What is the treatment approach for a patient with Drug-Induced Liver Injury (DILI)?

Treatment of Drug-Induced Liver Injury (DILI)

The cornerstone of DILI management is immediate discontinuation of the suspected hepatotoxic agent, with supportive care as the primary treatment strategy, while specific pharmacotherapy is reserved for acetaminophen overdose (N-acetylcysteine) and selected cases of cholestatic DILI (ursodeoxycholic acid) or immune-mediated liver injury (corticosteroids). 1

Immediate Drug Discontinuation Criteria

Discontinue the suspected drug immediately if any of the following thresholds are met: 1

• ALT or AST ≥8× ULN at any time 1
• ALT or AST ≥5× ULN persisting for more than 2 weeks 1
• ALT or AST ≥3× ULN with total bilirubin ≥2× ULN (Hy's Law—indicates severe DILI with mortality risk of 10-50%) 1
• ALT or AST ≥3× ULN with INR >1.5 (suggests synthetic dysfunction) 1
• ALT or AST ≥3× ULN with symptoms such as jaundice, fatigue, nausea, or right upper quadrant pain 1

For patients with elevated baseline ALT (≥1.5× ULN), use multiples of baseline rather than ULN: discontinue if ALT ≥5× baseline OR ≥500 U/L 1

Initial Assessment and Monitoring

Obtain comprehensive liver function tests including ALT, AST, alkaline phosphatase, total and direct bilirubin, and INR in all patients with suspected DILI 2

Monitoring frequency based on severity: 2, 1

• Mild elevations (ALT 1-3× ULN): Monitor every 1-2 weeks until normalization 1
• Moderate to severe elevations (ALT >3× ULN): Monitor every 3-7 days initially, then weekly once improving 1
• Hepatocellular DILI (elevated transaminases): Repeat tests within 2-5 days, then continue every 1-3 days until improvement noted 2

Specific Pharmacotherapy

Acetaminophen Overdose (Intrinsic DILI)

N-acetylcysteine is the specific antidote for acetaminophen-induced hepatotoxicity and must be initiated within 24 hours of ingestion for maximum efficacy. 3

This is the only DILI scenario with FDA-approved specific pharmacotherapy and should be started immediately when acetaminophen overdose is suspected 3

Cholestatic DILI Pattern

Consider ursodeoxycholic acid (UDCA) for cholestatic DILI patterns, which may benefit approximately two-thirds of cholestatic DILI cases 1

UDCA works by suppressing hepatic cholesterol synthesis, inhibiting intestinal cholesterol absorption, and solubilizing cholesterol in bile 4

Immune-Mediated Liver Injury from Checkpoint Inhibitors (ILICI)

For immune checkpoint inhibitor-induced liver injury, management differs from typical DILI and requires corticosteroids in addition to drug interruption: 5

• Grade 3-4 ILICI: Interrupt ICI treatment and initiate methylprednisolone or equivalent corticosteroids 5
• Expected response time: ILICI typically resolves within 4-6 weeks of interrupting ICI and initiating corticosteroids 5
• Failure to respond: If no improvement within 4-6 weeks, repeat evaluation for alternative causes and consider liver biopsy 5
• Second-line therapy: Mycophenolate mofetil (MMF) in addition to corticosteroids for cases worsening despite initial treatment 5

Corticosteroids for Non-ICI Idiosyncratic DILI

Corticosteroids should only be considered in highly selected cases with specific features such as hypersensitivity-induced cholestasis or autoimmune features, as there is no clear evidence that corticosteroids improve outcomes in most chemotherapy-induced or idiosyncratic DILI 1, 2

The efficacy of corticosteroids remains controversial, with limited data from randomized controlled trials 6, 7

Criteria for Hepatology Referral

Immediate hepatology consultation is mandatory for: 1

• ALT >8× ULN
• ALT >3× ULN with total bilirubin >2× ULN (Hy's Law)
• Evidence of synthetic dysfunction (elevated INR)
• Any signs of hepatic encephalopathy

Special Population Considerations

Oncology Patients

In oncology patients, higher risk tolerance exists due to life-threatening cancers and limited therapy options, allowing for consideration of drug continuation with mild/moderate ALT elevations 5

For oncology patients with hepatic metastases or primary liver tumors, use higher thresholds and obtain imaging to distinguish DILI from disease progression 1

Rechallenge may be considered more often than in non-oncology populations, but only when potential benefit outweighs risk and no alternative treatment options exist 2

If rechallenge is attempted, liver injury can recur much more rapidly than initial DILI 2

Patients with Pre-existing Liver Disease

For patients with pre-existing liver disease (NASH, cirrhosis, cholestatic diseases), use higher thresholds and monitor for hepatic decompensation rather than relying solely on transaminase levels 1

Patients with pre-existing liver disease are at higher risk for severe outcomes, including progression to liver failure 2

Common Pitfalls to Avoid

Do not use corticosteroids empirically in most cases of idiosyncratic DILI, as efficacy is unproven and may cause harm 2, 6

Do not delay drug discontinuation while awaiting causality assessment—stop the suspected drug first, then assess causality 1

Do not overlook alternative causes such as viral hepatitis, autoimmune hepatitis, ischemic hepatitis, or biliary obstruction, which can mimic DILI 5

For patients with elevated baseline ALP, an increase to ≥2× baseline should prompt evaluation for causes including tumor progression, biliary obstruction, or bone disease, not just DILI 5