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Prospective Studies on Celiac Disease. Alessio Fasano and Carlo Catassi Center for Celiac Research University of Maryland School of Medicine. On the Coeliac Affection .

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Prospective studies on celiac disease l.jpg
Prospective Studies on Celiac Disease

Alessio Fasano and Carlo Catassi

Center for Celiac Research

University of Maryland School of Medicine


On the coeliac affection l.jpg
On the Coeliac Affection

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?

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….

Gee S. On the celiac affection. St Bart Hosp Rep 1890; 24: 17-20.


Definition l.jpg
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 l.jpg
Pathogenesis

  • Genetic predisposition

  • Environmental triggers

    • Dietary

    • Non dietary?


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Genetics

Genes

  • 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


Slide6 l.jpg

Be aware DR3 should now be referred to as DR17

DQ2

DQ8

DR5/DR7

DR3/DR3

DR3

{

DQA1*0501

{

DQA: Any

DQA1*0201

DQ2

DQB1*03

DQB1*0201

Trans

CIS

CIS

Gluten

APC


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Dietary Factors

The Grass Family - (GRAMINEAE)

Subfamily

Tribe

Festucoideae

Zizaneae Oryzeae Hordeae Aveneae Festuceaea Chlorideae

wild rice rice wheat oat finger millet teff

(ragi)

rye

barley


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The Celiac Iceberg

Symptomatic

Celiac Disease

Manifest

mucosal lesion

Silent Celiac

Disease

Normal

Mucosa

Latent Celiac Disease

Genetic susceptibility: - DQ2, DQ8

Positive serology


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Option #1:Remove the genes

Option #2:Remove the grains

Treatment Options


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Treatment

  • Only treatment for celiac disease is a gluten-free diet (GFD)

    • Strict, lifelong diet

    • Avoid:

      • Wheat

      • Rye

      • Barley


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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


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OBVIOUS SOURCES

Bread

Bagels

Cakes

Cereal

Cookies

Pasta / noodles

Pastries / pies

Rolls

Sources of Gluten


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Sources of Gluten

  • POTENTIAL SOURCES

    • Candy

    • Communion wafers

    • Cured Pork Products

    • Drink mixes

    • Gravy

    • Imitation meat / seafood

    • Sauce

    • Self-basting turkeys

    • Soy sauce


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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

*for possible cross-contamination with gluten containing grains


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Other Items to Consider

  • Lipstick/Gloss/Balms

  • Mouthwash/Toothpaste

  • Play Dough

  • Stamp and Envelope Glues

  • Vitamin, Herbal, and

    Mineral preparations

  • Prescription or OTC Medications


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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


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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%


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Barriers to Compliance

  • Ability to manage emotions – depression, anxiety

  • Ability to resist temptation – exercising restraint

  • Feelings of deprivation

  • Fear generated by

    inaccurate information


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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



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The gluten microchallenge study

Coordinator: Carlo Catassi, M.D.


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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


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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


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Why performinging a new AMOUNTS OF GLIADIN IN CELIAC CHILDRENmicrochallenge 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 l.jpg

Wheat AMOUNTS OF GLIADIN IN CELIAC CHILDREN

Gluten and Giadins

200g

  • 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!)

Gluten

15g

Gliadin

7.5g

~52 toxic fragments


The new microchallenge study l.jpg
The new microchallenge study AMOUNTS OF GLIADIN IN CELIAC CHILDREN

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 l.jpg

INCLUSION CRITERIA AMOUNTS OF GLIADIN IN CELIAC CHILDREN

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 “new” Italian microchallenge study


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The Italian microchallenge study AMOUNTS OF GLIADIN IN CELIAC CHILDRENStudy-Design

Steps

GFD

GFD  2 yrs

Running-in

Baseline

Microchallenge T1

Intervention

Informed

consent

Strict

monitoring

of the GFD

Clinical

Serology

SB Biopsy

Randomization Clinical

Gluten exposure Serology

Monthly check SB biopsy

+ 50 mg gluten

Patient flow

+ 10 mg gluten

+ 0 mg gluten

Timeframe

Pre-T0

T0

T0 1 2

3 m


The italian microchallenge study methods l.jpg
The Italian microchallenge study AMOUNTS OF GLIADIN IN CELIAC CHILDRENMethods

  • 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


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


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The Italian microchallenge study products in Italy where currently food labeling policies for gluten free products are set at 20 ppmSubjects completing the study


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VH/CD Ratio products in Italy where currently food labeling policies for gluten free products are set at 20 ppm

Controls CD

The Italian microchallenge study:Biopsy findings at baseline

CD3+ T cells (x100 enterocytes)

Controls CD


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The Italian microchallenge study products in Italy where currently food labeling policies for gluten free products are set at 20 ppmBiopsy findings at baseline

IEL count (X100 enterocytes)

VH/CD Ratio


Slide34 l.jpg

The Italian microchallenge study products in Italy where currently food labeling policies for gluten free products are set at 20 ppmClinical findings

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


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10 products in Italy where currently food labeling policies for gluten free products are set at 20 ppm

25

8

20

6

15

IgG-AGA (U/mL)

IgA anti-tTG (U/mL)

4

10

2

5

0

0

Placebo

10 mg

50 mg

Placebo

10 mg

50 mg

Treatment

Treatment

The Italian microchallenge studySerological findings


Slide36 l.jpg

3 products in Italy where currently food labeling policies for gluten free products are set at 20 ppm

*

2

Vh/Cd ratio

1

0

Placebo

10 mg

50 mg

Treatment

  • 50 mg significantly different from placebo (Kruskal-Wallis test)

The Italian microchallenge study

Morphometry findings1


Slide37 l.jpg

45 products in Italy where currently food labeling policies for gluten free products are set at 20 ppm

40

35

30

25

IELs count

(no. x 100 enterocytes)

20

15

10

5

0

Placebo

10 mg

50 mg

Treatment

The Italian microchallenge study

Morphometry findings2


Slide38 l.jpg

12.5 products in Italy where currently food labeling policies for gluten free products are set at 20 ppm

10.0

7.5

ab cells (X100 enterocytes)

5.0

2.5

0.0

Placebo 10mg 50mg

The Italian microchallenge study

Morphometry findings



Toxicity of gluten traces the italian study on gluten microchallenge l.jpg

Toxicity of gluten traces: for celiacsthe 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.


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