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

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 肥胖和糖尿病。增幅最大的是南得克萨斯州的拉美裔美国人。我们在美国的研究 卡梅隆县西班牙裔队列(CCHC)成立于肥胖率较高的社区(52%)和 糖尿病(28%)，表明慢性肝病也很常见(42%)。非酒精性脂肪性肝病 非酒精性脂肪肝(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肝。 酒精性脂肪性肝炎(NASH)晚期纤维化是NAFLD患者发生肝细胞癌的主要危险因素。我们首先 报告了3.5%的CCHC晚期纤维化患病率，其中显著的人群可归因率为 中心性肥胖的比例为65%。然后，我们在CCHC中实施了肝纤维化筛查，使用振动控制 瞬时弹性成像(VCTE)，并报告了14%的临床显著纤维化患病率(≥F2期)。这个 在肥胖和糖尿病受试者中，显著肝纤维化的患病率达到28%。强烈的联想 肠道微生物区系变化与NAFLD向NASH和肝细胞癌进展之间的关系已有报道，胆汁 酸是这种肠道-肝脏串扰的重要媒介。此外，我们确定脂肪酸是非侵入性的。 NAFLD患者血清NAFLD活性与肝纤维化的关系我们的长期翻译目标是 年确定肥胖和糖尿病拉美裔人肝纤维化的促成因素和分子驱动因素 德克萨斯州南部，美国肝癌发病率最高的社区，并确定那些有患肝癌风险的人 进展为晚期纤维化，从而发展为肝细胞癌，因此可以实施预防性干预。我们 假设人口统计学、临床和分子(微生物组特征、胆汁酸、脂肪酸) 这些参数与肥胖的西班牙裔糖尿病患者的肝纤维化分期有关。我们做进一步的假设 基于这些参数的模型将预测肝纤维化的快速进展，从而增加肝细胞癌的风险 这些学科的发展。我们将招募900名肥胖和糖尿病CCHC患者和500名肥胖和糖尿病患者 糖尿病西班牙裔患者计划在参与的肝脏诊所进行肝脏活检。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查肝纤维化 将会被测量。确定为纤维化≥F2的研究参与者将进行前瞻性跟踪和肝纤维化 在36个月后再次接受VCTE和/或肝活检评估。在目标1中，我们将确定性能 抗肝纤维化VCTE在研究人群中的纤维化分期。我们还将确定流行率 以及与南得克萨斯州肥胖和糖尿病拉美裔人肝纤维化相关的危险因素。在目标2中，我们将 在所测量的那些与肝纤维化分期相关的分子标志物中确定。在《目标3》中， 我们将在中确定一个包含来自目标1的选定参数和来自目标2的分子标记的模型 预测患有糖尿病的西班牙裔肥胖患者的快速肝纤维化进展。这个项目的影响将是 通过早期干预和预防降低肝癌死亡率。

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.