Myths and Facts of Gluten Related Disorders. Martha Pacetti, PNP Celiac Research and Treatment Center Mass General Hospital

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1 Myths and Facts of Gluten Related Disorders Martha Pacetti, PNP Celiac Research and Treatment Center Mass General Hospital

2 Conflict of Interest Disclosure Martha Pacetti I have no financial relationships with a commercial entity producing healthcare-related products and/or services.

3 Objectives Discuss gluten related disorders Review recommended screening tests and diagnostic algorithms for patients suspected of having celiac disease Myths of gluten free diet

U.S. gluten-free products market revenue by product, 2014-2025 (USD Million)

4 U.S. gluten-free products market revenue by product, (USD Million)

5 Gluten Related Disorders GLUTEN FREE DIET CONSUMERS MEDICAL NECESSITY NO MEDICAL NECESSITY WHEAT ALLERGY (IGE-Mediated) (~0.1%) CELIAC DISEASE (Autoimmune) (~1%) GLUTEN SENSITIVITY (Unclear Pathophysiology) (~6%)

6 Fasano, 2003 Celiac Disease (CD) Chronic inflammatory disorder in genetically predisposed individuals caused by the ingestion of Wheat Rye Barley Inappropriate T cell mediated immune response Autoimmune enteropathy Small Intestinal Patchy Inflammation Gastrointestinal complaints Nutrient malabsorption Extra-intestinal symptoms: Fatigue, arthralgias etc

7 What is Gluten? Protein in wheat, rye, and barley Gluten: Gliadin +Glutenin Gliadin Resistant to gastric and pancreatic protease digestion to due high proline and glutamine content Several peptides known to elicit the immunological response in celiac disease

8 Gluten Causes Gut Leakiness in Everybody Clemente Gut 2003 Drago Scand J Gastroenterol 2006 Sapone A JADD 2010

9 Celiac Disease is a Unique Model of Autoimmunity Fasano A; Scientific American Aug. 2009

10 Clemente Gut 2003 Drago Scand J Gastroenterol 2006 Sapone A JADD 2010

11 Celiac Disease Is A Systemic Autoimmune Disease Fasano, 2003

12 2017: Pediatric Celiac Disease Looks Different 10 year old female with complete villous atrophy, ttg>300, EMA 1:80, normal CBC, B12 deficiency (205), Vit D 14

13 Celiac Disease Can Develop At Any Age Bach, NEJM, 2002 C. Catassi, Annal Med 2010

14 But is wheat more toxic? Is the rise of celiac disease a result of higher gluten content from wheat breeding? Research published in the Journal of Agricultural and Food Chemistry found no clear evidence of an increase in the gluten content of wheat in the US during the 20 th century. Increased per capita consumption of wheat flour and vital glutens? per person consumption: 1900 = 220 lbs 1970 = 110 lbs 2000 = 146 lbs 2008 = 134 lbs

15 Prevalence In At Risk Groups In The US Family Members 1st Degree 1:22 2 nd 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 Disease: Down s Syndrome 5-12% Autoimmune thyroid disease up to 7% Turners syndrome 2-5% Williams syndrome up to 9% Autoimmune liver disease 12-13% Type 1 Diabetes 2-12% 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 (2003):

16 Patients Must Remain On A Gluten Containing Diet For Accurate Testing

17 A Trial of A Gluten Free Diet (GFD) Should Not Be Recommended Without a Consultation with A Gastroenterologist Obscures the diagnosis of CD Only genetic testing can be sent on a GFD- often not covered by insurance Send to gastroenterology before a trial of the GFD The GFD is not a healthier option Processed products have more fat and sugar Lack of B vitamins, folate, iron Expensive- social isolation No recommendation that patients with a family history of celiac disease should refrain from eating gluten Reilly,N. J Peds 2016 Francavilla,J Peds 2014

18 Current Screening Algorithm

19 Serological Tests For Celiac Disease Initially Screen for IgA level; If < 7 send IgG DGP In Practice ttg sensitivity/spec~ 85-90% Leonard, JAMA, 2017

20 Why We Need Initial Biopsies: To Accurately Evaluate Remission Serology Cannot Predict Compliance or Remission Status ttg and EMA do not correlate with dietary compliance >100 children after 2.4 years on a GFD: ttg was elevated in 43% of subjects with persistent enteropathy and 32% of subjects with mucosal healing (Unpublished) Evaluate Healing Endoscopically 33~67% of adults with CD) on a gluten GFD persistent enteropathy after 2 years Leonard (Unpublished) Up to 19% of pediatric patients may have persistent enteropathy after 2.4 years on a GFD Ciacci,C. Digestion.2002 Rubio-Tapia. Am J. of Gastro. 2010

21 How we monitor CD Diagnosis: Nutritional labs, DEXA scan, teaching with physician and dietician 3 months: Evaluation with dietician 6 months: Recheck ttg, meet with physician and dietician 12 months: Recheck ttg, meet with physician and dieticians Once stable on a strict GFD Repeat endoscopy between 1-2 years Follow-up clinically yearly

22 Recommended Standard CD Labs CBC (hemoglobin, hematocrit, etc) 25 OH Vitamin D B12 Folate Iron and Ferritin Zinc Lipids Total IgA, IgA-tTG TSH (thyroid) Magnesium Calcium

23 Is Persistent Villous Atrophy In Patients with Celiac Disease An Issue? 30% of patients with celiac disease have signs, symptoms, and/or persistent enteropathy after 1 year on a gluten free diet More than 40% of adults with CD on a gluten free diet have persistent villous atrophy after 2-5 years Adults with CD are recommended to undergo a follow-up endoscopy Assumption that the majority of children heal after 1 year Based on data from %-19% of children with CD have persistent villous atrophy after a median of years Bannister, AM J Gastro, Vecsei, BMC Gastro, Ghazzawi, JPGN, Leonard, JPGN, Rubio-Tapa, AM J Gastro, 2010 Lebowohl, AP&T, 2013 Mahadev, AP&T,2017

24 Controversy and Mucosal Recovery: What are Clinical Consequences If Any Of Persistent Villous Atrophy? Morbidity: Growth failure Nutritional Deficiencies Other School performance, Peripheral neuropathy, Dental enamel defects Increased rates of osteoporosis Increased hypothyroidism Increased Lymphoma*Persistent VA Increased risk of developing other autoimmune disease Mortality: Mixed results in adults Choung, Gastro, 2017 Canavan, AP&T.2011 Godfrey, Gastro, Lebwohl, Ann Intern Med, Rubio-Tapa, Am J Gastro, Cosnes, Clin Gastro & Hep, Rubio-Tapa, Clin Gastro & Hep, 2011 McGowan, Pediatrics, 2009.

25 Why isn t the Gluten Free Diet Enough? ~30% of patients with celiac disease have signs, symptoms, and/or persistent enteropathy after 1 year on a gluten free diet Intentional Exposure Other GI Disorder Cross Contamination Difficult socially Expensive Non-Responsive CD Type 1 Refractory CD Type 2 Refractory CD

26 Check for Possible Gluten Exposure Recheck labels of favorite everyday foods as ingredients can change. Check label of foods not labeled gluten free for ingredients: Wheat, rye, barley, malt, oats, Brewer s yeast Look for sources of contamination at home and away from home. Toaster, condiment containers, Eating at restaurants, school, daycare or social events Recheck all over the counter and prescription medications:

Non-responsive celiac disease (NRCD) as biopsy-proven CD with persistence or relapse of symptoms and/or villous atrophy despite being on a gluten free diet for 12 months Gluten

27 Non-responsive celiac disease (NRCD) as biopsy-proven CD with persistence or relapse of symptoms and/or villous atrophy despite being on a gluten free diet for 12 months Gluten Contamination Elimination Diet (GCED) Goaleliminate exposure to any possible source of gluten crosscontamination from packaged/ processed foods, to include those labeled gluten-free

28 The Gluten Contamination Elimination Diet: Fruits/Vegetables Grains Proteins Beverages/Nutritional Supplements Seasoning/Condiments/Misc. Phase 1: Week 1-2 Foods Allowed All Fresh Fruits and Vegetables (no frozen or canned fruits/vegetables) Rice (brown and white) (preferably labeled gluten free) Chicken Turkey (not self-basting) Fresh Fish/seafood Eggs 100% Fruit/Vegetable Juices Gatorade Fresh ground coffee 100% black or green tea (no herbal teas) Boost, Ensure (no malt flavor) Fresh herbs (no dried herbs) Salt Fresh ground pepper Plain honey Olive oil Vinegar (excluding malt vinegar and flavored vinegars) Dairy (if tolerated*) Fruits/Vegetables Grains Proteins (fresh only) Beverages/Nutritional Supplements Seasoning/Condiments/Misc. Foods Allowed Butter Yogurt (plain, unflavored) Cream (plain, unflavored) Cheeses - Only ingredients: pasteurized milk, cheese cultures, salt, enzymes Cottage cheese - Only ingredients: cultured milk, cream, and salt All Fresh Fruits and Vegetables (no frozen or canned fruits/vegetables) Dried beans* - Carefully clean and sort for foreign particles Rice (brown and white) (preferably labeled gluten free) Chicken Turkey (not self-basting) Fresh fish/seafood Beef Pork and Lamb (no ham or bacon) Nuts in the shell or raw Eggs 100% Fruit/Vegetable Juices Gatorade Fresh ground coffee 100% black or green tea (no herbal teas) Boost, Ensure (no malt flavor) Fresh herbs (no dried herbs) Salt and fresh ground pepper Plain honey and sugar Lemon Olive oil Vinegar (excluding malt vinegar and flavored vinegars)

29 GCED Conclusions Trial of the GCED may prevent patients from unnecessary immunosuppressant therapy Not an attempt to enforce dietary adherence on a patient with detected persistent gluten ingestion, Modifies an already strict GFD to remove the possibility of trace gluten cross-contamination. Done for a limited time period under the supervision of a dietician Most CD patients can safely tolerate approximately 10 mg gluten cross-contamination daily, or 500 grams of food containing 20 ppm of gluten but there is variability Study that tested 22 single-ingredient inherently gluten-free grains, seeds and flours, 32% of these products contained >20 ppm gluten; one product contained 2,925 ppm of gluten Hollon, BMC, Thompson : Gluten contamination of grains, seeds, and flours in the United States: a pilot study. J Am Diet Assoc 2010

30 Non-Celiac Gluten Sensitivity Individuals in which ingestion of gluten-containing grains causes intestinal and/or extra-intestinal symptoms and in which both wheat allergy and celiac disease have been ruled out. Condition diagnosed by clinical symptoms as they occur in response to eating gluten. There is no diagnostic test capable of confirming the diagnosis.

31 Hill, JPGN, 2016 Non Celiac Gluten Sensitivity Syndrome characterized by a variable combination of intestinal and extra-intestinal symptoms, typically occurring soon after ingestion of gluten-containing foods and disappearing quickly upon their withdrawal, occurring in individuals where both CD and wheat allergy have been excluded Prevalence:5-30% of individuals Pathophysiology is unknown Gluten vs. other wheat proteins Wheat amylase-trypsin inhibitors Initial Testing: None Patients may be more likely to have an elevated anti-gliadin antibody test or carry HLA DQ2 or 8 Exclude CD and wheat allergy (IgE testing or SPT) Confirmation of NCGS: Assessment of clinical response to the GFD (6 weeks) Measuring the effect of reintroducing gluten

32 Symptoms: Gluten Sensitivity (NCGS): What Kind of Symptoms? Abdominal pain: 68% Eczema and/or rash: 40% Headache: 35% Foggy mind : 34% Fatigue: 33% Diarrhea: 33% Depression: 22% Anemia: 20% Numbness legs/arms/fingers: 20% Joint pain: 11% Sapone A. et al BMC Med 2012, Catassi C. Et al, Nutrients 2013

33 Case Presentation: Diagnosis of Gluten Sensitivity

34 Description of the Case AJ 19 y old F months history of: Recurrent abdominal pain (mainly epigastric) Heartburn Suspecting GERD, pt was placed on PPI, but no resolution of symptoms. One month after the onset of GERD symptoms pt developed headaches, dizziness, numbness of fingers, paresthesia, gradual reduction of legs muscle strength that forced her on a wheelchair.

35 Description of the Case Suspecting neurological causes, patient underwent to: MRI Evoked potentials Both resulted negative Other diagnoses that were considered include: Lyme disease; Epstein Barr Virus Pernicious Anemia Lupus All were ruled out

36 Description of the Case Because of the persistence of GERD symptoms pt underwent to an EGD reported as normal (including duodenal biopsy that showed only increased IEL). She was also screened for CD and tested negative Despite negative results, pt decided to embrace a GFD Within 3 weeks her GI symptoms resolved Within 2 months her neurological symptoms also improved. Six month after implementation of the GFD she was able to walk with the assistance of a cane. Twelve months later she regained completely her walking function.

37 A Comparison of The Various Reactions To Gluten Leonard, 2014.

38 The Gluten Free Diet: Consequences and Recommendation Removing gluten from the diet is not without consequences. If not done for the correct reasons and with great attention to nutrition, the GFD can lead to nutritional deficiencies as well as other social and economic implications.

39 Treatment Lifelong restriction of gluten ingestion Education of the patient and the family Vigilance about nebulous ingredients Wheat-free is not gluten free

40 Gluten-Containing Ingredients to Avoid Wheat Barley Barley Malt /Extract Brewer s yeast Rye Other Types of Wheat: Spelt Kamut Emmer Einkorn Semolina Faro Bulgur Couscous Durum Triticale Filler

41 How Much is 20 ppm? (0.02gm/kg=20 mg/kg) Average slice of bread weighs 30 gms and contains ~4.8 gms of gluten If 50 mg/day is safe, then 1/96 th of a slice of bread would be safe If gluten-free bread contained 20 ppm, then 83 slices would contain 50 mg from

42 Hidden Gluten Broth Candy Communion wafers** Imitation bacon Imitation seafood Marinades Processed meats Roux Sauces Soup base Soy sauce Thickeners Medications ** Unless GF

43 Nutritional Aspects of the GFD The GFD can be missing important nutrients needed for optimal health and wellness Lacks fiber Lacks iron Lacks B vitamins- folate, niacin, B12 Lacks calcium Phosphorous Zinc Nutrition deficiencies lead to Iron deficiency anemia Reduced bone mineral density Constipation Many gluten free foods are not enriched or fortified as their wheat counterpart Weight gain on GFD due to high fat, sugar and calorie content

44 Use the alternative whole grains Three servings of whole/enriched cereals and pseudo (oats, brown rice and quinoa) positively impacted the nutrient profile of the diet, increasing thiamin, riboflavin, niacin, folate, iron and fiber in the diet. Fiber Calcium Iron Folate & B vitamins Buckwheat Amaranth Quinoa Amaranth Brown rice Quinoa Amaranth Millet Amaranth Teff Teff Teff Quinoa Millet Quinoa

45 Other Considerations: Beauty Products

46 Other Considerations: Environment

47 Diet: Monitoring cross contamination in urine and stool Gluten Detective Issues 1. 50$ for 2 tests 2. Will it change outcomes? 3. Will it change care?

48 Hot topics in Maintaining a Gluten Free Diet: Food testing NIMA NIMA issues 1. Pea sized amount 2. Measures below 20ppm 3. Cannot detect malted barley! 4. Cannot test liquids

Reasons for the Occasional Consumer: Not Medical necessary The number of American following a GFD tripled between

) 27% of consumers who eat or used to eat gluten-free foods do so because they feel they aid in their weight loss

) 65% of consumers who eat or used to eat gluten-free foods do so because they think they are healthier* Popular

49 Reasons for the Occasional Consumer: Not Medical necessary The number of American following a GFD tripled between but diagnosis of CD remained stable during that same time. Weight loss (?) 27% of consumers who eat or used to eat gluten-free foods do so because they feel they aid in their weight loss efforts.* Better nutrition & other health benefits (?) 65% of consumers who eat or used to eat gluten-free foods do so because they think they are healthier* Popular Press Celebrity Endorsements Lady Gaga, Miley Cyrus Michael Douglas, 70, reveals that he is now gluten free and recommends the diet and says he has already lost weight. *

50 In Defense of Gluten Going gluten free and eliminating whole wheat in otherwise healthy individuals may have a downside Naturally high in fiber and B complex Offers great taste, variety, and palatability Flour based foods are required to be enriched or fortified with; Iron, thiamin, niacin, riboflavin, folate Contains fructan-type resistant starches that may help create healthy and beneficial gut bacteria Gluten reduced serum triglyceride levels, uric acid and LDL cholesterol vs. no change with wheat fiber/bran Positive effect on blood pressure

51 Weight Gain Research Leffler and colleagues showed that weight does change on the gluten-free diet 679 subjects, whose diet adherence was scored by an expert dietitian Type of presentation, i.e. GI vs non-gi, was not linked to average baseline BMI or diet adherence 15.8% of subjects who began the study at a low or normal BMI increased to an overweight BMI 22% of subjects who were overweight at the time of diagnosis also gained weight The more closely subjects followed the gluten-free diet, the more likely they were to gain weight however, there is a link between obesity at diagnosis and subsequent poor dietary adherence Kabbani et al. Aliment Pharmacol Ther ; 35(6):723-9.

52 Reasons for Weight Gain Weight gain on a gluten-free diet is due to a number of factors: Better absorption and healing of the intestine Patients feel better, and therefore eat more Higher calorie food items on the gluten-free food, i.e. packaged, processed foods Portion distortion - patients who were undiagnosed were often able to eat larger portions without gaining weight

Prospective observational international study recruiting 500 infants at risk of celiac disease Aims: Understand and investigate how environmental factors may play a key role in early steps involved

53 Prospective observational international study recruiting 500 infants at risk of celiac disease Aims: Understand and investigate how environmental factors may play a key role in early steps involved in the development of autoimmune disease Alteration of microbiome subsequent changes in metabolomic profiles ultimately result in physiologic changes Increase in gut permeability Loss of gluten tolerance Leading to CD autoimmunity

54 Ultimate Goals Identify and validate specific microbiota and metabolic profiles mechanistically linked to gut functions (including permeability, immune function, and stem cell niche biology) that can predict loss of gluten tolerance in subjects genetically at risk of autoimmunity Though the identification of these biomarkers our group aims to implement early interventions to reestablish tolerance Manipulate the host microbiota composition using prebiotics or probiotics to ultimately prevent the development of CD and other autoimmune disease.

55 What will be required Online questionnaires sent via Q6 months Monthly Food and antibiotic diaries Stool collection every 3 months for 3 years Materials sent to participants home for home collection Blood collection every 6 months then yearly after age 3 Obtained at PCP or MGH free of charge

56 Help Us Recruit!

Gluten Sensitivity Fact from Myth. Disclosures OBJECTIVES 18/09/2013. Justine Turner MD PhD University of Alberta. None Relevant

Gluten Sensitivity Fact from Myth Justine Turner MD PhD University of Alberta Disclosures None Relevant OBJECTIVES Understand the spectrum of gluten disorders Develop a diagnostic algorithm for gluten