1,25-dihydroxyvitamin D (1,25[OH]₂D) is the active, hormonal form of vitamin D. It is produced from its precursor (vitamin D) by two hydroxylation steps in the liver and the kidneys. Circulating 1,25(OH)₂D levels are regulated by serum calcium and phosphate concentrations, this is mediated by the calcium-regulating hormones, parathyroid hormone (PTH) and phosphate-regulating hormone, fibroblast growth factor-23 (FGF-23). In the human body, 1,25(OH)₂D has a broad range of actions which include endocrine, autocrine and paracrine properties. Due to its picomolar concentrations and its lipophilic nature, 1,25(OH)₂D is a difficult analyte and represents a challenge to the analytical biochemist with respect to quantification. Until recently, relatively large sample volumes and extensive purification and separation steps were required to quantify 1,25(OH)₂D.

The clinical relevance of circulating 1,25(OH)₂D is underappreciated. Besides the well-known suppression of circulating 1,25(OH)₂D in chronic kidney disease, evidence is accumulating that circulating 1,25(OH)₂D is also reduced in other diseases. In addition, several studies have demonstrated that circulating 1,25(OH)₂D is inversely associated with clinical outcome and may complement or substitute traditional laboratory tests. Nevertheless, in the clinical setting there are still several gaps in the present knowledge on circulating 1,25(OH)₂D. These gaps include incomplete data about the effect of activated vitamin D or the influence of dosing and initial 25OHD level on circulating 1,25(OH)₂D; and the effect of different diseases on circulating 1,25(OH)₂D.

In conclusion, circulating 1,25(OH)₂D is less tightly regulated than assumed and may become a reliable predictor of clinical outcomes in some conditions.   

Learning Objectives:

1. Understand the role several hormones, including 1,25-dihydroxyvitamin D play in calcium and phosphate homeostasis.
2. Understand why active vitamin D therapy should be accompanied by measuring 1,25 dihydroxyvitamin D.
3. List the clinical conditions that would benefit from follow-up measurement for 1,25 dihydroxyvitamin D.