Celiac disease has been recognized for centuries (Dowd and Walker-Smith 1974) by physicians aware of its major symptoms of diarrhea and gastrointestinal distress accompanied by a wasting away in adults and a failure to grow in children. The Greek physician Are-taeus (first century A. D.) called the condition coeliac diathesis - coeliac deriving from the Greek word koeliakos, or abdominal cavity. The British physician Samuel Gee provided what is generally considered the first modern, detailed description of the condition, which he termed the coeliac affection in deference to Aretaeus, in a lecture presented at St. Bartholomew’s Hospital in London (Gee 1888). At present, celiac disease (or, especially in Britain, coeliac disease) is the most commonly used term for the condition, although various others may be encountered, including celiac syndrome, celiac sprue, nontropical sprue, and gluten-sensitive enteropathy.
There were perceptions, certainly since Gee’s time, that celiac disease was a consequence of, or at least affected by, diet. Gee (1888: 20) noted that “[a] child, who was fed upon a quart of the best Dutch mussels daily, throve wonderfully, but relapsed when the season for mussels was over.” Such associations with diet led to wide-ranging dietary prescriptions and proscriptions (Haas 1924; Sheldon 1955; Weijers, Van de Kamer, and Dicke 1957; Anderson 1992). Some physicians recommended exclusion of fats - others, exclusion of complex carbohydrates. At times, so many restrictions were applied simultaneously that it became impossible to maintain a satisfactory intake of calories.
Because dietary treatments of celiac disease were of limited effectiveness, the food connection remained a puzzle until the end of the 1940s when a Dutch physician, W K. Dicke, observed that removal of wheat from the diet of celiac patients led to dramatic improvement (Dicke 1950). It eventually became clear that the efficacy of the various diets recommended prior to Dicke’s discovery was in proportion to the extent that wheat was excluded from them. Initial fractionation studies pointed to the gliadin protein fraction as being most harmful to celiac patients (Van de Kamer, Weijers, and Dicke 1953).
Soon after Dicke (1950) reported the harmful effects of wheat on celiac patients, a series of investigations indicated that rye, barley, and oats were also harmful, whereas rice and maize (corn) were not (Dicke, Weijers, and Van de Kamer 1953;Van de Kamer et al. 1953; Weijers et al. 1957). With children, and most adults, the exclusion of wheat, rye, barley, and oats from the diet usually brought about a complete, or largely complete, recovery.
During the 1950s, the development of intestinal biopsy techniques (Shiner 1956; Crosby and Kugler 1957; Brandborg, Rubin, and Quinton 1959) enabled pieces of tissue to be recovered from the intestine for examination and testing, and it was recognized that ingestion of wheat and related grains often resulted in damage to the intestinal mucosa, including the absorptive cells, or enterocytes, lining the interior surface of the intestine. The enterocytes are responsible for the absorption of almost all nutrients; the damage to them provided a basis for the gastrointestinal symptoms and malabsorption.
Familial associations, as well as its rarity among the Chinese, the Japanese, and blacks in sub-Saharan Africa (McNeish et al. 1974), indicated a likely genetic basis for celiac disease. Subsequent findings of strong associations with particular histocompatibility antigens supported this possibility (Kagnoff 1992) and, along with the presence of circulating antibodies to wheat gliadin proteins in patients on a gluten-containing diet, suggested that an abnormal immune response initiated intestinal damage in susceptible individuals.
A detailed understanding of the basis for celiac disease remains to be achieved. Neither the initiating event triggered by wheat gliadin proteins or products derived from them by digestion, nor the mechanisms leading to tissue damage in the small intestine following ingestion of wheat are completely understood. On the basis of current knowledge, it appears that celiac disease has resulted from the convergence of various evolutionary developments: These include human evolution (especially evolution of the immune system), the evolution of wheat and related grasses, the evolution of the protein structures apparently unique to wheat and closely related species, and the evolution of culture - specifically the development of agriculture and the spread of wheat farming (Figure IVE.2.1).
Figure IV. E.2.1. Evolutionary factors combine to produce celiac disease.
Geographical Distribution of Celiac Disease
Celiac disease is commonly thought of as largely afflicting people of European ancestry, and reports of cases among the Chinese, the Japanese (Kihara, Kukida, and Ichikawa 1977), and black Africans are sufficiently rare as to make it unlikely that this assumption is incorrect (also see McNeish et al. 1974; Simoons 1981). However, studies throughout much of the world either are inadequate or have yet to be done.
There are some parts of Asia where rice, a harmless grain (see ahead for definitions of harmful grains), is the predominant cereal grain in the diet, and in some parts of Africa, teff and millet - likely to be harmless cereal grains - predominate. To what extent a low intake of wheat, rye, barley, and oats in Asia and Africa contributes to the apparently low incidence of celiac disease is unknown. Furthermore, in some parts of the world - the United States, for example - medical personnel may have only minimal knowledge of celiac disease and fail to recognize it, whereas in Britain and much of Western Europe, physicians are much more attuned to its signs, which may be highly varied. The likelihood of failure to recognize celiac disease is doubtless substantially greater in some Asian and African countries and may contribute to the perception that it is rare in these places. The difficulties in diagnosing celiac disease and in developing statistical information about its incidence and prevalence have been discussed by R. FA. Logan (1992a, 1992b).
The incidence of celiac disease varies throughout Europe and with time. For example, crude incidence rates (number of cases per 1,000 births) in various parts of Sweden currently range from about 2.2 to 3.5 per 1,000, whereas in neighboring Denmark, the rate is about 0.1 per 1,000 (Greco et al. 1992). Furthermore, the incidence varies with time, possibly indicating the contribution of some environmental factor. Prior to 1983, incidence of the disease in Sweden was much lower, but it began to increase at about that time, and it has been speculated that an increase in the amount of gluten in infant formulas was responsible for the rise (Maki et al. 1992). The suggestion has also been made (on the basis of screening of blood donors for antigliadin antibodies) that the incidence of celiac disease in Denmark may be similar to that of Sweden although largely undiagnosed (E. Grodzinsky, personal communication, cited by Ascher and Kris-tiansson 1994).
Ireland was reported to have a high incidence of celiac disease - about 4 per 1,000 births during an 11-year period prior to 1973, particularly in the west near Galway (Mylotte et al. 1973). Since that time, however, the incidence among children under the age of 12 has fallen by 62 percent (Stevens, Egan-Mitchell, et al. 1988), in contrast to the rise experienced in Sweden. The reasons for the decline in Ireland are unclear; they perhaps involve dietary changes such as an increase in the frequency of breast feeding or a decrease in the early introduction of grains to the diet of infants. Or some other undefined factor, perhaps a change in the type of viral infections prevalent in the population, may be involved.
The incidence in the United States has not been established, but a recent study of a Minnesota population (Talley et al. 1994) estimated the incidence as 0.01 per 1,000 person-years and the prevalence at 1 per 5,000. Because of the diversity of the U. S. population, which includes significant numbers of people having African, Chinese, or Southeast Asian ancestry, it might be expected that prevalence would be less than that of Europe as a whole, which is about 1 per 1,000. Whether the prevalence among U. S. residents of European extraction approximates that of European populations remains to be established, but it would be surprising to find that it is different.
Most studies of incidence and prevalence have focused on clearly recognizable disease resulting from significant damage to the absorptive epithelium of the intestine, often diagnosed by intestinal biopsy to show loss of villous structure and followed by removal of wheat and other harmful grains from the diet to demonstrate recovery of mucosal structure and function. It is becoming obvious, however, that there are many people who have subclinical celiac disease (Marsh 1992a), so that the true incidence of celiac disease may be at least two to three times greater than that represented by those with significant damage to the epithelium.
Origins of Agriculture and Wheat Farming
A diploid wheat and barley were likely to have been among the first crops cultivated by humans who were spearheading the Neolithic Revolution about 10,000 years ago. Wild diploid species of wheat, probably Triticum boeoticum and Triticum urartu, or possibly the wild tetraploid species Triticum dicoc-coides, had most likely been harvested by hunter-gatherers for some considerable time. These species of Triticum were probably extant for perhaps 16 million years (Shewry et al. 1980) before domestication occurred (Harlan 1977) and thus those who pioneered in cultivating it probably had a reasonably good understanding of the plant’s life cycle. The origin of wheat cultivation is likely to have been somewhere in the Fertile Crescent area of the Middle East, perhaps near Jericho.
Frederick Simoons (1981) has discussed the possible effects of the spread of wheat farming (from likely centers of origin in the Middle East) on populations with members genetically susceptible to celiac disease. He used a genetic marker for celiac disease and compared the incidence of this marker in populations throughout the world with the incidence of celiac disease. The marker selected was a human leukocyte antigen, HLA-B8 (a class I major histocompatibility complex [MHC] protein). HLA-B8 had been demonstrated to have approximately threefold greater occurrence in celiac patients (Falchuk, Rogentine, and Strober 1972; Stokes et al. 1972) than in normal individuals of the same populations, although it is now known that certain class II MHC proteins show even better correlations and are more likely to play a direct role in the processes of celiac disease (Kagnoff, Morzycka-Wroblewska, and Harwood 1994). The data available to Simoons were, however, limited to HLA-B8.
Simoons reasoned that the greater rate of occurrence of celiac disease among people with the HLA-B8 antigen gave researchers a tool to use in their study of the illness. By determining the distribution of the antigen among human populations, researchers could predict which people were more at risk of developing the disease. Although there are exceptions, such that populations without HLA-B8 may yet have high levels of celiac disease (Logan 1992a), the assumption appears to have general validity.
It turned out that there were two geographic centers in Old World populations with noticeably higher frequencies of HLA-B8, one in western Europe, centered about the British Isles, and one in northwestern India, centered about the Punjab region. These regions also fell within the major areas of wheat cultivation, and in both there had been reports of relatively high incidences of celiac disease. They also represented, to a considerable degree, the boundaries of the spread of wheat farming throughout its geographical range up to relatively recent times (in this analysis, about 1000 B. C.) from its point of origin.
There appeared to be a gradient in the incidence of HLA-B8 throughout the range of wheat cultivation, such that low levels of the antigen were found at the likely origin of wheat cultivation and higher levels at the periphery. Simoons (1981) assumed that high levels of HLA-B8 were once typical of peoples at the origin and suggested that the gradient observed from the center to the periphery might well reflect the effects of a selective genetic disadvantage to members of the population carrying HLA-B8 - along with other genes for susceptibility to celiac disease. Thus, the high levels of HLA-B8 in populations that took up wheat farming late (in the west of Ireland, for example) in its spread from the center of origin, along with high incidences of celiac disease, would reflect the lesser time available for the selective disadvantage to have diminished marker levels.
One obvious discrepancy was northwestern China, where wheat farming was introduced quite late through trade. This major wheat-growing area, although somewhat beyond the contiguous area of the earlier spread of wheat farming, might reasonably be considered its periphery.
There was, however, neither evidence of celiac disease nor high levels of HLA-B8 in the wheat-growing regions of China. A possible explanation for this was the likelihood that immune systems evolved differently in different populations to protect against relatively specific infectious diseases. Geographically distant populations would have been exposed to different stresses, thereby resulting in different complements of histocompatibility antigens. Furthermore, histocompatibility antigens that provided resistance to one disease might, quite coincidentally, enhance susceptibility to another, and this may well be true of genes for susceptibility to celiac disease (Strober 1992). Thus, the absence of celiac disease in the wheat-growing areas of China may well reflect the absence of the susceptibility genes in the Chinese population. Although hampered by a lack of adequate information, the analysis by Simoons (1981) is at least a highly interesting attempt to deal with what must have been selective pressures on populations containing the genes for susceptibility to celiac disease as wheat farming spread from the Middle East throughout Western Europe.
World History
