Biliary strictures in primary sclerosing cholangitis : aspects on inflammation and malignancy

Sammanfattning: Primary sclerosing cholangitis (PSC) is a rare liver disease that is characterized by chronic inflammation of bile ducts with development of fibrosis and strictures. The pathogenic mechanisms involved in this disease are insufficiently understood. PSC is associated with a high risk of cholangiocarcinoma (CCA), lifetime prevalence is estimated to approximately 10%. Endoscopic retrograde cholangiopancreatography (ERCP) is a key method for diagnosing CCA and treating symptomatic bile duct strictures in PSC. In this thesis we have explored pathogenic and diagnostic aspects of biliary strictures in PSC with special focus on inflammation and malignancy. Specifically we aimed to evaluate (i) ERCP-related adverse events in PSC. (ii) Diagnostic methods for CCA in PSC. (iii) The role of mucosal associated invariant T-cells (MAIT cells) in PSC. In Paper I we investigated risk factors for ERCP-related adverse events using a nation-wide quality register (GallRiks). In a retrospective cohort of 8932 patients we found that the risk of adverse events was high in PSC patients and especially for pancreatitis and cholangitis. In Paper II we prospectively evaluated the feasibility, safety and diagnostic accuracy of single-operator cholangioscopy (SOC), a technique that allows visualization and targeted biopsies in the bile duct for detection of CCA. In a case-series of 47 PSC patients we showed that SOC could successfully be used in almost all patients (96%) and biopsies with sufficient material could be obtained from strictures in 95% of the cases. In a retrospective diagnostic study (Paper III), we evaluated the diagnostic accuracy of biliary brush cytology with stepwise use of fluorescence in-situ hybridization (FISH) for detection of CCA in PSC. This study included 208 PSC patients of whom 15 had CCA. We showed that this stepwise approach, with use of FISH in equivocal cytology cases, could correctly diagnose 95% of the patients. We also showed that sensitivity for detection CCA was higher (80%) than the expected using conventional cytology. In Paper IV we characterized circulating MAIT cells in blood in PSC and assessed their presence in bile ducts of PSC and non-PSC patients. We observed a reduction in levels of circulating MAIT cells in PSC patients compared to healthy controls, with remaining cells showing an activated phenotype with impaired function. These characteristics were also shared by patients with ulcerative colitis and primary biliary cholangitis. Using a novel approach to assess immune cells in bile ducts, we found MAIT cells to be specifically enriched within the biliary epithelium. Finally, we showed that PSC-patients had retained levels of MAIT cells within bile ducts. Taken together, our results provide insights into the clinical aspects of biliary strictures in PSC. We show that ERCP is associated with a high risk of procedure-related adverse events in PSC. Furthermore we found that SOC with targeted sampling can be utilized successfully in PSC. Also, that a stepwise use of FISH in biliary brush cytology has a high diagnostic accuracy for CCA in PSC. Finally, we give a detailed characterization of circulating MAIT cells in PSC and assessed their presence in the biliary epithelium.