Vitamin D

Glenville Jones. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, United Kingdom: Cambridge University Press, 2000.

Definition and Nomenclature

Vitamin D is a fat-soluble substance required by most vertebrates, including humans, to keep blood calcium and phosphate levels within a narrow normal range and thereby maintain a normal skeleton and optimal cellular function. The term, vitamin D, is a misnomer. Vitamin D is not a vitamin. It is synthesized in the skin, and so, unlike other vitamins, which are essential dietary components, it does not satisfy the criteria for classification as a vitamin. Nor is it a hormone because it is biologically inactive and must be metabolized by the body into a multihydroxylated version, known as calcitriol, which is biologically active and the true hormonal form.Thus vitamin D is more accurately described as a prohormone. The natural form of the vitamin, known as vitamin D3, is a cholesterol-like substance produced in the skin by a nonenzymatic process involving ultraviolet light and heat. An artificial form of the vitamin, with an altered side chain, known as vitamin D2, is derived from the plant sterol ergosterol and is often used instead of vitamin D3 as a dietary supplement.

Most of the complexity associated with the nomenclature in the vitamin D field stems from confusion surrounding its discovery during the period 1919 to 1922. Early research showed that the deficiency associated with lack of vitamin D (rickets in children or osteomalacia in adults) was cured by seemingly unrelated treatments: exposure to sunlight or ingestion of a fat-soluble substance.The early nutritional pioneers of that period, including Sir Edward Mellanby and Elmer V. McCollum, realized that several related factors would cure rickets and that one of these substances, vitamin D3, could be made in the skin. Students often ponder the fate of vitamin D1. It was a short-lived research entity comprising a mixture of vitamins D2 and D3, and the term has no value today.Vitamin D3 is sometimes referred to as cholecalciferol or, more recently, calciol; vitamin D2 is known as ergocalciferol or ercalciol. The discovery of the hydroxylated versions of vitamin D by Hector F. DeLuca and Egon Kodicek in the 1967 to 1971 period led to a major expansion of our knowledge of a number of biologically active compounds, but calcitriol is the singularly most important version of these. For purposes of discussing the history of foodstuffs, we shall use the term vitamin D to describe all substances that can be activated to produce biological effects on calcium and phosphate metabolism in humans.

History of Vitamin D Deficiency (Rickets)

Though the nutritional entity vitamin D has been known for only 75 years, the deficiency diseases of vitamin D (rickets and its adult-onset counterpart, osteomalacia) were clearly recognized by Daniel Whistler (1645) in the Netherlands and Francis Glisson (1650) in England as early as the mid-seventeenth century.

In reviewing the history of rickets, we must recognize that rickets and osteomalacia are not the only diseases that affect the skeleton. Others include osteoporosis, which results from loss of total bone (i.e., proteinaceous matrix and minerals), and hormonal imbalances (e.g., hyperparathyroidism). Because diagnostic procedures were primitive until the twentieth century, the term “rickets” may often have been applied to other skeletal abnormalities and conditions not caused by vitamin D deficiency. Nevertheless, in many cases there is sufficient detail in the descriptions provided to recognize the condition.

According to strict medical classification, rickets and osteomalacia encompass a group of skeletal malformations resulting from a spectrum of different causes but having the common feature that the bone matrix is insufficiently mineralized or calcified. By far the most common cause of rickets is a lack of vitamin D. This deficiency must be the result of inadequate skin synthesis of vitamin D3 compounded by low dietary intake of vitamin D. The term “rickets” is thought by most to have its origins in the verb in the Dorset dialect to rucket, which means to breathe with difficulty.Yet some claim that the term is derived from the Anglo-Saxon word wrikken, meaning to twist.

Rickets is characterized by a deformed and mis-shaped skeleton, particularly bending or bowing of the long bones and enlargement of the epiphyses of the joints of the rib cage, arms, legs, and neck.Victims have painful movements of the rib cage and hence difficulty breathing. In China, medical texts refer to deformities of the rib cage in severe rickets as “chicken breast.” Severe rickets is often accompanied by pneumonia. There is currently much research in progress on a second important function of vitamin D, namely to control the differentiation and development of cells of the bone marrow and immune system. Thus with rickets, the defects of the skeleton may be accompanied by reduced ability to fight infections. Rachitic patients have difficulty holding up their heads, which is sometimes depicted in lithographs from the period circa 1650 to 1700 (e.g., Glisson’s “De Rachitide,” 1650).A more thorough review of the history of rickets can be found in the extraordinarily detailed book of Alfred Hess (1929) entitled Rickets Including Osteomalacia and Tetany. Though rickets is rarely life-threatening, it certainly lowers the quality of life for the afflicted individual and probably leads to secondary problems. One of the best documented of these secondary problems is the development of deformities of the pelvis in young females, which can cause difficulties in childbirth. This topic has been given detailed analysis by the University of Toronto historian Edward Shorter (1982) in A History of Women’s Bodies. Shorter concludes that before 1920, women who had contracted rickets earlier in life had the risk of a “contracted pelvis” that must have caused numerous deaths during their first delivery.

Discovery of Vitamin D

Around the turn of the twentieth century, several physicians noted a seasonal variation in the incidence of rickets and that the disease was associated with lack of exposure to sunlight. In fact, several researchers also noted a higher incidence of rickets in the industrialized cities of northern Europe (which lay under a pall of smoke caused by burning coal in open fires and factories) than in the rural areas around these centers. The Dickensian character Tiny Tim, of the novel A Christmas Carol, clearly represents a child who must have been a common sight in the narrow alleyways of the dark cities of the late nineteenth century. In retrospect, it is easy to see how rickets could be prevalent among the occupants of the sweatshops of such dingy cities when their agrarian cousins on a similar diet, but out in the sun 12 hours a day, had no rickets. Sunbaths were recommended by Edwardian physicians as a cure for this condition, but some believed that the accompanying “fresh-air and exercise,” rather than sunlight, were the key ingredients in the cure. In 1912, J. Raczynski (1913; described in Hess 1929) performed a definitive experiment by exposing two rachitic puppies to either sunlight or shade for six weeks and showing that the sunlight-exposed animal had a 1.5-fold higher bone mineral content. Nevertheless, controversy persisted as other researchers claimed to show the importance of “country-air and exercise” in the prevention of rickets and still others showed that the onset of rickets could be accelerated by dietary manipulation. Yet it is now clear that a “rachitogenic diet” (a diet that can lead to rickets) is one that contains adequate amounts of all essential nutrients except vitamin D, calcium, and phosphate, the raw materials important in bone mineral formation. Diet alone, however, will not cause rickets. Animals deprived of sunlight and fed a rachitogenic diet grow normally in all respects except that, because they lack bone mineral, they develop severe or “florid” rickets. But animals deprived of sunlight and fed a diet inadequate in many of the chief nutrients grow poorly, and the rickets they develop is difficult to discern against a background of other vitamin deficiencies.

By 1919, it was becoming clear that sunlight was the crucial factor in preventing rickets. Kurt Huldschinsky (1919) cured the disease by exposing patients to a mercury-vapor lamp, thereby showing the importance of the ultraviolet (UV) portion of sunlight. In a stroke of genius, he also showed that irradiation of one arm of a rachitic child cured the skeleton throughout the body, including the other arm. He invoked the concept that vitamin D must be “a hormone” because it was a chemical that could heal at a distance. Only much later were Adolf Windaus and colleagues (1936) able to show that vitamin D is made in the skin from a precursor, 7-dehydrocholesterol, thereby completing our understanding of this aspect of vitamin D.

Meanwhile, in the 1920s, nutritional biochemists, including Mellanby and McCollum, were busy isolating several essential nutrients in foodstuffs. They too were able to cure rickets by administration of a fat-soluble substance, termed vitamin D by McCollum to distinguish it from vitamin A, which cured xerophthalmia or night blindness (Mellanby 1919; McCollum et al. 1922). In 1928, Windaus received the Nobel Prize principally for his elucidation of the structure of sterols, including vitamin D. Interestingly, Hess and Harry Steenbock separately had been able to produce vitamin D in food by irradiating it with ultraviolet light (Hess and Weinstock 1924; Steenbock and Black 1924). It became clear that the very process occurring in the skin could be mimicked in the test tube by subjecting certain plant oils or even yeast, containing plant sterols, to UV light. Thus vitamin D2 was born, and with it, food fortification.

In more recent times, DeLuca, the last graduate student of Steenbock at the University of Wisconsin, showed that vitamin D is converted in the liver to a metabolite, 25-hydroxyvitamin D (Blunt, Schnoes, and DeLuca 1968).This is the main transport form of vitamin D in the body, and its blood level reflects the body’s supply of vitamin D. Following this discovery, several groups, most notably those of Kodicek at Cambridge, DeLuca at Wisconsin, and Anthony Norman at the University of California, were able to demonstrate and identify the hormonally active form of vitamin D, calcitriol, for the first time (Fraser and Kodicek 1970; Myrtle, Haussler, and Norman 1970; Holick et al. 1971). Also known as 1,25-dihydroxyvitamin D, this hormone is made in the kidney, but it is important to note that its level in the blood is not simply a reflection of the exposure to sunlight or a measure of dietary intake. The human body can store the fat-soluble vitamin D precursor, make just enough calcitriol hormone for its needs, and save the rest of the vitamin D for “hard times.” In the case of our ancestors who lived in the higher latitudes of northern Europe and were exposed to sunlight on a seasonal basis, these stores of vitamin D must have been crucial to help them get through each winter without the development of rickets or osteomalacia.

Foodstuffs and Vitamin D

As already pointed out, diet plays a secondary role in maintaining our supply of vitamin D. Nevertheless, diet can assume a critical importance when exposure to sunlight is compromised. Somewhat surprisingly, most foodstuffs are devoid of vitamin D.The only significant sources are animal liver (vitamin D stores of other vertebrates), egg yolks, and fish oils. Milk, generally thought of as a major source of vitamin D, is not rich in the vitamin, and human milk is an extremely poor source of it. It is a well-established observation in contemporary pediatric medicine that most cases of rickets in infants are found in those who are breast-fed, born in the fall, and kept out of the sun during winter months. Of course, the formula-fed infant of today receives milk fortified with vitamin D.

Most grains, meat, vegetables, and fruits are virtually devoid of measurable amounts of vitamin D, although experts in this field are still perplexed by how such creatures as nocturnal bats surviving on a diet of fruit and insects can avoid rickets! It is possible (although unsubstantiated) that exposure of certain foods (e.g., vegetables or fruits) to sun-drying may generate antirachitic activity, presumably because plant ergosterol would be converted into vitamin D 2. Some cultures (e.g., the Chinese) have a tradition of drying vegetables in the sun, which may increase their vitamin D content.

Recent reports indicate that infants fed a so-called macrobiotic diet, consisting of unpolished rice, pulses, and vegetables with a high fiber content along with small additions of seaweeds, fermented foods, nuts, seeds, and fruits, are particularly susceptible to rickets. In one group of Caucasian children in the Netherlands (Dagnelie et al. 1990), 28 percent had physical symptoms of rickets in late summer, and this statistic rose to 55 percent by the following spring. (One might hope that those who extol this sort of diet will modify their teachings so that small amounts of fatty fish might be included, which would supply much-needed vitamin D.)

The association of vitamin D with fish oils, particularly fish-liver oils, is an interesting one recognized well before the formal discovery of vitamin D and predating even the discovery of the importance of sunlight. In 1789, a Manchester physician named Thomas Percival wrote about the medicinal uses of cod-liver oil at the Manchester Infirmary shortly after it had been introduced into British pharmacopoeia. In fact, one might argue that cod-liver oil is a medicine and not a food, but this is a fine point.There is, however, almost universal agreement that it is not a particularly good-tasting substance and hardly a favorite of children. Hess (1929) wrote that cod-liver oil’s chief disadvantages lay in taste and odor. Moreover, it was not always completely prophylactic against rickets.

Hess’s last comment is a reference to the variable potency of cod-liver oil because it is a natural product and thus subject to seasonal variation dependent upon the diet of the codfish. A more acceptable but less effective source of vitamin D is fish itself, particularly the fatty saltwater fish: herring, mackerel, tuna, halibut, and salmon. These fish have fat stores in the muscle, and because vitamin D is fat-soluble it is found throughout these fat deposits and is not confined to the liver, as in the cod. Fish roe, like eggs, also contain vitamin D. W. F. Loomis (1970), in a review of rickets, speculated that certain social practices, such as the Christian tradition of serving fish on Friday, might be adaptive responses to rickets. Another was June weddings, which tend to bring the first baby in the spring and permit the rapid growth phase of the first six months of life in summer sunshine. By contrast, the fall baby historically lacked vitamin D because of an infancy during the winter months.

Fortification of Food with Vitamin D

With the discovery that irradiation of ergosterol could produce a molecule (later identified as vitamin D2) with potent antirachitic activity came the realization that such a preparation could be added to foodstuffs rendering low-vitamin D foods useful in the fight against rickets. As noted earlier, the two problems with foods containing vitamin D are that there are too few of them and that even those foods that contain vitamin D vary widely in potency. Steenbock had the idea to fortify staples of the diet such as breakfast cereals, milk, and margarine with vitamin D in the form of irradiated ergosterol, and because this supplement has a narrower range of variability, the potency of such foods could be assured with some degree of confidence. Some U.S. states and Western countries fortify only milk or margarine; others include breakfast cereals as well. Nonetheless, fortifying even these few foods with vitamin D has virtually eradicated the incidence of rickets in the Western world.The fortification of foods with vitamins including vitamin D is arguably one of the most important medical achievements of the twentieth century and certainly a major achievement of the nutritional sciences.

Nowadays, pure crystalline vitamin D3 is used in food fortification rather than Steenbock’s irradiated ergosterol. Nevertheless, Steenbock’s “invention” represents one of the earliest examples of a university (Wisconsin-Madison) patenting the application of fundamental scientific research in the biomedical field. The discovery led to the inception of a new university structure, WARF (Wisconsin Alumni Research Foundation), an institution designed to manage patentable research and recycle profits from such discoveries. Aside from serving as a model for many other similar institutions in the United States and around the world, WARF has spawned a number of other products from its profits on vitamin D fortification, including the rodent poison warfarin and most of the new metabolites of vitamin D itself, including calcitriol, identified and synthesized in the laboratory of DeLuca.

Despite the incredible success of food fortification in the eradication of rickets, over the years the process has met some resistance and even outright opposition amid fears that vitamin D in megadoses could cause hypercalcemia and, consequently, kidney damage. These fears are largely groundless because the doses required to produce renal damage are massive and could not be acquired by ingestion of large amounts of foods, even those fortified with vitamin D (cod-liver oil excepted). Yet one of the most notable examples of resistance came in the Province of Quebec, Canada. Health authorities in this province steadfastly resisted the fortification of dairy products with vitamin D until the early 1970s, when finally they bowed to pressure from a group headed by the notable clinical geneticist Charles Scriver to reduce rickets in the French-Canadian population. Following this decision, statistics from one Montreal hospital (Sainte-Justine pour les Enfants) showed a decline in the annual incidence of rickets from 130 per 1,000 to zero in an eight-year span between 1968 and 1976, which coincided with the introduction of provincial legislation making it mandatory for dairies to fortify milk (Delvin et al. 1978). Today, a similar low incidence of rickets can be documented in every children’s hospital in North America. Gone too is the once familiar bowleggedness, the signature of rickets, which often remained with the victim for life and was so common in the Great Depression of the 1930s.

With the end of World War II came mandatory rationing and governmental food fortification in Western Europe. But in 1957 politicians in the United Kingdom bowed to political pressure and drastically reduced vitamin D fortification of cereals and powdered milk following an “outbreak” of infantile hyper-calcemia. At the time, the outbreak was believed to be caused by overfortification of food with vitamins D and A, although Donald Fraser, a noted Canadian pediatrician who researched the evidence at that time, now feels that this conclusion was probably incorrect (Fraser et al. 1966). The incidence of infantile hyper-calcemia today is now no greater in countries that fortify than those that do not. Furthermore, the disease seems to result from an insult to the fetus in utero rather than a problem of the young child overindulging in fortified food, such as infant formula. Nevertheless, the condition results in mental retardation and heart problems that are largely irreversible and thus must be taken seriously.

To this day, the United Kingdom permits fortification of margarine only, probably at the expense of some increased incidence of rickets and osteomalacia in the population. Certainly, blood plasma levels of vitamin D and its metabolites (except calcitriol) are lower, presumably reflecting reduced stores of vitamin D in Britons when compared to a similar population of Americans and Canadians at the same latitude but given fortified food. In summary, it can be stated that the advantages of food fortification with vitamin D far outweigh any disadvantages. The main value of food fortification with vitamin D is to provide a constant year-round supply of the essential nutrient in the diet to augment the seasonal production in the skin.

Geographical Aspects of Vitamin D

Synthesis of vitamin D is both season- and latitude-dependent because vitamin D is made in the skin only by exposure to wavelengths in the UV spectrum of sunlight, and these wavelengths are absorbed by the ozone layer of the atmosphere. Only near the equator does the sunlight remain at an angle high enough for UV rays to penetrate the atmosphere on a year-round basis. Michael Holick of Boston City Hospital conducted experiments in which test tubes containing 7-dehydrocholesterol (the skin precursor to vitamin D) were exposed to light at various times of the day at latitudes from Caracas to Edmonton or Glasgow. He concluded (Webb, Kline, and Holick 1988) that in a city such as Boston, vitamin D is synthesized only in the months from April to October. Such a result implies that in most of the northern cities of the world, production of vitamin D3 is seasonal and rickets might result at such latitudes if vitamin D stores are depletedand there is no dietary vitamin D.

Historical records also consistently reveal the geographical segregation of rickets to more northerly latitudes.August Hirsch (1883-6, vol. 3), for example, discussed the paucity of data on the geographical distribution of rickets.Theobald Palm, a Western medical missionary to Japan and China, concluded in a valuable paper in 1890 that sunshine is the main etio-logical factor in rickets. He compiled anecdotal reports suggesting that rickets was rare in southern China but more common in northern regions of the same country. However, reports in the early 1900s suggested a similar incidence of rickets in New Orleans (30° latitude) and New York (40° latitude). Hess (1929) ascribed this similarity to equivalent average annual sunshine exposure (2,519 versus 2,557 hours). It is interesting to note that of the cities cited by Hess for the year 1923, Phoenix, Arizona, has the highest amount of annual sunshine with 3,752 hours (and no rickets in the population), whereas Glasgow (a hotbed of rickets) has the lowest with 1,086 hours. Since UV light penetration is greater at higher altitudes, we would expect the incidence of rickets to be low in mountain cities, and early studies in cities like Denver (5,000 ft. above sea level) bear this out. Even earlier, in 1844, a Swiss physician had pointed out that rickets was more prevalent in the lowlands than the mountains, again presumably reflecting the relative exposure to UV light (Hess 1929: 50). In more recent times, the pollution of major cities has modified local UV exposure and may have increased our predisposition to rickets by reducing skin synthesis of vitamin D. Thus, geography plays a major role in the distribution of rickets, but the relationship is not a simple one directly dependent on degrees of latitude. It is further modified by climate, altitude, and degree of pollution.

The geography of vitamin D and rickets is also modified by diet. It is important to note that many of the peoples who live in northern latitudes depend upon the sea for their survival (e.g., Eskimos, Haida Indians, Greenlanders, Scandinavians). It is tempting to speculate that the natural incidence of rickets in these cultures has been ameliorated by the higher vitamin D content of their diets (e.g., from fish oils). One anecdotal story relating to the higher fat-soluble vitamin content of Arctic meats is the experience of early Arctic explorers. Several were forced to shoot Arctic animals (such as polar bears) and eat almost all edible organs in order to survive. As a result, some contracted hypervitaminosis A, which causes disorientation and brain swelling, probably from ingestion of polar bear liver containing vast stores of vitamins A and D. Eskimos apparently avoid the liver of the polar bear but still get enough vitamins D and A from the rest of their diet.

Social and Ethnic Aspects of Vitamin D

Because vitamin D is produced in the skin by exposure to UV light, social practices relating to exposure of the skin (such as clothing habits or sunbathing) can be of paramount importance to this production. Primitive humans evolved near the equator and are popularly depicted wearing minimal clothing. These considerations, plus the belief that primitive humans must have spent much of their lives outdoors, suggest that their contraction of rickets was unlikely. But as humans increased in numbers and moved into more and more inhospitable climes, the need for clothing would have become greater and the synthesis of vitamin D in the skin would have been compromised. It is possible that sun worship in early cultures reflects a realization of the importance to health of skin exposure to the sun.

Adaptation to sunlight exposure involved the development of melanin pigment in the skin. People exposed to maximal amounts of sunlight at the equator were the darkest, and those at the highest latitudes of Europe were the lightest. Although the subject is somewhat controversial, modern research indicates that skin melanin not only protects against the harmful effects of sunlight (e.g., skin cancer) but reduces the efficiency of the synthesis of vitamin D. Loomis (1970) suggests that summer bronzing in white populations is a seasonal adaptation to UV light exposure, though there is no evidence that vitamin D synthesis is regulated in an individual by such seasonal pigmentation. However, there is also no evidence that excessive exposure to sunlight can cause hypervitaminosis D and toxicity.The interrelationship of skin pigmentation and migration has some relevance to nutrition. Over the course of the past few centuries there has been considerable migration of certain peoples around the world so that cultural groups exist in climates that “their skin was not designed for.”

Much has been written about whites developing skin cancer in Arizona and Australia, and considerable evidence is accumulating that indicates rickets and osteomalacia are common among Asian groups in England and Scotland (Felton and Stone 1966; Ford et al. 1973; Dent and Gupta 1975). There is some possibility that the problems of Asians in Britain are exacerbated by a high-phytate, high-phosphate diet (which tends to chelate calcium in the lumen of the intestine) combined with the avoidance of the typical vitamin D-fortified staples that whites consume.

Black children growing up in southern U.S. cities during the last part of the nineteenth century and the first decades of the twentieth century endured rickets almost as a rite of passage.And Rastafarians living outside of the UV climate of the West Indies may also be at risk for rickets.This is because of strict dietary practices that forbid consumption of artificial infant formulas, coupled with reduced opportunities for UV exposure in inner-city apartment complexes and a skin pigment unsuited to their “new” more northerly homes. There is also speculation (Ward et al. 1982) that the vitamin D-rich fish component of the Jamaican Rastafarian diet has been dropped by those living abroad. With the generation of multicultural societies such as currently exist in the United States, Canada, and many former colonial European countries, this potential problem of widespread rickets needs to be better understood and dietary solutions need to be formulated.

Clothing must have been developed for both staying warm in cooler climates and combating the harmful effects of UV light in warmer climates. Some cultures, particularly Moslem and Hindu groups, have very strict traditions of purdah, the practice of keeping the female skin out of the gaze of the public and therefore out of the sun. Though this strict policy does not apply to female children below the age of puberty, Saudi Arabian physicians report a higher female to male ratio in rickets patients that they ascribe to the higher UV exposure of the male children. In most cases, however, the practice of purdah cannot be directly blamed for childhood rickets in Saudi Arabia and North Africa, but it can be held responsible for osteomalacia observed in older females in such populations. And because these women with low reserves of vitamin D bear infants, the low UV exposure might be indirectly responsible for rickets. Detailed studies of the etiology of the rickets observed in Moslem groups (Belton 1986; Under-wood and Margetts 1987; Elzouki et al. 1989) suggest the existence of maternal vitamin D deficiency, which results from the extra burden placed upon the mother to provide calcium for the skeleton of the growing fetus. Placental and lactational transfer of vitamin D stores from mother to the neonate are thus minimal, and such deficiencies, coupled with inadequate UV exposure, can result in infantile rickets. It is likely that the strict moral standards that prevailed in past centuries in western Europe leading to limited skin exposure also contributed to the well-documented higher incidence of osteomalacia in women.