What medications can cause hepatotoxicity and how can it be managed?

Hepatotoxic Medications and Management

The most common hepatotoxic medications include acetaminophen, isoniazid, rifampin, pyrazinamide, certain NSAIDs, methotrexate, valproic acid, and immune checkpoint inhibitors, and management involves immediate discontinuation of the offending agent, supportive care, and specific antidotes when available. 1

Common Hepatotoxic Medications

Analgesics and Anti-inflammatory Drugs

• Acetaminophen is the leading cause of drug-induced liver failure in the United States, especially at doses exceeding 4g per day or at lower doses in chronic alcohol users 1, 2
• NSAIDs are responsible for approximately 10% of drug-induced hepatitis cases and should be avoided in patients with existing liver disease 1, 3
• Skeletal muscle relaxants like tizanidine, chlorzoxazone, and dantrolene carry risks of hepatotoxicity, with dantrolene having a black box warning for potentially fatal hepatotoxicity 3

Antimicrobial Agents

• First-line antituberculosis drugs (isoniazid, rifampin, and pyrazinamide) commonly cause drug-induced liver injury, with pyrazinamide considered the most hepatotoxic 1, 4
• Isoniazid carries a boxed warning for severe and sometimes fatal hepatitis, with risk increasing with age (highest in 50-64 year age group at 23 per 1,000) 4
• Amoxicillin-clavulanic acid is one of the most frequently implicated causes of drug-induced liver injury worldwide 5

Other Common Hepatotoxic Medications

• Valproic acid can cause fatal hepatotoxicity, especially in children under two years of age 6
• Methotrexate can cause hepatotoxicity, particularly in patients with obesity, diabetes, hyperlipidemia, and alcohol use 3
• Immune checkpoint inhibitors can cause immune-related hepatitis requiring careful monitoring and management 3

Risk Factors for Drug-Induced Liver Injury

• Excessive alcohol consumption significantly increases risk, even if discontinued during treatment 1
• Underlying liver disease predisposes patients to drug-induced hepatotoxicity 1, 7
• Age is a significant factor for certain medications (e.g., isoniazid hepatotoxicity increases with age) 4
• Genetic polymorphisms in drug-metabolizing enzymes may account for individual susceptibility 5
• Obesity, diabetes, and hyperlipidemia increase risk, particularly with methotrexate 3

Diagnosis and Monitoring

• Drug-induced hepatitis is suspected when ALT levels are ≥3 times the upper limit of normal with symptoms, or ≥5 times without symptoms 1
• For patients on potentially hepatotoxic medications, regular monitoring of liver function tests is essential 3
• For isoniazid, patients 35 and older should have AST and ALT measured prior to starting therapy and periodically throughout treatment 4
• For immune checkpoint inhibitors, monitor liver tests before each infusion and consider weekly monitoring if grade 1 elevations occur 3
• For methotrexate, regular laboratory monitoring (CBC and liver function tests) should be performed every 3-6 months 3

Management of Drug-Induced Hepatotoxicity

General Principles

• Immediately discontinue the suspected hepatotoxic medication when significant liver injury is detected 1
• Perform thorough evaluation to rule out other causes of liver injury 3
• Consider liver biopsy in steroid-refractory cases or when other diagnoses are suspected 3

Specific Management Strategies

Acetaminophen Toxicity

• For known or suspected acetaminophen overdose within 4 hours of presentation, administer activated charcoal prior to starting N-acetylcysteine (NAC) 3
• Begin NAC promptly in all patients where acetaminophen levels, quantity ingested, or rising aminotransferases indicate impending or evolving liver injury 3
• NAC may be given orally (140 mg/kg loading dose followed by 70 mg/kg q4h for 17 doses) or intravenously (150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours) 3

Immune Checkpoint Inhibitor-Related Hepatitis

• For grade 2 hepatitis (AST/ALT >3.0 to ≤5.0 × ULN), temporarily hold immune checkpoint inhibitor and administer prednisone 0.5-1 mg/kg/day if no improvement after 3-5 days 3
• For grade 3 hepatitis (AST/ALT 5-20× ULN), consider permanently discontinuing immune checkpoint inhibitor and start methylprednisolone 1-2 mg/kg 3
• For grade 4 hepatitis, permanently discontinue immune checkpoint inhibitor, hospitalize patient, and administer methylprednisolone 2 mg/kg IV 3
• If steroid-refractory, consider adding mycophenolate mofetil; infliximab is contraindicated for immune-related hepatitis 3

Antituberculosis Drug-Induced Hepatotoxicity

• If abnormalities of liver function exceed three to five times the upper limit of normal, strongly consider discontinuation of isoniazid 4
• Patients with tuberculosis who develop hepatitis attributed to isoniazid should be given appropriate treatment with alternative drugs 4
• If isoniazid must be reintroduced, restart only after symptoms and laboratory abnormalities have cleared, using very small and gradually increasing doses 4

Prevention Strategies

• In patients with liver cirrhosis, reduce acetaminophen dosage to 2-3g per day instead of the standard 4g maximum 1
• For patients on methotrexate, consider baseline and periodic non-invasive liver fibrosis assessment 3
• Administer folic acid or folinic acid with methotrexate to reduce the incidence of GI and hepatic adverse effects 3
• For patients on isoniazid, educate about signs and symptoms of liver damage and perform monthly clinical evaluations 4
• Avoid combinations of hepatotoxic medications when possible (e.g., isoniazid potentiates acetaminophen hepatotoxicity) 8

Special Considerations

• Patients with pre-existing liver disease require more careful monitoring and often dose adjustments of potentially hepatotoxic medications 1, 7
• Patients with liver disease should avoid NSAIDs due to increased risk of hepatotoxicity and other adverse effects 1
• For patients with acute liver failure of any etiology, early contact with a transplant center is recommended 3, 2