Celiac Disease Among Children and Adolescents

M. Luisa Mearin, MD, PhD

eliac disease (CD) is a chronic disorder caused for the disease. However, the relationship between by an inflammatory T-cell response to the ingestion and the symptoms of CD was discov- C storage in wheat (), rye (seca- ered by the Dutch pediatrician Willem-Karel Dicke lin), and barley (hordein), which are collectively called (1905-1962).4 He became the medical director of the “gluten” and characterized by the presence of typical Juliana Children’s Hospital in The Hague (The Neth- autoantibodies and histological alterations of the small erlands) at the age of 31. Long before the start of the bowel mucosa. Genetic, immunological, and environ- Second World War (1934-1936) he started experi- mental factors are necessary for the expression of the ments with wheat-free diets. At the end of World War disease. Ingestion of gluten by genetically predisposed II, during the 1944-1945 winter of starvation, the people precipitates an uncontrolled T-cell-driven in- delivery of normal food such as to his young flammatory response that leads to disruption of the patients in his hospital was endangered. This period structural and functional integrity of the small bowel and dietary studies convinced him even more that mucosa. CD is treated with a gluten-free diet (GFD), eating less cereals and more uncommon food products which leads to resolution of the clinical disease and such as tulip bulbs improved the clinical condition of restoration of the histological abnormalities. CD was his patients and that a wheat-free diet had favorable once thought to be a rare condition, but at the present effects on children with CD. After World War II, in time it is accepted that CD is the most common form collaboration with Van de Kamer, a biochemist from of food hypersensitivity in children and adults. the Netherlands’ Central Institute for Nutritional Re- The first description of CD is attributed to Aretaeus search TNO in Utrecht, and with Weyers, a pediatri- the Cappadocian, who lived in the second century cian from the Wilhelmina Children’s Hospital in 1 AD. He noted the characteristic stool and chronic Utrecht, he extended his research and demonstrated nature of the condition and observed that children that , ie, the alcohol-soluble fractions of gluten could also be affected by the disease. In 1888, Samuel (wheat ), produced fat malabsorption in pa- Gee, a physician working at the St. Bartholomew tients with CD.5 His experiences with the wheat-free Hospital in London, provided a thorough description diet were at first published in “Het Nederlands Tijd- 2 of the clinical features of childhood CD. During the schrift voor Geneeskunde” (Dutch Journal of Medi- first half of the past century, it was generally agreed cine) in 1941.6 In his PhD dissertation, published in that the treatment for CD was rest and diet. In 1924 1950, he described a dietary study over a period of Sidney Haas described his treatment of childhood CD several years at the Juliana Children’s Hospital in 3 with a banana diet, but there was hardly any form of patients with CD.7 In his PhD thesis Dicke wrote: diet not frequently discussed at that time as a treatment “The starting point of this treatment (gluten-free diet) was to me an observation of M.E. van Dusseldorp and H. A. Stheemann, during the treatment of a celiac From the Department of Pediatrics, Leiden University Medical Center patient” (chapter 3: treatment with a diet free of corn). and Free University Medical Center, Amsterdam, The Netherlands. Dicke refers to a child with CD who went through The author has no commercial interest in the subject and no financial relationships or other relationships that would contribute to a conflict three attacks of “gastrointestinal catarrh” after eating of interest. corn-containing products during a stay in the hospital. Curr Probl Pediatr Adolesc Health Care 2007;37:86-105 This observation was presented by Dr. Stheemann (the 1538-5442/$ - see front matter © 2007 Mosby, Inc. All rights reserved. supervisor of Dicke in The Hague) in The Medical doi:10.1016/j.cppeds.2007.01.001 Society of The Hague in 1932. Van Dusseldorp would

86 Curr Probl Pediatr Adolesc Health Care, March 2007 succeed Dicke as one of the first women directors of a children with CD do not have malabsorption and the Hospital in The Netherlands. clinical picture at presentation is very variable. Not all A few years after Dicke’s discovery, the advent of CD patients are equal. While some develop CD very the peroral intestinal mucosal biopsy led to confirma- early in life, others may eat gluten for many years tion of the characteristic intestinal histopathology of before the disease becomes apparent. The clinical CD.8 picture of CD is very heterogeneous with a broad spectrum of symptoms, from malabsorption, chronic diarrhea, and failure to thrive (the classic “triad”) to Clinical Spectrum and the Iceberg of abdominal pain, lassitude, iron-deficiency anemia, de- CD layed puberty, nonspecific arthritis, depression, ataxia, low bone mineral density, or dental enamel hypoplasia CD occurs largely in Caucasians. The disease has without gastrointestinal complaints.11,20 This hetero- been well documented in Asians from India, Pakistan, geneity in the clinical presentation is one of the causes and Iran,9 but it is rare or nonexistent among native of poor diagnosis of the disease. At present it is not Africans, Japanese, and Chinese. Using simple sero- known what causes these differences in the clinical logical tests, it has gradually become clear that the expression of CD, but there is some evidence that both prevalence of CD in different countries in the Middle genetic and environmental factors may be in- East, North Africa, and India where wheat has been volved.21,22 The relationship between the different the major staple food for many centuries is almost the HLA-DR and -DQ haplotypes of the children with CD same as that in Western countries. Clinical studies and their clinical presentation has been thoroughly showed that presentation with nonspecific symptoms investigated. Some researchers have found a signifi- or no symptoms is as common in the Middle East as it cant relationship between the gene dose effect and the is in Europe. A high index of suspicion for CD should heterogeneity of the clinical disease,21-23 but others be maintained in all developing countries for patients have not noted an association.24 Congia and cowork- who present with chronic diarrhea or iron-deficiency ers22 found that a double dose of DQ2 (␣1*0501, anemia.10 ␤1*0201) predisposes for an early onset and more CD is a common, but frequently unrecognized, severe disease manifestations. The differences in out- disease. The disease is more frequent among females, come can be partially explained by the fact that, for with a female-to-male ratio of 2-3:1. Screening studies statistical analysis in this latter study, the groups were have shown that CD is severely underdiagnosed, with divided in double-, single-, or no-dose HLA-DQ2, and a prevalence of 0.5 to 1% among the white popula- the authors also limited the phenotypic distribution to tion,11 both in adults12,13 and in children.14-16 Assum- fully expressed disease versus mono-/oligosymptom- ing a conservative prevalence of 0.5%, this corre- atic. We have recently shown that children with the sponds to about 2.5 million CD cases in Europe. DR3DQ2-DR5DQ7 and DR5DQ7-DR7DQ2 genotype Approximately 85% of these cases are unrecognized are presented with CD at an earlier age and have a and thus also untreated. Findings from mass screening more severe clinical picture, which suggests a link studies in the USA show a prevalence of the disease between the genotype and phenotype. A correlation similar to that reported in Europe and suggest that CD between disease severity and the HLA-DQ2 gene dose is a much greater problem in the United States than has was not observed (Vermeulen B, Hogen Esch C, previously been appreciated.17 CD is also a frequent Yuksel Z, et al., unpublished data). It is possible that condition in South America, as shown by the preva- other, non-HLA genetic factors also play a role in the lence of undiagnosed CD of 1:681 among apparently different phenotypic expression of CD. healthy blood donors in Brazil18 and of 1:167 among The iceberg is a model frequently used to explain the the general urban population in Argentina, presenting clinical spectrum of CD (Fig 1). with a heterogeneous clinical picture and a predomi- nance of asymptomatic cases.19 ● The tip of the iceberg is formed by the children CD is frequently unrecognized by physicians, in part with clinically diagnosed CD, among others, because of its variable clinical presentation and symp- those with clear gastrointestinal symptoms such toms.20 CD is easily diagnosed in children with a as chronic diarrhea and malabsorption (Table 1), symptomatic malabsorption syndrome, but most of the those with so-called “classic CD.” The symptoms

Curr Probl Pediatr Adolesc Health Care, March 2007 87 FIG 2. Frequency of diagnosis of childhood celiac disease in the Netherlands. FIG 1. The iceberg of celiac disease.

● In the Netherlands, as in most countries, the major- TABLE 1. Some clinical manifestations of celiac disease in children ity of CD diagnoses are in children with the and adolescents System Manifestation (Possible) Cause “classic” symptoms. However, the results of a prospective national study of all the newly diag- Gastrointestinal Diarrhea Atrophy of the small Distended abdomen bowel mucosa nosed cases of CD throughout the country from Vomiting Malabsorption 1993 to 2000 show that the recognition of childhood Anorexia CD in the Netherlands has increased significantly Weight loss 20 Failure to thrive during the last few years (Fig 2), and that the Aphthous stomatitis clinical picture has changed as well with a decrease Hematology Anemia Iron malabsorption in the frequency of “classic” symptoms (Fig 3). The Skeleton Rachitis Calcium/vitamin D Osteoporosis malabsorption overall crude incidence rate of CD for 1993 to 2000 Enamel hypoplasia of the was 0.81/1000 live births. We found a significant teeth linear increase of the crude incidence rate from 0.55 Muscular Atrophy Malnutrition per 1000 live births in 1993 to 1.10 per 1000 live Neurology Peripheral neuropathy Thiamine/vitamin Epilepsy B12 deficiency births in 2000. From 1996 onward, there was a Irritability greater increase in incidence of CD among children Endocrinology Short stature Malnutrition older than 2 years than among the younger children. Pubertas tarda Calcium/vitamin D ● Secondary malabsorption This increasing frequency of diagnosis seems to be 25,26 17 hyperparathyroidism true worldwide, including the USA. An open Dermatology Dermatitis herpetiformis Autoimmunity question is whether the increase in diagnosed child- Alopecia areata Erythema nodosum hood CD is due to more children developing CD or Respiratory Idiopathic pulmonary whether it reflects a greater awareness of the disease hemosiderosis among the physicians who increasingly recognize more subtle expressions of the disease. ● Under the water level in the CD iceberg, we find the start typically after the introduction of gluten into children with unrecognized or nondiagnosed CD. the diet of babies or toddlers, but they may also These children have the typical CD histological present later in life. The severe clinical condition alterations in their small bowel mucosa and they in young children, known as “celiac-crisis,” ac- may or may not have health complaints or symp- companied by skin bleeding, hypocalcemic tet- toms. In the Netherlands, for every child with any, hypoalbuminemia, and edema is nowadays diagnosed CD, there are at least seven children with very rare. unrecognized CD.15 Identification of these children

88 Curr Probl Pediatr Adolesc Health Care, March 2007 FIG 3. Presenting clinical picture (% of symptoms) of childhood celiac disease in the Netherlands 1993 to 2000 (*P Ͻ 0.05).

TABLE 2. Some diseases associated with childhood celiac whole 1987 birth cohort (n ϭ 60,254 births) showed disease (CD) a significant increased cumulative incidence of Frequency Disease Reference of CD (%) asthma in children with CD (24.6%) than in chil- Down’s syndrome 8-15 Csizmadia 200032 dren without CD (3.4%) during the first 7 years of Turner’s syndrome 5-7 Ivarsson 199933 life, indicating that TH1 and TH2 immunological Diabetes mellitus type I 2-8 Green 200311 mediated diseases can coexist and may have a Auto-immune hepatitis 5 Green 200311 29 Selective IgA-deficiency 2-3 Green 200311 common environmental denominator. Another as- Auto-immune thyroidisme 5-6 Ansaldi 200327 sociated disease is idiopathic pulmonary hemosider- Dermatitis herpetiformis ? Lemberg 200531 osis, a rare condition of unknown autoimmune 29 Idiopathic pulmonary hemosiderosis ? Ertekin 2006 etiology mainly affecting children and adolescents, in which a GFD may be very effective for the regression of the pulmonary hemosiderosis.30 after mass screening programs in the general pop- ● An important associated disease is dermatitis her- ulation in different countries has shown that about petiformis, a dermatology disease also known as 0.5 to 1% of the children have CD14-16 and that CD “CD of the skin,” with a high frequency of CD in is the most common form of food intolerance in adults,31 but with a much lower frequency in children, adolescents, and adults. Children with childhood CD.32 Down syndrome is strongly asso- unrecognized CD may be asymptomatic, but they ciated with CD,33 and to a lesser degree, Turner’s frequently have symptoms such as chronic abdom- syndrome is associated with the disease.34 Under- inal pain or lassitude that is frequently a cause of diagnosis is common in children with Down syn- consultation with a pediatrician. CD may also be drome and we found only two cases of Down unrecognized if it is associated with other, fre- syndrome among 225 children with CD diagnosed quently autoimmune diseases such as type 1 diabe- in the Netherlands between 1975 and 1990, while tes mellitus, anemia, arthritis, and osteoporosis even CD was identified by screening in 7% of the in the absence of gastrointestinal symptoms11 (Ta- children with Down syndrome in the same area.35 ble 2). A link between CD and asthma has been The health complaints present in children with supported by some studies but not by others. Greco Down syndrome and CD are frequently and repeat- and coworkers found no difference in the preva- edly attributed to Down syndrome, but in most of lence of atopy in cases affected by CD and their the children the health status improves after a GFD. relatives compared with controls and their rela- Another possible manifestation of CD is short tives.28 On the other hand, an important study on stature. In two British population-based studies on the Finnish Medical Birth Register data of the short stature, where CD was not specifically inves-

Curr Probl Pediatr Adolesc Health Care, March 2007 89 tigated, the prevalence of CD was 2:18036 and ryngeal squamous carcinomas45 have been described. 0:149,37 respectively. In children with short stature However, these prevalence figures represent probably and no gastrointestinal symptoms investigated for an overestimation of the frequency of malignancy in CD, the prevalence increases to 2 to 8%. When CD since the studies were performed in centers for other (endocrine) causes for short stature are ex- CD. Recent population-based studies indicate that the cluded, the prevalence could rise to 59%.38 increased risk of malignancy associated with CD is ● CD may be asymptomatic both above and below the less than previously thought with an odds ratios (OR) water level of the CD iceberg, for example, among for non-Hodgkin lymphoma of 2.6 to 6.3.46-48 There is family members of CD patients (approximately 3 to a form of cancer, the enteropathy-associated T-cell 10% asymptomatic)39 and among young children lymphoma (EATL), with a very high association with with CD identified by mass screening (approxi- CD, but this in general is a rare condition with an mately 50% asymptomatic).15 Normal growth does absolute risk of only 1:1000 based on the local not exclude CD in children as it was demonstrated prevalence of CD.49 Small bowel lymphoma and in a mass screening program in the Netherlands: all EATL are very rare diseases, but CD is the most the children from the general population identified important risk factor for these conditions. with CD had normal growth for both weight and An inquiry among the members of ESPGHAN found height.15 25 cases of children with cancer and CD, suggesting ● The bottom of the CD iceberg is formed by the that an association between CD and cancer in child- children with the genetic predisposition for CD who hood is not likely,50 but it showed also that the may or may not develop CD during their lives. combination of cancer and CD in childhood is under- reported. The children described with CD and cancer Complications of CD were found only through a limited number of highly CD is an important health problem for the individual specialized pediatricians in Europe. Six of the 25 and the community, because of its high prevalence, children reported had malignant disease localized in association with nonspecific morbidity, and long-term the small bowel [4 of them a non-Hodgkin lymphoma complications. (NHL)], suggesting that in children and adults there is The health burden of CD is considerable. CD is an an association between CD and small bowel malig- immune-mediated disease that can affect any organ.11 nancy. However, NHL is a common cancer in child- The broad spectrum of symptoms varies considerably hood and small bowel localization frequently occurs. between children and within a single child over time, To get more data on this subject, the importance of often resulting in delayed or missed diagnosis. Many reporting all cases of CD and cancer in children to the undiagnosed children accept a chronic state of vague literature should be stressed. ill health as normal. Paradoxical constipation and The role of the pediatrician in counseling the parents symptoms more typical of peptic or reflux disease are of a child with CD regarding the long-term risks of common.40 Health problems due to untreated CD cancer should be to reassure them, since, in the big include anemia, delayed puberty, elevated serum series of CD complicated by cancer, there were no transaminases, depression, epilepsy with cerebral cal- patients in whom CD has been diagnosed during cifications, low bone mineral density, and dental childhood CD,46-48 suggesting that the association of enamel hypoplasia. CD subjects also have an in- childhood CD with cancer may be very low. creased risk for other autoimmune diseases, depending Osteoporosis. Osteoporosis is characterized by a low on the duration of gluten exposure.41 bone mass with an increase in bone fragility and Two severe eventual complications of CD are ma- susceptibility to fracture.51 Intestinal malabsorption lignancy and osteoporosis. may cause loss of bone mass and mineral metabolism CD and Malignancy. In adults, CD has been con- alteration. In CD the main mechanisms of osteoporosis sidered a premalignant condition, which could are malabsorption and the production of proinflamma- progress to lymphoma.42 Evidence that treatment of tory cytokines, activating osteoclasts. Osteoporosis CD with a GFD might reduce the risk of malignancy may complicate CD, in both adults52 and children53 was established by Holmes and coworkers.43 In adults, and it is mostly present in patients with overt malab- increased frequency for lymphoma (6%),44 small sorption at diagnosis, but it may also be present in bowel adenocarcinomas, and esophageal and oropha- subclinical or in asymptomatic CD.54 However, the

90 Curr Probl Pediatr Adolesc Health Care, March 2007 risk of bone fracture in CD seems to be lower that in multiple sclerosis, 36% in type I diabetes, and in 33% previously presumed.55 in Crohn’s disease, showing that CD has one of the Bone density improves after following a GFD,56,57 highest concordance rates of the complex multifactorial but in adult CD this improvement does not reach the diseases.59 The sibling relative risk (RR, defined as the normal sex- and age-matched values for the control risk for CD to a sibling of a CD patient divided by the population. In contrast, in childhood CD with a very risk for CD in the general population) is also useful to early treatment, gluten exclusion prevents bone loss measure the heritability of CD. Population studies esti- and most children reach a normal bone mass.58 This mate sibling RR for CD between 30 and 48, also discrepancy can be explained by the fact that bone loss suggesting a stronger genetic component in CD than in has an irreversible component (disappearance of tra- many other complex diseases.59 beculae and thinning of the cortex) and a reversible component (increased intracortical tunneling, thinning The Human Leukocyte Antigen (HLA) of trabeculae). While late treatment in adulthood may Complex revert only the reversible bone loss, very early treat- ment during infancy could prevent both the irrevers- CD is strongly associated with genetic factors ible and the reversible bone loss.58 Consequently, coded by the HLA complex, which occupies a 4-Mb there is no need to perform bone mass measurement in region on chromosome 6p21 and contains some 200 children if fully compliant with GFD.54 The question genes of which over half are known to have immu- is weather bone mass should be assessed at diagnosis nological function.60 Around 95% of patients with in cases of subclinical or silent disease in older CD express HLA-DQ2 (␣1*0501/␤1*0201), either children. Following the advice for adult CD, the in the cis- (encoded by HLA-DRB1*03-DQA1*05- evaluation of bone mass after the first year of strict DQB1*03) or in the trans- (encoded by HLA- adherence to GFD seems to be of more clinical use, DRB1*11/12-DQA1*05-DQB1*0301/DRB1*07-DQA1 since the treatment with mineral-active drugs may be *0201-DQB1*02) configuration and most of the re- started on the basis of the results of gluten exclusion. mainder express HLA-DQ8 (␣1*0301/␤1*0302) en- Risk factors for fractures have not been specifically coded by HLA-DRB1*04-DQA1*03-DQB1*0302, identified in CD, but are likely to include, in addition showing that the chance to develop CD in absence of to noncompliance with GFD, steroid treatment, un- HLA-DQ2 and/or HLA-DQ8 is very small61 (Table treated hypogonadism, age, low body mass index, and 3). However, HLA-DQ2 and DQ8 are frequently previous fragility fracture.54 The role of lifestyle present in the white population (approximately 30%), factors should be not underestimated in the prevention implying that HLA-DQ2 and DQ8 are very important, of osteoporosis and adolescent patients with CD but not enough, to explain the genetics of CD. This should be encouraged to follow a calcium-rich diet, to knowledge has triggered the search for other non-HLA maintain a high level of exercise, and to stop genetic variants predisposing to CD, but currently no smoking.54 other genetic variants have been found that exert a major influence similar to the HLA. The primary function of the HLA-DQ molecules is to present Genetics, Gluten, and Immunology exogenous peptide antigens (in CD gluten peptides) to helper T-cells. The strong relationship between the CD is a familial disorder: first-degree relatives of CD HLA genetic factors and CD is illustrated by the patients have an increased risk of 5 to 10% of impact of the HLA-DQ2 gene dose on the chance of developing the disease.57 disease development: HLA-DQ2 homozygous individ- Twin studies are very useful to assess the genetic and uals have an at least five times higher risk of disease environmental components to disease susceptibility. development compared with HLA-DQ2 heterozygous Both monozygotic and dizygotic twin pairs share the individuals.62,63 It is likely that the large HLA effect same environmental factors, but differ by sharing 100 size is related to the essential permissive role of DQ2 and 50% of genetic variability, respectively.59 In CD the peptide presentation in disease pathogenesis. The level concordance in monozygotic twins is approximately of HLA-DQ2 expression influences the magnitude of 83% and this is only 17% in dyzygotic twins.60 By way the gluten-specific T-cell response: it has been dem- of comparison monozygotic concordance rates are 25% onstrated that gluten presentation by HLA-DQ2 ho-

Curr Probl Pediatr Adolesc Health Care, March 2007 91 TABLE 3. Comparison of the distribution of the HLA-DR/DQ genotypes in Dutch children with celiac disease (CD) and in the Dutch general population General population Relative risk RR (149 ؍ CD (n Risk for CD DR DQ genotype (CI %95) (%) (2307 ؍ n) (%) High Homozygote DR3 DQ2 DR3 DQ2/DR7 DQ2 40 5 8.0 (6.1-10.5)* Medium DR3 DQ2/DR5 DQ7 DR5 DQ7/DR7 DQ2 15 5 3.1 (2.1-4.7)* Medium DR3 DQ2/DRX DQX** DR3 DQ2/DR4 DQ8 36 18 2.0 (1.6-2.6)* Low DR7 DQ2/DRY DQY** DR4 DQ8/DRZ DQZ** 9 72 0.1 (0.07-0.2)* DRX DQX/DRX DQX**

*P Ͻ 0.05. **DRX DQX ϭ not DR3DQ2, DR4DQ8, DR5DQ7, or DR7DQ2. DRY DQY ϭ DR7DQ2 of DRXDQX. DRZ DQZ ϭ DR4DQ8 or DRXDQX.

mozygous antigen-presenting cells is superior to pre- demonstrated by the HLA A1-B8-DR3-DQ2 haplo- sentation by HLA-DQ2/non-DQ2 heterozygous type).59 antigen-presenting cells and this correlates with the Newer methods including gene expression analysis risk of disease development.64 The question is if there will provide further insight in the genetic susceptibility may be additional alleles in the HLA region in for CD. addition to DQ2 and DQ8 that confer risk for CD. Although the association between CD and another Gluten HLA gene, such as and TNF and MICA, may be Gluten, the antigenic protein mixture for CD pa- explained by the linkage disequilibrium across the tients, present in wheat and related cereals, is the HLA; at the moment there is no evidence for addi- water-insoluble material in wheat flour that gives tional HLA risk factors. dough its elasticity. The major components are the glutenins and the gliadins, both representing complex Genome-Wide Linkage Studies families of proteins (Koning F, Mearin ML. Manu- Several genome-wide searches have been performed script submitted for publication, 2006). In a single in CD. Genome-wide linkage studies aim to identify wheat variety dozens of distinct gluten proteins are broad genomic regions that contain disease-predispos- found.67 Gluten contains a high amount of the amino ing variants and are successful to identify loci for acid proline, which renders gluten resistant to degra- monogenic disorders (eg, cystic fibrosis, hemochroma- dation in the gastrointestinal tract. Together with the tosis), but they are less useful to identify loci in the fact that gluten is a very much used protein in the food more common polygenic diseases. industry—the daily consumption of gluten is estimated Outside the HLA region there are at least three to be between 10 and 15 g—this indicates that gluten genomic areas related to CD: CELIAC2 on 5q31 to 33, exposure is high and continuous. CELIAC3 on 2q33, and CELIAC4 on 19p13. From Immunology two of these regions the responsible genes have been identified: CTLA4 on 2q65 and Myosin IXB on 19p,66 In celiac patients, gliadin and glutenin peptides are but their mode of action is unclear. presented by HLA-DQ2 or -DQ8 expressed on anti- T-lymphocyte regulatory genes CD28, CTLA4, and gen-presenting cells to gluten-specific CD4ϩ T-cells. ICOS are found in a 300-kb block of chromosome This generates a mixed Th0 and Th1 response. Anti- 2q33. All three genes control different aspects of the genic protein fractions (peptides) binding to HLA is in T-cell response, and their close genetic proximity part mediated by interactions between particular likely allows for integrated control of expression.59 amino acids in the bound peptide and pockets in the Chromosome 6q21-22 (distinct from the HLA) has HLA molecule. In the case of HLA-DQ2 and -DQ8 it been reported to be related to CD in type I diabetes, is well established that negatively charged amino acids rheumatoid arthritis, and multiple sclerosis and it is are required for these interactions.68,69 As gluten possible that a common variant at this locus might contains very few negatively charged amino acids, predispose to autoimmune diseases in general (as gluten peptides were therefore predicted to poorly bind

92 Curr Probl Pediatr Adolesc Health Care, March 2007 to HLA-DQ2 and -DQ8. This paradox was solved by may lead to a situation where gluten specific T-cell the observation that the enzyme tissue transglutami- responses are initiated instead of suppressed.66 nase (tTG) can convert the amino acid glutamine in In addition, it has also been shown that gluten gluten into glutamic acid, which introduces the nega- activates the innate immune system. A particular tive charge(s) required for strong binding to HLA- ␣-gliadin peptide, p31-43, which is not known to bind DQ2/8.70,71 to HLA-DQ2/8 and stimulate T-cells, has been shown Several studies have investigated the specificity of the to upregulate natural killer cells (NKG2D) and induce 77,78 gluten-specific T-cell response in CD and revealed that MICA expression in biopsies of patients. The polyclonal T-cell responses to multiple gluten peptides cytokine IL-15 appears to be a key factor in the are almost invariably found in patients.72,73 Most re- inflammatory intestinal response in CD. IL-15 pro- sponses are specific for tTG-modified gluten peptides. motes the maturation of intestinal dendritic cells and These peptides can be derived from all types of gliadins might stimulate the recognition of gluten-peptides- ϩ as well as glutenins. However, some peptides are immu- derived T-cell epitopes by lamina propria CD4 79 nodominant; in particular, a proline-rich stretch in alpha- T-cells. In addition, IL-15 stimulates the effector gliadin is found in the large majority of patients, while properties of intra epithelial lymphocytes (IEL), their ␥ other peptides are less frequently recognized.74,75 Similar synthesis of -interferon, and their cytotoxicity and peptides are found in the gluten-like molecules in barley can license IEL to kill enterocytes by signaling deliv- and rye and T-cells specific for gluten peptides can ered by their NKG2D receptor and by inducing the epithelial target of this receptor on enterocytes, the cross-react with those homologous peptides in these 78-81 other cereals.76 MHC Ib molecule MICA. However, it is clear that HLA-DQ2/8 and tTG are not the only factors that contribute to disease devel- opment since the physiological role of tTG is tissue Diagnosis repair and approximately 40% of the white population In 1970 the European Society for Pediatric Gastro- expresses HLA-DQ2 and/or -DQ8 and only 1% de- enterology, Hepatology, and Nutrition (ESPGHAN) velop CD. Therefore, it is possible that, although established the criteria for the diagnosis of CD in enhanced by tTG modification, gluten is in itself childhood, based on the recovery of the characteristic immunogenic. One proposed model for the pathogen- histological alterations of the small intestinal mucosa esis of CD states that tTG drives the diversification of after following a GFD and on the histological relapse the gluten-specific T-cell response: once a gluten- following a gluten-challenge (the reintroduction of specific T-cell response is initiated, the accompanying gluten into the diet).82 At least three small intestine tissue damage will lead to the release of intracellular biopsies (SIB) were necessary to diagnose CD. Cur- tTG which, in turn, allows the generation of additional rently SIB is still the gold standard for the diagnosis of gluten peptides that can trigger T-cell responses, more CD. SIB can be taken blindly with peroral suction tissue damage, more T-cell activation, etc. A vicious biopsy tubes or at the time of upper endoscopy from 76 circle is initiated that is driven by gluten intake. descending duodenum83: both techniques are consid- In a healthy situation the role of the intestinal ered relatively safe.84 Because the intestinal lesions in mucosal immune system is the maintenance of toler- CD may be patchy, it is recommended that multiple ance and, even though HLA-DQ2 and/or -DQ8-posi- biopsy specimens be obtained. In 1990 a working tive individuals are prone to the development of group of the ESPGHAN published revised criteria for gluten-specific T-cell responses, such responses will the diagnosis of childhood CD based on a retrospec- generally be suppressed. However, stress situations, tive study of the diagnosis procedure in a large group like, for example, intestinal infections, would force the of celiac children.85 According to the revised criteria, immune system to raise an inflammatory response gluten-challenge should only be necessary in those accompanied by the production of IFN␥. This would children who were younger than 2 years when the first increase the HLA-DQ expression and, combined with SIB was performed. In this group of young children a the fact that due to the high gluten intake gluten number of diseases other than CD may produce peptides are almost continuously present in the intes- histological small intestinal alterations similar to the tine, and that inflammation can raise tTG levels, this typical CD lesions (Table 4). However, in some cases

Curr Probl Pediatr Adolesc Health Care, March 2007 93 TABLE 4. Some enteropathies different from celiac disease that may patients whose small bowel mucosa is unresponsive cause villous atrophy of the small bowel gastroenteritis and postenteritis syndromes to gluten withdrawal: the so-called refractory CD. Giardiasis Cow’s milk protein allergy Marsh type 3 is accepted as a clear feature of CD, Autoimmune enteropathy but whether the hyperplasic changes of Marsh type Immunodeficiencies 2 lesions should be considered as distinctive for CD HIV/AIDS is still controversial. Tropical sprue Protein energy malnutrition In addition to the small intestine alterations, a lymphocytic gastritis has been described in CD.89 Serology Tests in the Diagnosis of CD gluten-challenge may be needed to prove the necessity For more than 25 years it has been possible to use of continuing lifelong GFD or to confirm the diagnosis serological markers to identify CD with high sensitiv- in those patients on a GFD who did not have a ity and specificity. The most useful are the IgA diagnostic SIB. antibodies to endomysium (EMA) and to human tissue The typical histological lesion of the SIB of a celiac transglutaminase (tTGA). The EMA is an immunoflu- child eating gluten is the subtotal villous atrophy with orescence test that requires expertise in the subjective elongated and hypertrofic crypts and a chronic inflam- interpretation of the results and the use of monkey’s matory infiltration in the mucosa (Fig. 4). The lamina primate esophagus or human umbilical cord as sub- propria contains an increased number of lymphocytes, strate.90 According to the evidence Report/Technol- plasma cells, and some eosinophils and histiocytes. ogy Assessment performed by the Agency for Health- The crypts contain an increased number of cells in care Research and Quality in 2004, the determination mitosis, Paneth cells, and argentaffin cells. There is a of EMA has a high sensitivity for CD of approxi- reduction in the number of goblet cells and an in- mately 90% and a very high specificity approaching creased number of intraepithelial gamma/delta T- 100%.91 The titer of EMA correlates with the degree lymphocytes. A widely used classification of the of mucosal damage; accordingly, the sensitivity in- histological alterations in CD was introduced by creases with higher prevalence of subtotal villous Marsh in 1992 and it ranges from type 0 (Marsh 0) to atrophy in the CD population studied.92 Marsh type 486: The recognition of the enzyme tTG as the sub- ● Type 0 concerns the normal stage of the small strate for the EMA formed the basis for the devel- bowel mucosa. opment of an enzyme-linked immunoassay (ELISA) ● Marsh type 1 or infiltrative lesion comprises normal for the determination of tTGA.93,94 Assays using mucosal architecture in which the villous epithe- human tTG, either recombinant or derived from lium is infiltrated by small, nonmitotic intraepithe- human red cells, have better results than these using lial lymphocytes and it is characteristically present guinea pig tTG.95 The sensitivity of tTGA is greater in first-degree relatives of children with celiac than 90%, but the specificity is lower than the one of disease.87 the EMA.91 It has been shown that TGA results may ● Type 2, or hyperplasic lesion, consists of a type 1 be positive in other diseases different from CD, such lesion with enlarged crypts. as in type 1 diabetes, chronic liver disease, or ● Marsh type 3 or destructive lesion is synonymous rheumatoid arthritis, although small bowel biopsy with the typical flat mucosa of CD and it is was not always performed to exclude CD in the subclassified according to the different degrees of cases described.96 A controlled European multi- villous atrophy present: Marsh type 3a, with partial center study performed in biopsy-proven CD cases villous atrophy; Marsh type 3b, in the presence of and control with other diseases different from CD subtotal villous atrophy; and Marsh type 3c, when controls to evaluate the value of IgA antibody total villous atrophy is present.88 measurement to human recombinant tTG in compar- ● Marsh type 4 or hypoplastic lesion (total villous ison to IgA-EMA in the diagnosis of CD found that atrophy with crypt hypoplasia) represents the ex- tTGA measurement were effective and at least as treme end of the gluten-sensitivity spectrum and an good as EMA in the case-finding of CD.97 Consid- irreversible lesion is present in some adult CD ering the time it spares, the quantitative character of

94 Curr Probl Pediatr Adolesc Health Care, March 2007 FIG 4. Characteristic subtotal villous atrophy of the small bowel mucosa in a child with celiac disease consuming gluten (A) and improvement of the histological lesions after gluten-free diet (B). (Color version of figure is available online.) the tTGA ELISA method, and its lower price, it is likely that, of all serological screening tests, tTGA determination will be the first choice. Selective IgA deficiency (SIgAD) occurs more fre- quently in children with CD than in the general population.97 These patients with CD lack IgA-EMA and IgA-tTG.98 To avoid missing CD in children with SIgAD, it is advisable to determine the total IgA level in serum when testing for CD. Children with already known SIgAD should be tested with an IgG antibody- based tTG test, the IgG-tTG.99 Figure 5 shows the scheme that is usually followed in the clinical diagnosis of CD in children. Who Should Be Tested for Celiac Disease? FIG 5. Flowchart for the diagnosis of celiac disease. (Color The availability of such sensitive and specific sero- version of figure is available online.) logical tests to identify CD, together with the increas- ing knowledge of the heterogeneous character of the clinical picture, opens the question about who should ogy, Hepatology and Nutrition on the diagnosis and be tested for CD. Nowadays, these serological tests are treatment of CD in children and adolescents, CD advised for active case-finding, among children who should be considered early in the differential diagnosis seek medical advice for health problems that suggest of children with failure to thrive and persistent diar- CD (Table 1). Targeted screening is also widespread, rhea. In addition, it is recommended that CD be aiming at high-risk groups such as relatives of CD considered in the differential diagnosis of children patients or individuals with associated conditions like with other persistent gastrointestinal symptoms, in- type I diabetes mellitus or Down syndrome (Table 2). cluding recurrent abdominal pain, constipation, and According to the official recommendations of the vomiting. Testing is recommended for children with North American Society for Pediatric Gastroenterol- nongastrointestinal symptoms of CD (dermatitis her-

Curr Probl Pediatr Adolesc Health Care, March 2007 95 petiformis, dental enamel hypoplasia of permanent of children of white ancestry,14-16 but most cases teeth, osteoporosis, short stature, delayed puberty, and remain undiagnosed. The prevalence of CD thus ex- iron-deficient anemia resistant to oral iron). Testing is ceeds by far that of a number of diseases for which also recommended for asymptomatic children who screening programs are currently applied such as have conditions associated with CD (type 1 diabetes congenital hearing loss (1/1000), congenital hypothy- mellitus, autoimmune thyroiditis, Down syndrome, roidism (1/3400), and phenylketonuria (1/18,000).39 Turner syndrome, Williams syndrome, selective IgA Mass screening is the only way to identify the majority deficiency, and first-degree relatives of celiac pa- of people with CD. tients). It is recommended that testing of asymptom- Mass screening for CD, ie, screening of the general atic children who belong to groups at risk begin population, is a controversial issue. To decide whether around 3 years of age provided they have had an mass-screening programs for CD would be performed, adequate gluten-containing diet for at least 1 year the principles for early disease detection as elaborated before testing.100 by Wilson and Jungner should be taken into ac- count.101 These principles are as follows: (1) The The Use of HLA-DQ Typing in the Diagnosis condition should be an important health problem; (2) of CD There should be an accepted treatment for the disease; Because CD is very unusual in the absence of (3) Facilities for diagnosis and treatment should be HLA-DQ2 or HLA-DQ8, the determination of these available; (4) There should be a recognizable latent or haplotypes may be used in the identification of CD, early symptomatic stage; (5) There should be a suit- among others, in high-risk groups for CD whose able test for disease detection; (6) The test should be members may develop the disease at a certain moment acceptable for the population; (7) The natural history in their lives, but in whom it is not known how often of the condition, including development from latent to CD should be tested. This is especially the case among declared disease, should be understood; (8) There first-degree relatives of CD children: in these families should be an agreed policy of whom to treat as a there is frequently anxiety to know who may or may patient; (9) The costs of case-finding should be eco- not develop CD. However, HLA-DQ2 and -DQ8 are nomically balanced in relation to possible expenditure not specific for CD since they are present in about 40% on medical care as a whole; and (10) Case-finding of the general white population, and their contribution should be a continuous process. Nine of the 10 to the identification of the disease resides in their high principles for mass-screening are met by CD, but the negative-predictive factor.91 Using HLA-DQ typing, a natural history of CD is not well known and it is not two-step model has been proposed to identify CD in clear if the children with none of subtle symptoms of children with high risk for CD.32 The first step should CD identified by mass screening have the same health consist of the typing for the molecularly defined risks and long-term complications that the children HLA-DQ2 and -DQ8, which has to be performed only with clinical diagnosed CD. Assuming a standardized once in life, because it does not change in time. This mortality ratio of 1.5 or higher for untreated CD will help to exclude the children without HLA-DQ2 patients, mass screening for CD has been shown to be and/or HLA-DQ3 from further unnecessary tests for cost-effective in populations with a relatively high CD. The second step should consist of total IgA and prevalence of CD over a wide range of ages at IgA-tTGA and/or IgA EMA determinations in serum screening.102 in the children selected by HLA-typing. Individuals To answer this question, limited screening programs with positive serological tests should be offered a in well-defined regions should be initiated with con- small bowel biopsy, and in the case of histological tinuous and prospective evaluation of their costs and alterations treatment with a GFD should be provided. benefits in comparison with control populations.38 The children with normal serological tests or normal small bowel biopsies should be further investigated for CD, for example, every 1 to 2 years. Treatment To Screen or not to Screen? A lifelong strict GFD with exclusion of gluten from CD is a hidden public health problem worldwide. wheat, rye, and barley is the treatment of CD.7 Wheat, Many studies have shown that CD affects about 1.0% rye, and barley are the predominant grains containing

96 Curr Probl Pediatr Adolesc Health Care, March 2007 the peptides known to cause CD. Triticale (a combi- 1. Contamination with wheat flour of foods that are nation of wheat and rye), kamut, and spelt are also “naturally” gluten-free, known to be harmful. Other forms of wheat are 2. Residual gluten in gluten-free wheat starch used semolina (durum wheat), farina, einkorn, bulgur, and for bread mixes, couscous. Malt is also harmful because it is a partial 3. Mislabeling of foods hydrolysate of barley prolamins. In general, any ingre- dient with malt in its name (barley malt, malt syrup, Lists of gluten-free food are available for patients. malt extract, malt flavorings) is made from barley.100 General awareness should be promoted to keep these The ingestion of very small amounts of gluten, even lists updated. without the accompaniment of clinical or serological The Codex Alimentarius Committee on Nutrition responses, induces changes that are detectable at the and Food for Special Dietary Uses (CCNFSDU) in small bowel level.103 1982 set the limit of gluten allowed in raw materials to The clinical response of children with CD after produce gluten-free food to 0.05 g nitrogen per 100 g starting a GFD may be observed within days or weeks. dry matter. Recently an R5 ELISA method for gluten/ The histological recovery of the small bowel mucosa gliadin determination in food has become available after GFD takes longer, but the recovery in children is based on a monoclonal antibody reacting with the much quicker and complete than in adults and 95% of specific gliadin pentapeptide glutamine-glutamine- the children show histological recovery after 2 years proline-phenylalanine-proline (QQPFP) with a sensi- 88 tivity and limit of detection (1.5 ppm gliadin), which is on a GFD. 114 Initially, oats were considered to be harmful for CD superior to older methods of detection. At the patients, but more recently it has been shown that, in moment a provisional level of [20 ppm] gluten for food gluten-free by nature and [200 ppm] for food general, oats are safe both for adults and for children rendered gluten-free has been accepted (Draft Revised with CD.104-110 One concern about oats consumption Standard for Gluten-free Foods (ALINORM 04/27/26) in a GFD is the frequent contamination of oats with CCNFSDU). The problem is that this standard refers gluten during the harvesting and milling process.111 In to the amount contained in a food and not to the addition, some CD patients have avenin-reactive mu- amount of food that can be taken by a person who is cosal T-cells that can cause mucosal inflammation and sensitive to it. Patients with CD need careful support clinical follow-up of CD patients eating oats is advis- 112 to provide them with up-to-date facts about a GFD. able. This may in part be given by the many Celiac Patients Recently, in vitro experiments showing the absence Societies around the world, among others the Associ- of gluten-derived T-cell epitopes in tef, suggest that ation of European Celiac Societies (www.aoecs.org) this cereal may be suitable for use in the diet of 113 and the American Celiac Sprue Association (www. patients with CD. Tef (Eragrostis tef), a cereal csaceliacs.org). traditionally grown in Ethiopia and used to make flat Nonadherence to the GFD may lead to complications bread, can substitute for wheat flour in almost all such as diarrhea, abdominal pain, anemia, and osteo- applications and has a nutritional value similar to that porosis.11 For many patients adherence to the diet may of wheat. Studies on tef consumption by patients with be difficult to achieve.115 This seems to be particularly CD are needed to determine whether tef is safe for true among adolescent patients with CD, with a these patients. reported compliance with the GFD between 52 and In principle, a GFD appears simple; in practice, it 81%.116-122 Determination of celiac antibodies in se- represents a challenge to children and their families, rum has been reported as a reliable way to monitor the dieticians, and physicians, since wheat products are compliance with the GFD.123 However, in a study added to many processed foods in the Western diet. among young celiacs in the Netherlands we did not Several helpful books distributed by the National find a correlation between the self-reported compli- Celiac Societies provide excellent dietary instructions ance with the diet and the results of the celiac and gluten-free recipes. antibodies in serum. Neither did we find a relation Adherence to the GFD diets is difficult, because between the amount of gluten consumed and the level sources of unintentional gluten intake are so numer- of antibodies (EMA, tTGA).122 It is also possible that ous; among others: the determination of the antibodies in serum is not an

Curr Probl Pediatr Adolesc Health Care, March 2007 97 adequate method to detect adherence to the GFD, both chronic illness like CD may reduce a child’s QOL. Not in adults and in adolescents, as it has been suggested only can physical function be affected, but also a by others.124-126 In addition, adherence to a GFD may child’s emotional and social world may change. The have negative nutritional consequences.127,128 Mariani illness can therefore be an important factor in the and coworkers121 reported overweight and an unbal- evaluation of QOL of a child.132 Health-related QOL anced diet rich in fat and protein, poor in carbohydrate, (HRQOL) is a multidimensional concept containing and deficient in calcium, iron, and fiber in 72% of the physical, emotional, social, and cognitive domains, Italian CD adolescents adhering strictly to the GFD. In variable over time, and is getting increasing attention a prospective study performed in Dutch adolescents in medical and health care settings.133 What matters in and young adults, we found a high dietary compliance HRQOL is the way patients feel about their function- (75%) with a median gluten intake of 44 mg per day ing, not their functioning itself.134 HRQOL can be (2-6382 mg). The nutritional state was adequate, with measured by generic, disease-generic, and disease- normal scores for height and body mass index, but the specific instruments. These instruments can be seen as nutrient intake was not adequate. The fiber and iron having a pyramid structure, with, at the bottom, the intake were significantly lower, and the saturated fat generic QOL questionnaires such as the DUX25135 intake was significantly higher than recommended, but and the TACQOL.136 In the second layer of the comparable with the general population. Most of the pyramid, disease-generic questionnaires are found, patients (61%) found the diet easy to follow. Regular which can be administered to children with any medical controls were reported by 86%, but regular disease, including chronic diseases. Finally, disease- dietary controls were reported by only 7% of the specific questionnaires complete the top layer. These patients.122 Better medical and dietary support is questionnaires can be given to children, healthy and necessary to prevent long-term complications and to ill. Generic HRQOL instruments offer specific possi- achieve an ongoing satisfying management in this bilities in the assessment of the QOL of patients with group of young patients with a chronic disorder. Most a particular disease: they allow comparison with nor- young patients with CD thought that avoiding cancer mative data and across disease populations. Most QOL was the most important reason to adhere to the GFD. instruments are designed as top-down instruments. It has been found that when patients with CD adhere to This means that they are developed by researchers and a GFD for five consecutive years or more, their risk of physicians who used their own experience as guide- malignancy is not increased compared with that of the lines. In the last few years there has been an increasing general population.42,129 On the other hand, over the interest in the development of generic and disease- last few years it has become clear that, although CD specific HRQOL instruments developed from the bot- patients have a higher risk of developing cancer than tom-up approach such as the KIDSCREEN and DIS- the general population, the risk is much lower than ABKIDS questionnaires. These questionnaires used a previously presumed.45-47 At present the GFD is the focus group based bottom-up approach.137 A bot- only effective treatment for CD and it is prudent to tom-up approach allows us to perceive the situation recommend strict adherence to the diet to all celiac from the child’s point of view. It can be seen as a patients. However, the fear of developing malignancy child-centered methodology, designed to ensure that is not necessarily the most important reason for the children, rather than their parents or health care advising a strict diet to CD patients.48 Physicians professionals, generate, prioritize, and explain the should mainly stress the advantages of the diet with issues of interest to them. It can produce data that adult regard to the prevention of other complications of CD, investigators and even parents have never considered. such as osteoporosis49 and autoimmune disorders.42 The HRQOL of children with CD has been previ- They should also point out the relation between ously assessed, making use of the TACQOLCD, a adherence to the GFD and improvement of fertility questionnaire especially designed for CD and based on and birth outcomes.50,130,131 the generic instrument TACQOL, in which the child’s well-being was estimated by the researchers and at- tending physicians.138 The TAQOLCD did not pro- Quality-of-Life vide information about the children’s view, nor that of Decreased quality-of-life (QOL) has been described their parents, and it contained only symptomatic ques- in adults with CD, especially in females.128 Having a tions mainly useful for the investigation of physical

98 Curr Probl Pediatr Adolesc Health Care, March 2007 complaints. In the absence of complaints, thanks to tion and inducing tolerance to gluten in predisposed compliance with the GFD or to coping with the individuals. The “Swedish epidemic of CD” started in disease, the results gave an optimal score which may 1983 when gluten introduction was postponed from not give an accurate view of the HRQOL. Recently, month 4 to 6 by changed national recommendations together with the Dutch foundation Doctors for Chil- for gluten introduction into the diet of young children. dren, a foundation that works for the improvement of Carefully performed studies exploring the epidemic in the QOL of children with chronic illness, an improved detail suggest that the causal factors of the epidemic questionnaire developed from the bottom up, to assess were whether breastfeeding was ongoing or not while the QOL of children with CD has been developed (van gluten was introduced and also the amount of gluten Doorn RK, Winkler LMF, Zwinderman KH, Mearin then given.140,141 Thus, when introduction of gluten in ML, Hendrik M, Koopman HM. Manuscript submited 1983 was postponed, it also implied that more infants for publication.): the Celiac Disease DUX (CDDUX). had ended breastfeeding, and that gluten was intro- Using the CDDUX children with CD appears to have duced by larger amounts. Moreover, the epidemic a lower QOL than the healthy reference group. Chil- subsided in1996 when gluten introduction was once dren with a better health status have a higher score on again “allowed” from 4 months of age when more of the CDDUX questionnaire. The new disease-specific the infants were still breastfed and gluten was intro- questionnaire CDDUX provides information about duced in smaller amounts. Thus, the Swedish studies how children with CD think and feel about their strongly support that ongoing breastfeeding during the illness. The use of a similar questionnaire enables period of gradual introduction of gluten-containing researchers and clinicians to determine the conse- foods into the infant diet reduces the risk of symptom- quences of CD on the daily living of the children. In atic CD.140,141 Based on an estimate of the attributable this context the results of an important study aimed to fraction, half of the CD cases during the Swedish evaluate the impact of the GFD on the 5240 members epidemic might have been avoided if all infants had of the Canadian Celiac Association shows that the been introduced to gluten in small amounts while still QOL in those with CD could be increased with early being breastfed. The latter finding opens the way to diagnosis, increased availability of gluten-free foods, possible prevention strategies. improved food labeling, and better dietary instruc- It is possible that gradual introduction of antigens tion.139 Education of physicians and dieticians about will lead to the development of oral tolerance.142,143 It CD and its treatment is essential. is also likely that the response of the immune system to gluten may be modified by breastfeeding.144,145 Several studies have been performed in different Future Prospects European countries on gluten consumption and breast- 143,146-150 Prevention feeding, but the methods used to assess gluten intake were mostly time consuming and dif- There is some evidence suggesting that prevention of fered from each other. An important American study CD may be possible. One observation is that the level has published the findings on a cohort of 1560 children of HLA-DQ2 expression is linked to the probability of who had an increased risk of developing CD or type 1 disease development: a double gene dose leads to an at diabetes, as defined by possessing either HLA-DR3 or least fivefold increased risk.61,76 Usually children are DR4 alleles, or having a first-degree relative with type exposed to high levels of gluten. The question is what 1 diabetes, derived from the Diabetes Autoimmunity will happen when we lower the amount of gluten in the Study in the Young project.150 At a mean follow-up of diet. It is conceivable that this may have a similar 4.8 years the authors concluded that (1) there is a effect as the HLA-DQ2 gene dose: lower gluten “window of opportunity” of introducing gluten into exposure would decrease the risk to develop CD. the diet when the child is aged between 4 and 6 months Epidemiological studies from Sweden suggest that with regard to the risk of developing CD; and (2) that early nutrition patterns may have a significant impact the contribution of breastfeeding was to be disregarded on the later risk of developing CD. The occurrence of in this respect. However, the authors did not make “epidemics” of CD after changes in the Swedish infant specific attempts to calculate the gluten amount in- feeding during the 1980s and 1990s suggested that the gested by the children or to correlate this important disease may be preventable by improving early nutri- early nutrition event with the presence or absence of

Curr Probl Pediatr Adolesc Health Care, March 2007 99 breastfeeding. A systematic review and a meta-analy- Novel Treatments? sis of observational studies published between 1966 and June 2004 that examined the association between A GFD is at present the only possible treatment for breastfeeding and the development of CD showed that CD children, but there are a number of drawbacks to a breastfeeding seemed to protect against CD.151 Pro- lifelong diet. At present there are four options that can spective cohort studies may shed light on the impor- be explored, as follows: (1) Enzymatic degradation of tance of the quantity of exposure to gluten in early life gluten before it reaches the small intestine; (2) Block- 152 ing of peptide binding to HLA-DQ2/8; (3) Blocking of in the development of CD. One problem in this 66 respect is that, until now, there were no validated tTG; (4) Blocking of IL-15. Of these four options, instruments to quantify gluten intake by young infants. the latter two may be dangerous. tTG is important for The instruments available were work intensive, time the maintenance of tissue integrity, while IL-15 is consuming, and difficult to use in population studies. required for normal functioning of the immune sys- Recently we have developed and validated food fre- tem. The fist two options, however, may provide quency questionnaires for this purpose, using the opportunities. However, due to its high proline con- 2-day food record as a reference (Hopman EG, tent, gluten is resistant to enzymatic degradation. Oral Kiefte-de Jong JC, le Cessie S, et al., unpublished supplementation with a postproline cutting enzyme data). This instrument may be used in collaborative has therefore been proposed as a potential way to destroy gluten before it can do damage in the small studies to assess the role of the quantity of gluten 156 consumption in the development of CD. intestine. Blocking HLA-DQ would also be highly The actual guidelines for infant nutrition recommend selective as it would block the gluten-specific T-cell introducing gluten into the diet no earlier than at the response but would leave non-HLA-DQ-mediated T- age of 6 months,153 and at this age, only a low cell responses intact. These two and other possible percentage of the children, ranging from 1 to 46% in options deserve further study. the different European countries, receive breastfeed- ing.154 On the other hand, the Swedish study only investigated the effect of the early dietary history on Practice Points symptomatic CD in children. It may be that the nutritional factors only have an effect on the symp- ● Celiac disease is a common, but frequently unrec- toms of CD and/or on the time of presentations of the ognized disease. Consequently, celiac disease is symptoms. In addition, there is no information on the severely underdiagnosed. biological mechanisms involved in the effect of early ● The health burden of celiac disease is considerable. nutrition in the development of CD. Prospective inter- Two important complications of celiac disease are vention nutritional studies in high-risk populations are malignancy and osteoporosis. necessary to provide parents with sensible advice to ● Recent population-based studies indicate that the prevent CD in their children. increased risk of malignancy associated with celiac disease is less that previously thought. Safer Foods ● There is no need to perform bone mass measure- Gluten is a complex mixture of proteins that contains ment in children if fully compliant with the GFD. a multitude of immunogenic peptides. This is because ● Celiac disease is strongly associated with genetic bread wheat and pasta wheat are hexaploid and factors coded by the HLA complex. Around 95% of tretraploid species, containing three and two entire the patients express HLA-DQ2 and most of the wheat genomes, respectively. These wheat varieties remainders express HLA-DQ8. The risk of devel- have been selected for good crop yield and superior oping celiac disease in the absence of HLA-DQ2 baking qualities. However, there are many wheat and/or HLA-DQ8 is very small. varieties and not all of those appear to be equally toxic ● It is possible to use serological markers to identify to patients.155 This offers two opportunities for the celiac disease with high sensitivity and specificity. generation of safer wheat strains. In addition, other The most useful are the IgA antibodies to EMA and cereals can be selected that do not contain harmful to human tTGA. gluten or gluten-like molecules, like the Ethiopian ● At the present time small bowel biopsy is the gold cereal tef.155 standard for the diagnosis of celiac disease.

100 Curr Probl Pediatr Adolesc Health Care, March 2007 ● CD should be considered early in the differential M, Karttunen T, et al. Prevalence of Celiac disease among diagnosis of children with failure to thrive and children in Finland. N Engl J Med 2003;348:2517-24. persistent diarrhea and in children with other per- 17. Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, et al. Prevalence of celiac disease in at-risk and not-at-risk sistent gastrointestinal symptoms in children with groups in the United States: a large multicenter study. Arch nongastrointestinal symptoms of CD and in condi- Intern Med 2003;163:286-92. tions associated with CD. 18. Gandolfi L, Pratesi R, Cordoba JCM, Tauil PL, Gasparin M, ● At present a GFD is the only effective treatment for Catassi C. Prevalence of celiac disease among blood donors celiac disease. in Brazil. Am J Gastroenterol 2000;95:689-92. ● 19. Gomez JC, Selvaggio GS, Viola M, Pizarro B, la Motta G, de Better medical and dietary support is necessary to Barrio S, et al. Prevalence of celiac disease in Argentina: prevent long-term complications and to achieve screening of an adult population in the La Plata area. Am J satisfying management in children and young pa- Gastroenterol 2001;96:2700-4. tients with celiac disease. 20. Steens RFR, Csizmadia CGDS, George EK, Ninaber MK, Hira Sing RA, Mearin ML. Better recognition of childhood celiac disease in the Netherlands and its changing clinical References picture: a national prospective study 1993-2000. J Pediatr 1. Adams F. The extant works of Aretaeus the Cappadocian. 2005;147:239-42. London: London Sydenham Society; 1856. p. 350. 21. Mearin ML, Koninckx CR, Biemond I, Polanco I, Pena AS. 2. Gee SJ. On the coeliac affection. St. Bartholomew’s Hospital Influence of genetic factors on the serum levels of antigliadin Report 1888;24:17-20. antibodies in celiac disease. J Pediatr Gastroenterol Nutr 3. Haas SV. The value of the banana in the treatment of coeliac 1984;3:373-7. disease. Am J Dis Child 1924;24:421-37. 22. Congia M, Cucca F, Frau F, Lampis R, Melis L, Clemente 4. van Bergen-Henegouwen GP, Mulder CJ, Dicke WK. Pio- MG, et al. A gene dosage effect of the QA80501/ neer in the gluten free diet: Willem-Karel Dicke 1905-1962, DQB1*0201 allelic combination influences the clinical het- over 50 years of gluten free diet. Gut 1993;34:1473-5. erogeneity of celiac disease. Hum Immunol 1994;40:138-42. 5. Van de Kamer JH, Weijers HA, Dicke WK. Coeliac disease 23. Ploski R, Ek J, Thorsby E, Sollid M. On the HLA-DQ IV. An investigation into the injurious constituents of wheat (␣1*0501, ␤1*0201)-associated susceptibility in celiac in connection with coeliac disease. Acta Paediatr disease: a possible gene dosage effect of DQB1*0201. Tissue 1953;42:223-31. Antigens 1993;41:173-7. 6. Dicke WK. Simple dietary treatment for the syndrome of 24. Greco L, Percopo S, Clot F, Bouguerra F, Babron MC, Gee-Herter. Ned Tijdschr Geneeskd 1941;85:1715-6 (in Eliaou JF, et al. Lack of correlation between genotype and Dutch). phenotype in celiac disease. J Pediatr Gastroenterol Nutr 7. Dicke WK. Coeliac disease: investigation of the harmful 1998;26:286-90. effects of certain types of cereal on patients with celiac 25. Dickey W, McMillan SA. Increasing numbers at a specialist disease (Thesis). University of Utrecht, the Netherlands, coeliac clinic: contribution of serological testing in primary 1950 (in Dutch). care. Dig Liver Dis 2005;37:928-33. 8. Shiner M. Duodenal biopsy. Lancet 1956;i:17-9. 26. Sood A, Midha V, Sood N, Avasthi G, Sehgal A. Prevalence 9. Masjedizadeh R, Hajiani E, Hashemi J, Shayesteh AA, of celiac disease among school children in Punjab, North Moula K, Rajabi T. Celiac disease in South-West of Iran. India. J Gastroenterol Hepatol 2006;21:1622-5. World J Gastroenterol 2006;12:4416-9. 27. Ansaldi N, Palmas T, Corrias A, Barbato M, D’Altiglia MR, 10. Malekzade H, Sachdev A, Fahid AS. Coeliac disease in Campanozzi A, et al. Autoimmune thyroid disease and celiac developing countries: Middle East, India and North Africa. disease in children. J Pediatr Gastroenterol Nutr Best Pract Res Clin Gastroenterol 2005;19:351-8. 2003;37:63-6. 11. Green PHR, Jabri B. Coeliac disease. Lancet 2003;362: 28. Greco L, De Seta L, D’Adamo G, Baldassarre C, Mayer M, 383-91. Siani P, et al. Atopy and coeliac disease: bias or true relation? 12. Johnston SD, Watson RG, McMillan SA, Sloan J, Love AH. Acta Paediatr Scand 1990;79:670-4. Prevalence of coeliac disease in Northern Ireland. Lancet 29. Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and 1997;350:1370. TH2 diseases coexist? Evaluation of asthma incidence in 13. Kolho KL, Farkkila MA, Savilahti E. Undiagnosed coeliac children with coeliac disease, type 1 diabetes, or rheumatoid disease is common in Finnish adults. Scand J Gastroenterol arthritis: a register study. J Allergy Clin Immunol 1998;33:1280-3. 2001;108:781-3. 14. Catassi C, Ratsch IM, Fabiani E, Rossini M, Bordicchia F, 30. Ertekin V, Selimoglu MA, Gursan N, Ozkan B. Idiopathic Candela F, et al. Coeliac disease in the year 2000: exploring pulmonary hemosiderosis in children with celiac disease. the iceberg. Lancet 1994;343:200-3. Respir Med 2006;100:568-9. 15. Csizmadia CG, Mearin ML, von Blomberg BM, Brand R, 31. Hervonen K, Hakanen M, Kaukinen K, Collin P, Reunala T. Verloove-Vanhorick SP. An iceberg of childhood coeliac First-degree relatives are frequently affected in coeliac dis- disease in the Netherlands. Lancet 1999;353:813. ease and dermatitis herpetiformis. Scand J Gastroenterol 16. Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti 2002;37:51-5.

Curr Probl Pediatr Adolesc Health Care, March 2007 101 32. Lemberg D, Day AS, Bohane T. Coeliac disease presenting Cancer in children with celiac disease: a survey of the as dermatitis herpetiformis in infancy. J Paediatr Child European Society for Paediatric Gastroenterology Health 2005;41:294-6. Hepatology and Nutricion. J Pediatr Gastroenterol Nutr 33. Csizmadia CGDS, Mearin ML, Oren A, Kromhout A, 2001;33:97-9. Crusius JB, von Blomberg BM, et al. Accuracy and cost- 51. Wood AJJ. Treatment of postmenopausal osteoporosis. effectiveness of a new strategy to screen for celiac disease in N Engl J Med 1998;336:736-46. children with Down syndrome. J Paediatr 2000;137:756-61. 52. Meyer D, Stavropolous S, Diamond B, Shane E, Green PH. 34. Ivarsson SA, Carlsson A, Bredberg A, Alm J, Aronsson S, Osteoporosis in a North American adult population with CD. Gustafsson J, et al. Prevalence of coeliac disease in Turner Am J Gastroenterol 2001;96:112-119. syndrome. Acta Paediatr 1999;88:933-6. 53. Hartman C, Hino B, Lerner A, Eshach-Adiv O, Berkowitz D, 35. George EK, Mearin ML, Bouquet J, von Blomberg BM, Shaoul R, et al. Bone quantitative ultrasound and bone Stapel SO, van Elburg RM, et al. High frequency of celiac mineral density in children with celiac disease. J Pediatr disease in Down syndrome. J Paediatr 1996;128:555-7. Gastroenterol Nutr 2004;39:504-10. 36. Voss LD, Mulligan J, Betts PR, Wilkin TJ. Poor growth in 54. Corazza GR, Di Stefano M, Mauriño E, Bai JC. Bones in school entrants as an index of organic disease: the Wessex coeliac disease: diagnosis and treatment. Best Pract Res Clin growth study. BMJ 1992;305:1400-2. Gastroenterol 2005;19:453-65. 37. Ahmed ML, Allen AD, Sharma A, Macfarlane JA, Dunger 55. West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture DB. Evaluation of a district growth screening programme: risk in people with CD: a population-based cohort study. the Oxford Growth Study. Arch Dis Child 1993;69:361-5. Gastroenterology 2003;125:429-36. 38. Van Rijn JCW, Grote FK, Oostdijk W, Wit JM. Short stature 56. Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of and the probability of coeliac disease, in the absence of osteopenia with diet in adult coeliac disease. Gut gastrointestinal symptoms. Arch Dis Child 2004;89:882-3. 1996;38:322-7. 39. Mustalahti K, Sulkanen S, Holopainen P, Laurila K, Collin P, 57. Babron MC, Nilsson S, Adamovic S, Naluai AT, Wahlstrom Partanen J, et al. Coeliac disease among healthy members of J, Ascher H, et al. European Genetics Cluster on Coeliac multiple case coeliac disease families. Scand J Gastroenterol Disease. Meta and pooled analysis of European coeliac 2002;37:161-5. disease data. Eur J Hum Genet 2003;11:828-34. 40. Mearin ML, Ivarsson A, Dickey W. Coeliac disease: is it 58. Mora S, Weber G, Barera G, Proverbio MC, Weber G, time for mass screening? Best Pract Res Clin Gastroenterol Bianchi C, et al. Effect of gluten-free diet on bone mineral 2005;19:441-52. content in growing patients with celiac disease. Am J Clin 41. Ventura A, Magazzu G, Greco L. Duration of exposure to Nutr 1993;57:224-30. gluten and risk for autoimmune disorders in celiac patients. 59. van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in Gastroenterology 1999;117:303-10. coeliac disease. Best Pract Res Clin Gastroenterol 42. Gough KR, Reade AE, Nash JM. Intestinal reticulosis as a 2005;19:323-39. complication of idiopathic steatorrhoea. Gut 1962;3:232-9. 60. Nistico L, Fagnani C, Coto I, Percopo S, Cotichini R, 43. Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Limongelli MG, et al. Concordance, disease progression, and Gut 1989;30:333-8. heritability of coeliac disease in Italian twins. Gut 44. Cooper BT, Holmes GKT, Cooke WT. Lymphoma risk in 2006;55:803-8. coeliac disease of later life. Digestion 1982;23:89-92. 61. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby 45. Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac E. Evidence for a primary association of celiac disease to a disease and malignancy. Lancet 1983;1:111-5. particular HLA-DQ alpha/beta heterodimer. J Exp Med 46. Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, 1989;169:345-50. Carella AM, et al. Risk of non-Hodgkin lymphoma in celiac 62. Mearin ML, Biemond I, Pena A, Polanco I, Vazquez C, disease. JAMA 2002;287:1413-9. Schreuder GT, et al. HLA-DR phenotypes in Spanish coeliac 47. Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, children: their contribution to the understanding of the Ekbom A. Cancer incidence in a population-based cohort of genetics of the disease. Gut 1983;24:532-7. individuals hospitalized with celiac disease or dermatitis 63. Mearin ML, Bouquet J, Mourad N, Schoorel E, Sinaasappel herpetiformis in Sweden. Gastroenterology 2002;123:1428- M, Biemond I, et al. HLA-DR antigens and phenotypes in 35. Dutch coeliac children and their families. Clin Genet 48. Mearin ML, Catassi C, Brousse N, Brand R, Collin P, 1985;27:45-50. Fabiani E, et al. European multicenter study on coeliac 64. van Belzen MJ, Mulder CJJ, Zhernakova A, Pearson PL, disease and non-Hodgkin lymphoma. Eur J Gastroenterol Houwen RHJ, Wijmenga C. CTLA4ϩ49 A/G and CT60 Hepat 2006;18:187-94. polymorphisms in Dutch coeliac disease patients Eur J Hum 49. Johnston SD, Watson RG. Small bowel lymphoma in unrec- Genet 2004;12:782-5. ognized coeliac disease: cause for concern? Eur J Gastroen- 65. Monsuur AJ, de Bakker PIW, Alizadeh BZ, Zhernakova A, terol Hepatol 2000;12:645-8. Bevova MR, Strengman E, et al. Myosin IXB variant 50. Schweizer JJ, Oren A, Mearin ML, and the Working Group increases the risk of celiac disease and points toward a on Celiac Disease and Malignancy of the European Society primary intestinal barrier defect. Nat Genet 2005;37:1341-4. for Paediatric Gastroenterology Hepatology and Nutricion. 66. Shewry PR, Tatham AS. The prolamin storage proteins of

102 Curr Probl Pediatr Adolesc Health Care, March 2007 cereal seeds: structure and evolution. Biochem J into lymphokine-activated killer cells in celiac disease. 1990;267:1-12. Immunity 2004;21:357-66. 67. van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning 81. Mention JJ, Ben Ahmed M, Begue B, Verkarre V, Asnafi V, F. Peptide binding characteristics of the coeliac disease- Colombel JF, et al. Interleukin 15: a key to disrupted associated DQ(␣1*0501,␤1*0201) molecule. Immunogenet- intraepithelial lymphocyte homeostasis and lymphomagen- ics 1996;44:246-53. esis in celiac disease. Gastroenterology 2003;125:730-45. 68. Johansen BH, Vartdal F, Eriksen JA, Thorsby E, Sollid LM. 82. Meeuwisse GW. Diagnostic criteria in coeliac disease. Acta Identification of a putative motif for binding of peptides to Paediatr Scand 1970;59:461-3. HLA-DQ2. Int Immunol 1996;8:177-82. 83. Branski D, Faber J, Freier S, Gottschalk-Sabag S, Shiner M. 69. Molberg Ø, McAdam S, Körner R, Quarsten H, Kristiansen Histologic evaluation of endoscopic versus suction biopsies C, Madsen L, et al. Tissue transglutaminase selectively of small intestinal mucosae in children with and without modifies gliadin peptides that are recognized by gut derived celiac disease. J Pediatr Gastroenterol Nutr 1998;27:6-11. T cells in celiac disease. Nat Med 1998;4:713-7. 84. Hogberg L, Nordwall M, Stenhammar L. One thousand 70. van de Wal Y, Kooy YMC, van Veelen P, Pena S, Mearin L, small-bowel biopsies in children. A single-port versus a Papadopoulos G, et al. Selective deamidation by tissue double-port capsule. Scand J Gastroenterol 2001;36:1230-2. transglutaminase strongly enhances gliadin-specific T cell 85. Walker-Smith JA, Guandalini S, Schmitz J, Schmerling DH, reactivity. J Immunol 1998;161:1585-8. Visakorpi JK. Revised criteria for the diagnosis of coeliac 71. Arentz-Hansen H, McAdam SN, Molberg Ø, Fleckenstein B, disease. Report of the working group of the European Lundin KE, Jorgensen TJ, et al. Celiac lesion T cells Society for Paediatric Gastroenterology and Nutrition. Arch recognize epitopes that cluster in regions of gliadins rich in Dis Child 1990;65:909-11. proline residues. Gastroenterology 2002;123:803-9. 86. Marsh MN. Gluten, major histocompatibility complex, and 72. Vader W, Kooy Y, van Veelen P, de Ru A, Harris D, the small intestine. A molecular and immunobiologic ap- Benckhuijsen W, et al. The gluten response in children with proach to the spectrum of gluten sensitivity (“celiac sprue”). recent onset celiac disease. A highly diverse response to- Gastroenterology 1992;102:330-54. 87. Marsh MN, Bjarnason I, Shaw S, Ellis A, Baker R, Peters TJ. wards multiple gliadin and glutenin derived peptides. Gas- Studies of intestinal lymphoid tissue. XIV-HLA status, troenterology 2002;122:1729-37. mucosal morphology, permeability and epithelial lympho- 73. Arentz-Hansen H, Körner R, Molberg Ø, Quarsten H, Vader cyte population in first degree relatives of patients with W, Kooy YM, et al. The intestinal T cell response to coeliac disease. Gut 1990;31:32-6. ␣-gliadin in adult celiac disease is focused on a single 88. Wahab PJ, Meijer JW, Mulder CJ. Histologic follow-up of deamidated glutamine targeted by tissue transglutaminase. J people with celiac disease on a gluten-free diet: slow and Exp Med 2000;191:603-12. incomplete recovery. Am J Clin Pathol 2002;118:459-63. 74. Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV. In 89. De Giacomo C, Gianatti A, Negrini R, Perotti P, Bawa P, vivo antigen challenge in celiac disease identifies a single Maggiore G, Fiocca R. Lymphocytic gastritis: a positive transglutaminase-modified peptide as the dominant A-gliadin relationship with celiac disease. J Pediatr 1994;124:57-62. T-cell epitope. Nat Med 2000;6:337-42. 90. Chan KN, Phillips AD, Mirakian R, Walker-Smith JA. 75. Vader W, Stepniak D, Bunnik EM, Mearin L, Thompson A, Endomysial antibody screening in children. J Pediatr Gastro- van Rood JJ, et al. Characterization of cereal toxicity for enterol Nutr 1994;18:316-20. celiac disease patients based on protein homology in grains. 91. Rostom A, Dubé C, Cranney A, Saloojee N, Sy R, Garritty C, Gastroenterology 2003;125:1105-13. et al. Evidence Report/Technology Assessment No. 104. 76. Vader W, Stepniak D, Kooy Y, de Haan W, Drijfhout JW, (Prepared by the University of Ottawa Evidence-based Prac- Van Veelen PA, et al. The HLA-DQ2 gene dose effect in tice Center, under Contract No. 290-02-0021.) AHRQ Pub- Celiac Disease is directly related to the magnitude and lication No. 04-E029-2. Rockville, MD: Agency for Health- breadth of gluten-specific T-cell responses. Proc Natl Acad care Research and Quality; July 2004. Sci USA 2003;100:12390-5. 92. Abrams J, Diamond B, Rotterdam H, Green PHR. Seroneg- 77. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auric- ative celiac disease: increased prevalence with lesser degrees chio S, et al. Association between innate response to gliadin of villous atrophy. Dig Dis Sci 2004;49:546-50. and activation of pathogenic T cells in coeliac disease. 93. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken Lancet 2003;362:30-7. EO, et al. Identification of tissue transglutaminase as the 78. Hüe S, Mention J-J, Monteiro RC, Zhang S, Cellier C, autoantigen of celiac disease. Nat Med 1997;3:797-801. Schmitz J, et al. Role for NKG2D/MICA interaction in 94. Dieterich W, Laag E, Schöpper H, Volta U, Ferguson A, villous atrophy during celiac disease. Immunity 2004; Gillett H, et al. Autoantibodies to tissue transglutaminase as 21:367-77. predictors of celiac disease. Gastroenterology 1998;115: 79. Koning F, Schuppan D, Cerf-Bensussan N, Sollid LM. 1317-21. Pathomechanisms in celiac disease. Best Pract Res Clin 95. Wong RC, Wilson RJ, Steele RH, Radford-Smith G, Adel- Gastroenterol 2005;19:373-87. stein S. A comparison of 13 guinea pig and human anti-tissue 80. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, transglutaminase antibody ELISA kits. J Clin Pathol Krausz TN, et al. Coordinated induction by IL15 of a 2002;55:488-94. TCR-independent NKG2D signaling pathway converts CTL 96. Lock RJ, Stevens S, Pitcher MC, Unsworth DJ. Is immuno-

Curr Probl Pediatr Adolesc Health Care, March 2007 103 globulin A anti-tissue transglutaminase antibody a reliable intolerance in patients with celiac disease. PLoS Med serological marker of coeliac disease? Eur J Gastroenterol 2004;1:e1. [Epub 2004 Oct 19]. Hepatol 2004;16:467-70. 113. Spaenij-Dekking L, Kooy-Winkelaar Y, Koning F. The 97. Collin P, Kaukinen K, Vogelsang H, Korponay-Szabo I, Ethiopian cereal tef in celiac disease. N Engl J Med Sommer R, Schreier E, et al. Anti-endomysial and anti- 2005;353:1748-9. human recombinant tissue transglutaminase antibodies in the 114. Mendez E, Vela C, Immer U, Janssen FW. Report of a diagnosis of coeliac disease. A biopsy-proven European collaborative trial to investigate the performance of the R5 multicentre study. Eur J Gastroenterol 2005;17:85-91. enzyme linked immunoassay to determine gliadin in gluten- 98. Rittmeyer C, Rhoads JM. IgA deficiency causes false- free food. Eur J Gastroenterol Hepatol 2005;17:1053-63. negative endomysial antibody results in celiac disease. J Pe- 115. Lamontagne P, West GE, Galibois I. Quebecers with celiac diatr Gastroenterol Nutr 1996;23:504-6. disease: analysis of dietary problems. Can J Diet Prac Res 99. Korponay-Szabo IR, Dahlbom I, Laurila K, Koskinen S, 2001;62:175-81. Woolley N, Partanen J, et al. Elevation of IgG antibodies 116. Kumar PJ, Walker-Smith J, Milla P, Harris G, Colyer J, against tissue transglutaminase as a diagnostic tool for Halliday R. The teenage coeliac: follow up study of 102 coeliac disease in selective IgA deficiency. Gut patients. Arch Dis Child 1988;63:916-20. 2003;52:1567-71. 117. Anson O, Weizman Z, Zeevi N. Celiac disease: parental 100. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, knowledge and attitudes of dietary compliance. Pediatrics Guandalini S, et al. Guidelines for the Diagnosis and Treat- 1990;85:98-103. ment of Celiac Disease in Children: Recommendations of the 118. Mayer M, Greco L, Troncone R, Auricchio S, Marsh MN. North American Society for Pediatric Gastroenterology, Compliance of adolescents with coeliac disease with a gluten Hepatology and Nutrition. J Pediatr Gastroenterol Nutr free diet. Gut 1991;32:881-5. 2005;40:1-19. 119. Ljungman G, Myrdal U. Compliance in teenagers with 101. Wilson JM, Jungner G. Principles and Practice of Screening coeliac disease—a Swedish follow-up study. Acta Paediatr for Disease. Geneva: World Health Organisation; 1968. 1993;82:235-8. 120. Fabiani E, Catassi C, Villari A, Gismondi P, Pierdomenico 102. Shamir R, Hernell O, Leshno M. Cost-effectiveness analysis R, Ratsch IM, et al. Dietary compliance in screening- of screening for celiac disease in the adult population. Med detected coeliac disease adolescents. Am J Clin Nutr Decis Making 2006;26:282-93. 1996;412(Suppl):65-7. 103. Ellis HJ, Ciclitira PJ. In vivo gluten challenge in celiac 121. Mariani P, Viti MG, Montuori M, La Vecchia A, Cipolletta disease. Can J Gastroenterol 2001;15:243-7. E, Calvani L, et al. The gluten-free diet: a nutritional risk for 104. Janatuinen EK, Pikkarainen PH, Kemppainen TA, Kosma adolescents with celiac disease. J Pediatr Gastroenterol Nutr VM, Jarvinen RM, Uusitupa MI, et al. A comparison of diets 1998;27:519-23. with and without oats in adults with celiac disease. N Engl 122. Hopman GD, le Cessie S, von Blomberg BME, Mearin ML. J Med 1995;333:1033-7. Nutritional management of the gluten-free diet in young 105. Janatuinen EK, Kemppainen TA, Julkunen RJ, Kosma VM, people with celiac disease in the Netherlands. J Pediatr Maki M, Heikkinen M, et al. No harm from five year Gastroenterol Nutr 2006;43:102-8. ingestion of oats in coeliac disease. Gut 2002;50:332-5. 123. Burgin-Wolff A, Dahlbom I, Hadziselimovic F, Petersson 106. Kumar PJ, Farthking MGJ. Oats and celiac disease. N Engl CJ. Antibodies against human tissue transglutaminase and J Med 1995;333:1075-6. endomysium in diagnosing and monitoring coeliac disease. 107. Hardman CM, Garioch JJ, Leonard JN, Thomas HJ, Walker Scand J Gastroenterol 2002;37:685-91. MM, Lortan JE, et al. Absence of toxicity of oats in patients 124. Troncone R, Mayer M, Spagnuolo F, Maiuri L, Greco L. with dermatitis herpetiformis. N Engl J Med 1997;337: Endomysial antibodies as unreliable markers for slight di- 1884-7. etary transgressions in adolescents with celiac disease. J Pe- 108. Hoffenberg EJ, Haas J, Drescher A, Barnhurst R, Osberg I, diatr Gastroenterol Nutr 1995;21:69-72. Bao F, et al. A trial of oats in children with newly diagnosed 125. Sategna-Guidetti C, Grosso S, Bruno M, Grosso SB. Reli- celiac disease. J Pediatr 2000;137:361-6. ability of immunologic markers of celiac sprue in the 109. Picarelli A, Di Tola M, Sabbatella L, Gabrielli F, Di Cello T, assessment of mucosal recovery after gluten withdrawal. Anania MC, et al. Immunologic evidence of no harmful J Clin Gastroenterol 1996;23:101-4. effect of oats in celiac disease. Am J Clin Nutr 126. Vahedi K, Mascart F, Mary JY, Laberenne JE, Bouhnik Y, 2001;74:137-40. Morin MC, et al. Reliability of antitransglutaminase antibod- 110. Holm K, Maki M, Vuolteenaho N, Mustalahti K, Ashorn M, ies as predictors of gluten-free diet compliance in adult celiac Ruuska T, et al. Oats in the treatment of childhood coeliac disease. Am J Gastroenterol 2003;98:1079-87. disease: a 2-year controlled trial and a long-term clinical 127. Kemppainen T, Uusitupa M, Janatuinen E, Jarvinen R, follow-up study. Aliment Pharmacol Ther 2006;15:1463-72. Julkunen R, Pikkarainen P. Intakes of nutrients and nutri- 111. Hernando A, Mujico JR, Juanas D, Mendez E. Confirmation tional status in coeliac patients. Scand J Gastroenterol of the cereal type in oat products highly contaminated with 1995;30:575-9. gluten. J Am Diet Assoc 2006;106:665-6. 128. Hallert C, Grännö C, Hultén S, Midhagen G, Strom M, 112. Arentz-Hansen H, Fleckenstein B, Molberg Ø, Scott H, Svensson H. Living with coeliac disease. Scand J Gastroen- Koning F, Jung G, et al. The molecular basis for oat terol 2002;37:39-42.

104 Curr Probl Pediatr Adolesc Health Care, March 2007 129. Lewis HM, Reunala TL, Garioch JJ, Leonard JN, Fry JS, 143. Strobel S. Oral tolerance, systemic immunoregulation and Collin P, et al. Protective effect of gluten-free diet against autoimmunity. Ann NY Acad Sci 2002;968:47-58. development of lymphoma in dermatitis herpetiformis. Br J 144. Falth-Magnusson Franzen L, Jansson G, Laurin P, Stemham- Dermatol 1996;135:363-7. mer L. Infant feeding history shows distinct differences 130. Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen between Swedish celiac and reference children. Pediatr P. Infertility and coeliac disease. Gut 1996;39:382-4. Allergy Immunol 1996;7:1-5. 131. Nørgård B, Fonager K, Sørensen HT, Olsen J. Birth out- 145. Hanson, LA. Breastfeeding provides passive and likely comes of women with celiac disease: a nationwide historical long-lasting active immunity. Ann Allergy Asthma Immunol cohort study. Am J Gastroenterol 1999;94:2435-40. 1998;81:523-37. 132. Eiser C, Morse R. Can parents rate their child’s health- 146. Boom van den SAM, Kimber AC, Morgan JB. Weaning related quality of life? Results of a systematic review. Qual practices in children up to 19 months of age in Madrid. Acta Life Res 2001;10:347-57. Paediatr 1995;84:854-8. 133. Petersen C, Schmidt S, Power M, Bullinger M. The 147. Ascher H, Holm K, Kristiansson B, Mäki M. Influence of DISABKIDS Group. Development and pilot-testing of a infant feeding and gluten intake on coeliac disease. Arch Dis health-related quality of life chronic generic module for children and adolescents with chronic health conditions: a Child 1997;76:113-7. European perspective. Qual Life Res 2005;14:1065-77. 148. Challacombe DN, Mecrow IK, Elliott K, Clarke FJ, Wheeler 134. Gill TM, Feinstein AR. A critical appraisal of the quality of EE. Changing infant feeding practices and declining inci- life measurements. JAMA 1994;272:619-26. dence of celiac disease in West Somerset. Arch Dis Child 135. Koopman HM, Theunissen NCM, Vogels TGC, Kamphuis 1997;77:206-9. RP, Verrips EGH. The DUX-25, a short form questionnaire 149. Mitt K, Uibo O. Low cereal intake in Estonian infants: the for measuring health related quality of life of children with possible explanation for the low frequency of coeliac disease chronic illness. Qual Life Res 1998;7:619. in Estonia. Eur J Clin Nutr 1998;52:85-8. 136. Loonen HJ, Grootenhuis MA, Last BF, Koopman HM, 150. Norris JM, Barriga K, Hoffenberg EJ. Risk of celiac disease Derkx HHF. Quality of life in paediatric inflammatory bowel autoimmunity and timing of gluten introduction in the diet of disease measured by a generic and a disease specific ques- infants at increased risk of disease. JAMA 2005;293: tionnaire. Acta Paediatr 2002;91:348-54. 2343-51. 137. Peterson C, Schmidt S, Power M, Bullinger M: The 151. Akobeng AK, Ramanan AV, Buchan I, Heller RF. Effect of DISABKIDS Group. Development and pilot-testing of a breast feeding on risk of coeliac disease: a systematic review health-related quality of life chronic generic module for and meta-analysis of observational studies. Arch Dis Child children and adolescents with chronic health conditions: a 2006;91:39-43. European perspective. Qual Life Res 2005;14:1065-77. 152. Farrel RJ. Infant gluten and celiac disease: too early, too late, 138. Kolsteren MMP, Koopman HM, Schalekamp G, Mearin ML. too much, too many questions. JAMA 2005;293:2410-2. Health-related quality of life in children with celiac disease. 153. WHO. The optimal duration of exclusive breastfeeding. J Pediatr 2001;138:593-5. Systematic Review, March 2001, Geneva, 28-30. 139. Zarkadas M, Cranney A, Case S, Molloy M, Switzer C, 154. Cattaneo A, Yngve A, Koletzko B, Guzman LR. Promotion Graham ID, et al. The impact of a gluten-free diet on adults of Breastfeeding in Europe Project. Protection, promotion with coeliac disease: results of a national survey. J Hum Nutr Diet 2006;19:41-9. and support of breast-feeding in Europe: current situation. 140. Ivarsson A, Persson LÅ, Nyström L, Ascher H, Cavell B, Public Health Nutr 2005, 8:39-46. Danielsson L, et al. Epidemic of celiac disease in Swedish 155. Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, children. Acta Paediatr 2000;89:65-71. Drijfhout JW, Jonker H, van Soest L, et al. Natural variation 141. Ivarsson A, Hernell O, Stenlund H, Persson LÅ. Breast- in toxicity of wheat accessions for celiac disease patients. feeding protects against celiac disease. Am J Clin Nutr Potential for selection and breeding of non-toxic wheat 2002;75:914-21. varieties. Gastroenterology 2005;129:797-806. 142. Brandtzaeg PE. Current understanding of gastrointestinal 156. Shan L, Molberg Ø, Parrot I, Hausch F, Filiz F, Gray GM, et immunoregulation and its relation to food allergy. Ann NY al. Structural basis for gluten intolerance in celiac sprue. Acad Sci 2002;964:13-45. Science 2002;297:2275-9.

Curr Probl Pediatr Adolesc Health Care, March 2007 105