The metabolism and radioimmunoassay of parathyroid hormone

Abstract

Parathyroid hormone (PTH), a single-chain polypeptide of 84 amino acids, plays a critical role in the regulation of mineral metabolism. An assessment of the activity of the parathyroid glands is frequently required in clinical medicine. Assay of PTH in serum is complicated by the fact that circulating PTH is immunoheterogeneous. Thus, circulating immunoreactive PTH consists of a mixture of intact hormone and smaller molecular weight hormone fragments. These hormone fragments arise as a consequence of direct secretion from the parathyroid glands and also from peripheral metabolism of PTH. The principle organs involved in the metabolism of PTH are the liver and the kidney. The liver metabolizes the intact PTH by proteolysis in an endosomal compartment of Kupffer cells and returns small molecular weight fragments to the circulation. Metabolism of PTH by the kidney involves uptake of biologically active PTH molecules at peritubular sites and glomerular filtration of both active and inactive forms of PTH. Intact PTH and biologically active amino-terminal PTH fragments have extremely short half-lives in serum, while the biologically inactive PTH fragments from the mid-region and C-terminal portion of PTH molecule, which depend upon glomerular filtration for clearance, have prolonged half-lives. Radioimmunoassays for PTH in blood may yield widely differing results depending on the portion of the PTH molecule at which the particular antiserum is directed. Accordingly, for the understanding and interpretation of PTH assay results, it is necessary to have an understanding of the characteritics of any given PTH assay. PTH assays may be categorized into (a) amino-terminal (N-terminal) assays which recognize intact PTH as well as immunoterminal PTH fragments; (b) assays directed towards the C-terminal or midregion of PTH which recognize intact PTH and any hormone fragments containing these regions of the PTH molecule. Recently assays have been developed which recognize two regions of PTH simultaneously and using this immunoradiometric (IRMA) technique intact PTH can be measured. Results of assays for amino-terminal PTH or the intact PTH molecule have the advantage of having a similar “normal range” regardless of renal function. These assays have the disadvantages of the ability of N-terminal or intact PTH in serum and of showing a transient or pulsatile changes in PTH levels, depending upon the conditions under which the samples were obtained and assayed. C-terminal or mid region assays have the advantage of rapid assay times, lack of effect of acute variations in PTH secretion, have extensive correlations with bone histology and may reflect an integrated index of PTH secretion. Because of the role of the kidney in the clearance of these fragments, extremely high values may be obtained in patients with severe hyperparathyroidism in renal failure. Thus, a different “normal range” is required for patients with advanced renal failure. However, with the use of a particular assay such experience is rapidly obtained. Thus, these types of assays have proven to be extremely valuable in that assessment of disorders of mineral metabolism. Thus, knowledge of the metabolism of PTH and the characteristics of PTH assays, a reliable assessment of the activity of parathyroid gland can be obtained in diverse clinical circumstances.