Which medications can cause elevated alanine aminotransferase (ALT) levels?

Medications That Cause Elevated ALT

Acetaminophen is the leading cause of drug-induced acute liver failure in the United States and Europe, with very high aminotransferases (often exceeding 3,500 IU/L) being highly correlated with acetaminophen poisoning. 1

Major Drug Classes Associated with ALT Elevation

Acetaminophen (Paracetamol)

• Most common medication causing severe ALT elevation and acute liver failure 1
• Dose-related hepatotoxin; most cases leading to acute liver failure involve ingestion exceeding 10 gm/day 1
• Severe liver injury can occur with doses as low as 3-4 gm/day 1
• Serum ALT levels exceeding 3,500 IU/L are highly correlated with acetaminophen poisoning and should prompt consideration even when history is lacking 1
• When combined with imatinib, liver failure and death occurred in one patient taking large doses of both drugs; acetaminophen use should be limited to ≤1,300 mg/day in patients taking imatinib 1
• ALT elevation can occur within 24 hours of ingestion, with rapid doubling time of approximately 9.5 hours in severely poisoned patients 2
• Even therapeutic doses of 4 g/day for 10 days caused asymptomatic ALT elevations in 58% of nondrinkers, with the largest elevation being 3.8 times the upper limit of normal 3

Antiretroviral Agents

• Nevirapine: Incidence of hepatotoxicity in 12.5% of patients initiating therapy, with clinical hepatitis in 1.1% 1

  • Grade 4 liver enzyme elevation occurred in 9.4% of nevirapine-treated patients versus none with efavirenz 1
  • Incidence in females was twice that of males (12% vs 6%) 1
  • Two-thirds of cases occur within first 12 weeks of treatment 1
  • Fulminant and fatal hepatic necrosis has been reported 1

• Lopinavir-ritonavir: ALT elevation to >5 times ULN in 5% of patients 1

  • Increased risk of hepatotoxicity in patients with chronic liver diseases, ALT elevation, or hepatic decompensation 1

• All marketed NNRTIs and PIs have been associated with serum transaminase elevation 1

Oncology Agents

Tyrosine Kinase Inhibitors

• Imatinib: Can cause liver function test abnormalities 1

  • Liver failure and death reported when combined with large doses of acetaminophen 1

• Tolvaptan: Approximately 5% of patients with ADPKD treated with tolvaptan (versus 1% on placebo) displayed ALT increases above 3-fold ULN 1

  • Increases most often occur during first 18 months of treatment 1
  • Resolve within 1-4 months after cessation 1

Immune Checkpoint Inhibitors

• Can cause immune-mediated liver injury with ALT elevations 1
• Grade 3-4 elevations (>5× ULN) require withholding therapy and corticosteroid treatment 1

Antimicrobials

• Interferon alfa: ALT may increase to >2 times ULN in >25% of patients with chronic viral hepatitis 1
• Interferon beta: ALT may increase to >3 times ULN in 10% of patients 1
• Nitrofurantoin: Associated with drug-induced autoimmune hepatitis 1
• Minocycline: Associated with drug-induced autoimmune hepatitis 1

COVID-19 Treatments

• Tocilizumab: ALT elevation in >20% of patients; ALT increase to >5 times ULN in <1% 1

  • Risk of HBV reactivation requiring antiviral prophylaxis 1

• Remdesivir: Mild ALT elevation to >2 times ULN; mild-to-moderate AST elevation to >3-4 times ULN 1

• Favipiravir: <10% of patients may have self-limiting ALT elevation 1

• Hydroxychloroquine/Chloroquine: ALT elevation in <5% of patients 1

  • Should be used with caution in patients with hepatic disease or in conjunction with known hepatotoxic drugs 1

Other Notable Medications

• Corticosteroids: Risk of HBV reactivation which can trigger hepatitis flare 1

  • Not directly hepatotoxic but can worsen non-alcoholic steatohepatitis 1

• Infliximab: Cases of autoimmune hepatitis have been reported 1

• Ezetimibe: Anecdotal reports of association with autoimmune hepatitis 1

• Herbal medicines: Have been reported to cause autoimmune hepatitis 1

Clinical Patterns and Monitoring

Pattern Recognition

• Very high ALT (>1,000 IU/L): Most commonly due to acute ischemia, acute drug-induced liver injury (usually acetaminophen), or acute viral hepatitis 4, 5
• Hepatocellular pattern (ALT/AST predominance): R value ≥5 suggests drug-induced hepatocellular injury 1
• Cholestatic pattern: R value ≤2 suggests cholestatic drug injury 1

Critical Monitoring Thresholds

• Hold drug if: ALT ≥3× ULN with total bilirubin ≥2× ULN (particularly if ALP ≤2× ULN) 1
• Permanent discontinuation: ALT >3× ULN with signs/symptoms of hepatic injury unless alternative explanation exists 1
• Increased monitoring: Required when ALT >2× ULN or >2× baseline values, with repeat testing within 48-72 hours 1