Defisiensi Vitamin D

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2008 American Society for Clinical Nutrition
Vitamin D deficiency: a worldwide problem

with health consequences1,2,3,4
1. Michael F Holick and
2. Tai C Chen
+ Author Affiliations
1.
From the Department of Medicine; Section of Endocrinology, Nutrition, and Diabetes;

Vitamin D, Skin and Bone Research Laboratory; Boston University Medical Center,
Boston, MA
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Abstract
Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency
is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for
most humans. Very few foods naturally contain vitamin D, and foods that are fortified with
vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement.
Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia,
osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased
risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A
circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize
vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800
1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be
equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given
in physiologic concentrations.
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HISTORICAL PERSPECTIVE
Some of the earliest phytoplankton life forms on earth that have existed unchanged in the
Atlantic ocean for >750 y can make vitamin D when exposed to sunlight (1, 2). Most vertebrates,
including amphibians, reptiles, birds, and lower primates, depend on sun exposure for their
vitamin D requirement (2). The lack of sunlight and its association with the devastating bonedeforming disease rickets in children was first recognized by Sniadecki in 1822 (3). One hundred
years would pass before it was observed that exposure to ultraviolet B radiation (UVB; 290315
nm) from a mercury arc lamp or sunlight prevented and treated rickets (4). In the early 1930s, the
US government set up an agency to provide recommendations to parents about the beneficial
effect of sensible exposure to sunlight for the prevention of rickets (4-6).
The fortification of milk in the 1930s with 100 IU vitamin D2 per 8 ounces was effective in
eradicating rickets in the United States and Europe. The unfortunate outbreak of hypercalcemia
in the 1950s in Great Britain was blamed on the overfortification of milk with vitamin D, even
though there was little evidence for this (7). Because milk was scarce at the end of the war, many
local stores that sold milk would add vitamin D to it if it was not purchased by the expiration
date. This was thought to extend the shelf-life of the vitamin Dfortified milk. This rise in the
incidence of hypercalcemia in infants in the 1950s resulted in Europe forbidding the fortification
of dairy products with vitamin D. Only recently have Finland and Sweden begun fortifying milk
with vitamin D.
SOURCES OF VITAMIN D
The major source of vitamin D for most humans is exposure to sunlight (1, 2, 4-6). As shown in
Figure 1, seasonal variation is found in the major circulating form of vitamin D, 25hydroxyvitamin D [25(OH)D] (8). Few foods naturally contain vitamin D, including oily fish
such as salmon, mackerel, and herring and oils from fish, including cod liver oil. We recently
conducted a study and observed that wild-caught salmon had on average 5001000 IU vitamin D
in 100 g (3.5 ounces), whereas farmed salmon contained 100250 IU vitamin D per 100-g
serving (9). The most likely reason is that vitamin D is plentiful in the food chain but is not
plentiful in the pelleted diet fed to farmed salmon. In the United States, milk, some juice
products, some breads, yogurts, and cheeses are fortified with vitamin D. Multivitamins that
contain 400 IU vitamin D and supplements containing vitamin D only are now available in
various amounts including 400, 1000, 2000, 4000, 5000 and 50 000 IU vitamin D3. The
pharmaceutical form of vitamin D in the United States is vitamin D2 and is available as 50 000
IU vitamin D2 in a capsule or 8000 IU vitamin D2/mL (4, 10). In Canada, Europe, Japan, and
India, vitamin D3 is available as a pharmaceutical.
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FIGURE 1.
A: Relation between hours of sunshine and serum 25-hydroxyvitamin D [25(OH)D]
concentrations. , hours of sunshine; , 25(OH)D. B: Seasonal fluctuation in serum 25(OH)D
according to frequency of sun exposure. , regular sun exposure; , occasional sun exposure; ,
avoiding direct sun exposure. Adapted from reference 8.
CONSEQUENCES OF VITAMIN D DEFICIENCY ON

THE MUSCULOSKELETAL SYSTEM
Much debate has taken place over the definition of vitamin D deficiency. Most agree that a
25(OH)D concentration <50 nmol/L, or 20 ng/mL, is an indication of vitamin D deficiency,
whereas a 25(OH)D concentration of 5174 nmol/L, or 2129 ng/mL, is considered to indicate
insufficiency; concentrations >30 ng/mL are considered to be sufficient (10-15; Figure 2) This
is based on the observation that intestinal calcium absorption is maximized above 80 nmol/L, or
32 ng/mL, in postmenopausal women (16) and that parathyroid hormone (PTH) concentrations
in adults continue to decline and reach their nadir at 75100 nmol/L, or 3040 ng/mL (11, 14,
15). It has been assumed that children have the same requirement as adults; however, no
comparable studies have been carried out on intestinal calcium transport or PTH levels in
children. Vitamin D intoxication typically does not occur until 25(OH)D concentrations are >375
nmol/L, or 150 ng/mL (10, 16, 17).
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FIGURE 2.
Schematic representation of the synthesis and metabolism of vitamin D for regulating calcium,
phosphorus, and bone metabolism. During exposure to sunlight, 7-dehydrocholesterol (7-DHC)
in the skin is converted to previtamin D3 (preD3) and then by a heat-dependent process to vitamin
D3. Vitamin D (D represents D2 or D3) made in the skin or ingested in the diet is converted by the
vitamin D-25-hydroxylase (25-OHase) to 25-hydroxyvitamin D [25(OH)D]. 25(OH)D is
converted in the kidneys by the 25-hydroxyvitamin D-1-hydroxylase (1-OHase) to its
biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D increases the
expression of the 25-hydroxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2D
and 25(OH)D to the water-soluble biologically inactive calcitroic acid. 1,25(OH)2D enhances
intestinal calcium absorption in the small intestine. 1,25(OH)2D is recognized by its receptor in
osteoblasts, causing an increase in the expression of receptor activator of NFB ligand
(RANKL). CaBP, calcium binding protein; ECaC, epithelial channel calcium; FGF23, fibroblast
growth factor 23; OJ, orange juice; Pi, inorganic phosphate; PTH, parathyroid hormone; UVB,
ultraviolet B radiation.
Vitamin D deficiency in children will cause growth retardation (5, 18) and classic signs and
symptoms of rickets (4-6, 18). In adults, vitamin D deficiency will precipitate and exacerbate
both osteopenia and osteoporosis and increase the risk of fracture (10, 11, 19, 20).
Muscle weakness has long been associated with vitamin D deficiency. A vitamin D receptor is
present in skeletal muscle (21), and vitamin D deficiency has been associated with proximal
muscle weakness, increase in body sway, and an increased risk of falling (22-24).
Vitamin D deficiency in adults can also cause a skeletal mineralization defect. The unmineralized
osteoid provides little structural support for the periosteal covering. As a result, patients with
osteomalacia often complain of isolated or global bone discomfort along with aches and pains in
their joints and muscles (25-27). These patients may be misdiagnosed with fibromyalgia,
dysthymia, degenerative joint disease, arthritis, chronic fatigue syndrome, and other diseases (10,
25, 28).
CAUSES OF VITAMIN D DEFICIENCY

The major source of vitamin D for humans is exposure to sunlight (4, 8, 10). Anything that
diminishes the transmission of solar UVB radiation to the earth's surface or anything that
interferes with the penetration of UVB radiation into the skin will affect the cutaneous synthesis
of vitamin D3 (2, 9; Figure 3) Melanin is extremely efficient in absorbing UVB radiation, and,
thus, increased skin pigmentation markedly reduces vitamin D3 synthesis (29). Similarly, a
sunscreen with a sun protection of 15 absorbs 99% of the incident UVB radiation, and, thus,
when topically applied properly will decrease the synthesis of vitamin D3 in the skin by 99%
(30). African Americans with very dark skin have an SPF of 15, and, thus, their ability to make
vitamin D in their skin is reduced by as much as 99% (9, 29). This along with decreased milk
intake are the explanations for why most African Americans who live in a temperate climate are
vitamin D deficient, whereas Africans living near the equator where vitamin D3 synthesis is more
efficient because of the higher flux of UVB photons are not (31, 32).
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FIGURE 3.
A schematic representation of the major causes of vitamin D deficiency and potential health
consequences. AODM, adult onset diabetes mellitus; CHD, coronary heart disease; FEV1, forced
expiratory volume in 1 s; HAART, highly active antiretroviral therapy; HBP, high blood
pressure; MS, multiple sclerosis; RA, rheumatoid arthritis; TB, tuberculosis; URI, urinary tract
infection.
The angle at which the sun reaches the earth has a dramatic effect on the number of UVB
photons that reach the earth's surface (2, 31). This is why when the zenith angle is increased
during the wintertime and in the early morning and late afternoon, little if any vitamin D3
synthesis occurs (2, 31). The practice of purdah, whereby all skin is covered and prevented from
being exposed to sunlight places those who practice it at high risk of vitamin D deficiency and
explains why in the sunniest areas of the world vitamin D deficiency is very common in both
children and adults (33, 34). No one is immune from vitamin D deficiency. This includes both
children and adults living in the United States, Europe, Middle East, India, Australia, and Asia.
These studies suggest that upwards of 3050% of children and adults are at risk of vitamin D
deficiency (33-42).
Aging is associated with decreased concentrations of 7-dehydrocholesterol, the precursor of
vitamin D3 in the skin. A 70-y-old has 25% of the 7-dehydrocholesterol that a young adult does
and thus has a 75% reduced capacity to make vitamin D3 in the skin (43). Because vitamin D is
fat soluble, it is readily taken up by fat cells. Obesity is associated with vitamin D deficiency, and
it is believed to be due to the sequestration of vitamin D by the large body fat pool (44).
Medications including antiseizure medications and glucocorticoids and fat malabsorption are
also common causes of deficiency (45; Figure 3).
NONSKELETAL CONSEQUENCES OF VITAMIN D

DEFICIENCY
More than 80 y ago, it was reported that living at higher latitudes in the United States correlated
with an increased risk of dying of common cancers (46). In the 1980s and 1990s, several
observations suggested that living at higher latitudes increased the risk of developing and dying
of colon, prostate, breast, and several other cancers (47-52). Because living at higher latitudes
diminishes vitamin D3 production, it was suggested that an association may exist between
vitamin D deficiency and cancer mortality. Both men and women exposed to the most sunlight
throughout their lives were less likely to die of cancer (50-54). Several retrospective and
prospective studies that evaluated circulating concentrations of 25(OH)D support the concept
that vitamin D deficiency increases the risk of developing and dying from cancer (52, 53). It has
been suggested that adults with 25(OH)D of <50 nmol/L who were then followed for up to 19 y
had a 3050% increased risk of developing colorectal, breast, prostate, and many other cancers
(50, 52, 54, 55). A meta-analysis showed that increasing intake of vitamin D to 1000 IU vitamin
D3/d would be associated with a decreased risk of colorectal and breast cancer of as much as
50% (53). Men who ingested >400 IU vitamin D/d had a markedly reduced risk of developing
several cancers, including those of the pancreas and esophagus and non-Hodgkin lymphoma
(52). Lappe et al (56) reported that postmenopausal women who received 1100 IU vitamin D3
and 1000 mg Ca daily for 4 y reduced their risk of developing cancer by 60%.
Living at higher latitudes is associated with an increased risk of type 1 diabetes (57), multiple
sclerosis (58, 59), and hypertension (60). Children who received 2000 IU vitamin D/d during the
first year of life and who were followed for 31 y were found to have a reduced risk of developing
type 1 diabetes by 78% compared with children who were not supplemented with vitamin D
(61). Women who received >400 IU vitamin D/d were found to have a >40% reduced risk of
developing multiple sclerosis (62) and rheumatoid arthritis (63). Hypertensive patients who were
exposed to a tanning bed raised their blood concentrations of 25(OH)D by >180% in 3 mo and
became normotensive (64). Patients who live at higher latitudes and are at risk of vitamin D
deficiency are also more prone to developing schizophrenia (65), and vitamin D deficiency has
been associated with depression (66). Vitamin D deficiency in pregnancy has also been
associated with an increased risk of preeclampsia (67).
African Americans are at higher risk of developing and having more severe cases of tuberculosis.
It has been known for >100 y that exposure to sunlight helped in the treatment of tuberculosis
(68). Liu et al (69) reported that the likely mechanism is that when a macrophage is infected with
tuberculosis, it stimulates the cell to increase the production of 1,25-dihydroxyvitamin D3
[1,25(OH)2D3] and increase the expression of the vitamin D receptor. In combination, they
enhanced the gene expression of the bacteriocidal protein cathelicidin, which is known to kill
tuberculosis and other infective agents (Figure 4).
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FIGURE 4.
Metabolism of 25-hydroxyvitamin D [25(OH)D] to 1,25 dihydroxyvitamin D [1,25(OH)2D] for
nonskeletal functions. When a monocyte or macrophage is stimulated through its toll-like
receptor 2/1 (TLR2/1) by an infective agent such as Mycobacterium tuberculosis (TB) or its
lipopolysaccharide (LPS), the signal up-regulates the expression of vitamin D receptor (VDR)
and the 25-hydroxyvitamin D-1-hydroxylase (1-OHase). 1,25(OH)2D increases the expression of
cathelicidin (CD). When 25(OH)D concentrations are 30 ng/mL, the risk of many common
cancers is reduced. It is believed that the local production of 1,25(OH)2D regulates genes that
control proliferation and apoptosis. AB, B-lymphocytes; AT, T-lymphocytes; BP, blood pressure;
BS, blood sugar; 24-OHase, 25-hydroxyvitaminD-24-hydroxylase; PTH, parathyroid hormone.
MECHANISMS OF ACTION OF VITAMIN D

Vitamin D is metabolized in the liver to 25(OH)D and then in the kidneys to 1,25(OH)2D (70, 71;
Figure 2). It is also recognized that many other tissues in the body, including macrophages,
brain, colon, prostate, breast, and others, have the enzymatic machinery to locally produce
1,25(OH)2D (72-76; Figure 4). 1,25(OH)2D produced by the kidneys enters the circulation and
travels to its major target tissues the intestine and bone, where it interacts with its vitamin D
receptor to enhance intestinal calcium absorption and mobilize osteoclastic activity (70; Figure
3).
The local production of 1,25(OH)2D in non-calcium-regulating tissues such as the colon,
prostate, and breast is thought to be for the purpose of regulating up to 200 genes, which helps to
control cell growth and cellular differentiation and may be responsible for decreasing the risk of
the cells being transformed into a malignant state (77). 1,25(OH)2D3 has been shown to inhibit
cancer cell growth, induce cancer cell maturation, induce apoptosis, and decrease angiogenesis
(77, 78; Figure 4). 1,25(OH)2D inhibits renin production in the kidney (79) and has a
immunomodulatory activity on monocytes and activated T and B lymphocytes (80-82; Figure
4).
PREVENTION AND TREATMENT OF VITAMIN D

DEFICIENCY
The Institute of Medicine recommended that all children (also endorsed by the American
Academy of Pediatrics) and adults up to the age of 50 y require 200 IU vitamin D/d and adults
aged 5170 and 71 y need 400 and 600 IU vitamin D/d (83). The National Osteoporosis
Foundation recently recommended that all postmenopausal women take 8001000 IU vitamin
D/d (84). Cheng et al (85) reported an association of low 25(OH)D concentrations with elevated
serum PTH concentrations and low cortical bone density in early pubertal and prepubertal
Finnish girls. This confirmed the earlier observations of Outila et al (86), who noted elevated
PTH concentrations and lower forearm bone density and vitamin D deficiency in the winter in
adolescent females, and Guillemant et al (87), who observed seasonal variation in PTH
concentrations in growing male adolescents. When 171 prepubertal girls were given 400 IU
vitamin D2/d from October to February and 500 mg Ca supplementation, their serum 25(OH)D
concentrations did not change. When these girls received 800 IU vitamin D2/d, their blood
concentrations rose during the winter but did not reach concentrations observed during the
summer (88). Thus, on the basis of these and other observations, many experts now agree that in
the absence of adequate sun exposure, 8001000 IU vitamin D/d is needed for children of all
ages and adults of all ages (84, 88-91), although this is not the current recommendation of
pediatric or governmental organizations. Higher doses may be required if fat malabsorption,
obesity, or other causes exist that would enhance vitamin D catabolism and its destruction (10,
45; Figure 2).
As many as 4 different enzymes have been suggested to be capable of converting vitamin D to
25(OH)D (92). These enzymes most likely have different Km values for vitamin D and have
different levels of negative feedback regulation by the serum 25(OH)D concentration. Thus,
circulating 25(OH)D concentrations in response to vitamin D may be influenced by the baseline
25(OH)D concentration. As can be seen in Figure 5, the baseline concentration of 25(OH)D is
an important factor for how a person responds to a vitamin D dose. When serum 25(OH)D
concentrations were <50 nmol/L (20 ng/mL) in nursing home patients, doses of 200, 400, and
600 IU vitamin D2/d for 5 mo (23) raised serum 25(OH)D concentrations by 100% to 62
nmol/L (24 ng/mL). Only when the dose was increased to 800 IU/d for 5 mo did concentrations
rise above 75 nmol/L, or 30 ng/mL (Figure 5). However, subjects who had starting mean
25(OH)D concentrations above 64 nmol/L (25 ng/mL) showed no significant change in their
serum 25(OH)D concentrations when they took 200, 400, 600, or 800 IU/d. When the baseline
25(OH)D concentration was above 50 nmol/L (20 ng/mL), only 800 IU vitamin D2/d for 5 mo
was effective in raising the serum 25(OH)D level (Figure 5). This study evaluated vitamin D2,
which has been reported to be only 30% to 50% as effective as vitamin D3 in maintaining serum
25(OH)D concentrations (93, 94). Our data suggest that vitamin D2 was effective in raising blood
concentrations of 25(OH)D by 1 ng/100 IU, as has been reported for vitamin D3 (91, 95). These
data are consistent with our recent observation that 1000 IU vitamin D2/d was as effective as
1000 IU vitamin D3/d in raising and maintaining serum 25(OH)D concentrations (91). Thus,
physiologic doses of vitamin D2 may be equally effective as vitamin D3 in maintaining serum
25(OH)D concentrations.
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FIGURE 5.
Mean (SE) circulating concentrations (A) and changes (B) in 25-hydroxyvitamin D [25(OH)D]
in nursing home residents with initial 25(OH)D serum concentrations of either <20 ng/mL ( )
or 20 ng/mL ( ) before and after receiving 0, 200, 400, 600, or 800 IU vitamin D2/d for 5
mo from October through March. Data are from 616 individuals. *P < 0.05; **P < 0.01; ***P <
0.001.
To treat vitamin D deficiency in the United States, 50 000 IU vitamin D2 (or vitamin D3, which is
available in Canada, Europe, Japan, and India) once a week for 8 wk often attains a 25(OH)D
concentration of 75 nmol/L (13). To maintain vitamin D sufficiency, Holick (10) recommends
that 50 000 IU vitamin D2 every 2 wk or its equivalent will sustain 25(OH)D concentrations
above 75 nmol/L.
CONCLUSION
Throughout evolution, humans have depended on the sun for their vitamin D requirement (1, 2).
Indeed, a likely reason that melanin pigmentation devolved was to permit humans who migrated
north and south of the equator to make enough vitamin D in their skin to satisfy their
requirement (96). The recommendation for the avoidance of all sun exposure has put the world's
population at risk of vitamin D deficiency (97). This has become apparent in Australia, where a
dramatic increase in skin cancer rates resulted in the promotion of never exposing the skin to
direct sunlight without sun protection, ie, clothing or sunscreen. The so-called sun-safe message
has resulted in a marked increase in the risk of vitamin deficiency in Australia (40).
The best method for determining a person's vitamin D status is to measure a 25(OH)D
concentration. Most commercial assays are reliable enough to determine a person's vitamin D
status (10). These include various radioimmunoassays (98) and what is now considered to be the
gold standard: liquid chromatographytandem mass spectroscopy (14). There has been much
discussion about vitamin D2 being only 3050% as effective as vitamin D3 in maintaining
serum concentrations of 25(OH)D (93, 94). This, however, did not mean that vitamin D2 was less
active than vitamin D3 once it was metabolized to 1,25(OH)2D2. It only meant that vitamin D2
may need to be given in higher doses to raise the blood concentrations of 25(OH)D above 75
nmol/L, or 30 ng/mL. Our data (Figure 5), as well as our recent observation that vitamin D2
was as effective as vitamin D3 in raising the blood concentrations of 25(OH)D (91), however,
calls into question whether this is really necessary.
A reevaluation needs to take place of what the adequate intakes of vitamin D should be for
children and adults. The literature over the past decade suggests that the Institute of Medicine
recommendations in 1997 (83) are inadequate, and some experts including us suggest that both
children and adults should take 8001000 IU vitamin D/d from dietary and supplemental
sources (4, 9, 77) when sunlight is unable to provide it. This recommendation, however, has not
yet been embraced either by official government or pediatric organizations in the United States,
Canada, or Europe for either children or adults.
Acknowledgments
Neither of the authors had a conflict of interest.
Footnotes
2 Presented at the symposium Assessment of Vitamin D in Population-Based Studies,

held at Experimental Biology 2007 in Washington, DC, 1 May 2007.
3 Supported in part by NIH grant M01RR00533 and by the UV Foundation.
4 Reprints not available. Address corrrespondence to MF Holick, Boston University

School of Medicine, 715 Albany Street, M-1013, Boston, MA 02118. E-mail:
mfholick@bu.edu.
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1. Top
2. Abstract
3. HISTORICAL PERSPECTIVE
4. SOURCES OF VITAMIN D
5. CONSEQUENCES OF VITAMIN D DEFICIENCY ON THE MUSCULOSKELETAL
SYSTEM
6. CAUSES OF VITAMIN D DEFICIENCY
7. NONSKELETAL CONSEQUENCES OF VITAMIN D DEFICIENCY
8. MECHANISMS OF ACTION OF VITAMIN D
9. PREVENTION AND TREATMENT OF VITAMIN D DEFICIENCY
10. CONCLUSION
11. Acknowledgments
12. Footnotes
13. REFERENCES
This Article
1. Am J Clin Nutr April 2008
vol. 87 no. 4 1080S-1086S
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3. Full Text (PDF)Free
Navigate This Article

1. Top
2. Abstract
3. HISTORICAL PERSPECTIVE
4. SOURCES OF VITAMIN D
5. CONSEQUENCES OF VITAMIN D DEFICIENCY ON THE MUSCULOSKELETAL
SYSTEM
6. CAUSES OF VITAMIN D DEFICIENCY

7. NONSKELETAL CONSEQUENCES OF VITAMIN D DEFICIENCY
8. MECHANISMS OF ACTION OF VITAMIN D
9. PREVENTION AND TREATMENT OF VITAMIN D DEFICIENCY
10. CONCLUSION
11. Acknowledgments
12. Footnotes
13. REFERENCES
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2008 American Society for Clinical Nutrition

Vitamin D deficiency: a worldwide problem

From the Department of Medicine; Section of Endocrinology, Nutrition, and Diabetes;

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CONSEQUENCES OF VITAMIN D DEFICIENCY ON

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CAUSES OF VITAMIN D DEFICIENCY

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NONSKELETAL CONSEQUENCES OF VITAMIN D

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MECHANISMS OF ACTION OF VITAMIN D

PREVENTION AND TREATMENT OF VITAMIN D

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2 Presented at the symposium Assessment of Vitamin D in Population-Based Studies,

3 Supported in part by NIH grant M01RR00533 and by the UV Foundation.

4 Reprints not available. Address corrrespondence to MF Holick, Boston University

Simpson RU, Thomas GA, Arnold AJ. Identification of 1,25-dihydroxyvitamin D3

Fuleihan GEH, Nabulsi M, Choucair M, et al. Hypovitaminosis D in healthy

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Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated

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