Vitamin D deficiency and disorders of vitamin D metabolism.

The disorders of vitamin D metabolism are inherited metabolic abnormalities involving mutations of the vitamin D receptor or enzymes involved in the metabolism of vitamin D to its biologically active form 1,25-dihydroxyvitamin D. Although these mutations are rare, studies in affected patients and animal models have helped to identify critical actions of vitamin D and the mechanism by which it exerts its effects. Vitamin D deficiency, however, is an increasingly recognized problem among the elderly and in the general population. Screening for vitamin D deficiency only in those patients with known risk factors will result in a large proportion of unrecognized affected patients.     

Vitamin D metabolism and the response to 1,25-dihydroxycholecalciferol in Osteoporosis.

The metabolism of isotopically-labelled cholecalciferol and the response to small doses of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) was studied in a group of women with osteoporosis presenting with crush vertebral fracture. No abnormality of vitamin D metabolism was detected. The administration of 1 microgram 1,25-(OH)2D3 for between 8 and 20 days was associated with an increased intestinal absorption and urinary excretion of calcium but caused no improvement in calcium balance. There was a small but significant rise in serum calcium and phosphorus and significant reduction in immunoassayable parathyroid hormone levels during treatment. It is concluded that 1,25-(OH)2D3 is unlikely to be of value in the management of osteoporosis.     

Interrelationships between vitamin D3 and 25-Hydroxyvitamin D3 during chronic ethanol administration in the rat

Vitamin D {D} depleted female Sprague-Dawley rats were fed for a period of 4 wk a D deficient diet containing 36% of total calories as ethanol while control animals received an isocaloric regimen where ethanol was substituted for by dextrins. In conjunction with the ethanol feeding 92 I.U. of {¹⁴C}-vitamin D₃ {{¹⁴C}-D₃} were administered by intragastric gavage 3 times 1 wk for 3 $\text{2}\text{3}$ wk. At the end of the experiment, {¹⁴C}-D₃ and {¹⁴C}-25-hydroxyvitamin D₃ {{¹⁴C}-25(OH)D₃} concentrations were analyzed in plasma, liver, striated muscle and adipose tissue. Body reserves in unchanged {¹⁴C}-D₃ were significantly reduced by ethanol treatment as seen by 24%, 26%, and 59% lower plasma (p < 0.02), muscle (p < 0.001) and adipose tissue (p < 0.001) {¹⁴C}-D₃ concentrations in ethanol-treated compared to control rats. In contrast total plasma and liver {¹⁴C}-25(OH)D₃ content were increased by 30% (p < 0.05) and 55% (p < 0.001) respectively. This increased liver and plasma {¹⁴C}-25(OH)D₃ following ethanol treatment was not accompanied by a proportional {¹⁴C}-25(OH)D₃ incorporation into muscle and adipose tissue. These results suggest that during steady state conditions 25(OH)D₃ production is increased during chronic ethanol administration while the body pool in unchanged D₃ is significantly lowered. These results also point out that in the rat plasma 25(OH)D concentrations are not a reliable guide for the determination of vitamin D status during chronic ethanol administration.     

Differences in the side-chain metabolism of vitamin D3 between chickens and rats.

In vitro metabolism of 25-hydroxy-24-oxovitamin D3 was studied in kidney homogenates from vitamin D-supplemented chickens and rats. In chicken homogenates, 25-hydroxy-24-oxovitamin D3 was converted predominantly to 23,25-dihydroxy-24-oxovitamin D3, 24,25-dihydroxyvitamin D3, and 23,24,25-trihydroxyvitamin D3. In rat homogenates, 25-hydroxy-24-oxovitamin D3 was not converted to either 24,25-dihydroxyvitamin D3 or 23,24,25-trihydroxyvitamin D3, but it was converted to 23,25-dihydroxy-24-oxovitamin D3 and 23-hydroxy-24,25,26,27-tetranorvitamin D3. The latter metabolite was not produced by the chicken preparations. The stereochemical configuration at C-24 of the 24,25-dihydroxyvitamin D3 produced by chicken homogenates was determined to be S. This contrasts with the R configuration of 24,25-dihydroxyvitamin D3 produced by 24-hydroxylation of 25-hydroxyvitamin D3. These results suggest that chickens have an enzyme that can reduce the 24-oxo group to 24S-hydroxyl group, whereas rats do not.     

Vitamin D3 metabolism in a pig strain with pseudo vitamin D-deficiency rickets, type I

Vitamin D metabolism was studied in the 'Hannover Pig', a strain which suffers from pseudo vitamin D-deficiency rickets, type I. Animals of this strain are known to be devoid of renal 25-hydroxyvitamin D3-1 alpha-hydroxylase and -24-hydroxylase activities. Pigs with florid rickets and hypocalcaemia were treated with single im injections of 0.25 to 1.25 mg of vitamin D3, doses that have been shown in previous studies to be effective in producing transient healing of rachitic symptoms. The levels of vitamin D3 and its most relevant physiological metabolites in plasma were estimated at intervals before and after this vitamin D3 treatment. Vitamin D3 rose from 14.8 +/- 8.1 to 364 +/- 190 nmol/l (mean +/- SD) 2 to 3 days post injectionem, 25-hydroxyvitamin D3 from 131.0 +/- 46.2 to 1068 +/- 160 nmol/l within 7 days post injectionem. The 1 alpha, 25-dihydroxyvitamin D3 concentration in plasma was elevated from 73.9 +/- 25.0 to 281 +/- 168 pmol/l 2 to 3 days post injectionem and declined continually from that time. 24R,25-dihydroxyvitamin D3 and 25S,26-dihydroxyvitamin D3 levels after treatment showed different responses in different animals being either elevated or unchanged. Clinical healing of the pigs with these doses of vitamin D3 was attributed to the transient rise of 1 alpha,25-dihydroxyvitamin D3 in plasma. It was assumed that 1 alpha,25-dihydroxyvitamin D3 synthesis takes place under these circumstances in extrarenal tissues.     

comparison of the effects on phosphocalcic metabolism and bone of 3 protocols of vitamin D administration in the elderly

According to recent studies, vitamin D deficiency may contribute to the osteoporosis observed in elderly subjects, with reduced intestinal calcium absorption and secondary hyperparathyroidism. Vitamin D deficiency is often present in elderly people, due to inadequate diet and confinement at home. The administration of either oral vitamin D in doses of 4,000 IU per day, or six-monthly intramuscular injections of ergocalciferol 600,000 IU, combined with a daily intake of at least 1 g of calcium brings back to normal both 25 OH D concentrations and parathyroid hormone levels. When pursued for one year, these treatments also maintain the formation of cortical bone, as shown by the metacarpal index. As for the concentration of 25 OH D, it seems that 60 to 75 nmol/l are necessary to restore calcium homeostasis. The dietary habits of elderly people are such that a supplement of medicinal calcium is required. Finally, we regard the parenteral form of ergocalciferol as being preferable to the oral form at that age for better compliance with treatment.     

Vitamin D and the vitamin D receptor in liver pathophysiology

Vitamin D through the vitamin D nuclear receptor (VDR) plays a key role in mineral ion homeostasis. The liver is central in vitamin D synthesis, however the direct involvement of the vitamin D-VDR axis on the liver remains to be evaluated. In this review, we will describe vitamin D metabolism and the mechanisms of homeostatic control. We will also address the associations between the vitamin D-VDR axis and pathological liver entities, such as non-alcoholic fatty liver disease, autoimmune liver disease, viral hepatitis and liver cancer. The link between liver diseases and the vitamin D-VDR axis will be discussed in light of evidences arising from in vitro and in vivo studies. Finally, we will consider the therapeutic potential of the vitamin D-VDR axis in liver diseases.     

Effects of long-term administration of vitamin D3 analogs to mice

This study explores the effects of chronic administration of vitamin D(3) compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D(3) analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunological disorders and bone diseases. Four unique vitamin D(3) analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) were administered i.p. for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4- to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH)(2)D(3) had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D(3) analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D(3) administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.     

Relationship between the vitamin D content of maternal milk and the vitamin D status of nursing women and breast-fed infants

This work was designed to study the effect of the vitamin D content of human milk on the vitamin D status of exclusively breast-fed infants, and the relation between milk and maternal serum concentrations of vitamin D during the first month of lactation. Serum levels of calcium (Ca), phosphorus (P), magnesium (Mg) and 25-hydroxyvitamin D (25-OH-D) were determined in a racially heterogeneous population of nursing women, between days 3 and 5 (L3), 15 and 18 (L15) and 30 and 45 (L30) post partum. The same parameters were determined in the serum of 1-month-old breast-fed infants. Maternal milk samples were obtained at L3, L15 and L30 and analysed for Ca, P, Mg, vitamin D and 25-OH-D content. Milk levels of Ca, P and Mg were found to be within the range previously described by other authors. No correlation was found between serum and milk levels of vitamin D and 25-OH-D in nursing mothers. The 25-OH-D concentration in milk was related to its vitamin D content and strongly correlated (P less than 0.001) with the 25-OH-D levels in the serum of exclusively breast-fed infants. No significant changes were observed in maternal serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3) measured at L3 and L30, or between maternal and infant levels of 1,25-(OH)2D3 at L30. This study emphasizes the importance of the 25-OH-D content of maternal milk, in being primarily responsible for the vitamin D concentrations found in the serum of exclusively breast-fed infants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vitamin D metabolism and function in the skin

The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but in possessing the enzymatic machinery to metabolize vitamin D to its active metabolite 1,25(OH)(2)D. Furthermore, these cells also express the vitamin D receptor (VDR) that enables them to respond to the 1,25(OH)(2)D they produce. Numerous functions of the skin are regulated by 1,25(OH)(2)D and/or its receptor. These include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, and promotion of the hair follicle cycle. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, the cosuppressor hairless (Hr), and β-catenin. This review will examine the regulation of vitamin D production and metabolism in the skin, and explore the various functions regulated by 1,25(OH)(2)D and its receptor.     

Hepatic metabolism of vitamin D3 in streptozotocin-induced diabetic rat

The effect of streptozotocin-induced diabetes on the in vitro conversion of vitamin D3 to 25-hydroxy-vitamin D3 (25-OHD3) by isolated liver microsomes from rachitic rats was examined. Enzymic activity was significantly less than that observed in control animals (P less than 0.001). Administration of insulin restored activity almost to control values. These findings provide evidence that diabetes in this animal model produces alterations in the metabolism of vitamin D.     

The effects of growth hormone treatment of thyroid-deficient pregnant rats on maternal and fetal carbohydrate metabolism.

Maternal hypothyroidism in rats has been shown previously to result in alterations of maternal, placental, and fetal metabolism. Maternal treatment with 2 IU GH/day for three days prior to autopsy (on the 22nd day of pregnancy) corrected many of the observed alterations of carbohydrate metabolism in hypothyroidism. The maternal and fetal liver glycogen concentrations and the fetal serum glucose levels of the hypothyroid animals were elevated significantly by the GH treatment. In most cases, the utilization of a [1-14C]glucose tracer dose was returned to normal by GH treatment. These results suggest that the impairment of fetal metabolism occurring in maternal hypothyroidism may be due in part to insufficient maternal GH secretion. However, GH alone in the absence of sufficient thyroid hormones did not totally correct all of the observed fetal abnormalities.     

Placental lactogen administration reverses the effect of low-protein diet on maternal and fetal serum somatomedin levels in the pregnant rat.

Female rats were studied on day 20 of pregnancy after being fed either a 5% lactalbumin (low protein) diet or a 20% lactalbumin (adequate) diet for the last 2 weeks of pregnancy. Rats on the lower intake of protein showed decreased serum levels of rat placental lactogen and reduced numbers of lactogenic receptors in the maternal liver. These changes were accompanied by much reduced serum levels of somatomedins IGF I(insulin-like growth factor) and II (multiplication-stimulating activity, MSA). Infusion of human placental lactogen or human growth hormone into the rats on the low-protein intake during the last 2 weeks of pregnancy partially restored the maternal serum levels of both somatomedins, but only human placental lactogen increased the number of lactogenic receptors on liver cell membranes. It was concluded that protein deficiency may reduce secretion of somatomedins by the liver (or other tissues) of the pregnant rat indirectly through reduction in output of rat placental lactogen by the placenta. In the same experiments, the effect of maternal protein deficiency on fetal development and serum somatomedin levels was examined. Protein deficiency resulted in smaller fetuses and placentas and lower fetal serum levels of IGF I and MSA. Unlike the response in maternal serum levels, the concentration of MSA in the fetal serum increased during infusion of hPL or hGH but the concentration of IGF I did not. This suggests that placental lactogen enters the fetal circulation and affects tissues producing MSA but not those making IGF I. Despite the restoration of MSA levels, fetal and placental weights did not increase when the rats on the protein-deficient diets were treated with human placental lactogen or growth hormone.     

Inhibition of fetal growth and survival by testosterone administration to pregnant sheep

Testosterone (as testosterone enanthate, 250 mg i.m. every 2 wk) was administered to pregnant ewes (n = 16), and injections of vehicle were used in 10 control pregnant ewes between days 75 of gestation and term (day 147). Fetal survival (7 of 16 in the treated group versus 10 of 10 in the controls) and growth (birth weights 4.00 +- 0.51 kg in the treated group versus 5.79 +- 0.93, mean +- SD, in the controls) were markedly impaired by testosterone administration. The mechanism of the testosterone effect is unknown, but could be through metabolism to estrogens by the feto-placental unit. These results imply that alterations in the production or metabolism of androgens by the mother or the feto-placement unit may exert important effects on fetal growth and survival.     

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11betaHSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11betaHSD1 and GRs, we treated pregnant ewes with betamethasone (0.5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0.05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0.05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11betaHSD1 mRNA and protein levels at 125 days of gestation (P<0.05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11betaHSD1 mRNA and protein expression. These changes in 11betaHSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.     

The calcium and vitamin D status in an elderly female population and their response to administered supplemental vitamin D3.

Recent reports have implicated the importance of impaired calcium absorption, inadequate dietary vitamin D, and low serum vitamin D levels in the genesis of metabolic bone diseases in the elderly. This study evaluated the dietary intakes of calcium and Vitamin D, calcium absorption, and serum 25 hydroxycholecalciferol (25 OH D) levels in a population of women (mean age 83 yrs) compared to healthy volunteers (mean age 35 yrs). Dietary intakes of both calcium and vitamin D and serum 25 OH D levels were found to be comparable in both groups. Calcium absorption was normal in the subjects studied and did not change significantly after two 2-week periods of oral supplementation with vitamin D3 in doses of 500 I.U./day and 10,000 I.U./day, although the serum 25 OH D levels rose significantly and comparably in both groups. Thus other etiological factors may play relevant roles in the causation of bone diseases in the elderly and unless deficient dietary or serum vitamin D levels are demonstrated, empirical supplementation with vitamin D should not be undertaken. The differences of the above findings from previously published data are discussed.