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PubMed1999

Calcium-sensing receptor and calcimimetic agents.

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependent fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.

Aniline Compounds↗
PubMed1991

The role of 1,25-dihydroxyvitamin D in the maintenance of hypercalcemia in a patient with an ovarian carcinoma producing parathyroid hormone-related protein.

The syndrome of humoral hypercalcemia of malignancy (HHM) is thought to be mainly a result of the production of parathyroid hormone-related protein (PTHRP) by malignant tumors. Serum 1,25-dihydroxyvitamin D (1,25-DHD) concentrations are generally low in such patients, which contrasts with the findings in animal studies. A patient is reported with HHM from a clear cell ovarian carcinoma and elevated serum immunoreactive PTHRP (about five times the upper limit of normal) in whom serum 1,25-DHD concentrations were abnormally high (200 pmol/l) and associated with increased intestinal calcium absorption. Treatment with two different nitrogen-containing bisphosphonates (pamidronate and [3-dimethyl-amino-1-hydroxypropylidene]-1,1-bisphosphonate) did not normalize serum and urinary calcium despite effective inhibition of bone resorption. These observations suggested an additional intestinal contribution to the maintenance of hypercalcemia. Tumor removal was followed by decreases in serum immunoreactive PTHRP and 1,25-DHD concentrations to their respective normal ranges and normocalcemia. Separating HHM into Types I and II, according to the prevailing serum 1,25-DHD concentrations, can provide a basis for a better understanding of the pathogenesis of hypercalcemia, and it also may have practical use in the successful management of these patients.

Aged↗
PubMed1990

Mid-mediastinal parathyroid lesions: preoperative localization and surgical approach in two cases.

Although hyperfunctioning mediastinal parathyroid lesions that require median sternotomy or thoracotomy for removal are occasionally present, the majority are located in the anterior mediastinum closely associated with the thymus. Only eight cases of ectopic hyperfunctioning parathyroid tumors in the middle mediastinum have been reported. We experienced two cases of either persistent or recurrent hyperparathyroidism in which abnormal parathyroid tissue was located in the aorticopulmonary window. One of the patients had a parathyroid adenoma and the other had metastatic lesions of parathyroid carcinoma. In both cases, thallium scanning proved useful in identifying the lesions while computed tomography scan was effective for mediastinal three-dimensional localization. In one case, single photon emission computed tomography imaging with thallium proved beneficial for both identification and localization of the middle mediastinal lesion. The surgical approach used in both cases was different. In one case, left thoracotomy was performed, after which the ligamentum arteriosum was divided, and an adenoma anterior to the left main bronchus and posterior to the left pulmonary artery removed. In the other case, two metastatic tumors of parathyroid carcinoma anterior to the right main bronchus and posterior to the right pulmonary artery were resected through a median sternotomy and opening of the pericardium.

Adenoma↗
PubMed2002

99mTc-MIBI radio-guided minimally invasive parathyroidectomy: experience with patients with normal thyroids and nodular goiters.

The surgical approach to primary hyperparathyroidism (HPT) is changing. In patients with a high probability to be affected by a solitary parathyroid adenoma (PA), a unilateral neck exploration (UNE) or a minimally invasive radio-guided surgery (MIRS) using the intraoperative gamma probe (IGP) technique have recently been proposed. We investigated the role of IGP in a group of 84 patients with primary HPT who were homogeneously evaluated before surgery by a single-day imaging protocol including 99mTcO4/MIBI subtraction scan and neck ultrasound (US) and then operated on by the same surgical team. Quick parathyroid hormone (QPTH) was intraoperatively measured in all cases to confirm successful parathyroidectomy. In 70 patients with scan/US evidence of a single enlarged parathyroid gland (EPG) and with a normal thyroid gland, MIRS was planned. In the other 14 patients, the IGP technique was utilized during a standard bilateral neck exploration (BNE) because of the presence of concomitant nodular goiter (11 cases) or multiglandular disease (MGD) (3 cases). The IGP technique consisted of the following: (1) in the operating room, a low 99mTc-MIBI dose (37 MBq) was injected intravenously during anesthesia induction; (2) subsequently, the patient's neck was scanned with the probe by the surgeon to localize the cutaneous projection of the EPG; (3) in patients who underwent MIRS, the EPG was detected intraoperatively with the probe and removed through a small, 2 to 2.5 cm skin incision; (4) radioactivity was measured on the EPG both in vivo and ex vivo, the thyroid, the background and the parathyroid bed after EPG removal. In patients with concomitant nodular goiter, the radioactivity was also measured on the thyroid nodules. Surgical and pathologic findings were consistent with a single PA in 78 patients, parathyroid carcinoma in 2, and MGD in 4. MIRS was successfully performed in 67 of the 70 patients (97.7%) in whom this approach was planned. It must be pointed out that the IGP technique was particularly useful in detecting the PAs located in ectopic site (5 in the upper mediastinum, 2 at the carotid bifurcation) and deep in the neck (6 in the paratracheal/paraesophageal space). Moreover, MIRS was also successfully performed in the seven patients who had undergone previous parathyroid or thyroid surgery. In the other 3 of 70 patients (4.3%), a conversion to BNE was required because a parathyroid carcinoma (2 cases) and a MGD (1 case) were diagnosed during surgical intervention. It is worth noting that in this latter patient affected by MGD, in contrast with the other patients from our series, QPTH remained elevated after the removal of the preoperatively visualized EPG suggesting the persistence of occult hyperfunctioning parathyroid tissue, and another contralateral EPG was found at BNE. Regarding the group of patients in whom a BNE was planned, the IGP helped the surgeon to localize a supernumerary EPG ectopic in the thymus in a patient with MGD, and to localize a PA ectopic to the right carotid bifurcation in a patient with nodular goiter. However, it has to be pointed out that it was difficult for the surgeon to differentiate intraoperatively with the probe the radioactivity of the EPG from that of thyroid nodule(s) in the other 10 patients with HPT with a concomitant nodular goiter, particularly in 6 patients in whom 99mTc-MIBI uptake was higher in thyroid nodule(s) than in EPG. On the basis of these data we can conclude that: (1) in patients with primary HPT with a high scan/US probability to be affected by a single PA and with a normal thyroid gland, IGP appears to be an useful technique with the aim of performing MIRS; (2) a 99mTc-MIBI dose as low as 37 MBq appears to be adequate to successfully perform MIRS; (3) the measurement of QPTH is strongly recommended in patients with HPT selected for MIRS to confirm complete removal of hyperfunctioning parathyroid tissue; (4) MIRS can be useful also in patients with HPT who previously received parathyroid/thyroid surgery with the aim of limiting surgical trauma at reoperation and minimizing the related risk of complications; (5) with the exception of PA located in ectopic sites, IGP does not seem to be a recommendable technique in patients with HPT concomitant nodular goiter.

Adenoma↗
PubMed1995

P-glycoprotein is expressed in parathyroid epithelium and is regulated by calcium.

P-glycoprotein (Pgp), the multidrug resistance (mdr) gene product, has been described in normal tissues with diverse physiologic functions. A broad role as a transporter protein for toxins, hormones, and physiologic metabolites has been provisionally deduced, based on structural analysis and immunoanatomic localization. Recently, significant levels of Pgp have been demonstrated in endocrine and hormonally responsive tissues and tumors. We examined calcium-regulated, clonal parathyroid epithelial (PT-r) and endothelial cells (BPE-1) and frozen parathyroid tissue from normal human parathyroid, parathyroid hyperplasia, parathyroid adenoma, and parathyroid carcinoma for expression of the multidrug resistance gene (Mdr1) and Pgp utilizing Northern and Western analysis and immunohistochemistry. We also investigated the effect of extracellular calcium (eCa) on Pgp expression in PT-r cells at the molecular/cellular level. Immunohistochemistry, utilizing three murine monoclonal antibodies (MAbs)--C494, JSB-1, and C219--which recognize spatially distinct cytoplasmic epitopes of Pgp, revealed strong immunoreactivity in PT-r cells, normal parathyroid, and parathyroid hyperplasia, and weak immunostaining in parathyroid adenomas. BPE-1 cells, endothelial cells, and parathyroid carcinoma were negative. PT-r cells showed a single 130 kDa band (120 KDa after glycosidase treatment) on Western blot and a 4.6 kb transcript on Northern analysis, consistent with Pgp. Western and Northern blot analysis of PTr cells cultured in different eCa concentrations showed that eCa up-regulated Pgp expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Microvessel density in human normal and neoplastic parathyroids.

Objective. Information on angiogenesis in parathyroid pathology is scanty and in particular no data are available in parathyroid carcinomas. The aim of this study was to analyze angiogenesis as microvascular density (MVD) in parathyroid neoplastic progression from normal gland to adenoma and carcinoma. Methods. Sections from formalin-fixed, paraffin-embedded specimens of 33 normal parathyroids, 43 sporadic parathyroid adenomas, and 6 parathyroid carcinomas were cut for immunohistochemistry using anti-endothelial marker CD34. MVD was evaluated in each specimen as number microvessels per mm2. MVD data were compared with some anatomoclinical parameters as tumor size, serum calcium, and parathyroid hormone (PTH) level. Results. All normal parathyroid glands, all carcinomas, and 8 adenomas out of 43 (18%) showed MVD less than 100 microvessels/mm2 (median 70.8; 95%CI 66.9-88.5); in the majority of parathyroid adenomas (n = 35; 82%) the number of microvessels/mm2 was higher than 100 (median 188.3; 95%CI 174.9-210.1). In adenomas both preoperative serum intact PTH concentration and the diameters were significantly and inversely related to the microvessel density (r = 0.320, p < 0.05 and r = 0.334, p < 0.05, respectively). Conclusions. This study shows that in parathyroid adenomas MVD is heterogeneous and negatively related to the endocrine activity (secretory status and tumor size). Therefore, angiogenesis in parathyroid adenomas and carcinomas appears to be an early event, which does not follow a parallel increase in size.

Adenoma↗
PubMed2002

Concurrent parathyroid adenomas and carcinoma in the setting of multiple endocrine neoplasia type 1: presentation as hypercalcemic crisis.

We describe a patient with multiple endocrine neoplasia type 1 characterized by the simultaneous occurrence of parathyroid cancer, parathyroid adenomas, and pancreatic gastrinoma, who presented with an episode of acute hypercalcemia. The rapid parathyroid hormone assay provided a basis for the diagnosis of parathyroid hyperfunction. Mediastinal metastasis of the parathyroid carcinoma was found at autopsy. However, the staining of pancreatic and gastric tissue for parathyroid hormone-related protein does not make it possible to exclude completely the contribution of this peptide in mediating the hypercalcemia. To our knowledge, this is the first reported case of parathyroid carcinoma as part of the multiple endocrine neoplasia type 1 syndrome.

Acute Disease↗
PubMed1997

Clinical and biochemical presentation of primary hyperparathyroidism in Kansai district of Japan.

Although the number of patients with primary hyperparathyroidism (pHPT) has increased since biochemical screening came to be widely employed, few data are available concerning the clinical analysis of Japanese patients. We therefore tried to determine the recent clinical and biochemical state of Japanese patients with pHPT. Clinical and biochemical data were analyzed in a series of 103 pHPT patients who had been hospitalized in Kobe University Hospital during a 17 year period from 1979 to 1995. The data were obtained from the hospital records and additionally from information through questionnaires performed in 1995. Patients were 29 males and 74 females. The average ages at diagnosis were 53.4 +/- 16.0 (SD) year-old and 53.9 +/- 15.2 year-old, respectively. The major clinical symptoms were nephrolithiasis (35.9%), thirst/polyuria (33.0%), easy fatigability (20.4%) and back pain/lumbago (16.5%), but 19.4% of the patients were asymptomatic. Out of 87 cases who received parathyroidectomy, 10 (11.5%) were diagnosed with parathyroid carcinoma. Age- and sex-corrected bone mineral density (BMD) of the radius was significantly lower in the group with back pain/lumbago than in the group without the symptom. Similarly, radial BMD was lower in the group with a high serum alkaline phosphatase value. Patients with nephrolithiasis had a lower urinary calcium/creatinine ratio (UCa/ UCr; 0.305 +/- 0.188 mg/mg) than the patients without nephrolithiasis (0.400 +/- 0.160 mg/mg). This inconsistent result suggests that some important factors except urinary calcium would contribute to urinary stone formation in pHPT. Our data mostly agreed with previous reports on a Caucasian population except for a relatively high prevalence of parathyroid carcinoma, but the negative correlation between nephrolithiasis and urinary calcium was not easily explicable. This finding should be confirmed by analyzing a larger number of cases.

Adolescent↗
PubMed2005

Identification of a functional bipartite nuclear localization signal in the tumor suppressor parafibromin.

Parafibromin is a putative tumor suppressor encoded by HRPT2, mutations in which have been implicated in the familial tumor syndrome hyperparathyroidism jaw tumor syndrome (HPT-JT), and sporadic parathyroid carcinoma. Recently, parafibromin has been shown to be an accessory factor for RNA polymerase II as part of the human Paf 1 complex, suggesting, as has been shown for its yeast homologue (Cdc 73), that it may have a role as an important regulator of transcription. Parafibromin has also been shown to interact with a histone methyltransferase complex that methylates histone H3 and to inhibit proliferation when overexpressed in mammalian cell lines. Despite these findings, the cellular localization of parafibromin has been controversial, with reports of both nuclear and nucleocytoplasmic localization. We have expressed wild-type and mutant parafibromin tagged with enhanced green fluorescent protein and have identified a functional bipartite nuclear localization signal (NLS) at residues 125-139 (nucleotides 373-417), KRAADEVLAEAKKPR, that is evolutionarily conserved and critical for the nuclear localization of parafibromin. We have also shown that the C-terminal arm of this bipartite NLS plays the primary role in nuclear localization. In support of these findings, specific HRPT2 mutations identified in HPT-JT or sporadic parathyroid carcinoma predicted to truncate parafibromin upstream of or within this NLS disrupt nuclear localization.

Amino Acid Sequence↗
PubMed2002

The calcimimetic agents: perspectives for treatment.

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca++), and control of urinary calcium excretion with small changes in blood Ca++. The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca++ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca++, can suppress PTH levels with a resultant fall in blood Ca++. Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca++, with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively short-term except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further long-term controlled studies are underway to further confirm the effectiveness and safety of these compounds.

Calcium-Binding Proteins↗
PubMed2006

Surgical approach to the patient with familial hyperparathyroidism.

Familial hyperparathyroidism encompasses the diagnoses of multiple endocrine neoplasia (MEN) type 1, MEN type 2A, and familial isolated primary hyperparathyroidism. All patients should undergo bilateral neck exploration and identification of all four or more parathyroid glands to evaluate for gross abnormalities. MEN-1 patients should have subtotal parathyroidectomy and cervical thymectomy because this operation achieves an appropriate balance between optimizing the potential for cure yet minimizing the risk of permanent hypocalcemia. However, MEN-2A patients may best be treated by selective resection of abnormal parathyroid glands, although some experts recommend a total parathyroidectomy and autotransplantation in the forearm. Familial isolated hyperparathyroidism is a rare disorder, and authors have described success in treatment with subtotal parathyroidectomy or limited adenoma resections. Some patients with familial isolated hyperparathyroidism also have jaw tumors, and members of these families are more likely to have parathyroid carcinoma. Concurrent cryopreservation of parathyroid tissue for all of these disorders is recommended if there is any concern for possible permanent hypoparathyroidism.

Humans↗
PubMed1996

Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic and carcinoid tumours.

OBJECTIVE: Allelic deletion of the retinoblastoma (Rb) gene on chromosome 13 has been reported in both pituitary and parathyroid tumours. We have investigated the roles of the Rb and the hereditary breast cancer susceptibility gene (BRCA2), which lie within 25 cM of each other on chromosome 13q12-14, in the multi-step aetiology of endocrine tumours. PATIENTS AND MEASUREMENTS: Seventy-seven endocrine tumours (43 anterior pituitary, 22 parathyroid, 7 carcinoid, and 5 pancreatic islet cell tumours) with paired leucocytes have been examined for loss of heterozygosity (LOH) at the Rb and BRCA2 loci by using specific oligonucleotide primers for the PCR amplification of microsatellite polymorphisms at three intragenic Rb markers, Rb1.20, Rbi4 and D13S153, and D13S260 which is linked to the BRCA2 locus. RESULTS: Seventy-five of the 77 tumour-leucocyte pairs were informative and LOH was detected in 1 of 16 non-functioning pituitary tumours, 1 of 8 prolactinomas, 3 of 19 parathyroid adenomas and 1 of 1 parathyroid carcinoma. All the 3 parathyroid adenomas with LOH were associated with aggressive clinical and histopathological features. Allele loss was not detected in any of the 16 somatotrophinomas, 2 corticotrophinomas, 1 gonadotrophinoma, 7 carcinoid tumours (6 bronchial, 1 metastatic intestinal) or 5 pancreatic islet cell tumours that were informative. CONCLUSIONS: These results demonstrate that allelic deletions of the 13q12-14 region occur in some pituitary adenomas and 16% of parathyroid adenomas. The extensive loss, which involves both the Rb gene and the BRCA2 locus, suggests that tumour suppressor genes in this region other than Rb or BRCA2 may be involved in the development and progression of some endocrine tumours.

BRCA2 Protein↗
PubMed2002

25-hydroxyvitamin D(3)-1alpha-hydroxylase expression in normal and pathological parathyroid glands.

Active vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], plays a pivotal role in calcium homeostasis and bone metabolism. Circulating levels of 1,25(OH)(2)D(3) are thought to be dependent mainly on the activity of the renal cytochrome P450 enzyme 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase), which is potently induced by PTH. However, 1alpha-hydroxylase activity or expression has also been reported at several extrarenal sites, at which local synthesis of 1,25(OH)(2)D(3) appears to fulfill autocrine or paracrine functions. This includes tissues such as placenta and brain that also express LRP-2/megalin, an endocytic receptor for multiple ligands, which is involved in the renal uptake of the substrate for 1alpha -hydroxylase, 25-hydroxyvitamin D(3). We have previously demonstrated LRP-2/megalin in parathyroid cells, and here we present results from RT-PCR and immunohistochemical analyses showing coincident expression of 1alpha-hydroxylase in normal and pathological parathyroid tissue. With real-time quantitative RT-PCR analysis, the expression of 1alpha-hydroxylase mRNA was higher in the majority of parathyroid adenomas and secondary hyperplastic glands but lower in parathyroid carcinomas, compared with normal parathyroid tissue. The findings imply that in addition to feedback control by circulating 1,25(OH)(2)D(3) levels, parathyroid cells may also be influenced by local 1alpha -hydroxylase activity with possible growth regulatory and differentiating effects.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1990

Thyroid and parathyroid cancer.

The epidemiology, etiology, pathology, and management of thyroid and parathyroid carcinoma are discussed. Emphasis is placed on the clinical differences in the management and treatment of the various histologic subtypes of thyroid cancer. The biologic and prognostic differences among the various histologic types of thyroid cancer and their relationship to age are stressed.

Aged↗
PubMed1987

Thyroid and parathyroid cancer.

The epidemiology, etiology, pathology, and management of thyroid and parathyroid carcinoma are discussed. Emphasis is placed on the clinical differences in the management and treatment of the various histologic subtypes of thyroid cancer. The biologic and prognostic differences among the various histologic types of thyroid cancer and their relationship to age are stressed.

Aged↗