A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis

Background/Aims

Oxidative stress is putatively involved in the pathogenesis of alcohol-induced liver injury. This trial was devised to determine whether antioxidant therapy, alone or as an adjunct to corticosteroids, improved survival in patients with acute alcoholic hepatitis.

Methods

Patients with a severe alcoholic hepatitis were stratified by sex and steroid use, and then randomized. The active group received N-acetylcysteine for one week, and vitamins A–E, biotin, selenium, zinc, manganese, copper, magnesium, folic acid and Coenzyme Q daily for 6 months. The trial was double blinded and placebo controlled. The primary end-point was mortality within 6 months.

Results

Thirty-six (20 male, 16 female; mean discriminant function (DF) 86.6) received active drug, and 34 (18 male, 16 female; mean DF 76.4) received placebo. 180-day survival was not significantly different between patients receiving drug and placebo (52.8% vs. 55.8%, p = 0.699). This was not affected by stratification for steroid use or sex. The only predictors of survival in multivariate analysis were initial bilirubin (p = 0.017), white cell count (p = 0.016) and age (p = 0.037). Treatment allocation did not affect survival in multivariate analysis (p = 0.830).

Conclusions

Antioxidant therapy, alone or in combination with corticosteroids, does not improve 6-month survival in severe alcoholic hepatitis.

Introduction

Alcoholic hepatitis is a disease with a wide clinical spectrum, ranging from sub-clinical forms to a severe acute disease. The mild forms have a good short-term prognosis, but the in-hospital mortality rate of the severe form is around 40% [1]. Features that identify patients with a high mortality include the presence of encephalopathy, a high serum bilirubin and a prolonged prothrombin time. These latter two variables have been combined to form the discriminant function (DF) [2], which has been shown to prospectively identify patients with a 40–50% risk of dying within 2 months [3]. Conventional management consists of abstinence from alcohol, the correction of dietary deficiencies and general support. Of the specific therapeutic agents evaluated prior to trial commencement, only glucocorticoids have been shown to have any benefit on survival. A recent analysis of individual patient data from the last three randomized controlled trials (RCTs) showed a higher 28 day survival (84.6 ± 3.4% vs. 65.1 ± 4.8%, p = 0.001) in corticosteroid compared to placebo treated patients with an initial DF of >32 [4]. Importantly, active infection and gastrointestinal bleeding are still contraindications to steroid treatment in most centers, and both are relatively common in these patients. Furthermore, mortality is still high whether patients do or do not receive steroids, implying the need for alternative therapeutic options.

Interest in the possible value of antioxidant therapy in the treatment of alcoholic hepatitis has arisen as a result of increasing evidence implicating oxidative stress as a key mechanism in alcohol-mediated hepatotoxicity [5]. This evidence falls into five categories. First, products of lipid peroxidation can be detected in the peripheral blood of heavy drinkers [6] and in the livers of patients with ALD [7], and the magnitude of lipid peroxidation correlates with the degree of liver injury [8]. Second, in patients and animal models of ALD, lipid peroxidation is most prominent in the perivenular region where the liver injury is typically most severe [7]. Third, a variety of sources of oxidative stress have been identified in patients with ALD and in animal models of disease. Considerable controversy remains over the most important source of the pro-oxidant reactive oxygen species (ROS) which are capable of initiating lipid peroxidation and damaging plasma and intracellular membranes [9], but the most likely appear to be microsomal cytochrome P4502E1 (CYP2E1; the only source of hydroxyethyl radicals [10], [11]), the mitochondrial electron transport chain [12], inducible nitric oxide synthase [13] and Kupffer cells [14], [15]. Fourth, ethanol consumption results in the depletion of endogenous antioxidant capabilities and patients with ALD have evidence of antioxidant deficiencies. Consumption of glutathione (GSH) during oxidative stress and inhibition of two enzymes involved in the synthesis of its precursor, S-adenosylmethionine (SAMe), methionine synthase (MS) and methionine adenosyltransferase (MAT), contribute to the decreased levels of hepatic SAMe and GSH observed in patients with ALD [16]. Heavy drinkers, including those with ALD, are also deficient in the antioxidant trace element selenium [17], which is required for the activity of the antioxidant enzyme GSH peroxidase, the antioxidant vitamins A, C and E [18], [19] and Coenzyme Q [20]. This latter compound is present in plasma and mitochondrial matrix membranes and has emerged as one of the most important natural free radical scavengers. It is partly derived from the diet, but is also synthesized in the liver. Finally, in animal models of ALD, dietary [21], [22] and genetic manipulations [23], [24] that increase oxidative stress increase the severity of liver injury and reducing oxidative stress ameliorates injury [25], [26].

Given the nature and extent of this evidence, we were keen to determine whether antioxidant supplementation conferred any benefit to patients with severe alcoholic hepatitis.