1. Inflammatory Bowel Diseases Endoscopy and Imaging Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina

2. Ulcerative colitis: Definition Recurrent inflammatory and ulcerating disease of the colon and rectum Diarrhea, bleeding, crampy abdominal pain, reduced appetite and weight loss Diffuse inflammation with ulcerations, crypt abscesses, inflammatory infiltrates and reduced number of goblet cells

3. leftsided Colitis Progression from rectum to cecum Proctitis Backwash Ileitis Pan- Colitis

4. Crohn’s disease: Definition Subacute or chronic inflammation of the digestive tract (mouth to anus) Crampy abdominal pain, weight loss, diarrhea and fever Local inflammation with microerosions, fissures, ulcers, granulomas, inflammatory infiltrates and lymphangiectasias

5. Clinical Symptom in IBDs Ulcerative colitis 80 % 90 % 47 % 0 % 5 % 1 % 40 % 38 % 11 % Crohn’s disease 22 % 73 % 77 % 16 % 54 % 35 % 27 % 29 % 10 % Bleeding Diarrhea Abdominal pain Fistulae Weight loss Fever Anemia Arthralgia Iridocyclitis, uveitis

6. Clinical symptoms Laboratory findings Microbiology findings Histology Endoscopy Radiologic Imaging

7. Endoscopy and X-ray small bowel Gastroscopy - Staging - Cancer screening - Suspicion of stricture - Need for more intensified therapy -Staging -Suspicion of stomach problems Small Bowel evaluation - Staging - Suspicion of fistulae - Suspicion of stricture Colonoscopy Small bowel follow through CT/MR-enterography Capsule endoscopy

9. Normal findings of the ileum and colon Ascending colonTerminal ileum

10. Normal findings in the transverse colon

11. UC - Spectrum of Disease Mild Moderate Severe Normal

12. CD: spectrum of endoscopic appearances

14. Inflammatory bowel disease and the risk of colon cancer

15. Lower CI Cumulative risk of CRC 1 Upper CI Copenhagen 1962–97 2 0 5 10 15 20 25 051015202530 Time from diagnosis (years) Cumulative probability (%) Eaden et al. 2001; Winther et al. 2001 Cumulative risk of developing colorectal cancer in ulcerative colitis

16. Frequency of surveillance colonoscopy not defined, every 1-2 years suggested Ulcerative Colitis –Extensive disease: 8-10 years after onset –Left-sided disease: 12-15 years after onset –Proctitis: not necessary –Primary sclerosing cholangitis: immediately Crohn’s Disease –Extensive colonic disease: 8-10 years after onset Recommendations for cancer screening colonoscopy in inflammatory bowel diseases

17. Small bowel diagnostics

18. Enteroclysis SBFT CTMRIUltrasoundScintigraphyPETPET-CT Imaging Modalities in IBD

19. Per Patient Sensitivity and Specificity StudiesPatients (n)Sensitivity % [Range] Specificity % [Range] Ultrasound9100090[78-96]96[67-100] Scintigraphy315288[76-95]85[78-93] CT411384[77-87]95[67-100] MRI729293[82-100]93[71-100] Horsthuis et al. 2008 Meta-Analysis of Prospective Studies MRI, CT, Scintigraphy, Ultrasound in IBD

23. Advantages individual techniques -MR, CT,(US): extraluminal pathologies. -US: Cheap and fast -MR, US: no radiation -SBFT: information about small bowel motility (adhesions) Disadvantages individual techniques -MR, CT, Scintigraphy, PET: no information about small bowel motility -US: no standardized documentation -MRI: Acquisition time, costs, availability (!) Advantages and Disadvantages of Different Imaging Modalities

24. First line Ultrasound Second line MRI or CT or SBFT Third line Capsule endoscopy Fourth line Enteroscopy (single or double balloon, spiral technique) Possible Diagnostic Approaches for Evaluation of the Small Bowel and Complications of IBD First line CT Second line Capsule endoscopy Third line Enteroscopy (single or double balloon, spiral technique)

25. Major significance12.1% Moderate significance19.7% Minor significance68.2% 710 patients with suspected or proven IBD Clinical Significance of Extraintestinal Findings in Patients with IBD Detected During MR-enterography Herfarth et al. 2009

28. CT: +840% SBFT: -65% Year Number of examinations Increasing Use of CT-enterography at a Tertiary Referral Center Peloquin et al. 2008

29. CT Scans Performed in the United States Brenner et al. 2007

30. Chest x- ray 0.02 mSV Plain film Abdomen 0.07 mSV SBFT 3 mSv Barium enema 7.2 mSv CT abdomen 10 mSv Radiation Dose for Commonly Used Imaging Studies in Gastroenterology Annual exposure to environmental radiation: Approx. 3 mSv Brenner et al. 2003 and 2007

31. DNA strand breaks Mismatch-repair Threshold effect (cancer risk only above 75-100 mSv) Linear dose-effect relationship? ? Radiation and Cancer Risk

32. Risk of Cancer Due To Diagnostic X-ray Exposure 3.2% 1.8% Berrington de Gonzalez and Darby 2004

33. 1992-1997 Mean number imaging studies/patient: 5.6 Mean CED: 7.9 mSv Radiation exposure due to CT: 46% 2002-2007 Mean number imaging studies/patient: 6.9 Mean CED: 25.1 mSv Radiation exposure due to CT: 85% Imaging Studies and Cumulative Effective Dose (CED) of Diagnostic Radiation in Crohn’s Disease Patients Desmond et al. 2008

34. 15.5% 354 patients Cumulative effective dose range (mSv) Exposed patients [%] Cumulative Effective Dose of Diagnostic Radiation over a 15 Years Time Period in Patients with Crohn’s Disease Desmond et al. 2008

35. Analysis of one Claims data base time period 2003-2004 for diagnostic imaging studies in children age 2-18. Moderate exposure to diagnostic radiation: 1 CT or 3 fluoroscopic procedures. Radiation Exposure of Children with IBD in the United States 2003-2004 (Claims Database Analysis) Palmer et al. 2009

36. Ulcerative Colitis Odds ratio (95% CI) Crohn’s Disease Odds ratio (95% CI) Hospitalization3.0 (1.8-5.0)4.9 (3.4-7.1) Surgery4.1 (1.9-9.2)2.9 (1.6-5.4) ED Encounter3.3 (2.1-5.0)2.7 (1.9-3.6) Therapies - Oral Steroids1.5 (0.9-2.6)2.3 (1.5-3.4) - Immunomodulators0.9 (0.5-1.5)0.7 (0.5-0.9) - Anti-TNF agents0.9 (0.6-1.5) Factors Associated with Receipt of Moderate Dose of Diagnostic Radiation Palmer et al. 2009

37. CT has evolved as the main imaging modality in IBD with a significant risk of high cumulative doses of diagnostic radiation exposure for IBD patients. The long term effects of low dose radiation exposure are still debated. Summary CT Imaging and Conclusion We need to Better define risk profiles of patients for diagnostic radiation exposure. Monitor exposure to radiation in the individual IBD patient. Long –term follow up (30-50 years) of IBD cohorts for complications of radiation injury. We need to Better define risk profiles of patients for diagnostic radiation exposure. Monitor exposure to radiation in the individual IBD patient. Long –term follow up (30-50 years) of IBD cohorts for complications of radiation injury.

38. Take Home CT- or MR-enterography CT-and MR-enterography have a a comparable sensitivity for intestinal pathologies as SBFT Advantage : extraluminal pathologies. No radiation (MR) Disadvantage: no information about small bowel motility

39. Capsule Endoscopy

40. 1.Optical Dom 2.Lens holder 3.Lens 4.LED’s 5.Camera 6.Batteries 7.Transmitter 8.Antenna Dimensions: Width: 11mm Length: 26mm Weight: 3.7g Capsule

45. Comparison Capsule Endoscopy (CE) – CT-enteroclysis (CTE) in IBD n=41 Voderholzer et al. 2005 CECTE Large lesions85 Small lesions23*10 *p<0.007 56 patients screened, 15 patients excluded due to suspicion of stricture (27%) !

47. Case Since 13 years Iron deficiency anemia despite iron supplementation Since 10 years recurrent episodes of abdominal cramps (2 days - 2 weeks duration) Multiple endoscopies of the upper and lower GI-tract without pathological findings Female patient, 44 years

48. Clinical examination and Lab results 44 years, overweight (155 cm, 72 kg) Physical examination unremarkable Lab results Hemoglobin (g/dl)11.411.7-15.7 MCV (fl)7580-100 MCHC(g/dl)2432-36 Iron (µg/dl)1350-170 Ferritin (ng/ml)10.810-120 Transferrinsaturation (%)216-45

49. Clinical work-up Endoscopy upper GI-tract MR-Enteroclysis Ileocolonoscopy (30cm into terminal ileum) Exclusion of celiac disease (transglutaminase antibodies) and bacterial overgrowth (H2-exhalation test). negative

50. Capsule endoscopy Multiple ulcerations jejunum (longitudinal) Two inflammatory stenoses jejunum  Suspected Crohn´s disease

52. Therapy and Follow-up Therapy: Budesonide (Entocort ® ) for 16 weeks Iron supplementation orally Follow-up (4 months): No bowel cramps, normal hemoglogin, no iron supplementation necessary Problem: Crohn´s disease is only suspected, not proven

54. Medical history Since 10 years diarrhea and constipation, constant pain right lower abdomen PMH: hysterectomy 20 years ago, lysis of adhesions 3 times (last repair of incarcerated hernia with Marlex mesh 9 years ago), arthritis, depression, hypertension, type II diabetes, GERD, obesity Upper and lower GI-endoscopy negative, SBFT questionable irregularities terminal ileum Female patient, 50 years

55. Clinical examination and Lab results 46 years, overweight (BMI 43) Physical examination unremarkable except pain during deep palpation right lower abdomen. Lab results Normal range: Hgb, MCV, platelets, ESR.

57. Capsule endoscopy and NSAIDs 40 volunteers 75 mg Diclofenac 2x daily for 14 days, (+ 20 mg Omeprazol 2 x daily) Capsule endoscopy and calprotectin - measurement before and after 2 weeks of Diclofenac intake Maiden et al. 2005 Calprotectin elevated75% Capsule endoscopy pathologic (Bleeding, Ulceration, Erythema) 68% Lesions not distinguishable from Crohn’s disease patients

58. Summary capsule endoscopy Suspicion of Crohn’s disease Capsule endoscopy should be performed in cases of negative upper and lower endoscopy and negative small bowel imaging (SBFT, CT- or MR-Enterography).  Problem: Verification (Double or single – balloon enteroscopy, ) Proven Crohn’s disease Capsule endoscopy significantly more sensitive compared to radiological imaging in detecting inflammatory lesions  momentarily no therapeutic consequences! Except:   in cases with “therapy refractory IBD” and negative upper and lower endoscopy and negative CT or SBFT ( in case of negative result: IBS/IBD!)

60. Endoscopy in the future