Is there a connection between Covid-19 and vitamin D?

HOT’s Chandra Masoliver asks a medical friend, Professor Edward Tuddenham, to explain what role vitamin D has in the Covid-19 pandemic, and if taking the vitamin might prevent us from getting the disease or reduce its worst effects? And if so why?

 

CM: I asked you about this in March last year just as the first lock down began, it’s taken you a long time to explain!

ET: I am a bad procrastinator at the best of times, but this delay has been exceptional even for me. Back in March there was a lot of debate about vitamin D and the new virus, with much speculation as to its role. I started to investigate and discovered that the experts only agreed on one thing, that more evidence was needed. So, I decided to follow Bertrand Russell’s advice to suspend judgement (1), whilst taking a daily dose of vitamin D and awaiting progress.

CM: What were the different views on vitamin D and Covid-19 back then?

ET: Most of us only know that vitamin D is necessary for healthy bones and preventing rickets, so linking it to an infection seemed tenuous. But several lines of evidence pointed to a role of vitamin D outside the historical association with bone health and disease. What came to be called rickets was first described by Glisson in 1650.Treatments that emerged from folklore and observation included sunlight and cod liver oil, both of which are beneficial, but the actual vitamin involved was not isolated until the 1920s. Confusingly the same symptoms – painful deformed bones – are caused by lack of calcium in diet, and often both deficiencies occur together. Vitamin D is unique amongst nutrients in its sources, being synthesized in our skin when exposed to bright sunlight. Rickets was effectively treated and prevented by giving supplements of cod liver oil, which happens to be rich in the vitamin, by fortifying food with the vitamin and by advocating exposure to sunlight.

By 1940 a disease that once affected almost all children in slums had become rare. As usual, once a problem appears to have been solved interest wains and research moves on to other topics. So it was with vitamin D, the sunshine vitamin. To say that it prevents rickets – giving it the name of anti-rachitic factor – says everything, but really says nothing about how it works and why.

CM: So how does it work and again why the connection to Covid-19?

ET: This is a tangled tale so before I start and before we lose any more readers, I want to emphasize that the connection between low vitamin D levels and susceptibility to respiratory tract viral infections, including Covid-19, has now been proved. The message coming from all parties, even those who were sceptical last year, is – take vitamin D daily. It has a clear role in immunity and resistance to infection and has been shown to reduce the severity of Covid-19 in people who are already infected. Even if you expect to get vaccinated soon you should take vitamin D, since you will respond better to the vaccine if you have normal vitamin D levels. Everyone has vitamin D deficiency in winter in the Northern latitudes unless they take supplements. There is no ultraviolet in the low weak sunlight and we are covered up and staying indoors. Take vitamin D daily. End of public health message.
[Editor’s note: The NHS website recommends that you should take 10 micrograms (400 IU) of vitamin D a day between October and early March to keep your bones and muscles healthy.]

The way vitamin D works on bone growth turns out to involve a complex interplay between a hormone made in tiny glands nestling in our necks on the surface of our thyroid glands, the parathyroid glands. They produce parathormone in response to the levels of calcium and phosphate in our blood. Sunlight falling on our skin breaks a single link in one of three benzene rings in 7-dehydroxycholesterol converting it to vitamin D3. There isn’t any vitamin D3 in our diet. No sunlight, no vitamin D3. So we depend on this mechanism to keep up levels of vitamin D in our blood.

Dark pigment in skin reduces the amount of vitamin D3 production. Natural selection has worked out the balance between our need for vitamin D3 production in Northern latitudes and the need to protect our skin against high ultra violet in sunlight in the tropics, by selecting for light skin tones near the pole and dark skin tones near the equator. Skin tone variation is purely an adaptation to these selective pressures.

The D3 is further converted to active vitamin by a chemical step in our livers, followed by another chemical step in our kidneys that finally produces the active form 1,25 dihydroxy D. This final step is tightly controlled by the said parathormone (positive effect), a growth factor called FGF23 and 1,25 dihydroxy D itself (negative effect). In engineering terms this is a way to achieve steady levels. Calcium and phosphate, building materials for bone, get into these feedback loops by suppressing the enzymes that carry out the conversion of D3 to the active form. Our knowledge about these processes has come from research carried out in the last 20 years which is still progressing with work on different forms of the vitamin for use in different diseases. The figure below condenses a lot of research in a diagram showing how the balance is maintained. It also shows that vitamin D influences the immune system.

CM: I don’t think you have yet explained what vitamin D actually does.

ET: Now this is where it gets really interesting, especially to me as a genetics researcher. vitamin D acts on genes by means of the vitamin D receptor (VDR). This is a kind of floating gene switch which is activated by binding to vitamin D. The complex then binds onto the starting point of different genes in different tissues. This binding then stimulates the gene into action, meaning that the gene starts to read out its message, sending to the little machines (ribosomes) that make proteins.

Proteins are the effector molecules in the cascade of effects that follow. There are thousands of binding sites for the VDR/vitamin D complex in different cells or tissues. For example in an osteoblast (the cell that builds bones) in the presence of the active vitamin there are 8,000 places where the complex binds to DNA. This is how the vitamin influences the way cells behave, with many pathways to achieve its effects. Conversely, we should expect that deficiency of the vitamin, as is common in winter in Britain, would have multiple adverse effects.

CM: Then could we expect to be able to treat a range of diseases with vitamin D, not just rickets? What are they?

ET: Given that VDR is present in most organs and tissues in the body, the list of conditions plausibly responsive to vitamin D is becoming a list of ‘the thousand natural shocks that flesh is heir to’ (Shakespeare, ‘Hamlet’) (2) I will just list a few here that have shown promise as targets. The inflammatory skin condition psoriasis responds to a vitamin D analogue. Metabolic syndrome, the association of weight gain with diabetes has shown response to vitamin D. Cell and animal studies suggest that some types of cancer respond to vitamin D. VDR is expressed in the heart and severe vitamin D deficiency has been associated with cardiomyopathy.

The immune system is influenced at many points by vitamin D, both in the adaptive and the innate systems. Adequate innate immunity requires normal levels of vitamin D. The initial response to viruses is via the innate immune pathway. Numerous association studies have linked low vitamin D levels to infections. However, until recently the direction of causation was unresolved. In other words does someone develop a low vitamin D level because they are ill or do they become ill because they have a low vitamin D level?

CM: Let’s address that question and the evidence that vitamin D is important in Covid-19 in the next article.

 

1. Bertrand Russell. “The scepticism that I advocate only amounts to this: (1) that when the experts are agreed, the opposite opinion cannot be held to be certain; (2) that when they are not agreed, no opinion can be regarded as certain by a non-expert; and (3) that when they all hold that no sufficient grounds for a positive opinion exist, the ordinary man would do well to suspend his judgement.” From the introduction to ‘Sceptical Essays.’ 1928

2. William Shakespeare ‘Hamlet’ Act III scene I. “The heart-ache and the thousand natural shocks that flesh is heir to.”

 

 

 

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