Continuation of ChiLDReN, the Childhood Liver Disease Research Network: Indiana University

项目摘要/摘要 儿科肝病的发病率和死亡率都很高。胆道闭锁(BA)所占比例超过 有一半的儿童肝移植。新生儿胆汁淤积症的遗传原因包括Alagille综合征 (ALGS)、α-1抗胰蛋白酶缺乏症(A1AT)、进行性家族性肝内胆汁淤积症(PFIC)、胆汁 酸性合成缺陷、线粒体肝病和囊性纤维化(CF)。所有这些疾病都可能 进展为肝硬变。儿童网络的目标是跟踪大量这样的主题 纵向上允许为有助于诊断的研究积累临床数据和生物标本， 使用生物标记物来预测和治疗这些疾病。建立在此基础上的翻译研究 卓越的数据库和生物信息库可以产生关于发病机制、疾病 修饰剂，并最终治疗。我们建议继续参与儿童研究 网络；我们中心将积极招募儿童疾病患者，纵向保留他们 后续行动，并为正在进行的研究作出贡献。我们将继续积极参与想象 一种肠道胆汁酸转运抑制剂治疗瘙痒的临床试验。我们将继续 参与瞬时弹性成像纵向力研究监测儿童肝纤维化 胆道闭锁、A1AT和ALGS。CF研究将继续评估超声波在以下方面的作用 瞬时弹性成像在预测CF(PUSH)儿童肝硬变发展中的作用 (弹性)和磁共振弹性成像(MRE)，以非侵入性监测纤维化进展， 以及这种疾病中的肝硬变的进展。我们将参与制定和实施 原发性硬化性胆管炎(PSC)研究的进展，从数据库研究开始，进展到 临床试验。该网络的最终目标是了解更多关于自然历史和发病机制的信息。 目的为儿童胆汁淤积性疾病的治疗和临床治疗提供参考。 Iu中心提出的中试和可行性临床试验是一项关于最小肝脏的研究 胆道闭锁所致肝硬变/门脉高压症患儿的脑病(MHE)一组 执行功能的神经认知测试和家长调查工具将用于评估儿童 与胆道闭锁相关的肝硬变。被诊断为MHE的儿童将参加一项临床试验 乳果糖治疗组作为自身对照，3个月后重复神经认知测试。 儿童数据将被用来开始检查这种情况的风险因素。该试验将生成数据 关于慢性肝病这一重要后遗症的频率，并指导未来的多中心研究 调查它的治疗方法。

PROJECT SUMMARY/ABSTRACT Pediatric liver disease has significant morbidity and mortality. Biliary atresia (BA) accounts for more than half of pediatric liver transplants. Genetic causes of neonatal cholestasis include Alagille's syndrome (ALGS), alpha-1 antitrypsin deficiency (A1AT), Progressive Familial Intrahepatic Cholestasis (PFIC), bile acid synthetic defects, mitochondrial hepatopathies, and cystic fibrosis (CF). All of these diseases can progress to cirrhosis. The goals of the ChiLDReN network are to follow large numbers of these subjects longitudinally to allow accumulation of clinical data and biospecimens for studies that can help diagnose, use biomarkers to prognosticate for, and treat these diseases. Translational research founded on this remarkable database and biorepository can result in new insights regarding pathogenesis, disease modifiers, and ultimately therapy. We propose to continue participation in the ChiLDReN Research Network; our center will recruit patients with ChiLDReN diseases aggressively, retain them for longitudinal follow-up, and contribute to ongoing studies. We will continue to actively participate in the IMAGINE clinical trial studying the effect of an intestinal bile-acid transport inhibitor on pruritus. We will continue to participate in the longitudinal FORCE study of transient elastography to monitor hepatic fibrosis in children with biliary atresia, A1AT, and ALGS. The CF studies will continue to evaluate the role of ultrasound in predicting the development of cirrhosis in children with CF (PUSH), the role of transient elastography (ELASTIC), and magnetic resonance elastography (MRE) to non-invasively monitor fibrosis progression, and the progression of cirrhosis in this disease. We will participate in the development and implementation of the Primary Sclerosing Cholangitis (PSC) study, beginning with a database study and progressing to a clinical trial. The ultimate goal of the network is to learn more about natural history and pathogenesis in order to inform therapy and clinical management of cholestatic diseases in children. The Pilot and Feasibility clinical trial proposed by the IU center is a study of Minimal Hepatic Encephalopathy (MHE) in children with cirrhosis/portal hypertension due to biliary atresia. A panel of neurocognitive tests of executive function and a parent survey instrument will be used to evaluate children with biliary atresia-related cirrhosis. Children who are diagnosed with MHE will participate in a clinical trial of lactulose therapy, acting as their own control, with repeat neurocognitive testing after 3 months. ChiLDReN data will be used to begin to examine risk factors for the condition. This pilot will generate data about the frequency of this important sequela of chronic liver disease and guide future multicenter studies investigating its treatment.