Vitamin D and COVID-19 - A Systems Approach
As the earth spins on its axis moving around the sun, with spring on the doorstep, the days are lengthening, the weather is warming, bulbs are emerging from the ground. Similar to the solar system, the human body is a system, a set of interconnected parts working together. In the infinitely complex landscape of the body, there are many potential points of intersection between vitamin D and COVID-19. Understanding the links requires careful knowledge of the vitamin D story. Once the story is known, the intersection with COVID-19 becomes clear. An epic tale from environment to cell, traversing the skin, gut, liver, kidney, brain, bone and muscles.
When the sun’s warmth and ultraviolet B rays contact the skin, 7-dehydrocholesterol is converted to previtamin D and vitamin D, in turn (fig1). A similar process occurs in humans, other animals and fungi. Therefore, as well as making vitamin D ourselves, we can obtain it from eating animals and mushrooms exposed to light. Plot twist, vitamin D is not biologically active, it has no downstream effect. Running the gauntlet towards activation, vitamin D hails a ride with vitamin D binding protein (DBP) from the skin to the liver, paying the fare with magnesium. In the liver, conversion to 25-hydroxyvitamin D is aided and abetted by enzymes, 25-hydroxylase, CYP2R1 and CYP27A1, in a magnesium dependent reaction. The quest continues with DBP transporting 25-hydroxyvitamin D from the liver to the kidney where, within the mitochondria, it is catalysed by 1-alpha-hydroxylase and CYP27B1 to 1,25-dihydroxyvitamin, a biologically active molecule. Victory!
Act two, the superpower is revealed. Elevated from taxi driver to chauffeur, DBP transports 1,25(OH)2 D to multiple target cells. In the inner sanctum of the cell, the nucleus, joined by vitamin D receptor, retinoid X receptor and vitamin D response element, aided by zinc, 1,25(OH)2 D unlocks the treasure, gene transcription (fig 2). It turns out that 1,25(OH)2 D regulates three percent of the human genome (Bouillon et al., 2008), affecting calcium regulation, phosphorous regulation, hormone homeostasis, erythropoiesis and protein expression of enzymes, receptors, extracellular matrix proteins, antimicrobial peptides, immunoglobulins, growth factors, cytokines, growth adhesion molecules and tumour suppressor genes, an awe inspiring array of effects.
Enter COVID-19. Increased mortality associated with co-morbidities, obesity, hypertension and Black, Asian and minority ethnic (BAME) community have been widely reported. From the story of vitamin D, we can start to see the linkages. Vitamin D attenuates the co-morbidities. Obesity correlates with insulin resistance. Vitamin D upregulates insulin hormone and insulin receptor expression. Vitamin D regulates the renin angiotensin aldosterone system, reducing blood pressure via fluid regulation. Melanin pigmentation in the skin reduces the absorption of UVB, therefore people of colour have lower levels of vitamin D with reduced protective effects.
On a cellular level, the SARS-CoV-2 virus binds to the angiotensin converting enzyme 2 (ACE2) receptor, upregulating production of ACE2. ACE2 converts angiotensin-1 to angiotensin-2 which activates pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant and vasoconstriction pathways, leading to tissue injury. Counteracting the effect of ACE2, 1,25(OH)2 D downregulates the expression of angiotensin-2, reducing tissue injury. Downregulating proinflammatory cytokine expression is a further effect of 1,25(OH)2 D, reducing the injury impact of the cytokine storm.
Combined, high prevalence of vitamin D deficiency (Chapuy et al., 1997) and a multiplicity of research correlating vitamin D deficiency with greater COVID-19 morbidity and mortality make the case for vitamin D supplementation. Scotland has been ahead of the curve, starting over fifteen years ago the government has recommended a vitamin D supplement for school age children (Scottish Government 2006). Driven by recent research, the UK Government has advised that vitamin D be taken by everyone age 4 years and over during the winter months. Rationale for the maintenance dose, 10 mcg (400 IU) per day, is that this is the average amount needed by 97.5% of the population to maintain a 25(OH)D serum concentration of 25 nmol/L when UVB sunshine is minimal (NICE 2020). Hurdles and pitfalls in vitamin D activation, namely feedback loops, genetic modification, nutrient insufficiency and tissue damage, present a strong argument to aim for the top half of the reference range, typically 24 to 167 nmol/L (10 to 67 ng/ml), namely > 90 nmol/L, titrating up the dose until the desired serum level is achieved. Our story ends walking into the sunset with a takeaway message that raising vitamin D status is an easy win in the response to COVID-19 and for improving health in general.
Bouillon R, et al. Vitamin D and health: perspectives from mice and man. Journal of Bone and Mineral Research, 2008;23(7):doi 10.1359/JBMR.080420
Chapuy MC, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporosis International, 1997;7:439-443
NICE. COVID-19 rapid guideline: vitamin D. 2020; https://www.nice.org.uk/guidance/ng187
Scottish Government. Nutritional Guidance for Early Years: food choices for children aged 1-5 years in early education and childcare settings. 2006;
Figure 1 source: https://lpi.oregonstate.edu/book/export/html/159
Figure 2 source: https://lpi.oregonstate.edu/book/export/html/159
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