What Is Known
- Celiac disease remains underdiagnosed in the United States.
- Identification of characteristic changes on small intestinal histology confirms the diagnosis of celiac disease.
What Is New
- Histologic changes in celiac disease can initially be patchy and isolated to the duodenal bulb.
- Guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the American College of Gastroenterology recommend obtaining multiple biopsies during esophagogastroduodenoscopy (≥1 bulb and 4 distal duodenal biopsies).
- Adherence to the biopsy recommendations by pediatric gastroenterologists is suboptimal.
- Following biopsy guideline recommendations in all children undergoing diagnostic esophagogastroduodenoscopy could result in more timely diagnosis of celiac disease.
Celiac disease (CD) is estimated to occur in about 1% of the general population in the United States, but the majority of affected individuals remain undiagnosed (1–7). This is in part because of health care professionals being unfamiliar with the varied clinical manifestations of the condition and hence not choosing appropriate tests to make the diagnosis (8,9). Although serologic tests are helpful in identifying people who may have CD, the diagnosis is usually considered confirmed only after finding the characteristic histologic changes on small intestinal biopsy (10–13). These histologic changes can initially be patchy or confined only to the duodenal bulb, and therefore it is recommended that multiple biopsies be obtained during diagnostic endoscopy. The American Gastroenterological Association (AGA) published recommendations in 2006 emphasizing the importance of obtaining 4 to 6 biopsy specimens from the proximal small intestine and using a single-pass method for each biopsy specimen when evaluating for CD (13). Clinical practice guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in 2012 and the American College of Gastroenterology (ACG) in 2013 recommend obtaining ≥1 duodenal bulb and 4 distal duodenal biopsy specimens during esophagogastroduodenoscopy (EGD) to maximize the chances of making a correct diagnosis (11,14).
Patients undergoing diagnostic EGD for any reason present an opportunity to identify CD even when the diagnosis is not clinically suspected beforehand. It has been suggested that all patients undergoing an EGD should routinely have the CD guideline recommended number of biopsies obtained from the duodenum regardless of the indication for the procedure (4,10,15,16). Review of biopsy practices among adult gastroenterologists demonstrated that the recommendations were followed in only 39.5% of the cases when CD was suspected and even less frequently when a diagnosis of CD was not the primary indication for performing the EGD (4,15).
There are presently no data describing whether pediatric gastroenterologists adhere to the recommendations for obtaining the minimum number of biopsy specimens from both the duodenal bulb and the more distal duodenum when testing for CD. It is also not known whether the biopsy practices of pediatric gastroenterologists differ when the primary indication for endoscopy is to look for CD compared with when it is not. Our aim was to assess whether pediatric gastroenterologists at our institution adhered to the guideline recommendations for both the site and the number of biopsies obtained during diagnostic EGD in children with CD and determine whether this practice differed from those with no histologic evidence of CD.
A retrospective review of endoscopies performed at Nationwide Children's Hospital (Columbus, OH) with Current Procedural Terminology code 43239 (EGD with biopsy) between July 1, 2012, and July 31, 2013, was undertaken. Endoscopies during this period were performed by 22 pediatric gastroenterology attending physicians and 6 trainee fellows. The need for the approval of the institutional review board was waved (K.A. White, PhD, chair, institutional review board of the Nationwide Children's Hospital, personal communication, January 7, 2015) because personal health information was not shared, and no interventions involving comparison of devices or therapies were used.
Two groups of children were identified. The first group (with CD) included all of the children with histologically confirmed CD. In the group with CD, endoscopy had been performed specifically to evaluate for CD based upon the presence of symptoms associated with the condition and/or a positive serologic test for CD. The modified Marsh criteria were used for the histologic evaluation, and a diagnosis of CD was considered positive if there were Marsh III changes or Marsh II changes together with a positive celiac serologic test. Patients were excluded from the group with CD during the final analysis if there were incomplete endoscopy and/or pathology reports.
The second group (without CD) comprised a random selection of age-matched children who had undergone endoscopy and did not have histologic evidence of CD. In the group without CD, the indication for endoscopy was to evaluate gastrointestinal symptoms such as abdominal pain, dyspepsia, nausea, and vomiting. A subgroup of children in the group without CD had previous negative serologic testing for CD, whereas the remainder had no prior serologic testing for CD. Review of the medical record suggested that a suspicion for CD was not the primary indication for performing the endoscopy in these cases. The random selection of the patients included in this group was evenly distributed across the 13 months under review and across all of the endoscopic providers. Children with a diagnosis of Crohn disease, eosinophilic esophagitis, or short bowel syndrome, and those having repeat endoscopy or undergoing a therapeutic procedure were excluded from the study.
The endoscopy and pathology reports for both the cohorts were reviewed. The total number of duodenal biopsy samples obtained and, where applicable, the number of biopsies obtained from each site was recorded. The number of children in whom there was documentation that biopsies had been obtained from both the duodenal bulb and the more distal duodenum was recorded. The Wilcoxon rank sum test (nonparametric) was used to compare the groups for the number of biopsies obtained.
As shown in Figure 1, a total of 1332 patients underwent EGD with biopsies during the 13-month interval under review. A total of 105 patients were diagnosed with CD. Seven were subsequently excluded from the analysis because of incomplete endoscopy and/or pathology reports. Of the 98 children with CD included in the final analysis, 95 (96.9%) had a positive serology test, 91(93.8%) had a positive tissue transglutaminase antibody (TTG), 1 (1.0%) had a positive endomysial antibody, and 3 (3.1%) had a positive antigliadin antibody. Three children did not have a positive serologic test. In 2 of these 3 cases, there was a high clinical suspicion for CD related to symptoms and family history, and therefore the EGD was specifically performed to evaluate for CD despite negative serologic testing. The third child was not clinically suspected of having CD and had not undergone serologic testing before endoscopy. In this case, the diagnosis was only considered after the pathology review described characteristic histologic features of CD. Subsequent serologic testing after the endoscopy in this case revealed an elevated TTG.
Of the remaining 1227 children undergoing EGD during the study period, 189 were initially randomly selected with an average of 14.5 patients (range 8–26) from each month. A total of 86 children were subsequently excluded because of history of Crohn disease, eosinophilic esophagitis, short bowel syndrome, or repeat endoscopy, or they had undergone a therapeutic procedure (Fig. 1). The final 103 children included in the group without CD represented an average of 8 patients (range 6–12) selected from each month. Of the 103 patients without CD, 70 (68.0%) had serologic tests for CD before undergoing EGD and all of them were negative. The clinical indications for endoscopy in these 70 were similar to 33 in the group without CD that did not have prior testing for CD. The groups with and without CD were similar with regards to sex and age (Table 1).
The total number of biopsies obtained in each group is shown in Table 1. The mean number of duodenal biopsies taken during EGD was significantly higher in the group with CD; 5.9 ± 1.6 (range 2–11) compared with the group without CD 3.6 ± 1.2 (range 2–8) (P < 0.0001). The 2 children in the group with CD with negative serologic tests but a strong clinical suspicion for CD had 4 and 6 biopsy samples obtained, respectively. In the child who was not clinically suspected of having CD and had not undergone serologic testing before endoscopy, there were 2 biopsies obtained.
In the group without CD, the mean number of biopsies obtained in those who had a previous serologic test for CD (3.7, range 2–8) was similar to those who had no prior testing (3.5, range 2–6). Significantly, more children in the group with CD (79/98, 80.6%) had ≥5 biopsies obtained than in the group without CD (12/103, 11.7%) (P < 0.0001). Of the 98 patients with CD, only 10 (10.2%) had documentation that biopsies were obtained from both the duodenal bulb and the distal duodenum. In the group without CD, there was no recorded documentation that biopsies were obtained from the duodenal bulb.
Despite increased awareness of CD and the availability of reliable serologic tests to identify people who may have CD, the condition continues to remain largely underdiagnosed (1–7). ESPGHAN suggested that in some cases it is acceptable to make a diagnosis of CD on the basis of clinical symptoms and positive serologic tests alone, but identification of the characteristic histologic changes on small intestinal biopsies is still considered by many to be the criterion standard for confirming the diagnosis. It is well known that initially the histologic findings can vary in severity, be patchy in distribution, or be confined only to the duodenal bulb (13,17–19). Correct interpretation of the histology can also be hampered by poor orientation of the specimen. For these reasons, it is recommended that during diagnostic EGD, multiple biopsy samples should be obtained, and specimens should be obtained from both the duodenal bulb and the more distal duodenum using a single biopsy per pass technique when evaluating for CD. A study has demonstrated significant improvement in orientation of the biopsy specimens with this technique because 66% of the specimens were correctly oriented when a single biopsy per pass was used compared with 42% when there were 2 biopsies per pass (P < 0.01) (20). Although interpretation of the histology from duodenal bulb biopsies can be more difficult because of the presence of Brunner glands, gastric metaplasia, peptic duodenitis, and lymphoid follicles in this region (17,21), experienced pathologists can identify the characteristic microscopic changes of CD in the duodenal bulb. It is noteworthy that in up to 10% of the pediatric patients, the duodenal bulb may be the only site with villous atrophy initially (17–19,21).
In 2006, the AGA released guidelines recommending that 4 to 6 biopsies be obtained when a diagnosis of CD is being considered (13). These recommendations were reiterated in 2013 when the ACG published their guidelines on the diagnosis and management of CD (11). Similarly, ESPGHAN has recommended obtaining ≥1 biopsy from the duodenal bulb and 4 from the more distal duodenum for the diagnosis of CD (14). A number of reports clearly demonstrate that obtaining multiple biopsy samples increases the likelihood of diagnosing CD. In 1 review involving 9 centers in Europe and the Middle East, Rostami-Nejad et al (10) found a strong correlation between the number of biopsy samples obtained and the diagnosis of CD, with the diagnostic rate increasing from 6.7% in those who had only 1 specimen obtained to 32.9% in those who had ≥3 specimens obtained (P = 0.0001). Similarly, Hopper et al (22) reported that 100% of the patients with villous atrophy were identified when ≥1 sample was obtained from the bulb and 2 from the more distal duodenum. The importance of obtaining multiple samples, including some from the bulb, was further demonstrated by Weir et al who found that in 10% of the cases the histologic changes were confined to the bulb and were not initially present in the more distal duodenum (21).
Studies of biopsy practices of adult gastroenterologists demonstrate relatively poor adherence to guideline recommendations for the number of specimens obtained (4,15). Adherence to the recommendations was decreased among physicians who performed the highest number of procedures and increased among those who worked in practices with higher numbers of gastroenterologists (4). In a retrospective database review of 132,352 adults undergoing EGD with biopsies, Lebwohl et al (15) found that the clinical indication for endoscopy correlated with the number of specimens submitted, with increased adherence to obtaining the recommended number of biopsies when CD was suspected. Even when the procedure was undertaken for suspected CD, adherence to the guideline recommendations occurred in only 39.5% of the cases (15). Additionally, a biopsy from the duodenal bulb was obtained in only 10% of the cases. This same review noted the probability of finding CD more than doubled when ≥4 biopsy specimens were obtained regardless of the indication for the endoscopy (15). Based on these findings, the authors suggested that the guideline recommendations for the number of biopsies taken when evaluating for CD should be considered in all of the patients undergoing an EGD, regardless of the indication because this has potential to identify additional patients who have CD.
Our single-center study demonstrates the practice among pediatric gastroenterologists differs in some respects to that of the adult gastroenterologists. Pediatric gastroenterologists at our institution generally obtained the recommended number of biopsy samples in children with histologically confirmed CD. In the group with CD, 80.5% of the children had ≥5 biopsies taken compared with 11.7% of the children in the group without CD, and in 94% of the cases the minimum number of 4 samples recommended by the AGA were obtained in the group with CD compared with 43% in the group without CD (Table 1). Conversely, and similar to adult gastroenterologists, pediatric gastroenterologists at our center were poor at documenting that biopsies were obtained from the duodenal bulb. In the group with CD, only 10% of the cases had documentation that biopsies were obtained from the duodenal bulb, whereas the group without CD had no cases documenting duodenal bulb biopsies. Although it is possible that biopsies were obtained from the duodenal bulb but not documented as such, we speculate that it is more likely the majority of cases had biopsies obtained only from the more distal duodenum. The 1 child in the group with CD in whom a diagnosis of CD was not suspected at the time of the endoscopy had only 2 biopsy samples obtained, and histology revealed Marsh III changes. This emphasizes the point that when the prime indication for an endoscopy is not to look for CD, the recommended number of biopsies is less likely to be obtained. Although the recommended number of samples in this case was not needed to make a diagnosis of CD, it could be argued that other cases with lesser degrees of intestinal mucosal damage may be missed by not taking more samples.
Failure to identify people with CD in a timely manner continues to be a problem. Delays in diagnosis have potential for adverse health consequences with increased morbidity and decreased quality of life because of persistent symptoms. All patients undergoing EGD present an opportunity to identify CD even if clinical suspicion for the diagnosis is low at the time of endoscopy. For this reason, taking multiple biopsies from both the duodenal bulb and the more distal duodenum in all of the patients undergoing EGD is a reasonable consideration and may increase diagnostic yield of the procedure (13). Robson et al (8) demonstrated an increased rate of diagnosis of CD when patients undergoing EGD have small intestinal biopsies obtained as a routine and speculate that this number could be further increased if more samples were obtained. Furthermore, a recent single-center study by Preston and Elitsur (16) demonstrated that when routinely taking multiple biopsy samples (≥2 from the bulb and ≥2 from the more distal duodenum) during all of the diagnostic EGDs, as many children with CD were identified when the procedure was performed without prior suspicion for CD as when the reason for the procedure was specifically to look for CD.
Speculation as to why adherence to guideline recommendations is generally poor among adult gastroenterologists includes the fact that the guidelines are relatively new and therefore may not be widely implemented. Another consideration is that additional time is needed to submit the required number of specimens (15). Physicians performing higher numbers of endoscopies had lower rates of adherence to the recommendations supporting the possibility that time is a factor in adhering to the guideline recommendations. In contrast, practices with larger numbers of gastroenterologists were more likely to adhere to the guidelines suggesting peer education on practice standards may play a role (4). At our center, patients undergoing endoscopy with subsequent histologic diagnosis of CD had ≥4 biopsies obtained 94% of the time, suggesting pediatric gastroenterologists are more likely than our adult colleagues to adhere to the guideline recommendations for the number of biopsies obtained when a diagnosis of CD is suspected. Documentation that biopsies are obtained from both the duodenal bulb and the distal duodenum is an area in need of improvement as this practice was only identified in 10% of the cases diagnosed with CD at our center. When a diagnosis of CD was not the prime indication for endoscopy, practitioners from our center obtained significantly fewer numbers of duodenal biopsies and apparently never obtained any from the duodenal bulb, similar to that in the adult practices. Not taking multiple biopsies and obtaining biopsies from both the duodenal bulb and the more distal duodenum could represent a lost opportunity to identify additional cases of CD in children undergoing an EGD when the diagnosis is not clinically suspected beforehand.
This study has several limitations. It was a retrospective analysis of pathology reports, and these varied based on different pathologists reviewing the histology, so it is possible that some cases of CD were misdiagnosed. It is also possible there were some children with positive serologic tests but with normal histology that were not included in the analysis. It is likely this, however, would have accounted for only a small number of cases, and there is no reason to suspect these would have been handled any differently from those with positive serology who were ultimately confirmed on biopsy to have CD. Finally, the study was from a single institution, and the number of patients and controls was relatively small thus limiting the generalizability of the results. Nevertheless, the results suggest there may be an opportunity to identify additional cases of CD if the guideline recommendations are followed more consistently when children undergo an EGD with biopsies.
In conclusion, this single-center study found that pediatric gastroenterologists at our institution generally obtain the guideline for recommended number of duodenal biopsies in children undergoing an EGD to look for CD that is subsequently confirmed on histology. When CD is not the prime indication for the endoscopy, however, significantly fewer biopsies are obtained. In both the groups, documentation of biopsy location from both the bulb and the distal duodenum was poor. More consistent adherence with guideline recommendations for both the number of specimens obtained and biopsy site in all of the children undergoing a diagnostic EGD regardless of the indication for the procedure could increase the identification of children with CD.
Eucharius Rösslin's (c. 1470–1526) German text Das Rosegarten appeared in 1512 and was translated into several languages. The English version by Richard Jonas was entitled The Byrth of Mankynd and was published in 1540. Rösslin's advice on the care of newborns was grounded in Avicenna and was divided into 36 short commentaries, among them this one on the treatment of constipation, which relies on oral fiber and scented smoke—per fumus—perfumes directed to the anus:
There is a disease of childhood called in Latin tenasmon in which the child has a desire to go to stool but does nothing or little. This generally comes from the cold. To help it take garden cress seeds and Roman kümmel seeds [caraway], of each equal parts, powder them well and temper with old butter and give it to the child to drink with cold water. Take turpentine and lay it on the glowing coals, and let the fumes in his anus.
His contemporary, Georg Pictorius (1500–c.1571), published Frawenzimmer in 1569, and, in contrast, addresses the treatment of constipation with bile and poultice:
When young children are completely constipated and cannot go to stool, take some oxbile and seethe in it a little wornwood [Artemisia], and if this produces no results and is too weak add a little aloe hepaticum to it and lay this [poutice] over the child's navel overnight.
—Contributed by Angel R. Colón, MD
1. Barada K, Habib RH, Malli A, et al. Prediction of celiac disease at endoscopy
2. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med
3. Kurppa K, Salminiemi J, Ukkola A, et al. Utility of the new ESPGHAN criteria for the diagnosis of celiac disease in at-risk groups. J Pediatr Gastroenterol Nutr
4. Lebwohl B, Genta RM, Kapel RC, et al. Procedure volume influences adherence to celiac disease guidelines. Eur J Gastroenterol Hepatol
5. Lohi S, Mustalahti K, Kaukinen K, et al. Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther
6. Rubio-Tapia A, Kyle RA, Kaplan EL, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology
7. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol
8. Robson K, Alizart M, Martin J, et al. Coeliac patients are undiagnosed at routine upper endoscopy
. PloS One
9. Tonutti E, Bizzaro N. Diagnosis and classification of celiac disease and gluten sensitivity. Autoimmun Rev
10. Rostami-Nejad M, Villanacci V, Hogg-Kollars S, et al. Endoscopic and histological pitfalls in the diagnosis of celiac disease: a multicentre study assessing the current practice. Rev Esp Enferm Dig
11. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol
12. Volta U. Coeliac disease: time for a new diagnostic approach in symptomatic children. J Pediatr Gastroenterol Nutr
13. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology
14. Husby S, Koletzko S, Korponay-Szabo IR, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr
15. Lebwohl B, Kapel RC, Neugut AI, et al. Adherence to biopsy guidelines increases celiac disease diagnosis. Gastrointest Endosc
16. Preston DL, Elitsur Y. Rate of celiac disease in children: view from the endoscopy
suite. J Pediatr Gastroenterol Nutr
17. Kurien M, Evans KE, Hopper AD, et al. Duodenal bulb biopsies for diagnosing adult celiac disease: is there an optimal biopsy site? Gastrointest Endosc
18. Levinson-Castiel R, Hartman C, Morgenstern S, et al. The role of duodenal bulb biopsy in the diagnosis of celiac disease in children. J Clin Gastroenterol
19. Prasad KK, Thapa BR, Nain CK, et al. Assessment of the diagnostic value of duodenal bulb histology in patients with celiac disease, using multiple biopsy sites. J Clin Gastroenterol
20. Latorre M, Lagana SM, Freedberg CE, et al. Endoscopic biopsy technique in the diagnosis of celiac disease: one bite or two? Gastrointest Endosc
21. Weir DC, Glickman JN, Roiff T, et al. Variability of histopathological changes in childhood celiac disease. Am J Gastroenterol
22. Hopper AD, Cross SS, Sanders DS. Patchy villous atrophy in adult patients with suspected gluten-sensitive enteropathy: is a multiple duodenal biopsy strategy appropriate? Endoscopy