Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute

      The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management.
      Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH).
      Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever.
      Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections.
      Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI).
      Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate.
      Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment.
      Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate.
      Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF.
      Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest.
      Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting.
      Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high.
      Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid.

      Abbreviations used in this paper:

      ABIC (age, bilirubin, international normalized ratio, and creatinine), AH (alcoholic hepatitis), AKI (acute kidney injury), ALD (alcoholic liver disease), ALT (alanine aminotransferase), AST (aspartate aminotransferase), BSC (best supportive care), GR (glucocorticoid receptor), MDF (Maddrey Discriminant Function), MELD (Model for End-Stage Liver Disease), MOF (multiorgan failure), NAC (N-acetylcysteine), NG (nasogastric), NIAAA (National Institute of Alcohol Abuse and Alcoholism), PDE (phosphodiesterase), PTx (pentoxifylline), SIRS (systemic inflammatory response syndrome), TNF (tumor necrosis factor)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jinjuvadia R.
        • Liangpunsakul S.
        Translational Research and Evolving Alcoholic Hepatitis Treatment Consortium. Trends in alcoholic hepatitis-related hospitalizations, financial burden, and mortality in the United States.
        J Clin Gastroenterol. 2015; 49: 506-511
        • Nguyen T.A.
        • DeShazo J.P.
        • Thacker L.R.
        • et al.
        The worsening profile of alcoholic hepatitis in the United States.
        Alcohol Clin Exp Research. 2016; 40: 1295-1303
        • Michelena J.
        • Altamirano J.
        • Abraldes J.G.
        • et al.
        Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.
        Hepatology. 2015; 62: 762-772
        • Mookerjee R.P.
        • Lackner C.
        • Stauber R.
        • et al.
        The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.
        J Hepatol. 2011; 55: 1103-1111
        • Altamirano J.
        • Miquel R.
        • Katoonizadeh A.
        • et al.
        A histologic scoring system for prognosis of patients with alcoholic hepatitis.
        Gastroenterology. 2014; 146 (e1–e6): 1231-1239
        • Crabb D.W.
        • Bataller R.
        • Chalasani N.P.
        • et al.
        Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia.
        Gastroenterology. 2016; 150: 785-790
        • Dunn W.
        • Angulo P.
        • Sanderson S.
        • et al.
        Utility of a new model to diagnose an alcohol basis for steatohepatitis.
        Gastroenterology. 2006; 131: 1057-1063
        • Maddrey W.C.
        • Boitnott J.K.
        • Bedine M.S.
        • et al.
        Corticosteroid therapy of alcoholic hepatitis.
        Gastroenterology. 1978; 75: 193-199
        • Carithers J.R.L.
        • Herlong H.F.
        • Diehl A.M.
        • et al.
        Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial.
        Ann Intern Med. 1989; 110: 685-690
        • Dunn W.
        • Jamil L.H.
        • Brown L.S.
        • et al.
        MELD accurately predicts mortality in patients with alcoholic hepatitis.
        Hepatology. 2005; 41: 353-358
        • Dominguez M.
        • Rincon D.
        • Abraldes J.G.
        • et al.
        A new scoring system for prognostic stratification of patients with alcoholic hepatitis.
        Am J Gastroenterol. 2008; 103: 2747-2756
        • Forrest E.H.
        • Morris A.J.
        • Stewart S.
        • et al.
        The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.
        Gut. 2007; 56: 1743-1746
        • Thursz M.R.
        • Richardson P.
        • Allison M.
        • et al.
        Prednisolone or pentoxifylline for alcoholic hepatitis.
        N Engl J Med. 2015; 372: 1619-1628
        • Louvet A.
        • Naveau S.
        • Abdelnour M.
        • et al.
        The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
        Hepatology. 2007; 45: 1348-1354
        • Louvet A.
        • Labreuche J.
        • Artru F.
        • et al.
        Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis.
        Gastroenterology. 2015; 149 (e8; quiz e16–e17): 398-406
        • De Bosscher K.
        • Haegeman G.
        Minireview: latest perspectives on antiinflammatory actions of glucocorticoids.
        Mol Endocrinol. 2009; 23: 281-291
        • Barnes P.J.
        • Adcock I.M.
        Glucocorticoid resistance in inflammatory diseases.
        Lancet. 2009; 373: 1905-1917
        • Ito K.
        • Chung K.F.
        • Adcock I.M.
        Update on glucocorticoid action and resistance.
        J Allergy Clin Immunol. 2006; 117: 522-543
        • Ito K.
        • Yamamura S.
        • Essilfie-Quaye S.
        • et al.
        Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression.
        J Exp Med. 2006; 203: 7-13
        • di Mambro A.J.
        • Parker R.
        • McCune A.
        • et al.
        In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis.
        Hepatology. 2011; 53: 1316-1322
        • Barnes P.J.
        Mechanisms and resistance in glucocorticoid control of inflammation.
        J Steroid Biochem Mol Biol. 2010; 120: 76-85
        • Rogatsky I.
        • Ivashkiv L.B.
        Glucocorticoid modulation of cytokine signaling.
        Tissue Antigens. 2006; 68: 1-12
        • Kucuktulu U.
        • Alhan E.
        • Tekelioglu Y.
        • et al.
        The effects of pentoxifylline on liver regeneration after portal vein ligation in rats.
        Liver Int. 2007; 27: 274-279
        • Raetsch C.
        • Jia J.D.
        • Boigk G.
        • et al.
        Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis.
        Gut. 2002; 50: 241-247
        • Spina D.
        PDE4 inhibitors: current status.
        Br J Pharmacol. 2008; 155: 308-315
        • Gobejishvili L.
        • Barve S.
        • Joshi-Barve S.
        • et al.
        Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease.
        Am J Physiol Gastrointest Liver Physiol. 2006; 291: G681-G688
        • Gobejishvili L.
        • Barve S.
        • Joshi-Barve S.
        • et al.
        Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease.
        Am J Physiol Gastrointest Liver Physiol. 2008; 295: G718-G724
        • Essayan D.M.
        Cyclic nucleotide phosphodiesterases.
        J Allergy Clin Immunol. 2001; 108: 671-680
        • Kwak H.J.
        • Song J.S.
        • No Z.S.
        • et al.
        The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide.
        Inflamm Res. 2005; 54: 508-513
        • Ouagued M.
        • Martin-Chouly C.A.
        • Brinchault G.
        • et al.
        The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-alpha production in whole blood from COPD patients.
        Pulm Pharmacol Ther. 2005; 18: 49-54
        • Le Moine O.
        • Marchant A.
        • De Groote D.
        • et al.
        Role of defective monocyte interleukin-10 release in tumor necrosis factor-alpha overproduction in alcoholics cirrhosis.
        Hepatology. 1995; 22: 1436-1439
        • Platzer C.
        • Fritsch E.
        • Elsner T.
        • et al.
        Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells.
        Eur J Immunol. 1999; 29: 3098-3104
        • Eigler A.
        • Siegmund B.
        • Emmerich U.
        • et al.
        Anti-inflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production.
        J Leukoc Biol. 1998; 63: 101-107
        • Verghese M.W.
        • McConnell R.T.
        • Strickland A.B.
        • et al.
        Differential regulation of human monocyte-derived TNF alpha and IL-1 beta by type IV cAMP-phosphodiesterase (cAMP-PDE) inhibitors.
        J Pharmacol Exp Ther. 1995; 272: 1313-1320
        • Kambayashi T.
        • Jacob C.O.
        • Zhou D.
        • et al.
        Cyclic nucleotide phosphodiesterase type IV participates in the regulation of IL-10 and in the subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages.
        J Immunol. 1995; 155: 4909-4916
        • Gobejishvili L.
        • Barve S.
        • Breitkopf-Heinlein K.
        • et al.
        Rolipram attenuates bile duct ligation-induced liver injury in rats: a potential pathogenic role of PDE4.
        J Pharmacol Exp Ther. 2013; 347: 80-90
        • Fleischhacker W.W.
        • Hinterhuber H.
        • Bauer H.
        • et al.
        A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder.
        Neuropsychobiology. 1992; 26: 59-64
        • Mathurin P.
        • Duchatelle V.
        • Ramond M.J.
        • et al.
        Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone.
        Gastroenterology. 1996; 110: 1847-1853
        • Mathurin P.
        • O'Grady J.
        • Carithers R.L.
        • et al.
        Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.
        Gut. 2011; 60: 255-260
        • Christensen E.
        • Gluud C.
        Glucocorticosteroids are not effective in alcoholic hepatitis.
        Am J Gastroenterol. 1999; 94: 3065-3066
        • Rambaldi A.
        • Saconato H.H.
        • Christensen E.
        • et al.
        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: 1167-1178
        • Mathurin P.
        • Louvet A.
        • Duhamel A.
        • et al.
        Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.
        JAMA. 2013; 310: 1033-1041
        • Ramond M.J.
        • Poynard T.
        • Rueff B.
        • et al.
        A randomized trial of prednisolone in patients with severe alcoholic hepatitis.
        N Engl J Med. 1992; 326: 507-512
        • O'Shea R.S.
        • Dasarathy S.
        • McCullough A.J.
        • et al.
        Alcoholic liver disease.
        Hepatology. 2010; 51: 307-328
        • European Association for the Study of the Liver
        EASL clinical practical guidelines: management of alcoholic liver disease.
        J Hepatol. 2012; 57: 399-420
        • Imperiale T.F.
        • McCullough A.J.
        Do corticosteroids reduce mortality from alcoholic hepatitis? a meta-analysis of the randomized trials.
        Ann Intern Med. 1990; 113: 299-307
        • Akriviadis E.
        • Botla R.
        • Briggs W.
        • et al.
        Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.
        Gastroenterology. 2000; 119: 1637-1648
        • Sidhu S.S.
        • Goyal O.
        • Singla M.
        • et al.
        Pentoxifylline in severe alcoholic hepatitis: a prospective, randomised trial.
        J Assoc Physicians India. 2012; 60: 20-22
        • De B.K.
        Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial.
        World J Gastroenterol. 2009; 15: 1613
        • Whitfield K.
        • Rambaldi A.
        • Wetterslev J.
        • et al.
        Pentoxifylline for alcoholic hepatitis.
        Cochrane Database Syst Rev. 2009; : CD007339
        • Parker R.
        • Armstrong M.J.
        • Corbett C.
        • et al.
        Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis.
        Aliment Pharmacol Ther. 2013; 37: 845-854
        • Sidhu S.S.
        • Goyal O.
        • Singla P.
        • et al.
        Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis (COPE trial).
        Dig Dis Sci. 2012; 57: 1664-1671
        • Singh S.
        • Murad M.H.
        • Chandar A.K.
        • et al.
        Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta-analysis.
        Gastroenterology. 2015; 149: 958-970.e12
        • Mezey E.
        • Potter J.J.
        • Rennie-Tankersley L.
        • et al.
        A randomized placebo controlled trial of vitamin E for alcoholic hepatitis.
        J Hepatol. 2004; 40: 40-46
        • Stewart S.
        • Prince M.
        • Bassendine M.
        • et al.
        A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.
        J Hepatol. 2007; 47: 277-283
        • Nguyen-Khac E.
        • Thevenot T.
        • Piquet M.A.
        • et al.
        Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.
        N Engl J Med. 2011; 365: 1781-1789
        • Felver M.E.
        • Mezey E.
        • McGuire M.
        • et al.
        Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis.
        Alcohol Clin Exp Res. 1990; 14: 255-259
        • McClain C.J.
        • Cohen D.A.
        Increased tumor necrosis factor production by monocytes in alcoholic hepatitis.
        Hepatology. 1989; 9: 349-351
        • Spahr L.
        • Rubbia-Brandt L.
        • Frossard J.L.
        • et al.
        Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study.
        J Hepatol. 2002; 37: 448-455
        • Menon K.V.N.
        • Stadheim L.
        • Kamath P.S.
        • et al.
        A pilot study of the safety and tolerability of etanercept in patients with alcoholic hepatitis.
        Am J Gastroenterol. 2004; 99: 255-260
        • Boetticher N.C.
        • Peine C.J.
        • Kwo P.
        • et al.
        A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.
        Gastroenterology. 2008; 135: 1953-1960
        • Naveau S.
        • Chollet-Martin S.
        • Dharancy S.
        • et al.
        A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.
        Hepatology. 2004; 39: 1390-1397
        • Louvet A.
        • Wartel F.
        • Castel H.
        • et al.
        Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor.
        Gastroenterology. 2009; 137: 541-548
        • Altamirano J.
        • Fagundes C.
        • Dominguez M.
        • et al.
        Acute kidney injury is an early predictor of mortality for patients with alcoholic hepatitis.
        Clin Gastroenterol Hepatol. 2012; 10: 65-71.e3
        • Safi W.
        • Rauscher I.
        • Umgelter A.
        Contrast-induced acute kidney injury in cirrhotic patients: a retrospective analysis.
        Ann Hepatol. 2015; 14: 895-901
        • Mendenhall C.L.
        • Moritz T.E.
        • Roselle G.A.
        • et al.
        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: 258-265
        • Cabre E.
        • Rodriguez-Iglesias P.
        • Caballeria J.
        • 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
        • Moreno C.
        • Deltenre P.
        • Senterre C.
        • et al.
        Intensive enteral nutrition is ineffective for patients with severe alcoholic hepatitis treated with corticosteroids.
        Gastroenterology. 2016; 150: 903-910.e8
        • Mohammad M.K.
        • Zhou Z.
        • Cave M.
        • et al.
        Zinc and liver disease.
        Nutr Clin Pract. 2012; 27: 8-20
        • Li F.
        • Duan K.
        • Wang C.
        • et al.
        Probiotics and alcoholic liver disease: treatment and potential mechanisms.
        Gastroenterol Res Pract. 2016; 2016: 5491465
        • Mathurin P.
        • Moreno C.
        • Samuel D.
        • et al.
        Early liver transplantation for severe alcoholic hepatitis.
        N Engl J Med. 2011; 365: 1790-1800
        • Addolorato G.
        • Bataller R.
        • Burra P.
        • et al.
        Liver transplantation for alcoholic liver disease.
        Transplantation. 2016; 100: 981-987
        • Chedid A.
        • Mendenhall C.L.
        • Gartside P.
        • et al.
        Prognostic factors in alcoholic liver disease: VA Cooperative Study Group.
        Am J Gastroenterol. 1991; 86: 210-216

      Linked Article