Understanding antituberculosis drug-induced hepatotoxicity: Risk factors and effective management strategies in the pediatric population

Table 1 Summary of pediatric studies on antitubercular therapy-induced hepatotoxicity in children

Ref.	Terminologies	Definition	Prevalence	Monitoring	Management
Mehra et al[9]	TB-DILI	Any 1: ALT/AST > 3 × ULN with symptoms; ALT/AST > 5 × ULN without symptoms; bilirubin > 1.5 mg/dL	12.3%	LFT baseline, 2/4/6 weeks, then every 2 months	Stop ATT, monitor LFTs every 3–5 days; Reintroduce full doses sequentially (Rifampicin, then Isoniazid, then Pyrazinamide)
Gafar et al[10]	ATLI	Any 1: ALT/AST > 3 × ULN with symptoms (> 5 × ULN without symptoms); bilirubin > 2 mg/dL with jaundice	26.8%	LFT at baseline, and 2 weeks. Then 4, 6, 8 weeks if 2 weeks LFT was abnormal	LFT weekly, Reintroduction of all 3 drug simultaneously
Yunivita et al[11]	ADIH	ALT/AST > 3 × ULN or > 1.5 × ULN if baseline is abnormal	27.9%	Not mentioned	Not mentioned
Indumathi et al[12]	ATDH	ALT > 3 or 5 × ULN with or without symptoms	2.7%	Clinical follow-up every 2 weeks (in IP); every 1 month (in CP)	Stop ATT; Rifampicin, INH and pyrazinamide were restarted in sequential manner
Aishatu et al[13]	Hepatotoxicity	ALT or AST > 3 × ULN	0%	LFT at baseline, at 2 and 5 months	ATT stopped; gradual reintroduction: Rifampicin first, then isoniazid
Nataprawira et al[14]	ADIH	Jaundice and/or total bilirubin > 1.5 mg/dL; and/or ALT > 3-5 × ULN above normal levels	3.5%	Not mentioned	Not mentioned
Hotchandani et al[15]	ATDIH	Jaundice and/or total bilirubin > 1.5 mg/dL; ALT 3-5 × ULN above normal level	13.92%	LFT baseline, 2/4/6 weeks, then every 2 months	ATT stopped; LFT twice per week; low-dose Rifampicin (7 days), then low-dose Isoniazid (7 days); increase doses of both over 10-14 days. PZA after 2 weeks
Mansukhani et al[16]	Hepatic Dysfunction	SGPT > 3 × ULN	15.2%	SGPT at baseline and after 15 days, then every 2 months	Not mentioned

TB-DILI: Tuberculosis drug-induced liver injury; ATLI: Antituberculosis liver injury, ADIH: Antituberculosis drug-induced hepatitis; ATDH: Antituberculosis drug hepatotoxicity; ATDIH: Antituberculosis drug-induced hepatotoxicity; ×: Times of; ATT: Antitubercular therapy; CLD: Chronic liver disease; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; LFT: Liver function test; ULN: Upper limit of normal; IP: Intensive Phase; CP: Continuation Phase; INH: Isoniazid.

Table 2 Management guidelines by various societies

	American Thoracic Society (2006: updated 2016) 14	British Thoracic Society (1998) 15	WHO (2010) 30	APASL (2021) 12	NTEP (2022) 16
Stopping hepatotoxic drugs in ATDIH	Yes	Yes	Yes	Yes	Yes
When to reintroduce ATT	ALT return to < 2 × ULN	ALT return to <2 × ULN	LFT return to normal and clinical Symptoms resolve	AST/ALT < 2× ULN Bilirubin < 1.5 × ULN	ALT return to < 2 × ULN
What drug and which regimen (sequentially or simultaneously)	RIF ± EMB full dose, after 3–7 days, INH full dose followed by PZA	INH → RIF→PZA (Dose titration every 2–3 days)	RIF→ introduce; INH after 3–7 days); PZA to avoid	RIF →INH→PZA (start low dose of each drug and titrate dose upwards every 3 days); Continue EMB full dose PZA (Restart only if mild DILI without jaundice)	RIF ± EMB full dose, after 3–7 days, INH full dose, followed by full dose PZA full dose
LFT monitoring during reintroduction	Check ALT 3–7 days after INH rechallenge	Daily Monitoring of LFT	LFT Monitoring (No recommendation on frequency)	Monitor LFT and INR every 3–7 days, earlier if symptoms arise	Check ALT 3–7 days after INH rechallenge

WHO: World Health Organization; APASL: Asia Pacific Association for the Study of the Liver; NTEP: National Tuberculosis Elimination Program, India; ATT: Antitubercular therapy; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; LFT: liver function test; ULN: Upper limit of normal; RIF: Rifampicin; INH: Isoniazid; EMB: ethambutol; PZA: Pyrazinamide; INR: International normalized ratio; DILI: Drug induced liver injury; →: Followed by; ×: Times of.