The Swedish initiative for the study of Primary sclerosing cholangitis (SUPRIM).

Background: Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation. Methods: We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016). Findings: Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided. Interpretation: We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040. Funding: This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.

Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives.

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.

Incidence, prevalence and mortality of chronic liver diseases in Sweden between 2005 and 2019.

BACKGROUND: Updated data on the incidence, prevalence, and regional differences of chronic liver disease are missing from many countries. In this study, we aimed to describe time trends, incidence, prevalence, and mortality of a wide range of chronic liver diseases in Sweden. METHODS: In this register-based, nationwide observational study, patients with a register-based diagnosis of chronic liver disease, during 2005-2019, were retrieved from the Swedish National Board of Health and Welfare. Annual age-standardized incidence and mortality rates, and prevalence per 100,000 inhabitants was calculated and stratified on age, sex, and geographical region. RESULTS: The incidence of alcohol-related cirrhosis increased by 47% (2.6% annually), reaching an incidence rate of 13.1/100,000 inhabitants. The incidence rate of non-alcoholic fatty liver disease and unspecified liver cirrhosis increased by 217% and 87% (8.0 and 4.3% annually), respectively, reaching an incidence rate of 15.2 and 18.7/100,000 inhabitants, and a prevalence of 24.7 and 44.8/100,000 inhabitants. Furthermore, incidence rates of chronic hepatitis C declined steeply, but liver malignancies have become more common. The most common causes of liver-related mortality were alcohol-related liver disease and unspecified liver disease. CONCLUSION: The incidence rates of diagnosed non-alcoholic fatty liver disease, alcohol-related cirrhosis, unspecified liver cirrhosis, and liver malignancies have increased during the last 15 years. Worryingly, mortality in several liver diseases increased, likely reflecting increasing incidences of cirrhosis in spite of a decreasing rate of hepatitis C. Significant disparities exist across sex and geographical regions, which need to be considered when allocating healthcare resources.

Impact on follow-up strategies in patients with primary sclerosing cholangitis.

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.

Age trends in biliary tract cancer incidence by anatomical subtype: A Swedish cohort study.

AIM: Studies from Western countries suggest that early-onset biliary tract cancer, a rare malignancy originating from the bile ducts (cholangiocarcinoma) or gallbladder, is increasing. We performed a population-based cohort study to outline age trends in biliary tract cancer incidence in Sweden. METHODS: All patients with biliary tract cancer, excluding non-biliary chiefly hepatocellular histopathology, recorded in the Swedish Cancer Register in year 1993-2019 and at age 20-84 were included. Analyses were stratified by anatomical subtype; intrahepatic, gallbladder, perihilar, distal, and not specified. We analyzed absolute incidence rates by calendar period (1993-2001, 2002-2010, and 2011-2019) and annual percentage change (APC) including 95% confidence intervals (CI) across 1993-2019 for all ages and stratified into younger (20-54 years) and older (55-84 years) patients. RESULTS: Among 14,083 patients with biliary tract cancer, 1377 (9.8%) were younger. Gallbladder cancer incidence decreased (APC -2.82, 95% CI: -3.18--2.46), while intrahepatic cholangiocarcinoma increased (APC 1.74, 95% CI: 1.30-2.18), and the latter surpassed gallbladder as the most common subtype during the study period. While both intrahepatic and perihilar cholangiocarcinoma increased in both age groups, the rise was most prominent in younger adults, APC 3.01, 95% CI: 1.84-4.20 and 3.93, 95% CI: 2.08-5.81, respectively. CONCLUSION: Intrahepatic and perihilar cholangiocarcinoma are increasing in Sweden and more so younger adults. Further studies are needed to elucidate the underlying reasons behind the observed trends.

Mucosal-associated invariant T-cell tumor infiltration predicts long-term survival in cholangiocarcinoma.

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.

Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. APPROACH AND RESULTS: Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77-0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow-up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSC ≤ 12 patients, all positive for the biomarkers, included both early-stage and late-stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels. CONCLUSIONS: Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.

Increased risk of cancer in patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary and colorectal cancer, but the risks of other cancer forms have not been explored. The aim of this study was to evaluate the risk of intestinal and extraintestinal cancers in a large, well-defined cohort of PSC patients. MATERIAL AND METHOD: A matched cohort study of Swedish PSC patients was performed with up to ten comparators for each patient, matched for sex, age, and residency. The data were retrieved from national registers. Patients were followed from PSC diagnosis until cancer diagnosis, liver transplantation, first emigration date, death, or December 31, 2016. The risk of cancer was estimated using the Kaplan-Meier method and Cox regression models. RESULTS: In total, 1432 PSC patients with a verified diagnosis and 14,437 comparators were studied. The mean follow-up time was 15.9 years. Eighty-eight percent of the PSC patients had concomitant inflammatory bowel disease. PSC patients ran significantly increased risks of developing any cancer [HR 3.8, 95% confidence interval (CI) 3.3-4.3], hepatobiliary cancer (HR 120.9, 95% CI 72.0-203.1), colorectal cancer (HR 7.5, 95% CI 5.6-10.0), pancreatic cancer (HR 8.0, 95% CI 3.2-20.2), gastric cancer (HR 4.2, 95% CI 1.5-11.3), small bowel cancer (HR 21.1, 95% CI 3.5-128.2), and lymphoma (HR 3.0, 95% CI 1.6-5.7). PSC was not associated with a lower risk of any cancer form. CONCLUSIONS: PSC patients have a four times overall increased risk of developing cancer compared to the general population, with increased risk of developing hepatobiliary, colorectal, and pancreatic cancer, as well as lymphoma.

A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells.

The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103+CD69+ effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.

Etiologies and outcomes of cirrhosis in a large contemporary cohort.

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.

Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities.

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.

Association between temperature, sunlight hours and alcohol consumption.

BACKGROUND: Alcohol is a major risk factor for liver cirrhosis. Recently, it was proposed that colder climate might causally lead to increased consumption of alcohol. METHODS: We performed an ecologic study, using monthly updated data on mean temperature, sunlight hours and alcohol consumption from ten regions in Sweden, using publicly available data. A generalised additive model, adjusted for region, was applied to examine the association between mean temperature and mean sunlight hours with mean alcohol consumption. RESULTS: We found a non-linear inverse association between mean monthly temperature and mean alcohol consumption, suggesting that warmer temperature was associated with increased alcohol consumption and colder temperature with a decreased consumption. We found no association between mean sunlight hours and alcohol consumption. Consumption was highest during public holidays. CONCLUSIONS: We found no association between a colder climate and increased alcohol consumption. Socio-economic factors are likely to explain the suggested association.

Diagnostic performance of a stepwise cytological algorithm for biliary malignancy in primary sclerosing cholangitis.

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.

Primary sclerosing cholangitis leads to dysfunction and loss of MAIT cells.

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.

Epidemiology of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a cancer arising from the intra- or extrahepatic bile ducts and mainly characterized by its late diagnosis and fatal outcome. CCA is the second most common primary liver tumour and accounts for approximately 10-15% of all hepatobiliary malignancies. The development of CCA is linked to a wide spectrum of conditions causing biliary inflammation, cholestasis and inflammation of the liver. The geographic diversity of risk factors is reflected in considerable differences in incidence worldwide. Although data are not consistent, incidence seems to be rising in the Western World. Given the limited opportunities of treating advanced CCA, surveillance has been suggested as a strategy for detection of early disease in the high-risk group of patients with primary sclerosing cholangitis (PSC). In this review we present an updated overview of the epidemiology of CCA. We also highlight the risk of CCA in PSC with special focus on surveillance strategies.

Prospective evaluation of the clinical utility of single-operator peroral cholangioscopy in patients with primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: The role of cholangioscopy in primary sclerosing cholangitis (PSC) using a single-operator peroral cholangioscopy direct visualization system is unknown. This study aimed to prospectively evaluate the clinical utility of the system in PSC patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: Patients with PSC or suspicion of PSC and a clinical indication for ERCP were enrolled between September 2008 and May 2011. Patients underwent cholangioscopy with sampling from biliary strictures. Clinical data, technical information from the ERCP procedure, and results from sampling by brush cytology and mini-forceps biopsy were collected. Long-term follow-up was conducted. Outcomes included technical success, sampling adequacy, and diagnostic accuracy of cholangioscopy-guided sampling for detection of cholangiocarcinoma (CCA). RESULTS: A total of 47 patients with PSC were included in the study. Median follow-up time was 27 months (range 2 - 64 months). Technical success was achieved in 96 % (45/47). In 9 % (4/45), the target lesion could not have been reached without the cholangioscopic visualization of the bile duct, which enabled further advancement of the investigation. A total of 64 biliary strictures were evaluated. Sample quality was adequate in 98 % (62/63) of the cytology brushings and in 95 % (21/22) of the mini-forceps biopsies. Of the three patients with a final diagnosis of CCA, one was diagnosed at the time of the investigation. The sensitivity, specificity, accuracy, and negative predictive value were 33 %, 100 %, 96 %, and 95 %, respectively. CONCLUSION: Cholangioscopy and cholangioscopy-guided sampling can be utilized successfully in patients with PSC. Cholangioscopy enabled targeted biopsies to be taken and was able to pass otherwise inaccessible strictures, making it potentially valuable for the management of biliary strictures in patients with PSC. Trial registered at ClinicalTrials.gov (NCT01556555).

Primary sclerosing cholangitis increases the risk for pancreatitis after endoscopic retrograde cholangiopancreatography.

BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) have an increased risk for adverse events following endoscopic retrograde cholangiopancreatography (ERCP), mainly caused by bacterial cholangitis. The risk of pancreatitis is less examined. Therefore, our aim was to study adverse events following ERCP and to evaluate if PSC is a risk factor for pancreatitis. METHODS: Data were collected through a Swedish nationwide quality registry comprising fifty-one Swedish ERCP centres. The final study cohort consisted of 8932 adults who had undergone ERCP from 1 January 2007 to 31 December 2009. A total of 141 patients had PSC. Variables of importance for adverse events were entered into a multivariate logistic regression model for risk factor analysis. RESULTS: The following adverse events were increased in PSC as compared with non-PSC patients: overall (18.4% vs. 7.3%), pancreatitis (7.8% vs. 3.2%, P = 0.002), cholangitis (7.1% vs. 2.1%, P < 0.001) and per-operative extravasation of contrast (5.7% vs. 0.7%, P < 0.001). PSC was shown to be an independent risk factor for all of these adverse events: pancreatitis, OR 2.02 (95% CI, 1.04-3.92), cholangitis, OR 2.88 (95% CI, 1.47-5.65), and extravasation of contrast, OR 5.84 (95% CI, 2.24-15.23). CONCLUSION: The rate of adverse events overall following ERCP in PSC is 18% and PEP occurs in 8%. PSC is an independent risk factor for PEP and the risk is doubled. These findings underline the importance of a careful selection of PSC patients eligible for ERCP as well as a need for high competence of the treating team.

Distribution of intraportally implanted microspheres and fluorescent islets in mice.

The aim of the study was to evaluate the distribution of intraportally transplanted islets in mice. We initially administered 2000 polystyrene microspheres with a diameter of 50 microm intraportally into normoglycemic C57BL/6 mice. In separate experiments other mice were injected similarly with 300 microspheres each with a diameter of 100 or 200 microm. One week later the animals were killed, and the lungs and livers were removed and divided into lobes. The number of microspheres in each individual liver lobe and in the lungs was counted using a stereomicroscope. In other experiments, athymic C57BL/6 mice were similarly implanted with 250 islets isolated from transgenic mice expressing the enhanced yellow fluorescent protein in the islet cells. The distribution of microspheres and islets was independent of size, and fairly homogenous within the liver, with the exception of the caudate lobe, which contained fewer microspheres and islets, respectively. Approximately one third of all microspheres and islets were present as aggregates. Eighty-five to 90% of the implanted microspheres were identified in the liver sections, whereas 60-65% of the implanted islets were recovered. Aggregates or single fluorescent cells were observed in the liver of islet-implanted mice. We conclude that islets and microspheres implanted into the liver distribute fairly homogenously and quite a few of them exist as aggregates or, with respect to islets, as fragments.