Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: Potential mechanism of improvement in transplant-free survival

R. Todd Stravitz, Arun J. Sanyal, Joan Reisch, Jasmohan S. Bajaj, Farid Mirshahi, Jenfeng Cheng, William M. Lee

Research output: Contribution to journalArticle

31 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1324-1331
Number of pages8
JournalLiver International
Volume33
Issue number9
DOIs
StatePublished - Oct 2013

Fingerprint

Acute Liver Failure
Acetylcysteine
Interleukin-17
Cytokines
Transplants
Survival
Hepatic Encephalopathy
Brain Diseases
International Normalized Ratio
Random Allocation
Enzyme-Linked Immunosorbent Assay
Placebos
Bilirubin
Logistic Models
Regression Analysis
Serum

Keywords

  • Acute liver failure
  • Cytokines
  • Liver transplantation
  • N-acetylcysteine

ASJC Scopus subject areas

  • Hepatology

Cite this

Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure : Potential mechanism of improvement in transplant-free survival. / Stravitz, R. Todd; Sanyal, Arun J.; Reisch, Joan; Bajaj, Jasmohan S.; Mirshahi, Farid; Cheng, Jenfeng; Lee, William M.

In: Liver International, Vol. 33, No. 9, 10.2013, p. 1324-1331.

Research output: Contribution to journalArticle

Stravitz, R. Todd ; Sanyal, Arun J. ; Reisch, Joan ; Bajaj, Jasmohan S. ; Mirshahi, Farid ; Cheng, Jenfeng ; Lee, William M. / Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure : Potential mechanism of improvement in transplant-free survival. In: Liver International. 2013 ; Vol. 33, No. 9. pp. 1324-1331.
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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. 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.",
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T1 - Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure

T2 - Potential mechanism of improvement in transplant-free survival

AU - Stravitz, R. Todd

AU - Sanyal, Arun J.

AU - Reisch, Joan

AU - Bajaj, Jasmohan S.

AU - Mirshahi, Farid

AU - Cheng, Jenfeng

AU - Lee, William M.

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N2 - 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.

AB - 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.

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