1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR FOOD SAFETY AND APPLIED NUTRITION
FOOD ADVISORY COMMITTEE MEETING
Advice on CFSAN'S Draft Report:
Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food
Thursday, July 14, 2005
8:30 A.M. to 5:20 P.M.
Greenbelt Marriott
6400 Ivy Lane
Grand Ballroom
Greenbelt, Maryland 20770
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P A R T I C I P A N T S
FOOD ADVISORY COMMITTEE STANDING MEMBERS:
Richard A. Durst, Ph.D. - Acting Chairman
Jeffrey A. Barach, Ph.D. (Industry Representative)
Patrick S. Callery, Ph.D.
Dennis Gonsalves, Ph.D., M.S.
Jean M. Halloran (Consumer Representative)
Douglas C. Heimburger, M.D., M.S.
Margaret C. McBride, M.D.
Mark Nelson, Ph.D. (Industry Representative)
Carol I. Waslien Ghazaii, Ph.D., R.D.
TEMPORARY VOTING MEMBERS:
Petr Bocek, M.D., Ph.D. (Absent 7/14/05 Session)
Margaret Briley, Ph.D., R.D.
Erica Brittain, Ph.D.
Ciaran P. Kelly, M.D.
Soheila June Maleki, Ph.D.
David O. Oryang
Marc D. Silverstein, M.D.
Suzanne Teuber, M.D.
FOOD AND DRUG ADMINISTRATION:
Robert E. Brackett, Ph.D. - Director
Food and Drug Administration, CFSAN
Catherine Copp, J.D. - Senior Policy Advisor
Food and Drug Administration, CFSAN
Steven M. Gendel, Ph.D. - Senior Scientist
Food and Drug Administration
National Center for Food Safety and Technology
Rhonda Kane, M.S., R.D. - Consumer Officer
Food and Drug Administration, CFSAN
Marcia Moore, Food Advisory Committee, Executive Secretary
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P A R T I C I P A N T S (Continued)
FOOD AND DRUG ADMINISTRATION STAFF:
Michael M. Landa, J.D. - Deputy Director for Regulatory Affairs
Food and Drug Administration, CFSAN
Stafano Luccioli, M.D. - Senior Medical Advisor
Food and Drug Administration, CFSAN
GUEST SPEAKERS:
Pekka Collin, M.D., M.P.H. - Professor
University of Tampere, Medical School, Finland
Catherine L. Copp, J.D.
Policy Advisor, CFSAN, FDA
Alessio Fasano, M.D. - Professor of Pediatrics
Medicine & Physiology and Director, the Mucosal
Biology Research Center, Center for Celiac
Research, University of Maryland School of
Medicine
Steven M. Gendel, Ph.D. - Senior Scientist
National Center for Food Safety and Technology, FDA
Rhonda R. Kane, M.S., R.D. - Consumer Safety
Officer CFSAN, FDA
Donald Kasarda, Ph.D. - Consultant and Retired
Senior Scientist, Agriculture Research Service,
USDA
Cynthia Kupper, R.D., C.D. - Executive Director
Gluten Intolerance Group of North America
Joseph A. Murray, M.D. - Professor of Medicine
The Mayo
Clinic of Rochester, Minnesota
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C O N T E N T S
PAGE
Call to Order and Welcome and Introductions
Richard Durst, Ph.D., Acting Chairman 6
Use of Gluten Thresholds
Catherine L. Copp, J.D., CFSAN, FDA 9
Introduction to Celiac Disease
Joseph Murray, M.D. 11
Patient Perspectives on Celiac Disease
Cynthia Kupper, R.D., C.D. 69
Grains
Donald Kasarda, Ph.D., USDA 84
Question and Answer Session 108
Prospective Studies
Alessio Fasano, M.D. 114
Question and Answer Session 146
Retrospective Studies
Pekka Collin, M.D., M.P.H. 161
Question and Answer Session 182
International Perspectives on Gluten-Free
Rhonda S. Kane, M.S., R.D., CFSAN, FDA 186
Question and Answer Session 198
Public Comments:
Elaine Monarch 212
Alice Bast 220
Mary Schluckabeer 225
Tom P. Sullivan 232
Steve Taylor 240
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C O N T E N T S
PAGE
Overview of Approaches to Establishing
Thresholds: Gluten
Steven M. Gendel, Ph.D. 253
Question and Answer Session 257
Committee Discussion:
Panel Discussion with Guest Speakers 259
Gluten and Celiac Disease - FDA Questions 287
Revisit Food Allergens 354
Adjournment
Richard Durst, Ph.D., Acting Chairman 363
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P R O C E E D I N G S
CALL TO ORDER AND WELCOME AND INTRODUCTIONS
CHAIRMAN DURST: Good morning. I would
like to call the meeting to order. All right, I
would like to welcome everyone back and also
welcome new participants in our meeting this
morning.
For those of you who weren't here
yesterday, there is a "Conflict of Interest
Statement" over on the table, if you want to refer
to that at all, otherwise I would also ask again
that maybe our participants or our members of the
Food Advisory Committee would introduce themselves
again for the benefit of those who were not here
yesterday.
I am Dick Durst, professor [of]chemistry at
Food Science and Technology Department at Cornell
University.
Marc, would you start it off?
DR. SILVERSTEIN: Marc Silverstein, I'm a
general internist and geriatrician at Baylor Health
Care System
in Dallas.
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DR. TEUBER: Suzanne Teuber, I am an
allergist at UC-Davis.
MR. ORYANG: I am David Oryang. I am a
risk analyst and agricultural engineer at the
United States Department of Agriculture, Animal and
Plant Health Inspection Service.
DR. KELLY: Good morning. Ciaran Kelly, I
am a gastroenterologist at Harvard Medical School
in Boston.
DR. MALEKI: I am Soheila Maleki. I am a
scientist with the USDA.
DR. BRITTAIN: Erica Brittain, I am a
statistician at the National Institute of Allergy
and Infectious Disease.
DR. BRILEY: Margaret Briley, University
of Texas at Austin, nutritionist.
MRS. MOORE: Marcia Moore, I am the
executive secretary for the Food Advisory Committee
and the Food and Drug Administration.
DR. WASLIEN: I am Carol Waslien,
nutritional epidemiologist at the School of
Medicine,
the University of Hawaii.
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DR. BRILEY: I am Margaret McBride, child
neurologist at Akron Children's Hospital.
DR. CALLERY: Pat Callery, West Virginia
University, pharmaceutical scientist.
DR. GONSALVES: I am Dennis Gonsalves, a
scientist at USDA.
DR. HEIMBURGER: I am Doug Heimburger, a
physician and nutrition specialist at the
University of Alabama at Birmingham.
DR. BARACH: Jeff Barach with Food
Products Association here, in Washington, D.C., in
regulatory affairs.
DR. NELSON: Mark Nelson with the Grocery
Manufacturers Association here, in Washington,
D.C., and I am responsible for scientific and
regulatory policy.
MS. HALLORAN: Jean Halloran with
Consumers Union located in Yonkers, New York, and I
am director of food policy initiatives.
CHAIRMAN DURST: Thank you very much.
I would also like to remind everyone and
also for
our new people here at the meeting that
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the "Charge" of the Committee is written out on the
meeting document. The most important thing is that
we are focusing on the "Threshold Working Group
Draft Report on Approaches to Establish Thresholds
for Major Food Allergens and for Gluten in Food."
We are not here to set any kind of
thresholds or discuss the labeling of these foods
for allergens, but strictly to make comments on the
best approaches to use for setting these
thresholds.
Did I cover everything that we need to?
(No verbal response.)
CHAIRMAN DURST: In that case, let's begin
with our first presentation. This is
Catherine Copp, the policy advisor for CFSAN, FDA,
on the use of gluten thresholds.
USE OF GLUTEN THRESHOLDS
MS. COPP: I have been asked this morning
to proceed with discussion on gluten and threshold
levels for gluten or possible thresholds for gluten
framework. It is similar to yesterday. I simply
want to
provide you with some context for the
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evaluating the Draft Report portion that addresses
gluten in food. This is the hazard of being first.
(Slide.)
MS. COPP: Yesterday, I mentioned the Food
Allergen Labeling and Consumer Protection Act.
This is a new law that Congress passed last August.
Although it focuses primarily on allergens, food
allergens, Congress also directed FDA to address
the separate problem of gluten in food.
When I say directed, I mean that Congress
has mandated that the Agency consider and then
establish regulations according to a schedule to
define "gluten-free" for use on food labels and
also to identify the appropriate use of the term.
As with Allergens, for consumers with
celiac disease, strict avoidance of gluten at
levels that will elicit an adverse effect is the
only means to prevent potentially serious
reactions.
Accurate, complete and informative
labeling on foods can help these consumers achieve
their
goal. We believe that understanding
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thresholds for gluten and having a sound scientific
framework for evaluating the existence of such
thresholds will help FDA develop a definition of
gluten-free and identify appropriate use of the
term. That's it.
Thank you.
CHAIRMAN DURST: Does anyone have any
comments or question on Catherine's presentation?
(No verbal response.)
CHAIRMAN DURST: Okay. We will move on
then to the presentation from Dr. Joseph Murray,
professor of medicine at the Mayo Clinic of
Rochester, Minnesota, on the introduction to celiac
disease.
INTRODUCTION TO CELIAC DISEASE
DR. MURRAY: Good morning, Committee
Members. I will be providing a general overview to
celiac disease.
(Slide.)
DR. MURRAY: First of all, we will discuss
what is celiac disease. We will discuss, briefly,
the
pathogenesis of the disease; who gets it; what
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the treatment is, at least in a very relatively
superficial fashion. We will discuss some of the
complications and compliance issues of celiac
disease and a prognosis or future of celiac
disease.
(Slide.)
DR. MURRAY: Obviously, yesterday was
focused on food allergies. "Celiac disease" is one
of the food intolerances that is immune-mediated,
though it is not thought to be IgE-mediated; so, it
comes into the non-IgE-mediated food intolerances
that are mediated by an immune response.
(Slide.)
DR. MURRAY: Where does it happen? It
happens within the smaller intestine, predominantly
the proximal, smaller intestine is the workhorse of
the digestive system. It is this surface of the
intestinal lining that is maximally expanded by the
development of circular folds and on top of these
circular folds the so-called "villi," these villi,
shown here in a histological picture, which
maximize
the digestive surface area.
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It is on the surface entrocytes of these
villi that most of the enzymes and in the layer
immediately above that in the lumen where most
digestion of the macromolecules from nutrition are
broken down and then absorbed. This is just a
picture. It looks like one of those shag-ply
carpets from the 1970s. This is a normal
appearance.
(Slide.)
DR. MURRAY: However, celiac disease is an
inflammatory state of the small intestinal mucosa.
It occurs in those who are genetically predisposed,
and it resolves, the damage resolves, with
exclusion of dietary gluten.
Here, on the left, is a normal intestine
with a normal villus structure; and on the right,
fully evolved celiac disease with complete
destruction.
The villi are gone, not only are they gone
but this entire intestinal mucosa is greatly
thickened and filled with inflammatory cells. This
is where
the primary site of injury occurs in
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celiac disease.
I didn't mention it, but it is a permanent
condition. While it will heal most of the time
with exclusion of gluten, the intolerance to gluten
is permanent and will recur when the individual is
reexposed to gluten.
(Slide.)
DR. MURRAY: Now, what causes celiac
disease?
(Slide.)
DR. MURRAY: We know there are two major
components to this disease: the first is the
genetic background of predisposition.
Much of that predisposition revolves in
the HLA type, which is part of our human leucocyte
antigen-recognition system. It is how we determine
self- and non-self and generate an immune response
as appropriate and its interaction with
environmental factors, primarily the environmental
factor of gluten.
These two conspire together to produce an
immune
response that becomes out of control
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resulting in inflammation, which we just showed to
you, that occurs primarily in the proximal small
intestine and then subsequently the consequences of
this inflammation leading to malabsorption and
symptoms.
(Slide.)
DR. MURRAY: What do we know about the
genetics of the disease? For many years, we know
there is a strong, familial predisposition to the
disease.
If you are unlucky enough to be a
monozygous twin of somebody affected with celiac
disease, your concordance rate is 80 percent. It
is not 100 percent, but it is about 80 percent. If
you are a sibling of a celiac, your chance of
having it is 10 percent. If you are a child of,
about 5 to 10 percent.
There is a very strong association with
certain HLA molecules. These are Class II MHC
molecules but particularly two types. First, DQ2
is the predominant type that is required for celiac
disease,
and in some populations DQ2 is also an
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enabling type.
These genes, however, while they are
essentially required for the disease, are not
sufficient alone to the development of the disease.
Probably 30 to 40 percent of the Caucasian
population carry one or both of these molecules,
but most of them don't get celiac disease. There
are other HLA genes that are likely involved,
though they have not been well elucidated and
certainly not confirmed in many populations.
There are other chromosomal disorders --
Down's syndrome, Turner's syndrome, and Williams
syndrome -- that are associated with a greatly
increased risk of developing celiac disease for
reasons that are not entirely clear, but probably
are associated with the increase risk of disease in
those chromosomal disorders.
(Slide.)
DR. MURRAY: Looking at the primary
environmental trigger for the disease -- that is,
gluten -- it is basically the storage proteins that
come from
these particular cultivated grasses:
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wheat, barley, rye, and other similar grains from
within those families. Other grasses -- for
example, rice, items such as corn, sorghum, millet,
and probably not even oats -- are not involved in
triggering the disease.
(Slide.)
DR. MURRAY: It is the storage proteins
from the endosperm compartment of the wheat kernel
particularly, and those are gliadins oar glutenins
that are thought to contain the antigenic moieties
that trigger the disease.
(Slide.)
DR. MURRAY: What is it about these wheat
proteins? Well, if you take wheat, as an example
of the others, these storage proteins are uniquely
high in certain amino acids, especially glutamines
and prolines.
Over 30 percent of the amino acids in
gliadin are glutamines. The glutamines, of course,
can be cross-linked to give the grain its
resiliency. Really the cooking ability, the
ability to
use wheat as such an effective way of
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making things that stick together like bread, for
example, and maintain their shape, is largely a
property of these particular combinations of amino
acids.
The proline sequences that contain or
proline residues contained within the wheat
proteins also appear to form helices, and these
helices are resistant to digestion within the
mammalian gut.
(Slide.)
DR. MURRAY: This may be a key factor in
what results in the likelihood of these peptides
basically being maintained and becoming, then,
still available for the immune system to recognize
in a patient with celiac disease.
Now, gliadin molecules are presented by
these HLA types to T-cells in the intestine, and
T-cells that are specifically primed to respond to
gluten. There are certain gliadin molecules that
have a higher affinity than others for these
Class II molecules and then the T-cell receptor.
These peptides may be processed or
altered
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within the gut, perhaps, to make them more
antigenic. They may not start out very antigenic,
but then they undergo some change within the gut
that may make them more antigenic.
It turns out that some of these peptides
that are particular immunodominant, these are the
ones that are most likely to produce an immune
response, that those immunodominant peptides may be
digestion resistant because they contain those
proline sequences that perform helix, making them
relatively poorly digestible by peptidases within
the gut.
(Slide.)
DR. MURRAY: Now, it turns out that there
is a contribution to this antigenic nature from
within the intestine itself, and this may well be
because of this enzyme tissue transglutaminase.
This is an enzyme that is present within
the gut mucosa. It is released by cells,
especially fibroblasts when they become inflamed,
and it cross-links cystine residues.
It turns out that it will also act on
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gliadin by deamidating some of those glutamine
residues, some specific glutamine residues, to
glutamates, making it more antigenic by deamidating
that gliadin peptide and making it fit more
perfectly or with a tighter affinity into the
binding groove of the DQ2-HLA molecule, and, hence,
producing a more vigorous immune response within
the gut.
(Slide.)
DR. MURRAY: This is a schema, a
relatively simplified schema, of what I have just
talked about. We start with wheat. You look at
particularly the ethanol-soluble fraction, and
gliadin is probably broken up into smaller
peptides, but still of a sufficient size to produce
an immune response.
It is taken up across the epithelium
presented by antigen presenting cells to the
T-cells. These are T-cells that will specifically
respond to gluten then producing two types of
responses: a cellular response, characterized by
lymphocytes
producing interferon gamma and possibly
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other cytokines. It is probably the cellular
response that leads to the "inflammatory cascade"
that produces the damaged epithelium characteristic
of celiac disease.
It also produces help to the B-cell side,
to produce plasma cells that produce antibodies.
These antibodies are directed both against the
exogenous antigen gliadin and also antibodies
against tissue transglutaminase or what was known
as an the endomysial antibody. It is not known
what the actual pathogenic role of this is, but it
is a very useful serologic or blood marker for the
disease.
I mentioned about the antigen getting
changed by tissue transglutaminase. This is a
little cartoon which shows the peptide derived from
gluten. If you change one specific glutamine to a
glutamic acid, which could be done by tissue
transglutaminase, this then binds much more
tightly. This is the HLA molecule here on the
surface of the antigen presenting cell, and it fits
more
perfectly into the T-cell receptor, producing
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a more potent T-cell response.
(Slide.)
DR. MURRAY: Now, there are other things
that happen in the setting of celiac disease, and I
am really touching just on the surface of many of
these, but there are other things that result in
this inflammation that damage the lining of the
intestine.
For example, there are metallic proteases
that damage the structural elements that maintain
the structure that maintain villus structure.
There is endothelial injury that occurs affecting
the blood vessels in the villus. There are
antibodies, autoantibodies, that are produced that
affect actin that are involved in the site
maintaining the structure of the entrocyte itself.
(Slide.)
DR. MURRAY: Recently, there has been work
suggesting that there is a molecule called
"zonulin" that may be released in the setting of
celiac disease.
This is important because it opens up
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tight junctions between entrocytes which may allow
even more ready access of the antigen, the foreign
antigens, between the cells into lamina propria
where antigen-presenting cells can then present
those peptides to the gluten-responsive T-cells,
further accelerating the disease.
(Slide.)
DR. MURRAY: Now, I pointed out that many
people, 30 percent or more of the Caucasian
population, carry DQ2 or DQ8. Virtually, the
entire population are exposed to gluten, but most
people don't get the disease.
There must be triggers that produce the
disease. There is evidence that suggests that
gluten in the infant diet, specifically the age of
introduction of gluten into the infant's diet, may
be important in triggering or at least producing
autoantibody markers suggestive of celiac disease
early in life.
It is not clear, however, if that changes,
whether you delay introduction or not whether that
changes,
the lifetime risk of celiac disease, but
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it certainly seems to be important in triggering or
producing evidence in childhood at least of celiac
disease immune markers.
The amount of gluten in the child's diet
may be important. There are other events such as
pregnancy, infection, or surgeries that may bring
previously asymptomatic celiac disease to clinical
presentation.
(Slide.)
DR. MURRAY: One could speculate, and I
think this is based on some data, putting data
together, that one's risk for celiac disease starts
with your HLA type. Only those who carry HLA types
are at risk. You, then, are exposed to gluten.
Perhaps the timing of exposure is important,
developing in some individuals a sensitivity to
gluten.
Then, with the interaction of other
factors such as other genes other than HLA, other
things that may predispose one to autoimmunity
including gender and other events that may occur --
gastroenteritis, aging, postsurgical or postpartum
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changes in the immune system that may occur -- may
lead to a loss of tolerance, inflammation, and
subsequent malabsorption.
(Slide.
DR. MURRAY: Don Kasarda, who is here once
used the term or suggested that celiac disease was
a collision between our evolution of our immune
system and our ability to recognize self and
non-self through the HLA system and our cultivation
of wheat and these other grasses. This collision
occurs in the intestine.
(Slide.)
DR. MURRAY: Now, when this collision
occurs and results in damage, how does it present?
And who gets the disease?
(Slide.)
DR. MURRAY: Well, this is classic celiac
disease, and this is the way that I certainly
learned about celiac disease. A severe
malnourished child with evidence of malnutrition
often associated with the large, swollen abdomen
but great
muscle, terrific muscle, wasting and
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protein-calorie malnutrition with symptoms that
would occur sometime after the onset of gluten
introduction into the diet, sometime between the
age of six months and seven years of age: with
failure to thrive; abdominal distention; anorexia;
diarrhea; steatorrhea, that is the passage of
malabsorptive stools laden with fat; anemia; growth
failure; and vitamin deficiencies. That was really
the picture that we had of celiac disease 30 years
ago.
(Slide.)
DR. MURRAY: However, we now see celiac
disease in adulthood. In fact, celiac disease can
present at any age. Symptoms can include things
such as abdominal pain, even upper-GI symptoms:
heartburn, nausea, vomiting, anemia, fatigue.
There are of course patients who have
symptoms of malabsorption, though not necessarily
the classic, fully evolved malabsorptive picture.
Steatorrhea as a presenting symptom is relatively
rare, even patients may have constipation.
(Slide.)
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DR. MURRAY: It can mimic other disorders
such as lactose intolerance. Indeed, lactose
intolerance may be secondary to the damage caused
by celiac disease. It may mimic the symptoms of
irritable bowel syndrome or symptoms of
inflammatory bowel disease.
(Slide.)
DR. MURRAY: There are specific
deficiencies that can occur in celiac disease,
especially the fat-soluble vitamins -- D, E, A,
and K -- with their resultant syndromes from
deficiencies.
Iron deficiency is especially common in
celiac disease because iron is absorbed in the
proximal small intestine; folate deficiency, again,
because it is absorbed in the proximal small
intestine; and, interestingly, B12 deficiency may
be relatively common in celiac disease by a variety
of mechanisms. Other trace elements -- zinc, B6,
selenium, and others -- may also be deficient in
celiac disease.
While in the past we would look for
28
combinations of these, often a patient would
present with many of these deficiencies at the time
of diagnosis, now it is relatively uncommon to see
the entire spectrum of deficiencies. Indeed, you
usually see one or two deficiencies that are
clinically evident, and the others may not even be
present.
(Slide.)
DR. MURRAY: How about non-intestinal? I
have mentioned that the major site of injury is in
the gut, but there are patients who will present
with non-intestinal presentations which can involve
into things such as the musculoskeletal system,
joint pains and osteoporosis or osteomalacia;
infertility or reproductive issues, delayed
puberty, spontaneous recurrent abortions have been
described; hematologic, which is predominantly
anemia; hyposplenism is an unusual consequence but
can present; and then dentition, enamel defects,
can be a presenting feature.
(Slide.)
DR. MURRAY: To focus on iron
deficiency
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anemia, which is probably one of the most common
reasons that I see celiac disease, about 5 to 8
percent of adults who present with unexplained iron
deficiency in some studies have celiac disease.
It is especially common in those who are
resistant to the use of oral iron. If you look at
individuals who are coming to gastroenterologists
for endoscopy, it may be 5 to 15 percent of those
patients, depending on the study, who may have
celiac disease if biopsies are taken from the small
intestine.
However, many of those patients are even
missed because the biopsies are still not taken
during routine endoscopy in patients who have got
anemia in about a third to a half of patients.
(Slide.)
DR. MURRAY: Osteomalacia or bone disease,
this is an example of severe disease with
pseudofractures in the pelvis of an individual,
whose only presentation was osteomalacia with no GI
symptoms, caused by celiac disease.
Other non-intestinal presentations
include
30
neurologic or even neuropsychiatric syndromes such
as neuropathy, ataxia, seizures, cognitive decline,
or dementias; fibromyalgia-like syndromes or
chronic fatigue syndrome-like presentations;
individuals with skin and mucous membranes, there
is a specific rash associated with celiac disease,
a recurrent aphthous ulceration of the mouth; the
dental enamel defects we mentioned.
(Slide.)
DR. MURRAY: And, then, dermatitis
herpetiformis was specifically mentioned, because
this very blistering, extremely itchy skin rash
that affects the extensor surfaces is a direct
manifestation of intestinal gluten sensitivity.
(Slide.)
DR. MURRAY: Now, what about other
associated conditions? Celiac disease is
associated with other autoimmune conditions. It
may be seen in 3 to 7 percent of Type I diabetics,
individuals with thyroid disease, individuals with
inflammatory arthritis, primary biliary cirrhosis,
as examples
of others; and then the congenital
31
disorders, especially those associated with
chromosomal abnormalities and also selective IgA
deficiency. If you look at relatives of celiacs,
it is anywhere between 5 to 20 percent, depending
on how one is related to someone with celiac
disease.
(Slide.)
DR. MURRAY: Now, beyond the symptomatic
celiac disease, there are also individuals who have
no symptoms, who already have fully evolved damage
within their intestine, and there may be no symptom
or there may not be occurring in someone with an
associated disease.
This is frequent to find this in first-
and second-degree relatives of patients with celiac
disease.
(Slide.)
DR. MURRAY: There is also what is termed
"latent" -- well, whether it is latent celiac
disease or latent gluten sensitivity -- individuals
who have a positive serologic response but have a
negative
small-bowel biopsy. Some of those
32
patients will go on to develop the full-blown
disease, if followed, on a normal diet.
(Slide.)
DR. MURRAY: What about the epidemiology?
To summarize, while it was first identified in
Europe, it occurs essentially in all populations,
which could be termed Caucasian. Its prevalence is
probably somewhere between 1 in 90 to 1 in 300;
however, the diagnosis rate is much lower, which
would suggest a prevalence of about 1 in 2,000, if
you just look at the diagnosed cases.
It is one of the most frequent genetically
based diseases. If you look at other countries --
Latin America, or other areas; Africa, especially
North Africa; if you look at Asian countries --
there is celiac disease present in those. The
worldwide average prevalence is somewhere very
close to 1 percent.
(Slide.)
DR. MURRAY: I'm coming a little closer to
home. This is the data from Olmsted County, that
we
published a couple of years ago, which looked at
33
the new case identification or the incidence rate.
The solid yellow line is the new cases per
100,000 in the population, which is essentially
quite low and stable over many decades until the
1990s and into 2000 to 2001, showing a greatly
increased rate of detection of celiac disease.
If we looked at who were being diagnosed,
this is the age of diagnosis by age category. This
is the incidence per 100,000 of people in that age
category in the community. You can see that the
new cases being diagnosed are predominantly people
between the age of 45 and 64.
The solid line indicates females; so,
females are diagnosed at a rate about twice that of
males of all ages.
There are a significant portion of
individuals, almost a third, who were diagnosed for
the first time over the age of 65.
(Slide.)
DR. MURRAY: One can term or consider
celiac disease like an iceberg. These are a series
of icebergs
where the tip of the iceberg is the
34
part that has been detected, and the part
underwater is the part that can be found if one
screens the population. Of note, these are numbers
per thousand not percent.
Obviously, there are some places like
Ireland, for instance, which is quite a big iceberg
with a lot above water but also a lot below water.
Finland, which this iceberg is probably even more
out of the water as they have got a very active
program for finding celiac disease.
This is circa 1996. The U.S.A. iceberg is
still close to a very low level of actually being
diagnosed; but this number, the part underwater,
has actually grown to be something very close to
what you would find in Finland or Ireland,
especially when one looks at, at least what we know
about is really from a Caucasian population.
(Slide.)
DR. MURRAY: One miniature study, this is
one we simply looked at, Natrona County in Wyoming.
This is a very isolated community. Anybody who has
been to
Wyoming, there is lots of nothing for miles
35
and miles.
We were able to study about 4,000
individuals from a health fair, generally healthy,
and found the numbers above just under 1 percent of
people who had serologic evidence for celiac
disease.
Only half of them had GI symptoms. Most
of them did not have other risk factors for celiac
disease, just two having family members with celiac
disease.
However, these are numbers that would
confirm basically the rest of the world's data that
suggests that the prevalence of celiac disease, if
you look for it, is probably slightly under
1 percent.
(Slide.)
DR. MURRAY: Now, how does one make the
diagnosis? It starts with suspicion. Serologic
tests may be very effective at detecting the
disease. The intestinal biopsies are regarded as
the gold standard. Then, one ultimately gets a
response to
a gluten-free diet to confirm the
36
diagnosis.
(Slide.)
DR. MURRAY: The pathology, as we have
mentioned already, is a pathology of chronic
inflammation within the intestine with features
such as intraepithelial lymphocytes on the surface,
villus atrophy or the loss of the villus surface,
great crypt hyperplasia, and then characterized by
being a lamina propria filled with lymphocytes,
macrophages, plasma cells, and even eosinophils.
(Slide.)
DR. MURRAY: There is however a spectrum
of damage that occurs, typified here by the Marsh
classification. This is classic disease, but there
are also milder forms of the disease that may be
asymptomatic in most individuals.
(Slide.)
DR. MURRAY: Our algorithm for finding
celiac disease, if we have a high clinical
suspicion, an individual with malabsorption, we
biopsy those individuals. If we have an individual
who is at
moderately increased risk, serology is
37
probably the most effective way of finding it.
Though, we yet do not depend on the serology alone
to detect this, there are other circumstances for
alternate; serologic testing may be necessary.
(Slide.)
DR. MURRAY: Now, what about treatment for
celiac disease, or, as one patient with celiac
disease called it, "playing gluten-free roulette"?
(Slide.)
DR. MURRAY: The nuts and bolts of a
gluten-free diet, basically one needs to avoid
foods that contain the offending grains: wheat,
barley, rye, and the wheatlike grains of spelt and
kamut.
I put down at the bottom that many corn or
rice commercial cereals do not appear to be
gluten-free because of their incorporation of
particularly barley extract in their flavor
ingredients.
(Slide.)
DR. MURRAY: Now, one of the issues and of
course the
issue for today is, How much gluten is
38
too much? We will be hearing a lot more when you
hear prospective and retrospective data later this
morning on this. I am not going to dwell on it.
One thing from clinical appreciation is
that symptoms are not a good indicator of gluten
ingestion. Many patients can have significant
damage to their intestine, despite the absence of
symptoms when they ingest gluten.
Most patients diagnosed clinically with
celiac disease have never suspected that wheat or
gluten products are what are precipitating their
symptoms. They may have or are often likely to
have blamed other foods that they weren't able to
digest because of the damage.
Antibodies such as tissue transglutaminase
antibodies are really only positive of the
substantial gluten contaminating the diet. At
least in my practice if somebody admits to cheating
more than once a month they will like continue to
have injury in their gut. However, there is a high
degree of variability in the sensitivity to gluten
ingestion,
at least clinically.
39
(Slide.)
DR. MURRAY: We will hear a little bit
about Codex Alimentarius draft standards. This,
however, is still a draft, I think a Stage IV
draft. I want to put this up really to demonstrate
that there is a variance between countries and what
one allows.
We will hear more from our colleagues from
Europe about some of the incorporation of rendered
gluten-free foods which use the gluten-containing
grains as a base and then remove the proteins from
them.
(Slide.)
DR. MURRAY: What about non-responsive
celiac disease? This is relatively common. By
far, the most common reason is inadvertent gluten
contamination of the diet and lymphocytic colitis,
pancreatic insufficiency, bacterial overgrowth, and
then only a few patients have true refractory
disease that no longer responds to exclusion of
gluten from the diet.
(Slide.)
40
DR. MURRAY: There are many potential
sources of contamination of the diet with gluten,
which include of course commercial cereals, eating
out, communion wafers, lipstick, airborne flour or
starch in certain work situations, so-called "soy"
sauces made from wheat, mislabeled or unlisted
ingredients have been an issue, and at least
allegedly some medications.
(Slide.)
DR. MURRAY: Some ingredients that people
are concerned about: seasonings and spice blends,
modified food starch, malt and malt extract,
modified hop extract or yeast-malts, sprout
extract, dextrins, caramel color. There are a
whole bunch of things that might be derived from
gluten-containing grains.
(Slide.)
DR. MURRAY: What about complications
associated with untreated celiac disease? We know
the mortality of symptomatic celiacs who do not
comply with the diet has doubled. The mortality of
celiac
disease even when it is diagnosed is also
41
double, even following out for several years after
the diagnosis.
The predominant excess in death comes from
GI malignancies. There are also morbidity
consequences such osteoporosis or osteomalacia,
stunted growth, infertility, chronic ill-health --
all of which could be prevented by early detection
and treatment.
(Slide.)
DR. MURRAY: What are the dangers of
non-compliance? The increased mortality we
discussed, the osteoporosis. Children who were
diagnosed and then did not remain on a gluten-free
often have osteoporosis or diminished bone density
when they get to adulthood, lymphoma, other
cancers, and then the psychological effects of
non-compliance.
(Slide.)
DR. MURRAY: One of the most feared
complications of this are the T-cell lymphoma.
This is celiac disease on this side, and the T-cell
lymphoma on
the other side is one of the more
42
feared complications with a very high mortality.
(Slide.)
DR. MURRAY: However, as I pointed out,
most celiac disease is probably not symptomatic, at
least when we look at a cross-section of the
population. We do not know whether those
identified by screening are less sick than
clinically diagnosed celiac disease.
We don't know the benefit or negative
effects of a gluten-free diet in those who are
found by screening alone. We don't know if they
are any more or less likely to comply with a
gluten-free diet. We don't know whether
intervening in those patients will actually affect
their ultimate mortality.
(Slide.)
DR. MURRAY: George Dennison Prentice
said, "What come call health, if purchased by
perpetual anxiety about diet, isn't much better
than tedious disease."
(Slide.)
DR. MURRAY: This comes to the
future.
43
There is, I think, a promising future in celiac
disease, a variety of approaches, which I have
listed, that individuals and research groups are
looking at as alternates to the gluten-free diet,
though none of them are really even close to
clinical use.
(Slide.)
DR. MURRAY: This is one that has been
tested in patients using a lactobacillus digestion
strategy, trying to reduce the potential, harmful
effects of gluten.
In summary, I would like to suggest that
gluten or celiac disease is common. It has been
largely unrecognized until recently. There are
many challenges that face patients and their
physicians in the treatment.
The gluten-free diet is not simple. There
is widespread use of grain proteins in good, and
that makes it challenging for individuals with
celiac disease. Food ingredient source
identification is of great concern to patients.
Dietitians and those who counsel patients
44
with celiac disease, we are here because of
regulation or potential regulations. Defining
acceptable thresholds and verification of those may
be very important to patients with celiac disease.
(Slide.)
DR. MURRAY: I finish with an aside on
another food safety issue, an invitation to come to
Minnesota and enjoy Joe's and have worms at the
same time.
Thank you.
CHAIRMAN DURST: Thank you very much,
Dr. Murray.
QUESTION-AND-ANSWER SESSION
CHAIRMAN DURST: I would like to ask the
Committee if they have any questions or discussion,
and also to point out that Dr. Murray will not be
able to stay around for discussion this afternoon.
If there are questions, now is the time to ask
them.
Doug.
DR. HEIMBURGER: Thank you very much for
that
presentation. It is very helpful. I do care
45
for some patients with celiac disease. As you
already mentioned, one of the big questions that
they have is, "What really are my risks if I play
with it a little bit? If I knowingly introduce a
little bit of gluten in my diet, how absolutely
obsessive do I need to be about it?"
With the mortality being primarily
associated with the risk of lymphoma, what is the
quality of the evidence that compliance with gluten
restriction is really correlated with the risk of
lymphoma?
DR. MURRAY: The evidence, the quality of
the evidence is largely observational, taking
cohorts and following them, and often their
self-assessment of their level of compliance. The
data is based on those cohorts. They are
predominantly referral cohorts.
The longest follow up comes from Britain.
In those, there is quite a clear increased risk not
just for lymphoma but other malignancies in those
who are considered not to be completely compliant
with the
diet. I would say the level of evidence
46
while it is not a prospective study, in retrospect
in fact it appears to be reasonably strong.
DR. BRILEY: Margaret Briley. I would
like to know what you can tell us what might be the
reason for the increased detection of celiac
disease? Is the serological test the definitive
reason? What is going on with those? It seems to
be more prevalent, as you said, in our society.
DR. MURRAY: I think there are probably
two reasons, one is probably serologic detection
has made this an acceptable diagnosis to primary
care physicians, number one; and the second is
suspicion, that is, the awareness of celiac disease
as a possibility.
I do not believe, however, we can rule out
the possibility that celiac disease is actually
increasing in prevalence over time.
We don't know, but we know that there
certainly were substantial increases in other
inflammatory bowel diseases over the last 50 years,
which may not have been accounted for by detection
rates, for
example.
47
I do agree with you it is probably the
sero-detection. It is a combination of those two
things, suspicion and ease of detection have made
the biggest difference. However, I would not rule
out the possibility of its actually increasing in
prevalence.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Soheila Maleki. I was
wondering how long does a person that is
asymptomatic go before they find they are
symptomatic? How do they usually find out?
DR. MURRAY: First of all, we don't know
when it starts. There is one study I didn't talk
about from Denver that suggested that children, if
you follow children at genetic risk for celiac
disease based on HLA type, that they will convert,
sero convert, by about the age of seven, though
most of them are asymptomatic.
It reaches all but 1 percent of that
childhood cohort, the same prevalence you find if
you look at adults. The suggestion is that you
have
developed that celiac autoimmunity probably by
48
the age of seven.
However, the age, the median age, of
diagnosis is 45 years of age. It is likely that
those individuals have some clinical disease for a
long time before they present.
In our population, the most common reason
for presentation is postmenopausal anemia. Women
who have anemia sometimes go a long time,
especially when they are menstruating. The doctor
says that menstruating is an excuse for the anemia.
Now that they are menopausal and are no longer
menstruating they no longer have an excuse for
their anemia, and they are referred for evaluation
for the cause of anemia.
Iron deficiency anemia at least is one of
the most common, but there are other things. For
example, the development of chronic GI symptoms.
Largely, as the earlier questioner said, probably
awareness of the possibility of this disease, with
primary care doctors using sero-diagnosis to find
celiac disease.
There a lot of atypical symptoms.
There
49
are reservoirs of celiac disease, the Type I
diabetics, the family members of celiacs, those
with chromosomal disorders. As the doctors looking
after those people become more aware of celiac
disease, they are testing their patients more.
DR. BRILEY: Could you speak a little bit more about
the evidence that you have in regard to physicians
using the serological test? Is it a pretty common
thing to do it at the very beginning of a patient's
coming in with GI problems, or is it more likely it
is down the road a while?
DR. MURRAY: If you look at the data on
patients’ presentation time, from presentation to
diagnosis of celiac disease, it is somewhere
between 8 and 11 years from the time they present
to their physician with a complaint to the time
their diagnosis is made.
I think that time period is now beginning
to shorten, thankfully. The serology is done close
to the end of that period, so it is often only when
the suspicion is generated. Partly that is because
it is not
considered at the early differential
50
diagnosis of celiac disease.
It is also difficult. It is difficult
because the symptoms are not very specific.
Fatigue and some bowel disturbance and a little
anemia, that is not a rare syndrome or not a rare
collection of symptoms you will see in individuals
in our community. It is hard to know where you
look for celiac disease and when you look for it.
It is often a very delayed diagnosis.
DR. BRILEY: Is the serological test one
that is pretty accurate? Could one count on it if
you did it early?
DR. MURRAY: If you use the more modern
autoimmune tissue transglutaminase test, for
example, it is reasonably good. It is not perfect,
but it is quite efficient at detecting celiac
disease at that level, in that period. It is not
perfect, though, but it is a pretty good test.
DR. BRILEY: It sounds like we need to do
some education, then.
DR. HEIMBURGER: A follow up to that --
Doug
Heimburger -- what is currently understood to
51
be the sensitivity specificity of anti-tissue
transglutaminase antibodies?
DR. MURRAY: Depending on the study, most
studies suggest that the sensitivity of tissue
transglutaminase for celiac disease is in the high
90 percent, so the high 90s.
The specificity is probably also in the
mid- to high 90s, so quite effective when you are
looking at a population you are suspicious of the
disease.
DR. BRILEY: One more question.
Margaret Briley. Do we have any data that shows
the celiac patient also maybe has been identified
with a lactose intolerance? Is there anything that
combines those two that you would know or does
that--?
DR. MURRAY: The combination is probably
the damage that is caused by celiac disease, the
damage to the entrocytes affects your disaccaridase
including lactase throughout the surface of the
small bowel, and, hence, you get a secondary
lactose
intolerance.
52
In general, if you think of the genetic
basis or the ethnic groups that are involved,
celiac disease tends to hit those of European
extraction more so. I know that population will
tend to retain their lactase activity for longer.
If you look at Subsaharan Africans, for
example, we don't know actually what the prevalence
of celiac disease is in Subsaharan Africans, but
they are individuals who tend to lose their
lactase.
Genetically, they are probably separate, but they
come together because of secondary lactase
deficiency caused by the damage in celiac disease.
DR. NELSON: Thank you, Dr. Murray. That
really was a very interesting presentation. I
think the last time I studied this was 30 years
ago.
CHAIRMAN DURST: Identify yourself,
please.
DR. NELSON: Mark Nelson. I wanted to
touch base on the couple of slides where you talked
about how
much gluten is too much and the proposed
53
Codex definition for gluten-free foods.
You had a question mark after the
threshold for damage being 20 to 100 milligrams per
day, and I guess that is similar to the naturally
gluten-free foods the Codex proposed.
Then, it goes on to talk about cheating is
greater than once per month. Also, is there an
issue of cumulative exposure, 20 milligrams per
day, or is the cheating an excursion of whole wheat
crackers, for example?
DR. MURRAY: Well, first of all, the
comment on cheating that is what the patients tell
me, those patients who will admit to gross
cheating, that is, eating a piece of bread or a
cookie or cake, which is what I regard as an
obvious source of gluten.
However, that may reflect some other
background, but a lack of detail of care, for
example, attention to detail in the rest of their
diet, maybe what they are not telling us. That
only applies to what they have told me.
The issue of actual threshold, I have a
54
question mark after that because we will hear a lot
more detail, science, about threshold testing for
thresholds of gluten contamination.
The intermittent contamination, once a
month obvious contamination. Something that is, to
some degree, under the patient's control with
appropriate education and exposure to information
then essentially it is under their control.
It is the low-level contamination on a
regular basis from sources they are not aware of,
and those are the patients that I see that make up
the majority of the patients I see who have
difficulty. They are coming to me because they are
trying to be gluten-free, but they are having
contamination of their diet on a daily basis,
probably a relatively small amount. We will hear a
lot more about the threshold, the actual testing of
the threshold using that type of low-level daily
contamination.
DR. MALEKI: Soheila Maleki. Is there an
adult onset or spontaneous development of celiac
disease, or
does this have to come with a genetic
55
component and hereditary?
DR. MURRAY: It probably only occurs in
people who have that HLA or genetic type. You have
to have it. However, that is 30-plus percent of
the Caucasian population.
Can it start first in adulthood? We have
very little data on that. The only data is the
stuff I have mentioned, looking at children and
showing about 1 percent by the age of seven or
eight, positive by the age of seven or eight, the
same prevalence if you look at adulthood.
There are a few cases of what we call
"latent celiac disease," individuals who have got
antibodies with apparently normal small intestinal
biopsies as adults, then go on over a space of
years to develop full-blown celiac disease within
years of that initial identification of a positive
serology. Those are very rare cases that have been
found.
Of course, if you find somebody who
suspects they have got a problem, they ought to
change
their diet anyway, and that changes
56
everything. There is very little data, I think, to
be sure of whether it first occurs, starts, in
adulthood.
If you look at the age of diagnosis, your
eighth or ninth decade can be the first time that
you are diagnosed with celiac disease. A lot of
those patients have suspicious symptoms going back
many years.
DR. BRITTAIN: Erica Brittain. Can you
quantify the level of damage? Is that only
possible with the biopsy, and is that very
invasive?
DR. MURRAY: You can -- well, if you take
biopsies, you can quantify the degree of injury. I
showed that slide which shows a spectrum of injury.
It tends to be variable, even within the same
individual. It started in the first part of the
small intestine and extends a variable distance
down the small intestine.
There has really only been one study,
which was done in the early 1960s, of taking
multiple
biopsies down the intestine -- a handful
57
of courageous volunteers.
It is not clear that there is a
correlation between the extent of injury and the
severity of symptoms. In fact, we don't know how
to predict the occurrence of symptoms in patients
with celiac disease, so that is a "black box."
DR. BRITTAIN: You are saying there is
really no simple way to quantify the extent of
damage? There is nothing that would correlate with
these multiple biopsies?
DR. MURRAY: Some people have suggested
that the level of the antibodies, the tighter the
antibodies might correlate: The higher, the
tighter, maybe the more severe the injury to the
intestinal biopsies.
When we take a biopsy of the intestine, we
are sampling a tiny fraction of a percentage of
1 percent, a fraction of 1 percent, of the
intestinal lining. We have tried to look using
other imaging techniques to assess the extent of
injury. Using some of those techniques seems to be
very
variable between individuals, and it doesn't
58
seem to predict their symptoms.
Really right now it is a yes or no issue:
yes, they have celiac disease; or, no, they do not.
It is very hard to measure the severity of the
disease.
We can look at the severity of
consequences: have they developed osteoporosis,
what their bone density is, have they lost a lot of
weight, whether they have severe malabsorption
based on fat malabsorption in their stool. We have
got other measures to look at the consequences or
impact of the disease, those we can assess.
DR. BRITTAIN: Do you think that it would
correlate with the intestinal damage? Not
necessarily?
DR. MURRAY: We have tried. I would say
that the data is not very good on that. People
with very mild injury may be more likely to be
asymptomatic, but the data is not sound.
CHAIRMAN DURST: Suzanne.
DR. MALEKI: Suzanne Teuber. I had a
question
about the neurologic presentations. I
59
have read some on screening of pediatric
populations, but with adults how often does it
present as dementia without it being diagnosed as a
GI problem? Is this something we should be adding
to dementia screening?
DR. MURRAY: It is probably relatively
rare. In fact, I think there has only been one
good study. Maybe Dr. Collin, who is here as a
speaker later, has done a study and has looked at
and reported on that.
We occasionally see cognitive decline at
the time of diagnosis, but there is really no good
epidemiologic study to address that. Some of the
other presentations, peripheral neuropathy, for
example, or ataxia, there is more data on it. Many
neurologists are beginning to include celiac
disease as part of their differential diagnosis for
those syndromes. Good epidemiology data is
relatively small, very little data.
CHAIRMAN DURST: Ciaran.
DR. KELLY: Ciaran Kelly. This is
actually
more clarification than a question. Dr.
60
Murray is quite correct that there isn't a measure
of either severity of intestine abnormality or even
height of antibody levels that reliably reflects
the degree of injury or correlates closely with
symptomatology.
However, with treatment one can use a
decline in antibody levels as a crude indicator of
at least reduced exposure to gross amounts of
gluten. It is not a very sensitive indicator, but
it is useful. Of course, with repeat biopsy, if
the histology has revered to normal, that of course
can be used. However, the less invasive test of
following antibody levels is used clinically to
follow response.
DR. MURRAY: Quite right. I think you
will agree, Joe.
DR. KELLY: If the antibody levels aren't
dropping, that is used as an indication that the
patient is successfully on a gluten-free diet.
DR. BRILEY: Margaret Briley. Can you
give us any idea of any behavior data that you may
have
received from your patients regarding their
61
willingness to try foods that are not gluten-free
labeled?
DR. MURRAY: Oh, well, there are many
different attitudes among patients with regard to
what they want to eat or what they are afraid to
eat.
I advise my patients to be prudent, that
they try to select things based on identification
of ingredients, source ingredients, not containing
things contained from gluten, the use of substitute
grains that are gluten-free.
Many patients are quite willing to do that
on their own. Many of them use support group
information where maybe a group has cooperatively
contacted manufacturers who in good faith provide
information on their source ingredients.
There are some patients who are entirely
paranoid about it, and want to obtain a kit to test
the food. I don't know that we've got a very
effective kit yet for testing food for gluten
contamination. There are many different attitudes.
Fear is a major concern among my patients.
62
I mean, fear of even the slightest potential, not
even actual but potential contamination. This can
verge on, "Do we avoid taking prescription
medications for things like hypertension?"
resulting in life-threatening changes to their
medication regimens because of fear of
contamination.
I would say fear is a major part or a
major influence on the quality of life. We will
hear more I think shortly on the impact of a
gluten-free diet on patients' lifestyles a little
later. Certainly that does affect a substantial
portion of my patients.
Patients go through a substantial grief
reaction and feel socially isolated because of
their difficulty of interacting with society,
because so much of our society activities or social
activities revolve around food. There is that
safety sense of insecurity, which I think pervades
or affects many patients with celiac disease.
DR. BRILEY: Thank you.
CHAIRMAN DURST: Soheila.
63
DR. MALEKI: Well, I just want to know if
there are any coordinated studies for a
determination of thresholds? I know you mentioned
the level of PPMs. Do you know of any studies?
DR. MURRAY: There are and you will hear
about them. There are both retrospective and
prospective studies, and you will be hearing some
data on those later this morning.
CHAIRMAN DURST: I have one question --
Dick Durst -- on the biopsy and histological
studies to see the morphology, morphological
changes, you showed from the shag rug. I am just
curious whether just one of these cameras you can
swallow would be able to detect those kind of
changes without having to go through a biopsy?
DR. MURRAY: Yes, you can detect them.
Nobody would suggest that it would replace the need
for biopsies to make the diagnosis. There is
really relatively little published data on it.
There has been a paper suggesting that you can see
those changes. With a magnified view, you can see
with a
capsule.
64
Yes, I think you can identify those
changes in a lot of individuals with celiac
disease, maybe all of them. Although, I really
can't comment more on that, because it hasn't
really been studied in any great detail.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: Erica Brittain. Do you
have any insight about the cumulative effect of
decades of low levels, very, very low levels of
gluten exposure? Certainly, we are going to have
to think about what chronic exposure could do when
we talk about the thresholds. Can you provide any
insight into that?
DR. MURRAY: Probably the best clinical
insight I can give are individuals who I see who
were diagnosed 20 years ago and have not come back
to medical attention in 20 years. I see those
patients maybe every week.
I would see somebody who is diagnosed 20
years ago, and they got instruction at that time
that allowed them to eat things like barley malt or
that people
weren't really instructed about some of
65
those rice or corn cereals that may have contained
malt, for example.
Those patients come back with anemia,
chronic GI complaints, maybe not as severe as they
had initially, but they certainly have accumulated
some health morbidity over those 20 years. Some of
them will come back with frank lymphomas and will
end up with a mortal complication of their celiac
disease.
Yes, at least my clinical observation is
that I frequently see individuals with problems
that we get rid of, once they now move to a much
more strict gluten-free diet, by eliminating those
things -- largely, because in 20 years they didn't
go back and get more education and realize that you
had to exclude those minor ingredients. That is
one way of looking at the effects of decades'
accumulation of low-level contamination.
CHAIRMAN DURST: Dick Durst again. On
your slide that showed the various causes, the
different grains, and so on, I believe you
indicated
oats was not one of the causes. Could
66
you expand on that?
DR. MURRAY: We will hear a little more, I
think, from Dr. Collin on that issue. While oats
had been thought to be one of the offending grains
in things done in the fifties and sixties, it turns
out from recent very well-done studies that it
doesn't appear to impair the healing of the
intestine in newly diagnosed celiac disease. It
doesn't seem to result in a significant worsening
of production of damage in patients who are already
diagnosed with celiac disease.
For the vast majority of celiacs, it is
probably safe in its native, pure form. However,
there are some sequences within oats that can
produce an immune response, at least in vitro, in
lymphocytes derived from a few celiacs.
It is not an absolute. There may be some
individuals with celiac disease that can respond to
oats, both in the laboratory test and possibly also
clinically there are a few.
There are probably a relatively small
minority of
celiacs in which that occurs. A bigger
67
concern is the issue of contamination of oats with
other grains that are well recognized to cause
injury.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc Silverstein. I
would like to inquire about the potential
subsequent lifelong increased risk of GI cancers.
I presume that the risk is predominantly small
bowel, but I wonder if there is any increased risk
of colorectal cancer?
Then, what are your thoughts about whether
there is sufficient risk that patients with celiac
disease should be in some sort of surveillance
program for early detection of GI cancer?
DR. MURRAY: Clarifying the risk of
cancers, it is particularly visceral cancer but
also includes: esophageal cancer, non-Hodgkin's
lymphoma of any site not just the intestine, and
probably also B-cell lymphomas, as well as the
T-cell lymphomas, small-bowel carcinoma.
There is a greatly increased relative risk
of
small-bowel carcinoma. Of course
small-bowel
68
carcinomas is a very rare disease to begin with, so
the lifetime risk of dying of a small-bowel cancer,
even in a celiacs, is still relatively small. The
data on colon cancer is mixed. There is some that
suggests there is an association; and some, that
does not.
When you look at other causes of
mortality, even non-cancer causes of mortality such
as infections, neurologic disorders and chronic
lung infections, there are other excesses of
mortality that occur in patients with celiac
disease.
There are some reductions in cancer
mortality. It appears, at least there is a
suggestion, that breast cancer may be less common
in celiac disease than non-celiac disease. There
were a couple of suggestions that lung cancer might
be less common in celiac disease than in non-celiac
disease.
Now, whether there is some competing issue
like smoking may be less common in celiac disease
than
non-celiac disease, so there may be some other
69
competing issues that are involved. Body size may
make a difference. It may be another confounding
issue that confounds or is a competing risk for
malignancies.
While small-bowel cancers and lymphomas
are the two that have the greatest relative risk,
it is a small, absolute risk because of the
relative rarity of those cancers.
CHAIRMAN DURST: Do we have any further
questions for Dr. Murray?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
Our next speaker is Cynthia Kupper, who is
the executive director of the Gluten Intolerance
Group of North America who will present on patient
perspectives on celiac disease.
PATIENT PERSPECTIVES ON CELIAC DISEASE
MS. KUPPER: Good morning. I am a
dietician, not a doctor. I appreciate the honorary
doctor status.
My job here today is to give a face for a
person with
celiac disease. I have been tasked
70
with letting you know who they are, letting you
know how they get their information and education,
and then also providing you with some information
about labeling that they have.
(Slide.)
MS. KUPPER: First of all, living with
celiac disease is very difficult. It is a chronic,
lifelong condition, as you have heard, and people
find this to impact greatly their quality of life.
Forty-four percent of the patients in a
Canadian study say that the diet is very difficult
to follow. In fact, there are some studies that
suggest that the compliance with the diet can be as
low as 50 percent in teenagers but probably ranges
around 70 percent compliance.
Eighty-four percent of these patients in
Canada suggested they have a difficult time
determining what is gluten-free and what is not.
They don't travel, and they don't eat out. It
impacts their family life and their career.
If you have celiac disease and are an
X-ray
technician, oftentimes you change careers
71
because sometimes the X-ray slides are dusted with
flour. Chronic exposure could impact your quality
of life.
(Slide.)
MS. KUPPER: I did a study online of 620
patients a few months ago. In response to that
study, 75 percent of them said that they can tell
the difference between a gluten reaction and other
intolerance or a food allergy.
When they discussed their reaction
symptoms, they ranged from anaphylaxis, which is
not a gluten reaction for celiac disease, to
delayed reactions which could impact any aspect of
their GI and other health systems, body systems.
The average time to reaction was somewhere
between four to eight hours, but some of them
complained of immediate, almost allergic type
responses, and many of them said that their
responses or the symptoms that they had would last
for several days.
Keep in mind, there is no medication we
can give
them to make this go away, so they just
72
have to let it work its course. This is really
disturbing to me.
(Slide.)
MS. KUPPER: As a dietitian, patients do
not rely on medical communities and professionals
for their information. They rely primarily on
support groups.
Actually, the Internet should probably be
the first one, because they are Internet savvy.
They have been out there and they have gotten all
kinds of information before they ever see a
dietitian. Not only do they get information from
the Internet and the support groups, but there are
list serves and chat groups that they belong to.
These can be very useful tools for a
person with celiac disease. However, they also
provide some very frightening and unreliable
information that the patients will hold onto as if
it were gospel. Then, they work with self-help
books as well.
Unfortunately, doctors, and especially
dietitians,
are seen as unreliable. It is sad for
73
me to say that as a dietitian my profession doesn't
get this disease. They also treat it like it is a
rare thing, and they don't know anything about it.
In the United States, I can tell you that there is
probably a handful of dietitians who would be
considered experts in celiac disease.
Doctors don't get much more respect,
primarily because it has taken so long for the
patient to get a diagnosis that the patient has
lost faith.
Then, they will go to research facilities
like the University of Maryland, Chicago, and
New York, or the Mayo Clinic. Lastly, they will go
to medical Web sites. The bulk of our information
is coming from potentially unreliable and
non-research-based sites.
(Slide.)
MS. KUPPER: The consumers perceive that
gluten exposure levels -- the question was asked to
me, "What do consumers believe about gluten
exposure? Are they concerned about the health
risks?" The answer is yes
and no.
74
On the study that I did, it depended upon
their confidence of the labeling, and it depended
on whether they accepted testimony or accepted
research. There is a group of celiacs, as
Dr. Murray suggested, who really don't want to
listen to what research suggests.
As you move forward, with not only
establishing how you are going to determine the
threshold but what that threshold will be, you will
have a fight in the celiac community for a lack of
education and understanding of research.
Consumers oftentimes also have an
inability to correctly interpret research findings.
These are people who have just enough medical
knowledge to be dangerous, so they don't have a
full understanding of the terminology they are
talking about.
There is this constant perpetuation of
misinformation. I don't know how many times when
we try to bury something that is inaccurate it gets
dug up.
(Slide.)
75
MS. KUPPER: There are varying levels of
gluten sensitivity, as you heard, too. There is
the perception that gluten is poison. Not unlike
the allergy people that we heard from yesterday,
this is a huge issue to the celiac consumer.
They believe most of the time that when
their gut hurts it is from gluten not from
something else. Consequently, we are trying to
help the patient understand that not everything
that makes their gut hurt is gluten.
As Dr. Murray said, there is a huge fear
reaction. If I had to put a psychological label to
a group or at least a portion of the celiac
community, they are filled with fear and a little
bit paranoid about what they can and can't do.
How do we define "gluten-free" in the
U.S.? This is a really interesting question. Of
the consumers, only 19 percent realize that there
is no definition right now for gluten-free in the
U.S. Many of them define that the true definition
is zero. This is a problem -- a lot don't know.
(Slide.)
76
MS. KUPPER: When I ask the question, "Do
you trust gluten-free labeling?" It was
interesting, too, because most of the people say
they do trust it. However, when you ask them if
they ever had a reaction to a product labeled
gluten-free, you can see that up to 50 percent
suggested that they might have had a reaction to a
gluten-free product.
When I talk to manufacturers that
manufacture only gluten-free products and ask them,
"Do you test, and what do you test to," many of
them are using older testing methods not the newer
testing methods, the monoclonal tests that we
talked about yesterday.
Some of them tested 200 parts per million,
some of them tested 20 parts per million, some of
them tested no detectible. For the gluten-free
consumer today, the label "gluten-free" really has
no meaning.
(Slide.)
MS. KUPPER: Again, the gluten-free
consumer is
compulsive about their medical needs.
77
This is their only treatment. It is often referred
to as our drug of choice. There is nothing else we
can do, except to follow a strict gluten-free diet.
They have very limited trust in the
manufacturing industry. They believe that labels
that say "may contain" and different things like
that need to be distrusted. When they call the
manufacturers, they are not quite sure that they
are getting the right answer all the time.
Also, they have a limited understanding of
what good manufacturing practices really mean, so
they are always questioning what the manufacturer
will say. Yet, at the same time they want
accountability and they want reliability.
They may translate information to the
extreme. Let me give you an example. A few months
ago on one of the list serves, someone put out a
message about bottled water being gluten-free.
That got taken in a week's time to the
point where consumers were calling asking why water
had gluten in it, and how dare the food industry do
that to
them. The reality is it never did.
78
A company, out of the graciousness of
their heart, put it on a list of gluten-free
products, and from that the consumer decided that
every other bottled water had gluten in it. This
is the extreme that the consumer can go to. Again,
they don't find descriptive labeling helpful at
all.
The changes that can occur in ingredients
in manufacturing processes make it difficult for
this consumer group to know what they can have.
The term "modified food starch" usually means
cornstarch, modified cornstarch, in this country.
However, if the manufacturer determines
that wheat starch is cheaper in the fall and they
switch and the consumer has determined that this
product is gluten-free, now they are in trouble if
they don't recheck.
When you talk to the food industry, you
will find that their calls have dramatically
increased over the last 2 to 5 years of consumers
calling in, and 90 percent of the questions do not
have to do
with other allergens but have to do with
79
gluten.
(Slide.)
MS. KUPPER: When the consumer asks the
question about gluten, the problem is that they are
asking the wrong question. The consumers believe
that if they don't have effective labeling how can
anybody possibly know that they are going to be
able to be healthy and protect themselves.
They want to know that if you call a
company they are really giving you the right
answer, and they are just never confident about
that. Oftentimes, when the company answers too
quickly, they get suspicious.
Oh, I've had that experience. I will call
on a product and I'll say, "I need to know the
source of the modified food starch."
"Oh, you're talking about gluten?"
"Yes. Tell me the source of your modified
food starch. Let me make that decision about
whether I'm talking about gluten." That makes a
consumer suspicious.
Finally, you know, if a person eats a
80
gluten-free food and they get sick, whether it is
related to gluten ingestion or not, they have
determined that they can't trust that company any
longer.
Again, these list serves and chat groups,
I have seen them take small companies out of
business because of the spreading of rumors --
which are probably unfounded.
(Slide.)
MS. KUPPER: In closing thoughts, I really
encourage that through this entire process related
to labeling thresholds, that we be talking a common
language.
Let me use the example of threshold.
Yesterday, as I listened to Anne Munoz talk about
thresholds for allergens, I realized that we have
three different definitions of thresholds -- or
tolerance, excuse me. I want to use the word
tolerance.
The consumer says, "Tolerance is zero."
What that means is they think there should be zero
gluten in
their food.
81
The medical community says "zero
tolerance." For them that means, you should be on
a strict diet, and you should never cheat.
The manufacturing industry wants to know
where that is. Is it 20? Is it 200? They know it
is not zero.
We are not talking the same language. The
consumer needs to know that the manufacturer and
the industry or the legal ramifications around any
labeling are all using common terminology in a
language they can understand.
Education is a huge component. As much as
I am a supporter of this regulation and this law,
one of the things that is going to happen, as you
heard yesterday in discussions about soy lecithin
and other ingredients, it is going to become a bag
of worms. For the consumer, it is going to be very
confusing, and we need to have an education
component as part of the new labeling laws.
I encourage you, too, although you heard
it yesterday and you will probably hear it today,
too, we
know that there is no testing kit available
82
that tests to zero. We know, as you will probably
hear later, that it is probably an impracticality
or unnecessary to even go there.
I implore that when you set a threshold
method and testing methods, when you set the
threshold level, that it be reasonable and
something that meets the health needs of the
consumer but also allows the industry to meet the
need.
(Slide.)
MS. KUPPER: As they found out in
Australia, when you set zero as the tolerance level
and as the magic number for food manufacturers, a
lot of gluten-free products that patients used no
longer can be labeled gluten-free. Now the
consumer is once again confused and outraged.
CHAIRMAN DURST: Thank you very much.
Do we have any questions for our speaker?
Yes, Jeff?
DR. BARACH: Hi. Thank you. Jeff Barach
with Food Products Association. If I interpret
what you
said correctly, you were talking about the
83
consumer really doesn't find descriptive labeling
very helpful in the case of gluten-free.
I assume then the consumer would go to the
ingredient list or the 800 numbers or their
internal chat groups to find out whether the
product really is gluten-free or not. Am I
interpreting that right? Your constituency does
not want gluten-free labeling?
MS. KUPPER: I would say that is probably
right, that is the message I got from the survey.
In fact, they found that labels that say "may
contain" or "processed in a plant with" really is
frightening to them. They will look at a product
like that, and they will simply avoid it.
They do go to chat rooms and there are
lists of gluten-free products. However, when you
look at those lists and you ask how they were
developed, there are no standards for developing
those lists.
DR. HEIMBURGER: Doug Heimburger, a follow
up to that. That is not the same, is it, as saying
"gluten-free"? Do they
not want a label except it
84
is gluten-free with a consistent and clear
definition of that?
MS. KUPPER: They do want a label that
says gluten-free with a clear and consistent
definition.
DR. HEIMBURGER: Yes.
MS. KUPPER: I believe that gluten-free is
not is not going to mean zero; it can't mean zero.
CHAIRMAN DURST: Any further questions or
comments?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
CHAIRMAN DURST: Our next speaker is
Dr. Donald Kasarda, who is a consultant and retired
senior scientist from the Agricultural Research
Service of the USDA. He will make a presentation
on grains.
GRAINS
DR. KASARDA: Good morning everyone. I am
a research chemist retired from the U.S. Department
of Agriculture, although I still maintain a
relationship with my old lab in Albany, California,
85
as a collaborator.
Now, Dr. Murray covered a lot of the
things I am going to talk about. Maybe I will be
able to add a little bit more detail to some of
them, but he did an excellent job of talking about
some of the grain topics.
(Slide.)
DR. KASARDA: Immunology textbooks often
classify hypersensitivities into these four types.
Celiac disease is a delayed type hypersensitivity
that involves T-cells in the primary mechanism. It
falls into Type IV. Allergy is Type I and is
mediated by IgE antibodies.
Now, in the case of celiac disease, it is
often suggested that there is a Th1 mechanism
involved in which T-cells are presented with
gliadin peptides, and, ultimately produce
cytokines, inflammatory cytokines such as
interferon gammas as an example.
Now, in the case of allergy, however, the
same molecules that can induce the symptoms of
celiac
disease are also capable of producing
86
allergies. We do have a certain amount of
confusion sometimes between immediate
hypersensitivities and the delayed-type, celiac
disease.
(Slide.)
DR. KASARDA: Now, this is the same
diagram that Dr. Murray showed. I want to talk
about primarily the endosperm, which is this white
part here (indicating) in the cutaway diagram.
The starchy endosperm is made up of about
75 percent starch, but it also contains about 7 to
17 percent protein, depending on the use of the
wheat. Most of this protein, about 75 percent of
it, is gluten protein.
The proteins are storage proteins. They
are used by the developing plant that comes from
the germ here. The germ is separated from the
outer layers and the endosperm during the milling
process after crushing and sieving.
The storage proteins are broken down upon
germination of the seed to produce a new plant.
The
resulting amino acids and nitrogen are used in
87
the synthesis of new molecules needed by the
developing plant. Now, as I mentioned, about 75
percent of the storage protein is, in fact, gluten
protein.
(Slide.)
DR. KASARDA: This is a picture of flour
particles, a scanning electron micrograph. These
round, spherical structures are starch granules.
These (indicating) are A type, there are some
B types which are small here. The surrounding
rough-edged material is the gluten protein or
storage protein.
(Slide.)
DR. KASARDA: If you mix together flour
and water, as most of you have had the experience,
you can form a cohesive elastic dough. If you need
a dough under water, say, in a large container of
water or under a stream of water, you can wash out
the starch granules; they pop right out of the
matrix. You are left with a cohesive, elastic mask
consisting mainly of the storage or gluten
proteins.
88
(Slide.)
DR. KASARDA: Now, this is the traditional
cereal chemist definition of gluten. You cannot
carry out this process with rye and barley.
Therefore, to the traditional cereal chemist, there
is no gluten in rye and barley. However, the
celiac disease community has adopted the term
"gluten" for any protein that is toxic or harmful
to a celiac patient.
This terminology problem sometimes is
confusing when patients go to a company where they
might be dealing with a traditional cereal chemist,
and there is a certain amount of confusion as to
what is gluten. As I said, this is the traditional
definition, but it has been expanded to include
other grains that are harmful to celiac patients.
Now, from time to time, you will hear
about these fractions of gluten. Going way back,
at least over a hundred years, it has been
traditional to divide gluten into two, roughly,
equal fractions based on their solubility. This is
not an
exact separation. No solubility
fraction is
89
ever perfect.
Traditionally, it was alcohol-water
solution and sometimes we used detergent solutions.
We divide it up into the soluble fraction, which we
call "gliadin."
This is made up of monomeric proteins of
the prolamin class. The prolamin terminology comes
from Osbourne back around 1900. It is derived from
the fact that there are two major amino acids found
in the composition of these proteins. Proline and
glutamine, hence, prolamin.
By structure, we have three types: the
alpha type, gamma type, or omega types. Sometimes
people speak of the alpha/beta. I will talk about
that in a little as we go along.
Now, the insoluble fraction is called
"glutenin" by the cereal chemists. In rye and
barley, there is an equivalent fraction that we
called just generically "glutelin."
Now, this polymeric fraction consists of
prolamin subunits. Again, large amounts of proline
and
glutamine in the composition of the proteins.
90
These subunits are linked together by disulfide
bonds into a higher level of polymer.
Of course, a protein is a polymer in
itself. It is divided into two main types the
low-molecular weight and the high-molecular weight
glutenin subunits.
(Slide.)
DR. KASARDA: This just is a table showing
the percentages in the various types of proteins.
For example, you have the sum of glutamine and
proline ranging from about 40 percent up to about
80 percent in some of the omega gliadins.
This is pretty unusual to have such a high
percentage of glutamine and proline. This is key
to the toxicity, because the toxic sequences
involve glutamine and proline and usually an
aromatic as well, either tyrosine or phenylalanine.
(Slide.)
DR. KASARDA: Now, the terminologies that
we use really go back to early electrophoretic
studies in the late sixties and early seventies.
Again, if
we follow this diagram here, this is an
91
acid gel in which the proteins are separated by an
electric field in a polyacrylamide gel.
The terminology actually came from a sort
of free-boundary electrophoresis that was carried
out at our Northern Regional Research Center back
in the sixties. When they developed the
polyacrylamide gel electrophoresis, it was found
that the fractions fit with the mobility in the
electrophoretic gel.
You have the alpha, fastest moving; beta;
gamma; and omega. Structurally, the alphas and
betas are pretty similar. Some people will talk
about alpha/beta types. I just lump them together
as alpha types.
Now, the alpha type and gamma type are
about the same size. If you carry out SDS page or
polyacrylamide gel electrophoresis in detergent,
sodium dodecyl sulfate, which is a very good
dissociating agent for proteins.
Reduced or unreduced the gliadins give a
pattern somewhat similar to this. It is not quite
as good at
resolving alpha, beta and gammas as you
92
find in the acid gels where aluminum lactate was
one of the favorite buffers.
If we go over to the glutenin fraction,
and these are the subunits linked together by
disulfide bonds, if you try to take a purified
glutenin fraction and run it into an acid gel or
into a detergent gel, mostly you've just got a
little bit of streaking around the origin because
the polymers are too large to migrate into the gel.
(Slide.)
DR. KASARDA: Upon reduction, however, you
begin to see this type of pattern here in which
there is a group of high-molecular-weight subunits
and a group of low-molecular-weight subunits. This
only occurs for the glutenin fraction when you
reduce the disulfide bond.
(Slide.)
DR. KASARDA: This is a two-dimensional
pattern, electrophoretic pattern, of the gluten
proteins. All you have to recognize is that each
spot here represents a separated protein. There
are quite a
few different gluten proteins, and we
93
can count easily 50, 60, 70 spots in such a
pattern. Therefore, there are at least 50, 60, 70
gluten protein components.
We know from genomic studies that, in
fact, there are probably at least a hundred genes
coding for these proteins, and probably several
hundred genes coding for the proteins. The loci in
the genome that code for these proteins are spread
out over about nine different loci in the genome.
Now, as far as we know, all of these
gluten proteins are toxic in celiac disease. This
group here (indicating) are the omega gliadins, and
they seem to be particularly active.
However, all of the gluten proteins have
been tested by Paul Ciclitira's group and
Peter Howdle's group in the U.K., and they all
indicated by direct installation into the small
intestine that these proteins, all of these
different classes are toxic.
These omega gliadins are noted for being
strong allergen in exercise-induced anaphylaxis.
They are
one of the really strong antigens involved
94
in that particular allergy.
(Slide.)
DR. KASARDA: This is a schematic diagram
that illustrates the fact that all of these
proteins are noted for a repetitive domain in which
certain amino acid sequences are repeated over and
over again.
They are somewhat degenerate, but we can
derive consensus sequences. These are glutenin
subunits, gamma-type gliadins. These red,
staplelike lines indicate intramolecular disulfide
bonds.
In a glutenin subunit, we also have free
cysteines which can link up to another molecule to
form these higher-level polymers. For example,
here is an alpha-gliadin -- I'm going to talk about
this a little bit more -- the end terminal, or the
first half of the molecule, is made up of these
repeating sequences.
The second half is not repetitive and
contains most of the disulfide bonds. Toxicity
seems pretty likely to be limited to the
repeat
95
regions. These are the high-glutamine, the
high-proline regions.
Now, the omega-type gliadin seems to have
lost -- well, we are not entirely sure whether they
lost this type of domain or not, but in any case
they are made up almost entirely of repeating
sequences.
(Slide.)
DR. KASARDA: This is a hypothetical model
of the gluten polymer or glutenin in which the
subunits are joined by intermolecular disulfide
bonds, there are also these intramolecular
disulfide bonds, to form a higher-level polymer
that provides elasticity to a dough.
The gliadins and the glutenins are
cohesive with one another, but the gliadins
contribute more to the extensibility of the dough,
and the elasticity comes primarily from the
glutenin fraction.
(Slide.)
DR. KASARDA: Now, here I show some of the
types of
sequences that you find in the repeats.
96
Now, they look pretty similar, a lot of glutamine,
which is represented by "Q"; a lot of proline
represented by "P"; and usually an aromatic
residue, either phenylalanine, "F," or tyrosine,
"Y."
Somewhere, and these are often degenerate.
They are not exactly according to the consensus
that I show here. Somehow along the line these
sequences have acquired toxicity in celiac disease.
(Slide.)
DR. KASARDA: Now, this is the complete
sequence of an alpha gliadin. This is the
end-terminal region up here (pointing). It starts
at one, and there are 263 amino acid residues.
Here, note the predominance of the blue Q's and the
red P's for the proline and glutamine residues.
This half of the molecule here is the
repeat region. There is also this interesting set
of glutamines, which really hasn't been studied in
celiac disease. It is probably not toxic, but, as
I say, there has been almost no study of this
polyglutamine stretch here.
97
Note also these vertical lines here which
I show. Those are sites that we have observed
where cleavages occur with gastric enzyme, pepsin
and pancreatic enzymes, trypsin and chymotripsin.
Now, most proteins would be broken down by
the digestive enzymes into single amino acids or
very small peptides: diatride, tetrapeptides that
are easily absorbed, which are probably not toxic.
(Slide.)
DR. KASARDA: In the case, as Dr. Murray
mentioned, because we have a lot of proline which
interferes with the breakdown by the proteolytic
enzymes, we can get some pretty large stretches.
This stretch here from 31 to 55 right here is
something that we have tested as toxic.
Other people have dealt with sequences
from this stretch and found them also to be at
given toxic. The fact that this gliadin and
glutenin proteins are difficult to digest by the
digestive enzymes allows these toxic stretches to
exist longer than you would find for other
proteins.
98
Now, this half of the molecule has a fair
amount of glutamine and proline, but as far as we
know toxicity does not reside in this C-terminal
half or sort of the end of the molecule. It is in
sort of the forward end of the molecule.
(Slide.)
DR. KASARDA: Now, this is what I would
call my string of beads model in which I have just
taken that sequence, 1 to 263, and shown it as
beads on a string.
Each bead represents a different amino
acid. I tried to assign the different amino acids
different code words to distinguish them. This is
the end terminal region of repeats. This
C-terminal where we have the disulfide bonds here.
Toxicity resides in this part here.
This sequence here from 31 to 43 was
synthesized by Mike Marsh in the U.K. first, and he
instilled the synthetic peptide directly into the
small intestine of several celiac patients and
found changes in the mucosa that were indicative of
celiac
disease. So this does seem to be a
toxic
99
sequence.
Here I show a computer molecular model of
what that sequence would look like in the
polyproline II left-handed helical confirmation
that Dr. Murray mentioned. We think that these
peptides do have a strong tendency to assume this
polyproline II confirmation.
Here, I show the sequence in three-letter
code as a string of beads model and here just a
single-letter code. I know most people are not
used to dealing with these codes. I apologize for
using them in some of the slides, but often I am
just trying to make a general point, and you don't
really have to follow the sequences according to
their exact correlations with the amino acids.
(Slide.)
DR. KASARDA: Now, this is a list of some
of the either toxic or immunoactive peptides that
have been described in the literature. This is
from Sean, et al, from Chaitan Khosla's lab at
Stanford. The 33-Mer appears to be a very active
sequence. I have indicated some
sort of homology
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here by the yellow boxes here.
All of these sequences, with the exception
of this one, have been found to be toxic by direct
installation into the small intestine or they have
been found to stimulate T-cells, T-cell clones,
derived from biopsies of celiac patients.
These are just some of the toxic
sequences. We don't know all of the toxic
sequences at this point. There are certainly
others to be found, so it is a pretty complicated
situation in trying to sort out exactly what it is
about the sequences that produces toxicity in
celiac disease.
(Slide.)
DR. KASARDA: Now I want to move on and
talk a little bit about the other grains. If we
start with the class flowering plants, which is one
of the major divisions or plants in terms of
taxonomy.
We go down to the major two subclasses,
monocotyledones plants and dicotyledones plants.
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We can follow the monocots down to the Gramineae or
the grass family.
Here, we have only wheat, rye and barley
that are toxic. Triticale is a cross between wheat
and rye, and so would be expected to be toxic.
Now, oats I have had to put in both
columns, and I will explain why. There are many
other grasses in which the grains do not have toxic
proteins as far as we know.
There are only two grains that have been
studied with modern methods and modern approaches
to understanding their relationship to celiac
disease, and that is wheat and oats.
These others have often been studied very
minimally including rye and barley, but rye and
barley do contain proteins that have sequences
quite close to those in wheat.
We assume that rye and barley are probably
toxic grains according to the early results of
Dicke in the Netherlands back around 1950, where
they considered rye, barley and oats as part of the
toxic
group.
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Now about 15 years ago, I suggested that
if there are only a few grasses that contain the
toxic sequences, and they are closely related as
you will see, and then there are many other grasses
that do not contain the toxic sequences.
I suggested that if you get into the dicot
group -- the buckwheat, quinoa, amaranth, and these
other grains -- it would not be toxic, simply
because of their distant taxonomic relationship to
wheat.
I was a little bit apprehensive about
suggesting this, but over the past 15 years since I
suggested this, people have been eating these other
grains. As far as I know, there hasn't been any
serious indication that these do, in fact, have
toxicity for celiac patients.
There have been some very fine studies
from Finland and throughout the world, indicating
that oats were safe for celiac patients. But
towards the end of last year the Oslo, Norway,
group under Knut Lundin and Ludvig Sollid. They
have found
-- well, I'm getting a little bit ahead
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of myself. Let's deal with this slide first.
(Slide.)
DR. KASARDA: If we take a subfamily,
festucoidiae, of the grass family and we look at
the tribal level, and I made this slide before the
results from Oslo were published. The hordeae --
which includes wheat, rye, and barley -- were one
tribe. I thought that oats were probably
non-toxic, so I put them in -- well, they belong in
a separate tribe. It was only this one tribe that
had the toxic sequences.
Now, it is pretty certain that the oats
are toxic to a few probably rare individuals, but
we don't really know how this works out. They
found three celiac patients who definitely reacted
to oats by the same mechanism that they reacted to
gliadin peptides. This, I think, was pretty well
demonstrated by the work from Norway.
Now, here I show the proteins that you
find in wheat, gamma-type gliadins and related
low-molecular-weight glutenin subunits, they are
found in
rye, barley, not in oats. Alpha-type
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gliadins are found in wheat, but you don't find
them in rye and barley or in oats, and so on down
the line.
Now, the avenins are a small fraction of
the total proteins in oats. These make up only
about 10 percent of the protein. Most of the
protein is oat globulin, which as far as we know if
not harmful or toxic to celiac patients. There are
low-molecular weight proteins related to the
avenins in rye, barley, and wheat.
(Slide.)
DR. KASARDA: Now, this is another one of
those sequence slides, but let me just try to make
a few points here. This top sequence is a gliadin
sequence. It starts here (indicating) and runs
down to here.
The bottom sequence is an avenin, which
shows a lot of homology with the C-terminal half of
this gamma-gliadin molecule. This is also true for
the alpha gliadins. Where the amino acids are the
same, I have colored them in blue.
There is a lot of homology here in the
105
C-terminal half, but that is not where the toxicity
lies. The Oslo group has shown that this
particular sequence, which I have underlined, does
have certain characteristics including glutamic
acid at key positions that are important, as Dr.
Murray pointed out, for binding to MHC proteins.
Consequently, most of the repeat region is
absent from the avenins. There is just this sort
of residual section here, which does have a lot of
glutamine and a lot of proline and some key
glutamic acid sequences or amino acids that seem to
be responsible in these few patients that have been
studied for the toxicity. This sequence is
certainly capable of stimulating T-cell clones from
these patients.
I think that the evidence is pretty good
that there are at least a few -- it seems as though
there are probably rare individuals who respond to
oats and probably most celiac patients do not
respond to oats.
This is a rather puzzling situation,
because I
have always thought of the proteins as
106
being pretty definitive for celiac disease, that
all celiac patients reacted to wheat and probably
to rye and barley, and that this was part of the
definition of celiac disease.
Now we have a situation here where it
appears that some patients react to oats and some
don't. This is some ongoing research that needs
some elucidation.
(Slide.)
DR. KASARDA: Just to jump back into the
classification, this is another subfamily,
panacoideae. Here we have maize and sorghum and
millet. We have actually done a little bit of
end-terminal sequencing on sorghum and millet
proteins, and they do seem fairly close to the maze
protein. This would explain to some degree why
they are not toxic in celiac disease. As far as we
know, it is still wheat, rye, and barley that are
harmful.
(Slide.)
DR. KASARDA: Now, this is my last slide.
The
currently favored method for determination of
107
gluten in food is the R5 monoclonal antibody ELISA
test developed by Mendez in Spain. This seems to
be a pretty good test; it is not perfect.
The antibody reacts to monomeric wheat,
rye and barley prolamins, but not the oat avenins,
and it reacts weakly or not at all with the
glutenin or glutelin, pretty good sensitivity,
recognizes these particular motifs more strongly,
although some others that are similar are
recognized weakly.
The Codex Committee on Methods agreed in
2004 to endorse temporarily the R5 ELISA for the
determination of gluten. Now, there are some
possible problems. There is the failure to detect
the glutenin proteins.
In some preliminary work from our
laboratory, for example, when we look at wheat
starch that is intended for use by celiac patients,
we find that the gliadins are pretty well washed
out, but we do find evidence of
high-molecular-weight glutenin subunits attached to
the starch
surface. These would not be picked up
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by the R5 ELISA.
Then, there is the question about small
peptides from hydrolases. There has been some work
described using a competitive assay, which might
possibly solve the problem of the small peptides
from hydrolases.
Also, there is a certain amount of data
indicating differences in the results from
different labs on the same sample. On the whole,
it seems like a pretty good test that can be used.
As I say, it is not perfect, but it is a pretty
impressive test on the whole, and it may be as
close as we are going to get.
Although, I certainly can think of some
ideas for maybe improving it. At any case I think
I will end my talk here and I thank you very much
for your attention.
CHAIRMAN DURST: Thank you.
QUESTION AND ANSWER SESSION
CHAIRMAN DURST: Are there questions?
Okay. Margaret?
DR. BRILEY: Margaret
Briley. Can you
109
give us any idea of the use of this ELISA test by
industry in terms of the frequency and the
acceptance and willingness to do it? Do you have
any feel for that?
DR. KASARDA: Well, I think it is being
used, and Dr. Collin can comment on this,
extensively used in Europe and it is becoming used
in the U.S. Susan Hefle, who spoke yesterday, I
think that they have done a certain amount of work
using this test for industry.
My impression is that not much testing is
done in the U.S. Maybe Cynthia could comment on
that. I think it is developing, but we are quite a
bit behind the Europeans in terms of a willingness
to test and desire to test products and make sure
that they are as close to gluten-free as they
possibly get. I can't give you a definitive
comment on that. I haven't made any surveys.
CHAIRMAN DURST: Any further questions or
discussion?
Yes?
DR. CALLERY: Pat Callery. Thank you for
110
the review of the relevant biochemistry. Could you
relate the transglutaminase substrate specificity
to these various glutamine-containing --
(Simultaneous discussion.)
DR. KASARDA: Not personally, but other
people have. There are certain sequences that are
susceptible to deamidation and probably
transamidation as well. These have been described
in some recent publications. There are many sites
in the gliadins that are susceptible to
transglutaminase.
DR. CALLERY: The transglutaminase I
understood was an important feature in binding
these proteins and causing the --
(Simultaneous discussion.)
DR. KASARDA: Well, you know, in the MHC
proteins there is a positive charge in the binding
pocket that binds well to a negatively charged
glutamic acid. This does enhance the strength of
the binding to the binding site of DQ2/DQ8.
Now, I didn't get into it, although
possibly
someone else will, there seems to be two
111
legs to the celiac disease situation. There is the
adaptive immune system, which has been worked on
quite a bit in terms of this presentation of
gliadin peptides to T-cells, to the T-cell
receptor, and stimulation along that leg.
However, one of the peptides I described
that Mike Marsh had studied, that particular
peptide is not immunoactive. It does not stimulate
the T-cells, yet when instilled directly into the
small intestine it produced changes that were
characteristic of celiac disease.
In the last couple of years, there has
been an interest in the role of the innate immune
system in possibly triggering the first leg of
celiac disease, which then progresses on to involve
the adaptive immune system and the CD4 T-cells of
the lamina propria.
I think that part is becoming pretty well
understood. Ludvig Sollid and his co-workers,
while he was on sabbatical at Stanford, they
actually crystalized a DQ2 with the gliadin peptide
in the
binding site. They have defined a
number of
112
characteristics of the peptides that are important
for binding.
However, I think we still don't understand
a good part of what is active or toxic about these
peptides, and it may have to do with this
triggering and innate immune response. That is
research that is really developing right now.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Soheila Maleki, USDA.
Essentially, the substrate for the transglutaminase
is the same peptide that is presented by the
antigen-presenting cells?
DR. KASARDA: Well, after you deaminate a
particular glutamine, then the binding strate goes
up for the receptor site on the MHC protein.
DR. MALEKI: Essentially, it is the same
substrate, just after deamination --
(Simultaneous discussion.)
DR. KASARDA: Well, there is also the
question of, Why do you have antibodies to the
transglutaminase? This may involve transamination
reactions
where you get a binding of gliadin in the
113
transglutaminase, and then this triggers the
apparent autoimmune antibodies to transglutaminase.
DR. MALEKI: I see. Well, I just find it
amazing that when you show the lineup of the
peptides, the homology, that you had a two amino
acid difference and went from immunoreactive to
non-toxic. I'm sure by now they probably can
explain that?
DR. KASARDA: No, they can't.
DR. MALEKI: Well, even in the fitting up
to the transglutaminase or to the processing by
antigen-presenting cells?
DR. KASARDA: Well, it is very puzzling,
very interesting. I really can't answer your
question.
DR. MALEKI: Thank you.
CHAIRMAN DURST: Any further discussion?
(No verbal response.)
CHAIRMAN DURST: All right. Thank you,
Dr. Kasarda.
We are now scheduled for a break. We are
just about
on schedule, so we will take a brief
114
break and reconvene at 10:45.
(Thereupon, from 10:25 a.m. to 10:45 a.m.,
there was a pause in the proceedings.)
CHAIRMAN DURST: Our first speaker after
the break is Dr. Alessio Fasano, professor of
pediatrics, medicine and physiology and director of
the Mucosal Biology Research Center, Center for
Celiac Research, University of Maryland School of
Medicine.
PROSPECTIVE STUDIES
DR. FASANO: Thanks so much. I've got to
do this. I need really to thank the FDA, who has
been so kind to invite me, but also to be so
sensitive to use Italian candies.
(Laughter.)
DR. FASANO: This is very nice of you
guys, and we appreciate that. I also want to tell
you guys that because of the other speakers, I
decided to reduce a little bit my talk, so a few
slides have been taken out from the handouts to go
straight to the point.
There has been a general perception that
115
this is a quite young disease, in other words,
something that we are dealing with kind of
recently. I want to put this in the right
perspective and give you some of the background to
justify this prospective study to decide what is
threshold of tolerable gluten.
First of all, believe it or not the first
trace of a description of this disease goes back to
the Roman Empire. This is not something that has
happened in the last few years.
(Slide.)
DR. FASANO: Who really put the disease on
the map is this fellow here. Samuel Gee, at the
end of the past century, around 1890, gave an
historical lecture to a place where I had the
privilege to study for a little while at Saint
Bart's Hospital in London.
He really put celiac disease on the
"scientific map." I took little sentences here and
there from his lectures to give you the sense of
how this guy got the story right more than 120
years ago.
116
He described these as a chronic
indigestion that is met in every single age.
Again, our misconception in the past was celiac
disease was confined to a specific age group. He
knew already that was not the case; it can affect
at any age.
Of course, it is particularly more
frequent in all kids between one and five years
old, and that was the observation at the time. He
spent time and effort to clarify the fact that
everybody can be affected.
Now, symbiotics, hands-on, was the way to
do a disease diagnosis at that time. We didn't
have a lot of sophisticated tools, so it was really
hands-on.
For a gastroenterologist, dealing with a
problem like that means describing feces, stools,
and that's what it is. He introduced with this
description a very important concept about celiac
disease in terms of classical GI presentation,
malabsorption.
In other words, right before they would
117
know about the genetics, right before they would
know about the grains, the eyes are telling us that
the feces are loose, malformed, but not watery,
definitely more bulky than the food taken seems to
account for, i.e., malabsorption.
What is remarkable is this part here. He
ventured also to understand what was the
pathogenesis of the disease and introduced two
concepts: the genetics and environmental trigger.
He said kids that suffer from it are not
all weak in constitution, errors in diet. I want
to clarify that the first time that the link
between celiac disease and grains was made was soon
after World War II. Until then we had no clue
whatsoever what was the trigger leading to celiac
disease.
The link was made during World War II
because there was a higher rate of mortality among
kids in Middle Europe that was not explained.
During World War II, grains were not available
anymore.
They were fed with potato starch, potato
118
flour, and the mortality dropped dramatically, to
reappear after the end of the war when flour was
again available. That is when the link was made.
This guy is already there. Errors in diet
may be perhaps a cause, but whatever. Why, out of
a family of kids all brought up in a much similar
way, should only one suffer?
Again, he is trying to understand what is
the genetic component, what is the environmental
component, why some people have got it and some not
from the same family eating the same stuff.
Then, he finished up by saying, "Okay, I
think that I have a way to get to the bottom line
in treatment. The treatment has to be regulating
food in the main part of the treatment. It is
amazing if you come already with this conclusion.
The allowance of farinaceous food must be small.
Again, I find this remarkable. Highly starchy
food, rice, sorghum, corn-flour are unfit.
Now he is losing himself a little bit when
he says malted food is better. Also, rusks or
bread,
provided it is cut thin and well-toasted on
119
both sides, will be all right.
Grant him the benefit of that. I believe
that, again, in 1890 making this kind of statement,
even if he [made] this little boo-boo here, I think
that it is absolutely remarkable.
(Slide.)
DR. FASANO: Now, fast forward that 120
years later, and that is what we understand about
celiac disease. You heard from Dr. Kasarda and
Dr. Murray already that this is an immune-mediated
reaction.
It is not an allergic reaction, but rather
right now we really truly believe that this is an
autoimmune condition. In other words, we are in
the same kind of range as multiple sclerosis, type
1 diabetes, and so on and so forth.
Therefore, as such there are two key
elements to develop the disease: You have to be
genetically susceptible. I'm not going to spend
more time about this DQ2/DQ8, but they are the
docking station, the "eyes," of the autoimmune
system to
see the trigger from the environment
120
coming in.
It is unique because the only other
autoimmune disease for which we know everything
specifically is the only autoimmune disease for
which we know the trigger, that is, gluten.
I wish that we had that kind of
information for other autoimmune diseases, for
which we will have a solution. Theoretically, we
have on hand the possibility of treatment of this
disease.
However, I will argue that unless we have
a clear rule of engagement, i.e., a food labeling
bill that will really clearly define what is
"gluten-free," this is a theoretical solution but
very difficult to put in practice.
(Slide.)
DR. FASANO: Again, it is pretty obvious
that you have to have these two ingredients, you
have the genes and you have to have the grains.
When they interplay, you may end up developing
celiac disease.
We heard already that variability in terms
121
of the timing, how long it is going to take, the
outcome in terms of symptoms, and so on and so
forth, is unbearable. However, they are all under
the same kind of umbrella of celiac disease.
What are our treatment options at the
moment? If these two elements are absolutely
necessary to developing the disease, I believe it
is a no-brainer, it is pretty simple, there are
only two solutions.
First, we can remove the genes, and I
don't think that we can do that. We are not quite
there yet anyhow. As Dr. Murray explained, we know
some of them but we don't know all of them. Or,
secondly, we eliminate the grains. Those are the
options that we have available. There is no other
way to turn from this.
Don Kasarda went extensively into this. I
didn't know that he was invited, by the way.
However, the bottom line is the only treatment
right now is strict, lifelong -- as you heard, you
don't grow out of this, so you have got to endure
it for the
rest of your life -- avoidance of wheat,
122
rye and barley. The oats story, again, I am not
going to go back because you heard about that.
(Slide.)
DR. FASANO: It is pretty obvious what are
the major sources of gluten. This is the easy part
when you have to deal with the patients freshly
diagnosed. It is easy to say, "You know what? No
bread, pasta, pizza, beer, cookies, muffins, and so
on and so forth.
(Slide.)
DR. FASANO: This is a little bit more
complicated, and that is where I believe a food
labeling bill will help. Of course, it is not
necessary to go and say, "You know what? This
muffin that you buy at the bakery needs a label."
We know that already whether it is gluten-free.
However, this stuff here (showing "Sources
of Gluten" slide) definitely needs a label, some of
them, because it is not clear if they have gluten
or not because they can be processed with or
without gluten.
Gluten is a formidable, extremely cheap
123
biological glue. Don told you the physical,
chemical characteristics of the molecule. The
reason why manufacturers use that is because when
you have two elements of a processed food that does
not stick together, the cheapest way to keep them
together over time is to use gluten. Right now,
the label can see just the nature of flavor but not
gluten, not necessarily so.
Then, there are really the tough ones in
which, this is not even food really, a source of
gluten needs to be considered. I can't
conceptualize enough how many times we've gotten
E-mails of people asking, "Is my husband, who has
celiac disease, going to be sick or whatever," or
the Playdough for the kids in kindergarten, and so
on and so forth. These are elements to keep in
mind that we deal with all the time.
Of course, the big deal is right here --
medications, prescriptions. As for foods,
processed foods, also medication they enjoy gluten
as an additive to keep elements together.
Now, while I was saying adhere to a diet
124
is a pure theoretical no-brainer, but in a
practical sense it is extremely complicated. It is
a chronic intervention that you have to do, and you
have to stick with it with full commitment for the
rest of your life.
Every single individual in this room I am
pretty sure that you have made some commitments
here and there to go on a certain diet or to
exercise or to decide to change your lifestyle. To
keep that constantly for the rest of your life, it
takes a lot of stamina. That is the reality of the
story.
That is true particularly in the American
society in which any chronic illness will require
chronic treatment, whether it be diet or exercise
or medication or whatever, will pose a problem of
compliance. Definitely among different
interventions, a diet compliance can be really a
difficult aspect of treatment.
In my book, food is one of the few joys in
life. How many times do we leave home and go to
work, we drive, we don't think about it,
and we
125
find ourselves at work without having to pay
attention to directions, streets, and so on and so
forth? We are used to it.
That is the same with food, we are used to
it. However, that is not the case for celiacs
because they have to think about this over and over
and over again. It will become not a natural,
spontaneous activity in life, but it will become a
very, very demanding operation.
(Slide.)
DR. FASANO: Why don't people stick with
diets? This is a survey that was done in
Upstate New York. This statement, and this is just
to paraphrase something that Cynthia was telling
us:
"If I eat less gluten, I will have less
intestinal damage."
Half of the people say, "You know what? I
really don't have to stay a hundred percent gluten
free. As far as I decrease this, I will have less
problems. I will be all right."
"I've lived this long eating gluten, how
126
much will a gluten-free diet really help me now? I
mean, you know, if it's not been a big deal so far,
why should I just dramatically change my lifestyle?
I've survived so far, I'm not going to die from
it."
"It's not me, that I have to do this.
It's my doctor who should tell me when I need
follow-up testing or whether I need to stick with a
diet, and so on and so forth." One-fourth of the
people say that.
Again, you heard Dr. Murray, that
unfortunately some of the confusion is generated by
the professionals, the healthcare professionals.
They don't know the rule of the game, and,
therefore, they cannot transmit how to play the
game.
It is pretty much the sense that you go to
the doctor as an individual that has to teach you
how to play chess, and this fellow has no clue
whatsoever how to move the pieces. Patients have
to learn how to play chess while playing against a
professional player. How fair is
that? It is an
127
ongoing process.
This is the one that disturbed me the
most: "Scientists and doctors still haven't proven
that gluten really hurts them." You know, there is
no clear information that gluten is dangerous to
celiacs, and that is quite disturbing.
(Slide.)
DR. FASANO: What are the current barriers
in compliance? Again, you heard about the emotion
of the person, anxiety. There is a tremendous
reaction when you are diagnosed with a chronic
illness, no matter how you want to put it. Now,
grief and fear and denial are part of the story.
The ability to resist temptation and to be
disciplined on a gluten-free diet is tough. There
are feelings of deprivation. A few years ago I was
with one of the patients, and he got the chance to
drink a gluten-free beer. Soon after he started to
drink the beer, I saw tears coming down his cheeks.
His simple statement was, "I've waited 25 years for
this." Imagine, 25 years to drink again beer.
He was disciplined, and he didn't touch
128
it. However, there are many others, particularly
adolescents, in which that kind of discipline is
really hard to obtain.
This is very much the heart of the
problem, fear generated by inaccurate information.
If we do not have clear ideas, we, as
professionals, and one says black and the other one
says white, and the other one says up and the other
one says down, that creates a lot of confusion and
a lack of trust.
(Slide.)
DR. FASANO: Other barriers to compliance
are of course we live in a society that drives 150
miles an hour, and we don't have the time to seek
to prepare our food to enjoy. My kids consider
that the stove is the microwave. The stove does
not exist.
Cynthia teaches us the fact that the new
generation believes that cooking is just powder
mixed with water, stick it in the microwave, and
the only thing that you've got to do is read how
long should that go on and that's it. What
129
sophistication.
Here, assessing gluten content in food and
label reading is the most compelling change in
lifestyle that these people go through. Right now,
I don't know about you guys, but I don't enjoy food
shopping. I really do not. I tend to go at
midnight when nobody is there, because I want in
and I want out.
That is not an option for celiacs. One
thing that will take you, I don't know, half an
hour will take four or five hours for celiacs
because you've got to read every single label to
the nitty-gritty and make decisions.
Many times now I see people with cell
phones calling an 800-number right there on the
spot saying, "I have your Box XYZ, is this
gluten-free or not?" It is cumbersome.
(Slide.)
DR. FASANO: All of this to come to the
heart of what I'm going to share with you guys.
How much is too much? Unfortunately, I can't
conceptualize and stress enough what Cynthia
130
already said. In biology, the absolute zero does
not exist. If you really do believe that we can
achieve zero as gluten-free, this is a pure
theoretical concept that nobody will ever be able
to achieve.
Assume, just for a moment, that we will
have a sophisticated, super-duper sophisticated,
monoclonal ELISA to really go down to zero. To
manufacture food in that way, people in that
particular factory should be dressed with spray
suits, all antiseptic. A piece of bread will cost
$250, because that is what that level of
sophistication and controlled environments will
take. Consequently, it is impossible.
At the same time we need to give industry,
manufacturers, a parameter of what is tolerable and
what is not. There have been many retrospective
studies that Dr. Collin is going to tell us about,
very few prospective studies because they are
extremely challenging to do right.
This study that I am going to show you the
data of has
really been coordinated by
131
Dr. Carlo Catassi, who has been involved in this
kind of topic for the past 15 years. He is a
member of our center, and we have been doing this
in coordination for the past four years.
Why do we need to do this? Because again
this is a long-term, strict gluten-free diet. If
we do a prospective study design, we can answer
questions that a retrospective study was not able
to answer.
How we did this? We did it in a way that
the gluten-free diet, people that come in are
already diagnosed on a gluten-free diet. We are
monitoring this gluten-free diet in a blind fashion
where a given amount of gluten is added to the
diet, then, the clinical, serological and biopsy
evaluation before and after the microchallenge.
The background noise, this is very
important, is caused by possible contamination of
the food was minimized by using a control group, in
other words, to really do this by the book.
(Slide.)
DR. FASANO: Studies done in the
past, for
132
example, from Dr. Catassi almost a decade ago,
showed a linear relationship between the amount of
gliadin -- that is the toxic part of the story here
-- a daily dose, and it causes damage between 100
and 1,000 milligrams a day.
The intraepithelial lymphocytes -- and we
are going to go back to what these intraepithelial
lymphocytes are all about, the meaning -- was the
most sensitive index, not the serology and not the
symptoms.
What you heard already from Dr. Murray is
that after all these red flags the antibodies may
not be sensitive enough to uncover exposure to
gluten. Indeed, even 10 years ago this was very
clear.
(Slide.)
DR. FASANO: Why do this again? If it was
done 10 years ago, why revisit this if we have
already the information? Several reasons. The
need, first of all, to investigate the effects of
lower gluten doses. Because at that time they were
using large
doses, because that was the level of
133
sensitivity of the tests for the foodstuff.
There is a need for prolonging the
duration of the microchallenge. In the past, the
longest that we went was a month, and people would
ask, "How about two months or three months?"
How about if the period, the lag period,
between the exposure to gluten and when you react
is longer? You believe it to be safe for one
month, but you keep going, and eventually you
react.
There is a need of a control group that
was never used before, and, most importantly, you
heard that gliadin is part of the story. They are
the glutamines.
If you do the study just as done in the
past, you may really not uncover what is really the
story; in other words, what you leave out there is
not pure gliadin but rather this mixture of
proteins that Don Kasarda was telling us about.
(Slide.)
DR. FASANO: I don't want to spend too
much time
on this, but for a matter of
134
quantification, to give a sense of what we are
talking about. In 200 grams of wheat-based
products -- bread, pasta, so on and so forth -- you
heard that the main proteic fraction in wheat is
gluten. For 8 to 14 percent of the overall amount
is wheat. Gluten is 75 percent of all the protein.
Between gluten and glutamine, we can say that all
of this 8 to 14 percent are these toxic proteins
for celiacs. This 8 to 14 percent translates into
15 grams.
The real toxicity, the main toxic, is due
to the gliadins. Again, glutamines contributed to
toxicity. Of the 200 grams, 8 to 14 percent is
equal to 15 grams. Half of it is gliadin. Gliadin
has more than 50 toxic fragments, and so on and so
forth.
If you go on a gluten-free diet, an adult
that is on a gluten-free diet, roughly, consumes --
I mean, in a normal diet, roughly, the amount that
you consume is this, 15 grams. Roughly, you
consume 200 grams of wheat-based products.
If you are on a gluten-free diet, a
135
typical gluten-free diet, the subject consumes
gluten-free flour-based, that is roughly 80 grams.
The key element is how much of this 80 grams of
gluten-free products can be contaminated with the
toxic element, gluten? How much is the amount that
you can tolerate? That is the heart of the problem
here.
(Slide.)
DR. FASANO: That prompted the design of
the study. It is a quite complicated study. The
aim was to evaluate the consequences of the
protracting just minimal intake, either 10 of 50
milligrams, a very small intake.
In a group of adult celiacs on long-term
treatment with the gluten-free diet, why this
amount? Because, again, 100 milligrams was already
tested and proved to be dangerous 10 years ago.
How the study was designed was as a
multicenter, prospective randomized,
placebo-controlled, double-blind and was a
three-year study. It was entirely sponsored by the
Italian
Celiac Society.
136
The reason why we did it in Italy, as I
was mentioning before, is mainly because economical
support of such a complicated and expensive study
could be executed at this time only in a place
other than the United States where we don't have
that kind of resources.
(Slide.)
DR. FASANO: Who was eligible? Patients
with biopsy-proven celiac disease had to be on a
gluten-free diet for at least two years. These
people that had been diagnosed with all of the
criteria are accepted and have to be complying with
the diet for at least two years.
If you are younger than 18 years old, poor
compliance, abnormal results at the baseline
evaluation or you have IgE deficiency, that will be
an exclusion criteria.
(Slide.)
DR. FASANO: Now, how we did this? Well,
again, these people were heroes to accept such a
study, but this was the only way to do it. These
people
would come in to be scrutinized to see if
137
they were eligible.
If they were eligible, a consent form was
obtained and there was an intense, strict
monitoring of their gluten-free diets for a month
before the beginning of the study was obtained.
Baseline clinical serological and a biopsy was
obtained. In other words, they underwent a
endoscopy with a biopsy to show that they were
fine.
They were blindly randomized in three
groups, either no gluten, 10 milligrams of gluten
or 50 milligrams of gluten. They were followed for
three months. At a monthly interval there was a
check with the serologist for symptoms.
At the end of the study, at the end of the
three months, once again there was a clinical
evaluation and a serological evaluation and a
second intestinal biopsy under endoscopy.
This was the kind of study that this was
the only way, given the fact that the we know
symptoms and serology tests cannot be sensitive
enough to
do this right.
138
(Slide.)
DR. FASANO: The purified gluten was used
for the challenge. Gluten -- or lactose-containing
placebo -- capsules were randomly prepared. The
lab tests were centralized. There was monthly
monitoring of adherence to the protocol; it was
checked by a nutritionist.
Measurement of gluten contamination in
commercially available gluten-free food that they
had during the challenge was checked by ELISA. The
serum AGA and anti-tTG antibodies were checked; a
biopsy was performed with morphometry; there was an
intraepithelial lymphocytes count; and control
biopsies from non-celiac patients were used.
(Slide.)
DR. FASANO: These are the foods that they
had a gluten-free foods. You keep in mind that in
Italy right now the food labeling policy is to be
labeled as gluten-free you have to have 20 parts
per million or less.
Indeed, with this simple exception, the
vast
majority of the foods that these people there
139
are eating was gluten-free, by definition of the 20
parts per million.
Consequently, the only gluten that these
people were seeing was actually the ones that were
dealing with the challenge, if they were in the
group of gluten exposure.
(Slide.)
DR. FASANO: We were able to recruit 39
people, who were divided equally into three groups.
There were a couple of things that were interesting
to us.
Of all the parameters that we measure, two
are extremely important to establish the health of
the intestine and the exposure to gluten damage,
one was the villous height/crypt depth ratio. It
is very typical use of morphometric analysis that
we do in clinical practice.
Typically, we want to see this: roughly, a
ratio of 3:1. In other words, the height of the
line has to be 3 times the depth of the crypt.
That is what typically we consider to be normal.
Despite the fact that they were on a
140
gluten-free diet, despite that, they fulfilled the
criteria. They were gluten-free, symptom-free,
immunologically negative, and all the 9 yards.
They went on a one-month controlled diet.
When we did the starting biopsy, there was
a slight decrease of the villus-crypt ratio,
meaning, the villi were a little bit shorter. That
is what happens when you have an insult, the villi
become short and the crypts go deeper.
The other parameter is the number of
CD3-positive cells, the intraepithelial lymphocytes
if you wish, was again 20 per hundred entrocytes
and controls and 30 in the celiacs on a gluten-free
diet.
Therefore, at baseline already something
was going on. It is like there is a status of
inflammation in which this is like a very
well-trained athlete, ready to react to anything if
it smells gluten coming through. It is really at
the edge, ready to jump.
There was a strong correlation between the
number of
intraepithelial lymphocytes and the
141
villus/crypt ratio, meaning, that the more healthy
is tissue, the less intraepithelial lymphocytes.
The healthier the tissue -- when the crypts are
elongated and the villa get short, the more
intraepithelial lymphocytes are there. The
intraepithelial lymphocytes are really soldiers
that the immune system sensed at the forefront and
ready to fight the battle. That is what it is.
(Slide.)
DR. FASANO: Now, what kind of symptoms
after the three months these people experienced in
the three groups? There were not really
significant differences: abdominal distention,
anemia, iron deficiency, loss of appetite,
bloating, and so on and so forth.
There were equally distributed in all
groups including the placebo, but two really stand
out -- all in the 50 milligrams. This stomatitis
and the mouth, there are the typical signs of
mucosal involvement of the oral cavity in celiacs,
well-described, it was present only in the
50
milligrams. Weight loss was experienced
only in
142
the 50 milligrams. For the rest, we didn't see any
major differences.
To revisit the concept that the antibodies
were useless -- these are the antibodies, IgA and
anti-tTG and IgG anti-gliadin antibodies -- before
and after the challenge in placebo 10 and 50
milligrams, there was no difference. Pretty much
there was no difference among the groups.
What we saw as the difference was the
villus/crypt ratio, that all in the 50 milligrams
started to decrease to a level of significance.
After three months, we saw the crypts become a
little bit deeper and the villi to become a little
bit shorter. This translates in the fact that
there was damage that started to occur, or possibly
damage that started to occur.
The intraepithelial lymphocytes, there are
these spots here (indicating). Again, these are
lymphocytes under normal circumstances you see in a
smaller quantity in between epithelial cells.
It came to be of a very increased number
in people
with 50 but not in 10, not reaching
143
statistical significance, but these are trends that
I have the obligation to report. It is not
significant that there are more of these cells in
the 50 milligrams compared to the starting point,
but it is a trend there.
(Slide.)
DR. FASANO: I believe the heart of all of
this is this table. I believe this really cuts to
the chase. It is extremely confusing, particularly
to patients, when you talk about milligrams and
parts per million. What the heck are you talking
about? Why do we use this parameter of parts per
million and not just straight milligrams?
Because, by the way, say, you do the study
and you show that 50 milligrams could be dangerous,
so how can it be 10 milligrams? How much is 10
milligrams? How much of a pizza is 10 milligrams?
You say, "Well, let me give you the bad news. It's
less than a fraction of a crumb of a piece of
bread. That is what we're talking about.
Still, it doesn't give you clearly what is
the
magnitude of the stuff that we are talking
144
about. The reason why we prefer to express in part
per million rather than in milligrams is because
the amount that is tolerable really depends on how
much you eat.
(Slide.)
DR. FASANO: As you see here, this is the
daily intake of gluten-free flour or whatever
products are based on gluten-free. If you eat
50 milligrams, of course you end up to ingest much
less than 300 milligrams of the substance that you
are eating.
Let's say that, for example, we set the
parameter at 200 parts per million. If we want to
accept the outcome of this study as something to
keep in mind, 10 milligrams is safe for everybody,
50 milligrams start to be questionable.
If you set the threshold at 200 parts per
million, if you eat a relatively small amount of
the stuff a day, you are okay. If you eat a little
bit more, you are in an area that we don't quite
know, because again it is between 10 to 50
milligrams. You can argue,
"Is 40 okay? Is 30
145
okay?" We don't know.
Definitely, if you eat 300 grams a day --
in other words, you eat large amounts of
gluten-free products that is contaminated to the
level of 200 parts per million -- you start to go
into the red zone. That is dangerous.
If you go down this table, you see that if
you set 20 parts per million, no matter how much
your Italian lifestyle of eating like crazy food
that is gluten-free based, no matter how far you
go, you still are well below the threshold.
Therefore, at least based on this study,
that I believe has been done really the way that it
is supposed to be done, long enough, because three
months is definitely a long period, a threshold of
20 parts per million should be safe for the vast
majority of the people because it will keep you way
below the cutoff that seems to be dangerous, i.e.,
the 10 milligrams.
(Slide.)
DR. FASANO: Now, this litany of names is
just to
explain that this was not a trivial study.
146
It was a multicenter study that involved a
tremendous amount of work and a tremendous amount
of dedication of people that have no business to
undergo this, particularly two endoscopies with two
biopsies. However, it is only because of the
dedication and the commitment of these people that
we have an answer and we have a chance to come to
you today with something that is a little bit less
foggy than so far we have had in terms of
prospective studies.
I will stop there, and I will take any
questions that you have.
CHAIRMAN DURST: Thank you very much.
QUESTION AND ANSWER SESSION
CHAIRMAN DURST: Questions?
Margaret.
DR. BRILEY: Margaret Briley. Can you
tell me, I didn't understand, how often did they do
the biopsies? Every month? Every three months?
DR. FASANO: No. No, no, no, that would
kill us if we do it every month. No, the biopsy
was done at
the beginning of the study, at the
147
entrance, and at the end of the study, three months
after, the idea being how much insult did you get
in two months.
What was done at intermediate intervals
was a survey of the diet, to make sure that they
were complying with a gluten-free diet, survey
compliance of taking the pill, and the serological
tests for the antibodies. Those were done on a
monthly basis.
DR. BRILEY: On a monthly basis?
DR. FASANO: That's right.
DR. BRILEY: Thank you. That was good.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: Erica Brittain. If I'm
understanding correctly, the conclusion of the
study is that 10 milligrams daily would be safe,
was shown at least to be fairly similar to your
placebo group in this four-month exposure. How
would you know how that would translate to four
decades of exposure?
DR. FASANO: Only with decades of
prospective
study. You are a statistician, and you
148
know better than I do that you've got to start
somewhere.
There is no question in my mind that the
only way to do that is like when you put a new drug
on the market, and you go to Phase I and you do 10
people. When you do Phase II, you do 100 people.
You do Phase III, and 10,000 people. Everything is
fine. Ten years later, because millions of people
took it, it may be that something wrong will come
up, a classical example.
I don't have an answer for you. How do I
know in 10 years what's going to happen? But, you
know, we have to have some way to start. I believe
that this study is giving us a parameter, a
justification, a scientific rationale to say,
"Let's start here."
CHAIRMAN DURST: Okay. Soheila.
DR. MALEKI: Soheila Maleki. I was just
wondering, this is probably not directly related to
your topic, I heard earlier mention of wheat flour
and exposure. How much is inhaled exposure
involved in
some of these reactions?
149
DR. FASANO: I don't think that anybody
can answer with scientific confidence that inhaling
is or is not a possible port of entry of gluten for
people with celiac disease to react to.
What we know as a fact, an undisputable
fact, is that the intestine is the port of entry,
the key port of entry. I can tell you anecdotally
that we have patients that react to inhalation of
gluten leading to asthma as an allergic reaction to
gluten rather than to celiac disease.
How confident am I that this could be an
alternative to the other route? I'm not really
confident, because I don't think that we have the
scientific proof beyond any reasonable doubt, as we
do with the other route, that it could be a
possibility.
DR. MALEKI: Thank you.
CHAIRMAN DURST: Ciaran.
DR. KELLY: Yes.
Thank you, Alessio, I agree. Thank you
for sharing the data with us, and I agree that at
least it is
a basis that we can begin to work from
150
and make some rational approaches to what is best
for our patients with celiac disease.
A couple of questions: The first relates
to the earlier question about the 40-year
experiment. There is one that there is a
20 part-per-million threshold set already in Italy.
Could you comment on how well that is tolerated by
every or the vast majority of celiac patients in
Italy?
DR. FASANO: Actually, it is much more
than that. There are interesting natural
experiments being done. Italy for many years now
reinforced the 20 parts per million. England has
this 20 to a hundred, and so on and so forth.
As far as I can tell you, this is
something that in Italy the food labeling
legislation setting it at 20 parts per million has
been there for 7 years. It has been considered to
be absolutely safe with very sporadical reports of
reactions.
Now, I think it was telling you when you
have a
stomachache and you are a celiac, you tend
151
to go that way to the extreme that some people say,
"Today's ache is because I had gluten."
I mean, this is the reality of the story.
But if you want to, statistically speaking, work on
the large numbers, I would say that 20 parts per
million has been proved to be safe.
DR. KELLY: In your study, then, and this
is something that we discussed a lot yesterday in
the context of food allergy and challenge studies,
is there the potential for bias in selection; in
other words, individuals who are highly sensitive,
in terms of symptomatically highly sensitive, to
low levels of gluten would either be afraid or not
choose to enter the study?
DR. FASANO: Absolutely. Absolutely, no
question about it. The reality of the story is
that if you are extremely sensitive to gluten, you
would be less willing to expose yourself to
something that you know is going to harm you.
The point is, What percentage of the
population does that represent? Is it 10 percent,
20 percent,
50 percent, or a fraction of 1 percent
152
of the celiac population?
You know, I'm pretty sure everybody that
is involved in the clinical care of people with
celiac disease has run into people who are
extremely, extremely sensitive to gluten out there.
The exception are people where actually the problem
is the opposite; these are people who can eat
dangerous amounts of gluten and they do not react.
That is a problem.
CHAIRMAN DURST: Dick Durst. Just to
follow up on that, How did you recruit the people
for these studies?
DR. FASANO: The method of recruitment is
a major advantage of the Italian setting is that
there is a single Celiac Society, and they are
extremely committed. What we did was very simple.
They have a national bulletin, both electronically
and on paper, that is read pretty much by the vast
majority of the members of the celiac community.
I believe that we originally asked for 45
volunteers. That is the number that the
biostatistician told us to go for to have a
153
meaningful outcome. We got 470 volunteers, so we
had to turn people down.
CHAIRMAN DURST: Did you at that point
know which ones were the hypersensitive or the more
sensitive versus other and select on that basis at
all?
DR. FASANO: No. The way that these
people were selected was completely random. In
other words, the least that we had every "X," three
or four up -- I don't know, to make the number --
were called to make that unbiased. We really
wanted a representative portion of the population.
This was done by also sex and age.
Yes?
DR. KELLY: Ciaran Kelly again. I do have
one other question, and it has to do with the
interpretation of the data on villus/crypt ratio
and IEL counts in the controls versus the
well-controlled celiacs.
You showed that there was a small
difference at baseline, even though those
individuals
were doing well on a gluten-free diet.
154
Your interpretation is that there is an underlying
immune activation. My question is, Is it possible
or likely or relevant that the 20 parts per million
that they are taking is perpetuating that?
DR. FASANO: What I am trying to convey is
the difference is that the recovery -- even if you
are completely, religiously gluten-free -- is not
100 percent. That is what I meant.
I don't know if this is due to an ongoing
immune response. I believe that to not probably be
the case. Because after all, after all with all of
the machinery in the community, these people have
been proved not to go back to normal. Whereas,
again, the fact is that no matter how you push it,
you can't really go back to normal.
I think that the fact that for three
months, even if you were really "touched," so to
speak, you did not react to 10 milligrams. For me
it was a great level of confidence that this is the
way to go -- together again with data with a
retrospective study, that we are going to hear
about in a
moment, and on-the-field exercise in
155
Italy.
CHAIRMAN DURST: Jean?
MS. HALLORAN: Another question about the
sample group. When you did the baseline study, how
much variability did you find in the members of
that group?
DR. FASANO: Let me see if I can go back
on this.
MS. HALLORAN: You had two factors that
you looked at, the villus height --
DR. FASANO: Can you put on the slide show
for a second?
(Ms. Sylvia Smith complies.)
DR. FASANO: You will see that there was
--
MS. HALLORAN: Slide 32.
DR. FASANO: Can you bring me over there,
please?
(Slide.)
DR. FASANO: There is a fair amount of
variability. You see that, and there is some
overlapping
at baseline.
156
If you go down -- keep going -- now, if
you can go up to 28, please?
(Slide.)
MS. HALLORAN: It is 32, I think.
DR. FASANO: You want 32? I thought that
you were talking about the variability of the
villus/crypt ratio. Is that what you are talking
about?
CHAIRMAN DURST: Yes.
MS. HALLORAN: Yes.
DR. FASANO: It is a little bit higher
than that.
Can you go higher?
MS. HALLORAN: Ah.
DR. FASANO: Stop here. I need 26.
(Slide.)
DR. FASANO: All right. You see here,
this is the variability. You see here that this is
the variability. These are the single points. If
there was somebody that was high right here
(indicating), and someone like here, these are the
celiacs. There was a continuum,
so it is not that
157
there are people here, people there; it is a
continuum.
This is the standard deviation, and this
is the mean. Again, there is some variability but
not huge. There is much more variability in the
intraepithelial lymphocytes -- you can see this
scatter -- that are being monitored.
CHAIRMAN DURST: Suzanne.
DR. TEUBER: Suzanne Teuber. I would
assume, and this may be a completely incorrect
assumption, that in the population that is
following a gluten-free diet strictly, as those you
indicated you recruited, would actually be a subset
of patients who perceive themselves to be very
sensitive, and thus would have a higher motivation
to follow such a diet.
This would bring up in Italy what percent
of patients do comply with the gluten-free diet?
We heard about the extreme difficulties here and
the poor compliance rate. Is it better in Italy?
Would this mean that, perhaps, this population that
you
recruited from really might be a good sensitive
158
population?
DR. FASANO: I think, and I'm paraphrasing
Joe Murray on this, that the compliance with the
diet is the results of many factors, some of them
diet there. Education I believe is at the top of
all.
It is not that you feel it to be more
sensitive or less sensitive. If you understand the
facts, if you understand the rules of the game, no
matter how you are perceived as being sensitive or
not sensitive, you know that you can't cheat. You
know that you need to start with that.
If you go to 10 doctors and they say all
the same things, "I'm sorry, you don't have an
alternative," then the level of confidence
increases. We don't have that here. We don't have
it, honestly.
Let's be honest. We have people, doctors,
that will tell you, "You know, you need to go on a
gluten-free diet." These are the teaching sheets
that were printed 20 years ago. "After three
months, go
back on a regular diet. You're going to
159
grow out of it." What level of confidence do you
have?
Definitely, a study like here, like this
done here, will have a tremendous amount of bias.
Because who is going to do that? It will be only
the ones that are extremely compliant. The
population in Italy that is compliant -- in Italy?
I should not say in Italy, in Europe --
because they are like 10 or 15 years ahead of us in
this, because the level of awareness has been there
for quite a long time -- is pretty high.
They understand exactly what is at risk.
That is the reality of the story. It is more than
to be the people with high cholesterol, high blood
pressure and to be on medication because there is
much more flexibility there.
These people they understand that if they
don't comply the pay a price, and they do. The
level of frustration, particularly here, is that
they want to do that, the ones that understand the
game, but they can't because there is no way in
their
current situation they can comply.
160
CHAIRMAN DURST: Doug.
DR. HEIMBURGER: Doug Heimburger. Would
you go to the next slide, please, after this one?
DR. FASANO: Sure.
(Slide.)
DR. HEIMBURGER: Does this graph include
the controls or only celiac patients?
DR. FASANO: These are only the celiacs.
DR. HEIMBURGER: Just out of interest, did
you test for this correlation in the controls?
DR. FASANO: Yes, it is the same. We put
it all together, yes. There is a strong
correlation. Again, if you conceptualize this
intraepithelial lymphocytes as, again, the first
folks to go there -- just two weeks ago, for
example, there was a paper in science in which they
claimed that the lymphocytes, they are called
gamma/delta, they are able to present antigens.
They can see gluten and they can start the
entire reaction, at least to the adaptive immunity
Th2 response to interferon-gamma, that will
translate
in damage, i.e., to make the villi short
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and the crypt deeper. That makes a lot of sense.
The more you have, the more cytokines you can use,
the more damage you have.
CHAIRMAN DURST: Dr. Fasano, will you be
around for the discussion this afternoon?
DR. FASANO: Yes. Yes, I will.
CHAIRMAN DURST: Because I think maybe we
will stop the questions.
DR. FASANO: I have my candy so I can't
leave you.
(General laughter.)
CHAIRMAN DURST: Okay. We will probably
move on so we don't go too far into the lunch hour.
Our next speaker is Dr. Pekka Collin. He
is a professor at the University of Tampere Medical
School in Finland. He will discuss retrospective
studies.
RETROSPECTIVE STUDIES
DR. COLLIN: Yes, good morning everyone.
I come from Tampere. You probably know where
Finland is and Tampere is a hundred miles north of
our
capitol, Helsinki.
162
(Slide.)
DR. COLLIN: We at least in Tampere think
that is the celiac center of Finland, but maybe
somebody disagrees with that. We have a half a
million people around our hospital and now our
clinical prevalence of celiac disease is
approaching 1 percent. I think it is .7 at the
moment, so we have 1,000 patients with celiac
disease. Consequently, we have tried to examine
both the symptoms and the diet.
(Slide.)
DR. COLLIN: I had some specific issues
which I should address at this meeting, and they
are here. I should explain why we carried out our
retrospective analysis of the gluten content in our
gluten-free products; then, also, calculate what is
the significance of daily gluten exposure in this
small amount of gluten; and then, also, to discuss
is there some variability in the sensitivity of
people with gluten intolerance which has been
discussed here already many times. That should
also
include patients who are taking with
163
starch-based, gluten-free products and who are
taking oats where we have a lot of experience.
(Slide.)
DR. COLLIN: I think that celiac disease
has been described very well by previous speakers,
so I will go straight into the point. However, I
will emphasize that now we are talking about parts
per million or 10 milligrams or 20 milligrams of
gluten intake.
(Slide.)
DR. COLLIN: In real life, if you have 100
patients with celiac disease, I think 90 percent of
them are taking 15 grams of gluten a day because
they do not know that they have celiac disease.
Only 10 out of 100, for instance, in the
U.S.A. I think know that they suffer from celiac
disease. Of the remainder 10, maybe 3 or 4 do not
follow a gluten-free diet strictly because they
don't care, or it is more likely because there are
not enough products when they are eating out or
eating in restaurants, and so on.
I
think that is very important, that we
164
have a good choice of products. That is more
important than some parts per million in order to
achieve a good percentage of compliance.
The amount of threshold, I think it
started more than 10 years ago in Europe. The
celiac societies were very, very active in these
respects. From southern countries, some people say
that we are in northern countries poisoning our
people because they know that we are giving them
wheat-starch-based, gluten-free products.
On the other hand, our society, I think
they are very -- I don't find the right word -- but
I admire them because they said, "Please make the
study. Look at what we are now eating. Celiac
patients are the last who will have some extra,
unnecessary dietary restrictions, so please make a
study where you show whether we are now eating
safely or not." I think that was the background
for our so-called "retrospective study."
At that time we were quite relaxed. We
were not afraid that we are poisoning our people,
because we
published a study where we showed that
165
in our patients we did not have, in treating
patients we did not have, any extra mortality and
even we did not have any extra risk of malignant
conditions at that time.
Then, we looked at what the Finnish
celiacs are eating. As expected, the majority of
them took wheat-starch-based, gluten-free products.
(Slide.)
We can also see that compliance was very
good. These patients they were invited, after 5 or
10 years on a gluten-free diet they were invited, a
cohort of those patients, both so-called
"sensitive" and not sensitive, and we can see that
only a small percentage of patients had dietary
transgressions. Although there were a few who
daily or twice a week or once a month had dietary
lapses, most people preferred to follow a naturally
gluten-free diet.
We also show that for these patients their
quality of life is good, and they did not have any
additional symptoms compared to the population. As
has been
mentioned many times earlier, symptom is
166
not a very reliable objective sign of gluten
intolerance.
(Slide.)
DR. COLLIN: This is an example how
symptoms can be misleading. This is maybe a little
bit out of the topic, but I think this is very
interesting.
We ask family doctors to send us all such
patients who spontaneously reported that they get
symptoms after taking wheat or rye. The majority
of them had also on their own account tried to
avoid or withdraw these products from their diets,
and they experienced clear improvement in symptoms.
We thought that many of them had latent or
overt celiac disease, but to our surprise only 10
percent of people with a clear history of
intolerance to gluten had really celiac disease.
Then, there are some which we thought that they
maybe had wheat allergy.
When I was here yesterday I heard about
that. Yes, the diagnosis is so difficult, so I
hope that I
don't have to discuss this in more
167
detail.
However, the majority of them, even with
sophisticated methods, they did not have any signs
of celiac disease and probably they have irritable
bowel syndrome. Hence, we cannot trust symptoms
even in the diagnosis of celiac disease.
(Slide.)
DR. COLLIN: Then, of course we have to go
to small bowel biopsy as they did also earlier. We
took a control biopsy after 5 to 10 years from
these patients who had been diagnosed with celiac
disease and who were asked to come to our hospital.
(Slide.)
DR. COLLIN: What we can see here is that
this is the same villous height/crypt depth ratio
which has been measured by, for instance,
Alessio Fasano. Here is our reference value for
people who have no suspicion of celiac disease.
They have come to endoscopy because of suspected
some gastrointestinal disorder, reflux symptoms or
dyspepsia.
We can see that in our long-term treated
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patients, there is a 95 confidence interval, so it
was exactly the same as in our non-celiac people.
I could show also a similar slide of
intraepithelial lymphocytes, very similar. They
did not have extra intraepithelial lymphocytes.
We did not either have any so-called
"highly sensitive" patients with celiac disease.
We had some here who had not a complete recovery in
the mucosa.
After dietary inspection, it turned out
that all of these people are taking occasionally
gluten. Even once a month, I think that was in the
data, the histological recovery was not complete
Then, we had also here are the celiac patients
where the ratio was of course low.
Then, we had some short-term treated
patients, that means from half year to one year.
We show that the healing was not complete at that
time. From this slide we had two questions.
First, when we have a complete recovery,
are those patients still taking some small amounts
of gluten or are their products complete
169
gluten-free?
The second question was, When we have this
incomplete recovery, does it depend on wheat starch
or gluten contamination or is it normal life in
celiac disease? In other words, would the healing
be better if instead of wheat starch used, the use
of naturally gluten-free products?
To the first issue, Are those products
contaminated which have shown that our people are
doing well and their mucosal is healthy? It was
not surprising that most of naturally gluten-free
products had less than 10 ppm gluten.
However, I think it is very important to
realize that some of the so-called naturally
gluten-free products, they may be contaminated with
gluten, even quite high. All of these were
fulfilling the current European Codex standard.
If we go to the wheat-starch-based,
gluten-free flours, there were two with zero
gluten, and as expected most of them contained
trace amounts of gluten. Two had more than 100,
but the
majority has less than 100. That was
our
170
idea that maybe we can set the limit to 100 ppm.
When I had this slide and my conclusion in
Europe, one of the representatives of industry said
that he was disappointed because I am talking about
100 ppm, and I should have talked about the limit
of 200 ppm because it is much easier for them.
However, I said that we had too few
products here to assert that 200 ppm would be
recommendable. I think I will remind you that
90 percent of our celiacs have used this product
for 40 years or even more, and we have
biopsy-proven results from that so-called challenge
from 5 to 10 years. The mucosal recovery, as I
said, was perfect.
(Slide.)
DR. COLLIN: We also looked at how much
they did use those flours. Maybe somebody who has
taken gluten-free products can know that they are
not necessarily as good as wheat, baking with
wheat.
Nevertheless, here are how the patients
used these
products. There was no difference
171
between wheat-starch-based products or a naturally
gluten-free diet. The average was 80 grams, and
the majority took less than 150 grams as you can
see here. There was no correlation between the
villus damage and the amount of data used of loss.
(Slide.)
DR. COLLIN: From here we come to this
conclusion, which maybe you have seen this kind of
table in Alessio Fasano's presentation. Provided
that we set the limit to 100 ppm, and provided that
each of these products also contained the maximum
amount allowed, when patients are taking 100 grams
of those or 200 grams of those the gluten
contamination is from 10 to 20 milligrams.
If you look at Fasano's results and if you
look at some earlier, small studies -- even the
Catassi study, which was referred to, and some
smaller studies made by Sturgis and so on -- I
think we are very, very safe here at the 100 ppm.
I think also that our clinical experience will show
that the same.
Of course, this is not a prospective
172
study, and we did not have any control group, and,
unfortunately, we did not have many patients who
have clear dietary restrictions, so we cannot make
any statistical analogies between those who are --
what is the word -- cheating with their diet and
who are not. However, I think with this kind of
system, we can treat our patients and have good
compliance.
(Slide.)
DR. COLLIN: If I can, go to the issue
whether patients are more sensitive or
hypersensitive patients with celiac disease. When
we look at those patients, we can see that their
mucosal recovery takes place in a different way in
different people. That has been very well shown in
some challenge studies. Where earlier it was
customary to accept diagnosis, we have once again
to challenge the patients to gluten-free diets and
look at if there will emerge new villus atrophy.
We show that in some cases it took two
months or one month to see a mucosal relapse, but
in some
cases it took two or three years. Our
173
record is 15 years. Fifteen years with normal diet
and earlier diagnosed celiac disease, after 15
years a mucosal relapse occurred.
Here we can see that in the short-term
some people do not respond, and you could think
that these might be so-called "hypersensitive." If
we give enough time and the patients are truly
following the gluten-free diet, which means that we
must be really accurate that they do not take wheat
at the same time, I think in the long-term we have
almost complete recovery. We did not have any
so-called "hypersensitive."
I think patients with refractory sprue
they can be very sensitive because they do not
respond at all to celiac disease, but that is a
different issue. It is probable that even zero
gluten would not help them. There is something
wrong in their gut. Probably the diagnosis has
been made too late, and it does not recover any
more. I think that refractory sprue is outside of
the topic of this day.
Also, we were discussing with Peter Chen,
174
when he wrote to "Gastrointestinal Endoscopy" that
complete mucosal recovery is not possible, and we
had a very friendly, friendly discussion in the
pages of that journal. However, we said that it is
possible when we have a good choice of products and
people also outside the home know what celiac
disease is what this means for the patient with a
gluten-free diet.
The second issue in my slide was that
could it be that the mucosal healing would be more
rapid in those who are on a naturally gluten-free
diet than in those who are maintaining
wheat-starch-based, gluten-free products?
Here, we carried out a randomized
prospective study of one year in newly detected
celiac disease patients. If we look at the villus
healing here and here, villous height/crypt depth
ratio, there were no differences between these two
groups. We can also see that in one year, you
cannot achieve the limit of three, which is
considered normal.
Similarly, when we look at intraepithelial
175
lymphocytes, they decreased in a similar way in
both patients. At that time, unfortunately, we
could not measure what was the exact amount of
gluten these patients were taking; we did not have
methods. We can assume they took those same
products which were mentioned in my last slide
which contained trace amounts of gluten but not
more than 100 ppm.
(Slide.)
DR. COLLIN: If I may say some words about
oats. It was in Finland, the first publication.
After that, very soon it was accepted for celiacs
in Finland that they may use oats. At the
beginning we were very careful. We followed up
with them each month and looked at what to do, but
now we do not do it anymore.
We made a question out, too. We sent a
question out to members of the Celiac Society, how
do they appreciate oats. As you can see, they like
about the permission to eat oats.
Almost all said that it is a very
significant
part of every day gluten-free diet in
176
terms of tasty and low lost. They even thought
that it is healthy, diversifies the diet, and we
have a good availability in Finland of oat
products. I understand that maybe in some
countries oat is not so important.
Some might say that in Finland they are
not eating good, so maybe people in Italy do not
operate yet in the same manner as in Finland, but
we can discuss it.
(Slide.)
DR. COLLIN: Here are how our people have
now used oats, the majority of patients -- not
great amounts, it is only 20 grams, 15 or 20 grams.
There, most of the studies are about approximately
50 grams, so less than in those randomized studies.
Some people do not prefer oats, and that
is the same thing in people in general not only in
celiac patients. Some of them had stopped, and the
reason is that they had developed symptoms. Some
even got a rash, basically dermatitis
herpetiformis. We do not have any proof that the
reason for
stopping would be that they
177
simultaneously had mucosal damage. Usually, the
mucosa is good even though the patient has stopped
the diet.
The rest, in dermatitis herpetiformis, we
also saw that even in patients with no oat diet, so
even they may have a temporary rash. There are
some clinical relapses in patients with dermatitis
herpetiformis also.
It is excellent to study these questions,
because we can change the subjective symptoms quite
rapidly to objective science, count the number of
blisters, for instance.
(Slide.)
DR. COLLIN: We also looked at the quality
of life in patients with oats. Actually, there was
no change, difference, compared to patients with no
oats. This also was a prospective, randomized
study in treating celiac disease.
Interestingly, those patients who were
taking oats, they reported more symptoms of
diarrhea, which was statistically significant.
They also
reported more constipation, which was not
178
significant. Even in these patients, we did not
have any mucosal deterioration.
From this we learned that if we start on a
gluten-free diet with oats, we must inform the
patient that "You may have symptoms after this. If
you have symptoms, why continue. But it is
improbable that we have done any harm to your
small-bowel mucosa.
We also saw that those who were taking
oats had a little bit more intraepithelial
lymphocytes, not CD3 lymphocytes, which we have
discussed today, but gamma/delta lymphocytes.
The gamma/delta lymphocytes were a little
bit increased in the oat group. I cannot explain
the reason for that, and that has not been
published elsewhere -- but that is the fact.
(Slide.)
DR. COLLIN: Here are my conclusions to
the questions which I was asked to answer. Maybe I
also specific questions which you have, specific
issues which you have to address in the final
report.
179
If I may say something about the
subpopulation, the most highly sensitive people, I
think such people of course may be, but eventually
they have good mucosal recovery, provided that they
follow a gluten-free diet. The majority of these
highly sensitive patients are probably such people
who have advertent or inadvertent gluten intake.
We can also remember that even if it
happens, the consequences are not disastrous,
because they do not develop an anaphylaxis aspect
as do people with peanut allergy as we heard today.
We can quite easily detect these highly
sensitive, if we after the diagnosis, one year
after the diagnosis, take a small-bowel biopsy and
look at whether there is an improvement in the
mucosal architecture. If there is not, we must
consider that they may be very sensitive, but
usually they do not follow the gluten-free diet.
About the risk of malignant diseases, I
think the whole literature tells that those people
who are at an increase risk of malignant lymphoma,
their
diagnosis has been made too late. They
180
already have lymphoma when the symptoms of celiac
disease appear and when they get the diagnosis of
celiac disease, or they have had dietary
transgressions for a prolonged time.
Of over 1,000 patients I have seen during
the 15 years, I have seen one patient who has
developed lymphoma after being 5 or 10 years on an
apparently gluten-free diet. The risk of these
severe complications in those small daily intake is
probably very low. Even our new data show the
same, which is now published only in abstract.
Similarly, the mortality, it depends on
those patients who come to the hospital together
with the diagnosis of celiac disease and later,
usually within six months, we can see that they
also have lymphoma.
(Slide.)
DR. COLLIN: What about the oats? Here I
summarized some studies. Those with plus signs
they are those who have shown that oats have no
adverse effect on the mucosa. I think nearly
almost all
of these studies are randomized,
181
open-randomized. They have a control group with
non-oat. We have hundred of patients who seem to
tolerate oats.
But I think I would be stupid if I did not
see also those two papers and patients who are
sensitive. I cannot close my eyes from the
results, because Don Kasarda told the data very
convincingly.
I don't know who they are. Maybe there
are some who really develop villus atrophy after
taking oats, but that must be an extremely rare
condition. Because, as you see, we have so many,
many patients who are taking oats, and we have not
seen this phenomenon.
Still, we must be careful, and we must be
careful because patients with oats may develop
symptoms. If everything does not go well, of
course we stop the use of oats. However, we must
be aware of that, that maybe there are some rare
patients where it acts the same as gliadin for most
people with celiac disease.
I don't know whether these, my
results and
182
recommendations, can be applied in the United
States but that is how we are doing now. Our
celiac society is very happy because we said that
you can continue with starch-based, gluten-free
products.
Thank you very much.
CHAIRMAN DURST: Thank you.
QUESTION AND ANSWER SESSION
CHAIRMAN DURST: Do we have questions?
Suzanne.
DR. TEUBER: Suzanne Teuber. My question
relates to the applicability of the diet parameters
to the United States dealing with how much
gluten-free flour do people in different parts of
the world ingest, if they were to have the option
of knowing that something was truly, truly
gluten-free.
You talk about 100 parts per million. It
was your data that came up with the 80 grams a day
that people ingest. I'm wondering -- you know, we
are not setting any level here today -- in terms of
United
States' folks, I have no idea how that would
183
apply. Would this be a safe level for them? Or,
here, would people be preferring to adjust much
more? Do you have any input on that?
DR. COLLIN: I think there is not much
data on that, how much people really in different
parts of the world are really using wheat or other
flours which may be harmful to patients with celiac
disease.
I think that this is a subject for further
studies. Maybe somebody here knows how much celiac
patients are here using gluten-free flours, but I
don't know. I have not seen any publications about
this issue.
CHAIRMAN DURST: Any other questions?
DR. McBRIDE: Margaret McBride. Did I
understand correctly that gluten-free in Finland
means 100 part per million?
I guess for me, as I'm thinking about it,
maybe part of the difference between the two
studies, aside from the obvious
retrospective/prospective, et cetera, is that in
Italy the
gluten-free diet did contain some,
184
although very little at 20 parts per million
gluten, in addition to what was administered.
I don't know if there is an estimation of
how much that would be. I'm also thinking maybe
there is more interest in pasta in Southern Europe
than in Northern Europe.
DR. COLLIN: I think that today we have
given the formal Codex standard which says that
200 ppm is okay, but of course we need to
reconsider that.
I think that in the whole of Europe there
will be two limits, that is the 20 milligram which
can be used in the highly sensitive people, but in
the majority of people it is 100 ppm.
Of course, there is a problem with
labeling, how we should label that. We cannot say
that it is "low gluten," because then people will
use that. That is our problem.
What our recommendation is, is that maybe
the majority of people with celiac disease can
tolerate products which are under the limit of
100 ppm.
185
DR. KELLY: Ciaran Kelly. I wonder in
terms of compliance with the diet and acceptance of
the diet, is there a big difference between 20
parts per million or 100 parts per million from the
perspective of the palatability of the food?
DR. COLLIN: I think the important thing
is, at least the industry in Europe says, that, if
we go to very low level, there are not so many
alternatives for gluten-free products, which again
may result in that general compliance will be worse
than I have shown now.
How the products, how they--? I think
that those wheat-starch products, I think they are
very tasteful. Does it depend on the small
milligrams of gluten or not? I don't know. But,
as can be seen, most of the people are preferring
those products instead of naturally gluten-free.
CHAIRMAN DURST: Anyone else?
(No verbal response.)
CHAIRMAN DURST: If not, thank you,
Dr. Collin.
Our final speaker for this morning is
186
Rhonda R. Kane from the Consumer Safety Office of
CFSAN, FDA, on international perspectives on
gluten-free.
INTERNATIONAL PERSPECTIVES ON GLUTEN-FREE
MS. KANE: Good afternoon. My name is
Rhonda Kane. I am with the Food and Drug
Administration, and I was asked to present
information to the Food Advisory Committee about
how the term "gluten-free" is defined in other
countries and the basis for those definitions.
(Slide.)
MS. KANE: My presentation today will
focus on four examples of international or national
definitions of the term "gluten-free" that apply to
labeled packaged foods.
The first two examples I will be
discussing pertain to Codex Alimentarius and they
include, the first one, Codex Standard 118-1981,
which pertains to the Codex standard for
gluten-free foods that was established in 1981, was
amended in 1983 and is in effect today; and, two,
the
Proposed Draft Revised Standard for Gluten-Free
187
Foods at Step 7 that is now under consideration by
the Codex Committee on Nutrition and Foods for
Special Dietary Uses as a replacement for the
current standard.
For ease in my presentation, I am going to
refer the Codex Committee on Nutrition and Foods
for Special Dietary Uses simply as the "Codex
Nutrition Committee."
In the early 1990s, members of the Codex
Nutrition Committee agreed that developments in the
characterization of gluten on studies on gluten
tolerance warranted a revisiting of the current
standard and an updating of it.
The current proposed standard has
undergone several revisions and is now at Step 7 of
an 8-step process pending resolution of certain
issues including what method of detection is going
to be used for gluten and the results of gluten
threshold studies in celiac patients. The Codex
Nutrition Committee will be meeting in November
2005, and will be discussing the proposed standard.
The third example of gluten-free that I
188
will be discussing is found in Canada's Food and
Drug Regulations at Section B.24.018. It became
effective on May 1, 1996.
Lastly, I will review the definitions of
both "gluten-free" and "low-gluten" that are found
in Clause 16 of Standard 1.2.8 of the Australia
New Zealand Food Standards Code, and I will also
discuss the definition of gluten found in Clause 1
of that same standard.
(Slide.)
MS. KANE: The current Codex standard that
is in effect today defines "gluten" as "Those
proteins commonly found in wheat, triticale, rye,
barley or oats to which some persons are
intolerant."
The current standard further defined the
term "gluten-free" to mean that "The total nitrogen
content of gluten-containing cereal grains used in
the product does not exceed 0.5 gram nitrogen per
100 grams of the cereal grains on a dry weight
basis."
(Slide.)
189
MS. KANE: The current standard states
that it does not apply to foods which in their
normal form do not contain gluten. Gluten-free
foods are defined according to two categories,
those that contain the cereal ingredients -- wheat,
triticale, rye, barley or oats or their
constituents, which have been rendered gluten-free
-- or those foods in which any ingredients normally
present that contain gluten have been substituted
by other ingredients that do not contain gluten.
(Slide.)
MS. KANE: In comparison, the Codex
Proposed Draft Revised Standard for Gluten-Free
Foods at Step 7 defines "gluten" to be "The protein
fraction from wheat, rye, barley oats or their
crossbred varieties and derivatives to which some
persons are intolerant and that is insoluble in
water and 0.5 molar solution of sodium chloride."
You will see that in this definition and
in others that are occurring in the proposed
standard information within brackets is intended to
indicate that that information is
pending
190
additional discussion at the Codex Nutrition
Committee. Their next session meets in November
2005.
The Proposed Standard also defines the
term "Prolamin" to mean "The fraction from gluten
that can be extracted by 40 to 70 percent aqueous
ethanol." This definition specifically identifies
the prolamins: gliadin from wheat, secalin from
rye, hordein from barley, and avenin from oats.
(Slide.)
MS. KANE: The Proposed Standard also
states that it applies to those foodstuffs and
ingredients which have been especially processed or
prepared to meet the dietary needs of persons
intolerant to gluten.
Therefore, this parameter is similar to
the one for the current standard in that neither of
the two standards, the current and the proposed,
would include foods that are naturally or
inherently free of gluten.
The proposed standard also identifies
three
categories of gluten-free foods where their
191
definitions specify certain limits on their gluten
content.
(Slide.)
MS. KANE: In the first proposed category,
gluten-free foods consisting of ingredients which
do not contain any prolamins from wheat or all
Triticum species -- rye, barley, oats -- or their
crossbred varieties cannot have a gluten level that
exceeds 20 parts per million. Again, you will see
that "20 parts per million" is within brackets,
therefore, this number is pending.
(Slide.)
MS. KANE: This proposed definition also
specifically cites three examples of grains within
different species of Triticum, they are: spelt,
kamut, and durum wheat.
Although triticale is not one of the
grains that is identified within the definition by
its name, it is included because it is a crossbred
hybrid of wheat and rye.
In the second proposed category of
gluten-free
foods, they are those consisting of
192
ingredients from wheat, rye, barley, oats, spelt or
their crossbred varieties that have been rendered
gluten-free and cannot have a gluten level that
exceeds 200 parts per million. Again, "200 parts
per million" is cited in brackets, and it is
therefore pending.
(Slide.)
MS. KANE: In the third proposed category,
gluten-free foods consisting of any mixture of the
ingredients as described in the previous two
categories, cannot have a gluten level that exceeds
200 parts per million. Again, "200 parts per
million" is cited in brackets and it is pending.
(Slide.)
MS. KANE: Based upon my reading of the
session reports for the Codex Nutrition Committee
and related documents, it appears that the
rationale for including two levels, the 20 and 200
parts per million, in the definition of gluten-free
foods was to accommodate different points of view
of the Codex member countries that thought there
should be a
different level of gluten based upon
193
their experience with their populations, what would
be adequately protective.
There were some countries that believed
either the lowest limits of detection or 20 parts
per million would be most protective of those that
are very sensitive to gluten.
Twenty parts per million was considered a
practical limit to make it more feasible for
industry to produce gluten-free foods in that
category.
Other countries believed that the higher
level of 200 parts per million would be
appropriate, because they had experiences with
citizens in their country that had celiac disease
where they had been consuming wheat-starch-based
products for years without harm, and they enjoyed
them.
The 20 parts per million level would
essentially prohibit the inclusion of those
wheat-starch-based products. Therefore, it was a
compromise, the low limit and the high limit, and
they
realized they could create some confusion on
194
the part of the consumer.
I also want to point out that the proposed
definition of gluten-free foods specifically cites
that whatever detection method is used it should
have a detection limit of at least 10 parts per
million gluten in the product on a dry weight
basis.
(Slide.)
MS. KANE: The next definition I will
discuss is that found in Canada's Food and Drug
Regulations at Section B.24.018, and it states:
"No person shall label, package, sell or advertise
a food in a manner likely to create an impression
that is a gluten-free food unless the food does not
contain wheat, including spelt and kamut, or oats,
barley, rye, triticale or any part thereof."
(Slide.)
MS. KANE: Canada's definition of
gluten-free prohibits the use of derivatives or
constituents of any of the cited grains.
Therefore, wheat starch would not be allowed in a
product
that was labeled gluten-free.
195
It is my understanding based upon
communication with staff who work with Health
Canada and the Canadian Food Inspection Agency,
that the definition that Canada is using was
developed using a rule-making process, but they
closely coordinated with the Canadian Celiac
Association in the parameters for this definition.
Canada underwent a rule-making process
similar to the one that we use in the United States
where they reviewed the relevant scientific
literature, they published a proposed rule,
considered comments before it went final, and they
determined that back in the mid-1990s that there
was insignificant or insufficient I should say
scientific evidence to support establishing a level
that would be safe for all celiac patients.
(Slide.)
MS. KANE: In the last definitions of
gluten-free that I will be discussing, in the
Australia New Zealand Food Standards Code, first,
in Clause 1 of Standard 1.2.8 of the "Code," which
I will
refer to simply as that rather than
196
repeating that long name, it defines "gluten" as
"'The main protein in wheat, oats, barley,
triticale and spelt relevant to the medical
conditions, Coealic disease and dermatitis
herpetiformis.'"
It also defines in Clause 16 of that same
standard the terms "gluten-free" and "low gluten."
(Slide.)
MS. KANE: "Gluten-free" is defined as
those foods that contain no detectable amount of
gluten. They also cannot contain any oats or their
products or any cereals containing gluten that had
been malted or their products. It has to meet all
of those three criteria not just one.
In addition, their Code defines the term
"low-gluten foods" to mean those that contain no
more than 20 milligrams of gluten per 100 grams of
food. Now, although not stated in the Code as
such, this level of gluten is equivalent to 200
parts per million.
(Slide.)
MS. KANE: It is my understanding
based
197
upon communication with Food Standards Australia
New Zealand's staff that they also underwent a
rule-making process where they proposed these
definitions for "gluten-free" and "low-gluten"
before they went final.
They did a review of the relevant
scientific literature. They considered public
comment, and they also consulted with experts in
the appropriate fields to develop the definitions
that are in effect today.
In addition, the fair trading laws in both
Australia and New Zealand were interpreted as
prohibiting the term "gluten-free" from being used
with any foods that contained any detectible amount
of gluten.
(Slide.)
MS. KANE: Further, the definition of
gluten-free was influenced by a lack of reliable
analytical methods to detect gluten in oats and
malted cereals. Essentially, their definition says
not only no detectible amount of gluten, but no
oats or
other products, no malted cereals
198
containing gluten and their products because of
this limitation of analytical methods.
(Slide.)
MS. KANE: The Code includes two
definitions, "gluten-free" and "low gluten," to
provide citizens who have celiac disease a choice
between which level of gluten-containing foods they
want to consume based upon their individual gluten
tolerance level and the advice of their healthcare
provider.
In closing, I would like to sincerely
thank the staff that I consulted with at Health
Canada, and the Canadian Food Inspection Agency, as
well as Food Standards Australia and New Zealand.
With that, I will take any questions.
CHAIRMAN DURST: Thank you very much.
QUESTION AND ANSWER SESSION
CHAIRMAN DURST: Does the Committee have a
question or comment?
Erica.
DR. BRITTAIN: Erica Brittain. I guess I
find it
appealing the idea of the two levels, just
199
as a comment, in the last one you cited. This
might be applicable to the allergy situation as
well.
CHAIRMAN DURST: Okay. Anything else?
Mark.
DR. NELSON: Mark Nelson. Did your
contacts in Australia, New Zealand and Canada give
any indication that they might change their
definitions or their categorizations if there were
more work done on thresholds, if that data based
changed?
MS. KANE: That sort of conversation
didn't occur between me and them, but I would think
because they are government agencies, just like FDA
is, if there were newer information on the horizon,
they would probably consider it. Whether they
would go through the rule-making process and change
it, I guess they would base it on the needs of
their own populations.
DR. NELSON: I guess the opportunity for
-- this is Mark Nelson again -- two categories does
have some
attractiveness. I guess at Codex it is
200
going to be gluten-free and really gluten-free.
(General laughter.)
CHAIRMAN DURST: Suzanne.
DR. TEUBER: Suzanne Teuber. To your
knowledge in talking with these folks, have their
been any consumer-preference studies or behavior
studies completed or underway with how the celiac
disease patient is using these standards in terms
of their overall intake?
MS. KANE: I don't have personal knowledge
of that. However, the Canadian Celiac Association
is very supportive of Canada's definition of
gluten-free. Because they were instrumental in
helping develop it, so they were very supportive of
it.
CHAIRMAN DURST: Yes.
DR. McBRIDE: Margaret McBride. Do I
understand from your slides about the Codex
proposed changes that the term "gluten-free" would
be applied both to those foods that contained none
of the products in question and are lower than 20
parts per
million, and to those foods that are
201
wheat-based and gluten has been removed but would
contain up to 200 parts per million? I realize the
numbers are in question.
MS. KANE: Right. They do not apply to
the term. They don't want the term "gluten-free"
to apply to naturally gluten-free foods but those
that have been specially processed or prepared
where the formulation has been controlled.
There is a substitution of ingredients or
a removal of gluten from ingredients. It would
cover categories that are wheat-starch-based. That
is where the 200 parts per million definition is
coming into play.
Member countries did not want
wheat-starch-based products to be excluded from
being called gluten-free, if there was only one
definition of 20 parts per million. That is why
they compromised and had the two levels that would
apply.
DR. McBRIDE: A follow-up. Would I assume
that they would then be called something different,
or would we
be expecting the consumer --
202
(Simultaneous discussion.)
MS. KANE: No. Right now, as it stands,
they are saying one definition "gluten-free" to
apply to three categories of gluten-free. However,
that could change.
Now, keep in mind all of this
is pending. It is at Step 7 of an 8-step process.
I know there is a Working Group, the Prolamin
Analysis and Toxicity Group. That information will
come into play. These levels are not definite and
they could change.
If both of those situations or all three
were called gluten-free, then we would have to
expect that the consumer who felt that they were
very sensitive and wanted truly a very low level,
below 20 parts per million, would have to read and
understand the names for the various grains,
et cetera, that would be on the ones where in fact
products that at least one time had contained
gluten were used.
I understand that, and the report I cited
on my
second slide, the "ALINORM Report" is the
203
latest one, to my knowledge, that contains the
language of the current proposed standard at
Step 7. It doesn't go into those details about how
it might be labeled alternatively or what
additional information it would include. You're
right, it does create confusion. How would you
know if it is 20 parts? How would you know if it
is 200 parts?
That issue was brought up in some related
documents, but it is not found in the latest
session report. However, you're absolutely right.
DR. NELSON: This is Mark Nelson. I just
want to address that question about the Codex
label. There is a separate committee, Codex
Committee on Food Labeling, and these definitions I
would expect would ultimately be referred to the
Codex Committee on Labeling to address the issue
you have just raised about the potential confusion.
CHAIRMAN DURST: Suzanne.
DR. TEUBER: Suzanne Teuber. I also see
an issue about cross-contamination problems with
foods that
you wouldn't expect to contain gluten
204
and yet might contain contaminants because some of
these, the rules that you are talking about, really
don't address that.
Do you have any information on that, like
say, corn that may be processed in a place that
also has processed wheat? It really would be
beneficial to the consumer if it were to undergo
testing and have a specific label, and yet these
other definitions in other countries don't seem to
cover that all. It would probably just come out
with no statement. Is that a correct
interpretation?
Or, actually maybe, Dr. Nelson--?
DR. NELSON: I think in Europe and Codex
also has a standard for good manufacturing
practices; the Europeans have the equivalent. I
think the issue there would be the responsibility
of the manufacturer to maintain good manufacturing
practices and prevent as much possible that cross
contact.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc
Silverstein. Would
205
you clarify the categories of foods to which this
would apply? I would like you to, because I'm not
sure I understood the criteria exactly. If a food
has multiple ingredients, does this apply to all of
the ingredients in the food?
This is packaged and labeled food. One or
the major ingredient may be a food which in its
normal form does not contain gluten, yet there
might be other ingredients perhaps mixed in with it
that would.
Would it be that it applies to a labeled
package food which any of the ingredients contain
gluten, or would it be just the major ingredient
does not contain gluten and there might be some
additive or some other component ingredient?
MS. KANE: It is my understanding it would
apply to all ingredients. It would be selectively.
If a packaged food that is labeled gluten-free, it
would have to conform to the proposed. Of course,
again, it is proposed so it is not a done deal.
However, there are categories going back.
Can we go back? Can you reverse
it back.
206
It is probably more towards the front. Okay, that
one right there.
(Slide.)
MS. KANE: That is the first category
consisting of ingredients. It doesn't say primary
ingredients. It means ingredients. That is how I
understand it. Keep in mind I've never been a
member of the U.S. delegation to a Codex Committee
meeting. I do not have firsthand knowledge of the
discussions. It is only based on my reading of
their session reports and related documents. The
way that is written I would interpret that to mean
all ingredients. Maybe someone who has attended
the Codex could speak to that?
CHAIRMAN DURST: Mark.
DR. NELSON: Mark Nelson. I think
everybody would interpret that as all ingredients
not just the main ingredients but including the
minor ingredients, flavors, spices, and so on.
I can just talk a little bit about my
experience in the food industry. I have worked
both for
packaged goods companies but also
207
suppliers to packaged goods companies.
They look at it very carefully to find out
what the subingredients might be in, say, flavors
or an additive or carriers or something like that.
I can assure you, being a supplier to companies
like Nestle or Kellogg's or Kraft, we have to
provide a fairly substantial dossier to them for
every ingredient we supply them to deal with issues
like allergens and gluten levels as well. The food
industry itself does take this very seriously.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Soheila Maleki. I guess this
is more a question. It seems to me that based on
what we have seen on some of the slides you've
shown today that there really isn't good analytical
method to be able to determine.
For example, the nitrogen content, you
could measure every protein in there and you could
weigh overestimate the amount of gluten. Measuring
gluten in the insoluble water fraction, that seems
to be, again, if you can solubilize it. If you
can't
really detect it, okay.
208
DR. NELSON: I'm sorry, you may have to
start over. Sorry about that.
(General laughter.)
DR. MALEKI: It is kind of a question.
Based on this, I don't think there is really an
analytical method that can make you comply to this,
so how does this work? How are they going to
enforce it?
MS. KANE: Keep in mind that the nitrogen
definition of gluten is the current one. They are
proposing it be defined as the protein fraction for
wheat, rye, barley, et cetera, to which persons are
intolerant and it is insoluble in water and a
0.5 molar solution to sodium chloride.
However, there is an analytical method
component of a standard, and that is pending
because they were talking about the R5 Mendez
method, ELISA. They knew that they would have to
have a method that was sensitive enough, reliable,
accurate and would detect the types of proteins
that they are talking about in their definition.
That is going to be, I'm assuming, part of
209
the discussion at the next Codex meeting is to
bring that information about the methodology into
play, because those were the two components, the
methodology and threshold levels. Those are the
two areas needed to be worked out, and so I think
that is going to be the crux of the discussion at
the next Codex meeting.
DR. MALEKI: I just wanted to make a
comment as a follow-up.
CHAIRMAN DURST: Oh, okay.
DR. MALEKI: I'm Soheila Maleki. It seems
like the antibodies, the R5 kit again doesn't
detect gluten it detects gliadin. Maybe Steve can
help with that somewhere along the line.
All right, go ahead.
DR. CALLERY: Pat Callery. If the
analytical part can be worked out, which I think it
can. I wonder if there is an analogy here with
caffeine where we have caffeine-free sodas and
such, which we expect to have no caffeine, and
coffee that is decaffeinated that does have
caffeine in
it. The word is not very pretty,
210
"deglutinated."
There may be an analogy that says when it
is gluten-free it is truly gluten-free and when it
is deglutinated, then there is a perhaps 20 parts
per million or something, whatever the standard
would be. That might be easier to understand.
CHAIRMAN DURST: Dick Durst. You
mentioned that the next meeting is in November of
this year. Do you get the sense that they will
finalize the document at that point?
MS. KANE: Oh, I wouldn't venture to say
that at all. I don't know, and I don't know how
close. Again, I've never been involved in their
meetings, and there is an eight-step process. They
could go back and revisit the issues; they could go
forward, and then it could advance. However, I
don't have a clue.
DR. NELSON: This is Mark Nelson. Even if
they did adopt it at the committee meeting, it
would then have to be forwarded to the overarching
body, which is the Codex Commission for them to
adopt it,
and that will be next July.
211
CHAIRMAN DURST: Thank you.
Any further discussion?
Jean.
MS. HALLORAN: I think everyone should
realize that Codex standards are not biding on
anybody.
CHAIRMAN DURST: Okay. Thank you, Rhonda.
MS. KANE: You're welcome.
CHAIRMAN DURST: We will take our lunch
break. We are about 15 minutes over, but I think
we have sufficient time to reconvene at 2 o'clock.
Marcia, do you have anything?
MRS. MOORE: No.
(Luncheon recess.)
212
A F T E R N O O N S E S S I O N
CHAIRMAN DURST: We will reconvene for our
afternoon session.
It turns out that we haven't been able to
locate our first speaker, Steve Gendel, but we will
go on then to the public comments portion.
PUBLIC COMMENTS
CHAIRMAN DURST: Since today we have only
five signed-up speakers, we are going to give them
5 minutes instead of the 3 minutes that we used
yesterday. Hopefully, all of our speakers are
here. The first one is Alice Bast from the
National Foundation for Celiac Awareness.
(No verbal response.)
CHAIRMAN DURST: She is not here; okay.
Our second speaker is Elaine Monarch from Celiac
Disease Foundation.
MS. MONARCH: Good afternoon. I was
slightly unprepared to make a statement until I was
called on earlier today, and I am more than pleased
to do so.
My name is Elaine Monarch. I am
the
213
founder and director of the Celiac Disease
Foundation, a national organization for individuals
with celiac disease and dermatitis herpetiformis.
Our offices are in Los Angeles California.
I am pleased to thank several of my
medical advisory board for making their appropriate
presentations today. I want to thank this
Committee for the opportunity to say a few words,
and for the hard work that you are doing on behalf
of all celiacs.
On behalf of the Celiac Foundation, I am
an active participant in creating more awareness of
this disease. As a member of the NIH Planning
Committee for the 2004 Consensus Conference, I was
hands on in the awareness process, and I am still
involved in getting the message out to the medical
community. I am also a member of the DDNC, the
NDDIC, and the American Celiac Disease Alliance.
It sounds like alphabet soup.
Oh, by the way, I am a celiac. I am a
typical celiac. I was not diagnosed as a child. I
was told
that I was a banana baby, that I would
214
outgrow whatever stomach distress my parents said I
had. I was diagnosed when I was 40. I fit right
into everybody's statistics for not being diagnosed
appropriately.
As validated by the 2004 NIH Celiac
Disease Conference, celiac disease affects 1
percent of the total population in the United
States. We have heard today that celiac disease is
the only digestive disease that we know the trigger
for, and we call that trigger "gluten."
It is also the only digestive disease that
doesn't require pharmaceutical intervention. It
can totally be controlled by the strict adherence
to a gluten-free diet.
Adhering to this diet or lifestyle is not
as easy at sounds as you have heard here today and
yesterday. For example, there are limited choices
that I will have later today as I wait an hour and
a half at the airport for my plane. I could
probably find drinks, possibly a banana at
Starbucks, and very few other food choices.
I
feel very fortunate that all I have to
215
eliminate from my life is gluten, yet there is no
standard for how much is too much, and that is what
I am hopeful will be the outcome of this meeting.
The simple casual snacking, something that
most of the population take for granted, is not so
for me. We need to examine everything that we
ingest. There is a wheat protein in everything
from Campbell's soup to licorice.
In today's busy society, fastfoods have
become a way of life for most people, convenience
foods. We talk to people on a daily basis in our
office, they are in a quandary of what to eat.
Fastfoods, sticking something simply in your mouth
at a cocktail party at somebody else's home is not
an option for a celiac.
There are as many stories in the celiac
community as there are diagnosed celiacs and those
yet to be diagnosed, and a broad range of
sensitivity. We are relying on this Committee to
supply our community with reliable, evidence-based
guidelines so that the majority of us can live the
gluten-free
lifestyle to its fullest.
216
This past summer I am very pleased to say
-- or this summer our organization sent 12 celiac
children to camps across the United States where
food wasn't an issue.
We put the word out through the Internet
through our newsletters and our fellow celiac
organizations that we had the opportunity to
provide this camping experience for these children.
We asked them to please supply us with essays.
Twelve essays came in. We were never
going to turn anybody down. Twelve essays came in
from 12 children. Their ages were between 8 and
14. Each essay focused on food.
They were afraid to eat at camp. Their
parents would send for them for their other camping
or overnight experiences. They were afraid that
whoever was in the kitchen was going to serve them
improperly.
When you take a gluten-free waffle out of
a package, you have no idea if it is gluten-free or
not gluten-free. If you took two, square waffles
out of a
package, is one gluten-free and one not?
217
You would have no way of knowing.
Every one of these 12 essays was based
around the fact that food was an issue for these
children. They didn't want to be different. They
didn't want the camp to run out of food. They
didn't want the camp to say, "Oh, Joey, this is
your meal."
We sent these 12 children to camp. We are
now just starting to get replies from the camps.
The smiles on the photographs go from ear to ear.
They had the best experience, because they could
experience the camping experience to its fullest
without the fear factor of food or being sick.
They weren't different; they were just campers.
All celiacs are totally dependent on the
food industry's manufacturing processes, practices,
and the accuracy of labels. Diligent label reading
is what we do. Yes, it does take us a little
longer to go through the food store. Yes, you do
have to read the label every time you buy a
product.
Warnings that foods are made in facilities
218
that also manufacture foods that may be toxic to
us, like the inclusion of wheat on a food label, is
going to be extremely helpful. We see the word
"wheat" and we know that we don't have to read any
further.
Patient compliance will improve when there
is a reliability on a food label. I think
compliance is low now because people aren't sure,
and they might as well cheat, because they are not
too sure if what they're eating is safe or not.
Food is truly our drug of choice. The
decision of this Committee will impact the quality
of life of 1 percent of our total population. That
is close to 2 million people.
Please decide on a standard that is
healthy, and that is doable by the food industry.
Thank you. Please help us to make more informed
decisions so we can take care of ourselves.
Thank you.
CHAIRMAN DURST: Thank you.
Does the Committee have any questions?
Yes?
219
DR. KELLY: Ciaran Kelly. I do have one
question. I think we are all in agreement about
the importance of clear, reliable labeling of
gluten-free foods. As we approach that,
approaching the question of thresholds, what we are
also struggling with are what the preferences of
individuals with celiac disease might be.
We all know that it is going to be
impossible to have zero gluten in food. The
question is, How rigorous a standard of gluten-free
do you think most individuals would like to see?
Do they want to see a highly rigorous or a less
rigorous standard?
MS. MONARCH: Well, we think that based on
the information that was provided here today, 20
parts per million to 100 parts per million, I think
each of us following the gluten-free diet would be
safe. I think that is probably a good industry
standard that the industry could comply with.
I think listening to some of the comments
yesterday from the allergy people I think catering
to the
small fraction of people that have the most
220
severe sensitivities would do the entire population
a disservice.
CHAIRMAN DURST: Any further questions?
(No verbal response.)
CHAIRMAN DURST: Thank you. We will go
back now to our first speaker, Alice Bast, from the
National Foundation for Celiac Awareness.
MS. BAST: Hello, my name is Alice Bast,
and I am the executive director of the National
Foundation for Celiac Awareness. I am co-chair of
the Greater Philadelphia Celiac Sprue Support
Group. I am also a celiac sufferer.
Thank you for the opportunity to speak
with you today about the importance of clear,
unambiguous labeling of food so that the estimated
3 million Americans with celiac disease can
confidently choose food that is safe for us to eat.
We agree with the consensus statement
published after the conference of experts convened
by the National Institutes of Health, which noted
that the strict definition of a gluten-free diet
remains
controversial due to the lack of accurate
221
method to detect gluten in food products and the
lack of scientific evidence for what constitutes a
safe amount of gluten ingestion.
These experts concluded that additional
research is needed to define the minimum, safe
exposure threshold of gluten in a diet relative to
celiac disease.
Celiac disease is underdiagnosed, in part,
because it has many forms. Patients suffering from
classical celiac disease exhibit digestive tract
reactions to gluten in the form of diarrhea,
bloating and constipation, but many more of us have
atypical or silent or latent celiac disease, and
many others are genetically predisposed waiting for
the disease to strike.
Unlike people suffering from food
allergies, addressed elsewhere in the draft report,
many celiac patients do not exhibit acute reactions
to food containing gluten.
Celiac disease must be confirmed through
blood antibody tests followed by an endoscopic
examination
of the villi of the small intestine.
222
The result of continual ingestion of gluten is
chronic suffering in the form of: anemia,
osteoporosis, diabetes, thyroid disease,
infertility, stillbirths, and cancer.
With the level of complexity, it is
understandable that there is not yet the consensus
regarding a threshold level for gluten in the diet
of a celiac sufferer. How can a no-observable or
lowest-observable effect level be set when many
celiac patients exhibit no obvious symptoms?
We are encouraged by the research that is
underway to set a threshold, but we believe it is
premature for the Working Group to recommend an
approach to setting the threshold without more
data.
We encourage the FDA to consider including
its report to Congress on this subject a request
for an appropriation to be made to the National
Institute of Health to fund further research in
this important area with the goal of defining an
appropriate and healthful threshold level.
Gluten is not one but a family of proteins
223
that separately and together can trigger reactions
in celiac patients. These proteins are present in
wheat including durum, spelt, kamut, barley, malt
and rye, and the cross-hybrids and related proteins
are present in oats causing reactions in some
people with celiac disease.
Flour milling and food manufacturing
processes are ripe with opportunities for
cross-contamination, putting celiac patients at
risk of ingesting gluten from apparently safe
sources.
Again, we suggest that funding be made
available to develop and refine analytical methods
that will enable food processors to determine the
level of gluten present. We believe this is the
first critical step not only in the rational food
labeling program, but making food safe to eat for
celiac sufferers.
Cross-contamination represents a risk that
we can manage through proper equipment clean out
and product isolation procedures that are routinely
practiced
by other industries. Providing standard
224
analytical methods to the food processing industry
will enable manufacturers to label their food
products properly, engendering the trust of celiac
patients throughout America.
Thank you for the opportunity to have me
speak to you today.
CHAIRMAN DURST: Thank you.
Are there any questions?
DR. MALEKI: Yes.
CHAIRMAN DURST: Okay. Soheila.
DR. MALEKI: Soheila Maleki. This could
have been asked for either one of the previous
speaker or you, but how does the consumer feel
about the labeling of two, like a double-scale
labeling, "low-gluten" versus "gluten-free"?
MS. BAST: I would have to speak on behalf
of myself. I would say that we have had one
incidence. There is a wafer, a communion wafer,
that has been labeled as low-gluten. There are a
number of people that are very hesitant in taking
that, because it is low-gluten.
I
think that at least they have an idea or
225
an understanding that there would be no gluten
versus low gluten. That might be a good
compromise, because they know that there are
potential risks. If they are feeling that they
don't want to take those risks, then they have a
choice.
CHAIRMAN DURST: Ciaran, did you have a--?
DR. KELLY: (Shaking head.)
CHAIRMAN DURST: All right. Thank you
very much.
MS. BAST: Thank you.
CHAIRMAN DURST: Our third speaker is
Mary Schluckebeer from the Celiac Sprue
Association.
MS. SCHLUCKEBEER: I want to than you all
for having listened to so many different parts and
pieces of this rather complex problem. You see how
many questions there are? That is what we get in
our office every day as we reach people who are
newly diagnosed in our Celiac Sprue Association.
We get about 80 calls a day. We get about
the same
number of E-mails and over 2 million hits
226
to our Web site every month. This is one where
people are looking for answers.
Like the researchers have shown you today,
answers aren't real easy to come by on this. We
really don't know the entire scope of the program.
This is probably because after diagnosis the
doctors are very pleased. They have figured out
what all of these strange little symptoms finally
came to, and it is diagnosed.
They are thrilled and they say, "All you
have to do is just go home and just eliminate all
of those amino acid sequences that you find in
wheat, barley, rye, oats, and their derivatives."
And you say, "I'm not going to die."
Then, you go home and you try to figure out what to
do.
Well, I am one of those people who is a
celiac. I was the daughter of a celiac. While I
was going to the University of Nebraska as a home
economist. "Oh, dad, a little bit won't hurt you."
Every time he got into a little bit he suffered a
lot.
227
At the time he was diagnosed, around 1959,
the smaller tube was introduced. The doctor said,
"I just read about this, and I think maybe we
should check you out." It was almost a fluke that
you got diagnosed around 1959, 1960.
At that time food was not labeled. Dairy
products had to have their recipe on file at the
state. You didn't know as a consumer exactly what
was in that.
Well, at that time ice milk was almost
always thickened with wheat flour, to help get that
feel in your mouth. Since you take the cream out,
you've got to put something in.
Oh, I never wanted to have his disease.
Now, he ate bread that was this (indicating) high.
I mean, that is as high as it ever got. At that
time wheat starch was allowed in the diet and was
in the packages that were said appropriate for
people with celiac disease.
Elaine Hartsook of the Gluten Intolerance
Group of North America started working with one of
the
companies and said, "You know, this is still
228
making people sick."
When they eliminated the wheat starch from
these packages, my father's final symptoms of some
of the rash disappeared. He assumed this was
something he could eat with confidence. He
figured, "It's got to be something else I'm getting
into." He just couldn't figure it out. It was
that little, tiny bit of wheat starch.
So I'm always a little hesitant about
saying, "Oh, let's put this in" or "Let's take this
out," because, again, symptoms are not specific.
You can't say "I chewed this piece of gum, and I
got symptoms."
You go around and you're trying to figure
out, "What all did I get into in my environment in
this last two or three days that may have created a
symptom?"
When a person is diagnosed and the doctor
says "Go home and be well and just eat," because
you don't die -- researchers aren't real interested
in us when there are other problems that people do
die and we
haven't solved and haven't gotten cures
229
for.
A celiac is left to have a team usually of
other people who have celiac disease, or they come
to support groups like ours where we have almost
10,000 members right now.
We are the largest celiac support
member-based group in the Western Hemisphere, and
we are very pleased. Canada has around 6,000
members in their association.
What we find is, though, that people get
very comfortable after they stick around with the
supports for a while and then they go off on their
own, because "Oh, I'm very comfortable in my diet."
I have learned how to live the lifestyle, and I
really don't need the help of everyone else.
We do a survey once a year of our
membership. One of the things that we did this
time was ask people to self rate where they
consider their sensitivity. Another question was,
How risk averse are you? Because it is a very
risk-averse population.
No matter what the sensitivity level a
230
person classified some of the cells as -- over 90
percent of the people put themselves at -- they
will take no risk, no known risk, in their food
choices.
That is a pretty high level of at least intent that
is expressed, no matter what they say their
sensitivity level is.
Again, that is why something like money
for research to find this threshold -- you notice
this threshold is the problem in each of these
countries. There is not any real good basis for us
to come up with a threshold.
That is why the physician said, "Go home
and don't eat any."
When you are talking to grandma she says,
"Just have a little," that's kind of where zero
comes out.
It is that place-taker or a way of
communicating, "I can't have some. I have to have
none." I don't know, if I could have some, I have
no idea how much "some" is.
It may be different when you are under
231
stress like in a hospital situation, at a childcare
center. What kind of risk do you want to take at
the training table, athletic training table, when
somebody else is picking out the food for those at
the table?
Again, without a threshold, it really
makes it very difficult to make some of these
choices because it is all subjective. Right now,
it would be awfully nice to be able to say it is
not subjective. We have some concrete information.
This is what will work as a workable definition for
the celiac patient and for the manufacturer, and it
is easy to communicate all of that information to
each other.
Thank you.
CHAIRMAN DURST: Thank you.
Any questions, Committee?
(No verbal response.)
CHAIRMAN DURST: I think there are not.
Thank you.
(Sotto voce discussion.)
CHAIRMAN DURST: Our next
speaker, also
232
from the Celiac Sprue Association, is
Tom P. Sullivan.
MR. SULLIVAN: Good afternoon and thank
you. My name is Tom Sullivan. I happen to be the
president this year for the Celiac Sprue
Association. I myself am not a celiac. However, I
have very, very good association, and that may be
one of the reasons the patients decided that I
should be their president this year.
I have a wife who is a celiac; I have a
son who is a celiac; and I have a great niece who
is a celiac. The horror stories that lead to the
11 years' average time for diagnosis I can
perfectly well relate to and admit to. Because I
sat in a gastroenterologist's office and shook my
head most emphatically no four times to force that
man to take a biopsy on my wife.
The man never spoke to me again, never
looked in my direction after coming out of the
biopsy room. It was flat out knowledgeable on his
face what she had. It took that kind of forcing
effort.
233
Education is still necessary. It is a
major factor. It is one of the reasons CSA exists.
When a patient is diagnosed, they are informed
basically "Go and sin no more, my child. Change
from a wheat-based lifestyle to a rice-based
lifestyle. Goodbye" (waving).
What the heck does that mean? I haven't a
clue. It turns out the only ones who have a clue,
who know what to buy, where to buy it, who sells
what, how to use it, what do I do in my kitchen,
how do I travel, who do I see for this or that
problem, what does this symptom mean are other
celiac patients.
That is why CSA came to be, that is why
its mission is to be celiacs helping celiacs, and
that is why its function is to be the voice of the
patient. The patients are very, very good. We go
out with surveys each year, and they tell us what
do we need, what don't we need.
With reference to this afternoon's
proceedings or this week's proceedings rather with
this draft,
the draft is a very good working draft.
234
It agrees with the patients, and that is, the
risk-assessment method is the method of desire.
In fact, the patients themselves have
moved to a risk-assessment process. It has been
done intuitively, it has been done with
cross-communication among all of them, and it has
produced the capabilities that CSA currently has to
speak for the patient.
What the patient does is very simple.
They say, "I have to eliminate wheat, barley, rye
and oats." Let's not talk gluten. Let's get away
from the. Source ingredients of wheat, barley, rye
and oats; okay? So my target is zero. Now we all
know, scientifically, zero is unmeasurable.
That isn't the situation. I have a
problem. I want none of it. How do I do it? Now
we get practical. Now we start asking
manufacturers, "What levels are you at? What do
you do? Can we trust you? Are you consistent?"
We put together lists of products. This
year's product listing is approximately 70 pages
listing
products that the manufacturers will stand
235
behind, because they have told us that they do not
use wheat, barley, rye or oats in their product, in
their packaging, or in their processing. It is a
great source to help people get started.
In fact, one of the fun things I have when
I get an E-mail or a telephone call -- and it comes
from all over the world by the way, both into the
office and personally -- my immediate reply is
"Relax, take a deep breath, and let it out very
slowly. There is life after diagnosis." Then, we
teach them how to do it.
From a practical standpoint, the patients
evaluate the products that are out there. They
evaluate them against their target of zero, and
they handle them as a result of their reactions to
the ingestion of that product.
If they have a problem, they go look in
the book and find another similar product, a
different brand name, or they go to another label
of the same product in the store.
However, they have a method and a
technique
that they have instinctively gone to, to
236
say, "How do I protect me? I have a health
problem. How do I protect me."
A very interesting result of this is that
when the patient starts on the gluten-free diet
they very quickly become better. This is why you
end up with a very wide range of variability in
your responses and in the reactions because most of
them, by and large, don't ever want to go back
there again. They didn't like it; they don't like
it; and they don't want it repeated.
One of the things that has helped is the
labeling and the information available out of the
manufacturers, the fact that they will respond, the
fact that the patient community is getting much,
much better on their knowledge of the questions to
ask and who to go to.
For example, not too long ago it was very
common to just pick up the phone and call the
manufacturer and say, "Do you have gluten in your
product?"
"Yes."
Okay, forget that product. Now,
the
237
question is because rice gluten and corn gluten are
no problems, most of the patients will now ask,
"What is the source of that ingredient?"
"Oh, it's corn."
"Thank you." Problem solved. They have
set the risk level at zero. They have evaluated
the products that are out there, and they have
communicated that among themselves. That is
celiacs helping celiacs. That is what keeps them
safe. That is the way they have done it.
I am very, very happy to see that that is
exactly the way you have chosen as the recommended
technique for doing it. I think in the long run it
is the only one that is going to do it, what is the
minimum level. Beyond that, then, I've got
problems I can go looking at. Right now, we have
nothing. I think it is a very good start. Thank
you kindly.
CHAIRMAN DURST: Thank you.
Do we have any questions?
CHAIRMAN DURST: Do we have any questions?
Soheila.
238
DR. MALEKI: Sure. I guess I'll pose the
same question as far as previously, How do you feel
about two-scale labeling such as low gluten versus
gluten free?
Sorry, Soheila Maleki.
MR. SULLIVAN: That is a question we have
not yet asked our members, so I can't answer for
the membership. That is a question we will ask on
this year's survey, however, and we will have the
answer for you probably sometime just after the
first of the year.
Personally and based upon the input I've
had from the other celiacs over the years, if a
definition is precise and they can depend upon it,
then I don't think they will have any problems.
Quite frankly, a celiac patient is one of
the smartest people you're ever going to meet. It
is their health, their body, and they and they
alone are completely responsible for it.
By the way, at the end of September of
this year and the first of October in Tyson's
Corner, CSA
is having our National Annual Education
239
Conference. You are all invited to come and find
out what the patients think and why they think it.
They will ask you some of the toughest
questions. It is a shame I didn't have Dr. Murray
say that this morning, because he has admitted they
ask nasty questions.
(General laughter.)
MR. SULLIVAN: They want to know because
it is my (pointing) body, and it is my
responsibility solely and completely. You tell me,
and I'll make the decision for me. That is where
it is coming from. It is more information. More
information is always to our benefit as a patient.
CHAIRMAN DURST: Ciaran, did you have a
question?
DR. KELLY: That addressed it.
CHAIRMAN DURST: Okay.
Anything else from anyone?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
MR. SULLIVAN: Thank you.
CHAIRMAN DURST: Our final public
comment
240
speaker is Steve Taylor from the University of
Nebraska.
MR. TAYLOR: Good afternoon. My name is
Steve Taylor, and I am a professor and co-director
of the Food Allergy Research and Resource Program
at the University of Nebraska.
In addition to what you all heard from me
yesterday, our group provides analytical services
to the food industry including gluten testing
services, so I thought perhaps I could get up here
and say a bit about testing methods.
I should also say that this is a
fee-for-service activity that we provide to the
industry, but we also provide services on a lesser
cost basis to the Celiac Sprue Association and to
the Food Allergy and Anaphylaxis Network.
I want to make several points. One is
about testing methods and frequency. Our
laboratory uses the R5 monocle antibody test that
you have heard about this morning. That test is
commercially available from a company called
R-Biopharm
in Germany as an ELISA kit. There are
241
other equivalent test methods that are on the
market as well.
This test detects prolamins, the prolamins
gliadin from wheat, secalin from rye, and hordein
from barley. It does not detect oats but will
detect the presence of wheat, rye and barley
proteins in oats, which is perhaps somewhat of a
significant concern to celiac sufferers. Our
advice is that they continue to avoid oats in
North America because of the chance that oats could
be contaminated with wheat, rye or barley.
The test detects the prolamin proteins
more reliably than it detects the glutelin
proteins, the higher-molecular weight ones, but we
can very easily detect the gluten levels in wheat
starch and other ingredients that you have
discussed today.
I think this test is very reliable for the
food industry to use to determine whether the
products are gluten free. I can say that the food
industry in North America has been using this and
similar
tests for a number of years now to help
242
assure that products that are labeled gluten-free
indeed fit that definition.
I can say that it is my experience that
the industry is doing a much finer job in that
regard than perhaps they were 6 or 7 or 10 years
ago. That is partly because the Government of
Canada established this regulatory framework that
you have heard about this morning.
In the countries where the legislation has
said "gluten-free" is "zero," it can't get to zero,
so operationally you still have to have some
definition of it. The Canadian Food Inspection
Agency uses less than 20 parts per million as their
operational definition of gluten-free.
When they established this regulation in
1996, they began to be very vigilant in the
analysis of U.S.-made, gluten-free products
crossing the border into Canada to be sure that
those products met the definition. Well, most of
them did not.
They met the previous definition that
you've
heard about this morning, the Codex
243
Alimentarius Commission's definition of less than
200 parts per million, but did not meet the
definition of less than 20.
I can tell you that since 1996 till today
almost all of those companies have succeeded in
protecting their Canadian market by now adhering to
the less than 20-part-per-million standard.
If you establish a standard of zero, many
of these companies will not be able to produce
gluten-free products because zero is unattainable.
We have heard that from some of your speakers this
morning.
I also want to say a few words about
grain-add mixtures, because the adventitious
presence of one grain in another grain is allowed
by something called "USDA grain standards." Wheat
can be in oats, soybeans can be in corn, soybeans
can be in wheat. That is allowed by USDA grain
standards, which are recognized around the world.
Raw agriculture commodities are another
exemption that is in the FALCPA legislation. I
think this
establishes another potential
244
consideration for the panel in terms of a
statutorily derived threshold.
Once you convert these raw agricultural
commodities that are exempt into milled wheat
flour, milled oat flour and milled cornmeal, then
they are not exempt anymore.
Yes, if you establish a threshold at zero,
then this contamination occurs on the farm, and
there is no way to completely prevent it. However,
it is quite possible to have safe and effective
gluten-free products meeting the strictest
definitions in the world, those of Italy and
Canada, with less than 20 parts per million gluten.
I was convinced by the data I saw this morning that
seems to protect the vast majority of celiac
suffers.
Thank you. Dick Durst. I have question
on what the Canadians use as far as their method of
detection? What is the limit of quantitation on
their immunoassay?
MR. TAYLOR: I think they use the same
test that
our laboratory uses, which is the
245
R-Biopharm Test. R-Biopharm sells several
different tests. I wish Dr. Hefle were still here.
I think the limit of sensitivity of the tests that
we are currently using is in the neighborhood of 5
parts per million slightly lower than that.
CHAIRMAN DURST: Okay. The limit of
quantitation is right near the limit that is set,
this 20 parts per million?
MR. TAYLOR: Well, it is severalfold below
that. I mean, it is 5 parts per million and the
limit is 20.
CHAIRMAN DURST: Yes. Well, the limit of
quantitation, I would think, is what you would need
to use in order to really verify the amount of
gluten or whatever or prolamin that is in the
product. I'm not sure the limit of detection is
the kind of best characterization.
MR. TAYLOR: Yes. The limit of
quantitation with that test is in the neighborhood
of five parts per million. I don't know what the
lowest limit of sensitivity is. We know that we
can
reliably test 5 parts per million with that
246
test. I know Dr. Hefle knows the answer to that
question, I just don't.
CHAIRMAN DURST: Marc had his hand up?
DR. SILVERSTEIN: Marc Silverstein. Do
manufacturers continually test during production,
or is it just in developing a new product for the
market?
MR. TAYLOR: It has been our experience
that many of the producers of products that are
labeled gluten-free test rather frequently. There
are several very noteworthy companies that make
gluten-free products that are rather popular among
celiac sufferers, and these companies test very
frequently.
One that I can cite as an example would be
Arrowhead Mills, which was one of our more frequent
clients for a number of years. They were doing so
many analysis that they built their own laboratory
at the plant in Texas, and they do the ELISA
testing on a regular basis in their own facility.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Yes. I just want to say that
247
you brought up a really good point about the
farmers that grow in and have rotation crops. That
essentially brings up a good point. I don't think
you could ever reach zero, even just because of
that, because of the same trucks they use, the same
dirt it is grown in, and so forth.
MR. TAYLOR: Yes. I mean, it is the same
farms, the same farmers, the same harvesting
equipment, the same on-farm transportation, the
same elevators, the same off-farm transportation.
The system, the commercial system, for handling
grains in the United States and around the world
doesn't offer you the opportunity to get to zero.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: Yes. Is it possible,
though, to drop somewhere between twenty versus
zero? Is that realistic at all? Or, do you really
think 20 is as far as you could go? Could you go
to 10?
MR. TAYLOR: Well, you can do anything you
want with the analytical testing capabilities. I
think I
would defer to the clinical experts, that
248
we have heard from already here, about what the
threshold level for celiac sufferers ought to be
and the way that ought to be established.
We don't do any clinical research on
celiac disease. We avidly read their papers, but
we are just analysts with respect to celiac
disease, and we do not pretend to be clinical
experts on this difficult subject.
I mean, in terms of being able to make
products that would pass that standard, 10 versus
20, would that make a big difference in terms of
making products?
MR. TAYLOR: Well, to me does 10 versus 20
make a difference? It depends upon whether it
makes a difference to the celiac sufferers in terms
of their health status.
The industry struggled when we went from
200 to 20. Many of them already could probably
come close to meeting 10, if they don't already do
it. Some of them might struggle to get there.
Consistently? Consistency is another key point.
CHAIRMAN DURST: Jeff.
249
DR. BARACH: Yes. Jeff Barach. Could you
speak to the validation of the test that you
described, the monoclonal antibody test? Do you
know if it is validated?
MR. TAYLOR: Well, I don't know if it has
been "validated" by the procedures that FDA prefers
to use when it uses that term, but it has been
validated by the company that made the kit. The
Prolamin Working Group has done some
interlaboratory testing of that kit as well. I am
not so sure that there have been comparisons
between that test and tests by competing companies
that are largely similar, so there may be some
analytical work to do. I am not so familiar with
the Prolamin Working Group. Dr. Hefle follows that
group, but I don't.
CHAIRMAN DURST: Margaret.
DR. BRILEY: Margaret Briley. Could you
give us any kind of estimate of the cost factor for
industry in terms of how often they use this test
and what it would add to the cost of the product?
Once you start testing it, I would think
250
you would test everything that came through,
whether it was for celiac or not. Am I wrong? I
mean, if you're going to run a test, wouldn't you
just run it? You're putting it out as an industry.
You wouldn't do a separate run just for celiacs?
MR. TAYLOR: Well, that is a very
complicated question as to how frequently you test,
how you devise a credible sample plan, and whether
the results of your test are reliable in terms of
all of the product manufacturers. Obviously, you
can't do a test on ever package of product, because
then you wouldn't have anything left to sell.
(General laughter.)
DR. BRILEY: No.
MR. TAYLOR: The tests are not very
expensive in some terms. We charge $50 to $75 for
the test per sample. I mean, that is some cost and
companies are going to question whether they want
to do 100 tests, 1,000 tests or 10,000 tests,
because it I going to be a cost factor.
DR. BRILEY: Well, I guess I was thinking
that you
would probably test a run. You wouldn't
251
test every package that came out.
MR. TAYLOR: Yes. You've got to design
your testing system very strategically depending
upon where you think your sources of contamination
are.
Companies typically test the source
materials that are coming into manufacturing. They
test the first product manufactured after
changeover, if they have shared equipment.
However, you've got to pay attention to
things like whether you think there are hangup
points in your manufacturing equipment. That
varies from facility to facility and line to line.
DR. BRILEY: From company to company.
MR. TAYLOR: I wouldn't give the same
advice to every company.
DR. BRILEY: Okay. Thank you.
CHAIRMAN DURST: Ciaran.
DR. KELLY: Dr. Taylor, thank you. Ciaran
here. I'm going to keep you on the podium for
another moment or two.
We heard about the line spots in the
252
currently available test, the inability using the
widely used test to detect gluten in oats. Are
there to your knowledge intrinsic, technical
challenges there, or is it simply that nobody has
bothered to try?
MR. TAYLOR: I don't think anyone has
tried to develop a test for oats. I am convinced
you could develop an ELISA test for any
protein-containing food known to man. Yes, you
could develop a specific oat test.
There is this debate about whether oats
are safe or unsafe, the companies that were
developing these tests for gluten-free products
targeted these peptide sequences in wheat, rye and
barley. You could argue that is what they should
have done. I would advise them to do the same
thing.
CHAIRMAN DURST: Anything further?
(No verbal response.)
CHAIRMAN DURST: Thank you.
Okay. Now we will jump back in time to
hearing
Steve Gendel, who is now with us, to speak
253
on the overview of approaches to establishing
thresholds for gluten.
OVERVIEW OF APPROACHES TO ESTABLISHING
THRESHOLDS: GLUTEN
MR. GENDEL: I guess I can say that one
way of keeping people from going into an
after-lunch slump is to mess with the agenda. You
have to pay attention to know where we are. I'll
take credit for that.
(General laughter.)
(Slide.)
MR. GENDEL: What I'm going to do today is
going to be an abbreviated form of my shortened
talk from yesterday, again, just to serve as a
refresher for what is in the "Draft Report"; to set
the stage for your discussion; and, again, to
remind you that the purpose of the report is to
identify approaches that can be used to establish
thresholds, not to decide on which approach to use
and not to discuss specific threshold values. We
are interested in potential approaches, the
advantages,
disadvantages and data needs of each.
254
(Slide.)
DR. GENDEL: The organization of the
report hasn't changed since yesterday. There is a
section where we review celiac disease and one
which we talk about the approaches we have
identified for setting thresholds for celiac or for
gluten.
(Slide.)
DR. GENDEL: In the section on celiac
disease, we reviewed the mechanism of pathogenesis,
information on prevalence, foods of concern, we
looked at the clinical challenge studies that were
available, and looked at issues related to
measuring gluten in food -- all of the things that
we have heard about this morning.
(Slide.)
DR. GENDEL: As with the allergens, we
identified four potential approaches, and really in
this case three: the analytical methods-based
approach, the safety assessment-based approach, and
a
quantitative risk-assessment-based approach.
255
I mentioned the statutorily derived one
here, for the sake of consistency with what we
talked about yesterday, where we felt that there
was no language in FALCPA comparable to that for
allergens that could be applied in the case of
gluten.
(Slides.)
DR. GENDEL: I am not going to go through
these approaches again. I think you are familiar
with them. The analytical-methods-based approach,
which is based on the sensitivity and detection
methods available; the safety-assessment-based
approach relies on LOAELS and NOAELS from clinical
data and appropriate uncertainty factors based on
the gaps in those data; and the
risk-assessment-based approach; and the
quantitative approach, which takes all of the dose
response information available into account.
(Slide.)
DR. GENDEL: The findings of the Working
Group, there were again five, the first one again
to
reiterate the fact that whatever approach -- if
256
a decision to set thresholds is made, whatever
approach is chosen at this time, that these
decisions should be reevaluated frequently as new
data became available.
We heard a lot of discussion this morning
about clinical studies here also that are in
progress, and new data will become available. We
recognize the fact that any decisions made in the
short term should be reevaluated periodically.
The Working Group found that the
analytical methods-based approach could be used for
gluten also. However, as we talked about
yesterday, if it is used, we feel that it should be
replaced by a risk- or public-health-based approach
as soon as that is feasible.
The safety-assessment-based approach, the
Working Group found that approach could be viable
also based on data from the literature and
appropriate safety factors, taking into account the
nature of the clinical studies available to use.
The risk-assessment-based approach we felt
was not
feasible at this time due to the lack of
257
data to quantitate risk in a dose-response type
manner.
Finally, as I mentioned, the statutorily
derived approach is not viable due to the lack of
appropriate statutory language.
That is really all I have to say about the
report. Are there are any questions about the
report itself?
QUESTION AND ANSWER SESSION
CHAIRMAN DURST: Thank you, Steve.
Do we have any questions?
Ciaran.
DR. KELLY: Yes -- Ciaran Kelly -- just a
technical question. When we are talking about the
safety-assessment approach, does that include
population observations in addition to prospective
studies? We heard this morning about a prospective
study, retrospective studies, and clinical
experience with a population that have been using
particular standards for many years. Is that
information incorporated within a safety-assessment
approach?
258
DR. GENDEL: I would say that the
safety-assessment approach would be one where any
data that can be used to establish a LOAEL or a
NOAEL is used. Then, depending upon where those
numbers come from with that number, then you would
apply appropriate uncertainty factors, and the
nature of the data which goes into establishing
those numbers would then be taken into account as
uncertainty factors would apply.
DR. KELLY: Would it be true to say, then,
that if similar numbers were arrived at from
different sources in the data, if independent
studies using different methodologies all arrived
at a similar number, that would reduce the
uncertainty factor?
DR. GENDEL: I would say that is probably
fair. Anytime you can replicate data, the degree
of uncertainty associated with it is less.
CHAIRMAN DURST: Any other questions for
Steve.
(No verbal response.)
CHAIRMAN DURST: All right. Thanks,
259
Steve.
DR. GENDEL: You're welcome.
CHAIRMAN DURST: We are now scheduled for
a break. We are about 15 minutes ahead of
schedule, so we will take our 15-minute break and
reconvene at 3:15.
Thank you.
(Thereupon, from 2:55 p.m. to 3:15 p.m.,
there was a pause in the proceedings.)
COMMITTEE DISCUSSION
CHAIRMAN DURST: Would everyone take their
seats please, and we can continue the afternoon
session.
All right. At this point I guess Steve
just before gave a nice review of the charge and
the questions that we are supposed to address.
What I would propose is that we initially begin
with just open discussions of the general points on
celiac disease; then address some of the specific
questions; and then, finally, if there is time at
the end of the day, also open discussion again on
the
allergens and perhaps any cross-reference to
260
the celiac disease. There are certainly similar
questions in both of those cases.
I would like to mention, just to expedite
tomorrow's discussions, I have asked three members,
Marc and Suzanne to deal with the allergens and
Ciaran to deal with the gluten, try to come up with
a summary or a consensus of what they felt our
discussions have been leading to in terms of how we
want to address these approaches for setting the
thresholds.
I think that would help us in the morning
to focus in on those particular aspects and, again,
have the discussion bring in any new points or
additional points that members may want to add to
those summaries. I think that is all I want to say
on this point. Let's open the discussion on the
gluten and celiac disease.
Does anyone want to start with any general
comments on that?
Soheila.
DR. MALEKI: Soheila Maleki. I actually
have
questions. Is that appropriate at the
time,
261
at this time, to ask the panel questions?
CHAIRMAN DURST: Yes.
DR. MALEKI: Well, I have some questions
for Dr. Fasano. Well, I've got multiple questions,
but I will try to go through them where you can
answer them. What is it the specificity of the
activated CD3 T-cells? Do you know if they are
gamma/delta, alpha/beta, CD8, CD4?
What is particularly their specificity as
far as are they transglutaminase-specific or the
PEQ-specific? Anyway, do you know of any studies
that have looked at gluten-specific T-cells that
actually are reacting to oats or one of the other
products? How about the antibody
cross-reactivities of gluten versus barley, wheat,
and then oats? I think that's it.
(General laughter.)
DR. FASANO: Let me tell you the facts the
way we know right now. The activation of the
intraepithelial lymphocytes, particularly through
CD3 and gamma/delta, are considered highly specific
for celiac
disease.
262
As a matter of fact, in the early Marsh
classification, Marsh I, we don't have any damage
whatsoever but you have all the infiltration,
intraepithelial infiltration, into the lymphocytes.
If you want to know that is malignancy of
the disease, you do the specific CD3 staining. If
it is positive, then you can say, "Okay, this is
Stage 1 of a Marsh grade for celiac disease."
Yes, as far as we know, there are
gluten-specific T-cells epitopes. You can isolate
T-cells for gluten or a fraction of gluten in terms
of a reaction activation of T-cell and K-cells and
so on and so forth. Absolutely, that is the way to
do that.
Of course, the specificity of
transglutaminase is an issue that is out there.
The only thing that I can tell you, at least based
on serological data, i.e., how specific is tissue
transglutaminase or inflammation-related celiac
disease, I would say that it is fairly specific,
with a few exceptions.
If it is true the current theory that the
263
reaction to transglutaminase is due to an initial
insult of the cells, it leaks transglutaminase, and
therefore becomes not naive anymore to the immune
system, leading to the immune response.
If this starts at the intestine level,
there is some specificity with celiac disease as
compared, for example, to Crohn's disease in which
we don't see that. However, we see patients with
Type I diabetes, for example, and not co-morbidity
with celiac disease in which the insult translates
with increased antitissue transglutaminase
antibodies.
In terms of cross activity among grains, I
will not give rights to the arguments. I believe
that Don will be much better than I am to give you
that kind of response. I can give you an
unprofessional, amateur response. The general
wisdom is, yes, there is cross-reaction.
DR. MALEKI: At T-cell level also?
DR. FASANO: Say that again?
DR. MALEKI: At the T-cell level? Of
course,
yes.
264
DR. FASANO: Yes.
DR. KASARDA: At the T-cell level? Is
that what you said?
DR. MALEKI: Both actually, antibody and
T-cell.
DR. KASARDA: That is difficult to answer.
The problem is that almost all of the studies focus
on wheat, and very little has been done with rye
and barley.
As far as immunological epitopes are
concerned and cross-reactivity with IgG and IgE and
probably IgA, yes, there is a lot of
cross-reactivity because there is sufficient
homologies. However, when it comes to the T-cell
and the T-cell receptors, that is a whole other
ball game. I can't answer that. Maybe Pekka
Collin can.
DR. MALEKI: Thank you.
DR. COLLIN: I would say about gamma/delta
T-cells that they are thought to be very specific
for celiac disease, but we are a little bit
disappointed. I think
specificity and sensitivity
265
for increased density is about 90 percent. The
strongest evidence against that they would be
specific is that in many cases those with elevated
gamma/delta T-cells they do not share their DQ2 or
DQ8, so they probably are not celiacs.
DR. FASANO: That is gamma/delta. The
CD3, that is the one that I was talking about, that
seems to be much more specific.
DR. MALEKI: Thank you.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: I have a totally different
question.
CHAIRMAN DURST: Okay.
DR. BRITTAIN: Yes, it is about the
Italian study again. As a statistician, it is my
job to be skeptical. I just wanted to ask, and I
know that you have demonstrated there was a
difference between the placebo group and the
50-milligram group. You didn't see a statistically
significant difference between the zero and ten.
In fact, the means were very, very similar.
Normally, when you want to show
that two
266
groups are equivalent or similar, you would
construct a confidence interval to define that
difference and estimate that difference. Is that
something that has been done?
DR. FASANO: Yes. The analysis for the
villus/crypt ratio was done on a confidence
interval level and there was no overlapping.
However, I have to be super-duper skeptical and say
that a morphometric measurement is not as accurate
as any other biological readout that you can
consider.
In other words, it is operated dependently
of course. That is how you make the measurement.
It is not a machine, so there is some degree of
possible error in there that you have to consider.
Nevertheless, if you did this in the blind
fashion, as we did, if you have two operators and
there is a 100 percent concordance, as happened to
us, the level of confidence that that was right
increases.
A more objective measurement, i.e., the
intraepithelial lymphocytes for which you say, "I
267
want to know how many there are per hundred
entrocytes, per hundred T-cells."
Why are we saying that 50 milligrams may
create a problem is because, again, we want to be
extremely conservative -- if we say, "Well,
actually this data is suggested but not conclusive
for damage" -- the answer is yes. We don't want
any question marks. It could be suggested, but
that is not the way that we want to go.
Conversely, with 10 milligrams, no matter
how you go, if you look at the intraepithelial
lymphocytes, if you look at the gamma/delta, if you
look at the alpha/beta that we did -- I didn't have
the time to show all the data -- in other words, if
you look at all of the parameters that you can
conceptualize to look at for possible histological,
serological, clinical evidence of a reaction, we
consistently in all of these patients found zero
reaction.
Consequently, our level of confidence is
associated also to the many years of implementation
of that
threshold; there have been hundreds.
That
268
makes us to say with some level of confidence that
we feel comfortable with 10 milligrams while with
50 we do not.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Just one quick follow up on
that. That is part of the reason I was asking this
question is you would have to have biopsies to get
T-cells. Is that like some type of valid
immunological method to try to test for dosage, and
so forth, although it is in vitro? Could that be
some method, too, you would look at exposure, and
so forth?
DR. FASANO: I hate to be the one to
answer all the questions here. Depending on the
scientist, you will find different answers. There
are people that strongly believe that if you take
blood and you isolate its lymphocytes and you do
this exercise in vitro, it reflects exactly what is
happening intestinally also.
For example, the group from Australia is
trying to develop a vaccine for celiac disease.
The types
of screening that they are using to
269
establish the many peptides can be toxic or
immunogenic, which one they have to look at, and
you target it for a vaccine.
They use an immunoblock reaction in which
they take blood from patients with celiac disease
to see with these peptides which one will react and
which one will not by the reaction of
interferon-gamma.
The skeptics of the group will say, "Well,
not necessarily does this reflect what happens at
the mucosal level." Technically, that is not
necessarily the same lymphocytes.
You can make an argument that you can test
negative in vitro, because you don't have the right
cells to migrate from the gut into the systemic
circulation. I don't think that there is a final
argument either way to sustain that you can do this
in vitro versus the biopsy.
CHAIRMAN DURST: Ciaran.
DR. KELLY: Ciaran Kelly. I've got a
question for Drs. Collin and Fasano. It relates to
a
safety-assessment-based approach again relating
270
to data, historical data.
Both of you mentioned, but I wonder if you
can expand a little, upon studies that have looked
at the outcomes of individuals on gluten-free diets
set at certain levels as regards morbidity and
mortality outcomes. You both mentioned it. I
wonder if you could tell us a little more maybe
about the methodologies and results of these
studies?
MRS. MOORE: Excuse me, I'm sorry. When
you reply, say your name.
DR. COLLIN: Pekka Collin. If you look at
the mortality figures and risk of malignancy, I
think the most quoted paper is from Dr. Holmes
where he showed that if the patient stays on a
gluten-free diet for five or six years the risk
virtually disappears.
At that time, I think it was from 1984, I
think that diet was not so strict as today. I
suppose that at that time also people in the
United Kingdom they used the wheat-starch products.
The
difference was between those who are on
271
gluten-free diet and between those who are on a
normal diet, which is very seldom today that people
are on a totally normal diet.
Then, the group from Italy, Corrao, the
excess mortality, it was all due to those patients
who had dietary lapses or who did not maintain the
gluten-free diet.
In our own studies, the first had 300
patients. We did not find any extra malignancy and
mortality in patients who were not on a gluten-free
diet. Now, later we have our odds ratio for
lymphoma, which is about four. It is almost the
same as that Peter Green had in New York and what
was in Corrao's paper and in the latest papers also
from Sweden.
However, each case except one has been not
on a strict gluten-free diet, and the majority have
occurred immediately, as I told you, after the
diagnosis of celiac disease. Probably, they had
celiac disease and lymphoma simultaneously. Only
one patient with celiac disease, presumably, on a
gluten-free diet developed lymphoma.
272
I think that all of the evidence shows
that if we try to avoid lymphoma, we should detect
the cases early enough, then put them on a
gluten-free diet, take care that they are on a
gluten-free diet, there is some circumstantial
evidence that those patients who remain undiagnosed
and who are asymptomatic the risk of lymphoma there
in them is very low.
In the United States, I don't know, maybe
you have 200 million people or even more, and you
should have 2 million with celiac disease, the
majority is undiagnosed.
Still, I think that small-bowel lymphoma,
especially small intestinal cancer, they are very
rare even here. That would be a serious risk
factor, I think we should see a lot of lymphomas
here.
Our mortality risk, our odds ratio is now
1.2, so it is very little excess mortality, and it
depends on the appearance of lymphoma at the same
time as the celiac in the patient.
DR. FASANO: I believe that what
you are
273
looking for is if there are any systemic studies
that would compare 20 versus 200 versus 400, and of
course there is none. However, there are studies
that Pekka already outlined between people
complying and people admitting to being less than
compliance. The lymphoma probably is the least
proper variable outcome to look at, because it is
very rare to start with.
I am not a biostatistician, but I am
assuming that if you are dealing with a condition
that is one in a million, that will go to 1 in
890,000, it is hard to make the difference.
However, if you see co-morbidities,
autoimmune diseases like diabetes or Hashimoto, in
which you reach as high as 17 or 18 percent, then
you start to really look at the differences in
which you have an outcome such as osteoporosis, the
same story, short stature, and so on and so forth.
DR. KELLY: Ciaran Kelly. Yes, I know
there are no systematic studies. I was more
wanting you to elaborate on the experience, the
clinical
experience, for many years at different
274
levels of definition of a gluten-free diet.
It seems as though there is a lot of
experience with 200 parts per million, 100 parts
per million, and 20 parts per million. I am trying
to get a sense for whether there have been any
studies to determine differences in outcomes with
those different levels.
DR. FASANO: Alessio Fasano here. Again,
in Italy the switch from the 200 parts per million
to 20 parts per million occurred, again, six or
seven years ago. There are no published studies to
show if this which translated into decreased
co-morbidity of that outcome.
The general wisdom for what is in there,
in terms of the co-morbidity reports within the
Celiac Society in Italy, seems to suggest that
indeed there has been a decrease of some of the
co-morbidities -- particularly, anemia,
osteoporosis, short stature, and miscarriages, the
fourth -- following the switch. However, these are
very anecdotical, and I don't think there is such a
strong
scientific outcome to make that statement as
275
a scientifically acceptable one.
DR. COLLIN: We have experience in Finland
that the important deviation is not between
200 milligrams and 50 milligrams. I think I do not
have a very strong scientific evidence but only
experience in what you were asking. I think that
the risk of lymphoma in those patients is very,
very low.
The problem is that we do not know what
our wheat starch was 15 years ago when everyone
also was using them, but it is logical to assume
that it may have contained even more wheat or
gluten as today. Even at that time, we did not
have any increased risk of malignancies. It has
been similar all the time when we have had this
follow up since 1970 or 1975.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc Silverstein. One
of the questions that comes up in study conditions
such as allergic diseases and celiac disease is the
spectrum of disease and selection or selection bias
in patients
who enter studies and about whom we
276
make inferences to the larger population.
As I'm understanding the available data,
it seems that clearly there would be a large number
of individuals who would have serologic evidence
and genetic susceptibility.
It seems there would be a large number of
individuals who probably have the disease, who have
manifestations that would be detectible were they
evaluated, but because they have very mild symptoms
don't come to attention.
What I'm asking is, then, would it be your
sense that the spectrum of patients who come to
clinical attention who have symptoms, who go to
medical centers, who ultimately get diagnosed, even
if it is 11 years on average later, that spectrum
of patients would be more severe?
Would they be more severe than the general
spectrum of patients who might be in the population
with a genetic predisposition, perhaps, with some
inflammatory changes in their bowels, yet are not
under medical care, so that the "selection bias,"
if you
will, is to exclude the relatively mild
277
disease and the ones you see would be the more
severe disease in the general population? I guess
it is a question to Dr. Murray, who is not here.
Dr. Kelly might step in and comment.
Dr. Collin.
DR. COLLIN: Of course, if you detect more
and more patients with celiac disease, then the
figures become less biased. We have a lot of
people who are asymptomatic, patients with celiac
disease. The question is very complex.
On one end, on one side, we have a patient
who has very mild, mild inflammation and very mild
villous shortening in the mucosa, and they may have
some symptoms such as iron-deficiency anemia. On
the other end, we have patients who have totally
flat mucosa, and they are totally asymptomatic.
We have learned a lot of data from family
studies where we are actively screening all of the
celiac disease patients. We have seen truly
asymptomatic patients who will not be detected
without the serology screening. Still, we do not
want to
extend the screening program to the whole
278
population.
I think our policy is that we apply
screening in risk groups and if they have even
minor symptoms and then we can achieve almost 1
percent of celiac disease, clinically diagnosed.
I'm not sure whether I answered your question. I
couldn't hear it very well.
DR. SILVERSTEIN: May I follow up? There
is a paper, also from Finland, the prevalence of
celiac disease in children in the New England
Journal paper a couple of years ago. Again, that
was serologic, serology was available, so you had
population-based samples.
Those who had abnormal serology, when they
were followed up, and then you found some spectrum
of undiagnosed disease in those children. It would
seem to me the children detected through that type
of mechanism, would have generally milder disease
than those who would have come forward because of
the clinical presentations.
DR. COLLIN: Yes. In that paper, I think
the
prevalence was not 1 percent, more than
279
1 percent of people, children in Oulu, Finland.
You are right, I think many of them who were not
detected earlier for celiac disease, who were
detected by this serologic screening, they were
asymptomatic.
We have also carried out some quality of
life studies from those patients who have been
screened for celiac disease not due to symptoms but
because they belong to the risk groups.
We have seen that their quality of like
with these measurements that we have used are very
similar to that of the population in general, and
it is better than those who are symptomatic
patients.
With a gluten-free diet, it still
increases, and it becomes after one year even
better than in the population. We call it maybe a
honeymoon period. We have no long-term data on
that, but that is very interesting that many people
really are asymptomatic.
DR. FASANO: Alessio Fasano. Marc, you
are
absolutely right. The people that come
to our
280
clinic with symptoms definitely are the biased part
of the population with celiac disease because they
are the ones that have symptoms that seek
attention. It is undisputable that compared to the
overall picture of celiac disease, the one that we
see on the clinical grounds are biased in that
direction. No question about it.
However, for example, it is policy for us
right now that every single time you make the
diagnosis of an individual the entire household is
screened.
Epidemiology studies out there suggest
that up to 10 percent of first-degree relatives
they have the disease, irrespective of if they have
symptoms or not. Sometimes when we diagnose these
people that apparently are completely clinically
silent, you do a truly, you know, well-done workup,
they have osteoporosis or osteopenia.
How would you consider the otherwise
completely silent? If you make the diagnosis on
time, and according to the current literature "on
time"
meaning two to five, you can fix and correct
281
the problem. If you are too late, you can't do
anything about that in these people.
I would consider that a great, great
danger, even if clinically they are absolutely
silent because these are people at risk for
fractures in their thirties. We have seen these
cases.
DR. SILVERSTEIN: If I could follow up --
in terms of the spectrum of disease, unlike the
situation where you have a patient with perhaps a
food allergy, who we heard about yesterday, whose
physician or family member or even the patient may
decide the risk of the food challenge test would be
too great and they would be excluded, in your
experience in caring for patients with celiac
disease, is there a similar phenomenon where the
patient who were more severe would be less likely
to undergo evaluation biopsy or participation in
studies?
DR. FASANO: In terms of a challenge, in
other words, I'll give you a practical scenario.
An individual
comes to our clinic because they have
282
symptoms for many years. They have never been
diagnosed, but they spoke with a friend or a
colleague or a family member that raised the issue
of the possibility of celiac disease.
They go on a gluten-free diet without
being diagnosed, and they are feeling better. They
come to your clinic, and they want to know if this
could be a definite diagnosis or not. You say,
"The only way to do this is you have to do a
challenge."
If this individual had a really hard time
in his or her life -- in other words, the symptoms
are severe -- the likelihood that this individual
will accept the challenge is much lower than the
person that had the stomachache or the bloating
here and there with vague symptoms that now are
gone away.
However, they want to know for sure,
because now they realize that a gluten-free diet
for life is not a joke, that this is indeed the
kind of direction to go. That individual is more
likely
amenable to a challenge.
283
However, an individual who has been
absolutely sick with tremendous symptoms that
affect their lifestyle, that individual will be
very, very unlikely to be open for a challenge.
That is my personal experience.
DR. KELLY: Ciaran Kelly. Just to expand
upon the question, that is certainly the case.
That is certainly my experience. However, we are
talking about clinical gluten challenges. Do you
think it is the same for a prospective study where
one would be performing a low-dose, a minimal dose,
gluten challenge? Do you think that highly
sensitive individuals would also be less likely to
participate?
DR. FASANO: I think that there is a
serious possibility. In other words, when you do a
prospective study like the one that was done in
Italy and say, "Look, there is a chance that we're
going to give you a placebo, i.e., water and you're
going to be all right, or you could get some amount
of gluten that we don't know if it's going to harm
you or
not," if this individual has a really hard
284
time, that individual will probably be less likely
inclined to participate.
Saying that, though, of the people that
have participated in this study, there was the
entire variation of the spectrum, if you wish, of a
gravity of symptoms. I can't tell you if there
were people that claimed to be hypersensitive to
gluten, those that will react like two hours after
eating.
If we have a few of these people because
this was randomized or because it was blind, I
can't remember. Actually, I don't know yet if they
were included in the study or not. There were
people like that who volunteered to do the study.
If they end up to do the study or not, I don't
know.
DR. COLLIN: Some half a year ago, we
started a study where we looked at hydrolyzed
products derived from wheat starch and the outcome
of histology where we have also to take one biopsy
before and one after a half year's period.
I
did not have the feeling that the most
285
sensitive would not come. I think that those
refuse to come who don't have a strict diet,
because they feel that maybe their small intestine
is not in a good condition, and the doctor will
blame him or her about that.
Again, I would like to say that I suspect
whether there are really highly sensitive people.
Usually, when we start a study, we take 100
patients, and another 100 call to ask us, "Why
can't I participate in this project?"
CHAIRMAN DURST: Okay. Marc.
DR. SILVERSTEIN: I have a question on a
different area, so if there are further questions
following up on this selection, then we should
pursue that--?
CHAIRMAN DURST: I don't think so, go
ahead.
DR. SILVERSTEIN: Could I ask
Cynthia Kupper a question, if I may?
MS. KUPPER: Certainly.
DR. SILVERSTEIN: I was interested in
understanding the extent to which a celiac
286
patient's likelihood of following up with a
healthcare provider, physician or dietitian as
opposed to a disease association or an informal
network with regard to dietary advice, how that
might be changed by more helpful information on
food labeling?
In other words, if the labeling were more
consistent, more trustworthy, more reliable, would
there be increasing reliance on the labeling or the
non-clinical advice, or would there be even more
likelihood that physicians, dieticians and others
would be able to be more effective in managing
their patients? How would that likely affect
patients' behavior, do you think?
MS. KUPPER: In many ways, it is two
different issues. First of all, patients when they
are diagnosed currently oftentimes they are
referred to a dietician, but in many states
dietician services are not paid for.
Consequently, many patients don't go, or,
if they do go, the dietician is inadequate in
preparing
them with the information they need, so
287
they are very frustrated.
Referrals back to dieticians should
happen, as suggested by the NIH Consensus
Conference, because part of the problems with
compliance is that they don't have that consistent
follow up and they aren't monitored by a dietician,
and there are some nutritional concerns about a
gluten-free diet.
In a sense, it is a different issue. They
need to be seeing a dietician, but they are just
not referred or their insurance isn't going to pay,
so they don't go.
Would a patient rely on labeling more than
a medical professional like a dietician, if the
labeling were more accurate? I really don't think
so. I think they still need the dietician.
I think they will be happier being able to
find sound advice from the labels, but it is still
a matter of teaching them how to read a label,
learning what the terminology is, and understanding
that so they can make wise choices.
QUESTIONS FROM FDA: GLUTEN AND
CELIAC DISEASE
288
CHAIRMAN DURST: All right. If there is
no more general discussion or immediate questions
for the speakers today, I would like to suggest
that we start addressing some of the specific
questions from the FDA, so that we don't run out of
time at the end -- unless someone feels there is
some other urgent question they want to bring up?
(No verbal response.)
CHAIRMAN DURST: Okay. The first one is
the question of whether there is a distinct
subpopulation of individuals with celiac disease
and then going into the uncertainty factors
involved in these measurements. Would anyone like
to make some comments on that?
DR. KELLY: Ciaran Kelly. I think you can
approach that question from two angles, one is easy
to answer and the other is more difficult to
answer.
From a clinical perspective, it is very
clear that there is a broad range of clinical
manifestations of the disease and that some
individuals
with celiac disease are able to ingest
289
the same amount of gluten in their diet as
everybody else and don't demonstrate any clinical
or nutritional ill-effects, at least in the
short-term.
Whereas others, if they ingest a tiny
amount of gluten, a crumb of bread, will have in a
very short period of time a gluten reaction, a
reproducible reaction that lasts a predictable
length of time; so, clinically there are.
What is more difficult, however in mind is
the fact that those clinical reactions don't
predict the severity of the mucosal abnormality.
At one level yes.
At another level there is also a variation
we saw earlier, the Marsh classification, of the
histologic abnormalities. There is a variation in
that also, but they don't overlap neatly. You
won't find always low-level lesions in silent
patients. The answer is yes, I believe.
If you ask it either way, clinically and
presentation, there is a huge spectrum
histologically. Immunologically
there is a
290
spectrum. It is just that they aren't always
parallel.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: Just to follow up, are they
reasonably correlated, even if they aren't
perfectly concordant?
DR. KELLY: I don't believe so. I will
ask Alessio and --
DR. FASANO: I can't hear you.
DR. KELLY: You can't hear?
DR. FASANO: No. What was the question?
(General laughter.)
DR. BRITTAIN: We are talking about the
relationship between clinical manifestations,
immediate clinical manifestations, and I guess what
you can observe in a biopsy? The people who are
sensitive with respect to immediate reactions don't
look the worst on biopsies? Is that what you're
saying?
I'm asking are they fairly correlated?
Could it also have to do with the length of
disease? I would think the
damage in the
291
intestines would be a function of a lengthy
disease, whereas the short-term reaction had
nothing to do with the length of disease.
DR. KELLY: Ciaran Kelly. As regards
duration of disease, well we seldom have the
opportunity to identify exactly when celiac disease
develops, except in children who manifest symptoms.
When an adult presents with celiac disease, it is
impossible to determine the duration of disease at
that stage. The other question is, Is there any
correlation -- can you hear me?
DR. FASANO: Yes, I can.
DR. KELLY: Is there a correlation between
histologic severity of disease and clinical
manifestation of disease in terms of
symptomatology?
DR. FASANO: The answer is no. It is
pretty much a straight no. Keep in mind that the
target organ of this autoimmune process is an organ
that has 200 square meters of surface, so it is
huge.
What do you define "severe" as? If you
292
define "severe" as 80 percent of the surface is
damaged, then it may be that we can have that kind
of correlation.
With our methodology right now, consider
that maybe there will be a change in that story,
but now with endoscopy we see the first few inches
of this 14 feet.
It can be absolutely destroyed what you
see. But there is absolutely no damage with many,
many times patch lesions where we go with the
endoscope, and these people are sick like dogs
because it is everywhere, all the way, to affect a
sizeable amount of the surface. Your processing
and absorption and digestion of foodstuffs is
dramatically affected.
That is the reason why there is no such
correlation on the clinical ground versus the
procedural ground, because the procedure cannot
give you the full breadth of the damage of the
intestines.
DR. COLLIN: May I comment?
CHAIRMAN DURST: That answer was given by
293
Dr. Fasano.
DR. FASANO: By now, because of the action
probably you know who we are, right?
(General laughter.)
DR. COLLIN: Pekka Collin. If I may
comment, I agree with Alessio that there is no
correlation because we have some patients with very
mild atrophy and severe osteoporosis, and then a
flat mucosa without any symptoms.
However, there is one correlation. Our
ultimate goal, if you look at who is sensitive and
who is not sensitive, if you look at how the mucosa
will recover, how is the mucosa recovery, if the
initial lesion is very severe and the patient has
remained undiagnosed for many, many decades, then
their recovery is very slow. Maybe in elderly
people it is seldom complete, but when the initial
mucosa is mild, I think we achieve full recovery
quite soon.
CHAIRMAN DURST: On that same question, I
think we have to address the uncertainty factors
and whether
tenfold is sufficient using a safety
294
assessment-based approach. That is a reasonable
uncertainty factor?
DR. MALEKI: What is the starting point?
CHAIRMAN DURST: Soheila.
DR. MALEKI: Oh, Soheila Maleki. I assume
you would imagine what would be the starting point.
If you imagine it would be 200 or 20 and then
hitting the limits of detection for the methods at
this point and whether you can detect it, if you go
tenfold below 20, then I think you will surpass the
methods of detection, whereas if you are 100 or
200, then you may be able to say that would be
sufficient. I think will wait to see if the
statisticians differ.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: This is Erica Brittain. It
also depends, I guess, we have been hinting or
talking about possibly having two levels,
gluten-free, which would probably be pretty close
to as low as you can go and maybe something that is
not so strict.
Obviously, you would use a different
295
uncertainty factor there for the two levels.
Again, it is the same discussion we had yesterday.
The 10 seems very arbitrary. It also depends on
which data set you start with. I mean, they all
have limitations.
DR. GONSALVES: This is Dennis Gonsalves.
It seems that a preponderance of data from all of
the different presentations suggest that 20 parts
per million for Canada and the various studies were
really more or less agreed upon. At that level you
don't get this reaction. If one looks at 20 and if
one looks a the uncertainty factor, it looks like
they licensed this at 20. If you have a tenfold
uncertainty factor, well, this was 18. I think
that there are data that suggest that --
DR. BRITTAIN: Two.
DR. GONSALVES: Yes. Ten percent up or
down?
DR. BRITTAIN: Down. It would be two.
DR. KELLY: Go down to two.
DR. GONSALVES: Two, yes. Well, so this
is five, so
you can adjust that. Anyway, my
296
suggestion is that there really is pretty good
information that you are very close.
You can argue all of these different
exceptions, but at some point you have to decide
whether this uncertainty factor of 10 is
sufficient. I won't argue that based on what I
have heard it is pretty sufficient.
DR. KELLY: Ciaran Kelly. In fact, I
agree based on the data that is available, albeit
limited and albeit imperfect but scientific data is
always limited and imperfect, that it appears as
though there is agreement around the general range
that appears to be below a threshold for injury.
If there is broad agreement across the
data, perhaps an uncertainty factor of 10 might
even be considered excessive. I think there has
already been a sort of de facto uncertainty factor
enacted in going in other communities from 200 to
20, and that was largely based on concerns about
whether or not the 200 was low enough. I would
suggest it might be worth considering that.
Again, it depends on where you start.
I
297
feel if you start at a conservative level below
which the scientific data that are available
suggest there is no evident injury, either by
symptoms or by histology, then that may be a
comfortable level without an uncertainty factor.
CHAIRMAN DURST: Okay. Marc and then
Erica.
DR. SILVERSTEIN: Marc Silverstein. I
would like to make a comment. It seems to me that
in medicine we have lots of uncertainty and
uncertainty from lots of sources. Some of the
uncertainty comes from bias and some of it comes
from confounding and some of it comes from
measurement error.
It seems to me that the rationale for
uncertainty factors that was applied to toxicology
for environmental exposures in our discussion
yesterday is we couldn't find a reasonable clinical
or biological reason to think that level of that
approach would be appropriate for IgE-mediated
immune reactions.
It seems to me that although we have
298
learned or heard about the non-IgE, cell-mediated
immune injury in celiac disease there is little
rationale, from what we understand about the
disease, to attach an uncertainty factor of tenfold
or whatever-fold.
I understand how a public safety
mechanism, it might be nice to have an uncertainty
factor, it doesn't seem to be consistent with our
understanding of either IgE-mediated immune injury
or cell-mediated immune injury for celiac disease.
It is kind of a comment.
For those who know more about celiac
disease than the biology of immune-mediated injury,
is there any reason to have a rationale for
thinking that you can measure the variation in the
response or the threshold for a response based on a
factor, whatever the factor might be?
I don't know what body of understanding,
whether from biology or medicine, would be
applicable so we are using toxicology here. I
would ask for some comment from those who study the
immune
response.
299
DR. FASANO: If I may? This is Alessio
Fasano. We had a long discussion in '99 and 2000
when we were designing the study about what would
be the biology readout, because that is what it
really boils down to.
What would be a satisfactory readout to
make us comfortable in saying the immune system,
genetically skewed to react in not immune fashion,
will be turned on by "X" amount of gluten? A study
designed that should take three months took almost
two years to reach a consensus, because there were
different philosophies that were on the table.
There were people that say clinical, serological,
biochemical, histological, combination and
permutation, all of the above.
The reality of the story was that we
weren't on evidence-based on the retrospective
studies done where some of the people that
participated plus our other colleagues, and we
realized, one, clinical was absolutely not
reliable.
Two, the biochemical, the other antibodies
300
was also not reliable because we still don't know
the role of these other antibodies, the
pathogenesis.
We all agree, while there was some
disagreement about the statement I just said, we
all agree though that the final product of the
autoimmune process, i.e., the autoimmune biological
readout, is the damage of the intestine. That was
the only confidence parameter that everybody agreed
upon.
The reason why this was not a joke is
because unfortunately, based on that decision, the
only way they could make a statement in terms of
biological readout implied two endoscopies. That
in terms of study design was inartful.
I mean, not only do you have to go to
somebody that is healthy who goes on a gluten-free
diet and asks to have an endoscopy that he or she
has no business to do, but then we heard this after
three months. A wheat starch level is the only way
to do it.
DR. SILVERSTEIN: Could I follow
up with
301
one question, then?
(No verbal response.)
DR. SILVERSTEIN: When you selected your
empirical doses of 10 milligrams and 50 milligrams,
was it based on a rationale that a ratio of a
5-to-1 dose, or was it sort of a sense that this
was a lower feasible dose and a higher feasible
dose of interest? I mean, how did you--?
DR. FASANO: As you can imagine, if we
were absolutely insane in how to design, also 6
months we discussed how much we should go. The
reality was you so package data in which the vast
majority of the North Europeans consumed, roughly,
150 grams of gluten-free-based grains.
If you take this European population and
extrapolate to the American one, because we want to
do a study as generalizable as possible, we consume
in general terms more than that.
Italians, it may be that they are at the
extreme of the spectrum, but definitely we want to
cover as much as we could. Dr. Catassi did a study
before in
which he used 100 milligrams and clearly
302
showed the damage. Other studies were done as well
that clearly showed the damage.
We designed to take two doses -- because
we wished to do 10, 20, 30, 40 or 50, but that was
not doable -- in which we pretty much covered the
spectrum between the 20 and the 200 parts per
million because the Codex Alimentarius, you heard
Rhonda, is around number 7.
They have been discussing this for ages.
This 220 has been on the map there for quite a
while. The 50 and 10, based on a max consumption
of 300 grams a day, were chosen to cover the two
ends of the spectrum of the 20 and 200 parts per
million. That was the rationale.
DR. SILVERSTEIN: I would just comment
that it seems to me in looking hard for a rationale
for an uncertainty factor, we don't get an
uncertainty factor approach. We get a clinical
approach based on the knowledge of the exposures
that have caused injury.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: I guess the
questions, we
303
are going to have a second question about an
uncertainty factor for the short-term versus
long-term exposure. I know we were just asked the
first question, but sort of we are talking about
everything all together.
For me there is still that long-term
question at least from the clinical trial, which is
a wonderful study, but it only goes four months. I
am thinking that I don't know if cigarette smoking
and lung cancer are at all analogous.
Obviously, the longer you smoke, the
greater your risk is. If we were just studying
smoking for four months, we might not pick anything
up. That to me is my strongest concern where the
uncertainty factor would come in, because clearly
with respect to that study we have uncertainty
about long-term exposure.
I guess what is hard for me to evaluate is
the observational data that might support the
validity of the result of the prospective trial. I
don't really have enough details about it, and
perhaps
strong enough to support it, in which case
304
there may not be all that much uncertainty.
DR. FASANO: May I comment on that? May
I?
CHAIRMAN DURST: Yes.
DR. FASANO: The three months was also not
pulled out of a hat; it was part of a long
discussion how we come up with the three months.
You are absolutely right, if you asked me, "Are you
absolutely unequivocally sure that the fellow on
10 milligrams that do not react today will not
react in 10 years from now," the answer is of
course not, I'm not.
Why do we choose the three months?
Because if you are exposed to dangerous levels of
gluten after you have been on a gluten-free diet,
because your immune system is primed, 90 percent of
the people will react within three months. That
was the reason why we went to three months.
In other words, the vast majority of
people that have been on a gluten-free diet and
they are challenged because of diagnostic purposes
or because
of cheating or because they said "to
305
heck with this diet, I want to go back and enjoy
myself," not only are we experienced in what you
read out there, but the vast majority will react,
not necessarily clinically, but they will react in
some shape or form within that period.
We are sure there are people that after 10
years they still don't react. These are the
extremes. Statistically, that is how we came up
with this three months. Does this for sure say
that in the long-run they are going to be all right
--
MS. KUPPER: The American Dietetic
Association --
CHAIRMAN DURST: Your name, please?
MS. KUPPER: My name is Cynthia Kupper.
The American Dietetic Association is in the process
of doing evidence analysis of the gluten-free diet.
Two of the questions they are looking at right now
are, Is the gluten-free diet useful in reversing or
stopping anemia and osteoporosis?
They are really struggling with these
questions
right now, because a lot of the studies
306
come from Europe. They are actually thinking about
separating the American studies from the European
studies, which might help to address this question
because then we are talking wheat-starch-based,
gluten-free diets versus non-wheat-starch-based,
gluten-free diets.
CHAIRMAN DURST: Let's see, David first.
MR. ORYANG: Yes. David Oryang. Talking
about the uncertainty, you mentioned you could not
be absolutely certain that the person would not
react the next time after some time. There is
always uncertainty. Somehow we need to keep in
mind, I think, the fact that the study was done at
10 and 50.
The other thing is I were to ask suppose
the study was done at five, what would the outcome
have been? Could there have been reactors? If we
say that, yes, there could have been reactors, then
we definitely have uncertainty.
Since we do have uncertainty, then we need
to put some uncertainty factors around this
parameter,
then the issue becomes what the
307
uncertainty factor should be.
I don't know whether the FDA
representatives maybe can say something about this,
but the whole issue of using a distribution for an
uncertainty factor, would that be considered
reasonable?
Maybe an expert panel could be put
together just to address that issue and at least
set bounds for what the uncertainty factor should
be and then look at the 95 percentile value of the
overall result when you divide by that uncertainty
factor, to determine the threshold value.
However, this is another issue of maybe
modifying the safety factor analysis methodology to
incorporate elasticity into some of those
parameters as opposed to just a plain value make it
a distribution. That is one alternative to deal
with uncertainty about uncertainty.
(General laughter.)
MRS. MOORE: Did you have a specific
question that you wanted the FDA to respond to?
MR. ORYANG: Yes, whether that
has been
308
considered, whether there is anything in the
literature about that having been applied.
MRS. MOORE: Well, wait for a moment. Did
I see somebody raise their--?
CHAIRMAN DURST: Yes, Margaret.
DR. McBRIDE: Margaret McBride. It seems
like one of the --
CHAIRMAN DURST: Well, he is ready to
speak. Sorry.
DR. McBRIDE: Sorry.
CHAIRMAN DURST: He is coming out of the
huddle.
DR. GENDEL: Steve Gendel. From my
consultation with the experts, I have been told
that this is not necessarily a normal way that this
is done, but it is certainly something that can be
considered. One of the things that we are
interested in hearing from the panel are
suggestions about approaches such as that.
CHAIRMAN DURST: Okay.
Margaret.
DR. McBRIDE: One of the biggest
309
uncertainty factors is how much starch a person is
going to eat. We have to rely on some kind of
judgment and education from the consumer.
If we tell them how many parts per million
or set a level that is a certain amount of parts
per million, then how many pieces of bread with the
alternative flour they eat affects much more than
any, or possibly significantly more at least
equally with any uncertainty factor we try to put
into deciding a parts per million.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc Silverstein. It
seems to me that we have lots of precedents in
clinical medicine where we studied either the
effect of large doses for shorter duration, or we
set practical limits to the amount of resources
that can be placed in doing studies, and we make
decisions about medications and treatments based on
courses of therapy.
There might be one month, three months,
six months, to a year, yet many of these conditions
and
exposures that patients will get, either their
310
treatments or medications or tests or radiation or
diet, are lifelong.
With regard to the issue of going from
short-term to long-term, short-term exposures and
effects to long-term outcomes, I think we should be
cognizant of, be aware of the fact that these are
individuals with a clinical condition, with a
disease, that have access to healthcare.
These individuals with the advice of their
physician are going to have a course of therapy
that could be periodic assessment of their response
to therapy, periodic assessment of their mucosa,
periodic assessment for the consequences of
long-term inflammatory disease.
I am less worried about the problem of
making inferences on long-term outcomes because, by
and large, these are patients with a clinical
condition who are having a dietary regimen under
the management of a physician.
It may be unfortunate that some patient's
experience has been, the physician has said, "Well,
now you
should change your diet. Goodbye and
good
311
luck." However, I think we should remember that is
not, indeed, the norm and probably is more the
exception I would hope.
In any case, I would think that we would
be able to make reasonable inferences based on the
short-term exposure, and three months seems to me
to be right now probably the upper limit of what
was feasible in a well-designed clinical study for
response to gluten.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: I guess my question about
that would be I assume these patients don't get
routine biopsies or anything like that, or maybe
they do? Maybe that is my question. Without that,
I don't know how you would necessarily know if they
are doing badly.
DR. SILVERSTEIN: That is what medicine
and clinical research is all about. The physicians
-- those under their care, the patients -- will
come up with a course of therapy.
I am sure there are physicians based on
current and
evolving data who will recommend either
312
no further surveillance or periodic surveillance or
surveillance at yearly or three yearly or monthly
or whatever it may be.
In the same way, for example, patients
with ulcerative colitis who have longstanding
disease and are at increased risk of colorectal
cancer are often in a periodic surveillance program
for that outcome. That would be separate from
saying how we should make recommendations about
pharmacotherapy for their disease.
Some people would say, okay, study a
reasonable period of time -- whether it is one
month, three months, or a year -- and let the
patients and the physicians together make their
best recommendations about long-term management.
I am just addressing this issue of
short-term and long-term. Clearly, you can't wait
20 years before you make any recommendations, and
experience will evolve as patients and physicians
together learn more about what works and what
doesn't work.
I
do believe that we have many precedents
313
where we do have reasonable time periods -- whether
it is one month, three months or six months -- for
clinical studies and then make recommendations that
patients and their physicians can look at the
long-term outcome.
I guess I am repeating myself. However, I
do feel that there is a scientific basis and
precedence in many other areas for best information
for a short- or moderate-term studies to be the
basis of practice over the long-term.
CHAIRMAN DURST: Okay. Thank you.
Mark.
DR. NELSON: Mark Nelson. I don't know
how we want to factor in the natural experiment, if
you will, of labeling gluten-free products in
Italy. While it is not as elegant and as
controlled as the Italian study that we heard about
today, my understanding is we have seven years of
this labeling in Italy. We must have some
real-world experience about severity of symptoms,
change in symptoms, and change in prevalence in
Italy with
that experience.
314
CHAIRMAN DURST: Dick Durst. I would just
like to make one comment on the uncertainty factor,
that is, we can certainly recommend that there has
to be a certain degree of uncertainty factors
associated with the recommendation, but it sounds
like from what I've been hearing that even a
tenfold uncertainty factor would be beyond what the
analytical methods can currently do. Therefore, it
is a luxury that we may not have the option at the
present time of setting.
Certainly technology in the future is,
hopefully, going to improve the point where we can
get down to a tenfold uncertainty below, say, that
20-part-per-million level.
DR. HEIMBURGER: Doug Heimburger. Related
to that, though, but the other problem is the
impossibility of creating products that are
significantly below that 20, even if you could
detect it. I'm not sure that new technologies will
necessarily change the true uncertainty factor with
regard to what is actually included.
CHAIRMAN DURST: Unless the
processing
315
technology also improves.
(General laughter.)
DR. BRITTAIN: It sounds like maybe 10, I
mean, I don't know if I was hearing correctly, from
a practical point of view something like that might
be the absolute lowest you could go and still be
able to produce food. I don't know if that's
right.
DR. HEIMBURGER: Doug Heimburger again.
From what Steve Taylor was telling us it is not
just a matter of farming technologies, either. You
would have to revolutionize the entire agricultural
methods that are used.
CHAIRMAN DURST: The infrastructure.
DR. HEIMBURGER: That is just not going to
happen, particularly because they are built on
efficiency now probably being as efficient and
cost-effective as possible. Any move in the other
direction would have all kinds of forces against
it, including our pocketbooks.
CHAIRMAN DURST: Jeff.
DR. BARACH: Yes, Jeff
Barach. I think
316
what we are really talking about here is risk
management and uncertainty factors, adding
uncertainty factors is one approach.
Another approach that we favor is really
to establish when the threshold is established, to
consider it as sort of an interim threshold, and
then with experience and more information perhaps
that interim threshold would change.
For us to assign uncertainty factors based
on numerical and environmental considerations at
this point does seem premature. With experience
and setting an interim threshold, we would have the
opportunity at some time to make an adjustment in
that, if we felt it was either too high or too low.
DR. KELLY: Ciaran Kelly. I wanted to
return to the question of timing and whether or not
three months is adequate to demonstrate a response
to gluten -- of course the longer, the better.
In reality, if you look at acute gluten
reactions, clinical symptoms, reproducible
symptoms, they tend to occur within a few hours.
If you look
at the acute challenge studies,
317
morphology could be demonstrated to be abnormal
within hours of instilling toxic peptides into the
duodenum. Those very acute studies were able to
show abnormalities within a very short period of
time.
It would seem to me that understanding
that this response appears to occur within hours in
vivo, having individuals exposed for three months
it would seem to me to be more than adequate to
demonstrate any at least medium-term effects.
There is nothing, to my knowledge, to
suggest that an individual should be triggered to
respond at a later period in time who hadn't
responded earlier, albeit the fact that there are
always exceptions to that.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: So are you saying that
someone, say, who is not very compliant and does
eat a lot of gluten, he would not get worse over
time if he had more exposure to gluten?
DR. KELLY: Yes, he would. I mean, if
somebody
has severe celiac disease and they are not
318
diagnosed or don't go on a gluten-free diet, they
can become malnourished. Before a gluten-free diet
was available, the condition was often fatal. Yes,
it can accumulate.
What I'm saying is that in an individual
who is on a gluten-free diet and well treated, the
response to inadvertent and purposeful gluten
intake, if there is a reproducible, reliable
clinical response, it is very rapid.
In those individuals who respond in a
particular way, the response is quite rapid. As we
heard, it is a delayed Type 4 reaction that occurs
within a few hours of exposure, typically.
CHAIRMAN DURST: David and then Soheila.
MR. ORYANG: Yes. David Oryang. Yes, I
think in an individual we can say that we expect
pretty much the same thing. What about between
individuals? Are we going to expect the same thing
between individuals?
The safety factor that we are talking
about, the intraspecies safety factor, is looking
at, okay,
how will he respond versus this person to
319
the same challenge. Can we say with a hundred
percent certainty -- in other words, a safety
factor of one -- that they are going to respond the
same?
CHAIRMAN DURST: Soheila.
DR. MALEKI: Soheila Maleki. One thing in
answer to yours, they are talking about being on a
gluten diet and they are talking about a certain
limit, not sitting around and eating a bunch of
known gluten. The study is about getting a limited
amount. It is showing within 45 people -- I think
that was the study group, right?
CHAIRMAN DURST: Thirty-nine.
DR. MALEKI: Oh. I'm sorry?
THE COMMITTEE: Thirty-nine.
CHAIRMAN DURST: It was 39.
DR. MALEKI: Thirty-nine people, close
enough. Anyway, within 39 people that they tested
with this particular limit over 3 months, given
that they would have a severe reaction and it would
show within 3 months, that they didn't. Just
clarifying
that, because you were saying if they
320
eat a lot of gluten.
DR. BRITTAIN: Oh, no, what I'm getting at
is what is the effect of cumulative exposure. Just
like smoking cigarettes for many, many years,
you're not going to get immediate damage from
smoking -- you may get slight damage, but it might
not be incurable.
I can just quickly describe a study design
you might do. I know it would be hard to do, but
perhaps a study for a year and do biopsies every
four months or every six months, so that you could
see if there is a change over time.
If the change happens right away and it
doesn't go down any further, then you know, you
have some confidence that there is not going to be
a continued change over time, but if you see a time
relationship, then you would know.
DR. FASANO: Can I make a comment on that?
May I, Mr. Chairman?
CHAIRMAN DURST: Yes.
DR. FASANO: Okay. Alessio Fasano here.
The
parallel between smoking and celiac disease I
321
don't think that is really pertinent, because
celiac disease is an autoimmune disease. It is a
step-by-step process. The variability is how long
it takes for Individual A versus Individual B to go
from point 1 to point 2.
The steps are well-known. You are exposed
to gluten, antigen presented in cells, and we see
them represented in intraepithelial lymphocytes,
there will be inflammation, cytokine production,
intracellular cells, and the damage.
People can do this journey in a few hours;
people can do the journey in a few days; people can
do the journey in a few months. The question is,
When do the vast majority of people go from point 1
to point 2? That is what I was alluding to.
When people genetically predisposed to
celiac disease are exposed to gluten because
challenged, a toxic amount of gluten, or challenged
because they decide to abandon the diet, the vast
majority of the people, they react within that time
limit. When I say "the vast majority," it is
because
again there is still the possibility and
322
there are reports that you can take much longer.
It is the same story on clinical grounds.
There are people that are exposed to gluten and
they develop symptoms as kids after a few months or
a few weeks because and then the damage will become
clinically apparent in the next few weeks, but
there are people that it would take nine years.
How do you explain the variability? We
don't know. The first steps in the process of
damage to the intestines are at the very beginning
and this is likely to switch on and off. It goes
on and it goes on.
That is the reason why I am pretty
comfortable with the three-month business, because
it is a very comfortable interval in which you
should see the immune system react with parameters
that can be biologically looked at as we did with
histology and morphology.
CHAIRMAN DURST: Dick Durst. I would just
like to say that, presumably, the whole point of a
threshold amount of the gluten or whatever the
problem is,
is that it is a level below which the
323
disease has not progressed. It doesn't get any
worse.
Using, even though it is a bad analogy,
the cigarette, if you can show that, okay, smoking
one cigarette a day is not hazardous, but smoking a
pack over time will really cause serious problems,
lung cancer or what have you, then the threshold is
that one cigarette a day.
Presumably, if you have done good studies,
it would show that, all right, that's safe to do.
However, I think if we set a threshold at a point
where the disease does not progress, even on a
short-term basis, then over the long term that
should still hold.
Marc.
DR. SILVERSTEIN: I think this is an
insightful discussion because I think we are
talking about immune-mediated injury, IgE, in the
case of the allergic diseases or cell-mediated for
celiac disease.
We are talking about carcinogenesis on
perhaps a
multistage process with genetic mutations
324
due to a variety of exposures, or we may be talking
about toxicologic injuries due to environmental
factors.
I think we've got a conceptual model,
certainly based on environmental toxins, that we
are extrapolating to these immune-mediated
processes. I am cautious about that. Because I
can't see that rationale coming from science, in
terms of the application of the risk management for
environmental exposures, toxins, being applied to
these immune-mediated conditions. That is why I'm
being fairly skeptical here.
The discussion has helped me think about
what are the underlying mechanisms in
immune-mediated carcinogenesis with damage to cell
growth or other toxic mechanisms due to the
environmental accumulation of small molecules.
CHAIRMAN DURST: Soheila and then Suzanne.
DR. MALEKI: Soheila Maleki. Bottom line,
I think that we can talk about this, and all the
complications which of course exist such as they do
in the case
of IgE-mediated allergy, but bottom
325
line based on the best data available, we have to
accept this as what we know.
This is the level within the three-month
study that has been done prospectively and the
retrospective study that they have actually
determined maybe seemingly short-term, but
clinically relevant according to Ciaran.
Of course, then, we have the limitation of
the methodological methods available to us. We can
discuss this for a long time and not really be able
to still answer that question as far as what fold
we would put that at.
I mean, I agree with you that it is very
complex and a multihit type of disease much the
same as cancer would be. With the data available
-- and, I mean, think it is good data -- that has
shown that these are some of the limits they react.
CHAIRMAN DURST: Suzanne and then
Margaret.
DR. TEUBER: Suzanne Teuber. It seems to
me that with the population data that Dr. Collin
presented
you actually have a higher level already
326
seen in the population with some long-term data
that was very reassuring.
It seems that if you use that as your
starting point, then apply an uncertainty factor
that we don't really know to that, and then your
data comes in from Italy that is very reassuring,
that a factor that has been theoretically applied
to that upper limit is coming down even lower over
a three-month period with no immunologic reaction
seen, that is very, very reassuring.
I think that would imply that the levels
that should be looked at initially would be what
Dr. Collin was discussing with this additional
safety.
DR. COLLIN: May I have a comment?
CHAIRMAN DURST: Oh, okay.
DR. COLLIN: Pekka Collin. Another issue
is that, if one stay on the safe side, if there is
somebody very sensitive, some celiacs who are very
sensitive, they might react after three months; so,
the period would be too short.
All our retrospective studies show that
327
ultimately we can achieve a complete response. We
have methods to detect those patients who might be
very, very sensitive.
One mechanism is that we take usually, at
least in Europe or maybe also in the United States,
take one biopsy after one year of a gluten-free
diet.
If there is no clear improvement, then we
can concentrate on those patients who might be
truly sensitive, or, as I said, who might take some
extra gluten, excess gluten not PPMs but grams of
gluten.
Therefore, I think that it is very high,
that uncertainty factor. Maybe it is not very
relevant. Maybe you go to the conclusion of zero
level instead of a little bit higher level, which
is very well tolerated by the vast majority of
celiac disease patients.
CHAIRMAN DURST: Finally, Margaret?
DR. McBRIDE: Margaret McBride. I think
in a certain way that the data that we heard this
morning
from both studies included some long-term
328
data. We know what the biopsy results were in
folks who had adhered to a diet, a gluten-free
diet, in both countries.
In one country, for seven years
"gluten-free" meant below 20 parts per million, and
we assumed that they were eating somewhere between
100 and 200 or, for real past lovers, 250 or
whatever.
We can calculate the amount of the number
of milligrams of gluten to which they may have been
exposed over a seven-year period. In fact, their
biopsies were like those of normal folks, at least
in regard to the height/crypt depth ratio.
Likewise, in Finland we have the same kind
of data. In other words, we almost really have a
NOAEL from both studies that is a long-term NOAEL.
In Finland, I think Peter and I, too, was under the
impression that there was a set limit, but, in
fact, I believe that is not true, that the limit is
in fact the current international group limit.
In fact, when the gluten-free foods were
tested, all
but two were below the 100 part per
329
million; but if you look at that slide, a good many
of them were down closer to the 20 part per
million.
We have data without any uncertainty
factor really needed that suggests that if you
adhere to a gluten-free diet in those situations,
that you do quite well.
CHAIRMAN DURST: Okay. May I suggest we
move on to number three?
Do you have another--?
DR. WASLIEN: Well, no, this is still part
of this. I hope that we are counting as celiac
disease only people who have shown clinical
symptoms, right? We are not counting silent?
Because if you count silent gluten sensitivity,
you've got a much, much higher level of gluten that
is still acceptable, right?
DR. MALEKI: Soheila Maleki. Well, if
it's silent, then they are not avoiding gluten.
DR. WASLIEN: No.
DR. MALEKI: They aren't eating
gluten-free.
330
DR. WASLIEN: It said two separate groups
of patients, and I know we talked about the range
of latent to silent to acute cases. The range of
acceptable intake between acute cases or ongoing
cases and latent is very large. I don't think we
count that in the disease.
If we count only those who have "symptoms"
of celiac disease, we do have this 100 parts per
million, it looks like, level. If we are talking
about the silent, we are talking about any level;
or the latent level, we're talking about any level
because they haven't shown any symptoms yet.
I think it goes back to this. Yes, we
said yes, there were differences in the patient
groups. We need to go back and say yes, there are
differences in the patient group, and this is the
group we are looking at, the ones who have acute
conditions.
CHAIRMAN DURST: Ciaran.
DR. KELLY: Ciaran Kelly. To respond to
that, there is a lot of debate as regards whether
some, many
or all individuals with silent celiac
331
disease should be or should not be on a gluten-free
diet. I think that is far beyond what we are going
to decide.
I think what I would suggest we should
think of this as in those individuals who decide to
go on to a gluten-free diet, whether they be silent
celiac disease or be individuals with severe
malabsorption, regardless of that, in those
individuals who decide to go on a gluten-free diet,
what appears to be a safe ingestion of gluten for
them.
CHAIRMAN DURST: David.
MR. ORYANG: Yes. Just going back to the
safety factor, assuming a safety factor of one, it
would indicate that we have a hundred percent
confidence that the parts per million, the 20 parts
per million, as an example, is an absolute value
below which we don't believe people would react, or
no one faced with a challenge below that would ever
come up with celiac disease.
I don't think that we can put ourselves in
a position
to say that; there is uncertainty. We
332
do need to look at it scientifically and be able to
communicate our uncertainty to people when we do
these kinds of assessments.
The way that you do that is through
something like a safety factor. This specific
approach uses the safety factor to communicate the
degree of uncertainty we have, in other words, to
ensure that we say, "Well, maybe they could react
at five times less of a dose." Or, "Maybe that is
the reasonable dose we believe that 95 percent of
the people will react at."
Somehow we need to be able to communicate
that as opposed to just saying, "Well, this is the
value." I think somehow it needs to be
communicated and transparent. Otherwise, I wouldn't
have confidence in it if someone just told me,
"Well, 10 is it." I think it really does need to
be considered. We can keep talking about it later.
The approach is basically so that people
can have confidence in the fact that we have
clearly evaluated the data, and based on our
evaluation
this is the degree of certainty we have
333
or the degree of confidence we have in the clinical
studies that were done. I think it does need to be
considered.
CHAIRMAN DURST: Dick Durst. I agree that
we can't be absolutely certain of the level and
there has to be some uncertainty associated with it
in the same way that we can't give a number for a
threshold, that is not our job here.
MR. ORYANG: That is what I thought.
CHAIRMAN DURST: We are looking at the
approaches. I think our suggestion to the FDA is
that they do attach some kind of uncertainty
factor, but that is something that, again, requires
more study to find out what level it really needs
to be.
Marc.
DR. SILVERSTEIN: Marc Silverstein. It
seems to me that if you have observational data or
you have clinical data from a randomized trial you
will have number of patients per person years of
observation and observational studies, or if you
have two
different doses, you will have risk
334
ratios.
Obviously, in clinical trials you have a
metric, and so it seems to me that rather than
saying whatever we do in looking at the literature
we pull out a number, the number is going to come
from a clinical study.
There will be data available in the study,
either presented by the primary authors or maybe
original data may be available in addition from the
office -- and a statistician or an epidemiologist
can look at the reported data and then calculate
confidence intervals around the various metrics in
the data.
It seems to me that it is not -- yes,
there are reports of values, but we are not just
saying, "Oh, we take 20 and that's it." You walk
away, and there is no uncertainty.
Of course, there is uncertainty, but it is
retrievable, either the reexamination of the
original data from the author in the publication or
by a review of the data. It could be that these
data have
some inherent uncertainty, as most rates
335
or rate ratios or effect differences or risk
differences do.
I am not worried about getting some
estimate, because I believe that we will be able to
derive confidence intervals or measures of
uncertainty from whatever studies that these
thresholds come from.
CHAIRMAN DURST: Yes. I would like to
move on now to number three, so that we can finish
up at a reasonable time. This has to do with the
susceptibility to oats. I guess we heard that it
is pretty inconclusive at this point.
Most of the studies indicate that there is
no problem with oats, whereas there were couple of
studies they were. From the question here, if
there is no certainty as far as the susceptibility
to oats, what additional data is needed to draw
such a conclusion?
Would someone like to--?
DR. MALEKI: I'll start.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Soheila Maleki. Again, the
336
majority of the studies by far have shown that
there is no cross reactivity with oats. However,
there have been some individuals that have felt
like they had reactions to oats, and documented.
Bottom line, and according to what
Dr. Taylor was talking about, that if they are
severely sensitive and there is contamination in
the product that comes from the far, then they
could have had wheat exposure with an oat
contaminant, otherwise oat exposure with a slight
wheat contaminant that could have seemed like an
oat exposure, or they could have had a real
reaction to the oats. Either way you look at it, I
think it is going to be hard to determine until
there is more data.
Thank you.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: I don't know the
original literature, but if these studies are a
series of observational studies or case control
studies or cohort studies, there are meta-analytic
techniques
for looking for heterogeneity and
337
homogeneity in published studies, and then if there
is homogeneity, making overall assessment so you
have an increased ability to make inferences based
on multiple published studies.
It seems to me that this would be a
wonderful area. Maybe there is a published
meta-analysis of these exposures; but, if not, it
seems to me that the recommendation of the type of
data that could be helpful might be a
well-constructed meta-analysis of the published
data for the oat exposed. If we are thinking about
it today, I'm sure there is somebody already
working on it; and if not, somebody should be.
CHAIRMAN DURST: Okay. Anything else on
that one?
DR. KELLY: Ciaran Kelly. Well, just a
comment, and that is that the prospective,
published studies are all in agreement regarding
safety. The other studies that suggest that there
are maybe a small proportion who are sensitive,
essentially these case series studies are in very
limited
groups of patients.
338
Basically, those individuals appear to be
outliers, and so it is not going to be possible to
devise a study, a prospective study, to identify
the very few patients who appear to be sensitive to
oats.
The problem is you can't just make a
blanket statement, "Nobody is sensitive to oats."
It is unfortunate, but it does appear that there
may be a small number of people.
DR. SILVERSTEIN: No, I fully understand.
What I'm suggesting is if you've got 10 studies
that show there is, essentially, no numerator
events, you are going to have a more precise
estimate about how close to zero the observed data
is when you do your meta-analysis and you
appropriately weight the estimate of zero and a
confidence interval around it by the sum total of
patients in all of the studies.
CHAIRMAN DURST: Dick Durst. While it is
inconclusive, should the FDA err on the side of
caution and include oats, then, or is the
preponderance of the evidence against oats
339
sufficient?
Mark.
DR. NELSON: Yes. Marc Nelson.
Basically, you asked the question I was going to
ask, which is considering that these individuals
seem to be very few and far between, should oats be
included, and does that limit further the broader
number of celiac patients enjoying other products?
As I understood it, these individuals if
they in fact were sensitive to oats, they would
obviously demonstrate symptoms, and then, as our
clinician colleagues mentioned, they would further
work with that patient to determine what the cause
actually was.
CHAIRMAN DURST: Jeff.
DR. BARACH: Jeff Barach. I think if we
go back to where we started with FALCPA and our
charge here of looking at major food allergens,
what we have found here is a subpopulation of
people who are allergic, to celiac disease. That
doesn't really fall under my thought about a major
food
allergen. It is kind of a sideline
issue that
340
maybe is interesting and important but not for this
group.
DR. KELLY: Ciaran Kelly. I wanted to say
something similar in a different way, and that is,
that the number of individuals who may be have an
immunologic reaction to oats to cause disease is
tiny.
A much larger issue is contamination of
oats by grains and proteins that are known to be
toxic. I think we shouldn't focus on a very, very
small subpopulation and forget the big picture.
DR. COLLIN: May I comment?
CHAIRMAN DURST: Okay.
DR. COLLIN: As to the studies in the oats
business, as you mentioned, there are several
studies and they almost all are randomized. There
are some studies which are five-year studies. That
was a continuum for randomized studies.
However, there are also some studies where
in Sweden they advised the patient to take 100
grams of oats per day. I can assure you that is a
huge
amount. It was a study by Strsrud, and
they
341
succeeded. I don't remember whether it was half a
year or one year. They did not see any adverse
effects, even when the patients took five times
more than our patients are willing to take.
As I mentioned, they took 20 grams, but in
Sweden they tested in a randomized manner with 100
grams. It seems that pure oats is very, very safe.
Of course, contamination is a problem. It is also
a problem in corn and rice. If we are talking
about contaminated foods to celiac people, then we
are talking about wheat, not about oats.
However, there is that small study by
Lundin. I would actually ask, Don Kasarda, as you
mentioned oats -- wheat has been studied most
thoroughly of all -- and celiacs, would it be
possible that also some people who eat corn or rice
would have similar reactions as those three
patients? What is your guess?
My name is Pekka Collin. Sorry I didn't
mention that.
DR. KASARDA: Don Kasarda here. I think
that is an
excellent question, and one that I've
342
thought about a lot. We just don't have the
information. It might turn out that if you studied
corn that you would find, because there are many
celiac patients who say I can't eat corn, the same
thing as Knut Lundin with oats.
I would like to just make one comment on
something that Ciaran Kelly mentioned. Yes,
contamination is a big problem, but we could
possibly remove the avenin fraction, which only
makes up about 10 percent of the proteins, with RNA
interference.
We could possibly silence 90 to 95 percent
of the avenin genes or the expression of the avenin
genes to get rid of the avenin fraction. This way
at least, I mean, you still have to deal with the
contamination problem, but that is dealable with in
my mind.
However, if you don't deal with the avenin
question, if you accept the Oslo results, there is
always the question, "Well, will I react to oats or
not?" I think it would be a good thing to do, but
we don't
have any money.
343
(General laughter.)
DR. BRILEY: Margaret Briley. I think it
is kind of interesting when we start talking about
contamination. When you have to think about going
back to the farm, wheat in most part of the
United States is not really grown on the same land,
generally, as corn and rice is not there, so the
contaminations are going to have to be at the silos
and at the mill area. It might be that would be an
easy way to solve it, other than having to do an
expensive kind of study.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Soheila Maleki. One comment
to Margaret is that I virtually like impossible,
especially at the silo level.
The comment I wanted to make is that we
have to keep in mind here that these are maybe
three or four patients and outliers. We can't
forget that we are looking here at what is best for
the general and the majority of the population and
don't revert to going into two or three outliers,
even though
they might have been true cases. That
344
is something that I don't think we are charged with
looking at as Dick Durst commented.
CHAIRMAN DURST: All right. Let's move on
again to conserve time here. The next question,
number four, has to do with the risk of developing
consequences such as cancer and increased
mortality. Would anyone like to address that one?
You're shaking your heads no.
(No verbal response.)
CHAIRMAN DURST: Okay. Let's skip that
question.
(General laughter.)
DR. BRITTAIN: We haven't heard any data
on this, have we?
DR. MALEKI: Exactly. Soheila Maleki. As
far as I know just physicians, and some of these
physicians like Dr. Kelly can comment, I know they
see patients that have complications as we all
heard based on the talks they gave today that, yes,
they can lead to cancers, they can lead to other
complications and mortality and morbidity in a lot
of
different cases. Yes, clearly I would
say the
345
answer is yes, because of clinical observations.
DR. BRITTAIN: Yes, that there are equally
at risk?
(Simultaneous discussion.)
DR. MALEKI: I don't think they are all
equally at risk.
DR. BRITTAIN: Then the answer is no.
(General laughter.)
DR. MALEKI: I mean, yes, that they are
actually these cases that are seen. Are they all
equally at risk? No. Clearly, if you can put them
on a gluten-free diet or an appropriate diet, then
they don't see as many of these risks. Like I
said, the clinicians can comment more about the
percentages and the people that they see.
DR. FASANO: May I?
CHAIRMAN DURST: Okay.
DR. FASANO: Alessio Fasano here. I think
that the way that the question is posed is kind of
deceptive. Focusing on the mortality part, yes, we
know that the mortality is twice as much in the
general
population in untreated celiac. The
346
general population is not going to go on a
gluten-free diet.
I don't think this issue is as much the
mortality as the morbidity. For the mortality, of
course the answer is no, not everybody is at the
same risk.
However, if you talk about morbidity, that
also equals quality of life, I also believe that it
will be undisputable to everybody that not only do
science with celiac disease but see patients, the
answer is undisputably yes.
I mean, these people will pay a price. We
are talking about the symptomatic. Otherwise, why
do they come to you? There is definitely increased
morbidity.
This morbidity can be reversed if, for
example, we are talking about anemia. It may not
be reverted if you are talking about short stature
and you missed the diagnosis, because that person
remains short for his or her life. That is
undisputable.
I
believe, again, this question should be
347
rephrased a little bit. Mortality? No, not
everybody is at the same risk maybe. The
morbidity? Definitely, everybody is at risk.
Morbidity depends on from individual to individual.
That is the way that I see it.
CHAIRMAN DURST: Pekka.
DR. COLLIN: I a little bit disagree with
you that the mortality is twofold in celiac
disease. We have to remember the iceberg
phenomenon. It was in 1950 or 1967 it was told
that 15 percent of patients with celiac disease
eventually developed lymphoma. Now we know that it
is 1 or 2 percent.
Still, we do not detect all patients with
celiac disease. I think in terms of mortality and
also in terms of morbidity there is a clear bias to
the most severe cases. Now, what is in clinical
practice? Only the most severe cases will be
detected.
Pekka Collin it was.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc
Silverstein. If I
348
were going to make estimates or inferences about
subpopulations at risk, I would want to see a
long-term, cohort study in which I had strata of
exposures, knowing full well there is always some
misclassification in epidemiologic data, but then
want to know for each strata of exposure what was
an element of the relative risk of an outcome
whether it was death or some long-term
complications.
While I certainly believe clinically these
risks are not uniformly distributed across people,
but when you make inferences about subpopulations,
you have to be able to characterize your
populations.
You could characterize your populations
based on serology, you could base it on extent of
involvement in inflammation in the small bowel.
You could base it on other characteristics of the
patient, whether it was age or gender, duration of
clinical symptoms, whether you had specific markers
of genetic exposure -- a whole variety of types of
putative
potential variables you might look at.
349
Unless a clinical study, a cohort study,
then shows me the risk and how the exposure groups
are characterized and what those risk ratios are, I
wouldn't have a basis to say that the risks are
unequal, although we all believe in the real world,
as we get more information, the risks are unequal.
I haven't heard yet any particular
markers, even gender-specific subpopulations, of
celiac disease patients who would be at increased
risk. Although I certainly believe there may yet
be discoverable subpopulations, I don't know that
there are any that we've heard about.
MRS. MOORE: In the interest of time and
for our code of conduct, we are going to have to
ask the guest speakers to only speak when they have
been given a question.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: Yes, I guess I certainly
agree with what you just said. I guess I am
wondering what the rationale -- how does it relate
to the threshold question? Do you think the idea
is that if
there were individuals at increased
350
risk, they might want to have a separate, a
different threshold, or you they might want to base
your threshold on those individuals? Is that the
motivation for the question? Otherwise, I am not
quite sure why we are addressing it.
CHAIRMAN DURST: Steve, can you address
that?
DR. GENDEL: [No microphone.] I don't
think it is necessary at this time.
CHAIRMAN DURST: Okay.
DR. BRITTAIN: He doesn't feel it is
necessary to.
CHAIRMAN DURST: Yes, he is probably
right, we're not dealing with thresholds.
Do you want to--?
DR. KELLY: Yes, just a comment.
Ciaran Kelly. I would agree. To sort of bring it
together, what I would say is clearly individuals
with celiac disease have different outcomes.
However, we don't have information as to what
specifically determines that. As far as we are
concerned,
from a practical perspective, the answer
351
is yes, as far as we know all individuals are at
equal risk, insofar as we can't identify
individuals at greater or lesser risk. Therefore,
when it comes to terms of management, we give all
of the individuals the same advice.
DR. HEIMBURGER: Right. Doug Heimburger.
If we interpret the question to mean, Is there a
subpopulation that is at lesser risk or at lower
risk? We don't know that there is, so we need to
proceed, assuming that all patients with celiac
disease are at higher risk and none lower than any
other from any data that we have.
CHAIRMAN DURST: Good. All right, let's
move on to number five. "Is evidence of minimal
intestinal pathological change -- following a
gluten challenge, an appropriate symptom upon which
to base a LOAEL for long-term consequences?" Are
there other biomarkers that would be more accurate
predictors?
DR. HEIMBURGER: Doug Heimburger. The
clinicians here are all unanimous in saying that
the word
"symptom" in there should be changed to
352
"signs."
(General laughter.)
DR. HEIMBURGER: It has to be changed
before we can even discuss the relevance.
(General laughter.)
CHAIRMAN DURST: Consider it done.
DR. HEIMBURGER: Okay. Consider that
done.
CHAIRMAN DURST: That was your comment?
DR. HEIMBURGER: No.
(General laughter.)
DR. HEIMBURGER: What was the term Ciaran
used yesterday? It burns a hole. There was a hole
burned in my mind, and that has to be patched.
CHAIRMAN DURST: Ciaran.
DR. KELLY: I think that in terms of a
sensitive marker of celiac disease activity and the
most widely accepted marker of celiac disease
activity is probably histologic change. It goes
back to the definition of celiac disease, which
"celiac disease" is immune-mediated enteritis.
The presence of intestinal inflammation
353
and the consequences of inflammation, which are the
architectural changes that you see in celiac
disease, define the disease. Therefore, I think we
are on fairly solid ground, if we use histologic
criteria and morphometric criteria to identify a
gluten reaction.
Certainly there are other criteria that
can be considered such as clinical criteria and
systemic, immunologic responses such as antibody
responses, as well as interferon-gamma responses in
peripheral blood. I am sure I'm forgetting
something. Oh, there are other intestinal
permeability studies.
There are actually quite a lot of
biological markers that could be considered, but I
think the field considers histology to still be not
perfect, but the closest thing we have to a gold
standard.
I don't know if Alessio or Dr. Collin
would like to comment on this? No?
CHAIRMAN DURST: I think that summed it up
very well.
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(General laughter.)
CHAIRMAN DURST: Any other comments on
that one?
(No verbal response.)
CHAIRMAN DURST: Yes, I think that was
quite good.
REVISITING FOOD ALLERGENS
CHAIRMAN DURST: Okay. I think we have
gotten through these questions. I did mention that
we would like to address a few more points on the
food allergens. A couple of the members have
indicated they have some additional comments to
make.
Erica, do you have one?
DR. BRITTAIN: I would like to say, I
think I mentioned it earlier, more today but maybe
even more yesterday that it seems like if there is
a way for the information to be given, like, in
terms of the allergic patients at least, that there
are peanuts in it in some quantity," to have that
information.
However, then there should be a second
355
threshold which is the threshold that the typical
allergic patient has, "You are safe to eat it, if
you are a typical allergic patient." Kind of like
what we are hearing today about the gluten-free and
the low-gluten.
For those patients who want to take the
most conservative approach, they have the
information that there is an extraordinarily low
level of peanuts or whatever the allergen is.
There could be another standard so that a
more typical patient could say this is the level
that would be safe for them. To me that provides
more information than a single threshold, which may
be too strict for the typical patient and not
strict enough for the most extreme patient.
CHAIRMAN DURST: Okay. I think Soheila
has a comment.
DR. MALEKI: Soheila Maleki. I think it
is a lot of difference actually between the two.
In the case of peanut allergy or food allergies,
the amount that you react to or the type of
reaction you
have can drastically change from one
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exposure to the next. It is not even comparable.
Plus, the consequences can be immediate mortality.
A celiac patient can decide the level they
want to be exposed to or how much they can handle
based on experience of having gluten-free food
knowing that it is 20 parts per million or 200
parts per million. A peanut allergic person, if
you tell them it is low peanut, they won't touch
it.
You can pretty much ask anybody. I don't
know if Anne is still here? She is probably gone.
Any food-allergic person will tell you that if you
gave them a low-, two-level thing that it wouldn't
make a bit of difference to them at all, they would
definitely not touch it.
DR. BRITTAIN: Again, I'm worried that
whatever threshold, if it is a single threshold, it
depends on how you want to set it. Do you want to
set it for the most extreme person or those with
almost no reaction? Then you are limiting the food
choices of the more typical allergic patient.
DR. MALEKI: Soheila Maleki. I don't
357
think there is like a more "typical" -- a peanut
allergic person would not eat anything that said
"low levels of peanut."
CHAIRMAN DURST: Mark.
DR. NELSON: Mark Nelson. I'm thinking of
your concept in terms of working with labeling and
communicating with the consumers. My sense I that
would be more confusing and, consequently, much
less helpful than to have some threshold below
which you could effectively label it
"allergen-free" or there would be no consequences.
Now, that threshold may need to be
different for different allergens, because of the
severity of the response. I think that is really
something that would be helpful for a consumer.
Above that level, then, you would have to label the
presence of the allergen because the typical
consumer would respond.
DR. BRITTAIN: I mean, I know we heard
today someone speaking in terms of the gluten, but
she said, "I know you shouldn't label it,"
referring
to the discussion yesterday, it would be
358
a disservice to most of the community if you set it
at a level that is for the most severe."
That is what I'm concerned about. There
are kind of two --
DR. NELSON: Yes. This is Mark Nelson.
You're right, I mean, that is FDA's responsibility
to set that number. I think that from a pragmatic
and a practical standpoint and a workable
standpoint, we might end up with something that was
described about the hypoallergenic formulas for
infants.
There is a confidence level that 90
percent of the population will not respond. That
is where population is taking all of their
nutrition from one food; their total food source is
that. It serves the great majority of that
allergic population.
In working with their physician, if they
are part of that 10 percent where they do respond,
then they just have to work harder to find a better
food supply that they can accept.
CHAIRMAN DURST: Okay.
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David.
MR. ORYANG: Yes. David Oryang. Yes, not
being a biologist by background, just listening to
the speakers yesterday and today, I can see clearly
that in the case of gluten, it is easier to define
the NOAELs. Those that have celiac disease are
more willing to go for the challenge tests, because
the symptoms are not acute.
I mean, they don't have acute signs, or I
will say symptoms of disease, whereas with some of
the other food allergens -- peanuts, and so forth
-- I mean, if someone is going to suffer from
shock, you are not as likely to go for those
challenge tests. The data is not available in the
more acute allergens as it is in celiac disease.
As far as our approaches are concerned,
you see an analogy in that when you can't define
the NOAEL correctly, because of no data out there,
if you can't get enough subjects that are very
reactive to come for the challenge test, then you
can't get good data on the NOAELs.
Consequently, you can't set any safe
360
threshold directly using the safety approach, so
you have to resort to other methods. With gluten
and celiac disease, I think the safety approach
seems to be a reasonable approach. If we can work
on the issue of the uncertainty factor.
Because the challenge tests are there, I
think there is some kind of agreement as to the
parts per million. I mean, at least there are some
values that we can see have already been
established.
However, with the food allergens, I don't
think that is really there yet, because not enough
challenge tests have been done or can be done, so
we have to resort to other methods.
I am just trying to look at it from a
methodology point of view and just point out these
differences, so that we can maybe think about it
and see what other approaches can be used in
specifically the food allergens.
I think the gluten, I think all of us have
come to a consensus that the safety approach is
reasonable,
at least so far I don't feel
361
uncomfortable with it. In the other case, I think
other approaches are better served.
CHAIRMAN DURST: Suzanne, did you have--?
DR. TEUBER: Suzanne Teuber. Again, in
terms of the individual response, I think there is
a greater uncertainty factor that applies to the
individual in this case because of day-to-day
variability. Again, those factors of exercise,
alcohol, illness, unstable asthma all play a role.
We have absolutely no data on repetitive
challenges for threshold in those threshold studies
that have been done on whether there are
differences in the circadian rhythm on the
threshold, on the NOAEL or the LOAEL, in the few
studies.
I think that food-allergic patients, as
Dr. Maleki said, if there were any detectable there
based on whatever limit the FDA chooses, those
consumers will choose to absolutely pay it safe and
avoid it.
They are not going to miss it knowing
that,
"Oh, it only had 200 micrograms that I could
362
have tolerated versus 2 milligrams that I would
have reacted to."
They will be happy that it is labeled,
that it had something, and that they can avoid it
safely. It is a little different perspective of
the patient than the patient with celiac.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Well, I was just going to
briefly say that essentially if it is not useful to
the consumer then -- I mean, as Mark commented, the
consumer, it wouldn't really help the consumer out
so it is not something --
CHAIRMAN DURST: Okay. Any other
comments?
(No verbal response.)
CHAIRMAN DURST: You mean we actually
might finish up early? Oh, that's right, there was
something left over from yesterday.
Steve, would you like to comment on
question number two?
DR. GENDEL: Thank you. After caucusing
with the
rest of the Working Group, I guess what I
363
wanted to say in response to your question is we
recognize that the questions and issues are not
straightforward and they don't lend themselves to
simple yes/no answers.
We listened to your discussion that
occurred around that question and after the request
for clarification. The Working Group believes that
the Committee's discussion was responsive to the
question and provided useful information to us, and
we don't feel that there is any need for any other
clarification.
CHAIRMAN DURST: Good. Thank you.
In that case, I will adjourn the meeting
and remind you that we are beginning tomorrow at
8 o'clock instead of 8:30. See you at that time.
(Thereupon, at 5:20 p.m., the meeting was
adjourned, to reconvene Friday, July 15, 2005, at
8:00 a.m., this same place.)
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