Treatment of Alcoholic Liver Disease Including Emerging Therapies, Novel Targets, and Liver Transplantation

  • Jan Petrasek
  • Gyongyi SzaboEmail author


Therapies in alcoholic liver disease and alcoholic hepatitis have not evolved in decades. This is in striking contrast to the high mortality of patients with acute alcoholic hepatitis indicating an unmet medical need for more effective treatments. In addition to alcohol cessation and abstinence that are difficult to achieve for many patients, pharmacotherapy with corticosteroids remains to be the main standard of care in acute alcoholic hepatitis. In a subset of patients, pentoxifylline may provide some benefits, while most studies failed to prove obvious benefits. This chapter summarizes the recent literature on abstinence, nutrition, corticosteroids, and pentoxifylline that are all used in the general clinical practice. The challenges of liver transplantation in patients with alcoholic liver disease are also discussed. We provide a list of ongoing clinical trials and identify novel targets and approaches that may deserve investigation in alcoholic liver disease based on evidence from preclinical studies or state-of-the-art pathomechanistic understanding.


Alcoholic hepatitis Corticosteroids Pentoxifylline Zinc IL-1 receptor antagonist Abstinence 



This work was supported by NIH grants U01AA021893 and U01AA021902. The authors would like to thank Merin MacDonald for help with the tables, artwork, and manuscript preparation.


  1. 1.
    Damgaard Sandahl T. Alcoholic hepatitis. Dan Med J. 2014;61(10):B4755.PubMedGoogle Scholar
  2. 2.
    Kim W, Kim DJ. Severe alcoholic hepatitis-current concepts, diagnosis and treatment options. World J Hepatol. 2014;6(10):688–95.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    O’Shea RS, Dasarathy S, McCullough AJ, Practice Guideline Committee of the American Association for the Study of Liver Diseases & Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology. 2010;51(1):307–28.PubMedCrossRefGoogle Scholar
  4. 4.
    Szabo G, Mandrekar P, Petrasek J, Catalano D. The unfolding web of innate immune dysregulation in alcoholic liver injury. Alcohol Clin Exp Res. 2011;35(5):782–6.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Szabo G, Petrasek J, Bala S. Innate immunity and alcoholic liver disease. Dig Dis. 2012;30 Suppl 1:55–60.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu CH, Xu CF, Ye H, Li L, Li YM. Early mortality of alcoholic hepatitis: a review of data from placebo-controlled clinical trials. World J Gastroenterol. 2010;16(19):2435–9.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Alexander JF, Lischner MW, Galambos JT. Natural history of alcoholic hepatitis. II. The long-term prognosis. Am J Gastroenterol. 1971;56(6):515–25.PubMedGoogle Scholar
  8. 8.
    Powell Jr WJ, Klatskin G. Duration of survival in patients with Laennec’s cirrhosis. Influence of alcohol withdrawal, and possible effects of recent changes in general management of the disease. Am J Med. 1968;44(3):406–20.PubMedCrossRefGoogle Scholar
  9. 9.
    Dominguez M, Rincon D, Abraldes JG, Miquel R, Colmenero J, Bellot P, Garcia-Pagan JC, Fernandez R, Moreno M, Banares R, Arroyo V, Caballeria J, Gines P, Bataller R. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008;103(11):2747–56.PubMedCrossRefGoogle Scholar
  10. 10.
    Potts JR, Goubet S, Heneghan MA, Verma S. Determinants of long-term outcome in severe alcoholic hepatitis. Aliment Pharmacol Ther. 2013;38(6):584–95.PubMedCrossRefGoogle Scholar
  11. 11.
    Mathurin P, Lucey MR. Management of alcoholic hepatitis. J Hepatol. 2012;56 Suppl 1:S39–45.PubMedCrossRefGoogle Scholar
  12. 12.
    European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012;57(2):399–420.CrossRefGoogle Scholar
  13. 13.
    Pessione F, Ramond MJ, Peters L, Pham BN, Batel P, Rueff B, Valla DC. Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence. Liver Int. 2003;23(1):45–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Veldt BJ, Laine F, Guillygomarc’h A, Lauvin L, Boudjema K, Messner M, Brissot P, Deugnier Y, Moirand R. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol. 2002;36(1):93–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Bell H, Jahnsen J, Kittang E, Raknerud N, Sandvik L. Long-term prognosis of patients with alcoholic liver cirrhosis: a 15-year follow-up study of 100 Norwegian patients admitted to one unit. Scand J Gastroenterol. 2004;39(9):858–63.PubMedCrossRefGoogle Scholar
  16. 16.
    Roselle GA, Mendenhall CL, Chedid A, Moritz TE, Gartside P. Alcohol modulation of immune function: clinical and experimental data. Veterans Affairs Cooperative Study Groups 119 and 275. Alcohol Clin Exp Res. 1995;19(3):551–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghoner A, Vidacek D, Siewert E, Bach J, Geier A, Purucker EA, Gressner AM, Matern S, Lammert F. Patients with acute on chronic liver failure display "sepsis-like" immune paralysis. J Hepatol. 2005;42(2):195–201.PubMedCrossRefGoogle Scholar
  18. 18.
    Michelena J, Altamirano J, Abraldes JG, Affo S, Morales-Ibanez O, Sancho-Bru P, Dominguez M, Garcia-Pagan JC, Fernandez J, Arroyo V, Gines P, Louvet A, Mathurin P, Mehal WZ, Caballeria J, Bataller R. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology. 2015;62(3):762–72.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, Augustin S, Mookerjee RP, Michelena J, Smyrk TC, Buob D, Leteurtre E, Rincon D, Ruiz P, Garcia-Pagan JC, Guerrero-Marquez C, Jones PD, Barritt 4th AS, Arroyo V, Bruguera M, Banares R, Gines P, Caballeria J, Roskams T, Nevens F, Jalan R, Mathurin P, Shah VH, Bataller R. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology. 2014;146(5):1231–9.e1–6.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Wilk AI, Jensen NM, Havighurst TC. Meta-analysis of randomized control trials addressing brief interventions in heavy alcohol drinkers. J Gen Intern Med. 1997;12(5):274–83.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Moyer A, Finney JW, Swearingen CE, Vergun P. Brief interventions for alcohol problems: a meta-analytic review of controlled investigations in treatment-seeking and non-treatment-seeking populations. Addiction. 2002;97(3):279–92.PubMedCrossRefGoogle Scholar
  22. 22.
    Kadden RM. Project MATCH: treatment main effects and matching results. Alcohol Clin Exp Res. 1996;20(8 Suppl):196A–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Friedmann PD. Clinical practice. Alcohol use in adults. N Engl J Med. 2013;368(4):365–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Jonas DE, Garbutt JC, Amick HR, Brown JM, Brownley KA, Council CL, Viera AJ, Wilkins TM, Schwartz CJ, Richmond EM, Yeatts J, Evans TS, Wood SD, Harris RP. Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2012;157(9):645–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Addolorato G, Leggio 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):1915–22.PubMedCrossRefGoogle Scholar
  26. 26.
    O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Sass H, Soyka M, Mann K, Zieglgansberger W. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53(8):673–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT. Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA. 1999;281(14):1318–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Delgrange T, Khater J, Capron D, Duron B, Capron JP. Effect of acute administration of acamprosate on the risk of encephalopathy and on arterial pressure in patients with alcoholic cirrhosis. Gastroenterol Clin Biol. 1992;16(8–9):687–91.PubMedGoogle Scholar
  30. 30.
    Hubbard AL, Cohn ZA. Externally disposed plasma membrane proteins. I. Enzymatic iodination of mouse L cells. J Cell Biol. 1975;64(2):438–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD, Iber FL, James KE, Lacoursiere RB, Lee KK, Lowenstam I. Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. JAMA. 1986;256(11):1449–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Mendenhall C, Roselle GA, Gartside P, Moritz T. Relationship of protein calorie malnutrition to alcoholic liver disease: a reexamination of data from two Veterans Administration Cooperative Studies. Alcohol Clin Exp Res. 1995;19(3):635–41.PubMedCrossRefGoogle Scholar
  33. 33.
    McClain CJ, Barve SS, Barve A, Marsano L. Alcoholic liver disease and malnutrition. Alcohol Clin Exp Res. 2011;35(5):815–20.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Singal AK, Charlton MR. Nutrition in alcoholic liver disease. Clin Liver Dis. 2012;16(4):805–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Mendenhall CL, Moritz TE, Roselle GA, Morgan TR, Nemchausky BA, Tamburro CH, Schiff ER, McClain CJ, Marsano LS, Allen JI. Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275. JPEN J Parenter Enteral Nutr. 1995;19(4):258–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Walker CL, Greenberger PA, Patterson R. Potentially fatal asthma. Ann Allergy. 1990;64(6):487–93.PubMedGoogle Scholar
  37. 37.
    Koromyslov GF. Maturity of a collective. Veterinariia. 1978;5(5):11–3.PubMedGoogle Scholar
  38. 38.
    Mendenhall CL, Anderson S, Weesner RE, Goldberg SJ, Crolic KA. Protein-calorie malnutrition associated with alcoholic hepatitis. Veterans Administration Cooperative Study Group on Alcoholic Hepatitis. Am J Med. 1984;76(2):211–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Rissanen A, Sarlio-Lahteenkorva S, Alfthan G, Gref CG, Keso L, Salaspuro M. Employed problem drinkers: a nutritional risk group? Am J Clin Nutr. 1987;45(2):456–61.PubMedGoogle Scholar
  40. 40.
    Simko V, Connell AM, Banks B. Nutritional status in alcoholics with and without liver disease. Am J Clin Nutr. 1982;35(2):197–203.PubMedGoogle Scholar
  41. 41.
    Lieber CS. ALCOHOL: its metabolism and interaction with nutrients. Annu Rev Nutr. 2000;20:395–430.PubMedCrossRefGoogle Scholar
  42. 42.
    Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360(26):2758–69.PubMedCrossRefGoogle Scholar
  43. 43.
    Dolz C, Raurich JM, Ibanez J, Obrador A, Marse P, Gaya J. Ascites increases the resting energy expenditure in liver cirrhosis. Gastroenterology. 1991;100(3):738–44.PubMedGoogle Scholar
  44. 44.
    Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, McIlroy K, Donaghy AJ, McCall JL. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology. 2008;48(2):557–66.PubMedCrossRefGoogle Scholar
  45. 45.
    Swart GR, Zillikens MC, van Vuure JK, van den Berg JW. Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver. BMJ. 1989;299(6709):1202–3.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Reinus JF, Heymsfield SB, Wiskind R, Casper K, Galambos JT. Ethanol: relative fuel value and metabolic effects in vivo. Metabolism. 1989;38(2):125–35.PubMedCrossRefGoogle Scholar
  47. 47.
    Cheung K, Lee SS, Raman M. Prevalence and mechanisms of malnutrition in patients with advanced liver disease, and nutrition management strategies. Clin Gastroenterol Hepatol. 2012;10(2):117–25.PubMedCrossRefGoogle Scholar
  48. 48.
    Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, DGEM (German Society for Nutritional Medicine), Ferenci P, Holm E, Vom Dahl S, Muller MJ, Nolte W, ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN guidelines on enteral nutrition: liver disease. Clin Nutr. 2006;25(2):285–94.PubMedCrossRefGoogle Scholar
  49. 49.
    Merli M, Romiti A, Riggio O, Capocaccia L. Optimal nutritional indexes in chronic liver disease. JPEN J Parenter Enteral Nutr. 1987;11(5 Suppl):130S–4.PubMedCrossRefGoogle Scholar
  50. 50.
    Plauth M, Cabre E, Campillo B, Kondrup J, Marchesini G, Schutz T, Shenkin A, Wendon J, ESPEN. ESPEN guidelines on parenteral nutrition: hepatology. Clin Nutr. 2009;28(4):436–44.PubMedCrossRefGoogle Scholar
  51. 51.
    Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeebhoy KN. What is subjective global assessment of nutritional status? JPEN J Parenter Enteral Nutr. 1987;11(1):8–13.PubMedCrossRefGoogle Scholar
  52. 52.
    Pikul J, Sharpe MD, Lowndes R, Ghent CN. Degree of preoperative malnutrition is predictive of postoperative morbidity and mortality in liver transplant recipients. Transplantation. 1994;57(3):469–72.PubMedCrossRefGoogle Scholar
  53. 53.
    DiCecco SR, Francisco-Ziller N. Nutrition in alcoholic liver disease. Nutr Clin Pract. 2006;21(3):245–54.PubMedCrossRefGoogle Scholar
  54. 54.
    Nielsen K, Kondrup J, Martinsen L, Stilling B, Wikman B. Nutritional assessment and adequacy of dietary intake in hospitalized patients with alcoholic liver cirrhosis. Br J Nutr. 1993;69(3):665–79.PubMedCrossRefGoogle Scholar
  55. 55.
    Figueiredo FA, Dickson ER, Pasha TM, Porayko MK, Therneau TM, Malinchoc M, DiCecco SR, Francisco-Ziller NM, Kasparova P, Charlton MR. Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease. Liver Transpl. 2000;6(5):575–81.PubMedCrossRefGoogle Scholar
  56. 56.
    Schlussel MM, dos Anjos LA, de Vasconcellos MT, Kac G. Reference values of handgrip dynamometry of healthy adults: a population-based study. Clin Nutr. 2008;27(4):601–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Andersen H, Borre M, Jakobsen J, Andersen PH, Vilstrup H. Decreased muscle strength in patients with alcoholic liver cirrhosis in relation to nutritional status, alcohol abstinence, liver function, and neuropathy. Hepatology. 1998;27(5):1200–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Cordoba J, Lopez-Hellin J, Planas M, Sabin P, Sanpedro F, Castro F, Esteban R, Guardia J. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004;41(1):38–43.PubMedCrossRefGoogle Scholar
  59. 59.
    Mullen KD, Dasarathy S. Protein restriction in hepatic encephalopathy: necessary evil or illogical dogma? J Hepatol. 2004;41(1):147–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr. 2006;136(1 Suppl):295S–8.PubMedGoogle Scholar
  61. 61.
    Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R, Italian BCAA Study Group. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124(7):1792–801.PubMedCrossRefGoogle Scholar
  62. 62.
    Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol. 1985;1(2):141–51.PubMedCrossRefGoogle Scholar
  63. 63.
    Mendenhall CL, Moritz TE, Roselle GA, Morgan TR, Nemchausky BA, Tamburro CH, Schiff ER, McClain CJ, Marsano LS, Allen JI. A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study. Hepatology. 1993;17(4):564–76.PubMedCrossRefGoogle Scholar
  64. 64.
    Mendenhall C, Bongiovanni G, Goldberg S, Miller B, Moore J, Rouster S, Schneider D, Tamburro C, Tosch T, Weesner R. VA Cooperative Study on Alcoholic Hepatitis. III: Changes in protein-calorie malnutrition associated with 30 days of hospitalization with and without enteral nutritional therapy. JPEN J Parenter Enteral Nutr. 1985;9(5):590–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Cabre E, Rodriguez-Iglesias P, Caballeria J, Quer JC, Sanchez-Lombrana JL, Pares A, Papo M, Planas R, Gassull MA. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology. 2000;32(1):36–42.PubMedCrossRefGoogle Scholar
  66. 66.
    Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ. Zinc and liver disease. Nutr Clin Pract. 2012;27(1):8–20.PubMedCrossRefGoogle Scholar
  67. 67.
    Marchesini G, Bugianesi E, Ronchi M, Flamia R, Thomaseth K, Pacini G. Zinc supplementation improves glucose disposal in patients with cirrhosis. Metabolism. 1998;47(7):792–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology. 1996;23(5):1084–92.PubMedCrossRefGoogle Scholar
  69. 69.
    Moreno C, Langlet P, Hittelet A, Lasser L, Degre D, Evrard S, Colle I, Lemmers A, Deviere J, Le Moine O. Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. J Hepatol. 2010;53(6):1117–22.PubMedCrossRefGoogle Scholar
  70. 70.
    Ray A, Prefontaine KE. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1994;91(2):752–6.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Petrasek J, Mandrekar P, Szabo G. Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol Res Pract. 2010. doi: 10.1155/2010/710381. Epub 2010 Aug 17.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Gao B, Seki E, Brenner DA, Friedman S, Cohen JI, Nagy L, Szabo G, Zakhari S. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol. 2011;300(4):G516–25.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Mathurin P, Mendenhall CL, Carithers Jr RL, Ramond MJ, Maddrey WC, Garstide P, Rueff B, Naveau S, Chaput JC, Poynard T. 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(4):480–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255–60.PubMedCrossRefGoogle Scholar
  75. 75.
    Davidson CS. Alcoholic hepatitis. N Engl J Med. 1971;284(24):1378.PubMedCrossRefGoogle Scholar
  76. 76.
    Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med. 1971;74(3):311–21.PubMedCrossRefGoogle Scholar
  77. 77.
    Porter HP, Simon FR, Pope 2nd CE, Volwiler W, Fenster LF. Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial. N Engl J Med. 1971;284(24):1350–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Maddrey WC, Boitnott JK, Bedine MS, Weber Jr FL, Mezey E, White Jr RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978;75(2):193–9.PubMedGoogle Scholar
  79. 79.
    Carithers Jr RL, Herlong HF, 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(9):685–90.PubMedCrossRefGoogle Scholar
  80. 80.
    Lesesne HR, Bozymski EM, Fallon HJ. Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements. Gastroenterology. 1978;74(2 Pt 1):169–73.PubMedGoogle Scholar
  81. 81.
    Ramond MJ, Poynard 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(8):507–12.PubMedCrossRefGoogle Scholar
  82. 82.
    Campra JL, Hamlin Jr EM, Kirshbaum RJ, Olivier M, Redeker AG, Reynolds TB. Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial. Ann Intern Med. 1973;79(5):625–31.PubMedCrossRefGoogle Scholar
  83. 83.
    Shumaker JB, Resnick RH, Galambos JT, Makopour H, Iber FL. A controlled trial of 6-methylprednisolone in acute alcoholic hepatitis. With a note on published results in encephalopathic patients. Am J Gastroenterol. 1978;69(4):443–9.PubMedGoogle Scholar
  84. 84.
    Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D, Foie-Alcool group of the Association Francaise pour l’Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004;39(5):1390–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Mathurin P, Abdelnour M, Ramond MJ, Carbonell N, Fartoux L, Serfaty L, Valla D, Poupon R, Chaput JC, Naveau S. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology. 2003;38(6):1363–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Rogler LH, Malgady RG, Tryon WW. Evaluation of mental health. Issues of memory in the Diagnostic Interview Schedule. J Nerv Ment Dis. 1992;180(4):215–22. Discussion 223–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Maher JJ. Treatment of alcoholic hepatitis. J Gastroenterol Hepatol. 2002;17(4):448–55.PubMedCrossRefGoogle Scholar
  88. 88.
    Forrest E, Mellor J, Stanton L, Bowers M, Ryder P, Austin A, Day C, Gleeson D, O’Grady J, Masson S, McCune A, Patch D, Richardson P, Roderick P, Ryder S, Wright M, Thursz M. Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial. Trials. 2013;14:262. doi: 10.1186/1745-6215-14-262.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    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(12):1167–78.PubMedCrossRefGoogle Scholar
  90. 90.
    Morgan TR. Corticosteroids can be used to treat alcoholic hepatitis after a recent upper gastrointestinal bleed. J Hepatol. 2015;62(4):759–60.PubMedCrossRefGoogle Scholar
  91. 91.
    Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009;137(2):541–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Rudler M, Mouri S, Charlotte F, Lebray P, Capocci R, Benosman H, Poynard T, Thabut D. Prognosis of treated severe alcoholic hepatitis in patients with gastrointestinal bleeding. J Hepatol. 2014;62(4):816–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med. 1990;113(4):299–307.PubMedCrossRefGoogle Scholar
  94. 94.
    Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables. Gut. 1995;37(1):113–8.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Imperiale TF, O’Connor JB, McCullough AJ. Corticosteroids are effective in patients with severe alcoholic hepatitis. Am J Gastroenterol. 1999;94(10):3066–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Phillips M, Curtis 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(4):784–90.PubMedCrossRefGoogle Scholar
  97. 97.
    Mendenhall CL, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T, Seeff LB, Sorrell M, Tamburro C, Weesner R, Zetterman R. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med. 1984;311(23):1464–70.PubMedCrossRefGoogle Scholar
  98. 98.
    Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12(4):231–42.PubMedCrossRefGoogle Scholar
  99. 99.
    Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, Castel H, Duhamel A, Pageaux GP, Leroy V, Dharancy S, Louvet A, Boleslawski E, Lucidi V, Gustot T, Francoz C, Letoublon C, Castaing D, Belghiti J, Donckier V, Pruvot FR, Duclos-Vallee JC. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1790–800.PubMedCrossRefGoogle Scholar
  100. 100.
    di Mambro AJ, Parker R, McCune A, Gordon F, Dayan CM, Collins P. In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis. Hepatology. 2011;53(4):1316–22.PubMedCrossRefGoogle Scholar
  101. 101.
    Dhanda AD, di Mambro AJ, Hunt VL, McCune CA, Dayan CM, Dick AD, Lee RW, Collins PL. Long-term outcome in patients with severe alcoholic hepatitis can be reliably determined using an in vitro measure of steroid sensitivity". Hepatology. 2015;61(3):1099.PubMedCrossRefGoogle Scholar
  102. 102.
    Louvet A, Naveau 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(6):1348–54.PubMedCrossRefGoogle Scholar
  103. 103.
    Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D, Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C, Pageaux GP, Sobesky R, Canva-Delcambre V, Dharancy S, Salleron J, Dao T. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA. 2013;310(10):1033–41.PubMedCrossRefGoogle Scholar
  104. 104.
    Markwick LJ, Riva A, Ryan JM, Cooksley H, Palma E, Tranah TH, Manakkat Vijay GK, Vergis N, Thursz M, Evans A, Wright G, Tarff S, O’Grady J, Williams R, Shawcross DL, Chokshi S. Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis. Gastroenterology. 2015;148(3):590–602.e10.PubMedCrossRefGoogle Scholar
  105. 105.
    Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA, Jalan R. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology. 2007;46(3):831–40.PubMedCrossRefGoogle Scholar
  106. 106.
    O’Brien J, Triantos C, Burroughs AK. Management of varices in patients with cirrhosis. Nat Rev Gastroenterol Hepatol. 2013;10(7):402–12.PubMedCrossRefGoogle Scholar
  107. 107.
    Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Soares-Weiser K, Uribe M. Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev. (9):CD002907. doi: 10.1002/14651858.CD002907.pub2.
  108. 108.
    de Franchis R, Baveno V, Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53(4):762–8.PubMedCrossRefGoogle Scholar
  109. 109.
    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(6):1637–48.PubMedCrossRefGoogle Scholar
  110. 110.
    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(13):1613–9.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Sidhu SS, Goyal O, Singla P, Gupta D, Sood A, Chhina RS, Soni RK. Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis (COPE trial). Dig Dis Sci. 2012;57(6):1664–71.PubMedCrossRefGoogle Scholar
  112. 112.
    Han J, Thompson P, Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med. 1990;172(1):391–4.PubMedCrossRefGoogle Scholar
  113. 113.
    Louvet A, Diaz E, Dharancy S, Coevoet H, Texier F, Thevenot T, Deltenre P, Canva V, Plane C, Mathurin P. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J Hepatol. 2008;48(3):465–70.PubMedCrossRefGoogle Scholar
  114. 114.
    Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O’Grady J, Patch D, Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH, STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619–28.PubMedCrossRefGoogle Scholar
  115. 115.
    Lucey MR. Liver transplantation for alcoholic liver disease. Nat Rev Gastroenterol Hepatol. 2014;11(5):300–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Singal AK, Bashar H, Anand BS, Jampana SC, Singal V, Kuo YF. Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database. Hepatology. 2012;55(5):1398–405.PubMedCrossRefGoogle Scholar
  117. 117.
    Donckier V, Lucidi V, Gustot T, Moreno C. Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy. J Hepatol. 2014;60(4):866–71.PubMedCrossRefGoogle Scholar
  118. 118.
    Szabo G, Bala S. Alcoholic liver disease and the gut-liver axis. World J Gastroenterol. 2010;16(11):1321–9.PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology. 2015;148(1):30–6.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Zhong W, Zhao Y, Sun X, Song Z, McClain CJ, Zhou Z. Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice: involvement of intrahepatic and extrahepatic factors. PLoS One. 2013;8(10):e76522.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, Gobejishvili L, Joshi-Barve S, Ayvaz T, Petrosino J, Kong M, Barker D, McClain C, Barve S. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS One. 2013;8(1):e53028.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Chang B, Sang L, Wang Y, Tong J, Zhang D, Wang B. The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury. BMC Gastroenterol. 2013;13(1):151. doi: 10.1186/1471-230X-13-151.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Ritze Y, Bardos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, Bischoff SC. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS One. 2014;9(1):e80169.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Lippai D, Bala S, Catalano D, Kodys K, Szabo G. Micro-RNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice. Alcohol Clin Exp Res. 2014;38(8):2217–24.PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, Penna G, Laverny G, Adorini L, Moschetta A, van Mil SW. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut. 2011;60(4):463–72.PubMedCrossRefGoogle Scholar
  126. 126.
    de la Monte SM, Pang M, Chaudhry R, Duan K, Longato L, Carter J, Ouh J, Wands JR. Peroxisome proliferator-activated receptor agonist treatment of alcohol-induced hepatic insulin resistance. Hepatol Res. 2011;41(4):386–98.PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147(3):577–594.e1.PubMedCrossRefGoogle Scholar
  128. 128.
    Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, Catalano D, Mandrekar P, Szabo G. Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology. 2011;53(5):1526–37.PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, Barrieau M, Min SY, Kurt-Jones EA, Szabo G. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122(10):3476–89.PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Spahr L, Rubbia-Brandt L, Frossard JL, Giostra E, Rougemont AL, Pugin J, Fischer M, Egger H, Hadengue A. Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study. J Hepatol. 2002;37(4):448–55.PubMedCrossRefGoogle Scholar
  131. 131.
    Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, Ludwiczek O, Shawcross D, Zoller H, Alisa A, Mookerjee RP, Graziadei I, Datz C, Trauner M, Schuppan D, Obrist P, Vogel W, Williams R. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol. 2003;38(4):419–25.PubMedCrossRefGoogle Scholar
  132. 132.
    Blendis L, Dotan I. Anti-TNF therapy for severe acute alcoholic hepatitis: what went wrong? Gastroenterology. 2004;127(5):1637–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Boetticher NC, Peine CJ, Kwo P, Abrams GA, Patel T, Aqel B, Boardman L, Gores GJ, Harmsen WS, McClain CJ, Kamath PS, Shah VH. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology. 2008;135(6):1953–60.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res. 2009;33(2):220–32.PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Mandrekar P, Szabo G. Signalling pathways in alcohol-induced liver inflammation. J Hepatol. 2009;50(6):1258–66.PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Pan CX, Tang J, Wang XY, Wu FR, Ge JF, Chen FH. Role of interleukin-22 in liver diseases. Inflamm Res. 2014;63(7):519–25.PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, Gao B. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology. 2010;52(4):1291–300.PubMedCentralPubMedCrossRefGoogle Scholar
  138. 138.
    Singh V, Sharma AK, Narasimhan RL, Bhalla A, Sharma N, Sharma R. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol. 2014;109(9):1417–23.PubMedCrossRefGoogle Scholar
  139. 139.
    Anstee QM, Day CP. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol. 2012;57(5):1097–109.PubMedCrossRefGoogle Scholar
  140. 140.
    Purohit V, Russo D. Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Alcohol. 2002;27(3):151–4.PubMedCrossRefGoogle Scholar
  141. 141.
    Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL, AAH-NAC Study Group. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1781–9.PubMedCrossRefGoogle Scholar
  142. 142.
    Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, Fitzgerald KA, Szabo G. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci U S A. 2013;110(41):16544–9.PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Dolganiuc A, Thomes PG, Ding WX, Lemasters JJ, Donohue Jr TM. Autophagy in alcohol-induced liver diseases. Alcohol Clin Exp Res. 2012;36(8):1301–8.PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Seth D, Duly A, Kuo PC, McCaughan GW, Haber PS. Osteopontin is an important mediator of alcoholic liver disease via hepatic stellate cell activation. World J Gastroenterol. 2014;20(36):13088–104.PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Morales-Ibanez O, Dominguez M, Ki SH, Marcos M, Chaves JF, Nguyen-Khac E, Houchi H, Affo S, Sancho-Bru P, Altamirano J, Michelena J, Garcia-Pagan JC, Abraldes JG, Arroyo V, Caballeria J, Laso FJ, Gao B, Bataller R. Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. Hepatology. 2013;58(5):1742–56.PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Madhotra R, Gilmore IT. Recent developments in the treatment of alcoholic hepatitis. QJM. 2003;96(6):391–400.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

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