It is not an exaggeration to describe vitamin D deficiency as an epidemic throughout the industrial world. What else would you call a condition that is now present in almost 90% of the population during some point of the year, and throughout the entire year in 70% to 90% of American postmenopausal women, 85% to 95% of all women in Saudi Arabia, 81% of newborns in New Jersey, 48% of 10-year-old girls in Boston, 100% of African-Americans in Minnesota, and 50% of adolescents in the United Kingdom?
The classic disorders associated with vitamin D deficiency are the bone diseases of rickets in children and osteomalacia in adults. But over the past 15 years, scientists have been adding to the expanding list of other diseases associated with or exacerbated by vitamin D deficiency. This list might surprise you. It includes not only osteoporosis, but also rheumatoid arthritis, multiple sclerosis, colon cancer, prostate cancer, breast cancer, depression, diabetes, tuberculosis, and schizophrenia. In fact, so many scientific claims have been made in the past decade about potential benefits of vitamin D that the science writer Chris Woolston went so far as to call vitamin D a “wonder pill” in a recent article touting its myriad benefits.
To understand what all the excitement is about, let’s back up a little bit and try to get our facts straight. First off, vitamin D is actually not a vitamin at all. Instead, it is a potent steroid hormone. “Vitamin D,” as the precursor D3, is not bioactive and must be metabolized to the hormonally active form (1,25-dihydroxyvitamin D3) through a complex process involving sunlight, skin, the liver, and the kidneys (see Table 1 for a list of terms). The process begins with sunlight exposure to the skin, where pre-vitamin D3 is converted to vitamin D3 and enters the circulatory system. The vitamin then travels to the liver, where it is metabolized through enzymatic action to 25-hydroxyvitamin D3, after which it is finally converted in the kidney to the biologically active hormone 1,25-dihydroxyvitamin D3.
Table 1. Definition of Terms
|calcifidiol 25-hydroxyvitamin D3 (the major circulating form of vitamin D)|
calcitriol 1,25-dihydroxyvitamin D3 (the active form of vitamin D)
cholecalciferol vitamin D3 (animal- derived; three times more potent than vitamin D2)
ergocalciferol vitamin D2 (plant- derived)
optimal vitamin D level serum 25- hydroxyvitamin 50-100 ng/ml.
osteomalacia low bone mass and associated increased fracture risk due to impaired mineralization of bone matrix from profound vitamin D deficiency; commonly associated with symptoms of body aches, myopathy, and muscle weakness
osteoporosis low bone mass and associated increased fracture risk due to microarchitectural deterioration of normal mineralized bone tissue; despite low bone volume in osteoporosis, the mineral-to-matrix ratio is preserved
vitamin D deficiency serum 25-hydroxyvitamin D <32 ng/ml
vitamin D toxicity serum 25-hydroxyvitamin D >150 ng/ml
Because pre-vitamin D3 is converted to biologically inert substances, prolonged exposure to sunlight does not result in excessive 1,25-dihydroxyvitamin D3 production. This phenomenon is an important distinction between sunlight-derived vitamin D3 and orally derived vitamin D3. The latter form is outside the normal feedback mechanism and could lead to toxicity at sustained high doses. More on this later.
Receptors for 1,25-dihydroxyvitamin D3 are present in almost every cell and tissue in the body. Although vitamin D is best known as a promoter of mineral homeostasis, it is also involved in other biological pathways, including cell proliferation, cell differentiation, and tissue development. In fact, vitamin D is one of the most potent regulators of cellular growth in both normal and cancer cells. Increased oral vitamin D3 intake has been shown to improve muscle strength, insulin action, myocardial contractility, thyroid function, and the immune system through modulation of activated T and B lymphocyte function.
If vitamin D is so important for overall health and only sunlight is required to activate vitamin D3, why is there an epidemic of vitamin D deficiency? The short answer is clothing and sunscreen, as well as human migration away from the tropics. Although vitamin D has appropriately been called the “sunshine vitamin,” the ultraviolet light that is required to produce vitamin D cannot be just any light. Only short ultraviolet B (UVB) waves can activate the skin receptors that ultimately lead to 1,25-dihydroxyvitamin D3 synthesis. Unfortunately, UVB is easily blocked with clothing and sunscreen. In addition, UVB rays cannot penetrate the ozone layer when the sun is at a lower angle in the sky, such as in the morning or afternoon or most any time of day between the months of November and March in the northern hemisphere (San Francisco northward) and May and September in the southern hemisphere (Buenos Aires southward).
Even when bare skin is exposed to UVB rays, the amount of melanin in the skin is a limiting factor. The darker a person’s skin, the more UVB exposure is necessary to activate vitamin D3. The relatively recent migration of darker-skinned people away from the equatorial region has further contributed to the worldwide epidemic of vitamin D deficiency. A white woman working outdoors in Santa Rosa during the midday in summer—wearing shorts, a T-shirt, and no sunscreen—can soak up enough ultraviolet rays to produce 12,000 IU of vitamin D in 20 minutes. A black woman would likely require more than 90 minutes of exposure to produce the same amount of vitamin D.
With the longstanding human custom of wearing clothes, the more recent widespread use of sunscreen, and the link between sunlight and skin cancer, we are not getting enough UVB light, regardless of skin color. (Although lack of UVB exposure is the most common cause of vitamin D deficiency, there are other conditions that contribute to vitamin D disorders; see Table 2). Rather than risking the ire of dermatologists by suggesting we omit sunscreen or, even worse, risking the wrath of the modest for suggesting we all shed clothing (all in support of vitamin D activation, of course), it is more appropriate to have people consume enough vitamin D3 in their diet through a combination of fortified foods and supplements.
Inadequate skin activation
Impaired or deficient intake
Accelerated loss of vitamin D
The only truly accurate way to determine if an individual is vitamin D sufficient is to measure serum concentrations of 25-hydroxyvitamin D3. Although biologically inactive, the molecule is stable, with a circulating half-life of up to two weeks. Serum 25-hydroxyvitamin D3 testing requires a simple blood test, without any dietary restrictions.
The active form of D3 (1,25-dihydroxyvitamin D3) is not suitable for monitoring overall vitamin D status because it correlates poorly with Vitamin D3 intake and production. Serum 1,25-dihydroxyvitamin D3 has a half-life of only a few days and is manufactured by the kidney on demand.
The human body probably uses up to 4,600 IU of vitamin D daily, depending on age and health condition. Nevertheless, the Food and Nutrition Board of the National Academies currently recommends that everyone under age 50 consume only 200 IU of vitamin D per day. The board further recommends that people over age 50 get 400 IU daily until age 70, when 600 IU is recommended. At these doses, virtually everybody would be vitamin D deficient if they always stayed indoors or, when outdoors, covered their skin with clothing or sunscreen.
In actuality, the correct dose of daily vitamin D for an individual should be that amount necessary to maintain a healthy serum 25-hydroxyvitamin D3 concentration. “Normal” reference values cited by large laboratories have recently been adjusted to a range of 37-100 ng/ml, but other authorities recommend a serum 25-hydroxyvitamin D3 level between 50-100 ng/ml for maximum health benefits.
Sunlight is a problematic source of vitamin D. In addition to being a possible carcinogen, sunlight can only be an effective source of vitamin D if a person’s skin is exposed to enough UVB. The amount of exposure required depends on type of skin, latitude, time of day and year, and amount of skin exposed. A more dependable means of getting adequate vitamin D is through supplements and/or fortified foods (see Table 3). Because of a high incidence of lactose intolerance, blacks have a particularly low intake of the most highly enriched vitamin D fortified food: milk. Is it any wonder that 100% of African-Americans in northern Minnesota are vitamin D deficient?
Food (unless fortified, few foods contain vitamin D)
Vitamin D3 is more potent than D2. Whenever possible, patients should be instructed to purchase D3 over-the-counter supplements. To achieve a serum 25-hydroxyvitamin D3 level of 50 ng/ml, most otherwise healthy individuals probably require 1,000 IU of vitamin D3 daily (OTC) or 50,000 IU of vitamin D2 monthly (Rx). Patients who present with vitamin D deficiency and secondary hyperparathyroidism should be monitored for serum 25-
hydroxyvitamin D3 concentrations and parathyroid levels. These patients often require significantly higher daily doses of vitamin D3 before achieving therapeutic levels. A weekly dose of 50,000 IU Vitamin D2 (Rx) for 12 to 16 weeks may be required to achieve normal parathyroid levels in these patients. For patients with conditions or medications (such as phenytoin) that interfere with intestinal vitamin D absorption or vitamin D activation, very high doses of vitamin D (e.g., Rx 50,000 IU vitamin D2 one to three times weekly) may be required to maintain adequate 25-hydroxyvitamin D3 levels.
Although the median vitamin D intake in the United States is only 320 IU/day, vitamin companies have been relatively slow to respond to the epidemic of vitamin D deficiency. A typical OTC multivitamin contains only 400 IU of vitamin D, a dose too low to achieve a healthy serum 25-hydroxyvitamin D3 concentration in most people. Taking two multivitamins daily is one possible solution, but that poses the risk of excessive vitamin A consumption because many multivitamins contain vitamin A doses far above the recommended daily allowance.
Unfortunately, finding adequate doses of separate vitamin D3 supplements may be a challenge for many of our patients. A recent informal survey of more than 20 pharmacies and vitamin shops in Sonoma County found that only five offered 1,000 IU vitamin D3 capsules (see Table 4). A few more carried 400 IU capsules, but most did not carry D3 at all.
The safety margin for vitamin D therapy is quite large, making vitamin D toxicity uncommon. One study reported no adverse effects in patients who took 10,000 IU vitamin D3 daily for five months. In fact, vitamin D toxicity has only been observed in patients whose vitamin D3 intake is in the range of 40,000 IU per day. Nonetheless, 25-hydroxyvitamin D3 concentrations of >150 ng/ml are associated with hypercalcemia and, when seen, are pathognomonic for vitamin D intoxication.
Until more widely consumed foods, such as grains and cereals, are fortified with vitamin D, it is essential that we instruct our patients to take vitamin D supplements on a regular basis. In general, a daily intake of 1,000 IU of vitamin D3 should be sufficient for most people of all ages, races, latitudes, and clothing preferences.
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