Helen C. Harrison

Familial benign hypercalcemia

Mild hypercalcemia was recognized in a 7-year-old boy during an evaluation for headaches. Subsequently, an additional eleven members of four generations of the family were found to have mild hypercalcemia, normal levels of immunoassayable parathyroid hormone (IPTH) during hypercalcemia, normal or low serum phosphate for age, and low urinary calcium excretion. Administration of prednisone for ten days did not decrease serum calcium values. Ionized calcium was increased proportional to the elevation of the total serum calcium. Surgical exploration of the proband revealed three histologically normal parathyroid glands and a fourth which was grossly normal, with no tumor in the anterior medastinum. Calcium infusion increased serum calcium values while IPTH leveis decreased. The persistence of normal IPTH concentration despite elevated serum total and ionized calcium values suggests an abnormality of the receptor mechanism for the calcium ion control of the secretion of parathormone by the parathyroid glands. The family pedigree indicates an autosomal dominant mode of inheritance.

The interaction of vitamin D and parathyroid hormone on calcium phosphorus and magnesium homeostasis in the rat

Abstract The effects of a single injection of 100 units of purified parathyroid hormone (Aurbach) were compared in vitamin D-deficient and vitamin D-primed rats. The rats of the latter group received 500 units of vitamin D 18 hours before the injection of parathyroid hormone. Injection of parathyroid hormone produced no significant alterations of serum calcium, phosphate or magnesium concentrations in the vitamin D depleted rats and only a questionable phosphaturic effect. Vitamin D by itself raised the serum calcium concentration to normal, depressed the serum magnesium level and possibly raised the serum phosphate concentration. This latter effect occurred in one series of rats but not in another. The injection of parathyroid hormone into vitamin D-primed rats produced the characteristic effects of this hormone: elevation of serum calcium concentrations to hypercalcemic levels, decrease of serum phosphate concentrations with associated increase of urinary phosphate excretion, and increase of the concentration of serum magnesium. The concentration of serum magnesium was inversely related to the concentration of phosphate. There is an interrelation between the functions of parathyroid hormone and vitamin D so that in the absence of vitamin D there is little or no response of rats to amounts of parathyroid hormone which produce a marked effect in vitamin D-treated animals. This failure of response involves both the calcium mobilizing and phosphaturic actions of parathyroid hormone.

Inhibition of Vitamin D-Stimulated Active Transport of Calcium of Rat Intestine by Diphenylhydantoin-Phenobarbital Treatment

Summary The effect of combined di-phenylhydantoin and phenobarbital administration on the response of vitamin D-de-pleted rats to ergocalciferol, cholecalciferol, and 25-hydroxycholecalciferol (25-OHCC) was measured by determinations of serum calcium and phosphate concentrations and of intestinal transport of calcium in vitroby everted loops of small intestine. The major action of this anticonvulsant drug treatment in the rat was to inhibit the action of the various forms of vitamin D including 25-OHCC in increasing active transport of calcium by the everted intestine. The increase of calcium diffusibility across the intestine by vitamin D was not blocked nor was the action of vitamin D in increasing serum calcium concentrations. A specific inhibitory effect of the anticonvulsant drugs on an energy-dependent calcium transport system in the intestinal mucosa is suggested. This work was supported by USPHS Grant AM-00668. 25-hydroxy-cholecalciferol was supplied to us by Dr. John Babcock, the Upjohn Company. We thank Mrs. Evelyn Bull for important technical assistance.

Rickets then and now

Since the introduction of irradiated ergosterol into our food supply, nutritional vitamin D-deficiency rickets has become an uncommon disease. However, skeletal disorders due to abnormalities of vitamin D function still occur. These disorders can now be classified more exactly into two groups: those in which there is a deficiency of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D, and those in which there is an abnormality of renal tubular function resulting in renal hypophosphatemia despite normal vitamin D metabolism. The various entities of these two groups are described and the theoretical basis of their treatment given.

Citrate metabolism and the mechanism of renal calcification induced by magnesium depletion

Abstract The effects of magnesium deficiency in rats on serum, bone, and urine citrate concentrations and the influence of concurrent vitamin D depletion were studied. Our findings are in agreement with the concept that a fall in serum magnesium stimulates parathyroid hormone output. Elevated serum calcium and citric acid levels, hypocalciuria, hypophosphatemia and hyperphosphaturia were found consistently in magnesium-deficient rats. The development of hypercalcemia and hypercitricemia was prevented by vitamin D deficiency which is in accord with the data indicating that full expression of parathyroid hormone activity does not occur in the absence of vitamin D. Citrate excretion was reduced in the magnesium-deficient rats. Whatever the mechanism involved in the reduction of urinary citrate by magnesium deficiency the sequence of events favors the precipitation of calcium phosphate in the renal tubules in a manner resembling that seen in acetazolamide administration. 13 Kidney calcinosis was prevented by vitamin D deficiency, by reduction of phosphorus excretion or by increasing urine citrate concentrations. Magnesium deficiency is an additional example of the association of hypocitricuria and nephrocalcinosis.

Vit. D and citrate metabolism; inhibition of vit. D effect by cortisol.

Summary Correlation of the effect of Vit. D in augmenting concentrations of citrate in plasma and bone with its antirachitic action has been studied. Rats were made rachitic by feeding a Vit. D deficient diet which was also low in available phosphorus. Addition of Cortisol to the diet of such rats reduced concentration of citrate in serum and also blocked the effect of Vit. D in increasing serum and bone citrate levels. Antirachitic action of Vit. D as measured by rise of serum phosphorus concentrations and by histological evidences of calcification of rachitic cartilage and osteoid was not suppressed by Cortisol. The antirachitic action of Vit. D and its effect upon citrate metabolism can, therefore, be separated. The tibias of Vit. D deficient Cortisol fed rats show evidences of increased calcification in comparison with rachitic controls which might in part be due to inhibition of bone resorption as well as retardation of cartilage growth by Cortisol. This increased calcification in Cortisol fed rats is associated with extreme depletion of extracellular phosphate.

Actinomycin D inhibition of intestinal transport of calcium and of vitamin D action.

Summary Actinomycin D injection inhibits the actions of vitamin D in increasing concentrative transport of calcium across the intestinal wall in vitro and in raising serum calcium concentrations of fasted vitamin D-deficient rats. Actinomycin D blocks the transport of calcium across the mucosal surface of vitamin D-deficient as well as vitamin D-treated rats so that its action is on the calcium transport system rather than on the stimulatory effect of vitamin D. This inhibitory effect of actinomycin D on calcium transport is present within 3 hours of its subcutaneous injection and is less marked at 18 hours which suggests a direct interaction with the calcium transport system. Under the same conditions actinomycin D does not influence the transport of 1-tyrosine across the intestinal wall in vitro.

Response to vitamin D of magnesium deficient rats.

Summary Measurements of concentrative calcium transport by the rat small intestine in vitro were made in preparations from vitamin D deficient and vitamin D fed magnesium deficient and control rats. The effects of vitamin D treatment on serum calcium and citrate concentrations of hypomagnesemic and control rats were also measured. These studies indicate that magnesium deficient rats are less responsive to physiologic amounts of vitamin D than control rats.

Electrolyte transport by bullfrog colon in vitro

Abstract 1. 1. Studies were done on the transport function of the large intestine of Rana catesbeiana by measurement of the electrical potential difference (PD) and solute concentration gradients developed by the everted sac preparation during incubation in different media in vitro , and the effect of acetazolamide on these gradients. 2. 2. A high PD, serosa positive to mucosa, is maintained by this preparation. The PD was dependent on the ambient Na + concentration and dropped when this was lowered to 15 mM or less. A decrease in PD associated with an increase in net serosal (s) to mucosal (m) K + movement was effected by elevating ambient K + concentration. 3. 3. Na + was transported from the m to the s fluid against this PD, resulting in a high concentration gradient. This concentration difference was independent of the presence of K + and HCO 3 − in the medium. 4. 4. A high osmolal gradient was developed along with the Na + gradient since there was little net transmural movement of water. 5. 5. Cl − and HCO 3 − moved in roughly equal amounts along with Na + . This anion movement occurred down an electrochemical gradient. Marked qualitative differences were demonstrated in the behaviour of these two anions, however. The net movement of HCO 3 − was positively correlated with that of Na + , whereas this was true for Cl − only in HCO 3 − -free medium or in the presence of acetazolamide. Further, HCO 3 − movement varied with K + transport in contrast to Cl − . Reversed net s to m movement of HCO 3 − was observed in Na + -free media and in the presence of acetazolamide. Reduction of m to s HCO 3 − movement was compensated for by an equal increase in that of Cl − , when caused by substitution of N -tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid for ambient HCO − 3 but only partially when caused by acetazolamide inhibition of HCO 3 − transport. 6. 6. Net s to m movement of K + was demonstrated to take place even against an electrochemical gradient. This movement increased in the absence of ambient HCO 3 − , K + movement was increased by acetazolamide in absence of ambient HCO 3 − but not in its presence. On prolonged incubation of the preparation, net movements of K + and HCO 3 − decreased together relative to the transport of other ions.

Intestinal transport of calcium and phosphate in experimental magnesium deficiency.

Summary The concentrative transport of calcium by everted intestinal loops in vitro and the permeability of the small intestinal wall to this ion were determined in intestinal preparations from vitamin D deficient and vitamin D treated magnesium deficient and control rats. These experiments indicate that concentrative transport of calcium by rat small intestine in vitro is altered by the presence or absence of magnesium in the medium but not by magnesium depletion of the animals. The permeability to calcium of the intestinal preparations was not influenced by magnesium deficiency. The effects of magnesium depletion of the rat and of the presence of magnesium in the medium on concentrative transport of inorganic phosphate by the small intestine in vitro were also studied. Concentrative transport of phosphate by intestinal loops incubated in Mg++ containing buffer was less than that by those incubated in Mg++ free buffer. Intestinal loop preparations from magnesium deficient animals transferred phosphate to a greater extent than those obtained from control rats; this difference was observed both in the presence and absence of Mg++ in the buffer solution. Magnesium deficiency in the rat also reduced the concentration of serum phosphorus and increased the excretion of phosphate in the urine. These findings are consistent with the theory that magnesium influences the phosphate transport systems which control phosphate concentrations in extracellular fluids.