The Pittsburgh Cholestatic Liver Disease Consortium

描述（由申请人提供）： 新生儿胆汁淤积性肝病包括Alagille综合征、α-1抗胰蛋白酶缺乏症、胆汁酸合成缺陷、胆道闭锁、囊性纤维化、线粒体肝病和进行性家族性肝内胆汁淤积症，导致儿童期显著的发病率和死亡率，并且经常需要肝移植。没有一个美国临床中心看到足够多的患者患有这些疾病，以允许对未解决的问题，包括病因和发病机制，诊断和治疗的最佳方法，以及影响疾病严重程度和预后的因素作出严格的回答。来自匹兹堡儿童医院匹兹堡胆汁淤积性肝病联盟的这项竞争性更新提案旨在继续胆道闭锁研究联盟（BARC）和胆汁淤积性肝病联盟（CLiC）正在进行的研究活动，作为新成立的儿童肝病研究和教育网络（ChiLDREN）的一部分。这一更新资金的申请包括继续进行正在进行的研究工作的坚定承诺和两个新的建议，一个基于现有的研究基础设施，另一个是一个新的临床试验。卫生防护中心的临床中心包括一批杰出的临床医生， 在基础研究、转化研究和临床研究方面具有良好记录的专业知识的研究者。迄今为止，BARC和CLiC正在进行的研究的表现堪称典范，并充分利用了宾夕法尼亚州西部的人群基础以及CHP作为儿科肝病和肝移植四级中心的独特转诊模式。将对现有的BARC数据库进行分析，以评估胆汁流动不良的胆道闭锁儿童的临床病程。据推测，在这组患者中进行先发制人的肝移植将产生上级的总体结局。一项关于肠胆汁酸转运抑制剂治疗家族性肝内胆汁淤积1型疾病相关瘙痒症的随机试验也被提出。本试验的主要终点是瘙痒评分的变化，而次要结局将 包括血清和粪便胆汁酸变化。 相关性：损害肝脏分泌胆汁能力的婴儿疾病（例如胆道闭锁）是儿童期肝移植的主要指征。多中心的前瞻性调查是必不可少的，以改善健康的儿童患有这些疾病。匹兹堡儿童医院的匹兹堡胆汁淤积性肝病联盟非常适合参与这些前瞻性研究。

DESCRIPTION (provided by applicant): Neonatal cholestatic liver diseases including Alagille syndrome, alpha-1 antitrypsin deficiency, bile acid synthesis defects, biliary atresia, cystic fibrosis, mitochondrial hepatopathies and progressive familial intrahepatic cholestasis, lead to significant morbidity and mortality in childhood and frequently necessitate liver transplantation. No single United States clinical center sees a large enough number of patients with these disorders to permit a rigorous answer to unresolved questions including etiology and pathogenesis, optimal methods of diagnosis and treatment, and factors that influence disease severity and prognosis. This competitive renewal proposal from the Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh of UPMC seeks to continue ongoing research activities in the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Disease Consortium (CLiC) as part of a newly constituted Childhood Liver Disease Research and Education Network (ChiLDREN). This application for renewal funding includes a strong commitment to continuing the on-going research efforts and two new proposals, one based upon the existing research infrastructure, the other a novel clinical trial. The clinical center at CHP includes an outstanding group of clinician investigators with well-documented expertise in basic, translational and clinical investigation. Performance to date in the on-going studies of BARC and CLiC has been exemplary and has taken full advantage of the population base within Western Pennsylvania and the unique referral patterns to CHP as a quaternary center for Pediatric Hepatology and Liver Transplantation. The existing BARC database will be analyzed to assess the clinical course of children with biliary atresia who have poor bile flow. It is hypothesized that pre-emptive liver transplantation in this group of patients will yield superior overall outcome. A randomized trial of an inhibitor of intestinal bile acid transport in the management of pruritus associated with familial intrahepatic cholestasis 1 disease is also proposed. The primary end-point of this trial will be change in pruritus score, while secondary outcomes will include changes in serum and fecal bile acids. Relevance: Diseases in infants that impair the liver's ability to secrete bile (e.g. biliary atresia) are the leading indication for liver transplantation in childhood. Multi-centered prospective investigations are essential to improve the health of children afflicted by these disorders. The Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh is ideally suited to participate in these prospective investigations.