Disorders in the Action of Vitamin D

Excerpt

Vitamin D is produced in the skin under the influence of UVB portion of the light spectrum in sunlight. This form of vitamin D is cholecalciferol or vitamin D₃. Vitamin D may also be part of the diet either in certain foods such as fatty fish or as supplements either ingested separately or in supplemented food such as milk. Such supplements can be either vitamin D₃ or vitamin D₂, the form produced in plants from UVB radiation of ergosterol. For the purposes of this chapter, we will make no distinction between these forms of vitamin D, although the differences in the side chain (double bond at C22-23 and methyl group at C24 of vitamin D₂) do alter both the binding of vitamin D₂ to vitamin D binding protein (DBP) and the metabolism of vitamin D₂. Vitamin D then must be metabolized to its most active form, 1,25 dihydroxyvitamin D (1,25(OH)₂D), by a series of steps involving first the conversion to 25 hydroxyvitamin D (25OHD), the principal circulating form of vitamin D, principally by the enzyme CYP2R1 in the liver, then to 1,25(OH)₂D principally in the kidney by the enzyme CYP27B1. That said there are a number of enzymes with 25-hydroxylase activity found in a number of tissues, and although CYP27B1 is essentially the only 1-hydroxylase, this enzyme is found in numerous tissues where it is thought to play primarily a paracrine/autocrine role. Putting a check to the production of 25OHD and 1,25(OH)₂D is the 24-hydroxylase CYP24A1, that metabolizes both 25OHD and 1,25(OH)₂D to inactive products. Like CYP27B1, CYP24A1 is widely distributed. Vitamin D and its metabolites are carried in blood tightly bound to DBP, such that only a small fraction (<1%) is free to enter most cells unless those cells express the megalin/cubilin complex which facilitates the transport of the DBP bound metabolites into the cell. DBP is produced in the liver, and its levels can vary in patients with limited hepatic synthetic capacity. Moreover, DBP is an acute phase reactant so a variety of conditions can alter DBP levels and thus the measurement of vitamin D and its metabolites. 1,25(OH)₂D is the major ligand for the vitamin D receptor (VDR), a nuclear transcription factor found in most if not all cells of the body and known to regulate thousands of genes in a cell specific manner. Although numerous physiologic functions have been attributed to vitamin D and its metabolites, clinically its major action is to control the availability of calcium and phosphate from the diet for the proper mineralization of the skeleton. Thus, disorders in vitamin D availability, metabolism, and action manifest first and foremost in the skeleton that when severe result in rickets in growing children and osteomalacia in adults in whom the growth plates have closed. After a brief review of vitamin D metabolism and molecular mechanisms of action this chapter will describe the pathologic changes in bone when the supply of mineral to bone is inadequate due to disorders in vitamin D action whether from dietary deficiency, metabolism, or mechanism of action. We will then look in depth at the causes of vitamin D deficiency including mutations resulting in altered metabolism, then discuss the range of effects different mutations in the VDR have on its function including the example of alopecia, which is best known function of VDR that is independent of its ligand 1,25(OH)₂D. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.