Assessment of Alcoholic Hepatitis with Multiparametric Magnetic Resonance Elastography

多参数磁共振弹性成像评估酒精性肝炎

• 批准号: 10205237
• 负责人: VIJAY H. SHAH
• 金额: $ 38.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205237
• 关键词: Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Biological Markers; Chemical Shift Imaging; Cirrhosis; Clinic; Clinical; Clinical Research; Clinical Trials; Diagnosis; Diagnostic; Disease; Disease Progression; Disease regression; Enrollment; Ethanol; Fatty Liver; Fibrosis; Goals; Hepatic; Histologic; Histology; Human; IgG2; Image; Inflammation; Liver; Liver Regeneration; Liver diseases; Longitudinal Studies; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Pathogenesis; Patients; Phase; Placebos; Recombinants; Research; Severities; Severity of illness; Statistical Models; Surrogate Markers; Technology; Testing; Therapeutic Agents; base; bench to bedside; clinical Diagnosis; clinical care; cohort; effective therapy; follow-up; high risk; imaging biomarker; innovation; interleukin-22; liver biopsy; mortality; mouse model; noninvasive diagnosis; novel; outcome forecast; patient oriented research; pre-clinical; preclinical study; prognostic; quantitative imaging; recruit; response; success; treatment response; treatment trial; virtual biopsy

PROJECT SUMMARY/ABSTRACT Alcoholic hepatitis (AH) is a major cause of morbidity and mortality due to a lack of effective treatments. There is an unmet need for reliable noninvasive diagnosis, prognosis, and disease monitoring surrogate markers in AH patients, who often have challenging clinical diagnoses and high risks of complications with invasive liver biopsy. The overall goals of this proposal are to perform both preclinical (phase UH2) and clinical (phase UH3) studies to evaluate multiple magnetic resonance elastography (MRE) biomarkers to assess AH disease severity and monitor treatment responses. Our central hypothesis is that a multiparametric liver MRE, called a hepatogram, can provide accurate parameters for assessing AH disease progression and regression, including changes in steatosis, inflammation, and fibrosis. We believe that AH disease severity and treatment responses can be quantified when the hepatogram is integrated into a composite metric that can serve as a “virtual biopsy,” providing a reliable noninvasive surrogate for assessing AH disease severity. In phase UH2 (years 1-2; Aim 1), we will advance MRE technology to validate the relationships between each imaging parameter and the corresponding histologic feature in mice administered ethanol (EtOH). A statistical model will expand the use of these imaging biomarkers to an all-in-one diagnostic or prognostic score for AH. Recombinant IL-22, an agent that ameliorates hepatic steatosis and inflammation in mouse models will be used to promote disease regression. We will test the ability of MRE in a longitudinal study for assessing AH severity and evaluate changes of each parameter for indicating both disease progression and regression in AH mouse models with placebo or IL-22 treatment. In phase UH3 (years 3-5; Aim 2), we will verify MRE reliability for assessing AH disease severity and treatment responses in patients with AH. Predicated on the upcoming translational patient-oriented studies (RFA AA-18-002 and RFA AA-18-005) in the AlcHepNet at Mayo Clinic, we will perform a baseline MRE in patients who have had liver biopsies as part of their clinical care. We will verify the reliability of each imaging surrogate from MRE for correlation with histology features (steatosis, inflammation, and fibrosis). Additionally, a statistical model of this all-in-one “virtual biopsy” will be verified. We will also perform baseline, 30-, and 90-day follow-up hepatograms in the placebo and IL-22 cohorts from patients enrolled in a Mayo treatment trial of IL-22 (in response to RFA AA-18-005). This will allow us to evaluate MRE parameter changes in AH progression and regression respectively by correlating changes in MRE with changes in Model of End Stage Liver Disease (MELD) scores. In summary, successful verification of this novel MRE based biomarker in the proposed preclinical and clinical studies would have tremendous applications for assessing AH disease severity and response to therapy.

项目摘要/摘要 由于缺乏有效的治疗，酒精性肝炎(AH)是发病率和死亡率的主要原因。那里 对可靠的非侵入性诊断、预后和疾病监测的替代标记物的需求是否未得到满足 AH患者，他们的临床诊断往往具有挑战性，并有侵袭性肝脏并发症的高风险 活组织检查。该提案的总体目标是执行临床前(UH2阶段)和临床(UH3阶段)。 评价多个磁共振弹性成像(MRE)生物标志物评估AH病的研究 严重程度和监测治疗反应。我们的中心假设是多参数肝脏MRE，称为 肝脏造影可以为评估AH疾病的进展和消退提供准确的参数，包括 脂肪变性、炎症和纤维化的变化。我们认为急性肝炎的严重程度和治疗反应 当肝图被集成到可以充当“虚拟的”的复合指标中时，可以被量化 活组织检查，“为评估急性髓细胞白血病的严重程度提供了可靠的非侵入性替代方法。UH2阶段(1-2年； 目的1)提出磁共振成像技术，以验证各成像参数之间的关系 乙醇(Etoh)组小鼠的相应组织学特征。统计模型将扩展 使用这些成像生物标记物对AH的诊断或预后进行综合评分。重组IL-22，ANN 改善小鼠模型肝脏脂肪变性和炎症的药物将用于促进疾病 回归。我们将在一项纵向研究中测试MRE评估急性肝炎严重性的能力，并评估 急性早幼粒细胞白血病模型小鼠病情进展和消退的各项参数变化 安慰剂或IL-22治疗。在UH3阶段(3-5年；目标2)，我们将验证用于评估AH的MRE可靠性 急性肝炎患者的病情严重程度和治疗反应。基于即将到来的翻译版本 梅奥诊所AlcHepNet的患者导向研究(RFA AA-18-002和RFA AA-18-005)，我们将 作为临床护理的一部分，对接受过肝活检的患者进行基线MRE。我们将核实 来自MRE的每个成像替代物与组织学特征(脂肪变性、炎症、 和纤维化)。此外，还将验证这种一体式“虚拟活检”的统计模型。我们还将 在安慰剂组和来自患者的IL-22队列中进行基线、30天和90天的随访肝图 参加IL-22的梅奥治疗试验(对RFA AA-18-005的回应)。这将使我们能够评估MRE 通过将MRE的变化与AH进展和回归的变化相关联来分别研究其参数变化 终末期肝病模型(MELD)评分变化。总之，对这部小说的成功验证 基于MRE的生物标记物在拟议的临床前和临床研究中将有巨大的应用前景 评估AH疾病的严重程度和对治疗的反应。