A 32-year-old man from rural Maharashtra presents with a 3-month history of productive cough, fever, and night sweats. Chest X-ray shows cavitary lesions in the right upper lobe. Sputum smear microscopy (Ziehl-Neelsen stain) is positive for acid-fast bacilli. He is started on standard anti-tuberculous therapy (RIPE). After 2 weeks of treatment, he develops sudden-onset jaundice, elevated transaminases (AST 320 U/L, ALT 280 U/L), and abdominal pain. Which drug is most likely responsible for this hepatotoxicity?

Explanation

## Hepatotoxicity in Anti-TB Therapy ### Clinical Presentation The patient develops acute hepatotoxicity (elevated transaminases, jaundice) within 2 weeks of starting standard RIPE therapy. The timing and severity of liver injury are critical diagnostic clues. ### Hepatotoxic Potential of First-Line Anti-TB Drugs | Drug | Hepatotoxicity Mechanism | Incidence | Onset | Severity | |------|--------------------------|-----------|-------|----------| | **Pyrazinamide** | Direct hepatocellular injury; hyperuricemia | 1–3% | 2–8 weeks | Dose-dependent; can be severe | | **Isoniazid** | Metabolite-mediated (acetylhydrazide); idiosyncratic | 0.5–2% | 4–12 weeks | Variable; slow onset | | **Rifampicin** | Enzyme induction; rare direct toxicity | <0.5% | Later onset | Usually mild | | **Ethambutol** | Minimal hepatotoxicity | <0.1% | N/A | Rare | **Key Point:** Pyrazinamide is the most hepatotoxic first-line anti-TB agent, with dose-dependent hepatocellular injury and a relatively early onset (2–8 weeks). It causes direct hepatocellular necrosis and is the first drug to suspect in acute hepatotoxicity during TB treatment. ### Why Pyrazinamide in This Case 1. **Early onset** (2 weeks fits the 2–8 week window for PZA) 2. **Dose-dependent** — standard dosing (25 mg/kg/day) is within the toxic range for susceptible individuals 3. **Marked transaminitis** — AST/ALT >250 U/L is typical of PZA hepatotoxicity 4. **Direct hepatocellular injury** — produces acute necrosis, not cholestasis **Clinical Pearl:** When acute hepatotoxicity occurs early in TB treatment (first 4 weeks), pyrazinamide should be withdrawn first. Isoniazid and rifampicin are continued if tolerated, and PZA is reintroduced cautiously after liver function normalizes. **High-Yield:** PZA is contraindicated in patients with baseline liver disease, gout (hyperuricemia), or prior TB hepatotoxicity. Always check baseline LFTs before starting TB therapy.