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Query: UMLS:C0221002 (primary hyperparathyroidism)
 4,921 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary hyperparathyroidism (HPT) has shown prevalence of up to 3% among elderly women in Nordic health screening surveys, and is increasingly diagnosed in patients with diffuse neuromuscular or psychiatric symptoms. Primary HPT, even with mild hypercalcemia, is associated with increased mortality risk, mainly from cardiovascular disease. Despite the efficacy of new methods, reliable histopathologic distinction between adenomatous and hyperplastic parathyroid disease may still be difficult, and indeed circumstantial evidence suggests that adenoma and chief cell hyperplasia are not always distinctly separate pathophysiologic entities. Irrespective of symptoms, the hyperplasia is associated mainly with mild to moderate hypercalcemia, and may thus constitute an early form of HPT. A more liberal attitude to surgery in primary HPT would increasingly extend treatment to less clear-cut cases. The demonstration by monoclonal antiparathyroid antibodies of a specialized calcium receptor mechanism on the surface of parathyroid cells and its reduced expression in pathologic parathyroid tissue seems to explain defective parathyroid cell function and ensuing hypercalcemia in HPT. These antibodies appear to offer new prospects in parathyroid histopathology and research.
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PMID:Clinical and experimental advances in sporadic primary hyperparathyroidism. 218 96

Inactivating mutations of the parathyroid cell calcium receptor (CaR) gene cause one form of familial benign/hypocalciuric hypercalcemia, and in homozygous form, cause neonatal severe primary hyperparathyroidism with parathyroid hyperplasia. Thus, we postulated that partial or total loss of CaR function might contribute to calcium insensitivity or even stimulate cell proliferation in sporadic parathyroid adenomas (PAds). To examine this possibility, we sought loss of heterozygosity (LOH) for markers flanking the CaR locus (3cen-3q21) in 35 PAds. We used 16 highly-polymorphic PCR-based markers in paired normal and tumor DNA, extracted from slices of archived surgical specimens. Nineteen to 24 of the DNA pairs were informative with at least one marker. In two informative pairs, we found LOH for markers D3S1303, D3S1267, or D3S1269, which are tightly-linked with and flank the CaR locus. In one tumor, deletion mapping confined the lost area between D3S1271 and D3S1238 (41.7 centimorgans, cM). In the other tumor, LOH spanned most of chromosome 3, ranging at least from D3S1307 to D3S1311 (271.4 cM). LOH was confirmed by repetition of the experiments and quantified by phosphorimaging. Thus, we found LOH encompassing the CaR locus in approximately 10% of sporadic PAds. These data are consistent with the hypothesis that loss of CaR function may occur in PAds, with functional consequences for calcium sensitivity and cell proliferation.
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PMID:Genetic abnormalities in sporadic parathyroid adenomas: loss of heterozygosity for chromosome 3q markers flanking the calcium receptor locus. 759 8

Familial benign hypercalcemia (or familial hypocalciuric hypercalcemia), a syndrome of lifelong hypercalcemia inherited as an autosomal dominant trait, is distinct from the multiple endocrine neoplasia syndromes and other forms of inherited parathyroid disease. Familial benign hypercalcemia results from the inappropriate secretion of parathyroid hormone despite hypercalcemia, enhanced renal tubular reabsorption of calcium (independent of parathyroid hormone), and apparent tissue resistance to adverse effects of hypercalcemia. Heterozygosity for the familial hypercalcemia trait is benign, although homozygosity for the trait may lead to severe neonatal primary hyperparathyroidism. Genetic linkage studies show that most persons affected with familial hypercalcemia have a mutation on the long arm of chromosome 3 (3cen-q21), although one phenotypically indistinguishable family appears to have a mutation on the short arm of chromosome 19 (19p), and another family has neither 3q nor 19p mutations. One group has recently shown mutations in a putative parathyroid cell-surface calcium receptor that are plausible causes for the chromosome 3q variant of the familial hypercalcemia syndrome. Perhaps the other genes for this syndrome encode proteins representing hitherto-unknown regulators of systemic calcium metabolism independent of parathyroid cell calcium sensing or proteins involved in signal transduction from the calcium receptor.
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PMID:Familial benign hypercalcemia--from clinical description to molecular genetics. 805 90

In vivo dynamic tests of parathyroid gland function have provided useful information about the secretory behavior of parathyroids in various clinical disorders, but the limitations of this approach must be recognized when applied to studies of parathyroid gland physiology. Set point abnormalities have been documented in vivo both in primary hyperparathyroidism and in familial hypocalciuric hypercalcemia. Such findings are consistent with in vitro results obtained in studies of dispersed parathyroid cells from patients with primary hyperparathyroidism and with recently described alteration in calcium receptor expression in patients with FHH. The assessment of parathyroid gland function in patients with end-stage renal disease presents distinct methodological problems, however, because of marked variation in the degree of parathyroid gland enlargement. Neither the four parameter model originally used to describe set point abnormalities both in vitro and in vivo or alternative approaches to the assessment of PTH secretion in vivo adequately address this important issue. Results from recent in vivo studies of patients with chronic renal failure do not support the view that the set point for calcium-regulated PTH release is abnormal in secondary hyperparathyroidism or that treatment with calcitriol lowers the set point for calcium-regulated PTH release in patients with uremic secondary hyperparathyroidism. The concept of set point disturbances has strongly influenced discussions about the pathogenesis of secondary hyperparathyroidism, and it has served as a focal point for examining the therapeutic response to calcitriol in patients with this disorder. This matter requires careful reconsideration, however, in light of recent clinical findings and the development of techniques to directly assess the molecular mechanisms responsible for regulating calcium-mediated PTH release in renal failure and other disorders of mineral metabolism. Although knowledge in this area remains limited, the extent of parathyroid hyperplasia and the role of factors that influence the development of parathyroid gland enlargement may ultimately prove to be particularly important modifiers of parathyroid gland function in chronic renal failure.
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PMID:In vivo assessments of calcium-regulated parathyroid hormone release in secondary hyperparathyroidism. 894 64

Parathyroid cells express a plasma membrane calcium receptor (CaR), which is stimulated by a rise in extracellular calcium concentration ([Ca2+]ext). A decreased sensitivity to [Ca2+]ext occurs in adenomatous parathyroid cells in patients with primary hyperparathyroidism, but the underlying functional mechanism is not yet fully understood. This study explored whether CaR responsiveness is influenced by increasing the affinity of IP3 receptors--a major signalling component of other G-protein-coupled receptors. The sulphydryl reagent thimerosal was used to increase the responsiveness of IP3-receptors. Quantitative fluorescence microscopy in Fura-2-loaded cells was used to investigate the effects of thimerosal on the cytoplasmic calcium concentrations ([Ca2+]i) in human parathyroid cells and to compare its effects in a rat medullary thyroid carcinoma cell line (rMTC6-23) also expressing CaR. During incubation in Ca(2+)-free medium, thimerosal 5 microM induced a rapid sustained rise in [Ca2+]i in human parathyroid cells and no further [Ca2+]i increase appeared in response to the CaR agonist Gd3+ (100 microM). Thimerosal 1 microM induced only slow and minimal changes of basal [Ca2+]i and allowed a rapid response to Gd3+ 20 nM (a concentration without effect in control cells). The slope of the thimerosal-induced [Ca2+]i responses was steeper following exposure to CaR agonists. In the presence of 1 mM [Ca2+]ext, thimerosal (0.5 microM) induced a sharp increase in [Ca2+]i to a peak (within 60 s), followed either by return to basal [Ca2+]i or by a plateau of slightly higher amplitude. Similar results were obtained using rMTC6-23 cells. Thimerosal increases the responsiveness to CaR agonists through modulation of the sensitivity of the IP3 receptor in both parathyroid and rMTC6-23 cells.
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PMID:Thimerosal increases the responsiveness of the calcium receptor in human parathyroid and rMTC6-23 cells. 1059 73

Effects of extracellular calcium ([Ca(2+)](ext)) on parathyroid cells are mainly due to the activation of a plasma membrane calcium receptor (CaR) coupled with release of intracellular calcium. In addition, high [Ca(2+)](ext) activates the sphingomyelin pathway in bovine parathyroid cells, generating ceramides and sphingosine. This study explored the direct effects of synthetic ceramides on [Ca(2+)](i) in human parathyroid cells. Cells from five parathyroid adenomas removed from patients with primary hyperparathyroidism were dispersed and maintained in primary culture. Intracellular calcium concentration ([Ca(2+)](i)) [Ca(2+)](i) was monitored using standard quantitative fluorescence microscopy in Fura-2/AM-loaded cells. Laser scanning microscopy was used to monitor the intracellular distribution of a fluorescent ceramide analogue (BODIPY-C5). After addition of 10 microM C2-ceramide (N-acetyl-d-erythro-sphingosine), [Ca(2+)](i) increased rapidly (30-60 s) to a peak three times above basal levels in 70% of cells (37/55 cells in four experiments). This effect appeared to be due to release of Ca(2+) from intracellular stores rather than Ca(2+) entry from the extracellular medium. C2-responsive cells had a smaller [Ca(2+)](i) response to subsequent stimulation with the CaR agonist-neomycin (1 mM). These responses were specific to C2 since C6-ceramide (N-hexanoyl-d-erythro-sphingosine) did not affect basal [Ca(2+)](i) nor the responses to an increase in [Ca(2+)](ext) and to neomycin. C5-BODIPY generated intense perinuclear fluorescence, suggesting targeting of the ceramides to the Golgi apparatus. These data demonstrate that endogenous generation of ceramides has the potential to modulate changes in [Ca(2+)](i) and secretion in response to [Ca(2+)](ext) in human parathyroid cells.
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PMID:C2-Ceramide increases cytoplasmic calcium concentrations in human parathyroid cells. 1067 56

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia due to excessive secretion of PTH, is usually associated with hypophosphatemia and elevated serum chloride. Although PHPT was often complicated by renal stone disease and osteitis fibrosa in the past, routine screening of serum calcium (Ca) and development of sophisticated assay of parathyroid hormone have contributed to earlier detection of asymptomatic PHPT (APHPT). The proportion of APHPT patients, who have a mild elevation of serum Ca levels, usually within 1.0 mg/dL above the upper limit of normal, rose from 10-20% to approximately 45% of all PHPT patients in 1990-1995 in our clinic. Although it has been reported that the prevalence of PHPT is about 0.1% of the American population, the prevalence of PHPT appears to be far less in the Japanese population. Determination of a strategy for the increasing number of APHPT patients, is a pressing need but has yet to be accomplished. Treatment with bone antiresorptive drugs has met with some success, although the long-term efficacy of this treatment is not clear. The therapeutic effects of Ca-sensing receptor agonists appear promising.
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PMID:Pathophysiology and diagnosis of primary hyperparathyroidism--strategy for asymptomatic primary hyperparathyroidism. 1091 83

Primary hyperparathyroidism has been associated with bone loss, especially at cortical skeletal sites. Results from studies evaluating the mineral density of cancellous bone have been more difficult to interpret. Most densitometry studies support the concept that the parathyroid hormone appears to be catabolic at cortical sites and may have anabolic effects at cancellous bone sites. Studies completed to date, however, have been limited by design, definitions of fracture and inadequate control groups. Primary hyperparathyroidism is now increasingly being detected during the asymptomatic phase. The need for parathyroidectomy has been questioned in such patients because there may be no disease progression in the absence of surgery. Medical management of primary hyperparathyroidism has to date been limited to estrogen replacement therapy in postmenopausal women. Identification of the calcium receptor has improved our understanding of calcium homeostasis, and significant reductions in calcium receptor levels have been detected in parathyroid adenomas. Thus, a new class of therapeutics may include the calcimimetic agents. Bisphosphonates are also currently being evaluated with regard to their impact on fracture prevention and their beneficial effects on bone mineral density.
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PMID:Primary hyperparathyroidism: pathophysiology and impact on bone. 1093 81

Whether activation of the calcium receptor (CaR) modulates secretory events was investigated by real-time fluorescence and confocal microscopy using fura 2 and FM1-43 fluorescent dye. Two paradigms were used: human parathyroid cells, which are stimulated by a step from a high to a low extracellular calcium concentration ([Ca(2+)](ext)), and rMTC6-23 cells, a rat medullary thyroid carcinoma cell line whose secretion is stimulated by an increase in [Ca(2+)](ext). Parathyroid cells were dispersed from parathyroid adenomas removed from 18 patients with primary hyperparathyroidism. In both cell types, incubation with FM1-43 (2 microM) resulted in staining of the plasma membranes, which was rapidly increased following changes in [Ca(2+)](ext) known to stimulate secretion. A high [Ca(2+)](ext) and lanthanum (La(3+)) decreased the membrane-associated FM1-43 fluorescence. Prolonged incubation (5-30 min) in the presence of FM1-43 resulted in accumulation of the dye in the cytoplasm, its granular distribution suggesting targeting of the secretory compartment. These data suggest that FM1-43 fluorescence is determined by: (i) changes in cell membrane surface area associated with secretion-associated events, (ii) displacement/quenching by extracellular cations and (iii) endocytosis of the dye. In parathyroid cells, a rise in FM1-43 fluorescence occurred during incubation in a high (inhibitory) [Ca(2+)](ext) if the cytoplasmic calcium concentration ([Ca(2+)](i)) was decreased by the calcium chelator BAPTA/AM [bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] (10-50 microM). Alternatively, the expected rise in FM1-43 fluorescence did not occur during incubation in a low (stimulatory) [Ca(2+)](ext) if [Ca(2+)](i) was increased by addition of the calcium ionophore A23187 (10-25 microM). These data suggest that [Ca(2+)](i), rather than the absolute value of [Ca(2+)](ext), is the main modulator of secretion from parathyroid cells.
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PMID:Changes in cytoplasmic calcium determine the secretory response to extracellular cations in human parathyroid cells: a confocal microscopy study using FM1-43 dye. 1108 28

Parathyroidectomy provides effective treatment for primary and secondary hyperparathyroidism with a predictable response of symptoms related to hypercalcemia and elevated parathyroid hormone. Calcium and vitamin D supplementation has reduced the need for parathyroidectomy in dialysis patients with secondary hyperparathyroidism. However, surgery continues to be the only effective treatment of primary hyperparathyroidism. Potential nonoperative treatments for hyperparathyroidism have included the use of estrogen replacement, bisphosphonates, and a new class of drugs known as calcimimetics. Hormone replacement therapy with estrogen has been reported to improve cortical bone density in postmenopausal women with asymptomatic or mildly symptomatic primary hyperparathyroidism. Calcimimetic agents are a new class of drugs that increase the sensitivity of the calcium receptor to ionized calcium. Initial studies have shown that calcimimetics can acutely lower parathyroid hormone levels in patients with primary and secondary hyperparathyroidism. These drugs are currently being evaluated in phase II clinical trials. Ultimately, these medical modalities will need to be compared to parathyroidectomy in randomized controlled clinical trials.
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PMID:Nonoperative management of hyperparathyroidism: present and future. 1114 83


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