Vitamin D and Health

higher than 1,25(OH) 2 D concentration and its half-life is about 2-3 weeks compared to that of plasma
1,25(OH) 2 D, which is less than 4 hours.
4.6 There is consensus that serum or plasma 25(OH)D concentration should be used to assess vitamin D
status because it reflects the contributions from both diet and cutaneous synthesis. Serum 25(OH)D
concentration has been shown to reach an equilibrium after 6-8 weeks of vitamin D supplementation
in adults (18-85y) (Harris & Dawson-Hughes, 2002; Viljakainen et al., 2006). A systematic review of
existing and potentially novel functional markers of vitamin D status reported that serum 25(OH)D
concentration was increased in response to supplemental vitamin D intake in all the included RCTs
irrespective of whether vitamin D 2 or D 3 was used, differing analytical techniques, study duration (6
weeks to > 2y), or age group of participants (Seamans & Cashman, 2009).
4.7 Serum 25(OH)D concentration was used as an indicator of vitamin D status by the IOM (IOM, 2011)
and the UK and EU authorities (Commission of the European Communities, 1993; DH, 1991; DH, 1998;
German Nutrition Society, 2012; Health Council of the Netherlands, 2012; Nordic Council of Ministers,
2014) to establish dietary reference intake/values for vitamin D. However, the extent to which serum
25(OH)D concentration serves as a biomarker of effect is not clearly established; i.e., whether serum
25(OH)D concentrations relate to health outcomes via a causal pathway and can serve as predictors of
such health outcomes (IOM, 2011).
4.8 A clearer understanding of the limitations of serum 25(OH)D concentration as a marker of exposure
and status will provide for a better understanding of its relationship to specific health outcomes. For
example, a study of patients who underwent elective knee arthroplasty has raised concerns about the
reliability of serum 25(OH)D concentration as a status marker in the face of a significant systemic
inflammatory insult (Reid et al., 2011). By day 2 post-operatively there was a large increase in C-
reactive protein (CRP) 33 concentration and a significant decrease in plasma 25(OH)D concentration of
~40%. CRP, 25(OH)D and calculated free 25(OH)D (i.e., 25(OH)D not associated with DBP or albumin)
had not returned to pre-operative concentration by 5 days post-operatively and, even at 3 months,
25(OH)D and free 25(OH)D concentrations remained significantly lower (20% and 30%). Mechanisms
for the decrease in plasma 25(OH)D concentration were not evident, although other studies suggest
that this might be a consequence of changes in DBP (Waldron et al., 2013).
4.9 Serum concentrations of other lipid-soluble vitamins (A, E, K and some carotenoids) decrease during
the systemic inflammatory response. While changes in CRP are likely to be of a lesser magnitude than
those seen after knee arthroplasty, low serum 25(OH)D concentration has been associated with many
chronic inflammatory conditions. The study by Reid et al. (2011) therefore raises an important
question in relation to reverse causality: low serum 25(OH)D concentration may be a consequence of
disease with an inflammatory component and not the cause.
4.10 A systematic review of longitudinal studies (n=8) evaluated the association of acute phase response
with serum 25(OH)D concentration during an inflammatory state (Silva & Furlanetto, 2015). Serum
25(OH)D concentration was measured before & after elective surgery in 4 studies, during the acute
phase response following intravenous treatment with nitrogen-containing bisphosphonates in 1 study
and soon after diagnosis and during the course of an acute illness in 3 studies. Serum CRP
concentration was used as an inflammatory marker in most studies. Serum 25(OH)D concentration
decreased after the inflammatory insult in 6 studies with no change observed in 2 studies. However,
33 CRP is an acute phase protein produced by the liver; plasma/serum concentrations rise in response to inflammation.
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