Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic—Pre-epidemic Cases

Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic—Pre-epidemic Cases

by William E. Crist

A Key to the EMS Puzzle?

"The existence of cases prior to those that constituted the great bulk of the epidemic is one of the most peculiar and interesting aspects of the EMS outbreak."
       — Edwin M. Kilbourne,1 epidemiologist, Center for Disease Control

For more than a decade now, researchers have been puzzled by cases of EMS that occurred for several years prior to the epidemic.

The Center for Disease Control (CDC) surveillance data revealed nearly 100 cases with onset of illness prior to May 1989, the beginning of the epidemic period.2 This represented about 7% of the patients for whom complete information was available.3 CDC estimated that the number of actual EMS cases could be about four times what was reported. This is because of the agency's passive surveillance system and its surveillance case definition, which stressed specificity over sensitivity. The definition was not sensitive enough to recognize the broad spectrum of EMS symptoms and excluded milder cases.3, 4

CDC researchers calculated that with a more sensitive case definition there could be as many as 5,000 to 10,000 EMS cases in the U.S.4 Using the 7% figure from CDC surveillance data, this would mean that there could be as many as 350 to 700 pre-epidemic cases of EMS. These early EMS victims would have consumed L-tryptophan (LT) pills that were contaminated prior to the manufacturing changes attributed to the etiology of the epidemic. In that scenario, Showa Denko's introduction of the Strain V bacterium and their reduction in activated carbon powder in the filtering process could not have been solely responsible.

Some researchers suggested that a low level of contaminants may have always been present in L-tryptophan-containing products,5 while others suggested that Showa Denko L-tryptophan might have contained the etiologic agent in lower concentrations or in fewer lots before the manufacturing changes were implemented.6,7

Evidence Points to Showa Denko

While limited data has been available on pre-epidemic EMS, findings from product trace-back studies on epidemic cases have been unambiguously clear.

In four epidemiological studies (Oregon, Minnesota, New York and South Carolina) 96-100 percent of epidemic cases traced to Showa Denko.6 In the two cases that didn't initially appear to trace to Showa Denko, tablets from one (in Minnesota) were analyzed and found to have a chromatographic pattern that was characteristic of Showa Denko L-tryptophan. The other victim (in Oregon) had consumed two different brands, one of which was untraceable and therefore could have been from Showa Denko.1 CDC researchers concluded, "Of 6 manufacturers of LT, only LT manufactured by Showa Denko KK was clearly associated with illness."8

Surprisingly little trace-back data is available on the pre-epidemic EMS cases. In the Minnesota study on the epidemic, four 1988 cases (September to November) were excluded from the analysis because they were pre-epidemic. Two of these cases were traced to Showa Denko and two were untraceable.6 In a CDC study, two case patients were found to have consumed pills manufactured by Showa Denko in April 1988, but they also had consumed pills from 1989 lots. Again, only Showa Denko product was found to be case-associated; no other manufacturer's product was linked to EMS.9

Curious if pre-epidemic or epidemic EMS cases were linked to other manufacturers' L-tryptophan, I faxed and called about a dozen law firms who had handled Showa Denko cases. None had handled or knew of any definite case associated with another manufacturer.

Stephen Sheller, a Philadelphia attorney whose firm handled over 100 EMS cases, including about 10 pre-epidemic, commented,

"We have always been suspicious that there were EMS cases caused by other L-tryptophan…. However, we have never had a case that we could confirm that with. All cases that we've had (have) been traced to Showa Denko.

"I thought I had a case with Ajinomoto.... We went through hoops in certain tracing. We had affidavits from companies who insisted they had no Showa Denko product. A diet food, for example, put out by some companies, we traced.... product to a time when Hormel had a strike and they sub-contracted out the work to another company that used Showa Denko L-tryptophan. We were able to confirm direct shipments of Showa Denko product to that company in 1986."10

In response to how many EMS victims claimed early onset of illness, Don Morgan, an attorney representing Showa Denko in the litigations, replied in a phone interview, "I don't have a good idea of that... See, there have been thousands of cases... My general impression is that there have been a good number of those cases of pre-epidemic onset of symptoms... more and more cases came up that involved onset before 1989." He said that SDKK has settled some EMS claims related to such tryptophan, and many epidemic-period claims, without admitting causation or legal liability.11

Gerald Gleich, M.D., a leading researcher on L-tryptophan/EMS at the Mayo Clinic, recently summed up the matter, saying, "Tryptophan itself clearly is not the cause of EMS in that individuals who consumed products from other companies, other than Showa Denko, did not develop EMS. The evidence points to Showa Denko product as the culprit and to the contaminants as the cause."12

Intrigued by the elusive pre-epidemic cases, I contacted a woman with the National EMS Network, a nonprofit organization composed of EMS victims and their families. She put me in touch with several pre-epidemic EMS victims, some with onset of illness dating back to 1984-85. I also found two early cases who had given testimony at the Congressional Committee Hearings on EMS.13 All of these had received settlements from Showa Denko (except for two who were offered settlements but declined them and then later lost their cases on statutes of limitation).

One case was particularly striking, because the man had onset of illness in November 1987 and stopped using L-tryptophan in February 1988. In his legal proceedings, his pills were tested and identified as from Showa Denko.14 His tablets had to have been from lots manufactured about a year and a half before October 1988, — the alleged date when L-tryptophan product became contaminated.15 (It took several months for product to be packaged in Japan, shipped to the U.S., pass through the distribution chain, and then be consumed for a few weeks before onset of symptoms.)

Birth of a New Disease: A Problem with Diagnosis

In late October 1989, when three physicians in New Mexico first linked L-tryptophan ingestion to patients with debilitating myalgia (muscle pain) and elevated eosinophil levels, the EMS epidemic had already been six months in progress. Prior to that time, no medical classification existed to accommodate the cluster of symptoms associated with EMS.1 Consequently, physicians were either baffled by this new disease and gave no clear diagnosis, or they gave a diagnosis that fit only one of the patient's predominant symptoms.

In addition to severe myalgia and elevated eosinophils, EMS patients often exhibited fasciitis, scleroderma, rashes, perimyositis, peripheral edema (swelling), and/or other symptoms.14Before news of the epidemic emerged in November 1989, patients seeking medical treatment were sometimes diagnosed with one of these illnesses. Of the eleven pre-epidemic cases on whom I collected information, two were initially diagnosed with eosinophilic fasciitis (EF), one with fibromyalgia, one with scleroderma, and one with neuritis and fibromyalgia. Six had no clear diagnosis, though their physicians had considered some of the above diseases. All were re-diagnosed with EMS after news of epidemic emerged.

One woman who had onset of illness in October 1988 told me she was initially diagnosed as having eosinophilic fasciitis "even though some of the symptoms didn't quite match." A man with onset in March 1989 said that he was not given a diagnosis though "fibromyalgia was tossed around." And a woman who testified at the Congressional Committee Hearings on L-tryptophan stated that her doctor noted elevated eosinophils, but gave no diagnosis because "he knew of no illness which had this cluster of symptoms."

Other Diseases Linked to L-Tryptophan Ingestion

I started searching the medical literature for L-tryptophan-related illnesses other than EMS, and found several studies and a few isolated case reports.

A study at the University of Miami School of Medicine reported (1991) that 65% of EF cases (11 of 17) and 20% of scleroderma patients (2 of 10) had ingested L-tryptophan prior to onset of disease. Eight of the eleven EF cases and both scleroderma patients had pre-epidemic onset, with one scleroderma case dating back to 1985.15

A study at the University of Pennsylvania reported (May 1990) that all eight patients with EF had taken L-tryptophan before the onset of their disease. All had myalgias and high peripheral eosinophil counts. Only one of 40 patients with scleroderma had used L-tryptophan preceding illness.16

An article on the Los Alamos Conference on EMS (1990) stated, "It is of interest that since 1986, one-half of the patients diagnosed with EF at the Mayo Clinic had been exposed to L-tryptophan; and 9 of 45 patients in the ARAMIS database with EF (1985-1986) remembered using L-tryptophan before onset of EF."4

EF is a rare disease with unknown cause, characterized by scleroderma-like skin changes and peripheral eosinophilia, two common symptoms of EMS. It was first diagnosed in 1974 by Shulman and by 1988 some 200-plus cases had been reported worldwide.17

Other studies on L-tryptophan-related EF reported similar findings.18,19 Some commentators have concluded that L-tryptophan products are the first agents to be implicated as a cause of EF in some patients.5 Others have suggested that L-tryptophan-related EF and EMS are the same disease.15 One 1988 case of EF was contacted after news of the EMS epidemic and it was found that she had used L-tryptophan before onset of her illness; she was re-diagnosed as having EMS.1

Isolated cases of other diseases have also been linked to L-tryptophan ingestion, including eosinophilic perimyositis20 and lichen sclerosus et atrophicus and acanthosis nigricans.15

Although L-tryptophan usage is also associated with cases of these other diseases, researchers never conducted trace back studies to determine whose product was causing all this damage. Commentators assumed that L-tryptophan-containing products in general were probably responsible, but no one did follow-up research to verify this.

To date, the available evidence, from both L-tryptophan trace back studies and EMS legal proceedings, appears to point to Showa Denko product as the source of the problem.

In retrospect, these pre-epidemic L-tryptophan-related illnesses may provide vivid demonstration of the mechanics of the birth of a disease, and how medical science grapples with diagnosing and accommodating a new entity into its medical repertoire. For several years, cases of the new disease were occurring unbeknownst to the manufacturer, government regulators and medical authorities. It took a tragic epidemic in 1989 to bring EMS into focus. For more than a decade since then, scientists have been trying to fit the pieces of the EMS puzzle together. These puzzle pieces fit together only one way, namely, when the scientific model and understanding are correct. The pre-epidemic EMS and other L-tryptophan-related diseases appear to be a key piece in solving the puzzle.

According to attorney Sheller, there is a huge lesson in all this. Because EMS cases went unrecognized for so many years, he said, "One has to wonder about a lot of different things that are in the food supply, because no one has really tested it to find out. The biggest problem is that most of the testing is done for short periods of time."10

For more information on the pre-epidemic cases of EMS, see:

With respect to Showa Denko's L-tryptophan, the next piece in the puzzle is to address the question, Where did the contaminants come from? >>


References         

  1. Edwin M Kilbourne, "Eosinophilia-Myalgia Syndrome: Coming to Grips with a New Illness," Epidemiological Reviews (1992), Vol. 4, pp. 16-36.
  2. Leslie A. Swygert, et al., "Eosinophilia-Myalgia Syndrome: Results of National Surveillance," Journal of the American Medical Association (October 3, 1990), Vol. 264, No. 13, pp. 1698-1703.
  3. Lee D. Kaufman and Rossanne M. Philen, "Tryptophan: Current Status and Future Trends for Oral Administration," Drug Safety (1993), Vol. 8, No. 2, pp. 89-98.
  4. Phillip A. Hertzman, et al., "The Eosinophilia-Myalgia Syndrome: The Los Alamos Conference," Journal of Rheumatology (1991), Vol. 18, No. 6, pp. 867-873.
  5. Richard W. Martin and Joseph Duffy, "Eosinophilic Fasciitis Associated With Use of L-Tryptophan: A Case- Control Study and Comparison of Clinical and Histopathologic Features," Mayo Clinic Proceedings (September 1991), Vol. 66, pp. 892-898.
  6. Edward A. Belongia and Gerald J. Gleich, Editorial, "The Eosinophilia-Myalgia Syndrome Revisited," Journal of Rheumatology (1996), Vol. 23, No. 10, pp. 1682-1685.
  7. Arthur N. Mayeno and Gerald J. Gleich, "Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale," Trends in Biotechnology (TIBTECH) (September 1994), Vol. 12, pp. 346-352.
  8. Edwin M. Kilbourne, et al., "Tryptophan Produced by Showa Denko and Epidemic Eosinophilia-Myalgia Syndrome," Journal of Rheumatology Supplement (October 1996), Vol. 23, No. 46, pp. 81-92.
  9. Samuel P. Caudill, et al., "Important Issues Affecting Eosinophilia-Myalgia Syndrome Investigations Based on Analyses of L-Tryptophan Samples," Journal of Occupational Medicine and Toxicology (1993), Vol. 2, No. 1, pp. 41-52.
  10. Stephen Sheller, attorney, personal interviews, March 25 and May 1, 1998.
  11. Don Morgan, attorney, Cleary, Gottlieb, Steen & Hamilton, Washington, D.C., personal interview, May 21, 1998.
  12. National Eosinophilia-Myalgia Syndrome Network, position statement, approved quote by Gerald J. Gleich, M.D., Mayo Clinic and Foundation, May 25, 2000.
  13. Dorothy C. Wilson and Paul L. Hauts, statements, Subcommittee on Human Resources and Intergovernmental Relations, House Committee on Government Operations, July 18, 1991.
  14. Anonymous pre-epidemic case, personal correspondences, January 10, 2000 to April 13, 2001.
  15. Andrew Blauvelt and Vincent Falanga, "Idiopathic and L-Tryptophan-Associated Eosinophilic Fasciitis Before and After L-Tryptophan Contamination," Archives of Dermatology (August 1991), Vol. 127, pp. 1159-1166.
  16. Frendlich B, et al., "L-tryptophan ingestion associated with eosinophilic fasciitis but not progressive systemic sclerosis," Annuals of Internal Medicine (May 15, 1990), Vol. 112, No. 10, pp. 758-762.
  17. Lakhanpal S, et al., "Eosinophilic Fasciitis: Clinical Spectrum and Therapeutic Response in 52 Cases," Seminars in Arthritis and Rheumatism (1988), Vol. 17, No. 4, pp. 221-231.
  18. Hibbs JR, et al., "L-tryptophan-associated eosinophilic fasciitis prior to the 1989 eosinophilia-myalgia syndrome outbreak," Arthritis Rheumatology (1992), Vol. 35, No. 3, pp. 299-303.
  19. Richard M. Silver, et al., "Scleroderma, Fasciitis, and Eosinophilia Associated with the Ingestion of Tryptophan," The New England Journal of Medicine (March 29, 1990), Vol. 322, No. 13, pp. 874-881.
  20. Richard M. Silver, editorial, "Unraveling the Eosinophilia-Myalgia Syndrome," Archives of Dermatology (August 1991), Vol. 127, pp. 1214-1216.

 

© Copyright 2005 William E. Crist. All Rights Reserved

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