2. Celiac Disease
• What is celiac?
• Etiology and Epidemiology
• Genetics and Pathogenesis
• Clinical Presentation and Associated Disorders
• Diagnosis
• Treatment
• The Spectrum of Gluten-Related Disorders
3. What is celiac?
• Celiac disease (CD), also known as celiac sprue or
gluten-sensitive enteropathy, is a chronic disorder
of the digestive tract that results in an inability
to tolerate gliadin, the alcohol-soluble fraction of
gluten. Gluten is a protein commonly found in
wheat, rye, and barley.
4. Etiology and Epidemiology
• CD is an immune-mediated systemic disorder elicited by
gluten in wheat and related prolamins from rye and barley in
genetically susceptible individuals, and is characterized by the
presence of a variable combination of:
1. gluten dependent clinical manifestations,
2. CD–specific antibodies,
3. human leukocyte antigen (HLA)-DQ2 or DQ8 haplotypes, and
4. enteropathy.
5. • CD–specific antibodies comprise:
• Autoantibodies against TG2 including endomysial antibodies
(EMAs), and antibodies against deamidated forms of gliadin
peptides (DMG)
• Although CD develops in genetically susceptible individuals,
environmental factors might affect the risk of developing CD
or the timing of its presentation.
• Neither breastfeeding during gluten introduction nor any
breastfeeding has been shown to reduce the risk of CD
6. • The earlier introduction of gluten is associated with the earlier
development of CD autoimmunity (positive serology) and CD, but the
cumulative incidence of each in later childhood is not affected.
• It is advised to introduce gluten into the infant's diet anytime between
4 and 12 months of age.
7. Infectious agents have been hypothesized to play a causative role as frequent rotavirus infections
were shown to be associated with an increased risk of developing CD.
It is plausible that the contact with gliadin at a time when there is an ongoing intestinal inflammation
alters intestinal permeability, and the enhanced antigen presentation can increase the risk of
developing CD, at least in a subset of persons.
The mode of delivery, socioeconomic status, season of birth, and the use of drugs have been
associated with the risk of developing CD, but the evidence is contradictory.
8. • CD is a common disorder with about 1% prevalence of biopsy-proven disease.
• Prevalence in Iran: 5-9.9% in general population (expressed as percentage
prevalence of elevated tissue transglutaminase antibody levels in unselected
adult and pediatric populations)
10. • A genetic predisposition is suggested by the family aggregation and the
concordance in monozygotic twins, which approaches 100%.
• The HLA locus is the most significant and dominant gene associated with
CD
• The strongest association is with HLA-DQ2.5 (1 or 2 copies encoded by
DQA1 *05 [for the alpha] and DQB1*02 genes [for the beta chain]).
• Such a DQ molecule has been found to be present in more than 90% of
CD patients.
• The highly homologous DQ2.2 molecule confers a much lower risk, while
the data available on DQ2- negative CD patients indicate that they almost
invariably are HLA-DQ8–positive (DQA1*0301/DQB1*0302).
11. • A gene dosage effect has been proved in prospective studies,
and a molecular hypothesis for such a phenomenon has been
proposed, based on the impact of the number and quality of
the HLA-DQ2 molecules on gluten peptide presentation to T
cells.
• Other loci known to contribute to CD have been documented.
Most have been found to be associated with other
autoimmune diseases such as type 1 diabetes.
12. Pathogenesis
• CD is a T-cell–mediated chronic inflammatory disorder with an
autoimmune component.
• Altered processing by intraluminal enzymes, changes in intestinal
permeability and activation of innate immunity mechanisms precede
the activation of the adaptive immune response.
• Immunodominant epitopes from gliadin are highly resistant to
intraluminal and mucosal digestion; incomplete degradation favors
the immunostimulatory and toxic effects of these sequences.
13. • Some gliadin peptides (p31-43) activate innate immunity,
in particular they induce interleukin (IL)-15.
• IL-15 and type 1 interferons, may alter the tolerogenic
phenotype of dendritic cells, resulting in lamina propria T-
cell activation by other peptides presented in the context
of HLA-DQ2 or HLA-DQ8 molecules.
• Gliadin-specific T-cell responses are enhanced by the
action of TG2: the enzyme converts particular glutamine
residues into glutamic acid, which results in higher affinity
of these gliadin peptides for HLA-DQ2 or HLA-DQ8.
14. The pattern of cytokines produced following gliadin activation is dominated by interferon-γ (T-helper
type 1 skewed); IL-21 is also upregulated.
In downstream T-cell activation a complex remodeling of the mucosa takes place, involving increased
levels of metalloproteinases and growth factors, which leads to the classical histologic finding of a flat
mucosa.
A severe impairment of intraepithelial lymphocytes (IELs) homeostasis is present in CD.
IL-15 is implicated in the expression of natural killer receptors CD94 and NKG2D, as well as in epithelial
expression of stress molecules, thus enhancing cytotoxicity, cell apoptosis, and villous atrophy.
15. • The most evident expression of autoimmunity is the presence of serum antibodies to TG2.
However, the mechanisms leading to autoimmunity are largely unknown, as well as their
pathogenetic significance.
• Potential CD, in which TG2 antibodies can be detected in situ without any histologic
abnormality, shows that the production of antibodies does not necessarily lead to
intestinal damage.
• The finding that IgA deposits on extracellular TG2 are not limited to the intestine but can
be found in the liver, lymph nodes, and muscles indicates that TG2 is accessible to the
gutderived autoantibodies, turning CD into a systemic disease.
17. • Clinical features of CD vary considerably.
• Intestinal symptoms are more common in children whose
disease is diagnosed within the first 2 years of life.
• Failure to thrive, chronic diarrhea, vomiting, abdominal
distention, muscle wasting, anorexia, and irritability are
present in most cases.
• Occasionally there is constipation, with cases presenting with
intussusception.
18. • As the age at presentation of the disease shifts to later in
childhood, and with the more extensive use of serologic screening
tests, extraintestinal manifestations, without any accompanying
digestive symptoms, have increasingly become recognized,
affecting almost all organs .
• One of the most common extraintestinal manifestation of CD is
iron-deficiency anemia, which is usually unresponsive to iron
therapy.
• Osteoporosis may be present; in contrast to adults, it can be
reversed by a gluten-free diet, with restoration of normal peak
bone densitometric values
24. • Some diseases-many with an autoimmune pathogenesis- are
found with a higher-than-normal incidence in CD patients.
• Among these are type 1 diabetes, autoimmune thyroid
disease, Addison disease, Sjögren syndrome, rheumatoid
arthritis, autoimmune cholangitis, autoimmune hepatitis,
and primary biliary cholangitis.
• Such associations have been interpreted as a consequence of
the sharing of identical HLA haplotypes, but a direct role of
gluten in promoting autoimmunity cannot be excluded.
•
25. • The relation between CD and other autoimmune diseases is
poorly defined; once those diseases are established, they are
not influenced by a gluten-free diet.
• Other associated conditions include selective IgA deficiency
and Down, Turner, and Williams syndromes.
27. • The diagnosis of CD is based on a combination of:
1. Symptoms,
2. Antibodies,
3. HLA status,
4. Duodenal histology.
• The initial approach to symptomatic patients is to test for
anti-TG2 IgA antibodies and for total IgA in serum to
exclude IgA deficiency.
• If IgA anti-TG2 antibodies are negative, and serum total IgA
is normal for age, CD is unlikely to be the cause of the
symptoms.
28. • If anti-TG2 antibody testing is positive the patients
should be referred to a pediatric gastroenterologist for
further diagnostic workup, which depends on the serum
antibody levels.
• IgA anti-TG2 decline if the patient is on a gluten free
diet.
• In patients with selective IgA deficiency, testing is
recommended with IgG antibodies to TG2.
• Patients with positive anti-TG2 antibody levels 10 times
the upper limit of normal, blood should be drawn for
HLA and EMA testing.
29. • If the patient is positive for EMA antibodies and positive for DQ2 or DQ8 HLA testing, the
diagnosis of CD is confirmed, a life-long gluten-free diet is started and the patient is followed for
the improvement of symptoms and the decline of antibodies.
• HLA testing is almost always positive; thus, it is possible that HLA testing will not be necessary
in the future to establish diagnosis.
• In the rare case of negative results for HLA and/or anti-EMA in a child with TG2 antibody titers
>10 times the upper limits of normal, the diagnostic workup should be extended, including
repeated testing and duodenal biopsies .
30. • In asymptomatic persons belonging to high- risk groups, CD should always be diagnosed
using duodenal biopsies.
• When biopsies are indicated, at least 4 fragments should be obtained from the descending
part of the duodenum and at least 1 from the duodenal bulb.
• The diagnosis is confirmed by an antibody decline and preferably a clinical response to a
gluten-free diet. CD is not the only cause for villous atrophy.
• Gluten challenge and biopsies will only be necessary in selected cases in which diagnostic
uncertainty remains.
35. • The only treatment for CD is lifelong strict adherence to a
gluten-free diet. This requires a wheat-, barley-, and rye-free
diet.
• Despite evidence that oats are safe for most patients with CD,
there is concern regarding the possibility of contamination of
oats with gluten during harvesting, milling, and shipping.
• Nevertheless, it seems wise to add oats to the gluten-free diet
only when the latter is well established, so that possible adverse
reactions can be readily identified.
36. • There is a consensus that all CD patients should be treated with a
gluten-free diet regardless of the presence of symptoms.
• The nutritional risks, particularly osteopenia and increased risk for
other autoimmune disorders, are those mainly feared for subjects
who have silent CD and continue on a gluten-containing diet.
• Little is known about the health risks in untreated patients with
potential CD.
37.
38.
39. • The Codex Alimentarius Guidelines define gluten-free food item for food containing
< 20 ppm (equivalent to 20 mg gluten in 1 kg of product);
• Although analytical methods for gluten detection have reached a satisfactory
degree of sensitivity, more information is needed on the daily gluten amount that
may be tolerated by CD patients.
• The data available so far seem to suggest that the threshold should be set to <50
mg/day, although individual variability makes it difficult to set a universal
threshold.
• It is important that an experienced dietician with specific expertise in CD
counseling educates the family and the child about dietary restriction.
40. • Compliance with a gluten-free diet can be difficult, especially in adolescents.
• It is recommended that children with CD be monitored with periodic visits for
assessment of symptoms, growth, physical examination, complete blood count,
thyroid diseases, and adherence to the gluten-free diet.
• Periodic measurements of TG2 antibody levels to document reduction in antibody
titers can be helpful as indirect evidence of adherence to a gluten-free diet, although
they are insensitive to slight dietary transgressions.
• If compliance is uncertain, bone health should be assessed.
41. Some patients do not respond to a gluten free diet; refractory or
nonresponsive CD requires a systematic approach to determine the
correct diagnosis, compliance, and therapeutic options.
42.
43. The Spectrum of Gluten-Related Disorders
CD is not the only disorder related to gluten ingestion. Symptoms in IgE mediated
wheat allergy are usually immediate (urticaria, angioedema, asthma, exercise-induced
anaphylaxis). Diagnosis is based on dietary challenge, in vitro assay for specific IgE and
skin testing. Non-celiac gluten sensitivity (NCGS) is a poorly understood condition.
Diagnosis is suspected in patients who do not have CD or wheat allergy, and yet show
GI and non-GI symptoms upon ingestion of gluten- or wheat-containing food. In the
general population, the incidence of self-reported gluten avoidance varies from 0.5 to
13%. Similar symptoms are often experienced by patients with irritable bowel
syndrome (IBS), and some patients with IBS respond positively to a gluten-free diet.
44. References:
1. Nelson textbook of pediatrics-21st edition-2020
2. Taheri M, Sabzali S, Hakim A, Sajadi N, Hakimzade M, Ziaieikajbaf T, et al. The
Prevalence of Celiac Disease in Children with Unexplained Failure to Thrive in
South West of Iran. Int J Pediatr 2017; 5(4): 4663-69. DOI:
10.22038/ijp.2016.20691.1728
