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Here are two items relating to the presentation made by Dr. Alesio Fasano
to the CDF membership in May. The first is a light, and I hope fun-to-read
review, mentioning some of the more fascinating points mentioned. The
second is a long summary that was done using a poor tape in conjunction
with two fine summaries that are in distribution: Jim Lyles and GIG's. In
the second part where the tape player batteries died, I relied heavily on
those summaries and my own elaborate written notes.  I hope I captured Dr.
Fasano's meaning, as well as the wonderful way he puts things.

Mary Courtney's Review of May 1995 CDF Meeting
Dr. Alessio Fasano's presentation on Celiac Disease

Dr. Alessio Fasano's presentation to Celiac Disease Foundation members at
the May meeting was no dull villi slide show. Instead, there were plenty of
insights and many glimpses into the future of celiac disease research. Here
are some highlights of a talk that featured something for everyone's
interests. (Due to the informal nature of the presentation, no research
sources are given for data.)

For those intrigued by their medical family tree, Dr. Fasano reports a 15%
incidence of villous atrophy in first degree relatives of persons with
celiac disease. If a (monozygotic) twin has CD, there is a 75% chance that
the other twin does too.

If you've ever wondered how our genes may be programmed for celiac disease,
European research shows a high recurrence of certain HLA types ("genetic
fingerprints") in celiacs, but--and here's the big question mark--there are
some celiacs who don't test positive for these "fingerprints." Keep an eye
on the medical literature for the rest of that story.

Celiacs who became symptomatic after having the flu, might be interested in
reports of adenovirus 12 which may be more common in persons with celiac
disease. Is adenovirus a trigger for adult CD onset? Another development to
watch.

Have your friends ever asked you what the prevalence of CD is? If you di
dn't know, you're not to blame. U.S. research is so sparse that there are
no statistics here. In Europe, where screening for CD is more common,
epidemiologists report incidence rates as high as 1 in 300.

Anyone diagnosed as an adult might recall having an assortment of health
complaints before ever experiencing the classic gastrointestinal or
dermatological symptoms. Dr. Fasano's main emphasis seemed to be that there
must be a change in the perception of how celiac disease presents itself.
In one of his slides, a pyramid illustrated a new way of perceiving celiac
disease clinical presentation. (The data is based on European immunological
studies.)
[snip--the formatting doesn't work on an ordinary email file]

The celiac disease that physicians in this country are trained to
recognized is the typical form which in Europe occurs in approximately 1 in
2500. Dr. Fasano defined the atypical form as that found in those who have
latent onset of the disease (typical + atypical = 1 in 1500). Asymptomatic
celiacs are discovered when relatives of celiacs are tested. Latent celiacs
are defined as those who have one of the companion diseases (other
autoimmune disorders such as diabetes, arthritis, Sjogren's syndrome,
thyroid disease, collagen vascular disease, and liver disease). When
combined, these various presentations of CD reach as high as 1 in 300.

Celiacs interested in the amazing interconnectedness of various bodily
systems will want to watch for research that studies these connections. Dr.
Fasano mentioned how toxins pass through the intestinal wall to affect the
mouth, kidneys, skin and joints. In his work with children, Dr. Fasano has
looked for gliadin antibodies in children with problems as varied as short
stature, dental enamel defects, epilepsy and erratic behavior. He presented
a theory on how gliadin may interfere with the normal binding of
casomorphine in the brain. (think: endorphins).

Those interested in how testing has changed since their biopsy learned how
blood tests are used, and that the biopsy is still the most reliable
diagnostic tool. Each year, Dr. Fasano uses the IgA antibody test on his
pediatric patients to see if they are complying with their diet.

It is clear that Dr. Fasano's goal is that even celiacs without severe
symptoms will someday be diagnosed promptly so that they may avoid chronic
ill health, a host of long- and short-term health problems, as well as
increased health care costs. He reminded CDF members that at the five-year
gluten-free mark, their risk for intestinal lymphoma becomes the same as
the general population.

Thanks to CDF for hosting an interesting and personable speaker normally
only heard at national conferences. CDF members are grateful for Dr.
Alessio Fasano's dedication to educating the medical community about celiac
disease.


Dr. Alessio Fasano
Presentation to CDC Membership
Summary
Los Angeles, May 19, 1995
[from audio tape, notes and printed sources]

Celiac Disease, or Gluten Sensitive Enteropathy, is a permanent condition.
 You got it, you got it forever.

The two major components of the disease are:
1.      A genetic background.  You have to be predisposed to have the disease.
 The genetic background plays a major role, as I will show you.
2.      You have to have also some environmental factors that will trigger the
disease to a full expression that can be typical or atypical.

Let's look at the environmental factors.  Here [slide] is an overview of
the family of grains.  The ones involved in the onset of the disease are
the four there on the left side:  wheat, rye, barley, and oats.  That also
gives you the idea of the four grains responsible for the disease: the
grains themselves are genetically related.

What is the poison?  Gliadin is chemically a prolamin, the alcohol soluble
part of grains.  So, gliadin is the alcohol soluble fraction of wheat.  So,
<prolamin> is the more appropriate way to define the entire family of
alcohol soluble prolamins that are dangerous to celiacs.

Environmental factors are not end of the story.  The genetic background is
crucial.  This [slide] is data that we generated years ago in Europe.
 Unfortunately, the data available in the States is very limited.  There is
no scientific interest in the States, because there is a general belief
among our physicians, a gut feeling, I should say, that celiac is not here.

Looking at the general population, there is a 2 to 5% risk of developing
classical (overt) celiac disease.  The rate it occurs can be as much as 10%
to-in the latest reports-up to 15% of first degree relatives of a patient
with typical celiac disease, with villous atrophy.  In other words, 1.5 out
of 10 people that belong to your family may be celiac and they don't know
that.  Another thing that suggests the crucial role of genetics is that
there is a important concordance of the disease among monozygotic twins
that is up to 75%.

HLA [Human Leukocyte Antigens] is a genetic fingerprint.  What is being
described in Europe is a high occurrence of certain HLA types in those with
celiac disease.  In Class I, between 70 and 80% are positive for HLA-B 8.
 In Class II, 70 to 80% are positive for HLA-DR 7, while HLA-DQx2 appears I
about 95% of those with celiac disease.  But since there are a certain
proportion of biopsy-proven persons with celiac disease who do not test
positive for these antigens, there must be more to the story.

The genetics are crucial, because what we believed were the landmarks of
the disease are not the reality anymore.  Chronic diarrhea, weight loss,
etc. is not the only way that celiac disease can express itself.  The
severity of the disease is also variable.  There are people who were
exposed to gluten, and in a matter of a few weeks or a month have the full
expression of the disease.  Other people have to be exposed to gluten for
years and years and years.  (Of course, you have to understand, that if you
'became' celiac at age 65, that does not mean that you've been healthy for
the previous sixty years.)

The HLA is not just a fingerprint.  There is a reason why people with a
particular HLA develop the disease.  The enterocytes, the cells on the
lining of the small intestine have some receptors which are 'programmed' by
the Class II antigens to recognize gluten.  The gluten will bind to HLA
receptors that are present on enterocytes.  When this binding occurs, there
is a kind of migration to the other side of the cells.  This
receptor-gluten complex will reach cells in the bloodstream.  They are like
lymphocytes.  They are responsible for the production of toxic compounds
that are ultimately responsible for tissue damage in the intestine.  The
HLA Class II profile plays a major role, because it's kind of a gate
through which gluten can reach inflammatory cells that eventually will turn
on an auto-immune process.  The T-cells work so well that they are not able
to discriminate between external substances (that they are intended to
attack to protect our body) and internal substances.  Gluten triggers an
auto-immune attack.  (Note that part of the energy that normally is there
to produce antibodies against flu, for example, is not available.)

In the mid-seventies, the European scientific community created a task
force to determine the prevalence of the disease and the most common
presentation of the disease.  This approach created a much better
understanding of the disease and a much better management of the disease.
 [Prevalence on slide map:  from 1 in 500 in Scandinavians to 1 in 300 in
Ireland.]

What is the prevalence of the disease in the United States?  With sporadic
reports from a very limited area, you can't make any kind of global
statement in terms of prevalence, unless you go for a multi-center study.

In Europe, there are changes in the past ten or twelve years in terms of
prevalence of the disease there because of the awareness of the total
presentation of the disease.  There's a way to classify the total
presentation of celiac disease.  You have symptomatic cases with typical
presentation (diarrhea), and atypical (short stature, anemia, for example).
 Unless the endocrinologist or pathologist has knowledge to think about
celiac disease, the diagnosis will be missed for years.

There are also asymptomatic patients with celiac disease who have no
symptoms whatsoever, but already have tissue damage in the small intestine.
 Then, there is a latent form where the tissue damage has not occurred yet,
but which can be discovered biochemically.  This latent form will later
develop into typical or atypical form of celiac disease.  [Dr. Fasano
mentioned delayed exposure to gluten in infancy in study of Danish
prevalency statistics as a possible cause of missed diagnoses.]

The typical form is just the tip of the iceberg.  In Italy, when we counted
just the typical (classical) form of celiac disease, we were diagnosing 1
in 2,500 people with celiac disease.  When screening programs became
available with the anti-gliadin and anti-endomysial antibodies, and we
looked at all forms of celiac disease, the incidence is more like 1 in 300
to 500.  [Cumulative Prevalence Pyramid: Typical: 1 in 2500; add atypical:
1 in 1500; add the asymptomatic form: 1 in 1000; all presentations of
celiac disease including latent form: 1 in 300-500.]

By crossing through the intestinal wall, celiac disease affects many other
organs:  the mouth, with stomatitis; the kidney, with nephropathy; the
joints and bones; and the skin, with dermatitis herpetiformis (DH).  It is
universally understood in Europe that dermatitis herpetiformis equals
celiac disease.  About 5% of those with celiac disease have the skin
lesions, too.  Immunocomplexes with gliadin antibodies are present in the
skin of those with DH.  The erythematacous blisters tend to be symmetrical
in distribution, and located on the elbows, buttocks, knees, back and/or
face.  [Dr. Fasano later mentions cracked lips as a possible celiac disease
symptom.]

Affects on the hematological system include: Anemia (Iron, Folate/B-12
deficiency); Leukopenia; Thrombocyotopenia; Vitamin K deficiency.

Another type of clinical presentation that should be considered atypical is
short stature.  In Europe, reports have been published which state that up
to 20% of short stature is due to celiac disease.  At the University of
Maryland, we have a serum bank where 20 years of serum samples are stored.
 I took advantage of this serum bank and had my colleagues pull samples
from all those children who were diagnosed with growth hormone deficiency
and who were followed in the growth failure clinic.  These serum samples
were analyzed for IgG anti-gliadin antibody.  Their medical records were
examined to see what their growth pattern was.  Two populations were seen:
 'good growers' and 'poor growers.'  The 'good growers' who responded well
to growth hormone therapy, all had antibody levels within normal range.
 Among those who did not respond to growth hormone, a large proportion had
high titers of anti-gliadin antibodies.  Of those in the high antibody
group who consented to undergo small intestinal biopsy, all were found to
have celiac disease.  Now, at the University of Maryland, children admitted
for growth failure are routinely tested for anti-gliadin antibodies.

Osteoporosis starts in childhood with Calcium and Vitamin D deficiencies.
 The potential health implications include needless bone fractures.

Enamel dysplasia is also common among those with celiac disease.  This
discoloration is due to gliadin antibodies along with gliadin in the matrix
of the teeth.  You can actually follow the evolution of celiac disease by
following the lines in the teeth, especially in those who have undergone
gluten challenge.

The central nervous system may also be affected.  Epilepsy occurs twenty
times more often in persons with celiac disease than those in the general
population.  Calcium deposits form in the brain because of a deficiency of
folic acid.  In one child, the calcifications disappeared after 1 to 2
years on a gluten-free diet.  Other ailments include schizophrenia,
dementia, and cerebellar degeneration.

The more we study celiac disease, the more we realize that it is an
immunological disorder which is associated with other immune-based
disorders.  Some of these are:  diabetes mellitus (Type I), thyroid
disease, Sjogren's syndrome, rheumatoid arthritis, collagen vascular
disease, and liver disease.  The genes responsible for diabetes, for
example, travel back-to-back on the same gene.

In pediatrics, another very dramatic presentation is mood changes.  One of
our studies suggests that gliadin may actually act on the brain by
interfering with the binding sites [opiate receptors] for B-casom orphine
[endorphins].

Persons with asymptomatic celiac disease complicate the problem.  Since
they feel fine, they are difficult to find.  One source is among the
first-degree relatives of those who have been diagnosed.  About 10% of them
will show small intestinal damage.  First, we screen parents, siblings and
children of those with celiac disease using the anti-gliadin and
anti-endomysial antibody blood tests.  Those who test positive are
biopsied.  Any who show damage to the lining of the small intestine are
diagnosed with celiac disease and place on a gluten-free diet.  It is
crucial to treat these people as true celiacs!

The diagnosis protocol has changed over the years.  Even though the
antibody screening is not totally reliable (still produces false
negatives), it has reduced the need for multiple biopsies, permeability
tests, etc.  The new protocol:  If you are positive for both the IgA and
IgG anti-gliadin and the IgG anti-endomysial antibodies, your chance of
having celiac disease is about 99.6% (positive predictive value).  Although
the biopsy is still necessary, the antibodies are certainly very useful in
identifying who should get biopsies.

For pediatric diagnosis of celiac disease:
If the patient has:
a history and clinical picture suggesting celiac disease
laboratory data (including antibodies) consistent with celiac disease
a clear histological picture of crypt hyperplasia and subtotal villous
atrophy
obvious clinical and laboratory response to a gluten-free diet
an age of more than two years
possibility of having cow milk protein sensitivity has been eliminated
responds to gluten-free diet
then, the patient has gluten sensitivity enteropathy for life.

Antibodies can easily be used to check for compliance to the gluten-free
diet.  At our clinic, we now check IgA antibodies every year.

Why is it so critical to make a diagnosis and keep people free of gluten,
even if they are asymptomatic?  Chronic ill health and increased health
care costs.  Permanent stunted growth.  Skeletal disorders, such as
osteoporosis.  Infertility.  The mortality rate is twofold greater in
persons with untreated celiac disease.  I am sure you are also aware of the
increased risk of malignancy in those with celiac disease who continue to
be exposed to wheat, rye, oats or barley.  The incidence of intestinal
lymphoma is much higher in celiacs chronically exposed to gluten than
persons in the general population.  Those who strictly follow their
gluten-free diet, however, can expect a reduction in their risk, so that at
the five-year gluten-free mark, their risk factors are the same as the
general population.