Minimising Mortality from
DEVELOPING INNOVATIVE STRATEGIES
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 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 consortium vision is to improve the survival from AH by refining the way we use prednisolone, repurpose existing drugs and facilitate commercial development of novel therapeutics.
Exacerbation of infection risk is the greatest challenge in new therapeutic development as illustrated in the trials of anti-TNFa therapy. Stratifying risk of infection, using 16S-DNA, could guide the use of prophylactic antibiotics to improve the outcome of prednisolone or alternative immunomodulatory treatment. Characterisation of innate immune defects will be undertaken to allow immune profiling of novel drugs and to provide a mechanistic understanding of immuneparesis.
Other challenges in AH management include the lack of a diagnostic test, inaccuracy of prognostic scores, inability to control persistent inflammation within the liver and failure of hepatic regeneration. Paucity of information on the mechanisms of disease exacerbate these clinical issues.
This programme aims to address these challenges by building on the results of the STOPAH trial. A diagnostic biomarker, taurocholate, arising from metabonomic analyses could replace the need for liver biopsy in most patients. Novel prognostic scores, derived using Bayesian sparse regression, will be used to identify high and low risk patients who might benefit from targeted treatment or early discharge.
Improving the outcome from AH requires coordinated input from immunological, metabolic, genetic and clinical studies which can only be achieved through large scale translational research employing the best hepatology investigators in the UK.
The aim of this research is to improve the way in which we predict the outcome of this disease and develop clinical tests (biomarkers) which improve the management of alcoholic hepatitis and which help the pharmaceutical industry to run trials in this area.
Development of a prognostic scoring system
Development of a diagnostic test
Define a panel of markers for immune profiling
Establish in-vitro models to test novel therapeutic agents