Liver Cirrhosis Network: Longitudinal and Clinical Trial Studies

项目摘要 肝硬化是任何慢性肝损伤的终末期，其发病率的上升是发病率的重要因素 和死亡率。预防性措施，包括治疗基础肝病， 监测和筛查并发症并解决与疾病进展相关的风险因素， 提高生存率的关键随着肝硬化的进展，并发症如肝衰竭和肝癌的发展， 导致死亡种族/族裔少数群体、有药物使用障碍的个人、艾滋病毒感染者以及 低社会经济地位的人由于合并症和肝硬化障碍， 获得医疗服务。肝移植是终末期肝病的唯一医学可行的选择， 器官短缺，甚至更多的患者无法考虑肝脏 移植列表中，我们非常需要提高对潜在的促纤维化和抗纤维化的了解 过程和风险因素沿着阻止疾病进展的潜在疗法。此外，评价 临床风险和健康的社会决定因素的贡献，可能会不同程度地影响肝硬化的负担， 风险人群对于解决这个国家肝硬化负担的差异至关重要。因此，有效的战略 预防肝硬化并发症是一个高度优先的需要。越来越多的证据表明，他汀类药物， 降脂药，对肝硬化有预防作用。他汀类药物可改善门静脉压力， 流行病学研究和有限的临床试验中肝硬化的肝癌风险和死亡率。但大型 需要在代偿性肝硬化患者中进行实用的随机对照试验来证实这些 意见。为了解决这些关于肝硬化的知识空白以及患者未满足的临床需求 与疾病，两个地点内的加州大学，旧金山弗朗西斯科（UCSF）和他们的多元化社区 链接将有助于肝硬化网络与以下具体目标：1.组装纵向 综合临床措施支持的不同病因和肝硬化分期的队列， 生物标本库，以促进肝硬化的临床和转化研究; 2.进行 一项随机对照双盲试验，检验瑞舒伐他汀与安慰剂相比在 代偿性肝硬化患者。我们的短期目标是更好地描述临床风险和社会风险 在高危人群中与肝硬化并发症相关的健康决定因素，以评估Hippo途径 肝硬化进展的相关机制（雅普评分），并评估瑞舒伐他汀在 代偿性肝硬化和临床显著的门静脉高压症的脂肪肝疾病（酒精和 非酒精性）和慢性病毒性肝炎（无论是否感染HIV）。结果预计将有 广泛的影响，鉴于进行性纤维化定义慢性损伤不仅在肝脏，但基本上所有 上皮组织

PROJECT SUMMARY The rising prevalence of cirrhosis, the end-stage of any chronic liver injury, is a significant contributor to morbidity and mortality in the United States. Preventative measures including treatment of underlying liver disease, monitoring and screening for complications and addressing risk factors associated with disease progression are key to improved survival. As cirrhosis progresses, complications such as liver failure and liver cancer develop, resulting in death. Racial/ethnic minorities, individuals with substance use disorders, HIV infection, and those with low socioeconomic status are all at high risk for cirrhosis complications due to comorbidities and barriers to healthcare access. Liver transplantation is the only medically viable option in end stage liver disease but given the shortage of organs and even more numerous patients who are unable to be considered for liver transplantation listing, there is a significant need to improve our understanding of underlying pro- and anti-fibrotic processes and risk factors along with potential therapies to halt disease progression. In addition, evaluation of contribution of clinical risk and social determinants of health that may differentially impact cirrhosis burden in at risk populations is critical to addressing disparities in cirrhosis burden in this country. Thus, effective strategies for prevention of cirrhosis complications is a high-priority need. Accumulating evidence suggests that statin, a lipid lowering drug, has a preventative role in cirrhosis. Statins improve portal venous pressure and decrease liver cancer risk and mortality in cirrhosis in epidemiologic studies and limited clinical trials. However, large pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations. To address these gaps in knowledge about cirrhosis as well as the unmet clinical needs of patients with the disease, two sites within the University of California, San Francisco (UCSF) and their diverse community links will contribute to the Liver Cirrhosis Network with the following specific aims: 1. To assemble a longitudinal cohort with diverse etiology and stage of cirrhosis supported by comprehensive clinical measures and a biospecimen repository in order to promote clinical and translational research in cirrhosis; 2. To conduct a randomized controlled double-blind trial testing the efficacy and safety of a rosuvastatin versus placebo in patients with compensated cirrhosis. Our short-term goals are to better characterize clinical risks and social determinants of health associated with cirrhosis complications in at risk populations, to evaluate a Hippo pathway related mechanism for cirrhosis progression (the YAP score), and to assess the role of rosuvastatin in compensated cirrhosis and clinically significant portal hypertension from fatty liver disease (alcoholic and nonalcoholic) and chronic viral hepatitis in those with or without HIV infection. The results are expected to have broad implications, given that progressive fibrosis defines chronic injury not only in the liver but in essentially all epithelial tissues.