Which drugs are considered to have a high likelihood of causing liver damage, according to the LiverTox (Liver Toxicity) database?

Drugs with High Likelihood of Causing Liver Damage According to LiverTox Database

Based on the most recent evidence, drugs with the highest likelihood of causing liver damage include acetaminophen (especially at doses >4g/day), rifampin plus pyrazinamide (RZ), valproic acid, methotrexate, and certain antibiotics including amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, and azithromycin. 1, 2, 3, 4

First-Line Hepatotoxic Medications

Acetaminophen

• Highest risk medication for acute liver failure in the United States - responsible for over half of all acute liver failure cases 5
• Risk factors for toxicity:
  • Doses exceeding 4g per day 6
  • Chronic alcohol use 6, 7
  • Malnutrition/negative nitrogen balance 7
  • Concomitant use with other hepatotoxic medications 6
• Even therapeutic doses (≤4g/day) can cause clinically significant hepatotoxicity in susceptible individuals 6
• Fixed-dose combinations containing acetaminophen should be limited to ≤325mg per dosage unit to reduce liver damage risk 6

Rifampin + Pyrazinamide (RZ) Combination

• Extremely high risk of severe liver injury and death 6
• CDC cohort analysis found hospitalization rates of 3.0 per 1,000 treatment initiations and death rates of 0.9 per 1,000 6
• Among first-line TB agents, pyrazinamide (PZA) is considered the most hepatotoxic 6
• The American Thoracic Society and CDC recommend against using this combination for latent TB treatment in most patients 6

Valproic Acid

• High risk of acute liver failure, particularly in patients with:
  • POLG gene mutations (mitochondrial DNA polymerase γ) 3
  • Children under 2 years of age 3
  • Pre-existing liver disease 3
• Can cause life-threatening pancreatitis in addition to hepatotoxicity 3

Methotrexate

• Associated with chronic liver injury leading to fibrosis and cirrhosis with long-term use 4, 8
• Risk factors for methotrexate hepatotoxicity:
  • Alcohol consumption 4
  • Pre-existing liver disease 4
  • Diabetes 1
  • Obesity 1
  • Concomitant use of other hepatotoxic medications 4
• Requires liver biopsy monitoring at high cumulative doses 1

Other High-Risk Medications

Antibiotics

• Amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, and azithromycin are most likely to cause chronic liver injury 9
• NSAIDs are responsible for approximately 10% of drug-induced hepatitis cases 6
• Tetracycline, chloramphenicol, and certain broad-spectrum antibiotics can interfere with methotrexate metabolism, increasing toxicity 4

Strong Opioids

• Morphine, oxycodone, hydromorphone, and fentanyl can cause liver injury, particularly when used at high doses or in patients with pre-existing liver disease 6

Tyrosine Kinase Inhibitors

• Ponatinib has been associated with liver failure, including fatal cases 1

Monitoring and Management Recommendations

Monitoring Guidelines

• Obtain baseline liver function tests (LFTs) before starting potentially hepatotoxic medications 1
• For high-risk medications: weekly monitoring for first 6-8 weeks, then every 1-3 months 1
• Essential tests include ALT, AST, ALP, and total bilirubin 1

Management of Abnormal LFTs

• ALT/AST <2× ULN: Repeat LFTs in 2-4 weeks 1
• ALT/AST 2-3× ULN: Consider dose reduction and close monitoring 1
• ALT/AST 3-5× ULN: Consider temporary discontinuation or dose reduction 1
• ALT/AST >5× ULN: Discontinue medication 1

Risk Reduction Strategies

• Avoid concomitant use of multiple hepatotoxic drugs 1, 4
• Educate patients to avoid alcohol consumption while taking hepatotoxic medications 1
• Consider alternative medications in patients with pre-existing liver disease 1
• For RZ treatment (if absolutely necessary), dispense no more than 2-week supply and reassess patients every 2 weeks 6

Special Considerations

• Most drug-induced liver injury is idiosyncratic and occurs within the first 6 months of therapy 1
• A medication used continuously for more than 1-2 years without liver problems is unlikely to cause new liver damage 1
• Pre-existing liver disease, alcohol consumption, obesity, diabetes, advanced age, and genetic factors affecting drug metabolism increase risk of medication-induced liver injury 1
• Drug-induced liver injury can present as acute hepatitis, cholestasis, steatosis, fibrosis, or cirrhosis 8, 9

Remember that the LiverTox database classifies drugs based on their likelihood of causing liver injury, with acetaminophen, rifampin+pyrazinamide, valproic acid, and methotrexate being among those with the highest risk of causing clinically significant hepatotoxicity.