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BackgroundUpdated 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.MethodsIn 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.ResultsThe 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.ConclusionThe 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., Funding Agencies|Karolinska Institute; ALF Grants, Region OEstergoetland; Lion Research Grant, Faculty of Medicine, Linkoeping University; Region Stockholm; Swedish Cancer Society; Swedish Research Council

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., Funding Agencies: Swedish Cancer Society; Stockholm County Council; Cancer Research Funds of Radiumhemmet

Background and aims: Chronic liver diseases affects approximately 844 million individuals and causes an estimated two million deaths per year. The most common causes are chronic viral hepatitis, alcohol-related liver disease and non-alcoholic fatty liver disease. With the availability of curative treatments and effective vaccines for viral hepatitis and increasing prevalence of metabolic syndrome-thel andscape of liver diseases is shifting. In this study, we aimed to describe the incidence and prevalence of a wide range of chronic liver diseases as well as their role in mortality in Sweden. Method: In this register-based, nationwide cohort study, aggregated statistics, stratified on categories of age, sex and geographic allocations, on all adult Swedish inhabitants with a diagnosis of liver disease during 2005 to 2019 were obtained from National registers. Results: During 2005 to 2019, there were substantial changes in the epidemiology of liver diseases in Sweden. The incidence of alcohol-related cirrhosis increased by 18% annually (incidence rate 13.1/100, 000 in 2019). The incidence rate of non-alcoholic fatty liver diseasea nd cirrhosis with unspecified etiology increased by 14% and 20% annually respectively (incidence rate 15.2 and 18.7/100, 000). Furthermore, incidence rates of chronic hepatitis C steeply declined, while autoimmune hepatitis increased (3.4/100, 000). In parallel with the increasing incidence of liver cirrhosis, liver malignancies have become more common. The most common causes of liver related mortality were alcohol-related disease without a code for cirrhosis, alcohol-related cirrhosis, and unspecified liver disease with mortality rates of 4.1, 2.9, and 2.8/100, 000. Most liver diseases were more frequent amongst men. Furthermore, varying differences was seen in the incidence ratebetween regions, with some etiologies (e.g. autoimmune liver diseases) being more common in rural areas. Conclusion: The incidence rates of non-alcoholic fatty liver

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.

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.

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.

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.