What is the role of steroids, such as prednisolone, in managing drug-induced liver injury?

Role of Steroids in Drug-Induced Liver Injury

Steroids should NOT be used routinely in most drug-induced liver injury (DILI), with the critical exception of immune checkpoint inhibitor-induced liver injury (ICI-DILI) and drug-induced autoimmune-like hepatitis where they are the standard of care. 1, 2

When Steroids ARE Indicated

Immune Checkpoint Inhibitor-Induced Liver Injury

This is the primary indication where steroids have proven efficacy:

• Grade 2 (ALT 3-5× ULN) with persistent elevation >1-2 weeks: Start oral prednisolone 0.5-1 mg/kg/day, taper over 4-6 weeks once improved to Grade 1 3

• Grade 3 (ALT >5-10× ULN): Start oral prednisolone 1 mg/kg/day immediately upon withholding the checkpoint inhibitor 3

• Grade 4 (ALT >10× ULN): Start IV methylprednisolone 2 mg/kg/day immediately 3

• If no response within 2-3 days: Add mycophenolate mofetil 500-1000 mg twice daily and consult hepatology for liver biopsy 3

• Critical threshold: Any Grade 2 ALT elevation with concurrent total bilirubin ≥2× ULN should be managed as Grade 3-4 (unless Gilbert's syndrome) 3

Drug-Induced Autoimmune-Like Hepatitis

Steroids are highly effective when specific features are present:

• Indications: Elevated IgG >2× ULN and/or anti-smooth muscle antibody titers >1:80 with hepatocellular injury pattern 1

• Dosing: Standard prednisolone 40 mg daily or equivalent 3

• Response: Observational studies show excellent response with rapid improvement and sustained remission after tapering 2

When Steroids Are NOT Indicated

Standard DILI (Non-ICI, Non-Autoimmune Pattern)

The only effective treatment is immediate withdrawal of the offending drug 1

• Cholestatic DILI: Steroids are NOT recommended when autoimmune markers (ANA, ASMA) and IgG levels are normal 1

• Hepatocellular DILI: No evidence supports steroid use in typical DILI without autoimmune features 2

• Drug-induced fulminant acute liver failure: Steroids have NOT shown improved overall survival 2

Alternative Management for Cholestatic DILI

• Consider ursodeoxycholic acid (UDCA) 13-15 mg/kg/day - may benefit approximately two-thirds of cholestatic DILI cases 1

Critical Pitfalls and Contraindications

Paradoxical Hepatotoxicity of Steroids Themselves

High-dose methylprednisolone can cause severe DILI, creating a dangerous diagnostic dilemma:

• Latency: Liver injury typically occurs 5 weeks after repeated pulsing, not immediately 4

• Severity: Can progress to acute liver failure requiring transplantation in severe cases 4, 5

• Pattern: Hepatocellular injury that mimics autoimmune hepatitis histologically but responds to prednisolone (not methylprednisolone) 4

• Rechallenge risk: Unintentional rechallenge with methylprednisolone causes rapid recurrence 6

Absolute Contraindications to Steroids in DILI

• Uncontrolled active infection - screen with chest x-ray, blood, urine, and ascites cultures before initiating steroids 3

• Acute kidney injury with creatinine >2.5 mg/dL 3

• Uncontrolled upper gastrointestinal bleeding 3

• Multiorgan failure or shock 3

• Concurrent active infections: HBV, HCV, HIV, tuberculosis 3

Monitoring Strategy

For ICI-DILI on Steroids

• Grade 2: Monitor liver tests twice weekly 3

• Grade 3-4: Daily monitoring until improvement, then twice weekly 3

• Taper only after: ALT improves to Grade 1, then taper over 4-6 weeks 3

For Standard DILI (No Steroids)

• Repeat liver tests within 7-10 days after drug discontinuation to confirm pattern and assess trend 1, 7

• Continue monitoring until: Alkaline phosphatase normalizes, total bilirubin normalizes, and clinical symptoms resolve 1

Evidence Quality Assessment

The evidence supporting steroid use in ICI-DILI comes from multiple 2020 consensus guidelines based on clinical trial protocols and expert consensus 3. However, a 2022 systematic review found that most studies on steroids in general DILI are observational with historical controls, making efficacy conclusions difficult 2. The strongest evidence supports steroids specifically for ICI-DILI and drug-induced autoimmune hepatitis, while evidence for routine DILI remains insufficient and potentially harmful given methylprednisolone's own hepatotoxic potential 4, 5, 8, 6.