Most Hepatotoxic Anti-TB Drug: Pyrazinamide
Among the first-line anti-tuberculosis drugs, pyrazinamide is the most hepatotoxic agent. 1, 2
Evidence from Guidelines
The CDC explicitly states that among first-line agents in the treatment of active TB disease, pyrazinamide (PZA) is the most hepatotoxic. 1 This finding led to major guideline revisions in 2003 when the CDC and American Thoracic Society recommended against using rifampin-pyrazinamide (RZ) regimens for latent TB infection due to unacceptably high rates of severe liver injury and death. 1
Pyrazinamide-containing regimens were specifically excluded from WHO and European Respiratory Society treatment recommendations because of high documented toxicity. 1, 3
Comparative Hepatotoxicity Data
Incidence Rates by Drug:
- Pyrazinamide: 3.71 per 100 person-months 4
- Rifampicin: 0.69 per 100 person-months 4
- Isoniazid: 0.59 per 100 person-months 4
This demonstrates that pyrazinamide has approximately 5-6 times higher hepatotoxicity incidence compared to isoniazid or rifampicin when analyzed using time-dependent methods. 4
Clinical Patterns of Hepatotoxicity:
Two distinct patterns of liver injury occur with combination therapy: 5
- Early pattern (within 15 days): Typically rifampicin-enhanced isoniazid hepatotoxicity with generally good prognosis 5
- Late pattern (>1 month): Associated with pyrazinamide hepatotoxicity with generally poor prognosis 5
Why Ethambutol is Not the Answer
Ethambutol is rarely or not hepatotoxic and is not associated with significant liver injury. 5 Its primary toxicity is ocular (optic neuritis), not hepatic.
Critical Clinical Implications
The 2-month rifampin-pyrazinamide regimen for latent TB should never be offered to patients who: 1
- Are taking other hepatotoxic medications
- Drink excessive alcohol (even if discontinued)
- Have underlying liver disease
- Have history of isoniazid-associated liver injury
When pyrazinamide causes hepatotoxicity, it should not be reintroduced due to risk of recurrence and poor prognosis. 5 In contrast, isoniazid can often be cautiously reintroduced at low doses after transaminases normalize. 5
Monitoring Recommendations for Pyrazinamide-Containing Regimens
If pyrazinamide must be used, patients require intensive monitoring: 1
- Baseline liver function tests
- Monitoring at 2,4,6, and 8 weeks
- Immediate discontinuation if ALT >5× upper limit of normal (asymptomatic) or >3× with symptoms 5, 4
The answer is A - Pyrazinamide.