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

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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 2
  • ALT elevation can occur within 24 hours of ingestion, with rapid doubling time of approximately 9.5 hours in severely poisoned patients 3
  • 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 4

Antiretroviral Agents

  • Nevirapine: Incidence of hepatotoxicity in 12.5% of patients initiating therapy, with clinical hepatitis in 1.1% 5

    • Grade 4 liver enzyme elevation occurred in 9.4% of nevirapine-treated patients versus none with efavirenz 5
    • Incidence in females was twice that of males (12% vs 6%) 5
    • Two-thirds of cases occur within first 12 weeks of treatment 5
    • Fulminant and fatal hepatic necrosis has been reported 5

  • Lopinavir-ritonavir: ALT elevation to >5 times ULN in 5% of patients 6

    • Increased risk of hepatotoxicity in patients with chronic liver diseases, ALT elevation, or hepatic decompensation 6

  • All marketed NNRTIs and PIs have been associated with serum transaminase elevation 5

Oncology Agents

Tyrosine Kinase Inhibitors

  • Imatinib: Can cause liver function test abnormalities 2

    • Liver failure and death reported when combined with large doses of acetaminophen 2

  • Tolvaptan: Approximately 5% of patients with ADPKD treated with tolvaptan (versus 1% on placebo) displayed ALT increases above 3-fold ULN 7

    • Increases most often occur during first 18 months of treatment 7
    • Resolve within 1-4 months after cessation 7

Immune Checkpoint Inhibitors

  • Can cause immune-mediated liver injury with ALT elevations 8
  • Grade 3-4 elevations (>5× ULN) require withholding therapy and corticosteroid treatment 8

Antimicrobials

  • Interferon alfa: ALT may increase to >2 times ULN in >25% of patients with chronic viral hepatitis 6
  • Interferon beta: ALT may increase to >3 times ULN in 10% of patients 6
  • Nitrofurantoin: Associated with drug-induced autoimmune hepatitis 9
  • Minocycline: Associated with drug-induced autoimmune hepatitis 9

COVID-19 Treatments

  • Tocilizumab: ALT elevation in >20% of patients; ALT increase to >5 times ULN in <1% 6

    • Risk of HBV reactivation requiring antiviral prophylaxis 6

  • Remdesivir: Mild ALT elevation to >2 times ULN; mild-to-moderate AST elevation to >3-4 times ULN 6

  • Favipiravir: <10% of patients may have self-limiting ALT elevation 6

  • Hydroxychloroquine/Chloroquine: ALT elevation in <5% of patients 6

    • Should be used with caution in patients with hepatic disease or in conjunction with known hepatotoxic drugs 6

Other Notable Medications

  • Corticosteroids: Risk of HBV reactivation which can trigger hepatitis flare 6

    • Not directly hepatotoxic but can worsen non-alcoholic steatohepatitis 6

  • Infliximab: Cases of autoimmune hepatitis have been reported 9

  • Ezetimibe: Anecdotal reports of association with autoimmune hepatitis 9

  • Herbal medicines: Have been reported to cause autoimmune hepatitis 9

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 10, 11
  • Hepatocellular pattern (ALT/AST predominance): R value ≥5 suggests drug-induced hepatocellular injury 12
  • Cholestatic pattern: R value ≤2 suggests cholestatic drug injury 12

Critical Monitoring Thresholds

  • Hold drug if: ALT ≥3× ULN with total bilirubin ≥2× ULN (particularly if ALP ≤2× ULN) 12
  • Permanent discontinuation: ALT >3× ULN with signs/symptoms of hepatic injury unless alternative explanation exists 7
  • Increased monitoring: Required when ALT >2× ULN or >2× baseline values, with repeat testing within 48-72 hours 7

References

2
Guideline

nccn clinical practice guidelines in oncology: chronic myelogenous leukemia.

Journal of the National Comprehensive Cancer Network : JNCCN, 2009

3
Research

When do the aminotransferases rise after acute acetaminophen overdose?

Clinical toxicology (Philadelphia, Pa.), 2010

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.