Eosinophilia–myalgia syndrome explained

Eosinophilia-myalgia syndrome
Synonyms:EMS

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. Some research suggests that certain genetic polymorphisms may be related to the development of EMS.[3] The presence of eosinophilia is a core feature of EMS, along with unusually severe myalgia (muscle pain).[4] [5] [6]

Signs and symptoms

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.[7]

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.[7]

Causes

Subsequent epidemiological studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko.[8] [9] [10] 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.[11] [12] While a total of 63 trace contaminants were eventually identified, only six of them could be associated with EMS.[13] 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).[14] The last of the six contaminants (peak AAA/"UV-28",[15] being "the contaminant most significantly associated with EMS" 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).[16] 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. 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).

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.[17] 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,[18] 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. 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.[19] [20] [21] 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".[22] 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.[23] [24] 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". 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".[25]

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. A portion of the contaminated batches had also bypassed another filtration step that used reverse-osmosis to remove certain impurities. 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.[26] 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).[27] 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".

Regulatory response

The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, but continued to limit the importation of tryptophan not intended for an exempted use until 2005.[19]

Treatment

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.

History

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.[28] [29] [30] [31] 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,[32] [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

Notes and References

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  2. Lindgren CE, Walker LA, Bolton P . L-tryptophan induced eosinophilia-myalgia syndrome . Journal of the Royal Society of Health . 111 . 1 . 29–30 . February 1991 . 2005606 . 10.1177/146642409111100111 . 31841865 .
  3. Okada S, Kamb ML, Pandey JP, Philen RM, Love LA, Miller FW . 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 . October 2009 . 19790128 . 2761987 . 10.1002/art.24460 .
  4. Milburn DS, Myers CW . Tryptophan toxicity: a pharmacoepidemiologic review of eosinophilia-myalgia syndrome . Annals of Pharmacotherapy . 25 . 11 . 1259–62 . November 1991 . 1763543 . 10.1177/106002809102501116 . 19913151 .
  5. Spitzer WO, Haggerty JL, Berkson L, Davis W, Palmer W, Tamblyn R, Laprise R, Mulder LJ . 6 . 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 . October 1996 . 8895183 .
  6. Blackburn WD . Eosinophilia myalgia syndrome . Seminars in Arthritis and Rheumatism . 26 . 6 . 788–93 . June 1997 . 9213377 . 10.1016/S0049-0172(97)80022-4 .
  7. Web site: Rare Disease Database: Eosinophilia-Myalgia Syndrome . National Organization for Rare Disorders . . 3 December 2019 . https://web.archive.org/web/20191203204048/https://rarediseases.org/rare-diseases/eosinophilia-myalgia-syndrome/ . 3 December 2019 . dead .
  8. Slutsker L, Hoesly FC, Miller L, Williams LP, Watson JC, Fleming DW . Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer . JAMA . 264 . 2 . 213–7 . July 1990 . 2355442 . 10.1001/jama.264.2.213 .
  9. Back EE, Henning KJ, Kallenbach LR, Brix KA, Gunn RA, Melius JM . Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York . The Journal of Rheumatology . 20 . 4 . 666–72 . April 1993 . 8496862 .
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  11. Mayeno AN, Lin F, Foote CS, Loegering DA, Ames MM, Hedberg CW, Gleich GJ . Characterization of "peak E," a novel amino acid associated with eosinophilia-myalgia syndrome . Science . 250 . 4988 . 1707–8 . December 1990 . 2270484 . 10.1126/science.2270484 . 1990Sci...250.1707M .
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  13. Hill RH, Caudill SP, Philen RM, Bailey SL, Flanders WD, Driskell WJ, Kamb ML, Needham LL, Sampson EJ . 6 . Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome . Archives of Environmental Contamination and Toxicology . 25 . 1 . 134–42 . July 1993 . 8346973 . 10.1007/bf00230724 . 1993ArECT..25..134H . 10182128 .
  14. Williamson BL, Johnson KL, Tomlinson AJ, Gleich GJ, Naylor S . On-line HPLC-tandem mass spectrometry structural characterization of case-associated contaminants of L-tryptophan implicated with the onset of eosinophilia myalgia syndrome . Toxicology Letters . 99 . 2 . 139–50 . October 1998 . 9817085 . 10.1016/S0378-4274(98)00223-9 .
  15. Allen JA, Varga J . Eosinophilia–Myalgia Syndrome . Encyclopedia of Toxicology (Third Edition) . 1 January 2014 . 419–425 . 10.1016/b978-0-12-386454-3.00018-x . Academic Press . 9780123864550 .
  16. Klarskov K, Gagnon H, Boudreault PL, Normandin C, Plancq B, Marsault E, Gleich GJ, Naylor S . 6 . Structure determination of disease associated peak AAA from l-Tryptophan implicated in the eosinophilia-myalgia syndrome . Toxicology Letters . 282 . 71–80 . January 2018 . 29037509 . 10.1016/j.toxlet.2017.10.012 .
  17. Smith MJ, Garrett RH . A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised histamine degradation . Inflammation Research . 54 . 11 . 435–50 . November 2005 . 16307217 . 10.1007/s00011-005-1380-7 . 7785345 .
  18. Fernstrom JD . Effects and side effects associated with the non-nutritional use of tryptophan by humans . The Journal of Nutrition . 142 . 12 . 2236S–2244S . December 2012 . 23077193 . 10.3945/jn.111.157065 . free . — 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.
  19. Allen JA, Peterson A, Sufit R, Hinchcliff ME, Mahoney JM, Wood TA, Miller FW, Whitfield ML, Varga J . 6 . Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan . Arthritis and Rheumatism . 63 . 11 . 3633–9 . November 2011 . 21702023 . 3848710 . 10.1002/art.30514 .
  20. Barešić . Marko . Bosnić . Dubravka . Bakula . Marija . Žarković . Kamelija . vanc . Eosinophilia-myalgia syndrome induced by excessive L-tryptophan intake from cashew nuts . Open Medicine . 1 January 2014 . 9 . 6 . 796–801 . 10.2478/s11536-013-0339-2. 32288933 . 7102313 . free .
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  24. Shapiro S . Epidemiologic studies of the association of L-tryptophan with the eosinophilia-myalgia syndrome: a critique . The Journal of Rheumatology. Supplement . 46 . 44–58; discussion 58–9 . October 1996 . 8895181 .
  25. Book: Gross B, Ronen N, Honigman S, Livne E . Tryptophan, Serotonin, and Melatonin . Tryptophan Toxicity—Time and Dose Response in Rats . Advances in Experimental Medicine and Biology . 467 . 507–16 . 1999 . 10721094 . 10.1007/978-1-4615-4709-9_63 . 978-1-4613-7133-5 .
  26. Raphals P . Does medical mystery threaten biotech? . Science . 250 . 4981 . 619 . November 1990 . 2237411 . 10.1126/science.2237411 . 1990Sci...250..619R .
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  28. Goronzy JJ, Weyand CM . Eosinophilia, myopathy, and neuropathy in a patient with repeated use of L-tryptophan . Klinische Wochenschrift . 68 . 14 . 735–8 . July 1990 . 2391954 . 10.1007/bf01647582 . 22468962 .
  29. Blauvelt A, Falanga V . Idiopathic and L-tryptophan-associated eosinophilic fasciitis before and after L-tryptophan contamination . Archives of Dermatology . 127 . 8 . 1159–66 . August 1991 . 1863073 . 10.1001/archderm.127.8.1159 .
  30. Lakhanpal S, Duffy J, Engel AG . Eosinophilia associated with perimyositis and pneumonitis . Mayo Clinic Proceedings . 63 . 1 . 37–41 . January 1988 . 3336240 . 10.1016/s0025-6196(12)62663-9 .
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  32. Web site: Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan . https://web.archive.org/web/20050225100757/http://www.cfsan.fda.gov/~dms/ds-tryp1.html . 2005-02-25 . 2001-02-01 . FU. S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements . 2012-02-08 .
  33. Web site: L-tryptophan: Uses and Risks . . 2017-05-12 . 2017-06-05.
  34. News: Altman. Lawrence K.. Studies Tie Disorder to Maker of Food Supplement. The New York Times. 27 April 1990.
  35. Castot A, Bidault I, Bournerias I, Carlier P, Efthymiou ML . ["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 . 1991 . 1754978 .
  36. Web site: COT Statement On Tryptophan and the Eosinophilia-Myalgia Syndrome. UK Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. June 2004. 2017-06-05. https://web.archive.org/web/20160331221646/http://cot.food.gov.uk/sites/default/files/cot/tryptophanamend200401.pdf. 2016-03-31. dead.
  37. Das YT, Bagchi M, Bagchi D, Preuss HG . Safety of 5-hydroxy-L-tryptophan . Toxicology Letters . 150 . 1 . 111–22 . April 2004 . 15068828 . 10.1016/j.toxlet.2003.12.070 .

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