Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets.

PURPOSE: After Glisson's description of rickets, it took two centuries to realize that rickets was due to the absence of antirachitic nutrients in the diet or lack exposure of the skin to ultraviolet rays. This bone disease caused by vitamin D deficiency was one of the most common diseases of children 100 years ago. This paper explores how the definition, diagnosis, and treatment of rickets shifted in the first decades of the twentieth century. MATERIAL AND METHODS: Although benefits of cod liver oil as food were known as early as the seventh century, cod liver oil was only proposed as medicinal for rickets in Northern Europe at the end of the eighteenth century. The relationship between rickets and nutritional deficiency was suspected and demonstrated between 1880 and 1915, at the same time of the discovery of other vital substances (vitamins) needed to prevent beriberi, scurvy, and pellagra. Understanding that the lack of photosynthesized vitamin D or the lack of dietary vitamin D was a similar risk of rickets was an important turn in the comprehension of the disease. We look at the sequence and turn of events related to the discovery of vitamin D. RESULTS: Rickets has been recognized first as a disease of urban living people. Cod liver oil had been used since 1700 as a nonspecific treatment for a range of diseases. Generations of children in cities of the north of Europe had learned to hate the taste and smell of the black oily liquid and then grown up to be parents who, in turn, hated to force it down their children's throats. Occasional papers before 1900 pointed to its efficacy for rickets, and most textbooks of the early 1900s mentioned it only as a treatment option. The discovery in the early 1900s that artificial and natural ultraviolet rays had both antirachitic activity allowed to produce antirachitic foods just by food irradiation with artificial ultraviolet irradiation. Clinical guidelines were adopted to propose exposure to sunlight or to artificial ultraviolet radiation to prevent rickets in children. By the mid-1920s, rickets was promoted as universal, at times invisible to non-experts, but present to some degree in nearly every young child regardless of race or class. It was thus used to promote the young disciplines of preventive medicine, pediatrics, and public health. Innovative advances were made in the understanding of vitamin D synthesis from 1915 to 1935. A public health campaign of the 1930s was a success to eradicate rickets, using irradiated ergosterol from yeast to enrich milk and other foods with vitamin D, ensuring that the general population was consuming sufficient vitamin D. CONCLUSION: Rickets therefore provides an excellent window into the early politics of preventive health and the promotion of targeted interventions in the world. It is also a relevant historical counterpoint for current debates over the role of risk factors (absence of light or sun) for disease (today's so-called "lifestyle" diseases).

Historical perspectives on advertising and the meme that personal oral hygiene prevents dental caries.

The consensus of a leading scientific panel in 1930 was that oral hygiene products could not prevent dental caries. Their view was that dental caries prevention required the proper mineralisation of teeth and that vitamin D could achieve this goal. Over a hundred subsequent controlled trials, conducted over seven decades, largely confirmed that this scientific panel had made the right decisions. They had, in 1930, when it comes to dental caries, correctly endorsed vitamin D products as dental caries prophylactics and oral hygiene products as cosmetics. And yet, despite this consistent scientific evidence for close to a century, an opposing conventional wisdom emerged which thrives to this day: oral hygiene habits (without fluoride) protect the teeth from dental caries, and vitamin D plays no role in dental caries prevention. This historical analysis explores whether persistent advertising can deeply engrain memes on dental caries prevention which conflict with controlled trial results. The question is raised whether professional organisations, with a dependence on advertising revenues, can become complicit in amplifying advertised health claims which are inconsistent with the principles of evidence-based medicine.

Vitamin D: part I; from plankton and calcified skeletons (500 million years ago) to rickets.

The vitamin D history started early in the evolution of life (billion years ago) as a photochemical reaction producing an inert molecule. During the early evolution of vertebrates, this molecule became essential for calcium and bone homeostasis of terrestrial animals and arrived to the status of hormone. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. The typical "vitamin D-deficiency" disorder was observed for growing children in the west and south of England in the early 1600s. This disease was described by Glisson and named "rickets" (known also as "the English disease") and was observed with epidemic proportions in northern Europe and North America. The corrections of deformities of rickets were at the origin of the name "orthopedia" and of the technique of osteotomies.

A short history of phototherapy, vitamin D and skin disease.

The earliest record between sun exposure and skin disease goes back five millennia to the ancient Egyptians. The modern scientific era of medical light therapy and skin diseases started in 1877 when Downs and Blunt reported that exposure to light inhibited fungal growth in test tubes. Continuing research generated a growing medical interest in the potential the effects of light to treat and cure skin diseases considered as parasitic. This culminated in the awarding of the 1903 Nobel Prize in Medicine to Niels Finsen for his pioneering work showing that light could successfully treat cutaneous mycobacterium tuberculosis (lupus vulgaris), a disfiguring disorder common at the time. Cod liver oil was used as a folk remedy to treat rickets prior to 1789 in Manchester, UK and sunlight was published as the cure for this disease in 1921. The work by Hess and Weinstock in 1925 showed that food irradiated with ultraviolet (UV) light prevented rickets in rats, which paved the way for the discovery of vitamin D. The range of skin diseases treated by light therapy increased in the following years, to the point where a 1932 review by the American Medical Association on the use of UV therapy in dermatology listed 34 skin conditions for which UV radiation may be useful. This period coincided with the development of sanatoria in Europe and North America which used heliotherapy for the treatment of tuberculosis. UV therapy and vitamin D continued to be used successfully for the treatment of tuberculosis up to the 1950s when it was superseded by more effective antibiotics. Modern phototherapy developed in the 1980s with the discovery of the action spectrum for psoriasis leading to the development of narrow band UVB. Subsequently a biological mechanism by which UV light and vitamin D treated tuberculosis was identified in 2006. This involves activation of human macrophages via toll-like receptors to upregulate the vitamin D receptor gene resulting in induction of the antimicrobial peptide cathelicidin. The role of UV light and vitamin D in the treatment of skin diseases is currently an active area of research.

Early animal models of rickets and proof of a nutritional deficiency hypothesis.

In the period between 1880 and 1930, the role of nutrition and nutritional deficiency as a cause of rickets was established based upon the results from 6 animal models of rickets. This greatly prevalent condition (60%-90% in some locales) in children of the industrialized world was an important clinical research topic. What had to be reconciled was that rickets was associated with infections, crowding, and living in northern latitudes, and cod liver oil was observed to prevent or cure the disease. Several brilliant insights opened up a new pathway to discovery using animal models of rickets. Studies in lion cubs, dogs, and rats showed the importance of cod liver oil and an antirachitic substance later termed vitamin D. They showed that fats in the diet were required, that vitamin D had a secosteroid structure and was different from vitamin A, and that ultraviolet irradiation could prevent or cure rickets. Several of these experiments had elements of serendipity in that certain dietary components and the presence or absence of sunshine or ultraviolet irradiation could critically change the course of rickets. Nonetheless, at the end of these studies, a nutritional deficiency of vitamin D resulting from a poor diet or lack of adequate sunshine was firmly established as a cause of rickets.

[Radiated drugs, the way of health]. / Médicaments irradiés, sources de santé.

During the inter-war years, the word "radiated" did not only suggest radioactivity, but it was also used to indicate exposure to others radiations, such as ultraviolets. The actinotherapy, a new therapy in vogue, was applied to many pathologies and tried on many substances. "Radiated drugs" result of those experimentations. Their therapeutical characteristics were found during searches on rickets. Our study relates the story of fight against rickets in France, from the use of cod liver oil to the synthesis of Vitamine D.

Nineteenth century Mexican statures in the United States and their relationship with insolation and vitamin D.

The use of height data to measure living standards is now a well-established method in economics. However, there are still some populations, places and times for which the comparison across groups remains unclear. One example is 19th century Mexicans in the US. This study demonstrates that after comparing the statures of Mexicans born in Mexico and the US the primary source of the stature difference between the two groups was birth year, and the stature gap increased as the US economy developed while the Mexican economy stagnated. Moreover, the stature growth of Mexicans born in the US was related to vitamin D, and the Mexican relationship between stature and insolation was more like that of Europeans than Africans.

The discovery and synthesis of the nutritional factor vitamin D.

Although vitamin D deficiency was first recognized as rickets/osteomalacia in the early 1600s, it was only a century ago that vitamin D, the nutritional factor responsible, was discovered. This discovery was made difficult by the fact that the substance could be synthesized in human skin by exposure to UV light and could also be present in the diet in animal-derived (D3) and plant-derived forms (D2). Prior to 1920, the frequency of vitamin D deficiency in the general population of industrialized cities was high. The discovery of vitamin D led to the widespread fortification of foods e.g. milk and the virtual eradication of rickets in developed nations. Vitamin D3 was first chemically synthesized in the 1930s and its metabolism to the active form 1,25-dihydroxyvitamin D3 and its mode of action in calcium and phosphate homeostasis were elucidated in the latter half of the 20th century. Synthetic vitamin D analogs that mimic the physiological effects of vitamin D are now used therapeutically in diseases such as bone disease, chronic kidney disease and psoriasis. Thus, a wide range of disciplines played critical roles in the rich history of vitamin D and these are described in this short historical overview.

SOLAR ultraviolet radiation and vitamin D: a historical perspective.

Rickets, the state of vitamin D deficiency, has reemerged as a potential problem in the United States. At the dawn of the 20th century, rickets was pervasive among infants residing in the polluted cities of Europe and the northeastern United States. Important milestones in the history of rickets were the understanding that photosynthesized vitamin D and dietary vitamin D were similar, the discernment of the antirachitic potency of artificial and natural ultraviolet rays, and the discovery that ultraviolet irradiation could render various foods antirachitic. Clinical guidelines were instituted to promote sensible exposure to sunlight and artificial ultraviolet radiation. In addition, irradiated ergosterol from yeast became the major vitamin D source for food fortification and the treatment of rickets, leading to a public health campaign to eradicate rickets by the 1930s. We review the sequence and turn of events pertaining to the discovery of vitamin D and the strategies for the eradication of the reemerging rickets problem.

[Vigantol--Adolf Windaus and the history of vitamin D]. / Vigantol--Adolf Windaus und die Geschichte des Vitamin D.

This publication shows the investigation of the chemistry and pharmacology, also the produce and the sale of vitamin D. Adolf Windaus was builded vitamin D by UV-irradiation from ergosterol of yeast. He gave his patents to Merck and Bayer, former I. G. Farbenindustrie, and they brang out the medical Vigantol in 1927. Also today you can buy Vigantol in the chemist's shop.

La accidentada historia del descubrimiento de la vitamina D, en su primer centenario / The checkered history of the discovery of vitamin D, in its first centenary

El año 2022 marca el primer centenario del descubrimiento de la vitamina D, hallazgo que recompensó la prolongada búsqueda de la causa del raquitismo, su prevención y tratamiento. Al mismo tiempo puso en marcha importantes investigaciones relaciona-das con su biotransformación y el mecanismo de su acción antirraquítica, además de estudios sobre diversos efectos biológicos sin relación directa con su papel en la salud ósea. Esta breve revisión se limitará a delinear la prehistoria de la vitamina D y los diversos estudios, básicos y clínicos, que condujeron a su descubrimiento y caracterización química. (AU)

The year 2022 marks the centenary of the discovery of vitamin D, a breakthrough that rewarded the long search for the cause of rickets, its prevention and treatment. At the same time, it launched important investigations related to its biotransformation and the mechanism of its antirachitic action, as well as studies on various biological effects without direct relation to its role in bone health. This brief review will be limited to an outline of the prehistory of vitamin D and the various basic and clinical studies that led to its discovery and chemical characterization. (AU)

Reemerging nutritional rickets: a historical perspective.

Recent case reports highlight the resurgence of rickets in certain groups of breastfed infants. Infants residing in the North, irrespective of skin color, and dark-skinned African American infants residing anywhere in the United States are most vulnerable to nutritional rickets if they are exclusively breastfed past age 6 months without vitamin D supplementation. At the turn of the 20th century, rickets was nearly universal among African American infants living in the North. The discovery of vitamin D, the initiation of public health campaigns to fortify infant foods with vitamin D, and the supplementation of vitamin D to breastfed infants were responsible for overcoming the rickets scourge. We review a classic nutritional study by Alfred F. Hess, one of the greatest clinical nutritional researchers of the early 20th century, in the context of the resurgence of rickets, especially among dark-skinned infants. The Columbus Hill district, a black community of New York, NY, served as the setting for the study. Sixty-five infants (aged 1-17 months) entered a 6-month open-label trial of daily cod liver oil therapy. Participants were assessed for signs of rickets at recruitment and at 2, 4, and 6 months. Cod liver oil prevented the development of rickets in 34 (92%) of 37 infants treated for 6 months and in 7 (58%) of 12 treated for 4 months. Of the 16 infants who did not take the prescribed treatment, rickets progressed unremittingly in 15. Hess translated his success into a public health campaign leading to the development of the first rickets clinic in 1917. This was the first step in the conquest of the rickets epidemic of the early 20th century.

History of the development of new vitamin D analogs: studies on 22-oxacalcitriol (OCT) and 2beta-(3-hydroxypropoxy)calcitriol (ED-71).

In 1981 Suda and his colleagues first reported the new activity of calcitriol namely its ability to differentiate the myeloid leukemia cells into normal monocytes-macrophages. However, the possibility of using calcitriol as an antileukemic drug was not feasible because of its potent calcemic effects. Based on these observations, several pharmaceutical companies initiated the synthesis of vitamin D analogs with the aim to separate the calcemic actions of calcitriol from its actions on regulating the cell growth and differentiation. As a result, numerous noncalcemic analogs with a potential for the treatment of leukemia and other cancers were synthesized. The group at Chugai introduced two characteristic analogs of opposite type namely, 22-oxacalcitriol (OCT) and 2beta-(3-hydroxypropoxy)calcitriol (ED-71) which have been shown to have therapeutic value and are already being used clinically. The work on OCT and ED-71 together with the work on calcipotriol and KH-1060 by Leo Laboratories, and 1alpha,25(OH)(2)-16-ene-23-yne-D(3) by Hoffmann-La Roche, vigorously stimulated research world-wide in the development of vitamin D analogs into pharmaceutical products. More recently new impressive vitamin D analogs such as 3-epi analogs, 19-nor analogs, 18-nor analogs, 2-methyl-20-epi-calcitriol, non-steroidal vitamin D analogs are being developed. The authors are convinced that various vitamin D analogs will become highly effective therapeutic agents at the clinical level in the new century, and also that a new theory on the mechanism of vitamin D action will be generated.

[70 years and 3 eras of vitamin D]. / Sedmdesát let a tri éry vitaminu D.

The author reviews the importance of vitamin D in human pathology in the past, at present and in future. Findings on vitamin D and their development can be divided into three eras each of which was or is of great importance. The author deals in particular with the third era which is promising as regards a further extensive and intensive role of vitamin D, metabolites and analogues in medicine.