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Gluten Sensitivity The Spectrum Of Gluten Related Disorders Alessio Fasano, M.D. W. Allan Walker Chair in Pediatric Gastroenterology and Nutrition Professor of Pediatrics Harvard Medical School Mucosal Biology and Immunology Research Center And Center for Celiac Research And Treatment Massachusetts General Hospital for Children The Controversy On Who Should Be On A GFD Only People With Celiac Disease Everybody The Source Supporting GFD For Everybody The Epidemics Of Gluten Related Disorders - Quality of gluten: GE grains - Quantity of gluten - Gluten cannot be digested The Epidemics Of Gluten Related Disorders - Quality of gluten: GE grains - Quantity of gluten - Gluten cannot be digested Kasarda D. J Agric Food Chem. 2013;61: 1155–1159. Kasarda D. J Agric Food Chem. 2013;61: 1155–1159. GMO Grains + T. turgidum AABB Aegilops tauschii DD T. aestivum AABBDD 28 chromosomes 14 chromosomes 42 chromosomes 100,000 genes 50,000 genes 150,000 genes The Epidemics Of Gluten Related Disorders - Quality of gluten: GE grains - Quantity of gluten - Gluten cannot be digested Kasarda D. J Agric Food Chem. 2013;61: 1155–1159. The Epidemics Of Gluten Related Disorders - Quality of gluten: GE grains - Quantity of gluten - Gluten cannot be digested What is so Special About Gluten? Gliadin Glutenin Gluten (gliadin+glutenin) Structural Characteristics of Alpha-Gliadin Shan L et al, Science. 2002; 297:2275-9. Lammer K et al, Immunology. 2011;132:432-40 Lammer K et al, Gastroenterology Maiuri et al. Scand J 2008;135:194-204. Gastroenterol. 1996; 31:247-53. Celiac Disease The Banana Babies WK Dicke, 1905 - 1962 1st case of CD at UMB: 1938 Celiac Disease as a Unique Model of Autoimmunity • The only autoimmune disease in which specific MHC class II HLA (DQ2 and/or DQ8) are present in >95% of patients; • The auto-antigen (tissue Transglutaminase) is known; • The environmental trigger (gluten) is known; • Elimination of the environmental trigger leads to a complete resolution of the autoimmune process that can be re-ignited following re-exposure to gluten Gastrointestinal Manifestations (“Classic”) Most common age of presentation: 6-24 months • Chronic or recurrent diarrhea • Abdominal distension • Anorexia • Failure to thrive or weight loss • Abdominal pain • Vomiting • Constipation • Irritability Rarely: Celiac crisis Non Gastrointestinal Manifestations Most common age of presentation: older child to adult • Dermatitis Herpetiformis • Iron-deficient anemia • Dental enamel hypoplasia resistant to oral Fe of permanent teeth • Hepatitis • Osteopenia/Osteoporosis • Arthritis • Epilepsy with occipital • Short Stature calcifications • Delayed Puberty Listed in descending order of strength of evidence The Clinical Manifestations of Celiac Disease are More Heterogeneous Than Previously Appreciated A. Fasano, N Engl J Med 2003;348:2568-70. The Epidemics of Celiac Disease 1.5 0.93% 1.0 0.45% 0.21% 0.5 CD prevalence (%)CD prevalence 0.0 1960 1970 1980 1990 2000 2010 year Not Only Celiac Disease Gluten Free Market For the American general population adopting a gluten-free diet is becoming an increasingly popular solution. The market for gluten-free food and beverage products grew at a compound annual growth rate of 28 percent from 2004 to 2011, to finish with almost $6.7 billion in retail sales last year. By the end of 2016 the market is expected to reach about $14.6 billion in sales. How Many People in the US Are Embracing a GFD?: Percentage of U.S. Adults Trying to Cut Down or Avoid Gluten in Their Diets Reaches New High in 2016, Reports NPD The Fad Factor of the GFD Why People in the US Embrace a GFD?: Approx 7M Approx 400,000 Approx 9M Approx 24M Approx 50M Based on internet interview users age 18y+ who eats GF food The Gluten Free Diet: Not Only Celiac Disease GLUTEN FREE DIET CONSUMERS NO MEDICAL MEDICAL NECESSITY NECESSITY CELIAC DISEASE WHEAT ALLERGY GLUTEN SENSITIVITY (AUTOIMMUNE- (IGE-MEDIATED) (INNATE IMMUNITY?) BASED) (~0.1%) (??) (~1%) Key Questions About Non-Celiac Gluten Sensitivity: • Does it exist? • How NCGS is diagnosed? • Are NCGS and IBS synonimous? • Are FODMAPs the only trigger of NCGS? • Is gluten the only trigger of NCGS? • Is gluten involved in triggering the symptoms of NCGS Gluten Sensitivity (NCGS): Facts Definition Cases of reaction to ingestion of gluten-containing grains in which both allergic and autoimmune mechanisms have been ruled out (diagnosis by exclusion criteria) • Triggered by the ingestion of gluten-containing grains; • Negative immuno-allergy tests to wheat; • Negative CD serology (EMA and/or tTG) and in which IgA deficiency has been ruled out; • Negative duodenal histopathology; • Possible presence of biomarkers of gluten immune-reaction (AGA+); • Presence of clinical symptoms that can overlap with CD or wheat allergy symptomatology; • Resolution of the symptoms following implementation of a GFD and relapse after re-exposure to gluten-containing grains (double blind) Sapone A. et al BMC Med 2012, Ludvigsson JF et al Gut 2013, Catassi C. Et al, Nutrients 2013 Gluten Sensitivity (NCGS): Consensus Conferences to Define NCGS Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13 Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C. The Oslo definitions for coeliac disease and related terms. Gut. 2013 Jan;62(1):43-52 Catassi C, Bai JC, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sep 26;5(10):3839-53. Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, Cellier C, Cristofori F, de Magistris L, Dolinsek J, Dieterich W, Francavilla R, Hadjivassiliou M, Holtmeier W, Körner U, Leffler DA, Lundin KE, Mazzarella G, Mulder CJ, Pellegrini N, Rostami K, Sanders D, Skodje GI, Schuppan D, Ullrich R, Volta U, Williams M, Zevallos VF, Zopf Y, Fasano A. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients. 2015 Jun 18;7(6):4966-77. doi: 10.3390/nu7064966. Clinical manifestaons of NCGS Frequency Intesnal Extra-intesnal Very Common Bloang Lack of wellbeing Abdominal pain Tiredness Common Diarrhea Headache Epigastric pain Anxiety Nausea Foggy mind Aerophagia Numbness GER Joint/muscle pain Aphtous stoma-s Skin rash/derma-s Alternang bowel habits Cons-paon Undetermined Hematochezia Weight loss Anal fissures Anemia Loss of balance Depression Rhini-s/asthma Weight increase Inters--al cys--s Ingrown hairs Oligo or polimenorrhea Sensory symptoms Disturbed sleep paern Hallucinaons Mood swings Au-sm Schizophrenia The Salerno NCGS diagnostic criteria (Nutrients, 2015) Gluten and The Brain Short Memory Loss Chronic Headache Anxiety Schizophrenia? Depression Irritability Autism? Seizures ADHD? Ataxia The Controversial Questions About Gluten Sensitivity Are The Epidemics Of Autism, ADHD and Schizophrenia Also Related to The Rise of Non-Celiac Gluten Sensitivity? Proposed New Classification of Gluten Related Disorders Gluten Related Disorders Biomarkers Pathogenesis YES Not Autoimmune Autoimmune Allergic NO Not allergic (Innate immunity?) YES Celiac Gluten Dermatitis Wheat Gluten Disease Ataxia herpetiformis allergy sensitivity Respiratory Food Contact Symptomitic Silent Potential WDEIA Allergy Allegy Urticaria Differential Diagnosis Between CD, GS, and WA Celiac Disease Gluten Sensitivity Wheat Allergy Time interval between gluten exposure and Weeks-Years Hours-Days Minutes-Hours onset of symptoms Pathogenesis Autoimmunity (Innate+ Immunity? Allergic Immune Response Adaptive Immunity) (Iinnate Immunity?) HLA HLA DQ2/8 restricted Not-HLA DQ2/8 restricted Not-HLA DQ2/8 restricted (~97% positive cases) (50% DQ2/8 positive cases) (35-40% positive cases as in the general population) Auto-antibodies Almost always present Always absent Always absent Enteropathy Almost always present Always absent Always absent (slight increase in IEL) (eosinophils in the lamina propria) Symptoms Both intestinal and Both intestinal and extra- Both intestinal and extra- extra-intestinal (not intestinal (not intestinal (not distinguishable from GS distinguishable from CD and distinguishable from CD and WA with GI WA with GI symptoms) and GS when presenting symptoms) with GI symptoms) Complications Co-morbidities Absence of co-morbidities Absence of co-morbidities. Long term complications and long term complications Short-term complications (long follow up studies (incliuding anaphylaxis) needed to confirm it) .
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