Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 2-week-old infant presented with bilateral rib fractures, hypercalcemia, and subperiosteal bone erosions. Parathyroid hormone levels were elevated and urine calcium low. Her parent's laboratory test results were normal. Gene sequencing revealed a new mutation of the calcium-sensing receptor gene, causing severe neonatal hyperparathyroidism, a variant of hypocalciuric hypercalcemia. This is a rare cause of neonatal hyperparathyroidism and nonabusive fractures.
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PMID:Hypocalciuric hypercalcemia presenting as neonatal rib fractures: a newly described mutation of the calcium-sensing receptor gene. 1711 Aug 64

Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous inactivation of the calcium-sensing receptor, which is notably expressed in parathyroid and kidney. FHH is characterized by asymptomatic hypercalcemia and hypophosphatemia and confers minimal, if any, morbidity. Renal transplantation in patients with FHH has not been described previously. This report describes a patient with FHH who developed end-stage renal disease from another cause and subsequently received a living related donor kidney transplant from her FHH-affected daughter. The excellent posttransplant clinical course of both recipient and donor is emphasized.
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PMID:Familial hypocalciuric hypercalcemia in the donor and recipient of a living related donor kidney transplant. 1721 34

The seven-spanning calcium-sensing receptor (CaSR) activates multiple G proteins including Gq and Gi, and thereby activates a variety of second messengers and inhibits parathyroid hormone (PTH) secretion. However, the exact signaling mechanisms underlying the functional activity of CaSR are not yet fully understood. The heterozygous inactivation of CaSR or its inhibition by antibody blocking results in either familial hypocalciuric hypercalcemia or acquired hypocalciuric hypercalcemia (AHH), respectively. Here, we report the identification of a unique CaSR autoantibody in an AHH patient. Paradoxically, we find that this autoantibody potentiates the Ca(2+)/Gq-dependent accumulation of inositol phosphates by slightly shifting the dose dependence curve of the Ca(2+) mediated activation of phosphatidylinositol turnover to the left, whereas it inhibits the Ca(2+)/Gi-dependent phosphorylation of ERK1/2 in HEK293 cells stably expressing human CaSR. Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca(2+), increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects. Our observations thus indicate that a calcium-stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi. Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion. This is the first report of a disease-related autoantibody that functions as an allosteric modulator and maintains G protein-coupled receptors (GPCRs) in a unique active conformation with its agonist. We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.
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PMID:An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. 1737 16

Secondary hyperparathyroidism (SHPT) is a common and serious consequence of chronic kidney disease (CKD). SHPT is a complex condition characterised by a decline in 1,25-dihydroxyvitamin D and consequent vitamin D receptor (VDR) activation, abnormalities in serum calcium and phosphorus levels, parathyroid gland hyperplasia, elevated parathyroid hormone (PTH) secretion, and systemic mineral and bone abnormalities. There are three classes of drugs used for treatment of SHPT: (i) nonselective VDR activators or agonists (VDRAs); (ii) selective VDRAs; and (iii) calcimimetics. The VDRAs act on the VDR, whereas the calcimimetics act on the calcium-sensing receptor. Calcimimetics are commonly used in conjunction with VDRA therapy. By virtue of the differences in their chemical structure, the nonselective and selective VDRAs differ in their effects on gene expression, and ultimately parathyroid gland, bone and intestine function. Medications in all three classes are effective in suppression of PTH; however, clinical studies show that calcimimetics are associated with an unfavourable tolerability profile and hypocalcaemia, whereas nonselective VDRAs, and to a lesser extent selective VDRAs, are associated with dose-limiting hypercalcaemia and hyperphosphataemia. Selective VDRAs also have minimal undesirable effects on calcium absorption in the intestine, and calcium and phosphorus mobilisation in the bone compared with nonselective VDRAs. Calcium load in patients with CKD can lead to vascular calcification, accelerated progression of cardiovascular disease and increased mortality. High serum phosphorus levels are also associated with adverse effects on cardiorenal function and survival. Recent evidence suggests that VDRAs are associated with a survival benefit in CKD patients, with a more favourable effect with selective VDRAs than nonselective VDRAs. Paricalcitol, a selective VDRA, is reported to exert specific effects on gene expression in various cell types that are involved in vascular calcification and the development of coronary artery disease. This article examines the molecular mechanisms that determine selectivity of VDRAs, and reviews the evidence for clinical efficacy, safety and survival associated with the three drug classes used for treatment of SHPT in CKD patients.
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PMID:Vitamin D receptor activator selectivity in the treatment of secondary hyperparathyroidism: understanding the differences among therapies. 1788 83

We describe the use of pamidronate to control marked hypercalcemia in an extremely premature infant with neonatal hyperparathyroidism that resulted from an inactivating mutation (R220W) of the calcium-sensing receptor. Despite improvement in bone mineralization and subsequent parathyroidectomy with normalization of the serum calcium level, the combination of chronic lung disease, osteomalacia, and poor thoracic cage growth ultimately proved fatal. Pamidronate therapy seems to be safe in the short-term and effective in helping control hypercalcemia even in the very premature infant, allowing for planned surgical intervention when it becomes feasible.
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PMID:Neonatal hyperparathyroidism and pamidronate therapy in an extremely premature infant. 1797 27

Successful kidney transplantation reverses mineral and bone disorder including secondary hyperparathyroidism, but persistent hyperparathyroidism with subsequent hypercalcemia emerges in a significant number of allograft patients. Among kidney-transplanted patients, approximately 5% will later require parathyroidectomy. Recently, the calcimimetic agent cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia where parathyroidectomy might be considered. Despite persistent down-regulation of vitamin D receptor and calcium-sensing receptor in nodular hyperplasia even after successful kidney transplantation, calcimimetics has been shown to be efficacious in reducing serum calcium levels in such patients. However, there still remain several problems of calcimimetics, such as long-term efficacy, safety, optimal time point for cessation, and long-term effect on cardiovascular morbidity and allograft function after kidney transplantation. Furthermore, surgical in dication for persistent hyperparathyroidism is also a clinically important question. Further researches are needed to elucidate these issues.
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PMID:[Basic and clinical aspects of calcimimetics. Calcimimetics : a promising treatment for persistent hypercalcemia after kidney transplantation]. 1817 73

The calcium-sensing receptor (CaR) is a seven transmembrane receptor incorporated into the cell membrane that is sensitive to extracellular calcium and other cations. The finding that the CaR is expressed on cancer cells has opened the door to a new understanding of the role of extracellular calcium as a promalignant stimulus through the CaR and its signaling apparatus as demonstrated in this thesis. I found, in a model of humoral hypercalcemia of malignancy (HHM), that stimulation of the CaR worsens the promalignant features of the testicular H-500 Leydig cancer cells that were used in my studies. The CaR upregulated the release of parathyroid hormone-related peptide (PTHrP), the main mediator of hypercalcemia in HHM. The growth rate of the tumor was also increased by stimulation of the CaR, as DNA synthesis and protection against apoptosis were enhanced. The oncogene, pituitary tumor-transforming gene (PTTG), was found to be upregulated by the CaR in the H-500 cells, whereas calcium had no effect on PTTG expression in the U-87 astrocytoma cell line, but other proproliferative agents did upregulate PTTG in the U-87 cells. This makes PTTG a potential marker of malignancy and a therapeutic target in cancer, where the CaR is promalignant. Nitric oxide synthase (NOS) exists in three isoforms, and I found that the CaR upregulated the inducible NOS but not the two other isoforms. This upregulation was accompanied by an increased production of NO. NO has been shown to be potentially promalignant, although such a role was not established in the H-500 cells. Therefore, the CaR stimulates several promalignant features in the H-500 cells. In turn, blocking these effects by targeting a proximal downstream signaling molecule of the CaR may be a future clinical approach, since blocking the CaR might have too many adverse effects on calcium homeostasis. In conclusion, the CaR plays diverse roles in cancer-acting as an inhibitor of cell proliferation in the colon crypt cells giving rise to colon cancer but as a promalignant receptor in most other cancer types, including Leydig cell cancers.
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PMID:The role of calcium-sensing receptor and signalling pathways in the pathophysiology in two in vitro models of malignant hypercalcemia: the rat rice H-500 Leydig testis cancer and prostate cancer (PC-3) cells. Expression and regulation of pituitary tumor transforming gene in Leydig testis cancer and astrocyte and astrocytoma cells. 1832 43

An increasing number of patients are diagnosed with primary hyperparathyroidism after having hypercalcaemia detected incidentally during routine biochemical screening. Many are asymptomatic at the time of diagnosis. An 80-year-old woman was found to have asymptomatic hypercalcaemia. Initial investigations suggested a diagnosis of primary hyperparathyroidism. Subsequent investigations revealed that, in fact, she had familial hypocalciuric hypercalcaemia. Direct DNA sequencing of the calcium-sensing receptor (CASR) gene confirmed that the patient was heterozygous for c.2501delC, a novel frame shift mutation predicted to cause loss of function of the CASR gene. Several other family members were subsequently found to carry the same mutation. Suspected cases of hypocalciuric hypercalcaemia should be confirmed by detection of mutations within the CASR gene. Establishing the correct diagnosis will enable the patient and family members to avoid unnecessary investigations or operations.
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PMID:A novel CASR gene mutation in an octogenarian with asymptomatic hypercalcaemia. 1852 93

Cinacalcet is a type II calcimimetic agent which is an allosteric modulator of the calcium-sensing receptor (CaR) located on the surface of the parathyroid cells. Cinacalcet increases the sensitivity of CaR via binding to the transmembrane region of CaR. Increasing sensitivity of CaR causes reduced secretion of parathyroid hormone (PTH) and suppression of serum calcium levels. Cinacalcet has recently been approved by Federal Drug Administration (FDA) for the treatment of patients with secondary hyperparathyroidism on maintenance dialysis and hypercalcemia in patients with parathyroid cancer. It is used also in Europe for both indications. Several controlled studies have shown that cinacalcet is effective in normalizing serum calcium levels also in primary hyperparathyroidism. Cinacalcet is metabolized primarily in the liver by N-dealkylation leading to carboxylic acid and oxidation of naphthalene ring to form dihydrodiols. The safety and optimal dosage of the drug in hypercalcemic patients with liver impairment remains unclear. We present a patient with Child-Pugh B class primary biliary cirrhosis who presented with moderate hypercalcemia and was diagnosed as primary hyperparathyroidism. As she refused having parathyroid surgery for her parathyroid adenoma at first, her hypercalcemia was treated successfully with 30 mg/day cinacalcet for 6 months. Cinacalcet was discontinued after 6 months. Her calcium level increased gradually. As she accepted surgery this time, her parathyroid adenoma was removed by minimally invasive parathyroidectomy. Parathyroid adenoma was confirmed pathologically. Her calcium levels maintained within the normal ranges after surgery.
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PMID:Hypercalcemia of primary hyperparathyroidism was treated by cinacalcet in a patient with liver cirrhosis. 1856 Oct 96

Secondary hyperparathyroidism (sHPT) is a frequent complication in patients with chronic kidney disease (CKD) and a known contributor to the development of vascular calcification and renal osteodystrophy (CKD-BMD). Secondary hyperparathyroidism is also related to increased cardiovascular mortality in CKD patients. With the discovery that molecules can modulate the calcium-sensing receptor (CaR) of the parathyroid gland, new treatment options are now available to control sHPT. Calcimimetics activate the CaR and-by increasing its sensitivity to calcium-can effectively decrease parathyroid hormone (PTH) secretion. Calcimimetic treatment with cinacalcet has resulted in an effective lowering of PTH levels in both animal and clinical studies. Most clinical studies have been performed in dialysis patients, and only a few studies have been carried out in patients with CKD stage 3 & 4 and renal transplant patients. In haemodialysis patients with sHPT, cinacalcet treatment could increase the number of patients achieving National Kidney Foundation Kidney Disease Outcomes Quality Initiative targets (PTH, calcium, phosphate) compared to standard therapy. In stage 3 and 4 CKD patients, cinacalcet has been reported to reduce PTH levels, however, at the expense of increasing phosphate serum levels. Several small studies have reported that calcimimetics reduced PTH levels and hypercalcaemia after renal transplantation. In addition, two studies on paediatric dialysis patients with sHPT reported effective PTH lowering. This review summarizes recent clinical studies with cinacalcet treatment in CKD patients.
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PMID:Calcimimetics in CKD-results from recent clinical studies. 1859 67


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