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)

Vitamin D intoxication is a rare cause of hypercalcemia, which is associated with severe and prolonged morbidity. Hypercalcemia and/or hypercalciuria are the consequence of increases in both intestinal absorption and bone resorption. We report on 7 cases of vitamin D overdose (25-hydroxyvitamin D: 710 +/- 179 nmol/l; normal range: 20-90). The indications for vitamin therapy were osteoporosis (5), hypoparathyroidism (1), and osteomalacia (1). Enhanced bone resorption was demonstrated by increased fasting urinary calcium excretion (0.192 +/- 0.067 mmol/l GFR, normal < 0.045). Sequential biochemical measurements in the hypoparathyroid patient showed the persistence of abnormally elevated fasting urinary calcium and of serum 25-hydroxyvitamin D concentrations, even after normalization of plasma calcium, emphasizing that enhanced bone resorption is a prominent feature of vitamin D action. The intravenous administration of a single infusion of the bisphosphonate clodronate to 3 patients led to a correction of hypercalcemia/hypercalciuria, whereas prednisone therapy given to 2 other cases barely affected the abnormal biochemical values. These results indicate that enhanced bone resorption encountered in vitamin D intoxication could be favorably influenced by bisphosphonate treatment.
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PMID:Hypercalcemia and hyperosteolysis in vitamin D intoxication: effects of clodronate therapy. 808 37

Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (Pi) cotransporter that is expressed in the proximal tubule where the bulk of filtered Pi is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of Pi homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal Pi reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhibit increased urinary Pi excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal Pi reabsorption. However, unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia. At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype. Our findings demonstrate that Npt2 is a major regulator of Pi homeostasis and necessary for normal skeletal development.
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PMID:Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. 956 Feb 83

This article reviews the clinical, biological, radiological, and pathological procedures and their respective indications for the practical diagnosis of the following various histological patterns of renal osteodystrophy: osteitis fibrosa due to parathyroid hormone (PTH) hypersecretion: osteomalacia or rickets due to native vitamin D deficiency and/or aluminum overload; and adynamic bone disease (ABD) due to aluminum overload and/or PTH secretion oversuppression. Our advice regarding bone biopsy is to restrict it to patients with symptoms and hypercalcemia, especially those who have been previously exposed to aluminum. In other cases, we propose relying merely on the determination of the plasma concentrations of calcium, protide, phosphate, bicarbonate, intact PTH, aluminum, 25(OH)D3, and alkaline phosphatase (total and bony if hepatic disease is associated) to choose the appropriate treatment. Because of the danger of the desferrioxamine treatment necessary to chelate and remove aluminum, the suspicion of aluminic bone disease (osteomalacia or ABD) will always be confirmed by a bone biopsy. In the case of nonaluminic osteomalacia, correction of the vitamin D deficiency by native vitamin D or 25(OH)D3, and of the calcium deficiency and acidosis by alkaline salts of calcium and if necessary sodium bicarbonate are sufficient to cure the disease. In the case of nonaluminic ABD, the stimulation of PTH secretion by the discontinuation of 1alpha hydroxylated vitamin D and the induction of a negative calcium balance during dialysis by decreasing the calcium concentration in the dialysate will allow an increase of the CaCO3 dose to correct for hyperphosphatemia without inducing hypercalcemia. For hyperparathyroidism, i.e., plasma intact PTH levels greater than two- or four-fold the upper limit of normal levels (according to the absence or presence of previous aluminum exposure), the treatment will consist in increasing the CaCO3 dose to correct for hyperphosphatemia together with a decrease of the calcium concentration in the dialysate if the dose of CaCO3 is so high that it induces hypercalcemia. When the hyperphosphatemia has been corrected and there is still a low or normal corrected plasma calcium level, 1alpha(OH)D3 in an oral bolus 2 or 3 times a week should be given at the minimal dose of 1 microg. When the PTH level stays above 400 pg while hypercalcemia occurs and hyperphosphatemia persists, surgical subtotal parathyroidectomy is recommended or the injection of calcitriol into the big nodular hyperplastic parathyroid glands under sonography control in high surgical risk patients. Special recommendations are given for children.
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PMID:Renal osteodystrophy in dialysis patients: diagnosis and treatment. 968 90

For adults, the 5-microg (200 IU) vitamin D recommended dietary allowance may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism. Other benefits of vitamin D supplementation are implicated epidemiologically: prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. Sailors in US submarines are deprived of environmentally acquired vitamin D equivalent to 20-50 microg (800-2000 IU)/d. The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D supply of 100 microg (4000 IU)/d is required. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin D supply of 250 microg (10000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of > or = 1000 microg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 microg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2000 IU)/d is too low by at least 5-fold.
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PMID:Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. 1172 70

Phosphate binders that contain aluminum or calcium are frequently prescribed to treat hyperphosphatemia in patients with end-stage renal disease (ESRD), but an accumulation of aluminum can lead to encephalopathy, aluminum-related bone disease (ARBD) such as osteomalacia, anaemia, and resistance to erythropoietin, and calcium accumulation can lead to hypercalcaemia. High phosphate concentrations are reduced in vitro and in vivo by a phosphate adsorption pill, which is synthesized by hydrolyzing ferrous sulfate in the presence of saccharides, to form an iron (III)-saccharide complex that is acid resistant and binds phosphate greater than iron (III) hydroxide alone. Under in vitro conditions, containing 3.26 mg P/dL, the iron (III)-sucrose complex showed the highest phosphate adsorption capacity at pH 2 with artificial gastric juice, 58.9 mg P/g binder. For the 7 day in vivo study, 0% (Group 1), 1% (Group 2), 4% (Group 3), and 8% (Group 4) iron (III)-sucrose complex was admixed into the rodent chow by weight and fed to 15 male Wistar rats. The weight and volume of the feces and urine, and the calcium, iron, and phosphorus excretions in the feces and urine samples were monitored for any signs of irregularity. Total urine outflow was collected during a 24-h period to determine the amount of phosphate recovered, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. The fecal iron excretion was significantly effected by the amount of binder ingested throughout the study for Group 2 (p < 0.001), Group 3 (p < 0.01), and Group 4 (p < 0.001). The urinary calcium excretion (mg/rat/24-h) significantly increased by the 7th day for Group 2 (p < 0.05) and Group 4 (p < 0.01) in comparison to the control. Finally, after 7 days, there was a significant drop in the urinary phosphorus levels (mg P/rat/24-h) in a dose dependent manner for Group 2: from 7.82 +/- 1.46 to 1.98 +/- 0.10 mg P/rat/24-h (102 mg P/dL/24-h; p < 0.05); Group 3: from 6.70 +/- 1.14 to 0.16 +/- 0.09 mg P/rat/24-h (6.0 mg P/dL/24-h; p < 0.01); and Group 4: from 8.25 +/- 0.67 to 0.04 +/- 0.01 mg P/rat/24-h (0.9 mg P/dL/24-h; p < 0.01). The results show that this new adsorbent might provide an alternative to conventional aluminum and calcium containing phosphate-binding agents for combating hyperphosphataemia.
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PMID:Oral phosphate binders: phosphate binding capacity of iron (III) hydroxide complexes containing saccharides and their effect on the urinary excretion of calcium and phosphate in rats. 1051 89

In 4 of our patients on chronic dialysis, we were intrigued by the association of hypercalcemia +/- hyperphosphatemia and normal intact PTH, with anicteric cholestasis without cytolysis. This picture occurred in 2 patients after they resumed dialysis because of a transplant rejection and in a third one after discontinuation of corticosteroids, prescribed for an idiopathic thrombocytopenia. No patient was under calcitriol, CaCO3 therapy, and their hypercalcemia persisted on a low calcium dialyzate (1.25 mmol/l). Obvious etiologies of hypercalcemia were not found: vitamin D or A intoxication, hyperparathyroidism, aluminum intoxication, hemopathy, HIV infection. The hypothesis of a granulomatous disease was made and a liver biopsy was performed showing granulomas with giant epitheloid cells. In one case foreign material (silicon ?) was present in the macrophages. Extensive investigations for sarcoidosis, tuberculosis and mycosis were negative. In 2 cases the so-called "dialysis" granulomatosis actually occurred in transplanted patients, suggesting the role of a transplantation related factor (toxic or virus). In the last case HCV seroconversion was present. In the 4 cases, corticotherapy led to the disappearance of hypercalcemia and to an increase of PTH. Our patients had the biological pattern of low bone turnover disease (hypercalcemia and normal intact PTH) and bone biopsy performed in 2 showed osteomalacia or ABD without aluminum. The association of this pattern with cholestasis should evoke liver granulomatosis, which should be confirmed by a liver biopsy and lead to a treatment by corticosteroids. The masking effect of previous corticoid therapy for transplantation should be pointed out. In 2 cases serial monitoring of plasma calcitriol showed a relation between decreasing high normal calcitriol with prednisone and normalization of calcemia, suggesting the role of inappropriate synthesis of calcitriol by the granuloma. In conclusion, liver granulomatosis should be looked for in dialysis patients on the association of unexplained hypercalcemia and normal PTH with anicteric cholestasis, and confirmed by a liver biopsy. Although still of unknown etiology, its evolution is favourable under corticotherapy.
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PMID:Liver granulomatosis is not an exceptional cause of hypercalcemia with hypoparathyroidism in dialysis patients. 1062 31

1. In the patient with renal insufficiency before dialysis, the phosphocalcic disorders appear insidiously. They are dominated by hyperparathyroidism which will be diagnosed on the initially yearly determination of plasma intact PTH as soon as creatinine clearance decreases below 60 ml/min, eventhough there is still no modification in plasma concentrations of calcium and phosphate. Its diagnosis should lead to initiate the therapeutic measures in order to prevent the irreversible thining of the corticals by endosteal resorption and later the occurrence of histological and radiological osteitis fibrosa favoring fractures. 2. Hyperparathyroidism prevention relies on two main measures: prevention of phosphate retention and hypocalcemia is implemented by progressive phosphate and protein restriction (from 1 g/kg/day when Ccr < 60 ml/min to 0.6 g/kg/day when Ccr < 20 ml/min) and administration of CaCO3 (1.5 g at lunch and dinner to better complex the phosphate) as soon as PTH is above normal; optimal vitamin D repeletion will be implemented by systematic supplementation of native vitamin D or 25OH vitamin D3 in order to bring P25OHD between 30-60 ng/ml (75-150 nmol/l) or more generally around the upper limit of the epidemiologic range of the laboratory; these measures should aim at maintaining plasma intact PTH in its optimal range variable with the degree of renal insufficiency: 0.5-1; 1-2.5 and 2-3 folds the upper limit of normal for creatinine clearance respectively at 60-30; 30-10 and < 10 ml/min. 3. Because of their hyperphosphatemic and hypercalcemic effect, 1 alpha-hydroxylated vitamin D derivatives will be regularly efficient and safe only when non-calcemic non-aluminic phosphate binder will be available and proven to be without side-effects. 4. Instrumental (surgical or by alcohol injection) parathyroidectomy should be considered when plasma intact PTH is > 5 to 7 times the upper limit of normal in the presence of hypercalcemia (> 2.60 mmol/l) and/or hyperphosphatemia (> 1.70 nmol/l) in spite of the above measures, the decision being reinforced by coexistence of bone radiologic abnormalities and metastatic calcifications. 5. Adynamic bone diseases are rare before hemodialysis in the absence of aluminum exposition by the drinking water or the aluminum-phosphate binders. In absence of aluminum it will be prevented by maintaining PTH in its optimal range. 6. Osteomalacia before hemodialysis is mainly due, in the absence of aluminum exposition, to vitamin D deficiency, hypocalcemia and acidosis. It is readily cured by physiological doses of native vitamin D or 25OH vitamin D3 bringing plasma 25 OHD above 16 ng/ml, in association with alkaline salts of calcium and if necessary of sodium bicarbonate.
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PMID:[Renal osteodystrophy (2): its treatment in renal insufficiency before dialysis]. 1111 6

The prevalence and the clinical gravity of the various histopathological varieties of renal osteodystrophy in dialysis patients depends on the severity of both the aluminium intoxication and that of hyperparathyroidism. The prevalence of bone pains, fractures and hypercalcemias are the highest in adynamic bone diseases (ABD) with severe aluminium intoxication, then in osteitis fibrosa and mixed osteopathy, in the ABD with moderate aluminium intoxication and rare in the mild lesion in spite of similar moderate aluminium intoxication. In the absence of aluminium intoxication, hypercalcemia and hyperphosphatemia prevalence is higher only when intact PTH is more that 4 times the upper limit of normal. When PTH is between 1 and 2 folds the ULN this prevalence is null and bone mineral density is the highest. 2. The low turnover aluminic bone diseases (osteomalacic or adynamic) will be cured by long term deferoxamine treatment. The hazards of such treatment justify the performance of a bone biopsy to ensure the diagnosis. Their prevention relies on adequate treatment of tapwater and definitive exclusion of long term administration of aluminum phosphate binders. 3. Non aluminic osteomalacia will be treated according to the same guidelines given for the uremic patients before dialysis. 4. Non aluminic adynamic bone disease will be cured by means aiming at stimulating PTH secretion as discontinuing 1 alpha hydroxylated vitamin D derivatives, and, if there is no hyperphosphatemia by discontinuation of calcium supplement. In case of hyperphosphatemia in dialysis patients CaCO3 doses have to be nevertheless increased after the dialysate calcium concentration (DCa) has been decreased in order to induce a negative perdialytic calcium balance for PTH secretion stimulation. In the near future substitution of CaCO3 by non calcemic non aluminic phosphate binders will suffice. 5. Osteitis fibrosa due to hyperparathyroidism will be treated first by securing an optimal vitamin D repletion (bringing plasma 25OH vitamin D around 30 and 60 ng/ml or 75-150 nmol/l) and by correcting hypocalcemia and hyperphosphatemia by CaCO3 at high doses (3-12 g/day) taken with the meals. In case of hypercalcemia dialysate calcium concentration will be decreased to correct it or, in a near future, CaCO3 will be decreased to 3 g/day and hyperphosphatemia will be controlled by non calcemic, non aluminic phosphate binders. When hyperphosphatemia is controlled whereas plasma calcium is normal or low, 1 alpha hydroxylated vitamin D derivatives can be administered. 6. Instrumental parathyroidectomy should be considered when plasma levels of intact PTH remain above 7 folds the upper limit of normal whereas hyperphosphatemia persists and hypercalcemia occurs in order to prevent thining of the corticals and subsequent fracture risk. In case of previous exposition to aluminum, a deferoxamine test and/or a bone biopsy will be performed to decide a long term DFO treatment before the parathyroidectomy in order to prevent the transformation of a mixed osteopathy into an aluminic adynamic bone disease. 7. The difficulty of hyperparathyroidism control in dialysis patients is due to poor compliance to phosphate binders and to irreversible parathyroid hyperplasia with occured before the dialysis stage. This stress the primary importance if its early prevention without iatrogenia by first CaCO3 and vitamin D repletion, as soon as the creatinine clearance decreases below 60 ml/min/1.73 m2.
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PMID:[Renal osteodystrophy (3); its treatment in dialysis patients]. 1121 85

Although bisphosponates are proposed as first-line treatment for posttransplant bone disease they are not optimal in all situations. A kidney transplant recipient developed hypercalcemia from mobilization of extraskeletal calcium. He had low serum parathyroid hormone and vitamin D; high calcium excretion; and normal calcium intake. Bone biopsy revealed severe osteomalacia. Bisphosphonates, used in the early treatment of acute hypercalcemia, were not indicated to treat osteomalacia. However, over several months serum calcium declined sufficiently to allow treatment of the bone disease with oral calcitriol. Dual-energy radiographic absorptiometry over the next 2 years documented dramatic improvements in bone density (percent of young-normal controls) : from 63 to 85%, at the lumbar spine; from 38 to 67%, at the femoral neck. This response to treatment could not have been achieved with an antiresorptive strategy. Optimal management of posttransplant bone disease requires a diagnostic approach, which considers all plausible contributing factors.
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PMID:Posttransplant bone disease: a case illustrating dramatic improvements in bone density with vitamin D replacement therapy. 1145 70

There is a spectrum of presentations of skeletal manifestations of malignancy that includes generalized osteopenia and hypercalcemia, focal osteolysis, focal osteogenesis, and osteomalacia and hypophosphatemia. In various preclinical animal models, parathyroid hormone-related protein (PTHrP) was seen to be produced by tumor cells, causing osteolytic lesions, either with or without hypercalcemia. EB1089, an analog of 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3], when used as a potential therapeutic agent, decreased both the number and size of metastatic bone lesions, the incidence of hind limb paralysis, and the volume of tumor burden within the bone, and also prolonged survival time. These findings were attributed to the interruption of pathways leading to PTHrP production. From studying osteoblastic metastases of prostate cancer in preclinical animal models, urokinase expression by the tumor was proposed as a growth factor and as an activator of other bone growth factors; however, the mechanism of action of osteoblastic metastases requires further research. The design of suitable preclinical animal models to study the pathophysiology of oncogenic osteomalacia also needs further investigation, though a genetic model of hypophosphatemic osteomalacia exists. The animal models and study designs used all establish methodologies that can be adapted for use in future clinical trials.
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PMID:Extending preclinical models of skeletal manifestations of malignancy to the clinical setting. 1154 70


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