Prediction and Prevention of Hepatic Decompensation in Patients with Cirrhosis

肝硬化患者肝功能失代偿的预测和预防

• 批准号: 10690120
• 负责人: MANAL F. ABDELMALEK
• 金额: $ 18.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10690120
• 关键词: AIDS/HIV problem; Address; Adult; Alcohol-Induced Disorders; Alcohols; Anti-Inflammatory Agents; Bile Acids; Biliary; Caring; Cessation of life; Cholesterol; Cirrhosis; Clinical; Clinical Research; Coenzyme A; Communities; Complement; Defect; Development; Diagnostic radiologic examination; Endoscopy; Enzymes; Evolution; Fibrosis; Functional disorder; Growth; HIV therapy; Health; Health system; Hepatic; Hepatocyte; Hepatology; Human; Human Resources; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Impairment; Individual; Injury; Intervention Trial; Interventional radiology; Knowledge; Lead; Liver; Liver Cirrhosis; Liver Dysfunction; Liver Failure; Liver Regeneration; Liver diseases; Liver parenchyma; Longitudinal cohort study; Malignant Neoplasms; Malignant neoplasm of liver; Medical; Medical Oncology; Metabolic; Metabolic syndrome; Metabolism; Morbidity - disease rate; Natural regeneration; North Carolina; Obesity; Operative Surgical Procedures; Organ; Organ failure; Outcome; Oxidoreductase; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Play; Population; Positioning Attribute; Pre-Clinical Model; Prevention; Primary Health Care; Regenerative pathway; Research; Risk; Role; Rural Population; Safety; Services; Severities; Signal Pathway; Suburban Population; Testing; Therapeutic; Tissues; United States; Urban Population; Viral hepatitis; Work; antiretroviral therapy; base; cancer risk; care providers; cell type; comorbidity; demographics; disability-adjusted life years; drug induced liver injury; effective therapy; efficacy evaluation; functional loss; geranylgeranyl pyrophosphate; high risk; improved; improved outcome; inhibitor; liver function; liver injury; liver preservation; liver transplantation; mevalonate; modifiable risk; mortality; multidisciplinary; non-alcoholic fatty liver disease; novel strategies; older patient; personalized approach; personalized medicine; pre-clinical research; prevent; problem drinker; programs; regenerative; repaired; success

ASTRACT Liver cirrhosis and its complications cause significant morbidity and mortality in the United States. Cirrhosis and cirrhosis-related mortality are rising in parallel with shifts in the demographics driven by increases in alcoholic- and nonalcoholic- fatty liver disease. Current cirrhotic populations are enriched with older patients with damage in other tissues caused by obesity, the metabolic syndrome, and/or alcohol. These factors confound cirrhosis management and often preclude liver transplantation as a therapeutic option. Consequently, the number of patients with decompensated cirrhosis is growing. Hepatic decompensation results from loss of functional liver parenchyma and the severity of liver dysfunction is a proven-predictor of cirrhosis-related morbidity and mortality. Therefore, our overall objective is to develop novel approaches to preserve liver function and prevent hepatic decompensation in cirrhosis. Success necessitates more information about: i) modifiable risks that drive hepatic dysfunction and ii) how hepatic dysfunction impacts the health of other organs. To address these gaps in knowledge, we will conduct a longitudinal cohort study of patients with cirrhosis (Aim 1) and develop/implement an interventional trial using an HMG CoA reductase inhibitor (statin) in cirrhotic patients who are at high risk for hepatic decompensation. Both aims are grounded by the scientific premise that cirrhosis is caused by defective, maladaptive liver regeneration. Our pre-clinical research: i) reveals that liver regeneration requires tightly scripted reactivation of developmental signaling pathways that were once thought to be silenced in adult livers (but known to reactivate in cancer) and ii) shows that when these pathways become dysregulated, they impair regeneration and drive liver disease to progress to cirrhosis and cancer. These findings explain why organ failure, fibrosis and cancer risk typically evolve in parallel and justify research in human cirrhotic populations to identify factors that impact the regenerative mechanisms (Aim1). They also provide a strong conceptual basis for evaluating the ability of statins to improve liver function in cirrhosis (Aim2) because statins have anti-inflammatory and metabolic actions that are predicted to favorably modulate regenerative pathways. The Duke Liver Program is ideally-positioned for membership in the new Cirrhosis Clinical Network which will be configured to accomplish these aims: our multidisciplinary team of providers cares for a large, diverse cirrhotic population and we have had strong institutional support to develop outstanding programs in liver disease research and personalized medicine. Successful accomplishment of our Aims will enable a more ‘personalized’ approach to management that will improve cirrhosis outcomes despite challenging co-morbid conditions.

ASTRACT 在美国，肝硬化及其并发症导致显著的发病率和死亡率。肝硬化和 与酒精中毒相关的死亡率正在上升，与此同时，由于酒精中毒的增加，人口结构发生了变化， 和非酒精性脂肪肝目前的阿尔茨海默病人群中有大量老年患者， 肥胖、代谢综合征和/或酒精引起的其他组织中的肿瘤。这些因素混淆了肝硬化 管理，并经常排除肝移植作为一种治疗选择。因此， 失代偿期肝硬化患者正在增加。肝功能失代偿是由于肝功能丧失所致 肝实质和肝功能障碍的严重程度是胰腺炎相关发病率和死亡率的一个经证实的预测因素。 因此，我们的总体目标是开发新的方法来保护肝功能和防止肝硬化。 肝硬化的失代偿成功需要更多关于以下方面的信息：i）驱动肝脏疾病的可改变风险 以及ii）肝功能障碍如何影响其他器官的健康。为了弥补这些差距， 知识，我们将进行肝硬化患者的纵向队列研究（目标1），并开发/实施 一项使用HMG CoA还原酶抑制剂（他汀类药物）治疗高风险阿尔茨海默病患者的干预性试验， 肝脏失代偿这两个目标都是基于肝硬化是由缺陷， 肝再生不良我们的临床前研究：i）揭示肝再生需要严格的脚本 重新激活发育信号通路，这些通路曾被认为在成人肝脏中沉默（但已知 在癌症中重新激活）和ii）表明当这些途径变得失调时，它们会损害再生 并促使肝病发展为肝硬化和癌症。这些发现解释了为什么器官衰竭纤维化 和癌症风险通常是平行发展的，因此有理由在人类癌症人群中进行研究，以确定 影响再生机制（Aim 1）。它们还为评估提供了强有力的概念基础 他汀类药物改善肝硬化患者肝功能的能力（Aim 2），因为他汀类药物具有抗炎作用， 代谢作用，预计有利地调节再生途径。杜克肝脏计划是 理想的定位为成员在新的肝硬化临床网络，将配置为实现 这些目标：我们的多学科团队的供应商照顾一个大的，多样化的移民人口，我们有 拥有强大的机构支持，以开发肝病研究和个性化的优秀项目 药成功实现我们的目标将使管理更加“个性化” 这将改善肝硬化的结果，尽管具有挑战性的共病条件。