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INTRODUCTION
Celiac disease (Non tropical sprue, gluten
senseitive enteropathy, Gee-Herter disease) is a
unique autoimmune disorder, unique because the
environmental precipitant is known.
The disorder was previously called celiac sprue,
based on the Dutch word sprue, which was used
to describe a disease similar to tropical sprue that
is characterized by diarrhea, emaciation,
aphthous stomatitis, and malabsorption.
Celiac disease is precipitated, in genetically
predisposed persons, by the ingestion of gluten,
the major storage protein of wheat and similar
grains. Originally considered a rare malabsorption
syndrome of childhood, celiac disease is now
recognized as a common condition that may be
diagnosed at any age and that affects many
organ systems.
Celiac disease results from the interaction between gluten
and immune, genetic, and environmental factors.
The Role of Gluten
Celiac disease is induced by the ingestion of gluten, which
is derived from wheat, barley, and rye. It is comprised of
hundreds of protein components, traditionally classified on
the basis of their solubility in alcohol-water solutions, in
prolamins (alcohol-soluble), and glutenins (alcohol
insoluble) (Wieser, 2007).
Gluten
Prolamins Glutenins
Gliadins, secalins,hordeins
A high content of glutamine and proline is a common
feature of gliadins, secalins and hordeins, while
prolamins of cereals considered to be non-toxic for
persons with CD, such as rice and corn, have a lower
content of these amino acids (Schuppan, 2000).
Undigested molecules of gliadin, such as a peptide from
an α-gliadin fraction made up of 33 amino acids, are
resistant to degradation by gastric, pancreatic, and
intestinal brush-border membrane proteases in the
human intestine.
These peptides pass through the epithelial barrier of the
intestine, possibly during intestinal infections or when
there is an increase in intestinal permeability, and
interact with antigen-presenting cells in the lamina
propria.
MUCOSAL IMMUNE RESPONSES
In patients with celiac disease, immune responses to
gliadin fractions promote an inflammatory reaction,
primarily in the upper small intestine, characterized by
infiltration of the lamina propria and the epithelium with
chronic inflammatory cells and villous atrophy.
This response is mediated by both the innate and the
adaptive immune systems.
The adaptive response is mediated by gliadin-reactive
CD4+ T cells in the lamina propria that recognize gliadin
peptides, which are bound to HLA class II molecules DQ2
or DQ8 on antigen- presenting cells; the T cells
subsequently produce proinflammatory cytokines,
particularly interferon-γ.
Tissue transglutaminase is an enzyme in the intestine
that deamidates gliadin peptides, increasing their
immunogenicity. The ensuing inflammatory cascade
releases metalloproteinases and other tissue-damaging
mediators.
Gliadin peptides also activate an innate immune
response in the intestinal epithelium that is
characterized by increased expression of interleukin- 15
by enterocytes, resulting in the activation of
intraepithelial lymphocytes expressing the activating
receptor NK-G2D, a natural-killer-cell marker.
These activated cells become cytotoxic and kill
enterocytes with surface expression of major-
histocompatibility-complex class I chainrelated A (MIC-
A), a cell-surface antigen induced by stress, such as an
infection.
GENETIC FACTORS
The genetic influence in the pathogenesis of celiac disease is
indicated by its familial occurrence. Celiac disease does not
develop unless a person has alleles that encode for HLA-DQ2
or HLA-DQ8 proteins, products of two of the HLA genes.
However, many people, most of whom do not have celiac
disease, carry these alleles; thus, their presence is necessary
but not sufficient for the development of the disease. Studies
in siblings and identical twins suggest that the contribution of
HLA genes to the genetic component of celiac disease is less
than 50%.
ENVIRONMENTAL FACTORS
These include a protective effect of breast-feeding and the
introduction of gluten in relation to weaning.
The initial administration of gluten before 4 months of age is
associated with an increased risk of disease development, and
the introduction of gluten after 7 months is associated with a
marginal risk. However, the overlap of gluten introduction with
breast-feeding may be a more important protective factor in
minimizing the risk of celiac disease. The occurrence of
certain gastrointestinal infections, such as rotaviral infection,
also increases the risk of celiac disease in infancy
CLINICAL MANIFESTATIONS
Clinical manifestations of celiac disease vary greatly
according to age group. Infants and young children
generally present with diarrhea, abdominal distention,
and failure to thrive. However, vomiting, irritability,
anorexia, and even constipation are also common. Older
children and adolescents often present with
extraintestinal manifestations, such as short stature,
neurologic symptoms, or anemia
Among adults, two to three times as many women have
the disease as men, for unknown reasons. In general,
the prevalence of autoimmune diseases is higher in
women than in men, and iron deficiency and
osteoporosis, each of which prompts an assessment for
celiac disease, are more often diagnosed in women. The
predominance of the disease in women diminishes
somewhat after the age of 65 years
The classic presentation in adults is diarrhea, which may
be accompanied by abdominal pain or discomfort. Other,
silent presentations in adults include iron-deficiency
anemia, osteoporosis etc. Less common presentations
include abdominal pain, constipation, weight loss,
neurologic symptoms, dermatitis herpetiformis,
hypoproteinemia, hypocalcemia, and elevated liver
enzyme levels.
Patients often have symptoms for a long time and
undergo multiple hospitalizations and surgical
procedures before celiac disease is diagnosed
Some cases are diagnosed because of increased
surveillance for celiac disease among people who have a
family history of the disease and among those with
Down syndrome, Turner’s syndrome, or type 1 diabetes,
all of which are associated with celiac disease.
Persons with celiac disease have an increased risk of
autoimmune disorders as compared with the general
population
Case-finding in persons with clinical conditions known to
be associated with CD is currently considered the most
appropriate way to detect atypical cases (Fasano, 2003);
based on their very high diagnostic accuracy, serologic
IgA EMA and IgA anti-tTG tests are the best available
tests for the screening of at-risk individuals (Rostom et
al., 2005).
Diagnosis
The diagnosis of celiac disease requires both a duodenal
biopsy that shows the characteristic findings of
intraepithelial lymphocytosis, crypt hyperplasia, and
villous atrophy and a positive response to a gluten-free
diet.
The diagnostic criteria developed by the European
Society for Pediatric Gastroenterology and Nutrition
require only clinical improvement with the diet, although
histologic improvement on a gluten-free diet is
frequently sought and is recommended in adults
because villous atrophy may persist despite a clinical
response to the diet.
SEROLOGIC TESTING
Indications for serologic testing include:
Unexplained bloating or abdominal distress;
Chronic diarrhea, with or without malabsorption
Or the irritable bowel syndrome;
Abnormalities on laboratory tests that might be caused
by malabsorption (e.g., folate deficiency and iron-
deficiency anemia);
First-degree relatives with celiac disease
The most sensitive antibody tests for the diagnosis of
celiac disease are of the IgA class.
The available tests include those for antigliadin
antibodies, connective-tissue antibodies (antireticulin
and antiendomysial antibodies), and antibodies directed
against tissue transglutaminase, the enzyme responsible
for the deamidation of gliadin in the lamina propria. The
antigliadin antibodies are no longer considered sensitive
enough or specific enough to be used for the detection
of celiac disease, except in children younger than 18
months of age.
The diagnostic standard in celiac serologies remains the
endomysial IgA antibodies; they are highly specific
markers for celiac disease, approaching 100% accuracy.
Overall, the sensitivity of the tests for both endomysial
antibodies and anti–tissue transglutaminase antibodies
is greater than 90%, and a test for either marker is
considered the best means of screening for celiac
disease
BIOPSY
Biopsy of the small intestine remains the standard for
diagnosing celiac disease, and it should always be
performed when clinical suspicion is high, irrespective of
the results of serologic testing. Biopsy confirmation is
crucial, given the lifelong nature of the disease and the
attendant need for an expensive and socially
inconvenient diet.
Who should undergo endoscopic biopsy?
In addition to patients whose serologic tests are positive,
any patient who has chronic diarrhea, iron deficiency, or
weight loss should undergo duodenal biopsy,
irrespective of whether serologic testing for celiac
disease has been performed.
The recognition of endoscopic signs of villous atrophy,
such as scalloping of mucosal folds, absent or reduced
duodenal folds, or a mosaic pattern of the mucosa,
should prompt biopsy.
CAUSES OF VILLOUS ATROPHY OTHER THAN CELIAC DISEASE.
Giardiasis Common-variable immunodeficiency Autoimmune enteropathy Radiation enteritis Tuberculosis Tropical sprue Eosinophilic gastroenteritis Human immunodeficiency virus enteropathy Intestinal lymphoma Zollinger–Ellison syndrome Crohn’s disease Intolerance of foods other than gluten (e.g., milk, soy, chicken,
tuna)
In this paper, they have reviewed studies that
evaluated:
(1) the possibility of using oral mucosa for the initial
diagnosis of CD or for local gluten challenge; and
(2) the possibility of using salivary CD-associated
antibodies as screening tests for the disease.
ORAL MUCOSA FOR INITIAL DIAGNOSIS OF CDOR FOR LOCAL GLUTEN CHALLENGE
Differences in histological features of the oral mucosa of
persons both with and without CD were demonstrated in a
study that involved persons with GFD-treated CD, those with
newly diagnosed CD, and healthy control individuals
(Lähteenoja et al., 1998). Moderate to severe lymphocytic
inflammation was observed in 42.7% of the oral biopsy
specimens from persons with treated CD, as compared with
10% of control individuals.
These results were confirmed in another study by the same
investigators (Lähteenoja et al., 2000), in which the T-cell
count in the epithelium of treated persons was higher than
that in untreated persons and control individuals, and the
mast cell count in the lamina propria of treated persons was
higher than that of untreated persons.
The authors concluded that the oral mucosa cannot be
used for the initial diagnosis of CD, since persons with
untreated CD did not differ from healthy control individuals
with regard to oral mucosal infiltration. In contrast, persons
with treated CD showed significantly increased numbers of T-
cell subsets in their oral mucosa
The observation that, in the oral mucosa of persons with
GFD-treated CD, an immunological ‘memory’ for gluten
hypersensitivity is perpetuated prompted the authors to
evaluate the reaction of the oral mucosa to a local
gluten challenge.
A solution of an a-gliadin-related synthetic peptide was
injected into the buccal submucosa of persons with GFD-
treated CD and healthy control individuals (Lähteenoja
et al., 2000b).
The peptide significantly increased the T-cell counts in the
lamina propria of persons with CD. The numbers of CD3+ and
CD4+ cells were significantly higher after than before peptide
challenge in persons with CD; the expression of the T-cell
activation marker CD25 was also observed in the lamina
propria of these persons after the challenge.
The oral challenge induced no statistically significant
difference in the cell counts of the control individuals.
Importantly, neither the persons with CD nor the control
individuals had any oral complaints or visible changes after
the challenge; similarly, results of the serum EMA test
remained negative after the challenge in all participants.
In another study, the same group performed the oral
gluten challenge both at supramucosal (gliadin powder
applied with an oral adhesive bandage) and submucosal
(injection of gliadin solution) sites (Lähteenoja et al.,
2000c).
After a supramucosal challenge on the oral mucosa of
persons with CD and on GFD, the number of intra-
epithelial CD4+ and CD8+ T-cells increased in 67.6%
and 73% of cases, respectively. Also, there was a
significant increase in the number of CD4+ cells in the
lamina propria of persons with CD.
After a submucosal gliadin challenge, the mean numbers
of total T-cells and CD4+ T-cells were significantly
increased in the lamina propria of persons with CD.
There were no differences in the mean cell counts of the
healthy control individuals after submucosal challenge.
Based on these results, the authors reported a 73%
sensitivity of the submucosal gliadin challenge in
persons with treated CD, and a specificity of 80%; the
positive predictive value was 93%, and the negative
predictive value was 44%.
Recently, results from two groups of investigators have
demonstrated that in vitro culture media of oral mucosa
biopsies from persons with untreated CD can release
IgA-class EMA and anti-tTG (Carroccio et al., 2007;
Vetrano et al., 2007). One of the groups (Carroccio et al.,
2007) found IgA EMA and antitTG in 53.6% and 57.2% of
cultured oral biopsies, respectively. IgA EMA and anti-tTG
assayed on culture media of duodenal biopsies were
positive in all persons with CD
The sensitivity of the EMA test on oral mucosa media
was 53.6%, the specificity was 100%, and the diagnostic
accuracy was 79%. For the anti-tTG test, sensitivity
specificity, and accuracy were 57.2%, 100%, and 79%,
respectively.
SALIVARY CD-ASSOCIATED ANTIBODIESAS SCREENING TESTS
Conflicting results have been reported regarding the
usefulness of measuring CD-associated antibodies in saliva to
screen for CD.
In 1989, IgA-class AGA levels in whole unstimulated saliva of
persons with untreated CD were significantly higher than
those of both persons with GFD-treated CD and individuals
without CD, with a reported diagnostic accuracy of 100% (al-
Bayaty et al., 1989). A similar result was obtained in a study
where a sensitivity of 100% was assumed, and the salivary
test for IgA AGA had a 90% specificity (Hakeem et al., 1992).
In addition, two studies that tested stimulated parotid
secretion, and not unstimulated whole saliva, reported
only little (O’Mahony et al., 1991) or no (Gibney and
Brady, 1991) elevation of IgA AGA levels in persons with
untreated CD.
Both IgA and IgG salivary AGA has been measured in
persons with treated and untreated CD; although
specificities were relatively high (93.3% for both IgA and
IgG), sensitivities were poor (50% for IgG, 61.2% for IgA)
(Rujner et al., 1996).
As to tTG antibodies, their presence in saliva was evaluated in
four studies, with different results. By means of a fluidphase
radio-immunoassay, IgA anti-tTG was detected in saliva from
97.4% of persons with untreated CD, while none of the saliva
samples from healthy control individuals was found to be IgA
anti-tTG-positive (Bonamico et al., 2004).
In contrast, an enzyme-linked immunosorbent assay (ELISA)
test detected IgA anti-tTG antibodies in saliva from persons
with CD and with low sensitivity (Baldas et al., 2004). A recent
study that used a commercial solid-phase ELISA test has
reported a sensitivity of 90% and a specificity of 96.7%
(Ocmant and Mascart, 2007).
Serum radioimmunoassay (RIA) tissue transglutaminase
autoantibodies (tTG-Abs) proved to be a sensitive test
during coeliac disease (CD) follow-up. This study
demonstrates that it is possible to detect salivary tTG-
Abs with high sensitivity not only at CD diagnosis, but
also during GFD. (M. BONAMICO, R. NENNA, R. P. L.
LUPARIA, C. PERRICONE, M. MONTUORI, F. LUCANTONI,A.
CASTRONOVO, S. MURA , A. TURCHETTI , P. STRAPPINI &
C. TIBERTI 2008)
DISCUSSION Histological examination of the oral mucosa of persons with
untreated CD did not show any significant alteration
(Lähteenoja et al., 2000a); consequently, the oral mucosa
cannot be used for an initial diagnosis of CD.
Nevertheless, the recent demonstration that the oral mucosa
of persons with untreated CD can produce IgA-class EMA and
anti-tTG in culture media (Carroccio et al., 2007; Vetrano et
al., 2007) offers a new approach for using the oral mucosa to
diagnose CD, although there are conflicting results regarding
the sensitivity of the tests
Evidence exists that activated B-cells can migrate from
gut-associated lymphoid tissue (GALT) to salivary glands
(Brandtzaeg, 2007a), and IgA-producing gliadin-specific
lymphocytes have been detected in the peripheral blood
of children with CD (Hansson et al., 1997). In view of this
‘plasmablast’ trafficking throughout the body, the
presence of CD-associated antibodies in saliva would
seem plausible
Oral mucosa and salivary glands are effector sites of the
mucosal immune system; the inductive sites of the
mucosal immune system consist of organized mucosa-
associated lymphoid tissue (MALT) (Johansen et al.,
2007).
Although GALT is the largest and most important part of
MALT, and primed lymphocytes can migrate from GALT
to salivary glands (Brandtzaeg, 2007a), there is now
compelling evidence that supports the
compartmentalization of the mucosal immune system
(Brandtzaeg and Johansen, 2005; Johansen et al., 2007).
Therefore, activated immune cells seem to home
preferentially to the sites where they were originally primed
(Brandtzaeg, 2007b). In this view, nasopharynx-associated
lymphoid tissue (NALT) and bronchus-associated lymphoid
tissue (BALT) may be more important than GALT in inducing an
immune response in the upper aerodigestive tract.
Moreover, a duct associated lymphoid tissue (DALT) of the
salivary glands has been described (Nair and Schroeder,
1986; Ciccone et al., 1998). It is accessible to oral antigens by
retrograde passage through salivary ducts; thus, DALT could
have an independent role in the gluten-related immune
response in the oral cavity (Baldas et al., 2004).
TREATMENT
Nutritional therapy, the only accepted treatment for
celiac disease, involves the lifelong elimination of wheat,
rye, and barley from the diet.
Fundamentals of the Gluten-free Diet.Grains that should be avoided Wheat, rye, barley (including malt)
Safe grains (gluten-free) Rice, buckwheat, corn, millet, quinoa, sorghum, teff (an
Ethiopian cereal grain), oats
Sources of gluten-free starches that can be used as flour alternatives
Cereal grains: amaranth, buckwheat, corn (polenta), millet, quinoa, sorghum, teff, rice (white, brown, wild, basmati, jasmine), montina (Indian rice grass)
Tubers: arrowroot, jicama, taro, potato, tapioca (cassava, manioc, yucca)
Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts,soybeans
Nuts: almonds, walnuts, chestnuts, hazelnuts, cashews Seeds: sunflower, flax, pumpkin
PROBLEMS OF DIETARY ADHERENCE High cost Poor availability of gluten-free products (in developing
countries) Poor palatability Absence of symptoms when dietary restrictions not observed Inadequate information on gluten content of food or drugs Inadequate dietary counseling Inadequate initial information supplied by diagnosing
physician Inadequate medical or nutritional follow-up Lack of participation in a support group Inaccurate information from physicians, dietitians, support
groups, or Internet Dining out of the home Social, cultural, or peer pressures Transition to adolescence Inadequate medical follow-up after childhood
CAUSES OF POORLY RESPONSIVE CELIAC DISEASE
Incorrect diagnosis Gluten ingestion (intentional or unintentional) Microscopical colitis Lactose intolerance Pancreatic insufficiency Bacterial overgrowth Intolerance of foods other than gluten (e.g., fructose, milk,
soy) Inflammatory bowel disease Irritable bowel syndrome Anal incontinence Autoimmune enteropathy Refractory celiac disease (with or without clonal T cells) Enteropathy-associated T-cell lymphoma
CONCLUSION Celiac disease occurs in nearly 1% of the population in
many countries. Increasing awareness of the
epidemiology and diverse manifestations of the disease,
as well as the availability of sensitive and specific
serologic tests, especially among primary care
physicians, will lead to more widespread screening and
diagnosis, which in turn will lead to greater availability of
gluten-free foods and efforts to develop drug therapies
that relieve patients of the burden of a gluten-free diet.
There is no consensus regarding the accuracy of a salivary
CD-associated antibody test in screening for CD. Lack of
standardized collection, handling, storage, and analysis
methods seems to affect the reliability and reproducibility of
the reported results.
Further studies should also investigate whether the oral
gluten-sensitized lymphocytes do originate exclusively from
homing of cells primed in gut-associated lymphoid tissue, or,
rather, whether they could also be primed directly in the oral
cavity. The latter would have important implications not only
for diagnostics, but also for the understanding of CD in
general.
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Tania Gerarduzzi, Gabriella Clarich, Daniele Sblattero, Roberto
Marzari, Fiorella Florian, Stefano Martellossi, and Alessandro
Ventura Testing for Anti-Human Transglutaminase Antibodies in
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