SELENIUM NOTES
Introduction
Selenium is incorporated into 25 selenoproteins,1 which have a broad range of functions - including
contribution to the production of thyroid hormone and healthy sperm cells, as well as working as
antioxidants and exerting anti-inflammatory effects. Associations between selenium status and disease risk have been made where selenium is both deficient and over-abundant, prompting the development of the theory that the relationship between selenium and disease risk is U-shaped.
Health Effects
1. Viral virulence & immune function
Selenium appears to play a role in suppressing viral virulence: rodent studies with influenza virus
have shown more active lung inflammation in selenium-deficient mice;2 faster clearance of the
polio virus was achieved in humans supplemented with selenium3 and selenium supplementation in
combination with a multivitamin was shown to reduce morbidity and immune decline in HIV-infected adults4. The data demonstrating an association between low selenium status and increased mortality in HIV-infected patients is prone to confounding though, as the acute phase response seen in
patients at an advanced stage of the illness has been shown to lower selenium5. A different trial
demonstrated no change in CD4+ count or of HIV-1 viral load with selenium supplementation, although there was a reduction in child mortality.6
Selenium has been demonstrated to function as an immunostimulant, where supplementation in a
small study of human subjects resulted in noticeably increased cytotoxic-lymphocyte-mediated tumour cytotoxicity and in Natural Killer-cell activity7, and in a separate study, where supplementation achieved the restoration of lymphocyte activity in elderly subjects to the equivalent of healthy
young adults8. However, research has not all been conclusive - a large double-blind randomised
placebo-controlled trial in 197 asthma patients demonstrated no benefit from selenium supplementation9, although the benefits of supplementation may have been reduced by concurrent inhaled steroid use10.
2. Fertility
A very clear relationship has been established in the case of fertility; decreased sperm motility and
viability has been found in men with reduced levels of the selenoproteins GPx4 and Sepp1,11,12 and
selenium status was shown to be much higher in fertile men over infertile men13. In women, lower
selenium status has been found in those who miscarry in the first trimester and who have recurrent
miscarriages14,15, although this is not a consistent finding.15,16 A large case-control study has found
that women with a particular polymorphism of selenoprotein S, which has a role in control of inflammation, had a higher risk of developing pre-eclampsia during pregnancy.17
3. Thyroid disease
A number of selenoproteins are active in the thyroid, and therefore there is a high demand for selenium here. Observational studies have linked selenium deficiency with thyroid cancer18-20and
goitre21, as well as autoimmune thyroid disease22,23. A meta-analysis and systematic review convincingly concluded that thyroid peroxidase autoantibody titre was significantly lowered at 3 months
with selenium supplementation24.
4. Mortality & Cancer
Research from 3 large prospective studies indicates that
high serum selenium concentration levels are associated
with decreased all cause mortality25-27, and Figure 110 displays the findings of one study, in which a clear U-shaped
association between selenium status and all-cause mortality
and cancer was found25. However, selenium status is higher
in fit older people than those who are malnourished or unwell28, and selenium can be depleted by poor kidney function29
Figure 1: Adjusted hazard ratios for all-cause mortality
according to selenium status in adult subjects of the
US Third National Health and Nutrition Examination
Survey, showing data for up to 18 years - 2006.25
Figure from Professor M Rayman’s paper on Selenium
and Human Health.10
and in the acute phase response5 - both features of disease - and
as such, the data in these studies is susceptible to confounding.
Studies in relation to cancer are conflicting; a meta-analysis of prospective studies show a decreased risk of cancer with higher selenium status30, while many RCTs show no difference. As with
the findings related to mortality, the results here are prone to confounding, where low selenium
could potentially be a product of the disease, not a cause. Additionally, studies where selenium is
supplemented in participants with already adequate selenium status (e.g. SELECT31) may push the
cancer risk up, instead of down, as a result of a non-linear relationship between selenium and dis-
ease risk. This demonstrates the importance of designing trials in which participants are screened
for pre-existing selenium status, particularly where there are known adverse effects at both ends of
the status scale.
5. Type 2 Diabetes Mellitus (T2DM)
The evidence linking T2DM to selenium status is conflicting32. Some cross-sectional studies have
shown a significant association between higher selenium status and T2DM33,34, with further associations found between SeP and HbA1c33. However, longitudinal studies do not support these findings and there is only 1 RCT that has found an increased risk of T2DM with selenium supplementation35. The inconsistency of findings could be explained by an association between selenium status
and T2DM that is U or S-shaped, where the risk of T2DM rises in both low and high selenium
status.
Intake and status
Guidelines for intake vary internationally. In the UK, the reference nutrient intake is 75 µg/day for men and 60 µg/day for
women36. Supplementation should be considered if patients
have a selenium status of less than 122 µg/L, but no higher than
this, as it is at this concentration at which the risk of cancer,
non-melanoma skin cancer and T2DM increases37,38. However,
it should be noted that the 130-150µg/L range is the concentraFigure 2: Combination of selenium concentration
data in 2 studies (NDNS, NHANES), with associated
concentration risk marker for non-melanoma cancer,
cancer, and T2DM, which indicates the point at
which risk increases/decreases (122μg/L), with
minimal mortality indicator bracket drawn from the
Third NHANES data. 25
Figure from Professor M Rayman’s paper on Selenium and Human Health10
tion associated with minimal mortality25 and this is therefore a
reasonable target bracket to aim for.
Conclusion
The complex balance and interaction of nutrients and the multifactorial nature of disease causation
can create difficulties in definitively linking individual factors to conditions, which may be why research in some areas is conflicting. Nevertheless, a range of adverse health effects have been associated with selenium status, and where single nuclear polymorphisms exist within the genes of selenoproteins. Selenium is incriminated at both ends of the status spectrum, and this supports the
premise that the association between selenium status and disease risk can be illustrated by a Ushape.
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doi: 10.3945/ajcn.2008.26205