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).  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. 
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. 
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.  (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.)
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.)
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. 
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]
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. 
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.  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.  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
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. 
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.
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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