Parathyroid Hormone Secretion in Primary Hyperparathyroidism ROGER BOUILLON* AND PIETER D E MOOR Rega Instituut, Laboratorium voor Experimented Geneeskunde, Departement voor Ontwikkelingsbiologie, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium ABSTRACT. The serum levels of parathyroid hormone (PTH) were measured in normal subjects and in hyperparathyroid patients, using an anti-PTH antiserum which reacts with the COOH-terminal half of PTH. The basal PTH concentrations permitted a complete discrimination between normal subjects (264 ± 18 pg/ml, mean ± SEM, n = 15) and patients with either a solitary parathyroid adenoma (737 ± 42 pg/ml, n = 27) or parathyroid hyperplasia (1198 ± 103 pg/ml, n = 6). After EDTA infusion (50 mg/kg/2 h), the absolute rise in serum PTH level was higher in patients with parathyroid hyperplasia (+403 pg/ml) than in patients with solitary tumor (+170 pg/ml) or than in normal subjects (+239 pg/ml). Preoperative discrimination between both diseases, however, was impossible due to a wide variation of the individual degree of autonomy of PTH secretion. Oral phosphorus loading did not increase serum PTH levels in normal subjects but was a significant
stimulus in primary hyperparathyroidism. A calcium infusion in 6 hyperparathyroid patients suppressed the PTH secretion, inferred from the serum PTH level and its half-life, from 0 to 100%. The changes in serum PTH induced by hypercalcemia or hypocalcemia were significantly correlated. This implies that a tumor secreting much PTH during EDTA infusion reacts similarly during phosphorus stimulation and suppresses its secretion during infusion of calcium, whereas other tumors are largely autonomous during all tests. From these PTH measurements with a COOHterminal antiserum we conclude: 1) Basal rather than stimulated PTH concentrations are diagnostically helpful; 2) Parathyroid tumors have an individual degree of autonomy of their secretion in response to changes in serum calcium and this autonomy is largely independent from the histologic appearance of the tumor. (J Clin Endocrinol Metab 45: 261, 1977)
T
HE INFLUENCE of various stimuli hyperparathyroidism or in the differentiaon the serum levels of parathyroid tion between parathyroid adenoma and hormone (PTH) has previously been docu- hyperplasia. mented by the measurement of serum conMaterials and Methods centrations of immunoreactive parathyroid hormone (1). EDTA infusion both in primary (2-4) and in secondary hyperpara- Patient selection An iv EDTA infusion test was performed in thyroidism (5,6) as well as in other condi15 normal control persons and in 31 consecutive tions (7,8) has been successfully used to patients with primary hyperparathyroidism. Durevaluate the functional capacity of the paraing subsequent surgical neck exploration a single thyroid glands. This was especially necesadenoma was found in 25 and hyperplasia of sary since most reported immunoassays all parathyroid glands in 6 patients. (9-13) could not differentiate normal from Oral phosphate loading was performed in six hyperparathyroid hormone secretion in the normal control persons and in 11 patients with basal state. The influence of the acute ad- primary hyperparathyroidism (9 adenomas and 2 ministration of oral phosphate on parathy- hyperplasias). roid function has until now only been docuIntravenous infusion of calcium was done in 6 mented in a few normal men (14). hyperparathyroid patients whose basal serum calThe present studies were undertaken to cium concentration did not exceed 11.5 mg/ analyze the usefulness of PTH measure- 100 ml. ments during an acute EDTA or phosphorus test in the diagnosis of primary Experimental protocol Received May 11, 1976. * Aangesteld navorser N.F.W.O.
Disodium EDTA, 50 or 70 mg per kg of body weight diluted in 500 ml of glucose 5% in water was administered iv over a 2 h period. Five to
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10 ml of lidocaine, 1%, was added to avoid painful venous irritation. Blood was taken before and at 1, 2, 3 and 4 h after the start of the infusion. Phosphorus, 1 g as a neutral sodium phosphate solution, was given by mouth after an overnight fast and blood was taken before and 30, 60, 90, 120 and 180 min later. Calcium infusions, 16 mg calcium per kg of body weight diluted in 500 ml NaCl 0.9% was infused over a 4 h period. Blood was collected before and 1, 2, 3 and 4 h after the start of the infusion. Methods Serum calcium and phosphorus were measured on the day of the test by autoanalyzer techniques (SMA 12.60, Technicon Instruments). Serum parathyroid hormone was measured as described (15). The antiserum, coded A-VI-2, was prepared in a guinea pig immunized with a crude bovine parathyroid hormone and afterwards several booster injections with a human parathyroid adenoma extract were given. Previous experiments have demonstrated that this antiserum reacts only with the COOH-terminal region of human PTH (7,15,17). This is further confirmed
o primary
JCE & M • 1977 Vol 45 • No 2
by the finding of an apparent half-life of PTH after parathyroidectomy of 3 h in case of normal kidney function and of about 3 days in patients with chronic renal failure (16). Serum from hyperparathyroid patients diluted serially with serum obtained from hypoparathyroid patients reacted in an identical way as the bovine PTH standard and results were therefore expressed as pg bovine PTH equivalents per ml (normal range:
stimulus in primary hyperparathyroidism. A calcium infusion in 6 hyperparathyroid patients suppressed the PTH secretion, inferred from the serum PTH level and its half-life, from 0 to 100%. The changes in serum PTH induced by hypercalcemia or hypocalcemia were significantly correlated. This implies that a tumor secreting much PTH during EDTA infusion reacts similarly during phosphorus stimulation and suppresses its secretion during infusion of calcium, whereas other tumors are largely autonomous during all tests. From these PTH measurements with a COOHterminal antiserum we conclude: 1) Basal rather than stimulated PTH concentrations are diagnostically helpful; 2) Parathyroid tumors have an individual degree of autonomy of their secretion in response to changes in serum calcium and this autonomy is largely independent from the histologic appearance of the tumor. (J Clin Endocrinol Metab 45: 261, 1977)
T
HE INFLUENCE of various stimuli hyperparathyroidism or in the differentiaon the serum levels of parathyroid tion between parathyroid adenoma and hormone (PTH) has previously been docu- hyperplasia. mented by the measurement of serum conMaterials and Methods centrations of immunoreactive parathyroid hormone (1). EDTA infusion both in primary (2-4) and in secondary hyperpara- Patient selection An iv EDTA infusion test was performed in thyroidism (5,6) as well as in other condi15 normal control persons and in 31 consecutive tions (7,8) has been successfully used to patients with primary hyperparathyroidism. Durevaluate the functional capacity of the paraing subsequent surgical neck exploration a single thyroid glands. This was especially necesadenoma was found in 25 and hyperplasia of sary since most reported immunoassays all parathyroid glands in 6 patients. (9-13) could not differentiate normal from Oral phosphate loading was performed in six hyperparathyroid hormone secretion in the normal control persons and in 11 patients with basal state. The influence of the acute ad- primary hyperparathyroidism (9 adenomas and 2 ministration of oral phosphate on parathy- hyperplasias). roid function has until now only been docuIntravenous infusion of calcium was done in 6 mented in a few normal men (14). hyperparathyroid patients whose basal serum calThe present studies were undertaken to cium concentration did not exceed 11.5 mg/ analyze the usefulness of PTH measure- 100 ml. ments during an acute EDTA or phosphorus test in the diagnosis of primary Experimental protocol Received May 11, 1976. * Aangesteld navorser N.F.W.O.
Disodium EDTA, 50 or 70 mg per kg of body weight diluted in 500 ml of glucose 5% in water was administered iv over a 2 h period. Five to
261
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 03:41 For personal use only. No other uses without permission. . All rights reserved.
262
BOUILLON AND DE MOOR
10 ml of lidocaine, 1%, was added to avoid painful venous irritation. Blood was taken before and at 1, 2, 3 and 4 h after the start of the infusion. Phosphorus, 1 g as a neutral sodium phosphate solution, was given by mouth after an overnight fast and blood was taken before and 30, 60, 90, 120 and 180 min later. Calcium infusions, 16 mg calcium per kg of body weight diluted in 500 ml NaCl 0.9% was infused over a 4 h period. Blood was collected before and 1, 2, 3 and 4 h after the start of the infusion. Methods Serum calcium and phosphorus were measured on the day of the test by autoanalyzer techniques (SMA 12.60, Technicon Instruments). Serum parathyroid hormone was measured as described (15). The antiserum, coded A-VI-2, was prepared in a guinea pig immunized with a crude bovine parathyroid hormone and afterwards several booster injections with a human parathyroid adenoma extract were given. Previous experiments have demonstrated that this antiserum reacts only with the COOH-terminal region of human PTH (7,15,17). This is further confirmed
o primary
JCE & M • 1977 Vol 45 • No 2
by the finding of an apparent half-life of PTH after parathyroidectomy of 3 h in case of normal kidney function and of about 3 days in patients with chronic renal failure (16). Serum from hyperparathyroid patients diluted serially with serum obtained from hypoparathyroid patients reacted in an identical way as the bovine PTH standard and results were therefore expressed as pg bovine PTH equivalents per ml (normal range:
