A 52-year-old man with newly diagnosed pulmonary tuberculosis is started on standard 4-drug therapy. He develops hepatotoxicity on day 8. Which antitubercular drug is the most likely culprit, and what distinguishes its hepatotoxicity from pyrazinamide-induced liver injury?

Explanation

## Hepatotoxicity: Isoniazid vs. Pyrazinamide in Tuberculosis ### Isoniazid-Induced Hepatotoxicity **Key Point:** Isoniazid causes **idiosyncratic (unpredictable) hepatitis** that is: - **NOT dose-dependent** — occurs at standard therapeutic doses - Mediated by toxic metabolite (acetylisoniazid → isonicotinic acyl-CoA) - More common in slow acetylators - Risk increases with age, alcohol use, pre-existing liver disease - Onset: typically 4–8 weeks, but can occur within days - Presentation: acute hepatocellular injury (↑ ALT/AST >> ALP) **Clinical Pearl:** Baseline LFTs and monthly monitoring are recommended. Discontinue immediately if ALT rises >3× ULN or if jaundice develops. ### Pyrazinamide-Induced Hepatotoxicity **High-Yield:** Pyrazinamide causes **dose-dependent hepatotoxicity** that is: - Predictable and concentration-dependent - Mediated by uric acid accumulation (pyrazinamide → pyrazinoic acid) - Reversible upon dose reduction or discontinuation - Presentation: usually mild transaminitis, often asymptomatic - Risk factors: high doses, renal impairment, gout ### Mechanistic Comparison Table | Feature | Isoniazid | Pyrazinamide | | --- | --- | --- | | **Type of Hepatotoxicity** | Idiosyncratic (unpredictable) | Dose-dependent (predictable) | | **Dose Relationship** | Independent of dose | Proportional to dose | | **Acetylator Status** | Slow acetylators at ↑ risk | No acetylator influence | | **Mechanism** | Toxic metabolite (acetyl-INH) | Uric acid accumulation | | **Severity** | Can be severe/fulminant | Usually mild | | **Reversibility** | May require permanent discontinuation | Reversible with dose ↓ | | **Onset** | 4–8 weeks (range: days to months) | Variable | | **LFT Pattern** | Hepatocellular (↑↑ ALT/AST) | Mixed or cholestatic | **Mnemonic:** **INH = Idiosyncratic** (Isoniazid Neuropathy and Hepatitis are Idiosyncratic) **Warning:** Do NOT assume all antitubercular hepatotoxicity is dose-dependent — isoniazid's idiosyncratic nature means it can occur at any dose and is unpredictable. [cite:Harrison 21e Ch 202]