Longitudinal Studies of Primary Biliary Cirrhosis

描述（由申请人提供）：本提案的广泛、长期目标是推进原发性胆汁性肝硬化（PBC）领域的临床、流行病学和转化研究。具体目标是：1)建立和维护一个公开的纵向临床数据库，用于PBC的研究，包括血清、胆汁、肝组织和DNA；2)利用这个知识库来确定疾病进展的最佳替代标记物。PBC是一种慢性进行性胆汁淤积性肝病，其中胆管是炎症损伤的目标。不幸的是，既没有确定这种疾病的病因，也没有确定防止最终进展为肝衰竭和死亡的治疗方法。由于缺乏疾病进展的合适替代标记物和该病的相对罕见性，这些领域的进展受到阻碍。初步数据表明，血清纤维化标志物可能是PBC中有用的替代标志物。本项目将利用在原发性胆汁性肝硬化熊二醇甲氨蝶呤/安慰剂研究（泵）中收集的标本和广泛的数据库来解决这些问题。该项目的健康相关性是本研究加速未来治疗试验和转化研究的能力，这些试验和转化研究需要确定有效的治疗方法和PBC的病因。一种有效的疾病进展替代标志物也可能对临床医生照顾PBC患者有用。研究设计和方法将包括分析泵数据库中几种不同的假定的疾病进展替代标志物。由于PBC患者死亡的替代标志物已经存在，因此本研究将重点关注能够检测PBC早期和/或中期进展的早期替代标志物。这将主要定义为预测门脉高压并发症未来发展的能力。纤维化、年龄、胆红素、白蛋白、凝血酶原时间、碱性磷酸酶、转氨酶和血小板计数的血清标志物将被输入一个逻辑模型，以得出一个特定的pbc算法。该算法以及其他先前发表的算法和不同的组织学分期方法将根据临床结果进行纵向分析。此外，将分析每个假定的替代标记物之间的相关性。该分析的结果将用于设计PBC领域的未来临床试验。

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to advance clinical, epidemiological, and translational research in the field of primary biliary cirrhosis (PBC). The specific aims are: 1) to establish and maintain a publicly available repository of longitudinal clinical data, serum, bile, liver tissue, and DNA for the study of PBC; and 2) to utilize this repository to identify the best surrogate marker of disease progression. PBC is a chronic progressive cholestatic liver disease in which the bile ducts are the target of inflammatory injury. Unfortunately, neither the etiology of this disease nor a treatment that prevents ultimate progression to liver failure and death has been identified. Progress in these areas has been hampered by the lack of a suitable surrogate marker of disease progression and the relative rarity of the disease. Preliminary data suggest that serum markers of fibrosis may be useful surrogate markers in PBC. This project will take advantage of the specimens and extensive database collected in the Primary Biliary Cirrhosis Ursodiol Methotrexate/Placebo Study (PUMPS) to address these problems. The health relatedness of the project is the ability of this study to expedite future treatment trials and translational studies that are needed to identify effective treatments and the etiology of PBC. An effective surrogate marker of disease progression might also be useful to clinicians taking care of patients with PBC. The research design and methods will include analysis of several different putative surrogate markers of disease progression within the PUMPS database. Because surrogate markers for death in PBC already exist, this study will focus on early surrogate markers that are able to detect progression during early and/or middle phases of PBC. This will be defined primarily as the ability to predict future development of portal hypertensive complications. Serum markers of fibrosis, age, bilirubin, albumin, prothrombin time, alkaline phosphatase, transaminases, and platelet count will be entered into a logistic model to derive a PBC-specific algorithm. This algorithm, as well as other previously published algorithms and different methodologies of histological staging will be analyzed longitudinally with respect to clinical outcomes. In addition, the correlation between each of the putative surrogate markers will be analyzed. The results of this analysis will then be used to design future clinical trials in the field of PBC.