45 results on '"Schrumpf, E."'
Search Results
2. Follow-up magnetic resonance imaging/3D-magnetic resonance cholangiopancreatography in patients with primary sclerosing cholangitis: challenging for experts to interpret
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Zenouzi, R., Liwinski, T., Yamamura, J., Weiler-Normann, C., Sebode, M., Keller, S., Lohse, A. W., Schramm, C., Aabakken, L., Arrivé, L., Bowlus, C. L., Bungay, H., van Buuren, H. R., Cardinale, V., Carey, E. J., Chazouillères, O., Cheung, A., Culver, E. L., Dufour, J. F., Dumonceau, J. M., Eaton, J. E., Eddowes, P. J., Färkkilä, M., Floreani, A., Franceschet, I., Hohenester, S. D., Kemmerich, G., Krawczyk, M., Zimmer, V., Lenzen, H., Levy, C., Marschall, H. U., Marzioni, M., Motta, R., Muratori, L., Pereira, S. P., Poley, J. W., Rimola, J., Ringe, K. I., Rushbrook, S., Simpson, B. W., Schrumpf, E., Spina, J. C., Terziroli Beretta-Piccoli, B., Trauner, M., Tringali, A., Venkatesh, S. K., Vesterhus, M., Villamil, A., Weismüller, T. J., Ytting, H., Zenouzi, R., Liwinski, T., Yamamura, J., Weiler-Normann, C., Sebode, M., Keller, S., Lohse, A.W., Schramm, C., Aabakken, L., Arrivé, L., Bowlus, C.L., Bungay, H., van Buuren, H.R., Cardinale, V., Carey, E.J., Chazouillères, O., Cheung, A., Culver, E.L., Dufour, J.F., Dumonceau, J.M., Eaton, J.E., Eddowes, P.J., Färkkilä, M., Floreani, A., Franceschet, I., Hohenester, S.D., Kemmerich, G., Krawczyk, M., Zimmer, V., Lenzen, H., Levy, C., Marschall, H.U., Marzioni, M., Motta, R., Muratori, L., Pereira, S.P., Poley, J.W., Rimola, J., Ringe, K.I., Rushbrook, S., Simpson, B.W., Schrumpf, E., Spina, J.C., Terziroli Beretta-Piccoli, B., Trauner, M., Tringali, A., Venkatesh, S.K., Vesterhus, M., Villamil, A., Weismüller, T.J., Ytting, H., Culver, E, and Gastroenterology & Hepatology
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Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Cholangiopancreatography, Magnetic Resonance ,Cholangitis, Sclerosing ,Constriction, Pathologic ,Primary sclerosing cholangitis ,Cholangiocarcinoma ,Diagnosis, Differential ,03 medical and health sciences ,Imaging, Three-Dimensional ,0302 clinical medicine ,Surveys and Questionnaires ,Image Interpretation, Computer-Assisted ,medicine ,Humans ,Pharmacology (medical) ,In patient ,Expert Testimony ,Cholangiopancreatography, Endoscopic Retrograde ,Magnetic resonance cholangiopancreatography ,Endoscopic retrograde cholangiopancreatography ,Hepatology ,medicine.diagnostic_test ,business.industry ,Elevated total bilirubin ,Gastroenterology ,Reproducibility of Results ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Clinical Competence ,Radiology ,Bilirubin levels ,business ,Follow-Up Studies - Abstract
Background: In patients with primary sclerosing cholangitis follow‐up magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is performed by many centres, particularly for the early detection of biliary malignancies and strictures. Clinically meaningful MRI‐based definitions of primary sclerosing cholangitis related complications are, however, lacking.Aim: To investigate how primary sclerosing cholangitis experts interpret follow‐up MRI/MRCP with a focus on conclusions that may impact clinical decision‐making in primary sclerosing cholangitis.Methods: Within the International Primary Sclerosing Cholangitis Study Group, an online survey on 16 real‐life primary sclerosing cholangitis cases including clinical and biochemical information as well as a T2‐weighted liver MRI/3D‐MRCP was conducted. The interpretation of images and subsequent recommendations were assessed using a multiple‐choice questionnaire. An inter‐rater reliability calculation (Fleiss′ kappa) was performed and factors potentially affecting the interpretation of magnetic resonance images were analysed using generalised linear mixed‐effect models.Results: Forty‐four members/associates of the International Primary Sclerosing Cholangitis Study Group (median experience in the care of primary sclerosing cholangitis patients: 14 years) completed the survey. The MRI interpretation significantly varied among the participants. The lowest agreement was found with respect to the indication to perform subsequent endoscopic retrograde cholangiopancreatography (ERCP; Κ = 0.12, 95%CI 0.11‐0.14). Elevated total bilirubin was the variable with the strongest effect on the rate of suspected dominant strictures, cholangiocarcinoma or ERCP recommendations. Liver cirrhosis did not prevent participants from recommending ERCP. Overall, the survey participants′ recommendations contrasted the real‐life management and outcome.Conclusions: In primary sclerosing cholangitis, the interpretation of follow‐up MRI/3D‐MRCP significantly varies even among experts and seems to be primarily affected by bilirubin levels. Generally accepted MRI‐based definitions of primary sclerosing cholangitis‐related complications are urgently needed.
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- 2018
3. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells
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Valestrand, L, primary, Berntsen, N L, additional, Zheng, F, additional, Schrumpf, E, additional, Hansen, S H, additional, Karlsen, T H, additional, Blumberg, R S, additional, Hov, J R, additional, Jiang, X, additional, and Melum, E, additional
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- 2020
- Full Text
- View/download PDF
4. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis
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Weismueller, T, Strassburg, C, Trivedi, P, Hirschfield, G, Bergquist, A, Said, K, Imam, M, Lazaridis, K, Juran, B, Cheung, A, Lindor, K, Lenzen, H, Manns, M, Ponsioen, C, Beuers, U, Holm, K, Naess, S, Karlsen, T, Schrumpf, E, Boberg, K, Gotthardt, D, Rupp, C, Faerkkilae, M, Jokelainen, K, Marschall, H, Benito De Valle, M, Thorburn, D, Saffioti, F, Weersma, R, Fevery, J, Mueller, T, Chazouillãres, O, Schulze, K, Schramm, C, Almer, S, Pereira, S, Levy, C, Mason, A, Bowlus, C, Floreani, A, Halilbasic, E, Trauner, M, Yimam, K, Milkiewicz, P, Huynh, D, Pares, A, Manser, C, Dalekos, G, Eksteen, B, INVERNIZZI, PIETRO, Berg, C, Kirchner, G, Sarrazin, C, Zimmer, V, Fabris, L, Braun, F, Marzioni, M, Chapman, R, Hansen, B, Hansen, B., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Weismueller, T, Strassburg, C, Trivedi, P, Hirschfield, G, Bergquist, A, Said, K, Imam, M, Lazaridis, K, Juran, B, Cheung, A, Lindor, K, Lenzen, H, Manns, M, Ponsioen, C, Beuers, U, Holm, K, Naess, S, Karlsen, T, Schrumpf, E, Boberg, K, Gotthardt, D, Rupp, C, Faerkkilae, M, Jokelainen, K, Marschall, H, Benito De Valle, M, Thorburn, D, Saffioti, F, Weersma, R, Fevery, J, Mueller, T, Chazouillãres, O, Schulze, K, Schramm, C, Almer, S, Pereira, S, Levy, C, Mason, A, Bowlus, C, Floreani, A, Halilbasic, E, Trauner, M, Yimam, K, Milkiewicz, P, Huynh, D, Pares, A, Manser, C, Dalekos, G, Eksteen, B, Invernizzi, P, Berg, C, Kirchner, G, Sarrazin, C, Zimmer, V, Fabris, L, Braun, F, Marzioni, M, Chapman, R, Hansen, B, Clinicum, Department of Medicine, Gastroenterologian yksikkö, HUS Abdominal Center, Universitat de Barcelona, Gastroenterology & Hepatology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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Male ,Risk Stratification ,Time Factors ,Cholangitis ,POPULATION-BASED COHORT ,Ulcerative ,Kaplan-Meier Estimate ,Gastroenterology ,Inflammatory bowel disease ,Sclerosing ,0302 clinical medicine ,Crohn Disease ,Retrospective Studie ,MED/12 - GASTROENTEROLOGIA ,Risk Factors ,Autoimmune Liver Disease ,Multivariate Analysi ,Crohn's disease ,Cholestasis ,Incidence ,Hazard ratio ,Immune-Mediated Liver Disease ,Adult ,Age Distribution ,Australia ,Chi-Square Distribution ,Cholangitis, Sclerosing ,Colitis, Ulcerative ,Disease Progression ,Europe ,Female ,Humans ,Liver Transplantation ,Middle Aged ,Multivariate Analysis ,North America ,Phenotype ,Prognosis ,Proportional Hazards Models ,Retrospective Studies ,Risk Assessment ,Sex Distribution ,Young Adult ,Colitis ,Ulcerative colitis ,Inflamació ,CROHNS-DISEASE ,3. Good health ,ULCERATIVE-COLITIS ,Cholestasi ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Human ,medicine.medical_specialty ,Time Factor ,Prognosi ,Lower risk ,Article ,Primary sclerosing cholangitis ,03 medical and health sciences ,Colitis ulcerosa ,Internal medicine ,medicine ,GENOME-WIDE ASSOCIATION ,PRIMARY BILIARY-CIRRHOSIS ,Inflammation ,Hepatology ,business.industry ,Proportional hazards model ,Risk Factor ,CLINICAL PRESENTATION ,Retrospective cohort study ,DOSE URSODEOXYCHOLIC ACID ,NATURAL-HISTORY ,medicine.disease ,digestive system diseases ,3121 General medicine, internal medicine and other clinical medicine ,RISK-FACTORS ,Proportional Hazards Model ,business ,SINGLE-CENTER - Abstract
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P
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- 2017
5. Pustuløst legemiddelutslett
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Rizvi Smh and Schrumpf E
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medicine.medical_specialty ,business.industry ,medicine ,General Medicine ,medicine.disease ,business ,Dermatology ,Drug eruption - Published
- 2018
6. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells.
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Valestrand, L., Berntsen, N. L., Zheng, F., Schrumpf, E., Hansen, S. H., Karlsen, T. H., Blumberg, R. S., Hov, J. R., Jiang, X., and Melum, E.
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CYTOTOXIC T cells ,KILLER cells ,CHRONICALLY ill ,BILE ,ANTIGENS - Abstract
Summary: Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non‐invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end‐stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non‐invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non‐invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT‐reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
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Alberts, R, De Vries, E, Goode, E, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, T, Mason, A, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, N, Beuers, U, Björnsson, E, Boberg, K, Bowlus, C, Bragazzi, M, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, E, Floreani, A, Franceschet, I, Gotthardt, D, Hirschfield, G, Hoek, B, Holm, K, Hohenester, S, Hov, J, Imhann, F, Invernizzi, P, Juran, B, Lenzen, H, Lieb, W, Liu, J, Marschall, H, Marzioni, M, Melum, E, Milkiewicz, P, Müller, T, Pares, A, Rupp, C, Rust, C, Sandford, R, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, M, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, A, Vries, B, Zachou, K, Chapman, R, Manns, M, Pinzani, M, Rushbrook, S, Lazaridis, K, Franke, A, Anderson, C, Karlsen, T, Ponsioen, C, Weersma, R, Alberts, R, De Vries, E, Goode, E, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, T, Mason, A, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, N, Beuers, U, Björnsson, E, Boberg, K, Bowlus, C, Bragazzi, M, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, E, Floreani, A, Franceschet, I, Gotthardt, D, Hirschfield, G, Hoek, B, Holm, K, Hohenester, S, Hov, J, Imhann, F, Invernizzi, P, Juran, B, Lenzen, H, Lieb, W, Liu, J, Marschall, H, Marzioni, M, Melum, E, Milkiewicz, P, Müller, T, Pares, A, Rupp, C, Rust, C, Sandford, R, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, M, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, A, Vries, B, Zachou, K, Chapman, R, Manns, M, Pinzani, M, Rushbrook, S, Lazaridis, K, Franke, A, Anderson, C, Karlsen, T, Ponsioen, C, and Weersma, R
- Abstract
Objective Primary 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. Design We 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. Results We 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. Conclusion We 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.
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- 2018
8. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis
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Weismüller, T.J. (Tobias J.), Strassburg, C.P. (Christian P.), Trivedi, A. (Amber), Hirschfield, G.M. (Gideon), Trivedi, P.J. (Palak J.), Bergquist, A. (Annika), Said, K. (Karouk), Imam, M. (Mohamad), Lazaridis, K.N. (Konstantinos N.), Juran, B.D. (Brian D.), Cheung, A.C. (Angela C.), Lindor, K.D. (Keith), Lenzen, H. (Henrike), Manns, M.P. (Michael), Ponsioen, C.Y. (Cyril), Beuers, U. (Ulrich), Holm, K. (Kristian), Naess, S. (Sigrid), Karlsen, T.H. (Tom), Schrumpf, E. (Erik), Boberg, K.M. (Kirsten M.), Gotthardt, D. (Daniel), Rupp, C. (Christian), Färkkilä, M. (Martti), Jokelainen, K. (Kalle), Marschall, H.-U., Benito de Valle, M. (Maria), Thorburn, D. (Douglas), Saffioti, F. (Francesca), Weersma, R.K. (Rinse K.), Fevery, J. (J.), Mueller, T. (Tobias), Chazouillères, O. (Olivier), Schulze, K. (Kornelius), Schramm, C. (Christoph), Almer, S. (Sven), Pereira, S.P. (Stephen P.), Levy, C. (Cynthia), Mason, A. (Andrew), Bowlus, C.L. (Christopher L.), Floreani, A. (Annarosa), Halilbasic, E. (Emina), Trauner, M. (Michael), Yimam, K.K. (Kidist K.), Milkiewicz, P. (Piotr), Huynh, D.K. (Dep K.), Parés, A. (Albert), Manser, C.N. (Christine N.), Dalekos, G. (George), Eksteen, B. (Bertus), Invernizzi, P. (Pietro), Berg, C.P. (Christoph P.), Kirchner, G.I. (Gabi I.), Sarrazin, C. (Christoph), Zimmer, V. (Vincent), Fabris, L. (Luca), Braun, F. (Felix), Marzioni, M. (Marco), Chapman, R.W. (Roger), Chapman, R.W. (Roger W.), Lindor, K.D. (Keith D.), Karlsen, T.H. (Tom H.), Hansen, B.E. (Bettina E.), Hansen, B.E. (Bettina), Weismüller, T.J. (Tobias J.), Strassburg, C.P. (Christian P.), Trivedi, A. (Amber), Hirschfield, G.M. (Gideon), Trivedi, P.J. (Palak J.), Bergquist, A. (Annika), Said, K. (Karouk), Imam, M. (Mohamad), Lazaridis, K.N. (Konstantinos N.), Juran, B.D. (Brian D.), Cheung, A.C. (Angela C.), Lindor, K.D. (Keith), Lenzen, H. (Henrike), Manns, M.P. (Michael), Ponsioen, C.Y. (Cyril), Beuers, U. (Ulrich), Holm, K. (Kristian), Naess, S. (Sigrid), Karlsen, T.H. (Tom), Schrumpf, E. (Erik), Boberg, K.M. (Kirsten M.), Gotthardt, D. (Daniel), Rupp, C. (Christian), Färkkilä, M. (Martti), Jokelainen, K. (Kalle), Marschall, H.-U., Benito de Valle, M. (Maria), Thorburn, D. (Douglas), Saffioti, F. (Francesca), Weersma, R.K. (Rinse K.), Fevery, J. (J.), Mueller, T. (Tobias), Chazouillères, O. (Olivier), Schulze, K. (Kornelius), Schramm, C. (Christoph), Almer, S. (Sven), Pereira, S.P. (Stephen P.), Levy, C. (Cynthia), Mason, A. (Andrew), Bowlus, C.L. (Christopher L.), Floreani, A. (Annarosa), Halilbasic, E. (Emina), Trauner, M. (Michael), Yimam, K.K. (Kidist K.), Milkiewicz, P. (Piotr), Huynh, D.K. (Dep K.), Parés, A. (Albert), Manser, C.N. (Christine N.), Dalekos, G. (George), Eksteen, B. (Bertus), Invernizzi, P. (Pietro), Berg, C.P. (Christoph P.), Kirchner, G.I. (Gabi I.), Sarrazin, C. (Christoph), Zimmer, V. (Vincent), Fabris, L. (Luca), Braun, F. (Felix), Marzioni, M. (Marco), Chapman, R.W. (Roger), Chapman, R.W. (Roger W.), Lindor, K.D. (Keith D.), Karlsen, T.H. (Tom H.), Hansen, B.E. (Bettina E.), and Hansen, B.E. (Bettina)
- Abstract
Background & Aims Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. Methods We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. Results Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21–30 years old, 9.0 per 100 patient-years for patients 31–40 years old, 14.0 per 100 patient-years for patients 41–50 years old, 15.2 per 100 patient-years for patients 51–60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P <.001 and HR
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- 2017
- Full Text
- View/download PDF
9. Is the 308 polymorphism in the tumor necrosis factor (alpha) (TNF alpha) promoter region a marker of disease susceptibility in European patients with primary sclerosing cholangitis (PSC)?
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Mitchell, SA, Spurkland, A, Boberg, K, Chapman, RW, Fleming, KA, Schrumpf, E, and Cholangit, ESGPS
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- 2016
10. HLA class II haplotypes in primary sclerosing cholangitis patients from five ethnic groups
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Saarinen, S, Boberg, KM, Spurkland, A, Mitchell, S, Broome, U, Rosina, F, Chapman, R, Pares, A, Olerup, O, and Schrumpf, E
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- 2016
11. Proteomic Analysis of Liver Fibrotic Septa and Periportal Spaces in Primary Sclerosing Cholangitis, Primary Biliary Cholangitis and Alcoholic Liver Disease
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Mazza, G., primary, Telese, A., additional, Schrumpf, E., additional, Gilbertson, J., additional, Rendell, N., additional, Lombardi, B., additional, Godovac-Zimmermann, J., additional, Taylor, G.W., additional, Thorburn, D., additional, Karlsen, T.H., additional, and Pinzani, M., additional
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- 2016
- Full Text
- View/download PDF
12. Lipid Antigens in Bile from Patients with Liver Diseases Activate Natural Killer T Cells
- Author
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Valestrand, L., primary, Berntsen, N.L., additional, Schrumpf, E., additional, Karlsen, T.H., additional, Blumberg, R.S., additional, and Melum, E., additional
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- 2016
- Full Text
- View/download PDF
13. Norursodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis: Results of a Phase II Dose Finding Study
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Trauner, M., primary, Fickert, P., additional, Hirschfield, G., additional, Reiter, F., additional, Altorjay, I., additional, Marschall, H.U., additional, Färkkilä, M., additional, Schramm, C., additional, Spengler, U., additional, Chapman, R., additional, Bergquist, A., additional, Schrumpf, E., additional, Nevens, F., additional, Halilbasic, E., additional, Greinwald, R., additional, Proels, M., additional, and Manns, M.P., additional
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- 2016
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14. Genotype-Phenotype Analysis across 130,422 Genetic Variants Identifies Rspo3 as the First Genome-Wide Significant Modifier Gene in Primary Sclerosing Cholangitis
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Alberts, R., primary, de Vries, E.M., additional, Alexander, G., additional, Alvaro, D., additional, Bergquist, A., additional, Beuers, U., additional, Björnsson, E., additional, Boberg, K.M., additional, Bowlus, C.L., additional, Chapman, R.W., additional, Chazouilléres, O., additional, Cheung, A., additional, Dalekos, G., additional, Eksteen, B., additional, Eaton, J.E., additional, Ellinghaus, D., additional, Färkkilä, M., additional, Festen, E.A., additional, Floreani, A., additional, Folseraas, T., additional, Goode, E., additional, Gotthardt, D.N., additional, Hirschfield, G.M., additional, van Hoek, B., additional, Hohenester, S., additional, Holm, K., additional, Hov, J.R., additional, Imhann, F., additional, Invernizzi, P., additional, Jiang, X., additional, Juran, B.D., additional, Lazaridis, K.N., additional, Leppa, V., additional, Liu, J.Z., additional, Löfberg, J., additional, Manns, M.P., additional, Marschall, H.-U., additional, Marzioni, M., additional, Mason, A.L., additional, Melum, E., additional, Müller, T., additional, Milkiewicz, P., additional, Pares, A., additional, Pelkonen, V., additional, Pinzani, M., additional, Rombouts, K., additional, Rupp, C., additional, Rushbrook, S.M., additional, Rust, C., additional, Sampaziotis, F., additional, Sandford, R.N., additional, Schramm, C., additional, Schreiber, S., additional, Schrumpf, E., additional, Silverberg, M., additional, Srivastava, B., additional, Sterneck, M., additional, Teufel, A., additional, Tittmann, L., additional, Vallier, L., additional, Vila, A.V., additional, de Vries, B.A., additional, Weismüller, T.J., additional, Wijmenga, C., additional, Zachou, K., additional, Franke, A., additional, Anderson, C.A., additional, Karlsen, T.H., additional, Ponsioen, C.Y., additional, and Weersma, K., additional
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- 2016
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15. P1190 : The role of NKT cells in a mouse model (NOD.C3C4) with spontaneous bile duct inflammation
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Schrumpf, E., primary, Jiang, X., additional, Zeissig, S., additional, Pollheimer, M.J., additional, Anmarkrud, J.A., additional, Tan, C., additional, Exley, M.A., additional, Karlsen, T.H., additional, Blumberg, R.S., additional, and Melum, E., additional
- Published
- 2015
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16. O082 : The gut microbiota in primary sclerosing cholangitis differs from that of healthy controls and ulcerative colitis patients without biliary disease
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Kummen, M., primary, Holm, K., additional, Anmarkrud, J.A., additional, Vesterhus, M., additional, Høivik, M.L., additional, Trøseid, M., additional, Marschall, H.-U., additional, Schrumpf, E., additional, Moum, B., additional, Aukrust, P., additional, Karlsen, T.H., additional, and Hov, J.R., additional
- Published
- 2015
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17. SAT-372 - Genotype-Phenotype Analysis across 130,422 Genetic Variants Identifies Rspo3 as the First Genome-Wide Significant Modifier Gene in Primary Sclerosing Cholangitis
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Alberts, R., de Vries, E.M., Alexander, G., Alvaro, D., Bergquist, A., Beuers, U., Björnsson, E., Boberg, K.M., Bowlus, C.L., Chapman, R.W., Chazouilléres, O., Cheung, A., Dalekos, G., Eksteen, B., Eaton, J.E., Ellinghaus, D., Färkkilä, M., Festen, E.A., Floreani, A., Folseraas, T., Goode, E., Gotthardt, D.N., Hirschfield, G.M., van Hoek, B., Hohenester, S., Holm, K., Hov, J.R., Imhann, F., Invernizzi, P., Jiang, X., Juran, B.D., Lazaridis, K.N., Leppa, V., Liu, J.Z., Löfberg, J., Manns, M.P., Marschall, H.-U., Marzioni, M., Mason, A.L., Melum, E., Müller, T., Milkiewicz, P., Pares, A., Pelkonen, V., Pinzani, M., Rombouts, K., Rupp, C., Rushbrook, S.M., Rust, C., Sampaziotis, F., Sandford, R.N., Schramm, C., Schreiber, S., Schrumpf, E., Silverberg, M., Srivastava, B., Sterneck, M., Teufel, A., Tittmann, L., Vallier, L., Vila, A.V., de Vries, B.A., Weismüller, T.J., Wijmenga, C., Zachou, K., Franke, A., Anderson, C.A., Karlsen, T.H., Ponsioen, C.Y., and Weersma, K.
- Published
- 2016
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18. SAT-347 - Lipid Antigens in Bile from Patients with Liver Diseases Activate Natural Killer T Cells
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Valestrand, L., Berntsen, N.L., Schrumpf, E., Karlsen, T.H., Blumberg, R.S., and Melum, E.
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- 2016
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19. LB02 - Norursodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis: Results of a Phase II Dose Finding Study
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Trauner, M., Fickert, P., Hirschfield, G., Reiter, F., Altorjay, I., Marschall, H.U., Färkkilä, M., Schramm, C., Spengler, U., Chapman, R., Bergquist, A., Schrumpf, E., Nevens, F., Halilbasic, E., Greinwald, R., Proels, M., and Manns, M.P.
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- 2016
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20. PS092 - Proteomic Analysis of Liver Fibrotic Septa and Periportal Spaces in Primary Sclerosing Cholangitis, Primary Biliary Cholangitis and Alcoholic Liver Disease
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Mazza, G., Telese, A., Schrumpf, E., Gilbertson, J., Rendell, N., Lombardi, B., Godovac-Zimmermann, J., Taylor, G.W., Thorburn, D., Karlsen, T.H., and Pinzani, M.
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- 2016
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21. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
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Martina Sterneck, Wolfgang Lieb, Christian Rust, Tom H. Karlsen, Massimo Pinzani, Erik Schrumpf, John E. Eaton, Gideon M. Hirschfield, Christoph Schramm, Richard Sandford, Ulrich Beuers, Andrew Mason, Espen Melum, Daniel Gotthardt, A. Boudewijn de Vries, I. Franceschet, Konstantinos N. Lazaridis, Floris Imhann, Marco Carbone, Pietro Invernizzi, Mark S. Silverberg, Simon Hohenester, Maria Consiglia Bragazzi, Andreas Teufel, Bart van Hoek, Martti Färkkilä, Einar Bjornsson, Cyriel Y. Ponsioen, Brijesh Srivastava, Joanne Verheij, Roger W. Chapman, Krista Rombouts, Niklas K. Björkström, Johannes R. Hov, Weiwei Wang, F. Sampaziotis, Ludovic Vallier, Albert Parés, Eleonora A. M. Festen, Kristian Holm, Kalliopi Zachou, Katrin Böttcher, Christopher L. Bowlus, Xiaojun Jiang, Trine Folseraas, Elisabeth M.G. de Vries, Simon M. Rushbrook, Piotr Milkiewicz, Carl A. Anderson, Georgios N. Dalekos, David Ellinghaus, Hanns-Ulrich Marschall, Rinse K. Weersma, Marco Marzioni, Olivier Chazouillères, Domenico Alvaro, Christian Rupp, Angela M. Cheung, Jimmy Z. Liu, Brian D. Juran, Michael P. Manns, Rudi Alberts, Bertus Eksteen, Tobias J. Weismüller, Graeme J.M. Alexander, Annarosa Floreani, Tobias Müller, Stefan Schreiber, Andre Franke, Elizabeth C. Goode, Henrike Lenzen, Arnau Vich Vila, Annika Bergquist, Kirsten Muri Boberg, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Pathology, Alberts, R, De Vries, E, Goode, E, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, T, Mason, A, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, N, Beuers, U, Björnsson, E, Boberg, K, Bowlus, C, Bragazzi, M, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, E, Floreani, A, Franceschet, I, Gotthardt, D, Hirschfield, G, Hoek, B, Holm, K, Hohenester, S, Hov, J, Imhann, F, Invernizzi, P, Juran, B, Lenzen, H, Lieb, W, Liu, J, Marschall, H, Marzioni, M, Melum, E, Milkiewicz, P, Müller, T, Pares, A, Rupp, C, Rust, C, Sandford, R, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, M, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, A, Vries, B, Zachou, K, Chapman, R, Manns, M, Pinzani, M, Rushbrook, S, Lazaridis, K, Franke, A, Anderson, C, Karlsen, T, Ponsioen, C, Weersma, R, Centre of Excellence in Complex Disease Genetics, Doctoral Programme in Drug Research, Department of Medicine, Clinicum, Gastroenterologian yksikkö, HUS Abdominal Center, and Universitat de Barcelona
- Subjects
Male ,0301 basic medicine ,Oncology ,Candidate gene ,Cholangitis ,medicine.medical_treatment ,Medizin ,Trasplantament hepàtic ,Genome-wide association study ,Kaplan-Meier Estimate ,LIVER FIBROSIS ,Liver transplantation ,Bioinformatics ,Sclerosing ,Oral and gastrointestinal ,Primary sclerosing cholangitis ,genetics ,liver transplantation ,Cohort Studies ,ACTIVATION ,0302 clinical medicine ,MED/12 - GASTROENTEROLOGIA ,MULTIPLE ,2.1 Biological and endogenous factors ,EPIDEMIOLOGY ,Aetiology ,CIRRHOSIS ,Bilious diseases and biliousness ,Liver Disease ,digestive, oral, and skin physiology ,Gastroenterology ,Single Nucleotide ,Primary sclerosing cholangiti ,Middle Aged ,3. Good health ,ULCERATIVE-COLITIS ,Disease Progression ,Female ,030211 gastroenterology & hepatology ,Adult ,medicine.medical_specialty ,Cholangitis, Sclerosing ,Chronic Liver Disease and Cirrhosis ,Clinical Sciences ,Malalties del tracte biliar ,Single-nucleotide polymorphism ,HEPATIC STELLATE CELLS ,Polymorphism, Single Nucleotide ,International PSC Study Group ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,Genetics ,medicine ,Humans ,Polymorphism ,GENOME-WIDE ASSOCIATION ,Allele ,Digestive Diseases - (Gallbladder) ,Survival analysis ,Proportional Hazards Models ,MALIGNANCY ,The UK PSC Consortium ,Transplantation ,Gastroenterology & Hepatology ,business.industry ,Proportional hazards model ,medicine.disease ,RISK LOCI ,Logistic Models ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,genetic ,Hepatic transplantation ,Thrombospondins ,Digestive Diseases ,business ,Genètica - Abstract
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.
- Published
- 2017
22. Microbial exposure during early life regulates development of bile duct inflammation.
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Oldereid TS, Jiang X, Øgaard J, Schrumpf E, Bjørnholt JV, Rasmussen H, and Melum E
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- Mice, Humans, Animals, Mice, Inbred NOD, Liver pathology, Inflammation pathology, Disease Models, Animal, Bile Ducts pathology, Cholangitis
- Abstract
Objectives: The early life microbiome has been linked to inflammatory diseases in adulthood and a role for the microbiome in bile duct inflammation is supported by both human and murine studies. We utilized the NOD.c3c4 mouse model that develops a spontaneous immune-driven biliary disease with a known contribution of the microbiome to evaluate the temporal effects of the early life microbiome., Materials and Methods: Germ-free (GF) NOD.c3c4 mice were conventionalized into a specific pathogen free environment at birth (conventionally raised, CONV-R) or at weaning (germ-free raised, GF-R) and compared with age and gender-matched GF and conventional (CONV) NOD.c3c4 mice. At 9 weeks of age, liver pathology was assessed by conventional histology and flow cytometry immunophenotyping., Results: Neonatal exposure to microbes (CONV-R) increased biliary inflammation to similar levels as regular conventional NOD.c3c4 mice, while delayed exposure to microbes (GF-R) restrained the biliary inflammation. Neutrophil infiltration was increased in all conventionalized mice compared to GF. An immunophenotype in the liver similar to CONV was restored in both CONV-R and GF-R compared to GF mice displaying a proportional increase of B cells and reduction of T cells in the liver., Conclusions: Microbial exposure during early life has a temporal impact on biliary tract inflammation in the NOD.c3c4 mouse model suggesting that age-sensitive interaction with commensal microbes have long-lasting effects on biliary immunity that can be of importance for human cholangiopathies.
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- 2024
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23. Successful treatment of subcorneal pustular dermatosis targeting an underlying monoclonal IgA gammopathy.
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Kreyberg I, Schrumpf E, Fredrik von Krogh C, Lilleng R, and Tjønnfjord GE
- Abstract
Competing Interests: None disclosed.
- Published
- 2023
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24. Mucosal-Associated Invariant T Cells Are Altered in Patients with Hidradenitis Suppurativa and Contribute to the Inflammatory Milieu.
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Gallagher C, Mahon JM, O'Neill C, Cassidy FC, Dunbar H, De Barra C, Cadden C, Pisarska MM, Wood NAW, Masterson JC, McNamee EN, Schrumpf E, English K, O'Shea D, Tobin AM, and Hogan AE
- Subjects
- Humans, Hidradenitis Suppurativa complications, Mucosal-Associated Invariant T Cells
- Published
- 2023
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25. Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction.
- Author
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Louwe MC, Olsen MB, Kaasbøll OJ, Yang K, Fosshaug LE, Alfsnes K, Øgaard JDS, Rashidi A, Skulberg VM, Yang M, de Miranda Fonseca D, Sharma A, Aronsen JM, Schrumpf E, Ahmed MS, Dahl CP, Nyman TA, Ueland T, Melum E, Halvorsen BE, Bjørås M, Attramadal H, Sjaastad I, Aukrust P, and Yndestad A
- Abstract
An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3
-/- mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1β and -18) in MI patients., Competing Interests: This work was supported by grants from the K.G. Jebsen Inflammation Research Centre, South-Eastern Norway Regional Health Authority, and Norwegian Research Council. Dr. Yndestad is currently an employee of Pfizer Norway; the current work was conducted when he was employed by Oslo University Hospital. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2020 The Authors.)- Published
- 2020
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26. Pustular drug eruption.
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Schrumpf E and Rizvi SMH
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- Adolescent, Humans, Male, Acute Generalized Exanthematous Pustulosis etiology, Acute Generalized Exanthematous Pustulosis pathology, Anti-Bacterial Agents adverse effects, Clindamycin adverse effects
- Published
- 2018
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27. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.
- Author
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Alberts R, de Vries EMG, Goode EC, Jiang X, Sampaziotis F, Rombouts K, Böttcher K, Folseraas T, Weismüller TJ, Mason AL, Wang W, Alexander G, Alvaro D, Bergquist A, Björkström NK, Beuers U, Björnsson E, Boberg KM, Bowlus CL, Bragazzi MC, Carbone M, Chazouillères O, Cheung A, Dalekos G, Eaton J, Eksteen B, Ellinghaus D, Färkkilä M, Festen EAM, Floreani A, Franceschet I, Gotthardt DN, Hirschfield GM, Hoek BV, Holm K, Hohenester S, Hov JR, Imhann F, Invernizzi P, Juran BD, Lenzen H, Lieb W, Liu JZ, Marschall HU, Marzioni M, Melum E, Milkiewicz P, Müller T, Pares A, Rupp C, Rust C, Sandford RN, Schramm C, Schreiber S, Schrumpf E, Silverberg MS, Srivastava B, Sterneck M, Teufel A, Vallier L, Verheij J, Vila AV, Vries B, Zachou K, Chapman RW, Manns MP, Pinzani M, Rushbrook SM, Lazaridis KN, Franke A, Anderson CA, Karlsen TH, Ponsioen CY, and Weersma RK
- Subjects
- Adult, Cholangitis, Sclerosing mortality, Cohort Studies, Disease Progression, Female, Humans, Kaplan-Meier Estimate, Logistic Models, Male, Middle Aged, Proportional Hazards Models, Cholangitis, Sclerosing genetics, Cholangitis, Sclerosing pathology, Polymorphism, Single Nucleotide genetics, Thrombospondins genetics
- Abstract
Objective: Primary 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., Design: We 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., Results: We 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., Conclusion: We 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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)- Published
- 2018
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28. Establishment of a surgical bile duct injection technique giving direct access to the bile ducts for studies of the murine biliary tree.
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Berntsen NL, Fosby B, Valestrand L, Tan C, Reims HM, Schrumpf E, Karlsen TH, Line PD, and Melum E
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- Animals, Biliary Tract pathology, Biliary Tract Diseases etiology, Biliary Tract Diseases pathology, Disease Models, Animal, Female, Injections, Ligation, Male, Mice, Inbred C57BL, Solvents toxicity, Biliary Tract drug effects, Biliary Tract Diseases drug therapy, Biliary Tract Surgical Procedures methods, Catheterization methods, Common Bile Duct surgery, Gallbladder surgery, Solvents administration & dosage
- Abstract
Cholangiopathies are progressive disorders with largely unknown pathoetiology and limited treatment options. We aimed to develop a novel surgical technique with direct access to the bile ducts that would complement existing mouse models of cholestasis, biliary inflammation, and fibrosis and present a new route of administration for testing of potential treatment strategies. We developed a surgical technique to access the murine biliary tree by injection of different solvents through catheterization of the gall bladder with simultaneous clamping of the common bile duct. To demonstrate the applicability of the technique, we injected either phosphate-buffered saline or dimethyl sulfoxide in concentrations of 50 or 65% and compared these groups with sham-operated mice. The surgery was optimized to achieve a mortality rate close to 0. There were no significant changes in pain, activity level, or mortality from the day of the surgery until euthanization for any groups. Injection of phosphate-buffered saline or 50% dimethyl sulfoxide was generally well-tolerated, whereas 65% dimethyl sulfoxide led to higher weight loss, an increase of serum alanine transaminase, and histological portal inflammation. There were no signs of inflammation in the gut. We have developed a bile duct injection technique that is well-tolerated, easily reproducible, and that may complement existing models of cholangiopathies. Direct access to the bile ducts without causing harm to the hepatobiliary or intestinal tissue may be valuable in future studies of normal biliary physiology and different pathophysiological mechanisms of disease and to test novel therapeutic strategies. NEW & NOTEWORTHY To evaluate tolerability of the bile duct to injection of both polar and nonpolar compounds, we established a novel biliary injection technique. This technique is well-tolerated, easily reproducible, and with direct access to the bile ducts for studies of the murine biliary tree. The bile duct injection technique may complement existing animal models and be a valuable tool in future studies of normal biliary physiology or pathophysiology and to test novel therapeutic strategies.
- Published
- 2018
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29. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis.
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Fickert P, Hirschfield GM, Denk G, Marschall HU, Altorjay I, Färkkilä M, Schramm C, Spengler U, Chapman R, Bergquist A, Schrumpf E, Nevens F, Trivedi P, Reiter FP, Tornai I, Halilbasic E, Greinwald R, Pröls M, Manns MP, and Trauner M
- Subjects
- Adult, Alkaline Phosphatase blood, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Ursodeoxycholic Acid adverse effects, Ursodeoxycholic Acid therapeutic use, Cholangitis, Sclerosing drug therapy, Cholestasis drug therapy, Ursodeoxycholic Acid analogs & derivatives
- Abstract
Background & Aim: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C
23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC., Methods: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit., Results: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups., Conclusions: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)- Published
- 2017
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30. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.
- Author
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Weismüller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, Holm K, Gotthardt D, Färkkilä MA, Marschall HU, Thorburn D, Weersma RK, Fevery J, Mueller T, Chazouillères O, Schulze K, Lazaridis KN, Almer S, Pereira SP, Levy C, Mason A, Naess S, Bowlus CL, Floreani A, Halilbasic E, Yimam KK, Milkiewicz P, Beuers U, Huynh DK, Pares A, Manser CN, Dalekos GN, Eksteen B, Invernizzi P, Berg CP, Kirchner GI, Sarrazin C, Zimmer V, Fabris L, Braun F, Marzioni M, Juran BD, Said K, Rupp C, Jokelainen K, Benito de Valle M, Saffioti F, Cheung A, Trauner M, Schramm C, Chapman RW, Karlsen TH, Schrumpf E, Strassburg CP, Manns MP, Lindor KD, Hirschfield GM, Hansen BE, and Boberg KM
- Subjects
- Adult, Age Distribution, Australia epidemiology, Chi-Square Distribution, Cholangitis, Sclerosing diagnosis, Cholangitis, Sclerosing mortality, Cholangitis, Sclerosing surgery, Colitis, Ulcerative diagnosis, Colitis, Ulcerative mortality, Colitis, Ulcerative surgery, Crohn Disease diagnosis, Crohn Disease mortality, Crohn Disease surgery, Disease Progression, Europe epidemiology, Female, Humans, Incidence, Kaplan-Meier Estimate, Liver Transplantation, Male, Middle Aged, Multivariate Analysis, North America epidemiology, Phenotype, Prognosis, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Risk Factors, Sex Distribution, Time Factors, Young Adult, Cholangitis, Sclerosing epidemiology, Colitis, Ulcerative epidemiology, Crohn Disease epidemiology
- Abstract
Background & Aims: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC., Methods: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates., Results: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002)., Conclusions: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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31. Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis.
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Vesterhus M, Holm A, Hov JR, Nygård S, Schrumpf E, Melum E, Thorbjørnsen LW, Paulsen V, Lundin K, Dale I, Gilja OH, Zweers SJLB, Vatn M, Schaap FG, Jansen PLM, Ueland T, Røsjø H, Moum B, Ponsioen CY, Boberg KM, Färkkilä M, Karlsen TH, and Lund-Johansen F
- Subjects
- Adolescent, Adult, Aged, Bile metabolism, Case-Control Studies, Cholangitis, Sclerosing diagnosis, Female, Humans, Interleukin-8 blood, Interleukin-8 metabolism, Kaplan-Meier Estimate, Male, Middle Aged, Norway, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Protein Array Analysis, Young Adult, Biomarkers blood, Biomarkers metabolism, Cholangitis, Sclerosing blood, Cholangitis, Sclerosing metabolism
- Abstract
Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC)., Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n=167 [1992-2006] and n=138 [2008-2012]), inflammatory bowel disease (n=96) and healthy controls (n=100)., Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p<0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p<0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival., Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC., Lay Summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
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- 2017
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32. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls.
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Kummen M, Holm K, Anmarkrud JA, Nygård S, Vesterhus M, Høivik ML, Trøseid M, Marschall HU, Schrumpf E, Moum B, Røsjø H, Aukrust P, Karlsen TH, and Hov JR
- Subjects
- Adult, Aged, Aged, 80 and over, Area Under Curve, Case-Control Studies, Cholangitis, Sclerosing complications, Cholangitis, Sclerosing drug therapy, Colitis, Ulcerative complications, Cross-Sectional Studies, Feces microbiology, Female, Healthy Volunteers, Humans, Male, Middle Aged, Prospective Studies, ROC Curve, Severity of Illness Index, Young Adult, Cholangitis, Sclerosing microbiology, Colitis, Ulcerative microbiology, Gastrointestinal Microbiome, RNA, Ribosomal, 16S analysis, Veillonella isolation & purification
- Abstract
Objective: Gut microbiota could influence gut, as well as hepatic and biliary immune responses. We therefore thoroughly characterised the gut microbiota in primary sclerosing cholangitis (PSC) compared with healthy controls (HC) and patients with ulcerative colitis without liver disease., Design: We prospectively collected 543 stool samples. After a stringent exclusion process, bacterial DNA was submitted for 16S rRNA gene sequencing. PSC and HC were randomised to an exploration panel or a validation panel, and only significant results (p<0.05, Q
FDR <0.20) in both panels were reported, followed by a combined comparison of all samples against UC., Results: Patients with PSC (N=85) had markedly reduced bacterial diversity compared with HC (N=263, p<0.0001), and a different global microbial composition compared with both HC (p<0.001) and UC (N=36, p<0.01). The microbiota of patients with PSC with and without IBD was similar. Twelve genera separated PSC and HC, out of which 11 were reduced in PSC. However, the Veillonella genus showed a marked increase in PSC compared with both HC (p<0.0001) and UC (p<0.02). Using receiver operating characteristic analysis, Veillonella abundance yielded an area under the curve (AUC) of 0.64 to discriminate PSC from HC, while a combination of PSC-associated genera yielded an AUC of 0.78., Conclusions: Patients with PSC exhibited a gut microbial signature distinct from both HC and UC without liver disease, but similar in PSC with and without IBD. The Veillonella genus, which is also associated with other chronic inflammatory and fibrotic conditions, was enriched in PSC., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)- Published
- 2017
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33. Antineutrophil antibodies define clinical and genetic subgroups in primary sclerosing cholangitis.
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Hov JR, Boberg KM, Taraldsrud E, Vesterhus M, Boyadzhieva M, Solberg IC, Schrumpf E, Vatn MH, Lie BA, Molberg Ø, and Karlsen TH
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- Adolescent, Adult, Aged, Biomarkers, Case-Control Studies, Cross-Sectional Studies, Databases, Factual, Female, Fluorescent Antibody Technique, Indirect, Genotype, Humans, Inflammatory Bowel Diseases genetics, Logistic Models, Male, Middle Aged, Norway, Young Adult, Antibodies, Antineutrophil Cytoplasmic blood, Cholangitis, Sclerosing blood, Cholangitis, Sclerosing genetics, HLA-B27 Antigen genetics, HLA-DRB1 Chains genetics
- Abstract
Background & Aims: The strongest genetic risk factors in primary sclerosing cholangitis (PSC) are encoded in the HLA complex. Antineutrophil cytoplasmic antibodies (ANCA) have been reported in up to 94% of PSC patients, but their clinical significance and immunogenetic basis are ill defined. We aimed to characterize clinical and genetic associations of ANCA in PSC., Methods: Antineutrophil cytoplasmic antibodies were analysed with indirect immunofluorescence in 241 Norwegian PSC patients. HLA-B and HLA-DRB1 genotyping was performed in the patients and in 368 healthy controls. Data on perinuclear ANCA (pANCA) and HLA-DRB1 were available from 274 ulcerative colitis (UC) patients without known liver disease., Results: Antineutrophil cytoplasmic antibodies were found in 193 (80%) of the PSC patients, with pANCA in 169 (70%). ANCA-positive patients were younger than ANCA negative at diagnosis of PSC and had a lower frequency of biliary cancer (9% vs 19%, P=.047). There were no differences between PSC patients with and without inflammatory bowel disease. Genetically, the strong PSC risk factors HLA-B*08 (frequency in healthy 13%) and DRB1*03 (14%) were more prevalent in ANCA-positive than -negative patients (43% vs 25%, P=.0012 and 43% vs 25%, P=.0015 respectively). The results were similar when restricting the analysis to pANCA-positive patients. In UC patients without liver disease, HLA-DRB1*03 was more prevalent in pANCA-positive compared with -negative patients (P=.03)., Conclusions: Antineutrophil cytoplasmic antibodies identified PSC patients with particular clinical and genetic characteristics, suggesting that ANCA may mark a clinically relevant pathogenetic subgroup in the PSC-UC disease spectrum., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2017
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34. The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation.
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Schrumpf E, Jiang X, Zeissig S, Pollheimer MJ, Anmarkrud JA, Tan C, Exley MA, Karlsen TH, Blumberg RS, and Melum E
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- Animals, Antigens, CD1d immunology, Bile Duct Diseases metabolism, Bile Duct Diseases pathology, Disease Models, Animal, Galactosylceramides pharmacology, Inflammation metabolism, Inflammation pathology, Liver immunology, Liver metabolism, Liver pathology, Mice, Mice, Knockout, Natural Killer T-Cells drug effects, Natural Killer T-Cells metabolism, Spleen immunology, Spleen metabolism, Spleen pathology, Thymus Gland immunology, Thymus Gland metabolism, Thymus Gland pathology, Antigens, CD1d genetics, Bile Duct Diseases immunology, Inflammation immunology, Natural Killer T-Cells immunology
- Abstract
Natural killer T (NKT) cells are activated by lipid antigens presented by CD1d molecules and represent a major lymphocyte subset of the liver. NODc3c4 mice spontaneously develop biliary inflammation in extra- and intrahepatic bile ducts. We demonstrated by flow cytometry that invariant NKT (iNKT) cells were more abundant in the thymus, spleen, and liver of NODc3c4 mice compared to NOD mice. iNKT cells in NODc3c4 mice displayed an activated phenotype. Further, NOD and NOD Cd1d
-/- mice were irradiated and injected with NODc3c4 bone marrow, and injection of NODc3c4 bone marrow resulted in biliary infiltrates independently of CD1d expression in recipient mice. Activation or blocking of NKT cells with α -galactosylceramide or anti-CD1d antibody injections did not affect the biliary phenotype of NODc3c4 mice. NODc3c4. Cd1d-/- mice were generated by crossing NOD Cd1d-/- mice onto a NODc3c4 background. NODc3c4. Cd1d-/- and NODc3c4 mice developed the same extent of biliary disease. This study demonstrates that iNKT cells are more abundant and activated in the NODc3c4 model. The portal inflammation of NODc3c4 mice can be transferred to irradiated recipients, which suggests an immune-driven disease. Our findings imply that NKT cells can potentially participate in the biliary inflammation, but are not the primary drivers of disease in NODc3c4 mice., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)- Published
- 2017
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35. Can Healthy Recipes Change Eating Behaviors? The Food Hero Social Marketing Campaign Recipe Project Experience and Evaluation.
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Tobey LN, Schrumpf E, Johnson T, Mouzong C, Veith RM, Braverman MT, Wong SS, and Manore MM
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- Child, Humans, Parents, Cookbooks as Topic, Feeding Behavior, Health Promotion methods, Social Marketing
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- 2017
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36. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.
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Ponsioen CY, Chapman RW, Chazouillères O, Hirschfield GM, Karlsen TH, Lohse AW, Pinzani M, Schrumpf E, Trauner M, and Gores GJ
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- Cholangitis, Sclerosing mortality, Cholangitis, Sclerosing pathology, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Consensus, Disease Progression, End Stage Liver Disease mortality, End Stage Liver Disease surgery, Evidence-Based Medicine, Female, Humans, Internationality, Liver Transplantation methods, Male, Needs Assessment, Rare Diseases, Risk Assessment, Survival Rate, Treatment Outcome, Biomarkers metabolism, Cholangitis, Sclerosing therapy, End Stage Liver Disease physiopathology, Practice Guidelines as Topic
- Abstract
Unlabelled: Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable., Conclusion: At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials., (© 2015 by the American Association for the Study of Liver Diseases.)
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- 2016
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37. Indications and Outcomes in Liver Transplantation in Patients With Primary Sclerosing Cholangitis in Norway.
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Andersen IM, Fosby B, Boberg KM, Clausen OP, Jebsen P, Melum E, Line PD, Foss A, Schrumpf E, and Karlsen TH
- Abstract
Background: Primary sclerosing cholangitis (PSC) is 1 of the leading causes of liver transplantation (LTX) in Scandinavia, and an increasing number of PSC patients have been transplanted in Norway during the last 2 decades. This trend is partly attributable to the recently established practice in Norway of offering LTX to PSC patients with cholangiocellular dysplasia. Based on the controversy associated with this practice, we herein aimed to report the main features and outcomes of our LTX program in PSC., Methods: The primary indication for LTX (quality of life/end-stage liver disease or suspected neoplasia) was retrospectively determined for 222 patients undergoing LTX for PSC or other autoimmune liver diseases (primary biliary cirrhosis/autoimmune hepatitis) with at least 5 years of follow-up., Results: In PSC patients impaired quality of life (43.5%) and end-stage liver disease (38.4%) were the most frequent indications for LTX, whereas suspected neoplasia accounted for 18.1%. The proportion of PSC patients with manifest encephalopathy, variceal bleeding, or ascites declined over time. In patients with suspected neoplasia as the primary indication for LTX (n = 25), neoplasia was confirmed in the explanted liver in 20 patients (80%). Five-year survival rates for PSC patients transplanted between 2001 and 2009 were 91.9% for patients receiving LTX due to impaired quality of life or end-stage liver disease and 83.3% for suspected neoplasia., Conclusions: The PSC patients are increasingly listed for LTX at an earlier stage of their liver disease. In patients with suspected neoplasia before LTX, 5-year survival was acceptable, despite confirmation of neoplasia in 80% of the liver explants.
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- 2015
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38. The biliary epithelium presents antigens to and activates natural killer T cells.
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Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, and Melum E
- Subjects
- Animals, Antigens, CD1d physiology, Cells, Cultured, Epithelial Cells immunology, Epithelium immunology, Humans, Mice, Mice, Inbred C57BL, Bile Ducts immunology, Lymphocyte Activation, Natural Killer T-Cells immunology
- Abstract
Unlabelled: Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as well as human primary cholangiocytes expressed CD1d as determined by flow cytometry and western blotting. Murine cholangiocyte cell lines were able to present both exogenous and endogenous lipid antigens to invariant and noninvariant NKT cell hybridomas and primary NKT cells in a CD1d-dependent manner. A human cholangiocyte cell line, cholangiocarcinoma cell lines, and human primary cholangiocytes also presented exogenous CD1d-restricted antigens to invariant NKT cell clones. CD1d expression was down-regulated in the biliary epithelium of patients with late primary sclerosing cholangitis, primary biliary cirrhosis, and alcoholic cirrhosis compared to healthy controls., Conclusions: Cholangiocytes express CD1d and present antigens to NKT cells and CD1d expression is down-regulated in diseased biliary epithelium, findings which show that the biliary epithelium can activate an important lymphocyte subset of the liver. This is a potentially important immune pathway in the biliary system, which may be capable of regulating inflammation in the context of biliary disease., (© 2015 by the American Association for the Study of Liver Diseases.)
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- 2015
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39. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.
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Sampaziotis F, de Brito MC, Madrigal P, Bertero A, Saeb-Parsy K, Soares FAC, Schrumpf E, Melum E, Karlsen TH, Bradley JA, Gelson WT, Davies S, Baker A, Kaser A, Alexander GJ, Hannan NRF, and Vallier L
- Subjects
- Biomedical Research, Cells, Cultured, Humans, Liver Diseases, Biliary Tract cytology, Drug Discovery, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells physiology, Models, Biological
- Abstract
The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.
- Published
- 2015
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40. Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis.
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Vesterhus M, Hov JR, Holm A, Schrumpf E, Nygård S, Godang K, Andersen IM, Naess S, Thorburn D, Saffioti F, Vatn M, Gilja OH, Lund-Johansen F, Syversveen T, Brabrand K, Parés A, Ponsioen CY, Pinzani M, Färkkilä M, Moum B, Ueland T, Røsjø H, Rosenberg W, Boberg KM, and Karlsen TH
- Subjects
- Adult, Case-Control Studies, Cholangitis, Sclerosing pathology, Female, Fibrosis, Humans, Male, Middle Aged, Norway epidemiology, Severity of Illness Index, Cholangitis, Sclerosing mortality, Liver pathology
- Abstract
Unlabelled: There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments., Conclusion: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score., (© 2015 by the American Association for the Study of Liver Diseases.)
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- 2015
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41. Primary sclerosing cholangitis - the Norwegian experience.
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Schrumpf E, Boberg KM, and Karlsen TH
- Subjects
- Humans, Morbidity, Prognosis, Scandinavian and Nordic Countries epidemiology, Cholangitis, Sclerosing diagnosis, Cholangitis, Sclerosing epidemiology, Cholangitis, Sclerosing therapy, Disease Management
- Abstract
Research related to primary sclerosing cholangitis (PSC) has since 1980 been a major activity at the Oslo University Hospital Rikshospitalet. The purpose of this publication is to describe the development of this research, the impact of this research on the clinical handling of the patients, and finally to describe what we believe are the most urgent, remaining problems to be solved. During the early years, our research dealt primarily with clinical aspects of the disease. The concomitant inflammatory bowel disease (IBD) seen in most patients with PSC was a major interest and we also started looking into genetic associations of PSC. Prognosis, malignancy development and treatment with special emphasis on transplantation have later been dealt with. These activities has had impact on several aspects of PSC management; when and how to diagnose PSC and variant forms of PSC, how to handle IBD in PSC and how to deal with the increased rate of malignancy? The problems remaining to be solved are many. What is the role of the gut and the gut microbiota in the development of PSC? Do the PSC patients have an underlying disturbance in the bile homeostasis? And how does the characteristic type of fibrosis in PSC develop? The genetic studies have supported a role for the adaptive immune system in the disease development, but how should this be dealt with? Importantly, the development of malignancy in PSC is still not understood, and we lack appropriate medical treatment for our patients.
- Published
- 2015
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42. Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.
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Fosby B, Melum E, Bjøro K, Bennet W, Rasmussen A, Andersen IM, Castedal M, Olausson M, Wibeck C, Gotlieb M, Gjertsen H, Toivonen L, Foss S, Makisalo H, Nordin A, Sanengen T, Bergquist A, Larsson ME, Soderdahl G, Nowak G, Boberg KM, Isoniemi H, Keiding S, Foss A, Line PD, Friman S, Schrumpf E, Ericzon BG, Höckerstedt K, and Karlsen TH
- Subjects
- Adult, Aged, Female, Humans, Kidney Failure, Chronic mortality, Male, Middle Aged, Reoperation, Retrospective Studies, Scandinavian and Nordic Countries epidemiology, Survival Rate trends, Intention to Treat Analysis methods, Kidney Failure, Chronic surgery, Liver Transplantation statistics & numerical data, Registries, Tissue and Organ Procurement methods, Waiting Lists
- Abstract
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).
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- 2015
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43. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma.
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Andresen K, Boberg KM, Vedeld HM, Honne H, Jebsen P, Hektoen M, Wadsworth CA, Clausen OP, Lundin KE, Paulsen V, Foss A, Mathisen Ø, Aabakken L, Schrumpf E, Lothe RA, and Lind GE
- Subjects
- Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology, Humans, Reproducibility of Results, Bile Duct Neoplasms genetics, Bile Duct Neoplasms metabolism, Bile Ducts, Intrahepatic, Cholangiocarcinoma genetics, Cholangiocarcinoma metabolism, DNA Methylation, Genetic Markers
- Abstract
Unlabelled: Early detection of the highly aggressive malignancy cholangiocarcinoma (CCA) remains a challenge but has the potential to render the tumor curable by surgical removal. This study evaluates a biomarker panel for the diagnosis of CCA by DNA methylation analyses of biliary brush samples. The methylation status of 13 candidate genes (CDO1, CNRIP1, DCLK1, FBN1, INA, MAL, SEPT9, SFRP1, SNCA, SPG20, TMEFF2, VIM, and ZSCAN18) was investigated in 93 tissue samples (39 CCAs and 54 nonmalignant controls) using quantitative methylation-specific polymerase chain reaction. The 13 genes were further analyzed in a test series of biliary brush samples (15 CCAs and 20 nonmalignant primary sclerosing cholangitis controls), and the methylation status of the four best performing markers was validated (34 CCAs and 34 primary sclerosing cholangitis controls). Receiver operating characteristic curve analyses were used to evaluate the performance of individual biomarkers and the combination of biomarkers. The 13 candidate genes displayed a methylation frequency of 26%-82% in tissue samples. The four best-performing genes (CDO1, CNRIP1, SEPT9, and VIM) displayed individual methylation frequencies of 45%-77% in biliary brushes from CCA patients. Across the test and validation biliary brush series, this four-gene biomarker panel achieved a sensitivity of 85% and a specificity of 98%, with an area under the receiver operating characteristic curve of 0.944., Conclusion: We report a straightforward biomarker assay with high sensitivity and specificity for CCA, outperforming standard brush cytology, and suggest that the biomarker panel, potentially in combination with cytological evaluation, may improve CCA detection, particularly among primary sclerosing cholangitis patients., (© 2015 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
- Published
- 2015
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44. Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population.
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Næss S, Lie BA, Melum E, Olsson M, Hov JR, Croucher PJ, Hampe J, Thorsby E, Bergquist A, Traherne JA, Schrumpf E, Boberg KM, Schreiber S, Franke A, and Karlsen TH
- Subjects
- Case-Control Studies, Humans, Proto-Oncogene Proteins genetics, Receptor, Notch4, Receptors, Notch genetics, Scandinavian and Nordic Countries, Cholangitis, Sclerosing genetics, HLA-B Antigens genetics, HLA-DRB1 Chains genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel., Methodology/principal Findings: A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10-11)., Conclusions/significance: Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.
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- 2014
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45. Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease.
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Naess S, Björnsson E, Anmarkrud JA, Al Mamari S, Juran BD, Lazaridis KN, Chapman R, Bergquist A, Melum E, Marsh SG, Schrumpf E, Lie BA, Boberg KM, Karlsen TH, and Hov JR
- Subjects
- Genotype, Humans, Inflammatory Bowel Diseases genetics, Linkage Disequilibrium, Norway, Odds Ratio, Risk Factors, Sweden, United Kingdom, United States, Cholangitis, Sclerosing classification, Cholangitis, Sclerosing genetics, HLA-B8 Antigen genetics, HLA-DRB1 Chains genetics, Phenotype
- Abstract
Background & Aims: Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC., Methods: Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions., Results: HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2-3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1-2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC., Conclusions: Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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