A review of ursodeoxycholic acid therapy for cholelithiasis and choledocholithiasis

Gallstone disease is highly prevalent, and over 20% of patients develop symptoms. Laparoscopic cholecystectomy is standard for symptomatic disease, but non-surgical candidates may receive ursodeoxycholic acid (UDCA) or extracorporeal shock wave lithotripsy (ESWL). UDCA lowers biliary cholesterol saturation and dissolves small, cholesterol-rich stones. It is well tolerated but limited by high recurrence. This review summarizes evidence on UDCA in cholelithiasis and choledocholithiasis.

Introduction

Cholelithiasis causes biliary colic and cholecystitis; choledocholithiasis can lead to cholangitis and pancreatitis. Over 75% of stones are cholesterol stones. Cholecystectomy is the gold standard for symptomatic gallbladder stones; ERCP with sphincterotomy is used for CBD stones. Older and comorbid patients often favor non-operative management. Non-surgical options include UDCA and ESWL, with success rates of 25–60% but high recurrence. This review focuses on UDCA rather than chenodeoxycholic acid (CDCA), which has poorer tolerability.

Mechanism of Action

UDCA is a hydrophilic secondary bile acid. It decreases cholesterol secretion into bile by ~40–60%, enriches the bile pool with hydrophilic components, displaces toxic hydrophobic bile acids, has immunomodulatory and anti-apoptotic effects, limits reactive oxygen species, and has a choleretic effect. It may also improve gallbladder motility.

Indications

UDCA is used for symptomatic gallstones, biliary sludge, post-cholecystectomy syndrome, and as treatment of choice for primary biliary cholangitis (PBC), intrahepatic cholestasis of pregnancy (ICP), primary sclerosing cholangitis (PSC), cystic fibrosis, and familial cholestatic diseases.

Efficacy in Cholelithiasis

Best evidence supports radiolucent, non-calcified stones <20 mm, especially in poor surgical candidates. Stone size and composition are the key determinants. A 1993 meta-analysis found complete dissolution with high-dose UDCA (>7 mg/kg/day) in 37.3%. Isodense (cholesterol-rich) stones on CT had an 87.1% response versus 6.2% for hyperdense/calcified stones. Complete dissolution occurred in 81% of stones ≤5 mm; stones >20 mm rarely dissolve. Lack of partial dissolution by 6–12 months predicts poor response.

UDCA with Endoscopic Treatment for Choledocholithiasis

Combined with endoscopic stenting, UDCA reduces the size of large and multiple CBD stones. In elderly patients with difficult stones, a plastic stent plus UDCA 600 mg and terpene 300 mg daily for six months enabled complete removal in 92.8%.

Recurrent Stone Disease

A Japanese trial suggested UDCA may lower CBD stone recurrence (6.6% vs. 18.6%), but significance was not achieved. Recent Korean data indicate UDCA monotherapy (12.7%) or CDCA plus terpene (9.8%) significantly reduced recurrence versus no medication (41.5%); triple therapy achieved 5.2%.

Efficacy in Different Populations

• Pediatric cholestasis: Meta-analysis of 32 RCTs found improved symptoms and biochemical markers with favorable safety.

• Pediatric cholelithiasis: Evidence limited; possible benefit in very young children, small (<5 mm) solitary or ceftriaxone-associated stones, or biliary sludge.

• Pregnancy: Used for ICP. The 2019 PITCHES trial found no significant difference in adverse perinatal outcomes; rationale has shifted to maternal symptom relief. Not recommended for gallstone disease in pregnancy or lactation.

• Sickle cell disease: Not indicated due to pigment stones.

• Post-bariatric surgery: 500–600 mg/day for six months reduces gallstone formation.

• LPAC syndrome and PFIC type 3: UDCA may alleviate symptoms and reduce recurrence.

Dosage and Administration

UDCA is orally administered with meals. Absorption is decreased in cholestasis, requiring higher doses. Co-administration with activated charcoal, aluminum antacids, high-dose calcium, or bile acid sequestrants can reduce absorption; separate by 2–6 hours. Standard dosing for gallstone dissolution is 8–10 mg/kg/day in 2–3 divided doses for up to 2 years with ultrasound every 6 months; prevention during rapid weight loss uses 600 mg twice daily.

Safety and Adverse Effects

UDCA is well tolerated. Diarrhea is most frequent. Less common effects include right upper quadrant pain, rash, and pruritus. It is safe in end-stage renal disease but not recommended in early pregnancy or lactation and is relatively contraindicated in complete biliary obstruction. Long-term high-dose UDCA and colorectal cancer risk remains uncertain; a 2012 trial found increased colorectal neoplasia in PSC with ulcerative colitis, while a 2016 Taiwanese study found lower CRC risk among users.

Clinical Limitations

UDCA is primarily effective for radiolucent, cholesterol-rich stones ≤20 mm, with highest rates in stones ≤5 mm (~81%). Effectiveness diminishes for stones >20 mm, calcified stones (response as low as 6.2%), pigment stones, impaired gallbladder motility, and multiple stones. Recurrence occurs in 30–50% within 2–5 years. Treatment requires up to 2 years with periodic monitoring.

Comparison with Other Treatments

Combination regimens (UDCA with CDCA, n-3 polyunsaturated fatty acids, or statins) may enhance dissolution. ESWL is appropriate for single, small, radiolucent stones and is more effective when followed by UDCA; cure rates are ~55%, with 30–50% recurrence within four years. Cholecystectomy remains the preferred treatment for symptomatic gallstone disease (success >95%). Routine cholecystectomy is not recommended for asymptomatic disease, except for porcelain gallbladder, polyps >1 cm, and stones >3 cm.

Future Directions

The gut–liver axis is an important research focus. UDCA may partially improve gut microbiome dysbiosis. Combination therapy such as UDCA plus an FXR agonist is promising but requires robust trials.

Conclusions

UDCA remains the primary medical therapy for symptomatic cholelithiasis in selected patients and poor surgical candidates. It has a good safety profile but is limited by high recurrence rates. Novel bile acid modulators and combination strategies may expand medical therapy in gallstone management.

Full text

https://www.xiahepublishing.com/2994-8754/JTG-2025-00035

The study was recently published in the Journal of Translational Gastroenterology.

Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.