Dermal Fibrosis Following Subcutaneous Injections of Serotonin Creatinine Sulphate.

MacDonald, Richard A.; Robbins, S L; Mallory, G. Kenneth

doi:10.3181/00379727-97-23734

Cited by 77 publications

(25 citation statements)

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“…Our study implicates EBT as one compound found in case-associated L-TRP that can cause some pathological changes in Lewis rats that are similar to some pathological features of L-TRP-associated EMS. The present observations also support previous literature postulating a role for tryptophan and its metabolites in fibrosing illness such as scleroderma, eosinophilic fasciitis, and carcinoid syndrome (28)(29)(30)(31)(32)(33)(34)(35)(36). Finally, these results support an immune pathogenesis for L-TRP-associated EMS, with EBT and case-associated L-TRP serving as important etiologic agents, and L-TRP itself a contributing factor to the syndrome.…”

Section: Discussionsupporting

confidence: 79%

Pathological and immunological effects of ingesting L-tryptophan and 1,1'-ethylidenebis (L-tryptophan) in Lewis rats.

Love¹,

Rader²,

Crofford³

et al. 1993

J. Clin. Invest.

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The eosinophilia-myalgia syndrome (EMS) has been associated with ingestion of L-tryptophan (L-TRP) produced by a single manufacturer. Epidemiological data implicated 1,1'-ethylidenebis(L-tryptophan) (EBT) (peak 97 or peak E) as a possible etiologic agent. We showed previously that Lewis rats treated with the L-TRP implicated in EMS develop fasciitis and perimyositis similar to those seen in human EMS. We now report the pathology associated with the treatment of Lewis rats with synthetic EBT and/or L-TRP. All animals treated for 6 wk with case-associated L-TRP or EBT developed significant myofascial thickening, compared with animals in the vehicle control and control L-TRP groups. However, even those animals receiving the control L-TRP showed a mild but significant increase in the thickness of the myofascia, compared with vehicle-treated control animals. All animals except vehicle controls also exhibited significant pancreatic pathology, including fibrosis and acinar changes. Only animals treated with case-associated L-TRP for 6 wk showed evidence of immune activation with increased frequency of CD8, Ia, and IL-2 receptor-positive cells in the peripheral blood. Animals receiving L-TRP or EBT for < 6 wk did not show significant differences in myofascial thickness, although these animals did show pancreatic acinar changes. Although these results demonstrate for the first time the pathological effects of EBT, they do not rule out the possibility that other impurities in the EMS-case-associated L-TRP may also contribute to some of the features of EMS. (J. Clin. Invest. 1993. 91:804-811.)

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Section: Discussionsupporting

confidence: 79%

Pathological and immunological effects of ingesting L-tryptophan and 1,1'-ethylidenebis (L-tryptophan) in Lewis rats.

Love¹,

Rader²,

Crofford³

et al. 1993

J. Clin. Invest.

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“…In addition to these criteria, a wide variety of signs and symptoms have been reported in patients with EMS. As of September 7,1990,1537 cases of EMS, including 27 deaths, had been reported to the CDC. Notably, this is an increase of only six new cases from 2 months earlier, suggesting perhaps that the epidemic is ending.…”

Section: 2mentioning

confidence: 99%

Idiopathic and L-Tryptophan-Associated Eosinophilic Fasciitis Before and After L-Tryptophan Contamination

Blauvelt

Falanga²

1991

Arch Dermatol

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Recently, a causative association has been made between the ingestion of levotryptophan (L-tryptophan) and the eosinophilia-myalgia syndrome (EMS), a new entity manifested by peripheral blood eosinophilia, myalgias, constitutional symptoms, and cutaneous edema with fibrosis. Contaminated levotryptophan preparations produced at a single manufacturing company between October 1988 and June 1989 have been implicated in all EMS cases. In this study, we analyzed retrospectively 49 patients with cutaneous fibrosis for a history of levotryptophan use. Levotryptophan ingestion prior to the onset of their disease was reported by 11 (65%) of 17 patients with eosinophilic fascilitis (EF), two (20%) of 10 patients with localized scleroderma, and none of 22 patients with systemic sclerosis. The onset of levotryptophan-associated cutaneous disease preceded the availability of contaminated levotryptophan preparations in seven (54%) of 13 patients. One patient with levotryptophan-associated generalized morphea also had lichen sclerosus et atrophicus and acanthosis nigricans, findings not previously reported in patients with EMS. In addition, we compared the clinical and laboratory features of levotryptophan-associated EF and idiopathic EF. Myalgias, muscle weakness, paresthesias, morpheaform plaques, cutaneous ulcers, and livedo reticularis were more common in patients with levotryptophan-associated EF. We conclude that levotryptophan-associated EF and localized scleroderma were present before the presumed date of contaminated levotryptophan availability. The clinical spectrum of cutaneous fibrosis associated with the ingestion of levotryptophan includes generalized morphea and EF, which are similar though not identical to their idiopathic counterparts.

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“…Animal studies reported here and by others (21, 22), however, suggest that L-tryptophan per se induces rather than inhibits fibrosis in vivo. The serotonin pathway of L-tryptophan metabolism may be an important mediator of such fibrosis, since serotonin has been shown to induce fibrosis in vivo (41 ) and fibroblast proliferation in vitro (42,43).…”

Section: Methodsmentioning

confidence: 99%

A murine model of the eosinophilia-myalgia syndrome induced by 1,1'-ethylidenebis (L-tryptophan).

Silver¹,

Ludwicka²,

Hampton³

et al. 1994

J. Clin. Invest.

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The eosinophilia-myalgia syndrome (EMS) is a recently described disease that has been associated with the ingestion of L-tryptophan containing trace amounts of several impurities. The first such contaminant to be identified and linked epidemiologically to the EMS epidemic was 1,1'-ethylidenebis(L-tryptophan) (EBT), but its role in the etiology and pathogenesis of the syndrome has been controversial. We report the development of inflammation and fibrosis affecting the dermis and subcutis, including the fascia and perimyseal tissues, after the daily intraperitoneal administration of EBT to female C57BL/ 6 mice. Such changes are accompanied by increased numbers of mast cells, many of which appear to be degranulating. Plasma levels of quinolinic acid, a metabolic product of L-tryptophan via the kynurenine pathway, are reduced initially, and then become elevated when inflammation and fibrosis are more pronounced. The nature and location of the inflammatory cell infiltrate and fibrosis, as well as the presence of mast cells and alterations of L-tryptophan metabolism, are consistent with findings reported in patients with EMS. This murine model suggests that EBT may have been one of the mediators of EMS and should facilitate studies of the pathogenesis of EMS. (J.

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Dermal Fibrosis Following Subcutaneous Injections of Serotonin Creatinine Sulphate.

Cited by 77 publications

References 0 publications

Pathological and immunological effects of ingesting L-tryptophan and 1,1'-ethylidenebis (L-tryptophan) in Lewis rats.

Pathological and immunological effects of ingesting L-tryptophan and 1,1'-ethylidenebis (L-tryptophan) in Lewis rats.

Idiopathic and L-Tryptophan-Associated Eosinophilic Fasciitis Before and After L-Tryptophan Contamination

A murine model of the eosinophilia-myalgia syndrome induced by 1,1'-ethylidenebis (L-tryptophan).

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