Fugu or Pufferfish Poisoning

Background

Pufferfish Poisoning or tetrodotoxin intoxication (Fugu) is a gastroenteritis with severe neurologic manifestations similar to PSP. It is found worldwide and is associated predominantly with the ingestion of pufferfish. Fugu poisoning was known as a fatal disease by the ancient Chinese as early as 2800 BC; an Egyptian carving of 2700 BC warned about eating fish without scales, probably referring to the pufferfish family.

Fugu poisoning is not due to dinoflagellates. The associated toxin, tetrodotoxin, is found in the order of fish known as Tetraodontiformes especially in the family Tetraodontidae (pufferfish). Marine bacteria colonize the gut and skin mucosal layers of the puffer following infection, and produce persistent levels of tetrodotoxin which the fish sequesters in gonads, liver, and to some extent muscle.

The tetraodontiformes (pufferfish) are found in both tropical and temperate waters with several hundreds of species. Concentrations of tetrodotoxin vary with season (especially high in Japan during October through March) and are especially high in the ovaries, livers and intestine. Other marine organisms are associated with tetrodotoxin: the Japanese ivory shell and the trumpet shell. Tetrodotoxin is also found in the skin of certain frogs and it is the principal poison in venom of blue-ringed octopus.

The most toxic pufferfish are found along the coasts of China and Japan where their consumption is considered a delicacy (known as "fugu" in Japan), and where they are eaten only after preparation by specially trained chefs. In Japan 1974-1979, 60 cases were reported with 20 deaths. About 50% of fatal food poisonings in Japan each year are due to eating fugu with a death rate in these reports of upto 59.5% reported cases. Of note, in Japan, cases are more common among men than women, probably related to eating habits. There are also exported cases reported in Europe due to mislabeling and elsewhere in the world due to ignorance. Thus, Fugu is a very circumscribed public health problem with a high mortality.

Clinical Presentation

The clinical presentation of Fugu is similar to PSP except for marked hypotension and a different ingestion history. There is a rapid onset of symptoms (5-30 minutes). Victims of PSP report weakness and dizziness, paresthesias in face spreading to the extremities, nausea, rarely vomiting, diarrhea, pallor, and sweating. In addition, diminished or absent superficial and deep reflexes have been reported as well as constriction then later dilation of the pupil. Progressive bulbar paralysis, extraocular muscle paralysis, and general body flaccid paralysis are seen with severe cases, although consciousness is usually maintained throughout. With severe cases there is gradual onset of respiratory distress with death within 6 hours of respiratory failure, and convulsions can occur upto 24 hours.

Fukuda and Tani have outlined 4 degrees of increasing tetrodotoxin intoxication by stages of progression:

1. oral paraesthesias, sometimes with gastroenteric symptoms;
2. advanced paraesthesias, motor paralysis of extremities, intact reflexes;
3. gross muscular incoordination, aphonia, dysphagia, respiratory distress, cyanosis, drop in blood pressure, but victim is conscious;
4. Mental faculties impaired, respiratory paralysis, extreme drop in blood pressure with continued pulsation of heart for short time.

The more rapid the onset of symptoms (ie. within 30 minutes) and the greater the degree of symptoms, the poorer the prognosis. If the person can survive 18-24 hours, the prognosis is favorable for complete recovery. No chronic manifestations of Fugu have been reported.

Diagnosis

The mouse assay for PSP can be used. Tetrodotoxin can be distinguished from saxitoxin by bioassay before and after heating to 100 C at pH 1 for 25 minutes: tetrodotoxin loses most of its toxicity, not saxitoxin. Fluorescence spectrometry can also distinguish between PSP toxins.

Management and Treatment

The present treatment for Fugu is supportive and symptomatic. The major concerns are the respiratory failure and severe hypotension. When the ingestion of contaminated food is recent, gut decontamination by the gastric lavage and administration of activated charcoal or dilute bicarbonate solution is recommended. Care must be taken concerning aspiration with the neurologically compromised patient. Hypotension may require infusion of fluids and/or catecholamines.

Clinical management for severe poisoning should include tracheal intubation for bulbar palsy and mechanic ventilation for respiratory insufficiency. It should be remembered that dilated unreactive pupils alone are not necessary consistent with brainstem neuromuscular block.

Anticholinesterase treatment has been used reportedly successfully in a few human cases, using a slow iv injection of edrophonium after intubation and artificial respiration; this has not been substantiated experimentally and may depend on the degree of tetrodotoxin intoxication, therefore should only be used conjointly with artificial respiration and other supportive interventions. Recent work by Kaufman et al (1991) has focused on the development of a therapeutic antiserum, although this is complicated by the wide range of PSP toxins.

As with many of the marine toxin induced diseases, the initial or index case(s) are often the tip of the iceberg. Therefore any suspected cases of Fugu should be reported to the appropriate public health authorities for follow up to ascertain other cases and to prevent further spread. And every effort should be made to obtain contaminated materials and their source. Obviously major prevention consists of not eating pufferfish! Or if you must partake of this Oriental delicacy, it is recommended that one employ the talents of a trained and certified Fugu cook.

Chemical Structure of Fugu

Molecular Mechanism of Action

Tetrodotoxin is one of the most toxic of the natural toxins. LD50 in cat is less than 10 ug/kg and lethal ingested dose for humans is 5-30 mg/kg wet tissue. It is classified as an aminoperhydroquanizole with molecular weight of 319.

The primary effect of the tetrodotoxin is to block the excitability of nerve axons by reducing their permeability to the inward flow of sodium ions. During the action potential, the membranes of excitable cells undergo a transient increase in sodium permeability; the toxin acts by preventing this flow of sodium ions by blocking the channels through with the sodium ions flow. In addition, the sodium pump inhibition prevents the usual increase in permeability to sodium ion, but leaves the potassium ion permeability unaltered. It blocks the sodium channels in a 1:1 fashion. Tetrodotoxin has been one of the most widely used tools for selective blockade of sodium channels in neurophysiology. Tetrodotoxin may have central nervous system effects.

Compared with saxitoxin, Tetrodotoxin is slightly less neuroactive but has more prolonged effects. It is less easily reversed and creates small transient potentiation of maximal muscular contraction with subliminal doses. Tetrodotoxin has less effect on muscle fiber (saxitoxin can cause neuromuscular muscle weakness without hypotension), however it causes hypotension via effect on the vasomotor tone through preganglionic fibers or direct action on cardiac muscle. Finally, with tetrodotoxin, the antagonistic action of anticurare drugs such as edrophonium are stronger.

References and Sites

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