Understanding the inherent hepatic risk and pathophysiology of individual agents is crucial for constructing safe bridging regimens and navigating dose-escalation rechallenges.
| Drug Class | Agent | DILI Propensity | Clinical Mechanism & Notes |
|---|---|---|---|
| First-Line (DS-TB) |
Pyrazinamide (Z) | HIGH RISK | Dose-dependent direct structural damage. Highest risk of fulminant necrosis. Never rechallenge if initial DILI was severe. |
| Isoniazid (H) | HIGH RISK | Idiosyncratic toxicity via toxic acetylhydrazine metabolites. Risk increases with age and slow NAT2 acetylator phenotype. | |
| Rifampicin (R) | MODERATE | Potent CYP450 inducer. Primarily causes transient unconjugated hyperbilirubinaemia by competing for biliary excretion, rather than true hepatocellular death. | |
| Ethambutol (E) | SAFE / RARE | Renally cleared. Serves as the backbone of liver-sparing bridging regimens. | |
| Group A (Core DR-TB) |
Lfx / Mfx | SAFE / RARE | Incidence <1%. Safe for bridging unless there is documented pre-existing fluoroquinolone resistance. |
| Bedaquiline (Bdq) | MODERATE | Can cause mild/moderate transaminitis, but rarely progresses to severe DILI. Monitor LFTs monthly. | |
| Linezolid (Lzd) | SAFE / RARE | Liver-sparing, but carries a high risk of myelosuppression and dose-dependent optic/peripheral neuropathy. | |
| Group B | Clofazimine (Cfz) | SAFE / RARE | Hepatotoxicity is extremely rare. |
| Cycloserine (Cs) | SAFE / RARE | Excellent bridging agent. Beware severe neuro-psychiatric side effects (psychosis, seizures). | |
| Group C (Add-on) |
Ethionamide (Eto) | HIGH RISK | Highly hepatotoxic (~5% incidence). Often permanently discontinued in severe DILI episodes. |
| PAS | MODERATE | Can cause severe hypersensitivity-driven hepatitis, often accompanied by rash and eosinophilia. | |
| Delamanid (Dlm) | SAFE / RARE | Generally safe for the liver. | |
| Aminoglycosides | SAFE / RARE | Renally cleared. No hepatic metabolism. Risk of nephrotoxicity and ototoxicity. |
A mild, asymptomatic elevation of transaminases (up to 3× ULN) occurs in up to 20% of patients initiating ATT. This is known as "hepatic adaptation" to Isoniazid. It is transient and typically resolves spontaneously without requiring treatment interruption. Unnecessary cessation of ATT in these asymptomatic patients is a major cause of treatment failure and acquired resistance.
AMA Style:
Umakanth S. ATT-Induced Hepatitis (DILI) Protocol. MEDiscuss. Published 2026. Accessed .
Vancouver Style:
Umakanth S. ATT-Induced Hepatitis (DILI) Protocol [Internet]. MEDiscuss.org; 2026 [cited ]. Available from:
