Celiac Disease Dig Dis 2015;33:162–166 DOI: 10.1159/000369539
Celiac Disease: Prevention in Children M. Luisa Mearin Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
Abstract Several studies have suggested a protective role of breastfeeding and/or the timing and quantity of gluten introduction in the subsequent development of celiac disease. Especially, prolonged breastfeeding during the introduction of gluten-containing feeding has been associated with a reduced risk of developing celiac disease in infancy. The mentioned results suggest the existence of a ‘window of opportunity’ between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends avoiding gluten introduction before the age of 4 months and after the age of 7 months and that gluten should be preferably introduced during ongoing breastfeeding. However, the influence of breastfeeding in the development of celiac disease is not clear, since some studies report prevention and others do not, and the studies reporting a protective effect of breastfeeding do not make clear if it concerns prevention of the disease or delays the onset of symptoms. In addition, most of the studies on this topic have been observational and retrospective. For these reasons, prospective studies are needed to understand the relation-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0162$39.50/0 E-Mail [email protected] www.karger.com/ddi
ship between early nutrition in particular and environmental factors in general, concerning the development and possible prevention of celiac disease. Some of these studies are ongoing. One example is the European multicenter PreventCD project (www.preventcoeliacdisease.com) among infants with a first-degree family member with celiac disease carrying HLA-DQ2 and/or -DQ8, randomized to a doubleblind dietary intervention with 100 mg of gluten daily or placebo between the age of 4–6 months. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl). © 2015 S. Karger AG, Basel
Introduction
Celiac disease (CD) is a common but frequently unrecognized disease, in part because of its variable clinical presentation and symptoms [1]. Screening studies have shown that CD is severely underdiagnosed, with a frequency of about 1–3% among the European population [2–4]. This frequency corresponds to about 5 million people in the European Community, and it is possibly the most common food intolerance in Europe [5]. CD increases the overall mortality risk [6], reduces quality of life [7] and has extensive negative economic consequences [8]. According to an estimate by the Dutch Celiac DisM. Luisa Mearin Department of Pediatrics Leiden University Medical Center PO Box 9600, NL–2300 RC Leiden (The Netherlands) E-Mail M.L.Mearin_Manrique @ lumc.nl
Downloaded by: Fudan University Library 61.129.42.30 - 5/12/2015 5:09:21 PM
Key Words Celiac disease · Gluten · Early nutrition · Breastfeeding · Prevention
Tertiary Prevention in CD
Since adherence to a gluten-free diet might reduce the long-term complications of CD, like chronic anemia, infertility, autoimmune disorders, malignancy and osteoporosis [11], adherence to the diet may be considered as a tertiary preventive measurement. However, adherence to the gluten-free diet has a negative impact on quality of life [12], stressing the need to develop adjunctive or alternative therapies [13].
Secondary Prevention in CD
Early diagnosis and treatment of CD represents secondary prevention, but it may only be achieved on a large scale by mass screening in the general population since the majority of screening-detected CD cases have no associated symptoms or conditions [2, 14, 15]. Screening for CD can be done by measuring specific antibodies against the enzyme transglutaminase type 2, endomysium or against deamidated gliadin peptides [16]. However, it is not clear if mass screening for CD should be performed since CD does not comply with all the 10 principles for early disease detection elaborated by Wilson and Jungner [17]. Especially, the lack of information on the natural history of CD in patients with none or subtle symptoms identified by mass screening, having or not the same health risks and long-term complications as these with clinically diagnosed CD, has been a traditional arguPrevention of Celiac Disease
ment against mass screening for CD. However, recent prospective studies have shown that undiagnosed CD in woman is associated with reduced fetal growth and birth weight [18], and in children with reduced bone mineral density and delayed growth at age 6 years [19]. In addition, prospective studies also show that treatment of CD patients detected by mass screening with a gluten-free diet results in health improvement, both in children [20] and adults [21]. These results support active screening for CD, and the discussion on mass screening for CD may be reopened in the future.
Primary Prevention in CD
In CD, primary prevention would mean that the tolerance for gluten has to be maintained or acquired since patients with CD do not develop it early in life or they lose their gluten tolerance later [22]. The potentiality for primary prevention of CD has been suggested based on: (a) the possibility to improve tolerance for (food) allergens, and (b) the existence of environmental factors involved in CD. The intestinal immune system has adaptive defenses to avoid systemic and peripheral inflammatory immune responses by activation of regulatory T cells to tolerate innocuous antigens, such as food proteins and commensal bacteria. This hyporesponsiveness to dietary protein antigens in the intestine is a phenomenon termed ‘oral tolerance’ [23]. Oral tolerance experimentally studied in rodents has revealed an overwhelming complexity, including genetics, age, feeding dose and timing, antigenic structure, epithelial barrier integrity, maturation state of mucosal antigen-presenting cells and the microenvironmental cytokine profiles [24]. Experiments in animal models have suggested possibilities for induction of tolerance for gluten: intravenous or intranasal administration of multiple doses of gliadin to mice was able to downregulate the specific immune response [25]. Breastfeeding protected young AVN rats from CD-like lesions [26]. The development of a gluten peptide or a T-cell vaccination could enable specific interference with T-cell function in CD, as it has been proposed for another autoimmune disorder, namely rheumatoid arthritis. In this aspect, the development of the Nexvax2 vaccine to be used as immunotherapy to induce tolerance to gluten is underway and in phase 1 trials (ImmusanT, Cambridge, Mass., USA). The indispensable environmental factor in CD is exposure to gluten ingestion. Theoretically, CD could be prevented by not introducing gluten in the diet of genetically Dig Dis 2015;33:162–166 DOI: 10.1159/000369539
163
Downloaded by: Fudan University Library 61.129.42.30 - 5/12/2015 5:09:21 PM
ease Society (www.glutenvrij.nl), the necessary glutenfree diet gives extra costs of EUR 1,200–1,300 per patient a year, which corresponds to a European financial burden of EUR 6.0–6.6 billion, when considering all 5 million CD cases (www.CDEUSA.com). The health status of the patients improves with a gluten-free diet, but primary prevention would be even more beneficial [9]. Prevention is usually defined as any activity which reduces the burden of mortality or morbidity from disease, which takes place at primary, secondary or tertiary level. The aim of tertiary prevention is to reduce the negative impact of an already established disease by restoring function and reducing disease-related complications. Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms. Primary prevention avoids the development of a disease [10].
164
Dig Dis 2015;33:162–166 DOI: 10.1159/000369539
demic (3%), suggesting that early infant feeding practices affect CD risk also later in life [4]. Breastfeeding is another environmental factor that has been associated with the induction of tolerance in young children [34]. Many studies have evaluated the role of breastfeeding and the risk of CD [4, 28–31, 33, 35–37]. A systemic review and meta-analysis including all the studies published on this topic between 1966 and 2004 found that children being breastfed had a 52% risk reduction of developing CD compared to those who were not breastfed at the time of gluten introduction (pooled OR 0.48; 95% CI: 0.40–0.59) [36]. However, the influence of breastfeeding on the development of CD is not well understood since some studies report prevention [4, 28, 29, 36, 38] and others do not [30, 31, 39]. A recent prospective study in a big cohort of Norwegian children shows an even higher risk of CD in children breastfed after 12 months of age [31]. A systematic review published by the PreventCD group (www.preventcd.com) shows that the most important difficulties in interpreting and comparing studies investigating the effect of early nutrition on the development of CD are caused by the inability to randomize and blind such studies, the retrospective design of many of them and their associated parental recall bias [37]. Infections have also been related to the development of CD, and a seasonal variation in the risk for the disease has been reported, suggesting causal environmental exposure(s) with a seasonal pattern [38]. The finding of rod-shaped bacteria attached to the small intestinal epithelium of some untreated and treated CD patients, but not to the epithelium of healthy controls, suggested that bacteria may be involved in the pathogenesis of CD and may trigger the aberrant innate immunity [40]. Repeated infection with rotavirus, the most common cause of acute gastroenteritis in children worldwide, has been reported to correlate with the development of CD [41]. An imbalance in the composition of the gut microbiome has also been suggested to be associated with the pathogenesis of CD [42], but the results of studies comparing intestinal microbiome in children with and without CD are contradictory [43, 44]. The optimal method to investigate the effect of environmental factors, both nutritional and others, in the development of CD is to perform prospective, randomized, placebo-controlled interventions in newborns with longterm follow-up. Some of these studies are ongoing and are presented below. PreventCD (Prevent Coeliac Disease) is an international, prospective, randomized, placebo-controlled intervention study among infants with a first-degree family Mearin
Downloaded by: Fudan University Library 61.129.42.30 - 5/12/2015 5:09:21 PM
predisposed infants. However, the strongest genetic factors in CD, HLA-DQ2 and DQ8, are present in about 40% of the general population, and other preventive possibilities have been sought in the timing and quantity of gluten introduction. The development of oral tolerance for gluten is initiated early in life, and the question is whether the age at first introduction of gluten in predisposed individuals could influence the onset of CD. However, until recently all studies investigating early nutrition and CD were observational and retrospective. Much knowledge about gluten introduction and CD has been obtained from the Swedish epidemic of symptomatic CD in the mid1980s [27]. The start of the epidemic was related to new dietary recommendations, delaying the introduction of all gluten-containing food to infants until 6 months of age. Results from other retrospective studies have shown different results, from protection by early introduction (4 months) [28] to no effect at all [29]. A prospective observational study in children genetically predisposed to CD and type 1 diabetes mellitus showed that both early (7 months) introduction of gluten was associated with an increased development of CD autoimmunity, but in this study the gluten ingested was not quantified, and the diagnosis of CD was not confirmed by small bowel biopsies [30]. Recently, a prospective birth cohort study found an increased risk of CD in children introduced to gluten after 6 months (OR 1.27; 95% CI: 1.01–1.65, p = 0.045) [31]. Altogether, these results suggest the existence of a ‘window of opportunity’ between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends that complementary feeding should not be introduced before 17 weeks and not later than 26 weeks, and that it is prudent to avoid gluten introduction before the age of 4 months and after the age of 7 months, and gluten should be preferably introduced during ongoing breastfeeding [32]. The Swedish epidemic of CD suggests also that the amount of gluten introduced in the food of young children plays a role in the development of the disease [27]. Later analysis of the epidemic revealed that in children under the age of 2 years, the risk of CD was greater when gluten was introduced in large amounts than when introduced in small or medium amounts [33]. Follow-up studies of Swedish children born during the CD epidemic have recently shown that 12-year-old children born after the Swedish epidemic, and thus exposed to a favorable way of gluten introduction, have a significantly lower risk of CD (2%) compared with those born during the epi-
member with CD and carrying HLA-DQ2 and/or -DQ8 [45]. From 2007 to 2010, soon after birth, and after parental informed consent, the children were randomized to a double-blind dietary intervention with 100 mg of gluten daily or placebo given between the age of 4 and 6 months. The children are repeatedly screened for CD. Breastfeeding for at least 6 months was explicitly encouraged. The gluten intake is quantified and the breastfeeding is analyzed. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl). The Environmental Determinants of Diabetes in the Young (TEDDY) is a multinational study that follows children at high genetic risk for type 1 diabetes, with the development of CD as a secondary outcome. TEDDY studies prospectively from birth 6,403 children with genetic predisposition to CD (HLA DQ2 or DQ8) in the United States, Finland, Germany, and Sweden. The risk of CD autoimmunity and CD by the age of 5 years was 11 and 3%, respectively, among children with a single DR3DQ2 haplotype, and 26 and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). Residence in Sweden was also independently associated with an increased risk of CD autoimmunity (hazard ratio, 1.90; 95% CI: 1.61–2.25), highlighting again the importance of studying environmental factors associated with CD [46]. The Generation R study, a population-based prospective cohort study from fetal life until young adulthood in Rotterdam, the Netherlands, suggests that early gluten introduction (
Celiac Disease: Prevention in Children M. Luisa Mearin Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
Abstract Several studies have suggested a protective role of breastfeeding and/or the timing and quantity of gluten introduction in the subsequent development of celiac disease. Especially, prolonged breastfeeding during the introduction of gluten-containing feeding has been associated with a reduced risk of developing celiac disease in infancy. The mentioned results suggest the existence of a ‘window of opportunity’ between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends avoiding gluten introduction before the age of 4 months and after the age of 7 months and that gluten should be preferably introduced during ongoing breastfeeding. However, the influence of breastfeeding in the development of celiac disease is not clear, since some studies report prevention and others do not, and the studies reporting a protective effect of breastfeeding do not make clear if it concerns prevention of the disease or delays the onset of symptoms. In addition, most of the studies on this topic have been observational and retrospective. For these reasons, prospective studies are needed to understand the relation-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0162$39.50/0 E-Mail [email protected] www.karger.com/ddi
ship between early nutrition in particular and environmental factors in general, concerning the development and possible prevention of celiac disease. Some of these studies are ongoing. One example is the European multicenter PreventCD project (www.preventcoeliacdisease.com) among infants with a first-degree family member with celiac disease carrying HLA-DQ2 and/or -DQ8, randomized to a doubleblind dietary intervention with 100 mg of gluten daily or placebo between the age of 4–6 months. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl). © 2015 S. Karger AG, Basel
Introduction
Celiac disease (CD) is a common but frequently unrecognized disease, in part because of its variable clinical presentation and symptoms [1]. Screening studies have shown that CD is severely underdiagnosed, with a frequency of about 1–3% among the European population [2–4]. This frequency corresponds to about 5 million people in the European Community, and it is possibly the most common food intolerance in Europe [5]. CD increases the overall mortality risk [6], reduces quality of life [7] and has extensive negative economic consequences [8]. According to an estimate by the Dutch Celiac DisM. Luisa Mearin Department of Pediatrics Leiden University Medical Center PO Box 9600, NL–2300 RC Leiden (The Netherlands) E-Mail M.L.Mearin_Manrique @ lumc.nl
Downloaded by: Fudan University Library 61.129.42.30 - 5/12/2015 5:09:21 PM
Key Words Celiac disease · Gluten · Early nutrition · Breastfeeding · Prevention
Tertiary Prevention in CD
Since adherence to a gluten-free diet might reduce the long-term complications of CD, like chronic anemia, infertility, autoimmune disorders, malignancy and osteoporosis [11], adherence to the diet may be considered as a tertiary preventive measurement. However, adherence to the gluten-free diet has a negative impact on quality of life [12], stressing the need to develop adjunctive or alternative therapies [13].
Secondary Prevention in CD
Early diagnosis and treatment of CD represents secondary prevention, but it may only be achieved on a large scale by mass screening in the general population since the majority of screening-detected CD cases have no associated symptoms or conditions [2, 14, 15]. Screening for CD can be done by measuring specific antibodies against the enzyme transglutaminase type 2, endomysium or against deamidated gliadin peptides [16]. However, it is not clear if mass screening for CD should be performed since CD does not comply with all the 10 principles for early disease detection elaborated by Wilson and Jungner [17]. Especially, the lack of information on the natural history of CD in patients with none or subtle symptoms identified by mass screening, having or not the same health risks and long-term complications as these with clinically diagnosed CD, has been a traditional arguPrevention of Celiac Disease
ment against mass screening for CD. However, recent prospective studies have shown that undiagnosed CD in woman is associated with reduced fetal growth and birth weight [18], and in children with reduced bone mineral density and delayed growth at age 6 years [19]. In addition, prospective studies also show that treatment of CD patients detected by mass screening with a gluten-free diet results in health improvement, both in children [20] and adults [21]. These results support active screening for CD, and the discussion on mass screening for CD may be reopened in the future.
Primary Prevention in CD
In CD, primary prevention would mean that the tolerance for gluten has to be maintained or acquired since patients with CD do not develop it early in life or they lose their gluten tolerance later [22]. The potentiality for primary prevention of CD has been suggested based on: (a) the possibility to improve tolerance for (food) allergens, and (b) the existence of environmental factors involved in CD. The intestinal immune system has adaptive defenses to avoid systemic and peripheral inflammatory immune responses by activation of regulatory T cells to tolerate innocuous antigens, such as food proteins and commensal bacteria. This hyporesponsiveness to dietary protein antigens in the intestine is a phenomenon termed ‘oral tolerance’ [23]. Oral tolerance experimentally studied in rodents has revealed an overwhelming complexity, including genetics, age, feeding dose and timing, antigenic structure, epithelial barrier integrity, maturation state of mucosal antigen-presenting cells and the microenvironmental cytokine profiles [24]. Experiments in animal models have suggested possibilities for induction of tolerance for gluten: intravenous or intranasal administration of multiple doses of gliadin to mice was able to downregulate the specific immune response [25]. Breastfeeding protected young AVN rats from CD-like lesions [26]. The development of a gluten peptide or a T-cell vaccination could enable specific interference with T-cell function in CD, as it has been proposed for another autoimmune disorder, namely rheumatoid arthritis. In this aspect, the development of the Nexvax2 vaccine to be used as immunotherapy to induce tolerance to gluten is underway and in phase 1 trials (ImmusanT, Cambridge, Mass., USA). The indispensable environmental factor in CD is exposure to gluten ingestion. Theoretically, CD could be prevented by not introducing gluten in the diet of genetically Dig Dis 2015;33:162–166 DOI: 10.1159/000369539
163
Downloaded by: Fudan University Library 61.129.42.30 - 5/12/2015 5:09:21 PM
ease Society (www.glutenvrij.nl), the necessary glutenfree diet gives extra costs of EUR 1,200–1,300 per patient a year, which corresponds to a European financial burden of EUR 6.0–6.6 billion, when considering all 5 million CD cases (www.CDEUSA.com). The health status of the patients improves with a gluten-free diet, but primary prevention would be even more beneficial [9]. Prevention is usually defined as any activity which reduces the burden of mortality or morbidity from disease, which takes place at primary, secondary or tertiary level. The aim of tertiary prevention is to reduce the negative impact of an already established disease by restoring function and reducing disease-related complications. Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms. Primary prevention avoids the development of a disease [10].
164
Dig Dis 2015;33:162–166 DOI: 10.1159/000369539
demic (3%), suggesting that early infant feeding practices affect CD risk also later in life [4]. Breastfeeding is another environmental factor that has been associated with the induction of tolerance in young children [34]. Many studies have evaluated the role of breastfeeding and the risk of CD [4, 28–31, 33, 35–37]. A systemic review and meta-analysis including all the studies published on this topic between 1966 and 2004 found that children being breastfed had a 52% risk reduction of developing CD compared to those who were not breastfed at the time of gluten introduction (pooled OR 0.48; 95% CI: 0.40–0.59) [36]. However, the influence of breastfeeding on the development of CD is not well understood since some studies report prevention [4, 28, 29, 36, 38] and others do not [30, 31, 39]. A recent prospective study in a big cohort of Norwegian children shows an even higher risk of CD in children breastfed after 12 months of age [31]. A systematic review published by the PreventCD group (www.preventcd.com) shows that the most important difficulties in interpreting and comparing studies investigating the effect of early nutrition on the development of CD are caused by the inability to randomize and blind such studies, the retrospective design of many of them and their associated parental recall bias [37]. Infections have also been related to the development of CD, and a seasonal variation in the risk for the disease has been reported, suggesting causal environmental exposure(s) with a seasonal pattern [38]. The finding of rod-shaped bacteria attached to the small intestinal epithelium of some untreated and treated CD patients, but not to the epithelium of healthy controls, suggested that bacteria may be involved in the pathogenesis of CD and may trigger the aberrant innate immunity [40]. Repeated infection with rotavirus, the most common cause of acute gastroenteritis in children worldwide, has been reported to correlate with the development of CD [41]. An imbalance in the composition of the gut microbiome has also been suggested to be associated with the pathogenesis of CD [42], but the results of studies comparing intestinal microbiome in children with and without CD are contradictory [43, 44]. The optimal method to investigate the effect of environmental factors, both nutritional and others, in the development of CD is to perform prospective, randomized, placebo-controlled interventions in newborns with longterm follow-up. Some of these studies are ongoing and are presented below. PreventCD (Prevent Coeliac Disease) is an international, prospective, randomized, placebo-controlled intervention study among infants with a first-degree family Mearin
Downloaded by: Fudan University Library 61.129.42.30 - 5/12/2015 5:09:21 PM
predisposed infants. However, the strongest genetic factors in CD, HLA-DQ2 and DQ8, are present in about 40% of the general population, and other preventive possibilities have been sought in the timing and quantity of gluten introduction. The development of oral tolerance for gluten is initiated early in life, and the question is whether the age at first introduction of gluten in predisposed individuals could influence the onset of CD. However, until recently all studies investigating early nutrition and CD were observational and retrospective. Much knowledge about gluten introduction and CD has been obtained from the Swedish epidemic of symptomatic CD in the mid1980s [27]. The start of the epidemic was related to new dietary recommendations, delaying the introduction of all gluten-containing food to infants until 6 months of age. Results from other retrospective studies have shown different results, from protection by early introduction (4 months) [28] to no effect at all [29]. A prospective observational study in children genetically predisposed to CD and type 1 diabetes mellitus showed that both early (7 months) introduction of gluten was associated with an increased development of CD autoimmunity, but in this study the gluten ingested was not quantified, and the diagnosis of CD was not confirmed by small bowel biopsies [30]. Recently, a prospective birth cohort study found an increased risk of CD in children introduced to gluten after 6 months (OR 1.27; 95% CI: 1.01–1.65, p = 0.045) [31]. Altogether, these results suggest the existence of a ‘window of opportunity’ between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends that complementary feeding should not be introduced before 17 weeks and not later than 26 weeks, and that it is prudent to avoid gluten introduction before the age of 4 months and after the age of 7 months, and gluten should be preferably introduced during ongoing breastfeeding [32]. The Swedish epidemic of CD suggests also that the amount of gluten introduced in the food of young children plays a role in the development of the disease [27]. Later analysis of the epidemic revealed that in children under the age of 2 years, the risk of CD was greater when gluten was introduced in large amounts than when introduced in small or medium amounts [33]. Follow-up studies of Swedish children born during the CD epidemic have recently shown that 12-year-old children born after the Swedish epidemic, and thus exposed to a favorable way of gluten introduction, have a significantly lower risk of CD (2%) compared with those born during the epi-
member with CD and carrying HLA-DQ2 and/or -DQ8 [45]. From 2007 to 2010, soon after birth, and after parental informed consent, the children were randomized to a double-blind dietary intervention with 100 mg of gluten daily or placebo given between the age of 4 and 6 months. The children are repeatedly screened for CD. Breastfeeding for at least 6 months was explicitly encouraged. The gluten intake is quantified and the breastfeeding is analyzed. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl). The Environmental Determinants of Diabetes in the Young (TEDDY) is a multinational study that follows children at high genetic risk for type 1 diabetes, with the development of CD as a secondary outcome. TEDDY studies prospectively from birth 6,403 children with genetic predisposition to CD (HLA DQ2 or DQ8) in the United States, Finland, Germany, and Sweden. The risk of CD autoimmunity and CD by the age of 5 years was 11 and 3%, respectively, among children with a single DR3DQ2 haplotype, and 26 and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). Residence in Sweden was also independently associated with an increased risk of CD autoimmunity (hazard ratio, 1.90; 95% CI: 1.61–2.25), highlighting again the importance of studying environmental factors associated with CD [46]. The Generation R study, a population-based prospective cohort study from fetal life until young adulthood in Rotterdam, the Netherlands, suggests that early gluten introduction (
