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MINI REVIEW
Celiac disease in children Hélène Garnier-Lengliné a,b,c,∗, Nadine Cerf-Bensussan a,c, Frank M. Ruemmele a,b,c a
Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France AP—HP, hôpital Necker—Enfants-Malades, service de gastroentérologie, hépatologie et nutrition pédiatriques, 149, rue de Sèvres, 75743 Paris cedex 15, France c Unité Inserm UMR S1163, Institut Imagine, Paris, France b
Summary Celiac disease is an autoimmune enteropathy, triggered by ingestion of gluten in genetically predisposed individuals. Since the use of anti-transglutaminase and antiendomysium antibodies in the early 1990s, two main groups of clinical presentation can be identified: patients with a symptomatic form of the disease, and patients with a pauci (a)symptomatic form detected during the work-up of another autoimmune disease or due to a family history of celiac disease. The prevalence of both forms of the disease is currently estimated between 1/100 and 1/400. Classical form of the disease is characterized by occurrence of diarrhoea, failure to thrive, and abdominal bloating in young infants in the months following gluten introduction. Serological tests show high level of anti-transglutaminase and anti-endomysium antibodies. Until recently, the diagnosis required duodenal biopsies that show villous atrophy. HLA genotype can help for diagnosis: the absence of the HLA-DQ2 or DQ8 alleles has a high negative predictive value. European guidelines recently proposed to reconsider the need for systematic endoscopy in typical symptomatic forms with high level of antitransglutaminase and positive anti-endomysium. These recommandations are being assessed now. Currently, the gluten-free diet remains the only effective treatment for celiac disease. Children with celiac disease have to exclude from their diet all products containing wheat, barley and rye. Gluten-free diet causes clinical remission within a few weeks, but normalization of the small bowel mucosa and negativity of anti-transglutaminase antibodies are obtained in several months or even years. Gluten-free diet is useful to obtain clinical assessment, but also to prevent long-term complications of celiac disease, mainly osteoporosis, other autoimmune diseases, decreased fertility and cancers. © 2015 Published by Elsevier Masson SAS.
∗ Corresponding author. Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Sorbonne Paris-Cité, 149, rue de Sèvres, 75743 Paris cedex 15, France. Tel.: +33 1 44 49 44 12; fax: +33 1 44 49 25 01. E-mail address: [email protected] (H. Garnier-Lengliné).
http://dx.doi.org/10.1016/j.clinre.2015.05.024 2210-7401/© 2015 Published by Elsevier Masson SAS.
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intraepithelial lymphocyte population independently of HLA presentation [9].
Definition Celiac disease (CD) is an immune-mediated enteropathy, induced by gluten ingestion in genetically predisposed individuals. Gluten is the major protein component of wheat, barley and rye that are widely consumed cereals in most countries of the world. Gluten sensitivity in CD is due to an abnormal cellular immune response responsible of a villous atrophy, which resolves under gluten-free diet.
Historical Symptoms of CD were first described by a Greek physician, Aretee de Cappadoce, in the first century. However, it was only in 1950 that the role of gluten peptides in triggering CD was identified. William Dicke was the first physician to propose a gluten-free diet to treat symptoms of celiac disease, which remains in 2014 the only effective treatment of CD [1]. Pathologic description of the specific lesions observed in CD was then reported in 1957 by Margot Shiner [2]. It is the discovery in the early 1990s of highly specific and sensitive antibodies that has changed the diagnostic conditions of the disease [3].
Pathophysiological aspects Celiac disease results from the interaction between gluten and immune, genetic and environmental factors. Gluten protein is derived from wheat, rye and barley. Gluten refers to the entire protein component of wheat, whereas gliadin is the alcohol-soluble fraction of gluten that contains the main toxic components. Gliadin is enriched in glutamine and proline residues that are highly resistant to degradation by intestinal proteases [4]. Peptides remaining after digestion of gluten in the upper gastrointestinal tract are thus long fragments (10—50 amino acids) [5] that can go through the epithelium to reach lamina propria and activate innate and adaptive immune system. Adaptive immune response HLA class II molecules are expressed on the surface of antigen-presenting cells in the gut lamina propria. Deamidation of gluten peptides, including a 33-mer (peptide 56—88), by tissue transglutaminase (tTG) modifies glutamine residues into glutamic acid residues, increasing their affinity for HLA-DQ2 or DQ8 [6]. Modified gluten peptides are then presented by HLA molecules to CD4+ T-cells, inducing a gliadin-specific adaptive immune response that is responsible for the priming of pathogenic T-cells and therefore for destruction for enterocytes leading to villous atrophy [7]. CD4+ T-cells are not the effector cell type that directly mediates tissue damage, but they contribute to set up the inflammatory environment that allows intraepithelial CD8+ lymphocytes to promote epithelial cell destruction [8]. Gluten-specific CD4+ T-cells may also help B-cells to differentiate into plasma cells that secrete gluten- and tTG specific antibodies. In addition, gluten can trigger CD8+ T cell responses in the lamina propria and may expand the
Innate immune response The gluten-derived peptide the most studied for its innate immune properties is the a-gliadin 31-43 peptide, which is not recognized by T-cells, but is able to mediate innate immune effects in organ cultures of biopsies from celiac patients [10]. Alpha-gliadin 31—43 peptide has also been shown to activate mitogen-activated protein kinases and upregulate expression of interleukin-15 [10,11]. Yet, no specific receptor has been identified for this peptide and how it may activate cell stress pathways remains to be defined. Furthermore, the alpha-amylase/trypsin inhibitors (ATIs), pest resistance molecules found in wheat, have been identified as strong activators of innate immune responses in monocytes, macrophages and dendritic cells via activation of toll-like receptor 4 in cells biopsies from celiac and nonceliac patients [12]. IL-15 There is now strong evidence that IL-15 plays a key role in CD pathogenesis [13]. Upregulation of IL-15 expression in the epithelium and in the lamina propria of patients with CD impairs local immunoregulation and stimulates the cytotoxic activation and the survival of intraepithelial (IEL) CD8+ T-cells in active celiac disease, and of clonal intrapithelial lymphocytes (IEL) in refractory celiac disease [14,15]. IL-15 thus promotes epithelial cell destruction (villous atrophy) and the onset of lymphoma, a rare but severe complication of CD. Currently, no genetic association for the gene encoding IL-15 was identified in CD [16]. CD71 Activation of the local immune system implies that undigested gliadin fragments can go from the gut lumen through the intestinal epithelium to reach the lamina propria. In CD, transport and processing of gliadin peptides are altered, leading to the release of intact peptides on the basal side whereas these peptides are almost entirely degraded in control individuals [17]. This protected transport is driven by retrotranscytosis of secretory IgA bound to gliadin peptides through CD71, the transferrin receptor, which is abnormally overexpressed at the apical pole of enterocytes in patients with untreated CD [18]. Upon binding to apical CD71, secretory IgA enters a recycling pathway and avoids lysosomal degradation, allowing protected transport of bound gliadin peptides via transcytosis [19,20].
Risk factors: genetical predisposition and environmental factors CD develops in genetically susceptible individuals and has a strong HLA-association. HLA class II haplotypes DQ2 and DQ8 are the best characterized and most important genetic susceptibility factors in CD, contributing about 40% to the risk of developing CD [21]. Approximately 25—40% of the Caucasian population wear these haplotypes, but only a minority is going to develop CD. Their absence can almost exclude the diagnosis of CD [22]. Other non-HLA genes also contribute to the genetic susceptibility of CD, many of these
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Celiac disease in children susceptibility genes being common to other autoimmune disorders, for example type 1 diabetes mellitus and rheumatoid arthritis. Recent genome wide association studies have identified several risk loci for CD, most candidate genes encoding immunologically relevant proteins that affect the function of antigen-presenting cells or T-cells [8,23]. Environmental factors play also an important role, as suggested by many epidemiological studies. Occurrence of gastrointestinal viral infections, like rotavirus infection, seems to increase the risk of CD in young children [24]. The role of intestinal microbiota has also been mentioned: some association between specific bacterial groups and presence of CD in children [25] have been observed, but this has to be further studied. The choice of the right period to introduce gluten in infant diet has been discussed for several decades. Currently, the window of opportunity to introduce gluten seems to be 4 to 7 months [26,27], even if it appears in some recent studies that age at gluten introduction in children genetically predisposed to CD is not an independent risk factor for developing CD [28]. Later introduction of gluten could only be associated with a delayed onset of disease [29]. A protective effect for breastfeeding was first suggested, as well as the introduction of gluten in relation to weaning, but this effect is now largely reconsidered [29].
Epidemiology The prevalence of CD varies greatly across and within different countries. The reported prevalence of CD ranges from 1/658 to 1/37. Three European studies found a prevalence of CD greater than 1/66, in United Kingdom [30], Germany [31] and Sweden [32]. Three of eight studies conducted in children reported a prevalence of CD greater than 1/100, in Finland [33], Sweden [32] and The Netherlands [34]. The prevalence of CD in Italian studies is similar to that reported in the United States, ranging from 1/500 to 1/93 [35—37]. Several studies on the prevalence of CD in the general US population have been conducted, the largest one finding a prevalence of CD of 1/105 in adults from ‘‘not at risk population’’, and of 1/322 in children [38]. Globally, the prevalence of CD in Western populations, including in the United States, appears to be currently approximately 1/100, with a reasonable range of 1/80 to 1/140. The two peaks of frequency of CD are between 1 and 2 years of life, and around 30 years. The first peak of frequency corresponds to a period of intense immune stimulation, with the introduction of many food allergens and the high occurrence of infections. There seems to be 2- to 3-fold more women than men diagnosed with CD in adults, whereas the sex ratio in children is 1/1 [39]. In adults, the higher prevalence of CD in women compared to men (also observed in most autoimmune diseases) and the peak of frequency around 30 years could be explained by the strong ovarian activity during this period. Three main forms of CD have been described depending on histologic findings, represented by the ‘‘celiac iceberg’’. The emerging part of the iceberg contains symptomatic patients and represents about 10% of the celiac patients [40]. The submerged part contains patients with a silent or a latent disease. In silent disease, patients are asymptomatic but histologic findings show villous atrophy. In latent
3 disease, an isolated increase in the number of intraepithelial lymphocytes is observed. Latent disease is considered as a pre-pathologic state, with a risk for evolution toward silent or symptomatic disease. Conversely, evolution toward latency has been described in other forms of CD [41]. At risk groups and associated diseases Patients with a first-degree relative with CD have a 5 to 10% risk of being affected [42]. CD is associated with autoimmune diseases, especially type 1 diabetes mellitus and autoimmune thyroïditis, but also autoimmune hepatitis, Addison disease and multiple sclerosis. Prevalence of CD is about 10% in patients with type 1 diabetes mellitus [43]. CD is also associated with selective IgA deficiency [44] (1 case in 40 as compared with 1 in 400 in the general population) and with chromosomal disorders, such as Down syndrome [45], Turner syndrome [46] and Williams syndrome [47]. Dermatitis herpetiformis (DH) is an autoimmune bullous disease that represents the cutaneous manifestation of gluten sensitivity, in the setting of CD [48]. As in CD, skin lesions in DH are likely mediated by IgA class autoantibodies against one of several transglutaminase enzymes. Classical DH is characterized by multiple vesicles on an erythematous base, but primary lesions are often absent owing to the intense prurit responsible for numerous overlying excoriations. Diagnosis CD must be suspected in two major situations: in case of symptoms suggestive of CD, or in case of asymptomatic patients belonging to a group at risk of developing CD (screening). Symptomatic disease CD has a very wide spectrum of manifestations, from severe diarrhoea to asymptomatic disease. During the past decades, a progressive shift of presentation from typical gastrointestinal to extra-digestive symptoms has been noticed. In childhood, clinical manifestations vary according to age group. In young infants, malabsorption syndrome is still predominant. The diarrhoea is frequently associated with abdominal pain, distention, vomiting, anorexia and failure to thrive. Mood disorders and delayed development are also common. Older children and young adults often present with minor symptoms, as constipation, isolated anemia, osteopenia and progressive growth retardation [39,49]. Atypical extra-digestive symptoms, as neurological or psychiatric disorders, arthritis or emal dysplasia should also be suggestive of CD [50,51]. In front of those misleading symptoms, the diagnosis of CD is challenging and there could be a long delay between the onset of symptoms and diagnosis. Silent (or latent) disease Current guidelines recommend case finding in people considered to be at risk of developing disease, but not in the general population. At risk population include patients with family history of CD (CD in siblings or other first-degree relative), patients with other autoimmune diseases, especially type 1 diabetes, autoimmune hepatitis, and autoimmune
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thyroïditis, and patients with chromosomal disorders associated with CD. Due to the frequent association between IgA deficiency and CD, determination of total IgA level with antitTG IgA level must be performed. In case of IgA deficiency, anti-tTG IgA will be falsely negative, thus IgG anti-tTG and anti-EM need to be performed, and diagnosis of CD will be excluded only if they are negative [52]. Serological tests The first step, when CD is suspected, is to perform serological tests. CD is characterized by the presence of highly specific autoantibodies reflecting the immunological response to gluten. The two main autoantibodies that appear to be highly accurate to diagnose CD are anti-tissue transglutaminase (anti-tTG) and anti-endomysial (EM) antibodies. Antigliadin and antireticulin antibodies have been surpassed by anti-EM and anti-TGt and should not be performed anymore [3]. The most sensitive antibodies are of the IgA class. IgG are mainly performed in cases of IgA deficiency. Anti-tTG antibodies are directed against tissue transglutaminase, the enzyme responsible for the deamidation of gliadin peptides in intestinal lamina propria. The autoantigen recognized by endomysial antibodies is also the enzyme tissue transglutaminase. Sensitivity of both anti-EM and anti-tTG tests are greater than 90% [53]. In children, the highest specificity is obtained with anti-EM antibodies, reaching 98% [54]. Anti-tTG is easily detected by ELISA (enzyme linked immuno sorbent assay) or by RLA (radio ligand binding assay) whereas anti-EM antibodies are detected by indirect immunofluorescence. The use of IgA anti-EM antibody tests was initially limited by high costs of monkey oesophagus commercial kits and by the rise of ethical problems related to the killing of endangered species, but then the use of human umbilical cord has been proposed to replace monkey oesophagus, with similar results [55]. Current guidelines recommend first-line measurement of IgA anti-tTG level due to their low cost, high reliability and feasibility compared to the higher cost of anti-EM antibody testing [56]. Recently IgG anti-DGP testing (but not IgA) has been proposed to help diagnosing CD, and seems to be useful especially in excluding CD [54]. However, some studies showed no increase in sensitivity nor specificity compared to antiEM and anti-tTG antibodies [57]. New point-of-care device based on deamidated gliadin peptides (DGP) also have to be further evaluated, even if some studies have showed their clinical accuracy. DGP-based rapid tests could be a useful screening tool for high-risk populations [58]. Pathology Until 2012, diagnosis of CD required positivity of anti-tTG and/or anti-EM antibodies, presence of HLA-DQ2 or DQ8 haplotypes and histological findings showing three major signs: intraepithelial lymphocytosis, inflammation of the lamina propria, and villous atrophy associated to crypt hyperplasia. Villous atrophy can be scored by using Marsh classification [59], modified by Oberhuber in 2000 [60]. Type 0 is pre-infiltrative stage (normal), type 1 infiltrative stage (increased intraepithelial lymphocytes), type 2 hyperplastic stage (type 1 plus hyperplastic crypts) and type 3 destructive
stage (type 2 plus villous atrophy), with 3 subcategories: 3a partial atrophy, 3b subtotal atrophy, 3c total atrophy. Duodenal lesions may vary among different biopsies [61], thus, many biopsies must be performed. At least, two samples should be taken in the bulb and four in the descending part of the duodenum. Lesion severity seems to have a proximalto-distal gradient. A villous atrophy is sometimes observed only in the bulb mucosa, whereas an isolated increase in IEL is observed in the descending part of the duodenum [62]. Another pitfall could be over interpretation of villous atrophy in case of poorly oriented biopsy specimens. For this reason, reliable interpretation of biopsies in CD requires an experimented anatomopathologist. Recent European paediatric guidelines suggest an algorithm to avoid biopsy in children with clinical symptoms, high antibody titers (anti-tTG IgA > 10-fold normal and positive anti-EM) with a HLA-DQ2 or DQ8 genotype [56]. The performance of those new diagnostic criteria is still being evaluated a large multicentric European study, so called ProCeDE (Prospective Celiac disease Diagnostic Evaluation) (results unpublished yet). In adults, duodenal biopsy is still recommended in all cases [63].
Differential diagnosis In most cases, diagnosis is relatively easy to confirm once it is suspected. However, in a few cases, a lack of concordance between clinical, serologic and histologic findings may be observed. Histologic findings in CD are characteristic but not specific: CD is not the only cause of villous atrophy. Differential diagnosis is rare in children, and is predominantly represented by wheat allergy, intestinal parasitosis (giardiasis, lambliasis), intolerance to other food components (milk, soy. . .) and autoimmune enteropathy. Wheat allergy is an IgE-mediated reaction against wheat components [64]. Most people allergic to wheat may tolerate other grains. Diagnosis of wheat allergy is made on positivity of wheat-specific IgE and of skin prick-tests. Symptoms are those of an allergic reaction, and can be mild (rashes, hives, itching, swelling. . .), or sometimes severe (anaphylaxis). Wheat allergy often disappears, like other food allergies, after the age of 6 years. Differential diagnosis between autoimmune enteropathy and CD may be difficult because anti-TGt or anti-EM may be positive in both cases. However, patients with autoimmune enteropathy often develop bloody diarrhoea, other autoimmune affections, and biological inflammatory syndrome. In patients with autoimmune enteropathy, anti-enterocyte antibodies are often found, and pathological results show a villous atrophy without any increase in the number of intraepithelial lymphocytes. Remission of symptoms under gluten-free diet is can be helpful to confirm CD diagnosis in uncertain cases. Another disorder related to gluten ingestion has been described in the last decade, in adults first and then in children [65], namely non-celiac gluten sensitivity (NCGS) [66]. However, even if there is increasing evidence for this entity, we have currently no precise understanding of its pathogenesis and no objective way to confirm this diagnosis. Symptoms of NCGS can mimic those of CD, but they are not associated to any biological or histological sign [66,67]. As in CD, diagnostic criteria of NCGS include the disappearance of symptoms under GFD.
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Treatment, evolution In 2015, gluten-free diet remains the only treatment for CD. It involves the suppression of wheat, rye and barley from the diet. Concerning pure oats, many clinical studies have shown that a consumption of up to 100 g per day of uncontamined oats is tolerated by most patients with CD, and that it may improve the nutritional content of the diet and its acceptability and adherence [68—70]. At diagnosis, any nutritional deficiency must be assessed and treated. The most commonly observed mineral and vitamin deficiencies are those in iron, folic acid, vitamin D and other fat-soluble vitamins. In case of iron deficiency, supplementation should be given for 4 months. Vitamin D should systematically be given orally once or twice per year, and more often in case of biologically proven deficiency or osteopenia. When CD is associated with IgA deficiency, an antibioprophylaxy may be prescribed in case of recurrent infections, and another immune deficiency must be eliminated. Vaccinations should be performed. Patients have to be informed at diagnosis that CD is a long-life disease, and thus that gluten-free diet has to be continued for a lifetime. Gluten challenge that was formerly performed around the age of six is no more recommended. Indeed even if about 50% of children with CD clinically tolerate the reintroduction of gluten after a longterm gluten-free diet, most of them will develop villous atrophy, bone mineral density deficiency and an increased risk to develop other autoimmune diseases [71,72]. The maximal threshold of gluten that can be tolerated by celiac patients is hard to define. Some patients can clinically tolerate relatively high amounts of gluten whereas others cannot tolerate one breadcrumb. In the European Union, the legislation concerning the composition of gluten-free products has set in 2009 the threshold at 20 mg of gluten per kilogram (regulation no 41/2009 of the EU). Gluten-free diet usually induces rapid clinical improvement (within days or weeks) whereas histologic recovery can take months or even years [73], as well as decrease in anti-tTG level [74]. Correction of nutritional deficiencies has to be monitored, but the outcome of children diagnosed with CD is very satisfactory when gluten-free diet is strictly followed. Adherence to gluten-free diet is much higher in children than in adults, especially if the child is young at diagnosis. Monitoring of anti-tTG level may be useful to determine adherence to GFD. For the management of DH also, glutenfree diet is the cornerstone of treatment, in association with dapsone in cases where diet is not sufficient. Complications of CD predominantly occur in adults and include other autoimmune diseases, cancers, decreased fertility in women and refractory CD. Patients with CD have twice the risk of developing cancer compared to the general population [75]. Most reported cancers include T- and Bcell lymphoma and intestinal adenocarcinoma [76,77]. The risk to develop these complications is greatly reduced under gluten-free diet [78].
5 gluten-free diet [79]. Given that gluten-free diet is an efficient and side-effect free treatment, the use of alternative therapeutics has to focus especially on complicated forms of the disease and on forms showing incomplete response to the diet. One strategy would be to inhibit the immune stimulatory effect of gluten, by using tissue transglutaminase inhibitors blocking antigen-presentation by HLA-DQ2 or DQ8 [80], or by using monoclonal antibodies to suppress pro-inflammatory cytokines (TNF-a, IFN-g, IL-15). Given the risk of significant side-effects, monoclonal antibodies, currently widely used in other autoimmune diseases, have to be strongly evaluated in CD, and might be most useful only in adult patients with refractory celiac disease despite adhering to a glutenfree diet [81,82]. Another lead of novel therapies in CD could be the decrease of gluten immunogenicity, by creating non-toxic wheat varieties [83], by giving oral administration of prolyl endopeptidases that can cleave proline- and glutamine-enriched sequences into smaller and less toxic sequences [84], or by modulating intestinal cell junctions to reduce the access of gluten peptides to lamina propria [85]. One of the difficulties to test efficiency and safety of new therapies in CD is the challenge of creating a good murine model recapitulating all principal aspects of CD [15]. First results of phase II clinical trials in adults, testing glutenase enzymes [86] and a tight junction modulator (larazotide acetate) have been published but have to be further assessed [87,88]. These non-dietary therapies should become available in adults patients with CD in the coming years, being investigated at present as additional treatments to the diet, but their safety and effectiveness have to be evaluated in large long-term clinical studies.
Conclusion Prevalence of CD has dramatically increased in the last two decades due to the use of serological tests. Only 10% of children having CD are symptomatic. A large part of asymptomatic patients remains undiagnosed, even if screening CD is now recommended in at risk groups, especially children having type 1 diabetes or in a context of a family history of CD. The typical clinical picture of malabsorptive syndrome remains frequent in young infant, but milder intestinal symptoms and extra-digestive symptoms are frequently seen in older children, and must evoke CD. In 2015, gluten-free diet remains the only efficient treatment for CD. This could change in the next years, due to alternative treatments being developed, some of them having entered clinical trials. Current challenges in pediatric CD are: • to widespread screening in at risk groups to increase the number of patients diagnosed; • to assess the recent European pediatric guidelines proposing to avoid biopsy in symptomatic children with high antibody titers and HLA compatible; • to develop clinical trials for alternative treatments to gluten-free diet.
Therapeutic perspectives
Disclosure of interest
Improved understanding of the molecular basis of CD has enabled researchers to suggest alternatives to the
The authors declare that they have no conflicts of interest concerning this article.
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Celiac disease in children Hélène Garnier-Lengliné a,b,c,∗, Nadine Cerf-Bensussan a,c, Frank M. Ruemmele a,b,c a
Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France AP—HP, hôpital Necker—Enfants-Malades, service de gastroentérologie, hépatologie et nutrition pédiatriques, 149, rue de Sèvres, 75743 Paris cedex 15, France c Unité Inserm UMR S1163, Institut Imagine, Paris, France b
Summary Celiac disease is an autoimmune enteropathy, triggered by ingestion of gluten in genetically predisposed individuals. Since the use of anti-transglutaminase and antiendomysium antibodies in the early 1990s, two main groups of clinical presentation can be identified: patients with a symptomatic form of the disease, and patients with a pauci (a)symptomatic form detected during the work-up of another autoimmune disease or due to a family history of celiac disease. The prevalence of both forms of the disease is currently estimated between 1/100 and 1/400. Classical form of the disease is characterized by occurrence of diarrhoea, failure to thrive, and abdominal bloating in young infants in the months following gluten introduction. Serological tests show high level of anti-transglutaminase and anti-endomysium antibodies. Until recently, the diagnosis required duodenal biopsies that show villous atrophy. HLA genotype can help for diagnosis: the absence of the HLA-DQ2 or DQ8 alleles has a high negative predictive value. European guidelines recently proposed to reconsider the need for systematic endoscopy in typical symptomatic forms with high level of antitransglutaminase and positive anti-endomysium. These recommandations are being assessed now. Currently, the gluten-free diet remains the only effective treatment for celiac disease. Children with celiac disease have to exclude from their diet all products containing wheat, barley and rye. Gluten-free diet causes clinical remission within a few weeks, but normalization of the small bowel mucosa and negativity of anti-transglutaminase antibodies are obtained in several months or even years. Gluten-free diet is useful to obtain clinical assessment, but also to prevent long-term complications of celiac disease, mainly osteoporosis, other autoimmune diseases, decreased fertility and cancers. © 2015 Published by Elsevier Masson SAS.
∗ Corresponding author. Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Sorbonne Paris-Cité, 149, rue de Sèvres, 75743 Paris cedex 15, France. Tel.: +33 1 44 49 44 12; fax: +33 1 44 49 25 01. E-mail address: [email protected] (H. Garnier-Lengliné).
http://dx.doi.org/10.1016/j.clinre.2015.05.024 2210-7401/© 2015 Published by Elsevier Masson SAS.
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intraepithelial lymphocyte population independently of HLA presentation [9].
Definition Celiac disease (CD) is an immune-mediated enteropathy, induced by gluten ingestion in genetically predisposed individuals. Gluten is the major protein component of wheat, barley and rye that are widely consumed cereals in most countries of the world. Gluten sensitivity in CD is due to an abnormal cellular immune response responsible of a villous atrophy, which resolves under gluten-free diet.
Historical Symptoms of CD were first described by a Greek physician, Aretee de Cappadoce, in the first century. However, it was only in 1950 that the role of gluten peptides in triggering CD was identified. William Dicke was the first physician to propose a gluten-free diet to treat symptoms of celiac disease, which remains in 2014 the only effective treatment of CD [1]. Pathologic description of the specific lesions observed in CD was then reported in 1957 by Margot Shiner [2]. It is the discovery in the early 1990s of highly specific and sensitive antibodies that has changed the diagnostic conditions of the disease [3].
Pathophysiological aspects Celiac disease results from the interaction between gluten and immune, genetic and environmental factors. Gluten protein is derived from wheat, rye and barley. Gluten refers to the entire protein component of wheat, whereas gliadin is the alcohol-soluble fraction of gluten that contains the main toxic components. Gliadin is enriched in glutamine and proline residues that are highly resistant to degradation by intestinal proteases [4]. Peptides remaining after digestion of gluten in the upper gastrointestinal tract are thus long fragments (10—50 amino acids) [5] that can go through the epithelium to reach lamina propria and activate innate and adaptive immune system. Adaptive immune response HLA class II molecules are expressed on the surface of antigen-presenting cells in the gut lamina propria. Deamidation of gluten peptides, including a 33-mer (peptide 56—88), by tissue transglutaminase (tTG) modifies glutamine residues into glutamic acid residues, increasing their affinity for HLA-DQ2 or DQ8 [6]. Modified gluten peptides are then presented by HLA molecules to CD4+ T-cells, inducing a gliadin-specific adaptive immune response that is responsible for the priming of pathogenic T-cells and therefore for destruction for enterocytes leading to villous atrophy [7]. CD4+ T-cells are not the effector cell type that directly mediates tissue damage, but they contribute to set up the inflammatory environment that allows intraepithelial CD8+ lymphocytes to promote epithelial cell destruction [8]. Gluten-specific CD4+ T-cells may also help B-cells to differentiate into plasma cells that secrete gluten- and tTG specific antibodies. In addition, gluten can trigger CD8+ T cell responses in the lamina propria and may expand the
Innate immune response The gluten-derived peptide the most studied for its innate immune properties is the a-gliadin 31-43 peptide, which is not recognized by T-cells, but is able to mediate innate immune effects in organ cultures of biopsies from celiac patients [10]. Alpha-gliadin 31—43 peptide has also been shown to activate mitogen-activated protein kinases and upregulate expression of interleukin-15 [10,11]. Yet, no specific receptor has been identified for this peptide and how it may activate cell stress pathways remains to be defined. Furthermore, the alpha-amylase/trypsin inhibitors (ATIs), pest resistance molecules found in wheat, have been identified as strong activators of innate immune responses in monocytes, macrophages and dendritic cells via activation of toll-like receptor 4 in cells biopsies from celiac and nonceliac patients [12]. IL-15 There is now strong evidence that IL-15 plays a key role in CD pathogenesis [13]. Upregulation of IL-15 expression in the epithelium and in the lamina propria of patients with CD impairs local immunoregulation and stimulates the cytotoxic activation and the survival of intraepithelial (IEL) CD8+ T-cells in active celiac disease, and of clonal intrapithelial lymphocytes (IEL) in refractory celiac disease [14,15]. IL-15 thus promotes epithelial cell destruction (villous atrophy) and the onset of lymphoma, a rare but severe complication of CD. Currently, no genetic association for the gene encoding IL-15 was identified in CD [16]. CD71 Activation of the local immune system implies that undigested gliadin fragments can go from the gut lumen through the intestinal epithelium to reach the lamina propria. In CD, transport and processing of gliadin peptides are altered, leading to the release of intact peptides on the basal side whereas these peptides are almost entirely degraded in control individuals [17]. This protected transport is driven by retrotranscytosis of secretory IgA bound to gliadin peptides through CD71, the transferrin receptor, which is abnormally overexpressed at the apical pole of enterocytes in patients with untreated CD [18]. Upon binding to apical CD71, secretory IgA enters a recycling pathway and avoids lysosomal degradation, allowing protected transport of bound gliadin peptides via transcytosis [19,20].
Risk factors: genetical predisposition and environmental factors CD develops in genetically susceptible individuals and has a strong HLA-association. HLA class II haplotypes DQ2 and DQ8 are the best characterized and most important genetic susceptibility factors in CD, contributing about 40% to the risk of developing CD [21]. Approximately 25—40% of the Caucasian population wear these haplotypes, but only a minority is going to develop CD. Their absence can almost exclude the diagnosis of CD [22]. Other non-HLA genes also contribute to the genetic susceptibility of CD, many of these
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Celiac disease in children susceptibility genes being common to other autoimmune disorders, for example type 1 diabetes mellitus and rheumatoid arthritis. Recent genome wide association studies have identified several risk loci for CD, most candidate genes encoding immunologically relevant proteins that affect the function of antigen-presenting cells or T-cells [8,23]. Environmental factors play also an important role, as suggested by many epidemiological studies. Occurrence of gastrointestinal viral infections, like rotavirus infection, seems to increase the risk of CD in young children [24]. The role of intestinal microbiota has also been mentioned: some association between specific bacterial groups and presence of CD in children [25] have been observed, but this has to be further studied. The choice of the right period to introduce gluten in infant diet has been discussed for several decades. Currently, the window of opportunity to introduce gluten seems to be 4 to 7 months [26,27], even if it appears in some recent studies that age at gluten introduction in children genetically predisposed to CD is not an independent risk factor for developing CD [28]. Later introduction of gluten could only be associated with a delayed onset of disease [29]. A protective effect for breastfeeding was first suggested, as well as the introduction of gluten in relation to weaning, but this effect is now largely reconsidered [29].
Epidemiology The prevalence of CD varies greatly across and within different countries. The reported prevalence of CD ranges from 1/658 to 1/37. Three European studies found a prevalence of CD greater than 1/66, in United Kingdom [30], Germany [31] and Sweden [32]. Three of eight studies conducted in children reported a prevalence of CD greater than 1/100, in Finland [33], Sweden [32] and The Netherlands [34]. The prevalence of CD in Italian studies is similar to that reported in the United States, ranging from 1/500 to 1/93 [35—37]. Several studies on the prevalence of CD in the general US population have been conducted, the largest one finding a prevalence of CD of 1/105 in adults from ‘‘not at risk population’’, and of 1/322 in children [38]. Globally, the prevalence of CD in Western populations, including in the United States, appears to be currently approximately 1/100, with a reasonable range of 1/80 to 1/140. The two peaks of frequency of CD are between 1 and 2 years of life, and around 30 years. The first peak of frequency corresponds to a period of intense immune stimulation, with the introduction of many food allergens and the high occurrence of infections. There seems to be 2- to 3-fold more women than men diagnosed with CD in adults, whereas the sex ratio in children is 1/1 [39]. In adults, the higher prevalence of CD in women compared to men (also observed in most autoimmune diseases) and the peak of frequency around 30 years could be explained by the strong ovarian activity during this period. Three main forms of CD have been described depending on histologic findings, represented by the ‘‘celiac iceberg’’. The emerging part of the iceberg contains symptomatic patients and represents about 10% of the celiac patients [40]. The submerged part contains patients with a silent or a latent disease. In silent disease, patients are asymptomatic but histologic findings show villous atrophy. In latent
3 disease, an isolated increase in the number of intraepithelial lymphocytes is observed. Latent disease is considered as a pre-pathologic state, with a risk for evolution toward silent or symptomatic disease. Conversely, evolution toward latency has been described in other forms of CD [41]. At risk groups and associated diseases Patients with a first-degree relative with CD have a 5 to 10% risk of being affected [42]. CD is associated with autoimmune diseases, especially type 1 diabetes mellitus and autoimmune thyroïditis, but also autoimmune hepatitis, Addison disease and multiple sclerosis. Prevalence of CD is about 10% in patients with type 1 diabetes mellitus [43]. CD is also associated with selective IgA deficiency [44] (1 case in 40 as compared with 1 in 400 in the general population) and with chromosomal disorders, such as Down syndrome [45], Turner syndrome [46] and Williams syndrome [47]. Dermatitis herpetiformis (DH) is an autoimmune bullous disease that represents the cutaneous manifestation of gluten sensitivity, in the setting of CD [48]. As in CD, skin lesions in DH are likely mediated by IgA class autoantibodies against one of several transglutaminase enzymes. Classical DH is characterized by multiple vesicles on an erythematous base, but primary lesions are often absent owing to the intense prurit responsible for numerous overlying excoriations. Diagnosis CD must be suspected in two major situations: in case of symptoms suggestive of CD, or in case of asymptomatic patients belonging to a group at risk of developing CD (screening). Symptomatic disease CD has a very wide spectrum of manifestations, from severe diarrhoea to asymptomatic disease. During the past decades, a progressive shift of presentation from typical gastrointestinal to extra-digestive symptoms has been noticed. In childhood, clinical manifestations vary according to age group. In young infants, malabsorption syndrome is still predominant. The diarrhoea is frequently associated with abdominal pain, distention, vomiting, anorexia and failure to thrive. Mood disorders and delayed development are also common. Older children and young adults often present with minor symptoms, as constipation, isolated anemia, osteopenia and progressive growth retardation [39,49]. Atypical extra-digestive symptoms, as neurological or psychiatric disorders, arthritis or emal dysplasia should also be suggestive of CD [50,51]. In front of those misleading symptoms, the diagnosis of CD is challenging and there could be a long delay between the onset of symptoms and diagnosis. Silent (or latent) disease Current guidelines recommend case finding in people considered to be at risk of developing disease, but not in the general population. At risk population include patients with family history of CD (CD in siblings or other first-degree relative), patients with other autoimmune diseases, especially type 1 diabetes, autoimmune hepatitis, and autoimmune
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thyroïditis, and patients with chromosomal disorders associated with CD. Due to the frequent association between IgA deficiency and CD, determination of total IgA level with antitTG IgA level must be performed. In case of IgA deficiency, anti-tTG IgA will be falsely negative, thus IgG anti-tTG and anti-EM need to be performed, and diagnosis of CD will be excluded only if they are negative [52]. Serological tests The first step, when CD is suspected, is to perform serological tests. CD is characterized by the presence of highly specific autoantibodies reflecting the immunological response to gluten. The two main autoantibodies that appear to be highly accurate to diagnose CD are anti-tissue transglutaminase (anti-tTG) and anti-endomysial (EM) antibodies. Antigliadin and antireticulin antibodies have been surpassed by anti-EM and anti-TGt and should not be performed anymore [3]. The most sensitive antibodies are of the IgA class. IgG are mainly performed in cases of IgA deficiency. Anti-tTG antibodies are directed against tissue transglutaminase, the enzyme responsible for the deamidation of gliadin peptides in intestinal lamina propria. The autoantigen recognized by endomysial antibodies is also the enzyme tissue transglutaminase. Sensitivity of both anti-EM and anti-tTG tests are greater than 90% [53]. In children, the highest specificity is obtained with anti-EM antibodies, reaching 98% [54]. Anti-tTG is easily detected by ELISA (enzyme linked immuno sorbent assay) or by RLA (radio ligand binding assay) whereas anti-EM antibodies are detected by indirect immunofluorescence. The use of IgA anti-EM antibody tests was initially limited by high costs of monkey oesophagus commercial kits and by the rise of ethical problems related to the killing of endangered species, but then the use of human umbilical cord has been proposed to replace monkey oesophagus, with similar results [55]. Current guidelines recommend first-line measurement of IgA anti-tTG level due to their low cost, high reliability and feasibility compared to the higher cost of anti-EM antibody testing [56]. Recently IgG anti-DGP testing (but not IgA) has been proposed to help diagnosing CD, and seems to be useful especially in excluding CD [54]. However, some studies showed no increase in sensitivity nor specificity compared to antiEM and anti-tTG antibodies [57]. New point-of-care device based on deamidated gliadin peptides (DGP) also have to be further evaluated, even if some studies have showed their clinical accuracy. DGP-based rapid tests could be a useful screening tool for high-risk populations [58]. Pathology Until 2012, diagnosis of CD required positivity of anti-tTG and/or anti-EM antibodies, presence of HLA-DQ2 or DQ8 haplotypes and histological findings showing three major signs: intraepithelial lymphocytosis, inflammation of the lamina propria, and villous atrophy associated to crypt hyperplasia. Villous atrophy can be scored by using Marsh classification [59], modified by Oberhuber in 2000 [60]. Type 0 is pre-infiltrative stage (normal), type 1 infiltrative stage (increased intraepithelial lymphocytes), type 2 hyperplastic stage (type 1 plus hyperplastic crypts) and type 3 destructive
stage (type 2 plus villous atrophy), with 3 subcategories: 3a partial atrophy, 3b subtotal atrophy, 3c total atrophy. Duodenal lesions may vary among different biopsies [61], thus, many biopsies must be performed. At least, two samples should be taken in the bulb and four in the descending part of the duodenum. Lesion severity seems to have a proximalto-distal gradient. A villous atrophy is sometimes observed only in the bulb mucosa, whereas an isolated increase in IEL is observed in the descending part of the duodenum [62]. Another pitfall could be over interpretation of villous atrophy in case of poorly oriented biopsy specimens. For this reason, reliable interpretation of biopsies in CD requires an experimented anatomopathologist. Recent European paediatric guidelines suggest an algorithm to avoid biopsy in children with clinical symptoms, high antibody titers (anti-tTG IgA > 10-fold normal and positive anti-EM) with a HLA-DQ2 or DQ8 genotype [56]. The performance of those new diagnostic criteria is still being evaluated a large multicentric European study, so called ProCeDE (Prospective Celiac disease Diagnostic Evaluation) (results unpublished yet). In adults, duodenal biopsy is still recommended in all cases [63].
Differential diagnosis In most cases, diagnosis is relatively easy to confirm once it is suspected. However, in a few cases, a lack of concordance between clinical, serologic and histologic findings may be observed. Histologic findings in CD are characteristic but not specific: CD is not the only cause of villous atrophy. Differential diagnosis is rare in children, and is predominantly represented by wheat allergy, intestinal parasitosis (giardiasis, lambliasis), intolerance to other food components (milk, soy. . .) and autoimmune enteropathy. Wheat allergy is an IgE-mediated reaction against wheat components [64]. Most people allergic to wheat may tolerate other grains. Diagnosis of wheat allergy is made on positivity of wheat-specific IgE and of skin prick-tests. Symptoms are those of an allergic reaction, and can be mild (rashes, hives, itching, swelling. . .), or sometimes severe (anaphylaxis). Wheat allergy often disappears, like other food allergies, after the age of 6 years. Differential diagnosis between autoimmune enteropathy and CD may be difficult because anti-TGt or anti-EM may be positive in both cases. However, patients with autoimmune enteropathy often develop bloody diarrhoea, other autoimmune affections, and biological inflammatory syndrome. In patients with autoimmune enteropathy, anti-enterocyte antibodies are often found, and pathological results show a villous atrophy without any increase in the number of intraepithelial lymphocytes. Remission of symptoms under gluten-free diet is can be helpful to confirm CD diagnosis in uncertain cases. Another disorder related to gluten ingestion has been described in the last decade, in adults first and then in children [65], namely non-celiac gluten sensitivity (NCGS) [66]. However, even if there is increasing evidence for this entity, we have currently no precise understanding of its pathogenesis and no objective way to confirm this diagnosis. Symptoms of NCGS can mimic those of CD, but they are not associated to any biological or histological sign [66,67]. As in CD, diagnostic criteria of NCGS include the disappearance of symptoms under GFD.
Please cite this article in press as: Garnier-Lengliné H, et al. Celiac disease in children. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.05.024
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Treatment, evolution In 2015, gluten-free diet remains the only treatment for CD. It involves the suppression of wheat, rye and barley from the diet. Concerning pure oats, many clinical studies have shown that a consumption of up to 100 g per day of uncontamined oats is tolerated by most patients with CD, and that it may improve the nutritional content of the diet and its acceptability and adherence [68—70]. At diagnosis, any nutritional deficiency must be assessed and treated. The most commonly observed mineral and vitamin deficiencies are those in iron, folic acid, vitamin D and other fat-soluble vitamins. In case of iron deficiency, supplementation should be given for 4 months. Vitamin D should systematically be given orally once or twice per year, and more often in case of biologically proven deficiency or osteopenia. When CD is associated with IgA deficiency, an antibioprophylaxy may be prescribed in case of recurrent infections, and another immune deficiency must be eliminated. Vaccinations should be performed. Patients have to be informed at diagnosis that CD is a long-life disease, and thus that gluten-free diet has to be continued for a lifetime. Gluten challenge that was formerly performed around the age of six is no more recommended. Indeed even if about 50% of children with CD clinically tolerate the reintroduction of gluten after a longterm gluten-free diet, most of them will develop villous atrophy, bone mineral density deficiency and an increased risk to develop other autoimmune diseases [71,72]. The maximal threshold of gluten that can be tolerated by celiac patients is hard to define. Some patients can clinically tolerate relatively high amounts of gluten whereas others cannot tolerate one breadcrumb. In the European Union, the legislation concerning the composition of gluten-free products has set in 2009 the threshold at 20 mg of gluten per kilogram (regulation no 41/2009 of the EU). Gluten-free diet usually induces rapid clinical improvement (within days or weeks) whereas histologic recovery can take months or even years [73], as well as decrease in anti-tTG level [74]. Correction of nutritional deficiencies has to be monitored, but the outcome of children diagnosed with CD is very satisfactory when gluten-free diet is strictly followed. Adherence to gluten-free diet is much higher in children than in adults, especially if the child is young at diagnosis. Monitoring of anti-tTG level may be useful to determine adherence to GFD. For the management of DH also, glutenfree diet is the cornerstone of treatment, in association with dapsone in cases where diet is not sufficient. Complications of CD predominantly occur in adults and include other autoimmune diseases, cancers, decreased fertility in women and refractory CD. Patients with CD have twice the risk of developing cancer compared to the general population [75]. Most reported cancers include T- and Bcell lymphoma and intestinal adenocarcinoma [76,77]. The risk to develop these complications is greatly reduced under gluten-free diet [78].
5 gluten-free diet [79]. Given that gluten-free diet is an efficient and side-effect free treatment, the use of alternative therapeutics has to focus especially on complicated forms of the disease and on forms showing incomplete response to the diet. One strategy would be to inhibit the immune stimulatory effect of gluten, by using tissue transglutaminase inhibitors blocking antigen-presentation by HLA-DQ2 or DQ8 [80], or by using monoclonal antibodies to suppress pro-inflammatory cytokines (TNF-a, IFN-g, IL-15). Given the risk of significant side-effects, monoclonal antibodies, currently widely used in other autoimmune diseases, have to be strongly evaluated in CD, and might be most useful only in adult patients with refractory celiac disease despite adhering to a glutenfree diet [81,82]. Another lead of novel therapies in CD could be the decrease of gluten immunogenicity, by creating non-toxic wheat varieties [83], by giving oral administration of prolyl endopeptidases that can cleave proline- and glutamine-enriched sequences into smaller and less toxic sequences [84], or by modulating intestinal cell junctions to reduce the access of gluten peptides to lamina propria [85]. One of the difficulties to test efficiency and safety of new therapies in CD is the challenge of creating a good murine model recapitulating all principal aspects of CD [15]. First results of phase II clinical trials in adults, testing glutenase enzymes [86] and a tight junction modulator (larazotide acetate) have been published but have to be further assessed [87,88]. These non-dietary therapies should become available in adults patients with CD in the coming years, being investigated at present as additional treatments to the diet, but their safety and effectiveness have to be evaluated in large long-term clinical studies.
Conclusion Prevalence of CD has dramatically increased in the last two decades due to the use of serological tests. Only 10% of children having CD are symptomatic. A large part of asymptomatic patients remains undiagnosed, even if screening CD is now recommended in at risk groups, especially children having type 1 diabetes or in a context of a family history of CD. The typical clinical picture of malabsorptive syndrome remains frequent in young infant, but milder intestinal symptoms and extra-digestive symptoms are frequently seen in older children, and must evoke CD. In 2015, gluten-free diet remains the only efficient treatment for CD. This could change in the next years, due to alternative treatments being developed, some of them having entered clinical trials. Current challenges in pediatric CD are: • to widespread screening in at risk groups to increase the number of patients diagnosed; • to assess the recent European pediatric guidelines proposing to avoid biopsy in symptomatic children with high antibody titers and HLA compatible; • to develop clinical trials for alternative treatments to gluten-free diet.
Therapeutic perspectives
Disclosure of interest
Improved understanding of the molecular basis of CD has enabled researchers to suggest alternatives to the
The authors declare that they have no conflicts of interest concerning this article.
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