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PubMed2002

[Parathyroid gland, calcium receptor and calcimimetics].

Parathyroid glands, bones, intestines and kidneys closely regulate ionized extracellular calcium concentration and thereby bone mineral density. This regulation is accomplished by a membrane associated receptor that responds to small changes in the extracellular calcium concentration (Ca2+)ec. The activation of this receptor regulates the secretion of PTH and the urinary excretion of calcium. The cloning of this calcium sensing receptor (RCa) in 1993 has allowed the identification of several hereditary disorders characterized by either a hyperparathyroidism or a hypoparathyroidism, as well as the development of pharmaceutical compounds potentially of interest for the treatment of these diseases. The calcimimetics are able either to directly stimulate the RCa or to make the RCa more sensitive to the effects of (Ca2+)ec. By this way, they decrease the secretion of PTH, but they also stimulate the secretion of calcitonin. The first clinical studies with a first-generation calcimimetic have demonstrated their efficacy lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low biodisponibility of these first calcimimetics predict a difficult clinical utilization. The preliminary results obtained with a second-generation calcimimetic, the AMG-073, are very promising and await long term evaluation. The goal of this manuscript is to review the physiological, biological and clinical bases for the development of calcimimetic. Moreover, to try to replace the potential use of these drugs in the context of chronic renal failure and in the treatment of secondary hyperparathyroidism.

Animals↗

PubMed1998

Effect of immobilization on the ultrastructure of the golden hamster parathyroid gland.

To investigate the morphological changes of the parathyroid gland of the immobilized hamsters, we studied the ultrastructure of the parathyroid gland of golden hamsters kept in special small cage (Ballman cage II). All hamsters of the control group were kept in one ordinary cage. Each hamster of the isolated group was kept in ordinary cage individually. Each hamster of the immobilized group was kept in Ballman cage II individually. All hamsters were kept for 5 days. On the first and fifth day of the experiment, bone mineral content (BMC) and bone mineral density (BMD) of whole body were measured by dual energy X-ray absorptiometry (DXA). In the control and isolated groups, BMD of the fifth day was significantly increased as compared to that of the first day. In the immobilized group BMC and body weight were significantly decreased. There was no significant difference among 3 groups concerning the mean serum calcium level. Volume density of the cell organelles and inclusions was estimated and compared among 3 groups. Volume density of the lysosomes and large vacuolar bodies of the isolated and immobilized groups was significantly higher than that of the control group. Much more lipid droplets were observed in the immobilized group than the control and isolated groups. No particular differences were observed as to the Golgi complex in the isolated and the immobilized groups compared to the control group. These findings suggest that the cellular activity of the parathyroid gland is suppressed with immobilization.

Absorptiometry, Photon↗

PubMed1998

Localization of parathyroid glands in hemodialysis patients using Tc-99m sestamibi imaging.

UNLABELLED: Tc-99m sestamibi parathyroid imaging was performed in 28 patients with chronic renal failure to localize abnormal parathyroid glands in patients receiving hemodialysis, and compared the localization with ultrasonography and magnetic resonance (MR) imaging. METHODS: We imaged 28 patients with secondary hyperparathyroidism using Tc-99m sestamibi (about 600 MBq) at 10 min and 2-3 h following radiotracer injection. In addition, mediastinal images were recorded at approximately 1 h following injection to identify ectopic parathyroid glands. All patients also were evaluated with ultrasonography and MR imaging. RESULTS: Tc-99m sestamibi scans demonstrated focal uptake in 60 glands of the 28 patients, and was categorized as slight uptake in 71.7% (43/60), and intense uptake in 28.3% (17/60). Seventeen of the 28 patients underwent parathyroidectomy. A total of 64 glands were resected. Sestamibi imaging was more sensitive for localizing abnormal parathyroid glands than ultrasonography or MR imaging. Histologic evaluation of 27 resected parathyroid glands revealed that the number of oxyphil or chief cells was not proportional to sestamibi uptake. CONCLUSION: Our data indicate that Tc-99m sestamibi imaging should be used initially to localize abnormal parathyroid glands in hemodialysis patients with secondary hyperparathyroidism, prior to MR imaging or ultrasonography. Sestamibi uptake in parathyroid glands may not correlate with the degree of hypercellularity of oxyphil cells.

Adult↗

PubMed2002

Parathyroid gland volume increases with postmaturational aging in the rat.

To examine the pathophysiology of the age-related rise in the plasma concentration of parathyroid hormone (PTH), we studied the relationships among plasma immunoreactive PTH (iPTH), parathyroid gland volume, parathyroid cell proliferation rate, renal function, and blood Ca(2+) in male Fischer 344 rats aged 6-28 mo. Plasma iPTH increased 2.5-fold between 6 and 28 mo and correlated with parathyroid gland volume (r = 0.87). Gland volume began to increase as early as 6-12 mo of age and by 28 mo was threefold greater than at 6 mo. Gland expansion was a consequence of hyperplasia stimulated in part by an increase in cell proliferative activity late in life. Blood Ca(2+) and plasma inorganic phosphorus did not change significantly with age. Glomerular filtration rate decreased with age but only after the age of 24 mo. Unlike what has been observed in the human, these data suggest that the age-related increase in plasma iPTH in the rat is linked to parathyroid gland hyperplasia and that early gland growth does not appear to be associated with hypocalcemia or renal insufficiency, but rather to developmentally related metabolic changes. Later in life (>24 mo), the increase in parathyroid cell proliferation rate, further hyperplastic expansion of the gland, and increase in iPTH secretion appear to be associated with renal insufficiency.

Aging↗

PubMed1993

Complications of surgery of the thyroid and parathyroid glands.

Surgery of the thyroid and parathyroid glands can be performed safely in the majority of patients. The greatest risk for postoperative morbidity arises from injury to the laryngeal nerves or the parathyroid glands. A sound knowledge of regional anatomy combined with an unhurried, meticulous operative technique are essential if injury to these structures is to be avoided.

Blood Loss, Surgical↗

PubMed2001

Heterogeneous expression of receptor mRNAs in parathyroid glands of secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (HPT) is characterized by inappropriate control of parathyroid hormone (PTH) secretion and asymmetric hyperplasia of the parathyroid glands. Receptors for calcium and vitamin D are involved in the control of secretion, as well as parathyroid cell proliferation. Defective receptor mechanisms therefore may play a role in the pathogenensis of secondary HPT. Previous studies have shown that the expression of calcium receptor (CaR), calcium-sensing receptor (CAS) and vitamin D receptor (VDR) protein, and mRNA is decreased in hyperplastic parathyroid glands of secondary HPT when compared with normal parathyroid glands. METHODS: Thirty-six hyperplastic glands from 18 patients with secondary hyperparathyroidism were analyzed with in situ hybridization in order to investigate the expression of CaR, CAS, VDR, and PTH mRNAs in the same specimens. In nine nodular parathyroid glands, it was possible to make a comparison between the expression of these mRNAs in nodular and internodular areas. RESULTS: The level of CaR was in the same order of magnitude in the hyperplastic glands and in the biopsies of normal parathyroid, whereas the levels of CAS, VDR and PTH were clearly reduced in the hyperplastic glands. There was a positive correlation between the expression of CaR and CAS (P = 0.02). Otherwise, no correlations between CaR, CAS, VDR, and PTH mRNAs were found. The expression of all four genes was highly variable as well between different glands as within individual glands. CONCLUSION: The expression of mRNAs for receptors of importance in the control of PTH secretion and parathyroid cell proliferation is heterogeneously decreased in parathyroid glands of secondary HPT. The expression pattern corroborates earlier studies in which it has been assumed that each nodule in secondary HPT is of monoclonal origin, but that the monoclonal origin of each nodule is independent.

Adult↗

PubMed2001

Failure of high doses of calcitriol and hypercalcaemia to induce apoptosis in hyperplastic parathyroid glands of azotaemic rats.

BACKGROUND: Whether calcitriol administration, which is used to treat secondary hyperparathyroidism in dialysis patients, induces regression of parathyroid-gland hyperplasia remains a subject of interest and debate. If regression of the parathyroid gland were to occur, the presumed mechanism would be apoptosis. However, information on whether high doses of calcitriol can induce apoptosis of parathyroid cells in hyperplastic parathyroid glands is lacking. Consequently, high doses of calcitriol were given to azotaemic rats and the parathyroid glands were evaluated for apoptosis. METHODS: Rats were either sham-operated (two groups) or underwent a two-stage 5/6 nephrectomy (three groups). For the first 4 weeks, all rats were given a high (1.2%) phosphorus (P) diet to stimulate parathyroid gland growth and then were changed to a normal (0.6%) P diet for 2 weeks. At week 7, three of the five groups were given high doses of calcitriol (500 pmol/100 g body weight) intraperitoneally every 24 h during 72 h before sacrifice. The five groups during week 7 were: (i) normal renal function (NRF)+0.6% P diet; (ii) NRF+0.6% P+calcitriol; (iii) renal failure (RF)+0.6% P; (iv) RF+1.2% P+calcitriol; and (v) RF+0.6% P+calcitriol. Parathyroid glands were removed at sacrifice and the TUNEL stain was performed to detect apoptosis. RESULTS: At sacrifice, the respective serum calcium values in calcitriol-treated groups (groups 2, 4, and 5) were 15.52+/-0.26, 13.41+/-0.39 and 15.12+/-0.32 mg/dl. In group 3, PTH was 178+/-42 pg/ml, but in calcitriol-treated groups, PTH values were suppressed, 8+/-1 (group 2), 12+/-2 (group 4), and 7+/-1 pg/ml (group 5). Despite, the severe hypercalcaemia and marked PTH suppression in calcitriol-treated groups, the percentage of apoptotic cells in the parathyroid glands was very low (range 0.08+/-0.04 to 0.25+/-0.20%) and not different among the five groups. CONCLUSIONS: We found no evidence in hyperplastic parathyroid glands that apoptosis could be induced in azotaemic rats by the combination of high doses of calcitriol and severe hypercalcaemia despite the marked reduction in PTH levels that was observed.

Animals↗

PubMed1987

Blood vascular architecture of the rat parathyroid glands: a scanning electron microscopic study of corrosion casts.

Blood vascular beds of the rat parathyroid glands were reproduced with a methacrylate casting medium and observed with a scanning electron microscope. The rat possesses only a single pair (one left and the other right) of parathyroid glands. Each gland was found to contain a rich capillary network which was completely isolated from the capillary plexus of the thyroid gland. Each parathyroid gland received some small afferent arteries from the superior thyroid artery and emitted a thick efferent vein continuous with the superior thyroid vein. The capillary network of the parathyroid gland consisted of freely anastomosing capillaries. The afferent arteries were divided in the superficial and deep layers of the gland. The thick efferent vein arose in the deep layer of the gland. Some small or accessory efferent veins arose in the superficial layers of the gland. These also drained into the superior thyroid vein.

Animals↗

PubMed1996

In vivo studies of parathyroid gland function in secondary hyperparathyroidism.

In contrast to studies in vitro, in vivo tests of parathyroid gland function in human subjects with secondary hyperparathyroidism present a number of technical and theoretical difficulties. The four-parameter model was originally developed to characterize the secretion of PTH in vitro by a defined number of parathyroid cells in tissue culture, whereas comparisons among in vivo studies in patients with varying degrees of parathyroid gland hyperplasia may not be feasible with this model. Maximum serum PTH levels during hypocalcemic stimuli in vivo reflect not only the amount of PTH released by each parathyroid cell but also the total number of cells available for hormone secretion. Parathyroid gland size varies markedly in patients with secondary hyperparathyroidism, and there is currently no reliable technique for accurately measuring the amount of parathyroid tissue present. Accordingly, in vivo comparisons of calcium-regulated PTH release among subjects with parathyroid glands of substantially different sizes may not be valid with the four-parameter model. Kwan et al. have suggested that parathyroid gland function be assessed over a wide range of different calcium concentrations. In this model, the set point for calcium-regulated PTH secretion is not calculated, but the relationship between serum ionized calcium and PTH levels is examined by linear regression after semilog transformation of the data. Linearizing the calcium-PTH curve eliminates the need for more complex curve-fitting analyses. Differences in parathyroid gland function have been reported before and after calcitriol therapy when this approach is used, but the severity of secondary hyperparathyroidism varied widely in the patients evaluated. Alternatively, the Cica-clamp technique to quantify PTH secretion has been developed by Schwarz et al. By employing sequential standardized hypocalcemia and hypercalcemia, set point values obtained with this method closely agree with in vitro data obtained by Brown in normal parathyroid tissues. Advantages of the Cica-clamp technique include a shorter duration of study, reproducibility of the method, and absence of adverse effects; its utility in evaluating patients with either primary or secondary hyperparathyroidism remains to be determined. Based on data currently available, separate assessments of the pattern of change in serum PTH levels during hypocalcemia and hypercalcemia, expressed as the percent change from baseline values (see Fig 4), may provide more useful information about disturbances in the regulation of PTH release by calcium in patients with secondary hyperparathyroidism. Nevertheless, alterations in the set point for calcium-mediated PTH secretion do not adequately explain the excess PTH secretion of patients with secondary hyperparathyroidism, nor do they account for the reduction in serum PTH levels after treatment with calcitriol.

Animals↗

PubMed1996

Blood supply and parathyroid hormone secretion in pathological parathyroid glands.

The blood supply of pathologic parathyroid glands and the relation between parathyroid hormone secretion and parathyroid blood perfusion was studied during surgery for hyperparathyroidism. Blood flow in 39 single adenomas and 20 glands classified as primary or secondary hyperplasia were studied intraoperatively with laser Doppler flowmetry. The ipsilateral inferior thyroid artery was occluded during continuous flowmetry recording, which resulted in a 40% reduction of parathyroid blood flow in both groups. In 12 patients with single adenomas, intact parathormone (iPTH) was measured intraoperatively before and during occlusion of the ipsilateral inferior thyroid artery and after extirpation of the adenoma. During occlusion the iPTH levels were mainly unchanged despite blood flow reduction of up to 80%. After removal of the adenoma the iPTH normalized within 15 minutes. In a control group of eight single adenomas, iPTH was measured similarly without vascular occlusion, demonstrating comparable iPTH levels. This study demonstrates similar routes of vascularization for single adenomas and hyperplastic glands, as was earlier seen for normal parathyroid glands. The increased parathyroid hormone secretion from single adenomas appears to remain mainly unchanged during significant blood flow reduction.

Adenoma↗

PubMed1991

Experimental study of the origin of the parathyroid glands.

The origin of the parathyroid glands was investigated in chick embryos (Gallus domesticus). Pieces of the third branchial arch were grafted, and its ectodermal layer formed a new structure (parathyroid III), which became separated from the placodial ectoderm. This structure continued to develop until, together with neural crest cells which gave rise to the mesenchyme, it formed a distinct parathyroid III gland by stage 28 of Hamburger and Hamilton.

Animals↗

PubMed1988

Effects of hypergravity environment of the ultrastructure of the golden hamster parathyroid gland.

The fine structure of the parathyroid glands of golden hamsters exposed to 2, 5 or 10 g environment for 5 h was studied. In the centrifuged hamsters, many secretory granules are located in a peripheral position just beneath the plasma membrane of chief cells, and the Golgi complexes and cisternae of the granular endoplasmic reticulum are significantly increased compared with those of control animals. There are no significant differences between the control and centrifuged animals with regard to secretory granules, large secretory granules, lysosomes, vacuolar bodies and lipid droplets. These findings suggest that the secretory activity of the parathyroid gland may be stimulated in response to hypergravity environment.

Animals↗

PubMed1998

Surgical significance of supernumerary parathyroid glands in renal hyperparathyroidism.

In secondary hyperparathyroidism (2HPT) fundamentally all parathyroid glands, including supernumerary glands, become hyperplastic, and stimulation of parathyroid glands continues after parathyroidectomy (PTx). Therefore supernumerary glands have special significance during surgery for 2HPT, whether persistent or recurrent HPT. In the present study 570 patients underwent initial total PTx with a forearm autograft. The frequency, type, location, histopathology, and clinical significance of the supernumerary glands were evaluated. At the initial operation 90 supernumerary glands were removed from 82 to 570 patients (14.4%); 12 patients (2.1%) required extirpation of supernumerary glands for persistent/recurrent HPT. Altogether 104 supernumerary glands were identified at operation in 94 of the 570 patients (16.5%). Among these 104 glands, 25 (24.0%) were of the rudimentary, or split, type and 79 (76.0%) of the proper type. Supernumerary glands were most frequently identified in the thymic tongue (53/104, 51.0%); 32 (60.4%) of these 53 glands were identified only microscopically. In 6 of the 570 cases (1.1%), reoperation was required for persistent HPT due to supernumerary glands located in the mediastinum, and 6 patients underwent neck reexploration for recurrence. Histopathologically, 61 of 104 (58.7%) supernumerary glands, including 36 glands recognized only microscopically, showed diffuse hyperplasia, and 43 (41.3%) displayed nodular hyperplasia. Residual small supernumerary glands with diffuse hyperplasia have the potential to be transformed to nodular hyperplasia during long-term hemodialysis. Therefore all parathyroid glands including supernumerary glands should, if possible, be removed at the initial operation. Routine removal of the thymic tongue and careful examination of the regions surrounding the lower poles of the thyroid, especially on the left side, are important steps in the surgical treatment.

Adult↗

PubMed2006

Ultrasonography in detection of single and multiple abnormal parathyroid glands in primary hyperparathyroidism: comparison with radionuclide scintigraphy and surgery.

BACKGROUND: Among the parathyroid imaging techniques, ultrasonography (USG) has the advantage of convenience, easy availability and low cost. OBJECTIVE: To study the role of USG in localization (side and/or site) of abnormal parathyroid glands in primary hyperparathyroidism (PHPT) and to compare with radionuclide scintigraphy and the 'gold standard', surgery. METHODS: Forty-six consecutive patients undergoing USG of the anterior neck for a diagnosis of PHPT in whom a nuclear scan (technetium-99m sestamibi and/or thallium-201/technetium-99m pertechnetate scintigraphy) was also performed, were studied. The results of imaging were independently interpreted and correlated with reference to surgical findings. RESULTS: Forty-six patients had 52 abnormal parathyroid glands on surgical exploration and surgery was successful in all but one. Forty-one patients had a single adenoma, four had multigland disease and one had a paraganglioma. USG correctly localized the abnormal gland in 30 (73%) and scintigraphy was positive in 40 (98%) out of 41 patients with a single adenoma as confirmed on surgical exploration. Scintigraphy showed a positive concordant test in all 30 patients with a single abnormal gland detected on USG and picked up 10 out of 11 abnormal glands where USG was negative. The sensitivity and positive predictive value of USG for detecting a single abnormal gland was 73% and 100%, respectively, whereas the sensitivity and positive predictive value for scintigraphy was 98%. In patients with multigland disease, USG missed 3 (30%) out of 10 and scintigraphy missed 6 (60%) out of 10 abnormal parathyroid glands as confirmed on surgical exploration (P < 0.05). However, in two patients who had ectopic parathyroid gland, both the modalities localized the lesion in one (paraganglioma), whereas in the other neither test was helpful (left retro-esophageal). CONCLUSION: USG is a convenient, affordable and useful modality to localize abnormal enlarged parathyroid glands in the majority of patients with PHPT. However, when USG is negative, scintigraphy is complementary to it.

Adenoma↗

PubMed1976

Influence of reserpine on high calcium perfusion of thyro-parathyroid glands in dogs.

Perfusion of the thyro-parathyroid glands in the dog with calcium-rich blood led to a significant decrease (P less than 0.001) in the systemic plasma calcium level. On the other hand, injection of reserpine (0.2 mg/kg ip) 16 and 2 h prior to infusion of hypercalcemic blood into thyro-parathyroid glands did not alter the systemic plasma calcium level significantly (P less than 0.05). This result provides evidence that reserpine blocks the release of hypocalcemic factor from the thyro-parathyroid glands in response to perfusion of high concentrations of calcium.

Animals↗

PubMed2006

Morphological features of enlarged parathyroid glands in B-mode-ultrasound.

Successful preoperative localisation of parathyroid glands is essential for minimal-invasive surgery of hyperparathyroidism. The knowledge of the sonomorphology of the parathyroid glands, therefore, is an important prerequisite. This article shows that the sonomorphology of normal and pathologically transformed parathyroid glands is subject to a wide variety. The often simplified standard description of parathyroid glands as hypoechogenic and oval may lead to false negative cervical ultrasound examinations.

Diagnosis, Differential↗

PubMed1995

Comparison of preoperative imaging techniques (thallium technetium scan and ultrasonography) and intraoperative staining (with methylene blue) in localizing the parathyroid glands.

We carried out a prospective study to compare the predictive value of preoperative thallium technetium scan, ultrasound (US) and intraoperative staining of the parathyroid glands (with methylene blue) in patients with parathyroid adenoma, parathyroid hyperplasia, thyroid carcinoma and thyrotoxicosis, in the Istanbul School of Medicine, Department of General Surgery. Methylene blue was given at a dose of 5 mg/kg/body weight in a 500 ml 5% Dextrose +0.9% saline solution 1 hour before surgery. All adenomas (10 patients), hyperplastic parathyroid glands (12 patients) and 45 of 52 suppressed glands (82%) were stained. In patients with thyroid carcinoma (7) and thyrotoxicosis (5), 42 of 48 normal parathyroid glands (87%) were stained. There were no maneuver-related complications. Thallium technetium scan (TT) accurately identified 10 of 10 (100%) parathyroid adenomas and 13 of 26 (50%) hyperplastic parathyroid glands. US successfully localized 10 of 10 (100%) adenomas and 18 of 26 (66%) hyperplastic glands. Neither technique was successful in identifying normal glands. The intraoperative identification of the parathyroid glands with methylene blue was found to be an effective, safe and cost-effective technique which helps the surgeon in the dissection and shows abnormal parathyroid glands more accurately than preoperative imaging techniques.

Adult↗

PubMed2000

Effects of long-term treatment with caffeine on the ultrastructure of the golden hamster parathyroid gland and tibia.

The ultrastructure of the parathyroid gland and the SEM appearances of the tibia were studied in hamsters with and without administration of caffeine. Caffeine was treated orally each day at either 2.5 mg (low dose) or 10 mg (high dose) per 100 g body weight for a period of 17 or 32 days. Statistical analysis showed no significant differences among all groups examined regarding the serum calcium level. Transmission electron microscopy of the parathyroid gland revealed that the volume densities occupied by the mitochondria, Golgi complexes and rough endoplasmic reticulum of caffeine-treated groups were found significantly higher when compared with controls. The number of secretory granules observed close to the cell membrane per total amount of these granules revealed significant increase in all caffeine-treated animals. The bone mineral content (BMC) values were closely related to body weight. In the high dose caffeine-treated hamsters increment of the mean BMC and body weight values was significantly lower than those of the controls after 32 days. In the scanning electron microscopic studies of the tibia, no alteration in the morphometric parameters was demonstrated. It is considered that the synthesis and release of parathyroid hormone is stimulated following caffeine consumption. Our data suggest that although chronic administration of caffeine in the hamster may slightly increase bone turnover as evidenced by the BMC decrease, bone morphometry was not altered. Thus the osteoporotic changes were not proved in this study.

Animals↗