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Introduction

Vitamin D is a fat-soluble secosteroid hormone precursor that plays a fundamental role in calcium and phosphate homeostasis, skeletal development, and bone mineralization. Unlike most vitamins, vitamin D can be synthesized endogenously in the skin following exposure to ultraviolet-B (UVB) radiation from sunlight. Therefore, it is often referred to as the “sunshine vitamin.”

Vitamin D is unique because its biologically active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)₂D] or calcitriol, functions as a steroid hormone by binding to the nuclear vitamin D receptor (VDR) and regulating the expression of numerous genes.

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General Characteristics

• Vitamin D is a fat-soluble vitamin absorbed along with dietary lipids.
• It can be stored in adipose tissue and other body compartments.
• Chemically, vitamin D belongs to a group of compounds known as secosteroids, because one of the rings of the steroid structure is broken.
• It can be obtained from dietary sources or synthesized in the skin.
• The biologically active form acts through the vitamin D receptor (VDR).
• Vitamin D plays a central role in maintaining calcium and phosphate balance.
• The major circulating indicator of vitamin D status is 25-hydroxyvitamin D [25(OH)D].

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Forms of Vitamin D

Vitamin D occurs mainly in two physiologically important forms:

1. Vitamin D₂ (Ergocalciferol)

Vitamin D₂ is derived primarily from:

• Fungi and yeast
• UV-irradiated mushrooms
• Fortified foods
• Some dietary supplements

It is produced when ultraviolet radiation acts upon ergosterol, a sterol present in fungi and yeast.

2. Vitamin D₃ (Cholecalciferol)

Vitamin D₃ is:

• Synthesized in human skin
• Present in certain animal-derived foods
• Found in fatty fish and fish liver oils
• Present in egg yolk and fortified foods

In human skin, vitamin D₃ is synthesized from 7-dehydrocholesterol following exposure to UVB radiation.

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Synthesis of Vitamin D in Skin

Vitamin D₃ synthesis begins in the epidermis.

The process occurs as follows:

7-Dehydrocholesterol

↓ UVB radiation

Previtamin D₃

↓ Thermal isomerization

Vitamin D₃ (Cholecalciferol)

The vitamin D₃ produced in the skin subsequently enters the circulation, where it is transported primarily by vitamin D-binding protein (DBP).

Vitamin D synthesis is influenced by several factors, including:

• Latitude
• Season
• Time of day
• Skin pigmentation
• Age
• Clothing
• Sunscreen use
• Duration of UVB exposure

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Activation of Vitamin D

Vitamin D obtained from sunlight or food is biologically inactive. It undergoes two major hydroxylation reactions before becoming fully active.

First Hydroxylation: Liver

Vitamin D is transported to the liver.

In the liver:

Vitamin D₂/D₃ → 25-hydroxyvitamin D [25(OH)D]

This reaction is mainly catalysed by the enzyme:

25-hydroxylase (CYP2R1)

The resulting compound is known as:

Calcidiol or Calcifediol

25(OH)D is:

• The major circulating form of vitamin D.
• The primary biomarker used for assessing vitamin D status.
• Relatively stable in circulation.

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Second Hydroxylation: Kidney

25-hydroxyvitamin D is transported to the kidneys.

There it undergoes another hydroxylation:

25(OH)D → 1,25-dihydroxyvitamin D

The reaction is catalysed by:

1α-Hydroxylase (CYP27B1)

The final product is:

Calcitriol

Calcitriol is the biologically active hormonal form of vitamin D.

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Regulation of Vitamin D Activation

The renal production of calcitriol is tightly regulated.

Important regulators include:

Parathyroid Hormone (PTH)

Low blood calcium stimulates PTH secretion.

PTH stimulates renal 1α-hydroxylase activity, thereby increasing calcitriol production.

Calcium

Low serum calcium indirectly promotes calcitriol synthesis through stimulation of PTH.

Phosphate

Low phosphate concentrations can stimulate vitamin D activation.

Fibroblast Growth Factor-23 (FGF23)

FGF23 suppresses renal 1α-hydroxylase activity and reduces calcitriol production.

Thus, vitamin D metabolism is closely integrated with calcium, phosphate, PTH and FGF23 regulation.

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Mechanism of Action

The active form, calcitriol, acts primarily through the:

Vitamin D Receptor (VDR)

VDR belongs to the nuclear receptor superfamily.

The sequence of action is:

Calcitriol

↓

Binds Vitamin D Receptor (VDR)

↓

VDR forms a complex with Retinoid X Receptor (RXR)

↓

Complex binds Vitamin D Response Elements (VDREs)

↓

Regulation of Gene Transcription

Through this mechanism, vitamin D regulates genes involved in:

• Calcium transport
• Phosphate homeostasis
• Bone metabolism
• Cell proliferation
• Cellular differentiation
• Immune regulation

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Major Functions of Vitamin D

1. Regulation of Calcium Absorption

Vitamin D increases intestinal absorption of calcium.

This is one of its most important physiological functions.

Calcitriol stimulates the synthesis of proteins involved in calcium transport across intestinal epithelial cells.

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2. Regulation of Phosphate Absorption

Vitamin D promotes intestinal absorption of phosphate.

Calcium and phosphate are essential minerals required for:

• Bone mineralization
• Teeth development
• Cellular metabolism

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3. Bone Mineralization

Vitamin D helps maintain adequate concentrations of calcium and phosphate necessary for proper mineralization of bone.

Normal vitamin D activity is essential for:

• Skeletal development
• Bone growth
• Bone remodeling
• Maintenance of bone strength

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4. Prevention of Rickets

Adequate vitamin D prevents defective mineralization of growing bones in children.

Deficiency may result in:

Rickets

Rickets is characterized by defective mineralization of growing bone and skeletal abnormalities.

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5. Prevention of Osteomalacia

In adults, severe vitamin D deficiency can result in:

Osteomalacia

Osteomalacia involves defective mineralization of bone matrix, resulting in soft and weakened bones.

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6. Regulation of Parathyroid Hormone

Vitamin D participates in the regulation of parathyroid hormone secretion.

The vitamin D endocrine system works together with:

• Parathyroid hormone
• Calcium
• Phosphate
• FGF23

to maintain mineral homeostasis.

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7. Muscle Function

Vitamin D is important for normal musculoskeletal function.

Vitamin D receptors and vitamin D-responsive pathways have been identified in various tissues, including skeletal muscle.

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8. Immunological Functions

Vitamin D and its receptor are involved in immune regulation.

Immune cells capable of expressing components of the vitamin D metabolic system include:

• Macrophages
• Dendritic cells
• T lymphocytes
• B lymphocytes

Vitamin D can influence immune cell differentiation and inflammatory responses.

However, associations between vitamin D status and various diseases should not automatically be interpreted as evidence that supplementation prevents all such diseases.

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Sources of Vitamin D

Natural Sources

Animal Sources

• Fatty fish
• Salmon
• Sardines
• Mackerel
• Fish liver oils
• Egg yolk
• Liver

Plant and Fungal Sources

• UV-exposed mushrooms
• Fortified plant-based foods

Fortified Foods

Vitamin D may be added to:

• Milk
• Dairy products
• Breakfast cereals
• Margarine
• Other fortified food products

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Major Source: Sunlight

For many individuals, cutaneous synthesis following UVB exposure is an important source of vitamin D₃.

The precursor molecule:

7-Dehydrocholesterol

present in the skin absorbs UVB radiation and initiates vitamin D₃ synthesis.

Vitamin D production varies considerably according to environmental and individual factors.

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Deficiency of Vitamin D

Vitamin D deficiency may occur due to:

• Limited exposure to sunlight
• Inadequate dietary intake
• Malabsorption disorders
• Liver disease
• Kidney dysfunction
• Increased requirements during growth
• Certain medications affecting vitamin D metabolism

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Manifestations of Vitamin D Deficiency

In Children

Rickets

Major features include:

• Defective bone mineralization
• Impaired skeletal development
• Abnormalities in growing bones

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In Adults

Osteomalacia

Vitamin D deficiency may cause:

• Defective bone mineralization
• Bone weakness
• Musculoskeletal symptoms

Long-term inadequate vitamin D status may also contribute to impaired skeletal health.

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Vitamin D Toxicity

Vitamin D is fat-soluble, and excessive intake of supplements can potentially result in toxicity.

The condition is known as:

Hypervitaminosis D

Excess vitamin D can cause excessive calcium absorption, leading to:

Hypercalcemia

Potential consequences may include abnormal calcium deposition in soft tissues and disturbances in normal physiological function.

Vitamin D toxicity is generally associated with excessive supplementation rather than ordinary dietary intake or physiological sunlight exposure.

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Important Forms of Vitamin D

Form	Chemical Name	Major Role
Vitamin D₂	Ergocalciferol	Dietary/fungal form
Vitamin D₃	Cholecalciferol	Skin synthesis and animal-derived form
25(OH)D	Calcidiol/Calcifediol	Major circulating form
1,25(OH)₂D	Calcitriol	Biologically active hormonal form

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Important Enzymes

Enzyme	Gene/Enzyme Name	Function
25-Hydroxylase	CYP2R1	Converts vitamin D to 25(OH)D
1α-Hydroxylase	CYP27B1	Converts 25(OH)D to calcitriol
24-Hydroxylase	CYP24A1	Involved in vitamin D catabolism

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Important Examination Points

One-Line Facts

• Vitamin D is a fat-soluble secosteroid.
• Vitamin D₃ is called cholecalciferol.
• Vitamin D₂ is called ergocalciferol.
• Vitamin D₃ is synthesized from 7-dehydrocholesterol.
• UVB radiation initiates vitamin D₃ synthesis in the skin.
• The major circulating form is 25-hydroxyvitamin D [25(OH)D].
• The active form is 1,25-dihydroxyvitamin D [calcitriol].
• The first hydroxylation occurs mainly in the liver.
• The second hydroxylation occurs principally in the kidney.
• CYP2R1 is an important 25-hydroxylase.
• CYP27B1 is the principal 1α-hydroxylase.
• Vitamin D acts through the vitamin D receptor (VDR).
• VDR belongs to the nuclear receptor superfamily.
• Vitamin D promotes intestinal absorption of calcium and phosphate.
• Deficiency causes rickets in children.
• Deficiency causes osteomalacia in adults.
• Excessive supplementation can cause hypervitaminosis D and hypercalcemia.

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Vitamin D Metabolism at a Glance

Skin

7-Dehydrocholesterol

↓ UVB

Previtamin D₃

↓

Vitamin D₃

↓

Liver

Vitamin D₃

↓ CYP2R1

25-Hydroxyvitamin D

[25(OH)D / Calcidiol]

↓

Kidney

25(OH)D

↓ CYP27B1

1,25-Dihydroxyvitamin D

[1,25(OH)₂D / Calcitriol]

↓

Target Tissues

Vitamin D Receptor (VDR)

↓

Regulation of Gene Expression

↓

Calcium and Phosphate Homeostasis

Bone Mineralization

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Academic References

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