I had the pleasure of contributing a few suggestions and helping to edit copy on the following speech, which was written by Ron Hoggan and presented at the Annual General Meeting of the Calgary Chapter of the Canadian Celiac Association on March 15, 1997. Hoggan is a noted writer on celiac disease whose work has appeared in numerous places, including at least one paper published in MEDICAL HYPOTHESES. Hoggan is also member of this mailing list, but agreed to let me post this as the first official message for this list. Comments or questions on the following speech are invited. Dean Esmay -=- Gluten is a Dubious Luxury of Non-Celiacs by Ron Hoggan (Note: In this paper I use the term "gluten" generically, as we celiacs use it, to refer to all proteins peculiar to cereal grains.) One must wonder why, in spite of increasing lifespans in the advanced industrialized nations, modern medicine has failed to clearly identify the cause of many neurological, autoimmune and malignant diseases. The gluten-free diet is only recommended where there is a clear indication of advanced, gluten-induced disease, but is this the best advice? We may sometimes feel disadvantaged by the strict gluten-free diet we have to follow. It is costly and inconvenient. But perhaps it is those who continue to consume glutinous foods who should be concerned. Gluten, while dangerous to celiacs, has never been investigated for deleterious effects on the general population. Yet we have studies that show that hunter-gatherers following traditional life-ways do not develop the neurological, auto-immune and malignant diseases that people living in the industrialized world experience, and these people rarely eat gluten-rich foods (1,2). There is already compelling evidence connecting the advent of agriculture to bone and joint disease (3), and humankind has only been cultivating cereal grains for approximately 10,000 years (2,4), which is but a brief moment in evolutionary terms. Remember too, it is only a small population located in the Near East, that has had that length of exposure to cereal grains (4); most of the world has had agriculture for an even shorter period of time. Neurological and auto-immune diseases, as well as malignancies, are over-represented among celiacs (5), suggesting that glutens/gliadins may be a major environmental contributor to such diseases. Yet this area of investigation appears to have been avoided in research on these health problems. One must wonder at the cause of this neglect of such an important possibility. There is abundant evidence connecting the advent of agriculture with retardation of long bone growth, dental enamel hypoplasia, iron deficiency anemia (indicated by porotic hyperostosis), juvenile osteoporosis, and joint disease (18). Do these conditions sound familiar? Many are the commonest signs of celiac disease, and they were apparently the rule, not the exception, in cultures adapting to agriculture. We know, from paleontologists' study of human remains from the ancient past, that when a culture begins to cultivate cereal grains they experience substantial reductions in height, which is variously reported as 5" and 6"(2,4). Clearly, the reduction is substantial and significant. We know, too, that these remains demonstrate weaker bone structure (through reductions in peak bone-mass) and evidence of articular damage(3). Additionally, ancient Egyptians, who consumed a diet that would be considered very "heart-healthy" in our culture, have left behind mummies which clearly demonstrate atherosclerosis (7). While the evidence from the ancients is compelling, there can always be counter-arguments and debates when we are reaching back as far as 10,000 years into the past. Yet a few marginal pockets of scientific enquiry have explored a few elements of modern implications of this issue. W.J.Lutz (4) has offered an alternative perspective on the "French Paradox." (The "French Paradox" is the unusually low rate of death by myocardial infarction among the French despite quite high per-capita rates of fat consumption.) Dr. Lutz has studied the spread of agriculture through Europe. He presents a picture whereby the spread of agriculture, and thus the period of time a culture has been exposed to cereal grains, is inversely related to the incidence of cardiovascular disease. The underlying assumption, of course, is that the longer the exposure, the greater the likelihood that those who were intolerant to these grains were trimmed from the gene pool of such cultures; it seems that the less time a culture has been exposed to gluten, the greater the portion of the population that continues to develop cancers and cardiovascular disease. (Lutz also provides similarly compelling data on the rates of breast cancer mortality.) This work is confirmed by Simmoon's observation that there is a negative correlation between the frequency of antigen HLA-B8 and the length of time wheat farming has been practised in various parts of Europe (19). Another interesting study done in China produced what the investigators found to be rather surprising results(8). In this investigation, the researchers plotted the diets of more than 3500 rural Chinese women, and measured their levels of SHBG (sex-hormone binding globulins). They were very surprised to find that wheat consumption, and perhaps reduced fish consumption, were the strongest predictors of levels of SHBG, which would indicate an increased risk of cardiovascular disease. Another study has connected gluten with neurological illness (9). This group of researchers tested 53 patients with neurological illness of unknown origin for antibodies against gliadin. More than half of them (30 people) demonstrated these antibodies. Nine of those folks proved to have celiac disease, but the other 21 only demonstrated an immune response to gluten, of a type that is often dismissed as meaningless. This study has some far-reaching implications for neurological research. Yet another indication that celiacs are not the only segment of the population to suffer from the adverse effects of gluten is a study that was carried out on a very small group of siblings of celiacs(10). When subjected to rectal gluten challenge, half of the siblings showed an immune response to gluten, but these results did not correlate with the hereditary predictors of celiac disease. As for the connection between autoimmunity and cereal grains, it is clear and compelling. The theoretical perspective of molecular mimicry suggests that gliadin-derived peptides may activate the immune system against collagenous tissues, and since intestinal permeability (not celiac disease) is all that is required to allow the passage of these peptides into the bloodstream, a significant number of many types of autoimmune diseases seem likely to benefit from a gluten-free diet (11 ). In total, then, there are several studies which demonstrate (often coincidentally) that a much larger group than those with celiac disease are mounting an immune response against gluten, and that this response is causing or contributing to serious illness. Phytic acid in whole cereal grains binds to minerals, including calcium. This chemical bond is not broken in the GI tract. The net result is the binding and wasting of much-needed dietary calcium, even among those whose immune systems can tolerate gluten, and these grains may be implicated in osteoporosis (12). I would now like to draw your attention back to the issue of malignancy. _Medical Hypotheses_ will soon publish a paper I have written which suggests (among other things) that gluten may be implicated in a great many cases of lymphoma (14). Gluten has been demonstrated to interfere with the celiac patient's ability to mount an immune response to malignancies (15,16,17). In my paper, I have postulated a dynamic whereby gluten may have a similar effect in others who are simply sensitive to gluten, or who have a sub-clinical form of this disease. Ray Audette, a populist writer, has said that Stanislaw Tanchou "....gave the first formula for predicting cancer risk. It was based on grain consumption and was found to accurately calculate cancer rates in major European cities. The more grain consumed, the greater the rate of cancer." Tanchou's paper was delivered to the Paris Medical Society in 1843(20). We hear all the time about pollution in the industrial world being the source for modern man's high incidence of cancer. It is the chemical additives, we are told, in the food we eat, that causes much of the problem. Perhaps. I would like to suggest that the evidence from antiquity, the pattern of the spread of agriculture in Europe coinciding with the patterns of civilizatory illnesses, the levels of SBHG associated with wheat consumption, the high incidence of gliadin antibodies among those with neurological illnesses of unknown origin, the sensitivity to gluten among siblings of celiacs in spite of the absence of genetic indicators associated with celiac disease, and my own investigation of the literature regarding lymphoma, all point to the strong possibility that gluten is a dangerous substance to many more people than just celiacs. Sources: 1. Eaton B, Konner M, Shostak M, " Stone Agers in the Fast Lane: Chronic Degenerative Diseases in Evolutionary Perspective" _The American Journal of Medicine_ 1988; 84:739-749 2. Eaton S, Konner M, "Paleolithic Nutrition" _NEJM_ 1985; 312(5): 283-289 3. Eaton S, Nelson D, "Calcium in evolutionary perspective" _Am. J. Clin. Nutr._1991; 54: 281S - 287S 4. Lutz W J, "The Colonisation of Europe and Our Western Diseases" _Medical Hypotheses_ 1995; 45: 115-120 5. Lindeberg S, et al. "Cardiovascular risk factors in a Melanesian population apparently free from stroke and ischaemic heart disease: the Kitava study" _J Intern Med_ 1994 Sep. 6. Lewin R, "A Revolution of Ideas in Agricultural Origins" _Science_ 1988; 240: 984-986 7. Zimmerman M, "The paleopathology of the cardiovascular system" _Tex Heart Inst J_ 1993; 20(4): 252-257 8. 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. 9. Hadjivassiliou M, Gibson A, Davies-Jones G, Lobo A, Stephenson T, Milford-Ward A, "Does cryptic gluten sensitivity play a part in neurological illness?" _Lancet_ 1996; 347: 369-371 10. Troncone R, Greco L, Mayer M, Mazzarella G, Maiuri L, Congia M, Frau F, deVirgilis S, Auricchio S, "In Siblings of Celiac Children, Rectal Gluten Challenge Reveals Gluten Sensitization Not Restricted to Celiac HLA" _Gastroenterology_ 1996; 111: 318-324 11. Ostenstad B, Dybwad A, Lea T, Forre O, Vinje O, Sioud M, "Evidence for monoclonal expansion of synovial T cells bearing V Alpha 2.1/V beta 5.5 gene segments and recognizing a syntehtic peptide that shares homology with a number of putative autoantigens" 12. Lindeberg, Staffan, personal correspondence Feb, 1997 14. Hoggan R, "Considering Wheat, Rye, and Barley Proteins as Aids to Carcinogens" _Medical Hypotheses_ In Press 1997. 15. Maclaurin B, Cooke W, Ling N, "Impaired lymphocyte reactivity against tumour cells in patients with coeliac disease" _Gut_ 1971; 12: 794-800 16. Egan L, Walsh S, Stevens F, Connolly C, Egan E, McCarthy C, "Celiac-Associated Lymphoma" _Journal of Clinical Gastroenterology_ 1995; 21(2): 123-129 17. Swinson C, Slavin G, Coles E, Booth C, "Coeliac Disease and Malignancy" _Lancet_ 1983; Jan 15: 111-115 18. Armelagos G, Van Gerven D, Martin D, Huss-Ashmore R, "Effects of Nutritional Change on the Skeletal Biology of Northeast African (Sudanese Nubian) Populations" _From Hunters to Farmers The Causes and Consequences of Food Production in Africa_ Clark & Brandt (eds.) 1984; II: 37-146 19. Simoons F, "Celiac disease as a geographic problem" _Food, Nutrition and Evolution_ 1981; eds. Walcher D, and Kretchmer N, Masson Publishing, New York 20. Audette R, lowcarb listserv at: <[log in to unmask]>, March 11, 1997 from: Vilhjalmur Stefansson's book _Cancer Disease of Civilization_ 1960; Hill and Wang, New York, NY. Background Sources: 21. Davis D, "Paleolithic Diet, Evolution, and Carcinogens" _Science_ 1987; 238: 1633-1634 22. Carpenter K, "Protein requirements of adults from an evolutionary perspective" _Am J Clin Nutr_1992; 55: 913-917 23. Eaton S, "Humans, Lipids and Evolution" _LIPIDS_ 1992; 27(10): 814-819 24. Troncone R, Greco L, Mayer M, Mazzarella G, Maiuri L, Congia M, Frau F, deVirgilis S, Auricchio S, "In Siblings of Celiac Children, Rectal Gluten Challenge Reveals Gluten Sensitization Not Restricted to Celiac HLA" _Gastroenterology_ 1996; 111: 318-324 25. Marsh M, "Bone Disease and Gluten Sensitivity: Time to Act, to Treat, and to Prevent" _The American Journal of Gastroenterology_ 1994; 89(12): 2105-2107 26. Young T, Hochman R, Scopelliti J, "Celiac Disease and Arthropathy: Case Report and Literature Review" _The Guthrie Journal_ 1993; 62(3): 99-104 27. Lindh E, Ljunghall S, Larsson K, Lavo B, " Screening for antibodies against gliadin in patients with osteoporosis" _Journal of Internal Medicine_ 1992; 231: 403-406 28. de Boer W, Maas M, Tytgat G, "Disappearance of Mesenteric Lymphadenopathy with Gluten-Free Diet in Celiac Sprue" _Journal of Clinical Gastroenterology_ 1993; 16(4): 317-319 29. Mathus-Vliegen E, Halteren H, Tytgat G, "Malignant lymphoma in coeliac disease: various manifestations with distinct symptomatology and prognosis?" _Journal of Internal Medicine_ 1994; 236: 43-49 30. Rosenberg S, "The Low-Grade Non-Hodgkin's Lymphomas: Challenges and Opportunities" _Journal of Clinical Oncology" 1985; 3(3): 299-310 28. Swinson C, Coles E, Slavin G, Booth C, "Coeliac Disease and Malignancy" _Lancet_ 1983; Jan 15: 111-115 31. Wright D, Jones D, Clark H, Mead G, Hodges E, Howell W, "Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes?" _Lancet_ 1991; 337: 1373-1374 32. Gouldie R, Lee F, "Coeliac disease and lymphoma" _Lancet_ 1991; 338: 570 33. Freeman H, Weinstein W, Shnitka T, Piercey J, Wensel R, " Pirmary abdominal Lymphoma" _The American Journal of Medicine_ 1977; 63: 585-594 34. Holmes G, Piror P, Lane M, Pope D, Allan R, "Malignancy in coeliac disease-effect of a gluten free diet" _Gut_ 1989; 30: 333-338 35. Sturgess R, Ciclitira P, "Coeliac disease and lymphoma" _Lancet_ 1991; 338: 318-319 36. Egan L, Walsh S, Stevens F, Connolly C, Egan E, McCarthy C, _Journal of Clinical Gastroenterology_ 1995; 21(20: 123-129 37. Lopes P, Morris D, Galbraith P, Lillicrap D, Pross H, "Lymphoproliferative Disease of "Lak Cell" precursor Large Granular Lymphocytes in Association with Celiac Disease" _American Journal of Hematology_ 1993; 43: 116-122 38. Black, Paul "Psychoneuroimmunology: Brain and Immunology" _Scientific American: SCIENCE & MEDICINE_ 1995; 2(6): 16-25 39. Kapur A, Isaacs P, Kelsey P, "Linear IgA dermatosis, coeliac disease, and extralinear B cell lymphoma" _Gut_ 1995; 37: 731-733 40. Ilyas M, Niedobitek G, Agathanggelou A, Barry R, Read A, Tierney R, Young L, Rooney N, "NON-HODGKIN'S LYMPHOMA, COELIAC DISEASE, AND EPSTIEN-BARR VIRUS: A STUDY OF 13 CASES OF ENTEROPATHY-ASSOCIATED T- AND B-CELL LYMPHOMA" _Journal of Pathology_ 1995; 177: 115-122 41. Cooke W, Holmes G, _Coeliac Disease_ 1984; Churchill Livingstone, NY