Vitamin D deficiency pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

Pathophysiology

Synthesis and Metabolism

• The main sources of vitamin D are sunlight exposure, diet, and dietary supplements.
• 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.
• 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.
• 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.
• 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:

• 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.

The Sequence of Events in Parathyroid, Vitamin D, and Mineral Homeostasis

Parathyroid hormone

Kidney

Bone

Decreased excretion of magnesium

Increasead conversion of inactive 25-hydroyx vitamin D to the active 1,25-dihydroy xvitamin D

Increase excretion of inorganic phosphate

Decrease excretion of calcium

Increased resorption of bone

Increased serum concentration of magnesium

Increased absorption of calcium from gut

Decreased serum concentration of inorganic phosphate

Prevents precipitation of calcium phosphate in bones

Increased serum concentration of calcium