|Year : 2020 | Volume
| Issue : 1 | Page : 1-6
Prevalence of celiac disease among children with Down syndrome attending the genetics clinic at Alexandria University Children Hospital
Ahmed F.M Khalil1, Iman M Marzouk1, Akram A Deghady2, Yahia A Mohamed1
1 Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||29-Oct-2019|
|Date of Decision||11-Nov-2019|
|Date of Acceptance||19-Dec-2019|
|Date of Web Publication||26-Jun-2020|
MD, PhD Ahmed F.M Khalil
Lecturer of Pediatrics and Pediatric Gastroenterology, Department of Pediatrics, Alexandria University, Alexandria, 2164655
Source of Support: None, Conflict of Interest: None
Background Celiac disease (CD) is an immune-mediated disease affecting the small intestine secondary to gluten exposure. The currently available treatment is lifelong adherence to a gluten-free diet. Several disorders have a higher risk to develop CD, including Down syndrome (DS). In several studies, the prevalence of CD in DS ranged between 4 and 17%. CD is prevalent in Arabs; however, few studies have been performed to determine the prevalence of CD in DS patients.
Aim This study aimed to estimate the prevalence of CD in Egyptian children with DS.
Patients and methods This study was performed as a cross-sectional study. The patients were recruited from the Genetics Outpatient Clinic at Alexandria University Children Hospital. Screening for CD was done by using only serological markers: anti-tissue transglutaminase-immunoglobulin A (IgA) and total IgA followed by anti-endomysial antibody and small bowel biopsy for positive cases. HLA typing was not performed before serology.
Results The total number of the study sample was 54. The mean age was 4.26±1. 94 years ranging from 2 to 12 years; 61.1% of cases were men. All studied children had normal serum total IgA. Serum transglutaminase-IgA was elevated in three (5.6%) cases. Endomysial antibody was positive in two of them. Histopathological analysis confirmed the diagnosis of CD in two (3.8%) patients; one of them was completely asymptomatic.
Conclusion Our study showed a confirmed prevalence of 3.8% for CD in the studied Egyptian patients with DS based on serology and biopsy. This result indicates the need for regular screening of these patients for CD.
Keywords: celiac disease, Down syndrome, screening approach, transglutaminase-immunoglobulin A
|How to cite this article:|
Khalil AF, Marzouk IM, Deghady AA, Mohamed YA. Prevalence of celiac disease among children with Down syndrome attending the genetics clinic at Alexandria University Children Hospital. Alex J Pediatr 2020;33:1-6
|How to cite this URL:|
Khalil AF, Marzouk IM, Deghady AA, Mohamed YA. Prevalence of celiac disease among children with Down syndrome attending the genetics clinic at Alexandria University Children Hospital. Alex J Pediatr [serial online] 2020 [cited 2020 Jul 7];33:1-6. Available from: http://www.ajp.eg.net/text.asp?2020/33/1/1/287728
| Introduction|| |
Celiac disease (CD) is an autoimmune disorder induced by gluten-containing foods: wheat, rye, and barley . It may develop at any age as a result of genetic predisposition together with exposure to gluten. Research carried out during the last two decades has proved that a central role in the pathogenesis of the disease is played by major histocompatibility complex class II HLA antigens: HLA-DQ2 and HLA-DQ8 . The absence of HLA-DQ2 and HLA-DQ8 has a strong negative predictive value for CD .
On the basis of clinical, serological, and histological variations, CD may be classified into two basic types: asymptomatic and symptomatic . The symptomatic form of CD can present with either classical or atypical presentation . The classical form usually occurs in infants and toddlers and manifest with a chronic diarrheal disorder, anorexia, vomiting, abdominal distension, and pain . Among adolescents and adults, CD presents with atypical form, with absent or mild gastrointestinal symptoms, and with more common extraintestinal manifestations, such as growth retardation, sideropenic anemia resistant to oral iron therapy, or dermatitis herpetiform .
Down syndrome (DS) is a chromosomal disorder caused by trisomy and other aberrations of chromosome 21 . The prevalence of DS is 1 : 733, therefore, it is considered the most common chromosomal disorder and one of the leading causes of mental retardation .
The association between CD and DS was first described in 1975 by Bentley . Children with DS have a higher risk for developing CD and are recommended for screening by both ESPGHAN, NASPGHAN, and European Down Syndrome Association. Compared with the general population, the atypical form of CD is more frequent in DS children . About one-third of DS patients with CD have no gastrointestinal symptoms at all and so screening is considered crucial in this group of patients especially in developing countries where CD is usually overlooked .
The diagnosis of CD is based on serological markers, genetic studies, and is confirmed by small intestine biopsy . Till now, no single approach for CD diagnosis has a worldwide acceptance. The 2012 ESPGHAN guidelines recommended screening using total immunoglobulin A (IgA) and transglutaminase (TGA)-IgA for symptomatic cases and HLA typing for asymptomatic high-risk groups . Following the publication of these guidelines, many studies have recommended not to use HLA typing for screening due to its high cost, especially in countries with limited resources ,. In the recently published guidelines, the ESPGHAN now recommends the start of screening by serology alone using total IgA and TGA-IgA for both symptomatic and asymptomatic high-risk groups .
| Aim|| |
The aim of this study is to estimate the prevalence of CD among children with DS in Alexandria.
| Patients and methods|| |
This work was conducted as a prospective cross-sectional study and included children with DS recruited from the Genetics Outpatient Clinic at Alexandria University Children’s Hospital during the period from 11/2018 to 4/2019. The minimum sample size required was 50 children. Cases who started gluten-containing diet for less than a year were excluded from the study . The study was approved by the Ethics Committee, Faculty of Medicine, Alexandria University. An informed written consent was taken from the parents or caregivers of all included children.
Full medical history focusing on nutritional history and gastrointestinal symptoms, clinical examination and laboratory investigations (complete blood count, iron profile, liver transaminases, and serum albumin) were done for all cases.
Screening for CD was performed by measuring the serum level of total IgA and TGA-IgA. Total IgA level was determined by turbidimetry and was considered abnormal when less than 10 ng/dl. TGA-IgA level was determined by enzyme-linked immunosorbent assay with human recombinant TGA as antigen using a commercially available kit (Eu-tTGA; Eurospital, Trieste, Italy), and the test was considered positive at levels more than 10 units/ml. Serum anti-endomysial antibody (EMA) level was tested for those with positive screening by using indirect immunofluorescence on commercially available cryosections of monkey esophagus as a substrate (Dahlewitz, Germany) and positive EMA results (from + to +++) were identified by the characteristic honeycomb pattern observed around the smooth muscle fibers of the esophagus.
Upper gastrointestinal endoscopy under general anesthesia was performed for cases with positive serology. Biopsies were obtained from the duodenum (at least two from the bulb and four from the second and third parts) . Biopsy specimens were taken and examined histologically for features of CD. Histologically proven CD was then classified according to the modified Marsh–Oberhuber classification .
Statistical analysis was carried out using SPSS statistics software version 23 (IBM SPSS Statistics for Windows, Version 23 Armonk, NY: IBM Corp). Data were expressed as percentage of the total for categorical variables, as mean with SD for normally distributed continuous variables, or as median with interquartile range for skewed distributed variables.
| Results|| |
Demographic, clinical, and laboratory characteristics of patients
The study included 54 children with DS. The mean age for the studied group ranged from 2 to 12 years (4.26±1.94 years); 61.1% of cases were men. Early introduction of gluten into the patients’ diets (before 6 months of age) and positive family history of CD were not reported among the study group.
Chronic abdominal pain was reported in 33.3% of cases and it was due to functional constipation (FC) in most of them (83.3%). Chronic watery diarrhea was present in one patient. Only 3.8% of the study cases were below the fifth centile as regards weight and height for age according to growth charts for children with DS. Two (93.7%) patients had hypothyroidism. Marked pallor was present in 9.3% of cases. About 20% of cases had abdominal distention but no organomegaly was felt. It was due to associated FC. In 18.5% of the patients, cardiac murmur was noticed (unoperated congenital heart disease). No children were found to have dental enamel defects or dermatitis herpetiformis. All children had normal values as regards complete blood count, iron profile, albumin, and hepatic transaminases except for five (9.2%) children who had hypochromic microcytic anemia with hemoglobin level ranging from 7 to 10.5 g/dl. The anemia was due to iron deficiency with serum iron ranging from 15 to 45 μg/dl.
Screening for celiac disease
All studied children showed normal levels of serum total IgA. Serum TGA-IgA was elevated in three (5.6%) cases. EMA was positive in two of these three (66.6%) cases. Biopsy samples taken during upper gastrointestinal endoscopy showed histological features of CD in only two (66.6%) of the three patients with positive screening. Thus, the prevalence of histologically confirmed CD in the studied group of DS children was 3.8%. One of the two confirmed cases was completely asymptomatic (50%). Both cases with confirmed CD were positive for anti-EMA.
Clinical, laboratory, and histopathological profile in patients with suspected celiac disease
CD was diagnosed in two female patients with high positive serology (>100). The first case was 12 years old, with a 3-month history of chronic watery diarrhea, anemia, and weight loss, while the other case was an asymptomatic 8-year-old girl with DS. The third patient was with positive serology, but with absent histological features of CD was a 5-year-old male patient with poor weight gain and iron-deficiency anemia (IDA), which can be attributed to poor nutritional intake rather than malabsorption ([Table 1], [Figure 1]).
|Table 1 Clinical and laboratory profile of patients with suspected celiac disease|
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|Figure 1 Flowchart for screening for CD in the studied DS patients. CD, celiac disease; DS, Down syndrome.|
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The association between clinical presentations among the whole group of patients and the results of serology and final diagnosis of CD is shown in [Table 2].
|Table 2 Association between the clinical presentations of the patients and results of serology and final diagnosis of CD|
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| Discussion|| |
Children with DS have a higher risk for developing CD and they may be totally asymptomatic or present with atypical presentation. In addition, typical presentations of CD-like growth failure, anemia, intermittent diarrhea, vomiting, and constipation are of little clinical significance in patients with DS because they can be attributed to other comorbid conditions such as congenital heart defects and hypothyroidism. Because of intellectual disability, DS patients may be unable to accurately describe their symptoms . This makes the diagnosis of CD in DS patients very challenging. Screening of children with DS for possible silent or atypical CD is the best way to detect CD in this particular population and is recommended by many different health authorities. Clinical screening is very important especially in developing countries such as Egypt where pediatricians are not familiar with CD and its wide range of possible presentations.
The present study aimed to estimate the prevalence of CD in children with DS through screening of all the DS cases attending the Genetics Outpatient Clinic of Alexandria University Children’s Hospital during the study period. This study included 54 patients with DS, 66% of them were men. Two of the three serologically positive cases were women and the diagnosis of CD was histopathologically confirmed in both of them. This correlates with the fact that CD affects women more than men with a ratio of 2 : 1 in the general population .
Patients with DS are more prone to chronic FC compared with general population due to feeding malpractice (including reduced fluid and fibers intake) and hypotonia with subsequent slowing of the intestinal motility allowing more water reabsorption from the colon with subsequent hardening of the stool and difficult painful defecation . In this study, almost one-third of the total patients had FC (27.7%). Multiple researchers reported that FC is one of the most common atypical clinical presentations of CD in children with DS (25–38.5%) ,. In this study, none of the CD patients presented with FC. Chronic diarrhea or even normal bowel movements were the predominant findings in our patients. Similarly, Dehghani et al.  found that constipation in children with CD is not significantly different from that of the general population and that chronic diarrhea was the predominant pattern of bowel movement.
IDA is a major public health problem which has an impact over the motor and cognitive development in children and can lead, if neglected, to irreversible compromise. Similar to the general population, DS patients are at risk for IDA and its complications. In this study, 9% of the cases were anemic (four patients), one of them had CD. Few researches studied IDA in DS and the reported prevalence ranged from 1.73 to 3%, which was comparable to the prevalence in the general population in these communities ,. The high prevalence in our cohort can be attributed to low socioeconomic conditions and poor health education especially about proper diet for children which is responsible for the higher prevalence of IDA in our population.
Most of the serological tests available for CD screening depend on detection of antibodies of the IgA class. IgA deficiency is the most common primary immunodeficiency and it is quite common in Caucasian populations with an incidence of 1 : 143 (0.69%) in Arab populations . We tested our individuals for total serum IgA level to exclude IgA deficiency syndrome, which is known to be commonly associated with CD and can result in false-negative results for serologic screening using TGA-IgA. None of our patients had total IgA deficiency, which may be due to the small sample size in our study.
At the initiation of this study, the ESPGHAN recommendations, published in 2012, were to screen all asymptomatic cases belonging to the high-risk groups including DS, with HLA typing DQ-2or DQ-8 followed by serologic testing for those who are positive using TGA-IgA. Upper gastrointestinal endoscopy and duodenal biopsy should be done if the antibody titer is three times more than the normal value or in case of positive EMA testing (which is done in cases with positive TGA-IgA but less than three times of normal) . The limitation of this approach is that HLA testing is expensive and not readily available especially in countries with limited resources. In this study, we adopted a different screening approach that started with serological screening of TGA-IgA followed by anti-EMA IgA (only for those positive for TGA-IgA). Upper GI endoscopy and duodenal biopsy were performed to all serologically positive patients. This approach is more practical and appropriate for countries with limited resources like ours.
In our cohort of DS children, 5.6% of DS children were seropositive for CD, yet 3.8% were biopsy proven to have CD. This represents a nearly seven-fold increase over the estimated prevalence of CD in the general pediatric population in Egypt which was found to be 0.53% . This highlights the importance of screening of DS patients for CD in our community even if they are asymptomatic.
The reported prevalence of CD in patients with DS worldwide differs significantly from one study to another. The prevalence ranges from 1%  up to as much as 18.6% . This wide range may be due to different sample sizes, different age groups, differences in sensitivity, and specificity of the chosen antibody test for screening and different ethnicity.
Data from the Middle East regarding screening of DS for CD are limited. Two studies conducted in Saudi Arabia and Heifa, using similar approach to ours, reported that the prevalence of seropositive patients was 4 and 9.6%, respectively, while the prevalence of histologically confirmed CD was 2 and 3.8%, respectively ,. In a more recent study from Saudi Arabia, the prevalence of histologically confirmed CD was 10.7%. This higher prevalence can be attributed to different selection criteria. This prevalence was reported based on a retrospective analysis of data of symptomatic DS patients who were referred for diagnosis at a tertiary center .
Many other studies conducted in Europe and USA using a screening approach similar to the one used in this study reported that the prevalence of histologically confirmed CD ranged from 4.6 to 7.5% ,. This higher prevalence is explained by the higher prevalence of CD among the general population in these countries.
Other studies using HLA typing as the first step for screening of CD reported a similar prevalence rate of CD in DS children . In their researches, Paul et al.  and Francavilla and Castellaneta  studied the cost of HLA typing plus the repeated serological screening for the positive HLA cases in comparison to the cost of TGA-IgA. They concluded that CD screening should not be started with HLA typing as it increases the cost by about 60%.
Based on the similarity of the prevalence rates of CD in DS patients using either of the two methods of screening together with the much higher cost of the HLA typing approach, we recommend that screening in high-risk groups to be performed using serological tests instead of HLA typing. Lately in 2019, ESPGHAN modified the previous recommendations published in 2012 and currently adopted using serology as the initial screening tool instead of HLA typing even in asymptomatic high-risk groups including DS . This matches with the approach used by many studies including the current one.
In this study, one of the two histologically confirmed CD patients was an asymptomatic child with DS (50% of CD cases). The prevalence of asymptomatic CD in children with DS was reported to range from 40 to 50% , This highlights again the importance of CD screening in DS cases even in the absence of symptoms especially in communities in which the awareness about CD is still low.
This study highlighted the increased prevalence of CD among children with DS and showed that non-HLA screening approach for high-risk groups is dependable and more practical and economical. The limitations of this study were the small sample size and screening of children in a single tertiary center. Screening of children with DS in multiple centers across the country will highlight the true prevalence of CD among Egyptian children with DS.
In conclusion, the prevalence of CD among our children with DS is higher than that of the general Egyptian population (5.6% as assessed by serology and 3.8% biopsy proven), which is similar to the reported worldwide prevalence. The adopted approach in this study is accurate, easy, and suitable for our limited resources. It can be used for screening of CD in all DS cases in Egypt whether symptomatic or not.
Furthermore, we recommend following the new screening guidelines of CD in children with DS and to screen DS children younger than 3 years with suspicious atypical symptoms as failure to thrive or refractory IDA . Periodic screening of CD every 3 years is strongly recommended regardless of the symptoms and yearly for those who are serologically positive with negative biopsy . Lastly, the case with positive serology yet negative histology for CD (latent celiac) is recommended for follow-up endoscopy and biopsies if the patient develops symptoms suggestive of CD anytime later or if the level of TGA-IgA rises to more than 10 ULN during the next follow-up screenings.
| Conclusion|| |
Our study showed a high prevalence of CD in patients with DS based on positive serology and biopsy results, and these patients included both symptomatic and asymptomatic individuals. This high prevalence indicates the need to screen such patients, even if they are asymptomatic.
The research was supported by Alexandria Faculty of Medicine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]