histamine fish poisoning

7/30/2019 Histamine Fish Poisoning

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H istamine F ish PoisoningSUMMARY

IntroductionHistamine fish poisoning (HFP) is a foodborne chemical intoxication caused by the

consumption of spoiled, or bacterially contaminated, fish. Fish species associated with

HFP are harmless when caught. They may still have a normal appearance and odour

after they have become toxic. Spoiled fresh fish, and frozen and smoked fish and

canned fish products have all caused the disease.

HFP occurs worldwide. Recent reports in the literature have suggested that it is a

significant public health and safety concern. Its true incidence has probably been

underestimated, because of under-reporting and misdiagnosis owing to confusion with

symptoms of other illnesses, particularly food allergy.

Histamine, a physiological amine involved in allergic reactions, is the main toxin

involved in HFP, but HFP is not uncomplicated histamine poisoning. Although the

disease is generally associated with high levels of histamine (50mg/100g) in spoiled

f ish, i ts pathogenesis has not been elucidated.Scientific information on HFP is reviewed here in a risk-assessment framework in

order to arrive at an informed characterisation of risk. An attempt has been made to

address, as accurately as possible, the questions: What causes outbreaks of HFP?

What are the underlying factors contributing to outbreaks? and What are the

consequences of outbreaks?

Hazard identificationThe involvement of histamine as the main hazard in HFP is supported by: symptoms

identical to those of intravenous histamine administration or allergic reaction; the

efficacy of antihistamine therapy; and the presence of increased levels of histamine in

spoiled fish that cause the syndrome.Histamine production in fish is related to the histidine content of the fish, the presence

of bacterial histidine decarboxylase (HD), and environmental conditions. Bacterial

decarboxylase enzymes acting on free histidine and other amino acids in the fish

muscle form histamine and other biogenic amines. Fish of the family Scombridae,

notably tuna and mackerel, contain abundant amounts of histidine and are most

commonly implicated. However, many species, both scombroid and non-scombroid

(e.g. mahi-mahi, bluefish and sardines), have caused HFP so the term scombroid fish

poisoning is a misnomer.

The main bacter ia r esponsible for histidine decarboxylation and HFP are members of

the famil y Enterobacteriaceae. Specific bacteria present in the marine environment or

introduced during food handling produce HD, which converts histidine to histamine,particularly when fish are not kept chilled or frozen. Other bacteria in spoiling fish

muscle, again often members of the Enterobacteriaceae family, produce other

breakdown products such as biogenic amines putrescine from ornithine and

cadaverine from lysine.

Histamine consumed in spoiled fish is more toxic than an equal amount of histamine

taken orally in an aqueous solution. It has been proposed that other biogenic amines

produced in spoiled fish may potentiate the action of histamine by inhibiting the

enzymes diamine oxidase (DAO, or histaminase) and histamine methyl transferase

(HMT). These two enzymes normally detoxify histamine in the intestinal tract and

prevent the absorption of unmetabolised histamine into the circulation. Putrescine andcadaverine have been identified as histamine potentiators. However, resul ts of


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experiments to support the potenti ator hypothesis are not total ly convincing. Another

possible mechanism of potentiation of histamine by other biogenic amines is the

barrier disruption hypothesis, which suggests that potentiators might in ter fere with

the protective actions of intestinal mucin, which binds histamine.

Still more hypotheses have been proposed in an attempt to explain the pathogenesis of

HFP. Some scientists have suggested that a scombroid toxin (or toxins) inscombrotoxic fish causes the release of endogenous histamine from mast cells, which

augments the exogenous histamine consumed in spoiled fish in causing symptoms of

toxicity. Others have proposed that paralytic and/or diarrhetic shellfish poisons are

responsible. Yet another hypothesis, long discarded, is that histamine in a fish

substrate may be better absorbed from the mouth or throat than pure histamine in

solution.

Thus, the pathogenesis of HFP remains obscure. After sifting the evidence, the present

authors believe that endogenous release of histamine from mast cells probably does

occur in HFP, at least in some cases. We suggest that urocanic acid may be the

missing factor (scombroid toxin) in HFP for the following reasons. In spoiling fish,

histidine may be metabolised to histamine, or to urocanic acid and glutamate by analternative metabolic pathway. The first step in the alternative pathway is the loss of

ammonia from histidine by the action of L-histidine ammonia lysase (HAL, or

histidase). HAL has a wide distribution among bacteria and, unlike HD, is also found

naturally in fish muscle. Bacteria also produce urocanase, but HAL activity is greater

than that of urocanase and urocanic acid accumulates with histamine in spoiling fish.

Most importantly, urocanic acid has recently been recognised as a mast cell

degranulator.

Histamine is catabolised by several routes in the human body. The main catabolic

pathways involve the enzymes DAO and HMT. HMT activity in particular is

widespread in many body tissues and imidazole histamine metabolites are excreted in

the urine.

Histamine exerts its toxicity by interacting with histamine receptors (H1, H2 and H3)

on cellular membranes. The most common symptoms of histamine poisoning are

cardiovascularf lushing, ur ticaria, hypotension and headache. Other symptoms are

gastrointestinalabdominal cramps, diarr hoea and vomiti ngand neurological

pain and itching associated with urticarial lesions. However, HFP is usually a mild

disease of quick onset (several minutes) and short duration (about 8 h). It responds

well to antihistamine treatment.

Numerous tests are available for detecting histidine decarboxylating bacteria (HDB)

and histamine. Problems associated with histamine detection in fish as a control ordiagnostic measure for HFP include: the lack of uniform distribution of histamine in

toxic fish; the large numbers of methods available and the lack of standardisation

between countries; and the fact that histamine is not the only factor involved in the

pathogenesis of HFP. High-performance liquid chromatography (HPLC) and capillary

electrophoresis are often used, and rapid enzyme-linked immunosorbent assay

(ELISA) test kits are also available. Methods including HPLC are used for detecting

other biogenic amines and urocanic acid.


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Doseresponse assessment

Since 1970, most reports of HFP have come from Japan, the US and Great Britain.

Outbreaks have been reported less frequently in various other countries, including

Australia and New Zealand. There are only two reports of HFP in Australia in the

scientific literature. Juvenile Western Australian salmon caught in South Australianwaters were responsible for two outbreaks, affecting a total of seven people; and two

people were affected by eating a tuna meal at a restaurant in Brisbane. The true

incidence of HFP in Australia is unknown.

Scombroid fish that cause HFP include mackerel (Scomberspp.), tuna (Thunnus spp.),

saury (Cololabis saira) and bonito (Sarda app.) (scombroid fish). Non-scombroid fish

that cause HFP include mahi-mahi or dolphin fish (Coryphaena spp.), sardines

(Sardinella spp.), pilchards (Sardina pilchardus), anchovies (Engraulis spp.), herring

(Clupea spp.), marlin (Makaira spp.) and tailor or bluefish (Pomatomus spp.). Other

non-scombroid species, Western Australian salmon (Arripis truttaceus), sockeye

salmon (Oncorhynchus nerka) and Cape yellowtail (Seriola lalandii), have also been

implicated.Since free histidine in fish muscle is the substrate for microbial decarboxylation to

produce histamine, species difference in free histidine content has a large effect on the

potential hazards of poor handling and storage practices. Levels of ornithine (to

produce putrescine) and lysine (to produce cadaverine) may also be important.

Histamine concentrations in fish tend to be greater adjacent to the gills or intestines.

Spoilage and ammonia and biogenic amine production are enhanced at elevated

temperatures, with histamine production by bacteria such asMorganella morganii,

Klebsiella pneumoniae andHafnia alveibeing optimal at 30oC. Once a large bacterial

population has been established, residual enzyme activity continues slowly at

refrigeration temperatures (05oC), although bacterial growth ceases. Histamine is

also produced, but to a lesser extent, by bacteria that can grow at refrigeration

temperatures (e.g Vibrio spp.,Photobacterium spp.).

It is not possible to predict accurately the effect of temperature abuse on histamine

formation. Different bacterial species have different temperatures for maximum

growth, and the histamine concentration in any part of a fish represents that produced

by a population of bacteria with capacities for histamine production and/or destruction

ranging from high to zero. However, as spoilage progresses, the proportion of HDB in

the microbial population increases. In addition, quantifi cation of bacteri al

contamination is not meaningfu l. Subsequent heat processing can destroy bacterial

contaminants and even HD (histidine decarboxylase) activity, but has little or no effect on

histamine levels.

Although histamine is not solely responsible for HFP, levels of histamine in suspect

fish serve as an important indicator of bacterial contamination, and many countries

have set guidelines for maximum permitted levels. The current level for histamine in

fish in the Australian Food Standards Code is 100 mg/kg. However, concentrations of

histamine within a fish are extremely variable, as is the threshold toxic dose.

If we regard 10 mg histamine/100 g of fish as the highest level that can be consumed

safely by most people, this must be related to the amount of fish eaten and the weight

of the person to calculate a likely safe dose. If a 60-kg person eats, say, 300 g (wet

weight) of this fish, this dose would be 0.5 mg/kg bodyweight. Such a calculation is of

limited value, however, considering the variable nature of HFP and the lack ofunderstanding of its pathogenesis.


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The severity of the clinical response depends on the amount of toxin(s) ingested and

the variation in individual susceptibility. In some outbreaks the morbidity rate may

reach 100%. There is large variation in individual susceptibility. Certain dietary

components and medications such as isoniazid, aminoguanidine and some

antihistaminic drugs increase susceptibility. Disease states, such as allergies and

mastocytosis, may also affect the clinical manifestation of HFP.

Exposure assessment

If fish are subject to elevated temperatures, even for short periods, a large microbial

population is established. During subsequent refrigeration, although bacterial growth

ceases, residual enzyme activity continues slowly and histamine (and putrescine and

cadaverine) levels continue to increase. If the fish are then hot smoked or canned, the

heat will destroy the residual microflora and HD, but not histamine.

Indications that HFP is not common in Australia are supported by results of limitedsurveys and routine monitoring. Of 104 cans of tuna screened in Melbourne retail

markets in 1987 (45 from Australia and 59 from Asian countries), 101/104 cans had

100 mg/kg

putrescine, and two contained >100 mg/kg cadaverine.

Ongoing random monitoring of imports and domestic product by the AustralianGovernment Analytical Laboratories (AGAL) has revealed only a small percentage of

samples with >100 mg/kg histamine. The only remaining tuna cannery in Australia,

Port Lincoln Tuna Processors Pty Ltd, South Australia, monitors histamine levels in

all batches of fish entering the cannery, as well as in finished product, to ensure that

strict food safety standards are maintained.

In developed countries where HFP still occurs quite frequently, such as the United

States and Japan, most outbreaks are the result of consumption of fish caught by

recreational fishers, with insufficient knowledge of the problem and without proper

chilling facilities on fishing boats.

Although not reported to any extent, HFP is probably still common in developing

countries, where fish preserved by traditional methods is an important part of the diet.The problem would be expected to be greater in tropical countries, where high

ambient temperatures promote the growth of the most active HDB.

Great progress has been made in ensuring the quality of fish products despite the huge

expansion in trade in recent years. This is the result of the introduction of international

standards in food hygiene and the application of risk analysis and Hazard Analysis and

Critical Control Point (HACCP) principles. Although incidents of HFP caused by high

levels of histamine in canned tuna have occurred all over the world, improvements in

handling and processing associated with the establishment of quality control

procedures are now widespread and taking effect.


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Risk characterisationHFP does not have a major impact on human health in Australia, partly because fish

does not form a large part of the diet of most Australians. However, the disease is

important from the food safety aspect and it is possible that toxic products,

particularly imports, will escape the random monitoring safety net from time to time.

Consumers are becoming more demanding and litigation following food poisoningincidents is becoming more common. Producers, distributors and restaurants will

increasingly be held liable for the quality of the products they handle and sell.

If a major outbreak of HFP were to occur in Australia, as has happened in Japan and

the United States, resulting media attention would affect fish consumption and have a

negative impact on the marketing of seafood. An outbreak in another country caused

by Australian exports would seriously affect trade. Although such events are

becoming increasingly less likely because of the widespread adoption of HACCP

analysis and quality assurance, constant monitoring is necessary to allow for factors

such as equipment failure, human error or negligence.

Other activities could also place Australia in a better position to characterise the risk

of HFP and prevent or rapidly manage an outbreak should it occur. The pathogenesisof HFP requires elucidation. More research is needed to determine the threshold of

toxic dose for histamine and the role that potentiators or other toxins play in causing

toxicity. The possible role of urocanic acid in HFP, as a potential mast cell

degranulator, should be investigated, initially in laboratory animals. There is also a

need to better assess the actual incidence of fish allergy and to estimate what

percentage of cases diagnosed as fish allergy represent misdiagnosis of HFP.

There is a need for global standardisation of histamine detection methods, and

laboratory accreditation and proficiency testing, if histamine is to remain the main

indicator of microbial spoilage in histidine-containing fish. From an environmental

health perspective, a rapid and cheap assay for detecting histamine in fish would be of

value if made available to the public and, in particular, to recreational fishers.

However, monitoring fish histamine levels alone may not always ensure protection

from HFP. There may be advantage in the simultaneous detection of other biogenic

amines, such as cadaverine and putrescine. The detection of histamine, cadaverine and

putrescine can be achieved satisfactorily by the use of two-dimensional TLC or

HPLC, but this is neither rapid nor cheap. Urocanic acid may be a useful alternative to

histamine as a spoilage index in scombroid and other fish that are rich in endogenous

histidine, and may be linked to the potential of fish to cause HFP.

Reporting of suspected cases of HFP to local food authorities should lead to removal

of contaminated fish from the marketplace and prevention of additional cases.

Mechanisms should be put in place, where these are not present already, to allowefficient and complete traceback of incriminated fish to point of origin, in order to

rectify problems leading to spoilage. In addition, there needs to be education of

recreational fishers and the public about the need for good refrigeration and hygiene to

minimise the possible hazards of consuming fish.

histamine fish poisoning

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