Harold E. 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.

Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors

The antidiuretic effect of two prostaglandin synthetase inhibitors, ibuprofen (25 mg/kg/day) and indomethacin (2 mg/kg/day), was studied in patients aged 8 to 18 years with hereditary nephrogenic diabetes insipidus. Ibuprofen (studied in five patients) did not have demonstrable effects on urine volume, free water clearance, or osmolar clearance, but fractional excretion of sodium decreased from a mean of 0.38% to 0.19% (P less than 0.05). In contrast, indomethacin (studied in three patients) was associated with a decrease in mean urine volume from 5.8 to 2.8 mL/min and a decrease in mean free water clearance from 3.1 to 1.1 mL/min (both P less than 0.05). Fractional excretion of sodium decreased from 0.77% to 0.27% (P less than 0.01) and was accompanied by an increase in serum urea nitrogen level (P less than 0.01) and a decrease in urea nitrogen clearance (P less than 0.025). Thus, prostaglandin synthetase inhibitors are not uniformly effective in treatment of nephrogenic diabetes insipidus. The inhibitory effect of indomethacin on urine volume and free water clearance in our patients may have been mediated by an enhancement of antidiuretic hormone (ADH)-stimulated cyclic adenosine monophosphate generation, or by increased ADH-independent water reabsorption resulting from an increase in solute reabsorption and consequent medullary hypertonicity.

The Fanconi syndrome

Abstract It is now customary to refer to the triad of the skeletal lesions of hypophosphatemia (rickets or osteomalacia), renal aminoaciduria, and renal glycosuria as the Fanconi syndrome. This combination of physiologic disturbances results from impairment of renal tubule mechanisms which are concerned with tubular reabsorption of phosphate, amino acids, and glucose. Other renal tubular systems may also be affected so that hyperchloremic acidosis, hypokalemia, and polyuria may be associated with the main triad. The Fanconi syndrome can probably result from injury of renal tubule cells by a wide variety of agents. These may be of endogenous origin due to hereditary metabolic disorders or may be exogenous toxic substances. Cystine storage disease which is an hereditary disturbance transmitted by a recessive gene is the most common cause of the Fanconi syndrome in infancy and early childhood. The Fanconi syndrome in late childhood and adult life is usually not hereditary and may be of diverse pathogenesis. Heavy metal poisoning and multiple myeloma are among the possible etiologic factors of the Fanconi syndrome but in most instances the mechanism of the renal tubule injury is unknown. The disturbance of regulation of serum phosphate levels in the Fanconi syndrome can be overcome by large amounts of vitamin D so that the hypophosphatemia can be corrected and more normal calcification and growth of the rachitic or osteomalacic bone can be achieved. In some instances, the other renal tubular dysfunctions are also ameliorated by vitamin D therapy so that the aminoaciduria is lessened and the chronic acidosis is improved. Studies of amino acid excretion in the urine should be made in all cases of refractory rickets or osteomalacia if the problem is to be accurately classified since marked generalized aminoaciduria is one of the constant diagnostic characteristics of the Fanconi syndrome.

Potassium deficiency in a case of lymphosarcoma with the sprue syndrome.

Abstract A patient with chronic diarrhea was studied who showed marked reduction of the concentrations of potassium, calcium and phosphorus in the serum, associated with excessive losses of fat, nitrogen, water, potassium, calcium and phosphorus in the stools. At autopsy, a lymphosarcoma of the small intestine and mesenteric lymph nodes was found which was the basis for the disturbance of intestinal function. Balance studies were made on various dietary regimens. These studies indicated that the loss of potassium in the stools was responsible for the reduction of serum potassium found in this patient. Comparison of the nitrogen and potassium balances indicated that during periods of potassium deficit, intracellular potassium was lost in excess of that expected from nitrogen loss. The severity of the diarrhea was reduced by a diet low in fat and in starch. Large doses of vitamin D were found to be effective in further reducing the loss of water, potassium, calcium and phosphorus in the stools.

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.