Treatment of alcoholic hepatitis: is this a “dead-end”?

Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and liver failure that develops in subjects with chronic and active alcohol abuse [1]. The shortterm mortality in patients with severe disease, as defined by the Maddrey’s discriminant function, exceeds 30% [2]. Up to now, only two drugs, prednisolone and pentoxifylline, have shown some efficacy for the treatment of this condition. In a Cochrane meta-analysis published in 2008, glucocorticoids showed a nonsignificant trend toward a benefit in mortality [3]. However, a later reanalysis of the five largest studies that evaluated glucocorticoids indicated a significant benefit [4]. On the other hand, pentoxifylline has been shown to significantly increase survival in patients with severe AH, without any serious adverse effects [5]. This favorable outcome is mediated through a decrease in the rate of hepatorenal syndrome. Controversy over the treatment of choice for AH persists for many years as neither drug has convincingly shown superiority. This trial -the STOPAH trialevaluating the effect of treatment of AH with prednisolone or pentoxifylline has long been awaited with eagerness as it was expected to answer the question which drug is more efficient [6]. STOPAH trial was a large (1103 patients), multicenter, double-blind, randomized trial using a 2-by-2 factorial design. Four arms (placebo, prednisolone, pentoxifylline and prednisolone plus pentoxifylline) were incorporated. All drugs were prescribed for 28 days at doses of 40 mg daily for prednisolone and 400 mg three times daily for pentoxifylline. Patients with renal failure (serum creatinine >5.7 mg/dL or requiring renal replacement therapy) or other dismal characteristics such as untreated sepsis were excluded from the trial. All patients were followed for 12 months or until their death with the exception of patients enrolled at the end of the trial. The primary endpoint was mortality at 28 days and secondary endpoints included mortality or liver transplantation at 90 days and after 1 year. Neither drug showed mid(90 days) or long-term (12 months) survival benefit. However, prednisolone was associated with an improvement in 28-day mortality with an odds ratio of 0.72 (95%CI 0.52-1.01; P=0.06). In multivariate analysis, baseline age, encephalopathy, white cell count, prothrombin ratio and levels of bilirubin, creatinine and urea were found to be additional significant factors for mortality. In a secondary analysis adjusting for these prognostic variables the odds ratio for 28-day mortality among the patients who received prednisolone compared with those who did not was 0.61 (95%CI 0.41-0.91; P=0.02). Serious adverse events were reported in 42% of the patients with approximately half of them resulting in death. No significant differences in the rate of adverse events were noted between treatment groups. However, infection occurred more frequently in patients who received prednisolone compared with those who did not (13% vs. 7%, P=0.002). Of note, infections were the main reason for death in this trial (24% of deaths). Finally, pentoxifylline was associated with numerically fewer cases of acute kidney injury.