From: kja@cbnewsf.cb.att.com (krista.j.anderson)
Newsgroups: misc.kids,sci.med
Subject: Cow's Milk Intolerance (was Re: Attention Deficit Disorder Resources)
Summary: cow's milk, eczema, celiac
Date: 16 Oct 92 19:11:07 GMT
Followup-To: sci.med
Organization: AT&T

Disclaimer:  I'm a layperson sometimes given to creative
             embellishments of what I read.

COW'S MILK

Milk is the food most commonly causing problems in babies and young
children.  While lactose intolerance is often a problem in adults,
in the first reference listed below, the authors pointed out that
in the infants they were studying, lactose intolerance was not a
factor since the infants could tolerate breast milk.

The milk proteins to which babies most often react are
beta-lactoglobulin, casein, alpha-lactalbumin and bovine serum
albumin.  Milk intolerance is not a true allergy, since IgE is not
the major antibody causing the reaction.  Nevertheless, because the
symptoms are so similar, the authors use the term cow's milk allergy
(CMA) to refer to it.

SYMPTOMS

The article cited three studies with the percentage of symptoms that
the infants had.  Atopic eczema is the same as atopic dermatitis.
Cyanosis is a "bluish discoloration of the skin and mucous membranes
from lack of oxygen".  [4]

Symptom        Clein       Goldman        Gerrard
---------------------------------------------------
Eczema           43%          42%             45%
Vomiting         38           27              22
Colic            31           31              20
Diarrhea         23           40              40
Irritability     19           13
Bronchitis       17                           20
Asthma           15           31              12
Constipation      3
Refusing milk     3
Apathy, cyanosis  2            4
   and collapse
Urticaria and     2            8
   angioedema 
                n=209        n=89            n=787      [1, p.345]

In addition, the authors mention rhinitis and rhinorrhea and
sleeplessness and the babies pictured with advanced symptoms had
distended abdomens and muscular atrophy.  One had overall edema.

MECHANISMS

The mechanism they hypothesize involves a deficiency of Secretory
IgA (SIgA).  But let me start at the beginning with the way proteins
are supposed to be digested.

Protein Digestion

Proteins are made of peptide chains held in a helical structure by
hydrogen bonds.  A secondary structure may be held in place by other
bonds such as disulfide bonds.  In the stomach, proteins are broken
into peptide chains with the enyzme pepsin.  (I'm not sure if the
stomach acids and those in saliva do any denaturing.)  Peptides
are chains of amino acids with an amine group (-NH2) at one end and
a carboxyl group (-COOH) at the other.  The bond between the amine
group of one amino acid and the carboxyl group of the next is
called a peptide bond.

At the bottom of the stomach is the pyloric sphincter which remains
closed while there are solids in there.  Once everything is
liquified into chyme, the pyloric sphincter opens and the chyme
enters the small intestine, the beginning of which, the duodenum,
neutralizes the stomach acids.  The pancreas and liver add enzymes
and bile to the chyme and it passes on to the next part of the small
intestine, the jejunum.  Here, villi line the walls and glands
secrete more enzymes, such as maltase, sucrase, lactase, peptidase
and lipase.

The peptidase breaks the peptide chains into amino acids which pass
into the blood stream through the capillary network in the villi.
These tiny finger-like villi greatly increase the surface area of
the small intestine to make absorption efficient. 

The amino acids now in the blood stream are taken to the liver which
reconstructs proteins from them.  When I first read this I wasn't
sure why the bloodstream couldn't handle proteins directly, but what
I assume is going on is that the liver tacks on some special HLA
(human leukocyte antigen) peptides to mark them as "self" and
therefore safe whereas the proteins from food can be targeted as
invaders by the immune system. 

Body cells can either metabolize proteins they get from the
blood, or break them into amino acids and use them to rebuild their
own proteins.  Either way, nitrogen products are left over,
converted to urea and dumped into the blood.  Later, the kidneys
remove urea and other wastes from the blood.

Undigested Proteins

In everyone, some proteins get past the digestive enzymes, some of
which simply pass through, but others of which stick to the inner
surface of the small intestine.  I guess they may stick due to
electrostatic charges, but the intestinal cells may also have
receptors for particular proteins.  Usually the proteins are too
big to pass into the capillaries of the villi, but if there is an
inflammation response going on, the capillaries will be dilated and
the unmarked proteins may get into the bloodstream. 

In most people there is Secretory IgA to many of the proteins they
normally eat and this IgA complexes with the proteins, drawing
phagocytes that engulf and digest them into harmless products.  The
IgA-protein complexes are big and hence less likely to get into the
blood stream.

SIgA Deficiency

If there is not enough SIgA to do the job, IgE and IgG antibodies
may develop to do battle with the proteins.  These antibodies are
more destructive than IgA.  IgA doesn't usually trigger the
complement cascade, but IgG does.  The complement cascade results in
a chain of chemical reactions that explode the cell to which the
antigen is stuck.  In this case, the antigen may be stuck to a cell
of the villi.  IgE, which is a protein also containing some
carbohydrate, doesn't normally trigger the complement cascade
either, but it can do so via an alternative pathway triggered by 
carbohydrate if it is present in large enough quantities.

In addition, IgE will cause mast cells and basophils to disintegrate
and the resulting mediators will dilate the capillaries and
otherwise contribute to the inflammation.  The complement cascade
also dilates the capillaries and produces anaphylatoxins that
disintegrate mast cells which release mediators that cause smooth
muscle contractions, in this case the small intestine, resulting in
diarrhea.

The worst result of this destructive means of getting rid of
foreign proteins is that the villi can be destroyed.  Biopsies of
the small intestines of people with advanced celiac disease (wheat
gluten intolerance), for example, show no villi at all; the
intestinal walls are completely smooth making the surface area so
limited that nutrients can't be adequately absorbed. 

Peyer's Patches

As food passes through the terminal ilium before it gets to the
colon, some lymph nodes called Peyer's patches sample the
contents.  According to reference 6 below, these patches induce
production of suppressor T cells and stimulate production of IgA in
response to the antigens they sample.  One hypothesis of IgE
allergies is that they are caused by a deficiency in suppressor T
cells resulting in a reaction at too low a concentration of the
antigen.

Mechanism Summary

The description above was still a hypothesis for both cow's milk
allergy and celiac disease in 1987 and I assume it is still a
subject of research.  In celiac disease it is also thought by some
that gluten may be acting as a lectin and that an IgE mechanism may
be involved that makes the intestine leakier.  It should be noted
that the role of IgE in cow's milk and gluten intolerances is *not*
popularly accepted at this time.  That celiac disease involves Type
III hypersensitivity (the IgG mechanism above) is well accepted,
but there is not yet general agreement on the details.

OTHER ALLERGENS

When babies are intolerant of milk, they may also develop other
sensitivities, especially to soy, egg, citrus fruits and tomatoes.
Allergy to egg white is a classic allergy with IgE detectable in
RAST tests and so on.  If there is IgE involved in cow's milk
and/or gluten intolerance, it is not in amounts large enough to be
detected by RAST tests.

Eczema

The most common foods causing eczema are milk, egg, peanut, citrus
fruits, artificial colors and preservatives, nuts fish, wheat,
tomatoes, lamb, chicken and soy.  An IgA deficiency is also a
hypothesis for eczema in general, with IgG and IgE complexing with
proteins in the bloodstream resulting in "damage to the superficial
dermal microvasculature, leading in its turn to oedema and
infiltration of the dermal papillae by inflammatory cells." [2,p.598]

Also note that eczema can be caused by inhalent allergens,
especially the fecal matter of dust mites, to which there are
desensitizing injections available.  Of all the allergic symtoms,
eczema is associated with the greatest number of offending
allergens and the greatest levels of IgE and eosinophils.

Celiac disease is more likely to have gastrointestinal symptoms and
problems with malabsorption but can also include symptoms normally
associated with classic allergies.

TREATMENT

The best treatment for intolerance to cow's milk and other major
intolerances is avoidance.  In particular, as another poster
mentioned (Mark Flebowitz? sorry if name is wrong), the intestines
of infants are leakier for the first year, so it is better to
introduce cow's milk after that age. For minor intolerances, sodium
cromoglycate (SCG) might be helpful in adults but I don't know if
it can be given to infants.  Since SCG works by inhibiting
degranulation of mast cells it would only work if IgE were
involved.  Eczema is also a sign of dry skin and it can be helpful
to keep the skin moist.

References

1. Gerrard, John W., "Cow's Milk and Breast Milk", in Brostoff,
   Jonathan and Challacombe, Stephen J., eds., _Food 
   Allergy and Intolerance_, London:Bailliere Tindall, 1987.
2. Brostoff, Jonathan and Challacombe, Stephen J., eds., _Food
   Allergy and Intolerance_, London:Bailliere Tindall, 1987.
3. Asimov, Isaac, _The Human Body_, NY:Penguin, 1963/1992.
4. Glanze, Walter D., et al, eds., _The Mosby Medical Encyclopedia_,
   NY:Penguin, 1985/1992.
5. Joneja, Janice Vickerstaff and Bielory, Leonard, _Understanding
   Allergy, Sensitivity & Immunity_, NJ:Rutgers University Press, 1990.
6. Brostoff, Jonathan and Gamlin, Linda, _The Complete Guide to
   Food Allergy and Intolerance_, NY: Crown Publishers Inc., 1989.
-- 
Krista Anderson, att!ihlpf!krista