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