Biliary Atresia Clinical Research Consortium

描述（由申请人提供）： 胆道闭锁有两种类型。胚胎型或胎儿型通常与先天性畸形有关，表明损伤发生在产前。更常见的围产期类型通常出现在4-8周的生活。由于这种疾病发生在围产期的早期，因此必须考虑到遗传因素是因果关系或贡献。以前的数据是相互矛盾的;有胆道闭锁发生在家族和HLA同卵双胞胎中的病例报告，胆道闭锁不一致。在一项研究中，发现HLA-B12在胆道闭锁儿童中比预期更常见。HLA-Cw 4/7在胆道闭锁的儿童和原发性硬化性胆管炎的成人中也增加。然而，所有这些研究都受到受试者数量少和单中心研究的影响。胆道闭锁的病因机制仍然是个谜。通过分析一大群胆道闭锁和新生儿肝炎患儿的HLA类型，应加速确定这些疾病的遗传易感性。在美国，胆道闭锁仍然是小儿肝移植的主要适应症。最近，儿科肝病严重程度评分（PELD）被提出来改善需要肝移植的儿童的器官分配。PELD评分的主要局限性在于尚未进行前瞻性验证。然而，PELD评分仅基于几个可以客观评估且可重现的变量。没有一个中心有足够的胆道闭锁或新生儿肝炎患者来确定PELD评分是否可以前瞻性地预测结果。该提案汇集了加州州内的研究者和资源的独特联盟，并计划在胆道闭锁临床研究联盟中建立一个参与临床中心。我们的研究计划描述了一个大型多组分临床中心患者数据库的建立，该数据库将有助于拟议的多中心胆道闭锁临床研究联盟。其中包括大型大学医疗中心的三级护理转诊专科诊所和HMO患者人群。我们建议从这些来源中识别胆道闭锁和新生儿肝炎患者，以允许参与该联盟。其次，我们提出了两个研究方案，将使用胆道闭锁临床研究联盟探讨HLA类型和胆道闭锁之间可能的病因关系，并允许PELD评分的前瞻性评价。

DESCRIPTION (provided by applicant): Two forms of biliary atresia have been recognized. The embryonic or fetal type is often associated with congenital malformations suggesting the insult occurs prenatally. The more common perinatal type usually presents at 4-8 weeks of life. Because the disease occurs so early in the perinatal period, a genetic factor being causal or contributory must be considered. Previous data has been conflicting; there are case reports of biliary atresia occurring in families and HLA identical twins that are discordant for biliary atresia. In one study, HLA-B 12 was found more commonly then expected in children with biliary atresia. HLA-Cw4/7 has also been increased in children with biliary atresia and in adults with primary sclerosing cholangitis. However, all these studies suffer from the small number of subjects and single-center studies. The etiologic mechanism(s) for biliary atresia remain enigmatic. By analyzing HLA types in a large cohort of children with biliary atresia and neonatal hepatitis, determination of any genetic predisposition to these disorders should be accelerated. Biliary atresia remains the leading indication for pediatric liver transplantation in the United States. Recently, the Pediatric Liver Disease Severity Score (PELD) was proposed to improve organ allocation for children in need of liver transplants. The major limitation of the PELD score is that it has not been prospectively validated. However, the PELD score is based on only a few variables that can be objectively assessed and are reproducible. No individual center has sufficient patients with biliary atresia or neonatal hepatitis to ascertain whether the PELD score can predict outcomes prospectively. This proposal brings together a unique consortium of investigators and resources within the State of California with a plan for a participating Clinical Center in the Biliary Atresia Clinical Research Consortium. Our research plan describes the establishment of a large multicomponent Clinical Center patient database that would contribute to the proposed multicenter Biliary Atresia Clinical Research Consortium. These include tertiary care referral specialty clinics at a large university medical center and an HMO patient population. We propose to identify patients with biliary atresia and neonatal hepatitis from these sources, to allow participation in the Consortium. Secondly, we propose two research protocols that would use the Biliary Atresia Clinical Research Consortium to explore a possible etiologic relationship between HLA type and biliary atresia and allow a prospective evaluation of the PELD score.