Understanding Diagnostic Challenges Sheryl Pfeil, MD Professor of Clinical Medicine Division of Gastroenterology, Hepatology and Nutrition Department of Internal Medicine The Ohio State University Wexner Medical Center Immune mediated systemic disorder triggered by gluten and related prolamins Occurs in genetically susceptible individuals who have HLA-DQ2 and/or HLA-DQ8 haplotypes Inflammatory enteropathy with variable severity Range of GI and/or systemic symptoms Presence of celiac-specific autoantibodies Affects ~ 1% of the USA population Small bowel inflammation, villous atrophy, crypt hyperplasia, intraepithelial lymphocytes Malabsorption- improves with withdrawal of gluten : Why Diagnose Differentiate from non-celiac gluten sensitivity Identify risk for nutritional deficiency, complications Determine necessity of lifelong adherence to gluten-free diet Screen family members Variable degree of symptoms and small bowel damage Diagnosis across the age spectrum 1
: Why Diagnose Non-Celiac Gluten Sensitivity May have impaired absorption, nutrient deficiencies (fat soluble vitamins, iron, potentially folate, vitamin B 12) Without gluten free diet have increased risk of intestinal malignancies Diet is costly, challenging, risk for nutrient deficiencies Poorly defined syndrome: No test for NCGS Variable combination of intestinal and extraintestinal symptoms that occur after ingestion of gluten (hours to days) and disappear quickly upon withdrawal Must exclude celiac disease and wheat allergy Possibly related to fructans (FODMAPs) Symptoms often IBS-like but more commonly have extraintestinal symptoms (HA, fatigue, joint/muscle pain) Who to Test? GI symptoms suggestive of malabsorption: diarrhea, weight loss, postprandial pain, bloating Symptoms/signs: iron deficiency, elevated transaminases, osteopenia, etc. First-degree relatives of celiac patients? Unexplained elevation of LFT s Type 1 diabetes mellitus Transaminitis Abdominal Distension Constipation Anorexia Weight Loss Nausea Vomiting Diarrhea Steatorrhea Pain Bloating Flatulence 2
Non Gastrointestinal Symptoms Elevated Transaminases in Mild elevation (2-3 times upper limit of normal) Dermatitis herpetiformis Short stature Aphthous ulcers Rickets Osteopenia Osteoporosis Arthritis Fractures AST and ALT Majority normalize within 4-8 months of GFD Persistent elevation: check for autoimmune hepatitis or other condition Anemia as Manifestation of Most iron deficiency More common in patients with atrophic mucosa Dermatitis Herpetiformis Considered a skin presentation of celiac disease Symmetric pruritic blisters and excoriations Elbows (90%), knees (30%), shoulders, buttocks, sacrum, face Skin biopsy: typical IgA deposits 3
Miscellaneous Extraintestinal Manifestations Low bone mineral density Oral aphthous ulcers Familial Risk of Monozygotic twins: 75% HLA-identical siblings: 40% Arthritis and arthralgias First degree relatives: 5-11% Neuropsychiatric symptoms (HA, foggy mind ) Amenorrhea, infertility or recurrent pregnancy loss Genetic Risks for HLA DQ2 (~95%) or HLA DQ 8 (~5%) Present in almost all if absent, NPV>99% Prevalent in population so PPV only ~12% When to Consider Testing Asymptomatic Patients First degree relatives of CD patients (especially if symptoms); risk 20% siblings and 10% other FDR Type I diabetes if symptoms (3-10% prevalence) Elevated transaminases without other etiology (normalize in >95% on GFD) Autoimmune thyroid or liver disease Down or Turner syndrome (prevalence 10% in Down s syndrome) IgA deficiency 4
Diagnostic Testing for Celiac Disease: What NOT to do Try gluten free diet before testing Testing for Serology endoscopy High suspicion but serology negative endoscopy Have a myopic view of clinical features of celiac disease Order the wrong antibody test Gliadin Ab s Deamidated Gliadin Peptide Ab s Esophagus Endoscope Light Ask if symptoms follow gluten ingestion Commercially Available Serologic Tests Gliadin IgA AGA & IgG AGA Transglutaminase IgA ttg (IgG ttg) Endomysium IgA EMA (IgG EMA) Deamidated gliadin peptides IgA DGP & IgG DGP Table of Sensitivity and Specificity of Serological Tests for Test Sensitivity (%) Specificity (%) Antigliadin antibody IgG (AGA-IgG) Antigliadin antibody IgA (AGA-IgA) Tissue Transglutaminase antibody IgA (ttg-iga) Anti-EMA antibody IgA (EMA-IgA) Deamidated gliadin antibody IgA (DGP-IgA) Deamidated gliadin antibody IgG (DGP-IgG) 83 100 47 94 52 100 72 100 90 100 95 100 93 100 98 100 80 91 91 95 88 95 86 98 5
Endoscopic "Clues" in Endoscopy in Atrophy Visible fissures and nodular appearance Scalloping of the margins of folds If endoscopy is normal, still MUST biopsy Scallop Shell Endoscopy in EGD sufficient (not enteroscopy) Minimum of 6 biopsies (4 distal duodenum and 2 bulb) Histology includes lymphocyte infiltration in epithelium, crypt hyperplasia, progressive flattening of villi Histologic changes graded by severity (Marsh/Oberhuber stages 0-3) Unremarkable Small Bowel Low power shows usual villous architecture High power shows usual distribution of intraepithelial lymphocytes Normal Partial atrophy 6
Classic Findings in Low power shows villous blunting High power shows increased intra-epithelial lymphocytes Capsule Endoscopy in Not a first-line test Villi are readily visualized Does not permit biopsy Useful for patchy disease (before enteroscopy) or complicated CD (stenosis, ulcers, lymphoma) Used for patients with positive serology, unable/unwilling to have EGD Celiac Mimics Tropical sprue Small intestinal bacterial overgrowth Autoimmune enteropathy Immune deficiencies: CVID Medications: olmesartan Crohn s disease Peptic disease Giardiasis Whipple disease Hypogammaglobulinemia and others What To Do in the Already Gluten Free Patient? If less than a month, serology and histology often still abnormal Check HLA testing Consider gluten challenge (3 g/d for 2-8 weeks) followed by serology and biopsy Treat as if celiac disease 7
Diagnosis of Clinical features + positive serology + villous atrophy: celiac disease Gluten free diet Follow symptoms and serologies Repeat EGD not required Patient with Clinical Features but Negative Serologies Ig A deficiency: check Ig G antibodies Prior gluten restriction (gluten challenge or HLA test) False negative serology Consider other causes (eg wheat allergy) Celiac HLA Haplotypes More than 99% of celiac patients: HLA DQ2 and/or DQ8 positive Caution: 40% of general population HLA DQ2 and/or DQ8 positive Patient with Positive Serologies and Normal Biopsies False positive anti-ttg Patchy disease or inadequate sampling Latent celiac disease Negative testing essentially excludes celiac disease Symptomatic Celiac Disease Silent Mucosal Lesion Positive testing does not diagnose celiac disease Latent No Mucosal Lesion 8
Recommendations for Initial Evaluation Identify clinical symptoms or family history that trigger testing Obtain an lg A TTG antibody and a total lg A level If serologies positive refer for EGD If serologies negative, confirm gluten ingestion and consider GI referral Treatment of Lifelong gluten free diet Refer to dietitian Decline and normalization of antibody levels by 12-24 months (80% test neg after 6-12 months of GFD) Normalization of antibodies does not fully correlate with resolution of villous atrophy Check CBC, iron, LFT s, calcium, vitamin D, thyroid tests at diagnosis (and consider other labs as indicated) Consider bone densitometry Annual follow up Non-responsive Review original diagnosis/exclude alternative diagnosis Review diet adherence serologic testing to confirm GFD Evaluate for associated disorders: microscopic colitis, pancreatic insufficiency Evaluate for complications: enteropathy associated lymphoma, refractory celiac disease Medical Nutrition Therapy for Celiac Disease Kristen M. Roberts, PhD, RDN, LD Assistant Professor - Clinical Department of Internal Medicine Division of Gastroenterology, Hepatology and Nutrition The Ohio State University Wexner Medical Center Repeat EGD 9
Objectives Identify the common nutritional deficiencies associated with Celiac Disease (CeD). Demonstrate the ability to identify foods restricted for CeD medical nutrition therapy. Outline the steps to prevent cross contamination of gluten in daily life. Need for Registered Dietitian referral for Medical Nutrition Therapy Defining Gluten Specific prolamins toxic to the small intestine: Gliadin (wheat) Secalin (rye) Hordein (barley) Treatment for CeD is a Gluten Free Diet Omit all ingredients derived from wheat, rye and barely Wheat: Flour, white flour, plain flour, bromated flour, enriched flour, phosphated flour, selfrising flour, durum flour, graham flour, farina, semolina Rye Barley: Beer, ale, porter, stout, and other such fermented beverages, malt (beverages, chocolate, vinegar) Fruits Dietary Pattern Recommended for CeD Vegetables Meats, beans, legumes Dairy Gluten-free grains Amaranth Quinoa Buckwheat Millet Teff Nut flours Montina Sorghum Arrowroot Wild Rice Rice, all forms Corn: corn bran, corn grits, hominy, hasa marina Potato: potato starch & potato flour Soy Tapioca Bean 10
Contamination is a Problem! Oats Oats do not contain gliadin, secalin or hordein, but often contaminated with prolamins. Table 1. Gluten content as a function of type of oat product. Type of oat Range (mg kg -1 ) Median (mg kg -1 ) Mean (mg kg -1 ) Steel-cut oats 55 1467 660 645+512 Rolled/flaked/ 0 2485 81 316+497 oatmeal Quick/minute oats 13 3784 534 655+694 Oat bran 37 3469 280 704+862 41 Koerner et al, Food Additives & Contaminations:Part A.2011;28:6,705-710 Oats Certified Gluten Free Oats are recommended Safe Limit for Gluten Consumption Virtually impossible to be completely gluten-free 10 mg to 30 mg considered safe for most 1 slice of Bread ~2500mg of gluten 62,000 ppm gliadin 1/50 th to 1/500 th of piece bread 11
Food Allergen Labeling and Consumer Protection Act 2006 (FALCPA) Covers the top 8 allergens in the US Wheat, eggs, milk, peanuts, tree nuts, shellfish, fish, soybean NOTE: Rye, oats, barley are not part of the top 8 allergens! Allergens can be listed within the ingredient list or in the contains statement Defining Gluten Free on Packaging FALCPA directed FDA to develop regulations for the voluntary labeling of gluten-free foods When can Gluten Free be used on packaging? No wheat, barley or rye are included or an ingredient derived from one of these grains that has not been processed to remove gluten A product with less than 20 parts per million of gluten (ex: wheat starch) Gluten Content in GF Foods in the US Prevention of Contamination Home Toaster Butter Condiment Cutting boards Cooking pans Restaurant GF menu Cooking practices Fried foods? Avoid salad bars Grocery Store Avoid bulk bins Wash produce Thompson T and Simpson S. European Journal of Clinical Nutrition. 2015;69:143-146 12
Nutritional Concerns for Patients with CeD Common nutrient deficiencies: iron, folate, vitamin B12, calcium, vitamin D 1 Deficiencies manifest as: Musculoskeletal abnormalities Short stature Dental enamel defects of unknown etiology Cutaneous defects: ulcerations Weight loss Etiology: Malabsorption and poor diet quality 1 Potential nutritional deficiencies of a GF Diet Improvement after starting GF Diet May be inadequate after starting GF diet (consult with RD) Iron X X Zinc X X Folate X X Carbohydrate Fiber Niacin B12 Calcium X X X X X X Phosphorus X 1 Vici et al. Clin Nutr. 2016 Academy of Nutrition and Dietetics, Evidence Based Library Registered Dietitian Nutritionist (RDN) Referral All RDNs have passed registration confirming the ability to educated a patient on the parameters of a gluten free diet For a list of specialists, see http://www.eatright.org/find-an-expert for a RDN in your area Medical Nutrition Therapy Goals Identify gluten-containing grains that need avoided Identify gluten-free grains that can be included How to read a food label Identify grocers selling gluten-free products Discuss nutritional risks of the gluten-free nutrition prescription Plan healthful, gluten-free meals at home Explain cross-contamination and prevention tactics Identify supplements and medications that contain gluten CeD support groups, online resources 13
Resources for Providers and Patients Medications: www.glutenfreedrugs.com Recipes and support groups: www.glutenfreegang.org Regulations and testing: www.glutenfreewatchdog.org 14