Vitamin D

Overview

• Vitamin D is a fat-soluble secosteroid hormone primarily existing as vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol).
• It's synthesized in the skin after ultraviolet-B (UV-B) exposure or obtained from diet and supplements.
• Its main role is maintaining calcium and phosphorus homeostasis, supporting bone mineralization and skeletal health.

Benefits

• Bone health: Enhanced calcium absorption and reduced risk of osteomalacia, rickets, and fractures, especially in older adults.
• Immune modulation: Lowered incidence of acute respiratory infections and modest reduction in autoimmune disease activity (e.g., multiple sclerosis, type 1 diabetes) in meta-analyses.
• Metabolic function: Improved insulin sensitivity and lower risk of type 2 diabetes progression in observational cohorts; supplementation improves insulin secretion in some vitamin D-deficient patients.
• Musculoskeletal performance: Modest gains in muscle strength and reduced falls in the elderly.
• Cognitive and mood effects: Observational data link higher vitamin D levels with better executive function and lower depressive symptom scores, though causality remains under investigation.

How It Works

• Vitamin D is first hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol).
• A second hydroxylation in the kidney (or activated immune cells) generates 1,25-dihydroxyvitamin D (calcitriol), the biologically active form.
• Calcitriol binds the intracellular vitamin D receptor (VDR), a nuclear receptor that heterodimerizes with retinoid X receptor (RXR) and binds vitamin-D response elements (VDREs) in DNA.
• This regulates transcription of >200 genes involved in calcium transport (e.g., TRPV6, calbindin), immune regulation (e.g., cathelicidin, IL-10), and cell-cycle control (e.g., p21, p27).
• In the intestine, VDR-mediated up-regulation of calcium-binding proteins enhances calcium and phosphate absorption.
• In immune cells, VDR activation modulates innate and adaptive responses, contributing to the observed anti-inflammatory and antimicrobial effects.

Dosage

• General adult recommendations (Institute of Medicine/Health Canada) are 600–800 IU/day (15–20 µg) for maintenance.
• Many clinicians target 1,000–2,000 IU/day (25–50 µg) for most adults to achieve serum 25-OH-D ≥ 30 ng/mL.
• For deficiency correction, 2,000–4,000 IU/day (50–100 µg) for 8–12 weeks is common, followed by a maintenance dose.
• Vitamin D₃ is preferred due to superior serum rise.
• Timing: Absorption improves with a fatty meal; split dosing (morning vs evening) does not change efficacy.
• Special cases:
  • Elderly or limited sun exposure: 2,000 IU/day often recommended.
  • Obesity (BMI > 30 kg/m²): May require 1.5–2× higher dose.
  • Pregnancy/lactation: 600–800 IU/day plus additional 400 IU if deficient.
• Always personalize based on baseline serum level and physician guidance.

Safety & Side Effects

• Vitamin D toxicity is rare and usually linked to chronic intake > 10,000 IU/day, leading to hypercalcemia, nephrolithiasis, and vascular calcification.
• Common adverse effects at high doses include nausea, polyuria, and muscle weakness.
• Contraindications:
  • Hypercalcemia or hyperparathyroidism
  • Granulomatous diseases (e.g., sarcoidosis) where extra-renal conversion can cause excess calcitriol
  • Renal failure (impaired 1-α-hydroxylation)
• Notable drug interactions: Thiazide diuretics (increase hypercalcemia risk), glucocorticoids (reduce vitamin D metabolism), anticonvulsants (induce hepatic catabolism), and cholesterol-lowering agents that affect absorption.
• Routine monitoring of serum calcium and 25-OH-D is advised when > 4,000 IU/day is used, especially in children, pregnant women, and patients on interacting medications.

Chemistry

• Vitamin D₃ (cholecalciferol) has the molecular formula C₂₇H₄₄O, molar mass 384.64 g·mol⁻¹.
• Its IUPAC name is (3S,5Z,7E)-9,10-secocholesta-5,7,10-trien-3-ol.
• Vitamin D₂ (ergocalciferol) is C₂₈H₄₄O, differing by a double bond in the side chain (C22–C23).
• Both are secosteroids, derived from a sterol scaffold where the B-ring is broken (“seco”), producing a triene system (C5–C7–C10) and a hydroxyl group at C3 essential for VDR binding.
• They are lipophilic (log P ≈ 6–7), require fat for intestinal absorption, and are stable to heat but degrade under UV-C, requiring opaque, airtight packaging.

Sources & Quality

• Natural vitamin D is produced in human skin from 7-dehydrocholesterol upon UV-B exposure.
• Dietary sources include fatty fish (salmon, mackerel), cod liver oil, egg yolk, and fortified foods (milk, cereal).
• Commercially, vitamin D₃ is most commonly extracted from lanolin (sheep wool) or produced via synthetic pathways from 7-dehydrocholesterol derived from plant sterols.
• Vitamin D₂ is produced by UV-irradiating ergosterol from yeast or fungi.
• High-quality supplements use pharmaceutical-grade cholecalciferol with ≥ 98% purity, verified by HPLC.
• Quality considerations include: absence of heavy-metal contaminants, validated potency (± 5% of label), and stability (protected from light and oxygen).
• Third-party testing (e.g., USP, NSF) ensures compliance with label claims and safety standards.