1 Literature Review Peter R. McNally, DO, FACP, FACG University of Colorado School of Medicine, Center for Human Simulation Aurora, Colorado 80045

2 Video Capsule Enteroscopy in the Diagnosis of Celiac Disease: A multicenter Study. Am J Gastroenterol. 2007;102; Rondonotti E, Spada C, Cave D, Pennazio M, Riccioni M, De Vitis I, Schneider D, Sprujevnik T, Villa F, Langeleir J, Arrigoni A, Costamagna G, de Franchis R.

3 Introduction Celiac Disease (CD) is one of the most common genetic disorders seen in North America. Estimates of prevalence range from 1 in persons. 1 Celiac Disease (CD) is one of the most common genetic disorders seen in North America. Estimates of prevalence range from 1 in persons. 1 The clinical manifestations of CD are many, when CD is full blow is it manifest by diarrhea weight loss, anemia, & malabsorption. 2 The clinical manifestations of CD are many, when CD is full blow is it manifest by diarrhea weight loss, anemia, & malabsorption. 2 Rondonotti E, et al. Am J Gastro. 2007;1902: Statement NIH Consensus Development Conference on Celiac Disease AGA Institute medical position statement on the diagnosis and management of celiac disease. Gastroenterology. 2006;131;

4 Serologic tests have become the preferred method of screening patients for CD and include: AGA, AmEA, & TTG. 3 Serologic tests have become the preferred method of screening patients for CD and include: AGA, AmEA, & TTG. 3 “Gold Standard” for the diagnosis of Celiac Disease is identification of Marsh Criteria by small bowel biopsy. 2 “Gold Standard” for the diagnosis of Celiac Disease is identification of Marsh Criteria by small bowel biopsy. 2 Video Capsule Endoscopy (VCE) is a new technology opening a window for “non-invasive” examination of the small intestine. Common VCE findings of Celiac Disease include: scalloping, nodular mucosa, reduced mucosal folds, &/or erosions. 5 Video Capsule Endoscopy (VCE) is a new technology opening a window for “non-invasive” examination of the small intestine. Common VCE findings of Celiac Disease include: scalloping, nodular mucosa, reduced mucosal folds, &/or erosions. 5 Rondonotti E, et al. Am J Gastro. 2007;1902: Rostom A, et al. Gastroenterol. 2005;128:S38-S46 5. Korman LY, et al. Endoscopy 2005;37:951-9.

5 Aim Test the performance of VCE in patients with both signs/symptoms of and (+) CD serology compared to conventional endoscopy and duodenal biopsy. Determine the longitudinal extent of mucosal involvement of CD beyond the duodenum and its correlation with clinical & serologic markers. Rondonotti E, et al. Am J Gastro. 2007;1902:

6 Study Design:Design: Prospective multi-center enrollment of 43 consecutive subjects with clinical signs and symptoms and at least one positive serologic test (+) for CD. Center Enrollment: 10 Milan, 10 Truin, 15 Rome, 8 Boston Signs & Symptoms – Chronic diarrhea – Weight Loss – Dermatitis Herpetiformis – History of Multiple spontaneous abortions – Iron Deficiency – Osteoporosis – Autoimmune Thyroid Disease – Diabetes Mellitus Type I Serologic Tests – IgA-AGA67% (+) – IgG-AGA 67% (+) – IgA-AmEA67% (+) – IgA-TTG77% (+) AGA: Antigliadin Antibody AmEA: Endomysial Antibody TTG: TissueTransglutaminase Rondonotti E, et al. Am J Gastro. 2007;1902: Inclusion Criteria: >1 Sign and Symptom (+) >1 serologic Test

7 Study Design:Design: Prospective multi-center enrollment of 43 consecutive subjects with clinical signs and symptoms for and at least one positive serologic test (+) for CD. Center Enrollment: 10 Milan, 10 Truin, 15 Rome, 8 Boston Rondonotti E, et al. Am J Gastro. 2007;1902: Exclusion Criteria: – History Small Bowel Obstruction – History Dysphagia – Cardiac Pacemaker – Electrical Implants – Prior gastric/small bowel surgery – IgA deficiency – Chronic NSAID use or occasional use previous month

8 Study Design: Diagnostic Procedures VCE (Given Imaging, Yoqneam, Isreal). VCE (Given Imaging, Yoqneam, Isreal). – Pill cam swallowed after 12 hr overnight fast – Image analysis using Given Imaging software – Small bowel transit time divided in thirds Prox 1/3 rd Prox 1/3 rd Mid 1/3 rd Mid 1/3 rd Distal 1/3 rd Distal 1/3 rd EGD’s > 4 biopsies of 2 nd portion duodenum: Marsh Criteria on histologic examination EGD’s > 4 biopsies of 2 nd portion duodenum: Marsh Criteria on histologic examination Rondonotti E, et al. Am J Gastro. 2007;1902:

9 Study Design: Diagnostic Criteria Biopsy: Marsh Histologic Criteria for CD – Type 0 : normal histology – Type I :  Intraepithelial lymphocytes (IEL) – Type II : crypt hyperplasia + normal villi – Type III : villous atrophy Video Capsule Endoscopy Criteria for CD – Scalloping – Nodular mucosa – Reduced mucosal folds – Erosions Rondonotti E, et al. Am J Gastro. 2007;1902:

10 VCE showing scalloping and nodular mucosa Rondonotti E, et al. Am J Gastro. 2007;1902:

11 VCE showing ulceration (a) and decreased mucosal folds (b) Rondonotti E, et al. Am J Gastro. 2007;1902: a b

12 Demographics Gender (M/F) & mean age 19/24 & 35 yrs Diarrhea49% Wt loss 14% Abd pain 65% Dermatitis Herpetiformis 7% Iron Deficiency 32% Duodenal Histology Marsh 0 11/43 (26%) Marsh I 1/43 (2.3%) Marsh II 3/43 (7%) Marsh III 28/43 (65%) Rondonotti E, et al. Am J Gastro. 2007;1902:

13 Results: VCE Changes observed Rondonotti E, et al. Am J Gastro. 2007;1902: VCE Mucosal ChangesN (%) Scalloping25 (89%) Nodularity – mosaic pattern12 (43%) Reduction of mucosal folds10 (35%) Erosions – ulcers 2 (7%)

14 Histologic Grading vs. VCE findings Rondonotti E, et al. Am J Gastro. 2007;1902: VCE Marsh 0 IIIIIITotal Normal Abnormal Total

15 Serology & VCE vs. Histology Rondonotti E, et al. Am J Gastro. 2007;1902: Marsh 0 Marsh I Marsh II Marsh III IgA AmEA 1/10 (10%) 1/1(100%)2/3(66%)22/25(88%) IgA TTG 1/9(11%)1/1(100%)3/3(100)25/26(96%) VCE Abn: prox 1/3 rd 1/11(9%)0/1(0%)3/3(100%)25/28(89%) VCE Abn: middle 1/3 rd 0/10(0%)0/1(0%)2/2(100%)16/27(59%) VCE Abn: distal 1/3 rd 0/10(0%)0/1(0%)0/3(0%)3/27(11%)

16 Result Summary 1. One of 43 pts with dermatitis herpetiformis & (+) AmEM was Marsh 0 on biopsy, but positive for patchy mucosal changes on VCE. 2. Four pts with (+) CD serology and Marsh Criteria [(Gr I (1) & Gr III (3)] were negative on VCE (12.5%). 3. No patients had distal CD changes without coincident proximal VCE mucosal changes. 4. VCE mucosal changes in distal 1/3 rd were only seen with advanced Marsh III changes. Rondonotti E, et al. Am J Gastro. 2007;1902:

17 Conclusion 1. This study showed that the miss rate for VCE to detect CD among symptomatic, serology and biopsy proven subjects is 4/32 (12%). 2. VCE identified CD mucosal changes in one subject with Dermatitis Herpetiformis and (+) EMA with biopsy negative CD. Suggesting endoscopic sampling error in 1/43 (2%). 3. Mucosal changes of CD seen with VCE, always start proximally and tend to predict more advanced Marsh Criteria II & III when the 2 nd and 3 rd portions of the small bowel exhibit VCE mucosal changes. Rondonotti E, et al. Am J Gastro. 2007;1902:

18 Reviewer Comments 1. Endoscopy and mucosal biopsy remains the gold standard for the diagnosis of CD. However, when biopsies are (-) and clinical suspicion is still high, i.e., (+) EMA & TTG, then VCE may be helpful in identifying subtle, patchy mucosal abnormalities that may support directed mucosal biopsies. 2. Although VCE changes are common among CD pts (87.5%), the finding in this study that 4 of 32 (12%) CD pts with (+) serologies and Marsh histology have ‘normal’ VCE should emphasize the need for CAUTION as the negative predictive value is 71.4%.