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

基本信息

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
项目类别：
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

项目摘要

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.

抽象肝硬化及其并发症在美国引起显着的发病率和死亡率。与肝硬化相关的死亡率正在上升，同时酒精摄入增加导致人口结构发生变化。和非酒精性脂肪性肝病目前的肝硬化人群以患有损害的老年患者为主。由肥胖、代谢综合征和/或酒精引起的其他组织中的这些因素与肝硬化相混淆。管理并经常排除肝移植作为治疗选择的可能性。失代偿性肝硬化患者越来越多，肝功能丧失导致肝代偿失调。实质和肝功能障碍的严重程度已被证明是肝硬化相关发病率和死亡率的预测因素。因此，我们的总体目标是开发新的方法来保护肝功能并预防肝病肝硬化失代偿的成功需要更多关于以下方面的信息：i) 导致肝病的可改变风险。功能障碍以及肝功能障碍如何影响其他器官的健康。知识，我们将对肝硬化患者进行纵向队列研究（目标 1）并制定/实施一项针对高危肝硬化患者使用 HMG CoA 还原酶抑制剂（他汀类药物）的介入试验这两个目标均以肝硬化是由肝功能缺陷引起的科学前提为基础。我们的临床前研究：i) 揭示肝脏再生需要严格的脚本化。曾经被认为在成人肝脏中沉默的发育信号通路重新激活（但已知在癌症中重新激活）和 ii）表明，当这些途径失调时，它们会损害再生这些发现解释了为什么会出现器官衰竭、纤维化。癌症风险通常是平行发展的，这证明了对人类肝硬化人群进行研究以确定因素的合理性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肝功能的能力（目标2），因为他汀类药物具有抗炎和预计可有利地调节再生途径的代谢作用是杜克大学肝脏计划。非常适合成为新的肝硬化临床网络的成员，该网络将被配置为实现这些目标：我们的多学科医疗服务提供者团队为大量、多样化的肝硬化人群提供护理，并且我们拥有拥有强大的机构支持来开发肝病研究和个性化方面的杰出项目成功实现我们的目标将使管理方法更加“个性化”。尽管存在挑战性的共病状况，这仍将改善肝硬化的结果。