Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease that occurs in 1 in 1000 women above the age of 40 years. It is characterised by autoimmune destruction of the small, interlobular bile ducts. In patients with active disease, PBC may progress to end-stage liver disease with attendant need for liver transplantation (LT). PBC is therefore a leading indication for LT in Europe and North America.
The only medication licensed for treatment of PBC is ursodeoxycholic acid (UDCA), a hydrophilic bile acid. UDCA response is an important prognostic variable. Several groups have shown that survival in patients UDCA responders is comparable to that of the general population, whereas LT-free survival in UDCA non-responders is substantially reduced. In a recent study of 2,300 patients enrolled in the UK-PBC Research Cohort, we confirmed that UDCA response strongly predict prognosis. In our study, UDCA non-responders by the Paris I definition had a hazard ratio (HR) of 2.2 for LT or death from liver failure, compared to responders. We also found that younger age-at-presentation and male sex are independent risk factors for UDCA non-response – and therefore for progressive liver disease.
It is well-established that risk-stratification based on UDCA response is essential for management of PBC. However, there are no proven second-line therapies for UDCA non-responders at high risk of progressive liver disease. Furthermore, there are no data on the mechanisms involved in UDCA response that might guide development of second-line therapies. In addition, there are no robust measures to identify high-risk patients without 12 months of failed treatment.
The PBC Genetics Study
The PBC Genetics Study is an ongoing, UK-wide project that was initiated by Richard Sandford and Graeme Alexander in 2007 to establish a large, well-characterised PBC cohort for high-throughput genetic studies of PBC. The UK-PBC Consortium is a research collaboration consisting of 150 NHS Trusts or Health Boards in the UK. It was established as part of the PBC Genetics Study in order to recruit sufficient patients for well-powered genome-wide level genetic studies of PBC. The PBC Genetics Study is a portfolio study of the National Institute for Health Research (NIHR) Clinical Research Network (CRN), which means that recruitment across the UK is supported by Comprehensive Local Research Networks (CLRNs) in England and equivalent organizations in the devolved nations.
The UK-PBC Nested Cohort Study
The Nested Cohort Study is aimed at elucidating the mechanisms involved in UDCA response. This will facilitate the development of second-line therapies for high-risk patients and help to identify biomarkers for early and more-accurate stratification of patients based on their risk of disease progression and their treatment responsiveness.
The UK-PBC Project
The PBC Genetics Study and the UK-PBC Nested Cohort Study are now a fundamental part of the UK-PBC Project, which is an ambitious, all-encompassing project to understand the pathogenesis of PBC and to develop better treatments for the disease. Click here for more information.