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: 10459414
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459414
• 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; Longitudinal Studies; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Pathogenesis; Patients; Phase; Placebos; Prognosis; Recombinants; Research; Severities; Severity of illness; Statistical Models; Surrogate Markers; Technology; Testing; Therapeutic Agents; base; bench to bedside; clinical care; clinical diagnosis; cohort; effective therapy; end stage liver disease; follow-up; high risk; imaging biomarker; innovation; interleukin-22; liver biopsy; liver inflammation; liver stiffness; mortality; mouse model; noninvasive diagnosis; novel; 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 是对可靠的非侵入性诊断，预后和疾病监测替代标志物的未满足的需求 AH患者经常挑战临床诊断和侵入性肝脏并发症的高风险 活检。该提案的总体目标是执行临床前（UH2期）和临床（UH3期） 评估多种磁共振弹性图（MRE）生物标志物以评估AH疾病的研究 严重性和监测治疗反应。我们的中心假设是多参数肝MRE，称为A 肝图，可以提供准确的参数来评估AH疾病的进展和回归，包括 脂肪变性，感染和纤维化的变化。我们认为AH疾病的严重程度和治疗反应 当将肝图集成到可以用作“虚拟的复合度量标准中）时，可以量化 活检，“为评估AH疾病的严重程度提供可靠的无创替代物。在UH2期（1 - 2年； 目标1），我们将促进MRE技术来验证每个成像参数和 小鼠施用乙醇（ETOH）的相应组织学特征。统计模型将扩展 将这些成像生物标志物用于AH的多合一诊断或预后评分。重组IL-22，an 改善肝脂肪变性和小鼠模型炎症的药物将用于促进疾病 回归。我们将在纵向研究中测试MRE的能力，以评估AH的严重性和评估 在AH小鼠模型中指示疾病进展和回归的每个参数的变化 安慰剂或IL-22治疗。在UH3期（3-5年； AIM 2）中，我们将验证MRE可靠性以评估AH AH患者的疾病严重程度和治疗反应。基于即将进行的翻译 在Mayo Clinic的Alchepnet中，面向患者的研究（RFA AA-18-002和RFA AA-18-005），我们将 在患有肝活检的患者中，作为其临床护理的一部分进行基线MRE。我们将验证 每种成像替代物从MRE的可靠性与组织学特征相关（脂肪变性，炎症， 和纤维化）。此外，将验证该多合一“虚拟活检”的统计模型。我们也会 在安慰剂中执行基线，30天和90天的随访肝脏，并对患者进行IL-22队列 参加了IL-22的蛋黄酱治疗试验（响应RFA AA-18-005）。这将使我们能够评估MRE 参数分别通过将MRE的变化与AH进展和回归变化 末期肝病（MELD）评分模型的变化。总之，这部小说的成功验证 在拟议的临床前和临床研究中，基于MRE的生物标志物将对 评估AH疾病的严重程度和对治疗的反应。