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Chelation: Therapy or “Therapy”?

Introduction

Lead, mercury, and arsenic serve no function in the human body. If they accumulate in large enough amounts, they cause poisoning.  Other metals which are essential to human function can become toxic if they accumulate in large amounts; examples include iron and copper. Effects differ according to the metal involved, whether it is introduced into the body by ingestion, inhalation, or skin contact, and the age of the victim.

People with very high levels of these heavy metals are treated with drugs called “chelators” [KEY-lay-ters]. These medicines bind to the metals in the blood stream; this metal-chelator compound is then eliminated in the urine. While chelators are valuable drugs, they have side effects which limit their use to only a few medical conditions involving heavy metal toxicity, especially those due to lead, mercury, arsenic, and iron.(a)

Even though there are limited approved indications for the use of chelators, they are often advertised as treatments for numerous other conditions. Many of these expensive, lengthy “treatments” are administered directly into the bloodstream (intravenous, IV) in an office setting. Others are advertised for use at home. Purported uses include:

  1. treating damaged arteries (atherosclerosis) by removing calcium from arterial plaques, though there is little to no evidence that this is possible or effective;

  2. treating intermittent claudication (painful leg cramps due to arteriosclerosis [narrowed arteries]), though there is no evidence that this works;

  3. curing or improving symptoms of autism, though there is no evidence that metals are a cause of autism;

  4. preventing or curing neurodegenerative conditions such as Alzheimer’s disease, though there is no evidence that currently-available chelators have any effect on these conditions.

Unapproved uses of chelation therapy have resulted in harm, even death. This is an unacceptable risk in the absence of proven benefit. Several unapproved “chelators” are marketed for home use. The U.S. Food and Drug Administration (FDA) recently warned several companies that they are breaking the law by marketing such “therapies”. FDA noted that all approved chelating drugs require a prescription.

Chelating drugs
Chelating with drugs is indicated primarily for acute poisonings by some metals, especially lead, arsenic, mercury, and iron.1 Though the drugs may have dangerous side effects, the risks are considered worthwhile in the face of toxicity which may be fatal or cause serious, even permanent injury. [1]

Approved chelating drugs in the U.S. include succimer, dimercaprol (BAL), edetate calcium disodium, deferoxamine, and penicillamine. They are given only for diagnosed metal toxicity because 1) they may have serious side effects, even when their use is needed; and 2) they are non-specific and can bind even essential “trace” metals in the body, for example copper and zinc. They can sometimes bind calcium, too. Chelation of these substances can cause symptoms related to their deficiency.

  • Succimer (DMSA, 2,3-dimercaptosuccinic acid) is taken by mouth to treat poisoning by lead, mercury and arsenic. Serious side effects are uncommon. [2]

  • Dimercaprol  (British Anti-Lewisite, BAL) is given by injection to treat severe lead poisoning (with edetate calcium disodium), mercury poisoning, and arsenic poisoning. A variety of side effects have been reported, usually dose-related; high doses can cause coma and seizures.  [3]

  • Edetate calcium disodium (CaNa2EDTA) is given intravenously to treat severe lead poisoning. This drug can be toxic to the kidneys; doses and dosing schedules must be carefully calculated and kidney function must be monitored during treatment. [4]

  • Deferoxamine is given intravenously to treat iron poisoning. Possible side effects include very low blood pressure, lung injury, and infections. [5]

  • Penicillamine is sometimes used to treat bismuth, copper, lead, mercury, and nickel toxicity. When used for acute poisoning, the primary adverse effect is an allergic reaction in people who are also allergic to penicillin. [6]

In 2007, the National Center for Health Statistics reported that 111,000 adults said they used chelation therapy, along with 72,000 children under the age of 18. [7] It is highly unlikely that 183,000 US residents required chelation therapy for the limited number of approved indications. It is much more likely that therapies were received for conditions attributed to heavy metals without scientific validation.

The FDA recently warned several companies that marketed chelation products and tests for home use that they are violating federal law. [8] These products purported to treat such serious conditions as “autism spectrum disorder, cardiovascular diseases, Parkinson’s disease, Alzheimer’s disease, macular degeneration, and other serious conditions”. Related products were advertised to detect the presence of heavy metals. FDA strongly stated that chelating products are approved for prescription use only.

Chelation therapy has been associated with fatalities. [9, 10] A 2-year-old girl with lead poisoning died after the wrong chelation drug caused her blood calcium to drop too low. A 5-year-old boy with autism died after being inappropriately treated in a doctor’s office with a chelating drug; autism is not caused by heavy metals and is not an indication for chelation. A 53-year-old woman without evident heavy metal poisoning died during chelation therapy by a naturopath.

Heavy metal poisoning
Lead, mercury, arsenic, and iron account for most cases of diagnosed heavy metal poisoning in the United States. Laboratory studies are required for diagnosis. Treatment includes removing the victim from the source of the metal and treating the patient’s symptoms, when that is possible. For very high levels or severe symptoms, chelating drugs may be given.

Lead poisoning
Humans have been poisoned by lead for thousands of years. Ancient Roman water pipes were made of lead. Since lead must be mined, miners (and often their families) have been exposed. Now, most cases of lead poisoning are in children who swallow lead-based paint in homes built before the 1970s. Among many other causes are water carried through pipes made of lead or containing lead solder; soil around homes painted with lead-based paint; toys, charms, and amulets worn and/or mouthed by children; pica (eating non-food items); old homes being renovated without proper safety precautions (also a source of lead poisoning in pets); some imported cosmetics, ceramics, candy, and spices; hobbies in which lead is heated and breathed in without protection, e.g. casting bullets and fishing weights; lead bullets retained in a joint; firing ranges with inadequate ventilation; and industries that use or re-claim lead, e.g. battery manufacturing and removing paint from industrial sites. [11]

There is no necessary or safe level of lead in human bodies. Children are especially susceptible to the toxic effects of lead. Lead affects the developing brain and nervous system, potentially causing lower IQs, learning difficulties, hearing loss, and behavior difficulties. Abdominal complaints are common. Anemia is often found in children with lead poisoning. In adults, lead poisoning can cause high blood pressure and kidney damage.

Lead poisoning is diagnosed by a blood test.

  • In children who may be exposed to lead on a regular basis, a screening test is done with a finger-prick test. If that level shows the possibility of lead poisoning, a blood sample from a vein is tested. If that level is higher than 10 µg/dL (micrograms of lead per 100 milliliters of blood), the child’s home and other places where the child spends time are examined for a source of lead. Once identified, that source must be removed from the child’s environment and the child re-tested. If the lead level rises, further investigation is required until the source is definitely found. [12]

  • Lead poisoning in adults is addressed by identifying the source of the lead, taking necessary steps to stop the exposure, monitoring levels, and treating with chelators if levels are high enough. [13]

At levels of 45 µg/dL and above, treatment with the oral chelating drug succimer (DMSA) is given. At higher levels, and in children with coma or seizures, IV drugs (dimercaprol/BAL, calcium disodium EDTA) are given. These are selected carefully, with carefully calculated doses, to derive maximum benefit with the fewest possible side effects. Patients are monitored while the lead level decreases.

Mercury poisoning
Mercury is found in several forms.

  • Metallic mercury is an inorganic mercury compound also called quicksilver. As a silver-colored liquid at room temperature, it rarely causes poisoning, even if swallowed. However, if it is heated and the fumes are breathed in, poisoning readily occurs. Metallic mercury left open at room temperature, for example in an open container or from a broken thermometer, also can contaminate the air and cause poisoning. Effects include lung injury and kidney damage. Symptoms may include cough, fever, chills, headache, nausea, vomiting and abdominal pain. (This is the type of mercury found in silver dental fillings, which have not been associated with human poisoning).

  • Other forms of inorganic mercury such as mercurous chloride and mercuric chloride are used in industry, as fungicides and pesticides, in batteries, and in preservatives for wood and laboratory specimens.  Inorganic mercury is sometimes found in skin-whitening creams. After long exposure, symptoms may include gastrointestinal effects, weight loss, and fatigue. Children can develop a rash accompanied by weakness and numbness.

  • Organic mercury, such as ethyl mercury and methyl mercury, can cause central nervous system effects and kidney damage. Contaminated fish and industrial chemicals are the primary sources of organic mercury exposure in humans. Symptoms of poisoning can include tremors, blindness, nerve damage, and coma, among many others. Thimerosal, a mercury-containing preservative, is found in some vaccines in very small amounts.  (Mercury in vaccines has not been associated with human poisonings).

Mercury can be measured in the blood stream soon after someone is poisoned, but it quickly moves to other body organs. After that, measuring the amount of mercury eliminated in the urine during a 24-hour period is the most accurate way to diagnose poisoning.

Chelating drugs used to treat mercury poisoning may include succimer, edetate calcium disodium, BAL, or penicillamine. Whether a chelator is indicated or not will depend on the form of mercury involved, the person’s mercury level, and if the person is having symptoms.

Arsenic poisoning
Arsenic is a naturally occurring substance. In some areas of the world, low-level arsenic exposure occurs because of the continuing presence of arsenic in ground water. Arsenic is found in some fish and seafood and so can confuse laboratory findings in people whose diets include seafood. At one time, arsenic was common in weed killers. It has uses in laboratories and some industries.

If large amounts of arsenic are swallowed, victims quickly develop gastrointestinal symptoms including profuse vomiting and diarrhea. Shock and coma can follow. People with lower levels of arsenic exposure, especially over a long period of time, may develop muscle weakness, numbness and tingling in their arms and legs, skin changes, Mees lines (which look like horizontal white stripes) on their nails, and cancer. (But note that most white lines on nails aren’t related to arsenic.) 

Arsenic poisoning usually is diagnosed by measuring the amount of arsenic excreted in the urine. Chelators used to treat arsenic poisoning include dimercaprol, succimer, and penicillamine.

Iron poisoning
At one time, iron was a leading cause of poisoning death in children. The source was adult-strength iron supplements, toxic to children in small amounts. [14] Many manufacturers changed the way the pills were packaged and labels warn of the dangers of iron poisoning in children. Fatalities are now uncommon but serious poisonings still occur.

Iron poisoning initially causes damage to the gastrointestinal tract. Someone who swallows an overdose may quickly develop bloody vomiting and bloody diarrhea. As the iron is metabolized, or broken down in the body, shock develops and liver damage occurs. A few weeks later, scar tissue in the gastrointestinal tract may develop and eventually require surgery to repair. The chelating drug used to treat iron poisoning is deferoxamine.

Chelation “therapy”:  unapproved uses of chelation
As noted above, chelation therapy is approved for a limited number of indications involving documented poisoning by heavy metals; it is carried out under medical supervision with prescription drugs. However, entering “chelation therapy” into an internet search engine yields more than 500,000 hits. Alongside entries relating to lead and iron poisoning are entries referring to “veggie caps”, chelation “without chemicals”, “dissolve artery blockages”, “chelation suppositories”, and “undesirable ionic material”, plus many ads for over-the-counter chelating substances. There is at least one entry offering chelation therapy while traveling overseas; this destination also offers cosmetic surgery.

Chelation “therapy” is offered for a number of conditions: arteriosclerosis, angina, poor circulation to the legs and feet, autism, Parkinson’s disease, Alzheimer’s disease, cancer, diabetes, and many other conditions. Even when it is implausible or impossible for chelation to be effective, it has been made to sound rational to people unfamiliar with the causes of these conditions. 

To “diagnose” heavy metal poisoning as a cause of these conditions, and therefore appropriate for chelation therapy, practitioners will often administer a test or challenge dose of a chelator. In a day or two, a urine test is done to measure metals. Since some metals are found in all humans, these tests are always “positive”, though they are not measured against established or medically accepted standards. These results are then used to market chelation therapy to the individuals. The American College of Medical Toxicology warns that basing chelation therapy on these types of tests is without benefit to patients and may prove harmful. [15]

Some chelation regimes involve intravenous infusions of EDTA several times weekly for months at a time, with “maintenance” doses at regular intervals – sometimes hundreds of treatments in all. Usually, the infusions contain vitamins and other proprietary preparations. Other regimes involve the purchase of oral proprietary formulations that supposedly will provide benefits of chelation. Based on current research, there are risks to patients without established benefits. These therapies are expensive, with all charges paid by individual patients, as insurance companies will not pay for inappropriate use of chelation.

Atherosclerosis (arterial plaques)
Atherosclerosis is narrowing of arteries due to plaques; these are fatty deposits on the inside walls of arteries. Because they narrow the arteries, blood flow is limited to the heart, brain, and limbs. When present, they can cause chest pain (angina), leg pain due to decreased circulation (intermittent claudication), and compromised circulation to the brain (strokes).

Calcium is a component of these plaques. It is known that chelators can remove calcium from the blood stream. Some chelation practitioners state that their treatments will dissolve arterial plaques by removing calcium from them, thus eliminating the need for drug therapy and coronary bypass grafts. On the surface, this may appear plausible, but it is not; there is little if any evidence that circulating chelators actually reach the calcium in arterial plaques. [16] Other purported benefits of using EDTA chelation therapy in patients with coronary artery disease include decreasing the ability of platelets to clot, reducing free radicals which cause cell damage, and lowering iron and cholesterol in the blood stream. [17]

Chelation therapy for heart disease was first described in the 1950s. A trial of chelation for intermittent claudication was published in 1994; the authors found chelation to be no better than placebo. [18] In 2000, Ernst summarized clinical studies of chelation for cardiovascular disease published between 1955 and 1993. [19] He found 22 studies and case reports without control groups, most reporting symptomatic improvement but without documentation of improvement. There were two case reports with objective measurements of results; neither documented benefit. There were two controlled clinical studies, one with nine patients and one with sixteen. Neither documented benefit. The author attributes symptomatic improvement without measurable clinical improvement to “a powerful placebo effect”. He states that “The most striking finding is the almost total lack of convincing evidence for efficacy” and further states that “this treatment should now be considered obsolete.”

An editorial in the same journal challenged Ernst’s conclusions. [20] The authors stated that Ernst drew his conclusions from insufficient data, that it seems plausible that chelation therapy could work because of proposed antioxidant effects of chelating drugs plus the vitamins and minerals typically co-administered, and recommended that a definitive trial be carried out to determine if chelation therapy helped people with cardiovascular disease.

In 2002, the National Institutes of Health (NIH) announced a large clinical trial to assess the safety and effectiveness of chelation therapy for coronary artery disease. The Trial to Assess Chelation Therapy (TACT) was intended to study more than 2,300 patients who had evidence of coronary artery disease, including a history of heart attack. The press release announcing the study focused on the fact that chelation therapy is widely administered, though it has never been proved safe and effective. TACT was designed to provide answers: Is chelation for coronary artery disease safe? Does it work? Do specific vitamins and minerals make a difference in how patients do? Is it cost-effective? [21]

The trial was hailed by many chelation practitioners, including the American College for Advancement in Medicine (www.acamnet.org), which promotes chelation therapy and provided a protocol. There was also vigorous dissent, as illustrated by an article concluding that “TACT is unethical, dangerous, pointless, and wasteful.” [22]

In 2008, the Cochrane Collaborative concluded that available evidence was insufficient to determine whether or not chelation therapy is effective for atherosclerosis. The authors noted the need for randomized clinical trials. [23] In its current statement about chelation therapy, the American Heart Association finds “no scientific evidence to demonstrate any benefit from this form of therapy”. [24]

In 2008, the NIH chelation trial stopped enrolling patients, approximately two years early; there were allegations that the consent forms were improper. NIH is, however, continuing with data analysis of the patients who were treated. Data analysis is scheduled to be completed by the end of 2011, with results to be announced in 2012. [25] (Update: The trial determined that IV chelation with disodium EDTA slightly reduced the risk of “adverse cardiovascular outcomes” and that the results could guide further research but do not support the routine use of chelation for patients who had a myocardial infarction. [25A])

Autism
Chelation therapy as a treatment for autism is based on the erroneous belief that mercury in childhood vaccines is a cause of autism. This belief arose when it was noted that 1) the number of cases of autism was growing and 2) the number of recommended childhood vaccines was increasing. Some correlated the two and attributed the link to thimerosal, a mercury-containing preservative in some vaccines. The theory that thimerosal is responsible for autism has been scientifically refuted. [26, 27. Also, see article posted on www.poison.org for further discussion of this topic, with references]

If autism is not caused by mercury in vaccines, chelating children for mercury “toxicity” cannot help them. Despite this, chelation therapy is widely promoted as a treatment for autistic children. Practitioners administer succimer, vitamins, minerals, oral chelation products, and IV chelation drugs, exposing children to side effects for no clear benefit. In fact, IV chelation therapy resulted in the death of a five-year-old boy; he went into cardiac arrest during his third chelation treatment. The authors who reported this death state that “The use of chelation therapy in autistic children has not been validated and can have tragic consequences.” [10]

Succimer is sometimes used to chelate mercury, from environmental sources if not from vaccines, in an attempt to treat autism. There is no evidence that this works. Cao and colleagues studied mercury elimination in children who needed chelation with succimer for lead poisoning; they found “limited efficacy”. [28]  

An alternate belief is that removing an excess body burden of heavy metals can improve autism symptoms. In a pilot study, Soden and colleagues gave DMSA (succimer) to children with and without autism. Then, they compared the amounts of arsenic, cadmium, lead, and mercury excreted in their urine before and after chelation.  They reported that the results did NOT demonstrate an excess body burden of any of these metals and that “there is no evidence that any of the 15 autistic participants would benefit from chelation therapy.” [29]

The American Academy of Pediatrics issued a policy statement saying that “…unless there is clear evidence of current heavy metal toxicity, chelation by any method is not indicated outside of monitored clinical trials.” [30] This policy was reaffirmed in December 2010.

In 2006, the U.S. National Institute of Mental Health (NIMH) had announced that it had begun three clinical studies of autism. One was of chelation therapy for children with autism, in part because chelation was already being administered to large numbers of children with no proof of efficacy or safety. [31] In late 2006, a study in rodents cast doubt on the safety of succimer as it would have been used in this study. Treatment with succimer improved cognitive outcomes in rats with lead poisoning, but actually caused lasting impairment in animals without lead poisoning. [32] NIMH re-evaluated the proposed study in light of these findings and determined that children would be put at disproportionate risk. In 2008, NIMH announced that the study was cancelled. It was also noted that there were other, more promising areas of research. [33]

Alzheimer’s disease
Alzheimer’s disease is a leading cause of memory impairment in older adults. The Alzheimer’s Association estimates that 5.2 million Americans have Alzheimer’s disease, most of them over 65. In addition to difficulty with memory, victims may suffer from depression, confusion, impaired judgment, and difficulty managing everyday activities. In its later stages, trouble speaking, walking, and eating may develop. Being immobilized can lead to pneumonia, other infections, and death. [34]

The cause, or causes, of Alzheimer’s disease are not yet known. Nothing has been shown to prevent the development of Alzheimer’s disease. There are drugs that can delay the symptoms of the disease in some people, but there are no treatments. [35]

It is known that abnormal deposits called amyloid plaques are present in the brain of many Alzheimer’s victims. (These can only be found after death, if an autopsy is conducted on the brain.) It is thought that iron, aluminum, copper, and zinc in the brain may be involved with these plaques in some way, but it is not yet known how. Perhaps there is a problem with how the brain uses metals that are normally present; perhaps exposure to metals is a cause; or there may be other explanations. Science doesn’t yet have the answers. [36]

Aluminum is the metal which has received the most attention in the popular press. [37] Ever since aluminum was identified in the brains of patients with Alzheimer’s disease, it was proposed that people absorbed aluminum from food, drinking water, aluminum pots and pans, and underarm deodorant. But as early as 1992, some researchers disputed that hypothesis, finding that aluminum was a contaminant of the materials used to study brain tissue rather than a component of plaques. [38]

A review of several studies of occupational exposure to aluminum found no association with Alzheimer’s disease. [39] A study of 89 people with Alzheimer’s disease concluded that lifetime workplace exposures to solvents and to aluminum were “not likely to be important risk factors for Alzheimer’s disease”. [40] One study found that high concentrations of aluminum in drinking water may be a risk factor for Alzheimer’s disease [41], while another found “little association between Alzheimer’s disease and higher aluminum…concentrations in drinking water”. [42]

Other metals being studied include iron [43, 44], copper, and zinc. [45]

Since researchers believe that metals are involved in some way with the development of Alzheimer’s disease, some chelation practitioners recommend courses of chelation therapy for these patients. This may sound intuitive, but the reality is that available chelators cannot work in the brain. The protective “blood-brain barrier” will allow only the smallest of particles to leave the bloodstream and enter brain tissue. Currently-available chelating drugs circulate in the bloodstream but they are unable to cross the blood-brain barrier, making them useless for decreasing the amount of metals in the brain.

There is a great deal of research being conducted on nanoparticles, agents small enough to enter brain tissue to chelate metals. [46, 47] For now, though, there is no indication for exposing patients with dementia to the risks of chelation therapy because current chelators cannot help them.(b)

Summary
Chelation therapy is an approved treatment for poisonings caused by such heavy metals as iron, mercury, arsenic, and lead. Based on erroneous theories of disease causation, some practitioners advocate chelation therapy for such conditions as cardiovascular disease, autism, and Alzheimer’s disease. There is no scientific basis for these expensive treatments, which expose patients to risks without benefit. One condition, cardiovascular disease, is the subject of a large clinical trial to assess possible benefits of chelation therapy; the results are not expected until 2012.

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a Other approved indications for chelation therapy include Wilson’s disease, an abnormality in how the body uses and stores copper; hemochromatosis, an abnormal accumulation of iron in red blood cells; an accumulation of excess aluminum in patients on chronic kidney dialysis; and an accumulation of excess iron in patients who require blood transfusions for certain chronic diseases.

b Other current areas of research into causes and treatment of Alzheimer’s disease include brain imaging, genetics, and several types of drug therapy. For examples, see the NIH National Institute on Aging site.

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