The majority of 25-OH vitamin D (25-D) in the
circulation is derived from the conversion of 7-dehydrocholesterol in
the skin that is irradiated with ultraviolet radiation in the UVB range
(wavelength 290 nm to 315 nm).1-5 The extent of vitamin D
formation is not tightly controlled and depends primarily on the
duration and intensity of the UV irradiation. Levels produced typically
reach a plateau within 30 minutes of exposure. Unfortunately, use of a
sunscreen with SPF as low as 15 reduces the rate of vitamin D production
by 99.9%. Overproduction of vitamin D in the skin is prevented by the
photosensitive conversion of vitamin D to tachysterol or lumisterol.
Vitamin D is not very water-soluble, so it must be delivered to and
carried in the blood as a complex with vitamin D-binding protein. Once
in the circulation, vitamin D is metabolized to 25-hydroxy vitamin D
(25-D) by the liver. The 25-D form of the hormone is the principle
circulating reservoir in plasma and is generally the best indicator of
overall vitamin D status. 25-D is further metabolized by the kidney to
produce the biologically active form of vitamin D, 1,25-dihydroxy
vitamin D (1,25-D). Renal production of 1,25-D is tightly controlled by
parathyroid hormone and is important in the regulation of serum calcium
homeostasis.
The hormonally active form of vitamin D,1,25-D plays
an integral role in calcium homeostasis and the maintenance of healthy
bone.1-4 1,25-D stimulates the absorption of calcium at the
level of the intestine and may also serve to increase calcium and
phosphate resorption at the kidney level. Vitamin D deficiency leads to
the mobilization of calcium from bone. Individuals with more severe
vitamin D deficiency can develop osteomalacia and/or osteoporosis.
Osteomalacia in children, also referred to as rickets, results in
well-described skeletal malformations, since children's bones are
actively growing. Recent clinical and epidemiological studies suggest
that vitamin D deficiency may play a role in several conditions
unrelated to bone, including prostate cancer, breast cancer, colon
cancer, heart disease, hypertension, multiple sclerosis, and type 1
diabetes.
A number of studies have shown that vitamin D deficiency is very common, especially in certain high-risk populations.1,2
This situation has occurred, in part, because the foods in the typical
American diet are very low in vitamin D. Fatty fish, such as mackerel
and salmon, and fish liver oils are some of the few natural dietary
sources of vitamin D. Most people do not eat enough of these foods to
maintain adequate vitamin D levels. In the United States, vitamin D is
added to milk in order to prevent the occurrence of rickets in the
pediatric population. Unfortunately, too many children do not drink
enough milk to raise their vitamin D levels to the optimum range. Also,
recent studies have shown that the level of vitamin D in fortified milk
is frequently much lower than that recommended by the FDA. Human milk
contains very little vitamin D because many mothers are deficient, so
children of mothers who choose to breast-feed are at risk of developing
rickets if they are not given supplemental vitamin D. The American
Academy of Pediatrics recommends that infants who are exclusively
breast-feeding should be given a supplement of vitamin D.
Several factors are associated with an increased risk of developing vitamin D deficiency. At risk populations include:1-5
•
Individuals with low dietary vitamin D levels. Infants fed only
mother's milk and children who do not drink fortified milk are at risk.
•
Individuals with malabsorption syndromes. Patients with pancreatic
enzyme deficiency, Crohn's disease, cystic fibrosis, celiac disease, and
surgical resection of stomach or intestines are at risk.
•
Individuals with severe liver disease. Hepatic disease can reduce the
conversion of vitamin D to 25-D and can lead to malabsorption of vitamin
D.
• Individuals with kidney disease. Nephrotic syndrome can increase the urinary loss of vitamin D.
•
Individuals taking certain drugs. Several medications, including
phenytoin, phenobarbital, and rifampin accelerate the breakdown of
vitamin D by the liver.
• Individuals who live at higher
latitudes. Individuals who live in northern climates are at increased
risk of deficiency, especially in winter months due to diminished
exposure to UVB radiation.
• Individuals who spend little time
outside. Individuals who are homebound or simply choose to remain inside
are at increased risk.
• Older adults. The skin becomes less
efficient at producing vitamin D as one ages because of diminished
levels of vitamin D precursors in the skin.
• Individuals with
decreased sun exposure for cultural reasons. Women in some societies are
required to cover themselves with heavy clothing, reducing exposure to
the sun's rays.
• Races with high melanin levels. Increased skin
pigmentation can reduce the efficiency of vitamin D conversion in the
skin as much as 50-fold. Individuals with dark complexions living at
higher latitudes are at increased risk.
Serum concentrations of
25-D are known to vary with age, sex, race, season, and geographic
location. This has led to the establishment of seasonal expected ranges
for geographic locations and local populations. This approach provides a
“reference interval” but does not adequately determine health status
with regard to vitamin D levels if a significant portion of the
reference population is, in fact, deficient. A more useful parameter in
clinical practice would be a nutritional threshold below which an
individual could be characterized as vitamin D-deficient. Vitamin D
deficiency has been defined by the Institute of Medicine and an
Endocrine Society practice guideline as a level of serum 25-hydroxy
vitamin D <20 ng/mL.1,3 The Endocrine Society went on to define vitamin D insufficiency as levels between 21 and 29 ng/mL.3
Vitamin
D plays an integral role in calcium homeostasis and the maintenance of
healthy bone. Vitamin D stimulates the absorption of calcium at the
level of the intestine and may also serve to increase calcium and
phosphate resorption at the kidney level. Deficiency of vitamin D leads
to the mobilization of calcium from bone, which can lead to
osteoporosis, osteomalacia, and rickets.1-3 Numerous recent studies have shown a strong association between diminished vitamin D levels and risk for falls6 and for both vertebral and nonvertebral fractures.7
The
World Health Organization's International Agency for Research on Cancer
(IARC) has concluded that there is a strong link between an
individual's vitamin D levels and the risk of developing colorectal
cancer.5 Studies have also revealed that low vitamin D levels
are associated with an increased incidence of other malignancies,
including breast cancer.8
Many tissues and cells in the body have vitamin D receptors.1-3
It has been estimated that the expression of as much as one third of
the human genome is influenced by 1,25-(OH)2 vitamin D. Many studies
have demonstrated an association of vitamin D deficiency with increased
risk for:
• Autoimmune diseases, including both type 1 and type 2
diabetes, rheumatoid arthritis, Crohn's disease, and multiple
sclerosis.
• Infectious diseases and asthma
• Cardiovascular disease and hypertension
There are, however, few randomized, controlled trials with a dosing
range adequate to provide strong evidence of the benefit of vitamin D in
reducing the risk of these chronic diseases.3
