Journal Mobile Options
Table of Contents
Vol. 60, Suppl. 2, 2012
Issue release date: April 2012
Section title: Paper
Ann Nutr Metab 2012;60(suppl 2):22–29
(DOI:10.1159/000335335)

Timing of Introduction of Gluten and Celiac Disease Risk

Ludvigsson J.F.a · Fasano A.b
aClinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institute, Stockholm, and Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; bMucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Md., USA
email Corresponding Author

Abstract

Breast milk is the natural nutrition for infants, but in the second half of the first year of life, complementary feeding is needed. Many complementary foods contain gluten, but gluten exposure is associated with the risk of developing celiac disease (CD). CD is a disease with considerable morbidity and mortality. Although CD is associated with certain genetic features, carrying the human leukocyte antigen haplotypes DQ2 or DQ8 (a prerequisite for CD development) cannot fully explain who will or who will not develop CD. Potential risk factors for CD include perinatal events and infant feeding practice. With the exception that children who are breastfed at and beyond gluten introduction into the diet probably may be at a lower risk of developing CD, and that heavy gluten load early in life may increase the risk of future CD, data on the impact of infant feeding are inconsistent.

© 2012 S. Karger AG, Basel


  

Key Words

  • Autoimmunity
  • Breastfeeding
  • Celiac disease
  • Gluten

 Key Messages

• Infant nutrition affects the risk of developing celiac disease.

• Most studies suggest that breastfeeding reduces the risk of future celiac disease.

• Data on the impact of complementary feeding on celiac disease are inconsistent.

 

 Introduction

Celiac disease (CD) is a lifelong immune-mediated disease that occurs in 1–2% of Western populations [1,2,3]. CD originates in the upper part of the small intestine and is characterized by villous atrophy and inflammation of the duodenum and/or jejunum [4,5,6] (fig. 1). The disease develops as a consequence of gluten exposure in some genetically predisposed individuals carrying the human leukocyte antigen (HLA) DQ2/DQ8 haplotypes [7], and is associated with considerable mortality [8] and morbidity [9,10]. In recent years, it has become evident that CD is not only a disease of the Western world [1] but also occurs with similarly high prevalence in some developing countries [11,12,13,14,15,16].

FIG01
Fig. 1. Histopathology of the small intestine.

In this paper, we review several factors that impact on the risk to develop CD, with special emphasis on the role of breastfeeding and timing of gluten introduction in CD development. The importance of these factors is demonstrated by the epidemic of CD experienced in Sweden in the mid-1980s, in part triggered by the mode (timing and dose) of gluten introduction in infants’ diet (fig. 2) [17,18].

FIG02
Fig. 2. The ‘Swedish epidemic’ of CD. Differences in the incidences of CD in Sweden over time [reprinted with permission from ref. [17] ].

 

 Genetics

CD is a multifactorial condition with unparalleled evidence of the pivotal role of HLA DQA1*05-DQB1*02 (DQ2) and DQA1*03-DQB1*0302 (DQ8) in disease predisposition [19]. The most likely mechanisms to explain the association of CD pathogenesis with HLA class II genes is that these DQ molecules bind gliadin peptides to present them to T cells. Mapping of this binding has clarified the importance of proline spacing and gliadin peptide deamidation in this process [20]. However, HLA alone does not explain genetic susceptibility because the concordance rate between identical twins (approximately 70%) is higher than that between HLA identical siblings (30%) [21], suggesting that additional genetic factors influence disease propensity. Recent genetic studies have identified 39 non-HLA risk genes, mostly related to immune responses (both innate and adaptive immune responses), inflammation, and intestinal barrier function [22]. Several genes present in the extended HLA complex have been implicated in CD predisposition. Associations with the tumor necrosis factor (TNF)-2 allele have also been reported, the polymorphism of which is associated with increased TNF-α expression [23]. A series of whole genome screening studies has been performed in patients with CD. The data regarding specific genes or genome areas possibly involved have not been consistently replicated in different population groups, suggesting an inter-population variation of extra-HLA genes associated to CD. The region that has most consistently been linked to CD is located on the long arm of chromosome 5 (5q31–33) [24]. There is also evidence for susceptibility factors on chromosome 19 [25]. Fine mapping of the latter region has identified the gene MYO9b, coding for a myosin probably involved in actin-based processes and, therefore, intestinal barrier regulation [26]. Taken together, it is possible that non-HLA genes together contribute more to the genetic susceptibility for CD than the identified HLA genotypes do, but the contribution from each single, predisposing non-HLA gene appears to be modest.

 

 Non-Dietary Risk Factors for CD

Several reports have shown that intrauterine and perinatal conditions influence the risk of CD. In 2002, Sandberg-Bennich et al. [27 ] reported that both neonatal infections [odds ratio (OR) = 1.52; 95% confidence interval (CI) = 1.19–1.95) and being small for gestational age (OR = 1.45; 95% CI = 1.20–1.75) increased the risk of CD.

Although several studies have shown smoking to be associated with a lower risk of CD, maternal smoking may actually increase the risk of CD in the offspring [26]. The detrimental effects of maternal smoking with regard to CD risk has since been confirmed in two more recent studies [28,29], reaching statistical significance in the largest study [27] but not in the second one [28].

To date, it is unclear whether a cesarean section increases [30] or decreases [28] the risk for CD in the offspring. The hypothesis behind the cesarean section leading to a higher risk of CD is that such infants are not exposed to the maternal vaginal flora (that may establish a ‘tolerogenic’ gut microbiome), since they do not pass through the birth canal.

Since Kagnoff et al. [31 ] reported in their landmark paper that adenoviruses may be involved in the pathogenesis of CD, researchers have tried to identify the role of infectious disease in its pathogenesis. The parallel findings of a potential role of virus infections in type 1 diabetes, another autoimmune disease that also confers increased risk for CD [32,33,34], has raised this interest. At least 4 studies have evaluated birth season and CD [35,36,37,38], with the 2 largest studies [36,37] suggesting that being born during spring-summer months may be associated with an increased CD risk in children. Evidence is less clear when actual infections are examined. A German study found that children with CD had more often experienced earlier gastrointestinal (GI) disease (including both infections and non-infectious disease) prior to CD diagnosis (adjusted OR = 2.97; 95% CI = 1.08–8.14) [30]. However, this study was based on retrospective data; recall bias mixed with actual CD symptoms preceding CD diagnosis cannot be ruled out as an explanation [30]. In contrast, Welander et al. [39] used prospectively collected data to examine the role of infectious disease prior to CD diagnosis in children. Although 40.9% of children with CD had an infection at the time of gluten introduction compared with 26.8% of children without a CD diagnosis (p = 0.035), the difference diminished after adjustment for age at gluten introduction and breastfeeding duration (adjusted hazard ratio = 1.8; 95% CI = 0.9–3.6; p = 0.111) [39]. For gastroenteritis at the time of gluten introduction, the adjusted hazard ratio was higher (2.6) but the 95% CIs were wide due to insufficient power (0.2–30.8) [39]. A US study found that children with at least 2 rotavirus infections had an increased risk of CD but only when the data were analyzed using tests for trend (p = 0.037) [38]. The unadjusted rate ratio for developing CD after at least 2 rotavirus infections was 3.76 (95% CI = 0.76–18.7; with p = 0.244 when re-calculated by us using Fisher’s exact test) [38].

 

 Breastfeeding

Several studies on breastfeeding and CD suggest that breastfeeding reduces the risk for future CD [40]. However, randomized trials are lacking and with few exceptions [28,39,41], existing studies have been based on retrospectively collected data [42,43,44,45,46,47]. The largest case-control study so far is that by Ivarsson et al. [46], where the authors found a reduced risk of future CD in children aged 0–1.9 years at diagnosis but not in children aged 2.0–14.9 years at diagnosis. The protective effect in children <2 years was stronger in those being breastfed beyond the introduction of gluten (OR = 0.36; 95% CI = 0.26–0.51). Two other studies [44,46] found similar results while a case-control study controlling for HLA status found no association between breastfeeding at the time of gluten introduction and CD; however, this study was only based on 8 cases with silent CD [45].

In contrast, the most recent case-control study by Decker et al. [30] reported opposite results. In their study, breastfeeding was associated with a statistically significant increase for CD (OR = 1.99, 95% CI = 1.12–3.51) [29]. However, it should be underlined that this was a secondary analysis, as the primary objective of the Dekker et al. study [29] was to examine the risk of pediatric gastrointestinal disease in offspring to mothers undergoing cesarean section.

The US study by Norris et al. [41 ] followed up 1,560 children with HLA-DR3 or -DR4 through regular blood tests and questionnaires. The main outcome was CD autoimmunity, which required either 2 positive CD serology blood tests or 1 positive blood test and 1 small intestinal biopsy consistent with CD. Some 49% (25/51) of children with CD autoimmunity were breastfed when first introduced to wheat, barley or rye compared with 44% (660/1,509) in controls (p > 0.05). The actual breastfeeding duration was longer in children with CD autoimmunity (median duration: 8.8 months) than in controls (6.8 months) [41]. One of the main strengths of this paper is that the authors screened their population for CD [40]. Many other studies have only looked at symptomatic CD leading to a physician diagnosis [18,28,39] and it could then be argued that their findings apply only to CD symptoms, or that breastfeeding may postpone the onset of symptoms [18] and lead to fewer diagnosed cases with CD early in life.

In a Swedish study, Welander et al. [39 ] used prospectively collected data from the ABIS (All Babies in Southeast Sweden) study and detected no association between breastfeeding duration and subsequent development of CD. The authors also found no association between breastfeeding duration and later CD when taking age at gluten introduction and prospectively recorded infections at the time of gluten introduction into account. Actually, the authors reported a trend towards early ending of breastfeeding being protective against CD (e.g. risk of later CD in offspring to mothers ending breastfeeding at 0–2 months of infant age: OR = 0.7; at 3–4 months: 0.7, and at 4–5 months: 0.3). However, it should be noted that none of these risk estimates reached statistical significance [39].

In a British study by Roberts et al. [28], the authors used data from the Oxford record linkage study. That study found no difference in the cumulative incidence of CD among breastfed (32.4/100,000) and non-breastfed infants (43.2/100,000; p = 0.28). But the exposure in the British study was ‘ever breastfed’ and therefore added little information to whether breastfeeding at the time of gluten introduction protects against CD or not.

To summarize, most studies point toward a protective effect of breastfeeding against CD, but it is unclear if this protective effect is persistent or only represents a delay in the diagnosis of CD [48]. One of the mechanisms potentially explaining an inverse relationship between breastfeeding and CD is that continuing breastfeeding could reduce the amount of gluten given [18]. Human milk IgA antibodies could also decrease the immune response against gluten.

 

 Timing of Gluten Introduction

Two large Swedish studies have both failed to show any association between timing of gluten introduction and risk of CD [39,18]. Introducing gluten at the age of 5–6 months did not increase the risk of CD in the study by Ivarsson et al. [18] (OR = 1.4; 95% CI = 0.87–2.4). Furthermore, this disappeared in the multivariate analysis as an independent risk factor. Using the age of 5–6 months as a reference when estimating hazard ratios for future CD, Welander et al. [39 ] showed that there was no difference in the risk of CD in infants aged 3–4 months or 7–8 months at gluten introduction. Other studies confirm the lack of an association between timing of gluten introduction and later CD [42,43,44,46,48].

The one study that showed an association between age at gluten introduction and CD is that by Norris et al. [40]. Using the age of 4–6 months as the reference category for gluten introduction, infants who first consumed gluten at the age of 1–3 months were at a 23-fold increased risk of CD; those who consumed gluten after the age of 6 months were at a 4-fold increased risk of CD [41]. It should, however, be emphasized that the number of children developing CD in those exposed to gluten before 4 months of age was small (3 children developed CD in this category, as opposed to an expected ‘0.13 child’) [41].

 

 Amount of Gluten

The mean intake of gluten in a pediatric cohort in the Netherlands was around 1 g at 6 months of age, rising fast to 6 g/day at the age of 8 months and then remaining at that level until 12 months of age [49]. It seems likely that the amount of gluten influences the risk of CD [18]. In a Swedish study, children with CD had significantly more often been given large (as opposed to ‘small-medium’) daily amounts of gluten 2 weeks after gluten introduction compared to age- and sex-matched controls. But this association was only seen in children diagnosed before 2 years of age [18]. There was no difference in the amount of flour introduced in the first portion between cases with CD and healthy controls [18]. Several authors have also implicated divergent flour consumption as an explanation for the geographic differences in CD incidence in Europe [50,51,52]. Furthermore, it is known that the amount of gluten in the diet correlates with the mucosal damage [53,54], and we speculate that large amounts of gluten in the early non-breast milk diet could trigger more symptoms in children with CD and, thus, a diagnosis of CD. We have also shown that adults with CD may tolerate up to 50 mg/day of gluten without mucosal injury [55].

 

 Ongoing Studies

As previously summarized, several retrospective studies have suggested that the age at gluten introduction in the diet of infants at risk for CD may affect the incidence of the disease. However, the data supporting this hypothesis are circumstantial, limited by their retrospective design, and often criticized by alternative interpretations suggesting that the delay in gluten exposure merely postpones the onset of symptoms rather than prevents the disease. Due to the cross-sectional design of these studies, it remains unclear whether the reported microbial associations (see below) are pathogenic or merely the consequence of CD intestinal inflammation. In order to clarify the role of infant nutrition on the risk of CD development, at least two prospective, intervention studies have recently been initiated. The results of these long-term studies will be available within the next few years.

 The PreventCD Family Study

This prospective, double-blind, placebo-controlled study is currently ongoing in 10 European countries and a total of 1,000 children are involved [56]. The participating children and mothers are to be followed for a period of 1–3 years. The project will study the influence of early diet on CD prevention. The general concept is that small amounts of food substances are administered gradually to ‘teach’ the immune system not to respond to this foodstuff. This is also called ‘desensitization’ or ‘induction of oral tolerance’. After HLA-typing, DQ2 and/or DQ8+ newborns from families at risk of CD are randomized and blindly allocated to intervention with either 100 mg gluten or placebo (lactose). After 6 months of age, gluten is gradually introduced into their diet. CD autoantibodies are then monitored every 3–6 months to disclose gluten sensitization.

 The Italian Baby Study

This is another initiative aimed at evaluating the role of (a) age at gluten introduction on CD-related autoimmune serological changes in a large cohort of at-risk infants (first-degree relatives of patients with CD); (b) other early environmental factors, particularly the role of breastfeeding; (c) different HLA-DQ2/DQ8 genotypes (high risk vs. low risk) on CD predisposition, and their interplay with infant nutrition patterns. Between October 2004 and June 2007, 729 infants (51% male) at increased risk for CD were enrolled in this prospective, multicenter intervention study conducted in Italy. At weaning, infants were assigned to gluten introduction into their diet either between the 4th and 6th month (group A) or after the 12th month (group B), then entered a follow-up period of 5 years. Diet (duration of breastfeeding, type of formula, adherence to the dietary plan and amount of gluten ingested) and clinical data were collected during telephone or face-to-face interviews at 4, 7, 9 and 12 months of age. CD serology (IgA anti-transglutaminase antibodies) was performed at 15 (plus HLA-DQ genotype), 24, 36 and 60 months of age. Small intestinal biopsy was recommended for all infants showing positivity of CD serological tests. At the last study update (September 2011), 100% of children had completed the 36-month follow-up. Fifty-two percent of infants were enrolled in group A and 48% in group B. Prevalence of biopsy-proven CD at 24 months was 8% in group A and 2% in group B (p < 0.01). However, this difference decreased at the 36-month follow-up, when the prevalence of CD became similar in the two groups (approximately 10%). Combined, these results suggest that delaying gluten introduction merely delays the onset of CD rather than prevents it. However, there was no increased risk of developing CD as previously reported [40].

 Intestinal Microbiota and Onset of CD

One follow-up study of the intestinal colonization processes of gut microbiota was conducted in 20 Swedish children stratified by high, intermediate and low genetic risk of developing CD. The total bacterial proportions were significantly higher in the high and intermediate genetic risk group than in the low genetic risk group. Gram-negative bacteria and Bacteroides-Prevotella proportions were higher in the high genetic risk group than in the intermediate and low genetic risk groups. In this study, the analysis of the fecal microbiota was conducted by fluorescence in situ hybridization and flow cytometry [57]. Both phenotypic methods present a substantial amount of variability and may rely on an individual and subjective interpretation, while the 16S rDNA sequencing, based on ribosomal small subunit species-specific variability, has become the qualitative reference technique for bacterial taxonomy and identification [58].

In healthy infants, as described by Palmer et al. [58], Bacteroidetes colonize and establish in the GI tract. Although varying from baby to baby in the timing of their first appearance, they are consistently present in nearly all infants by 24 months. The healthy microbiota evolves during different life stages and in infants it shows a lower ratio of Firmicutes to Bacteroidetes than in adults. Overall, the microbial ecosystems in each healthy baby achieve stability converging toward a profile characteristic of the adult GI tract in the first year of life [59]. Conversely, our recent prospective studies on the gut microbiome of infants at risk for CD suggest that their microbial ecosystem is different than that of children not predisposed for CD [Ravel and Fasano, pers. commun.]. Our studies revealed that the colonization process is very dynamic, with a high degree of inter-subject variation over time. Unlike children not predisposed for CD, the GI microbiota of infants at risk for CD does not stabilize towards an adult-like microbiota. Members of the phylum Bacteroidetes are absent from the GI microbiota up to 24 months, while they are predominant in children not predisposed for CD. These data suggest that early dietary and/or probiotic interventions may potentially stabilize the gut microbiota of these at-risk children, so preventing and/or delaying the onset of CD.

 

 Conclusion

Breastfeeding is the natural food for infants, but from around 6 months of age, the infant is in need of complementary feeding. The intricate interplay between breastfeeding and gluten introduction (amount and timing) has been the topic of several studies. Despite some recent reports showing no (or a positive) association between breastfeeding and later CD, most data suggest that breastfeeding at the time of gluten introduction reduces the risk to develop CD. It is also plausible that rapidly reaching a comparatively large daily intake of gluten after starting complementary feeding may increase the risk of CD. In the future, when we are able to analyze more carefully the outcomes of some of the ongoing studies, we may come up with refined conclusions, taking also genetic predisposition into account. This may result in evidence-based recommendations on gluten introduction into infants’ diet.

 

 Acknowledgement

J.F.L. was supported by the Swedish Research Council (522-2A09-195) and the Swedish Society of Medicine. This project was supported by grants from the Swedish Society of Medicine and the Swedish Research Council – Medicine (522-2A09-195).

 

 Disclosure Statement

The authors declare that they have no conflicts of interest. None of the funders had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data, and preparation, review or approval of the manuscript. The writing of this article was supported by Nestlé Nutrition Institute.


References

  1. Fasano A, Berti I, Gerarduzzi T, et al: Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286–292.
  2. Maki M, Mustalahti K, Kokkonen J, et al: Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348:2517–2524.
  3. Walker MM, Murray JA, Ronkainen J, et al: Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112–119.

    External Resources

  4. Marsh MN: Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–354.
  5. Oberhuber G, Granditsch G, Vogelsang H: The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11:1185–1194.
  6. Corazza GR, Villanacci V: Coeliac disease. J Clin Pathol 2005;58:573–574.
  7. Sollid LM, Thorsby E: HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 1993;105:910–922.
  8. Ludvigsson JF, Montgomery SM, Ekbom A, et al: Small-intestinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–1178.
  9. West J, Logan RF, Smith CJ, et al: Malignancy and mortality in people with coeliac disease: population based cohort study. BMJ 2004;329:716–719.
  10. Elfström P, Granath F, Ekström Smedby K, et al: Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst 2011;103:436–444.

    External Resources

  11. Gandolfi L, Pratesi R, Cordoba JC, et al: Prevalence of celiac disease among blood donors in Brazil. Am J Gastroenterol 2000;95:689–692.
  12. Gomez JC, Selvaggio GS, Viola M, et al: Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area. Am J Gastroenterol 2001;96:2700–2704.
  13. Abu-Zekry M, Kryszak D, Diab M, et al: Prevalence of celiac disease in Egyptian children disputes the east-west agriculture-dependent spread of the disease. J Pediatr Gastroenterol Nutr 2008;47:136–140.
  14. Remes-Troche JM, Ramirez-Iglesias MT, Rubio-Tapia A, et al: Celiac disease could be a frequent disease in Mexico: prevalence of tissue transglutaminase antibody in healthy blood donors. J Clin Gastroenterol 2006;40:697–700.

    External Resources

  15. Sood A, Midha V, Sood N, et al: Prevalence of celiac disease among school children in Punjab, North India. J Gastroenterol Hepatol 2006;21:1622–1625.

    External Resources

  16. Akbari MR, Mohammadkhani A, Fakheri H, et al: Screening of the adult population in Iran for coeliac disease: comparison of the tissue-transglutaminase antibody and anti-endomysial antibody tests. Eur J Gastroenterol Hepatol 2006;18:1181–1186.

    External Resources

  17. Ivarsson A, Persson LA, Nystrom L, et al: Epidemic of coeliac disease in Swedish children. Acta Paediatr 2000;89:165–171, comments pp 140–141, 749–750.
  18. Ivarsson A, Hernell O, Stenlund H, et al: Breast-feeding protects against celiac disease. Am J Clin Nutr 2002;75:914–921.
  19. Karell K, Louka AS, Moodie SJ, et al: HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003;64:469–477.
  20. Qiao SW, Bergseng E, Molberg O, et al: Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J Immunol 2005;175:254–261.
  21. Greco L, Romino R, Coto I, et al: The first large population based twin study of coeliac disease. Gut 2002;50:624–628.
  22. Trynka G, Wijmenga C, van Heel DA: A genetic perspective on coeliac disease. Trends Mol Med 2010;16:537–550.
  23. Louka AS, Lie BA, Talseth B, et al: Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles. Immunogenetics 2003;55:339–343.
  24. Greco L, Corazza G, Babron MC, et al: Genome search in celiac disease. Am J Hum Genet 1998;62:669–675.
  25. Van Belzen MJ, Meijer JW, Sandkuijl LA, et al: A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003;125:1032–1041.
  26. Monsuur AJ, Bakker PI, Alizadeh BZ, et al: Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 2005;37:1341–1344.
  27. Sandberg-Bennich S, Dahlquist G, Kallen B: Coeliac disease is associated with intrauterine growth and neonatal infections. Acta Paediatr 2002;91:30–33.
  28. Roberts SE, Williams JG, Meddings D, et al: Perinatal risk factors and coeliac disease in children and young adults: a record linkage study. Aliment Pharmacol Ther 2009;29:222–231.
  29. Ludvigsson JF, Ludvigsson J: Parental smoking and risk of coeliac disease in offspring. Scand J Gastroenterol 2005;40:336–342.
  30. Decker E, Engelmann G, Findeisen A, et al: Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 2010;125:e1433–e1440.

    External Resources

  31. Kagnoff MF, Paterson YJ, Kumar PJ, et al: Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987;28:995–1001.
  32. Yoon JW, Austin M, Onodera T, et al: Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 1979;300:1173–1179.
  33. Oldstone MB, Nerenberg M, Southern P, et al: Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 1991;65:319–331.
  34. Hyoty H, Hiltunen M, Knip M, et al: A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes 1995;44:652–657.
  35. Kokkonen J, Simila S, Vuolukka P: The incidence of coeliac disease and pyloric stenosis in children in Northern Finland. Ann Clin Res 1982;14:123–128.
  36. Ivarsson A, Hernell O, Nystrom L, et al: Children born in the summer have increased risk for coeliac disease. J Epidemiol Community Health 2003;57:36–39.
  37. Tanpowpong P, Vassallo M, Katz AK, et al: Season of birth and celiac disease in Massachusetts children (abstract Su1254). Gastroenterology 2011;140(suppl 1):S442.

    External Resources

  38. Stene LC, Honeyman MC, Hoffenberg EJ, et al: Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 2006;101:2333–2340.
  39. Welander A, Honeyman MC, Hoffenberg EJ, et al: Infectious disease and risk of later celiac disease in childhood. Pediatrics 2010;125:e530–e536.

    External Resources

  40. Akobeng AK, Ramanan AV, Buchan I, et al: Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch Dis Child 2006;91:39–43.
  41. Norris JM, Barriga K, Hoffenberg EJ, et al: Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA 2005;293:2343–2351.
  42. Auricchio S, Follo D, de Ritis G, et al: Does breast feeding protect against the development of clinical symptoms of celiac disease in children? J Pediatr Gastroenterol Nutr 1983;2:428–433.
  43. Greco L, Auricchio S, Mayer M, et al: Case control study on nutritional risk factors in celiac disease. J Pediatr Gastroenterol Nutr 1988;7:395–399.
  44. Falth-Magnusson K, Franzen L, Jansson G, et al: Infant feeding history shows distinct differences between Swedish celiac and reference children. Pediatr Allergy Immunol 1996;7:1–5.
  45. Ascher H, Krantz I, Rydberg L, et al: Influence of infant feeding and gluten intake on coeliac disease. Arch Dis Child 1997;76:113–117.
  46. Peters U, Schneeweiss S, Trautwein EA, et al: A case-control study of the effect of infant feeding on celiac disease. Ann Nutr Metab 2001;45:135–142.
  47. Rinne M, Kalliomaki M, Arvilommi H, et al: Effects of probiotics and breastfeeding on the bifidobacterium and lactobacillus/enterococcus microbiota and humoral immune responses. J Pediatr 2005;147:186–191.
  48. Greco L, Mayer M, Grimaldi M, et al: The effect of early feeding on the onset of symptoms in celiac disease. J Pediatr Gastroenterol Nutr 1985;4:52–55.
  49. Hopman EG, Kiefte-de Jong JC, le Cessie S, et al: Food questionnaire for assessment of infant gluten consumption. Clin Nutr 2007;26:264–271.
  50. Michaelsen KF, Weile B, Larsen P, et al: Does the low intake of wheat in Danish infants cause the low incidence rate of coeliac disease? Acta Paediatr 1993;82:605–606.
  51. Weile B, Cavell B, Nivenius K, et al: Striking differences in the incidence of childhood celiac disease between Denmark and Sweden: a plausible explanation. J Pediatr Gastroenterol Nutr 1995;21:64–68.
  52. Mitt K, Uibo O: Low cereal intake in Estonian infants: the possible explanation for the low frequency of coeliac disease in Estonia. Eur J Clin Nutr 1998;52:85–88.
  53. Doherty M, Barry RE: Gluten-induced mucosal changes in subjects without overt small-bowel disease. Lancet 1981;1:517–520.
  54. Catassi C, Rossini M, Ratsch IM, et al: Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study. Gut 1993;34:1515–1519.
  55. Catassi C, Fabiani E, Iacono G, et al: A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr 2007;85:160–166.
  56. Hogen Esch CE, Rosen A, Auricchio R, et al: The PreventCD Study design: towards new strategies for the prevention of coeliac disease. Eur J Gastroenterol Hepatol 2010;22:1424–1430.

    External Resources

  57. De Palma G, Capilla A, Nadal I, et al: Interplay between human leukocyte antigen genes and the microbial colonization process of the newborn intestine. Curr Issues Mol Biol 2010;12:1–10.
  58. Mignard S, Flandrois JP: 16S rRNA sequencing in routine bacterial identification: a 30-month experiment. J Microbiol Methods 2006;67:574–581.
  59. Palmer C, Bik EM, DiGiulio DB, et al: Development of the human infant intestinal microbiota. PLoS Biol 2007;5:e177.

  

Author Contacts

Jonas F. Ludvigsson
Department of Pediatrics
Örebro University Hospital
SE–70185 Örebro (Sweden)
Tel. +46 19 6021 000, E-Mail jonasludvigsson@yahoo.com

  

Article Information

Published online: April 30, 2012
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 0, Number of References : 59

  

Publication Details

Annals of Nutrition and Metabolism

Vol. 60, No. Suppl. 2, Year 2012 (Cover Date: April 2012)

Journal Editor: Koletzko B. (Munich)
ISSN: 0250-6807 (Print), eISSN: 1421-9697 (Online)

For additional information: http://www.karger.com/ANM


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Breast milk is the natural nutrition for infants, but in the second half of the first year of life, complementary feeding is needed. Many complementary foods contain gluten, but gluten exposure is associated with the risk of developing celiac disease (CD). CD is a disease with considerable morbidity and mortality. Although CD is associated with certain genetic features, carrying the human leukocyte antigen haplotypes DQ2 or DQ8 (a prerequisite for CD development) cannot fully explain who will or who will not develop CD. Potential risk factors for CD include perinatal events and infant feeding practice. With the exception that children who are breastfed at and beyond gluten introduction into the diet probably may be at a lower risk of developing CD, and that heavy gluten load early in life may increase the risk of future CD, data on the impact of infant feeding are inconsistent.

© 2012 S. Karger AG, Basel


  

Author Contacts

Jonas F. Ludvigsson
Department of Pediatrics
Örebro University Hospital
SE–70185 Örebro (Sweden)
Tel. +46 19 6021 000, E-Mail jonasludvigsson@yahoo.com

  

Article Information

Published online: April 30, 2012
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 0, Number of References : 59

  

Publication Details

Annals of Nutrition and Metabolism

Vol. 60, No. Suppl. 2, Year 2012 (Cover Date: April 2012)

Journal Editor: Koletzko B. (Munich)
ISSN: 0250-6807 (Print), eISSN: 1421-9697 (Online)

For additional information: http://www.karger.com/ANM


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 4/30/2012
Issue release date: April 2012

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 0

ISSN: 0250-6807 (Print)
eISSN: 1421-9697 (Online)

For additional information: http://www.karger.com/ANM


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Fasano A, Berti I, Gerarduzzi T, et al: Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286–292.
  2. Maki M, Mustalahti K, Kokkonen J, et al: Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348:2517–2524.
  3. Walker MM, Murray JA, Ronkainen J, et al: Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112–119.

    External Resources

  4. Marsh MN: Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–354.
  5. Oberhuber G, Granditsch G, Vogelsang H: The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11:1185–1194.
  6. Corazza GR, Villanacci V: Coeliac disease. J Clin Pathol 2005;58:573–574.
  7. Sollid LM, Thorsby E: HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 1993;105:910–922.
  8. Ludvigsson JF, Montgomery SM, Ekbom A, et al: Small-intestinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–1178.
  9. West J, Logan RF, Smith CJ, et al: Malignancy and mortality in people with coeliac disease: population based cohort study. BMJ 2004;329:716–719.
  10. Elfström P, Granath F, Ekström Smedby K, et al: Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst 2011;103:436–444.

    External Resources

  11. Gandolfi L, Pratesi R, Cordoba JC, et al: Prevalence of celiac disease among blood donors in Brazil. Am J Gastroenterol 2000;95:689–692.
  12. Gomez JC, Selvaggio GS, Viola M, et al: Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area. Am J Gastroenterol 2001;96:2700–2704.
  13. Abu-Zekry M, Kryszak D, Diab M, et al: Prevalence of celiac disease in Egyptian children disputes the east-west agriculture-dependent spread of the disease. J Pediatr Gastroenterol Nutr 2008;47:136–140.
  14. Remes-Troche JM, Ramirez-Iglesias MT, Rubio-Tapia A, et al: Celiac disease could be a frequent disease in Mexico: prevalence of tissue transglutaminase antibody in healthy blood donors. J Clin Gastroenterol 2006;40:697–700.

    External Resources

  15. Sood A, Midha V, Sood N, et al: Prevalence of celiac disease among school children in Punjab, North India. J Gastroenterol Hepatol 2006;21:1622–1625.

    External Resources

  16. Akbari MR, Mohammadkhani A, Fakheri H, et al: Screening of the adult population in Iran for coeliac disease: comparison of the tissue-transglutaminase antibody and anti-endomysial antibody tests. Eur J Gastroenterol Hepatol 2006;18:1181–1186.

    External Resources

  17. Ivarsson A, Persson LA, Nystrom L, et al: Epidemic of coeliac disease in Swedish children. Acta Paediatr 2000;89:165–171, comments pp 140–141, 749–750.
  18. Ivarsson A, Hernell O, Stenlund H, et al: Breast-feeding protects against celiac disease. Am J Clin Nutr 2002;75:914–921.
  19. Karell K, Louka AS, Moodie SJ, et al: HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003;64:469–477.
  20. Qiao SW, Bergseng E, Molberg O, et al: Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J Immunol 2005;175:254–261.
  21. Greco L, Romino R, Coto I, et al: The first large population based twin study of coeliac disease. Gut 2002;50:624–628.
  22. Trynka G, Wijmenga C, van Heel DA: A genetic perspective on coeliac disease. Trends Mol Med 2010;16:537–550.
  23. Louka AS, Lie BA, Talseth B, et al: Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles. Immunogenetics 2003;55:339–343.
  24. Greco L, Corazza G, Babron MC, et al: Genome search in celiac disease. Am J Hum Genet 1998;62:669–675.
  25. Van Belzen MJ, Meijer JW, Sandkuijl LA, et al: A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003;125:1032–1041.
  26. Monsuur AJ, Bakker PI, Alizadeh BZ, et al: Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 2005;37:1341–1344.
  27. Sandberg-Bennich S, Dahlquist G, Kallen B: Coeliac disease is associated with intrauterine growth and neonatal infections. Acta Paediatr 2002;91:30–33.
  28. Roberts SE, Williams JG, Meddings D, et al: Perinatal risk factors and coeliac disease in children and young adults: a record linkage study. Aliment Pharmacol Ther 2009;29:222–231.
  29. Ludvigsson JF, Ludvigsson J: Parental smoking and risk of coeliac disease in offspring. Scand J Gastroenterol 2005;40:336–342.
  30. Decker E, Engelmann G, Findeisen A, et al: Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 2010;125:e1433–e1440.

    External Resources

  31. Kagnoff MF, Paterson YJ, Kumar PJ, et al: Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987;28:995–1001.
  32. Yoon JW, Austin M, Onodera T, et al: Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 1979;300:1173–1179.
  33. Oldstone MB, Nerenberg M, Southern P, et al: Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 1991;65:319–331.
  34. Hyoty H, Hiltunen M, Knip M, et al: A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes 1995;44:652–657.
  35. Kokkonen J, Simila S, Vuolukka P: The incidence of coeliac disease and pyloric stenosis in children in Northern Finland. Ann Clin Res 1982;14:123–128.
  36. Ivarsson A, Hernell O, Nystrom L, et al: Children born in the summer have increased risk for coeliac disease. J Epidemiol Community Health 2003;57:36–39.
  37. Tanpowpong P, Vassallo M, Katz AK, et al: Season of birth and celiac disease in Massachusetts children (abstract Su1254). Gastroenterology 2011;140(suppl 1):S442.

    External Resources

  38. Stene LC, Honeyman MC, Hoffenberg EJ, et al: Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 2006;101:2333–2340.
  39. Welander A, Honeyman MC, Hoffenberg EJ, et al: Infectious disease and risk of later celiac disease in childhood. Pediatrics 2010;125:e530–e536.

    External Resources

  40. Akobeng AK, Ramanan AV, Buchan I, et al: Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch Dis Child 2006;91:39–43.
  41. Norris JM, Barriga K, Hoffenberg EJ, et al: Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA 2005;293:2343–2351.
  42. Auricchio S, Follo D, de Ritis G, et al: Does breast feeding protect against the development of clinical symptoms of celiac disease in children? J Pediatr Gastroenterol Nutr 1983;2:428–433.
  43. Greco L, Auricchio S, Mayer M, et al: Case control study on nutritional risk factors in celiac disease. J Pediatr Gastroenterol Nutr 1988;7:395–399.
  44. Falth-Magnusson K, Franzen L, Jansson G, et al: Infant feeding history shows distinct differences between Swedish celiac and reference children. Pediatr Allergy Immunol 1996;7:1–5.
  45. Ascher H, Krantz I, Rydberg L, et al: Influence of infant feeding and gluten intake on coeliac disease. Arch Dis Child 1997;76:113–117.
  46. Peters U, Schneeweiss S, Trautwein EA, et al: A case-control study of the effect of infant feeding on celiac disease. Ann Nutr Metab 2001;45:135–142.
  47. Rinne M, Kalliomaki M, Arvilommi H, et al: Effects of probiotics and breastfeeding on the bifidobacterium and lactobacillus/enterococcus microbiota and humoral immune responses. J Pediatr 2005;147:186–191.
  48. Greco L, Mayer M, Grimaldi M, et al: The effect of early feeding on the onset of symptoms in celiac disease. J Pediatr Gastroenterol Nutr 1985;4:52–55.
  49. Hopman EG, Kiefte-de Jong JC, le Cessie S, et al: Food questionnaire for assessment of infant gluten consumption. Clin Nutr 2007;26:264–271.
  50. Michaelsen KF, Weile B, Larsen P, et al: Does the low intake of wheat in Danish infants cause the low incidence rate of coeliac disease? Acta Paediatr 1993;82:605–606.
  51. Weile B, Cavell B, Nivenius K, et al: Striking differences in the incidence of childhood celiac disease between Denmark and Sweden: a plausible explanation. J Pediatr Gastroenterol Nutr 1995;21:64–68.
  52. Mitt K, Uibo O: Low cereal intake in Estonian infants: the possible explanation for the low frequency of coeliac disease in Estonia. Eur J Clin Nutr 1998;52:85–88.
  53. Doherty M, Barry RE: Gluten-induced mucosal changes in subjects without overt small-bowel disease. Lancet 1981;1:517–520.
  54. Catassi C, Rossini M, Ratsch IM, et al: Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study. Gut 1993;34:1515–1519.
  55. Catassi C, Fabiani E, Iacono G, et al: A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr 2007;85:160–166.
  56. Hogen Esch CE, Rosen A, Auricchio R, et al: The PreventCD Study design: towards new strategies for the prevention of coeliac disease. Eur J Gastroenterol Hepatol 2010;22:1424–1430.

    External Resources

  57. De Palma G, Capilla A, Nadal I, et al: Interplay between human leukocyte antigen genes and the microbial colonization process of the newborn intestine. Curr Issues Mol Biol 2010;12:1–10.
  58. Mignard S, Flandrois JP: 16S rRNA sequencing in routine bacterial identification: a 30-month experiment. J Microbiol Methods 2006;67:574–581.
  59. Palmer C, Bik EM, DiGiulio DB, et al: Development of the human infant intestinal microbiota. PLoS Biol 2007;5:e177.