What medications can cause toxic hepatitis?

Medications That Cause Toxic Hepatitis

The most common medications causing toxic hepatitis include acetaminophen (the leading cause of drug-induced liver failure in the United States), antituberculosis drugs (isoniazid, rifampin, and pyrazinamide), NSAIDs, antibiotics (particularly amoxicillin-clavulanate, macrolides, and trimethoprim-sulfamethoxazole), methotrexate, statins, azathioprine, retinoids, antiretroviral agents (especially nevirapine and protease inhibitors), and certain herbal medications. 1, 2

Major Drug Categories and Specific Agents

Analgesics and Anti-inflammatory Drugs

• Acetaminophen is the single most common cause of drug-induced liver failure, particularly at doses exceeding 4g per day, though hepatotoxicity can occur even at therapeutic doses in chronic alcohol users 1, 2
• NSAIDs (including diclofenac, ibuprofen, naproxen, and indomethacin) account for approximately 10% of drug-induced hepatitis cases 1, 2
• Diclofenac specifically causes meaningful elevations (>3 times upper limit of normal) of liver enzymes in about 2-4% of patients, with marked elevations (>8 times ULN) in approximately 1% 3

Antituberculosis Medications

• Isoniazid, rifampin, and pyrazinamide are first-line antituberculosis drugs that commonly cause drug-induced liver injury 4, 1, 2
• Pyrazinamide is considered the most hepatotoxic among first-line tuberculosis agents 1, 2
• These medications should be stopped immediately if AST levels exceed 3 times the upper limit of normal with symptoms, or 5 times without symptoms 4, 1

Antibiotics

• Amoxicillin-clavulanate and penicillinase-resistant penicillins (oxacillin, cloxacillin, flucloxacillin) cause predominantly cholestatic hepatitis that can be protracted 5, 6
• Macrolide antibiotics including erythromycin, roxithromycin, and azithromycin cause cholestatic hepatitis 4, 7, 5, 6
• Erythromycin causes hepatic dysfunction including hepatocellular and/or cholestatic hepatitis, with or without jaundice 7
• Trimethoprim-sulfamethoxazole can cause severe hepatotoxicity, especially in patients with AIDS 5, 6
• Fluoroquinolones, particularly ciprofloxacin, have been associated with serious hepatitis 6
• Nitrofurantoin causes acute cholestatic and hepatocellular reactions as well as chronic hepatitis mimicking autoimmune hepatitis 5
• Ceftriaxone has been reported to cause toxic hepatitis, though cephalosporins generally have low hepatotoxicity 8

Immunosuppressive and Dermatologic Agents

• Methotrexate causes hepatotoxicity, particularly when combined with other hepatotoxic drugs including alcohol, azathioprine, and retinoids 4, 2
• Statins are hepatotoxic and increase methotrexate toxicity when used concomitantly 4
• Azathioprine causes hepatotoxicity and should be used cautiously with other hepatotoxic medications 4
• Retinoids are hepatotoxic and increase risk when combined with methotrexate 4

Antiretroviral Medications

• Nevirapine causes severe hepatotoxicity, with grade 4 liver enzyme elevations occurring in up to 9.4% of patients, particularly in the first 12 weeks of therapy 4
• Female patients have twice the incidence of nevirapine-associated hepatotoxicity compared to males (12% versus 6%) 4
• Fulminant and fatal cases of hepatic necrosis have been reported with nevirapine, sometimes progressing rapidly to hepatomegaly, jaundice, and hepatic failure within days 4
• Protease inhibitors (ritonavir, ritonavir/saquinavir combinations) cause severe hepatotoxicity more frequently than indinavir, nelfinavir, or saquinavir alone 4
• Stavudine is associated with increased hepatotoxicity risk 4

Other Medications

• Phenytoin increases methotrexate toxicity through reduced protein binding 4
• Proton pump inhibitors may reduce renal elimination of methotrexate, potentially increasing hepatotoxicity 4
• Barbiturates and sulfonamides contribute to folic acid deficiency when combined with methotrexate 4

Critical Risk Factors

Patient-Related Risk Factors

• Excessive alcohol consumption significantly increases risk, even if discontinued during treatment 1, 2
• Underlying liver disease (including hepatitis B or C coinfection) predisposes patients to drug-induced hepatotoxicity 4, 1, 2
• Advanced age increases susceptibility, particularly with NSAIDs and methotrexate interactions 4
• Renal impairment increases risk, especially with renally eliminated drugs like methotrexate 4
• Obesity, diabetes, and hyperlipidemia increase risk, particularly with methotrexate 2
• Female gender doubles the risk of nevirapine-associated hepatotoxicity 4

Drug-Related Risk Factors

• Concomitant use of multiple hepatotoxic agents substantially increases risk 4, 3
• Higher doses and longer duration of therapy increase hepatotoxicity risk, particularly with diclofenac (doses ≥150 mg for >90 days) 3
• Baseline elevated liver enzymes predict increased risk of hepatotoxicity 4

Monitoring and Detection

Diagnostic Criteria

• Drug-induced hepatitis is suspected when ALT levels are ≥3 times the upper limit of normal with hepatitis symptoms (nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, flu-like symptoms), or ≥5 times the upper limit of normal without symptoms 4, 1, 2

Monitoring Recommendations

• For diclofenac, measure transaminases at baseline and within 4-8 weeks after initiating treatment, though severe reactions can occur at any time 3
• For nevirapine, monitor liver enzymes every 2 weeks for the first month, then monthly for the first 12 weeks, and every 1-3 months thereafter 4
• For methotrexate, perform regular laboratory monitoring (CBC and liver function tests) every 3-6 months 2
• For patients on long-term NSAIDs, consider periodic monitoring with CBC and chemistry profile 3

Management Approach

Immediate Actions

• Immediately discontinue the suspected hepatotoxic medication when significant liver injury is detected (ALT ≥3× ULN with symptoms or ≥5× ULN without symptoms) 4, 1, 2, 3, 7, 3
• Stop all potentially hepatotoxic drugs including isoniazid, rifampin, and pyrazinamide if hepatitis occurs 4
• Perform serologic testing for hepatitis viruses A, B, and C if not done at baseline 4
• Question carefully regarding exposure to other hepatotoxins, especially alcohol 4

Specific Antidotes

• For acetaminophen overdose within 4 hours of presentation, administer activated charcoal prior to starting N-acetylcysteine 2
• For mushroom poisoning (Amanita phalloides), consider penicillin G (300,000 to 1 million units/kg/day IV) and silymarin (30-40 mg/kg/day for 3-4 days) 4

Prevention Strategies

• In patients with liver cirrhosis, reduce acetaminophen dosage to 2-3g per day instead of the standard 4g maximum 1, 2
• Avoid NSAIDs in patients with existing liver disease due to increased risk of hepatotoxicity and other adverse effects 1, 2
• Use the lowest effective dose for the shortest duration possible for all potentially hepatotoxic medications 3
• Avoid concomitant use of multiple hepatotoxic agents whenever possible, including alcohol 4, 3
• For methotrexate patients, administer folic acid or folinic acid to reduce hepatic adverse effects 2

Common Pitfalls

• Do not continue potentially hepatotoxic medications based solely on minor elevations in liver enzymes—establish clear thresholds for discontinuation 4, 1
• Do not assume cephalosporins are completely safe—while generally having low hepatotoxicity, cases of toxic hepatitis with ceftriaxone have been reported 8
• Do not overlook herbal medications and dietary supplements as causes of toxic hepatitis, as they account for a substantial proportion of cases (up to 41.5% in some series) 9
• Do not restart nevirapine in patients who have experienced severe clinical hepatotoxicity, as this is contraindicated 4
• Do not use trimethoprim or co-trimoxazole with methotrexate due to severe bone marrow suppression and immunosuppression risk 4