Celiac Disease Among Children and Adolescents pot

Celiac Disease Among Children and Adolescents
M. Luisa Mearin, MD, PhD
C
eliac disease (CD) is a chronic disorder caused
by an inflammatory T-cell response to the
storage proteins in wheat (gliadin), rye (seca-
lin), and barley (hordein), which are collectively called
“gluten” and characterized by the presence of typical
autoantibodies and histological alterations of the small
bowel mucosa. Genetic, immunological, and environ-
mental factors are necessary for the expression of the
disease. Ingestion of gluten by genetically predisposed
people precipitates an uncontrolled T-cell-driven in-
flammatory response that leads to disruption of the
structural and functional integrity of the small bowel
mucosa. CD is treated with a gluten-free diet (GFD),
which leads to resolution of the clinical disease and
restoration of the histological abnormalities. CD was
once thought to be a rare condition, but at the present
time it is accepted that CD is the most common form
of food hypersensitivity in children and adults.
The first description of CD is attributed to Aretaeus
the Cappadocian, who lived in the second century
AD.
1
He noted the characteristic stool and chronic
nature of the condition and observed that children
could also be affected by the disease. In 1888, Samuel
Gee, a physician working at the St. Bartholomew
Hospital in London, provided a thorough description
of the clinical features of childhood CD.

2
During the
first half of the past century, it was generally agreed
that the treatment for CD was rest and diet. In 1924
Sidney Haas described his treatment of childhood CD
with a banana diet,
3
but there was hardly any form of
diet not frequently discussed at that time as a treatment
for the disease. However, the relationship between
gluten ingestion and the symptoms of CD was discov-
ered by the Dutch pediatrician Willem-Karel Dicke
(1905-1962).
4
He became the medical director of the
Juliana Children’s Hospital in The Hague (The Neth-
erlands) at the age of 31. Long before the start of the
Second World War (1934-1936) he started experi-
ments with wheat-free diets. At the end of World War
II, during the 1944-1945 winter of starvation, the
delivery of normal food such as bread to his young
patients in his hospital was endangered. This period
and dietary studies convinced him even more that
eating less cereals and more uncommon food products
such as tulip bulbs improved the clinical condition of
his patients and that a wheat-free diet had favorable
effects on children with CD. After World War II, in
collaboration with Van de Kamer, a biochemist from
the Netherlands’ Central Institute for Nutritional Re-
search TNO in Utrecht, and with Weyers, a pediatri-

cian from the Wilhelmina Children’s Hospital in
Utrecht, he extended his research and demonstrated
that gliadins, ie, the alcohol-soluble fractions of gluten
(wheat protein), produced fat malabsorption in pa-
tients with CD.
5
His experiences with the wheat-free
diet were at first published in “Het Nederlands Tijd-
schrift voor Geneeskunde” (Dutch Journal of Medi-
cine) in 1941.
6
In his PhD dissertation, published in
1950, he described a dietary study over a period of
several years at the Juliana Children’s Hospital in
patients with CD.
7
In his PhD thesis Dicke wrote:
“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
patient” (chapter 3: treatment with a diet free of corn).
Dicke refers to a child with CD who went through
three attacks of “gastrointestinal catarrh” after eating
corn-containing products during a stay in the hospital.
This observation was presented by Dr. Stheemann (the
supervisor of Dicke in The Hague) in The Medical
Society of The Hague in 1932. Van Dusseldorp would
From the Department of Pediatrics, Leiden University Medical Center
and Free University Medical Center, Amsterdam, The Netherlands.
The author has no commercial interest in the subject and no financial

relationships or other relationships that would contribute to a conflict
of interest.
Curr Probl Pediatr Adolesc Health Care 2007;37:86-105
1538-5442/$ - see front matter
© 2007 Mosby, Inc. All rights reserved.
doi:10.1016/j.cppeds.2007.01.001
86 Curr Probl Pediatr Adolesc Health Care, March 2007
succeed Dicke as one of the first women directors of a
Hospital in The Netherlands.
A few years after Dicke’s discovery, the advent of
the peroral intestinal mucosal biopsy led to confirma-
tion of the characteristic intestinal histopathology of
CD.
8
Clinical Spectrum and the Iceberg of
CD
CD occurs largely in Caucasians. The disease has
been well documented in Asians from India, Pakistan,
and Iran,
9
but it is rare or nonexistent among native
Africans, Japanese, and Chinese. Using simple sero-
logical tests, it has gradually become clear that the
prevalence of CD in different countries in the Middle
East, North Africa, and India where wheat has been
the major staple food for many centuries is almost the
same as that in Western countries. Clinical studies
showed that presentation with nonspecific symptoms
or no symptoms is as common in the Middle East as it
is in Europe. A high index of suspicion for CD should

be maintained in all developing countries for patients
who present with chronic diarrhea or iron-deficiency
anemia.
10
CD is a common, but frequently unrecognized,
disease. The disease is more frequent among females,
with a female-to-male ratio of 2-3:1. Screening studies
have shown that CD is severely underdiagnosed, with
a prevalence of 0.5 to 1% among the white popula-
tion,
11
both in adults
12,13
and in children.
14-16
Assum
-
ing a conservative prevalence of 0.5%, this corre-
sponds to about 2.5 million CD cases in Europe.
Approximately 85% of these cases are unrecognized
and thus also untreated. Findings from mass screening
studies in the USA show a prevalence of the disease
similar to that reported in Europe and suggest that CD
is a much greater problem in the United States than has
previously been appreciated.
17
CD is also a frequent
condition in South America, as shown by the preva-
lence of undiagnosed CD of 1:681 among apparently
healthy blood donors in Brazil

18
and of 1:167 among
the general urban population in Argentina, presenting
with a heterogeneous clinical picture and a predomi-
nance of asymptomatic cases.
19
CD is frequently unrecognized by physicians, in part
because of its variable clinical presentation and symp-
toms.
20
CD is easily diagnosed in children with a
symptomatic malabsorption syndrome, but most of the
children with CD do not have malabsorption and the
clinical picture at presentation is very variable. Not all
CD patients are equal. While some develop CD very
early in life, others may eat gluten for many years
before the disease becomes apparent. The clinical
picture of CD is very heterogeneous with a broad
spectrum of symptoms, from malabsorption, chronic
diarrhea, and failure to thrive (the classic “triad”) to
abdominal pain, lassitude, iron-deficiency anemia, de-
layed puberty, nonspecific arthritis, depression, ataxia,
low bone mineral density, or dental enamel hypoplasia
without gastrointestinal complaints.
11,20
This hetero
-
geneity in the clinical presentation is one of the causes
of poor diagnosis of the disease. At present it is not
known what causes these differences in the clinical

expression of CD, but there is some evidence that both
genetic and environmental factors may be in-
volved.
21,22
The relationship between the different
HLA-DR and -DQ haplotypes of the children with CD
and their clinical presentation has been thoroughly
investigated. Some researchers have found a signifi-
cant relationship between the gene dose effect and the
heterogeneity of the clinical disease,
21-23
but others
have not noted an association.
24
Congia and cowork
-
ers
22
found that a double dose of DQ2 (
␣
1*0501,
␤
1*0201) predisposes for an early onset and more
severe disease manifestations. The differences in out-
come can be partially explained by the fact that, for
statistical analysis in this latter study, the groups were
divided in double-, single-, or no-dose HLA-DQ2, and
the authors also limited the phenotypic distribution to
fully expressed disease versus mono-/oligosymptom-
atic. We have recently shown that children with the

DR3DQ2-DR5DQ7 and DR5DQ7-DR7DQ2 genotype
are presented with CD at an earlier age and have a
more severe clinical picture, which suggests a link
between the genotype and phenotype. A correlation
between disease severity and the HLA-DQ2 gene dose
was not observed (Vermeulen B, Hogen Esch C,
Yuksel Z, et al., unpublished data). It is possible that
other, non-HLA genetic factors also play a role in the
different phenotypic expression of CD.
The iceberg is a model frequently used to explain the
clinical spectrum of CD (Fig 1).
● The tip of the iceberg is formed by the children
with clinically diagnosed CD, among others,
those with clear gastrointestinal symptoms such
as chronic diarrhea and malabsorption (Table 1),
those with so-called “classic CD.” The symptoms
Curr Probl Pediatr Adolesc Health Care, March 2007 87
start typically after the introduction of gluten into
the diet of babies or toddlers, but they may also
present later in life. The severe clinical condition
in young children, known as “celiac-crisis,” ac-
companied by skin bleeding, hypocalcemic tet-
any, hypoalbuminemia, and edema is nowadays
very rare.
● In the Netherlands, as in most countries, the major-
ity of CD diagnoses are in children with the
“classic” symptoms. However, the results of a
prospective national study of all the newly diag-
nosed cases of CD throughout the country from
1993 to 2000 show that the recognition of childhood

CD in the Netherlands has increased significantly
during the last few years
20
(Fig 2),
and that the
clinical picture has changed as well with a decrease
in the frequency of “classic” symptoms (Fig 3). The
overall crude incidence rate of CD for 1993 to 2000
was 0.81/1000 live births. We found a significant
linear increase of the crude incidence rate from 0.55
per 1000 live births in 1993 to 1.10 per 1000 live
births in 2000. From 1996 onward, there was a
greater increase in incidence of CD among children
older than 2 years than among the younger children.
● This increasing frequency of diagnosis seems to be
true worldwide,
25,26
including the USA.
17
An open
question is whether the increase in diagnosed child-
hood CD is due to more children developing CD or
whether it reflects a greater awareness of the disease
among the physicians who increasingly recognize
more subtle expressions of the disease.
● Under the water level in the CD iceberg, we find the
children with unrecognized or nondiagnosed CD.
These children have the typical CD histological
alterations in their small bowel mucosa and they
may or may not have health complaints or symp-

toms. In the Netherlands, for every child with
diagnosed CD, there are at least seven children with
unrecognized CD.
15
Identification of these children
FIG 1. The iceberg of celiac disease.
TABLE 1. Some clinical manifestations of celiac disease in children
and adolescents
System Manifestation (Possible) Cause
Gastrointestinal Diarrhea
Distended abdomen
Vomiting
Anorexia
Weight loss
Failure to thrive
Aphthous stomatitis
Atrophy of the small
bowel mucosa
Malabsorption
Hematology Anemia Iron malabsorption
Skeleton Rachitis
Osteoporosis
Enamel hypoplasia of the
teeth
Calcium/vitamin D
malabsorption
Muscular Atrophy Malnutrition
Neurology Peripheral neuropathy
Epilepsy
Irritability

Thiamine/vitamin
B12 deficiency
Endocrinology Short stature
Pubertas tarda
Secondary
hyperparathyroidism
Malnutrition
Calcium/vitamin D
malabsorption
Dermatology Dermatitis herpetiformis
Alopecia areata
Erythema nodosum
Autoimmunity
Respiratory Idiopathic pulmonary
hemosiderosis
FIG 2. Frequency of diagnosis of childhood celiac disease in
the Netherlands.
88 Curr Probl Pediatr Adolesc Health Care, March 2007
after mass screening programs in the general pop-
ulation in different countries has shown that about
0.5 to 1% of the children have CD
14-16
and that CD
is the most common form of food intolerance in
children, adolescents, and adults. Children with
unrecognized CD may be asymptomatic, but they
frequently have symptoms such as chronic abdom-
inal pain or lassitude that is frequently a cause of
consultation with a pediatrician. CD may also be
unrecognized if it is associated with other, fre-

quently autoimmune diseases such as type 1 diabe-
tes mellitus, anemia, arthritis, and osteoporosis even
in the absence of gastrointestinal symptoms
11
(Ta
-
ble 2). A link between CD and asthma has been
supported by some studies but not by others. Greco
and coworkers found no difference in the preva-
lence of atopy in cases affected by CD and their
relatives compared with controls and their rela-
tives.
28
On the other hand, an important study on
the Finnish Medical Birth Register data of the
whole 1987 birth cohort (n ϭ 60,254 births) showed
a significant increased cumulative incidence of
asthma in children with CD (24.6%) than in chil-
dren without CD (3.4%) during the first 7 years of
life, indicating that TH1 and TH2 immunological
mediated diseases can coexist and may have a
common environmental denominator.
29
Another as
-
sociated disease is idiopathic pulmonary hemosider-
osis, a rare condition of unknown autoimmune
etiology mainly affecting children and adolescents,
in which a GFD may be very effective for the
regression 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 in
adults,
31
but with a much lower frequency in
childhood CD.
32
Down syndrome is strongly asso
-
ciated with CD,
33
and to a lesser degree, Turner’s
syndrome is associated with the disease.
34
Under
-
diagnosis is common in children with Down syn-
drome and we found only two cases of Down
syndrome among 225 children with CD diagnosed
in the Netherlands between 1975 and 1990, while
CD was identified by screening in 7% of the
children with Down syndrome in the same area.
35
The health complaints present in children with
Down syndrome and CD are frequently and repeat-
edly attributed to Down syndrome, but in most of
the children the health status improves after a GFD.
Another possible manifestation of CD is short

stature. In two British population-based studies on
short stature, where CD was not specifically inves-
FIG 3. Presenting clinical picture (% of symptoms) of childhood celiac disease in the Netherlands 1993 to 2000 (*P Ͻ 0.05).
TABLE 2. Some diseases associated with childhood celiac
disease (CD)
Disease
Frequency
of CD (%)
Reference
Down’s syndrome 8-15 Csizmadia 2000
32
Turner’s syndrome 5-7 Ivarsson 1999
33
Diabetes mellitus type I 2-8 Green 2003
11
Auto-immune hepatitis 5 Green 2003
11
Selective IgA-deficiency 2-3 Green 2003
11
Auto-immune thyroidisme 5-6 Ansaldi 2003
27
Dermatitis herpetiformis ? Lemberg 2005
31
Idiopathic pulmonary hemosiderosis ? Ertekin 2006
29
Curr Probl Pediatr Adolesc Health Care, March 2007 89
tigated, the prevalence of CD was 2:180
36
and
0:149,

37
respectively. In children with short stature
and no gastrointestinal symptoms investigated for
CD, the prevalence increases to 2 to 8%. When
other (endocrine) causes for short stature are ex-
cluded, the prevalence could rise to 59%.
38
● CD may be asymptomatic both above and below the
water level of the CD iceberg, for example, among
family members of CD patients (approximately 3 to
10% asymptomatic)
39
and among young children
with CD identified by mass screening (approxi-
mately 50% asymptomatic).
15
Normal growth does
not exclude CD in children as it was demonstrated
in a mass screening program in the Netherlands: all
the children from the general population identified
with CD had normal growth for both weight and
height.
15
● The bottom of the CD iceberg is formed by the
children with the genetic predisposition for CD who
may or may not develop CD during their lives.
Complications of CD
CD is an important health problem for the individual
and the community, because of its high prevalence,
association with nonspecific morbidity, and long-term

complications.
The health burden of CD is considerable. CD is an
immune-mediated disease that can affect any organ.
11
The broad spectrum of symptoms varies considerably
between children and within a single child over time,
often resulting in delayed or missed diagnosis. Many
undiagnosed children accept a chronic state of vague
ill health as normal. Paradoxical constipation and
symptoms more typical of peptic or reflux disease are
common.
40
Health problems due to untreated CD
include anemia, delayed puberty, elevated serum
transaminases, depression, epilepsy with cerebral cal-
cifications, low bone mineral density, and dental
enamel hypoplasia. CD subjects also have an in-
creased risk for other autoimmune diseases, depending
on the duration of gluten exposure.
41
Two severe eventual complications of CD are ma-
lignancy and osteoporosis.
CD and Malignancy. In adults, CD has been con-
sidered a premalignant condition, which could
progress to lymphoma.
42
Evidence that treatment of
CD with a GFD might reduce the risk of malignancy
was established by Holmes and coworkers.
43

In adults,
increased frequency for lymphoma (6%),
44
small
bowel adenocarcinomas, and esophageal and oropha-
ryngeal squamous carcinomas
45
have been described.
However, these prevalence figures represent probably
an overestimation of the frequency of malignancy in
CD since the studies were performed in centers for
CD. Recent population-based studies indicate that the
increased risk of malignancy associated with CD is
less than previously thought with an odds ratios (OR)
for non-Hodgkin lymphoma of 2.6 to 6.3.
46-48
There is
a form of cancer, the enteropathy-associated T-cell
lymphoma (EATL), with a very high association with
CD, but this in general is a rare condition with an
absolute risk of only 1:1000 based on the local
prevalence of CD.
49
Small bowel lymphoma and
EATL are very rare diseases, but CD is the most
important risk factor for these conditions.
An inquiry among the members of ESPGHAN found
25 cases of children with cancer and CD, suggesting
that an association between CD and cancer in child-
hood is not likely,

50
but it showed also that the
combination of cancer and CD in childhood is under-
reported. The children described with CD and cancer
were found only through a limited number of highly
specialized pediatricians in Europe. Six of the 25
children reported had malignant disease localized in
the small bowel [4 of them a non-Hodgkin lymphoma
(NHL)], suggesting that in children and adults there is
an association between CD and small bowel malig-
nancy. However, NHL is a common cancer in child-
hood and small bowel localization frequently occurs.
To get more data on this subject, the importance of
reporting all cases of CD and cancer in children to the
literature should be stressed.
The role of the pediatrician in counseling the parents
of a child with CD regarding the long-term risks of
cancer should be to reassure them, since, in the big
series of CD complicated by cancer, there were no
patients in whom CD has been diagnosed during
childhood CD,
46-48
suggesting that the association of
childhood CD with cancer may be very low.
Osteoporosis. Osteoporosis is characterized by a low
bone mass with an increase in bone fragility and
susceptibility to fracture.
51
Intestinal malabsorption
may cause loss of bone mass and mineral metabolism

alteration. In CD the main mechanisms of osteoporosis
are malabsorption and the production of proinflamma-
tory cytokines, activating osteoclasts. Osteoporosis
may complicate CD, in both adults
52
and children
53
and it is mostly present in patients with overt malab-
sorption at diagnosis, but it may also be present in
subclinical or in asymptomatic CD.
54
However, the
90 Curr Probl Pediatr Adolesc Health Care, March 2007
risk of bone fracture in CD seems to be lower that
previously presumed.
55
Bone density improves after following a GFD,
56,57
but in adult CD this improvement does not reach the
normal sex- and age-matched values for the control
population. In contrast, in childhood CD with a very
early treatment, gluten exclusion prevents bone loss
and most children reach a normal bone mass.
58
This
discrepancy can be explained by the fact that bone loss
has an irreversible component (disappearance of tra-
beculae and thinning of the cortex) and a reversible
component (increased intracortical tunneling, thinning
of trabeculae). While late treatment in adulthood may

revert only the reversible bone loss, very early treat-
ment during infancy could prevent both the irrevers-
ible and the reversible bone loss.
58
Consequently,
there is no need to perform bone mass measurement in
children if fully compliant with GFD.
54
The question
is weather bone mass should be assessed at diagnosis
in cases of subclinical or silent disease in older
children. Following the advice for adult CD, the
evaluation of bone mass after the first year of strict
adherence to GFD seems to be of more clinical use,
since the treatment with mineral-active drugs may be
started on the basis of the results of gluten exclusion.
Risk factors for fractures have not been specifically
identified in CD, but are likely to include, in addition
to noncompliance with GFD, steroid treatment, un-
treated hypogonadism, age, low body mass index, and
previous fragility fracture.
54
The role of lifestyle
factors should be not underestimated in the prevention
of osteoporosis and adolescent patients with CD
should be encouraged to follow a calcium-rich diet, to
maintain a high level of exercise, and to stop
smoking.
54
Genetics, Gluten, and Immunology

CD is a familial disorder: first-degree relatives of CD
patients have an increased risk of 5 to 10% of
developing the disease.
57
Twin studies are very useful to assess the genetic and
environmental components to disease susceptibility.
Both monozygotic and dizygotic twin pairs share the
same environmental factors, but differ by sharing 100
and 50% of genetic variability, respectively.
59
In CD the
concordance in monozygotic twins is approximately
83% and this is only 17% in dyzygotic twins.
60
By way
of comparison monozygotic concordance rates are 25%
in multiple sclerosis, 36% in type I diabetes, and in 33%
in Crohn’s disease, showing that CD has one of the
highest concordance rates of the complex multifactorial
diseases.
59
The sibling relative risk (RR, defined as the
risk for CD to a sibling of a CD patient divided by the
risk for CD in the general population) is also useful to
measure the heritability of CD. Population studies esti-
mate sibling RR for CD between 30 and 48, also
suggesting a stronger genetic component in CD than in
many other complex diseases.
59
The Human Leukocyte Antigen (HLA)

Complex
CD is strongly associated with genetic factors
coded by the HLA complex, which occupies a 4-Mb
region on chromosome 6p21 and contains some 200
genes of which over half are known to have immu-
nological function.
60
Around 95% of patients with
CD express HLA-DQ2 (
␣
1*0501/
␤
1*0201), either
in the cis- (encoded by HLA-DRB1*03-DQA1*05-
DQB1*03) or in the trans- (encoded by HLA-
DRB1*11/12-DQA1*05-DQB1*0301/DRB1*07-DQA1
*0201-DQB1*02) configuration and most of the re-
mainder express HLA-DQ8 (
␣
1*0301/
␤
1*0302) en-
coded by HLA-DRB1*04-DQA1*03-DQB1*0302,
showing that the chance to develop CD in absence of
HLA-DQ2 and/or HLA-DQ8 is very small
61
(Table
3). However, HLA-DQ2 and DQ8 are frequently
present in the white population (approximately 30%),
implying that HLA-DQ2 and DQ8 are very important,

but not enough, to explain the genetics of CD. This
knowledge has triggered the search for other non-HLA
genetic variants predisposing to CD, but currently no
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
exogenous peptide antigens (in CD gluten peptides) to
helper T-cells. The strong relationship between the
HLA genetic factors and CD is illustrated by the
impact of the HLA-DQ2 gene dose on the chance of
disease development: HLA-DQ2 homozygous individ-
uals have an at least five times higher risk of disease
development compared with HLA-DQ2 heterozygous
individuals.
62,63
It is likely that the large HLA effect
size is related to the essential permissive role of DQ2
peptide presentation in disease pathogenesis. The level
of HLA-DQ2 expression influences the magnitude of
the gluten-specific T-cell response: it has been dem-
onstrated that gluten presentation by HLA-DQ2 ho-
Curr Probl Pediatr Adolesc Health Care, March 2007 91
mozygous antigen-presenting cells is superior to pre-
sentation by HLA-DQ2/non-DQ2 heterozygous
antigen-presenting cells and this correlates with the
risk of disease development.
64
The question is if there
may be additional alleles in the HLA region in
addition to DQ2 and DQ8 that confer risk for CD.

Although the association between CD and another
HLA gene, such as and TNF and MICA, may be
explained by the linkage disequilibrium across the
HLA; at the moment there is no evidence for addi-
tional HLA risk factors.
Genome-Wide Linkage Studies
Several genome-wide searches have been performed
in CD. Genome-wide linkage studies aim to identify
broad genomic regions that contain disease-predispos-
ing variants and are successful to identify loci for
monogenic disorders (eg, cystic fibrosis, hemochroma-
tosis), but they are less useful to identify loci in the
more common polygenic diseases.
Outside the HLA region there are at least three
genomic areas related to CD: CELIAC2 on 5q31 to 33,
CELIAC3 on 2q33, and CELIAC4 on 19p13. From
two of these regions the responsible genes have been
identified: CTLA4 on 2q
65
and Myosin IXB on 19p,
66
but their mode of action is unclear.
T-lymphocyte regulatory genes CD28, CTLA4, and
ICOS are found in a 300-kb block of chromosome
2q33. All three genes control different aspects of the
T-cell response, and their close genetic proximity
likely allows for integrated control of expression.
59
Chromosome 6q21-22 (distinct from the HLA) has
been reported to be related to CD in type I diabetes,

rheumatoid arthritis, and multiple sclerosis and it is
possible that a common variant at this locus might
predispose to autoimmune diseases in general (as
demonstrated by the HLA A1-B8-DR3-DQ2 haplo-
type).
59
Newer methods including gene expression analysis
will provide further insight in the genetic susceptibility
for CD.
Gluten
Gluten, the antigenic protein mixture for CD pa-
tients, present in wheat and related cereals, is the
water-insoluble material in wheat flour that gives
dough its elasticity. The major components are the
glutenins and the gliadins, both representing complex
families of proteins (Koning F, Mearin ML. Manu-
script submitted for publication, 2006). In a single
wheat variety dozens of distinct gluten proteins are
found.
67
Gluten contains a high amount of the amino
acid proline, which renders gluten resistant to degra-
dation in the gastrointestinal tract. Together with the
fact that gluten is a very much used protein in the food
industry—the daily consumption of gluten is estimated
to be between 10 and 15 g—this indicates that gluten
exposure is high and continuous.
Immunology
In celiac patients, gliadin and glutenin peptides are
presented by HLA-DQ2 or -DQ8 expressed on anti-

gen-presenting cells to gluten-specific CD4ϩ T-cells.
This generates a mixed Th0 and Th1 response. Anti-
genic protein fractions (peptides) binding to HLA is in
part mediated by interactions between particular
amino acids in the bound peptide and pockets in the
HLA molecule. In the case of HLA-DQ2 and -DQ8 it
is well established that negatively charged amino acids
are required for these interactions.
68,69
As gluten
contains very few negatively charged amino acids,
gluten peptides were therefore predicted to poorly bind
TABLE 3. Comparison of the distribution of the HLA-DR/DQ genotypes in Dutch children with celiac disease (CD) and in the Dutch general population
Risk for CD DR DQ genotype
CD (n ؍ 149)
(%)
General population
(n ؍ 2307) (%)
Relative risk RR
(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 Ͻ 0.05.

**DRX DQX ϭ not DR3DQ2, DR4DQ8, DR5DQ7, or DR7DQ2. DRY DQY ϭ DR7DQ2 of DRXDQX. DRZ DQZ ϭ DR4DQ8 or DRXDQX.
92 Curr Probl Pediatr Adolesc Health Care, March 2007
to HLA-DQ2 and -DQ8. This paradox was solved by
the observation that the enzyme tissue transglutami-
nase (tTG) can convert the amino acid glutamine in
gluten into glutamic acid, which introduces the nega-
tive charge(s) required for strong binding to HLA-
DQ2/8.
70,71
Several studies have investigated the specificity of the
gluten-specific T-cell response in CD and revealed that
polyclonal T-cell responses to multiple gluten peptides
are almost invariably found in patients.
72,73
Most re
-
sponses are specific for tTG-modified gluten peptides.
These peptides can be derived from all types of gliadins
as well as glutenins. However, some peptides are immu-
nodominant; in particular, a proline-rich stretch in alpha-
gliadin is found in the large majority of patients, while
other peptides are less frequently recognized.
74,75
Similar
peptides are found in the gluten-like molecules in barley
and rye and T-cells specific for gluten peptides can
cross-react with those homologous peptides in these
other cereals.
76
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
repair and approximately 40% of the white population
expresses HLA-DQ2 and/or -DQ8 and only 1% de-
velop CD. Therefore, it is possible that, although
enhanced by tTG modification, gluten is in itself
immunogenic. One proposed model for the pathogen-
esis of CD states that tTG drives the diversification of
the gluten-specific T-cell response: once a gluten-
specific T-cell response is initiated, the accompanying
tissue damage will lead to the release of intracellular
tTG which, in turn, allows the generation of additional
gluten peptides that can trigger T-cell responses, more
tissue damage, more T-cell activation, etc. A vicious
circle is initiated that is driven by gluten intake.
76
In a healthy situation the role of the intestinal
mucosal immune system is the maintenance of toler-
ance and, even though HLA-DQ2 and/or -DQ8-posi-
tive individuals are prone to the development of
gluten-specific T-cell responses, such responses will
generally be suppressed. However, stress situations,
like, for example, intestinal infections, would force the
immune system to raise an inflammatory response
accompanied by the production of IFN
␥
. This would
increase the HLA-DQ expression and, combined with
the fact that due to the high gluten intake gluten
peptides are almost continuously present in the intes-

tine, and that inflammation can raise tTG levels, this
may lead to a situation where gluten specific T-cell
responses are initiated instead of suppressed.
66
In addition, it has also been shown that gluten
activates the innate immune system. A particular
␣
-gliadin peptide, p31-43, which is not known to bind
to HLA-DQ2/8 and stimulate T-cells, has been shown
to upregulate natural killer cells (NKG2D) and induce
MICA expression in biopsies of patients.
77,78
The
cytokine IL-15 appears to be a key factor in the
inflammatory intestinal response in CD. IL-15 pro-
motes the maturation of intestinal dendritic cells and
might stimulate the recognition of gluten-peptides-
derived T-cell epitopes by lamina propria CD4ϩ
T-cells.
79
In addition, IL-15 stimulates the effector
properties of intra epithelial lymphocytes (IEL), their
synthesis of
␥
-interferon, and their cytotoxicity and
can license IEL to kill enterocytes by signaling deliv-
ered by their NKG2D receptor and by inducing the
epithelial target of this receptor on enterocytes, the
MHC Ib molecule MICA.
78-81

Diagnosis
In 1970 the European Society for Pediatric Gastro-
enterology, Hepatology, and Nutrition (ESPGHAN)
established the criteria for the diagnosis of CD in
childhood, based on the recovery of the characteristic
histological alterations of the small intestinal mucosa
after following a GFD and on the histological relapse
following a gluten-challenge (the reintroduction of
gluten into the diet).
82
At least three small intestine
biopsies (SIB) were necessary to diagnose CD. Cur-
rently SIB is still the gold standard for the diagnosis of
CD. SIB can be taken blindly with peroral suction
biopsy tubes or at the time of upper endoscopy from
descending duodenum
83
: both techniques are consid
-
ered relatively safe.
84
Because the intestinal lesions in
CD may be patchy, it is recommended that multiple
biopsy specimens be obtained. In 1990 a working
group of the ESPGHAN published revised criteria for
the diagnosis of childhood CD based on a retrospec-
tive study of the diagnosis procedure in a large group
of celiac children.
85
According to the revised criteria,

gluten-challenge should only be necessary in those
children who were younger than 2 years when the first
SIB was performed. In this group of young children a
number of diseases other than CD may produce
histological small intestinal alterations similar to the
typical CD lesions (Table 4). However, in some cases
Curr Probl Pediatr Adolesc Health Care, March 2007 93
gluten-challenge may be needed to prove the necessity
of continuing lifelong GFD or to confirm the diagnosis
in those patients on a GFD who did not have a
diagnostic SIB.
The typical histological lesion of the SIB of a celiac
child eating gluten is the subtotal villous atrophy with
elongated and hypertrofic crypts and a chronic inflam-
matory infiltration in the mucosa (Fig. 4). The lamina
propria contains an increased number of lymphocytes,
plasma cells, and some eosinophils and histiocytes.
The crypts contain an increased number of cells in
mitosis, Paneth cells, and argentaffin cells. There is a
reduction in the number of goblet cells and an in-
creased number of intraepithelial gamma/delta T-
lymphocytes. A widely used classification of the
histological alterations in CD was introduced by
Marsh in 1992 and it ranges from type 0 (Marsh 0) to
Marsh type 4
86
:
● Type 0 concerns the normal stage of the small
bowel mucosa.
● Marsh type 1 or infiltrative lesion comprises normal

mucosal architecture in which the villous epithe-
lium is infiltrated by small, nonmitotic intraepithe-
lial lymphocytes and it is characteristically present
in first-degree relatives of children with celiac
disease.
87
● Type 2, or hyperplasic lesion, consists of a type 1
lesion with enlarged crypts.
● Marsh type 3 or destructive lesion is synonymous
with the typical flat mucosa of CD and it is
subclassified according to the different degrees of
villous atrophy present: Marsh type 3a, with partial
villous atrophy; Marsh type 3b, in the presence of
subtotal villous atrophy; and Marsh type 3c, when
total villous atrophy is present.
88
● Marsh type 4 or hypoplastic lesion (total villous
atrophy with crypt hypoplasia) represents the ex-
treme end of the gluten-sensitivity spectrum and an
irreversible lesion is present in some adult CD
patients whose small bowel mucosa is unresponsive
to gluten withdrawal: the so-called refractory CD.
Marsh type 3 is accepted as a clear feature of CD,
but whether the hyperplasic changes of Marsh type
2 lesions should be considered as distinctive for CD
is still controversial.
In addition to the small intestine alterations, a
lymphocytic gastritis has been described in CD.
89
Serology Tests in the Diagnosis of CD

For more than 25 years it has been possible to use
serological markers to identify CD with high sensitiv-
ity and specificity. The most useful are the IgA
antibodies to endomysium (EMA) and to human tissue
transglutaminase (tTGA). The EMA is an immunoflu-
orescence test that requires expertise in the subjective
interpretation of the results and the use of monkey’s
primate esophagus or human umbilical cord as sub-
strate.
90
According to the evidence Report/Technol
-
ogy Assessment performed by the Agency for Health-
care Research and Quality in 2004, the determination
of EMA has a high sensitivity for CD of approxi-
mately 90% and a very high specificity approaching
100%.
91
The titer of EMA correlates with the degree
of mucosal damage; accordingly, the sensitivity in-
creases with higher prevalence of subtotal villous
atrophy in the CD population studied.
92
The recognition of the enzyme tTG as the sub-
strate for the EMA formed the basis for the devel-
opment of an enzyme-linked immunoassay (ELISA)
for the determination of tTGA.
93,94
Assays using
human tTG, either recombinant or derived from

human red cells, have better results than these using
guinea pig tTG.
95
The sensitivity of tTGA is greater
than 90%, but the specificity is lower than the one of
the EMA.
91
It has been shown that TGA results may
be positive in other diseases different from CD, such
as in type 1 diabetes, chronic liver disease, or
rheumatoid arthritis, although small bowel biopsy
was not always performed to exclude CD in the
cases described.
96
A controlled European multi
-
center study performed in biopsy-proven CD cases
and control with other diseases different from CD
controls to evaluate the value of IgA antibody
measurement to human recombinant tTG in compar-
ison to IgA-EMA in the diagnosis of CD found that
tTGA measurement were effective and at least as
good as EMA in the case-finding of CD.
97
Consid
-
ering the time it spares, the quantitative character of
TABLE 4. Some enteropathies different from celiac disease that may
cause villous atrophy of the small bowel gastroenteritis and
postenteritis syndromes

Giardiasis
Cow’s milk protein allergy
Autoimmune enteropathy
Immunodeficiencies
HIV/AIDS
Tropical sprue
Protein energy malnutrition
94 Curr Probl Pediatr Adolesc Health Care, March 2007
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?
The availability of such sensitive and specific sero-
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
be tested for CD. Nowadays, these serological tests are
advised for active case-finding, among children who
seek medical advice for health problems that suggest
CD (Table 1). Targeted screening is also widespread,
aiming at high-risk groups such as relatives of CD
patients or individuals with associated conditions like
type I diabetes mellitus or Down syndrome (Table 2).
According to the official recommendations of the
North American Society for Pediatric Gastroenterol-
ogy, Hepatology and Nutrition on the diagnosis and
treatment of CD in children and adolescents, CD
should be considered early in the differential diagnosis
of children with failure to thrive and persistent diar-
rhea. In addition, it is recommended that CD be
considered in the differential diagnosis of children
with other persistent gastrointestinal symptoms, in-
cluding recurrent abdominal pain, constipation, and
vomiting. Testing is recommended for children with
nongastrointestinal symptoms of CD (dermatitis her-
FIG 4. Characteristic subtotal villous atrophy of the small bowel mucosa in a child with celiac disease consuming gluten (A) and
improvement of the histological lesions after gluten-free diet (B). (Color version of figure is available online.)
FIG 5. Flowchart for the diagnosis of celiac disease. (Color
version of figure is available online.)
Curr Probl Pediatr Adolesc Health Care, March 2007 95
petiformis, dental enamel hypoplasia of permanent
teeth, osteoporosis, short stature, delayed puberty, and
iron-deficient anemia resistant to oral iron). Testing is
also recommended for asymptomatic children who
have conditions associated with CD (type 1 diabetes

mellitus, autoimmune thyroiditis, Down syndrome,
Turner syndrome, Williams syndrome, selective IgA
deficiency, and first-degree relatives of celiac pa-
tients). It is recommended that testing of asymptom-
atic children who belong to groups at risk begin
around 3 years of age provided they have had an
adequate gluten-containing diet for at least 1 year
before testing.
100
The Use of HLA-DQ Typing in the Diagnosis
of CD
Because CD is very unusual in the absence of
HLA-DQ2 or HLA-DQ8, the determination of these
haplotypes may be used in the identification of CD,
among others, in high-risk groups for CD whose
members may develop the disease at a certain moment
in their lives, but in whom it is not known how often
CD should be tested. This is especially the case among
first-degree relatives of CD children: in these families
there is frequently anxiety to know who may or may
not develop CD. However, HLA-DQ2 and -DQ8 are
not specific for CD since they are present in about 40%
of the general white population, and their contribution
to the identification of the disease resides in their high
negative-predictive factor.
91
Using HLA-DQ typing, a
two-step model has been proposed to identify CD in
children with high risk for CD.
32

The first step should
consist of the typing for the molecularly defined
HLA-DQ2 and -DQ8, which has to be performed only
once in life, because it does not change in time. This
will help to exclude the children without HLA-DQ2
and/or HLA-DQ3 from further unnecessary tests for
CD. The second step should consist of total IgA and
IgA-tTGA and/or IgA EMA determinations in serum
in the children selected by HLA-typing. Individuals
with positive serological tests should be offered a
small bowel biopsy, and in the case of histological
alterations treatment with a GFD should be provided.
The children with normal serological tests or normal
small bowel biopsies should be further investigated for
CD, for example, every 1 to 2 years.
To Screen or not to Screen?
CD is a hidden public health problem worldwide.
Many studies have shown that CD affects about 1.0%
of children of white ancestry,
14-16
but most cases
remain undiagnosed. The prevalence of CD thus ex-
ceeds by far that of a number of diseases for which
screening programs are currently applied such as
congenital hearing loss (1/1000), congenital hypothy-
roidism (1/3400), and phenylketonuria (1/18,000).
39
Mass screening is the only way to identify the majority
of people with CD.
Mass screening for CD, ie, screening of the general

population, is a controversial issue. To decide whether
mass-screening programs for CD would be performed,
the principles for early disease detection as elaborated
by Wilson and Jungner should be taken into ac-
count.
101
These principles are as follows: (1) The
condition should be an important health problem; (2)
There should be an accepted treatment for the disease;
(3) Facilities for diagnosis and treatment should be
available; (4) There should be a recognizable latent or
early symptomatic stage; (5) There should be a suit-
able test for disease detection; (6) The test should be
acceptable for the population; (7) The natural history
of the condition, including development from latent to
declared disease, should be understood; (8) There
should be an agreed policy of whom to treat as a
patient; (9) The costs of case-finding should be eco-
nomically balanced in relation to possible expenditure
on medical care as a whole; and (10) Case-finding
should be a continuous process. Nine of the 10
principles for mass-screening are met by CD, but the
natural history of CD is not well known and it is not
clear if the children with none of subtle symptoms of
CD identified by mass screening have the same health
risks and long-term complications that the children
with clinical diagnosed CD. Assuming a standardized
mortality ratio of 1.5 or higher for untreated CD
patients, mass screening for CD has been shown to be
cost-effective in populations with a relatively high

prevalence of CD over a wide range of ages at
screening.
102
To answer this question, limited screening programs
in well-defined regions should be initiated with con-
tinuous and prospective evaluation of their costs and
benefits in comparison with control populations.
38
Treatment
A lifelong strict GFD with exclusion of gluten from
wheat, rye, and barley is the treatment of CD.
7
Wheat,
rye, and barley are the predominant grains containing
96 Curr Probl Pediatr Adolesc Health Care, March 2007
the peptides known to cause CD. Triticale (a combi-
nation of wheat and rye), kamut, and spelt are also
known to be harmful. Other forms of wheat are
semolina (durum wheat), farina, einkorn, bulgur, and
couscous. Malt is also harmful because it is a partial
hydrolysate of barley prolamins. In general, any ingre-
dient with malt in its name (barley malt, malt syrup,
malt extract, malt flavorings) is made from barley.
100
The ingestion of very small amounts of gluten, even
without the accompaniment of clinical or serological
responses, induces changes that are detectable at the
small bowel level.
103
The clinical response of children with CD after

starting a GFD may be observed within days or weeks.
The histological recovery of the small bowel mucosa
after GFD takes longer, but the recovery in children is
much quicker and complete than in adults and 95% of
the children show histological recovery after 2 years
on a GFD.
88
Initially, oats were considered to be harmful for CD
patients, but more recently it has been shown that, in
general, oats are safe both for adults and for children
with CD.
104-110
One concern about oats consumption
in a GFD is the frequent contamination of oats with
gluten during the harvesting and milling process.
111
In
addition, some CD patients have avenin-reactive mu-
cosal T-cells that can cause mucosal inflammation and
clinical follow-up of CD patients eating oats is advis-
able.
112
Recently, in vitro experiments showing the absence
of gluten-derived T-cell epitopes in tef, suggest that
this cereal may be suitable for use in the diet of
patients with CD.
113
Tef (Eragrostis tef), a cereal
traditionally grown in Ethiopia and used to make flat
bread, can substitute for wheat flour in almost all

applications and has a nutritional value similar to that
of wheat. Studies on tef consumption by patients with
CD are needed to determine whether tef is safe for
these patients.
In principle, a GFD appears simple; in practice, it
represents a challenge to children and their families,
dieticians, and physicians, since wheat products are
added to many processed foods in the Western diet.
Several helpful books distributed by the National
Celiac Societies provide excellent dietary instructions
and gluten-free recipes.
Adherence to the GFD diets is difficult, because
sources of unintentional gluten intake are so numer-
ous; among others:
1. Contamination with wheat flour of foods that are
“naturally” gluten-free,
2. Residual gluten in gluten-free wheat starch used
for bread mixes,
3. Mislabeling of foods
Lists of gluten-free food are available for patients.
General awareness should be promoted to keep these
lists updated.
The Codex Alimentarius Committee on Nutrition
and Food for Special Dietary Uses (CCNFSDU) in
1982 set the limit of gluten allowed in raw materials to
produce gluten-free food to 0.05 g nitrogen per 100 g
dry matter. Recently an R5 ELISA method for gluten/
gliadin determination in food has become available
based on a monoclonal antibody reacting with the
specific gliadin pentapeptide glutamine-glutamine-

proline-phenylalanine-proline (QQPFP) with a sensi-
tivity and limit of detection (1.5 ppm gliadin), which is
superior to older methods of detection.
114
At the
moment a provisional level of [20 ppm] gluten for
food gluten-free by nature and [200 ppm] for food
rendered gluten-free has been accepted (Draft Revised
Standard for Gluten-free Foods (ALINORM 04/27/26)
CCNFSDU). The problem is that this standard refers
to the amount contained in a food and not to the
amount of food that can be taken by a person who is
sensitive to it. Patients with CD need careful support
to provide them with up-to-date facts about a GFD.
This may in part be given by the many Celiac Patients
Societies around the world, among others the Associ-
ation of European Celiac Societies (www.aoecs.org)
and the American Celiac Sprue Association (www.
csaceliacs.org).
Nonadherence to the GFD may lead to complications
such as diarrhea, abdominal pain, anemia, and osteo-
porosis.
11
For many patients adherence to the diet may
be difficult to achieve.
115
This seems to be particularly
true among adolescent patients with CD, with a
reported compliance with the GFD between 52 and
81%.

116-122
Determination of celiac antibodies in se
-
rum has been reported as a reliable way to monitor the
compliance with the GFD.
123
However, in a study
among young celiacs in the Netherlands we did not
find a correlation between the self-reported compli-
ance with the diet and the results of the celiac
antibodies in serum. Neither did we find a relation
between the amount of gluten consumed and the level
of antibodies (EMA, tTGA).
122
It is also possible that
the determination of the antibodies in serum is not an
Curr Probl Pediatr Adolesc Health Care, March 2007 97
adequate method to detect adherence to the GFD, both
in adults and in adolescents, as it has been suggested
by others.
124-126
In addition, adherence to a GFD may
have negative nutritional consequences.
127,128
Mariani
and coworkers
121
reported overweight and an unbal
-
anced diet rich in fat and protein, poor in carbohydrate,

and deficient in calcium, iron, and fiber in 72% of the
Italian CD adolescents adhering strictly to the GFD. In
a prospective study performed in Dutch adolescents
and young adults, we found a high dietary compliance
(75%) with a median gluten intake of 44 mg per day
(2-6382 mg). The nutritional state was adequate, with
normal scores for height and body mass index, but the
nutrient intake was not adequate. The fiber and iron
intake were significantly lower, and the saturated fat
intake was significantly higher than recommended, but
comparable with the general population. Most of the
patients (61%) found the diet easy to follow. Regular
medical controls were reported by 86%, but regular
dietary controls were reported by only 7% of the
patients.
122
Better medical and dietary support is
necessary to prevent long-term complications and to
achieve an ongoing satisfying management in this
group of young patients with a chronic disorder. Most
young patients with CD thought that avoiding cancer
was the most important reason to adhere to the GFD.
It has been found that when patients with CD adhere to
a GFD for five consecutive years or more, their risk of
malignancy is not increased compared with that of the
general population.
42,129
On the other hand, over the
last few years it has become clear that, although CD
patients have a higher risk of developing cancer than

the general population, the risk is much lower than
previously presumed.
45-47
At present the GFD is the
only effective treatment for CD and it is prudent to
recommend strict adherence to the diet to all celiac
patients. However, the fear of developing malignancy
is not necessarily the most important reason for
advising a strict diet to CD patients.
48
Physicians
should mainly stress the advantages of the diet with
regard to the prevention of other complications of CD,
such as osteoporosis
49
and autoimmune disorders.
42
They should also point out the relation between
adherence to the GFD and improvement of fertility
and birth outcomes.
50,130,131
Quality-of-Life
Decreased quality-of-life (QOL) has been described
in adults with CD, especially in females.
128
Having a
chronic illness like CD may reduce a child’s QOL. Not
only can physical function be affected, but also a
child’s emotional and social world may change. The
illness can therefore be an important factor in the

evaluation of QOL of a child.
132
Health-related QOL
(HRQOL) is a multidimensional concept containing
physical, emotional, social, and cognitive domains,
variable over time, and is getting increasing attention
in medical and health care settings.
133
What matters in
HRQOL is the way patients feel about their function-
ing, not their functioning itself.
134
HRQOL can be
measured by generic, disease-generic, and disease-
specific instruments. These instruments can be seen as
having a pyramid structure, with, at the bottom, the
generic QOL questionnaires such as the DUX25
135
and the TACQOL.
136
In the second layer of the
pyramid, disease-generic questionnaires are found,
which can be administered to children with any
disease, including chronic diseases. Finally, disease-
specific questionnaires complete the top layer. These
questionnaires can be given to children, healthy and
ill. Generic HRQOL instruments offer specific possi-
bilities in the assessment of the QOL of patients with
a particular disease: they allow comparison with nor-
mative data and across disease populations. Most QOL

instruments are designed as top-down instruments.
This means that they are developed by researchers and
physicians who used their own experience as guide-
lines. In the last few years there has been an increasing
interest in the development of generic and disease-
specific HRQOL instruments developed from the bot-
tom-up approach such as the KIDSCREEN and DIS-
ABKIDS questionnaires. These questionnaires used a
focus group based bottom-up approach.
137
A bot
-
tom-up approach allows us to perceive the situation
from the child’s point of view. It can be seen as a
child-centered methodology, designed to ensure that
the children, rather than their parents or health care
professionals, generate, prioritize, and explain the
issues of interest to them. It can produce data that adult
investigators and even parents have never considered.
The HRQOL of children with CD has been previ-
ously assessed, making use of the TACQOLCD, a
questionnaire especially designed for CD and based on
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
-
vide information about the children’s view, nor that of
their parents, and it contained only symptomatic ques-

tions mainly useful for the investigation of physical
98 Curr Probl Pediatr Adolesc Health Care, March 2007
complaints. In the absence of complaints, thanks to
compliance with the GFD or to coping with the
disease, the results gave an optimal score which may
not give an accurate view of the HRQOL. Recently,
together with the Dutch foundation Doctors for Chil-
dren, a foundation that works for the improvement of
the QOL of children with chronic illness, an improved
questionnaire developed from the bottom up, to assess
the QOL of children with CD has been developed (van
Doorn RK, Winkler LMF, Zwinderman KH, Mearin
ML, Hendrik M, Koopman HM. Manuscript submited
for publication.): the Celiac Disease DUX (CDDUX).
Using the CDDUX children with CD appears to have
a lower QOL than the healthy reference group. Chil-
dren with a better health status have a higher score on
the CDDUX questionnaire. The new disease-specific
questionnaire CDDUX provides information about
how children with CD think and feel about their
illness. The use of a similar questionnaire enables
researchers and clinicians to determine the conse-
quences of CD on the daily living of the children. In
this context the results of an important study aimed to
evaluate the impact of the GFD on the 5240 members
of the Canadian Celiac Association shows that the
QOL in those with CD could be increased with early
diagnosis, increased availability of gluten-free foods,
improved food labeling, and better dietary instruc-
tion.

139
Education of physicians and dieticians about
CD and its treatment is essential.
Future Prospects
Prevention
There is some evidence suggesting that prevention of
CD may be possible. One observation is that the level
of HLA-DQ2 expression is linked to the probability of
disease development: a double gene dose leads to an at
least fivefold increased risk.
61,76
Usually children are
exposed to high levels of gluten. The question is what
will happen when we lower the amount of gluten in the
diet. It is conceivable that this may have a similar
effect as the HLA-DQ2 gene dose: lower gluten
exposure would decrease the risk to develop CD.
Epidemiological studies from Sweden suggest that
early nutrition patterns may have a significant impact
on the later risk of developing CD. The occurrence of
“epidemics” of CD after changes in the Swedish infant
feeding during the 1980s and 1990s suggested that the
disease may be preventable by improving early nutri-
tion and inducing tolerance to gluten in predisposed
individuals. The “Swedish epidemic of CD” started in
1983 when gluten introduction was postponed from
month 4 to 6 by changed national recommendations
for gluten introduction into the diet of young children.
Carefully performed studies exploring the epidemic in
detail suggest that the causal factors of the epidemic

were whether breastfeeding was ongoing or not while
gluten was introduced and also the amount of gluten
then given.
140,141
Thus, when introduction of gluten in
1983 was postponed, it also implied that more infants
had ended breastfeeding, and that gluten was intro-
duced by larger amounts. Moreover, the epidemic
subsided in1996 when gluten introduction was once
again “allowed” from 4 months of age when more of
the infants were still breastfed and gluten was intro-
duced in smaller amounts. Thus, the Swedish studies
strongly support that ongoing breastfeeding during the
period of gradual introduction of gluten-containing
foods into the infant diet reduces the risk of symptom-
atic CD.
140,141
Based on an estimate of the attributable
fraction, half of the CD cases during the Swedish
epidemic might have been avoided if all infants had
been introduced to gluten in small amounts while still
being breastfed. The latter finding opens the way to
possible prevention strategies.
It is possible that gradual introduction of antigens
will lead to the development of oral tolerance.
142,143
It
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
European countries on gluten consumption and breast-
feeding,
143,146-150
but the methods used to assess
gluten intake were mostly time consuming and dif-
fered from each other. An important American study
has published the findings on a cohort of 1560 children
who had an increased risk of developing CD or type 1
diabetes, as defined by possessing either HLA-DR3 or
DR4 alleles, or having a first-degree relative with type
1 diabetes, derived from the Diabetes Autoimmunity
Study in the Young project.
150
At a mean follow-up of
4.8 years the authors concluded that (1) there is a
“window of opportunity” of introducing gluten into
the diet when the child is aged between 4 and 6 months
with regard to the risk of developing CD; and (2) that
the contribution of breastfeeding was to be disregarded
in this respect. However, the authors did not make
specific attempts to calculate the gluten amount in-
gested by the children or to correlate this important
early nutrition event with the presence or absence of
Curr Probl Pediatr Adolesc Health Care, March 2007 99
breastfeeding. A systematic review and a meta-analy-
sis of observational studies published between 1966
and June 2004 that examined the association between
breastfeeding and the development of CD showed that
breastfeeding seemed to protect against CD.

151
Pro
-
spective cohort studies may shed light on the impor-
tance of the quantity of exposure to gluten in early life
in the development of CD.
152
One problem in this
respect is that, until now, there were no validated
instruments to quantify gluten intake by young infants.
The instruments available were work intensive, time
consuming, and difficult to use in population studies.
Recently we have developed and validated food fre-
quency questionnaires for this purpose, using the
2-day food record as a reference (Hopman EG,
Kiefte-de Jong JC, le Cessie S, et al., unpublished
data). This instrument may be used in collaborative
studies to assess the role of the quantity of gluten
consumption in the development of CD.
The actual guidelines for infant nutrition recommend
introducing gluten into the diet no earlier than at the
age of 6 months,
153
and at this age, only a low
percentage of the children, ranging from 1 to 46% in
the different European countries, receive breastfeed-
ing.
154
On the other hand, the Swedish study only
investigated the effect of the early dietary history on

symptomatic CD in children. It may be that the
nutritional factors only have an effect on the symp-
toms of CD and/or on the time of presentations of the
symptoms. In addition, there is no information on the
biological mechanisms involved in the effect of early
nutrition in the development of CD. Prospective inter-
vention nutritional studies in high-risk populations are
necessary to provide parents with sensible advice to
prevent CD in their children.
Safer Foods
Gluten is a complex mixture of proteins that contains
a multitude of immunogenic peptides. This is because
bread wheat and pasta wheat are hexaploid and
tretraploid species, containing three and two entire
wheat genomes, respectively. These wheat varieties
have been selected for good crop yield and superior
baking qualities. However, there are many wheat
varieties and not all of those appear to be equally toxic
to patients.
155
This offers two opportunities for the
generation of safer wheat strains. In addition, other
cereals can be selected that do not contain harmful
gluten or gluten-like molecules, like the Ethiopian
cereal tef.
155
Novel Treatments?
A GFD is at present the only possible treatment for
CD children, but there are a number of drawbacks to a
lifelong diet. At present there are four options that can

be explored, as follows: (1) Enzymatic degradation of
gluten before it reaches the small intestine; (2) Block-
ing of peptide binding to HLA-DQ2/8; (3) Blocking of
tTG; (4) Blocking of IL-15.
66
Of these four options,
the latter two may be dangerous. tTG is important for
the maintenance of tissue integrity, while IL-15 is
required for normal functioning of the immune sys-
tem. The fist two options, however, may provide
opportunities. However, due to its high proline con-
tent, gluten is resistant to enzymatic degradation. Oral
supplementation with a postproline cutting enzyme
has therefore been proposed as a potential way to
destroy gluten before it can do damage in the small
intestine.
156
Blocking HLA-DQ would also be highly
selective as it would block the gluten-specific T-cell
response but would leave non-HLA-DQ-mediated T-
cell responses intact. These two and other possible
options deserve further study.
Practice Points
● Celiac disease is a common, but frequently unrec-
ognized disease. Consequently, celiac disease is
severely underdiagnosed.
● The health burden of celiac disease is considerable.
Two important complications of celiac disease are
malignancy and osteoporosis.
● Recent population-based studies indicate that the

increased risk of malignancy associated with celiac
disease 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 genetic
factors coded by the HLA complex. Around 95% of
the patients express HLA-DQ2 and most of the
remainders express HLA-DQ8. The risk of devel-
oping celiac disease in the absence of HLA-DQ2
and/or HLA-DQ8 is very small.
● It is possible to use serological markers to identify
celiac disease with high sensitivity and specificity.
The most useful are the IgA antibodies to EMA and
to human tTGA.
● At the present time small bowel biopsy is the gold
standard for the diagnosis of celiac disease.
100 Curr Probl Pediatr Adolesc Health Care, March 2007
● CD should be considered early in the differential
diagnosis of children with failure to thrive and
persistent diarrhea and in children with other per-
sistent gastrointestinal symptoms in children with
nongastrointestinal symptoms of CD and in condi-
tions associated with CD.
● At present a GFD is the only effective treatment for
celiac disease.
● Better medical and dietary support is necessary to
prevent long-term complications and to achieve
satisfying management in children and young pa-
tients with celiac disease.
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