Scribd Logo
Upload

Welcome to Scribd!

  • Sunlight and Vitamin D - Compressed

    Uploaded by

    BERTO SIGALA
    12 views59 pages

    Original Title

    Sunlight and Vitamin D_Compressed

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Report this Document

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    12 views59 pages

    Sunlight and Vitamin D - Compressed

    Uploaded by

    BERTO SIGALA

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    of 59
    Tavorroncie Dermato Entocrinology Dermato-Endocrinology {SS (Prine) 1938-1980 (Online) journal homepage: hrps:/wwwy.tandfonline comili/kcler20 Sunlight and Vitamin D A global perspective for health Matthias Wacker & Michael F. Holick To cite this article: Matthias Wacker & Michael F. Holick (2013) Sunlight and Vitamin D, Dermato-Endocrinology, 5:1, 51-108, DOI: 10.4161/derm.24494 To link to this article: https://doi.org/10.4161/derm.24494 conyrehte 2013 andes osience ER) Putts ontne: on 2013 GF submityourarticie otis journal al Articie views: 31396 BE View related arcies oF CR) cing articles: 281 View iting articles Full Terms & Conditions of access and use can be found at https.“ wonrtandfonline.comvaction/journallnformation?journalCodeskder20 sty br REVIEW Bloscience Sunlight and Vitamin D A global perspective for health Matthias Wacker and Michael F, Holick* Deparment Made: Sectlon of Erect Nuvian, and Diabetes Vth, hn anon Research Labora: oston Une Medel Cate Keywords: sunlight, vitamin D, UV radiation, UVB, rickets, Vitamin D isthe sunshine vitamin that has been produced on this earth for more than 500 milion years. During exposure 10 sunlight -dehydrocholesterolintheskin absorbs UV Bradiation and is converted to previtarin D, which in turn isomerizes Jnto vitamin D,. Previtamin D, and vitamin D, also absorbsUV B radiation and are converted into 2 variety of photoprodtcts some of which have unique biologic properties. Sun induced Vitamin © synthesis is greatly influenced by season, time of day, latitude, alttude, air pollution, skin pigmentation, sunscreen use, passing through glass and plastic, and aging. Vitamin Dis metabolized sequentially in the liver and kidneys Into 25-hydroxyvitamin D which is a major circulating form. and 1,25-dinydroxyvitamin D which is the biologically active form respectively 1,25-dihydroxyvitamin Dplaysanimportant role In regulating calcium and phosphate metabolism for maintenance of metabolic functions and for skeletal health. Most cells and organs in the body have a vitamin D receptor and many cells and organs are able to produce 1125-dihydroxyultamin D. As a result 1,25-dihydroxyvitamin D influences a large number of biologic pathways which may help explain association studies relating vitamin D deficiency and living at higher latitudes with increased risk for many chronic diseases induding autoimmune diseases, some cancets, cardiovascular disease, infectious disease, schizophrenia and type 2 diabetes. A three-part strategy of {increasing food fortification programs with vitamin D, sensible sun exposure recommendations and encouraging ingestion of ‘vitamin Osupplement when needed shoulel be implemented to prevent global vitamin D deficiency and ts negative health consequences, Prehistoric Perspective Life forms began to evolve in the oceans over 1 billion years ago. They took advantage of sunlight and used ie as an energy source to generate carbohydrates ext phytoplankton including Emiliania huxleyi (which is @ eoc- colithophore, ie, has a calcium casbonate exoskeleton) which hhas existed unchanged in the Sargasso Sea (Atlantic Ocean) for ‘more than 500 million years when exposed to sunlight noc only “ously some of the extl *Conespondence to: Michiel F Holek Email mihotkkgbueds Sub tead:035/1 Ace ed 0228/13 a76 wovwlandesbioselence corn hydroxyvitamin D, latitude, cancer, autoimmune, UV lamp photosynthesized glucose bu also produced vitamin D (Fig. 1)! This phytoplankton produces a luge amount of ergosterol that ‘when exposed to sunlight absorbs ultravioler B (UVB) radiation and undergoes photolysis reaction to form previtamin D,. Once formad this thermodynamically unstable isomer is eranstormed ito vitamin D,. Similarly yeast and fang) also contain high amounts of ergosterol and when exposed to sunlight produce vitamin D,! Although the functions of ergosterol and vitamin D, are unknown in these primitive unicellular phorosymthesizing facto- les there are at least three possible functions that have been pro- posed. Ergosterol can efficiently absoeb UVB radiation, which would make itan ideal nacural sunscreen to protect UVB sensi- tive macromolecules inthe organism including ts proteins, RNA and DNA (Fig. 2) ‘After absorbing UVB radiation previtamin D, is produced. lus absorpeion spectrum with a wavelength maximum at 260 nm ‘overlaps the UV absorption spectrum for both DNA and RNA and thus would be able wo protect DNA and RNA from phowo- damage (Fig. 2),’ When previtamin D, is exposed to UVB radia- tion itis comerted t0 tachysterol, which has 2 UV absorption spectrum with a wavelengeh maximum at 282 nm which over laps the UV absorprion spectrum for amino acids in proains that have conjugated double bonds including tryptophan and tyrosine (Fig. 1 and 2)!" Thus early ia evolution a8 organisms began to utilize solar energy for photosynthesis they needed a sun protee- tion factor to absorb solar UVB radiation to minimize damage to UVB sensitive molecules. Frgostcrol, previtamin D., and its photoproducts could have acted asan ideal UVB sunscreen since they could absorb UVB radiation and dissipate its energy by the rearrangement of the double bonds.* ‘The amount of previtamin D, and photoproducts produced during sun exposure could also have been a photochemical signal (ectinometer) «0 tell che organism thac ic has been exposed to ‘enough solar UVB radiation and to signal it to leave che surface ito deeper water where it would no longer be exposed to UVB radiation due to che oceans ability wo absorb ehis solar energy. Ie has also been speculated that if ergosterol was principally present in the plasma membrane and contained within the lipid bilayer that this rigid planar seructuse after exposure « solar UVB radiation would be transformed into a more flexible vita- min D, molecule that would likely be cclease lular space. This process could alter membrane permeability and osibly open up a pore to permit the entrance and exit of ions co the extracel- Dermato Endocrinology st ©2013 Landes Bioscience. Do not distribute. Figure 1. Microscopie plete of Frlians hualeywhichisa cocalitho- ‘hore Le, has a calcium carbonate exoskeleton, Holic, copyght 213 Reproduced with permission. including calcium. This could be the connection for why verte Dbrates including humans have depended on sun exposuze for the ‘maintenance of thei calcium metabolism.” Historical Perspective As the industrial revolution swept acoss Northean Europein the 6005 resulting in buildings bile in close proximity and coal burning causing a pall of air pollation (Fig. 3) so too appeared a bone deforming disease sickers in childzen that had devastating health consequences (Fig. 4).7 ‘The fin insight into the possible relationship between the industrialization of Northen Europe and ricees was made by Sniadecki® (Fig, $A) in 1822 when he concluded that children ‘who lived in the inner city of Warsaw had a high i ets bocauseof thei lack of sun exposure. This w. his clinical observations tha children living in rural areas outside of Warsaw di nor suffer fom rickets while childzen born and raised in Warsaw were plagued with the disease. More than 70 y luver Palm" came to the sime conclusion based on reports from uuesin thied world countries including India and Chin that rickets was uncommon compared with die high prevalence of the disease in children living in London. Anocher 30 y would pass before Huldschinsky’*" (Fig. 5B) would repore chat rachitic children exposed to a mercury arc lamp had dramatic radiologic improvement of their rickets several months later. He clevesly also realized that exposing one acm of a child with rickets had the same dramatic radiologic improvement in che forearm of the arm not exposed to the meraury arc lamp, He therefore correctly concluded that it was likely that something was being made in the skin and entered into the cireulation to improve the global bone health of the child (Fig, 6). Finally in 1921 Hess and Ungee (Fig. 5C) exposed rachitic children to sunlight on the roof of their hospital in New York City and demonstrated signifi cant tadiologic improvement in the children’s rickets. These phy- ans also realized chat children of color were at much higher risk for rickets and concluded that they needed longer expostr to sunlight ro both rrear and prevent rickets, By turn of the 20th century it was estimated that upwards ‘of 80-90% of children living in Northeen Europe and in Northeastern United States had evidence of rickets.” Steenbock and Black” (Fig, 5D) and Hess and Weinstock’ exposed various foods including cotton seed oil, corn oil, and milk to UVB radia demonstrated that this process imparted antirachitic activity for zodents, This led to the addition oF ergosterol co milk followed by UVB irradiation or the addition of hhad been previously exposed to UVB radiation or to the addition of vitamin D, co the milk (Fig, 7) Absorption 240 20 280 800 320 340 WAVELENGTH (nm) tecol that Absorption = 240 280 2B 300 320 340 | Figure 2. UWabsorption specta fori previamin , (B eachyterl VELENCTH {€ provieaminD,-dehydrocholesterll (D)lumisteol, |EIONA,and Ne (om) (Flalbumin. Hoek, copyright 2007 Reproduced with permission. 32 Dematendoctinelgy Volume Sissue ©2013 Landes Bioscience. Do not distribute. This process was quickly embraced by the dairy processors and in the early 1930s estetially all milk in the United Staves and in including Great Britain and other European countries had vitamin D fortified mill, The United States government also established an agency in 1951 whose goal ‘was «0 promore sensible sun exposure of young children to pre vent rickets and improve their bone health (Fig. 8)?" Within a few years these interventions essentially eradicated rickers}7™" Vitamin D became so popular that in the 1930s and 1940s a wide variety of foods and beverages as well as personal care ‘most industrialized count products were fortified with vitamin D.” They included not only milleand other dairy products bur also soda pop, beer, ht dogs, custard and even soapand shaving cream (Figs. 9A-D).”” However in the early 1950s an ourbseak of hypercalcemia in infants who had tion led to an investigation by che Royal College of Physicians The experts concluded thar this was most likely duc to vitamin D intoxication since a similar presentation had been observed in neonatal rodents born of mothers who were fed high doses of vitamin De lation quickly followed banning the Forif cation of any food o personal use products with vitamin D in Great Britain. This ban quickly spread across Europe and for the most part remains in ellecc today with che exception of a few foods including margarine and some cereals being fortified with vitamin D.°"” Ie is however likely that these children had fn faces, heart problems, and mental wetasda- Williams syndrome which is associated with elf faces, mental retardation, heart problems, and hypercalcemia due to @ hyper sensitivity o vitamin D.” Sweden and Finland now permic mille to be fortified with vitamin D."™ Iris worth noting that mill ure 3 Photograph from Glasgow, Gest ten, Inaba 170 show. Ing thatthe bulldings are built in cose proximity wo each ator. Hoick ‘opylight 1994. Reproduced with permission. hhas been fortified with 100 IU vitamin D/8 oz for the past 80+ yeurs without any reposts of toxicity in infants. In che past 10 y juice products including orange juice have bees fortified in the United States with 100 TU vitamin D/8 ox without any reports of toxicity? Photochemistry of Provitamin D, During exposure sunlighe solar radia- tion with wavelengths of 290-315 nm penetrate into the skin and are absorbed by proteins, DNA and RNA as well as T-dchydrocholesterol Mos of this UVB radiation is absorbed in the

    ) and in human shin in vito a€37°C Reproduced with (30g) an dhe nadir was observed in February (-14 nglsil) (Fig. 44)" A similar observation was made in posumenopausal women in Denmark. Those who had regular sun exposuce achieved a blood level of 25(QH)D of ~45 ng/ml. compared with women who aveided divest sun exposure had a 25(OH)D of -23 ng/ml. This was ako supposted by the fact tht hours of sun exposure was directly elated to czculating concentrations of 25(0H)D (Fig. 45). Dermato Endocrinology 9 ©2013 Landes Bioscience. Do not distribute. “1025 10.00 9.75 Ink 950 925 9.00 22 29 24 28 26 27 28 29 30 31 Inn Figure 15 fects ofphorpholipid earbon chain ength and saturation onthe ratéof pre D, to vitamin, Komerzatonin liposomes, te ‘Sunlight and Non-Calcemic Health Benefits Historical perspective, People have a feeling of wellbeing when exposed to sunlight, This may be due to the fact chat kerat- nocytes produce B-endorphin when exposed to UV radiation.” In the carly 1900s Finsen (Fig. 47) observad that exposure © sunlight (Fig. 48) dramatically improved cutaneous skin lesions caused by a tuberculosis infection (lupus vulgaris) and received the Nobel Prize in 1903 for his enlightening observations. This led to che use of solariums as a way to treat patients with tuberculosis and. gave rise to the use of heliotherapy to improve health." Heliotherapy was uscd weat a wide variety of chronic illnesses in the easly 1900s and i is still practiced throughout the world and especially in Northern Furope ‘The rise inthe use of pharmaceuticals to treat acute and chronic diseases led to the demise of haliotherapy especially in United Constontn.carbon numberof phospholipid chain Reproduced with States." “80177 Permasion rm et Sunlight and Vitamin D: RT = The Cancer Connection = One of the Fis association studies ae selating sun exposure with reducad z fib arcades wed reported ia 1916 i by Hoffman,” who found dat bi Et i ing at a higher laiaade was asso- is ciated wich an increased sis for Z ae mortality from cancer, He caea- a ~ | pared cancer mortalicy between CS ee sew ns | 1908 and 1912 and obnerved that cancer mortality increased with increasing distance from the equa- Figure 16, The se healthy 31 yen old female eceWeda whole body exposire na Bikini Kathing si) 101175 MED of ultiaviolet 8 radietion and weeks later received 50,000 Us f vitamin D3. Blood samples ‘were collected or 168 hours andthe blood was measured fe vtanin D3 by high pesfoemance 20 aglml. These results together suggested that living at higher latitudes meant less exposuze to vitamin D producing sunlighe and therefore the tac chere was wovwlandesbioselence corn ‘connection with the association with latitude and cancer moztal- lationship with cancer mortal- D status. Even in California where there is a ity could be inked to an inverse ity and vit large difference in latitude there was « positive assodation with, colorectal cancer prevalence with latitude (Fig. 52). ‘A mukiude of epidemiologic studies folloed these ini tial observations not only in the United States and Canada but worldwide. Grane reported a dramatic inverse rdationship between premature mortality duc to cancer with UV exposure in both men and women (Fig. $3). In che United States, imerse Dermato Endocrinology a ©2013 Landes Bioscience. Do not distribute. 7-DHC and photoproducts (%) Figure 18. n analyst ofthe phtolys of 7-dehydrochoesterl (7-DHC) athe basal-cal ayer andthe appearance ofthe photaprod- ets previtamind, (Pre) lumistra, Land tachysteral, (7) with Increasing time of exposute to equator simulated so UV radiation. Bars above datapoints shou the standard era of the mean of tee determinations Holic, copytigt 981 Beprodiced wlth permission. associations with exposure to solar UVB radiation and cancer tisk and mortality were reported for ovarian™ and breast can- cen cancers of the digestive system” and prostate cancet!™ ‘A meteanalysis of studies reporting eancer incidence races for more than 100 countries including Auserali, China, Japan, Spain among, others revealed an inverse relationship with solar UVB exposure for 15 types of cancer inchiding bladder, breast, cervical, colon, endomettial, esophageal, gastric, ling, ovarian, pancreatic, rectal, renal and vulvar cancer as well as Hodgkin's and non-Hodgkin's lymphoma." Boscoe and Schymusa™ found thar the relative risk of cancer incidence and mortality for numer fous malignancies was strongly related to solar UVB exposure (Fig. 54). Giovannucci et al." conducted 2 prospective study in ‘men relating predictors of vitamin D status and cancer incidence and also found an inverse association (Fig. 55). Luscombe ct al. reported men who worked outdoors had a 3y hiarus before developing prostate cancer compared with indoor workers (Fig. 56). It was also reported that aduls who developed lymphoma hhad a decreased risk for mortality if chey had more sun expo- sure asa wenaget:” Knight et al.” asked women in Canada who hhad breast cancer how much sun exposure they had during their teenage and young adult life and compared this sun exposure w women matched for age, ethnicity and place of residence. She coneluded thar women who had the most sun exposure from ages 1010 19y reduced their risk of developing breast cancer by more than 60% when comparing che highest quartile of outdoor activ- ities with the lowest. Also women over 40 y who had die most os Dermatondactinalagy sun exposure lost dhe benefit since their isk was no diferent than those who had che lease sun exposure, The observational and epidemiologic studies relaxing increased latitude with increased risk for cancers suggest a pos- sible role of sun induced vitamin D, synthesis as the beneficial factor responsible for these observations.” eis known chat expo- sure to sunlight also has other physiologic effects on the skin including akering the immune system,""” increasing production ‘of B endorphin and nitric oxide." There are however a vatiety ‘of seudies including interventional studies and association stude ies supporting the notion that improvement in vitamin D stax tus reduced risk of many deadly cancers?" Woo et al. reported thar more than 50% of men with completed local teat= ment of prostate cancer and ising PSA levels in the absence of | symproms had a decrease in their PSA serum levels when com mening the supplementation of 2000 TUs vitamin D per day had a sttistcaly significant decrease in the rate of PSA vise (Fig, 7). Lappe ot al" reported a more than 60% reduction in the development ofall cancers in a small study of postmenopausal ‘women who received calcium supplementation (1500 mg) along ‘with 1100 TUs of vitamin D, daily compared with women who received placebo (Fig. 58). The Womens Health Inidtive (WHD initially reported chat women who wok 1000 mg of calcium and 400 IUs of vitamin D, daily for up to 8 y had no euced risk for colorectal cancer."® However the women in this study who bad a baseline 25(OH)D < 12 ngiml. had a 253% increased risk for developing colorectal cancer compered with women who had baseline 25(OH)D of at least 23 ngimL, Further scrutiny of the data from che WHI revealed that only (60% of che women admitted taking their calcium and vieamin supplement at least 80% of the time. However those women not on penonal calcium and or vitamin D supplementation but ‘who took 400 1Us of vitamin D, daily along with calcium sup- plemeneation as pare of the WHI study for 8 y had a 14-20% reduced risk for developing breast cancer and a 179 reduced rik for developing colorectal cancer” The importance of vitamin Din seducing sisk of colorectal cancer has also been supported by the observation that the vitamin D receptor polymorphisms ‘were associated with color ative meta- analysis on the optimal status for colorectal cancer prevention showed thar a 25(OH)D level of 34 ng/ml was associated with 1 509% reduced risk of developing colorectal cancer." Another study showed thar the 25(OH)D level and the risk for developing colorectal adenoma were inversdy correlated and chat the assodia- tion was modified by the Tag! polymomphism of the VDR." The United States Preventative Services Task Force evaluated vieamin supplementation and risk for colorectal cancer and concluded that for every 4 ng/ml increase in Greulating concentrations of 25(OH)D was associated with 2 6% (95% Cl 3-99%) reduced Fisk for colorectal cancer ‘Sunlight and Vitamin D: Innate Immune Health Codliveroil was used in the mid-180s to treat tuberculosis" In the easly 1900s heliotherapy was promoted for treating both Volume Stee ©2013 Landes Bioscience. Do not distribute. Figure 19. whan vitain Ds tadated rs converted 1056 ane vitamin D, andat east 6 photopreducts knownassuprastrols Holic copyright 2013, Reproduced with permission, PrevitaminD — Tox.C1,C2_— Tox. B1-3 Tox.A2 Tox. A1,A3_—Tachysterol Figure 20. Once presitanin, formed, thas theabilty to wotate ound the 6-7 bond, Relaxation vis tation about the 7 hondfollowed by UY Imnadiation can verse toa wide variety of wxsteols and tachysteto. Hollck,copnight 2013, Reproduced with permission. skin and pulmonary tuberculosis? Ie yas also recognized chat likely wo die of chem." !""Therefore sun exposure and vitamin young children with rickets had 2 much higher risk of developing were used in che eadly 1900s to treat and prevent tuberculo- pneumonia and upper respiratory tact infections and were more sis and upper respiratory tract infections. wovwlandesbioselence corn Dermato Endocrinology a ©2013 Landes Bioscience. Do not distribute. Ay * | 100 I % Control by 4206.2 A study of 156 neonates revealed thatthe risk for acquiring respiratory syncytial virus (RSV), « pathogen causing severe lower respiratory act infection, was 6-fold higher in infants who had a blood leva of 25(0H)D < 20 ngiml compared with infants who had a blood level of 35(OH)D > 30 ng/mL.” ‘Macrophages play an important cole in fighting infectious diseases by ingesting and then destroying them.” When a macrophage 3 ingests an infectious agent like cuberculo- Sis tolldike receptors ar¢ activated to initiate an innate immune response." One of the fest responses is signal teansduction to the rnucleus to increase the expression of the VDR and the 25-hydroxyvitaminT)-1-hydeoxylase B™ 8 2 : i. 128000, senses ipa (C¥P27B1). This resules in the conversion fof 25(OH)D to 1.25(OH),D. 1,25(0H) interacts with the VDR and incx ‘expression of cathelicidin which is amember of the defensin proteins and rapidly permeal- ines susceprible infectious agents resulting in their destruction (Fig, 60). This is one of the mechanisms believal to be zesponsble for vitamin D reducing tisk of infectious diseases. Liu et al’ also reported chat the extent of antimicrobial activity of a monocyte exposed to Mycobacterium tuberculosis depended on the 25(OH)D levels of the medium in whieh the monocytes were cultured. Monocytes ccultuzed in serum of Afican-American indi- the Concsraton Figure 21. A) Folfefation ofhuman keratinocytes afterineubation with diferent supraster. olscompored with negative conto (100%. Suprasterls and. shawa stang antiproifta tive actity as well as the positive conti! 125)0H),D, (B) Dose dependent antiproliferatve Inberatinocytes Maan SEM*p pytight 2013, Reproduced wlth activity of supeasteras nd compated with 1.25(0H) 001,*¥p 0.001 compared with cortio! 100% Hol, permission, Hope-Simpson' had speculated that there was a seasonal stimulus responsible for reducing infectious diseases during the summer Ie is known for example that influenza infeetion is most prevalent in the winter months at latitudes North and South of the equator but is sporadic throughoue the year in children and adults who live near the equator (Fig. 59). Ie has been hypoth: ‘sized char the seasonal variation could be due toa seasonal varia ‘Greulating levels of 25(OH)D, and intervention studies have hdped to support this hypothesis. Healehy adults living in New England who had 25(OH)D blood levels of -38 ng/mL approximately halved their sisk of develop ing acute viral espiratory act infections.” School children in Japan who received 1200 IUs of vitamin D, daily for4 mo during the winter reduced their cisk of developing influenza infection tion Several observational os Dermato Endocrinology viduals who were vitamin D deficient (ean 8 ngloL) mounted an ineffective eathel- cidin mRNA response upon exposure to M. tuberculosis, however the supplementation of fh 25(OH)D (mean -30 ng/mL) restored the tll-like receptor mediated indue- tion of cathelicidin mRNA, This was substan- tiated by Adams ct al. who not only showed, that the expresion of cathelicidin by mon: cytes exposed to M. ruberculasis lipapep- tides was significantly enhanced by addition ‘of exogenous 25(OH)D to the vitamin D doficiene serum but that sesum from vitamin D-supplemented ssbjets hed the same cflece. This data added support forthe imp ingaserum 25(OH)D » 30 ngiml.to genaave an effective cathe- licidin esponse following activation of monocytes /macrophages. Ic has also been suggested besed on studies in mice and in vito that the local kerainoeyte production of 1,25(OH),D. fiom 25(OH)D, in the skin and oral pharynx enhanced che pro” duction of cathelicidin supporting the concept chat maineaining sccum 25(OH)D above 30 ng/ml may alsobe important i Fight ing snd oropharynx!” This may also help explain the observation thatthe risk for periodontal dis- ‘ascis higher in adults who have the lowes cicculating coucentza- tions of 25(OH)D." Calcium and vitamin D supplementation the sera ance of maincain- fections in both che d Volume Stee ©2013 Landes Bioscience. Do not distribute. was assodated with 2 lower tsk of woth loss in elderly men and women’ respectively and with beter periodontal health," ‘Sunlight and Vitamin D: Autoimmunity Protection There ate a vatiety of association seuies dem onstrating that being born o Living near che equator reduces risk of several autoimmune diseases" Being born and living for the fist 10 ya alatinude of -40" North compared with -33" North increaes a person's tsk of developing sukiple sclerosis by 100% (Fig 61). Manger etal made the observ tion that high circulating levels of 25(OH)D were associated with lower rise of mulrple salerosis and tha women who had an intake of vitamin D of 2 400 TU vitamin D por day reduced thir tsk of developing mulkiple le tosis hy more than 409%." ‘A plor of the incidence of type 1 diahe tes vs. latitude demonstrated an impressive Usshaped carve. Children younger than 14 y during 1990-1994 in 51 regions worldwide demonstrated a 10-15 fold increase ia id for developing type 1 diabetes if chey were born far Norcheen and Southern laiudes (Fig ae 1 was also reported chat spring births were associated with ineseased Fikeibood of developing ype 1 diabetes. These findings indicate a potential sole of vitamin D in che pathogenesis of type 1 diabetes mck Titus. This hypothesis is supposted by an observational study that childzeo in Finland who received 2000 TUs of vitamin D daily ding their ise yearoflifein the 19603 reduced their risk of developing type | diabetes 31 y later by 88%. Because of concem % Provtamin D, formation > Zenith Figure 22. The sola zenith angleistheangle made by thesun'slghtwith espect othe vertical the sun bing rectly overhead. Ths angle is ncreased a higher latitudes cary ‘matning and late afternoon when the sun kenotdecty overhead, and ding the winter ‘month. Asthe sola zenith angle increases, the amount ofUV8 radiation reaching the earth's surface'stedced, Therefore at higher latitudes greater distance from the equatar more of ‘the UW radation|sabsorbedby the ozone layer thereby teducing oF eliminating the cutane- ‘4 production vt D, Hole, eopyight 206 Reproduced with permis, 24 Prtaminb tomato © bout vitamin D toxicity theamount of vitamin D_ recommended foe infants in Finland was reduced fise to 1000 1Us daily and then co 400 Us daily, Inserestingly as a resule of this decrease in vitamin D intake Figure 23.lauence of season time fay andatitide onthe synthesis ofprevtamind, inNerhern (and ©) and Southern hem spheres (B and D) “Thehout indeated inCand Dis the B | i endothe th exposute de: Holick, copytight 1988, Reproduced wth permission wovwlandesbioselence corn our of Oxy rrevtonind,fomaton SS eh : i Hour of Day Dermato Endocrinology 6 ©2013 Landes Bioscience. Do not distribute. PRED, AND D, FORMED JAN FEB MAR APR NAY JUW JUL AUG SEP OCT NOY DEC Ampoules Boston 2011 % conversion SP LSE EELS Figure 25. conversion ate of 7-dehydrocholest0l(-DHCito wtamin| [Depending on sme of the day and sean in Hostan 2" Nom. The measurements were conducted after exposing arpa es led with {-DHC wo sunlight. Hole, copy ight 2013, reproduced with permislon. ‘Sacramento ep on Frasleca Latitude ‘Sulfur Dioxlde (opm) Figure 26. heamount of sulfur dioxide ppm measured over one hou ped inSan Diego Los ‘Angeles Son Francisco, and Sacramento on thesame day. Hlick copyright 2005. Reproduced with permision, 6 Dermatondactinalagy Figure 24. Photopiodvctlonef prestaminD, and vitamin from 7DHC thoughout the year in Ushuaia Argenta (lashed bas, 55 de- ‘grees South) and Suenos Ars closed bars, 34docrces South Values fre percentages final 7-DHC. Each bar represents the mean = SEM of ‘three determinations ofthe sample ampules Reproduced with permis sion from Ladizesy there isan impresive increase in che incidence of type | diabetes coccutting in Finland over the past 3 decades (Fig. 63)."* A pronounced Nareh-South gradient hus also been ported for inflammatory bowel disease, in particular Crohn's disease (Fig. 64) & complete data set including demographic daca and lifestyle factors based on the rwo prospective Nurses’ Health Studies (NHS9) and comprising almost 240,000 nurses, ako showed that women from lower lairudes had a consistently lower tisk of developing ulcerative coitisand Crohn's disease compared with women living in higher latitudes.” These observations ‘were supported by 2 prospective cohort study of 72.719 women enrolled in the Nurses’ Health Study showing that 2 higher pre- dicted vitamin D status was associated with a reduced risk of Crohns disease: * ‘A case-control study investigating the association etwaen lativude and cheumatoid arthritis using data from the Nurses’ Healch Smdy suggested that women living in higher lavcudes were at greater risk for rheumawid arthritis (Fig. 65):"” These lnvitude dependent differences in the prevalence of sheumatoid arthritis could be explained by differences in the vitamin D sta- tus, Medio et ao showed in a study in Towa dhae women with the higheseincake of vieamin D reduced their risk of developing sheumatoid arthits by more than 30%.” However, other inves- ‘igaors did noe find such an association when reviewing the daca from this seu." Aldhough the exact mechanisms by which vieamin D may reduce risk forautoimmune diseasesare not fully understood we do knows thae vitamin plays an important role in celli- lar immunity" Inactivated T= and Bdymphocytesare unable to respond 0 1,25(OH),D because they lack a DR. However when they become activated they express. a VDR and fare now responsive to the immuno- modulatory activity of 1,25(OH),D (Big. 60). In Beeells 1,25(OH),D down- regulates imawnoglobulin synthe- sis” and B-cell memory. Thus by doing so it may reduee production of autoantibodies responsible for causing aueoimmune diseases.” 1,25(OH),D also has a mulieude of functions in activated T eels." This hormone decreases T cdl proliferation’ as well as che num ber of Th.-Th,. lymphocytes while Volume Stee ©2013 Landes Bioscience. Do not distribute. increasing Tregulatory lymphocytes™ by increasing the pro- duction of Th,Th, lymphocytes" 1.25(OH),D also dteety inluences the eapretsion and synthesis of several immunomods- Jatory cytokines, Bouillon eval." summarized that 1,25(OH),D downzegulates pro-inflammetory cytokines and. interleukins (IL) such a IL-2, IL-4, IL-8, 1L-12, tumor necrosis factor-c, and incerferoney and upzegulatesan-inflasmmatory ateleukins such as IL-0, ‘Sunlight and Vitamin D: Cardiovascular Health Jn 1997 Rostand et al reported that there was an Inverse asso- ciation with latitude and blood pressure (Fig. 66) and the preva- lence of hypertension. This was followed by the observation of Krause ot al. who reported that exposure to UVB radiation. ina dinical setting not only improved circulating concentea- tions of 25(OH)D by more than 160% bur also significantly reduced both systolic and diastolic blood pressure in patients with hypertension, A control group was exposed to che sime UV lamps that were covered by an aceylic shield absorbing all UVB. radiation and thuswas exposed ro UVA radiation only. The con- tro group's subjects demonstrated no significant change in thei circulating concentrations of 25(OH)D as well as no change in hypertension (Fig, 67), These data suggested that vitamin D may somehow be involved in canliovasculaz health. One of the first insights as co how vitamin D could influence casdiovas OH)_D, suppressed the production of renin,"® This observation was also supported by the repore thae VDR knockout mice havea dysregulation of the renin-angiotensin-aldosterone axis. There have bees a multitude of asociation studics suggest shac vitamin D deficiency noc only increases risk for a myocar- dial infarction by as much as 50% but also was associated with more than one 100% increased sisk of mortal- ity from the heare attack” In the US an estimated 50 million teenagers are vitamin 1D deficiene or insufficient and this was ass0- 24 fold increased risk for high blood pressure! Dong et al: conducted 8 16-week randomized, blinded, clinical trial in 49 normotensive black boys and girls aged 163 + 1.4 y co evaluate the effect of enhanc- ing vitamin D intake ftom 400 TUs or 2000 TU viramin D, daily on arterial wall stiff ness, determined by measuring carotid Fem coral pulse wave velocity, The teenagers who received 400 [Us of vieamin D daily increased their circulating concentrations of 25(OH)D from V4 w 24 ng/mL and had an increase in the carotid-femoral pulse wave velocity (5.38 0 £0.53 m{see t0 5.71 = 0.75 msec; p = 0.016). By contrase teenagers who received 2000 [Us of vitamin D daily for 4 mo noc only increased their blood level of 25(OH)D from 13 to 34 ng/mL. but also showed a significant decrease caular health was che observation chat 25 ciated with Photoproducts (%) wovwlandesbioselence corn > Intonsity (x 10-19 ema) Figure 27. (A Absorption spectia ot NO,NO.,andS0, The absorption spectra show that 50, and NO, absorb UV adhation [280-315 nn) ro: Qultedforeutaneous production of vitamin D.(B) Absorption specttum ‘fozane which also absorbs UVE radiation. Hock copyright 2005, Reproduced with permision. Bot JosaleBNamchoo 1000 2000 3000 4000 5000 Altitude (Meters) Figure 28. Ampoules containing 7-dehydrocholestero| in ethanol were exposed fort h between 130..m. and 12320 pm. at 27"Nowthin India st various aitbdes, The conversion ‘of -dehydrocholestertoprevtarinD, andits photoproducts was determined by HPLC Repeoduced with permision Fonte 6, Dermato Endocrinology ©2013 Landes Bioscience. Do not distribute. a SMe ‘WAVELENGTH fom) 590% ‘4 PREVITAMIN D, SYNTHESIS ‘uss siBaus Vitamin D3 (ng/ml) Figure 30. Vcan = SNM) serum vitamlsD, concentationsin elght orm subjects Four subjects () plied PAEA (para sminobenzbe oc with a SPF of and fur applied vehicle (@)tothe entire skin before exposure to VE. On day 0, al subjects underwent total body exposure to 1 MED minimal erythema dose) UVR UV tation. To convert nanograms of vitamin per mL to nanomoles pet L rmultipiy by 2588. Reproduced with permission one. oa Dematendoctinelgy Figure 28. (A) Teansmission of UV adition through a, glass, plas, and Plavalas (Dupont Chemical Compary, Memphis TN) Holic, copy- right 2003. (8) Plevention of provtamin 0, formation asa resultof gas, plastic or plexllass Dupont chermcal Company, Memphis, 7N) placed between the simulptedsunight our nd the provramlsD, (ONC) Reproduced with peemssion frm fe 3. in carotid-femoral pulse wave velocity (5.41 = 0.73 msec w 5.33 20.79 misec; p = 0.031), Two major coneriburing factors for cardiovascular disease are type 2 diabetes and obesity Ie is well known both in children and adults that there is an inverse association between secum, concentrations of 25(OH)D and body mass index (BMI) due to a sequestration and volumetric dilution of the lipophilic vitamin Din the fat tissue." Furthermoce there i also an association with vitamin D deficiency and increased risk for type 2 diahe- tes." A similar observation was made in the Nurses) Health Study where a combined daily intake of > 1200 mg calcium and > 800 TU vitamin D was associated with a 33% lower risk of type 2 diaberes."” An inverse association between vitamin D sta tus and diabetes was also shown in a study by Seragg et al. ‘The odds ratio for diabetes in non-Hispanic whites and Mexican Ameticans who had 25(OH)D levelsin the highest quartile cu pated with the lowest was reduced by up to 83%." However, this inverse association was not observed in non-Hispanic blacks.” Several epidemiologic studies and prospective studies have reported abighly significantasociation with vitamin D deficiency With nor only type 2 diabetes bur also hypertension, bypedipid. cemia and peripheral vascular disease all causative factors for comnary artery disease, myocandial infarction, heart failure and stroke." The prospective Intermountain Heart Collaborative Study revealed chat in more than 40,000 participants a circulating concentration of 25(OH) D © 15 ngiml. compared with a concentration of > 30 ng/ml. sig nificantly increased all of these risk facto” A meta-analysis examining the association herween vitamin D status of vitamin D_ supplementa tion revealed that adults with the highest circulating concenttation of 25(OH)D had a 43% lower risk of developing cardiometabolic disor ders compared with adults with low levels of 25(OH)D." Furthermore a prospective seudy following up with ‘more chan 2000 adults showed dat the risk of progression from pretype 2 diabetes to type 2 diabetes as reduced by 48% in adults who bad the highest cisculating concentra- tions of 25(OH)D compared with those with the lowest"* Volume Stee ©2013 Landes Bioscience. Do not distribute. Beca idee cells in che pancreas havea VDR and 1,25(OH),D, is & potenc stimulator of insulin production." Ieprovement is vitamin D status bas aso been associated with lzmprovement i insulin sensitivity" mediced by upregulation of insulin recep tor There is evidence that vascular smooch muscle and car dliomyocytes have a VDR™""" and chat 1,25(OH),D, causes vascular relaxation by suppresing the renin-angiotensin-aldo- 710.0% and impeoves casdiomyoeyte coutactl- ity. In addition 1,25(O1),D, inbibits maczophage cholesterol uptake and foam cell fomnation thereby reducing risk for ath- crosclerotc plague formation (Fig. 68). Vieumin D def- cicney negatively affects numerous physiological proceses thar ateimportant inthe pathogenesis of cardiovascular disease, This could explain why vitamin D defcicaey is aswciated with an increased overall and cardiovascular mortality in patients wich metabolic syndrome!" ‘Sunlight, Vitamin D and Mental Health Schinophrenia has hecn associated with inadequate sun exposure and vitamin D (Fig. 69):"” Schizophrenia is more common in the Scandinavian counties." Winter bisths have been asociated with an increased tsk for developing schizophre nia later in ie ev dence in schizoph the Caribbean who moved to cities in countries farther North.” Finnish male infants who secsived 2000 Us of vitamin D dail ducing their fise year of life reduced thai sisk of developing schizophrcaia by 7% compared with infants who received les than 2000 1Us of vitamin D daily Vitamin D could play an indirect role in the pathogen esis of schizophrenia, Several sudies suggest thae prenatal flucnza exposure increases the tink For schizophrenia later in life" The vitamin D status scoms to influence the sek foe an influenza infection. respectivdy vitamin D supplementation hhas proven to deciease the visk for influenza des tchating vitamin D- deficiency with increased risk for depression," Alzheim disease." epilepsy and neurocognitive decline The brain nor only has a VDR buc also a 1-OHase:** Bvidence suggests that 1,25(OH},D, could increase calcium bind ing protein expresion,*” although this could snot be shown in all studies." 1,25(OH),D, could also act by increasing serowonin levds in dhe brain." Furduermore 1,25(OH).D, has ako been demonsteatal to stimulaxe amyloid-B phagocytosis and dearance by macrophages is. Ald ° This ‘may help explain the association between ° dive decline," dementia,” 300 depression” and Alubeimer disease” a high prevaleuce of vitamin D deficiency. 1h. a community seting depressed adults had w 2 S B 8 2 & = = = mer patients wovwlandesbioselence corn 0 — c - «0 : § =» £ 5 oo 10 —— Contrel subjects Long-term PABA Users Figure 31. Serum concenttion of 25-hydioxyvitamin Din longterm Sunscteen usrsand inage- and sex matched conto from same ‘geographical area Sleod samples wete obtained siuitaneousy fam patients and contol. Mean serum 25 hydroxyvtami D level wassiy hifeantly lower kong term sunscreen users (p< 0001), Two long term Sunscreen ers had absolie vitamin D deiciene. 25-hydexyvitamn Devel below 20 mol/L PABA indlcates p-aminobenzoe ack open lice subjects from Philadelphia; close cies, subjects from Spilng- ‘eld Reproduced with permission fem et 4, 400 500 600 WAVELENGTH (nm) 700 800 Figure 32. Absorption spectaumof melanin. Holekcooytight 2008 Reproduced with permision Dermato Endocrinology « ©2013 Landes Bioscience. Do not distribute. «o| A 45 30] 4 zy 2% 7 Serum vitamin D, (ng/ml) 20] 10] dl a 30) Cc 20] 10] dl '{. 0 2 4 6 8 10 12 14 21 Time after UVB exposure (days) oe Typensain wt PreDg formed (%) ioe 2D 2 1 35 Exposure time (min) Figure 34. The conversion of 7dehydrocholesterol to previtamin D, Inan ampoule model, Iypeltand Type skin after exposing to noon Sunlight June at Boston (2°N) Massachusetts. Thedataepresent the means = SEM of duplicate determinations, Reproduced with perission foom ret i gs) “‘salse ° Be Ba a x i: Lightness (L*) 70 Dematendoctinelgy Figure 33. intwa lightly plgmented Caucasan Ajand teeheavily pigmented Afroamericen subjects (8) after total body exoosureto (0.054 Jem of UVR. (C) Seri change incliculating wtaminD after re {exposureofon Afroamerican subject '@ in pand 8) 102032 Jer dose fF UVR. Reproduced with permission from ff 50, significandy lower serum concentrations of 25(OH)D than those withou depression.” Approaches for Preventing and Treating Vitamin D Deficiency ‘The Institute of Medicine using a population modd defined wita- min D deficiency for bone health as a ciculating concentration of 25(OH)D < 20 ng/ml. They re: 975% of the United States population's nceds for vitaimin D that children 0-1 y, and adults 1-70 y and 70+ years require 400, 600 and 800 TUs of vitamin D daily respectively (Fig, 70). The Endocrine Society used a medical model ro make recommenda: tions for the prevention and treatment of vitamin D deficiency [25(OH)D < 20 ng/ml] and vitamin D insufficiency [25(OH) D of 21-29 ngfmL| and concluded that @ range rather than an absolute amour of vitamin D could be recommended for chil dren 0-1 y, child:es 1-18 y and all adults of 400-1000 1Us, {600-1000 IUs and 1500-2000 1Us of vitamin D daily respec tively (Fig. 70)." Both the JOM" and The Endocrine Society” concluded that a cireulting concentration of 25(OH)D up 10 100 ng/mL. was safe. They also found thae most but not all of the literature sup- smmended that ¢o satisfy ports che concept that vitamin D, is as effective as vitamin D. in maineaining circulating concentrations of 25(OH)D.97-2"1 Foralmost 100 ya varity of strategies have been used to treat and prevent vitamin D deficiency especially in children." From 1930 through 1950s parents purchased a lamp a thie local pharmacy that emitted vitamin D, producing UVB radiation (Fig. 71). Children wearing ee protection had their arms abdomen and legs were routinely exposed to-a UV emitting lamp several times a week (Fig, 6)" Ta Russa children in school in wintertime were tutinely exposed to-a mercury arc lamp placed in the center of the school room that emitted UVB radi prevent vitamin D deficiency rickets (Fg, 72): The Sperti lamp which originally was designed with @ sin gle mercury arc lamp" was commonly used in the United States in the 1940s and 1950s to prevent rickets and children (Fg. 71).1°"" This lamp was also effective in improving the centrations of 25(OH)D in individuals who had tic fibrosis and who were unable to absorb vitamin D from ciscularing o * Because the lamp produced a lot of hear the Sperti lamp was redesigned and the mercury are lamp was replaced wih 4 fluorescent lamps (Fig. 74) char emitted UVB radiation and produced previcamin D, (Fig. 75). This lamp was effective in mising cisculating dietary and supplemental sousces (Fig; 734 and B). Figure 35. Setter plot ofboseline senim25 hydrosyetamin D 25-OF Dyan ss igntnes (sere for unexposed skin showing sgnieant positive cortelation of serum 25-OH Dand L (= 0.1856) Heaney, copyright 005, Reproduced with petnission, Volume Stee ©2013 Landes Bioscience. Do not distribute. concentrations of 25(OH)D in healthy adults with skin types 2 and 3 (Fig. 76." Tanning beds which emit UVB radiation (estimared about 95% of tanning beds in the United States) can be 2 good source of vitamin D especially for patients with malabsorption sya. ddromes.*"°™ A patient with Crohn's disease and only 2 feet of hher small intestine remaining had severe debilitating osteoma- lacic bone discomfort. Supplementing 400 1U dietary vitamin D froma multivitamin and 200 TU vitanin D from rotal paren- teral nutrition couldn’ correct hee severe vitamin D deficiency Exposuze to a tanning bed emitting UVB radiation was effec- tivein improving her cinculating concentration of 5(OH)D and as a result markedly improved her hone discomfort Fig. 77)" Tanners in Boston who frequented a tanning salon at least once a week had robust healthy circulating concentrations of 25(OH) 1D on average 46 ng/ml. compared with age and sex marched contzols whese blood level on aveeage was 24 ng/ml. (Fig. 78). Furthermore an evaluation oftheir bone mineral density revealed thar the tanners had a significantly higher bone mineral density in their hip compared with the control group.” Sensible sun exposure can also be an excellent source of vita sin D for both children and adults Sensible means never to be exposed 10 an amoune of sunlighe that would cause a sun. burn since this is che major cause for both melanoma and non: Studies conducted woddwide using jo ampule moda” and measucing 25(OH)D levels after quantitative UVB exposure in a tanning bed have been used develop guidelines for sensible sun exposure bused on latitude, season, time of day, altitude, and skin sensitivity, i.e, degree of skin pigmentation,??°"2"°"22"The rule of dura is to be exposed co an amount of sunlight dha is about 50% of what it ‘would take to cause a mild sunburn ie, slight pinkness © the skin 24/h later (exinimal erythemal dose) followed by good sun protection ic, clothing, hat and or The “rule of nines ‘melanoma skin cancer.” helps to estimate the percentage of skin exposed to sunlight or UVE radiation and can be used to caleu- late the amount of vitamin D, being produced, The face accounts tor 9% of the body surface, each arm for 19%, each leg for 18%, and the abd ‘men and the back for 18% each.” Exposure of the whole body in a bathing suit co 0.5 MED of UVB radiation is approximately equiva lent to ingesting about 7000-10,000 1Us of vitamin D,. exposing 20% of the body surface to an amount of sunlight equal co 05 MED is equivalent to ingesting approximately 1400-2000 [Us of vitamin D,. This is effective forall skin types and the increase in serum 25(OH)D attained from exposure «0 9" Therefore UVES radiation is often more effective wovwlandesbioselence corn z 2 3 Figure 36. Three dimensional seater plat of4 week senim 25 by 30 often need 3-5 rimes as much vitamin D to both teat and prevent recurrence of vitamin D deficiency absorption syndromes or who have had gastsic bypass surgery quire 50,000 IUs of vitamin D at least up co 7 times a Monitoring serum levels of 25(QH)D is important 09 prevent toxicity. Patients on ghicocorticoids, antiseiaure medi- cations and AIDS medications may also need more vitamin D to both treat and prevent vitamin D deficiency.” Patients however with granulomatous disorders such as sarcoidosis have a byper- sensitivity to vitamin D because of the uncontclled conversion of 25(QH)D to 1,25(QH),D by activated macrophages within the granulomas. This can alko occur in patients with some Iymphomas 2 week. Concern about Vitamin D Intoxication Vitamin D intoxication is one of the rarest medical conditions and is often caused by inadvertent or intentional ingestion of extremely high doses of vitamin D for prolonged periods of time, Vitamin D intoxication is associatad with hypercalcemia, hyper phosphatemiz, suppression of PTH chat can lead ro nephrocal: cinosis and sofe tissue calcification especially of blood vessels. Usually vitamin D intoxication is not observed until 2 25(OH) D> 200 ng/mL!" ‘Nomatterhow much sun exposurea peeson has this will never cause vitamin D intoxication because sunlight itself destroys any excess vitamin D and previtamin D.™ However there are several zeports in adults thac ingesting up wo 1 million IUs of vitamin D, daily for several months ean raise blood levels of 25(QHYD >500 nngimal. which was associated with hypercalcemia in the range of 15 mgidL. Ofen simply removing all sources of vitamin D along, with hydration can result in che serum caleium returning to normal within a ecatively short period of time and with no sequelae "27 A recent report ofa 3 mo old inadvertently receiv- jing 14,000 10s of vitamin D daily for 20 d (total of 280,000 TUs of vitamin D,) and achieving a circulating concentration of 25(H)D of 425 ng/mL. with suppression of PTH demon strated nosignificant change in cither the infant's serum calcium or phosphorus level and no change in kidney Function demon strates that short-teem high doses of vitamin D resulting in very high serum concentrations of 25(OH)D > 400 ng/ml, was well toleravd even in infants.” Even pregnant women who received Figure 41 Production of prevtamin D, and serum love of 210410 at terthe exposure 7;DNC solution in ampoulesand human volunteers toa tanning bedlamp. |) rmposlescontalnieg ONC wee paced exposed toa tanning bedlamp Atvatous mes an ampoule was Femaved and the conceislon of -DHCo prevtaminD, was measited by HPLC. (B) Healthy young adults were exposed 1208 MEDIn atan- flag bed three tmes a week for7 wecks.Ciculatingconcentiatlons of 25(OHD were determined at baseline and once a week theteate.(C)A healthy 7657 old man was exposed to tanning bed radiation equivalent 00175 MED three smes aweek for weeks Hlsckclating concent tlonsof25(0}1D were obtained at weekly Intervals Holick copyright 2007 reproduced with permission wovwlandesbioselence corn ‘Serum Concentration of Vitamin D From Oral Vitamin D, or UV Exposure g bs Oral 25,000 10 Serum Vitamin D (ngiml) es 8Ss Time (hours) Figure 40. Compason of seu vitamin D, levels ater whole-body ‘exposure tina bathing sits bikini for women to 1 MED (minimal etythemal dose) of simulated sunlight compared with single orl 200 ngiml = but also results in hypexcaleemia, hypesphos- z Phacmia and if reared can ead ro Katey = 2 fsilure, soft visue calication and ultimately a death 229 Ss & Conclusion and Perspective ge g Our ancestors routinely worshiped the sun Bis for its life giving. properties (Fig. 82). s Iris curious char some of the earliest phovo 4 symcetic lie forms for more than 500 sul lion years have bean prxducing vitamin D ° and thie chroughout evolution mose verte paseline apaapaia rs Iwates inchiding humans have depended on sain exposure for their skeletal health. The driver for che evolution of hypopigmenced Figure ean 1 8) 25(0HvRamin Dales prewradetion, B-2eweeksendS6-72 | humans jew Caucasians is likey due to the weeks afterindlation in7 subjects with abnormal baseline vais (25 nmol! Reproduced _mithpenmissontromeef 60. UV radiation to penetrate into the skin to need w have more vitamin D producing solar produce vitamin D,, Females born with vitae howed no min D deficiency and suffering fiom infantile rickets resulted ion” in them having a Aat pelvis and a small pelvic outlet. These 4000 TU vitamin D/day through cheir pregnancy change in dither serum calcium of urinary caium secte ” Dematendoctinelgy Volume Sissue ©2013 Landes Bioscience. Do not distribute. females although fetle would have had « difficult time, if not impos 2 sible, to give vaginal birth resulting in boch matemal and fetal death. Indeed it was because ofthe vitamin ra D deficiency pandemic in late 1800s thae Cesarean sectioning became a common practice for the delivery of healthy childzen of mothers who had suffered fiom vieamin D deficieney 2 jn ueero and during their fist few i years of life. Vieamin D defic ciency in pregnant women today is « sill associated with 3 400% inerease in the predicted probability for a Cestean section (Fig. 83). It is remarkable that for more than 100 y investigators have been reporting an inverse association with Jaginude and many chronic illnesses including common cancers." sev- enal autoimmune diseases induding type 1 diabetes and multiple sleo- sis!" as well as hypertension.” In addition the revelation that expo- sure to sunlight or UV radiation could eure and prevent rickets * led to the widespread recommendation by health regulators and gov emment agencies to encourage sensiblesun exposure, iz. amount of sun dhat would be beneficial for producing vieamin D and seducing risk for rickets while preventing sunburning (Fig. 8). The global appreciation of the beneficial effects of vitamin D for health lead wo widespread vitamin D fertification chroughout rope and the United Srates in the 19808-1940. Nor only mill but hoe dogs, soda, custard, bread, cevealsand even beer was forti~ fied with vitamin (Fig. 9). Schlitz even promored thei vitamin 1 fortified beer in the winter with the slogan “if you want to keep sunnyenergyall winterlong deinkvitamin D fortified Schlitz beer” (Fig, 84). They may have been correct now with the revelation thatvitamin D deficiency was associated with depression, seasonal affective disorder and neurocognitive dysfunction,"*28-48= Unfortunately in the easly 1950s the outbreak of hypercalee mia in British infants, who also had bireh defects which included altered facial Features, mental retardation, and heart problems, was incorectly acributed to be over fortification of milk: with vitamin D since ic was believed that these were signs of vitamin D into The more likely explanation i that these children had aesyndrome which is assocaned with a hypersensitivity to vitamin D causing hypercalcemia ancl also with an elfin appearance and heart problems.” However because tis “outbreak was associate with infanes who had birch defects and mental retardation las were quickly passed forbidding the forifcarion of not only foods bbut any consumer produce including skin exeam wich vitamin D, ‘This legislation was quickly adopred in most European countries and was used as a reason by other countries not t foctfy mill with vitamin D, Serva 25 myrjeamin (ng) e wovwlandesbioselence corn 1 3 i il | I i —————, Te of measurement Figure 44. Geometic mean (85% Cl) monthly variation nserum 25-bydxyitamin D [25(0H0D) ‘concentrations inmen (m:n 3725) and women (n= 3712) the 1958 Butsh bith cohortatage4s The interaction between sox and month was ignificant [p= 0.02 near regression analyses onlog 25(CHION.n sr sex and month ranged flom 171 240:98 in December 2003 for women and < 100for both sexes in December 2002 n= 40 M,37F),Januory 2008 in =95 M, 75. February 2008 (n= 58 M70, and March 2008 (>= 22 M17 F) Reproduced with permission fom 61 Clearly the paranoia ebout food fortification wih vitamin D ‘causing toxicity needs co be revonsidered in light of observations that infants who consumed 2000 TU vitamin D per day dusing their fest year of life wo only did not have any evidence of toxicity but for the ensuing 31 y markedly decreased their sis for type | sliaberes.* Tn the 1970s sunscreens were frst introduced as a way to prevent sunbuming. The sunsezeens contained UVB absorbing chemicals such as pariaminoberoic acid bocause it was believed that only UVB radiation damaged the skin and caused skin cancer. It is now cealized that UVA radiation not only alters the immune system making it more immanorolerane but also increases isk for non-melanoma and melanoma skin cancers, (Over the past four decades with very litle thought as to its con- sequences, several national and international health organira- tions have condemned any direct sun exposure. The American ‘Academy of Dermatology has taken the extreme position of rec- ‘ommending thar no one should ever be exposed wo ditectsualight without sun protection, This adical view of sunlight and UVB radiation has led to its designation as a carcinogen. To suggest that one should never be exposed to sunlight because excessive ‘exposure to sunlight is inked co an increased tsk for non-mela- ‘noma skin cancers ike suggesting that because breathing 100% ‘oxygen can cause lung damage and death, thar no one should breath an atmosphere chat contains 20% oxygen. The lack of appreviation of the importance of sensible sun exposure for providing children and adults with their vitamin D requirement has led w a worldwide vitamin D deficiency pandemic.” Tn che United States the Center for Disease Dermatondactinalagy 18 ©2013 Landes Bioscience. Do not distribute. Figure 45. (A) Seasonal uctuation of setum25(OH|D in healthy perimeno- aus Danish women and relationship between hours of sunshine andsenum 25IOHD. |B) Seasonal fluctuation of se tum 25(0HD according to frequency of sunexpasuie. regular sun expose ‘¢occesional sunexposute;@, avoiding dkoct sun exposure Reproduced with permission fem ef 173 Control and Peevention (CDC) reported ‘of children and adults have a concentration of 25(OH) D < 20 nglml.. Reporss from Mexico, South Americs, Europe, Asia, India and even Affica suggest chat more than 50% of che world population is at tsk for vitamin D deficiency. Australia, the skin cancer capital of the woud, ics now recognized chat che sip, slap, slop message has led to more than 40% of the population being vitamin D defies Dermatology Sociay now recommends sensible mun exposure asa source of vitae amin D, A study of Ausealin desmatolo- gis at the end of che summer svealed thae 87%¢had a 25(OH)D <20-ng/mt.2? = Even in ® Even che Australian > & Hours of sunshine 950] [a 25040 ingrid _ | 300 230 tours of sunsnine per month g More than 908% of the healthcare profes: sionals in India were found to be vitamin D deficient. The CDC concluded that vitamin D deficiency is becoming more prevalent in the US because of obesity, decrease in the consumption of vitamin D fortified milk and increased sun protection. thiee-part straegy should be employed worldwide to prevent vitamin D def ciency and its many negative health eon- sequences (Fig, 89). Sensible sun exposure which is fre, eating foods that nacurally contain yieamin D or ate fortified with Vitamin D as wall as taking a vitamin D supplement should guarantee vitamin D sufficiency.” A global suacegy to reduce the risk of vitamin D deficiency should be Thus & Dermato Endocrinology as 2% 25040 (anim!) a 1% 10 to consider not only incteasing programs food fortification not only of dairy products but also juice products, flour, and other commonly used food sources ‘There is no downside to increasing vita- min D intake and there could be « sub- santial upside, ey improvement not ‘only of musculoskelaal health but overall health and welfare, Ir has been estimated thar as much as 25% of health care dol- lars could be saved just by improving the world’s vieerin D status.” Acknowledgments This wosk was supported in pare by the National Institutes of Health Volume Stee ©2013 Landes Bioscience. Do not distribute. Flamin D fers epovlaigen w homes bo Al, Veeck K fase Klalodé 8 moira washings pr shin phyilog: a D-ighifal mary.) Bowe Mics Rex dehing DOOM 6 Wolk Mi, Tan XQ. Alen BE, Enda opr ‘nls Hoe Nal Bad So U8 AHS, BIE SUIS P2426 biden. an XQ, Chen TC, Masha, Wir Hal, ME Kies homed ute fhe oe su sips Dy Octet Dylatoeee sc 9. Ramnemi J, Meu na: WE Thor 4 10. loki Weg Seki (768 1830 1M, Hes Af, Gp OTe ae ofl alc nl) fon Mel Ae 124677 sed tmotngatel aking propo aac by xp ‘doit hide anda cn rotable by lil, ition. J Bel Chem 124 62501-15 righ td sdk mah Co Opa faloctna Baden Oh -APH12006 0517 enpenncs Relig Eso igh Ey Hal ed gC Boron Kars Anche wovwlandesbioselence corn serum 25-hydroxyvtamin D 8 8 0.68; e001 40 20 ° 0 10 20 9 4 60 60 70 60 lattude (degrees Nor) Figure 6. Mean cliclatng 25-hydeoxyvtamin D levels a chen, adolescents, and adults 3c

    You might also like