Clinical Presentation of Celiac Disease Alessio Fasano, M.D. Mucosal Immunology and Biology Research Center And Center for Celiac Research – Celiac Program.

Clinical Presentation ofCeliac 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 RESEARCHClinical Care Support Services Education Research

18 years of discovery

www.celiaccenter.org

CFCR identifies possible

biomarker for gluten

sensitivity (GS) and provided proof of

concept that schizophrenic

patients affected by GS benefit

from gluten- free diet

2011Zonulin 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

2009Cloned

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

2007Research leads to 1st

clinical trials for CD,

developed genetic

screening test for CD

2004Conducted Celiac

Prevalence Study-results are 1 out of

133 Americans have CD

2000Developed 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 risk2008

Established guidelines for

safe gluten levels for new food labeling

law2005

Spearheaded the American

Celiac Disease Alliance2003

Discovered Zonulin – key element for all autoimmune

diseases1996

2013-2014Joined 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, 1905 - 19621st 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;131:822-6.Fry L. Baillieres Clin Gastroenterol. 1995;9:371-93.

Reunala T, et al. Br J Dermatol. 1997;136-315-8.

Anemia in Celiac Disease

• 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 Downsyndrome

0

4

8

12

16

20

per

cen

tage

GeneralPopulation

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: 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%

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: 286-292, 2003

Celiac Disease Epidemiological Study in USA

Prevalence1:39

Prevalence1:22

Population screened13145

Positive31

Negative4095

Positive81

Negative3155

Positive205

Negative4303

Positive33

Negative1242

Prevalence1:40

Symptomatic subjects3236

1st degree relatives4508

2nd degree relatives1275

Healthy Individuals4126

Risk Groups9019

Prevalence1:133

Projected number (conservative) of celiac disease patients in the U.S.A.: 2,615,954MAJOR 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 GFDOne 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