www.thelancet.com Vol 379 March 31, 2012
Lancet 2012; 379: 1256–68
February 29, 2012
Faculty of Health and Medical
Sciences, University of Surrey,
(Prof M P Rayman DPhil [Oxon])
Prof Margaret P Rayman, Faculty
of Health and Medical Sciences,
University of Surrey,
Guildford GU2 7XH, UK
Selenium and human health
Margaret P Rayman
Selenium is incorporated into selenoproteins that have a wide range of pleiotropic eff ects, ranging from anti oxidant
and anti-infl ammatory eff ects to the production of active thyroid hormone. In the past 10 years, the discovery of disease-
associated polymorphisms in seleno protein genes has drawn attention to the relevance of selenoproteins to health.
Low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline.
Higher selenium status or selenium supplementation has antiviral eff ects, is essential for successful male and female
reproduction, and reduces the risk of autoimmune thyroid disease. Prospective studies have generally shown some
benefi t of higher selenium status on the risk of prostate, lung, colorectal, and bladder cancers, but fi ndings from trials
have been mixed, which probably emphasises the fact that supplementation will confer benefi t only if intake of a
nutrient is inadequate. Supplementation of people who already have adequate intake with additional selenium might
increase their risk of type-2 diabetes. The crucial factor that needs to be emphasised with regard to the health eff ects of
selenium is the inextricable U-shaped link with status; whereas additional selenium intake may benefi t people with
low status, those with adequate-to-high status might be aff ected adversely and should not take selenium supplements.
A decade ago, investigators believed that identifi cation of
optimal selenium status would benefi t health. However,
since then, excessive zeal for increasing selenium intake
has at times had adverse consequences—a reminder that
selenium was fi rst known as a toxic element.1 This Review
updates an earlier one2 and discusses present contro-
versies, especially the eff ect of selenium on cancer and
type-2 diabetes, with emphasis on clinically relevant
Appendix pp 1–4 provides additional rele-
Role of selenium: selenoproteins
In human beings, the nutritional functions of selenium are
achieved by 25 selenoproteins that have selenocysteine at
their active centre.3 The insertion of selenocysteine to
form a selenoprotein is specifi ed by the UGA codon in
mRNA under specifi c conditions, but many other inter-
acting factors are necessary.3,4 In low selenium supply, the
synthesis of some selenoproteins (eg, glutathione peroxi-
dase, GPx4) is prioritised over that of others.4 Many
selenoproteins are important enzymes and their impor-
tance to human health is shown by the eff ect of single
nucleotide polymorphisms (SNPs) in selenoprotein genes
on disease risk or mortality (table 1
In contrast to many other micronutrients, the intake of
selenium varies hugely worldwide, ranging from
defi cient (associated with selenium-defi ciency diseases;
appendix p 5) to toxic concentrations that cause garlic
breath, hair and nail loss, disorders of the nervous
system and skin, poor dental health, and paralysis.22
Dietary selenium intake ranges from 7 μg per day to
4990 μg per day, with mean values of 40 μg per day in
Europe and 93 μg per day (in women) to 134 μg per day
(in men) in the USA.1,23,24 Selenium-containing supple-
ments add to these intakes, especially in the USA where
50% of the population takes dietary supplements.24
Selenium status, as measured by plasma or serum
selenium, varies by country and corresponds to intake.2
Intakes are high in Venezuela, Canada, the USA, and
Japan, and much lower in Europe, particularly in
eastern Europe. China has areas of both selenium
defi ciency and excess. Intakes in New Zealand, which
were formerly low, have improved after increased
importation of high-selenium Australian wheat.1
Recom mendations for selenium intake average 60 μg
per day for men and 53 μg per day for women.25
Reasons for the variability in intake relate not only to the
selenium content of the soil on which crops and fodder
are grown, but also to factors that determine the availability
of selenium to the food chain (panel
panel), including selenium
Search strategy and selection criteria
I searched PubMed and the Cochrane Library for publications
from January, 1990, to February, 2011. I used the search
terms “selenium”, “selenoprotein”, and the names of the
individual selenoproteins in combination with the terms
“polymorphism”, “Keshan disease”, “Kashin-Beck disease”,
“mortality”, “immune function”, “immunity”, “regulatory
T cells”, “Tregs”, “virus”, “antiviral-eff ect”, “HIV”, “brain”,
“seizures”, Parkinson’s disease”, “cognitive decline”,
“dementia”, “Alzheimer’s disease”, “fertility”, “miscarriage”,
“preeclampsia”, “preterm birth”, “autoimmune thyroid
disease”, “cardiovascular disease”, “coronary heart disease”,
“type 2 diabetes”, “cancer”, “thyroid cancer”, “colorectal
cancer”, “prostate cancer”, lung cancer”, and “bladder cancer”.
Searches were also based on author name in their known
specialist areas. Further articles were included from personal
knowledge, reference lists, and review articles. Information
presented at the international symposium on selenium in
biology and medicine in 2010, in Kyoto, Japan, was also a
useful source. Many review articles have been included
because they capture a range of useful articles that cannot be
cited individually, in view of the overall limitation on the
number of references. Two additional papers published in
May and June, 2011, were added.
See Online for appendix
www.thelancet.com Vol 379 March 31, 2012 1257
speciation, soil pH and organic-matter content, and the
presence of ions that can complex with selenium.22
Health eff ects of selenium
In at least three prospective studies,32–34 high selenium
status has been associated with low overall mortality.
A non-linear association was noted between selenium
status and all-cause and cancer mortality in 13 887 adult
participants followed up for up to 12 years (until the
end of 2000) in the US Third National Health and
Nutrition Examination Survey.32 Figure 3 shows the
updated follow-up of these participants to the end of
2006. Increasing serum selenium concentrations up to
about 135 μg/L were associated with decreased mortality.
In the 9-year longitudinal Epidemiology of Vascular
Ageing (EVA) study33 of 1389 elderly French individuals
living independently, low plasma selenium at baseline
(mean 87 μg/L) was associated with increased overall and
cancer mortality. In the Baltimore Women’s Health and
Aging Study,34 low serum selenium was a signifi cant
independent predictor of all-cause 5-year mortality in
older women living in the community. By contrast, no
association was noted between total death and baseline
Function or health eff ect Health eff ects associated with polymorphisms (or haplotypes) in the
Glutathione peroxidases (GPxs) Family of antioxidant enzymes: remove hydrogen peroxide, lipid
hydroperoxides, and (GPx4) phospholipid and cholesterol hydroperoxides4
Reduces retroviral virulence by preventing viral mutations;5 defi ciency
Cardiometabolic eff ects: metabolic syndrome, CVD, CAD, blood pressure,
restenosis, coronary-artery calcium score, intimamedia thickness, peripheral
vascular disease, thoracic aortic aneurysm, intracerebral haemorrhage.
Cancer: lung, prostate, bladder, primary liver; Keshan disease, GPx1-198Leu
carriers had low blood selenium and low GPx1 activity; Kashin-Beck disease,
GPx activity lower in GPx1-198Leu carriers; autism
GPx2 (gastrointestinal) Antiapoptotic function in colon crypts; helps to maintain intestinal
Antioxidant in extracellular fl uids; kidney is source of GPx3 in plasma;4,8
thyroid protection from hydrogen peroxide in thyrocytes and
Membrane-associated; present at high concentrations in the testis,
where it is essential for sperm motility and viability10–12
Production of active thyroid hormone T3, and reverse T3 (rT3)13
Production of T3 in the thyroid and peripheral tissues13
T3 production in peripheral tissues13
Ischaemic stroke; diff erentiated thyroid cancer
Adenomatous polyps, colorectal adenocarcinomas; colorectal cancer;
breast cancer survival
Free IGF-1 concentrations, muscle strength, lean body mass
Type-2 diabetes and insulin resistance; osteoarthritis and bone-mineral
density; mental retardation (in iodine defi cient areas)
Dio1 (thyroid, liver, kidney, etc)
Dio2 (brain, pituitary, muscle,
BAT, ear, heart, etc)
Dio3 (cerebral cortex, skin,
placenta, pregnant uterus)
Selenoprotein P (SEPP1)
Production of rT3; prevents overexposure of fetus to T3
Contains 10 selenocysteine residues; major contributor to plasma selenium
and a good indicator of selenium status;14 transports selenium from the
liver via the plasma: brain, testis, and kidney have special receptors;14
has some antioxidant function;14 needed for brain; defi ciency causes
spasticity, abnormal movements, and spontaneous seizures in mice;14,15
essential for male fertility; defi ciency causes infertility with kinked and
hypomotile spermatozoa in mice;14,16 correlated with fasting plasma
glucose;17,18 may serve as heavy-metal (eg, mercury) chelator4
Redox active with a wide range of substrates, notably thioredoxin,
required for DNA synthesis4
Controls activity of transcription factors, cell proliferation, apoptosis;
reduction of expression leads to slower tumour-cell growth4
Indispensable for cardiomyocyte viability4
Anti-infl ammatory,19 located in the ER;4 might protect cells from
ER stress-induced apoptosis;4 linked to glucose metabolism and
Located in the ER; may aff ect glycoprotein folding4
Located in the ER; may regulate calcium mobilisation required for early
muscle development; mutations cause myopathies including
Prostate cancer; aff ects selenium status (plasma selenium and plasma
SEPP) and expression of other selenoproteins; colorectal adenoma,
Thioredoxin reductases (TrxR)
Advanced colorectal adenoma; familial amyotrophic lateral sclerosis
TrxR3 (testis-specifi c)
Selenoprotein S (SEPS1)
Gastric cancer: an SNP in TrxR2 interacts with GPx1 (Pro/Leu) to aff ect risk
Risk of pre-eclampsia; risk of CHD, ischaemic stroke; W:H ratio, BMI;
gastric, colorectal, and rectal cancers
15kDa selenoprotein (SEP15)
Selenoprotein N (SelN)
Prostate cancer mortality; lung cancer; rectal cancer
CVD=cardiovascular disease. CAD=coronary artery disease. IGF-1=insulin-like growth factor 1. BAT=brown adipose tissue. SNP=single nucleotide polymorphism. ER=endoplasmic reticulum. CHD=coronary heart
disease. W:H=waist to hip. BMI=body-mass index. *Appendix pp 6–12 shows table with full list of references.
Table 1: A selection of selenoproteins with known functions relevant to health or with associated health eff ects
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