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 />
108 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 109<br />
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012<br />
One study comparing pentoxifylline to corticosteroids, reported a significant prevention <strong>of</strong> <strong>the</strong> HRS, resulting<br />
in a better outcome in pentoxifylline-treated patients [32]. In a recent trial in 270 patients with severe ASH<br />
(PTX) <strong>the</strong> combination <strong>of</strong> pentoxifylline to prednisolone did not bring any benefit over corticosteroids alone.<br />
Finally, in patients with severe ASH and a poor response to corticosteroids defined by <strong>the</strong> lack <strong>of</strong> decrease<br />
in serum bilirubin, an early switch to pentoxifylline does not modify outcome [33].<br />
Thus, in patients with severe ASH and uncontrolled sepsis representing a contraindication to steroids,<br />
pentoxyfilline can be considered as a first line <strong>the</strong>rapy. However, pentoxyfilline does not seem to be useful<br />
as a rescue tool in non-responders to steroids at day 7 <strong>of</strong> <strong>the</strong>rapy, with or without <strong>the</strong> HRS.<br />
Anti- TNFα agents<br />
Because strong evidence supported a central role <strong>for</strong> TNFα in experimental models <strong>of</strong> ALD, a randomized<br />
pilot study in patients with severe ASH tested single dose infliximab in combination with corticosteroids.<br />
It showed a significant improvement <strong>of</strong> liver function [34]. However, <strong>the</strong> effectiveness <strong>of</strong> anti-TNFα was<br />
not confirmed in 2 randomized controlled trials testing multiple doses <strong>of</strong> Infliximab [35] or Etanercept [36].<br />
In fact, anti-TNFα treatment, compared to placebo, was associated with a higher probability <strong>of</strong> severe<br />
infections and deaths [35, 36]. It may be speculated that prolonged or excessive TNF blockade negatively<br />
impacts liver regeneration.<br />
N-acetylcysteine<br />
N-acetylcysteine replenishes glutathione stores in hepatocytes and can be seen as an antioxidant. Adding<br />
N-acetyl cysteine (NAC) to enteral nutrition did not bring any benefit in patients with severe ASH, possibly<br />
because glutathion stores may be restored ei<strong>the</strong>r by TEN or by NAC [37]. N-acetylcysteine alone is inferior<br />
to corticosteroids on short-term survival [14]. In a recent trial, however, combining N-acetylcysteine with<br />
corticosteroids resulted in a lower incidence <strong>of</strong> both <strong>the</strong> HRS and infection, and in an improved 1-month<br />
survival compared to corticosteroids alone [38]. This benefit was not maintained at 6-months, raising <strong>the</strong><br />
question <strong>of</strong> optimal duration <strong>of</strong> N-acetylcysteine administration.<br />
<strong>Liver</strong> transplantation<br />
ASH is usually considered as a contraindication <strong>for</strong> transplantation (OLT). This is related both to <strong>the</strong> fact<br />
most patients with ASH will improve <strong>for</strong> at least 6 months after abstinence has been reached, and to <strong>the</strong><br />
“6-month abstinence rule” [39]. The 6 months’ abstinence rule, although socially acceptable and associated<br />
with low harmful alcohol relapse after OLT, can be substituted by o<strong>the</strong>r elements predictive <strong>of</strong> abstinence,<br />
such as social / family support and absence <strong>of</strong> psychiatric / addictive disorders [39]. New prognostic models<br />
now allow <strong>the</strong> early identification <strong>of</strong> non- or poor-responders to corticosteroids with a Lille score above<br />
0.45 or 0.56 at day 7 <strong>of</strong> <strong>the</strong>rapy and only a 25% chance <strong>of</strong> being alive at 6 months. Recently a French and<br />
Belgian group initiated an early OLT program in patients with a first episode <strong>of</strong> severe ASH not responding<br />
to medical <strong>the</strong>rapy. Unequivocal improvement <strong>of</strong> survival in patients was observed in patients who received<br />
early transplantation compared both to non-random controls matched <strong>for</strong> age, sex, MDF, and Lille score,<br />
or to randomly sampled controls from a prospective database [40]. Obviously, early OLT in ASH may be<br />
relevant only in a very small minority <strong>of</strong> patients after a highly selective selection process involving patient’s<br />
families and multidisciplinary medical teams.<br />
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