Journal of Investigative Medicine:
EB Symposium Manuscripts
Vitamin D: A D-Lightful Solution for Health
Holick, Michael F. MD, PhD
From the Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, MA.
Received October 22, 2010, and in revised form February 3, 2011.
Accepted for publication February 3, 2011.
Reprints: Michael F. Holick, MD, PhD, Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin and Bone Research Laboratory, Boston University School of Medicine, 85 East Newton St, M-1013, Boston MA 02118. E-mail: firstname.lastname@example.org.
Supported in part by a grant from the National Center for Research Resources (R13 RR023236).
This work was supported in part by the UV Foundation.
Throughout evolution, sunlight-produced vitamin D in the skin has been critically important for health. Vitamin D, known as the sunshine vitamin, is actually a hormone. Once it is produced in the skin or ingested from the diet, it is converted sequentially in the liver and kidneys to its biologically active form 1,25-dihydroxyvitamin D. This hormone interacts with its receptor in the small intestine to increase the efficiency of intestinal calcium and phosphate absorption for the maintenance of the skeleton throughout life. Vitamin D deficiency during the first few years of life results in a flattened pelvis, making it difficult for childbirth. Vitamin D deficiency causes osteopenia and osteoporosis, increasing risk of fracture. Essentially, every tissue and cell in the body has a vitamin D receptor. Therefore, vitamin D deficiency has been linked to increased risk for preeclampsia, requiring a cesarean section for birthing, multiple sclerosis, rheumatoid arthritis, types I and II diabetes, heart disease, dementia, deadly cancers, and infectious diseases. Therefore, sensible sun exposure along with vitamin D supplementation of at least 2000 IU/d for adults and 1000 IU/d for children is essential to maximize their health.
At the turn of the 20th century, rickets was rampant in the industrialized cities of northern Europe and North America.1 Vitamin D deficiency resulted in severe growth retardation and poor mineralization of the skeleton resulting in bony deformities especially of the lower extremities, classically known as rickets. What is not fully appreciated, however, is that vitamin D deficiency in utero and during the first few years of life had additional potentially deadly consequences for women during their childbearing years. Their pelvis often was flattened, and their pelvic outlet was reduced in size, making it difficult if not impossible to have a vaginal delivery. It was because of rickets in childbearing women that led to the common practice of cesarean sectioning. It has been suggested that the driver in evolution for skin pigment to have decreased was due to the fact that heavily pigmented women who migrated into Europe would have had an especially difficult time in making enough vitamin D, thus increasing their risk as well as their infant's risk for vitamin D deficiency. For female infants and children who developed rickets, this would have made it very difficult for them during their childbearing years to have given birth successfully. Therefore, within a few generations, skin pigmentation would have had to be substantially reduced to sustain the reproductive capacity of humans who migrated north and south of the equator. This is the likely reason why Neanderthals were not dark skinned and hairy hominids but rather redheaded with Celtic white skin.2
Vitamin D Sources and Metabolism
The major source of vitamin D is exposure to sunlight. When the sun strikes the skin, the ultraviolet B portion of the sun spectrum enters into the viable epidermis and dermis and is absorbed by 7-dehydrocholesterol, which is converted to vitamin D3 (Fig. 1).3 Once formed, previtamin D3 is rapidly converted to vitamin D3 by a temperature-dependent process. Time of day, season of the year, latitude, aging, sunscreen use, and degree of skin pigmentation can have a dramatic influence on the cutaneous production of vitamin D3. For example, living above Atlanta, GA, essentially, no vitamin D can be produced in the skin from November through February. Vitamin D production does not occur before 9 am and ceases after 4 pm even in the summer (Fig. 2).4-6 People of color require much longer exposure to sunlight because their skin pigment acts as a natural sunscreen, reducing their ability to make vitamin D3 in the skin when compared with a white person exposed to the same amount of sunlight.7 African Americans often need 5 to 10 times longer exposure compared with whites to make the same amount of vitamin D in the skin which explains why they are at much higher risk for vitamin D deficiency. A sunscreen with an SPF of 30 absorbs approximately 95% of incident UV-B radiation and thus reduces the production of vitamin D in the skin by approximately 95%.8 Aging also influences the production of vitamin D, and a person 70 years of age has only approximately 25% of the capacity to produce vitamin D compared with a 20-year-old.9 Exposure to sunlight through glass will not produce any vitamin D because glass absorbs all UV-B radiation.
Few foods naturally contain vitamin D (Table 1).3 The major sources are wild caught salmon, other oily fish, cod liver oil, and mushrooms, which have enhanced vitamin D when exposed to UV-B radiation. Some foods are fortified with vitamin D, including milk and some other dairy products such as yogurt and some cheeses, cereals, and some juices. There are 2 forms of vitamin D. Vitamin D3 is produced in the skin and also is generated from lanolin which is then used for food fortification and vitamin D3 supplements. Vitamin D2 is made in yeast and mushrooms exposed to UV-B radiation. Vitamin D2 is the only pharmaceutical form of vitamin D and available by prescription in the United States and is used in some supplements and food fortification. Vitamin D2 is as effective as vitamin D3 in maintaining both children's and adults' vitamin D status.10
Once vitamin D (D represents D2 or D3) is made in the skin or ingested, it travels to the liver where it is converted to 25-hydroxyvitamin D (25[OH]D) (Fig. 1). 25-Hydroxyvitamin D is the major circulating form of vitamin D that is measured by a physician to determine a person's vitamin D status.2 However, 25(OH)D is biologically inert and is transported to the kidneys where it is converted to its active form, 1,25-dihydroxyvitamin D [1,25(OH)2D] (Fig. 1). 1,25-Dihydroxyvitamin D travels to the intestine and interacts with its receptor, the vitamin D receptor, to enhance intestinal calcium absorption. It also travels to the skeleton to help maintain a healthy skeleton by enhancing the bone remodeling process.
Consequences of Vitamin D Deficiency on Bone and Muscle Health
It is now recognized that vitamin D deficiency is one of the most common medical conditions in the world.1,3,11 It has been estimated that upward of 50% of both children and adults living in the United States, Canada, Mexico, Europe, Asia, New Zealand, and Australia are vitamin D deficient.3 When a child or adult is vitamin D deficient, he or she is unable to absorb enough calcium from their diet to satisfy their body's calcium requirement, and this results in an increase in the production of parathyroid hormone. Parathyroid hormone efficiently removes calcium from the skeleton to maintain the blood calcium level which is essential for neuromuscular and all metabolic activities.5 As a result, a child will not be able to accrue his or her maximum bone density especially during their growth spurt. Young and middle-aged adults will begin to lose, on average, 0.5% of their skeletal mass per year and, over a period of 10 to 20 years, can lose as much as 5% to 10% of their skeletal mass, increasing their risk for osteoporosis and fracture. After menopause, women begin to rapidly lose as much as 3% to 5% of their bone mass because of the loss of estrogen stimulation on the skeleton, and vitamin D deficiency exacerbates this loss, increasing further risk, for women, of developing osteoporosis earlier in life, putting her at higher risk for fracture.5,11
Vitamin D deficiency in early childhood causes rickets, which is rarely seen except for children who are exclusively breast-fed and who do not receive any vitamin D supplementation.1,12,13 Vitamin D deficiency in an older child and in all adults causes a mineralization defect of the skeleton identical to what happens in a younger child developing rickets. The difference is that the young child essentially has no mineral in the skeleton and, as a result, has a variety of skeletal deformities. Older children and adults have enough mineral in the skeleton, preventing them from developing overt skeletal deformities. Instead, the mineralization defect prevents the collagen from being properly mineralized. This not only results in a decrease in the bone mineral density but also causes throbbing aching bone pain as well as muscle weakness and muscle pain. This disease is known as osteomalacia and often is misdiagnosed as fibromyalgia.14,15 Ninety percent of 150 children and adults (ages, 10-65 years) who presented to a local emergency department with aches and pains in their bones and muscles were found to be vitamin D deficient.14
Vitamin D deficiency increases risk for muscle weakness and falling.1 Studies in both female children and women have demonstrated that increasing their vitamin D status improves their muscle strength.16 For older men and women, this can reduce their risk of falling by as much as 72%, thereby reducing risk of fracture.17,18
Other Consequences of Vitamin D Deficiency
It is now recognized that pregnant women are at very high risk for vitamin D deficiency. It was reported that 76% of moms at the time that they gave birth were vitamin D deficient despite the fact that they took a prenatal vitamin and drank 2 glasses of milk a day on average, thus obtaining approximately 600 IU of vitamin D a day. Eighty-one percent of their newborns also were found to be vitamin D deficient.19 During pregnancy, vitamin D deficiency has been associated with a 3- to 4-fold increase risk for developing preeclampsia, the most serious complication of pregnancy.20 Because vitamin D is so important for muscle function, it was not a surprise that in more than 400 women who were having their first child, there was a more than 300% increase risk for them requiring a cesarean section if they were vitamin D deficient.21
Lactating moms are at high risk for vitamin D deficiency even if they are taking their prenatal vitamin. As a result, they put their infant at risk for vitamin D deficiency if the infant receives, as his or her sole source of nutrition, human breast milk.12,13 It is for this reason that the American Academy of Pediatrics has now recommended that all infants and all children should receive 400 IU of vitamin D supplement daily.22 For a lactating woman to put enough vitamin D in her milk to satisfy her infant's requirement, she would need to take 4000 to 6000 IU of vitamin D a day.13 Although this sounds like an extraordinarily high amount of vitamin D, it is very likely that our hunter gatherer forefathers exposed to sunlight daily were making thousands of IUs of vitamin D a day in their skin, and therefore, it is reasonable to believe that 4000 to 6000 IU of vitamin D a day is what we all require to satisfy our bodies' requirement.
Infants who received 2000 IU of vitamin D daily during their first year of life were found 31 years later to have reduced their risk of developing type I diabetes by 88%.23 Infants born above 35°N and who live above this latitude for the first 10 years of life have 100% increased risk of developing multiple sclerosis for the rest of their life.24 Women who had the highest intake of vitamin D reduced their risk of developing multiple sclerosis by 41%.25 Women who had the highest intake of vitamin D also were found to reduce their risk of developing rheumatoid arthritis by 44%.26
It has been recognized for more than 20 years that living at higher latitudes increases risk of developing and dying of a variety of cancers including colorectal cancer, breast cancer, prostate cancer, and pancreatic cancer.27,28 Women who had the most sun exposure as teenagers and young adults reduce their risk of developing breast cancer later in life by 50% to 60%.29 Women who had the highest intake of vitamin D reduce their risk of developing breast cancer by 50%.30 Postmenopausal women who took 1100 IU of vitamin D3 a day for 4 years reduce their risk of developing all cancers by 60%.31
It is well documented more than 100 years ago that vitamin D deficiency in children markedly increased their risk for upper respiratory tract infections.1 There have been several studies reporting that vitamin D deficiency is associated with increased risk for upper respiratory tract infections, wheezing disorders, and asthma in children.32 Japanese schoolchildren who took 1200 IU of vitamin D a day from December through March reduced their risk of developing influenza infection by almost 50%.33
It has been estimated that upward of 50 million teenage boys and girls are at risk for vitamin D deficiency or insufficiency. They have a 2.4-fold higher risk for developing high blood pressure, 2.5-fold higher risk for having elevated blood sugar, and a 4-fold increased risk for having pre-type II diabetes (metabolic syndrome).34,35
Vitamin D deficiency also has been associated with a 33% increased risk of developing type II diabetes in men and women.36 Vitamin D deficiency is associated with increased risk for hypertension. Men and women who were vitamin D deficient had a 50% increased risk for having a myocardial infarction,37 and those who had a myocardial infarction and were vitamin D deficient had 100% increased risk of dying from their heart attack.38
Definition and Causes of Vitamin D Deficiency and Insufficiency
Based on provocative testing and other clinically relevant data, vitamin D deficiency has been defined as a 25(OH)D of less than 20 ng/mL.3,39 However, to maximize intestinal calcium absorption in women and to have all of the other health benefits of vitamin D, it has been recommended that children and adults should have a blood level of 25(OH)D of greater than 30 ng/mL.40 Therefore, vitamin D insufficiency has been defined as a 25(OH)D of 21 to 29 ng/mL (Fig. 1).3
The major cause for vitamin D deficiency globally is a lack of appreciation that sun-induced vitamin D synthesis was the major source of vitamin D for most children and adults with the exception of people living far north and south of the equator. These people quickly realized that eating fatty fish, blubber from seals, and liver from polar bears was essential for overall health and well-being. They are excellent dietary sources for vitamin D.
The message that you should never be exposed to direct sunlight has caused the vitamin D deficiency pandemic.41 In the skin cancer capital of the world, Australia, the slip, slap, slop message has caused widespread vitamin D deficiency. Approximately 87% of dermatologists in Australia were found to be vitamin D deficient at the end of the summer.42 People who always wear sunscreen before going outdoors place themselves at high risk for vitamin D deficiency because a sun protection factor of 30 used properly reduces vitamin D3 synthesis in the skin by more than 95%.8 People of color including both Hispanics and blacks are at much higher risk for vitamin D deficiency because not only do they avoid sun exposure so as not to enhance the color of their skin but often put a sunscreen on before going outdoors. Their skin pigment often gives them a sun protection factor of at least 8, thereby reducing their efficiency to make vitamin D3 in their skin by 50% to 90%. When African American men and women were exposed to simulated sunlight, they were unable to raise their blood levels of vitamin D3, whereas white adults who received the same amount of simulated sunlight raised their blood levels of vitamin D3 by almost 50 fold.7 African American adults required 5 to 10 times longer exposure and they only raised their blood levels by about 10 to 20 fold.
Obesity is associated with vitamin D deficiency. Vitamin D is fat soluble and is therefore efficiently sequestered in the body fat, making it difficult to return into the circulation.43 This is the reason why men and women with a body mass index greater than 30 require at least 2- to 5-fold increase in their vitamin D requirement.3
Patients with a variety of fat malabsorption syndromes including inflammatory bowel diseases such as Crohn disease, ulcerative colitis, and cystic fibrosis and patients who have had gastric bypass surgery are unable to efficiently absorb vitamin D and often require much higher doses to satisfy their vitamin D requirement.3 A silent cause for vitamin D deficiency due to intestinal malabsorption is caused by celiac disease. Often, this disease is diagnosed when it is realized that a patient who is vitamin D deficient does not respond appropriately to vitamin D therapy and thus has a malabsorption problem.
Prevention and Treatment for Vitamin D Deficiency
It has been assumed that drinking a couple of glasses of milk each containing 100 IU of vitamin D along with a multivitamin and a balanced diet was more than adequate to satisfy a child's and adult's vitamin D requirement. However, it is now realized that, for adults and probably also for children older than 1 year, for every 100 IU of vitamin D ingested, the blood level of 25(OH)D increases by approximately 0.6 to 1 ng/mL.10,44 When healthy adults in Boston at the end of the winter received 1000 IU of vitamin D2 or vitamin D3 daily for 3 months, they raised their blood level of 25(OH)D by approximately 10 ng/mL (Fig. 3).10 The white men and women had an average 25(OH)D of 18 ng/mL, and the black men and women had, on average, a 25(OH)D of 15 ng/mL. Thus, 1000 IU of vitamin D3 a day raised the blood level of the white men and women to 28 ng/mL and that of the black men and women to 25 ng/mL. Therefore, based on this and other studies, it is clear that 1000 IU of vitamin D a day in the winter without any contribution of vitamin D from the sun was unable to raise and sustain a blood level of 25(OH)D above 30 ng/mL.
Prepubertal and teenage girls who received 2000 IU of vitamin D3 a day for 1 year were able to raise their blood levels of 25(OH)D above 30 ng/mL and were found to have better bone density and improved muscle function compared with girls who received only 400 IU of vitamin D a day for the same period.16
When an adult in a bathing suit (woman in a bikini-type bathing suit) has his/her whole body exposed to a tanning bed that was equivalent to being exposed to sunlight that caused a light pinkness to his/her skin 24 hours later (defined as one minimal erythemal dose) he/she raised their blood level of vitamin D similar to the adult taking approximately 15,000 to 20,000 IU of vitamin D as a single dose (Fig. 4). Vitamin D made in the skin has at least 2 to 3 times longer in the circulation when compared with ingesting vitamin D (Fig. 4).45 Therefore, the body has a large capacity to make vitamin D with minimum sun exposure. This is the reason for the recommendation that exposure to arms and legs (which is approximately 20%-25% of the body surface when wearing shorts and a short sleeve shirt or blouse) to approximately 5 to 15 minutes 3 times a week (of course depending on time of day, season of the year, latitude, and degree of skin pigmentation) between the hours of 10 am and 3 pm for white adults during the spring, summer, and fall can help provide them with their vitamin D requirement. As can be seen in Figure 5, sensible exposure to ultraviolet radiation (similar to sunlight) is very effective in raising blood levels of 25(OH)D into a healthy range above 30 ng/mL and is more effective than ingesting 1000 IU of vitamin D a day. I recommend that because one cannot always depend on sun exposure because of work habits, concerns about the damaging effects from sunlight, and others, healthy adults should take a supplement containing 2000 IU of vitamin D a day along with ingesting a multivitamin containing 400 IU of vitamin D and 3 servings of dairy or other vitamin D-fortified foods for a total of 3000 IU of vitamin D a day. Men and women who took an equivalent of 3000 IU of vitamin D a day for up to 6 years were able to maintain a blood level of 25(OH)D on average of between 40 and 60 ng/mL (Fig. 6).46
Children, from the day they are born, should take at least 400 IU of vitamin D a day as recommended by the American Academy of Pediatrics.3-5,22 However, based on a variety of studies, a total of 1000 IU of vitamin D a day from supplements and diet may be more beneficial for infants and children.22 Teenagers, like adults, should take a 2000 IU supplement a day if they are not active outside and getting adequate sensible sun exposure to produce an adequate amount of vitamin D. Children and adults of color cannot depend on sun exposure for their vitamin D requirement unless they are outside for prolonged periods either because of outdoor activities or an outdoor occupation. Therefore, children should take at least 1000 IU of vitamin D a day, and black teenagers and adults should take at least 2000 IU of vitamin D a day. If they are obese, they may need 2 to 5 times more vitamin D to satisfy their requirement (Table 2).
To effectively treat vitamin D deficiency quickly, it is wise to fill up the vitamin D tank which is empty. To accomplish this, I give 50,000 IU of vitamin D2 once a week for 8 weeks that is equivalent to taking 6000 IU of vitamin D a day.46 A similar strategy also is effective in children.47 After treating the vitamin D deficiency to prevent recurrence, I give my patients 50,000 IU of vitamin D2 once every 2 weeks thereafter which is equivalent to 3000 IU/d. Six years on this therapy is effective in maintaining blood levels of 25(OH)D above 30 ng/mL with no observed toxicity (Fig. 6).46
Use of the 25(OH)D Assays
There are several assays that are used commercially to measure 25(OH)D, which is the gold standard for determining a patient's vitamin D status. The antibody-based assays are able to measure the total 25(OH)D, and the liquid chromatography tandem mass spectroscopy (LCMSMS) assay separates 25(OH)D2 from 25(OH)D3. Therefore, the antibody-based assay provides the total blood level of 25(OH)D, which is used to determine a person's vitamin D status. The LCMSMS assay provides not only the total 25(OH)D but also the individual blood levels of 25(OH)D2 and 25(OH)D3. Because there is little vitamin D2 in the diet, most children and adults have essentially 100% of their total 25(OH)D as 25(OH)D3. Therefore, patients who are being treated for vitamin D deficiency with vitamin D2 the advantage of having a follow-up blood sample sent for an LCMSMS assay is that there should be a significant increase in the serum 25(OH)D2. The serum 25(OH)D3 would be reflective of sun exposure that produces vitamin D3 in the skin and the ingestion of a vitamin D supplement that contains vitamin D3. If there is no significant increase in the 25(OH)D2 in patients who are being treated with vitamin D2, then either the patient is not compliant or is malabsorbing the vitamin. If there is a small increase in the serum 25(OH)D2, then I usually recommend increasing the frequency of taking the vitamin D2. An alternative is to cut the capsule in half and add it to a small amount of milk swirl and then drink it because some patients are unable to digest the gelatin capsule or are allergic to the gelatin and glycerin components of the capsule.
Recently, the Institute of Medicine recommended a significant increase in vitamin D intake of up to 3 fold for older children and adults.48 They also recognize that vitamin D is less toxic than once thought and therefore increased the tolerable upper limit (UL) for children and adults (Table 2). However, there were several recent studies that have suggested that higher intakes for children and adults may have some additional nonskeletal health benefits.31,33-35,37,49,50
There is no downside to increasing either a child's or adult's vitamin D intake to what is recommended in Table 2. The only time that you should be concerned about taking the amount of vitamin D recommended in Table 2 is if you are experiencing a chronic granulomatous disorder, such as sarcoidosis.5 These patients still need some vitamin D but usually only enough to raise their blood level of 25(OH)D to between 20 and 30 ng/mL to avoid causing hypercalcemia and hypercalciuria.51 Children and women of all ages should be particularly concerned about their vitamin D status. Vitamin D deficiency will result in growth retardation and inadequate bone mineralization especially for teenage girls during their growth spurt. Women of childbearing age also should be vigilant about their vitamin D status because it can improve pregnancy outcomes and improve the health of their developing infant. Young and middle-aged adults benefit from increasing their vitamin D status from sensible sun exposure and vitamin D supplementation by decreasing their risk for autoimmune diseases; deadly cancers including prostate, colon, and breast cancer; type II diabetes; heart disease; cognitive dysfunction; and infectious disease (Fig. 2). Children need an adequate supply of vitamin D to reduce their risk of developing asthma, wheezing disorders, and upper respiratory tract infections including influenza infection. It also may reduce their risk for developing many of the chronic diseases that have now been associated with vitamin D deficiency (Fig. 7).
Not only has the sun been demonized for more than 40 years unchallenged41 which is the major cause for the vitamin D deficiency epidemic, but it also has been accepted by the medical community and lay public that fat-soluble vitamin D is potentially highly toxic. Vitamin D can cause intoxication, which is associated with a high blood calcium causing calcification of blood vessels and the kidneys that can lead to death.3 However, vitamin D intoxication is one of the rarest medical conditions.52,53 The reason is that adults can take up to 10,000 IU of vitamin D a day for at least 5 months without any untoward toxicity.44 It is caused by inadvertent or intentional ingestion of excessively high amounts of vitamin D. This is usually in the range of 50,000 IU of vitamin D a day for several months. We reported an adult who took, on average, 1 million IU of vitamin D3 a day that he had purchased on the internet. His calcium was more than 15 mg percent, and his 25(OH)D was greater than 500 ng/mL.53 Therefore, a blood level of 25(OH)D up to 100 ng/mL is considered to be safe. Usually, blood levels of 25(OH)D above 200 ng/mL have been associated with vitamin D intoxication resulting in hypercalcemia, hyperphosphatemia, nephrocalcinosis, and soft tissue calcification. It should be noted that even excessive exposure to sunlight will not cause vitamin D intoxication because any excess vitamin D is destroyed by the sun.13
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47. Gordon CM, Williams AL, Feldman HA, et al. Treatment of hypovitaminosis D in infants and toddlers. J Clin Endocrinol Metab. 2008;93:2716-2721.
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