Timing of introduction of gluten into infant's diet associated with appearance of celiac disease


Children with gluten exposure from cereal grains at 4 to 6 months of age have a lower risk of celiac disease than children with exposure before or after this time period, according to a study in the May 18 issue of JAMA.

Celiac disease, also called gluten-sensitive enteropathy (a disease of the intestinal tract), is characterized by chronic inflammation in the small intestine, induced by gluten (a protein substance) present in wheat, rye, or barley, according to background information in the article. The classic form of celiac disease typically presents in early childhood with abdominal pain and diarrhea, malabsorption, and nutrient deficiencies. Most patients with celiac disease carry the gene HLA-DRB1*03 (usually associated with HLA-DQ2) or HLA-DRB1*04 (associated with HLA-DQ8). These gene variations also confer increased risk for type 1 diabetes; thus, individuals with type 1 diabetes and their first-degree relatives have increased risk of celiac disease. However, few genetically susceptible individuals develop celiac disease, even though virtually all individuals in wheat-consuming populations are exposed to gluten. This suggests that additional factors play a role in disease risk.

Jill M. Norris, M.P.H., Ph.D., of the University of Colorado at Denver and Health Sciences Center, and colleagues investigated whether there was an association between timing of exposure to cereals and subsequent development of celiac disease autoimmunity (CDA) in children with a genetic predisposition for celiac disease. The study was conducted from 1994-2004 with 1,560 children at increased risk for celiac disease or type 1 diabetes, as defined by possession of either HLA-DR3 or DR4 gene variations, or having a first-degree relative with type 1 diabetes. The average follow-up was 4.8 years.

Fifty-one children developed CDA. The researchers found that findings adjusted for HLA-DR3 status indicated that children exposed to foods containing wheat, barley, or rye (gluten-containing foods) in the first 3 months of life (3 [6 percent] CDA positive vs. 40 [3 percent] CDA negative) had a 5-fold increased risk of CDA compared with children exposed to gluten-containing foods at 4 to 6 months (12 [23 percent] CDA positive vs. 574 [38 percent] CDA negative). Children not exposed to gluten until the seventh month or later (36 [71 percent] CDA positive vs. 895 [59 percent] CDA negative) had a marginally increased risk of CDA compared with those exposed at 4 to 6 months.

Of the 25 children with biopsy-confirmed CDA-positive status, 3 (12 percent) were exposed to wheat, barley, or rye at 1 to 3 months, 3 (12 percent) at 4 to 6 months, and 19 (76 percent) at 7 months or later vs. 40 (3 percent), 583 (38 percent), and 912 (59 percent) of unaffected children, respectively. Initial exposure to wheat, barley, or rye in the first 3 months or in the seventh month or later significantly increased risk of biopsy-confirmed CDA compared with exposure at 4 to 6 months.

"Given that our study population was selected for specific genetic and family history characteristics, our findings are generalizable only to children at increased risk for celiac disease. We cannot exclude the possibility that earlier exposure to gluten simply leads to earlier appearance of CDA and that all exposed at-risk children will eventually develop CDA. Long-term follow-up of this cohort may be necessary to address this question. Given the small number of CDA-positive children and wide CIs [confidence intervals], we recommend that these results be confirmed in other prospective cohorts of children at risk for celiac disease before any interventions are implemented," the authors write.

(JAMA. 2005;293:2343-2351. Available post-embargo at JAMA.com)

Editor's Note: This research was supported by grants from the National Institutes of Health, Autoimmune Prevention Center, Diabetes Endocrine Research Center, Clinical Investigation & Bioinformatics Core, and the General Clinical Research Centers Program, National Center for Research Resources.

Editorial: Infant Gluten and Celiac Disease - Too Early, Too Late, Too Much, Too Many Questions

In an accompanying editorial, Richard J. Farrell, M.D., of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, discusses the findings by Norris et al.

"Long-term follow-up of this cohort may help clarify whether earlier exposure to gluten results in a real increased risk of celiac disease, an earlier presentation of the disease, or neither. Longitudinal data may also clarify whether earlier exposure to gluten simply leads to earlier appearance of tTG [tissue transglutaminase, an autoantigen] or whether all exposed at-risk children will eventually develop tTG."

"Ultimately, much larger, international prospective studies are required to unravel the complex interplay between multiple infant diet factors and an immature immune system in a genetically predisposed individual at risk for celiac disease. Only then will it be possible to know the true effect of exclusive vs. partial breastfeeding, gluten amount vs. gluten timing, and infant cereal vs. follow-up infant formula on celiac disease risk and presentation," Dr. Farrell writes.

(JAMA. 2005;293:2410-2412. Available post-embargo at JAMA.com)

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