Tetrodotoxin Toxicity

Practice Essentials

Poisoning with the neurotoxin tetrodotoxin (TTX) occurs after ingestion of various species of puffer fish (see the image below).

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Puffer fish.

The flesh of the puffer fish (ie, fugu) is considered a delicacy in Japan. It is prepared by chefs specially trained and certified by the government to prepare the flesh free of the toxic liver, gonads, and skin. Despite these precautions, many cases of tetrodotoxin poisoning are reported each year in patients ingesting fugu.

Poisonings usually occur after eating fish caught and prepared by uncertified handlers.

The toxic dose is not clear because puffer fish have different concentrations of tetrodotoxin. A dose of 1-2 mg of purified toxin can be lethal. Reported cases from the Centers for Disease Control and Prevention (CDC) have documented toxicity with ingestion of as little as 1.4 ounces of puffer fish.

Tetrodotoxin also is found in the the following:

• Gastropod mollusc
• The eggs of horseshoe crabs
• Newts of the genus Taricha
• The skin of Atelopid frogs
• The skin and viscera of porcupine fish, globefish, balloon fish, blowfish, sunfish, toadfish, blue-ringed octopus, and some species of salamanders^[1]

Detection of tetrodotoxins in European bivalve shellfish in the United Kingdom along the English Channel has been reported, although concentrations were low in comparison to published minimum lethal doses for humans.^[2]  

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Pathophysiology

Puffer fish contain the potent neurotoxin tetrodotoxin. TTX is thought to be synthesized by a bacterial or dinoflagellate species associated with the puffer fish.^{[3, 4]}

The toxin is concentrated in the liver, gonads, and skin. The level of toxicity is seasonal, and, in Japan, fugu is served only from October through March.

Tetrodotoxin is a heat-stable (except in alkaline environments) and water-soluble nonprotein.

It is a heterocyclic, small, organic molecule that acts directly on the electrically active sodium channel in nerve tissue (see the image below).

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Chemical structure of tetrodotoxin.

Tetrodotoxin blocks diffusion of sodium through the sodium channel, thus preventing depolarization and propagation of action potentials in nerve cells.

All of the observed toxicity is secondary to blockade of the action potential. Tetrodotoxin acts on the central and the peripheral nervous systems (ie, autonomic, motor, sensory nerves).

Tetrodotoxin also stimulates the chemoreceptor trigger zone in the medulla oblongata and depresses the respiratory and vasomotor centers in that area.

Recent study using tetrodotoxin therapeutically shows that tetrodotoxin used in conjunction with bupivacaine prolonged the local anesthetic effect.^[5] If tetrodotoxin begins to be used clinically, the incidence of toxicity may increase.

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Epidemiology

Frequency

United States

Reports of tetrodotoxin poisoning are rare in the United States. A 1996 report documents three cases of tetrodotoxin toxicity from persons who ingested contaminated fugu imported by a coworker from Japan.^[6] A 2014 report describes two patients in Minneapolis, Minnesota, who developed tetrodotoxin poisoning  after consuming dried puffer fish purchased during a recent visit to New York City; the patients noted that two friends who consumed the same fish had similar but milder symptoms and had not sought care.^[7]

International

Despite the careful training and certification of fugu chefs in Japan, cases of mortality and morbidity from puffer fish ingestion continue to be reported. Estimates vary, but up to 50 deaths may occur each year from tetrodotoxin poisoning in Japan.

Mortality/Morbidity

Mortality rates are difficult to calculate, but estimates of mortality approach 50%, even with modern supportive medical care. Patients who live through the acute intoxication (ie, first 24 h) usually recover without residual deficits. Recovery takes days to occur.

Race

No known racial predilection exists. However, the poisoning is more common in Japanese people because of their dietary preferences for fugu.

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History

See the list below:

• The first symptoms occur 15 minutes to several hours postingestion of tetrodotoxin-containing food. A recent report on toxicity found that initial symptoms may occur up to 20 hours after ingestion.
• Initial symptoms include lip and tongue paresthesias, followed by facial and extremity paresthesias and numbness.
• Salivation, nausea, vomiting, and diarrhea with abdominal pain develop early.
• Motor dysfunction with weakness, hypoventilation (may be from dysfunction of central and peripheral nervous systems), and speech difficulties then develop. A rapid ascending paralysis occurs over 4-24 hours. Extremity paralysis precedes bulbar paralysis, which is followed by respiratory muscle paralysis. Deep tendon reflexes are preserved early in the course of paralysis.
• Finally, cardiac dysfunction with hypotension and dysrhythmias (bradycardia), central nervous system (CNS) dysfunction (eg, coma), and seizures develop. Patients with severe toxicity may have deep coma, fixed nonreactive pupils, apnea, and loss of all brain stem reflexes.
• Death can occur within 4-6 hours. Typically, death occurs from respiratory muscle paralysis and respiratory failure.

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Physical

See the list below:

• Loss of sensory and motor neuron function is a prominent finding.
• Ascending paralysis with respiratory depression.
• Cyanosis occurs with respiratory failure.
• Hypotension can occur with myocardial dysfunction.
• Cardiac rhythm disturbances, especially bradycardia, atrioventricular (AV)–nodal block, and bundle-branch block, can be life threatening.
• GI effects are not prominent, but vomiting and abdominal tenderness can occur.

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Causes

See the list below:

• Ingestion of tetrodotoxin causes the syndrome.
• Almost all toxicity is caused by the ingestion of fugu, but other species of animals have been shown to produce tetrodotoxin (eg, California newt, parrot fish, blue-ringed octopus). A death from ingestion of tetrodotoxin from a California newt has been documented.

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Laboratory Studies

See the list below:

• No specific laboratory test that confirms tetrodotoxin ingestion exists; thus, dietary history is key for diagnosis.
• Mouse bioassays for paralytic shellfish toxin (ie, saxitoxin) exist that are positive with tetrodotoxin. There are research chromatography techniques for tetrodotoxin as well, but neither is available in the acute clinical situation.^[8] Tetrodotoxin also may be detected by fluorescent spectrometry.
• Measure routine serum electrolytes, calcium, magnesium, and ABGs to rule out metabolic causes of diffuse sensory and motor neuron dysfunction.

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Imaging Studies

See the list below:

• Patients with evidence of cyanosis or respiratory insufficiency should have a chest x-ray to exclude local lung pathology (eg, aspiration pneumonia).
• Obtain a plain film and upright x-ray of the abdomen in patients with persistent vomiting or severe abdominal pain to exclude obstruction or hollow viscus perforation.
• Perform a CT scan of the brain if the patient exhibits any focal neurologic dysfunction or seizures.

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Prehospital Care

Prehospital care includes the following:

• Provide careful attention to the airway, breathing, and circulation (ABCs).
• Patients may require endotracheal intubation for oxygenation and airway protection in the setting of muscle weakness and respiratory failure, which can occur soon after ingestion of the tetrodotoxin.
• Cardiac dysfunction may require IV intervention with fluids, pressors, and antiarrhythmics.
• Severely poisoned patients may be very weak, have difficulty speaking, and be unable to provide a history; thus, clues from the environment and bystanders are very important.

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Emergency Department Care

Emergency department (ED) management includes the following:

• Focus initially on the ABCs.
• Secure the airway before frank respiratory failure or aspiration occurs.
• Establish an IV early in the event acute antiarrhythmics or vasopressors are needed.
• Remove toxin from the intestinal tract by the usual toxicologic modalities. The use of nasogastric or orogastric lavage is theoretically beneficial but can be complicated by aspiration and damage to the esophagus. The administration of activated charcoal (with or without a cathartic) is recommended for all symptomatic patients.
• If vomiting has occurred, gastric lavage is not indicated.
• Carefully monitor vital signs and oxygenation in the ED because patients can decompensate suddenly. Treat all alterations in vital signs aggressively.
• Further treatment should focus on supporting cardiovascular function until the toxin is eliminated from the body.
• Neostigmine has been used to treat acute respiratory failure from tetrodotoxin poisoning; however, a systematic review concluded that the current literature contained insufficient data to provide an evidence base for or against this practice.^[9]
• No specific antidote has been tested in humans. An animal study using monoclonal antibodies against TTX has been done.^[10] Monoclonal antibodies were shown to be life saving in mice treated both before and after the ingestion of a lethal dose of TTX. Further studies are needed to document the efficacy in humans.
• In another animal study, 4-aminopyridine (a potassium channel blocker) was used in guinea pigs intoxicated with tetrodotoxin or saxitoxin.^[11] A dramatic improvement in respiratory, cardiac, and CNS status occurred after administration of the drug. No human studies of this drug for use in tetrodotoxin poisoning are in progress.
• Admit all patients with documented or suspected puffer fish ingestion to an intensive care unit; symptoms usually develop within 6 hours but may be delayed for 12-20 hours.

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Medication Summary

No drug has been shown to reverse the effects of tetrodotoxin poisoning. Treatment is symptomatic. Specific drug efficacy has only been documented anecdotally.

Anticholinesterase drugs (eg, neostigmine) have been proposed as a treatment option but have not been tested adequately.^[9]

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Activated charcoal (Liqui-Char)

• Dosing, Interactions, etc.

Clinical Context:  Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingesting poison. Generally mixed and given with a cathartic (eg, 70% sorbitol), except in young pediatric patients in whom electrolyte disturbances may be of concern.

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Class Summary

Empirically used to minimize systemic absorption of the toxin. May only benefit if administered within 1-2 h of ingestion.

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Neostigmine (Prostigmin)

• Dosing, Interactions, etc.

Clinical Context:  Although not clinically proven, neostigmine has been used anecdotally to restore motor strength. Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across myoneural junction.

Repeat doses based on patient's response.

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Class Summary

May be useful in reversing the neurological complications of the venom; however, they should not be a substitute for airway management.

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Prognosis

See the list below:

• Mortality rates are difficult to establish; however, anecdotal reports suggest 50-60% mortality, even with good supportive care.
• Symptoms may last several days, even in nonlethal ingestions.
• One report suggests that prognosis is good if the patient survives the first 24 hours.

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Patient Education

For patient education information, see the First Aid and Injuries Center, as well as Food Poisoning and Activated Charcoal.

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