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)

The unusual causes of hypercalcemia have been reviewed. These disorders are rarely derived as the cause of hypercalcemia from the usual tests that one obtains in working up hypercalcemic patients (such as PTH level, phosphorus, urinary calcium). These diagnoses (particularly drug-related hypercalcemia) can be determined only from a careful history. The vast majority of hypercalcemic patients have disease secondary to cancer, hyperparathyroidism, or disorders of vitamin D metabolism. It should be noted that some hypercalcemic patients may have more than one disease. Therefore, before assuming that a hypercalcemic patient with Paget's disease, thiazide ingestion, immobilization, or so forth has hypercalcemia secondary to the primary disorder, hyperparathyroidism and cancer should also be considered. Similarly, serum calcium levels can normalize in some patients with mild hyperparathyroidism or bony metastases with mobilization and/or cessation of thiazide therapy.
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PMID:Unusual causes of hypercalcemia. 267 71

Many factors, such as interleukin 1, TGF alpha, tumor necrosis factor alpha and beta, and PGs, have been implicated in etiological roles in HHM (Martin and Mundy, 1987). Much interest in the past has also centered upon the likelihood of ectopic secretion of PTH in this condition. We have purified a protein (PTHrP) implicated in HHM from a human lung cancer cell line (BEN). Full-length cDNA clones have been isolated and were found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino acids were identical with human PTH, although antisera directed to the NH2 terminus of PTHrP do not recognize PTH; this homology is not maintained in the remainder of the molecule. PTHrP therefore represents a previously unrecognized hormone, possibly related to the PTH gene by a gene duplication mechanism. In support of this notion, the PTHrP gene has been localized to the short arm of chromosome 12; it is believed that chromosome 11, containing the PTH gene, and chromosome 12 are evolutionarily related. In addition, the human PTHrP gene has been isolated, characterized, and shown to have a similar intron--exon organization as the PTH gene. It is possible that the original ancestral gene is indeed the PTHrP gene; resolution of this question awaits studies in lower species. Peptides synthesized to the predicted protein sequence have enabled detailed structure-function studies that have identified NH 2-terminal sequences to be responsible for the biological effects of the molecule. Antibodies raised against the various synthetic peptides have led to the immunohistochemical localization of PTHrP in many human squamous cell carcinomas as well as in a subpopulation of keratinocytes of normal skin. The availability of these antibodies has opened the way for the development of a radioimmunoassay to detect PTHrP in the sera of cancer patients at risk of developing hypercalcemia. The recent characterization of PTHrP-like activity in the ovine fetus suggests some physiological function for PTHrP. It is possible that PTHrP, as the fetal counterpart of PTH, has the role of maintaining the maternal-fetal calcium gradient. The isolation and characterization of PTHrP have added to our understanding of the mechanisms of hypercalcemia and may contribute to the understanding of other metabolic bone diseases, such as osteoporosis and Paget's disease. Finally, and perhaps most importantly, PTHrP may play a hitherto unrecognized role in normal cell physiology.
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PMID:Parathyroid hormone-related protein: isolation, molecular cloning, and mechanism of action. 268 46

Bisphosphonates, associated with rehydration, became the treatment of choice of malignant hypercalcemia when it became apparent that these compounds normalized plasma calcium in most cases within a few days and with almost no side effects, and that their effect was prolonged. Dichloromethylene bisphosphonate and aminobisphosphonate, especially APD, were shown to inhibit bone resorption with no noticeable inhibition of bone formation, and were highly effective in the long-term treatment of Paget's disease. APD was used in almost 300 patients with malignant hypercalcemia published in the literature and has been used in the medical clinic at Lausanne for several years. When given to 14 patients with malignant hypercalcemia at the dose of 25 mg/day until plasma calcium became normal for two consecutive days, APD had to be given for 4-11 days, severe hypercalcemia needing longer treatment than mild hypercalcemia (Adami et al. 1982). When given for a fixed period of 6 days, again plasma calcium normalized in all patients, whether APD was given i.v. (30 mg/day, ten patients) or orally (1200 mg/day, ten patients) (Adami et al. 1985). Further shortening of the treatment to one single infusion given over 24 h did not decrease the efficacy, as long as high enough doses were given (Blomqvist 1986). For severe hypercalcemia of above 3.5 mmol/liter 60-90 mg had to be given, while 30-45 mg was sufficient in milder cases (Body 1984). Otherwise, mild, transient, and asymptomatic hypocalcemia could occur. Normalization of plasma calcium went along with clinical improvement, sometimes even with correction of coma. Renal function was improved, even when the initial plasma creatinine levels were up to twice normal. Hypercalcemia could reoccur, but the duration of the effect of APD (1 week to several months) depended among other things on the dose administered. The decrease in plasma calcium was accompanied by a decrease in urinary calcium and hydroxyproline, both showing inhibition of bone resorption. In the case of recurrency, the treatment could be repeated with almost unaltered efficacy, except in end-stage cancer disease. When given to 13 normocalcemic patients with bone metastases from breast cancer, hydroxyproline and urinary calcium again decreased. Bone pains and radiologic signs of metastatic bone resorption also showed significant improvement, although these latter effects could also be explained by the antitumoral treatment, in this uncontrolled open trial.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Treatment of tumor-induced osteolysis by APD. 276 65

We have measured classic markers of bone turnover, serum alkaline phosphatase (sAP), urinary hydroxyproline/creatinine ratio (uOH-Prol/creatinine) and osteocalcin (sBGP), in two bone disorders characterized by an increase in bone remodelling, namely Paget's disease of bone and primary hyperparathyroidism (PHPT) and in two other bone diseases characterized by an increase in bone resorption without the concomitant increase in bone formation, hypercalcaemia of malignancy (HM) and involutional osteoporosis (IO). Serum BGP was increased in patients with Paget's disease of bone (6.7 +/- 3.1; n = 25; p less than 0.01) and in PHPT patients (8.3 +/- 5.3; n = 20; p less than 0.005) with respect to control patients (4.2 +/- 1.2 ng/ml; n = 12). Two subgroups of patients with high and normal levels of sBGP were found in both pathologies. Serum BGP was decreased in HM patients (2.1 +/- 1.7; n = 9; p less than 0.01) and in IO patients (1.9 +/- 1.4; n = 31; p less than 0.001). Two subgroups of patients with normal and low sBGP values were found in these two last disorders. A positive linear correlation was found between sBGP and sAP (y = 14.6x + 73.7; r = 0.44; p less than 0.05) and between sBGP and uOH-Prol/creatinine (y = 0.008x + 0.007; r = 0.67; p less than 0.001) in Paget's disease of bone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Osteocalcin and bone remodelling in Paget's disease of bone, primary hyperparathyroidism, hypercalcaemia of malignancy and involutional osteoporosis. 278 49

Osteitis deformans is a focal disease of the osteoclasts characterised by increased bone resorption subsequently followed by increased bone formation leading to abnormal bone. A viral etiology seems increasingly probable, but remains unproven. 5-30% of the patients present with symptoms such as pain, deformity and fracture. Hearing loss, nerve- or root-compression, arthrosis and hyperuricaemia may complicate the disease while malignant degeneration, hypercalcemia and high output cardiac failure are rare. The diagnosis is based on X-ray findings but biopsy may be necessary in selected cases. The extent of the disease is revealed by bone scintigraphy and the activity of the disease reflected by urine hydroxyproline excretion and serum alkaline phosphatase.
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PMID:[Paget's osteitis deformans. Epidemiology and clinical picture]. 292 39

Based on the author's experience with more than 20 cases of immobilization hypercalcemia following spinal cord injury, current concepts of this condition are presented. Symptoms may be mild or severe: laboratory findings are essential for differential diagnosis in older individuals, in whom preinjury Paget's disease and mild primary hyperparathyroidism must be ruled out. Most cases of immobilization hypercalcemia are seen in adolescent boys following recent spinal cord injury. Besides sex (male), risk factors include age (less than 21 years), complete neurologic injuries, high cervical levels of spinal cord injury, dehydration, and a prolonged period of immobilization. A preinjury history of large ingestion of milk and/or extreme exposure to sunshine may also be contributory factors. Therapy includes vigorous hydration, saline infusions and diuretics, calcitonin, and steroids. The clinical course, without treatment, may be prolonged to 14 months, but the condition is always self-limiting.
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PMID:Immobilization hypercalcemia following spinal cord injury. 293 20

The development of specific inhibitors of bone resorption has revolutionized the treatment of Paget's disease. The diphosphonates, the calcitonins, and mithramycin are capable of inducing marked suppression of disease activity for prolonged periods as judged by biochemical, kinetic, and histologic techniques. Whereas the effects of the calcitonins and mithramycin persist only for the duration of treatment, diphosphonate treatment consistently results in a reduction of disease activity for many months or even years after stopping treatment. The question arises whether the long-term control of the disease activity confers significant clinical advantages to the patient. Relief of bone pain, spinal neurologic syndromes, immobilization hypercalcemia, and high-output cardiac failure are related to the degree of biochemical control attained by treatment. New bone formed during treatment is lamellar and radiologic progression of disease is favorably modified. It is not yet known whether long-term treatment will decrease bone enlargement and deformity or reduce the risk of fracture.
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PMID:Long-term follow-up observations on treatment in Paget's disease of bone. 295 Oct 50

Many factors, such as interleukin 1, transforming growth factor alpha, tumour necrosis factor alpha and beta, and prostaglandins, have been implicated in the pathogenesis of the humoral hypercalcaemia of malignancy (Mundy and Martin, 1982; Martin and Mundy, 1987; Mundy et al, 1984). Much interest in the past has also centred upon the likelihood of ectopic secretion of PTH in this condition. We have purified a protein (PTHrP) implicated in HHM from a human lung cancer cell line (BEN). Full-length cDNA clones have been isolated and found to encode a pre-pro-peptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino acids were identical with human PTH, although antisera directed to the aminoterminus of PTHrP do not recognize PTH; this homology is not maintained in the remainder of the molecule. PTHrP therefore represents a previously unrecognized hormone, possibly related to the PTH gene by a gene duplication mechanism. In support of this notion, the PTHrP gene has been localized to the short arm of chromosome 12; it is believed that chromosome 11, containing the PTH gene, and chromosome 12 are evolutionarily related. In addition, the human PTHrP gene has been isolated, characterized, and shown to have an intron-exon arrangement that is more complex than the PTH gene. It is possible that the original ancestral gene is indeed the PTHrP gene; resolution of this question awaits studies in lower species. Peptides synthesized to the predicted protein sequence have allowed detailed structure-function studies that have identified aminoterminal sequences to be responsible for the biological effects of the molecule. Antibodies raised against the various synthetic peptides have led to the immunohistochemical localization of PTHrP in many human squamous cell carcinomas as well as in a subpopulation of keratinocytes of normal skin. The availability of these antibodies has opened the way for the development of a radioimmunoassay to detect PTHrP in the sera of cancer patients at risk of developing hypercalcaemia. The recent characterization of PTHrP-like activity in the ovine fetus suggests some physiological function for PTHrP. It is possible that PTHrP, as the fetal counterpart of PTH, has the role of maintaining the maternal-fetal calcium gradient. The isolation and characterization of PTHrP has added to our understanding of the mechanisms of hypercalcaemia and may contribute to the understanding of other metabolic bone diseases, such as osteoporosis and Paget's disease. Finally, and perhaps most importantly, PTHrP may play a hitherto unrecognized role in normal cell physiology.
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PMID:Parathyroid hormone-related protein: a novel gene product. 307 45

The induction of hypercalcemia in malignant disease is almost invariably associated with increased bone resorption. However, tumor-induced changes in bone formation and renal tubular resorption of calcium are also important factors that induce hypercalcemia in some patients. In addition, alterations in calcium fluxes to and from the extracellular fluid secondary to hypercalcemia are important in maintaining or aggravating the hypercalcemic effects of increased bone resorption. These factors significantly affect the responses to treatment of hypercalcemia with inhibitors of bone resorption. This study examined the relative importance of these factors and the effects of intravenous etidronate disodium (etidronate) in neoplastic bone disease with and without hypercalcemia and in Paget's disease of bone. It is concluded that intravenous etidronate is an effective inhibitor of bone resorption, which accounts in large measure for its effects on serum calcium concentrations. These studies of etidronate in hypercalcemia suggest the response is sustained for several weeks.
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PMID:Effects of intravenous etidronate disodium on skeletal and calcium metabolism. 310 37

Paget's disease of bone is often discovered incidentally, but can have extensive metabolic and local mechanical complications. Treatment is not required for all patients and should only be undertaken for certain indications, and with a clear understanding of the three types of drugs available. Bone pain unmanageable with analgesics and pathologic fractures are the most common indications, while neurologic symptoms, hypercalcemia and congestive heart failure are less frequent ones. Calcitonin or mithramycin is used for the more urgent indications, and calcitonin or the diphosphonate, etidronate sodium (EHDP), for the more chronic ones. The drugs are generally efficacious and well tolerated.
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PMID:Paget's disease of bone: clinical features and treatment. 315 5


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