1,25-dihydroxyvitamin D2

Vitamin D, recognized for its essential role in human health, encompasses various forms crucial for physiological functions such as bone health, immune system regulation, and cellular growth. 

Among these forms,1,25-dihydroxyvitamin D2 is the active form of vitamin D2, the form of vitamin D commonly found in the human diet in plants and also in supplements.  

1,25-dihydroxyvitamin D2 is a lesser-known variant of the active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D).  Calcitriol encompasses the active forms of vitamin D2 and vitamin D3, so understanding the actions and implications of the active form of vitamin D is essential to understand 1,25-dihydroxyvitamin D2.  [14.]

Calcitriol, considered a hormone, is the active form of vitamin D in the body.  It plays a crucial role in various physiological processes, including calcium metabolism, parathyroid hormone secretion, bone health, and immune function. 

This informational article provides an in-depth exploration of 1,25-dihydroxyvitamin D2, covering its definition and function, as well as its clinical uses and indications. Additionally, it discusses the mechanism of action in the body and examines the available testing options for assessing 1,25-dihydroxyvitamin D2.  

What is the Difference Between Vitamin D2 and Vitamin D3?

Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are two forms of vitamin D that differ primarily in their sources and structures. 

Vitamin D2 is derived from plant-based sources, such as mushrooms exposed to ultraviolet light, while vitamin D3 is primarily synthesized in the skin upon exposure to sunlight or obtained from animal-based foods.  Vitamin D2 and vitamin D3 are also available as supplements. 

Structurally, vitamin D2 has a double bond between carbons 22 and 23, while vitamin D3 has an additional methyl group at carbon 24. Despite these structural differences, both forms undergo similar metabolic processes in the body, ultimately being converted into the active form of vitamin D, calcitriol. 

While both forms are effective at raising serum 25-hydroxyvitamin D levels, some studies suggest that vitamin D3 may be more potent and bioavailable than vitamin D2. However, the clinical significance of this difference remains a topic of ongoing research and debate.  [2., 3.]

Definition and Overview: What is 1,25-dihydroxyvitamin D2?

1,25-dihydroxyvitamin D2 is the active form of vitamin D2 in the human body.  It plays a vital role in regulating calcium and phosphate levels which are essential for bone health, muscle function, and nerve transmission.  It also is important in immune function.  

1,25-dihydroxyvitamin D2 is synthesized in the kidneys through a series of enzymatic reactions from calcidiol, or 25(OH) vitamin D, which is considered a prohormone.  

Together with 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2 makes up the body’s available pool of active vitamin D, calcitriol.  [9., 14.] 

Biological Functions of 1,25-dihydroxyvitamin D2  [1., 6., 13.,15.]

• Regulates plasma calcium levels alongside parathyroid hormone (PTH) through various mechanisms:some text
  • Enhances absorption of dietary calcium and phosphate in the gastrointestinal tract
  • Promotes renal tubular reabsorption of calcium in the kidneys
  • Stimulates the release of calcium from skeletal stores
• Promotes fatty acid synthesis and inhibits lipolysis
• Increases energy efficiency by suppressing UCP2 expression, mediated by classical nuclear receptor signaling pathways where calcitriol acts as a natural ligand
• Modulates the action of cytokines and may regulate immune and inflammatory responses, as well as cell turnover and differentiation
• Promotes a healthy immune balance, prioritizing TH1 cellular immunity and the generation of CD4+CD25+ regulatory T cells (Tregs), underscoring its pivotal role in immune regulation and autoimmune conditions 
• Stimulates bone mineralization by promoting a healthy balance of bone resorption and remodeling 
• Modulates the activity of parathyroid hormone (PTH), helping to maintain normal serum calcium levels
• Plays a role in cellular growth, differentiation, and apoptosis in various tissues, including through topical use

Clinical Uses and Indications of 1,25-dihydroxyvitamin D2: What is Vitamin D2 Used For?

The active form of vitamin D2 is a hormone in the human body.  Common uses include:

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• Treating hypocalcemia, osteoporosis, and preventing corticosteroid-induced osteoporosis.
• Controlling hypocalcemia in patients on chronic renal dialysis.
• Managing secondary hyperparathyroidism in chronic kidney disease patients not on dialysis.
• Treating hypocalcemia in patients with hypoparathyroidism and pseudohypoparathyroidism.
• Topically, the ointment may be used for managing mild to moderate plaque psoriasis.
• Off-label uses:some text
  • Off-label uses may include type 1, vitamin D-dependent rickets, and pseudo-vitamin D deficiency rickets.
  • Off-label use of topical ointment may include psoriasis in children and adolescents.

Mechanism of Action of 1,25-dihydroxyvitamin D2: What Organs Does Vitamin D2 Act On?

1,25-dihydroxyvitamin D2 exerts its mechanism of action primarily through two main pathways:

Regulation of Calcium and Phosphate Metabolism

The 1,25-dihydroxyvitamin D2 form of calcitriol plays a crucial role in maintaining calcium and phosphate homeostasis in the body. 

By inducing dimerization of the vitamin D receptor, calcitriol exerts regulatory control over calcium levels in the bloodstream by promoting calcium absorption from the intestines, calcium reabsorption in the kidneys, and mobilization of calcium from bone when needed.

Additionally, it enhances the absorption of phosphate from the intestines. 

By regulating the levels of these minerals, 1,25-dihydroxyvitamin D2 helps in various physiological processes such as bone formation, muscle function, and nerve transmission.

Interaction with Receptors and Cellular Signaling Pathways

1,25-dihydroxyvitamin D2 functions by binding to the vitamin D receptor (VDR) present in the nuclei of target cells. This binding initiates a series of cellular signaling events that ultimately lead to the modulation of gene expression. 

The activated VDR forms a heterodimer with the retinoid X receptor (RXR), which then binds to specific DNA sequences called vitamin D response elements (VDREs) within the promoter regions of target genes. This binding regulates the transcription of genes involved in calcium and phosphate metabolism, as well as other physiological processes such as cell proliferation, differentiation, and immune function.

The vitamin D receptor (VDR) is found in various tissues beyond those involved in calcium and phosphate regulation, including epidermal keratinocytes, immune cells (such as activated T cells, antigen-presenting cells, macrophages, monocytes, and cytotoxic T cells). 

Gene array studies reveal that calcitriol influences numerous genes across the body, potentially impacting up to 5 percent of the human genome.  [6., 12.]

In summary, 1,25-dihydroxyvitamin D2 regulates calcium and phosphate metabolism by influencing their absorption, reabsorption, and mobilization, while also exerting its effects on target cells through interaction with vitamin D receptors and modulation of gene expression.

Why Do Doctors Prescribe Vitamin D2 Instead of Vitamin D3? 

Doctors may prescribe vitamin D2 (ergocalciferol) instead of vitamin D3 (cholecalciferol) in certain situations based on patient-specific factors and clinical considerations. 

For example, the decision to prescribe vitamin D2 could be due to its availability in different formulations, such as vegetarian or vegan-friendly options, making it suitable for individuals with dietary restrictions or preferences. 

Additionally, some patients may have medical conditions or allergies that preclude the use of vitamin D3 sourced from animal products. 

Furthermore, cost considerations or insurance coverage may influence the choice of vitamin D formulation, as vitamin D2 may be more affordable or covered by insurance plans. 

However, it's essential to note that while vitamin D2 and D3 are both effective at raising serum vitamin D levels, there is ongoing debate regarding their comparative efficacy and bioavailability.  In the absence of contraindications, many experts recommend vitamin D3 supplementation.   [8.]

The decision to prescribe vitamin D2 over D3 should be based on individual patient needs, preferences, and clinical judgment.

Testing Options for 1,25-dihydroxyvitamin D2 Levels

Laboratory Testing Methods

Vitamin D measurements are typically done via serum, although they may also be done via plasma or blood spot analysis.  Fasting or other special preparation is not typically required for a vitamin D test, but patients should consult their healthcare provider to confirm.  

Sample Collection and Preparation

Sample collection and preparation for testing calcitriol levels typically involve obtaining blood samples through venipuncture.  It is a relatively simple and easy sample collection, although some people find blood draws unpleasant.  

Alternatively, blood spot testing for vitamin D involves collecting a small sample of blood from a finger prick onto filter paper. This method offers convenience for both patients and healthcare providers and can provide accurate measurements of vitamin D levels, making it useful for screening and monitoring vitamin D status.  A blood spot sample can be taken from the comfort of a patient’s home.  

Interpretation of Vitamin D Blood Tests

What is Measured in a Vitamin D Blood Test?

Vitamin D blood testing measures the concentration of specific forms of vitamin D in the blood. 

This typically includes the measurement of 25-hydroxyvitamin D (25(OH)D), which is the major circulating form of vitamin D and is considered the best indicator of overall vitamin D status as it reflects dietary intake and skin synthesis.  [6.]

Serum analysis of 25(OH) vitamin D comprises 25(OH) vitamin D2 and 25(OH) vitamin D3.  [6.]

Some labs may also measure the active form of vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D) or calcitriol] although this is less commonly done as it has a shorter half-life and may not reflect long-term vitamin D status as accurately as 25(OH)D.  

When calcitriol  levels are run, this often includes 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 levels.  [14.]  

Some labs offer the option to test for levels of vitamin D2 and vitamin D3 as separate fractions, which may be clinically useful to monitor treatment progress.  [8.]

Reference Ranges for Vitamin D in the Blood

Typical reference ranges for the total 25-OH vitamin D, measured in ng/mL, is 25-80 ng/mL.  [11.]

Results may also be reported as nmol/L, which has a reference range of 75-125 nmol/L.  [7.]

Many experts define vitamin D deficiency according to the following levels, although it is important to note that there is some discrepancy regarding vitamin D insufficiency:  [7.]

• Severe deficiency: a serum 25-hydroxyvitamin D (25(OH)D) level below 12 ng/mL (30 nmol/L)
• Deficiency:  a serum 25-hydroxyvitamin D (25(OH)D) level between 12-20 ng/mL (30-50 nmol/L)
• Vitamin D sufficiency:  a serum 25-hydroxyvitamin D (25(OH)D) level above 30 ng/mL (75 nmol/L)
• Vitamin D toxicity: serum 25(OH)D levels greater than 150 ng/mL (374 nmol/L)  [17.]

Diet and Lifestyle Factors to Support 1,25-dihydroxyvitamin D2 Function in the Body

Dietary Sources of Vitamin D  [10.]

Vitamin D3 is synthesized in the skin in humans, and it can also be obtained through the consumption of animal-based foods in the diet.  In contrast, vitamin D2 is available in plant sources and is synthesized and added to supplements.  

• Fatty fish such as salmon, mackerel, and tuna are rich dietary sources of vitamin D.
• Egg yolks and fortified foods such as fortified milk, orange juice, and cereals also contribute to dietary intake of vitamin D.
• Some mushrooms, particularly those exposed to ultraviolet light, contain small amounts of vitamin D.  Mushrooms contain a compound called ergosterol that is converted to vitamin D2, ergocalciferol, in the presence of UV light.  [5.]

Sun Exposure and Vitamin D Synthesis

Exposure of the skin to sunlight triggers vitamin D synthesis: Vitamin D3 (cholecalciferol) is produced in human skin from 7-dehydrocholesterol upon exposure to sunlight.  

Sun exposure is most effective when the sun is high in the sky, typically between 10 a.m. and 3 p.m.  Other factors such as latitude, season, cloud cover, sunscreen use, and skin pigmentation influence the amount of vitamin D synthesized through sun exposure.

Lifestyle Habits for Optimal Bone Health

• Regular weight-bearing and muscle-strengthening exercises, such as walking, jogging, weightlifting, and resistance training, promote bone health by stimulating bone formation and density.
• Adequate intake of calcium and vitamin D through diet or supplements supports bone health by providing essential nutrients for bone formation and maintenance.
• Avoiding smoking and excessive alcohol consumption helps maintain optimal bone health, as smoking and alcohol can negatively impact bone density and increase the risk of fractures.

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