Abstract
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 (GFD). Several disorders are known to be associated with celiac disease, 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. Our study aimed to determine the prevalence of CD in Saudi Down syndrome patients using serological markers and small bowel biopsy.
This is a retrospective study in which files relating to Down syndrome patients who were followed up in a general pediatric clinic at King Faisal Specialist Hospital and Research Center were reviewed regarding demographic data, serological markers and biopsy results.
Of the total number of patients reviewed (91), 7 were excluded because data were missing; the remaining 84 patients included 35 females and 49 males. The age range of the patients at the time of screening was from 1 to 18 years. Patient demographic data are shown in Table 1. Among the studied patients, antigliadin antibody (AGA) IgA was high in 27 patients (32.14%), and AGA IgG was high in 44 patients (52.38%). Twelve patients (14.28%) tested positive and 58 (69.04%) tested negative for anti-endomysial antibodies. Anti-tissue glutaminase antibody IgA was found to be high in 13 patients (15.5%) and normal in 54 patients (64.28%). Serum IgA levels were normal in 36 patients (43%) and low in 1 patient (1.2%). Biopsy was performed in 22 patients who tested positive for anti-endomysial or anti-tissue transglutaminase antibodies. The biopsies provided positive results in 9 patients (10.7%).
Our study showed a confirmed prevalence of 10.7% for celiac disease in Saudi patients with Down syndrome based on serology and biopsy; together with previous cases reported in the literature, this result indicates a need to screen these patients for celiac disease.
Keywords: Celiac disease, CD, Down syndrome, DS, Saudi, Children
1. Introduction
Celiac disease (CD) is an autoimmune-mediated disease affecting the small intestine secondary to gluten exposure in genetically susceptible individuals. The currently available treatment is life-long adherence to a gluten-free diet (GFD).
The globally accepted diagnostic criteria were promulgated by the European Society of Pediatric Gastroenterology Hepatology and Nutrition in 1990 [1]. Celiac disease can present with a variety of gastrointestinal and non-gastrointestinal symptoms, although some patients are asymptomatic [2]. The diagnosis can be based on serological markers, genetic studies and confirmed by small intestine biopsy. The serological markers include anti-gliadin antibodies (AGA) IgA and IgG which are sensitive but less specific and can be elevated in other conditions [3]. Tests based on anti-endomysial antibodies (EMA-IgA) have high sensitivity and specify (95% and 100%, respectively), and the current practice is to conduct an intestinal biopsy when a patient tests positive [4]. Anti-tissue transglutaminase IgA antibodies (TTG) are similar to EMA-IgA in terms of sensitivity and specify. Although these tests are good, they exhibit some limitations [5]. Intestinal biopsy is the gold standard procedure for diagnosing CD [6], [7], [8]. Histological changes can range from increased intraepithelial lymphocytes and crypt hyperplasia to total villous atrophy. Those changes have been graded by March from 0 to 4, where grade one is considered non-specific and grades 3 and above are considered diagnostic for celiac disease [8], [9].
Several disorders are known to be associated with celiac disease, including Down syndrome and Turner syndrome [10], [11]. Additionally, the disease can be found with other autoimmune disorders; e.g., type 1 diabetes mellitus, Addison's disease, and auto-immune thyroiditis [12].
Down syndrome (DS) is chromosomal anomaly that can lead to multiple systemic involvements, such as those with the cardiac, gastrointestinal and central nervous systems. In addition, DS can be associated with autoimmune diseases, such as celiac disease. The prevalence of celiac disease in DS ranges between 4 and 17%.
In a small-population study by Saadah et al examining 51 Saudi children with Down syndrome, 4% had positive serological markers, and 2% had proven biopsy of celiac disease [13].
The aim of our study was to determine the prevalence of biopsy proven celiac disease in Saudi children with Down syndrome and to describe the serological characteristics, presence of symptoms and other disorders associated with this disease.
2. Patients and methods:
This is retrospective chart review study of Saudi children with Down syndrome visiting King Faisal Specialist Hospital and Research Center, Riyadh between 2003 and 2013 who were screened for celiac disease. Our inclusion criteria were as follows: children less than 18 years of age and confirmed Down syndrome by chromosomal analysis; both males and females were included.
The collected data included age, gender, serological test and biopsy results.
Children with positive biopsy results were further reviewed regarding the presence of symptoms, growth patterns (plotted against a specific Down syndrome growth chart) and hemoglobin level.
Total IgA levels were determined by turbidimetry and were considered normal when <70 ng/dl. Anti-tissue glutaminase antibodies were determined by enzyme-linked immunosorbent assay (ELISA) with human recombinant TTGA as antigen using a commercially available kit (Eu-tTGA, Eurospital, Trieste, Italy), and the test was considered positive at levels >20 units. Anti-gliadin IgA and IgG were determined using a modified enzyme-linked immunosorbent assay (ELISA) method named the fluoroenzyme immune assay (FEIA) using a Pharmacia UniCAP-100 system; children were considered IgA-positive if levels were >3 mg/l and IgG-positive if levels were >18 mg/l.
Anti-EMA and ARA were determined using indirect immunofluorescence methods involving rat kidney and monkey esophagus tissue substrates, respectively (INOVA CAT#508170 and 5083300), and the results are reported as positive, weakly positive or negative [15]. Biopsy was considered positive at March grade 3 and above [8], [9].
Statistical analysis was performed using SPSS software; the Chi square test was used for categorical variables, and Fisher's exact test was used for continuous variables. P values < 0.05 were considered significant.
3. Results
The total number of patients reviewed was 91; of these, 7 were excluded because data were missing, and the remaining 84 patients included 35 females and 49 males. The age range of the patients at the time of screening was 1–18 years. Patient demographic data are reported in AGA Table 1. Among all patients, AGA IgA was high in 27 (32.14%) and IgG was high in 44 (52.38%). Twelve patients (14.28%) tested positive and 58 (69.04%) tested negative for anti-endomysial antibodies. Anti-tissue glutaminase antibody IgA was found to be high in 13 patients (15.5%) and normal in 54 patients (64.28%). Serum IgA levels were normal in 36 patients (43%) and low in 1 patient (1.2%) and were not measured in the remaining patient (1.2%) Table 2.
Table 1.
Baseline demographic data of patients with Down syndrome who were screened for celiac disease.
| Baseline characteristics | Mean ± SD | range |
|---|---|---|
| Age (y) | 6.1 ± 3.1 | 1-18 y |
| Female (n) | 35 | |
| Male (n) | 49 | |
| Height (cm) | 101 ± 22.2 | (53–154) |
| Weight (kg) | 20.5 ± 14.3 | (3.2–77.5) |
| Hgb (mg/dl) | 128.5 ± 17.1 | (77–170) |
| TSH (μmol/l) | 6.1 ± 2.8 | (1.4–14.4) |
Table 2.
Serological marker and biopsy results.
| Serological markers | Frequency (%) |
|---|---|
| Antigliadin antibody | |
| IgG | |
| High | 45 (57.7%) |
| Normal | 33 (42.3%) |
| IgA | |
| High | 27 (32.14%) |
| Normal | 50 (52.38%) |
| EMS | |
| Positive | 12 (14.3%) |
| Negative | 58 (69.04%) |
| tTG | |
| High | 13 (15.47%) |
| Normal | 54 (64.28%) |
| Biopsy | |
| Positive | 9 (41%) |
| Negative | 13 (60%) |
Biopsy was performed in 22 patients who tested positive for anti-endomysial or anti-tissue transglutaminase antibodies. The biopsies were positive in 9 of these patients (10.7%).
Patients with positive biopsy were reviewed; 6 patients had symptoms including poor weight gain in 2, vomiting in 2, diarrhea in 1 and constipation in 2. Three of these patients were asymptomatic Table 3.
Table 3.
Characteristics of down syndrome patients with positive biopsy.
| Patient | Sex | IgA | AGA IgA | AGA IgG | EMS | TTG | WT (percentile) | Hgb mg/dl | symptoms | Thyroid status |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | ND | H | H | POS | H | 75 | 11 | Gastritis | Hypo |
| 2 | F | N | H | H | POS | H | 50 | 14 | No | Hypo |
| 3 | F | N | H | H | NEG | N | 25 | 14 | FTT | Hypo |
| 4 | F | N | H | H | POS | H | 5 | 9.9 | Vomiting/FTT | Hypo |
| 5 | F | N | N | H | NEG | H | 95 | 14 | NO | Hypo |
| 6 | F | H | H | H | POS | H | 50 | 12 | NO | N |
| 7 | F | H | H | N | NEG | N | 95 | 13.5 | Constipation | Hypo |
| 8 | F | H | N | N | NEG | ND | 5 | 9.9 | Diarrhea | N |
| 9 | F | ND | N | H | POS | ND | 50 | 9 | constipation | Hypo |
(M = male; F = female; N = normal; ND = not done; H = high; POS = positive; NEG = negative; FTT = failure to thrive; Hypo = hypothyroidism).
(WT based on a standard Down syndrome growth chart).
4. Discussion
Several disorders are known to be associated with celiac disease; these diseases include Down syndrome (in 4–14% of patients), type I diabetes mellitus (in 3–8% of patients), Turner's syndrome (in 4.1–8.1% of patients), William's syndrome (in 8.2% of patients) and IgA deficiency (in 2% of patients) [7]. Strong evidence also exists that first-degree relatives of celiac patients are at increased risk of developing CD, with a prevalence of 4–5% [10].
Down syndrome (DS, also known as trisomy 21) is a major cause of mental retardation, affecting 1 of 800 newborns. Approximately 95% of DS cases are caused by the presence of 3 copies of chromosome 21 (complete T21). DS can lead to multiple system involvement, including the cardiac, gastrointestinal, and central nervous systems, among others. In addition, DS can also be associated with autoimmune diseases such as celiac disease, autoimmune thyroiditis, and type I DM [11], [16], [18], [19], [20], [21], [22].
CD is also prevalent in other Arab populations and is under-diagnosed in high-risk groups; however, limited studies have been conducted in Arabic countries to determine the prevalence of CD in DS patients. In a study performed in Tunisia, in which 27 patients with DS were studied prospectively, more than 10% of the patients were confirmed to have CD by intestinal biopsy [16]. In other studies, the prevalence was found to range between 2 and 3.8% [13], [17].
In a study of 123 Saudi children with type I diabetes mellitus, six (4.9%) had histological evidence of CD, and all were asymptomatic [14].
Another cross-sectional study was conducted in 42 Saudi children with idiopathic juvenile rheumatoid arthritis (JRA) (2.38%) with positive AEA and showed histological evidence of intestinal villous atrophy [15].
The prevalence of CD in patients with DS is high based on biopsy results; these results are similar to those found in the previous studies mentioned. Most patients with positive biopsies are symptomatic; however, some had no symptoms despite showing features of CD in their biopsy; this might have occurred because detection was early and occurred before the patients became symptomatic. The patients also had other associated autoimmune disorders, such as hypothyroidism, which is quite common in patients with Down syndrome. The prevalence found in our study might have been greater if we consider that some patients were not measured for total IGA level and normal serological markers. In addition, not all patients were measured for TTG IgA levels because this test was unavailable at the time of screening.
The study was performed at a tertiary hospital with certain acceptance criteria, and this might have affected our result.
5. Conclusion
Our study showed a high prevalence of celiac disease in patients with Down syndrome based on positive serology and biopsy results, and these patients included both symptomatic and asymptomatic individuals. The prevalence might be higher when we consider that patients with minimal histological changes might have celiac disease. This high prevalence indicates the need to screen such patients, even if they are asymptomatic.
Conflict of interest
We confirm that none of the authors have any conflicts of interest associated this manuscript.
Footnotes
Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.
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