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  • 1.
    Browaldh, Lars
    et al.
    Sachsska barnsjukhuset, Södersjukhuset, Stockholm.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Agardh, Daniel
    barnmedicinska kliniken Malmö och Lund, Skånes universitetssjukhus.
    Stenhammar, Lars
    Vrinnevisjukhuset, Norrköping.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Celiaki är en vanlig sjukdom som är lätt att missa2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 11, p. 484-488Article in journal (Refereed)
    Abstract [sv]

    Celiaki ansågs länge som en ovanlig barnsjukdom, men är en vanlig sjukdom som drabbar alla åldrar.  Genomförda screeningar av normalbefolkningen visar att merparten inte fått dia­gnos eller behandling. Den kliniska bilden varierar: alltifrån diffusa besvär eller inga symtom alls till allvarliga gastrointestinala symtom med grav avmagring och tillväxtrubbning till följd av malabsorption. Klinisk misstanke om eller hereditet för celiaki bör föranleda analys av specifika serologiska markörer. Gastroskopi med tunntarmsbiopsi bör övervägas för att bekräfta eller utesluta diagnosen.

  • 2.
    Hedberg, Maria E.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Moore, Edward R. B.
    Svensson-Stadler, Liselott
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pietz, Grzegorz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarstrom, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Prevotella jejuni sp nov., isolated from the small intestine of a child with coeliac disease2013In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 63, no 11, p. 4218-4223Article in journal (Refereed)
    Abstract [en]

    Five obligately anaerobic, Gram-stain-negative, saccharolytic and proteolytic, non-spore-forming bacilli (strains CD3 :27, CD3 :28(T), CD3 :33, CD3 :32 and CD3 :34) are described. All five strains were isolated from the small intestine of a female child with coeliac disease. Cells of the five strains were short rods or coccoid cells with longer filamentous forms seen sporadically. The organisms produced acetic acid and succinic acid as major metabolic end products. Phylogenetic analysis based on comparative 16S rRNA gene sequence analysis revealed close relationships between CD3 : 27, CD3 :28(T) and CD3 :33, between CD3 :32 and Prevotella histicola CCUG 55407(T), and between CD3 :34 and Prevotella melaninogenica CCUG 4944B(T). Strains CD3 : 27, CD3 :28(T) and CD3 :33 were clearly different from all recognized species within the genus Prevotella and related most closely to but distinct from P. melaninogenica. Based on 16S rRNA, RNA polymerase) beta-subunit (rpoB) and 60 kDa chaperonin protein subunit (cpn60) gene sequencing, and phenotypic, chemical and biochemical properties, strains CD3 :27, CD3 :28(T) and CD3 :33 are considered to represent a novel species within the genus Prevotella, for which the name Prevotella jejuni sp. nov. is proposed. Strain CD3 : 28(T) (=CCUG 60371(T)=DSM 26989(T)) is the type strain of the proposed novel species. All five strains were able to form homologous aggregates, in which tube-like structures were connecting individual bacteria cells. The five strains were able to bind to human intestinal carcinoma cell lines at 37 degrees C.

  • 3. Högberg, L
    et al.
    Webb, C
    Fälth-Magnusson, K
    Forslund, T
    Magnusson, K-E
    Danielsson, L
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sundqvist, T
    Children with screening-detected coeliac disease show increased levels of nitric oxide products in urine2011In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 100, no 7, p. 1023-1027Article in journal (Refereed)
    Abstract [en]

    Aim: Increased concentration of nitric oxide (NO) metabolites, nitrite and nitrate, in the urine is a strong indication of ongoing small intestinal inflammation, which is a hallmark of the enteropathy of coeliac disease (CD). It has previously been shown that children with symptomatic, untreated CD have increased levels of NO oxidation products in their urine. The aim of this study was to investigate whether screening-detected, asymptomatic coeliac children display the same urinary nitrite/nitrate pattern.

    Methods: In a multicenter screening study, serum samples were collected from 7208 12-year-old children without previously diagnosed CD. Sera were analysed for anti-human tissue transglutaminase (tTG) of isotype IgA. Small bowel biopsy was performed in antibody-positive children, yielding 153 new cases of CD. In the screening-detected individuals, the sum of nitrite and nitrate concentrations in the urine was analysed and used as an indicator of NO production. For comparison, 73 children with untreated, symptomatic CD were studied.

    Results: The nitrite/nitrate levels in children with screening-detected CD and those with untreated symptomatic CD did not differ significantly. Both groups had significantly increased urinary nitrite/nitrate concentrations compared to the children with normal small bowel biopsy (p < 0.001).

    Conclusion: Children with screening-detected CD have increased production of NO just as children with untreated symptomatic CD. High NO metabolite levels in the urine may indicate a pathogenetic feature of CD and be a marker of major clinical importance.

  • 4.
    Ivarsson, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Norström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    van der Pals, Maria
    Department of Pediatrics, Clinical Sciences, Skånes University Hospital, Lund University, Lund, Sweden.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Högberg, Lotta
    Pediatric Clinic, Norrköping Hospital, Norrköping, Sweden, and Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden .
    Danielsson, Lars
    Pediatric Clinic, Norrtälje Hospital, Norrtälje, Sweden.
    Halvarsson, Britta
    Pathology and Cytology, Aleris Medilab, Täby, Sweden.
    Hammarroth, Solveig
    Pediatric Clinic, Norrtälje Hospital, Norrtälje, Sweden.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Karlsson, Eva
    Pediatric Clinic, Växjö Hospital, Växjö, Sweden..
    Stenhammar, Lars
    Pediatric Clinic, Norrköping Hospital, Norrköping, Sweden, and Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden .
    Charlotta, Webb
    Department of Pediatrics, Clinical Sciences, Skånes University Hospital, Lund University, Lund, Sweden.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Department of Pediatrics, Clinical Sciences, Skånes University Hospital, Lund University, Lund, Sweden.
    Reduced prevalence of childhood celiac disease: an effect of changes in infant feeding?Manuscript (preprint) (Other academic)
  • 5.
    Ivarsson, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Norström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    van der Pals, Maria
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Högberg, Lotta
    Danielsson, Lars
    Halvarsson, Britta
    Hammarroth, Solveig
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Karlsson, Eva
    Stenhammar, Lars
    Webb, Charlotta
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Prevalence of childhood celiac disease and changes in infant feeding2013In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 131, no 3, p. e687-e694Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Between 1984 and 1996, Sweden experienced an "epidemic" of clinical celiac disease in children <2 years of age, attributed partly to changes in infant feeding. Whether infant feeding affects disease occurrence and/or the clinical presentation remains unknown. We investigated and compared the total prevalence of celiac disease in 2 birth cohorts of 12-year-olds and related the findings to each cohort's ascertained infant feeding.

    METHODS: A 2-phase cross-sectional screening study was performed in which 13 279 children from 2 birth cohorts participated: children born during the epidemic (1993) and children born after the epidemic (1997). Previously diagnosed cases were reported and confirmed. Blood samples were analyzed for serological markers and children with positive values were referred for small intestinal biopsy. Infant feeding practices in the cohorts were ascertained via questionnaires. Prevalence comparisons were expressed as prevalence ratios.

    RESULTS: The total prevalence of celiac disease was 29 in 1000 and 22 in 1000 for the 1993 and 1997 cohorts, respectively. Children born in 1997 had a significantly lower risk of having celiac disease compared with those born in 1993 (prevalence ratio: 0.75; 95% confidence interval: 0.60-0.93; P = .01). The cohorts differed in infant feeding (specifically, in the proportion of infants introduced to dietary gluten in small amounts during ongoing breastfeeding).

    CONCLUSIONS: A significantly reduced prevalence of celiac disease in 12-year-olds indicates an option for disease prevention. Our findings suggest that the present infant feeding recommendation to gradually introduce gluten-containing foods from 4 months of age, preferably during ongoing breastfeeding, is favorable.

  • 6.
    Myléus, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Webb, Charlotta
    Danielsson, Lars
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Högberg, Lotta
    Karlsson, Eva
    Lagerqvist, Carina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stenhammar, Lars
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Wall, Stig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Carlsson, Annelie
    Celiac disease revealed in 3% of Swedish 12-year-olds born during an epidemic2009In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 49, no 2, p. 170-176Article in journal (Refereed)
    Abstract [en]

    Objetive: Sweden experienced a marked epidemic of celiac disease between 1984 and 1996 in children younger than 2 years of age, partly explained by changes in infant feeding. The objective of this study was to determine the prevalence of celiac disease in 12-year-olds born during the epidemic (1993), including both symptomatic and screening detected cases.

    Patients and methods: All sixth-grade children in participating schools were invited (n = 10,041). Symptomatic and, therefore, previously diagnosed celiac disease cases were ascertained through the National Swedish Childhood Celiac Disease Register and/or medical records. All serum samples were analyzed for antihuman tissue transglutaminase (tTG)-IgA (Celikey), and serum-IgA, and some for tTG-IgG and endomysial antibodies. A small intestinal biopsy was recommended for all children with suspected undiagnosed celiac disease.

    Results: Participation was accepted by 7567 families (75%). Previously diagnosed celiac disease was found in 67 children; 8.9/1000 (95% confidence interval [CI] 6.7-11). In another 192 children, a small intestinal biopsy was recommended and was performed in 180. Celiac disease was verified in 145 children, 20/1000 (95% CI 17-23). The total prevalence was 29/1000 (95% CI 25-33).

    Conclusions: The celiac disease prevalence of 29/1000 (3%)-with two thirds of cases undiagnosed before screening-is 3-fold higher than the usually suggested prevalence of 1%. When these 12-year-olds were infants, the prevailing feeding practice was to introduce gluten abruptly, often without ongoing breast-feeding, which might have contributed to this unexpectedly high prevalence.

  • 7.
    Myléus, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Stenhammar, Lars
    Högberg, Lotta
    Browaldh, Lars
    Daniels, Ing-Marie
    Fagerberg, Ulrika L.
    Gudjónsdóttir, Audur H.
    Malmquist, Marianne
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Questionnaire showed that Swedish paediatric clinics complied well with the revised European guidelines for diagnosing coeliac disease2019In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, no 6, p. 1140-1143Article in journal (Refereed)
    Abstract [en]

    Aim: In 2012, revised criteria for diagnosing childhood coeliac disease were published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and incorporated into the revised Swedish guidelines the same year. These made it possible, in certain cases, to diagnose coeliac disease without taking small bowel biopsies. This survey assessed the extent to which the new guidelines were implemented by Swedish paediatric clinics two years after their introduction.

    Methods: In October 2014, we distributed a paper questionnaire including five questions on diagnostic routines to the 40 paediatric clinics in university or regional hospitals in Sweden that perform small bowel biopsies.

    Results: All 36 (90%) clinics that responded used anti-tissue transglutaminase antibodies as the initial diagnostic test and some also used serological markers. Most clinics (81%) used endoscopy and took multiple duodenal biopsies, whereas only a few (19%) occasionally employed a suction capsule. Almost all clinics (86%) omitted taking small bowel biopsies in symptomatic children with repeatedly high coeliac serology and positive genotyping, thereby avoiding the need for invasive endoscopy under anaesthesia.

    Conclusion: The 2012 Swedish Paediatric Coeliac Disease Diagnostic Guidelines had been widely accepted and implemented in routine health care two years after their introduction.

  • 8.
    Namatovu, Fredinah
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. olof.sandstrom@pediatri.umu.se.
    Maternal and perinatal conditions and the risk of developing celiac disease during childhoodManuscript (preprint) (Other academic)
  • 9.
    Namatovu, Fredinah
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. olof.sandstrom@pediatri.umu.se.
    Season and region as risk factors for celiac disease: a key to the etiology?Manuscript (preprint) (Other academic)
  • 10.
    Namatovu, Fredinah
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Season and region of birth as risk factors for coeliac disease a key to the aetiology?2016In: Archives of Disease in Childhood, ISSN 0003-9888, E-ISSN 1468-2044, Vol. 101, no 12, p. 1114-1118Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Coeliac disease (CD) incidence has increased in recent decades, characterised by variations according to sex, age at diagnosis, year of birth, month of birth and region of birth. Genetic susceptibility and exposure to gluten are the necessary factors in CD aetiology, although several environmental factors are considered.

    METHODS: A nationwide prospective cohort longitudinal study was conducted consisting of 1 912 204 children aged 0-14.9 years born in Sweden from 1991 to 2009. A total of 6569 children were diagnosed with biopsy-verified CD from 47 paediatric departments. Using Cox regression, we examined the association between CD diagnosis and season of birth, region of birth and year of birth.

    RESULTS: Overall, CD risk was higher for children born during spring, summer and autumn as compared with children born during winter: adjusted HR for spring 1.08 (95% CI 1.01 to 1.16), summer 1.10 (95% CI 1.03 to 1.18) and autumn 1.10 (95% CI 1.02 to 1.18). Increased CD risk was highest if born in the south, followed by central Sweden when compared with children born in northern Sweden. Children diagnosed at <2 years had an increased CD risk if born in spring while those diagnosed at 2-14.9 years the risk was increased for summer and autumn births. The birth cohort of 1991-1996 had increased CD risk if born during spring, for the 1997-2002 birth cohort the risk increased for summer and autumn births, while for the birth cohort of 2003-2009 the risk was increased if born during autumn.

    CONCLUSIONS: Season of birth and region of birth are independently and jointly associated with increased risk of developing CD during the first 15 years of life. Seasonal variation in infectious load is the likely explanation.

  • 11.
    Namatovu, Fredinah
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Högberg, Ulf
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Maternal and perinatal conditions and the risk of developing celiac disease during childhood.2016In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 16, article id 77Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Celiac disease (CD) is increasing worldwide, which might be due to the changing environmental and lifestyle exposures. We aimed to explore how conditions related to maternity, delivery and the neonatal period influence CD onset during childhood.

    METHODS: Using Sweden's national registers we had access to information on 1 912 204 children born between 1991 and 2009, 6 596 of whom developed CD before 15 years of age. Logistic regression analyses were performed to determine how CD is associated with maternity, delivery and the neonatal period.

    RESULTS: Regardless of sex, a reduction in CD risk was observed in children born to mothers aged ≥35 years (odds ratio [OR] 0.8; 95 % confidence interval [CI] 0.7-0.9) and with high maternal income (OR 0.9; 95 % CI 0.8-0.9). Being a second-born child, however, was positively associated with CD. Among boys, elective caesarean delivery increased the risk of CD (OR 1.2; 95 % CI 1.0-1.4), while maternal overweight (OR 0.9; 95 % CI 0.8-0.9), premature rupture of the membrane (OR 0.4; 95 % CI 0.2-0.8) and low birth weight showed a negative association. Girls had an increased CD risk compared to boys and in girls the risk was increased by repeated maternal urinary tract infections (OR 1.1; 95 % CI 1.0-1.2).

    CONCLUSIONS: Elective caesarean delivery and repeated maternal urinary tract infections during pregnancy are associated with increased risk of CD onset during childhood, suggesting the role of dysbiosis during early life. High maternal age and high income reduced the risk of CD, which might be due to infant-feeding practices and life style.

  • 12.
    Namatovu, Fredinah
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. olof.sandstrom@pediatri.umu.se.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Celiac disease risk varies between birth cohorts, generating hypotheses about causality: evidence from 36 years of population-based follow-up2014In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 14, article id 59Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Celiac disease (CD) is a major public health problem with estimated 1-3% prevalence in the general population. In recent years an increase in CD prevalence has been reported both in Sweden and worldwide. This study aimed at examining the annual incidence rate of biopsy-proven celiac disease among children in Sweden over a 36-year period, to assess variations by age, sex and birth cohort, and to assess the clinical impact of these changes.

    METHODS: The National Swedish Childhood CD Register was used to identify 9107 children aged 0-14.9 years who were diagnosed with CD during the period 1973 to 2009. From 1973 to 1990 the register covered 15% of the nation, this increased to 40% during 1991-1997; a full national coverage was obtained from 1998 onwards. Estimations for the annual incidence rate, cumulative incidence and clinical impact by age groups, calendar month and birth cohorts were made.

    RESULTS: CD incidence is continuing to increase in the child population aged 2-14.9 years. A continued variation in CD incidence was observed in children aged 0-1.9 years, characterized by a marked decrease in most recent years. The median age at diagnosis has increased from 1.0 year in the 1970s to 6.8 years in 2009. The average number of new cases has risen from ~200 during 1973-1983 to ~600 during 2004-2009. In the birth cohorts of 2000-2002 the cumulative incidence even exceeded that of the epidemic cohorts at comparable ages. The highest cumulative incidence was observed in the birth cohorts of 1985-1995 and 2000-2002.

    CONCLUSIONS: CD risk varies between birth cohorts, suggesting cyclic environmental and/or lifestyle risk factors in CD etiology. More research on underlying risk factors is required in order to move forward with preventive strategies.

  • 13.
    Namatovu, Fredinah
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Strömgren, Magnus
    Umeå University, Faculty of Social Sciences, Department of Geography and Economic History.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindgren, Urban
    Umeå University, Faculty of Social Sciences, Department of Geography and Economic History.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Neighborhood conditions and celiac disease risk among children in Sweden2014In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 42, no 7, p. 572-580Article in journal (Refereed)
    Abstract [en]

    Aim: To investigate celiac disease (CD) clustering at different geographical levels and to examine the association between neighborhood demographic and socioeconomic conditions and the risk of neighborhood CD.

    Methods: We included 2080 children diagnosed with CD between 1998 and 2003, identified from 43 of the 47 reporting hospitals in Sweden. A total of 8036 small area market statistics (SAMS) areas were included; these were nested in 253 municipalities that were further nested into eight ‘nomenclature of territorial units for statistics’ (NUTS) 2 regions. We performed multilevel logistic regression analyses.

    Results: We found the highest geographical variation in CD incidence at the municipality level, compared to the region level. The probability of having CD increased in the statistical areas of (SAMS) areas with higher average annual work income, with an odds ratio (OR) of 2.24 and 95% CI of 1.76–2.85. Reduced CD risk in neighborhoods was associated with higher average age (OR 0.96; 95% CI 0.95–0.97), higher proportion of residents with a university education (OR 0.98; 95% CI 0.97–0.99), and higher level of industrial and commercial activity (OR 0.59; 95% CI 0.44–0.82). We found no significant association between CD risk and population density, proportion of Nordic to non-Nordic inhabitants, nor share of the population with only a compulsory education.

    Conclusions: Neighborhood composition influences CD risk. This is one of the first attempts to identify factors explaining geographical variation in CD.

  • 14.
    Norström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nordyke, Katrina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Carlsson, A.
    Hammarroth, S.
    Högberg, L.
    Stenhammar, L.
    Lindholm, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    The Cost-Effectiveness of a Screening for Celiac Disease2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, p. 250-250Article in journal (Other academic)
  • 15.
    Norström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindholm, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandstrom, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Nordyke, Katrina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Delay to celiac disease diagnosis and its implications for health-related quality of life2011In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 11, no 1, p. 118-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To determine how the delay in diagnosing celiac disease (CD) has developed during recent decades and how this affects the burden of disease in terms of health-related quality of life (HRQoL), and also to consider differences with respect to sex and age.

    METHODS: In collaboration with the Swedish Society for Coeliacs, a questionnaire was sent to 1,560 randomly selected members, divided in equal-sized age- and sex strata, and 1,031 (66%) responded. HRQoL was measured with the EQ-5D descriptive system and was then translated to quality-adjusted life year (QALY) scores. A general population survey was used as comparison.

    RESULTS: The mean delay to diagnosis from the first symptoms was 9.7 years, and from the first doctor visit it was 5.8 years. The delay has been reduced over time for some age groups, but is still quite long. The mean QALY score during the year prior to initiated treatment was 0.66; it improved after diagnosis and treatment to 0.86, and was then better than that of a general population (0.79).

    CONCLUSIONS: The delay from first symptoms to CD diagnosis is unacceptably long for many persons. Untreated CD results in poor HRQoL, which improves to the level of the general population if diagnosed and treated. By shortening the diagnostic delay it is possible to reduce this unnecessary burden of disease. Increased awareness of CD as a common health problem is needed, and active case finding should be intensified. Mass screening for CD might be an option in the future.

  • 16.
    Norström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lindholm, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    A gluten-free diet effectively reduces symptoms and health care consumption in a Swedish celiac disease population2012In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 12, no 1, p. 125-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A gluten-free diet is the only available treatment for celiac disease. Our aim was to investigate the effect of a gluten-free diet on celiac disease related symptoms, health care consumption, and the risk of developing associated immune-mediated diseases.

    METHODS: A questionnaire was sent to 1,560 randomly selected members of the Swedish Society for Coeliacs, divided into equal-sized age- and sex strata; 1,031 (66%) responded. Self-reported symptoms, health care consumption (measured by health care visits and hospitalization days), and missed working days were reported both for the year prior to diagnosis (normal diet) and the year prior to receiving the questionnaire while undergoing treatment with a gluten-free diet. Associated immune-mediated diseases (diabetes mellitus type 1, rheumatic disease, thyroid disease, vitiligo, alopecia areata and inflammatory bowel disease) were self-reported including the year of diagnosis.

    RESULTS: All investigated symptoms except joint pain improved after diagnosis and initiated gluten-free diet. Both health care consumption and missed working days decreased. Associated immune-mediated diseases were diagnosed equally often before and after celiac disease diagnosis.

    CONCLUSIONS: Initiated treatment with a gluten-free diet improves the situation for celiac disease patients in terms of reduced symptoms and health care consumption. An earlier celiac disease diagnosis is therefore of great importance.

  • 17.
    Ou, Gangwei
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hedberg, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hörstedt, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Forsberg, Göte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Drobni, Mirva
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease2009In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 12, p. 3058-3067Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Alterations in the composition of the microbiota in the intestine may promote development of celiac disease (CD). Using scanning electron microscopy (SEM) we previously demonstrated that rod-shaped bacteria were present on the epithelium of proximal small intestine in children with CD but not in controls. In this study we characterize the microbiota of proximal small intestine in children with CD and controls and identify CD-associated rod-shaped bacteria. METHODS: Proximal small intestine biopsies from 45 children with CD and 18 clinical controls were studied. Bacteria were identified by 16S rDNA sequencing in DNA extracted from biopsies washed with buffer containing dithiothreitol to enrich bacteria adhering to the epithelial lining, by culture-based methods and by SEM and transmission electron microscopy. RESULTS: The normal, mucosa-associated microbiota of proximal small intestine was limited. It was dominated by the genera Streptococcus and Neisseria, and also contained Veillonella, Gemella, Actinomyces, Rothia, and Haemophilus. The proximal small intestine microbiota in biopsies from CD patients collected during 2004-2007 differed only marginally from that of controls, and only one biopsy (4%) had rod-shaped bacteria by SEM (SEM+). In nine frozen SEM+ CD biopsies from the previous study, microbiotas were significantly enriched in Clostridium, Prevotella, and Actinomyces compared with SEM- biopsies. Bacteria of all three genera were isolated from children born during the Swedish CD epidemic. New Clostridium and Prevotella species and Actinomyces graevenitzii were tentatively identified. CONCLUSIONS: Rod-shaped bacteria, probably of the indicated species, constituted a significant fraction of the proximal small intestine microbiota in children born during the Swedish CD epidemic and may have been an important risk factor for CD contributing to the fourfold increase in disease incidence in children below 2 years of age during that time.

  • 18.
    Pietz, Grzegorz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    De, Rituparna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hedberg, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sjöberg, Veronika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Immunopathology of childhood celiac disease: Key role of intestinal epithelial cells2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185025Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria.

    METHODS: Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.

    RESULTS: More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.

    CONCLUSION: A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.

  • 19.
    Pietz, Grzegorz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hedberg, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nyunt Wai, Sun
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Influences of celiac disease associated bacteria on functions of intestinal epithelium: an in vitro studyManuscript (preprint) (Other academic)
  • 20.
    Pietz, Grzegorz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sjöberg, Veronika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Gene expression profile of the epithelial reaction in childhood Celiac diseaseManuscript (preprint) (Other academic)
  • 21.
    Rosén, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Department of Clinical Sciences, Pediatrics, Lund University, Lund, Sweden.
    Högberg, Lotta
    Department of Clinical and Experimental Medicine, Linköping University.
    Olén, Ola
    Department of medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, .
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Symptoms do not predict celiac disease in a mass screening of Swedish 12-year-oldsManuscript (preprint) (Other academic)
    Abstract [en]

    Ej publicerat manuscript

  • 22.
    Rosén, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Högberg, Lotta
    Olén, Ola
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Usefulness of symptoms to screen for celiac disease2014In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 133, no 2, p. 211-218Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe the frequency of symptoms and associated conditions among screening-detected celiac disease (CD) cases and non-CD children and to evaluate questionnaire-based case-finding targeting the general population.

    METHODS: In a population-based CD screening of 12-year-olds, children and their parents completed questionnaires on CD-associated symptoms and conditions before knowledge of CD status. Questionnaire data for those who had their CD detected in the screening (n = 153) were compared with those of children with normal levels of CD markers (n = 7016). Hypothetical case-finding strategies were also evaluated. Questionnaires were returned by 7054 (98%) of the children and by 6294 (88%) of their parents.

    RESULTS: Symptoms were as common among screening-detected CD cases as among non-CD children. The frequency of children with screening-detected CD was similar when comparing the groups with and without any CD-related symptoms (2.1% vs 2.1%; P = .930) or CD-associated conditions (3.6% vs 2.1%; P = .07). Case-finding by asking for CD-associated symptoms and/or conditions would have identified 52 cases (38% of all cases) at a cost of analyzing blood samples for 2282 children (37%) in the study population.

    CONCLUSIONS: The current recommended guidelines for finding undiagnosed CD cases, so-called active case-finding, fail to identify the majority of previously undiagnosed cases if applied in the general population of Swedish 12-year-olds. Our results warrant further studies on the effectiveness of CD case-finding in the pediatric population, both at the clinical and population-based levels.

  • 23.
    Sandström, Olof
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lönnerdal, Bo
    Graverholt, Gitte
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of alpha-lactalbumin-enriched formula containing different concentrations of glycomacropeptide on infant nutrition.2008In: Am J Clin Nutr, ISSN 0002-9165, Vol. 87, no 4, p. 921-8Article in journal (Other academic)
  • 24.
    Sandström, Olof
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Role of HLA-DQ Genotyping in Celiac Disease2016In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 62, no 3, p. E30-E31Article in journal (Refereed)
  • 25.
    Sandström, Olof
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Role of HLA-DQ Genotyping in Celiac Disease2016In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 62, no 3, p. E30-E31Article in journal (Refereed)
  • 26.
    Sandström, Olof
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lagerqvist, Carina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Depertment of Clinical Sciences, Pediatrics, Lunds university.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Högberg, Lotta
    Department of Clinical and Experimental Medicine, Linköping University.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Transglutaminase IgA antibodies in a celiac disease mass screening and the role of HLA-DQ genotyping and endomysial antibodies in a sequential testing2013In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 57, no 4, p. 472-476Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to evaluate hypothetical screening strategies in a Swedish celiac disease (CD) mass screening.

    Methods: Of 10,041 Swedish sixth graders born in 1993 invited to a population-based CD mass screening, 7208 participated. Anti-tissue transglutaminase (tTG) immunoglobulin (Ig) A were analyzed in all children and total serum IgA (s-IgA) in 7161 children. Additional analyses of tTG-IgG, endomysial antibodies (EMA) IgA and IgG, and human leukocyte antigen (HLA) alleles were performed according to a standardized protocol. Children with elevated levels of serological markers were recommended to undergo a small intestinal biopsy to verify diagnosis, and 153 children with CD were thus identified. Sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and receiver operating characteristic curves were plotted.

    Results: By lowering the cutoff for tTG-IgA, 17 additional cases of CD were identified at the cost of 32 biopsies. All children with tTG-IgA >50 U/mL (10 times the recommended upper limit of normal) had gluten enteropathy. Area under the receiver operating characteristic curve for tTG-IgA was 0.988. All cases carried HLA-DQ2 or HLA-DQ8, as did 53% of the controls. For different hypothetical screening strategies, sensitivity, specificity, PPV, and NPV ranged between 87.6% and 100%, 99.5% and 99.9%, 79.7% and 89.7%, and 99.7% and 100%, respectively. Efforts to increase sensitivity by lowering tTG-IgA cutoff would result in increased number of small intestinal biopsies and lower PPV. Sequential testing for both EMA and HLA-DQ genotyping would reduce the number of negative small intestinal biopsies.

    Conclusions: tTG-IgA is a robust marker when used in CD mass screening and its performance can be enhanced by sequential testing for EMA or HLA-DQ genotyping.

  • 27.
    Sjöberg, Veronika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hollén, Elisabet
    Pietz, Grzegorz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Magnusson, Karl-Eric
    Fälth-Magnusson, Karin
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Holmgren Peterson, Kajsa
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Högberg, Lotta
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease2014In: Clinical and Translational Gastroenterology, ISSN 2155-384X, E-ISSN 2155-384X, Vol. 5, article id e58Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Life-long, strict gluten-free diet (GFD) is the only treatment for celiac disease (CD). Because there is still uncertainty regarding the safety of oats for CD patients, the aim was to investigate whether dietary oats influence the immune status of their intestinal mucosa.

    METHODS: Paired small intestinal biopsies, before and after >11 months on a GFD, were collected from children with CD who were enrolled in a randomized, double-blind intervention trial to either of two diets: standard GFD (GFD-std; n=13) and noncontaminated oat-containing GFD (GFD-oats; n=15). Expression levels of mRNAs for 22 different immune effector molecules and tight junction proteins were determined by quantitative reverse transcriptase (RT)-PCR.

    RESULTS: The number of mRNAs that remained elevated was higher in the GFD-oats group (P=0.05). In particular, mRNAs for the regulatory T cell (Treg) signature molecules interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1), the cytotoxicity-activating natural killer (NK) receptors KLRC2/NKG2C and KLRC3/NKG2E, and the tight junction protein claudin-4 remained elevated. Between the two groups, most significant differences were seen for claudin-4 (P=0.003) and KLRC3/NKG2E (P=0.04).

    CONCLUSIONS: A substantial fraction of pediatric CD patients seem to not tolerate oats. In these patients, dietary oats influence the immune status of the intestinal mucosa with an mRNA profile suggesting presence of activated cytotoxic lymphocytes and Tregs and a stressed epithelium with affected tight junctions. Assessment of changes in levels of mRNA for claudin-4 and KLC3/NKG2E from onset to after a year on oats containing GFD shows promise to identify these CD patients.

  • 28.
    Sjöberg, Veronika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hollén, Elisabeth
    Department of Clinical and Experimental Medicine, Medical Microbiology, Linköping University, Sweden.
    Pietz, Grzegorz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Magnusson, Karl-Eric
    Department of Clinical and Experimental Medicine, Medical Microbiology, Linköping University, Sweden.
    Fälth-Magnusson, Karin
    Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Sweden.
    Laurin, Pia
    Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Sweden.
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Holmgren-Peterson, Kajsa
    Department of Clinical and Experimental Medicine, Medical Microbiology, Linköping University, Sweden.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Högberg, Lotta
    Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Sweden and Division of Pediatrics in Norrköping, County Council of Östergötland, Norrköping, Sweden.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Dietary oats may hamper normalization of the intestinal immune status in childhood celiac diseaseManuscript (preprint) (Other academic)
  • 29.
    Sjöberg, Veronika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hedberg, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Intestinal T-cell responses in celiac disease: impact of celiac disease associated bacteria2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53414-Article in journal (Refereed)
    Abstract [en]

    A hallmark of active celiac disease (CD), an inflammatory small-bowel enteropathy caused by permanent intolerance to gluten, is cytokine production by intestinal T lymphocytes. Prerequisites for contracting CD are that the individual carries the MHC class II alleles HLA-DQ2 and/or HLA-DQ8 and is exposed to gluten in the diet. Dysbiosis in the resident microbiota has been suggested to be another risk factor for CD. In fact, rod shaped bacteria adhering to the small intestinal mucosa were frequently seen in patients with CD during the "Swedish CD epidemic" and bacterial candidates could later be isolated from patients born during the epidemic suggesting long-lasting changes in the gut microbiota. Interleukin-17A (IL-17A) plays a role in both inflammation and anti-bacterial responses. In active CD IL-17A was produced by both CD8(+) T cells (Tc17) and CD4(+) T cells (Th17), with intraepithelial Tc17 cells being the dominant producers. Gluten peptides as well as CD associated bacteria induced IL-17A responses in ex vivo challenged biopsies from patients with inactive CD. The IL-17A response was suppressed in patients born during the epidemic when a mixture of CD associated bacteria was added to gluten, while the reverse was the case in patients born after the epidemic. Under these conditions Th17 cells were the dominant producers. Thus Tc17 and Th17 responses to gluten and bacteria seem to pave the way for the chronic disease with interferon-γ-production by intraepithelial Tc1 cells and lamina propria Th1 cells. The CD associated bacteria and the dysbiosis they might cause in the resident microbiota may be a risk factor for CD either by directly influencing the immune responses in the mucosa or by enhancing inflammatory responses to gluten.

  • 30. Webb, Charlotta
    et al.
    Halvarsson, Britta
    Norström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Carlsson, Annelie
    Danielsson, Lars
    Högberg, Lotta
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Karlsson, Eva
    Stenhammar, Lars
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Accuracy in Celiac Disease Diagnostics by Controlling the Small-bowel Biopsy Process.2011In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 52, no 5, p. 549-553Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: In a Swedish celiac disease screening study (Exploring the Iceberg of Celiacs in Sweden), we systematically reviewed the clinical diagnostic procedures with the aim to evaluate the diagnostic accuracy and to take advantage of lessons learned for improving diagnostic routines. MATERIALS AND METHODS:: A school-based celiac disease screening study involving 5 Swedish centers, with 10,041 invited 12-year-olds with 7567 consenting participation. All 192 children with elevated serological markers were recommended to undergo small-bowel biopsy, performed and evaluated according to local clinical routines. All of the mucosal specimens were reevaluated by 1 and, when needed, 2 expert pathologists to reach diagnostic consensus. RESULTS:: Small-bowel biopsies were performed in 184 children: 130 by endoscopy and 54 by suction capsule. Endoscopic biopsies were inconclusive in 0.6%, compared with 7.4% of biopsies by suction capsule. A patchy enteropathy was found in 9.1%. Reevaluation by the expert pathologist resulted in 6 additional cases with celiac disease and 1 cleared. Sixteen children with normal or inconclusive biopsies, 4 after endoscopy, and 12 after suction capsule were endoscopically rebiopsied, resulting in another 8 cases. The celiac disease prevalence of 30 of 1000 (95% confidence interval 26-34) was not statistically different from that previously reported. CONCLUSIONS:: The present review revealed the importance of controlling each step of the diagnostic procedure. Several cases would have been missed by relying only on local routines. To improve the quality of childhood celiac disease diagnostics, we recommend multiple endoscopic biopsies from both proximal and distal duodenum and standardized evaluation by a pathologist with good knowledge of celiac disease.

  • 31. Webb, Charlotta
    et al.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Norström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hammarroth, Solveig
    Högberg, Lotta
    Lagerqvist, Carina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stenhammar, Lars
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Carlsson, Annelie
    High adherence to a gluten-free diet in adolescents with screening-detected celiac disease2015In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 60, no 1, p. 54-59Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate the gluten-free diet (GFD) adherenceafter one year of follow-up in children with screening-detected celiac disease (CD) in a general population. METHODS: A total of 18,325 12 year olds were invited to participate in apopulation-based CD screening (ETICS- Exploring the Iceberg of Celiacs in Sweden), of whom 13,279 participated. In 240 children, CD was detected through elevated anti-tissue transglutaminase antibodies 2 (TG2-IgA) and verified by a small-intestinal biopsy. This sub-study included the 210 children with TG2-IgAevaluated both at the initialbiopsy occasion and at the one-year follow-up. GFD adherence was evaluated by a combination of TG2-IgA measurements and self-reported adherence (n = 193). RESULTS: After one year, 83% (179/210) had normalizedTG2-IgA levels (<5U/mL). Among those who had >50 U/mL at diagnosis,25% (16/63) still had elevated TG2-IgA but for the majority their initial values were more than halved. Most reported a high level ofGFD adherence ('always' 75%(158/193) and 'often' 14%(30/193)), and 75% (145/193) reported always adhereingcombined with normalized TG2-IgA. Although reporting that they were always adherent, 13 (6.7%) had not yet normalized their TG2-IgA levels completely, however, a majority of these initially had the highestTG2-IgA levels. CONCLUSIONS: GFD adherence is high in adolescents with CD detected by screening of the general population of Swedish 12yearolds. Almost all had normalized serology and reported GFD adherenceat the one-year follow-up. However, a few adolescents whoreported GFD adherence still had elevated TG2-IgA levelssuggesting more severe disease and/or non-adherence.

  • 32. Webb, Charlotta
    et al.
    Norström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Halvarsson, Britta
    Högberg, Lotta
    Lagerqvist, Carina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stenhammar, Lars
    Carlsson, Annelie
    Celiac disease can be predicted by high levels of anti-tissue transglutaminase antibodies in population-based screening2015In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 60, no 6, p. 787-791Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate any potential correlation between anti-tissue transglutaminase antibodies of type immunoglobulin A (tTG-IgA) and the degree of gluten induced enteropathy in children participating in a screening study for celiac disease (CD) and to assess to what extent the revised ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) guidelines cover this group of patients.

    METHODS: This is a sub-study of a cross-sectional CD screening study, ETICS (Exploring the Iceberg of Celiacs in Sweden), a two-phased study performed during 2005-2006 and 2009-2010. The 13,279 participating children had a blood test obtained and those with positive tTG-IgA were recommended a small intestinal biopsy. The tTG-IgA levels at the time of biopsy were compared with the assessment of the biopsy.

    RESULTS: There were 267 children included, of whom 230 were diagnosed with CD. Out of all children, 67 children had low tTG-IgA levels (<5 U/mL), whereof 55% had Marsh 3 lesions. All children with tTG-IgA levels exceeding 10 times the upper limit of normal values of 5 U/mL, i.e. 50 U/mL, were diagnosed with CD. Lowering the cut-off to 3 U/mL, all but one child with 30 U/mL got CD diagnosis.

    CONCLUSION: By adapting the revised ESPGHAN criteria, biopsies could have been omitted in a fourth of all cases. Our results indicate, that the criteria might be useful even on screened children. Further studies are needed to confirm whether the 2012 ESPGHAN guidelines should be revised to also apply to the populations being screened.

  • 33.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome2013In: Cardiology in the Young, ISSN 1047-9511, E-ISSN 1467-1107, Vol. 23, no 3, p. 325-334Article in journal (Refereed)
    Abstract [en]

    Aim We investigated extra-cardiac clinical symptoms and signs in the rare Jervell and Lange-Nielsen Syndrome, characterised by impaired KCNQ1 function, a gene essential for gastric acid secretion. METHODS: All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers. RESULTS: A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed. Previous endoscopy in five cases had revealed no case of coeliac or inflammatory bowel disease but three cases of mucosal hyperplasia/dysplasia. Current signs of anaemia or iron substitution were present in 9 of 12 tested cases. Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present. A significant correlation between elevated gastrin levels and concurrent iron-deficiency and/or anaemia was revealed (p-value 0.039). CONCLUSIONS: A high frequency of extra-cardiac clinical symptoms and previous medical investigations was found. We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer. Clinical monitoring with regard to developing anaemia and hypergastrinaemia should be considered in the Jervell and Lange-Nielsen Syndrome.

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