Part 2: Tetrodotoxin (TTX)

A neuromuscular paralytic compound

The reason I researched this is because of many videos and social media posts that perked my curiosity. Given the tetrodotoxin, you will note that some of the curiosity is professional, as an anesthesiologist. And given the 'conspiracy’, of course I had to look into it.

See my original article HERE. In the article, I review that it is said that tetrodotoxin is a poison that Uncategorized Subterranean Lifeforms or USLs are said to emit from their nails if they scratch you.

Tetrodotoxin

Dictionary.com says to pronounce it “te-troh-duh-tok-sin”, a bit of a tongue-twister. In Japanese, it is written, “フグ”.

A natural source of tetrodotoxin is as a poison found in pufferfish. In some written, countries like Japan, if you eat the delicacy menu item “pufferfish”, you may experience symptoms.

As an anesthesiologist, we commonly paralyze during anesthesia, both to put in the breathing (endotracheal) tube, and to keep patients from moving during certain procedures like brain surgery. When the surgery is over, we simply reverse the paralysis with certain drugs, or we can simply wait for them to wear off.

With the chemical formula C11H17N3O8, it is 319.27 g/mol molecular weight.

… actually produced by bacteria such as Vibrio alginolyticus, Pseudoalteromonas tetraodonis, and other vibrio and pseudomonas bacterial species.

An aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order TETRAODONTIFORMES, which are eaten. The toxin causes paresthesia and paralysis through interference with neuromuscular conduction.

Source: https://pubchem.ncbi.nlm.nih.gov/compound/Tetrodotoxin

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As a neurotoxin, the primary symptom is neurologic, or nerve damage. After consuming a pufferfish, the lips may go numb, i.e., causing perioral numbness. In later stages, you can stop breathing.

Emphases are mine.

Objectives:

• Identify the causes of tetrodotoxin toxicity and how to provide immediate medical care.

• Determine the evaluation of a patient with suspected tetrodotoxin toxicity.

• Select the treatment strategy for a patient with tetrodotoxin toxicity.

• Strategize with the interprofessional team to improve care coordination and communication, leading to more effective management of tetrodotoxin toxicity.

Access free multiple choice questions on this topic.

Introduction

Tetrodotoxin is a neurotoxin found in marine animals, most commonly the pufferfish, but can also be found in some terrestrial animal species. The pufferfish is the most common animal species containing tetrodotoxin, with over 20 pufferfish able to produce it.[1] There are 26 known naturally occurring analogs. 

As a toxin, tetrodotoxin is known for its poisonous properties, but the animals that produce it have genetic mutations that make them immune to these effects. The toxin is known to cause perioral numbness in consumers of pufferfish sushi, known in Japan as fugu. Due to heat stability, cooking does not destroy the toxin. By blocking sodium channels, the toxin paralyzes humans who consume it, rendering immediate complications if not promptly recognized.

Tetrodotoxin toxicity is most likely to occur in areas where tetrodotoxin-containing animals are located, particularly seafood. Less commonly, improperly prepared food may lead to poisoning in areas where tetrodotoxin is not typically found.[2] No known antidote exists.[3][4][5] There is also no definitive treatment, so identifying the symptoms and signs is critical to ensuring that fatal sequelae do not ensue.

Etiology

The toxin is found naturally in various 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 over 20 pufferfish species[1] and certain angelfish. Mollusks containing the toxin include several species of the blue-ringed octopus, Niotha gastropods, and the 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.[6][7][8]

Many distantly related taxa have evolved the ability to produce tetrodotoxin because the animals themselves do not produce the toxin. Bacteria produce a toxin that accumulates in animals higher up the food chain. 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 pufferfish were fed the livers of wild pufferfish, leading to accumulated tetrodotoxin. 

The bacteria implicated in the production of tetrodotoxin include members of the following genera: Pseudoalteromonas, Pseudomonas, Vibrio, Aeromonas, Alteromonas, Shewanella, Roseobacter, Raoultella, Actinomycetes, Microbacterium, and Serratia.[9][10] Some animals have tetrodotoxin-producing bacteria in their natural microbiome, contributing to the toxin accumulation. The exception is newts, and it is 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. Typically, 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 immune to tetrodotoxin.[11] Garter snakes, which do not contain tetrodotoxin but prey on toxic newts that do, have also acquired this mutation.[12] Additionally, tetrodotoxin-binding proteins that filter out the toxin exist in some animals, such as the shore crab, pufferfish, and gastropods.[8]

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 Pacific newts of the genus Taricha species 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. A single species of newt on the east coast, the Eastern newt (Notophthalmus viridescens), contains the toxin.[13] The toxin produced by the Eastern newt is only 1/100th as potent as that found in Pacific newts.

Worldwide, the sources of toxicity vary based on local wildlife. 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 been reported in China, Japan, and Taiwan. People who have eaten the eggs of horseshoe crabs have been poisoned in Thailand. Multiple dogs in New Zealand were poisoned after eating grey side-grilled sea slugs.[14]

Epidemiology

The incidence of tetrodotoxin poisoning is rare and variable depending on the geographic locale and organism involved. The most commonly implicated exposures affected pufferfish, and the incidence 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 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.[15] In 2008, cheap pufferfish sold in fish markets led to 3 outbreaks in Bangladesh, affecting 141 people, 17 of whom died from respiratory arrest. An additional outbreak resulted from the ingestion of the roe of Takifugu oblongus, resulting in 5 deaths.[16] Another cluster of patients was reported in Oman in 2018, where 5 patients suffered poisoning after frying locally caught pufferfish.[17] Poisonings involving other tetrodotoxin-containing species are rare, as these animals are generally not edible. Case reports document exposure to poisonous species of newts, often kept as exotic pets,[18][19] and to xanthid crab species.[20]

Pathophysiology

At room temperature, tetrodotoxin is a colorless, crystalline substance with weak basic properties. Tetrodotoxin functions by inhibiting voltage-gated sodium channels. This occurs by interacting with the positively charged guanidine group on tetrodotoxin and the negatively charged carboxylate groups in the mouth of the sodium channel pore.[11] The blockade effect does not change the resting potential of the neuronal membrane but rather prevents the influx of sodium through the channel, effectively preventing transmission of an action potential. The blockade disrupts the function of the brainstem and motor, sensory, and autonomic nerves. This subsequently leads to gastrointestinal, cardiac, and neurologic dysfunction.

Toxicokinetics

Tetrodotoxin is rapidly absorbed from the gastrointestinal tract. [21] The distribution following ingestion is not well described in the literature. One study looking at the distribution of subcutaneous tetrodotoxin found a peak concentration of 1.5 hours and half-life of 4.5 hours at all doses studied, with the maximum dose studied being 45 μg.[22] 

NOTE: Why in the heck would anyone subject themselves to getting a subcutaneous injection of tetrodotoxin? This is the sutdy in Reference 22:

In the above study, they took 25 healthy people and tried to see if this could be used for chronic pain! From the study:

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (C_max) within 1.5 h. Both extent of exposure (AUC) and C_max increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥ 5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.

Because lidocaine and other agents also change voltage gated sodium channels, the authors thought this would be a novel agent for chronic pain. They cited preliminary trials using TTX:

To date, preclinical studies have shown TTX to be effective at inhibiting neuropathic [13,14] and inflammatory pain [15,16,17]. In patients with moderate to severe pain due to either cancer or chemotherapy-induced neuropathy who failed other treatments, TTX was seen to reduce pain by 30% below baseline levels in some patients [18,19,20,21]. In addition, given the continued discovery of the role of aberrant VGSC activity in other pathophysiological conditions including cancer, migraine, and several muscle and immune system disorders [22], the therapeutic potential for TTX in these other disease conditions is significant.

They defend the use of pufferfish extract by citing other novel agents used in medicine:

Toxins, including morphine, botulinum toxin, and curare have made significant contributions in the field of pain management and their success continues to prompt the development of further analogues. Yet, despite their success and FDA approval for a TTX phase 3 clinical trial, there continue to be concerns about the safety of TTX. This safety concern includes the potential for TTX to impair the neuromuscular or respiratory system functions or induce cardiac arrythmias at therapeutic concentrations due to the prominent role of TTX-sensitive VGSCs in these systems [11,23,24] and the discovery of a low fraction of TTX-sensitive VGSCs [25,26] alongside the dominant TTX-resistant cardiac VGSC [27] on human cardiomyocytes.

They addressed paralysis and heart troubles (i.e., the prolonged QT interval on an EKG, something that also happens with hydroxychloroquine so rarely that it’s as statistically likely as having a family member who is deaf) were not an issue:

Despite the role of TTX-sensitive VGSCs on the neuromuscular [11,23] or respiratory system functioning [24], the lack of clinically significant changes in motor control, muscle strength, detection of vibration, oxygen saturation, or peak expiratory flow rate indicate that the effect of low therapeutic concentrations of up to 45 µg TTX on these systems are not of clinical concern. Thus, the minimal adverse events profile and lack of changes in safety assessments performed in this study indicate therapeutic doses up to 45 µg TTX do not pose any safety concerns in healthy adults. Other in vitro and in vivo studies which directly evaluated cell lines, histological examinations of nerves and muscle tissues also support a lack of neurotoxic, myotoxic, and genotoxic activity with TTX [37,38,39,40].

This Phase 1 study tested safety only, and the authors concluded their small doses were safe.

Source: https://www.mdpi.com/2072-6651/12/8/511

History and Physical

The patient’s history will involve the consumption of tetrodotoxin-containing organisms, such as pufferfish, newts, or sea snails. The onset and severity of symptoms in tetrodotoxin poisoning depend on the time since ingestion and the dose administered. In most cases, symptoms usually occur within 30 minutes of ingestion. A few cases report symptoms starting after 20 hours.[23][24][25][26]

Mild toxicity can have symptom onset between 30 minutes to 6 hours and general recovery after 24 hours. More severe toxicity can lead to rapid onset of symptoms and progression to respiratory failure within 15 to 20 minutes.[27]

There are 4 grades of poisoning based on a scale created by Fukuda and Tani in 1941:

• Grade 1: Paresthesias and perioral numbness, with or without gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea)

• Grade 2: Facial numbness, slurred speech, early motor paralysis, and incoordination, but with normal reflexes

• Grade 3: Generalized flaccid paralysis, aphonia, respiratory failure, and fixed or dilated pupils (in a conscious patient)

• Grade 4: Severe respiratory failure with hypoxia, bradycardia, hypotension, cardiac dysrhythmias, and unconsciousness.

Evaluation

Testing should be directed at evaluating other potential etiologies for a patient's presenting symptoms. These may include an electrocardiogram to assess chest pain and tachycardia, a computed tomography (CT) scan of the brain to evaluate for potential stroke or intracranial pathology, and bloodwork to evaluate electrolyte status, kidney function, and blood counts.

No specific laboratory tests 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. Confirmatory testing by LC-MS/MS can be performed by sending urine or serum testing to specialized labs, such as at the CDC, to measure levels of tetrodotoxin.[17][28] Decisions about clinical care should not be delayed waiting for these confirmatory tests.

Treatment / Management

No known antidote exists for tetrodotoxin poisoning. The mainstay of treatment is respiratory support and supportive care until the tetrodotoxin is eliminated.

If ingestion occurs within 60 minutes and no contraindications, such as decreased mental status or active vomiting, are present, activated charcoal and/or gastric lavage may be administered.

Hemodialysis may be helpful in patients with renal disease, but the evidence supporting toxin removal is conflicting. Tetrodotoxin is not water-soluble enough to benefit from hemodialysis.[29] A case report from Japan describes a patient with renal dysfunction and uremia who recovered after receiving multiple sessions of hemodialysis despite persistent mild toxicity symptoms.[30] Another case series of 5 patients supports toxin removal by hemodialysis.[17] Another case series found that hemodialysis may have improved recovery, but the information provided was inadequate to support this intervention.[31]

A monoclonal antibody against tetrodotoxin (anti-tetrodotoxin) exists [32] and has neutralized tetrodotoxin in mice.[33] No reports regarding humans are available.

Neostigmine has been used to treat acute respiratory failure from tetrodotoxin poisoning.[34] However, a recent review found insufficient data to provide evidence for or against this practice.[35]

Neostigmine is an IV reversal agent we use to reverse pharmacologically-induced paralysis in the operating room. Interesting that they did not find it clinically helpful. Perhaps they did not use a high enough dose.

For suspected tetrodotoxin poisoning, patients should be observed in the intensive care unit due to the possibility of delayed symptom onset, which can occur up to 20 hours postexposure.

Differential Diagnosis

The list of differential diagnoses includes the following:

• Ciguatera toxicity: this is from consuming a reef fish

• First-degree AV block

• Guillain-Barré syndrome

• Hypocalcemia

• Lambert-Eaton myasthenia syndrome

• Octopus envenomation

• Second-degree AV block

• Shellfish toxicity

• Third-degree AV block

Prognosis

Left untreated, patients who have severe toxicity and develop cardiac complications or respiratory paralysis will die. With sufficient supportive care, most patients fully recover without permanent neurologic sequelae. 

Complications

Tetrodotoxin toxicity is commonly associated with the ingestion of pufferfish or certain other marine organisms, and can lead to severe and potentially fatal complications. Complications associated with tetrodotoxin toxicity: [17]

Neurological Symptoms

Tetrodotoxin primarily affects the nervous system. Symptoms may include numbness and tingling, especially around the mouth and extremities. Paralysis, starting with the face and spreading to other parts of the body, can occur. Muscle weakness and difficulty speaking or swallowing may also be observed.

Respiratory Distress

Tetrodotoxin can lead to respiratory muscle paralysis, causing difficulty in breathing. Severe cases may result in respiratory failure, requiring immediate medical intervention, such as mechanical ventilation.

Cardiovascular Effects

Tetrodotoxin can cause a drop in blood pressure, leading to hypotension. Bradycardia (slow heart rate) or arrhythmias may occur, contributing to cardiovascular instability.

Gastrointestinal Symptoms

Nausea, vomiting, and abdominal pain may manifest shortly after ingestion of tetrodotoxin-containing seafood.

Seizures

In some cases, tetrodotoxin toxicity can lead to seizures, adding to the neurological complications.

Coma

Severe poisoning can result in a state of unconsciousness and coma.

Death

Tetrodotoxin toxicity can be fatal, primarily due to respiratory failure or cardiovascular collapse.

Delayed Onset

Symptoms may take several hours to appear after ingestion of contaminated seafood, which can complicate diagnosis and treatment.

No Antidote

No specific antidote for tetrodotoxin poisoning exists. Treatment mainly involves supportive care and symptom management.

Deterrence and Patient Education

The primary source of tetrodotoxin poisoning results from ingestion of improperly prepared pufferfish. Pufferfish is a common delicacy in Japan and other East and South Asian countries. The best treatment is prevention and to avoid eating pufferfish.

Potential signs of toxicity include peri-oral numbness that progresses to facial numbness, slurring of speech, and incoordination. Gastrointestinal distress with nausea and vomiting, diarrhea, and abdominal pain is another potential sign of severe toxicity. Other concerning symptoms include chest pain, depressed mental status, and difficulty breathing. If these symptoms occur, a visit to the emergency room is indicated. Although no antidote exists, full recovery is expected with appropriate supportive care and monitoring.

Other sources of tetrodotoxin poisoning typically involve ingesting animals that are not considered food, such as the blue-ringed octopus and the rough-skinned newt. Poisoning can occur by envenomation, such as the bite of the blue-ringed octopus. Care should be exercised if handling animals that are potential vectors of the toxin.

Enhancing Healthcare Team Outcomes

Tetrodotoxin toxicity is a potentially lethal diagnosis without appropriate supportive care. Management of patients requires an interprofessional team to ensure proper care is provided. Because historical information is key in diagnosing tetrodotoxin toxicity, an emergency clinician can identify and begin stabilization in this exposure.

The nurses, technicians, advanced practice professionals, and clinicians in the emergency room must identify and work together to stabilize a patient who may require intubation. Subsequent supportive care by the hospitalist team, intensive care team, and pharmacists is important to ensure appropriate cardiac monitoring, respiratory monitoring, and medication administration. The involvement of a medical or clinical toxicologist through an in-house consultation service or the poison control center will further assist with identifying and managing tetrodotoxin toxicity. With appropriate supportive care, most patients will fully recover with little to no sequelae.

Review Questions

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References

1.

Noguchi T, Arakawa O, Takatani T. TTX accumulation in pufferfish. Comp Biochem Physiol Part D Genomics Proteomics. 2006 Mar;1(1):145-52. [PubMed]

2.

Cole JB, Heegaard WG, Deeds JR, McGrath SC, Handy SM., Centers for Disease Control and Prevention (CDC). Tetrodotoxin poisoning outbreak from imported dried puffer fish--Minneapolis, Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015 Jan 02;63(51):1222-5. [PubMed]

3.

Finch SC, Boundy MJ, Harwood DT. The Acute Toxicity of Tetrodotoxin and Tetrodotoxin⁻Saxitoxin Mixtures to Mice by Various Routes of Administration. Toxins (Basel). 2018 Oct 23;10(11) [PMC free article] [PubMed]

4.

Rey V, Botana AM, Antelo A, Alvarez M, Botana LM. Rapid analysis of paralytic shellfish toxins and tetrodotoxins by liquid chromatography-tandem mass spectrometry using a porous graphitic carbon column. Food Chem. 2018 Dec 15;269:166-172. [PubMed]

5.

Nagashima Y, Ohta A, Yin X, Ishizaki S, Matsumoto T, Doi H, Ishibashi T. Difference in Uptake of Tetrodotoxin and Saxitoxins into Liver Tissue Slices among Pufferfish, Boxfish and Porcupinefish. Mar Drugs. 2018 Jan 08;16(1) [PMC free article] [PubMed]

6.

Santamaria CM, Zhan C, McAlvin JB, Zurakowski D, Kohane DS. Tetrodotoxin, Epinephrine, and Chemical Permeation Enhancer Combinations in Peripheral Nerve Blockade. Anesth Analg. 2017 Jun;124(6):1804-1812. [PMC free article] [PubMed]

7.

Indumathi SM, Khora SS. Toxicity assessment and screening of tetrodotoxin in the oblong blowfish (Takifugu oblongus) from the Tamil Nadu Coast of Bay of Bengal, India. Asian Pac J Trop Med. 2017 Mar;10(3):278-284. [PubMed]

8.

Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A. Tetrodotoxin: chemistry, toxicity, source, distribution and detection. Toxins (Basel). 2014 Feb 21;6(2):693-755. [PMC free article] [PubMed]

9.

Turner AD, Fenwick D, Powell A, Dhanji-Rapkova M, Ford C, Hatfield RG, Santos A, Martinez-Urtaza J, Bean TP, Baker-Austin C, Stebbing P. New Invasive Nemertean Species (Cephalothrix Simula) in England with High Levels of Tetrodotoxin and a Microbiome Linked to Toxin Metabolism. Mar Drugs. 2018 Nov 16;16(11) [PMC free article] [PubMed]

Tetrodotoxin Toxicity

Kotipoyina HR, Kong EL, Chen RJ, et al.

Publication Details

Continuing Education Activity

Tetrodotoxin is a neurotoxin most commonly found in marine animals. Known for inducing perioral numbness in individuals who consume pufferfish, this toxin poses a unique challenge due to its heat stability, rendering conventional cooking methods ineffective in neutralizing its effects. By elucidating the mechanism of action involving the blockade of sodium channels, this activity explores the diverse array of symptoms, encompassing gastrointestinal, neurologic, and cardiac manifestations in patients with tetrodotoxin toxicity.

This learning activity significantly emphasizes the comprehensive management of tetrodotoxin toxicity, particularly in addressing cardiovascular and respiratory signs. Participating clinicians will gain valuable insights into this condition's etiology, pathophysiology, and clinical presentation. Currently, no established antidote exists. Therefore, the emphasis shifts to tailored supportive measures within the temporal window following exposure. The empowered interprofessional healthcare learns to promptly recognize and effectively treat tetrodotoxin toxicity, ultimately improving patient outcomes.

Objectives:

• Identify the causes of tetrodotoxin toxicity and how to provide immediate medical care.

• Determine the evaluation of a patient with suspected tetrodotoxin toxicity.

• Select the treatment strategy for a patient with tetrodotoxin toxicity.

• Strategize with the interprofessional team to improve care coordination and communication, leading to more effective management of tetrodotoxin toxicity.

Access free multiple choice questions on this topic.

Introduction

Tetrodotoxin is a neurotoxin found in marine animals, most commonly the pufferfish, but can also be found in some terrestrial animal species. The pufferfish is the most common animal species containing tetrodotoxin, with over 20 pufferfish able to produce it.[1] There are 26 known naturally occurring analogs. 

As a toxin, tetrodotoxin is known for its poisonous properties, but the animals that produce it have genetic mutations that make them immune to these effects. The toxin is known to cause perioral numbness in consumers of pufferfish sushi, known in Japan as fugu. Due to heat stability, cooking does not destroy the toxin. By blocking sodium channels, the toxin paralyzes humans who consume it, rendering immediate complications if not promptly recognized.

Tetrodotoxin toxicity is most likely to occur in areas where tetrodotoxin-containing animals are located, particularly seafood. Less commonly, improperly prepared food may lead to poisoning in areas where tetrodotoxin is not typically found.[2] No known antidote exists.[3][4][5] There is also no definitive treatment, so identifying the symptoms and signs is critical to ensuring that fatal sequelae do not ensue.

Etiology

The toxin is found naturally in various 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 over 20 pufferfish species[1] and certain angelfish. Mollusks containing the toxin include several species of the blue-ringed octopus, Niotha gastropods, and the 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.[6][7][8]

Many distantly related taxa have evolved the ability to produce tetrodotoxin because the animals themselves do not produce the toxin. Bacteria produce a toxin that accumulates in animals higher up the food chain. 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 pufferfish were fed the livers of wild pufferfish, leading to accumulated tetrodotoxin. 

The bacteria implicated in the production of tetrodotoxin include members of the following genera: Pseudoalteromonas, Pseudomonas, Vibrio, Aeromonas, Alteromonas, Shewanella, Roseobacter, Raoultella, Actinomycetes, Microbacterium, and Serratia.[9][10] Some animals have tetrodotoxin-producing bacteria in their natural microbiome, contributing to the toxin accumulation. The exception is newts, and it is 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. Typically, 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 immune to tetrodotoxin.[11] Garter snakes, which do not contain tetrodotoxin but prey on toxic newts that do, have also acquired this mutation.[12] Additionally, tetrodotoxin-binding proteins that filter out the toxin exist in some animals, such as the shore crab, pufferfish, and gastropods.[8]

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 Pacific newts of the genus Taricha species 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. A single species of newt on the east coast, the Eastern newt (Notophthalmus viridescens), contains the toxin.[13] The toxin produced by the Eastern newt is only 1/100th as potent as that found in Pacific newts.

Worldwide, the sources of toxicity vary based on local wildlife. 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 been reported in China, Japan, and Taiwan. People who have eaten the eggs of horseshoe crabs have been poisoned in Thailand. Multiple dogs in New Zealand were poisoned after eating grey side-grilled sea slugs.[14]

Epidemiology

The incidence of tetrodotoxin poisoning is rare and variable depending on the geographic locale and organism involved. The most commonly implicated exposures affected pufferfish, and the incidence 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 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.[15] In 2008, cheap pufferfish sold in fish markets led to 3 outbreaks in Bangladesh, affecting 141 people, 17 of whom died from respiratory arrest. An additional outbreak resulted from the ingestion of the roe of Takifugu oblongus, resulting in 5 deaths.[16] Another cluster of patients was reported in Oman in 2018, where 5 patients suffered poisoning after frying locally caught pufferfish.[17] Poisonings involving other tetrodotoxin-containing species are rare, as these animals are generally not edible. Case reports document exposure to poisonous species of newts, often kept as exotic pets,[18][19] and to xanthid crab species.[20]

Pathophysiology

At room temperature, tetrodotoxin is a colorless, crystalline substance with weak basic properties. Tetrodotoxin functions by inhibiting voltage-gated sodium channels. This occurs by interacting with the positively charged guanidine group on tetrodotoxin and the negatively charged carboxylate groups in the mouth of the sodium channel pore.[11] The blockade effect does not change the resting potential of the neuronal membrane but rather prevents the influx of sodium through the channel, effectively preventing transmission of an action potential. The blockade disrupts the function of the brainstem and motor, sensory, and autonomic nerves. This subsequently leads to gastrointestinal, cardiac, and neurologic dysfunction.

Toxicokinetics

Tetrodotoxin is rapidly absorbed from the gastrointestinal tract.[21] The distribution following ingestion is not well described in the literature. One study looking at the distribution of subcutaneous tetrodotoxin found a peak concentration of 1.5 hours and half-life of 4.5 hours at all doses studied, with the maximum dose studied being 45 μg.[22] 

History and Physical

The patient’s history will involve the consumption of tetrodotoxin-containing organisms, such as pufferfish, newts, or sea snails. The onset and severity of symptoms in tetrodotoxin poisoning depend on the time since ingestion and the dose administered. In most cases, symptoms usually occur within 30 minutes of ingestion. A few cases report symptoms starting after 20 hours.[23][24][25][26]

Mild toxicity can have symptom onset between 30 minutes to 6 hours and general recovery after 24 hours. More severe toxicity can lead to rapid onset of symptoms and progression to respiratory failure within 15 to 20 minutes.[27]

There are 4 grades of poisoning based on a scale created by Fukuda and Tani in 1941:

• Grade 1: Paresthesias and perioral numbness, with or without gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea)

• Grade 2: Facial numbness, slurred speech, early motor paralysis, and incoordination, but with normal reflexes

• Grade 3: Generalized flaccid paralysis, aphonia, respiratory failure, and fixed or dilated pupils (in a conscious patient)

• Grade 4: Severe respiratory failure with hypoxia, bradycardia, hypotension, cardiac dysrhythmias, and unconsciousness

Evaluation

Testing should be directed at evaluating other potential etiologies for a patient's presenting symptoms. These may include an electrocardiogram to assess chest pain and tachycardia, a computed tomography (CT) scan of the brain to evaluate for potential stroke or intracranial pathology, and bloodwork to evaluate electrolyte status, kidney function, and blood counts.

No specific laboratory tests 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. Confirmatory testing by LC-MS/MS can be performed by sending urine or serum testing to specialized labs, such as at the CDC, to measure levels of tetrodotoxin.[17][28] Decisions about clinical care should not be delayed waiting for these confirmatory tests.

Treatment / Management

No known antidote exists for tetrodotoxin poisoning. The mainstay of treatment is respiratory support and supportive care until the tetrodotoxin is eliminated.

If ingestion occurs within 60 minutes and no contraindications, such as decreased mental status or active vomiting, are present, activated charcoal and/or gastric lavage may be administered.

Hemodialysis may be helpful in patients with renal disease, but the evidence supporting toxin removal is conflicting. Tetrodotoxin is not water-soluble enough to benefit from hemodialysis.[29] A case report from Japan describes a patient with renal dysfunction and uremia who recovered after receiving multiple sessions of hemodialysis despite persistent mild toxicity symptoms.[30] Another case series of 5 patients supports toxin removal by hemodialysis.[17] Another case series found that hemodialysis may have improved recovery, but the information provided was inadequate to support this intervention.[31]

A monoclonal antibody against tetrodotoxin (anti-tetrodotoxin) exists [32] and has neutralized tetrodotoxin in mice.[33] No reports regarding humans are available.

Neostigmine has been used to treat acute respiratory failure from tetrodotoxin poisoning.[34] However, a recent review found insufficient data to provide evidence for or against this practice.[35]

For suspected tetrodotoxin poisoning, patients should be observed in the intensive care unit due to the possibility of delayed symptom onset, which can occur up to 20 hours postexposure.

Differential Diagnosis

The list of differential diagnoses includes the following:

• Ciguatera toxicity

• First-degree AV block

• Guillain-Barré syndrome

• Hypocalcemia

• Lambert-Eaton myasthenia syndrome

• Octopus envenomation

• Second-degree AV block

• Shellfish toxicity

• Third-degree AV block

Prognosis

Left untreated, patients who have severe toxicity and develop cardiac complications or respiratory paralysis will die. With sufficient supportive care, most patients fully recover without permanent neurologic sequelae. 

Complications

Tetrodotoxin toxicity is commonly associated with the ingestion of pufferfish or certain other marine organisms, and can lead to severe and potentially fatal complications. Complications associated with tetrodotoxin toxicity: [17]

Neurological Symptoms

Tetrodotoxin primarily affects the nervous system. Symptoms may include numbness and tingling, especially around the mouth and extremities. Paralysis, starting with the face and spreading to other parts of the body, can occur. Muscle weakness and difficulty speaking or swallowing may also be observed.

Respiratory Distress

Tetrodotoxin can lead to respiratory muscle paralysis, causing difficulty in breathing. Severe cases may result in respiratory failure, requiring immediate medical intervention, such as mechanical ventilation.

Cardiovascular Effects

Tetrodotoxin can cause a drop in blood pressure, leading to hypotension. Bradycardia (slow heart rate) or arrhythmias may occur, contributing to cardiovascular instability.

Gastrointestinal Symptoms

Nausea, vomiting, and abdominal pain may manifest shortly after ingestion of tetrodotoxin-containing seafood.

Seizures

In some cases, tetrodotoxin toxicity can lead to seizures, adding to the neurological complications.

Coma

Severe poisoning can result in a state of unconsciousness and coma.

Death

Tetrodotoxin toxicity can be fatal, primarily due to respiratory failure or cardiovascular collapse.

Delayed Onset

Symptoms may take several hours to appear after ingestion of contaminated seafood, which can complicate diagnosis and treatment.

No Antidote

No specific antidote for tetrodotoxin poisoning exists. Treatment mainly involves supportive care and symptom management.

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Bottom Line, And This is Meant to Go with Part 1 on this Topic: If you don't eat pufferfish, you probably will never have to worry about tetrodotoxin in your life. If the government releases zombies (Uncategorized Subterranean Lifeforms), or they otherwise come out of their caves, it looks like all you have to do is shine light on them, throw a fire on them, or shoot them. If you are paralyzed by tetrodotoxin and they don't eat you, then someone can perform Basic Life Support and breathe for you until you get to an ICU and a ventilator. When it wears off, you can move again.

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