MICA: Minimising Mortality from Alcoholic Hepatitis

与酒精相关的肝病(ALD)每年导致英国6000多人死亡，英国国民健康保险制度(NHS)花费了35亿英镑。酒精性肝炎是酒精性肝病的一种典型表现，患者出现黄疸和肝功能衰竭。不幸的是，大约30%的这种情况下入院的人会在3个月内死亡。酒精性肝炎的治疗是复杂的，因为肝脏内有巨大的炎症，而患者非常容易受到感染。因此，使用抑制免疫系统的药物(如类固醇)治疗可能会加剧感染的风险。在我们最近的试验中，我们证明了强的松龙(一种类固醇)在入院一个月后可少量降低死亡率，但这一优势在入院三个月后就消失了。因此，目前还没有针对这种情况的有效治疗方法。这项研究的目的是开发临床测试(生物标记物)，以改善酒精性肝炎的管理，并帮助制药行业在这一领域进行试验。首先，我们将使用一种测量血液中细菌DNA数量的测试来对感染风险进行分层。识别高感染风险的患者将使我们能够通过避免使用类固醇或增加预防性抗生素来改进治疗。这项测试还将确定一组将从新的治疗方案中受益的患者。我们的第二个目标是改进我们预测这种疾病结果的方法。我们之前已经证明，低转铁蛋白(一种血清蛋白)和PNPLA3基因的一个变异与预后不良有关。现有的一种血液检测(ELF)是一种对慢性肝炎很好的预后测试，将在酒精性肝炎患者中进行测试。我们建议将新的生物标记物与常规临床数据相结合，并使用复杂的统计技术来生成更准确的预后评分系统。这将使我们能够更仔细地选择病人进行临床试验、重症监护和肝脏移植。虽然根据临床表现可以诊断为酒精性肝炎，但有时我们需要进行肝脏活检才能确认诊断。此外，在临床试验中通常需要活检。我们正计划开发一种基于胆汁酸牛磺胆酸盐水平的血液测试，这将减少或消除肝脏活检的需要。在酒精性肝炎患者中，免疫系统受损，使他们容易受到感染，从而增加死亡的风险。对血液中免疫细胞特征的分析将使我们能够识别对感染易感性的免疫图谱。我们将使用这些免疫图谱来评估新药，以评估它们是否可能增加感染风险，无论是通过在实验室中对免疫细胞进行测试，还是通过在临床试验的早期阶段进行免疫图谱。如果我们的研究方案成功，我们应该能够通过避免感染等并发症来更有效地使用现有药物。此外，我们将鼓励和便利制药公司在这一疾病领域进行投资，在那里有大量未得到满足的医疗需求。

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.