Vitamin D

What It Is

Vitamin D is a fat-soluble vitamin that functions more like a steroid hormone than a classic vitamin. It exists in two main dietary forms:

Vitamin D3 (cholecalciferol) - from animal sources (fatty fish, fish oils, eggs, fortified milk) and made in the skin
Vitamin D2 (ergocalciferol) - from plant sources (plants, yeasts) exclusively

Metabolism (How It Is Activated)

The activation process requires two sequential hydroxylation steps:

Step 1 - Skin synthesis: Cholesterol → 7-dehydrocholesterol → Vitamin D3 (via UVB sunlight). This reaction requires UVB radiation and is reduced by:

High skin melanin content
Sunscreen with SPF 8 or higher
Living at higher latitudes (less sunlight)

Step 2 - Liver hydroxylation: D3 or D2 binds to vitamin D-binding protein (DBP) and is carried to the liver, where CYP27A1 (25-hydroxylase) converts it to 25(OH)D (calcidiol). This step is largely unregulated.

Step 3 - Kidney activation: Calcidiol is converted by CYP27B1 (1-alpha-hydroxylase) in the proximal tubule of the kidney to 1,25(OH)2D (calcitriol) - the biologically active form. Calcitriol is ~1,000x more active than calcidiol.

Degradation: CYP24A1 (24,25-hydroxylase) and CYP3A4 in the kidney inactivate calcitriol.

Medical Physiology, p. 1558-1560
Brenner and Rector's The Kidney, p. 2394

Mechanism of Action

Calcitriol (1,25(OH)2D) is a steroid hormone. Inside target cells:

It binds the Vitamin D Receptor (VDR) in the cytoplasm
The VDR-ligand complex translocates to the nucleus
It heterodimerizes with the Retinoid X Receptor (RXR)
The complex binds vitamin D response elements (VDRE) on target genes
Recruits coactivators/corepressors to modulate gene transcription

Physiological Actions

Target	Effect
Intestine	Stimulates transcellular Ca2+ absorption (via TRPV6 channels and calbindin) and phosphate absorption (via NaPi cotransporter)
Kidney	Promotes Ca2+ and phosphate reabsorption from renal tubules
Bone	At normal levels: promotes mineralization (raises Ca x PO4 ion product). At excess: promotes bone mobilization/resorption
Parathyroid gland	Suppresses PTH secretion (negative feedback)
Immune system	Modulates innate and adaptive immunity

The net result of normal vitamin D activity is a rise in both plasma calcium and phosphate, which drives bone mineralization.

Regulation

PTH increases renal 1-alpha-hydroxylase → more calcitriol production
Low phosphate also stimulates calcitriol synthesis
Calcitriol itself provides negative feedback by suppressing PTH and 1-alpha-hydroxylase
High calcium intake → suppresses PTH → less 1-hydroxylation → less calcitriol (reduces gut absorption over time)

Laboratory Testing

25(OH)D (calcidiol) is the standard serum test for vitamin D status (reflects body stores)
Reference ranges commonly used:
- Deficient: < 20 ng/mL
- Insufficient: 20-29 ng/mL
- Sufficient: ≥ 30 ng/mL

Deficiency

Causes:

Inadequate sun exposure (elderly, institutionalized, dark skin, high latitudes)
Poor dietary intake
Fat malabsorption (Crohn's, celiac, pancreatic insufficiency) - vitamin D is fat-soluble and needs bile salts
Chronic kidney disease (impaired 1-hydroxylation)
Liver disease (impaired 25-hydroxylation)

Effects in children: Rickets - unmineralized osteoid, bowed legs, abnormal bone rigidity

Effects in adults: Osteomalacia - increased unmineralized osteoid, bone pain, stress fractures, hypocalcemia

Consequences of chronic mild deficiency:

Secondary hyperparathyroidism (elevated PTH compensating for low Ca2+)
Worsening osteoporosis from persistent PTH-driven bone resorption
Hypocalcemia → nerve hypersensitivity → numbness, tingling, tetany
Medical Physiology, p. 1560

Toxicity (Excess)

Vitamin D toxicity causes hypercalcemia (excess bone mobilization + intestinal absorption). Symptoms include nausea, weakness, polyuria, nephrocalcinosis, and soft tissue calcification. This cannot occur from sun exposure alone (skin synthesis is self-limiting), only from excessive supplementation.

Recent Evidence (2024-2026)

A 2024 meta-analysis (PMID 39421966) found that vitamin D supplementation significantly reduces asthma exacerbations in children. Research on vitamin D's role in hair loss (androgenetic alopecia) and dermatological conditions continues to be investigated, though evidence remains mixed.

Sources: Medical Physiology (Boron & Boulpaep), Brenner and Rector's The Kidney

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