Chelation therapy

Chelation therapy is the administration of chelating agents to remove heavy metals from the body. For the most common forms of heavy metal intoxication—those involving lead, arsenic or mercury—the standard of care in the United States dictates the use of dimercaptosuccinic acid (DMSA).^{[citation needed]} Other chelating agents, such as 2,3-dimercapto-1-propanesulfonic acid (DMPS) and alpha lipoic acid (ALA), are used in conventional and alternative medicine. No approved medical research has found any benefits to chelation therapy for other diseases or ailments.^{[1] [2]}

History

Chelating agents were introduced into medicine as a result of the use of poison gas in World War I. The first widely used chelating agent, the organic dithiol compound dimercaprol (also named British anti-lewisite or BAL), was used as an antidote to the arsenic-based poison gas, lewisite. The sulphur atoms in BAL's mercaptan groups strongly bond to the arsenic in lewisite, forming a water-soluble compound that entered the bloodstream, allowing it to be removed from the body by the kidneys and liver. BAL had severe side-effects.

After World War II, a large number of navy personnel suffered from lead poisoning as a result of their jobs repainting the hulls of ships. The medical use of ethylenediaminetetraacetic acid (EDTA) as a lead chelating agent was introduced. Unlike BAL, it is a synthetic amino acid and contains no mercaptans. EDTA side effects were not considered as severe as BAL.

In the 1960s, BAL was modified into DMSA, a related dithiol with far fewer side effects.^[3] DMSA quickly replaced both BAL and EDTA, becoming the US standard of care for the treatment of lead, arsenic, and mercury poisoning, which it remains today. More recently, esters of DMSA have been developed which are reportedly more effective; for example, the monoisoamyl ester (MiADMSA) is reportedly more effective than DMSA at clearing mercury and cadmium.^[3]

Research in the former Soviet Union led to the introduction of DMPS, another dithiol, as a mercury-chelating agent. The Soviets also introduced ALA, which is transformed by the body into the dithiol dihydrolipoic acid, a mercury- and arsenic-chelating agent. DMPS has experimental status in the US FDA, while ALA is a common nutritional supplement.

Since the 1970s, iron chelation therapy has been used as an alternative to regular phlebotomy to treat excess iron stores in people with haemochromatosis.^[4]

Other chelating agents have been discovered. They all function by making several chemical bonds with metal ions, thus rendering them much less chemically reactive. The resulting complex is water-soluble, allowing it to enter the bloodstream and be excreted harmlessly.

Calcium-disodium EDTA chelation is approved by the U.S. Food and Drug Administration (FDA) for treating lead poisoning and heavy metal toxicity.^[5] In 1998, the U.S. Federal Trade Commission (FTC) pursued the American College for Advancement in Medicine (ACAM), an organization that promotes "complementary, alternative and integrative medicine" over the claims made regarding the treatment of atherosclerosis in advertisements for EDTA chelation therapy. The FTC concluded that there was a lack of scientific studies to support these claims and that the statements by the ACAM were false.^[6] In 1999, the ACAM agreed to stop misrepresenting chelation therapy as effective in treating heart disease, avoiding legal proceedings.^[7]

Medical use

Two molecules of deferasirox, an orally administered chelator, binding iron. Deferasirox is used in the treatment of transfusional iron overload in people with thalassemia.

Chelation therapy is used as a treatment for acute mercury, iron (including in cases of thalassemia), arsenic, lead, uranium, plutonium and other forms of toxic metal poisoning. The chelating agent may be administered intravenously, intramuscularly, or orally, depending on the agent and the type of poisoning.^[8]

One example of successful chelation therapy is the case of Harold McCluskey, a nuclear worker who became badly contaminated with americium in 1976. He was treated with diethylene triamine pentaacetic acid (DTPA) over many years, removing 41 MBq (1.1 mCi) of americium from his body. His death, 11 years later, was from unrelated causes.

Several chelating agents are available, having different affinities for different metals. Common chelating agents follow:

Chelator	Used in
Dimercaprol (BAL)	acute arsenic poisoning[9] acute mercury poisoning[9] lead poisoning (in addition to EDTA)[9]
Dimercaptosuccinic acid (DMSA)	lead poisoning[9] arsenic poisoning[9] mercury poisoning [9]
Dimercapto-propane sulfonate (DMPS)	severe acute arsenic poisoning[9] severe acute mercury poisoning[9]
Penicillamine	Mainly in: copper toxicity[9] Occasionally adjunctive therapy in: gold toxicity[9] arsenic poisoning[9] lead poisoning[9] rheumatoid arthritis[9]
Ethylenediamine tetraacetic acid (calcium disodium versante) (CaNa2-EDTA)	lead poisoning[9]
Deferoxamine and Deferasirox	acute iron poisoning[9] iron overload[9]

Medically diagnosed heavy metal poisoning

Some common chelating agents are EDTA (ethylenediaminetetraacetic acid), DMPS (2,3-dimercaptopropanesulfonic acid), TTFD (thiamine tetrahydrofurfuryl disulfide), and DMSA (2,3-dimercaptosuccinic acid). Calcium-disodium EDTA and DMSA are only approved for the removal of lead by the Food and Drug Administration while DMPS and TTFD are not approved by the FDA. These drugs bind to heavy metals in the body and prevent them from binding to other agents. They are then excreted from the body. The chelating process also removes vital nutrients such as vitamins C and E, therefore these must be supplemented.^[10]

Use in alternative medicine

Alternative medicine uses chelation therapy as a non-standard treatment for some ailments, including heart disease and autism.^[11][12] Attempts have been made to use it in treating kidney dysfunction, calcific band keratopathy (an eye disorder), and ovarian cancer. Currently there is a US National Center for Complementary and Alternative Medicine (NCCAM) trial being conducted on the chelation therapy's safety and efficacy for patients with coronary artery disease.^[13] NCCAM Director Stephen E. Straus cited the "widespread use of chelation therapy in lieu of established therapies, the lack of adequate prior research to verify its safety and effectiveness, and the overall impact of coronary artery disease" as factors motivating the trial.^[14] The proposed study has been criticized as unethical, unnecessary and dangerous, with multiple studies conducted in the past demonstrating that it provides no benefits.^[15]

Heart disease

Some alternative medicine practitioners^[who?] administer chelating agents, usually EDTA, to patients with atherosclerosis. The use of EDTA chelation therapy as a treatment for coronary artery disease has not been shown to be effective and is not approved by the U.S. Food and Drug Administration (FDA).^[1] Several possible mechanisms have been proposed, though none have been scientifically validated. The US National Center for Complementary and Alternative Medicine began conducting the Trial to Assess Chelation Therapy (TACT) in 2003.^[13] Patient enrollment was to be completed around July 2009^[5] with final completion around July 2010,^[16] but enrollment in the trial was suspended on September 26, 2008 for an investigation by OHRP after complaints about ethical concerns such as inadequate informed consent.^[17] The trial has been criticized for lacking prior Phase I and II studies, and particularly because previous controlled trials have not indicated benefits.^[15] The American College for Advancement in Medicine, a controversial organization created to promote chelation therapy, has played a part in the adoption of the TACT clinical trial, which has led to further criticism of the trial.^[15] Atwood et al. have argued that methodological flaws and lack of prior probability make this trial "unethical, dangerous, pointless, and wasteful."^[15]

The American Heart Association states that there is "no scientific evidence to demonstrate any benefit from this form of therapy" and that the "United States Food and Drug Administration (FDA), the National Institutes of Health (NIH) and the American College of Cardiology all agree with the American Heart Association" that "there have been no adequate, controlled, published scientific studies using currently approved scientific methodology to support this therapy for cardiovascular disease."^[1] Like other scientific commentators, they note that any improvement among heart patients undergoing chelation therapy can be attributed to the placebo effect and lifestyle changes discovered in conventional medicine but recommended by chelationists; "quitting smoking, losing weight, eating more fruits and vegetables, avoiding foods high in saturated fats and exercising regularly".^[18] They note their concern that patients could put off proven treatments for heart disease like drugs or surgery.^[18] A 2005 systematic review found that controlled scientific studies did not support chelation therapy for heart disease.^[19] It found that very small trials and uncontrolled descriptive studies have reported benefits while larger controlled studies have found results no better than placebo. The Mayo Clinic states that 'chelation studies have found that chelation didn't work as a heart disease treatment.'^[20]

Autism

Main article: Thiomersal controversy

Based on the discredited hypothesis that mercury poisoning may trigger the symptoms of autism,^[21] chelation therapy is widely used by alternative therapists to treat autism, with some surveys^{[citation needed]} suggesting 2–8% of children with autism have had the therapy. Parents either have a doctor use a treatment for lead poisoning, or buy unregulated supplements.^[22] Aspies For Freedom, an autistic rights organization, considers this use of chelation therapy unethical and potentially dangerous.^[2] There is strong epidemiological evidence that refutes links between environmental triggers, in particular thiomersal-containing vaccines, and the onset of autistic symptoms.^{[23][24][25][26]} There is no scientific support for chelation therapy as a treatment for autism.^[12][27]

Controversy

The efficacy, safety, and much of the theory behind these alternative practices are disputed by the medical community. In 2001, researchers at the University of Calgary reported that cardiac patients receiving chelation therapy fared no better than those who received placebo treatment.^[28]

In 1998, the U.S. Federal Trade Commission (FTC) charged that the web site of the American College for Advancement in Medicine (ACAM) and a brochure they published had made false or unsubstantiated claims. In December 1998, the FTC announced that it had secured a consent agreement barring ACAM from making unsubstantiated advertising claims that chelation therapy is effective against atherosclerosis or any other disease of the circulatory system.^[29][30]

The use of chelation therapy by alternative medicine practitioners for behavioural and other disorders is considered pseudoscientific as there is no proof that it is effective.^[31]

Prevalence

The American College for Advancement in Medicine estimates that 800,000 patient visits for chelation therapy were made in the United States in 1997.^[32]

Side effects and safety concerns

There is a low occurrence of side effects when chelation is used at the dose and infusion rates approved by the U.S. FDA as a treatment for heavy metal poisoning^{[citation needed]}. A burning sensation at the site of delivery into the vein is common. Other side effects include fever, headache, nausea, stomach upset, vomiting, convulsions, bone marrow depression, hypotension, cardiac arrhythmias, respiratory arrest, and hypocalcemia. Other concerns include kidney failure, which can require permanent life-limiting and expensive dialysis, or cause death.^[18]

2007 research with lab rats indicates giving chelating agent DMSA to rats without high levels of lead may cause lasting cognitive damage.^[33]

When EDTA is not administered by a health professional for the treatment of heavy metal poisoning more serious side effects can occur.^[5]

Chelation therapy can be hazardous, even conducted with the FDA-approved chelation agents. In August 2005, botched chelation therapy conducted by an ACAM member killed a 5-year-old autistic boy;^[15] a 3-year-old nonautistic girl died in February 2005, and a nonautistic adult died in August 2003. These deaths were due to cardiac arrest caused by hypocalcemia during chelation therapy.^[34] Only the 3-year-old girl had been medically assessed and found to have an elevated blood lead level and resulting low iron levels and anemia, a proper medical cause for chelation therapy to be conducted.^[35]

More than 30 deaths have been recorded in association with IV-administered disodium EDTA since the 1970s.^[15]

References

1. ^ ^{a b c} "American Heart Association: Chelation Therapy". http://www.americanheart.org/presenter.jhtml?identifier=4493. Retrieved 2008-04-03. 
2. ^ ^{a b} "Aspies For Freedom". Aspies For Freedom. http://www.aspiesforfreedom.com/. Retrieved 2009-02-24. 
3. ^ ^{a b} Kalia K, Flora SJ (January 2005). "Strategies for safe and effective therapeutic measures for chronic arsenic and lead poisoning". J Occup Health 47 (1): 1–21. doi:10.1539/joh.47.1. PMID 15703449. http://www.jstage.jst.go.jp/article/joh/47/1/47_1/_article. 
4. ^ "Hemochromatosis: Monitoring and Treatment". National Center on Birth Defects and Developmental Disabilities (NCBDDD). 2007-11-01. Archived from the original on 2008-02-24. http://web.archive.org/web/20080224192906/http://www.cdc.gov/ncbddd/hemochromatosis/training/treatment/monitoring_treatment.htm. Retrieved 2008-03-29. 
5. ^ ^{a b c} "Questions and Answers: The NIH Trial of EDTA Chelation Therapy for Coronary Artery Disease". National Center for Complementary and Alternative Medicine (NCCAM). Archived from the original on 2007-10-15. http://web.archive.org/web/20071015044954/http://nccam.nih.gov/news/2002/chelation/q-and-a.htm. Retrieved 2007-11-11. 
6. ^ "United States of America Federal Trade Commission In the Matter of American College for Advancement in Medicine, a corporation". Federal Trade Commission. 1999-07-01. http://www.ftc.gov/os/1999/07/9623147c3881acamcmp.htm. Retrieved 2010-07-01. 
7. ^ "United States of America Federal Trade Commission In the Matter of American College for Advancement in Medicine, a corporation. File no. 962 3147. Agreement containing consent order". Federal Trade Commission. 1998-12-01. http://www.ftc.gov/os/1998/12/9623147agr.htm. Retrieved 2010-07-01.  notification letter
8. ^ Natural Standard Professional Monograph. http://www.naturalstandard.com/monographs/monoframeset.asp?monograph=/monographs/alternativemodalities/chelation.asp%3Fprintversion%3Dtrue Accessed June 16, 2009.
9. ^ ^{a b c d e f g h i j k l m n o p} Page 481-483 in: Masters, Susan B.; Trevor, Anthony J.; Katzung, Bertram G. (2008). Katzung & Trevor's pharmacology: examination & board review. s.l: McGraw Hill Medical. ISBN 0-07-148869-3. 
10. ^ Bridges, S. (2006). The promise of chelation. Mothering , 54-61.
11. ^ Ernst E (2000). "Chelation therapy for coronary heart disease: An overview of all clinical investigations". Am. Heart J. 140 (1): 139–41. doi:10.1067/mhj.2000.107548. PMID 10874275. 
12. ^ ^{a b} Weber W, Newmark S (2007). "Complementary and alternative medical therapies for attention-deficit/hyperactivity disorder and autism". Pediatr Clin North Am 54 (6): 983–1006. doi:10.1016/j.pcl.2007.09.006. PMID 18061787. 
13. ^ ^{a b} NCCAM.Trial to assess chelation therapy
14. ^ NIH Launches Large Clinical Trial on EDTA Chelation Therapy for Coronary Artery Disease [NCCAM Health Information]
15. ^ ^{a b c d e f} Atwood KC, Woeckner E, Baratz RS, Sampson WI (2008). "Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned". Medscape J Med 10 (5): 115. PMC 2438277. PMID 18596934. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2438277. 
16. ^ "Trial to Assess Chelation Therapy (TACT)". U.S. National Institutes of Health. http://www.clinicaltrials.gov/ct/show/NCT00044213?order=1. Retrieved 2007-11-11. 
17. ^ "Government probes chelation-heart disease study". Washington Post (AP). http://www.washingtonpost.com/wp-dyn/content/article/2008/09/25/AR2008092503085.html. Retrieved 2008-09-26. ^{[dead link]}
18. ^ ^{a b c} http://www.americanheart.org/presenter.jhtml?identifier=3000843
19. ^ Seely DM, Wu P, Mills EJ (2005). "EDTA chelation therapy for cardiovascular disease: a systematic review". BMC Cardiovasc Disord 5: 32. doi:10.1186/1471-2261-5-32. PMC 1282574. PMID 16262904. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1282574. 
20. ^ Chelation therapy for heart disease: Results - MayoClinic.com
21. ^ Bernard S, Enayati A, Roger H, Binstock T, Redwood L (2002). "The role of mercury in the pathogenesis of autism" (PDF). Mol Psychiatry 7 (Suppl 2): S42–3. doi:10.1038/sj.mp.4001177. PMID 12142947. http://www.nature.com/mp/journal/v7/n2s/pdf/4001177a.pdf. 
22. ^ Stokstad E (2008). "Stalled trial for autism highlights dilemma of alternative treatments". Science 321 (5887): 326. doi:10.1126/science.321.5887.326. PMID 18635766. 
23. ^ Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention, Institute of Medicine (2004). Immunization Safety Review: Vaccines and Autism. Washington, DC: The National Academies Press. ISBN 0-309-53275-2. http://www.nap.edu/catalog/10997.html. 
24. ^ Doja A, Roberts W (2006). "Immunizations and autism: a review of the literature". Can J Neurol Sci 33 (4): 341–6. PMID 17168158. 
25. ^ Thompson WW, Price C, Goodson B et al. (2007). "Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years". N Engl J Med 357 (13): 1281–92. doi:10.1056/NEJMoa071434. PMID 17898097. http://content.nejm.org/cgi/content/full/357/13/1281. 
26. ^ Rutter M (2005). "Incidence of autism spectrum disorders: changes over time and their meaning". Acta Paediatr 94 (1): 2–15. doi:10.1111/j.1651-2227.2005.tb01779.x. PMID 15858952. 
27. ^ Blakeslee, Sandra (2004-05-19). "Panel Finds No Evidence To Tie Autism To Vaccines". New York Times. http://query.nytimes.com/gst/fullpage.html?res=9C02E2D6123FF93AA25756C0A9629C8B63. Retrieved 2008-02-01.  "An examination of scientific studies worldwide has found no convincing evidence that vaccines cause autism, according to a committee of experts appointed by the Institute of Medicine."
28. ^ Knudtson ML, Wyse DG, Galbraith PD, et al. (2002). "Chelation therapy for ischemic heart disease: a randomized controlled trial". JAMA 287 (4): 481–6. doi:10.1001/jama.287.4.481. PMID 11798370. 
29. ^ "American College for Advancement in Medicine, File No. 962 3147, Docket No. C-3882". Federal Trade Commission. http://www.ftc.gov/os/caselist/c3882.shtm. Retrieved 2007-11-11. 
30. ^ "Medical Association Settles False Advertising Charges Over Promotion of 'Chelation Therapy'". Quackwatch. December 8, 1998. http://www.quackwatch.org/02ConsumerProtection/ftcchelation.html. Retrieved 2007-11-11. 
31. ^ Behavior Analysis Association, University of Michigan
32. ^ "Physician Group Backs New NIH Chelation Therapy Study For Heart Disease" (Press release). American College for Advancement in Medicine. August 14, 2002. http://web.archive.org/web/20070204053351/http://www.acam.org/press_releases/20020814.htm. Retrieved 2007-11-11. 
33. ^ Succimer Chelation Improves Learning, Attention, and Arousal Regulation in Lead-Exposed Rats but Produces Lasting Cognitive Impairment in the Absence of Lead Exposure
34. ^ Hazards of chelation therapy:
    • Brown MJ, Willis T, Omalu B, Leiker R (2006). "Deaths resulting from hypocalcemia after administration of edetate disodium: 2003–2005". Pediatrics 118 (2): e534–6. doi:10.1542/peds.2006-0858. PMID 16882789. http://pediatrics.aappublications.org/cgi/content/full/118/2/e534. 
    • Baxter AJ, Krenzelok EP (2008). "Pediatric fatality secondary to EDTA chelation". Clin Toxicol (Phila) 46 (10): 1083–4. doi:10.1080/15563650701261488. PMID 18949650. 
35. ^ Deaths Associated with Hypocalcemia from Chelation Therapy - Texas, Pennsylvania, and Oregon, 2003-2005

External links

• Chelation Therapy: Unproven Claims and Unsound Theories Quackwatch