Hypercalcemia parathyroid hormone

The overall effect in most animals is to stimulate intestinal absorption of calcium with a concomitant increase in semm calcium and a reduction in parathyroid hormone (PTH). Modest hypercalcemia allows the glomerular filtration rate to remain stable and hypercalciuria to occur because of increased filtered load of calcium and reduction of tubular resorption of calcium with reduced PTH. However, with further increases in semm calcium, the glomerular filtration rate decreases, resulting in an even more rapid increase in semm calcium and the subsequent fall in urinary calcium. 

The delicate balance maintained by these factors is altered in patients with cancer by two principal mechanisms tumor production of humoral factors that alter calcium metabolism (humoral hypercalcemia) and local osteolytic activity from bone metastases.27 Humoral hypercalcemia causes around 80% of all hypercalcemia cases and is mediated primarily by systemic secretion of parathyroid hormone-related protein... 

FIGURE 96-4. Pathophysiology of the hypercalcemia of malignancy. PTHrP, parathyroid hormone-related protein TGF-P, transforming growth factor P TNF-a, tumor necrosis factor alpha Ca2+, calcium IL-1, interleukin 1 IL-2, interleukin 2. 

PTHrP). This protein mimics the action of endogenous parathyroid hormone on bones. Local osteolytic activity causes 20% to 30% of hypercalcemia cases, although local osteolytic activity also may have a humoral component. Local production of various factors directly stimulates osteoclastic... 

The answer is c. (Hardman, p 15230 Administration of intravenous CaG would immediately correct the tetany that might occur in a patient in whom a thyroidectomy was recently performed. Parathyroid hormone would act more slowly but could be given for its future stabilizing effect. Long-term control of a patient after a thyroidectomy can be obtained with vitamin D and dietary therapy Calcitonin is a hypocalcemic antagonist of parathyroid hormone. Plicamycin (mithramycin) is used to treat Paget s disease and hypercalcemia. The dose employed is about one-tenth the amount used for plicamycin s cytotoxic action. 

Cholecalciferol Regulate gene transcription via the vitamin D receptor Stimulate intestinal calcium absorption, bone resorption, renal calcium and phosphate reabsorption decrease parathyroid hormone (PTH) promote innate immunity inhibit adaptive immunity Osteoporosis, osteomalacia, renal failure, malabsorption Hypercalcemia, hypercalciuria the vitamin D preparations have much longer half-life than the metabolites and analogs... 

Reviews of parathyroid hormone have suggested that it is generally well tolerated (4,5,6). The adverse effects of parathyroid hormone that have been reported in clinical trials are mild and include transient bone pain, nausea, dizziness and local irritation at the injection site (7). Hypercalcemia, which is common, is usually mild and asymptomatic. Adverse effects, including hypercalcemia, appear to be dose related in the therapeutic range. 

Mild asymptomatic hypercalcemia is common during treatment with parathyroid hormone (15). The hypercalcemia is persistent, and requires dosage reduction in 3% of patients using 20 micrograms/day and in 11% using 40 micrograms/day (16). Transient mild hypercalciuria and increased serum phosphate are common but do not usually limit therapy. 

Hypercalcemia was present in 11% of 541 women 4-6 hours after parathyroid hormone 20 micrograms/day and in 28% of 552 women after 40 micrograms/day (12). The dose was halved because of hypercalcemia in 3 and 11% of the women taking 20 and 40 micrograms/day respectively. Nine of the women taking 40 micrograms/day stopped treatment because hypercalcemia persisted after dosage reduction. 

Combining parathyroid hormone with antiresorptive agents may prevent or minimize hypercalcemia. None of... 

Poliak, MR, Chou, YH, Marx, SJ, Steinmann, B, Cole, DE, Brandi, ML, Papapoulos, SE, Menko, FH, Hendy, GN, Brown, EM and et al., 1994b, Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype, J Clin Invest 93 1108-1112 Posillico, JT, Wortsman, J, Srikanta, S, Eisenbarth, GS, Mallette, LE and Brown, EM, 1986, Parathyroid cell surface autoantibodies that inhibit parathyroid hormone secretion from dispersed human parathyroid cells, J Bone Miner Res 1 475-483... 

Sanders, JL, Chattopadhyay, N, Kifor, O, Yamaguchi, T and Brown, EM, 2000, Extracellular calciumsensing receptor (CaR) expression and its potential role in parathyroid hormone-related peptide (PTHrP) secretion in the H-500 rat Ley dig cell model of humoral hypercalcemia of malignancy, Biochem Biophys Res Commun 269 127 132... 

Schwarz, P, Larsen, NE, Lonborg Friis, IM, Lillquist, K, Brown, EM and Gammeltoft, S, 2000, Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism associated with mutations in the human Ca2+ -sensing receptor gene in three Danish families, Scand J Clin Lab Invest 60 221-227 Schwarz, P, Sorensen, HA, McNair, P and Transbol, I, 1993, Cica-clamp technique a method for quantifying parathyroid hormone secretion a sequential citrate and calcium clamp study, Eur J Clin Invest 23 546-553... 

Hyperparathyroidism Increased parathyroid hormone secretion, usually caused by parathyroid tumors leads to excessive bone resorption and hypercalcemia Usually treated surgically by partial or complete resection of the parathyroid gland... 

Potts JT, Jr., Bringhurst FR, Gardella TJ, et al. Parathyroid hormone Physiology, chemistry, biosynthesis, secretion, metabolism, and mode of action. In Degroot LJ (Ed.), Endocrinology. W.B. Saunders, Philadelphia, PA (1996) 920-965. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive two-site immuno-radiometric assay of parathyrin and its clinical utility in evaluation patients with hypercalcemia. Clin. Chem. (1987) 33 1364-1367. 

P2. Pandian, M. R., Morgan, C. H., Carlton, E., and Serge, G. V., Modified immunoradiometric assay of parathyroid hormone-related protein Clinical application in the differential diagnosis of hypercalcemia. Clin. Chem. 38, 282-288 (1992). 

I. Parathyroid Hormone-induced Hypercalcemia in the Thyroparathyroidectomized Rat Model of Bone Resorption... 

In the kidneys, parathyroid hormone increases 1 -hydroxylation of calcidiol and reduces 24-hydroxylation. This is not the result of de novo enzyme synthesis, but an effect on the activity of the preformed enzymes, mediated by cAMP-dependent protein kinases. In turn, calcitriol has a direct role in the control of parathyroid hormone, acting to repress expression of the gene. In chronic renal failure, there is reduced synthesis of calcitriol, leading to the development of secondary hyperparathyroidism that results in excess mobilization of bone mineral, hypercalcemia, hypercalciuria, hyperphosphaturia, and the development of calcium phosphate renal stones. 

Calcitonin Calcitonin is secreted hy the C cells ofthe thyroid gland in response to hypercalcemia. Its primary action is to oppose the actions of parathyroid hormone hy suppressing osteoclast actions. It also stimulates... 

SEDA-22, 172) (1,2). However, hypercalcemia has also been reported in a few patients using no more than the recommended doses (3,4). Calcipotriol exerts its effects on systemic calcium homeostasis by increasing intestinal absorption of calcium and probably phosphate. This results in suppression of parathyroid hormone and 1,25-dihydroxycolecalciferol (5). 

Combining parathyroid hormone with antiresorptive agents may prevent or minimize hypercalcemia. None of 27 women randomized to estrogen plus parathyroid hormone PTHi 34 25 micrograms/day became hypercal-cemic during a 3-year study (13). 

Of these alfacalcidol has been the most widely used. It is hydroxylated in the liver to calcitriol, thus bypassing the kidney. Unlike calcitriol, which acts in the small intestine to stimulate absorption, doxercalciferol remains inactive until it reaches the liver, where it undergoes transformation to active vitamin D (2). As a result, doxercalciferol minimizes the risk of hypercalcemia by 67-80%. The manufacturers claim that doxercalciferol is as potent as calcitriol in lowering parathyroid hormone concentrations. 

The efficacy of intravenous paricalcitol and calcitriol and the risks of hypercalcemia and hyperphosphatemia have been studied in an international, randomized, doubleblind comparison in 38 patients in dialysis units (3). The end points were a reduction of at least 50% in basehne parathyroid hormone concentration and the occurrence of hypercalcemia and hyperphosphatemia. Paricalcitol was started at a dose of 0.04 micrograms/kg and increased in 0.04 micrograms/kg increments every 4 weeks to a maximum allowable dose of 0.24 micrograms/kg or until there was at least a 50% fall in serum parathyroid... 

Because of its potent effects on parathyroid hormone, intestinal calcium absorption, and bone calcium mobilization, calcitriol can cause hypercalcemia, often precluding its use in therapeutic doses (32). Hyperphosphatemia is also a persistent problem in patients on chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol. The use of large doses of calcium carbonate or acetate to control phosphate absorption can increase the risk of hypercalcemia from calcitriol (33). 

A 31-year-old woman developed diffuse musculoskeletal pain. She had been taking calcium and dihydrota-chysterol up to 4 mg/day for 6 months for hypoparathyroidism after subtotal thyroid resection. She had severe hypercalcemia (4.1 mmol/1), no detectable intact parathyroid hormone, renal insufficiency (serum creatinine 486 pmol/l), and a normochromic anemia (6.6 g/dl). Rehydration and forced diuresis initially improved renal function and reduced the serum calcium concentration, but the calcium concentration after 4 weeks was still 3.0 mmol/1 and it did not normalize until she was given a single intravenous dose of pamidronate 15 mg. 

When the secretion of parathyroid hormone is excessive, the physiologic effects of this peptide on the gut, the skeleton, and the kidney tubules are enhanced. The percentage of dietary calcium absorbed into the circulation is increased, calcium ions are released from bone and enter the blood more rapidly, and the renal tubules reabsorb more calcium than usual from the luminal urine, all leading to hypercalcemia. Chronic hypercalcemia is associated with vague generalized musculoskeletal pain, fatigue, and eventually, slowed mentation. 

Figure 49-15 Midregion (A) and intact (B) PTH in normal subjects and patients with primary hyperparathyroidism, hypercalcemia associated with malignancy, and hypoparathyroidism. (From Endres DB, Viifanueva R, Sharp CF jr. Singer FR. /Vleasurement of parathyroid hormone. Endocrinol Metab Clin North Am 1989 18 611-29.)...

Parathyroid Hormone-Related Protein PTHrP was discovered in 1987 by investigators studying the mechanism by which certain cancers produce humoral hypercalcemia of malignancy (HHM). ... 

Figure 49-22 PTHrP in normal subjects and patients with malignancies and other disorders. Hatched area indicates the normal reference interval. (Adapted from Pandian AIR, Morgan CH, Carlton E, Segre GV. Modified /mmunorod/ometr/c ossoy of parathyroid hormone-related protein clinical app/icatfon in the differential diagnosis of hypercalcemia. Clin Chem 1992 38 282 SS.)...

Budayr AA, Nissenson RA, Klein RF. Increased serum levels of parathyroid hormone-like protein in mafig-nancy associated with hypercalcemia. Ann Intern Med 1989 111 807-12. 

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