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Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.

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.

Background and aims Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine–tryptophanratio (KT-ratio) in PSC. Methods Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. Results Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50–0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23–0.42) in all cohorts. Conclusions Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts. publishedVersion

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.

Contains fulltext : 245473.pdf (Publisher’s version ) (Open Access) BACKGROUND: Resection for perihilar cholangiocarcinoma (pCCA) in primary sclerosing cholangitis (PSC) has been reported to lead to worse outcomes than resection for non-PSC pCCA. The aim of this study was to compare prognostic factors and outcomes after resection in patients with PSC-associated pCCA and non-PSC pCCA. METHODS: The international retrospective cohort comprised patients resected for pCCA from 21 centres (2000-2020). Patients operated with hepatobiliary resection, with pCCA verified by histology and with data on PSC status, were included. The primary outcome was overall survival. Secondary outcomes were disease-free survival and postoperative complications. RESULTS: Of 1128 pCCA patients, 34 (3.0%) had underlying PSC. Median overall survival after resection was 33 months for PSC patients and 29 months for non-PSC patients (p = .630). Complications (Clavien-Dindo grade ≥ 3) were more frequent in PSC pCCA (71% versus 44%, p = .003). The rate of posthepatectomy liver failure (21% versus 17%, p = .530) and 90-day mortality (12% versus 13%, p = 1.000) was similar for PSC and non-PSC patients. CONCLUSION: Median overall survival after resection for pCCA was similar in patients with underlying PSC and non-PSC patients. Complications were more frequent after resection for PSC-associated pCCA, with no difference in postoperative mortality.

Background & Aims: Magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis and follow-up of individuals with primary sclerosing cholangitis (PSC). The aim of our study is to develop an MRCP-score based on chol-angiographic findings previously associated with outcomes and assess its reproducibility and prognostic value in PSC. Methods: The score (DiStrict score) was developed based on the extent and severity of cholangiographic changes of intra-hepatic and extrahepatic bile ducts (range 0-8) on 3D-MRCP. In this retrospective, multicentre study, three pairs of radiol-ogists with different levels of expertise from three tertiary centres applied the score independently. MRCP examinations of 220 consecutive individuals with PSC from a prospectively collected PSC-cohort, with median follow-up of 7.4 years, were reviewed. Inter-reader and intrareader agreements were assessed via intraclass correlation coefficient (ICC). After consensus, the prognostic value of the score was assessed using Cox-regression and outcome-free survival rates were assessed via Kaplan-Meier estimates. Harrell's C-statistic was calculated. Results: Forty patients developed outcomes (liver transplantation or liver-related death). Inter-reader agreement between experienced radiologists was good (ICC 0.82; 95% CI 0.74-0.87, and ICC 0.81; 95% CI 0.70-0.87, respectively) and better than the agreement for the pair of experienced/less-experienced radiologists (ICC 0.48; 95% CI 0.05-0.72). Agreement between radiologists from the three centres was good (ICC 0.76; 95% CI 0.57-0.89). Intrareader agreement was good to excellent (ICC 0.85-0.93). Harrell's C was 0.78. Patients with a DiStrict score of 5-8 had 8.2-fold higher risk (hazard ratio 8.2; 95% CI 2.97-22.65) of developing outcomes, and significantly worse survival (p

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.

Purpose ANALI-scores are two prognostic magnetic resonance imaging (MRI)-based scores developed for patients with primary sclerosing cholangitis (PSC). Our study aims to assess the interreader agreement between expert radiologists of the two ANALI-scores and of the radiological parameters they utilize, and to test the prognostic performance of the scores in our population. Method Three radiologists evaluated MRIs of 98 PSC-patients from a prospectively collected cohort with median follow-up of 6.7 years. Each parameter of ANALI-scores was assessed, and the scores were calculated. Interreader agreement was assessed with intraclass correlation coefficient (ICC). After consensus reading was reached, the prognostic value of ANALI-scores was assessed with Cox regression, and outcome-free survival rates were evaluated with Kaplan-Meier estimates. Results The ANALI-score without gadolinium had poor to moderate (ICC = 0.56, 95 %CI: 0.42–0.68) and with gadolinium poor (ICC = 0.30, 95 %CI: 0.16–0.44) agreement. Liver deformity (ICC = 0.28, 95 %CI: 0.13–0.44) and parenchymal enhancement heterogeneity (ICC = 0.24, 95 %CI: 0.12–0.38) had poor agreement. Portal hypertension had poor to moderate (ICC = 0.48, 95 %CI: 0.36–0.59) and dilatation of the intrahepatic ducts had moderate (ICC = 0.64, 95 %CI: 0.54–0.73) agreement. Hazard ratios for liver-related death, transplantation or cirrhosis decompensation of the ANALI-scores with and without gadolinium were 3.53 (95 %CI: 1.40–8.93) and 2.25 (95 %CI: 1.56–3.24), respectively. Outcome-free survival was better for patients with low ANALI-scores. Conclusions The ANALI-scores show poor to moderate agreement, which challenges their usefulness in clinical practice. They are associated with clinical outcomes, confirming the value of imaging in prognosis of PSC, but need further multicenter evaluation.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in SEMA4D, encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon-γ (IFN-γ) production after stimulation. Homologous mutation knock-in mice developed similar IFN-γ impairment in T cells and were more prone to develop severe cholangitis when exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Transfer of wild-type T cells to knock-in mice before and during DDC exposure attenuated cholangitis. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects. Our findings suggest a protective role for T cells in PSC that might be used therapeutically.

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 asTP53(35.5%),KRAS(28.0%),CDKN2A(14.5%), andSMAD4(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.

Objectives: Interpretation of MRI/MRCP in primary sclerosing cholangitis (PSC) at a single time point has low inter-reader agreement. Agreement of interpretation of the dynamic course of du...

Background: Despite the close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the association between colectomy and the prognosis of PSC remains cont ...

Background: Patients with primary sclerosing cholangitis (PSC) have increased risk of cholangiocarcinoma (CCA). We evaluated pre-transplant work-up in PSC patients, to search for the most effective strategy for the detection of biliary dysplasia or early CCA. Methods: Two hundred and twenty five consecutive PSC patients undergoing liver transplantation (LTx) in Sweden between 1999 and 2013 were studied. Patients with CCA or dysplasia in the explanted liver were compared with those with benign histopathology. Measures of test performance were calculated for patients having brush cytology on one endoscopic retrograde cholangiopancreaticography (ERCP) occasion, for those having repeated examinations with or without cholangioscopy, and for fluorescence in situ hybridization (FISH). Survival after LTx was analyzed. Results: Brush cytology on a single ERCP occasion had moderate sensitivity (57%) and high specificity (94%) for the detection of CCA/high grade dysplasia (HGD) in the explanted liver. The corresponding sensitivity and specificity for FISH were 84% and 90%, respectively. Utilizing repeated ERCP and brush cytology to confirm the initial finding improved sensitivity to 82%. Using single operator cholangioscopy (SOC) for targeted examination at the second ERCP improved sensitivity (100%) and specificity (97%) significantly. Mortality rate in patients with incidentally discovered CCA (n = 16) in the explanted liver was significantly higher than in patients with HGD or benign histopathology (HR 16.0; 95% CI, 5.6–45.4; p Conclusions: Repeated brush cytology especially when combined with targeted examination under SOC guidance is superior to single brush examinations. This strategy improves the detection of malignancy in PSC and is of importance for selection of patients for LTx.

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; similar to 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r(G)) between PSC and ulcerative colitis (UC) (r(G) = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r(G) = 0.04) (P = 2.55 x 10(-15)). UC and CD were genetically more similar to each other (r(G) = 0.56) than either was to PSC (P

Background & Aims: Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. Methods: We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. Results: Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P =.035). Factors associated with lower ALP were normal ALP at baseline (P

Purpose First, to evaluate and describe the clinical and MRI progression of patients with small duct primary sclerosing cholangitis (sdPSC), and second, to look for MRI features associated with disease progression to large duct PSC. Method 16 patients (7 female, 9 male; median age 27 years) with diagnosis of sdPSC and available MR imaging were included in this retrospective dual-center study. Liver function tests (LFTs) and imaging was reviewed in consensus by two radiologists at baseline and follow-up, and compared by means of non-parametric tests, with p Results At baseline and follow-up patients had a cholestatic liver profile with elevated LFTs. Progressive liver deformity, heterogeneous enhancement and hilar lymphadenopathy were common findings. In 9 patients follow-up MRI was available with a mean interval between imaging of 10.6 years (range 3.6−15.3 years). 5 patients (55.5 %) developed cholangiographic changes diagnostic of large duct PSC. No correlation was observed between MRI findings or LFTs at baseline and the endpoint of developing PSC typical cholangiographic changes at follow-up imaging (p > 0.05). Conclusions More than half of sdPSC patients developed cholangiographic changes, supporting that sdPSC may be an early stage of large duct PSC rather than an entity of its own. Larger studies are needed to address the value of MRI for prediction of sdPSC disease progression.

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 (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.

Background Studies on surgical procedures in patients with concomitant primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have mainly been restricted to single centers. The aim was to compare surgical treatment of UC with or without PSC in a nationwide study. Methods A cohort study including all patients diagnosed with UC between 1987 and 2014 in Sweden was undertaken. The impact of PSC on the risk of colectomy, the chance of restorative surgery, and risk of failure (presence of a stoma) following restorative surgery were estimated. Survival analyses were performed using the Kaplan-Meier method and multivariable Cox regression models. Results Of 49 882 UC patients, 2079 had a PSC diagnosis at the end of follow-up. The risk of colectomy was unaffected by PSC diagnosis, whereas the chance of restorative surgery was elevated in PSC-UC patients (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.02-1.44). Ileorectal anastomosis (IRA) was performed in 63% of the PSC-UC patients and 43% of the non-PSC-UC-patients, and the corresponding numbers for ileal pouch anal anastomosis (IPAA) were 35% and 53%. There was no significantly increased risk of failure following restorative surgery in PSC patients (HR, 1.44; 95% CI, 0.93-2.22). In PSC-UC patients, the cumulative failure rates following an IRA at 3 and 5 years were 15% and 18%, and following an IPAA they were 11% and 18%, respectively. Conclusions Presence of PSC is not associated with the risk of colectomy, whereas the chance of restorative surgery in PSC-UC patients is higher than in UC alone.

The risk for recurrent primary sclerosing cholangitis (rPSC) after liver transplantation is associated with inflammatory bowel disease (IBD). We assessed the frequency of rPSC and studied risk factors for recurrent disease with special focus on IBD. We also evaluated the importance of rPSC for prognosis.All liver transplanted PSC patients in the Nordic countries between 1984 and 2007 (n = 440), identified by the Nordic Liver Transplant Registry, were studied. Data were retrieved from patients' chart reviews. Multivariable Cox regression models were used to calculate risk factors for rPSC and death.Of the 440 patients with a follow-up time after liver transplantation of 3743 patient years, rPSC was diagnosed in 19% (n = 85). Colectomy before liver transplantation was associated with a reduced risk of rPSC (HR 0.49; 95% CI, 0.26-0.94, p = 0.033). Neither high IBD activity nor presence of IBD flares before or after liver transplantation was associated with rPSC. Treatment with tacrolimus was an independent risk factor associated with increased risk for rPSC (HR, 1.81; 95% CI, 1.15-2.86, p = 0.010). The risk of dying or needing a re-transplantation after rPSC was increased in all age groups, but highest in patients transplanted before 40 years of age (HR 7.3; 95% CI, 4.1-12.8, p = 0.0001).This study confirms that colectomy before liver transplantation is associated with a decreased risk of rPSC. Inflammatory activity of IBD was not associated with the risk of rPSC. Tacrolimus was an independent risk factor for PSC recurrence and its use as first line immunosuppression in PSC needs further study.

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013.MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report.RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively.CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Epidemiological studies of autoimmune hepatitis (AIH) show varying figures on prevalence and incidence, and data on the long-term prognosis are scarce. Objective To investigate the epidemiology, long-term prognosis and causes of death in a Swedish AIH cohort.Data collected from 634 AIH patients were matched to the Cause of Death Registry, and survival analyses were made. Prevalence and incidence were calculated for university hospitals with full coverage of cases and compared to the County of Västerbotten in Northern Sweden.AIH point prevalence was 17.3/100,000 inhabitants in 2009, and the yearly incidence 1990-2009 was 1.2/100,000 inhabitants and year. The time between diagnosis and end of follow-up, liver transplantation or death was in median 11.3 years (range 0-51.5 years). Men were diagnosed earlier (p .001) and died younger than women (p = .002). No gender differences were found concerning transplant-free, overall survival and liver-related death. Cirrhosis at diagnosis was linked to an inferior survival (p .001). Liver-related death was the most common cause of death (32.7%). The relative survival started to diverge from the general population 4 years after diagnosis but a distinct decline was not observed until after more than 10 years.Long-term survival was reduced in patients with AIH. No gender difference regarding prognosis was seen but men died younger, probably as a result of earlier onset of disease. Cirrhosis at diagnosis was a risk factor for poor prognosis and the overall risk of liver-related death was increased.

Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease that if left untreated may lead to the development of cirrhosis. Previous studies on AIH patients have suggested that fibrosis and even cirrhosis can be reversed by medical treatment. The aim of this study was to evaluate the efficacy of medical treatment for protection of developing fibrosis and cirrhosis. A total of 258 liver biopsies from 101 patients (72 women, 29 men) were analyzed by a single pathologist and classified according to the Ishak grading (inflammation) and staging (fibrosis) system. Liver histology was stratified according to the temporal changes of fibrosis stage (increased, decreased, or stable), and groups were compared. Complete or partial response to medical treatment was 94.9%. Reduction of fibrosis stage from the first to the last biopsy was seen in 63 patients (62.4%). We found an association between a reduction in the fibrosis stage and continuous glucocorticoid medication, as well as lowered scores of inflammation at last biopsy. Twenty-one patients had cirrhosis (Ishak stage 6) at least in one of the previous biopsies, but only 5 patients at the last biopsy. Histological improvement is common in AIH patients that respond to medical treatment, and a reduction or stabilization of fibrosis stage occurs in about 2/3 of such patients. Funding Agencies|Albireo, Gothenburg, Sweden; Intercept, San Diego, CA, USA; Bengt Ihres fund; Vasterbotten County, Umea University Hospital

Background & Aims Primary sclerosing cholangitis (PSC) is associated with increased mortality. Cardiovascular disease is a leading cause of death in the Western world. We examined the risk of cardiovascular disease and diabetes (type 1 and type 2) in patients with PSC and their first-degree relatives. Methods This prospective multicentre cohort study included 678 individuals with PSC diagnosed between 1970 and 2004, and 6347 non-PSC reference individuals matched for age, and sex. Through linkage of the Swedish Multigeneration Register we identified 3139 first-degree relatives to PSC patients and 30,953 first-degree relatives to the matched comparison cohort. We retrieved data on cardiovascular disease and type 1 and type 2 diabetes (T1D and T2D) from the National Patient Register, and then examined the association with PSC or having a family history of PSC using Poisson regression. Results During 125,127 person-years of follow-up, 203 individuals with PSC had a diagnosis of cardiovascular disease. This corresponded to a 3.34-fold increased relative risk (RR) of cardiovascular disease in individuals with PSC (95% CI=2.86–3.91). The highest risk estimates were seen for diseases of the arteries, veins, and lymphatic vessels while the RR was neutral for ischemic heart disease (0.90) or only slightly elevated for cerebrovascular disease (1.74). Meanwhile, PSC first-degree relatives were at no increased risk of cardiovascular disease (RR=0.87; 95% CI=0.80–0.95). Individuals with PSC (RR=7.95; 95% CI=4.82–13.12), and to some extent also their first-degree relatives (RR=1.73; 95% CI=1.19–2.52) were at increased risk of T1D. Also for T2D were the RR is higher in individuals with PSC (RR=2.54; 95% CI=1.56–4.13) than in PSC first-degree relatives (RR=0.81; 95% CI=0.65–1.02). Conclusions PSC was associated with T1D, T2D, and non-ischemic cardiovascular disease. In contrast, first-degree relatives to PSC patients were only at a moderately increased risk of T1D, and at no increased risk of either cardiovascular disease or T2D.

Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44(-) ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment

Background & Aims There is increasing evidence that statins can benefit patients with chronic liver diseases, but their effects have not been studied in patients with primary sclerosing cholangitis (PSC). We performed a nationwide study in Sweden to determine the effects of exposure to drugs, including statins, in patients with PSC. Methods We studied a population-based cohort of patients in Sweden with PSC and concomitant ulcerative colitis or Crohn’s disease from 2005 through 2014 (n = 2914), followed through 2016. We collected analyzed data from the patient register, the prescribed drug register, the death certificate register and the cancer register. We calculated risk or death, liver transplantation, bleeding of esophageal varices, and cancer in relation to drug exposure. Results The mean age of patients at the time of diagnosis with PSC was 41.4 years (inter-quartile range [IQR], 25.6–56.1 years). The total follow-up time was 11769 person-years, during which 3.4% of patients received liver transplants and 19.9% died. Proportions of patients exposed to drugs were: ursodeoxycholic acid, 60.2%; 5-aminosalicylic acid, 74.4%; azathioprine or mercaptopurins, 33.7%; and statins, 13.9%. Statin use was associated with a reduced risk of all-cause mortality (hazard ratio [HR], 0.68; 95% CI, 0.54–0.88) and death or liver transplantation (HR, 0.50; 95% CI, 0.28–0.66). Use of azathioprine was also associated with reduced mortality (HR, 0.66; 95% CI, 0.52–0.84) and risk of death or liver transplantation (HR, 0.65; 95% CI, 0.50–0.83). Exposure to ursodeoxycholic acid did not affect mortality (HR, 1.04; 95% CI, 0.87–1.25). Conclusion In a population-based cohort of patients in Sweden with PSC, we associated use of statins and azathioprine with decreased risks of death and death or liver transplantation. Exposure to ursodeoxycholic acid was not associated with reduced mortality.

Purpose To evaluate dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) for the assessment of global and segmental liver volume and function in patients with primary sclerosing cholangitis (PSC), and to explore the heterogeneous distribution of liver function in this patient group. Materials and Methods Twelve patients with primary sclerosing cholangitis (PSC) and 20 healthy volunteers were examined using DHCE-MRI with Gd-EOB-DTPA. Segmental and total liver volume were calculated, and functional parameters (hepatic extraction fraction [HEF], input relative blood-flow [irBF], and mean transit time [MTT]) were calculated in each liver voxel using deconvolutional analysis. In each study subject, and incongruence score (IS) was constructed to describe the mismatch between segmental function and volume. Among patients, the liver function parameters were correlated to bile duct obstruction and to established scoring models for liver disease. Results Liver function was significantly more heterogeneously distributed in the patient group (IS 1.0 versus 0.4). There were significant correlations between biliary obstruction and segmental functional parameters (HEF rho −0.24; irBF rho −0.45), and the Mayo risk score correlated significantly with the total liver extraction capacity of Gd-EOB-DTPA (rho −0.85). Conclusion The study demonstrates a new method to quantify total and segmental liver function using DHCE-MRI in patients with PSC. J. Magn. Reson. Imaging 2014;39:879–886. © 2013 Wiley Periodicals, Inc.

The international normalized ratio (INR) is used to prioritize liver disease patients for transplantation. Previous studies have shown high interlaboratory variability in Quick-based INR determinations in samples of patients with liver disease. We assessed Owren-based INR reagents for analyzing INR in patients with liver disease. Further, we determined the difference between international sensitivity index (ISI) for patients on vitamin K antagonists (ISIVKA) and ISI for patients with liver disease (ISIliver).Twenty patients with liver disease were included, 10 with INR 1.8-3.6 (group A1) and 10 with INR 1.2-1.5 (group C1). Plasma from these patients was analyzed for Owren-based INR in eight Swedish laboratories using either of following reagents: SPA+, Owrens PT or Nycotest PT. To determine ISI liver, the reference thromboplastin RBT/05 and additional 41 patients with liver disease and 20 normal controls were included. ISIVKA was determined according to the WHO procedure. The difference between the ISIVKA and ISIliver was calculated.The coefficients of variance for the Owren based INR methods were 6.2% in group A1, 3.9 % in group C1 and 5.3% for all patients. The difference between ISIVKA and ISIliver were -0.4%, -0.7% and -0.2% for SPA+, Owrens PT and Nycotest PT respectively.Interlaboratory variation in INR analyses according to Owren in patients with liver disease is low and the difference between ISIVKA and ISIliver is below 10% with this method. ISIVKA can therefore be used in the INR calibration, for the Owren reagents studied, when analyzing plasma from patients with liver disease.

Background & Aims Ursodeoxycholic acid (UDCA) has not been shown to stop progression of primary sclerosing cholangitis (PSC). However, patients with primary biliary cirrhosis treated with UDCA whose levels of alkaline phosphatase (ALP) decrease have longer survival times than patients whose levels do not decrease. We compared survival times between patients with PSC treated with UDCA or placebo, with and without decreased levels of ALP. Methods We collected data from patients enrolled in the Scandinavian PSC UDCA trial. Patients were randomly assigned to groups given UDCA (17–23 mg/kg/day, n=97) or placebo (n = 101) from 1996–2001 and were followed until 2010. End points were death, liver transplantation, or cholangiocarcinoma. They were considered to be biochemical responders if they had serum levels of ALP that were normal or reduced by ≥40% after 1 year in the trial (regardless of whether they received UDCA or placebo). Numbers of patients surviving until the study end point were compared by using the Kaplan–Meier method. Results There were no differences in survival at the end of the study between patients given UDCA or placebo ( P = .774, log-rank); 26 patients in the UDCA group and 29 in the placebo group reached an end point. On the basis of ALP levels, there were 79 responders and 116 nonresponders overall. Of patients given UDCA, significantly more biochemical responders survived for 10 years than nonresponders ( P = .03, log-rank). However, differences remained significant regardless of group assignment; overall, patients with reductions in ALP level survived longer than patients without reductions in ALP ( P = .0001, log-rank). Conclusions There is no significant difference in long-term survival between patients with PSC given UDCA (17–23 mg/kg/day) or placebo for 5 years. However, patients who have reduced or normal levels of ALP have longer survival times, regardless of whether they receive UDCA or placebo.

Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 x 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 x 10(-8), OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2013;58:1074-1083)

Background and study aims: Primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD) is characterized by a high risk of colorectal dysplasia. Surveillance colonoscopies with random biopsies have doubtful power for dysplasia detection. Our aim was to prospectively investigate the feasibility and efficacy of pCLE in surveillance colonoscopies in patients with PSC-IBD. Patients and methods: Sixty-nine patients with PSC-IBD underwent colonoscopy in 2 steps. On the way from rectum to cecum, the mucosa was inspected with high definition endoscopy (HDE) and random biopsies were taken according to the standard routine. On the way from cecum to rectum, fluorescein-enhanced pCLE and chromoendoscopy were performed. Regions where random biopsies had been taken, as well as visible lesions, were examined with pCLE and targeted biopsies were taken of lesions suspicious for dysplasia. Two investigators, blinded to histology and endoscopy results, analyzed all pCLE videos off-line. Results: Nineteen biopsies obtained in 13 patients (17 targeted biopsies, 2 random biopsies) revealed the presence of low-grade dysplasia. Thirteen lesions with dysplasia were endoscopically visible but by using pCLE-targeted biopsies, additional endoscopically invisible dysplasias in 4 biopsies obtained from 3 patients were detected. The sensitivity, specificity, and accuracy of pCLE in predicting dysplasia were respectively 89 % (95 % CI: 65 – 98), 96 % (95 % CI: 94 – 97), and 96 % (95 % CI: 94 – 97). pCLE showed a good performance for differentiating neoplastic from non-neoplastic mucosa with negative predictive value of 99 %. Conclusions: pCLE in PSC-IBD surveillance is feasible and may be a good complement to HDE. Future research should aim at elucidating whether real-time pCLE is applicable in PSC-IBD surveillance.

Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant.In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis.Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia.The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.

Autoimmune hepatitis (AIH) is a liver disease that primarily affects women. Many become ill during childbearing age, and medication can be lifelong. Few studies exist on pregnancy outcome in women with AIH. Objectives The aim was to assess the outcome of women with AIH and their children during pregnancy and postpartum.Sixty-four women from a well-characterised cohort with AIH filled out a questionnaire with information about their disease, miscarriage/abortion, pregnancies and potential birth defects in 2012. In 2004, 106 women answered the same questionnaire and their results were analysed along with the new questionnaires.One hundred and thirty-eight women have completed the questionnaire and 100 children have been born by 58 women. Fifty-seven women (41%) had cirrhosis. In 84% of the pregnancies, the AIH was stable or milder, 32% had an increase in activity postpartum. The proportion of preterm births (before week 38) was 22%, caesarean sections 17%, malformations 3%, and two children died. Twenty-three women with cirrhosis had children after diagnosis of cirrhosis but without more complications than for non-cirrhotic mothers. However, they did have a higher prevalence of caesarean sections.Pregnancy and childbirth in AIH appear to be safe for both child and mother, even in women with compensated liver cirrhosis.

The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 x 10(-32) and P = 1.8 x 10(-22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DR beta chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented. (HEPATOLOGY 2011;53:1967-1976)