Histamine Fish Poisoning

What is Histamine?

Histamine fish poisoning is among the most common toxicities related to fish ingestion, constituting almost 40% of all seafood-related foodborne illnesses reported to the US Centers for Disease Control and Prevention (CDC) where 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, pseudo-allergic 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 whereas term histamine fish poisoning is now considered more appropriate because many cases are from non-scombroid fish. Examples include mahi-mahi, amberjack, herring, sardine, anchovy, and bluefish.

Scombrotoxin (histamine) formation as a result of time and temperature abuse of certain species of fish can cause consumer illness whereas the illness is closely linked to the development of histamine in these fish. In most cases, histamine levels in illness-causing fish have been above 200 ppm, often above 500 ppm. However, there is some evidence that other chemicals (e.g., biogenic amines such as putrescine and cadaverine) may also play a role in the illness.

Histamine is an organic amine that is produced as part of a local immune response to cause inflammation which also performs several important functions in the bowel and acts as a neurotransmitter or chemical messenger that carries signals from one nerve to another. Histamine is secreted by basophils and mast cells as part of a local immune response to the presence of invading bodies. The basophils and mast cells are found in nearby connective tissue. This histamine release causes capillaries to become more permeable to white blood cells and other proteins, which proceed to target and attack foreign bodies in the affected tissue. Aside from humans, histamine is found in virtually all animals.

Histamine, 4-(2-aminoethyl)imidazole (MW = 111), is a primary amine arising from the decarboxylation of the amino acid L-histidine. This chemical reaction is catalyzed by the enzyme L-histidine decarboxylase. Histamine is a hydrophilic vasoactive amine and once formed, it is either quickly inactivated or stored. When released at synapses, it is broken down by acetaldehyde dehydrogenase. When this enzyme is deficient, there is an increased risk of allergic reactions, as histamine accumulates in the synapses. Histamine is broken down by the enzymes diamine oxidase and histamine-N-methyltransferase. Thus, histamine formed in foods is the result of the growth of bacteria that possess the enzyme histidine decarboxylase.

Scombrotoxin poisonings have primarily been associated with the consumption of tuna, mahi mahi, and bluefish where scombrotoxin formation that causes consumer illness is closely linked to the development of histamine in these fish. However, a number of other species are also capable of developing elevated levels of histamine as a result of time/temperature abuse. Histamine is heat-stable and survives thermal processing.

Bacterial Scombrotoxin (Histamine) Formation

Certain bacteria produce the enzyme histidine decarboxylase during growth. This enzyme reacts with histidine, a naturally occurring amino acid that is present in larger quantities in some fish than in others. The result is the formation of scombrotoxin (histamine). Histamine-forming bacteria are capable of growing and producing histamine over a wide range of temperature. Development of histamine concentration is more rapid, however it is particularly rapid at temperatures near 90°F (32.2°C), but histamine growth is somewhat retarded at moderate-abuse temperatures (e.g., 45°F (7.2°C) than at high-abuse temperatures (e.g., 70°F (21.1°C) or higher). Thus histamine is more commonly the result of high temperature spoilage than of long-term, relatively low temperature spoilage, which is commonly associated with organoleptically detectable decomposition. Nonetheless, there are a number of opportunities for histamine to form under more moderate-abuse temperature conditions.

Once the enzyme histidine decarboxylase is present in the fish, it can continue to produce histamine in the fish even if the bacteria are not active because the enzyme can be active at or near refrigeration temperatures. On the other hand, enzyme remains stable while in the frozen state and may be reactivated very rapidly after thawing whereas freezing may inactivate some of the enzyme forming bacteria. Both the enzyme and the bacteria can be inactivated by cooking. However, once histamine is produced, it cannot be eliminated by heat (including retorting) or freezing. After cooking, recontamination of the fish with the enzyme-producing bacteria is necessary for additional histamine to form. For these reasons, histamine development is more likely in raw, unfrozen fish but should not be discounted in other product forms of scombrotoxin-forming fish species. The kinds of bacteria that are associated with histamine development are commonly present in the saltwater environment. They naturally exist on the gills, on external surfaces, and in the gut of live, saltwater fish, with no harm to the fish. Upon death, the defense mechanisms of the fish are no longer inhibiting bacterial growth in the muscle tissue, and histamine forming bacteria may start to grow, resulting in the production of histamine.

Critical Processing Operations

Evisceration and removal of the gills may reduce, but not eliminate, the number of histamine forming bacteria. Packing of the visceral cavity with ice may aid in chilling large fish in which internal muscle temperatures are not easily reduced. However, when done improperly, these steps may accelerate the process of histamine development in the edible portions of the fish by spreading the bacteria from the visceral cavity to the flesh of the fish. With some harvesting practices, such as long lining and gillnetting, death may occur many hours before the fish is removed from the water. Under the worst conditions, histamine formation can already be underway before the fish is brought onboard the vessel. This condition can be further aggravated with certain tuna species that generate heat, resulting in internal temperatures that may exceed environmental temperatures and increasing the likelihood of conditions favorable to growth of enzyme forming bacteria. The potential for histamine formation is increased when the scombrotoxin-forming fish muscle is in direct contact with the enzyme forming bacteria. This direct contact occurs when the fish are processed (e.g., butchering or filleting) and can be particularly problematic when the surface-to-volume ratio of the exposed fish muscle is large, such as minced tuna for salads.

Even when such products are prepared from canned or pouch retorted fish, recontamination can occur during salad preparation, especially with the addition of raw ingredients. The mixing spread the bacteria throughout the product and the high surface-to-volume ratio can result in substantial histamine formation if time and temperature abuse occurs. At least some of the histamine forming bacteria are halotolerant (salt tolerant) or halophilic (salt loving). Some are more capable of producing histamine at elevated acidity (low pH). As a result, histamine formation is possible during processes such as brining, salting, smoking, drying, fermenting, and pickling until the product is fully shelf-stable. Refrigeration can be used to inhibit histamine formation during these processes. A number of the histamine forming bacteria are facultative anaerobes that can grow in reduced oxygen environments. As a result, reduced oxygen packaging (e.g., vacuum packaging, modified atmosphere packaging, and controlled atmosphere packaging) should not be viewed as inhibitory to histamine formation. Histamine is water soluble (dissolves in water) and would not be expected in significant quantity in products such as fish oil that do not have a water component. However, histamine could be present in products such as fish protein concentrate that are prepared from the muscle or aqueous (water-based) components of fish tissue.

Symptoms

When a person is allergic to a particular substance, such as a food or dust, the immune system mistakenly believes that this usually harmless substance is actually harmful to the body. In an attempt to protect the body, the immune system starts a chain reaction that prompts some of the body's cells to release histamine and other chemicals into the bloodstream. The histamine then acts on a person's eyes, nose, throat, lungs, skin, or gastrointestinal tract, causing allergy symptoms. You've probably heard of antihistamine medications - these help to fight symptoms caused by the release of histamine during an allergic reaction. Thus increase in blood histamine levels due to consumption of contaminated fish or fish products create similar situations.  The symptoms of scombrotoxin poisoning include tingling or burning in or around the mouth or throat; rash or hives on the upper body; drop in blood pressure; headache; dizziness; itching of the skin; nausea; vomiting; diarrhea; asthmatic-like constriction of the air passage; heart palpitation; and respiratory distress. Symptoms usually occur within a few minutes to a few hours of consumption and last from 12 hours to a few days.

Controlling Scombrotoxin (Histamine) Formation

Rapid chilling of scombrotoxin forming fish immediately after death is the most important element in any strategy for preventing the formation of scombrotoxin (histamine), especially for fish that are exposed to warm waters or air, and for tunas which generate heat in their tissues. Following methods can be used to reduce or control the histamine formation:

Fish exposed to air or water temperatures above 83°F (28.3°C) should be placed in ice, or in refrigerated seawater, ice slurry, or brine of 40°F (4.4°C) or less, as soon as possible after harvest, but not more than 6 hours from the time of death; or

Fish exposed to air and water temperatures of 83°F (28.3°C) or less should be placed in ice, or in refrigerated seawater, ice slurry, or brine of 40°F (4.4°C) or less, as soon as possible after harvest, but not more than 9 hours from the time of death; or

Fish that are gilled and gutted before chilling should be placed in ice, or in refrigerated seawater, ice slurry, or brine of 40°F (4.4°C) or less, as soon as possible after harvest, but not more than 12 hours from the time of death; or

Fish that are harvested under conditions that expose dead fish to harvest waters of 65°F (18.3°C) or less for 24 hours or less should be placed in ice, or in refrigerated seawater, ice slurry, or brine of 40°F (4.4°C) or less, as soon as possible after harvest, but not more than the time limits listed above, with the time period starting when the fish leave the 65°F (18.3°C) or less environment.

Detection

Sensory Evaluation – Sensory evaluation is generally used to screen fish for indicators of spoilage that develop when the fish is exposed to time and temperature abuse. Odor in particular is an effective means of detecting fish that have been subjected to a variety of abusive conditions. However, odors of decomposition that are typical of relatively low temperature spoilage may not be present if the fish has undergone high temperature spoilage. This condition makes sensory examination alone an ineffective control for preventing scombrotoxin (histamine) formation.

Enzyme Immunoassay – The enzyme immunoassay for histamine is based on the competition between the histamine to be assayed and the histamine-alkaline phosphatase conjugate, for binding to antibody directed against histamine, coated onto microtiter wells. The sample containing the histamine, and the histamine-alkaline phosphatase conjugate, when added to the microtiter wells, compete for binding to a limiting number of antibody sites. After incubation, each well is rinsed in order to remove non-bound components. The bound enzymatic activity is then measured by the addition of a chromogenic substrate. The intensity of the color developed is inversely proportional to the concentration of histamine in the sample. The concentration is estimated by comparison with standard histamine solution.