title: Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free survival.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Section of Hepatology, Division of Gastroenterology, Hepatology and Nutrition and the Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Stravitz
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: Joan
authors.initials: J
authors.lastname: Reisch
authors.forename: Jasmohan S
authors.initials: JS
authors.lastname: Bajaj
authors.forename: Farid
authors.initials: F
authors.lastname: Mirshahi
authors.forename: Jenfeng
authors.initials: J
authors.lastname: Cheng
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D006801:Humans; D017114:Liver Failure, Acute / Q000188:drug therapy*; D016015:Logistic Models
chemical_list: D016207:Cytokines; D000111:Acetylcysteine
keywords: N-acetylcysteine; acute liver failure; cytokines; liver transplantation