What Is Vitamin D Deficiency?

Abstract

Vitamin D derived from the diet or produced in the skin is converted to its active form by two sequential hydroxylation reactions (1, 2). The first occurs in the liver, forming 25-hydroxyvitamin D₃ (25-(OH)D₃), and the second occurs in the kidney, forming the active hormonal form 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃). The activity of the renal 25-(OH)D₃-1 α-hydroxylase enzyme (1-hydroxylase), which is tightly regulated according to the calcium and phosphorus requirements of the body, is stimulated predominantly by parathyroid hormone and low plasma calcium and phosphate concentrations. 1,25-Dihydroxyvitamin D₃ acts to increase intestinal active calcium transport and, in concert with parathyroid hormone, to stimulate renal tubular calcium reabsorption and bone mineral mobilization (1, 2). Vitamin D restriction by dietary deficiency and/or by reduced exposure to sunlight can lead to the development of vitamin D-deficiency rickets (2, 3).

The best recognized definition of vitamin D-deficiency, i.e., bony rickets, has its origin in the evolving understanding of this bone disease and the fact that vitamin D deficiency is the most frequent cause (Table I). In more recent times, many investigators have considered animals to be vitamin D deficient if they exhibit rickets, reduced intestinal calcium transport, hypocalcemia, or “undetectable” levels of 25-(OH)D₃ (Table II; 7–27). However, in a series of studies (28–30) directed toward establishing a normocalcemic rat model exhibiting vitamin D-deficiency, we realized that understanding or defining vitamin D deficiency is extremely complex. For example, most workers would probably agree that vitamin D deficiency should entail 1,25-(OH)₂D₃ deficiency. However, as described below, absence of 1,25-(OH)₂D₃ may not always be associated with absence of vitamin D or 25-(OH)D₃. Conversely, physiological levels of 1,25-(OH)₂D₃ can exist in the presence of extremely low levels of vitamin D or 25-(OH)D₃.