The use of vitamins, minerals and other dietary supplements in The Netherlands.

By means of a two-day dietary record, information on the use of dietary supplements has been collected in 1987 and 1988 in a representative sample of the Dutch population aged 1-75 years. More than 17 percent of the population had been using at least one dietary supplement on at least one day of the survey. Age, sex, season, social class, alternative food habits, smoking and diet were related to the use of supplements. In young persons mainly fluoride and vitamin AD preparations were used, while a shift towards other supplements, like garlic and brewer's yeast preparations, was observed as age progresses. The use of single vitamin C supplements was not related to the level of mean daily vitamin C intake by food consumption.

[Utilization of food supplements in The Netherlands]. / Gebruik van voedingssupplementen in Nederland.

In 1987 and 1988 a dietary survey was carried out in a representative sample of the Dutch population, under the authority of the Ministries of Welfare, Health and Cultural Affairs, and Agriculture and Fisheries. By means of a two day dietary record data were collected on food consumption and the use of dietary supplements. More than seventeen percent of the Dutch population has been using at least one dietary supplement on at least one day of the survey. Age, sex, season, social class, alternative food habits, smoking and diet are related to the use of supplements. In young persons mainly fluoride and vitamin AD preparations are used, while as age progresses a shift towards other supplements, like garlic and brewer's yeast preparations, is observed. The use of single vitamin C supplements is not related to the level of mean daily vitamin C intake from foods.

Vitamin D and parathyroid hormone status in children with the nephrotic syndrome and chronic mild glomerulonephritis.

The serum concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), calcium, creatinine, albumin and immunoreactive parathyroid hormone (iPTH) were measured in eight children with chronic glomerulonephritis not treated with prednisone (group I), in nine non-edematous children with the nephrotic syndrome treated with prednisone for more than 18 months (group II) and in five children with overt edema also treated with prednisone (group III). Serum creatinine was under 1.2 mg/dl in all 22 patients. Reductions in serum calcium, albumin and 25(OH)D were found in group III patients only, whereas both group II and group III patients showed reduced values of 1,25(OH)2D (p less than 0.001 vs. group I or controls). Chronic glucocorticoid administration in children with glomerulonephritis and minimally impaired renal function (group II) is associated with a reduction in the circulating level of 1,25(OH)2D, since children with comparable type and degree of renal disease but non glucocorticoid treatment (group I) have normal 1,25 (OH)2D values. Children with nephrotic edema (group III) have greater reduction of 1,25(OH)2D values, as well as lower 25(OH)D values and serum calcium values, presumably related to a urinary loss of vitamin D-binding protein. No changes in iPTH were evident in either glucocorticoid-treated or edematous patients, suggesting that the acute elevation in iPTH seen after prednisone treatment is an acute phenomenon. Additional short-term studies are needed to more clearly define the effect of glucocorticoids on vitamin D metabolism.

Vitamin D metabolites in renal insufficiency and other vitamin D disorders of children.

Serum vitamin D metabolites were measured in relation to factors responsible for the synthesis of 1,25(OH)2D in children with renal disease and other disorders of vitamin D metabolism. Severe renal failure (CCr less than 15 ml/min/1.73 m2) was associated with a reduction in 1,25(OH)2D to 25% of mean normal levels, a very high PTH/1,25(OH)2D ratio of 75 (normal = 0.74), and a 60% reduction of serum 24,25(OH)2D. At CCr values between 15 and 50 ml/min 1.73 m2, 1,25(OH)2D was 50% of normal, despite a PTH/1,25(OH)2D ratio of 7 and a normal 24,25(OH)2D value. Above clearance values of 75 ml/min/1.73 m2, 1,25(OH)2D and the ratio were normal. Oral 1,25(OH)2D therapy in severe chronic renal insufficiency caused a fall in this ratio from 75 to 8. High PTH/1,25(OH)2D ratios were found in hypophosphatemic rickets and vitamin D-deficiency rickets, indicating reduced synthesis of 1,25(OH)2D relative to PTH. Low ratios were found in hypoparathyroidism and sarcoidosis, possibly indicating independence of PTH stimulation in 1,25(OH)2D production. The ratios of calcium/1,25(OH)2D and phosphate/1,25(OH)2D also provided useful information in each of these conditions, indicating that the use of such series of ratios in selected patients may promote a better understanding of pathogenic mechanisms and of the response to therapy.

Purification of the receptor for 1 alpha,25-dihydroxyvitamin D3 from chicken intestine.

Methods were investigated for use in the purification of the chicken intestinal receptor for 1 alpha,25-dihydroxyvitamin D3. The techniques investigated include column isoelectric focusing, gel exclusion, polyacrylamide gel electrophoresis, and DNA-cellulose, DEAE-cellulose, and hydroxylapatite chromatography. For the starting receptor preparation, a nuclear extract of chicken intestinal mucosa was found to be enriched above cytosol preparations and a plentiful source of receptor. A five-step purification scheme that resulted in the purification of the receptor protein by 5800-fold with 8% yield has been described. Analysis of the purified proteins on polyacrylamide gel electrophoresis containing sodium dodecyl sulfate suggests homogeneity. Analysis using two-dimensional polyacrylamide electrophoresis characterized the purified protein as having a molecular weight of approximately 63 000 and a pI of 6.0-6.2. Furthermore, assessment of protein purity by 125I iodination followed by sucrose gradient analysis revealed that approximately 90% of the iodinated macromolecules have the same sedimentation coefficient as the titrated 1 alpha,25-dihydroxyvitamin D3 receptor complex. The final purified receptor that bound tritiated 1 alpha,25-dihydroxyvitamin D3 retained affinity for DNA-cellulose and possesses a 3.7S sedimentation coefficient. The receptor has an estimated Stokes radius of 37 A.

Long-term influence of calcitriol (1,25-dihydroxyvitamin D) and supplemental phosphate in X-linked hypophosphatemic rickets.

Ten patients with hypophosphatemic rickets (eight with X-linked familial form) were treated with vitamin D2 (10,000 to 75,000 units per day) and oral phosphate (1.5 to 3.6 gm) for a total of 438 treatment months. Therapy was then changed to calcitriol (17 to 34 ng/kg/day) and the same phosphate dose. Patients served as their own controls, and significant biochemical changes noted were an increase in immunoreactive parathyroid hormone from 29 +/- 9 (SD) microliters Eq/ml (pre-phosphate) to 62 +/- 34 on vitamin D2 plus PO4, then decreasing to 40 +/- 20 on a regimen of 1,25-dihydroxyvitamin D (1,25(OH)2D) plus PO4; serum PO4 rose from 2.44 +/- 0.45 (SD) mg/100 ml to 3.06 +/- 0.79 and then to 3.43 +/- 0.76; alkaline phosphatase activity decreased from 677 +/- 298 (SD) IU/liter to 457 +/- 183 to 290 +/- 176. Serum calcium and creatinine levels were unchanged. Both urinary calcium excretion and calcium-creatinine ratio decreased after therapy with 1,25(OH)2D. Urinary phosphate excretion was higher after calcitriol administration. Serum 1,25(OH)2D levels were low in these vitamin D2-treated patients, and an inverse relationship between serum 25(OH)D and 1,25(OH)2D was found. Improved bone mineralization was evident from serial assessment by photon absorptiometry, and radial bone mineral content rose from 75.3% +/- 2.2% of expected to 82.2% +/- 1.4% (P less than .005). Stature was improved when assessed by standard deviation for chronologic age but did not reach statistical significance. Long-term 1,25(OH)2D plus phosphate therapy appears to be more efficacious than vitamin D2 in this form of rickets, particularly in improving phosphate homeostasis.

Circulating vitamin D metabolite concentrations in childhood renal diseases.

Vitamin D metabolites were measured in children, untreated with glucocorticoids, who had renal disease. Two groups were defined in relation to endogenous creatinine clearance values: those with impaired clearance , 0 to 48 ml/min per 1.73 m2; and those with unimpaired clearance, 75 to 150 ml/min per 1.73 m2. Serum 1.25(OH)2D was 16 +/- (SD) 12 pg/ml in impaired patients (N=24) and 48 +/- 16 pg/ml in unimpaired patients (N=18). The latter level is not different from healthy childhood controls (43 +/- 12 pg/ml; N=194). Serum samples of 25(OH)D2 and D3 were comparable in each group and not different from control values of 33.2 +/- 10.3 ng/ml. Serum 24,25(OH)2D was 0.6 +/- (SD) 0.14 ng/ml in patients with a clearance of less than 13 ml/min per 1.73 m2, 1.39 +/- 0.54 ng/ml in those with a clearance of 18 to 48 ml/min per 1.73 m2, and 152 +/- 0.91 ng/ml in patients without an impairment of clearance. Only patients with the lowest clearance had values different from control values of 1.70 +/- 0.57 ng/ml. In our study we suggest that a significant reduction in 24,25(OH)2D and 1,25(OH)2D are found at low clearance values in children with tubulointerstitial disease. Our study further suggests that a reduction in renal tubular mass is important in accounting for these changes in vitamin D metabolite values.

Vitamin D metabolite concentrations in vitamin D deficiency. Are calcitriol levels normal.

The levels of vitamin D metabolites were measured in three children with a decreased dietary intake of calcium and vitamin D and sun exposure. All three children had hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase activities. Two children had rickets, aminoaciduria, and elevated immunoreactive parathyroid hormone (iPTH) concentrations. The concentrations of vitamins D2 and D3, 25-hydroxyvitamins D2 and D3 (25-OH-D2 and 25-OH-D3), and 24,25-dihydroxyvitamin D (24,25-[OH]2D) were reduced. Nonetheless, the levels of calcitriol (1,25-[OH]2D) were normal. The combination of hypocalcemia, hypophosphatemia, and increased iPTH concentrations should result in supranormal calcitriol concentrations. Moreover, the ratio of PTH to calcitriol is significantly higher than in normal subjects. Accordingly, in patients with vitamin D deficiency and "normal" calcitriol values, the synthesis of this compound may be reduced. The evaluation of vitamin D deficiency should include the measurement of all metabolites.

Assessment of 25-hydroxyvitamin D 1 alpha-hydroxylase reserve in postmenopausal osteoporosis by administration of parathyroid extract.

Previous studies have shown that the mean serum concentration of 1,25-dihydroxyvitamin D [1,25-(OH)2D] is lower than normal in patients with postmenopausal osteoporosis. We studied the mechanism of this abnormality in 12 women with postmenopausal osteoporosis and 10 age-comparable normal women. Parathyroid extract (200 U, twice daily for 3 days) was administered to stimulate the enzymatic conversion of 25-hydroxyvitamin D (25OHD) to 1,25-(OH)2D. The serum concentration of 1,25-(OH)2D was lower (P less than 0.05) at a baseline determination in the osteoporotic subjects than in the normal women and increased significantly (P less than 0.001) above basal values after the administration of parathyroid extract in both groups; however, the degrees of increase in the control and osteoporotic subjects were similar. We conclude, at least under the conditions of our study, that 25OHD 1 alpha-hydroxylase is normally responsive to parathyroid hormone in postmenopausal osteoporosis. Thus, the apparently impaired metabolism of 25OHD to 1,25-(OH)2D appears to be secondary to a decrease in factors that abnormally stimulate 25OHD 1 alpha-hydroxylase activity rather than a primary defect in enzyme reserve capacity.

Absence of seasonal variation in serum concentrations of 1,25-dihydroxyvitamin D despite a rise in 25-hydroxyvitamin D in summer.

The serum concentrations of the vitamin D metabolites 25-hydroxyvitamin D2 (25OHD2), 25-hydroxyvitamin D3 (25OHD3), and 1,25-dihydroxyvitamin D (calcitriol) have been measured in normal subjects whose ages varied from 18 months to 35 yr. Samples were obtained in all months of the year in order to assess the effects of season on serum concentration. During the months of April to September, 25OHD3 levels are higher than in the winter months. No seasonal variation in the 25OHD2 or calcitriol serum concentration was observed. Age-related differences in 25OHD2 and D3 concentrations did not exist. The levels of calcitriol are higher in adolescence and increase from 35 +/- 19 pg/ml (SD) at 1.5-10 yr of age to 54 +/- 21 pg/ml at 10-20 yr of age. In young adults, the levels fall again to 28 +/- 16 pg/ml. Accordingly, despite a seasonal variation in the precursor of calcitriol, the levels of this most active metabolite of vitamin D do not change in relation to sunlight exposure. This lack of seasonal variation is further evidence of the tight feedback regulation of calcitriol.

Rickets of prematurity. Supranormal levels of serum 1,25-dihydroxyvitamin D.

Rickets, hypocalcemia, hypophosphatemia, and hyperparathyroidism were found in a low-birth-weight premature infant. The concentration of plasma calcitriol (1,25-dihydroxyvitamin D) was 145 pg/mL. With additional exogenous calcitriol (37.5 ng/kg/24 hr) given for eight weeks, the biochemical abnormalities were corrected and healing of rickets was evident. Three months later, while receiving only 400 IU of ergocalciferal daily, the patient had normal levels of serum calcium, phosphate, and alkaline phosphatase with a serum calcitriol concentration of 36 pg/mL. These observations suggest that rickets of prematurity may involve a malabsorption of calcium and phosphorus with an elevated calcitriol level needed to overcome this inadequate absorption. Additional doses of calcitriol may be of benefit in these infants, although it must be given carefully. Furthermore, the role of phosphate supplementation in these infants requires consideration.

Normal intrauterine development of the fetus of a woman receiving extraordinarily high doses of 1,25-dihydroxyvitamin D3.

We monitored the course of pregnancy in a 28-yr-old patient with hereditary insensitivity to 1,25-dihydroxyvitamin D (1,25-(OH)2D). During pregnancy, she received 1,24-(OH)2D3 in doses of 17--36 micrograms/day (usual dose for hypocalcemia, 0.25--1.0 microgram/day). We separately measured 25-hydroxyvitamin D3 (25OHD3), 25OHD2, 1,25-(OH)2D3, and 1,25-(OH)2D2 to assess contributions to total 1.25-(OH)2D from endogenous biosynthesis (1 alpha-hydroxylation of 25OHD2 or 25OHD3) vs. contributions from exogenously administered 1.25-(OH)2D3. Serum concentrations of 1,25-(OH)2D were extraordinarily high throughout gestation. The evaluations of total 1,25-(OH)2D in maternal plasma reflected large amounts from both 1 alpha-hydroxylation of 25OHD and oral intake of 1,25-(OH)2D3. At parturition, the calcium concentration was 9.6 mg/dl in maternal serum and 10.2 mg/dl in cord serum. The concentration of total 1,25-(OH)2D in cord serum was high (470 pg/ml; normal mean for placental venous serum, 19 pg/ml); most derived from transplacental passage of maternal 1,25-(OH)2D3 and not from fetoplacental biosynthesis. The child manifested mild hypercalcemia in the first 2 days of life, indicating that the 1,25-(OH)2D3 measured in cord serum was active in vivo. The child showed no somatic features of the syndrome of elfin facies and supravalvular aortic stenosis. We conclude that an extraordinarily high concentration of 1.25-(OH)2D in maternal serum throughout gestation was not apparently toxic to the fetoplacental unit, though the maternal metabolite entered the fetal circulation.

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.

Supranormal 25-hydroxyvitamin D and subnormal 1,25-dihydroxyvitamin D: their role in X-linked hypophosphatemic rickets.

Serum 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) and bone mineral content by the photon-absorption technique were determined in eight patients with X-linked hypophosphatemic rickets treated for at least 24 months with oral sodium phosphate and high-dosage ergocalciferol (vitamin D2). Mean 25-OH-D2 level was 129.5 +/- 67.5 ng/mL (mean +/- SD); the level of 25-OH-D3 was 10.5 +/- 5.8 ng/mL. These values were significantly higher than in normal subjects (total 25-OH-D mean of 27 +/- 10 ng/mL). Serum 1,25-(OH)2D was 16.9 +/- 8.5 pg/mL (mean +/- SD) in the eight patients, significantly lower than 47 +/- 16 pg/mL in 27 age-matched controls. Values indicative of significant demineralization were found in seven of the eight phsophate-treated patients, who had no radiologic evidence of rickets. These results suggest that any theory of the pathogenesis of this disorder must account for inappropriate renal vitamin D metabolism and for renal hyperphosphaturia. The failure of high-dosage oral phosphate and ergocalciferol to fully correct demineralization may suggest a role for calcitriol (1,25-(OH)2D3) as a therapeutic agent.

Serum 1,25-dihydroxyvitamin D levels in normal children and in vitamin D disorders.

Using a precise assay for 1,25-dihydroxyvitamin D in serum, the levels in 103 children, aged 13 months to 16 years, were found to be 43 +/- 2 pg/mL (mean +/- SE). This value is higher than reported values in adults and in neonates. Age-related changes in 1,25-dihydroxyvitamin D levels during childhood were also evident. Older children have significantly higher levels than children less than 11 years, possibly indicating changes with puberty and the adolescent growth spurt. The values were significantly reduced in childhood uremia (13 +/- 5 pg/mL), in hypoparathyroidism (16 +/- 1 pg/mL), and in children with Fanconi's syndrome. Treatment with oral calcitriol in these three groups of patients led to increased serum levels.

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.

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.