Download PDF
Semin Liver Dis 2016; 36(01): 056-068
DOI: 10.1055/s-0036-1571297
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Therapeutic Strategies for the Treatment of Alcoholic Hepatitis

Ashwani K. Singal
1   Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama
,
Vijay H. Shah
2   Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
› Author Affiliations
Further Information

Publication History

Publication Date:
12 February 2016 (online)

    Permissions and Reprints

Abstract

Acute alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active heavy alcohol use. Presenting with acute or chronic liver failure, a severe episode has a potential for 30 to 40% mortality at 1 month from presentation, if not recognized and left untreated. Alcoholic hepatitis patients need supportive therapy for abstinence and nutritional supplementation for those patients with markedly reduced caloric intake. Results of the recently published STOPAH (Steroids or Pentoxifylline for Alcoholic Hepatitis) Study showed only a benefit of corticosteroids on short-term mortality without any benefit of pentoxifylline. Neither of these two drugs impacts medium- and long-term mortality, which is mainly driven by abstinence from alcohol. With the emerging data on the benefits of liver transplantation, liver transplantation could be an important salvage option for a very highly select group of AH patients. More data are needed on the use of liver transplantation in AH as the basis for deriving protocols for selecting cases and for posttransplant management. Currently, many clinical trials are examining the efficacy and safety of new or repurposed compounds in severe AH. These drugs are targeted at various pathways in the pathogenesis of AH: the gut–liver axis, the inflammatory cascade, and liver injury. With increasing interest of researchers and clinicians, supported by funding from the National Institute on Alcohol Abuse and Alcoholism, the future seems promising for the development of effective and safe pharmacological interventions for severe AH.

Keywords

alcoholic liver disease - liver transplantation - corticosteroids - pentoxifylline
 

  • References

  • 1 Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009; 360 (26) 2758-2769
    CrossrefPubMedSearch in Google Scholar
  • 2 Singal AK, Kamath PS, Gores GJ, Shah VH. Alcoholic hepatitis: current challenges and future directions. Clin Gastroenterol Hepatol 2014; 12 (4) 555-564 , quiz e31–e32
    CrossrefPubMedSearch in Google Scholar
  • 3 Singal AK, Shah VH. Alcoholic hepatitis: prognostic models and treatment. Gastroenterol Clin North Am 2011; 40 (3) 611-639
    CrossrefPubMedSearch in Google Scholar
  • 4 Michelena J, Altamirano J, Abraldes JG , et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology 2015; 62 (3) 762-772
    CrossrefPubMedSearch in Google Scholar
  • 5 Hardy T, Wells C, Kendrick S , et al. White cell count and platelet count associate with histological alcoholic hepatitis in jaundiced harmful drinkers. BMC Gastroenterol 2013; 13 (1) 55
    CrossrefPubMedSearch in Google Scholar
  • 6 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) 307-328
    CrossrefPubMedSearch in Google Scholar
  • 7 Maddrey WC, Boitnott JK, Bedine MS, Weber Jr FL, Mezey E, White Jr RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978; 75 (2) 193-199
    CrossrefPubMedSearch in Google Scholar
  • 8 Dunn W, Jamil LH, Brown LS , et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology 2005; 41 (2) 353-358
    CrossrefPubMedSearch in Google Scholar
  • 9 Shah VH. Alcoholic liver disease: the buzz may be gone, but the hangover remains. Hepatology 2010; 51 (5) 1483-1484
    CrossrefPubMedSearch in Google Scholar
  • 10 Singal AK, Charlton MR. Nutrition in alcoholic liver disease. Clin Liver Dis 2012; 16 (4) 805-826
    CrossrefPubMedSearch in Google Scholar
  • 11 Singal AK, Kamath PS, Francisco Ziller N , et al. Nutritional status of patients with alcoholic cirrhosis undergoing liver transplantation: time trends and impact on survival. Transpl Int 2013; 26 (8) 788-794
    CrossrefPubMedSearch in Google Scholar
  • 12 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) 635-641
    CrossrefPubMedSearch in Google Scholar
  • 13 Habeeb SBH, Kuo YF, Singal AK. Impact of nutritional supplementation in patients with alcoholic cirrhosis and alcoholic hepatitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2013; 108: S133
    CrossrefPubMedSearch in Google Scholar
  • 14 Porter HP, Simon FR, Pope II CE, Volwiler W, Fenster LF. Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial. N Engl J Med 1971; 284 (24) 1350-1355
    CrossrefPubMedSearch in Google Scholar
  • 15 Blitzer BL, Mutchnick MG, Joshi PH, Phillips MM, Fessel JM, Conn HO. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double-blind randomized study. Am J Dig Dis 1977; 22 (6) 477-484
    CrossrefPubMedSearch in Google Scholar
  • 16 Lesesne HR, Bozymski EM, Fallon HJ. Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements. Gastroenterology 1978; 74 (2 Pt 1): 169-173
    PubMedSearch in Google Scholar
  • 17 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) 443-449
    PubMedSearch in Google Scholar
  • 18 Depew W, Boyer T, Omata M, Redeker A, Reynolds T. Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy. Gastroenterology 1980; 78 (3) 524-529
    PubMedSearch in Google Scholar
  • 19 Theodossi A, Eddleston AL, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut 1982; 23 (1) 75-79
    CrossrefPubMedSearch in Google Scholar
  • 20 Carithers Jr RL, Herlong HF, Diehl AM , et al. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med 1989; 110 (9) 685-690
    CrossrefPubMedSearch in Google Scholar
  • 21 Ramond MJ, Poynard T, Rueff B , et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992; 326 (8) 507-512
    CrossrefPubMedSearch in Google Scholar
  • 22 Cabré E, Rodríguez-Iglesias P, Caballería 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 (1) 36-42
    CrossrefPubMedSearch in Google Scholar
  • 23 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) 784-790
    CrossrefPubMedSearch in Google Scholar
  • 24 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) 625-631
    CrossrefPubMedSearch in Google Scholar
  • 25 Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med 1971; 74 (3) 311-321
    CrossrefPubMedSearch in Google Scholar
  • 26 Thursz MR, Richardson P, Allison M , et al; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372 (17) 1619-1628
    CrossrefPubMedSearch in Google Scholar
  • 27 Mendenhall CL, Anderson S, Garcia-Pont P , et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984; 311 (23) 1464-1470
    CrossrefPubMedSearch in Google Scholar
  • 28 Mathurin P, O'Grady J, Carithers RL , et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011; 60 (2) 255-260
    CrossrefPubMedSearch in Google Scholar
  • 29 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) 1167-1178
    CrossrefPubMedSearch in Google Scholar
  • 30 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 (6) 1348-1354
    CrossrefPubMedSearch in Google Scholar
  • 31 Mathurin P, Bataller R. Trends in the management and burden of alcoholic liver disease. J Hepatol 2015; 62 (1, Suppl) S38-S46
    CrossrefPubMedSearch in Google Scholar
  • 32 Singal AK, Walia I, Singal A, Soloway RD. Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: Current status. World J Hepatol 2011; 3 (8) 205-210
    CrossrefPubMedSearch in Google Scholar
  • 33 Franchimont D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci 2004; 1024: 124-137
    CrossrefPubMedSearch in Google Scholar
  • 34 Taïeb J, Delarche C, Paradis V , et al. Polymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitis. J Hepatol 2002; 36 (3) 342-348
    CrossrefPubMedSearch in Google Scholar
  • 35 Spahr L, Rubbia-Brandt L, Pugin J , 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 (5) 582-589
    CrossrefPubMedSearch in Google Scholar
  • 36 Richardet JP, Dehoux M, Mal F , et al. Influence of corticosteroids (CS) on plasma cytokines concentrations in patients with severe alcoholic hepatitis: results of a randomized study. J Hepatol 1993; 18: S75
    PubMedSearch in Google Scholar
  • 37 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) 1316-1322
    CrossrefPubMedSearch in Google Scholar
  • 38 Mookerjee RP, Stadlbauer V, Lidder S , et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46 (3) 831-840
    CrossrefPubMedSearch in Google Scholar
  • 39 Markwick LJ, Riva A, Ryan JM , et al. Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis. Gastroenterology 2015; 148 (3) 590-602.e10
    CrossrefPubMedSearch in Google Scholar
  • 40 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 (2) 541-548
    CrossrefPubMedSearch in Google Scholar
  • 41 Garcia Rodríguez LA, Hernández-Díaz S. The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthritis Res 2001; 3 (2) 98-101
    CrossrefPubMedSearch in Google Scholar
  • 42 Douros A, Bronder E, Andersohn F , et al. Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases. Aliment Pharmacol Ther 2013; 38 (7) 825-834
    CrossrefPubMedSearch in Google Scholar
  • 43 Louvet AAF, Colin M, Lassaily G , et al. Patients with severe alcoholic hepatitis and hepatorenal syndrome require a new therapeutic strategy. Hepatology 2012; 56 (Suppl. 01) 986A-987A
    PubMedSearch in Google Scholar
  • 44 Singal AK, Kuo YF, Anand BS. Hepatitis C virus infection in alcoholic hepatitis: prevalence patterns and impact on in-hospital mortality. Eur J Gastroenterol Hepatol 2012; 24 (10) 1178-1184
    CrossrefPubMedSearch in Google Scholar
  • 45 Singal AK, Sagi S, Kuo YF, Weinman S. Impact of hepatitis C virus infection on the course and outcome of patients with acute alcoholic hepatitis. Eur J Gastroenterol Hepatol 2011; 23 (3) 204-209
    CrossrefPubMedSearch in Google Scholar
  • 46 Segev DL, Sozio SM, Shin EJ , et al. Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials. Liver Transpl 2008; 14 (4) 512-525
    CrossrefPubMedSearch in Google Scholar
  • 47 Shoreibah M, Anand BS, Singal AK. Alcoholic hepatitis and concomitant hepatitis C virus infection. World J Gastroenterol 2014; 20 (34) 11929-11934
    CrossrefPubMedSearch in Google Scholar
  • 48 Orntoft NW, Sandahl TD, Jepsen P, Vilstrup H. Short-term and long-term causes of death in patients with alcoholic hepatitis in Denmark. Clin Gastroenterol Hepatol 2014; 12 (10) 1739-44.e1
    CrossrefPubMedSearch in Google Scholar
  • 49 Hmoud BS, Patel K, Bataller R, Singal AK. Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a metaanalysis of randomized trials. Liver Int 2015; Aug. 15 [ePub]
    PubMedSearch in Google Scholar
  • 50 Bajaj JS, O'Leary JG, Reddy KR , et al; NACSELD. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012; 56 (6) 2328-2335
    CrossrefPubMedSearch in Google Scholar
  • 51 Gustot T, Maillart E, Bocci M , et al. Invasive aspergillosis in patients with severe alcoholic hepatitis. J Hepatol 2014; 60 (2) 267-274
    CrossrefPubMedSearch in Google Scholar
  • 52 Wernlund PG, Støy S, Lemming L, Vilstrup H, Sandahl TD. Blood culture-positive infections in patients with alcoholic hepatitis. Scand J Infect Dis 2014; 46 (12) 902-905
    CrossrefPubMedSearch in Google Scholar
  • 53 Faria LC, Ichai P, Saliba F , et al. Pneumocystis pneumonia: an opportunistic infection occurring in patients with severe alcoholic hepatitis. Eur J Gastroenterol Hepatol 2008; 20 (1) 26-28
    CrossrefPubMedSearch in Google Scholar
  • 54 Sundaram V, May FP, Manne V, Saab S. Effects of Clostridium difficile infection in patients with alcoholic hepatitis. Clin Gastroenterol Hepatol 2014; 12 (10) 1745-52.e2
    CrossrefPubMedSearch in Google Scholar
  • 55 Helsinki University. Randomised Open-label Multicenter Study Evaluating Ciprofloxacin in Severe Alcoholic Hepatitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02326103 . Accessed December 30, 2015
    PubMed
  • 56 University Hospital, Lille. Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated with Prednisolone (AntibioCor). Available at: https://clinicaltrials.gov/ct2/show/NCT02281929 . Accessed December 30, 2015
    PubMed
  • 57 Hospital Universitari Vall d'Hebron Research Institute. Effects of Rifaxicin in Patients with Acute Alcoholic Hepatitis (RIFA-AAH). Available at: https://clinicaltrials.gov/ct2/show/NCT02116556 . Accessed December 30, 2015
    PubMed
  • 58 Saint Vincent's Hospital, Korea. Rifaxicin Use in Severe Alcoholic Hepatitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02485106 . Accessed December 30, 2015
    PubMed
  • 59 Alvarez MA, Cabré E, Lorenzo-Zúñiga V, Montoliu S, Planas R, Gassull MA. Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic hepatitis? Results of a pilot study. Eur J Gastroenterol Hepatol 2004; 16 (12) 1375-1380
    CrossrefPubMedSearch in Google Scholar
  • 60 Reuter BK, Wallace JL. Phosphodiesterase inhibitors prevent NSAID enteropathy independently of effects on TNF-alpha release. Am J Physiol 1999; 277 (4 Pt 1): G847-G854
    PubMedSearch in Google Scholar
  • 61 McClain CJ. Tumor necrosis and alcoholic hepatitis. Hepatology 1991; 14 (2) 394-396
    PubMedSearch in Google Scholar
  • 62 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) 1637-1648
    CrossrefPubMedSearch in Google Scholar
  • 63 Paladugu HS, Dalvi P, Kudalkar L. Role of pentoxifylline in treatment of severe alcoholic hepatitis - a randomized controlled trial. J Gastroenterol Hepatol 2006; 21: A459
    CrossrefPubMedSearch in Google Scholar
  • 64 McHutchison JGRB, Draguesku JO , et al. Pentoxifylline may prevent renal impairment (hepatorenal syndrome) in severe acute alcoholic hepatitis. Hepatology 1991; 14: 96A
    PubMedSearch in Google Scholar
  • 65 Sidhu SSM, Bhatia K. Pentoxifylline reduces disease severity and prevents renal impairment in severe acute acloholic hepatitis: a double-blind placebo-controlled trial. Hepatology 2006; 44 (Suppl. 01) 373A
    PubMedSearch in Google Scholar
  • 66 Leebrec D, Thabut D, Oberti F , et al. Pentoxifylline for treatment of patients with advanced cirrhosis. A randomzied placebo controlled double blind trial. Hepatology 2007; 46: A249-A250
    PubMedSearch in Google Scholar
  • 67 Whitfield K, Rambaldi A, Wetterslev J, Gluud C. Pentoxifylline for alcoholic hepatitis. Cochrane Database Syst Rev 2009; (4) CD007339
    PubMedSearch in Google Scholar
  • 68 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) 1613-1619
    CrossrefPubMedSearch in Google Scholar
  • 69 Park SH, Kim DJ, Kim YS , et al; Korean Association for the Study of the Liver (KASL)-Alcohol Related Problems Study Group. Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: a randomised, non-inferiority, open trial. J Hepatol 2014; 61 (4) 792-798
    CrossrefPubMedSearch in Google Scholar
  • 70 Sidhu SS, 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 (6) 1664-1671
    CrossrefPubMedSearch in Google Scholar
  • 71 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 (10) 1033-1041
    CrossrefPubMedSearch in Google Scholar
  • 72 Louvet A, Diaz E, Dharancy S , et al. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J Hepatol 2008; 48 (3) 465-470
    CrossrefPubMedSearch in Google Scholar
  • 73 Parker R, Armstrong MJ, Corbett C, Rowe IA, Houlihan DD. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Aliment Pharmacol Ther 2013; 37 (9) 845-854
    CrossrefPubMedSearch in Google Scholar
  • 74 Forrest E, Mellor J, Stanton L , et al. Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial. Trials 2013; 14: 262
    CrossrefPubMedSearch in Google Scholar
  • 75 Singh S, Murad MH, Chandar AK , et al. Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta-analysis. Gastroenterology 2015; 149 (4) 958-970.e12
    CrossrefPubMedSearch in Google Scholar
  • 76 Singal AK, Salameh H, Singal A , et al. Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians. World J Gastrointest Pharmacol Ther 2013; 4 (2) 16-22
    CrossrefPubMedSearch in Google Scholar
  • 77 Ahn JMT, Cohen SM. Evaluation and management of alcoholic hepatitis: a survey of current practices. Hepatology 2009; 50: 612A
    CrossrefPubMedSearch in Google Scholar
  • 78 Sanyal AJ, Gao B, Szabo G. Gaps in knowledge and research priorities for alcoholic hepatitis. Gastroenterology 2015; 149 (1) 4-9
    CrossrefPubMedSearch in Google Scholar
  • 79 Chacko BK, Kramer PA, Ravi S , et al. The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci (Lond) 2014; 127 (6) 367-373
    CrossrefPubMedSearch in Google Scholar
  • 80 Keshavarzian A, Holmes EW, Patel M, Iber F, Fields JZ, Pethkar S. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol 1999; 94 (1) 200-207
    CrossrefPubMedSearch in Google Scholar
  • 81 Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 2000; 32 (5) 742-747
    CrossrefPubMedSearch in Google Scholar
  • 82 Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology 2015; 148 (1) 30-36
    CrossrefPubMedSearch in Google Scholar
  • 83 Keshavarzian A, Farhadi A, Forsyth CB , et al. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J Hepatol 2009; 50 (3) 538-547
    PubMedSearch in Google Scholar
  • 84 Safety and efficacy of IMM 124-E for the treatment of severe alcoholic hepatitis (TREAT). Available at: https://clinicaltrials.gov/ct2/show/NCT01968382?term=anti-LPS&rank=1
    PubMed
  • 85 Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ. Zinc and liver disease. Nutr Clin Pract 2012; 27 (1) 8-20
    CrossrefPubMedSearch in Google Scholar
  • 86 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
    CrossrefPubMedSearch in Google Scholar
  • 87 Sun Q, Zhong W, Zhang W , et al. Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways. Am J Physiol Gastrointest Liver Physiol 2015; 308 (9) G757-G766
    CrossrefPubMedSearch in Google Scholar
  • 88 Mitchell M. Efficacy Study of Anakinra, Pentoxyfilline, and Zinc Compared to Methylprednisone in Severe Acute Alcoholic Hepatitis. Available at: https://clinicaltrials.gov/ct2/show/NCT01809132 . Accessed December 30, 2015
    PubMed
  • 89 Benloucif S, Burgess HJ, Klerman EB , et al. Measuring melatonin in humans. J Clin Sleep Med 2008; 4 (1) 66-69
    PubMedSearch in Google Scholar
  • 90 Forsyth CB, Voigt RM, Shaikh M , et al. Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability. Am J Physiol Gastrointest Liver Physiol 2013; 305 (2) G185-G195
    CrossrefPubMedSearch in Google Scholar
  • 91 Swanson G, Forsyth CB, Tang Y , et al. Role of intestinal circadian genes in alcohol-induced gut leakiness. Alcohol Clin Exp Res 2011; 35 (7) 1305-1314
    CrossrefPubMedSearch in Google Scholar
  • 92 Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014; 60 (1) 197-209
    CrossrefPubMedSearch in Google Scholar
  • 93 Bull-Otterson L, Feng W, Kirpich I , et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 94 Yan AW, Fouts DE, Brandl J , et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011; 53 (1) 96-105
    CrossrefPubMedSearch in Google Scholar
  • 95 Hartmann P, Chen P, Wang HJ , et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 2013; 58 (1) 108-119
    CrossrefPubMedSearch in Google Scholar
  • 96 Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol 2009; 43 (2) 163-172
    CrossrefPubMedSearch in Google Scholar
  • 97 Wang Y, Liu Y, Sidhu A, Ma Z, McClain C, Feng W. Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury. Am J Physiol Gastrointest Liver Physiol 2012; 303 (1) G32-G41
    CrossrefPubMedSearch in Google Scholar
  • 98 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: 151
    CrossrefPubMedSearch in Google Scholar
  • 99 Chuncheon Sacred Heart Hospital. Effect of Probiotics on Gut-Liver Axis of Alcoholic Liver Disease (EPALD). Available at: https://clinicaltrials.gov/ct2/show/ NCT01501162 . Accessed December 30, 2015
    PubMed
  • 100 University of Texas Southwestern Medical Center. Novel Therapies in Moderately Severe Acute Alcoholic Hepatitis (NTAH-Mod). Available at: https://clinicaltrials.gov/ct2/show /NCT01922895 . Accessed December 30, 2015
    PubMed
  • 101 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140 (6) 821-832
    CrossrefPubMedSearch in Google Scholar
  • 102 Petrasek J, Bala S, Csak T , et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 2012; 122 (10) 3476-3489
    CrossrefPubMedSearch in Google Scholar
  • 103 Mertens M, Singh JA. Anakinra for rheumatoid arthritis. Cochrane Database Syst Rev 2009; (1) CD005121
    PubMedSearch in Google Scholar
  • 104 Opal SM, Fisher Jr CJ, Dhainaut JF , et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997; 25 (7) 1115-1124
    CrossrefPubMedSearch in Google Scholar
  • 105 Marques-Rocha JL, Samblas M, Milagro FI, Bressan J, Martínez JA, Marti A. Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J 2015; 29 (9) 3595-3611
    CrossrefPubMedSearch in Google Scholar
  • 106 Bala S, Petrasek J, Mundkur S , et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 2012; 56 (5) 1946-1957
    CrossrefPubMedSearch in Google Scholar
  • 107 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) 2217-2224
    CrossrefPubMedSearch in Google Scholar
  • 108 McDaniel K, Herrera L, Zhou T , et al. The functional role of microRNAs in alcoholic liver injury. J Cell Mol Med 2014; 18 (2) 197-207
    CrossrefPubMedSearch in Google Scholar
  • 109 Naveau S, Chollet-Martin S, Dharancy S , et al; Foie-Alcool group of the Association Française pour l'Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004; 39 (5) 1390-1397
    CrossrefPubMedSearch in Google Scholar
  • 110 Boetticher NC, Peine CJ, Kwo P , et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 2008; 135 (6) 1953-1960
    CrossrefPubMedSearch in Google Scholar
  • 111 Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med 2015; 3 (1) 5
    PubMedSearch in Google Scholar
  • 112 Wu W, Zhu B, Peng X, Zhou M, Jia D, Gu J. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochem Biophys Res Commun 2014; 443 (1) 68-73
    CrossrefPubMedSearch in Google Scholar
  • 113 Wu WB, Chen YY, Zhu B, Peng XM, Zhang SW, Zhou ML. Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice. Biochimie 2015; 115: 86-92
    CrossrefPubMedSearch in Google Scholar
  • 114 Chalasani NP. Trial of Obeticholic Acid in Patients with Moderately Severe Alcoholic Hepatitis (AH). (TREAT). Available at: https://clinicaltrials.gov/ct2/show/NCT02039219 . Accessed December 30, 2015
    PubMed
  • 115 Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int 2011; 31 (10) 1432-1448
    CrossrefPubMedSearch in Google Scholar
  • 116 Nguyen-Khac E, Thevenot T, Piquet MA , et al; AAH-NAC Study Group. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011; 365 (19) 1781-1789
    CrossrefPubMedSearch in Google Scholar
  • 117 Higuera-de la Tijera F, Servín-Caamaño AI, Serralde-Zúñiga AE , et al. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis. World J Gastroenterol 2015; 21 (16) 4975-4985
    CrossrefPubMedSearch in Google Scholar
  • 118 PharmaKing. Efficacy and Safety of MG in the Patients with Alcoholic Fatty Liver Disease and Alcoholic Hepatitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02019056 . Accessed December 30, 2015
    PubMed
  • 119 Brown University. A Novel Pharmacotherapy for Alcoholism and Alcoholic Liver Disease. Available at: https://clinicaltrials.gov/ct2/show/NCT01504295 . Accessed December 30, 2015
    PubMed
  • 120 Conatus Pharmaceuticals, Inc. Study of IDN-6556 in Patients with Severe AH and Contradictions to Steroid Therapy. Available at: https://clinicaltrials.gov/ct2/show/NCT01912404 . Accessed December 30, 2015
    PubMed
  • 121 Dubuquoy L, Louvet A, Lassailly G , et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut 2015; 64 (12) 1949-1960
    CrossrefPubMedSearch in Google Scholar
  • 122 Lanthier N, Rubbia-Brandt L, Lin-Marq N , et al. Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis. J Hepatol 2015; 63 (3) 609-621
    CrossrefPubMedSearch in Google Scholar
  • 123 Grove JE, Bruscia E, Krause DS. Plasticity of bone marrow-derived stem cells. Stem Cells 2004; 22 (4) 487-500
    CrossrefPubMedSearch in Google Scholar
  • 124 Garg V, Garg H, Khan A , et al. Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure. Gastroenterology 2012; 142 (3) 505-512.e1
    CrossrefPubMedSearch in Google Scholar
  • 125 Kedarisetty CK, Anand L, Bhardwaj A , et al. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology 2015; 148 (7) 1362-70.e7
    CrossrefPubMedSearch in Google Scholar
  • 126 Chung T, Martin CS, Winters KC. Diagnosis, course, and assessment of alcohol abuse and dependence in adolescents. Recent Dev Alcohol 2005; 17: 5-27
    PubMedSearch in Google Scholar
  • 127 Yam FGJ, Groessel EJ, Lau JW , et al. Quality of care and predictors of readmission in hospitalized patients with alcoholic liver disease care in two academic medical centers. Hepatology 2012; 56: 947A
    PubMedSearch in Google Scholar
  • 128 Weinrieb RM, Van Horn DH, Lynch KG, Lucey MR. A randomized, controlled study of treatment for alcohol dependence in patients awaiting liver transplantation. Liver Transpl 2011; 17 (5) 539-547
    CrossrefPubMedSearch in Google Scholar
  • 129 Ipser JC, Wilson D, Akindipe TO, Sager C, Stein DJ. Pharmacotherapy for anxiety and comorbid alcohol use disorders. Cochrane Database Syst Rev 2015; 1: CD007505
    PubMedSearch in Google Scholar
  • 130 Vuittonet CL, Halse M, Leggio L , et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. American journal of health-system pharmacy. Am J Health Promot 2014; 71 (15) 1265-1276
    PubMedSearch in Google Scholar
  • 131 Yamini D, Lee SH, Avanesyan A, Walter M, Runyon B. Utilization of baclofen in maintenance of alcohol abstinence in patients with alcohol dependence and alcoholic hepatitis with or without cirrhosis. Alcohol Alcohol 2014; 49 (4) 453-456
    CrossrefPubMedSearch in Google Scholar
  • 132 Barrault CLH, Roudot-Thoraval F, Garioud A , et al. One year effectiveness of baclofen treatment in 100 alcohol-dependent patients. J Hepatol 2015; 62 (Suppl. 02) S758-S759
    PubMedSearch in Google Scholar
  • 133 Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013; 95 (5) 755-760
    CrossrefPubMedSearch in Google Scholar
  • 134 Burra P, Senzolo M, Adam R , et al; ELITA; ELTR Liver Transplant Centers. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am J Transplant 2010; 10 (1) 138-148
    CrossrefPubMedSearch in Google Scholar
  • 135 Singal AK, Chaha KS, Rasheed K, Anand BS. Liver transplantation in alcoholic liver disease current status and controversies. World J Gastroenterol 2013; 19 (36) 5953-5963
    CrossrefPubMedSearch in Google Scholar
  • 136 Singal AK, Duchini A. Liver transplantation in acute alcoholic hepatitis: Current status and future development. World J Hepatol 2011; 3 (8) 215-218
    CrossrefPubMedSearch in Google Scholar
  • 137 Hoofnagle JH, Kresina T, Fuller RK , et al. Liver transplantation for alcoholic liver disease: executive statement and recommendations. Summary of a National Institutes of Health workshop held December 6–7, 1996, Bethesda, Maryland. Liver Transpl Surg 1997; 3 (3) 347-350
    CrossrefPubMedSearch in Google Scholar
  • 138 McCallum S, Masterton G. Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection criteria. Alcohol Alcohol 2006; 41 (4) 358-363
    CrossrefPubMedSearch in Google Scholar
  • 139 Mathurin P, Moreno C, Samuel D , et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365 (19) 1790-1800
    CrossrefPubMedSearch in Google Scholar
  • 140 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) 1398-1405
    CrossrefPubMedSearch in Google Scholar
  • 141 Hasanin M, Dubay DA, McGuire BM, Schiano T, Singal AK. Liver transplantation for alcoholic hepatitis: A survey of liver transplant centers. Liver Transpl 2015; 21 (11) 1449-1452
    CrossrefPubMedSearch in Google Scholar
  • 142 Singal AK, Anand BS. Epidemiology of alcoholic liver disease. Clin Liver Dis 2013; 2: 53-56
    CrossrefPubMedSearch in Google Scholar
  • 143 University Hospital, Lille. Validation of the Procedure of Early Liver Transplantation in Alcoholic Hepatitis Resisting to Medical Treatment (Quick Trans). Available at: https://clinicaltrials.gov/ct2/show/NCT01756794 . Accessed December 30, 2015
    PubMed
  • 144 Bañares R, Nevens F, Larsen FS , et al; RELIEF study group. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013; 57 (3) 1153-1162
    CrossrefPubMedSearch in Google Scholar
  • 145 Gustot T, Fernandez J, Garcia E , et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015; 62 (1) 243-252
    PubMedSearch in Google Scholar