Calcifediol Explained

Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 (abbreviated 25(OH)D3),[1] is a form of vitamin D produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme vitamin D 25-hydroxylase.[2] [3] [4] Calcifediol can be further hydroxylated by the enzyme 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.[2] [3] [4]

Calcifediol is strongly bound in blood by the vitamin D-binding protein.[4] Measurement of serum calcifediol is the usual test performed to determine a person's vitamin D status, to show vitamin D deficiency or sufficiency.[3] [4] Calcifediol is available as an oral medication in some countries to supplement vitamin D status.[3] [5] [6]

Biology

Calcifediol is the precursor for calcitriol, the active form of vitamin D.[2] [3] It is synthesized in the liver, by hydroxylation of cholecalciferol (vitamin D3) at the 25-position.[2] 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.[4] [7] Variations in the expression and activity of CYP2R1, such as low levels in obesity, affect circulating calcifediol.[7] Similarly, vitamin D2, ergocalciferol, can also be 25-hydroxylated to form 25-hydroxyergocalciferol, (25(OH)D2);[1] both forms are measured together in blood as 25(OH)D.[2] [3]

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.[8] Calcifediol binds in the blood to vitamin D-binding protein (also known as gc-globulin) and is the main circulating vitamin D metabolite.[3] [4] Calcifediol has an elimination half-life of around 15 to 30 days.[3] [8]

Calcifediol is further hydroxylated at the 1-alpha-position in the kidneys to form 1,25-(OH)2D3, calcitriol.[2] [3] This enzymatic 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.[2] [4] [7] 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.[7] [9]

Calcifediol is also converted into 24,25-dihydroxycholecalciferol by 24-hydroxylation.[2] This enzymatic reaction is performed by CYP24A1 which is expressed in many vitamin D target tissues including kidney, and is induced by calcitriol.[4] This will inactivate calcitriol to calcitroic acid, but 24,25-(OH)2D3 may have some biological actions itself.[4]

Blood test for vitamin D deficiency

In medical practice, a blood test for 25-hydroxy-vitamin D, 25(OH)D, is used to determine an individual's vitamin D status.[10] The name 25(OH)D refers to any combination of calcifediol (25-hydroxy-cholecalciferol), derived from vitamin D3, and (25-hydroxy-ergocalciferol),[1] 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.[10] Clinical tests for 25(OH)D often measure the total level of both of these two compounds together, generally without differentiating.[11]

This measurement is considered the best indicator of overall vitamin D status.[10] [12] [13] 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.[3]

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.[3] [14] 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.[14] 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.[14] Physicians may advise low risk patients to take over-the-counter vitamin D supplements in place of having screening.[14]

It is the most sensitive measure, though experts have called for improved standardization and reproducibility across different laboratories.[3] According to MedlinePlus, the recommended range of 25(OH)D is 20 to 40 ng/mL (50 to 100 nmol/L) though they recognize many experts recommend 30 to 50 ng/mL (75 to 125 nmol/L).[10] The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20 to 150 nmol/L (8-60 ng/mL) has also been suggested,[15] while other studies have defined levels below 80 nmol/L (32 ng/mL) as indicative of vitamin D deficiency.[16]

Increasing calcifediol levels up to levels of 80 nmol/L (32 ng/mL) are associated with increasing the fraction of calcium that is absorbed from the gut.[12] Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400 nmol/L (160 ng/mL).[17]

Supplementation

Calcifediol supplements have been used in some studies to improve vitamin D status.[3] 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.[18]

Calcifediol may have advantages over cholecalciferol for the correction of vitamin D deficiency states.[5] 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.[5] Calcifediol is better absorbed from the intestine and has greater affinity for the vitamin-D-binding protein, both of which increase its bioavailability.[19] Orally administered calcifediol has a much shorter half-life with faster elimination.[19] These properties may be beneficial in people with intestinal malabsorption, obesity, or treated with certain other medications.[19]

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.[6]

History

Research in the laboratory of Hector DeLuca identified 25(OH)D in 1968 and showed that the liver was necessary for its formation.[20] The enzyme responsible for this synthesis, cholecalciferol 25-hydroxylase, was isolated in the same laboratory by Michael F. Holick in 1972.[21]

Research

Studies are ongoing comparing the effects of calcifediol with other forms of vitamin D including cholecalciferol in prevention and treatment of osteoporosis.[2] [19]

Notes and References

  1. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981 . European Journal of Biochemistry . 124 . 2 . 223–7 . May 1982 . 7094913 . 10.1111/j.1432-1033.1982.tb06581.x . free .
  2. Web site: Vitamin D . Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis . 14 March 2022 . 11 February 2021.
  3. Web site: Office of Dietary Supplements - Vitamin D . ods.od.nih.gov . 9 October 2020 . 31 October 2020 . en.
  4. Bikle DD . Vitamin D metabolism, mechanism of action, and clinical applications . Chemistry & Biology . 21 . 3 . 319–29 . March 2014 . 24529992 . 3968073 . 10.1016/j.chembiol.2013.12.016 .
  5. Quesada-Gomez JM, Bouillon R . Is calcifediol better than cholecalciferol for vitamin D supplementation? . Osteoporosis International. 29 . 8 . 1697–1711 . August 2018 . 29713796 . 10.1007/s00198-018-4520-y . 14005489 . review.
  6. Web site: Rayaldee (calcifediol) FDA Approval History - Drugs.com. 4 March 2021.
  7. Bouillon R, Bikle D . Vitamin D Metabolism Revised: Fall of Dogmas . Journal of Bone and Mineral Research . 34 . 11 . 1985–1992 . November 2019 . 31589774 . 10.1002/jbmr.3884 . 9000993 . Review. free .
  8. Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW . 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions . The American Journal of Clinical Nutrition . 87 . 6 . 1738–42 . June 2008 . 18541563 . 10.1093/ajcn/87.6.1738 . free .
  9. Adams JS, Hewison M . Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase . Arch Biochem Biophys . 523 . 1 . 95–102 . July 2012 . 22446158 . 3361592 . 10.1016/j.abb.2012.02.016 .
  10. https://www.nlm.nih.gov/medlineplus/ency/article/003569.htm "25-hydroxy vitamin D test: Medline Plus"
  11. Web site: 25HDN - Clinical: 25-Hydroxyvitamin D2 and D3, Serum . Mayo Clinic Labs. 2021. 4 March 2021.
  12. Heaney RP . Functional indices of vitamin D status and ramifications of vitamin D deficiency . The American Journal of Clinical Nutrition . 80 . 6 Suppl . 1706S–9S . December 2004 . 15585791 . 10.1093/ajcn/80.6.1706S . free .
  13. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP . Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials . BMJ . 348 . g2035 . April 2014 . 24690624 . 3972415 . 10.1136/bmj.g2035 .
  14. , which cites
      • Sattar N, Welsh P, Panarelli M, Forouhi NG . Increasing requests for vitamin D measurement: costly, confusing, and without credibility . Lancet . 379 . 9811 . 95–6 . January 2012 . 22243814 . 10.1016/S0140-6736(11)61816-3 . 12669468 .
      • Bilinski KL, Boyages SC . The rising cost of vitamin D testing in Australia: time to establish guidelines for testing . The Medical Journal of Australia . 197 . 2 . 90 . July 2012 . 22794049 . 10.5694/mja12.10561 . 45880893 .
      • Lu CM . Pathology consultation on vitamin D testing: clinical indications for 25(OH) vitamin D measurement . American Journal of Clinical Pathology . 137 . 5 . 831–2 . May 2012 . 22645788 . . 10.1309/ajcp2gp0ghkqrcoe. free ., which cites
        • Arya SC, Agarwal N . The measurement of vitamin D3 requires maintaining quality control . American Journal of Clinical Pathology . 137 . 5 . 832; author reply 833 . May 2012 . 22523224 . 10.1309/AJCP2GP0GHKQRCOE . free .
      • Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM . 6 . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline . The Journal of Clinical Endocrinology and Metabolism . 96 . 7 . 1911–30 . July 2011 . 21646368 . 10.1210/jc.2011-0385 . free .
  15. Book: Bender, David A. . vanc . Vitamin D . Nutritional biochemistry of the vitamins . Cambridge University Press . Cambridge . 2003 . 978-0-521-80388-5 . https://books.google.com/books?id=pxEJNs0IUo4C. Retrieved December 10, 2008 through Google Book Search.
  16. Hollis BW . Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D . The Journal of Nutrition . 135 . 2 . 317–22 . February 2005 . 15671234 . 10.1093/jn/135.2.317 . free .
  17. Kimball SM, Ursell MR, O'Connor P, Vieth R . Safety of vitamin D3 in adults with multiple sclerosis . The American Journal of Clinical Nutrition . 86 . 3 . 645–51 . September 2007 . 17823429 . 10.1093/ajcn/86.3.645 . free .
  18. Web site: Calcifediol . go.drugbank.com . 7 March 2021.
  19. Cesareo R, Falchetti A, Attanasio R, Tabacco G, Naciu AM, Palermo A . Hypovitaminosis D: Is It Time to Consider the Use of Calcifediol? . Nutrients . 11 . 5 . May 2019 . 1016 . 31064117 . 6566727 . 10.3390/nu11051016 . Review. free .
  20. Ponchon G, Kennan AL, DeLuca HF . "Activation" of vitamin D by the liver . The Journal of Clinical Investigation . 48 . 11 . 2032–7 . November 1969 . 4310770 . 297455 . 10.1172/JCI106168 .
  21. Holick MF, DeLuca HF, Avioli LV . Isolation and identification of 25-hydroxycholecalciferol from human plasma . Archives of Internal Medicine . 129 . 1 . 56–61 . January 1972 . 4332591 . 10.1001/archinte.1972.00320010060005 .