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The future of therapy for alcoholic hepatitis – Beyond corticosteroids

Open AccessPublished:February 18, 2019DOI:https://doi.org/10.1016/j.jhep.2019.01.016

      Background

      Corticosteroids are the only treatment proven to reduce mortality from severe alcoholic hepatitis (SAH), though the benefit is short-lived.
      • 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.
      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, PMID
      Portal translocation of gut microbiotaIntestinal dysbiosisRifaximinNCT02116556, EudraCT 2014-002264-33
      Oral vancomycin, gentamycin, meropenemNCT03157388
      Faecal microbiota transplantNCT03091010 NCT02458079
      Probiotics Lactobacillus spp.NCT01922895

      NCT02335632
      Intestinal mucosal integrityZinc

      Obeticholic acid,

      Canakinumab,

      Anakinra
      NCT01809132

      NCT02039219

      NCT03775109
      Enterohepatic circulation of bile acidsFarnesoid receptorObeticholic acidNCT02039219
      Hepatic inflammationIL-1βAnakinra

      Canakinumab
      NCT01809132

      NCT03775109
      TLR-4

      Non-specific
      Anti-LPS IgG

      Bovine colostrum
      NCT01968382

      NCT02473341
      Hepatocellular injury and repairOxidative stressMetadoxineNCT02019056

      NCT02161653

      PMID 24756009
      N-acetylcysteineNCT00863785 PMID 22070475
      S-Adenosyl methionineNCT00851981 NCT02024295
      Omega 5NCT03732586
      Hepatocyte regenerationIL-22NCT02655510
      G-CSFNCT01820208 NCT02971306 NCT02442180 NCT01341951 NCT02776059 NCT03703674
      ComplicationsInfectionCo-amoxiclavNCT02281929
      CiprofloxacinNCT02326103
      RifaximinNCT02116556
      N-acetylcysteineNCT03069300
      Kidney injuryTerlipressinEudraCT 2006-002837-19

      Nutritional supplements

      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.
      • 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.
      However, achieving a calorific intake >21.5 kcal/kg per day is associated with a reduction in complications and mortality.
      • 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.

      Portal translocation of gut microbiota

      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.
      • 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.
      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.

      Enterohepatic circulation of bile acids

      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.
      • 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.
      Additional beneficial effects from FXR agonism in ameliorating portal hypertension have been suggested in rodent models of liver disease (reviewed in
      • Schwabl P.
      • Laleman W.
      Novel treatment options for portal hypertension.
      ). Obeticholic acid (OCA) is a semi-synthetic agonist of FXR that has shown promise in non-alcoholic fatty liver disease
      • 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.
      and has established efficacy in primary biliary cholangitis.
      • 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.
      Clinical trial data are awaited (NCT02039219).

      Immune dysfunction

      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
      • 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.
      or corticosteroid therapy,
      • 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.
      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).

      Hepatocellular injury and repair

      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
      • Nguyen-Khac E.
      • Thevnot T.
      • Piquet M.A.
      • Benferhat S.
      • Goria O.
      • Chatelain D.
      • et al.
      Glucocorticoids plus N -acetylcysteine in severe alcoholic hepatitis.
      or oral metadoxine
      • 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.
      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,
      • 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.
      has been suggested by small studies
      • 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.
      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).

      Extrahepatic complications of alcoholic hepatitis

      Infection: up to 50% of SAH patients will develop infection during the acute illness and nosocomial infections reduce survival.
      • 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.
      Defective immune cells have been identified in the systemic circulation of patients with SAH and their presence is associated with the development of infection.
      • Mookerjee 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.
      • Markwick 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.
      • Vergis 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.
      • Rolas 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.
      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.

      Financial support

      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) .

      Conflicts of interest

      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.

      Supplementary data

      The following are the Supplementary data to this article:

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