Overproduction and Secretion of a Novel Amino-Terminal Form of Parathyroid Hormone from a Severe Type of Parathyroid Hyperplasia in Uremia

Abstract

Measurement of bioactive parathyroid hormone (PTH) is essential for optimal management of bone abnormalities in dialysis patients. This can be accomplished by PTH measurements using third-generation PTH assays, which detect more or less of the first six amino acids of the PTH structure. Such assays do not detect non-(1-84) PTH fragments, such as human PTH (7-84), which are recognized by the second-generation PTH assays that use a detection antibody that recognizes an epitope within the 13-34 region of the PTH structure. Therefore, third-generation PTH results are expected to be lower than those that are obtained with second-generation PTH assays. Rare exceptions to this rule have been reported for patients with severe primary hyperparathyroidism or parathyroid cancer. Sera and gland extracts were analyzed from a dialysis patient with high bone turnover disease and with surprising higher PTH levels by a third-generation assay than by a second-generation assay. This finding normalized after the surgical removal of an enlarged gland with a single nodule, an advanced type of nodular hyperplasia. HPLC fractionation of sera and gland extracts revealed the overproduction and secretion of a PTH molecule with an intact amino-terminus structure distinct from (1-84) PTH. This form of PTH was readily detectable by third-generation PTH assays but was poorly reactive in second-generation PTH assays. Therefore, parathyroid glands with advanced uremic nodular hyperplasia may overproduce and secrete a novel, biologically active form of PTH with an intact 1-6 region but a presumably modified 12-18 region required for the detection in second-generation PTH assays.

An N-Terminal Molecular Form of Parathyroid Hormone (PTH) Distinct from hPTH(1–84) Is Overproduced in Parathyroid Carcinoma

“…These results extend earlier findings of N-PTH overproduction in patients with severe primary or secondary hyperparathyroidism (2,4,5 ). The high N-PTH concentrations detected in these profoundly hyperparathyroid groups contrasts markedly with the low concentrations typically detected in routine PHPT cases and in healthy control individuals.…”

“…Rarely, N-PTH can be overproduced in patients with severe primary or secondary hyperparathyroidism, where it represents a much larger proportion of the circulating PTH immunoreactivity in the 3rd-generation assay (2,4,5 ). This overproduction is manifested as an increased ratio of the PTH immunoreactivity as measured with the 3rd-generation assay to the immunoreactivity measured with the 2nd-generation assay (2,4,5 ).…”

“…This overproduction is manifested as an increased ratio of the PTH immunoreactivity as measured with the 3rd-generation assay to the immunoreactivity measured with the 2nd-generation assay (2,4,5 ). Usually, this ratio is Ͻ0.8 because 2nd-generation PTH assays detect large non-(1-84) fragments (whereas 3rd-generation assays do not) that represent a much larger proportion of circulating PTH than N-PTH, which the 2nd-generation assay does not detect very well.…”

Whole or Fragmentary Information on Parathyroid Hormone?

“…In contrast, for others, (9,10,13) this ratio stays for whole PTH/iPTH. In the exceptional cases in which the PTH-(1-84) level is paradoxically higher than that of iPTH, it is obvious that one cannot calculate PTH- as the difference between iPTH and PTH-(1-84), because this would yield a negative value.…”

“…Second-generation PTH assays recognize PTH fragments other than only large C-PTH fragments, and third-generation assays also seem to measure PTH moieties other than whole PTH-(1-84) alone. The occurrence of the latter, which is characterized by an abnormally high PTH-(1-84)/iPTH ratio (12), was recently demonstrated by Tanaka et al (10) and Arakawa et al (13) in association with severe secondary hyperparathyroidism and by Rubin et al (9) in association with parathyroid cancer.…”