Griffin et al. recently made a cogent case for increasing the SACN (Specialist Advisory Committee on Nutrition) recommended daily intakes of vitamin D₃ for the adult UK population, as used by other official UK advisory bodies, from the long- standing 400 IU/day to 800–1000 IU/day in order to reduce vitamin D deficiency rates and related health risks, possibly including Covid-19 severity. [1] Rickets and potentially fatal infantile hypocalcaemic fits and cardiomyopathy have been reported regularly in infants and young children amongst the south Asian diaspora arriving in the UK from the mid-20th Century. [2,3] Similarly, osteomalacia due to vitamin D deficiency (VDD) has been seen, especially in south Asian women covering their faces and arms as many amongst these British communities still do for cultural and religious reasons.[4]. Furthermore, the well-known increases in non-skeletal health problems in those groups, including type 2 diabetes, obesity, cardiovascular disease and early mortality, are all consistently reported as associating inversely with vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] concentrations). [5,6] Similarly, Covid-19 illness severity (hospital admission, need for intensive care and mortality) associates inversely with current and pre-existing vitamin D status (VitDS) generally and is recognised to be more severe in dark-skinned Britons. [7,8] However, these well-known inverse associations are commonly taken to reflect ‘reverse causation’,[9] and to mean that there is no contributory role of vitamin D deficiency (VitDD) in the causality of such disorders despite the observational associations, an assumption that this commentary challenges.

VDD recognition in UK immigrant groups, initially south Asians, coincided with 25(OH)D assay development from the mid-20th century. [2,10] Mechanistic effects of the active hormonal metabolite, 1,25-dihydroxyvitamin D (Calcitriol) eventually provided an understanding of how vitamin D promotes bone health decades after the medical profession finally accepted that rickets was prevented and cured by both sunlight and cod-liver-oil, leading to the discovery of vitamins D₂ and D₃ in the 1920s. [2,11,12] Rickets was virtually abolished in the UK after the ‘great depression’ of the 1930s, from early in world war II (1941/2) by provision of cod-liver-oil amongst the 5 welfare foods for pregnant and nursing mothers and 1–5-year-old children (with extra milk, meat and eggs, each adding some vitamin D). Free cod- liver oil was then provided in antenatal clinics until its withdrawal in 1994 due to demonstrable teratogenicity of an excessive vitamin A content (since corrected), but with no provision of alternative sources of vitamin D. This unfortunate situation allowed rickets to return, most commonly in dark-skinned Britons, (currently grouped as ‘Black, south Asian and Mixed Ethic minorities’ [BAME ]), along with the frequently fatal problems of infantile hypocalcaemic fits and cardiomyopathy. [2,13]

It is well known that renal vitamin D activation forms hormonal calcitriol, essential for bone health through well understood mechanisms. However, this is as much as most people, including most health professionals, usually know about the effects of vitamin D. [14] Continuing research, however, has established that vitamin D is also necessary for normal function in most tissues, and has elucidated many mechanisms involved that are induced through the identical activation of 25(OH)D to form calcitriol that is now known to take place within target tissues, though differently regulated. [15] Vitamin D signalling pathways modulating different intracellular effects of vitamin D are increasingly well understood, and ‘triggered’ through 3 basic mechanisms. 1) Rapid non-genomic effects following calcitriol-binding to cell membrane caveolar vitamin D receptors (VDRs) that raise intracellular ionised calcium (e.g., increasing islet beta cell insulin release). [16,17] 2) Slower genomic effects, mostly following the binding of ligand-bound-VDR:RXR complexes to nuclear VDR- response elements in the promoter regions of ~3000 human genes (e.g., increasing insulin secretion) [18,19] and 3), various types of epigenetic effect including many relevant to early life development and dependent on maternal vitamin D status, (e.g increasing pre-adipocyte differentiation, likely reducing adult obesity).[20] Other examples of known non-skeletal mechanistic effects of vitamin D include; reducing hepatic synthesis of triglycerides and hepatic glucose output and promotion   of improved skeletal muscle function (together reducing insulin resistance); suppressing renin secretion (lowering blood pressure in the young and reducing tissue damage due to excessive free radical production]; increasing innate immune responses (by raising antimicrobial defensin[s] and cathelicidin secretion); preventing excessive acquired immune responses important in infections and in inflammatory disorder, including atheromatous arterial wall disease (by suppressing pro-inflammatory and stimulating anti-inflammatory-cytokine secretion and by suppressing the MMP2/9 secretion that aggravates plaque disruption); suppressing pro-carcinogenic processes (e.g increasing cell differentiation); promoting ACE2 receptor production in the lungs that is protective against ARDS (acute respiratory distress syndrome) a major risk in severe Covid-19 illness.[21–29]

Serum 25(OH)D concentrations (Vitamin D status [VitDS]) are reduced by obesity, partly through dilution into enlarged fat stores but also due to reduced activity/production of the specific hepatic 25-hydroxylase. Serum 25(OH)D levels are also reduced in diabetes due to increased production of the 24-hydroxylase enzyme catabolic for both 25(OH)D and calcitriol and of the FGF23 (fibroblast growth factor 23) that reduces intracellular calcitriol production by suppressing the activating 1α-hydroxylase. Severe illness also lowers serum 25(OH)D values by reducing hepatic 25-hydroxylase activity.[30,31]

Investigators carrying out vitamin D supplementation trials have generally assumed that their ‘failure’ confirms that the consistent associations of health outcomes with vitamin D status, often strongly supported by prospective data, are due to reverse causation. As a result, many investigators take it that the adverse effects of inadequate VitDS suggested by observational associations, and by mechanistic effects, must be without clinical significance. However, all target tissues relevant to health produce intracellular calcitriol in amounts relating directly to circulating 25(OH)D concentrations (the substrate for intracellular vitamin D activation).[1] ‘Reverse confounding’, therefore, will aggravate tissue disorders associated with low VitDS since reductions in VitDS (circulating 25(OH)D concentrations) must, necessarily, reduce autocrine and paracrine tissue effects dependent on locally produced calcitriol, whatever the mechanisms involved.

Failures of RCTs to confirm causality for many known mechanistic effects of vitamin D have often reflected unavoidable delays in the application of knowledge of vitamin D’s biological effects to RCT design and analysis but the many ‘negative trial results have led to the wide- spread view that such results confirm the irrelevance of vitamin D status to human ill-health, as discussed above. However, such inferences can now be challenged for several reasons. Firstly, there are variations in serum 25(OH)D thresholds for different effects of vitamin D and, while it has long been assumed that health-effects will simply reflect supplemental dosages, in fact they depend on adequate correction of VDD for the condition of interest.[32,33] This is because association of effects with VDD is S-shaped rather than linear.[34] thus, no benefits are seen with supplementation in deficiency unless 25(OH)D values rise into the steep part of the S-shaped associations of effects/outcomes with VitDS and reach the threshold value needed for induction of the desired outcome (e.g., a serum 25(OH)D of 50 nmol/l for bone but 80–100 nmol/l for lowering insulin resistance).[35,36] Additionally, few health benefits can be expected with supplementation in vitamin D repletion where effects already lie along the upper plateaus of their S-shaped associational relationships. With increasing appreciation of the implications of these facts, RCT re-analyses are increasingly reporting health benefits expected from adequate correction of VitDS. In the D2d study, for example, no T2DM risk reductions were found initially with supplementation at up to 4000 IU/day in pre-diabetes, but reanalysis by achieved VitDS revealed that those maintaining intra-trial serum 25(OH)D values of ≥100 nmol/l, (requiring daily intakes of 4000 IU/day) had up to 70% reductions in T2DM incidence.[37,38] Similarly, re-analysis of 25 earlier randomised controlled trials (RCTs) with variable results for upper respiratory tract infection (URTI) reductions, revealed significant risk reductions in those with baseline deficiency with daily supplementation but not with interval dosing.[39]

The information just discussed suggests that 25(OH) D reductions induced by disorders like obesity and diabetes create vicious circles aggravating health risks are likely to require higher vitamin D intakes for VDD correction. Support for this view is provided by the finding that correcting VDD requires higher vitamin D supplemental intakes in overweight and obese people than in the non-obese (by x1.5 and x2–3-fold respectively) and by the DD2d data reanalysis, showing that T2DM risk reduction would be impossible on current UK or US intake recommendations. Thus, for example, unless the UK acts to promote adequate vitamin D intakes and abolish deficiency, high T2DM prevalence rates will continue to be aggravated by deficiency.

Furthermore, since obesity increases T2DM risk, even higher intakes than 4000 IU/day may be needed for reduction in T2DM incidence rates in obese pre- diabetics. BAME Britons are known to need higher intakes than pale-skinned Britons as vitamin D synthesis is reduced by increased skin pigmentation and modest clothing and will be increased by their raised rates of both obesity and T2DM. Together these several problems must    worsen VDD, aggravating associated health risks, likely including those for Covid-19 severity which are already known to be increased by obesity, T2DM and BAME ethnicity.[41–43]

VDD is a suggested risk factor for Covid-19 severity because it reduces protective immune responses to infection and reduces lung protection in ARDS, as mentioned above, Covid-19 illness is also associated with reduced D status at presentation. Covid-19 has, therefore, been treated with vitamin D, often with large bolus doses, with some possible benefits.[44–48] However, bolus- dosing rapidly upregulates effects protective against VitD toxicity, increasing 24-hydroxylase activity (catabolic for 25(OH)D and calcitriol) and increasing production of FGF-23, (known to inactivate the vitamin D activating 1a-hydroxylase) for at least 3 months. Thus, bolus-dose treatment failures are understandable as are their adverse effects +on bone and muscle health (increasing risks of falls and failing to prevent rickets).[49–51] Covid-19 survivors treated with bolus doses may, therefore, be at risk of aggravation of ‘long-COVID’ by those adverse effects.[52]

If vitamin D deficiency is a risk factor for Covid-19, then pre-infection repletion should be protective, as is suggested by reductions in infection rates in subjects with increasingly higher serum 25(OH)D values over the year pre-infection in a large American cohort study and in UK biobank subjects ‘habitually’ taking vitamin D (but not other supplements) vs, no supplements]. [53,54] Reduced Covid-19 severity is reported with 25(OH)D (calcifediol) treatment of hospitalised patients and notably, slow-release oral 25(OH)D treatment does not increase catabolic 24-hydroxylase activity. A larger Spanish study of calcifediol usage also suggests beneficial effects with reductions in transfers to intensive care and in mortality rates.[55,56]

Unfortunately, the large and still evolving body of knowledge about the non-skeletal effects of vitamin D must be unfamiliar to many health professionals since UK VDD is being allowed to persist at such high rates (20–40%, as defined for bone health by a serum 25(OH)D <25 nmol/l); those high rates themselves demonstrating the lack of efficacy of the long-standing UK intake recommendations (at 400 IU/day), made without the provision of higher intakes for BAME and other high-risk groups (including the elderly, care home residents, shift workers and the obese).[57]

Current rates of deficiency are clearly undesirable, even if only as defined for bone health and UK mortality rates from Covid-19 have been amongst the highest reported world-wide.[58] Furthermore, the groups hardest hit by Covid-19 coincide with those recognised as at ‘high-risk’ for vitamin D deficiency, warranting urgent programmes to correct D deficiency generally, but most especially in groups currently in double-jeopardy for these risks.[59] Though increased vitamin D deficiency rates in dark- skinned immigrant groups have been widely known and discussed they were often attributed to persisting cultural factors and non-assimilation of UK ways of life over the last 50 years,[2,60] explaining why no effective measures were set up to increase their vitamin D intakes. Margarine was fortified by statute when the south Asian diaspora reached the UK, but only to match butter content at 1.25 µg/100 grams.[13] This woeful situation has been described, historically, as reflecting that “diet frequently became a proxy or shorthand for culture (and religion, and race), while disease justified pressure to assimilate”.[2] and remains uncorrected despite some local efforts and the ‘Sure Start’ scheme that hoped to reach all pregnant women from 2000, though supplements had to be claimed (often difficult for women not fluent in English), and often poorly taken up [13,61] while VDD rates in infants and children remain unacceptably high and admissions for hypocalcaemic emergencies have increased in recent years, mainly in babies of black and south Asian extraction.[62]

Many authors, and the Lawrence enquiry, have concluded that increased Covid-19 severity and mortality rates in BAME Britons reflects ‘racial discrimination,’ causing increased poverty, overcrowding, and other reductions in socio-economic status.[63,64] While it is undeniable that multiple socio-economic and health risk factors contribute to increased Covid-19 risks, vitamin D status was not considered in those reports. [63] When vitamin D status was included in a UK- Biobank data analysis large numbers of subjects untested for Covid-19 were used as negative controls for covid-19 positivity, adjustment was made for more factors than the data could support, and adjustments were made for factors specifically reducing 25(OH)D values (ethnicity, obesity and diabetes, see above) and, though baseline VitD deficiency 5 to 10 years pre-pandemic did predict increased Covid-19 risks, this variable was, unsurprisingly, eliminated by adjustment for the last 3 factors.[65,66,67]

NICE advises treating adult vitamin D deficiency (a serum 25(OH)D <25nmol/l) as follows “Choose the most appropriate treatment regimen. For the treatment of vitamin D deficiency, the recommended treatment is based on fixed loading doses of vitamin D (up to a total of about 300,000 international units [IU]) given either as weekly or daily split doses, followed by lifelong maintenance treatment of about 800 IU a day” NICE also states that “Several treatment regimens are available, including 50,000 IU once a week for 6 weeks (300,000 IU in total), 20,000 IU twice a week for 7 weeks (280,000 IU in total), or 4000 IU daily for 10 weeks (280,000 IU in total)”.[68] Thus, current UK intake recommendations, at 400 IU/day all year round, cannot be expected to correct the 40% overall UK deficiency rates or the increased deficiency rates seen in south Asian and Black Britons,[69] and the provision of 4 months supply of vitamin D at 400 IU/day to vulnerable groups in the UK from early 2021 is unlikely to reduce current VDD rates significantly.

Advice on short-term self-supplementation through the current pandemic at 1000–2000 IU/day for younger and older adults respectively, but at 2000–4000 IU/day in the first 2 weeks in high-risk groups would, however, be within UK safe intake levels.[70] It could also prove a useful adjunct for Covid-19 risk reduction by raising 25(OH)D values towards the 50–75 nmol/l recently reported as being the most protective against respiratory tract infections.[71] However, a long-term programme is also needed to abolish UK vitamin D deficiency, ideally through food fortification, perhaps of flours plus high- risk group supplementation, as already suggested,[72] (together with efficacy audits) as already achieved in Finland.[73,74] Such a programme would correct a long- standing failure of public health advice and correct the long-standing racial disparities in vitamin D status that can be regarded as discriminatory, and, additionally would have the potential to reduce the severity of future viral pandemics.

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