Prospective Studies on Celiac Disease

1
Prospective Studies on Celiac Disease
Alessio Fasano and Carlo Catassi Center for
Celiac Research University of Maryland School of
Medicine
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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.
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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

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Pathogenesis

• Genetic predisposition
• Environmental triggers
• Dietary
• Non dietary?

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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

Genes
?
?
?
HLA
?

Gluten
Celiac Disease
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Be aware DR3 should now be referred to as DR17
DQ2
DQ8
DR5/DR7
DR3/DR3
DR3
DQA10501


DQA Any
DQA10201
DQ2
DQB103
DQB10201
CIS
Trans
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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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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Sources of Gluten

• OBVIOUS SOURCES
• Bread
• Bagels
• Cakes
• Cereal
• Cookies
• Pasta / noodles
• Pastries / pies
• Rolls

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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 AdherenceA 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
• Ive 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 havent 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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• Gluten and treatment of Celiac Disease
• How Much is Too Much?

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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 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

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Gluten and Giadins
Wheat

• 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
Gluten
15g
Gliadin
7.5g
52 toxic fragments
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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)

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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

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The Italian microchallenge studyStudy-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 1 2
3 m
T0
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The Italian microchallenge studyMethods

• 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 studySubjects
completing the study
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The Italian microchallenge studyBiopsy findings
at baseline
CD3 T cells (x100 enterocytes)
Controls CD
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The Italian microchallenge studyBiopsy findings
at baseline
IEL count (X100 enterocytes)
VH/CD Ratio
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The Italian microchallenge studyClinical
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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The Italian microchallenge studySerological
findings
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The Italian microchallenge study Morphometry
findings1
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The Italian microchallenge study Morphometry
findings2
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The Italian microchallenge study Morphometry
findings
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Tolerable daily intake of gluten and ppm of
gluten in food for celiacs
50 g 100 g 200 g 300 g
200 ppm 10 mg 20 mg 40 mg 60 mg
100 ppm 5 mg 10 mg 20 mg 30 mg
50 ppm 2.5 mg 5 mg 10 mg 15 mg
20 ppm 1 mg 2 mg 4 mg 6 mg
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Toxicity of gluten tracesthe Italian study on
gluten microchallenge
Catassi C1,2, Fabiani E1, Mandolesi A3, Bearzi
I3, Iacono G4, DAgate 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.