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)

Absorptive hypercalciuria (a stone-forming condition) is characterized by gut hyperabsorption of calcium, hypercalciuria, and reduced bone density. Inasmuch as these features implicate enhanced calcitriol action in gut and bone, we analyzed the vitamin D receptor (VDR) gene to ascertain whether an abnormality of this gene marks patients with intestinal hyperabsorption of calcium. We have compared the frequency of a restriction fragment length polymorphism (Bsm I) associated with different alleles of the VDR gene in a group of 33 well characterized absorptive hypercalciuric patients and a group of 36 normal race- and age-matched control subjects. There was no difference between the distribution of the VDR alleles in the patient population when compared with the normal population. The coding region of VDR messenger RNA was also normal, as determined by both DNA sequence analysis and chemical mismatch cleavage analysis of copy DNA from 11 index absorptive hypercalciuric patients. On the basis of these results, we propose that the enhanced intestinal calcium absorption invariably seen in absorptive hypercalciuria and attendant symptoms of this disorder are not attributable to mutations of the VDR and are not linked to a common VDR genotype.
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PMID:Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria. 755 81

Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.
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PMID:[Immune modulation by vitamin D analogs in the prevention of autoimmune diseases]. 857 69

The author demonstrates on a group of 292 patients (207 women, 85 men) treated on account of various diseases with corticoids laboratory parameters and bone density and records of bone fractures. The bone metabolism is negatively influenced by the action of corticoids on the vitamin D transformation into its active metabolites; as a result of reduced calcium absorption from the gut the reduced calcium level in blood causes secondary hyperparathyroidism and osteoclastic bone resorption is enhanced. On the other hand, corticoids inhibit new formation of bone by suppressing the proliferation of osteoblasts and by interfering with osteoid formation. One quarter of the patients suffers moreover from osteoporomalacia. Two and a half times as many women have steroid osteoporosis, and bone demineralization is enhanced also by other factors caused by the basic disease (immobilization, hypercalciuria, lactose intolerance). By comprehensive treatment using a combination of Ca + F, vitamin D, exercise, thyrocalcitonin, Osteogenon and recently also the third series of bisphosphonates it proved possible to increase within one year the bone density on average by 4.5% of normal values. The number of fractures declined dramatically.
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PMID:[Steroid osteoporosis]. 982 82

Laboratory animal, clinical and epidemiological studies in the published literature have been reviewed in order to establish whether excessive salt intake is an important risk factor for the development of osteoporosis and whether an intervention strategy based on salt restriction would be beneficial in the prevention of osteoporosis. Genetic factors appear to be far more important than the combination of nutritional, hormonal, environmental and lifestyle factors in the pathogenesis of osteoporosis. The most important single non-genetic factor is oestrogen deficiency in postmenopausal women. Preventive measures should be aimed at maximizing peak bone mass at skeletal maturity and retarding bone loss thereafter. Apart from postmenopausal oestrogen deficiency, various factors have been incriminated as risk factors for osteoporosis, and these include age at menarche, age at and years since menopause, insufficient physical exercise, alcohol, smoking, low calcium intake, low or high protein intake and high intake of phosphorus, sodium or caffeine. Many of the risk factors are considered to be weak, although when combined they could impact significantly on bone health. Increased intakes of various nutritional factors (potassium, magnesium, zinc, vitamin C), fibre and alkaline-producing fruit and vegetables favour adult bone health. Calcium homeostasis is normally well regulated such that increased calcium loss via the urine leads to increased calcium absorption from the gut. However, the duration of this adaptive process may be greater than that of many of the studies demonstrating that increased salt intake leads to both increased sodium and calcium in the urine. In any case, higher urinary calcium output appears to be seen only in a minority of humans in response to increased salt intake. As numerous factors-genetic, nutritional, hormonal and lifestyle-are involved in the maintenance of calcium homeostasis, it is difficult to devise human studies which adequately take into account all the important factors. Another difficulty is that many past studies have relied on imprecise methods for the measurement of bone resorption. Nor have studies based on the use of the laboratory rat produced clear answers to the problem because the rat, as a species, is uniquely deficient in its ability to handle the relevant minerals. Limited studies to date indicate that increased sodium intake neither exerts a consistent effect on various biomarkers of bone health nor leads to irreversible changes in the bone modelling process in men or in pre- or postmenopausal women. We conclude from the available evidence that increased sodium (or salt) intake is not an important risk factor for osteoporosis and that a reduction of salt intake from 9 to 6g/day in the diet would not be beneficial as an intervention measure in the prevention of osteoporosis. More research is needed to (i) assess the effects (especially long-term) of various nutrients including sodium on bone health, (ii) assess the long-term value of any intervention strategy involving reduced intake of a particular nutrient such as sodium; and (iii) determine whether subpopulations exist particularly in the elderly (e.g. sodium-responsive subjects) in which adaptation to sodium-induced hypercalciuria may be compromised. General prudence dictates that excessively high levels of dietary salt should be eschewed by those persons with raised blood pressure or a limited range of genetic disorders. However, for the generally healthy person there is no sound evidence that the consumption of salt at the present average level of 9g/day constitutes a risk factor for osteoporosis.
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PMID:Review of risk factors for osteoporosis with particular reference to a possible aetiological role of dietary salt. 1071 63

To investigate the role of the pro alpha 2(I) collagen chains of type I collagen in mineralization we used the oim (osteogenesis imperfecta model) mouse as our model system. The oim/oim mouse (homozygous for a null mutation in its COL1A2 gene of type I collagen) fails to synthesize functional pro alpha 2(I) collagen chains, synthesizing only homotrimers of pro alpha 1(I) collagen chains. To evaluate the role of pro alpha 2(I) collagen in type I collagen structure/function in mineralized tissues, we examined age-matched oim/oim, heterozygous (oim/+), and wild-type (+/+) mouse femurs and incisors for mineral composition (calcium, phosphorus, magnesium, fluoride, sodium, potassium, and chloride) by neutron activation analyses (NAA), and bone mineral content (BMC) and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) in a longitudinal study (7 weeks to 16 months of age). NAA demonstrated that oim/oim femurs had significant differences in magnesium, fluoride, and sodium content as compared with +/+ mouse femurs, and oim/oim teeth had significant differences in magnesium content as compared to +/+ teeth. The ratio of calcium to phosphate was also significantly reduced in the oim/oim mouse femurs (1.58 +/- 0.01) compared with +/+ femurs (1.63 +/- 0.01). DEXA demonstrated that oim/oim mice had significantly reduced BMC and BMD as compared to oim/+ and +/+ mice. Serum and urine calcium, magnesium, and phosphorus levels, and Ca(47) absorption across the gut were equivalent in oim/oim and +/+ mice, with no evidence of hypercalciuria. These studies suggest that the known decreased biomechanical properties of oim/oim bone reflect both altered mineral composition as well as the decreased BMD, which further suggests that the presence of alpha2(I) chains plays an important role in mineralization.
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PMID:Oim mice exhibit altered femur and incisor mineral composition and decreased bone mineral density. 1091 14

Hypercalciuria with or without hypercalcemia is a well-known complication of sarcoidosis, the pathogenesis of which is not fully understood. Pregnancy is associated with physiologic alterations in calcium metabolism. These changes can further alter the derangement of calcium metabolism that occurs in sarcoidosis, if the two conditions coexist. We had the opportunity to study prospectively the changes in serum and urine calcium along with all the hormonal changes that occur during pregnancy in a young woman with sarcoidosis, who had hypercalciuria at presentation. We believe that an increased level of calcitriol is central to the calcium abnormalities in our patient. In her case, the increased calcitriol is derived from sarcoid granulomas and renal sources enhanced by the effect of estradiol and prolactin on the conversion of 25(OH)D to 1,25(OH)(2) D. She acquired hypoparathyroidism, with normal serum calcium, which probably was due to the direct suppression of parathyroid hormone (PTH) secretion by calcitriol. Finally, hypercalciuria is the result of the combined effect of hyperabsorption of calcium from the gut (the result of increased calcitriol levels leading to increased filtration of calcium) and decreased tubular reabsorption of calcium, as a result of undetectable PTH.
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PMID:Pregnancy and sarcoidosis: an insight into the pathogenesis of hypercalciuria. 1536 85

We identified the human ortholog of soluble adenylyl cyclase (hsAC) in a locus linked to familial absorptive hypercalciuria and cloned it from a human cDNA library. hsAC transcripts were expressed in multiple tissues using RT-PCR and RNA blotting. RNA blot analysis revealed a predominant 5.1-kb band in a multiple human tissue blot, but three splice transcript variants were detected using RT-PCR and confirmed by performing sequence analysis. Immunoblot analysis showed 190- and 80-kDa bands in multiple human cell lines from gut, renal, and bone origins in both cytosol and membrane fractions, including Caco-2 colorectal adenocarcinomas, HEK-293 cells, HOS cells, and primary human osteoblasts, as well as in vitro induced osteoclast-like cells. The specificity of the antiserum was verified by peptide blocking and reduction using sequence-specific small interfering RNA. Confocal immunofluorescence cytochemistry localized hsAC primarily in cytoplasm, but some labeling was observed in the nucleus and the plasma membrane. Cytoplasmic hsAC colocalized with microtubules but not with microfilaments. To test the function of hsAC, four constructs containing catalytic domains I and II (aa 1-802), catalytic domain II (aa 231-802), noncatalytic domain (aa 648-1,610), and full-length protein (aa 1-1,610) were expressed in Sf9 insect cells. Only catalytic domains I and II or full-length proteins showed adenylyl cyclase activity. Mg(2+), Mn(2+), and Ca(2+) all increased adenylyl cyclase activity in a dose-dependent manner. While hsAC had a minimal response to HCO(3)(-) in the absence of divalent cations, HCO(3)(-) robustly stimulated Mg(2+)-bound hsAC but inhibited Mn(2+)-bound hsAC in a dose-dependent manner. In summary, hsAC is a divalent cation and HCO(3)(-) sensor, and its HCO(3)(-) sensitivity is modulated by divalent cations.
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PMID:Cloning and characterization of the human soluble adenylyl cyclase. 1565 11

1alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.
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PMID:Vitamin D receptor modulators for inflammation and cancer. 1610 12

The polyol isomalt (Palatinit) is a well established sugar replacer. The impact of regular isomalt consumption on metabolism and parameters of gut function in nineteen healthy volunteers was examined in a randomised, double-blind, cross-over trial with two 4-week test periods. Volunteers received 30 g isomalt or 30 g sucrose daily as part of a controlled diet. In addition to clinical standard diagnostics, biomarkers and parameters currently discussed as risk factors for CHD, diabetes or obesity were analysed. Urine and stool Ca and phosphate excretions were measured. In addition, mean transit time, defecation frequency, stool consistency and weight were determined. Consumption of test products was affirmed by the urinary excretion of mannitol. Blood lipids were comparable in both phases, especially in volunteers with hyperlipidaemia, apart from lower apo A-1 (P=0.03) for all subjects. Remnant-like particles, oxidised LDL, NEFA, fructosamine and leptin were comparable and not influenced by isomalt. Ca and phosphate homeostasis was not affected. Stool frequency was moderately increased in the isomalt phase (P=0.006) without changes in stool consistency and stool water. This suggests that isomalt is well tolerated and that consumption of isomalt does not impair metabolic function or induce hypercalciuria. In addition, the study data indicate that isomalt could be useful in improving bowel function.
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PMID:Effects of isomalt consumption on gastrointestinal and metabolic parameters in healthy volunteers. 1619 83

Approximately 4 million Germans suffer from stone disease. In the majority of cases (70-75%) it is calcium oxalate. Its pathophysiology is complex and comprises disorders such as hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria, and hypomagnesuria. These biochemical changes in urine are well known as "classic" risk factors of calcium oxalate stone formation. However, studies in the last decade showed that calcium oxalate stones are strongly related with other diseases or disorders such as overweight, hypertension, or a lack of oxalate-degrading bacteria in the gut. The evidence for these "new" risk factors in the literature is very strong. It is particularly important in regard to effective treatment and aftercare of patients with calcium oxalate stones to be familiar with both the "classic" and the new risk factors.
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PMID:[Calcium oxalate stones and hyperoxaluria. What is certain? What is new?]. 1623 94


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