Predicting outcomes in nonalcoholic steatohepatitis with advanced fibrosis

预测伴有晚期纤维化的非酒精性脂肪性肝炎的结果

• 批准号: 10696227
• 负责人: ARUN J SANYAL
• 金额: $ 58.05万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696227
• 关键词: Adipose tissue; Ascites; Biological Markers; Biology; Cessation of life; Child; Cirrhosis; Clinic; Clinical; Collaborations; Compensation; Consensus; Data; Data Set; Development; Disease; Emerging Technologies; Encephalopathies; Endoscopy; Etiology; Event; Exposure to; Extrahepatic; Fasting; Fatty acid glycerol esters; Fibrosis; Glycosylated hemoglobin A; Goals; Hemorrhage; Hepatic; Image; Industry; Infiltration; Insulin; Intervention; Knowledge; Life; Liver; Longitudinal cohort study; Machine Learning; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolic dysfunction; Methods; Minority; Modeling; Monitor; Muscle; Outcome; Patient Care; Patients; Perfusion; Phenotype; Population; Portal Hypertension; Prevention; Probability; Protocols documentation; Publishing; Regression Analysis; Reproducibility; Research; Research Personnel; Risk; Scanning; Science; Spleen; Statistical Models; Technology; Testing; Therapeutic; Time; Toxic effect; Training; Translating; Variant; Varicosity; Venous Pressure level; Visceral; Visceral fat; attributable mortality; care delivery; clinical care; clinical development; clinical imaging; drug development; elastography; health care delivery; hemodynamics; improved; individual patient; innovation; insight; instrument; liver function; liver imaging; liver stiffness; liver transplantation; magnetic resonance imaging biomarker; mortality; mortality risk; nature center; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; outcome prediction; patient population; prevent; prognostic; prognostic value; routine practice; therapeutic development; therapeutically effective; tool; uptake

Hepatic decompensation (overt ascites, encephalopathy and variceal hemorrhage) and mortality in patients with nonalcoholic steatohepatitis (NASH) increases exponentially with the development of cirrhosis. Prevention of such liver-associated clinical events (LACE) is therefore a major goal of therapeutics. This requires identification of those at risk and targeting them with effective therapeutics. Current approaches to identify this population include the use of fibrosis markers such as FIB4, liver-stiffness measurement (LSM), assessment of hepatic venous pressure gradient and/or varices (endoscopy) and traditional measures of liver function. These are unfortunately limited by modest accuracy of some models, retrospective, single center nature of most data-sets published and lack of information on the impact of changes in these parameters over time with respect to dynamic changes in risk profile. This proposal innovates by novel application and integration of systemic, hepatic perfusion and function, and portal hypertension related parameters to holistically model the risk of LACE and generate a probability score that is sensitive to change. We will specifically focus on MRI-based measures of systemic metabolic dysfunction (metabo-phenotype), gadoxetate uptake and clearance (integrated measure of hepatic perfusion and clearance function) and spleen stiffness measurement (SSM) as a surrogate for portal hypertension. We further propose the novel hypothesis that holistic models including these measures and capturing the multi-factorial origin of hepatic decompensation events are superior to conventional tools used in routine practice to define the probability of LACE in patients with compensated cirrhosis due to NASH. The hypothesis will be tested in a longitudinal cohort study of compensated cirrhosis due to NASH. The specific measures of the metabo-phenotype will include visceral adipose tissue volume, fat-free muscle volume, muscle fat infiltration. Gadoxetate uptake and clearance will be measured in a 10-minute exam. The SSM probe was recently approved and will be deployed on Fibroscan 630 the flagship instrument for transient elastography. Metabo-phenotyping requires implementing an imaging protocol, based on a routine clinical imaging sequence, onto standard clinical scanners which adds less than 10 minutes of scan-time while gadoxetate is routinely used for liver-imaging. Sub-aim 1 will model baseline parameters, alone and in combination, to define outcome risk within 1-2 years. Sub-aim 2 will evaluate dynamic changes in values of the test measures over time and relate them to changes in the risk of outcomes. Both regression and machine learned approaches will be taken to generate probability scores of the outcomes. Sensitivity analyses will be performed to test the robustness of the models. The patient populations needed and all of the methods/expertise are available. The rationale of this proposal is that it will provide a method for risk-identification in those with NASH-cirrhosis which can be incorporated in to clinical care. This will have a strong positive impact by improving individual patient care, drug development and optimizing care delivery by identifying the population that will benefit most from therapeutics.

肝失代偿（明显腹水、脑病和静脉曲张出血）和死亡率 非酒精性脂肪性肝炎（NASH）随着肝硬化的发展呈指数增加。预防 因此，这种肝脏相关临床事件（LACE）是治疗的主要目标。这就需要鉴定 并针对他们进行有效的治疗。目前确定这一群体的方法 包括使用纤维化标志物如FIB 4、肝硬度测量（LSM）、肝硬化的评估、肝硬化的诊断和治疗。 静脉压梯度和/或静脉曲张（内窥镜检查）和肝功能的传统测量。这些是 不幸的是，某些模型的准确性有限，大多数数据集的回顾性、单中心性质 这些参数随着时间的推移而发生变化， 风险状况的变化。该提案通过系统性、肝脏性、 灌注和功能，以及门静脉高压相关参数，以全面模拟LACE的风险， 生成对变化敏感的概率分数。我们将特别关注基于MRI的措施， 全身代谢功能障碍（代谢表型）、钆塞酸盐摄取和清除（ 肝灌注和清除功能）和脾硬度测量（SSM）作为门静脉替代物 高血压我们进一步提出了新的假设，包括这些措施和 捕获肝功能失代偿事件的多因素起源优于用于 定义NASH所致代偿性肝硬化患者发生LACE概率的常规实践。的 将在NASH所致代偿性肝硬化的纵向队列研究中检验这一假设。具体 代谢表型的测量将包括内脏脂肪组织体积、无脂肪肌肉体积、肌肉 脂肪浸润将在10分钟的检查中测量甘胆酸盐摄取和清除。 最近获得批准，并将部署在瞬时弹性成像的旗舰仪器Fibroscan 630上。 代谢表型分析需要基于常规临床成像序列实施成像方案， 在常规使用钆塞酸盐的情况下， 用于肝脏成像子目标1将单独和组合建模基线参数，以定义结局风险 在1 - 2年内。次级目标2将评估测试措施值随时间的动态变化， 结果风险的变化。回归和机器学习方法都将被用来 生成结果的概率得分。将进行敏感性分析，以检验 模型所需的患者人群和所有方法/专业知识都可用。这种做法的理由是， 建议是，它将提供一种方法，风险识别在那些与NASH肝硬化，可以 纳入临床护理。这将通过改善个体患者护理、药物治疗、 通过确定将从治疗中受益最多的人群，开发和优化护理服务。

项目成果

Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

开发利用振动控制瞬态弹性成像检测肝移植受者晚期肝纤维化的临床算法。

• DOI: 10.1007/s10620-024-08366-0
• 发表时间: 2024
• 期刊: Digestive diseases and sciences
• 影响因子: 3.1
• 作者: Arshad,Tamoore;Vainer,Dylan;Khan,Hiba;Baral,Alok;Garg,Shreya;Ang,Audrey;Patel,Vaishali;Kumaran,Vinay;Bruno,David;Lee,Seung;Sharma,Amit;Muthiah,Mark;Bui,AnhT;Siddiqui,MohammadShadab
• 通讯作者: Siddiqui,MohammadShadab