Acute Hypercalcemia Research Articles

Indications and late results of subtotal parathyroidectomy for hyperparathyroidism after renal transplantation

AbstractIn view of the current controversy about the relative merits of subtotal versus total parathyroidectomy plus autograft for the treatment of parathyroid hyperplasia, we reviewed the results of subtotal parathyroidectomy in 6 patients with hyperparathyroidism after successful renal transplantation. All had normal renal function and hypercalcemia (mean 11.4 mg/100 ml). The time elapsed between renal transplantation and parathyroidectomy ranged from 3 months to 10 years (mean 42 months). The indications for subtotal parathyroidectomy were: severe acute hypercalcemia after transplantation (1 case), persistent asymptomatic hypercalcemia (2 cases), allograft lithiasis (2 cases), and bone disease (1 case). Subtotal parathyroidectomy was performed, aiming to leave about 30–50 mg of parathyroid tissue, and included a routine transcervical thymectomy. The weight of resected tissue ranged between 0.6 and 2.4 g per patient (mean 1.58 g). Immediate control of hypercalcemia was achieved in all cases. No patient needed replacement therapy with calcium and/or vitamin D after the operation. The 6 patients were followed from 8 months to 4.5 years (mean 34 months) and all had normal calcium, phosphate, and alkaline phosphatase serum values at the time of their last visit. A reappraisal of the surgical indications for hypercalcemia after renal transplantation is needed because severe longterm complications (allograft lithiasis) may develop in patients with minimal hypercalcemia. Subtotal parathyroidectomy is a good operation for treating hyperparathyroidism in patients with functioning renal allografts.

Inhibition of transcellular NaCl reabsorption in dog kidneys during hypercalcemia.

Reduced concentrating and diluting capacity of the kidney in acute and chronic hypercalcemia may partly be due to inhibition of transcellular sodium reabsorption (RNa) in the thick ascending limb of Henle's loop. To examine this hypothesis, local heat production and RNa were measured during normo- and hypercalcemia at comparable glomerular filtration rate (GFR) in volume expanded, anesthetized dogs. Changes in proximal RNa which might occur during CaCl2 infusion, were minimized by infusing acetazolamide (75 mg/kg body wt iv). When ultrafiltrable calcium was increased from 1.12 +/- 0.09 to 2.95 +/- 0.10 mmol/l, cortical heat production was unchanged, whereas outer medullary heat production fell by 32 +/- 4%. RNa was reduced by 32 +/- 6%. Bicarbonate reabsorption did not change but calcium reabsorption and potassium excretion increased significantly. The potassium content of cortex and outer medulla increased during hypercalcemia, whereas ouabain, an inhibitor of Na+, K+-ATPase reduces the potassium content. We conclude that hypercalcemia does not inhibit transcellular RNa in the diluting segment by a direct effect on the Na+, K+-ATPase or the mitochondria, but by interfering with the coupled NaCl transport across the luminal cell membrane.

Rapid increase of calcitonin-specific mRNA after acute hypercalcemia.

The regulation of calcitonin (CT) secretion by calcium was studied by measuring CT mRNA extracted from thyroids of normal rats subjected to acute calcium stimulation in vivo. The 15000-Mr primary translation product of CT mRNA was identified by immunoprecipitation using specific antibodies. While total mRNA and total radioactivity incorporated after translation of total mRNA remained unaffected by the calcium stimulation, a fourfold increase in radioactivity incorporated in CT primary translation product occurred as early as 2 min after calcium administration. This peak coincided with a rise in plasma levels of the hormone and preceded a detectable decrease in tissue stores. These results suggest that calcium ion, either directly or indirectly via its action on intracellular stores of the hormone or its precursors, causes a rapid increase in cell levels of translatable CT mRNA. In view of the extremely short time (2 min) in which this increase occurs, the action is probably at the post-transcriptional level as no increase in CT mRNA levels could be detected by hybridization assay using a specific cDNA probe for human CT mRNA.

Suppression of secondary hyperparathyroidism in uraemia: acute and chronic studies.

A study was conducted evaluating the response of serum parathyroid hormone to acute hypercalcaemia and long term administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients receiving maintenance haemodialysis. During infusion of elemental calcium 4 mg/kg/h over four hours in 12 patients not receiving vitamin D the concentration of serum amino terminal parathyroid hormone fell by 31-96% (mean 74.8 (SD 17.6)%) while that of carboxy terminal parathyroid hormone changed little. There was a strong inverse correlation between baseline serum calcium concentration and percentage fall in amino terminal parathyroid hormone during infusion (r = 0.88; p less than 0.001). In seven patients who received prolonged treatment with 1,25(OH)2D3 after calcium infusion there was a positive correlation between maximum percentage fall in amino terminal parathyroid hormone during infusion and the percentage fall in amino terminal parathyroid hormone after 1,25(OH)2D3 treatment (r = 0.79; p less than 0.05). The responsiveness of the parathyroid glands to changes in calcium in acute studies may be used to predict the efficacy of long term treatment with 1,25(OH)2D3. Patients in whom calcium infusion does not suppress parathyroid hormone may have true parathyroid autonomy and require early parathyroidectomy.

Symmetrical Bone Scan in a Patient With Acute Hypercalcemia

A previously healthy 49-year-old woman had symptoms of acute hypercalcemia that was not parathyroid-hormone mediated. Despite no clinical signs or symptoms of arthritis, a bone scan showed increased uptake in the juxtaarticular areas of the joints in the upper and lower extremities. The biopsy specimen of skeletal lesions noted on roentgenograms supported a diagnosis of multiple myeloma. Symmetrical lesions on bone scan in a patient with asymptomatic joints and acute hypercalcemia may be the first sign of an underlying hematologic malignant neoplasm.

Symmetrical bone scan in a patient with acute hypercalcemia

Symmetrical bone scan in a patient with acute hypercalcemia

Calcium and blood pressure regulation in normal and hypertensive subjects.

To elucidate the mechanisms involved in calcium-mediated blood pressure (BP) control, plasma norepinephrine (NE), epinephrine, renin activity, and angiotensin II (AII) levels and the cardiovascular pressor responsiveness to NE and AII were assessed before and during acute mild hypercalcemia or short-term calcium (Ca) inhibition with nifedipine in 20 normal and five borderline hypertensive subjects. In normal subjects, systolic BP and plasma NE and epinephrine concentrations were increased significantly (p less than 0.05) during an acute rise in serum Ca of 3.1 mg/dl (intermediate rate Ca infusion, 0.05 mg/kg/min for 3 hours), but not following an increase of 1 mg/dl (low rate Ca infusion, 0.034 mg/kg/min for 2 hours). In the borderline hypertensive group, low-rate Ca infusion elevating serum Ca by 1 mg/dl was associated with a slight increase in systolic BP (p less than 0.05) and plasma catecholamines. In both groups, the pressor responses to infused NE and AII, and plasma renin and AII levels, were unchanged during mild to moderate hypercalcemia. Nifedipine given for 2 weeks (average dose, 48 mg/d) reduced BP significantly (p less than 0.05) in the borderline hypertensive subjects only and NE pressor responses in both groups (p less than 0.025), but had no significant effect on plasma catecholamines, renin, or AII levels. These findings suggest that the adrenergic BP control mechanism may be more dependent on clinical variations in calcium metabolism than the angiotensin BP regulatory mechanism. Acute hypercalcemia may increase BP at least in part by causing an increase in adrenergic activity without an equivalent decrease in cardiovascular reactivity. Calcium inhibition with nifedipine may modify noradrenergic BP control by lowering the NE pressor reactivity without causing an equivalent increase in adrenergic activity.

Prolactin release in man: influence of cimetidine, thyrotrophin-releasing hormone and acute hypercalcaemia

The responsiveness of anterior pituitary lactotrophs and thyrotrophs to cimetidine (Cim) was investigated in healthy volunteers. Four-hundred mg Cim, injected iv, raised the serum prolactin level (Prl) from 14 +/- 2 to 58 +/- 9 ng/ml (P less than 0.001), but left the serum thyrotrophin level (TSH) unaffected. Acute hypercalcaemia, induced by iv infusion of calcium, blunted this Cim-elicited Prl response by 35 +/- 4% (P less than 0.01). Iv injection of 25 micrograms thyrotrophin-releasing hormone (TRH) had similar Prl-releasing potency as 400 mg Cim, and raised the Prl level from 14 +/- 1 to 51 +/- 6 ng/ml (P less than 0.001). In contrast to Cim, TRH also increased the TSH level significantly. Although oral pre-treatment with Cim for 3 days (1000 mg/day) failed to affect the Prl response to TRH in this study, iv injection of the drug more than doubled the above mentioned Prl response to TRH. The TSH response to TRH remained unaffected both by oral and by iv administration of Cim. These results imply that acute changes in serum calcium affect the release pattern of Prl, and that iv administration of Cim may add Prl-releasing power to TRH in healthy individuals.

The effect of acute hypercalcemia on the insulin response to OGTT.

The effect of acute hypercalcemia on the insulin response to OGTT.

Studies on aldosterone responsiveness to angiotensin II during clinical variations in calcium metabolism in normal man.

1. Angiotensin II was infused at stepwise increasing dose rates (2, 4 and 10 pmol min-1 kg-1) in 12 normal subjects. Infusions were performed in the presence of normocalcaemia, mild hypercalcemia induced by concomitant calcium gluconate infusion, and after 2 weeks of treatment with nifedipine. 2. Pre-infusion plasma levels of angiotensin II, renin or aldosterone were not altered by acute mild hypercalcaemia or administration of nifedipine. The angiotensin II-induced increases in plasma aldosterone were also similar under the three study conditions. 3. Variations in calcium metabolism occurring under clinical conditions appear to play a minor role in modulating the angiotensin II-dependent pathway of aldosterone regulation in normal man.

Calcium-prostaglandin interaction on the action of antidiuretic hormone in the dog.

The effect of interaction between calcium and prostaglandin (PG) on the action of antidiuretic hormone (ADH) was studied in the water-diuresing anesthetized dog. Maximal urinary osmolality after 100 mU or ADH was 331 +/- 24 in the normocalcemic state versus only 228 +/- 31 mosmol/kg (P less than 0.01) in dogs made acutely hypercalcemic when their serum Ca concentration was increased from 8.9 +/- 0.2 to 11.6 +/- 0.4 mg/100 ml (P less than 0.001). To define the role of PG in this effect, studies were performed in the presence of PG inhibition with indomethacin (10 mg/kg). The antidiuretic response to 100 mU of ADH was decreased by hypercalcemia, as maximal osmolality was 1,096 +/- 65 in the normocalcemic PG-inhibited dog but only 555 +/- 50 mosmol/kg in the acutely hypercalcemic PG-inhibited dog (P less than 0.001). Conversely, the effect of PG inhibition to enhance the hydroosmotic effect of ADH was also demonstrable in acutely hypercalcemic dogs, as maximal urinary osmolality following 100 mU of ADH was 257 +/- 9 before and 557 +/- 60 mosmol/kg after PG inhibition (P less than 0.001). These studies demonstrate, therefore, that the effect of acute hypercalcemia on the hydroosmotic response to vasopressin is not dependent on the synthesis of an endoperoxide metabolite. Likewise, hypercalcemia blunts but does not abolish the effect of PG inhibitors to potentiate the hydroosmotic effect of ADH.

The effect of calcium on the release of gastric inhibitory polypeptide (GIP) - with reference to the release of GIP in patients with hyperparathyroidism (author's transl)

Plasma gastric inhibitory polypeptide (GIP), insulin, glucagon concentrations and blood glucose levels in response to the ingestion of 100 g glucose were measured in 5 patients with hyperparathyroidism in order to elucidate the effect of hypercalcemia on the release of these hormones. In addition, the effect of acute hypercalcemia on the release of these hormones in response to glucose ingestion was investigated in normal subjects. Fasting plasma GIP concentration in patients with hyperparathyroidism was significantly greater than the value in seventeen normal subjects. Significantly higher responses of plasma GIP and insulin were observed after the glucose ingestion in the patients with hyperparathyroidism as compared with the values in the normal subjects, and integrated GIP and insulin responses to the glucose ingestion for 120 min in the patients with hyperparathyroidism were significantly greater than the values in the normal subjects. On the other hand, plasma glucagon concentration after the glucose ingestion in the patients with hyperparathyroidism remained unchanged, although plasma glucagon concentrations after the glucose ingestion decreased significantly from the basal value in the normal subjects. Blood glucose levels after the glucose ingestion in two groups increased significantly from the basal value in the same manner. In nine normal subjects calcium infusion (4 mg/kg bolus injection followed by continuous infusion of 4 mg/kg/hr for 3 hr) caused a significantly high concentration of plasma calcium (11.5 approximately 13.0 mg/dl) from the basal value. Significantly higher responses of plasma GIP and insulin to the glucose ingestion were observed during calcium infusion as compared with the values during saline infusion. On the other hand, plasma glucagon concentration after the glucose ingestion was not significantly changed during calcium infusion in contrast with a significant decrease of plasma glucagon after the glucose ingestion during saline infusion. Consequently, calcium was considered to play a major part in the release of GIP and insulin. The characteristic response of plasma glucagon during calcium infusion was considered, at least in part, to protect the hypoglycemia caused by hyperinsulinemia.

Acute hypercalcemic hypertension in man: Role of hemodynamics, catecholamines, and renin

The effect of acute hypercalcemia on blood pressure, blood volume, hemodynamic parameters, plasma norepinephrine, epinephrine, dopamine, renin, and aldosterone concentrations was investigated. After 1 hour of equilibration, 10 patients received an infusion of calcium gluconate in 5% dextrose (calcium 15 mg/kg of body wt in 3 hours). The calcium infusion increased the mean serum calcium from 8.7 to 13.0 mg/dl, the systolic blood pressure from 144 +/- 10 to 184 +/- (SEM) 12 mm Hg (P less than 0.001), the diastolic pressure from 78 +/- 4 to 93 +/- 5 mm Hg (P less than 0.01). The plasma volume was decreased by 9% (P less than 0.001), whereas the hematocrit was increased (P less than 0.05). Heart rate and cardiac output remained unchanged. Total peripheral resistance was increased from 1643 +/- 223 to 2256 +/- 387 dyne.sec/cm5 (P less than 0.05). The plasma epinephrine concentration rose from 4.5 +/- 0.7 to 6.9 +/- 1.2 ng/dl (P less than 0.01). The plasma norepinephrine concentration was unchanged after 2 hours and increased only slightly after 3 hours of calcium infusion. Plasma renin, aldosterone, and dopamine concentrations were not significantly changed. These findings demonstrate that acute hypercalcemic hypertension is mediated by an increase in peripheral vascular resistance. Hypercalcemic hypertension may be induced by a direct effect of calcium on blood vessels; calcium-mediated increase in adrenal epinephrine release may play a mild contributory role, and plasma volume contraction, an inhibitory role.

Response of the exocrine pancreas to graded doses of secretin in calcium-treated and normal dogs

Persisting modifications induced by repeated intravenous calcium infusion (acute hypercalcaemia) were investigated in 6 Thomas fistula dogs: 4 controls and 4 calcium-treated dogs, two of which were studied as controls. 1. (a) The pancreatic response to graded doses of synthetic secretin (water and bicarbonate outputs) was significantly reduced in calcium-treated dogs when compared with controls. As both the D 50 for secretin-induced response increased, and the maximal secretory response decreased, it may be concluded that calcium treatment decreased the sensitivity of duct cells to secretin and reduced their secretory capacity. 2. (b) A similar dose—response relationship was observed between secretin and pancreatic calcium outputs in controls and calcium-treated dogs. The secretin induced pancreatic calcium secretion was independent of protein secretion the latter not being modified by secretin. Thus it may be assumed that the secretory fluid calcium originated from a protein independent pool and had a dose-dependent relationship to secretin. 3. (c) These results help to illuminate the aetiology of chronic pancreatitis induced by acute hypercalcaemia and by hyperparathyroidism.

The effect of acute hypercalcemia on prolactin release in man.

The serum prolactin response to acute hypercalcemia during calcium infusion was studied in 7 normal subjects. Prolactin, and calcium levels were determined at 30 minute intervals during the 210 minutes of the infusion. The infusion performed consisted of either normal saline at 3 ml/min for 210 minutes, or 15 mg calcium/kg at 3 ml/min for 180 minutes followed by normal saline infusion for the final 30 minutes. Calcium concentration increased from a base line of 10.0 +/- 0.26 (mean +/- SEM) to a maximal level of 13.6 +/- 0.26 (mean +/- SEM) mg/100 ml, in response to calcium level in response to normal saline infusion. Prolactin level decreased significantly (P less than 0.05) from 9.5 +/- 1.45 (mean +/- SEM) to 3.7 +/- 0.2 (mean +/- SEM) ng/ml at 180 minutes.

Role of haemodynamics, catecholamines and renin in acute hypercalcaemic hypertension in man.

1. The effect of acute hypercalcaemia on blood pressure, blood volume, haemodynamic indices, plasma catecholamines, renin and aldosterone levels was investigated in 10 patients. 2. Calcium infusion (15 mg/kg over 3 h) increased (P < 0.05) plasma calcium and adrenaline levels, blood pressure, total peripheral resistance and packed cell volume. Plasma volume was decreased, and heart rate, cardiac output and plasma renin, aldosterone or dopamine levels were not significantly changed. Plasma noradrenaline was increased only minimally after 3 h of calcium infusion. 3. Mean blood pressure before and during calcium infusion correlated with concomitant serum calcium (r = 0.39; P < 0.02) or adrenaline levels (r = 0.57; P < 0.01); changes in blood pressure correlated with variations in plasma adrenaline (r = 0.68; P < 0.001). 4. Acute hypercalcaemic hypertension is mediated by an increase in peripheral vascular resistance and may be induced by a direct effect of calcium on blood vessels. The calcium-mediated increase in adrenaline release may play a contributory, and plasma volume contraction an inhibitory, role.

Role of the autonomic nervous system in the pressor response to calcium in conscious dogs.

The effects of acute hypercalcaemia on arterial pressure and vascular tone have been poorly understood. We analysed the effect of a bolus of calcium chloride (15 mg . kg-1 iv) on arterial pressure, total peripheral resistance, and left ventricular function in 25 conscious dogs studied with or without pharmacological autonomic blockade. Without autonomic blocking drugs, the maximum response to calcium included increases of +139.4 kPa . s-1 (+1046 mmHg . s-1) in maximum rate of change of left ventricular pressure, +2.2 cm3 in stroke volume, +2.6 kPa (+ 19.2 mmHg) in aortic systolic pressure, and +0.6 kPa (+4.4 mmHg) in mean aortic pressure, but total peripheral resistance was unchanged. During beta-adrenergic blockade with propranolol, calcium again increased maximum rate of change of pressure and stroke volume, increased mean aortic pressure (2.2 kPa [+16.5 mmHg]), and increased resistance by 35%. When calcium was given during alpha-adrenergic blockade with phenoxybenzamine or phentolamine, mean aortic pressure did not rise, and resistance fell by 19%. The calcium-induced rise in resistance during beta-adrenergic blockade was abolished by surgical adrenalectomy. We conclude that excess extracellular calcium ion may influence vascular resistance by increasing autonomic nervous system excitation of alpha- and beta-adrenergic vascular receptors. A major mechanism by which the sympathetic nervous system effects occur is through increased release of catecholamines from the adrenal medulla.

Effect of acute hypercalcaemia on glucose tolerance and insulin release in human beings.

Insulin secretion in response to an oral glucose challenge during acute hypercalcaemia was studied. Oral glucose tolerance tests (OGTT) were performed in 12 non-diabetic, non-obese human volunteers, aged 20-28 years. Blood samples were collected for calcium, glucose and insulin determination. The next day the same volunteers received a 4 h infusion of calcium gluconate (15 mg/kg/4 h) and were administered glucose 1 h after starting the infusion. Serum calcium, glucose and insulin concentrations were measured again. Infusion of calcium gluconate resulted in an increase in serum calcium concentration of 5 mg/100 ml over 4 h. During these infusions no significant changes in glucose concentrations were noted. On the other hand, the total mean insulin concentration, expressed as the area under the 3 h glucose tolerance curve, and the insulin peak at 30 min were significantly increased during hypercalcaemia (P < 0.001). These data indicate that acute hypercalcaemia does not affect carbohydrate tolerance but increases insulin secretion in human beings.

Acute hypercalcemia in hemodialysis patients: distinction from 'dialysis dementia'.

The clinical, laboratory and EEG findings of 4 uremic patients on hemodialysis who accidently developed acute hypercalcemia were reviewed. An acute central nervous system syndrome developed, associated with the clinical changes of disorientation, dysarthria, seizures, myoclonic jerks, hallucinations, irritability, confusion, memory and judgment defects plus bizarre behavior. The EEG findings demonstrated diffusely severe slow background activity in all tracings. In addition, the EEG abnormalities as well as the clinical findings disappeared when serum calcium returned to normal. Hypercalcemia, a reversible condition, seems to have been the cause of this clinical syndrome which should be differentiated from dialysis dementia, a condition known to be irreversible and fatal.

Antiphosphaturic action of 25 (OH) vitamin D3 in experimental Fanconi syndrome.

Renal handling of phosphorus was studied in the following groups of parathyroidectomized rats with maleate-induced Fanconi syndrome: 1) 6 rats receiving intravenous parathyroid hormone, 2) 6 rats receiving intravenous dibutyryl cyclic AMP (DBcAMP), 3) 6 rats undergoing volume expansion with saline, 4) 12 rats receiving intravenous 25 (OH)vitamin D3, 5) 12 rats with acute hypercalcemia induced by intravenous CaCl2, 6) 6 rats with phosphate deprivation, and 7) 6 rats receiving intravenous calcitonin. Parathyroid hormone and calcitonin failed to increase the urinary excretion of both cAMP and phosphorus. Likewise, DBcAMP failed to increase the urinary excretion of phosphorus. Extracellular volume expansion and hypercalcemia (serum calcium 12.9 +/- 0.7 mg/100 ml) did not alter the tubular reabsorption of phosphorus. In phosphate-deprived animals, the fractional excretion 0.16 +/- 0.05 (mean +/- SE) was lower than that in the control animals (maleate-treated without phosphate depletion), 0.46 +/- 0.04 (P less than 0.001). 25 (OH)vitamin D3 decreased the fractional excretion of phosphorus from 0.39 +/- 0.03 in the control (maleate-treated not receiving 25 (OH)vitamin D3) to 0.23 +/- 0.02 (P less than 0.001) in the experimental animals. The present study demonstrated an antiphosphaturic effect of 25(OH)vitamin D3 in experimental Fanconi syndrome; the mechanism of this action is not well understood.