HCC Risk Stratification in MAFLD Cirrhosis

MAFLD 肝硬化的 HCC 风险分层

• 批准号: 10410750
• 负责人: Hashem B El-Serag
• 金额: $ 61.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410750
• 关键词: Address; Alcohol abuse; American; Anti-Inflammatory Agents; Biological Assay; Biological Markers; Body fat; Body mass index; CSPG3 gene; Calibration; Cancer Etiology; Cessation of life; Characteristics; Chemoprevention; Chronic; Chronic viral hepatitis; Cirrhosis; Cities; Collection; Data; Diabetes Mellitus; Diastolic blood pressure; Discrimination; Early Diagnosis; Ethnic Origin; Etiology; Event; Fatty acid glycerol esters; General Population; Genetic; Genetic Markers; Glycosylated hemoglobin A; Goals; Growth; Hepatitis B; Hepatitis C; High Density Lipoprotein Cholesterol; High Prevalence; Hispanic Populations; Image; Individual; Infrastructure; Insulin; Insulin Resistance; Lesion; Life Style; Lipids; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Methods; Modeling; Nature; Nested Case-Control Study; Obesity; Pathway interactions; Patients; Performance; Persons; Phenotype; Physical activity; Predictive Value; Prevention; Primary carcinoma of the liver cells; Prospective cohort; Prospective cohort study; Race; Research; Risk; Risk Factors; Sampling; Sensitivity and Specificity; Serum; Site; Skin; Smoking; Subgroup; Survival Rate; Texas; Triglycerides; Ultrasonography; Validation; Variant; Waist-Hip Ratio; adipokines; base; biomarker discovery; blood-based biomarker; candidate marker; capsule; clinical practice; cohort; comparative cost effectiveness; cost effectiveness; cytokine; ethnic minority; fatty liver disease; follow-up; genetic risk factor; high risk; imaging biomarker; indexing; lipidomics; liver imaging; metabolic phenotype; metabolic-associated fatty liver disease; metabolomics; molecular marker; novel; novel marker; polygenic risk score; practice setting; programs; prospective; quantitative imaging; racial and ethnic; radiomics; recruit; risk prediction; risk stratification; sex; synergism; tool; ultrasound

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.

肝细胞癌（HCC）及其前体病变（肝硬化）的病因危险因素在美国具有 在过去的十年中，动态变化从主要活跃的慢性病毒肝炎（乙型肝炎和C）转变为 代谢（功能障碍）相关的脂肪肝病（MAFLD）。考虑到很高的患病率 定义黑手党及其慢性无法治愈性的代谢疾病（例如肥胖和糖尿病），重点 关于与MAFLD有关的HCC预防是至关重要的。预防HCC需要更好地理解 这种风险的决定因素，以及随之而来的模型和风险分层工具的构建。我们建议 利用最大的德克萨斯州HCC联盟（THCCC）队列的数据，生物测量和基础设施 基于美国的肝硬化患者的活跃前瞻性队列研究，其中80％的患者患有MAFLD。我们 提案将THCCC队列的随访扩展并扩展到> 350例HCC的患者> 5000例 案例。我们在项目1中的研究具有以下具体目的： 1。确定大量当代前瞻性队列中HCC的代谢危险因素 肝硬化。我们将研究现有和新型代谢候选标记的关联，包括（1）MAFLD 表型特征：体重指数，腰围比，甘油三酸酯水平，HDL胆固醇水平，糖尿病和 胰岛素抵抗的标记，（2）选择使用代谢组和代谢组鉴定的新型代谢生物​​标志物候选者 来自THCCC内的发现病例对照研究的样品的脂质组学评估，（3）可疑 代谢功能障碍的分子标记（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，遗传危险因素和肝脏成像标记 有肝硬化患者患HCC的风险。我们将研究有关的风险 HCC具有候选风险因素/标记的HCC，即（1）人口统计学（年龄，种族/种族，性别）和生活方式（吸烟， 体育活动）特征，（2）基于MAFLD的遗传标记的多基因风险评分（PNPLA3， TM6SF3，MBOAT7，NCAN，PP1R3B）和（3）身体脂肪的新型定量成像标记（皮肤至肝 胶囊距离）和肝脏脂肪（肝烯醇指数）从肝脏超声图像的放射学分析估计。 3。开发和优化适应性风险指数，以预测患者中HCC的风险 与肝硬化。我们将开发一组自适应模型，包括（a）结合人口统计的“基本”索引 和具有表型代谢预测因子的生活方式预测因子，（b）添加基于血液的标记（例如，多基因风险 得分，代谢风险评分）为“基本”指数，（c）添加肝超声放射素指数。我们将评估 风险预测指数的性能特征 风险预测指数将对比较成本有效性具有重要的翻译意义 HCC预防（例如，化学预防，HCC监视），构成了宽阔的灌木丛 肝硬化的方法尽管存在HCC的个体风险存在显着差异。