Amount May Beat Timing: Gluten Intake and Risk of Childhood Celiac Disease
2015; Elsevier BV; Volume: 14; Issue: 3 Linguagem: Inglês
10.1016/j.cgh.2015.11.016
ISSN1542-7714
AutoresJonas F. Ludvigsson, Benjamin Lebwohl, Peter H.R. Green,
Tópico(s)Microscopic Colitis
ResumoIn the current issue of Clinical Gastroenterology and Hepatology, Aronsson et al1Aronsson C.A. Lee H.S. Koletzko S. et al.Effects of gluten intake on the risk of celiac disease: a case-control study on a Swedish birth cohort.Clin Gastroenterol Hepatol. 2016; 14: 403-409Abstract Full Text Full Text PDF Scopus (78) Google Scholar from The Environmental Determinants of Diabetes in the Young (TEDDY) study group explore the relationship between gluten intake and risk of celiac disease (CD) in genetically at-risk children. Although the data in this nested case-control study originated from Sweden where the rate of CD is highest, the TEDDY study group has its scientific center in Florida, and a novel by one of that state’s most famous authors may serve as an introduction to this article. In Ernest Hemingway’s book The Sun Also Rises, two of the main characters, Bill and Mike, discuss financial matters, and Bill asks: “How did you go bankrupt?”, and Mike answers, “Two ways. Gradually, then suddenly.” This article shows that even if you introduce gluten gradually into an infant’s diet, the child can still develop CD suddenly. Children with early diagnosed CD had a lower gluten consumption at 6 months of age than controls (albeit nonsignificant), but children with CD consumed larger amounts of gluten later at the age of 1–2 years than genetically predisposed children who did not subsequently develop the disease. Because of the abundant previous literature on infant feeding2Ascher H. Krantz I. Rydberg L. et al.Influence of infant feeding and gluten intake on coeliac disease.Arch Dis Child. 1997; 76: 113-117Google Scholar, 3Auricchio 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: 428-433Google Scholar, 4Challacombe D.N. Mecrow I.K. Elliott K. et al.Changing infant feeding practices and declining incidence of coeliac disease in West Somerset.Arch Dis Child. 1997; 77: 206-209Google Scholar, 5Falth-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: 1-5Google Scholar, 6Greco L. Auricchio S. Mayer M. et al.Case control study on nutritional risk factors in celiac disease.J Pediatr Gastroenterol Nutr. 1988; 7: 395-399Google Scholar, 7Peters U. Schneeweiss S. Trautwein E.A. et al.A case-control study of the effect of infant feeding on celiac disease.Ann Nutr Metab. 2001; 45: 135-142Google Scholar, 8Ivarsson A. Hernell O. Stenlund H. et al.Breast-feeding protects against celiac disease.Am J Clin Nutr. 2002; 75: 914-921Scopus (384) Google Scholar, 9Stordal K. White R.A. Eggesbo M. Early feeding and risk of celiac disease in a prospective birth cohort.Pediatrics. 2013; 132: e1202-e1209Google Scholar, 10Radlovic N.P. Mladenovic M.M. Lekovic Z.M. et al.Influence of early feeding practices on celiac disease in infants.Croat Med J. 2010; 51: 417-422Google Scholar, 11Welander A. Tjernberg A.R. Montgomery S.M. et al.Infectious disease and risk of later celiac disease in childhood.Pediatrics. 2010; 125: e530-e536Google Scholar, 12Ivarsson A. Myleus A. Norstrom F. et al.Prevalence of childhood celiac disease and changes in infant feeding.Pediatrics. 2013; 131: e687-e694Google Scholar, 13Vriezinga S.L. Auricchio R. Bravi E. et al.Randomized feeding intervention in infants at high risk for celiac disease.N Engl J Med. 2014; 371: 1304-1315Google Scholar, 14Lionetti E. Castellaneta S. Francavilla R. et al.Introduction of gluten, HLA status, and the risk of celiac disease in children.N Engl J Med. 2014; 371: 1295-1303Google Scholar and other risk factors,15Stordal K. Haugen M. Brantsaeter A.L. et al.Association between maternal iron supplementation during pregnancy and risk of celiac disease in children.Clin Gastroenterol Hepatol. 2014; 12 (624–631 e1–2)Google Scholar, 16Lebwohl B. Ludvigsson J.F. Green P.H. The unfolding story of celiac disease risk factors.Clin Gastroenterol Hepatol. 2014; 12: 632-635Google Scholar what does this article add? It actually adds a lot. In recent years, prospective cohort studies9Stordal K. White R.A. Eggesbo M. Early feeding and risk of celiac disease in a prospective birth cohort.Pediatrics. 2013; 132: e1202-e1209Google Scholar, 11Welander A. Tjernberg A.R. Montgomery S.M. et al.Infectious disease and risk of later celiac disease in childhood.Pediatrics. 2010; 125: e530-e536Google Scholar, 17Aronsson C.A. Lee H.S. Liu E. et al.Age at gluten introduction and risk of celiac disease.Pediatrics. 2015; 135: 239-245Google Scholar and 2 randomized clinical trials13Vriezinga S.L. Auricchio R. Bravi E. et al.Randomized feeding intervention in infants at high risk for celiac disease.N Engl J Med. 2014; 371: 1304-1315Google Scholar, 14Lionetti E. Castellaneta S. Francavilla R. et al.Introduction of gluten, HLA status, and the risk of celiac disease in children.N Engl J Med. 2014; 371: 1295-1303Google Scholar have shown that age at gluten introduction and breastfeeding duration may be less important for the risk of developing CD (at least in childhood) than previously thought. However, no earlier study has used prospectively collected data to investigate the range of gluten quantity in early infant nutrition and risk of CD. Aronsson et al1Aronsson C.A. Lee H.S. Koletzko S. et al.Effects of gluten intake on the risk of celiac disease: a case-control study on a Swedish birth cohort.Clin Gastroenterol Hepatol. 2016; 14: 403-409Abstract Full Text Full Text PDF Scopus (78) Google Scholar analyzed a subset of the prospective cohort TEDDY study, matching 146 Swedish children with CD with 436 controls. The authors found that for each additional gram of gluten consumed per day before tissue transglutaminase seroconversion, the risk of future CD increased by 28%. They also found that children receiving large amounts of gluten (>5 g per day) during their first 24 months had a 2.6-fold increased risk of CD compared with those who consumed lower quantities. Importantly, the relationship between the intake of gluten and underlying HLA in patients did not differ. Although the study should be commended for its rigorous study design, particularly the efforts to measure the amount of gluten intake, some questions remain. The appropriate approach of an infant feeding study would be to examine previously reported infant feeding risk factors, and that was clearly done in this study. Neither breastfeeding duration (odds ratio [OR], 0.99) nor age at first gluten introduction (OR, 0.99) was associated with future CD. However, the picture gets blurred when the authors suggest that their findings should be taken into account for future infant feeding recommendations, likely meaning the amount of gluten offered to children at risk of CD. It is not yet clear what such infant feeding recommendations should be. Although the highest gluten consumers had a doubling of CD risk (OR, 2.65; 95% confidence interval [CI], 1.70–4.13) in this study, the total amount of gluten intake was only marginally increased in CD cases vs controls (OR, 1.05; 95% CI, 1.01–1.10), an association that decreased when individuals with first-degree relatives with CD were excluded. One might speculate that mothers with CD themselves may differ in how they breastfeed and introduce gluten to their children, but earlier data from Sweden suggest that is not the case18Welander A. Montgomery S. Ludvigsson J. et al.Breast-feeding duration and gluten introduction among mothers with celiac disease.J Pediatr Gastroenterol Nutr. 2014; 59: 89-92Google Scholar; thus, the lack of statistical significance when excluding first-degree relatives could be a chance finding. Autoimmune disease is more common in first-degree relatives of patients with CD.19Emilsson L. Wijmenga C. Murray J.A. et al.Autoimmune disease in first-degree relatives and spouses of individuals with celiac disease.Clin Gastroenterol Hepatol. 2015; 13: 1271-1277Google Scholar The authors do not report on the amount of gluten consumed at age 6 months. The period around 6 months was previously regarded as crucial because of the dramatic increase in childhood CD seen after the change of recommendations in infant feeding practices in Sweden.20Ivarsson A. Persson L.A. Nystrom L. et al.Epidemic of coeliac disease in Swedish children.Acta Paediatr. 2000; 89: 165-171Google Scholar In fact, the 3-day food records at 9 months of age show that a larger consumption of gluten is less likely to be followed by CD than a small amount (OR, 0.63; 95% CI, 0.19–2.05), although the findings are nonsignificant. Therefore, we are left with uncertainty whether quantity of gluten has a unidirectional effect on CD risk throughout infancy, or whether this risk changes over time. The Kaplan-Meier curve (Figure 1)1Aronsson C.A. Lee H.S. Koletzko S. et al.Effects of gluten intake on the risk of celiac disease: a case-control study on a Swedish birth cohort.Clin Gastroenterol Hepatol. 2016; 14: 403-409Abstract Full Text Full Text PDF Scopus (78) Google Scholar also shows that the amount of gluten (low, medium, or high tertiles) does not influence the risk of CD in children younger than 24 months. Instead, the influence on CD onset is seen only later, primarily from the age of 4 years (with the median age at CD diagnosis occurring at 38 months). This is important because it means that for the majority of children diagnosed with CD, the positive association with gluten intake was at 24 months (last record of measured gluten intake), potentially several years before serologic conversion. It is possible that gluten intake at 24 months exerts an influence on CD risk years later; it is also possible that it is merely a marker for subsequent gluten intake during ages 3 and 4 years (not measured in this study), which exerts a more immediate risk. This was not addressed in 2 earlier studies that involved giving small amounts of gluten between 4 and 6 months13Vriezinga S.L. Auricchio R. Bravi E. et al.Randomized feeding intervention in infants at high risk for celiac disease.N Engl J Med. 2014; 371: 1304-1315Google Scholar and restricting gluten until age 12 months.14Lionetti E. Castellaneta S. Francavilla R. et al.Introduction of gluten, HLA status, and the risk of celiac disease in children.N Engl J Med. 2014; 371: 1295-1303Google Scholar Of note, the strongest association between high gluten intake and later CD was seen at 12 months of age, suggesting that it may be at 1–2 years of age when parents should be “soft on gluten” rather than at 6–9 months, when most parents will seek recommendations on gluten amount. Because the TEDDY group has previously shown that HLA DQ2 homozygosity is an important predictor for future CD, it is notable that the amount of gluten does not seem to interact with DQ2 status. It is also interesting that the risk of CD seems to be similar in children consuming low or moderate amounts of gluten. Only the highest tertile stands out. It would be helpful to see whether within the highest tertile there was a relationship with CD, so that those children exposed to very high amounts of gluten (eg, the highest centile) were at an even higher risk of CD. Although timing of gluten introduction has been studied previously (and appears to have no effect on CD risk), it would be worthwhile to explore whether timing or amount of gluten interacts with simultaneous infection to influence the risk of CD. On this subject, Swedish11Welander A. Tjernberg A.R. Montgomery S.M. et al.Infectious disease and risk of later celiac disease in childhood.Pediatrics. 2010; 125: e530-e536Google Scholar and Norwegian21Marild K. Kahrs C.R. Tapia G. et al.Infections and risk of celiac disease in childhood: a prospective nationwide cohort study.Am J Gastroenterol. 2015; 110: 1475-1484Google Scholar data from cohort studies suggest that either timing11Welander A. Tjernberg A.R. Montgomery S.M. et al.Infectious disease and risk of later celiac disease in childhood.Pediatrics. 2010; 125: e530-e536Google Scholar or total infectious disease burden21Marild K. Kahrs C.R. Tapia G. et al.Infections and risk of celiac disease in childhood: a prospective nationwide cohort study.Am J Gastroenterol. 2015; 110: 1475-1484Google Scholar could play a role in CD pathogenesis. In summary, the well-designed infant nutrition study by Aronsson et al1Aronsson C.A. Lee H.S. Koletzko S. et al.Effects of gluten intake on the risk of celiac disease: a case-control study on a Swedish birth cohort.Clin Gastroenterol Hepatol. 2016; 14: 403-409Abstract Full Text Full Text PDF Scopus (78) Google Scholar points to the importance of the amount of gluten in infant nutrition for the risk of CD in Swedish children. It is slightly surprising that it is the amount from 1 year and onward that seems to be of greatest importance, and that the high consumers do not develop CD in the first 2 years of life but later. These findings need to be confirmed in other studies before changes in feeding recommendations in Sweden (between age 4 and 6 months, infants should be introduced to gradually increased amounts of gluten)22Swedish National Food Agency (Livsmedelsverket): Eating habits, health and environment: infants. Available at: http://www.livsmedelsverket.se/matvanor-halsa--miljo/kostrad-och-matvanor/barn-och-ungdomar/spadbarn. Accessed November 5, 2015.Google Scholar and elsewhere are implemented. The authors should present the similar diet information from the TEDDY study involving children from lower risk countries such as the United States. Whereas many of Hemingway’s books end with a tragedy, CD research seems to have a bright future. Since the discovery of the autoantigen in CD,23Dieterich W. Ehnis T. Bauer M. et al.Identification of tissue transglutaminase as the autoantigen of celiac disease.Nat Med. 1997; 3: 797-801Google Scholar there has been a steady stream of research findings increasing our knowledge of this disease. Although Aronsson et al1Aronsson C.A. Lee H.S. Koletzko S. et al.Effects of gluten intake on the risk of celiac disease: a case-control study on a Swedish birth cohort.Clin Gastroenterol Hepatol. 2016; 14: 403-409Abstract Full Text Full Text PDF Scopus (78) Google Scholar offer only a small piece in the puzzle, the picture is nevertheless getting clearer and clearer. Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth CohortClinical Gastroenterology and HepatologyVol. 14Issue 3PreviewEarly nutrition may affect the risk of celiac disease. We investigated whether amount of gluten in diet until 2 years of age increases risk for celiac disease. Full-Text PDF
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