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  • 1.
    Aleman, Soo
    et al.
    Departments of Gastroenterology and Hepatology, Karolinska University Hospital/Karolinska Institutet, Stockholm.
    Endalib, Sanam
    Departments of Gastroenterology and Hepatology, Karolinska University Hospital/Karolinska Institutet, Stockholm.
    Stal, Per
    Departments of Gastroenterology and Hepatology, Karolinska University Hospital/Karolinska Institutet, Stockholm.
    Loof, Lars
    Clinincal Research Centre, Västerås.
    Lindgren, Stefan
    Skåne University Hospital, Lund/Malmö.
    Sandberg-Gertzen, Hanna
    Örebro University Hospital, Örebro.
    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.
    Olsson, Sigvard
    Sahlgrenska University Hospital, Göteborg.
    Danielsson, Ake
    Umeå University Hospital, Umeå.
    Wallerstedt, Sven
    Sahlgrenska University Hospital, Göteborg.
    Hultcrantz, Rolf
    Departments of Gastroenterology and Hepatology, Karolinska University Hospital/Karolinska Institutet, Stockholm.
    Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population2011In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 46, no 9, p. 1118-1126Article in journal (Refereed)
    Abstract [en]

    Objective. The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. Patients and methods. 373 patients with hemochromatosis detected through routine health checkups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 +/- 5.8 years. The degree of liver fibrosis and survival were analyzed. Results. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Conclusion. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.

  • 2.
    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.
    Genetiskt genombrott 2: NOD2-genen och Crohns sjukdom2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, p. 3809-3809Article in journal (Other academic)
  • 3.
    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.
    Genetiskt genombrott vid inflammatorisk tarmsjukdom.2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, p. 2795-2795Article in journal (Other academic)
  • 4.
    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.
    Novel Strategies in the Thiopurine Treatment of Inflammatory Bowel Disease2010In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 29, no 04-Jun, p. 267-277Article in journal (Refereed)
    Abstract [en]

    Thiopurine drugs are widely used as immunomodulatory and corticosteroid-sparing agents in inflammatory bowel disease. Despite being old drugs, a renewed research and clinical interest in their application has emerged during the last decade. The application of pharmacogenetic insights and metabolic monitoring, together with treatment strategies in combination with anti-TNF-antibodies and possibilities to modulate their metabolism, has paved the way to a omoderno use of the thiopurines. These aspects are briefly overviewed herein.

  • 5.
    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.
    När dimman lättar. Artikelserie "Aktuellt om inflammatorisk tarmsjukdom"2001In: Patientkanalen, ISSN 1403-7149Article in journal (Other (popular science, discussion, etc.))
  • 6.
    Almer, Sven
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Ulcerative colitis: Imaging of inflammation1995Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ulcerative colitis is a chronic inflannnatory disorder of unknown origin engaging the large bowel. Based on the need for accurate assessment of inflammation, three different non-invasive techniques, two leukocyte scintigraphy techniques and one radiological method, were evaluated in the assessment of active inflammation in altogether 131 patients with ulcerative colitis. Results were compared to those of endoscopy with biopsy, and with histopathological grading of depth of ulceration in colectomy specimens. Nine non-inflamed controls were also included

    Leukoeyte scintigraphy using technetium-99m exarnetazime-labelled lenkocytes was found to reliably differ between patients with and without colonic inflammation. A good correlation existed between a simple visual scoring system of lenkocyte scans and colonic inflannnation viewed endoscopically and histologically in ulcerative colitis. In active disease, inflammation was better visualized with technetiurn-99m exametazimelabelled leukocytes than with technetium-99m anti-granulocyte antibody BW 250/183.

    Air enema radiology was of value in estimating severe mucosal inflammation in acute ulcerative colitis. Presence of faecal residue or a normal air enema film were associated with normal or only mildly inflamed mucosa at colonoscopy, i.e. a friable or ulcerated mucosa can be excluded. The absence of faecal residue or an abnormal finding at air enema X-ray were predictive of endoscopically inflamed mucosa. Air enema radiology underestimated the extent of inflannnation compared to endoscopy or lenkocyte scintigraphy. Air enema radiology was able to demonstrate presence of deep histopathological ulceration in the colectomy specimens from patients with an acute attack of ulcerative colitis.

    In conclusion, scintigraphy with technetium-99m exarnetazime-labelled lenkocytes can be applied in excluding or confirming bowel inflammation in individual patients, and, in assessing intensity and extent of ulcerative colitis. Air enema radiology should be a first-line investigation in acute colitis to assess the presence of mucosal or deeper ulceration.

  • 7.
    Almer, Sven
    et al.
    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.
    Befrits, R.
    Gastrocentrum medicin, Karolinska universitetssjukhuset, Solna, Sweden.
    Eriksson, A.S.
    Medicinkliniken, Sahlgrenska universitetssjukhuset/Östra, Göteborg, Sweden.
    Halfvarson, J.
    Sektionen för gastroenterologi, Medicinska kliniken, Universitetssjukhuset, Örebro, Sweden.
    Hindorf, U.
    VO gastroenterologi, Universitetssjukhuset i Lund, Sweden.
    Lofberg, R.
    IBD-enheten, Sophiahemmet, Stockholm, Sweden.
    Modern läkemedelsterapi vid crohn - Nationella riktlinjer2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 45, p. 2988-2993Article in journal (Refereed)
    Abstract [sv]

    Lättanvända begrepp och definitioner på sjukdomsaktivitet och behandlingseffekt bör få ökad spridning inom sjukvården.

    Majoriteten av patienter med Crohns sjukdom behöver långvarig läkemedelsbehandling, och ungefär hälften genomgår en eller flera operationer någon gång under sjukdomstiden.

    Det är viktigt att tidigt i sjukdomsförloppet identifiera riskfaktorer för utveckling av komplicerad och aggressiv sjukdom och behandla intensivt i dessa fall.

    En aktiv strategi med regelbundet övervägande av tillgängliga behandlingsalternativ medför att de flesta patienter med Crohns sjukdom behåller en god livskvalitet.

  • 8.
    Almer, Sven
    et al.
    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.
    Granerus, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Ström, Magnus
    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.
    Olaison, Gunnar
    Bonnet, Joëlle
    Lémann, Marc
    Smedh, Kennet
    Franzén, Lennart
    Bertheau, Philippe
    Cattan, Pierre
    Rain, Jean-Didier
    Modigliani, Robert
    Leukocyte scintigraphy compared to intraoperative small bowel enteroscopy and laparotomy findings in Crohn's disease2007In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 2, p. 164-174Article in journal (Refereed)
    Abstract [en]

    Background: Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings. Methods: Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy, 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data. Results: In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients, at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71 %) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed. Conclusions: Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery. Copyright © 2006 Crohn's & Colitis Foundation of America, Inc.

  • 9.
    Almer, Sven
    et al.
    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.
    Hindorf, U
    Inflammatorisk tarmsjukdom (IBD) och biologiska läkemedel2008Report (Other academic)
  • 10.
    Almer, Sven
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Hindorf , U
    Lund University.
    6-Thioguanine therapy in Crohns disease-Observational data in Swedish patients2009In: Digestive and Liver Disease, ISSN 1590-8658, E-ISSN 1878-3562, Vol. 41, no 3, p. 194-200Article in journal (Refereed)
    Abstract [en]

    Background and aims: Adverse events (AE) leading to discontinuation or dose-reduction of thiopurine therapy (TP) occur in 9-28% of patients with inflammatory bowel disease. 6-Thioguanine (6-TG) has been proposed as an alternative treatment in patients intolerant for azathioprine (AZA), but some concerns have been raised about drug safety.

    Methods: We evaluated in a prospective manner the tolerance and efficacy of 6-TG in 23 Crohns disease (CD) patients (13 men, median age 41 (19-65) years) with prior intolerance (n = 18) or resistance (It = 5) to AZA and/or 6-mercaptopurine (6-MP). In addition, eight patients had tried mycophenolate mofetil. Seventeen patients (74%) had undergone intestinal resection, often several times.

    Results: Patients were treated with a median daily dose of 40 mg 6-TG (range 20-60) for 259 (15-2272) days. Seven of 13 patients (54%) with active disease went into remission after 8 (4-26) weeks. Sixteen patients (70%) experienced AE that lead to discontinuation (n=10) after 85 (15-451) days or dose reduction (n=6) after 78 (10-853) days. Ten of 18 patients (56%) with prior TP-intolerance discontinued 6-TG treatment due to AE compared to none of five patients with TP-resistance (p=0.046). Of 13 patients that tolerated 6-TG, eight discontinued the drug due to therapeutic failure (n=5) or safety concerns (n=3). Eight patients (35%) continued treatment beyond 12 months. There was no significant difference in maximum thioguanine nucleotide levels between patients with AE leading to discontinuation/dose reduction and patients without AE, 652 (99-2488) vs. 551 (392-1574) pmol/8 x 10(8) RBC; p=0.80.

    Conclusions: In this cohort of CD patients with severe disease failing traditional thiopurine treatment, a small fraction (22%) had long-term benefit of 6-TG-treatment. 6-TG therapy seems to offer a limited therapeutic gain for patients intolerant to both AZA and 6-MP and other treatment options should be considered.

  • 11.
    Almer, Sven
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Tysk, Curt
    Sektionen för gastroenterologi, medicinska kliniken, Universitetssjukhuset, Örebro .
    Andersson, Magnus V.
    Kirurgiska kliniken, Universitetssjukhuset, Örebro.
    Befrits, Ragnar
    Gastrocentrum medicin, Karolinska universitetssjukhuset, Solna.
    Hertervig, Erik
    VO gastroenterologi och nutrition, Universitetssjukhuset , Lund.
    Kilander, Anders
    Sektionen för gastroenterologi, Sahlgrenska universitetsjukhuset, Göteborg.
    Lindgren, Stefan
    Sektionen för gastroenterologi, Universitetssjukhuset MAS, Malmö.
    Suhr, Ole
    Sektionen för gastroenterologi, Norrlands universitetssjukhus, Umeå.
    Handläggning av svårt skov av ulcerös kolit. In: Löfberg R (ed): Inflammatorisk tarmsjukdom.2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 45, p. 62-75Article in journal (Refereed)
    Abstract [sv]

    Patienter med svårt skov av ulcerös kolit bör vårdas på sjukhus och handläggas av gastroenterolog och kolorektal kirurg i nära samarbete.

    Skovets svårighetsgrad kan underskattas, varför noggrann bedömning av inflammationens utbredning och svårighetsgrad enligt validerade kriterier är viktigt.

    Intravenös behandling med kortikosteroider är en av hörn­stenarna i den akuta behandlingen.

    Patienter som inte förbättras på denna behandling, bör erbjudas medicinsk »rescue-behandling« eller kolektomi.

    Infliximab har visats vara en effektiv rescue-behandling och kan minska behovet av kol­ektomi inom de första 3 månaderna och upp till 3 år.

  • 12.
    Andersson, Peter
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Arvidsson, M.
    Dabrosin-Söderholm, J.
    Nyström, Per-Olof
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Smedh, K.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Sjödahl, Rune
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Low symptomatic load in Crohn's disease with surgery and medicine as complementary treatments1998In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 33, no 4, p. 423-429Article in journal (Refereed)
    Abstract [en]

    Background: The treatment of Crohn's disease has changed owing to the recognition of its chronicity. Medical maintenance treatment and limited resections have evolved as major concepts of management, regarded as complementary, and both aim at reducing the symptoms.

    Methods: We investigated the symptomatic load in Crohn's disease as reflected in a cross-sectional study of the symptom index, physicians' assessment, and the patients' perception of health. A cohort of 212 patients from the primary catchment area and 125 referred patients were studied.

    Results: Of catchment area patients, 83% were receiving medication, and the annual rate of abdominal surgery was 5.7%. Corresponding figures for the referred patients were 82% and 10.3%. According to the symptom index, 87% of catchment area patients were in remission or had only mild symptoms; according to the physicians' assessment, 90% were. The patients' median perception of health was 90% of perfect health according to the visual analogue scale. The figures were similar for referred patients, except that referrals were considered more diseased by the physician.

    Conclusion: The great majority of patients with Crohn's disease are able to live in remission or experience only mild symptoms.

  • 13.
    Andersson, Thord
    et al.
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Anette
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Smedby, Örjan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Borga, Magnus
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Consistent intensity inhomogeneity correction in water–fat MRI2015In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 42, no 2, p. 468-476Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To quantitatively and qualitatively evaluate the water-signal performance of the consistent intensity inhomogeneity correction (CIIC) method to correct for intensity inhomogeneities METHODS: Water-fat volumes were acquired using 1.5 Tesla (T) and 3.0T symmetrically sampled 2-point Dixon three-dimensional MRI. Two datasets: (i) 10 muscle tissue regions of interest (ROIs) from 10 subjects acquired with both 1.5T and 3.0T whole-body MRI. (ii) Seven liver tissue ROIs from 36 patients imaged using 1.5T MRI at six time points after Gd-EOB-DTPA injection. The performance of CIIC was evaluated quantitatively by analyzing its impact on the dispersion and bias of the water image ROI intensities, and qualitatively using side-by-side image comparisons.

    RESULTS:

    CIIC significantly ( P1.5T≤2.3×10-4,P3.0T≤1.0×10-6) decreased the nonphysiological intensity variance while preserving the average intensity levels. The side-by-side comparisons showed improved intensity consistency ( Pint⁡≤10-6) while not introducing artifacts ( Part=0.024) nor changed appearances ( Papp≤10-6).

    CONCLUSION:

    CIIC improves the spatiotemporal intensity consistency in regions of a homogenous tissue type. J. Magn. Reson. Imaging 2014.

  • 14.
    Andersson, Thord
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Romu, Thobias
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Forsgren, Mikael
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    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.
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Borga, Magnus
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Self-calibrated DCE MRI using Multi Scale Adaptive Normalized Averaging (MANA)2012In: Proceedings of the annual meeting of the International Society for Magnetic Resonance in Medicine (ISMRM 2012), 2012, 2012Conference paper (Other academic)
  • 15. Bergquist, A
    et al.
    Ekbom, A
    Olsson, R
    Kornfeldt, D
    Lööf, L
    Danielsson, P
    Hultcrantz, R
    Lindgren, S
    Prytz, H
    Sandberg-Gertzén, H
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    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, EMK-magtarm.
    Hepatic and extrahepatic malignancies in primary sclerosing cholangitis2002In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 36, no 3, p. 321-327Article in journal (Refereed)
    Abstract [en]

    Background/Aims: To assess the risk of hepatic and extrahepatic malignancies in a large cohort of Swedish primary sclerosing cholangitis (PSC) patients compared with that of the general Swedish population. Methods: The study cohort comprised 604 PSC patients identified between 1970 and 1998. Follow-up was provided through linkages to the Swedish Cancer and Death registries. Cumulative incidence of malignancies and standard incidence ratio were calculated with the incidence rates in the Swedish population, taking into account: sex, age and calendar year as comparison group. Results: Median time of follow-up was 5.7 years (range 0-27.8). Seventy-nine percent had concomitant inflammatory bowel disease. The cause of death was cancer in 44%. The frequency of hepatobiliary malignancies was 13.3% (81/604). Thirty-seven percent (30/81) of all hepatobiliary malignancies were diagnosed less than 1 year after the diagnosis of PSC. The risk for hepatobiliary malignancy was increased 161 times, for colorectal carcinoma 10 times and for pancreatic carcinoma 14 times, compared with that of the general population. Conclusions: In this national-based study including the largest cohort of PSC patients ever presented, the frequency of cholangiocarcinoma is 13 %. The risk of hepatobiliary carcinoma is constant after the first year after PSC diagnosis with an incidence rate of 1.5% per year. The risk of pancreatic carcinoma is increased 14 times compared with the general Swedish population. These results are suggestive of an increased risk of pancreatic carcinoma in patients with PSC.

  • 16.
    Bergquist, A.
    et al.
    Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institute, Huddinge and Solna, Stockholm.
    Montgomery, S.M.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Clinical Research Centre, Örebro University Hospital, Örebro.
    Bahmanyar, S.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm.
    Olsson, R.
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Danielsson, A.
    Danielsson, Å., Department of Medicine, Section for Gastroenterology and Hepatology, University Hospital, Umeå.
    Lindgren, S.
    Department of Gastroenterology and Hepatology, University Hospital, Malmö.
    Prytz, H.
    Division of Gastroenterology and Hepatology, University Hospital, Lund.
    Hultcrantz, R.
    Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institute, Huddinge and Solna, Stockholm.
    Loof, L.A.R.S.
    Lööf, L.A.R.S., Centre for Clinical Research, Central Hospital, Västerås.
    Sandberg-Gertzen, H.
    Sandberg-Gertzén, H., Division of Gastroenterology and Hepatology, Department of Medicine, Medical Center Hospital, Örebro.
    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.
    Askling, J.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm.
    Ehlin, A.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm.
    Ekbom, A.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm.
    Increased Risk of Primary Sclerosing Cholangitis and Ulcerative Colitis in First-Degree Relatives of Patients With Primary Sclerosing Cholangitis2008In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 6, no 8, p. 939-943Article in journal (Refereed)
    Abstract [en]

    Background & Aims: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. Methods: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. Results: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohn's disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9). Conclusions: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC. © 2008 AGA Institute.

  • 17. Björnsson, Einar
    et al.
    Wei, Gu
    Bergquist, Annika
    Broomé, Ulrika
    Wallerstedt, Sven
    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.
    Sangfelt, Per
    Danielsson, Åke
    Sandberg-Gertzén, Hanna
    Lööf, Lars
    Prytz, Hanne
    Lindgren, Stefan
    Akut leversvikt - viktigt med snabb multidisciplinär handläggning.2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 4, p. 210-213Article in journal (Other academic)
    Abstract [sv]

       

  • 18.
    Bodemar, Göran
    et al.
    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.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    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.
    Danielson, BG
    Treatment of anaemia in inflammatory bowel disease with iron sucrose2004In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 39, no 5, p. 454-458Article in journal (Refereed)
    Abstract [en]

    Background: Inflammatory bowel disease (IBD)-associated anaemia usually responds to intravenous iron. If not, additive treatment with erythropoietin has been proposed. The objective of the present retrospective study was to evaluate the effectiveness of treatment with iron sucrose alone. Methods: Sixty-one patients with IBD and anaemia (average haemoglobin 97 g/L) were treated with iron sucrose (iron dose 1.4 ± 0.5 g). The indications for iron sucrose were poor response and/or intolerance to oral iron. Treatment response was defined as an increase in haemoglobin of ≥20 g/L or to normal haemoglobin levels (>120 g/L). Two independent investigators retrospectively assessed laboratory variables, clinical findings, and concomitant medication. Results: Two patients were transferred to other hospitals after treatment and therefore could not be evaluated. Fifty-four of the remaining 59 patients (91%) responded within 12 weeks. Sixty percent of the patients had responded within 8 weeks. Five patients had no or only a partial response to iron sucrose of which three had prolonged gastrointestinal blood losses. Eight patients with normal or elevated levels of ferritin could be considered to have anaemia of chronic disease, and all of them responded to iron sucrose. During a follow-up period of 117 ± 85 (4-291) (mean ± s (standard deviation) (range)) weeks 19 patients (32%) needed at least one second course of iron sucrose because of recurrent disease. Conclusions: Anaemia associated with IBD can be successfully treated with intravenously administered iron sucrose, provided that bowel inflammation is treated adequately and enough iron is given. Treatment with iron sucrose is safe. Follow-up of haemoglobin and iron parameters to avoid further iron deficiency anaemia is recommended.

  • 19.
    Bostrom, E A
    et al.
    University of Gothenburg.
    Bokarewa, M
    University of Gothenburg.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    HIGH PLASMA RESISTIN LEVELS IN AUTOIMMUNE HEPATITIS2009In: in JOURNAL OF HEPATOLOGY, vol 50, 2009, Vol. 50, p. S242-S242Conference paper (Refereed)
  • 20.
    Boström, E A
    et al.
    University of Gothenburg.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Bokarewa, M I
    University of Gothenburg.
    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.
    Resistin is Associated with Breach of Tolerance and Anti-nuclear Antibodies in Patients with Hepatobiliary Inflammation2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, no 5, p. 463-470Article in journal (Refereed)
    Abstract [en]

    Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohns disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P andlt; 0.001) and PSC (P andlt; 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P andlt; 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody-mediated gastrointestinal inflammatory diseases.

  • 21. Broomé, U
    et al.
    Glaumann, H
    Lindström, E
    Lööf, L
    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, EMK-magtarm.
    Prytz, H
    Sandberg-Gertzén, H
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    Lindgren, S
    Fork, F-T
    Järnerot, G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    Olsson, R
    Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC)2002In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 36, no 5, p. 586-589Article in journal (Refereed)
    Abstract [en]

    Background/Aims: This study aims at describing the natural history and outcome of small duct primary sclerosing cholangitis (PSC). Methods: Thirty-two patients with small duct PSC were studied. The average time taken for diagnosis was 69 (1-168) months. The median follow-up time was 63 (1-194) months. Results: All patients including one who underwent liver transplantation because of end-stage liver disease and hepatocellular carcinoma were alive at follow-up. None developed cholangiocarcinoma. In 27 patients repeated cholangiographic examinations were done after a median time of 72 (12-192) months from first ERCP. Four developed features of large duct PSC. Conclusions: Small duct PSC rarely progresses to large bile duct PSC and it seems to have a benign course in most patients and no development of cholangiocarcinoma was found.

  • 22.
    Burisch, J.
    et al.
    Herlev University Hospital, Denmark .
    Pedersen, N.
    Herlev University Hospital, Denmark .
    Cukovic-Cavka, S.
    University of Zagreb, Croatia .
    Brinar, M.
    University of Zagreb, Croatia .
    Kaimakliotis, I.
    Nicosia Private Practice, Cyprus .
    Duricova, D.
    Charles University of Prague, Czech Republic .
    Shonova, O.
    Hospital Ceske Budejovice, Czech Republic .
    Vind, I.
    Amager Hospital, Denmark .
    Avnstrom, S.
    Amager Hospital, Denmark .
    Thorsgaard, N.
    Herning Central Hospital, Denmark .
    Andersen, V.
    Viborg Regional Hospital, Denmark Hospital Southern Jutland, Denmark University of Southern Denmark, Denmark .
    Krabbe, S.
    Viborg Regional Hospital, Viborg, Denmark.
    Dahlerup, J.F.
    Aarhus University Hospital, Denmark .
    Salupere, R.
    Tartu University Hospital, Estonia .
    Nielsen, K.R.
    National Hospital Faroe Isl, Denmark .
    Olsen, J.
    National Hospital Faroe Isl, Denmark .
    Manninen, P.
    Tampere University Hospital, Finland .
    Collin, P.
    Tampere University Hospital, Finland .
    Tsianos, E.V.
    University Hospital, Greece University Hospital, Greece .
    Katsanos, K.H.
    University Hospital, Greece University Hospital, Greece .
    Ladefoged, K.
    Dronning Ingrids Hospital, Greenland .
    Lakatos, L.
    Semmelweis University, Budapest, Hungary.
    Bjornsson, E.
    National University Hospital Reykjavik, Iceland .
    Ragnarsson, G.
    National University Hospital Reykjavik, Iceland .
    Bailey, Y.
    ACD, Ireland .
    Odes, S.
    Ben Gurion University of Negev, Israel Ben Gurion University of Negev, Israel .
    Schwartz, D.
    Ben Gurion University of Negev, Israel Ben Gurion University of Negev, Israel .
    Martinato, M.
    University of Padua, Italy .
    Lupinacci, G.
    UO Gastroenterol Endoscopia Digest, Italy .
    Milla, M.
    Careggi Hospital, Italy .
    De Padova, A.
    Osped Morgagni Pierantoni, Italy .
    D'lnca, R.
    Azienda Ospedaliera—Università di Padova, Padova, Italy.
    Beltrami, M.
    Azienda Osped Arcispedale S Maria Nuova, Italy .
    Kupcinskas, L.
    Az Osped Osped Cremona, Italy Lithuanian University of Health Science, Lithuania .
    Kiudelis, G.
    Lithuanian University of Health Science, Lithuania .
    Turcan, S.
    State University of Medicine and Pharmacy of the Republic of Moldova, Chisinau, Republic of Moldova.
    Tighineanu, O.
    Centre Mother and Child, Moldova .
    Mihu, I.
    Centre Mother and Child, Moldova .
    Magro, F.
    Hospital Sao Joao, Portugal Oporto Medical Sch, Portugal University of Porto, Portugal .
    Barros, L.F.
    Hospital Vale Sousa, Portugal .
    Goldis, A.
    University of Medical Victor Babes, Romania .
    Lazar, D.
    University of Medical Victor Babes, Romania .
    Belousova, E.
    Moscow Regional Research Clin Institute, Russia .
    Nikulina, I.
    Moscow Regional Research Clin Institute, Russia .
    Hernandez, V.
    Complexo Hospital University of Vigo, Spain .
    Martinez-Ares, D.
    Complexo Hospital University of Vigo, Spain .
    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.
    Zhulina, Y.
    Örebro University Hospital, Sweden .
    Halfvarson, J.
    Örebro University Hospital, Sweden Rebro University, Sweden .
    Arebi, N.
    University of London Imperial Coll Science Technology and Med, England .
    Sebastian, S.
    Hull and E Yorkshire NHS Trust and Hull and York, England .
    Lakatos, P.L.
    Semmelweis University, Budapest, Hungary.
    Langholz, E.
    Gentofte University Hospital, Denmark .
    Munkholm, P.
    Herlev University Hospital, Denmark .
    East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort2014In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 63, no 4, p. 588-597Article in journal (Refereed)
    Abstract [en]

    Objective The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East–West gradient in the incidence of IBD in Europe exists.

    Design A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience.

    Results 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100 000 in 2010 for CD were 6.5 (range 0–10.7) in Western European centres and 3.1 (range 0.4–11.5) in Eastern European centres, for UC 10.8 (range 2.9–31.5) and 4.1 (range 2.4–10.3), respectively, and for IBDU 1.9 (range 0–39.4) and 0 (range 0–1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy.

    Conclusions An East–West gradient in IBD incidence exists in Europe. Among this inception cohort—including indolent and aggressive cases—international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

  • 23.
    Burisch, Johan
    et al.
    Herlev University Hospital.
    Cukovic-Cavka, Silvija
    University Hospital Rebro.
    Kaimakliotis, Ioannis
    Nicosia private practice, Cyprus.
    Shonova, Olga
    Hospital Ceske Budejovice.
    Andersen, Vibeke
    Viborg Reg Hospital.
    Dahlerup, Jens F.
    Arhus University Hospital.
    Elkjaer, Margarita
    Herlev University Hospital.
    Langholz, Ebbe
    Gentofte University Hospital.
    Pedersen, Natalia
    Herlev University Hospital.
    Salupere, Riina
    Tartu University Hospital.
    Kolho, Kaija-Leena
    University Helsinki.
    Manninen, Pia
    Tampere University Hospital.
    Laszlo Lakatos, Peter
    Semmelweis University Med.
    Shuhaibar, Mary
    Adelaide and Meath Hospital.
    Odes, Selwyn
    Soroka Med Centre.
    Martinato, Matteo
    University Padua.
    Mihu, Ion
    Centre Mother and Child University Hospital.
    Magro, Fernando
    Hospital Sao Joao.
    Belousova, Elena
    Moscow Reg Research Clin Institute.
    Fernandez, Alberto
    Hospital Povisa.
    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.
    Halfvarson, Jonas
    Orebro University Hospital.
    Hart, Ailsa
    University London Imperial Coll Science Technology and Med.
    Munkholm, Pia
    Herlev University Hospital.
    Construction and validation of a web-based epidemiological database for inflammatory bowel diseases in Europe An EpiCom study2011In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 5, no 4, p. 342-349Article in journal (Refereed)
    Abstract [en]

    Background: The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. Aim: To construct and validate a web-based inception cohort database available in both English and Russian language. Method: The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. Results: The EpiCom database fulfills the requirements of the participating countries local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. Conclusion: A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu. (C) 2011 European Crohns and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  • 24. de Boer, NKH
    et al.
    Reinisch, W
    Teml, A
    van Bodegraven, AA
    Schwab, M
    Lukas, M
    Ochsenkuhn, T
    Petritsch, W
    Knoflach, P
    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.
    van der Merwe, SW
    Herrlinger, KR
    Seiderer, J
    Vogelsang, H
    Mulder, CJJ
    6-thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party2006In: Digestion, ISSN 0012-2823, E-ISSN 1421-9867, Vol. 73, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity. Copyright (c) 2006 S. Karger AG, Basel.

  • 25.
    Elmberg, M.
    et al.
    Dept. of Gastroenterol. and Hepatol., Karolinska Hospital, S-171 76 Stockholm, Sweden.
    Hultcrantz, R.
    Dept. of Gastroenterol. and Hepatol., Karolinska Hospital, S-171 76 Stockholm, Sweden.
    Ekbom, A.
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Hospital, Stockholm, Sweden.
    Brandt, L.
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Hospital, Stockholm, Sweden.
    Olsson, S.
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Olsson, R.
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lindgren, S.
    Department of Medicine, Malmö University Hospital, Malmö, Sweden.
    Loof, L.
    Lööf, L., Department of Medicine, Uppsala Academic Hospital, Uppsala, Sweden.
    Stal, P.
    Department of Medicine, Danderyds Hospital, Danderyd, Sweden.
    Wallerstedt, S.
    Department of 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.
    Sandberg-Gertzen, H.
    Sandberg-Gertzén, H., Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Askling, J.
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Hospital, Stockholm, Sweden.
    Cancer Risk in Patients with Hereditary Hemochromatosis and in Their First-Degree Relatives2003In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 125, no 6, p. 1733-1741Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Iron overload may be carcinogenic. Patients with hereditary hemochromatosis (HH) are reportedly at a 20-200-fold risk of intrahepatic cancer, but the reported risks for nonhepatobiliary cancers are conflicting. The risk of cancer in heterozygous individuals (estimated allele frequency, 1/10 to 1/20) is unknown. This study aimed to better assess these risks. Methods: We performed a population-based cohort study of 1847 Swedish patients with HH and 5973 of their first-degree relatives using nationwide, population-based health and census registers. We used standardized incidence ratios (SIRs) as relative risk. Results: With 62 liver cancers and 128 nonhepatobiliary cancers, patients with HH were at a 20-fold risk of liver cancer (SIR, 21, 95% confidence interval [Cl], 16-22) but an almost unaltered risk of all other cancers (SIR, 1.2, 95% Cl, 1.0-1.4), including nonelevated risks for several gastrointestinal tract cancers. At 10 years of follow-up, the absolute risk of liver cancer was 6% among men and 1.5% among women. With 21 liver cancers and 508 nonhepatobiliary cancers, first-degree relatives were at an unaltered risk of extrahepatic cancer (SIR, 1.0, 95% Cl, 0.9-1.1, including unelevated risks for gastrointestinal cancers) but at a modest and historic increased risk of hepatobiliary cancer (SIR, 1.5, 95% Cl, 1.0-2.4), the histopathologic spectrum of which differed from the patients. Conclusions: Patients (particularly men) with HH are at increased risk for hepatocellular cancer, although the magnitude of the risk is lower than previous estimates. Overall cancer risk in first-degree relatives does not seem to be increased.

  • 26.
    Elmberg, Maria
    et al.
    Karolinska Hospital.
    Hultcrantz, Rolf
    Karolinska Hospital.
    Ebrahim, Fereshte
    Natl Board Hlth & Welf, Centre Epidemiol, Stockholm.
    Olsson, Sigvard
    Sahlgrens University Hospital.
    Lindgren, Stefan
    University Hospital MAS.
    Loof, Lars
    Central Hospital Vasterås.
    Stal, Per
    Karolinska Hospital.
    Wallerstedt, Sven
    Sahlgrens 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.
    Sandberg-Gertzen, Hanna
    Örebro University Hospital.
    Ekbom, Anders
    Karolinska Hospital.
    Askling, Johan
    Karolinska Hospital.
    Increased Mortality Risk in Patients With Phenotypic Hereditary Hemochromatosis But Not in Their First-Degree Relatives2009In: GASTROENTEROLOGY, ISSN 0016-5085, Vol. 137, no 4, p. 1301-1309Article in journal (Refereed)
    Abstract [en]

    BACKGROUND andamp; AIMS: Hereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. METHODS: We performed a matched population-based cohort study of 3832 patients with HH and their 14,496 first-degree relatives using data collected from 1990 through 2007. Mortality data from these groups were compared with that of 38,969 population controls and their 143,349 first-degree relatives using Cox regression analyses. RESULTS: Patients identified on the basis of hospitalization with HH had an increased risk (relative risk [RR]) for death (RR, 2.45; 95% confidence interval [CI], 2.27-2.64; 857 deaths). Patients identified through other means had a mortality risk that was lower than those identified in the hospital but higher than controls (RR, 1.15; 95% CI, 1.00-1.33; 216 deaths). Their first-degree relatives had only a marginally increased mortality risk (RR, 1.05; 95% CI, 1.01-1.10); this RR was similar to that of patients spouses (RR, 1.09; 95% CI, 0.86-1.38; 82 deaths). Patients with HH who also had a family history of HH did not have an increased mortality risk compared with other groups (RR, 1.05; 95% CI 0.67-1.62; 21 deaths). CONCLUSIONS: Patients with HH have a modestly increased mortality risk compared with controls. The mortality of relatives is increased marginally compared with controls, and is similar among biological and nonbiological relatives.

  • 27.
    Forsgren, Mikael
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Ekstedt, Mattias
    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.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Andregård, O.
    Dahlström, Nils
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    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.
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Prospective evaluation of liver steatosis comparing stereological point-counting biopsy analysis and 1H MRS2012Conference paper (Other academic)
  • 28.
    Fransson, Martin
    et al.
    Linköping University, Department of Computer and Information Science, PELAB - Programming Environment Laboratory. Linköping University, The Institute of Technology.
    Fritzson, Peter
    Linköping University, Department of Computer and Information Science, PELAB - Programming Environment Laboratory. Linköping University, The Institute of Technology.
    Lindqvist Appell, Malin
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Hindorf, Ulf
    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 Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    A preliminary study of modeling and simulation in individualized drug dosage – azathioprine on inflammatory bowel disease2007In: SIMS 2006: Proceedings of the 47th Conference on Simulation and Modelling, Helsinki, Finland, Helsinki: Kopio Niini Oy , 2007, p. 216-220Conference paper (Refereed)
    Abstract [en]

    Individualized drug dosage based on population pharmacokinetic/dynamic models is an important future technology used to reduce or eliminate side effects of certain drugs, e.g. cancer drugs. In this paper we report preliminary results from work-in-progress: a simplified linear model of the metabolism of a cancer treatment drug was estimated from experimental data. The model was then validated against the same data as a test of the adequacy of the model structure. From this investigation it became apparent that the model structure could not be used due to its inability to recreate the dynamic properties of the system.

  • 29.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. 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.
    Söderman, Jan
    Ryhov County Hospital, Jönköping, Sweden .
    Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease: Novel Clues to Drug Targets and Disease Mechanisms?2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed)
    Abstract [en]

    Background and Aims

    Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity.

    Methods

    Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0–14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately.

    Results

    Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn’s disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes.

    Conclusions

    Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.

  • 30.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    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.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Söderman, Jan
    Division of Medical Diagnostics, Laboratory medicine, Ryhov Hospital, Jönköping, Sweden.
    Pharmacotranscriptomics in thiopurine treated IBD patients with different metabolite profiles2008Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Thiopurine drugs are used to induce and maintain remission in inflammatory bowel disease. The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been related to drug response and adverse reactions. Here we investigated for differences in gene expression levels between patients with different metabolite profiles.

    Methods: Transcriptional profiles in blood samples from an exploratory patient cohort (n=21) comprising three groups; patients with normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN concentration ratio >20, ratio 10.0-14.0 and ratio ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with reverse transcription qPCR [exploratory and a validation cohort of patients (n=33)]. Additionally, known genes of the thiopurine metabolic pathway were analysed separately.

    Results: The whole genome expression analysis did not identify any significant differences between metabolite profiles. Analysis of thiopurine related genes revealed a large interindividual variation in gene expression, but only small differences between metabolite profiles. Three clusters of co-regulated genes were defined based on correlations between gene expression levels. The concentration of meTIMP correlated to the expression of NT5E (rs = 0.33, P = 0.02) and TPMT (rs = - 0.37, P = 0.007). The concentration of 6-TGN correlated to the expression of HPRT1 (rs = - 0.31, P = 0.03) and SLC29A1 (rs = 0.33, P = 0.02). With the exception of SLC29A1, these genes belonged to the same cluster of genes.

    Conclusions: Our results illustrates the complexity of the thiopurine metabolism and suggest that differences between metabolite profiles are explained either by interactions between several genes, each with a small contribution, or at the post-transcriptional level. Search for more precise tools in order to explain differences in metabolite profiles is needed.

  • 31.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Lindqvist Appell, Malin
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    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.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Taipalensuu, J.
    Div. of R. and D. in Lab. Medicine, Ryhov County Hospital, SE-551 85 Jönköping, Sweden.
    Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease2004In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 50, no 2, p. 288-295Article in journal (Refereed)
    Abstract [en]

    Background: Interindividual differences in therapeutic efficacy in patients treated with thiopurines might be explained by the presence of thiopurine S-methyltransferase (TPMT) alleles that encode for reduced TPMT enzymatic activity. It is therefore of value to know an individual's inherent capacity to express TPMT. Method: We developed a pyrosequencing method to detect 10 single-nucleotide polymorphisms (SNPs) in TPMT. A Swedish population (n = 800) was examined for TPMT*3A, TPMT*3B, TPMT*3C, and TPMT*2. Patients with inflammatory bowel disease (n = 24) and healthy volunteers (n = 6), selected on the basis of TPMT enzymatic activity, were investigated for all 10 SNPs to determine the relationship between TPMT genotype and phenotype. Results: In the general population we identified the following genotypes with nonfunctional alleles: TPMT*1/*3A (*3A allelic frequency, 3.75%), TPMT*1/*3C (*3C allelic frequency, 0.44%), TPMT*1/*3B (*3B allelic frequency, 0.13%), and TPMT*1/*2 (*2 allelic frequency, 0.06%). All nine individuals with normal enzymatic activity were wild-type TPMT*1/*1. Thirteen individuals with intermediate activity were either TPMT*1/*3A (n = 12) or TPMT*1/*2 (n = 1). Eight individuals with low enzymatic activity were TPMT*3A/*3A (n = 4), TPMT*3A/*3C (n = 2), or TPMT*1/*3A (n = 2). Conclusion: Next to wild type, the most frequent alleles in Sweden are TPMT*3A and TPMT*3C. A previously established phenotypic cutoff for distinguishing normal from intermediate metabolizers was confirmed. To identify the majority of cases (90%) with low or intermediate TPMT activity, it was sufficient to analyze individuals for only 3 of the 10 SNPs investigated. Nevertheless, this investigation indicates that other mutations might be of relevance for decreased enzymatic activity. © 2004 American Association for Clinical Chemistry.

  • 32.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Taipalensuu, Jan
    1Research and Development in Laboratory Medicine Laboratory Medicine, Ryhov Hospital, Jönköping.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    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.
    IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - Relation to TPMT activity and metabolite concentrations2008In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, no 1, p. 69-77Article in journal (Refereed)
    Abstract [en]

    AIMS: Azathioprine and 6-mercaptopurine are steroid-sparing drugs used in inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and occurrence of adverse events. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the role of inosine-5′- monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo synthesis of guanine nucleotides and also strategically positioned in the metabolic pathway of thiopurines. METHODS: IMPDH was measured in 100 healthy blood donors. IMPDH, TPMT and metabolite concentrations were studied in 50 patients with IBD on stable thiopurine therapy. IMPDH activity was measured in peripheral blood mononuclear cells. TPMT activity, 6-methylthioinosine 5′-monophosphate (meTIMP) and 6-thioguanine nucleotide (6-TGN) concentrations were measured in red blod cells, which is the current practice in clinical monitoring of thiopurines. Enzyme activities were related to metabolite concentrations and clinical characteristics. RESULTS: A wide range of IMPDH activity was observed both in healthy blood donors (median 13.1, range 4.7-24.2 nmol mg-1 protein h-1) and IBD patients (median 14.0, range 7.0-21.7). There was a negative correlation between IMPDH activity and dose-normalized meTIMP concentrations (rs = -0.31, P = 0.03), but no evident correlation to 6-TGN concentration or the meTIMP/6-TGN ratio. There were no significant correlations between TPMT activity and metabolite concentrations. CONCLUSION: Even though the meTIMP concentrations correlated inversely to the IMPDH activity, the role of IMPDH in balancing the formation of methylated and phosphorylated metabolites was not evident. Taken together, the results give cause to question established opinions about thiopurine metabolism. © 2007 The Authors.

  • 33.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Söderman, Jan
    Division of Medical Diagnostics, Laboratory Medicine, Ryhov Hospital, Jönköping;.
    Hindorf, Ulf
    Department of Gastroenterology, Lund University Hospital, Lund.
    Grännö, Christer
    Department of Medicine, Ryhov Hospital, Jönköping.
    Danelius, Margareta
    Department of Internal Medicine, Ersta Hospital, Stockholm, Sweden.
    Coulthard, Sally
    Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
    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.
    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.
    The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease2011In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 33, no 2, p. 200-208Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated.

    METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities.

    RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001).

    CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.

  • 34.
    Hindorf, U.
    et al.
    Skåne 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, Heart and Medicine Center, Department of Gastroentorology.
    Letter: successful mercaptopurine therapy after azathioprine-related pancreatitis in patients with IBD – authors' reply2013In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 37, no 1, p. 162-163Article in journal (Other academic)
  • 35.
    Hindorf, U
    et al.
    Lund University Hospital.
    Johansson, M
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Eriksson, A
    Sahlgrens University Hospital.
    Kvifors, E
    Sahlgrens 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.
    Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease2009In: ALIMENTARY PHARMACOLOGY and THERAPEUTICS, ISSN 0269-2813, Vol. 29, no 6, p. 654-661Article in journal (Refereed)
    Abstract [en]

    Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance.

    To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance.

    We identified 135 patients (74 women; median age 40 years) with Crohns disease (n = 88) or ulcerative colitis (n = 47) and reviewed their medical records.

    A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362-1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8-92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4-15.3) vs. 11.8 (9.6-14.2) U/mL red blood cells; P = 0.04; n = 81].

    A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.

  • 36.
    Hindorf, U.
    et al.
    Division of Gastroenterology, Department of Internal Medicine, University Hospital, Lund, Sweden, Division of Gastroenterology, Department of Internal Medicine, University Hospital, SE-221 85 Lund, Sweden.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    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.
    Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy: Results from a large swedish patient population2004In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 26, no 6, p. 673-678Article in journal (Refereed)
    Abstract [en]

    This study examined thiopurine methyltransferase (TPMT) and the relationship to thioguanine nucleotides (TGN) and methylthioinosine monophosphate (meTIMP) in a large Swedish patient population. The current hypothesis is that the cytotoxic effects of thiopurine drugs are mediated by the incorporation of TGN into DNA. The authors assayed the TPMT activity in red blood cells from 1151 subjects and the concentrations of TGN (n = 602) and meTIMP (n = 593) from patients treated with thiopurine drugs. The TPMT frequency distribution in both adults and children showed some differences from what had been found in unselected general populations. Children had lower median TPMT activity than adults (12.0 versus 12.9 U/mL RBC, P < 0.001). Relative differences in both TGN formation [medians: normal TPMT, 1.3, intermediate TPMT, 3.3, low TPMT, 47.9 pmol/8 × 108 RBC per mg azathioprine (AZA), P < 0.001] and meTIMP formation (medians: normal TPMT, 13, intermediate TPMT, 7.3, low TPMT, 0 pmol/8 × 108 RBC per mg AZA, P = 0.001) per 1 mg administered drug were noted among the 3 TPMT activity groups. Women formed higher concentrations of both TGN (1.5 versus 1.3 pmol/8 × 108 RBC per mg AZA, P = 0.01) and meTIMP (14.4 versus 10.7 pmol/8 × 108 RBC per mg AZA, P = 0.01) than men did. There was a significant correlation between the AZA dose and the meTIMP concentrations (r = 0.45, P < 0.001). Furthermore, dose alterations made in subjects with normal TPMT (n = 84) and intermediate TPMT (n = 22) activity resulted in more pronounced increases in TGN concentrations (170 versus 30 pmol/8 × 10 8 RBC, P < 0.001) in intermediate TPMT activity, whereas in normal TPMT activity changes in meTIMP concentrations were more pronounced (1.3 versus 0 nmol/8 × 108 RBC, P < 0.001). In normal TPMT activity both metabolites increased in a dose-dependent fashion, whereas in intermediate TPMT activity only TGN concentrations increased. The results of this study demonstrate the dynamic nature of thiopurine metabolism and its importance for thiopurine dosing.

  • 37. Hindorf, U
    et al.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    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.
    Assessment of Thiopurine Methyltransferase and Metabolite Formation During Thiopurine Therapy: Results from a Large Swedish Patient Population2004In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 26, p. 673-678Article in journal (Refereed)
  • 38.
    Hindorf, Ulf
    et al.
    Lund University Hospital.
    Jahed, Khatoon
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Bergquist, Annika
    Karolinska University Hospital.
    Verbaan, Hans
    Malmo University Hospital.
    Prytz, Hanne
    Lund University Hospital.
    Wallerstedt, Sven
    Sahlgrens University Hospital.
    Werner, Marten
    Umeå University Hospital.
    Olsson, Rolf
    Sahlgrenska University Hospital.
    Bjoernsson, Einar
    Sahlgrenska University Hospital.
    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.
    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.
    Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis2010In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 52, no 1, p. 106-111Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Corticosteroids alone or in conjunction with azathioprine (AZA) is the standard treatment in autoimmune hepatitis (AiH). Individual variations in thiopurine (TP) metabolism may affect both drug efficacy and toxicity. Our aim was to investigate the utility of thiopurine methyl transferase (TPMT) as well as thioguanine nucleotide (TGN) and methylthioinosine monophosphate (meTIMP) metabolite measurements with regard to clinical outcome. Methods: Two hundred thirty-eight patients with AM were included in this cross-sectional study. TPMT status was assessed in all patients, while TGN and meTIMP were measured in patients with ongoing TP medication. Clinical outcome was evaluated by liver tests and the ability to withdraw steroids. Results: TPMT genotyping (n = 229) revealed 207 (90.4%) wildtype and 22 heterozygous patients. One hundred forty-three patients had ongoing TP therapy with AZA (n = 134) or mercaptopurine (MP; n = 9): response was judged as complete response (CR) in 113 patients and partial response (PR) in 30 patients. Both TP dose (1.64 vs 1.19 mg/kg; p = 0.012) and TPMT activity (14.3 vs 13.5; p = 0.05) were higher in PR, resulting in similar TGN levels (PR: 121 pmol/8 x 10(8) red blood cells [RBC]; CR: 113 pmol/8 x 10(8) RBC; p = 0.33) but higher meTIMP levels in PR (1350 vs 400 pmol/8 x 10(8) RBC; p = 0.004). Patients able to withdraw steroids or who were using less than= 5 mg prednisolone daily were treated with lower TP doses than patients on higher steroid doses (1.15 vs 1.18 vs 1.82 mg/kg; p less than 0.001). Conclusions: TP metabolite measurements are of clinical value in AM patients who do not respond to standard TP treatment and for the identification of a shifted metabolism, which may demand an alternative treatment strategy.

  • 39.
    Hindorf, Ulf
    et al.
    Lund.
    Lindqvist Appell, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Hildebrand, Hans
    Stockholm.
    Fagerberg, Ulrika
    Stockolm.
    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.
    Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease2006In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 24, no 2, p. 331-342Article in journal (Refereed)
    Abstract [en]

    Background: Adverse events leading to discontinuation or dose reduction of thiopurine therapy occur in 9-28% of patients with inflammatory bowel disease. Aims: To evaluate the influence of thiopurine methyltransferase status and thiopurine metabolites in a large patient population for the risk of developing adverse event. Methods: Three hundred and sixty-four patients with inflammatory bowel disease and present or previous thiopurine therapy were identified from a local database. Results: The adverse event observed in 124 patients (34%) were more common in adults than children (40% vs. 15%, P < 0.001) and in low to intermediate (≤9.0 U/mL red blood cell) than normal thiopurine methyltransferase activity (P = 0.02). Myelotoxicity developed later than other types of adverse event. An increased frequency of adverse event was observed in patients with tioguanine (thioguanine) nucleotide above 400 or methylated thioinosine monophosphate above 11 450 pmol/ 8 × 108 red blood cell. A shift to mercaptopurine was successful in 48% of azathioprine-intolerant patients and in all cases of azathioprine-induced myalgia or arthralgia. Conclusions: A pre-treatment determination of thiopurine methyltransferase status might be appropriate as patients with low to intermediate thiopurine methyltransferase activity are more prone to develop an adverse event, determination of metabolite levels can be useful in the case of an adverse event. Mercaptopurine therapy should be considered in azathioprine-intolerant patients. © 2006 The Authors.

  • 40.
    Hindorf, Ulf
    et al.
    Lund .
    Lindqvist Appell, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Ström, Magnus
    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.
    Hjortswang, Henrik
    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.
    Pousette, A
    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.
    Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease2006In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 55, no 10, p. 1423-1431Article in journal (Refereed)
    Abstract [en]

    Background: Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking. Aim: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. Patients: 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study. Methods: Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored. Results: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)), 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio, p = 0.02). Patients with meTIMP concentrations > 11 450 pmol/8 × 108 red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0, p = 0.015). Conclusions: After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

  • 41.
    Hindorf, Ulf
    et al.
    Lunds Universitet.
    Lindqvist Appell, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Ström, Magnus
    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.
    Hjortswang, Henrik
    Linköping University, Department of Molecular and Clinical Medicine.
    Pousette, Anneli
    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.
    High methylthioinosine monophosphate levels as a cause of myelotoxicity when introducing thiopurine therapy in patients with inflammatory bowel disease2005In: 13th United European Gastroenterology week,2005, Stuttgart: Georg Thieme Verlag KG , 2005, p. A169-Conference paper (Refereed)
  • 42.
    Hjortswang, Henrik
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    The network: a strategy to describe the relationship between quality of life and disease activity. The case of inflammatory bowel disease1999In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 11, no 10, p. 1099-1104Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Health is a complex and multi-dimensional entity and is neither easily determined nor easily conveyed to others. Publications have often combined various variables of disease activity and health-related quality of life (HRQoL), used the variables interchangeably or utilized summation indices to compare health assessment. The aim of this study is to investigate the relationship between measurements of disease activity and HRQoL.

    STUDY:

    design Cross-sectional evaluation of disease activity and HRQoL.

    STUDY POPULATION:

    Two hundred and eleven consecutive patients with ulcerative colitis.

    SETTING:

    The catchment area of Linköping University Hospital.

    MEASUREMENTS:

    HRQoL was measured using two questionnaires, the Sickness Impact Profile (SIP) and the Rating Form of IBD Patient Concerns (RFIPC). Patients were also asked if they were 'feeling fit and well', as a measurement of general health perception. Disease activity was measured by means of symptom cards, laboratory tests and sigmoidoscopy.

    RESULTS:

    The correlations (Spearman's r (r5)) between variables of disease activity and HRQoL were low. 'Feeling fit and well' was best correlated to worries and concerns (the RFIPC, rs 0.32, P < 0.05), while there was a decreasing association with subjective functional status (the SIP, rs 0.31, P < 0.05), symptoms (stools per day, rs 0.15, not significant) and biological variables (endoscopy score, rs 0.04, not significant).

    CONCLUSION:

    The correlations between traditional measurements of disease activity and various measures of HRQoL are low. We therefore propose a system whereby the process is conceptualized using a 'network strategy', ordering the measurements of disease activity and HRQoL into five dimensions: biological variables, symptoms, functional status, worries and concerns, and health perceptions. We feel that this method of interpretation more accurately reflects the overall health of a group of patients with IBD than more traditional summation indices.

  • 43.
    Hjortswang, Henrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Järnerot, G.
    Division of Gastroenterology, Dept. of Medicine, Örebro Medical Centre Hospital, Örebro, Sweden.
    Curman, B.
    Division of Gastroenterology, Dept. of Medicine, Örebro Medical Centre Hospital, Örebro, Sweden.
    Sandberg-Gertzén, H.
    Division of Gastroenterology, Dept. of Medicine, Örebro Medical Centre Hospital, Örebro, Sweden.
    Tysk, C.
    Division of Gastroenterology, Dept. of Medicine, Örebro Medical Centre Hospital, Örebro, Sweden.
    Blomberg, B.
    Division of Gastroenterology, Dept. of Medicine, Örebro Medical Centre Hospital, Örebro, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Validation of the inflammatory bowel disease questionnaire in Swedish patients with ulcerative colitis2001In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 36, no 1, p. 77-85Article in journal (Refereed)
    Abstract [en]

    Background: The Inflammatory Bowel Disease Questionnaire (IBDQ) is a disease-specific health-related quality of life (HRQOL) questionnaire including four dimensions and a sum score. The aim of this study was to assess the internal and external validity, reliability, and sensitivity of a Swedish version of the IBDQ.

    Methods: Three hundred consecutive patients with ulcerative colitis completed the IBDQ and three other health-related quality of life questionnaires (the Rating Form of IBD Patient Concerns (RFIPC), the Short Form-36 (SF-36) and the Psychological General Well-Being (PGWB) index). Disease activity was evaluated using a 1-week symptom diary, blood tests and rigid sigmoidoscopy. One hundred and fourteen patients filled in the questionnaire a second time, of whom 75 had been in stable remission for over 6 months and 39 had a significant clinical change in disease activity.

    Results: Factor analysis of the 32 IBDQ items did not support the four dimensional scores. The dimensional scores had sufficient convergent validity, but low discriminative validity and homogeneity. The homogeneity was also low for the sum score. The inter-dimensional correlations were high. The concurrent validity was supported by correlations between the dimensional scores and other measures of disease activity and HRQOL. Patients in relapse scored significantly less on the sum score and the four dimensions compared to patients in remission. The test-retest correlations for the dimensional scores were 0.40-0.76. Patients with a change in disease activity during the 6-month follow-up period had a significant change in IBDQ scores not found in those who remained in remission.

    Conclusions: The Swedish version of the IBDQ had external validity and was shown to be a reliable and sensitive measure of HRQOL in ulcerative colitis, though there are some concerns regarding the internal validity. The use of a sum score was not supported and the questionnaire may benefit from a redivision of items into dimensions with better homogeneity and discriminative validity.

  • 44.
    Hjortswang, Henrik
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Järnerot, Gunnar
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Sandberg-Gertzén, Hanna
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, 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, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    The influence of demographic and disease-related factors on health-related quality of life in patients with ulcerative colitis2003In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 15, no 9, p. 1011-1020Article in journal (Refereed)
    Abstract [en]

    Objective: The aims of this study were to analyse the health-related quality of life of patients with ulcerative colitis and to assess in what way demographic and disease-related factors influence patients' experiences of this, in order to interpret the results of health-related quality of life assessment more correctly.

    Patients and methods: We carried out a cross-sectional evaluation of 300 consecutive patients with ulcerative colitis from the catchment areas of Linköping University Hospital and Örebro University Hospital in Sweden. Health-related quality of life was measured using four questionnaires: the IBDQ, the RFIPC, the SF-36 and the PGWB. Disease activity was evaluated using a one-week symptom diary, blood tests and rigid sigmoidoscopy. Demographic factors (gender, age, civil status, educational level), disease-related factors (disease duration, disease extent, disease activity) and presence of co-morbidity were obtained.

    Results: Health-related quality of life was mainly impaired in the psychological and social areas and to a much lesser degree in physical areas. Patients with relapse had significantly more disease-related worries and concerns (the RFIPC), more impaired social functioning (the IBDQ and SF-36), and a lower feeling of well being (the IBDQ, the SF-36 and the PGWB). However, their physical function (SF-36) was no worse than patients in remission. Besides the symptom burden of the current disease, co-morbidity and female gender were associated with a lower health-related quality of life.

    Conclusion: To correctly interpret health-related quality of life assessments, it is necessary to consider co-morbidity and gender distribution in addition to the symptom burden of the disease studied.

  • 45.
    Hjortswang, Henrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Järnerot, Gunnar
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Curman, Bengt
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Sweden.
    Sandberg-Gertzén, Hanna
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Sweden.
    Tysk, Curt
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Sweden.
    Blomberg, Björn
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    The Short Health Scale: a valid measure of subjective health in ulcerative colitis2006In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 41, no 10, p. 1196-1203Article in journal (Refereed)
    Abstract [en]

    Objective. Assessment of health-related quality of life (HRQOL) is important in both clinical practice and clinical trials, and several multi-item questionnaires are currently in use. We have devised and evaluated a simplified four-item questionnaire, the Short Health Scale (SHS), representing each of four health dimensions: (a) symptom burden, (b) social function, (c) disease-related worry and (d) general well-being.

    Material and methods. Three hundred patients with ulcerative colitis completed the SHS and three other HRQOL questionnaires (IBDQ, RFIPC and PGWB). Half of the patients repeated the questionnaires after 6 months – or earlier if disease activity changed. Test–retest reliability was derived from measurements of the SHS questions, 2 weeks apart, on 18 patients in remission.

    Results. Patients in relapse scored higher on each of the four SHS questions than patients in remission (p < 0.001). Each of the four SHS scores were associated with results of their corresponding health dimension obtained with the other three questionnaires (rs=0.57–0.78, p < 0.001) (validity). The results of the SHS proved stable on repeated measurement with a 2-week interval in patients in remission (rs=0.71–0.91, p < 0.01) (test–retest reliability). Patients with a change in disease activity had a significant change in their SHS scores (p < 0.05) (responsiveness).

    Conclusions. The SHS is a valid, reliable and responsive measure of subjective health in patients with ulcerative colitis. It is simple to administer, quickly completed and the results do not need further calculations. The SHS can be used in clinical trials and in clinical practice to identify the patient's main problems affecting health.

  • 46.
    Hjortswang, Henrik
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Almeida, R. T.
    Dept. of Biomedical Engineering/COPPE, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Almer, Sven
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Evaluation of the RFIPC, a disease-specific health-related quality of life questionnaire, in Swedish patients with ulcerative colitis1997In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 32, no 12, p. 1235-1240Article in journal (Refereed)
    Abstract [en]

    Background: We wanted to characterize a Swedish version of the Rating Form of Inflammatory Bowel Disease Patient Concerns (RFIPC) with regard to validity, reliability, and responsiveness.

    Methods: Two hundred and three consecutive patients with ulcerative colitis were studied. Health-related quality of life (HRQOL) was measured with the disease-specific questionnaire, the RFIPC, and a general questionnaire, the Sickness Impact Profile (SIP). Concerns about general well-being were also reported. Disease activity was measured by means of symptom cards, laboratory tests, and two clinical indices for disease activity.

    Results: Test-retest reliability using Spearman's r (rs) was 0.79, and internal consistency measured with Cronbach's alpha was 0.95. RFIPC had a fair correlation with concerns about general well-being (rs = 0.69, P < 0.001). There was also a stronger correlation with another measure of HRQOL, the overall SIP score (rs = 0.43), than with measures of disease activity such as stool frequency (rs = 0.28) and sigmoidoscopic grading (NS). The group of patients in relapse had a higher RFIPC sum score than patients in remission (P = 0.001). Measures of HRQOL had a low correlation with disease activity and did not respond to changes in disease activity.

    Conclusion: The Swedish version of the RFIPC is a valid and reliable measure of HRQOL. The SIP and the RFIPC have a good discriminative ability between groups of patients in remission and in relapse. However, they do not seem to be useful in predicting the disease activity or change in disease activity over time in the individual patient.

  • 47.
    Hjortswang, Henrik
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Health-related quality of life in Swedish patients with ulcerative colitis1998In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 9,, no 00, p. 2203-2211Article in journal (Refereed)
    Abstract [en]

    Objective:  The aim of this study was to characterize the health-related quality of life (HRQOL) in a Swedish population of patients with ulcerative colitis.

    Methods:  A total of 211 patients with ulcerative colitis were studied. Demographic and disease-related factors were noted. HRQOL was measured by one disease specific questionnaire, the Rating Form of IBD Patient Concerns (RFIPC) and one generic, The Sickness Impact Profile (SIP). Additional questions regarding information needs, medication, and well-being were asked. Disease activity was measured by symptom cards, laboratory samples, endoscopy, and two indices of disease activity. The influence of additional concomitant disease was also evaluated.

    Results:  Functional impairment as measured by the SIP was primarily in psychological and social areas and to a lesser extent in the physical areas. The highest scores for individual items of the RFIPC were those related to potential complications, e.g., needing an ostomy appliance, needing surgery, developing cancer, losing bowel control, and uncertainty about the disease and effects of medication. Patients with active disease scored higher on both SIP and RFIPC when compared to patients in remission. Presence of coexisting disease weighted heavily on HRQOL.

    Conclusion:  Ulcerative colitis has a negative influence on the subjective functional status and seems to cause many worries and concerns. Patients in relapse had greater concerns, more impairment of functional status, and a reduced subjective sense of well-being than patients in clinical remission. Nevertheless, the patients in this Swedish study scored a much better HRQOL than has previously been reported using these questionnaires in patients with ulcerative colitis from the US, France, and Austria.

  • 48. Hugot, JP
    et al.
    Cezard, JP
    Colombel, JF
    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
    Montague, S
    Gassull, M
    Christensen, S
    Finkel, Y
    Gower-Rousseau, C
    Modigliani, R
    Zouali, H
    Lesage, S
    Chamaillard, M
    Marcy, J
    Thomas, G
    Victor, JM
    Belaiche, J
    Clustering of Crohn's disease within affected sibships2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 2, p. 179-184Article in journal (Refereed)
    Abstract [en]

    Crohn's disease (CD) is a complex genetic disorder for which aetiology is unknown. Recently, genetic factors for susceptibility have been described. Several genetic loci have been mapped and partially explain the familial aggregations of the disease. However, environmental factors may also contribute to these aggregations. We considered that if the role of non-genetic factors was negligible, CD patients would be randomly distributed in sibships with multiple affected siblings. On the other hand if there was a significant environmental contribution, the siblings would be affected non-randomly over exposure status. In order to test this hypothesis, we studied 102 sibships with two or more affected siblings. A statistical test, named Cluster of Affected Sibling Test or CAST, was developed, based on the exact calculation of the probability of observing a given number of clusters of affected siblings in multiplex families. The null hypothesis of a random distribution of affected siblings was rejected (P=0,005). The observed excess of affected sibling clusters indicates that birth order influences the disease status. Considering that an adjacent order of birth is a global estimate of environmental sharing, this observation strongly suggests that environmental factors contribute to the observed familial aggregations of the disease. This observation provides evidence that familial CD is a relevant tool for further studies of environmental factors and gene-environment interaction. More generally, the CAST statistics may be widely applicable to estimate the involvement of environmental factors in the aetiology of other binary traits which may be observed in multiple members of the same sibship.

  • 49. Hugot, J-P
    et al.
    Chamaillard, M
    Zouali, H
    Lesage, S
    C´zard, J-P
    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
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    O'Morain, A
    Gassull, M
    Binder, V
    Finkel, Y
    Cortot, A
    Modigliani, R
    Laurent-Puig, P
    Gower-Rousseau, C
    Macry, J
    Comombel, J-F
    Sahbatou, M
    Thomas, G
    Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 411, no 6837, p. 599-603Article in journal (Refereed)
    Abstract [en]

    Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-?B, this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-?B in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

  • 50. Lesage, L
    et al.
    Zouali, H
    Colombel, J-F
    Belaiche, J
    C´zard, J-P
    Tysk, C
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    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.
    Gassull, M
    Binder, V
    Chamaillard, M
    Le Gall, I
    Thomas, G
    Hugot, J-P
    Genetic analyses of chromosome 12 loci in Crohn's disease.2000In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 47, p. 787-791Article in journal (Refereed)
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