Vitamin D, 1,25-Dihydroxy (Calcitriol)

Overview:

Aid in the diagnosis of primary hyperparathyroidism, hypoparathyroidism, pseudohypoparathyroidism, renal osteodystrophy, and vitamin D-resistant rickets.

The 25-(OH) vitamin D form of the hormone is the principle circulating reservoir in plasma and is generally the best indicator of overall vitamin D status. Heterophilic antibodies in human serum can react with reagent immunoglobulins, interfering with in vitro immunoassays. Patients routinely exposed to animals or to animal serum products can be prone to this interference, and anomalous values may be observed.

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-1α-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 1α-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 1α-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 1α-hydroxylase enzyme activity.27 However, unlike the kidney, the 1α-hydroxylase activity in the macrophages is not controlled by the usual physiologic regulators.14,28

1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19; 357(3):266-281. PubMed 17634462

2. Holick MF, Binkley NC, Bischoff-Ferrare HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul; 96(7):1911-1930. PubMed 21646368

3. Hollis BW. Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the clinical environment. Endocrinol Metab Clin North Am. 2010 Jun; 39(2):271-286. PubMed 20511051

4. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004 Dec; 80(6 Suppl):1689S-1696S. PubMed 15585789

5. Norman AW. From vitamin D to hormone D: Fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008 Aug; 88(2):491S-499S. PubMed 18689389

6. Hruska KA, Mathew S. The roles of the skeleton and phosphorus in the CKD mineral bone disorder. Adv Chronic Kidney Dis. 2011 Mar; 18(2):98-104. PubMed 21406294

7. Penido MG, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012 Nov; 27(11):2039-2048. PubMed 22552885

8. Prié D, Friedlander G. Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clin J Am Soc Nephrol. 2010 Sep; 5(9):1717-1722. PubMed 20798257

9. Endres DB, Rude RK. Mineral and bone metabolism. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. 3rd ed. Philadelphia, Pa: WB Saunders;1999:1395-1457.

10. Souberbielle JC, Body JJ, Lappe JM, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmune Rev. 2010 Sep; 9(11):709-715. PubMed 20601202

11. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: The National Academies Press; 2011.