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: 10700075
• 负责人: Cynthia A Moylan
• 金额: $ 26.49万
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700075
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; 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; HIV/AIDS; Health; Health system; Hepatic; Hepatocyte; Hepatology; Human; Human Resources; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA reductase; Impairment; Individual; Inflammatory; Injury; Institution; Intervention Trial; Interventional radiology; Knowledge; 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; 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 肝肝硬化及其并发症在美国引起明显的发病率和死亡率。肝硬化和 与肝硬化有关的死亡率与人口统计学的变化同时增加。 和非酒精性脂肪肝病。当前的肝硬化群体富含损害的老年患者 在其他时候，由肥胖，代谢综合征和/或酒精引起。这些因素混淆了肝硬化 管理和通常排除肝移植作为治疗选择。因此， 代偿性肝硬化的患者正在增长。肝功能肝脏丧失导致肝功能补偿 实质和肝功能障碍的严重程度是与肝硬化相关的发病率和死亡率的事实证明。 因此，我们的总体目标是开发新颖的方法来保护肝功能并防止肝 肝硬化的代偿作用。成功提供了有关以下信息的更多信息：i）驱动肝的可修改风险 功能障碍和ii）肝功能障碍如何影响其他器官的健康。解决这些差距 知识，我们将对肝硬化患者（AIM 1）和开发/实施进行纵向队列研究 使用HMG COA进行的介入试验减少了持发证患者的抑制剂（他汀类药物） 肝脏代表。这两个目标都是由科学前提扎根的，即肝硬化是由缺陷引起的 适应不良的肝脏再生。我们的临床前研究：i）揭示肝脏再生需要紧密脚本 开发信号通路的重新激活，这些信号通路曾经被认为是在成年生活中被沉默的（但已知） 在癌症中重新激活）和ii）表明，当这些途径失调时，它们会损害修订 并推动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 癌症的风险通常在人类肝硬化种群中并行发展，并证明识别因素的研究是合理的 这会影响再生机制（AIM1）。他们还为评估的概念基础提供了强大的概念基础 他汀类药物在肝硬化中提高肝功能的能力（AIM2），因为他汀类药物具有抗炎和 预测将有利地调节再生途径的代谢作用。杜克肝脏计划是 理想地定位是新的肝硬化临床网络的会员资格，该网络将被配置为完成 这些目的：我们的多学科提供者团队关心大型，潜水的cirhotic人群，我们有 拥有强大的机构支持，以制定肝病研究中的出色计划并个性化 药品。成功实现我们的目标将使更“个性化”的管理方法 这将改善肝硬化的结果迫切挑战合并症。