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Tetrodotoxin Toxicity

  • Author: Theodore I Benzer, MD, PhD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Dec 28, 2015
 

Background

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

Puffer fish. 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]
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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.[2, 3]

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).

Chemical structure of tetrodotoxin. 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.[4] 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.[5] 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.[6]

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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Contributor Information and Disclosures
Author

Theodore I Benzer, MD, PhD Assistant Professor in Medicine, Harvard Medical School; Director of the ED Observation Unit, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital

Theodore I Benzer, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Robert L Norris, MD Professor, Department of Emergency Medicine, Stanford University Medical Center

Robert L Norris, MD is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, International Society of Toxinology, American Medical Association, California Medical Association, Wilderness Medical Society

Disclosure: Nothing to disclose.

References
  1. Nagashima Y, Matsumoto T, Kadoyama K, Ishizaki S, Taniyama S, Takatani T, et al. Tetrodotoxin poisoning due to smooth-backed blowfish, Lagocephalus inermis and the toxicity of L. inermis caught off the Kyushu coast, Japan. Shokuhin Eiseigaku Zasshi. 2012. 53(2):85-90. [Medline].

  2. Moczydlowski EG. The molecular mystique of tetrodotoxin. Toxicon. 2013 Mar 1. 63:165-83. [Medline].

  3. Lago J, Rodríguez LP, Blanco L, Vieites JM, Cabado AG. Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses. Mar Drugs. 2015 Oct 19. 13 (10):6384-406. [Medline].

  4. Padera RF, Tse JY, Bellas E, Kohane DS. Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity. Muscle Nerve. 2006 Dec. 34(6):747-53. [Medline].

  5. San Diego Department of Environmental Health, FDA. Tetrodotoxin poisoning associated with eating puffer fish transported from Japan--California, 1996. MMWR Morb Mortal Wkly Rep. 1996 May 17. 45(19):389-91. [Medline].

  6. 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 2. 63 (51):1222-5. [Medline]. [Full Text].

  7. Liu SH, Tseng CY, Lin CC. Is neostigmine effective in severe pufferfish-associated tetrodotoxin poisoning?. Clin Toxicol (Phila). 2015 Jan. 53 (1):13-21. [Medline].

  8. Rivera VR, Poli MA, Bignami GS. Prophylaxis and treatment with a monoclonal antibody of tetrodotoxin poisoning in mice. Toxicon. 1995 Sep. 33(9):1231-7. [Medline].

  9. Chang FC, Spriggs DL, Benton BJ, et al. 4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs. Fundam Appl Toxicol. 1997 Jul. 38(1):75-88. [Medline].

  10. Ahasan HA, Mamun AA, Karim SR, et al. Paralytic complications of puffer fish (tetrodotoxin) poisoning. Singapore Med J. 2004 Feb. 45(2):73-4. [Medline].

  11. U.S. Food and Drug Administration. Advisory on Puffer Fish. FDA. Available at vm.cfsan.fda.gov/~mow/chap39.html. January 17, 2014; Accessed: December 28, 2015.

  12. How CK, Chern CH, Huang YC, et al. Tetrodotoxin poisoning. Am J Emerg Med. 2003 Jan. 21(1):51-4. [Medline].

  13. Lange WR. Puffer fish poisoning. Am Fam Physician. 1990 Oct. 42(4):1029-33. [Medline].

 
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Puffer fish.
Chemical structure of tetrodotoxin.
 
 
 
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