Acta Pædiatrica ISSN 0803-5253

REGULAR ARTICLE

Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings Tony Hansson ([email protected])1,2, Ingrid Dahlbom1,3, Torsten Tuvemo1, Gun Frisk2 1.Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden 2.Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden 3.Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden

Keywords Autoantibodies, Coeliac disease, tissue transglutaminase, Type 1 diabetes

ABSTRACT Aim: This study measured autoantibodies against tissue transglutaminase (anti-tTG) to

Correspondence Tony Hansson, PhD, Department of Women’s and Children’s Health, Uppsala University Hospital, SE- 751 85 Uppsala, Sweden. Tel: +46-18-6115923 | Fax: +46-18-6115583 | Email: [email protected]

Methods: Anti-tTG was measured in prospectively collected sera from 169 children at the

Received 18 June 2014; revised 14 August 2014; accepted 1 October 2014. DOI:10.1111/apa.12823

detect untreated coeliac disease in children with type 1 diabetes and their siblings. onset of diabetes, 88 of their siblings and 96 matched control children. Coeliac disease was confirmed with a small intestinal biopsy. Results: Coeliac disease was diagnosed in five children before diabetes onset. A further 12 children were diagnosed after diabetes onset, without any gastrointestinal symptoms, and 11 of these had anti-tTG at the onset of diabetes, with the remaining child showing seroconversion within 6 months. Hence, all the children with both diseases had anti-tTG at or before diabetes diagnosis, and the prevalence of coeliac disease was 10.1%. Moreover, 6.8% of the siblings and 3.1% of the control children had elevated levels of anti-tTG. None of the siblings reported any coeliac-related symptoms, despite being positive for anti-tTG, and coeliac disease has so far been biopsy confirmed in 4.5%. Conclusion: Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. All diabetes children and their siblings should be tested and followed for the presence of anti-tTG and coeliac disease.

The incidence of type 1 diabetes mellitus, especially in childhood, has increased rapidly in the western world during the past 30 years, with the highest incidence rate in the Nordic countries (1,2). Type 1 diabetes is caused by the destruction of the insulin-secreting pancreatic islet beta cells, and genetic factors are important. However, as the concordance rate among homozygote twins is about 30–45%, environmental factors such as virus infections and/or dietary antigens could be involved in the development of the disease and the increase in incidence. Children with type 1 diabetes are at high risk of developing other diseases such as coeliac disease and autoimmune thyroiditis, (3) and the prevalence of coeliac disease is higher in patients with type 1 diabetes than in the general population (4,5). Patients with type 1 diabetes can develop coeliac disease and/or, autoimmune thyroiditis prior to, simultaneously, or after the onset of type 1 diabetes (6–9), and this coincidence can be due to the presence of the same predisposing HLA-DQ2 (DQA1*0501-B1*0201) and DQ8 (DQA1*301-B1*0302) antigens (10,11). Moreover, there are

Abbreviations ESPGHAN, European Society of Paediatric Gastroenterology, Hepatology and Nutrition; IA-2, Thyrosine phosphatase; IU/mL, International units per mL; tTG, tissue transglutaminase.

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd

several non-HLA regions associated with both type 1 diabetes and coeliac disease, but also alleles that confer protection in type 1 diabetes and susceptibility in coeliac disease (12). Approximately 70% of newly diagnosed patients with type 1 diabetes have autoantibodies against the islet cell enzymes glutamic acid decarboxylase (GAD65) and tyrosine phosphates (IA-2), and these antibodies can be present in serum years before the appearance of clinical symptoms (13). However, increased antibody levels do not necessarily implicate the development of type 1 diabetes and there are seasonal variations in the emergence of autoantibodies,

Key notes 





This study measured coeliac-related autoantibodies and coeliac disease in children with type 1 diabetes and their siblings. Untreated coeliac disease was present in 10.1% of the children with diabetes and in 4.5% of their siblings, despite a lack of coeliac-related symptoms. Silent coeliac disease was over-represented in children with type 1 diabetes and their siblings and such children should be routinely and longitudinally tested for the presence of coeliac-related autoantibodies.

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Type 1 diabetes and coeliac disease

suggesting that an infectious agent may be involved in the initiation of the autoimmune reaction (14). The epidemiological situation of coeliac disease is similar to the situation of type 1 diabetes, and the prevalence of coeliac disease in the western world is at least 1% (15). Coeliac disease is characterised by an infiltration of inflammatory cells in the small intestinal mucosa, and the exposure to wheat gluten is crucial in the development of coeliac disease. Some reports show a direct correlation between the age of coeliac disease diagnosis and the development of other autoimmune diseases (16,17), indicating that the duration of gluten exposure could influence the disease frequency. Coeliac disease is associated with the production of autoantibodies against the enzyme tissue transglutaminase (tTG). Elevated serum levels of antibodies against tTG can be used in the diagnosis of coeliac disease (18–20) and can be detected several years before the intestinal inflammation of individuals who will develop coeliac disease later in life. Moreover, high levels of both IgA and IgG anti-tTG antibodies correlate with the mucosal deterioration and constitute a reliable sign of untreated coeliac disease, irrespective symptoms (21,22). Considering all the above, type 1 diabetes and coeliac disease have a common genetic relationship and may share the same inflammatory mechanisms and triggering environmental factors. In this study, we wanted to examine the presence of antitTG and untreated coeliac disease in children with newly diagnosed type 1 diabetes and in their siblings.

PATIENTS AND METHODS Patients We prospectively collected samples from all children attending Uppsala University Hospital during the years 1999–2008 at the onset of type 1 diabetes. This study included serum samples from 169 children with type 1 diabetes (75 girls, 94 boys, median age 10 years, range 1–17 years), and all samples were collected when diabetes was diagnosed. All children with type 1 diabetes have a yearly health check up, and this meant that there were also 114 follow-up samples available from 75 of the children with diabetes, collected after median 11 months (range 1–95 months). We also collected samples from first-degree relatives of the children with type 1 diabetes, and these included serum samples from 88 siblings (40 girls, 48 boys, median age 12 years, range 2–20 years) collected when their brother or sister was diagnosed with type 1 diabetes. The study also included serum samples from 96 time, age and sex matched control children with other complaints than type 1 diabetes and no known gastrointestinal diseases (41 girls, 55 boys, median age 10 year, range 2–17 years). A small intestinal biopsy was offered to all patients with positive anti-tTG results and to all children with a clinical suspicion of coeliac disease, independent of the antibody results. Coeliac disease was then confirmed, according to the revised 1990 European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria

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for childhood coeliac disease (23). Families who had a child diagnosed with coeliac disease were offered the opportunity to have all the child’s siblings investigated for the presence of coeliac disease and type 1 diabetes-related autoantibodies. Written informed consent was obtained from all the included children or their parents. The study was approved by the Regional Ethical Review Board at Uppsala, Sweden. Measurement of coeliac-related autoantibodies IgA anti-tTG antibodies were measured in all serum samples with the Celikey assay, and IgG anti-tTG antibodies were measured with the IgG RecombitTG assay (Phadia, Freiburg, Germany) according to the manufacturer’s instructions. Serum samples were diluted 1:101, antibody levels were expressed as arbitrary units calculated from a six-point calibrator curve, and optimal cut-off values for the assays were calculated from receiver operator characteristic curves. Samples with antibody levels above the highest calibrator point were further diluted and retested. Antibody values above 4 U/mL and 5 U/mL, respectively, were considered positive for the IgA and IgG anti-tTG antibodies (19,20). Measurement of type 1 diabetes-related autoantibodies IgG antibodies against human recombinant IA-2 were measured with a quantitative ELISA (Euroimmune, € beck, Germany) according to the manufacturer’s instrucLu tions. The upper limit of the normal range recommended by the manufacturer was 10 international units per mL (IU/mL), and values above 10 IU/mL were considered as positive. Antibodies against GAD65 were measured with Diamyd anti-GAD65 RIA (Mercodia AB, Uppsala, Sweden) according to the manufacturer’s instructions, and the cutoff was set to 9.5 U/L. Statistics The serum levels of antibodies are reported as median (with 10th and 90th centiles in brackets). The Kruskal–Wallis test with Dunn’s multiple post hoc test was used to calculate the differences in the antibody levels between the different groups of children. Correlations were calculated using the Spearman’s rank correlation and are reported with 95% confidence interval (CI) in brackets. p-values

Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings.

This study measured autoantibodies against tissue transglutaminase (anti-tTG) to detect untreated coeliac disease in children with type 1 diabetes and...
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