What is Vitamin D (Vitamin D hydroxylated)?

Vitamin D Hydroxylated: Understanding the Forms and Functions

Vitamin D hydroxylated refers to the metabolically active forms of vitamin D that have undergone enzymatic hydroxylation in the body, primarily calcidiol [25(OH)D3] and calcitriol [1,25(OH)2D3], which function as steroid hormones rather than true vitamins. 1

Forms of Vitamin D

• Vitamin D is technically a misnomer as it's not a true vitamin but rather a steroid hormone that can be synthesized endogenously through ultraviolet exposure of the skin 1
• There are six different steroid hormones that go by the name "vitamin D" with varying degrees of activity 1:
  • Cholecalciferol (D3) - endogenous precursor derived from cholesterol
  • Calcidiol [25(OH)D3] - hydroxylated derivative with partial activity
  • Calcitriol [1,25(OH)2D3] - "active" dihydroxy form
  • Ergocalciferol (D2) - plant-derived form
  • 25-hydroxyvitamin D2 [25(OH)D2] - monohydroxy metabolite of D2
  • 1,25-dihydroxyvitamin D2 [1,25(OH)2D2] - dihydroxy metabolite of D2 1, 2

Metabolism and Activation

• Vitamin D undergoes a two-step sequential hydroxylation process to become biologically active 3:

  1. First hydroxylation: Occurs primarily in the liver where vitamin D is converted by 25-hydroxylase to 25-hydroxyvitamin D [25(OH)D] 1
  2. Second hydroxylation: Occurs primarily in the kidneys where 25(OH)D is converted by 1-alpha hydroxylase to 1,25-dihydroxyvitamin D [1,25(OH)2D] - the active form 1

• 25(OH)D (calcidiol) is the metabolite measured clinically to assess vitamin D status due to its longer half-life (2 weeks to 3 months) 1

• 1,25(OH)2D (calcitriol) is the biologically active form that binds to vitamin D receptors 2

Sources and Transport

• Sources of vitamin D include:

  • Endogenous synthesis through ultraviolet light exposure of 7-dehydrocholesterol in skin (carried in blood by vitamin D binding protein) 1
  • Dietary sources like fatty fish, fish liver oils, eggs (carried in blood by lipoproteins) 1, 4
  • Supplements (typically vitamin D2 or D3) 1

• As a fat-soluble hormone, vitamin D metabolites require special mechanisms for delivery in the aqueous bloodstream 1:

  • Endogenously synthesized forms are carried by vitamin D binding protein (DBP) 1
  • Dietary forms are carried within lipoprotein particles (about 35% of ingested vitamin D) 1

Clinical Significance

• Vitamin D hydroxylated forms are essential for:

  • Calcium and phosphorus homeostasis 3
  • Bone health and mineralization 5
  • Immune system function 5, 6

• 25(OH)D levels are used to diagnose clinical deficiency 1:

  • Deficiency: <20 ng/ml (<50 nmol/L) 1
  • Insufficiency: 20-30 ng/ml (50-75 nmol/L) 1

• Vitamin D deficiency can contribute to:

  • Bone diseases like osteoporosis 7
  • Potential increased risk of autoimmune diseases 1, 6
  • Possible cardiovascular implications 1

Important Clinical Considerations

• The Institute of Medicine suggests daily vitamin D intake of 600 IU for individuals 1-70 years and 800 IU for those over 71 years 1

• Safe upper limit is considered 4000 IU daily, above which toxicity risk increases 1

• Vitamin D supplementation should be approached with caution as:

  • Excess vitamin D can cause calcific vasculopathy in animal models 1
  • High-potency supplements are not recommended for children, pregnant women, or individuals with liver disease 5
  • The relationship between vitamin D levels and cardiovascular risk may be U-shaped rather than linear 1

• Local tissue activation of vitamin D occurs as 1-alpha hydroxylase is found in various tissues beyond the kidneys, including vascular cells and monocytes 1

Human vitamin D metabolism represents a complex system where the hydroxylated forms play crucial roles in numerous physiological processes, extending well beyond the traditional understanding of vitamin D's role in bone health.