The Effect of Gut Sterilisation on Macrophage Activation in Patients With Alcoholic Hepatitis.
Condition: Alcoholic Hepatitis
MeSH terms: Hepatitis A; Hepatitis; Hepatitis, Alcoholic
Study type: Interventional

Summary: 
      Alcoholic hepatitis (AH) is a severe alcohol induced hepatic inflammation that leads to
      jaundice and liver failure. Gut derived bacterial translocation to the liver is currently
      thought to be one of the main inflammatory drivers of the disease.

      This project investigates the effects of gut sterilisation with broad spectrum antibiotics in
      patients with AH
    

Detailed description: 
      Alcoholic hepatitis (AH) is a severe alcohol induced hepatic inflammation that leads to
      jaundice and liver failure. The incidence of AH is increasing and the disease is associated
      with a high mortality. In spite of numerous clinical trials both treatment and prognosis have
      remained essentially unchanged for decades, emphasizing the need to improve our understanding
      of the disease mechanisms behind AH.

      The current perception of the pathogenesis of alcohol-induced liver injury mainly derives
      from animal models, and the resident hepatic macrophages, the Kupffer cells, seem to play an
      important role. Activation of these cells may give rise to most of the hallmark clinical
      findings of AH: The cytokines released initiate hepatic inflammation and an acute phase
      response, recruit neutrophils, and activate stellate cells, contributing to the acute portal
      hypertension. Jaundice is due to intrahepatic cholestasis caused by down regulation of the
      bilirubin transporters on the basolateral hepatocyte membrane. Hepatic macrophages are
      thought to be activated by the bacterial derived endotoxins/lipopolysaccharides (LPS) present
      in the portal blood because of an alcohol-induced increase in gut-blood permeability with
      translocation of bacteria, as found in patients with alcoholic liver injury. LPS is
      recognized by the hepatic macrophages via a membrane complex including the pathogen
      recognition receptor molecule Toll-like receptor 4 (TLR-4). LPS Binding Proteins (LBP)
      produced by hepatocytes then bind and present LPS to the membrane glycoprotein CD14 that in
      turn activates TLR-4. In support of these mechanisms, alcohol-induced liver injury is reduced
      in knockout mice missing LBP, CD14, and TLR-4. Likewise, chemical destruction of hepatic
      macrophages in rats prevents alcohol-induced liver injury, as does cleansing the gut flora
      with antibiotics.

      Human hepatic macrophages when activated, express their surface receptor CD163. We and others
      have previously shown that sCD163 is released from the liver in alcoholic liver disease, that
      its plasma concentration predicts mortality in patients with acute liver failure and is as a
      marker of portal hypertension and a predictor of clinical decompensation in patients with
      liver cirrhosis. Very recently we have directly demonstrated hepatic macrophage activation in
      human AH paralleling the disease severity, and to suggest this to be elicited by LPS.

      The line of evidence presented above provides rationale for testing whether intervention
      toward bacterial translocation may result in a diminished immune response in human AH.
      Consequently, in this study the investigators seek to perform total gut microbiota
      eradication by combining 3 different orally administered antibiotics. The investigators have
      chosen antibiotics that are not absorbed into the systemic circulation, because the
      investigators want to limit the effects to the gastrointestinal tract.
    

Intervention name(s): Combined Vancomycin and Gentamycin and Meropenem
Intervention type(s): Drug
Intervention description(s): The following combined antibiotic regime will be administered for eradication of gut bacteria.
7 days combined antibiotic treatment, per oral route, once daily: vancomycin 500 mg (Vancomycin "Hospira"), powder for concentrate and gentamycin 40 mg ("Hexamycin®"), solution and meropenem 500 mg (Meropenem "Hospira"), powder for concentrate; The three drugs are dissolved and combined in approximately 100 ml of apple juice.
Intervention MeSH terms: Vancomycin; Gentamicins; Meropenem
Intervention model: Single Group Assignment
Intervention model description: 15 patients with alcoholic hepatitis will be consecutively included and compared to a historical cohort of AH patients
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: inflammation; Macrophages; CD163