To determine the relative importance of parathyroid gland enlargement and alterations in calcium sensing (set-point changes) in the pathogenesis of uremic secondary hyperparathyroidism (2°HPT), we investigated the relationship between estimates of parathyroid gland size and calcium-mediated parathyroid hormone (PTH) suppression in 19 normocalcemic 2°HPT patients on chronic maintenance hemodialysis. We compared our results to calcium mediated PTH suppression in 12 normal volunteers, 12 patients with familial benign hypocalciuric hypercalcemia (FBHH), a disorder of abnormal calcium sensing, and 9 subjects with primary hyperparathyroidism (1°HPT), which is characterized by both calcium set-point abnormalities and parathyroid gland enlargement. We found that the 2°HPT group displayed a distinctive pattern of calcium-mediated PTH suppression characterized by a failure to normally suppress PTH at supraphysiologic ionized calcium concentrations, similar to 1°HPT, but without the rightward shift of the calcium-PTH suppression curve that characterizes calcium sensing abnormalities in FBHH and 1°HPT. In the patients with 2°HPT, hypercalcemic suppression resulted in an ending PTH (as a percent of baseline) that was significantly higher (39.8 ± 4.47%), and a slope of the calcium-PTH suppression curve that was significantly less negative (-4.8 ± 0.53), compared to respective values of 19.4 ± 1.81% (P = 0.0009) and -9.0 ± 1.02 (P = 0.001) in normals and 19.1 ± 2.49% (P = 0.001) and -9.6 ± 1.11 (P = 0.0006) in FBHH. Values of ending PTH and slope in 2°HPT patients, however, were similar to those found in 1°HPT (49.8 ± 6.35%, P = 0.21 and -4.5 ± 0.74, P = 0.72). The ionized calcium concentration required to attain half maximal PTH suppression (EC50) in 2°HPT (1.20 ± 0.02 mmol/liter) was not significantly different from normals (1.25 ± 0.01 mmol/liter, P = 0.12) but was significantly less than in 1°HPT (1.52 ± 0.02 mmol/liter, P < 0.0001) and in FBHH (1.44 ± 0.02 mmol/liter, P < 0.0001). More importantly, we found a significant linear correlation between the natural logarithm of gland size and ending PTH suppression (r = 0.71, P < 0.001) and slope of the calcium-PTH curve (r = 0.67, P = 0.002) in 2°HPT. Thus, calcium non-suppressible PTH secretion in 2°HPT does not represent a simple set-point error, but rather correlates with the degree of parathyroid gland enlargement.
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