Inflammatory Bowel Disease

1. Inflammatory Bowel Disease Francisco A. Sylvester, MD Associate Professor of Pediatrics

2. Goals - IBD • Definitions: Crohn disease – ulcerative colitis • Epidemiology • Pathophysiology - Genetics • Diagnosis • Treatment

3. Definitions Crohn disease – Ulcerative colitis

4. Normal colon

5. IBD - Colon Crohn Disease Ulcerative Colitis

6. IBD – Disease Location Crohn disease Ulcerative colitis http://www.hopkins-gi.org/

7. Distribution of Crohn Disease http://www.hopkins-gi.org/

8. Types of Crohn Disease http://www.hopkins-gi.org/

9. Diagnostic Certainty Crohn Disease Ulcerative Colitis IBD-U

10. Dr. Burrill B. Crohn (1884-1983)

11. Epidemiology • ~1.4 million Americans have IBD • Mean age at diagnosis ~30 years of age • 25% diagnosed as children • M = F (in children with Crohn M > F) • At CCMC: ~80-90 new patients/year

12. Smoking Crohn’s Disease Ulcerative Colitis Appendicitis - Appendectomy Crohn’s Disease Ulcerative Colitis (< 20 years of age)

13. North-To-South Gradient

14. Pathophysiology

16. Intestinal Flora Stomach 0-10² Duodenum 10² Jejunum 10² Proximal Ileum 103 * Distal Ileum 107 - 108 * Colon 1011 - 1012 Sartor B. Gastroenterology 2008;134:577-94

17. “Our” DNA 10% Human 90% Bacterial

18. So, Why Doesn’t Everybody Have IBD?

19. Microbial Molecular Patterns Muramyl dipeptide (MDP) Flagellins Bacterial DNA Lipopolysaccharide (LPS)

20. ~ ~ Intestine: Steady State Intestinal Lumen Microbes ~ ~ ~ M Cells ~ ~ ~ ~ ~ Intact Epithelial Cell Barrier ~ ~ DC ~ Blood Intestinal LP T cells Treg MLN

21. “Controlled Inflammation”

22. Intestinal Inflammation Intestinal Lumen Microbes ~ ~ ~ ~ ~ ~ ~ Damage to Epithelial Cell Barrier Microbial Invasion ~ ~ ~ ~ ~ DC ~ ~ T cells Activated T cells Cytokines/Chemokines Intestinal LP

23. http://www.randymays.com/Rugersr9-1.jpg

24. IBD - Genetics • NOD2/CARD15 (chromosome 16q12) • 20-40-X risk in individuals carrying 2 abnormal alleles • Ileal Crohn disease • Stricturing – penetrating • Caucasians only

25. IBD - Genetics • GWAS • ATG16L1 (Crohn disease) • IL-23R (Crohn disease and ulcerative colitis) • IL-23/Th17 pathway • > 30 novel loci

26. What is Changing? Genes vs. Jeans?

27. Environmental Factors • Microbial Ecology • Hygiene (Parasites) • Antibiotics • Refrigeration • Diet • Vaccines • Tobacco • North-to-south gradient • Vitamin D deficiency?

28. Pathophysiology - IBD • Genetic predisposition • Defective innate immunity • Hyperactivation of effector cells • Microbial ecology alterations • Environmental factors

29. Genes Environment Microbiota

30. Diagnosis • History – Physical Exam • Laboratory • CBC, ESR, CRP, albumin • Stool culture • Serology (antibodies to PAMPs) • Endoscopy • Imaging

31. Skin Mouth Joints Bone Liver Hypercoagulability Kidney Eye Extraintestinal Manifestations • Present in ~50% patients • 25% patients may have more than one • May be presenting symptom!

32. Growth Failure – Pediatric IBD

33. Complications • Intra-abdominal sepsis (Crohn disease) • Fecal incontinence • Short gut syndrome (Crohn disease) • Colon cancer • Infertility • Medication adverse effects (infection, cancer)

34. Arrow shows narrowing of the distal ileum

35. Arrow shows a phlegmon

36. Step Up vs. Top Down Biologics Biologics AZA/6-MP CD: MTX AZA/6-MP CD: MTX Steroids/ 5_ASA Mesalamine (5-ASA)/ Corticosteroids Crohn disease: Nutritional therapy

37. Challenges for School-Aged Children • School absences • Bathroom needs • Psychosocial issues • Self-perception and self-esteem • Peer relationships • Special diets (nutritional therapy)