1. Who Am I?

2. Where I’ve Been High School: Roncalli HS, Manitowoc, WI
College: Marquette University, Milwaukee, WI
Med School: University of Toledo, Toledo, OH
Pediatrics Residency: MetroHealth Hospitals, Cleveland, OH
Fellowship in Peds GI: University of Maryland, Baltimore, MD

3. What I Love

4. What I Do

5. Where I Work
Starting Oct 2017
Starting Jan, 2018

6. Who I Serve

7. Celiac Disease: What You Need to Know
Douglas Zabrowski, MD
Pediatric Gastroenterology
9/19/2017

8. Topics NOT Discussed Gluten Sensitivity
In-depth discussion of possible neurological symptoms linked to gluten

9. Definition
A Chronic small-intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals
First described in 1888 by Samuel Gee, but not linked with gluten protein from wheat/rye until the 1950s

11. Background
Gluten is comprised of polymeric glutenins and monomeric gliadins w/ gliadins being the toxic element
Glutenins can be immunogenic as well
Wheat, rye, barley all contain gliadins
Oats have close taxonomic relation to wheat and have shown no microscopic or serologic effect on disease, but many patients are sensitive to it (?contamination?)
Rice & corn are okay & often used as substitutes

12. Epidemiology
Prevalence of 1:1000, and women>men, but overall underdiagnosed
Sweden 1:250, Denmark 1:4000
up to 1% of the population in some parts of the world
Many new diagnoses are through screening of asymptomatic at-risk individuals
Incidence however is increasing beyond anticipated change of improved detection
High concordance rates in monozygotic twins (75%) & siblings
Risk of CD in 1st degree relatives is 10%
30% if HLA-identical (Chromosome #6)
Recent evidence does NOT support strong link between breastfeeding or time of gluten introduction and Celiac disease

13. Genetics
HLA-DQ2 + in ~95% of CD patients, but + in 20-40% of healthy controls
HLA-DQ8 + in ~4-5% of CD patients, but can be in healthy controls as well
Originally thought <1-2% of CD (-) for both, but experts believe that it is unlikely that CD can be present without these markers due to pathogenesis
HLA on CELIAC1 locus seem to be necessary for CD
may be responsible for gliadin antigen presentation to T-cells
changes in other gene loci also needed (CELIAC2-4 on cr5/2/19 respectively)
Association w/ DM-1 and other autoimmune diseases that share the HLA loci

15. Pathology
T-cell mediated disease that affects superficial mucosa down to lamina propria
Gliadin is resistant to digestion and is able to activate both innate & adaptive immunity
Gliadin is cleaved by tTG-2 into fragments more immunogenic to T-cells triggering anti-gliadin responses
tTG-2 is inactive in normal conditions and the mechanism of its activation is unclear
Speculative evidence that rotavirus may increase risk of CD
one of its proteins shares homology with tTG
there is correlation with the seasonality of birth month
Activation pattern is TH-1 predominant with interferon-gamma
includes pro-inflammatory cytokines IL-6/18/21
Downstream activation of metalloproteinases and factors of angiogenesis lead to prototypical histology findings

16. Pathology
There is migration of lymphocytes to the epithelium which lead to apoptosis signaling and villous atrophy
Anti-tTG antibodies produced by gut mucosa
reduce tTG-2 activity
interfere w/ epithelial cell differentiation
promote proliferation
speculated that circulation of these Abs leads to systemic manifestations
This process upregulates tTG-2 and further gliadin cleaving exposes the antigenic sites, thus increasing presentation to T-cells and auto-antibody production (theoretical)
Auto-antibodies to actin, calreticulin, enolase, and ATP Synthase have been found in CD, but with unclear significance

18. Endoscopy
Visible changes: scalloping, atrophic patches, mosaic appearance, fissuring
Histology: changes alone are not specific to CD
CMSPA, intractable diarrhea of infancy, Giardia, HPylori, Crohn’s, Peptic disease, immunodeficiency, tropical sprue, lymphoma, CVID, and SBBO have to be considered
Requires establishing a gluten-dependent link to the lesions

22. Presentation
Toddlers: most commonly FTT, chronic diarrhea/steatorrhea, vomiting, abdominal distention, anorexia, irritability
Classic symptoms: vomiting, GERD Sx, diarrhea, constipation, erratic BMs, bloating, steatorrhea
Older children may present with solely extra-intestinal manifestations or be clinically silent
EIMs due to either circulating auto-ABs (theory) or to malnutrition

24. Extraintestinal Manifestations
Iron-Deficiency anemia (8.5% of adults w/ anemia resistant to Iron Tx have CD)
Difficult-to-treat Fe-deficiency anemia should be screened
Elevated transaminases: 9% of cases of cryptogenic transaminitis
Short stature (up to 10% of children with this have CD)
Vitamin deficiencies: D, B12, B6, zinc (macrocytosis often masked by Fe-Deficiency)
Dermatitis Herpetiformis
subepidermal IgA deposits, symmetric blistering rash, Tx w/ GFD + Dapsone
Osteopenia (higher chance of normalizing if GFD adopted in youth)
Arthritis/Arthralgias
Headaches

25. Less Common Manifestations
Epilepsy
Infertility, difficult/premature pregnancy, delayed puberty
Early Atherosclerosis
Recurrent aphthous stomatitis
Hyposplenism
Enamel Hypoplasia
Fatigue
Alopecia areata

26. Associations
CD pts have higher childhood rates of Learning disorder, ADHD, Dev Delays, Psychiatric illness
Not responsive to GFD, effect of GFD closer to onset of Sx unclear
No clear mechanism
Associated diseases: AI Thyroid disease, Addison’s, pernicious anemia, AIT, sarcoidosis, DM-1, alopecia, AIH, PBC
10% of pts w/ DM-1 have CD, CD pts have 2.4xrisk of DM-1
7% of pts w/ AI thyroid disease have CD, CD patients have 4xrisk of AI thyroid disease
WHY? There are some shared HLA haplotypes, but some evidence of increased risk of AI disease with longer duration of gluten exposure
Patients with Downs, Turner’s, Williams, and IgA Deficiency all have increased incidence of CD

27. Diagnosis - Serology
Anti-endomysial (EMA), anti-deaminated gliadin (DGP), and Anti-tTG antibody ELISAs have high specificity and sensitivity for CD
IgA endomysial ABs – sensitivity 85-98% (88-100); specificity % (91-100)
IgA tTG-2 ABs – sensitivity 90-98% (92-100); specificity 95-97% (91-100)
IgA deamidated gliadin peptide – sensitivity 94% (66-72); specificity 99% (92-97)
IgG deamidated gliadin peptide – sensitivity 92%; specificity 100%
Anti-tTG IgA is firstline screen and EMA can be used for equivocal results
EMA may be more sensitive in patients with known AI disease
Anti-endomysial Abs against monkey esophagus or human umbilical cord
Reacts to tTG and is a very specific marker of mucosal damage in untreated patients
Very operator-dependent
Positive tTG IgA or EMA with negative biopsies is still a risk for future development of CD (Potential Celiac)

28. Diagnosis – Serology IgA deficiency must be ruled out concurrently
IgA deficiency present in up to 2% of CD patients, rare in general population
If known to be IgA deficient, anti-tTG & anti-endomysial IgG levels are recommended
DGP ABs are more specific in children <4yo than tTG Abs (not true in adults)
As all these antibodies are produced in gut mucosa, negative results may still miss mild disease without spillover into serum
2-3% of CD patients have serologies that are (-), low +, or fluctuate
Rapid/Point of Care tTG IgA testing screens are being developed

29. Disease Prediction by Antibodies
Positive Likelihood Ratio
Negative Likelihood Ratio
Odds Ratio
EMA/IgA
31.8
( )
0.067
( )
553
( )
Anti-TG2/IgA
21.8
( )
0.060
( )
469
( )
Anti-DGP/IgG
13.6
( )
0.061
( )
234
( )
Anti-DGP/IgA
9.4
( )
0.121
( )
86.1
(56-132)
AGA/IGA
7.3
( )
0.186
( )
40.6
(14-117)
95% confidence intervals in parentheses
Giersiepen, Evidence report, JPGN 2012

30. Diagnosis – next level
EGD with biopsy is the gold standard to confirm diagnosis
Diagnosis requires histological evidence and clinical remission on GFD
Biopsy to prove efficacy of GFD on mucosal healing is standard (6-12months)
Otherwise, only repeat EGD when symptoms relapse or if serologies increase
Important to consider screening at risk individuals, those w/ + 1st degree relative or other AI diseases
HLA-typing: Strong negative predictive value, low PPV
Often difficult to get insurance coverage
Limited utility
May be useful for screening asymptomatic at-risk individuals (if results are negative)

31. Gluten Challenge Many patients trial GFD prior to coming to PCP office
Testing may be falsely negative if following GFD
Due to long-term complications, establishing diagnosis is necessary
Challenge requires (at least 3g per day) for at least 2-3wks
If asymptomatic/negative screens, but high suspicion, challenge only recommended after 7yo, not during adolescent growth spurt

33. Treatment
Gluten free diet: no wheat, barley, rye, +/- oats. Maximum of <50g/day, though some patients require stricter restrictions as they can have symptoms on 50mg/day (food w/ <20ppm)
Difficult due to intensive, expensive diet, and requires education
Can lead to symptomatic nutritional deficiencies, constipation, and weight gain due to altered diet
Mucosal healing is better in children than adults, but no clear explanation

34. Treatment
Nondietary Tx is not currently available, but 2 drugs in Phase II trials
ALV003 (recombinant gluten-specific protease) – reduces the amt of mucosal injury on 6wk gluten challenge
Larazotide acetate (modulates intestinal tight junctions) – reduced symptoms in patients on gluten challenge
These are being targeted to help with chronic low-grade or intermittent gluten exposures

35. Treat All CD Patients
GFD recommended for CD even if asymptomatic to avert increased risk of
intestinal adenocarcinoma (80x baseline risk)
enteropathy-associated T-cell lymphoma (EATL)
malnutrition sequellae

37. Nonresponsive Celiac Disease (NRCD)
NRCD: symptoms and findings of CD despite 12-18mth on GFD
7-30% of CD patients
Most common cause: inadvertent or intentional gluten exposure
Normal serologies do not rule out gluten exposure
Other food intolerances such as FODMaPs may contribute
GI and Nutrition re-evaluation is most important to rule out Gluten exposure

38. Prognosis of CD
Increased malignancy risks, but these reduce to population baseline after 5yrs on GFD for responders
2-3x Increase in risk of Non-Hodgkin’s Lymphoma
10x risk of Small intestinal adenocarcinoma
Future research areas:
Non-immunogenic wheat strains
Pharmological targets: HLA-binding drugs that don’t activate T-cell receptors, Anti-IL10 agents, inhibition of gliadin antigen presentation, TG2 inhibitors
Inducing immune-tolerance to gluten

39. Takeaways
Have a high suspicion for Celiac in Autoimmune patients, Down’s, primary relatives and in those with short stature
1st degree relatives can be screened starting at 3yo and 1yr after 1st gluten exposure
Early detection and referral improves health outcomes

40. Takeaways
Screen patients 1-3yo with tTG IgA/IgG, DeAmidated Gliadin IgA/IgG, and Total IgA
Screen patients >4yo with tTG IgA and total IgA
EMA as an initial screen should be reserved for patients with known AI disease

41. References
Hadithi M, et al. Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease. Annals of Internal Medicine Vol 147, No 5.
UpToDate.com
Kelly C, Bai J, Liu E, Leffler D. Celiac Disease: Clinical Spectrum and Management, Advances in Diagnosis and Management of Celiac Disease. Gastroenterology ;148:
Guideline for Diagnosis and Treatment of Celiac Disease in Children: Recommendations of NASPGHAN JPGN 40:1-19.
ESPGHAN Guidelines for the Diagnosis of Coeliac Disease JPGN 54:1:
Hill ID, Fasano A, Guandalini S, et al. NASPGHAN Clinical Report on the Diagnosis and Treatment of Gluten-related Disorders JPGN 63:

42. Thank You!