Tetrodotoxin is a neurotoxin that is most commonly found in marine animals. It is famously known to cause perioral numbness in consumers of pufferfish sushi, known in Japan as fugu. The toxin is heat-stable, meaning that cooking does not destroy the toxin. There are 26 known naturally occurring analogs. The toxin blocks sodium channels leading to gastrointestinal, neurological, and cardiac symptoms in poisoned patients. There is currently no known antidote.
The toxin is found naturally in a wide variety of vertebrates and invertebrates with no close phylogenetic relationship. Of terrestrial vertebrates, the toxin is found in Western, rough-skinned newts of the genus Taricha, the Eastern Newt (Notophthalmus viridescens), and toads of the genus Atelopus. In marine vertebrates, the toxin is found in more than 20 pufferfish species and certain angelfish. Mollusks that contain the toxin include several species of the blue-ringed octopus, species of Niotha gastropods, and species of genus Naticidae (moon snails). Other invertebrates that contain the toxin include several starfish species, several species of xanthid crabs, species of the phylum Chaetognatha (arrow worms), species of the phylum Nemertea (ribbon worms), some flatworms, and planarians of the genus Bipalium.
The reason that many distantly related taxa have evolved the ability to produce tetrodotoxin is that the animals themselves do not produce the toxin. The animals bioaccumulate the toxin from their diets. Bacteria produce the toxin and are then consumed up the food chain and accumulate in high doses in high trophic level animals. This was discovered in an experiment by collecting pufferfish raised in captivity and measuring levels of tetrodotoxin in their organs, particularly the liver. All captive specimens had undetectable levels of tetrodotoxin. Some of these captive puffer fish were then fed the livers of wild pufferfish that contained tetrodotoxin. These captive pufferfish then accumulated the toxin themselves. The bacteria known to be implicated in the production of tetrodotoxin include members of the following genera: Pseudoalteromonas, Pseudomonas, Vibrio, Aeromonas, Alteromonas, Shewanella, Roseobacter, Raoultella, Actinomycetes, Microbacterium, and Serratia. Some of these tetrodotoxin-producing bacteria are also a part of the animal’s natural microbiome and is another mechanism of tetrodotoxin accumulation in these animals. The exception to this are newts, in which it is still unclear whether the tetrodotoxin is produced endogenously or exogenously due to conflicting results from experiments.
Animals that contain tetrodotoxin are resistant to the neurological effects of the toxin themselves. Normally, sodium channels have an aromatic amino acid chain in the P-loop region of domain I. Animals that accumulate tetrodotoxin in their bodies have a non-aromatic amino acid substitution that causes the sodium channel to have a low affinity for tetrodotoxin. Therefore, sodium channels in these species are not blocked by tetrodotoxin. Garter snakes, which do not contain tetrodotoxin, but prey on toxic newts that do, have also acquired this mutation. Additionally, tetrodotoxin-binding proteins are present in some animals, such as the shore crab, pufferfish, and gastropods.
Poisoning in humans occurs when they ingest tetrodotoxin-containing organisms. In the United States, the most common sources of poisoning are pufferfish imported from Japan and Mexico, pufferfish mislabeled as another fish, Pacific newts, and the Eastern newt. There are 4 species of Pacific newts of the genus Taricha that contain the toxin. They are distributed along the Pacific coast from Southern Alaska to Baja, Mexico. The most toxic newts are found in Oregon. There is a single species of newt on the east coast, called the Eastern newt (Notophthalmus viridescens), that contains the toxin. The toxin produced by the Eastern newt is only 1/100th as potent as that of the toxin found in Pacific newts.
Worldwide, pufferfish are implicated in the poisoning of patients in Bangladesh, Japan, Australia, and India, in addition to the United States. Toadfish are another source of poisoning in Australia. Ingestions of marine gastropods and thread-sail fish are additional sources of toxicity in Japan. Poisonings from marine gastropods have also been reported in China, Japan, and Taiwan. People who have eaten the eggs of horseshoe crab have been poisoned in Thailand. Multiple dogs in New Zealand were poisoned after eating grey side-gilled sea slugs they found on the beach.
The incidence of tetrodotoxin poisoning is very rare but is higher in countries where people eat pufferfish regularly, such as Japan, Taiwan, and some Southeast Asian countries. From 2002 to 2006, 223 Japanese patients have suffered tetrodotoxin poisoning, and 13 of these patients died. From 2001 to 2006, 53 patients in Singapore were diagnosed with tetrodotoxin poisoning, and 8 of these patients died. In 2008, cheap pufferfish sold in fish markets led to three outbreaks in Bangladesh, affecting 141 people, 17 of whom died from respiratory arrest. Due to the rarity of the disease, exact mortality rates are difficult to establish.
The mechanism of action of this toxin is that it inhibits voltage-gated sodium channels, preventing cell membranes from depolarizing. This, in turn, inhibits action potential propagation and prevents neurons and myocytes from functioning.
The patient’s history will involve consumption of tetrodotoxin-containing organisms, such as pufferfish, newts, or sea snails. Onset and severity of the symptoms of tetrodotoxin poisoning are dependent on time after ingestion and is dose-dependent. In the majority of cases, symptoms usually occur within 30 minutes of ingestion. A few cases have had symptoms start to occur after 20 hours.
There are 4 grades of poisoning base on a scale created by Fukuda and Tani in 1941:
There are no specific laboratory tests that exist to confirm tetrodotoxin poisoning in the acute clinical setting. Therefore, diagnosis is largely based on history and symptoms. In the research laboratory setting, however, mouse bioassays and liquid chromatography coupled with mass spectrometry can be used to detect tetrodotoxin.
There is no known antidote. The mainstay of treatment is respiratory support and supportive care until the tetrodotoxin is excreted in the urine. Activated charcoal and/or gastric lavage can be done if the patient presents within 60 minutes of ingestion. Hemodialysis may be useful, especially in patients with renal disease. A monoclonal antibody against tetrodotoxin (anti-tetrodotoxin) is available. No studies on efficacy have been published. Healthcare professionals use neostigmine to treat acute respiratory failure from tetrodotoxin poisoning. However, a review of the current literature indicates that there is not enough data to provide evidence for or against this practice. For suspected tetrodotoxin poisoning, patients should be observed in the intensive care unit (ICU) for 24 hours due to some patients having a delayed onset of symptoms of up to 20 hours.
Since there is no known antidote for tetrodotoxin, the management is an interprofessional. All symptomatic patients must be monitored closely in the ICU and resuscitated according to the trauma ABCDE protocol. Specialists should be involved depending on the organ involved. Healthcare professionals use neostigmine to treat acute respiratory failure from tetrodotoxin poisoning. However, a review of the current literature indicates that there is not enough data to provide evidence for or against this practice. No patient should be discharged until he or she has been observed for at least 12-24 hours in an ICU setting. The prognosis for most patients is good. (Level V)
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