ACG Postgraduate Course Copyright 2012 ACG October 2012 1 Celiac Disease and Gluten Sensitivity: New Tests and Approaches Celiac Disease and Gluten Sensitivity: New Tests and Approaches Approaches Approaches Joseph A Murray Joseph A Murray Joseph A Murray Mayo Clinic, Rochester, MN Joseph A Murray Mayo Clinic, Rochester, MN DISCLOSURE DISCLOSURE Relevant Financial Relationship(s) Alba Therapeutics: grant support Relevant Financial Relationship(s) Alba Therapeutics: grant support Alba Therapeutics: grant support Alvine Inc: Advisory Board Consultant: Ferring, Ironwood, Bayer, Flamentera, Arteille, Actiogenix, Shire, NexPep Alba Therapeutics: grant support Alvine Inc: Advisory Board Consultant: Ferring, Ironwood, Bayer, Flamentera, Arteille, Actiogenix, Shire, NexPep
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ACG Postgraduate Course Copyright 2012 ACG
October 2012 1
Celiac Disease and Gluten Sensitivity: New Tests and
Approaches
Celiac Disease and Gluten Sensitivity: New Tests and
• Celiac disease is well defined• Celiac disease is well defined• Celiac disease is well defined disease
• Non-Celiac Gluten sensitivity is not so well defined
• May share common pathways to
• Celiac disease is well defined disease
• Non-Celiac Gluten sensitivity is not so well defined
• May share common pathways to ay s a e co o pat ays tosymptoms
ay s a e co o pat ays tosymptoms
ACG Postgraduate Course Copyright 2012 ACG
October 2012 3
What is Celiac Disease?What is Celiac Disease?
• It is a inflammatory state of the small intestine that occurs in genetically
• It is a inflammatory state of the small intestine that occurs in geneticallyintestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.
intestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.
Normal CeliacDisease
PathogenesisPathogenesis
Genetics Gluten NecessaryCausesCauses
GenderInfant feedingInfections*OthersPathogenesis
?
Celiac disease
Risk Factors
*Rotavirus at weaningGastroenteritis in Adults
Stene et al, AJG 2006Riddle et al. AJG 2012
ACG Postgraduate Course Copyright 2012 ACG
October 2012 4
Presentations of Celiac DiseasePresentations of Celiac Disease
• People with other immune disorders• Type one diabetes mellitus
• Sjogren’s syndrome
• Worldwide, mostly Caucasians
• Any age including elderly
• People with other immune disorders• Type one diabetes mellitus
• Sjogren’s syndrome• Sjogren s syndrome
• Thyroid disease
• Lupus, Addison’s disease
• Family members of celiacs
• Sjogren s syndrome
• Thyroid disease
• Lupus, Addison’s disease
• Family members of celiacs
ACG Postgraduate Course Copyright 2012 ACG
October 2012 7
How Common in the United States?How Common in the United States?
www.2010.census.gov
The Prevalence of Celiac DiseaseThe Prevalence of Celiac Diseasein the United Statesin the United States
The Prevalence of Celiac DiseaseThe Prevalence of Celiac Diseasein the United Statesin the United States
Alberto Rubio-Tapia, Jonas F. Ludvigsson,
Tricia L. Brantner, Joseph A M rra James E
Alberto Rubio-Tapia, Jonas F. Ludvigsson,
Tricia L. Brantner, Joseph A M rra James EA. Murray, James E.
Everhart
Mayo Clinic and NIDDK*
A. Murray, James E. Everhart
Mayo Clinic and NIDDK*
ACG Postgraduate Course Copyright 2012 ACG
October 2012 8
Assessment of Celiac Disease Status
Assessment of Celiac Disease Status
• Direct Interview (two structured questions):• Has a doctor or other health professional ever
• Direct Interview (two structured questions):• Has a doctor or other health professional everHas a doctor or other health professional ever
told you that you have celiac disease?
• Are you on a gluten-free diet?
• Serology testing: coded serum specimens shipped to celiac disease research
Has a doctor or other health professional ever told you that you have celiac disease?
• Are you on a gluten-free diet?
• Serology testing: coded serum specimens shipped to celiac disease research laboratory at Mayo Clinic and tested between Jan 2009 and Jan 2011laboratory at Mayo Clinic and tested between Jan 2009 and Jan 2011
Gluten Free Diet Gluten Free Diet
Prevalence of Celiac Disease and Gluten Free Diet: NHANES 2009-2010
Celiac DiseaseCeliac Disease
Diagnosed CD
GFD without Dx of CD
Untreated CD17%
83%
RubioRubio--Tapia, et al. AJG 2012 .Tapia, et al. AJG 2012 .
1.6 million 1.8 million1% of Caucasians
ACG Postgraduate Course Copyright 2012 ACG
October 2012 9
World Map Indicating Prevalence of Celiac DiseaseWorld Map Indicating Prevalence of Celiac Disease
CP1253156-1
~1% 1-2% >2% <0.5% Report of cases N/A
Remes-Troche JM. Ramirez-Iglesias MT. Rubio-Tapia A. Alonso-Ramos A. Velazquez A. Uscanga LF.
Journal of Clinical Gastroenterology. 40(8):697-700, 2006
How Do You Find It?How Do You Find It?
Diagnostic TestsDiagnostic Tests
ACG Postgraduate Course Copyright 2012 ACG
October 2012 10
Duration Of Symptoms Before Diagnosis
Duration Of Symptoms Before Diagnosis
Stoven et al. Poster, P154 ACG 2012
Detection versus DiagnosisDetection versus Diagnosis
• Detecting CD is the not the same as• Detecting CD is the not the same as• Detecting CD is the not the same as confirming it!
• For detection you do not want to miss a case; maximize sensitivity
• For diagnosis you need confirmation: maximize specificity
• Detecting CD is the not the same as confirming it!
• For detection you do not want to miss a case; maximize sensitivity
• For diagnosis you need confirmation: maximize specificitymaximize specificity
• Traditionally serology first then biopsy
maximize specificity
• Traditionally serology first then biopsy
ACG Postgraduate Course Copyright 2012 ACG
October 2012 11
Diagnostic Criteria Diagnostic Criteria
• Villous atrophy with chronic inflammation in the proximal small intestine while eating gluten*
• Villous atrophy with chronic inflammation in the proximal small intestine while eating gluten*gluten
• Objective clinical response to a gluten free diet
• Serology provides important supportive evidence
ESPHGAN i d id li A id
gluten
• Objective clinical response to a gluten free diet
• Serology provides important supportive evidence
ESPHGAN i d id li A id• ESPHGAN revised guidelines - Avoid Biopsy in some children?
• ESPHGAN revised guidelines - Avoid Biopsy in some children?
Comparison of Serological TestsComparison of Serological Tests
Test Sens Spec Tech Cost
HtTg 96-98 88-100 Low $$
EMA 75-98 99-100 High $$$$
Gliadin-IgA 53-100 65-100 Low $
Gliadin-IgG 57-100 42-98 Low $
DeamidatedGliadin P
80 95 Low $
Sensitivity of TTg-IGA Sensitivity of TTg-IGA
ACG Postgraduate Course Copyright 2012 ACG
October 2012 13
Decrease in Sensitivity of ELISA Tests After Treatment with GFD
Decrease in Sensitivity of ELISA Tests After Treatment with GFD
80 8084
100GCDGCDGCDGCD GFDGFDGFDGFD
******** ******** ********
Sen
siti
vity
Sen
siti
vity
80
66
80
69
42
3434
17
37
24
16 1720
40
60
80 ****************
************
*P<0.05*P<0.05*P<0.05*P<0.05
**P<0.0001**P<0.0001**P<0.0001**P<0.0001
17
8
16 17
0
20
AGA IIAGA II AGA IIAGA II AGA IIAGA II AGAAGA AGAAGA TTGTTG TTGTTGIgAIgA IgGIgG IgA+GIgA+G IgAIgA IgGIgG IgAIgA IgGIgG
AGA IIAGA II AGA IIAGA II AGA IIAGA II AGAAGA AGAAGA TTGTTG TTGTTGIgAIgA IgGIgG IgA+GIgA+G IgAIgA IgGIgG IgAIgA IgGIgG
New ESPGHAN GuidelinesNew ESPGHAN Guidelines• Biopsy can be avoided if all of
the following apply:• Biopsy can be avoided if all of
the following apply:• tTg-IGA > 10 x upper limit of
normal
• Symptoms suggestive of celiac disease
• EMA+ (on a new blood sample)
• tTg-IGA > 10 x upper limit of normal
• Symptoms suggestive of celiac disease
• EMA+ (on a new blood sample)( p )
• HLA = DQ2 or DQ8
• Responds to gluten diet
( p )
• HLA = DQ2 or DQ8
• Responds to gluten diet
Husby et al, JPGN 2012Highly Controversial!
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Can Serology Replace Biopsy? Can Serology Replace Biopsy?
How Good is Serology in PracticeHow Good is Serology in Practice
• Specificity of the tests
• TTg-IGA high >95%
• Specificity of the tests
• TTg-IGA high >95%
• EMA-IGA high 76*-100%
• Variability:• Lab to lab
• EMA-IGA high 76*-100%
• Variability:• Lab to lab
• Kit to kit
• Reference ranges
• Performance
• Kit to kit
• Reference ranges
• Performance
* Mubarak et al, JPGN 2011
ACG Postgraduate Course Copyright 2012 ACG
October 2012 15
“A Biopsy Is Not Always Necessary to Diagnose Celiac Disease”
“A Biopsy Is Not Always Necessary to Diagnose Celiac Disease”
Accuracy of High Titer Results
Specificity (%)
Sensitivity(%)
PPV(%) NPV(%)
EMA-IGA 66 96 79 93
TTg-IGA >10 83 96 88 93
y g
TTg-IgA >100 97 76 97 75
Mubarak et al. JPGN., May 2011.
Issues:Retrospective study of real clinical practiceEffect of serum testing prior to scope!Low accuracy of EMA
PhilosophyPhilosophy
• Is a blood test a solid enough• Is a blood test a solid enough• Is a blood test a solid enough foundation upon which to build a lifetime of treatment for a patient?
• Should CD be the first autoimmune disease where the diagnosis is based on a serological test?
• Is a blood test a solid enough foundation upon which to build a lifetime of treatment for a patient?
• Should CD be the first autoimmune disease where the diagnosis is based on a serological test?on a serological test?
• Would you believe a single test if it were you?
on a serological test?
• Would you believe a single test if it were you?
ACG Postgraduate Course Copyright 2012 ACG
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Histopathology of Celiac DiseaseHistopathology of Celiac Disease
• Effect not HLA dependent• Highly select group• Highly select group• Highly select group
“Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial”.Biesiekierski JR et al. AJG 2011
Are there other potential mechanism of gluten in symptoms in IBS?
Are there other potential mechanism of gluten in symptoms in IBS?
Epithelial activationUpregulation of IL-15 and EGFRUpregulation of stress-induced MHC-Ib
APC maturationInflammatory cytokines IFN-α
HLA-E surface expressionand stabilization
IL-15?IFN−α?
Altered Permeability and Mucosal Immune gene expression in Non-Celiac
Gluten Sensitivity
Altered Permeability and Mucosal Immune gene expression in Non-Celiac
Gluten Sensitivity
• Decreased IP in GS• Increased expression of claudin 4• Reduced Fox p3• Increased TLR2• Comparison group Dyspepsia• 5 hour urinary excretion of LA/MA
• Decreased IP in GS• Increased expression of claudin 4• Reduced Fox p3• Increased TLR2• Comparison group Dyspepsia• 5 hour urinary excretion of LA/MA• 5 hour urinary excretion of LA/MA• LA/MA is affected by transit
• Transit may be affected HLA
• 5 hour urinary excretion of LA/MA• LA/MA is affected by transit
• Transit may be affected HLASapone et al, BMC Medicine, 2011Vazquez-Roque, AJP , in press
••Double blind Placebo controlledDouble blind Placebo controlled••Duration?Duration?••Safety in neurological syndromeSafety in neurological syndrome
D fi h i ( )D fi h i ( )••Define mechanism(s)Define mechanism(s)••Detection/diagnosisDetection/diagnosis
Challenge: How Can We Detect NCGS?
Challenge: How Can We Detect NCGS?
••Most patients have to find Most patients have to find themselves despite us!themselves despite us!themselves despite us! themselves despite us! ••Self treatment is not Self treatment is not satisfactorysatisfactory••Missed disease Missed disease
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Challenge: DiagnosisChallenge: Diagnosis
••Diagnosis:Diagnosis:••Rule out celiac disease/ other diseaseRule out celiac disease/ other disease••Role of antibodies: Role of antibodies:
••specific for NCGI ( need good specific for NCGI ( need good controls) IBS for GS IBScontrols) IBS for GS IBSAb t l i l tiAb t l i l ti••Ab to luminal antigens Ab to luminal antigens