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

项目3-概要/摘要 在美国，HCC的发病率和死亡率正在迅速增加，部分原因是 肥胖和糖尿病。增长最快的是德克萨斯州南部的西班牙裔。我们的研究在 卡梅隆县西班牙裔队列（CCHC）建立于肥胖率高的社区（52%）， 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酒精性脂肪变性。 酒精性脂肪性肝炎（NASH）。晚期纤维化是NAFLD患者发生HCC的主要危险因素。我们首先 报道CCHC中晚期纤维化的患病率为3.5%， 65%的中心性肥胖。然后，我们在CCHC中实施了肝纤维化筛查，使用振动控制 一过性弹性成像（VCTE），并报告了14%的临床显著纤维化（分期≥ F2）患病率。的 肥胖和糖尿病受试者中严重肝纤维化的患病率达到28%。强关联 肠道微生物群变化与NAFLD向NASH和HCC的进展之间的关系，已经报道， 酸是这种肠-肝相互作用的重要介质。此外，我们将脂肪酸确定为非侵入性的 NAFLD患者的NAFLD活性和肝纤维化标志物。我们的长期目标是 确定肥胖和糖尿病西班牙裔美国人肝纤维化的促成因素和分子驱动因素， 南德克萨斯州是美国HCC发病率最高的社区，并确定那些有HCC风险的人。 进展为晚期纤维化，因此可以实施预防性干预措施。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） 参数与肥胖西班牙裔糖尿病患者的肝纤维化分期相关。我们进一步假设 基于这些参数的模型将预测快速的纤维化进展，从而增加HCC的风险 这些学科的发展。我们将招募900名肥胖和糖尿病CCHC受试者和500名肥胖和 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 将被衡量。将对确定为纤维化≥ F2的研究受试者进行前瞻性随访， 将在36个月时通过VCTE和/或肝活检再次评估。在目标1中，我们将确定性能 VCTE对肝纤维化的影响，用于研究人群的纤维化分期。我们还将确定 以及与德克萨斯州南部肥胖和糖尿病西班牙裔人肝纤维化相关的危险因素。在目标2中，我们 在所测量的与肝纤维化阶段相关的分子标志物中识别出这些分子标志物。在目标3中， 我们将确定一个模型，该模型结合了目标1中的选定参数和目标2中的分子标记， 预测肥胖西班牙裔糖尿病患者肝纤维化快速进展。该项目的影响将是 通过早期干预和预防降低HCC死亡率。

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.