GF Science: Celiac Disease Risk in Children

gf scienceThe GF Science series analyzes recent research on gluten-free related topics. I will provide a link to the original research (if possible), present a brief summary of the research, review the author-reported results, posit contextual factors that may affect these results, suggest practical ways to use this research in your life, and begin a discussion with you about some aspect of this research. Your participation is this discussion is essential to further the dialogue about this particular research as well as the overall importance of increased scientific research on gluten-free related topics.

DISCLAIMER: GF Science posts are intended to provide guidance about reading scientific articles to gather practical information for daily living. The information in this post should not be considered a substitute for professional medical advice.

Introduction of Gluten, HLA Status, and the Risk of Celiac Disease in Children

The New England Journal of Medicine (peer-reviewed journal)

Vol. 371, No. 14, pp. 1295-1303, 2014

Authors: Elena Lionetti, M.D., Stefania Castellaneta, M.D., Ruggiero Francavilla, M.D., Ph.D., Alfredo Pulvirenti, Ph.D., Elio Tonutti, M.D., Sergio Amarri, M.D., Maria Barbato, M.D., Cristiana Barbera, M.D., Graziano Barera, M.D., Antonella Bellantoni, M.D., Emanuela Castellano, M.D., Graziella Guariso, M.D., Maria Giovanna Limongelli, M.D., Salvatore Pellegrino, M.D., Carlo Polloni, M.D., Claudio Ughi, M.D., Giovanna Zuin, M.D., Alessio Fasano, M.D., and Carlo Catassi, M.D., M.P.H. for the SIGENP (Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition) Working Group on Weaning and CD Risk

Summary

To clarify the relationship between the age at which gluten is introduced to a child’s diet and the risk of celiac disease, we undertook the Risk of Celiac Disease and Age at Gluten Introduction (CELIPREV) trial, a multicenter, prospective intervention trial comparing early and delayed introduction of gluten to the diet of infants with a familial risk of celiac disease, and we followed these children from birth to at least 5 years of age.”

Building on previous research (see below), researchers intended to study the relationship between risk of Celiac Disease (based on genetic testing) and 1) age at which gluten is introduced and 2) effect (if any) of breast-feeding. In other words, researchers used this study to better understand the effects of nature (genes) versus nurture (exposure to gluten, exposure to breast-milk, dietary patterns) on the development of Celiac Disease.

Theories from Previous Research
  • “The introduction of gluten at 6 months of age is a long-standing practice… Many clinicians advise that the introduction of gluten to the diet of infants who have a familial risk of the disease should be delayed…[which] may permit the maturation of the small intestinal barrier and the mucosal immune response…”
  • “…Investigations of the epidemic of celiac disease that occurred in Sweden during the 1980s and 1990s indicate that the introduction of a small amount of gluten during breast-feeding of infants between 4 and 6 months of age reduces the risk of disease.”
  • “…There is a window of time, between 4 and 7 months, during which the introduction of gluten might facilitate induction of tolerance.”
Study Methods

Evaluated 832 newborns with first-degree relative with Celiac Disease:

  • Randomly assigned to 2 groups
    • Group A: Introduced to dietary gluten at 6 months (379)
    • Group B: Introduced to dietary gluten at 12 months (328)
  • Gene-based risk tested at 15 months old
    • High risk
    • Standard risk
    • No risk: absence of genes (excluded from study)
  • Blood-based screening (if positive, follow-up with intestinal biopsy, graded as overt CD or potential CD)
    • 15 months old
    • 24 months old
    • 36 months old
    • 5 years old
    • 8 years old
    • 10 years old

Results*

“…Postponing the introduction of gluten until 12 months of age had no effect on the risk of the development of celiac disease in the long term…[but it] had two potentially positive consequences. First, it delayed the development of celiac disease, which might reduce the negative effect of the disease on vulnerable organs such as the brain. Second, it reduced the prevalence, albeit nonsignificantly, of celiac disease autoimmunity at any age among children carrying the high-risk HLA genotype…”

  • “Our data showed no difference in the risk of celiac disease between children who were introduced to gluten at 6 months (during the open “window”) and those who were introduced to gluten at 12 months (when the window was closed). Thus, our findings do not support the “window of tolerance” hypothesis.”
  • “We did not detect an effect of breast-feeding on the development of celiac disease: the mean duration of breast-feeding was very similar for at-risk children among whom celiac disease developed and at risk-children among whom the disorder did not develop (5.6 and 5.8 months, respectively). We did not observe a protective effect of introducing gluten during breast-feeding, but our study was not designed to address this issue…”

Our results support early determination of the HLADQ haplotype in infants with a familial risk of celiac disease, not only to exclude infants who are negative for HLA-DQ2 and HLA-DQ8 from further investigation but also to identify those with two copies of the HLA-DQ2 allele, who require close monitoring because of the high risk of disease…”

  • “…Celiac disease autoimmunity tends to develop in genetically predisposed children early in life, usually before the age of 5 years. Early dietary factors, particularly the child’s age at the introduction of gluten, seem to play a minor role in the risk of the development of celiac disease. However, delaying the introduction of gluten in at-risk infants may delay the onset of the disease, with potential benefit related to maintenance of a state of health during a crucial period of child development.”

*Findings are not consistent with previous research. More research is needed to clarify these results.

Context

Whenever you are analyzing scientific research, it is important to understand both the assumptions that make up the hypothesis as well as the study limitations. Comprehensive scientific research articles will include this information because it provides appropriate context for interpreting the results.

Study Assumptions:
  1. “…The prevalence of this disease is higher among persons who have first-degree relatives with celiac disease…”
  2. “The prevalence of celiac disease has increased in developed countries over recent decades; this finding points to the role of one or more possible environmental triggers other than gluten.”
Limitations:*
  1. Conclusions about breast-feeding may not be appropriate for discussion in this study:
    • There was no accurate way to evaluate effect of breast-feeding based on this study because (1)  “our study was not designed to address this issue” and (2) the number of months breast-fed varied a great deal within all study groups (based on the large standard deviations listed in Table 2 on pp.1301).
    • No mention if breast-feeding mother was also eating gluten. Gluten can pass through breast-milk and may affect study results!
  2. No thorough measurement or discussion of severity of symptoms in positive results (other than overt or potential CD). Is it possible that breast-feeding and/or delayed gluten exposure may mediate severity of symptoms? Yes!
  3. Children were not biopsied unless they had a positive blood test result, which may result in missed correlational or causational factors that were unexpected.
    • “It is possible that we underestimated the number of children in whom celiac disease developed because of incomplete follow-up, but overt celiac disease developed in the large majority of children within the first 5 years of life, and in 80% of those in whom celiac disease developed, it did so during the first 3 years. We therefore suggest that efficient screening for celiac disease may be carried out by testing school-age children.”
  4. “We diagnosed celiac disease autoimmunity and overt celiac disease according to current guidelines…”
    • The study was conducted from 2003-2008, but the science of Celiac Disease is still relatively young.
  5. People not included in the study:
    • “…Participants who were lost to follow-up before 36 months or for whom we had no serologic data were excluded from the analysis.”
    • “…125 patients who dropped out…”
    • “Of the 707 infants tested for HLA status, 154 were in the HLA no-risk group (21.8%) and were excluded from further analysis.”
    • Children related to people following a gluten-free diet who are not formally diagnosed with Celiac Disease.
  6. This study was conducted only in Italy, but it was based on international research. It is important to note that cultural factors may skew results or affect assumptions used to create the hypothesis.

*Limitations are listed in order of importance. This study is well-designed, so all limitations should also be taken in that context.

Practical Usage

If a child is born into a family with a genetic pattern of Celiac Disease AND has genes that are “high risk” for developing Celiac Disease, that child will most likely benefit from early and continued screenings for Celiac Disease to begin treatment (gluten-free diet) as early as possible to prevent additional health complications. In other words, high risk children benefit from early identification of risk level even if they develop Celiac Disease. Prevention of additional gluten-related complications may be a more realistic goal for high risk children than tolerance to gluten. Delaying exposure to gluten and breast-feeding may continue to benefit children in other ways.

Discussion

I chose to breast-feed my son and delay gluten exposure for a variety of reasons:

  •  I have “high risk” genes.
    • Many members of my immediate family have both severe symptoms and serious complications from exposure to gluten.
  • I experience severe gluten-related symptoms.
    • I wanted to limit potential exposure to gluten in our home (for my benefit).
    • I wanted to (potentially) mediate severity of gluten-related symptoms in him.
  • There are many other benefits to breast-feeding that I wanted to give him.

Although this study was released after my son weaned, I would make the choice to delay exposure to gluten and breast-feed again (even if these choices did not ultimately protect my son from needing to live gluten-free). It helped (our family) simplify an already major life transition—it was not always easy, but it kept decision-making (at least on these matters) straightforward.

Did you delay gluten exposure in your children? Why or why not?

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