Abnormal Parathyroid Tissue Research Articles

Concomitant graves' disease and primary hyperparathyroidism. Influence of hyperthyroidism on serum calcium and parathyroid hormone

Two patients with coexistent Graves' disease and primary hyperparathyroidism were studied during medical treatment of their hyperthyroidism. Serum free calcium level was initially quite elevated (1.61 and 1.71 mM, normal 1.12 to 1.28 mM), but immunoreactive parathyroid hormone values were only slightly increased. The immunoreactive parathyroid hormone values of 153 and 173 nleq/ml (normal less than 150 nleq/ml) were far lower than expected in hyperparathyroid patients with a similar degree of hypercalcemia. As the patients became euthyroid during thionamide treatment, calcium values decreased to 1.39 and 1.61 mM, respectively, and parathyroid hormone increased to values clearly suggestive of hyperparathyroidism (454 and 229 nleq/ml, respectively). Parathyroidectomy and subtotal thyroidectomy cured both the hyperparathyroidism and the thyrotoxicosis in each case. These observations suggest that thyroid hormone had potentiated the osteoclastic effects of parathyroid hormone and that the resulting exacerbation of hypercalcemia had produced a relative suppression of hormone secretion by the abnormal parathyroid tissue.

Pancreatic Islet Cell Carcinoma With Hypercalcemia. Primary Hyperparathyroidism or Humoral Hypercalcemia of Malignancy

Abstract A 60-year-old woman presented with hypercalcemla and was found to have metastatic pancreatic Islet cell carcinoma. Although clinical features were very suggestive of hyperparathyroldism, her parathyroid hormone levels were not elevated and no abnormal parathyroid tissue was detected by thallium-technetium or computed tomographic scanning techniques. Her hypercalcemia appeared to be due to a humoral factor-distinct from parathyrold hormone-that mimics the action of parathyroid hormone almost exactly. The various tools that may be used to differentiate primary hyperparathyroldism from the humoral hypercalcemia of malignancy are reviewed.

Dual Isotope Subtraction Parathyroid Scintigraphy in the Preoperative Evaluation of Suspected Hyperparathyroidism

Ninety-five percent of primary hyperparathyroidism is caused by either a solitary hyperfunctioning adenoma or chief cell hyperplasia. While there is a great deal of variation in the location of the parathyroid glands, 90-95% of all abnormal parathyroid tissue will be identified at initial exploration regardless of the preoperative localization procedure. Adenomas not identified at initial exploration are likely to be ectopic. Reexploration is a difficult and time-consuming procedure. The challenge, therefore, is to develop a reliable, noninvasive test that will locate aberrant parathyroid tissue preoperatively with the goal of simplifying the surgical procedure and reducing the incidence of reexploration. A radiopharmaceutical which localizes selectively in parathyroid tissue would be ideal. Currently, no single radiopharmaceutical is adequate. Recently, dual isotope subtraction scintigraphy using T1-201 chloride and Tc-99m pertechnetate has yielded promising results. The authors have investigated this procedure in 42 patients, 25 of whom to date have had surgical exploration. Of the 25 adenomas or focal hyperplasia sites found at surgery, 23 (92%) were correctly located preoperatively. There were two false-negative sites and five false-positive sites. The purpose of this paper is not only to describe the methods used and results obtained but also to discuss the merits and limitations of the technique in comparison with other imaging modalities so that its role, in today's climate of cost containment, may better be defined.

Parathyroid adenomas and hyperplasia. Dual radionuclide scintigraphy and bone densitometry studies.

Dual radionuclide imaging of the neck (Tc-99m pertechnetate and TI-201 thallous chloride) was performed in 22 patients with chemical evidence of hyperparathyroidism (elevated blood calcium and parathormone [PTH] levels). Of these, 19 of 22 had localization of a TI-201 "excess" area on radiothallium-radiotechnetium subtraction images. In 13 patients who have had operative confirmation at this writing, the dual radionuclide imaging was positive in 12 (12/13 = 92.3%). One patient had two parathyroid adenomas, both of which were seen on the images; thus, overall detection was 13 out of 14 or 92.8%. The parathyroid adenomas visualized weighed from 0.06 to 3.0 g; the one not detected weighed 0.25 g. In three patients with parathyroid hyperplasia secondary to renal disease, the subtraction imaging detected eight of 12 glands (66.7%). The forearm bone mineral content and bone density were determined in eight patients with parathyroid adenomas; results were abnormally low in five of these eight. One of the three patients with secondary hyperparathyroidism had an abnormally low radial bone mass. The combination of dual radionuclide imaging and radial bone mass determination may present a useful approach in both localizing abnormal parathyroid tissue and in examining its functional consequences.

Pancreatic islet cell carcinoma with hypercalcemia. Primary hyperparathyroidism or humoral hypercalcemia of malignancy

A 60-year-old woman presented with hypercalcemla and was found to have metastatic pancreatic Islet cell carcinoma. Although clinical features were very suggestive of hyperparathyroldism, her parathyroid hormone levels were not elevated and no abnormal parathyroid tissue was detected by thallium-technetium or computed tomographic scanning techniques. Her hypercalcemia appeared to be due to a humoral factor-distinct from parathyrold hormone-that mimics the action of parathyroid hormone almost exactly. The various tools that may be used to differentiate primary hyperparathyroldism from the humoral hypercalcemia of malignancy are reviewed.

Assessment of thallium-pertechnetate subtraction scintigraphy in hyperparathyroidism.

Reliable techniques for detecting and localising abnormal parathyroid tissue have been a persistent problem. We have evaluated thallium-pertechnetate subtraction scintigraphy in a prospective study of 40 patients with clinical and biochemical evidence of hyperparathyroidism prior to parathyroid surgery. Four patients were excluded as they were shown to have goitre, making subtraction scanning non-diagnostic. 89% of parathyroid adenomas (totalling 27 glands in 26 patients) and 41% of hyperplastic glands (17 glands in 6 patients) were accurately localised prior to surgery. These included three retrosternal glands, four patients with renal failure and tertiary hyperparathyroidism and five patients who had previously undergone neck exploration. The apparent discrepancy between detecting hyperplastic and adenomatous glands was associated with the smaller size of the former. For both types of gland, scintigraphy successfully located parathyroids 0.6 g or more in weight. These results suggest that this simple and non-invasive method is a useful technique for locating parathyroid tissue before parathyroid surgery.

Parathyroid venous sampling and ultrasonography in primary hyperparathyroidism due to multigland disease.

The results of pre-operative venous sampling and ultrasonography in 20 patients with primary hyperparathyroidism, who were shown histologically to have multigland disease, were reviewed. Ultrasonography (15 patients) demonstrated abnormal parathyroid tissue in 46% (seven patients), but correctly predicted only 33% of the involvement or non-involvement of individual glands. The main deficiency was the high number of false negatives. Parathyroid venous sampling (19 patients) showed elevated levels of parathyroid hormone in 18 (94.7%), but overall the sites of normal and abnormal glands were predicted in 56 of 76 sites (73.6%). The investigation was misleading in one patient (5.2%), in that no abnormal glands were predicted. The sampling maps of the above 19 patients were randomly mixed with those of 100 consecutive patients, whose disease was due to a single adenoma. All but one of the multigland disease cases were identified correctly but six of the single adenoma patients were predicted as having two glands involved, and were therefore thought to be multigland. The usefulness of, and difficulties in, diagnosing multigland disease in primary hyperparathyroidism are discussed.

Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue.

We employed a computer program to curve-fit data relating PTH release in vitro to the extracellular calcium concentration in parathyroid cells prepared from normal bovine and human as well as pathological human parathyroid tissue. In bovine cells and 82% of human cell preparations in which PTH release was more than 50% suppressible by high calcium concentrations, the data were successfully fitted to symmetrical sigmoidal curves. Such curves were defined by four parameters [A = maximum PTH release, B = slope of the curve at the setpoint, C = set-point (calcium concentration causing half-maximal inhibition of secretion), and D = minimum PTH release]. There was excellent agreement between the predicted values for these parameters and those we have obtained previously using visual fits. We also generated theoretical curves with the program to assess the possible contribution of changes in parameters A through D to hypersecretion of PTH in hyperparathyroidism. These analyses suggested that changes in maximal PTH secretion, slope of the curve, set-point, and maximal suppressibility of PTH release all might contribute to hormonal hypersecretion. On a quantitative basis, however, changes in the set-point produced the largest alteration in secretory rate for a given change in the value of a parameter. These results provide a mathematical model for the relationship between PTH release and the extracellular calcium concentration. Moreover, they provide a means of analyzing theoretically the contribution of various qualitative changes in this relationship to states of hypo- and hypersecretion of PTH.

Reoperative surgery for hyperparathyroidism

The difficulties created by an unsuccessful initial operation can usually be avoided by choosing experienced surgeons, identifying four glands, and selectively excising grossly abnormal parathyroid tissue. Patients with multiple endocrine adenomatosis or familial hyperparathyroidism should have a subtotal parathyroidectomy. Reoperative surgery is difficult and although it is successful in approximately 70 to 80 percent of patients, it is associated with a significant morbidity which includes persistent hypercalcemia, hypoparathyroidism, and nerve injury. Reoperative parathyroid surgery should be done in specialized centers where the sophisticated methods of preoperative localization and surgeons experienced in this field are available.

A Lack of Unique Pathophysiologic Background for Nephrolithiasis of Primary Hyperparathyroidism

The metabolic picture of 32 patients with surgically proven primary hyperparathyroidism presenting with renal stones was compared with that of 37 patients without stones. Between stone-forming and nonstone-forming groups, there was no significant difference in serum 1,25-dihydroxyvitamin D [6.82 ± 2.62 vs. 6.22 ± 2.33 ng/dl (mean ± SD); P > 0.05], fractional (intestinal) calcium absorption (0.726 ± 0.141 vs. 0.690 ± 0.120), urinary clacium (299 ± 139 vs. 284 ± 144 mg/day), serum calcium, phosphorus, and parathyroid hormone, or bone density. Similarly, no differences were found between 29 patients presenting with stones alone and 9 presenting with bone disease alone with respect to the above measures. Moreover, urinary environment was typically supersaturated with respect to stoneforming salts regardless of the presence of stones. The results indicate that there is no unique pathophysiological background for the nephrolithiasis of primary hyperparathyroidism. (J Clin Endocrinol Metab 53: 536,1981) C nephrolithiasis is a frequent complication of primary hyperparathyroidism (1, 2). It is generally recognized that the formation of renal stones is pathogenetically related to the hyperparathyroid state and is not a coincidental occurrence. The most convincing evidence for the existence of this etiological relationship is provided by the favorable response to parathyroid surgery. After successful parathyroidectomy, the new stone formation often ceases, unless there has been a complication by a chronic urinary tract infection. The exact cause of the formation of renal stones in primary hyperparathyroidism has not been elucidated. It has been suggested that the biochemical and clinical picture of patients with primary hyperparathyroidism presenting with nephrolithiasis may be unique from that of patients without stones. Patients with stones were believed to have a longer duration of the disease process, a less severe hypercalcemia, and a smaller size of abnormal parathyroid tissue than patients who present with reduced bone density (3, 4). Hypercalciuria is frequently encountered in stone-forming patients with primary hyperparathyroidism (4,5). This disturbance has often been implicated as one of the causes of renal stone formation, since it is a frequent metabolic derangement associated Received February 9, 1981. Address requests for reprints to: Dr. Charles Y. C. Pak, Department of Internal Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235. * This work was supported by USPHS Grants P50-AM20543, R01AM16061, and M01-RR-00633. with calcium nephrolithiasis (6). The hypercalciuria could have resulted from an excessive parathyroid hormone (PTH)-dependent bone resorption and/or an enhanced intestinal absorption of calcium ensuing from the PTH-dependent synthesis of 1,25-dihydroxyvitamin D [1,25-(OH)2D] (7, 8). There is some evidence that the hypercalciuria of intestinal origin may be more critical in the formation of renal stones (9). Thus, an apparent predilection for nephrolithiasis has been reported in the group of patients with primary hyperparathyroidism who possess a high circulating concentration of 1,25-(OH^D (9) and an increased intestinal absorption of calcium (9, 10). The current study was undertaken to determine if the stone-forming patients with primary hyperparathyroidism could be distinguished from their nonstone-forming counterpart on the basis of metabolic and biochemical presentations. It will be shown that the two groups of patients cannot be readily separated from the above criteria. Materials and Methods Sixty-nine patients with primary hyperparathyroidism participated in the study after informed written consent was obtained. These patients represented all of the patients with surgically proven primary hyperparathyroidism who were evaluated by us during the past 7 yr. Before surgery, they underwent an in-patient diagnostic evaluation according to the protocol previously described (5,8). The evaluation permitted an assessment not only of parathyroid function and vitamin D status,

The medical management of primary hyperparathyroidism.

Primary hyperparathyroidism has become a relatively common endocrine disorder. Greater recognition of this disease has led to earlier detection. Consequently, primary hyperparathyroidism is now characterized frequently by asymptomatic mild hypercalcemia rather than by the more classical presentation with bone or renal involvement. Patients who have hypercalcemia and signs or symptoms should undergo neck surgery and removal of the abnormal parathyroid tissue. For the growing population of asymptomatic patients, however, indications for surgery are not as clear. The natural history of primary hyperparathyroidism is variable, and predicting who will develop complications of this disorder is not possible. Alternatives to surgery are careful and regular observation combined with various general and specific approaches currently receiving attention. Available information on the medical management of asymptomatic, mild primary hyperparathyroidism is summarized.

Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma

The regulation of parathyroid hormone (PTH) secretion by calcium was studied in normal and abnormal parathyroid tissue from five patients with a parathyroid adenoma. Dispersed cells were prepared from the adenoma and from a portion of a normal parathyroid gland and were incubated for two hours with varying concentrations of calcium. PTH release as a function of the concentration of calcium was determined by radioimmunoassay (C-terminal). Cells from the normal glands showed a lower set-point for calcium (the concentration of calcium causing half of the maximal inhibition of PTH release) than those from the adenomas in four of five cases. Moreover, both set-point and maximal PTH release at low concentrations of calcium were significantly lower in normal glands from patients with an adenoma than in normal glands from patients with normal calcium homeostasis (0.77 ± 0.04 [SEM] versus 0.99 ± 0.03 mM calcium and 3.4 ± 0.43 versus 10.1 ± 0.78 ng/10 5 cells/hr, respectively). These observations may explain, in part, the transient hypocalcemia frequently seen in patients after removal of a parathyroid adenoma. In addition, they suggest that the set-point for calcium and maximal PTH release in normal parathyroid tissue may be altered by prior exposure to chronic hypercalcemia or other physiologic variables. Finally, the “normal” set-point that we have noted previously in parathyroid tissue from some patients with primary parathyroid hyperplasia may be inappropriately high for the hypercalcemia seen in those cases.

Management of Acute Hyperparathyroidism in a Community Hospital

Primary hyperparathyroidism is a common entity that routinely lends itself to prompt surgical cure. Infrequently, multiple surgical explorations are required to effect a cure. A case is reported of a 27-year-old man with hypercalcemia and nephrocalcinosis. The initial surgical exploration failed to identify the abnormal parathyroid tissue. Hypercalcemia necessitated rigorous antihypercalcemic therapy; three subsequent operations, including a mediastinal exploration, were unsuccessful. On the fifth exploration, which took barely an hour, a 35-g adenoma was removed from the left superior posterior mediastinum. This report illustrates that a detailed knowledge of the possible locations of aberrant parathyroid tissue and the skills of the operating surgeon are the sine qua non for those patients requiring one or more parathyroid reexplorations. (<i>JAMA</i>1981;246:1334-1336)

Parathyroid hormone secretion: effect of beta-adrenergic blockade before and after surgery for primary hyperparathyroidism.

Serum immunoreactive parathyroid hormone (iPTH) response to beta-adrenergic blockade by propranolol infusion was determined in 11 normal subjects and 6 patients with primary hyperparathyroidism (PHPT) before and again after the surgical removal of abnormal parathyroid tissue. Propranolol infusion in PHPT patients before surgery resulted in no significant decrease in serum iPTH except at 2 h, when the mean value was 83 +/- 4.4% of baseline. After surgery and achieving a euparathyroid state, the same patients showed a significant propranolol-induced decrease in serum iPTH from baseline at all time periods tested, reaching the nadir value of 57 +/- 7.5% of baseline at 2 h after the start of the propranolol infusion. This response in PHPT patients after surgery was very similar to the response seen in normal subjects. Therefore, this impaired suppressibility of serum iPTH in PHPT is corrected after removal of the abnormal parathyroid tissue. The studies indicate that abnormal parathyroid tissue (either per se or via a metabolic state induced by it) is responsible for the impaired response to beta-adrenergic blockade. It therefore appears unlikely that the impaired beta-adrenergic responsiveness is involved in the pathogenesis of PHPT.

Persistent and recurrent hyperparathyroidism

Twenty-six patients with persistent or recurrent primary hyperparathyroidism after an initial cervical exploration are presented. Failure of the first operation was related in part to an ectopic location of the abnormal parathyroid tissue (in 58 percent), and to a discrepancy in the histologic diagnosis between the frozen-section analysis at the time of operation and the final pathologic interpretation (in 55 percent). Before secondary operation, selective venous sampling for parathormone levels and arteriography were accurate in localizing the lesion in 88 and 71 percent of cases, respectively. A plan for intraoperative management of these difficult problems is suggested.

Parathyroid imaging after intraarterial injections of [75Se]selenomethionine.

Thirteen patients with persistent hyperparathyroidism after unsuccessful neck surgery were given up to 250 microCi [75Se]selenomethionine intraarterially during parathyroid arteriography, gamma-Camera images of the neck and mediastinum localized abnormal parathyroids in four of five patients receiving complete injections, despite very small glands or unsuccessful arteriograms in some of the patients. Correctly localizing images were obtained in three patients receiving incomplete injections. However, images in five of eight of the remaining patients receiving incomplete injections showed areas of false positive uptake, and there was no way preoperatively to distinguish these from the true positive studies. We conclude that intraarterial injection of radioselenomethionine is a simple supplementary procedure in patients undergoing arteriography that may, with proper technique, be useful in identifying small foci of abnormal parathyroid tissue.

Direct ComparisonIn VivoandIn Vitroof Suppressibility of Parathyroid Function by Calcium in Primary Hyperparathyroidism*

ABSTRACT The effects of increased ambient calcium concentration on parathyroid function in vivo and in vitro were assessed in each of 12 patients with primary hyperparathyroidism. Calcium injection and/or infusion were carried out preoperatively and parathyroid suppressibility was tested by the effect of calcium on nephrogenous cAMP (NcAMP). Dispersed parathyroid cells were then prepared after surgical excision of abnormal parathyroid tissue. Immunoreactive parathyroid hormone (iPTH) release was determined by RIA after incubation for 2 h at calcium concentrations ranging from 0.3-3.0 mM. Of nine patients with adenoma, iPTH release from dispersed parathyroid cells was inhibited less than 50% in 3 (26-40%); in these patients, NcAMP was suppressed 20% or less. In the remaining six patients, iPTH release in vitro and NcAMP release in vivo were inhibited 62-90% and 34-75%, respectively, by elevated calcium concentrations. In three patients with primary parathyroid hyperplasia, iPTH release was inhibited 75-81%...

Urinary cAMP Excretion during Surgery: An Index of Successful Parathyroidectomy in Patients with Primary Hyperparathyroidism*

Urinary phosphate (Up) and urinary cAMP (UcAMP) excretion were determine in patients undergoing neck exploration for primary hyperparathyroidism in order to evaluate these parameters as indices of successful surgery. UcAMP fell below 1.5 micro mol/g creatinine in all 12 patients in whom single gland removal corrected hypercalcemia and in 0 of 3 patients in whom no parathyroid tissue was found. The mean time to drop below 1.5 was 2.0 +/- 0.8 h (mean /+- SD) from the time of parathyroidectomy. UcAMP fell below 1.5 in only 1 of 6 patients who had multiple enlarged parathyroid glands removed, irrespective of the outcome of surgery. Changes in Up excretion lagged behind UcAMP changes, so that within the time period studied Up fell to varying degrees in only 10 of 15 patients in whom hypercalcemia was corrected. A spurt in UcAMP excretion, possibly reflecting parathyroid hormone release due to manipulation of a parathyroid gland, occurred in 3 patients. The results suggest that an intraoperative fall in UcAMP below 1.5 predicts successful parathyroidectomy and that an intraoperative spurt in UcAMP may provide a clue to the location of abnormal parathyroid tissue.

TWENTY YEARS' EXPERIENCE WITH PARATHYROID EXPLORATION

Eighty-four patients have undergone surgical exploration following a clinical diagnosis of hyperpathyroidism over a 20-year period. Urinary tract calculi were the major indication for exploration, and 90% of these patients had recurrent calculi. Osteitis fibrosa was a rare presentation of hyperparathyroidism. Lethargy, sometimes profound, was an important symptom, in some instances the dominant feature. Persistent hypercalcaemia remains the chief diagnostic investigation, with helpful confirmation from estimation of the parathyroid hormone level. Little attempt was made in this series to utilize preoperative localization techniques, reliance being placed on meticulous bloodless surgery to find normal and abnormal parathyroid tissue. Eighty-five explorations were carried out in the 84 patients. Seventy-four of the explorations were successful, converting the patient to a normocalcaemic state. Of these, 63 had a single adenoma (86%).

Parathyroid identification by methylene blue infusion.

A preoperative infusion of methylene blue was employed in 20 patients undergoing neck exploration for hyperparathyroidism. The dye was noted to stain adenomas and hyperplastic glands a deep purple-blue colour. Normal parathyroid tissue stained to a lesser extent or not at all. All unstained parathyroid tissue was normal histologically. Methylene blue infusion is a safe method of more rapidly identifying parathyroid tissue. Its preferential staining of abnormal parathyroid tissue can assist the surgeon in deciding the extent of his parathyroid excision.