Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism: Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism

S. Miedlich, K. Krohn, R. Paschke

Disclosures

Clin Endocrinol. 2003;59(5) 

In This Article

Which Mechanisms Underlie the Defective Calcium-Sensing in Patients With pHPT?

In parathyroid cells, elevation of the extracellular calcium concentration results in a reduction of secretion, synthesis and gene expression of PTH (Russell et al., 1983; Ishimi et al., 1990; Tsukamoto et al., 1995). This effect is mediated by CaR. Hypercalcaemia in the presence of hyperparathyroidism, the hallmark of pHPT, points to a defect in the above-mentioned signalling cascade. In vivo, the calcium set-point, defined as the serum calcium concentration at half-maximal inhibition of PTH secretion, is variably increased in patients with pHPT (Khosla et al., 1993). Furthermore, normal suppression of PTH secretion when challenged by a calcium infusion test is impaired in most patients with pHPT. Increased calcium set-points have also been reported in patients with heterozygous inactivating mutations of CaR (FHH). But when challenged by calcium infusions, the suppression of PTH secretion in patients with FHH appears to be similar to that of healthy probands (Khosla et al., 1993). In vitro, it could be shown that mRNA and protein expression of the CaR in parathyroid adenomas in the setting of sporadic pHPT are reduced (Kifor et al., 1996; Farnebo et al., 1997; Gogusev et al., 1997; Kaneko et al., 1999; Corbetta et al., 2000). However, the extent of this receptor downregulation is quite variable, and no correlation to clinical parameters such as serum calcium concentration, PTH levels or tumour mass has been found (Kifor et al., 1996; Farnebo et al., 1997; Kaneko et al., 1999; Corbetta et al., 2000). However, greater reductions of the CaR expression on parathyroid tumours were observed in patients with higher basal, minimum and maximum levels of PTH when preoperatively challenged with hypo- and hypercalcaemia. The latter result indicates that the impaired sensitivity of PTH secretion to changes of the serum calcium concentration in vivo may be related to the decreased CaR expression in parathyroid neoplasms. Somatic mutations within the CaR which would explain impaired function and altered receptor expression have not been detected thus far (Hosokawa et al., 1995; Cetani et al., 1999).

Several lines of evidence support an association between downregulation of CaR expression and increased cellular proliferation of the parathyroids: (i) Inactivating mutations of CaR are associated with hyperparathyroidism and hyperplasia of the parathyroids (reviewed in Brown et al., 1998); (ii) CaR knockout mice develop hyperplastic parathyroid glands (Ho et al., 1995); (iii) CaR expression is downregulated in hyperplastic parathyroid glands of patients with chronic renal insufficiency (Kifor et al., 1996; Gogusev et al., 1997; Inagaki et al., 1998). Furthermore, regression analyses displayed a significant relationship between the Ki-67 score as a marker of the growth fraction and the CaR expression in parathyroid glands of patients with severe secondary hyperparathyroidism due to chronic renal failure (Yano et al., 2000). (iv) Application of the calcimimetic NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency (Wada et al., 1997). Yet, the precise mechanisms by which cellular proliferation and CaR receptor function are associated within the parathyroids remain to be elucidated. Recent studies suggest a CaR-dependent activation of the mitogen-activated protein kinase (MAPK) signalling cascade via Gq, Gi and tyrosine kinase-related pathways (Kifor et al., 2001, see Fig. 3). Vice versa, transgenic mice with parathyroid-targeted overexpression of the cell cycle regulator cyclin D1, modelling the genetic rearrangement found in parathyroid tumours as described earlier, develop overt hyperparathyroidism with increased cellular proliferation of the parathyroids as well as hypersecretion of PTH. In addition, it could be shown that the expression of CaR is decreased on the parathyroid glands of these animals (Imanishi et al., 2001).

Schematic representation of the calcium sensing receptor signalling cascades with regard to PTH secretion and cellular proliferation. Gq/11, Gi, G proteins; PLC, phospholipase C; AC, adenylate cyclase; IP3, inositol-1,4,5-phosphate; DAG, diacylglycerol; PKC, protein kinase C; MAPK, mitogen-activated protein kinase.

Factors that may regulate the expression of CaR on parathyroid glands are for instance calcium and vitamin D. In rats, vitamin D but not calcium deficiency resulted in a decrease of CaR mRNA by 40% (Brown et al., 1996). A coexisting vitamin D deficiency is associated with a more severe clinical phenotype of pHPT in human beings (discussed below). Thus, vitamin D deficiency, directly or indirectly, via downregulation of CaR, could promote cellular proliferation and increase the probability of somatic mutations which may then initiate the development of clonal tumours within the parathyroid glands.

processing....