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)

In a retrospective review of 241 patients with active pulmonary tuberculosis, hypercalcemia was found in 62 (26%). It was detected on presentation in 48 patients and developed in 14 patients 4 to 6 weeks aftr the start of antituberculous therapy. The mean (+/- SD) serum calcium level in those cases was 2.78 (+/- 0.137) mmol/L. The majority of cases (67.6%) had a mild rise in the calcium level that remained below 2.8 mmol/L but 35% had a level that ranged between 2.8 and 3.0 mmol/L. Only 2.4% had serum level higher than 3.0 mmol/L, which could explain the predominant absence of hypercalcemia-related symptoms. Hypercalcemia was more common in patients older than 50 years (P<0.05), but this did not correlate with the extent of the tuberculosis shown on radiological evaluation. Spontaneous return to normocalcemia occurred in all 42 patients who underwent serial assessments of their serum calcium concentration, 6 to 8 weeks after the start of chemotherapy. Saudi Arabia is known to have a high prevalence of vitamin D deficiency, but none of our patients were immobilized or had received vitamin D supplements or multivitamins. This supports the view that vitamin D intake does not play a major role in inducing hypercalcemia in cases of active pulmonary tuberculosis, as has been suspected.
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PMID:Hypercalcemia in active pulmonary tuberculosis. 1758 5

Vitamin D deficiency is strongly associated with the risk of developing colorectal cancer (CRC). Because of the propensity of bioactive 1,25-dihydroxyvitamin D3 to cause toxic hypercalcemia, considerable effort has been directed to identifying safer drugs while retaining the efficacy of the parent compound. However, vitamin D precursors do not present toxicity concerns and may be sufficient for CRC chemoprevention or chemotherapy, providing the appropriate enzymes are present in colonic epithelia. We previously showed that CYP27B1 is present at equally high levels in the colon and CRC irrespective of differentiation but was not present in metastases. In this study we used quantitative immunohistochemistry to show that CYP27A1, converting D3 to 25-hydroxycholecalciferol, is present in increasing concentrations in the nuclei of normal colonic epithelia, aberrant crypt foci (ACF), and adenomatous polyps. Whereas total cellular CYP27A1 remains high in CRC and lymph node metastases, the amount of enzyme present in the nuclei decreases with tumor cell dedifferentiation while rising in the cytoplasm. Similarly, increasing amounts of the deactivating enzyme CYP24 are present in the nuclei of normal colonic epithelia, ACFs, and adenomatous polyps. Although the amount of total CYP24 decreases slightly in CRC as a function of tumor cell dedifferentiation and metastasis, location of this enzyme shifts almost entirely from the nuclear compartment to the cytoplasmic compartment. These data indicate that non-toxic vitamin D precursors should be sufficient for CRC chemoprevention, but that neither vitamin D nor its precursors may be sufficient for CRC chemotherapy.
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PMID:CYP27A1 and CYP24 expression as a function of malignant transformation in the colon. 1787 55

This review examines the dynamics of parathyroid hormone secretion in health and in various causes of secondary hyperparathyroidism. Although most studies of parathyroid hormone and calcium have focused on the modification of parathyroid hormone secretion by serum calcium, the relationship between parathyroid hormone and serum calcium is bifunctional because parathyroid hormone also modifies serum calcium. In normal animals and humans, factors such as phosphorus and vitamin D modify the basal parathyroid hormone level and the maximal parathyroid hormone response to hypocalcemia. Certain medications, such as lithium and estrogen, in normal individuals and sustained changes in the serum calcium concentration in hemodialysis patients change the set point of calcium, which reflects the serum calcium concentration at which parathyroid hormone secretion responds. Hypocalcemia increases the basal/maximal parathyroid hormone ratio, a measure of the relative degree of parathyroid hormone stimulation. The phenomenon of hysteresis, defined as a different parathyroid hormone value for the same serum calcium concentration during the induction of and recovery from hypo- and hypercalcemia, is discussed because it provides important insights into factors that affect parathyroid hormone secretion. In three causes of secondary hyperparathyroidism--chronic kidney disease, vitamin D deficiency, and aging--factors that affect the dynamics of parathyroid hormone secretion are evaluated in detail. During recovery from vitamin D deficiency, the maximal parathyroid hormone remains elevated while the basal parathyroid hormone value rapidly becomes normal because of a shift in the set point of calcium. Much remains to be learned about the dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism.
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PMID:Dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism. 1794 77

Sixteen patients with primary hyperparathyroidism presenting as rickets have so far been reported in the English literature. However, no report of an ectopic thymic parathyroid adenoma presenting as rickets has been published. We report a 14-year-old Caucasian American, wheelchair-ridden male who presented with signs and symptoms suggestive of vitamin D deficiency rickets subsequently confirmed by laboratory and radiological findings. Following the intramuscular administration of 125,000 U ergocalciferol (vitamin D2), he developed hypercalcemia with persistently elevated parathyroid hormone (PTH) levels suggestive of primary hyperparathyroidism. Sestamibi scan demonstrated significant uptake in the superior chest, without uptake at the normal parathyroid glands location. Surgical exploration revealed normal parathyroid glands and a thymic mass, which was removed and confirmed by pathology to be a parathyroid adenoma. With subsequent oral ergocalciferol solution and calcium carbonate therapies, the patient's symptoms resolved, blood chemistries normalized, and radiological evidence of rickets significantly improved. To our knowledge, this is the first case of an ectopic thymic parathyroid adenoma in a patient presenting with rickets. Our patient demonstrates that hyperparathyroidism-induced hypercalcemia may be masked by severe vitamin D deficiency. Prolonged treatment with ergocalciferol after removal of the parathyroid adenoma was necessary to normalize iPTH and replenish vitamin D store.
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PMID:Ectopic thymic parathyroid adenoma and vitamin D deficiency rickets: a 5-year-follow-up case report and review of literature. 1824 58

Temporally associated with the improvement in vitamin D nutrition in many Western countries in the mid-20th century, there was a change in many characteristics of primary hyperparathyroidism. Osteitis fibrosa cystica became a rare manifestation of what is now frequently an asymptomatic disease. At the same time, in patients with the disease, levels of PTH and parathyroid adenoma weights have fallen dramatically. In view of these observations and others, an association between vitamin D deficiency and severity of primary hyperparathyroidism has been proposed. Data support an association on two distinct levels. First, regardless of the clinical severity of primary hyperparathyroidism, the disease seems to be more severe in those with concomitant vitamin D deficiency. Second, vitamin D deficiency and insufficiency seem to be more prevalent in patients with primary hyperparathyroidism than in geographically matched populations. The association between vitamin D deficiency and primary hyperparathyroidism has clear implications. Co-existing vitamin D deficiency may cause the serum calcium level to fall into the normal range, which can lead to diagnostic uncertainty. With regard to management, preliminary data on vitamin D repletion in patients with mild primary hyperparathyroidism suggest that, in some cases, correction of vitamin D deficiency may be accomplished without worsening the underlying hypercalcemia. Vitamin D-deficient patients undergoing parathyroidectomy are also at increased risk of postoperative hypocalcemia and "hungry bone syndrome," which underscores the importance of preoperative assessment of vitamin D status in all patients with primary hyperparathyroidism.
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PMID:Vitamin D deficiency and primary hyperparathyroidism. 1829 Jul 10

In mammals a complicated homeostatic mechanism has evolved to maintain near consistency of extracellular calcium ion levels. The homeostatic mechanism involves several hormones, which comprise among others, parathyroid hormone and vitamin D. The recent resurge in vitamin D deficiency, as a global health issue, has increased interest in the hormone. In addition to vitamin D deficiency, other causes of rickets are calcium deficiency and inherited disorders of vitamin D and phosphorus metabolism. Vitamin D-resistant syndromes are caused by hereditary defects in metabolic activation of the hormone or by mutations in the vitamin D receptor, which binds the hormone with high affinity and regulates the expression of genes through zinc finger mediated DNA binding and protein-protein interaction. Current interest is to correlate the type/position of mutations that result in disorders of vitamin D metabolism or in vitamin D receptor function with the variable phenotypic features and clinical presentation. The calcium sensing receptor plays a key role in calcium homeostasis. Loss of function mutations in the calcium sensing receptor can cause familial benign hypocalciuric hypercalcemia in heterozygotes and neonatal severe hyperparathyroidism when homozygous mutations occur in the calcium sensing receptor. Gain of function mutation can cause the opposite effect causing autosomal dominant hypocalcemia. Mouse models using targeted gene disruption strategies have been valuable tools to study the effect of mutations on the calcium sensing receptor or in the vitamin D activation pathway. Dysfunctional calcium sensing receptors with function altering mutations may be responsive to treatment with allosteric modulators of the calcium sensing receptor. Vitamin D analogs which induce unusual structural conformations on the vitamin D receptor may have a variety of therapeutic indications. This review summarises recent advances in knowledge of the molecular pathology of inherited disorders of calcium homeostasis.
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PMID:Inherited disorders of calcium homeostasis. 1847 31

The presence of vascular calcification (VC) is a predictor of poor survival in the general population. The development of VC is an active process that requires a pre-existing injury as an inducer and promoting factors such as hyperphosphatemia and hypercalcemia, as well as a deficiency in calcification repressor factors. Vascular smooth muscle cells possess an endogenous enzyme system for the biosynthesis of the vitamin D hormone calcitriol from its precursor 25-hydroxyvitamin D and also a cytosolic calcitriol receptor, indicating that the vasculature is an important target tissue for vitamin D. The toxic effects of supra-physiological vitamin D dosages on the vasculature have been known for several decades. Recent experimental data also demonstrate important physiological effects of vitamin D on factors that are protective for vascular health. This review article summarises the molecular basis of protective and toxic vitamin D actions on the vasculature. Chronic kidney disease can be considered as a human model of severe VC and poor survival. The disease is associated with calcitriol deficiency, hyperparathyroidism, and hyperphosphatemia. Evidence is increasing that phosphate overload plays a key role in the process of VC in chronic kidney disease. The first clinical studies indicate that vitamin D receptor activation can improve survival in these patients. Although less severe than in chronic kidney disease, vitamin D deficiency and secondary hyperparathyroidism are also frequent in the general population, especially in elderly and obese subjects. Future studies should focus on the impact of vitamin D deficiency on VC and clinical outcome in these groups.
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PMID:Protective and toxic effects of vitamin D on vascular calcification: clinical implications. 1853 38

Studies of vitamin D and prostate cancer have advanced rapidly from the hypothesis that vitamin D deficiency increases the risk of prostate cancer to intervention trials of vitamin D administration in clinical cancer. The hormonal form of vitamin D, 1,25(OH)(2)D, exerts prodifferentiating, antiproliferative, anti-invasive, and antimetastatic effects on prostate cells. Moreover, normal prostate cells synthesize 1,25(OH)(2)D from serum levels of the prohormone, 25-hydroxyvitamin D. The autocrine synthesis of 1,25(OH)(2)D by prostatic cells provides a biochemical mechanism whereby vitamin D may prevent prostate cancer. Many prostate cancer cells have lost the ability to synthesize 1,25(OH)(2)D but still possess 1,25(OH)(2)D receptors. This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice.
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PMID:Vitamin D and intervention trials in prostate cancer: from theory to therapy. 1861 54

We present a male patient with neonatal severe primary hyperparathyroidism, whose manifestation was exceptionally serious for the heterozygous inactivating mutation he carried in the CASR gene. The patient presented soon after birth with respiratory distress requiring long-term mechanical ventilation, bone and chest deformities, feeding problems, and hypotonia. He had hypercalcaemia, hypophosphataemia, and hyperparathyroidism. There was no known history of calcium metabolism disorders in the family. As the impact on calcaemia of a rescue therapy with bisphosphonates was only transient, a subtotal and subsequently total parathyroidectomy were performed in the fourth month of life. Afterwards his clinical status improved and the fractures healed, but his neuropsychological development is delayed due to cerebral atrophy. Genetic analysis revealed a heterozygous missense CASR mutation R185Q, and an approximately equal expression of the mutated and wild-type RNA in the parathyroid tissue. The mother of the child was homozygous for the wild-type allele; the father is unknown. In conclusion, this patient demonstrates how serious neonatal hyperparathyroidism can be when caused by a heterozygous mutation. This may be attributable to a combination of dominant-negative action of the mutant allele with an intrauterine foetal hyperparathyroidism developed in the mother's normocalcaemic environment, further aggravated by a putative maternal vitamin D deficiency during pregnancy.
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PMID:Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. 1875 24

Calcium and bone disorders in paediatrics are treated with a variety of drugs, many of which, although licensed for use in adults, are not so in children but are nevertheless used on the basis of accepted practice. The mainstay of drug treatment for osteoporosis is the bisphosphonates which alter the balance between bone accretion and reabsorption mainly by temporarily reducing the activity of osteoclasts. Vitamin D and its metabolites are used for the treatment of various forms of rickets and vitamin D deficiency and the active metabolites are also employed when hypoparathyroidism causes hypocalcaemia. Phosphate supplements may also be required in some forms of rickets. Hypercalcaemia is treated initially with hyperhydration and diuretics but may require more specific treatment with either calcitonin or bisphosphonates. Several newer drugs have either recently been introduced or are under consideration. These include the calcimimetics (cinacalcet), rank ligand inhibitors (osteoprotegerin and denusomab), cathepsin K inhibitor, sclerostin, bone morphogenic protein 2, and calciolytic drugs. More recently, recombinant alkaline phosphatase and PTH have been used to treat hypophosphatasia and hypoparathyroidism respectively. These developments promise to direct treatment more specifically to targeting individual conditions as our understanding of these conditions increases.
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PMID:Drugs used in paediatric bone and calcium disorders. 1949 69


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