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      The future of therapy for alcoholic hepatitis – Beyond corticosteroids

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      Journal of Hepatology
      Elsevier

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          Abstract

          Background Corticosteroids are the only treatment proven to reduce mortality from severe alcoholic hepatitis (SAH), though the benefit is short-lived. 1 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 1 Active 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 . Pathology Therapeutic target Therapy Trial ID: clinicaltrials.gov , EudraCT, PMID Portal translocation of gut microbiota Intestinal dysbiosis Rifaximin NCT02116556, EudraCT 2014-002264-33 Oral vancomycin, gentamycin, meropenem NCT03157388 Faecal microbiota transplant NCT03091010 NCT02458079 Probiotics Lactobacillus spp. NCT01922895NCT02335632 Intestinal mucosal integrity ZincObeticholic acid, Canakinumab, Anakinra NCT01809132NCT02039219NCT03775109 Enterohepatic circulation of bile acids Farnesoid receptor Obeticholic acid NCT02039219 Hepatic inflammation IL-1β AnakinraCanakinumab NCT01809132NCT03775109 TLR-4Non-specific Anti-LPS IgG Bovine colostrum NCT01968382 NCT02473341 Hepatocellular injury and repair Oxidative stress Metadoxine NCT02019056NCT02161653PMID 24756009 N-acetylcysteine NCT00863785 PMID 22070475 S-Adenosyl methionine NCT00851981 NCT02024295 Omega 5 NCT03732586 Hepatocyte regeneration IL-22 NCT02655510 G-CSF NCT01820208 NCT02971306 NCT02442180 NCT01341951 NCT02776059 NCT03703674 Complications Infection Co-amoxiclav NCT02281929 Ciprofloxacin NCT02326103 Rifaximin NCT02116556 N-acetylcysteine NCT03069300 Kidney injury Terlipressin EudraCT 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. 2 However, achieving a calorific intake >21.5 kcal/kg per day is associated with a reduction in complications and mortality. 2 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. 3 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. 4 Additional beneficial effects from FXR agonism in ameliorating portal hypertension have been suggested in rodent models of liver disease (reviewed in 5 ). Obeticholic acid (OCA) is a semi-synthetic agonist of FXR that has shown promise in non-alcoholic fatty liver disease 6 and has established efficacy in primary biliary cholangitis. 7 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 8 or corticosteroid therapy, 9 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 10 or oral metadoxine 11 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 has been suggested by small studies 13 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. 14 Defective immune cells have been identified in the systemic circulation of patients with SAH and their presence is associated with the development of infection.[15], [16], [17], [18] 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.

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          EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis

          Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in end-stage biliary cirrhosis. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse and risk stratification is important to ensure all patients receive a personalised approach to their care. The goals of treatment and management are the prevention of end-stage liver disease, and the amelioration of associated symptoms. Pharmacologic approaches in practice, to reduce the impact of the progressive nature of disease, currently include licensed therapies (ursodeoxycholic acid and obeticholic acid) and off-label therapies (fibric acid derivatives, budesonide). These clinical practice guidelines summarise the evidence for the importance of a structured, life-long and individualised, approach to the care of patients with PBC, providing a framework to help clinicians diagnose and effectively manage patients.
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            Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.

            There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH).
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              Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice

              Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant-a human FGF15 ortholog-was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis.
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                Author and article information

                Contributors
                Journal
                J Hepatol
                J. Hepatol
                Journal of Hepatology
                Elsevier
                0168-8278
                1600-0641
                1 April 2019
                April 2019
                : 70
                : 4
                : 785-787
                Affiliations
                [1 ]Department of Hepatology, Imperial College, London, United Kingdom
                Author notes
                [* ]Corresponding author. Address: Liver Unit, 10th Floor QEQM Building, St Mary’s Hospital, London W2 1NY, United Kingdom. Tel.: +44 (0)203 312 6454, fax: +44 (0)207 724 9369. nvergis@ 123456ic.ac.uk
                Article
                S0168-8278(19)30030-3
                10.1016/j.jhep.2019.01.016
                6420340
                30791978
                8600d7b6-7055-411a-b9d3-e3d6e2bb3c13
                © 2019 The Authors. European Association for the Study of the Liver. Published by Elsevier B.V.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 5 November 2018
                : 28 December 2018
                : 11 January 2019
                Categories
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                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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