Celiac Disease Among Children and Adolescents
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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
C by an inflammatory T-cell response to the
storage proteins in wheat (gliadin), rye (seca-
gluten ingestion and the symptoms of CD was discov-
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 bread 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
AD.1 He noted the characteristic stool and chronic Utrecht, he extended his research and demonstrated
nature of the condition and observed that children that gliadins, ie, the alcohol-soluble fractions of gluten
could also be affected by the disease. In 1888, Samuel (wheat protein), 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-
of the clinical features of childhood CD.2 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
with a banana diet,3 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 87FIG 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
Gastrointestinal Diarrhea Atrophy of the small
prospective national study of all the newly diag-
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
Failure to thrive during the last few years20 (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
Neurology Peripheral neuropathy Thiamine/vitamin
per 1000 live births in 1993 to 1.10 per 1000 live
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
hyperparathyroidism true worldwide,25,26 including the USA.17 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 2007FIG 3. Presenting clinical picture (% of symptoms) of childhood celiac disease in the Netherlands 1993 to 2000 (*P ⬍ 0.05).
TABLE 2. Some diseases associated with childhood celiac whole 1987 birth cohort (n ⫽ 60,254 births) showed
disease (CD)
a significant increased cumulative incidence of
Frequency
Disease
of CD (%)
Reference 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
Selective IgA-deficiency 2-3 Green 200311
common environmental denominator.29 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
Idiopathic pulmonary hemosiderosis ? Ertekin 200629
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 89tigated, 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 2007risk 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 91TABLE 3. Comparison of the distribution of the HLA-DR/DQ genotypes in Dutch children with celiac disease (CD) and in the Dutch general population
CD (n ⴝ 149) General population Relative risk RR
Risk for CD DR DQ genotype
(%) (n ⴝ 2307) (%) (95% CI)
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 ⬍ 0.05.
**DRX DQX ⫽ not DR3DQ2, DR4DQ8, DR5DQ7, or DR7DQ2. DRY DQY ⫽ DR7DQ2 of DRXDQX. DRZ DQZ ⫽ 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.
Gluten
Although the association between CD and another
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 CD4⫹ 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 2007to 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
gluten-specific T-cell response in CD and revealed that MICA expression in biopsies of patients.77,78 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-
as well as glutenins. However, some peptides are immu- derived T-cell epitopes by lamina propria CD4⫹
nodominant; in particular, a proline-rich stretch in alpha- T-cells.79 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
cross-react with those homologous peptides in these epithelial target of this receptor on enterocytes, the
other cereals.76 MHC Ib molecule MICA.78-81
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
circle is initiated that is driven by gluten intake.76 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 93TABLE 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 2007FIG 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 95petiformis, 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 2007the 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-
on a GFD.88 tivity and limit of detection (1.5 ppm gliadin), which is
Initially, oats were considered to be harmful for CD superior to older methods of detection.114 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-
to provide them with up-to-date facts about a GFD.
able.112 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 and the American Celiac Sprue Association (www.
patients with CD.113 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 97adequate 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 2007complaints. 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-
Prevention feeding,143,146-150 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
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