Regulation of Parathyroid Hormone Release in Hyperparathyroidism

Derangement of calcium-controlled PTH release is an obligatory characteristic of the pathologic parathyroid tissue from hypercalcemic patients with adenoma and hyperplasia of sporadic primary HPT; familial HPT resulting from multiple endocrine neoplasias (MENs); secondary or tertiary HPT of renal, gastrointestinal, and lithium-induced diseases; and parathyroid carcinoma.6,57 The disturbance is characterized by variable calcium insensitivity of PTH secretion. The calcium-PTH response curve is shifted to the right, and the slope is decreased (see Figs. 39-1A and 39-3). The sigmoidal dose-response relationship is essentially maintained, and very few, if any, individuals demonstrate nonsuppressible secretion. This shift in the position and the inclination of the calcium-PTH curve correspond to similar changes in the regulation of Ca2* within abnormal parathyroid tissues (see Fig. 39-1B). The inverse linear relationship between Ca2+j and PTH secretion is thus maintained, but it is less steep than in the normal parathyroid parenchyma. Rare exceptions to this rule involve individuals with minimal calcium suppression of PTH secretion despite considerable increases in Ca2*.58"60 The calcium insensitivities of Ca2+, and PTH release correlate with one another and with the degree of hypercalcemia in the patient.6,58 The correlation with serum calcium values may explain the finding of less pronounced derangements in calcium regulation of PTH

release among primary parathyroid hyperplasias61,62 because the chief cell hyperplasia of sporadic primary HPT might be overrepresented in mild hypercalcemia.63 There is also evidence that the functional cellular abnormality may be more pronounced in larger compared with smaller glands as well as in nodular compared with diffusely enlarged portions of hyperplastic parathyroid tissue.64,65

The abnormal parathyroid tissue from patients with HPT is also characterized by decreases in the maximal and minimal Ca2+j values (Fig. 39-IB), which can be obtained at high and low steady-state concentrations of extracellular calcium, respectively.35,66 Corresponding changes, however, in the rate of PTH secretion have not been consistently observed.6,59 Although the clinical significance of the PTH secretory rate remains to be clarified,2,5 patients with HPT secrete more intact PTH during induction of both hypo- and hypercalcemic conditions in vivo.7,8 This increase is partially explained by the mass of parathyroid parenchyma, but this is difficult to evaluate, especially because the cells of abnormal glands are heterogeneous in their functional derangement.65-67 Nevertheless, PTH release per unit cell is reduced in HPT, and this reduction seems more pronounced in larger parathyroid glands.6,68 Ca2+; is poorly regulated in oxyphilic parathyroid cells in comparison with chief cells from the same glands, and the potential for PTH secretion of these cells is unclear.66 Another intriguing finding from studies of human parathyroid tissue is the presence of decreased calcium sensitivity of Ca2* in the chief cells from normal-sized glands associated with single parathyroid adenomas.66 Although the extent of this derangement is less pronounced than in adenomas, it may explain why serum PTH is transiently elevated after adenomectomy.69,70

The consistent findings of impaired regulation of Ca2*, despite maintained Ca2"1", inhibition of secretion in pathologic parathyroid cells, suggest that the principal pathophysiologic disturbance may be confined to the calcium sensing and gating of the cell surface. This assumption is supported by observations of normalization of the calcium-controlled secretion upon experimental increases in calcium permeability of the surface membrane.71 It is also emphasized by studies with monoclonal antiparathyroid antibodies,67,72 which reveal reduced expression of the 500-kd calcium sensor in the pathologic parenchyma of all previously investigated adenomatous and hyperplastic glands. The reduced immunoreactivity is accompanied by diminished mRNA levels for the receptor protein. These derangements are evidently not secondary to the hypercalcemia per se because "rims of normal parathyroid tissue" outside adenoma capsules as well as adenoma-associated glands display an intense and virtually normal receptor expression.49,67 The intensity of antibody reactivity, however, differs considerably within the pathologic parathyroid parenchyma and further supports variable secretory disturbances among the cells of individual glands.

Elevated protein kinase C activity may contribute to the hypersecretion of PTH in HPT.51 This elevation is presumed to cause a right shift in the dependence of Ca2+j on extracellular calcium, mainly through partial uncoupling of the calcium sensor from the signaling machinery of the parathyroid cells.73 Furthermore, the suppressive effects of calcitriol on PTH mRNA synthesis are decreased in parathyroid adenomas, which may exhibit dysfunctional vitamin D receptors.74 Because calcitriol inhibits the rate of PTH release without altering the suppressive effects of calcium,27,75 parathyroid vitamin D resistance may contribute to PTH hypersecretion even at normal calcitriol levels. A similar line of reasoning applies to the evidence for a decreased number of vitamin D receptors in the enlarged glands of patients with uremic HPT.76 Because the prevalence of primary HPT rises with age for both men and women,77 age-related reductions in the serum calcitriol concentration, the concomitant elevation of intact serum PTH values, and the reduced calcium responsiveness of PTH secretion substantiate a central role for calcitriol in the pathogenesis of HPT.78

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