Celaic Sprue

1. CelaicSprue Eric Trevelline MD Gastroenterology and Hepatology Private Practice Missoula Montana

2. CELAIC SPRUE • “gluten sensitive enteropathy

3. CELAIC SPRUE • 2ND century description Cappadonia (Turkey) • Samuel Gee 1888 • Wm. Dicke WWII Dutch pediatratian • Dicke and Van De Kamer experiments revealing “wheat, barley, and rye”

6. Celiac Sprue: Pathogenesis • HLA DQ2/DQ8 • Gene loci for immunological response to environmental agent • Gliadan component of gluten • 36% risk in first degree relatives • 15Q26 = DM1 suscepteability loci • Non-HLA genes

7. Celiac Sprue: serum autoantibodies • IgA antiendomysium 100% PPV • IgG antigliadin 2% PPV • IgA antigliadin 12% PPV • IgG + IgA antigliadin 33% PPV

8. Gliadin reactive T cells • Tissue transglutiminase (tTG) • Ubiquitous intracellular enzyme • Released by inflammatory & endothelial & Fibroblast cells in response to inflammation • Crosslinks glutamine rich proteins such as wheat gluten • Damination of gluten increases binding to HLA-DQ2/DQ8 , potentiating T-cell stimulation • T-cells recognize epitopes in gliadin rich in proline residues • Decreasddegredation by enterocytes in celiac dz • Thus gluten-mediated activation of pathogenic T cells

9. Gluten Intolerence: Non-gluten proteins • Amylase-trypsin inhibitors (ATIs) • Activate innate immunity in macrophages,monocytes,dendritic cells via toll-like receptor 4 for LPS • “pest resistance proteins” of gluten containing cereals -marked increase in prevalence in past decades (GMF) • Highly resistant to intestinal degredation • Induce low level inflammation – dose dependent • “gluten intolerance”

10. Celiac Sprue: innate immunity • Intraepithelial lymphocytes: “IELs” • tTG autoantibodies block epithelial cell differenation in small bowel • IELs bear gamma-delta T cell receptors • IELs also activated by enteric infections, drug reactions, food allergies

11. Celiac Sprue: epidemiology • Prevalence study 8,000 individuals USA: • 1:141 (previous dx or +IgA Abs TTg or EMA • 1:70 – 1:300 most countries • Screening for asymptomatic not yet proven

12. Celiac Sprue: epidemology • USA study 13,145 subjects • 1:22 first degree relatives • 1:39 second degree relatives • 1:56 symptomatic • 1:133 not-at-risk groups

13. Celiac Sprue: epidemiology • Punjabis & Gujaratis form India: • When moved to England and eat gluten rich diet 2.7x increased incidence of celiac disease

16. Celiac Sprue: Classification • Classic • Atypical • Asymptomatic (silent) • Latent

17. Celiac Sprue: classification • Classic disease: 3 features • Villous atrophy • Symptoms of malabsorption (steatorrhea, weight loss, nutrient or vitdef) • Resolution of mucosal lesions & Sx upon withdrawl of gluten • Diarrhea • Wt loss • Malabsorption • Antibodies against gliadin (esp TTG)

18. Celiac Sprue: classic disease • SB histologic changes may not correlate with severity of Sx • Proximal to distal histological gradient • Stage 0 increased IELs only • Stage 3 flat mucosa w/total villous atrophy, epithelial apoptosis, crypt hyperplasia • Stage 4 flat mucosa w/total villous atrophy, epithelial apoptosis, crypt hypoplasia = T cell lymphoma

19. Celiac sprue: Atypical disease • Minor GI complaints • Anemia, dental enamel defects, osteoporosis, arthritis, Increased AST/ALT, neurological Sx or infertility • Fairly typical histology and antibody pattern

20. CelaicSpure: asymptomatic silent • Lesser degree of histological change • Picked up on screening • Usually fatigue as only Sx

21. Celiac Sprue: Latent disease • Normal or near normal histology on gluten laiden diet with minimal or no Sx • Celiac disease present before (usually childhood) w + Abs but now normal histology on gluten laiden diet • Normal mucosa on gluten laiden diet earlier in life but now symtptomaticDx later

22. Clinical Manifestations: • Gastrointestinal: • Diarrhea w bulky foul-smelling , floating steatorrhea stools w/ flatulence • Consequences of malabsorption: • Growth failure, weight loss anemia • Neurologic d/o from B vitamin deficiency • Osteopenia from D & Ca+ deficiency • Shift in presenting Sx from classic to atypical • IBS Sx 38% • Adults present with milder Sx

23. Asymptomatic & subclinical disease • Malignancy risk • Unsuspected nutritional deficiencies • Low birth weight infants to affected mothers • Associated autoimmune disorders (DM1, thyroiditis, collagen vascular disease)

24. Asymptomatic & subclinical disease • Fe+ defic with or without anemia • Recurrent abdominal pain • Mood changes • Recurrent aphthousstomatisis • Poor appetitie • Constipation • Pubertal delay • Hypoalbuminemia • Short stature • Abdominal distention • Recurrent diarrhea

25. Non GI Manifestations of Celiac Dz • Infertility • Rheumatic disorders • Peripheral neuropathy (up to 50%) • polyneuropathy • Osteomalacia • Osteoporosis • Depression 10.6% • Epilepsy 3.5% • Migraine HA 3.2% • Anxiety • Suicidal tendencies • Carpel tunnel • myopathy

26. Non GI Manifestations of Celiac Dz • Hyposplenism • Pneumovax • Benign glomerular IgA deposition • Idiopathic pulmonary hemosiderosis (Lane-Hamilton Syndrome)

27. Celiac disease: Mortality & Cancer Increase in overall mortality

28. Cancer risk: • Lymphoma (NHL) • Oropharyngeal SCCA • Adenocarcinoma of small bowel • Colorectal ca. • HCC • Reduced breast and lung

29. Celiac Sprue: associated conditions • Dermatitis herpetiformis: • Multiple intenslypuritic papules & vesicles in grouped “herpetiform” arrangement • Elbows, dorsal forearms, knees, scalp, back, buttocks

30. Dermatitis herpetiformis

31. Dermatitis herpetiformis

32. Dermatitis herpetiformis

33. Dermatitis herpetiformis

34. Dermatitis herpetiformis

35. Dermatitis herpetiformis

36. Dermatitis herpetiformis • Autoantibodies against epidermal tTG • Dx histologically granular IgA along subepidermal basement membrane • 85% of DH patients have celiac disease • Approx 24% of celiac patients have DH • Months to years to respond to diet alone

37. Diabetes mellitus • 2.5-8% of DM 1 patients have celiac disease • Many asymptomatic • HLA DQ2/DQ8 & DR3 • No proven change in onset of DM1 or CD with dietary changes in humans • Polyglandular syndrome

38. Diabetes mellitus- GF diet?

39. Diabetes mellitus- GF diet? • NOR • If fed high gluten diet in infancy than increased islet autoantibodies • ORs • Did not make a difference

40. Selective IgA deficiency • 8% of selective IgA defic. pts w/ celiac disease • 1-2% of celiac disease pts have selective IgA defic

41. Downs syndrome • 20 x increased risk if celiac disease • 16% of trisomy 21 pts have celiac disease

42. Liver disease • Aminotransferase elevations common • Advanced liver disease • PBC

43. Celiac disease associations • Thyroid disease • GERD • EoE • IBD (UC > CD) • Pancreatitis • Lymphocytic colitis/enteritis

44. Celaic disease diagnosis: • Who should be tested? • GI Sx: recurrent diarrhea, malabsorption, wt loss, abd distension, bloating, IBS, severe lactose intolerance • Unexplained Fe+ deficiency anemia, folate deficiency, B12, aminotransferase elevation, short stature, delayed puberty, recurrent fetal loss, low birthweight infants, reduced fertility, recurrent aphthous stomatitis, dental enamel hypoplasia, idiopathic peripheral neuropathy, nonhereditary cerebellar ataxia, recurrent migrane Has • DM1, first degree relatives of celiac patients if signs/Sx • Downs (trisomy 21) • Consider in asymptomatic first degree relatives • Consider in osteoprosis

45. Celaic diagnostic algorithm

46. Approach to Dx if on gluten free diet

47. “Duodenal scalloping”

49. Serum antibody assays for celiac • IgA endomysial Ab (IgA EMA) • Positive/negative $$$ • Highly specific for untreated dz (97-100%) • Sensitivity (85-98%) • Drop or become neg on gluten free diet • Target ag is tTG

50. Serum assays • IgA tissue transglutiminase Ab (IgA tTG) $ • $Sensitivity 85-98% • Specificity 95-97% • IgG tTG • IgA deamidatedgliadin peptide (IgA DGP) • Sensitivity 94% Specificity 99% • IgG deamidatedgliadin peptide (IgG DGP) • Sensitivity 92% specificity 100%