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Alessio Fasano, M.D.
Mucosal Immunology and Biology Research Center
And Center for Celiac Research
Massachusetts General Hospital, Boston MA – U.S.A.
Laboratorio e Diagnosis di
Celiachia: Update 2014 46o Congresso Nazionale SIBioC
Roma 13-15 Ottobre 2014
Objectives
• Definition of celiac disease;
• Pathogenesis of celiac disease;
• Overview of clinical presentations of celiac
disease;
• Current and immediate future diagnostic tools;
• Clinical performance and technical challanges of
current diagnostic tools;
• Epidemiology (getting in celiac disease
diagnostics is a good business decision!);
• Future diagnostic directions.
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
The Celiac Iceberg
Symptomatic
Celiac Disease
Silent Celiac
Disease
Latent Celiac Disease
Genetic susceptibility: - DQ2, DQ8
Positive serology
Manifest
mucosal lesion
Normal
Mucosa
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
• Dermatitis Herpetiformis
• Dental enamel hypoplasia
of permanent teeth
• Osteopenia/Osteoporosis
• Short Stature
• Delayed Puberty
• Iron-deficient anemia
resistant to oral Fe
• Hepatitis
• Arthritis
• Epilepsy with occipital
calcifications
Most common age of presentation: older child to adult
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.
Diagnostic principles
• Confirm diagnosis before treating
– Diagnosis of Celiac Disease mandates a strict
gluten-free diet for life
• following the diet is not easy
• QOL implications
• Failure to treat has potential long term
adverse health consequences • increased morbidity and mortality
Diagnosis
Serological Tests
• Antigliadin antibodies (AGA)
• Anti-deamidated gliadin antibodies (AGA II or
DGP)
• Antiendomysial antibodies (EMA)
• Anti tissue transglutaminase antibodies (TTG)
– first generation (guinea pig protein)
– second generation (human recombinant)
• HLA typing
Antigliadin Antibodies
• Antibodies (IgG and IgA) to the gluten
protein in wheat, rye and barley
• Advantages
– relatively cheap & easy to perform
• Disadvantages
– poor sensitivity and specificity
Endomysial Antibody - EMA
• IgA based antibody against reticulin connective
tissue around smooth muscle fibers
• Advantages
– high sensitivity and specificity
• Disadvantages
– false negative in young children
– operator dependent
– expensive & time consuming
– false negative in IgA deficiency
Endomysial Antibody - EMA
Antibodies against the outer
layer of the smooth muscle
of monkey esophagus or
human umbilical cord
NEGATIVE POSITIVE
Tissue Transglutaminase - TTG
• IgA based antibody against tissue transglutaminase (Celiac Disease autoantigen)
• Advantages
– high sensitivity and specificity (human TTG)
– non operator dependent (ELISA/RIA)
– relatively cheap
• Disadvantages
– false negative in young children
– false negative in IgA deficiency
– possibly less specific than EMA
Deamidated Gliadin (AGA II): Differences in Sensibility Based on the
Degree of Intestinal Atrophy
Rashtak S. and al. Clin Gastroenterol Hepatol 2008;6:426-444.
Deamidated Gliadin (AGA II): Differences in Sensibility Following
Implementation of a Gluten Free Diet
Rashtak S. and al. Clin Gastroenterol Hepatol 2008;6:426-444.
Serological Test Comparison
Fasano & Catassi NEJM 2012;367:2419-26
Hill I et al. J Ped Gastroenterol Nutr 2005
Diagnostic Approach: Symptomatic Patients
Asymptomatic Patients in at-risk groups
Hill I et al. J Ped Gastroenterol Nutr 2005
HLA Tests
Schuppan. Gastroenterology 2000;119:234
Kaukinen. Am J Gastroenterol 2002;97:695
HLA alleles associated with Celiac Disease
• DQ2 found in 95% of celiac patients
• DQ8 found in remaining patients
• DQ2 found in ~30% of general population
Value of HLA testing
• High negative predictive value
– Negativity for DQ2/DQ8 excludes diagnosis of
Celiac Disease with 99% confidence
HLA Tests
• Potential role for DQ2/DQ8
• asymptomatic relatives
• Down, Turner & Williams syndrome
• type 1 diabetes
• diagnostic dilemmas
Epidemiology The “old” Celiac Disease Epidemiology:
• A rare disorder typical of infancy
• Wide incidence fluctuates in space (1/400 Ireland
to 1/10000 Denmark) and in time
• A disease of essentially European origin
Diagnostic
Developments
CD Epidemiology
Milestones
1970
1980
1990
2000
AGA
EMA
Human TTG
1970
1980
1990
2000
Screening in blood donors (Sweden)
Screening in healthy population (Italy)
Screening in developing countries (W Sahara)
Screening in the US
Quick TTG
HLA on a drop of whole blood 2005 2005
Quick Screening in
Developing Countries
(Lybia, Egypt, Iran)
2006 Deamidated gliadin
1960 1970 1980 1990 2000 20100.0
0.5
1.0
1.5
year
CD
pre
vale
nce (
%)
C. Catassi et al, Annal Med 2010;42:530-8.
During the past 35 years the true prevalence of CD in USA
doubled every 15 years.
0.21%
0.45%
0.93%
Autoimmunity Epidemics:
Celiac Disease
The Epidemics Of Celiac Disease: Which Additional Factors are
Driving this Epidemics?
- Quality of gluten;
- Quantity of gluten;
- Breast Feeding;
- Timing of gluten introduction
- Maturity of gut functions influencing Ag trafficking and
handling:
- GALT
- PRRs
- Mucous production
- Barrier function
- Changes in microbiome composition.
Published on October 2, 2014 (today)
Published on October 2, 2014 (today)
Home Take Messages • Window of tolerance concept not supported anymore;
• Breast feeding in general or introduction of gluten while breast feeding
showed no protective effect on CD onset in at-risk infants;
• Early introduction (16 weeks) of gluten traces to potentially induce
tolerance did not protect against CD in at-risk infants;
• Delaying the introduction of gluten in at-risk infants does not prevent
CD but merely postpones its onset by approximately 8 months
(significant difference at 2 years FU that disappeared by 5 years FU);
• GI infections during the first year of life seems not influential in
increased the risk of CD onset;
• High-risk HLA profiles seems to be the most influential factor predictor
of increased risk of CD onset;
• The high prevalence of CD among the study cohort suggests that the
CD epidemics continues.
Diagnosis:
The Future to Come •Diagnostic algorithms to avoid
intestinal biopsy;
•Biomarkers to predict onset of
celiac disease in genetically
susceptible individuals;
•Host-intestinal microbiome
interaction;
•Pharmacometabonomics.
The 4 out of 5 Signs Rule
1. Presence of signs or symptoms compatible with CD;
2. Positive serology (TTG +/- EMA);
3. Compatible HLA (DQ2 e/o DQ8 positive);
4. Positive intestinal biopsy (enteropathy typical of CD);
5. Resolution of symptoms following implementation of a gluten free diet
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