SELENIUM DEFICIENCY VS. INSUFFICIENCY
Vladimir Badmaev, MD PhD
GreenSelenium® in a Changing World
Historically, minerals and trace elements were naturally abundant in the diet. Through decades of mass food production, combined with steady soil degradation through overharvesting, supply of minerals and trace elements like selenium in the food gradually decreased. Selenium is an essential trace element in nutrition because it is irreplaceable in sustaining health and prevention disease in humans and animals. Epidemiological studies indicate an association between low nutritional selenium status and increased risks of cancer and cardiovascular disease and numerous conditions due to lack of class of proteins (selenoproteins) requiring selenium for their physiological roles in the body. The nutritionally recommended dose of elemental selenium is estimated at 50 to 200 micrograms per day. The seleno-organic compounds, primarily L-(+)-selenomethionine, generally are recognized as safe and effective forms of nutritional and preferred selenium supplementation. The GreenSelenium® technology obtaining selenomethionine substantially lowers the byproduct molecules, i.e. methyl selenol and dimethyl diselenide, lowering the characteristic garlicky odor of selenomethionine, which also is obtained in an environmentally friendly process.
Mineral selenium and its role in the body
The nonmetal mineral selenium named from Greek selene or “Moon” was discovered in 1817 by Jöns Jacob Berzelius, a Swedish chemist and a physician. In the periodic tables, selenium (Se) is adjacent to elements sulfur and tellurium, and is a member of the sulfur family of elements, sharing some chemical properties with sulfur. Selenium is present in soil at concentrations ranging from 0.1 mcg to 1, 000 mcg/kg. In drinking water Se rarely exceeds 10 micrograms/liter with higher concentrations found in alkaline waters. In various geographic regions selenium is deficient in soil and water. Commercially, selenium is produced as a byproduct in the refining of the metal sulfide ores.
In the late 1950s the work of Schwartz and Foltz helped to elucidate the role of selenium as a necessary (essential) component of balanced nutrition and good health. Schwartz found that selenium could prevent a specific liver condition in experimental animals due to diets deficient in vitamin E, sulfur amino acids (cysteine, methionine) and selenium. In the 1970s Rotruck and colleagues discover that the enzyme glutathione peroxidase which operates the body’s own antioxidant, glutathione system (GSH), has selenium as an indispensable part of its structure. Glutathione peroxidase promotes oxidation of glutathione, which is a mechanism to neutralize free radicals, prevent lipid peroxidation and safeguard the integrity of cell membranes. The GSH which is a key anti-oxidant protecting the body exemplifies an important class of proteins which functionality depends on presence of selenium in the protein’s structure, i.e. class of selenoproteins.
In addition to the GSH, the mineral is included in between 50-100 different proteins in the body with a multitasking roles including building muscles, healthy bones, healthy sperm and preventing viral and bacterial infections. Some of the important selenoproteins discovered in mammals include:
* type I iodothyronine deiodinase (an enzyme necessary for the proper thyroid function and conversion of thyroxine (T4) into triiodotyronine (T3) – T3 is the active thyroid hormone);
* selenoprotein in the sperm mitochondria (assisting in sperm mobility – an important factor for fertility);
* selenoprotein found in skeletal muscle (assisting functioning of the muscles);
* selenoprotein in prostate (the potential importance of this selenoprotein stems from epidemiological studies that show an inverse relationship between the status of selenium and the incidence of prostate cancer);
* selenoproteins which may encode the human genes responsible for expression and regulation of cellular immunity important in preventing and combating bacterial and viral infections.
Selenium in health and disease
The role of selenium supplementation as an essential microelement for human health is becoming increasingly important because selenium deficiency in the food chain is now well recognized. Selenium deficiency poses a serious problem to livestock worldwide which ultimately may affect the selenium status in humans.
Selenium deficiency has been linked with a number of disease symptoms in different animals. [Table 1].
Table 1. Selenium Deficiency Associated Diseases in Livestock Animals
Disease Species Disease Species
Exudative diathesis Chicken Nutritional muscular dystrophy Fish
Nutritional pancreatic dystrophy “ “ Nutritional muscular dystrophy Horse
Encephalomalacia “ “ Hepatosis dietica Pig
Impaired immunodevelopment “ “ Mulbery heart disease “ “
Reduced egg production “ “ Nutritional muscular dystrophy “ “
Increased embryonic mortality “ “ Edema “ “
Impaired growth “ “ Impaired spermatogenesis “ “
Reduced fertility Cow Nutritional muscular dystrophy “ “
Retained placenta “ “ Un-thriftiness Sheep
Cystic ovarian disease “ “ Infertility in ewes “ “
Un-thriftiness “ “
Anemia “ “
Mastitis “ “
Human selenium deficiency has been well documented in the pathogenesis and pathology of Keshan disease - a multifocal myocarditis (inflammation of the heart muscle) occurring in a particular region of China, province of Keshan, where soil is lacking selenium. Besides cardiomyopathy the following clinical and/or laboratory manifestations of selenium deficiency in humans have been described: myositis (inflammation of the muscles), whitening of the fingernail beds, pseudoalbinism, and osteoarthropathy (degeneration of joints and bones) known as Kashin-Beck disease.
Role of selenium as body’s most important antioxidant
The reaction of GSH with hydrogen peroxide, an example of a free-radical, may illustrate the antioxidant mechanism of glutathione and the selenium containing glutathione peroxidase:
Reduced GSH + hydrogen peroxide ---> Oxidized GSH + Water
The oxidized glutathione formed in this reaction is regenerated to its reduced form by a subsequent reaction with nicotinamide-adenine-dinucleotide phosphate (NADPH). The discovery of the role of selenium in the glutathione system also provided a rationale for classifying selenium as an antioxidant, because it was established that the glutathione peroxidase-dependent mechanism protects cellular components from oxidative stress and damage.
The selenium dependent glutathione system is a key mechanism in maintaining the body’s homeostasis and preventing disease. In one study, glutathione concentrations were measured in 33 people over 60 years of age, residents of Michigan, and the values were related to the self-reporting of their health status. Glutathione concentrations correlated positively with age and good health. The association with health was independent of age.
Role of selenium in development and prevention of cancer
Despite conflicting research results including inverse, null and direct associations reported for some cancer types, the cancer prevention remains one of the major benefits of selenium, and selenium is the only mineral that qualifies for the FDA approved health claims for cancer reduction incidence. The most recent epidemiological study published in 2013 has found the low levels of blood selenium (below 60 µg/l) associated with a high risk of both lung and laryngeal cancers.
Correlation between selenium deficiency and higher death rates due to cancer has been found for both sexes worldwide. In a study conducted in China, a strong association was demonstrated between low selenium content in grains and the incidence of liver cancer. In South Africa, significantly lower blood selenium levels were demonstrated in populations with high incidence of esophageal cancer, as compared to populations with a low incidence of the disease. An inverse association was found between selenium levels in the water and cancer mortality in Texas. Low colorectal cancer mortality in Seneca County, New York State, was observed in conjunction with high environmental selenium - conversely, high colorectal cancer mortality (colorectal cancer is second deadliest cancer in the US causing 50,000 deaths per year in this country alone) was found in surrounding counties with low environmental selenium.
Selenium, as a single ingredient or in combination with other antioxidants (e.g. alpha-tocopherol and beta-carotene) has been shown to reduce total cancer incidence and mortality in cancer prevention trials. In a pioneering trial conducted by Dr. Larry Clark in the USA from 1983 to 1993 there was a 37% reduction in total cancer incidence with a 200 microgram supplement of elemental selenium daily for 10 years, as compared to the non-supplemented group. A 50% reduction in total cancer mortality (death) was also observed in the selenium supplemented population which developed cancer. In a preventive trial in China, the study population received 200 micrograms of elemental selenium for four years which resulted in a significantly lower incidence of primary liver cancer as compared to the placebo group. The results of the exemplified trials strongly indicate that selenium supplementation may reduce the incidence of, and mortality from, various forms of cancer.
The data on the role of selenium in cancer prevention is particularly important in view of epidemiologic data that implicate selenium deficiency in the development of cancer in various sites of the body including cancers of the liver, mammary glands, esophagus, stomach, colon, rectum, lung, urinary tract, prostate, female reproductive organs, thyroid, hematologic system, oral cavity, larynx, lungs and skin. However, the effect of selenium supplementation on cancer prevention may still depend on primary risk factors, e.g., smoking history, alcohol use, age, gender, and diet.
Interestingly, it has been reported that areas of low selenium ingestion also tend to be areas of greater affluence. Also, the level of environmental selenium may have an impact on the magnitude of the protective effects from nutritional supplementation of selenium. For example, nutritional intervention with selenium in areas with low environmental selenium, like Finland, may have a greater protective effect against cancer. Conversely, populations with levels of selenium exposure above or approaching the levels at which cancer risk plateau, may not benefit from dietary selenium supplementation. The anti-carcinogenic action of selenium may not be solely mediated by its antioxidant properties or alterations in the glutathione peroxidase function. Another anti-carcinogenic mechanism of selenium is restoring the programmed cell death in cancerous cells, i.e. restoring the mortality of cancer cells and/or ability of a damaged cell to repair its genetic code and replace malfunctioning organelle.
Selenium in prevention and management of infectious diseases
The potential protective effect of selenium in viral diseases including human immune-deficiency virus (HIV) infection has been considered because of selenium’s recognized effect against a number of viral pathogens and because symptoms of impaired immune response, similar to that in AIDS, were associated in vitro and in vivo with selenium deficiency.
The relationship between selenium deficiency and coxackie virus-caused myocarditis (inflammation of heart muscle leading to severe impairment the heart function) in mice has been studied. It was found that selenium deficient mice inoculated with the benign virus produced a mutant virus with a virulent phenotype, which resulted in severe myocarditis. Animals that had adequate levels of selenium did not develop the disease. The authors of this report hypothesize that this selenium adequate status prevented viral genome mutations directly and/or by strengthening the immune response to a viral challenge. According to a theory by Taylor on the mechanism of HIV infection, a class of selenoproteins may have a propensity to bind with viral genetic material (DNA), acting as a suppressor of HIV virus proliferation. According to Taylor’s theory, once the virus uses up the reserves of selenium in the infected cell, the virus’s repressed ability to proliferate is de-repressed, thus infecting adjacent cells in a "search" for the unexploited sources of selenium, thereby spreading the infection throughout the body.
There is general agreement that the nutritional requirement for selenium needs to be considered addressing the complex requirements of patients with compromised immune system and infectious disease, including AIDS patients. In a study of population of HIV patients in Africa (Malavi) poor selenium status has been shown to increase the risk of developing pulmonary tuberculosis. The effective dose of selenium required for intervention in the disease development is of particular importance. Some researchers predict that this dose needs to be higher than the nutritional dose range required for dietary selenium supplementation.
Selenium in thyroid health
The results of clinical evaluation of the role of selenium in thyroid function with population of healthy schoolchildren from northern Zaire, Africa, where goiter is endemic and selenium deficiency prevalent, showed that selenium supplementation corrected the low levels of serum selenium and red blood cell glutathione peroxidase activity. Supplementation of selenium in this study decreased serum levels of T4 without affecting the levels of T3, thyroid stimulating hormone and thyroxine-binding globulin. However, supplementation of selenium to the individuals in northern Zaire with severe impairment of thyroid function resulted in a significant decrease in serum levels of T4, with a significant increase in levels of thyroid stimulating hormone. In view of these results selenium supplementation, particularly in areas in which goiter is endemic, should be carefully considered, and possibly combined with iodine supplementation.
Selenium in cardiovascular health
Selenium supplementation may play role modifying the body’s homeostasis related to the cardiovascular health, in prevention of cardiovascular disease risks. Selenium deficiency in experimental animals significantly decreased aortic prostacyclin synthesis (a compound preventing blood clotting) but did not affect the platelet thromboxane synthesis (a compound increasing blood clotting). It has been postulated that the unusually high mortality rate from cardiovascular disease in southeastern Georgia may, in part, be due to selenium deficiency. Cardiovascular disease, a leading cause of mortality in the world, is no longer considered solely a disorder of blood lipids, but rather a disease process characterized by low-grade inflammation of the vascular lining (endothelial cells) and an inappropriate "wound healing response" of the blood vessels, leading to arterial calcification and atherosclerosis. Recent epidemiological study indicates that selenium in the body decreases with aging and the low selenium in elderly maybe associated with increased markers of chronic inflammation, e.g. interleukin-6. In the above mentioned study, the prevalence of selenium deficiency (serum Se <80 ug/L) in aging and old population was determined at 35.6% in men and 43.2% in women.
Selenium supplementation is increasingly considered to be nutritional adjuvant helpful in cardiovascular disease and also in patients with the irregular heartbeat. In one report, ventricular tachycardia, resistant to several standard therapeutic agents was normalized after selenium supplementation.
Selenium in metabolic diseases and diabetes
Despite conflicting research results including inverse, and potential direct associations with diabetes type 2 the preponderance of epidemiological, preclinical and clinical evidence indicates that selenium plays a significant role in prevention and management of diabetes type 2. Cardiovascular disease, nephropathy, neuropathy and retinopathy are major causes of morbidity and mortality among patients with diabetes, and the role of selenium supporting the internal antioxidant system is important in preventing and combating the condition. Essentially, diabetes is free-radical pathology and body’s primary antioxidant system, as previously mentioned the glutathione system depends on the dietary availability of selenium. Without an adequate supply of selenium the first line of antioxidant defense in diabetes, i.e. the glutathione will be compromised.
The beneficial role of selenium in diabetes has been found in both preclinical and clinical studies. When supplemented to diabetic animals, selenium augmented the antioxidant defense by increasing glutathione activity and this effect was more prominent with selenium in form of selenomethionine, rather than sodium selenite (inorganic form of selenium). The increase in glutathione levels exerted positive effects on glucose homeostasis especially in selenomethionine treated animals as compared to untreated diabetic controls. In a clinical study, a dietary selenium in healthy adults has been inversely associated with serum sialic acid levels, triglyceride levels as well as the insulin resistance.
In another clinical study direct relatives of patients with diabetes (i.e. relatives prone to diabetes) were evaluated for risk of cardiovascular disease. The direct relatives showed inverse correlation between serum selenium levels and the blood levels of c-reactive protein (hsCRP), insulin resistance, and homocysteine levels. The authors concluded that selenium deficiency may contribute to cardiovascular disease risk in relatives of diabetic patients. In an epidemiological study done at Albert Einstein College of Medicine, NY, the toenail selenium was lower among diabetic men as compared to healthy controls.
The importance of selenium supplementation in diabetes is further underscored by a clinical study that found the NF-kappaB activity, a factor linked to cardiovascular disease in diabetes, increased by 80% in diabetic patients. In patients receiving selenium supplementation the NF-kappaB activity was significantly reduced, reaching the same level as the non-diabetic control group. In conclusion, the authors of this study stressed the role of selenium supplementation in diabetes and its particular importance in prevention of the cardiovascular disease.
The joint study of Korean Yeungnom University and Harvard University evaluated two separate U.S. cohorts, including 3,630 women and 3,535 men, who were free of diabetes type 2 and heart disease at baseline in 1982-1983 and 1986-1987, respectively. In a follow-up through 2008, 780 cases of diabetes type 2 was diagnosed. The Se concentration was quantified in toenails, and the highest levels of selenium in toenails was associated with 24% reduction in the risk of developing diabetes type 2.
Safety and efficacy of selenium supplementation
The bioavailability, efficacy and ultimately the safety of selenium supplementation may depend on a number of factors, including the amount of selenium in the diet, its chemical form, its interaction with other nutrients and the physiological state of the host.
The biological effectiveness of seleno-organic (e.g. L-selenomethionine, gamma-glutamyl-Se-methylselenocysteine) compounds vs. inorganic selenium (sodium selenite) is one of the important aspects of safety and efficacy in selenium supplemeentation. L-selenomethionine is recognized as a safer and more biologically effective form of selenium than sodium selenite. The role of methionine in aiding the safe metabolism of selenium is part of that safety mechanism. Methionine yields in the body S-adenosylmethionine which provides methyl groups for the sequential methylation, an important aspect of the body detoxification process.
Seleno-organic compounds, like selenomethionine, are also generally recognized as biologically more effective that the inorganic forms of selenium such as selenite. Dietary supplementation with L-selenomethionine, sodium selenite and selenocysteine in experimental animals showed that the highest increase in tissue selenium levels was accomplished with L-selenomethionine.
Both organic and inorganic forms of selenium have a synergistic effect in lowering the risk of cancer when administered with vitamin A, vitamin E and beta carotene. On the other hand, any protective effect of sodium selenite against mammary carcinoma in rats was nullified by supplementation with ascorbic acid or vitamin C. It is significant to note that the protective effect of L-selenomethionine was not affected by vitamin C administration.
The preventive trials support the notion that the health benefits of selenium supplementation can be accomplished at much higher doses than the currently recommended 50 to 100 micrograms per day elemental selenium supplementation. Based on preventive trials building up the selenoproteins like glutathione the effective dose of selenium should be considered 200 micrograms per day.
Vanderbilt University jointly with Chinese Academy of Preventive Medicine has recently carried out a supplementation trial in a selenium-deficient population in China to assess the requirement for selenium as sodium selenite and as selenomethionine. One hundred twenty subjects were administered tablets containing no selenium (placebo) or up to 66 mcg Se/d for 20 weeks. Plasma was sampled before supplementation and at 4-wk intervals during supplementation. Comparing to the baseline, the increased levels of glutathione peroxidase were achieved with 37 mcg Se/d from selenomethionine and with almost double the amount of Se/d as selenite. In conclusion of the above cited paper the authors made the following statements:
- Selenium is an essential micronutrient with a recommended dietary allowance for adults of 55 mcg/day.
- Selenium functions as an essential constituent of selenoproteins.
- People in many areas of the world are selenium deficient and are unable to express their selenoproteins in health supporting range.
- Selenium as selenomethionine had nearly twice the bioavailability of selenium as selenite.
- RDA of selenium should be much higher than 55 mcg/day.
Because the essentiality of selenium for human nutrition is well established, and because it has considerable potential in the prevention and treatment of a broad range of pathology, its intelligent use is at stake now. The supplemental role of selenium should be stressed in both human and animal health.
The new generation of nutritional selenium in organic form
As previously mentioned the effective way increasing the blood levels of bioavailable selenium is to use seleno-organic compounds like L-(+)-selenomethionine, which are more bioavailable than inorganic forms of selenium like sodium selenite. However, the current manufacture process obtaining selenomethionine has a drawback yielding high levels of byproducts with a strong garlic-like odor; the process results in selenomethionine with high content of byproduct molecules, i.e. methyl selenol and dimethyl diselenide, which tend to evaporate and oxidize in room temperature, resulting in the odor typical of the currently available commercial products of selenium.
The new technology providing selenomethionine code-named GreenSelenium ™ provides an innovative and proprietary process for selenomethionine manufacture that significantly lowers the load of garlic-like odor producing byproducts in the end-product. In addition GreenSelenium technology is an environmentally friendly process, cutting off the polluting waste from the manufacture which, with the still practiced method is estimated at 40 liters/kg of the finished product.
The triage mechanism in selenium status and insufficiency
Selenium nutritional status has recently been explained with the triage mechanism. The word triage derives from the French trier meaning to sort and select. This term has been used on the battlefield by military doctors to prioritize treatments for survival of the wounded. In a similar way as practiced in a triage on the battlefield body selects means and ways, e.g. micronutrients and vitamins for an immediate need (survival) over the long-term needs by borrowing micronutrients from less critical depots in the body and securing the emergency requirements. To a large degree, the lack of dietary selenium is not clinically obvious, because this nutrient is prioritized to build essential selenoproteins at the expense of non-essential selenoproteins. However, in long term the insufficient status of selenium that prevents functioning of non-essential proteins may result in development of chronic degenerative conditions, e.g. cardiovascular disease and cancer and ultimately shorten the life span and quality of life. The triage explains and addresses a growing concern with clinically non-apparent deficiencies or insufficiencies of certain micronutrients, like selenium, and vitamins like vitamin K. The triage theory and insufficiency are particularly relevant to selenium status, since even modest low levels of selenium during the lifetime may increase risk of diseases of aging.
References available upon request.