Vitamin D and primary hyperparathyroidism: more insights into a complex relationship.

In primary hyperparathyroidism (PHPT), low levels of vitamin D are found more often than in the general population [1, 2]. This well established observation is based upon measurement of the serum 25-hydroxyvitamin D level (25OHD). The operational definition of vitamin D deficiency, again based upon 25OHD levels, is viewed by The Institute of Medicine as <20 ng/mL (50 nM/l) [3]. Many experts, however, define two categories of “low” vitamin D: one in which the level is between 20 and 30 ng/mL (insufficiency) and the other in which the level is <20 ng/mL (deficiency). These cut points, while controversial, do not address the special setting of PHPT. The most recent guidelines on the management of asymptomatic PHPT, recommend maintaining or repleting 25OHD to levels >20 ng/ml [4]. The controversy was acknowledged in that publication, noting that some experts and societies favor a level >30 ng/mL. These threshold values relate to of the concentration of total 25OHD; that is, the forms that are both protein bound and free. It is the unbound or free 25OHD that is biologically active, constituting approximately only 1 % of the total concentration. Another small fraction, approximately 10 % is bound to albumin as a complex that is theoretically also biologically available since the binding partition is relatively “loose”. The vast majority of circulating 25OHD is bound to its binding protein, vitamin D binding protein (DBP) and not biologically available. In PHPT, there is limited information regarding the relative amounts of these various forms of circulating 25OHD. Whether genetic factors, such as polymorphisms in DBP, affect 25OHD levels in PHPT has not previously been investigated. The exact pathophysiological mechanism(s) explaining the association between low 25OHD and PHPT are not clear. Several proposed mechanisms are likely to play a role. Parathyroid hormone (PTH) enhances the conversion of 25OHD to 1,25-dihydroxyvitamin D [1,25(OH)2D] by inducing the renal 1-alpha hydroxylase enzyme [5]. Increased levels of 1,25(OH)2D in PHPT, in turn, may inhibit the further production of active vitamin D from precursors in the skin and liver. The half-life of 25OHD may also be shortened in PHPT, with increased metabolic clearance due to enhanced hepatic inactivation [6]. Another view of the pathophysiology of PHPT places chronic 25OHD deficiency as an inciting event leading to parathyroid gland hyperplasia and subsequent adenomatous change. There is some evidence to suggest that vitamin D deficiency may increase the likelihood of a more symptomatic presentation of PHPT. This idea is supported by data indicating that the clinical and laboratory features of PHPT are more severe in areas of the world where vitamin D deficiency is endemic [7, 8]. Others have proposed that changes in the clinical presentation of PHPT in the Western world from a highly symptomatic disorder prior to the 1970’s to a predominantly asymptomatic one over the last 40 years is due, in part, to higher vitamin D levels resulting from fortification of dairy products with vitamin D during that time or from simply taking vitamin D supplements [9, 10]. The exact influence of vitamin D status upon the modern presentation of PHPT has yet to be fully defined. * Marcella D. Walker [email protected]