Vitamin D3 25-Hydroxyvitamin D - Medscape Reference

Description

Vitamin D is a group of fat-soluble compounds with a four-ringed cholesterol backbone; it is now recognized as a prohormone.

Vitamin D exists in two major forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). The precursor for vitamin D2 is a plant sterol ergosterol. D2 can be synthesized by ultraviolet irradiation of ergosterol from yeast. Similarly, vitamin D3 is synthesized in the body when sunlight (ultraviolet B, wavelength 280-315 nm) photoisomerizes 7-dehydroxycholesterol found in the skin. D3 is also found in animal-based foods (eg, fatty fish, liver, milk, eggs).

Vitamin D2 and D3, regardless of the source, are biologically inactive. They are transformed into the biologically active molecule 1,25 dihydroxyvitamin D. After being synthesized in the skin or absorbed (in chylomicrons) from the gastrointestinal (GI) tract, most vitamin D is bound to specific carrier proteins in the blood (vitamin D–binding protein [DBP] and albumin) and transported to the liver. In the liver, vitamin D is hydroxylated by the enzyme 25-hydroxylase (CYP2R1) to become 25(OH)D. 25(OH)D is the major circulating form of vitamin D. From the liver, 25(OH)D is transported to the kidneys via the same carrier proteins as above.

1,25 dihydroxyvitamin D (1,25(OH)2 D) is formed when 25(OH)D is hydroxylated by the enzyme 1α-hydroxylase (CYP27B1), which is located in the mitochondria of proximal tubules of the kidney. 1,25(OH)2 D is the biologically active form of vitamin D. As a result of 1 and 25 hydroxylation, the prohormone vitamin D has been transformed into an active hormone.

1,25(OH)2 D is a steroidlike hormone. In target cells, such as classic steroid hormones, it binds to a specific cytoplasmic VDR; the vitamin D bound to VDR then translocates to the nucleus, where its effects are initiated at a transcriptional level. [17] The main established actions of 1,25(OH)2 D collectively increase calcium in the body and modulate the skeleton. It increases the intestinal absorption of calcium and phosphate, decreases renal excretion of calcium and phosphate, suppresses PTH production, and regulates osteoblast function and bone resorption. It has been suggested that 1,25(OH)2 D has roles beyond the calcium-skeletal axis. [17]

The identification of VDRs in various cells has prompted the investigation of vitamin D in immunomodulation, cancer prevention and therapy, autoimmune disease, cardiovascular disease, and other nonskeletal organs.

The synthesis of 1,25(OH)2 D is tightly regulated by PTH, serum calcium, serum phosphate, and fibroblast-like growth factor 23 (FGF-23). Increased levels of PTH and hypophosphatemia stimulate the enzyme 1α-hydroxylase and, subsequently, the synthesis of 1,25(OH)2 D. FGF-23 is a circulating hormone synthesized by osteocytes and osteoblasts. 1,25(OH)2 D and phosphate intake stimulates the synthesis of FGF-23, which, in turn, inhibits 1,25(OH)2 D production, reduces the expression of renal sodium–phosphate transporters, and activates the metabolizing of active 1,25(OH)2 D to the inactive metabolite 24,25(OH)2 D. [18]

As a fat-soluble molecule, vitamin D is stored in adipose tissue; however, the exact mechanism by which vitamin D is regulated and mobilized from adipose tissue has not been elucidated at this time. Most vitamin D products are excreted through bile into the gut. Very little is eliminated via kidneys (see graph below).

Vitamin D metabolism. View Media Gallery

Indications/Applications

Measurement of 25(OH)D levels can be considered to evaluate suspected vitamin D toxicity or deficiency. Deficiency can result from several factors and affect people of all ages and health (see image below). [19] Serial monitoring is also recommended during treatment with vitamin D to prevent hypercalcemia. [20]

Causes of vitamin D deficiency. View Media Gallery

Current guidelines do not recommend screening the general population for deficiency. The Endocrine Society recommends a measurement of 25(OH)D for those at risk, which include pregnant patients. [20] On the other hand, the American College of Obstetricians and Gynecologists advocates testing only for pregnant patients at high-risk for deficiency, such as vegetarians, those with limited sun exposure, and members of ethnic minorities. [21]

Considerations

The serum level of 25(OH)D is currently considered the best indicator of total body vitamin D stores. However, it is unclear if this reflects the actual physiological state of vitamin D activity in the body. It is possible that there are effects of vitamin D that occur intracellularly independent of the measured serum level of vitamin D. Thus, there is a need for future research that more specifically relates the measured levels of D in blood with the vitamin D activities that are mediated through the VDR effects on transcription.

25(OH)D and 1,25(OH)2 D, when transported in the circulation, are bound primarily to DBP and albumin. A very small fraction (0.02%–0.05% of 25(OH)D and 0.2%-0.6% of total 1,25(OH)2 D) remains free or unbound. Physiological and pathological changes in the concentrations of DBP and albumin, such as in pregnancy, in malnutrition, in liver disease, in nephrotic syndrome, and in association with medications, among others, can affect the total and free fractions of 25(OH)D.

It is controversial whether determination of free vitamin D metabolites would be important. In a recent population-based cohort study with 2085 participants (blacks and whites), black Americans had lower levels of total 25(OH)D and vitamin D–binding protein compared with whites. [22] However, the 2 groups had similar concentrations of estimated bioavailable 25(OH)D. How the lower vitamin D–binding protein levels affect the risk of fracture is unknown.

Until now, owing to the lack of data on the physiological and clinical impact of free vitamin D, total 25(OH)D remains the best indicator of total body vitamin D stores and its availability for biologic functions.