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Effects of N ‐acetylcysteine on cytokines in non‐acetaminophen acute liver failure: potential mechanism of improvement in transplant‐free survival
Author(s) -
Stravitz R. Todd,
Sanyal Arun J.,
Reisch Joan,
Bajaj Jasmohan S.,
Mirshahi Farid,
Cheng Jenfeng,
Lee William M.
Publication year - 2013
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12214
Subject(s) - medicine , hepatic encephalopathy , gastroenterology , randomization , placebo , encephalopathy , acetylcysteine , acetaminophen , randomized controlled trial , univariate analysis , multivariate analysis , pharmacology , cirrhosis , pathology , biochemistry , chemistry , alternative medicine , antioxidant
Background N ‐Acetylcysteine ( NAC ) improves transplant‐free survival in patients with non‐acetaminophen acute liver failure ( ALF ) when administered in early stages of hepatic encephalopathy. The mechanisms of this benefit are unknown. Aim To determine whether NAC improves transplant‐free survival in ALF by ameliorating the surge of pro‐inflammatory cytokines. Methods Serum samples were obtained from 78 participants of the randomized, ALF Study Group NAC Trial with grade 1 or 2 hepatic encephalopathy on randomization. Concentrations of ten cytokines, chosen to represent a wide array of inflammatory responses, were determined by multiplex enzyme‐linked immunosorbent assay ELISA . Results In univariate analysis, predictors of transplant‐free survival included NAC administration ( P = 0.012), admission bilirubin ( P = 0.003), international normalized ratio INR ( P = 0.0002), grade 1 vs. grade 2 encephalopathy ( P = 0.006) and lower admission interleukin ( IL )‐17 concentrations ( P = 0.011). IL ‐17 levels were higher in patients with grade 2 vs. grade 1 encephalopathy on randomization ( P = 0.007) and in those who progressed to grade 3 or grade 4 encephalopathy over the following 7 days ( P ≤ 0.01). Stepwise multivariate logistic regression analysis identified only NAC administration and lower IL ‐17 concentrations as independent predictors of transplant‐free survival. In patients with detectable IL ‐17 concentrations on admission, 78% of those who received NAC vs. 44% of those who received placebo had undetectable levels by day 3–5 ( P = 0.042), and the mean decrease in IL ‐17 concentrations between admission and late samples was significantly greater in patients who received NAC vs. placebo ( P = 0.045). Conclusions N ‐acetylcysteine ( NAC ) may improve transplant‐free survival in patients with non‐acetaminophen ALF by ameliorating the production of IL ‐17, which is associated with progression of hepatic encephalopathy and poor outcome.