BARC: BILLIARY ATRESIA STUDY IN INFANTS AND CHILDREN (BASIC)

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 一、假说 假设1：遗传缺陷可能是导致胆道闭锁(BA)儿童胆道闭锁和多发性先天性畸形的原因之一。 假设2：自身免疫因素可能有助于疾病的进展或获得性疾病，可以通过将患有BA的儿童与健康对照组的HLA进行关联，以及将那些出现早期并发症(包括静脉曲张出血、腹水和生长障碍)的儿童与没有发生这种疾病的儿童进行比较来确定。 假设3a：与儿科终末期肝病评分(PELD)相比，前哨事件(如静脉曲张出血、腹水和生长衰竭)是死亡或需要肝移植的早期预测因素。假设3b：与健康的年龄匹配的儿童相比，与健康相关的生活质量将受到损害，并与疾病的严重程度有关。假设3c：通过人体测量学和营养补充剂测量的生长障碍将预测在接下来的24个月中哨兵事件(腹水、静脉曲张出血、死亡和移植)的发生。 二、具体目标 引起胆道闭锁的因素或影响疾病进展的因素知之甚少。各种遗传、自身免疫和环境影响被认为是重要的。到目前为止，大多数研究都集中在患有BA的新生儿和幼儿身上，但患有BA的较大存活儿童可以提供关于遗传学和自然历史的重要信息。 这个数据库的目的是收集相关的临床信息、遗传物质和体液样本，以使研究人员能够解决上述假设和以下相关目标： 具体目的1.确定与BA的病因有关的基因 具体目的2.确定可能在疾病进展中起重要作用的基因多态性，如人类白细胞抗原(HLA)基因多态性。对胆道闭锁患者进行高分辨率的HLA-A、B、C、DRB1、DRB3、DRB4、DRB5、DQA1、DQB1、DPA1和DPB1基因分型。利用一种新的计算机算法来检测胆道闭锁患者的共享表位，该算法可以筛查大量的HLA等位基因。使用传统的等位基因频率分析和一种新的共享表位算法来评估人类白细胞抗原多态在胆道闭锁发生率和严重程度中的作用。 具体目标3.描述年龄较大、未移植的BA儿童的自然病史。 三、背景和意义 肝外胆道闭锁(BA)是婴儿期的一种破坏性疾病，在从肝门部肝炎到十二指肠的任何时间点，肝或胆总管都有闭塞或中断。如果不治疗，这种情况会导致严重的肝脏损伤和所有病例的死亡。1959年Kasai开发的肝门肠造口术只允许20%的受影响婴儿长期存活。肝脏替代疗法的出现使许多剩余婴儿得以长期存活，但并不是没有成本和发病率。 据估计，BA的发病率为每8,000名活产儿中有1名至18,000名活产儿中有1名。在美国，大约50%的儿童肝脏移植是为患有BA的婴儿进行的--构成了每年140-180例肝脏移植。尽管这种疾病具有破坏性，其治疗费用高昂，但我们对其发病机制和疾病进展所涉及的因素仍然知之甚少。BA很可能不是一种单一的疾病，而是几种潜在的特定疾病的表型，婴儿的肝脏以一种刻板的方式通过一系列复杂的过程做出反应，包括炎症、胆管增殖、细胞凋亡和纤维化。在我们更好地了解这些进程所涉及的机制之前，不会出现结果的改善。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. I. HYPOTHESIS Hypothesis 1: A genetic defect is a likely causative factor for biliary atresia (BA) among children with BA and multiple congenital anomalies. Hypothesis 2: Autoimmune factors are likely to contribute to disease progression or acquisition and can be identified by correlating HLA among children with BA to healthy controls and by comparison of those who develop early complications including, variceal bleed, ascites, and growth failure compared to those who do not. Hypothesis 3a: Sentinel events such as variceal bleeding, ascites and growth failure are earlier predictors of death or need for liver transplantation than the pediatric end-stage liver disease score (PELD). Hypothesis 3b: Health related quality of life will be impaired compared to healthy age matched children and relate to severity of illness. Hypothesis 3c: Growth failure as measured by anthropometrics and nutritional supplementation will be predictive of onset of sentinel events (ascites, variceal bleed, death, and transplant) in the following 24 months. II. SPECIFIC AIMS Little is known about the factors that cause biliary atresia nor the factors that influence disease progression. A variety of genetic, autoimmune and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics, as well as, natural history. The purpose of this database is to collect the pertinent clinical information, genetic material and body fluid samples to enable investigators to address the above hypotheses and the following related aims: Specific Aim 1. To identify the gene or genes implicated in the etiology of BA Specific Aim 2. To identify polymorphisms that may be important in disease progression such as HLA polymorphisms i.To perform high resolution HLA-A, B, C, DRB1, DRB3 DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 typing on patients with biliary atresia. ii.To utilize a novel computer algorithm that permits screening large numbers of HLA alleles to detect shared epitopes in patients with biliary atresia. iii.To assess the role of HLA polymorphism in incidence and severity of biliary atresia using traditional analysis of allele frequency and a novel shared epitope algorithm. Specific Aim 3. Characterize the natural history of the older, non-transplanted child with BA. III. BACKGROUND AND SIGNIFICANCE Extrahepatic biliary atresia (BA) is a devastating condition of infancy in which there is obliteration or discontinuity of the hepatic or common bile ducts at any point from the porta hepatitis to the duodenum. When untreated, the condition results in severe liver injury and death in all cases. The development of the hepatoportoenterostomy procedure in 1959 by Kasai has permitted long-term survival in only 20% of the affected infants. The advent of liver replacement therapy has permitted long-term survival in many of the remaining infants, but not without cost and morbidity. The estimated incidence of BA is 1 in 8,000 to 1 in 18,000 live births. Approximately 50 percent of all liver transplantations in children in the United States are for infants with BA-constituting 140-180 liver transplants per year. Despite the devastating nature of this illness and the high cost of its treatment, we still know very little about its pathogenesis nor the factors implicated in disease progression. It is likely that BA is not a single disease, but rather a phenotype of several underlying specific disorders to which the infant liver responds in a stereotypic manner by a complex series of processes, including inflammation, bile duct proliferation, apoptosis and fibrogenesis. Improvement in outcomes will not occur until we have a better understanding of the mechanisms involved in these processes.