Timing of gluten introduction and the risk for developing celiac disease Can we intervene ? גלו - תן או אל תתן Ron Shaoul Pediatric Gastroenterology Bnai Zion Medical Center

Introduction For a long time, investigators have wondered how gluten cause the disease. We now know that CD as an autoimmune reaction to tissue transglutaminase in the intestinal mucosa initiated by exposure to dietary gluten in genetically predisposed individuals.

Introduction (cont.) Yet basic questions about the amount of gluten needed to trigger CD and the possible role of the timing of its introduction into the diet have remained unanswered in spite of research in this area since the 70s.

Celiac disease occurs as a result of the interplay between genetic and environmental factors. For its development an individual must carry the alleles that encode for the HLA CLASS II MOLECULES DQ2 or DQ8 (related to HLA-DR3 and HLA-DR4) and ingest gluten.

The questions….. The HLA genes, account for 40% of the genetic influence for this disorder and these genes occur in up to 40% of the population. In addition, a vast number of people ingest wheat products. Why then does celiac disease only occur in 1% of the population when so many are at risk? The answer lies in the other genetic and environmental factors that contribute to the disease.

One study revealed that children with celiac disease who were breast-fed had delayed onset and less severe, more atypical presentations of celiac disease compared with children who were not breast-fed. In addition, information has been provided by an analysis of the Swedish epidemic of celiac disease in infants in the early 1980s. Factors associated with this epidemic were lack of breast-feeding, large amounts of gluten in infant formula and the occurrence of infections in early life. D’Amico MA et al. Clin Pediatr (Phila) (2005) 44: 249–258 Ivarsson A et al. Acta Paediatr (2000) 89: 165–171

Previous case-control studies have reported that children with celiac disease were less likely to have been breastfed or were breastfed for a shorter period of time than children without celiac disease. Ivarsson et al. found that children with celiac disease were less likely to have been breastfeeding when gluten was introduced into the diet than children without celiac disease. No effect of the timing of the introduction of gluten into the infant diet on risk of celiac disease has been observed in six publications. Ivarsson A et al. Am J Clin Nutr (2002) 75: 914–921

This prospective, 10 year observational study enrolled 1560 children considered at increased risk for celiac disease or type 1 diabetes to determine whether the timing of gluten introduction into the diet was related to the development of celiac disease. Increased risk for celiac disease or type 1 diabetes was defined as having either HLA DR3 or DR4 alleles or a first degree relative with type 1 diabetes.

The majority (1307) were identified at birth, while the remaining 253 were recruited between age 2 and 3 years. The children were followed for a mean of 4.8 years. At intervals (3, 6, 9, 12, and 15 months in children enrolled at birth) Data on diet were collected from parents by telephone or face-to-face interview. Each time, mothers were asked to report all types of milk, formula, and solid food consumed by the infant over the previous 3 months. Children followed from birth had serum tTG measured at 9, 15, and 24 months and yearly thereafter. Children enrolled between 2 and 3 years of age had tTG measurements at enrollment and yearly thereafter.

CD was defined as a positive tTG on 2 or more consecutive visits or a positive tTG once with a small bowel biopsy consistent with celiac disease.

Fifty-one (3.3%) children developed CD: 50 with two positive tTG measurements and one with one positive measurement and a positive small bowel biopsy. Of the 51 children, 34 had a duodenal biopsy.

The mean age at first positive tTG of the 51 CDA positive children was 4.7  1.5 years The mean age at last follow-up for the 1509 CD- negative children was 4.8  2.9 years. Of the CD positive children, three (6%) were exposed to wheat, barley, or rye between 1 and 3 months, 12 (23%) at 4 to 6 months, and 36 (71%) at 7 months or later. Among CD-negative children, only 40 (3%), 574 (38%), and 895 (59%) were positive at the same time intervals.

Children exposed to gluten in the first 3 months of life had a 5-fold increased hazard of CDA compared with those exposed at 4 to 6 months. Children not exposed to gluten until seven months or later were at a slightly increased hazard (1.87) of CDA compared with those exposed in the 4- to 6-month period. This difference was only marginally significant

Restricting the analysis to the 25 children with biopsy-proven celiac disease, the hazard ratio for exposing between 1-3 months and after 7 months was 22.97, P = 0.001; and 3.98; P = 0.04, respectively).

Thus, initial exposure to gluten in the first 3 months or at 7 months and later, significantly increased the risk of biopsy confirmed CD compared with exposure at 4 to 6 months. Previous study of the same group showed that children initially exposed to cereals between ages 0 and 3 months (hazard ratio 4.32); and those who were exposed at 7 months or older (HR, 5.36) had increased hazard of Islet autoimmunity compared with those who were exposed during the fourth through sixth month,

They found no association between the development of CD and the timing of introduction of oats or of rice, suggesting that the association is antigen-specific.

An unexpected finding of this study was the lack of evidence a protective effect of prolonged breast feeding. This finding is in contradiction to previous studies Ivarsson A, et al. Am J Clin Nutr 2002;75:914–21. Greco L, et al. J Pediatr Gastroenterol Nutr 1988;7:395–9. Peters U, et al. Ann Nutr Metab 2001;45:135–42.

Possible explanations Gliadin deamidation by tTG has been demonstrated to enhance the recognition of gliadin peptides by T cells and this might initiate the cascade of autoimmune reactions leading to celiac disease. For this to happen, gliadin has to cross the intestinal epithelial barrier so that it can be recognized by antigen-presenting cells. At very young ages this barrier may not be as complete as at older ages, thus allowing gliadin to pass even with small amounts of intake.

The reason why late gluten exposure is also associated with CDA is less clear. When wheat is introduced to an older child, it tends to be introduced in greater amounts, thus increasing the amount of gliadin available to cross the gut. Ivarsson et al found that children with celiac disease were exposed to a larger amount of gluten at first exposure than children without celiac disease,

In this study, infants first exposed to cereals at or after the seventh month were more likely to have been given 1 or more servings per day in the first month of exposure compared with children who were first exposed before 4 months (52% vs 31%,respectively). Recent finding suggests that gliadin may actually activate a zonulin-dependent enterocyte intracellular signaling pathway leading to increased intestinal permeability Clemente MG, et al. Gut. 2003;52:

the first positive tTG autoantibody result did not occur until 2 years of age, with a mean age at conversion of 4.7 years, showing a delay in the appearance of tTG autoantibodies.

Criticism The findings must be interpreted with caution, as the results are based on a very small numbers. Even though 1560 children were followed up as part of the study, only 51 developed CD and only 3 children who were exposed to gluten before 3 months developed tTG autoantibodies. This raises concerns about reproducibility and a type II error.

The aim of this study was to examine the association between cereal-grain exposures (wheat, barley, rye, oats) in the infant diet and development of wheat allergy.

Methods A total of 1612 children were enrolled at birth and followed to the mean age of 4.7 years. Questionnaire data and dietary exposures were obtained at 3, 6, 9, 15, and 24 months and annually thereafter. The main outcome measure was parent report of wheat allergy. Children with celiac disease were excluded. Wheat-specific immunoglobulin E levels on children reported to have wheat allergy were obtained.

Results Sixteen children (1%) reported wheat allergy. Children who were first exposed to cereals after 6 months of age had an increased risk of wheat allergy compared with children first exposed to cereals before 6 months of age (after controlling for confounders including a family history of allergic disorders and history of food allergy before 6 months of age). All 4 children with detectable wheat-specific immunoglobulin E were first exposed to cereal grains after 6 months. A first-degree relative with asthma, eczema, or hives was also independently associated with an increased risk of wheat-allergy development.

conclusions Delaying initial exposure to cereal grains until after 6 months may increase the risk of developing wheat allergy. These results do not support delaying introduction of cereal grains for the protection of food allergy.

What’s behind the delay of solid introduction ? The reasons to delay introduction of solid foods for allergy prevention have centered on the notion that the infant’s gut-mucosal barrier is immature and early exposure to allergens (food proteins) may result in allergic sensitization against food allergens. Evidence in humans to support this hypothesis comes from a few studies demonstrating an increased risk of eczema and possibly asthma in children first introduced to solids before 3 to 4 months of age. Kajosaari M. Adv Exp Med Biol. 1991;310:453–458 Fergusson DM, et al. Pediatrics. 1990;86:541–546

Systematic review and meta-analysis of observational studies published between 1966 and June 2004 that examined the association between breast feeding and the development of CD. Results: Six case-control studies met the inclusion criteria. With the exception of one small study, all the included studies found an association between increasing duration of breast feeding and decreased risk of developing CD.

The meta-analysis showed that the risk of CD was significantly reduced in infants who were breast feeding at the time of gluten introduction (pooled odds ratio 0.48, 95% CI 0.40 to 0.59) compared with infants who were not breast feeding during this period.

Preventive effect of breast milk The actual mechanism through which breast milk protect against the development of CD is unclear. It could be that continuing breast feeding limits the amount of gluten that the child receives. Another mechanism is by preventing gastrointestinal infections in the infant. Infections of the gastrointestinal tract in early life could lead to increased permeability, allowing the passage of gluten into the lamina propria. Gut infections are also known to increase tissue transglutaminase expression and this could favor the generation of deamidated gluten peptides triggering CD in susceptible individuals.

Preventive effect of breast milk Juto et al have suggested two other possible mechanisms Firstly, human milk IgA antibodies may diminish immune response to ingested gluten by mechanisms such as agglutination of the antigen to immune complexes on the mucosal surface so that uptake is prevented. Secondly, the immune modulating property of human milk may be exerted through its T-cell specific suppressive effect Juto et al. Lancet 343(8909):1372.

Conclusions: Breast feeding may offer protection against the development of CD. Breast feeding during the introduction of dietary gluten, and increasing duration of breast feeding were associated with reduced risk of developing CD. It is, however, not clear from the primary studies whether breast feeding delays the onset of symptoms or provides a permanent protection against the disease.

Final conclusions The best advice seems to be that infants born into families with celiac disease should be breast-fed for at least 6 months and receive gluten in their diet at age 4–6 months following birth.

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