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

BARCELONA . SPAIN
108 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 109
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
One study comparing pentoxifylline to corticosteroids, reported a significant prevention of the HRS, resulting
in a better outcome in pentoxifylline-treated patients [32]. In a recent trial in 270 patients with severe ASH
(PTX) the combination of pentoxifylline to prednisolone did not bring any benefit over corticosteroids alone.
Finally, in patients with severe ASH and a poor response to corticosteroids defined by the lack of decrease
in serum bilirubin, an early switch to pentoxifylline does not modify outcome [33].
Thus, in patients with severe ASH and uncontrolled sepsis representing a contraindication to steroids,
pentoxyfilline can be considered as a first line therapy. However, pentoxyfilline does not seem to be useful
as a rescue tool in non-responders to steroids at day 7 of therapy, with or without the HRS.
Anti- TNFα agents
Because strong evidence supported a central role for TNFα in experimental models of ALD, a randomized
pilot study in patients with severe ASH tested single dose infliximab in combination with corticosteroids.
It showed a significant improvement of liver function [34]. However, the effectiveness of anti-TNFα was
not confirmed in 2 randomized controlled trials testing multiple doses of Infliximab [35] or Etanercept [36].
In fact, anti-TNFα treatment, compared to placebo, was associated with a higher probability of severe
infections and deaths [35, 36]. It may be speculated that prolonged or excessive TNF blockade negatively
impacts liver regeneration.
N-acetylcysteine
N-acetylcysteine replenishes glutathione stores in hepatocytes and can be seen as an antioxidant. Adding
N-acetyl cysteine (NAC) to enteral nutrition did not bring any benefit in patients with severe ASH, possibly
because glutathion stores may be restored either by TEN or by NAC [37]. N-acetylcysteine alone is inferior
to corticosteroids on short-term survival [14]. In a recent trial, however, combining N-acetylcysteine with
corticosteroids resulted in a lower incidence of both the HRS and infection, and in an improved 1-month
survival compared to corticosteroids alone [38]. This benefit was not maintained at 6-months, raising the
question of optimal duration of N-acetylcysteine administration.
Liver transplantation
ASH is usually considered as a contraindication for transplantation (OLT). This is related both to the fact
most patients with ASH will improve for at least 6 months after abstinence has been reached, and to the
“6-month abstinence rule” [39]. The 6 months’ abstinence rule, although socially acceptable and associated
with low harmful alcohol relapse after OLT, can be substituted by other elements predictive of abstinence,
such as social / family support and absence of psychiatric / addictive disorders [39]. New prognostic models
now allow the early identification of non- or poor-responders to corticosteroids with a Lille score above
0.45 or 0.56 at day 7 of therapy and only a 25% chance of being alive at 6 months. Recently a French and
Belgian group initiated an early OLT program in patients with a first episode of severe ASH not responding
to medical therapy. Unequivocal improvement of survival in patients was observed in patients who received
early transplantation compared both to non-random controls matched for age, sex, MDF, and Lille score,
or to randomly sampled controls from a prospective database [40]. Obviously, early OLT in ASH may be
relevant only in a very small minority of patients after a highly selective selection process involving patient’s
families and multidisciplinary medical teams.
REFERENCES
Sandahl TD, J.P., Thomsen KL, Vilstrup H, Incidence and mortality of alcoholic hepatitis
in Denmark 1999-2008: a nationwide population based cohort study. J Hepatol, 2011. 54(4):
p. 760-4.
National Hospital Discharge Survey: 2007, C.f.D.C., Atlanta, USA.
Kryger P, S.P., Dietrichson O, Juhl E, The accuracy of the clinical diagnosis in acute hepatitis
and alcoholic liver disease. Clinical versus morphological diagnosis. Scand J Gastroenterol,
1983. 18(5): p. 691-6.
Ramond MJ, P.T., Rueff B, Mathurin P, Theodore C, Chaput JC, Benhamou JP, A randomized
trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med, 1992. 326:
p. 507-512.
Spahr, L., et al., Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients
with alcoholic steatohepatitis. BMC Gastroenterol, 2011. 11: p. 115.
Mookerjee RP, L.C., Stauber R, Stadlbauer V, Deheragoda M, Aigelsreiter A, Jalan R,
The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration
of alcoholic cirrhosis. J Hepatol, 2011. 55(5): p. 1103-11.
Naveau S, G.V., Borotto E, Aubert A, Capron F, Chaput JC, Excess weight risk factor for
alcoholic liver disease. Hepatology, 1997. 25: p. 108-111.
Nyblom H, B.U., Balldin J, Olsson R, High AST/ALT ratio may indicate advanced alcoholic
liver disease rather than heavy drinking. Alcohol Alcohol, 2004. 39(4): p. 336-9.
Louvet A, W.F., Castel H,Dharancy S,Hollebecque A, Canva-Delcambre V, Deltenre
P, Mathurin P, Prospective screening of infection in patients with severe alcoholic hepatitis
treated with steroids: early response to therapy is the key factor. Gastroenterology, 2009.
137 p. 541-548.
Gelsi E, D.R., Truchi R, Marine-Barjoan E, Anty R, Autuori M, Burroni S, Vanbiervliet G,
Evesque L, Cherikh F, Tran A, Effect of Detoxification on Liver Stiffness Assessed by
Fibroscan((R)) in Alcoholic Patients. Alcohol Clin Exp Res, 2011. in press.
Mueller S, M.G., Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F,
Longerich T, Schirmacher P, Seitz HK, Increased liver stiffness in alcoholic liver
disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol, 2010. 16(8):
p. 966-72.
Maddrey WC, B.J., Bedine MS, Weber FL, Mezey E, White RI, Corticosteroid therapy
of alcoholic hepatitis. Gastroenterology, 1978. 75: p. 193-9.
Carithers RL Jr, H.H., Diehl AM, Shaw EW, Combes B, Fallon HJ, Maddrey WC,
Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized
multicenter trial. Ann Intern Med, 1989. 110: p. 685-90.
Phillips M, C.H., Portmann B, Donaldson N, Bomford A, O’Grady J Antioxidants versus
corticosteroids in the treatment of severe alcoholic hepatitis--a randomised clinical trial.
J Hepatol, 2006. 44 p. 784-790.
Dunn W, J.L., Brown LS, Wiesner RH, Kim WR, Menon KVN, Maclinchoc M, Kamath PS,
Shah V, MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology,
2005. 41: p. 353-358.
Forrest E H, E.C., Stewart S, Phillips M, Oo YH, McAvoy N C, Fisher NC, Singhal S,
Brind A, Haydon G, O’Grady J, Day CP, Hayes PC, Murray LS, Morris AJ, Analysis
of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the
Glasgow alcoholic hepatitis score. Gut, 2005. 54(8): p. 1174-1179.
Dominguez M, R.D., Abraldes JG, Miquel R, Colmenero J, Bellot P, Joan-Carles
Pagan G, Fernandez R, Moreno M,Banares R, Arroyo V, Caballerıa J, Gines P, Bataller R,
A New Scoring System for Prognostic Stratification of Patients With Alcoholic Hepatitis.
Am J Gastroenterol 2008. 103: p. 2747–2756.
Louvet A, N.S., Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F,
Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P,
The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis
treated with steroids. Hepatology, 2007. 45: p. 1348-1354.
Addolorato G, L.L., Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C,
Caputo F, Zambon A, Haber PS, Gasbarrini G, Effectiveness and safety of baclofen for
maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis:
randomised, double-blind controlled study. Lancet, 2007. 370(9603): p. 1915-1922.
Sullivan, J.T., et al., Assessment of alcohol withdrawal: the revised clinical institute
withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict, 1989. 84(11): p. 1353-7.
Plauth, M., et al., ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr, 2006.
25(2): p. 285-94.
Cabre E, R.-I.P., Caballeria J, Quer JC, Sanchez-Lombrana JL, Pares A, Papo M, Planas R,