Are some cases of atherosclerosis another form of Gluten Intolerance?
                         by
             Ron Hoggan
     
      This article is intended as suggestive, only. No clinical data have 
yet been gathered on this question, so it remains purely speculative at 
this time.


     According to Tortora & Anagnostakos, atherosclerosis "..... is a
process in which fatty substances, especially cholesterol (CH) and
triglycerides (ingested fats) are deposited in the walls of medium sized and
large arteries in response to certain stimuli. It is believed that the first
event in atherosclerosis is damage to the endothelial lining of the
artery"(1). The presence of cholesterol and triglycerides in the blood does
not appear to be the primary agent of plaquing.  

     The common misapprehension that low fat/low cholesterol diets protect
against atherosclerosis and/or cardiac event, appears to be a dangerous
myth. The above text also asserts: "As it turns out, foods containing
cholesterol are not the main source of cholesterol in the blood" (1). A
growing body of evidence seems to be pointing out that the culprit in many
cases of atherosclerosis is the agent that damages the endothelial lining of
the vessel, thus beginning the entire process. 

     While many possible explanations for this complex problem have been
postulated, none has yet been fully substantiated by the myriad, often
conflicting clinical and epidemiological experience which is reported in the
literature. The author herein tenders yet another possibility for consideration:

     There is a dynamic, in individuals afflicted with celiac disease (cd)
which may offer insight into the broader realm of atherosclerosis. An 
autoimmune response, triggered by gliadin peptides in the circulatory 
system, may be causing the endothelial lesions which offer a site for 
plaque to adhere. 

     Celiac disease is a condition in which a group of proteins derived from
wheat, rye, barley, and perhaps oats, which is loosely referred to as
gluten, damages the walls of the jejunum, resulting in malabsorption, and a
symphony of other ills. In cd, rectal exposure to gluten causes "increased
microvascular permeability, as evidenced by the diffuse leakage of
fibrinogen throughout the lamina propria" (2). Increased ICAM-1 expression
has also been demonstrated in rectal gluten challenge, in celiac disease
(3). Perhaps that same agent, loosely identified as gluten, is causing
increased permeability in many vascular locations.

     The root cause of increased vascular permeability appears to be
endothelial damage (1). There is a very reasonable sequence of
immunological/biochemical events which offer a plausible explanation for the
initiating injury to the endothelium. Using celiac disease as a model to
explicate this process, is *not* predicated on the underlying assumption
that all individuals suffering from arterial plaquing are also suffering
from occult celiac disease. 

     It is the author's understanding that, in celiac disease, the
pathogenic protein molecules attach to the intercellular adhesion molecules
(ICAM) in the jejunal epithelium. The lymphocytes then attack both the
invading molecule, and the ICAM (4). The specific ICAM involved in this
process is the ICAM-1. It is worthy of note that it is the intercellular
adhesion molecule, ICAM-1, that also figures largely in the integrity of
vascular endothelium. 

     Intestinal permeability has long been accepted as a normal feature in
some healthy adults (5). In celiac disease, intestinal permeability is a
standard feature (6). If we can accept the possibility that intestinal
permeability in others may be a milder, but similar condition to that in
celiac disease, then attachment of pathogenic molecules to the ICAM-1 in the
jejunal epithelium may be the agent of damage causing the increased
permeability. 

     The above process is highly suggestive of a parallel process, following
increased intestinal permeability and subsequent absorption of the
macromolecular, protein-derived peptides into the blood. These same peptides
which may have caused the intestinal permeability now attach to ICAM-1s
(and, perhaps, other adhesion molecules) in the cardiovascular system,
resulting in an assault on the peptide/ICAM-1 complex at the endothelium.

    It is a combination of environmental factors and an autoimmune process,
which results in lesions to the endothelium, thus providing sites for the
plaquing process to begin. Ronda, et. al. have identified variations in
autoantibody activity in serum, between patients with autoimmune disease
(7). Further support for this notion is offered by Jones et. al., who
studied blood samples taken from patients with inflammatory bowel disease.
They state: ".... patients with active Crohn's disease had significantly
higher ICAM-1 concentrations" (8).
     
     Many investigators assert the association of immune inflammatory
process with atherosclerosis, in which ICAM-1 presentation is a significant
factor. (9,10,11,12,13,14)

     In one investigation of atherosclerosis in rabbits, the report suggests
the possibility of an autoimmune dynamic: "The initial alterations in the
endothelium appear to include evidence of endothelial injury and white blood
cell adhesion" (15). 

     Lutz, in a correlation of epidemiological data on coronary deaths, some
types of cancer, and the spread of agriculture through Europe shows an
inverse relationship between time a culture has had to adapt to the high
carbohydrate diet associated with agriculture, and the frequency of
civilisatory diseases. (16) The particular type of carbohydrates referred to
by Lutz happens to be that which is pathogenic in celiac disease. 

     Eades and Eades also provide epidemiological data, arising out of the
dissection and study of the remains of Egyptian mummies. They assert a clear
relationship between atherosclerosis and wheat and barley consumption in
that culture. They go further to show that hunter-gatherer cultures showed
much less evidence of atherosclerosis (17).
     
    A report on the sex hormone-binding globulin levels in 3,250 Chinese
women suggests a much greater risk of cardiac illness in predominantly wheat
consuming areas of China, when compared to subjects where rice is the
primary cereal grain in their diet. The authors conclude, in part, with the
following statement: "Significant differences in the diet of rural Chinese
populations studied suggest that wheat consumption may promote higher
insulin, higher triacylglycerol, and lower SHBG values. Such a profile is
consistent with that  commonly associated with obesity, dyslipidemia,
diabetes, hypertension, and heart disease"(19).
 
     The Merck Manual identifies Type IV Hyperlipoproteinemia as a common
disorder, which is "frequently associated with mildly abnormal glucose
tolerance curves and obesity, and may be exaggerated when dietary fat is
restricted and carbohydrate added reciprocally (with caloric intake kept
constant)....."(20). Many anecdotal reports of reduced cholesterol levels,
and improved health may be seen on many listservs and newsgroups on the
Internet. 

     The primary distinguishing feature, this author would suggest, between
celiac disease and some cases of atherosclerosis, is the specific locale of
the body's most vigorous immune response to the offending proteins found in
wheat, rye, barley, and perhaps, oats. This may be due to the number of
available receptors for gliadin molecules. Whatever the cause, a clinical
trial of a gluten-free diet seems reasonable. Because this diet has been
demonstrated to enhance the ratio of serum HDL to LDL (18), it appears to
pose no threat to the health of the patient, but may prove highly beneficial. 


                         References:

1. Tortora & Anagnostakos _Principles of Anatomy and Physiology_ 6th ed. 
   Harper & Row, New York, 1990; pages 594-597.
2. Marsh MN, _Immunopathology of the Small Intestine_ John Wiley & Sons, 
   Toronto, 1987; pages 374-377.
3. Ensari, et. al. "Time-course adhesion molecule expression in rectal 
   mucosa of gluten-sensitive subjects after gluten challenge" Clin Exp
   Immunol 1993; 92: 303-307.
4. Sturgess, et. al. "Differential upregulation of intercellular adhesion 
   molecule-1 in coeliac disease" Clin Exp Immunol 1990; 82:489-492.
5. Husby et. al. "Passage of Undegraded Dietary Antigen into the Blood
   of Healthy Adults" 1985; 22: 83-92.
6. Marsh, MN "Gluten, Major HIstocompatibility Complex, and the Small 
   Intestine" Gastroenterology 1992; 102: 330-354.
7. Ronda et. al. "Selectivity of recognition of variable (V) regions
   of autoantibodies by intravenous immunoglobulin (IVIg)" Clinical 
   Immunology & Immunopathology 1994; 70(2): 124-128.
8. Jones et. al. "Adhesion molecules in inflammatory bowel disease" Gut
   1995; 36(5): 724-730.
9. Van der Wal, et. al. "Adhesion molecules on the endothelium and 
   mononuclear cells in human atherosclerotic lesions" Am J Pathology
   1992; 142(6): 1427-1433.
10. Coufinhal et. al. "Regulation of vascular cell adhesion molecule-1
   and intercellular adhesion molecule-1 in human vascular smooth muscle
   cells" Circulation Research 1994; 74(2): 225-234.
11. Wood et. al. "The distribution of adhesion molecules in human 
   atherosclerosis" Histopathology 1993; 22(5): 437-444.
12. Ramshaw & Parums "The distribution of adhesion molecules in chronic
   periaortitis" Histopathology 1994; 24(1): 23-32.
13. Davies et. al. "The expression of the adhesion molecules ICAM-1, 
   VCAM-1, PECAM, and E-selectin in human atherosclerosis" Journal of
   Pathology 1993; 171(3): 223-229.
14. Languino, et. al. "Regulation of leukocyte-endothelium interaction
   and leukocyte transendothelial migration by intercellular adhesion
   molecule 1-fibrinogen recognition" Proceedings of the National
   Assembly of Sciences of the United States of America 1995; 92(5):
   1505-1509.
15. Richardson et. al. "Early lesion development in the aortas of rabbits 
   fed low-fat, cholesterol-free, semipurified casein diet" 
   Atherosclerosis 1994; 107(2): 165-178.
16. Lutz WJ "The Colonisation of Europe and Our Western Diseases" 
   Med Hypoth 1995; 45: 115-120.
17. Eades & Eades _Protein Power_ Bantam Books, New York, N.Y. 1996. 
   pages 12-21.
18. Vuoristo, et. al. "Metabolism of Cholesterol and Apolipoprotein B in 
   Celiac Disease" Metabolism 1993; 42(11): 1386-1391.
19. Gates et. al. "Association of dietary factors and selected plasma 
   variables with sex hormone-binding globulin in rural Chinese women"
   Am J Clin Nutr 1996; 63: 22-31.
20. _The Merck Manual of Diagnosis and Therapy_, Merck Research 
   Laboratories, Rahway, N.J., 1992, page 1047.