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  • 101.
    Stjernman, Henrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Grännö, Christer
    Division of Gastroenterology, Department of Medicine, County Hospital Ryhov, Jönköping, Sweden.
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Järnerot, Ggunnar
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Ockander, Leif
    Division of Gastroenterology, Department of Medicine, County Hospital Ryhov, Jönköping, Sweden.
    Tysk, Curt
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Blomberg, Björn
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ström, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Hjortswang, Henrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Evaluation of the Inflammatory Bowel Disease Questionnaire in Swedish patients with Crohn's disease2006In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 41, no 8, p. 934-943Article in journal (Refereed)
    Abstract [en]

    Objective. Health-related quality of life (HRQoL) is an important measure of inflammatory bowel disease (IBD) health outcome. The Inflammatory Bowel Disease Questionnaire (IBDQ) comprising 32 items grouped into four dimensions is a widely used IBD-specific HRQoL instrument. The purpose of this study was to evaluate the validity, reliability and responsiveness of the Swedish translation of the IBDQ in patients with Crohn's disease (CD). Material and methods. Four hundred and forty-eight patients with CD completed the IBDQ and three other HRQoL questionnaires (Rating Form of IBD Patient Concerns, Short Form-36, and the Psychological General Well-Being Index) in connection with their regular visit at the outpatient clinic. Disease activity was assessed by the physician on a 4-point Likert scale. Thirty-two patients who were stable in remission completed the questionnaires a second time, 4 weeks later. A total of 418 patients repeated all measurements after 6 months. Results. The dimensional scores were highly correlated with other measures of corresponding aspects of HRQoL and were significantly better in remission than in relapse. High test-retest correlations indicated good reliability. Responsiveness was confirmed in patients whose disease activity changed over time. However, high correlations between the dimensions, poor correlations between items within each dimension, and factor analysis all indicated that the original grouping of the items is not valid for Swedish CD patients. Conclusions. Although the Swedish IBDQ has good external validity, reliability and responsiveness for patients with CD, our results did not support the original grouping of the items. © 2006 Taylor & Francis.

  • 102.
    Stjernman, Henrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Tysk, Curt
    Orebro Univ Hosp, Dept Med, Div Gastroenterol, Orebro, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Factors Predicting the Outcome of Disease Activity Assessment in Crohns Disease2009In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 15, no 12, p. 1859-1866Article in journal (Refereed)
    Abstract [en]

    Background: The Crohns Disease Activity Index (CDAI) has become the gold standard for assessment of disease activity in CD. This study investigated the relationship between CDAI and the physicians global assessment of disease activity (PGA) and whether different demographic and disease-related factors predict the outcome. Methods: Multiple linear regression analysis was used to investigate the relationship between CDAI and PGA obtained from 405 CD patients. Predictors of the CDAI and the PGA outcome were identified. Results: The correlation between CDAI and PGA was moderate. In patients with CDAI greater than 150, 72% of the total score were derived froth the subjective variables. The regression coefficients were not significant for 3 of the CDAI variables. In regression analysis, C-reactive protein (CRP), stenosis, smoking, bowel resection, concomitant disease, and gender predicted the CDAI outcome. The PGA outcome was predicted only by CRP, stenosis, and fistula. Conclusions: The correlation between CDAI and PGA was moderate and the subjective variables had a high impact on CDAI. Factors with no obvious relation to inflammatory activity predicted the outcome of CDAI, but not PGA. In trials of CD therapies, separation of subjective (symptoms, well-being) from objective (endoscopy, inflammatory markers) variables should be considered in the assessment of disease activity.

  • 103.
    Stjernman, Henrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Tysk, Curt
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, S-701 85 Örebro/School of Health and Medical Sciences, Örebro University, Örebro; Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Unfavourable outcome for women in a study of health-related quality of life, social factors, and work disability in Crohn’s disease2011In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 23, no 8, p. 671-679Article in journal (Refereed)
    Abstract [en]

    Objective. The aim was to describe health-related quality of life (HRQL) and social factors, sickness and disability variables in a large population-based cohort of patients with Crohn’s disease (CD).

    Methods. HRQL was measured with SF-36 in 497 adult CD patients at three outpatient clinics. Comparisons were made with age-gender-matched background population and with ulcerative colitis (UC). Social factors, employment, sickness compensation, and disability pension for CD, were compared with national population registers.

    Results. CD had a greater negative effect on HRQL than did UC. This difference was more pronounced for women. Compared with background population, CD patients had lower educational level, and had a two-fold rise in long-term sickness and disability pension rate. CD women had higher rates of sickness and disability than CD men and were more often living single, though procreation was not affected.

    Conclusion. This study characterized the burden of CD in a large population-based cohort. CD had higher impact on HRQL, compared with UC. CD women had worse outcome in subjective health status, but not in objective assessment of disease activity. Women also had higher rates of sickness, disability pension, and single living. The mechanism underlying the gender-related inequalities in outcome for CD warrants further elucidation.

  • 104.
    Stjernman, Henrik
    et al.
    Division of Gastroenterology, Department of Medicine, County Hospital Ryhov, Jönköping, Sweden.
    Tysk, Curt
    Örebro University Hospital, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Worries and concerns in a large unselected cohort of patients with Crohns disease2010In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 45, no 6, p. 696-706Article in journal (Refereed)
    Abstract [en]

    Objective. Disease-related worries constitute an important dimension of patient-reported perception of health status in inflammatory bowel disease (IBD). The Rating Form of IBD Patient Concerns (RFIPC) questionnaire is purported to measure IBD-related worries. This study evaluated the psychometric properties of a Swedish translation of RFIPC in an unselected population of Crohns disease (CD) patients. The degree and nature of the worries were characterized and predictive factors for outcome of RFIPC and underlying dimensions were identified. Material and Methods. The RFIPC was completed by 447 CD patients in conjunction with regular visits. A physician global assessment of disease activity and four other health-related quality of life (HRQL) questionnaires were used for construct validity. Reliability and responsiveness were evaluated with follow-up visits. Underlying dimension and predictive factors were identified with factor analysis and multiple linear regression analysis. Results. Test-retest reliability was 0.90, correlation with corresponding HRQL measures 0.60-0.80 and responsiveness ratio 0.84. Median RFIPC sum score was lower than in previous studies. Top three concerns were ostomy, energy level and bowel control. Four dimensions were identified in descending order of concern: disease-related complications, daily-life achievements, intimacy, and stigmatization. Predictors of RFIPC score were disease activity, gender, and BMI (p andlt; 0.001-0.008). Conclusions. The Swedish version of RFIPC exhibited an adequate psychometric performance in CD patients, but was less sensitive to change in disease activity. The patients were more concerned about complications and achievement than intimacy and stigmatization. The strongest predictors of more worry were active disease, female gender and higher BMI.

  • 105. Teml, Alexander
    et al.
    Schwab, Matthias
    Hommes, Daan W
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Lukas, Milan
    Feichtenschlager, Thomas
    Florin, Timothy
    Seiderer, Julia
    Petritsch, Wolfgang
    Bokemeyer, Bernd
    Kreisel, Wolfgang
    Herrlinger, Klaus R
    Knoflach, Peter
    Bonaz, Bruno
    Klugmann, Thomas
    Herfarth, Hans
    Pedarnig, Nikolaus
    Reinisch, Walter
    A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease2007In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 119, no 17-18, p. 519-526Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients, using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy. © 2007 Springer-Verlag.

  • 106.
    Theibaut, R
    et al.
    AP HP, INSERM.
    Douchin, V
    AP HP, INSERM.
    Jung, C
    AP HP, INSERM.
    Merlin, F
    AP HP, INSERM.
    Colombel, J F
    Hop Calmette.
    Lemann, M
    Hop St Louis.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Tysk, C
    Orebro University Hospital.
    OMorain, C
    Trinity College Dublin.
    Gassull, M
    Hospital Badalona Germans Trias and Pujol.
    Finkel, Y
    Karolinska Institute.
    Zouali, H
    Fdn Jean Dausset.
    Pascoe, L
    Fdn Jean Dausset.
    Hugot, J P
    AP HP, INSERM.
    Letter: RIP2 Polymorphisms in Inflammatory Bowel Diseases2011In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 17, no 4, p. 1055-1055Article in journal (Other academic)
    Abstract [en]

    n/a

  • 107.
    Thiebaut, R
    et al.
    University of Paris.
    Kotti, S
    University of Paris.
    Jung, C
    University of Paris.
    Merlin, F
    University of Paris.
    Colombel, J F
    Hop Calmette.
    Lemann, M
    Hop St Louis.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Tysk, C
    University of Örebro.
    Morain, M O
    Adelaide & Meath Hospital.
    Gassull, M
    Hospital University Germans Trias & Pujol.
    Binder, V
    Herlev Hospital.
    Finkel, Y
    Karolinska Children's Hospital.
    Pascoe, L
    CEPH, Paris.
    Hugot, J-P
    Hop Robert Debre.
    TNFSF15 Polymorphisms Are Associated With Susceptibility to Inflammatory Bowel Disease in a New European Cohort2009In: AMERICAN JOURNAL OF GASTROENTEROLOGY, ISSN 0002-9270, Vol. 104, no 2, p. 384-391Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Inflammatory bowel disease (IBD), e. g., Crohns disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD.

    METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied.

    RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P = 0.001) (OR = 1.25 (1.05-1.50)) and CD (P = 0.02) (OR = 1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A.

    CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

  • 108. Tysk, C
    et al.
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Andersson, M
    Befrits, R
    Hertervig, E
    Kilander, A
    Lindgren, S
    Suhr, O
    Nationella riktlinjer för handläggning av akut svårt skov av ulcerös kolit2008Report (Other academic)
    Abstract [sv]

      

  • 109.
    van Asseldonk, Dirk P
    et al.
    Vrije University Amsterdam Medical Centre, Amsterdam, The Netherlands.
    Sanderson, Jeremy
    Guys and St Thomas Hospital, London, UK.
    de Boer, Nanne K H
    Vrije University Amsterdam Medical Centre, Amsterdam, The Netherlands.
    Sparrow, Miles P
    Alfred Hospital, Melbourne, Australia.
    Lemann, Marc
    Hôpital Saint Louis, Paris, France.
    Ansari, Azhar
    East Surrey Hospital, Red Hill, UK.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Florin, Timothy H J
    University of Queensland, Brisbane, Australia.
    Gearry, Richard B
    University of Otago, Christchurch, New Zealand.
    Mulder, Chris J
    Vrije University Amsterdam Medical Centre, Amsterdam, The Netherlands.
    Mantzaris, Gerassimos
    Evangelisms Hospital, Athens, Greece.
    van Bodegraven, Ad A
    Vrije University Amsterdam Medical Centre, Amsterdam, The Netherlands.
    Difficulties and possibilities with thiopurine therapy in inflammatory bowel disease-Proceedings of the first Thiopurine Task Force meeting2011In: DIGESTIVE AND LIVER DISEASE, ISSN 1590-8658, Vol. 43, no 4, p. 270-276Article in journal (Refereed)
    Abstract [en]

    Background: Thiopurines, such as azathioprine and mercaptopurine, are of pivotal importance in the treatment of inflammatory bowel disease. Although these drugs have been used for several decades, still many questions remain unanswered. Aim: To provide an overview of clinically and scientifically challenging topics concerning thiopurine therapy in inflammatory bowel disease treatment. Methods: The first meeting of the Thiopurine Task Force Interest Group was held during the 2009 United European Gastroenterology Week in London (GASTRO2009). The topics of this meeting were of particular clinical and scientific interest. Additional literature was identified by performing a Pubmed search using the search terms inflammatory bowel disease, azathioprine, 6-mercaptopurine and thioguanine. Results: The following topics were discussed: therapeutic drug monitoring; the synergy of thiopurines with aminosalicylates and allopurinol; serious adverse events such as opportunistic infections, hepatotoxicity, carcinogenicity and pancreatitis; prolongation of thiopurines during clinical remission; indications for thiopurines in the postoperative setting; and the potential use of thioguanine. Specific interesting and clinically relevant topics for potential future research are provided. Conclusions: Thiopurines remain central to inflammatory bowel disease treatment, although future studies are required to substantiate a more personalised medicine approach to their use.

  • 110.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use2013In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 75, p. 145-152Article in journal (Refereed)
    Abstract [en]

    A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. less thanbrgreater than less thanbrgreater thanThe method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). less thanbrgreater than less thanbrgreater thanLOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 x 10(8) RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 degrees C for 8 h after sampling.

  • 111.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical useManuscript (preprint) (Other academic)
    Abstract [en]

    high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBC:s were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials in thiopurine therapy and proven valid by analysis of authentic patient samples.

    The method measured thioguanosine mono- (TGMP), di- (TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine).

    LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8x10^8 RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 5 °C for 8 hours after sampling.

  • 112.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Andersson, David
    Skåne University Hospital, Sweden; Danderyd Hospital, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Hindorf, Ulf
    Skåne University Hospital, Sweden.
    Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease2014In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 8, no 12, p. 1702-1709Article in journal (Refereed)
    Abstract [en]

    Background and aims: The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums. Methods: Samples from 79 patients with Crohns disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey-Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined. Results: TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p = 0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p = 0.01). When TGN was measured by the routine assay the correlation was not evident (p = 0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500 pmol/8 x 10less than^greater than8 RBCs were more likely to have active disease (p = 0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R-2 greater than 0.88). Conclusions: The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity. (C) 2014 European Crohns and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  • 113.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, David
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Hindorf, Ulf
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separatelyManuscript (preprint) (Other academic)
    Abstract [en]

    The thiopurines are widely used in the treatment of inflammatory bowel diseases but are limited by poor dose-effect relationship and large interindividual variability in clinical effects. Many attempts have been made to predict response by therapeutic drug monitoring of phosphorylated and methylated metabolites grouped together as thioguanine nucleotides and methylthioinosine monophosphate. We have developed a method to determine the individual metabolites, thioguanosine mono-, di-, and triphosphates, as well as methylthioinosine mono-, di-, and triphosphates, separately in red blood cells.

    This aim of this study was to assess the ability of our novel method to predict clinical outcome compared to the routine method in 82 patients with inflammatory bowel diseases.

    TPMT wild-type patients with TGN levels below the cut-off level were more likely to have an active disease when TGN was measured by both the routine method (p < 0.05), the novel method (p<0.05), and when TGTP was measured separately (p < 0.01). TGN levels and TGTP were, however, not correlated to disease activity in TPMT defective patients. Patients with meTIN levels above 1500 pmol were more likely to have an active disease (39%, 18/46 vs. 17%, 5/30; p = 0.02). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2 > 0.88) and the TGTP ratio (TGTP/(TGDP+TGTP)) was not different in patients with active disease or in clinical remission.

    Thiopurine metabolites should still be measured by the routine method, since the novel and technically more challenging method, including determination of TGTP and TGTP ratio, does not offer a clinical advantage compared to the routine method.

  • 114.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Almer, Sven H C
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?2009In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, no 3, p. 345-50Article in journal (Refereed)
    Abstract [en]

    Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

  • 115.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    How Should Thiopurine Treatment be Monitored? Methodological Aspects2010In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 29, no 04-Jun, p. 278-283Article in journal (Refereed)
    Abstract [en]

    Monitoring of thiopurine metabolites is important due to a complex metabolism with large interindividual variation, but the suitability of currently used methods has been questioned. The drawbacks include poor reproducibility, the inability to differentiate between the different analytes, as well as the use of a nontarget matrix. Further research should be directed toward measuring thiopurine metabolites in mononuclear cells, measuring the different nucleotides specifically, as well as measuring the incorporation of thioguanine into DNA. The studies should not be limited to thioguanosine nucleotides but include methylthioinosine nucleotides as well.

  • 116.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Coulthard, S
    Newcastle University, Northern Institute for Cancer Research.
    Josefsson, Martin
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linkoping.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rapid Method to Measure Thioguanine Incorporation Into DNA2011In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, no Supplement 1, p. S650-S650Article in journal (Other academic)
    Abstract [en]

    Background: The thiopurine drugs, 6-mercaptopurine, azathioprine, and thioguanine, are used in the treatment of acute lymphoblastic leukaemia (ALL). During treatment the thioguanine nucleotides formed are incorporated into the DNA, causing apoptosis due to the cells inability to repair the resulting damage. This mechanism is believed to be important for the effects of thiopurine drugs. We have developed a novel method for the determination of thioguanine incorporation into DNA which is both faster and cheaper than earlier methods.

    Monitoring the effects of thiopurine treatment by measuring thiopurine metabolites in erythrocytes has proven to be elusive due to the lack of good correlation between measured concentrations and thiopurine effects. If the incorporation is the main mechanism of thiopurine action, a reliable method capable of measuring the incorporation in an ordinary blood sample, such as the method we have developed, should provide a significantly better correlation with treatment effect.

    Material and Methods: Briefly, DNA extracted from buffy coat is degraded using nuclease P1 and alkaline phosphatase to produce free nucleosides which are purified by filtration. Thioguanosine and thymidine are separated and detected using an LC-MS/MS system and the ratio between the bases provides a measurement of the extent of thioguanine incorporation in DNA. The method has been successfully applied to cell culture samples as well as samples from patients treated orally with thiopurines.

    Results: In 8 inflammatory bowel disease patients treated with azathioprine the measured incorporation ranged from 2.2 to 8.4 thioguanine bases for every 10 000 thymidine bases (median 5.2). This is in agreement with earlier reports on incorporation in childhood leukemia patients.

    Conclusions: With the presented method it is possible to determine the incorporation of thioguanine into DNA during thiopurine treatment in a cost effective manner, but further research is needed to determine if there is a place for this type of methods in the monitoring of thiopurine treatment.

    An ongoing study aims to compare the incorporation to treatment effects as well as conventional measurements of erythrocyte metabolite levels. By this study we hope to determine if incorporation is a more reliable measurement to predict treatment effect and if the erythrocyte metabolite levels correlate with the incorporation.

  • 117. Wallerstedt, Sven
    et al.
    Olsson, Rolf
    Simrén, Magnus
    Broomé, Ulrika
    Wahlin, Staffan
    Lööf, Lars
    Hultcrantz, Rolf
    Sjöberg, Klas
    Sandberg Gertzén, Hanna
    Prytz, Hanne
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Abdominal tenderness in ascites patients indicates spontaneous bacterial peritonitis2007In: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828, Vol. 18, no 1, p. 44-47Article in journal (Refereed)
    Abstract [en]

    Background: Spontaneous bacterial peritonitis (SBP), which has been reported to be present in 10-30% of patients with cirrhotic ascites, may easily be overlooked. An important aim of our study was to determine whether there are any clinical signs which, in clinical practice, may predict or exclude SBP. Methods: We studied 133 patients with cirrhotic ascites from medical units at nine Swedish university hospitals where there had been at least one diagnostic ascites tap with analysis of polymorphonuclear leukocytes in the ascites fluid. The patients had initially been questioned about background factors and physically examined according to a standardized case record form. Samples of blood, urine, and ascites were then drawn for analysis according to a structured schedule. Results: SBP could be excluded in 80% of all the cases and was confirmed in 8% of the 133 patients in the final analysis. Abdominal pain and abdominal tenderness were more common in patients with SBP (p < 0.01), but no other physical sign or laboratory test could separate SBP cases from the others. Conclusions: SBP was present in about one-tenth of the hospitalized patients with cirrhotic ascites in this cohort. Performing repeated physical examinations and paying particular attention to abdominal tenderness may be the best way to become aware of the possible development of this complication. © 2006 Elsevier B.V. All rights reserved.

  • 118.
    Wallerstedt, Sven
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden .
    Simren, Magnus
    Sahlgrenska University Hospital, Göteborg, Sweden .
    Wahlin, Staffan
    Karolinska University Hospital Huddinge, Sweden .
    Loof, Lars
    Center for Clinical Research, Västerås, Sweden.
    Hultcrantz, Rolf
    Karolinska University Hospital, Solna, Sweden .
    Sjöberg, Klas
    Skåne University Hospital, Malmö, Sweden .
    Sandberg Gertzen, Hanna
    University Hospital, Örebro, Sweden.
    Prytz, Hanne
    Skåne University Hospital, Lund, Sweden .
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Oden, Anders
    Chalmers University, Gothenburg, Sweden.
    Moderate hyperkalemia in hospitalized patients with cirrhotic ascites indicates a poor prognosis2013In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, no 3, p. 358-365Article in journal (Refereed)
    Abstract [en]

    Objective. Development of ascites in patients with liver cirrhosis is an ominous sign with a poor outcome. A liver transplantation must be considered, and it then becomes important to know if there are any factors indicating a worsened prognosis. Material and methods. We used official registers for a follow-up study of at least 5 years considering the prognosis of 155 prospectively recruited in-patients with cirrhotic ascites from medical units at nine Swedish university hospitals. All patients had undergone at least one diagnostic ascites tap, and had initially been questioned about background factors and physically examined according to a standardized case record form, followed by sampling of blood, urine, and ascites. Results. Death occurred within 1 year after inclusion in 53% of the cases, and was primarily liver-related in 70%. In a multivariable analysis, the two ordinary variables that showed the strongest correlation with risk of death were serum potassium and abdominal tenderness. All 22 patients with a serum potassium concentration of at least 4.8 mmol/L (maximum 5.8 mmol/L) died within 1 year after inclusion. Potassium concentration was related to renal function and potassium-saving drugs. Conclusion. This follow-up study of a prospectively recruited cohort of in-patients with cirrhotic ascites confirms their poor prognosis. Awareness of an elevated serum potassium value, which would reflect a threatened renal function, seems essential, because it may offer a simple way to identify cases with the worst prognosis. An area for further research should be to explore the significance of including serum potassium in prognostic models.

  • 119.
    Wei, G.
    et al.
    Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Bergquist, A.
    Department of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Broome, U.
    Broomé, U., Department of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Lindgren, S.
    Gastroenterology and Hepatology Division, Department of Medicine, University Hospital MAS, Malmö, Sweden.
    Wallerstedt, S.
    Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Sangfelt, P.
    Gastroenterology and Hepatology Division, Department of Medicine, University Hospital, Uppsala, Sweden.
    Danielsson, A.
    Danielsson, Å., Gastroenterology and Hepatology Division, Department of Medicine, University Hospital, Umeå, Sweden.
    Sandberg-Gertzen, H.
    Sandberg-Gertzén, H., Gastroenterology and Hepatology Division, Department of Medicine, University Hospital, Örebro, Sweden.
    Loof, L.
    Lööf, L., Center for Clinical Research, Central Hospital, Västerås, Sweden.
    Prytz, H.
    Gastroenterology and Hepatology Division, Department of Medicine, University Hospital, Lund, Sweden.
    Bjornsson, E.
    Björnsson, E., Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Internal Medicine, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
    Acute liver failure in Sweden: Etiology and outcome2007In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 262, no 3, p. 393-401Article in journal (Refereed)
    Abstract [en]

    Objective. To determine the causes and outcome of all patients with acute liver failure (ALF) in Sweden 1994-2003 and study the diagnostic accuracy of King's College Hospital (KCH) criteria and the model for end-stage liver disease (MELD) score with transplant-free deaths as a positive outcome. Research design and methods. Adult patients in Sweden with international normalized ratio (INR) of =1.5 due to severe liver injury with and without encephalopathy at admission between 1994-2003 were included. Results. A total of 279 patients were identified. The most common cause of ALF were acetaminophen toxicity in 42% and other drugs in 15%. In 31 cases (11%) no definite etiology could be established. The KCH criteria had a positive-predictive value (PPV) of 67%, negative-predictive value (NPV) of 84% in the acetaminophen group. Positive-predictive value and negative-predictive value of KCH criteria in the nonacetaminophen group were 54% and 63% respectively. MELD score >30 had a positive-predictive value of 21%, negative-predictive value of 94% in the acetaminophen group. The corresponding figures for the nonacetaminophen group were 64% and 76% respectively. Conclusions. Acetaminophen toxicity was the most common cause in unselected patients with ALF in Sweden. KCH criteria had a high NPV in the acetaminophen group, and in combination with MELD score <30 predicts a good prognosis in acetaminophen patients without transplantation. © 2007 Blackwell Publishing Ltd.

  • 120. Werner, M
    et al.
    Prytz, H
    Ohlsson, B
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bjornsson, E
    Bergquist, A
    Wallerstedt, S
    Sandberg-Gertzen, H
    Hultcrantz, R
    Sangfelt, P
    Weiland, O
    Danielsson, A
    Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: A nationwide study2008In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 43, no 10, p. 1232-1240Article in journal (Refereed)
    Abstract [en]

    Objective. Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. Material and methods. Analyses were performed in 473 patients identified as having probable or definite AIH. Results. The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected "en passant" to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). Conclusions. The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1. © 2008 Informa UK Ltd.

  • 121.
    Werner, Marten
    et al.
    Umeå University Hospital.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Prytz, Hanne
    Lund University Hospital.
    Lindgren, Stefan
    Malmö University Hospital.
    Wallerstedt, Sven
    Karolinska University Hospital.
    Sandberg-Gertzen, Hanna
    Örebro University Hospital.
    Hultcrantz, Rolf
    Karolinska University Hospital.
    Sangfelt, Per
    Uppsala University Hospital.
    Weiland, Ola
    Karolinska University Hospital.
    Danielsson, Ake
    Umeå University Hospital.
    Hepatic and extrahepatic malignancies in autoimmune hepatitis. A long-term follow-up in 473 Swedish patients2009In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 50, no 2, p. 388-393Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Autoimmune Hepatitis (AIH) is a liver disease which may lead to liver cirrhosis. Cirrhosis is a well-known risk factor for hepatocellular cancer. Lymphoma is a disease, where immune modulating drugs as well as the autoimmune disease itself may contribute to the elevated risk. The aim was to investigate the risks of malignancies in a large cohort of AIH patients.

    Methods: Four hundred and seventy-three patients with AIH were matched to the Swedish national cancer register as well as to the death cause register.

    Results: We found an overall higher risk of malignancies in the cohort of A I H patients from the date of diagnosis with a SIR of 1.51 (95% CI 1.10-2.03). SIR in the subpopulation of well defined catchment areas and complete case finding was 23.28 (95% CI 7.5-54.34) for HCC. Lymphomas were found a SIR of 13.09 (95% CI 4.22-30.56).

    Conclusions: There was an overall increased risk of malignancies in a cohort of AIH patients, which manly was caused by hepatobiliary cancers. However, the true risk of HCC in an AIH cirrhotic cohort has yet to be investigated. A significantly higher risk of lymphomas was also found, but no clear cut association to the use of immune modulators.

  • 122.
    Werner, Marten
    et al.
    Umeå University Hospital.
    Wallerstedt, Sven
    Sahlgrens University Hospital.
    Lindgren, Stefan
    Malmö University Hospital.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bjornsson, Einar
    Sahlgrens University Hospital.
    Bergquist, Annika
    Karolinska University Hospital.
    Prytz, Hanne
    Lund University Hospital.
    Sandberg-Gertzen, Hanna
    Örebro University Hospital.
    Hultcrantz, Rolf
    Karolinska University Hospital.
    Sangfelt, Per
    Uppsala University Hospital.
    Weiland, Ola
    Karolinska University Hospital.
    Ohlsson, Bodil
    Malmö University Hospital.
    Danielsson, Ake
    Umeå University Hospital.
    Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response2010In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 45, no 4, p. 457-467Article in journal (Refereed)
    Abstract [en]

    Objectives. Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH. Material and methods. A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers. Results. At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding. Conclusions. Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.

  • 123. Werner, Mårten
    et al.
    Björnsson, Einar
    Prytz, Hanne
    Lindgren, Stefan
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Broomé, Ulrika
    Wallerstedt, Sven
    Sandberg-Gertzén, Hanna
    Hultcrantz, Rolf
    Sangfeldt, Per
    Nilsson, Jenny
    Danielsson, Åke
    Autoimmune hepatitis among fertile women: Strategies during pregnancy and breastfeeding?2007In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 42, no 8, p. 986-991Article in journal (Refereed)
    Abstract [en]

    Objective. In published studies there is a lack of data about the risks, management and how women with autoimmune hepatitis (AIH) decide on and are advised about pregnancy. The aim of this study was to investigate how women with AIH consider pregnancies, are advised and pharmacologically treated, as well as the outcome. Material and methods. A questionnaire was mailed to 128 women with AIH diagnosed during their fertile period and data from the Swedish National Birth Register was also used for matched controls. Results. There was an 83% response rate to the questionnaires. Sixty-three pregnancies were reported by 35 women. 48% did not consult their doctors before getting pregnant. More than half of the women reduced or stopped the immune suppression during pregnancy or breastfeeding. Some women were advised to abstain from pregnancy or even to have an abortion. Caesarean sections were performed more frequently in the AIH group (16% compared with 6.5% in the control group p<0.01).There were no significant differences in the number of stillborn infants or infants with malformations. However, 30% of the patients experienced flare-up after delivery. Conclusions. In general, the outcome of pregnancy in women with AIH seems to be good. Current pharmacological treatment appears to be safe, including azathioprine during pregnancy and lactation. After delivery an active preparedness to increase pharmacotherapy should be considered. © 2007 Taylor & Francis.

  • 124. Zouali, H
    et al.
    Chamaillard, M
    Lesage, S
    Cezard, JP
    Colombel, JF
    Belaiche, J
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: gastromed.
    Tysk, C
    Montague, S
    Gassull, M
    Christensen, S
    Finkel, Y
    Gower-Rousseau, C
    Modigliani, R
    Macry, J
    Selinger-Leneman, H
    Thomas, G
    Hugot, JP
    Genetic refinement and physical mapping of a chromosome 16q candidate region for inflammatory bowel disease2001In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 9, no 10, p. 731-742Article in journal (Refereed)
    Abstract [en]

    Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37 ╫ 10-4) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P<0.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1.

  • 125.
    Zouali, H
    et al.
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Lesage, S
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Merlin, F
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Cezard, J
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Colombel, J
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Belaiche, J
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Tysk, C
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    O'Morain, C
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Gassull, M
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Modigliani, R
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Gower-Rousseau, C
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Chamaillard, M
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Thomas, G
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    Hugot, JP
    Hop St Louis, Dept Gastroenterol, Paris, France Hosp Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain Adelaide & Meath Hosp, Dept Gastroenterol, Dublin, Ireland Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden Linkoping Univ, Inst Mol & Klin Med, Linkoping, Sweden CHU Liege, Dept Gastroenterol, Liege, Belgium Hop Calmette, Lille, France Hop Robert Debre, F-75019 Paris, France Fdn Jean Dausset, Paris, France.
    CARD4/NOD1 in inflammatory bowel disease.2002In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 71, no 4, p. 1877-Conference paper (Other academic)
  • 126. Zouali, H
    et al.
    Lesage, S
    Merlin, F
    Cezard, JP
    Colombel, JF
    Belaiche, J
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-magtarm.
    Tysk, C
    O'Morain, C
    Gassull, M
    Christensen, S
    Finkel, Y
    Modigliani, R
    Gower-Rousseau, C
    Macry, J
    Chamaillard, M
    Thomas, G
    Hugot, JP
    CARD4/NOD1 is not involved in inflammatory bowel disease2003In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 52, no 1, p. 71-74Article in journal (Refereed)
    Abstract [en]

    Background and aims: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic Factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. Patients and methods: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. Results: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. Conclusion: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

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