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CELIAC DISEASE Michael H. Piper, MD, FACP, FACG Gastroenterology Program Director Chief of Gastroenterology Providence-Providence Park Hospitals/St. John Macomb Hospital

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10 Things to Know About Celiac Disease..In 20 minutes..

10 Things to Know About Celiac Disease 1. Definition 2. Epidemiology 3. Pathogenesis 4. Pathology 5. Clinical Features 6. Diagnosis 7. Treatment 8. Follow-up 9. Nonresponders 10. Non-celiac gluten sensitivity

1. Definition It is an autoimmune disease Occurs upon exposure to dietary gluten in genetically susceptible individual Characterized by: Intraepithelial lymphocytosis Crypt hyperplasia Villous atrophy Improves after gluten withdrawal May have intestinal and/or extra-intestinal manifestations

2. Epidemiology CD occurs primarily in whites of northern European ancestry (classic) US Prevalence ~ 1:140 (however, thought to be underdiagnosed) At-risk groups: Type 1 diabetes (3-12%) Down syndrome (5.5%) IgA deficiency (3%) Autoimmune thyroid disease (3%)

3. Pathogenesis Interplay of environmental, genetic, and immunological factors Environmental: Gluten- activating proteins in Wheat, Rye and Barley May have cross reaction with Oats Rice, Maize, Millet are usually ok Genetic: Chromosome 6 HLA- DQ2 and DQ 8 (high NPV, low PPV) 75% concordance in monozygotic twins 5-15% prevalence in affected families

3. Pathogenesis

4. Pathology Mucosal atrophy with crypt hyperplasia Flattened villi

5. Clinical Features

5. Clinical Features: GI Gastrointestinal Abdominal pain, bloating, distention, gas Diarrhea: bulky, foul-smelling, floating stools Constipation GERD Malabsorption: growth failure, weight loss, severe anemia, Vit B12, Vit D, copper, zinc and calcium def. Liver disease GI presentation may not be as common as originally thought (only 38% presented with IBS-type symptoms)

5. Clinical Features: Skin Dermatitis Herpetiformis Very itchy papules and vesicles that occur in grouped ( herpetiform ) arrangements Elbows, forearms, knees, scalp, back, buttocks Resolves with withdrawal of gluten

5. Clinical Features: Everywhere

6. Diagnosis: Who Should Be Tested? GI symptoms: chronic or recurrent diarrhea, malabsorption, weight loss, abdominal distension or bloating, constipation Laboratory evidence of possible CD: iron deficiency anemia, folate/vit B12 deficiency, AST/ALT Disease associations: Type I DM, 1 st degree family members with CD, Down Syndrome

6. Diagnosis: How to Test Serum Preferred Tests: IgA-Tissue Transglutaminase Antibody (TTG-IgA) Sensitivity and Specificity in non-gfd is >95%. Preferred Test IgG-Deaminated gliadin peptide (DGP-IgG) Sensitivity and specificity 80-96%: Preferred Test in IgA def. patient Endomysial (EMA) Specificity >99%. Sensitivity varies. More expensive. Used only when discordance exists between other markers and biopsy HLA DQ2/DQ8: May be useful for discordance (between serology and histology)

6. Diagnosis: How to Test Small bowel biopsy Gold standard of diagnosis (confirmatory) Confirm serology If serology negative but high suspicion May appear atrophic (loss of folds) or scalloped

6. Diagnosis: Normal Duodenum Well-demarcated folds Healthy-appearing mucosa

6. Diagnosis: Celiac Disease Scalloping Atrophic mucosa Flattened folds

6. Diagnosis: Flow Diagram ACG clinical guidelines: Diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108:656.

7. Treatment

7. Treatment: C.E.L.I.A.C. C.E.L.I.A.C. Consultation with a skilled dietitian Education about the disease Lifelong adherence to a gluten-free diet Identification and treatment of nutritional deficiencies Access to an advocacy group Continuous long-term follow-up by a multidisciplinary team

7. Treatment: Gluten Free Diet- Brief Main sources: wheat, rye, and barley Soybean or tapioca flours, rice, corn, buckwheat, and potatoes are felt to be safe Always read dietary labels Alcoholic beverages Distilled are safe Beers, ales, lagers, and malts are not Dairy products generally not well-tolerated

7. Treatment: Other than diet Refractory Sprue: Immunosuppression Steroids Systemic: (ie Prednisone 60mg once a day) Topical: Budesonide (case-series) Immunomodulators: Azathioprine/6-MP, and Methotrexate Alemtuzumab: Anti-CD52 monoclonal antibody:(not good evidence) Cladribine: synthetic purine neucleoside

7. Treatment: Healthcare Maintenance Replete nutritional deficiencies Prevent bone loss: Dexa Scan Vaccinations: CD associated with hyposplenism Pneumococcal vaccination Dermatitis Herpetiformis: GFD. If no improvement, can use Dapsone.

8. Follow-up: Monitoring Response Serologic testing: TTG-IgA 3-6 months after GFD started, then annually thereafter Follow Nutritional Panel Reassurance Women can develop breast tenderness within 3 months of GFD Dermatitis Herpetiformis: Can take 3-6 months to improve. Endoscopy with biopsy: Usually not necessary Reserved for non-responders, and perform usually 2 years after institution of GFD

9. Nonresponsive Celiac Disease (NRCD) 1. Poor compliance or inadvertent gluten ingestion: Most common reason Dietary history and medication history important 2. Other disorders that mimic celiac disease 3. Concurrent disorders (i.e.,ibs, SIBO, microscopic colitis) 4. Refractory celiac disease (Type I and Type II) 5. Ulcerative jejunitis or intestinal lymphoma

9. NRCD: Mimickers

9. NRCD: Refractory Celiac Disease Type I Normal population of intraepithelial lymphocytes Less severe, better prognosis Type II Aberrant or premalignant population of intraepithelial lymphocytes Can progress to lymphoma Treated initially with high-dose steroids, but 6MP or azathioprine may be necessary Poor prognosis Very rare

9. NRCD: Ulcerative Jejunitis and Lymphoma Ulcerative Jejunitis: Multiple chronic ulcers that may be benign-appearing (most common in jejunum) Lymphoma: Enteropathy-associated T-Cell lymphoma (EATL)- poor prognosis Both: Malabsorption, anorexia, weight loss, abdominal pain, diarrhea, fever and strictures (small bowel obstruction) Both: Usually does not respond to GFD

10. Non-celiac gluten sensitivity Non-specific immune response Affects up to 18 Million American Also responds to gluten-free diet Minimal or NO intestinal damage Negative celiac workup HLA testing may be considered in difficult-to-diagnose cases

11. Extra! Future of Celiac Disease Therapy Reduce gluten exposure Genetically engineered grains, enzymatic degradation, probiotics, and synthetic polymers Immune-modulating therapies Anticytokine agents, vaccines, enzyme inhibition, HLA DQ2/8 blockade, and helminth infection (promotes immune regulation with tolerance to gluten) Counteract gluten exposure and uptake Larazotide acetate: oral peptide that prevents tight junction opening, and may reduce gluten uptake

References Kagnoff M. Overview and Pathogenesis of Celiac Disease. Gastroenterology 2005; 128: S10-S18. Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11(4):359. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: Diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108:656. Oxentenk A, Murray J. Celiac Disease: Ten Things That Every Gastroenterologist Should Know. Clinical Gastroenterology and Hepatology 2015; 13:1396-1404. Singh P, Arora S, Lal S et al. Risk of Celiac Disease IN the First- and Second-Degree Relatives of Patients with Celiac Disease: A systematic Review and Meta-Analysis. Am J Gastroentero. 2015.100:1539-1548. Celiac Disease Program. Celiac vs Gluten-Sensitivity vs Wheat Allergies. UCLA Health. Gastro.ucla.edu. Shannahan S, Leffler DA. Diagnosis and Updates in Celiac Disease. Gastrointest Endoscopy Clin N Am. 2017;27:79-92. Leonard MM, Sapone A, Catassi C, et al. Celiac Disease and Noncelaic Gluten Sensitivity. JAMA. 2017;318(7):647-656.