24-Hydroxylase Deficiency Due to <i>CYP24A1</i> Sequence Variants: Comparison With Other Vitamin D−mediated Hypercalcemia Disorders

Azer, Sarah; Vaughan, Lisa E.; Tebben, Peter J.; Sas, David J.

doi:10.1210/jendso/bvab119

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…However, in hospital settings, it is commonly related to cancer due to the inappropriate secretion of parathyroid hormone-related peptide (PTHrP) and metastatic bone disease [ 91 , 92 ]. Other causes of hypercalcemia, such as genetic mutations of CYP24A1, etc., are extremely rare [ 93 , 94 ].…”

Section: Summary Of Evidence From Clinical Trailsmentioning

confidence: 99%

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

Wimalawansa¹

2022

Nutrients

112

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Vitamin D deficiency is a global public health problem, a pandemic that commonly affects the elderly and those with comorbidities such as obesity, diabetes, hypertension, respiratory disorders, recurrent infections, immune deficiency, and malignancies, as well as ethnic minorities living in temperate countries. The same groups were worst affected by COVID-19. Since vitamin D deficiency weakens the immune system, it increases the risk of infections, complications, and deaths, such as from sepsis and COVID-19. Deficiency can be remedied cost-effectively through targeted food fortification, supplementation, and/or daily safe sun exposure. Its endocrine functions are limited to mineral metabolism, musculoskeletal systems, specific cell membrane interactions, and parathyroid gland functions. Except for the rapid, endocrine, and cell membrane-based non-genomic functions, all other biological and physiological activities of vitamin D depend on the adequate intracellular synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells via the genome. Calcitriol mediates autocrine (intracrine) and paracrine signalling in immune cells, which provides broader, protective immune functions crucial to overcoming infections. The synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells is dependent on diffusion and endocytosis of D3 and 25(OH)D from the circulation into them, which requires maintenance of serum 25(OH)D concentration above 50 ng/mL. Therefore, in acute infections such as sepsis and respiratory infections like COVID-19, it is necessary to rapidly provide its precursors, D3 and 25(OH)D, through the circulation to generate adequate intracellular calcitriol. Immune defence is one of the crucial non-hormonal functions of vitamin D. A single oral (bolus) dose or divided upfront loading doses between 100,000 and 500,000 IU, using 50,000 IU vitamin D3 increase the serum 25(OH)D concentrations to a therapeutic level of above 50 ng/mL that lasts between two to three months. This takes three to five days to raise serum 25(OH)D. In contrast, a single oral dose of calcifediol (0.014 mg/kg body weight) can generate the needed 25(OH)D concentration within four hours. Considering both D3 and 25(OH)D enter immune cells for generating calcitriol, using the combination of D3 (medium-term) and calcifediol (immediate) is cost-effective and leads to the best clinical outcome. To maximise protection against infections, particularly to reduce COVID-19-associated complications and deaths, healthcare workers should advise patients on safe sun exposure, adequate vitamin D supplementation and balanced diets containing zinc, magnesium, and other micronutrients to support the immune system. Meanwhile, governments, the World Health Organisation, the Centers for Disease Control, and governments should consider similar recommendations to physicians and the public, change the outdated vitamin D and other micronutrient recommendations directed to their population, and organise targetted food fortification programs for the vulnerable groups. This article discusses a rational approach to maintaining a sustained serum 25(OH)D concentration above 50 ng/mL, necessary to attain a robust immune system for overcoming infections. Such would cost-effectively improve the population’s health and reduce healthcare costs. It also describes three cost-effective, straightforward protocols for achieving and sustaining therapeutic serum 25(OH)D concentrations above 50 ng/mL (>125 nmol/L) to keep the population healthy, reduce absenteeism, improve productivity, and lower healthcare costs.

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Section: Summary Of Evidence From Clinical Trailsmentioning

confidence: 99%

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

Wimalawansa¹

2022

Nutrients

112

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“…A normal serum calcium level is 8.6 to 10 mg/dL. 20 The results of the test are presented in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Methotrexate Increases Serum Calcium Levels in Patients with Rheumatoid Arthritis: A Retrospective Study at a Referral Hospital in Indonesia

Destiani,

Utami,

Farhanah

et al. 2023

Current Therapeutic Research

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“…This supports that once entering the circulation, 25(OH)D 3 is likely equilibrated into different tissues such as the fat, muscles, breast, colon, prostate, and skin, which have the ability to convert 25(OH)D 3 into 1,25(OH) 2 D 3 (15). Then, it slowly gets catabolized by the enzyme 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), which exists in multiple tissues expressing the vitamin D receptor (16). Interestingly, the second increase in 25(OH)D level was observed at 48 h in four participants (participants 1, 2, 4, 6) and later in the other two participants.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of 14-day Concentration-time Curves of Vitamin D₃ and 25-Hydroxyvitamin D₃ in Healthy Adults With Varying Body Mass Index

Charoenngam¹,

MUELLER²,

Holick³

2022

Anticancer Res

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Background/Aim: To analyze the concentration-time curves of single-dose oral 25(OH)D 3 in comparison with vitamin D 3 in healthy adults. Patients and Methods: The pharmacokinetics observed over two weeks after orally administering single 900 μg doses of vitamin D 3 and 25(OH)D 3 to six otherwise healthy vitamin D insufficient/deficient adults participating in a broader randomized, double-blind, crossover, single center trial was analyzed. The study protocol was approved by the institutional review board (H-37167). Results: Individual concentration-time curves revealed that vitamin D 3 took longer than 25(OH)D 3 to reach its maximal concentration after ingestion in five participants. After 25(OH)D 3 ingestion, 25(OH)D 3 reached its maximal concentration, dropped rapidly, and plateaued before starting to decrease slowly. There were observable inter-individual variations in the bioavailability of vitamin D 3 and 25(OH)D 3 and the pattern of changes in 25(OH)D 3 concentration after their ingestion. Conclusion: Pharmacokinetics of 25(OH)D 3 in comparison with vitamin D 3 was illustrated and described in this study. Vitamin D plays a crucial role in regulating calcium and phosphate metabolism (1). Vitamin D exists in two forms, vitamin D 3 (cholecalciferol) and vitamin D 2 (ergocalciferol). Vitamin D 3 is synthesized by the skin and found naturally in cod liver oil and oily fish. Vitamin D 2 is synthesized from ergosterol and found in yeast and mushrooms exposed to ultraviolet B radiation from sunlight or an artificial source. Once vitamin D 2 and vitamin D 3 enters the circulation, they are converted by the enzyme vitamin D-25-hydroxylase in the liver to 25-hydroxyvitamin D 2 [25(OH)D 2 ] and 25hydroxyvitamin D 3 [25(OH)D 3 ], which are the major circulating metabolites of vitamin D that are clinically measured for determining vitamin D status (1, 2). Vitamin D is a non-polar and highly lipophilic substance that is easily incorporated into lipid bilayers. Due to its lipophilic character, the gastrointestinal absorption of vitamin D takes place predominantly via the lymphatic pathway. Thus, vitamin D gets packed into micelles and chylomicrons and enters the lymph before being delivered to the bloodstream. It is estimated that 60% of the absorbed vitamin D binds with vitamin D-binding protein, while the rest 40% is cleared in the lipoprotein bound fraction (3). Once entering the circulation, vitamin D either binds with the vitamin D-binding protein, gets distributed mostly into the fat tissue, or gets metabolized by the liver to become the more hydrophilic form of 25(OH)D. It has been suggested that if one ingests 25(OH)D, its absorption takes place predominantly via the enterohepatic pathway, and, in addition, 25(OH)D is distributed more evenly throughout the body in fat, muscle, serum and other tissues (4). Previous clinical studies have shown that 25(OH)D is markedly superior to vitamin D in raising and maintaining serum levels of 25(OH)D when being orally administered as either single dose or continuous daily doses ...

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24-Hydroxylase Deficiency Due to CYP24A1 Sequence Variants: Comparison With Other Vitamin D−mediated Hypercalcemia Disorders

Cited by 7 publications

References 48 publications

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

Methotrexate Increases Serum Calcium Levels in Patients with Rheumatoid Arthritis: A Retrospective Study at a Referral Hospital in Indonesia

Evaluation of 14-day Concentration-time Curves of Vitamin D₃ and 25-Hydroxyvitamin D₃ in Healthy Adults With Varying Body Mass Index

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24-Hydroxylase Deficiency Due to CYP24A1 Sequence Variants: Comparison With Other Vitamin D−mediated Hypercalcemia Disorders

Cited by 7 publications

References 48 publications

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

Methotrexate Increases Serum Calcium Levels in Patients with Rheumatoid Arthritis: A Retrospective Study at a Referral Hospital in Indonesia

Evaluation of 14-day Concentration-time Curves of Vitamin D3 and 25-Hydroxyvitamin D3 in Healthy Adults With Varying Body Mass Index

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Evaluation of 14-day Concentration-time Curves of Vitamin D₃ and 25-Hydroxyvitamin D₃ in Healthy Adults With Varying Body Mass Index