HPC › Nutrition › Glossary
Vitamin D is a fat-soluble prohormone synthesised in the skin under UVB radiation and activated by sequential hydroxylation in the liver and kidneys to calcitriol, the biologically active form. It governs calcium and phosphate homeostasis, supports immune defence, and modulates gene expression in neural tissue via nuclear vitamin D receptors distributed throughout the brain.
The principal clinical marker of status is 25-hydroxyvitamin D (25(OH)D), measured in serum to assess adequacy; the threshold most guidelines recognise as sufficient is 50 nmol/L.
How it works
UVB radiation converts 7-dehydrocholesterol in the dermis to pre-vitamin D3, which undergoes thermal isomerisation to cholecalciferol. The liver enzyme CYP2R1 hydroxylates cholecalciferol to 25-hydroxyvitamin D (25(OH)D), the principal circulating storage form and standard clinical marker of vitamin D status 1. Dietary sources, including oily fish, egg yolk, and fortified foods, contribute only modestly to circulating 25(OH)D; cutaneous synthesis under adequate sunlight is the primary source for the majority of people worldwide 1.
The kidneys convert 25(OH)D to calcitriol (1,25-dihydroxyvitamin D) via the enzyme CYP27B1. Calcitriol binds the nuclear vitamin D receptor (VDR), which heterodimerises with the retinoid X receptor to regulate hundreds of target genes governing calcium absorption, cell differentiation, and immune modulation 1.
VDRs are expressed throughout the brain, including in the hippocampus, prefrontal cortex, and cerebellum. Calcitriol upregulates neurotrophic factors such as nerve growth factor and attenuates neuroinflammatory signalling, providing plausible mechanisms for observed associations between vitamin D status and cognitive function 2. Mendelian randomisation analysis found that individuals with 25(OH)D levels at 25 nmol/L had a 54% higher predicted risk of dementia compared with those at 50 nmol/L, with an estimated 17% of dementia cases potentially preventable if the population reached 50 nmol/L 2.
Example
An otherwise healthy adult living at a high latitude, working indoors year-round, presents with a serum 25(OH)D of 28 nmol/L and a history of three upper respiratory infections in the preceding winter. Targeted supplementation raises 25(OH)D above 50 nmol/L within eight to twelve weeks. The following winter brings a single mild infection.
Benefit concentrates where status was genuinely low; supplementing an already-replete individual adds little by way of immune protection.
Why it matters
Vitamin D deficiency, defined as 25(OH)D below 50 nmol/L, is estimated to affect approximately 1 billion people globally 1. In children, sustained deficiency causes rickets; in adults, it produces osteomalacia. Subclinical insufficiency is widespread even in high-income countries, driven by indoor lifestyles and widespread sunscreen use. Supplementation in genuinely deficient individuals reliably corrects these skeletal conditions and may reduce the frequency and severity of upper respiratory tract infections 3.
The picture is more qualified for extraskeletal outcomes. Large randomised controlled trials find that supplementing adults whose 25(OH)D is already at or above 50 nmol/L produces no meaningful reduction in fractures, cancer incidence, or cardiovascular events 3 4. The cognitive link carries genuine causal weight from Mendelian randomisation data, but the trial evidence needed to confirm whether correcting deficiency prevents dementia remains forthcoming 2.
What is vitamin D deficiency and how common is it?+
Vitamin D deficiency is defined as a serum 25(OH)D concentration below 50 nmol/L. Globally, an estimated 1 billion people meet this threshold, including many in high-income countries where indoor work and sunscreen use limit sun exposure. In children, deficiency causes rickets; in adults, it produces osteomalacia and impairs immune function {{cite:10.1056/nejmra070553}}.
Does vitamin D supplementation prevent bone fractures and falls?+
Only in people with genuine deficiency. Large randomised trials find that supplementing adults whose 25(OH)D is already at or above 50 nmol/L does not meaningfully reduce fracture risk, falls, or bone mineral density loss {{cite:10.1016/s2213-8587(18)30265-1}} {{cite:10.1038/s41574-021-00593-z}}. Correcting true deficiency remains the clear clinical goal.
Can vitamin D status affect dementia and brain health?+
Mendelian randomisation data show that a 25(OH)D level of 25 nmol/L is associated with a 54% higher predicted risk of dementia compared with 50 nmol/L {{cite:10.1093/ajcn/nqac107}}. Vitamin D receptors are present in the hippocampus and prefrontal cortex, providing a biological basis for this link. Whether supplementation actively prevents cognitive decline has not yet been established in trials.
What are the main dietary and lifestyle sources of vitamin D?+
Cutaneous synthesis under UVB sunlight is the primary source of vitamin D for most people worldwide. Dietary contributions, from oily fish, egg yolk, and fortified milk or cereals, are typically modest {{cite:10.1056/nejmra070553}}. Those with limited sun exposure or malabsorption conditions face the highest risk of insufficiency, as diet alone rarely provides adequate amounts.
