Charles P.B. Vanderpool, MD Assistant Professor of Clinical Pediatrics Celiac Disease and Gluten Intolerance Separating the wheat from the chaff Charles P.B. Vanderpool, MD Assistant Professor of Clinical Pediatrics

Celiac Disease (CD) vs Gluten Sensitivity (GS) http://noglutensolution.com/?p=571

Objectives Celiac Disease (CD) Gluten Sensitivity (GS) Recognize classic, atypical, and extraintestinal manifestations of CD Identify appropriate screening and diagnostic testing for CD Gluten Sensitivity (GS) Define GS, including symptoms Discuss cause of GS and dietary interventions

Celiac Disease (CD) - Definition Autoimmune enteropathy Occurs in genetically susceptible individuals DQ2 or DQ8; ‘required’ but not sufficient Triggered by ingestion of gluten Permanent sensitivity to gluten Unique: Both autoantigen and trigger known Elimination of trigger results in cure of disease

QUESTION What is gluten? A. Carbohydrate component of wheat B. Naturally occurring preservative found in wheat, rye, barley C. Component of the protein found in wheat D. The unquestionable enemy of modern day society

What is Gluten? Gluten: Grain Starch Makes bread chewy, retain shape 60-70% Starch Protein Moisture Lipids Gluten: Makes bread chewy, retain shape Does not lose integrity in water Can serve as thickening agent Retains flavor – additive in processed foods Albumin Gluten Globulins WHAT EXACTLY IS GLUTEN???? Gluten itself is a protein, one of the components found in grain. Starch makes up the majority of grain, up to 60-70% of grain exists as starch. The protein source in grain is made up of albumin, golbulins, and gluten – of which gluten is the predominant form. Gluten is the part that makes bread chewy and retain its shape. It does not dissolve in water when wet or lose integrity. It can thus serve as a thickening agent and can also promote absorption. As such, it is often used as a filler for processed foods such as meat or an additive in foods to improve the protein content. Gluten is made up of equal parts of gliadins and glutenin polypeptides. Gliadins are monomers whereas glutenins form large polymeric structures. Gliadin Glutenin

CD – USA Statistics 1st degree relatives in large US study Prevalence increases from ~1% up to ~5% European studies have suggested a risk in 1st degree relatives ranging from 10% - 20% CDHNF/NASPGHAN slide set. www.naspghan.org From: A Fasano et al. Arch Int Med. 2003; 163: 286-292

Pediatric Celiac Disease Clinical symptoms observed have changed in era of blood testing for celiac disease (CD) Traditionally: CD thought of as a disease of young children Weight loss, diarrhea, abdomen swelling Now: shift from “Classic CD” to “Atypical” or “Silent” CD in older children

Pediatric Celiac Disease 2009 study from Canada 266 children diagnosed from 1990 to 2006 CD diagnoses increased fourfold Average age of diagnosis 1990 – 1996: 2 years old 2000 – 2006: 9 years old “Classic” CD decreased 1990 – 1996: 67% 2000 – 2006: 19% Antibody testing (IgA-EMA) for CD introduced in 1997 in this group Classic CD: diarrhea, weight loss Atypical CD: any GI symptom (pain, vomiting, constipation, diarrhea) without weight loss Extraintestinal CD: anemia, short stature, etc Silent: no symptoms McGowan et al. Pediatrics 2009; 124; 1572

CD - Clinical Manifestations Classic CD: common in ages 6 – 24 mo Chronic diarrhea, anorexia, failure to thrive Abdominal distension Celiac crisis: severe diarrhea, dehydration, hypotension, electrolyte abnormalities (hypokalemia)  now rare Atypical CD: Older children/Adults Chronic abdominal pain or bloating Diarrhea or constipation Recurrent nausea and vomiting Can be very similar to FGIDs (Functional GI Disorders)

CD in Pediatric FGIDs Symptoms can overlap IBS and FGIDs 2014 prospective cohort study of 782 children with FGIDs CD present in 4.4% children with IBS diagnosis No difference in weight or height percentiles between CD and FGIDs control Cristofori et al. JAMA Pediatr. 2014 June; 168(6): 555-60

Extraintestinal Manifestations of CD Dermatitis Herpetiformis Most common skin manifestation of CD More common in adults; less common pre-puberty Itchy, papular, vesicular eruption Elbows, knees, buttocks, trunk IgA deposition on skin biopsy Improves with GFD Intestinal biopsy not necessary www.naspghan.org DH estimated to occur in as much as 24% of adult patients with CD

Extraintestinal Manifestations of CD Dental enamel defects Involves secondary dentition May be only presenting sign of CD Symmetrically distributed Discolored opacities, loss of enamel, horizontal grooves, shallow pits www.naspghan.org

Extraintestinal Manifestations of CD Iron-deficiency anemia Thought to be most common extraintestinal manifestation Up to 8-10% of individuals with microcytic anemia unresponsive to iron therapy More common in teens and young adults No clear indication for CD screening in initial evaluation of children with iron deficiency

Other Extraintestinal Manifestations Short stature: up to 10% prevalence of CD Delayed puberty Osteoporosis: improves with GFD Hepatitis: nonspecific; improves on GFD Autoimmune hepatitis: associated condition Arthritis Neurologic: headaches, epilepsy (slight), developmental delay, cerebellar ataxia Recurrent stomatitis Many more described in case reports

Celiac and the Internet

CD – Diagnostic Principles A diagnosis of Celiac Disease should be confirmed without doubt Life-long Strict adherence to treatment (GFD) Significant quality of life implications Response to GFD ≠ CD Failure to adequately treat has serious health consequences

QUESTION What is the preferred initial diagnostic test for celiac disease in children? A. Tissue transglutaminase IgA (tTG IgA) B. Tissue transglutaminase IgA and IgG (tTG IgA and IgG) C. tTG IgA and endomysial antibody IgA (EMA IgA) D. Native gliadin peptide IgA (anti-gliadin IgA) E. Trial of gluten free diet, test only if symptoms improve

CD Serology Anti-tissue transglutaminase (anti-TG2 or tTG) High sensitivity, specificity; most cost effective Endomysial antibodies (EMA) Considered to have highest specificity Anti-deamidated gliadin peptide (anti-DGP) Have replaced antibodies to native or conventional gliadin due to low sensitivity and specificity Role in diagnosis of young individuals (< 2-3 yrs) HLA type Not used as a screening tool, may be useful in at-risk populations

CD - Diagnosis Who to consider testing: How to test: Total IgA level Individuals with the following unexplained signs: Failure to thrive Persistent diarrhea Recurrent abdominal pain Idiopathic short stature Pubertal delay (significant) Fe-def anemia unresponsive to Fe Unexplained/frequent bone fractures Dermatitis herpetiformis-like rash Recurrent aphthous stomatitis Individuals belonging to a high risk group Total IgA level Anti-tTG IgA level Refer to Pediatric GI for any positive test STRESS importance of continuing gluten in diet If IgA deficient & high suspicion, consider referral to Pediatric GI

Gluten Sensitivity (GS)

QUESTION Who on this list is gluten free because of actual celiac disease? A. Chelsea Clinton B. Miley Cyrus C. Lady Gaga D. Keith Olbermann

Question What is the suspected dietary cause of non-celac gluten sensitivity? A. Wheat-based protein B. Wheat-based starch C. Wheat-based lipid D. All of the above

Gluten Sensitivity (GS) Intestinal and non-intestinal symptoms related to ingestion of gluten-containing foods Not caused by celiac disease or wheat allergy Originally described in 1980s, exact prevalence unknown Majority of published data on GS within the last 5 years

Gluten Sensitivity in Children 15 children with GS, celiac disease excluded Gluten challenge (non-blinded) after GFD x 8 wks, continued for 2 wks GS symptoms – appeared within median of 44hrs Native antigliadin IgG positive in 66% (10/15) of children with GS 13% in controls, 86% in CD Rest of celiac serology negative in GS individuals Francavilla et al. J Pediatr 2014 Mar; 164 (3): 463-467

Gluten Sensitivity – the Data 2011 DBRPC rechallenge trial in 34 patients with IBS symptoms (CD excluded) 1 muffin and 2 slices of bread containing gluten or no gluten x 6 weeks Gluten group: worse control of symptoms, pain, bloating, stool consistency, tiredness NS: wind and nausea No mechanism elucidated CD antibodies, inflammation, permeability Biesiekierski et al. Am J Gastroenterol 2011; 106: 508-514

Does GS extend beyond gluten? FODMAPs Fermentable Oligo-, Di-, Mono-saccharides and Polyols Short-chain sugars and sugar alcohols (sorbitol, mannitol, zylitol) Fructose, lactose, fructans, galactans FODMAPS: poorly absorbed, rapidly fermented, laxative Wheat – major source of fructans Fructose polymers, intestines cannot break fructose-fructose bonds Fructans largely unabsorbed

GS and FODMAPs DB cross-over trial 37 adults with GS 2 week diet of reduced FODMAPs, continued low FODMAP diet then randomized: High-gluten (16gm/day) Low-gluten (2gm/day + 14gm/day whey) Control (16gm/day whey) Symptoms consistently improved with low FODMAP diet Symptoms worsened to similar degree in all experimental groups Biesiekierski et al. Gastroenterology 2013; 145: 320-328

Diagnosis of GS Diagnose with the aide of a medical professional No blood studies exist for GS diagnosis CD and wheat allergy needs to be ruled against in some fashion prior to self-elimination of gluten from diet Elimination of gluten from GS individuals based on symptom severity, quality of life

CD vs GS – Does it Matter? Not all that improves on a GFD is Celiac Disease Diagnosis of Celiac Disease CANNOT be made or confirmed on a gluten free diet One positive CD serologic test deserves further testing before GFD Celiac Disease = Life-long GFD Gluten Sensitivity = GFD based on symptoms, QOL Reintroducing gluten into the diet of someone with significant symptoms often difficult

CD (not GS) – a little dab may do you Catassi et al CD (not GS) – a little dab may do you Catassi et al. Am J Clin Nutr 2007; 85: 160-6 50mg/day of gluten can cause small intestinal damage seen on biopsy in patients with TRUE celiac disease Given daily over 3 month period in form of capsule 50mg/day gluten: 1/60th – 1/75th slice of regular bread If you have CD Crumbs can matter, cross contamination can have health implications If you have GS Avoidance of gluten based on symptoms alone No data to suggest that GS turns into CD

Summary Celiac Disease Classic CD (diarrhea, weight loss) common < 2yrs of age Atypical and silent CD become more common with advancing age Screen with tTG and total IgA level, any positive test warrants GI referral and further testing prior to GFD

Gluten Sensitivity Abdominal pain and diarrhea most common symptom No serologic testing CD and wheat allergy should be ruled against prior to GFD Avoidance based on QoL and symptoms GFD not medical requirement

Questions?