What is the drug of choice and appropriate dosing for treating drug‑induced cholestatic liver injury in an adult patient (approximately 70 kg) after discontinuation of the offending medication?

Drug of Choice for Cholestatic Liver Injury

There is no effective pharmacologic treatment for drug-induced cholestatic liver injury—immediate withdrawal of the offending medication is the only proven intervention that prevents progression to severe liver damage or death. 1

Primary Management: Drug Discontinuation

The cornerstone of treatment is prompt cessation of the suspected hepatotoxic agent, as delayed discontinuation can result in irreversible liver failure, vanishing bile duct syndrome, and progression to biliary cirrhosis. 1, 2 Prevention and early detection of abnormal liver tests with immediate drug withdrawal are crucial to avoid serious liver injury and potential need for liver transplantation. 1

Adjunctive Pharmacotherapy: Ursodeoxycholic Acid (UDCA)

While drug withdrawal remains the definitive treatment, ursodeoxycholic acid (UDCA) at 13-15 mg/kg/day may beneficially affect cholestasis in approximately two-thirds of cases, though evidence remains limited and this approach is considered experimental. 1, 2

UDCA Dosing for a 70 kg Adult:

• Recommended dose: 910-1050 mg daily (approximately 13-15 mg/kg/day), divided into 2-3 doses 2
• This translates to approximately 300-350 mg three times daily with meals
• UDCA should be continued until liver enzymes normalize, typically within 3 months in most cases 1

Evidence Quality Caveat:

The recommendation for UDCA is based on uncontrolled studies showing potential benefit, but no adequate randomized controlled trials exist to definitively support its use. 1 The European Association for the Study of the Liver classifies therapeutic attempts with UDCA as experimental (Level III/C2 evidence). 1

Corticosteroids: Limited Role

Corticosteroids are NOT recommended for typical cholestatic DILI and should only be considered in specific hypersensitivity-induced cholestasis with immunologic features. 1, 2

When to Consider Corticosteroids:

• Presence of systemic hypersensitivity features (rash, fever, eosinophilia >5%) 2
• Elevated IgG >2× ULN and/or anti-smooth muscle antibody titers >1:80 suggesting drug-induced autoimmune-like hepatitis 2
• Even in these cases, evidence is anecdotal with no controlled trials available 1

Critical Pitfall: Do not confuse cholestatic DILI with drug-induced autoimmune-like hepatitis, which presents with elevated aminotransferases >5× ULN, positive autoantibodies, and elevated IgG—these cases may require corticosteroids. 2

Monitoring Protocol After Drug Withdrawal

Repeat liver function tests within 7-10 days after drug discontinuation to confirm the cholestatic pattern and assess trend. 1, 2 Continue monitoring until:

• Alkaline phosphatase normalizes or returns to baseline
• Total bilirubin normalizes
• Clinical symptoms (pruritus, jaundice, fatigue) resolve 2

Expected Timeline:

Most cases normalize within 3 months after drug cessation, though some patients may develop prolonged cholestasis lasting >6 months (particularly with chlorpromazine, which can cause vanishing bile duct syndrome). 1

When Liver Biopsy is Indicated

Liver biopsy is NOT mandatory for diagnosis but should be considered if: 1

• Severe, progressive, or prolonged course despite drug withdrawal
• Need to exclude other causes of cholestasis
• Uncertainty about diagnosis after 3 months of persistent abnormalities

Prognosis and Long-term Outcomes

The outcome after drug withdrawal is generally good in most cases, with cholestatic DILI having better prognosis than hepatocellular injury. 2, 3 However:

• Mortality can reach 10% in severe cases 3
• A minority of patients show persistent liver damage on follow-up histology 1
• Vanishing bile duct syndrome can lead to permanent liver damage and biliary cirrhosis 1

Symptomatic Management

For pruritus associated with cholestasis, cholestyramine 4-16 grams daily (divided into 2 doses) can be used for symptomatic relief, though this addresses symptoms rather than the underlying liver injury. 4 Start with 4 grams once or twice daily and titrate gradually based on response. 4

Critical Warning: Never rechallenge with the offending medication, as this is potentially harmful, unethical, and not indicated in clinical practice. 1