Post on 19-Dec-2015
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