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: 10687043
• 负责人: LAURA BERETTA
• 金额: $ 102.38万
• 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/10687043
• 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; Health; Hepatic; High Prevalence; Hispanic; Hispanic Populations; Incidence; Infiltration; Joints; Ligands; Liver; Liver Fibrosis; Macrophage; Mass Spectrum Analysis; Measurement; Measures; Mediator; 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; chronic liver disease; clinically significant; cohort; diabetic; elastography; gut microbiome; gut microbiota; health disparity; high risk; hispanic community; liver biopsy; liver injury; male; microbiome; molecular marker; mortality; multidisciplinary; non-alcoholic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; participant enrollment; preventive intervention; programs; progression risk; prospective; screening; sequencing platform; simple steatosis; study population; surveillance strategy; translational goal; 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/摘要 在美国，肝癌的发病率和死亡率正在迅速上升，部分原因是以下疾病的流行： 我们在德克萨斯州南部的西班牙裔人群中发现了肥胖和糖尿病的增加最多。 卡梅伦县西班牙裔群体 (CCHC) 是在肥胖率高 (52%) 的社区建立的 糖尿病（28%），表明慢性肝病也很常见（42%）。 （NAFLD）是肥胖和糖尿病最常见的肝脏表现，范围从单纯性脂肪变性到非脂肪性变性。 酒精性脂肪性肝炎（NASH）是 NAFLD 患者发生 HCC 的主要危险因素。 据报道，CCHC 中晚期纤维化的患病率为 3.5%，其中显着的人群归因比例为 然后，我们使用振动控制在 CCHC 中实施了肝纤维化筛查，诊断率为 65%。 瞬时弹性成像 (VCTE)，报告临床显着纤维化（≥F2 期）的患病率为 14%。 肥胖和糖尿病受试者显着肝纤维化的患病率达到 28%。 肠道微生物群变化与 NAFLD 进展为 NASH 和 HCC 之间的关系已被报道，而胆汁 脂肪酸是肠道-肝脏相互作用的重要介质。此外，我们还发现脂肪酸是非侵入性的。 NAFLD 患者的 NAFLD 活性和肝纤维化标志物 我们的长期转化目标是 确定肥胖和糖尿病西班牙裔肝纤维化的影响因素和分子驱动因素 德克萨斯州南部是美国 HCC 发病率最高的社区，并确定那些有患 HCC 风险的人 晚期纤维化和进展，从而导致肝癌，因此可以实施预防性干预措施。 保留人口统计学、临床和分子（微生物组特征、胆汁酸、脂肪酸） 参数与肥胖西班牙裔糖尿病患者的肝纤维化阶段相关。 基于这些参数的模型将预测纤维化的快速进展，从而增加患 HCC 的风险 我们将招募 900 名肥胖和糖尿病 CCHC 受试者以及 500 名肥胖和糖尿病受试者。 计划在参与的肝脏诊所进行肝活检的西班牙裔糖尿病患者 所有研究参与者都将参加。 通过 VCTE 和血浆胆汁酸、血浆脂肪酸和肠道微生物组特征筛查肝纤维化 将对确定患有纤维化≥F2的研究参与者进行前瞻性随访，并进行肝纤维化。 将在 36 个月时再次通过 VCTE 和/或肝活检进行评估。在目标 1 中，我们将确定表现。 我们还将确定 VCTE 对抗肝纤维化的研究人群的纤维化分期。 在目标 2 中，我们将研究与德克萨斯州南部肥胖和糖尿病西班牙裔患者肝纤维化相关的风险因素。 在目标 3 中，确定与肝纤维化阶段相关的测量分子标记。 我们将确定一个模型，其中包含目标 1 中选定的参数和目标 2 中的分子标记 预测患有糖尿病的肥胖西班牙裔人的快速肝纤维化进展。 通过早期干预和预防降低 HCC 死亡率。