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            "Etiology and Pathogenesis of Celiac Disease"
            ---------------------------------------------
                 a talk by William O. Dobbins, M.D.
                       summarized by Jim Lyles

Dr. William O. Dobbins is Professor Emeritus of the Gastroenterology
Section, Internal Medicine Department, at the University of Michigan.
He gave the keynote address at the CSA/USA Conference, held on
October 7-9, 1994, in Detroit Michigan.  What follows are some
highlights of Dr. Dobbins' talk.

Inside the normal small intestine there is a series of long,
finger-like projections called villi.  These markedly increase the
surface area of the small intestine making absorption more efficient.
On the surface of the villi is a layer of "epithelial cells" through
which all nutrients must pass from the intestine to the bloodstream.
In the core of each villus and in the underlying tissue are various
types of inflammatory cells.  A normal intestine has macrocytes,
lymphocytes, plasma cells that make antibodies, and macrophages.

The key lesion in celiac disease affects the lining of the small
intestine.  In the classic untreated celiac, the villi are completely
flat.  The villi cores and underlying tissue are filled with
increased numbers of inflammatory cells.  The surface epithelial
cells are severely injured.

In the untreated celiac, there are there are 10 to 15 times as many
lymphocytes in the intestinal lining than in a normal intestine.  The
role of cytotoxic type lymphocytes is to destroy what they recognize
as "foreign proteins".  They are assisted by "helper" lymphocytes and
are kept from going out of control by "suppresser" lymphocytes.  For
some reason, in the effort to fight off the gliadin molecule, these
cytotoxic lymphocytes injure the epithelial cell.  This may be an
"innocent bystander" effect, with the epithelial cells not being the
intended target; or it could be that the gluten causes the
lymphocytes to mistakenly attack the epithelial cells.  Also, the
cores are filled with plasma cells, which make the IgA, IgM, and
other antibodies.  These antibodies are primarily directed against
the gliadin component of gluten.  So what you are seeing is an
intense immune system response directed against gluten, just as if
the body were being invaded by bacteria and responding to fight it
off.  This results in poor absorption and many of the nutrients
passing through the intestines and out in the stool.

There are other conditions besides celiac sprue that can cause
flattened villi.  However, if you detect flattened villi and then
find a dramatic increase in the number of epithelial lymphocytes,
then that is almost always related to celiac disease and nothing
else.  If you don't see a marked increase in epithelial lymphocytes
when you perform a biopsy, then it is very unlikely that it is celiac
sprue and something else is causing the flattened villi.

From each epithelial cell on the villi there extend numerous
microvilli.  In an untreated celiac, these are about half of the size
of the microvilli in a normal intestine.  The epithelial cell is full
of lysosomes, which are the by-products of cell degradation that show
the injury to the cell.  At the bottom of the epithelial cell is the
basement membrane.  There is a great deal of thickening in this
membrane in the untreated celiac.  This is caused by a tremendous
deposition of collagen under the epithelial cell.  (Collagen is the
same substance that makes up scar tissue.)  This can be found in all
untreated celiacs, though it is not easy to see except in cases of
refractory sprue.  At this point it will be 20- 30 times as thick as
in an earlier-diagnosed celiac patient.

The first part of the small intestine is always the most severely
affected by celiac sprue, though damage can occur throughout the
small intestine.  After starting a gluten-free diet, the lower
portion of the small intestine recovers first; whereas the first part
of the small intestine might still show some damage a year after the
gluten-free diet is started.

In most cases, a gluten-free diet reverses the effects of celiac
disease, and the patient returns to normal both clinically and
biochemically in the intestine.  Sometimes a patient does not respond
to a gluten-free diet, or after several years of responding well to
the diet begins to have problems again.  Biopsies of these people
show that the epithelial cells are sick.  This is called collagenous
or refractory sprue.  At one time this was considered an
irreversible, and therefore untreatable, condition.  However, there
are some newer treatment techniques that now offer some hope for this
condition.

The thick layer of collagen, especially for those that have been
responding well for years on the diet and then sudden begin having
trouble, may be caused by an over-enthusiastic immune system that is
producing collagen as a by-product or innocent bystander type of
effect.

The large intestine can also be involved in celiac sprue.  An
experiment was conducted with a celiac patient that had been on a
gluten-free diet for years.  They gave the patient a gluten enema
(editor's note:  cringe!), and in a matter of a few hours he went
from being happy and amiable to a level of irritability so intense he
threw some of the equipment at a nurse.  He began experiencing
diarrhea and other symptoms of celiac disease.  This experiment may
show how some celiacs can have such a severe and immediate reaction
when they accidentally ingest some gluten.  Tests conducted 12 hours
later showed a very quick, acute response by the immune system with a
dramatic increase in the number of lymphocytes in the area of the
large intestine where the gluten had been placed

In most situations with chronic inflammation there is an increased
risk of cancer.  With celiac disease, there is a slight increase in
the risk cancer or lymphoma of the intestine.  He stressed that the
risk of lymphoma is not very great in celiac patients.  In one study,
318 celiacs were followed for many years and none developed lymphoma.
In all of the studies in which Dr. Dobbins has been involved, there
have been only one or two cases in which lymphoma developed.
Therefore, Dr. Dobbins feels that the risk of lymphoma should not be
a big worry.

(Editor's note:  It is not clear whether the studies Dr. Dobbins
refers to involved treated or untreated celiac patients.  One would
suspect the former as most patients being followed long term are
being treated.  It is probable that the risk of cancer and lymphoma
is low in treated celiacs, i.e., celiacs that are maintaining a
gluten-free diet.  It is possible that untreated celiacs, i.e.,
celiacs that continue to ingest gluten, would have a higher risk of
cancer or lymphoma of the small intestine.)

The question arises:  Why is it that only one in 3000 people have
this problem with gluten?  It is genetic in part.  In a study
involving 17 patients and their families, a biopsy was performed on
96 relatives of the 17 patients.  It was found that 11 of the 96
relatives were celiacs that didn't realize they had the disease.  Of
these 11, five had no symptoms.  From this study it was concluded
that 10% of the relatives of a celiac patient were likely to also
have celiac disease.  Later studies have dropped that figure to 2-5%.
This makes the incidence of celiac disease higher in the families of
confirmed celiacs, but not high enough to justify routine biopsies of
other family members, unless symptoms of the disease are present.

Why does the immune system of a celiac try to attack gluten and end
up damaging the epithelial layer in the small intestine?  There is a
gastrointestinal virus called adenovirus- 12 that causes a viral flu
where you feel awful for a day or so and then feel fine again.  Most
people will have 2-3 bouts of this type of virus during a lifetime.
Adenovirus-12 is almost identical in structure to the gliadin
molecule found in gluten.  So one theory is that people who are
genetically susceptible to celiac disease will have it triggered by
an attack of adenovirus-12.  Once the immune system responds to
adenovirus-12, it is thought that from then on it each time it
encounters gliadin it believes it is under attack from adenovirus-12
again and continually attempts to fight it off.

At this point, Dr. Dobbins began taking questions from the floor.

  Q: Why do untreated celiacs often get a burning or sore tongue?

  A: It is due to riboflavin and vitamin B-12 deficiencies, and
possibly other deficiencies.  Multiple vitamin supplements will
usually eliminate this problem.  Also, once you go on a gluten-free
diet, within a few weeks or months the vitamins should no longer be
needed.


  Q: What about mouth sores/ulcers for celiacs?

  A: These are more common with other types of intestinal disorders,
but they do occasionally occur with celiac sprue.  When the cause is
celiac sprue, going on a gluten free diet should eliminate these
mouth sores.


  Q: I have celiac disease.  How can I tell if my children have it?

  A: If you have celiac sprue, and you wish to know if your children
also have it, your best bet is to have the antigliadin blood test.
It is fairly accurate.  If the test comes back negative, then you
don't need to worry about a biopsy.  If the test comes back positive,
then you should discuss the possibility of a biopsy with your doctor.

     He believes there are studies which show that these antibody
tests can come back positive before any symptoms begin to show, which
makes it easier to track down celiacs that have no symptoms and
therefore don't realize they have a problem.


  Q: What about vitamin B-12 deficiency in celiacs?

  A: Vitamin B-12 is absorbed by the very last section of the small
intestine.  Most celiac patients don't even have any damage in the
last section of the small intestine; as the gluten is usually broken
down before it gets to that part of the intestine.  Therefore, most
celiac patients don't have a problem with vitamin B-12 absorption.

     If a celiac does have a vitamin B-12 deficiency, that tells us
there is severe injury along the entire length of the small
intestine.  Once a gluten-free diet is started, that injury is
reversed very quickly.  So if a vitamin B-12 supplement is required,
it won't be needed for very long; a few months or at most a year.

     At this point Dr. Dobbins cautioned the audience that he is
giving simplistic answers for the typical cases, and that individual
cases may vary.


  Q: Does going on a gluten-free diet relieve bloating, and if so,
how quickly?

  A: There are a variety of causes of excess bloating.  The classic
cause is celiac sprue, but there are many others as well.  So, if the
bloating is caused by celiac sprue, then bloating will diminish and
eventually be eliminated by a gluten-free diet.  If something else is
causing the bloating, then a gluten-free diet will not help.

     Dr. Dobbins stressed that most causes of bloating are not
serious, and result more in anxiety than in actual trouble.


  Q: I've been on the diet for about five months, and now I am
experiencing joint pain.

  A: Apparently, joint pain shows up in a lot of people with
intestinal diseases.  It seems to be caused by the immune system.
The antibodies involved in the digestive system tend to sometimes
attack the tissues of the joints.  Sometimes people recovering from a
digestive ailment go through a period in which the increased immune
response results in attacks to the joint tissues.  Eventually this
problem clears up on its own.  In the interim, the best way to treat
the pain is by taking aspirin.


  Q: Is there a relationship between eye problems and celiac sprue?

  A: There is none that Dr. Dobbins is aware of.  For an untreated
celiac with a vitamin A deficiency, there may be a temporary effect
on eyesight until the condition is reversed by the gluten-free diet.
There is no connection between cataracts and celiac disease.