Research ArticleEnteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: A randomized multicenter controlled trial
Introduction
Acute alcoholic hepatitis (AAH) is the most severe form of alcoholic liver disease (ALD) and is characterized by hepatocellular necrosis, ballooning degeneration, an inflammatory reaction with numerous polymorphonuclear leukocytes and fibrosis [1], [2].
Severe AAH is identified by the presence of encephalopathy and/or a discriminant function (DF) ⩾32 [3], [4]. DF ⩾32 prospectively identifies patients with a 40–50% risk of dying within 2 months [5]. Treatment of AAH consists of abstinence from alcohol and correction of nutritional deficiencies [6]. Corticosteroids are generally recommended in patients with severe AAH. Indeed, a recent analysis of individual data from the last three randomized-controlled trials showed significantly higher 1-month survival in corticosteroid-treated patients than in controls with severe AAH [7]. However, corticosteroids do not improve long-term survival in patients with severe AAH [7]. Therefore, the search for alternative therapeutic options is crucial. Antioxidant therapy is of theoretical interest in the treatment of alcoholic hepatitis due to increasing evidence that oxidative stress is a key mechanism in alcohol-mediated hepatotoxicity [6], [8]. Ethanol consumption results in depletion of endogenous antioxidant capacities, and patients with ALD show evidence of antioxidant deficiencies [9]. In particular, chronic ethanol consumption has been reported to cause selective deficiency in the availability of reduced glutathione (GSH) in mitochondria due to impaired functioning of the specific mitochondrial carrier that translocates GSH from the cytosol into the mitochondrial matrix [10], [11].
Due to its effect on glutathione store restoration, and consequently, upon limitation of oxidative stress, N-acetylcysteine (NAC), which has an excellent tolerance and safety profile, is a potential therapeutic agent in the treatment of AAH. NAC also inhibits apoptosis and proinflammatory cytokine production [12], [13].
In addition, patients with severe AAH are frequently malnourished and may often remain anorectic for several weeks [14]. Recent evidence has indicated that adequate enteral nutritional support might have an important impact on long-term survival in these patients [15]. In this context, we hypothesized that NAC in association with adequate nutritional support, might be beneficial in severe AAH.
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Patient selection and treatment
This Belgian multicenter, single-blinded, controlled trial under the auspices of the Belgian Association for the Study of the Liver (BASL) recruited patients from three participating centers (Erasme University Hospital, Brussels; Brugmann Hospital, Brussels; Ghent University Hospital, Ghent). Inclusion criteria included biopsy-proven alcoholic hepatitis (defined by the presence of satellitosis) and severe disease defined by a DF ⩾32 at baseline [total bilirubin in mg% + 4.6 × (patient prothrombin
Results
Among 54 eligible patients, 52 were randomized between September 2000 and November 2005 (28 into the NAC group and 24 into the control group). Among these 52 patients, five were excluded from analysis because of a baseline DF <32. From the 47 analyzed patients, 27 were randomized into the NAC group and 20 into the control group (Fig. 1). No significant difference between the NAC and control groups was observed for age, gender distribution, DF, model for end-stage liver disease (MELD) score,
Discussion
This multicentric-randomized trial showed that administration of high doses of intravenous N-acetylcysteine for 14 days to patients with severe biopsy-proven AAH had no significant impact on 1- or 6-month survival in patients receiving adequate nutritional support.
Through numerous and complex pathways, alcohol affects the liver and leads to the development of alcoholic liver disease and alcoholic hepatitis. One factor which plays a central role in numerous pathways of alcohol-induced liver
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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