Vitamin D Abstracts 8

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Vitamin D. Monograph.
            (2008)  Download
Vitamin D is a secosteroid molecule which, in its active 1,25 di-hydroxylated form, has hormone activities in humans. Most cells and tissues in the body have vitamin D receptors (VDRs) that stimulate the nuclear transcription of various genes to alter cellular function or provide a rapid response in cellular membranes. Vitamin D appears to have an effect on numerous disease states and disorders, including chronic musculoskeletal pain, diabetes (types 1 and 2), multiple sclerosis, cardiovascular disease, osteoporosis, and cancers of the breast, prostate, and colon. According to many researchers there is currently a worldwide vitamin D deficiency in various populations, including infants, pregnant and lactating women, the elderly, individuals living in latitudes far from the equator, persons who avoid the sun or ultraviolet radiation in the blue spectrum (UVB), and populations with dark skin pigmentation. Vitamin D in the food supply is limited and most often inadequate to prevent deficiencies. Supplemental vitamin D is likely necessary to avoid deficiency in winter months; however, all forms of vitamin D supplementation may not be equal in efficacy for maintaining optimal blood levels.

Vitamin D metabolism, mechanism of action, and clinical applications.
            (Bikle, 2014)  Download
Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to the hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D). CYP2R1 is the most important 25-hydroxylase; CYP27B1 is the key 1-hydroxylase. Both 25OHD and 1,25(OH)2D are catabolized by CYP24A1. 1,25(OH)2D is the ligand for the vitamin D receptor (VDR), a transcription factor, binding to sites in the DNA called vitamin D response elements (VDREs). There are thousands of these binding sites regulating hundreds of genes in a cell-specific fashion. VDR-regulated transcription is dependent on comodulators, the profile of which is also cell specific. Analogs of 1,25(OH)2D are being developed to target specific diseases with minimal side effects. This review will examine these different aspects of vitamin D metabolism, mechanism of action, and clinical application.


 

Age-related alteration of vitamin D metabolism in response to low-phosphate diet in rats.
            (Chau et al., 2005)  Download
The responses of renal vitamin D metabolism to its major stimuli alter with age. Previous studies showed that the increase in circulating 1,25-dihydroxyvitamin D (1,25(OH)2D3) as well as renal 25-hydroxyvitamin D3 1-alpha hydroxylase (1-OHase) activity in response to dietary Ca or P restriction reduced with age in rats. We hypothesized that the mechanism involved in increasing circulating 1,25(OH)2D3 in response to mineral deficiency alters with age. In the present study, we tested the hypothesis by studying the expression of genes involved in renal vitamin D metabolism (renal 1-OHase, 25-hydroxyvitamin D 24-hydroxylase (24-OHase) and vitamin D receptor (VDR)) in young (1-month-old) and adult (6-month-old) rats in response to low-phosphate diet (LPD). As expected, serum 1,25(OH)2D3 increased in both young and adult rats upon LPD treatment and the increase was much higher in younger rats. In young rats, LPD treatment decreased renal 24-OHase (days 1-7, P<0.01) and increased renal 1-OHase mRNA expression (days 1-5, P<0.01). LPD treatment failed to increase renal 1-OHase but did suppress 24-OHase mRNA expression (P<0.01) within 7 d of LPD treatment in adult rats. Renal expression of VDR mRNA decreased with age (P<0.001) and was suppressed by LPD treatment in both age groups (P<0.05). Feeding of adult rats with 10 d of LPD increased 1-OHase (P<0.05) and suppressed 24-OHase (P<0.001) as well as VDR (P<0.05) mRNA expression. These results indicate that the increase in serum 1,25(OH)2D3 level in adult rats during short-term LPD treatment is likely to be mediated by a decrease in metabolic clearance via the down-regulation of both renal 24-OHase and VDR expression. The induction of renal 1-OHase mRNA expression in adult rats requires longer duration of LPD treatment than in younger rats.

Normocalcemia in the Face of Marked Hypervitaminosis D: The Utility of Vitamin D Metabolite Profiling.
            (Griffin et al., 2019)  Download
The clinical history, medical examination, and biochemical results for our patient were unremarkable for vita- min D toxicity despite the reported total concentration of 25(OH)D of 254 ng/mL (635 nmol/L) being 5-fold the 25(OH)D level of 50 ng/mL (125 nmol/L) at which it is suggested that toxicity can occur. As the patient was normocalcemic when vitamin D was measured, no active treat- ment was undertaken. However, all vitamin D supplementation was immediately discontinued.  Her daily vitamin D intake was 50 800 IU for the preceding 2 months. Upregulation of CYP24A1 (the enzyme that degrades 25(OH)D and 1,25(OH)2D) as part of the normal physiological protective response to prevent vitamin D toxicity, the dose of the calcimimetic drug cinacalcet, and renal impairment (CKD stage 3b) leading to reduced α-hydroxylation of 25(OH)D to its metabolically active form, 1,25(OH)2D.  In this case, vitamin D metabolite profiling was a useful adjunct in determining the cause of this patient's hypervitaminosis D.


 

Vitamin D Testing-Where Are We and What Is on the Horizon
            (Heureux, 2017)  Download
Vitamin D testing is part of laboratory practice since more than 30 years but has become a routine parameter only recently, due to a highly increasing amount of research in the field resulting in new clinical applications. Vitamin D actually represents a family of molecules of which 25OH Vitamin D and 1,25(OH)

The case against ergocalciferol (vitamin D2) as a vitamin supplement.
            (Houghton and Vieth, 2006)  Download
Supplemental vitamin D is available in 2 distinct forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Pharmacopoeias have officially regarded these 2 forms as equivalent and interchangeable, yet this presumption of equivalence is based on studies of rickets prevention in infants conducted 70 y ago. The emergence of 25-hydroxyvitamin D as a measure of vitamin D status provides an objective, quantitative measure of the biological response to vitamin D administration. As a result, vitamin D3 has proven to be the more potent form of vitamin D in all primate species, including humans. Despite an emerging body of evidence suggesting several plausible explanations for the greater bioefficacy of vitamin D3, the form of vitamin D used in major preparations of prescriptions in North America is vitamin D2. The case that vitamin D2 should no longer be considered equivalent to vitamin D3 is based on differences in their efficacy at raising serum 25-hydroxyvitamin D, diminished binding of vitamin D2 metabolites to vitamin D binding protein in plasma, and a nonphysiologic metabolism and shorter shelf life of vitamin D2. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification.

The Fructoborates: Part of a Family of Naturally Occurring Sugar-Borate Complexes-Biochemistry, Physiology, and Impact on Human Health: a Review.
            (Hunter et al., 2019)  Download
Sugar-borates (SBs) are mono- or di-sugar-borate esters (SBEs) comprised of one or two monosaccharide molecules linked to a boron (B) atom. SBEs occur naturally in commonly consumed herbs, vegetables, fruits, seeds, and nuts and, other than greatly varying levels of B found in local drinking water, are the primary natural dietary sources of B-containing molecules in humans. To date, the most studied SBE is calcium fructoborate (CaFB). CaFB represents an important example of how organic B-containing molecules are significantly distinct from their inorganic counterparts. During these past two decades, CaFB has been researched for its physical and biochemical characteristics, safety, and clinical outcomes. Results of these researches are presented and discussed herein. CaFB has been characterized using Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), high-performance thin-layer chromatography (HPTLC), nuclear magnetic resonance (NMR), liquid chromatography-multistage accurate mass spectrometry (LC-MSn), X-ray diffraction (XRD), Raman spectroscopy, and inductively coupled plasma (ICP) in non-biological and biological specimens. Potential health benefits of CaFB have been clinically investigated in pilot and efficacy studies demonstrating (i) significant reductions in knee discomfort and improved flexibility within 7, 14, and 90 days and (ii) significant effect on blood levels of inflammatory, cardiovascular, and other biomarkers. These studies support the use of CaFB as a dietary supplement for the management of joint discomfort. CaFB is presented here in order to illustrate how physiological benefits are imparted by distinct organic boron-containing molecules rather than solely by the element B itself. Considering recent National Health and Nutrition Examination Survey (NHANES) data reporting increases in age-related joint pain and an increasing elderly demographic, SBEs offer potential for safe, natural, and effective management of joint discomfort and improved mobility in human and animal health applications. Several of these studies may also open new opportunities for use of SBEs for health benefits beyond joint health.

High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile.
            (Jorde et al., 2010)  Download
BACKGROUND/OBJECTIVES:  Low serum 25-hydroxyvitamin D (25(OH)D) concentrations are related to increased mortality. One possible explanation could be an association between serum 25(OH)D and serum lipids. SUBJECTS/METHODS:  The study was performed at the University of Tromsø, Northern Norway. In total, 8018 nonsmoking and 2087 smoking subjects were included in a cross-sectional study performed in 2008, and 1762 nonsmoking and 397 smoking subjects in a longitudinal study from 1994/1995 to 2008. Nonfasting serum 25(OH)D, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio and triacylglycerol (TAG) were measured. RESULTS:  After adjustment for gender, age, sample month and body mass index in the cross-sectional study, there was a significant increase in serum TC, HDL-C and LDL-C, and a significant decrease in serum LDL-C/HDL-C ratio and TAG across increasing serum 25(OH)D quartiles. For serum HDL-C and TAG in nonsmokers the differences between the means for the highest and lowest serum 25(OH)D quartiles were 6.0 and 18.5%, respectively. In the longitudinal study, an increase in serum 25(OH)D was associated with a significant decrease in serum TAG. CONCLUSIONS:  There is a cross-sectional association between serum 25(OH)D and serum lipids, and a longitudinal association over 14 years between serum 25(OH)D and TAG, which may contribute to explain the relation between low serum 25(OH)D concentrations and mortality.

Vitamin D metabolism in hyperthyroidism.
            (MacFarlane et al., 1982)  Download
The serum concentrations of 25-hydroxycholecalciferol (25 OH D3), 24,25-dihydroxycholecalciferol [24,25(OH)-2D3] and 1,25-dihydroxycholecalciferol [1,25(OH)2D3] were measured in twenty-one patients with untreated hyperthyroidism. Compared with control subjects, 25 OH D3 concentrations were not altered, 24,25(OH)2D3 concentrations were increased, although not significantly and 1,25(OH)2D3 concentrations were decreased (P = 0.01). Following oral carbimazole therapy, 24,25(OH)2D3 concentrations fell (P less than 0.01), 1,25(OH)2D3 concentrations increased (P less than 0.01) and 25 OH D3 concentrations were unchanged. The altered 1,25(OH)2D3 and 24,25(OH)2D3 concentrations found in hyperthyroidism are probably due to the effects of thyroid hormone on bone and mineral metabolism. Increased serum calcium and phosphate concentrations with secondary hypoparathyroidism result in stimulation of the renal 24-hydroxylase and suppression of the 1-hydroxylase enzymes. In addition, serum 24,25(OH)2D3 concentrations were significantly correlated with serum triiodothyronine levels (T3) (r = 0.66, P less than 0.002) before treatment. This may indicate a direct stimulatory effect of T3 on 24-hydroxylase activity. No relationship was found between serum 1,25(OH)2D3 concentrations before therapy and serum T3.

Vitamin D Toxicity-A Clinical Perspective.
            (Marcinowska-Suchowierska et al., 2018)  Download
Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally. Although VDT is rare, the health effects can be serious if it is not promptly identified. Many forms of exogenous (iatrogenic) and endogenous VDT exist. Exogenous VDT is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of VDT due to vitamin D overdosing. Endogenous VDT may develop from excessive production of an active vitamin D metabolite - 1,25(OH)|2|D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous VDT may also develop from an excessive production of 25(OH)D and 1,25(OH)|2|D in congenital disorders, such as Williams-Beuren syndrome. Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism. Researchers have proposed many processes to explain VDT. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. Increased public awareness of vitamin D-related health benefits might increase the risk of VDT due to self-administration of vitamin D in doses higher then recommended for age and body weight or even higher than the established upper limit intake values. Consequently, the incidence of hypercalcemia due to hypervitaminosis D might increase.

Vitamin D toxicity redefined: vitamin K and the molecular mechanism.
            (Masterjohn, 2007)  Download
The dose of vitamin D that some researchers recommend as optimally therapeutic exceeds that officially recognized as safe by a factor of two; it is therefore important to determine the precise mechanism by which excessive doses of vitamin D exert toxicity so that physicians and other health care practitioners may understand how to use optimally therapeutic doses of this vitamin without the risk of adverse effects. Although the toxicity of vitamin D has conventionally been attributed to its induction of hypercalcemia, animal studies show that the toxic endpoints observed in response to hypervitaminosis D such as anorexia, lethargy, growth retardation, bone resorption, soft tissue calcification, and death can be dissociated from the hypercalcemia that usually accompanies them, demanding that an alternative explanation for the mechanism of vitamin D toxicity be developed. The hypothesis presented in this paper proposes the novel understanding that vitamin D exerts toxicity by inducing a deficiency of vitamin K. According to this model, vitamin D increases the expression of proteins whose activation depends on vitamin K-mediated carboxylation; as the demand for carboxylation increases, the pool of vitamin K is depleted. Since vitamin K is essential to the nervous system and plays important roles in protecting against bone loss and calcification of the peripheral soft tissues, its deficiency results in the symptoms associated with hypervitaminosis D. This hypothesis is circumstantially supported by the observation that animals deficient in vitamin K or vitamin K-dependent proteins exhibit remarkable similarities to animals fed toxic doses of vitamin D, and the observation that vitamin D and the vitamin K-inhibitor Warfarin have similar toxicity profiles and exert toxicity synergistically when combined. The hypothesis further proposes that vitamin A protects against the toxicity of vitamin D by decreasing the expression of vitamin K-dependent proteins and thereby exerting a vitamin K-sparing effect. If animal experiments can confirm this hypothesis, the models by which the maximum safe dose is determined would need to be revised. Physicians and other health care practitioners would be able to treat patients with doses of vitamin D that possess greater therapeutic value than those currently being used while avoiding the risk of adverse effects by administering vitamin D together with vitamins A and K.

Up-regulatory impact of boron on vitamin D function -- does it reflect inhibition of 24-hydroxylase
            (Miljkovic et al., 2004)  Download
Nutritional intakes of boron have been shown to lessen the adverse consequences of vitamin D deficiency in rodents. Pilot clinical studies suggest that this effect may be mediated, in whole or in part, by an increase in serum 25-hydroxyvitamin D. We propose that, in concentrations achievable with good diets, boron suppresses the activity of the microsomal enzyme 24-hydroxylase, chiefly responsible for catabolism of this steroid. This inhibition may reflect a direct interaction with the enzyme, or perhaps boron's ability to form a covalent complex with the product of its activity, 24,25-dihydroxyvitamin D. An up-regulatory impact of boron on 25-hydroxyvitamin D is potentially beneficial in light of the fact that the vitamin D status of many individuals is poor during winter months, and traditional supplemental doses of this vitamin are often too low to correct this problem. There is growing evidence that good vitamin D status -- as reflected by 25-hydroxyvitamin D levels -- may reduce risk for a host of prominent disorders; thus, boron may have the ability to potentiate this protection. Clinical studies also suggest that nutritional boron can up-regulate 17beta-estradiol levels in women, including postmenopausal women receiving hormone replacement therapy. The catabolism of this hormone is achieved by microsomal enzymes catalyzing vicinal hydroxylations -- a description that also applies to 24-hydroxylase. This suggests the more general hypothesis that nutritional boron can inhibit a range of microsomal enzymes which insert hydroxyl groups vicinal to existing hydroxyls in steroids -- including the enzymes which catabolize estradiol and 25-hydroxyvitamin D.

Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition
            (Molin et al., 2017) Download
Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH)|2| D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)|2| D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D|3| or alfacalcidol (1α-OH-D|3| ) treatment, and we observed a dramatic increase in the 1,25-(OH)|2| D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D|3| ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research.

Hypervitaminosis D without toxicity.
            (Rahesh et al., 2020)  Download
Vitamin D deficiency is highly prevalent and there are an increasing number of reports of vitamin D toxicity, mostly related to the misuse of over-the-counter supplements. We report a case with marked hypervitaminosis D (25(OH)D 196 ng/mL) without clinical or biochemical toxicity and normal serum calcium, phosphorus, and 1,25(OH)2D levels. The decline and normalization of the patient's 25(OH)D and urine calcium after cessation of supplements indicated that these supplements were the likely etiology of her hypervitaminosis D. Over-the-counter medications would benefit from regulation by the Food and Drug Administration to prevent incidental toxicity, as seen in our patient.


Metabolism of vitamin D3 by cytochromes P450.
            (Sakaki et al., 2005)  Download
The vitamin D3 25-hydroxylase (CYP27A1), 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) and 1alpha,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1) are members of the cytochrome P450 superfamily, and key enzymes of vitamin D3 metabolism. Using the heterologous expression in E. coli, enzymatic properties of the P450s were recently investigated in detail. Upon analyses of the metabolites of vitamin D3 by the reconstituted system, CYP27A1 surprisingly produced at least seven forms of minor metabolites including 1alpha,25(OH)2D3 in addition to the major metabolite 25(OH)D3. These results indicated that human CYP27A1 catalyzes multiple reactions involved in the vitamin D3 metabolism. In contrast, CYP27B1 only catalyzes the hydroxylation at C-1alpha position of 25(OH)D3 and 24R,25(OH)2D3. Enzymatic studies on substrate specificity of CYP27B1 suggest that the 1alpha-hydroxylase activity of CYP27B1 requires the presence of 25-hydroxyl group of vitamin D3 and is enhanced by 24-hydroxyl group while the presence of 23-hydroxyl group greatly reduced the activity. Eight types of missense mutations in the CYP27B1 gene found in vitamin D-dependent rickets type I (VDDR-I) patients completely abolished the 1alpha-hydroxylase activity. A three-dimensional model of CYP27B1 structure simulated on the basis of the crystal structure of rabbit CYP2C5 supports the experimental data from mutagenesis study of CYP27B1 that the mutated amino acid residues may be involved in protein folding, heme-propionate binding or activation of molecular oxygen. CYP24A1 expressed in E. coli showed a remarkable metabolic processes of 25(OH)D3 and 1alpha,25(OH)2D3. Rat CYP24A1 catalyzed six sequential monooxygenation reactions that convert 1alpha,25(OH)2D3 into calcitroic acid, a known final metabolite of C-24 oxidation pathway. In addition to the C-24 oxidation pathway, human CYP24A1 catalyzed also C-23 oxidation pathway to produce 1alpha,25(OH)2D3-26,23-lactone. Surprisingly, more than 70 % of the vitamin D metabolites observed in a living body were found to be the products formed by the activities of CYP27A1, CYP27B1 and CYP24A1. The species-based difference was also observed in the metabolism of vitamin D analogs by CYP24A1, suggesting that the recombinant system for human CYP24A1 may be of great use for the prediction of the metabolism of vitamin D analogs in humans.

Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole.
            (Sayers et al., 2015)  Download
Mutations in CYP24A1, encoding the vitamin D 24-hydroxlase enzyme, are known to cause a range of clinical phenotypes and presentations including idiopathic infantile hypercalcaemia and adult-onset nephrocalcinosis and nephrolithiasis. In the context of raised or borderline high serum calcium levels, suppressed PTH and persistently elevated 1,25 dihydroxy vitamin D levels, this rare condition should be considered. We present a case where this biochemical pattern was seen and mutations in CYP24A1 were confirmed. We were able to successfully control serum calcium levels and reduce urinary calcium excretion by treatment with low-dose fluconazole, which inhibits vitamin D-synthesizing enzymes (including 25-hydroxylases and 1-α-hydroxylase) thereby reducing levels of 1,25-dihydroxy vitamin D.


Extraskeletal effects and manifestations of Vitamin D deficiency.
            (Visweswaran and Lekha, 2013)  Download
The actions of vitamin D are not confined to bone. Vitamin D receptors are present in nearly all the nuclei and its actions are manifold. Populations deficient in vitamin D are at higher risk of developing autoimmune diseases, diabetes, cancer, infections, allergies and other chronic illnesses.

Interplay between vitamin D and the drug metabolizing enzyme CYP3A4.
            (Wang et al., 2013)  Download
Cytochrome P450 3A4 (CYP3A4) is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. This review focuses on two aspects: regulation of CYP3A4 expression by vitamin D and metabolism of vitamin D by CYP3A4. Enterohepatic circulation of vitamin D metabolites and their conjugates will be also discussed. The interplay between vitamin D and CYP3A4 provides new insights into our understanding of how enzyme induction can contribute to vitamin D deficiency. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

CYP24A1 mutations and hypervitaminosis D.
            (Willows and Sayer, 2019)  Download
While noting that hypervitaminosis D is rare and can occur with excessively high doses of supplementation, they omit from their differential diagnoses the possibility of CYP24A1 mutations, a well-described alternate cause of the phenotype described in their patient. Loss of function mutations in CYP24A1 result in reduced action of 1,25-hydroxyvitamin-D3-24-hydroxylase, which usually inactivates active vitamin D. As well as a neonatal presentation, patients with CYP24A1 mutations can present with adult-onset hypercalcaemia, together with low parathyroid hormone levels and high urinary calcium. If this genetic condition is present, even modest vitamin D supplementation can lead to significant hypercalcaemia. Indeed, high levels of active vitamin D metabolites are found in some CYP24A1-deficient individuals even without supplementation. In cases of hypercalcaemia, a renal tract ultrasound, looking for nephrocalcinosis, suggestive of a more longstanding kidney disorder, should be performed. Finally we would always advocate taking a detailed family history in such cases, irrespective of the patient’s age, to identify any familial pattern of renal stones, nephrocalcinosis or hypercalcaemia .

 


References

Bikle, DD (2014), ‘Vitamin D metabolism, mechanism of action, and clinical applications.’, Chem Biol, 21 (3), 319-29. PubMed: 24529992
Chau, TS, et al. (2005), ‘Age-related alteration of vitamin D metabolism in response to low-phosphate diet in rats.’, Br J Nutr, 93 (3), 299-307. PubMed: 15877868
Griffin, TP, et al. (2019), ‘Normocalcemia in the Face of Marked Hypervitaminosis D: The Utility of Vitamin D Metabolite Profiling.’, J Appl Lab Med, 4 (2), 264-69. PubMed: 31639673
Heureux, N (2017), ‘Vitamin D Testing-Where Are We and What Is on the Horizon’, Adv Clin Chem, 78 59-101. PubMed: 28057189
Houghton, LA and R Vieth (2006), ‘The case against ergocalciferol (vitamin D2) as a vitamin supplement.’, Am J Clin Nutr, 84 (4), 694-97. PubMed: 17023693
Hunter, JM, et al. (2019), ‘The Fructoborates: Part of a Family of Naturally Occurring Sugar-Borate Complexes-Biochemistry, Physiology, and Impact on Human Health: a Review.’, Biol Trace Elem Res, 188 (1), 11-25. PubMed: 30343480
Jorde, R, et al. (2010), ‘High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile.’, Eur J Clin Nutr, 64 (12), 1457-64. PubMed: 20823896
MacFarlane, IA, et al. (1982), ‘Vitamin D metabolism in hyperthyroidism.’, Clin Endocrinol (Oxf), 17 (1), 51-59. PubMed: 6981469
Marcinowska-Suchowierska, E, et al. (2018), ‘Vitamin D Toxicity-A Clinical Perspective.’, Front Endocrinol (Lausanne), 9 550. PubMed: 30294301
Masterjohn, C (2007), ‘Vitamin D toxicity redefined: vitamin K and the molecular mechanism.’, Med Hypotheses, 68 (5), 1026-34. PubMed: 17145139
Miljkovic, D, N Miljkovic, and MF McCarty (2004), ‘Up-regulatory impact of boron on vitamin D function -- does it reflect inhibition of 24-hydroxylase’, Med Hypotheses, 63 (6), 1054-56. PubMed: 15504575
Molin, A, et al. (2017), ‘Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition’, J Bone Miner Res, 32 (9), 1893-99. PubMed: 28548312
Rahesh, J, V Chu, and AN Peiris (2020), ‘Hypervitaminosis D without toxicity.’, Proc (Bayl Univ Med Cent), 33 (1), 42-43. PubMed: 32063764
Sakaki, T, et al. (2005), ‘Metabolism of vitamin D3 by cytochromes P450.’, Front Biosci, 10 119-34. PubMed: 15574355
Sayers, J, et al. (2015), ‘Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole.’, Clin Kidney J, 8 (4), 453-55. PubMed: 26251716
Visweswaran, RK and H Lekha (2013), ‘Extraskeletal effects and manifestations of Vitamin D deficiency.’, Indian J Endocrinol Metab, 17 (4), 602-10. PubMed: 23961475
(2008), ‘Vitamin D. Monograph.’, Altern Med Rev, 13 (2), 153-64. PubMed: 18590351
Wang, Z, et al. (2013), ‘Interplay between vitamin D and the drug metabolizing enzyme CYP3A4.’, J Steroid Biochem Mol Biol, 136 54-58. PubMed: 22985909
Willows, J and JA Sayer (2019), ‘CYP24A1 mutations and hypervitaminosis D.’, Clin Med (Lond), 19 (1), 92-93. PubMed: 30651269