Vitamin D Synthesis: 5 Essential Steps & Associated Diseases
1. Skin: UVB-Induced Synthesis
- Process:
- 7-dehydrocholesterol (provitamin D3) in the skin absorbs UVB radiation (290-315 nm).
- It is converted to pre-vitamin D3, which then undergoes thermal isomerization to form cholecalciferol (Vitamin D3).
- Abnormalities/Diseases:
- Reduced sun exposure → Vitamin D deficiency.
- Sunscreen use, darker skin pigmentation, aging → Decreased synthesis.
- Rickets (children) & Osteomalacia (adults) due to deficiency.
2. Liver: 25-Hydroxylation
- Process:
- Cholecalciferol (Vitamin D3) is transported to the liver via Vitamin D-binding protein (DBP).
- 25-hydroxylase (CYP2R1, CYP27A1) in hepatocytes converts it to 25-hydroxyvitamin D (25(OH)D) (calcidiol), the major circulating form.
- Abnormalities/Diseases:
- Liver diseases (cirrhosis, fatty liver, hepatitis) → Impaired 25-hydroxylation → Low 25(OH)D levels.
- CYP2R1 mutations → Vitamin D-dependent rickets type 1B.
3. Kidney: 1α-Hydroxylation (Activation)
- Process:
- 25(OH)D is converted to active 1,25-dihydroxyvitamin D (1,25(OH)₂D) (calcitriol) by 1α-hydroxylase (CYP27B1) in the proximal renal tubules.
- This step is stimulated by PTH (parathyroid hormone) and inhibited by FGF23 & high phosphate levels.
- Abnormalities/Diseases:
- Chronic kidney disease (CKD) → Reduced 1α-hydroxylation → Low calcitriol → Renal osteodystrophy.
- Vitamin D-dependent rickets type 1A (CYP27B1 mutation).
- FGF23 excess (e.g., tumor-induced osteomalacia) → Inhibits activation.
4. Target Organs: Biological Effects
- Process:
- Calcitriol binds to Vitamin D Receptor (VDR) in target cells, mainly in the intestine, bone, kidney, and parathyroid glands.
- Increases calcium & phosphate absorption in intestines.
- Stimulates bone mineralization by increasing osteoblast activity.
- Regulates PTH secretion for calcium homeostasis.
- Abnormalities/Diseases:
- Vitamin D receptor mutation (VDR gene mutation) → Vitamin D-dependent rickets type 2.
- Hypocalcemia, secondary hyperparathyroidism due to resistance.
- Osteoporosis & fractures due to chronic deficiency.
5. Degradation & Regulation
- Process:
- 24-hydroxylase (CYP24A1) inactivates calcitriol to 24,25(OH)₂D for excretion.
- High FGF23 & high phosphate levels enhance degradation.
- Abnormalities/Diseases:
- CYP24A1 mutations → Increased active Vitamin D → Hypercalcemia, nephrocalcinosis.
- Vitamin D toxicity due to excessive intake.
Summary of Key Diseases
