Clinical Presentation of Celiac Disease Alessio Fasano, M.D. Mucosal Immunology and Biology Research Center And Center for Celiac Research – Celiac Program at HMS Massachusetts General Hospital, Boston MA – U.S.A.

DISCLOSURE Alba Therapeutics: Co-founder and stock holder; Mead Johnson Nutrition: Sponsored research; Inova Diagnostics: Sponsored research; Regeneron: Sponsored research; Pfizer: Consultant 2

CENTER for CELIAC RESEARCH Clinical Care  Support Services  Education  Research 18 years of discovery CFCR identifies possible biomarker for gluten sensitivity (GS) and provided proof of concept that schizophrenic patients affected by GS benefit from gluten- free diet 2011 Zonulin assay licensed for the purpose of developing diagnostic tests CFCR participating in a new international research initiative, partly funded by the Vatican, to explore therapeutic potential of intestinal stem cells 2009 Cloned Zonulin, after 10 years of its discovery identifying it as an ancient protein that is found only in humans Proved that testing people who are at-risk for CD is cost- effective 2007 Research leads to 1 st clinical trials for CD, developed genetic screening test for CD 2004 Conducted Celiac Prevalence Study-results are 1 out of 133 Americans have CD 2000 Developed the celiac disease (CD) test currently used by physicians. tTG CFCR established first Celiac Center in the world affiliated with the University of Maryland School of Medicine, providing clinical care for children and adults Recent findings imply possible window of opportunity to prevent celiac disease in at- risk children 2012 CFCR identifies key pathogenic differences between CD and gluten sensitivity Published the study that followed over 8,000 people since 1970 showing that CD prevalence doubled every 15 years 2010 Infant study to explore the possibility to prevent CD in infants at risk 2008 Established guidelines for safe gluten levels for new food labeling law 2005 Spearheaded the American Celiac Disease Alliance 2003 Discovered Zonulin – key element for all autoimmune diseases Joined MGH! New fund raising initiatives (Opening event, visiting day) FDA ruling approved based on the CFCR research findings Opening of the Research Institute in Salerno-Italy Agreement with two industrial partners finalized. Approval of the Celiac Program at Harvard (with Children’s and Beth Israel Deaconess Hospital)

The Banana Babies WK Dicke, st 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

CD: THE PAST AND THE PRESENT 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 Arthritis and/or joint pain Behavioral changes Delayed puberty Dental enamel hypoplasia of permanent teeth Dermatitis Herpetiformis Eczema Epilepsy with occipital calcifications Headache/Migraine Hepatitis Iron-deficient anemia resistant to oral Fe Osteopenia/Osteoporosis Short Stature Most common age of presentation: older child and teenager Listed in alphabetic order

Recurrent Aphtous Stomatitis By permission of C. Mulder, Amsterdam (Netherlands)

Dermatitis Herpetiformis Erythematous macule > urticarial papule > tense vesicles Severe pruritus Symmetric distribution 90% no GI symptoms 75% villous atrophy Gluten sensitive Garioch JJ, et al. Br J Dermatol. 1994;131: Fry L. Baillieres Clin Gastroenterol. 1995;9: Reunala T, et al. Br J Dermatol. 1997;

Anemia in Celiac Disease Microcytic anemia - iron absorption most efficient in the duodenum Megaloblastic/Macrocytic anemia – folate is absorbed primarily in the proximal third of the small intestine (location of folate hydrolases) Vitamin B-12 deficiency occurs rarely Most common non-GI manifestation in adults: 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease

Osteoporosis Low bone mineral density improves in children but not in adults (~ >30 y old) on a gluten-free diet.

Short Stature/Delayed Puberty Short stature in children / teens:   10% of short children and teens have evidence of celiac disease Delayed menarche:  Higher prevalence in teens with untreated Celiac Disease

CT Scan Showing Occipital Calcifications in a Boy with Celiac Disease and Epilepsy Neurological Symptoms

Celiac Disease Complicated by Enteropathy- Associated T-cell Lymphoma (EATL) By permission of G. Holmes, Derby (UK) Intestinal Lymphoma

Asymptomatic Asymptomatic patients are still at risk of osteopenia/osteoporosis Treatment with a gluten-free diet is recommended for asymptomatic children with proven intestinal changes of Celiac Disease who have: –type 1 diabetes –selective IgA deficiency –Down syndrome –Turner syndrome – Williams syndrome – autoimmune thyroiditis – a first degree relative with Celiac Disease

Associated Conditions The prevalence of Celiac Disease is higher in patients who have the following: –Certain genetic disorders or syndromes –Other autoimmune conditions –Relative of a biopsy-proven celiac

Associated Conditions Relatives IDDM Thyroiditis Down syndrome percentage General Population

Genetic Disorders Down Syndrome: 4-19% Turner Syndrome: 4-8% Williams Syndrome: 8.2% IgA Deficiency: 2-3% Can complicate serologic screening

Prevalence of Celiac Disease is Higher in Other Autoimmune Conditions Type 1 Diabetes Mellitus: % Thyroiditis:4 - 8% Arthritis: % Autoimmune liver diseases:6 - 8% Sjögren’s syndrome:2 - 15% Idiopathic dilated cardiomyopathy:5.7% IgA nephropathy:3.6% Co-Morbidities

Relatives Healthy population: 1:133 1st degree relatives: 1:18 to 1:22 2nd degree relatives: 1:24 to 1:39 Fasano, et al, Arch of Intern Med, Volume 163: , 2003

Celiac Disease Epidemiological Study in USA Prevalence 1:39 Prevalence 1:22 Population screened Positive 31 Negative 4095 Positive 81 Negative 3155 Positive 205 Negative 4303 Positive 33 Negative 1242 Prevalence 1:40 Symptomatic subjects st degree relatives nd degree relatives 1275 Healthy Individuals 4126 Risk Groups 9019 Prevalence 1:133 Projected number (conservative) of celiac disease patients in the U.S.A.: 2,615,954 MAJOR PUBLIC HEALTH PROBLEM NATIONWIDE WITH SOME REGIONAL DIFFERENCES A. Fasano et al., Arch Int Med 2003;163:

The Clinical Manifestations of Celiac Disease are More Heterogeneous Than Previously Appreciated A. Fasano, N Engl J Med 2003;348:

CURRENT MANAGEMENT: COMPLIANCE TO THE GFD One of the most challenging issues related to the treatment of CeD is proper compliance of strict gluten free diet for life. Beside facing the same issues that adult CD patients experience, including risk of cross-contamination while traveling, vacationing, eating out, etc, pediatric patients have unique challenges that make the compliance to the GFD extremely difficult

Efficacy Readout From Patient Prospective Adults: Improvement of quality of life Pediatrics: Blend with peers, being not different from others