Humans get vitamin D from their normal diet, dietary supplements and from exposure to sunlight.1-5 Ultraviolet B irradiation of the skin drives the conversion of 7-dehydrocholesterol to previtamin D3, which is then rapidly converted to vitamin D3.1 Vitamin D from the skin and diet is further metabolized in the liver to 25-(OH) vitamin D (or calcidiol).1-5
Calcidiol is the principle circulating reservoir of vitamin D in plasma
and is generally the best indicator of overall vitamin D status.
Calcidiol is further converted by the enzyme 25-(OH) D-1a-hydroxylase
(CYP27B1) in the proximal tubules of the kidney to the biologically
active form of vitamin D, 1,25-(OH)2 vitamin D (or calcitriol).1-5 The renal production of calcitriol is tightly regulated by plasma parathyroid hormone (PTH)1-5 and fibroblast growth factor 23 (FGF-23). FGF-23 is a circulating hormone synthesized by osteocytes and osteoblasts.5-8
Calcitriol and phosphate intake stimulates the synthesis of FGF-23,
which, in turn, suppresses calcitriol synthesis and activates calcitriol
conversion to inactive metabolites.1-6
Calcitriol is a
steroid-like hormone that binds to a specific cytoplasmic vitamin D
receptor (VDR) in the cytoplasm of target cells. The calcitriol-VDR
complex then migrates into the nucleus, where its effects are mediated
at a transcriptional level.5 Renal production of calcitriol
is important in the regulation of serum calcium homeostasis and in the
maintenance of healthy bone.1,2,9-11 Calcitriol stimulates
the absorption of calcium and phosphate by the intestine and increases
calcium and phosphate resorption by the kidney.1-6,12,13 Calcitriol also suppresses PTH production and regulates osteoblast function and bone resorption.5 It has been suggested that calcitriol has roles beyond the calcium-skeletal axis.1-5,14
Vitamin
D deficiency can affect the production of calcitriol owing to the lack
of substrate. A positive correlation between serum levels of calcidiol
and calcitriol was observed during seasonal changes. Treatment with
calcidiol can normalize calcitriol concentrations in patients with
vitamin D deficiency.12,15,16
Calcitriol assessment
may be beneficial in patients with chronic kidney failure. Diminished
levels of calcitriol can be seen in patients with kidney failure due to
reduced 1a-hydroxylase activity and phosphate retention resulting in
increased FGF-23 levels.17,18 Impaired calcitriol production
plays a major role in the development of secondary hyperparathyroidism
as calcitriol deficiency promotes parathyroid gland hyperplasia and
increased parathyroid hormone (PTH) synthesis due to the loss of the
ability to upregulate vitamin D receptor expression within parathyroid
cells.19 This ultimately results in elevated serum PTH and abnormal calcium and phosphorus balance.
Calcitriol measurement may be of use in patients with early-onset
rickets or a family history of rickets. Serum calcitriol levels can also
be increased in patients with hereditary vitamin D-resistant rickets, a
very rare autosomal recessive disorder in which mutations of vitamin D
receptor (VDR) impair calcitriol binding to the VDR.20 Patients usually present with hypocalcemia, early-onset rickets, alopecia, and other ectodermal anomalies.20
Other heritable disorders associated with low calcitriol levels include
vitamin D–dependent rickets type 1 (inactivating mutation in the
1-hydroxylase gene),21 autosomal-dominant hypophosphatemic rickets (mutation of the gene coding for FGF-23, which prevents its breakdown),22 and X-linked hypophosphatemic rickets (mutations that elevate levels of FGF-23).23
Individuals treated with glucocorticoids or anticonvulsants are at
risk of hypocalcemia associated with a low concentration of calcitriol.
HIV protease inhibitors have been reported to markedly suppress
calcitriol synthesis24,25 In tumor-induced osteomalacia,
tumor-secreted FGF-23 inhibits enzyme 1a-hydroxylase and subsequently
results in decreased calcitriol synthesis.26
Calcitriol
may also be helpful in the diagnosis of parathyroid function disorders.
A high serum level of calcitriol, for example, may suggest of primary
hyperparathyroidism, whereas a normal or low serum level is more likely
found in secondary hyperparathyroidism. Increased calcitriol levels can
be seen in some individuals with lymphoproliferative disorders and
granulomatous disease including, sarcoidosis, tuberculosis, and
inflammatory bowel disease where increased macrophage activity is
associated with extrarenal 1a-hydroxylase enzyme activity.27
However, unlike the kidney, the 1a-hydroxylase activity in the
macrophages is not controlled by the usual physiologic regulators.14,28
