Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of idiopathic hypercalciuria (IH) has not been elucidated yet, but a correlation between IH and altered bone metabolism has been proposed. Since nitric oxide (NO) regulates osteoclasts' bone resorption, a possible role for NO can be suggested. In this study we evaluated iNOS gene expression by reverse transcription of mRNA from monocytes, followed by polymerase chain reaction in patients with IH subdivided into fasting (FH) and absorptive (AH) hypercalciuria. Since superoxide (O2-), which metabolizes NO, is overproduced by osteoclasts during bone resorption, peroxynitrite plasma level was evaluated as index of O2-. Vertebral BMD in IH as a whole group was lower vs controls (C) (Z score=-1.78+/-0.2 vs 0.51+/-0.25, p<0.001), but only FH patients showed a reduced bone density (2.13+/-0.18 vs 0.51+/-0.25, p<0.0001). PTH and calcitriol were not different. FH showed an increase in b-ALP vs AH and C (41.1+/-2.6 vs 30.1+/-3.9 vs 26.6+/-3.6 U/l p<0.02), and higher uHP, either on NCD (17.7+/-1.6 vs 11.4+/-1.3 mg/g uCr, p<0.04) or after LCD (26.7+/-2.5 vs 16.7+/-1.9, p<0.01). Cells from FH patients, but not from both AH patients and C, expressed iNOS. Peroxynitrite plasma level was elevated in FH (0.30+/-0.07) pmol/l while not detectable in AH and C. This study confirms an altered bone metabolism only in FH which shows an abnormal NO system. The increased iNOS gene expression in FH, in fact, points toward an altered NO system's activity downstream the generation of NO. A possible interaction of NO with O2-, which breaks down NO, and the role of this interaction in the pathophysiology of IH is discussed.
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PMID:Idiopathic hypercalciuria: O2(-)NO relationship and altered bone metabolism. 1080 Jul 59

Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.
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PMID:Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. 1084 46

Cloning of the CaR has increased understanding of the normal control of mineral ion homeostasis and has clarified the pathophysiology of PTH-dependent hypercalcemia. Cloning of the CaR has enabled identification of FHH and NSHPT as inherited conditions with generalized resistance to Ca2+o, which is caused in many cases by inactivating mutations in the CaR gene. In most kindreds with FHH, there is resetting of Ca2+o to a mildly elevated level that does not require an increase in the circulating level of PTH above the normal range to maintain it. FHH is not accompanied by the usual symptoms, signs, and complications of hypercalcemia. The kidney participates in the genesis of the hypercalcemia in FHH by avidly reabsorbing Ca2+; consequently, there is no increased risk of forming urinary calculi in most cases. Generally, there is no compelling rationale for attempting to lower the level of Ca2+o in these patients to a nominal normal level. In contrast, in primary hyperparathyroidism, the Ca2+o resistance is limited to the pathologic parathyroid glands, and the rest of the body suffers the consequences of high circulating levels of calcium, PTH, or both. In this condition, removal of the offending parathyroid glands is often the treatment of choice. Parathyroidectomy may also be appropriate in disorders with generalized resistance to Ca2+o owing to inactivating CaR mutations in the following special circumstances: in selected families with FHH in which there is unusually severe hypercalcemia, frankly elevated PTH levels, or atypical features such as hypercalciuria; in cases of NSHPT with severe hypercalcemia and hyperparathyroidism; and in the occasional mild case of homozygous FHH owing to CaR mutations that confer mild-to-moderate resistance to Ca2+o that escapes clinical detection in the neonatal period. As discussed elsewhere in this issue, selective calcimimetic CaR activators are being tested in clinical trials, which potentiate the activation of the CaR by Ca2+o, thereby resetting the elevated set point for Ca2+o-regulated PTH release in primary and secondary hyperparathyroidism toward normal. It is hoped that these agents may become an effective medical therapy for the acquired Ca2+o resistance in primary and secondary hyperparathyroidism and perhaps for that present in the unusual cases of FHH and NSHPT, resetting the "calciostat" downward and thereby reducing Ca2+o and PTH toward normal.
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PMID:Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium. 1103 58

Gain-of-function mutations in the calcium ion-sensing receptor (CaR) cause hypocalcemia with low PTH levels. It is stated that patients with activating CaR mutations generally show milder degree of hypocalcemia before treatment and more profound hypercalciuria during treatment than those with idiopathic hypoparathyroidism (IHP). To test this validity we analyzed the data of serum and urinary calcium collected from 85 patients with IHP and 15 with activating CaR mutations. The mean (+/-SEM) serum calcium concentration before treatment was significantly higher (P: < 0.001) in patients with activating CaR mutations (1.76 +/- 0.05 mmol/L; n = 15) than in those with IHP (1.41 +/- 0.03; n = 58), but there was a substantial overlap in the range of hypocalcemia between the two groups (1.25-2. 05 vs. 0.90-1.95). The mean urinary calcium/creatinine ratio (Ca/Cr) in patients with activating CaR mutations before treatment (0.362 +/- 0.045 mmol/mmol; n = 9) was almost equal to that in normocalcemic controls (0.331 +/- 0.022; n = 56) and markedly higher (P: < 0.001) than in patients with IHP (0.093 +/- 0.008; n = 57). The overlap of pretreatment urinary Ca/Cr between the 2 disorders was relatively small; subnormal urinary Ca/Cr was observed in only 1 of 9 patients with CaR mutations and in the majority (49 of 57) of patients with IHP. In contrast to pretreatment findings, the degree of hypercalciuria during treatment was not different between the 2 disorders. The data points of urinary Ca/Cr plotted as a function of the serum calcium concentration were not separable between patients with CaR mutations (n = 8) and those with IHP (n = 40). Comparison of urinary Ca/Cr between 2 patients with a CaR mutation and 7 with IHP over a wide range of serum calcium concentrations measured during 4-8 yr of treatment also indicated that the 2 disorders were inseparable. These results suggested that inappropriately normal urinary Ca/Cr in patients with untreated hypocalcemia, mostly of mild degree, might be a better biochemical clue than the development of severe hypercalciuria during treatment to suspect gain-of-function mutations in the CaR.
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PMID:Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor: is it possible to differentiate the two disorders? 1113 12

In this study, the biochemical and clinical profile of primary hyperparathyroidism, diagnosed in 155 patients (106 females and 49 males) in the Department of Nephrology of the Silesian University School of Medicine in the years 1972-1998 was analyzed. The mean age of patients was 48.5 +/- 12.8 years. In all cases the diagnosis was confirmed by the pathomorphological examination. In the majority of cases PNP was diagnosed in a phase of advanced organic injuries. The leading clinical finding in these patients was nephrolithiasis. Asymptomatic hypercalcemia was diagnosed only in 9% of cases. In the years 1972-1992 elevated serum total calcium concentration was found in 92.6% while after introduction of routine estimation of ionized calcium concentration in 1993, hypercalcemia was found in all patients. The incidence of hypercalciuria increased significantly in patients diagnosed in the period 1993-1998 while in this same period the incidence of impaired renal function declined significantly. The elevated serum PTH was found in 86% of patients regardless whether C-terminal fragments of PTH or intact PTH-1-84 were assessed. Elevated levels of ionized serum calcium with normal or increased plasma iPTH-1-84 level are the most constant symptoms of primary hyperparathyroidism.
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PMID:[Clinical and biochemical picture of primary hyperparathyroidism based on 155 observed cases]. 1123 60

In general, bone loss from glucocorticoid treatment occurs rapidly within the first 6 months of therapy. Glucocorticoids alter bone metabolism by multiple pathways; however, the bone loss is greatest in areas rich in trabecular bone. Preventive measures should be initiated early. It is the author's opinion that all subjects initiating treatment with prednisone at 7.5 mg or greater require calcium supplementation (diet plus supplement) at a dose of 1500 mg and vitamin D at a dose of 400 to 800 IU/d. If the patient is going to remain on this dose of glucocorticoid for more than 4 weeks, an antiresorptive agent should be started (e.g., estrogen, bisphosphonate, raloxifene). If a patient has established osteoporosis and is either initiating glucocorticoid therapy or is chronically treated with prednisone at 5 mg d or greater in addition to calcium and vitamin D supplementation, a potent antiresorptive agent (bisphosphonate) should be started. A bone mineral density measurement of either the lumbar spine or the hip may be helpful is assessing an individual's risk of osteoporosis, may improve compliance with treatment, and can be used to monitor the efficacy of the prescribed therapy. There is no reason to withhold treatment for glucocorticoid-induced bone loss until a bone mass measurement is taken, however. In motivated patients, a weight-bearing and resistance exercise program should be prescribed to help retain muscle strength and prevent depression. If hypercalciuria develops with glucocorticoid use, either thiazide diuretics or sodium restriction may be helpful. In patients who continue to lose bone or experience fracture's despite antiresorptive therapy while on glucocorticoids, bone-building anabolic agents (e.g., hPTH 1-34 or PTH 1-84) may be available someday soon.
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PMID:An update on glucocorticoid-induced osteoporosis. 1128 98

We report a new kindred of hereditary hypophosphatemic rickets with hypercalciuria. The symptomatic child and several relatives had increased renal phosphate clearance leading to hypophosphatemia, hyperabsorptive hypercalciuria, low PTH and increased 1,25-(OH)2D serum level. However, association with vitamin D deficiency and normal urinary excretion of cyclic AMP might suggest another tubular defect in phosphate transport.
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PMID:Hereditary hypophosphatemic rickets with hypercalciuria: report of a new kindred. 1134 Mar 56

Decreased bone density and increased fracture risk are seen in patients with SCI. The bone resorption rate is markedly increased. Hypercalciuria, low PTH, and low 1,25 (OH)2 vitamin D are commonly seen. Bed-rest studies show similar findings, but of lesser magnitude. Therapies to treat or prevent osteoporosis include optimal nutrition (with care to avoid exacerbating hypercalciuria). Weight-bearing or functional electrical stimulation cycle ergometry may prevent some of the bone loss, especially in acutely injured patients. Estrogen should be considered in postmenopausal or amenorrheic women, but not if they are at high risk of thromboembolism. More research on effects of estrogen is needed in this population. Bisphosphonates may also help prevent the acute bone loss; oral routes must not be used in recumbent patients. Thiazides could be useful as adjunct therapy.
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PMID:Osteoporosis in women with spinal cord injuries. 1185 32

The cloning of the extracellular calcium-sensing receptor(CaSR) has helped to define a key component in the control of the calcium homeostasis. Gain-of-function mutations in the CaSR gene were identified as the cause of autosomal dominant hypocalcemia (ADH). This clinical condition is compatible with hypoparathyroidism because of low PTH levels compared with serum calcium levels. Until now, 21 missense mutations of the CaSR were identified as a cause of hypoparathyroidism (HP). Mutations present in transmembrane domain may produce more severe hypocalcemia than those present in other domains. We emphasize that it is important to differentiate ADH from PTH-deficient HP, because treatment with vitamin D to correct the hypocalcemia in the former may lead to more severe hypercalciuria, nephrocalcinosis, and renal impairment.
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PMID:[Familial hypoparathyroidism due to activating mutations in the calcium-sensing receptor gene]. 1185 22

Parathyroid hormone-related protein (PTHrP) and PTH share the common PTH/PTHrP receptor. Although an elevated level of circulating PTHrP in patients with malignancies causes hypercalcemia as does PTH, chronic and systemic effects of PTHrP on bone metabolism in humans are not well understood because tumor-burden patients showing hypercalcemia usually have a poor prognosis. We investigated bone and calcium metabolism in a patient with malignant islet cell tumors showing hypercalcemia due to the elevated plasma PTHrP level for 7 years. Hypercalcemia and hypercalciuria continued throughout the clinical course in spite of frequent infusions of bisphosphonates. Bone resorption markers and a bone formation marker were consistently elevated as seen in primary hyperparathyroidism, a disease caused by an autonomous hypersecretion of PTH. Based on biochemical measurements including bone markers and serum 1,25-dihydroxyvitamin D, the clinical features of this case essentially are the same as those of primary hyperparathyroidism except for the elevated level of plasma PTHrP with suppressed intact PTH level. Therefore, it is suggested that chronic and systemic effects of PTHrP on bone as well as calcium metabolism are indistinguishable from those of PTH in human.
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PMID:Parathyroid hormone-related protein induced coupled increases in bone formation and resorption markers for 7 years in a patient with malignant islet cell tumors. 1200 5


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