What is the management approach for Drug-Induced Liver Injury (DILI)?

Management of Drug-Induced Liver Injury (DILI)

The primary management approach for Drug-Induced Liver Injury (DILI) is immediate discontinuation of the suspected causative agent followed by close monitoring and supportive care, with specific interventions based on injury severity and pattern. 1

Diagnosis and Assessment

• Calculate R value to determine injury pattern:

  • R = (ALT/ALT ULN)/(ALP/ALP ULN)
  • Hepatocellular pattern: R ≥ 5
  • Mixed pattern: R > 2 but < 5
  • Cholestatic pattern: R ≤ 2 1

• Perform comprehensive workup to exclude alternative causes:

  • Viral hepatitis serologies
  • Autoimmune hepatitis serologies
  • Cross-sectional imaging (ultrasound, CT, or MRI)
  • Thorough medication history including supplements and herbal products 1, 2

Severity Assessment

• Assess severity based on ALT levels:
  • Mild: ALT < 5× ULN
  • Moderate: ALT ≥ 5× ULN but < 8× ULN
  • Severe: ALT ≥ 8× ULN, or ALT ≥ 3× ULN with total bilirubin ≥ 2× baseline, or ALT ≥ 5× ULN with symptoms 3, 1

Management Algorithm

Step 1: Immediate Actions

• Discontinue the suspected medication immediately 1, 4
• Repeat liver tests within 2-5 days for hepatocellular injury and within 7-10 days for cholestatic injury 3, 1
• Initiate close monitoring for signs of hepatic decompensation (jaundice, coagulopathy, encephalopathy) 1

Step 2: Based on Severity

• For mild cases (ALT < 5× ULN):

  • Monitor liver tests until resolution
  • Provide supportive care for symptoms 1

• For moderate cases (ALT ≥ 5× ULN but < 8× ULN):

  • More frequent monitoring (every 2-3 days)
  • Consider referral to hepatologist 1

• For severe cases (ALT ≥ 8× ULN or ALT ≥ 3× ULN with TBL ≥ 2× baseline):

  • Immediate referral to hepatologist
  • Consider hospitalization for close monitoring
  • Evaluate for liver transplantation if signs of liver failure develop 3

Step 3: Specific Interventions

• For acetaminophen toxicity:

  • Administer N-acetylcysteine (NAC) as antidote 5
  • NAC protects the liver by maintaining or restoring glutathione levels 5

• For immune-mediated DILI (especially from immune checkpoint inhibitors):

  • Consider corticosteroids if immune-mediated mechanism is suspected 3
  • Permanently discontinue immune checkpoint inhibitors if ALT > 10× ULN or if ALT elevation is accompanied by TBL > 2× ULN 3

• For cholestatic DILI:

  • Consider ursodeoxycholic acid 6
  • Monitor for longer period as resolution may be slower 1

Special Considerations

Patients with Elevated Baseline Liver Tests

• Use multiples of baseline ALT rather than ULN as threshold for monitoring and intervention
• Interrupt study drug when ALT ≥ 8× baseline or ALT ≥ 3× baseline with TBL ≥ 2× baseline 3

Rechallenge Considerations

• Generally avoid rechallenge in severe liver injury cases 1
• Rechallenge may be considered in specific circumstances when the medication is critical to treatment and no alternatives exist 3
• If rechallenge is attempted:
  • Use lower dose
  • Monitor liver tests more frequently (every 2-3 days initially)
  • Be prepared to discontinue immediately if liver injury recurs 3

Prevention and Monitoring

• Increase vigilance with known hepatotoxic medications
• Adjust dosing in patients with pre-existing liver disease
• Educate patients to avoid alcohol and other hepatotoxic substances while taking potentially hepatotoxic medications 1
• Consider genetic testing in select cases where pharmacogenetic factors are known to influence risk 1

Pitfalls and Caveats

• Delayed recognition of DILI can lead to progression to chronic liver disease or acute liver failure 4
• Herbal and dietary supplements are significant causes of DILI but may be overlooked in medication history 2
• DILI can mimic other liver diseases, making diagnosis challenging 7
• Patients with pre-existing liver disease may be at higher risk for DILI and require more careful monitoring 8
• Resolution of DILI may take time, with improvement after drug discontinuation (positive dechallenge) supporting the diagnosis 1