1. Should we Screen for Celiac Disease in IBS? Brennan Spiegel, MD, MSHS

2. Dietary factors High sorbitol diet High-fiber diet FODMAP Diet Caffeine Alcohol Inflammation Ulcerative colitis Crohn’s disease Microscopic colitis Endocrine Hyperthyroidism Diabetes Carcinoid Gastrinoma Psychological Anxiety Somatization Depression PTSD Infection SIBO C. diff Giardiasis Malabsorption Celiac sprue Carb intolerance Pancreatic disease Bile acid malabsorption Existential Question: What Is IBS? IBS

3. Is IBS an absence of other things? Or is it some thing… unto itself? IBS

4. Inflammation Altered brain– gut interactions Visceral hypersensitivity Genetic factors Psychosocial factors Bacterial-Host Interactions IBS Proposed Pathophysiological Mechanisms Involved in IBS

5. IBS Celiac How often is overlap? When to screen? How to screen?

6. Patient C.M. Case History 34 year old woman with 10-years of loose stools 4-6 bowel movements per day LLQ crampy pain that improves with stool passage Always feels “bloated” No weight loss, nighttime symptoms, incontinence, fevers, vomiting, or rectal bleeding No dairy intolerance, unusual travel, acute GI illnesses, recent antibiotics or other relevant meds No alarm features on physical examination

7. Patient C.M. – Laboratories Normal studies included: –Complete blood count –Serum electrolytes –Stool cultures, sensitivity, and leukocytes –Stool occult blood –Erythrocyte sedimentation rate –C Reactive Protein

8. Patient C.M. – Treatment Course Treated with antispasmodics  No improvement, felt sleepy Treated with rifaximin  “Little better at first, then worse again” Treated with loperamide  Diarrhea improved, but still had abdominal pain

11. “My IBS went away once I started the gluten free diet. And then, soon after trying bread again, it all came back.”

12. Clinical Questions Does she have celiac disease (CD), gluten sensitivity, or both? Does gluten exposure explain her symptoms? Could she still have IBS in addition to CD? Is a gluten-free diet appropriate at this point? What about gluten challenge, then re-biopsy? Need to check HLA-DQ2 or HLA-DQ8?

13. IBS Celiac 100% have symptoms consistent with celiac 20-75% have symptoms consistent with IBS Zipser RD, et al. Dig Dis Sci 2003;48:761 O’Leary C, et al. Am J Gastro 2002;97:1463

14. Inflammation SIBO IBS 66% have SIBO 15-80% have SIBO Tursi A, et al. Am J Gastro 2003;98:839 O’Leary C, Quigley E. Am J Gastro 2003;98:720 Verdu E, et al. Am J Gastro 2009 Celiac

15. Is this just a case of “true, true, and unrelated?”

16. Clinical Spectrum – Definitions Overt celiac: Positive serology with Marsh III lesion. Latent celiac: Normal serology and mucosa despite gluten, but genetic predisposition for sprue, persistent underlying immunologic abnormalities, with potential to express overt celiac with gluten challenge. Gluten sensitivity: Minimal enteropathy (Marsh I-II) that improves histologically and symptomatically to gluten withdrawal in a patient with HLA DQ positivity Wahnschaffe U, et al. Gastro 2001;1329 Weinstein W. Gastro 1972;66:489 Verdu E, et al. Am J Gastro, 2009

17. Serology +Serology - Villlous Blunting No Villous Blunting Simplified Sprue 2x2 Table Overt Sprue 1.Latent Sprue 2.False Pos Serology 3.False Neg Biopsy False Negative (or other Dx) 1.No Sprue 2.Latent Sprue 3.Gluten sensitivity

18. More Realistic Sprue Table TTG – AGA - TTG – AGA + TTG + AGA - TTG + AGA + Marsh 0 Marsh I-II Marsh III 1.No Sprue 2.Latent Sprue 1.Gluten sens. 2.False Pos AGA Overt Sprue 1.Latent Sprue 2.False Pos AGA & TTG 1.Latent Sprue 2.False Pos Gluten sens. 1.Gluten sens. 2.False Neg 1.Other Dx 2.False Neg 1.Overt Sprue 2.Other Dx with FP AGA 1.Gluten sens. 2.False Pos TTG Overt Sprue 1.No Sprue 2.Latent Sprue

19. Pre-Test Likelihood Low Medium High Histology Marsh 0Marsh IIMarsh IMarsh III Serology -/- +/- -/+ +/+ Clinical Reality: the Sprue Cube

20. Biopsy-Proven Celiac Disease in IBS: Results of Meta-Analysis Ford A, Chey W, Talley N, Malhotra A, Spiegel B, Moayyedi P. Arch Int Med 2009;13:169 It is cost-effective to screen for celiac sprue in IBS if pre-test likelihood exceeds 1% Spiegel et al. Gastroenterology 2004;126:1721 It is cost-effective to screen for celiac sprue in IBS if pre-test likelihood exceeds 1% Spiegel et al. Gastroenterology 2004;126:1721

21. Data from U.S. – Link is Weaker Cash et al. Gastroenterol 2011;141:1178 Biopsy proven sprue in IBS: 0.41%

22. Patient C.M. – Continued Reluctant to diagnose celiac disease –Only Marsh I lesion –Anti-TTG negative  98% NPV –Anti-GA equivocal –Lifetime diagnosis has significant implications Opted for gluten challenge with re-biopsy with HLA testing –Cannot yet rule-out gluten sensitivity

23. Patient C.M. – Continued Enteroscopy with duodenal and jejunal biopsies normal after 2 month gluten challenge Follow-up labs –ESR / CRP normal –CBC normal –IBD Panel negative –HLA-DQ2 positive, HLA-DQ8 negative

24. Prometheus Sprue Panel Does she have gluten sensitivity?

25. Latent Sprue and Gluten Sensitivity in IBS Wahnschaffe et al. studied 102 IBS patients: –0% had positive antibodies in serum –35% were HLA-DQ2 + –23% had elevated IELs (Marsh I), none Marsh II+ –30% had positive anti-TTG IgA in duodenal aspirate Treated sub-set with gluten-free diet –Compared to controls, GFD improved stool frequency in HLA+ and duodenal anti-TTG+ patients –Elevated IELs did not predict symptom response Wahnschaffe U, et al. Gastro 2001;1329

26. D-IBS Patients: Predicting Response to Gluten-Free diet Wahnschaffe U, et al. CGH 2007;5:844 ProfilePPVNPV DQ2 + 44%94% Antibody + (AGA/TTG) 45%86% DQ2+ and Ab+ 56%88%

27. Impact of Gluten on EMA Positive Patients with Marsh I-II Lesions Kurppa K, et al. Gastroentrol 2009;136:816-823

28. Impact of Gluten on Symptoms Kurppa K, et al. Gastroentrol 2009;136:816-823

29. Patients with mild enteropathy and positive serologies may benefit from early treatment with a gluten free diet even if they don’t meet strict criteria for celiac disease Current diagnostic criteria for celiac disease may need to be expanded to include patients with mild enteropathy (Marsh I-II) Patients with mild enteropathy and positive serologies may benefit from early treatment with a gluten free diet even if they don’t meet strict criteria for celiac disease Current diagnostic criteria for celiac disease may need to be expanded to include patients with mild enteropathy (Marsh I-II)

30. What About if Negative Serologies?

31. Vazquez-Roque, et al. Gastroentrol 2013;144:903-911

32. Patient C.M. – Continued Has been on strict gluten-free diet for 6 years, and has remained considerably better but still has some “IBS symptoms with stress.”

33. Take Home Messages Non-U.S. IBS patients around 4x more likely to harbor underlying biopsy-proven celiac disease Testing for celiac cost-effective if pre-test likelihood exceeds 1% – but probably lower in U.S. Even if no celiac disease, may still harbor latent celiac disease or gluten sensitivity If borderline, consider checking HLA DQ2 – if negative, probably no celiac; if positive, consider GFD