Selenium Deficiency

Etiology

Selenium occurs naturally in soil, affecting the selenium content in plant-based foods. Brazil nuts, green vegetables, shiitake and button mushrooms, and various kinds of seeds, such as young barley seedlings, are excellent organic sources of selenium in regions with adequate selenium levels in the soil.[6]

Selenium yeast is another significant source of this essential mineral and is even used in bread production. Animals that consume selenium-rich plant-based foods, especially fish, seafood, beef, and poultry, are valuable sources of selenium in regions with an adequate supply. In plant-based foods, selenium is present in an organic form called selenomethionine, which has 90% bioavailability. In supplemental forms, inorganic variations such as selenate and selenite are utilized, exhibiting high levels of bioavailability.[7]

Several factors can affect selenium content within various foods. The rate at which plants absorb selenium plays a pivotal role, and it is determined by factors such as plant type, pH levels, soil composition, rainfall patterns, microbial activity, and other biogeochemical elements.[8] Selenium deficiency results from inadequate dietary intake of selenium, typically due to a lack of selenium sources in a specific region. Interestingly, many selenium-deficiency diseases are associated with concurrent vitamin E deficiency.

As per the April 2000 recommendations, the Recommended Dietary Allowance (RDA) for selenium is set at 70 µg/d for men and 55 µg/d for women to support optimal biological functioning. However, this level is considered low based on alternative studies, with some literature suggesting a minimum requirement of 90 µg/d per adult. The World Health Organization specifies a tolerable upper intake level for selenium in adults aged 19 and older, established at 400 µg/d or 5.1 µmol/d. Consuming amounts beyond this limit is considered potentially toxic.[9]

Epidemiology

Selenium deficiency impacts a significant global population, ranging from 500 million to 1 billion individuals, primarily due to insufficient dietary intake. In the United States, regions with the lowest selenium levels in soil and plant sources include the Northwest, Northeast, Southeast, and areas of the Midwest adjacent to the Great Lakes. The Great Plains and the Southwest generally possess adequate selenium content.[10]

Notably, individuals with conditions such as phenylketonuria or other diet-related diseases are especially vulnerable to selenium deficiency. This susceptibility arises from their dietary restrictions, frequently resulting in insufficient consumption of products rich in this vital element. 

Selenium levels in many parts of Europe are notably lower than those in the United States, with Eastern Europe having a lower average selenium intake than Western Europe.[11] Finland initially had the most insufficient selenium intake, but they took measures to address this issue by fortifying their fertilizers with selenium, resulting in a positive shift. Brazil nuts are the primary source of selenium in these countries, while crab, liver, other shellfish, and fish serve as moderate sources. However, the utility of these sources is limited by the existence of various selenium compounds within fish and the occurrence of known contaminants such as arsenic and mercury.

Selenium deficiency has been extensively documented in countries such as China and New Zealand.[12][13] In the Middle East, selenium intake varies significantly based on socioeconomic status—a pattern substantiated by the limited available data.

Pathophysiology

Selenium deficiency can lead to various systemic issues, some of which are listed below.

Cardiovascular System

Keshan disease is a type of congestive cardiomyopathy characterized by symptoms like heart failure, cardiac enlargement, electrocardiogram (ECG) irregularities, gallop rhythm, and cardiogenic shock. This condition predominantly impacts children and women of reproductive age. Initially discovered in areas of China plagued by selenium deficiency, Keshan disease was associated with a significant morbidity rate of 50%, often accompanied by occurrences of mortality. Additional factors such as chemical exposure or the presence of Coxsackievirus frequently compounded the severity of the disease.[14][15] 

Notably, selenium supplementation has shown promise in combating this ailment. The use of fortified salt enriched with selenium has been associated with a reduced incidence of Keshan disease, offering a potential approach for prevention and management.

Endocrine System

Among the 35 identified selenoproteins, 3 hold a significant role and are recognized as iodothyronine deiodinases—pivotal contributors in thyroid hormone metabolism. Notably, the thyroid gland contains the highest selenium concentration among all organs in the human body. The initial iodothyronine deiodinase converts inactive T4 into its active form, T3. The second enzyme is abundant within the central nervous system, brown fat, and skeletal muscles, contributing to the activation of thyroid hormones. The third enzyme is involved in deactivating thyroid hormones, serving as a crucial regulatory element in thyroid function.[16][17]

Immune System and Host Defense

G-Px is a selenium-dependent enzyme that protects cell membranes and organelles containing lipids from peroxidative damage through inhibition and neutralization processes. This enzymatic action, combined with vitamin E, preserves the structural integrity of the cell membranes and counteracts the effects of hydrogen peroxide through redox reactions with glutathione. Selenium deficiency exacerbates redox byproduct toxicity and leads to oxidative damage to cell membranes.

Furthermore, selenium deficiency has been observed to transform otherwise benign viruses within hosts into highly virulent pathogens, potentially playing a role in developing conditions such as Keshan disease. The recurring emergence of novel influenza virus strains within China with its selenium-deficient belt has new implications, highlighting the link between immune response and selenium deficiency.

Individuals living with HIV infection require selenium as a crucial nutrient. Over 20 studies have reported the correlation between declining plasma selenium levels and diminishing CD4 counts. Notably, selenium has been demonstrated to facilitate the differentiation of CD4+ T cells into T-helper-1 (Th1) cells. This phenomenon has been associated with decreased hospital admissions, especially for co-infections, such as mycobacterial infections, in individuals with HIV. Thus, it appears that selenium's influence is related to impeding the progression of HIV to AIDS.[18]

In addition to its effects on HIV, selenium protects individuals with hepatitis B or C, impeding the transition to malignancy. This multifaceted role underscores the broader significance of selenium in immune function and disease progression.

Although selenium has been associated with an improved immune response, its role in cancer prevention is somewhat restricted. Selenium has been known to augment the cytotoxic effect of natural killer cells and increase the activity of T cells and macrophages. In addition, selenium stimulates antibody production and exhibits a synergistic relationship with vitamin E regarding the cellular aging process.

In addition to its immunological functions, selenium extends its protective effects to mitigate the toxicity of heavy metals, including lead, cadmium, arsenic, mercury, and organic compounds such as paraquat herbicides. These attributes underline selenium's diverse and significant role in safeguarding the body from a spectrum of potentially harmful substances.

Musculoskeletal System

Kashin-Beck disease is a debilitating condition known for causing deformities in bones, cartilage, and joints, leading to joint enlargement and restricted mobility. This ailment is particularly prevalent in Tibet, China, Siberia, and North Korea. The origin of this disease is multifaceted, among which selenium deficiency is an implicating cause.[19]

Keshan disease and muscular syndrome have been reported in individuals receiving total parenteral nutrition without selenium supplementation. In these cases, symptoms described include intermittent myalgias, tenderness, and the eventual development of white fingernail beds.

Neurological and Psychiatric Systems

Research has indicated that inadequate selenium intake can contribute to depressed mood and increased hostile behavior. Notably, during a selenium deprivation state, the brain receives prioritized supplies of selenium, indicating the importance of selenium in maintaining brain health. Furthermore, selenium deficiency has been observed to affect the turnover rate of certain neurotransmitters.

Reproductive System

Selenium plays a pivotal role in various aspects of male reproductive health. It is essential for testosterone biosynthesis and contributes to the formation and development of normal spermatozoa. Moreover, testicular tissue contains significant selenium concentrations responsible for maintaining sperm quality and male fertility health. 

Although the connection between selenium and male reproductive health is well-established, there is relatively limited information regarding the relationship between selenium and female fertility. Additional research is required to gain a comprehensive understanding of the potential role of selenium in supporting female reproductive processes and fertility.

History and Physical

The assessment of selenium deficiency involves a comprehensive approach, which includes taking the patient's medical history and performing physical examinations, to gather relevant information and identify potential symptoms. Severe selenium deficiency primarily manifests with symptoms affecting the heart muscles and joints. A moderate deficiency is notably associated with increased male infertility, heightened risk of prostate cancer, and susceptibility to neurological disorders.[15] Therefore, a comprehensive evaluation is essential due to the broad spectrum of symptoms linked to selenium deficiency. 

Patient History

Medical history: The healthcare provider gathers information about the patient's medical history, including any preexisting conditions, current medications, and family history of selenium-related disorders.

Dietary history: The healthcare provider seeks information about the patient's diet, focusing on selenium-rich foods such as nuts, seeds, seafood, and vegetables. Particular attention is given to any dietary restrictions or significant changes in eating habits.

Geographical location: The healthcare provider determines the patient's geographical location or travel history, as regions with selenium-deficient soil may increase the risk of deficiency.

Symptom assessment: The healthcare provider investigates any symptoms associated with heart health, joint discomfort, male infertility, neurological issues, growth disorders in children, or any other relevant complaints of patients.

Physical Examinations

Cardiovascular examination: The healthcare provider evaluates the heart's function, including heart rate, rhythm, and any signs of cardiac enlargement or irregularities.

Musculoskeletal examination: The healthcare provider examines the patient's joints for tenderness, swelling, and restricted movement. The presence of specific symptoms such as rheumatoid arthritis, abnormally shortened fingers and toes, or growth disorders in areas characterized by selenium-deficient soil should raise heightened suspicion of selenium deficiency. This is particularly relevant when evaluating children between the ages of 5 and 13.

Neurological examination: The healthcare provider evaluates the patient's neurological function, including sensory perception, reflexes, and coordination, while looking for any signs of neurological disorders.

Skin and nails: The healthcare provider inspects the patient's skin for any symptoms of selenium deficiency, such as skin texture or pigmentation changes. They also examine the patient's nails for signs of white spots or brittleness.

Reproductive health assessment: The healthcare provider inquires about fertility concerns, conducts relevant examinations for male patients, and gathers information about menstrual irregularities or other reproductive issues for female patients.

Growth assessment: The healthcare provider monitors growth patterns and assesses for any growth disorders in children.

General physical health: The healthcare provider conducts a comprehensive physical examination to assess the patient's overall health status, paying attention to any signs that could indicate selenium deficiency.

Evaluation

Evaluating selenium deficiency involves laboratory tests, radiographic assessments, and other clinical measures. However, it is important to note that although some guidelines exist, standardized protocols for selenium deficiency evaluation may not be universal.

Selenium Deficiency Evaluation Tests and Imaging

Tests commonly used to assess selenium deficiency in individuals are mentioned below.

Serum selenium levels: Evaluating serum selenium concentration is a standard method to assess selenium deficiency. National and international guidelines often provide reference ranges. For example, the U.S. Institute of Medicine recommends a reference range of 70 to 155 μg/L for selenium in serum.

Plasma G-Px activity: This test measures the activity of the selenium-dependent enzyme G-Px and can offer valuable insights into selenium status.

Urinary selenium levels: The urinary selenium levels can reflect recent selenium intake, although their interpretation can be complex due to variations in urinary excretion.

X-ray imaging: In cases of suspected Kashin-Beck disease or other skeletal abnormalities related to selenium deficiency, x-rays can assist in identifying bone and joint deformities.

Magnetic resonance imaging (MRI): MRI can be used to assess joint and tissue health, especially when symptoms such as joint pain or restricted movement are present.

Bone density scans: Bone density scans or dual-energy x-ray absorptiometry (DEXA) scans assess bone health and density and can identify selenium deficiency, which may affect bone structure and increase the risk of fractures.

Selenium deficiency can present with a wide range of symptoms and is often more prevalent within a community rather than occurring sporadically. When suspicion arises, serum selenium levels or selenium levels in scalp hair or nails can be assessed, as a strong correlation exists between serum and hair or nail selenium levels.

In regions where deficiency is endemic, scalp hair samples are preferred over blood samples due to ease of collection by unskilled workers. Additional parameters for assessment include measuring G-Px activity in various blood components, including plasma (G-Px3), erythrocytes (G-Px1), thrombocytes (G-Px1), or whole blood (G-Px1 and G-Px3). Another effective laboratory indicator of selenium status in patients is the selenoprotein P (SePP) concentration.[20]

Treatment / Management

Selenium deficiency is typically a concern that affects entire communities at the population level rather than being an isolated individual issue. Biofortification strategies have been implemented to address this challenge, which involves soil enrichment through agricultural practices. Another approach involves increasing the selenium content of food sources, which is achieved by supplementing animal fodder with selenium compounds. This method can lead to selenium-enriched eggs or egg yolks, which are more effective in boosting nutritional selenium intake.

Selenium-fortified eggs, meat, and milk have been successfully introduced in many countries. Harnessing microorganisms to produce functional foods, such as selenium yeast, is an innovative method. This approach highlights efforts to combat selenium deficiency and improve public health and nutrition.[21]

Organic selenium sources typically have a slower accumulation of toxic levels than the more rapid potential of selenite and selenate supplementation, which are inorganic salt forms of selenium supplements. However, using inorganic salts offers a swift means to address selenium deficiency in cases of acute and immediate deficiency. The recommended supplementation level to target is approximately 90 mcg/d for adults.

According to the World Health Organization, the upper limit for selenium intake in adults 19 and older is 400 µg or 5.1 µmol/d. Exceeding this limit is considered hazardous due to potential toxicity. Emphasizing a well-balanced diet is the most effective approach to preventing selenium deficiency, thereby ensuring optimal health and avoiding the need for excessive supplementation.[9]

Differential Diagnosis

Selenium is a mineral that can influence various systems of the body. The conditions that should be considered when suspecting a case of selenium deficiency include Addison disease, anemia, anovulation, autoimmune thyroid disease and pregnancy, cardiac tamponade, constipation, euthyroid sick syndrome, goiter, hypothyroidism, nutritional cardiomyopathy, pericardial effusion, pituitary macroadenomas, prolactin deficiency, thyroid lymphoma, and T4-binding globulin deficiency.

Prognosis

The prognosis for selenium deficiency varies based on factors such as the severity and duration of deficiency, the individual's overall health, and the effectiveness of intervention measures. If left untreated, selenium deficiency can cause various health issues, including impaired immune function, cardiovascular effects, reproductive and fertility problems, thyroid dysfunction, neurological symptoms, and musculoskeletal abnormalities.

The prognosis for selenium deficiency typically improves with timely recognition and appropriate intervention. Selenium deficiency can often be resolved through dietary modifications or supplementation. After correcting the deficiency, many associated symptoms and health risks can be reversed. However, the extent and recovery speed can vary among individuals depending on the severity of the deficiency and the individual's underlying health status.

Although mild-to-moderate selenium deficiency can be effectively managed, severe or prolonged deficiency can result in irreversible health complications. Notably, severe selenium deficiency is independently associated with reduced exercise tolerance, a 50% higher mortality rate, and mitochondrial dysfunction in vitro within human cardiomyocytes.[22]

Complications

Selenium deficiency can be associated with various complications, including thyroid disorders, cardiomyopathy, male and female infertility, heart failure [23], miscarriage, preeclampsia, fetal growth restriction, Keshan disease, Kashin-Beck disease, cognitive decline, preterm labor, and gestational diabetes.[24]