Review
Vitamin D for Health: A Global Perspective

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Abstract

It is now generally accepted that vitamin D deficiency is a worldwide health problem that affects not only musculoskeletal health but also a wide range of acute and chronic diseases. However, there remains cynicism about the lack of randomized controlled trials to support the association studies regarding the nonskeletal health benefits of vitamin D. This review was obtained by searching English-language studies published up to April 1, 2013, in PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials (search terms: vitamin D and supplementation) and focuses on recent challenges regarding the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D concentrations from dietary sources, supplements, and sun exposure. The effect of vitamin D on fetal programming epigenetics and gene regulation could potentially explain why vitamin D has been reported to have such wide-ranging health benefits throughout life. There is potentially a great upside to increasing the vitamin D status of children and adults worldwide for improving musculoskeletal health and reducing the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality.

Section snippets

Vitamin D Metabolism and Biological Functions

Vitamin D (D represents D2, D3, or both) is a secosterol produced endogenously in the skin from sun exposure or obtained from foods that naturally contain vitamin D, including cod liver oil and fatty fish (eg, salmon, mackerel, and tuna); UV-irradiated mushrooms; foods fortified with vitamin D; and supplements.2, 7

During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin is converted to previtamin D3. The 7-DHC is present in all the layers of human skin.7, 8, 9 Approximately 65% of

Vitamin D Metabolism During Pregnancy

Vitamin D metabolism is enhanced during pregnancy and lactation. The placenta is formed at 4 weeks of gestation.2, 25 From this time to term, 25(OH)D is transferred across the placenta, and the fetal cord blood concentration of 25(OH)D is correlated with the mother's concentration.27 However, the active metabolite 1,25(OH)2D does not readily cross the placenta.25, 27 The fetal kidneys and the placenta provide the fetal circulation with 1,25(OH)2D by expressing CYP27B1 (Figure 2).28

The maternal

Vitamin D, Placenta Development, Fetal Programming, and Epigenetic Modification

Epidemiologic evidence has suggested a link between fetal life events and susceptibility to disease in adult life.45, 46, 47 This paradigm, referred to as fetal programming or developmental origins of health and disease, may have a profound effect on public health strategies for the prevention of major illnesses.2, 48 The role of vitamin D in implantation tolerance and placental development has been studied. The 1,25(OH)2D3 regulates key target genes associated with implantation, such as

Definition of Vitamin D Deficiency

The blood level of 25(OH)D is the best method to determine vitamin D status. Although 1,25(OH)2D is the biologically active form, it provides no information about vitamin D status because it is often normal or even elevated in children and adults who are vitamin D deficient.7, 15, 60, 61, 62, 63 Recently, the Institute of Medicine (IOM) and the Endocrine Society released separate guidelines for vitamin D requirements.60, 62 The recommended dietary allowances (RDAs) of the IOM and the Endocrine

Musculoskeletal Consequences of Vitamin D Deficiency

According to current evidence from biochemical testing, observational studies, and randomized controlled trials (RCTs), serum 25(OH)D levels of at least 20 ng/mL are required for normalization of PTH levels, to minimize the risk of osteomalacia, and for optimal bone and muscle function, with many experts regarding 30 ng/mL as the threshold for optimal bone health.7, 16, 61, 64, 65, 66 The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone

Evidence-Based Skeletal and Nonskeletal Health Benefits of Vitamin D

Observational studies have found a decreased risk of many disorders, including certain types of cancer, mental disorders, infectious disease, cardiovascular disease, type 2 diabetes mellitus, and autoimmune disorders, associated with serum 25(OH)D levels greater than 28 to 32 ng/mL.7, 60, 67 It has, therefore, been argued that 25(OH)D levels should be in the range of 28 to 40 ng/mL to maximize these nonskeletal benefits.1, 2, 7, 19, 60, 61

The results of some clinical trials provide evidence

Cancers

Association studies have related higher serum levels of 25(OH)D to reduced incidence of many types of cancers. It has been hypothesized that the local conversion of 25(OH)D to 1,25(OH)2D in healthy cells in the colon, breast, and prostate can help prevent malignancy by inducing cellular maturation, inducing apoptosis, and inhibiting angiogenesis while enhancing the expression of genes including P21 and P27 to control cellular proliferation (Figure 1).1, 2, 7, 16, 26 Another vitamin D–regulated

Assessing Vitamin D Status

Although the generally accepted measure of vitamin D status is circulating 25(OH)D concentration, there is little consensus on which assay method should be used. Commonly used assays include competitive protein-binding assay, radioimmunoassay, enzyme immunoassay, chemiluminescence immunoassay, high-performance liquid chromatography, and liquid chromatography–tandem mass spectrometry (LC-MS/MS), each with its own advantages and disadvantages.212, 213 Binkley et al214 reported that 25(OH)D

Vitamin D Status During Pregnancy, Birth, and Childhood

Maternal vitamin D deficiency predisposes to low vitamin D stores in the newborn and increases infantile rickets224 because the mother is the only source of vitamin D during pregnancy. The prevalence of vitamin D deficiency and insufficiency during pregnancy is of special concern and ranges from 8% to 100%, depending on the country of residence and the definitions of vitamin D deficiency and insufficiency (Figure 5).2 In the United States, vitamin D deficiency and insufficiency is estimated to

Prevalence of Vitamin D Deficiency in Adolescents and Adults

It has been estimated that 20% to 80% of US, Canadian, and European men and women are vitamin D deficient.228, 229 The prevalence of serum 25(OH)D levels less than 20 ng/mL was almost one-third of the US population (32%).217 More than 70% of non-Hispanic black individuals and more than 40% of Hispanic/Mexican individuals were at risk for a 25(OH)D level less than 20 ng/mL.228 In a national Canadian cohort, serum 25(OH)D levels less than 30 ng/mL were evident in 57.5% of men and in 60.7% of

Causes of Vitamin D Deficiency and Risk Factors

Traditional risk groups for vitamin D deficiency include pregnant women, children, older persons, the institutionalized, and nonWestern immigrants.7, 228 The major source of vitamin D for children and adults is exposure to natural sunlight.7, 61 The Maasai and Hadzabe tribes in Tanzania (East Africa) with traditional lifestyles, living in the presumed cradle of humankind, who are exposed daily to tropical sunlight had a mean circulating 25(OH)D level of 46 ng/mL.140

A variety of factors

Treatment and Prevention of Vitamin D Deficiency and Insufficiency With Sun Exposure and UV-B Irradiation

Humans obtain a considerable amount of their vitamin D requirement from sun exposure.7, 140 Although excessive exposure to sunlight increases the risk of nonmelanoma skin cancer, which is easy to detect and easy to treat, there is no evidence that sensible sun exposure, as our hunter-gatherer forefathers likely experienced, increases risk.124, 246 More importantly, the most deadly form of melanoma skin cancer that occurs on the least sun-exposed areas is less likely to occur in adults who have

Safety and Intoxication

Vitamin D intoxication is characterized by hypercalcemia, hypercalciuria, and hyperphosphatemia, which, in turn, are responsible for soft-tissue and vascular calcifications and nephrolithiasis in the long term. Serum 25(OH)D levels are usually markedly elevated (>150 ng/mL) in individuals with vitamin D intoxication.7, 60, 90 Daily doses of vitamin D3 up to 10,000 IU were safe in healthy males, and there was no evidence of hypercalcemia or hypercalciuria for 5 months.253, 268 This amount is far

Conclusion

Vitamin D deficiency is a common underdiagnosed condition that has received increasing attention in the world. The US Endocrine Society guidelines and the IOM recommend screening only in populations at risk, as no evidence currently exists to support screening at a population level. Candidates for vitamin D screening include those who are at specific risk for vitamin D deficiency and patients who are experiencing or are at risk for specific medical conditions associated with hypovitaminosis D.

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  • Cited by (0)

    Grant Support: This work was supported, in part, by grant UL-1-RR-25711 from the National Institutes of Health and by the Mushroom Council.

    Potential Competing Interests: Dr Holick is a consultant for Quest Diagnostics, Ontometrics, Vital Choice, Merck, and Bioceuticals.

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