CELIAC SPRUE: AN UPDATE Sami N. Arslanlar, MD DIGESTIVE HEALTH ASSOCIATES OF TEXAS November 14, 2009

1. CELIAC SPRUE: AN UPDATESami N. Arslanlar, MDDIGESTIVE HEALTH ASSOCIATES OF TEXASNovember 14, 2009

2. CASE • 53 year old white male presents with fatigue • Daily diarrhea for years, peripheral neuropathy, osteoporosis • No family history • Drinks beer daily • 117 lbs 5 feet 10 inches • Cachectic, guaiac positive • Hgb 7.6 Hct 26.2 MCV 72 Plt 612 Ferritin <10 • Alb 1.8 INR 1.6 TB 0.1 AST 119 ALT 118 Alk phos 227 Calcium 5.6 Phos 1

3. CASE • Colonoscopy – normal • EGD – normal • Small bowel biopsies • severe villous atrophy with increased intraepithelial lymphocytes and lamina propria plasma cells • Serologies – • Anti endomysial IgA antibody + • Anti gliadin IgA antibody + • Anti gliadin IgG antibody +

4. CASE • Educated on gluten free diet • Improved clinically • Seen in clinic 6 months later with ascites • EGD, enteroscopy twice • Diagnosed with refractory celiac sprue • Treated with Prednisone

5. OBJECTIVES • What is celiac disease? • Will I ever see a patient with celiac disease? • Why do I need to know about it? • How do I diagnose celiac disease? • If I ever diagnose celiac disease, what should I worry about? • What is the treatment?

6. DEFINITION • Gluten-sensitive enteropathy • Small intestinal malabsorption of nutrients after the ingestion of wheat gluten or related proteins from rye and barley • Characteristic villous atrophy of small intestinal mucosa • Prompt clinical and histologic improvement after strict gluten-free diet • Clinical relapse when gluten reintroduced

7. HISTORY • W.K. Dicke, Dutch pediatrician in early 1930s • Observation of relationship between celiac disease and bread • During WW II in Netherlands, food, particularly cereals, was scarce • Children with CD improved • At end of war, Swedish Air Forces supplied bread • Children with CD relapsed

8. CELIAC DISEASE: PEDIATRICS • Classic presentation • Present 1-2 yo after cereals introduced in diet • Steatorrhea, vomiting, crampy abdominal pain • Failure to thrive, muscle wasting, abdominal distention

9. CELIAC DISEASE: ADULTS

10. PRESENTATION IN ADULTS AND PEDIATRICS

11. CELIAC ICEBERG

12. WHEAT CONSUMPTION

13. PREVALENCE BY COUNTRY

14. CELIAC DISEASE IN US • Prevalence is 1/3000 • EMA + in 1/250 blood donors • Green et al surveyed support groups nationwide • Median age of diagnosis 46 • Diagnosis delayed mean of 12 months but up to 10 years • Initial diagnoses • IBS • Psychological disorder • Fibromyalgia

15. CELIAC DISEASE: PREVALENCE IN US

16. CELIAC DISEASE: PREVALENCE IN US

17. THE CHARACTERS • HLA-DQ2, HLA-DQ8 • Cereals • Gliadin • Tissue transglutaminase

18. GENETICS

19. TAXONOMY OF GRAINS

20. CEREALS

21. GLIADIN • Digestion studies reveal persistent 33-mer, residues 56-89 • Carries multiple copies of three epitopes that are immunogenic in CS • Similar sequences in hordeins (barley) and secalins (rye) • Residues 57-68 and 62-75 stimulated all small intestinal gluten sensitive T cell clones from 4 adult celiac patients with HLA-DQ2

22. DIRECT TOXIC EFFECTS OF GLIADIN • Reduction in number of junctional complexes altering intestinal permeability • Upregulation of HLA-DR expression • Changes in cell shape and size • Reduction in growth and viability • Decreased synthesis of nucleic acids and proteins • Cell damage mediated by lysosomes with signs of apoptosis Similar changes seen in duodenal biopsy of CS patients

23. TRANSGLUTAMINASE • Liver enzyme that incorporates amines into proteins • Mediators of biological glue • Factor XIIIa • Tranglutaminase I • Crosslinks proteins that comprise the cell envelope

24. TRANSGLUTAMINASE II (tTG) IN DISEASE • Inclusion body myositis • Alzheimer’s disease • Parkinson’s disease • Progressive supranuclear palsy • Huntingtons disease

25. CURRENT THEORY

26. SEROLOGICAL TESTS • Antigliadin (AGA) IgA • Antiendomysial (EMA) IgA • Antitissue transglutaminase (tTG) IgA • Total serum IgA level • Genetic testing • HLA DQ2 or HLA DQ8

27. DIAGNOSIS • Up to 3% of celiac patients have selective IgA deficiency • IgG serologies of utility in these patients

28. ENDOSCOPY Normal duodenum Scalloped folds Mosaic pattern

29. BIOPSY Normal Partial atrophy I Partial atrophy II Partial atrophy III Subtotal atrophy Total atrophy

30. Cows milk protein intolerance Gastroenteritis Giardiasis Eosinophilic gastroenteritis Bowel ischemia Severe malnutrition Diffuse small intestinal lymphoma Autoimmune enteropathy Hypogammaglobulinemia Peptic duodenitis (Zollinger-Ellison syndrome) Soy protein intolerance Crohns disease Small intestinal bacterial overgrowth Radiation or cytotoxic chemotherapy Tropical sprue Kwashiorkor Immunodeficiency syndromes GVHD Alpha chain disease Refractory sprue Collagenous sprue All villous atrophy is not celiac disease ….

31. CAPSULE ENDOSCOPY

32. DIAGNOSTIC DILEMMA • ARE SEROLOGIES ADEQUATE FOR DIAGNOSIS? • ARE BIOPSIES ESSENTIAL? • ARE SEROLOGIES AND BIOPSIES BOTH NEEDED? • HOW MUCH EVIDENCE DO YOU NEED TO CONVINCE YOURSELF AND YOUR PATIENT OF THE DIAGNOSIS AND ITS NECESSARY TREATMENT?

33. CELIAC DISEASE IS A SYSTEMIC DISEASE • GENERAL • GROWTH DELAY • MALIGNANCIES • ANEMIA • CNS • ATAXIA • SEIZURES • DEPRESSION • GI • DIARRHEA • VOMITING • DISTENTION • ABDOMINAL PAIN • MALNUTRITION • WEIGHT LOSS • HEPATITIS • CHOLANGITIS • HEART • CARDITIS • SKIN • DERMATITIS HERPETIFORMIS • APHTHOUS STOMATITIS • HAIR LOSS • BONE • OSTEOPOROSIS • ARTHRITIS • DENTAL ANAMOLIES • REPRODUCTIVE • MISCARRIAGE • INFERTILITY

34. ASSOCIATED CONDITIONS

35. DERMATITIS HERPETIFORMIS

36. MALIGNANCY • Non-Hodgkin lymphoma • Main cause of mortality • Holmes reported a 43x increased risk • GI carcinomas • Esophageal • Small intestinal • Risk reduced with GFD • Returns to that of general population after 5 y • Special consideration if patient with known CD presents with exacerbation of symptoms • Enteropathy associated T-cell lymphoma

37. AUTOIMMUNE DISORDERS • Prevalence of CD in patients with AIH 2.7-8% • Prevalence of PBC in CD patients up to 3% • 6% of patients with CD affected by PBC • CD found in 15% of Sjogren’s syndrome • Increased incidence of autoimmune disease in relatives of CD patients • Serologic testing of CD patients found up to 25% positive for other autoantibodies • Anti-ssDNA 14% • Anti-dsDNA 23% • Anticardiolipin 14%

38. OSTEOPOROSIS • Most common extraintestinal manifestation after dermatitis herpetiformis • Found in 34% of adults at diagnosis • GFD does positively affect BMD • Mechanism • Calcium malabsorption • Vitamin D deficiency • Secondary hyperparathyroidism • Reduce muscle mass • Intestinal inflammation

39. DIABETES MELLITUS 1-1.5% of diabetic children have CD Classical symptoms, poor glycemic control, frequent hypoglycemia Associated with HLA-DR1-DQ2 and DR4-DQ8 THYROID DISEASE Subclinical hypothyroidism very common Increased prevalence of autoimmune thyroid disease ENDOCRINE DISORDERS

40. TREATMENT GLUTEN FREE DIET GLUTEN FREE DIET GLUTEN FREE DIET GLUTEN FREE DIET

41. Avoid all foods containing wheat, rye, & barley Avoid all foods containing oats, (at least initially) Use only rice, corn, maize, buckwheat, potato, soybean, or tapioca flours, meals or starches Look for foods that have the gluten free symbol Read all labels and study the ingredients of processed foods Avoid all beers, lagers, ales, & stouts Beware of gluten in medications, food additives, emulsifiers, & stabilizers Wine, liquers, most ciders, & other spirits, including whiskey & brandy, are allowed! TREATMENT

42. FUTURE TREATMENTS • Bacterial endopeptidase • tTG inhibitors • Modification of cereal • Immunomodulators

43. CONCLUSION • More common than previously thought • Presentation can be atypical • Serologic tests and biopsy for diagnosis • Associated conditions are numerous and can be affected by treatment • Gluten-free diet is effective treatment

44. RESOURCES • Lone Star Celiac Support Group • dfwceliac.org • Celiac Sprue Association • csaceliacs.org • Celiac Disease Foundation • celiac.org • National Institutes of Health • digestive.niddk.nih.gov/ddiseases/pubs/celiac