Vitamin D

Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium and phosphate, along with numerous other biological functions. In humans, the most important compounds within this group are vitamin D₃ and vitamin D₂.
Unlike the other twelve vitamins, vitamin D is only conditionally essential, as with adequate skin exposure to the ultraviolet B radiation component of sunlight there is synthesis of cholecalciferol in the deeper layers of the skin's epidermis. Vitamin D can also be obtained through diet, food fortification and dietary supplements. For most people, skin synthesis contributes more than dietary sources. In the United States, milk and plant-based milk substitutes are fortified with vitamin D₃, as are many breakfast cereals. US dietary guides generally assume that all of a person's vitamin D is taken orally, given the potential for insufficient sunlight exposure due to urban living, cultural choices for the amount of clothing worn when outdoors, and use of sunscreen because of concerns about safe sunlight exposure.
Cholecalciferol is converted in the liver to calcifediol, while ergocalciferol is converted to ercalcidiol. These two vitamin D metabolites, collectively referred to as 25-hydroxyvitamin D or 25D, are measured in serum to assess a person's vitamin D status. Calcifediol is further hydroxylated by the kidneys and certain immune cells to form calcitriol, the biologically active form of vitamin D. Calcitriol attaches to vitamin D receptors, which are nuclear receptors found in various tissues throughout the body.
The discovery of the vitamin in 1922 was due to an effort to identify the dietary deficiency in children with rickets. Adolf Windaus received the Nobel Prize in Chemistry in 1928 for his work on the constitution of sterols and their connection with vitamins. Present day, government food fortification programs in some countries and recommendations to consume vitamin D supplements are intended to prevent or treat vitamin D deficiency rickets and osteomalacia. There are many other health conditions linked to vitamin D deficiency. However, the evidence for the health benefits of vitamin D supplementation in individuals who are already vitamin D sufficient is unproven.

History

In northern European countries, cod liver oil had a long history of folklore medical uses, including applied to the skin and taken orally as a treatment for rheumatism and gout. There were several extraction processes. Fresh livers cut to pieces and suspended on screens over pans of boiling water would drip oil that could be skimmed off the water, yielding a pale oil with a mild fish odor and flavor. For industrial purposes such as a lubricant, cod livers were placed in barrels to rot, with the oil skimmed off over months. The resulting oil was light to dark brown, and exceedingly foul smelling and tasting. In the 1800s, cod liver oil became popular as a bottled medicinal product for oral consumptiona teaspoon a daywith both pale and brown oils being used. The trigger for the surge in oral use was the observation made in several European countries starting with Germany in the 1820s and spreading to other countries into the 1860s that young children fed cod liver oil did not develop rickets. In northern Europe and the United States, the practice of giving children cod liver oil to prevent rickets persisted well in the 1950s. This overlapped with the fortification of cow's milk with vitamin D, which began in the early 1930s.
Knowledge of cod liver oil being rickets-preventive in humans carried over to treating animals. In 1899, London surgeon John Bland-Sutton was asked to investigate why litters of lion cubs at the London Zoo were dying with a presentation that included rickets. He recommended that the diets of the pregnant and nursing females and the weaned cubs be switched from lean horse meat to goatincluding calcium- and phosphorus-containing bonesand cod liver oil, solving the problem. Subsequently, researchers realized that animal models such as dogs and rats could be used for rickets research, leading to the identification and naming of the responsible vitamin in 1922.
In 1914, American researchers Elmer McCollum and Marguerite Davis had discovered a substance in cod liver oil which later was named "vitamin A". Edward Mellanby, a British researcher, observed that dogs that were fed cod liver oil did not develop rickets, and concluded that vitamin A could prevent the disease. In 1922, McCollum tested modified cod liver oil in which the vitamin A had been destroyed. The modified oil cured the sick dogs, so McCollum concluded the factor in cod liver oil which cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named.
In 1925, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble substance is produced, now known as vitamin D₃. Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928 "for the services rendered through his research into the constitution of the sterols and their connection with the vitamins". Alfred Fabian Hess, his research associate, stated: "Light equals vitamin D." In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids, and soon thereafter collaborated with Kenneth Callow and others on the isolation and characterization of vitamin D. Windaus further clarified the chemical structure of vitamin D.
In 1969, a specific binding protein for vitamin D called the vitamin D receptor was identified. Shortly thereafter, the conversion of vitamin D to calcifediol and then to calcitriol, the biologically active form, was confirmed. The photosynthesis of vitamin D₃ in skin via previtamin D₃ and its subsequent metabolism was described in 1980.
The discovery of vitamin D helped to increase the viability and prevalence of intensive animal farming. Prior to its discovery, mortality rates were higher whenever farm animals were moved indoors during winter. Being able to place vitamin D in the feed removed that issue and enabled placing a high number of animals in year-round indoor farming.

Types

Several forms of vitamin D exist, with the two major forms being vitamin D₂ or ergocalciferol, and vitamin D₃ or cholecalciferol. The common-use term "vitamin D" refers to both D₂ and D₃, which were chemically characterized, respectively, in 1931 and 1935. Vitamin D₃ was shown to result from the ultraviolet irradiation of 7-dehydrocholesterol. Although a chemical nomenclature for vitamin D forms was recommended in 1981, alternative names remain commonly used.
Chemically, the various forms of vitamin D are secosteroids, meaning that one of the bonds in the steroid rings is broken. The structural difference between vitamin D₂ and vitamin D₃ lies in the side chain: vitamin D₂ has a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D analogues have also been synthesized.
US dietary guides generally assume that all of a person's vitamin D is taken orally, given the potential for insufficient sunlight exposure due to urban living, cultural choices for the amount of clothing worn when outdoors, and use of sunscreen because of concerns about safe levels of sunlight exposure, including the risk of skin cancer.

Biology

The active vitamin D metabolite, calcitriol, exerts its biological effects by binding to the vitamin D receptor, which is primarily located in the nuclei of target cells. When calcitriol binds to the VDR, it enables the receptor to act as a transcription factor, modulating the gene expression of transport proteins involved in calcium absorption in the intestine, such as TRPV6 and calbindin. The VDR is part of the nuclear receptor superfamily of steroid hormone receptors, which are hormone-dependent regulators of gene expression. These receptors are expressed in cells across most organs. VDR expression decreases as age increases.
Activation of VDR in the intestine, bone, kidney, and parathyroid gland cells plays a crucial role in maintaining calcium and phosphorus levels in the blood, a process that is assisted by parathyroid hormone and calcitonin, thereby supporting bone health. VDR also regulates cell proliferation and differentiation. Additionally, vitamin D influences the immune system, with VDRs being expressed in several types of white blood cells, including monocytes and activated T and B cells.

Deficiency

Worldwide, more than one billion peopleinfants, children, adults and elderlycan be considered vitamin D deficient, with reported percentages dependent on what measurement is used to define "deficient". A 2023 systematic review in The Lancet Regional Health estimated that ~15% of the global population is vitamin D deficient when defined as serum 25D <30 nmol/L, with higher prevalence in regions with limited sunlight exposure. Deficiency is common in the Middle-East, Asia, Africa and South America, but also exists in North America and Europe. Dark-skinned populations in North America, Europe and Australia have a higher percentage of deficiency compared to light-skinned populations that had their origins in Europe.
Serum 25D concentration is used as a biomarker for vitamin D deficiency. Units of measurement are either ng/mL or nmol/L, with oneng/mL equal to 2.5nmol/L. There is no consensus on defining vitamin D deficiency, insufficiency, sufficiency, or optimal for all aspects of health. According to the US Institute of Medicine Dietary Reference Intake Committee, below 30nmol/L significantly increases the risk of vitamin D deficiency caused rickets in infants and young children and reduces absorption of dietary calcium from the normal range of 60–80% to as low as 15%, whereas above 40nmol/L is needed to prevent osteomalacia bone loss in the elderly, and above 50nmol/L to be sufficient for all health needs. Other sources have defined deficiency as less than 25nmol/L, insufficiency as 30–50nmol/L and optimal as greater than 75nmol/L. Part of the controversy is because studies have reported differences in serum levels of 25D between ethnic groups, with studies pointing to genetic as well as environmental reasons behind these variations. African-American populations have lower serum 25D than their age-matched white population, but at all ages have superior calcium absorption efficiency, a higher bone mineral density, and as elderly, a lower risk of osteoporosis and fractures. Supplementation in this population to achieve proposed 'standard' concentrations could, in theory, cause harmful vascular calcification.
Using the 25D assay as a screening tool of the generally healthy population to identify and treat individuals is considered not as cost-effective as a government-mandated fortification program. Instead, there is a recommendation that testing should be limited to those showing symptoms of vitamin D deficiency or who have health conditions known to cause vitamin deficiency.