Editorial

Prednisolone vs. pentoxifylline for severe alcoholic hepatitis

Alexandre Louvet
Hpital Huriez, Service des maladies de lappareil digestif, Lille, France; INSERM 995, Lille, France
See Article, pages 792798

In this issue, the Journal of Hepatology is publishing a non-inferiority trial by a Korean group on severe alcoholic hepatitis
addressing the question of the efcacy of pentoxifylline and corticosteroids. Although several studies have been performed in
this eld, this subject remains controversial. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) have published
guidelines [1,2] stating that pentoxifylline and corticosteroids
are effective in decreasing mortality in severe alcoholic hepatitis.
Studies have shown that the efcacy of pentoxifylline is due to a
reduction of the incidence of hepatorenal syndrome [3]. Several
papers including meta-analyses [4,5] have reported a benet in
survival in randomized patients treated with a 28-day course of
corticosteroids. Nevertheless, regardless of the molecule, 6month mortality rate remains high, around 3040% [4]. Very
few studies have compared pentoxifylline and corticosteroids
with a sufciently large population, and it is difcult to denitely
conrm that one drug is better than the other.
Some clinicians are still reluctant to use corticosteroids
because of the risk of infection. However, decompensated cirrhosis per se is associated with a marked risk of infection, mainly
because of liver impairment [6]. In the specic eld of severe
alcoholic hepatitis, our group has observed that up to 25% of
patients are admitted with active sepsis, which strongly suggests
that systematic screening for infection should be performed in
these patients. Another 25% will develop infection after corticosteroid treatment has begun, mainly in case of non-response to
this drug, supporting the strong link between liver impairment
and the incidence of infection [7]. This latter result is not in
favour of a direct relationship between increased infection and
the use of corticosteroids. An early assessment by the Lille model
can help clinicians tailor therapeutic management according to
the predicted risk of complications, including the risk of infection
[8]. For example, in patients with a Lille model above 0.56, we
strongly recommend withdrawing corticosteroids due to the lack
of benet of this drug in this subgroup [4].
The study by Park et al. published in this issue of the Journal of
Hepatology reports their work in 124 patients with severe
q

DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.05.014.

Address: Hpital Huriez, Service des maladies de lappareil digestif, Rue
Polonovski, Lille 59037, France. Tel.: +33 3 20 44 55 97; fax: +33 3 20 44 55 64.
E-mail address: alexandre.louvet@chru-lille.fr.

alcoholic hepatitis. Patients were randomized to receive pentoxifylline or prednisolone according to conventional doses recommended in this eld (1200 mg/day and 40 mg/day respectively).
Survival was 64.5% in the pentoxifylline-treated group and
72.9% in the prednisolone group. These results are close to those
in patients with severe alcoholic hepatitis published by other
groups. Complications were low with no signicant differences
between the two groups. Response to treatment assessed by
the Lille model [8] adequately predicted outcome in both
groups. This conrms the prognostic value of the Lille model
for predicting outcome in these two randomized groups. The latter result emphasizes the importance of early improvement in
liver function to improve survival.
In the study design of this paper, results with pentoxifylline
were not statistically equivalent to prednisolone and the authors
concluded that corticosteroids were better than pentoxifylline for
severe alcoholic hepatitis. The disappointing survival with pentoxifylline compared to prednisolone was also suggested by a
recent randomized controlled trial showing a lack of benet of
the association of pentoxifylline with prednisolone compared to
prednisolone alone [9].
Six-month survival was the primary endpoint of this trial, as
well as of previous trials in the eld [1012]. However, in the Corpentox study, a decrease in the incidence of hepatorenal syndrome was suggested although the sample size was not
calculated to address this issue. Because many studies have had
interesting results but did not show an improvement in 6-month
survival in severe alcoholic hepatitis [9,12], an international consensus is needed to dene new endpoints. This would help clinicians modify the design of future trials so that rather than shortterm survival, other surrogates markers predicting survival
would be the primary endpoint such as improvement in liver failure and/or the reduction of the incidence of severe complications
leading to death.
Although this study was well designed with a sufcient sample size, it comports some limitations, which were acknowledged
and discussed by the authors. An important limitation was the
absence of a histological diagnosis of alcoholic hepatitis. This
issue is crucial in severe alcoholic hepatitis because there are
no clinical or biological features to denitely establish the
diagnosis. For example, in a recent work [13], only 63% of
patients admitted with acute-on-chronic deterioration of alcoholic cirrhosis had satellitosis dened by a neutrophil inltration

Journal of Hepatology 2014 vol. 61 j 723724

Editorial
surrounding injured hepatocytes. This shows that all patients
with cirrhosis admitted with jaundice who continue drinking
should not be automatically considered as having alcoholic hepatitis. In a similar vein, EASL guidelines have stated that clinical
trials evaluating new strategies in severe alcoholic hepatitis
should be based on histological conrmation of the diagnosis
[1]. The controversy on the prerequisite of liver biopsy for studies
testing molecules emphasizes the urgent need for an expert consensus to establish the optimal design for future therapeutic
studies in patients with severe alcoholic hepatitis.
In summary, although this study has some limitations, the
work by Park is an important step in this setting because of the
quality of the design, the sufcient sample size and the quality
of the data. It reports that results with pentoxifylline were not
statistically equivalent to those of prednisolone. It supports that
corticosteroids may be considered rst-line therapy for severe
alcoholic hepatitis, although this is still being actively debated
by experts in this eld.
Conict of interest
The authors who have taken part in this study declared that they
do not have anything to disclose regarding funding or conict of
interest with respect to this manuscript.
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