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July 24, 2014

Boosting defences with vitamin D

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One billion people worldwide are estimated to have vitamin D deficiency

As the days shorten, it is time to consider vitamin D status in the Irish population, write Dr Mark Kilbane, Ms Myra O’Keane and Dr Malachi McKenna

Vitamin D is the name given to a group of fat-soluble steroids, the two major physiologically-relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D is carried in the bloodstream to the liver, where it is enzymatically converted to 25-hydroxyvitamin D (25OHD).

Further hydroxylation by the kidney results in the formation of the active form of the vitamin: 1,25-dihydroxyvitamin D [1,25(OH)2D]. This is the hormonal form of vitamin D; its production is tightly regulated by parathyroid hormone (PTH) and the recently described phosphate-regulating hormone, fibroblast growth factor 23 (FGF23). It circulates as a hormone, regulating, among other things, the concentration of calcium and phosphate in the bloodstream, promoting the healthy mineralisation, growth and remodelling of bone. Vitamin D insufficiency can result in thin, brittle or misshapen bones, while sufficiency prevents rickets in children and osteomalacia in adults, and together with calcium, helps to protect older adults from osteoporosis.

By binding to the vitamin D receptor 1,25(OH)2D, it modulates neuromuscular function, reduces inflammation and influences the action of many genes involved in cell regulation. When synthesised by monocyte-macrophages, 1,25(OH)2D acts locally as a cytokine, defending the body against bacterial infection.

Prevalence of vitamin D deficiency
The best indicator of vitamin D status is serum 25OHD, an assay that is now widely available. The terminology for defining vitamin D status has shif-ted over the past two decades. While there is currently no consensus on optimal levels of serum 25OHD, the lowest threshold for defining insufficiency is 50 nmol/L.

Investigators have shown serum 25OHD levels to be inv-ersely associated with PTH up to 75-100 nmol/L, at which point the decline in PTH flattens.

Increased intestinal calcium transport (from 45 per cent to 65 per cent) has also been achieved by increasing 25OHD levels from an average of 50 and 80 nmol/L. Given such data, a level of 25OHD between 50 to 80 nmol/L could be described as sub-optimal for all health outcomes and a level of 80 nmol/L or greater for optimal bone health.
With the use of such definitions, it has been estimated that one billion people worldwide have vitamin D deficiency or insufficiency. Predisposing factors contributing to risk of deficiency include: age; ethnicity; residential latitude; and seasonal differences in solar UVB availability.  Also at risk are pregnant and lactating women and their infants, over three quarters of whom have been shown to be 25OHD deficient at the time of birth, despite taking vitamin D supplements during the gestational period.

In Europe and Ireland, in particular, our high residential latitude puts children and adults at especially high risk of 25OHD deficiency.

Vitamin D and disease
In the absence of vitamin D, only 10 per cent to 15 per cent of dietary calcium and 60 per cent of phosphorus can be absorbed. The interaction of 1,25(OH)2D with the vitamin D receptor increases the efficiency of intestinal calcium and phosphate absorption by 40 per cent to 80 per cent respectively.

Studies have shown that serum 25OHD levels are directly related to bone mineral density in adult men and women, with maximum density achieved at levels of 100 nmol/L or more.

Deficiencies of 25OHD in utero and childhood can prevent maximal calcification of the skeleton if left untreated. As deficiency progresses, the parathyroid glands are maximally stimulated, causing secondary hyperparathyroidism, which increases 25OHD hydroxylation to 1,25(OH)2D, further exacerbating 25OHD deficiency.
The high PTH levels promote phosphate excretion, which negatively impacts on the ability of the collagen matrix of bone to be mineralised.

This leads to the classic signs of rickets in children (bone pain, dental and muscle problems) and osteomalacia in adults.

Particular attention should be paid to the breast-fed infant and the mother who is likely to be 25OHD-deficient at the time of birth

High PTH levels also activate osteoclasts, which dissolve the mineralised collagen matrix of bone, causing osteopaenia and osteoporosis and increasing the risk of fracture.
In the region of one third of women between 60-70 years have osteoporosis. Approximately 47 per cent of women and 50 per cent of men over the age of 50 will sustain an osteoporotic fracture in their rem-aining lifetime.

Conflicting evidence
Conflicting evidence exists for the role of parent vitamin D supplementation as an agent for the prevention of osteoporotic fractures. Meta-analyses of clinical trials evaluating the risk of fractures in older patients supplemented with vitamin D 400 IU daily showed little benefit in the risk of fractures.

A major study – the Women’s Health Initiative, of 36,000 postmenopausal subjects – confirmed these results but also identified a cohort who benefitted from supplementation. They were able to show that optimal prevention of osteoporotic fractures occurred (29 per cent versus placebo) in trials providing vitamin D 700-800 IU daily in women whose baseline 25OHD concentration was less than 42 nmol/L at the start of the trial, rising to 100 nmol/L following supplementation.

Vitamin D deficiency has also been linked to autoimmune diseases such as type I diabetes mellitus and multiple sclerosis, due to the potent immunoimodulatory effects of the active hormone 1,25(OH)2D.

A role for vitamin D in cancer prevention has also been postulated because 1,25(OH)2D has been shown to have control over 200 genes (both directly and indirectly) responsible for regulation, differentiation, apoptosis and angiogenesis.

It can increase the cellular proliferation of both normal and cancer cells and induce terminal differentiation. A practical example of this is in the use of 1,25(OH)2D and its active analogues in the treatment of psoriasis.

Latterly, 25OHD deficiency has been linked with a whole host of disorders from cardiovascular disease, to schizophrenia and depression. It is not clear, however, if the vitamin D deficiency has a causal link or is merely a feature of disease presentation.

Measurement of vitamin D
The serum concentration of 25OHD is typically used to determine vitamin D status. It reflects vitamin D produced in the skin as well as that acquired from the diet, and has a fairly long circulating half-life of 15 days. It does not, however, reveal the amount of vitamin D stored in other body tissues. The level of serum 1,25(OH)2D is not usually used to determine vitamin D status because it has a short half-life of 15 hours and is tightly regulated – by PTH and FGF23, as well as by calcium and phosphate – such that it does not decrease significantly until vitamin D deficiency is already well advanced.

The measurement of serum 25OHD is technically complex and as with any analytical technique, the value delivered by laboratories is only an estimation of the true value, due to inherent measurement uncertainty. Studies have found that for a measured 25OHD concentration close to the clinical cut-off of 80 nmol/L, the true concentration may be 11.5-27.5 per cent lower or higher, depending on the method used.

The major factor contributing to the measurement uncertainty in 25OHD testing is the non-availability of an international standard for use in assay development.
As a result, manufacturers use their own standards, which introduces a bias between assays and increases measurement uncertainty for 25OHD overall.

This will probably be solved in the near future once an international standard is agreed upon, which should reduce (but not eliminate) measurement uncertainty and allow more accurate measurements of vitamin D in the patient population.

Most experts agree that, in areas of inadequate sun exposure, the optimal supplementation in adults is approximately 800-1,000 IU/day of vitamin D. Deficiency should be treated aggressively using the vitamin D3 form of the vitamin, where possible (cholecalciferol).

Particular attention should be paid to the breast-fed infant, and the mother who is likely to be 25OHD deficient at the time of birth.

Public health initiative
The Food Safety Authority in Ireland recently launched a campaign recommending that all infants under the age of one year old be given vitamin D 200 IU daily in order to satisfy the infant’s requirements. This is a most important public health initiative targeting one of the most vulnerable and at-risk groups for vitamin D deficiency in Ireland.
From late October to the end of March, there is no skin production of vitamin D by sunlight. So we are dependent on vitamin D stores accumulated during the preceding six months of the year and on dietary sources of vitamin.

Fortunately, many milk products in Ireland for the past 25 years have been fortified with vitamin D. The general public should be encouraged to purchase and consume fortified milk during the spell from October to March. Some, especially the frail elderly, will need additional oral supplements in low doses of less than 1,000 IU daily, at least during the winter months and probably throughout the year.

In conclusion, differing degrees of low vitamin D status are seen in most of the Irish population. Measurement of serum 25OHD is a simple indicator to assess status and low-dose oral vitamin D supplements are a means of correcting and preventing vitamin D deficiency.

Supplementation should be considered in all at-risk groups, especially those who are unable to avail of the benefit of exposure to natural sunlight during the months of April to October.

  • Dr Mark Kilbane,
  • Ms Myra O’Keane,
  • Dr Malachi J McKenna,

Metabolism Laboratory,
St Vincent’s University Hospital, Dublin 4