Selenium: Clinical Use. Dosage

DEFICIENCY STATES: PREVENTION AND TREATMENT

Traditionally, selenium supplementation has been used to treat deficiency or prevent deficiency in conditions such as malabsorption syndromes.

CANCER: PREVENTION AND POSSIBLE ADJUNCT TO TREATMENT

Selenium supplementation is used to reduce total cancer incidence and mortality. Chemoprevention Collectively, geographical studies, epidemiological data, laboratory bioassays, studies in over 12 different animal models and human intervention trials generally support a protective role for selenium against the development of cancer. Populations who live in low selenium environments and have low selenium intakes tend to have higher cancer mortality rates. However, the results from epidemiological studies have been less consistent and show the effect is strongest in males.

Total cancer incidence and mortality The Nutritional Prevention of Cancer Trial was a large multicentre, double-blind, randomised, placebo-controlled trial conducted with 1312 patients with a history of basal cell or squamous cell carcinomas of the skin, which investigated the effects of 200 µg selenium daily (as 500 mg brewer’s yeast) as a cancer protective agent. Selenium supplementation in this population did not alter future incidence of skin cancer; however, it significantly reduced total cancer mortality, total cancer incidence by 37% and the incidences of lung, colorectal and prostate cancers by 46%, 58% and 63%, respectively. Results from further continuation of the trial has continued to find a protective effect for selenium in total cancer incidence and the individual cancers; however, this now appears to be restricted to people with low baseline plasma levels and most pronounced for colorectal cancer and current smokers, whereas protective effects in prostate cancer was further restricted to lower baseline levels of prostate-specific antigen (PSA: ≤4 ng/mL). Liver cancer A trial involving 130,471 individuals living in a high-risk area for viral hepatitis and liver cancer (Quidong, China) found that table salt enriched with sodium selenite reduced the incidence of liver cancer by 35% during the 8-year follow-up period, whereas no changes were observed for the control groups. Additionally, incidences of liver cancer began to rise after withdrawal of selenium supplementation.

Prostate cancer Epidemiological and clinical data suggest that selenium may prevent prostate cancer. To date, the largest case control study involved 33,737 males and identified an association between higher selenium status and a reduced risk of prostate cancer. The study showed that men consuming the most dietary selenium (assessed indirectly by measuring toenail selenium levels) developed 65% fewer cases of advanced prostate cancer than those with the lowest intake.

Strong evidence for a protective effect of selenium against prostate cancer comes from the Nutritional Prevention of Cancer Trial, as described above, in which the incidence of prostate cancer was reduced in the selenium group by two-thirds as compared to placebo. Further follow-up has revealed that selenium supplementation continues to show a marked reduction on the incidence of prostate cancer with strongest effects seen in men with a PSA <4 ng/ml and those with the lowest serum selenium levels at study entry.

Currently underway is the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which is a randomised, prospective, double-blind study designed to determine whether 200 µg l-selenomethionine, 400 mg of racemicalpha-tocopheryol and an optional multivitamin containing no selenium or vitamin E can reduce the risk of prostate cancer among healthy men. It is anticipated that over 32,000 men will be involved in the study and final results will be available in 2013. Stomach and oesophageal cancer A large study of nearly 30,000 people demonstrated a protective effect for a combination of selenium, beta-carotene and vitamin E against the development of cancer of the gastric cardia and oesophagus. Supplementation also reduced the cancer mortality rate compared with those not receiving supplementation. Protective effects on total cancer deaths developed slowly, appearing after 1 year of treatment and the effect on stomach cancer appeared after 2 years.

REDUCING MORTALITY FROM HIV INFECTION

Selenium appears to be important in HIV infection, with plasma selenium a strong predictor of disease outcome in both adults and children.

Low selenium status is common in HIV-positive patients and is associated with a decline in Th (CD4) cell counts. It is also associated with an increased incidence of mycobacterial diseases in HIV-1 -seropositive drug users. One small intervention trial using low-dose selenium supplements (80 µg/day with 25 mg vitamin E) over 2 months has shown an improvement in general symptoms but no alterations to immunological or haemotological parameters.

CARDIOVASCULAR DISEASE PREVENTION

Selenium may decrease cardiovascular disease mortality; however, epidemiological studies have produced mixed results.

A case-control study from a population of 11,000 people found that individuals with low serum selenium levels had a two- to three-fold increase in cardiovascular morbidity and mortality. A more recent study of just over 3000 middle-aged and elderly men also established an association between low serum selenium levels and a significantly increased risk of ischaemic heart disease. Alternatively, no association was identified between serum selenium levels and coronary deaths or myocardial infarctions in a study of 1110 men; however, a significant association with stroke mortality was detected. No significant primary preventative effect was seen for selenium supplementation (200 µg/day) and incidence of cardiovascular disease, myocardial infarction, stroke or all cardiovascular disease mortality in the Nutritional Prevention of Cancer study. Lack of association was confirmed when analyses were further stratified by tertiles of baseline plasma selenium concentrations.

With regard to secondary prevention, an intervention study conducted by Korpela et al (1989) in subjects having suffered acute myocardial infarction has produced encouraging results. The randomised, double-blind trial compared the effects of selenium-rich yeast (100 µg/day) with placebo, concurrently with standard treatment in 81 patients with acute myocardial infarction. During the 6-month follow-up period, there were no cardiac deaths in the selenium-treated group compared with four receiving placebo, and two non-fatal re-infarctions in the placebo group compared with only one receiving selenium supplementation.

ASTHMA

Asthma, respiratory symptoms and ventilatory function have been associated with lowered circulatory selenium status and glutathione peroxidase activity. When these observations are coupled with in vivo evidence of anti-inflammatory activity in the lung for selenium, it is not surprising that there is growing interest in using selenium supplementation to improve asthmatic symptoms and disease management. A small number of intervention studies have been conducted, producing mixed results.

Hasselmark et al conducted a randomised double-blind study involving 24 patients with intrinsic asthma. A dose of 100 µg sodium selenite was administered for 14 weeks, resulting in significant increases in serum selenium and platelet glutathione peroxidase activity, while no changes were observed with placebo. Clinical results varied, with significantly more treated patients improving on several parameters of lung function such as airway responsiveness, clinical examination, medication use, and subjective patient impressions. However, there were no significant improvements over baseline in any individual clinical parameter. A small pilot study of 17 asthmatics dependent on corticosteroid medication found that a dose of 200 µg selenium daily taken over a 96-week period reduced both inhaled and systemic corticosteroid requirements. The same study observed selenium supplementation enhancing immunity.

AUTOIMMUNE THYROIDITIS

Selenium supplementation may improve inflammatory activity in chronic autoimmune thyroiditis patients, as evidenced by a significant reduction in the concentration of thyroid peroxidase antibodies (TPO-Ab) to 63.8% in selenium-supplemented subjects versus 88% (P = 0.95) in placebo subjects. The randomised study of 70 females (mean age 47.5 years) compared 200 µg sodium selenium daily orally for 90 days to placebo. A follow-up crossover study of 47 patients from the initial 70 was conducted for a further 6 months. The group that continued to take sodium selenite(200 µg/day) experienced further significant decreases whereas the group that ceased selenium use experienced a significant increase. The patients who received 200 µg sodium selenite after placebo also experienced a significant decrease in levels of TPO-Ab.

RHEUMATOID ARTHRITIS

Selenium supplements have been used in RA because of its antioxidant activity and the observation that some patients with RA have been reported with low selenium status. One double-blind, placebo-controlled intervention study of 55 patients with moderate RA found that both placebo and selenium appeared to have significant effects on a number of symptoms; however, only selenium significantly improved arm movements and sense of wellbeing.

LOWERED MALE FERTILITY

Xu et al (2003) identified a significantly positive correlation between selenium levels and sperm density, sperm number, sperm motility and sperm viability in human volunteers. Supplementation with selenium in selenium-replete subfertile men has been shown to improve sperm motility and the chance of successful conception in over half of treated patients. When taken with vitamin E over 6 months, selenium produces a statistically significant increase in sperm motility, per cent live and per cent normal spermatozoa, with effects reversing after supplement cessation. Although results are encouraging, particularly for subfertile men with low selenium status, one negative intervention trial was located that found that supplementation had no effect.

GENERAL IMMUNE ENHANCEMENT

Several intervention trials of either double-blind or open design have shown selenium supplementation can enhance immune function and decrease the risk of developing certain infections in selenium-replete subjects, healthy adults and the elderly.

The largest was a 3-year study of 20,847 people that showed that substituting conventional table salt with table salt fortified with sodium selenite significantly reduced the incidence of viral hepatitis compared with controls provided with normal table salt.

MOOD ELEVATION AND REDUCED ANXIETY

Considering that low dietary intakes of selenium have been linked with greater incidence of anxiety, depression and tiredness, several research groups have investigated whether higher dietary intakes or selenium supplementation will elevate mood and/or reduce anxiety. Currently, results are equivocal; however, it appears that selenium-replete individuals are most likely to respond to supplementation, if a response is observed.

An early double-blind, crossover, study showed that short-term selenium supplementation (100 µg/day for 5 weeks) significantly elevated mood and decreased anxiety, depression and tiredness, with effects most marked in people with low dietary intake. A study of 30 selenium replete men who were fed either a low (32.6 µg/day) or a high (226.5 µg/day) selenium diet for 15 weeks found that the mood of those with the higher selenium intake increased whereas mood worsened with low intake. Alternatively, another study involving 11 men of adequate selenium intake failed to show effects on mood when high (356 µg/day) and low (13 µg/day) selenium diets were followed for 99 days. Most recently, a large (n = 448), 2-year, randomised study also failed to find evidence that additional selenium enhanced mood or any of its subscales, despite significant increases in plasma selenium levels. This study compared the effects of 100, 200 or 300 µg/day of selenium to placebo for effects on mood and QOL. Selenium supplementation was given as high-selenium yeast, SelenoPrecise™ (Pharma Nord, Vejle, Denmark).

REDUCING MORBIDITY IN PRE-TERM BABIES

Preterm infants are born with slightly lower selenium and glutathione peroxidase concentrations than term infants and have low hepatic stores of selenium. In very preterm infants low selenium concentrations have been associated with an increased risk of chronic neonatal lung disease and retinopathy of prematurity. Although the full consequences of low selenium concentrations in this population are not fully known, observation from animal studies has found an association between selenium deficiency and increased susceptibility to oxidative lung injury. This has special significance for sick, very preterm infants as they are exposed to many possible sources of oxygen radical products, including high concentrations of inspired oxygen. A Cochrane review of three randomised studies that reported outcomes on 297 infants receiving selenium supplements and 290 control infants concluded that selenium supplementation in very preterm infants is associated with benefit in terms of a reduction in one or more episodes of late-onset sepsis, but is not associated with improved survival, a reduction in neonatal chronic lung disease or retinopathy of prematurity. It should be noted that most of the evidence derives from research conducted in New Zealand, a country with low soil and population selenium concentrations, and may not be readily translated to other populations.

Selenium: Other Uses

Used in combination with other antioxidants or administered intravenously, selenium has been used in pancreatitis and as adjunctive therapy in cancer patients.

RADIATION-ASSOCIATION LYMPHOEDEMA

Oral sodium selenite (350 µg/m2 body surface area) was given daily for 4-6 weeks to 52 patients with extensive, persistent or progressive lymphoedema from radiation and resulted in the majority experiencing some reduction in oedema. A further study of 48 patients found that sodium selenite supplementation had a positive effect on secondary lymphoedema caused by radiation therapy alone or by irradiation after surgery. The group consisted of 12 patients with oedema of the arm and 36 with oedema of the head-and-neck region.

Selenium: Dosage Range

RECOMMENDED DIETARY INTAKES

Children

• 1-3 years: 25 µg

• 4-8 years: 30 µg

• 9-13 years: 50 µg

• 14-18 years:
Boys: 70 µg
Girls: 60µg

Adults

• Males >18 years: 70 µg

• Females >18 years: 60 µg

Pregnancy: 65 µg

Lactation: 75 µg

ACCORDING TO CLINICAL STUDIES

Asthma: 100-200 µg/day of sodium selenite.

• Cancer prophylaxis: 200 µg/day selenium (supplied as 500 mg brewer’s yeast).

• Infertility: 100 µg/day.

• Mood disturbances: 100 µg/day.

• Post myocardial infarction: selenium-rich yeast 100 µg/day.

• Rheumatoid arthritis: 200 µg/day.

• Autoimmune thyroiditis: 200 µg/day sodium selenite.

• HIV positive status: 80 µg/day has been used but it is most likely that higher doses are required.