ATT Liver Injury and Rechallenge

What to hold, what to bridge with, and the order to rechallenge in. NTEP and APASL · v1.6

  • Say what you are deciding: whether to stop anti-tuberculosis treatment, or whether it can be restarted.
  • Enter the regimen the patient is on, the highest transaminase, the bilirubin, and whether there are symptoms or markers of hepatic failure.
  • You get the injury graded against the APASL and NTEP cessation criteria, a stop or continue decision, and a liver-sparing bridging regimen at NTEP weight-band doses where treatment is held.
  • Come back for the rechallenge and you get the stepwise reintroduction sequence, rifampicin then isoniazid then pyrazinamide, with the day-by-day doses.
  • Read the drug table below the form first. Which agent is most likely responsible is what decides the bridge and the order of return.

  • Whether the anti-tuberculosis drugs are the cause at all. The pathway assumes them, and viral hepatitis, alcohol and other hepatotoxic medicines have to be considered separately in every case.
  • The reintroduction sequence after drug-resistant tuberculosis. Standard rifampicin, isoniazid and pyrazinamide rechallenge does not apply, and the Nodal DR-TB Centre sets the order.
  • The management of established acute liver failure past stopping the drugs and arranging intensive care. No N-acetylcysteine schedule and no transplant criteria are printed.
  • The non-hepatic adverse effects the drug table names: optic neuritis, myelosuppression, neuropathy, and the neuro-psychiatric effects of cycloserine.

1. Clinical Management Phase

2. Laboratory & Clinical Parameters

Which ATT Drug Injures the Liver, and How

A bridging regimen is only as safe as the drugs left in it. Before holding treatment or restarting it, you need to know which agent is most likely to have caused the injury, and by what mechanism, because that decides which drugs can stay and in what order the rest come back.

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 Useful in a bridging regimen, and not hepatotoxic. Watch for neuro-psychiatric effects: psychosis and 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.

1. Hepatic Adaptation, and Why It Is Not DILI

A mild, asymptomatic elevation of transaminases (up to 3× ULN) occurs in up to 20% of patients initiating ATT. This is hepatic adaptation to Isoniazid. It is transient, and it settles on its own with treatment continuing. Unnecessary cessation of ATT in these asymptomatic patients is a major cause of treatment failure and acquired resistance.

Abbreviations ALF (Acute Liver Failure) · ALT (Alanine Aminotransferase) · APASL (Asia Pacific Association of Study of Liver) · AST (Aspartate Aminotransferase) · ATT (Anti-Tubercular Therapy) · Bdq (Bedaquiline) · BPaLM (Bedaquiline, Pretomanid, Linezolid, Moxifloxacin) · Cfz (Clofazimine) · Cs (Cycloserine) · CYP450 (Cytochrome P450) · DILI (Drug-Induced Liver Injury) · Dlm (Delamanid) · DR-TB (Drug-Resistant Tuberculosis) · DS-TB (Drug-Susceptible Tuberculosis) · E (Ethambutol) · Eto (Ethionamide) · FQ (Fluoroquinolone) · H (Isoniazid) · HRE (Isoniazid, Rifampicin, Ethambutol) · HRZE (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) · ICU (Intensive Care Unit) · INR (International Normalised Ratio) · IV (Intravenous) · LFT (Liver Function Test) · Lfx (Levofloxacin) · Lzd (Linezolid) · Mfx (Moxifloxacin) · NAC (N-Acetylcysteine) · NAT2 (N-Acetyltransferase 2) · NTEP (National Tuberculosis Elimination Programme) · PAS (Para-Aminosalicylic Acid) · PO (Per Os) · R (Rifampicin) · TB (Tuberculosis) · ULN (Upper Limit of Normal) · Z (Pyrazinamide)
References
  1. Central TB Division, Ministry of Health and Family Welfare, Government of India. Guidelines for Programmatic Management of Drug-Resistant Tuberculosis in India. New Delhi: MoHFW; March 2021, with the 2024 guidance on BPaLM.
  2. Indian Council of Medical Research. Standard Treatment Workflow: Anti-Tubercular Therapy (ATT) Related Hepatitis. New Delhi: ICMR; 18 March 2022.
  3. Devarbhavi H, et al. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines. Hepatol Int. 2021;15(2):258-282.
  4. Saukkonen JJ, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935-952.
  5. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):e147-e195.
  6. Sharma SK, Singla R, Sarda P, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis. 2010;50(6):833-839.
  7. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy. J Clin Gastroenterol. 1996;22(3):211-214.
  8. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med. 2002;166(7):916-919.
  9. Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WCM, van der Ven AJAM, Dekhuijzen R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol. 2008;23(2):192-202.
  10. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment. Drug-susceptible tuberculosis treatment. Geneva: WHO; 2022.
How to Cite This Tool

DOIhttps://doi.org/10.5281/zenodo.22401556

AMA Style:Umakanth S. ATT Liver Injury and Rechallenge. Version 1.6. MEDiscuss Clinical Decision Support System. Published 2026. Accessed . https://mediscuss.org/cdss/att-dili-management. doi:10.5281/zenodo.22401556

Vancouver Style:Umakanth S. ATT Liver Injury and Rechallenge [Internet]. Version 1.6. MEDiscuss.org; 2026 [cited ]. Available from: https://mediscuss.org/cdss/att-dili-management. doi:10.5281/zenodo.22401556

Disclaimer and scope
Disclaimer: This decision-support system is written for healthcare professionals. It does not substitute clinical judgment, and the treating physician retains absolute responsibility for every diagnostic, dosing and therapeutic decision. The algorithms are built on the evidence as it stands, and the evidence moves. Verify the output against your current institutional protocol, and against the patient in front of you.
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Category Therapeutic & Management PathwaysPathway
Specialties Internal Medicine

Written and maintained by

Dr Shashikiran Umakanth

Last revised 24 August 2026

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