barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
112 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 113
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH
ALCOHOLIC HEPATITIS ANSWER: YES
Jean-Charles Duclos-Vallée
Villejuif, France
E-mail: jean-charles.duclos-vallee@pbr.aphp.fr
KEY POINTS
• The benefits of liver transplantation (LT) in severe acute alcoholic hepatitis resistant to medical
treatment have now been demonstrated.
• The weakness of the 6-month abstinence rule is evidenced by the low relapse rate after LT in
highly selected patients.
• Before extending the indications for liver transplantation to patients with severe alcoholic
hepatitis, it is necessary to define new prognostic factors for relapse and interventional
therapies under a multidisciplinary approach.
In Europe, alcohol is the cause of about 30% cases of end-stage liver disease and is the leading reason
for liver transplantation (LT) (1). The post-LT survival rate is good, and 5-year survival is better than in
patients with other indications (78% vs. 64%, p= 0.016), with an alcohol relapse rate of 15.6% (2). Alcoholic
toxic liver disease (ALD) encompasses a spectrum of injuries that range from simple steatosis through
severe steatohepatitis to complete progression to cirrhosis with or without alcoholic hepatitis (AH). Although
patients with mild to moderate AH may respond to conservative management and abstinence, patients with
severe disease (Maddrey score ≥32) have an overall mortality rate of 40% within 6 months (3). The most
frequent treatment option available at present is corticosteroid therapy; if the lack of response assessed by
a Lille score is greater than 0.45, then 6-month survival is lower than 25% (4). Depending on the severity
of their liver disease, these patients are good candidates for liver transplantation. In patients with alcoholic
cirrhosis, the benefits of LT have been demonstrated in patients with Child –Pugh class C, who have
displayed a higher 1- and 5-year survival rates than their matched controls (5). Here, we shall be discussing
and focusing on the major factors that justify a reassessment of our policies regarding the acceptance of
liver transplantation in patients with severe acute alcoholic hepatitis.
THE WEAKNESS OF THE 6-MONTH ABSTINENCE RULE – THE STRENGTH OF OTHER FACTORS
Until now, alcoholic hepatitis has been considered as an absolute contraindication to liver transplantation
because most transplant centres require 6 months of abstinence prior to transplantation (6). But there is
now strong evidence that this 6 month abstinence rule is not scientifically relevant. The prospective study
performed by DiMartini et al. showed that among patients who had been sober for 36 months, only 40%
remained sober after LT (7); 36 months of pre-LT sobriety was 80% sensitive but only 40% specific in
predicting post-LT abstinence. Each additional month of pre-LT sobriety reduced the risk of drinking post-
LT by 33%. However, the authors could not identify a specific length of pre-LT sobriety that could predict
abstinence (7). They emphasised the fact that other factors such as alcohol dependence, family history,
depressive disorders and social support (i.e. marital status) should be evaluated and taken into account
because of their influence on patient and graft survival (8). Moreover, during a retrospective study on
long-term follow-up, patients who relapsed back into harmful drinking had poorer survival when compared
to abstainers (45% vs. 86%, p< 0.05) (9). Different trajectories of depressive symptoms can predict longterm
survival after LT. In a recent prospective study analyzing different trajectories of alcohol use, 113
of 208 patients (54%) had no reported alcohol use post-LT using any measure (10). Among the 95 nonabstainers,
four distinct trajectories of alcohol consumption could be identified. The majority (n=55) drank
small quantities infrequently, but three other groups also emerged; early onset moderate use that diminished
over time (n=13), later onset moderate use that increased over time (n=15, group 4) and an early onset,
heavy and increasing pattern of use (n=12, group 5). In terms of the comparative outcome between these
groups, deaths due to recurrent alcoholic liver disease, steatohepatitis or rejection were more frequent in
groups 3 and 5.
CURRENT EXPERIENCE OF LIVER TRANSPLANTATION FOR SEVERE ACUTE ALCOHOLIC
HEPATITIS
Few data are available concerning retrospective studies which have analysed the influence of acute alcoholic
hepatitis on survival following liver transplantation. In the study by Tomé et al. on patients transplanted for
alcoholic cirrhosis, survival was similar in patients with superimposed alcoholic hepatitis and with liver
cirrhosis alone (n=32) (11). Moreover, there was no difference in survival between patients with mild and
severe alcoholic hepatitis. In the study by Wells (12), histologically acute alcoholic hepatitis in the explanted
recipient liver did not predict a poorer outcome in terms of relapse, allograft survival or patient survival
among liver transplant recipients (12).
We recently reported our French experience from seven centres (13) in a study that included 26 patients
with severe alcoholic hepatitis with at a high risk of fatality because of a Median Lille score of 0.88. These
patients were carefully selected: all had good social support, no prior episodes of known alcoholic liver
disease and no evidence of severe psychological disorders. This selection represented fewer than 2% of
patients admitted for an episode of severe alcoholic hepatitis. Survival was excellent, with 6-month survival
and 24-month survival rates of 77 % and 71%, respectively. The 6-month survival rate was significantly
higher than among matched controls, in whom 6-month survival was 23%. Despite counselling with an
addiction specialist, three patients restarted their alcohol consumption during the post-LT period: one at 720
days, one at 740 days and one at 1140 days post-LT. Two of these patients remained daily consumers (30 g
per day and >50 g per day), whereas one only drank occasionally (approximately 10 g per week). However,
none of them experienced graft dysfunction. This highlighted the somewhat arbitrary nature of the 6-month
rule of abstinence. But we should of course bear in mind that these patients were highly selected. Because
there may have been bias in the selection of candidates, we must now take the opportunity to define new
prognostic factors for a relapse of alcohol consumption after LT for severe acute alcoholic hepatitis.
In the same way, it is necessary to define any clear patterns in the evolution of alcohol consumption that
might emerge following LT.
A RETHINK OF OUR APPROACH TO TRANSPLANTATION FOR ALCOHOLIC LIVER DISEASE:
OBJECTIVES FOR THE NEAR FUTURE; AN ETHICAL POINT OF VIEW
The approval of liver transplantation for severe acute alcoholic hepatitis in selected patients is an important
step towards accepting that addiction is a chronic, relapsing disease of the brain (14). Once this situation
has been accepted, and new prognostic markers have been developed, we will be able to define new
protocol strategies for severe liver disease in alcoholic patients. In this context, it is crucial to include geneenvironment
interactions in order to unravel the aetiological factors underlying alcohol outcomes before
and after LT (15). In a recent study, it was shown that gene polymorphism of Val66Met Brain-Derived