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Celiac Disease Among Children and Adolescents

M. Luisa Mearin, MD, PhD

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C eliac disease (CD) is a chronic disorder causedby an inflammatory T-cell response to thestorage proteins in wheat (gliadin), rye (seca-

in), and barley (hordein), which are collectively calledgluten” and characterized by the presence of typicalutoantibodies and histological alterations of the smallowel mucosa. Genetic, immunological, and environ-ental factors are necessary for the expression of the

isease. Ingestion of gluten by genetically predisposedeople precipitates an uncontrolled T-cell-driven in-ammatory response that leads to disruption of thetructural and functional integrity of the small bowelucosa. CD is treated with a gluten-free diet (GFD),hich leads to resolution of the clinical disease and

estoration of the histological abnormalities. CD wasnce thought to be a rare condition, but at the presentime it is accepted that CD is the most common formf food hypersensitivity in children and adults.The first description of CD is attributed to Aretaeus

he Cappadocian, who lived in the second centuryD.1 He noted the characteristic stool and chronicature of the condition and observed that childrenould also be affected by the disease. In 1888, Samuelee, a physician working at the St. Bartholomewospital in London, provided a thorough descriptionf the clinical features of childhood CD.2 During therst half of the past century, it was generally agreed

hat the treatment for CD was rest and diet. In 1924idney Haas described his treatment of childhood CDith a banana diet,3 but there was hardly any form ofiet not frequently discussed at that time as a treatment

rom the Department of Pediatrics, Leiden University Medical Centernd Free University Medical Center, Amsterdam, The Netherlands.he author has no commercial interest in the subject and no financialelationships or other relationships that would contribute to a conflictf interest.urr Probl Pediatr Adolesc Health Care 2007;37:86-105538-5442/$ - see front matter2007 Mosby, Inc. All rights reserved.

Soi:10.1016/j.cppeds.2007.01.001

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or the disease. However, the relationship betweenluten ingestion and the symptoms of CD was discov-red by the Dutch pediatrician Willem-Karel Dicke1905-1962).4 He became the medical director of theuliana Children’s Hospital in The Hague (The Neth-rlands) at the age of 31. Long before the start of theecond World War (1934-1936) he started experi-ents with wheat-free diets. At the end of World War

I, during the 1944-1945 winter of starvation, theelivery of normal food such as bread to his youngatients in his hospital was endangered. This periodnd dietary studies convinced him even more thatating less cereals and more uncommon food productsuch as tulip bulbs improved the clinical condition ofis patients and that a wheat-free diet had favorableffects on children with CD. After World War II, inollaboration with Van de Kamer, a biochemist fromhe Netherlands’ Central Institute for Nutritional Re-earch TNO in Utrecht, and with Weyers, a pediatri-ian from the Wilhelmina Children’s Hospital intrecht, he extended his research and demonstrated

hat gliadins, ie, the alcohol-soluble fractions of glutenwheat protein), produced fat malabsorption in pa-ients with CD.5 His experiences with the wheat-freeiet were at first published in “Het Nederlands Tijd-chrift voor Geneeskunde” (Dutch Journal of Medi-ine) in 1941.6 In his PhD dissertation, published in950, he described a dietary study over a period ofeveral years at the Juliana Children’s Hospital inatients with CD.7 In his PhD thesis Dicke wrote:The starting point of this treatment (gluten-free diet)as to me an observation of M.E. van Dusseldorp and. A. Stheemann, during the treatment of a celiacatient” (chapter 3: treatment with a diet free of corn).icke refers to a child with CD who went through

hree attacks of “gastrointestinal catarrh” after eatingorn-containing products during a stay in the hospital.his observation was presented by Dr. Stheemann (theupervisor of Dicke in The Hague) in The Medical
ociety of The Hague in 1932. Van Dusseldorp would
Curr Probl Pediatr Adolesc Health Care, March 2007

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ucceed Dicke as one of the first women directors of aospital in The Netherlands.A few years after Dicke’s discovery, the advent of

he peroral intestinal mucosal biopsy led to confirma-ion of the characteristic intestinal histopathology ofD.8

linical Spectrum and the Iceberg ofD

CD occurs largely in Caucasians. The disease haseen well documented in Asians from India, Pakistan,nd Iran,9 but it is rare or nonexistent among nativefricans, Japanese, and Chinese. Using simple sero-

ogical tests, it has gradually become clear that therevalence of CD in different countries in the Middleast, North Africa, and India where wheat has been

he major staple food for many centuries is almost theame as that in Western countries. Clinical studieshowed that presentation with nonspecific symptomsr no symptoms is as common in the Middle East as its in Europe. A high index of suspicion for CD shoulde maintained in all developing countries for patientsho present with chronic diarrhea or iron-deficiency

nemia.10

CD is a common, but frequently unrecognized,isease. The disease is more frequent among females,ith a female-to-male ratio of 2-3:1. Screening studiesave shown that CD is severely underdiagnosed, withprevalence of 0.5 to 1% among the white popula-

ion,11 both in adults12,13 and in children.14-16 Assum-ng a conservative prevalence of 0.5%, this corre-ponds to about 2.5 million CD cases in Europe.pproximately 85% of these cases are unrecognized

nd thus also untreated. Findings from mass screeningtudies in the USA show a prevalence of the diseaseimilar to that reported in Europe and suggest that CDs a much greater problem in the United States than hasreviously been appreciated.17 CD is also a frequentondition in South America, as shown by the preva-ence of undiagnosed CD of 1:681 among apparentlyealthy blood donors in Brazil18 and of 1:167 amonghe general urban population in Argentina, presentingith a heterogeneous clinical picture and a predomi-ance of asymptomatic cases.19

CD is frequently unrecognized by physicians, in partecause of its variable clinical presentation and symp-oms.20 CD is easily diagnosed in children with a
ymptomatic malabsorption syndrome, but most of the
urr Probl Pediatr Adolesc Health Care, March 2007

hildren with CD do not have malabsorption and thelinical picture at presentation is very variable. Not allD patients are equal. While some develop CD veryarly in life, others may eat gluten for many yearsefore the disease becomes apparent. The clinicalicture of CD is very heterogeneous with a broadpectrum of symptoms, from malabsorption, chroniciarrhea, and failure to thrive (the classic “triad”) tobdominal pain, lassitude, iron-deficiency anemia, de-ayed puberty, nonspecific arthritis, depression, ataxia,ow bone mineral density, or dental enamel hypoplasiaithout gastrointestinal complaints.11,20 This hetero-eneity in the clinical presentation is one of the causesf poor diagnosis of the disease. At present it is notnown what causes these differences in the clinicalxpression of CD, but there is some evidence that bothenetic and environmental factors may be in-olved.21,22 The relationship between the differentLA-DR and -DQ haplotypes of the children with CD

nd their clinical presentation has been thoroughlynvestigated. Some researchers have found a signifi-ant relationship between the gene dose effect and theeterogeneity of the clinical disease,21-23 but othersave not noted an association.24 Congia and cowork-rs22 found that a double dose of DQ2 (�1*0501,1*0201) predisposes for an early onset and moreevere disease manifestations. The differences in out-ome can be partially explained by the fact that, fortatistical analysis in this latter study, the groups wereivided in double-, single-, or no-dose HLA-DQ2, andhe authors also limited the phenotypic distribution toully expressed disease versus mono-/oligosymptom-tic. We have recently shown that children with theR3DQ2-DR5DQ7 and DR5DQ7-DR7DQ2 genotype

re presented with CD at an earlier age and have aore severe clinical picture, which suggests a link

etween the genotype and phenotype. A correlationetween disease severity and the HLA-DQ2 gene doseas not observed (Vermeulen B, Hogen Esch C,uksel Z, et al., unpublished data). It is possible thatther, non-HLA genetic factors also play a role in theifferent phenotypic expression of CD.The iceberg is a model frequently used to explain the

linical spectrum of CD (Fig 1).

The tip of the iceberg is formed by the childrenwith clinically diagnosed CD, among others,those with clear gastrointestinal symptoms suchas chronic diarrhea and malabsorption (Table 1),
those with so-called “classic CD.” The symptoms
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start typically after the introduction of gluten intothe diet of babies or toddlers, but they may alsopresent later in life. The severe clinical conditionin young children, known as “celiac-crisis,” ac-companied by skin bleeding, hypocalcemic tet-any, hypoalbuminemia, and edema is nowadays

IG 1. The iceberg of celiac disease.

ABLE 1. Some clinical manifestations of celiac disease in childrennd adolescents

System Manifestation (Possible) Cause

astrointestinal DiarrheaDistended abdomenVomitingAnorexiaWeight lossFailure to thriveAphthous stomatitis

Atrophy of the smallbowel mucosa

Malabsorption

ematology Anemia Iron malabsorptionkeleton Rachitis

OsteoporosisEnamel hypoplasia of the

teeth

Calcium/vitamin Dmalabsorption

uscular Atrophy Malnutritioneurology Peripheral neuropathy

EpilepsyIrritability

Thiamine/vitaminB12 deficiency

ndocrinology Short staturePubertas tardaSecondary

hyperparathyroidism

MalnutritionCalcium/vitamin D

malabsorption

ermatology Dermatitis herpetiformisAlopecia areataErythema nodosum

Autoimmunity

espiratory Idiopathic pulmonaryhemosiderosis

very rare.

8

In the Netherlands, as in most countries, the major-ity of CD diagnoses are in children with the“classic” symptoms. However, the results of aprospective national study of all the newly diag-nosed cases of CD throughout the country from1993 to 2000 show that the recognition of childhoodCD in the Netherlands has increased significantlyduring the last few years20 (Fig 2), and that theclinical picture has changed as well with a decreasein the frequency of “classic” symptoms (Fig 3). Theoverall crude incidence rate of CD for 1993 to 2000was 0.81/1000 live births. We found a significantlinear increase of the crude incidence rate from 0.55per 1000 live births in 1993 to 1.10 per 1000 livebirths in 2000. From 1996 onward, there was agreater increase in incidence of CD among childrenolder than 2 years than among the younger children.This increasing frequency of diagnosis seems to betrue worldwide,25,26 including the USA.17 An openquestion is whether the increase in diagnosed child-hood CD is due to more children developing CD orwhether it reflects a greater awareness of the diseaseamong the physicians who increasingly recognizemore subtle expressions of the disease.Under the water level in the CD iceberg, we find thechildren with unrecognized or nondiagnosed CD.These children have the typical CD histologicalalterations in their small bowel mucosa and theymay or may not have health complaints or symp-toms. In the Netherlands, for every child withdiagnosed CD, there are at least seven children with

IG 2. Frequency of diagnosis of childhood celiac disease inhe Netherlands.

unrecognized CD.15 Identification of these children


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after mass screening programs in the general pop-ulation in different countries has shown that about0.5 to 1% of the children have CD14-16 and that CDis the most common form of food intolerance inchildren, adolescents, and adults. Children withunrecognized CD may be asymptomatic, but theyfrequently have symptoms such as chronic abdom-inal pain or lassitude that is frequently a cause ofconsultation with a pediatrician. CD may also beunrecognized if it is associated with other, fre-quently autoimmune diseases such as type 1 diabe-tes mellitus, anemia, arthritis, and osteoporosis evenin the absence of gastrointestinal symptoms11 (Ta-ble 2). A link between CD and asthma has beensupported by some studies but not by others. Grecoand coworkers found no difference in the preva-lence of atopy in cases affected by CD and theirrelatives compared with controls and their rela-tives.28 On the other hand, an important study on

IG 3. Presenting clinical picture (% of symptoms) of childhood

ABLE 2. Some diseases associated with childhood celiacisease (CD)

DiseaseFrequencyof CD (%)

Reference

own’s syndrome 8-15 Csizmadia 200032

urner’s syndrome 5-7 Ivarsson 199933

iabetes mellitus type I 2-8 Green 200311

uto-immune hepatitis 5 Green 200311

elective IgA-deficiency 2-3 Green 200311

uto-immune thyroidisme 5-6 Ansaldi 200327

ermatitis herpetiformis ? Lemberg 200531

diopathic pulmonary hemosiderosis ? Ertekin 200629

the Finnish Medical Birth Register data of the


whole 1987 birth cohort (n � 60,254 births) showeda significant increased cumulative incidence ofasthma in children with CD (24.6%) than in chil-dren without CD (3.4%) during the first 7 years oflife, indicating that TH1 and TH2 immunologicalmediated diseases can coexist and may have acommon environmental denominator.29 Another as-sociated disease is idiopathic pulmonary hemosider-osis, a rare condition of unknown autoimmuneetiology mainly affecting children and adolescents,in which a GFD may be very effective for theregression of the pulmonary hemosiderosis.30

An important associated disease is dermatitis her-petiformis, a dermatology disease also known as“CD of the skin,” with a high frequency of CD inadults,31 but with a much lower frequency inchildhood CD.32 Down syndrome is strongly asso-ciated with CD,33 and to a lesser degree, Turner’ssyndrome is associated with the disease.34 Under-diagnosis is common in children with Down syn-drome and we found only two cases of Downsyndrome among 225 children with CD diagnosedin the Netherlands between 1975 and 1990, whileCD was identified by screening in 7% of thechildren with Down syndrome in the same area.35

The health complaints present in children withDown syndrome and CD are frequently and repeat-edly attributed to Down syndrome, but in most ofthe children the health status improves after a GFD.Another possible manifestation of CD is shortstature. In two British population-based studies on

iac disease in the Netherlands 1993 to 2000 (*P � 0.05).

short stature, where CD was not specifically inves-

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tigated, the prevalence of CD was 2:18036 and0:149,37 respectively. In children with short statureand no gastrointestinal symptoms investigated forCD, the prevalence increases to 2 to 8%. Whenother (endocrine) causes for short stature are ex-cluded, the prevalence could rise to 59%.38

CD may be asymptomatic both above and below thewater level of the CD iceberg, for example, amongfamily members of CD patients (approximately 3 to10% asymptomatic)39 and among young childrenwith CD identified by mass screening (approxi-mately 50% asymptomatic).15 Normal growth doesnot exclude CD in children as it was demonstratedin a mass screening program in the Netherlands: allthe children from the general population identifiedwith CD had normal growth for both weight andheight.15

The bottom of the CD iceberg is formed by thechildren with the genetic predisposition for CD whomay or may not develop CD during their lives.

omplications of CD

CD is an important health problem for the individualnd the community, because of its high prevalence,ssociation with nonspecific morbidity, and long-termomplications.The health burden of CD is considerable. CD is an

mmune-mediated disease that can affect any organ.11

he broad spectrum of symptoms varies considerablyetween children and within a single child over time,ften resulting in delayed or missed diagnosis. Manyndiagnosed children accept a chronic state of vaguell health as normal. Paradoxical constipation andymptoms more typical of peptic or reflux disease areommon.40 Health problems due to untreated CDnclude anemia, delayed puberty, elevated serumransaminases, depression, epilepsy with cerebral cal-ifications, low bone mineral density, and dentalnamel hypoplasia. CD subjects also have an in-reased risk for other autoimmune diseases, dependingn the duration of gluten exposure.41

Two severe eventual complications of CD are ma-ignancy and osteoporosis.CD and Malignancy. In adults, CD has been con-

idered a premalignant condition, which couldrogress to lymphoma.42 Evidence that treatment ofD with a GFD might reduce the risk of malignancyas established by Holmes and coworkers.43 In adults,

ncreased frequency for lymphoma (6%),44 small
owel adenocarcinomas, and esophageal and oropha- s
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yngeal squamous carcinomas45 have been described.owever, these prevalence figures represent probably

n overestimation of the frequency of malignancy inD since the studies were performed in centers forD. Recent population-based studies indicate that the

ncreased risk of malignancy associated with CD isess than previously thought with an odds ratios (OR)or non-Hodgkin lymphoma of 2.6 to 6.3.46-48 There is

form of cancer, the enteropathy-associated T-cellymphoma (EATL), with a very high association withD, but this in general is a rare condition with anbsolute risk of only 1:1000 based on the localrevalence of CD.49 Small bowel lymphoma andATL are very rare diseases, but CD is the most

mportant risk factor for these conditions.An inquiry among the members of ESPGHAN found5 cases of children with cancer and CD, suggestinghat an association between CD and cancer in child-ood is not likely,50 but it showed also that theombination of cancer and CD in childhood is under-eported. The children described with CD and cancerere found only through a limited number of highly

pecialized pediatricians in Europe. Six of the 25hildren reported had malignant disease localized inhe small bowel [4 of them a non-Hodgkin lymphomaNHL)], suggesting that in children and adults there isn association between CD and small bowel malig-ancy. However, NHL is a common cancer in child-ood and small bowel localization frequently occurs.o get more data on this subject, the importance of

eporting all cases of CD and cancer in children to theiterature should be stressed.The role of the pediatrician in counseling the parentsf a child with CD regarding the long-term risks ofancer should be to reassure them, since, in the bigeries of CD complicated by cancer, there were noatients in whom CD has been diagnosed duringhildhood CD,46-48 suggesting that the association ofhildhood CD with cancer may be very low.Osteoporosis. Osteoporosis is characterized by a lowone mass with an increase in bone fragility andusceptibility to fracture.51 Intestinal malabsorptionay cause loss of bone mass and mineral metabolism

lteration. In CD the main mechanisms of osteoporosisre malabsorption and the production of proinflamma-ory cytokines, activating osteoclasts. Osteoporosisay complicate CD, in both adults52 and children53

nd it is mostly present in patients with overt malab-orption at diagnosis, but it may also be present in
ubclinical or in asymptomatic CD.54 However, the

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isk of bone fracture in CD seems to be lower thatreviously presumed.55

Bone density improves after following a GFD,56,57

ut in adult CD this improvement does not reach theormal sex- and age-matched values for the controlopulation. In contrast, in childhood CD with a veryarly treatment, gluten exclusion prevents bone lossnd most children reach a normal bone mass.58 Thisiscrepancy can be explained by the fact that bone lossas an irreversible component (disappearance of tra-eculae and thinning of the cortex) and a reversibleomponent (increased intracortical tunneling, thinningf trabeculae). While late treatment in adulthood mayevert only the reversible bone loss, very early treat-ent during infancy could prevent both the irrevers-

ble and the reversible bone loss.58 Consequently,here is no need to perform bone mass measurement inhildren if fully compliant with GFD.54 The questions weather bone mass should be assessed at diagnosisn cases of subclinical or silent disease in olderhildren. Following the advice for adult CD, thevaluation of bone mass after the first year of strictdherence to GFD seems to be of more clinical use,ince the treatment with mineral-active drugs may betarted on the basis of the results of gluten exclusion.isk factors for fractures have not been specifically

dentified in CD, but are likely to include, in additiono noncompliance with GFD, steroid treatment, un-reated hypogonadism, age, low body mass index, andrevious fragility fracture.54 The role of lifestyleactors should be not underestimated in the preventionf osteoporosis and adolescent patients with CDhould be encouraged to follow a calcium-rich diet, toaintain a high level of exercise, and to stop

moking.54

enetics, Gluten, and Immunology

CD is a familial disorder: first-degree relatives of CDatients have an increased risk of 5 to 10% ofeveloping the disease.57

Twin studies are very useful to assess the genetic andnvironmental components to disease susceptibility.oth monozygotic and dizygotic twin pairs share the

ame environmental factors, but differ by sharing 100nd 50% of genetic variability, respectively.59 In CD theoncordance in monozygotic twins is approximately3% and this is only 17% in dyzygotic twins.60 By way
f comparison monozygotic concordance rates are 25% o

n multiple sclerosis, 36% in type I diabetes, and in 33%n Crohn’s disease, showing that CD has one of theighest concordance rates of the complex multifactorialiseases.59 The sibling relative risk (RR, defined as theisk for CD to a sibling of a CD patient divided by theisk for CD in the general population) is also useful toeasure the heritability of CD. Population studies esti-ate sibling RR for CD between 30 and 48, also

uggesting a stronger genetic component in CD than inany other complex diseases.59

he Human Leukocyte Antigen (HLA)omplex

CD is strongly associated with genetic factorsoded by the HLA complex, which occupies a 4-Mbegion on chromosome 6p21 and contains some 200enes of which over half are known to have immu-ological function.60 Around 95% of patients withD express HLA-DQ2 (�1*0501/�1*0201), either

n the cis- (encoded by HLA-DRB1*03-DQA1*05-QB1*03) or in the trans- (encoded by HLA-RB1*11/12-DQA1*05-DQB1*0301/DRB1*07-DQA10201-DQB1*02) configuration and most of the re-ainder express HLA-DQ8 (�1*0301/�1*0302) en-

oded by HLA-DRB1*04-DQA1*03-DQB1*0302,howing that the chance to develop CD in absence ofLA-DQ2 and/or HLA-DQ8 is very small61 (Table). However, HLA-DQ2 and DQ8 are frequentlyresent in the white population (approximately 30%),mplying that HLA-DQ2 and DQ8 are very important,ut not enough, to explain the genetics of CD. Thisnowledge has triggered the search for other non-HLAenetic variants predisposing to CD, but currently nother genetic variants have been found that exert aajor influence similar to the HLA. The primary

unction of the HLA-DQ molecules is to presentxogenous peptide antigens (in CD gluten peptides) toelper T-cells. The strong relationship between theLA genetic factors and CD is illustrated by the

mpact of the HLA-DQ2 gene dose on the chance ofisease development: HLA-DQ2 homozygous individ-als have an at least five times higher risk of diseaseevelopment compared with HLA-DQ2 heterozygousndividuals.62,63 It is likely that the large HLA effectize is related to the essential permissive role of DQ2eptide presentation in disease pathogenesis. The levelf HLA-DQ2 expression influences the magnitude ofhe gluten-specific T-cell response: it has been dem-
nstrated that gluten presentation by HLA-DQ2 ho-
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ozygous antigen-presenting cells is superior to pre-entation by HLA-DQ2/non-DQ2 heterozygousntigen-presenting cells and this correlates with theisk of disease development.64 The question is if thereay be additional alleles in the HLA region in

ddition to DQ2 and DQ8 that confer risk for CD.lthough the association between CD and anotherLA gene, such as and TNF and MICA, may be

xplained by the linkage disequilibrium across theLA; at the moment there is no evidence for addi-

ional HLA risk factors.

enome-Wide Linkage Studies

Several genome-wide searches have been performedn CD. Genome-wide linkage studies aim to identifyroad genomic regions that contain disease-predispos-ng variants and are successful to identify loci foronogenic disorders (eg, cystic fibrosis, hemochroma-

osis), but they are less useful to identify loci in theore common polygenic diseases.Outside the HLA region there are at least threeenomic areas related to CD: CELIAC2 on 5q31 to 33,ELIAC3 on 2q33, and CELIAC4 on 19p13. From

wo of these regions the responsible genes have beendentified: CTLA4 on 2q65 and Myosin IXB on 19p,66

ut their mode of action is unclear.T-lymphocyte regulatory genes CD28, CTLA4, and

COS are found in a 300-kb block of chromosomeq33. All three genes control different aspects of the-cell response, and their close genetic proximity

ikely allows for integrated control of expression.59

Chromosome 6q21-22 (distinct from the HLA) haseen reported to be related to CD in type I diabetes,heumatoid arthritis, and multiple sclerosis and it isossible that a common variant at this locus might

ABLE 3. Comparison of the distribution of the HLA-DR/DQ genotypes in

Risk for CD DR DQ genotypeCD (n

igh Homozygote DR3 DQ2DR3 DQ2/DR7 DQ2

edium DR3 DQ2/DR5 DQ7DR5 DQ7/DR7 DQ2

edium DR3 DQ2/DRX DQX**DR3 DQ2/DR4 DQ8

ow DR7 DQ2/DRY DQY**DR4 DQ8/DRZ DQZ**DRX DQX/DRX DQX**

P � 0.05.*DRX DQX � not DR3DQ2, DR4DQ8, DR5DQ7, or DR7DQ2. DRY DQY � DR7

redispose to autoimmune diseases in general (as g

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emonstrated by the HLA A1-B8-DR3-DQ2 haplo-ype).59

Newer methods including gene expression analysisill provide further insight in the genetic susceptibility

or CD.

luten

Gluten, the antigenic protein mixture for CD pa-ients, present in wheat and related cereals, is theater-insoluble material in wheat flour that givesough its elasticity. The major components are thelutenins and the gliadins, both representing complexamilies of proteins (Koning F, Mearin ML. Manu-cript submitted for publication, 2006). In a singleheat variety dozens of distinct gluten proteins are

ound.67 Gluten contains a high amount of the aminocid proline, which renders gluten resistant to degra-ation in the gastrointestinal tract. Together with theact that gluten is a very much used protein in the foodndustry—the daily consumption of gluten is estimatedo be between 10 and 15 g—this indicates that glutenxposure is high and continuous.

mmunology

In celiac patients, gliadin and glutenin peptides areresented by HLA-DQ2 or -DQ8 expressed on anti-en-presenting cells to gluten-specific CD4� T-cells.his generates a mixed Th0 and Th1 response. Anti-enic protein fractions (peptides) binding to HLA is inart mediated by interactions between particularmino acids in the bound peptide and pockets in theLA molecule. In the case of HLA-DQ2 and -DQ8 it

s well established that negatively charged amino acidsre required for these interactions.68,69 As glutenontains very few negatively charged amino acids,

h children with celiac disease (CD) and in the Dutch general population

49) General population(n � 2307) (%)

Relative risk RR(95% CI)

5 8.0 (6.1-10.5)*

5 3.1 (2.1-4.7)*

18 2.0 (1.6-2.6)*

72 0.1 (0.07-0.2)*

of DRXDQX. DRZ DQZ � DR4DQ8 or DRXDQX.

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luten peptides were therefore predicted to poorly bind


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o HLA-DQ2 and -DQ8. This paradox was solved byhe observation that the enzyme tissue transglutami-ase (tTG) can convert the amino acid glutamine inluten into glutamic acid, which introduces the nega-ive charge(s) required for strong binding to HLA-Q2/8.70,71

Several studies have investigated the specificity of theluten-specific T-cell response in CD and revealed thatolyclonal T-cell responses to multiple gluten peptidesre almost invariably found in patients.72,73 Most re-ponses are specific for tTG-modified gluten peptides.hese peptides can be derived from all types of gliadinss well as glutenins. However, some peptides are immu-odominant; in particular, a proline-rich stretch in alpha-liadin is found in the large majority of patients, whilether peptides are less frequently recognized.74,75 Similareptides are found in the gluten-like molecules in barleynd rye and T-cells specific for gluten peptides canross-react with those homologous peptides in thesether cereals.76

However, it is clear that HLA-DQ2/8 and tTG areot the only factors that contribute to disease devel-pment since the physiological role of tTG is tissueepair and approximately 40% of the white populationxpresses HLA-DQ2 and/or -DQ8 and only 1% de-elop CD. Therefore, it is possible that, althoughnhanced by tTG modification, gluten is in itselfmmunogenic. One proposed model for the pathogen-sis of CD states that tTG drives the diversification ofhe gluten-specific T-cell response: once a gluten-pecific T-cell response is initiated, the accompanyingissue damage will lead to the release of intracellularTG which, in turn, allows the generation of additionalluten peptides that can trigger T-cell responses, moreissue damage, more T-cell activation, etc. A viciousircle is initiated that is driven by gluten intake.76

In a healthy situation the role of the intestinalucosal immune system is the maintenance of toler-

nce and, even though HLA-DQ2 and/or -DQ8-posi-ive individuals are prone to the development ofluten-specific T-cell responses, such responses willenerally be suppressed. However, stress situations,ike, for example, intestinal infections, would force themmune system to raise an inflammatory responseccompanied by the production of IFN�. This wouldncrease the HLA-DQ expression and, combined withhe fact that due to the high gluten intake gluteneptides are almost continuously present in the intes-
ine, and that inflammation can raise tTG levels, this t

ay lead to a situation where gluten specific T-cellesponses are initiated instead of suppressed.66

In addition, it has also been shown that glutenctivates the innate immune system. A particular-gliadin peptide, p31-43, which is not known to bind

o HLA-DQ2/8 and stimulate T-cells, has been showno upregulate natural killer cells (NKG2D) and induce

ICA expression in biopsies of patients.77,78 Theytokine IL-15 appears to be a key factor in thenflammatory intestinal response in CD. IL-15 pro-otes the maturation of intestinal dendritic cells andight stimulate the recognition of gluten-peptides-

erived T-cell epitopes by lamina propria CD4�-cells.79 In addition, IL-15 stimulates the effectorroperties of intra epithelial lymphocytes (IEL), theirynthesis of �-interferon, and their cytotoxicity andan license IEL to kill enterocytes by signaling deliv-red by their NKG2D receptor and by inducing thepithelial target of this receptor on enterocytes, theHC Ib molecule MICA.78-81

iagnosis

In 1970 the European Society for Pediatric Gastro-nterology, Hepatology, and Nutrition (ESPGHAN)stablished the criteria for the diagnosis of CD inhildhood, based on the recovery of the characteristicistological alterations of the small intestinal mucosafter following a GFD and on the histological relapseollowing a gluten-challenge (the reintroduction ofluten into the diet).82 At least three small intestineiopsies (SIB) were necessary to diagnose CD. Cur-ently SIB is still the gold standard for the diagnosis ofD. SIB can be taken blindly with peroral suctioniopsy tubes or at the time of upper endoscopy fromescending duodenum83: both techniques are consid-red relatively safe.84 Because the intestinal lesions inD may be patchy, it is recommended that multipleiopsy specimens be obtained. In 1990 a workingroup of the ESPGHAN published revised criteria forhe diagnosis of childhood CD based on a retrospec-ive study of the diagnosis procedure in a large groupf celiac children.85 According to the revised criteria,luten-challenge should only be necessary in thosehildren who were younger than 2 years when the firstIB was performed. In this group of young children aumber of diseases other than CD may produceistological small intestinal alterations similar to the
ypical CD lesions (Table 4). However, in some cases
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luten-challenge may be needed to prove the necessityf continuing lifelong GFD or to confirm the diagnosisn those patients on a GFD who did not have aiagnostic SIB.The typical histological lesion of the SIB of a celiac

hild eating gluten is the subtotal villous atrophy withlongated and hypertrofic crypts and a chronic inflam-atory infiltration in the mucosa (Fig. 4). The lamina

ropria contains an increased number of lymphocytes,lasma cells, and some eosinophils and histiocytes.he crypts contain an increased number of cells initosis, Paneth cells, and argentaffin cells. There is a

eduction in the number of goblet cells and an in-reased number of intraepithelial gamma/delta T-ymphocytes. A widely used classification of theistological alterations in CD was introduced byarsh in 1992 and it ranges from type 0 (Marsh 0) toarsh type 486:

Type 0 concerns the normal stage of the smallbowel mucosa.Marsh type 1 or infiltrative lesion comprises normalmucosal architecture in which the villous epithe-lium is infiltrated by small, nonmitotic intraepithe-lial lymphocytes and it is characteristically presentin first-degree relatives of children with celiacdisease.87

Type 2, or hyperplasic lesion, consists of a type 1lesion with enlarged crypts.Marsh type 3 or destructive lesion is synonymouswith the typical flat mucosa of CD and it issubclassified according to the different degrees ofvillous atrophy present: Marsh type 3a, with partialvillous atrophy; Marsh type 3b, in the presence ofsubtotal villous atrophy; and Marsh type 3c, whentotal villous atrophy is present.88

Marsh type 4 or hypoplastic lesion (total villousatrophy with crypt hypoplasia) represents the ex-treme end of the gluten-sensitivity spectrum and an

ABLE 4. Some enteropathies different from celiac disease that mayause villous atrophy of the small bowel gastroenteritis andostenteritis syndromes

iardiasisow’s milk protein allergyutoimmune enteropathymmunodeficienciesIV/AIDSropical spruerotein energy malnutrition

irreversible lesion is present in some adult CD e

4

patients whose small bowel mucosa is unresponsiveto gluten withdrawal: the so-called refractory CD.

Marsh type 3 is accepted as a clear feature of CD,ut whether the hyperplasic changes of Marsh typelesions should be considered as distinctive for CD

s still controversial.In addition to the small intestine alterations, a

ymphocytic gastritis has been described in CD.89

erology Tests in the Diagnosis of CD

For more than 25 years it has been possible to useerological markers to identify CD with high sensitiv-ty and specificity. The most useful are the IgAntibodies to endomysium (EMA) and to human tissueransglutaminase (tTGA). The EMA is an immunoflu-rescence test that requires expertise in the subjectiventerpretation of the results and the use of monkey’srimate esophagus or human umbilical cord as sub-trate.90 According to the evidence Report/Technol-gy Assessment performed by the Agency for Health-are Research and Quality in 2004, the determinationf EMA has a high sensitivity for CD of approxi-ately 90% and a very high specificity approaching

00%.91 The titer of EMA correlates with the degreef mucosal damage; accordingly, the sensitivity in-reases with higher prevalence of subtotal villoustrophy in the CD population studied.92

The recognition of the enzyme tTG as the sub-trate for the EMA formed the basis for the devel-pment of an enzyme-linked immunoassay (ELISA)or the determination of tTGA.93,94 Assays usinguman tTG, either recombinant or derived fromuman red cells, have better results than these usinguinea pig tTG.95 The sensitivity of tTGA is greaterhan 90%, but the specificity is lower than the one ofhe EMA.91 It has been shown that TGA results maye positive in other diseases different from CD, suchs in type 1 diabetes, chronic liver disease, orheumatoid arthritis, although small bowel biopsyas not always performed to exclude CD in the

ases described.96 A controlled European multi-enter study performed in biopsy-proven CD casesnd control with other diseases different from CDontrols to evaluate the value of IgA antibodyeasurement to human recombinant tTG in compar-

son to IgA-EMA in the diagnosis of CD found thatTGA measurement were effective and at least asood as EMA in the case-finding of CD.97 Consid-
ring the time it spares, the quantitative character of

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he tTGA ELISA method, and its lower price, it isikely that, of all serological screening tests, tTGAetermination will be the first choice.Selective IgA deficiency (SIgAD) occurs more fre-uently in children with CD than in the generalopulation.97 These patients with CD lack IgA-EMAnd IgA-tTG.98 To avoid missing CD in children withIgAD, it is advisable to determine the total IgA level

n serum when testing for CD. Children with alreadynown SIgAD should be tested with an IgG antibody-ased tTG test, the IgG-tTG.99

Figure 5 shows the scheme that is usually followedn the clinical diagnosis of CD in children.

ho Should Be Tested for Celiac Disease?

The availability of such sensitive and specific sero-ogical tests to identify CD, together with the increas-ng knowledge of the heterogeneous character of thelinical picture, opens the question about who shoulde tested for CD. Nowadays, these serological tests aredvised for active case-finding, among children whoeek medical advice for health problems that suggestD (Table 1). Targeted screening is also widespread,iming at high-risk groups such as relatives of CDatients or individuals with associated conditions likeype I diabetes mellitus or Down syndrome (Table 2).According to the official recommendations of the

IG 4. Characteristic subtotal villous atrophy of the small bowemprovement of the histological lesions after gluten-free diet (B

orth American Society for Pediatric Gastroenterol- n


gy, Hepatology and Nutrition on the diagnosis andreatment of CD in children and adolescents, CDhould be considered early in the differential diagnosisf children with failure to thrive and persistent diar-hea. In addition, it is recommended that CD beonsidered in the differential diagnosis of childrenith other persistent gastrointestinal symptoms, in-

luding recurrent abdominal pain, constipation, andomiting. Testing is recommended for children with

cosa in a child with celiac disease consuming gluten (A) andolor version of figure is available online.)

IG 5. Flowchart for the diagnosis of celiac disease. (Colorersion of figure is available online.)

l mu

ongastrointestinal symptoms of CD (dermatitis her-

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etiformis, dental enamel hypoplasia of permanenteeth, osteoporosis, short stature, delayed puberty, andron-deficient anemia resistant to oral iron). Testing islso recommended for asymptomatic children whoave conditions associated with CD (type 1 diabetesellitus, autoimmune thyroiditis, Down syndrome,urner syndrome, Williams syndrome, selective IgAeficiency, and first-degree relatives of celiac pa-ients). It is recommended that testing of asymptom-tic children who belong to groups at risk beginround 3 years of age provided they have had andequate gluten-containing diet for at least 1 yearefore testing.100

he Use of HLA-DQ Typing in the Diagnosisf CD

Because CD is very unusual in the absence ofLA-DQ2 or HLA-DQ8, the determination of theseaplotypes may be used in the identification of CD,mong others, in high-risk groups for CD whoseembers may develop the disease at a certain moment

n their lives, but in whom it is not known how oftenD should be tested. This is especially the case amongrst-degree relatives of CD children: in these families

here is frequently anxiety to know who may or mayot develop CD. However, HLA-DQ2 and -DQ8 areot specific for CD since they are present in about 40%f the general white population, and their contributiono the identification of the disease resides in their highegative-predictive factor.91 Using HLA-DQ typing, awo-step model has been proposed to identify CD inhildren with high risk for CD.32 The first step shouldonsist of the typing for the molecularly definedLA-DQ2 and -DQ8, which has to be performed onlynce in life, because it does not change in time. Thisill help to exclude the children without HLA-DQ2

nd/or HLA-DQ3 from further unnecessary tests forD. The second step should consist of total IgA and

gA-tTGA and/or IgA EMA determinations in serumn the children selected by HLA-typing. Individualsith positive serological tests should be offered a

mall bowel biopsy, and in the case of histologicallterations treatment with a GFD should be provided.he children with normal serological tests or normalmall bowel biopsies should be further investigated forD, for example, every 1 to 2 years.

o Screen or not to Screen?

CD is a hidden public health problem worldwide.
any studies have shown that CD affects about 1.0% r
6

f children of white ancestry,14-16 but most casesemain undiagnosed. The prevalence of CD thus ex-eeds by far that of a number of diseases for whichcreening programs are currently applied such asongenital hearing loss (1/1000), congenital hypothy-oidism (1/3400), and phenylketonuria (1/18,000).39

ass screening is the only way to identify the majorityf people with CD.Mass screening for CD, ie, screening of the generalopulation, is a controversial issue. To decide whetherass-screening programs for CD would be performed,

he principles for early disease detection as elaboratedy Wilson and Jungner should be taken into ac-ount.101 These principles are as follows: (1) Theondition should be an important health problem; (2)here should be an accepted treatment for the disease;

3) Facilities for diagnosis and treatment should bevailable; (4) There should be a recognizable latent orarly symptomatic stage; (5) There should be a suit-ble test for disease detection; (6) The test should becceptable for the population; (7) The natural historyf the condition, including development from latent toeclared disease, should be understood; (8) Therehould be an agreed policy of whom to treat as aatient; (9) The costs of case-finding should be eco-omically balanced in relation to possible expendituren medical care as a whole; and (10) Case-findinghould be a continuous process. Nine of the 10rinciples for mass-screening are met by CD, but theatural history of CD is not well known and it is notlear if the children with none of subtle symptoms ofD identified by mass screening have the same health

isks and long-term complications that the childrenith clinical diagnosed CD. Assuming a standardizedortality ratio of 1.5 or higher for untreated CD

atients, mass screening for CD has been shown to beost-effective in populations with a relatively highrevalence of CD over a wide range of ages atcreening.102

To answer this question, limited screening programsn well-defined regions should be initiated with con-inuous and prospective evaluation of their costs andenefits in comparison with control populations.38

reatment

A lifelong strict GFD with exclusion of gluten fromheat, rye, and barley is the treatment of CD.7 Wheat,

ye, and barley are the predominant grains containing


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he peptides known to cause CD. Triticale (a combi-ation of wheat and rye), kamut, and spelt are alsonown to be harmful. Other forms of wheat areemolina (durum wheat), farina, einkorn, bulgur, andouscous. Malt is also harmful because it is a partialydrolysate of barley prolamins. In general, any ingre-ient with malt in its name (barley malt, malt syrup,alt extract, malt flavorings) is made from barley.100

he ingestion of very small amounts of gluten, evenithout the accompaniment of clinical or serological

esponses, induces changes that are detectable at themall bowel level.103

The clinical response of children with CD aftertarting a GFD may be observed within days or weeks.he histological recovery of the small bowel mucosafter GFD takes longer, but the recovery in children isuch quicker and complete than in adults and 95% of

he children show histological recovery after 2 yearsn a GFD.88

Initially, oats were considered to be harmful for CDatients, but more recently it has been shown that, ineneral, oats are safe both for adults and for childrenith CD.104-110 One concern about oats consumption

n a GFD is the frequent contamination of oats withluten during the harvesting and milling process.111 Inddition, some CD patients have avenin-reactive mu-osal T-cells that can cause mucosal inflammation andlinical follow-up of CD patients eating oats is advis-ble.112

Recently, in vitro experiments showing the absencef gluten-derived T-cell epitopes in tef, suggest thathis cereal may be suitable for use in the diet ofatients with CD.113 Tef (Eragrostis tef), a cerealraditionally grown in Ethiopia and used to make flatread, can substitute for wheat flour in almost allpplications and has a nutritional value similar to thatf wheat. Studies on tef consumption by patients withD are needed to determine whether tef is safe for

hese patients.In principle, a GFD appears simple; in practice, it

epresents a challenge to children and their families,ieticians, and physicians, since wheat products aredded to many processed foods in the Western diet.everal helpful books distributed by the Nationaleliac Societies provide excellent dietary instructionsnd gluten-free recipes.Adherence to the GFD diets is difficult, because

ources of unintentional gluten intake are so numer-
us; among others: t

. Contamination with wheat flour of foods that are“naturally” gluten-free,

. Residual gluten in gluten-free wheat starch usedfor bread mixes,

. Mislabeling of foods

Lists of gluten-free food are available for patients.eneral awareness should be promoted to keep these

ists updated.The Codex Alimentarius Committee on Nutrition

nd Food for Special Dietary Uses (CCNFSDU) in982 set the limit of gluten allowed in raw materials toroduce gluten-free food to 0.05 g nitrogen per 100 gry matter. Recently an R5 ELISA method for gluten/liadin determination in food has become availableased on a monoclonal antibody reacting with thepecific gliadin pentapeptide glutamine-glutamine-roline-phenylalanine-proline (QQPFP) with a sensi-ivity and limit of detection (1.5 ppm gliadin), which isuperior to older methods of detection.114 At theoment a provisional level of [20 ppm] gluten for

ood gluten-free by nature and [200 ppm] for foodendered gluten-free has been accepted (Draft Revisedtandard for Gluten-free Foods (ALINORM 04/27/26)CNFSDU). The problem is that this standard refers

o the amount contained in a food and not to themount of food that can be taken by a person who isensitive to it. Patients with CD need careful supporto provide them with up-to-date facts about a GFD.his may in part be given by the many Celiac Patientsocieties around the world, among others the Associ-tion of European Celiac Societies (www.aoecs.org)nd the American Celiac Sprue Association (www.saceliacs.org).Nonadherence to the GFD may lead to complications

uch as diarrhea, abdominal pain, anemia, and osteo-orosis.11 For many patients adherence to the diet maye difficult to achieve.115 This seems to be particularlyrue among adolescent patients with CD, with aeported compliance with the GFD between 52 and1%.116-122 Determination of celiac antibodies in se-um has been reported as a reliable way to monitor theompliance with the GFD.123 However, in a studymong young celiacs in the Netherlands we did notnd a correlation between the self-reported compli-nce with the diet and the results of the celiacntibodies in serum. Neither did we find a relationetween the amount of gluten consumed and the levelf antibodies (EMA, tTGA).122 It is also possible that
he determination of the antibodies in serum is not an
97

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dequate method to detect adherence to the GFD, bothn adults and in adolescents, as it has been suggestedy others.124-126 In addition, adherence to a GFD mayave negative nutritional consequences.127,128 Marianind coworkers121 reported overweight and an unbal-nced diet rich in fat and protein, poor in carbohydrate,nd deficient in calcium, iron, and fiber in 72% of thetalian CD adolescents adhering strictly to the GFD. In

prospective study performed in Dutch adolescentsnd young adults, we found a high dietary compliance75%) with a median gluten intake of 44 mg per day2-6382 mg). The nutritional state was adequate, withormal scores for height and body mass index, but theutrient intake was not adequate. The fiber and ironntake were significantly lower, and the saturated fatntake was significantly higher than recommended, butomparable with the general population. Most of theatients (61%) found the diet easy to follow. Regularedical controls were reported by 86%, but regular

ietary controls were reported by only 7% of theatients.122 Better medical and dietary support isecessary to prevent long-term complications and tochieve an ongoing satisfying management in thisroup of young patients with a chronic disorder. Mostoung patients with CD thought that avoiding canceras the most important reason to adhere to the GFD.

t has been found that when patients with CD adhere toGFD for five consecutive years or more, their risk ofalignancy is not increased compared with that of the

eneral population.42,129 On the other hand, over theast few years it has become clear that, although CDatients have a higher risk of developing cancer thanhe general population, the risk is much lower thanreviously presumed.45-47 At present the GFD is thenly effective treatment for CD and it is prudent toecommend strict adherence to the diet to all celiacatients. However, the fear of developing malignancys not necessarily the most important reason fordvising a strict diet to CD patients.48 Physicianshould mainly stress the advantages of the diet withegard to the prevention of other complications of CD,uch as osteoporosis49 and autoimmune disorders.42

hey should also point out the relation betweendherence to the GFD and improvement of fertilitynd birth outcomes.50,130,131

uality-of-LifeDecreased quality-of-life (QOL) has been described

n adults with CD, especially in females.128 Having a t

8

hronic illness like CD may reduce a child’s QOL. Notnly can physical function be affected, but also ahild’s emotional and social world may change. Thellness can therefore be an important factor in thevaluation of QOL of a child.132 Health-related QOLHRQOL) is a multidimensional concept containinghysical, emotional, social, and cognitive domains,ariable over time, and is getting increasing attentionn medical and health care settings.133 What matters inRQOL is the way patients feel about their function-

ng, not their functioning itself.134 HRQOL can beeasured by generic, disease-generic, and disease-

pecific instruments. These instruments can be seen asaving a pyramid structure, with, at the bottom, theeneric QOL questionnaires such as the DUX25135

nd the TACQOL.136 In the second layer of theyramid, disease-generic questionnaires are found,hich can be administered to children with anyisease, including chronic diseases. Finally, disease-pecific questionnaires complete the top layer. Theseuestionnaires can be given to children, healthy andll. Generic HRQOL instruments offer specific possi-ilities in the assessment of the QOL of patients withparticular disease: they allow comparison with nor-ative data and across disease populations. Most QOL

nstruments are designed as top-down instruments.his means that they are developed by researchers andhysicians who used their own experience as guide-ines. In the last few years there has been an increasingnterest in the development of generic and disease-pecific HRQOL instruments developed from the bot-om-up approach such as the KIDSCREEN and DIS-BKIDS questionnaires. These questionnaires used a

ocus group based bottom-up approach.137 A bot-om-up approach allows us to perceive the situationrom the child’s point of view. It can be seen as ahild-centered methodology, designed to ensure thathe children, rather than their parents or health carerofessionals, generate, prioritize, and explain thessues of interest to them. It can produce data that adultnvestigators and even parents have never considered.The HRQOL of children with CD has been previ-usly assessed, making use of the TACQOLCD, auestionnaire especially designed for CD and based onhe generic instrument TACQOL, in which the child’sell-being was estimated by the researchers and at-

ending physicians.138 The TAQOLCD did not pro-ide information about the children’s view, nor that ofheir parents, and it contained only symptomatic ques-
ions mainly useful for the investigation of physical

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omplaints. In the absence of complaints, thanks toompliance with the GFD or to coping with theisease, the results gave an optimal score which mayot give an accurate view of the HRQOL. Recently,ogether with the Dutch foundation Doctors for Chil-ren, a foundation that works for the improvement ofhe QOL of children with chronic illness, an improveduestionnaire developed from the bottom up, to assesshe QOL of children with CD has been developed (vanoorn RK, Winkler LMF, Zwinderman KH, MearinL, Hendrik M, Koopman HM. Manuscript submited

or publication.): the Celiac Disease DUX (CDDUX).sing the CDDUX children with CD appears to havelower QOL than the healthy reference group. Chil-

ren with a better health status have a higher score onhe CDDUX questionnaire. The new disease-specificuestionnaire CDDUX provides information aboutow children with CD think and feel about theirllness. The use of a similar questionnaire enablesesearchers and clinicians to determine the conse-uences of CD on the daily living of the children. Inhis context the results of an important study aimed tovaluate the impact of the GFD on the 5240 membersf the Canadian Celiac Association shows that theOL in those with CD could be increased with earlyiagnosis, increased availability of gluten-free foods,mproved food labeling, and better dietary instruc-ion.139 Education of physicians and dieticians aboutD and its treatment is essential.

uture Prospectsrevention

There is some evidence suggesting that prevention ofD may be possible. One observation is that the levelf HLA-DQ2 expression is linked to the probability ofisease development: a double gene dose leads to an ateast fivefold increased risk.61,76 Usually children arexposed to high levels of gluten. The question is whatill happen when we lower the amount of gluten in theiet. It is conceivable that this may have a similarffect as the HLA-DQ2 gene dose: lower glutenxposure would decrease the risk to develop CD.pidemiological studies from Sweden suggest thatarly nutrition patterns may have a significant impactn the later risk of developing CD. The occurrence ofepidemics” of CD after changes in the Swedish infanteeding during the 1980s and 1990s suggested that the
isease may be preventable by improving early nutri- e

ion and inducing tolerance to gluten in predisposedndividuals. The “Swedish epidemic of CD” started in983 when gluten introduction was postponed fromonth 4 to 6 by changed national recommendations

or gluten introduction into the diet of young children.arefully performed studies exploring the epidemic inetail suggest that the causal factors of the epidemicere whether breastfeeding was ongoing or not whileluten was introduced and also the amount of glutenhen given.140,141 Thus, when introduction of gluten in983 was postponed, it also implied that more infantsad ended breastfeeding, and that gluten was intro-uced by larger amounts. Moreover, the epidemicubsided in1996 when gluten introduction was oncegain “allowed” from 4 months of age when more ofhe infants were still breastfed and gluten was intro-uced in smaller amounts. Thus, the Swedish studiestrongly support that ongoing breastfeeding during theeriod of gradual introduction of gluten-containingoods into the infant diet reduces the risk of symptom-tic CD.140,141 Based on an estimate of the attributableraction, half of the CD cases during the Swedishpidemic might have been avoided if all infants hadeen introduced to gluten in small amounts while stilleing breastfed. The latter finding opens the way toossible prevention strategies.It is possible that gradual introduction of antigensill lead to the development of oral tolerance.142,143 It

s also likely that the response of the immune systemo gluten may be modified by breastfeeding.144,145

everal studies have been performed in differenturopean countries on gluten consumption and breast-

eeding,143,146-150 but the methods used to assessluten intake were mostly time consuming and dif-ered from each other. An important American studyas published the findings on a cohort of 1560 childrenho had an increased risk of developing CD or type 1iabetes, as defined by possessing either HLA-DR3 orR4 alleles, or having a first-degree relative with typediabetes, derived from the Diabetes Autoimmunity

tudy in the Young project.150 At a mean follow-up of.8 years the authors concluded that (1) there is awindow of opportunity” of introducing gluten intohe diet when the child is aged between 4 and 6 monthsith regard to the risk of developing CD; and (2) that

he contribution of breastfeeding was to be disregardedn this respect. However, the authors did not makepecific attempts to calculate the gluten amount in-ested by the children or to correlate this important
arly nutrition event with the presence or absence of
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reastfeeding. A systematic review and a meta-analy-is of observational studies published between 1966nd June 2004 that examined the association betweenreastfeeding and the development of CD showed thatreastfeeding seemed to protect against CD.151 Pro-pective cohort studies may shed light on the impor-ance of the quantity of exposure to gluten in early lifen the development of CD.152 One problem in thisespect is that, until now, there were no validatednstruments to quantify gluten intake by young infants.he instruments available were work intensive, timeonsuming, and difficult to use in population studies.ecently we have developed and validated food fre-uency questionnaires for this purpose, using the-day food record as a reference (Hopman EG,iefte-de Jong JC, le Cessie S, et al., unpublishedata). This instrument may be used in collaborativetudies to assess the role of the quantity of glutenonsumption in the development of CD.The actual guidelines for infant nutrition recommend

ntroducing gluten into the diet no earlier than at thege of 6 months,153 and at this age, only a lowercentage of the children, ranging from 1 to 46% inhe different European countries, receive breastfeed-ng.154 On the other hand, the Swedish study onlynvestigated the effect of the early dietary history onymptomatic CD in children. It may be that theutritional factors only have an effect on the symp-oms of CD and/or on the time of presentations of theymptoms. In addition, there is no information on theiological mechanisms involved in the effect of earlyutrition in the development of CD. Prospective inter-ention nutritional studies in high-risk populations areecessary to provide parents with sensible advice torevent CD in their children.

afer Foods

Gluten is a complex mixture of proteins that containsmultitude of immunogenic peptides. This is becauseread wheat and pasta wheat are hexaploid andretraploid species, containing three and two entireheat genomes, respectively. These wheat varietiesave been selected for good crop yield and superioraking qualities. However, there are many wheatarieties and not all of those appear to be equally toxico patients.155 This offers two opportunities for theeneration of safer wheat strains. In addition, otherereals can be selected that do not contain harmfulluten or gluten-like molecules, like the Ethiopian
ereal tef.155
00

ovel Treatments?

A GFD is at present the only possible treatment forD children, but there are a number of drawbacks to a

ifelong diet. At present there are four options that cane explored, as follows: (1) Enzymatic degradation ofluten before it reaches the small intestine; (2) Block-ng of peptide binding to HLA-DQ2/8; (3) Blocking ofTG; (4) Blocking of IL-15.66 Of these four options,he latter two may be dangerous. tTG is important forhe maintenance of tissue integrity, while IL-15 isequired for normal functioning of the immune sys-em. The fist two options, however, may providepportunities. However, due to its high proline con-ent, gluten is resistant to enzymatic degradation. Oralupplementation with a postproline cutting enzymeas therefore been proposed as a potential way toestroy gluten before it can do damage in the smallntestine.156 Blocking HLA-DQ would also be highlyelective as it would block the gluten-specific T-cellesponse but would leave non-HLA-DQ-mediated T-ell responses intact. These two and other possibleptions deserve further study.

ractice Points

Celiac disease is a common, but frequently unrec-ognized disease. Consequently, celiac disease isseverely underdiagnosed.The health burden of celiac disease is considerable.Two important complications of celiac disease aremalignancy and osteoporosis.Recent population-based studies indicate that theincreased risk of malignancy associated with celiacdisease is less that previously thought.There is no need to perform bone mass measure-ment in children if fully compliant with the GFD.Celiac disease is strongly associated with geneticfactors coded by the HLA complex. Around 95% ofthe patients express HLA-DQ2 and most of theremainders express HLA-DQ8. The risk of devel-oping celiac disease in the absence of HLA-DQ2and/or HLA-DQ8 is very small.It is possible to use serological markers to identifyceliac disease with high sensitivity and specificity.The most useful are the IgA antibodies to EMA andto human tTGA.At the present time small bowel biopsy is the gold
standard for the diagnosis of celiac disease.

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CD should be considered early in the differentialdiagnosis of children with failure to thrive andpersistent diarrhea and in children with other per-sistent gastrointestinal symptoms in children withnongastrointestinal symptoms of CD and in condi-tions associated with CD.At present a GFD is the only effective treatment forceliac disease.Better medical and dietary support is necessary toprevent long-term complications and to achievesatisfying management in children and young pa-tients with celiac disease.

References1. Adams F. The extant works of Aretaeus the Cappadocian.

London: London Sydenham Society; 1856. p. 350.2. Gee SJ. On the coeliac affection. St. Bartholomew’s Hospital

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