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Histamine Toxicity from Fish

  • Author: Alexei Birkun, III, MD, PhD; Chief Editor: Timothy E Corden, MD  more...
 
Updated: Apr 22, 2016
 

Background

Histamine fish poisoning is among the most common toxicities related to fish ingestion, constituting almost 40% of all seafood-related food-borne illnesses reported to the US Centers for Disease Control and Prevention (CDC).[1] Histamine fish poisoning results from the consumption of inadequately preserved and improperly refrigerated fish. It resembles an allergic reaction but is actually caused by bacterially-generated toxins in the fish's tissues.[2]

Previous terms for histamine fish poisoning were scombroid fish poisoning, pseudoallergic fish poisoning, histamine overdose, or mahi-mahi flush. The term scombroid was used because the first fish species implicated in this poisoning were from the suborder Scombridae, which includes mackerel, tuna, marlin, swordfish, albacore, bonito, skipjack, and almost 100 other species (Scombridae is derived from the Greek word scombros, which means mackerel or tunny).

The term histamine fish poisoning is now considered more appropriate because many cases are from nonscombroid fish. Examples include mahi-mahi (dolphin fish), amberjack, herring, sardine, anchovy, and bluefish.[3]

Typical manifestations of histamine fish poisoning include skin flushing on the upper half of the body, rash (see the image below), gastrointestinal (GI) complaints, and throbbing headache.[4] (See Presentation.) Generally, the diagnosis is made on clinical grounds; no laboratory tests are necessary. If confirmation is required, histamine levels in uneaten portions of the suspect fish can be measured. In addition, elevated histamine levels can be measured in patients’ urine.[4, 5] (See Workup.)

An example of a typical histamine toxicity rash, i An example of a typical histamine toxicity rash, in this case from tuna. Image courtesy of Amanda Oakley, MBChB, FRACP.

See 5 Cases of Food Poisoning: Can You Identify the Pathogen?, a Critical Images slideshow, to help identify various pathogens and symptoms related to foodborne disease.

Antihistamines usually relieve the symptoms and support histamine as the causative agent. In severe cases, patients may require treatment for bronchospasm or hypotension. (See Treatment and Medication.)

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Pathophysiology

Histamine poisoning directly relates to improper preservation and inadequate refrigeration. Histidine decarboxylase (HDC), found in Escherichia coli, Morganella morganii, and in Proteus and Klebsiella species, converts histidine, present in fish tissue, to histamine. Without adequate cooling, these bacteria multiply, increasing the histidine-to-histamine conversion rate and raising histamine levels. In fish left at room temperature, the histamine concentration rapidly increases, reaching toxic concentrations within 12 hours.

In healthy fish, histamine is normally present at levels less than 0.1 mg per 100 g. In contrast, samples of fish that produce poisoning contain histamine levels of at least 20-50 mg per 100 g of fish.[6]

A second agent in fish tissues has been theorized to play a role in histamine toxicity because attempts to recreate the symptoms by orally feeding people histamine have failed. This may be because pure histamine is poorly absorbed in the GI tract, and the liver and intestinal mucosa can deactivate histamines.

This putative second causative agent, possibly saurine (histamine hydrochloride), may enhance the activity of histamine, facilitate its absorption, or prevent its inactivation by histamine N- methyltransferase or diamine oxidase. Other postulated second agents are cadaverine or putrescine.[7, 8]

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Etiology

The fish species most commonly implicated in histamine toxicity are scombroid dark-meat fish (eg, tuna, mackerel, skipjack, bonito, marlin) and nonscombroid species, such as mahi-mahi (dolphinfish), amberjack, sardine, yellowtail, herring, and bluefish.[3, 4] Although rare, cases involving whitefish also have been reported.[9]

Toxin production occurs when inadequate refrigeration after the catch allows the multiplication of bacteria that contain histidine decarboxylase, which converts amino acid histidine in the fish tissues to histamine. Histidine decarboxylase can continue to produce histamine in the fish even if the bacteria are inactivated; in addition, the enzyme remains stable while frozen and may be reactivated very rapidly after thawing.[10] Subsequent cooking, smoking, or canning of the fish does not eliminate the histamine, so both raw and cooked fish may cause symptoms.

Proper refrigeration and transport prevents histamine fish poisoning. Fish should be chilled immediately after being caught; the goal is to achieve an internal temperature of 50°F (10°C) within 6 hours of the fish's death. The ambient storage temperature should be below 40°F (< 4.4°C) throughout the entire handling process.[1] Toxicity can result from the consumption of fresh fish that has been inadequately cooled and refrigerated, or of frozen fish that has been allowed to sit at room temperature for a prolonged time after thawing.

Affected fish do not have a distinctive appearance or odor. After preparation, the fish may look honeycombed. Taste is a relatively insensitive measure of toxicity, since the lowest levels of histamine sufficient to cause symptoms cannot be tasted. Occasionally, fish with higher histamine concentrations may have a pungent, peppery taste.

Bacterial proliferation (and thus, histamine production) occurs unevenly in the fish, depending partly on temperature discrepancies. For example, tissue closer to the surface of a previously frozen mass of fish will thaw sooner and may contain more histamine.

The degree of symptoms in individuals consuming the same meal may be quite variable. Magnitude of symptoms may be related to the following:

  • Individual differences in sensitivity to or metabolism of histamine (eg, symptoms may be markedly worse in persons taking isoniazid because of blockade of GI tract histaminase)
  • Size of the portion consumed
  • The amount of histamine in the consumed portion
  • Whether the portion was from the same fish
  • The amount and type of other foods consumed along with the fish
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Epidemiology

The fish species most commonly implicated in histamine toxicity live in temperate or tropical waters, making populations on adjacent land areas more likely to experience outbreaks. Nevertheless, histamine fish toxicity is worldwide in scope, affecting people of all races, both sexes, and all ages.

Histamine toxicity from fish makes up 5% of food-borne disease outbreaks reported to the CDC, but is likely highly underreported. During 1998-2008, 262 confirmed and 71 suspected outbreaks of histamine fish poisoning were reported to the CDC. Taken together, these affected 1,383 people, causing a total of 59 hospitalizations. In the great majority of cases, the fish that caused the outbreak was prepared in a restaurant or deli.[1]

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Prognosis

Patients with histamine fish toxicity have a good prognosis. Improvement is usually rapid and sequelae are rare. The clinical course may be prolonged and of greater severity in patients with a history of atopy.

Reported complications include severe bronchospasm, angioedema, hypotension, pulmonary edema, and cardiogenic shock. Patients with comorbid illnesses such as coronary artery disease are at risk for acute coronary syndromes caused by the tachycardia and hypotension associated with severe cases. However, no known fatalities have been linked directly to histamine fish poisoning.

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Patient Education

Patients should be informed that their illness was caused by toxins in the fish they consumed, and be reassured that the episode did not result from allergy to fish. The clinician should explain that histamine toxicity results from bacterial proliferation in inadequately refrigerated fish and advise patients on proper handling to prevent toxicity in fish prepared at home.

Patients should be advised that in most cases, histamine does not impart a distinctive appearance or odor to affected fish. However, patients should not continue eating a fish if they note an unusual peppery, bitter taste.

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Contributor Information and Disclosures
Author

Alexei Birkun, III, MD, PhD Assistant Professor of the Chair of Emergency Medicine and Anesthesiology, Medical Academy named after SI Georgievsky of VI Vernadsky Crimean Federal University; Critical Care Physician, Anesthesiologist, Department of Laparoscopic Surgery and New Medical Technologies, Crimea State Medical University Clinic

Alexei Birkun, III, MD, PhD is a member of the following medical societies: European Respiratory Society, International Society for Infectious Diseases, The Aerosol Society

Disclosure: Nothing to disclose.

Coauthor(s)

John D Patrick, MD Corresponding Member of the Faculty in Emergency Medicine, Harvard Medical School; Emeritus Staff Physician, Emergency Department, Mount Auburn Hospital

John D Patrick, MD is a member of the following medical societies: American College of Emergency Physicians, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Daniel Noltkamper, MD, FACEP EMS Medical Director, Department of Emergency Medicine, Naval Hospital of Camp Lejeune

Daniel Noltkamper, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Chief Editor

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Acknowledgements

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Director of Medical Toxicology, Allegheny General Hospital

Disclosure: Nothing to disclose.

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

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

Disclosure: Nothing to disclose.

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.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

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.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
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  2. Feng C, Teuber S, Gershwin ME. Histamine (Scombroid) Fish Poisoning: a Comprehensive Review. Clin Rev Allergy Immunol. 2016 Feb. 50 (1):64-9. [Medline].

  3. Hungerford JM. Scombroid poisoning: a review. Toxicon. 2010 Aug 15. 56(2):231-43. [Medline].

  4. Lavon O, Lurie Y, Bentur Y. Scombroid fish poisoning in Israel, 2005-2007. Isr Med Assoc J. 2008 Nov. 10(11):789-92. [Medline].

  5. Morrow JD, Margolies GR, Rowland J. Evidence that histamine is the causative toxin of scombroid-fish poisoning. N Engl J Med. 1991 Mar 14. 324(11):716-20. [Medline].

  6. Taylor SL, Stratton JE, Nordlee JA. Histamine poisoning (scombroid fish poisoning): an allergy-like intoxication. J Toxicol Clin Toxicol. 1989. 27(4-5):225-40. [Medline].

  7. Prester L. Biogenic amines in fish, fish products and shellfish: a review. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011 Nov. 28(11):1547-60. [Medline].

  8. Al Bulushi I, Poole S, Deeth HC, Dykes GA. Biogenic amines in fish: roles in intoxication, spoilage, and nitrosamine formation--a review. Crit Rev Food Sci Nutr. 2009 Apr. 49(4):369-77. [Medline].

  9. Russell FE, Maretic Z. Scombroid poisoning: mini-review with case histories. Toxicon. 1986. 24(10):967-73. [Medline].

  10. [Guideline] US Food and Drug Administration. Scombrotoxin (Histamine) Formation. Fish and Fishery Products Hazards and Controls Guidance. Fourth Edition. April 2011. 113-152. [Full Text].

  11. Feldman KA, Werner SB, Cronan S, Hernandez M, Horvath AR, Lea CS, et al. A large outbreak of scombroid fish poisoning associated with eating escolar fish (Lepidocybium flavobrunneum). Epidemiol Infect. 2005 Feb. 133(1):29-33. [Medline]. [Full Text].

  12. Ricci G, Zannoni M, Cigolini D, Caroselli C, Codogni R, Caruso B, et al. Tryptase serum level as a possible indicator of scombroid syndrome. Clin Toxicol (Phila). 2010 Mar. 48(3):203-6. [Medline].

  13. Wilson BJ, Musto RJ, Ghali WA. A case of histamine fish poisoning in a young atopic woman. J Gen Intern Med. 2012 Jul. 27(7):878-81. [Medline]. [Full Text].

  14. Waldo OA, Snipelisky DF, Dawson NL. 46-year-old man with abdominal pain and hypotension. Mayo Clin Proc. 2015 Jan. 90(1):135-8. [Medline]. [Full Text].

  15. Anastasius M, Yiannikas J. Scombroid fish poisoning illness and coronary artery vasospasm. Australas Med J. 2015. 8 (3):96-9. [Medline]. [Full Text].

  16. Grinda JM, Bellenfant F, Brivet FG, Carel Y, Deloche A. Biventricular assist device for scombroid poisoning with refractory myocardial dysfunction: a bridge to recovery. Crit Care Med. 2004 Sep. 32(9):1957-9. [Medline].

  17. [Guideline] Diagnosis and management of foodborne illnesses: a primer for physicians and other health care professionals. MMWR Recomm Rep. 2004 Apr 16. 53:1-33. [Medline]. [Full Text].

 
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Mackerel.
An example of a typical histamine toxicity rash, in this case from tuna. Image courtesy of Amanda Oakley, MBChB, FRACP.
An example of a typical histamine toxicity rash, in this case from tuna. Image courtesy of Amanda Oakley, MBChB, FRACP.
 
 
 
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