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

1996 CFCR established first Celiac Center in the world affiliated with the University of Maryland School of Medicine, providing clinical care for children and adults

Discovered Zonulin – key element for all autoimmune diseases

2000 Developed the celiac disease (CD) test currently used by physicians. tTG

2003 Conducted Celiac Prevalence Study-results are 1 out of 133 Americans have CD

Spearheaded the American Celiac Disease Alliance

2004

Established guidelines for safe gluten levels for new food labeling law

2005 Research leads to 1st clinical trials for CD, developed genetic screening test for CD

2007

2008 Proved that testing people who are at-risk for CD is costeffective

Infant study to explore the possibility to prevent CD in infants at risk

2009 Cloned Zonulin, after 10 years of its discovery identifying it as an ancient protein that is found only in humans

www.celiaccenter.org

Published the study that followed over 8,000 people since 1970 showing that CD prevalence doubled every 15 years

2010 CFCR participating in a new international research initiative, partly funded by the Vatican, to explore therapeutic potential of intestinal stem cells

CFCR identifies key pathogenic differences between CD and gluten sensitivity

2011 Zonulin assay licensed for the purpose of developing diagnostic tests

Recent findings imply possible window of opportunity to prevent celiac disease in atrisk children

2012 CFCR identifies possible biomarker for gluten sensitivity (GS) and provided proof of concept that schizophrenic patients affected by GS benefit from gluten- free diet

2013-2014 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

1st case of CD at UMB: 1938 WK Dicke, 1905 - 1962

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 Most common age of presentation: older child and teenager • • • • • • • • • • • •

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

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;131:822-6. Fry L. Baillieres Clin Gastroenterol. 1995;9:371-93. Reunala T, et al. Br J Dermatol. 1997;136-315-8.

Anemia in Celiac Disease Most common non-GI manifestation in adults: 5-8% of adults with unexplained iron deficiency anemia have 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

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

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

Intestinal Lymphoma Celiac Disease Complicated by EnteropathyAssociated T-cell Lymphoma (EATL)

By permission of G. Holmes, Derby (UK)

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 20

percentage

16 12 8 4 General Population

0 Relatives

IDDM

Thyroiditis

Down syndrome

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

Co-Morbidities Prevalence of Celiac Disease is Higher in Other Autoimmune Conditions Type 1 Diabetes Mellitus:

3.5 - 10%

Thyroiditis:

4 - 8%

Arthritis:

1.5 - 7.5%

Autoimmune liver diseases:

6 - 8%

Sjögren’s syndrome:

2 - 15%

Idiopathic dilated cardiomyopathy:

5.7%

IgA nephropathy:

3.6%

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: 286-292, 2003

Celiac Disease Epidemiological Study in USA Population screened 13145

Healthy Individuals 4126

Risk Groups 9019

Symptomatic subjects 3236

Positive 31

Negative 4095

Prevalence 1:133

Positive 81

Negative 3155

Prevalence 1:40

1st degree relatives 4508

Positive 205

Negative 4303

Prevalence 1:22

2nd degree relatives 1275

Positive 33

Negative 1242

Prevalence 1:39

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;163:286-292.

The Clinical Manifestations of Celiac Disease are More Heterogeneous Than Previously Appreciated

A. Fasano, N Engl J Med 2003;348:2568-70.

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