Risk of Celiac Disease Autoimmunity and Timing of Gluten Introduction in the Diet of Infants at Increased Risk of Disease
Authors: Goldsobel Alan B. 
Published: September 2006

Purpose of the Study.
Patients with HLA-DR3 or DR4 alleles are at increased risk for the development of celiac disease. However, not all genetically susceptible individuals develop celiac disease. The objective of this study was to investigate whether there was an association between the timing of exposure to gluten and subsequent development of celiac disease autoimmunity (CDA) in children with a genetic predisposition for celiac disease.

Study Population.
Children (n = 1560) were identified in the Denver, Colorado, metropolitan area with an increased risk for celiac disease (or type 1 diabetes), defined as having either a first-degree relative with type 1 diabetes or positive cord blood screening for HLA-DR3 or DR4 alleles. This study was conducted over 10 years with a mean follow-up of 4.8 years.

Methods.
This was a prospective, observational study. Infant diet data were collected during telephone or face-to-face interviews at 3, 6, 9, 12, and 15 months of age. No dietary advice was given to the families. Children had blood drawn at 9, 15, and 24 months and annually thereafter for the measurement of the celiac disease autoantigen, and tissue transglutaminase (tTG). After 1 or 2 positive tTG autoantibody results, small-bowel biopsy was offered to the families, although not all had this procedure performed. The primary outcome of the study was the time to development of CDA defined as the presence of tTG autoantibodies on 2 consecutive results or a positive small-bowel biopsy after a single tTG-positive test.

Results.
Fifty-one children developed CDA. Children exposed to foods containing wheat, barley, or rye in the first 3 months of life had a 5 times increased odds ratio (P = .02) of CDA as compared with children first exposed to gluten at 4 to 6 months of age. Twenty-five of the CDA-positive children had biopsy-proven celiac disease. In these children, exposure to gluten in the first 3 months of life had a 23 times increased risk (P = .001) of CDA. In the biopsy-proven cohort, children not exposed to gluten until &gt;7 months of age also had a significantly increased risk of CDA (odds ratio: 4; P = .04). There was no association between the development of CDA and the timing of introduction of oats or rice. No protective effect of breastfeeding was found with the development of CDA. Although all children in the cohort were exposed to gluten by 12 months of age, the first positive tTG autoantibody test did not occur until 2 years of age, with a mean age of positive conversion of 4.7 years.

Conclusions.
In children at increased risk of developing celiac disease, timing of gluten exposure in the diet is associated with the appearance of CDA. Exposure to gluten in the first 3 months of life is thought to be associated with increased risk because of immature or incomplete intestinal barrier function. The authors speculate that late gluten exposure may have been associated with CDA because of greater amounts introduced in the older infants.

Reviewer Comments.
It is important to understand that this study population was specific children with genetic and family history characteristics at increased risk for the development of celiac disease and may not be generalizable to the entire population. Mean follow-up of this population was just under 5 years, and long-term follow-up of these patients is needed to determine if earlier exposure to gluten simply leads to earlier appearance of CDA and that many (if not all) exposed at-risk children would eventually develop CDA. This study also does not address the relationship between CDA and celiac disease.