Vitamin d review Научные исследования Октябрь, 2014 Солнечный свет и витамин D: глобальная перспектива для здоровья

It was observed that 7-dehydrocholesterol concentrations in human epidermis were inversely related to age (Fig. 38).⁵⁸ The effect of aging on the cutaneous production of vitamin D₃ was demonstrated in a study that exposed healthy young adults and older adults to the same amount of UVB radiation in a tanning bed. The increase in the blood level of vitamin D₃ in six young adults aged 20–30 was at least three-fold higher compared with the six older adults aged 62–80 demonstrating that aging significantly decreased the capacity of the skin to produce vitamin D₃ (Fig. 39).⁵⁹ With this marked age-related decrease in the cutaneous production of vitamin D₃ could the elderly benefit from being exposed to sunlight or UVB radiation? The skin has a large capacity to produce vitamin D₃. Exposure of a young adult in a bathing suit to one minimal erythemal dose (MED) of UV radiation in a tanning bed was equivalent to ingesting approximately 20,000 IUs of vitamin D₂ (Fig. 40).²⁵ When a healthy 75 y old male in a bathing suit was exposed to UVB radiation in a tanning bed three times a week for 7 weeks he was able to raise and maintain his blood levels of 25(OH)D into the healthy normal range of ~50 ng/ml (Fig. 41C). The percent increase in circulating 25(OH)D concentrations was similar to what was observed in healthy young adults (Fig. 41B). Ampoules containing 7-DHC that were also irradiated served to demonstrate the efficacy of the tanning bed in producing previtamin D₃ (Fig. 41A).⁵ A study in elderly in a nursing home that had an activity room with an UVB emitting lamps on the ceiling (Fig. 42) reported that this was effective in raising and maintaining 25(OH)D levels in these residents (Fig. 43).⁶⁰

It is well documented that seasonal differences in cutaneous vitamin D₃ production has a dramatic influence on both children’s and adults’ vitamin D status (D represents vitamin D₂ or vitamin D₃).²² A study of 7437 Caucasian men and women from the 1958 British birth cohort at age 45 y revealed that the peak blood levels for 25(OH)D were observed in September (~30 ng/mL) and the nadir was observed in February (~14 ng/mL) (Fig. 44).⁶¹ A similar observation was made in postmenopausal women in Denmark. Those who had regular sun exposure achieved a blood level of 25(OH)D of ~45 ng/mL compared with women who avoided direct sun exposure had a 25(OH)D of ~23 ng/mL. This was also supported by the fact that hours of sun exposure was directly related to circulating concentrations of 25(OH)D (Fig. 45).⁶²

Latitude also has a dramatic influence on the cutaneous production of vitamin D₃ and therefore on a person’s vitamin D status (Fig. 46).^39,63 Mean circulating 25(OH)D in children, adolescents and adults at various latitudes revealed that there was a significant inverse relationship with the highest levels for those living near the equator with blood levels of 25(OH)D ~40 ng/mL compared with those living far North and South of the equator with blood levels of 25(OH)D ~15 ng/mL (Fig. 46).⁶⁴

However another study reported that those living at the highest latitudes in Europe at higher circulating concentrations of 25(OH)D (Fig. 47).⁶⁵

The likely explanation is that some people living far North and South of the equator who could not make any significant amount of vitamin D₃ in their skin for more than half of the year (Fig. 24) adapted by eating foods rich in vitamin D including oily fish^22,42,43 while others did not.^39,44,66

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 that keratinocytes produce β-endorphin when exposed to UV radiation.⁶⁷ In the early 1900s Finsen (Fig. 48) observed that exposure to sunlight (Fig. 49) 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 the use of solariums as a way to treat patients with tuberculosis and gave rise to the use of heliotherapy to improve health.^19,68,69 Heliotherapy was used to treat a wide variety of chronic illnesses in the early 1900s and it is still practiced throughout the world and especially in Northern Europe.^19,70-72 The rise in the use of pharmaceuticals to treat acute and chronic diseases led to the demise of heliotherapy especially in United States.^19,68,69,73

One of the first association studies relating sun exposure with reduced risk for cancer was reported in 1916 by Hoffman,⁷⁴ who found that living at a higher latitude was associated with an increased risk for mortality from cancer. He compared cancer mortality between 1908 and 1912 and observed that cancer mortality increased with increasing distance from the equator (Fig. 50). In 1937 Peller and Stephenson⁷⁵ analyzed the incidence of cancer in navy personnel in the United States Navy who were documented to have increased exposure to solar UV radiation with age matched controls and reported that the rate of skin cancer was eight times higher in the navy personnel while the total number of deaths from other cancers was 60% less than the civilian population.⁷⁵

Four years later, Apperly⁷⁶ compared total cancer mortality in the populations studied with the percentage of Americans and Canadians in the same population who were engaged in agriculture. He concluded that cancer mortality was highest in farmers living in the Northeast compared with those living in the South (Fig. 51).⁷⁶ He also reported that farmers living in the South exposed to more sunlight were at a higher risk for nonmelanoma skin cancer which he noted was easy to detect and easy to treat. He concluded that the fact that these Southern farmers had nonmelanoma skin cancer resulted in them developing an immunity to the skin cancer which also resulted in an immunity to all cancers including those with high mortality rate.⁷⁶

These observations essentially went unnoticed and the curious relationship of increased sun exposure and living at a lower latitude reducing risk of cancer mortality was buried in the literature. Forty years would pass before Garland et al.⁷⁷ reported that there was a strong significant negative correlation with colon cancer mortality and mean daily solar radiation in the United States (Fig. 52).

They followed up these findings with an eight-year prospective case-control study of adults living in Washington County and reported that the risk of getting colon cancer decreased three-fold in people with a serum 25(OH)D > 20 ng/ml. These results together suggested that living at higher latitudes meant less exposure to vitamin D producing sunlight and therefore the connection with the first association with latitude and cancer mortality could be linked to an inverse relationship with cancer mortality and vitamin D status.⁷⁸ Even in California where there is a large difference in latitude there was a positive association with colorectal cancer prevalence with latitude (Fig. 53).⁴⁵

Figure 53. (A) Latitude vs. number of individuals diagnosed with colon cancer in California, independent of race. (B) Latitude vs. the number of Caucasian individuals diagnosed with colon cancer in the state of California. Reproduced with permission ...

A multitude of epidemiologic studies followed these initial observations not only in the United States and Canada but worldwide. Grant⁷⁹ reported a dramatic inverse relationship between premature mortality due to cancer with UV exposure in both men and women (Fig. 54). In the United States, inverse associations with exposure to solar UVB radiation and cancer risk and mortality were reported for ovarian⁸⁰ and breast cancer,⁸¹ cancers of the digestive system^79,82 and prostate cancer.^83,84 A meta-analysis of studies reporting cancer incidence rates for more than 100 countries including Australia, China, Japan, Spain among others revealed an inverse relationship with solar UVB exposure for 15 types of cancer including bladder, breast, cervical, colon, endometrial, esophageal, gastric, lung, ovarian, pancreatic, rectal, renal and vulvar cancer as well as Hodgkin's and non-Hodgkin's lymphoma.⁸⁵ Boscoe and Schymura⁸⁶ found that the relative risk of cancer incidence and mortality for numerous malignancies was strongly related to solar UVB exposure (Fig. 55). Giovannucci et al.⁸⁷ conducted a prospective study in men relating predictors of vitamin D status and cancer incidence and also found an inverse association (Fig. 56). Luscombe et al.⁸⁸ reported men who worked outdoors had a 3-y hiatus before developing prostate cancer compared with indoor workers (Fig. 57). It was also reported that adults who developed lymphoma had a decreased risk for mortality if they had more sun exposure as a teenager.⁸⁹ Knight et al.⁹⁰ asked women in Canada who had breast cancer how much sun exposure they had during their teenage and young adult life and compared this sun exposure to women matched for age, ethnicity and place of residence. She concluded that women who had the most sun exposure from ages 10 to 19 y reduced their risk of developing breast cancer by more than 60% when comparing the highest quartile of outdoor activities with the lowest. Also women over 40 y who had the most sun exposure lost the benefit since their risk was no different than those who had the least sun exposure.

The observational and epidemiologic studies relating increased latitude with increased risk for cancers suggest a possible role of sun induced vitamin D₃ synthesis as the beneficial factor responsible for these observations.⁸⁷ It is known that exposure to sunlight also has other physiologic effects on the skin including altering the immune system,^91-93 increasing production of β endorphin⁶⁷ and nitric oxide.⁹⁴ There are however a variety of studies including interventional studies and association studies supporting the notion that improvement in vitamin D status reduced risk of many deadly cancers.^73,87,95-104 Woo et al.¹⁰⁵ reported that more than 50% of men with completed local treatment of prostate cancer and rising PSA levels in the absence of symptoms had a decrease in their PSA serum levels when commencing the supplementation of 2000 IUs vitamin D₃ per day had a statistically significant decrease in the rate of PSA rise (Fig. 58).

Lappe et al.¹⁰¹ reported a more than 60% reduction in the development of all cancers in a small study of postmenopausal women who received calcium supplementation (1500 mg) along with 1100 IUs of vitamin D₃ daily compared with women who received placebo (Fig. 59). The Women's Health Initiative (WHI) initially reported that women who took 1000 mg of calcium and 400 IUs of vitamin D₃ daily for up to 8 y had no reduced risk for colorectal cancer.¹⁰⁶ However the women in this study who had a baseline 25(OH)D < 12 ng/mL had a 253% increased risk for developing colorectal cancer compared with women who had a baseline 25(OH)D of at least 23 ng/mL. Further scrutiny of the data from the WHI revealed that only 60% of the women admitted taking their calcium and vitamin D supplement at least 80% of the time. However those women not on personal calcium and or vitamin D supplementation but who took 400 IUs of vitamin D₃ daily along with calcium supplementation as part of the WHI study for 8 y had a 14–20% reduced risk for developing breast cancer and a 17% reduced risk for developing colorectal cancer.¹⁰⁷ The importance of vitamin D in reducing risk of colorectal cancer has also been supported by the observation that the vitamin D receptor polymorphisms were associated with colorectal cancer¹⁰⁸ and a quantitative meta-analysis on the optimal status for colorectal cancer prevention showed that a 25(OH)D level of 34 ng/ml was associated with a 50% reduced risk of developing colorectal cancer.¹⁰⁹ Another study showed that the 25(OH)D level and the risk for developing colorectal adenoma were inversely correlated and that the association was modified by the Taql polymorphism of the VDR.¹¹⁰ The United States Preventative Services Task Force evaluated vitamin D supplementation and risk for colorectal cancer and concluded that for every 4 ng/ml increase in circulating concentrations of 25(OH)D was associated with a 6% (95% Cl 3–9%) reduced risk for colorectal cancer.¹¹¹

Cod liver oil was used in the mid-1800s to treat tuberculosis.^73,112,113 In the early 1900s heliotherapy was promoted for treating both skin and pulmonary tuberculosis.^69,114 It was also recognized that young children with rickets had a much higher risk of developing pneumonia and upper respiratory tract infections and were more likely to die of them.^8,14,115,116 Therefore sun exposure and vitamin D were used in the early 1900s to treat and prevent tuberculosis^113,114,117 and upper respiratory tract infections.⁷²

Hope-Simpson¹¹⁸ had speculated that there was a seasonal stimulus responsible for reducing infectious diseases during the summer. It is known for example that influenza infection is most prevalent in the winter months at latitudes North and South of the equator but is sporadic throughout the year in children and adults who live near the equator (Fig. 60). It has been hypothesized that the seasonal variation could be due to a seasonal variation in circulating levels of 25(OH)D.¹¹⁹ Several observational and intervention studies have helped to support this hypothesis. Healthy adults living in New England who had 25(OH)D blood levels of ~38 ng/mL approximately halved their risk of developing acute viral respiratory tract infections.¹²⁰ School children in Japan who received 1200 IUs of vitamin D₃ daily for 4 mo during the winter reduced their risk of developing influenza infection by 42%.¹²¹ A study of 156 neonates revealed that the risk for acquiring respiratory syncytial virus (RSV), a pathogen causing severe lower respiratory tract infection, was 6-fold higher in infants who had a blood level of 25(OH)D < 20 ng/mL compared with infants who had a blood level of 25(OH)D > 30 ng/mL.¹²²

Macrophages play an important role in fighting infectious diseases by ingesting and then destroying them.¹²³ When a macrophage ingests an infectious agent like tuberculosis toll-like receptors are activated to initiate an innate immune response.¹²⁴ One of the first responses is signal transduction to the nucleus to increase the expression of the VDR and the 25-hydroxyvitaminD-1-hydroxylase (CYP27B1). This results in the conversion of 25(OH)D to 1,25(OH)₂D. 1,25(OH)₂D interacts with the VDR and increases the expression of cathelicidin¹²⁵ which is a member of the defensin proteins and rapidly permealizes susceptible infectious agents resulting in their destruction (Fig. 61). This is one of the mechanisms believed to be responsible for vitamin D reducing risk of infectious diseases. Liu et al.¹²⁵ also reported that the extent of antimicrobial activity of a monocyte exposed to Mycobacterium tuberculosis depended on the 25(OH)D levels of the medium in which the monocytes were cultured. Monocytes cultured in serum of African-American individuals who were vitamin D deficient (mean ~8 ng/mL) mounted an ineffective cathelicidin mRNA response upon exposure to M. tuberculosis, however the supplementation of the sera with 25(OH)D (mean ~30 ng/mL) restored the toll-like receptor mediated induction of cathelicidin mRNA. This was substantiated by Adams et al.¹²⁶ who not only showed, that the expression of cathelicidin by monocytes exposed to M. tuberculosis lipopeptides was significantly enhanced by addition of exogenous 25(OH)D to the vitamin D deficient serum but that serum from vitamin D-supplemented subjects had the same effect. This data added support for the importance of maintaining a serum 25(OH)D > 30 ng/mL to generate an effective cathelicidin response following activation of monocytes/macrophages.

It has also been suggested based on studies in mice and in vitro that the local keratinocyte production of 1,25(OH)₂D₃ from 25(OH)D₃ in the skin and oral pharynx enhanced the production of cathelicidin supporting the concept that maintaining serum 25(OH)D above 30 ng/ml may also be important in fighting infections in both the skin and oropharynx.^127-130 This may also help explain the observation that the risk for periodontal disease is higher in adults who have the lowest circulating concentrations of 25(OH)D.¹³¹ Calcium and vitamin D supplementation was associated with a lower risk of tooth loss in elderly men and women¹ respectively and with better periodontal health.^132,133

Sunlight and Vitamin D: Autoimmunity Protection

There are a variety of association studies demonstrating that being born or living near the equator reduces risk of several autoimmune diseases.^73,134-139 Being born and living for the first 10 y at a latitude of ~40° North compared with ~33° North increases a person's risk of developing multiple sclerosis by 100% (Fig. 62).^134,140,141 Munger et al.¹⁴² made the observation that high circulating levels of 25(OH)D were associated with a lower risk of multiple sclerosis and that women who had an intake of vitamin D of ≥ 400 IU vitamin D per day reduced their risk of developing multiple sclerosis by more than 40%.¹⁴³

It was also reported that spring births were associated with increased likelihood of developing type 1 diabetes. These findings indicate a potential role of vitamin D in the pathogenesis of type 1 diabetes mellitus. This hypothesis is supported by an observational study that children in Finland who received 2000 IUs of vitamin D daily during their first year of life in the 1960s reduced their risk of developing type 1 diabetes 31 y later by 88%.¹⁴⁵ Because of concern about vitamin D toxicity the amount of vitamin D recommended for infants in Finland was reduced first to 1000 IUs daily and then to 400 IUs daily. Interestingly as a result of this decrease in vitamin D intake there is an impressive increase in the incidence of type 1 diabetes occurring in Finland over the past 3 decades (Fig. 64).¹⁴⁵

A pronounced North-South gradient has also been reported for inflammatory bowel disease, in particular Crohn's disease (Fig. 65).¹³⁸ A complete data set including demographic data and lifestyle factors based on the two prospective Nurses’ Health Studies (NHSs) and comprising almost 240,000 nurses, also showed that women from lower latitudes had a consistently lower risk of developing ulcerative colitis and Crohn’s disease compared with women living in higher latitudes.¹³⁹ These observations were supported by a prospective cohort study of 72,719 women enrolled in the Nurses' Health Study showed that a higher predicted vitamin D status was associated with a reduced risk of Crohn's disease.¹⁴⁶

A case-control study investigating the association between latitude and rheumatoid arthritis using data from the Nurses’ Health Study suggested that women living in higher latitudes were at greater risk for rheumatoid arthritis (Fig. 66).¹⁴⁷ These latitude-dependent differences in the prevalence of rheumatoid arthritis could be explained by differences in the vitamin D status. Merlino et al.¹⁴⁸ showed in a study in Iowa that women with the highest intake of vitamin D reduced their risk of developing rheumatoid arthritis by more than 30%.⁷³ However, other investigators did not find such an association when reviewing the data from this study.¹⁴⁹

Although the exact mechanisms by which vitamin D may reduce risk for autoimmune diseases are not fully understood we do know that vitamin D plays an important role in cellular immunity.¹³⁵ Inactivated T- and B-lymphocytes are unable to respond to 1,25(OH)₂D because they lack a VDR. However when they become activated they express a VDR and are now responsive to the immunomodulatory activity of 1,25(OH)₂D (Fig. 61).^22,63,150

In B-cells 1,25(OH)₂D downregulates immunoglobulin synthesis¹⁵¹ and B-cell memory. Thus by doing so it may reduce production of autoantibodies responsible for causing autoimmune diseases.¹⁵² 1,25(OH)₂D also has a multitude of functions in activated T cells.^153-158 This hormone decreases T cell proliferation¹⁵⁴ as well as the number of Th₁-Th₁₇ lymphocytes while increasing T-regulatory lymphocytes¹⁵⁵ by increasing the production of Th₂-Th₃ lymphocytes.¹⁵⁶ 1,25(OH)₂D also directly influences the expression and synthesis of several immunomodulatory cytokines. Bouillon et al.¹⁵¹ summarized that 1,25(OH)₂D downregulates pro-inflammatory cytokines and interleukins (IL) such as IL-2, IL-4, IL-8, IL-12, tumor necrosis factor-α, and interferon-γ and upregulates anti-inflammatory interleukins such as IL-10 (Fig. 67).

Sunlight and Vitamin D: Cardiovascular Health

In 1997 Rostand et al.¹⁵⁹ reported that there was an inverse association with latitude and blood pressure (Fig. 68) and the prevalence of hypertension (Fig. 69). This was followed by the observation of Krause et al.¹⁶⁰ who reported that exposure to UVB radiation in a clinical setting not only improved circulating concentrations of 25(OH)D by more than 160% but also significantly reduced both systolic and diastolic blood pressure in patients with hypertension. A control group was exposed to the same UV lamps that were covered by an acrylic shield absorbing all UVB radiation and thus was exposed to UVA radiation only. The control group’s subjects demonstrated no significant change in their circulating concentrations of 25(OH)D as well as no change in their hypertension (Fig. 70). These data suggested that vitamin D may somehow be involved in cardiovascular health. One of the first insights as to how vitamin D could influence cardiovascular health was the observation that 1,25(OH)₂D₃ suppressed the production of renin.¹⁶¹ This observation was also supported by the report that VDR knockout mice have a dysregulation of the renin-angiotensin-aldosterone axis.¹⁶²

There have been a multitude of association studies suggesting that vitamin D deficiency not only increases risk for a myocardial infarction by as much as 50% but also was associated with more than one 100% increased risk of mortality from the heart attack.^{73,106,163-168} In the US an estimated 50 million teenagers are vitamin D deficient or insufficient and this was associated with a 2.4 fold increased risk for high blood pressure.^167,169 Dong et al.¹⁶⁸ conducted a 16-week randomized, blinded, clinical trial in 49 normotensive black boys and girls aged 16.3 ± 1.4 y to evaluate the effect of enhancing vitamin D intake from 400 IUs or 2000 IU vitamin D₃ daily on arterial wall stiffness, determined by measuring carotid-femoral pulse wave velocity. The teenagers who received 400 IUs of vitamin D daily increased their circulating concentrations of 25(OH)D from 14 to 24 ng/mL and had an increased in the carotid-femoral pulse wave velocity (5.38 ± 0.53 m/sec to 5.71 ± 0.75 m/sec; p = 0.016). By contrast teenagers who received 2000 IUs of vitamin D daily for 4 mo not only increased their blood level of 25(OH)D from 13 to 34 ng/mL but also showed a significant decrease in carotid-femoral pulse wave velocity (5.41 ± 0.73 m/sec to 5.33 ± 0.79 m/sec; p = 0.031).

Two major contributing factors for cardiovascular disease are type 2 diabetes and obesity.¹⁷⁰ It is well known both in children and adults that there is an inverse association with serum concentrations of 25(OH)D with body mass index (BMI) due to a sequestration and volumetric dilution of the lipophilic vitamin D in the fat tissue.^73,171-174 Furthermore there is also an association with vitamin D deficiency and increased risk for type 2 diabetes.^175,176 A similar observation was made in the Nurses’ Health Study where a combined daily intake of > 1200 mg calcium and > 800 IU vitamin D was associated with a 33% lower risk of type 2 diabetes.¹⁷⁷ An inverse association between vitamin D status and diabetes was also shown in a study by Scragg et al.¹⁷⁸ The odds ratio for diabetes in non-Hispanic whites and Mexican Americans who had 25(OH)D levels in the highest quartile compared with the lowest was reduced by up to 83%.¹⁷⁸ However, this inverse association was not observed in non-Hispanic blacks.¹⁷⁸

Several epidemiologic studies and prospective studies have reported a highly significant association with vitamin D deficiency with not only type 2 diabetes but also hypertension, hyperlipidemia and peripheral vascular disease all causative factors for coronary artery disease, myocardial infarction, heart failure and stroke.^166,175,179 The prospective Intermountain Heart Collaborative Study revealed that in more than 40,000 participants a circulating concentration of 25(OH)D < 15 ng/mL compared with a concentration of > 30 ng/mL significantly increased all of these risk factors.¹⁷⁵ A meta-analysis examining the association between vitamin D status or vitamin D supplementation revealed that adults with the highest circulating concentration of 25(OH)D had a 43% lower risk of developing cardiometabolic disorders compared with adults with low levels of 25(OH)D.¹⁸⁰ Furthermore a prospective study following up with more than 2000 adults showed that the risk of progression from pretype 2 diabetes to type 2 diabetes was reduced by 48% in adults who had the highest circulating concentrations of 25(OH)D compared with those with the lowest.¹⁸¹

Beta islet cells in the pancreas have a VDR and 1,25(OH)₂D₃ is a potent stimulator of insulin production.¹⁸² Improvement in vitamin D status has also been associated with improvement in insulin sensitivity¹⁸³ mediated by upregulation of insulin receptors.¹⁸⁴ There is evidence that vascular smooth muscle and cardiomyocytes have a VDR^73,166,171 and that 1,25(OH)₂D₃ causes vascular relaxation by suppressing the renin-angiotensin-aldosterone system^{73,163,185,186} and improves cardiomyocyte contractility.¹⁷¹ In addition 1,25(OH)₂D₃ inhibits macrophage cholesterol uptake and foam cell formation thereby reducing risk for atherosclerotic plaque formation (Fig. 71).^73,166,187 Vitamin D deficiency negatively affects numerous physiological processes that are important in the pathogenesis of cardiovascular disease. This could explain why vitamin D deficiency is associated with an increased overall and cardiovascular mortality in patients with metabolic syndrome (Fig. 72).¹⁸⁸

Schizophrenia has been associated with inadequate sun exposure and vitamin D deficiency (Fig. 73).¹⁸⁹ Schizophrenia is more common in the Scandinavian countries.^189,190 Winter births have been associated with an increased risk for developing schizophrenia later in life even in Australia.^191,192 In British immigrants, incidence in schizophrenia is higher in children of immigrants from the Caribbean who moved to cities in countries farther North.¹⁹³ Finnish male infants who received 2000 IUs of vitamin D daily during their first year of life reduced their risk of developing schizophrenia by 77% compared with infants who received less than 2000 IUs of vitamin D daily.¹⁹⁴

Vitamin D could play an indirect role in the pathogenesis of schizophrenia. Several studies suggest that a prenatal influenza exposure increases the risk for schizophrenia later in life.^195-197 The vitamin D status seems to influence the risk for an influenza infection respectively vitamin D supplementation has proven to decrease the risk for influenza infection. ^{2–4118,119,121}

There are a variety of association studies relating vitamin D deficiency with increased risk for depression,^198,199 Alzheimer disease,²⁰⁰ epilepsy,²⁰¹ and neurocognitive decline.^202,203 The brain not only has a VDR but also a 1-OHase.204 Evidence suggests that 1,25(OH)₂D₃ could increase calcium binding protein expression,²⁰⁵ although this could not be shown in all studies.²⁰⁶ 1,25(OH)₂D₃ could also act by increasing serotonin levels in the brain.^207,208 Furthermore 1,25(OH)₂D₃ has also been demonstrated to stimulate amyloid-β phagocytosis and clearance by macrophages in Alzheimer patients.²⁰⁹ This may help explain the association between neurocognitive decline,^202,203 dementia,²¹⁰ depression,^198,199 and Alzheimer disease²⁰⁰ with a high prevalence of vitamin D deficiency.²¹¹ In a community setting depressed adults had significantly lower serum concentrations of 25(OH)D than those without depression.²¹²

The Institute of Medicine using a population model defined vitamin D deficiency for bone health as a circulating concentration of 25(OH)D < 20 ng/mL. They recommended that to satisfy 97.5% of the United States population’s needs for vitamin D that children 0–1 y, and adults 1–70 y and 70+ years require 400, 600, 800 IUs of vitamin D daily respectively (Fig. 74).²¹³ The Endocrine Society used a medical model to make recommendations 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 ng/mL] and concluded that a range rather than an absolute amount of vitamin D could be recommended for children 0–1 y, children 1–18 y and all adults of 400–1000 IUs, 600–1000 IUs and 1500–2000 IUs of vitamin D daily respectively (Fig. 74).²⁴

Both the IOM²¹³ and The Endocrine Society²⁴ concluded that a circulating concentration of 25(OH)D up to 100 ng/mL was safe. They also found that most but not all of the literature supports the concept that vitamin D₂ is as effective as vitamin D₃ in maintaining circulating concentrations of 25(OH)D.^{24,73,213-221}

For almost 100 y a variety of strategies have been used to treat and prevent vitamin D deficiency especially in children.^5,68,73,114 From 1930 through 1950s parents purchased a lamp at their local pharmacy that emitted vitamin D₃ producing UVB radiation (Fig. 75).^70,222,223 Children wearing eye protection had their arms, abdomen and legs were routinely exposed to a UV emitting lamp several times a week (Fig. 6).^12,13 In Russia children in school in wintertime were routinely exposed to a mercury arc lamp placed in the center of the school room that emitted UVB radiation to prevent vitamin D deficiency rickets (Fig. 76).²²⁴

The Sperti lamp which originally was designed with a single mercury arc lamp^225,226 was commonly used in the United States in the 1940s and 1950s to prevent rickets and children (Fig. 75).^8,70,114 This lamp was also effective in improving the circulating concentrations of 25(OH)D in individuals who had cystic fibrosis and who were unable to absorb vitamin D from dietary and supplemental sources (Fig. 77A and B).^227,228 Because the lamp produced a lot of heat the Sperti lamp was redesigned and the mercury arc lamp was replaced with 4 fluorescent lamps (Fig. 78) that emitted UVB radiation and produced previtamin D₃ (Fig. 79).²²⁹ This lamp was effective in raising circulating concentrations of 25(OH)D in healthy adults with skin types 2 and 3 (Fig. 80).^227,228

Tanning beds which emit UVB radiation (estimated about 95% of tanning beds in the United States) can be a good source of vitamin D especially for patients with malabsorption syndromes.^227,228 A patient with Crohn's disease and only 2 feet of her small intestine remaining had severe debilitating osteomalacic bone discomfort. Supplementing 400 IU dietary vitamin D from a multivitamin and 200 IU vitamin D from total parenteral nutrition couldn’t correct her severe vitamin D deficiency. Exposure to a tanning bed emitting UVB radiation was effective in improving her circulating concentration of 25(OH)D and as a result markedly improved her bone discomfort (Fig. 81).²³⁰ Tanners in Boston who frequented a tanning salon at least once a week had robust healthy circulating concentrations of 25(OH)D on average 46 ng/mL compared with age and sex matched controls whose blood level on average was 24 ng/mL (Fig. 82). Furthermore an evaluation of their bone mineral density revealed that the tanners had a significantly higher bone mineral density in their hip compared with the control group.²³¹

Sensible sun exposure can also be an excellent source of vitamin D for both children and adults.^232,233 Sensible means never to be exposed to an amount of sunlight that would cause a sunburn since this is the major cause for both melanoma and non-melanoma skin cancer.^234-237 Studies conducted worldwide using the in vitro ampule model³⁹ and measuring 25(OH)D levels after quantitative UVB exposure in a tanning bed have been used to develop guidelines for sensible sun exposure based on latitude, season, time of day, altitude, and skin sensitivity, i.e., degree of skin pigmentation.^{22,46,51,66,231–233,238,2397–14} The rule of thumb is to be exposed to an amount of sunlight that is about 50% of what it would take to cause a mild sunburn i.e., slight pinkness to the skin 24 h later (minimal erythemal dose) followed by good sun protection i.e., clothing, hat and or sunscreen.^22,239 The “rule of nines” helps to estimate the percentage of skin exposed to sunlight or UVB radiation and can be used to calculate the amount of vitamin D₃ being produced. The face accounts for 9% of the body surface, each arm for 9%, each leg for 18%, and the abdomen and the back for 18% each.²⁴⁰ Exposure of the whole body in a bathing suit to 0.5 MED of UVB radiation is approximately equivalent to ingesting about 7000–10,000 IUs of vitamin D₂.^22,25,31 Therefore exposing 20% of the body surface to an amount of sunlight equal to 0.5 MED is equivalent to ingesting approximately 1400–2000 IUs of vitamin D₃. This is effective for all skin types and the increase in serum 25(OH)D attained from exposure to UVB radiation is often more effective than ingesting 1000 IU vitamin D₂ or vitamin D₃ daily (Fig. 83).²⁴¹ Always protect the face with a hat or sunscreen since it provides very little vitamin D₃ and is most sun exposed and more prone to skin damage and skin cancer from sun exposure.^242-244

Because foods contain very little vitamin D it is difficult to obtain enough vitamin D from dietary sources even when consuming foods fortified with vitamin D.^22,51,246 The exception is indigenous populations including Inuits who consumed foods with high content of vitamin D such as oily fish, seal and whale blubber and polar bear liver.²⁴⁷ Therefore it is necessary without adequate sun exposure to improve childrens’ and adults’ vitamin D status by encouraging them to take a vitamin D supplement (Fig. 74).^22,24,213

Infants should receive 400 IUs of vitamin D soon after they are born. This has been endorsed by the American Academy of Pediatrics, the Endocrine Society and the Institute of Medicine.^24,213,248 However infants who are vitamin D deficient should be aggressively treated with pharmacologic doses of vitamin D in order to build up the body stores and quickly correct the vitamin D deficiency. The best method to treat and cure rickets is to give a total dose of 5–15 mg (200,000–600,000 IUs) of vitamin D₂ or vitamin D₃ orally with adequate dietary calcium.^8,249 These doses can be given safely either as a single-day therapy or as daily doses of 2000–4000 IUs/day (50–100 µg/d) for 3–6 mo.⁸

Children one year and older should receive at least 600 IUs of vitamin D daily. The Endocrine Society recommends at least 600 IUs and up to 1000 IUs daily is safe and effective to prevent vitamin D deficiency and insufficiency.²⁴ Infants and toddlers who received 50,000 IUs of vitamin D₂ once a week or 2000 IUs of vitamin D₂ or vitamin D₃ daily for 6 weeks corrected their vitamin D deficiency without any untoward side effects.^8,24,217 A study done in the young Lebanese girls who received 14,000 IUs of vitamin D weekly for one year were able to maintain their blood level of 25(OH)D in what is considered to be a healthy physiologic range above 30 ng/mL.²⁵⁰

The Endocrine Society recommends that all adults receive 1500–2000 IUs of vitamin D daily.¹⁵ A study in healthy adults in Boston who had a baseline serum concentration of 25(OH)D ~18 ng/mL in the winter revealed that ingesting 1000 IUs of vitamin D₂ or vitamin D₃ was ineffective in raising and maintaining blood levels 25(OH)D above 30 ng/mL (Fig. 84).²¹⁵ This is not at all unexpected since it is documented that for every 100 IUs of vitamin D ingested the circulating concentration of 25(OH)D increases by approximately 0.6–1.0 ng/mL.^215,251

Because vitamin D is fat soluble upon its ingestion or production in the skin vitamin D₃ gets incorporated into the body fat and is also transported to the liver to be converted to 25(OH)D.^{22,73,171-174} As a result to treat vitamin D deficiency and prevent recurrence, vitamin D can be given daily, weekly and even monthly with the same outcome i.e., improvement in circulating concentrations of 25(OH)D.²⁴ One strategy that is effective to quickly fill up the empty vitamin D tank is to give 50,000 IUs of vitamin D₂ or 50,000 IUs of vitamin D₃ once a week for 8 weeks.²⁵² This is equivalent to ingesting approximately 6600 IUs of vitamin D daily.²⁵³ To prevent recurrence of vitamin D deficiency patients have been instructed to take 50,000 IUs of vitamin D₂ (equivalent to 3300 IUs of vitamin D daily) once every 2 weeks forever. This strategy has been effective in maintaining blood levels of 25(OH)D in the range of 40–60 ng/mL for up to 6 y without any toxicity (Fig. 85).²⁵³ Other strategies that have been equally effective have been to take 50,000 IUs of vitamin D daily for several days followed by maintenance therapy. Patients who have a BMI > 30 often need 3–5 times as much vitamin D to both treat and prevent recurrence of vitamin D deficiency.²⁴ Patients with malabsorption syndromes or who have had gastric bypass surgery may require 50,000 IUs of vitamin D at least up to 7 times a week.²² Monitoring serum levels of 25(OH)D is important to prevent toxicity. Patients on glucocorticoids, anti-seizure medications and AIDS medications may also need more vitamin D to both treat and prevent vitamin D deficiency.²² Patients however with granulomatous disorders such as sarcoidosis have a hypersensitivity to vitamin D because of the uncontrolled conversion of 25(OH)D to 1,25(OH)₂D by activated macrophages within the granulomas. This can also occur in patients with some lymphomas.^22,24

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 associated with hypercalcemia, hyperphosphatemia, suppression of PTH that can lead to nephrocalcinosis and soft tissue calcification especially of blood vessels. Usually vitamin D intoxication is not observed until a 25(OH)D > 200 ng/mL.^254-256

No matter how much sun exposure a person has this will never cause vitamin D intoxication because sunlight itself destroys any excess vitamin D and previtamin D.²⁵⁶ However there are several reports in adults that ingesting up to 1 million IUs of vitamin D₃ daily for several months can raise blood levels of 25(OH)D > 500 ng/mL which was associated with hypercalcemia in the range of 15 mg/dL. Often simply removing all sources of vitamin D along with hydration can result in the serum calcium returning to normal within a relatively short period of time and with no sequelae.^254-257 A recent report of a 3 mo old inadvertently receiving 14,000 IUs of vitamin D₃ daily for 20 d (i.e., total of 280,000 IUs of vitamin D₃) and achieving a circulating concentration of 25(OH)D of 425 ng/mL with suppression of PTH demonstrated no significant change in either the infant's serum calcium or phosphorus level and no change in kidney function demonstrates that short-term high doses of vitamin D resulting in very high serum concentrations of 25(OH)D > 400 ng/mL was well tolerated even in infants.²⁵⁸ Even pregnant women who received 4000 IU vitamin D/day through their pregnancy showed no change in either serum calcium or urinary calcium secretion.²⁵⁹ It is prolonged intake of extremely high doses of vitamin D for at least several months that not only markedly increases the circulating concentrations of 25(OH)D > 200 ng/mL but also results in hypercalcemia, hyperphosphatemia and if untreated can lead to kidney failure, soft tissue calcification and ultimately death.^22,260

Conclusion and Perspective

Our ancestors routinely worshiped the sun for its life giving properties (Fig. 86).^261,262 It is curious that some of the earliest photosynthetic life forms for more than 500 million years have been producing vitamin D and that throughout evolution most vertebrates including humans have depended on sun exposure for their skeletal health.²⁶³ The driver for the evolution of hypopigmented humans i.e., Caucasians is likely due to the need to have more vitamin D producing solar UVB radiation to penetrate into the skin to produce vitamin D₃. Females born with vitamin D deficiency and suffering from infantile rickets resulted in them having a flat pelvis and a small pelvic outlet. These females although fertile would have had a difficult time, if not impossible, to give vaginal birth resulting in both maternal and fetal death.^54,55 Indeed it was because of the vitamin D deficiency pandemic in late 1800s that Cesarean sectioning became common practice for the delivery of healthy children of mothers who had suffered from vitamin D deficiency in utero and during their first few years of life.^8,54,55 Vitamin D deficiency in pregnant women today is still associated with a 400% increase in the predicted probability for a Cesarean section (Fig. 87).⁵⁴

It is remarkable that for more than 100 y investigators have been reporting an inverse association with latitude and many chronic illnesses including common cancers,⁸⁵ several autoimmune diseases including type 1 diabetes and multiple sclerosis^73,134-139 as well as hypertension.¹⁵⁹ In addition the revelation that exposure to sunlight or UV radiation could cure and prevent rickets^12,13 led to the widespread recommendation by health regulators and government agencies to encourage sensible sun exposure, i.e., amount of sun that would be beneficial for producing vitamin D and reducing risk for rickets while preventing sunburning (Fig. 8).

The global appreciation of the beneficial effects of vitamin D for health lead to widespread vitamin D fortification throughout Europe and the United States in the 1930s-1940s. Not only milk but hot dogs, soda, custard, bread, cereals and even beer was fortified with vitamin D (Fig. 9). Schlitz even promoted their vitamin D fortified beer in the winter with the slogan “if you want to keep sunny energy all winter long drink vitamin D fortified Schlitz beer.” (Fig. 88) They may have been correct now with the revelation that vitamin D deficiency was associated with depression, seasonal affective disorder and neurocognitive dysfunction.^{198-200,202,203,210}

Unfortunately in the early 1950s the outbreak of hypercalcemia in British infants, who also had birth defects which included altered facial features, mental retardation, and heart problems, was incorrectly attributed to be over fortification of milk with vitamin D since it was believed that these were signs of vitamin D intoxication.^20,22 The more likely explanation is that these children had a syndrome which is associated with a hypersensitivity to vitamin D causing hypercalcemia and also with an elfin appearance and heart problems.²⁰ However because this “outbreak” was associated with infants who had birth defects and mental retardation laws were quickly passed forbidding the fortification of not only foods but any consumer product including skin cream with vitamin D. This legislation was quickly adopted in most European countries and was used as a reason by other countries not to fortify milk with vitamin D.

Clearly the paranoia about food fortification with vitamin D causing toxicity needs to be reconsidered in light of observations that infants who consumed 2000 IU vitamin D per day during their first year of life not only did not have any evidence of toxicity but for the ensuing 31 y markedly decreased their risk for type 1 diabetes.¹⁴⁵

In the 1970s sunscreens were first introduced as a way to prevent sunburning. The sunscreens contained UVB absorbing chemicals such as paraaminobezoic acid because it was believed that only UVB radiation damaged the skin and caused skin cancer. It is now realized that UVA radiation not only alters the immune system making it more immunotolerant but also increases risk for non-melanoma and melanoma skin cancers. Over the past four decades with very little thought as to its consequences, several national and international health organizations have condemned any direct sun exposure. The American Academy of Dermatology has taken the extreme position of recommending that no one should ever be exposed to direct sunlight without sun protection. This radical 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 linked to an increased risk for non-melanoma skin cancer is like suggesting that because breathing 100% oxygen can cause lung damage and death, that no one should breath an atmosphere that contains 20% oxygen.

The lack of appreciation of the importance of sensible sun exposure for providing children and adults with their vitamin D requirement has led to a worldwide vitamin D deficiency pandemic.^22,173 In the United States the Center for Disease Control and Prevention (CDC) reported that 32% of children and adults have a circulating concentration of 25(OH)D < 20 ng/mL. Reports from Mexico, South America, Europe, Asia, India and even Africa suggest that more than 50% of the world population is at risk for vitamin D deficiency.^22,265,266 Even in Australia, the skin cancer capital of the world, it is now recognized that the slip, slap, slop message has led to more than 40% of the population being vitamin D deficient.^265-267 Even the Australian Dermatology Society now recommends sensible sun exposure as a source of vitamin D. A study of Australian dermatologists at the end of the summer revealed that 87% had a 25(OH)D < 20 ng/mL. More than 90% of the physicians in India were found to be vitamin D deficient.