HCC Risk Stratification in MAFLD Cirrhosis

在美国，肝细胞癌及其前驱病变(肝硬变)的病因危险因素有 在过去十年中发生了巨大变化，从以活动性慢性病毒性肝炎(乙肝和丙型肝炎)为主到 代谢(功能障碍)相关性脂肪肝(MAFLD)。鉴于该病的高流行率 定义MAFLD及其慢性不治之症的代谢紊乱(如肥胖和糖尿病)，重点 在预防肝癌方面，与MAFLD相关的是至关重要的。预防肝癌需要更好地了解 这一风险的决定因素，以及由此产生的风险分层模型和工具的构建。我们建议 为了利用最大的德克萨斯肝细胞癌联盟(THCCC)队列的数据、生物制品和基础设施 美国对肝硬变患者进行了积极的前瞻性队列研究，其中80%的患者估计患有MAFLD。我们 建议将THCCC队列的随访范围扩大到&gt；5000名发生&gt；350例肝细胞癌的患者 案子。我们在项目1中的研究有以下具体目标： 1.在一大批当代前瞻性队列患者中确定肝细胞癌的代谢危险因素。 肝硬变。我们将检查现有的和新的代谢候选标记的关联，包括(1)MAFLD 表型特征：体重指数、腰臀比、甘油三酯水平、高密度脂蛋白水平、糖尿病和 胰岛素抵抗的标志物，(2)选择新的代谢生物标志物，利用代谢组学和 来自THCCC内嵌套的发现病例对照研究样本的脂质组学分析，以及(3)怀疑 代谢功能障碍的分子标志物(例如，血清脂肪因子水平、促炎/抗炎细胞因子)。 2.确定人口统计、生活方式特征、遗传风险因素和相关的肝脏成像标记物 在有肝硬变的患者中有发生肝癌的风险。我们将研究以下风险与 具有候选危险因素/标记的肝细胞癌，即(1)人口统计学(年龄、种族/民族、性别)和生活方式(吸烟、 体力活动)特征，(2)基于MAFLD已建立的遗传标记的多基因风险评分(PNPLA3， TM6SF3、MBOAT7、NCAN、PP1R3B)，以及(3)新的体脂定量成像标记物(皮肤到肝脏- 从肝脏超声图像的放射学分析中估计的肝脏脂肪(肝肾指数)。 3.开发和优化适应性风险指数，以预测患者进展为肝癌的风险 患有肝硬变。我们将开发一套适应性模型，包括：(A)结合人口统计学的基本指数 和具有表型代谢预测指标的生活方式预测指标，(B)增加基于血液的标记物(例如，多基因风险 (C)添加肝脏超声放射组学指数。我们将评估 风险预测指标的绩效特征 风险预测指数将对以下项目的比较成本效益产生重要的转换影响 肝细胞癌预防(例如，化学预防、肝细胞癌监测)，并构成对一刀切的背离 尽管个体患肝细胞癌的风险存在显著差异，但还是采取了治疗肝硬变的方法。

The etiological risk factors for hepatocellular carcinoma (HCC) and its precursor lesion (cirrhosis) in the US have dramatically changed in the past decade from predominantly active chronic viral hepatitis (hepatitis B and C) to Metabolic (dysfunction) Associated Fatty Liver Disease (MAFLD). Given the high prevalence of the metabolic disorders (e.g., obesity and diabetes) that define MAFLD and their chronic incurable nature, the focus on HCC prevention related to MAFLD is paramount. Prevention of HCC requires better understanding of the determinants of this risk, and the consequent construction of models and tools for risk stratification. We propose to leverage data, biospecimens and infrastructure of the Texas HCC Consortium (THCCC) Cohort, the largest US-based active prospective cohort study of cirrhosis patients, of whom 80% is estimated to have MAFLD. We propose expanding and extending the follow-up of the THCCC cohort to >5000 patients with >350 incident HCC cases. Our study in Project 1 has the following Specific Aims: 1. Identify metabolic risk factors for HCC in a large contemporary prospective cohort of patients with cirrhosis. We will examine associations of existing and novel metabolic candidate markers including (1) MAFLD phenotypic features: body mass index, waist-to-hip ratio, triglyceride level, HDL cholesterol level, diabetes, and markers of insulin resistance, (2) select novel metabolic biomarker candidates identified using metabolomic and lipidomic assays of samples from a discovery case-control study nested within THCCC, and (3) suspected molecular markers of metabolic dysfunction (e.g., serum adipokines level, pro/anti-inflammatory cytokines). 2. Identify demographic, lifestyle features, genetic risk factors, and liver imaging markers associated with the risk of developing HCC among patients with cirrhosis. We will examine associations of the risk of HCC with candidate risk factors/markers i.e., (1) demographic (age, race/ethnicity, sex) and lifestyle (smoking, physical activity) features, (2) a polygenic risk score based on established genetic markers of MAFLD (PNPLA3, TM6SF3, MBOAT7, NCAN, PP1R3B), and (3) novel quantitative imaging markers of body fat (skin-to-liver- capsule distance) and liver fat (hepatorenal index) estimated from radiomic analyses of liver ultrasound images. 3. Develop and optimize adaptive risk indices for predicting risk of progression to HCC among patients with cirrhosis. We will develop a set of adaptive models including (a) a ‘basic’ index that combines demographic and lifestyle predictors with phenotypic metabolic predictors, (b) add blood-based markers (e.g., a polygenic risk score, metabolic risk score) to the ‘basic’ index, and (c) add liver ultrasound radiomics indices. We will assess the performance characteristics of the risk prediction indices The risk prediction index will have important translational implications to the comparative cost effectiveness of HCC prevention (e.g., chemoprevention, HCC surveillance), and constitutes a departure from the broad-brush approach to cirrhosis despite the presence of remarkable variations in individual risk of HCC.