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Capsule endoscopy in adult celiac disease: a potential role in equivocal cases of celiac disease?
ORIGINAL ARTICLE: Clinical Endoscopy
Capsule endoscopy in adult celiac disease: a potential role in equivocal cases of celiac disease? Matthew Kurien, MRCP, Kate E. Evans, MRCP, Imran Aziz, MRCP, Reena Sidhu, MRCP, MD, Kaye Drew, BSc, Thea L. Rogers, Mark E. McAlindon, BMed Sci, DM, FRCP, David S. Sanders, MD, FRCP, FACG Sheffield, South Yorkshire, United Kingdom
Background: There have been limited studies evaluating capsule endoscopy (CE) in equivocal celiac disease (CD). Objective: To determine the role CE may have in equivocal CD cases, compared with patients with biopsyproven and serology-proven CD who have persisting symptoms. Design: Prospective cohort study. Setting: University hospital. Patients: A total of 62 patients with equivocal CD and 69 patients with nonresponsive CD. Intervention: CE. Main Outcome Measurements: Diagnostic yield of CE in equivocal cases and accuracy of mucosal abnormality detection in patients with nonresponsive CD. Results: Equivocal cases (n ⫽ 62) were divided into two subgroups: group A (antibody-negative villous atrophy, n ⫽ 32) and group B (Marsh 1-2 changes, n ⫽ 30). In group A, CE secured a diagnosis of CD or Crohn’s disease in 28% (9/32), significantly higher than the diagnostic yield in group B (7%; P ⫽ .044). In patients with CD with persisting symptoms, significant CE findings were identified in 12% (8/69), including 2 cases of enteropathyassociated lymphoma, 4 type 1 refractory disease cases, 1 polypoidal mass histologically confirmed to be a fibroepithelial polyp, and 1 case of ulcerative jejunitis. This outcome was significantly lower than the diagnostic yield of CE in antibody-negative villous atrophy (P ⫽ .048). Limitations: Single center. Conclusion: There have been no previous reports systematically evaluating equivocal CD by using CE. The diagnostic yield of CE in patients with antibody-negative villous atrophy is better than that of CE in patients with CD with persisting symptoms. We advocate the use of CE in equivocal cases, particularly in patients with antibody-negative villous atrophy. (Gastrointest Endosc 2013;77:227-32.)
Celiac disease (CD) is an autoimmune condition characterized by a heightened immunologic response to ingested gluten, with prevalence rates in the United States and European populations estimated to range between 0.2% and 1%.1,2 The current criterion standard diagnostic test for CD is EGD, with duodenal biopsy specimens taken to dem-
onstrate the presence of villous atrophy.3 Corroborative evidence used to support the diagnosis of CD comes from positive immunologic markers (tissue transglutaminase [tTG] and endomysial antibodies [EMA]) and a clinical response to a gluten-free diet.4,5 Occasionally, when diagnostic uncertainty exists, human leucocyte antigen (HLA) typing is un-
Abbreviations: CE, capsule endoscopy; CD, celiac disease; EMA, endomysial antibodies; HLA, human leukocyte antigen; tTG, tissue transglutaminase.
Copyright © 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2012.09.031
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.
Use your mobile device to scan this QR code and watch the author interview. Download a free QR code scanner by searching ‘QR Scanner’ in your mobile device’s app store. www.giejournal.org
Received June 25, 2012. Accepted September 20, 2012. Current affiliations: Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, South Yorkshire, United Kingdom. Reprint requests: Professor David S. Sanders, Room P39, Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS FoundationTrust, Sheffield, South Yorkshire S10 2JF, United Kingdom.
Volume 77, No. 2 : 2013 GASTROINTESTINAL ENDOSCOPY 227
Capsule endoscopy in adult celiac disease
TABLE 1. Modified Marsh criteria Marsh grade
Histologic findings
0
Normal
1
Raised IEL levels (⬎25/100 enterocytes)
2
Raised IEL levels with crypt hyperplasia
3a
Raised IEL levels, crypt hyperplasia, and partial villous atrophy
3b
Raised IEL levels, crypt hyperplasia, and subtotal villous atrophy
3c
Raised IEL levels, crypt hyperplasia, and total villous atrophy
IEL, Intraepithelial lymphocyte.
dertaken, which may help to exclude CD, given the high negative predictive value of this test.6 Limitations of EGD as part of this diagnostic pathway include its invasive nature and its inability to evaluate small-bowel mucosa beyond the duodenum, where rarely encountered complications of CD are seen (eg, ulcerative jejunitis, enteropathy-associated T-cell lymphoma). In addition, when duodenal biopsy sampling is considered, orientation may be problematic, and biopsies could miss definitive histologic lesions (Marsh grade 3a-3c, Table 1) because of the patchy distribution of CD lesions seen within the small bowel.7,8 CE is a well-tolerated, minimally invasive test, increasingly being used to evaluate the small bowel. Although CE is predominantly used for the assessment of obscure GI bleeding, inflammatory bowel disease, and polyposis syndromes, there has been increasing interest in the role CE may have in CD.9-11 With an 8-fold magnification power comparable to that of a dissecting microscope, CE has been shown to have high accuracy in detecting the 4 endoscopic markers of villous atrophy—reduction or absence of Kerckring’s folds, mosaic mucosal pattern, micronodular pattern, and scalloping (Figs. 1 and 2).9,12,13 In a recent meta-analysis assessing the accuracy of CE as a diagnostic tool in CD, sensitivity of this modality was 89% (95% confidence interval [CI] [82%-94%]), with a specificity of 95% (95% CI [89%-98%]).14 The main limitation of this modality as a diagnostic tool for CD is the absence of histology, which remains the criterion standard. Nevertheless, CE maybe useful when patients decline EGD, are too frail to undergo invasive investigations, or where EGD examination is not satisfactorily completed. A further role being advocated for CE in patients with CD is in managing individuals with nonresponsive disease.11,15-17 Approximately 7% to 30% of patients with CD will have persisting symptoms despite being treated with a gluten-free diet, which is usually secondary to continued ingestion of gluten.18 228 GASTROINTESTINAL ENDOSCOPY Volume 77, No. 2 : 2013
Kurien et al
Take-home Message ●
●
In this series, capsule endoscopy had a higher diagnostic yield in patients with antibody-negative villous atrophy compared with the yield seen in patients with celiac disease with persisting symptoms. Capsule endoscopy may have a potential role in equivocal cases of celiac disease.
There are limited data assessing the role of CE in equivocal cases of CD. In a study of 8 patients with positive serology (EMA or tTG) and a normal duodenal biopsy, CE did not reveal any endoscopic features of CD.19 Thus, the investigators concluded that there was no benefit in performing CE for this subgroup of patients. This contrasts with findings from another study in which 22 patients with irritable bowel syndrome with positive celiac serology and normal duodenal histology underwent CE.20 This study detected “subtle” abnormalities within the small bowel in 55% (12/22) of cases. An example of this would be “patchy segments of denuded villi.” This inconsistency raises questions about the merits of CE in equivocal cases. Furthermore, there are specifically no studies evaluating in a systematic manner equivocal cases related to antibodynegative villous atrophy or increased levels of intraepithelial lymphocytes. For this reason, this study aims to prospectively evaluate the role CE may have in equivocal cases and compares this to patients with biopsy and serology proven CD who have persisting symptoms.
METHODS Study population Data were collected prospectively from a single, tertiarycare, referral university hospital in the United Kingdom between June 2004 and December 2011. This hospital serves a population of approximately 250,000 people and currently does approximately 500 CEs annually. This is the largest single-center unit in Europe.21 This unit also has ⬎1000 patients with CD and has the largest patient cohort in the United Kingdom. In the first cohort of patients in which CE was evaluated, consecutive patients who had equivocal disease were included. These individuals were patients suspected of having CD but who had equivocal histologic or serologic findings after EGD and duodenal biopsy. In a second cohort of patients, 69 consecutive patients with biopsy-proven CD (determined by a combination of positive antibodies [EMA or tTG] and villous atrophy [Marsh grade 3a-3c]) and persisting symptoms (on a gluten-free diet ⬎12 months) underwent CE to further evaluate symptoms. CE assessed the extent of CD (proximal or diffuse), potential CD complications, and other www.giejournal.org
Kurien et al
Capsule endoscopy in adult celiac disease
Figure 1. Mosaic pattern of mucosa.
Figure 2. Scalloping.
pathologies that may have accounted for symptoms. Concurrently, serology (EMA and tTG) and a duodenal biopsy (Marsh grading, and, where appropriate, T-cell clonality) were performed. In both cohorts (histologically equivocal and nonresponsive cases), demographic data, serology, and any subsequent histology were recorded prospectively. All patients participating in this prospective study signed a consent form, permitting their outcomes to be analyzed for the purpose of a research study.
also by combinations of HLA typing (DQ-2 or DQ-8), gluten challenge/response to a gluten-free diet, and in some cases repeated duodenal biopsy. In the cohort with persisting symptoms in which CE identified significant pathology, push enteroscopy or double-balloon enteroscopy would be considered if histologic confirmation of pathology was required.
CE procedure CE was done by using either the Pillcam SB or Pillcam SB2 (Given Imaging Ltd, Yoqneum, Israel) after informed consent was obtained. Patients underwent a 12-hour overnight fast and ingested two sachets of polyethylene glycol solution (Kleen-Prep, Norgine, UK) before commencing the test. Patients were allowed to drink 2 hours after ingestion of the capsule and eat a light snack 4 hours after ingestion of the capsule. The sensor array and recorder pack were disconnected after 8 hours, and images were downloaded onto a work station. Patients were examined 30 minutes after capsule ingestion by use of the Real Time Viewer (Given Imaging) and given metoclopramide intramuscularly if the capsule remained within the stomach. Videos were analyzed by 3 experienced CE readers (R.S., K.D., M.E.M.). All CE readers had knowledge of the patient’s clinical symptoms before CE reporting but were blinded to serologic, histopathologic, and HLA status findings
Outcomes after CE In the histologically equivocal cohort, a diagnosis of CD was further supported not only by the CE appearances but www.giejournal.org
Laboratory test data All patients in this study had immunoglobulin A (IgA), EMA, and tTG antibody measurements before undergoing their CEs. Total IgA levels were measured on a Behring BN2 nephelometer. The tTG antibodies were assayed by using enzyme-linked immunosorbent assay kits (Aesku Diagnostics, Wendelsheim, Germany). A tTG titer of ⬎15 U/mL was regarded as positive. IgA EMA was detected by immunofluorescence on primate esophagus sections (Binding Site, Birmingham, UK).
Statistics and ethical issues Statistical analysis was carried out by using SPSS version 17.0 software (SPSS Inc, Chicago, Ill). In the equivocal cases, differences in diagnostic yield were tested by using the Fisher exact test, with P values being 2-sided and considered significant if ⬍ .05. Where appropriate, descriptive statistics were used to summarize patient demographic data, clinical factors, and CE characteristics, including counts and percentages. In the patients with biopsy-proven CD with persistent symptoms, concordance between serology, histology, and CE findings was assessed by using the Spearman coefficient. This study was discussed and registered with Sheffield Health Service Evaluation and Ethics Committee, United Volume 77, No. 2 : 2013 GASTROINTESTINAL ENDOSCOPY 229
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TABLE 2. Equivocal cases— demographic data summary and CE findings Group A (antibody-negative villous atrophy)
Group B (Marsh score 1/2)
32
30
25 female, 7 male
20 female, 10 male
53 (31-92)
46 (21-75)
0/32 (0)
6/30 (20)
Normal
23 (72)
28 (93)
Endoscopic markers of CD
7 (22)
1 (3)
2 (6)
1 (3)
9 (28)
2 (7)
Characteristic n Sex Age, median (range), y Positive serology at time of CE, no (%)
P value
CE findings, no (%)
Other findings Crohn’s disease Positive findings
.04*
CE, Capsule endoscopy; CD, celiac disease. *Significant difference (P ⬍ .05) in CE findings between group A and group B.
Kingdom, and was conducted according to principles of the Declaration of Helsinki and Good Clinical Practice Guidelines.
RESULTS
diologic findings to establish a diagnosis of Crohn’s disease. When comparing the subgroups of equivocal cases, we found that CE had a significantly higher diagnostic yield in identifying CD or Crohn’s disease in those individuals in group A compared with those in group B (28% vs 7%; P ⫽ .04).
Histologically equivocal cohort A total of 62 histologically equivocal cases were referred for CE between June 2004 and December 2011. Of these patients, 32 (52%) had antibody-negative villous atrophy (group A). These patients had undergone systematic evaluation of villous atrophy before being referred for CE. This included in the first instance a history review (including a thorough drug history), immunoglobulin levels, and review of histopathology. Thereafter, a combination of HLA typing, gluten challenges, repeat celiac serology and duodenal biopsies, and exclusion of infection/ autoimmune causes were performed. No alternative diagnosis for the villous atrophy was identified in any cases, with 63% of patients (20/32) being HLA positive for DQ2 or DQ8 haplotypes. The remaining 30 patients (48%) in the histologically equivocal cohort had either Marsh 1 or Marsh 2 changes on duodenal biopsy (group B). Of these patients in group B, 6 (20%) had positive serology (4 being tTG positive and 2 having both EMA antibody and tTG positivity). Table 2 highlights the demographic data, clinical characteristics, and endoscopic findings for the patients with histologically equivocal CD. The two cases of Crohn’s disease had numerous erosions and ulcerations within the distal small bowel at CE. Histologic findings from this area demonstrated the presence of noncaseating granulomas in both cases, with clinicopathologic findings supporting ra230 GASTROINTESTINAL ENDOSCOPY Volume 77, No. 2 : 2013
Patients with CD with persisting symptoms A total of 69 patients with CD with persisting symptoms were referred for CE, of which 47 patients were female, with a median age of 56 years (range 22-83 years). All of the patients had been on a self-reported gluten-free diet for a minimum of 12 months, with a mean (⫾ standard deviation) duration of 5.3 ⫾ 4.9 years. Endoscopic markers of villous atrophy were identified in 45% (31/69) of cases, with reduction or absence of Kerckring’s folds being the most frequently identified endoscopic marker of CD, occurring in 65% (20/31). Scalloping was the second most frequently observed endoscopic marker, occurring in 55% of cases (17/31), with both mosaic pattern and nodularity occurring in 32% of cases (10/31). A total of 8 patients of the 69 (13%) had significant abnormal CE findings with mass lesions, extensive disease, or ulceration identified. After extensive biopsy sampling from these areas; 2 had enteropathy-associated lymphoma, 4 had type 1 refractory disease, and 1 had ulcerative jejunitis. A 3-cm polypoid mass was identified at CE in the remaining case, which was removed surgically with subsequent histology demonstrating a fibroepithelial polyp. Of the 4 (6%) refractory type 1 cases, 2 patients were treated with immunosuppressants, 1 died of unrelated causes, and another was a tertiary-care referral case for which outcome data are unknown. Comparisons with www.giejournal.org
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Capsule endoscopy in adult celiac disease
TABLE 3. Comparing diagnostic yield of CE in patients with CD with persisting symptoms and equivocal cases
No. of patients CD patients with persistent symptoms
Diagnostic yield, no. (%)
P value
69
Significant pathology 8 (12)
Group A (antibody-negative villous atrophy)
32
9 (28)
.048*
Group B (Marsh score 1/2)
30
2 (7)
.718
Equivocal cases
CE, Capsule endoscopy; CD, celiac disease. *Significant difference (P ⬍ .05) in CE findings between group A (antibody-negative villous atrophy) and patients with CD with persisting symptoms.
diagnostic yields in the equivocal cohort are detailed in Table 3. When evaluating predictors of CD complications and CD extent, we identified no correlation between the likelihood of having complicated CD and the serologic titers (either a positive EMA test result or significantly raised tTG level). However, there was a positive correlation between more extensive changes at CE (diffuse) and the level of tTG (r ⫽ 0.448; P ⫽ .001). A similar observation was made for the relationship between diffuse involvement at CE and EMA positivity (r ⫽ 0.351; P ⫽ .003). There was also a correlation between the extent of disease observed at CE and histology (r ⫽ 0.455; P ⬍ .0001).
DISCUSSION The diagnostic yield of CE in patients with antibodynegative villous atrophy is better than the yield of CE in identifying significant pathology in those patients with CD with persisting symptoms. Based on our findings, we advocate the use of CE in helping establish a diagnosis in patients with antibody-negative villous atrophy. Although previous studies have demonstrated a potential role for CE as a diagnostic tool in celiac disease,13,14,22 we believe that this is the first study to specifically evaluate in a systematic manner equivocal cases related to antibodynegative villous atrophy or increased levels of intraepithelial lymphocytes. Concerns have been raised previously regarding the actual diagnostic yield of CE in CD, because previously undertaken studies have frequently evaluated patients with a high before-test probability (positive celiac serology), potentially leading to an overestimation of CE performance.9 Where this study adds to the literature is that in 90% (56/62) of the patients with equivocal disease, serology was negative; however, despite this, the diagnostic yield of CE in this cohort was still 18% (11/62). In patients with CD with persisting symptoms, CE accurately identified endoscopic markers of villous atrophy in 45% of patients, and it identified severe complications of www.giejournal.org
CD in 12% of cases. These detection rates are comparable to those of previous studies, in which smaller cohorts of patients with nonresponsive CD have been evaluated by using CE.10,11,15,16 In our cohort, 48% (33/69) had either EMA or tTG positivity despite being maintained on a gluten-free diet for ⬎12 months. This may explain the high levels of villous atrophy identified in our cohort related to possible inadvertent gluten ingestion. This has been previously described as the most frequent cause of persisting symptoms in nonresponsive patients.23 Furthermore, identification of markers of villous atrophy may reflect the established knowledge that recovery of small-bowel lesions is slow, incomplete, and often takes years to resolve after a gluten-free diet is begun.24 Limitations to this work are the lack of an adequate control group in either the equivocal or persistent symptoms cohorts, which potentially could affect the validity of our findings. Furthermore, the relatively small sample size of both cohorts and the academic medical setting could have biased our patient selection. Nevertheless, the findings are unique and have bearing on clinical practice. When faced with patients who have antibody-negative villous atrophy we would suggest that other causes of villous atrophy should be ruled out, including HIV enteropathy, medication-induced villous atrophy, and common variable immunodeficiency and other infective causes, before commencing individuals on a gluten-free diet.25-27 Furthermore, although diagnostic yield in the equivocal cases with Marsh 1 to 2 changes is low, this may not totally exclude its role as a diagnostic aid in these patients, because any confirmatory changes/alternative pathology identified by CE may inform clinicians. The presence of subtle mucosal changes may support the selection of patients who could be considered for a gluten free diet.28 In conclusion, this is the first study to specifically evaluate in a systematic manner equivocal cases related to antibody-negative villous atrophy or increased levels of intraepithelial lymphocytes. Although CE is by no means the criterion standard test in CD, our study demonstrates that the CE diagnostic yield in patients with antibodyVolume 77, No. 2 : 2013 GASTROINTESTINAL ENDOSCOPY 231
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negative villous atrophy (in this data set) is greater than that seen for CE in patients with CD with persisting symptoms. We advocate the use of CE in equivocal cases, particularly in patients with antibody-negative villous atrophy. REFERENCES 1. Schapira M, Maisin JM, Ghilain JM, et al. Epidemiology of coeliac disease. Acta Gastroenterol Belg 2003;66:234-6. 2. Sanders DS, Patel D, Stephenson TJ, et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;15:407-13. 3. Richey R, Howdle P, Shaw E, et al. Recognition and assessment of coeliac disease in children and adults: summary of nice guidance [abstract]. BMJ 2009;338:b1684. 4. United European Gastroenterology. When is a coeliac a coeliac? Report of a working group of the United European Gastroenterology Week in Amsterdam, 2001. Eur J Gastroenterol Hepatol 2001;13:1123-8. 5. Hopper AD, Cross SS, Hurlstone DP, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. BMJ 2007;334:729. 6. Cassinotti A, Birindelli S, Clerici M, et al. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009;104:195-217; quiz 194, 218. 7. 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 2008;40:219-24. 8. Gonzalez S, Gupta A, Cheng J, et al. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease. Gastrointest Endosc 2010;72:758-65. 9. Spada C, Riccioni ME, Urgesi R, et al. Capsule endoscopy in celiac disease. World J Gastroenterol 2008;14:4146-51. 10. Collin P, Rondonotti E, Lundin KE, et al. Video capsule endoscopy in celiac disease: current clinical practice. J Dig Dis 2012;13:94-9. 11. Atlas DS, Rubio-Tapia A, Van Dyke CT, et al. Capsule endoscopy in nonresponsive celiac disease. Gastrointest Endosc 2011;74:1315-22. 12. Petroniene R, Dubcenco E, Baker JP, et al. Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement. Am J Gastroenterol 2005;100:685-94. 13. Hopper AD, Sidhu R, Hurlstone DP, et al. Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in coeliac disease? Dig Liver Dis 2007;39:140-5.
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14. Rokkas T, Niv Y. The role of video capsule endoscopy in the diagnosis of celiac disease: a meta-analysis. Eur J Gastroenterol Hepatol 2012;24: 303-8. 15. Daum S, Wahnschaffe U, Glasenapp R, et al. Capsule endoscopy in refractory celiac disease. Endoscopy 2007;39:455-8. 16. Culliford A, Daly J, Diamond B, et al. The value of wireless capsule endoscopy in patients with complicated celiac disease. Gastrointest Endosc 2005;62:55-61. 17. Maiden L, Elliott T, McLaughlin SD, et al. A blinded pilot comparison of capsule endoscopy and small bowel histology in unresponsive celiac disease. Dig Dis Sci 2009;54:1280-3. 18. O’Mahony S, Howdle PD, Losowsky MS. Review article: management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther 1996;10:671-80. 19. Lidums I, Cummins AG, Teo E. The role of capsule endoscopy in suspected celiac disease patients with positive celiac serology. Dig Dis Sci 2011;56:499-505. 20. Adler SN, Jacob H, Lijovetzky G, et al. Positive coeliac serology in irritable bowel syndrome patients with normal duodenal biopsies: video capsule endoscopy findings and HLA-DQ typing may affect clinical management. J Gastrointestin Liver Dis 2006;15:221-5. 21. Sidhu R, McAlindon ME, Drew K, et al. Evaluating the role of small-bowel endoscopy in clinical practice: the largest single-centre experience. Eur J Gastroenterol Hepatol 2012;24:513-9. 22. Rondonotti E, Spada C, Cave D, et al. Video capsule enteroscopy in the diagnosis of celiac disease: a multicenter study. Am J Gastroenterol 2007;102:1624-31. 23. Abdulkarim AS, Burgart LJ, See J, et al. Etiology of nonresponsive celiac disease: results of a systematic approach. Am J Gastroenterol 2002;97: 2016-21. 24. Wahab PJ, Meijer JW, Mulder CJ. Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery. Am J Clin Pathol 2002;118:459-63. 25. Pallav K, Leffler DA, Tariq S, et al. Noncoeliac enteropathy: the differential diagnosis of villous atrophy in contemporary clinical practice. Aliment Pharmacol Ther 2012;35:380-90. 26. Shah VH, Rotterdam H, Kotler DP, et al. All that scallops is not celiac disease. Gastrointest Endosc 2000;51:717-20. 27. Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc 2012;87:732-8. 28. Kurppa K, Collin P, Viljamaa M, et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology 2009; 136:816-23.
www.giejournal.org
Capsule endoscopy in adult celiac disease: a potential role in equivocal cases of celiac disease? Matthew Kurien, MRCP, Kate E. Evans, MRCP, Imran Aziz, MRCP, Reena Sidhu, MRCP, MD, Kaye Drew, BSc, Thea L. Rogers, Mark E. McAlindon, BMed Sci, DM, FRCP, David S. Sanders, MD, FRCP, FACG Sheffield, South Yorkshire, United Kingdom
Background: There have been limited studies evaluating capsule endoscopy (CE) in equivocal celiac disease (CD). Objective: To determine the role CE may have in equivocal CD cases, compared with patients with biopsyproven and serology-proven CD who have persisting symptoms. Design: Prospective cohort study. Setting: University hospital. Patients: A total of 62 patients with equivocal CD and 69 patients with nonresponsive CD. Intervention: CE. Main Outcome Measurements: Diagnostic yield of CE in equivocal cases and accuracy of mucosal abnormality detection in patients with nonresponsive CD. Results: Equivocal cases (n ⫽ 62) were divided into two subgroups: group A (antibody-negative villous atrophy, n ⫽ 32) and group B (Marsh 1-2 changes, n ⫽ 30). In group A, CE secured a diagnosis of CD or Crohn’s disease in 28% (9/32), significantly higher than the diagnostic yield in group B (7%; P ⫽ .044). In patients with CD with persisting symptoms, significant CE findings were identified in 12% (8/69), including 2 cases of enteropathyassociated lymphoma, 4 type 1 refractory disease cases, 1 polypoidal mass histologically confirmed to be a fibroepithelial polyp, and 1 case of ulcerative jejunitis. This outcome was significantly lower than the diagnostic yield of CE in antibody-negative villous atrophy (P ⫽ .048). Limitations: Single center. Conclusion: There have been no previous reports systematically evaluating equivocal CD by using CE. The diagnostic yield of CE in patients with antibody-negative villous atrophy is better than that of CE in patients with CD with persisting symptoms. We advocate the use of CE in equivocal cases, particularly in patients with antibody-negative villous atrophy. (Gastrointest Endosc 2013;77:227-32.)
Celiac disease (CD) is an autoimmune condition characterized by a heightened immunologic response to ingested gluten, with prevalence rates in the United States and European populations estimated to range between 0.2% and 1%.1,2 The current criterion standard diagnostic test for CD is EGD, with duodenal biopsy specimens taken to dem-
onstrate the presence of villous atrophy.3 Corroborative evidence used to support the diagnosis of CD comes from positive immunologic markers (tissue transglutaminase [tTG] and endomysial antibodies [EMA]) and a clinical response to a gluten-free diet.4,5 Occasionally, when diagnostic uncertainty exists, human leucocyte antigen (HLA) typing is un-
Abbreviations: CE, capsule endoscopy; CD, celiac disease; EMA, endomysial antibodies; HLA, human leukocyte antigen; tTG, tissue transglutaminase.
Copyright © 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2012.09.031
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.
Use your mobile device to scan this QR code and watch the author interview. Download a free QR code scanner by searching ‘QR Scanner’ in your mobile device’s app store. www.giejournal.org
Received June 25, 2012. Accepted September 20, 2012. Current affiliations: Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, South Yorkshire, United Kingdom. Reprint requests: Professor David S. Sanders, Room P39, Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS FoundationTrust, Sheffield, South Yorkshire S10 2JF, United Kingdom.
Volume 77, No. 2 : 2013 GASTROINTESTINAL ENDOSCOPY 227
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TABLE 1. Modified Marsh criteria Marsh grade
Histologic findings
0
Normal
1
Raised IEL levels (⬎25/100 enterocytes)
2
Raised IEL levels with crypt hyperplasia
3a
Raised IEL levels, crypt hyperplasia, and partial villous atrophy
3b
Raised IEL levels, crypt hyperplasia, and subtotal villous atrophy
3c
Raised IEL levels, crypt hyperplasia, and total villous atrophy
IEL, Intraepithelial lymphocyte.
dertaken, which may help to exclude CD, given the high negative predictive value of this test.6 Limitations of EGD as part of this diagnostic pathway include its invasive nature and its inability to evaluate small-bowel mucosa beyond the duodenum, where rarely encountered complications of CD are seen (eg, ulcerative jejunitis, enteropathy-associated T-cell lymphoma). In addition, when duodenal biopsy sampling is considered, orientation may be problematic, and biopsies could miss definitive histologic lesions (Marsh grade 3a-3c, Table 1) because of the patchy distribution of CD lesions seen within the small bowel.7,8 CE is a well-tolerated, minimally invasive test, increasingly being used to evaluate the small bowel. Although CE is predominantly used for the assessment of obscure GI bleeding, inflammatory bowel disease, and polyposis syndromes, there has been increasing interest in the role CE may have in CD.9-11 With an 8-fold magnification power comparable to that of a dissecting microscope, CE has been shown to have high accuracy in detecting the 4 endoscopic markers of villous atrophy—reduction or absence of Kerckring’s folds, mosaic mucosal pattern, micronodular pattern, and scalloping (Figs. 1 and 2).9,12,13 In a recent meta-analysis assessing the accuracy of CE as a diagnostic tool in CD, sensitivity of this modality was 89% (95% confidence interval [CI] [82%-94%]), with a specificity of 95% (95% CI [89%-98%]).14 The main limitation of this modality as a diagnostic tool for CD is the absence of histology, which remains the criterion standard. Nevertheless, CE maybe useful when patients decline EGD, are too frail to undergo invasive investigations, or where EGD examination is not satisfactorily completed. A further role being advocated for CE in patients with CD is in managing individuals with nonresponsive disease.11,15-17 Approximately 7% to 30% of patients with CD will have persisting symptoms despite being treated with a gluten-free diet, which is usually secondary to continued ingestion of gluten.18 228 GASTROINTESTINAL ENDOSCOPY Volume 77, No. 2 : 2013
Kurien et al
Take-home Message ●
●
In this series, capsule endoscopy had a higher diagnostic yield in patients with antibody-negative villous atrophy compared with the yield seen in patients with celiac disease with persisting symptoms. Capsule endoscopy may have a potential role in equivocal cases of celiac disease.
There are limited data assessing the role of CE in equivocal cases of CD. In a study of 8 patients with positive serology (EMA or tTG) and a normal duodenal biopsy, CE did not reveal any endoscopic features of CD.19 Thus, the investigators concluded that there was no benefit in performing CE for this subgroup of patients. This contrasts with findings from another study in which 22 patients with irritable bowel syndrome with positive celiac serology and normal duodenal histology underwent CE.20 This study detected “subtle” abnormalities within the small bowel in 55% (12/22) of cases. An example of this would be “patchy segments of denuded villi.” This inconsistency raises questions about the merits of CE in equivocal cases. Furthermore, there are specifically no studies evaluating in a systematic manner equivocal cases related to antibodynegative villous atrophy or increased levels of intraepithelial lymphocytes. For this reason, this study aims to prospectively evaluate the role CE may have in equivocal cases and compares this to patients with biopsy and serology proven CD who have persisting symptoms.
METHODS Study population Data were collected prospectively from a single, tertiarycare, referral university hospital in the United Kingdom between June 2004 and December 2011. This hospital serves a population of approximately 250,000 people and currently does approximately 500 CEs annually. This is the largest single-center unit in Europe.21 This unit also has ⬎1000 patients with CD and has the largest patient cohort in the United Kingdom. In the first cohort of patients in which CE was evaluated, consecutive patients who had equivocal disease were included. These individuals were patients suspected of having CD but who had equivocal histologic or serologic findings after EGD and duodenal biopsy. In a second cohort of patients, 69 consecutive patients with biopsy-proven CD (determined by a combination of positive antibodies [EMA or tTG] and villous atrophy [Marsh grade 3a-3c]) and persisting symptoms (on a gluten-free diet ⬎12 months) underwent CE to further evaluate symptoms. CE assessed the extent of CD (proximal or diffuse), potential CD complications, and other www.giejournal.org
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Figure 1. Mosaic pattern of mucosa.
Figure 2. Scalloping.
pathologies that may have accounted for symptoms. Concurrently, serology (EMA and tTG) and a duodenal biopsy (Marsh grading, and, where appropriate, T-cell clonality) were performed. In both cohorts (histologically equivocal and nonresponsive cases), demographic data, serology, and any subsequent histology were recorded prospectively. All patients participating in this prospective study signed a consent form, permitting their outcomes to be analyzed for the purpose of a research study.
also by combinations of HLA typing (DQ-2 or DQ-8), gluten challenge/response to a gluten-free diet, and in some cases repeated duodenal biopsy. In the cohort with persisting symptoms in which CE identified significant pathology, push enteroscopy or double-balloon enteroscopy would be considered if histologic confirmation of pathology was required.
CE procedure CE was done by using either the Pillcam SB or Pillcam SB2 (Given Imaging Ltd, Yoqneum, Israel) after informed consent was obtained. Patients underwent a 12-hour overnight fast and ingested two sachets of polyethylene glycol solution (Kleen-Prep, Norgine, UK) before commencing the test. Patients were allowed to drink 2 hours after ingestion of the capsule and eat a light snack 4 hours after ingestion of the capsule. The sensor array and recorder pack were disconnected after 8 hours, and images were downloaded onto a work station. Patients were examined 30 minutes after capsule ingestion by use of the Real Time Viewer (Given Imaging) and given metoclopramide intramuscularly if the capsule remained within the stomach. Videos were analyzed by 3 experienced CE readers (R.S., K.D., M.E.M.). All CE readers had knowledge of the patient’s clinical symptoms before CE reporting but were blinded to serologic, histopathologic, and HLA status findings
Outcomes after CE In the histologically equivocal cohort, a diagnosis of CD was further supported not only by the CE appearances but www.giejournal.org
Laboratory test data All patients in this study had immunoglobulin A (IgA), EMA, and tTG antibody measurements before undergoing their CEs. Total IgA levels were measured on a Behring BN2 nephelometer. The tTG antibodies were assayed by using enzyme-linked immunosorbent assay kits (Aesku Diagnostics, Wendelsheim, Germany). A tTG titer of ⬎15 U/mL was regarded as positive. IgA EMA was detected by immunofluorescence on primate esophagus sections (Binding Site, Birmingham, UK).
Statistics and ethical issues Statistical analysis was carried out by using SPSS version 17.0 software (SPSS Inc, Chicago, Ill). In the equivocal cases, differences in diagnostic yield were tested by using the Fisher exact test, with P values being 2-sided and considered significant if ⬍ .05. Where appropriate, descriptive statistics were used to summarize patient demographic data, clinical factors, and CE characteristics, including counts and percentages. In the patients with biopsy-proven CD with persistent symptoms, concordance between serology, histology, and CE findings was assessed by using the Spearman coefficient. This study was discussed and registered with Sheffield Health Service Evaluation and Ethics Committee, United Volume 77, No. 2 : 2013 GASTROINTESTINAL ENDOSCOPY 229
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TABLE 2. Equivocal cases— demographic data summary and CE findings Group A (antibody-negative villous atrophy)
Group B (Marsh score 1/2)
32
30
25 female, 7 male
20 female, 10 male
53 (31-92)
46 (21-75)
0/32 (0)
6/30 (20)
Normal
23 (72)
28 (93)
Endoscopic markers of CD
7 (22)
1 (3)
2 (6)
1 (3)
9 (28)
2 (7)
Characteristic n Sex Age, median (range), y Positive serology at time of CE, no (%)
P value
CE findings, no (%)
Other findings Crohn’s disease Positive findings
.04*
CE, Capsule endoscopy; CD, celiac disease. *Significant difference (P ⬍ .05) in CE findings between group A and group B.
Kingdom, and was conducted according to principles of the Declaration of Helsinki and Good Clinical Practice Guidelines.
RESULTS
diologic findings to establish a diagnosis of Crohn’s disease. When comparing the subgroups of equivocal cases, we found that CE had a significantly higher diagnostic yield in identifying CD or Crohn’s disease in those individuals in group A compared with those in group B (28% vs 7%; P ⫽ .04).
Histologically equivocal cohort A total of 62 histologically equivocal cases were referred for CE between June 2004 and December 2011. Of these patients, 32 (52%) had antibody-negative villous atrophy (group A). These patients had undergone systematic evaluation of villous atrophy before being referred for CE. This included in the first instance a history review (including a thorough drug history), immunoglobulin levels, and review of histopathology. Thereafter, a combination of HLA typing, gluten challenges, repeat celiac serology and duodenal biopsies, and exclusion of infection/ autoimmune causes were performed. No alternative diagnosis for the villous atrophy was identified in any cases, with 63% of patients (20/32) being HLA positive for DQ2 or DQ8 haplotypes. The remaining 30 patients (48%) in the histologically equivocal cohort had either Marsh 1 or Marsh 2 changes on duodenal biopsy (group B). Of these patients in group B, 6 (20%) had positive serology (4 being tTG positive and 2 having both EMA antibody and tTG positivity). Table 2 highlights the demographic data, clinical characteristics, and endoscopic findings for the patients with histologically equivocal CD. The two cases of Crohn’s disease had numerous erosions and ulcerations within the distal small bowel at CE. Histologic findings from this area demonstrated the presence of noncaseating granulomas in both cases, with clinicopathologic findings supporting ra230 GASTROINTESTINAL ENDOSCOPY Volume 77, No. 2 : 2013
Patients with CD with persisting symptoms A total of 69 patients with CD with persisting symptoms were referred for CE, of which 47 patients were female, with a median age of 56 years (range 22-83 years). All of the patients had been on a self-reported gluten-free diet for a minimum of 12 months, with a mean (⫾ standard deviation) duration of 5.3 ⫾ 4.9 years. Endoscopic markers of villous atrophy were identified in 45% (31/69) of cases, with reduction or absence of Kerckring’s folds being the most frequently identified endoscopic marker of CD, occurring in 65% (20/31). Scalloping was the second most frequently observed endoscopic marker, occurring in 55% of cases (17/31), with both mosaic pattern and nodularity occurring in 32% of cases (10/31). A total of 8 patients of the 69 (13%) had significant abnormal CE findings with mass lesions, extensive disease, or ulceration identified. After extensive biopsy sampling from these areas; 2 had enteropathy-associated lymphoma, 4 had type 1 refractory disease, and 1 had ulcerative jejunitis. A 3-cm polypoid mass was identified at CE in the remaining case, which was removed surgically with subsequent histology demonstrating a fibroepithelial polyp. Of the 4 (6%) refractory type 1 cases, 2 patients were treated with immunosuppressants, 1 died of unrelated causes, and another was a tertiary-care referral case for which outcome data are unknown. Comparisons with www.giejournal.org
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TABLE 3. Comparing diagnostic yield of CE in patients with CD with persisting symptoms and equivocal cases
No. of patients CD patients with persistent symptoms
Diagnostic yield, no. (%)
P value
69
Significant pathology 8 (12)
Group A (antibody-negative villous atrophy)
32
9 (28)
.048*
Group B (Marsh score 1/2)
30
2 (7)
.718
Equivocal cases
CE, Capsule endoscopy; CD, celiac disease. *Significant difference (P ⬍ .05) in CE findings between group A (antibody-negative villous atrophy) and patients with CD with persisting symptoms.
diagnostic yields in the equivocal cohort are detailed in Table 3. When evaluating predictors of CD complications and CD extent, we identified no correlation between the likelihood of having complicated CD and the serologic titers (either a positive EMA test result or significantly raised tTG level). However, there was a positive correlation between more extensive changes at CE (diffuse) and the level of tTG (r ⫽ 0.448; P ⫽ .001). A similar observation was made for the relationship between diffuse involvement at CE and EMA positivity (r ⫽ 0.351; P ⫽ .003). There was also a correlation between the extent of disease observed at CE and histology (r ⫽ 0.455; P ⬍ .0001).
DISCUSSION The diagnostic yield of CE in patients with antibodynegative villous atrophy is better than the yield of CE in identifying significant pathology in those patients with CD with persisting symptoms. Based on our findings, we advocate the use of CE in helping establish a diagnosis in patients with antibody-negative villous atrophy. Although previous studies have demonstrated a potential role for CE as a diagnostic tool in celiac disease,13,14,22 we believe that this is the first study to specifically evaluate in a systematic manner equivocal cases related to antibodynegative villous atrophy or increased levels of intraepithelial lymphocytes. Concerns have been raised previously regarding the actual diagnostic yield of CE in CD, because previously undertaken studies have frequently evaluated patients with a high before-test probability (positive celiac serology), potentially leading to an overestimation of CE performance.9 Where this study adds to the literature is that in 90% (56/62) of the patients with equivocal disease, serology was negative; however, despite this, the diagnostic yield of CE in this cohort was still 18% (11/62). In patients with CD with persisting symptoms, CE accurately identified endoscopic markers of villous atrophy in 45% of patients, and it identified severe complications of www.giejournal.org
CD in 12% of cases. These detection rates are comparable to those of previous studies, in which smaller cohorts of patients with nonresponsive CD have been evaluated by using CE.10,11,15,16 In our cohort, 48% (33/69) had either EMA or tTG positivity despite being maintained on a gluten-free diet for ⬎12 months. This may explain the high levels of villous atrophy identified in our cohort related to possible inadvertent gluten ingestion. This has been previously described as the most frequent cause of persisting symptoms in nonresponsive patients.23 Furthermore, identification of markers of villous atrophy may reflect the established knowledge that recovery of small-bowel lesions is slow, incomplete, and often takes years to resolve after a gluten-free diet is begun.24 Limitations to this work are the lack of an adequate control group in either the equivocal or persistent symptoms cohorts, which potentially could affect the validity of our findings. Furthermore, the relatively small sample size of both cohorts and the academic medical setting could have biased our patient selection. Nevertheless, the findings are unique and have bearing on clinical practice. When faced with patients who have antibody-negative villous atrophy we would suggest that other causes of villous atrophy should be ruled out, including HIV enteropathy, medication-induced villous atrophy, and common variable immunodeficiency and other infective causes, before commencing individuals on a gluten-free diet.25-27 Furthermore, although diagnostic yield in the equivocal cases with Marsh 1 to 2 changes is low, this may not totally exclude its role as a diagnostic aid in these patients, because any confirmatory changes/alternative pathology identified by CE may inform clinicians. The presence of subtle mucosal changes may support the selection of patients who could be considered for a gluten free diet.28 In conclusion, this is the first study to specifically evaluate in a systematic manner equivocal cases related to antibody-negative villous atrophy or increased levels of intraepithelial lymphocytes. Although CE is by no means the criterion standard test in CD, our study demonstrates that the CE diagnostic yield in patients with antibodyVolume 77, No. 2 : 2013 GASTROINTESTINAL ENDOSCOPY 231
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negative villous atrophy (in this data set) is greater than that seen for CE in patients with CD with persisting symptoms. We advocate the use of CE in equivocal cases, particularly in patients with antibody-negative villous atrophy. REFERENCES 1. Schapira M, Maisin JM, Ghilain JM, et al. Epidemiology of coeliac disease. Acta Gastroenterol Belg 2003;66:234-6. 2. Sanders DS, Patel D, Stephenson TJ, et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;15:407-13. 3. Richey R, Howdle P, Shaw E, et al. Recognition and assessment of coeliac disease in children and adults: summary of nice guidance [abstract]. BMJ 2009;338:b1684. 4. United European Gastroenterology. When is a coeliac a coeliac? Report of a working group of the United European Gastroenterology Week in Amsterdam, 2001. Eur J Gastroenterol Hepatol 2001;13:1123-8. 5. Hopper AD, Cross SS, Hurlstone DP, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. BMJ 2007;334:729. 6. Cassinotti A, Birindelli S, Clerici M, et al. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009;104:195-217; quiz 194, 218. 7. 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 2008;40:219-24. 8. Gonzalez S, Gupta A, Cheng J, et al. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease. Gastrointest Endosc 2010;72:758-65. 9. Spada C, Riccioni ME, Urgesi R, et al. Capsule endoscopy in celiac disease. World J Gastroenterol 2008;14:4146-51. 10. Collin P, Rondonotti E, Lundin KE, et al. Video capsule endoscopy in celiac disease: current clinical practice. J Dig Dis 2012;13:94-9. 11. Atlas DS, Rubio-Tapia A, Van Dyke CT, et al. Capsule endoscopy in nonresponsive celiac disease. Gastrointest Endosc 2011;74:1315-22. 12. Petroniene R, Dubcenco E, Baker JP, et al. Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement. Am J Gastroenterol 2005;100:685-94. 13. Hopper AD, Sidhu R, Hurlstone DP, et al. Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in coeliac disease? Dig Liver Dis 2007;39:140-5.
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