Eosinophilia-myalgia syndrome
Encyclopedia
Eosinophilia–myalgia syndrome (EMS) is an incurable and sometimes fatal flu-like neurological condition that is believed to have been caused by ingestion of poorly produced L-tryptophan supplements. Similar to regular eosinophilia
, it causes an increase in eosinophil granulocyte
s in the patient's blood.
Eosinophilia–myalgia syndrome was first recognized after the doctors of 3 American women with mysterious symptoms talked together in 1989. However, many people became ill as long as 2–3 years before the illness was reported to the Centers for Disease Control and Prevention
in November 1989. Rheumatologists experienced a large surge of new patients with mysterious symptoms during this period. It is possible that as many as 60,000 individuals became ill from using L-tryptophan. Additionally, when first marketed, 27 people died.
Some epidemiologist studies traced the cause to consumption of L-tryptophan from a single Japanese manufacturer, Showa Denko
. The company supplied the majority of L-tryptophan to the United States under various brand names. There was evidence that new batches of L-tryptophan may have been improperly prepared. First, the specific bacterial culture used to synthesise this tryptophan had recently been genetically engineered
to greatly increase tryptophan production. The increased concentrations of tryptophan in the fermentor may in turn have led to increased production of trace impurities. It is also likely that contaminants were increased because the L-Tryptophan producing bacteria were being grown in an open vat in a fertilizer factory. Second, shortcuts had been taken in the purification process to reduce costs. For example, a purification step that used charcoal
adsorption
to remove impurities had been modified to reduce the amount of charcoal used. It is possible that one or more of these modifications and/or the environment for manufacture allowed new or greater impurities through the purification system. More than 60 different impurities were identified in the L-tryptophan lots which had been associated with cases of EMS.
The specific impurity (or impurities) responsible for the toxic effects was never firmly established, however two compounds, EBT (1,1'-ethylidene-bis-L-tryptophan) and MTCA (1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid), which are close chemical relatives of L-tryptophan were implicated.
Regardless of the origin of the toxicity, L-tryptophan was banned from sale in the US in 1991; and other countries followed suit. In February 2001, the FDA loosened the restrictions on the marketing of tryptophan (though not on importation). The supplement 5-HTP (a hydroxylated
form of tryptophan and a precursor to serotonin) remains widely available.
degradation. Furthermore, excessive histamine activity has been linked with blood eosinophilia
and myalgia
.
Eosinophilia
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...
, it causes an increase in eosinophil granulocyte
Eosinophil granulocyte
Eosinophil granulocytes, usually called eosinophils or eosinophiles , are white blood cells that are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with...
s in the patient's blood.
History
See also tryptophan and EMS.Eosinophilia–myalgia syndrome was first recognized after the doctors of 3 American women with mysterious symptoms talked together in 1989. However, many people became ill as long as 2–3 years before the illness was reported to the Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
in November 1989. Rheumatologists experienced a large surge of new patients with mysterious symptoms during this period. It is possible that as many as 60,000 individuals became ill from using L-tryptophan. Additionally, when first marketed, 27 people died.
Some epidemiologist studies traced the cause to consumption of L-tryptophan from a single Japanese manufacturer, Showa Denko
Showa Denko
is a leading Japanese chemical engineering firm.Formed in 1939 by the merger of Nihon Electrical Industries and Showa Fertilizers, Showa Denko K.K. manufactures chemical products and industrial materials. SDK's products serve a wide array of fields ranging from heavy industry to the electronic...
. The company supplied the majority of L-tryptophan to the United States under various brand names. There was evidence that new batches of L-tryptophan may have been improperly prepared. First, the specific bacterial culture used to synthesise this tryptophan had recently been genetically engineered
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
to greatly increase tryptophan production. The increased concentrations of tryptophan in the fermentor may in turn have led to increased production of trace impurities. It is also likely that contaminants were increased because the L-Tryptophan producing bacteria were being grown in an open vat in a fertilizer factory. Second, shortcuts had been taken in the purification process to reduce costs. For example, a purification step that used charcoal
Charcoal
Charcoal is the dark grey residue consisting of carbon, and any remaining ash, obtained by removing water and other volatile constituents from animal and vegetation substances. Charcoal is usually produced by slow pyrolysis, the heating of wood or other substances in the absence of oxygen...
adsorption
Adsorption
Adsorption is the adhesion of atoms, ions, biomolecules or molecules of gas, liquid, or dissolved solids to a surface. This process creates a film of the adsorbate on the surface of the adsorbent. It differs from absorption, in which a fluid permeates or is dissolved by a liquid or solid...
to remove impurities had been modified to reduce the amount of charcoal used. It is possible that one or more of these modifications and/or the environment for manufacture allowed new or greater impurities through the purification system. More than 60 different impurities were identified in the L-tryptophan lots which had been associated with cases of EMS.
The specific impurity (or impurities) responsible for the toxic effects was never firmly established, however two compounds, EBT (1,1'-ethylidene-bis-L-tryptophan) and MTCA (1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid), which are close chemical relatives of L-tryptophan were implicated.
Regardless of the origin of the toxicity, L-tryptophan was banned from sale in the US in 1991; and other countries followed suit. In February 2001, the FDA loosened the restrictions on the marketing of tryptophan (though not on importation). The supplement 5-HTP (a hydroxylated
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
form of tryptophan and a precursor to serotonin) remains widely available.
Alternative theory
An alternative explanation for tryptophan associated EMS has recently been proposed. Consumption of large doses of tryptophan leads to production of metabolites, some of which may interfere with normal histamineHistamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
degradation. Furthermore, excessive histamine activity has been linked with blood eosinophilia
Eosinophilia
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...
and myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
.