Calcifediol/ja: Difference between revisions

| ImageAlt = Skeletal formula of calcifediol

| ImageAlt1 = Ball-and-stick model of the calcifediol molecule

'''Calcifediol''', also known as '''calcidiol''', '''25-hydroxycholecalciferol''', or '''25-hydroxyvitamin D₃''' (abbreviated '''25(OH)D₃'''), is a form of [[vitamin D]] produced in the [[liver]] by [[hydroxylation]] of [[vitamin D3|vitamin D₃]] (cholecalciferol) by the enzyme [[vitamin D 25-hydroxylase]]. Calcifediol can be further hydroxylated by the [[enzyme]] [[25-Hydroxyvitamin D3 1-alpha-hydroxylase|25(OH)D-1α-hydroxylase]], primarily in the kidney, to form [[calcitriol]] (1,25-(OH)₂D₃), which is the active hormonal form of vitamin D.

Calcifediol is strongly bound in blood by the [[vitamin D-binding protein]].Measurement of serum calcifediol is the usual test performed to determine a person's vitamin D status, to show [[vitamin D deficiency]] or sufficiency. Calcifediol is available as an oral medication in some countries to supplement vitamin D status.

==Biology==

Calcifediol is the precursor for calcitriol, the active form of vitamin D. It is synthesized in the liver, by hydroxylation of cholecalciferol (vitamin D₃) at the 25-position. This enzymatic 25-hydroxylase reaction is mostly due to the actions of [[CYP2R1]], present in [[microsomes]], although other enzymes such as [[mitochondrial]] [[CYP27A1]] can contribute. Variations in the expression and activity of CYP2R1, such as low levels in [[obesity]], affect circulating calcifediol. Similarly, vitamin D₂, [[ergocalciferol]], can also be 25-hydroxylated to form 25-hydroxyergocalciferol, (ercalcidiol, 25(OH)D₂); both forms are measured together in blood as 25(OH)D.

At a typical intake of cholecalciferol (up to 2000 IU/day), conversion to calcifediol is rapid.  When large doses are given (100,000 IU), it takes 7 days to reach peak calcifediol concentrations.  Calcifediol binds in the blood to vitamin D-binding protein (also known as gc-globulin) and is the main circulating vitamin D metabolite. Calcifediol has an [[elimination half-life]] of around 15 to 30 days.

Calcifediol is further hydroxylated at the 1-alpha-position in the kidneys to form 1,25-(OH)₂D₃, calcitriol. This enzymatic [[25-Hydroxyvitamin D3 1-alpha-hydroxylase|25(OH)D-1α-hydroxylase]] reaction is performed exclusively by [[CYP27B1]], which is highly expressed in the kidneys where it is principally regulated by [[parathyroid hormone]], but also by [[FGF23]] and calcitriol itself. CYP27B1 is also expressed in a number of other tissues, including [[macrophages]], [[monocytes]], [[keratinocytes]], [[placenta]] and [[parathyroid gland]] and extra-renal synthesis of calcitriol from calcifediol has been shown to have biological effects in these tissues.

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Calcifediol is also converted into [[24,25-dihydroxycholecalciferol]] by 24-hydroxylation. This enzymatic reaction is performed by [[CYP24A1]] which is expressed in many vitamin D target tissues including kidney, and is induced by calcitriol. This will inactivate calcitriol to [[calcitroic acid]], but 24,25-(OH)₂D₃ may have some biological actions itself.

==Blood test for vitamin D deficiency==

{{main|Vitamin D#Recommended serum levels}}

In medical practice, a  blood test for 25-hydroxy-vitamin D, 25(OH)D, is used to determine an individual's vitamin D status.  The name 25(OH)D refers to any combination of calcifediol (25-hydroxy-cholecalciferol), derived from vitamin D₃, and ercalcidiol (25-hydroxy-ergocalciferol), derived from vitamin D₂.  The first of these (also known as 25-hydroxy vitamin D3) is made by the body, or is sourced from certain animal foods or cholecalciferol supplements. The second (25-hydroxy vitamin D2) is from certain vegetable foods or ergocalciferol supplements.

This measurement is considered the best indicator of overall vitamin D status. US labs generally report 25(OH)D levels as ng/mL. Other countries use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L.

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This test can be used to diagnose [[vitamin D deficiency]], and is performed in people with high risk for vitamin D deficiency, when the results of the test can be used to support beginning replacement therapy with vitamin D supplements.

Patients with [[osteoporosis]], [[chronic kidney disease]], [[malabsorption]], [[obesity]], and some other infections may be at greater risk for being vitamin D-deficient and so are more likely to have this test. Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not usually requested for the entire population. Physicians may advise low risk patients to take [[Over-the-counter drug|over-the-counter]] vitamin D supplements in place of having screening.

It is the most [[sensitivity and specificity|sensitive]] measure, though experts have called for improved standardization and reproducibility across different laboratories. According to [[MedlinePlus]], the recommended range of 25(OH)D is 20 to 40&nbsp;ng/mL (50 to 100&nbsp;nmol/L) though they recognize many experts recommend 30 to 50&nbsp;ng/mL (75 to 125&nbsp;nmol/L). The normal range varies widely depending on several factors, including age and geographic location. A broad [[reference ranges for blood tests|reference range]] of 20 to 150&nbsp;nmol/L (8-60&nbsp;ng/mL) has also been suggested, while other studies have defined levels below 80&nbsp;nmol/L (32&nbsp;ng/mL) as indicative of vitamin D deficiency.

Increasing calcifediol levels up to levels of 80&nbsp;nmol/L (32&nbsp;ng/mL) are associated with increasing the fraction of calcium that is absorbed from the gut. Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400&nbsp;nmol/L (160&nbsp;ng/mL).

==Supplementation==

Calcifediol supplements have been used in some studies to improve vitamin D status. Indications for their use include vitamin D deficiency or insufficiency, refractory rickets ([[vitamin D resistant rickets]]), [[familial hypophosphatemia]], [[hypoparathyroidism]], hypocalcemia and [[renal osteodystrophy]] and, with calcium, in primary or corticosteroid-induced [[osteoporosis]].

Calcifediol may have advantages over cholecalciferol for the correction of vitamin D deficiency states. A review of the results of nine [[randomized control trials]] which compared oral doses of both, found that calcifediol was 3.2-fold more potent than cholecalciferol.  Calcifediol is better absorbed from the intestine and has greater affinity for the vitamin-D-binding protein, both of which increase its bioavailability. Orally administered calcifediol has a much shorter half-life with faster elimination. These properties may be beneficial in people with intestinal [[malabsorption]], obesity, or treated with certain other medications.

In 2016, the FDA approved a formulation of calcifediol (Rayaldee) 60 microgram daily as a prescription medication to treat secondary [[hyperparathyroidism]] in patients with [[chronic kidney disease]].

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==Interactive pathway map==

==History==

Research in the laboratory of [[Hector DeLuca]] identified 25(OH)D in 1968 and showed that the liver was necessary for its formation. The enzyme responsible for this synthesis, [[cholecalciferol 25-hydroxylase]], was isolated in the same laboratory by [[Michael F. Holick]] in 1972.

==Research==

Studies are ongoing comparing the effects of calcifediol with other forms of vitamin D including cholecalciferol in prevention and treatment of [[osteoporosis]].

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== See also ==

* [[Hypervitaminosis D]]

* [[Hypovitaminosis D]]

* [[Vitamin D]]

{{Vitamins}}

{{Calcium homeostasis}}

{{Vitamin D receptor modulators}}