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Vitamin D
FN 4320
Dr. Anderson
By: Tiffany Smith & Susan Greener
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Vitamin D
Vitamin D, which is a nutrient that is of concern for many people worldwide, refers to a
series of vitamin D molecules that are fat soluble and stored in the body. Unlike many other
vitamins, vitamin D is not strictly obtained from dietary sources and there are few sources of
food that contain naturally occurring vitamin D. The body relies on a significant source of
vitamin D to be naturally synthesized in the body, but it can also be obtained through
supplementation and certain foods (1). The two main forms that human health relies on are
vitamin D2 and more commonly, vitamin D3 (1).
Chemical Name and Structure
Vitamin D2, ergocalciferol, is commonly recognized as the plant form of vitamin D
because plants convert ergosterol, a naturally produced steroid hormone found in plants, to
vitamin D2 when exposed to UV irradiation (1). The IUPAC name for Vitamin D2 is (1S,3Z)-3-
[(2E)-2-[(1R ,3aS,7aR)-1-[(E,2R,5R)-5,6 -dimethylhept-3-en-2-yl]-7a-methyl -2,3,3a,5,6,7-
hexahydro-1H- inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol (2). The molecular
formula is C28H44O (2). The structure of vitamin D includes 2 hexagons, 4 double bonds,
methyl side chains, and a pentagon (2).

Vitamin D3, cholecalciferol, is naturally synthesized by the skin of humans, and some
animals, when 7-dehydrocholesterol, a cholesterol naturally found in the body of humans and
some animals, is converted to vitamin D through a series of hydroxylation reactions (1). The
IUPAC name for Vitamin D3 is (1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-7a-methyl-1-[(2R)- 6-
methylheptan-2-yl]-2,3,3a,5,6 ,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidene
cyclohexan-1-ol (2). The molecular formula of vitamin D 3 is C27H440 (2). The structure varies
from vitamin D2 because it has one less double bond and one less methyl group attached (2).
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Chief functions
Bone Health

Vitamin D is essential in maintaining good bone health because it helps maintain a


balanced uptake of calcium (1). Vitamin D assists in the absorption of calcium through the small
intestine which brings calcium to the bones, meaning it is very important to be consuming
adequate levels of both vitamin D and calcium together so that bones can be strengthened
properly (3). In a research study involving 36,282 women with a mean age of 62 years, it was
found that the group who received calcium and vitamin D supplementation had increased bone
density loss at the hip, which is notable because the hip is one of the most common fractures in
elderly women and an increase of bone density at the hip decreases the likelihood of a hip bone
fracture (3). Vitamin D also helps maintain bone health by stimulating the absorption of
phosphate and magnesium ions to promote further bone mineralization (4).
Immune Function
Lower vitamin D concentration (15-35 ng/mL) has been associated with an increased
frequency of upper respiratory tract infections (4). This has been related to the fact that the
growth of vascular smooth muscle cells is regulated by vitamin D and is needed to support a
healthy immune system (4). Adequate Vitamin D does not improve immune function by itself,
but deficiencies have been linked to increases of infection, leading health professionals to believe
that adequate vitamin D intake is directly linked to good immune health (4). There is also new
research that has been showing a relationship between low vitamin D levels and the prevalence
of some cancers due to the newly acknowledged role of vitamin D in the immune system (4).
Gene Transcription
Vitamin D is involved in transcriptional regulation of over one thousand genes. This
accounts to about 5% of human genes that are dependent upon adequate vitamin D absorption
(4). 1,25(OH)2D has nuclear vitamin D receptors that it interacts with Vitamin D receptors on
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the gene sequence, which can regulate the expression of specific genes. By targeting gene
expression and protein transcription within the skeletal muscles, vitamin D can ultimately
regulate muscle cell growth (4). Vitamin D regulates cytokine production, which can enhance the
production of anti-inflammatory cytokines and also inhibit to an extent the expression of
proinflammatory cytokines (4).

Metabolic Pathways
Absorption, Transportation, Storage, and Excretion
Vitamin D is naturally synthesized in skin and plants when exposed to ultraviolet B rays
from the sun or irradiation (1).The photons from the ultraviolet B rays pass through skin and
bind to 7-dehydrocholesterol to form pro- vitamin D3(1). Irradiation that passes through certain
plants that contain ergosterol generates the formation of pro-vitamin D2. The pro-vitamin D that
is generated from these reactions pass from the skin or intestines and into the blood to be further
absorbed and circulated (1). When absorbed, Vitamin D2 and D3 are both considered
biologically inactive and therefore do not get digested, but get activated instead. To become
active, the inactive forms both undergo a series of hydroxylation reactions with different
enzymes.
Vitamin D is directly absorbed into a micelle after synthesis (4). Once the vitamin D is
absorbed into the micelle, it uses passive diffusion to transport vitamin D to the small intestines,
where 50% of vitamin D is absorbed (1). After consumption or synthesis of vitamin D that ends
up in the small intestines, it is converted in the liver to form of vitamin D, calcitriol,or 25(OH) D,
by the enzyme 25-hydroxylase, and is then absorbed into intestinal mucosal cells from micelles
(1). 25(OH) D is reflective of how much vitamin D is currently stored in the body and it also has
a longer half-life, meaning it will be able to be stored for later use when the body is not receiving
enough vitamin D (4). From there, the vitamin D in incorporated into chylomicrons and begins
circulation in the lymphatic system. In the intestinal cells, the majority of vitamin D is stored in
the chylomicrons (1). Once the vitamin D gets absorbed in the lymphatic system, some of it
enters the blood (1).
The vitamin D that is left circulating in the lymphatic system travels from the
chylomicrons to vitamin D binding proteins, fat tissues, and muscle tissues (1). Any remaining
chylomicrons that are carrying vitamin D get sent to the mitochondria in the kidney (1). When
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vitamin D gets transported from the liver to the kidneys, it undergoes a reaction with the enzyme
1-alpha-hydroxylase that produces 1,25 (OH) D2, which is the hormonal and active form of
vitamin D (4). This is the active form of vitamin D that gets sent out to the body to promote

intestinal absorption of calcium and phosphate, increase bone mineralization, and can also
promote bone resorption if needed to maintain calcium levels in the body (1). The 25(OH)D that
does not end up getting stored or converted binds to vitamin D binding proteins, then gets carried
to the blood to supply various tissues with vitamin D (1). If excess vitamin D is synthesized or
consumed, it is mainly excreted through the bile in feces and less than 30 % through urine (4).

Dietary Reference Intake (DRI)


Adequate Intake, Estimated Average Requirement, and Upper Limit of Vitamin D
While vitamin D is naturally synthesized in the skin via UVB rays, dietary intake of
vitamin D is usually necessary to reach sufficient levels of vitamin D to prevent deficiencies. The
DRI for vitamin D remains the same for males and females (4). Adults over 70 require more
vitamin D because of the decrease in organ function associated with aging. There is also a
decrease in the amount of vitamin D3 synthesis that occurs due to the decrease in 7-
dehydrocholesterol in the skin (4).
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Age (male & female) Vitamin D Daily Recommended Vitamin D Estimated


Intake (IU) Average Requirement (IU)
0-1 year 400 IU/day 400 IU/day
1-70 years 600 IU/day 400 IU/day
Lactating women 600 IU/day 400 IU/day
>70 years 800 IU/day 400 IU/day

Age (male & female) Vitamin D Upper Limit (IU)


0-1 year 1,000-1,500 IU/day
1-8 years 2,5000-3,000 IU/day
9+ years 4,000 IU/day
Lactating Women 4,000 IU/day

Adequate Vitamin D Serum Levels


Vitamin D levels are tested by taking a blood sample and testing the amount of 25-
hydroxyvitamin D, which is the circulating storage form of vitamin D. This has been determined
to be the most accurate measure of vitamin D levels based on its long half-life and because it
reflects the total production of vitamin D from both exogenous and endogenous sources (5). The
ideal vitamin D content in the blood is greater than 32 ng/mL (4), but should ideally be above 40
ng/mL (5). Deficiencies may require larger doses to build up 25(OH)D stores in the body.
25(OH)D Reference Values
Ng/mL
Deficient <20
Insufficient <30-32
Sufficient >/= 30-32
Ideal 40-100
Toxicity >150

Significant sources
There are limited sources of vitamin D in the diet, but typically people do not reach their
recommended intake of vitamin D by food alone. The amount of vitamin D synthesized through
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the skin by sunlight varies depending on a wide range of factors such as skin pigment, location,
time of day, and genetics, but can ultimately make up 95% of the bodys vitamin D status (6).
The main source of vitamin D in the human body is the sun; however with increases in skin
cancer rates, it is avoided by many through the use of sunscreen, layers of clothing, hats, etc.
Vitamin D synthesis is inhibited by any sun protective factor >8 by about 95%, which therefore
suggests adequate sun exposure without any protective agents on exposed skin (4). Vitamin D
also cannot be synthesized unless skin is directly exposed to sunlight, so synthesis cannot occur
if skin is completely covered by clothing. Safe sun exposure is recognized as exposing the arms,
legs, and torso for 5-30 minutes during the hours of 10 a.m. to 3 p.m. without sunscreen twice a
week (4). The amount of time that skin should be exposed varies based on the different season,
latitudes, and skin pigmentation or melanin content (5). As a general rule, research has shown
that it is possible to synthesize about 10,000 IU of vitamin D from 10 minutes during peak sun
hours; however weather, skin types, safety, and other factors may prevent people from receiving
enough vitamin D via UVB ray synthesis alone and may have to rely on dietary sources of
vitamin D to reach their recommended vitamin D levels (4).
There are few naturally occurring dietary sources of vitamin D which are limited to plants
and animals that also synthesize vitamin D via UVB rays (5). Many types of fish are great
sources of vitamin D3 because of their ability to synthesize and store vitamin D. Since vitamin D
is fat soluble, Cod liver oil is a very high source of vitamin because of its fat content. Some types
of fresh mushrooms provide a good source of vitamin D2 (5). Other examples of good vitamin D
sources are included in the table below (4):
Food Serving size Amount of Vitamin D (IU)
Cod Liver Oil 1 Tbsp. 1300 IU
Wild Salmon 3.5 oz. 980 IU
Mushrooms 1 oz. 400-500 IU
Liver 3.5 oz. 12-30 IU
Milk, fortified 1 cup 100 IU
Orange Juice, fortified 1 cup 100 IU
Cereal, fortified 1 cup 40 IU
Cheese 1 oz. 85 IU
Egg Yolk 1 yolk 20 IU
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Deficiency
There is a high prevalence of vitamin D deficiency worldwide and it can have different
effects depending on different life stages and many other factors. People at risk for vitamin D
deficiency include breastfed infants, older adults, people who do not get adequate sun exposure,
darker skin tones, and certain religious groups that dress so that no skin is exposed (5). Gender
does not influence vitamin D requirements and there is also little variance with age, however
there is individual variance. In one study, it was observed than many individuals who were
exposed to adequate sunlight were deficient in vitamin D because of different absorption and
synthesis rates (5). A difference in melanin content in the skin can also influence the rate of
vitamin D synthesis that occurs when exposed to sunlight (4).
Children
Vitamin D deficiency can cause rickets in the developing bones of children, a disease that
is characterized by bow legs and a bending of the bones (1). A severe vitamin D deficiency
inhibits the uptake of calcium and phosphorus in the bones, which causes a lack of bone
mineralization (1). When bones are not mineralized and hardened, they can begin bowing under
pressure, which is why bowed legs are the most visible sign of bones bending and softening (1).
Rickets can also occur in ribs, wrists, feet, hands, and spine. Upon the discovery of vitamin D,
the prevalence of rickets has greatly decreased in the U.S.
Adults
Due to limited dietary sources, nutrient poor diets, and inadequate sunlight exposure,
nearly 30% of are deficient in vitamin D. Vitamin D deficiencies have been linked to an
increased risk of cardiovascular disease (6). Obesity has been linked to a vitamin D deficiency in
some cases because of its role in regulating parathyroid hormone throughout the body (7). A
higher intake of dietary calcium was linked to lower parathyroid hormone levels, which is
ultimately related to a lower body weight. Alternatively, high parathyroid hormone levels are
associated with weight gain and obesity (7). Research has also shown how low vitamin D status
is also linked to a higher risk of multiple sclerosis, rheumatoid arthritis, osteoarthritis,
hypertension, cardiovascular disease, and cancers (4).
Elderly
The elderly population is susceptible to developing osteoporosis when consuming or
receiving inadequate vitamin D levels over time. Osteoporosis refers to a decrease in bone
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density but a normal ratio of minerals to bone matrix (4). Osteoporosis is a very common bone
disease in older adults that is caused because their bones have stopped growing and have begun
to go through the bone resorption process where bone is broken down to regulate blood serum
calcium levels (1). Post-menopausal women are most susceptible to this since they lose more
bone mass than men and because of the change in hormones (4).
Osteomalacia is another vitamin D related disease that refers to a decrease in bone
density as well as a decrease in the ratio of mineral to bone matrix (4). Osteomalacia causes
bones to demineralize over time and become porous, brittle, and weak. Both of these bone
diseases are caused by a vitamin D deficiency and also cause porous bones that are weaker and
more prone to fractures (3). Patients undergoing kidney transplants, which are typically the
elderly generation, are also very susceptible to vitamin D deficiencies because of inadequate
sunlight and poor dietary choices (8).
Correcting Deficiencies
New research is showing the correlation between vitamin D toxicity and correcting a
vitamin D deficiency (9). People and doctors do not realize that people absorb vitamin D at
different rates when prescribing large doses of vitamin D, so it can ultimately cause toxicity if
large doses are continually administered. People respond differently to vitamin D and can be a
high or low responder to vitamin D3, meaning high responders require less vitamin D to reach
the same levels that a low responder would reach from a larger dose of vitamin D (10). These
things are important for health professionals to consider when discussing vitamin D deficiencies.
Supplements
There is a lot of recent concern about what type of vitamin D is the most effective. People
that do not receive enough sun exposure need around 1,500-2,000 IU/day to keep vitamin D
levels within a sufficient range without creating a deficit. Supplements are usually in D3 form
and may be necessary for those who live at a latitude of greater than 35 degrees north, since they
cannot make vitamin D in the winter months due to a lack of UVB rays that convert cholesterol
to the active form of vitamin D(5). Supplements may also be needed for people with pale skin
because spending adequate time in the sun results in sunburn, which is harmful to the skin and
increases skin cancer rates (5). People with darker skin may also need supplements because their
increased levels of melanin in the skin may inhibit vitamin D synthesis from the sun (4).
Toxicity
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Too much vitamin D can become a burden to the kidneys once the upper limit has been
passed. This is because Vitamin D moderates the amount of calcium that is being absorbed into
the body, and if too much calcium is passed through the urine, it puts a strain on the kidneys (1).
The kidneys could be damaged if there is too large of a calcium load in the urine, which is
referred to as hypercalcemia (5). Hypercalcemia is directly caused by vitamin D toxicity because
it disrupts the balance in the bloodstream and allows too much calcium to circulate.
Hypercalcemia symptoms include fatigue, back pain, nausea, vomiting, constipation, frequent
urination, poor appetite, and forgetfulness (5)
Vitamin D toxicity does not usually happen from synthesizing too much vitamin D
naturally or consuming foods with vitamin D, but is usually caused by consumption of mega
doses of vitamin D supplements that can reach up to 50,000 IU per dose (5). Vitamin D toxicity
is usually caused by mega dose prescriptions or over the counter. Although the RDA of vitamin
D is from 400-800 IU per day, larger doses have been suggested by health professionals to help
those with low vitamin D levels to increase their vitamin D stores. However, if someone if not
actually deficient in vitamin D and continues to take mega doses of 50,000 IU a day for several
weeks or months, then toxic side effects can occur, like hypercalcemia (11).
Conclusion
In conclusion, Vitamin D is an essential vitamin that plays a significant role in
maintaining bone health, regulating genes, promoting immune system function, and maintaining
an overall healthy lifestyle. Although many people are deficient in vitamin D stores, blood serum
levels should be tested before large doses are administered to correct a vitamin D deficiency. It is
also important to consider how regular vitamin D intake is being met, especially since vitamin D
is found in few dietary sources and is mainly synthesized in the skin via sunlight (11).

References
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United States of America : Yolanda Cossio; 2013.
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from: https://pubchem.ncbi.nlm.nih.gov/compound/Vitamin_D3
3. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T,
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Beresford SA, Black HR, Blanchette P, Bonds DE. Calcium plus vitamin D
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4. MF Holick. Vitamin d, friend or foe?. Am J Clin Nutr. 2016 Oct; 1
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disorders. 2013 Apr 29;13(1):14.
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Virtanen JK, Tuomainen TP, Carlberg C. Dissecting high from low responders in a
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