Vitamin D deficiency pathophysiology

• The main sources of vitamin D are sunlight exposure, diet, and dietary supplements.^[1]
• The vitamin D synthesized in the skin is ergocalciferol or vitamin D3. The vitamin D which comes from plant sources is called D2 or cholecalciferol.
• Both cholecalciferol and ergocalciferol are inactive forms of vitamin D and sequentially activated in the liver and kidney to the active form of vitamin D, which exerts the biologic effects.
• Vitamin D refers to both cholecalciferol and ergocalciferol or vitamin D2 and vitamin D3.

Synthesis in the skin

• The synthesis of ergocalciferol (vitamin D3) occurs in the deeper layers of epidermis namely stratum spinosum and stratum basalis by the help of a chemical reaction involving UVB radiations (wavelength, 290 – 315 nm ) from sunlight.^[2]
• The UVB (wavelength, 290 – 315 nm ) radiations convert 7- dehydrocholesterol to pre-vitamin D3, which isomerizes to D3.
• The formation of vitamin D3 in the skin depends on sunlight exposure, the intensity of UVB and level of melanin pigment in the skin.
• The UVB intensity varies with season and latitude.
• The clothing and sun-screen also limit the exposure.
• Vitamin D synthesized in the skin and ingested from food is transported in the blood to the liver, while it is bound to vitamin D binding protein.

25 – Hydroxylation in the liver

• In the liver, vitamin D undergoes hydroxylation into 25 – hydroxyvitamin D3 with the help of one or more cytochrome P450 vitamin D hydroxylases.^[1]
• The common P 450 hydroxylases involved are CYP2R1, CYP2D11, and CYP2D25.
• The homozygous mutation of CYP2R1 gene was found in a patient with low circulating levels of 25 – hydroxyvitamin D3 with symptoms of vitamin D3 deficiency which suggests that CYP2R1 is the main enzyme involved in vitamin D hydroxylation in the liver.
• 25 – hydroxyvitamin D3 or calcifediol is the major circulating form of vitamin D and its serum level is used to assess the individual’s vitamin D status.
• After hydroxylation, 25 – hydroxyvitamin D3 is released into plasma where it is bound to the vitamin D binding protein and carried to the kidneys for activation.

1 Alpha hydroxylation in kidneys

• In the proximal renal tubule of the kidney, 25 – hydroxylated vitamin D undergoes further hydroxylation into 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) or calcitriol.^[3]
• The hydroxylation in the kidney is carried by 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene.
• This hydroxylation is under the influence of parathyroid hormone (PTH).
• 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) or calcitriol is the active form of vitamin D and responsible for most of the biologic actions of vitamin D.

Parathyroid hormone (PTH), Vitamin D and mineral homeostasis The effect of parathyroid hormone on mineral metabolism is as follows:^[4][5]

• Effect of parathyroid hormone on calcium metabolism:
  • Direct effect:
    • Increased resorption of bones.
    • Decreases excretion from kidney.
  • Indirect effect:
    • Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
    • Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
    • Both these direct and indirect mechanism results in an increased serum calcium concentration.
• Effect of parathyroid hormone on inorganic phosphate metabolism:
  • Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
• Effect of parathyroid hormone on magnesium concentration:
  • Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

Effect of minerals and vitamin D on parathyroid hormone:

• Decrease in serum calcium concentration stimulates parathyroid hormone.
• Calcium provides negative feedback on parathyroid hormone.
• Magnesium provides negative feedback on parathyroid hormone.
• Vitamin D decreases the concentration of parathyroid hormone.

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