Vitamin D: Shining a light on health and disease
Vitamin D has become something of a ‘super’ vitamin in recent years but what is it and how does it work?
To start with, calling vitamin D a vitamin is a bit of a misnomer; it’s actually a fat-soluble pro-hormone that is primarily produced in the skin in response to ultraviolet-B (UVB) light; hence the nickname, the ‘sunshine vitamin’.
Where does vitamin D come from?
Vitamin D3 is the form we make in our skin, and this is the main natural source of vitamin D. Vitamin D can also be derived from a limited number of dietary sources; vitamin D2 from plant sources such as wild mushrooms, as well as from fortified foods, and vitamin D3 from animal sources such as oily fish, liver and egg yolks. However, even with the best diet, it is difficult to get enough vitamin D solely from food.
Vitamin D (either as vitamin D2 or vitamin D3) is not biologically active and must be metabolized in the body to generate ‘active vitamin D3’. I’ve included a description below of this process for those of you who are interested. For simplicity, I refer to biologically active vitamin D3 as VitD in this article.
To understand antibody detection, we first need to understand the components of the virus that may be recognized by the immune system. Like all coronaviruses, and in fact most other viruses, SARS-CoV-2 has four main structural proteins: the spike (S), nucleocapsid (N), membrane (M) and envelope (E) proteins.
Lack of vitamin D is a global issue
Vitamin D deficiency/insufficiency in adults is very common and it is viewed as a global public health problem¹. Indeed, 35%–67% of all adults in Ireland are deficient in vitamin D and this increases to 93% in dark-skinned Irish BAME communities².
The reasons for this are several fold³:
- Reduced exposure to sunlight, particularly in winter
- Air pollution
- Darker skin tones
Note: Sunscreen is often included in this list; however, whether sunscreen use actually contributes to vitamin D deficiency is heavily debated. Given that the benefits of using sunscreen to reduce the risk of skin cancer far outweigh any possible reduction in vitamin D production, particularly given that vitamin D supplements are readily available, it is not recommended to stop using sunscreen to ‘boost’ your vitamin D levels.
Symptoms of vitamin D deficiency
The most common symptoms of vitamin D insufficiency in adults are:
- Bone pain
- Muscle weakness, muscle aches or muscle cramps
- Mood changes
Prolonged or severe vitamin D deficiency can have serious consequences in both children and adults.
¹Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem?. J Steroid Biochem Mol Biol. 2014;144 Pt A:138-145. doi:10.1016/j.jsbmb.2013.11.003
Vitamin D and the musculoskeletal system
The ‘classical’ function of vitamin D (the function you would have been taught in school) is to facilitate the efficient absorption of calcium, as well as phosphate and magnesium, from food in the intestine. It also has other roles in bone formation and maintenance, as well as in normal muscle function and regeneration.
Vitamin D deficiency in children can result in the bone condition rickets, while in adults it is associated with osteomalacia. With the advent of vitamin D supplementation, such as with cod liver oil or fortified foods, rickets was virtually unheard of in industrialized nations in the mid-1900s. Concerningly, the incidence of rickets is on the rise, most likely due to a combination of vitamin D deficiency, and insufficient calcium intake (particularly in developing countries where lack of sun exposure is less of an issue), as well as reduced levels of exercise, which has an important physiological role in bone compaction and muscle strengthening.
Vitamin D deficiency/insufficiency is also associated with osteoporosis, osteoarthritis and muscle weakening in older age.
So, the message is clear, vitamin D and calcium are good for your bones.
Nothing new there!
‘Non-classical’ functions of vitamin D
The reason vitamin D has hit the headlines of late is due to its links with other diseases, some of which might surprise you, including COVID-19.
Over the past 20 years or so, a body of scientific research has shown important roles for VitD in immune function. In fact, several types of immune cells express an enzyme that is involved in the activation of VitD as well as the receptor that it binds to, thereby allowing immune cells to both activate and response directly to VitD.
Vitamin D and the immune system
VitD has predominantly an anti-inflammatory role in the body. Activation of an immune response is essential to protect us from foreign invaders, but turning off that immune response when the threat has been dealt with is equally important.
VitD acts on several different types of immune cells to help shut down an inflammatory response . Macrophages and dendritic cells are part of the innate (nonspecific) immune response that acts as a first line of defence. These cells also convey messages to cells of the adaptive immune system (B and T cells) to inform them of the type of threat they’re facing.
VitD blocks macrophages from producing pro-inflammatory cytokines (molecules that pass between immune cells to instruct the type of immune response that is needed). It also stops dendritic cells from presenting antigens to adaptive immune cells (this is how immune cells identify and communication what the target is).
VitD also directly acts on B and T cells. It reduces the production of antibodies by B cells and switches T cells that produce pro-inflammatory cytokines (called Th1 cells) to those that produce the anti-inflammatory cytokine IL-10 (called regulatory T cells).
Given that VitD has numerous ways of shutting down an inflammatory response, it is not that surprising that vitamin D deficiency has been associated with a higher incidence of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, diabetes, lupus and Crohn disease¹. Vitamin D deficiency has also been associated with other diseases such as certain cancers, cardiovascular disease², dementia³ and even depression³.
Several factors influence the development of these diseases, including genetics, diet, environmental factors and age, but common among them all is the presence of chronic, often low grade, inflammation.
So, without the brake on the inflammatory response that VitD provides, inflammation may persist in the body and may contribute to the development of numerous disorders over time. However, more research is needed to prove a causal link between vitamin D deficiency and chronic inflammation in these disorders.
¹Yang CY, Leung PS, Adamopoulos IE, Gershwin ME. The implication of vitamin D and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):217-226.
²Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol. 2016 Jul;13(7):404-17.
³Hazazi A. Low Vitamin D and Its Association with Cognitive Impairment and Dementia. J Aging Res. 2020 Apr 30;2020:6097820.
³Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. 2014;6(4):1501-1518.
Vitamin D deficiency has also been associated with increased rates of infection, including influenza, tuberculosis and viral upper respiratory tract illness. This might seem counterintuitive, given its role in suppressing inflammation. But the immune system is complex and has numerous lines of defence. VitD promotes the production of molecules called antimicrobial peptides, in particular one called cathelicidin. Cathelicidin perforates the cell membrane of pathogens, thereby killing them…think of small bullets that punch holes in the enemy’s armour.
Vitamin D has recently hit the headlines again with a link between vitamin D deficiency/insufficiency and higher COVID-19 severity and mortality . So, how might that work? As mentioned above, vitamin D serves as a brake on the immune system and given that much of COVID-19 severity and mortality is due to the inflammatory response getting out of hand, it is possible that reduced levels of vitamin D in patients is behind this (at least in part). But this is still conjecture and more scientific research is needed!
That being said, a very recent study has provided evidence to support the above idea. The study showed that a molecule produced during an inflammatory response induces a feedback loop involving VitD that shuts down inflammatory T cells and that this control mechanism is disrupted in T cells from the lungs of patients with severe COVID-19 .
This is actually a pretty cool study (or maybe I’m just an immunology geek) as it describes a mechanism of self-regulation that involves an inflammatory molecule acting on an inflammatory immune cell (Th1 cell) to shut that cell down by directly activating and responding to VitD.
Treatments with vitamin D
Given all the evidence linking low vitamin D levels with numerous diseases, it seems logical that vitamin D could be used to treated these diseases. However, in most but not all disease settings, the evidence to date from clinical trials giving vitamin D as a treatment for that disease is less than convincing.
There are many reasons why this might be, such as the dose, form of vitamin D given and/or route of administration. Or it might simply be a case of trying to close the barn door after the horse has bolted. Perhaps what is needed is to maintain adequate levels of vitamin D from birth until death to help reduce the risk of chronic diseases, particularly in later life.
Indeed, recently published results from The Vitamin D and Omega 3 trial (VITAL), which is a US-based randomized double-blind placebo-controlled clinical trail following over 25,000 individuals aged 50 years and older, showed that vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced the incidence of autoimmune disease by 22%.
I’m generally very skeptical of the whole ‘supplements’ industry, as in most cases there is very little scientific evidence for their benefit. However, given the difficulties in getting enough vitamin D from diet, the lack of sunlight during winter and the need to protect our skin against sunburn in summer, vitamin D is one of the few cases where taking a supplement could have a real impact on health, particularly in later life.
It is, however, important to ensure that you take the right dose, as taking too much vitamin D over a prolonged period of time can result in vitamin D toxicity. So, talk to your doctor or pharmacist if you have low vitamin D levels and need a supplement.
Production of active vitamin D3
The production of active vitamin D3 (1,25(OH)2D3) involves a series of steps that take place in different organs. First, UVB radiation converts 7-dehydrocholesterol to pre-vitamin D3 in the upper layers of the skin and then heat converts this to inactive vitamin D3 (cholecalciferol) in the lower skin layers. From there, cholecalciferol travels through the blood to fat tissues for storage or to the liver, where it is catalyzed to 25(OH)D3 (25-hydroxycholecalciferol). This is also where dietary forms of vitamin D2 or vitamin D3, which are absorbed through the intestines, are converted to 25(OH)D3. This is the major circulating form of vitamin D in the body and is what is measured in a vitamin D test. From there, 25(OH)D3 is converted to 1,25(OH)2D3 (1,25-dihydroxycholecalciferol) primarily in the kidneys. But, as mentioned in this article, this conversion step can also be mediated by immune cells throughout the body.