MICA: Minimising Mortality from Alcoholic Hepatitis

MICA：最大限度地减少酒精性肝炎死亡率

• 批准号: MR/R014019/1
• 负责人: Mark Thursz
• 金额: $ 617.22万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR014019%2F1
• 关键词: MICA; Minimising; Mortality; Alcoholic; Hepatitis

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.

在英国，酒精相关性肝病（ALD）每年导致6000多人死亡，NHS为此花费了35亿英镑。酒精性肝炎是ALD的一种华丽表现，患者表现为黄疸和肝功能衰竭。不幸的是，大约30%的住院患者将在3个月内死亡。酒精性肝炎的治疗是复杂的事实，有严重的炎症在肝脏内，而病人是非常容易感染。因此，用类固醇等抑制免疫系统的药物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）在入院后一个月少量降低死亡率，但在三个月时优势就消失了。因此，目前尚无有效的治疗方法。这项研究的目的是开发临床试验（生物标志物），以改善酒精性肝炎的管理，并帮助制药工业在这一领域进行试验。首先，我们将使用一项测试，测量血液中细菌DNA的数量，以对感染风险进行分层。确定感染风险高的患者将使我们能够通过避免使用类固醇或添加预防性抗生素来修改治疗方法。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式。我们之前已经表明，低转铁蛋白（一种血清蛋白）和基因PNPLA3的变异与预后不良有关。现有的血液测试（ELF）是慢性肝炎的良好预后测试，将在酒精性肝炎患者中进行测试。我们建议将新的生物标志物与常规临床数据相结合，并使用复杂的统计技术，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患者进行临床试验、重症监护和肝移植。虽然根据临床表现可以诊断酒精性肝炎，但有时我们需要进行肝活检来确诊。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，牛磺胆酸水平的血液测试，这将减少或消除肝脏活检的需要。酒精性肝炎患者的免疫系统受损，易受感染，增加死亡风险。对血液中免疫细胞特征的分析将使我们能够确定对感染易感性的免疫特征。我们将使用这些免疫图谱来评估新药，以便通过在实验室中对免疫细胞进行测试或在临床试验的早期阶段进行免疫图谱来评估它们是否可能增加感染风险。如果我们的研究方案取得成功，我们应该能够通过避免感染等并发症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医疗需求大量未得到满足的疾病领域进行投资。

项目成果

Serum Transferrin Is an Independent Predictor of Mortality in Severe Alcoholic Hepatitis.

• DOI: 10.14309/ajg.0000000000000492
• 发表时间: 2020-03
• 期刊: The American journal of gastroenterology

People who survive an episode of severe alcoholic hepatitis should be advised to maintain total abstinence from alcohol

应建议在严重酒精性肝炎发作后幸存的人保持完全戒酒

• DOI: 10.1002/hep.29825
• 发表时间: 2018
• 期刊: Hepatology
• 影响因子: 13.5
• 作者: Atkinson S