Reduced vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis.

Abstract

Parathyroid adenomas discovered fortuitously grow very slowly and their cell birth rate greatly declines, features explicable by an initial increase in secretory set-point. In the nodules of severe uraemic parathyroid hyperplasia, there is an increased set-point and decreased expression of both the calcium sensing receptor (CaSR) and the vitamin D receptor (VDR). Accordingly, we examined VDR and CaSR expression in parathyroid adenomas. We studied 24 patients with primary hyperparathyroidism with a wide range of vitamin D nutritional status (plasma 25-hydroxyvitamin D range 10-107 nmol/l). Eighteen patients discovered by biochemical screening were enrolled in a natural history or treatment option study, and six additional US patients matched a group studied concurrently in India with low plasma 25-hydroxyvitamin D level (< 37 nmol/l). Receptor expression was determined by immunocytochemistry in each tumour and in 11 cases also in adjacent nonadenomatous tissue. VDR expression was reported as the proportion of positive cells (strongly rather than weakly stained) determined by systematic random sampling and CaSR expression as grey scale values of staining intensity in arbitrary units determined by image analysis. The mean (SD) proportion of cells positive for VDR was 2.93 (2.17)% in the parathyroid adenomas and 95.7 (5.10)% in the nonadenomatous tissue. In about two-thirds of the cases VDR positive cells could have been remnants of a normal gland, but in the remaining one-third they were too numerous to be accounted for by this explanation. The mean (SD) intensity of CaSR expression was 151 (4.71) units in parathyroid adenomas and 218 (5.0) units in nonadenomatous tissue (P<0.001). The frequency of VDR loss and the changes in CaSR immunohistochemistry were unrelated to race, sex, or disease severity, except that the reduction in CaSR was significantly greater in patients with normal vitamin D nutrition (32.1% vs. 29.0%). (1) There is reduction of vitamin D receptor expression in almost all cells in parathyroid adenomas. This defect was probably present in the founder cell of the tumour clone in the majority of cases. Since mutations in the vitamin D receptor gene have been sought but not found, possible explanations include inhibition of vitamin D receptor gene transcription, decreased amount of the corresponding mRNA, or failure of normal translation. (2) Reduction in calcium sensing receptor could be either the primary defect or (more commonly) secondary to loss of vitamin D receptor and is of sufficient magnitude to account for the increase in secretory set-point and consequent asymptotic growth and stable clinical course.