Table 1.

Current evidence on the use of N-acetylcysteine in patients with non-paracetamol acute liver failure.

Author, Year	Type of Study	Number of Cases	Age of Participants (Years)	Dose of NAC	Co-Treatment/ Comparator	Observed Effects	Mortality
Mushroom poisoning (Amanita phalloides)
Locatelli C. et al., 1992 [27]	Case series	73	2–84	150 mg/kg bolus, followed by 50 mg/kg at 4 h intervals for 3–18 days	Forced diuresis	-low mortality regardless of LT	8%
Schneider S. et al., 1992 [33]	Experimental animal model	NA	NA	1.2 g/kg	None	-no benefits on survival -no improvement in LFT	NA
Locatelli C. et al., 2010 [36]	Cohort of patients	157	Mean: 52	150 mg/kg followed by 300 mg/kg/day until 48 h	Forced diuresis, activated charcoal	-no progression of severity of liver dysfunction	2.5%
Ahishali E. et al., 2012 [37]	Cohort of patients	77	Mean: 42	210 mg/kg/day for 3–5 days	Activated charcoal, Penicillin G, Sylibin, hemofiltration	-improvement in LFT -low mortality	2.6%
Akin A. et al., 2013 [38]	Case–control	40 patients: 24 in the NAC group vs. 16 in the control group	NAC: mean 32 Control: mean 34	12 g/day in four divided doses	Standard medical care	-decreased mortality -improved LFT from 24 h to 2 weeks in the NAC group	4.4% in the NAC group vs. 18.7% in the control group
Tan J. et al., 2022 [41]	Review of 133 studies	877 cases	NA	variable	NR	-improved survival of patients receiving NAC and silybin	NR
Viral hepatitis
Parkas A. et al., 2016 [53]	Cohort of patients	32 patients: 12 receiving NAC and 12 control	NAC: mean 7.2 Control: mean 7.3	100 mg/kg/day	Standard medical care	-decreased hospital LoS -non-significant decrease in mortality	44% in NAC group vs. 69% in control group
Gunduz H. et al., 2003 [55]	Randomized control trial	41 patients with VHA or VHB ALF	15–52	200 mg orally, three times per day	Standard medical care	-no improvement in LFT -no decrease in hospital LoS	NR
Dissanayake D. et al., 2021 [56]	Case series	30 patients with dengue fever and severe hepatitis	Mean: 49.9	100 mg/h for 3–5 days	Standard medical care	-faster recovery of liver enzymes after NAC administration	3.3%
Drug-induced liver injury
Moosa M. et al., 2020 [67]	Randomized control trial	53 patients with tuberculostatic-induced liver injury	NAC: mean 37 Placebo: mean 38	150 mg/kg over 1 h, 50 mg/kg over 4 h, and 100 mg/kg over 16 h	NR	-no faster improvement in LFT -decreased hospital LoS	14%
Eroglu N. et al., 2020 [68]	Case–control	102 pediatric patients with chemotherapy-induced hepatotoxicity: 70 received NAC	2–17 in both groups	3 μg/kg in a 24 h infusion	NR	-faster improvement of LFT	NR
Chughlay M. et al., 2016 [72]	Meta-analysis	45 patients: 19 in NAC group vs. 27 controls	NR	150 mg/kg/h over 1 h, then 12.5 mg/kg/h for 4 h, then 6.25 mg/kg/h for 67 h	NR	-improved transplant-free survival -no improvement in overall survival	21% in NAC group vs. 35% in controls
Sanabria-Cabrera J. et al., 2022 [73]	Systematic review	11 studies	NR (≥18)	Varying in different studies	NR	-improved transplant-free survival	NR
Shrestha D. et al., 2021 [74]	Meta-analysis	11 studies: 565 patients in the NAC group vs. 552 in the control group	NR	Varying in different studies	standard of care	-decreased mortality -shorter hospital LoS -improved HE	23.7% in NAC group vs. 35.1% in control group
Pregnancy-related ALF
Shabani S. et al., 2021 [82]	Randomized control trial	60 patients with severe pre-eclampsia	Mean: 26	600 mg at 0, 12, and 24 h after delivery	70 mg of silymarin	-improvement of LFT in both groups	NR
Roes E. et al., 2006 [83]	Randomized control trial	38 patients with severe pre-eclampsia and/or HELLP	NAC: 22–34 Control: 23–40	1800 mg every 8h	placebo	-no improvement in organ dysfunction or LoS	NR
Pooled analysis (all etiologies)
Lee W. et al., 2009 [84]	Randomized control trial	81 patients in the NAC group vs. 92 patients in the placebo group	NAC: 17–69 Control: 18–71	150 mg/kg/h for 1 h, followed by 12.5 mg/kg/h for 4 h and 6.25 mg/kg/h for 67 h	placebo	-increased transplant-free survival (in mild HE patients) -no difference in overall survival	30% in NAC group vs. 34% in control group
Mumtaz K. et al., 2009 [54]	Prospective study	47 patients in NAC group vs. 44 patients in historical cohort	NAC: 27 Control: 37	140 mg/kg orally, followed by 70 mg/kg at 4 h intervals for a total of 17 doses	Standard of care	-improved survival -worse neurological outcome	53.2% in NAC group vs. 72.7% in historical cohort
Darweesh S. et al., 2017 [85]	Randomized control trial	85 patients in the NAC group vs. 70 patients in the control group	NAC: 33 Placebo: 34	150 mg/kg for 1/2 h, followed by 70 mg/kg for 4 h, then 70 mg/kg for 16 h, and 150 mg/kg/day afterward	placebo	-improved overall survival -decreased need for LT -improved LFT -decreased incidence of HE	3.3% in treatment group vs. 23.3% in control group
Hu J. et al., 2015 [87]	Meta-analysis	4 studies: 331 patients in the NAC group vs. 285 patients in the control group	NR (adults and children)	orally or intravenously, in different doses	NR	-increased transplant-free survival -increased survival after LT -no difference in overall survival	29.0% in treatment group vs. 33.0% in control group
Walayat S. et al., 2021 [88]	Meta-analysis	7 studies: 472 patients in the NAC group vs. 411 in the control group	NAC: 21 Control: 26	orally or intravenously, in different doses	NR	-increased overall, transplant-free, and post-LT survival -shorter hospital LoS	23.7% in treatment group vs. 35.7% in control group

Abbreviations: NAC—N-acetylcysteine; LT—liver transplantation; h—hour; NA—not applicable; LFT—liver functional test; NR—not recorded; LoS—length of stay; VHA—viral hepatitis A; VHB—viral hepatitis B; ALF—acute liver failure; HE—hepatic encephalopathy.