<i>CYP24A1</i>Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait

Molin, Arnaud; Baudoin, R.; Kaufmann, Martin; Souberbielle, Jean Claude; Ryckewaert, A.; Vantyghem, Marie-Christine; Eckart, P.; Bacchetta, Justine; Deschenes, Georges; Kesler-Roussey, G.; Coudray, Nadia; Richard, Nicolas; Wraich, M.; Bonafiglia, Q.; Тюльпаков, Анатолий Николаевич; Jones, Glenville; Kottler, Marie‐Laure

doi:10.1210/jc.2014-4387

Cited by 121 publications

(115 citation statements)

References 23 publications

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“…Considering the fact that loss-of-function mutations in CYP24A1 causes elevated blood levels of 1,25(OH)2D3, hypercalcemia and complications of hypercalcemia [6][7][8][9], it is important to note the study of pancreas biopsies from patients with chronic pancreatitis by Hummel et al [70]. In this study, Hummel et al The inflamed pancreas is a site of CYP27B1-catalyzed conversion of 25(OH)D3 to 1,25(OH2D3.…”

Section: Discussionmentioning

confidence: 98%

“…However, it is unlikely that even a lack of 25(OH)D3 synthesis in the liver could cause the observed very low blood levels of 25(OH)D3 in the patients with acute pancreatitis since the half-life of 25(OH)D3 in the blood is at least 15 days [11,12]. Therefore, there must be an alternative mechanism(s), such as CYP24A1-mediated degradation of both 25(OH)D3 and 1,23(OH)2D3 (see discussion below), that is responsible for causing the low levels of 25(OH)D3 and 1,25(OH)2D3 in patients with pancreatitis.Considering the fact that loss-of-function mutations in CYP24A1 causes elevated blood levels of 1,25(OH)2D3, hypercalcemia and complications of hypercalcemia [6][7][8][9], it is important to note the study of pancreas biopsies from patients with chronic pancreatitis by Hummel et al [70]. In this study, Hummel et al The inflamed pancreas is a site of CYP27B1-catalyzed conversion of 25(OH)D3 to 1,25(OH2D3.…”

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confidence: 98%

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Vitamin D Deficiency in Patients with Pancreatitis: Is Vitamin D Replacement Required?

Han¹,

Margulies²

2016

Pancreat Disord Ther

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Clinical findings have shown that approximately 40% of patients with pancreatitis, acute or chronic, have severe vitamin D deficiency; this can reach up to 60% of patients with chronic pancreatitis. These findings raise an important question: Is vitamin D deficiency a cause or a result of pancreatitis? The answer(s) to this question is clinically important given that high oral doses of vitamin D supplementation are widely prescribed for individuals with vitamin D deficiency. Considering that there is active conversion of 25(OH)D3 to 1,25(OH)2D3 by activated macrophages in tissues undergoing inflammation, that elevation of the blood levels of 1,25(OH)2D3 levels can cause hypercalcemia, that hypercalcemia can precipitate pancreatitis, that excessive use of vitamin D supplementation can cause acute pancreatitis and that sarcoidosis causes elevated blood levels of 1,25(OH)2D3, hypercalcemia and acute pancreatitis, it is reasonable to consider both 25(OH)D3 and 1,25(OH)2D3 as negative acute-phase reactants, specifically in the context of the pathogenesis of pancreatitis. Thus, down-regulation of blood levels of 25(OH)D3 and 1,25(OH)2D3 in patients with pancreatitis appears to be a protective mechanism to prevent the development hypercalcemia, which would exacerbate the pancreatitis. Therefore, it is reasonable to consider that vitamin D replacement treatment may produce more harm than benefit for patients with pancreatitis.Keywords: Vitamin D deficiency; Inflammation; Acute pancreatitis; Sarcoidosis; Negative-Phasereactant; Hypercalcemia Classic View of Vitamin D MetabolismUnlike most other vitamins that are dietary essential nutrients for the human body, vitamin D is synthesized in the human body and acts like a steroid hormone [1]. As outlined in Figure 1, vitamin D metabolism in the human body starts with the UVB (ultraviolet light B) photon-stimulated structural change in 7-dehydrocholesterol to yield vitamin D3 in the epidermis of the skin. Vitamin D3 is then converted to the biologically active 1,25(OH)2D3 through two sequential hydroxylation reactions. Vitamin D3 is first hydroxylated mainly by the enzyme, CYP2R1, to become 25(OH)D3 in the liver; then 25(OH)D3 is hydroxylated to become 1,25(OH)2D3 by the enzyme, CYP27B1, in the epithelial cells of the proximal convoluted tubule in the kidney [1]. PTH (parathyroid hormone), which is released by the parathyroid glands in response to decreasing blood calcium level, stimulates CYP27B1 activity in the epithelial cells of the proximal convoluted tubules in the kidney, thereby regulating the rate of renal conversion of 25(OH)D3 to 1,25(OH)2D3 [1]. The PTHregulated renal production of 1,25(OH)2D3 is the primary source of the 1,25(OH)2D3 in the blood circulation because individuals with renal failure have decreased blood levels of 1,25(OH)2D3 [2]. The biologically active 1,25(OH)2D3 binds to and stimulates the transcription activity of the nuclear VDR (vitamin D receptor) in target cells to regulate expression of genes, thus changing cellular activities [1]. Sp...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 98%

Vitamin D Deficiency in Patients with Pancreatitis: Is Vitamin D Replacement Required?

Han¹,

Margulies²

2016

Pancreat Disord Ther

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“…This stage is catalysed by 1α-hydroxylase, an enzyme encoded by the CYP27B1 [2]. The inactivation of vitamin D metabolites relies upon two pathways which both include steps catalysed by 1,25-hydroxyvitamin-D 3 -24-hydroxylase; CYP24A1 encodes this mitochondrial enzyme which is part of the cytochrome P450 system [6]. The enzyme is present in vitamin D target cells, predominantly located in the intestine and kidneys (Figure 1) [5].…”

Section: Cyp24a1 and The Vitamin D Pathwaymentioning

confidence: 99%

“…A recent study screening patients with known calcium nephrolithiasis for CYP24A1 mutations did not identify any biallelic variants in a cohort of 166 patients, suggesting CYP24A1 mutations are a rare cause of idiopathic nephrolithiasis [8]. However, given our increased understanding of this phenotype, it is imperative that recognition of the typical biochemical pattern (suppressed PTH, hypercalcaemia, hypercalciuria) in any patients with nephrolithiasis prompts investigation for CYP24A1 mutations [4,6,8]. Establishing a molecular diagnosis in this small cohort of patients can facilitate correct treatment and lifestyle modification (Table 1) [9].…”

Section: Adult Nephrolithiasismentioning

confidence: 99%

“…A continuing focus on preventative medicine, including oral vitamin D supplementation for maintenance of bone health and during pregnancy, is likely to continue to risk triggering manifestations of vitamin D toxicity in individuals carrying biallelic mutations in CYP24A1. As diagnostic tests and successful treatments are starting to emerge, it is important to recognise clinical presentations which should prompt screening for CYP24A1 deficiency [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Biochemical Features of Patients with CYP24A1 Mutations

Hill¹,

Sayer²

2017

A Critical Evaluation of Vitamin D - Basic Overview

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The CYP24A1 gene encodes 1,25-hydroxyvitamin-D 3 -24-hydroxylase, a key enzyme responsible for the catabolism of active vitamin D (1,25-dihydroxyvitamin D 3 ). Loss-offunction mutations in CYP24A1 lead to increased levels of active vitamin D metabolites. Clinically, two distinct phenotypes have been recognised from this: infants with CYP24A1 mutations present with infantile idiopathic hypercalcaemia, often precipitated by prophylactic vitamin D supplementation. A separate phenotype of nephrolithiasis, hypercalciuria and nephrocalcinosis often presents in adulthood. CYP24A1 mutations should be suspected when a classical biochemical profile of high active vitamin D metabolites, high or normal serum calcium, high urine calcium and low parathyroid hormone is detected. Successful treatment with fluconazole, a P450 enzyme inhibitor, has been shown to be effective in individuals with CYP24A1 mutations. Although CYP24A1 mutations are rare, early recognition can prompt definitive diagnosis and ensure treatment is commenced.

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The vitamin D metabolome: An update on analysis and function

Jenkinson

2019

Cell Biochemistry & Function

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Current understanding of vitamin D tends to be focussed on the measurement of the major circulating form 25‐hydroxyvitamin D3 (25OHD3) and its conversion to the active hormonal form, 1α,25‐dihydroxyvitamin D3 (1α,25(OH)2D3) via the enzyme 25‐hydroxyvitamin D‐1α‐hydroxylase (CYP27B1). However, whilst these metabolites form the endocrine backbone of vitamin D physiology, it is important to recognise that there are other metabolic and catabolic pathways that are now recognised as being crucially important to vitamin D function. These pathways include C3‐epimerization, CYP24A1 hydroxylase, CYP11A1 alternative metabolism of vitamin D3, and phase II metabolism. Endogenous metabolites beyond 25OHD3 are usually present at low endogenous levels and may only be functional in specific target tissues rather than in the general circulation. However, the technologies available to measure these metabolites have also improved, so that measurement of alternative vitamin D metabolic pathways may become more routine in the near future. The aim of this review is to provide a comprehensive overview of the various pathways of vitamin D metabolism, as well as describe the analytical techniques currently available to measure these vitamin D metabolites.

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CYP24A1Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait

Cited by 121 publications

References 23 publications

Vitamin D Deficiency in Patients with Pancreatitis: Is Vitamin D Replacement Required?

Vitamin D Deficiency in Patients with Pancreatitis: Is Vitamin D Replacement Required?

Clinical and Biochemical Features of Patients with CYP24A1 Mutations

The vitamin D metabolome: An update on analysis and function

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