Assessment of Alcoholic Hepatitis with Multiparametric Magnetic Resonance Elastography

项目概要/摘要 酒精性肝炎（AH）是由于缺乏有效治疗而导致发病和死亡的主要原因。那里 是一个未满足的需要，可靠的非侵入性诊断，预后，和疾病监测替代标志物， AH患者，通常具有挑战性的临床诊断和高风险的侵袭性肝脏并发症 活检本提案的总体目标是进行临床前（UH 2阶段）和临床（UH 3阶段） 评价多种磁共振弹性成像（MRE）生物标志物以评估AH疾病的研究 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，可以提供评估AH疾病进展和消退的准确参数，包括 脂肪变性、炎症和纤维化的变化。我们认为AH疾病的严重程度和治疗反应 当肝脏造影片被整合到一个复合度量中时， 活检，”提供了一个可靠的非侵入性替代评估AH疾病的严重程度。UH 2阶段（第1-2年; 目的1），我们将推进磁共振成像技术，以验证各成像参数之间的关系， 给予乙醇（EtOH）的小鼠中相应的组织学特征。统计模型将扩展 使用这些成像生物标志物对AH进行一体化诊断或预后评分。重组IL-22， 在小鼠模型中改善肝脂肪变性和炎症的药剂将用于促进疾病 回归分析我们将在一项纵向研究中测试MRE评估AH严重程度的能力， 用于指示AH小鼠模型中疾病进展和消退的每个参数的变化， 安慰剂或IL-22治疗。在UH 3阶段（第3-5年;目标2），我们将验证MRE评估AH的可靠性 AH患者的疾病严重程度和治疗反应。预测即将到来的翻译 在马约诊所的AlcHepNet中进行的以患者为导向的研究（RFA AA-18-002和RFA AA-18-005），我们将 在临床护理中，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，还将验证这种一体化“虚拟活检”的统计模型。我们还将 在安慰剂和IL-22队列中对患者进行基线、30天和90天随访肝脏造影 入组了一项IL-22的马约治疗试验（对RFA AA-18-005的反应）。这将使我们能够评估MRE 通过将MRE的变化与 终末期肝病模型（MELD）评分的变化。总之，成功验证了这部小说 在所提出的临床前和临床研究中，基于MRE的生物标志物将具有巨大的应用， 评估AH疾病的严重程度和对治疗的反应。

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.