January 23, 2008

Selenium: A Trace Element with Real Potential

Mark Sutter, M.D. and Jennifer Brown, M.D.
Dr. Sutter is Assistant Professor and Medical Toxicologist, Department of Emergency Medicine, and Dr. Brown is Clinical Fellow, Division of Infectious Diseases, Department of Internal Medicine, University of California, Davis.

Selenium is a trace element and essential nutrient that is found mainly in meats, grains, and nuts — food sources that almost always provide enough selenium to meet our daily nutritional requirements. Since selenium is actually a micronutrient, we need very small amounts of it for our bodies to function properly. Given the abundance of common foods containing selenium, it is very rare for a healthy person, eating a traditional American diet, to become selenium deficient.

About two weeks after its onset, the patient began to lose the hair on her head, and the hair loss was continuing to worsen.

While selenium deficiency and toxicity (from taking in too much of the compound) are rare, their symptoms illustrate just what this mineral does for our health. Instances of toxicity in this country are mainly due to errors in formulation of nutritional supplements that contain selenium. There have been three major outbreaks of selenium poisoning in the past 25 years, all of which were the result of formulation errors of these supplements. The selenium content in these mis-formulations ranged from 180 to 1,000 times the amount that was indicated in the supplement's contents. The last outbreak, which occurred in March 2008, was thought to affect over 100 people, the greatest number poisoned by selenium in recent history.

A Case Study
To understand the progression and symptoms involved in selenium toxicity, let's consider the following case study:

A 55-year-old, previously healthy woman sought medical attention regarding a six-week history of diarrhea. About two weeks after its onset, the patient began to lose the hair on her head, and the hair loss was continuing to worsen. The hair loss was distributed evenly about her scalp. Then it progressed to the underarms, genitalia, and finally to the arms and legs (her eyebrows were the only areas that were spared). She also complained of muscle cramps, joint pain, fatigue, and difficulty concentrating. A recent evaluation by her primary doctor revealed that her blood chemistries and thyroid levels were all within normal ranges. She did not appear to be suffering from any kind of toxicity, and her vital signs were all normal. Her fingernails had reddish discoloration and Mees' lines, which generally appear after poisoning with one of several heavy metals (Figure 1). Neurological examination revealed nothing unusual.
Figure 1.
Hair manifestations and Mees' lines from of selenosis

About one week before the start of her diarrhea, the patient and her husband had received a new shipment of a liquid nutritional supplement that they were taking to improve their health. This supplement was the same brand that they had been taking for several years without any problems or ill effects. The supplement's ingredients included multiple vitamins, trace minerals, and elements, including selenium.

Fourteen days after the patient's last consumption of the nutritional supplement, her serum selenium level was measured: it was much higher than normal levels, at 534 µg/l (the normal range is 80-150 g/l). The newest bottle of the supplement was then analyzed and found to have a selenium level of 800.5 µg/ml, which was 300 times the amount stated on the label. Given the patients reported dose of 30 ml per day, her actual daily selenium intake was approximately 24,015 µg — over 400 times the U.S. recommended allowance of 55 µg per day. The makers of the supplement recalled it from the market after the formulation error was discovered.

After being diagnosed with selenium toxicity (also called selenosis), our patient, of course, quit taking the supplement. Over the next four months, most of her symptoms disappeared on their own. Her hair returned to normal 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 she had stopped taking the product, the patient felt that she had returned to normal without any lingering effects.

The case described above is a classic example of selenium toxicity. Although the symptoms may be clear-cut, the mechanism of how the toxicity works has yet to be fully worked out. The hair loss has been attributed to the disruption of the proteins that make up keratin, a building block of human skin and hair. Like our patient, previous reports of selenosis have described symptoms of nausea, vomiting, fatigue, irritability, hair loss, and paresthesias (a numb or tingling feeling in the skin). These symptoms are similar to the ones seen in arsenic and other metal poisonings, although the biochemical pathways by which selenium might exert these effects are still largely unknown (for that matter, limited information also exists regarding the toxicity of other heavy metals). Due to the low number of human cases of selenosis, much of our knowledge is based on animal studies. It appears from these studies that selenium toxicity is a dose-related phenomenon; meaning that the more selenium one ingests, the more numerous and severe the side effects will be.

Eight months after she had stopped taking the product, the patient felt that she had returned to normal without any lingering effects.

Information regarding the long-term effects of selenosis just doesn't exist. Most people affected with it are somewhat difficult to diagnose early, because their initial symptoms do not differ significantly from any common viral illness. Given the rare diagnosis of selenosis, doctors rarely even consider it until the onset of hair loss, which typically does not show up until later on.

Animating Enzymes and Hormones
Despite the shortage of research on selenium poisoning, there is a little more known about its normal everyday functions in the human body. One of these involves its use in enzymatic reactions. Enzymes are proteins that help accelerate chemical reactions without themselves being used up in the process. Some enzymes use a form of selenium to do their work, which ultimately allows the enzyme to be even more reactive. For example, glutathione peroxidase, containing a form of selenium, can help the body rid itself more effectively of reactive oxygen species (ROS), which are known to wreak havoc on our DNA. This enzyme helps reduce hydrogen peroxide, a dangerous ROS, to a harmless end product — water. Getting rid of these destructive ROS compounds helps reduce oxidative stress on the body, which is thought to be an underlying cause of a variety of diseases, as well as the aging process.

Selenium also appears to play a role in converting the thyroid hormone thyroxine (T-4) to its active form, triiodothyronine (T-3). Or, in times of severe physiologic stress, it can help convert T-4 to the inactive hormone reverse T-3. These pathways are important in maintaining normal levels in times of rest, while still allowing the body to adapt during stress or injury.

Another enzyme that uses selenium is thioredoxin reductase, which plays an important role in regenerating the body's antioxidants, such as vitamin C. It also helps regulate cells' growth and general well being. Because of its function in cell growth and division, thioredoxin reductase is being studied as possible therapy for immune system diseases and in chemotherapy.

Other Cases of Toxicity
To date, there have been no reports of fatalities from selenium when used as a nutritional supplement. There have, however, been deaths associated with industrial and environmental exposures. (An interesting note: selenium was first discovered in 1817 by the Swedish scientist Jons Berzelius while investigating an outbreak of a diarrhea in factory workers.) Selenious acid is the major cleaning agent in gun-bluing solution, a product used to clean the exterior of firearms. In a tragic case, a healthy 22-month old toddler who consumed an estimated 15 milliliters of gun-bluing solution died from the incident. Selenium also has several applications in the industrial setting, including the manufacturing process of photography-related equipment, fungicides, electronics, and glass manufacturing. In these settings, fatalities have occurred due to exposures to selenious acid and selenium dioxide.

People living in regions with high selenium content in plants can also develop selenosis. These areas — Venezuela and China, in particular — have soil that is rich in selenium, so agricultural products grown in the soil can be contaminated with high levels of it. For example, the Brazil nut grown in the Andes Mountains has the highest concentration of selenium that has been measured in food. In these areas, selenosis shows itself in hair loss and nail changes. Dietary selenosis is especially evident when diets are estimated to contain more than 100 times the U.S. recommended daily allowance, 55 g. These outbreaks are often seasonal and geographically isolated, which suggests that environmental factors play a large role in overexposure to selenium.

While no clinical trials exist to suggest good treatment methods for selenosis, efforts have focused on pain management and on finding an effective chelation therapy — that is, a method of removing the offending compound from the body. The basis of this kind of therapy is to identify a substance that will bind to the toxin and pull it out of the body without redistributing it to other vital areas (like the Central Nervous System). Unfortunately, there are no proven chelators for selenium, but investigators continue to look into the possibilities.

Pain management of selenosis can often be difficult. The cornerstone therapy is simply to remove the patient from the exposure. In the most recent outbreak of selenosis from the supplement formulation error in 2008, complaints of painful skin and nails were often noted; for exposures like this, topical analgesics and ointments are the best options for therapies.

Selenium Deficiency
Selenium-deficient diets are not seen very often, but there have been some illnesses associated with them, particularly in certain regions of the world. The three diseases connected to selenium deficiency are Keshan's disease, Kashin-Beck disease, and Myxedematous Endemic Cretinism.
  • In Keshan's disease, mainly seen in China, patients develop problems with the function of the heart muscle (cardiomyopathy), which has been associated with low selenium
  • Kashin-Beck disease, also seen most often in China, and less so in Russia and Korea, is also linked to selenium deficiency. This disorder results in severe joint pain and short stature due to the death of chondrocytes, the cells that make up cartilage. However, there may be other causes for this disease, in addition to the lack of selenium.
  • Myxedematous Endemic Cretinism, mainly seen in Africa, has also been at least partly related to selenium deficiency. But because there is overlap with iodine deficiency in the region, pinpointing the underlying cause of the disorder has been difficult. Patients of the disease often show symptoms of mental retardation and hypothyroidism, due to decreased production of the thyroid hormone T-3, and the build-up of harmful hydrogen peroxide in the thyroid gland itself.
  • Finally, intestinal diseases like Crohn's disease and ulcerative colitis have been linked to deficiencies in selenium and other micronutrients. Decreased absorption of micronutrients and vitamins in the intestine can lead to a variety of symptoms. Because nutritional deficiencies are known to be complications of aggressive forms of inflammatory bowel diseases, education and nutritional supplements are still the main forms of treatment.

Selenium and Cancer, Coronary Artery Disease, and HIV
Since selenium is known to help the body get rid of harmful reactive oxygen species and is important in cell growth, it makes sense that researchers would be interested in looking at the connection between selenium and cancer. Some have proposed that selenium may limit tumor growth by enhancing immune system activity and by limiting the generation of tumor blood vessels. This connection was made after studies found lower death rates from prostate, lung, and colorectal cancer in patients who had higher blood selenium levels than a control group. But since these studies were observational in nature (rather than truly experimental), researchers cannot say for certain that there exists a causal relationship between selenium and cancer. In another study, adding selenium to the diet did not affect the recurrence of skin cancer, but did significantly reduce the occurrence and death from total cancers. Again, these studies are observational in nature, and a randomized control trial did not demonstrate these results. However, researchers are still looking into the possible link between selenium supplements and cancer incidences.

Some have proposed that selenium may limit tumor growth by enhancing immune system activity and by limiting the generation of tumor blood vessels.

Other possible benefits of selenium may include a role in cardiovascular disease, since it lessens oxidative stress injury in the body. Though there is currently no data to support it, there is an ongoing study on the potential connection between selaenium and cardiovascular disease, using over 12,000 participants. Another disease for which selenium supplementation is being evaluated is HIV/AIDS. The HIV disease can lead to problems in nutrient absorption, which leads to malnutrition, including selenium deficiency. Research has linked HIV patients who are selenium-deficient to higher rates of death from HIV. Future studies will continue to address the connection between selenium and HIV/AIDS.

Selenium is a trace element and key player in many physiologic processes. Using its unique properties, it is able to exist in various forms and play many different roles; it facilitates enzymatic reactions and by doing so, helps keep our bodies in a healthy resting state. As research continues to advance our knowledge in the field of nutrition, additional roles of selenium may be discovered.
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