A 28-year-old woman with newly diagnosed pulmonary TB is started on standard anti-TB therapy (HRZE). After 1 week, she develops jaundice, elevated transaminases (AST 320 U/L, ALT 280 U/L), and total bilirubin 4.2 mg/dL. Viral hepatitis serology is negative. Abdominal ultrasound is normal. She denies alcohol use. Which anti-TB drug is most likely responsible, and what is the most appropriate management?

Explanation

## Clinical Diagnosis This patient has **drug-induced hepatotoxicity** from anti-TB therapy, presenting within 1 week of initiation. The pattern of hepatocellular injury (elevated transaminases > bilirubin) with negative viral serology and normal imaging points to a direct drug effect. ## Hepatotoxicity Risk Among Anti-TB Drugs | Drug | Hepatotoxicity Risk | Mechanism | Onset | Management | |------|-------------------|-----------|-------|-------------| | **Isoniazid** | High (1–2%) | Idiosyncratic/dose-dependent | 1–8 weeks | Discontinue; rechallenge after recovery | | **Rifampicin** | Moderate (0.5%) | Enzyme induction; rare cholestasis | 2–8 weeks | Continue if mild; monitor closely | | **Pyrazinamide** | High (1–5%) | Hyperuricemia + direct hepatotoxicity | **Days 1–2 weeks** | **Discontinue; rechallenge after recovery** | | **Ethambutol** | Very low (<0.1%) | Rare; usually asymptomatic | Variable | Continue; monitor | ## High-Yield: **Pyrazinamide is the most common cause of early hepatotoxicity in anti-TB therapy** — it accounts for up to 50% of drug-induced liver injury in TB patients. The onset is typically **within the first 2 weeks**, which matches this case. ## Key Point: **Management of TB drug-induced hepatotoxicity (AST/ALT >3× ULN or bilirubin >2× ULN):** 1. **Discontinue all hepatotoxic drugs** (INH, RIF, PZA) immediately 2. Continue **non-hepatotoxic drugs** (ETH, fluoroquinolones) if available 3. Monitor liver function weekly 4. Once LFTs normalize, **rechallenge drugs one at a time** in order: INH → RIF → PZA 5. In this case: **Stop HRZE, continue ETH alone**, then reintroduce HRE after recovery, and finally add PZA back ## Clinical Pearl: Pyrazinamide-induced hepatotoxicity is dose-dependent and more common at standard doses (25 mg/kg/day). Unlike isoniazid, which is idiosyncratic, PZA toxicity is predictable and dose-related. Rechallenge is usually successful after a washout period. ## Mnemonic: **HIP** — **H**epatotoxic **I**soniazid, **P**yrazinamide (and **R**ifampicin to a lesser extent) [cite:RNTCP Guidelines 2023, Robbins 10e Ch 8]