Susan B. Oldham

Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency

Hypocalcaemia is a well‐recognized manifestation of magnesium deficiency. We have studied seventeen patients with this syndrome in an attempt to determine the pathogenesis of the hypocalcaemia. Mean initial serum calcium concentration was 5.6 mg/dl and mean initial serum magnesium concentration was 0.75 mg/dl. Serum immunoreactive parathyroid hormone (IPTH) was measured in sixteen patients in the untreated state. Despite severe hypocalcaemia, serum IPTH was either undetectable (<150 pg/ml) or normal (<550 pg/ml) in all but two patients. Serial measurments made during the initial 4 days of magnesium therapy in four patients showed an increase in serum IPTH within 24 h, but a delayed increase in serum calcium, which required approximately 4 days to reach normal values. The effect of the rapid normalization of serum magnesium on serum IPTH and serum calcium concentration was studied in three patients. Within 1 min after 144‐300 mg of elemental magnesium was administered i.v., serum IPTH had risen from undetectable to 3600 pg/ml and 1725 pg/ml in two patients and from 425 pg/ml to 937 pg/ml in the third. Serum calcium concentrations were unchanged after 30‐60 min. These data provide evidence for impaired parathyroid gland function in most of the magnesium deficient patients. The rapidity with which serum IPTH rose in response to magnesium therapy indicates that this may reflect a defect in parathyroid hormone (PTH) secretion rather than its biosynthesis. The failure of serum calcium concentration to increase during the initial days of magnesium repletion, at a time when serum IPTH concentrations were normal or elevated, suggests end‐organ resistance to PTH in these patients.

Urinary cyclic AMP analyzed as a function of the serum calcium and parathyroid hormone in the idfferential diagnosis of hypercalcemia.

Urinary cyclic AMP (UcAMP) appropriate for the serum calcium concentration was determined in normal subjects during the base-line state and during alteration in their serum calcium concentrations by saline and calcium infusions. This was compared to the UcAMP in 76 patients with hypercalcemia and 5 patients with hypocalcemia. In 54 of 56 patients with primary hyperparathyroidism, the UcAMP was inappropriately high for their serum calcium concentration, the 2 exceptions having renal failure. In four patients with vitamin D intoxication, sarcoidosis, milkalkali syndrome, and thiazide-induced hypercalcemia and in five patients with hypocalcemia due to hypoparathyroidism, the UcAMP was appropriately low for their serum calcium concentration. In 16 patients with nonparathyroid neoplasms, 10 had UcAMP levels that were inappropriately high suggesting ectopic parathyroid hormone (PTH)-mediated hypercalcemia and 6 had UcAMP levels that were appropriately low suggesting that their hypercalcemia was due to osteolytic factors other than PTH. Correlations between UcAMP, serum calcium concentration, and carboxyl-terminal immunoreactive PTH suggest that random UcAMP is a sensitive accurate reflection of circulating biologically active PTH. If there is adequate renal function (serum creatinine concentration less than 2.0 mg/dl), a random UcAMP expressed as mumol/g creatinine and analyzed as a function of the serum calcium concentration completely separates patients with PTH and non-PTH-mediated hypercalcemia.

Treatment of Thyrotoxic Hypercalcemia with Propranolol

A noteworthy elevation in mean total and ionized serum calcium concentration has previously been documented in hyperthyroidism.1 2 3 Numerous cases of overt hypercalcemia in hyperthyroidism also ha...

Parathyroid hormone clearance in man

The role of the kidney, liver, and bone and/or muscle, in the metabolic clearance of parathyroid hormone (PTH), has been examined in man. Serum was obtained from the femoral artery and the renal, hepatic, and femoral veins of nine hyperparathyroid patients undergoing selective venous catheterization. The concentration of immunoreactive parathyroid hormone (IPTH) was measured in the samples by radioimmunoassay using an antiserum predominantly specific for the aminoterminal (N-terminal) portion of the PTH molecule. Gel filtration of hyperparathyroid sera demonstrated this antiserum to measure essentially only intact PTH. The mean arteriovenous (AV) difference measured across the liver was 44%; across the kidney, 34%; and across the leg, 16%. These arteriovenous differences were all statistically significant (p less than 0.005). A significant positive correlation was found between the AV difference in IPTH across the kidney and the serum calcium concentration (r = 0.50, p less than 0.05). These studies suggest that both the liver and the kidney play major roles in the clearance of PTH in man and indicate that PTH is cleared by bone and/or muscle as well. The correlation observed between the serum calcium concentrations and the AV differences in IPTH across the kidney suggest that the rate of clearance of PTH in man may be modulated by changes in the concentration of serum calcium.

Studies on adrenal cortical cytochrome P-450: I. Effects of substrates and electron donors on its catalytic, spectral, and electron paramagnetic resonance properties

Abstract The optical, electronic, and catalytic properties of cytochrome P-450 of bovine adrenal cortical mitochondria have been studied. 11-Deoxycortisol and other substrates for 11β-hydroxylation induce a characteristic difference spectrum in aerobic mitochondria showing absorption minima at 575, 530–535, and 420 mμ. Selective reduction of the hydroxylating enzymes in the absence of steroid substrate produces a typical hemoprotein reduced-minus-oxidized difference spectrum with α, β, and Soret absorption maxima at 575, 530–535, and 420 mμ, respectively. The kinetics of reduction and oxidation of this cytochrome have been correlated with oxygen uptake and steroid hydroxylation. Equilibration of the reduced hemoprotein with increasing carbon monoxide/oxygen ratios results in a progressive conversion of its 420mμ absorption band to the intense 450mμ absorption maximum characteristic of cytochrome P-450-CO. Electron paramagnetic resonance studies of aerobic mitochondria show signals ascribed to mitochondrial cytochrome P-450 at g values 2.42 and 2.26 which can be intensified by 11-deoxycortisol.

The role of calmodulin in insulin secretion: The presence of a calmodulin-stimulatable phosphodiesterase in pancreatic islets of normal and pregnant rats

Abstract Calmodulin-stimulatable phospodiesterase activity has been demonstrated to be present in islets of Langerhans. Under the conditions used in the present study, this activity contributes approximately 25% of the total cyclic AMP phosphodiesterase activity measureable in islet sonicates of normal rats. The addition of calcium alone to the sonicates resulted in a partial stimulation equivalent to approximately half that achieved by the addition of both calcium and calmodulin. This partial stimulation is attributed to the presence of endogenous calmodulin since the calcium-stimulated activity could be decreased to a similar basal level by the addition of either EGTA or phenothiazine. The possibility that changes in the activity of this enzyme might account for the increased insulin secretion seen in late preganancy was examined. Cyclic AMP phosphodiesteras activity was measured in sonicates of islets prepared from age-matched normal female and 20-day pregnant rats. There was no significant difference in the amounts of either the total or calmodulin-stimulated activity between pregnant and control animals. The presence of calmodulin-stimulatable cyclic AMP phosphodiesterase in pancreatic islets indicates that its role should be considered in models of calcium mediated regulation of insulin secretion. Although it does not appear that an alteration in the activity of this enzyme is involved in the increased insulin secretion which occurs late in pregnancy, changes in this enzyme may well occur in other states of altered insulin secretion.

Effectiveness of 1 α-hydroxyvitamin D3 in children with renal osteodystrophy associated with hemodialysis

Two children who were receiving maintenance hemodialysis were treated with 1 to 4 microng/day of 1 alpha-hydroxyvitamin D3 for 500 to 700 days, respectively. Sequential parathyroid hormone levels and radiologic evaluations showed considerable improvement in one patient. The second patient initially responded with healing of the bone disease. Subsequent deterioration may be related either to medical noncomplicance and/or interference by diphenylhydantoin in the subsequent hepatic 25-hydroxylation of 1 alpha-OH-D3.

The Dynamic Insulin Secretory Response of Isolated Pancreatic Islets of the Diabetic Mouse: Evidence for a Gene Dosage Effect on Insulin Secretion

Expression of the autosomal recessive (db) gene in homozygous (db/db) C57BL/KsJ mice results in a severe and eventually fatal diabetic syndrome. Many studies of the diabetic mouse have used lean litter-mates (+ /?) as controls despite evidence suggesting a gene dosage effect in heterozygous animals. In order to study the gene dosage effect of the diabetes (db) gene on insulin release in the heterozygote, perifusion experiments were performed on isolated islets of Langerhans of diabetic (db/db), heterozygous (+/db), and normal (+ / +) control mice. Islets of normal controls exhibited a fivefold greater increase in insulin release than did those of diabetics in response to 16.7 mM D-glucose. The insulin secretory response of islets of heterozygotes to glucose was intermediate, being twofold greater than that of diabetics but only about half of that of normal controls. Biphasic insulin release in response to glucose was observed only in islets of normal controls. Islets of all three genotypes exhibited biphasic insulin release in response to 10 mM D-glyceraldehyde; however, overall insulin release in both heterozygotes and diabetics remained diminished as compared with the response of normal controls. This is in contrast to the situation we have previously reported in islets of fasted or aging rats in which, though manifesting defects in glucose-stimulated insulin release, the islets are able to respond normally to 10 mM D-glyceraldehyde in respect to both the dynamic secretory pattern and quantity of insulin released. Our data suggest a gene dosage effect of the (db) gene on glucose-stimulated insulin release in heterozygous (+/db) C57BL/KSJ mice.

Effects of 1,25-Dihydroxycholecalciferol on Serum Calcium, Phosphate, and Immunoreactive Parathyroid Hormone in Dogs

Parathyroid hormone (PTH) has been shown to stimulate the formation of 1,25-dihydroxycholecalciferol (1,25(OH)2D3), the most biologically active form of vitamin D3, by the kidney (1, 2). It has been postulated that 1,25(OH)2D3 or other vitamin D3 metabolites might directly influence the secretion of PTH. Receptors for 1,25(OH)2D3 have been identified in chick (3) and pig (4) parathyroid glands and in human parathyroid adenoma (5). Accumulation of 1,25(OH)2D3 by the parathyroid gland has been reported in the chick (6), and 1,25(OH)2D3 when administered to-gether with 24,25-dihydroxycholecalciferol (24,25(OH)2D3), caused the size of the parathyroid glands in vitamin D-deficient chicks to regress (7). The effect of vitamin D metabolites on PTH secretion has been examined in several species. Studies several years ago by Oldham, et al, showed that the administration of pharmacological amounts of 25-hydroxycholecalciferol (250H D3) to vitamin D-deficient dogs appeared to decrease the circulating concentrations of immunoreactive parathyroid hormone (IPTH) before significant increases in serum calcium concentration occurred (8). Chertow, et al, reported a decrease in IPTH in rats administered 1,25(OH)2D3 and an inhibition of IPTH released from slices of bovine parathyroid tissue in vitro when 1,25(OH)2D3 was added to the culture medium (9).

USE OF 1 ALPHA-HYDROXYVITAMIN D3 ON CHILDREN WITH CHRONIC RENAL FAILURE

It is now well accepted that the kidney activates 25-hydroxyvitamin D3 to the highly potent metabolite, 1,25-dlhydroxyvitamin D3. Impaired activation in uremia may contribute to renal osteodystrophy.Recently, we tested the short-term effects of a highly potent analog, 1 alpha-hydroxyvitamin D3 (1α-OH-D3) which is relatively inexpensive to synthesize. Thirty-two mineral balance studies, each comprising a 3 day period, were performed before, during and after oral administration of 1α-OH-D3 (1-4 micrograms/day) to four children, aged 11 to 16 years, with renal osteodystrophy and stable chronic uremia (BUN > 60mg% and creatinine > 5mg%). Serial determinations of iPTH were measured. The results showed that physiological amounts of 1α-OH-D3 stimulated increased absorption of calcium in the gastrointestinal tract and promoted positive calcium balances. In addition, serum calcium levels returned to normal and iPTH secretion was suppressed. No complications were encountered.These data would infer that 1Pα-OH-D3 has major therapeutic value in the treatment of renal osteodystrophy.