Vitamin D is a precursor to a number of biologically active metabolites (Figure 42–3). Vitamin D is first hydroxylated in the liver and other tissues to form 25(OH)D, (calcifediol). As noted earlier there are a number of enzymes with 25-hydroxylase activity. This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25(OH)2D (calcitriol) and 24,25-dihydroxyvitamin D (secalciferol, 24,25[OH]2D), by the enzymes CYP27B1 and CYP24A1, respectively. The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which are PTH, which stimulates, and FGF23, which inhibits the production of 1,25(OH)2D by the kidney while reciprocally inhibiting or promoting the production of 24,25(OH)2D. The importance of CYP24A1, the enzyme that 24-hydroxylates 25(OH)D and 1,25(OH)2D, is well demonstrated in children lacking this enzyme who have high levels of calcium and 1,25(OH)2D resulting in kidney damage from nephrocalcinosis and stones. Of the natural metabolites, vitamin D, 25(OH)D (calcifediol) and 1,25(OH)2D (as calcitriol) are available for clinical use (Table 42–1). A number of analogs of 1,25(OH)2D have been synthesized to extend the usefulness of this metabolite to a variety of nonclassic conditions. Calcipotriene (calcipotriol), for example, is being used to treat psoriasis, a hyperproliferative skin disorder (see Chapter 61). Doxercalciferol and paricalcitol are approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Eldecalcitol is approved in Japan for the treatment of osteoporosis. Other analogs are being investigated for the treatment of various malignancies.
Vitamin D and its metabolites circulate in plasma tightly bound to the DBP. This α-globulin binds 25(OH)D and 24,25(OH)2D with comparable high affinity and vitamin D and 1,25(OH)2D with lower affinity. There is increasing evidence that it is the free or unbound forms of these metabolites that have biologic activity. This is of clinical importance because patients with liver disease or nephrotic syndrome have lower levels of DBP, whereas DBP levels are increased with estrogen therapy and during the later stages of pregnancy. Furthermore, there are several different forms 25 (OH)D3 CH2 + P +Ca + 1,25(OH)2D − PTH + FGF23 − P −Ca + PTH − FGF23 O H Kidney 24,25 (OH)2D3 (secalciferol) CH2 O H O H HO CH2 O H OHHO 1,25 (OH)2D3 (calcitriol)