Click on Alessio Fasano MD Webinar Description Page

11/5/2018

COPE WEBINAR SERIES FOR HEALTH PROFESSIONALS

November 5, 2018

Gluten-Related Disorders: How to Distinguish Facts from Fantasies

Moderator: Lisa Diewald MS, RD, LDN Program Manager MacDonald Center for Obesity Prevention and Education

Nursing Education Continuing Education Programming Research

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OBJECTIVES

1.Recognize the differences between celiac disease, non-celiac gluten sensitivity and wheat allergy. 2.Discuss the epidemiology of celiac disease and why prevalence is increasing 3.Identify the role of the gut microbiome and intestinal permeability in autoimmune disease

CE DETAILS

• Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center Commission on Accreditation

• Villanova University College of Nursing Continuing Education/COPE is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration

• The American College of Sports Medicine’s Professional Education Committee certifies that Villanova University College of Nursing Continuing Education, Center for Obesity Prevention and Education (COPE) meets the criteria for official ACSM Approved Provider status (10/2018-9/2021). Providership #698849

CE CREDITS

• This webinar awards 1 contact hour for nurses and 1 CPEU for dietitians

• Suggested CDR Learning Need Codes: 2000, 5110, 5220 and 6000

• Level 2

• CDR Performance Indicators: 8.1.2, 8.1.5, 8.3.1, 8.3.6

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GLUTEN AND GLUTEN-RELATED DISORDERS: HOW TO DISTINGUISH FACTS FROM FANTASIES

Alessio Fasano, MD Chief of Pediatric Gastroenterology and Nutrition Mass General Hospital for Children Professor of Pediatrics Harvard Medical School

DISCLOSURE

The planners of this program have no conflicts of interest to disclose.

Any presenter conflict of interest was resolved prior to the planning of this program. Any additional disclosure information will be provided to participants during the live activity. The Nurse Planner has reviewed the presentation and determined that it is evidence-based, balanced and unbiased

Accredited status does not imply endorsement by Villanova University, COPE or the American Nurses Credentialing Center of any commercial products or medical/nutrition advice displayed in conjunction with an activity.

Celiac Disease And Other Gluten Related Disorders: How To Distinguish Facts From Fantasies Alessio Fasano, M.D. W. Allan Walker Chair in Pediatric Gastroenterology and Nutrition Professor of Pediatrics Harvard Medical School Mucosal Biology and Immunology Research Center And Center for Celiac Research And Treatment Massachusetts General Hospital for Children

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Conflict of Interest Disclosure Alessio Fasano, MD

I disclose the following financial relationships with commercial entities that produce health care related products or services relevant to the content I am planning, developing, or presenting: Company Relationship Content Area Alba Therapeutics Stock Holder Alternative treatments to gluten free diet for celiac patients

Inova Diagnostics Consultant Innovate Consultant Biopharmaceuticals, Inc. Mead Johnson Nutrition Speaking Agreement

The Controversy On Who Should Be On A GFD

Only People With Celiac Disease Everybody

The Source Supporting GFD For Everybody

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The Epidemics Of Gluten Related Disorders

- Quality of gluten: GE grains

- Quantity of gluten

- Gluten cannot be digested

The Epidemics Of Gluten Related Disorders

- Quality of gluten: GE grains

- Quantity of gluten

- Gluten cannot be digested

Kasarda D. J Agric Food Chem. 2013;61: 1155–1159

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Kasarda D. J Agric Food Chem. 2013;61: 1155–1159.

GMO Grains

T. turgidum AABB Aegilops tauschii DD T. aestivum AABBDD 28 chromosomes 14 chromosomes 42 chromosomes 100,000 genes 50,000 genes 150,000 genes

The Epidemics Of Gluten Related Disorders

- Quality of gluten: GE grains

- Quantity of gluten

- Gluten cannot be digested

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Kasarda D. J Agric Food Chem. 2013;61: 1155–1159

The Epidemics Of Gluten Related Disorders

- Quality of gluten: GE grains

- Quantity of gluten

- Gluten cannot be digested

What is so Special About Gluten?

Gliadin Glutenin

Gluten (gliadin+glutenin)

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Structural Characteristics of Alpha-Gliadin

Shan L et al, Science. 2002; 297:2275-9.

Lammer K et al, Immunology. 2011;132:432-40

Lammer K et al, Gastroenterology Maiuri et al. Scand J 2008;135:194-204. Gastroenterol. 1996; 31:247-53.

Celiac Disease

The Banana Babies

WK Dicke, 1905 - 1962 1st case of CD at UMB: 1938

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Celiac Disease as a Unique Model of Autoimmunity

• The only autoimmune disease in which specific MHC class II HLA (DQ2 and/or DQ8) are present in >95% of patients; • The auto-antigen (tissue Transglutaminase) is known; • The environmental trigger (gluten) is known; • Elimination of the environmental trigger leads to a complete resolution of the autoimmune process that can be re-ignited following re-exposure to gluten

Gastrointestinal Manifestations (“Classic”) Most common age of presentation: 6-24 months

• Chronic or recurrent diarrhea • Abdominal distension • Anorexia • Failure to thrive or weight loss • Abdominal pain • Vomiting • Constipation • Irritability Rarely: Celiac crisis

Non Gastrointestinal Manifestations Most common age of presentation: older child to adult

• Dermatitis Herpetiformis • Iron-deficient anemia • Dental enamel hypoplasia resistant to oral Fe of permanent teeth • Hepatitis • Osteopenia/Osteoporosis • Arthritis • Epilepsy with occipital • Short Stature calcifications • Delayed Puberty

Listed in descending order of strength of evidence

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The Clinical Manifestations of Celiac Disease are More Heterogeneous Than Previously Appreciated

A. Fasano, N Engl J Med 2003;348:2568-70.

The Epidemics of Celiac Disease

0.93%

0.45%

0.21%

The Epidemics Of Celiac Disease: Which Additional Factors are Driving this Epidemics?

- Quality of gluten; - Quantity of gluten; - Breast Feeding; - Timing of gluten introduction - Maturity of gut functions influencing Ag trafficking and handling: -GALT - PRRs - Mucous production - Barrier function - Changes in microbiome composition.

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Published on October 2, 2014

Take Home Messages

• Window of tolerance concept not supported anymore;

• Breast feeding in general or introduction of gluten while breast feeding showed no protective effect on CD onset in at-risk infants;

• Early introduction (16 weeks) of gluten traces to potentially induce tolerance did not protect against CD in at-risk infants;

• Delaying the introduction of gluten in at-risk infants does not prevent CD but merely postpones its onset by approximately 8 months (significant difference at 2 years FU that disappeared by 5 years FU);

• GI infections during the first year of life seems influential in increased the risk of CD onset;

• High-risk HLA profiles seems to be the most influential factor predictor of increased risk of CD onset;

• The high prevalence of CD among the study cohort suggests that the CD epidemics continues.

The Epidemics Of Celiac Disease: Which Additional Factors are Driving this Epidemics?

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Key Open Questions Concerning Celiac Disease:

• Best diagnostic strategies? • Endoscopy yes/no for diagnosis? • How to properly follow up CD patients? • Should CD patients be actively screened for other autoimmune diseases? • How to manage CD patients with discrepancies between serology and histology? • Are POC tests useful/appropriate for diagnosis and/or management of CD? • Is the GFD highly effective in controlling CD? • How to properly check for gluten cross-contamination? • Are there any alternative/complementary treatments to the GFD at the horizon?

Not Only Celiac Disease

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Gluten Free Market

For the American general population adopting a gluten-free diet is becoming an increasingly popular solution. The market for gluten-free food and beverage products grew at a compound annual growth rate of 28 percent from 2004 to 2011, to finish with almost $6.7 billion in retail sales last year. By the end of 2016 the market is expected to reach about $14.6 billion in sales.

How Many People in the US Are Embracing a GFD?:

Percentage of U.S. Adults Trying to Cut Down or Avoid Gluten in Their Diets Reaches New High in 2016, Reports NPD

The Fad Factor of the GFD

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Why People in the US Embrace a GFD?:

Approx 7M Approx 400,000 Approx 9M

Approx 24M Approx 50M

Based on internet interview users age 18y+ who eats GF food

The Gluten Free Diet: Not Only Celiac Disease

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Gluten Sensitivity (NCGS): Facts Definition Cases of reaction to ingestion of gluten-containing grains in which both allergic and autoimmune mechanisms have been ruled out (diagnosis by exclusion criteria) • Triggered by the ingestion of gluten-containing grains; • Negative immuno-allergy tests to wheat; • Negative CD serology (EMA and/or tTG) and in which IgA deficiency has been ruled out; • Negative duodenal histopathology; • Possible presence of biomarkers of gluten immune-reaction (AGA+); • Presence of clinical symptoms that can overlap with CD or wheat allergy symptomatology; • Resolution of the symptoms following implementation of a GFD and relapse after re-exposure to gluten-containing grains (double blind)

Sapone A. et al BMC Med 2012, Ludvigsson JF et al Gut 2013, Catassi C. Et al, Nutrients 2013

Immune-Mechanisms Involved in the Pathogenesis of Gluten Related Disorders C. Adaptive Immunity Events B. Innate Immunity Events Timeline: Weeks-Years A. Epithelial Events Timeline: Days Timeline: Hours

Clemente MG et al Gut 2003; Drago et al Scand J Gastroenterol 2006; Sapone A. et al. JADD 2012

Gluten Sensitivity (NCGS): Consensus Conferences to Define NCGS

Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A. Spectrum of gluten- related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13

Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C. The Oslo definitions for coeliac disease and related terms. Gut. 2013 Jan;62(1):43-52

Catassi C, Bai JC, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A. Non- Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sep 26;5(10):3839-53.

Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, Cellier C, Cristofori F, de Magistris L, Dolinsek J, Dieterich W, Francavilla R, Hadjivassiliou M, Holtmeier W, Körner U, Leffler DA, Lundin KE, Mazzarella G, Mulder CJ, Pellegrini N, Rostami K, Sanders D, Skodje GI, Schuppan D, Ullrich R, Volta U, Williams M, Zevallos VF, Zopf Y, Fasano A. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients. 2015 Jun 18;7(6):4966-77. doi: 10.3390/nu7064966.

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Gluten Sensitivity (NCGS): Facts Pathogenesis

Immune-mediated (likely innate immune)

Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Cartenì M, Casolaro V, Fasano A. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2010;152(1):75-80.

Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, Stefanile R, Mazzarella G, Tolone C, Russo MI, Esposito P, Ferraraccio F, Cartenì M, Riegler G, de Magistris L, Fasano A. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011 Mar 9;9:23

Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, Zevallos V, Libermann TA, Dillon S, Freitag TL, Kelly CP, Schuppan D. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012 Dec 17;209(13):2395-408.

Clinical manifestations of NCGS Frequency Intestinal Extra‐intestinal

Very Common Bloating Lack of wellbeing Abdominal pain Tiredness Common Diarrhea Headache Epigastric pain Anxiety Nausea Foggy mind Aerophagia Numbness GER Joint/muscle pain Aphtous stomatitis Skin rash/dermatitis Alternating bowel habits Constipation Undetermined Hematochezia Weight loss Anal fissures Anemia Loss of balance Depression Rhinitis/asthma Weight increase Interstitial cystitis Ingrown hairs Oligo or polimenorrhea Sensory symptoms Disturbed sleep pattern Hallucinations Mood swings Autism Schizophrenia The Salerno NCGS diagnostic criteria (Nutrients, 2015)

Gluten and The Brain

Short Memory Loss Chronic Headache Anxiety

Schizophrenia? Depression

Irritability Autism?

Seizures ADHD? Ataxia

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The Controversial Questions About Gluten Sensitivity

Are The Epidemics Of Autism, ADHD and Schizophrenia Also Related to The Rise of Non-Celiac Gluten Sensitivity?

Case Presentation: Diagnosis of Gluten Sensitivity

Description of the Case

AJ 39 y old F

•6 months history of: 0 1 2 3 4 5 6 • 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.

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Description of the Case

0 1 2 3 4 5 6 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

Description of the Case

0 1 2 3 4 5 6 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.

Proposed New Classification of Gluten Related Disorders

Gluten Related Disorders Biomarkers

Pathogenesis YES Not Autoimmune Autoimmune Allergic NO Not allergic (Innate immunity?) YES Celiac Gluten Dermatitis Wheat Gluten Disease Ataxia herpetiformis allergy sensitivity

Respiratory Food Contact Symptomitic Silent Potential WDEIA Allergy Allegy Urticaria

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Differential Diagnosis Between CD, GS, and WA

Celiac Disease Gluten Sensitivity Wheat Allergy Time interval between gluten exposure and Weeks-Years Hours-Days Minutes-Hours onset of symptoms

Pathogenesis Autoimmunity (Innate+ Immunity? Allergic Immune Response Adaptive Immunity) (Iinnate Immunity?)

HLA HLA DQ2/8 restricted Not-HLA DQ2/8 restricted Not-HLA DQ2/8 restricted (~97% positive cases) (50% DQ2/8 positive cases) (35-40% positive cases as in the general population) Auto-antibodies Almost always present Always absent Always absent

Enteropathy Almost always present Always absent Always absent (slight increase in IEL) (eosinophils in the lamina propria) Symptoms Both intestinal and Both intestinal and extra- Both intestinal and extra- extra-intestinal (not intestinal (not intestinal (not distinguishable from GS distinguishable from CD and distinguishable from CD and WA with GI WA with GI symptoms) and GS when presenting symptoms) with GI symptoms) Complications Co-morbidities Absence of co-morbidities Absence of co-morbidities. Long term complications and long term complications Short-term complications (long follow up studies (incliuding anaphylaxis) needed to confirm it)

Gluten Sensitivity and IBS

No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. Source Department of Gastroenterology, Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia; Department of Gastroenterology, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, Victoria, Australia.

Abstract BACKGROUND & AIMS: Patients with non-celiac gluten sensitivity (NCGS) do not have celiac disease but their symptoms improve when they are placed on gluten-free diets. We investigated the specific effects of gluten after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates (fermentable, oligo-, di-, monosaccharides, and polyols [FODMAPs]) in subjects believed to have NCGS. METHODS: We performed a double-blind cross-over trial of 37 subjects (aged 24-61 y, 6 men) with NCGS and irritable bowel syndrome (based on Rome III criteria), but not celiac disease. Participants were randomly assigned to groups given a 2-week diet of reduced FODMAPs, and were then placed on high-gluten (16 g gluten/d), low-gluten (2 g gluten/d and 14 g whey protein/d), or control (16 g whey protein/d) diets for 1 week, followed by a washout period of at least 2 weeks. We assessed serum and fecal markers of intestinal inflammation/injury and immune activation, and indices of fatigue. Twenty-two participants then crossed over to groups given gluten (16 g/d), whey (16 g/d), or control (no additional protein) diets for 3 days. Symptoms were evaluated by visual analogue scales. RESULTS: In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten-specific effects were observed in only 8% of participants. There were no diet-specific changes in any biomarker. During the 3-day rechallenge, participants' symptoms increased by similar levels among groups. Gluten-specific gastrointestinal effects were not reproduced. An order effect was observed. CONCLUSIONS: In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed diets low in FODMAPs. www.anzctr.org.au. ACTRN12610000524099.

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Non Celiac Gluten Sensitivity: Facts Definition of Food Reactions (Consensus NIAID 2011)

Food intolerance occurs when the body lacks a particular enzyme to digest nutrients, nutrients are too abundant to be completely digested, or a particular nutrient cannot be properly digested, Common examples are lactose intolerance, FODPAM intolerance, or lactulose intolerance (side effect of laxatives).

Food sensitivity, an understudied area, are immune-mediated reaction to some nutrients and these reactions do not always occur in the same way when eating that particular nutrient.

Food allergy is a very specific immune system response involving either the immunoglobulin E (IgE) antibody or T-cells. Both are immune system cells that react to a particular food protein, such as milk protein.

Food sources of FODMAPs (where FODMAPs are problematic based on standard serving size) and suitable alternatives

Oligosaccharides (fructans FODMAP Excess fructose Lactose Polyols and/or galactans) Vegetables: artichokes, Fruits: apples, pears, nashi asparagus, beetroot, Brussels Fruits: apples, apricots, pears, clingstone peaches, sprout, broccoli, cabbage, cherries, longon, lychee, nashi mango, sugar snap peas, fennel, garlic, leeks, okra, pears, nectarine, pears, watermelon, tinned fruit in onions, peas, shallots. peaches, plums, prunes, natural juice Milk: cow, goat and sheep watermelon (regular & low-fat), Ice cream Cereals: wheat & rye when Honey eaten in large amounts (e.g. Problem high FODMAP food Vegetables: avocado, Yoghurt (regular & low-fat) bread, pasta, couscous, source cauliflower, mushrooms, snow Sweeteners: fructose, high crackers, biscuits) peas fructose corn syrup Cheeses: soft & fresh (e.g. ricotta, cottage) Legumes: chickpeas, lentils, red Sweeteners: sorbitol(420), Large total fructose dose: kidney beans, baked beans mannitol(421), xylitol(967), concentrated fruit sources; maltitol (965), isomalt (953) & large serves of fruit, dried fruit, Fruits: watermelon, custard others ending in '-ol' fruit juice apple, white peaches, rambutan, persimmon Fruit: banana, blueberry, Vegetables: bamboo shoots, carambola, durian, grapefruit, Milk: lactose-free, rice milk bok choy, carrot, celery, Fruits: banana, blueberry, grape, honeydew melon, capsicum, choko, choy sum, carambola, durian, grapefruit, kiwifruit, lemon, lime, Cheese:'hard' cheeses corn, eggplant, green beans, grape, honeydew melon, mandarin, orange, including brie, camembert lettuce, chives, parsnip, kiwifruit, lemon, lime, passionfruit, paw paw, pumpkin, silverbeet, spring mandarin, orange, Suitable alternative low- raspberry, rockmelon, Yoghurt: lactose-free onion (green only), tomato passionfruit, paw paw, FODMAP food source strawberry, tangelo. raspberry, rockmelon Ice cream substitutes: gelati, Onion/garlic substitutes: garlic- Honey substitutes: maple sorbet infused oil Sweeteners: sugar (sucrose), syrup, golden syrup glucose, other artificial Butter Cereals: gluten-free & spelt sweeteners not ending in 'ol' Sweeteners: any except bread/cereal products polyols

Gibson PR, Sheperd SJ. J Gastroenterol Hepatol. 2010;25:252-258

Pathogenesis Of IBS‐Like Syndromes

Czaja-Bulsa G et al, Clin Nutr 2014

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The diagnosis of NCGS

Self- Elimination diagnosis diagnosis

Positive diagnosis (clinical and DBPC test)

Proposed Algorithm for Differential Diagnosis Of Gluten Related Disorders

Catassi C. et al. Nutrients 2015; 7:4966-77

Key Questions About Non-Celiac Gluten Sensitivity:

• Are current diagnostic tools (dietary rechallenge – Salerno criteria) feasible in clinical practice? • Are there any validated biomarkers for the diagnosis of NCGS? • How gluten and possibly other wheat components cause symptoms on NCGS?

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Facing Today’s Facts on Celiac Disease and Gluten Sensitivity November 10-11, 2018

Registration: https://nationalceliac.org/2018‐celiac‐disease‐ symposium/

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QUESTIONS & ANSWERS

Moderator: Lisa K. Diewald MS, RD, LDN Email: [email protected] Website: www.willanova.edu/COPE