HCC Risk Stratification in MAFLD Cirrhosis

在美国，肝细胞癌（HCC）及其前病变（肝硬化）的病因风险因素有 在过去的十年中，从主要的活动性慢性病毒性肝炎（B和C型肝炎）急剧变化为 代谢（功能障碍）相关性脂肪肝（MAFLD）。鉴于艾滋病毒/艾滋病的高流行率， 代谢紊乱（例如，肥胖和糖尿病），定义MAFLD及其慢性不可治愈的性质，重点是 与MAFLD相关的HCC预防至关重要。预防肝细胞癌需要更好地了解 这一风险的决定因素，以及随之而来的风险分层模型和工具的建设。我们提出 利用德克萨斯州HCC联盟（THCCC）队列的数据，生物标本和基础设施， 在肝硬化患者中开展的基于美国的积极前瞻性队列研究，估计其中80%患有MAFLD。我们 我建议将THCCC队列的随访范围扩大到> 5000例患者，其中> 350例发生HCC 例我们在项目1中的研究有以下具体目标： 1.在一个大型的当代前瞻性队列中确定HCC的代谢危险因素， 肝硬化我们将研究现有的和新的代谢候选标志物的关联，包括（1）MAFLD 表型特征：体重指数、腰臀比、甘油三酯水平、HDL胆固醇水平、糖尿病和 （2）选择使用代谢组学鉴定的新的代谢生物标志物候选物， 来自THCCC内嵌套的发现病例对照研究的样本的脂质组学测定，以及（3）疑似 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.确定人口统计学、生活方式特征、遗传风险因素和相关的肝脏成像标志物 与肝硬化患者发生肝细胞癌的风险有关。我们将研究的风险协会 具有候选风险因素/标志物的HCC，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）基于已建立的MAFLD遗传标记的多基因风险评分（PNPLA3， TM6SF3、MBOAT7、NCAN、PP1R3B），和（3）新的体脂肪定量成像标记物（皮肤-肝脏- 囊距离）和肝脏脂肪（肝肾指数），这些指标由肝脏超声图像的放射组学分析估计。 3.开发和优化自适应风险指数，用于预测患者进展为HCC的风险 肝硬化我们将开发一套适应性模型，包括：（a）一个结合人口统计数据的“基本”指数 和生活方式预测因子与表型代谢预测因子，（B）添加基于血液的标记物（例如，多基因风险 评分、代谢风险评分）添加到"基本"指数，以及（c）添加肝脏超声放射组学指数。我们将评估 风险预测指标的性能特征 风险预测指数将对以下方面的比较成本效益产生重要的转化影响： HCC预防（例如，化学预防，HCC监测），并构成了对广泛的 尽管个体HCC风险存在显著差异，但我们仍然可以采用一种治疗肝硬化的方法。

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.