Case Study

A 55-year-old, previously healthy woman sought medical attention concerning a six-week history of diarrhea followed by progressive hair loss. The hair loss began two weeks after the onset of diarrhea and was first noted on her head in a diffuse, symmetrical distribution. Subsequently, the hair loss progressed to the axillae, genitalia and extremities. She also complained of generalized muscle cramps, joint pain, fatigue and difficulty with concentration. A recent evaluation by her primary medical provider revealed normal serum chemistries, hematology and thyroid studies.

On physical examination, she appeared non-toxic with normal vital signs and a weight of 58 kg. Diffuse generalized alopecia was noted except for sparing of the hair present on her eyebrows (Figure 1 top). Her fingernails had reddish discoloration and Mees' lines (Figure 1 bottom). Neurological examination revealed no weakness or focal deficits.

About one week before the start of her diarrhea, she and her husband had received a new shipment of a liquid nutritional supplement that they were taking in order improve their health. This supplement was the same brand and formulation that they had been taking for several years without apparent adverse effects. The supplement's stated ingredients included multiple vitamins, trace minerals and elements, including selenium. The patient's environmental history did not reveal any additional possible toxic exposures, and she was not taking any other medications to explain her symptoms.

Fourteen days after the patient's last consumption of the nutritional supplement, her serum selenium level was measured by inductively coupled plasma dynamic reaction cell mass spectrometry. This level was markedly elevated at 534 micrograms per liter (normal 80-150 micrograms per liter). The newest bottle of the nutritional supplement was then analyzed and found to have a selenium level of 800.5 micrograms per milliliter, which was approximately 300 times the amount stated on the label. Given the patient's reported dose of 30 milliliters per day, her resultant daily selenium intake was approximately 24,015 micrograms- over 400 times the U.S. recommended allowance of 55 micrograms per day.(1) The offending supplement was voluntarily recalled from the market after the formulation error was discovered.

After being diagnosed with selenium toxicity, the offending dietary agent causing this toxicity was stopped. Over the next four months, most of our patient's symptoms resolved. Her hair returned to baseline and her nails began the growth process. She did note significant pain as her damaged nails eventually sloughed off and new growth began. Eight months after cessation of the product, our patient felt that she had returned to normal without residual effects.

Background

Selenium is a non-metal element that is present naturally in large quantities in the earth's crust and in the soil of various geographic regions. It is also prevalent in meats, grains and nuts. These food sources, as a part of a balanced diet, typically provide enough selenium to meet daily nutritional requirements.(2)(3) Given the abundance of commonly consumed foods containing selenium, it would be exceedingly rare for a healthy individual consuming a traditional American diet to become selenium deficient.

In 1817, the Swedish scientist Jons Berzelius discovered selenium while investigating an outbreak of a diarrheal illness in factory workers. Initially, the unknown toxin was thought to be a previously known element, tellurium, but further testing identified this to be something new. Since "tellus" was Latin for "earth", in contrast he named the new substance selenium from the Greek word "selene," which represented the moon.(4) On the periodic table of elements, selenium is located in the same group as oxygen, sulfur and tellurium. Given its similar properties to sulfur, it is easy to see why selenium interacts in many physiological processes.

Selenium can exist in elemental, organic and inorganic forms, and it can achieve several different oxidation states. The elemental and inorganic forms of selenium (selenides, selenites, selenates) are generally considered more toxic, but these have less oral absorption. Most of the selenium consumed as part of a normal diet is in the organic form as dimethylselenide or selenobetaine. However, multivitamins and dietary supplements commonly include inorganic forms of selenium such as sodium selenate. Thus, patients can have significant exposures to both organic and inorganic forms of this element.

Selenium Physiology

Selenium is an essential micronutrient with several important physiologic roles in the human body. One of these involves the incorporation of selenium in the active sites of enzymes. By definition, enzymes are proteins that facilitate the conversion of one substance into another without being consumed in the conversion process. The efficiency of an enzyme depends in part on the strength of bond between the substrate and enzyme at the active site. Enzymes that contain selenocysteine residues in their active sites instead of just cysteine a stronger nucleophile, allowing for more reactivity. This increased reactivity makes possible participation in the detoxification of reactive oxygen species (ROS).(9)(10)

When an enzyme contains a selenocysteine in the active site, it is termed a selenoprotein. The most familiar selenoprotein in the body is glutathione peroxidase. This enzyme is the best studied of the selenoproteins. Using reduced glutathione (GSH) as a substrate, glutathione peroxidase catalyses the reduction of hydrogen peroxide to water.(4) Glutathione peroxidase demonstrates the important role of selenoproteins in reduction-oxidation (redox) physiology. This enzyme limits oxidative stress on the body by detoxifying reactive oxygen species (ROS).

Other selenoproteins of note are the iodothyronine deiodinases. This family of enzymes plays a role in converting thyroxine (T-4) to the predominantly active thyroid hormone, triiodothyronine (T-3) or, in times of severe physiologic stress, to inactive reverse T-3.(7) These conversion pathways are integral to the maintenance of normal physiologic homeostasis, while allowing metabolic adaptation to severe stress or injury.

Another selenoprotein enzyme, thioredoxin reductase, plays an important role in regenerating antioxidants such as vitamin C. It also helps regulate both cell growth and viability.(8) Because of its function in cell growth and division, thioredoxin reductase is actively being investigated as both an immunomodulator and a chemotherapeutic agent.

There are other selenium containing proteins in the body, for example, selenomethionine. Though its exact functional effects have not been fully elucidated, selenomethione may simply represent a storage protein for selenium. Other potential storage locations for selenium include plasma proteins (such as albumin) which are known to be selenium binders. Because selenium plays important roles in normal physiology, there are clinical consequences when too much or too little selenium is stored in the body.

Selenium Toxicity

Selenium toxicity, known as selenosis, is diagnosed very infrequently. Information regarding its long-term health outcomes does not exist. Previous reports of selenosis have described symptoms of nausea, vomiting, fatigue, irritability, paresthesias and hair loss.(9)(10)(11) Most people with selenosis are extremely difficult to diagnose early in their course as their initial symptoms do not differ significantly from a typical viral illness. Given the infrequent diagnosis of selenosis, clinicians rarely consider it until the later onset of hair loss.

The case described earlier in this Cyberounds^® typifies the clinical manifestations of selenium toxicity. However, the pathophysiological mechanisms of this toxicity have only been partially elucidated. The hair loss has been attributed to the disruption of structural proteins in keratin. It is proposed that selenium interpolates into disulfide bridges, causing a structural weakness that leads to hair loss.(12) In contrast to site-specific, androgen-induced hair loss or alopecia areata, hair loss caused by selenium toxicity is generalized.(13)

The nausea, vomiting, fatigue, irritability and paresthesias in selenosis are similar to those symptoms associated with arsenic and other metal toxicities. Despite these similarities, no direct biochemical pathways have yet to be identified by which selenium might exert these effects, and limited information exists regarding other heavy metals as well.(12) As a consequence of inadequate human cases of selenosis, much of our knowledge is based on animal models. It appears from these animal studies that selenium toxicity is a dose-related phenomenon.(14)

The most frequent cause of selenosis in the United States is the incorrect formulation of selenium-containing nutritional supplements or chronic selenium supplementation overdose. Formulation errors in selenium supplements have been reported three times in the past twenty-five years. In 1984, selenium tablets were prepared with a 180-fold error resulting in tablets containing 27.3 milligrams instead of 150 micrograms.(10) The clinical manifestations of the 12 persons described in that report were consistent with those reported in our aforementioned case of selenosis. In 1996, a 500-1000-fold formulation error in selenium supplement tablets occurred, which resulted in similar clinical findings in one patient.(15) In neither of these previous reports was the selenium level in patients' biological samples tested.

The third event occurred in March of 2008. In this outbreak, a liquid selenium supplement had a formulation error of approximately 400-500-fold. Biological sample testing did occur in several patients, and demonstrated elevated blood and urine selenium levels which far exceeded normal values.(16) Because of the non-specific nature of symptoms and the distribution of the supplement via Internet sites, surveillance on the exact number of people affected in this outbreak has been difficult, but estimates of well over 100 cases of toxicity have been made based on calls to regional poison centers and health departments.

To date, there have been no reports of fatalities from selenium used as a nutritional supplement. However, fatalities have been associated with industrial and environmental exposures to selenium. Selenious acid is the major cleaning agent in gun-bluing solution, a product used to clean the exterior surface of firearms. A tragic case of a previously healthy 22-month-old toddler who consumed an estimated 15 milliliters of gun bluing solution resulted in a rapid death, expiring despite optimal supportive therapy.(17) Selenium also has several applications in the industrial setting. Currently, selenium is used in the manufacturing process of photography-related equipment, fungicides, electronics and glass manufacturing. In these settings, fatalities have occurred from exposures of selenious acid and selenium dioxide.(17)

Persons living in regions with high selenium content in plants can also develop selenosis. Notable areas of endemic selenosis include parts of Venezuela and China. These regions have soil rich in selenium, and agricultural products grown in this soil can be contaminated with elevated levels of selenium. For example, the Brazil nut grown in the Andes mountain range of Venezuela has the highest concentration of selenium measured in food.(18) In these endemic areas, selenosis is manifested by typical integumentary findings, including hair loss and nail changes. Dietary selenosis is especially evident when diets consumed were estimated to contain more than 100 times the U.S. recommended daily allowance of 55 micrograms of selenium. These outbreaks are often geographically isolated and seasonal, suggesting important environmental factors on locally produced agriculture.(11)(19)(20)

Treatment of Selenium Toxicity

While no clinical trials exist to suggest treatment algorithms for selenosis, efforts have focused on chelation therapy and pain management. The basis of chelation therapy is to identify a compound that will bind to the toxic substance and enhance elimination without redistributing the substance to other vital areas in the body (such as the CNS). Unfortunately, there are no proven chelators for selenium. Animal data with British Anti-Lewisite (BAL), edentate calcium disodium, and succimer have demonstrated the formation of nephrotoxic complexes with selenium that likely worsen toxicity. Vitamin C has been suggested, but no clinical studies have demonstrated efficacy. It is proposed that vitamin C will compete with selenium absorption and uptake into vital enzymatic processes, thereby limiting selenium toxicity. However, this hypothesis has not gained popular acceptance nor has it been rigorously studied.(21)

Pain management can often be difficult, particularly with neuropathic pain. The cornerstone of therapy is removal of the patient from the exposure. In the most recent outbreak of selenosis from the liquid supplement formulation error, common complaints of painful skin and nails were noted. These patients described the skin pain as a burning sensation and nail pain as throbbing pressure.(16) For exposures to dietary supplementation, analgesics are the mainstay of therapy. If dermal pain is from a topical occupational exposure to selenious acid or selenium dioxide, then sodium thiosulfate solution or ointment may provide symptomatic relief. The suggested mechanism of action of thiosulfate is as a reducing agent, forming selenium byproducts that are less irritating to the skin.

Selenium Deficiency

Historically, selenium-deficient diets are uncommon but have led to endemic illnesses. There are three distinct clinical entities associated with deficiencies of selenium -- Keshan's disease, Kashin-Beck disease and Myxedematous Endemic Cretinism.(22)

Keshan's disease dates back to the early 1930s in China, but was not fully described until 1979. Patients presented with symptoms of a cardiomyopathy that was epidemiologically linked to insufficient dietary selenium intake. Epidemics occurred with a seasonal preference and affected predominantly children under the age of 15.(23) In addition to selenium deficiency, an epidemiological link and mouse models have implicated co-infection with coxsackie B-3. (4) While Keshan's disease has a cardiomyopathy as a prominent feature, additional findings of multifocal myonecrosis, periacinar pancreatic fibrosis and mitochondrial dysfunction have all been described as well.(25)

Kashin-Beck disease, which is also linked to selenium deficiency, is characterized by severe joint pain and short stature secondary to chondrocyte necrosis.(26) The chondrocyte necrosis appears to be multi-factorial in origin and not solely the result of selenium deficiency. Kashin-Beck disease also appears endemic to certain areas of China where dietary deficiencies occur, but it has been reported in Russia and Korea. Treatment consists of supportive therapy and selenium supplementation, which have demonstrated improvement in clinical symptomatology.(18)

Myxedematous Endemic Cretinism, particularly in Africa, has also been partially related to selenium deficiency. Because iodine deficiency also occurs in this region of Africa, direct causal relationships for this condition are more difficult to prove. Decreased function of iodothyronine deiodinases can lead to decreased T-3 production; and selenium dependent glutathione peroxidase detoxifies injurious hydrogen peroxide, which abounds in the thyroid. Thus, there are two mechanisms by which deficiencies of selenoproteins might play roles in the development of myxedematous endemic cretinism. These patients often manifest symptoms of mental retardation and hypothyroidism.(27)(28)

Non-endemic causes of selenium deficiencies do exist. However, they usually appear as part of multiple combined micronutrient deficiencies rather than from an isolated selenium deficit. Prolonged use of total parenteral nutrition (TPN) has been associated with selenium as well as other nutritional deficiencies. These usually correct once the patient is transitioned to traditional diets.(29) Additionally, severe Crohn's disease and ulcerative colitis have been associated with deficiencies in selenium and other micronutrients. Decreased intestinal absorption of micronutrients and vitamins can lead to the development of a variety of clinical symptoms. Because nutritional deficiencies are known complications of aggressive forms of inflammatory bowel diseases, education and supplementation continue to be cornerstones of treatment.(30)

Selenium and Cancer, Coronary Artery Disease and HIV

Since selenium is known to detoxify free radicals, limit oxidative damage and play vital roles in cell growth, it is easy to understand the development of research interest involving selenium and cancer. Researchers have also proposed that selenium can limit tumor grown by enhancing immune system activity and limiting tumor angiogenesis.(31)

Initial observations about possible benefits of selenium were made after epidemiological studies suggested decreased death from prostate, lung and colorectal cancer in patients who were found to have higher blood selenium levels than a matched study group.(32) However, given the observational nature of these studies, extrapolation of cause and effect relationship could not be made, and the beneficial effects of selenium on cancer risks must be interpreted cautiously. Additional observations have suggested that dietary selenium supplementation might be beneficial in cancer risk. The addition of 200 micrograms of selenium to the daily diet did not affect the recurrence of skin cancer but significantly reduced the occurrence and death from total cancers. While these observational studies were promising, no randomized control trial had yet been conducted to demonstrate these results.(32)

To address the question of the role of selenium in cancer prevention, the National Institute of Health (NIH) began the SELECT (Selenium and Vitamin E Cancer Prevention Trial) study to evaluate if selenium or vitamin E decrease the risk of prostate cancer in healthy men. The selenium group was given 200 micrograms daily, and the combination group was given 200 micrograms of selenium and 400 milligrams of vitamin E daily. The study was initially planned to continue until 2013; however, in October, 2008, participants were told to stop taking their supplements. Interim data analysis done by an independent group concluded that selenium alone or in combination with vitamin E did not prevent the development of prostate cancer. The analysis also concluded that data would not show the 25% reduction in prostate cancer that the study was designed to demonstrate. Follow-up data collection will continue.(33) Although the SELECT study failed to demonstrate the desired results, continued research into benefits of nutritional supplementation of selenium is necessary and ongoing.

As our knowledge of cardiovascular disease continues to increase, the role of oxidative damage in the pathogenesis of atherosclerosis is an area of active research. While selenium may potentially lessen oxidative stress injury, there is currently insufficient evidence to recommend selenium supplementation for the prevention of coronary artery disease. However, this possibility is being evaluated in France in a study that began in 1994 and enrolled over 12,000 participants. Results of this study may soon provide data to address whether or not dietary selenium supplementation can decrease the risk of coronary artery disease.(22)

Investigators are also evaluating selenium supplementation for patients with HIV/AIDS. The HIV disease process can cause malabsorption leading to malnutrition including selenium deficiency.(34) Additionally, as HIV destroys the immune system, oxidative damage occurs suggesting possible therapy with antioxidants such as selenium to minimize this effect. Research has linked HIV patients who are deficient in selenium to higher rates of death from HIV.(35) Given the small number of study participants and multiple confounders, results must be interpreted with caution. However, selenium treatment of HIV patients remains a possible source of therapeutic benefit, which future research studies will address.

Summary

Selenium is a trace element that plays vital roles in many physiologic processes. Utilizing its unique biochemical properties to exist in various forms and oxidation states, it optimizes enzymatic reactions that help maintain our physiologic homeostasis. As our knowledge and research continues to advance in the field of nutrition, additional roles of selenium may be discovered.