Abstract
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.
Highlights
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts
PSC is a biliary disease, and β-catenin is strongly positive in cholangiocytes as well as in other non-parenchymal cells, we focused on hepatocyte localization because the role of activated β-catenin in cholangiocytes is unknown, whereas β-catenin activation in hepatocytes plays a variety of critical functions in cholestatic liver disease, including regulating bile acid metabolism and hepatocyte proliferation
farnesoid X receptor (FXR) agonists, which decrease bile acid biosynthesis and increase transport, have been touted as potential treatments for cholestatic liver disease associated with accumulation of toxic b ile[20,21,22,23]
Summary
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts. 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. Elevated levels of alkaline phosphatase (ALP), a serum marker of biliary injury, are associated with greater risk of negative outcomes, such as liver transplantation and death[6]. Β-catenin is expressed throughout the adult liver, and can be found at the cell membrane, where it exists as a part of adherens junctions, as well as inside the cell, where it is normally degraded in the absence of Wnts Activation of this pathway occurs when Wnt protein binds to its receptor Frizzled and co-receptor low density lipoprotein–related protein 5 or 6 on the cell surface, resulting in a cascade of events that frees β-catenin from destruction, allowing it to accumulate in the cytoplasm and eventually translocate to the nucleus, where it activates target gene expression. In pathological conditions such as hepatocellular carcinoma (HCC), β-catenin can become constitutively activated and translocate to the nucleus irrespective of location within the hepatic lobule
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