Primary biliary cirrhosis (PBC) recurs in the allograft after liver transplantation. Study of early tissue changes in the time-course of disease recurrence provides a unique insight into the initial stages of the disease process, which, in nontransplant patients, occurs long before clinical presentation. We describe a patient who developed classical clinical, biochemical, immunological, and histological features of PBC within 9 months after transplantation. Use of tissue from this patient before and during the development of PBC allowed us to identify biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT) as a key pathogenetic process. BEC expression of S100A4 (an early fibroblast lineage marker established as a robust marker of EMT), vimentin, and pSmad 2/3 [a marker of transforming growth factor beta (TGF-β€) pathway signaling] were identified immunohistochemically in most BECs in liver tissue from this patient at the point of diagnosis of recurrent disease. BEC expression of S100A4 and pSmad 2/3 was seen as early as 24 days after orthotopic liver transplantation (OLT), although no other features of recurrent PBC were present at this time. Conclusion: S100A4, vimentin, and pSmad 2/3 expression in early recurrent PBC after OLT suggests that BEC EMT is occurring (potentially explaining BEC loss) and that this process is driven by TGF-β€. S100A4 expression by BEC appears to occur before the development of any other features of recurrent PBC, suggesting that EMT may be an initiating event. (HEPATOLOGY 2007;45:977-981.) See Editorial on Page 837.
P rimary biliary cirrhosis (PBC) is a chronic cholestatic condition of presumed autoimmune etiology 1,2 characterized by loss of the biliary epithelial cells (BECs) in small intrahepatic bile ducts and portal/ periportal fibrosis. The mechanisms of BEC loss and pro-gressive portal fibrosis remain unclear. Data suggest that apoptosis is an important mechanism for BEC loss in PBC, 3 but this is thought to predominate in the middle stages (II-III) of the disease and may be relatively infrequent in the earlier stages when BEC injury is at its height. 4 PBC has often been present in patients for many years before they present clinically. It therefore can be difficult to study the very earliest stages of disease pathogenesis when the key originating damage to BECs is occurring. One of the settings in which very early disease may be studied is in the context of recurrence after orthotopic liver transplantation (OLT). [5][6][7] We describe a patient who developed recurrent PBC within 9 months of transplantation. The study of tissue from this liver affected, by definition, by very early PBC provides us with important insights into a novel, potentially pathogenetic, mechanism that may predominate in very early PBC: epithelial-mesenchymal transition (EMT). 8
Methods
Diagnostic biopsy tissue blocks were obtained from the tissue archives of Newcastle upon Tyne Hospitals NHS Foundation Trust in accordance with local Ethics Com-