Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0221002 (primary hyperparathyroidism)
 4,921 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor. They lower the threshold for receptor activation by extracellular calcium ions and, in parathyroid cells, diminish parathyroid hormone secretion. Calcimimetic compounds represent a novel class of therapeutic agents that may provide a way of controlling excess parathyroid hormone secretion in several clinical disorders. Although experience from clinical trials in humans is limited, available data suggest that calcimimetic agents effectively lower plasma parathyroid hormone levels in patients with primary hyperparathyroidism and those with secondary hyperparathyroidism caused by end-stage renal disease. Calcimimetic compounds thus have considerable potential as a new approach to the medical management of several important clinical disorders of bone and mineral metabolism.
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PMID:Calcimimetic agents for the treatment of hyperparathyroidism. 1149 49

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.
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PMID:The calcimimetic agents: perspectives for treatment. 1198 29

Primary hyperparathyroidism is a life-threatening rare disorder. It is seen as a result of neonatal primary hyperparathyroidism, familial hypocalciuric hypercalcemia, increased vitamin D levels and inactivation of calcium sensing receptor mutations. The clinical findings are hypotonia, bone demineralization, hypercalcemia and parathyroid hyperplasia. We present a six-month-old female patient, the first child of nonconsanguineous parents, who was referred for the investigation of failure to thrive, vomiting, constipation, fever, abdominal distention and hypotonia. Physical examination revealed weight under 3rd percentile, height 3rd-10th percentile, decreased subcutaneous fat, and distention of the abdomen. In neurological examination, hypotonia, motor-mental retardation, and active deep tendon reflexes were found. The biochemical values at the time of admission revealed primary hyperparathyroidism. Since hypercalcemia did not respond to calcitonin therapy and due to the mortality of hypercalcemia, parathyroidectomy was performed. Because hyperparathyroidism and hypercalcemia continued, angiography was done which revealed increased parathyroid hormone levels in the periphery of the innominate vein. Exploratory surgery followed, but hyperparathyroidism and hypercalcemia persisted after all of these procedures. Calcium-sensing receptor mutations and supernumerary gland were considered. Because hypercalcemia persisted, pamidronate therapy was initiated on a monthly basis.
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PMID:Persistent elevated serum levels of intact parathyroid hormone after reoperation for primary hyperparathyroidism and after pamidronate therapy. 1469 11

The most important step in calcium homeostasis is the regulation of parathyroid hormone (PTH) secretion. The discovery and characterization of the calcium sensing receptor (CaR) of the parathyroid cell has led to a better understanding not only of the physiology of the parathyroid glands, but also of the development of hyperparathyroidism. Drugs acting on CaR can now be designed to treat hyperparathyroidism and osteoporosis. The workshop on primary hyperparathyroidism held at the National Institutes of Health in 2002 has recommended new guidelines for the treatment of asymptomatic hyperparathyroidism. Controversy still exists regarding the treatment of patients with non-classical symptoms, such as weakness, fatigue and depression. Primary hyperparathyroidism as a risk factor for cardiovascular disease and mortality is also debated. Improved techniques for the preoperative localization of pathological parathyroid glands have led to a shift in surgical strategy: surgeons abandon the traditional bilateral neck exploration in favor of a more limited approach. This change of strategy has not been based on the results of prospective randomized studies and the long term results are not known.
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PMID:Primary hyperparathyroidism. Update on pathophysiology, clinical presentation and surgical treatment. 1565 69

Although a diagnosis of primary hyperparathyroidism and hypothyroidism becomes very easy at the present time due to development of highly sensitive assay for parathyroid hormone, the diagnosis of hyper- and hypothyroidism should be made by excluding the loss and gain of function mutation of calcium sensing receptor, respectively. When a diagnosis of primary hyperparathyroidism is made but the localization of adenoma(s) is not identified, the patient should be referred to specialists for parathyroid surgery. Although patients with primary hypoparathyroidism can be followed by a general physician, they should be referred to specialists when they become pregnant, since active vitamin D is increased and decreased in the late pregnancy and in the postpartum period, respectively.
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PMID:[Referral of patients with parathyroid dysfunction to specialists--which patients should be referred to parathyroidologists?]. 1632 80

The frequency of hypercalciuria is increasing in western countries with an incidence of nephrolithiasis which can reach 13%. Hypercalciuria appears as an alteration of the calcium transport system (kidney, bowel, bone) which is regulated by calcitriol and parathormone. The aim of this review was to screen etiologies of hypercalciuria taking into account recent genetic advances (calcium epithelial channel and calcium sensing receptor). Hypercalciuria may be favored by nutritional causes (diet rich in calcium, sodium, carbohydrates, proteins, poor in phosphates and potassium). It may also be related to an increase in calcium absorption (vitamin D excess, primary hyperparathyroidism, sarcoidosis, lymphoma, estrogens, and certain genetic causes), an increase in osteoresorption (bone metastasis, myeloma, Paget, hyperthyroidism, immobilization, hypercortisolism and corticosteroid therapy), or a decrease of kidney tubular resorption (diuretics, Cacci and Ricci, acromegally, Bartter, familial dominant hypocalcemia, Fanconi, Dent, familial hypomagnesemia-hypercalciuria syndrome, type 1 distal tubular acidosis, pseudohypoaldosteronism, diabetes). If no cause is identified, persistence of hypercalciuria after instituting a correct diet is defined as idiopathic hypercalciuria. Treatment of the cause is essential in secondary hypercalciuria, in addition to diet (low sodium intake, normocalcic diet, hydration), associated with thiazide diuretics and biphosphonates if necessary.
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PMID:[Hypercalciuria]. 1635 16

The calcium-sensing receptor has a key role in calcium homeostasis, it is involved in the regulation of the serum calcium level within minutes via the secretion and action of parathyroid and the excretion of calcium in the kidney in a negative feedback manner. Mutations of the calcium sensing receptor gene leads to inactivating and activating mutations resulting in diseases with hypercalcaemia and hypocalcaemia. The loss of function mutations are associated with familial benign hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease characterised by lifelong mild hypercalcaemia, low urinary calcium excretion, and inappropriate high parathyroid hormone levels, sometimes difficult to distinguish from mild asymptomatic primary hyperparathyroidism. Patients with FHH did not profit from parathyroidectomy, a calcium lowering therapy is not necessary. The gain of function mutations of the calcium-sensing receptor are associated with autosomal dominant hypocalcaemia (ADH), a disease characterised by a generally asymptomatic hypocalcaemia, inappropriately high urinary calcium excretion and normal PTH levels. A therapy to raise the serum calcium concentration has to be done carefully and is only indicated in symptomatic patients, because of enhancement of hypercalciuria with the risk of nephrocalcinosis and nephrolithiasis. Molecular genetic analysis of the calcium sensing receptor gene facilitates the sometimes difficult diagnosis. The development of compounds modulating the calcium sensing receptor function and thereby the section of PTH may become an important role in treatment of diseases of calcium metabolism.
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PMID:The role of the extracellular calcium-sensing receptor in health and disease. 1703 19

The cloning of the calcium sensing receptor (CaR) confirmed that parathyroid cells monitor extracellular calcium concentration ([Ca2+]ext) via a receptor-type mechanism. This lead to the hypothesis that abnormalities in the expression and/or function of the CaR could explain the biochemical abnormalities in primary hyperparathyroidism (PHPT). Cultured cells from parathyroid adenomas of patients operated for PHPT were used to monitor real-time changes in intracellular calcium concentration ([Ca2+]i) as measured by fluorescent microscopy using the Fura-2/AM dye. We found that CaR agonists trigger release of intracellular calcium pools and such responses are amplified by increasing the affinity of IP3 receptors. Using confocal microscopy to monitor membrane trafficking in living parathyroid cells labelled with the fluorescent dye FM1-43, we found that a decrease in [Ca2+]i rather than an absolute change in [Ca2+]ext is the main stimulus for exocytosis from human parathyroid cells. These data suggest that, in PHPT, a defective signalling mechanism from the CaR allows cells from parathyroid adenomas to maintain low [Ca2+]i with uninhibited PTH secretion in the face of hypercalcaemia. Over longer periods of time, CaR controls parathyroid proliferation via changes in tyrosine phosphorylation. We found that multiple proteins of molecular weight 20-65 kDa are phosphorylated within 10-60 min in response to CaR agonists. Further work demonstrated that high [Ca2+]i stimulates the expression of bcl-2 oncoprotein in cultured human parathyroid cells and that, in parathyroid adenomas, predominant expression of bcl-2 rather than bax oncoprotein might prevent apoptosis and explain the slow growth rate of these tumours. More recently, it became apparent that CaR stimulates cell proliferation in several cell types not involved in calcium homeostasis. Using archived histological material from 65 patients who died with metastatic breast cancer, we identified CaR expression predominantly in tumours from patients who developed bone rather than visceral metastases (35 of 49 versus 7 of 16; P < 0.01, chi-squared test). These data suggest that CaR expression has the potential to become a new biological marker predicting the risk of bone metastases in patients with breast cancer. A prospective study should investigate if patients with CaR-positive tumours are more likely to develop bone metastases and whether they could benefit more from prophylactic treatment with bisphosphonates or the newly developed CaR antagonists.
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PMID:The calcium sensing receptor: from understanding parathyroid calcium homeostasis to bone metastases. 1849 87

The calcium sensing receptor (CaSR) is expressed in cells secreting calcium-regulating hormones, in cells involved in calcium transport and in many other tissues, with an as yet not completely defined role. In parathyroid cells, the CaSR stimulation inhibits parathyroid hormone (PTH) secretion, synthesis and parathyroid cell proliferation. Cinacalcet belongs to calcimimetic type II compounds that can interact with CaSR, increasing its affinity for calcium. Clinical studies have proved cinacalcet to be effective in reducing calcium and PTH levels in primary hyperparathyroidism and in reducing PTH, calcium and phosphate in patients with secondary hyperparathyroidism owing to chronic renal failure, with a relatively safe profile, the only reported adverse events being hypocalcaemia and gastrointestinal symptoms. However, though calcimimetics do represent a real advancement in the field of the treatment of PTH secretion disturbances, there is a need for clinical trials, which should aim to demonstrate that a better control of biochemical parameters is also matched with better clinical outcomes.
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PMID:Cinacalcet: pharmacological and clinical aspects. 1904 Mar 30

We report a patient with familial hypocalciuric hypercalcemia (FHH) associated with primary hyperparathyroidism (PHPT) and incidental papillary thyroid carcinoma. The patient showed hypercalcemia, high parathyroid hormone (PTH) levels and low urinary calcium excretion. A computed tomography (CT) scan revealed an enlarged parathyroid gland. Ultrasonography (US) and aspiration cytology revealed microcarcinoma of the left lobe of the thyroid gland. Screening studies of his family revealed that four of five family members had hypocalciuric hypercalcemia and normal PTH level. Sequencing analysis of the calcium sensing receptor gene revealed a novel heterozygous mutation (3193delA) in the patient and his family members with hypercalcemia, but one with normocalcemia. The patient underwent total thyroidectomy, central node dissection and extirpation of the enlarged parathyroid gland. Surgery is not indicated for FHH; however, FHH may be accompanied with parathyroid adenoma causing PHPT, as reported here, for which surgical treatment is indicated.
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PMID:A patient with primary hyperparathyroidism associated with familial hypocalciuric hypercalcemia induced by a novel germline CaSR gene mutation. 1942 60


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