1. Celiac Disease (CD) Diagnosis and Whom to Screen Maureen Leonard MD Fellow, MassGeneral Hospital for Children

2. Conflicts of Interest I have no conflicts of interest to disclose

3. 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

4. Increased Prevalence Over Time in U.S.A. (in Line with Other Autoimmune Diseases) 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%

5. Serological Test Comparison Fasano & Catassi NEJM 2012;367:2419-26 Initially Screen for IgA level; If < 7 send IgG DGP

6. Signs or symptoms concerning for Celiac Disease or pt, belonging to a high risk group IgA, IgA tTG IgA <7 -IgA tTG + IgA tTG CD unlikely Consider HLA testing in high risk groups IgG DGP Duodenal biopsy HLA, EMA Repeat tTG Other causes Negative EGD for persistent or concerning symptoms Celiac Disease NegativePositive Current Screening Algorithm

7. 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

8. 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

9. Alternative Strategies for Diagnosis 4 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

10. Alternative Strategies For Diagnosis Do 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 2 nd time point – Genetics Compatible with CD HLA DQ2 or DQ8 Husby, S., et al. 2012

11. Why We Need Initial Biopsies: Alternative Treatments Are On the Horizon TypePhaseClinical trial identification Polymeric Binder P(HEMA-co-ss)-BL-7010Phase I/IINCT01990885 Enzyme Supplementation AN- PEPPhase IINCT01335503 ALV1003Phase IIBNCT01917630 Zonulin Inhibitor Larazotide AcetateCompleted Phase IIBNCT01396213 TTG inhibitors ElafinPreclinical- DQ2 blockers SeveralDiscovery Phase- Induction of Tolerance NexVax2Phase 1bNCT00879749

12. 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 well Vehadi et al. AmGastro 2003. Hopper, AD et al. ClinGastroenterol Hepatol 2008.

13. 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/wh at-the-pill-sees Fritscher-Ravens et al. Gastroenterology (2014):

14. Future Diagnostic Directions HLA DQ2/DQ8 screening for high risk patients

15. 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.org Email: cdgemm@mgh.harvard.edu

16. Whom To Screen

17. 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

18. Decreased Height Velocity

19. BMI

20. 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

21. 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

22. Follow-up: 3 months on a GFD

23. 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

24. Asymptomatic Family Members Father tTG>100 EGD Confirms CD Mother tTG negative Adolescent F w/ abdominal pain, bloating, and fatigue HT: 87% Wt: 97% Sibling HT: 57% Wt 75% tTG>100, EGD confirms CD Sibling tTG negative

25. 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

26. 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.

27. Prevalence In At Risk Groups In The US Family Members 1st Degree – 1:22 2 nd 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.

28. 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.

29. Who Should We Consider Testing? Hill, Ivor D., et al. JPGN 40.1 (2005): 1-19.

30. Thank You