Celiac Disease (CD)Diagnosis and Whom to Screen

Maureen Leonard MDFellow, MassGeneral Hospital for Children

Conflicts of Interest

• I have no conflicts of interest to disclose

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

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%

Serological Test Comparison

Fasano & Catassi NEJM 2012;367:2419-26

Initially Screen for IgA level;If < 7 send IgG DGP

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

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

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

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

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

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

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.

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):

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

• 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: cdgemm@mgh.harvard.edu

Whom To Screen

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

Decreased Height Velocity

BMI

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

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

Follow-up: 3 months on a GFD

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

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

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

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.

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.

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.

Who Should We Consider Testing?

Hill, Ivor D., et al. JPGN 40.1 (2005): 1-19.

Thank You