What is Vitamin D?
Vitamin D is not really a vitamin; rather, it is a steroid hormone. The most biologically active form is called 1,25-dihydroxyvitamin D3 (calcitriol). Active calcitriol is derived from 7- dehyrdrocholesterol, produced in the skin. 7-dehyrdrocholesterol is converted into vitamin D3 (cholecalciferol) following UV irradiation (1). The metabolic conversion in the body from prohormone to active hormone is accomplished by a two-step process. First, in the liver it is hydroxylated to become 25(OH)D3 (calcidiol), and then in the kidneys to 1-25-dihydroxyvitamin D3 (calcitriol) by the enzyme 1-α-hydroxylase (FIG 1.). This enzyme is found mainly in the kidney but is also present in lymphocyte and colon cells, the placenta, breast, prostate, and pancreas (2).
The biosynthesis in the skin is the most important source of vitamin D as long as the individual is exposed to sunlight on a regular basis. In that case, no dietary requirement is necessary for this vitamin; however, if there is inadequate exposure to sunlight, dietary intake is critical. Vitamin D2 is synthesized by the irradiation of ergosterol and ingested through the diet (3). Vitamin D2 has also been shown to be less effective than vitamin D3 according to a limited number of studies. A study mapping the time course of serum 25(OH)D after a single dose showed that vitamin D3 raises and maintains serum 25(OH)D levels to a greater degree than vitamin D2 with a potency of at least 3-fold, but closer to 10-fold (4).
25-hydroxylation occurs in the liver, followed by 1-α-hydroxylation in the kidney to activate vitamin D (5). 1,25-dihydroxyvitamin D3 interacts with its nuclear vitamin D receptor, which bonds with the retinoic acid-X-receptor and the genetic information is in a sense unlocked from the molecule in order for it to exert its biological action. The small intestine and PTH also play an important role because 1,25-dihydroxyvitamin D3 maintains calcium homeostasis by increasing the efficiency of intestinal calcium absorption and mobilizing the calcium from the skeleton (6). Nuclear vitamin D receptors are located on almost all tissues and cells in the body.
Sources of Vitamin D
There are three primary sources of vitamin D: its synthesis in the skin from exposure to UVB sunlight, food, and vitamin supplementation (7).
UVB radiation reddens the skin, causing sunburn, and is possibly a contributing factor to an increased risk of non-melanoma skin cancer. However, the UVB radiation also contributes to the reaction in the skin that stimulates the production of vitamin D3 (8). The level of UV radiation varies depending on ozone, time of day, altitude, weather conditions, reflection and –important to our study – the time of year and geographic latitude (8). Vitamin D levels are usually lower in the winter when the sunlight exposure is not as great, compared to the summer or the fall. Additionally, an individual’s geography (particularly with respect to the distance from the Equator) may also play a role. At latitudes above 37o north of the equator or below 37o south of the equator, vitamin D production does not take place from November through February regardless of sun exposure; however, in lower latitudes vitamin D synthesis is adequate year-round (7). However, a recent study in Hawaii showed inadequate vitamin D levels even after the individuals had an average sunlight exposure for 11 hours/week (9). Even in the sunniest of areas vitamin D deficiency can be common if most of the skin is shielded from the sun. Adequate skin exposure to sunlight several times a week or using tanning
bed facilities is helpful (8).
Very few foods are naturally rich sources of vitamin D, but cod liver oil and oily fish like salmon, mackerel and sardines are some of the best sources (10). For example, a serving of 3.5 ounces of salmon contains 400 IU; cod liver oil contains 400 IU per teaspoon (11). Sun-dried mushrooms and other food products such as milk, orange juice, cereals and some bread are fortified with vitamin D in the United States. However, it should be noted that fortification of
milk with vitamin D is not standard world-wide (6). Egg yolks also contain approximately 20 IU and some yogurts may contain 100 IU per serving (11).
Finally, multivitamin supplementation is still another way to obtain the many benefits of vitamin D. Multivitamins typically contain 400 IU of either vitamin D2 or vitamin D3 (6). It is important to note that compliance with supplementation especially among elderly is problematic when using multivitamins due to the increased number of other medications the population takes, as well as an unreliable consumption of milk due to a higher prevalence of lactose intolerance(11).
Vitamin D Deficiency
Vitamin D levels are assessed by measuring an individual’s serum 25(OH)D level, which represents short-term vitamin D exposures during the previous few weeks or months (12). Serum 25(OH)D level is the best indication of adequate vitamin D and its concentration reflects absorption from diet and synthesis from skin (13). According to Dr. Michael Holick of the Boston University School of Medicine (8), healthy vitamin D levels should not be less than 20 ng/mL and should ideally be in the 30 to 50 ng/mL range. Dr. Holick and fellow researchers used data that had been collected as part of a
federal National Health and Nutrition Examination Survey between 1999 and 2000 and analyzed the diets of 16,500 people selected as a cross-section of the entire U.S. population. The researchers found that children between the ages of 1 and 8 years old were most likely to get the recommended daily intake (RDI) of vitamin D (currently estimated at 200 to
600 IU, depending upon age). Approximately 60.0% of this population obtained their RDI from diet alone, largely because milk is fortified with vitamin D in the United States and children are more likely than the other age groups to consume significant amounts of milk on a daily basis.
Individuals ages 9 to 50 received nearly as much vitamin D as the young children, but a far higher proportion of their vitamin D intake resulted from using supplements. This was particularly true in young women; only 20-40% typically got the RDI for vitamin D from diet alone.
Vitamin D deficiency reached epidemic proportions among people over 50. Only about 5.0% of men and 1-3% of women received their RDI of vitamin D from diet alone. Even with the use of supplements, only 35.0% of whites, 17.0% of Hispanics, and 10.0% of blacks had received the RDI of vitamin D (14).
Lower vitamin D levels may also be present among patients with osteoporosis, non-white individuals and among populations with low dietary vitamin D supplementation or little sunlight exposure. Blacks have greater skin pigmentation, which can reduce the cutaneous vitamin D3 production by as much as 99.9% (11). In addition, with the same exposure to sunlight as whites, blacks have lower circulating levels of 25(OH)D during the winter, and are less likely to use dietary supplements (15). People living in countries at higher latitudes are also more prone to seasonal vitamin D levels that are sub-optimal because during the winter, sunlight does not promote the formation of the vitamin D precursor in the skin (16). In addition, obese patients appear to also have a greater difficulty utilizing the vitamin D stores in their
skin and put them at greater risk of the consequences of deficiency (12).
The consequences of vitamin D deficiency are numerous and quite varied. Vitamin D deficiency among the elderly can cause secondary hyperparathyroidism and osteomalacia, which can exacerbate osteoporosis, leading to an increased incidence of skeletal fractures (13). This deficiency can also cause muscle weakness, thereby increasing the risk of the elderly to fall and fracture. Vitamin D deficient children may suffer from the bone disorder rickets. Chronic nonspecific musculoskeletal pain is another consequence of deficiency (17). Patients may be diagnosed with fibromyalgia or chronic fatigue syndrome, while their symptoms of muscle aches and bone pain may be due to vitamin D deficiency (11). Recent evidence has also suggested that a low serum 25(OH)D level is associated with an increased risk of metabolic syndrome (2). Other risks are type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular disease and many cancers such as breast, colon and prostate cancer. On the other hand, numerous research studies have demonstrated that sufficient levels of vitamin D may help regulate cell growth and maturation, thus inhibiting cancer cell growth. It may also stimulate insulin secretion, inhibit renin production and modulate immune function (6).