Download PDF
Semin Liver Dis 2023; 43(01): 060-076
DOI: 10.1055/s-0042-1759614
Review Article

Therapeutic Pipeline in Alcohol-Associated Liver Disease

Nimish Thakral
1   Division of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky
,
Sasha Deutsch-Link
2   Department of Medicine, University of North Carolina at Chapel Hill, North Carolina
,
Ashwani K. Singal
3   Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
4   Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
› Author Affiliations
› Further Information
   Permissions and Reprints


Abstract

Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.

Keywords

alcohol-associated liver disease - alcoholic hepatitis - alcohol-use disorder - therapeutic - emerging therapies


Publication History

Article published online:
26 December 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019; 70 (01) 151-171
    CrossrefPubMedGoogle Scholar
  • 2 Singal AK, Mathurin P. Diagnosis and treatment of alcohol-associated liver disease: a review. JAMA 2021; 326 (02) 165-176
    CrossrefPubMedGoogle Scholar
  • 3 Chacko KR, Reinus J. Spectrum of alcoholic liver disease. Clin Liver Dis 2016; 20 (03) 419-427
    CrossrefPubMedGoogle Scholar
  • 4 World Health Organization. Global Status Report on Alcohol and Health 2018. World Health Organization. 2018 . Accessed July 2, 2022 at: https://apps.who.int/iris/handle/10665/274603
    PubMedGoogle Scholar
  • 5 Boersma P, Villarroel MA, Vahratian A. Heavy drinking among U.S. adults, 2018. NCHS Data Brief 2020; (374) 1-8
    PubMedGoogle Scholar
  • 6 Pollard MS, Tucker JS, Green Jr HD. Changes in adult alcohol use and consequences during the COVID-19 pandemic in the US. JAMA Netw Open 2020; 3 (09) e2022942
    CrossrefPubMedGoogle Scholar
  • 7 Shaheen AA, Kong K, Ma C. et al. Impact of the COVID-19 pandemic on hospitalizations for alcoholic hepatitis or cirrhosis in Alberta, Canada. Clin Gastroenterol Hepatol 2022; 20 (05) e1170-e1179
    CrossrefPubMedGoogle Scholar
  • 8 Cholankeril G, Goli K, Rana A. et al. Impact of COVID-19 pandemic on liver transplantation and alcohol-associated liver disease in the USA. Hepatology 2021; 74 (06) 3316-3329
    CrossrefPubMedGoogle Scholar
  • 9 Julien J, Ayer T, Tapper EB, Barbosa C, Dowd WN, Chhatwal J. Effect of increased alcohol consumption during COVID-19 pandemic on alcohol-associated liver disease: a modeling study. Hepatology 2022; 75 (06) 1480-1490
    CrossrefPubMedGoogle Scholar
  • 10 Singal AK, Kodali S, Vucovich LA, Darley-Usmar V, Schiano TD. Diagnosis and treatment of alcoholic hepatitis: a systematic review. Alcohol Clin Exp Res 2016; 40 (07) 1390-1402
    CrossrefPubMedGoogle Scholar
  • 11 Arab JP, Izzy M, Leggio L, Bataller R, Shah VH. Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation. Nat Rev Gastroenterol Hepatol 2022; 19 (01) 45-59
    CrossrefPubMedGoogle Scholar
  • 12 Asken MJ, Grossman D, Christensen LW. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Arlington, VA: American Psychiatric Publishing; 2013
    Google Scholar
  • 13 Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med 1998; 158 (16) 1789-1795
    CrossrefPubMedGoogle Scholar
  • 14 Bradley KA, DeBenedetti AF, Volk RJ, Williams EC, Frank D, Kivlahan DR. AUDIT-C as a brief screen for alcohol misuse in primary care. Alcohol Clin Exp Res 2007; 31 (07) 1208-1217
    CrossrefPubMedGoogle Scholar
  • 15 Frank D, DeBenedetti AF, Volk RJ, Williams EC, Kivlahan DR, Bradley KA. Effectiveness of the AUDIT-C as a screening test for alcohol misuse in three race/ethnic groups. J Gen Intern Med 2008; 23 (06) 781-787
    CrossrefPubMedGoogle Scholar
  • 16 Shah ND, Ventura-Cots M, Abraldes JG. et al. Alcohol-related liver disease is rarely detected at early stages compared with liver diseases of other etiologies worldwide. Clin Gastroenterol Hepatol 2019; 17 (11) 2320-2329.e12
    CrossrefPubMedGoogle Scholar
  • 17 Shoreibah M, Raff E, Bloomer J. et al. Alcoholic liver disease presents at advanced stage and progresses faster compared to non-alcoholic fatty liver disease. Ann Hepatol 2016; 15 (02) 183-189
    PubMedGoogle Scholar
  • 18 2020 National Survey of Drug Use and Health (NSDUH) Releases | CBHSQ Data. Accessed July 6, 2022 at: https://www.samhsa.gov/data/release/2020-national-survey-drug-use-and-health-nsduh-releases
    PubMedGoogle Scholar
  • 19 Harris AHS, Oliva E, Bowe T, Humphreys KN, Kivlahan DR, Trafton JA. Pharmacotherapy of alcohol use disorders by the Veterans Health Administration: patterns of receipt and persistence. Psychiatr Serv 2012; 63 (07) 679-685
    CrossrefPubMedGoogle Scholar
  • 20 Louvet A, Labreuche J, Artru F. et al. Main drivers of outcome differ between short term and long term in severe alcoholic hepatitis: a prospective study. Hepatology 2017; 66 (05) 1464-1473
    CrossrefPubMedGoogle Scholar
  • 21 Altamirano J, López-Pelayo H, Michelena J. et al. Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: prediction and impact on long-term survival. Hepatology 2017; 66 (06) 1842-1853
    CrossrefPubMedGoogle Scholar
  • 22 Singal AK, DiMartini A, Leggio L, Arab JP, Kuo YF, Shah VH. Identifying alcohol use disorder in patients with cirrhosis reduces 30-days readmission rate. Alcohol Alcohol 2022; 57 (05) 576-580
    CrossrefPubMedGoogle Scholar
  • 23 Lackner C, Spindelboeck W, Haybaeck J. et al. Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease. J Hepatol 2017; 66 (03) 610-618
    CrossrefPubMedGoogle Scholar
  • 24 Pearson MM, Kim NJ, Berry K. et al. Associations between alcohol use and liver-related outcomes in a large national cohort of patients with cirrhosis. Hepatol Commun 2021; 5 (12) 2080-2095
    CrossrefPubMedGoogle Scholar
  • 25 Santos SGRD, Mattos AA, Guimarães MM, Boger BS, Coral GP. Alcohol consumption influences clinical outcome in patients admitted to a referral center for liver disease. Ann Hepatol 2018; 17 (03) 470-475
    CrossrefPubMedGoogle Scholar
  • 26 Peeraphatdit TB, Kamath PS, Karpyak VM. et al. Alcohol rehabilitation within 30 days of hospital discharge is associated with reduced readmission, relapse, and death in patients with alcoholic hepatitis. Clin Gastroenterol Hepatol 2020; 18 (02) 477-485.e5
    CrossrefPubMedGoogle Scholar
  • 27 Abdallah M, Elfeki MA, Leggio L, Singal AK. Simultaneous management of alcohol use disorder and of liver disease: a systematic review and meta-analysis. J Addict Med. 2022 ; Epub ahead of print
    PubMedGoogle Scholar
  • 28 Tyson LD, Cheng A, Kelleher C. et al. Acamprosate may be safer than baclofen for the treatment of alcohol use disorder in patients with cirrhosis: a first description of use in real-world clinical practice. Eur J Gastroenterol Hepatol 2022; 34 (05) 567-575
    CrossrefPubMedGoogle Scholar
  • 29 Vannier AGL, Shay JES, Fomin V. et al. Incidence and progression of alcohol-associated liver disease after medical therapy for alcohol use disorder. JAMA Netw Open 2022; 5 (05) e2213014
    CrossrefPubMedGoogle Scholar
  • 30 Lund JL, Richardson DB, Stürmer T. The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application. Curr Epidemiol Rep 2015; 2 (04) 221-228
    CrossrefPubMedGoogle Scholar
  • 31 Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One 2014; 9 (02) e87366
    CrossrefPubMedGoogle Scholar
  • 32 Ayyala D, Bottyan T, Tien C. et al. Naltrexone for alcohol use disorder: hepatic safety in patients with and without liver disease. Hepatol Commun. 2022 ; Epub ahead of print
    PubMedGoogle Scholar
  • 33 Addolorato G, Leggio L, Ferrulli A. et al. 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): 1915-1922
    CrossrefPubMedGoogle Scholar
  • 34 Leggio L, Ferrulli A, Zambon A. et al. Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection. Addict Behav 2012; 37 (04) 561-564
    CrossrefPubMedGoogle Scholar
  • 35 Morley KC, Baillie A, Fraser I. et al. Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial. Br J Psychiatry 2018; 212 (06) 362-369
    CrossrefPubMedGoogle Scholar
  • 36 Kranzler HR, Feinn R, Morris P, Hartwell EE. A meta-analysis of the efficacy of gabapentin for treating alcohol use disorder. Addiction 2019; 114 (09) 1547-1555
    CrossrefPubMedGoogle Scholar
  • 37 Blodgett JC, Del Re AC, Maisel NC, Finney JW. A meta-analysis of topiramate's effects for individuals with alcohol use disorders. Alcohol Clin Exp Res 2014; 38 (06) 1481-1488
    CrossrefPubMedGoogle Scholar
  • 38 Gandhi KD, Mansukhani MP, Karpyak VM, Schneekloth TD, Wang Z, Kolla BP. The impact of varenicline on alcohol consumption in subjects with alcohol use disorders: systematic review and meta-analyses. J Clin Psychiatry 2020; 81 (02) 19r12924
    CrossrefPubMedGoogle Scholar
  • 39 O'Malley SS, Zweben A, Fucito LM. et al. Effect of varenicline combined with medical management on alcohol use disorder with comorbid cigarette smoking: a randomized clinical trial. JAMA Psychiatry 2018; 75 (02) 129-138
    CrossrefPubMedGoogle Scholar
  • 40 Jonas DE, Amick HR, Feltner C. et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014; 311 (18) 1889-1900
    CrossrefPubMedGoogle Scholar
  • 41 Bertolotti M, Ferrari A, Vitale G. et al. Effect of liver cirrhosis on the systemic availability of naltrexone in humans. J Hepatol 1997; 27 (03) 505-511
    CrossrefPubMedGoogle Scholar
  • 42 Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113 (04) 1264-1269
    CrossrefPubMedGoogle Scholar
  • 43 Topiramate. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012 . Accessed July 29, 2022 at: http://www.ncbi.nlm.nih.gov/books/NBK548632/
    PubMedGoogle Scholar
  • 44 Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2020; 71 (01) 306-333
    CrossrefPubMedGoogle Scholar
  • 45 Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG Clinical Guideline: alcoholic liver disease. Am J Gastroenterol 2018; 113 (02) 175-194
    CrossrefPubMedGoogle Scholar
  • 46 Reus VI, Fochtmann LJ, Bukstein O. et al. The American Psychiatric Association Practice Guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry 2018; 175 (01) 86-90
    CrossrefPubMedGoogle Scholar
  • 47 DiMartini AF, Leggio L, Singal AK. Barriers to the management of alcohol use disorder and alcohol-associated liver disease: strategies to implement integrated care models. Lancet Gastroenterol Hepatol 2022; 7 (02) 186-195 DOI: https://doi.org/10.1016/S2468-1253(21)00191-6
    CrossrefPubMedGoogle Scholar
  • 48 Chartier KG, Miller K, Harris TR, Caetano R. A 10-year study of factors associated with alcohol treatment use and non-use in a U.S. population sample. Drug Alcohol Depend 2016; 160: 205-211
    CrossrefPubMedGoogle Scholar
  • 49 Probst C, Manthey J, Martinez A, Rehm J. Alcohol use disorder severity and reported reasons not to seek treatment: a cross-sectional study in European primary care practices. Subst Abuse Treat Prev Policy 2015; 10 (01) 32
    CrossrefPubMedGoogle Scholar
  • 50 Schuler MS, Puttaiah S, Mojtabai R, Crum RM. Perceived barriers to treatment for alcohol problems: a latent class analysis. Psychiatr Serv 2015; 66 (11) 1221-1228
    CrossrefPubMedGoogle Scholar
  • 51 DiMartini AF, Leggio L, Singal AK. Barriers to the management of alcohol use disorder and alcohol-associated liver disease: strategies to implement integrated care models. Lancet Gastroenterol Hepatol 2022; 7 (02) 186-195
    CrossrefPubMedGoogle Scholar
  • 52 Im GY, Mellinger JL, Winters A. et al. Provider attitudes and practices for alcohol screening, treatment, and education in patients with liver disease: a survey from the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group. Clin Gastroenterol Hepatol 2021; 19 (11) 2407-2416.e8
    CrossrefPubMedGoogle Scholar
  • 53 Carrique L, Quance J, Tan A. et al. Results of early transplantation for alcohol-related cirrhosis: integrated addiction treatment with low rate of relapse. Gastroenterology 2021; 161 (06) 1896-1906.e2
    CrossrefPubMedGoogle Scholar
  • 54 Magistri P, Marzi L, Guerzoni S. et al. Impact of a multidisciplinary team on alcohol recidivism and survival after liver transplant for alcoholic disease. Transplant Proc 2019; 51 (01) 187-189
    CrossrefPubMedGoogle Scholar
  • 55 Dasarathy S. Nutrition and alcoholic liver disease: effects of alcoholism on nutrition, effects of nutrition on alcoholic liver disease, and nutritional therapies for alcoholic liver disease. Clin Liver Dis 2016; 20 (03) 535-550
    CrossrefPubMedGoogle Scholar
  • 56 Martin P. Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the AASLD and the American Society of Transplantation. Published online. 2013: 98
    PubMedGoogle Scholar
  • 57 Singal AK, Kamath PS, Gores GJ, Shah VH. Alcoholic hepatitis: current challenges and future directions. Clin Gastroenterol Hepatol 2014; 12 (04) 555-564 , quiz e31–e32
    CrossrefPubMedGoogle Scholar
  • 58 Crabb DW, Bataller R, Chalasani NP. et al; NIAAA Alcoholic Hepatitis Consortia. Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia. Gastroenterology 2016; 150 (04) 785-790
    CrossrefPubMedGoogle Scholar
  • 59 Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG Clinical Guideline: alcoholic liver disease. Off J Am Coll Gastroenterol 2018; 113 (02) 175-194
    CrossrefPubMedGoogle Scholar
  • 60 European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of alcohol-related liver disease. J Hepatol 2018; 69 (01) 154-181
    CrossrefPubMedGoogle Scholar
  • 61 Diagnosis and Treatment of Alcohol-Associated Liver Diseases. 2019 Practice Guidance from the American Association for the Study of Liver Diseases - Crabb - 2020 - Hepatology - Wiley Online Library. Accessed July 28, 2022 at: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.30866
    PubMedGoogle Scholar
  • 62 Singal AK, Walia I, Singal A, Soloway RD. Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: current status. World J Hepatol 2011; 3 (08) 205-210
    CrossrefPubMedGoogle Scholar
  • 63 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 (04) 958-70.e12
    CrossrefPubMedGoogle Scholar
  • 64 Louvet A, Thursz MR, Kim DJ. et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials. Gastroenterology 2018; 155 (02) 458-468.e8
    CrossrefPubMedGoogle Scholar
  • 65 Mathurin P, Moreno C, Samuel D. et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365 (19) 1790-1800
    CrossrefPubMedGoogle Scholar
  • 66 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 (02) 541-548
    CrossrefPubMedGoogle Scholar
  • 67 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 (06) 1348-1354
    CrossrefPubMedGoogle Scholar
  • 68 Vergis N, Atkinson SR, Knapp S. et al. In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, and is associated with high circulating levels of bacterial DNA. Gastroenterology 2017; 152 (05) 1068-1077.e4
    CrossrefPubMedGoogle Scholar
  • 69 Singal AK, Shah VH, Kamath PS. Infection in severe alcoholic hepatitis: yet another piece in the puzzle. Gastroenterology 2017; 152 (05) 938-940
    CrossrefPubMedGoogle Scholar
  • 70 Singal AK, Chacko B, Darley-Usmar V. Cellular Bioenergetics: A Promising Biomarker in Management of Patients with Alcoholic Liver Disease. In: Hepatology. Vol 66. 92A. Accessed November 12, 2022 at: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.29500
    Google Scholar
  • 71 Singal AK, Bailey SM. Cellular abnormalities and emerging biomarkers in alcohol-associated liver disease. Gene Expr 2018; 19 (01) 49-60
    CrossrefPubMedGoogle Scholar
  • 72 Sharma S, Maras JS, Das S. et al. Pre-therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness. Sci Rep 2017; 7 (01) 6816
    CrossrefPubMedGoogle Scholar
  • 73 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 (03) 538-547
    CrossrefPubMedGoogle Scholar
  • 74 Sidhu S, Goyal O, Gupta A, Kishore H, Gupta A. Corticosteroids and bovine colostrum in treatment of alcoholic hepatitis ‘in extremis’: a pilot study. J Clin Exp Hepatol 2015; 5: S19-S20
    CrossrefPubMedGoogle Scholar
  • 75 Singal AK, Charlton MR. Nutrition in alcoholic liver disease. Clin Liver Dis 2012; 16 (04) 805-826
    CrossrefPubMedGoogle Scholar
  • 76 Moran JR, Lewis JC. The effects of severe zinc deficiency on intestinal permeability: an ultrastructural study. Pediatr Res 1985; 19 (09) 968-973
    CrossrefPubMedGoogle Scholar
  • 77 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
    CrossrefPubMedGoogle Scholar
  • 78 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 (09) G757-G766
    CrossrefPubMedGoogle Scholar
  • 79 IL-1 receptor antagonist in combination with pentoxifylline and zinc for severe alcoholic hepatitis. A multicenter randomized double-bind placebo-controlled clinical trial. Hepatology 2018; 68 (06) 1444A-1471A
    CrossrefPubMedGoogle Scholar
  • 80 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 (01) e53028
    CrossrefPubMedGoogle Scholar
  • 81 Llopis M, Cassard AM, Wrzosek L. et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 2016; 65 (05) 830-839
    CrossrefPubMedGoogle Scholar
  • 82 Philips CA, Pande A, Shasthry SM. et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol 2017; 15 (04) 600-602
    CrossrefPubMedGoogle Scholar
  • 83 Philips CA, Phadke N, Ganesan K, Ranade S, Augustine P. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018; 37 (03) 215-225
    CrossrefPubMedGoogle Scholar
  • 84 Philips CA, Abduljaleel JK, Zulfikar RA, Rajesh S, Augustine P. Three Year Follow-up of Alcohol-Related hepatitis Patients Undergoing Healthy Donor Fecal Transplant: Analysis of Clinical Outcomes, Relapse, Gut Microbiota and Comparisons with Standard Care. Vol 74. Hoboken, NJ: Wiley; 2021: 8A-9A
    Google Scholar
  • 85 Bajaj JS, Gavis EA, Fagan A. et al. A randomized clinical trial of fecal microbiota transplant for alcohol use disorder. Hepatology 2021; 73 (05) 1688-1700
    CrossrefPubMedGoogle Scholar
  • 86 Philips CA, Ahamed R, Rajesh S, Abduljaleel JKP, Augustine P. Long-term outcomes of stool transplant in alcohol-associated hepatitis - analysis of clinical outcomes, relapse, gut microbiota and comparisons with standard care. J Clin Exp Hepatol 2022; 12 (04) 1124-1132
    CrossrefPubMedGoogle Scholar
  • 87 Louvet A, Labreuche J, Dao T. et al. Combination of Amoxicillin/Clavulanate and Prednisolone in Severe Alcoholic Hepatitis: Results of the Randomized Controlled Trial Antibiocor. Vol 75. Amsterdam, The Netherlands: Elsevier; 2021: S201-S202
    Google Scholar
  • 88 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140 (06) 821-832
    CrossrefPubMedGoogle Scholar
  • 89 Szabo G, Petrasek J. Gut-liver axis and sterile signals in the development of alcoholic liver disease. Alcohol Alcohol 2017; 52 (04) 414-424
    CrossrefPubMedGoogle Scholar
  • 90 Afford SC, Fisher NC, Neil DA. et al. Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J Pathol 1998; 186 (01) 82-89
    CrossrefPubMedGoogle Scholar
  • 91 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 (03) 342-348
    CrossrefPubMedGoogle Scholar
  • 92 Yiu JHC, Dorweiler B, Woo CW. Interaction between gut microbiota and toll-like receptor: from immunity to metabolism. J Mol Med (Berl) 2017; 95 (01) 13-20
    CrossrefPubMedGoogle Scholar
  • 93 Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res 2009; 33 (02) 220-232
    CrossrefPubMedGoogle Scholar
  • 94 Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 2015; 12 (04) 231-242
    CrossrefPubMedGoogle Scholar
  • 95 Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11 (08) 633-652
    CrossrefPubMedGoogle Scholar
  • 96 Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease | NEJM. Accessed April 17, 2022 at: https://www.nejm.org/doi/full/10.1056/nejmoa1707914
    PubMedGoogle Scholar
  • 97 Vergis N, Patel V, Bogdanowicz K. et al. IL-1Beta Signal Inhibition in Acute Alcoholic Hepatitis: A Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase 2 Trial of Canakinumab Therapy (ISAIAH). Vol 7. Elsevier Publications; 2022: S35-S37
    Google Scholar
  • 98 Mathurin P, Dufour JF, Bzowej NH. et al. Selonsertib in Combination with Prednisolone for the Treatment of Severe Alcoholic Hepatitis: A Phase 2 Randomized Controlled Trial. Vol 68. Hoboken, NJ: Wiley; 2018: 8A-9A
    Google Scholar
  • 99 Frenette CT, Morelli G, Shiffman ML. et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol 2019; 17 (04) 774-783.e4
    CrossrefPubMedGoogle Scholar
  • 100 Verbeke L, Farre R, Trebicka J. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59 (06) 2286-2298
    CrossrefPubMedGoogle Scholar
  • 101 Thompson J, Jones N, Al-Khafaji A. et al; VTI-208 Study Group. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: a multinational, prospective, controlled, randomized trial. Liver Transpl 2018; 24 (03) 380-393
    CrossrefPubMedGoogle Scholar
  • 102 Arab JP, Sehrawat TS, Simonetto DA. et al. An open-label, dose-escalation study to assess the safety and efficacy of IL-22 agonist F-652 in patients with alcohol-associated hepatitis. Hepatology 2020; 72 (02) 441-453
    CrossrefPubMedGoogle Scholar
  • 103 Forrest EH, Storey N, Sinha R. et al; STOPAH NLR Group. Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis. Aliment Pharmacol Ther 2019; 50 (04) 442-453
    CrossrefPubMedGoogle Scholar
  • 104 Altamirano J, Miquel R, Katoonizadeh A. et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014; 146 (05) 1231-9.e1 , 6
    CrossrefPubMedGoogle Scholar
  • 105 Shasthry SM, Sharma MK, Shasthry V, Pande A, Sarin SK. Efficacy of granulocyte colony-stimulating factor in the management of steroid-nonresponsive severe alcoholic hepatitis: a double-blind randomized controlled trial. Hepatology 2019; 70 (03) 802-811
    CrossrefPubMedGoogle Scholar
  • 106 Marot A, Dubois M, Trépo E, Moreno C, Deltenre P. Liver transplantation for alcoholic hepatitis: a systematic review with meta-analysis. PLoS One 2018; 13 (01) e0190823
    CrossrefPubMedGoogle Scholar
  • 107 Engelmann C, Herber A, Franke A. et al. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: a multicenter randomized trial (GRAFT study). J Hepatol 2021; 75 (06) 1346-1354
    CrossrefPubMedGoogle Scholar
  • 108 Kim MJ, Lin WQ. DUR-928, an endogenous regulatory molecule, exhibits anti-inflammatory and antifibrotic activity in a mouse model of NASH. Poster session presented at: AASLD's Emerging Trends in NAFLD; March 17–18, 2017. DURECT Corporation. Accessed April 17, 2022 at: https://www.durect.com/pipeline/larsucosterol/publications/
    PubMedGoogle Scholar
  • 109 Hassanein T, Stein LL, Flamm SL. et al. Safety and efficacy of DUR-928: a potential new therapy for acute alcoholic hepatitis. Hepatology 2019; 70 (06) 1483A-1484A
    PubMedGoogle Scholar
  • 110 McClain CJ, Vatsalya V, Rex R. et al. DUR-928 therapy for acute alcoholic hepatitis: a pilot study. Hepatology 2019; 70: 1483-1484
    PubMedGoogle Scholar
  • 111 Alcohol and oxidative liver injury - Dey - 2006 - Hepatology - Wiley Online Library. Accessed July 21, 2022 at: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.20957
    PubMedGoogle Scholar
  • 112 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 (02) 277-283
    CrossrefPubMedGoogle Scholar
  • 113 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 (04) 784-790
    CrossrefPubMedGoogle Scholar
  • 114 Addolorato G, Ancona C, Capristo E, Gasbarrini G. Metadoxine in the treatment of acute and chronic alcoholism: a review. Int J Immunopathol Pharmacol 2003; 16 (03) 207-214
    CrossrefPubMedGoogle Scholar
  • 115 Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141 (05) 1572-1585
    CrossrefPubMedGoogle Scholar
  • 116 Jeon S, Carr R. Alcohol effects on hepatic lipid metabolism. J Lipid Res 2020; 61 (04) 470-479
    CrossrefPubMedGoogle Scholar
  • 117 Greuter T, Malhi H, Gores GJ, Shah VH. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight 2017; 2 (17) 95354
    CrossrefPubMedGoogle Scholar
  • 118 Massey V, Parrish A, Argemi J. et al. Integrated multiomics reveals glucose use reprogramming and identifies a novel hexokinase in alcoholic hepatitis. Gastroenterology 2021; 160 (05) 1725-1740.e2
    CrossrefPubMedGoogle Scholar
  • 119 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 (05) 755-760
    CrossrefPubMedGoogle Scholar
  • 120 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 (05) 1398-1405
    CrossrefPubMedGoogle Scholar
  • 121 Im GY, Kim-Schluger L, Shenoy A. et al. Early liver transplantation for severe alcoholic hepatitis in the United States – a single-center experience. Am J Transplant 2016; 16 (03) 841-849
    CrossrefPubMedGoogle Scholar
  • 122 Lee BP, Im GY, Rice JP. et al. Underestimation of liver transplantation for alcoholic hepatitis in the national transplant database. Liver Transpl 2019; 25 (05) 706-711
    CrossrefPubMedGoogle Scholar
  • 123 Cotter TG, Sandıkçı B, Paul S. et al. Liver transplantation for alcoholic hepatitis in the United States: excellent outcomes with profound temporal and geographic variation in frequency. Am J Transplant 2021; 21 (03) 1039-1055
    CrossrefPubMedGoogle Scholar
  • 124 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
    CrossrefPubMedGoogle Scholar
  • 125 Neuberger J, Adams D, MacMaster P, Maidment A, Speed M. Assessing priorities for allocation of donor liver grafts: survey of public and clinicians. BMJ 1998; 317 (7152): 172-175
    CrossrefPubMedGoogle Scholar
  • 126 Dixon J, Welch HG. Priority setting: lessons from Oregon. Lancet 1991; 337 (8746): 891-894
    CrossrefPubMedGoogle Scholar
  • 127 Chan HM, Cheung GMY, Yip AKW. Selection criteria for recipients of scarce donor livers: a public opinion survey in Hong Kong. Hong Kong Med J 2006; 12 (01) 40-46
    PubMedGoogle Scholar
  • 128 Neuberger J. Public and professional attitudes to transplanting alcoholic patients. Liver Transpl 2007; 13 (11, Suppl 2) S65-S68
    CrossrefPubMedGoogle Scholar
  • 129 Louvet A, Labreuche J, Moreno C. et al; QuickTrans Trial Study Group. Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study. Lancet Gastroenterol Hepatol 2022; 7 (05) 416-425
    CrossrefPubMedGoogle Scholar