D is a hormone and it is critical to our biology
It is conventional to refer to vitamin D as a vitamin, however this underplays its significance. The active metabolite of vitamin D is more akin to a hormone and has a ubiquitous role in our biology through modifying DNA expression in a cell-specific manner. Further, in contrast to other vitamins, we can’t get sufficient vitamin D from our diet, even with food fortification. Rather miraculously, we manufacture it using the radiant energy of the sun. Hence, vitamin D is not an essential nutrient and arguably not a vitamin either.
It’s thought that phytoplankton began synthesising vitamin D ~1 billion years ago, making it the oldest of hormones. Its early evolution may have been to protect critical molecules, such as DNA, from exposure to ultraviolet sunlight during photosynthesis. There are other theories.
The synthesis of vitamin D in the skin
In the animal kingdom, vitamin D synthesis is tied to the production of cholesterol (as are all of our steroid hormones). Our cells make cholesterol in a complex multi-threaded process taking about 30 steps to complete. In the second-last step of this process, dehydro-cholesterol (DHC) is formed, which would normally be converted to cholesterol in the last step. However, ultraviolet B (UVB) radiation (wavelength 290–315 nm) impinging on skin cells delivers sufficient energy to break one of DHC’s carbon bonds, forming pre-vitamin D. A process then gets underway, independent of further UVB radiation, that slowly converts pre-vitamin D to vitamin D. Vitamin D is not water-soluble, so vitamin D-binding proteins in skin blood capillaries pick it up and transport it away in the blood. This clearance from the skin allows the conversion of remaining pre-vitamin D to vitamin D to continue in skin cells. The complete conversion can continue for several days following a single UVB exposure.
However, vitamin D is biologically inactive (although it may still have certain roles, e.g. stabilising blood vessels) and it must undergo two further transformations to produce its active hormonal form. First, it is transported to the liver, where a hydroxyl group (a oxygen-hydrogen, OH, combination) is added. I will refer to this as (OH)D (although this is a simplification of conventional notation). This is the storage form — it is primarily stored in the liver or fat cells. It is still not biologically active. From the liver (OH)D is transported, primarily (but not solely) to the kidneys, where it undergoes a second hydroxylation that I will denote by (OH)2D. This is the active form, and it is now a steroid hormone. More strictly, a secosteroid (from the Latin verb secare meaning “to cut”, referring to the initial breaking of DHC’s carbon bond).
D can be categorised as a vitamin, (OH)D as a prohormone and (OH)2D as a hormone. Each has a chemical name — cholecalciferol, calcidiol and calcitriol respectively. One last complexity is that the vitamin D synthesised by animals (which includes us) is vitamin D3, whereas vitamin D from plants and fungi is vitamin D2 (ergocalciferol). I will use the abbreviation ‘D’ as a generic term.
Blood D levels
D blood tests measure the level of circulating (OH)D, which comes from liver stores and is an indicator of reserves and thus the capacity to synthesise the active hormonal form, (OH)2D. Vitamin D itself is not measured. A potential confound is that if there is some disease process or environmental toxin (such as glyphosate), that interferes with the conversion of (OH)D to (OH)2D, then D levels may seem normal by a blood test, while the hormonal form is deficient.
Recommendations vary, but usually a level of (OH)D greater than 50 to 75 nmol/L ( 20 to 30 ng/mL, imperial) is conservatively considered a marker of sufficiency. Many, if not most, of the western world are deficient or borderline when measured against this range. This is true even in sunny climates, where fear of skin cancer, sunscreen, hats, protective clothing, sun-avoidance behaviour and indoor air-conditioning keep their populations from the sun. Also to be factored in are natural skin pigmentation, latitude, altitude, socio-economic circumstances, age and obesity. Obesity is an issue because (OH)D is fat-soluble, and it is sequestered in fat cells from where it doesn’t seem to be retrievable. There are those who consider these levels too conservative, and suggest aiming for at least twice the range (100–150 nmol/L). There is probably no benefit above ~200 nmol/L, while 400 nmol/L is considered the safe upper limit, although it is an arbitrary limit and no harms have been associated with much higher levels than that.
Dosage for the fat-soluble vitamins (A, E, D and K) is usually given in a metric known as ‘International Units’ abbreviated IU. These IU were developed so that different forms of the vitamins (e.g. D2 and D3, K1 and K2 etc) would have around the same biological activity when measured by IU. It is common for D-supplements to be 1,000 IU, which translates to 25 micrograms (0.025 milligrams), so it is a tiny dose. While it is not settled, the current IU system assumes D2 is biologically-equivalent to D3. There are studies supporting this, while others show D3 is more biologically effective in animals than is D2 from plant sources. A daily dose of 4,000 IU is considered the safe upper limit, but the consequences of overdose, or even what constitutes overdose, are not certain. It seems that overdose is rare. Vitamin D3 from the skin is naturally regulated by various mechanisms.
D from the sun
In my locale (latitude ~30 degrees, sea level) 30 minutes of mid-late morning sun (clear summer skies, ~70% skin exposure and Fitzpatrick skin-type III typical of caucasians) can generate ~10,000 IU. Figures of 20,000 IU are not inconceivable with tweaking of some of these parameters. If repeated most days, this puts artificial supplementation doses in perspective.
Time of day needs to balance the intensity vs. availability of UVB. The UVB spectrum accounts for only ~5% of the total ultraviolet (UV) spectrum, the other 95% is UVA, which is not energetic enough to break the DHC bond and trigger the synthesis of vitamin D. There may be insufficient UVB in the early morning or late afternoon, when incoming radiation is weaker, and when UVB radiation passes more tangentially through the atmosphere with a greater chance of encountering ozone. Thus, while it may be pleasant to walk the dog early or late on a summer’s day, as a rule of thumb if your shadow is longer than your height, it is too early or late to synthesise significant D.
The discovery of vitamin D followed from an increase in childhood rickets (bone deformities) in polluted industrial cities where buildings blocked out the sun and air pollution blocked out even more. As a result, some foods are supplemented with D. However the dosage for a single serving is usually no more than 100 IU. This dose is not meant to restore healthy D levels in adults, but to be sufficient to avoid rickets and other bone disorders in children. Hence, for adults, reliance on food fortification for health is not likely to be sufficient, and supplementation may be necessary when sun exposure is not possible.
What does D do and how does it work?
Following its identification in the 1920s, D has been shown to increase intestinal absorption of calcium (and phosphorous), promote resorption of calcium by the kidneys, and inhibit parathyroid hormone (PTH) activity. PTH is released when blood calcium levels drop below a critical level and causes a compensatory release of calcium from bone stores, temporarily sacrificing bone density to maintain adequate circulating calcium (amongst other things, calcium is essential for muscles to contract and for nerve cells to conduct, both of which are more important than bone density). Thus D has important and multifactorial roles in maintaining body calcium and bone mineral density. Until as recently as the 1970s, the mechanism wasn’t known.
But then, the hormonal form of D was discovered, i.e. (OH)2D. Soon after, the vitamin D receptor (VDR) for hormonal D was identified, and it was realised that this receptor was in virtually all tissues of the body. This meant that hormonal D had the potential to widely regulate multiple biological systems.
The mechanism of action is much the same regardless of the cells involved. When (OH)2D binds to a VDR on a cell, a sequence of events are set off that up-regulate and/or down-regulate the expression of certain genes relevant to that cell’s function. The only differences in this mechanism across tissues and cells are the specific genes involved. Thus, D is a powerful epigenetic regulator that helps to maintain cellular identity and function across multiple tissues.
To give some insight into the ubiquity of D’s actions, the VDR has been identified in the following partial list of tissues and cells: kidney, bone, brain, virtually all cells of the immune system, pancreas, muscle, skin and hair follicles, small intestine and colon, prostate, ovary, uterus, and placenta. Clinically, D-deficiency has been associated with muscle weakness and pain, and hypertension. D seems to reduce the proliferation of some common cancers, including colon, breast and prostate and, perhaps ironically, melanoma. D-deficiency associates with some autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and a number of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. However, clinical associations do not guarantee causation, and reverse causation (the clinical condition causes D-levels to decline) may be operating. Even then, D stores might be being mined, but not replenished, to combat the disease.
D and the immune system
D is intimately involved with the immune system, not just as an adjunct to its function, but rather more mechanistically. For example, certain cells of the adaptive immune system (T-cells) are quiescent until needed (thereby minimising chronic inflammation). However, when they are needed, their transition to an active state requires hormonal D. Further, D can suppress certain T-cell subsets that are responsible for triggering a “cytokine storm” (an immune overreaction). Immune cells can convert (OH)D (the circulating form from liver stores) to hormonal (OH)2D, just like cells in the kidney (and some other tissues). It’s as though the immune system isn’t taking any chances with D. Overall, laboratory and clinical studies have demonstrated an association between D status and susceptibility to infectious bacterial and viral diseases.
D and COVID-19 (C19)
All of which suggests a deficiency in D may have implications for the severity of C19 symptoms arising from SARS-CoV-2 infection. There is ample associative evidence for a poorer outcome in hospitalised C19 patients who present with D deficiency. However, as is often the case, the evidence from randomised controlled trials (RCTs) is more mixed. These trials are often compromised in various ways, and in some cases seem designed to fail. For example, the first substantial RCT of D-supplementation recruited only 240 patients, administered a single massive 200,000 IU dose with uncertain physiological sequelae, and only about half the patients were D deficient in the first place. Furthermore, these RCTs are usually hospital-based and while convenient to run, don’t tell us if good D status for individuals in the community protects against C19 or severity, or whether supplementation earlier, e.g. at the time of diagnosis rather than hospitalisation, would help people with confirmed D deficiency.
D and vaccines
If D modulates the immune response to infection, then it could potentially boost the immune response to a vaccine and thus increasing the vaccine’s efficacy. There has been interest in this concept in the pre-C19 era, and D supplementation has been investigated for a variety of vaccines and clinical conditions including influenza, rubella, hepatitis B and tuberculosis. Again, there are conflicting results and limitations to many of these studies. Perhaps the strongest evidence is for hepatitis B in people with chronic kidney disease, given that hormonal D is mainly synthesised in the kidney.
The season in which a vaccine is administered may also be a consideration, given seasonal variations in D status. Vaccines that are administered seasonally, such as post-summer for influenza, may be a little more effective in this situation.
The Power of the Sun
It’s long been known that there is an association between population mortality (from cardiovascular disease, cancer and other causes) and sun exposure — more sun associates with reduced mortality and is thus beneficial. In these studies, D-levels are often used as an index of sun exposure, and for the reasons already outlined, D may indeed contribute to the favourable outcomes.
However, there is more to sunlight than D production. For example, nitric oxide (NO) forms in the skin under the more abundant UVA radiation. NO reduces arterial blood pressure and may confer some cardiovascular disease protection. Blood pressure in mild hypertensives is lower in summer and hypertension increases with latitude. These changes are independent of D, but still associate with it. As well, multiple signalling pathways in the skin and blood are activated by UV radiation, including epigenetic pathways. Hormonal D is photoprotective and reduces UVB induced DNA damage. Certain skin cells (keratinocytes) release β-endorphin when exposed to UV radiation, increasing feelings of wellbeing. Ultraviolet radiation is still radiation, and thus inherently anti-microbial.
Historically, sunlight and fresh air was a treatment for a range of ailments, including tuberculosis and influenza. Heliotherapy (Helios, the sun) was widely practiced in hospitals, solariums and sanatoriums in the early 1900s until it was overtaken by antibiotics.
This knowledge has not been completely lost. The image below was taken in 2020 — a Spanish hospital, known as the Hospital by the Sea, took to wheeling patients out of their wards into a more life-affirming setting as an adjunctive therapy. Even ignoring everything we’ve learned about sunlight and D, there must at least be a placebo effect from being in a natural environment compared to a hospital ward.
Sunburn (erythema) is the most obvious acute clinical effect, and the potential for skin cancers a chronic effect. However, chronic effects may also be beneficial as the skin adapts to sun exposure — for example, melanoma is less common in outdoor workers compared to indoor office workers. There are various explanations.
However, sun exposure should clearly be sensible and gradual. Sensible sun exposure includes wearing a hat and sunglasses — it is needless to expose the face and eyes. The dosage is a ‘U’ curve, with too little or too much sun detrimental, and a Goldilocks zone in the middle that is just right. It is possible that the present guidelines promoting sun avoidance are acting against public health. The global sun-avoidance market was worth ~USD 12 billion in 2018, and is forecast to reach twice that by the end of the current decade. Something to ponder.
The energy provided by sunlight enabled life to evolve on Earth — it’s as fundamental as that. Humans (and other land vertebrates) in their natural environments rely on the sun for skeletal health. It has now emerged this may also apply to immune health and even be a factor for all-cause mortality. However, what was once worshipped is now feared. Health organisations have mostly condemned sun exposure at virtually any level, without thought to the consequences, or even it seems evaluating the consequences, of their advice. This radical stance, lacking in nuance, is a conceivable public health hazard. Perhaps sacrificing health through sun-avoidance is our modern offering to the sun gods.