MICA: Minimising Mortality from Alcoholic Hepatitis

Lead Research Organisation: Imperial College London
Department Name: Dept of Surgery and Cancer

Abstract

Alcohol related liver disease (ALD) is responsible for more than 6000 deaths a year in the UK and costs the NHS £3.5 billion. Alcoholic hepatitis is a florid presentation of ALD in which patients present with jaundice and liver failure. Unfortunately, around 30% of people admitted to hospital with this condition will die within 3 months.
The treatment of alcoholic hepatitis is complicated by the fact that there is tremendous inflammation within the liver whilst the patient is very susceptible to infection. As a result treatment with drugs, such as steroids, which suppress the immune system may exacerbate the risk of infection. In our recent trial we demonstrated that prednisolone (a steroid) reduced mortality by a small amount one month after admission but the advantage was lost at three months. Therefore, at present there is no effective treatment for this condition.

The aim of this research is to develop clinical tests (biomarkers) which improve the management of alcoholic hepatitis and which help the pharmaceutical industry to run trials in this area. Firstly, we will use a test which measures the amount of bacterial DNA in blood to stratify the risk of infection. Identifying patients who are at high risk of infection will allow us to modify treatment, either by avoiding steroids or adding in prophylactic antibiotics. This test will also identify a group of patients who would benefit from new treatment options.

Our second aim is to improve the way in which we predict the outcome of this disease. We have previously shown that low transferrin (a serum protein) and a variant of the gene PNPLA3 are associated with a poor prognosis. An existing blood test (ELF), which is a good prognostic test in chronic hepatitis, will be tested in alcoholic hepatitis patients. We propose to combine the new biomarkers with routine clinical data and, using sophisticated statistical techniques, generate a more accurate prognostic scoring system. This will allow us to select patiets more carefully for clinical trials, for intensive care and for liver transplantation.

Although it is possible to make a diagnosis of alcoholic hepatitis based on the clinical presentation, we sometimes need to perform a liver biopsy to confirm the diagnosis. Furthermore, a biopsy is usually required in clinical trials. We are planning to develop a blood test based on the levels of a bile acid, taurocholate, which will reduce or eliminate the need for liver biopsy.

In patients with alcoholic hepatitis the immune system is impaired making them susceptible to infections that increase the risk of dying. Analysis of the characteristics of immune cells in the blood will allow us to identify immune profiles which confer susceptibility to infection. We will use these immune profiles to evaluate new drugs in order to assess whether they are likely to increase the risk of infection either by testing the drugs on immune cells in the laboratory or by conducting immune profiling in the early stages of clinical trials.

If our programme of research is successful we should be able to use existing drugs more effectively by avoiding complication such as infection. In addition we will encourage and facilitate pharmaceutical companies to invest in this disease area where there is a substantial unmet medical need.

Technical Summary

Alcoholic hepatitis (AH), a florid presentation of alcohol related liver disease, carries a mortality risk of 30% over 90 days. In this programme, we will carry out studies to develop biomarkers for diagnosis, prognosis and stratification of infection risk which arose from the NIHR-funded STOPAH trial(1).
Metabonomic analysis revealed high levels of taurocholate in AH compared to decompensated controls. Once taurocholate is validated, we will generate a miniaturized LC-MS assay to replace biopsy for diagnosis.
Prognostic information provides a basis for selecting patients for admission, treatment (or trials), transfer to ITU and for transplantation. Current models lack sufficient precision to support clinical decisions. We have generated new prognostic models using data from STOPAH and have identified transferrin and PNPLA3 genotype as prognostic biomarkers. The ELF score, a validated prognostic marker in chronic hepatitis will be evaluated in AH(2). Prognostic models will be revised to incorporate the new biomarkers and validated in the cohort study.
STOPAH demonstrated a borderline survival advantage with prednisolone treatment at 28 days but short term survival benefits were lost by 90 days due to increased incidence of infection(3). Data and samples from the STOPAH study facilitated analysis of serum, genetic and cellular biomarkers and development of prognostic models. We identified bacterial 16S ribosomal DNA (16S-DNA), monocyte oxidative burst and HLA-DR expression as biomarkers for infection susceptibility(4). When validated these would be used to stratify patients for use of prophylactic antibiotics, potentially leading to a survival benefit. A prospective cohort study with nested case control studies for survival, infection, diagnosis and acute kidney injury will be conducted to validate the results generated in STOPAH.
Mechanistic studies using precision-cut liver slices and gene expression analysis will be used to support biomarker validation

Planned Impact

Patients
Primarily we would hope and expect that patients will benefit from this research. Stratification by risk of infection should facilitate the use of effective management strategies which reduce the incidence of infection and reduce mortality rates

Clinical academics
Stratification of clinical studies and trials using biomarkers for infection risk and/or prognosis will improve the outcomes of clinical research by reducing heterogeneity. Recruitment into trials is currently impaired by the need for liver biopsy which is not universally available or acceptable. A new diagnostic may overcome this obstacle.

Basic / translations academics
Mechanisms of immunoparesis identified in patients with alcoholic hepatitis are likely to be relevant in other disease states. Furthermore, the mechanisms underlying the immune defects will undoubtedly reveal details about immune regulation and monocyte function.

Pharmaceutical companies
Pharmaceutical companies have been reluctant to invest in the area of alcoholic hepatitis due to the high rates of complications (such as infection) and the heterogeneity in patient outcomes. Stratification of patients on the risk of infection will allow companies to run trials with appropriate strategies (positive or negative selection or prophylactic antibiotics) to manage complications arising from infection. Similarly, accurate baseline prognostic scores will assist in patient selection or stratification in clinical trials. Finally, investment by MRC, NIHR and the US NIH has a strongly motivating effect on pharmaceutical investment.

BioTech companies.
A number of companies are working in areas of immunology and inflammation which are directly relevant or overlap with alcoholic hepatitis. This research will encourage them to look at alcoholic hepatitis as a target therapeutic area which is less crowded and with higher unmet need

Professional associations and NICE
As chair of the European Association for Study of the Liver guidelines panel on alcohol related liver disease it is easy to see how the results of this research would directly impact clinical guidelines on the management of alcoholic hepatitis.

FDA & EMA
This research is expected to provide evidence which would underpin new endpoints for clinical trials in alcoholic hepatitis. In particular the risk of complications of treatment, such as infection, will need to be considered in licensing new drugs

NHS
Stratification of patients at high risk of infection could benefit the NHS either by avoiding the use of antibiotics and reducing mortality or by targeting the use of prophylactic antibiotics thereby reducing the risks of antimicrobial resistance associated with widespread antibiotic use.
The current pilot study of early transplantation for alcoholic hepatitis conducted by UK Transplant has stalled due to inadequate selection criteria. Accurate prognostic tests would improve selection of candidates for liver transplantation.
A novel diagnostic test should reduce the need for tranjugular liver biopsy which is an expensive procedure
 
Description Isaiah trial funding
Amount £1,290,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 12/2017 
End 12/2020
 
Description Birmingham - DA 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide patient samples for research analysis.
Collaborator Contribution Determine the response of different hepatic cell types to exposure to bacterial products and the benefit of cytokine inhibition by using precision cut liver slices.
Impact None at this stage
Start Year 2018
 
Description Cambridge - PN 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide patient data and biomarkers analysis results.
Collaborator Contribution Apply state-of-the-art sparse regression methods to build prognostic models for 90 day mortality and infection from the rich biomarker data collected in this project
Impact None at this stage
Start Year 2018
 
Description Edinburgh - SF 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide patient samples for research analysis.
Collaborator Contribution Analysis of liver histology using CK7 immunohistochemistry and gene expression profiling will be used to assess the impact of treatment on liver regeneration.
Impact None at this stage
Start Year 2018
 
Description Imperial - EH 
Organisation Imperial College London
Department Department of Surgery and Cancer
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide patient samples for research analysis
Collaborator Contribution UPLC-MS/MS assays will be carried out within the MRC-NIHR National Phenome Centre. Using validated in house analytical pipelines for spectroscopic analysis, preprocessing and data modelling we will aim to stratify patients based on their prognostic risk.
Impact None at this stage
Start Year 2018
 
Description Plymouth - AD 
Organisation University of Plymouth
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide patient samples for research analysis.
Collaborator Contribution PBMCs will be used to measure steroid resistance in the BLISS assay. If the results are promising we will explore lymphocyte cytokine expression and epigenetic markers of steroid resistance which could be used as biomarkers in future studies.
Impact None at this stage
Start Year 2018
 
Description UCL - WR 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide patient samples for research analysis.
Collaborator Contribution Candidate approaches will be taken to evaluate the performance of existing biomarkers of liver disease and a discovery approach will be taken to the identification of new biomarkers using nanotechnology, metabonomics and genomics. This collaboration will allow the measurement of ELF and exploration of novel prognostic markers using nanobeads.
Impact None at this stage
Start Year 2018
 
Title Isaiah Clinical Trial 
Description To explore the potential benefits of the IL-1ß antibody, Canakinumab, in the treatment of alcoholic hepatitis. In the first instance, it is therefore essential to establish the efficacy of Canakinumab in a proof-of-principle Phase II) study in alcoholic hepatitis. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Under active development/distribution
Clinical Trial? Yes
Impact None at this stage. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003724-79