Every year in the UK, more than 6,000 people die from alcohol-related liver disease, and roughly 30% of patients hospitalised with alcoholic hepatitis die within three months. The core problem is a medical paradox: the liver is dangerously inflamed, yet the patient’s immune system is too weak to fight off infections. Steroids can reduce inflammation but also suppress immunity further, raising infection risk. A recent trial found that prednisolone lowered deaths slightly at one month, but the benefit vanished by three months. There is currently no effective treatment. This research aims to fix that by developing three practical tools. First, a blood test for bacterial DNA will identify patients at high risk of infection, allowing doctors to avoid steroids or add preventive antibiotics. Second, combining existing blood markers—such as low transferrin, a variant of the PNPLA3 gene, and the ELF test—with routine clinical data should produce a more accurate scoring system to predict outcomes. That would help select patients for intensive care, liver transplantation, or clinical trials. Third, a blood test based on the bile acid taurocholate could replace the need for a liver biopsy to confirm diagnosis. If successful, the work would let clinicians use existing drugs more safely and give pharmaceutical companies the tools to run better trials in a disease area with no effective therapy.
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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 patients 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.
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