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: 10490294
• 负责人: ANNA MAE ELIZABETH DIEHL
• 金额: $ 49.01万
• 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/10490294
• 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，肝硬变及其并发症会导致严重的发病率和死亡率。肝硬变和 与肝硬变相关的死亡率上升的同时，酗酒者的增加导致了人口结构的变化 以及非酒精性脂肪性肝病。目前的肝硬变人群中有更多的老年损害患者 在肥胖、代谢综合征和/或酒精引起的其他组织中。这些因素使肝硬变变得混乱 管理和经常排除肝移植作为一种治疗选择。因此，这一数字 失代偿性肝硬变的患者正在增加。功能性肝功能丧失导致肝脏失代偿 肝实质和肝功能障碍的严重程度是与肝硬变相关的发病率和死亡率的被证实的预测因子。 因此，我们的总体目标是开发新的方法来保护肝功能和预防肝病 肝硬变时的失代偿。成功需要更多关于以下方面的信息：i)导致肝脏疾病的可修改风险 肝功能障碍对其他器官的健康有何影响。要解决这些方面的差距 知识，我们将对肝硬变患者进行纵向队列研究(目标1)，并制定/实施 一项使用HMG CoA还原酶抑制剂(他汀类药物)治疗高危肝硬变患者的介入试验 肝脏失代偿。这两个目标都基于这样一个科学前提，即肝硬变是由缺陷引起的， 适应不良的肝脏再生。我们的临床前研究：i)揭示肝脏再生需要严格的脚本 曾被认为在成人肝脏中沉默的发育信号通路的重新激活(但已知 在癌症中重新激活)和ii)表明，当这些途径变得不受调控时，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 癌症风险通常是平行发展的，并证明在人类肝硬变人群中进行研究以确定因素是合理的 这影响了再生机制(Aim1)。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变患者肝功能的能力(AIM2)，因为他汀类药物具有抗炎和 被预测为有利于调节再生途径的新陈代谢作用。杜克大学的肝脏项目 理想的定位，适合成为新的肝硬化临床网络的成员，该网络将配置为实现 这些目标：我们的多学科提供者团队为庞大的、多样化的肝硬变人群提供服务，我们有 在肝病研究和个性化方面有强大的制度支持来开发优秀的项目 医药。成功地实现我们的目标将使我们能够采取更个性化的管理方法 这将改善肝硬变的预后，尽管具有挑战性的共病条件。