Why Moss Nutrition is no Longer Selling L-Tryptophan Supplements (at least for now) – Part II

Based on the Belongia et al (1) paper from 1992 that I reviewed in part I of this series, there is, in fact, no controversy in the so-called tryptophan – eosinophilia-myalgia syndrome (EMS) controversy.  Contaminated batches of supplemental tryptophan were involved in the vast majority of EMS cases, which ceased to appear after the FDA banned all further sales of supplemental tryptophan.  Therefore, the contaminant must have been the sole causative factor.

While the case certainly seems “cut and dry” so to speak, there has existed a small group of researchers who, since the EMS/tryptophan crisis in 1989, have never been totally convinced that the contaminant was the whole story.  They felt that there is significant likelihood that, in certain susceptible individuals, something inherent in the biochemistry and physiology of tryptophan, when consumed as a supplement in significant amounts, could have caused or contributed to the 1989 epidemic of EMS.  Now, in part II of this series, I would like to tell their story.

A CASE OF EMS 20 YEARS LATER

Of course, the most powerful and compelling argument for the contaminant theory has been the overwhelming evidence that cases of EMS that might have been related to tryptophan supplementation stopped occurring after the tainted batches were removed from the marketplace.  However, it must also be kept in mind that, since the FDA removed all supplemental tryptophan from the over-the-counter marketplace in 1989, the decrease in occurrence may also, at least partially, have been related to the fact that the supplement was no longer available in any form – contaminated or uncontaminated.

As I mentioned in part I of this series, there exists a paper that presents compelling evidence against the theory that the contaminant is the only issue.  This paper, interestingly, received little attention either from the mass media or the nutritional community.  This paper, “Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan” by Allen et al (2) was published in 2009, six years after the FDA began to again allow over-the-counter sales of supplemental L-tryptophan.  While, as I will describe, the paper is far from conclusive in disproving the contaminant theory, I feel it certainly introduces enough doubt to warrant serious consideration.

The paper, which presents a case report of a woman who developed EMS in 2009, begins by presenting a basic overview of the 1989 epidemic:

“Eosinophilia-myalgia syndrome (EMS), a chronic multisystem disorder first recognized in 1989, is characterized by subacute onset of myalgias and peripheral eosinophilia associated with chronic muscle, nerve, fascia, and skin involvement.  This apparently new disease occurred in an epidemic outbreak that affected 1,500 individuals and was associated with >30 deaths over a 6-month period.”

The authors then discuss the specifics of the involved contaminant and what happened after the FDA action:

“Initial analysis of implicated L-tryptophan revealed an impurity that was identified as 1’1′-ethylidenebis[tryptophan] (EBT).  Removal of L-tryptophan from the market was followed by swift resolution of the EMS epidemic.”

Of course, as I mentioned above, it was widely assumed that resolution of the EMS epidemic was solely related to elimination of the contaminant from the marketplace.  Could part of the reason also be that all supplemental L-tryptophan, contaminated and uncontaminated, was removed from the marketplace?  In support of the “yes” answer to this question, consider the following quote from the Allen et al (2) paper:

“Although rodents exposed to implicated L-tryptophan developed EMS-like histopathologic changes, similar changes were also observed in rodents that received L-tryptophan without EBT.  Moreover, in some cases of EMS there was no known L-tryptophan exposure, while in others the disease antedated the epidemic.”

Yes, you read that right.  The authors referenced a 1996 paper that pointed out cases of EMS had occurred before the contaminant-related crisis.

Next, the authors present another quote that introduces doubt to the idea that the contaminant was the only issue:

“Even among people using L-tryptophan during the EMS epidemic, the estimated incidence rate of EMS was <2%.”

Could a third variable be, beyond the issues of the contaminant and something inherent in the metabolism of L-tryptophan, that there was something very unusual about those who were ultimately afflicted with EMS?  For me, the fact that over 98% of those ingesting supplemental L-tryptophan in 1989 did not demonstrate development of EMS suggests that that answer to this question could certainly be in the affirmative.

The next quote I would like to present from the Allen et al (2) paper presents some compelling evidence suggesting that the reality of the contamination was much more complicated than what was stated in reports from 1989 and soon after:

“The pathobiologic basis of EMS remains unknown.  Epidemiologic studies tracing implicated L-tryptophan to a single manufacturer and quantitative analyses of EBT suffered from methodologic limitations.  EBT was just one of more than 60 minor impurities detected in implicated L-tryptophan, 6 of which were associated with EMS.  One of these, 3-(phenylamino) alanine (PAA), shares chemical properties with 3-(N-phenylamino)-1,2-propanediol, which was implicated in the 1981 Spanish toxic oil syndrome epidemic linked to consumption of aniline-denatured rapeseed oil.”

With the above information in mind, now consider the case report that forms the central theme of the Allen et al (2) paper.  The case report begins with the following description of the patient and related circumstances:

“The patient, a 44-year-old woman, started using L-tryptophan (1,500 mg per day; sold in Chicago, IL and labeled as ‘Uber Rest’ [Heartland Products]) in January 2009 for insomnia.  She had undergone duodenal switch weight-loss surgery in 2007 to treat obesity, and during the following 12 months lost 140 pounds.  In addition to L-tryptophan, she used L-carnitine, flax oil, and alpha-lipoic acid, but was not receiving any prescribed medications.  Within 3 weeks of starting to take L-tryptophan, she developed swelling in the upper and lower extremities followed by severe myalgia and weakness.  During the next 4 weeks, she noted progressive skin induration in her upper and lower extremities, with no involvement in the fingers and toes.  Physical examination findings in August 2009 were remarkable for woody induration of the forearms and leg.  Myalgias were provoked by proximal extremity palpation.”

Concerning laboratory analyses:

“Laboratory examinations revealed an elevated white blood cell count with 24% eosinophils (absolute count 1,600 cells/mm3). 

Before continuing, please note again from the above description that the patient, before the ingestion of L-tryptophan, had suffered from significant obesity that was treated by a major surgical procedure.  Under such circumstances, as we all know, it is very likely that, even after the surgery and weight loss, significant systemic inflammation was still present.  As I pointed out in part I of this series, chronic inflammation can lead to aberrations in L-tryptophan metabolism that favor the kynurenine pathway and subsequent production of increased amounts of quinolinic acid, a potentially neurotoxic metabolite.  Therefore, as I suggested above, L-tryptophan ingestion is only one-half of the story in this case report.  The other half, which I feel is equally important, is increased patient susceptibility.

The next quote I would like to present addresses the crucial question of whether the L-tryptophan supplements ingested by the patient contained contaminants identical or similar to those found in the tainted 1989 batches.  Unfortunately, what you are about to read is compelling but inconclusive:

“Although the L-tryptophan taken by the patient prior to the onset of symptoms was no longer available, multiple contemporaneous samples from the same batch were subjected to high-performance liquid chromatography with mass spectrometry.  No impurities were detected at >10 ppm in any of the samples.  In particular, the hydroxylated tryptophan derivative peak C (EBT), peak E (PAA), 2-(2-hydroxy indoline)-Trp peak FF, and 2-(3-indolyl)-L-tryptophan were not detected.”

Before continuing, I should point out that I had a chance to speak with a representative of the International Council on Amino Acid Sciences (ICAAS), the organization mentioned in part I of this series that initially brought the issue of contaminated Uber Rest to my attention, about this case report.  He vehemently disagreed with the findings reported above that the batch of L-tryptophan that contained the supplements ingested by the patient was not contaminated.  He insisted that the analytical methodology used by Allen et al was flawed and that testing performed by his group on the same batch demonstrated a similar toxicity profile that they found in the batches I was selling.

Unfortunately, as I suggested above, both of these conflicting claims about toxicity must be considered inconclusive because, as pointed out in the above quote, the actual bottle of L-tryptophan used by the patient was not available.

How was the patient treated and what were the results of that treatment?  Unfortunately, the results were less than optimal:

“Although treatment with prednisone and mycophenolate mofetil resulted in modest improvement in proximal muscle strength and myalgia, along with prompt resolution of peripheral blood eosinophilia and ground-glass opacifications seen on computed tomography scans, skin induration and neuropathy progressed.  Repeat nerve conduction studies revealed reduced or absent sensory and motor response amplitudes compatible with a new length-dependent axonal sensorimotor polyneuropathy affecting the upper and lower extremities.  Adding treatment with methotrexate (20 mg weekly for 5 months) followed by daily injections of anakinra for 3 months failed to result in further improvement in myalgia, neuropathy, or skin induration.”

In concluding this review of the Allen et al (2) paper, I would like to present two thought-provoking quotes from the discussion section.  The first highlights the authors’ thoughts on the pathogenesis of EMS in relation to L-tryptophan:

“The pathogenesis of EMS is thought to involve exposure to certain preparations of L-tryptophan in a genetically susceptible host, which triggers acute inflammation and eosinophil activation and degranulation with resulting chronic tissue fibrosis.  However, because EMS has been reported in individuals who have never consumed L-tryptophan, it is likely that xenobiotic agents other than L-tryptophan preparations can also trigger a similar immune response.”

In particular, please note again the last sentence of the above quote.  What seemed like a clear-cut, black and white scenario implicating contaminated L-tryptophan and nothing else shortly after the EMS disaster in 1989 now, with the benefit of time, additional data, and hindsight, is a bit less clear.  Knowing that other xenobiotic agents can create an EMS-like response plus knowing, as stated above, that cases of EMS occurred before the 1989 outbreak and that many people who ingested the contaminated L-tryptophan demonstrated no evidence of EMS signs and symptoms, I feel it is imperative that I check the “it was obviously a contaminant” agenda at the door and re-examine the L-tryptophan/EMS relationship with a new set of fresh, unbiased eyes. 

And, if that were not enough to cloud the situation, consider this second quote:

“A search of the Center for Food Safety and Applied Nutrition Adverse Reporting System (CAERS), the FDA passive surveillance system, for reports of adverse events associated with single-ingredient tryptophan products from January 1, 2003 to August 31, 2010 yielded 2 reports of possible EMS (1 in 2005 and 1 in 2008) and 2 reports of myalgias (1 in 2005 and 1 in 2008).  No adverse event reports for tryptophan sold under the ‘Uber Rest’ or ‘Heartland products’ brand names were identified, but the manufacturer of the tryptophan in all of these cases is unknown.”

While Allen et al (2) note that the statistics mentioned in the above quote need to be considered in context with the inherent limitations of “passive surveillance reporting systems” in mind, I feel that they are significant enough to further cloud the notion that EMS/contaminant connection is an “open and shut case.” Beyond just creating more doubt and uncertainty, though, can any clinically constructive hypotheses be derived from this case report?  With emphasis on the hypothetical nature of the following, I would like to suggest that this case report, probably due to both the unique patient health issues and increased susceptibility to adverse effects of L-tryptophan supplementation which may or may not be contaminated, is very likely not the norm.  However, regardless of whether or not current or past batches of Uber Rest or any other brands of L-tryptophan supplements were contaminated, the apparent permanence of symptomatology in this case report cannot be taken lightly.  Therefore, as I continue with this review that will reinforce the idea that adverse reactions to uncontaminated L-tryptophan supplements is a legitimate consideration, I feel it is important to err on the side of caution in terms of selling L-tryptophan supplements.

LABORATORY EVALUATION OF POSSIBLE SIDE EFFECTS OF UNCONTAMINATED L-TRYPTOPHAN SUPPLEMENTATION

Is it possible that much of the uncertainty discussed above could be a function of the limited methods used to define reactions to the L-Tryptophan supplements?  For, other than elevations of eosinophils, determination of whether a reaction occurred was based solely on gross signs and symptoms.  Would a functional medicine approach to diagnosis of possible reactivity to uncontaminated tryptophan lend clarity to the question of whether EMS could be more than just an issue of contamination?  More specifically, could determination of a metabolic imbalance that is not directly related to EMS help us to decide whether supplementation of uncontaminated L-tryptophan is a legitimate risk to the health of some of our patients?  Some evidence that the answer to this question is yes was provided by the paper “Tryptophan loading induces oxidative stress” by Forrest et al (3).

This paper discusses an experiment where 145 healthy subjects (4 males and 11 females aged 21 to 56 years) were provided with a loading dose of 6 g of L-tryptophan in liquid form.  Blood was drawn 5 and 7 hours after the tryptophan load was administered.  What were the results?  Most notably, levels of oxidative metabolites were significantly elevated:

“Basal levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal before loading were 0.67 ± 0.08 µM (n = 15).  There was a significant increase of peroxidation products at 5h (71.08% increase; P < 0.01 and a further increase at 7 h (109% increase; P < 0.01) after tryptophan loading.”

However, even more interesting and possibly significant was the impact of the tryptophan load on kynurenine metabolites of tryptophan, including the one with the greatest capacity for adversely affecting neurologic function, quinolinic acid:

“Significant increases were recorded in the plasma concentrations of tryptophan itself, kynurenine, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid, at 5h after tryptophan loading, with maintained increases of tryptophan, kynurenine, 3-hydroxyanthranilic acid and quinolinic at 7h.  The kynurenine/tryptophan (k/t) ratio was also increased significantly at both times (P < 0.01), consistent with the evidence that tryptophan can induce activity of the liver enzyme tryptophan-2,3-dioxygenase.”

The authors then go on to discuss the possible clinical relevance of these findings:

“The results indicate increased lipid peroxidation as a result of tryptophan loading.  Interest in the potential neuropathological relevance of the kynurenine pathway has centered on two primary hypotheses.  The first is the ability of kynurenine metabolites to modulate activity at glutamate receptors, especially those sensitive to N-methyl-D-aspartate (NMDA).  Activation of NMDA receptors is known to activate free radical formation both by the conversion of xanthine dehydrogenase into xanthine oxidase, and by stimulation of nitric oxide synthase.  The second reason for interest is in the direct generation of reactive oxygen species such as hydrogen peroxide by 3-hydroxykynurenine and 3-hydroxyanthranilic acid as well as quinolinic acid.  These properties of the kynurenine pathway could lead to cellular oxidative stress and cellular damage or death.”

With the above in mind, Forrest et al (3) conclude with the following recommendation:

“Caution should be exercised in the use of tryptophan loading in subjects in whom the induction of oxidative stress would be contra-indicated.  The present results could also have implications for dietary regimens which include a chronically raised intake of tryptophan, such as the Atkins Diet…”

This last quote provides a very interesting “wrinkle” to the EMS/tryptophan controversy.  Probably your initial reaction to the study just described was the same as mine – what about dose issues?  For, it is highly unlikely that those individuals who reacted to L-tryptophan supplements by developing EMS were ingesting 6 grams all at once.  But is it possible, as suggested by Forrest et al (3), that the supplements could have an additive effect with the elevated amounts of dietary tryptophan that are the result of a high protein diet?  Given that it is highly unlikely that data collectors in 1989 plus those involved with the 2007 case discussed above evaluated levels of dietary tryptophan, it is difficult, if not impossible, to answer this question with any degree of certainty.  However, in my opinion, it adds more “fuel to the fire” that the EMS/tryptophan story is more than just an issue of contamination.

STUDIES THAT DIRECTLY EXAMINE KYNURENINE METABOLISM IN EMS PATIENTS

While the Forrest et al (3) is suggestive and compelling, it really proves nothing in terms of the suggestion that kynurenine pathway disturbances could contribute to or cause EMS independent of any contamination issues.  Therefore, I would now like to discuss two papers that directly discuss kynurenine pathway dynamics in relation to EMS.

The first is from a Japanese journal and is entitled “Elevated L-kynurenine level and its normalization by prednisolone in a patient with eosinophilia-myalgia syndrome” by Hisatomi et al (4).  In this paper a case of L-tryptophan-induced EMS in a Japanese woman is discussed.  Unfortunately, little is mentioned about the specifics of tryptophan supplementation, such as analysis for toxicity, in the abstract, which was all that was available to me.  All that is stated about supplementation is the following:

“She had taken 1.0 g of the implicated L-tryptophan daily.”

After being diagnosed with EMS, she was treated successfully with the anti-inflammatory steroid prednisolone.  However, before being treated, the following was noted about the kynurenine pathway:

“Before prednisolone treatment, her serum L-kynurenine level was 10.2 µmol/L, a level about three-fold higher than the normal value, while serum tryptophan level was abnormally low (23.1 µmol/L).  On the 14th day of prednisolone treatment (40 mg daily), L-kynurenine was declined to 8.1 µmol/L and, concomitantly, L-tryptophan level increased to the normal range (51.0 µmol/L).  Subsequently, on the 42nd day of therapy, serum L-kynurenine was normalized.  In contrast, serum serotonin level was unchanged throughout the course of this therapy.”

With these findings in mind, the authors conclude:

“Prednisolone dramatically reduced the elevated serum L-kynurenine with a reciprocal increase in serum L-tryptophan, which indicates that abnormal tryptophan metabolism, may play a role in the pathogenesis of eosinophilia myalgia syndrome, and that the observed effect of steroid treatment was due to suppression of elevated activity of indoleamine 2,3-dioxygenase, a first rate-limiting enzyme of the kynurenine pathway.”

Of course, the paper still does not answer the central question of whether the L-tryptophan per se, a contaminant, or both contributed to the EMS development.  However, I do believe that it does provide further support for the idea that L-tryptophan contamination is not the only possible explanation for EMS development.

The next paper I am about to review, though, for which I have full text, provides a very detailed examination of L-tryptophan metabolism, with emphasis on the kynurenine pathway and the formation of the neurotoxic compound quinolinic acid, in several EMS patients.  While, like the Hisatomi et al (4) paper, it does not definitively rule in or rule out the idea that a contaminant was the sole cause of EMS, it provides an extremely compelling argument for the hypothesis that, even if a contaminant was involved, alterations in L-tryptophan metabolism very likely played an equal role in creating EMS.

The first quote I would like to present from this paper, “Tryptophan metabolism via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome” by Silver et al (5) boldly states that even though a key contaminant was found in batches of L-Tryptophan supplements ingested by EMS patients in 1989, it was never conclusively proven that this was a cause and effect scenario:

“Although one contaminant has been characterized (1,1′-ethylidenebis[L-tryptophan]), it has not been determined whether this is the etiologic agent or merely a marker for an as-yet-unidentified agent.  The mechanism by which this contamination induces EMS is unknown.”

I feel the last sentence in this quote is particularly significant.  The proof provided for the contamination theory was, to borrow a term from the legal profession, “circumstantial.”  Because a certain contaminant was found in the vast majority of L-tryptophan supplements ingested by the EMS patients in 1989, it was assumed that this was the cause.  Unfortunately, according to Silver et al (5) it was never actually demonstrated how the contaminant could cause EMS.

However, as pointed out by the authors, compelling circumstantial evidence also exists that suggests L-tryptophan and/or one of its metabolites could also cause EMS:

“Several factors suggest that L-tryptophan or one of its metabolites may be important in the pathogenesis of EMS.  First, the contaminant epidemiologically linked to EMS is an L-tryptophan (LT) analog.  Second, abnormal metabolism of LT has been identified in several conditions which share many of the clinical and pathologic features of EMS, including scleroderma (systemic sclerosis), eosinophilic fasciitis, and toxic oil syndrome.  Third, some cases of LT-associated EMS occurred before the recent epidemic and the changes in the manufacturing process, which were believed to be responsible for contamination of the LT preparations.  Fourth, LT metabolites are potential mediators of vascular permeability, fibrosis, and neurotoxicity characteristic of EMS.”

Before continuing, please note again the timeline issue in the above quote – cases of EMS related to L-tryptophan ingestion had been reported before the time the contaminant appeared in L-tryptophan supplement batches.

To evaluate the possibility L-tryptophan metabolism was and is a major contributor to EMS, Silver et al (5) studied 23 EMS patients in great detail.  Specifically, several diagnostic procedures were performed to analyze these EMS patients in several different ways.  First:

“After informed consent, plasma was obtained from 16 EMS patients and from 17 normal subjects.  In addition, plasma samples from 6 asymptomatic LT users, 2 of whom were taking LT at the time of blood sampling, were kindly provided by Dr. Edward A. Belongia (Acute Disease Epidemiology Section, Minnesota Department of Health, Minneapolis, MN).  Plasma samples were obtained from 3 EMS patients prior to and at various intervals after corticosteroid treatment of their illness.”

In addition:

“Six EMS patients and 5 age- and sex-matched normal subjects underwent studies of LT metabolism, according to a protocol approved by the institutional review board (1RB) for human research at the Medical University of South Carolina.  The subjects consumed a diet providing 1,800 kcal and 70 gm of protein during the 2 study days.  Plasma was obtained prior to oral administration of 1 gm of L-tryptophan (Goldline Laboratories, Fort Lauderdale, FL) and at 30- or 60-minute intervals for 8 hours afterward.”

Still another experimental protocol was initiated:

“Ten EMS patients underwent lumbar puncture as part of an evaluation of neurologic signs and symptoms.  Cerebrospinal fluid (CSF) from 23 age-matched normal subjects served as controls.”

The final experimental protocol I would like to mention was designed to see what would happen to L-tryptophan metabolites when inflammation is induced in a controlled fashion by administration of the pro-inflammatory cytokine interferon-γ (IFNγ) to individuals highly prone to adverse sequelae of inflammation, scleroderma patients:

“To determine the effect of interferon-γ (IFNγ) on LT metabolism, serum was obtained from 4 patients with scleroderma who were enrolled in a clinical trial of recombinant IFNγ…”

As I hope you can see, the authors instituted a very thorough investigative protocol to gain an in depth understanding of the true metabolic nature of EMS patients.  Based on the data from these experiments, you will shortly be reading some conclusions about EMS patients that are significantly different from the “open and shut – it’s the contaminant” scenario that was reported in the media and research papers such as those discussed in part I of this series.

Before presenting the conclusions, though, I would like to quote some text that discusses the raw data.

Raw data regarding the kynurenine pathway in EMS patients

As you may recall from the discussion on this subject in part I of this series, L-tryptophan is metabolized along two distinct pathways.  In optimally healthy individuals there is good balance where some L-tryptophan goes down a pathway that leads to serotonin and melatonin production and even more goes down a pathway that leads to kynurenine production and other metabolites, including the neurotoxic compound quinolinic acid.  However, I do want to emphasize that, when optimal health exists, production of kynurenine and all its metabolites have a net positive effect because the ultimate endpoint of the kynurenine pathway is vitamin B3.  It is only when ill-health exists, primarily in the form of excessive systemic inflammation, that excess formation of kynurenine and its metabolites occurs, which, in turn, can lead to a further decline in health.

What can be stated about kynurenine formation in EMS patients?  Based on their experiments, Silver et al (5) state:

“L-kynurenine was significantly higher in the untreated EMS patients…than in normal controls…and than in asymptomatic users of LT.  The plasma L-kynurenine concentration in corticosteroid-treated EMS patients did not differ significantly from that in normal controls or in asymptomatic users of LT.”

The last sentence of the above quote is important to note because it suggests that, because corticosteroids are well known suppressors of inflammation, the elevations in kynurenine seen in EMS patients are heavily mediated by inflammation.

What about the neurotoxic compound, quinolinic acid?  The authors point out:

“Plasma quinolinic acid was also significantly higher in untreated EMS patients than in corticosteroid-treated EMS patients…and asymptomatic users of LT.  There was a strong correlation between L-kynurenine and quinolinic acid levels in both treated and untreated EMS patients.  Also, there was a strong correlation between eosinophil count in EMS patients at the time of blood sampling and the plasma L-kynurenine and quinolinic acid concentrations.”

Again, please note that in untreated patients who were much more likely to experience significant systemic inflammation compared to treated patients and asymptomatic users of L-tryptophan, kynurenine metabolites such as quinolinic acid tended to be higher.  Furthermore, one of the key findings in EMS, elevations of eosinophils, tended to be higher when kynurenine metabolites were higher.  Finally, by extension, we can assume that elevations in eosinophils were related to increased levels of inflammation.

One of the most valuable aspects of this paper is that it was one of the few that did not just consider what happened to the EMS patients “after the fact” in terms of what happened upon L-tryptophan ingestion.  Silver et al (5) also made an effort to replicate what happened with L-tryptophan ingestion by providing L-tryptophan supplements which were presumably free of contaminants, to EMS patients in a controlled research environment.  The findings from this aspect of the study were not only truly enlightening but made a powerful statement against the hypothesis that EMS is purely an issue of a contaminant.  As the quote suggests, inflamed EMS patients metabolize L-tryptophan supplements free of contamination differently:

“The metabolism of LT by untreated EMS patients differed from that by corticosteroid-treated patients and that by normal controls.”

What about formation of kynurenine and quinolinic acid upon uncontaminated L-tryptophan ingestion?  Silver et al (5) note:

“L-kynurenine and quinolinic acid were significantly elevated in the fasting state in all but 1 untreated patient, and rose to very high levels following a single 1-gm loading dose of LT.  L-kynurenine concentrations peaked ~3-4 hours after the ingestion of LT, and quinolinic acid levels peaked several hours later.  L-kynurenine and quinolinic acid concentrations remained elevated in the untreated EMS patients 8 hours following ingestion of 1 gm of LT.  The response of corticosteroid-treated EMS patients was similar to that of normal controls, with L-kynurenine peak levels never exceeding 6.0 µmoles/liter and quinolinic acid peak levels never exceeding 2,000 nmoles/liter, well below even the baseline levels in untreated EMS patients.”

Therefore, as you can see, even with as little ingestion as 1 gram of L-tryptophan, which is the standard capsule size for most L-tryptophan products, when patients are inflamed, metabolism of L-tryptophan greatly favors formation of kynurenine and the neurotoxic compound quinolinic acid.

Another interesting aspect of the Silver et al (5) study is that it was able to include in the study population individuals for whom data could be obtained before and after corticosteroid therapy.  As you will see in the quote below, corticosteroid therapy, which has potent anti-inflammatory properties, was very effective in reducing kynurenine and quinolinic acid levels:

“In all 3 patients from whom plasma samples were obtained prior to and after corticosteroid therapy, L-kynurenine and quinolinic acid values returned to normal and remained normal as the prednisone dosage was tapered and discontinued.”

What were the results concerning levels of L-tryptophan metabolites when a pro-inflammatory agent was administered to patients prone to adverse effects of inflammation, scleroderma patients?  The authors note:

“To investigate the role of IFNγ in the induction of L-tryptophan metabolism via the kynurenine pathway, we measured L-kynurenine and quinolinic acid in the serum of 4 patients with scleroderma, before and after administration of IFNγ.  Daily administration of IFNγ resulted in a 2-6-fold rise in L-kynurenine and quinolinic acid levels.  The levels of both metabolites returned to normal by the 28th day following cessation of IFNγadministration.”

The final result I would like to report from this paper addresses the important issue of whether all these findings, which were based on blood analyses, could be justifiably extrapolated to central nervous dysfunction, a key aspect of EMS.  As you will see in the quote below, EMS patients who demonstrate disturbances in levels of blood-based kynurenine and quinolinic acid findings also demonstrate parallel disturbances in central nervous system analytes:

“In the view of the known neurologic properties of kynurenine-pathway metabolites, we evaluated levels of L-kynurenine and quinolinic acid in cerebrospinal fluid (CSF) from EMS patients.  The mean ± SEM CSF L-kynurenine level in 9 EMS patients was 95.5 ± 13.4 nmoles/liter, compared with a value of 56.4 ± 9.0 nmoles/liter in 12 normal subjects.  The mean CSF quinolinic acid level in 10 EMS patients was 74.2 ± 12.1 nmoles/liter, compared with 21.9 ± 1.5 nmoles/liter in CSF from 23 normal subjects.  There was a positive correlation between CSF L-kynurenine and CSF quinolinic acid values in the EMS patients.”

As I hope you can see, the data presented suggests that EMS is much more than just a random “wrong place at the wrong time” scenario where totally healthy individuals suffered life altering consequences from ingesting solely an unwanted contaminant in the manufacture of L-tryptophan supplements.  In contrast, it appears that the affected individuals may have encountered one of two possible scenarios.  First, due to pre-existing chronic inflammation that may have led to pre-existing disturbances in L-tryptophan metabolism and its downstream metabolites kynurenine and quinolinic acid, these individuals encountered a powerful “perfect storm” where a significant dose of L-tryptophan accompanied by, in many cases, a pro-inflammatory contaminant “trigger” acted together to create EMS signs and symptoms.  Second, as suggested by Silver et al {Silver RM et al, 1992 #2265} in their discussion of cases of EMS that occurred after ingestion of contaminant-free L-tryptophan, it is quite possible that, for some affected individuals, even though a contaminant was present in the ingested L-tryptophan supplements, it may have had nothing to do with the initiation of EMS signs and symptoms.

However, that’s just my opinion.  How did Silver et al (5) interpret this data?  In part III of this series I will present a review of the discussion section of the Silver et al (5) paper along with reviews of still other papers that suggest the EMS-contaminant connection is only part of a very complex and interesting story.

MNR Newsletter #254 – 12/01/2013 – PDF Version

REFERENCES

  1. Belongia EA et al. The eosinophilia-myalgia syndrome and tryptophan. Ann Rev Nutr. 1992;12:235-56.
  2. Allen JA et alPost-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. Arthritis & Rheumatism. 2011;63(11):3633-9.
  3. Forrest CM et alTryptophan loading induces oxidative stress. Free Rad Res. 2004;38(11):1167-71.
  4. Hisatomi A et alElevated L-kynurenine level and its normalization by prednisoloine in a patient with eosinophilia-myalgia syndrome. Fukuoka Igaku Zasshi. 1997;88(1):11-7.
  5. Silver RM et al. Tryptophan metabolism via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome. Arthritis & Rheumatism. 1992;35(9):1097-105.