Cica‐clamp technique: a method for quantifying parathyroid hormone secretion: a sequential citrate and calcium clamp study

Abstract

Abstract.Objectives of the present study were to establish and investigate a standardized method for quantifying of intact parathyroid hormone secretion during sequential induction of hypo-and hypercalcaemia, and to explore the applicability to these data of a mathematical model derived from in tritro studies as presented in the literature.Twenty-two healthy volunteers aged 20-80 years participated in one or more experiments. The experiments comprised three different protocols of sequential induction of a regular hypocalcaemic (citrate) clamp followed by increases in blood ionized calcium, ending in a regular hypercalcaemic (calcium) clamp.During protocol I, the induction of hypocalcaemia, blood ionized calcium 0.2 1 mmol 1-(SD 0.01, n = 76) below baseline, the release of serum parathyroid hormone rapidly increased to a concentration of four to seven times above baseline. The serum parathyroid hormone declined gradually to a steady state of about two to three times above baseline. During stepwise increases in blood ionized calcium, the serum parathyroid hormone rapidly declined to new steady state concentrations. When a hypercalcaemia of 0.20 mmol I-' (SD 0.02, n=76) above baseline was reached, serum parathyroid hormone was suppressed to about one-fourth of baseline concentration. Protocol TI, the Cica-clamp, and protocol 111, are short versions of protocol I using a slow and gradual increase in blood ionized calcium from hypo-to hypercalcaemia. Protocol I1 reached a hypocalcaemia of blood ionized calcium 0.22 mmol I-] (SD 0.03, n= 57) below baseline and a hypercalcaemia of 0.19 mmol I-' (SD 0.04, n = 57) above baseline, whereas protocol 111 reached a hypocalcaemia of 0.38 mmol I-' (SD 0.06, n=57) below baseline and a hypercalcaemia of 0.34 mmol 1-' (SD 0.04, n=57) above baseline blood ionized calcium. During protocol TI and I11 we obtained identical results of serum parathyroid hormone compared to protocol I (P>0.70), indicating that serum parathyroid hormone could neither be suppressed nor Blood ionized calcium and serum parathyroid hormone demonstrate an inverse sigmoidal relationship with a blood ionized calcium concentration to the parathyroid hormone-midpoint of 1.1 3 mmol I-' (SD 0.04, n = 19), distinctly different from mean baseline blood ionized calcium, 1.25 mmol I -' (SD 0.04, n = 38). Our data suggest an asymmetrical control of blood ionized calcium by serum Parathyroid hormone with a true calcium set-point corresponding to about 8 5 % inhibition of maximal parathyroid hormone secretion.In conclusion, the present data shows that it is possible to establish a standardized test for sequential induction of hypo-and hypercalcaemia suitably for quantifying of serum parathyroid hormone secretion in vivo. The Cica-clamp test is short, easy to handle, reproducible and without discomfort to normocalcemic subjects. Its clinical usefulness remain to be determined.

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

“…Several studies have shown that a hypocalcemic clamp results in a reduction in PTH values as compared with those achieved at maximal PTH even though the same degree of hypocalcemia is maintained (92)(93)(94). Some (95-97) have suggested that the reduction in PTH values during a hypocalcemic clamp is due to depletion of PTH stores; however, we have a different explanation for the reduction in PTH levels seen during a hypocalcemic clamp.…”

The Calcium-Sensing Receptor: Physiology, Pathophysiology and Car-Based Therapeutics

“…As noted earlier, there is a functionally critical inverse relationship between Ca 2+ o and PTH, a calciumelevating hormone. This relationship is mediated by the CaR (Ho et al, 1995;Schwarz et al, 1993). In contrast, high Ca 2+ o stimulates the secretion of calcitonin (CT), a Ca 2+ o -lowering hormone; this action of calcium on CT secretion is likewise mediated by the CaR (Fudge and Kovacs, 2004).…”

Parathyroid hormone dynamics in hypoparathyroidism and primary hyperparathyroidism

“…Our present finding of an r value of 0.91 in untreated PHPT is in accordance herewith. We found that Parfitt's calcium set-point correspond to about 84 % inhibition of PTH maximum [6], in untreated PHPT patients the values scatter more widely, but the average is the same, about 85 %.…”

“…It is noteworthy that Brown's calcium set-point is significantly smaller than Parfitt's calcium set-point in each of the three conditions we have studied, but strikingly well correlated including untreated PHPT [33]. To explain the excellent correlation between values within the narrow ranges of normality, we deducted that both calcium set-points, Brown's and Parfitt's, represent different points on each individual inverse sigmoidal curve [6]. Our present finding of an r value of 0.91 in untreated PHPT is in accordance herewith.…”

“…Confirming the normal reactivity, induction of hypercalcaemia readily suppressed S-PTH to below the detection limit in all patients with surgical HP except one. Suppres sion to this extent was not seen in normals [6,13], but this difference is rather a quantitative than a qualitative one. Taken together these observations leave no evidence in support of the view that the low but detectable levels of S-PTH in surgicals HP [10,11,141 should derive from nonspecific interference with the immunometrical assay.…”