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Eosinophilia–myalgia syndrome

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Eosinophilia–myalgia syndrome is a rare, sometimes fatal neurological condition linked to the ingestion of the dietary supplement L-tryptophan.[1][2] The risk of developing EMS increases with larger doses of tryptophan and increasing age.[3] Some research suggests that certain genetic polymorphisms may be related to the development of EMS.[4] The presence of eosinophilia is a core feature of EMS, along with unusually severe myalgia (muscle pain).[5][6][7]

Eosinophilia-myalgia syndrome
Other namesEMS
SpecialtyRheumatology Edit this on Wikidata

Signs and symptoms

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The initial, acute phase of EMS, which last for three to six months, presents as trouble with breathing and muscle problems, including soreness and spasm, but which may also be intense. Muscle weakness is not a feature of this phase, but some people experience muscle stiffness. Additional features can include cough, fever, fatigue, joint pain, edema, and numbness or tingling, usually in the limbs, hands and feet.[8]

The chronic phase follows the acute phase. Eosinophilic fasciitis may develop, primarily in the limbs. CNS signs may appear, including numbness, increased sensation, muscle weakness, and sometimes cardiac or digestive dysfunction. Fatigue is present to some degree, while the muscle pain (which may be extremely intense) and dyspnea continue in this phase.[8]

Causes

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Subsequent[clarification needed] epidemiological studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko.[9][10][11][12] It eventually became clear that recent batches of Showa Denko's L-tryptophan were contaminated by trace impurities, which were subsequently thought to be responsible for the 1989 EMS outbreak. The L-tryptophan was produced by a bacterium grown in open vats in a Showa Denko fertilizer factory.[9][13][14] While a total of 63 trace contaminants were eventually identified, only six of them could be associated with EMS.[3][15] The compound EBT (1,1'-ethylidene-bis-L-tryptophan, also known as "Peak E") was the only contaminant identifiable by initial analysis, but further analysis revealed PAA (3-(phenylamino)-L-alanine, also known as "UV-5"), and peak 200 (2[3-indolyl-methyl]-L-tryptophan). Two of the remaining uncharacterized peaks associated with EMS were later determined to be 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]-indole-2-carboxylic acid (peak C) and 2-(2-hydroxy indoline)-tryptophan (peak FF). These were characterized using accurate mass LC–MS, LC–MS/MS and multistage mass spectrometry (MSn).[16] The last of the six contaminants (peak AAA/"UV-28",[17] being "the contaminant most significantly associated with EMS" [3] has been characterized as two related chain-isomers; peak AAA1 ((S)-2-amino-3-(2-((S,E)-7-methylnon-1-en-1-yl)-1H-indol-3-yl)propanoic acid, a condensation product between L-tryptophan and 7-methylnonanoic acid) and peak AAA2 ((S)-2-amino-3-(2-((E)-dec-1-en-1-yl)-1H-indol-3-yl)propanoic acid, a condensate between L-tryptophan and decanoic acid).[18] No consistent relationship has ever been firmly established between any specific trace impurity or impurities identified in these batches and the effects of EMS. While EBT in particular has been frequently implicated as the culprit, there is no statistically significant association between EBT levels and EMS.[3] Of the 63 trace contaminants, only the two AAA compounds displayed a statistically significant association with cases of EMS (with a p-value of 0.0014).[18]

As most research has focused on attempts to associate individual contaminants with EMS, there is a comparative lack of detailed research on other possible causal or contributing factors. Tryptophan itself has been implicated as a potentially major contributory factor in EMS.[19] While critics of this theory have argued that this hypothesis fails to explain the near-absent reports of EMS prior to and following the EMS outbreak,[20] this fails to take into account the sudden rapid increase in tryptophan's usage immediately prior to the 1989 outbreak, and ignores the strong influence of the EMS outbreak's legacy and the extended FDA ban on later usage of tryptophan.[19] Crucially, this also ignores the existence of a number of cases of EMS that developed both prior to and after the primary epidemic, including at least one case where the tryptophan was tested and found to lack the contaminants found in the contaminated lots of Showa Denko's tryptophan, as well as cases with other supplements inducing EMS, and even a case of EMS induced by excessive dietary L-tryptophan intake via overconsumption of cashew nuts.[21][22][23][24][9][19][25][26][27][excessive citations] A major Canadian analysis located a number of patients that met the CDC criteria for EMS but had never been exposed to tryptophan, which "brings causal interpretations of earlier studies into question".[6][28] Other studies have highlighted numerous major flaws in many of the epidemiological studies on the association of tryptophan with EMS, which cast serious doubt on the validity of their results.[29][30] As the FDA concluded, "other brands of L-tryptophan, or L-tryptophan itself, regardless of the levels or presence of impurities, could not be eliminated as causal or contributing to the development of EMS".[9] Even animal studies have suggested that tryptophan itself "when ingested by susceptible individuals either alone or in combination with some other component in the product, results in the pathological features in EMS".[9][31]

At the time of the outbreak, Showa Denko had recently made alterations to its manufacturing procedures that were thought to be linked to the possible origin of the contaminants detected in the affected lots of tryptophan. A key change was the reduction of the amount of activated charcoal used to purify each batch from >20 kg to 10 kg.[3] A portion of the contaminated batches had also bypassed another filtration step that used reverse-osmosis to remove certain impurities.[3] Additionally, the bacterial culture used to synthesize tryptophan was a strain of Bacillus amyloliquefaciens that had been genetically engineered to increase tryptophan production. Although the prior four generations of the genetically engineered strain had been used without incident, the fifth generation used for the contaminated batches was thought to be a possible source of the impurities that were detected. This has been used to argue that the genetic engineering itself was the primary cause of the contamination, a stance that was heavily criticized for overlooking the other known non-GMO causes of contamination, as well as for its use by anti-GMO activists as a way to threaten the development of biotechnology with false information.[32] The reduction in the amount of activated carbon used and the introduction of the fifth generation Bacillus amyloliquefaciens strain were both associated with the development of EMS, but due to the high overlap of these changes, the precise independent contribution of each change could not be determined (although the bypass of the reverse-osmosis filtration for certain lots was determined to be not significantly associated with the contaminated lots of tryptophan).[3] While Showa Denko claimed a purity of 99.6%, it was noted that "the quantities of the known EMS associated contaminants, EBT and PAA, were remarkably small, of the order of 0.01%, and could easily escape detection".[3]

Regulatory response

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The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001,[9] but continued to limit the importation of tryptophan not intended for an exempted use until 2005.[25]

Diagnosis

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Treatment

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Treatment is withdrawal of products containing L-tryptophan and the administration of glucocorticoids. Most patients recover fully, remain stable, or show slow recovery, but the disease is fatal in up to 5% of patients.[citation needed]

History

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The first case of eosinophilia–myalgia syndrome was reported to the Centers for Disease Control and Prevention (CDC) in November 1989, although some cases had occurred as early as 2–3 years before this.[5][21][22][23][24] In total, more than 1,500 cases of EMS were reported to the CDC, as well as at least 37 EMS-associated deaths. After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) recalled tryptophan supplements in 1989 and banned most public sales in 1990,[9][33][34] with other countries following suit. This FDA restriction was loosened in 2001, and fully lifted in 2005.[35][36] Since the initial ban on L-tryptophan, a normal metabolite of the compound in mammals, 5-hydroxtryptophan (5-HTP) has become a popular replacement dietary supplement.[37]

See also

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References

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  1. ^ Bolton P, Lindgren CE, Redmon GL (1991). "A mystery ailment revealed". American Fitness. 9 (5 (Sept–Oct)): 34–5. Archived from the original on 2005-03-16. Retrieved 2008-05-04.
  2. ^ Lindgren CE, Walker LA, Bolton P (February 1991). "L-tryptophan induced eosinophilia-myalgia syndrome". Journal of the Royal Society of Health. 111 (1): 29–30. doi:10.1177/146642409111100111. PMID 2005606. S2CID 31841865.
  3. ^ a b c d e f g h Mayeno AN, Gleich GJ (September 1994). "Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale". Trends in Biotechnology. 12 (9): 346–52. doi:10.1016/0167-7799(94)90035-3. PMID 7765187.
  4. ^ Okada S, Kamb ML, Pandey JP, Philen RM, Love LA, Miller FW (October 2009). "Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms". Arthritis and Rheumatism. 61 (10): 1305–11. doi:10.1002/art.24460. PMC 2761987. PMID 19790128.
  5. ^ a b Milburn DS, Myers CW (November 1991). "Tryptophan toxicity: a pharmacoepidemiologic review of eosinophilia-myalgia syndrome". Annals of Pharmacotherapy. 25 (11): 1259–62. doi:10.1177/106002809102501116. PMID 1763543. S2CID 19913151.
  6. ^ a b Spitzer WO, Haggerty JL, Berkson L, Davis W, Palmer W, Tamblyn R, et al. (October 1996). "Analysis of Centers for Disease Control and Prevention criteria for the eosinophilia-myalgia syndrome in a geographically defined population". The Journal of Rheumatology. Supplement. 46: 73–9, discussion 79–80. PMID 8895183.
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  19. ^ a b c Smith MJ, Garrett RH (November 2005). "A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised histamine degradation". Inflammation Research. 54 (11): 435–50. doi:10.1007/s00011-005-1380-7. PMID 16307217. S2CID 7785345.
  20. ^ Fernstrom JD (December 2012). "Effects and side effects associated with the non-nutritional use of tryptophan by humans". The Journal of Nutrition. 142 (12): 2236S–2244S. doi:10.3945/jn.111.157065. PMID 23077193. — Important: While this article may appear to be a normal peer-reviewed scientific publication at first glance, it is in fact actually a paid supplement (sponsored content, which is a form of native advertising) that did not go through the normal peer review process (or even the normal editorial process) for The Journal of Nutrition. It is legally required to be marked as a paid advertisement (a fact that was buried in a long footnote on the first page of the article rather than being clearly highlighted anywhere). Its sole author also disclosed a major conflict of interest due to them being "an occasional scientific advisor to the Ajinomoto Company" (the Ajinomoto Company specializes in producing animo acids, including tryptophan), and was sponsored by the International Council on Amino Acid Science (ICAAS), a non-profit association established for/by amino acids producers and users with a membership consisting exclusively of corporations with major financial conflicts of interest in the area, at least half of which are corporations which actually currently manufacture tryptophan (such as and including the Ajinomoto Company). This reference should not be considered a reliable source for anything beyond the sole claim it is used to support ("critics of this theory have argued that this hypothesis fails to explain the near-absent reports of EMS prior to and following the EMS outbreak"), and it is only used as the supporting reference for that claim in the first place because no higher-quality alternative to it currently exists.
  21. ^ a b Goronzy JJ, Weyand CM (July 1990). "Eosinophilia, myopathy, and neuropathy in a patient with repeated use of L-tryptophan". Klinische Wochenschrift. 68 (14): 735–8. doi:10.1007/bf01647582. PMID 2391954. S2CID 22468962.
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  25. ^ a b Allen JA, Peterson A, Sufit R, Hinchcliff ME, Mahoney JM, Wood TA, et al. (November 2011). "Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan". Arthritis and Rheumatism. 63 (11): 3633–9. doi:10.1002/art.30514. PMC 3848710. PMID 21702023.
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  27. ^ Grangeia T, Schweller M, Paschoal IA, Zambon L, Pereira MC (December 2007). "[Acute respiratory failure as a manifestation of eosinophilia-myalgia syndrome associated with L-tryptophan intake]" [Acute respiratory failure as a manifestation of eosinophilia - myalgia syndrome associated with L- tryptophan intake]. Jornal Brasileiro de Pneumologia (in Portuguese). 33 (6): 747–51. doi:10.1590/S1806-37132007000600021. PMID 18200378.
  28. ^ Spitzer WO, Haggerty JL, Berkson L, Davis W, Palmer W, Tamblyn R, et al. (March 1995). "Continuing occurrence of eosinophilia myalgia syndrome in Canada". British Journal of Rheumatology. 34 (3): 246–51. doi:10.1093/rheumatology/34.3.246. PMID 7728400.
  29. ^ Daniels SR, Hudson JI, Horwitz RI (December 1995). "Epidemiology of potential association between L-tryptophan ingestion and eosinophilia-myalgia syndrome". Journal of Clinical Epidemiology. 48 (12): 1413–27, discussion 1429–40. doi:10.1016/0895-4356(95)00503-x. PMID 8543957.
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  31. ^ Gross B, Ronen N, Honigman S, Livne E (1999). "Tryptophan Toxicity—Time and Dose Response in Rats". Tryptophan, Serotonin, and Melatonin. Advances in Experimental Medicine and Biology. Vol. 467. pp. 507–16. doi:10.1007/978-1-4615-4709-9_63. ISBN 978-1-4613-7133-5. PMID 10721094.
  32. ^ Raphals P (November 1990). "Does medical mystery threaten biotech?". Science. 250 (4981): 619. Bibcode:1990Sci...250..619R. doi:10.1126/science.2237411. PMID 2237411.
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  35. ^ Castot A, Bidault I, Bournerias I, Carlier P, Efthymiou ML (1991). "["Eosinophilia-myalgia" syndrome due to L-tryptophan containing products. Cooperative evaluation of French Regional Centers of Pharmacovigilance. Analysis of 24 cases]". Therapie. 46 (5): 355–65. PMID 1754978.
  36. ^ "COT Statement On Tryptophan and the Eosinophilia-Myalgia Syndrome" (PDF). UK Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. June 2004. Archived from the original (PDF) on 2016-03-31. Retrieved 2017-06-05.
  37. ^ Das YT, Bagchi M, Bagchi D, Preuss HG (April 2004). "Safety of 5-hydroxy-L-tryptophan". Toxicology Letters. 150 (1): 111–22. doi:10.1016/j.toxlet.2003.12.070. PMID 15068828.
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