The Effect of Gut Sterilisation on Macrophage Activation in Patients With Alcoholic Hepatitis.

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

Study Overview

• Status: Completed
• Conditions: Alcoholic Hepatitis
• Intervention / Treatment: Drug: Combined Vancomycin and Gentamycin and Meropenem

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

A first time diagnose of AH by a combination of physical and laboratory criteria:

1. A history of excessive alcohol ingestion (10 units or more per day) until at least three weeks before admission
2. Acute jaundice (developed over at most 2 weeks, serum bilirubin > 80 μmol/l).
3. liverbiopsy will be performed in case of doubt regarding the diagnosis.

Exclusion Criteria:

1. Non-native speaking Danish
2. Viral hepatitis,
3. Autoimmune liver disease,
4. Bile duct obstruction,
5. Liver tumours or any other cancer,
6. Presence of an infectious focus (either clinically assessed or based on chest x-ray, urine samples or ascites puncture),
7. On-going gastrointestinal bleeding or bleeding within the previous three months
8. Any prior immune-modulating therapy.
9. Any known gastrointestinal disease
10. Contraindications against/allergy towards the used antibiotics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Intervention; Combined Vancomycin and Gentamycin and Meropenem

Drug: Combined Vancomycin and Gentamycin and Meropenem; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrophage activation cd163	Difference in serum levels of macrophage activation markers sCD163	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LBP	serum levels of Lipopolysaccaride binding protein	1 year
TNF alfa	serum levels of, Tumor Necrosis Factor-alfa	1 year
Interleukin-1b	serum levels of, Interleukin-1b	1 year

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Study Director: Hendrik D Vilstrup, Professor, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2017
• Primary Completion (ACTUAL): June 1, 2018
• Study Completion (ACTUAL): December 1, 2018

Study Registration Dates

• First Submitted: May 15, 2017
• First Submitted That Met QC Criteria: May 16, 2017
• First Posted (ACTUAL): May 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 23, 2019
• Last Update Submitted That Met QC Criteria: May 22, 2019
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: inflammation; Macrophages; CD163
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis A; Hepatitis, Alcoholic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Vancomycin; Gentamicins; Meropenem
• Other Study ID Numbers: 1-10-72-1-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No