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Transglutaminase IgA antibodies in a celiac disease mass screening and the role of HLA-DQ genotyping and endomysial antibodies in a sequential testing
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.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Depertment of Clinical Sciences, Pediatrics, Lunds university.
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2013 (English)In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 57, no 4, 472-476 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2013. Vol. 57, no 4, 472-476 p.
Keyword [en]
celiac disease, mass screening, transglutaminase antibodies, HLA-DQ2 and DQ8
National Category
Public Health, Global Health, Social Medicine and Epidemiology Gastroenterology and Hepatology Nutrition and Dietetics Pediatrics
URN: urn:nbn:se:umu:diva-60845DOI: 10.1097/MPG.0b013e31829ef65dOAI: diva2:563699
Swedish Research Council, 521 2004 7093, 521 2007 2953Formas, 222-2004-1918, 222-2007-1394EU, European Research Council, FP6-2005-FOOD-4B-36383-PREVENTCD
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2015-04-29Bibliographically approved
In thesis
1. Mass screening for celiac disease in 12-year-olds: Finding them and then what?
Open this publication in new window or tab >>Mass screening for celiac disease in 12-year-olds: Finding them and then what?
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Mass screening for celiac disease (CD) as a public health intervention is controversial. Before implementation, a suitable screening strategy should be outlined, and the acceptability of the screening scrutinized. Also, the benefits of early detection and possible negative consequences should be explored and compared. The overall aim of this thesis was to evaluate different strategies for finding 12-year-olds with undiagnosed CD in the general population, and to explore the experiences of those receiving the diagnosis in a mass screening.

Methods A school-based CD screening of 12-year-olds was conducted in five study sites across Sweden. Out of 10041 children who were invited, 7208 had a blood sample analyzed for CD-marker tissue transglutaminase of isotype IgA (tTG-IgA) and 7161 for total serum IgA (s-IgA). If the s-IgA value was low, tTG-IgG was also measured. Additional analysis of endomysial antibodies (EMA) was performed if borderline values of tTG were found. In total, 192 had elevated CD-markers, 184 underwent a small intestinal biopsy and 153 eventually had CD diagnosed. Before receiving knowledge about their CD status, children and their parents filled in questionnaires regarding symptoms and CD-associated conditions. Questionnaires were returned by 7054 children (98%) and 6294 parents (88%). Later, all adolescents who had been diagnosed with CD more than one year ago (n=145), and their parents, were invited to a mixed-method follow-up study in which they shared their experiences in questionnaires, written narratives and focus group discussions. In total, we have information on 117 (81%) of these adolescents, either from the adolescents themselves (n=101) and/or from their parent/s (n=125). Data were analyzed using a combination of descriptive and analytical quantitative and qualitative methodologies.

Results We found that information on symptoms and CD-associated conditions were poor predictors for finding undiagnosed CD in the study population. Questionnaire-based case-finding by asking for CD-associated symptoms and conditions would have identified 52 cases (38% of all cases) at a cost of blood-sampling 2282 children (37% of the study population). The tTG-IgA test had an excellent diagnostic accuracy with the area under the receiver operating characteristic curve of 0.988. If using the recommended cut-off for tTG-IgA (>5 U/mL) 151 had fulfilled biopsy criteria and 134 CD cases had been identified. The strategy of lowering the cut-off to tTG-IgA>4 U/mL, and adding the EMA analysis in those with tTG-IgA between 2-4 U/mL, identified another 17 cases (a 12% increase) at the cost of performing 32 additional biopsies. Measuring total s-IgA in 7161 children discovered only two additional cases at the cost of performing 5 additional biopsies. The positive predictive value of our screening strategy was 80%. 

Results from the follow-up study of the screening-detected CD cases illustrated that 54% reported health improvement after initiated treatment, but also that these health benefits had to be balanced against social sacrifices. We also found that although the screening-detected diagnosis was met with surprise and anxiety, the adolescents and their parents were grateful for being made aware of the diagnosis. A majority of parents (92%) welcomed a future screening, but both adolescents and parents suggested that it should be conducted earlier in life.

Conclusion Obtaining information on symptoms and CD-associated conditions was not a useful step in finding undiagnosed CD cases in a general population. The serological marker tTG-IgA, however, had excellent diagnostic accuracy also when lowering the cut-off. The diagnosis had varying impact on adolescents’ quality of life, and their perceived change in health had to be balanced against the social sacrifices resulting from the diagnosis. Overall, CD mass screening seemed acceptable to most of those who were diagnosed and their parents.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 105 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1520
adolescent, celiac disease, children, coeliac disease, focus groups, mass screening, qualitative methodology, questionnaire, transglutaminase antibodies
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology; Public health
urn:nbn:se:umu:diva-58950 (URN)978-91-7459-479-9 (ISBN)
Public defence
2012-12-06, Tandläkarhögskolan, Sal B, Umeå universitet, Umeå, 13:00 (Swedish)
Available from: 2012-11-05 Created: 2012-09-06 Last updated: 2015-04-29Bibliographically approved

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