Longitudinal Studies of Primary Biliary Cirrhosis

描述（由申请人提供）：该提案的广泛，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可用的纵向临床数据库，血清，胆汁，肝组织和DNA用于PBC的研究; 2）利用这个库来识别疾病进展的最佳替代标志物。PBC是一种慢性进行性胆汁淤积性肝病，其中胆管是炎性损伤的靶点。不幸的是，这种疾病的病因学和防止最终进展为肝功能衰竭和死亡的治疗方法都尚未确定。由于缺乏疾病进展的合适替代标志物以及疾病相对罕见，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有用的替代标志物。本项目将利用原发性胆汁性肝硬化熊去氧胆酸甲氨蝶呤/安慰剂研究（ARMPS）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快未来治疗试验和转化研究的能力，这些试验和转化研究是确定有效治疗方法和PBC病因所必需的。一个有效的疾病进展的替代标志物也可能是有用的临床医生照顾PBC患者。研究设计和方法将包括分析几个不同的假定的替代标志物的疾病进展的数据库中。由于PBC死亡的替代标志物已经存在，因此本研究将重点关注能够在PBC早期和/或中期检测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。将纤维化血清标志物、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输入logistic模型，以推导出PBC特异性算法。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纵向分析的临床结果。此外，还将分析每种推定替代标志物之间的相关性。分析结果将用于设计PBC领域未来的临床试验。

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.