scholarly journals Parathyroid hormone-independent hypercalcemia and hypercalciuria of a patient with nephrolithiasis and nephrocalcinosis and impaired vitamin D metabolism due to a defect in the CYP24A1 gene

2021 ◽  
Vol 24 (1) ◽  
pp. 26-33
Author(s):  
L. Ya. Rozhinskaya ◽  
A. S. Pushkareva ◽  
E. O. Mamedova ◽  
V. P. Bogdanov ◽  
V. V. Zakharova ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Calcium Absorption ◽  
Genetic Research ◽  
Autosomal Recessive Disorder ◽  
Malignant Neoplasms ◽  
Vitamin D Metabolites ◽  
Active Metabolites ◽  
Vitamin D Metabolism ◽  
Severe Hypercalcemia

Hypercalcemia associated with impaired vitamin D metabolism is a rare autosomal recessive disorder. The mechanism of this pathology is the impairment of inactivation of active metabolites of vitamin D because of mutations in the CYP24A1 gene, which leads to an increase of calcium absorption and the development of hypercalcemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. The phenotype of the disease ranges from severe forms which are diagnosed in early infancy (severe hypercalcemia associated with dehydration, vomiting, nephrocalcinosis, and sometimes death) to milder forms, that often are diagnosed in adulthood and manifested with recurrent nephrolithiasis and nephrocalcinosis. Differential diagnosis is carried out with the most common causes of hypercalcemia: primary hyperparathyroidism and malignant neoplasms. To diagnose, the determination of vitamin D metabolites and genetic research are used. As a treatment for mild forms, it is recommended to limit dairy products, to keep a drinking regimen, to refuse taking vitamin D and calcium preparations, and use of sunscreens. The article presents a clinical case of parathyroid hormone-independent hypercalcemia due to mutation of the CYP24A1 gene of a 20-year-old patient suffering from nephrolithiasis and nephrocalcinosis since the age of 16 with a confirmed violation of vitamin D metabolism.

Role of prolactin in vitamin D metabolism and calcium absorption during lactation in the rat

1982 ◽  
Vol 94 (3) ◽  
pp. 443-453 ◽  
Author(s):  
C. J. Robinson ◽  
E. Spanos ◽  
M. F. James ◽  
J. W. Pike ◽  
M. R. Haussler ◽  
...  
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Parathyroid Hormone ◽  
Alkaline Phosphatase Activity ◽  
Plasma Levels ◽  
Calcium Absorption ◽  
High Plasma ◽  
Intestinal Calcium Absorption ◽  
Vitamin D Metabolism

Intestinal calcium absorption and plasma levels of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) were measured in lactating and non-lactating rats and the effects of bromocriptine and exogenous prolactin treatment were evaluated. In lactating rats calcium absorption and plasma levels of parathyroid hormone, 1,25(OH)2D3 and alkaline phosphatase activity were significantly increased. Bromocriptine treatment significantly reduced the enhanced calcium absorption and levels of plasma 1,25(OH)2D3 and alkaline phosphatase but had no significant effect on plasma levels of parathyroid hormone. Prolactin administered with bromocriptine to lactating animals prevented all the changes observed with bromocriptine treatment alone. It was concluded that the increased plasma levels of prolactin during lactation lead to high plasma levels of 1,25(OH)2D3 which are responsible for the enhanced intestinal calcium absorption.

scholarly journals Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin D(3)-1 alpha-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy

2001 ◽  
Vol 171 (2) ◽  
pp. 249-257 ◽  
Author(s):  
T Michigami ◽  
H Yamato ◽  
H Suzuki ◽  
Y Nagai-Itagaki ◽  
K Sato ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Severe Hypercalcemia ◽  
25 Hydroxyvitamin D

In patients with humoral hypercalcemia of malignancy (HHM), serum levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) are generally low, although the pathophysiology of the impaired vitamin D metabolism is not fully understood. In the present study, we have investigated vitamin D metabolism in our newly developed rat model of HHM in which a human infantile fibrosarcoma producing parathyroid hormone-related protein (PTHrP), named OMC-1, was inoculated s.c. into athymic nude rats. In OMC-1-bearing rats, the serum concentration of 1,25(OH)(2)D was markedly reduced when the animals exhibited severe hypercalcemia (Ca > or =15 mg/dl), while it was rather elevated in those with mild hypercalcemia. To further examine whether serum Ca levels affect 1,25(OH)(2)D concentration, we administered bisphosphonate YM529 to OMC-1-bearing rats when they exhibited severe hypercalcemia. The restoration of the serum Ca level by administration of YM529 was accompanied by a marked increase in the 1,25(OH)(2)D level, suggesting that the serum Ca level itself plays an important role in the regulation of the 1,25(OH)(2)D level in these rats. On the other hand, when the OMC-1-bearing rats were treated with a neutralizing antibody against PTHrP, serum 1,25(OH)(2)D levels remained low despite the reduction in serum Ca levels. Expression of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) in kidney was decreased in OMC-1-bearing rats with severe hypercalcemia, and markedly enhanced after treatment with bisphosphonate. This enhancement in 1 alpha-hydroxylase expression was not observed after treatment with the antibody against PTHrP. These results suggest that PTHrP was responsible for the enhanced expression of 1 alpha-hydroxylase in YM529-treated rats, and that hypercalcemia played a role in reducing the serum 1,25(OH)(2)D level in OMC-1-bearing rats by suppressing the PTHrP-induced expression of the 1 alpha-hydroxylase gene.

scholarly journals CYP27A1 expression in gilthead sea bream (Sparus auratus, L.): effects of calcitriol and parathyroid hormone-related protein

2007 ◽  
Vol 196 (3) ◽  
pp. 625-635 ◽  
Author(s):  
Gideon S Bevelander ◽  
Elsa S L C Pinto ◽  
Adelino V M Canario ◽  
Tom Spanings ◽  
Gert Flik
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Gilthead Sea Bream ◽  
Sea Bream ◽  
Vitamin D Metabolites ◽  
Related Protein ◽  
Vitamin D Metabolism ◽  
Parathyroid Hormone Related Protein ◽  
25 Hydroxy Vitamin D ◽  
Sparus Auratus

Little is known about vitamin D metabolism in fishes. Several reports have shown hydroxylase activities in various organs to produce vitamin D metabolites, but the enzymes involved have not been isolated or characterized. We isolated and characterized a renal mitochondrial hydroxylase, CYP27A1, that governs vitamin D metabolism in gilthead sea bream, Sparus auratus. The enzyme is highly expressed in kidney and to a far lesser extent in liver. When treated with 25-hydroxy vitamin D or calcitriol, the kidney responded differentially and time dependently with CYP27A1 mRNA expression levels. This response substantiates a role for CYP27A1 in fish vitamin D metabolism. This notion is strengthened by upregulation of CYP27A1 in sea bream treated with parathyroid hormone-related protein (PTHrP), and suggests an original role for PTHrP in calcitriol-regulated processes n fish similar to the role of PTH in mammalian vitamin D-dependent processes.

scholarly journals Importance of Extra-Renal CYP24A1 Expression for Maintaining Mineral Homeostasis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A234-A234
Author(s):  
Melody Shi ◽  
Alexander Grabner ◽  
Myles Wolf
Keyword(s):  
Vitamin D ◽  
Mrna Expression ◽  
Calcium Absorption ◽  
Clinical Importance ◽  
P Value ◽  
Loss Of Function ◽  
Vitamin D Metabolism ◽  
Severe Hypercalcemia ◽  
Functional Measure ◽  
Serum Pth

Abstract Calcium homeostasis involves a complex interplay between kidneys, parathyroid glands, intestine and bone. Specifically, 1,25(OH)2D3 is a key calciotropic hormone which stimulates intestinal calcium absorption. A growing body of evidence suggests that circulating levels of 1,25(OH)2D3 depend not only on its synthesis under the action of PTH in the kidneys, but also its catabolism by 24-hydroxylase, herein referred to as CYP24A1. The clinical importance of CYP24A1 has been demonstrated by human loss-of-function mutations, which lead to severe hypercalcemia due to exaggerated levels of 1,25(OH)2D3. Despite its growing importance, little is known about its tissue-specific contributions to normal vitamin D metabolism. To explore the physiology of CYP24A1 and delineate renal-specific effects of CYP24A1 in calcium metabolism, we generated a mouse with constitutive kidney-specific deletion of Cyp24a1 (Six2Cre-Cyp24flox). Six2 marks the nephron progenitor population throughout nephrogenesis. We hypothesized that hypercalcemia as seen in CYP24A1 inactivating mutations is related to lack of both renal and extrarenal expression, and that renal deletion does not lead to severe hypercalcemia. To confirm Cyp24a1 deletion, we measured mRNA expression in the kidney using qPCR and RNA in situ hybridization. All mice were fed a standard commercial rodent diet and followed longitudinally for five months with interval calcium measurements. At time of termination, serum PTH levels were measured along with vitamin D-dependent calcium transporters as a functional measure of 1,25(OH)2D3 action. Cyp24a1 expression was significantly knocked down in total kidneys from Six2Cre-Cyp24flox mice as compared to intestinal expression suggesting successful gene deletion. Compared to age-matched wildtype controls, Six2Cre-Cyp24flox mice were mildly but persistently hypercalcemic (diff between means= 0.46 mg/dL, p-value: 0.03, n=8 per group). As expected, 1,25D-dependent calcium transporters in the kidney (Calb1, Trpv5, Slc8a1, Atp2b1) and intestine (Trpv6, s100g) were all increased, consistent with increased systemic 1,25(OH)2D3 activity. PTH levels were appropriately suppressed in the Six2Cre-Cyp24flox mice (diff between means=83 pg/mL, p-value 0.2, n=9 control, n=3 exp) as were renal cyp27b1 mRNA expression. These data suggest that renal CYP24A1 is important for systemic 1,25(OH)2D3 regulation, but the lack of severe hypercalcemia supports critical contributions of extra-renal CYP24A1.

scholarly journals Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption

2009 ◽  
Vol 297 (6) ◽  
pp. G1193-G1197 ◽  
Author(s):  
Sara Balesaria ◽  
Sonia Sangha ◽  
Julian R. F. Walters
Keyword(s):  
Vitamin D ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Calcium Absorption ◽  
Bone Mineralization ◽  
Duodenal Mucosa ◽  
Vitamin D Metabolites ◽  
Vitamin D Metabolism ◽  
Normal Human ◽  
Major Factors

Calcium absorption by the intestine is necessary for bone mineralization. Much has been learned about this process and the role of vitamin D metabolites in gene transcription from animal studies, but the molecular mechanisms in humans are less well understood. We have used samples of normal human duodenal mucosa, obtained at endoscopy, to investigate the effects of the vitamin D metabolites, 1α-dihydroxycholecalciferol [1,25(OH)2D3] and 25-hydroxycholecalciferol (25OHD), on transcripts on genes involved in calcium absorption and vitamin D metabolism. TRPV6 transcripts were significantly higher after incubation for 6 h with 1,25(OH)2D3 (10−9 mol/l) than after control incubations (median difference 3.1-fold, P < 0.001). Unexpectedly, TRPV6 expression was also higher (2.4-fold, P < 0.02) after incubation with 25OHD (10−7 mol/l). Transcripts for the calcium-ATPase, PMCA1, were significantly higher with 1,25(OH)2D3; CYP24 transcripts were reliably detected after incubation with either metabolite, but calbindin-D9k transcripts were unaffected. The response of TRPV6 to 25OHD and the expression of transcripts for CYP27B1, the 25OHD-1α-hydroxylase, were significantly correlated ( r = 0.82, P < 0.02). Basal duodenal expression of TRPV6 and CYP27B1 were significantly associated ( r = 0.72, P < 0.001) in a separate previously reported series of subjects. Multiple regression analysis of the associations with basal duodenal TRPV6 expression identified CYP27B1 expression and serum 1,25(OH)2D as major factors. Expression of the CYP27B1 protein was demonstrated immunohistochemically in duodenal mucosa. This study has shown that human duodenal TRPV6, PMCA1, and CYP24 transcripts respond rapidly to 1,25(OH)2D3 and provides evidence suggesting that local duodenal production of 1,25(OH)2D3 by 25OHD-1α-hydroxylase may have a role in human calcium absorption.

scholarly journals Infantile hypercalcaemia type 1: a vitamin D-mediated, under-recognised cause of hypercalcaemia

2021 ◽  
Vol 2021 ◽  
Author(s):  
Ryizan Nizar ◽  
Nathan W P Cantley ◽  
Jonathan C Y Tang
Keyword(s):  
Vitamin D ◽  
Autosomal Recessive Disorder ◽  
Molecular Genetic Analysis ◽  
The Body ◽  
List Type ◽  
Vitamin D Metabolites ◽  
Vitamin D Metabolism ◽  
History Of ◽  
25 Oh Vitamin D

Summary A 33-year-old gentleman of Egyptian heritage presented with a 21 years history of unexplained and recurrent hypercalcaemia, nephrolithiasis, nephrocalcinosis, and myocarditis. A similar history was also found in two first-degree relatives. Further investigation into the vitamin D metabolism pathway identified the biochemical hallmarks of infantile hypercalcaemia type 1 (IIH). A homozygous, likely pathogenic, variant in CYP24A1 was found on molecular genetic analysis confirming the diagnosis. Management now focuses on removing excess vitamin D from the metabolic pathway as well as reducing calcium intake to achieve serum-adjusted calcium to the middle of the reference range. If undiagnosed, IIH can cause serious renal complications and metabolic bone disease. Learning points Infantile hypercalcaemia type 1 (IIH) is an autosomal recessive disorder characterised by homozygous mutations in the CYP24A1 gene that encodes the 24-hydroxylase enzyme used to convert active vitamin D metabolites such as 1,25-(OH)2-vitamin D into their inactive form. IIH should be questioned in individuals presenting with a history of unexplained hypercalcaemia, especially if presenting from childhood and/or where there is an accompanying family history of the same in first and/or second degree relatives, causing complications such as nephrocalcinosis, pericarditis, and calcium-based nephrolithiasis. Associated biochemistry of IIH is persistent mild to moderate hypercalcaemia, normal or raised 25-(OH)-vitamin D and elevated 1,25-(OH)2-vitamin D. An elevated ratio of 25-(OH)-vitamin D to 24,25-(OH)2-vitamin D can be a useful marker of defects in the 24-hydroxylase enzyme, whose measurement can be facilitated through the supra-regional assay service. Management should focus on limiting the amount of vitamin D introduced into the body either via sunlight exposure or supplementation in addition to calcium dietary restriction to try and maintain appropriate calcium homeostasis

Adaptation of vitamin D metabolism to calcium challenge: is it dependent on parathyroid hormone?

1989 ◽  
Vol 120 (3_Suppl) ◽  
pp. S122-S123
Author(s):  
S. H. SCHARLA ◽  
H. W. MINNE ◽  
U. G. LEMPERT ◽  
C. OSWALD ◽  
H. SCHMIDT-GAYK ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Vitamin D Metabolism

scholarly journals Implications of Vitamin D Research in Chickens can Advance Human Nutrition and Perspectives for the Future

2021 ◽  
Author(s):  
Matthew F Warren ◽  
Kimberly A Livingston
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Vitamin D Supplementation ◽  
The Body ◽  
Human Nutrition ◽  
Vitamin D Metabolites ◽  
Vitamin D Metabolism ◽  
Related Research ◽  
Vitamin D Intake ◽  
Increased Risk

Abstract The risk of vitamin D insufficiency in humans is a global problem that requires improving ways to increase vitamin D intake. Supplements are a primary means for increasing vitamin D intake, but without a clear consensus on what constitutes vitamin D sufficiency, there is toxicity risk with taking supplements. Chickens have been used in many vitamin D-related research studies, especially studies involving vitamin D supplementation. Our state-of-the-art review evaluates vitamin D metabolism and how the different hydroxylated forms are synthesized. We provide an overview with how vitamin D is absorbed, transported, excreted, and what tissues in the body store vitamin D metabolites. We also discuss a number of studies involving vitamin D supplementation with broilers and laying hens. Vitamin D deficiency and toxicity are also described and how they can be caused. The vitamin D receptor (VDR) is important for vitamin D metabolism. However, there is much more that can be understood with VDR in chickens. Potential research aims involving vitamin D and chickens should explore VDR mechanisms which could lead to newer insights with VDR. Utilizing chickens in future research to help with elucidating vitamin D mechanisms has great potential to advance human nutrition. Finding ways to increase vitamin D intake will be necessary because the coronavirus 2019 disease (COVID-19) pandemic is leading to increased risk of vitamin D deficiency in many populations. Chickens can provide a dual purpose with addressing pandemic-caused vitamin D deficiency: 1) vitamin D supplementation gives chickens added value with possibly leading to vitamin D-enriched meat and egg products; and 2) chickens’ use in research provides data for translational research. Expanding vitamin D-related research in chickens to include more nutritional aims in vitamin D status has great implications with developing better strategies to improve human health.

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