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Abstract Details
The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis
Hepatology. 2021 Jun 15. doi: 10.1002/hep.32011. Online ahead of print.
Ben Barron-Millar1, Laura Ogle1, George Mells2, Steven Flack2, Jonathan Badrock2, Richard Sandford2, John Kirby1, Jeremy Palmer1, Laura Jopson1, John Brain1, Graham R Smith3, Steve Rushton4, Vinod S Hegade5, Rebecca Jones5, Simon Rushbrook6, Douglas Thorburn7, Steve Ryder8, Gideon Hirschfield910, UK-PBC Research Consortium; Jessica K Dyson111, David Jones111
Author information
1Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.
2Dept of Human Genetics, University of Cambridge, Cambridge, UK.
3Bioinformatics Support Unit (BSU), Newcastle University, Newcastle-upon-Tyne, UK.
4School of Natural and Environmental Science, Newcastle University, Newcastle-upon-Tyne, UK.
5Liver Unit, St James' Hospital, Leeds, UK.
6Norfolk and Norwich University Hospital, Norwich, UK.
7Liver Unit, Royal Free Hospital, London, UK.
8Queen's Medical Centre, Nottingham, UK.
9Queen Elizabeth Hospital, Birmingham, UK.
10Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada.
11Freeman Hospital, Newcastle-upon-Tyne, UK.
Abstract
Background and aims: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in non-responders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for non-response to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA non-response in PBC and to identify markers to enhance treatment.
Approach and results: Discovery serum proteomics (O-link) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n=68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n=416 treated patients). 19 proteins remained at a significant expression level (defined using stringent criteria) in UDCA treated patients, 6 of them representing a tightly-linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BEC) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and non-responders in both the discovery and validation cohorts. A linear discriminant analysis using serum levels of CXCL11 and CCL20 as markers of responder status indicated a high level of discrimination with an area under the curve of 0.91 (CI 0.83-0.91).
Conclusions: UDCA under-response in PBC is characterised by elevation of serum chemokines potentially related to cellular senescence and previously shown to be released by biliary epithelial cells in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease and their clinical utility as biomarkers should be evaluated further in prospective studies.