Navigating the Celiac Universe

Douglas S. Fishman, MD FASGE FAAPDirector, GI Procedure Suite Texas Children’s HospitalAssociate Professor of PediatricsBaylor College of Medicine

Disclosures•None

A little history

“Celiac disease is not seen in breast-fed infants and is rarely seen during the first year of life. In some cases there is a history of improper feeding, especially with large amounts of fats or with raw milk.”

-W. M. Marriott in Infant Nutrition, 1930

My timeline (20 years in 1 minute)•Residency interviews (“we don’t see it”)

•Pediatric residency in St. Louis‐March: Accepted GI fellowship GI (2nd year)

‐September: Landmark article on celiac disease

‐Week of Halloween: My first endoscopy

‐Gluten-free diet

•Fellowship to present: Pediatric Gastroenterologist

Goals1) Differentiate between celiac disease, wheat allergy, and

non-celiac sensitivity (screening and diagnostic options)

2) Discuss the implications of the gluten-free diet in children without celiac disease

3) Explain the “in’s and outs” of the gluten-free diet.

4) Describe resources for patients to assist in maintaining a gluten-free diet.

Spectrum of GFD•Patients with celiac disease

•Gluten-intolerant

•Gluten sensitivity

•Autistic spectrum

•Fad diet

•Athletic boost

Celiac Disease-definition• An immune-mediated enteropathy caused by a

permanent sensitivity to gluten in genetically susceptible individuals.

• Damage to the intestinal villi with blunting and intestinal inflammation

• Leads to malabsorption

Celiac definition

- Type 1 diabetes - Williams syndrome

- Down syndrome - Selective IgA deficiency

- Turner syndrome - First degree relatives of

individuals with celiac disease

• Occurs with gastrointestinal and non-gastrointestinal symptoms (some asymptomatic individuals), including subjects affected by:

Expanded definition• Occurs in genetically susceptible individuals

– DQ2 and/or DQ8 positive HLA haplotype is necessary but not sufficient

• A unique autoimmune disorder because:– both the environmental trigger (gluten) and the

autoantigen tissue Transglutaminase (tTG) are known

– elimination of the environmental trigger leads to a complete resolution of the disease

“Classic” Celiac Disease

Fifty years later

Gastrointestinal Manifestations(“Classic”)

•Most common age of presentation: 6-24 months

•Chronic or recurrent diarrhea

•Abdominal distension

•Abdominal pain

•Vomiting

•Constipation

•Irritability

•Failure to thrive or weight loss

Nutritional deficiencies in CD•Anemia

‐Microcytic (Iron) and Macrocytic (B12 and Folic Acid)

•Zinc and Copper

•Vitamin K

•Vitamin D and Calcium malabsorption

•Vitamin A and E

Atypical Manifestations•Dermatitis Herpetiformis

•Dental enamel hypoplasia

•Osteopenia

•Short Stature

•Delayed puberty

Atypical manifestations•Hepatitis

•Arthritis

•Infertility

•Migraines

•Epilepsy with occipital

calcifications

•IntussusceptionFishman et al. J Pediatr Gastroenterol Nutr 2010

Complications of Celiac Disease•Risk of autoimmune disease

•Intussusception

•Osteopenia-Osteoporosis

•Small bowel adenocarcinoma

•Lymphoma

Who gets celiac disease

•Healthy population: 1:133

•1st degree relatives: 1:18 to 1:22

•2nd degree relatives: 1:24 to 1:39

Fasano, et al, Arch of Intern Med, Volume 163: 286-292, 2003

~1%

Celiac Disease and Autoimmune Disorders•Evaluated 909 pts with CD for autoimmune disorders

‐Age at Dx < 2y 5.1%‐2-10 years 17%‐>10y 24%‐Healthy ctrls 2.8%‐Crohn’s 13%

•Prevalence of autoimmune disorders in celiac disease increased with increasing age at diagnosis

•Duration of exposure to gluten does influence risk of autoimmune disorders

Ventura et al. Gastroenterology 1999; 117: 297-303

Celiac Disease and Risk of T1DM

•Individuals with celiac were at an increased risk of ketoacidosis or diabetic coma

•No evidence to support that earlier introduction of gluten-free diet protective against subsequent TIDM

•GI symptoms were not predictive

•Children with T1DM should be “screened” at diagnosis and repeatedly during first 2 years

Ludvigsson et al. Diabetes Care, November 2006

Bybrant MC et al Scand J Gastroenterol 2013

Thyroid Disease, Adrenal Insufficiency, Infertility

•Both Hypo- and Hyper- Thyroidism (3-5%)

•Anectdotal reports of improvement of thyroid disease while on gluten-free diet

•Small series of Addison’s suggest up to 12.5% may have concomittant celiac disease

•Celiac disease found in 4-8% of women with infertility

Making the Diagnosis

Role of Serological Tests

•Identify symptomatic individuals who need a biopsy

•Screening of asymptomatic “at risk” individuals

•Supportive evidence for the diagnosis

•Monitoring dietary compliance/inadvertantexposure?

Serological Tests

•Anti-gliadin antibodies (IgA and IgG-AGA) and deaminated gliadin

•Anti-endomysial antibodies (IgA-EMA)

•Anti-tissue transglutaminaseantibodies (IgA-tTG)

NASPGHAN consensus statement

Celiac Test Costs•Dozens of companies

•Some hospitals run serologic tests internally

•Basic testing for ~ $100

• Full panels including HLA ranges from $250-1600

Pitfalls of serological testing•10% of patients with CD have a normal tTG

•3% of patients with CD have abnormal IgA level rendering the tests inadequate

•IgA tTG can be elevated for other reasons:‐Cell turnover, Apoptosis

‐T1D, Hashimoto’s thyroiditis, IBD

•Not validated as a marker for screening

TTG post-diagnosis (Leonard et al.)•1 in 5 pediatric patients treated with a GFD for a median of 2.4 years had persistent enteropathy (M3)

•At the time of the repeat biopsy ‐tTG was elevated in 43% of cases with persistent enteropathy

‐tTG was elevated 32% of cases in which there was mucosal recovery.

‐Overall PPV of the tTG was 25% and NPV was 83% in patients on a gluten free diet for a median of 2.4 years.

•These findings suggest revisiting the monitoring and management criteria of celiac disease in childhood.

HLA DQ2 and DQ8•DQ2 allele present in 95% of patients with celiac disease

‐30-40% of Western populations carry DQ2

•DQ8 present in remaining 5%

•HLA testing is not appropriate for initial screening

•Not really “celiac genetics” or the “gene for celiac disease”

Current NASPGHAN Guidelines•Tissue Transglutaminase IgA and total IgA level

•No initiation of gluten-free diet until labs and endoscopy

•Evaluate first degree family members with TTG

•European society suggests symptomatic patient: tTG-IgA> 10 ULN and DQ2/8 positive

‐Requires EMA positivity at a second time point

‐Not for young children

Diagnosis of Celiac Disease in 2018•Abnormal serology (TTG or EMA)

AND

Abnormal histologic features by endoscopy

OR improvement on diet***

Need 2 of 3

Patient 1-ANYTOWN, USA

‐Tissue Transglutaminase IgA (TTG-IgA): 18

(positive>8 U/mL)

‐Serum IgA: 183 (81-463 mg/dl)

‐Gliadin IgA Antibody 55 (positive >17 U/mL)

‐Endomysial IgA (EMA-IgA): 1:40 (negative)

Patient 2- 10 y/o female

‐Tissue Transglutaminase IgA: <3 (positive>8)‐Serum IgA: 183 (81-463 mg/dl) ‐Gliadin IgA Antibody negative (positive >17)‐Gliadin IgG Antibody 55 (positive >17)‐Endomysial IgA: negative (negative)

–? Family history, symptoms, endoscopic findings–? HLA–Food allergy testing?–tTG-IgG? (3% positive predictive value)

Patient 3- 10 y/o male‐Tissue Transglutaminase IgA: <3 (positive>8 U/mL)

‐Serum IgA: 5 (81-463 mg/dl) ‐Gliadin IgA Antibody negative (positive >17)‐Gliadin IgG Antibody 55 (positive >17)‐Endomysial IgA: negative (negative)‐Other tests? ‐HLA?

From the “biopsy” dissenters•Does it change you management?

•I feel better on the diet so why does it matter

•Expensive

•Risk

Favoring Biopsy•Provides definitive diagnosis or other diagnosis

‐Very rare to “challenge” a patient

•Enrollment in studies, stratification

•tTG issues; monitoring autoimmunity

•Endoscopy is “relatively safe” and efficient

•Insurance, taxes and stipends?

Endoscopic Findings

NodularityScallopingNormal Appearing

Scalloping

Capsule Endoscopy

Capsule Endoscopy: Celiac

Endoscopy and Histology

Normal Duodenum 40xVilli

Post-biopsy•Strict gluten-free diet (no other therapy)

•Consider short term lactose elimination

•Screen first degree family members

•Give support group information

•Dietician visit

Gluten Sensitivity•Gluten reaction in which allergic and autoimmune mechanisms are excluded

•Negative immuno-allergy tests to wheat

•Negative EMA and/or tTG serology

•Negative duodenal histopathology

•Resolution of symptoms following GFD (double blind)

Sapone et al. BMC Medicine 2012

Non-celiac wheat or gluten sensitivity (NCGS or NCWS)•Symptom overlap with celiac disease:

•Resolves with gluten removal

•Alaedini at Columbia reported gluten did trigger a systemic immune reaction and accompanying intestinal cell damage

Gluten causes symptoms in IBS patients•RCT: 45 IBS-D patients (+DQ2/8 and –DQ2/8)

•Several parameters improved on GFD related to intestinal permeability

•RCT: 34 patients (19 GFD vs 15 GCD)

•Increase in symptoms in one week with gluten:‐Overall symptoms

‐Pain, bloating, stool consistency, tirednessBiesierski et al. Am J Gastroenterol 2011; 106: 508

Vazquez‐Roque et al. Gastroenterology 2013

Gluten mediated antibodies in autism?•Higher levels of anti-gliadin IgG compared with unrelated healthy controls (p<0.01).

•Anti-gliadin IgG response was greater in the autistic children with GI symptoms (p<0.01).

•No difference in gliadin-IgA, antibodies to deamidated gliadin and TTG2, or HLA

•A subset of children with autism displays increased immune reactivity to gluten

Lau et al. PLOS One 2013

Gluten-free diet in autism•Only two small randomized controlled trials

•35 patients

•Three significant effects in favor of diet included: overall traits, social isolation and ability to communicate

•No harm

•Conclusion: Evidence for efficacy is poorCochrane Database Syst Rev 2008

“What do you call someone who puts gluten in your food?”

http://glutenfreeoptimist.blogspot.com/2009/02/gluten‐free‐jokes.html

A Villi‐ain

What is gluten?•Protein found in:

‐Wheat (gliadin)

‐Rye (secalin)

‐Barley (hordein)

•Obvious sources (pastas, breads)

•Hidden sources (malt, candy, sauces, imitation meats)

Not-so Hidden ingredients•Soy Sauce

Lone Star State Lookouts•Blue Bell Ice Cream

Other Lone Star Lookouts•Mammasitos?

‐Tex-Mex with soy sauce in marinade

•Corn tortillas with added wheat flour

•Low gluten?

Gluten-Free Grains•Amaranth

•Arrowroot

•Buckwheat

•Corn

•Flax

•Millet

•Quinoa

•Rice, Tapioca

•Sorghum

•Soy

What about oats?

Oats•3 different oats

•12 samples

•9/12 had >20 ppm

•All had one assay ‐Above 200 ppm

Thompson T NEJM 2004; 351: 2021

Oats in Italy•Double blinded randomized controlled trial

•177 patients with celiac disease (oats or placebo)

•No differences in BMI, GI symptoms, serologies or intestinal permeability

•Non-reactive oats are safe for a gluten-free diet

J Pediatr 2018. Lionetti E et al.

Grains to Avoid• Durham wheat• All purpose flour• White enriched flour• Wheat flour• Wheat germ• Wheat starch*• Wheat bran• Bulgar• Graham• Kasha

• Kamut• Spelt• Triticale• Matzah• Rusks• Semolina• Farina• Eikorn• Emmer• Farro

CELIAC DISEASE AND GLUTEN-FREE DIET:IN THE INTERNET AGE

Recent food labeling laws•2004- FALCPA (8 allergens)

•2008 CODEX Alimentarius‐20 ppm vs 200 ppm

•2012 Appropriate use of terms:‐Gluten-free

‐Risk for cross-contamination

•2014; 20 ppm required for GF labeling

Which way are we going?

How much for a loaf of bread?

Regular price $2.49•7 cents/ounce

Gluten-Free price $4.99•30 cents/ounce

Age of Onset and Introduction of Gluten•Sweden - Andersen, et al.

Era Onset Gluten intro‐1950-1952 43 m 9.4 m‐1968-1969 9 m 3.4 m

•London – 1975 recommendation to delay introduction of gluten until 4-6 m led to apparent decrease in incidence – possible delay in onset

•Breast-feeding may be protective

Timing of Gluten Introduction•Controversial

•Timing of gluten exposure

•Amount of gluten exposure

•Breast-feeding

•Hoffenberg (JAMA, 2005), in a prospective study from 1994-2004 describes an increased risk based on timing of gluten-exposure

Gluten Introduction, JAMA•1560 children at risk for celiac or diabetes based on HLA markers or family history

•51 children developed CDA

•5-fold increased risk in children fed gluten before 3 months of age compared to those at 4-6 months of age

•Slight increased risk for those 7 months and older at time of first exposure (71%) compared to those introduced to gluten at 4-6 months (59%)

Concerns •Only 51 patients developed celiac disease (of 1560)

•Of those only 3 were exposed to gluten before 3 months of age

•Only 25 had biopsy proven celiac disease

•Failed to show any difference in breast feeding as a protection as seen in several other studies

•Mean f/u 4.8 years

Breastfeeding and Gluten Introduction•Prospective infant feeding data on 9414 children

•22 mothers with celiac disease

•63% of children breastfed for at least 9 months

•60% of children exposed between months 5 + 6

•No association between maternal CD and early weaning

JPGN Feb 2014, Welander et al.

More feeding and risk of celiac disease•Prospective cohort of 107,000 Norwegian children

•324 children with CD

•Delayed gluten introduction after month 6 was associated with higher rate of developing celiac disease (1.27 Odds Ratio)

•Breastfeeding more than 12 months was also associated with an increased risk of celiac disease (1.5 Odds Ratio)

Pediatrics 2013, Stordal K et al.

So where are we?•Multicenter DBRCT with 944 patients +DQ2 or DQ8

•From 16 to 24 weeks of age received 100mg of gluten vs. placebo

•Celiac disease in 77 patients

•5.9 vs. 4.5% by age 3 (similar)

•Breast feeding did not influence development of CD

Vriezinga et al. NEJM. October 2014

More in Age of Introduction Study•N=6436 prospective births

‐Gluten introduction before 17 weeks or later than 26 was not associated with increased risk for positive TTG or CD

‐Time to first introduction-not an independent risk

•N=13279 Swedish children‐Reduced prevalence of celiac disease based on introduction of gluten (small amounts) during breast feeding

Aronsson et al. Pediatrics 2015Ivarrson et al. Pediatrics 2015

Any Conclusions?•Early gluten exposure before 4 months or after 6 months may increase risk

•Breast feeding likely protective, but for how long?

•At this time, introduction around 5-6 months of age seems appropriate~ No clear recommendations

•Case by case

Gluten-Free First Steps•Become the expert and educate

•Make a list of all favorite foods

•Start investigating (read labels, ask questions)

•Trust other experts

•Consult a dietician

Celiac Websites•Celiac.com

•NASPGHAN.org

•Gikids.org

•beyondceliac.com (Celiac Disease Foundation)

GIKIDS.org

Celiac Disase Foundation

www.gigcstx.org

houstonceliacs.org

Gluten Free Expos

Celiac Welcome Pack-U of Chicago

www.cureceliacdisease.org/educational_essentials_kit/screener/

Iphone Apps

More Apps

Taking the diet home:Getting “grainular”•Decide if whole family GF or just patient

•Buy a breadmaker or mixer

•Partition a section of pantry

•Label containers

•Minimize cross-contamination (new colanders)

Barriers to Compliance•Diet too restrictive

•Uncomfortable in social setting

•Too difficult

•Tasteless

•Too expensive

School Daze•Discuss with teacher

•Pack lunch and check school lunch calendar

•Have/Send treats for parties, special events

•Good hand-washing

•No Play-Doh

Gluten Free Travel Tips•Hotels, Condos with Kitchen and Refrigerator

•Check the map for potential stops

•Check with local support groups for restaurant recommendations

•Pack favorite non-perishables (snack bars)

More Travel Trips•Buy fresh produce when you arrive (Farmer’s market)

•Have a picnic

•Walt Disney

•International travel

Gluten-free Austin

Gluten-free Napa

Gluten-free New Zealand

Gluten-free Scandinavia

Brisbane, Queensland, AUS

Final thoughts•Celiac disease can present with atypical symptoms

•Gluten intolerance and sensitivty can overlap

•Screening family members is recommended

•Gluten-free diet to begin only after biopsy

•GF diet more accessible, but more challenging?

Future questions•When to introduce gluten in infancy?

•New treatment options?

•Role of HLA testing?

•Do we still need endoscopy and histology for diagnosis?

Thank you! •NASPGHAN

•Mark Gilger and Waqar Qureshi (Baylor)

•Maureen Leonard (MassGeneral Hospital for Children)

To refer a patient 832-822-1050 LBJ Library 2015

Email douglas.fishman@bcm.edu

Follow on twitter @celiacuniverse