Tetrodotoxin Toxicity

Puffer fish contain the potent neurotoxin tetrodotoxin. TTX is thought to be synthesized by a bacterial or dinoflagellate species associated with the puffer fish.[9, 8]  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.

TTX in terrestrial animals is limited to newts, toads and frogs. The origin of TTX in these animals is thought to be endogenous because this toxin has a role in defence. In particular, the levels of TTX in newts are higher in the skin than in the liver, leading to the theory that TTX is biosynthetically produced as a protection mechanism against predators.[8]

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).

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.

TTX exerts analgesic properties by inhibiting the initiation and conduction of impulses in the peripheral nervous system. Clinical trials have been ongoing to evaluate the analgesic effect of TTX in cancer pain.[10]   If tetrodotoxin begins to be used clinically, the incidence of toxicity may increase.

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. 

According to the 2019 Annual Report of the American Association of Poison Control Center National Poison Data System (AAPC-NPDS), 209 single exposures to tetrodotoxin were reported.[11]   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.[12]

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

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. Symptoms may last several days, even in nonlethal ingestions. The prognosis is generally good if the patient survives the first 24 hours.[2]

The first symptoms occur 15 minutes to several hours postingestion of tetrodotoxin-containing food; however, initial symptoms have been reported to 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.

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

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; liquid chromatography–mass spectrometry (LC–MS) and liquid chromatography–tandem mass spectrometry (LC–MS/MS) are the most simple, powerful, and sensitive methods for qualitative and quantitative determination of TTX from human urine, blood, or other fluids.[13]  However, neither is available in the acute clinical situation.[14]

Measure routine serum electrolytes, calcium, magnesium, and ABGs to rule out metabolic causes of diffuse sensory and motor neuron dysfunction.

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.

The following is the classic grading system for tetrodotoxin poisoning based on symptoms and signs[8] :

• Grade 1 - Perioral numbness and paraesthesia, with or without GI symptoms (mainly nausea)

• Grade 2 - Numbness of tongue, face, and other areas (distal); early motor paralysis and incoordination; slurred speech; normal reflexes

• Grade 3 - Generalized flaccid paralysis, respiratory failure (dyspnea), aphonia, and fixed/dilated pupils; patient still conscious

• Grade 4 - Severe respiratory failure and hypoxia; hypotension, bradycardia, and cardiac dysrhythmias; unconsciousness may occur

Prehospital Care

Prevent others from eating until the source of tetrodotoxin exposure can be ascertained, in order to avoid more casualties. 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. 

Provide careful attention to the airway, breathing, and circulation (ABCs). Do not induce vomiting (emesis). 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.

Emergency Department Care

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. Carefully monitor vital signs and oxygenation in the ED because patients can decompensate suddenly. Treat all alterations in vital signs aggressively. The administration of activated charcoal (with or without a cathartic) is recommended for all symptomatic patients.

If the patient/victim can be rapidly transported to an emergency department, gastric lavage may be considered after the airway has been secured. Gastric lavage is recommended only after ingestion of a life-threatening amount of tetrodotoxin and only if it can be done shortly after ingestion (generally within 1 hour). The risk of worsening injury to the lining of the gastrointestinal (GI) tract must be considered.[2] If vomiting has occurred, gastric lavage is not indicated.

Further treatment should focus on supporting cardiovascular function until the toxin is eliminated from the body. Heart function should be monitored, and the patient/victim should be evaluated for hypotension, dysrhythmias, and respiratory depression. The patient should be evaluated for hypoglycemia, electrolyte disturbances, and hypoxia.[2]

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.

Neostigmine has been used to treat acute respiratory failure from tetrodotoxin poisoning; however, a systematic review concluded that the literature contained insufficient data to provide an evidence base for or against this practice.[15]

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.[15]

Class Summary

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

Activated charcoal (Liqui-Char)

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.

Class Summary

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

Neostigmine (Prostigmin)

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.