The overall rate of celiac disease in the United States in the general population has been estimated at approximately 1% (1,2). In a large epidemiological study, the prevalence of celiac disease in not at-risk children was reported as 1:320 patients (3). The rate of celiac disease in Western societies has since been increasing. Swedish investigators reported that in Swedish children (>12 years of age), the rate of celiac disease increased to 3% (4). The authors implicated that the increase in the national epidemic that occurred between 1984 and 1996 was related to governmental dietary recommendations.
The diagnostic criteria for celiac disease were modified throughout the years. In the position guidelines of 2 expert committees, it was suggested that in a symptomatic child, positive celiac serology and characteristic histology are mandatory before the diagnosis of celiac disease can be established (5,6). Because of the patchy distribution of the mucosal pathology, it was recommended that tissue samples from at least 4 biopsies obtained from the small intestine (SI) and 1 to 2 biopsies from the duodenal bulb (DB) are needed to make the diagnosis (2,5,7).
The common clinical approach for the diagnosis of celiac disease initiates with clinical suspicions followed by positive celiac serology, leading to a confirmatory intestinal biopsy. The rate of celiac disease that is discovered unintentionally following a routine diagnostic endoscopy, performed for other medical reasons, is unknown. In the present study, we retrospectively investigated the rate of celiac disease that was discovered after positive serology (serology-led diagnosis) compared with the rate of celiac disease diagnosed accidentally after positive histology (histology-led diagnosis). The results of the present study may underscore the importance of performing adequate number of intestinal biopsies during routine endoscopic procedures scheduled for other clinical reasons.
Charts of all of the first diagnostic upper endoscopy procedures performed by the Gastroenterology Division, Marshall University School of Medicine (2009–2013), were reviewed. In each procedure, tissue biopsies from the SI (at least 2) and from the DB (at least 2) were performed irrespective of the mucosal appearance. Histology was performed by the different board-certified pathologists who serve our hospital. Celiac histology was defined using Marsh criteria. Celiac serology was performed by an outside laboratory and always included endomysial antibody, anti–tissue transglutaminase, and immunoglobulin A levels. Other antibodies (eg, gliadin antibodies) were sometimes included depending on the practice of the referring physicians. Clinical and laboratory follow-up was recorded. Our study population comprised patients who were ultimately diagnosed with celiac disease.
The patients were then divided according to the following groups: patients who had an initial positive histology followed by positive serology (histology-led diagnosis) (group A), patients with initial positive serology followed by positive histology (serology-led diagnosis) (group B), patients with characteristic histology followed by negative serology (group C), and patients with initial positive serology followed by normal histology (group D).
Statistical analyses were performed using SAS software release 9.2 (SAS Institute Inc, Cary, NC). Chi-square analysis was calculated to assess the difference between the groups.
A total of 761 upper endoscopic charts were reviewed (January 2009–July 2013). A total of 15 children were confirmed with celiac disease (1.97%). The most common clinical symptom was abdominal pain followed by vomiting, diarrhea, anemia, and failure to thrive (Table 1). Family history, and clinical and laboratory follow-up were recorded and are reported in Table 1. There was no significant difference in the demographic data or clinical symptoms between histology-led and serology-led groups. In the histology-led celiac diagnosis (group A), a minimal mucosal change (Marsh 1) was noted in 2 (22%) patients, and subtotal villous atrophy (Marsh 3) was noted in 7 (78%) patients. In the serology-led celiac diagnosis (group B), 1 (16.6%) patient had Marsh 1 and 5 (83%) patients had Marsh 3.
Of the 15 patients with positive celiac serology, 3 patients (2 in the histology-led group and 1 from the serology-led group) had minimal histological changes in the SI (Marsh 1) and characteristic celiac findings in the DB biopsies (mucosal blunting, increased intraepithelial lymphocytes). To assure celiac disease in those patients, we report that the initial serology titers were positive in all of the patients, but a high titer was noted in 1 patient (>60 U/mL). Positive family history for celiac disease was noted in 2 children, and improved symptoms on gluten-free diet were noted in all of the patients. Repeat serology was performed in 1 patient and showed decreased serologic titers compared with baseline. The other 2 patients refused repeat serology and were not followed by our clinic (Table 1). Accordingly, we believe that those 3 children with Marsh 1 histology are confirmed celiac patients.
DB biopsies were available in all of the patients. In 14 (93%) of the celiac positive patients, DB showed histological finding compatible with celiac disease. Two symptomatic patients in group D had positive serology first followed by a negative histology. Those patients were offered repeat evaluation in the future, but they did not return. No significant difference was observed in the rate of celiac disease between histology-led celiac diagnosis (group A) and serology-led celiac diagnosis (group B) (1.18% vs 0.79%, P = 0.273) (Table 2).
The rate of celiac disease in the United States is comparable to the rate reported from Europe (2,3). The common diagnostic approach for the disease typically initiates with clinical symptoms that indicate the need for celiac serology testing. Following positive serology, intestinal biopsies are performed to confirm celiac diagnosis in those patients. The rate of celiac disease is probably underestimated in the United States because higher rates have been reported from different European countries (2). It is plausible that lower serum antibody levels will not lead to endoscopic evaluation, thus missing the diagnosis of celiac disease. To our knowledge, there are no pediatric studies to assess the rate of celiac disease discovered after routine diagnostic endoscopy scheduled for clinical suspicions other than celiac disease. Information related to that practice may support the recommendation for increasing the number of intestinal biopsies that need to be performed in any diagnostic procedure in children irrespective of whether celiac serology was previously obtained, celiac disease was included in the differential diagnosis, and/or mucosa was present at the time of the procedure.
In the present article, we showed that the overall rate of celiac disease in the children included in the present study was almost double the rate reported from the United States (1.97% vs 1%). Moreover, the absolute rate of the endoscopy-led celiac diagnosis was at least comparable to the absolute rate of serology-led celiac diagnosis. It is important to note that in contrast to the pediatric recommendations for celiac disease (5), in the children of the endoscopy-led group (group A), only 2 biopsies were available from the SI and 2 biopsies from the DB. This may suggest that our rate of celiac disease in the endoscopy-led celiac diagnosis group may be underestimated and could have been higher if 4 biopsies from the SI had been performed. We are not aware of any similar reports published in children.
The lower rate of celiac disease detected in the United States was attributed to the lack of public and physician awareness. Since the National Institutes of Health meeting on celiac disease in 2004, there has been a significant increase in the disease's awareness. Subsequently, the topic is now shifted to the diagnostic procedures, specifically the gastroenterologists’ clinical practices. Several reports have shown that 4 intestinal biopsies and 1 to 2 DB biopsies are needed to increase the accuracy and the disease's detection in adults (2,8). Review of the literature suggested that the rate of intestinal biopsies performed during endoscopies performed in adult patients with clinical suspicion of celiac disease is below acceptable rates (<50%) (9–12). Moreover, in a retrospective study, Lebwohl et al showed that the probability of celiac disease in adults increased once the clinical guideline for duodenal biopsies for celiac disease was followed (1.8% vs 0.7%) (13).
As the number of intestinal biopsies performed during endoscopic procedures became crucial to increase the diagnostic rate of celiac disease in children, it is important to review this topic in children. Unfortunately, the rate of adherence to the duodenal biopsy guideline for celiac disease in children has not been published. Instead, there are few reports that describe the overall rate of intestinal biopsies performed during routine diagnostic upper endoscopy. Results showed that the rate of obtaining duodenal biopsies is better during prospective studies (following study protocols) (14,15). In a review of 20 years of upper endoscopic procedures, Franciosi et al reported that the duodenal biopsy rate in their institution increased from 17.7% to 95.2% (16). Nevertheless, this report was limited to a large academic medical center that may not represent private practices, or other smaller medical centers.
The most common reason for not performing biopsies during endoscopy is a normal-appearing mucosa. It is thus not surprising that many adult gastroenterologists will skip duodenal biopsies when the characteristic endoscopic features of celiac disease are missing (10–12). In the present study, biopsies from the duodenum (second part) and DB were performed in all of the diagnostic procedures performed in our center irrespective of the endoscopic appearance. Although the number of duodenal biopsies reviewed did not reach the number of biopsies recommended for celiac disease (≥4 biopsies), we report that the diagnosis of celiac disease was comparable to the rate of celiac disease found following positive serology. It is thus concluded that routine intestinal biopsies from the duodenum (second part) and the DB should be performed in any diagnostic upper endoscopy in children, and the number should follow the experts’ recommendation (duodenum: ≥4; DB: 1–2). It is expected that following those recommendations, the diagnosis of celiac disease in the pediatric population will increase.
In conclusion, we investigated the rate of celiac disease diagnosed as an “incidental finding” in patients who had upper endoscopic procedures with no serologic suspicion of celiac disease. The data suggest that to improve celiac disease detection in children, the number of intestinal biopsies recommended by the pediatric experts’ guideline should be followed in all of the diagnostic upper endoscopic procedures irrespective of the clinical indications that led to the procedure.
1. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology
2. Green PHR, Cellier C. Celiac disease. N Engl J Med
3. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not at risk groups in the United States. Arch Intern Med
4. Myleus A, Ivarsson A, Webb C, et al. Celiac disease revealed in 3% of Swedish 12 years old born during an epidemic. J Pediatr Gastroenterol Nutr
5. Husby S, Koletzko S, Korponay-Szabo IR, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of celiac disease. J Pediatr Gastroenterol Nutr
6. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr
7. Green PHR. Celiac disease: how many biopsies for diagnosis? Gastrointest Endosc
8. Pais WP, Duerksen DR, Pettigrew NM, et al. How many duodenal biopsy specimens are required to make a diagnosis of celiac disease? Gastrointest Endosc
9. Abbass R, Hopkins M, Dufour DR, et al. Celiac disease in an urban VA population with iron deficiency: the case against routine duodenal biopsy. Dig Dis Sci
10. Harewood GC, Holub JL, Lieberman DA. Variations in small bowel biopsy performance among diverse endoscopy setting: results from a national endoscopic database. Am J Gastroenterol
11. Lebwohl B, Tennyson CA, Holub JL, et al. Sex and racial disparities in duodenal biopsy to evaluate for celiac disease. Gastrointest Endosc
12. Lebwohl B, Bhagat G, Markoff S, et al. Prior endoscopy in patients with newly diagnosed celiac disease: a missed opportunity? Dig Dis Sci
13. Lebwohl B, Kapel R, Neugut AI, et al. Adherence to biopsy guidelines increases celiac disease diagnosis. Gastrointest Endosc
14. Hyams JS, Davis P, Sylverster FA, et al. Dyspepsia in children and adolescents: a prospective study. J Pediatr Gastroenterol Nutr
15. Puzanovova M, Rudzinski E, Shirkey KC, et al. Sex, psychological factors, and reported symptoms influence referral for esophagogastroduodenoscopy and biopsy results in children with chronic abdominal pain. J Pediatr Gastroenterol Nutr
16. Franciosi JP, Fiorino K, Ruchelli E, et al. Changing indications for upper endoscopy in children during a 20-year period. J Pediatr Gastroenterol Nutr