Is It Celiac Disease or Gluten Sensitivity?

Is It Celiac Disease or Gluten Sensitivity? Mark T. DeMeo MD, FACG Rush University Med Center Case Study 35 y/o female Complains of diarrhea, bloating, arthralgias, and foggy mentation Cousin with celiac disease Feels better on a gluten free diet Page 1 of 13

Classification of Wheat related disorders Wheat- related disorders Celiac Disease (autoimmune) Wheat allergy (allergic) Non-celiac wheat sensitivity (innate/adaptive immunity) IgE mediated Non IgE mediated Gluten based Non-gluten based Multiple food hypersensitivity Non-celiac wheat sensitivity 3 Marchioni RM Exp Rev Gastro Hep 2015 Pathogenesis of Celiac disease Chronic immune mediated enteropathy triggered by exposure to gluten in genetically predisposed individuals Positive serologies and histology Farrell RJ NEJOM 2002 Page 2 of 13

Definition of Non Celiac Gluten/Wheat Sensitivity (NCG/WS) Syndrome characterized by intestinal and extra-intestinal symptoms occurring shortly after ingestion of gluten/wheat in the absence of celiac disease or wheat allergy Rapid response to a gluten free diet NCGS Diagnostic protocol Symptomatic Patient on a Gluten Containing Diet Improved GFD + A or B GFD GFD + B or A Stop NCGS confirmed or excluded 6 wks GD Full Evaluation to exclude Celiac Disease and Wheat Allergy Initiation of a Gluten Free Diet 0 1 2 3 4 5 6 Not Improved NCGS excluded Catassi C. Nutrients 2015 Page 3 of 13

Prevalence of Celiac Disease in at-risk and not at-risk subjects 5 Prevalence,% (EMA positive) 4 3 2 1 0 First degree relatives Second degree relatives Symptomatic adults Symptomatic children Not-at-risk adults Not-at-risk children Fasano A,. Arch Int Med 2003 Prevalence of Non Celiac Gluten Sensitivity 14 12 10 8 6 4 2 0 New Zealand USA USA UK Italy Molina-Infante J. APT 2015 Page 4 of 13

Population use of a gluten-free diet 45 40 35 30 25 20 15 10 5 0 New Zealand US UK Australia Australia US Mexico Aziz I, Cur Opin Gastroenterol 2016 Sapone A, BMC Med 2012 Diagnostic Tools Celiac Disease Gluten Sensitivity Celiac Disease Serology Anti-tissue transglutaminase Anti-gliadin antibodies Anti-endomysial antibodies Deaminated gliadin antibodies Duodenal histology HLA haplotypes (DQ2 DQ8) IgE- based assays Clinical features positive positive positive positive positive (Marsh 1-3) present negative symptoms caused by gluten ingestion with resolution on a GFD negative positive ( 50% of cases) negative negative negative (Marsh 0-1) absent/present negative symptoms caused by wheat ingestion with resolution on a gluten free/wheat free diet Mansueto P. J Am Col Nut 2014 Page 5 of 13

Serological Markers in Celiac Disease Antibody Endomysial Antibody (IgA EMA) Tissue transglutaminase (IgA ttg) Anti-gliadin antibody (IgG AGA) Antibodies to deaminated gliadin Peptides (DPG-AGA) (IgG) Sensitivity Specificity 90-97 % 99.6% 95.1% 98.3% 65-100% 50-60% 82.3% 98.9% ttg Marsh Stage Rostom A, et al. Gastroenterol 2006;131:1981-200 Volta U, et al J Clin Gastro 2010;44:186-90 Tursi A, J Clin Gastro 2003:219-21 Serological Testing in NCGS Caio G, BMO Gastro 2014 Infantino M Clin Chim Acta 2015 Page 6 of 13

Mark T. DeMeo, MD, FACG Mild Enteropathy/lymphocytic Duodenitis 35 30 25 20 15 10 5 0 Aziz I, APT 2010 Sapone A, BMC Med 2012 Kurppa K Gastroenterol 2009 Autoimmunity in NCWS Carroccio A, Gastro 2015 Page 7 of 13

Intestinal and Extra Intestinal Symptoms in NCGS Volta U BMC Med 2014 15 NCGS in an IBS population 80 70 60 50 40 30 20 10 0 Carroccio A, Am J Gastro 2012 Page 8 of 13

Differential diagnosis of the three wheat sensitivities Time from exposure to symptom onset Pathogenesis Celiac Disease NCGS Wheat Allergy Days to weeks Hours to days Minutes to hours TH1:autoimmunity/ adaptive immunity Innate immunity /other TH2:allergic immune response Symptoms Intestinal and extraintestinal Intestinal and extraintestinal Intestinal and extraintestinal Complications Co-morbidities, Long term complications Long term (extra intestinal) complications? No co-morbidities, short-term complications (anaphylaxis) Schuppan D, Best Prac & Res Clin Gastro 17 2015 α-gliadin 18 Fasano A, Gastro 2015 Page 9 of 13

Gluten Intolerance 40 35 30 25 20 15 10 5 overall sx p overall sx pain p pain bloating p bloating tiredness p tiredness 0-5 week 1 week 2 week 3 week 4 week 5 week 6 Biesiekierski J Am J Gastro 2011 NCGS and FODMAPs Biesiekierski J, Gastro 2013 Page 10 of 13

Mark T. DeMeo, MD, FACG Amylase Trypsin Inhibitors in NCWS 21 Fasano A, Gastro 2015 Food associated changes in IBS patients 22 Fritscher-Ravens, A Gastro 2014 Page 11 of 13

Wheat Protein Carbohydrate α amylase Trypsin inhibitors Other proteins WGA Fructans Innate immune response IL-15 IELs Gliadin Myenteric plexus Opiod-like activity Acetylcholine release Cholinergic NS stimulation Epithelial Cells Permeation Apoptosis Oxidative stress Gastrointestinal Symptoms Intestinal microbiota Toxic agents Systemic Effects Poorly absorbed Molina-Infante J, APT 2015 Celiac Disease or NCGS 24 Kabbani TA, AM J Gastro 2014 Page 12 of 13

Celiac Associated Genes CD 28 CTL α 4 FASLG RGS1 IL 2 CCR5 CCR2 IL-21 CCR3 CD 80 IL 12 α SOCS1 TLR 8 TLR 7 CCR1 IL-15 α-inf Abadie V., Ann Rev Immunol 2011 Page 13 of 13