Histamine fish poisoning results from the consumption of inadequately preserved and improperly refrigerated fish.[1] 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. 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]
Symptoms of histamine fish poisoning resemble an acute allergic reaction and usually appear 10–60 minutes after eating contaminated fish. 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.)
View Image
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.
Without treatment, histamine fish poisoning resolves within 12 to 48 hours with no long-term sequelae. Even severe cases improve rapidly within one to three hours from initiation of antihistamines.[1, 6] In severe cases, patients may require treatment for bronchospasm or hypotension. (See Treatment and Medication.)
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.[7, 8]
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.[9, 10]
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.[11]
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.[12] Subsequent cooking, smoking, or canning of the fish does not eliminate the histamine, so both raw and cooked fish may cause symptoms.
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
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.
According to the 2016 Annual Report of the American Association of Poison Control Center National Poison Data System (AAPC-NPDS), 165 single exposures to histamine toxicity were reported.[13]
Histamine toxicity from fish makes up 3% of food-borne disease outbreaks reported to the CDC, but is likely highly underreported. During 2009-2015, 85 outbreaks of confirmed histamine fish poisoning involving 250 illnesses were reported to the CDC, with one hospitalizaiton and no deaths.[14]
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. In 2016, the AAPCC-NPDS reported 26 minor outcomes, 17 moderate outcomes, 1 major outcome, and no deaths.[11]
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.
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.
Most patients present within 10-60 minutes of toxin ingestion. The patient may have noted a sharp, metallic, bitter, or peppery taste to the fish and describe its appearance as honeycombed.
In situations where several people have eaten portions of a fish that was contaminated with histamine, their presentations may vary. Uneven distribution of histamine in the fish’s tissues, differences in the amount consumed, and individual susceptibility to histamine all can affect the severity of the episode. For example, patients taking isoniazid (INH) or monoamine oxidase inhibitors (MAOIs) may have more significant reactions because of histaminase blockade in the gastrointestinal (GI) tract.
Manifestations of histamine fish poisoning include the following:
The initial physical presentation easily can be mistaken for an allergic reaction if the history of fish ingestion is not obtained. Physical signs include the following:
Diffuse erythematous rash, well demarcated and typically on the head, neck, and upper trunk (see the images below)
Conjunctival injection
Tachycardia
Bronchospasm
Hypotension
Angioedema
Urticaria
View Image
An example of a typical histamine toxicity rash, in this case from tuna. Image courtesy of Amanda Oakley, MBChB, FRACP.
View Image
An example of a typical histamine toxicity rash, in this case from tuna. Image courtesy of Amanda Oakley, MBChB, FRACP.
Generally, the diagnosis of histamine toxicity from fish is made on clinical grounds; no laboratory tests are necessary. If proof is required for epidemiologic or other reasons, uneaten portions of the fish may be tested for histamine levels. In addition, affected patients have increased histamine levels in plasma and high levels of histamine methabolites (N- methylhistidine) in urine.[3, 12] Although these findings support the diagnosis, these measurements are poorly correlated to clinical manifestations and do not affect clinical decisions.[7]
A patient with respiratory complaints may require chest radiography to exclude foreign body aspiration or other respiratory pathology. A patient with cardiac complaints may need a cardiac evaluation that includes an electrocardiogram (ECG) to exclude other causes of palpitations or chest tightness.
One study has suggested that serum tryptase levels, if obtained very early (1-2 h) after symptom onset, may also help to make this distinction. If tryptase levels are elevated, an allergic reaction is more likely, since the tryptase level is usually within the normal range in histamine food poisoning.[16]
Most cases of histamine fish poisoning are self-limited; duration is less than 6 hours. However, comorbid atopic conditions (ie, asthma) have been reported to extend course duration and severity.[17]
Bronchospasm is treated with oxygen and beta-adrenergic agents. Hypotension is treated with IV fluids and, rarely, pressors. Administration of epinephrine, because of the mistaken belief that the patient is experiencing an acute allergic reaction, will also result in rapid resolution of symptoms.[18]
Hospital admission is required only under exceptional circumstances. Criteria for admission are severe comorbidity or refractory toxicity that mandates respiratory or pressor support.
Most cases require no consultation for medical management. Consultation may be requested from the local health department to help confirm diagnosis. Contact the regional poison control center or a local medical toxicologist for additional information and patient care recommendations. Notify the local health department of any case of histamine fish poisoning, especially if the source was public, in order to help prevent additional cases.
Prehospital care is primarily supportive. Emergency personnel may provide oxygen and monitor cardiac function as needed. Advanced life support personnel may use antihistamines and bronchodilators as appropriate.
In the emergency department (ED), if the patient has only minimal symptoms of histamine toxicity, reassurance and observation may be the only treatment necessary. If clinically necessary, obtain an ECG and institute intravenous access, oxygen, and cardiac monitoring. H1 and H2 blockers can provide symptom relief.
Consider use of activated charcoal only if the patient ate a large amount of fish, presents very early after the meal (within 1 hour), and can adequately protect his or her airway. Use of ipecac or gastric lavage is not recommended, as these can result in complications.
Bronchospasm is a rare manifestation of histamine toxicity. If it occurs, use standard treatment, as follows:
Inhaled beta2-adrenergic agonists
Inhaled ipratropium bromide (may be particularly useful for the treatment of histamine-induced bronchospasm)
Epinephrine
Corticosteroids
Extremely rare reported cases of myocardial dysfunction, ischemia, or infarction related to histamine fish poisoning exist[19] ; standard treatment for these complications should be used. One reported case documents successful treatment of a 36-year-old woman with severe myocardial dysfunction refractory to pressor support by using a biventricular assist device for 8 days.[20]
The vast majority of patients may be discharged from the ED with oral H1- and H2-blockers for the next 3-5 days. Headache often responds H2 blocker treatment. The patient may return to normal activity as tolerated.
Patients may express concern about future allergic reactions to fish and seafood. Reassure patients that their illness resulted from improper fish handling and storage, not from an allergic reaction.
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. The ambient storage temperature should be below 40°F (< 4.4°C) throughout the entire handling process.[14] 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.
If a patient with histamine fish poisoning is ill enough to require treatment, antihistamines are used to counteract the symptoms; both histamine 1 (H1) and histamine 2 (H2) blockers may be used. Epinephrine or other adrenergic agents are rarely necessary because the entire cascade of mediators released by a true allergic reaction is not found in histamine poisoning, but adrenergic agents may be considered in the rare case of secondary bronchospasm or refractory hypotension associated with this type of poisoning. Corticosteroids are generally not indicated, except in cases of severe bronchospasm and angioedema.
Clinical Context:
An H1 blocker, diphenhydramine is considered the drug of choice for histamine fish poisoning. It may be given orally or intravenously. It provides relief of symptoms caused by release of histamine.
Clinical Context:
Hydroxyzine antagonizes H1 receptors in the periphery and may suppress histamine activity in the subcortical region of the central nervous system (CNS). This agent is used to manage histamine-mediated pruritus; it is an alternative to diphenhydramine.
These agents are used to reverse symptoms of the causative agent (ie, histamine). Initiate treatment with H1 blockers. H2 blockers may be added for synergistic effects.
Clinical Context:
Famotidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.
Clinical Context:
Ranitidine is a competitive, reversible inhibitor of histamine at the H2 receptor that may be used in conjunction with H1-blockers for severely symptomatic cases. It has fewer drug interactions than cimetidine and may be better for patients who take other medications metabolized by the cytochrome p450 system.
Clinical Context:
Cimetidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone..
These agents block H2 receptors of gastric parietal cells, leading to inhibition of gastric secretions. They can be used in combination with H1 blockers for patients with severe histamine fish poisoning that does not respond to H1 blockers alone.
Clinical Context:
Methylprednisolone is a glucocorticoid that ameliorates delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis.
Clinical Context:
Prednisone, a commonly used oral agent, may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It must be metabolized to the active metabolite prednisolone for it to have an effect. Conversion may be impaired in liver disease.
Clinical Context:
Prednisolone controls inflammation by suppressing migration of PMNs and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level. Since prednisolone is extensively metabolized in liver, there may be enhanced effect on patients with cirrhosis.
These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to certain stimuli.
Clinical Context:
Albuterol stimulates adenyl cyclase to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), relaxing bronchial smooth muscle and causing bronchodilation. It has little effect on cardiac muscle contractility. This agent may decrease mediator release from mast cells and basophils and inhibit airway microvascular leakage. It is available as liquid for nebulizer use, in metered-dose inhalers, and dry powder inhalers.
Clinical Context:
Epinephrine stimulates alpha-, beta1, and beta2-adrenergic receptors, which, in turn, results in bronchodilation, increased peripheral vascular resistance, hypertension, increased chronotropic cardiac activity, and positive inotropic effects. It is the drug of choice for emergency treatment of severe allergic reactions, but provides relief for patients with histamine fish toxicity mistaken for allergic reactions.
Sympathomimetic agents produce direct or indirect stimulation of adrenergic receptors and have various actions depending on the specific receptors involved.
Clinical Context:
Ipratropium is a quaternary ammonium anticholinergic bronchodilator acting at muscarinic receptors of the parasympathetic nervous system. It is chemically related to atropine. Ipratropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. It may be particularly useful for the treatment of histamine-induced bronchospasm.
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
Disclosure: Nothing to disclose.
Coauthor(s)
Daniel Noltkamper, MD, FACEP, EMS Medical Director, Department of Emergency Medicine, Naval Hospital of Camp Lejeune
Disclosure: Nothing to disclose.
John D Patrick, MD, Corresponding Member of the Faculty in Emergency Medicine, Harvard Medical School; Emeritus Staff Physician, Emergency Department, Mount Auburn Hospital
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
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
Ansdell, VE. Food Poisoning from Marine Toxins. Gary W. Brunette, Editor in Chief. CDC Yellow Book 2018: Health Information for International Travel. New York: Oxford University Press; May 15, 2017. 77-80.
[Guideline] US Food and Drug Administration. Scombrotoxin (Histamine) Formation. Fish and Fishery Products Hazards and Controls Guidance. Fourth Edition. April 2011. 113-152.
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