Challenges with Celiac Disease and Gluten Intolerances
Matthew R. Riley, MD Northwest Pediatric Gastroenterology Portland, OR Objectives
Differentiate celiac disease from other wheat-related ailments. Be aware of the cost, appropriate use and limitations of available screening tests for celiac disease. Discuss emerging therapeutic options for celiac disease. State how to provide family-centered support for those affected by celiac disease and other gluten intolerances. Wheat-related conditions
Celiac Disease Wheat Allergy Non-Celiac Gluten Sensitivity Fructan Sensitivity
Why do I care? Why should my patients care?
Treatment differs Long term follow up and Gluten elimination testing differs Wheat elimination Mandated follow up vs. Gluten minimization prn Fructan minimization Child-specific Medication Final adult height Long term prognosis Bone density differs School accommodations Family risk differs Self-identity and eventual autonomy Screening? Celiac Disease What is celiac disease?
Permanent, autoimmune enteropathy caused by an abnormal immune response to gluten proteins in genetically susceptible individuals
Previously known as celiac sprue, gluten-sensitive enteropathy
Celiac Disease What are the symptoms?
“Classic”: young child with diarrhea, abdominal distention, failure to thrive, irritability “Atypical”: any other symptom(s) known to be caused by celiac disease, esp. non-GI symptoms
Short stature Dental enamel hypoplasia Pubertal delay Refractory iron-deficiency anemia Osteopenia Arthritis Hepatitis Neuropathy Fatigue Asymptomatic/Silent Celiac Disease Who gets celiac disease?
About 1-2% of the world population Almost all of whom are DQ2 or DQ8 positive Increased risk (>4%) Down, William and Turner syndromes IgA deficiency Type I Diabetes Autoimmune thyroiditis 1st degree relatives of a celiac
Celiac Disease Gliadin
TTG Cytokines (IL2, IL15) Tk
P T APC AGA, EMA, B TTG IgA How is celiac disease diagnosed?
Must show immunologic process (abnormal serology) Multiple serologies available, few are helpful Must show intestinal damage (enteropathy) Requires endoscopy Marsh grading system
Celiac Disease Celiac serologies
Tissue Transglutaminase IgA Sensitivity >90%, specificity >90% Highly reproducible Endomysial IgA Sensitivity >90%, specificity >98% More user-dependent Confirmatory test in Type I Diabetes Tissue Transglutaminase IgG Less sensitive/specific Can be used in the setting of IgA deficiency
J Pediatr Gastroenterol Nutr. 2012, 54(2) Celiac Disease Anti-gliadin antibodies
Antibody Sensitivity Specificity Accuracy Gliadin IgG 42% 90% 69%
Gliadin IgA 63% 90% 79%
Deamidated 65-98% 80-97% 84% gliadin IgG Deamidated 74-95% 86-95% 86% gliadin IgA
Most Oregon labs only offer deamidated gliadin antibodies.
Clin Gastroenterol Hepatol, 2008, 6(4) Celiac Disease J Pediatr Gastroenterol Nutr. 2012, 54(2)
Celiac serologies
Beware the ‘celiac panel’ or ‘celiac reflex panel’ Can include a variety of unneeded serology May reflex to unneeded HLA-typing Positive anti-gliadin antibodies with negative TTG May lead to unnecessary worry and specialty referrals Not cost-effective for patient (? for lab ?)
Celiac Disease Thinking about cost
Ordered test Included components Cost IgA IgA $49 TTG IgA TTG IgA $79-85 Gliadin IgA/IgG DGP IgA, DPG IgG $71-109 EMA IgA EMA IgA $80-125 TTG IgG TTG IgG $85-123 TTG Antibody Panel TTG IgA, TTG IgG $150 Celiac Disease Profile IgA, EMA IgA, TTG IgA $272 Celiac Disease Profile II, Celiac IgA, EMA IgA, TTG IgA, TTG IgG $149-499 Silver Panel Celiac Gold Panel, Celiac Disease IgA, EMA IgA, TTG IgA, TTG IgG, DGP IgA, DGP IgG $179-189 Comprehensive HLA DQ 2/8 HLA DQ 2/8 $284-761 Celiac histopathology: Marsh
Normal 0 Infiltrative 1 Hyperplastic 2
Partial atrophy 3a Subtotal atrophy 3b Total atrophy 3c Celiac Disease Diagnostic Pitfalls
Pre-treatment with gluten-free diet Within a few weeks, mucosa can start to heal Could improve histology to Grade 1 or 2 Well-treated celiac disease looks like no celiac disease +TTG IgA + Marsh 0-1 OR –TTG IgA + Marsh 1 Evolving celiac disease? Simple false-positive screening? Non-specific finding?
Celiac Disease Celiac disease and HLA-typing
HLA alleles associated with Celiac Disease DQ2 found in 95% of celiac patients DQ8 found in remaining patients DQ2 found in ~30% of general population DQ8 found in ~10% of general population Value of HLA testing High negative predictive value – Negativity for DQ2/DQ8 excludes diagnosis of Celiac Disease with 99% confidence
Celiac Disease Celiac disease and HLA-typing
General population
DQ2 or DQ8 positive
Celiac disease
Celiac Disease Celiac disease and HLA-typing
Having DQ2 or DQ8 does not mean you have disease Having DQ2 or DQ8 means that you are part of the 40% of the world that may one day develop celiac (and a host of other diseases) Can lead to unnecessary testing or worry May decrease need for regular blood testing for at- risk populations (e.g. Type I diabetes) Often not covered by insurance: genetic testing
Celiac Disease
Other tests Stool testing Just Food-specific IgG tests say Trial of gluten-free diet “No!”
Celiac Disease Associations
Trisomy 21 (Downs syndrome) Autoimmune thyroiditis (Hashimoto’s thyroiditis) Dermatitis herpetaformis Autoimmune hepatitis Type I diabetes mellitus
Celiac Disease Wheat Allergy IgE-Mediated Wheat Allergy
Immune-mediated reaction to food protein Food allergies are most common in first year of life Wheat is among top 10 most common food allergens Allergy to albumin, globulin, gliadin or gluten in wheat
Wheat Allergy Symptoms of Wheat Allergy
Abdominal pain, nausea, vomiting, rash, rhinitis, conjunctivitis, oral allergy syndrome Must be reproducible General poor reliability between parents’ report of suspected allergen and objective findings
Wheat Allergy Diagnosis of Wheat Allergy
Wheat-specific IgE Sensitivity: 20% / Specificity: 93% Skin prick testing Sensitivity 23% / Specificity: 100% Patch testing Sensitivity 86% / Specificity 35% Double blind food elimination and challenge GOLD STANDARD
Wheat Allergy Associations
Can also be allergic to grain with similar proteins: Barley, oat, rye Baker’s asthma Asthma-like reaction of inhalation of uncooked wheat flours Can usually tolerate ingestion of cooked wheat Wheat-dependent exercise-induced anaphylaxis Anaphylaxis with exercise or aspirin ingestion within a few hours of eating wheat
Wheat Allergy Non-Celiac Gluten Sensitivity What is non-celiac gluten sensitivity?
Syndrome of gluten reactions in which both allergy and autoimmune mechanisms have been ruled out (not allergy, not celiac) Negative wheat-specific IgE Negative TTG IgA and/or EMA IgA Normal duodenal histopathology (if done) +/- positive anti-gliadin antibodies +/- positive HLA DQ2/8
Non-Celiac Gluten Sensitivity What are the symptoms?
Abdominal pain Eczema/rash Headache Mild cognitive impairment / ‘foggy head’ / focus problems Fatigue Headache Frequently vague, somatic Diarrhea symptoms that cannot be clinically Depression distinguished from celiac disease Numbness on a purely clinical basis Joint pain
Non-Celiac Gluten Sensitivity How is it diagnosed?
Diagnosis of exclusion Negative TTG IgA and/or EMA IgA Negative wheat-specific IgE Improvement with gluten-free diet
Non-Celiac Gluten Sensitivity Fructan Sensitivity What are fructans?
One of family of fermentable carbohydrates FODMAP: Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols Oligos: fructans, galactans Disaccs: lactose Monos: fructose Polyols: sorbitol, mannitol, xylitol, isomalt
Fructan Sensitivity What are fructans?
Chains of fructose molecules Those with short chains are fructooligosaccharides Those with long chains are called inulins Both are soluble fibers
Fructan Sensitivity Where are fructans?
They occur in many plants Energy storage Confer tolerance to freezing Used as dietary fiber supplements Beans, Onions, Garlic, Peas, Artichokes, Asparagus, Leeks, Wheat, Rye
Fructan Sensitivity What happens to fructans?
Fructans are frequently incompletely digested in the small intestine Residual fructans are delivered to the colon and fermented by colonic bacteria Can result in excessive flatulence, bloating, constipation, diarrhea, nausea, abdominal pain Sensitivity can vary widely!
Fructan Sensitivity Diagnosis of Fructan Sensitivity
Usually empiric Rule out celiac disease and wheat allergy ?Fructose breath test
Fructose Breath Test 30
20 Hydrogen 10 Methane
Parts per millionper Parts 0 0 30 60 90 120 150 180 Minutes after ingestion Fructan Sensitivity Associations
Frequently part of irritable bowel syndrome Frequent sensitivities to other FODMAPs, especially in combination Other functional GI disorders Functional dyspepsia Other chronic pain syndromes Insomnia Migraines
Fructan Sensitivity Treatment What to avoid Levels of tolerance Length of therapy Treatment of Celiac Disease
<20ppm gluten Wheat (gliadin), rye (secalin), barley (hordein) Lifelong Wheat-free foods are NOT necessarily gluten-free
Celiac Disease Gluten and the FDA
2004: Food Allergen Labeling and Consumer Protection Act of directed HHS to define and permit the use of the term "gluten- free" in the labeling of foods Final rule defines "gluten-free" as meaning: The food either is inherently gluten free (e.g. rice) Or does not contain an ingredient that is: 1) a gluten-containing grain (e.g. spelt wheat); 2) derived from a gluten-containing grain that has not been processed to remove gluten (e.g. wheat flour); or 3) derived from a gluten-containing grain that has been processed to remove gluten (e.g. wheat starch), if the use of that ingredient results in the presence of 20 parts per million (ppm) or more gluten in the food. Also, any unavoidable presence of gluten in the food must be less than 20 ppm.
Celiac Disease http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm362510.htm Gluten and the FDA
Does this apply to restaurants? YES What about oats? Must contain <20 ppm to be labeled gluten-free. What about cross-contact? Must contain <20 ppm to be labeled gluten-free. No specific testing mandated. Compliance by summer/fall 2014 Does not apply to drugs
Celiac Disease Future Directions of Treatment of Celiac Disease Gliadin
TTG Cytokines (IL2, IL15) Tk
P T APC AGA, EMA, B TTG IgA Future Directions of Treatment of Celiac Disease
Genetically modified gluten: decreases gluten exposure by transamidation of gluten Zonulin inhibitor: larozotide acetate-decreases zonulin secretion and inhibits intestinal permeability, going into Phase III trials; preliminary data in celiac patients shows fewer symptoms after intentional gluten ingestion
Celiac Disease Future Directions of Treatment of Celiac Disease
Tissue transglutaminase inhibitors: stop TTGs from modifying gluten fragments, avoiding triggering an immune response Therapeutic vaccine: Nexvax2: creates immune tolerance to gluten fragments and desensitizes celiac patients to their T-cell response to gluten; going into Phase IIa trial Probiotics: Lactobacillus fermentum, Bifibobacterium lactis-detoxify gliadin and promote intestinal healing
Celiac Disease Treatment of Non-Celiac Gluten Sensitivity
Avoid/minimize gluten ? Amount ? Duration No known additional side effects if diet is not strict
Non-Celiac Gluten Sensitivity Treatment of Wheat Allergy
Wheat elimination Gluten-free foods are wheat-free Anti-histamines Epinephrine Medical identification bracelet for anaphylaxis
Wheat Allergy Treatment of Fructan Sensitivity
Avoidance of high-fructan foods Artichokes, asparagus, Brussel sprouts, broccoli, cabbage, fennel, garlic, leeks, okra, onions, peas, shallots Wheat, rye Chickpeas, lentils, kidney beans Watermelon, peaches, persimmon Small amounts may be OK Beware combination of foods with other FODMAPs
Fructan Sensitivity Health Maintenance for Celiac Disease
NASPGHAN guidelines (2005) “periodic assessment by physician and nutritionist” Repeat TTG IgA by 6 months Yearly f/u if asymptomatic American Dietetic Association (2009) Strong recommendation for RD consultation Check vitamin and mineral levels (folate, ferritin, thiamin, Vitamin B12, B6, D, zinc, copper, lipid profile, electrolytes) Supplement calcium and Vitamin D in those with reduced bone density or low 25-OH Vitamin D level Daily multivitamin if diet intake shows nutritional inadequacies
Journal of Pediatric Gastroenterology and Nutrition, 40:1-19, Jan 2005 Celiac Disease American Dietetic Association, 2009 Health Maintenance for Celiac Disease
American College of Gastroenterology (2013) Referral to RD Test iron, folic acid, vitamin D, Vitamin B12 (low level of evidence) Periodic medical follow-up, including verification of normalization of lab abnormalities American Gastroenterologic Association (2004) Follow-up at regular intervals, with periodic visits with physician and dietician
American Journal of Gastroenterology 2013: 108:656-676 Celiac Disease Health Maintenance for Celiac Disease
How are we doing? Not great… Study of 122 patients in Olmstead County, MN with biopsy-proven celiac disease
by 1 year after Dx By 5 years after Dx Had f/u visit 41% 88.7% Assessed for compliance 33.6% 79.8% Met with RD 3.3% 15.8% Repeat serology 22.1% 65.6%
Clin Gastroenterol Hepatol 2012;10:893-899 Celiac Disease Celiac and Hepatitis B Immunity
Park et al.—2007 26 children with celiac disease + control group, all previously immunized 53.9% of celiacs were HBsAb negative vs. 11% of controls Ertem et al—2010 63 celiac patients on strict GFD + control group 32.5% of celiacs were HBsAb negative vs. 14.8% of controls 96.4% of HBsAb negative celiacs seroconverted after prospective immunization
J Pediatr Gastroenterol Nutr. 2007 Apr;44(4):431-5. Celiac Disease Eur J Gastroenterol Hepatol. 2010 Jul;22(7):787-93
Health Maintenance for Celiac Disease
My practice Referral to knowledgeable RD at time of diagnosis Repeat serology Q3-4 months until normal or stable low value, then Q12 months Follow up in 3 months, 6 months, yearly Monitor growth, adherence, developmentally- appropriate guidance Baseline CBC, CMP, Vitamin D, HBsAb Daily gluten-free multivitamin TTG IgA for parents, siblings >2 years of age
Celiac Disease
Take Aways
Not everything wheat/gluten-related is celiac disease. If you’re thinking celiac, check TTG IgA + IgA. Non-celiac gluten sensitivity is real, but difficult to diagnosis. Don’t forget about irritable bowel syndrome and FODMAPs. Celiac disease is a chronic inflammatory disease and needs regular follow up and monitoring. Additional Resources
North American Society for Pediatric Gastroenterology, Hepatology and Nutrition: www.gikids.org Celiac Disease Foundation: www.celiac.org American Academy of Allergy, Asthma & Immunology: www.aaaai.org/conditions-and-treatments/allergies/food-allergies.aspx American College of Gastronterology Patient Education Center: www.patients.gi.org International Foundation for Functional Gastrointestinal Disorders: www.iffgd.org Monash University low FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap/diet.html U.S. Food and Drug Administration http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryI nformation/Allergens/default.htm