Nephrocalcinosis, Hypercalciuria and Elevated Serum Levels of 1,25-Dihydroxyvitamin D in Children Possible Link to Vitamin D Toxicity

The effects on general and bone metabolism of femoral neck fracture patients of 0.25 μg α-calcoid given orally twice daily ( n=9) and 25 μg calcitonin given subcutaneously 30 times ( n=10) in 10 weeks were studied against a control ( n=ll). Bone histology and histomorphometry showed non-age related osteoporosis in 30% and osteomalacia in 22% of the patients studied. Impaired serum vitamin D status was found in 47 – 88% of patients, secondary hyperparathyroidism and increased serum parathyroid hormone in 59% and decreased serum calcitonin levels in 69%. On histology, normal findings and non-age related osteoporosis on histology were associated with low serum levels of 25-hydroxyvitamin D3,1,25- and 24,25-dihydroxy vitamin D3. Very high serum levels of 1,25-dihydroxyvitamin D3 and low levels of 25-hydroxyvitamin D3 occurred in fracture patients with osteomalacia. Calcitonin improved calcium balance, reduced osteoporosis and increased the serum 1,25- and 24,25-dihydroxyvitamin D3 levels but had no effect on osteomalacia. Vitamin D reduced osteomalacia, slightly increased the serum 1,25-dihydroxyvitamin D3 concentration and decreased serum levels of parathyroid hormone. Both treatments gave a similar slight decrease in serum calcitonin concentrations. A mechanism of action for the treatments is suggested.

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Effect of Parathyroid Hormone on cAMP and 1,25-Dihydroxyvitamin D Formation and Renal Handling of Phosphate in Vitamin D-Dependent Rickets

PEDIATRICS ◽

10.1542/peds.71.1.59 ◽

1983 ◽

Vol 71 (1) ◽

pp. 59-63

Author(s):

Dagfinn Aarskog ◽

Lage Aksnes ◽

Trond Markestad

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Serum Concentration ◽

Urinary Excretion ◽

Serum Levels ◽

Renal Handling ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Control Subjects

Studies were carried out to compare the effects of parathyroid extract (PTE) on the serum concentration of 1,25-dihydroxyvitamin D (1,25[OH]2D), 24,25-dihydroxyvitamin D (24,25[OH]2D), 25,26-dihydroxy vitamin D (25,26[OH]2D) and cAMP, and the urinary excretion of calcium, phosphorus, and cAMP in two normal adult subjects, and in a girl with vitamin D-dependent rickets. The concentration of 1,25[OH]2D was markedly decreased even when she was receiving a daily dose of 25,000 IU of ergocalciferol. PTE infusion resulted in a prompt and distinct increase in the serum levels and the urinary excretion of cAMP in the patient and control subjects. In the control subjects the serum concentration of 1,25[OH]2D increased after the PTE infusion, whereas there was no response in the patient with vitamin D-dependent rickets. The two other dihydroxylated metabolites of vitamin D showed no consistent response to the PTE infusion in the control subjects or the patient. The patient showed no phosphaturic response to PTE while she was receiving high-dosage ergocalciferol treatment. By contrast, when the patient was re-studied after therapy with lα-hydroxyvitamin D, PTE infusion resulted in an increase in urinary phosphate excretion. These findings might lend support for the notion that 1,25[OH]2D has an effect on tubular phosphate resorption and has a permissive role in the phosphaturic effect of parathyroid hormone. The present findings also confirm that the formation of 1,25[OH]2D is impaired in vitamin D-dependent rickets and indicate that the renal 25-hydroxyvitamin D-lα-hydroxylase is unresponsive to the stimulatory effect of parathyroid hormone in this condition.

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LOW SERUM LEVELS OF 25-HYDROXYVITAMIN D AND 1,25-DIHYDROXYVITAMIN D IN INSTITUTIONALIZED OLD PEOPLE: INFLUENCE OF SOLAR EXPOSURE AND VITAMIN D SUPPLEMENTATION

Age and Ageing ◽

10.1093/ageing/16.1.35 ◽

1987 ◽

Vol 16 (1) ◽

pp. 35-40 ◽

Cited By ~ 32

Author(s):

CHARLOTTE EGSMOSE ◽

BIRGER LUND ◽

PETER MCNAIR ◽

BJARNE LUND ◽

TOMMY STORM ◽

...

Keyword(s):

Vitamin D ◽

Serum Levels ◽

Vitamin D Supplementation ◽

Old People ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Solar Exposure ◽

25 Hydroxyvitamin D ◽

Low Serum

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The interaction effect of aerobic exercise and vitamin D supplementation on inflammatory factors, anti-inflammatory proteins, and lung function in male smokers: a randomized controlled trial

BMC Sports Science Medicine and Rehabilitation ◽

10.1186/s13102-021-00333-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Leila Nikniaz ◽

Morteza Ghojazadeh ◽

Hooman Nateghian ◽

Zeinab Nikniaz ◽

Mahdieh Abbasalizad Farhangi ◽

...

Keyword(s):

Vitamin D ◽

Lung Function ◽

Aerobic Exercise ◽

Serum Levels ◽

Vitamin D Supplementation ◽

Inflammatory Factors ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Tnf Α ◽

Inflammatory Proteins

Abstract Background This study aimed to investigate the interaction effect of aerobic exercise and vitamin D supplementation on inflammation (TNF-α, IL-6, CC16, SP-D, and CC16/SP-D ratio) and lung function (FEV1, FVC, and FEV1/FVC ratio) in male smokers. Methods After applying inclusion criteria, a total of 40 healthy male smokers were recruited in this study. The participants were randomly divided into four groups as follows: Aerobic Exercise + vitamin D Supplementation (AE + VitD, n = 10), Aerobic Exercise (AE, n = 10), vitamin D Supplementation (VitD, n = 10), and Control (C, n = 10). The participants in the AE + VitD and AE groups performed aerobic exercise training (running) up to 50% of the maximum heart rate, three times a week for four weeks. Participants in AE + VitD and VitD groups received 6000 IU/w vitamin D3 for four weeks. The participants in control group did not receive any intervention. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, Clara cell protein (CC16), surfactant protein (SP)-D, CC16/SP-D ratio, and lung function (FEV1, FVC, and FEV1/FVC ratio) were measured before and after four weeks of intervention. Results Serum levels of TNF-α, IL-6, and CC16 decreased significantly in AE + VitD, VitD, and AE groups after four weeks (P < 0.05). Serum SP-D level decreased significantly only in the AE + VitD group (P = 0.011). In addition, FEV1 and FVC increased significantly (P < 0.05) in AE + VitD and AE groups after four weeks of intervention. However, the interventions did not have a significant effect on CC16/SP-D ratio and FEV1/FVC ratio (P > 0.05). Furthermore, serum levels of 1,25-dihydroxyvitamin D increased significantly in AE + VitD and VitD groups (P < 0.05) after four weeks of intervention. However, except for TNF-α, between-group comparisons showed no significant differences in levels of IL-6, CC16, SP-D, CC16/SP-D ratio, FEV1, FVC, FEV1/FVC, and 1,25-dihydroxyvitamin D (P > 0.05). Conclusions The results of present study were that aerobic exercise combined with vitamin D supplementation can reduce serum inflammatory factors and anti-inflammatory proteins and improve lung function after four weeks of intervention. Further trials with larger sample size and longer duration are suggested to confirm these results. Trial registration Retrospectively registered. IRCT20180513039637N4. Registration date: 2020/10/20. URL: https://www.irct.ir/search/result?query=IRCT20180513039637N4

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A Case Report of Compound Heterozygous CYP24A1 Mutations Leading to Nephrolithiasis Successfully Treated with Ketoconazole

Case Reports in Nephrology and Dialysis ◽

10.1159/000485243 ◽

2017 ◽

Vol 7 (3) ◽

pp. 167-171 ◽

Cited By ~ 3

Author(s):

Emma Davidson Peiris ◽

Raghav Wusirika

Keyword(s):

Vitamin D ◽

Treatment Options ◽

Elevated Serum ◽

Compound Heterozygous ◽

Loss Of Function ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Idiopathic Infantile Hypercalcemia

CYP24A1 is an enzyme that inactivates vitamin D. Loss-of-function mutations in this enzyme are rare but have been linked with idiopathic infantile hypercalcemia as well as adult-onset nephrocalcinosis and nephrolithiasis. Genetic testing for this mutation should be considered in the presence of calciuria, elevated serum calcium, elevated 1,25-dihydroxyvitamin D, and suppressed parathyroid hormone. We present a case with these lab findings as well as an elevated 25-hydroxyvitamin D/24,25-dihydroxyvitamin D ratio in whom compound heterozygous CYP24A1 mutations were found. His hypercalciuria resolved and 1,25-vitamin D level improved with ketoconazole treatment. We suggest that it is clinically important to identify patients with this phenotype as testing and treatment options are available which could reduce progression to chronic kidney disease in this population.

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Effect of Parathyroid Hormone on Vitamin D Metabolism in Osteopetrosis

PEDIATRICS ◽

10.1542/peds.68.1.109 ◽

1981 ◽

Vol 68 (1) ◽

pp. 109-112

Author(s):

Dagfinn Aarskog ◽

Lage Aksnes ◽

Trond Markestad

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Serum Levels ◽

Target Cells ◽

Normal Range ◽

Vitamin D Metabolism ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Basal Serum ◽

Parathyroid Extract

Indices of vitamin D metabolism were studied before and after infusion of bovine parathyroid hormone extract in three children with osteopetrosis. Basal serum concentrations of calcium, alkaline phosphatase, and 25-hydroxyvitamin D tended to be low. Serum immunoreactive parathyroid hormone levels were in the upper normal range in two patients. A marked increase in urinary cyclic adenosine 3': 5'-monophosphate(cAMP) in all patients was solely due to an increase in the nephrogenous cAMP. The basal concentration of 1,25-dihydroxyvitamin D was clearly more than the upper limit of normal range in all three patients and increased after parathyroid extract infusion in one patient. The basal serum levels of 24,25-dihydroxyvitamin D were within normal limits and tended to decrease after parathyroid extract infusion in two of the patients. Parathyroid hormone and 1,25-dihydroxyvitamin D act in concert to increase calcium resorption from bone, and the increased serum levels of both these factors may reflect lack, or unresponsiveness, of target cells in bone.

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MON-388 Total and Free 1,25dihydroxyvitamin D Levels in Postmenopausal Patients with Primary Hyperparathyroidism

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1302 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Lingqiong Meng ◽

Sue A Shapses ◽

Xiangbing Wang

Keyword(s):

Vitamin D ◽

Primary Hyperparathyroidism ◽

Active Form ◽

Serum Levels ◽

Accurate Estimate ◽

Biologically Active ◽

Free Form ◽

Vitamin D Metabolites ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

Abstract Background: Vitamin D3 is metabolized to 25-hydroxyvitamin D [25(OH)D] in liver, and only after it goes to kidney is it converted to its biologically active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. Also, the majority of both total 25(OH)D and 1,25(OH)2D are tightly bound to vitamin D bind protein (DBP) and only a small portion remains in free form. In certain patient populations, like primary hyperparathyroidism (PHPT), concentrations of free vitamin D metabolites may be affected by altered levels of binding protein. Objective: To evaluate total and free 1,25(OH)2D levels in PHPT patients and healthy controls. Methods: Thirty female patients with PHPT and 30 healthy age and body mass index (BMI) matched controls were enrolled (57.1 ± 9.8 years and BMI of 32.2 ± 7.2 kg/m2). Serum levels of calcium, intact parathyroid hormone (iPTH), DBP, total 25(OH)D and 1,25(OH)2D levels were examined. Serum free 25(OH)D and 1,25(OH)2D levels were calculated using equations adapted from Bikle et al. Results: There were no significant differences in age and BMI between groups. Compared to controls, patients with PHPT had lower total 25(OH)D (25.2 ± 7.5 vs. 19.3 ± 6.4 ng/mL; p <0.001) and DBP levels (40.7± 3.1 vs. 36.5 ± 5.7 mg/dL; p <0.001). There were no significant differences in total 1,25(OH)2D levels or calculated free 25(OH)D levels between PHPT patients and controls; but the calculated free 1,25(OH)2D levels were 27% higher in the PHPT patients compared to controls (p<0.001). The calculated free (but not total) 1,25(OH)2D level was inversely correlated with DBP (r=-0.35, p<0.01) and positively correlated with iPTH levels (r=0.33, p<0.01). Conclusion: Postmenopausal patients with PHPT had lower serum total 25(OH)D, but similar free 25(OH)D levels. In contrast, total 1,25(OH)2D levels did not differ between patients and controls; however, patients had higher free 1,25(OH)2D. Because total 25(OH)D and 1,25(OH)2D levels do not reflect free levels, standard clinical measures of circulating vitamin D may not be an accurate estimate of true vitamin D status in patients with PHPT. References: Bikle et al. Serum Protein Binding of 1,25-Dihydroxyvitamin D: A Reevaluation by Direct Measurement of Free Metabolite Levels. JCEM 1985;61:969-75.

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A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia

Molecular Endocrinology ◽

10.1210/me.2002-0152 ◽

2002 ◽

Vol 16 (11) ◽

pp. 2538-2546 ◽

Cited By ~ 69

Author(s):

Peter J. Malloy ◽

Rong Xu ◽

Lihong Peng ◽

Pamela A. Clark ◽

David Feldman

Keyword(s):

Vitamin D ◽

Ligand Binding ◽

Binding Site ◽

Vitamin D Receptor ◽

Genetic Disorder ◽

Elevated Serum ◽

Cultured Fibroblasts ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Resistant Rickets

Abstract Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)2D3]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [3H]1,25-(OH)2D3 in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)2D3 or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)2D3-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.

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Ablation of the Stimulatory G Protein α-Subunit in Renal Proximal Tubules Leads to Parathyroid Hormone-Resistance With Increased Renal Cyp24a1 mRNA Abundance and Reduced Serum 1,25-Dihydroxyvitamin D

Endocrinology ◽

10.1210/en.2015-1639 ◽

2015 ◽

Vol 157 (2) ◽

pp. 497-507 ◽

Cited By ~ 6

Author(s):

Yan Zhu ◽

Qing He ◽

Cumhur Aydin ◽

Isabelle Rubera ◽

Michel Tauc ◽

...

Keyword(s):

Vitamin D ◽

G Protein ◽

Elevated Serum ◽

Proximal Tubules ◽

Mrna Abundance ◽

Α Subunit ◽

Renal Proximal Tubules ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Stimulatory G Protein

Abstract PTH regulates serum calcium, phosphate, and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels by acting on bone and kidney. In renal proximal tubules (PTs), PTH inhibits reabsorption of phosphate and stimulates the synthesis of 1,25(OH)2D. The PTH receptor couples to multiple G proteins. We here ablated the α-subunit of the stimulatory G protein (Gsα) in mouse PTs by using Cre recombinase driven by the promoter of type-2 sodium-glucose cotransporter (GsαSglt2KO mice). GsαSglt2KO mice were normophosphatemic but displayed, relative to controls, hypocalcemia (1.19 ±0.01 vs 1.23 ±0.01 mmol/L; P < .05), reduced serum 1,25(OH)2D (59.3 ±7.0 vs 102.5 ±12.2 pmol/L; P < .05), and elevated serum PTH (834 ±133 vs 438 ±59 pg/mL; P < .05). PTH-induced elevation in urinary cAMP excretion was blunted in GsαSglt2KO mice (2- vs 4-fold over baseline in controls; P < .05). Relative to baseline in controls, PTH-induced reduction in serum phosphate tended to be blunted in GsαSglt2KO mice (−0.39 ±0.33 vs −1.34 ±0.36 mg/dL; P = .07). GsαSglt2KO mice showed elevated renal vitamin D 24-hydroxylase and bone fibroblast growth factor-23 (FGF23) mRNA abundance (∼3.4- and ∼11-fold over controls, respectively; P < .05) and tended to have elevated serum FGF23 (829 ±76 vs 632 ±60 pg/mL in controls; P = .07). Heterozygous mice having constitutive ablation of the maternal Gsα allele (E1m−/+) (model of pseudohypoparathyroidism type-Ia), in which Gsα levels in PT are reduced, also exhibited elevated serum FGF23 (474 ±20 vs 374 ±27 pg/mL in controls; P < .05). Our findings indicate that Gsα is required in PTs for suppressing renal vitamin D 24-hydroxylase mRNA levels and for maintaining normal serum 1,25(OH)2D.

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