Interest in vitamin D has grown exponentially particularly during the Covid-19 pandemic and also due to the increasing number of papers exploring the potential for extra-skeletal health benefits such as chronic disease delay or prevention. This mini-update and commentary reviews the latest developments in vitamin D relevant to the Irish context. 

What is vitamin D?

Vitamin D is made through the action of ultra-violet B (UVB) sunlight on the skin, where it is then transported to the liver for hydroxylation to form 25-hydroxyvitamin D (25(OH)D) – this is the inactive form but is the biomarker measured in the laboratory.¹ Further hydroxylation occurs in the kidneys, creating the biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]2D) which acts on cells and tissues via the vitamin D receptor.¹

In Ireland, vitamin D production is almost negligible from Halloween to St Patrick’s day each year due to changes in the angle of the sun and the decreased availability of UVB light.² However, even during the summer it can be difficult to make enough vitamin D due to cloud cover, lack of sunshine and rainy conditions. Typically 10-15 minutes of sunshine during the summer is enough to make sufficient vitamin D for each day and application of sun cream is recommended thereafter. However, other factors can influence how much can be made including age, obesity, clothing, pollution, skin tone and genetics.¹

Vitamin D can also be obtained from dietary sources (see Table 1) though unfortunately the foods that are high in vitamin D are typically not often consumed. Currently in Ireland, there is no official Government vitamin D food fortification policy. What we do have is a policy of a voluntary, but very liberal fortification of foods. However, these fortified foods make a significant contribution to dietary intakes and fortification now occurs in certain cereals, milk and dairy products, bread, mushrooms and more recently flour. 

Recommended intakes for adults for vitamin D are 10µg daily and for older adults it is 15µg for those who are generally healthy and living independently, and 20µg for those who are housebound with limited or no sunlight exposure.²

What does vitamin D do?

The primary accepted role of vitamin D is in relation to bone health in adults and in reducing the risk of rickets in children. When blood calcium concentrations are low, parathyroid hormone (PTH) secretion is stimulated and this increases the production of 1,25(OH)2D in the kidney, which interacts with the vitamin D receptor in intestinal cells to increase uptake of calcium into cells and the absorption of calcium in the intestine to maintain optimal physiological range.¹

With low or deficient vitamin D, there is an increased leaching of calcium from the bones to maintain adequate levels. Continuous bone turnover and resorption weakens the architecture of bones and can increase fracture risk via secondary hyperparathyroidism, ultimately leading to the development of osteomalacia and osteoporosis.

How is vitamin D measured and what are the definitions?

Vitamin D status is routinely assessed through the blood measurement of 25(OH)D, the universally recognised biomarker of choice. A fasting sample is not necessary and measurement is not adversely affected by freezing or thawing. The accepted gold standard in the laboratory is liquid chromatography-tandem mass spectrometry. Other methods can be used (such as immunoassay), though they have the potential to over-or underestimate concentrations depending on the method used. 

There is significant disagreement about what constitutes a ‘normal’ vitamin D concentration. Different thresholds have been suggested for different medical conditions or different population sub-groups. Given that robust scientific evidence for impact of vitamin D on extra-skeletal functions is still lacking, the majority of public health bodies worldwide have issued dietary and treatment guidelines based solely on the effects on bone health. 

In 2011 the Institute of Medicine (IOM), a joint US/Canada body, published target values (deficiency < 30.0nmol/L; insufficiency 30-50nmol/L and sufficiency > 50nmol/L).³ The UK SACN committee currently uses target values (deficiency < 30.0nmol/L; insufficiency 30-50nmol/L and sufficiency > 50nmol/L).⁴

What is known on current deficiency rates?

Important risk factors for deficiency include geographic location, season, age, sunscreen use, pollution, skin pigmentation, time spent outdoors, clothing and body mass index.¹ Physiological factors that can influence vitamin D levels include malabsorption syndromes (Coeliac, Crohn’s) and genetic differences in the way vitamin D is processed. Low vitamin D can be a particular issue for older adults as their ability to synthesise vitamin D is reduced and they can experience age-related changes such as increased food malabsorption and dietary patterns characterised by decreased food quality, quantity, and variety.¹

The most recent data on deficiency rates are presented in Table 2. In a nationally representative population study (The Irish Longitudinal Study on Ageing, TILDA) it was observed that 13.1% of older Irish adults were deficient.⁵ Deficiency status was more prevalent in non-vitamin D supplement users, in winter, in smokers, in obese adults, the physically inactive, those living alone and in the oldest old (> 80 years). 

Across seasons, the Leinster province had both the lowest prevalence of deficiency and insufficiency. A higher proportion of deficiency (26.4%) was observed in the English Longitudinal Study of Ageing.⁶ Being female, over 80 years, smoking, of non-white ethnicity, being obese and of poor self-reported health were all more likely to be deficient. Notably, those living in the comparatively wealthier south of England had a reduced risk of deficiency. In a large study of adults in the community and in outpatient clinics in the West of Ireland, 17% were deficient, with nursing home residents having the worst levels of low status.⁷

In terms of vitamin D status in large urban area, two studies investigated trends of deficiency in Dublin city and the surrounding area.^8,9 The most socially/economically deprived areas of Dublin had the highest rates of deficiency in addition to those who were male. A full breakdown of deficiency by age of the latest geomapping Dublin study is given in Figure 1 (see overleaf).⁹ Interestingly, the youngest age group (18-39 yrs) had the highest prevalence of deficiency (21%) and insufficiency (26%). This prevalence was only matched by those in the very oldest age group (> 90+ yrs). 

In fact, there was a ‘U’ shaped relationship, with the best vitamin D status in those aged 60-69 years, and then progressively declining when moving towards both the younger and older ends of the age spectrum.⁹ It has been suggested that perhaps these were a less healthier cohort as they were all attending a GP, however it has become more or less standard for vitamin D to be tested as a normal practice check-up. 

Deficiency has also been examined for the first time in an Irish ethnic minority group¹⁰ where from laboratory records, 186 participants from the Irish South-East Asian population were identified and investigated. In total, 66.7% of the sample were deficient while 93.3% were insufficient with males having lower status than females. Of concern, the traditional seasonality of vitamin D cycling was absent with low vitamin D levels evident in both winter and summer. This population group is known to be at a higher risk for cardiovascular disease/diabetes and an association with chronically low vitamin D levels has been speculated.¹¹

Finally, a large meta-analysis of European studies demonstrated that deficiency rates across the EU was 13%, with sunnier countries displaying similar deficient levels to higher latitude countries.¹² One exception is Finland, where a recent food fortification programme has resulted in < 1% of the population being vitamin D deficient¹³ which is in comparison to rates of 13-26% in Ireland and the UK. 

Vitamin D testing – cost-effective or needed?

In Ireland, there has been a substantial increase in vitamin D testing over the last decade, with a 37% rise in requests between 2014 and 2018.¹⁴ Testing in the UK has increased 50-fold between 2005 and 2015 while varying increases have been identified elsewhere such as in the US where it was one of the most requested tests, costing $350 million.¹⁴ This increase may be related to greater public awareness and media interest in vitamin D (particularly during the last 18 months) and its potential benefits beyond bone health. 

Vitamin D testing by GPs for non-specific conditions such as fatigue has been reported in the Netherlands while in Canada, a quarter of vitamin D tests were repeated too early, with undefined clinical indications in many instances.¹⁴

In Ireland, the Health Service Executive (HSE) suggests testing for metabolic bone disorders where vitamin D may improve outcomes such as osteoporosis, hyperparathyroidism, and Paget’s disease. It includes other conditions that might lead to or be attributed to deficiency including malabsorption conditions (coeliac/inflammatory bowel disease), unexplained musculoskeletal symptoms, liver disease and for certain medications (eg. anti-epileptics). 

However, screening for otherwise asymptomatic individuals at-risk of deficiency is not recommend. It also advises against routine re-testing but provides no specific criteria for who should be retested. However, much about testing in Ireland has been unknown due to the lack of data.

In 2021, a new study¹⁴ examined this issue, where 36,458 patient vitamin D tests were examined from St James’s Hospital Dublin over a period from 2014-2018. Cost analysis estimated the number of patients needed to test (NNT) to detect one with deficiency, insufficiency or excess vitamin D (>125nmol/L) by gender, age and location. The percentage in each vitamin D category was divided into 100 to calculate the NNT. 

Inappropriate testing costs was estimated, defined as:

• Retests within three months of the first or initial test
• Two or more retests within one year, and
• Retests in those who were initially vitamin D replete (50-75nmol/L). 

The calculation was predicated on a laboratory cost of €40 per 25(OH)D sample. Overall, 22.8% of patients were retested, accounting for 27.2% of vitamin D requests. The retested cohort were more likely to be female, older and less likely to live in South or North Dublin versus the non-retested. The proportion of young people (< 50yrs) who were retested was smaller and retesting was more prevalent in the older age categories. 

The number needed to test (NNT) to detect deficiency increased with the number of tests, ranging from six on initial testing to 17 on retesting. The NNT to detect excess vitamin D (>125nmol/L) varied from 20-33. The NNT for deficiency was highest in 60-79 years and lowest in 18-39 years. Assuming €40 per vitamin D test, the cost of identifying one case of deficiency on initial testing ranged from €120 in those aged 18-39 years to €400 in those aged 60-79 yrs. On subsequent testing this rose to €1,000 or more. 

Retesting costs within three months of an initial test was €66,560. Furthermore, 29% of retests comprised a second or later retest within 12 months, costing €156,240. Additionally, 26% of first retests were in those with an initial 25(OH)D level between 50-74 nmol/L, costing €87,080. The total expenditure of inappropriate testing was €309,880 (over four years) or €61,976 per year. Thus, testing the youngest adults was the most cost-effective for every case of deficiency identified. Importantly, this study found 12% of retests were completed within three months and two or more retests were done within one year in nearly a third of cases. 

Retests within three months may be considered redundant as it does not allow sufficient time for therapeutic correction of vitamin D deficiency and the significant level of early and repeat retesting is likely due to a lack of awareness of guidelines. Excess vitamin D testing and rising costs have been highlighted in many countries, with different strategies employed to curb this. The solutions fall into two categories: computer-based interventions at the point of ordering to reduce the number of inappropriate and unnecessary tests and population-based approaches, via supplementation or fortification, to eliminate deficiency and reduce the need for 25(OH)D monitoring. However at the most basic level, it is evident that clear guidelines for GPs on vitamin D retesting are needed as this issue and costs will become more problematic given the popularity of vitamin D. 

Vitamin D and extra-skeletal health

Some but not all studies have suggested that vitamin D may have extra-skeletal benefits such as the prevention or delay of cardiovascular disease, diabetes, inflammation and cognitive decline.¹⁵ However, recent RCTs have produced null results. For instance, the VITamin D and OmegA-3 TriaL (VITAL),^16,17 was a nationwide, randomised, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day in the US of 25,871 participants in those aged > 50 yrs with a median follow-up of 5.3 yrs (3.8 - 6.1 yrs). They found that supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events or decreased fall risk than placebo. These null results could be in part due to the relatively high baseline blood vitamin D level in both placebo and intervention group (few were deficient) while some of the placebo group reported taking vitamin containing supplements.  

 In an Irish context, the TILDA study has recently investigated associations of vitamin D and depression and frailty in older Irish adults.¹⁸ Previous large population studies of older people have shown that vitamin D concentrations are inversely related to depressive symptom burden across diverse settings.^19,20 Further studies have suggested that these findings may be due to a direct effect of vitamin D on brain tissue, and vitamin D receptors are widespread throughout the brain, including the frontal lobe.²¹

Vitamin D may also protect the brain from inflammatory or vascular insults, both of which are seen as key steps in the pathogenesis of depression in later life.²² Understanding the link between vitamin D status and depression in later life is important as vitamin D status is relatively easy and inexpensive to modify through supplementation or fortification. 

Late life depression significantly reduces quality of life and is a potent risk factor for functional decline, admission to residential care and early mortality. In TILDA, vitamin D status and risk of incident depression over four years was examined in 4,000 people. The paper found that after controlling for other important variables, vitamin D deficiency was associated with a 75% increase in the likelihood of developing depression. The findings were important, given the high prevalence of vitamin D deficiency among older people, the fact that supplementation confers an overall health benefit with low risk of toxicity or side-effects, as well as the significant adverse effect depression can have on functional status and longevity in later life. 

A second TILDA study investigated frailty risk and micronutrient status (including vitamin D) in older adults.²³ Frailty is characterised by multisystem loss of physiological reserve, systemic decompensation in response to stressors, and increased risk of adverse outcomes including falls, disability, and mortality.²³ Frailty is modifiable, representing a transition between healthy ageing and disability, and is a target condition for increasing healthy life years.²⁴ Frailty impacts multiple functional domains including nutrition, strength, mobility, physical activity and cognition. 

Inadequate dietary intake has been implicated in the increased risk of chronic diseases and frailty, and the importance of nutrition to postponing frailty and sarcopaenia (a central component) among older adults is well-established.^25,26 In the TILDA study it was observed that after adjusting for other covariates, higher blood vitamin D concentrations were associated with reduced pre-frailty and frailty. This is in keeping with other studies such as NHANES, which found that vitamin D deficiency was associated with a 3.7-fold increased odds of frailty, adjusting for season and latitude. More work is currently underway in TILDA and other cohorts in Ireland investigating vitamin D and health outcomes. 

Vitamin D, inflammation and Covid-19 

Vitamin D has been demonstrated to modulate the immune system via regulation of cell-signalling pathways through the vitamin D receptor (VDR) which is present on a number of immune cells including monocytes, T lymphocytes and macrophages.²⁷ Vitamin D has also been observed to regulate the proliferation of these cells and to influence the production of inflammatory cytokines such as Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha).²⁸

Regulation of inflammation and cytokine expression is of crucial importance given the hypothesis of ‘inflamm-ageing’ – with increased age the shift toward a more pro-inflammatory state can lead to chronic low level grade inflammation and a slow accumulation of damage, with subsequent progression to chronic disease.²⁹ Vitamin D may also play a significant role related to immune function in the context of respiratory infection. Recent cross-sectional and randomised controlled trials (RCTs) have shown that low vitamin D status has been associated with a higher risk of infection, and vitamin D supplementation has been associated with reduced symptoms and antibiotic use.^30,31

These associations are particularly pertinent given the context of the Covid-19 pandemic, where vitamin D deficiency has been associated with Covid mortality and severity of the immune response in older adults in some studies.³²

Currently, research designs that have been used to postulate a relationship between low vitamin D status and the severity of Covid-19 infection are either ecological, demographic with risk groups for deficiency (Mendelian randomisation), or studies on the association of 25(OH)D levels with the risk of having a positive test for the virus. 

Observational studies examining prevalence rates of infection and deficiency have shown positive associations. In a recent systematic review and meta-analysis of 23 studies (n =  2,692),³³ deficiency was associated with increased risk of severe SARS-CoV-2 disease (RR 2.00; 95% CI 1.47–2.71, 17 studies) and mortality (RR 2.45; 95% CI 1.24–4.84, 13 studies). However, the findings do not imply causation because they only summarise the conclusions of observational studies. There is also the possibility that the low concentrations of 25(OH)D reported are an epiphenomenon of the inflammatory process associated with severe SARS-CoV-2 infection. 

However, it may be a common misconception that inflammation lowers vitamin D as other studies have reported no change in 25(OH)D concentrations during for example malarial infection or myocardial infarction, both of which lead to a significant increase in inflammation.^34,35

Finally RCTs have shown so far little or no effect of vitamin D with Covid-19. This could be attributed to the ‘horse has already bolted’ where it is too late to give vitamin D as it is theorised optimal concentrations leading up to infection may give the most benefit. In addition, most studies have been administrating mega bolus doses in addition to giving these to patients where 25(OH)D levels are already above the sufficient range. It is logical to assume that optimal vitamin D concentrations can contribute to a healthy immune system (along with several other micronutrients and sufficient macronutrient intakes) which would help with respiratory infection. 

Future research

More research will certainly be undertaken in the areas of vitamin D and Covid-19 until the pandemic is over. Research is also being undertaken investigating the associations of vitamin D with heart disease, cancer, diabetes and mortality. However RCTs have again been limited due to the lack of a true deficient group, no consensus on doses to administer and supplementing groups who already have sufficient vitamin D status. 

In the Irish context, much is still unknown about vitamin and health in vulnerable groups in the population such as nursing homes, homeless, ethnic minorities, prisons, children, lower socio-economic status, etc. Furthermore, given the recent confirmation of folic acid fortification in the UK, it remains to be seen if Ireland will follow suit in addition to adding vitamin D and how we could monitor blood population levels.

In summary, vitamin D deficiency is widespread in the population with rates higher in males, lower socio-economic groups and younger adults and much is unknown about other population groups. Vitamin D testing has accelerated with increasing costs, with the question remaining if the right groups within the population are being tested. Finally, studies have indicated that optimal vitamin D status has a positive association with immune function and it maybe be prudent to optimise intakes and status to sufficient levels during the Covid-19 pandemic.  

References

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