Longitudinal Studies of Primary Biliary Cirrhosis

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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.