2005 4160s2 06 Fasano

Prospective Studies on Celiac Disease: 

Prospective Studies on Celiac Disease Alessio Fasano and Carlo Catassi Center for Celiac Research University of Maryland School of Medicine

On the Coeliac Affection : 

To regulate the food is the main part of treatment…. The allowance of farinaceous food must be small; highly starchy food, rice, sago, corn-flour are unfit. Malted food is better, also rusks or bread cut thin and well toasted on both sides…. There is a kind of chronic indigestion which is met with in persons of all ages, yet is especially apt to affect children between one and five years old…. Signs of the disease are yielded by the faeces; being loose, not formed, but not watery; more bulky than the food taken would seem to account for… The causes of the disease are obscure. Children who suffer from it are not all weak in constitution. Errors in diet may perhaps be a cause, but what error? Why, out of a family of children all brought up in much the same way, should one alone suffer? Gee S. On the celiac affection. St Bart Hosp Rep 1890; 24: 17-20. On the Coeliac Affection

Definition: 

Definition Celiac disease is an autoimmune condition 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) are known elimination of the environmental trigger leads to a complete resolution of the disease

Pathogenesis: 

Pathogenesis Genetic predisposition Environmental triggers Dietary Non dietary?

Genetics: 

Several genes are involved The most consistent genetic component depends on the presence of HLA-DQ (DQ2 and / or DQ8) genes Other genes (not yet identified) account for 60 % of the inherited component of the disease HLA-DQ2 and / or DQ8 genes are necessary (No DQ2/8, no Celiac Disease!) but not sufficient for the development of the disease HLA ? ? ? ? Gluten Celiac Disease + Genes Genetics

Slide6: 

DQA1*0501 DQB1*0201 DQ2 { DQA1*0201 { DR3 CIS DR5/DR7 Trans DR3/DR3 CIS DQB1*03 DQA: Any APC Gluten DQ2 DQ8 Be aware DR3 should now be referred to as DR17

Dietary Factors: 

Dietary Factors Festucoideae Subfamily Tribe Zizaneae Oryzeae Hordeae Aveneae Festuceaea Chlorideae wild rice rice wheat oat finger millet teff (ragi) rye barley The Grass Family - (GRAMINEAE)

The Celiac Iceberg: 

The Celiac Iceberg Symptomatic Celiac Disease Silent Celiac Disease Latent Celiac Disease Genetic susceptibility: - DQ2, DQ8 Positive serology Manifest mucosal lesion Normal Mucosa

Treatment Options: 

Treatment Options

Treatment: 

Treatment Only treatment for celiac disease is a gluten-free diet (GFD) Strict, lifelong diet Avoid: Wheat Rye Barley

Gluten-Containing Grains to Avoid: 

Gluten-Containing Grains to Avoid Wheat Bulgar Filler Wheat Bran Couscous Graham flour Wheat Starch Durum Kamut Wheat Germ Einkorn Matzo Flour/Meal Barley Emmer Semolina Barley Malt/ Extract Faro Spelt Rye Triticale

Sources of Gluten: 

Sources of Gluten OBVIOUS SOURCES Bread Bagels Cakes Cereal Cookies Pasta / noodles Pastries / pies Rolls

Sources of Gluten: 

Sources of Gluten POTENTIAL SOURCES Candy Communion wafers Cured Pork Products Drink mixes Gravy Imitation meat / seafood Sauce Self-basting turkeys Soy sauce

Gluten-Free Grains and Starches: 

Amaranth Arrowroot Buckwheat Corn Flax Millet Montina Oats* Potato Quinoa Rice Sorghum Tapioca Teff Flours made from nuts, beans and seeds Gluten-Free Grains and Starches *for possible cross-contamination with gluten containing grains

Other Items to Consider: 

Other Items to Consider Lipstick/Gloss/Balms Mouthwash/Toothpaste Play Dough Stamp and Envelope Glues Vitamin, Herbal, and Mineral preparations Prescription or OTC Medications

Dietary Adherence:A Common Problem: 

Only 50% of Americans with a chronic illness adhere to their treatment regimen including: diet exercise medication Dietary compliance can be the most difficult aspect of treatment Dietary Adherence: A Common Problem

Health Beliefs of Adults with Celiac Disease: 

Health Beliefs of Adults with Celiac Disease Survey of 100 people in Celiac Disease support group (Buffalo, NY) Number of people who agreed with following statements: “If I eat less gluten I will have less intestinal damage.” –51% “I’ve lived this long eating gluten, how much will the gluten- free diet really help me now?” –33% “My doctor should be the one to tell me when I need follow up testing.” –26% “Scientist/doctors still haven’t proven that gluten really hurts them.” –16%

Barriers to Compliance: 

Barriers to Compliance Ability to manage emotions – depression, anxiety Ability to resist temptation – exercising restraint Feelings of deprivation Fear generated by inaccurate information

Barriers to Compliance: 

Barriers to Compliance Time pressure – time to plan, prepare food is longer Planning – work required to plan meals Competing priorities – family, job, etc. Assessing gluten content in foods/label reading Eating out – avoidance, fear, difficult to ensure food is safe

Slide20: 

Gluten and treatment of Celiac Disease: How Much is Too Much?

The gluten microchallenge study: 

The gluten microchallenge study Coordinator: Carlo Catassi, M.D.

Investigating the dose-effect relationship the gluten microchallenge: 

Investigating the dose-effect relationship the gluten microchallenge CD patients on long-term, strict GFD Perspective study design While the GFD is maintained throughout the study-period, a given amount of gluten/gliadin is added to the diet Clinical, serological and biopsy evaluation before and after the microchallenge The background noise caused by possible gluten contamination of the GFD was minimized by inclusion of a control group

Slide23: 

DOSE-DEPENDENT EFFECTS OF PROTRACTED INGESTION OF SMALL AMOUNTS OF GLIADIN IN CELIAC CHILDREN Positive linear relationship between gliadin daily dose and mucosal damage between 100 and 1000 mg/day IEL count is the most sensitive index Serological markers are not reliable tools for detecting minimal dietary transgressions Catassi et al, Gut 1996

Why performinging a new microchallenge study: 

Why performinging a new microchallenge study Need of investigating the effects of lower gluten doses Need of prolonging the duration of the microchallenge Need of a control group Need of investigating gluten rather than gliadin

Gluten and Giadins: 

Gluten and Giadins Gluten is the main proteic fraction in wheat (8-14 %); The toxicity is mainly due to the gliadins (50 %), however glutenins also contribute to toxicity; Daily intake of gluten in adults: ~ 15 g (Dautch data); Daily consumption of flower for a typical GFD in celiac subjects: ~ 80 g; 200 mg/Kg of gluten = 100 mg/Kg of gliadin = 100 ppm of gliadin (=2.5g of bread!) 200g Wheat Gluten 15g Gliadin 7.5g ~52 toxic fragments

The new microchallenge study : 

The new microchallenge study AIM To evaluate the consequences of the protracted ingestion of minimal daily gluten intake (either 10 or 50 mg) in a group of adult celiacs on long-term treatment with the gluten-free diet (GFD) TYPE OF STUDY Multicentre, prospective, randomized, placebo-controlled, double-blind STUDY PERIOD Years 2001-2004 SPONSOR Italian Celiac Society (AIC)

The “new” Italian microchallenge study: 

The “new” Italian microchallenge study INCLUSION CRITERIA Patients with biopsy-proven CD on a GFD for at least 2 years EXCLUSION CRITERIA Younger than 18 yrs Poor compliance to the GFD Abnormal results at the baseline evaluation Associated selective IgA deficiency

The Italian microchallenge studyStudy-Design: 

The Italian microchallenge study Study-Design Steps GFD  2 yrs Running-in Baseline Microchallenge T1 GFD Intervention Informed consent Strict monitoring of the GFD Clinical Serology SB Biopsy Patient flow + 50 mg gluten + 10 mg gluten + 0 mg gluten Timeframe Pre-T0 T0 1 2 3 m Randomization Clinical Gluten exposure Serology Monthly check SB biopsy T0

The Italian microchallenge studyMethods: 

The Italian microchallenge study Methods Purified gluten was used for the microchallenge study (Amygluten 110, Tate & Lyle, UK) Gluten- or lactose (placebo) containing capsules were centrally prepared All laboratory tests were centrally performed Monthly monitoring of adherence to the protocol Measurement of gluten contamination in commercially available GF food by ELISA (Ridascreen Gliadin, R-Biopharm AG, Germany) Serum AGA (ELISA) and anti-tTG (ELISA) Small bowel biopsy and morphometry on 10 villi, IEL count (CD3+), ab IEL count Control biopsies from non-celiac GE patients

Gluten content in commercially-available gluten free products in Italy where currently food labeling policies for gluten free products are set at 20 ppm: 

Gluten content in commercially-available gluten free products in Italy where currently food labeling policies for gluten free products are set at 20 ppm

The Italian microchallenge studySubjects completing the study : 

The Italian microchallenge study Subjects completing the study

Slide32: 

The Italian microchallenge study: Biopsy findings at baseline Controls CD CD3+ T cells (x100 enterocytes)

Slide33: 

The Italian microchallenge study Biopsy findings at baseline IEL count (X100 enterocytes) VH/CD Ratio

Slide34: 

Symptoms Placebo 10 mg 50 mg None 6 8 7 Abdominal pain and distension 2 1 2 Anemia and/or iron deficiency 1 0 0 Loss of appetite 0 0 1 Bloating, mood changes 2 1 0 Apthous stomatitis 0 0 1 Constipation 2 0 0 Headache, abdominal distention 1 0 0 Weight loss 0 0 1 The Italian microchallenge study Clinical findings

Slide35: 

The Italian microchallenge study Serological findings

Slide36: 

The Italian microchallenge study Morphometry findings1

Slide37: 

The Italian microchallenge study Morphometry findings2

Slide38: 

The Italian microchallenge study Morphometry findings

Tolerable daily intake of gluten and ppm of gluten in food for celiacs: 

Tolerable daily intake of gluten and ppm of gluten in food for celiacs

Toxicity of gluten traces:the Italian study on gluten microchallenge: 

Toxicity of gluten traces: the Italian study on gluten microchallenge Catassi C1,2, Fabiani E1, Mandolesi A3, Bearzi I3, Iacono G4, D’Agate C5, Francavilla R6, Corazza GR7, Volta U8, Accomando S9, Picarelli A10, De Vitis I11, Bardella MT12, Pucci A13, Fasano A2 1 Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy; 2 Center For Celiac Research, University of Maryland School of Medicine, Baltimore (USA); 3 Department of Pathology, Università Politecnica delle Marche, Ancona (Italy); 4 Department of Gastroenterology, Children Hospital, Palermo; 5 University Department of Gastroenterology, Catania; 6 University Department of Pediatrics, Bari; 7 University Department of Gastroenterology, Pavia; 8 University Department of Internal Medicine, Bologna; 9 University Department of Pediatrics, Palermo; 10 Department of Gastroenterology, “La Sapienza” University, Rome; 11 University Department of Internal Medicine, “Gemelli” University, Rome; 12 University Department of Medical Sciences, Milan; 13 Italian Celiac Society.