Alan J. Hamstra

Intestinal Calcium Absorption and Serum Vitamin D Metabolites in Normal Subjects and Osteoporotic Patients: EFFECT OF AGE AND DIETARY CALCIUM

Intestinal calcium absorption assessed by a double-isotope method, decreased significantly with aging in 94 normal subjects (r = -0.22, P < 0.025). In 52 untreated patients with postmenopausal osteoporosis, calcium absorption was significantly lower than normal when either age or habitual calcium intake was used as a covariable (P < 0.001). Serum 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) were measured in 44 normal subjects and 27 osteoporotic patients. For all normals, calcium absorption and serum 1,25(OH)(2)D were positively correlated (r = 0.50, P < 0.001). In nonelderly normal subjects (ages 30-65 yr), dietary calcium intake correlated inversely with both calcium absorption (r = -0.39, P < 0.01) and with serum 1,25(OH)(2)D (r = -0.50, P < 0.01). Both osteoporotic patients and elderly normal subjects (ages 65-90 yr) differed from nonelderly normals in that these correlations were not present. In addition although serum 25-OH-D was normal, serum 1,25(OH)(2)D was significantly decreased in both osteoporotic patients and elderly normals (P < 0.001). In osteoporotic patients, calcium absorption increased significantly (P < 0.001) after 7 d administration of a small dose (0.4 mug/d) of synthetic 1,25(OH)(2)D(3). In osteoporotics mean serum immunoreactive parathyroid hormone was either normal (COOH-terminal assay) or low (NH(2)-terminal assay) relative to age-matched controls, and mean serum phosphate was increased. The data suggest that inadequate metabolism of 25-OH-D to 1,25(OH)(2)D contributes significantly to decreased calcium absorption and adaptation in both osteoporotics and elderly normal subjects. In patients with osteoporosis this abnormality could result from a decrease in factors that normally stimulate 1,25(OH)(2)D production, such as the decreased parathyroid hormone secretion and increased serum phosphate demonstrated in this group. In elderly subjects a primary abnormality in metabolism of 25-OH-D to 1,25(OH)(2)D, analagous to that seen in aging rats, cannot be excluded.

A sensitive, precise, and convenient method for determination of 1,25-dihydroxyvitamin D in human plasma

Abstract A new, highly sensitive and relatively convenient method has been developed for the determination of 1,25-dihydroxyvitamin D 3 and 1,25-dihydroxyvitamin D 2 in blood plasma. The method involves a simplified and more specific extraction procedure, new rapid and effective methods of purification, and a competitive binding assay using intestinal cytosol from rachitic chicks. The method also includes a procedure for stabilizing the cytosol binding protein and a convenient procedure for the separation of bound from free 1,25-dihydroxyvitamin D 3 with the use of polyethylene glycol. The recovery of 1,25-dihydroxyvitamin D 3 during extraction and purification is 68% and triplicate determinations can be made on a 5-ml plasma sample. With this method, rachitic chick plasma, plasma from anephric patients, and plasma from patients suffering severe endstage renal failure show no detectable 1,25-dihydroxyvitamin D, while normal human values have been found to be 29 ± 2 pg/ml.

Vitamin-D-Dependent Rickets Type II: Resistance of Target Organs to 1,25-Dihydroxyvitamin D

Studies were done to determine the cause for hypocalcemia, secondary hyperparathyroidism, osteomalacia and osteitis fibrosa cystica in a 22-year-old black woman. The patient had normal serum 25-hydroxyvitamin D (14 ng per milliliter) and markedly elevated serum 1,25-dihydroxyvitamin D (137 pg per milliliter). Vitamin D3, 4000 units per day for four weeks, increased the serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to as high as 29 and 297 pg per milliliter, respectively, and corrected the hypocalcemia and secondary hyperparathyroidism. The results suggest that the disorder results from impaired end-organ response to 1,25-dihydroxyvitamin D. We propose that the entity be called vitamin-D-dependent rickets Type II.

Serum 1,25-Dihydroxyvitamin D Levels in Normal Subjects and in Patients with Hereditary Rickets or Bone Disease

The serum concentration of 1,25-dihydroxylvitamin D (1,25-[OH]2D) in normal children and in children with inherited diseases of bone was compared by use of a competitive binding assay. Observed values were: in 12 normal children and adolescents, 37.1 +/- 1.9 pg per milliliter (mean +/- S.D.); in 14 patients with X-linked hypophosphatemic rickets treated with vitamin D2 and phosphate supplements, 15.6 +/- 7.8 (P less than 0.01 versus control); in six patients with autosomal recessive vitamin D dependency treated with vitamin D2, 9.5 +/- 2.9 (P less than 0.01 versus control); and in four untreated patients with autosomal dominant hypophosphatemic (non-rachitic) bone disease, 30.2 +/- 6.3 (not significantly different from the controls). The difference in bone disease between X-linked hypophosphatemia (severe) and hypophosphatemic bone disease (mild) at comparable low serum levels of phosphate implies that 1,25-(OH)2D and phosphate may have independent roles in the pathogenesis of defective bone mineralization.

Vitamin D homeostasis in the perinatal period. 1,25-Dihydroxyvitamin D in maternal, cord, and neonatal blood.

To investigate vitamin D homeostasis in term pregnancy, we measured 1,25-dihydroxyvitamin D (1,25(OH)2D) in serum samples from 19 term pregnant women and in samples from the placental veins of their infants. Samples were obtained from 14 neonates at 24 hours of age. At delivery, maternal concentrations of 1,25(OH)2D were elevated above normal adult values; placental-vein concentrations in the infants were significantly lower than adult normal or maternal values and bore no relation to maternal values. By the time the infants reached 24 hours of age, their serum concentrations had reached normal adult values, concomitant with a decrease in serum concentration of ionized calcium. We speculate that low 1,25(OH)2D concentrations in utero suggest that there is no need for intestinal calcium absorption in the fetus. Postnatal increase of 1,25(OH)2D may result from its production as a prerequisite to extrauterine requirements for intestinal absorption of calcium and phosphorus.

Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption.

STUDIES in laboratory animals have demonstrated that a diet low in calcium increases lead retention and that there are associated biochemical and morphologic manifestations of enhanced lead toxicit...

Vitamin D Metabolite Levels in Oncogenic Osteomalacia

Measurements of 1,25 (OH)2D3 and other metabolites of vitamin D in a patient with oncogenic osteomalacia confirm the selective, reversible deficiency of 1,25 (OH)2D3 in this syndrome, and indicate the rapidity of normalization (within days) of the hormone level and associated hypophosphatemia after resection of the tumor. In this patient, the tumor was an intranasal hemangiopericytoma.

Synthesis of 25-hydroxy[26,27-3H]vitamin D3 with high specific activity

Abstract A synthesis of radiochemically pure 25-hydroxy[26,27- 3 H]vitamin D 3 with a specific activity of 160 Ci/mmol is reported. The structure and biological activity of the radiolabeled compound was verified by comigration on high-pressure liquid chromatography with synthetic 25-hydroxyvitamin D 3 to constant specific activity, and by conversion in vitro to 1α,25-dihydroxy[26,27- 3 H]vitamin D 3 with the chick kidney 1α-hydroxylase.

Elevated serum 1,25-dihydroxyvitamin D concentrations in the hypercalcemia of sarcoidosis: Correction by glucocorticoid therapy

AN EVALUATION of hypercalcemia in a 9-year-old girl revealed a low normal immunoreactive PTH level, cutaneous anergy, and abnormal macrophage suppressor activity. Numerous noncaseating granulomata were seen in a liver biopsy specimen confiming diagnosis of sarcoidosis. The patient had hypercalcemia (serum calcium of 14.8 mg/dl), hypercalcuria ( > 300 mg daily), an abnormal urinary calcium/creatinine ration, and a reduced creatinine clearance. An assay of vitamin D metabolites revealed normal 25(OH)-vitamin D~ and D3 levels, normal 24,25(OH)~-vitamin D, and supranormal 1,25(OH)~-vitamin D (calcitriol) concentrations of 91 and 75 pg/ml (normal 42 + 12 pg/ml; SD). Oral prednisone therapy resulted in lower serum calcitriol concentrations and normalized the abnormalities of calcium metabolism. This is the first case in a child supporting the hypothesis that abnormalities of calcium metabolism in sarcoidosis are related to elevated calcitriol concentrations. Sarcoidosis is infrequent during childhood, but abnormalities of calcium metabolism are found in 30 to 50% of childhood cases? These abnormalities of calcium metabolism are similar to those found in vitamin D intoxication. 2 Subjects with sarcoidosis have increased sensitivity

Absence of seasonal fluctuation in serum concentration of 24,25(OH)2-vitamin D in childhood

SummaryBlood samples taken during all months of the year from 71 healthy children, aged 18 months to 19 years, were examined for the serum concentrations of 24,25-dihydroxyvitamin D [24,25-(OH)2D]. The mean serum 24,25(OH)2D value was 1.45±0.63 ng/ml (range=0.6–3.5 ng/ml). An analysis of values month by month failed to reveal any seasonal variation in the circulating levels of this metabolite.A relationship between the total 25-hydroxyvitamin D (25 OHD) and 24,25(OH)2D was found in 62 children; 10 of these children had disorders of vitamin D metabolism, with low serum 25-hydroxyvitamin D and 24,25(OH)2D values. As has recently been reported [8, 17], there is no seasonal variation in serum 1,25-dihydroxyvitamin D concentrations. Our data suggest there does not appear to be any seasonal variation in serum 24,25(OH)2D values as well.