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PubMed1992

A comparison of the effects of concanavalin-A and tetradecanoylphorbol acetate on the modulation of parathyroid function by extracellular calcium and neomycin in dispersed bovine parathyroid cells.

Ca2+ and other polyvalent cations as well as polycations, such as neomycin, produce similar effects on intracellular second messengers and PTH release in dispersed bovine parathyroid cells, but it is unclear whether all of these agents share the same mechanism of action. The lectin Concanavalin-A (Con-A) and the activator of protein kinase-C tetradecanoylphorbol acetate (TPA) blunt the effects of elevated extracellular calcium (Ca2+) concentrations on several aspects of parathyroid function, including PTH release, the cytosolic calcium concentration, and the accumulation of cAMP and inositol phosphates. In the present studies we used these two agents as well as pertussis toxin as probes to investigate further whether neomycin acts on parathyroid cells through the same receptor-like mechanism used by extracellular Ca2+ to regulate parathyroid function. Con-A and TPA both enhanced PTH release by about 2-fold at 0.5-1 x 10(-4) M neomycin, concentrations that inhibited PTH release to an extent (40-50%) similar to that seen with high (1.5-2 mM) Ca2+. Con-A also reduced the inhibition of agonist-stimulated cAMP accumulation by the same concentrations of neomycin. Conversely, Con-A and TPA produced 70-80% decreases in the cytosolic calcium concentration transient and the accumulation of inositol phosphates stimulated by neomycin. The effects of these two agents on neomycin-regulated parathyroid function were similar in magnitude to their actions on the modulation of these same parameters by extracellular Ca2+. Pertussis toxin, however, which we have previously shown to block the inhibitory effects of high Ca2+ and neomycin on cAMP accumulation, had no effect on the inhibition of PTH release by these two agents. These results provide further indirect evidence that polyvalent cations and polycations act on the parathyroid cell through related pathways, which probably involve cell surface moieties containing carbohydrate(s).

Animals↗
PubMed1995

Calcium-activated proteases in the bovine parathyroid gland: potential role in degradation of parathyroid hormone to peptide fragments.

Our studies suggest that protein kinase C is involved in low calcium (Ca2+)-stimulated secretion of parathyroid hormone (PTH) but not directly in high Ca(2+)-stimulated intracellular degradation of PTH to secreted carboxyl-terminal fragments (C-PTH), an important component of Ca(2+)-regulated PTH secretion. The present study was undertaken to determine the presence of calcium-activated proteases, 84 kDa (micro)-calpain and 80 kDa (milli)-calpain, in the bovine parathyroid, and whether they could degrade PTH to C-terminal fragments. Immunocytochemistry of bovine parathyroid tissue using antibodies raised against bovine heart micro- and milli-calpain detected both isoforms of calpain. Western blotting of total bovine parathyroid cell protein prepared from primary cell cultures confirmed the presence of both isoforms of calpain, demonstrated by specific milli- and micro-calpain bands. Purified bovine PTH (bPTH) was incubated in vitro with human erythrocyte micro-calpain and the cleavage products were separated by reverse-phase HPLC. Eluant fractions were assayed with an RIA with equimolar sensitivity to C-PTH and bPTH, and peak areas integrated. Micro-calpain produced a C-PTH peak from bPTH which co-eluted with the major C-PTH secreted by parathyroid cells in culture. C-PTH production by micro-calpain, expressed as per cent area under the curve, increased from 0% in the absence of either micro-calpain or Ca2+, to 71.5% when a 5:1 molar ratio of bPTH to calpain was used. Amino acid sequencing and analysis of the immunoreactive PTH cleavage products indicated the presence of two fragments of bPTH in the C-PTH peak, bPTH47-48 and bPTH69-84. In summary, both isoforms of calpain are present in the bovine parathyroid and calpains may play a role in the Ca(2+)-dependent degradation of PTH to secreted C-terminal fragments.

Amino Acid Sequence↗
PubMed2005

Calcium-sensing receptor expression and parathyroid hormone secretion in hyperplastic parathyroid glands from humans.

In uremic patients, severe parathyroid hyperplasia is associated with reduced parathyroid calcium-sensing receptor (CaR) expression. Thus, in these patients, a high serum Ca concentration may be required to inhibit parathyroid hormone (PTH) secretion. This study compares the magnitude of reduction in CaR expression and the degree of the abnormality in Ca-regulated PTH release in vitro. A total of 50 glands from 23 hemodialysis patients with refractory hyperparathyroidism were studied. Tissue slices were incubated in vitro to evaluate (1) the PTH secretory output in a normal Ca concentration (1.25 mM) and (2) the PTH secretory response to high (1.5 mM) and low (0.6 mM) Ca concentration. Tissue aliquots were processed for determination of CaRmRNA expression. The results showed that, corrected for DNA, parathyroid tissue with lowest CaR expression secreted more PTH than that with relatively high CaR expression (146 +/- 23 versus 60 +/- 2 pg/microg DNA; P < 0.01). Furthermore, glands with low CaR expression demonstrated a blunted PTH secretory response to both the inhibitory effect of high Ca and the stimulatory effect of low Ca. The study also showed that the larger the gland, the lower the CaRmRNA expression. Thus, large parathyroid glands produce a large amount of PTH not only as a result of the increased gland size but also because the parathyroid tissue secretory output is increased. These abnormalities in PTH regulation are related to low CaR expression.

Female↗
PubMedDate not supplied

Surgical approaches to solitary parathyroid adenoma: state of the art. Our early experience with intraoperative parathyroid hormone measurement.

We report our early experience with focused radioguided parathyroidectomy with intraoperative parathyroid hormone measurement in patients affected by primary hyperparathyroidism. Over a period of 2 months we performed 4 consecutive focused parathyroidectomies with intraoperative parathyroid hormone measurement, 3 of which radioguided. All patients had a preoperative localization of single gland disease by sestamibi scanning and/or ultrasound. Blood samples for parathyroid hormone measurement were taken at baseline (induction of anaesthesia), 10 minutes after adenoma excision and the day after surgery. Three of the 4 patients were discharged within 24 hours. In all cases a solitary adenoma was successfully identified and removed. As predicted by the appropriate fall in intraoperative parathyroid hormone levels, all patients were considered cured on the basis of normal levels of calcium and parathyroid hormone at 1-month follow-up. Targeted parathyroidectomy can be successfully performed in patients with preoperatively localized solitary adenoma. The appropriate decrease in intraoperative parathyroid hormone levels assures a curative operation. The use of radioguidance should be recommended when difficulties with gland identification are foreseen.

Adenoma↗
PubMed1992

Intraoperative parathyroid hormone estimation: a valuable adjunct to parathyroid surgery.

Serial measurements of serum intact parathyroid hormone (PTH) and adjusted total calcium levels were performed on 10 patients during unilateral neck exploration for a solitary parathyroid adenoma localised preoperatively by ultrasound scan. Frozen section was performed peroperatively to establish the presence of parathyroid tissue. Levels of PTH were shown to be within the normal range within 15 min of adenoma removal (a mean of 13.4% of their preoperative values), allowing clear early distinction from unsuccessful surgery where no change occurred. Frozen section wrongly identified thyroid tissue as parathyroid in one case leading to a failure of the initial neck exploration. Our findings show that intraoperative PTH measurements can accurately predict whether all hyperfunctioning parathyroid tissue has been removed. This is not always possible using frozen section techniques. The wider use of intraoperative PTH measurement, particularly in difficult cases, may avoid the need for prolonged explorations to identify all four glands and, perhaps, biopsy of normal glands, replacing the current standard use of frozen section as a more reliable indicator of the success of parathyroid surgery.

Adenoma↗
PubMed1981

Hyperfunctioning intrathyroid parathyroid gland: a potential cause of failure in parathyroid surgery.

Four patients with hyperfunctioning intrathyroid parathyroid are reported. In each case the intrathyroid parathyroid was embedded within the thyroid parenchyma and appeared as a solitary 'cold' thyroid nodule by radioactive iodine scanning. It is believed that the intrathyroid parathyroid evolves as the lateral lobe of the thyroid fuses with the isthmus in the early development of the thyroid. Embryologically, and intrathyroid parathyroid is thus likely to be the superior gland. When the superior parathyroid gland is missing at the time of exploration, a nodule within the ipsilateral lobe of the thyroid may well be an intrathyroid parathyroid. Under these conditions, lobectomy for the exclusion of such a gland is mandatory.

Adenoma↗
PubMed2003

Immunogenicity of parathyroid allografts in the rat: immunosuppressive dosages effective in passenger leukocyte-rich small bowel transplants are not effective in parathyroid gland transplants with few passenger leukocytes.

BACKGROUND AND AIMS: The passenger leukocytes harboured within an allograft induce a massive allo-immune response that leads to allograft rejection if not countered by immunosuppression. We compared the response to short-term immunosuppression of parathyroid gland transplants possessing few passenger leukocytes with that of passenger leukocyte-rich small bowel transplants. METHODS: Heterotopic parathyroid and orthotopic small bowel transplantation was performed in a Wistar Furth-to-Lewis rat strain combination. Immunosuppression with cyclosporine A (CsA) was administered in different dosages for 14 days. Dysfunctional allografts were examined immunohistologically. RESULTS: CsA more effectively suppressed the immune response provoked by immunogenic small bowel grafts than that induced by less-immunogenic parathyroid grafts. Immunosuppression with 20 mg/kg per day induced long-term survival in the small bowel (165+/-21 days) but not in the parathyroid (28+/-3 days). All rejected grafts featured massive cellular infiltration by activated T cells as a sign of immune rejection. CONCLUSION: Immunosuppressive dosages effective in passenger leukocyte-rich small bowel transplants were not as effective in parathyroid gland transplants harbouring few passenger leukocytes. In spite of the paucity of passenger leukocytes in parathyroid grafts it is more difficult to control by immunosuppression the immune response to them than that to the passenger leukocyte-rich small bowel.

Animals↗
PubMedDate not supplied

Concurrent nonfunctioning parathyroid carcinoma and parathyroid adenoma.

Parathyroid carcinoma is a rare etiology of primary hyperparathyroidism characterized by severe clinical symptoms of hypercalcemia and markedly elevated serum parathormone levels. Nonfunctioning parathyroid carcinoma is an inactive form of the disease. There are less than 30 reports of nonfunctioning parathyroid carcinoma in the English literature and the association with parathyroid adenoma has not been described. This report describes a patient with concurrent nonfunctioning parathyroid carcinoma and a functioning parathyroid adenoma.

Adenoma↗
PubMed2003

Tc-99m MIBI parathyroid scintigraphy and intact parathyroid hormone levels in hyperparathyroidism.

Tc-99m MIBI has been widely used to evaluate hyperparathyroidism based on increased tracer uptake in hyperfunctioning parathyroid tissue. The functional status measurement of parathyroid glands with intact parathyroid hormone (iPTH) levels is also one of the most important diagnostic studies in this disorder. The aim of the current study was to assess the relation between MIBI imaging and iPTH levels. The authors retrospectively reviewed the records of patients with hyperparathyroidism who were referred to their department for Tc-99m MIBI scintigraphy. Sixty-five patients (24 primary and 41 secondary hyperparathyroidism) were included. The iPTH levels ranged from 66.06 to 2,836 pg/ml (normal, 10 to 55 pg/ml). Forty-two patients were MIBI positive and 23 were negative. The iPTH level in the MIBI-positive group was significantly greater than in the negative group in the primary (548 +/- 478 versus 124 +/- 45; = 0.002), secondary (1,155 +/- 692 versus 501 +/- 352; < 0.001), and overall (909 +/- 678 versus 386 +/- 341; < 0.001) groups. For the primary hyperparathyroidism group, 17 of the 24 patients were MIBI positive (71%). When iPTH levels exceeded 200 pg/ml (100%), the diagnostic sensitivity reached 100%. For the secondary hyperparathyroidism group, 25 of 41 patients (61%) were MIBI positive; 24 of 38 patients (63%) had an iPTH level greater than 200 pg/ml, 21 of 27 patients (78%) had an iPTH level greater than 500 pg/ml, and 11 of 12 patients (92%) had an iPTH value greater than 1,000 pg/ml. Tc-99m MIBI parathyroid scintigraphy showed a good correlation with iPTH level for both primary and secondary hyperparathyroidism. Visualization of hyperfunctioning parathyroid glands on Tc-99m MIBI parathyroid scintigraphy was more likely with a higher serum iPTH level in a dose-dependent manner.

Adult↗
PubMed1996

Recurrent secondary hyperparathyroidism due to parathyroid carcinoma: usefulness of Ki-67 immunostaining in the diagnosis of a malignant parathyroid tumor.

Parathyroid carcinoma is a very rare disease occurring in less than 2-3% of all the cases showing clinical features of primary hyperparathyroidism. Several histological markers have been used for distinguishing between benign and malignant tumors of the parathyroid glands. However, most of these markers are not easily applicable and clinical prognosis cannot be predicted by histopathological criteria alone. A recent study has drawn attention to the role of the cell cycle associated antigen Ki-67 detected by MIB-1 monoclonal immunocytochemistry in parathyroid tumors: in fact, Ki-67 seems to be a valuable marker of malignancy in such tumors since it permits an easy detection of proliferating and dividing cells. Here we report in detail a case of severe recurrent hyperparathyroidism in a 51-year-old female patient undergoing regular hemodialysis treatment. In the surgical specimens of the parathyroid glands, the tumor proliferative fraction of 56, expressed as the number of Ki-67-positive nuclei per thousand cells, and the mean mitosis count of 0.5, expressed as the percentage of the total amount of Ki-67 positive nuclei, support the diagnosis of parathyroid carcinoma despite the scanty amount of microscopical signs considered characteristic of malignancy, i.e. extensive thick fibrous bands or prominent nucleoli. To our knowledge this paper is the first clinical report that supports the diagnostic role of the cell cycle associated antigen Ki-67 in parathyroid carcinoma in a case of secondary hyperparathyroidism in a patient undergoing hemodialysis.

Female↗
PubMed1977

Immunoheterogeneity of parathyroid hormone in venous effluent serum from hyperfunctioning parathyroid glands.

The immunoreactive parathyroid hormone (iPTH) in the plasma of hyperparathyroid man consists largely of carboxyl (COOH)-terminal fragments of the hormone. Although these fragments have been thought to arise principally or solely from peripheral metabolism of intact human PTH {hPTH(1-84)} secreted from the parathyroid gland, there is disagreement about the source of iPTH fragments in vivo. To reexamine this question, we fractionated peripheral and thyroid or parathyroid venous effluent sera from four patients with primary hyperparathyroidism using a high-resolution gel filtration system (Bio-Gel P-150 columns run by reverse flow). The column effluents were analyzed using two PTH radioimmunoassays, one directed toward the amino(NH(2))-terminal region of the molecule, the other toward the COOH-terminal region. In all four thyroid or parathyroid venous effluent sera studied, iPTH was 9-180 times higher than in peripheral serum from the same patient; after fractionation, hPTH(1-84) accounted for only a portion of the total iPTH (35-55% with the assay directed toward the COOH-terminal region of hPTH, >90% with the NH(2)-terminal directed assay.) The remaining iPTH eluted from Bio-Gel P-150 after hPTH(1-84) as NH(2)-or COOH-terminal hPTH fragments. These results suggest that parathyroid tumors secrete large quantities of hPTH fragments. Based on estimates of their molar concentrations in serum, tumor-secreted COOH-terminal hPTH fragments could account for most of these peptides in peripheral serum if their survival times were, as estimated by several other workers, 5-10 times that of hPTH(1-84). We conclude that, in contrast to published information, secretory products of hyperfunctioning parathyroid tissue are probably a major source of serum PTH immunoheterogeneity.

Adult↗
PubMed1989

[Biosynthetic activity of parathyroid cells during different function of the parathyroid glands].

By means of autoradiograph c and morphometric methods parathyroid glands of 31 rats after single injection of 3H-leucin (2,5 mc Cu/g of body mass 25 min. before killing) were investigated. Parathyroid glands were inhibited by multiple injections of calcium gluconate solution or by a diet with increased content of calcium and vitamin D2. Parathyroids were stimulated by multiple injections of Trilon B solution, by a diet with increased content of phosphates or by subtotal parathyroid resection. Straight correlation between parathyroid function, average section area of parathyrocytes and average number of silver granules per one parathyrocyte was revealed. Hence, average section area of parathyrocytes is objective morphometric criterion of parathyroid function.

Animals↗
PubMed1984

[Our experience with autotransplantation and cryopreservation of parathyroid tissue in thyro-parathyroid surgery].

Results are reported of four and a half years of experience with autotransplantation and cryopreservation of parathyroid tissue in thyro-parathyroid surgery. One hundred patients with hyperparathyroidism secondary to renal insufficiency were treated by total parathyroidectomy and partial autotransplantation, immediate in 98 cases and secondarily using their frozen stored tissue in the other two cases. Results were compared with those in 13 other patients treated during the same period by subtotal parathyroidectomy. Seven of 46 patients with primary parathyroid hyperplasia underwent total parathyroidectomy with immediate partial autotransplantation. Grafts were not used in the other two previously cervicotomized patients. All parathyroid tissue removed during these operations was frozen and stored if not used for grafting. Of 116 patients treated by enlarged total thyroidectomy for cancer, 34 received parathyroid autotransplants; complementary in 19 cases and substitutive in 15. Technique and results are described, and respective indications for autotransplantation and parathyroid cryopreservation discussed with respect to primary, secondary, persisting or recurrent hyperparathyroidism, and to total thyroidectomy for cancer.

Calcium↗
PubMed1991

The expression of parathyroid hormone messenger RNA in normal and abnormal parathyroid tissue.

The distribution and expression of preproparathyroid hormone (PTH) mRNA were investigated in parathyroid tissue from 57 parathyroidectomy specimens. PTH mRNA was detected by in situ hybridization using digoxigenin-labelled oligonucleotide probes. Cell morphology was seen to correlate with PTH mRNA expression. Strong expression of PTH mRNA was confined to cells which on haematoxylin and eosin staining had large vesicular nuclei. These included both vacuolated and non-vacuolated cells. Chief cells with small dark nuclei and scanty cytoplasm had little or no expression. In both adenoma and chief cell hyperplasia, the striking difference from normal was the greatly increased proportion of cells expressing PTH mRNA. In adenomas, the rim of uninvolved parathyroid tissue showed PTH mRNA expression similar to that of normal parathyroid. In hyperplasia, there was frequently concordance of staining within individual nodules. The findings establish morphological criteria for activity of parathyroid tissue and support current concepts of the different pathogenesis of hyperplasia and adenoma. The expression of PTH mRNA in oxyphil change and parathyroid carcinoma was also investigated.

Humans↗
PubMed1991

Identification of a dopamine- and 3'5'-cyclic adenosine monophosphate-regulated phosphoprotein of 32 kD (DARPP-32) in parathyroid hormone-producing cells of the human parathyroid gland.

The cellular localization of DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein of 32 kD, enriched in dopamine-innervated brain regions, was investigated in the human parathyroid gland using indirect immunofluorescence histochemistry. Monoclonal antibodies were used to demonstrate DARPP-32-like immunoreactivity (LI) in chief cells of the normal human parathyroid gland and in cells of human parathyroid adenoma. Direct double-labelling revealed coexistence of DARPP-32-LI with parathyroid hormone (PTH)-LI. It has previously been demonstrated that dopamine D1-receptors are present in the parathyroid gland and that dopamine and D1-agonists stimulate the release of PTH. The present results suggest that DARPP-32 may play a role in the cellular mechanisms leading to dopamine-induced PTH secretion.

Adenoma↗
PubMed2002

Comparison of quick parathyroid assay for uniglandular and multiglandular parathyroid disease.

BACKGROUND: The quick intraoperative parathyroid assay (qPTH) has been proposed as an effective tool in the surgical management of hyperparathyroidism. This assay may facilitate directed, unilateral exploration for uniglandular disease; however, its role in the management of multiglandular disease remains unclear. The purpose of this study is to evaluate the use of qPTH in parathyroid surgery, and to compare the results for uniglandular and multiglandular disease. METHODS: A prospective analysis of 63 consecutive patients explored for hyperparathyroidism using the qPTH assay was performed. Preoperative localization studies including ultrasonography and sestamibi scan were routinely obtained. Blood samples for qPTH were routinely drawn prior to the surgical incision, prior to gland excision, as well as 5 and 10 minutes after gland excision. Patients with primary or secondary hyperplasia had blood samples drawn relative to a 3-1/2 gland resection. Additional samples were drawn as needed for patients with a double adenoma. A qPTH decline of greater than or equal to 50% of the highest preincision or gland preexcision level was considered successful. Unilateral neck exploration was routinely performed unless multiglandular disease was identified. Patients were followed up postoperatively with serum calcium levels and an 8-month median follow-up was recorded. RESULTS: Forty-nine of 63 (78%) patients were found to have a solitary parathyroid adenoma. The qPTH assay was successful in 48 (97%) patients with uniglandular disease. Forty-four of these 48 patients showed an appropriate assay decline 5 minutes after adenoma excision. One patient with a single adenoma showed a delayed 50% decline in qPTH at 20 minutes. Fourteen (22%) patients were found to have multiglandular disease: 6 patients with primary hyperplasia, 4 patients with hyperplasia secondary to renal failure, and 4 patients with double adenomas. All patients with multiglandular disease demonstrated a successful decrease in qPTH levels. All patients with hyperplasia secondary to renal failure showed a successful assay decline 5 minutes after 3-1/2 gland resection. Eight of 14 (57%) patients with multiglandular disease (4 double adenomas, and 4 hyperplasia) were suspected to have solitary adenomas preoperatively. Overall, 62 of 63 (98%) patients showed an appropriate assay decline within 10 minutes after gland excision. Postoperatively, all patients were normocalcemic with a median follow-up of 8 months. CONCLUSIONS: These data suggest that qPTH can accurately facilitate unilateral, directed neck exploration for uniglandular parathyroid disease, as well as guide the extent of gland resection for multiglandular disease. This assay reliably eliminates the most common cause of parathyroidectomy failure, which is unrecognized multiglandular disease. The qPTH assay can reliably be used with similar accuracy for patients with multiglandular disease as has been shown for uniglandular parathyroid disease.

Adenoma↗
PubMed1964

IMMUNOCHEMICAL IDENTIFICATION OF PARATHYROID HORMONE IN NON-PARATHYROID NEOPLASMS ASSOCIATED WITH HYPERCALCEMIA.

1. Immunochemical cross-reactivity, but not identity, has been demonstrated between bovine parathyroid hormone and an antigen in biologically active extracts of human parathyroid tissue by quantitative C' fixation and C' fixation inhibition. 2. An antigen that fixes C' with rabbit antibody to bovine parathyroid hormone has been found in urea extracts of six human non-parathyroid neoplasms associated with a hypercalcemic syndrome mimicking primary hyperparathyroidism. Comparable extracts of control tissues and other tumors were serologically negative. 3. It is concluded that the tumor antigen is parathyroid hormone or a very closely related protein, and that its production by these neoplasms was the cause of the hypercalcemic syndrome in these six patients.

Allergy and Immunology↗
PubMed2000

Complementary nature of radiotracer parathyroid imaging and intraoperative parathyroid hormone assays in the surgical management of primary hyperparathyroid disease: case report and review.

PURPOSE: This article illustrates the complementary nature of preoperative radionuclide parathyroid imaging and intraoperative rapid parathyroid hormone (PTH) assays in primary hyperparathyroid disease. The authors review the literature on these procedures and compare this protocol and its cost-effectiveness with those of the classic four-gland exploration. MATERIALS AND METHODS: Preoperative parathyroid imaging with Tc-99m MIBI and intraoperative rapid PTH assays were performed at the time of neck exploration. RESULTS: One of two parathyroid adenomas seen on radionuclide images would have been missed if the authors had relied solely on the initial decrease in PTH assay value to a normal level. CONCLUSIONS: Tc-99m MIBI imaging and intraoperative rapid PTH assays are complementary; when used together, they lessen the likelihood that abnormal parathyroid glands will be overlooked. This experience and that of others suggest these combined procedures are cost-effective.

Adenoma↗