1,25-DIHYDROXYCHOLECALCIFEROL IN HYPOPHOSPHATAEMIC OSTEOMALACIA PRESENTING IN ADULTS

1978 ◽  
Vol 88 (2) ◽  
pp. 408-416 ◽  
Author(s):  
G. Offermann ◽  
G. Delling ◽  
M. R. Haussler
Keyword(s):  
Late Onset ◽  
Bone Mineralization ◽  
Urinary Calcium ◽  
Primary Defect ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Hydroxyproline Excretion ◽  
Dose Dependent ◽  
Hypophosphataemic Osteomalacia

ABSTRACT The effects of exogenous 1,25-dihydroxycholecalciferol (1,25(OH)2D3) in two adults with late-onset hypophosphataemic osteomalacia were studied. In the presence of elevated 25-hydroxyvitamin D levels 1,25(OH)2D3 improved intestinal 17Ca absorption and increased urinary calcium, phosphate and hydroxyproline excretion. Hypophosphataemia, parathyroid hormone and bone mineralization were not significantly affected. The rise of the 1,25-dihydroxyvitamin D concentrations was dose dependent. The results indicate that the impaired renal phosphate conservation - the primary defect in this disorder - is not corrected by exogenous 1,25-dihydroxycholecalciferol.

scholarly journals Hypercalcemia Due to Immobilization

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A196-A196
Author(s):  
Irshad Ahamed ◽  
Niyati Jauhar
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Spinal Cord Injuries ◽  
Bone Mineralization ◽  
Weight Bearing ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Underlying Malignancy

Abstract Background: Hypercalcemia associated with immobilization is an infrequent diagnosis. It is usually associated with prolonged immobility due to traumatic brain injury or spinal cord injuries. It results from rapid bone turnover. Diagnosis requires workup to rule out other causes of hypercalcemia. Keywords: Hypercalcemia; immobilizationCASE REPORT: We report a case of a 49 year old woman with severe traumatic brain injury and paraplegia following an electric-scooter accident. She had an extended stay in hospital and was noted to be hypercalcemic after six months’ in-patient. Laboratory investigations showed increased calcium level at 3.34 mmol/l (ref. 2.15–2.50 mmol/l) with diminished parathyroid hormone (PTH) level of 0.2 pmol/l (ref. 1.6–6.9 pmol/l), low 25-hydroxyvitamin D at 26.7 ug/l (toxicity >100 ug/l) and low 1,25-dihydroxyvitamin D at 13 pg/l (ref. 18–78 pg/l) with increased 24-H urinary calcium at 11.74 mmol/day (ref. 2.50 – 7.50 mmol/day). There was no clinical or biochemical evidence of other endocrinopathies such as hyperthyroidism or adrenal insufficiency. There was also no underlying malignancy to explain the hypercalcemia. In the context of recent prolonged immobility, a diagnosis of immobilisation hypercalcemia (IH) was made. The pathophysiology of IH is unclear. It is said that muscle activity transmits signal for bone formation through osteocytes and with immobility, mechanical stimulation is reduced, causing unopposed resorption. Another cause may be increased acidic environment due to low blood flow which impairs bone mineralization. There is also increased osteoclastic resorption, leading to loss of calcium from bones and hypercalciuria. Hypercalcemia occurs when calcium efflux from bone exceeds renal calcium excretion. For our patient, hydration therapy was initiated with no improvement in calcium. SC calcitonin was added and IV pamidronate given. Two weeks after treatment serum calcium improved to 2.38 mmol/L and remained normal on subsequent monitoring. Conclusion: IH is a known but uncommonly recognized complication in immobile patients. If not treated properly patients may develop typical complications of hypercalcemia including dehydration, confusion and renal impairment. Mobilization by using weight bearing exercises where possible is a cornerstone of long term management. In conclusion, our case serves as an important reminder of this differential and illustrates the management of IH.

Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D3 production

1990 ◽  
Vol 258 (5) ◽  
pp. E780-E789 ◽  
Author(s):  
R. Vieth ◽  
K. McCarten ◽  
K. H. Norwich
Keyword(s):  
Specific Activity ◽  
Metabolic Clearance ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Dose Dependent

To understand the relationships among 1) the dose of 25-hydroxyvitamin D [25(OH)D] in vivo, 2) the activity of 1-hydroxylase in renal mitochondria, and 3) the production of 1,25-dihydroxyvitamin D [1,25(OH)2D] in vivo, we gave rats different chronic or acute doses of 25-hydroxyvitamin D3 [25(OH)D3]. We followed the metabolism of intracardially administered [25-hydroxy-26,27-methyl-3H]cholecalciferol [25(OH)[3H]D3] for 24 h before killing by measuring extracts of serum by chromatography. Specific activity of 1-hydroxylase in kidney was measured at death. In rats given 0-2,000 pmol 25(OH)D3 chronically by mouth, there was a dose-dependent decline in the percent of serum radioactivity made up of 1,25-dihydroxy-[26,27-methyl-3H]cholecalciferol [1,25(OH)2[3H]D3] as well as a decline in mitochondrial 1-hydroxylase, and these correlated significantly (r = 0.83, P less than 0.001). Serum %1,25(OH)2[3H]D3 in this experiment ranged from 0.8 to 42%. A small part of this range could be accounted for by a faster metabolic clearance rate (MCR) of 1,25(OH)2D3 from rats supplemented with 25(OH)D3 (MCR, 2.12 +/- 0.10 ml/min) compared with rats restricted in vitamin D (MCR, 0.94 +/- 0.06 ml/min, P less than 0.001). The activity of 1-hydroxylase was by far the major factor determining serum %1,25(OH)2[3H]D3. When different acute doses of 25(OH)D3 were given to rats with identical specific activities of 1-hydroxylase, the resulting 1,25(OH)2D3 concentrations in serum correlated with the 25(OH)D3 dose (r = 0.99, P less than 0.001). We conclude that the behavior of 1-hydroxylase in vivo is analogous to the classic behavior in vitro of an enzyme functioning below its Michaelis constant (Km). The amount of 1-hydroxylase present in renal mitochondria determines the fraction (not simply the quantity) of 25(OH)D metabolized to 1,25(OH)2D3 in vivo.

CYP24A1 and SLC34A1 Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria

2021 ◽  
pp. 1-9
Author(s):  
Isabelle Rousseau-Nepton ◽  
Glenville Jones ◽  
Karlpiet Schlingmann ◽  
Martin Kaufmann ◽  
Caroline S. Zuijdwijk ◽  
...  
Keyword(s):  
Late Onset ◽  
Loss Of Function ◽  
Cascade Screening ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Liquid Chromatography Tandem Mass ◽  
25 Hydroxyvitamin D ◽  
Idiopathic Infantile Hypercalcemia

<b><i>Objectives:</i></b> Biallelic pathogenic variants in <i>CYPA24A1</i> and <i>SLC34A1</i> are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of <i>CYP24A1</i> or <i>SLC34A1</i> variants in children with early hypercalcemia or late-onset hypercalciuria. <b><i>Method:</i></b> Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D<sub>3</sub> to 24,25-dihydroxyvitamin D<sub>3</sub>, (25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub>), an elevation pathognomonic for the loss of function of the <i>CYP24A1</i> enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. <b><i>Results:</i></b> Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in <i>CYP24A1.</i> Four <i>CYP24A1</i> pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No <i>SLC34A1</i> pathogenic variants were detected. <b><i>Conclusion:</i></b> In Canada, pathogenic variants in <i>CYP24A1</i> appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> ratio is an excellent tool for screening for biallelic pathogenic variants in <i>CYP24A1</i>. We confirm that cascade testing is important for these variants.

Metabolism of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 and its sensitivity to ketoconazole in 1α,25-dihydroxyvitamin D3-differentiated HL60 cells

1989 ◽  
Vol 3 (3) ◽  
pp. 199-205 ◽  
Author(s):  
M. E. Hayes ◽  
D. Bayley ◽  
E. B. Mawer
Keyword(s):  
High Performance ◽  
Cell Number ◽  
Dependent Manner ◽  
Macrophage Phenotype ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Dose Dependent

ABSTRACT Regulation of the metabolism of [3H]25-hydroxyvitamin D3 ([3H]25-(OH)D3) in vitro to material with the characteristics of [3H]24,25-dihydroxyvitamin D3 ([3H]24,25-(OH)2D3) has been studied in the human promyelocytic cell line HL60. Synthesis of 24,25-(OH)2D3 was induced in a dose-dependent manner in cells pretreated with 0·1–100 nm 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) for 4 days. This treatment also inhibited cell proliferation and stimulated differentiation to a macrophage phenotype that was characterized by staining for non-specific esterase (NSE) activity. The ability to synthesize [3H]24,25-(OH)2D3 from [3H]25-(OH)D3 and the expression of NSE activity both responded to changes in concentration of 1α,25-(OH)2D3 in the culture medium in a parallel manner. Synthesis of [3H]24,25-(OH)2D3 was linear when the incubation time was between 1 and 8 h and the cell number between 1 and 12×106 cells/incubation. The optimum substrate concentration for its synthesis was 125 nm, giving an apparent Michaelis constant of 360 nm. The identity of the [3H]24,25-(OH)2D3 synthesized by these cells was confirmed by co-chromatography with authentic 24,25-(OH)2D3 on normal-phase and reverse-phase high-performance liquid chromatography systems and by its reaction to sodium-m-periodate. Cells that had been exposed to 100 nm 1α,25-(OH)2D3 for 4 days synthesized 2·17±0·07 (s.e.m.) pmol 24,25-(OH)2D3/106 cells per h. This synthesis was inhibited in a dose-dependent manner over a concentration range of 0·01–1 μm by the drug ketoconazole, an antimycotic imidazole which is a known inhibitor of certain cytochrome P-450 enzyme systems, suggesting that the HL60 25-(OH)D3-24-hydroxylase is also a P-450-dependent enzyme system.

scholarly journals Vitamin D upregulates the macrophage complement receptor immunoglobulin in innate immunity to microbial pathogens

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Annabelle G. Small ◽  
Sarah Harvey ◽  
Jaspreet Kaur ◽  
Trishni Putty ◽  
Alex Quach ◽  
...  
Keyword(s):  
Vitamin D ◽  
Innate Immunity ◽  
Surface Expression ◽  
Microbial Pathogens ◽  
Cell Surface Expression ◽  
Complement Receptor ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Multistep Process ◽  
25 Hydroxyvitamin D

AbstractVitamin D deficiency remains a global concern. This ‘sunshine’ vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.

scholarly journals Sex and body mass index dependent associations between serum 25-hydroxyvitamin D and pulse pressure in middle-aged and older US adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jung Hyun Kwak ◽  
Yoon-Hyeong Choi
Keyword(s):  
Body Mass Index ◽  
Vitamin D ◽  
Body Mass ◽  
Pulse Pressure ◽  
Lower Risk ◽  
Hydroxyvitamin D ◽  
Vascular Stiffening ◽  
25 Hydroxyvitamin D ◽  
Dose Dependent ◽  
Overweight Subjects

AbstractHigh pulse pressure (PP) is a valid indicator of arterial stiffness. Many studies have reported that vitamin D concentration is inversely associated with vascular stiffening. This association may differ depending on sex and body mass index (BMI). This study investigated the associations between vitamin D and PP and evaluated whether these associations differ according to sex and BMI, using data for individuals aged ≥ 50 years from the National Health and Nutrition Examination Survey (NHANES) 2007–2010. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were used as biomarkers of vitamin D levels. High PP was defined as ≥ 60 mmHg. Total 25(OH)D concentrations were dose-dependently associated with lower odds ratios (ORs) for high PP (p-trend = 0.01), after controlling for sociodemographic, behavioral, and dietary factors. When stratified by sex, there was a dose-dependent association between total 25(OH)D concentrations and lower risk of high PP (p-trend < 0.001) in females, but not in males. When stratified by BMI, there was a dose-dependent association between total 25(OH)D concentrations and lower risk of high PP (p-trend < 0.001) in non-overweight subjects, but not in overweight subjects. Improving the vitamin D status could delay elevation of PP and vascular stiffening in female and non-overweight subjects.

scholarly journals Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

2016 ◽  
Vol 37 (5) ◽  
pp. 521-547 ◽  
Author(s):  
Peter J. Tebben ◽  
Ravinder J. Singh ◽  
Rajiv Kumar
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Elevated Serum ◽  
Diagnosis And Treatment ◽  
Vitamin D Metabolites ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Stone Formers ◽  
25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

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