Vol. 9(8), pp.

98-104, August 2017

DOI: 10.5897/IJMMS2016.1281
Article Number: 5F9B5EF65651
ISSN 2006-9723
International Journal of Medicine
Copyright © 2017 and Medical Sciences
Author(s) retain the copyright of this article
http://www.academicjournals.org/IJMMS

Full Length Research Paper

Is there a relationship between occult celiac disease

and functional dyspepsia?
Hanaa Kh. Fath-Elbab1, Magdy Fouad1*, Elham Ahmed Mohammed2, Nehad M. Reda3 and
Hend Mones4
1
Tropical Medicine Department, Faculty of Medicine, El-Minia University, Egypt.
2
Internal Medicine Department, Faculty of Medicine, El-Minia University, Egypt.
3
Pathology Department, Faculty of Medicine, El-Minia University, Egypt.
4
Clinical Pathology Department, Faculty of Medicine, El-Minia University, Egypt.
Received 14 December, 2016; Accepted 31 May, 2017

This is a study to answer the question: Is there a relationship between occult celiac disease and
functional dyspepsia? The study was carried out on 400 dyspeptic patients. Upper gastrointestinal tract
(GIT) endoscopy was done for all patients and those with non-functional dyspepsia were excluded from
the study. Duodenal biopsies with histopathological examination according to the Marsh-Oberhuber
criteria were done. Serum tissue transglutaminase IgA antibody (anti-tTG-IgA) was done for patients
with histopathological findings suggestive to have celiac disease (subtotal and total villous atrophy).
172 patients with endoscopic findings explaining their dyspeptic symptoms were excluded. Only
patients with functional dyspepsia were enrolled in this study (228 patients). Bloating was the most
common symptom (46.5%). Normal villous pattern was found in 199 cases (87.2%). Villous atrophy was
found in 29 patients, subtotal atrophy in 20 cases (8.7%) and total atrophy in 9 cases (3.9%). Age group
of 14-20 years (20/29, 90.9% patients) with villous atrophy was reported to have statistically significant
difference (P value =0.000). Serum anti-tTG-IgA level was measured in all cases of abnormal villous
pattern. Nine patients (3.9%) were proved to have a celiac disease (total villous atrophy and high serum
anti-tTG-IgA) and fourteen dyspeptic patients (6.1%) had subtotal villous atrophy with high anti-tTG-IgA
level could be diagnosed as occult celiac disease. Occult celiac disease should be suspected among
patients with functional dyspepsia complaining of bloating, especially in age 14 to 20. Subtotal villous
atrophy and high anti-tTG-IgA could be considered as occult celiac disease.

Key words: Celiac disease, endoscopy, duodenal biopsy, functional dyspepsia.

INTRODUCTION

Celiac disease (CD) is an immune-mediated systemic of a variable combination of gluten-dependent clinical

disorder elicited by gluten and related prolamins ingestion manifestations and celiac disease specific antibodies
in genetically susceptible individuals and characterized (Abadie et al., 2011).
by atrophy of the proximal small intestinal villi, presence It has been considered for years to be a rare pathology

*Corresponding author. E-mail : [email protected]. Tel: +201001350923.

Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution
License 4.0 International License
 Fath-Elbab et al. 99

that affects, in particular, pediatric patients who present patients with functional dyspepsia. 3-5 biopsies were taken from the
with a clinical picture of malabsorption. During the past distal duodenum and sent for histopathological examination
according to "Marsh" Criteria for diagnosis of CD as follows:
years, researches have shown that the prevalence of Stage 0: Preinfiltrative mucosa (small-intestinal biopsy specimens
celiac disease has increased dramatically, especially with that appear normal).
the development of sensitive and specific serological Stage 1: Increase in the number of intraepithelial lymphocytes
tests and their administration to subjects who are (IELs) to more than 30 per 100 enterocytes.
apparently healthy (Corazza and Villanacci, 2005). CD is Stage 2: Crypt hyperplasia: In addition to the increased IELs, there
still under diagnosed in all age groups and the form with is an increase in crypt depth without a reduction in villus height.
Stage 3: Villous atrophy: A, partial; B, subtotal; C, total. This is the
clear symptoms is found in a limited number of cases; in classic celiac lesion.
most patients, the disease has atypical symptoms or Despite marked mucosal changes, many individuals are
completely asymptomatic (Gujral et al., 2012). asymptomatic and therefore classified as having occult or silent
CD is reported to be associated with many functional cases. This lesion is characteristic, but not diagnostic, of celiac
gastrointestinal tract (GIT) disorders especially in its disease and can also be seen with severe giardiasis, infantile food
sensitivities, graft-versus-host disease, chronic ischemia of the
occult form; so many studies discussed the prevalence of
small intestine, tropical sprue, immunoglobulin deficiencies, and
CD in such functional disorders such as irritable bowel other immune deficiencies and allograft rejection.
syndrome and functional dyspepsia. In comparison with Serum tissue transglutaminase IgA antibody (anti-tTG-IgA) was
the general population, it was observed that CD had a measured for patients with histopathological findings suggestive to
greater prevalence in dyspeptic patients and that 30 to have CD (subtotal and total villous atrophy). It was measured using
40% of CD patients have dyspeptic symptoms. These the ELiA Celikey IgA kit (Phadia AB, Uppsala, Sweden). As
recommended by the manufacturer, levels greater than 10 U/mL
findings suggested that it would be useful to carry out, in were considered positive.
subjects undergoing esophago-gastro-duodenoscopy
(EGD), biopsies of the descending duodenum
independently of the endoscopic aspect of the mucosa Statistical analysis
(Keshavarz et al., 2010).
Until the year 2000, CD was almost unknown in Egypt, The Statistical Package for Social Science (SPSS), version 20, was
to the authors’ knowledge, few data are available on its used for the statistical analysis. Simple statistics such as frequency,
prevalence in Egypt and the relationship between mean and standard deviation (SD) were used. Also, Chi-square, t-
test was used for comparison. The results were considered
dyspepsia and CD. The diagnosis of celiac disease is statistically significant when the P values were<0.05.
based on demonstrating characteristic villous abnormality
of duodenal biopsy together with positive celiac serology.
Among the serological tests, endomysial antibody (EMA) RESULTS
and anti-tissuetransglutaminase antibodies (anti-tTG-IgA
or IgG) are commonly used (Gujral et al., 2012). Only patients with functional dyspepsia according to
Tissue transglutaminase is an intracellular enzyme Rome III criteria were enrolled in this study (228/400
present in many tissues. It has been found that it is not patients). One hundred and seventy two (172) patients
only increased in patients with celiac disease but also with endoscopic findings explaining their dyspeptic
correlated with duodenal histology and confirmed that this symptoms (gastritis or gastric ulcer etc.) were excluded.
enzyme is a target in the autoimmune process of celiac The included patients were 126 males and 102 females
disease (Rahmati et al., 2014). with age range of 14 to 50 years, mean age of
st
33.46±10.47 classified in four age groups; 1 from 14 to
nd rd
20 years, 2 from 21 to 30 years, 3 from 31 to 40 years
MATERIALS and METHODS th
and 4 from 41 to 50 years.
The study was carried out on 400 patients complaining of
Clinical bloating was the most common symptom
dyspepsia and attending the Gastroenterology Unit of Endemic (46.5%), normal villous pattern was found in 199 cases
Diseases and Internal Medicine Departments, Minia University (87.3%). Twenty nine patients (14 females and 15 males)
Hospital, Egypt. Patients already diagnosed with CD, with family had villous atrophy either subtotal atrophy in 20 cases
history of celiac disease, with inflammatory bowel disease or (8.8%) or total atrophy in 9 cases (3.9%). All these data
irritable bowel syndrome, diarrhea or malabsorption, significant
are shown in Table 1.
weight loss, any organ failure or refusing to be entitled in the study
were excluded. Regarding the relation between villous pattern and age
All patients were subjected to written informed consent before grouping, Table 2 showed that age grouping category of
participation in the study, full history taking, clinical examination and 14-20 years, 20/22 (90.9%) had villous atrophy with
underwent EGD using Pentax EPM-5000 after using the standard high statistically significant difference (P value
technique. Patients with endoscopic findings explaining their =0.000), while no statistically significant difference was
dyspeptic symptoms were also excluded from the study while
patients with no endoscopic findings explaining their dyspeptic
noticed between presence of villous atrophy and sex
symptoms were diagnosed as functional dyspepsia according to or residence. Table 2 shows also that bloating was the
Rome III criteria (Jung, 2011). most frequent symptom between patient with total
Duodenal biopsies were obtained by UGI endoscopy from those villous atrophy than abdominal pain and nausea with
100 Int. J. Med. Med. Sci.

Table 1. Demographic, clinical and pathological data of the patients.

Item
14-20 years 22 (9.6%)
21-30 years 54 (23.6%)
Age
31-40 years 84 )36.8%)
41-50 years 68 )29.8%)
Demographic data
Male 126 (55.3%)
Sex
Female 102 (44.7%)
Rural 91 (40%)
Residence
Urban 137 (60%)

Bloating 106)46.5%)
Clinical data Abdominal pain 94 (41.2%)
Nausea 62 )27.2%)

Normal villous pattern 199)87.3%)

Pathological findings Subtotal atrophy 20 )8.8%)
Total villous atrophy 9 )3.9%)

Table 2. Relation between villous pattern and different parameters.

Pathological findings
Item No Normal villous Abnormal villous
P value
pattern pattern
14-20 years 22 (9.6%) 2)9.1%) 20 (90.9%)
21-30 years 54 (23.6%) 50 (92.6%) 4 (7.4 %)
0.0000*
Age 31-40 years 84 (36.8%) 80 (95.2%) 4 (4.8%)
41-50 years 68 (29.8%) 67 (98.5%) 1 (1.5%)

Male 126 (55.3%) 111 (88.1%) 15 (11.9%)

Sex 0.681
Female 102 (44.7%) 88 (86.3%) 14 (13.7%)

Rural 91)40%) 78 (85.7%) 13 (14.3%)

Residence 0.563
Urban 137 (60%) 121 (88.3%) 16 (11.7%)

Bloating 106)46.5%) 85(35.8%) 21 (64.2%)

Complaint Abdominal pain 94 (41.2%) (91.5%)86 8 (8.5%) 0.006*
Nausea 62)27.2%) (95.2%)59 (4.8%)3

Table 3. Pathology and Ttg-IgA results.

Pathology
No. P value
Clinical data Subtotal v.atrophy Total v.atrophy
Negative 6 6(100%) 0(0%)
Serum TG 0.175
Positive 23 14(61%) 9(39%)

statistically significant difference (P value =0.006). with subtotal villous atrophy and positive anti-tTG-IgA. All
Nine patients are proved to have a celiac disease (total patients with total atrophy had positive anti-tTG-IgA
villous atrophy and positive anti-tTG-IgA) that could be (Table 3). Finally, Figures 1, 2 and 3 show normal villous
diagnosed as occult celiac disease. There are 14 patients pattern, subtotal and total atrophy, respectively.
 Fath-Elbab et al. 101

Figure 1. Normal villous pattern, with H&E (original magnification 100).

Figure 2. Subtotal villous atrophy, with H&E (original magnification 100).

102 Int. J. Med. Med. Sci.

Figure 3. Total villous atrophy, intense lymphocytic infiltration of the lamina propria and
intraepithelial lymphocytes (with H&E, original magnification 400).

DISCUSSION similar to the study done by Petrarca et al. (2014) which

revealed that 40 to 60% of the investigated patients with
The prevalence of clinically diagnosed disease is 0.05 to dyspepsia had normal endoscopic findings.
0.27% in various studies. African and American Those patients according to Rome criteria were
population studies indicate that a large proportion of diagnosed as functional dyspepsia and examined for
celiac disease remains undiagnosed; this is due to many villous atrophy by histopathological examination of the
clinicians being unfamiliar with the condition or the biopsies taken. Pathologically, the study revealed two
atypical presentation of the disease (Brar et al., 2006). As categories, patients with normal villous pattern (199
such, endoscopy with biopsy is still considered the gold patients) and patients with villous atrophy (29 patients)
standard in the diagnosis of celiac disease. who were subclassified according to the degree of villous
CD is reported to be associated with many functional atrophy into two subgroups: group of patients with total
GIT disorders, especially in its occult form; so many villous atrophy (9 patients), and group of patients with
studies discussed the prevalence of CD in such subtotal villous atrophy (20 patients).
functional disorders such as irritable bowel syndrome and This study revealed that the age group, 14 to 20 years
functional dyspepsia. These studies recommended that showed statistically significant relationship with abnormal
screening for CD in patients suffering from functional GIT villous pattern patients (90.9%) (P value=0.000), this in
disorders should be done and confirmed by the data accordance with Emami et al. (2008), who found that
which revealed that the prevalence of celiac disease 10% of patients with villous atrophy were under the age
among patients with functional dyspeptic symptoms and of 18 years, while Farahmand et al. (2012), revealed that
patients with IBS ranges from 0.5 to 2% (Petrarca et al., 0.5% of patients under 18 years have occult celiac
2014). disease, this difference may be explained by the different
This study was done on 400 patients with dyspeptic sample types and different races.
symptoms. Upper GIT endoscopy was done to all As confirmed by most of the studies on occult celiac
patients and those with endoscopic findings explaining disease, the current study revealed no significant
their dyspeptic symptoms (non-functional dyspepsia) relationship between sex or residency and the presence
were excluded from the study. 228 (57%) patients with of villous atrophy; however. Ganji et al. (2014) showed a
dyspepsia showed macroscopically normal mucosa when significant relation between female sex and the presence
performing upper gastrointestinal endoscopy. This was of CD.
 Fath-Elbab et al. 103

Bloating was the predominant complaint (64.2%) in available literature. Based on this discussion, during
both subtotal and total villous atrophy groups, similar endoscopic examination for dyspepsia if indicated,
results have been reported by Rahmati et al. (2014), who endoscopists should carefully inspect the duodenum for
found that 65.4% patients with different degrees villous CD findings and should take biopsies, especially for
atrophy complained of bloating, also, Nejad and Zali patients with bloating and age group ranging from 14 to
(2012) showed that 16% of patients with bloating 20 years.
symptoms have high anti-tTG level; 60% of them had
different degrees of villous atrophy. This is different from
study of Emami et al. (2008) that about 1.3% of patients Conclusion
with non-specific gastrointestinal symptoms like bloating
and abdominal pain have celiac disease and villous In conclusion, based on the results obtained, it can be
atrophy. The difference in these studies may be due to hypothesized that for patients who have been diagnosed
the different geographical areas. as having functional dyspepsia with normal upper GIT
In the present study, anti-tTG-IgA level was assessed endoscopic findings, endoscopic examination should be
in cases with villous atrophy and it was found that all completed with duodenal biopsies and histopathological
patients with total villous atrophy have positive anti-tTG- examination of the biopsies taken to exclude any degree
IgA and they were confirmed to have celiac disease. of villous atrophy and the presence of occult celiac
Lima et al. (2005) found that out of 142 patients with disease. Particular attention should be given to patients
dyspeptic symptoms, two were found to have total villous with high tissue transglutaminase level especially at the
atrophy and positive tissue transglutaminase. age group of 14 to 20 years and the presence of bloating
Although, many studies have confirmed the correlation as a predominant dyspeptic symptom. Such an approach
between anti-tTG and the degree of duodenal damage could reveal another submerged part of the "Celiac
and the high sensitivity and specificity of anti-tTG to Icberg" but it must be validated as regards the cost
diagnose CD, in this study, the authors emphasized on effectiveness, bearing in mind the variable prevalence of
the detection of the occult CD by both histopathology and the disease in the different geographical areas.
anti-tTG-IgA level. A combination of clinical presentation, histology and
This study revealed that, out of the 228 investigated serology would contribute to making a more accurate
patients with functional dyspepsia, 14 patients were diagnosis.
diagnosed as occult celiac disease and had subtotal
villous atrophy with positive anti-tTG-IgA with prevalence
of about 6.1%. It is demonstrated that the prevalence of CONFLICT OF INTERESTS
occult CD in patients with dyspepsia is higher than that of
the general population in Egypt (Abu-Zekry et al., 2008). The authors have not declared any conflict of interests.
Another study from eastern country was conducted on
225 dyspeptic Iranian patients, revealing that about 6% of
the selected patients with functional dyspepsia had occult ACKNOWLEDGEMENT
celiac disease (Keshavarz et al., 2010). Also, Nakazawa
et al. (2014) found that seven of the eleven patients with The authors thank the team in GIEndoscopy unit, Minia
anti-tTG exhibited villous atrophy and partial infiltration of University Hospital.
intraepithelial lymphocyte. On the other hand, Rostami et
al. (1999) showed that 3 out of 1000 patients had partial REFERENCES
villous atrophy with anti-tTG results and was defined as
Abadie V, Sollid L, Barreiro LB (2011). Integration of genetic and
occult celiac disease. immunological insights into a model of celiac disease pathogenesis.
In this study, comparison between the group of celiac Annu. Rev. Immunol. 29:493-525.
disease (total villous atrophy with positive anti-tTG-IgA) Abu-Zekry M, Kryszak D, Diab M, Catassi C, Fasano A (2008).
and the group of occult celiac disease (subtotal villous Prevalence of celiac disease in Egyptian children disputes the east-
west agriculture-dependent spread of the disease. J. Pediatr.
atrophy and positive anti-tTG-IgA) as regard anti-tTG-IgA
Gastroenterol. Nutr. 47(2):136-140.
level using student t test revealed that, there was no Brar P, Lee AR, Lewis SK (2006). Celiac disease in African-Americans.
statistically significant difference between the two groups Digest. Dis. Sci. 51:1012-1015.
as regard anti-tTG-IgA level which predicts the high Corazza GR, Villanacci V (2005). "Coeliac disease". J. Clin. Path.
58(6):573-74. Available at:
probability of the patients with subtotal villous atrophy to http://pubmedcentralcanada.ca/pmcc/articles/PMC1770677/
develop overt celiac disease and total villous atrophy Emami MH, Karimi S, Kouhestani S, Hashemi M, Taheri H (2008).
within time. Diagnostic Accuracy of IgA anti-Tissue Transglutaminase in Patients
Therefore, celiac disease and occult CD should be kept Suspected of Having Coeliac Disease in Iran. J. Gastrointestin. Liver
Dis.17(2):141-146.
in mind as a cause of functional dyspepsia during clinical Farahmand F, Shahraki T, Yourdkhani F, Ghotb S, Modaresi V,
activities. Routine serologic screening of CD among Khatami GR (2012). Prevalence of Occult Celiac Disease in Healthy
dyspeptic patients cannot be recommended based on Iranian School Age. Children Arch. Iran. Med. 15(6):342-345.
104 Int. J. Med. Med. Sci.

Ganji A, Esmaielzadeh A, Aghayee MA, Goshayeshi L, Ghaffarzadegan Nejad MR, Zali MR (2012). Specific Coeliac Disease Antibodies and
K (2014). The Clinical Presentation of Celiac Disease: Experiences Microenteropathy: Serological Diagnosis of Certain Human, Animal
from Northeastern Iran. Middle East J. Digest. Dis. 6(2):93-97. and Plant Diseases pp.153-160.
Gujral N, Freeman HJ, Thomson AB (2012). Celiac disease: Petrarca L, Nenna R, Mastrogiorgio G, Florio M, Brighi M, Pontone S
prevalence, diagnosis, pathogenesis and treatment. World J. (2014). Dyspepsia and celiac disease: Prevalence, diagnostic tools
Gastroenterol. 18 (42):6036-6059. and therapy. World J. Methodol.4(3):189-196.
Jung HK (2011). Rome III criteria for functional gastrointestinal Rahmati A, Shakeri R, Sohrabi MR, et al (2014). Correlation of Tissue
disorders is there a need for a better definition? J. Transglutaminase Antibody with Duodenal Histologic Marsh Grading.
Neurogastroenterol. Motil. 17(3):211-212. Middle East J. Dig. Dis. 6(3):131-136.
Keshavarz AA, Bashiri H, Ahmadi A, Bazargan-Hejazi S (2010). The Rostami K, Mulder CJJ, Werre JM, Van Beukelen FR, Kerckhaert J,
prevalence of occult celiac disease among patients with functional Crusius JBA, Pena AS, Willekens FLA. Meijer JWR (1999). High
dyspepsia: A study from the Western Region of Iran. Gastroenterol. Prevalence of Celiac Disease in Apparently Healthy Blood Donors
Res. Pract. 2010:170702 Suggests a High Prevalence of Undiagnosed Celiac Disease in the
Lima VM, Gandolfi L, Pires JA, Pratesi R (2005). Prevalence of celiac Dutch Population. Scand. J. Gastroenterol. 34(3):276-279.
disease in dyspeptic patients. Arq. Gastroenterol. 42(3):153-156.
Nakazawa H, Makishima H, Ito T, Ota H, Momose K, Sekiguchi N,
Yoshizawa K, Akamatsu T, Ishida F (2014). Screening tests using
serum tissue transglutaminase IgA may facilitate the identification of
undiagnosed celiac disease among Japanese population. Intl. J.
Med. Sci. 11(8):819-823.