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Objectives: Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were ≥ 10 times the upper limit of normal (10× ULN) predicted CD in T1D., Methods: Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhüber classification., Results: All of the 60 children with anti-tTG ≥10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8., Conclusions: As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method., (© 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Objectives: The aims of the study were to ascertain whether the Celiac Dietary Adherence Test (CDAT) could contribute in determining adherence to a gluten-free diet in patients with celiac disease and to evaluate the diet adherence and well being of a study population 5 years after a celiac disease screening known as "Exploring the Iceberg of Celiacs in Sweden.", Methods: Through the screening, 90 adolescents (born 1997) were diagnosed with biopsy-proven celiac disease at 12 years of age. Of them, 70 (78%) came to a 5-year follow-up where anti-tissue transglutaminase antibodies 2 was tested and a questionnaire was filled in, including CDAT, which consists of 7 questions related to adherence. Nonparametrical tests were used to determine associations between adherence measures., Results: Among the adolescents, 86% were adherent to a gluten-free diet 5 years after screening, 38% reported their general well being as excellent, 50% very well, and 12% well. Statistically significant associations were seen between anti-tissue transglutaminase antibodies 2 and the CDAT score (P = 0.033), and the self-reported adherence question and the CDAT score (P < 0.001)., Conclusions: The screening-detected adolescents reported a high level of well being and adherence to a gluten-free diet 5 years after screening. We conclude that the CDAT can be used in clinical practice as an estimation of adherence to a gluten-free diet. It would be most suitable to use in conjunction with currently used adherence measures, but can also be used as a stand-alone method when others are not accessible.

Objectives: This study explored the association between tissue transglutaminase autoantibody (tTGA), high-risk human leucocyte antigen (HLA) genotypes and islet autoantibodies in children with newly diagnosed type 1 diabetes (T1D)., Patients and Methods: Dried blood spots and serum samples were taken at diagnosis from children <18 years of age participating in Better Diabetes Diagnosis (BDD), a Swedish nationwide prospective cohort study of children newly diagnosed with T1D. We analyzed tTGA, high-risk HLA DQ2 and DQ8 (DQX is neither DQ2 nor DQ8) and islet auto-antibodies (GADA, IA-2A, IAA, and three variants of Zinc transporter; ZnT8W, ZnT8R, and ZnT8QA)., Results: Out of 2705 children diagnosed with T1D, 85 (3.1%) had positive tTGA and 63 (2.3%) had borderline values. The prevalence of tTGA was higher in children with the HLA genotypes DQ2/2, DQ2/X or DQ2/8 compared to those with DQ8/8 or DQ8/X (p = .00001) and those with DQX/X (p ≤ .00001). No significant differences were found in relation to islet autoantibodies or age at diagnosis, but the presence of tTGA was more common in girls than in boys (p = .018)., Conclusion: tTGA at T1D diagnosis (both positive and borderline values 5.4%) was higher in girls and in children homozygous for DQ2/2, followed by children heterozygous for DQ2. Only children with DQ2 and/or DQ8 had tTGA. HLA typing at the diagnosis of T1D can help to identify those without risk for CD.

Objectives: The aim was to determine the prevalence of celiac disease autoimmunity in children with type 1 diabetes (T1D) diagnosed in Denmark and Sweden., Methods: A total of 662 Swedish children with T1D were matched with 1080 Danish children with T1D and 309 healthy children from Sweden and 283 from Denmark served as controls. Sera were analyzed for the presence of IgA and IgG (IgAG) autoantibodies against deamidated gliadin peptide (DGP) and tissue transglutaminase (tTG) with enzyme-linked immunosorbent assay (ELISA) and IgG-tTG separately in a radioligand binding assay (RBA). Human leukocyte antigen (HLA)-DQB1 and DQA1 genotyping were determined in the T1D cohorts., Results: In the Swedish T1D cohort, 17.2% (114/662) were IgAG-DGP/tTG positive compared with 11.7% (126/1080) in the Danish T1D cohort (p = 0.001) and with 9.4% (29/309) Swedish (p = 0.001) and 5.7% (16/283) Danish (p = 0.003) controls. In the Swedish T1D cohort, both levels of IgAG-DGP/tTG and IgG-tTG were higher compared with the levels in the Danish T1D (p < 0.001). In the control group, 2.8% of the Danish children were positive for both IgAG-DGP/tTG and IgG-tTG, compared to 0.3% of the Swedish. Presence of HLA-DQ2 was equally distributed among 89 children with T1D positive for both IgAG-DGP/tTG and IgG-tTG., Conclusion: The discrepancy in levels of IgAG-DGP/tTG and IgG-tTG between Swedish and Danish T1D cohorts was independent of HLA and suggests that regional variations in comorbidity of celiac disease in T1D is caused by difference in exposure to environmental factors., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The aim of the study was to evaluate the gluten-free diet (GFD) adherence after 1 year of follow-up in children with screening-detected celiac disease (CD) in a general population., Methods: A total of 18,325 twelve-year-olds were invited to participate in a population-based CD screening (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 substudy included 210 children with TG2-IgA, evaluated both at the initial biopsy occasion and at 1-year follow-up. GFD adherence was evaluated by a combination of TG2-IgA measurements and self-reported adherence (n = 193)., Results: After 1 year, 85% (179/210) had normalized TG2-IgA levels (<5 U/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 of GFD adherence ("always" 82% [158/193] and "often" 16% [30/193]), and 75% [145/193] reported always adhering combined 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 highest TG2-IgA levels., Conclusions: GFD adherence is high in adolescents with CD detected by screening of the general population of Swedish 12-year-olds. Almost all of them had normalized serology and reported GFD adherence at the 1-year follow-up. A few adolescents who reported GFD adherence, however, had elevated TG2-IgA levels, suggesting more severe disease and/or nonadherence.

Background: Untreated celiac disease is traditionally believed to be associated with malabsorption and underweight. However, studies describing body mass index (BMI) in individuals at the time of diagnosis have shown contradictory results. We investigated the differences in weight, height, and BMI in 12- year-old children with screening-detected celiac disease compared to their healthy peers., Methods: In a population-based screening study of 12,632 12-year-old children, blood samples were analyzed for markers of celiac disease. Children with elevated markers were referred for a small bowel biopsy. Weight and height were measured in 239 out of 242 children with screening-detected celiac disease (57.3% girls) and in 12,227 children without celiac disease (48.5% girls). BMI was categorized according to the International Obesity Task Force. Age- and sex-specific cut-off points for underweight, normal weight, and overweight were used., Results: Children with celiac disease weighed less and were shorter than their peers (median weight 45.2 kg, interquartile range (IQR) 40.2-52.2 kg vs. 47.0 kg, IQR 41.1-54.4 kg, respectively, p = 0.01; median height 156.5 cm, IQR 151.0-162.0 cm vs. 157.5 cm, IQR 152.0-163.0 cm, respectively, p = 0.04). In comparing those with celiac disease to their healthy peers, 4.2% vs. 5.2% were underweight, 82.0% vs. 72.8% were normal weight, and 13.8% vs. 21.9% were overweight, respectively. There was no association between being underweight and the risk of having undiagnosed celiac disease (Odds ratio (OR) 1.3, 95% CI 0.7-2.4), but the risk was significantly lower among overweight children (OR 0.56, 95% CI 0.4-0.8). Median BMI was slightly lower among the children with screening-detected celiac disease compared to their healthy peers (18.6 kg/m2, IQR 17.1-19.8 kg/m2 vs. 18.8 kg/m2, IQR 17.2-21.1 kg/m2, respectively, p = 0.05), but most of the celiac disease cases had a normal BMI., Conclusions: At a population level, children with celiac disease weigh less, are shorter, and have a lower BMI compared to their peers without celiac disease, and this emphasizes the importance of early recognition and treatment of the condition. However, at an individual level, growth parameters are not reliable in establishing the diagnosis.

Aim: The aim was to determine the prevalence and clinical and temporal relationship of celiac disease (CD) in a population of Swedish children with type 1 diabetes mellitus (T1DM) before, during, and after the Swedish epidemic of CD (birth cohorts 1984-1996)., Methods: Retrospective chart review between 1995 and 2005 was conducted of 1151 children (0-18 years old, born 1981-2004) with T1DM., Results: A prevalence of 9.1% (95% CI: 7.2-11.2) of CD in T1DM children was found. No significant difference in prevalence of CD was observed in different birth years, in contrast to the Swedish epidemic of CD. Sixty-two percent of children diagnosed with CD after T1DM onset had pathological levels of antibodies within the first 24 months. The presence or absence of gastrointestinal symptoms had no predictable value for biopsy-confirmed CD or not., Conclusion: The onset of CD in the T1DM population does not follow the pattern of the general population during the Swedish epidemic of CD. The shared genetic component in the human leukocyte antigen region in cases with comorbidity of CD and T1DM may overrule other CD-causing factors in the general population. Children with T1DM should be screened for CD at diagnosis and repeatedly at least during the first 2 years, even if asymptomatic.

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.

Background: Case reports and smaller case-control studies suggest an association between celiac disease (CD) and urticaria but risk estimates have varied considerably across studies and as yet there are no studies on CD and the risk of future urticaria., Objective: To examine the association between CD and urticaria., Methods: We identified 28,900 patients with biopsy-verified CD (equal to Marsh stage 3) and compared them with 143,397 age- and sex-matched controls with regards to the risk of urticaria and chronic urticaria (duration ≥6 weeks). Hazard ratios (HRs) were estimated using a Cox regression model., Results: During follow-up, 453 patients with CD and no previous diagnosis of urticaria developed urticaria (expected n = 300) and 79 of these 453 had chronic urticaria (expected n = 41). The corresponding HRs were 1.51 for any urticaria (95%CI = 1.36-1.68) and 1.92 for chronic urticaria (95%CI = 1.48-2.48). The absolute risk for urticaria in CD was 140/100,000 person-years (excess risk = 47/100,000 person-years). Corresponding figures for chronic urticaria were 24/100,000 person-years and 12/100,000 person-years. Patients with CD were also at increased risk of having both urticaria (odds ratio, OR = 1.31; 95%CI = 1.12-1.52) and chronic urticaria (OR = 1.54; 95%CI = 1.08-2.18) prior to the CD diagnosis., Conclusion: This study suggests that CD is associated with urticaria, especially chronic urticaria.

Background: Tissue transglutaminase (tTG) autoantibodies are serological markers for celiac disease. The aim was to study the efficacy of the pTnT-rhtTG plasmid and subsequent diagnostic accuracy of tTG autoantibodies for childhood celiac disease using radioligand binding assays., Methods: Coupled in vitro transcription and translation of tTG were performed by pTnT-rhtTG as well as by the pGEMt Easy-rhtTG vectors using the TNT SP6 Coupled Reticulocyte Lysate System in the presence of [³⁵S] methionine. Sera from 190 celiac disease children and 74 controls were measured for tTG autoantibodies in two separate radioligand binding assays using anti-human IgA agarose and protein A sepharose beads for the detection of IgA-tTG and IgG-tTG, respectively., Results: Median incorporation of [³⁵S] methionine into the pTnT-rhtTG was 26% compared to 16% for the pGEMt Easy-rhtTG plasmid (p = 0.0016). Using pTnT-rhtTG (as compared to pGEMt Easy-rhtTG), sensitivities were IgA-tTG = 96.3% (95.7%) and IgG-tTG = 95.8% (97.3%) and specificities were IgA-tTG = 91.9% (90.5%) and IgG-tTG = 94.6% (98.4%). According to receiver operator characteristics for the pTnT (pGEMt Easy) assays, area under the curves were IgA-tTG = 98.4% (98.4%) and IgG-tTG = 97.7% (97.2%), respectively., Conclusion: The pTnT-rhtTG plasmid increased the efficacy of tTG antigen usage without reducing the diagnostic accuracy of IgA-tTG and IgG-tTG for childhood celiac disease. The pTnT-rhtTG plasmid is therefore recommended over the pGEMt Easy-rhtTG for the assessment of IgA-tTG and IgG-tTG using radioligand binding assays.

Objective: The aim of this study is to determine Swedish parents' willingness to pay (WTP) for coeliac disease (CD) screening of their child., Subjects and Methods: CD screening was undertaken involving 10,041 12-year-old children, with 7567 (75%) agreeing to participate. Blood samples from the children were analysed for CD serological markers. Parents received a questionnaire including a scenario describing the health-related risks of having CD and screening and diagnostic procedures. Parents were also asked whether they were willing to pay for CD screening, should this not be offered free of charge, and, if so, what their maximum WTP would be. Their WTP was compared with the average cost per child for the screening and case ascertainment procedures., Results: The questionnaire was answered by 6524 parents, and of 6057 valid responses 63% stated that they were willing to pay something. The mean WTP was 79 EUR and the median 10 EUR. The average cost per child for the screening and case ascertainment procedures was 47 EUR, which 23% of the parents stated they were willing to pay. Parents' WTP increased with higher education and income, and with child symptoms that may indicate CD., Conclusions: Swedish parents' WTP for school-based CD screening of their child was higher than the average cost per child; however, only a minority of the parents were willing to pay that amount.

Objectives: Screening for celiac disease (CD) in the apparently healthy members of 107 nuclear families with two affected siblings (sib pair) and estimating the risk of CD in siblings and parents., Methods: One hundred seven families from Sweden and southern Norway with at least two affected children were investigated. Frozen sera from 187 of the 192 healthy parents and from 94 of 95 siblings without diagnosed CD were examined for total immunoglobulin A (IgA) and anti-endomysial antibodies (EMA). Individuals with positive antibody titers underwent small intestinal biopsy., Results: Positive test for EMA was found in 6 of 94 (6.3%) siblings without previously diagnosed CD and in 8 of 189 (4.2%) parents. CD was confirmed by small intestinal biopsy in all siblings and seven parents. The estimated risk for CD in multiply affected families was 26.3% for siblings and 12.9% for parents. An unexpected male preponderance was found among the new CD cases (10 males, 3 females)., Conclusion: The risk of CD in the members of nuclear families with two affected children is approximately three times higher than that when only one child is affected. The high male preponderance of new cases is unexpected and could not be explained fully by more silent disease in males as compared with females. Considering the high level of knowledge about CD in these families, the number of undiagnosed cases is surprisingly high. The authors suggest that serologic screening should be offered to all first-degree relatives of patients with CD.

This study was undertaken to investigate the prevalence of coeliac disease in children and adolescents with Turner syndrome. Eighty-seven children and adolescents with Turner syndrome were screened for IgA-antiendomysium antibodies (EMA) and IgA-antigliadin antibodies (AGA), 5% (4/87) being found to be EMA-positive, and 15% (13/87) to have AGA levels above normal. Of the 10 patients who were either AGA- or EMA-positive and further investigated with intestinal biopsy, four manifested villous atrophy (i.e. all three of the EMA-positive patients, but only one of the seven AGA-positive patients). The results suggest EMA-positivity to be a good immunological marker for use in screening for coeliac disease, and such screening to be justified in patients with Turner syndrome.