Clinical Information

25-Hydroxyvitamin D2 and D3 (25-OH-VitD) are steroid hormones that require 1-alpha-hydroxylation before expressing biological activity. Vitamin D compounds are derived from dietary ergocalciferol (from plants, VitD2) or cholecalciferol (from animals, VitD3), or by conversion of 7-dihydrocholesterol to VitD3 in the skin upon ultraviolet exposure. VitD2 and VitD3 are subsequently 25-hydroxylated in the liver to 25-OH-VitD. 25-OH-VitD represents the main body reservoir and transport form of vitamin D, being stored in adipose tissue and tightly bound by a transport protein while in circulation. A fraction of circulating 25-OH-VitD is converted to its active metabolites 1,25-dihydroxy vitamin D2 and D3 (1,25-OH-VitD), mainly by the kidneys. This process is regulated by parathyroid hormone (PTH), which increases 1,25-OH-VitD synthesis at the expense of the alternative, biologically inactive hydroxylation product 24,25-OH-VitD. Like other steroid hormones, 1,25-OH-VitD binds to a nuclear receptor, influencing gene transcription patterns in target organs.

1,25-OH-VitD plays a primary role in the maintenance of calcium homeostasis. It promotes intestinal calcium absorption and, in concert with PTH, skeletal calcium deposition, or less commonly, calcium mobilization. Renal calcium and phosphate reabsorption are also promoted, while prepro-PTH mRNA expression in the parathyroid glands is down-regulated. The net result is a positive calcium balance, increasing serum calcium and phosphate levels, and falling PTH concentrations.

In addition to its effects on calcium and bone metabolism, 1,25-OH-VitD regulates the expression of a multitude of genes in many other tissues including immune cells, muscle, vasculature, and reproductive organs.

The exact 25-OH-VitD level reflecting optimal body stores remains unknown. Mild-to-modest deficiency can be associated with osteoporosis or secondary hyperparathyroidism. Severe deficiency may lead to failure to mineralize newly formed osteoid in bone, resulting in rickets in children and osteomalacia in adults. The consequences of vitamin D deficiency on organs other than bone are not fully known, but may include increased susceptibility to infections, muscular discomfort, and an increased risk of colon, breast, and prostate cancer.

Modest 25-OH-VitD deficiency is common; in institutionalized elderly, its prevalence may be >50%. Although much less common, severe deficiency is not rare either.

Reasons for suboptimal 25-OH-VitD levels include lack of sunshine exposure, a particular problem in Northern latitudes during winter; inadequate intake; malabsorption (eg, due to Celiac disease); depressed hepatic vitamin D 25-hydroxylase activity, secondary to advanced liver disease; and enzyme-inducing drugs, in particular many antiepileptic drugs, including phenytoin, phenobarbital, and carbamazepine, that increase 25-OH-VitD metabolism.

In contrast to the high prevalence of 25-OH-VitD deficiency, hypervitaminosis D is rare, and is only seen after prolonged exposure to extremely high doses of vitamin D. When it occurs, it can result in severe hypercalcemia and hyperphosphatemia.