TABLE 2.

Characteristics of observational studies included in the systematic review.

Study, year (country)	Design	Mean age (y) (Ex/Cn)	Patients (Ex/Cn) a	Treatment regimen	Outcomes primary (P) secondary (S)	TD	DILI criteria/severity	Events d (Ex/Cn)	AE (Ex/Cn)	Summary of conclusion
DILI prevention
Torres-Diaz et al., 2018 c (United States)	Study type: retrospective	49	11	Ex: 600 mg oral NAC (b.d)	P: INH-induced DILI incidence	Average of 47 days	DILI criteria: NA	2	0	NAC is a safe and effective measure to prevent INH-induced DILI
	SSE: NA			Cn: uncontrolled			Severity: NA
DILI Treatment
Mumtaz et al. 2009 (Pakistan)	Study type: ambispective	28/38.5	47/44	Ex: Oral NAC (140 mg/kg, followed by 70 mg/kg, for a total of 17 doses, 4 h apart within 6 h of admission	P: Mortality	72 h	DILI criteria: NA	25/32	6/NA	NAC causes reduction in mortality and is safe to use in NAI-ALF patients
	SSE: 88			Cn: Patients not treated with NAC (historical controls)	S: AE and factors predicting mortality		Severity: ALF: impaired liver function tests and encephalopathy
Darweesh et al. 2017 (Eqypt)	Study type: ambispective	34/35	85/70	Ex: Infusion of 150 mg/kg in 100 ml GLC 5% over 30 min, followed by 70 mg/kg in 500 ml GLC 5% over 4 h, then 70 mg/kg in 500 ml GLC 5% over 16 h. Continuous infusion of 150 mg/kg in 500 ml GLC 5% over 24 h (until INR < 1.3, twice), then oral 600 mg NAC/d	P: Mortality and LT	10 days (mean)	DILI criteria: NA	1/16 b	96/NA	NAC reduces mortality, LT, encephalopathy, hospital stay, ICU admission, and other organ failures in NAI-ALF patients
	SSE: 88			Cn: Patients not treated with NAC (historical controls)	S: length of ICU stays, hospital stays, organ system failure, hepatic encephalopathy		Severity: ALF: TBil > 25 umol/L and INR > 1.5) with or without encephalopathy
Borlak et al. 2018 (Germany)	Study type: retrospective	54/53	20/30	Ex: IV 5% GLC with NAC (10 g, 42 ml/h over 24 h × 7 days) and prednisolone (1 mg/kg/d until serum transaminases returned to normal)	P: ALT, AST and TBil levels	Average of 21 days	DILI criteria: NA.	3.03/8.41 (ALT mean value at at 2 weeks)	0	NAC/prednisolone was well tolerated and led to significant ALT, AST and INR improvements within 2 weeks
	SSE: NA			Cn: sFILI not treated with NAC (external group)			Severity: MELD score
Torres-Diaz et al., 2018 c (United States)	Study type: retrospective	49	8	Ex: NA	P: ALT and AST levels	Variable duration	DILI criteria: NA	100 (ALT mean value at 30 days)	0	NAC is a safe and effective measure to treat INH-induced DILI
	SSE: NA			Cn: uncontrolled			Severity: NA
Bass et al. (2021) (United States)	Study type: retrospective	52./52	13/40	Ex: IV NAC > 72 h	P: Time (d) to INR <1.3 or 1.5	Ex:5 days (median)	DILI criteria: NA	4/4 (median value)	NA	Extended duration of NAC leads to higher transplant-free survival, but does not appear to influence time to INR normalization or overall survival
	SSE: NA			Cn: IV NAC for 72 h	S: All-cause mortality and transplant-free survival at 3 weeks	Cn: 3 days	Severity: ALF: Encephalopathy and coagulopathy (INR ≥ 1.5) in the absence of chronic underlying liver disease, caused by illness of duration <24 weeks

^aPatients included in the final analysis.

^bNumber of patients who died.

^cThis study evaluated NAC as prevention and treatment in the same study.

^dRelated to primary outcome.

Abbreviations: AE, adverse events; ALF, acute liver failure; ALT, alanine aminotransferase; AST, aspartate aminotransferase; b.d., twice daily; Cn, control group; d, day; DILI, drug-induced liver injury; Ex, experimental group; h, hours; GLC, glucose; INH, isoniazid; IV, intravenous; INH, isoniazid; LT, liver transplantation; NA, not available; NAC, N-acetylcysteine; NAI-ALF, non-acetaminophen-induced ALF; INR, international normalized ratio; sFILI, severe flupirtine-induced liver injury; SSE, sample size estimation; TBil, total bilirubin; TD, treatment duration.