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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, 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.

  • 3.
    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.

  • 4.
    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)
  • 5.
    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.

  • 6.
    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)
  • 7.
    Bager, P.
    et al.
    Aarhus University Hospital, Denmark .
    Befrits, R.
    Karolinska University Hospital, Sweden .
    Wikman, O.
    Stockholm S Gen Hospital, Sweden .
    Lindgren, S.
    Lund University, Sweden .
    Moum, B.
    Oslo University Hospital, Norway .
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Hjollund, N.H.
    Aarhus University Hospital, Denmark Hospital Unit Western Jutland, Denmark .
    Dahlerup, J.F.
    Aarhus University Hospital, Denmark .
    Fatigue in out-patients with inflammatory bowel disease is common and multifactorial2012In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 35, no 1, p. 133-141Article in journal (Refereed)
    Abstract [en]

    Background similar to Patients with inflammatory bowel disease (IBD) often complain of fatigue. Aim similar to To investigate the prevalence and characteristics of fatigue among IBD out-patients in Scandinavia and to provide normative values for fatigue in IBD patients. Methods similar to A cross-sectional study was conducted on 425 IBD patients from six out-patient centres in Denmark, Norway and Sweden. Fatigue was measured using the Multidimensional Fatigue Inventory. The patients were also screened for anaemia and iron deficiency. Each centre included approximately 5% of their IBD cohort. The patients were enrolled consecutively from the out-patient clinics, regardless of disease activity and whether the visit was scheduled. The fatigue analysis was stratified for age and gender. Results similar to Using the 95th percentile of the score of the general population as a cut-off, approximately 44% of the patients were fatigued. When comparing the IBD patients with disease activity to the IBD patients in remission, all dimensions of fatigue were statistically significant (P less than 0.05). Being anaemic or iron deficient was not associated with increased fatigue. Being a male patient with ulcerative colitis treated with corticosteroids was a strong determinant for increased fatigue. The normative ranges for IBD fatigue were calculated. Conclusions similar to Fatigue in IBD is common regardless of anaemia or iron deficiency. Fatigue in IBD is most marked for patients less than60 years of age. Stratifying for gender and age is necessary when analysing fatigue, as fatigue is expressed differently between groups.

  • 8.
    Bager, Palle
    et al.
    Aarhus University Hospital, Denmark .
    Befrits, Ragnar
    Karolinska University Hospital, Sweden .
    Wikman, Ola
    Stockholm South Gen Hospital, Sweden .
    Lindgren, Stefan
    Lund University, Sweden .
    Moum, Bjorn
    Oslo University Hospital, Norway .
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Dahlerup, Jens F.
    Aarhus University Hospital, Denmark .
    High burden of iron deficiency and different types of anemia in inflammatory bowel disease outpatients in Scandinavia: A longitudinal 2-year follow-up study2013In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, no 11, p. 1286-1293Article in journal (Refereed)
    Abstract [en]

    Objective. The prevalence of anemia in inflammatory bowel disease (IBD) has been broadly described. The recurrence, type and burden of anemia remain unenlightened. The primary objective was to describe this. The secondary objective was to evaluate the implementation of European guidelines. Materials and methods. This longitudinal follow-up study included 300 IBD outpatients from six centers in Scandinavia. Patients were enrolled in a research cohort, in which each center included 5% of their IBD cohort. The study was prospectively planned, while data were retrospectively collected. The burden of anemia was calculated as number of months with anemia. A Markov model was used to calculate the probabilities of transitioning between stages. The European guidelines were used as the standard for anemia management. Results. Anemia affected andgt; 50% of IBD outpatients during the 2-year observation period. Totally, 20% of the total observation time was spent in anemia. Over the 7200 months of observation, anemia was found in 1410 months. The most frequent type was combined anemia (63%). Combined anemia covers both anemia of chronic disease (ACD) and iron-deficiency anemia (IDA). Pure ACD was present in 21% of burden time, while pure IDA was present in 16% of burden time. The European guidelines have mainly been implemented. Conclusion. Anemia affected a majority of the IBD outpatients. One in five months, the patients were anemic. Anemia related to inflammation dominated the different types of anemia. Pure IDA was found in for 16%. These findings, despite a fair implementation of guidelines.

  • 9.
    Bager, Palle
    et al.
    Aarhus University Hospital.
    Befrits, Ragnar
    Karolinska University Hospital.
    Wikman, Ola
    Stockholm S General Hospital.
    Lindgren, Stefan
    Lund University.
    Moum, Bjorn
    Oslo University Hospital.
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Dahlerup, Jens F
    Aarhus University Hospital.
    The prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia2011In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 46, no 3, p. 304-309Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate the prevalence of anemia and iron deficiency (ID) among patients with inflammatory bowel disease (IBD) in the Scandinavian countries. Material and methods. A cross-sectional study including 429 IBD patients from six centers in Denmark, Norway and Sweden. Patients were screened for anemia and ID. Each center included similar to 5% of their IBD cohort. Patients were consecutively seen in the outpatient clinic, regardless of disease activity and whether the visits were scheduled or not. Results. The overall prevalence of anemia was 19% (95% CI: 16--23%). The prevalence was higher among patients with Crohns disease than among patients with ulcerative colitis (p = 0.01). The etiology of anemia was as follows: iron deficiency anemia (20%), anemia of chronic disease (12%), and both conditions (68%). Less than 5% had folate acid or vitamin B12 deficiency. ID was found in 35% (CI: 31-40%) of the patients. Conclusions. Anemia was present in every fifth IBD patient and ID in every third IBD patient.

  • 10.
    Bager, Palle
    et al.
    Aarhus University Hospital.
    Befrits, Ragnar
    Karolinska University Hospital.
    Wikman, Ola
    Stockholm South General Hospital.
    Lindgren, Stefan
    Malmo University Hospital.
    Moum, Bjorn
    Oslo University Hospital.
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Dahlerup, Jens F
    Aarhus University Hospital.
    The "true" prevalence of anemia in IBD outpatients in Scandinavia in SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, vol 45, issue , pp 55-562010In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, Informa Healthcare , 2010, Vol. 45, p. 55-56Conference paper (Refereed)
    Abstract [en]

    n/a

  • 11.
    Befrits, Ragnar
    et al.
    Karolinska University Hospital, Sweden .
    Wikman, Ola
    Soder Sjukhuset, Sweden .
    Blomquist, Lars
    Karolinska University Hospital, Sweden .
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Hammarlund, Per
    Angelholm Hospital, Sweden .
    Bajor, Antal
    Sahlgrens University Hospital, Sweden .
    Klintman, Daniel
    MAS University Hospital, Sweden .
    Blom, Hakan
    Sunderby Hospital, Sweden .
    Anemia and iron deficiency in inflammatory bowel disease: an open, prospective, observational study on diagnosis, treatment with ferric carboxymaltose and quality of life2013In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, no 9, p. 1027-1032Article in journal (Refereed)
    Abstract [en]

    Objective. Iron deficiency and anemia are being increasingly recognized as a complication of inflammatory bowel disease (IBD). The aim of this study was to observe, in a non-interventional way, how Swedish gastroenterologists adhere to guidelines in IBD outpatients treated with intravenous ferric carboxymaltose (FCM), and the result of treatment. Material and methods. Altogether 394 IBD patients (Crohns disease (CD) 60%, ulcerative colitis (UC) 40%) from 14 centers were included. Group A (n = 216) was observed from November 2008 and group B (n = 178) from March 2010. Time of observation ranged from 12 to 29 months. Results. S-Ferritin (mmol/l) and transferrin saturation (T-Sat; %) were recorded at baseline in 62% and 50% in group A. Median values for Hb, ferritin and T-Sat at baseline were 111 g/l, 10 mu mol/l and 10%, respectively, and 134 g/l, 121 mmol/l and 20% after iron treatment (p andlt; 0.001 for all three parameters). Similar results were found in group B. Approximately three-quarters of all patients had only one iron infusion during the study period. Median time to reinfusion was 6 (1-25) months. Only previously described infusion reactions occurred in 27 (7%) patients. Conclusions. Adherence to European guidelines was rather poor and needs to be improved. The effect on iron parameters of intravenous FCM was significant, and resulted in a ferritin level that indicates an effect on the iron stores. The effect was mostly sustained for a year since only one-quarter of the patients were given repeated iron infusions. No unforeseen safety concerns emerged during the observation period.

  • 12.
    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.

  • 13.
    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)
  • 14.
    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.

  • 15.
    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.

  • 16.
    Dahle, Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Hagman, A.
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Antibodies against deamidated gliadin peptides identify adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase2010In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 32, no 2, p. 254-260Article in journal (Refereed)
    Abstract [en]

    Background This study was done to evaluate the diagnostic utility of antibodies against deamidated gliadin peptides compared to traditional markers for coeliac disease. Aim To evaluate diagnostic utility of antibodies against deamidated gliadin peptide (DGP). Methods Sera from 176 adults, referred for endoscopy without previous analysis of antibodies against tissue transglutaminase (tTG) or endomysium (EmA), were retrospectively analysed by ELISAs detecting IgA/IgG antibodies against DGP or a mixture of DGP and tTG, and compared with IgA-tTG and EmA. Seventy-nine individuals were diagnosed with coeliac disease. Results Receiver operating characteristic analyses verified the manufacturers cut-off limits except for IgA/IgG-DGP/ tTG. In sera without IgA deficiency, the sensitivity was higher for IgA/IgG-DGP (0.85-0.87) compared with IgA-tTg (0.76) and EmA (0.61). All tests showed high specificity (0.95-1.00). Eighteen coeliac disease-sera were negative regarding IgA-tTG, nine of which were positive for IgA/IgG-DGP. Sera from coeliac disease-patients greater than70 years were more often negative for IgA-tTG (50%) and IgA/IgG-DGP (36%) than younger patients (15% and 8% respectively) (P less than 0.01). Three of the four IgA-deficient patients were positive in the IgA/IgG-DGP assay. Conclusions In this study of patients unselected regarding IgA-tTg/EmA, thus unbiased in this respect, IgA/IgG-DGP identified adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase. Serology is often negative in elderly patients with coeliac disease; a small bowel biopsy should therefore be performed generously before coeliac disease is excluded.

  • 17. 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.

  • 18.
    Ekstedt, Mattias
    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.
    Non-Alcoholic Fatty Liver Disease: A clinical and histopathological study2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fatty liver has previously often been associated with excessive alcohol consumption. During the last two decades, the interest in fatty liver occurring in non-drinkers i.e. non-alcoholic fatty liver disease (NAFLD) has increased dramatically. Today, NAFLD is considered as the most common liver disease in the developed world. It is strongly associated with obesity, insulin resistance, and hypertension. Thus, NAFLD is considered as the hepatic manifestation of the metabolic syndrome.

    The spectrum of NAFLD includes: simple fatty liver without necroinflammatory activity; non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocellular injury, inflammation, and fibrosis; cirrhosis; and in some individuals hepatocellular carcinoma.

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the pathologist uses a four-graded scale: 0–3 or none, slight, moderate and severe. In this thesis we show that there is a considerable inter- and intraindividual variation in such scoring methods and that a more standardised and quantitative approach is preferable. The area/volume of fat in liver biopsies is greatly overestimated when assessed semiquantitatively. Moreover, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis.

    The long-term clinical and histopathological course of 129 consecutively enrolled NAFLD patients was studied. Mean follow-up (SD) was 13.7 (1.3) years. Survival of NASH patients was reduced compared with a matched reference population. These subjects more often died from cardiovascular and liver-related causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

    During follow-up, 17 patients had been prescribed a statin. At follow-up, patients on medication with statins had significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Although patients under statin treatment exhibited a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. It is concluded that statins can be prescribed safely in patients with elevated liver enzymes because of NAFLD.

    Alcohol consumption was evaluated with a validated questionnaire combined with an oral interview. In a multivariate analysis moderate alcohol consumption, particularly when frequency of heavy episodic drinking was analysed, consistent with the diagnosis of NAFLD to be set, was independently associated with fibrosis progression in NAFLD.

    The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. We evaluated the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in our cohort of NAFLD patients. Although the NAS was independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score was limited due to significant overlap in clinical development between NAS-score groups.

    List of papers
    1. Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
    Open this publication in new window or tab >>Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
    2005 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 18, no 7, p. 912-916Article in journal (Refereed) Published
    Abstract [en]

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.

    Keywords
    Liver, quantification, steatosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17322 (URN)10.1038/modpathol.3800370 (DOI)15920560 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    2. Long-term follow-up of patients with NAFLD and elevated liver enzymes.
    Open this publication in new window or tab >>Long-term follow-up of patients with NAFLD and elevated liver enzymes.
    Show others...
    2006 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 44, no 4, p. 865-873Article in journal (Refereed) Published
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

    Keywords
    Liver, quantification, steatosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17323 (URN)10.1002/hep.21327 (DOI)17006923 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    3. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
    Open this publication in new window or tab >>Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
    Show others...
    2007 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 1, p. 135-141Article in journal (Refereed) Published
    Abstract [en]

    Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins.

    Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up.

    Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage.

    Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.

    Keywords
    Non-alcoholic fatty liver disease, Histology, Statin, Metabolic syndrome
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17324 (URN)10.1016/j.jhep.2007.02.013 (DOI)17400325 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    4. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease
    Open this publication in new window or tab >>Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease
    Show others...
    2009 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 44, no 3, p. 366-374Article in journal (Refereed) Published
    Abstract [en]

    Objective: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD.

    Material and methods: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up.

    Results: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p0.001) and insulin resistance (p0.01) were independently associated with significant fibrosis progression.

    Conclusions: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.

    Keywords
    Alcoholic liver disease, fatty liver, histopathology, liver fibrosis, non-alcoholic fatty liver disease
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17133 (URN)10.1080/00365520802555991 (DOI)
    Available from: 2009-03-07 Created: 2009-03-07 Last updated: 2017-12-13Bibliographically approved
    5. The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression
    Open this publication in new window or tab >>The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression
    Show others...
    2008 (English)Article in journal (Other academic) Submitted
    Abstract [en]

    Objective: The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD.

    Methods: One hundred and twenty-nine patients with biopsy proven NAFLD were included in a long-term histological follow-up study. Clinical and histological course were compared between NASH, “borderline NASH”, and “not NASH” patients. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up.

    Results: Eighty-eight patients accepted re-evaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend towards higher baseline NAS was seen in patients (n = 7) that developed end-stage liver disease (3.1 ± 0.9 vs. 2.4 ± 1.0; P = 0.062). Baseline NAS was significantly higher in patients with progressive fibrosis (2.9 ± 0.9 vs. 2.2 ± 0.9; P = 0.017), and NAS was independently associated with significant fibrosis progression tested in a multivariate analysis (P = 0.023). However, 18% of patients without NASH progressed significantly in fibrosis stage.

    Conclusion: Although the NAS is independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS-score groups.

    Keywords
    Steatohepatitis, Fatty liver, Fibrosis progression, Clinical follow-up, Histopathology
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17325 (URN)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2009-08-17Bibliographically approved
  • 19.
    Ekstedt, Mattias
    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.
    Franzén, Lennart E
    Department of Histopathology and Cytology, Aleris Medilab, Täby, Sweden.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bendtsen, Preben
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland, Department of Medical Specialist.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Bodemar, Göran
    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.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease2009In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 44, no 3, p. 366-374Article in journal (Refereed)
    Abstract [en]

    Objective: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD.

    Material and methods: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up.

    Results: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p0.001) and insulin resistance (p0.01) were independently associated with significant fibrosis progression.

    Conclusions: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.

  • 20.
    Ekstedt, Mattias
    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.
    Franzén, Lennart E.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L.
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Bodemar, Göran
    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.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression2008Article in journal (Other academic)
    Abstract [en]

    Objective: The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD.

    Methods: One hundred and twenty-nine patients with biopsy proven NAFLD were included in a long-term histological follow-up study. Clinical and histological course were compared between NASH, “borderline NASH”, and “not NASH” patients. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up.

    Results: Eighty-eight patients accepted re-evaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend towards higher baseline NAS was seen in patients (n = 7) that developed end-stage liver disease (3.1 ± 0.9 vs. 2.4 ± 1.0; P = 0.062). Baseline NAS was significantly higher in patients with progressive fibrosis (2.9 ± 0.9 vs. 2.2 ± 0.9; P = 0.017), and NAS was independently associated with significant fibrosis progression tested in a multivariate analysis (P = 0.023). However, 18% of patients without NASH progressed significantly in fibrosis stage.

    Conclusion: Although the NAS is independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS-score groups.

  • 21.
    Ekstedt, Mattias
    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.
    Franzén, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    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.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.2007In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 1, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins.

    Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up.

    Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage.

    Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.

  • 22.
    Ekstedt, Mattias
    et al.
    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.
    Franzén, Lennart E
    Aleris Medilab, Täby.
    Mathiesen, Ulrik L
    County Hospital, Oskarshamn.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL. Linköping University, Faculty of Health Sciences.
    Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 47, no 1, p. 108-115Article in journal (Refereed)
    Abstract [en]

    Background/Aims. The nonalcoholic fatty liver disease (NAFLD) activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD. Methods. One hundred and twenty-nine patients with biopsy-proven NAFLD were included in a long-term histological follow-up study. Clinical course and change in fibrosis stage were compared between nonalcoholic steatohepatitis (NASH), “borderline NASH,” and “not NASH” patients. Significant fibrosis progression was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up. Results. Eighty-eight patients accepted reevaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3–16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend toward higher baseline NAS was seen in patients (n = 7) who developed end-stage liver disease (3.1 ± 0.9 vs. 2.2 ± 1.0; p = 0.050). Baseline NAS was associated with progressive disease in a univariate binary logistic regression analysis (p = 0.024), but no difference was seen in the multivariate analysis including the NAS, portal inflammation, and perisinusoidal fibrosis. Moreover, 18% of patients without NASH progressed significantly in fibrosis stage. Conclusions. The ability of the NAS to predict progression of NAFLD is poor. The clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS score groups. To use the NAS as endpoint in treatment trial is not justified.

  • 23.
    Ekstedt, Mattias
    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.
    Franzén, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden;.
    Thorelius, Lars
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    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.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Long-term follow-up of patients with NAFLD and elevated liver enzymes.2006In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 44, no 4, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

  • 24.
    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.

  • 25.
    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.

  • 26.
    El-Salhy, Magdy
    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.
    Combined treatment with octreotide, Galanin and serotonin in gastrointestinal malignancies2005In: Letters in Drug Design & Discovery, ISSN 1570-1808, E-ISSN 1875-628X, Vol. 2, no 6, p. 439-443Article in journal (Refereed)
    Abstract [en]

    Triple therapy with octreotide, galanin and serotonin reduces the volume and weight of both rat and human colon carcinoma in xenografts. The reduction in tumour volume and weight seems to be caused by tumour necrosis, reduced proliferation and decreased expression of epidermal growth factor EGF of cancer cells, as well as induction apoptosis in cancer cells. Tumour necrosis has been suggested to be caused by induction of tumour ischemia due to a reduction in the tumour blood flow, which is caused by decreased incidence of tumour-feeding blood vessels and by constrictions of tumour feeding arterioles. The effects of single, double and triple therapy with octreotide, galanin and serotonin on rat colon cancer have shown that galanin alone reduced significantly the tumour-feeding blood vessels. The single and double treatment had a certain effect, but far from the triple treatment. Triple therapy had no apparent side effects. Triple therapy has equivalent antitumour and therapeutic efficacy as standard treatment with 5-fluorouracil/leucovorin. Triple therapy prolongs the survival rate of the mice bearing human pancreatic carcinoma and decreased both the volume and weight of tumours. However, the proliferation index and the labelling index for EGF were increased. It did not affect the apoptotic index, necrosis, or density of tumour blood vessels. In vitro investigations with single and double combinations of octreotide, galanin and serotonin have shown that single treatment with octreotide or serotonin reduces the number of viable cells and the proliferation index. Galanin increases the number of viable cells and the proliferation index. It has been concluded that treatment with a combination of octreotide, serotonin and galanin antagonist may be useful in clinical settings. The effect of triple therapy on gastric cancer is doubtful. © 2005 Bentham Science Publishers Ltd.

  • 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.
    Franzen, L.
    et al.
    Department of Pathology, Clinical Research Centre, University Hospital Örebro, Örebro, Sweden.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bodin, L.
    Unit of Biostatistics and Epidemiology, Clinical Research Centre, University Hospital, Örebro, Sweden.
    Fiorini, R.N.
    Fiorini, R.N..
    Kirtz, J.
    Kirtz, J..
    Periyasamy, B.
    Periyasamy, B..
    Evans, Z.
    Evans, Z..
    Haines, J.
    Haines, J..
    Cheng, G.
    Cheng, G..
    Polito, C.
    Polito, C..
    Rodwell, D.
    Rodwell, D..
    Zhou, X.
    Zhou, X..
    Campbell, C.
    Campbell, C..
    Birsner, J.
    Birsner, J..
    Schmidt, M.G.
    Schmidt, M.G..
    Lewin, D.
    Lewin, D..
    Chavin, K.D.
    Chavin, K.D..
    Letter to the editor (multiple letter)2005In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 19, no 4, p. 571-572p. 571-Article in journal (Other academic)
    Abstract [en]

    [No abstract available]

  • 30.
    Franzén, Lennart E
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bodin, Lennart
    Unit of Biostatistics and Epidemiology, Clinical Research Centre, University Hospital, Örebro, Sweden.
    Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.2005In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 18, no 7, p. 912-916Article in journal (Refereed)
    Abstract [en]

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.

  • 31.
    Gustavsson, A
    et al.
    Örebro University Hospital, Sweden.
    Järnerot, G
    Örebro University Hospital, Sweden.
    Hertervig, E
    Lund University Hospital, Sweden.
    Friis-Liby, I
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Blomquist, L
    Karolinska University Hospital, Sweden.
    Karlén, P
    Södersjukhuset, Stockholm, Sweden.
    Grännö, C
    Ryhov Hospital, Jönköping.
    Vilien, M
    Hilleroed Hospital, Denmark.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Verbaan, H
    Malmö General University Hospital, Sweden.
    Hellström, P M
    Karolinska University Hospital, Sweden.
    Magnuson, A
    Örebro University Hospital, Sweden.
    Halfvarson, J
    Örebro University Hospital, Sweden.
    Tysk, C
    Örebro University Hospital, Sweden.
    Clinical trial: colectomy after rescue therapy in ulcerative colitis-3-year follow-up of the Swedish-Danish controlled infliximab study2010In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 32, no 8, p. 984-989Article in journal (Refereed)
    Abstract [en]

    Background The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described.

    Aim To examine the long-term efficacy of infliximab as a rescue therapy through a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis.

    Method In the original study, 45 patients were randomized to a single infusion of infliximab 5 mg/kg or placebo, and at 3 months, 7/24 patients given infliximab were operated vs. 14/21 patients given placebo. Three years or later, patients were asked to participate in a clinical follow-up.

    Results Another seven patients underwent colectomy during follow-up: five in the infliximab group and two in the placebo group. After 3 years, a total of 12/24 (50%) patients given infliximab and 16/21 (76%) given placebo (P = 0.012) had a colectomy. None of eight patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients who were not in remission (P = 0.02). There was no mortality.

    Conclusion The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later risk of colectomy.

  • 32.
    Haglund, Sofie
    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.
    Interindividual differences in thiopurine metabolism: studies with focus on inflammatory bowel disease2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The thiopurines, 6-mercaptopurine and its prodrug azathioprine, are used in the treatment of inflammatory bowel disease, ulcerative colitis and Crohn´s disease. The main active metabolites are the phosphorylated thioguanine nucleotides (6-TGNs) and methylated thioinosine monophosphate (meTIMP). Both groups contribute to the immunomodulatory effects. About 30-40% of patients fail to benefit from thiopurine treatment. A well-known cause of adverse reactions is decreased or absent thiopurine S-methyltransferase (TPMT) activity. Low TPMT activity is inherited as an autosomal codominant recessive trait and is present in approximately 10% of the population. Although several clinical issues can be solved from determination of TPMT activity, there are cases where it is not possible. In Sweden approximately 25% of IBD-patients display suboptimal 6-TGN concentrations and unexpectedly high concentrations of meTIMP despite a normal TPMT activity. A high meTIMP/6-TGN concentration ratio has been associated with both unresponsiveness to therapy and emergence of adverse reactions. Inosine 5’-monophosphate dehydrogenase (IMPDH) may constitute a candidate gene to explain this metabolite profile, as it is strategically positioned in the metabolic pathway of thiopurines where it competes with TPMT for their common substrate 6-TIMP.

    In paper I a pyrosequencing method was developed for genotyping of at that time all known genetic variants of TPMT. The concordance between genotype and phenotype in 30 individuals was 93%. The allele frequencies of TPMT*3A, *3B, *3C and *2 in a Swedish background population (n=800) were in agreement with those in other Caucasian or European populations. In Paper II-IV we explored the molecular basis of different metabolite profiles, i.e. low, normal and high meTIMP/6-TGN concentration ratios. The activity of IMPDH was measured in mononuclear cells (MNC). Patients with high metabolite ratios had lower IMPDH activity than patients with normal or low ratios, explained by an inverse correlation to red blood cells concentration of meTIMP. No correlation to 6-TGN was observed. Downregulation of IMPDH activity in HEK293 cells with genetically engineered TPMT activity was associated with an increase in meTIMP, but unexpectedly also of 6-TGN, irrespective of the TPMT status. These results suggest effects of pharmacogenes other than TPMT and IMPDH. A whole genome expression analysis was performed, (1) to identify new candidate genes that could explain differences in metabolite profiles, and (2) to study genes with known associations to the metabolic pathway of (thio)purines. The whole genome expression analysis did not identify any significant group differences. In analysis of the thiopurine related genes, three clusters of co-regulated genes were defined. A co-operation between expression levels of SLC29A1 and NT5E in explaining the meTIMP/6-TGN concentration ratio was observed, and individually SLC29A1 and NT5E correlated to 6-TGN and meTIMP, respectively.

    Pysosequencing is a convenient and flexible method which is now run in parallel to phenotyping in our laboratory. Our results also illustrate 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 to explain differences in metabolite profiles is needed. Furthermore, in order to investigate small effects it is necessary to analyse metabolite concentrations and gene expression levels, as well as enzyme activities in the target cells of therapy (MNC).

    List of papers
    1. Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease
    Open this publication in new window or tab >>Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease
    Show others...
    2004 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 50, no 2, p. 288-295Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-45829 (URN)10.1373/clinchem.2003.023846 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
    2. IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - Relation to TPMT activity and metabolite concentrations
    Open this publication in new window or tab >>IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - Relation to TPMT activity and metabolite concentrations
    2008 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, no 1, p. 69-77Article in journal (Refereed) Published
    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.

    Keywords
    6-Mercaptopurine/*pharmacology Adult Aged Aged, 80 and over Azathioprine/*pharmacology Biological Markers Female Humans IMP Dehydrogenase/genetics/*metabolism Immunosuppressive Agents/*pharmacology Inflammatory Bowel Diseases/*drug therapy Male Methyltran
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-43268 (URN)10.1111/j.1365-2125.2007.02985.x (DOI)73262 (Local ID)73262 (Archive number)73262 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    3. The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease
    Open this publication in new window or tab >>The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease
    Show others...
    2011 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 33, no 2, p. 200-208Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Lippincott Williams & Wilkins, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-66431 (URN)10.1097/FTD.0b013e31820b42bb (DOI)000288498100010 ()21311411 (PubMedID)
    Available from: 2011-03-15 Created: 2011-03-15 Last updated: 2017-12-11Bibliographically approved
    4. Pharmacotranscriptomics in thiopurine treated IBD patients with different metabolite profiles
    Open this publication in new window or tab >>Pharmacotranscriptomics in thiopurine treated IBD patients with different metabolite profiles
    2008 (English)Manuscript (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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-66432 (URN)
    Available from: 2011-03-15 Created: 2011-03-15 Last updated: 2011-03-15Bibliographically approved
  • 33.
    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.

  • 34.
    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.

  • 35.
    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.

  • 36.
    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.

  • 37.
    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.

  • 38.
    Haglund, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Zimdahl Kahlin, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Vikingsson, Svante
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Almér, Stefan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Söderman, Jan
    Division of Medical Diagnostics, Ryhov County Hospital, Jönköping, Sweden.
    P658 Effects of allopurinol on thiopurine metabolism and gene expression levels in HepG2 cells2014Conference paper (Other academic)
  • 39.
    Hallberg, I
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Toss, G
    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.
    Ek, A-C
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Hjortswang, H
    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.
    Bachrach-Lindström, M
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Health-related Quality of Life after Vertebral or Hip Fracture in Women - Short Health Scale Useful for Clinical Practice?2010Conference paper (Other academic)
  • 40. Hallert, C
    et al.
    Granno, C
    Linkoping Univ, Coeliac Ctr, Fac Hlth Sci, SE-58191 Linkoping, Sweden Jonkoping Hosp, Dept Internal Med, Jonkoping, Sweden Skovde Cty Hosp, Dept Internal Med, Skovde, Sweden Varnamo Hosp, Dept Internal Med, Varnamo, Sweden.
    Hulten, S
    Midhagen, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology .
    Strom, M
    Svensson, H
    Valdimarsson, T
    Linkoping Univ, Coeliac Ctr, Fac Hlth Sci, SE-58191 Linkoping, Sweden Jonkoping Hosp, Dept Internal Med, Jonkoping, Sweden Skovde Cty Hosp, Dept Internal Med, Skovde, Sweden Varnamo Hosp, Dept Internal Med, Varnamo, Sweden.
    Living with coeliac disease - Controlled study of the burden of illness2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 37, no 1, p. 39-42Article in journal (Refereed)
    Abstract [en]

    Background: Coeliac patients improve vastly when started on a.-gluten-free diet. After 10 years, however, women show a lower level of subjective health than men do. We investigated whether this could be explained by differences in the perceived disease burden. Methods: We studied 68 coeliac patients (34 women) (mean age 57 years, range 32-75) and matched type-2 diabetes controls treated for a mean of 10 years. They were examined by a 9-item Burden of Illness (BI) protocol comprising perceived worries, restriction., and subjective outcome. The subjective health was assessed with the Short Form 36 Health Survey (SF-36) questionnaire. Results: The importance of complying with the diet was ranked similarly high by male and female coeliac patients, However, women were less satisfied with the outcome at 10 years than men were, and expressed more concern about the impact on socializing with friends and having to abstain from important things in life. None of these aspects distinguished male and female diabetic patients, Coeliac women showed a higher BI sum score than men did, and this was inversely related to their SF-36 General health, Vitality and Mental Health scores. Conclusions: Coeliac women adhering to the treatment regimen for several years perceive the disease burden to be worse than men do. In the light of similar differences in their quality of life, inquiry is warranted into the way coeliac men and women are coping with the disorder.

  • 41.
    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)
  • 42.
    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.

  • 43.
    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.

  • 44.
    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.

  • 45.
    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.

  • 46.
    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.

  • 47.
    Hjortswang, Henrik
    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.
    Oxelmark, L.
    Institutionen för neurobiologi, Vårdvetenskap och samhälle, Karolinska institutet, Huddinge, Sweden.
    Sänkt livskvalitet vid skov grundar för alternativ terapi2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 45, p. 3010-3013Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 48.
    Hjortswang, Henrik
    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.
    Tysk, Curt
    Orebro Univ Hosp, Dept Med, Div Gastroenterol, Orebro, Sweden.
    Bohr, Johan
    Orebro Univ Hosp, Dept Med, Div Gastroenterol, Orebro, Sweden.
    Benoni, Cecilia
    MAS Univ Hosp, Dept Med, Div Gastroenterol, Malmo, Sweden.
    Kilander, Anders
    Sahlgrenska Univ Hospital, Div Gastroenterol, Dept Med, Gothenburg, Sweden.
    Larsson, Lasse
    Sahlgrenska Univ Hospital, Div Gastroenterol, Dept Med, Gothenburg, Sweden.
    Vigren, Lira
    MAS Univ Hosp, Dept Med, Div Gastroenterol, Malmo, Sweden.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Defining Clinical Criteria for Clinical Remission and Disease Activity in Collagenous Colitis2009In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 15, no 12, p. 1875-1881Article in journal (Refereed)
    Abstract [en]

    Background: Collagenous colitis is a chronic inflammatory bowel disease accompanied mainly by nonbloody diarrhea. The objectives of treatment are to alleviate the symptoms and minimize the deleterious effects on health-related quality of life (HRQOL). There is still no generally accepted clinical definition of remission or relapse. The purpose of this study was to analyze the impact of bowel symptoms on HRQOL and accordingly suggest criteria for remission and disease activity based on impact of patient symptoms on HRQOL. Methods: The design was a cross-sectional postal survey of 116 patients with collagenous colitis. The main outcome measures were 4 HRQOL questionnaires: the Short Health Scale, the Inflammatory Bowel Disease Questionnaire, the Rating Form of IBD Patient Concerns, and the Psychological General Well-Being Index, and a 1-week symptom diary recording number of stools/day and number of watery stools/day. Results: Severity of bowel symptoms had a deleterious impact on patients HRQOL. Patients with a mean of greater than= 3 stools/day or a mean of greater than= 1 watery stool/day had a significantly impaired HRQOL compared to those with less than3 stools/day and less than 1 watery stool/day. Conclusions: We propose that clinical remission in collagenous colitis is defined as a mean of less than3 stools/day and a mean of less than 1 watery stool per clay and disease activity to be a daily mean of greater than= 3 stools or a mean of greater than= 1 watery stool.

  • 49.
    Hjortswang, Henrik
    et al.
    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.
    Tysk, Curt
    University of Orebro.
    Bohr, Johan
    University of Orebro.
    Benoni, Cecilia
    MAS University Hospital.
    Vigren, Lina
    MAS University Hospital.
    Kilander, Anders
    Sahlgrens University Hospital.
    Larsson, Lasse
    Sahlgrens University Hospital.
    Taha, Yesuf
    Karolinska Institute.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Health-related quality of life is impaired in active collagenous colitis2011In: DIGESTIVE AND LIVER DISEASE, ISSN 1590-8658, Vol. 43, no 2, p. 102-109Article in journal (Refereed)
    Abstract [en]

    Objectives: The characteristic clinical symptoms of collagenous colitis are non-bloody diarrhoea, urgency and abdominal pain. Treatment is aimed at reducing the symptom burden and the disease impact on patients health-related quality of life. The objective of this study was to analyse health-related quality of life in patients with collagenous colitis. Methods: In a cross-sectional, postal HRQL survey, 116 patients with collagenous colitis at four Swedish hospitals completed four health-related quality of life questionnaires, two disease-specific (Inflammatory Bowel Disease Questionnaire and Rating Form of IBD Patient Concerns), and two generic (Short Form 36, SF-36, and Psychological General Well-Being, PGWB), and a one-week symptom diary. Demographic and disease-related data were collected. Results for the collagenous colitis population were compared with a background population controlled for age and gender (n = 8931). Results: Compared with a Swedish background population, patients with collagenous colitis scored significantly worse in all Short Form 36 dimensions (p andlt; 0.01), except physical function. Patients with active disease scored worse health-related quality of life than patients in remission. Co-existing disease had an impact on health-related quality of life measured with the generic measures. Lower education level and shorter disease duration were associated with decreased well-being. Conclusion: Health-related quality of life was impaired in patients with collagenous colitis compared with a background population. Disease activity is the most important factor associated with impairment of health-related quality of life. Patients in remission have a health-related quality of life similar to a background population.

  • 50.
    Johansson, E
    et al.
    Östergötlands Läns Landsting.
    Walter, Susanna
    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.
    Ingemansson, A
    Östergötlands Läns Landsting.
    Ryn, A-K
    Hallbook, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Randomized trial of biofeedback or medical treatment for fecal incontinence in NEUROGASTROENTEROLOGY AND MOTILITY, vol 24, issue , pp 183-1832012In: NEUROGASTROENTEROLOGY AND MOTILITY, Blackwell Publishing , 2012, Vol. 24, p. 183-183Conference paper (Refereed)
    Abstract [en]

    n/a

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