Non-suppressible parathyroid hormone secretion is related to gland size in uremic secondary hyperparathyroidism

Abstract

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 degrees HPT), we investigated the relationship between estimates of parathyroid gland size and calcium-mediated parathyroid hormone (PTH) suppression in 19 normocalcemic 2 degrees 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 degree HPT), which is characterized by both calcium set-point abnormalities and parathyroid gland enlargement. We found that the 2 degrees 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 degree HPT, but without the rightward shift of the calcium-PTH suppression curve that characterizes calcium sensing abnormalities in FBHH and 1 degree HPT. In the patients with 2 degrees 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 degrees HPT patients, however, were similar to those found in 1 degree 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 degrees 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 degree 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 degrees HPT. Thus, calcium non-suppressible PTH secretion in 2 degrees HPT does not represent a simple set-point error, but rather correlates with the degree of parathyroid gland enlargement.

Progression of secondary hyperparathyroidism involves deregulation of genes related to DNA and RNA stability

“…In early stages, this is a reversible phenomenon, and the overexpression of PTH can still be controlled by calcium, phosphate, and calcitriol [4]. Nevertheless, in the late stages of this disease, the excessive PTH secretion and the gland growth no longer responds to biophysiologic influences or to aggressive medical treatment [5,6]. Even after kidney transplantation, some patients do not recover and worsen their parathyroid hyperplasia with a nonresponsive behavior [7,8].…”

Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy

“…The failure of medical therapy is primarily due to progressive downregulation (8, 9, 10) of both calcium-sensing receptors (CaSR) and vitamin D receptors (VDR) (4,11,12,13). Actually, it is widely acknowledged that the PTG volume (maximum diameter O10 mm or volume O500 mm 3 ) negatively influences the response to calcitriol or vitamin D analog treatment (14,15). In these cases, parathyroidectomy (PTx) may be indicated (16).…”

Calcium-Mediated Parathyroid Hormone Suppression to Assess Progression of Secondary Hyperparathyroidism During Treatment Among Incident Dialysis Patients

“…Several reports indicate that the regulation of PTH secretion is affected adversely among subjects with enlarged parathyroid glands resulting from either primary hyperparathyroidism (HPT) or SHPT due to CKD (8,9). Although increases in blood ionized calcium concentration normally activate the CaR and inhibit PTH secretion, parathyroid cells continue to release basal amounts of PTH even when the extracellular calcium concentration is high (10).…”