A Short Circular History of Vitamin D from its Discovery to its Effects

The discovery of vitamin D. It was as early as the mid-1600s that Whistler (1) and Glisson (2)independently published scientific descriptions (in Latin!) of rickets, caused, we now know, by a vitamin D deficiency. However neither treatise recognised the crucial role of diet or exposure to sunlight on the prevention of this disease. Around 200 years later, in 1840, a Polish physician called Sniadecki realised that cases of rickets occurred in children living in the industrial centre of Warsaw but did not occur in children living in the country outside Warsaw. He surmised that lack of exposure to sunlight in the narrow, crowded streets of the city where there was considerable pollution due to the burning of coal and wood, caused the disease. Such a view was poorly received at the time as it seemed inconceivable that the sun could have any useful benefit on the skeleton. The prevalence of rickets increased as industrial processes and labour expanded and, by the end of the nineteenth century, this bone disorder was estimated to affect more than 90% of children living in such urban polluted environments in Europe. Similarly, as Boston and New York City grew in the late 1800s, so did the number of cases until, in 1900, more than 80% of children in Boston were reported to suffer from rickets. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service url: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: ISSN 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, Volume 268, Issue 2, 2005: 57-58 doi:10.2218/resmedica.v268i2.1031 A Short Circular History of Vitamin D from its Discovery to its Effects

A Short Circular History of Vitamin D from its Discovery to its Effects The discovery of vitamin D It was as early as the m id-1600s that W histler1 and Glisson2 independently published scientific descriptions (in Latin!) o f rickets, caused, we now know, by a vitamin D deficiency.However neither treatise recognised the crucial role o f diet or exposure to sunlight on the prevention o f this disease.Around 200 years later, in 1840, a Polish physician called Sniadecki realised that cases o f rickets occurred in children living in the industrial centre o f Warsaw but did not occur in children living in the country outside Warsaw.He surmised that lack o f exposure to sunlight in the narrow, crowded streets o f the city where there was considerable pollution due to the burning o f coal and wood, caused the disease.Such a view was poorly received at the time as it seemed inconceivable that the sun could have any useful benefit on the skeleton.The prevalence o f rickets increased as industrial processes and labour expanded and, by the end o f the nineteenth century, this bone disorder was estimated to affect more than 90% o f children living in such urban polluted environments in Europe.
Similarly, as Boston and New York City grew in the late 1800s, so did the number o f cases until, in 1900, more than 80% o f children in Boston were reported to suffer from rickets.
In 1918 Sir Edward M ellanby discovered that beagles, housed exclusively indoors and fed a diet o f oatmeal, developed rickets but that the addition o f cod liver oil to the food treated the disease successfully3.He wrote in 1921 "The action o ffa ls in rickets is due to a vitamin or accessory fo o d fa cto r which they contain, probably identical with the fat-soluble vitamin Various experiments by Hess, Steenbock and Black in the 1920s followed in which excised pieces o f rat skin were UV-irradiated or rat food was UV-irradiated.It must have been astonishing at the time to establish that both could be used as a d ietary source to treat rats w ith rickets.
Concurrently the first fat-soluble vitamin (A) and water-soluble vitamins (B and C) were being discovered; the factor protecting against rickets was known to be fat-soluble and was given the next letter in the alphabet -D.It was classified as a vitamin although it was recognised from the beginning that it was not necessarily required as a dietary constituent.
The chemical structures o f the various forms o f vitamin D were determined in the 1920s and 1930s by W indaus and colleagues'1 in G oettingen, Germany.Windaus was awarded the Nobel Prize in Chemistry in 1928 " for services rendered through his research into the constitution o f the sterols and their connection with the vitamins".The biologically active form o f vitamin D, found in the skin and called D3, was characterised in 1936 (see Figure 1), and was shown to result from the ultraviolet (UV) radiation o f 7-dehydrocholesterol. Thus vitamin D was established as a steroid.Very soon after this, the component in cod liver oil that prevented rickets was identified as vitamin D3.
Vitamin D in the diet is present as either vitamin D, if the source is plant, or D3 if animal.Few foods naturally contain vitamin D. Most is found in oily fish such as salmon, meat and eggs.Fat spreads and breakfast cereals are fortified with vitamin D. In the States orange juice, milk and some breads are also fortified.In the 1930s, vitamin D was added to many more American food-stuffs including peanut butter and hot dogs and even to a beer, marketed as having "sunny energy" .

Too much vitamin D docs you no good
It has been recognised for more than 50 years that too much vitamin D can result in intoxication, possibly due to the increased activity o f l,2 5 (O H )2D. T his is m anifest by nausea, vom iting, poor appetite, weakness and weight loss.Calcium levels are raised in the blood leading to a confused mental state and heart rhythm abnormalities.Calcinosis can also occur.There is no evidence that sun exposure, even at high levels, can cause vitamin D intoxication, and diet is also unlikely to either, although this can happen on occasion.After the second World War, excess amounts o f vitamin D were added to some milk products and this resulted in sporadic outbreaks in Britain o f vitamin D intoxication in infants and young children7.Such an outcome is not entirely past history as vitamin D toxicity was reported as recently as last year to occur in babies in Japan who had received prolonged feeding o f premature infant formula with a high vitamin D content.
With increasing interest by the general public in a "healthy" diet, it is possible that toxicity could occur nowadays from a high intake o f vitamin D in supplem ents, such a m ulti-vitam in pills.The safe upper limit recommended for the ingestion o f vitamin D is generally considered to be 25 mg/day for infants and 50 mg/day for all other ages, although some reports suggest that amounts considerably higher than these would still not represent a health hazard8.

Too little vitamin D does you no good
As vitam in D plays a m ajor role in the grow th, developm ent and maintenance o f bone health, any deficiency leads to mineralization defects with an increased risk o f osteoporosis, osteomalacia and fractures in adults, and rickets in children w ith a decrease in their genetically programmed height.An exciting discovery was made in 1979 by Stum pf and colleagues9 that vitamin D receptors are present in many part o f the body, in addition to the obvious locations associated with calcium metabolism -the gastro-intestinal tract, bone and kidney.This work led to the idea that vitamin D deficiency may be important in various nonskeletal disorders.Subsequently 1,25(OH)2D was demonstrated to inhibit the proliferation o f several cell types, to stimulate them to differentiate and, most recently, to act as an anti-apoptotic factor.As a result o f these various properties, many physiological functions have been attributed to vitamin D, including stimulation o f insulin production, modulation o f antigen presenting cell and T lym phocyte activities, prevention o f inflammatory bowel disease, photoprotection o f skin and reduction in blood pressure (reviewed in l0).
In addition to this remarkable list, vitamin D has been proposed to lower the risk o f several types o f internal cancers and autoimmune diseases.
Evidence to support this hypothesis has been gathering over the past 20 years or so with Cedric Garland and colleagues in the States being the first to note the association".More recent work along similar lines has been carried out by W illiam G rant12.The main indications have come from epidemiological studies at a population level in which a latitude gradient has been established for various tumours, such as colorectal, large bowel, breast and prostate.The results revealed that the lower the latitude, and hence the higher the ambient sun exposure, the lower the risk o f developing or dying from these cancers.Similar studies reached the same conclusion when the autoimmune disease, multiple sclerosis, was considered13.For example, in Australia where the genetic background o f the population is sim ilar throughout the whole country, the prevalence o f multiple sclerosis per 100,000 people is 12 in N.Queensland at latitudes o f 12-23°S and 76 per 100,000 people in Tasmania at latitude 45°S.It seem s that high exposure to the sun during childhood and early adolescence is particularly related to a reduced risk o f m ultiple sclerosis.Further reports have associated the consumption o f vitamin D supplements with a lowered risk o f cancer development.
So, how common is vitamin D deficiency? M any experts agree that babies who are entirely breast-fed (there is little vitamin D in human milk) and the elderly who seldom venture outdoors are frequently vitam in D deficient.For the ages in between, much controversy exists at present.Some argue that many working adults and children who do not spend much time outdoors or who rarely exposure their skin to sunlight may be at high risk o f vitamin D deficiency, especially during the winter period.

• RES M ED I C A
between the hours o f 10 am and 3 pm in the spring, sum m er and autumn is crucial.As vitamin D, is fat soluble, it can be stored in the body fat, thus providing a means o f seeing us through the winter months when there is essentially no solar UVB irradiation.
Secondly human behaviour with respect to sun exposure is very variable.In some cases, clothes are thrown o ff and lying in the full sun to develophe increased risk o f skin cancer induction due to excessive sun exposure is taken into account with the wearing o f protective clothing, hats, sunglasses and use o f sunblocks.For example a sunscreen with a sun protection factor o f 8 (thus allowing 8x greater time in the sun without burning) reduces the capacity o f the skin to produce vitamin D3 by more than 95%.What a dilemma -how to exposure yourself to sufficient sun to ensure the production o f vitamin D while, at the same time, not increasing your chances o f developing skin cancer!Michael Holick, in particular, has put forward the view that the population at large in developed countries may be becoming vitamin D deficient.He published a book in 2004 called "The UV Advantage".In it, he explained how we need solar irradiation on unprotected skin to create vitamin D. T his point w as considered contrary to governm ent health warnings regarding the dangers o f being out in the sun, and Holick was asked to resign late in 2004 from the Department o f Dermatology at the Boston School o f Medicine.
The consensus view at present is that we should expose ourselves to an "intelligent" amount o f sunlight.The dose should certainly be less than that required to redden the skin.Indeed as little as exposure o f the hands, arms and face 2-3 times weekly for 15 minutes on each occasion when the weather allows is probably sufficient1415.
So the history o f vitamin D is certainly not at an end.The story continues to unfold, even after 400 years o f research, and more revelations will surely follow as further knowledge regarding this intriguing molecule emerges.
M edical M icrobiology, School o f B iom edical and L aboratory Sciences, University o f E dinburgh, T eviot Place E D IN B U R G H , EM 8 9AG

For
most people living "normal" lives, more than 90% o f their vitamin D requirement is derived from exposure to the UV radiation in sunlight.The body has a huge capacity to produce vitamin D: for example, exposure of 6% o f the skin surface to summer sunlight for approximately 30 minutes around noon on a clear day in the UK would be equal to ingesting about 10 mg vitamin D. A 25(OH)D blood level o f between 50 and 125 nmol/L (20-50 ng/m L) is considered optim al, with levels below 25 nm ol/L indicating severe deficiency.An interesting study published in 19956 involved the crew o f an American submarine and revealed a steady decline in the 25(OH)D concentration from a starting level o f 78 nmol/L to 48 nmol/L after 2 months under the sea.This was despite a Navy diet that included milk and breakfast cereals fortified with vitamin D. Since the 1960s, a daily dietary allowance for children o f 10 m g vitamin D has been recommended -this was based on nothing more scientific than the vitamin D content o f a teaspoon o f cod-liver oil!In adults 5m g daily was recommended.Many experts today believe that these values are too low by several-fold.

First the amount o
f UV radiation in sunlight varies markedly depending on factors such as the time o f day, season, latitude, cloud cover and aerial pollution.Because o f the zenith angle o f the sun to the earth in the early morning and late afternoon and in winter, most UVB photons are efficiently absorbed by the ozone layer.As a result, little or no UVB reaches the skin and so the production of vitamin D, does not occur.Therefore sun exposure F i g u r e 1 : T h e m e ta b o lic p a t h w a y a n d f u n c tio n s o f v ita m in D .
Astonishing figures have been published recently, such as 40% o f the US population, 48% o f girls aged 9-11 years old and 80% o f nursing home of patients suffer from a vitamin D insufficiency.Even in areas o f the world intense insolation such as Queensland, high rates o f vitamin D insufficiency have been reported.Indeed the lack o f vitamin D has been called "an unrecognised epidemic" in adults over 50 years o f age.H ow do we e n su re a "p e rfe c t" a m o u n t o f vitam in D :' As almost all o f our vitamin D normally comes from the action o f sunlight on our skins, attempts have been made to calculate how much exposure is required to maintain adequate vitamin D levels for good health.For several reasons, such estimates are very difficult to establish.