Project 3: Non-invasive assessment of liver fibrosis stage and progression in obesity and diabetes: a Hispanic population study

项目 3：肥胖和糖尿病肝纤维化阶段和进展的无创评估：西班牙裔人群研究

• 批准号: 10246499
• 负责人: LAURA BERETTA
• 金额: $ 67.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246499
• 关键词: Address; Adult; Advanced Development; Affect; Area; Bile Acids; Biological Assay; Central obesity; Child; Cirrhosis; Clinic; Clinical; Communities; Country; County; Data; Development; Diabetes Mellitus; Diet; Early Intervention; Enrollment; Equipment; Fatty Acids; Fibrosis; Funding; Goals; Health; Hepatic; High Prevalence; Hispanics; Incidence; Infiltration; Joints; Ligands; Liver; Liver Fibrosis; Mass Spectrum Analysis; Measurement; Measures; Mediator of activation protein; Modeling; Molecular; Molecular Profiling; Mus; Obesity; Obesity Epidemic; Participant; Patient Schedules; Patients; Performance; Pilot Projects; Plasma; Play; Population; Population Attributable Risks; Population Study; Prevalence; Prevention; Prevention strategy; Primary carcinoma of the liver cells; Publications; Reporting; Research; Resources; Risk; Risk Factors; Role; Serum; Signal Transduction; Site; South Texas; Staging; Study Subject; Target Populations; Texas; Tissues; United States; University of Texas M D Anderson Cancer Center; base; chronic liver disease; clinically significant; cohort; diabetic; elastography; gut microbiome; gut microbiota; health disparity; high risk; liver biopsy; liver injury; macrophage; male; microbiome; molecular marker; mortality; multidisciplinary; non-alcoholic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; preventive intervention; programs; prospective; screening; sequencing platform; study population; surveillance strategy; vibration

PROJECT 3 – SUMMARY/ASTRACT HCC incidence and mortality rates are rapidly increasing in the United States, in part due to the epidemics of obesity and diabetes. The greatest increase has been seen in Hispanics in South Texas. Our studies in the Cameron County Hispanic Cohort (CCHC) established from a community with high rates of obesity (52%) and diabetes (28%), showed that chronic liver disease is also common (42%). Non-alcoholic fatty liver disease (NAFLD), the most common liver manifestation of obesity and diabetes, ranges from simple steatosis to non- alcoholic steatohepatitis (NASH). Advanced fibrosis is the main risk factor for HCC in NAFLD patients. We first reported a 3.5% prevalence of advanced fibrosis in CCHC, with a remarkable population attributable fraction of 65% for central obesity. We then implemented liver fibrosis screening in CCHC, using vibration-controlled transient elastography (VCTE), and reported a 14% prevalence of clinically significant fibrosis (stage ≥F2). The prevalence of significant liver fibrosis reached 28% in obese and diabetic subjects. Strong associations between gut microbiota changes and progression of NAFLD to NASH and HCC, have been reported and bile acids are important mediators in this gut-liver cross-talk. Furthermore, we identified fatty acids as non-invasive markers of NAFLD activitiy and liver fibrosis in patients with NAFLD. Our long-term translational goal is to determine the contributing factors and molecular drivers of liver fibrosis in obese and diabetic Hispanics in South Texas, the community in the United States with the highest rate of HCC, and identify those at risk of progression to advanced fibrosis and therefore HCC, so preventive interventions can be implemented. We hypothesize that demographic, clinical, and molecular (microbiome features, bile acids, fatty acids) parameters are associated with liver fibrosis stages in obese Hispanics with diabetes. We hypothesize further that a model based on these parameters will predict fast fibrosis progression and thus increased risk for HCC development in these subjects. We will enroll 900 obese and diabetic CCHC subjects and 500 obese and diabetic Hispanic patients scheduled for liver biopsy at participating liver clinics. All study participants will be screened for liver fibrosis with VCTE and plasma bile acids, plasma fatty acids and gut microbiome features will be measured. Study participants identified with fibrosis ≥F2 will be followed prospectively and liver fibrosis will be again assessed by VCTE and/or liver biopsy at 36 months. In Aim 1, we will determine the performance of VCTE against liver fibrosis for fibrosis staging in the study population. We will also determine the prevalence and risk factors associated with liver fibrosis in obese and diabetic Hispanics in South Texas. In Aim 2, we will identify the molecular markers among those measured that are associated with liver fibrosis stages. In Aim 3, we will identify a model incorporating selected parameters from Aim 1 and molecular markers from Aim 2 in predicting fast liver fibrosis progression in obese Hispanics with diabetes. The impact of this project would be reduction of HCC mortality rates through early intervention and prevention.

项目3 - 摘要/ASTRAST 美国的HCC发病率和死亡率在美国迅速增加，部分原因是 肥胖和糖尿病。在南德克萨斯州的西班牙裔人士中，最大的增长是最大的增长。我们在 卡梅伦县西班牙裔队列（CCHC）是从一个肥胖率高的社区（52％）和 糖尿病（28％）表明慢性肝病也很常见（42％）。非酒精性脂肪肝病 （NAFLD），肥胖和糖尿病最常见的肝脏表现，范围从简单的脂肪变形到非 - 酒精性脂肪性肝炎（NASH）。晚期纤维化是NAFLD患者HCC的主要危险因素。我们首先 报道了CCHC中晚期纤维化患病率3.5％，归因于可观的人群 中央肥胖症为65％。然后，我们使用振动控制在CCHC中实施肝纤维化筛查 瞬态弹性图（VCTE），报告临床上显着的纤维化患病率为14％（≥f2期）。 肥胖和糖尿病患者的明显肝纤维化患病率达到28％。牢固的联想 已经报道了肠道菌群变化和NAFLD向NASH和HCC的发展和胆汁 酸是此肠道横向词中的重要介体。此外，我们确定脂肪酸是无创的 NAFLD患者的NAFLD活动和肝纤维化的标记。我们的长期翻译目标是 确定肥胖和糖尿病西班牙裔肝纤维化的因素和分子驱动因素和分子驱动因素 南德克萨斯州，美国肝癌率最高的社区，并确定有风险的人 发展为晚期纤维化，因此可以进行HCC，因此可以实施预防性干预措施。我们 假设人口，临床和分子（微生物组，胆汁酸，脂肪酸） 参数与糖尿病肥胖西班牙裔的肝纤维化阶段有关。我们进一步假设 基于这些参数的模型将预测快速纤维化进展，从而增加HCC的风险 这些主题的发展。我们将注册900名肥胖和糖尿病性CCHC受试者以及500个肥胖和 糖尿病西班牙裔患者计划在参与肝诊所进行肝活检。所有研究参与者都将 用VCTE和血浆胆汁酸，血浆脂肪酸和肠道微生物组特征筛选肝纤维化 将测量。前瞻性遵循纤维化≥F2的研究参与者和肝纤维化 将在36个月后通过VCTE和/或肝活检再次评估。在AIM 1中，我们将确定性能 研究人群中针对肝纤维化的VCTE进行纤维化分期。我们还将确定患病率 与肥胖和糖尿病西班牙裔肝纤维化有关的风险因素和德克萨斯州的糖尿病西班牙裔。在AIM 2中，我们将 确定与肝纤维化阶段有关的分子标记。在AIM 3中， 我们将确定从AIM 1和AIM 2中编码所选参数的模型 预测患有糖尿病肥胖西班牙裔的快速肝纤维化进展。该项目的影响将是 通过早期干预和预防降低HCC死亡率。