INTRODUCTION
Over the past few years, there have been numerous publications with regards to vitamin D. These include randomized clinical trials (RCTs) assessing primary and secondary outcomes in bone health, cardiovascular disease, cancer, diabetes and most recently as supplementary therapy in the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).(1,2) With the wealth of new literature that has become available, this necessitates re-evaluation of this vitamin.
BACKGROUND
Vitamin D is a generic term that encompasses a group of fat-soluble compounds. The major circulating form of vitamin D is 25-hydroxyvitamin D (25[OH]D) whilst the most biologically active form is 1,25-dihydroxyvitamin D (1,25[OH]2D).
There are very few foods which naturally contain vitamin D. These include fatty fish (salmon, sardine etc.), fish oils, egg yolk and mushrooms. Most dietary sources of vitamin D come from fortified foods. As a result, dermal synthesis remains a major natural source of vitamin D. Exposure to ultraviolet light in sunlight, non-enzymatically synthesizes pre-vitamin D3 from 7-dehydrocholesterol in the skin. In an exceedingly efficient system, pre-vitamin D3 undergoes a temperature-dependent rearrangement to form vitamin D3 (cholecalciferol).
Very few foods naturally contain vitamin D; fatty fish and eggs are the exceptions.
The prevalence of vitamin D deficiency varies based on how deficiency is defined.
The clinical manifestations of vitamin D deficiency depend upon the severity and duration of the deficiency, with prolonged and severe vitamin D deficiency associated with significant bone pain and tenderness, muscle weakness, fractures, difficulty walking and eventually, osteomalacia.
A causal association between poor vitamin D status and cancer, infections, autoimmune diseases, and cardiovascular and metabolic diseases has not been established. Due to the lack of good quality evidence, routine supplementation of vitamin D for extra- skeletal benefits is NOT recommended.
Cholecalciferol (vitamin D3) when available, rather than ergocalciferol (vitamin D2) is recommended for vitamin D supplementation.
Routine screening and supplementation in the absence of good clinical indication is lacking.
It is estimated that brief exposure (10–20 min) to sunlight is equivalent to ingesting 200 international units (IU) of vitamin D.(3) However, this is dependent on a variety of factors, including skin type, age, latitude, season and time of day.(3,4) Sunlight also induces melanin production which limits the production of vitamin D3 in the skin. This, in addition to the production of inactive metabolites, means that prolonged sunlight exposure of the skin does not produce vitamin D3 toxicosis.
Regardless of the source (dietary or dermal synthesis) vitamin D is biologically inactive and requires enzymatic conversion to active metabolites. Both cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are converted to 25[OH]D (calcidiol) in the liver and then to the active metabolite 1,25[OH]2D (calcitriol) in the kidney. The plasma concentration of 1,25[OH]2D is dependent on multiple factors, including the availability of 25[OH]D, activities of 1-alpha and 24-alpha-hydroxylase and, indirectly, fibroblast growth factor 23.
1,25[OH]2D exerts action through a single vitamin D receptor (VDR) which is universally expressed in nucleated cells. The most important biological action of 1,25[OH]2D is to promote an intestinal absorption of calcium. Other effects include the direct suppression of parathyroid hormone (PTH) release, regulation of osteoblast function as well as PTH-induced osteoclast activation and to a lesser degree, stimulating intestinal phosphate absorption.
VITAMIN D DEFICIENCY
The best indicator of an individuals’ vitamin D status is serum 25[OH]D concentration. However, there is no consensus as to what level constitutes an optimal serum concentration. The Institute of Medicine (IOM) concluded that a concentration of 20 ng/mL (50 nmol/L) is sufficient for most individuals but other experts suggest that the level should be 30 ng/mL (75 nmol/L).(5) It is generally accepted that a vitamin D level of under 20 ng/mL (50 nmol/L) is considered insufficient, a level of under 12 ng/mL (<30 nmol/mL) as deficient and a level above 100 ng/mL (>250 nmol/mL) as a risk for toxicity.
The prevalence of vitamin D deficiency depends upon the definition used. In the United States of America National Health and Nutrition Examination Survey 2005–2006, 41.6% of individuals over the age of 20 had a 25[OH]D level below 20 ng/mL (50 nmol/L).(6) Using a cut-off of 30 ng/mL (75 nmol/L), a recent survey of vitamin D status in the northern suburbs of Johannesburg showed that 82.8% of participants were 25[OH]D deficient.(7) Another study in pre-adolescent children in South Africa (SA) also highlighted the fact that 66% of participants had a vitamin D level under 30 ng/mL (75 nmol/L).(8)
This high prevalence of vitamin D insufficiency and deficiency is not unique to SA. A systematic review and meta-analysis assessing vitamin D status in Africa showed a mean 25[OH]D level of 27 ng/mL (68 nmol/L) and 59·54% of individuals have a vitamin D level of under 30 ng/mL (75 nmol/L).(9) Vitamin D deficiency was found in 18% of individuals in the study.(9)
Vitamin D deficiency may be caused by one of four main mechanisms:
impaired availability of vitamin D (poor dietary intake or lack of sunlight),
impaired conversion by the liver to produce 25[OH]D,
impaired hydroxylation by the kidneys to produce 1,25[OH]2D and
end-organ insensitivity to vitamin D.
In addition, taking medications that accelerate the metabolism of vitamin D (such as phenytoin), being hospitalized or institutionalized, having increased skin pigmentation, having malabsorption syndromes, being obese and limited effective sun exposure due to protective clothing or sun screens have all been associated with low vitamin D levels.
VITAMIN D AND BONE
The clinical sequelae of vitamin D deficiency depends upon the severity and duration of the deficiency. Patients with vitamin D insufficiency (serum 25[OH]D between 20 and 30 ng/mL (50–75 nmol/L)) are asymptomatic with normal blood workup. The majority of patients have mild-to- moderate deficiency with serum 25[OH]D between 15 and 20 ng/mL (37.5–50 nmol/L). These patients are also typically asymptomatic and have normal serum calcium and phosphorus levels.
Prolonged and severe vitamin D deficiency may be associated with significant bone pain, bone tenderness, muscle weakness, fractures and difficulty walking. At a cellular level, there is a reduced intestinal absorption of calcium and phosphorus resulting in hypocalcaemia and secondary hyperparathyroidism. This leads to phosphaturia, demineralization of bones and in the long-term osteomalacia in adults and rickets in children. Serum PTH levels may be elevated in up to 40% of patients with serum 25[OH]D levels less than 20 ng/mL (50 nmol/L). This group of patients (low vitamin D and elevated PTH) are at an increased risk of having increased fracture and accelerated bone loss which is evident on dual-energy X-ray absorptiometry.(10)
The effect of vitamin D on fall risk remains murky due to discordant outcomes of meta-analyses and RCTs. The greatest benefit is supplementation in the group with 25[OH]D levels below 10 ng/mL (25 nmol/L) resulting in improved muscle strength and thereby decreasing falls.(11) Paradoxically, high annual intermittent doses of vitamin D and elevated 25[OH]D levels have been shown to increase fall risk.(12,13)
VITAMIN D AND EXTRA-SKELETAL HEALTH
Numerous epidemiological and observational studies indicate that the risk of autoimmune disease, cancer, cardiovascular disease and endocrine disorders all increase with 25[OH]D levels under 20 ng/mL (50 nmol/L) and that the risks decrease with increasing concentrations of 25[OH]D. However, to date there are no convincing RCT data that support these claims.
Based on a number of in vitro studies, there is increasing interest in vitamin D and its metabolites and their role in decreasing cell proliferation.(14) Several observational studies have evaluated the relationship between serum vitamin D levels and cancer. Although some suggest an association between vitamin D deficiency and cancer (e.g. colon), others have shown an increased risk of some cancers (e.g. pancreatic) at higher 25[OH]D levels.(15) Other studies have shown inconsistent results (e.g. breast cancer in post-menopausal women).(16) The majority of intervention trials do not show a reduction in cancer risk. However, these studies have often been carried out in patients with normal vitamin D levels.(17) Currently there is insufficient evidence to support vitamin D supplementation as a cancer prevention strategy.
Nearly all cells of the immune system are affected by vitamin D due to the fact that antigen-presenting cells express the VDR. The VDR-vitamin D endocrine system has the ability to modulate most aspects of the innate and acquired immune system. Significant vitamin D deficiency has been reported to increase the risk of autoimmune disease in animals.
Studies have linked vitamin D deficiency with an increase as well as a decrease in the frequency of respiratory and allergic diseases. RCTs examining the effect of vitamin D supplementation on asthma outcomes are inconclusive. Whilst the association between vitamin D deficiency and tuberculosis (TB) is well known, supplementation with vitamin D does not improve clinical outcomes in patients with active TB.(18)
With regards to SARS-CoV-2 infection, there is a growing body of research concerning the role of vitamin D in facilitating the innate immune response. Large observational studies report mixed results and there is no clear evidence that supplementation reduces the risk, severity of infection, length of hospital stay or mortality.(2)
A few observational studies have shown an association between low vitamin D status and hypertension and cardiovascular events.(19) However, most RCTs have shown no benefit of supplementation on risk of myocardial infarction and stroke.(20)
The majority of observational studies suggest an association between low vitamin D levels and the development of type 1 diabetes.(21) This link is largely mediated by the effects of vitamin D on the immune system. The mechanisms linking type 2 diabetes and vitamin D status include beta-cell activity and insulin sensitivity.(21) In a meta-analysis of 23 trials evaluating the effect of vitamin D supplementation on glycaemia, there was no effect on glycaemia or measures of insulin resistance.(22)
Finally, large-scale epidemiologic data and meta-analysis from the Western world suggest an association between low 25[OH]D levels (<20 ng/mL [50 nmol/L]) and increased mortality risk.(23) In a handful of RCTs, there is a modest reduction in mortality when elderly vitamin D deficient patients are given daily vitamin D3 supplementation.(17)
In summary, due to the lack of good quality RCTs, routine supplementation of vitamin D for extra-skeletal benefits is NOT recommended.
EVALUATION AND MANAGEMENT
The majority of individuals with vitamin D insufficiency do not require any additional evaluation. However, those with vitamin D deficiency are at risk for developing osteomalacia and would require further investigations (appropriate blood tests and radiographs if bone pain exists).
Various opinions have been expressed about which form of vitamin D should be used for supplementation. Generally, supplementation with cholecalciferol (vitamin D3) increases serum 25[OH]D more efficiently than ergocalciferol (vitamin D2).(24) However, this difference is of uncertain clinical significance.
In individuals with normal absorptive and conversion capacity, for every 100 units (2.5 mcg) of added vitamin D3, serum 25[OH]D concentrations increase by approximately 0.7–1.0 ng/mL (1.75–2.5 nmol/L).
Multiple dosing regimens have been demonstrated to successfully treat vitamin D deficiency. However, large, intermittent doses of vitamin D3 (monthly or annually) are not recommended as they may be associated with an increase in falls and fractures in the elderly.(13)
The IOM released a report in 2010 on dietary intake requirements for calcium and vitamin D. The Recommended Dietary Allowance (RDA) of vitamin D for individuals aged 1–70 years (including pregnant and lactating mothers) is 600 IU per day (15 mcg).(6) For individuals over the age of 70, the RDA is 800 IU (20 mcg) and for infants under the age of 1, the recommended RDA is 400 IU (10 mcg).
When it comes to treating patients with known malabsorption disorders, high doses of approximately 10–50 thousand IU daily (250–1250 mcg) may be necessary. An alternate strategy is to treat these patients with vitamin D metabolites (e.g. calcidiol or calcitriol) because they are more readily absorbed. In patients with chronic kidney disease stage 5, as well as those on dialysis, vitamin D supplementation may need to be adjusted in terms of both dose and type.
All patients should maintain a daily total calcium intake (diet plus supplemental) of between 1000 and 1200 mg.(6)
The optimal serum 25[OH]D concentration for skeletal health is controversial, and it has not been rigorously established for the population in general or for specific ethnic groups. We favour maintaining the serum 25[OH]D concentration between 20 and 40 ng/mL (50–100 nmol/L).
Routine monitoring in patients receiving vitamin D supplementation is not recommended. In patients with a baseline serum 25[OH]D <20 ng/mL (50 nmol/L), this should be repeated 3–4 months after initiating therapy, where the dose of vitamin D may require further adjustment.
The initial consequences of vitamin D toxicity are hypercalciuria and hypercalcemia. These tend to occur when 25[OH]D levels rise above 88 ng/mL (220 nmol/L). In addition, elderly patients (25) above the age of 70 have an increased risk of falls and fractures which are associated with high levels of 25[OH]D.(13)
CONCLUSION
Very few foods naturally contain vitamin D. The prevalence of vitamin D deficiency varies based on how deficiency is defined. Given the current evidence, the benefits of large screening programs to detect vitamin D deficiency are not recommended. Among asymptomatic populations with low vitamin D levels, the evidence suggests that routine supplementation with vitamin D has no effect on mortality or the incidence of depression, diabetes, cardiovascular disease, cancer, immunity or adverse events.