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

Authors

  • R. Todd Stravitz,

    Corresponding author
    • Section of Hepatology, Division of Gastroenterology, Hepatology and Nutrition and the Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
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  • Arun J. Sanyal,

    1. Section of Hepatology, Division of Gastroenterology, Hepatology and Nutrition and the Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
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  • Joan Reisch,

    1. Division of Biostatistics, Department of Clinical Sciences, University of Texas, Southwestern Medical Center, Dallas, TX, USA
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  • Jasmohan S. Bajaj,

    1. Section of Hepatology, Division of Gastroenterology, Hepatology and Nutrition and the Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
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  • Farid Mirshahi,

    1. Section of Hepatology, Division of Gastroenterology, Hepatology and Nutrition and the Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
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  • Jenfeng Cheng,

    1. Section of Hepatology, Division of Gastroenterology, Hepatology and Nutrition and the Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
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  • William M. Lee,

    1. Division of Digestive Diseases, Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
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  • The Acute Liver Failure Study Group


Correspondence

R. Todd Stravitz, M.D., Professor of Medicine, Medical Director of Liver Transplantation, Virginia Commonwealth University

PO Box 980341, Richmond, VA 232998-0341, USA

Tel: + 804 828 8514

Fax: + 804 828 4945

e-mail: rstravit@vcu.edu

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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