Claude D. Arnaud

Primary hyperparathyroidism: A prospective clinical study

Abstract The results of the first thirty months of a long-term prospective study of primary hyperparathyroidism are presented. This study was designed to evaluate the course of asymptomatic patients without complications for whom surgical treatment is deferred as well as the effects of successful surgical treatment on the complications of the disease. Included in the last fifteen months of the study was the measurement of serum immunoreactive parathyroid hormone (IPTH). The majority of the patients without symptoms or complications did well without surgical treatment. Operation eventually was required in 13.8 per cent of these patients. There was no trend in serial serum IPTH values in the thirty patients for whom they were available. Removal of the parathyroid lesion does not ensure cure of primary hyperparathyroidism. Four patients had persistent hyperparathyroidism and three had recurrent hyperparathyroidism among the 171 patients with proved hyperparathyroidism. In patients with significant renal impairment prior to parathyroid surgery further renal deterioration may develop after the removal of an adenoma, but so far this has been reversible. The serum calcium was less than 11 mg/100 ml in fifty-one (31 per cent) of the patients with proved hyperparathyroidism. Serum IPTH values correlated positively with serum calcium values and tumor weights, differing from normal in which there is a negative correlation with serum calcium. Serum IPTH values have been most useful in the evaluation of hypercalcemia when the etiology is not clear. Renal lithiasis was present in 51 per cent of the patients with proved hyperparathyroidism but was thought to be metabolically active in only 10.5 per cent. Roentgenographic bone disease, occurring in 24 per cent of patients with proved hyperparathyroidism, appeared to represent a subpopulation with higher serum calcium, alkaline phosphatase and IPTH values as well as larger tumors. Primary hyperparathyroidism may be much more common than previously suspected, occurring frequently in an asymptomatic form without complications and detected by screening technics. As yet, it is not clear which of these patients should have surgical treatment.

Radioimmunoassay of parathyroid hormone in hypercalcemic patients with malignant disease

Abstract Serum immunoreactive parathyroid hormone (iPTH) concentration was determined in 108 unselected hypercalcemic patients with malignant disease utilizing a sensitive radioimmunoassay system that is specific for the COOH-terminal region of the parathyroid hormone (PTH) molecule. In 103 (95.3 per cent) of these patients, serum iPTH concentration was abnormal for the concomitant serum calcium level. In the 48 patients in this series with clinically evident skeletal metastasis or bone marrow involvement, serum iPTH values were similar to those in the other patients. These results do not support a recent suggestion that ectopic production, by malignant tissue, of a non-PTH osteolytic substance is at least as common as ectopic production of PTH in hypercalcemic patients with cancer. Rather, ectopic hyperparathyroidism seems to be present in the overwhelming majority of hypercalcemic patients with cancer even when clinically evident bone metastasis is present. Also, the radioimmunoassay system used in this study was of practical help in differentiating ectopic from primary hyperparathyroidism. On the basis of a lower serum iPTH value for a given serum calcium increase, ectopic hyperparathyroidism could be separated from primary hyperparathyroidism with an overlap of the two groups of 7.7 per cent.

Human parathyroid hormone: Glandular and secreted molecular species

Abstract Purified human parathyroid hormone (hPTH) from urea extracts of parathyroid adenomata (gland-extracted PTH) is immunochemically different from the hPTH in hyperparathyroid serum (serum PTH) and from the hPTH secreted into the medium of cultures of parathyroid adenoma slices (culture medium PTH). However, serum PTH is immunologically indistinguishable from culture medium PTH. Crude urea extracts of parathyroid adenomas are immunologically heterogeneous, and gel filtration studies of medium from scaled-up parathyroid adenoma cultures show that the medium contains at least two and probably three immunologic species of PTH, indicating that it also is immunochemically heterogeneous. The major fraction of culture medium PTH is immunologically similar to serum PTH, with a molecular weight (gel filtration) in the range of 5,000 to 7,000 and an amino acid composition similar to Rasmussens bovine parathyroid hormone B. The other immunologic species in culture medium have molecular weights in the ranges of 9,000 and 14,000 and are immunologically distinct but more closely resemble gland-extracted hormone. These observations have important bearing on the possible existence of a glandular precursor to secreted PTH and on the great difficulties which have been experienced in the development of useful radioimmunoassays for human parathyroid hormone in serum.

Control of secondary hyperparathyroidism during long-term hemodialysis

Abstract The hyperparathyroidism which occurs during long-term hemodialysis of patients with chronic renal failure has been successfully controlled without the need for subtotal parathyroidectomy. Utilizing a highly sensitive radioimmunoassay for plasma parathyroid hormone (iPTH), it was found that iPTH was correlated negatively with dialysate calcium concentration and positively with plasma phosphate concentration. Manipulation of these factors separately demonstrated that iPTH could be significantly decreased in two to three weeks by simultaneously decreasing plasma phosphate and increasing dialysate calcium. On the basis of calcium flux studies across the dialyzer, it was determined that the optimal calcium concentration in the dialysate was 8 mg/100 ml. Ten patients were treated by initially decreasing their plasma phosphate to less than 6 mg/100 ml (by giving them oral aluminum hydroxide) and using dialysis against a calcium concentration of 8 mg/100 ml. All patients have manifested a substantial and progressive decrease in plasma iPTH toward normal, with alleviation of bone pain and absence of complications, during use of this regimen.

Dynamics of parathyroid hormone secretion in vitro

Abstract The dynamics of parathyroid hormone (PTH) secretion from slices of normal porcine parathyroid tissue have been studied in a continuous flow superfusion system. The rates of secretion have been shown to be rapidly altered by changes in the calcium and magnesium concentrations in the superfusing medium. The change in rates reflects the inverse relationship between these cations and PTH secretion previously demonstrated in vivo and in vitro. The increased secretion of PTH in response to a low calcium concentration appears to occur in two phases. The initial increase was not inhibited by puromycin but could not be sustained in the presence of this inhibitor of protein synthesis. The superfused tissue underwent extensive ultrastructural alterations, in response to a stimulatory or inhibitory calcium concentration in the medium, in as little as two and a half hours. Changes in ultrastructure were correlated with changes in secretory rates. Acute inhibition after a period of stimulation led to an accumulation of secretory granules in the cells, suggesting that the inhibition of secretion preceded the inhibition of synthesis of the hormone. Calcitonin was found to stimulate PTH secretion during short-term experiments with normal or high calcium concentrations in the superfusing medium.

Prevention and reversal of progressive secondary hyperparathyroidism in patients maintained by hemodialysis

Abstract In a group of patients maintained by hemodialysis, serum calcium and phosphorus values were not restored completely to normal, but there was a progressive decrease in serum parathyroid hormone (PTH) concentration and prevention or reversal of roentgenographic evidence of subperiosteal bone resorption. Although bone biopsies did not show a return of bone to normal, it was clear that the decrease in bone resorption was a direct function of decreased secretion of PTH. None of the patients required parathyroidectomy; in three of the nine patients who died the parathyroids were normal at autopsy. Although some patients showed minor evidence of metastatic calcification, only two showed a slight increase in vascular calcification, and none of the autopsies revealed calcification of vital organs.

Recent studies on the chemistry of human, bovine and porcine parathyroid hormones

Abstract The amino acid sequence of the NH 2 -terminal 34 residues of human parathyroid hormone (PTH) has been determined and duplicated synthetically to produce a peptide that is biologically active. In the amino acid sequences of the bovine and porcine hormones, the glutamic acid function at position 22 has been revised to glutamine. Among these initial 34 residues, human PTH differs from bovine PTH by 5 residues and from porcine PTH by 4 residues. Native human PTH and the synthetic human PTH (1–34) peptide are not rigid structures, and significant changes in conformation were observed during pH titration. In addition, at physiologic pH, native human PTH appeared to differ in structure from human PTH (1–34) in the region of the tryptophan residue (residue 23). The fluorescence spectrum of human PTH revealed a maximum at 344 nm, but the spectrum of human PTH (1–34) had a peak at 343 nm; the spectrum of human PTH (1–34) was normalized to 346 nm in 6 M guanidine hydrochloride, but there was no shift with the intact hormone. Fluorescence titration of human PTH in the alkaline region revealed no loss of tryptophanyl fluorescence in aqueous solution or in 6 M guanidine hydrochloride. The synthetic human PTH (1–34) peptide, however, showed an approximately 25 per cent loss of indole fluorescence during alkaline titration which could be normalized with denaturing reagents. These studies suggest that synthetic fragments of the native hormone may not have the same tertiary conformation as the same sequence in the intact hormone. These findings may be of major significance with regard to the biologic activity and immunologic cross reactivity of synthetic fragments and the native hormone.

Osteomalacia and celiac disease: Response to 25-hydroxyvitamin D

In this 54 year old woman with celiac disease, osteomalacia developed while she was on a gluten-free diet which had caused regression of her steatorrhea. She was not responsive to large doses of parenterally administered dihydrotachysterol and calcium, but she was responsive to the oral administration of 25-hydroxyvitamin D3 (25-OHD3). The data suggest that 25-OHD3 is the treatment of choice for patients with vitamin D deficiency due to intestinal malabsorption.