Diagnostic Testing in IBS: Evidence-Based Updates

Diagnostic Testing in IBS: Evidence-Based Updates Brennan Spiegel, MD, MSHS Cedars-Sinai Medical Center Cedars-Sinai Center for Outcomes Research and Education (CS-CORE)

The Brain-Gut Axis Higher brain activation in response to stress Thinner grey matter density Altered amygdala reactivity Central nervoussystem (CNS) Brain-gut axis Intestinal infections “Leaky” gut Low-grade inflammation Visceral hypersensitivity Dysmotility Enteric nervoussystem (ENS) • Mayer E. et al; Gastroenterol 2010;139:48 • Mayer E. et al; Gastroenterol 2011;140:1943

“Hit” Stress Infection Diet Allergy Disease Expression • Underlying dysfunction in: • Intestinal dysbiosis • Mast cell number and function • Serotonin trafficking • HPA Axis • Cortical pain processing Evolving IBS Disease Model Susceptible Host

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

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

0 Proposed Pathophysiological Mechanisms Involved in IBS Visceral hypersensitivity Altered brain–gut interactions Inflammation IBS Geneticfactors Bacterial-Host Interactions Psychosocialfactors

Risk for PI-IBS Increases After Traveler’s Diarrhea 0 Overall PI-IBS Incidence (Pooled from 6 studies) Pooled OR: 3.51 (95% CI: 2.25-5.48) Overall PI-IBS, % Scwille-Kiuntke J et al. Aliment Pharmacol Ther. 2015;41:1029-1037.

Case History • 42-year-old white man complains of intermittent abdominal pain and diarrhea for 2 years • Has 4-8 bowel movements daily • Stools “loose” and often come on urgently • LLQ crampy pain that improves with stool passage, and worse with eating • No recent travel, unusual food ingestions, antibiotics, gastroenteritis, or intolerance of dairy products. Spiegel et al. Amer J Gastroenterol 2010;105:848-58

Case History – Continued • No nighttime symptoms • No GI “alarm symptoms” • No GI “alarm signs” • Stool guaiac negative • CBC and chemistries normal Spiegel et al. Amer J Gastroenterol 2010;105:848-58

Question #1  Does this patient have IBS? A) Yes B) No C) Unsure – need more data

Believes patient probably has IBS Prepared to confidently affirm diagnosis with patient Does this Patient Have IBS? Results of U.S. Survey Spiegel et al. Amer J Gastroenterol 2010;105:848-58

Diagnostic Battery Breath-testing Stool Ova & Parasites Thyroid function testing ESR / CRP / Colonoscopy Breath-testing Stool leukocytes / C&S / C. diff Colonoscopy / Flexsig Sprue Serologies Diagnostic Battery is Extensive Performing the wrong tests can lead to excessive resource utilization and worsen patient outcomes IBS “Look-Alikes” Bacterial overgrowth Giardiasis Hyperthyroidism IBD Lactose intolerance Infectious colitis Microscopic colitis Celiac sprue

Predictors of Diagnostic Testing in IBS In study of 201,322 IBS patients in US claims database, diagnostic testing predicted by… Higher age Higher symptom burden Female gender More specialist visits Luo et al. DDW 2016; AB 363

100% 98% 65% How Accurate are the Rome Criteria? 100 50 0 Retrospective Sensitivity Retrospective Specificity Prospective Positive Predictive Value Vanner S. et al, Am J Gastro 1999

96% 82% 17% 50% How Accurate are the Rome III Criteria? 100 50 0 NPV Sensitivity Specificity PPV Ford A. et al, Gastroenterol 2013;145:1262

Diagnostic Battery Breath-testing Stool Ova & Parasites Thyroid function testing ESR / CRP / Colonoscopy Breath-testing Stool leukocytes / C&S / C. diff Colonoscopy / Flexsig Sprue Serologies Diagnostic Battery is Extensive IBS “Look-Alikes” Bacterial overgrowth Giardiasis Hyperthyroidism IBD Lactose intolerance Infectious colitis Microscopic colitis Celiac sprue

100% 100% 98% 99% How Often is Structural Colon Evaluation Normal in IBS? 100 % Normal Exams 50 0 Tolliver et al. AJG 1994 Hamm et al. AJG 1999 MacIntosh et al. AJG 1992 Francis et al. AJG 1996

So Why Perform Colonoscopy? • May provide reassurance if normal • May improve quality of life if normal • May reduce later resource utilization if normal

87% 83% 69% Differences in Reassurance Negative colonoscopy may not provide reassurance or improve quality of life in IBS 100 Percent “Reassured” 50 0 No previous colonoscopy Distant Normal Colonoscopy Recent Normal Colonoscopy Spiegel et al, Gastrointest Endo 2005

Colitis in IBS P<0.01 4.9 1.8 1.5% IBS-D / IBS-M Healthy Controls 10 % Patients 5 0 Mucosal “Erythema” or Ulcerations Microscopic Colitis Chey et al. Amer J Gastroenterol 2010;105:859-64

Yield of Stool Studies in IBS Stool ova & parasite: Hamm et al: 0.09% positive (N=1154) Tolliver et al: 0.0% positive (N=170) Stool leukocytes No data, though yield likely very low Stool C. diff / stool culture No data, though yield likely very very low Hamm LR, et al. Am J Gastro 1999;94:1279 Tolliver BA, et al. Am J Gastro 1994;89:176

Yield of ESR / CRP / TSH Yield of ESR / CRP Sanders et al Lancet 2001 1/300 with elevated ESR  diagnosed with IBD 2/300 with elevated CRP  diagnosed with IBD Yield of TSH Hamm et al AJG 1999  3% hyper-, 3% hypo- Tolliver et al AJG 1994  0.6% “abnormal” TSH Yield not different from normal population (5-9%) Sanders DS, et al. Lancet 2001;358:1504 Hamm LR, et al. Am J Gastro 1999;94:1279 Tolliver BA, et al. Am J Gastro 1994;89:176

IBS 20-75% Have Symptoms Consistent with IBS Celiac Sprue 100% Have Symptoms Consistent with Sprue O’Leary C, et al. Am J Gastro 2002;97:1463 Zipser RD, et al. Dig Dis Sci 2003;48:761

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

OR=26.2 (95% CI=4.7, 104) 84% 20% Prevalence of Abnormal* Lactulose Breath Tests in Rome I IBS 100 50 0 IBS Controls N=111 N=15 • *Single peak >20 ppm rise of H2 by 90 min • Pimentel et al. Am J Gastro 2003;98:412

NS NS NS NS <0.001 IBS Control Grover et al NGM 2008 Bratten et al AJG 2008 Walters et al AJG 2005 Posserud et al Gut 2006 N=204 N=126 N=42 N=192 IBS vs. Controls: H2 rise > 20 ppm by 180 90 80 70 60 50 % Positive 40 30 20 10 0 Pimentel et al AJG 2003 N=126

Positive Lactulose Breath Test: Odds in IBS vs. Controls Lupascu 2005 10.89 (3.33, 45.67) Parodi 2007 14.00 (3.26, 124.54) Posserud 2007 1.13 (0.14, 52.89) Bratten 2008 0.45 (0.18, 1.23) Grover 2008 2.29 (0.86, 7.16) Rana 2008 12.38 (1.96, 513.13) Pooled OR (95% CI) 3.45 (0.94, 12.72) 0.1 0.2 0.5 1 2 5 10 100 1000 Ford, Talley, Spiegel, Moayeddi . Clin Gastro Hep 2009

Biomarkers for IBS?The IBS Microbial Hypothesis At Work Food poisoning Bacterial toxin Gut nerve damage Bacterial overgrowth IBS Auto-immunity E. Coli C. jejuni Shigella Salmonella Breath testing Culture qPCR Deep sequencing Cytolethal Distending toxin (CDT B) Reduced ICC Reduced MMC Anti-vinculin Pimentel M et al. PLoS ONE. 2015;10(5):e0126438.

Anti-Vinculin / CdtB Antibody

IBS Diagnosis: Take-Away Messages • If patient fulfills Rome criteria, there is rarely underlying organic disease (that we can reliably identify) • Guidelines indicate IBS is a diagnosis of exclusion, but many disagree • Structural colonic abnormalities are no higher in IBS vs. controls, but 1.5% have microscopic colitis • ESR and sprue serologies are useful in some patients • Breath testing is of unclear clinical utility • Anti-vinculin/Anti-CdtB antibody promising new IBS diagnostic • Bottom line: we should remain judicious in performing exclusionary diagnostic testing in IBS; the yield remains generally low Questions or Comments? Email: brennan.spiegel@cshs.org @BrennanSpiegel

Diagnostic Testing in IBS: Evidence-Based Updates