celiac disease (cd) diagnosis and whom to screen maureen leonard md fellow, massgeneral hospital for...
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Celiac Disease (CD)Diagnosis and Whom to Screen
Maureen Leonard MDFellow, MassGeneral Hospital for Children
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Conflicts of Interest
• I have no conflicts of interest to disclose
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Objectives• Diagnosis– Review the Current Classic Diagnostic Algorithm– Discuss Alternative Strategies For Diagnosis– Consider Future Diagnostic Directions
• Whom to Screen– Identification of Individuals via Case-Based
Approach– Identify High Risk Groups
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Increased Prevalence Over Time in U.S.A. (in Line with Other Autoimmune Diseases)
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
During the past 35 years the true prevalence of CD in USA doubled every 15 years.
0.21%
0.45%
0.93%
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Serological Test Comparison
Fasano & Catassi NEJM 2012;367:2419-26
Initially Screen for IgA level;If < 7 send IgG DGP
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Signs or symptoms concerning for Celiac Disease or pt, belonging to a high risk group
IgA, IgA tTG
IgA <7 -IgA tTG
- IgA tTG+ IgA tTG
CD unlikely
Consider HLA testing in high risk
groups
IgG DGP
Duodenal biopsy
HLA, EMARepeat tTG
Other causes
Negative
EGD for persistent or concerning symptoms
Celiac Disease
NegativePositive
Positive
Current Screening Algorithm
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Gluten Ingestion Is Key To A Successful Diagnosis
• Patients must be eating gluten for accurate serological testing and duodenal biopsy
• Time to complete serological improvement and endoscopic improvement after cessation of gluten is unknown
• Reintroduction of gluten prior to diagnostic testing is warranted to ensure an accurate diagnosis
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Modified Gluten Challenge Algorithm
Leffler, Daniel, et al (2013)
Key Points•3g of gluten Daily for 2 weeks
•tTG rises 28 days
•Aim for minimum of 6-8 weeks
•3-4 months if patient is asymptomatic
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Alternative Strategies for Diagnosis4 out of 5 Rule
1. History of symptoms typically associated with celiac disease.
2. Positive serological biomarkers– IgA tTg or IgA EMA
3. Compatible genetics HLA-DQ2 or DQ8 alleles 4. Small intestinal biopsy showing blunting or
absence of the villi (Marsh III) and CD3+ intraepithelial lymphocytosis
5. Improvement of symptoms with a gluten free diet. Catassi C+ Fasano. Am J Med. 2010
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Alternative Strategies For DiagnosisDo We Really Need a Biopsy?
• Pediatric European Guidelines 2012– Signs and symptoms suggestive of CD– IgA tTG >10x the cutoff value– IgA EMA positive at a 2nd time point– Genetics Compatible with CD• HLA DQ2 or DQ8
Husby, S., et al. 2012
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Why We Need Initial Biopsies:Alternative Treatments Are On the Horizon
Type Phase Clinical trial identificationPolymeric BinderP(HEMA-co-ss)-BL-7010 Phase I/II NCT01990885
Enzyme Supplementation
AN- PEP Phase II NCT01335503ALV1003 Phase IIB NCT01917630Zonulin Inhibitor
Larazotide Acetate Completed Phase IIB NCT01396213TTG inhibitors
Elafin Preclinical -DQ2 blockers
Several Discovery Phase -Induction of Tolerance
NexVax2 Phase 1b NCT00879749
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Why We Need Initial Biopsies: To Accurately Evaluate Remission
Evaluate Healing Endoscopically
• Murray et. al 2010– 381 adults– 34% remission after 2 years– 66% at 5 years
• Hopper et al. 2008– 67% adults Marsh 0-2 after
2 years
• Remission between 62-85%
Serology Cannot Predict Compliance or Remission
Status• tTG and EMA do not
correlate with dietary compliance
• Hopper et al. – 7/16 of Adult pts on a GFD
>1 year– Normal tTG and EMA– Persistent villous atrophy
• True in adolescents as wellVehadi et al. AmGastro 2003. Hopper, AD et al. ClinGastroenterol Hepatol 2008.
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Alternative Ways to Scope
• Capsule Endoscopy
• Confocal Laser Endomicroscopy
• Tethered capsule endomicroscopy– Three-dimensional microscopic images
http://www.tearneylab.org/clinical/celiac-disease/http://protomag.com/articles/what-the-pill-sees
Fritscher-Ravens et al. Gastroenterology (2014):
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Future Diagnostic Directions• HLA DQ2/DQ8 screening for high risk patients
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• Prospective observational study based at MGH • Enrolling infants with a first degree family member with
CD who have not yet been introduced to solid foods (<6 months)
• Collection of blood, stool and clinical information until age 5
• Goals: Identify the natural history of CD.• Understand the environmental factors that contribute to
the development of CD.• Identify changes in the micobiota that can predict the
onset of CD to implement early interventions to prevent CD
Celiac Disease Genomic Environmental Microbiome and Metabolomic Study
www.CDGEMM.orgEmail: [email protected]
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Whom To Screen
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Case: Poor appetite + Growth
• 7y/o male with poor intake due to picky eating• Denies any other symptoms• Family history : – Uncle with T1D and thyroid disease– Grandfather with thyroid disease
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Decreased Height Velocity
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BMI
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Diagnostic Workup: Static Growth
• CBC: HCT: 33 HgB: 9 MCV 65• Ferritin: 5• IgA level: 217• IgA tTG: >300• Endoscopy with Duodenal Biopsy: Total villous
atrophy Marsh 3C• Diagnosis: CD
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Diagnostic Work-up Celiac Disease
• CBC, CMP, ferritin, Vitamin D, B12, zinc• Bone density Scan• Dietician Consultation– At diagnosis– After 3 months
• Repeat tTG at 6 months and 12 months after diagnosis
• Consider repeat endoscopy to document healing
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Follow-up: 3 months on a GFD
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Case: Poor Growth
• 5 y/o female followed by GI for poor growth which had been thought to be secondary to VSD and cleft lip and palate
• G tube placed for supplemental nutrition• tTG accidently sent : >300• Endoscopy consistent with diagnosis of Celiac
Disease
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Asymptomatic Family Members
FathertTG>100
EGD Confirms CD
MothertTG negative
Adolescent F w/ abdominal pain,
bloating, and fatigueHT: 87% Wt: 97%
SiblingHT: 57% Wt 75%
tTG>100, EGD confirms CD
SiblingtTG negative
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Case: Osteopenia• 30 y/o male with Down syndrome– Diarrhea and Fatigue– Diagnosed with CD based on blood and duodenal
biopsy• Hypothyroid Disease
• DEXA: bone loss• Strict GFD x 10 years • Presents now with– Fatigue and bone loss– Repeat DEXA: ongoing bone loss
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Ongoing Bone Loss: Active CD
• Down Syndrome• Body Composition• Muscle Mass• Vitamin D• Endocrine
Abnormalities• Activity Level
• Active Celiac Disease– Underwent EGD w/
Biopsy– Marsh 3 damage– Gluten Contamination
Elimination Diet
Baptista, Fatima, Ana Varela, and Luis B. Sardinha. Osteoporosis international 16.4 (2005): 380-388.
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Prevalence In At Risk Groups In The US
• Family Members• 1st Degree– 1:22
• 2nd Degree– 1:33
• Symptomatic– Adults: 1:68– Children: 1:25
• Infertility 1:16• Anemia 1:24• Short Stature 1:25• Joint Pain 1:33• Fatigue 1:34
Fasano, Alessio, et al. "Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study." Archives of internal medicine 163.3 (2003): 286-292.
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Prevalence in Associated Conditions
Fasano, Alessio, et al. "Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study." Archives of internal medicine 163.3 (2003): 286-292.
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Who Should We Consider Testing?
Hill, Ivor D., et al. JPGN 40.1 (2005): 1-19.
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Thank You