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.