Zusammenfassung
Die alkoholische Hepatitis (AH) ist ein klinisches Syndrom, welches durch eine schwere Leberentzündung (dominiert durch Infiltration mit neutrophilen Granulozyten), Leberzellschädigung und Fibrose charakterisiert ist und durch massiven Alkoholkonsum ausgelöst wird. Diese klinisch oft lebensbedrohliche Erkrankung entwickelt sich meist auf dem Boden einer bereits bestehenden Leberzirrhose. Klinische Leitsymptome sind Ikterus, Malaise, Gerinnungsstörung und Enzephalopathie. Typische Komplikationen sind dabei Sepsis und Organversagen und die Mortalität dieser Erkrankung beträgt unverändert bis zu 50 %. Im Vordergrund der Therapie stehen Alkoholabstinenz und supportive Maßnahmen. Kortikosteroide stellen seit Jahrzehnten die einzige Therapieoption dar. Die Indikation für eine Kortikosteroidtherapie wird bei einem Maddrey Score > 32 gestellt und nach 7 Tagen wird diese Therapie je nach Ansprechen (erfaßt über den Lille Score) beendet oder für insgesamt 4 Wochen fortgesetzt. Letzlich ist eine Kortikosteroidtherapie allerdings nur in einer Patientensubgruppe möglich und erfolgreich. Eine frühe Lebertransplantation (innerhalb Tagen bis wenigen Wochen nach Therapieversagen) stellt für streng selektionierte Patienten (keine Komorbiditäten, soziale Integration) eine Therapiealternative dar. In der Pathophysiologie dieser Erkrankung spielen pro-inflammatorische Zytokine wie Tumor Nekrose Faktor-alpha (TNFα) oder Interleukin-1 (IL-1) eine herausragende Rolle und diese Erkrankung ist heute der Prototyp einer zytokin-mediierten Erkrankung. Die Neutralisation dieser Schlüsselzytokine vor allem von IL-1 reflektiert das zur Zeit attraktivste Therapiekonzept für die Zukunft. Es ist zu hoffen, dass bei dieser von der (klinischen) Forschung leider zu sehr vernachlässigten Erkrankung in Zukunft bessere Therapieoptionen zur Verfügung stehen werden
Summary
Severe alcoholic hepatitis is still associated with high mortality and presence of liver failure manifested by jaundice, coagulopathy and encephalopathy is a poor prognostic indicator. The management of these patients includes at first hand several supportive measures as treatment of alcohol withdrawal, administration of fluid and vitamins and admission to an intensive care unit in the unstable patient. Glucocorticoids have been since decades the most intensively studied therapy in alcoholic hepatitis and are effective in certain subgroups. Indication for such a therapy is usually defined on a Maddrey Discriminant Function > 32. The Lille score at day 7 is used to decide whether corticosteroid therapy should be stopped or continued for a 1 month course. Nutritional supplementation is also likely to be beneficial. The main progress in better understanding its pathophysiology has come from cytokine studies. Various proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) or interleukin-1 (IL-1) have been proposed to play a role in this disease. This advancement has recently led to pilot studies investigating anti-TNF drugs such as pentoxifylline, infliximab (anti-TNF antibody) or etanercept in the treatment of this disease. These studies revealed besides for pentoxifylline rather negative results. Despite this fact, targeting of certain cytokines such as IL-1 remains an attractive treatment concept for this devastating disorder in the future.
Literatur
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360:2758–69.
Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7:599–612.
Stewart SF, Day CP. The management of alcoholic liver disease. J Hepatol. 2003;38(Suppl 1):2–13.
Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transpl. 2011;17:751–9.
Stickel F, Hampe J. Genetic determinants of alcoholic liver disease. Gut. 2012;61:150–9.
Tilg H, Moschen AR, Kaneider NC. Pathways of liver injury in alcoholic liver disease. J Hepatol. 2011;55:1159–61.
Easl clinical practical guidelines. management of alcoholic liver disease. J Hepatol. 2012;57:399–420.
Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60:255–60.
Sandahl TD, Jepsen P, Thomsen KL, Vilstrup H. Incidence and mortality of alcoholic hepatitis in denmark 1999–2008: a nationwide population based cohort study. J Hepatol. 2011;54:760–4.
O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51:307–28.
Maddrey WC, Boitnott JK, Bedine MS, Weber FL, Jr., Mezey E, White RI, Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978;75:193–9.
Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, et al. The lille model: A new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45:1348–54.
Tilg H, Day CP. Management strategies in alcoholic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:24–34.
Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365:1790–800.
Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003;348:1786–95.
Easl clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010; 53:397–417.
Boyer TD, Sanyal AJ, Garcia-Tsao G, Blei A, Carl D, Bexon AS, et al. Predictors of response to terlipressin plus albumin in hepatorenal syndrome (hrs) type 1: relationship of serum creatinine to hemodynamics. J Hepatol. 2011;55:315–21.
Cabre E, Rodriguez-Iglesias P, Caballeria J, Quer JC, Sanchez-Lombrana JL, Pares A, et al. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology. 2000;32:36–42.
Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med. 1992;326:507–12.
Carithers RL Jr, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, et al. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med. 1989;110:685–90.
Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med. 1990;113:299–307.
Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables. Gut. 1995;37:113–8.
Mathurin P, Mendenhall CL, Carithers RL, Jr., Ramond MJ, Maddrey WC, Garstide P, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (ah): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe ah. J Hepatol. 2002;36:480–7.
Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a cochrane hepato-biliary group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther. 2008;27:1167–78.
Louvet A, Diaz E, Dharancy S, Coevoet H, Texier F, Thevenot T, et al. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J Hepatol. 2008;48:465–70.
Mathurin P, Abdelnour M, Ramond MJ, Carbonell N, Fartoux L, Serfaty L, et al. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology. 2003;38:1363–9.
Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009;137:541–8.
Spahr L, Rubbia-Brandt L, Pugin J, Giostra E, Frossard JL, Borisch B, et al. Rapid changes in alcoholic hepatitis histology under steroids: correlation with soluble intercellular adhesion molecule-1 in hepatic venous blood. J Hepatol. 2001;35:582–9.
Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, et al. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol. 2003;38:419–25.
Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R, Jalan R. Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. Gut. 2003;52:1182–7.
Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004;39:1390–7.
Boetticher NC, Peine CJ, Kwo P, Abrams GA, Patel T, Aqel B, et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology. 2008;135:1953–60.
Tilg H, Eibl B, Pichl M, Gachter A, Herold M, Brankova J, et al. Immune response modulation by pentoxifylline in vitro. Transplantation. 1993;56:196–201.
Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:1637–48.
Lebrec D, Thabut D, Oberti F, Perarnau JM, Condat B, Barraud H, et al. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology. 2010;138:1755–62.
Tyagi P, Sharma P, Sharma BC, Puri AS, Kumar A, Sarin SK. Prevention of hepatorenal syndrome in patients with cirrhosis and ascites: a pilot randomized control trial between pentoxifylline and placebo. Eur J Gastroenterol Hepatol. 2011;23:210–7.
De BK, Gangopadhyay S, Dutta D, Baksi SD, Pani A, Ghosh P. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J Gastroenterol. 2009;15:1613–9.
Moreno C, Langlet P, Hittelet A, Lasser L, Degre D, Evrard S, et al. Enteral nutrition with or without n-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. J Hepatol. 2010;53:1117–22.
Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, et al. Glucocorticoids plus n-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365:1781–9.
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Wieser, V., Tilg, H. Management bei schwerer alkoholischer Hepatitis. Wien Med Wochenschr 164, 3–8 (2014). https://doi.org/10.1007/s10354-013-0221-5
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DOI: https://doi.org/10.1007/s10354-013-0221-5