Vitamin D

Vitamin D is an essential fat-soluble nutrient that plays a vital role in maintaining bone health, immune regulation, and numerous metabolic processes in the human body. Often referred to as the “sunshine vitamin”, it is unique among vitamins because it can be synthesised endogenously when the skin is exposed to sunlight, specifically ultraviolet B (UVB) radiation. Its significance extends beyond skeletal functions, encompassing roles in cardiovascular health, cellular growth, neuromuscular function, and disease prevention. This article provides a comprehensive 360° overview of vitamin D, covering its discovery, chemistry, metabolism, physiological functions, sources, deficiency implications, recommended intake, toxicity, and recent research trends.

Historical Background

The recognition of vitamin D’s importance arose from studies of rickets, a childhood bone deformity prevalent during the industrial revolution in northern Europe. In the early 20th century, scientists discovered that exposure to sunlight or cod-liver oil could prevent rickets. In 1922, Elmer McCollum isolated the substance responsible and named it vitamin D — the fourth vitamin identified after A, B, and C. The discovery revolutionised nutritional science and public health, leading to fortification of foods and the eradication of rickets in most developed nations.

Chemical Structure and Forms

Vitamin D refers to a group of related secosteroids (steroid molecules with a broken ring structure). The two major biologically relevant forms are:

• Vitamin D₂ (ergocalciferol): Derived from ergosterol in plants and fungi upon exposure to ultraviolet light.
• Vitamin D₃ (cholecalciferol): Formed in the skin of humans and animals from 7-dehydrocholesterol when exposed to UVB radiation.

Both forms are biologically inactive precursors (provitamins) that must undergo hydroxylation in the liver and kidneys to form the physiologically active compound, 1,25-dihydroxyvitamin D (calcitriol).

Biosynthesis and Metabolism

The metabolism of vitamin D involves a complex series of transformations and regulatory mechanisms:

1. Cutaneous Synthesis:
   • When skin is exposed to sunlight, UVB photons convert 7-dehydrocholesterol to previtamin D₃, which spontaneously isomerises to cholecalciferol (vitamin D₃).
   • Factors affecting synthesis include latitude, season, time of day, skin pigmentation, age, clothing, and sunscreen use.
2. Liver Hydroxylation:
   • Cholecalciferol (D₃) and ergocalciferol (D₂) are transported to the liver, where they are hydroxylated by the enzyme 25-hydroxylase (CYP2R1) to form 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. This is the main circulating form and the best indicator of vitamin D status.
3. Kidney Activation:
   • In the kidneys, 1α-hydroxylase (CYP27B1) converts calcidiol into 1,25-dihydroxyvitamin D [1,25(OH)₂D] (calcitriol), the active hormonal form.
   • This process is tightly regulated by parathyroid hormone (PTH), calcium, and phosphate levels.
4. Degradation:
   • The enzyme 24-hydroxylase (CYP24A1) inactivates calcitriol, maintaining homeostasis.

Physiological Functions

1. Calcium and Phosphate Homeostasis

Vitamin D’s most established function is maintaining serum calcium and phosphate levels necessary for bone mineralisation. Calcitriol enhances intestinal absorption of calcium and phosphate and works synergistically with PTH to mobilise calcium from bone when needed.

2. Bone Formation and Remodelling

Vitamin D stimulates osteoblast differentiation and promotes mineral deposition. Deficiency leads to defective bone mineralisation, resulting in rickets in children and osteomalacia in adults. It also helps prevent osteoporosis by improving bone density and reducing fracture risk.

3. Immune System Regulation

Calcitriol influences innate and adaptive immunity. It enhances antimicrobial peptide production (such as cathelicidin), modulates T-cell responses, and helps suppress excessive inflammation. Adequate vitamin D levels are linked with lower susceptibility to respiratory infections and autoimmune disorders.

4. Cell Growth and Differentiation

Vitamin D has antiproliferative and pro-differentiation effects on various cell types. These properties contribute to potential roles in cancer prevention, particularly against colorectal, breast, and prostate cancers.

5. Neuromuscular and Cardiovascular Health

Vitamin D receptors (VDR) are found in muscle and cardiac tissues, influencing muscle strength, coordination, and possibly blood pressure regulation through the renin-angiotensin system.

Dietary Sources and Fortification

Although sunlight exposure provides most of the body’s vitamin D, dietary intake is important, particularly in regions with limited sun exposure.
Natural Sources:

• Fatty fish (salmon, mackerel, sardines, tuna)
• Cod liver oil
• Egg yolks
• Beef liver
• Butter

Fortified Foods:

• Milk and dairy products
• Margarine and plant-based milks
• Breakfast cereals
• Orange juice
• Infant formulas

Supplements: Both D₂ and D₃ supplements are available, though D₃ is considered more effective in raising and maintaining blood 25(OH)D levels.

Deficiency and Associated Disorders

Vitamin D deficiency is widespread, affecting populations globally due to lifestyle, environmental, and dietary factors.

Causes of Deficiency

• Limited sunlight exposure (urban living, indoor lifestyle, northern latitudes)
• Darker skin pigmentation (melanin reduces UV absorption)
• Ageing (reduced cutaneous synthesis capacity)
• Malabsorption syndromes (coeliac disease, Crohn’s disease)
• Liver or kidney disorders (impaired hydroxylation)
• Obesity (vitamin D sequestered in adipose tissue)

Health Consequences

• Rickets: Soft, deformed bones in children leading to bowed legs and skeletal deformities.
• Osteomalacia: In adults, defective mineralisation causing bone pain and muscle weakness.
• Osteoporosis: Long-term insufficiency contributing to reduced bone mass and increased fracture risk.
• Increased infection risk: Particularly respiratory tract infections due to weakened immune function.
• Autoimmune disorders: Associations with multiple sclerosis, type 1 diabetes, and rheumatoid arthritis.
• Cardiovascular and metabolic diseases: Observational studies suggest correlations with hypertension, diabetes, and metabolic syndrome.

Recommended Intakes

Recommended daily intakes vary by age, sex, and exposure to sunlight. In the absence of sufficient sun exposure, the following intakes are generally advised:

• Infants (0–12 months): 400 IU (10 µg)
• Children and adults (1–70 years): 600 IU (15 µg)
• Older adults (>70 years): 800 IU (20 µg)
• Pregnant and lactating women: 600 IU (15 µg)

The optimal serum 25(OH)D concentration for health is considered to be above 50 nmol/L (20 ng/mL), though some experts recommend maintaining levels between 75–125 nmol/L for broader benefits.

Toxicity and Overdose

While deficiency is far more common, excessive intake of vitamin D can lead to toxicity, primarily through supplementation rather than sun exposure (the body self-regulates synthesis).
Symptoms of Toxicity:

• Hypercalcaemia (elevated calcium levels)
• Nausea, vomiting, dehydration
• Muscle weakness, confusion
• Calcification of soft tissues and kidneys (nephrocalcinosis)
• Kidney stones and renal impairment

Toxic effects generally occur when blood 25(OH)D concentrations exceed 375 nmol/L (150 ng/mL). The tolerable upper intake level (UL) for adults is around 4000 IU (100 µg) per day.

Interactions and Factors Influencing Absorption

• Fat Intake: As a fat-soluble vitamin, absorption improves when taken with dietary fat.
• Medications: Corticosteroids, anticonvulsants, and some cholesterol-lowering drugs can reduce vitamin D activity or absorption.
• Health Conditions: Gastrointestinal disorders affecting fat absorption reduce vitamin D uptake.

Emerging Research and Non-Skeletal Roles

Recent studies continue to reveal new roles for vitamin D in various physiological processes:

• Cancer Prevention: Observational studies indicate inverse relationships between vitamin D levels and risk of certain cancers, although clinical evidence remains inconclusive.
• Mental Health: Deficiency has been linked with depression, seasonal affective disorder, and cognitive decline.
• COVID-19 and Immunity: During the pandemic, research explored vitamin D’s potential to reduce infection severity, but results remain mixed.
• Diabetes and Obesity: Vitamin D may influence insulin secretion and sensitivity, suggesting a potential role in metabolic regulation.
• Autoimmune Regulation: It may suppress pro-inflammatory cytokines and modulate immune tolerance, contributing to lower autoimmune activity.

Public Health and Fortification Strategies

In many countries, food fortification and supplementation campaigns have been implemented to combat widespread deficiency. Public health strategies include:

• Fortifying staple foods like milk, flour, and oils.
• Encouraging moderate sun exposure while balancing skin cancer risk.
• Promoting supplementation in at-risk groups such as infants, elderly individuals, pregnant women, and those with limited sunlight exposure.

Vitamin D stands as a cornerstone of human health, extending its influence far beyond skeletal maintenance. As both a nutrient and a hormone, it orchestrates calcium metabolism, immune function, and cellular processes critical to life.