Vitamin D meets Hill’s causation criteria by helping prevent disease, decrease sepsis- and COVID-19-related deaths, as well as minimize infection-induced complications and hospitalizations. Supplementation or daily sun exposure are the least costly and most efficient means of improving population health.

This article will explore how diseases such as cancer alter the pathway from vitamin D to active 1,25(OH)2D metabolite 1,25(OH)2D. Furthermore, this piece will look at metabolic changes caused by these conditions.

Vitamin D Production

UV radiation from the sun is the main source of vitamin D for most people; however, too much exposure may result in skin damage. Our body’s ability to produce vitamin D in response to sunlight varies based on season, time of day, latitude and skin pigmentation – so production will differ accordingly. Ideal vitamin D production occurs in the outer layers of skin, where UVB absorption is highest. Once vitamin D enters the bloodstream, it travels bound to two proteins – DBP and albumin; very little circulating freely. Liver disease reduces production of DBP and albumin, thus decreasing overall vitamin D levels. Meanwhile, in kidneys the vitamin picks up oxygen and hydrogen molecules to form 1,25 dihydroxy vitamin D or 25(OH)D/calcitriol.

Vitamin D helps the body absorb calcium more easily through intestinal absorption, providing adequate amounts of it into its bloodstream to support bone health and promote overall well-being. Furthermore, this nutrient also has other biological effects which contribute to overall wellbeing.

Studies suggest that vitamin D can have protective effects against various conditions and diseases, including cancer, depression, multiple sclerosis (MS), type 2 diabetes, heart disease and low back pain. Unfortunately, not all studies have been rigorous enough to establish an exact link between vitamin D consumption and these outcomes.

Individuals who spend too much time indoors or use sunscreen with an SPF above 30 are at greater risk for inadequate vitamin D levels.

Limited Dietary Intake: Certain food sources of Vitamin D such as salmon, sardines and mackerel; fortified milk products; egg yolks and mushrooms are considered reliable sources.

Malabsorption Disorders: Conditions such as inflammatory bowel disease or surgical removal of parts of the GI tract reduce your body’s ability to absorb vitamin D consumed from food sources.

Vitamin D status can be assessed with serum 25(OH)D concentration measurements, which represent both endogenously produced vitamin D as well as that from food or supplements taken orally. It provides the most reliable indicator of vitamin D status.

Vitamin D Metabolism

As soon as vitamin D is produced in the skin, it must be processed through several steps to become active. The first of these processes is called hydroxylation and takes place in the liver via an enzyme known as CYP27A1. When added with analogs at its 24 position, vitamin D becomes active, with 25-dihydroxyvitamin D (1,25(OH)2D being the major bioactive form. Hydroxylation depends heavily upon skin pigment thickness (skin pigmentation), sunlight exposure levels, and individual genetic makeup; people with light skin produce more active vitamin D when exposed to sunlight than those with dark-colored skin (34).

Once inside a target cell, 1a,25-dihydroxyvitamin D binds to its receptor – the vitamin D receptor (VDR), then heterodimerizes with another nuclear receptor called the retinoid X receptor (RXR). This complex then binds specifically sequences of nucleotides containing vitamin D response elements (VDREs). VDREs have been identified in thousands of DNA sequences; binding by VDR/RXR complex triggers gene transcription.

1.25(OH)2D serves a variety of functions that regulate calcium homeostasis. These include increasing intestinal absorption of dietary calcium, increasing renal reabsorption of calcium filtered in urine and mobilizing bone calcium when diet-borne calcium sources become insufficient.

These actions are controlled by the VDR/RXR complex and its cofactors, including protein phosphatase 2A. Furthermore, this complex has an influence on gene expression that regulates calcium transport between intestine and kidney. An increased expression of sodium-phosphate transporter may indicate protein synthesis (234).

Colon cancer mortality follows closely behind that of rickets mortality rates, providing circumstantial evidence that decreased sunlight exposure and vitamin D nutritional status are associated with an increase in risk for colorectal cancer (95). Numerous observational studies involving both men and women have confirmed that those within the top quartile for serum 25-hydroxyvitamin D levels are at reduced risk of colon cancer. Results of multiple experimental trials on vitamin D supplementation have been inconsistent, leading some investigators to speculate as to whether increasing one’s consumption will actually lower cancer incidence or mortality (96). Researchers have proposed that high concentrations of 25(OH)D may have detrimental effects on cell functions rather than having direct actions on cancer cells (97), leading to much controversy regarding vitamin D’s role in cancer prevention.

Vitamin D Receptors

Vitamin D is a hormone, with its actions orchestrated according to tissue and cell type specific actions. Although best-known for regulating calcium homeostasis, vitamin D also plays an integral part in energy metabolism, immune regulation, cell growth and differentiation as well as inhibiting unrestrained cancer cell growth by restricting angiogenesis and increasing death of tumor cells by inducing apoptosis. In laboratory conditions it has even shown great promise at inhibiting unrestrained cancer cell growth while attenuating cancerous cell death by increasing death by inducing apoptosis.

Vitamin D acts as a hormone by binding to specific membrane receptors. It has long been established that calcitriol is converted to 1,25 dihydroxyvitamin D3 via conversion by the Vitamin D Receptor (VDR). VDR forms a heterodimer with Retinoid-X Receptor in order to enter nuclei and bind vitamin D responsive elements found in genomic DNA.

VDR-mediated gene expression can be controlled by multiple coregulator proteins, including vitamin D receptor interacting protein (DRIP) and members of the Steroid receptor coactivator family (SRC), both present in keratinocytes. Additionally, other protein complexes present across tissues bind directly to VDR’s LBD to either enhance or suppress its activity.

Many years ago it was discovered that picomolar concentrations of 25(OH)D3 could induce rapid non-genomic responses in chondrocytes at low doses, likely owing to its hydrophobic nature penetrating biological membranes and binding with proteins such as DBP. Subsequent research showed DBP binding to G-coupled receptor kinase DDR caused activation of intracellular phosphatase called calcineurin that is responsible for converting calcitriol into 1.25(OH)2D3.

Recent findings demonstrated the rapid non-genomic effects of vitamin D in bone cells and immune cells, suggesting its system had an expansive signalling profile that goes beyond musculoskeletal and immunological functions. Hypovitaminosis D among adults over 65 years old has been associated with increased dementia risk [47], as have more recently conducted studies which show its benefits against Alzheimer’s disease by reducing brain soluble and insoluble amyloid beta peptides; suggesting VDR as a possible neuroprotective agent.

Vitamin D Deficiency

Vitamin D is a fat-soluble vitamin produced naturally in response to sunlight by our bodies, as well as being present naturally in some food (egg yolks and fish) or supplements; however, most adults fail to meet their recommended daily intake from natural sources alone.

Vitamin D deficiency can lead to numerous health issues, with most evident impacts in the bones. Vitamin D plays a crucial role in bone health by increasing calcium absorption from digestion; without enough of it, your body cannot form new bones and absorb existing ones; symptoms of vitamin D deficiency include rickets in children and osteomalacia in adults.

vitamin D deficiency is common, particularly among people who do not spend much time outside. As we age, our skin’s ability to produce vitamin D in response to sunlight decreases, and melanin reduces how much vitamin D the skin synthesizes. People with certain medical conditions such as intestinal disorders that limit absorption of fat-soluble vitamins; kidney diseases that reduce conversion into its active form; or medications which inhibit renal enzyme activity may also be vulnerable.

People with darker skin tones are at increased risk for vitamin D deficiency due to melanin’s sun-blocking properties; their diets typically include fewer vitamin D-rich foods than diets of people with lighter skin tones; additionally, older adults’ kidneys are less efficient at converting vitamin D into its active form so those in their later years are prone to vitamin D deficiency.

Vitamin D deficiency can also result from too much time indoors without enough exposure to sunlight. Excessively high levels of vitamin D in the blood can be toxic, leading to nausea, confusion, pain, muscle weakness, excessive urination and thirst, kidney failure or death.