Lisa M. Emery

Rotavirus Infection Frequency and Risk of Celiac Disease Autoimmunity in Early Childhood: A Longitudinal Study

OBJECTIVE:Few studies have assessed the role of specific gastrointestinal infections in celiac disease. We investigated whether increased frequency of rotavirus infection, a common cause of gastrointestinal infection and inflammation, predicts increased risk of celiac disease autoimmunity.METHODS:A cohort of 1,931 children from the Denver metropolitan area who carried celiac disease human leukocyte antigen (HLA) risk alleles were followed from infancy for development of celiac disease autoimmunity, defined as positivity at two or more subsequent clinic visits for tissue transglutaminase (tTG) autoantibodies measured using a radioimmunoassay with human recombinant tTG. Blood samples were obtained at ages 9, 15, and 24 months, and annually thereafter. Rotavirus antibodies were assayed using an indirect enzyme immunoassay in serial serum samples from each case and two matched controls. Frequency of infections were estimated by the number of increases (>2 assay coefficient of variation) in rotavirus antibody between clinic visits.RESULTS:Fifty-four cases developed celiac disease autoimmunity at a median age of 4.4 yr. Thirty-six had an intestinal biopsy, of which 27 (75%) were positive for celiac disease. Frequent rotavirus infections predicted a higher risk of celiac disease autoimmunity (compared with zero infections, rate ratio 1.94, 95% confidence interval [CI] 0.39–9.56, for one infection and rate ratio 3.76, 95% CI 0.76–18.7, for ≥2 infections, rate ratio for trend per increase in number of infections = 1.94, 95% CI 1.04–3.61, p = 0.037). The result was similar after adjustment for gender, ethnic group, maternal education, breast-feeding, day-care attendance, number of siblings, season of birth, and number of HLA DR3-DQ2 haplotypes.CONCLUSIONS:This prospective study provides the first indication that a high frequency of rotavirus infections may increase the risk of celiac disease autoimmunity in childhood in genetically predisposed individuals.

Natural history of antibodies to deamidated gliadin peptides and transglutaminase in early childhood celiac disease.

Introduction: Gliadin proteins play a key role in the pathogenesis of celiac disease; however, as a screen for celiac disease, anti-gliadin antibody testing has been replaced by the more sensitive and specific serological assays for transglutaminase autoantibodies (TGAA). A new generation of anti-gliadin antibody assays has been developed to detect synthetic, deamidated homologous gliadin peptides (DGP) with high sensitivity and specificity. Methods: Sera were collected prospectively from children with an increased risk for celiac disease as part of an ongoing study at Denver, and studied for the development of celiac autoimmunity. We investigated the high-performance DGP antibody assay in 50 TGAA-positive children both before the development of celiac autoimmunity and following the institution of a gluten-free diet to determine the relationship of DGP antibodies to TGAA. TGAA were measured by an in-house radioassay. Results: DGP antibodies and TGAA parallel each other over the period of years children were studied. DGP antibodies resolved sooner than TGAA in subjects on a gluten-free diet. DGP antibodies appeared earlier than TGAA in 9 children. Conclusions: Measuring DGP antibodies may be more useful than TGAA in monitoring children on a gluten-free diet. DGP antibodies can precede the appearance of TGAA in some at-risk children.

Newborn HLA-DR,DQ genotype screening: age- and ethnicity- specific type 1 diabetes risk estimates

Objective:  Certain human leukocyte antigen (HLA)‐DR,DQ genotypes have been associated with type 1 diabetes mellitus (T1DM) risk, although it is unknown whether the association is due to alleles, haplotypes, genotypes, the formation of heterodimers, or all of the above. To characterize the role of the HLA‐DR,DQ genotype and ethnicity on the onset age of T1DM, we analyzed these factors in patients with T1DM and the general population.

395 IMPACT OF CELIAC AUTOIMMUNITY ON SUBJECTS WITH TYPE 1 DIABETES

Purpose Children with type 1 diabetes mellitus (T1DM) have an increased risk for celiac disease (CD), despite absence of clinical symptoms of CD. Benefits of screening and early treatment of CD are unknown. Our objective is to evaluate the impact of early treatment of CD on the growth, intestinal permeability, diabetes control, and bone density of subjects with diabetes and celiac autoimmunity (tissue tranglutaminase antibody (TG) positivity). Methods This is a prospective, observational study of children with T1DM characterized as TG+ or TG- through screening. TG+ subjects self-select to gluten-free diet (GFD) or regular diet (RD). Primary outcomes are diabetes control, intestinal permeability, growth, and bone density. Data are mean ± SD. Results To date, 42 TG+ subjects have completed the baseline visit (22 GFD, 20 RD), 30 have completed the 6 month visit (17 GFD, 13 RD), and 21 have completed the 12 month visit (10 GFD, 11 RD). At baseline there are no significant differences between the TG+ groups (mean age for GFD group was 10.2 ± 3.3 years, and RD group was 11.4 ± 3.4; duration of diabetes was 5.4 ± 3.9 years for GFD group and 7.2 ± 3.4 for RD group; mean duration of GFD was 10.4 ± 1.0 months; TG index was 0.63 ± .56 in GFD group and 0.4 ± 0.38 in RD group; HbA1C was 8.15% ± 1.2 for GFD group and 8.9% ±1.5 for RD group; and the height z-score was -0.24 ± 1.18 for GFD group, and 0.07 ± 1.1 for RD group). There were also no significant differences between the TG+ groups at 6 or 12 months for any variables including race, gender, ethnicity, age, diabetes duration, TG index, HbA1C, urine microalbumin, and z-scores for body mass index, height-for-age, and weight-for-age. Additionally, there were no differences for lumbar or volumetric spine z-scores for chronological or bone age, nor differences in intestinal permeability as measured by sucrose breath test between groups at baseline or 12 months. Report of symptoms also did not differ at baseline or 12 months, but an increase in flatulence was reported in the RD group at 6 months. Conclusions There were no significant differences between the TG+ groups at baseline, 6 months, or 12 months. Therefore, there is no evidence of benefit of GFD at one year. Further enrollment and follow-up is needed to determine whether there are benefits to screening for CD in children with T1DM and whether early initiation of GFD is necessary in patients with CD.