1,25-dihydroxyvitamin D

Calcitriol is the most 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. 

Calcitriol is considered a hormone; it is made in the kidneys, and is also often prescribed as a medication.  As the active form of vitamin D, it is crucial for regulating calcium absorption in the gut and suppressing parathyroid hormone secretion. 

Cholecalciferol is the primary form of vitamin D found in nature and is commonly supplemented, and calcidiol is a major circulating metabolite of cholecalciferol. Calcitriol is converted from calcidiol in the kidneys. 

This informational article provides an in-depth exploration of calcitriol, covering its definition, structure, and function, as well as its clinical uses and indications. Additionally, it discusses the potential side effects and adverse reactions associated with calcitriol supplementation, elucidates its mechanism of action in the body, and examines the available testing options for assessing calcitriol levels. 

Furthermore, the article offers insights into the dietary and lifestyle factors that support optimal calcitriol levels and overall health and wellness.

Definition and Overview: What is Calcitriol?

Calcitriol, also known as 1,25-dihydroxyvitamin D is the active form of vitamin D in the human body.  It is considered a hormone.  Calcitriol is comprised of the active forms of vitamins D2 and D3, 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3.  

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.  

Calcitriol is synthesized in the kidneys through a series of enzymatic reactions from calcidiol, or 25(OH) vitamin D3.

Calcitriol is also available as a medication that is prescribed for many indications involving hypocalcemia.  [6.] 

Production of Calcitriol: What Organs in the Body Make Calcitriol?

In the human body, calcitriol is primarily synthesized in the kidneys from its precursor, calcidiol, which is produced in the liver from cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) obtained through dietary sources or sunlight exposure.  [10.]

Calcitriol is regarded as the most potent form of vitamin D metabolite in humans. Its synthesis in the kidneys is triggered by parathyroid hormone (PTH), as well as low levels of calcium and phosphate.

Structure and Function of Calcitriol

Chemical Structure

Calcitriol, also known as 1,25-dihydroxyvitamin D, is a steroid hormone derived from vitamin D2 or vitamin D3. 

Its chemical structure consists of a tricyclic seco-steroid backbone with hydroxyl groups at positions 1 and 25, crucial for its biological activity.  Calcitriol has powerful effects on vitamin D receptors in various tissues, regulating calcium and phosphate metabolism.

Biological Functions of Calcitriol [1., 4., 10., 11.]

• 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

Balance of Calcitriol in the Body

Calcitriol’s potent effects are balanced by several factors:  [1.]

• The presence of its carrier protein in the blood, vitamin D binding protein (DBP) which renders calcitriol inactive until it is released in the bloodstream
• The P450 enzyme CYP24 hydroxylase converts 25(OH)D3 to the inactive metabolite, 24,25(OH)2D3, in the kidney.some text
  • This conversion limits the production of calcitriol, the active form of vitamin D.
• Similarly, calcitriol is converted to 1,24,25(OH)2D3, an excretion product, by CYP24A1 after calcitriol binds to and activates a VDR (vitamin D receptor)  [4.]

Calcitriol metabolites are primarily excreted in feces.  Some vitamin D may be stored in adipose tissue, although further research is needed to understand the intricacies of this process.  

Vitamin D stored in adipose tissue may not be readily available, suggesting that obese individuals might need higher doses of vitamin D supplements to reach comparable serum 25OHD levels as those with normal weight. Studies on weight reduction show an increase in serum 25OHD levels when obese individuals lose body fat, supporting the hypothesis of vitamin D storage in adipose tissues.  [4.]

Both the production and excretion of the active constituent of vitamin D can be controlled.  This mechanism helps maintain a constant level of vitamin D in the body, ensuring a balance of its availability.

Clinical Uses and Indications of Calcitriol: What is Calcitriol Used For?

Calcitriol is a naturally-occurring hormone in the human body; it is also available as a hormonally active synthetic vitamin D analog.

• Prescribed for treating hypocalcemia, osteoporosis, and preventing corticosteroid-induced osteoporosis.
• FDA indication for systemic calcitriol includes controlling hypocalcemia in patients on chronic renal dialysis.
• Also indicated for managing secondary hyperparathyroidism in chronic kidney disease patients not on dialysis.
• Additionally FDA approved for treating hypocalcemia in patients with hypoparathyroidism and pseudohypoparathyroidism.
• Topical calcitriol ointment approved by FDA in 2009 for managing mild to moderate plaque psoriasis.
• Off-label uses:some text
  • Off-label uses of systemic calcitriol include type 1, vitamin D-dependent rickets, and pseudo-vitamin D deficiency rickets.
  • Off-label use of topical calcitriol ointment includes psoriasis in children and adolescents.

Mechanism of Action of Calcitriol: What Organs Does Calcitriol Act On?

Calcitriol exerts its mechanism of action primarily through two main pathways:

Regulation of Calcium and Phosphate Metabolism

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, calcitriol enhances the absorption of phosphate from the intestines. 

By regulating the levels of these minerals, calcitriol helps in various physiological processes such as bone formation, muscle function, and nerve transmission.

Interaction with Receptors and Cellular Signaling Pathways

Calcitriol 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.  [4., 9.]

In summary, calcitriol 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.

Side Effects and Adverse Reactions of Excessive Calcitriol Use

Common Side Effects

• Hypercalcemia is the most common adverse reaction in patients taking systemic calcitriol:some text
  • Early signs include fatigue, weakness, nausea, vomiting, abdominal pain, constipation, diarrhea, vertigo, and irritability. 
  • Late signs comprise polyuria, polydipsia, cardiac arrhythmias, and sensory disturbances.
• Less than 10% of adverse reactions include headache, skin rash, polydipsia, nausea, abdominal pain, and urinary tract infection. 
• Less than 1% involve hypertension, increased hematocrit, drowsiness, hyperthermia, and ophthalmic conditions like conjunctivitis.
• Hypercalciuria, nephrolithiasis, and elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) levels are confirmed complications. 
• Hyperphosphatemia, secondary hyperparathyroidism, renal osteodystrophy, and ectopic calcification may also occur.
• Hypersensitivity reactions, including pruritus, rash, and urticaria, are possible, along with rare cases of anaphylactoid reactions with intravenous calcitriol. Post-marketing reports indicate pruritus, erythema, acute generalized exanthematous pustulosis, psoriasis, and contact dermatitis associated with calcitriol ointment.

Testing Options for Calcitriol 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.  [4.]

Serum analysis of 25(OH) vitamin D comprises 25(OH) vitamin D2 and 25(OH) vitamin D3.  [4.]

Some labs may also measure the active form of vitamin D, known as 1,25-dihydroxyvitamin D (1,25(OH)2D), 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.

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.  [8.]

Results may also be reported as nmol/L, which has a reference range of 75-125 nmol/L.  [5.]

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:  [5.]

• 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)  [13.]

Diet and Lifestyle Factors to Support Calcitriol Function in the Body

Dietary Sources of Vitamin D  [7.]

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.

• 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.  [3.]

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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