditions and cirrhosis.
• Brown pigment stones (right, brown) - infected bile ducts, associated with bacterial beta-glucuronidase activity and biliary parasites.