Clinical Context

In the general pediatric population of children born between 1993 and 2004, estimated 15-year cumulative incidence of biopsy-proven celiac disease (CD) is remarkably high, from 1.9% up to 3.1% when including those with high, persistent autoantibody levels who did not undergo biopsy. Children may have celiac disease autoimmunity (CDA) without CD.

The Environmental Determinants of Diabetes in the Young (TEDDY) study protocol is designed for timely, thorough ascertainment of development of persistent tissue transglutaminase (tTGA) positivity or CDA and subsequent CD, as it prospectively follows children born between 2004 and 2010 at genetic risk for both type 1 diabetes and CD. The population contains various DQ2.5 and DQ8.1 combinations representing the highest risk human leukocyte antigen (HLA)-DQ haplogenotypes for CD.

Study Synopsis and Perspective

The incidence of new celiac disease with onset by age 10 years appears to be rising and varies widely by region, suggesting different environmental, genetic, and epigenetic influences within the United States, according to a new report.

The overall high incidence among pediatric patients warrants a low threshold for screening and additional research on region-specific celiac disease triggers, the authors write.

“Determining the true incidence of [CD] is not possible without nonbiased screening for the disease. This is because many cases occur with neither a family history nor with classic symptoms,” write Edwin Liu, MD, a pediatric gastroenterologist at the Children’s Hospital Colorado Anschutz Medical Campus and director of the Colorado Center for Celiac Disease, and colleagues.

“Individuals may have CDA without having CD if they have transient or fluctuating antibody levels, low antibody levels without biopsy evaluation, dietary modification influencing further evaluation, or potential [CD],” they write.

The study was published online in the American Journal of Gastroenterology.

The TEDDY study prospectively follows children born between 2004 and 2010 who are at genetic risk for both type 1 diabetes and CD at 6 clinical sites in 4 countries: the United States, Finland, Germany, and Sweden. In the United States, patients are enrolled in the states of Colorado, Georgia, and Washington.

As part of TEDDY, children are longitudinally monitored for CDA by assessment of autoantibodies to tTGA. The protocol is designed to analyze the development of persistent tTGA positivity, CDA, and subsequent CD. The study population contains various DQ2.5 and DQ8.1 combinations, which represent the highest-risk HLA-DQ haplogenotypes for CD.

From September 2004 through February 2010 more than 424,000 newborns were screened for specific HLA haplogenotypes and 8676 children were enrolled in TEDDY at the 6 clinical sites. The eligible haplogenotypes included DQ2.5/DQ2.5, DQ2.5/DQ8.1, DQ8.1/DQ8.1, and DQ8.1/DQ4.2.

Blood samples were obtained and stored every 3 months until age 48 months and at least every 6 months after that. At age 2 years, participants were screened annually for tTGA. With the first tTGA-positive result, all prior collected samples from the patient were tested for tTGA to determine the earliest point of autoimmunity.

CDA, a primary study outcome, was defined as positivity in 2 consecutive tTGA tests at least 3 months apart.

In seropositive children, CD was defined on the basis of a duodenal biopsy with a Marsh score of 2 or higher. The decision to perform biopsy was determined by the clinical gastroenterologist and was outside of the study protocol. When a biopsy was not performed, participants with an average tTGA of 100 units or greater from 2 positive tests were considered to have CD for the study purposes.

As of July 2020, among the children who had undergone 1 or more tTGA tests, 6628 HLA-typed eligible children were found to carry the DQ2.5, D8.1, or both haplogenotypes and were included in the analysis. The median follow-up period was 11.5 years.

Overall, 580 children (9%) had a first-degree relative with type 1 diabetes and 317 children (5%) reported a first-degree relative with CD.

Among the 6628 children, 1299 (20%) met the CDA outcome and 529 (8%) met the study diagnostic criteria for CD on the basis of biopsy or persistently high tTGA levels. The median age at CDA across all sites was 41 months. Most children with CDA were asymptomatic.

Overall, the 10-year cumulative incidence was highest in Sweden, at 8.4% for CDA and 3.0% for CD. Within the United States, Colorado had the highest cumulative incidence for both endpoints, at 6.5% for CDA and 2.4% for CD. Washington State had the lowest incidence across all sites, at 4.6% for CDA and 0.9% for CD.

“CDA and CD risk varied substantially by haplogenotype and by clinical center, but the relative risk by region was preserved regardless of the haplogenotype,” the authors write. “For example, the disease burden for each region remained highest in Sweden and lowest in Washington state for all haplogenotypes.”

In the HLA, sex, and family-adjusted model, Colorado children had a 2.5-fold higher risk for CD as compared with Washington. Likewise, Swedish children had a 1.8-fold higher risk for CD than children in Germany, a 1.7-fold higher than children in the United States, and a 1.4-fold higher risk than children in Finland.

Among DQ2.5 participants, Sweden demonstrated the highest risk, with 63.1% of patients developing CDA by age 10 years and 28.3% developing CD by age 10 years. Finland consistently had a higher incidence of CDA than Colorado, at 60.4% vs 50.9%, for DQ2.5 participants but a lower incidence of CD than Colorado, at 20.3% vs 22.6%.

The research team performed a post hoc sensitivity analysis using a lower tTGA cutoff to reduce bias in site differences for biopsy referral and to increase sensitivity of the CD definition for incidence estimation. When the tTGA cutoff was lowered to an average 2-visit tTGA of 67.4 or higher, more children met the serologic criteria for CD.

“Even with this lower cutoff, the differences in the risk of CD between clinical sites and countries were still observed with statistical significance,” the authors write. “This indicates that the regional differences in CD incidence could not be solely attributed to detection biases posed by differential biopsy rates.”

Multiple environmental factors likely account for the differences in autoimmunity among regions, the authors write. These variables include diet, chemical exposures, vaccination patterns, early-life gastrointestinal infections, and interactions among these factors. For instance, the Swedish site has the lowest rotavirus vaccination rates and the highest median gluten intake among the TEDDY sites.

Future prospective studies should capture environmental, genetic, and epigenetic exposures to assess causal pathways and plan for preventive strategies, the authors write. The TEDDY study is pursuing this research.

“From a policy standpoint, this informs future screening practices and supports efforts towards mass screening, at least in some areas,” the authors write. “In the clinical setting, this points to the importance for clinicians to have a low threshold for CD screening in the appropriate clinical setting.”

The TEDDY study is funded by several grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the Centers for Disease Control and Prevention, and the Juvenile Diabetes Research Foundation. The authors have disclosed no relevant financial relationships.

Am J Gastroenterol. Published October 10, 2022.^[1]

Clinical Implications

• CD was common in all studied regions, with high regional variability.
• The findings may inform policy regarding screening practices and support mass screening, especially in areas of higher relative risk.

Earn Credit