Search

Background and aims: Detection of early cholangiocarcinoma (CCA) in primary sclerosing cholangitis (PSC) is challenging. The aim of this study was to evaluate the diagnostic accuracy of a stepwise approach to biliary brush cytology with sequential use of fluorescence in‐situ hybridization (FISH) for the detection of biliary malignancy in PSC. Method: We retrospectively studied consecutive patients with PSC who underwent biliary brushings at Karolinska University Hospital between 2009 and 2015 (n = 208). Brush samples were categorized as benign, equivocal (atypical or suspicious) and malignant. Equivocal cases were further analysed with FISH. Samples with a malignant cytology or positive FISH were considered positive. The diagnosis was determined after 12 months of follow‐up. Results: The diagnosis CCA was confirmed in 15 patients (7%), high‐grade dysplasia in three patients, and low‐grade dysplasia in five patients at follow‐up. Using the diagnostic algorithm, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for a diagnosis of CCA were 80% (95%CI 52%‐96%), 96% (95%CI 92%‐98%), 60% (95%CI 36%‐81%) and 98% (95% CI 95%‐100%). In patients with equivocal cytology (n = 61), the sensitivity for CCA diagnosis increased to 100% (95%CI 72%‐100%) with a lower PPV of 58% (95%CI 34%‐78%). The diagnostic accuracy for detection of CCA in all patients was 95% (95%CI 91%‐97%). Conclusion: Biliary brush cytology with sequential use of FISH in equivocal cases seems to be a highly predictive diagnostic test for CCA in PSC. These results support the use of FISH when cytology is equivocal for detection of biliary malignancy in PSC. [ABSTRACT FROM AUTHOR]

Background and Aims: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel disease (IBD). However, there is limited overlap between IBD and PSC risk genes, but a stronger association between PSC and other autoimmune conditions. We aimed to assess the coexistence and familial association of autoimmune disorders in PSC, and the influence of autoimmune comorbidity on severe outcomes., Approach and Results: In a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives were evaluated. National registries provided data on diagnoses and outcomes (liver transplantation, hepatobiliary cancer, and liver-related death). The OR of autoimmune disease was estimated by logistic regression. The Fine and Gray competing risk regression estimated HRs for severe outcomes. The prevalence of non-IBD, non-autoimmune hepatitis, and autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77 (95% CI: 1.53-2.05). Highest odds were seen for celiac disease [OR: 4.36 (95% CI: 2.44-7.49)], sarcoidosis [OR: 2.74 (95% CI: 1.29-5.33)], diabetes type 1 [OR: 2.91 (95% CI: 2.05-4.05)], and autoimmune skin disease [OR: 2.15 (95% CI: 1.52-2.96)]. First-degree relatives of individuals with PSC had higher odds of developing IBD, autoimmune hepatitis, and any autoimmune disease than relatives of the comparators [OR: 3.25 (95% CI: 2.68-3.91); OR: 5.94 (95% CI: 2.82-12.02); OR: 1.34 (95% CI: 1.19-1.50)]. Autoimmune comorbidity in PSC was not associated with poorer outcomes [HR: 0.96 (95% CI: 0.71-1.28)]., Conclusions: Individuals with PSC and their first-degree relatives had higher odds of autoimmune disease compared to matched comparators. This finding provides validation for prior genetic discoveries at a phenotypic level. Autoimmune comorbidity did not impact severe outcomes., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: The duration of an endoscopic retrograde cholangiopancreatography (ERCP) is influenced by a multitude of factors. The aim of this study was to describe the factors influencing ERCP time and to create a tool for preintervention estimation of ERCP time., Methods: Data from 74 248 ERCPs performed from 2010 to 2019 were extracted from the Swedish National Quality Registry (GallRiks) to identify variables predictive for ERCP time using linear regression analyses and root mean squared error (RMSE) as a loss function. Ten variables were combined to create an estimation tool for ERCP duration. The tool was externally validated using 9472 ERCPs from 2020 to 2021., Results: Mean (SD) ERCP time was 36.8 (25.3) minutes. Indications with the strongest influence on ERCP time were primary sclerosing cholangitis and chronic pancreatitis. Hilar and intrahepatic biliary strictures and interventions on the pancreatic duct were the anatomic features that most strongly affected ERCP time. The procedure steps with most influence were intraductal endoscopy, lithotripsy, dilation, and papillectomy. Based on these results, we built and validated the SW: edish E: stimation of E: RCP T: ime (SWEET) tool, which is based on a 10-factor scoring system (e.g. 5 minutes for bile duct cannulation and 15 minutes for pancreatic duct cannulation) and predicted ERCP time with an average difference between actual and predicted duration of 17.5 minutes during external validation., Conclusions: Based on new insights into the factors affecting ERCP time, we created the SWEET tool, the first specific tool for preintervention estimation of ERCP time, which is easy-to-apply in everyday clinical practice, to guide efficient ERCP scheduling., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background & Aims: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival., Methods: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality., Results: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed., Conclusions: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Cholangiocarcinoma (CCA) is a malignancy arising from biliary epithelial cells of intra- and extrahepatic bile ducts with dismal prognosis and few nonsurgical treatments available. Despite recent success in the immunotherapy-based treatment of many tumor types, this has not been successfully translated to CCA. Mucosal-associated invariant T (MAIT) cells are cytotoxic innate-like T cells highly enriched in the human liver, where they are located in close proximity to the biliary epithelium. Here, we aimed to comprehensively characterize MAIT cells in intrahepatic (iCCA) and perihilar CCA (pCCA)., Approach and Results: Liver tissue from patients with CCA was used to study immune cells, including MAIT cells, in tumor-affected and surrounding tissue by immunohistochemistry, RNA-sequencing, and multicolor flow cytometry. The iCCA and pCCA tumor microenvironment was characterized by the presence of both cytotoxic T cells and high numbers of regulatory T cells. In contrast, MAIT cells were heterogenously lost from tumors compared to the surrounding liver tissue. This loss possibly occurred in response to increased bacterial burden within tumors. The residual intratumoral MAIT cell population exhibited phenotypic and transcriptomic alterations, but a preserved receptor repertoire for interaction with tumor cells. Finally, the high presence of MAIT cells in livers of iCCA patients predicted long-term survival in two independent cohorts and was associated with a favorable antitumor immune signature., Conclusions: MAIT cell tumor infiltration associates with favorable immunological fitness and predicts survival in CCA., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: Patients with liver cirrhosis have high mortality, often estimated by the Child-Pugh or MELD scores. Etiologies of cirrhosis are rapidly shifting, and it is unclear if these scores perform similarly across subgroups of patients. Here, we describe the characteristics and outcomes of a large contemporary cohort of patients with cirrhosis., Methods: This was a cohort study with retrospectively collected data. All patients with a verified diagnosis of cirrhosis during 2004-2017 at the Karolinska University Hospital, Sweden, were identified. Data at baseline to calculate Child-Pugh, MELD and confounders for mortality was collected. Competing risk regression was used to estimate risk for outcomes, adjusted for age, sex, baseline Child-Pugh score, etiology of cirrhosis and type 2 diabetes., Results: We identified 2609 patients, with a median age of 61 years, and 68% men. Etiologies of cirrhosis shifted during the study period, with a -29% relative decrease in hepatitis C-cirrhosis and a + 154% increase in cirrhosis due to non-alcoholic fatty liver disease. The highest overall mortality was seen in patients with alcohol-related cirrhosis. MELD and Child-Pugh scores predicted 3-month and 1 to 2-year mortality reasonably well, but with a lower predictive performance in alcohol-related cirrhosis. Men were more likely than women to receive a liver transplant (sHR = 1.39, 95%CI = 1.08-1.78)., Conclusions: We confirm previous findings of a rapid shift in the etiologies of cirrhosis. Differences in sex in regard to access to liver transplantation deserve further attention.

Background and Aims: Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC)., Approach and Results: We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%)., Conclusions: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: Detection of early cholangiocarcinoma (CCA) in primary sclerosing cholangitis (PSC) is challenging. The aim of this study was to evaluate the diagnostic accuracy of a stepwise approach to biliary brush cytology with sequential use of fluorescence in-situ hybridization (FISH) for the detection of biliary malignancy in PSC., Method: We retrospectively studied consecutive patients with PSC who underwent biliary brushings at Karolinska University Hospital between 2009 and 2015 (n = 208). Brush samples were categorized as benign, equivocal (atypical or suspicious) and malignant. Equivocal cases were further analysed with FISH. Samples with a malignant cytology or positive FISH were considered positive. The diagnosis was determined after 12 months of follow-up., Results: The diagnosis CCA was confirmed in 15 patients (7%), high-grade dysplasia in three patients, and low-grade dysplasia in five patients at follow-up. Using the diagnostic algorithm, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for a diagnosis of CCA were 80% (95%CI 52%-96%), 96% (95%CI 92%-98%), 60% (95%CI 36%-81%) and 98% (95% CI 95%-100%). In patients with equivocal cytology (n = 61), the sensitivity for CCA diagnosis increased to 100% (95%CI 72%-100%) with a lower PPV of 58% (95%CI 34%-78%). The diagnostic accuracy for detection of CCA in all patients was 95% (95%CI 91%-97%)., Conclusion: Biliary brush cytology with sequential use of FISH in equivocal cases seems to be a highly predictive diagnostic test for CCA in PSC. These results support the use of FISH when cytology is equivocal for detection of biliary malignancy in PSC., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary sclerosing cholangitis (PSC) is a severe chronic liver disease of the small and large bile ducts. The pathogenesis is unknown but a strong immune cell component has been suggested. Mucosal-associated invariant T (MAIT) cells are abundant in human liver and localize around bile ducts. Yet, the role of MAIT cells in PSC remains unclear. Here, we performed a detailed characterization of MAIT cells in circulation and assessed their presence in bile ducts of PSC patients as well as non-PSC controls. We observed a dramatic reduction in MAIT cell levels in PSC patients. High-dimensional phenotypical analysis using stochastic neighbor embedding revealed the MAIT cells to be activated, a phenotype shared by the investigated disease control groups. In line with the noted phenotypic alterations, MAIT cell function was reduced in response to Escherichia coli and to cytokine stimulation in PSC patients as compared to healthy controls. Using a novel sampling approach of human bile ducts, we found MAIT cells to be specifically enriched within bile ducts. Finally, distinct from the dramatic decline observed in circulation, PSC-patients had retained levels of MAIT cells within bile ducts. Altogether, our results provide a detailed insight into how the human MAIT cell compartment is affected in PSC., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)