1. Celiac Disease Jeffrey Fine, MD

2. Celiac disease ) Autoimmune disorder with a prevalence of approximately 0.5 to 1 percent in the United States. (1 in every 100-200 persons) Inappropriate immune response to the dietary protein gluten, which is found in rye, wheat, and barley. After absorption in the small intestine these proteins interact with the antigen-presenting cells in the lamina propria causing an inflammatory reaction that targets the mucosa of the small intestine in genetically sensitive people. Manifestations range from no symptoms to overt malabsorption with involvement of multiple organ systems and an increased risk of some malignancies.

3. Genetics Most all patients with celiac disease express human leukocyte antigen (HLA)-DQ2 or HLA-DQ8, which facilitate the immune response against gluten protein Concordance rates of 70 to 75 % among monozygotic twins and 5 to 22 % among first-degree relatives. Genome wide associations (GWAS) identified -8 new genes,7/8 contained immune related genes and 4/8 loci share other autoimmune /inflammatory disorders –one of SNP associated w/ Crohn’s

4. Diagnosis Classic Celiac Disease –occurs 5% -easy to make Atypical -Difficult to make The Great Masquerader

5. Phenotype Grade 1 Typical symptoms Grade 2 Mild symptoms Grade 3 Asymptomatic T -lymphocyte associated protein cytotoxic T-lymphocyte antigen 4 Polymorphism (CTLA-4+49 A/G) genotype on Chromosome 2 q33

6. Epigenic Factors Adenovirus/Enteric Infections Stressors Surgery

7. Risk Factors for Celiac Disease Prevalence among Dermatitis herpetiformis 100 First-degree relative with5 to 22 celiac disease Autoimmune thyroid disease 1.5 to 14 Down syndrome5 to 12 Turner's syndrome2 to 10 Type 1 diabetes mellitus 10 Children3 to 8 Adults2 to 5

8. Dermatitis Herpetiformis

9. Signs and Symptoms Classic Diarrhea Fatigue Borborygmus Abdominal pain Weight loss Abdominal distention Flatulence Atypical Osteopenia/ osteoporosis Abnormal liver function Vomiting Folate /Iron-deficiency anemia Neurologic dysfunction Brain Fog/ dementia Constipation Nausea Esophageal reflux Up to 38 % Asymptomatic

10. Test selectively as part of the medical evaluation when symptoms could be secondary to celiac disease: Autoimmune thyroid disease Cerebellar ataxia First- or second-degree relative with celiac disease Irritable bowel syndrome Peripheral neuropathy Recurrent migraine Refractory Crohn’s Disease Psoriasis Selective immunoglobulin A deficiency Short stature (in children) Sjögren's syndrome Turner's syndrome Type 1 diabetes mellitus Unexplained delayed puberty Unexplained recurrent fetal loss/Infertility Seizures

11. SEROLOGY Serum IGA and IgA tissue transglutaminase (tTG) antibodies. Sensitivity and specificity > 95%. Do Deaminated Antigliadin antibodies DE –AGA IgG And IgA and do TTG IGG as well. Testing for gliadin antibodies is no longer recommended because of the low sensitivity and specificity for celiac disease, but should be considered for gluten sensitivity. TTG is less costly because it uses an enzyme-linked immunosorbent assay; When the prevalence is low, as in the general U.S. population, the risk of a false-positive result is high Confirmatory testing, including small bowel biopsy, is advised.

12. TESTING Serologic Testing Stool Testing Genetic HLA Testing Endoscopy, Pill Endoscopy and SB series

13. SMALL BOWEL BIOPSY Required to confirm the diagnosis of celiac disease for most patients. Should be considered in patients with negative serologic test results who are at high risk or in whom the physician strongly suspects celiac disease. Mucosal changes may vary from partial to total villous atrophy, or may be characterized by subtle crypt lengthening or increased epithelial lymphocytes. To avoid false-negative results on endoscopic biopsy, most authorities recommend obtaining at least four tissue samples, which increases the sensitivity of the test.

14. ENDOSCOPIC FINDING Scalloped folds Decrease in Kerckring folds Mucosal fissuring Flattened folds Normal appearing

15. Normal small intestine Celiac DiseaseVillous atrophy Normal villi

16. BENIGN COMPLICATIONS Small bowel adenomatous polyps Identified on sbft, vce or enteroscopy

17. MALIGNANT COMPLICATIONS Enteropathy –type Intestinal T cell Lymphoma - 30-40x ^ if GFD, 70x if not Other Lymphomas 23x Small Bowel Adenocarcinomas -80x Head and Neck cancer-23x Esophageal Squamous Cell cancers 23x Other cancers ^ risk

18. TREATMENT Avoidance of food products that contain gluten proteins. It is essential that the diagnosis be confirmed before submitting patients to this therapy. Key elements to successful treatment include the motivation of the patient, the attentiveness of the physician to comorbidities that need to be addressed. Formal consultation with a trained dietitian is necessary. The dietitian plays a vital role in helping the patient successfully adapt to the necessary behavioral changes and may provide much of the required follow-up. National celiac disease support organizations can provide patients invaluable resources for information and support.

20. COMORBIDITIES Thyroid dysfunction Deficiencies in folic acid, vitamin B12, fat-soluble vitamins, calcium, magnesium, copper,zinc and iron Osteoporosis Increased mortality due to increased risk of malignancy Non-Hodgkin's lymphoma (3-6x more likely) Oropharyngeal, esophageal, and small intestinal adenocarcinoma.

21. Vitamin and Mineral Deficiencies Vitamin D and other Fat soluble Vitamins Folate and B12 Calcium, Magnesium, Copper and Zinc

22. Follow-up. Antibody levels return to normal within 12 months of starting a gluten-free diet. A repeat small bowel biopsy three to four months after initiation of a gluten-free diet is not necessary if the patient responds appropriately to therapy. If the patient does not respond as expected despite adherence to a gluten-free diet, the physician should consider diseases that may mimic celiac disease vs refractory sprue

23. Screening. Screening an asymptomatic patient for celiac disease must be weighed against the psychological, emotional, and economic impact of a false positive result Also, it would necessitate further evaluation with small bowel biopsy. The need to follow a strict diet indefinitely can adversely affect the patient's perceived quality of life. Routine screening of the general population is not recommended. But should be considered Persons at high risk for celiac disease who exhibit any level of symptoms, appropriate testing is indicated.

24. Special Topics FERTILITY PROBIOTICS NON IMMUNE GLUTEN SENSITIVITY REFRACTORY SPRUE MY PARADIGM NEW TESTING POTENTIAL THERAPIES

25. Fertility in Celiac Disease Delayed menses/ Premature Menopause Amenorrhea Recurrent abortions Relative Infertility Women and Men Low birth weight babies Increased Perinatal Mortality Poor Outcomes of Fertility may be corrected GFD – minimum 6-9 mos

26. Probiotics Good bacteria such as lactobacillus and bifidiobacterium decrease on gluten free diet Pathogenic bacteria proliferated RX : probiotic should be taken-lactobacillus and bifidiobacterium 10 billion CFUS to start daily

27. Differential Diagnosis of Celiac Disease Anorexia nervosa Autoimmune enteropathy Bacterial overgrowth Collagenous sprue Crohn's disease- co-exist Giardiasis Human immunodeficiency virus enteropathy Hypogammaglobulinemia Infective gastroenteritis Intestinal lymphoma Irritable bowel syndrome Ischemic enteritis Lactose intolerance Pancreatic insufficiency Soy protein intolerance Tropical sprue Tuberculosis Whipple's disease Zollinger-Ellison syndrome

28. Non Immune Gluten Sensitivity This is Real ! Antigenic nature of gliadin Zonulin –protein suggested to increase intestinal permeability- “Leaky Gut” DQ1 alleles are GS genes subtype DQ5, 6 DQ2subtype DQ2, DQ3 st7,8,9 As are Celiac Genes

29. Refractory Celiac Disease RCD 1-IELS w/ polyclonal and have nl Phenotype RCD 2 abberant IELS and monoclonality 50% Develop Enteropathy Associated Lymphoma

30. CELIAC DISEASE IgA and IGG tissue transglutaminase and,DeAGA antibodies, IgA and IGG levels and IgA and IGG endomysial antibodies are appropriate first-line serologic tests to rule in celiac disease. If negative I do enterolab’s stool for AGA if positive I do HLA testing, small bowel biopsy and a pill cam IF I BELIEVE THEY HAVE CELIAC DISEASE- Check labs for CBC, CMP,25 D b12,, TSH, Minerals and vitamin testing, Bone Dexa and follow lifelong

31. New Testing on Horizon Not clinically available Measuring –serum levels of Th-2 Cytokines IL-4 and 10 and inflammatory cytokines IL-1a,1B and 8- correlates w/ IGA –TTG titres Galectin -10 –lysophospholipase in WBC associated in gut epithelium correlates w/ Histology T -lymphocyte associated protein cytotoxic T-lymphocyte antigen 4 Polymorphism sCTLA-4-gene higher in celiac disease and other auto immune disease

32. Potential Therapies Breast feed, delay/decrease infant gluten exposure Farrell RJ, JAMA 2005 Predigest Gluten Molecules – endopetidases Genetic Modified Wheat Strains – for better? Inhibit Zonulin - AT-1001- larazotide- in Phase 2 trials Immunotherapy Anti-interferon-gamma and TNF alpha

33. Potential Therapies Anti-TTG blockers Anti-HLA DR2/DR8

34. Questions www.drfoodsensitivity.com

35. Reference Presutti J,Cangemi J, Cassidy H, Hill D, Celiac Disease. American Family Physician. December 15, 2007: 1795-1802. Enterolab website and HLA info from Gluten Seminar Fasano, A,Zonulin Physiol Rev 91, 151-175,2011 Tennyson C, Lewis S and Green P, New and Developing Therapies for Celiac disease, Therap Adv Gastroenterol. 2009 Sept 2(5): 303-309 Advances in Celiac Disease 2011, Curr Opin Gastroenterol. 2011;27(2):112- 118. © 2011 Lippincott Williams & Wilkins

36. References Advances in Coelic Disease, Alimentary Pharmacology & Therapeutics. 2012;35(7):768-781. © 2012 Blackwell Publishing

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