The future of therapy for alcoholic hepatitis – Beyond corticosteroids
Authors: Nikhil Vergis, Stephen R. Atkinson, Mark R. Thursz
Journal: Journal of Hepatology (2019)

Corticosteroids are the only treatment proven to reduce mortality from severe alcoholic hepatitis (SAH), though the benefit is short-lived.[1]Louvet A. Thursz M.R. Kim D.J. Labreuche J. Atkinson S.R. Sidhu S.S. 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; Abstract Full Text Full Text PDF Scopus (105) Google Scholar Several potential therapies are currently under evaluation in human clinical trials (Table 1). These therapies target: i) malnutrition; ii) intestinal dysbiosis and its portal translocation; iii) bile acid production; iv) hepatocyte death; v) hepatocyte regeneration; and vi) life-threatening complications of the disease itself.Table 1Active published clinical trials for alcoholic hepatitis listed by the U.S. National Library of Medicine at clinicaltrials.gov and European Clinical Trials Database at EudraCT.ema.europa.eu.PathologyTherapeutic targetTherapyTrial ID: clinicaltrials.gov, EudraCT, PMIDPortal translocation of gut microbiotaIntestinal dysbiosisRifaximinNCT02116556, EudraCT 2014-002264-33Oral vancomycin, gentamycin, meropenemNCT03157388Faecal microbiota transplantNCT03091010 NCT02458079Probiotics Lactobacillus spp.NCT01922895NCT02335632Intestinal mucosal integrityZincObeticholic acid, Canakinumab, AnakinraNCT01809132NCT02039219NCT03775109Enterohepatic circulation of bile acidsFarnesoid receptorObeticholic acidNCT02039219Hepatic inflammationIL-1βAnakinraCanakinumabNCT01809132NCT03775109TLR-4Non-specificAnti-LPS IgG Bovine colostrumNCT01968382 NCT02473341Hepatocellular injury and repairOxidative stressMetadoxineNCT02019056NCT02161653PMID 24756009N-acetylcysteineNCT00863785 PMID 22070475S-Adenosyl methionineNCT00851981 NCT02024295Omega 5NCT03732586Hepatocyte regenerationIL-22NCT02655510G-CSFNCT01820208 NCT02971306 NCT02442180 NCT01341951 NCT02776059 NCT03703674ComplicationsInfectionCo-amoxiclavNCT02281929CiprofloxacinNCT02326103RifaximinNCT02116556N-acetylcysteineNCT03069300Kidney injuryTerlipressinEudraCT 2006-002837-19 Open table in a new tab Malnutrition is common in this group of patients. Good nutrition is a central tenet of SAH management. Intensive nutrition delivered enterally or parenterally does not appear to confer clinical benefit.[2]Moreno C. Deltenre P. Senterre C. Louvet A. Gustot T. Bastens B. et al.Intensive enteral nutrition is ineffective for individuals with severe alcoholic hepatitis treated with corticosteroids.Gastroenterology [Internet]. 2016; 150 (903–910.e8. Available from)http://www.ncbi.nlm.nih.gov/pubmed/26764182PubMed Google Scholar However, achieving a calorific intake >21.5 kcal/kg per day is associated with a reduction in complications and mortality.[2]Moreno C. Deltenre P. Senterre C. Louvet A. Gustot T. Bastens B. et al.Intensive enteral nutrition is ineffective for individuals with severe alcoholic hepatitis treated with corticosteroids.Gastroenterology [Internet]. 2016; 150 (903–910.e8. Available from)http://www.ncbi.nlm.nih.gov/pubmed/26764182PubMed Google Scholar Intestinal dysbiosis has been implicated in a range of hepatic diseases. Alcohol consumption causes intestinal dysbiosis and impaired intestinal barrier function. Transfer of intestinal microbiota from humans with SAH to mice confers susceptibility to alcohol-induced steatohepatitis, which can be reversed by faecal microbiota transplantation from humans who drink heavily but do not develop SAH.[3]Llopis M. Cassard A.M. Wrzosek L. Boschat L. Bruneau A. Ferrere G. et al.Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.Gut. 2016; : 1-10Google Scholar Current trials aim to improve bacterial dysbiosis using i) orally administered non-absorbable antibiotics (rifaximin or combined gentamicin, vancomycin and meropenem); ii) probiotics (Lactobacillus rhamnosus [NCT01922895] and acidophilus [NCT02335632]); or iii) faecal microbiota transplantation. SAH is characterised by marked biochemical and histological cholestasis. The farnesoid receptor (FXR) is a key regulator of bile acid synthesis. Receptor agonism also improves gut barrier function in mouse models of alcohol-related liver disease.[4]Hartmann P. Hochrath K. Horvath A. Chen P. Seebauer C.T. Llorente C. et al.Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.Hepatology. 2018; Crossref PubMed Scopus (142) Google Scholar Additional beneficial effects from FXR agonism in ameliorating portal hypertension have been suggested in rodent models of liver disease (reviewed in[5]Schwabl P. Laleman W. Novel treatment options for portal hypertension.Gastroenterol Rep. 2017; Crossref Scopus (22) Google Scholar). Obeticholic acid (OCA) is a semi-synthetic agonist of FXR that has shown promise in non-alcoholic fatty liver disease[6]Neuschwander-Tetri B.A. Loomba R. Sanyal A.J. Lavine J.E. Van Natta M.L. Abdelmalak M.F. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; Abstract Full Text Full Text PDF Scopus (1515) Google Scholar and has established efficacy in primary biliary cholangitis.[7]Hirschfield G.M. Beuers U. Corpechot C. Invernizzi P. Jones D. Marzioni M. et al.EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis.J Hepatol. 2017; 67: 145-172Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar Clinical trial data are awaited (NCT02039219). Immunotherapy for SAH is challenging because hepatic immunopathology exists concurrently with systemic immune defects. Accordingly, attempts to control hepatic immunopathology with systemic immunosuppressants, such as anti-TNFα[8]Boetticher N.C. Peine C.J. Kwo P. Abrams G.A. Patel T. Aqel B. et al.A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.Gastroenterology. 2008; 135: 1953-1960Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar or corticosteroid therapy,[9]Vergis N. Atkinson S.R. Knapp S. Maurice J. Allison M. Austin A. 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; 152Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar are hampered by high rates of infection that offsets clinical benefit. Pre-clinical data suggest that anti-IL-1β therapy does not confer such susceptibility to opportunistic infection and reduces hepatic inflammation, fibrogenesis, stellate cell activation and consequent portal hypertension (NCT02655510, NCT01903798, NCT01809132, EudraCT 2017-003724-79, NCT03775109). Ethanol metabolism and immune responses lead to the generation of reactive oxygen species (ROS) that cause oxidative stress and hepatocellular damage. In single studies, the combination of intravenous N-acetylcysteine[10]Nguyen-Khac E. Thevnot T. Piquet M.A. Benferhat S. Goria O. Chatelain D. et al.Glucocorticoids plus N -acetylcysteine in severe alcoholic hepatitis.N Engl J Med. 2011; Crossref PubMed Scopus (273) Google Scholar or oral metadoxine[11]Higuera-De La Tijera F. Servin-Caamano A.I. Serralde-Zuniga A.E. Cruz-Herrera J. Perez-Torres E. Abdo-Francis J.M. et al.Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis.World J Gastroenterol. 2015; PubMed Google Scholar with corticosteroids appears to confer a survival benefit and is the subject of ongoing investigation (N-acetylcysteine [NCT03069300]; metadoxine [NCT02019056, NCT02161653]) along with S-adenosyl-l-methionine (SAMe) [NCT00851981, NCT02024295]. The efficacy of G-CSF, in part mediated via hepatic regeneration,[12]Spahr L. Lambert J.F. Rubbia-Brandt L. Chalandon Y. Frossard J.L. Giostra E. et al.Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial.Hepatology. 2008; Crossref PubMed Scopus (166) Google Scholar has been suggested by small studies[13]Singh V. Sharma A.K. Narasimhan R.L. Bhalla A. Sharma N. Sharma R. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study.Am J Gastroenterol. 2014; Crossref Scopus (159) Google Scholar and several trials are in progress aiming to replicate these findings. Similarly, IL-22 has been ascribed hepatoprotective and pro-regenerative features; therapeutic agents are under clinical evaluation (NCT02655510). Infection: up to 50% of SAH patients will develop infection during the acute illness and nosocomial infections reduce survival.[14]Louvet A. Wartel F. Castel H. Dharancy S. Hollebecque A. Canva-Delcambre V. et al.Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor.Gastroenterology. 2009; 137: 541-548Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Defective immune cells have been identified in the systemic circulation of patients with SAH and their presence is associated with the development of infection.15Mookerjee R.P. Stadlbauer V. Lidder S. Wright G.A.K. Hodges S.J. Davies N.A. et al.Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome.Hepatology. 2007; 46: 831-840Crossref PubMed Scopus (242) Google Scholar, 16Markwick L.J.L. Riva A. Ryan J.M. Cooksley H. Palma E. Trannah T.H. et al.Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis.Gastroenterology. 2015; 148Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 17Vergis N. Khamri W. Beale K. Sadiq F. Aletrari M.O. Moore C. et al.Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.Gut. 2017; 66Crossref PubMed Scopus (41) Google Scholar, 18Rolas L. Boussif A. Weiss E. Letteron P. Haddad O. El-Benna J. et al.NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation.Gut. 2018; Crossref PubMed Scopus (23) Google Scholar Reversing these defects (NCT03069300) or predicting infections are attractive prospects. An alternative approach is to treat all SAH patients with broad-spectrum adjunctive antimicrobial therapy such as co-amoxiclav (NCT02281929) and ciprofloxacin (NCT02326103) and these two agents are currently under evaluation. Acute kidney injury: kidney injury that occurs with SAH portends a poor prognosis. Primed immune cells release a plethora of inflammatory mediators, in particular ROS and nitric oxide, which cause vasodilatation in the splanchnic circulation. The vasopressin analogue terlipressin reduces this vasodilatation and is under investigation for SAH specifically. We are grateful for support from the Imperial College NIHR Biomedical Research Centre, the Wellcome Trust, UK (294834/Z/16/Z) and the Medical Research Council UK Stratified Medicine Award: Minimising Mortality from Alcoholic Hepatitis (MR/R014019/1). MT reports grants and personal fees from Gilead and CN_BIO; personal fees from AbbVie and MSD; grants from Vital Therapeutics. All other authors report no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the Supplementary data to this article: Download .pdf (.24 MB) Help with pdf files Supplementary Data 1