Selenium

1.1. Origin and Composition

Selenium is an essential trace mineral that can be found in organic and inorganic forms. The primary organic forms are the selenoamino acids, selenocysteine, selenomethione, and Se-methylselenocysteine. The main active dietary form is selenomethionine.^[1] Other notable organic forms are selenoneine, which is the major form in tuna ^[2], and γ-glutamyl-Se-selenomethyl-selenocysteine, which is found in a variety of plant foods.^[3]

Selenite and selenate, the inorganic forms found in soil and water, are used by plants and animals to synthesize the organic forms. Plants mainly synthesize selenomethionine, whereas animal synthesis of selenomethionine from selenite is negligible, with synthesis of selenocysteine being more viable.^[1]

1.2. Sources and Structure

The selenium content of food correlates with the total protein content due to the ability of Se-amino acids to replace sulfur in proteins, although there are many notable exceptions depending on the physiology of the organism. Intake varies considerably by region depending on the levels in soil, the growing conditions of crops, the diets of livestock, and the local diet.^[3][4]

Brazil nuts contain the most selenium per gram of any measured food; two Brazil nuts daily for 12 weeks has been observed to increase serum selenium levels by 64.2% in adults from New Zealand.^[4][5] Other nuts and seeds provide more modest amounts of selenium, with Greek sesame seeds being a known region-specific exception, showcasing the extreme variability by region.^[6]

Selenium is consistently high in seafood and generally high in meats and eggs, although subject to variation depending on feed and animal supplementation.^[4] Dairy, particularly cheese, is also a significant source, with selenium content being inversely correlated with the fat content^[7]

Legumes such as lentils can be notable sources but vary depending on the species of legume. Wheat flour used in bread and pasta also provides nutritionally important amounts of selenium. Vegetables and fruits are not usually significant sources of selenium, however there are reports of Indian onions and portobello mushrooms being potent sources.^[4]

A wide variety of foods can supply significant amounts of selenium, with fish and Brazil nuts being the most consistent sources.

1.3. Biological Significance

It normally acts in concert with a class of enzymes and transporters called Selenoproteins (proteins with selenium in them), many of which are intrinsic anti-oxidant enzymes. In these selenoproteins, selenium acts as a prosthetic group or active site.^[8] Distinctly, Selenoprotein S is involved in protection against endoplasmic reticulum stress and regulation of proinflammatory cytokine release.^[9]

Selenium is essential for the functioning of the iodothyronine deiodinases which catalyze the deiodination of thyroid hormones, converting T4 to T3 and rT3, with implications for growth and thermogenesis.^[9]

In thioredoxin reductases it plays a role in redox reactions that control transcription factors, cell proliferation and apoptosis.^[9][10] Thioredoxin reductases can also reduce dehydroascorbic acid, an oxidized form of ascorbic acid.^[11] 

1.4. Recommended Intake

RDA is based on the amount of selenium required to maximize the activity of glutathione peroxidase (GPx) in serum. Due to inadequate evidence in infants, an adequate intake (AI) is set based on the average intake, primarily from breast milk. This is 15ug/day from 0-6 months of age and 20ug from 7-12 months. The RDAs are 20ug/day from age 1-3, 30ug from 4-8, 40ug from 9-13, and 55ug for 14 and older, with no differences between males and females. The RDAs for pregnant and breastfeeding women are 60ug and 70ug, respectively.^[12]

1.5. Deficiency

Deficiency of Selenium occurs when overall intake is less than 11ug, and 40ug is typically recommended as the minimum intake.^[13] Selenium deficiency in children can result in Keshan disease, named for the county in China where where patients exhibited a severe and often fatal form of cardiomyopathy.^[14] Keshan disease is correlated with selenium intake, status, and GPx activity; supplementation of selenium reduces its incidence. There is a likely role of various viral infections, which are likely exacerbated by selenium deficiency.^[15]

1.6. Sufficiency and Excess

Intake of 55ug is sufficient to support the needs of 25 selenoproteins^[16][17] although there may be some interindividual differences.^[18] Levels above this, but not yet into therapeutic dosages (200-300ug) are possibly in the range of what is needed to exert anti-carcinogenic effects^[19][20] and doses up to the range of 750-800ug daily seem to be relatively free of harm.^[21] Dosages of 1,500-1,600ug or above start to become associated with harm and doses nearing 3,000-5,000ug can cause direct DNA damage.^[22][23][24]

1.7. Formulations and Variants

Non-organic forms typically revolve around Selenite, a triple-oxidized form of selenium. It can be converted via Glutathione into Selenade; this multiple step process produces some superoxide radicals.^[25] 

Organic forms include the selenoamino acids, which include selenocysteine, selenomethione, and Se-methylselenocysteine. The main active dietary form is selenomethionine.^[1] Selenomethionine is a relatively stable compound, but has pro-oxidative metabolites such as Selenid and Methylselenol.^[26]

Selenium metabolites can also regulate cell cycles and apoptosis, and aid in tumor regulation.^[24]

The synthetic form called MethylSelenic Acid can be directly reduced into methylselenol and can avoid the B-lysase enzyme intermediate commonly seen with dietary selenium.^[27]

2.1. Insulin

Selenium has been noted in the past to aid glucose metabolism by acting as an insulin mimetic^[28] and thus, aiding the deposition of glucose into both fat and muscle cells.^[29][30] These effects have also been seen in vivo.^[31]

2.2. Diabetes

In populations that have sufficient selenium status, epidemiological research^[32] and one intervention^[33] have suggested that further supplementation may increase the risk for insulin resistance and type 2 diabetes. The intervention was dosed at 200mcg daily.

The theorized mechanism of action is that after a certain threshold of selenium intake (past the RDA, nearing the TUL), selenium builds up in pancreatic tissue^[34] and exerts oxidative stress on beta-cells that secrete insulin.^[35]

This may be an issue of selenium being anti-diabetic acutely (via acting as an insulin-mimetic and aiding in glucose deposition) but over time damaging beta-cells and exerting the opposite effect and being pro-diabetic.^[36]

However, one intervention found that supplementation of selenium by pregnant women who were not deficient in selenium, did not result in increases of adiponectin, a marker of insulin resistance. ^[37]

Supplementation of selenium for insulin resistance or type 2 diabetes is not recommended due to its possible pro-diabetic effects.

2.3. Gestational Diabetes

Several studies have found that selenium levels decrease in women during pregnancy due to several phenomena such as increased lipid peroxidation, increased fetal requirement, hemodilutional phenomena, and deposition in the placenta.^{[38][39][40][41][42][43]}

A systematic review and meta-analysis, found that selenium concentrations are lower in women with gestational hyperglycemia, when compared to normoglycemic pregnant women. ^[43] The same study found that women with gestational diabetes mellitus had lower concentrations of selenium than normal pregnant women in the second and third trimester. However, the differences were only significant in the third trimester. It is believed that this is due to the higher tendency of insulin resistance and higher activity of peroxidase enzymes, such as erythrocyte glutathione peroxidase, in the third trimester.^[43] 

Women with GDM or impaired glucose tolerance are more likely to be impacted by oxidative stress and more likely to have lower concentrations of selenium. Increasing selenium intake through food or dietary supplements may be beneficial for such populations.

3.1. General

Selenium was first discovered to be related to cancer via correlational research showing higher cancer rates in areas with lower crop selenium content.^[44]

Several metabolites of selenium may be involved with cancer regulation. Methylselenol is thought to play a role^[45][46][24]

Selenoproteins themselves, rather than individual selenoamino acids, are also implicated in cancer prevention. These selenoproteins are typically those that exert anti-oxidative effects^[47] (Glutathione Peroxidases and Selenoprotein P) and alleviate cancer during the promotion stage.^[48][49]

Specific selenoproteins that have been investigated for being linked to specific cancers include Glutathione Peroxidase 1 being associated with head and neck, lung and breast, and bladder and prostate cancers,^{[50][51][52][53]} Glutathione Peroxidase 2 being associated with colorectal adenoma,^[54][55] Selenoprotein P being associated with both colorectal adenoma and prostate cancer,^[56][57] Selenoprotein 15 being associated Head, Neck, breast and lung cancer,^[58][59][60] and Thioredoxin reductase 1 being associated generally with most cancers.^[61][62] Selenium also enhances the effects of tumor protein p53 which promotes DNA repair, apoptosis and inhibits proliferation.^[63]

3.2. Prostate Cancer

Circulating selenium (independent of supplementation) is associated with a decrease in prostate cancer as assessed by a relatively small meta-analysis in a relatively dose-dependent manner up to a serum concentration of 170ng/mL, where it results in a relative risk ratio of 0.8 relative to 60ng/mL (set as baseline).^[64] The same meta-analysis found a decreased risk of prostate cancer associated with toenail selenium levels at up to 1 μg/g, where the risk then rose again.

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no association between selenium status (as measured in toenails) and prostate cancer in any of five selenum concentration quintiles in the population, whose selenium levels ranged from 0.48-8.97μg/g (mean 0.89μg/g, 95% CI 0.55-1.43μg/g).^[65] Since there were only 13 cancer cases with toenail selenium levels less than 0.617μg/g included in this analysis,^[65] this study represents a relatively selenium-replete United States population compared to patients who were in included in the previous meta-analysis.^[64]

3.3. Breast Cancer

Higher selenium levels are correlated with a reduced risk of breast cancer.

One meta-analysis, which examined 16 epidemiological studies, found that high selenium concentrations in serum were associated with a significant decrease in the risk of breast cancer (P=0.002), however, no such association was found between risk of breast cancer and selenium concentration in toe nails (P=0.17)^[63]

4.1. Skin

Acne vulgaris is a chronic skin disease characterized by follicular hyperkeratinization, hormonally-mediated sebum overproduction, and chronic inflammation of the pilosebaceous unit.^[66] It is believed that the damaging of lipids in the skin via free radicals is responsible for the inflammatory component of acne. Recent research has found that those who suffer from acne are unable to mitigate this damage efficiently because their antioxidant defense system is overwhelmed. ^[66]

Thus, based on this research, new studies have aimed to look at the effect of antioxidant supplementation on lesion counts.

A single-blind, placebo-controlled study that aimed to compare silymarin, n-acetylcysteine, and selenium to placebo in reducing lesion counts, found that after eight weeks of supplementation, there was a notable reduction in lesion count in all of the experimental groups, however, the reduction in lesion count was only statistically significant in the n-acetylcysteine and silymarin groups.^[67]

Selenium supplementation is not very effective in reducing lesion counts in those who suffer from acne.

5.1. Kashin-Beck disease

Kashin-Beck disease (KBD) is a endemic, degenerative osteoarthropathy, which is mainly distributed from northeastern to southwestern China. It is a disease characterized by enlarged and shortened fingers, arthritic pain, morning stiffness, deformed joints with limited motion in the extremities, excessive apoptosis, and dedifferentiation of chondrocytes.^[68]

Several studies have found that KBD is prominent in areas that have soils, plants, animals, and humans that are deficient in selenium. One particular study found that in the Heilongjiang Province in China, the mean serum selenium concentration is roughly 20 ng/L, nearly one-tenth of the mean found in the United States.^[69] Such studies have found that KBD is almost exclusive to selenium-poor belts like this. Other studies have found that the severity of KBD in a particular area is closely tied to the selenium content there.^[69]

A meta-analysis conducted in 2015, examined twenty-six studies and found that there were significant differences in whole blood selenium levels, serum selenium levels, selenium levels in the hair, and urinary selenium levels between subjects with KBD and healthy controls, with the former having significantly lower levels of selenium on all indicated measures.^[68]

Ever since selenium deficiency has been recognized as a possible factor in the onset of KBD, several interventional studies have aimed to look at the effects of selenium supplementation on the incidence of developing KBD, with the majority finding that supplementation reduced the risk of developing KBD.^[69]

It is theorized that selenium’s role in preventing the incidence of KBD may be attributed to its ability to protect cartilage tissue from the effects of the T-2 toxin, a mycotoxin found in grains that has been hypothesized to contribute to the onset of KBD.^[69]

This possible mechanism likely explains why one epidemiological interventional study found that the experimental groups that were given either selenium-iodine salt or rice from areas where there was no prevalence of KBD, were less likely to develop more X-ray lesions, and more likely to have higher metaphyseal repair rates than the control groups.^[70]

KBD is exclusive to areas where foods are contaminated by the T-2 toxin and where there exists a deficiency of selenium. Supplementation of selenium can prevent the onset of KBD and help treat it.

5.2. Pre-eclampsia

Pre-eclampsia is a disease that affects pregnant women. It is known to be a leading cause of maternal mortality and morbidity worldwide. The disorder is diagnosed by high blood pressure and large amounts of protein in the urine on or after the 20th week of gestation. ^[71] In more severe cases of the disorder, there is the presence of systemic endothelial dysfunction, microangiopathy, elevated liver enzymes and red blood cell breakdown. ^[72]

An animal study found that pregnant rats that were fed selenium free-diets, prior to and following conception, were found to have significant increases in systolic blood pressure and proteinuria, when compared to pregnant rats fed normal selenium diets (239 μg/kg selenium) or high selenium diets (1000 μg/kg selenium). The rats that were deprived of selenium were also found to have significant decreases in liver glutathione peroxidase and thioredoxin peroxidase. ^[73]

Several observational studies have established that women who suffer from pre-eclampsia, have significantly lower levels of selenium plasma and lower toenail selenium concentrations. ^{[74] [75] [76] [77] [78]} Lower levels were also found to be significantly associated with more severe expression of the disorder. ^[78]

Serum soluble vascular endothelial growth factor receptor-1 (sFlt-1) is a tyrosine kinase protein and anti-angiogenic factor that is associated with the risk of pre-eclampsia.

A randomized controlled trial, with 230 primiparous pregnant women, found that supplementation of selenium (60 μg/d, as Se-enriched yeast) by the experimental group (n=115), from 12 to 14 weeks of gestation until delivery, resulted in significantly lower concentrations of sFlt-1 when compared to the control group (n=115). ^[79]

A double-blind, randomized, placebo-controlled trial found that pregnant women who were given 100 μg of selenium per day, from the first trimester until the day of delivery, were less likely to develop pre-eclampsia, however, this was not found to be significant (p > 0.05). ^[42]

A systematic review and meta-analysis, concluded from thirteen observational studies and three randomized control trials, that there exists an inverse association of blood selenium levels and the risk of pre-eclampsia. This review found that supplementation of selenium significantly reduces the incidence of pre-eclampsia (p=0.02). ^[80] However, the authors of one of the studies which this meta-analysis uses, have critiqued this interpretation because the authors of the meta-analysis failed to distinguish that there was a significant reduction in selenium concentrations in umbilical venous samples in the pre-eclampsia group. The authors also critiqued several other aspects of the review, stating that the errors would affect the results of the meta-analysis. ^[81]

Several observational studies have found that women with lower levels of selenium in their blood are more likely to develop pre-eclampsia than women with adequate levels of Selenium in their blood. Supplementation of selenium has been demonstrated in randomized controlled trials to lower the incidence of pre-eclampsia.

6.1. General

Much danger of excessive selenium comes through the pro-oxidant compound sodium selenite (thrice oxygenated selenium bound to sodium); this compound is able to induce tumor death via its pro-oxidant abilities, but is also toxic to other cells.^[13]

6.2. Genotoxicity

In vitro studies noted that high Se intake can be toxic and have adversely effect on the integrity of genomic DNA in various tissues and organs.^[82] When human peripheral blood lymphocytes was exposed to high concentrations of two inorganic salts of selenium-sodium selenite (2.9 x 10^-5 M) and sodium selenate (2.65 x 10^-5 M), it was found to be lethal.^[83] One study that examined DNA oxidation in rats suggests that high dietary intake of inorganic selenium may induce DNA damage in the liver.^[84] Although the mechanisms responsible for the adverse effects of high doses of Se are not completely understood, the effects can be severe with DNA damage, oxidative stress, and cell death induction.^[82]

6.3. Human Toxicity

Toenails and fingernails damage^[85] can occur after high ingestion of selenium. Nail samples are in fact frequently used to estimate selenium status.^{[86][87][88][89]} 

One clinical trial examined the plasma response and toxicity reports from 24 men with prostate cancer who received either 1600 or 3200 mcg/day of selenized yeast for up to 24 months. The 3200 mcg/day doses produced more symptoms of selenium toxicity (garlic breath, brittle hair and nails, stomach upset, dizziness) than the 1600 mcg/day doses, but these symptoms were not severe and did not correlate with peaks in plasma selenium levels. The study suggests that doses of selenized yeast greater than 400 mcg/day can be given in controlled situations, for extended periods of time, without serious toxicity.^[22]

6.4. Side-Effects with Safe Usage

An observational study shows that dietary exposure to selenium compounds of around 300 mcg per day can have early toxic effect on endocrine function, particularly on the synthesis of thyroid hormones, and NK-cell suppression.^[90] One clinical trial randomized subjects to 100 mcg, 200 mcg, or 300 mcg selenium-enriched yeast or placebo tablets for 5 years and found that in euthyroid subjects, selenium supplementation decreased serum TSH and FT4 concentrations by 0.066mIU/I and 0.11 pmol/I, respectively, per 100 mcg/day increase.^[91]

Human experimental trials have associated selenium intake with an increased risk for type 2 diabetes.^[33] One observational study found that after a median follow-up of 16 years, subjects developed diabetes with an average dietary selenium intake of 55.7 mcg/day, with an odds ratio of 1.29 (95% CI: 1.10, 1.52) for diabetes associated with a 10 mcg/day increase in selenium intake.^[92] A clinical trial that assigned subjects with type 2 diabetes to 200 μg/day or placebo for 3 months revealed deterioration in blood glucose control and noted a significant increase in fasting plasma glucose by almost 20 mg/dL in the selenium group and a decrease of about 20 mg/dL in the placebo group.^[93] Another clinical trial assigned nondiabetic patients to selenium 200 mcg/day or placebo and found that after a follow up of about 7.7 years, selenium supplementation significantly increased the risk for the disease, with a hazard ratio of 1.55 (95% CI, 1.03 to 2.33).^[33] 

6.5. Case Studies

A case report of 201 subjects who ingested a liquid dietary supplement that contained 200 times the labeled concentration of selenium (~41,749 mcg/day) noted symptoms including diarrhea, fatigue, hair loss, joint pain, nail discoloration or brittleness, and nausea. Patients often continued to experience hair and nail changes, memory loss, mood swings, fatigue, muscle pains, and garlic breath 90 days after the exposure to selenium had ended.^[94] 

Another case of a misformulated dietary supplement which contained over 40,000 mcg of Se examined selenium exposure in 97 subjects through nail sample tests. Subjects self-reported high occurrences of dermatological lesions, muscle and joint pain, and neuropsychological signs and symptoms including fatigue, confusion, memory loss, anxiety, fingertip tingling, depression, anger, irritability, insomnia, dizziness and imbalance, eye and vision problems and headache.^[95] 

A case of xanthotrichia, or yellow hair discoloration, has been reported with selenium sulfide 2.5% shampoo and dihydroxyacetone.^[96]