Biomarkers of Disease in Alcoholic Hepatitis

摘要 酒精性肝炎（AH）是酒精引起的肝脏器官损害中最严重的形式，临床表现为肝硬化， 严重肝病的表现和高死亡率。临床疾病的诱发因素和决定因素 结果仍然难以捉摸的AH。AH的临床结局取决于关键因素，例如：1）受损的宿主 酒精中毒患者的防御，易感染; 2）AH的全身炎症，有助于 全身炎症反应综合征（SIRS）和多器官衰竭的发展;和3） 肝脏的再生能力。在这份提案中，我们的目标是回答与这些关键问题有关的关键问题。 临床结果的决定因素使用床旁到长凳的方法。我们将前瞻性地利用生物样本 在观察性研究（Aim#1）中的AlcHepNet临床试验中收集，以评价功能、表型和 明确定义的患者中主要循环免疫细胞群的代谢组学特征 本研究中的人群：重度AH、中度AH、无临床肝病证据的重度饮酒者，以及 正常对照组来自晚期临床试验的样品，其包括泼尼松、IL-10、IL-11、IL-12、IL-14、IL-16、IL-18、IL-19 1受体拮抗剂（IL-1 ra，也称为阿那白滞素，加锌）和G-CSF将用于获得机制 通过转化研究来深入了解这些新的治疗方法。因为这些干预措施针对的是 炎症、免疫应答和/或肝再生的影响，对前瞻性收集的 生物样本将为补充临床研究的机制性离体研究提供有价值的工具。 主要临床试验中收集的观察结果。AlcHepNet临床试验将收集明确定义的临床数据。 与独特生物标本相关的患者和对照人群，以支持高质量的转化研究 并解决AH中一些最紧迫的临床问题。具体目标是： 目的#1：评估酒精诱导的免疫抑制和先天免疫反应失调， 与患者的自然史、感染和临床结果相关的病原体源性信号 使用来自AlcHepNet观察性研究的样本进行AH。 目的#2：测试使用IL-1 ra和G-CSF的新型疗法对先天免疫的生物学后果。 激活，肠漏标志物和肝再生的循环标志物， 从AlcHepNet晚期临床试验中收集的样本。 ! !

ABSTRACT Alcoholic hepatitis (AH) is the most severe form of alcohol-induced organ damage in the liver with clinical manifestations of severe liver disease and high mortality. The precipitating factors and determinants of clinical outcome remain elusive in AH. The clinical outcome of AH depends on key factors such as 1) impaired host defense in the alcoholic patient that predisposes to infections; 2) systemic inflammation in AH that contributes to the development of Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure; and 3) the regenerative capacity of the liver. In this proposal, we aim to answer critical questions related to these key determinants of clinical outcomes using bedside to bench approaches. We will utilize biospecimens prospectively collected in the AlcHepNet clinical trial in the observational study (Aim#1) to evaluate the functional, phenotypic and metabolomics characteristics of major circulating immune cell populations in the well-defined patient populations in this study: severe AH, moderate AH, heavy drinkers without evidence of clinical liver disease, and normal control. Samples from the Late Stage Clinical Trial that include the treatment arms of prednisone, IL- 1receptor antagonist (IL-1ra, also known as anakinra, plus zinc) and G-CSF will be utilized to gain mechanistic insights into these novel treatments through translational research. Because these interventions target elements of inflammation, immune responses and/or liver regeneration, evaluation of the prospectively collected biospecimens will provide a valuable tool for mechanistic ex vivo studies that complement the clinical observations collected in the main clinical trial. The AlcHepNet clinical trial will collect clinical data on well-defined patient and control populations linked with unique biospecimens to support high-quality translational research and address some of the most burning clinical questions in AH. The Specific Aims are: Aim #1: To assess alcohol-induced immunosuppression and dysregulated innate immune responses to pathogen-derived signals in relation to the natural history, infections and clinical outcomes in patients with AH using samples from the AlcHepNet Observational Study. Aim #2: To test the biological consequences of novel therapies with IL-1ra and G-CSF on innate immune activation, markers of gut leakiness and circulating markers of liver regeneration using prospectively collected samples from the AlcHepNet Late Stage Clinical Trial. ! !