What tuberculosis (TB) medications can cause transaminitis in patients?

TB Medications That Cause Transaminitis

The primary TB drugs that cause transaminitis are rifampicin, isoniazid, and pyrazinamide, with pyrazinamide being the most hepatotoxic, followed by rifampicin and isoniazid. 1, 2

First-Line Hepatotoxic TB Drugs

High Hepatotoxicity Risk

• Pyrazinamide is the most hepatotoxic first-line TB drug and should be stopped first when severe transaminitis occurs 1, 2
• Rifampicin causes significant hepatotoxicity and must be stopped when AST/ALT rises to five times the upper limit of normal 1, 2
• Isoniazid causes hepatotoxicity with an incidence of 9.2 per 1,000 compliant patients, with a case fatality rate of 4.7% 3

Combination Regimen Risks

• The rifampin-pyrazinamide combination has unacceptably high severe liver toxicity rates and should be avoided 4
• Fixed-dose combinations containing rifampicin, isoniazid, and pyrazinamide (2FDC-HRZE) show positive rates of AT-DILI or abnormal liver functioning of 56.03% 5

Non-Hepatotoxic TB Drugs

Safe Alternatives

• Streptomycin has no hepatotoxic effects and is eliminated primarily by the kidneys rather than metabolized by the liver 4
• Ethambutol can be safely used without dose adjustment for hepatic impairment, with primary concern being ocular toxicity rather than hepatotoxicity 4

Second-Line Drug Hepatotoxicity

Moderate to High Risk

• Ethionamide/prothionamide can cause hepatotoxicity and should be used cautiously 1
• Para-aminosalicylic acid (PAS) has fair to poor tolerability with potential hepatotoxic effects 1

Lower Risk Second-Line Drugs

• Fluoroquinolones (levofloxacin, moxifloxacin) have minimal hepatotoxicity 1
• Linezolid does not cause significant hepatotoxicity 1
• Cycloserine/terizidone are not primarily hepatotoxic 1, 6
• Bedaquiline and clofazimine have acceptable hepatic safety profiles 1

Clinical Thresholds for Drug Discontinuation

Immediate Action Required

• Stop rifampicin, isoniazid, and pyrazinamide immediately if AST/ALT rises to five times the upper limit of normal, regardless of bilirubin levels or symptoms 1, 2
• Stop all hepatotoxic drugs if any elevation of transaminases occurs with symptoms (fever, malaise, vomiting, jaundice) or elevated bilirubin 1, 2

Monitoring Thresholds

• If AST/ALT is two or more times normal at baseline, monitor liver function weekly for two weeks, then biweekly until normal 1
• If AST/ALT is under two times normal, repeat at two weeks; if it has fallen, further tests are only required for symptoms 1

Management After Transaminitis

Bridge Therapy

• When hepatotoxicity develops, continue treatment with streptomycin and ethambutol until liver function normalizes, as this combination is safe and effective 2, 4
• For infectious TB or clinically unwell patients, streptomycin and ethambutol should be initiated immediately as bridge therapy 2

Sequential Reintroduction Protocol

• Reintroduce isoniazid first, starting at 50 mg/day and increasing to 300 mg/day after 2-3 days if no reaction occurs 2
• Add rifampicin second, starting at 75 mg/day, increasing to 300 mg after 2-3 days, then to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days 2
• Add pyrazinamide last, starting at 250 mg/day, increasing to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (>50 kg) 2
• Monitor liver function tests daily during reintroduction 2

Risk Factors for Increased Hepatotoxicity

Patient-Specific Factors

• Male gender has significantly higher positive rates (42.91% vs 28.52% in females) 5
• Increasing age correlates with higher incidence of isoniazid hepatotoxicity 3
• Pre-existing liver disease requires weekly monitoring for two weeks, then biweekly for the first two months 1, 2
• Chronic alcohol use significantly increases hepatotoxicity risk 2
• HIV co-infection increases risk of malabsorption and side effects 7

Treatment Duration

• The positive rate of AT-DILI or abnormal liver functioning increases gradually with duration of medication across all prescription regimes 5