What are the potential side effects of ursodeoxycholic acid (UDCA)?

Ursodeoxycholic Acid Side Effects

Ursodeoxycholic acid is generally well tolerated with mild gastrointestinal symptoms being the most common side effects, occurring in up to 27% of patients, while serious adverse events are rare and primarily limited to specific high-risk populations. 1, 2

Common Side Effects (>5% incidence)

Gastrointestinal Effects

• Diarrhea occurs in 25-27% of patients and represents the most frequent adverse effect 2, 3
• Abdominal pain affects 43% of patients in gallstone dissolution trials 2
• Nausea (14-17%), dyspepsia (12-17%), and flatulence (8%) are commonly reported 2
• Constipation occurs in 9-26% depending on the indication 2
• Vomiting affects approximately 10-14% of patients 2

Neurological Effects

• Headache is reported in 18-25% of patients 2
• Dizziness occurs in 13-17% of patients receiving UDCA for gallstone prevention 2

Other Common Effects

• Upper respiratory tract infections (12-16%) 2
• Fatigue (5-10%) 2
• Mild nausea and dizziness occur in up to 25% of patients 1

Rare but Serious Adverse Effects

Hepatic Decompensation

• Decompensation of liver cirrhosis has been reported in single cases of end-stage primary biliary cirrhosis 3
• In advanced PBC (stages III/IV), complications including esophageal variceal hemorrhage, deteriorating liver function, and need for transplantation can occur despite UDCA therapy 4
• High-dose UDCA (28-30 mg/kg/day) in primary sclerosing cholangitis resulted in more than double the number of deaths and liver transplantations compared to controls, necessitating trial termination 5

Dermatologic Reactions

• Rare skin reactions have been reported, though these appear related to drug adjuvants rather than UDCA itself 3
• Alopecia occurs in approximately 5% of patients 2

Other Serious Effects

• Recurrent right upper quadrant abdominal pain has been incidentally observed 3
• Pruritus (paradoxically, despite being used to treat itching) 5
• Cholangitis, ascites, and vanishing bile duct syndrome in rare cases 5

Dose-Related Toxicity

The therapeutic window is narrow, with recommended doses of 13-15 mg/kg/day for PBC versus toxic effects observed at 28-30 mg/kg/day 1, 5. Higher doses are explicitly contraindicated in primary sclerosing cholangitis due to increased mortality and adverse outcomes 1.

Drug Interactions Causing Adverse Effects

Reduced UDCA Absorption

• Bile acid sequestrants (cholestyramine, colestipol) significantly impair UDCA absorption and should not be co-administered 2, 3
• Aluminum-based antacids and smectite similarly reduce absorption 2, 3

Metabolic Interactions

• Cytochrome P450 3A substrates (cyclosporine, nitrendipine, dapsone) have documented interactions with UDCA 3
• Estrogens, oral contraceptives, and clofibrate may counteract UDCA effectiveness by increasing cholesterol secretion 2

Long-Term Safety Considerations

Carcinogenicity Concerns

• Statistically significant dose-related increases in adrenal pheochromocytomas were observed in 2-year rat studies 2
• Lithocholic acid, a metabolite of UDCA, is hepatotoxic and may accumulate in patients with sulfation deficiencies 2
• Increased hepatocellular carcinoma incidence (9% at 10 years, 20% at 15 years) in PBC patients who fail to achieve biochemical response 5

Pregnancy and Lactation

• UDCA is considered safe during pregnancy and breastfeeding for intrahepatic cholestasis of pregnancy 1
• However, FDA labeling notes that reproduction studies at 100-200 fold human doses showed reduced fertility and litter size in rats 2
• Inadvertent first-trimester exposure in 4 women showed no fetal harm 2

Monitoring Requirements

Regular monitoring of liver biochemistry (AST, ALT) is recommended at treatment initiation and as clinically indicated 1, though UDCA therapy itself has not been associated with liver enzyme elevations and typically decreases enzyme levels 2.

Critical Pitfalls to Avoid

• Never use high-dose UDCA (>20 mg/kg/day) in any cholestatic condition, particularly PSC 1
• Do not administer UDCA to patients with end-stage cirrhosis or decompensated liver disease 3, 4
• Avoid co-administration with bile acid sequestrants, which negate therapeutic effects 2, 3
• Do not expect UDCA to improve pruritus significantly despite its use for this indication 6