Cholecalciferol is a steroid hormone produced in the skin when exposed to ultraviolet light or obtained from dietary sources. The active form of cholecalciferol, 1,25-dihydroxycholecalciferol (calcitriol) plays an important role in maintaining blood calcium and phosphorus levels and mineralization of bone. The activated form of cholecalciferol binds to vitamin D receptors and modulates gene expression. This leads to an increase in serum calcium concentrations by increasing intestinal absorption of phosphorus and calcium, promoting distal renal tubular reabsorption of calcium and increasing osteoclastic resorption.
Cholecalciferol also is known as vitamin D3 and cholecalciferol is a type of vitamin D which is made by the skin, found in some foods, and taken as a dietary supplement. It is used to treat and prevent vitamin D deficiency and associated diseases, including rickets. It is also used for familial hypophosphatemia, hypoparathyroidism that is causing low blood calcium, and Fanconi syndrome. The derivative of 7-dehydroxycholesterol formed by ultraviolet rays breaking of the C9-C10 bond. It differs from ergocalciferol in having a single bond between C22 and C23 and lacking a methyl group at C24.
Types of Cholecalciferol / Vitamin D3
Vitamin D deficiency is typically diagnosed by measuring the concentration of the 25-hydroxyvitamin D in the blood, which is the most accurate measure of vitamin D status.
| Name | Chemical composition | Structure |
|---|---|---|
| Vitamin D1 | Mixture of molecular compounds of ergocalciferol with lumisterol, 1:1 | |
| Vitamin D2 | ergocalciferol (made from ergosterol) |  |
| Vitamin D3 | cholecalciferol (made from 7-dehydrocholesterol in the skin). |  |
| Vitamin D4 | 22-dihydroergocalciferol |  |
| Vitamin D5 | sitocalciferol (made from 7-dehydrositosterol) |
- Deficiency: <20 ng/mL
- Insufficient: 20–29 ng/mL
- Normal: 30–100 ng/mL
Vitamin D levels falling within this normal range prevent clinical manifestations of vitamin D insufficiency as well as vitamin D toxicity from taking in too much vitamin D.
Mechanism of Action of Cholecalciferol / Vitamin D3
The first step involved in the activation of vitamin D3 is a 25-hydroxylation which is catalyzed by the 25-hydroxylase in the liver and then by other enzymes. The mitochondrial sterol 27-hydroxylase catalyzes the first reaction in the oxidation of the side chain of sterol intermediates. The active form of vitamin D3 (calcitriol) binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription. Calcitriol increases the serum calcium concentrations by increasing GI absorption of phosphorus and calcium, increasing osteoclastic resorption, and increasing distal renal tubular reabsorption of calcium. Calcitriol appears to promote intestinal absorption of calcium through binding to the vitamin D receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through the formation of a calcium-binding protein.
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Most individuals naturally generate adequate amounts of vitamin D through the ordinary dietary intake of vitamin D (in some foods like eggs, fish, and cheese) and natural photochemical conversion of the vitamin D3 precursor 7-dehydrocholesterol in the skin via exposure to sunlight. Conversely, vitamin D deficiency can often occur from a combination of insufficient exposure to sunlight, inadequate dietary intake of vitamin D, genetic defects with endogenous vitamin D receptor, or even severe liver or kidney disease. Such deficiency is known for resulting in conditions like rickets or osteomalacia, all of which reflect inadequate mineralization of bone, enhanced compensatory skeletal demineralization, resultant decreased calcium ion blood concentrations, and increases in the production and secretion of parathyroid hormone. Increases in parathyroid hormone stimulate the mobilization of skeletal calcium and the renal excretion of phosphorus. This enhanced mobilization of skeletal calcium leads towards porotic bone conditions. Ordinarily, while vitamin D3 is made naturally via photochemical processes in the skin, both itself and vitamin D2 can be found in various food and pharmaceutical sources as dietary supplements. The principal biological function of vitamin D is the maintenance of normal levels of serum calcium and phosphorus in the bloodstream by enhancing the efficacy of the small intestine to absorb these minerals from the diet [A223]. At the liver, vitamin D3 or D2 is hydroxylated to 25-hydroxyvitamin D and then finally to the primary active metabolite 1,25-dihydroxy vitamin D in the kidney via further hydroxylation. This final metabolite binds to endogenous vitamin d receptors, which results in a variety of regulatory roles – including maintaining calcium balance, the regulation of parathyroid hormone, the promotion of the renal reabsorption of calcium, increased intestinal absorption of calcium and phosphorus, and increased calcium and phosphorus mobilization of calcium and phosphorus from bone to plasma to maintain balanced levels of each in bone and the plasma
Indications of Cholecalciferol / Vitamin D3
Vitamin D deficiency can be asymptomatic, but may also cause several problems including:
- Osteomalacia – a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility.
- Osteoporosis – a condition characterized by reduced bone mineral density and increased bone fragility.
- Increased risk of fracture
- Rickets – a childhood disease characterized by impeded growth and deformity of the long bones. The earliest sign of subclinical vitamin D deficiency is craniotabes, abnormal softening or thinning of the skull.
- Muscle aches and weakness
- Muscle twitching (fasciculations) – is commonly seen due to reduced ionized calcium, arising from a low vitamin D.
- Periodontitis – the local inflammatory bone loss that can result in tooth loss.
- Pre-eclampsia – There has been an association of vitamin D deficiency and women who develop pre-eclampsia in pregnancy. The exact relationship of these conditions is not well understood. Maternal vitamin D deficiency may affect the baby, causing overt bone disease from before birth and impairment of bone quality after birth.
- Depression – Hypovitaminosis D is a risk factor for depression. Some studies have found that low levels of vitamin D are correlated with depressed feelings and are found in patients who have been diagnosed with depression.
- Light-headedness
- Vitamin D Deficiency
- Prevention of Falls
- Prevention of Fractures
Inadequate sun exposure of Cholecalciferol / Vitamin D3
The use of sunscreen with a sun protection factor of 8 can theoretically inhibit more than 95% of vitamin D production in the skin. In practice, however, sunscreen is applied so as to have a negligible effect on vitamin D status. The vitamin D status of those in Australia and New Zealand is unlikely to have been affected by campaigns advocating sunscreen. Instead, wearing clothing is more effective at reducing the amount of skin exposed to UVB and reducing natural vitamin D synthesis. Clothing which covers a large portion of the skin, when worn on a consistent and regular basis, such as the burqa, is correlated with lower vitamin D levels and an increased prevalence of hypovitaminosis D.
Regions far from the equator have a high seasonal variation of the amount and intensity of sunlight. In the UK the prevalence of low vitamin D status in children and adolescents is found to be higher in winter than in summer. Lifestyle factors such as indoor versus outdoor work and time spent in outdoor recreation play an important role.
Additionally, vitamin D deficiency has been associated with urbanization in terms of both air pollution, which blocks UV light, and an increase in the number of people working indoors. The elderly are generally exposed to less UV light due to hospitalization, immobility, institutionalization, and being housebound, leading to decreased levels of vitamin D.
Dosage of Cholecalciferol / Vitamin D3
Strengths: 400 intl units/mL; 1000 intl units; 2000 intl units; 400 intl units; 5000 intl units; 50,000 intl units; 14,000 intl units; 10,000 intl units/mL; 4000 intl units; 5000 intl units/mL; 400 intl units/0.028 mL; 2000 intl units/mL; 1000 intl units/drop; 10000 intl units; 25,000 intl units; 1000 intl units/10 mL.
The Endocrine Society, National, and International Osteoporosis Foundation, and American Geriatric Society define vitamin D deficiency as the level of 25-hydroxyvitamin (25 OH D) of less than 30 ng/mL. The Endocrine Society recommends a preferred range of 40-60 ng/mL. To maintain this level, the Endocrine Society recommends an intake of 400 to 1000 International Units (IU) daily for infants less than one year, 600 to 1000 IU for children and adolescents from 1 to 18 years and 1500 to 2000 IU for all adults.
Vitamin D Insufficiency
- 600 to 2,000 international units, orally, once a day
- Maximum dose: 4,000 international units per day
Vitamin D Deficiency
Initial dose
- 50,000 international units, once a week, for 8 weeks
- 6,000 international units, once a day, for 8 weeks
- Maintenance dose: 1,500 to 2,000 international units, once a day
- Maximum dose: 10,000 international units per day
Usual Adult Dose for Prevention of Falls
- 800 international units, orally, once a day
- 1,500 to 2,000 international units, once a day, may be needed to achieve blood levels of 25(OH)D above 30 ng/mL.
Prevention of Fractures
- Over 70 years: 800 to 2,000 international units, orally, once a day
Vitamin D Insufficiency
- 0 to 12 months: 400 international units once a day
- 1 to 18 years: 600 international units once a day
Maximum dose
- Up to 6 months: 1,000 international units per day
- 7 months to 1 year: 1,500 international units per day
- 1 to 3 years: 2,500 international units per day
- 4 to 8 years: 3,000 international units per day
- 9 years and older: 4,000 international units per day
Pediatric Vitamin D Deficiency
- Up to 1-year-old: 2,000 international units, orally, once a day, for 6 weeks
- 50,000 international units, once a week, for 6 weeks
- Maintenance dose: 400 to 1,000 international units per day
- 1 to 18 years: 2,000 international units, orally, once a day for at least 6 weeks
- 50,000 international units, once a week, for at least 6 weeks
- Maintenance dose: 600 to 1,000 international units per day.
Maximum dose
- Up to 1 year: 2,000 international units per day
- 1 to 18 years: 4,000 international units per day
Side Effects of Cholecalciferol / Vitamin D3
- A cough
- difficulty swallowing
- dizziness
- fast heartbeat
- hives or itching
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- skin rash
- tightness in the chest
- unusual tiredness or weakness
Too much vitamin D can cause harmful high calcium levels. Tell your doctor right away if any of these signs of high vitamin D/calcium levels occur: nausea/vomiting, constipation, loss of appetite, increased thirst, increased urination, mental/mood changes, unusual tiredness.
A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
Source of Cholecalciferol / Vitamin D3
In some countries, staple foods are artificially fortified with vitamin D.Natural sources include the following:
Plant or fungal sources
Lichen
- Cladina arbuscular specimens grown under different natural conditions: The contents of vitamin D3 range from 0.67 to 2.04 μg/g (27 to 82 IU/g) dry matter in the thalli of C. arbuscula specimens grown under different natural conditions.[13]
Animal sources
- Fish liver oils, such as cod liver oil, 4.5 g (1 teaspoon) provides 450 IU (100 IU/g)
- Fatty fish species –
- Salmon, pink, cooked, dry heat, 100 grams (3.5 oz): 522 IU (5.2 IU/g)
- Mackerel, Pacific and jack, mixed species, cooked, dry heat, 100 grams (3.5 oz): 457 IU (4.6 IU/g)
- Tuna, canned in oil, 100 grams (3.5 oz): 269 IU (2.7 IU/g)
- Sardines, canned in oil, drained, 100 grams (3.5 oz): 193 IU (1.9 IU/g)
- Cooked egg yolk: 44 IU for a 61 g egg (0.7 IU/g)
- Beef liver, cooked, braised, 100 grams (3.5 oz): 49 IU (0.5 IU/g)
Diet of Cholecalciferol / Vitamin D3
Recommended levels
Different institutions propose different recommendations concerning daily amounts of the vitamin. The recommended daily intake of vitamin D may not be sufficient if sunlight exposure is limited. Conversion : 1 µg = 40 IU.
Australia and New Zealand
About a third of Australians have vitamin D deficiency. Australia and New Zealand have established guidelines for dietary vitamin D intake as follows:
| Age group | Adequate Intake (μg) | Upper Level of Intake (μg) |
|---|---|---|
| Infants 0–12 months | 5.0 | 25.0 |
| Children 1–18 years | 5.0 | 80.0 |
| Adults 19–50 years | 5.0 | 80.0 |
| Adults 51–70 years | 10.0 | 80.0 |
| Adults > 70 years | 15.0 | 80.0 |
Canada
According to Health Canada the recommended dietary allowances (RDA) for vitamin D are:
| Age group | RDA (IU) | Tolerable upper intake (IU) |
|---|---|---|
| Infants 0–6 months | 400* | 1,000 |
| Infants 7–12 months | 400* | 1,500 |
| Children 1–3 years | 600 | 2,500 |
| Children 4–8 years | 600 | 3,000 |
| Children and Adults 9–70 years | 600 | 4,000 |
| Adults > 70 years | 800 | 4,000 |
| Pregnancy & Lactation | 600 | 4,000 |
Note*: Adequate intake rather than recommended dietary allowance
European Union
The European Food Safety Authority (EFSA) refers to the collective set of recommendations as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of the EAR. AI and UL defined the same as in the United States. For all people over the age of 1, including women who are pregnant or lactating, the Adequate Intake (AI) is set at 15 μg/day (600 IU).
The UK National Health Service recommends babies and young children aged six months to five years, pregnant or breastfeeding women, and sun-deprived elderly people should take daily vitamin supplements to ensure sufficient vitamin D intake. In July 2016, Public Health England recommended that everyone consider taking a daily supplement containing 10 µg of vitamin D during autumn and winter because of inadequate sunlight for vitamin D synthesis.
Non-government organizations in Europe have made their own recommendations. The German Society for Nutrition recommends 20 µg. The European Menopause and Andropause Society recommends postmenopausal women consume15 µg (600 IU) until age 70, and 20 µg (800 IU) from age 71. This dose should be increased to 100 µg (4,000 IU) in some patients with very low vitamin D status or in the case of co-morbid conditions.
United States
According to the United States Institute of Medicine, the recommended dietary allowances (RDA) of vitamin D are:
| Age group | RDA (IU/day) |
|---|---|
| Infants 0–6 months | 400* |
| Infants 6–12 months | 400* |
| 1–70 years | 600 (15 μg/day) |
| 71+ years | 800 (20 μg/day) |
| Pregnant/Lactating | 600 (15 μg/day) |
- Asterisk for infants indicates adequate intake (AI) for infants, as an RDA has yet to be established for infants.
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin D labeling purposes 100% of the Daily Value was 400 IU (10 μg), but as of May 27, 2016 it was revised to 800 IU (20 μg) to bring it into agreement with the RDA. A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017, the FDA released a proposed rule that extended the deadline to January 1, 2020, for large companies and January 1, 2021, for small companies.
The tolerable upper intake level (UL) is defined as “the highest average daily intake of a nutrient that is likely to pose no risk of adverse health effects for nearly all persons in the general population.” Although tolerable upper intake levels are believed to be safe, information on the long-term effects is incomplete and these levels of intake are not recommended:ULs in the United States:
| Age group | Tolerable upper intake level |
|---|---|
| Infants 0–6 months | 1,000 IU/day (25 µg/day) |
| Infants 6–12 months | 1,500 IU/day (37.5 µg/day) |
| 1–3 years | 2,500 IU/day (62.5 µg/day) |
| 4–8 years | 3,000 IU/day (75 µg/day) |
| 9+ years | 4,000 IU/day (100 µg/day) |
| Pregnant/lactating | 4,000 IU/day:5(100 µg/day) |
The EFSA also reviewed the safety question and reached the same conclusion as in United States, setting the adult UL at 100 μg/day (4000 IU).
Pregnancy for Cholecalciferol / Vitamin D3
Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small infants. Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term, the extent of benefits for the mother or fetus is unclear. Pregnant women who take an adequate amount of vitamin D during gestation may experience a lower risk of pre-eclampsia and positive immune effects. Pregnant women often do not take the recommended amount of vitamin D.
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