Changes in beta-catenin expression and activation during progression of primary sclerosing cholangitis predict...

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts. We have previously demonstrated the importance of Wnt/β-catenin signaling in mouse models of PSC. In this study, we wished to determine the clinical relevance of β-catenin localization in patient samples. In livers explanted from patients diagnosed with PSC, the majority (12/16; 75%) lacked β-catenin protein expression. Biopsies from patients post-transplant were classified as recurrent or non-recurrent based on pathology reports and then scored for β-catenin activation as a function of immunohistochemical localization. Despite lack of statistical significance, patients with recurrent primary disease (n = 11) had a greater percentage of samples with nuclear, transcriptionally active β-catenin (average 58.8%) than those with no recurrence (n = 10; 40.53%), while non-recurrence is correlated with β-catenin staining at the cell surface (average 52.63% for non-recurrent vs. 27.34% for recurrent), as determined by three different methods of analysis. β-catenin score and years-to-endpoint are both strongly associated with recurrence status (p = 0.017 and p = 0.00063, respectively). Finally, there was significant association between higher β-catenin score and increased alkaline phosphatase, a marker of biliary injury and disease progression. Thus, β-catenin expression and activation changes during the progression of PSC, and its localization may be a useful prognostic tool for predicting recurrence of this disease.