HCC Risk Stratification in MAFLD Cirrhosis

MAFLD 肝硬化的 HCC 风险分层

• 批准号: 10657413
• 负责人: Hashem B El-Serag
• 金额: $ 68.37万
• 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/10657413
• 关键词: Address; Age; Alcohol abuse; American; Anti-Inflammatory Agents; Biological Assay; 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; Functional disorder; 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; Physical activity; Predictive Value; Prevention; Primary carcinoma of the liver cells; Prospective cohort; Prospective, cohort study; Race; Research; Risk; Risk Factors; Sampling; Serum; Site; Skin; Smoking; Specificity; Subgroup; Survival Rate; Texas; Triglycerides; Ultrasonography; Validation; Variant; Waist-Hip Ratio; adipokines; biomarker discovery; biomarker selection; blood-based biomarker; candidate identification; candidate marker; capsule; clinical practice; cohort; comparative cost effectiveness; cost effectiveness; cytokine; disease phenotype; ethnic minority; fatty liver disease; follow-up; genetic risk factor; high risk; imaging biomarker; improved; indexing; lipidomics; liver imaging; metabolic phenotype; metabolic-associated fatty liver disease; metabolomics; molecular marker; novel; novel marker; polygenic risk score; practice setting; programs; progression risk; prospective; quantitative imaging; racial minority; 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.

在美国，肝细胞癌 (HCC) 及其前驱病变（肝硬化）的病因学危险因素 在过去的十年中，从主要活跃的慢性病毒性肝炎（乙型和丙型肝炎）到 代谢（功能障碍）相关脂肪肝病（MAFLD）。鉴于该病的高患病率 定义 MAFLD 的代谢性疾病（例如肥胖和糖尿病）及其慢性无法治愈的性质是焦点 与 MAFLD 相关的 HCC 预防至关重要。预防 HCC 需要更好地了解 该风险的决定因素，以及随后构建的风险分层模型和工具。我们建议 利用最大的德克萨斯 HCC 联盟 (THCCC) 队列的数据、生物样本和基础设施 美国一项针对肝硬化患者的积极前瞻性队列研究，估计其中 80% 患有 MAFLD。我们 建议将 THCCC 队列的随访范围扩大到超过 5000 名患有超过 350 例 HCC 的患者 案例。我们的项目 1 研究有以下具体目标： 1. 在当代大型前瞻性患者队列中确定 HCC 的代谢危险因素 肝硬化。我们将检查现有和新型代谢候选标记物的关联，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 胰岛素抵抗的标志物，（2）选择使用代谢组学和代谢组学鉴定的新型代谢生物​​标志物候选物 对来自 THCCC 内发现病例对照研究的样本进行脂质组学测定，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/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 肝硬化患者有患 HCC 的风险。我们将检查风险的关联 HCC 具有候选风险因素/标记，即 (1) 人口统计（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）新型体脂肪定量成像标记物（皮肤到肝脏） 通过肝脏超声图像的放射组学分析估计肝脏脂肪（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 HCC 的风险 患有肝硬化。我们将开发一套自适应模型，包括（a）结合人口统计的“基本”指数 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 风险预测指数的表现特征 风险预测指数将对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），并构成了对粗略的偏离 尽管 HCC 的个体风险存在显着差异，但仍采取了治疗肝硬化的方法。