HISTAMINE POISONING

BY

BACTERIA

Debarshi Dasgupta PALB-4137

SOMETHING as simple as storing fish in a colder area could have saved the lives

of Noelene Bischoff and her teen daughter Yvana.

Queensland authorities, who took over the autopsy from Indonesian investigators at the

request of the Bischoff family, have said early indications show scombroid food

poisoning, coupled with asthma suffered by the pair as well as mother Noelene's

migraine medication, may have caused their deaths.

●Histamine poisoning is a food-borne chemical

intoxication resulting from the ingestion of foods that

contain unusually high levels of histamine.

Incubation period ranges from several minutes to a few

hours after ingestion of meal.

Centre for Disease Control(CDC) refers to it as :

●SCOMBROID FISH POISONING/HISTAMINE

FISH POISONING(in fish)

●HISTAMINE POISONING (in other food items

like Cheese,Sauerkraut,Ham etc.)

HISTAMINE

• Histamine, 4-(2-aminoethyl)imidazole , is a primary amine

arising from the decarboxylation of the amino acid, L-histidine.

• Tissues like liver and spleen contain endogenous histamine.

• Mast cells, basophils, entero-endocrine cells produce histamine.

• Mediated by receptors , effects include : cell proliferation and

differentiation, vasodilation, hematopoiesis, embryonic

development, wound healing, neurotransmission.

• Influences cognition, memory, vigilance and Circadian rhythms.

HAZARD IDENTIFICATION

Evidences of histamine being hazardous include: 1. Symptoms identical to those of IV histamine administration.

2. Efficient antihistamine therapy.

3. Presence of increased levels of histamine in the fish.

• Consuming spoiled fish containing histamine is more likely

to cause toxic effects than taking the same amount of pure

histamine by mouth.

• This has led to speculation that there are other „„scombroid

toxins‟‟ acting with histamine.

OCCURRENCE OF FISH POISONING

• Perhaps the most common type of food poisoning globally.

• Under-reporting of the disease is a worldwide problem.

• Many probable cases have been ignored as mild allergies, or

misdiagnosed.

• First described in 1799 in Great Britain.

• Re-emerged in medical consciousness when outbreaks in

Japan were noted in 1950‟s.

• USA,UK and Japan are the countries with most incidences.

• In 1973, Japan recorded the largest outbreak involving 2656

people.

• The fish mostly involved are Tuna, Mahi-mahi, Escolar,

Marlin and Salmon.

• Tuna and Mahi-mahi make up more than 80%of the

reported cases.

“SCOMBROID”: Associated with the fish in families Scombridae and

Scomberesocidae.

(a)Scombridae

Yellowfin tuna Thunnus albacares

Blackfin tuna T. atlanticus

Skipjack tuna Katsuwonas pelamis

Bullet tuna or bullet mackerel Auxis rochei

Atlantic bonito Sarda sarda

Atlantic mackerel Scomber scombrus

King mackerel Scomberomorus cavalla

(b)Scomberesocidae

Atlantic saury Scomberesox saurus

Pacific saury or mackerel pike Cololabis saira

SKIPJACK TUNA

BULLET TUNA ATLANTIC BONITO

ATLANTIC SAURY

NON-SCOMBROID FISH INVOLVED IN HFP:

(a)Pomatomidae

Bluefish Pomatomus saltatrix

(b)Coryphaenidae

Dolphin fish, dorado, or mahi-mahi Coryphaena hippurus

(c) Carangidae

Horse mackerel Trachurus trachurus / T. japonicus

Pacific amberjack Seriola colburni

(d) Clupeidae

Atlantic herring Clupea harengus harengus

Pacific sardine or pilchard Sardinops sagax

Golden sardine Sardinella aurita

(e)Engraulidae

European anchovy Engraulis encrasicolus

BLUEFISH MAHI MAHI

HORSE MACKEREL ATLANTIC HERRING

ANCHOVY

PACIFIC

PILCHARD

OCCURRENCE OF CHEESE POISONING

• In Netherlands, in 1967, a person fell sick due to

consumption of Gouda cheese.

• In 1970‟s, cases were recorded in USA after consumption of

Swiss cheese.

• Gruyere cheese poisoning occurred in France.

• Cheshire cheese and Cheddar cheese poisoning have also

been reported in patients under Isoniazid therapy.

OTHER FOOD ITEMS PRONE TO POISONING:

Proteinaceous foods subjected to putrefaction and fermented

foods are particularly likely to contain large amounts of

histamine. Eg:-

• Sauerkraut ,wine, and fermented, dry sausage such as Italian

salami and pepperoni

• Chicken, Shellfish and Ham.

SALAMI PEPPEROMI SHELLFISH

SYMPTOMOLOGY

Cutaneous

• Rash

• Urticaria

• Edema

• Localized inflammation

Gastrointestinal

• Nausea

• Vomiting

• Diarrhea

• Cramping

Hemodynamic

• Hypotension

Neurological

• Headache

• Palpitations

• Flushing

• Tingling

• Burning

• Itching

URTICARIA

DIARRHEA

FLUSHING ITCHING

FORMATION OF HISTAMINE

• Related to the enhanced histidine content of the fish, the

presence of histidine decarboxylase (HD) from bacteria.

• During spoilage, decarboxylases help in the formation of

other biogenic amines like:

a. Putrescine: from ornithine

b. Cadaverine: from lysine

c. Spermidine: from arginine

d. Spermine: from arginine

• Spoilage by bacteria are enhanced at higher temperatures

post-mortem.

• Proteolysis, either autolytic or bacterial, may play a role in

the release of free histidine from tissue proteins.

• (Milk does not contain large quantities of free histidine.)

• An alternate pathway, favoured by most bacteria,involves

glutamate as the ultimate product.

1. Histidine histidine ammonia lyase Urocanic acid

2. Urocanic acid α-ketoglutarate+ glutamate

Urocanic acid, like histamine, an imidazole compound derived

from histidine in spoiling fish, may be the „„missing factor‟‟ in

HFP.

METABOLISM OF HISTAMINE IN MAMMALS

Several routes:

1. Oxidative deamination by Diamine Oxidase (DAO) to form imidazole

acetaldehyde and imidazole acetic acid.

2. Methylation by histamine methyl transferase(HMT).

Oxidative deamination pathway is dominant in rats and guinea pigs.

Methylation pathway is prevalent in humans, mice, cats,pigs, hamsters.

• HMT-mainly in liver.

• DAO- GI tract.

• Monoamine Oxidase(MAO) is also important in histamine

metabolism

• MAO,DAO,HMT-inhibitors accentuate Histamine poisoning.

METABOLIC PATHWAYS OF HISTAMINE

MICROBIAL ASPECTS OF HISTAMINE POISONING

• Around 112 species of bacteria are known to possess Histidine

decarboxylase.

• Enterobacteriaceae, Clostridium sp., Lactobacillus sp. are widely

prevalent.

• Morganella morganii, Klebsiella pneumoniae and Hafnia alvei are

most prolific histamine producers when fish are maintained at 4°C or

more.

• Recently , Clostridium perfringens has been identified as a prolific

producer from skipjack tuna.

• For HFB: 2 media have been prepared:

1. Tuna fish infusion broth(TFIB): prepared from muscle tissue of raw

tuna.

2. Histidine-fortified trypticase soy broth: to maximize histamine

production.

3. MRS broth: For Lactobacilli

M. morganii K.pneumoniae

Lactobacillus sp.

According to temperature-growth relationships, the available data

suggests that there are no clear-cut distinctions between the temperature

groups………. But it‟s a continuum of values.

(A=Photobacterium phosphoreum; B= Vibrio sp.; C= Klebsiella, Morganella, Hafnia; D= if

present)

Lower limits for production of toxicologically significant

levels of histamine in tuna fish infusion broth(TFIB) for some

common HDB:

• 7°C- for Klebsiella pneumoniae

• 15°C- for Morganella morganii

• 30°C-for Hafnia alvei, Citrobacter freundii and

Escherichia coli.

Diversity of microflora in spoiling fish is varied, depends on

species, handling procedures, holding times and temperatures.

Character of microflora is influenced by the fish‟s feeding

habits, geographical location, season, temperature etc.

Indian preservatives like garlic,ginger, turmeric and black

pepper have been seen to have an inhibitory effect on the HDB

at concentrations 1%-5%.

Behling and Taylor(1982) divided HDB into 2 groups:

1. Those capable of producing

• >100mg Histamine/100ml TFIB

• in short incubation under 24 hours

• at temperature more than 15°C.

2. Those capable of producing

• <25mg Histamine/100ml TFIB

• in prolonged incubation more than 48 hours

• at temperature more than 30°C.

• Salt-tolerant lactobacilli may have been responsible for

histamine formation in the Gouda cheese implicated in a

histamine poisoning episode in the Netherlands.

• From swiss cheese some non-prolific histamine-producing

bacteria including Streptococcus faecium, S. mitis,

Lactobacillus bulgarius, L. plantarum, streptococci of the

viridans group, and propionibacteria, were isolated.

• Recently, a strain of L. buchneri from a sample of Swiss

cheese implicated in an outbreak of histamine poisoning, was

shown to be a prolific histamine producer.

• Further research will be needed to determine if additional

species of dairy-related bacteria are capable of significant

histamine production.

ANALYTICAL METHODS FOR DETECTION OF

HISTAMINE

• For detection of HDB, selective or differential media are used.

Histamine is usually extracted and measured commonly by

fluorometric assay.

• Various methods have been employed like:

1. Fluorometric assay

2. Thin-layer chromatographic method

3. High performance liquid chromatography

4. Capillary electrophoresis

5. Copper chelation method

6. Capillary zone electrophoresis, etc.

ELISA kits like ALERT provide good reproducibility. Enzyme

immunoassay kits like Histamarine kit is also increasing in popularity.

These are more sensitive, but expensive for routine studies.

POSSIBLE MECHANISMS OF TOXICITY

1. TOXICITY OF BIOGENIC AMINES:-

• By interaction with receptors on cell

membranes(H1,H2,H3,H4)

• But the dose-response relationship is not straightforward.

• Variable factors associated with the bacteria as well as the

host, are tough to quantify or disentangle.

• Normally , content of histamine 50mg/100g or more is

considered toxic.

• Histidine levels vary from 1g/kg in Herring to as much as

15g/kg in Tuna.

2. HISTAMINE POTENTIATORS:

• Potentiators act to decrease the threshold dose of histamine

needed to cause adversity.

• Histamine-potentiator hypothesis states that

“Adsorption,metabolism and potency of one biogenic amine

might be modified in presence of a second amine”.

• Cadaverine and putrescine have been found to completely

inhibit DAO.

• Most potent inhibitors include tyramine(MAO inhibitor), β-

phenylethylamine(DAO,HMT inhibitor) and

tryptamine(DAO inhibitor).

• Pharmacological inhibitors are more potent. Include

cadaverine hydrochloride, tyramine hydrochloride, isoniazid

compounds.

3. BARRIER-DISRUPTION HYPOTHESIS:

• “Potentiators might interfere with the protective actions of

intestinal mucin, which is known to bind histamine”

• Cadaverine exhibits a marked influence on the rate of

transport of C-14 labelled histamine and metabolites across

the gut wall in isolated gut sections of guinea pig.

4. ABSORPTION FROM MOUTH AND THROAT:

• Histamine maybe absorbed by mucous membranes of

mouth and throat, thus bypassing the digestive process that

destroys it

5. RELEASE OF ENDOGENOUS (MAST CELL) HISTAMINE BY

SCOMBROID TOXIN:

• Mast cells contain a histamine-heparin complex.

• In 1972, Olley postulated “some other basic substance

produced during spoilage may release histamine from the

histamine –heparin complex.”

• Scombroid toxin is a mast cell degranulator.

• Imidazole compounds have been known to release

histamine from mast cells.

• Urocanic acid(imidazolic nature) has been found as a mast-

cell degranulator in human skin organ cultures. It may be

one of the “scombroid toxins” that scientists have been

searching for decades.

HISTAMINE LEVELS AND TOXIC DOSE

Threshold toxic dose for histamine in foods is not precisely

known and its difficult to determine.

Shalaby suggested the following guideline levels:

• <5mg/100g= safe for consumption

• 5-20mg/100g= possibly toxic

• 20-100mg/100g=probably toxic

• >100mg/100g=toxic and unsafe for consumption

FDA Guidelines for tuna,mahi-mahi and related fish:

• 500ppm(50mg/100g) as the toxicity level

• 50ppm(5mg/100g) as defect action level.

HUMAN FACTORS DETERMINING CLINICAL

RESPONSE:

1. VARIATION IN INDIVIDUAL SUSCEPTIBILITY:

Varies according to the amount of toxin ingested and variation

in individual susceptibility. Gradation of symptomatic

intensity.

2. INFLUENCE OF DIET:

• Geiger(1955) found that prior intake of seasoned spoiled

fish items and alcohol makes more adverse impact on the

system.

• Absorption is greater when taken with a meal like bread-

butter or milk etc.

• Potentiators from other foods like meat, cheese, fermented

foods like soy sauce and sauerkraut increase poisoning.

• Mixed seafood dishes may promote HFP.

3. DISEASES AND AGE:

• Histidinaemia affected people lack HAL, so easily

poisoned.

• Histamine metabolism reduces with age.

4. INFLUENCE OF MEDICATION:

• HMT is inhibited by analogues of methylmethionine

such as adenosyl-homocysteine, anti-malarial drugs

and antagonists of histamine receptors.

• DAO inhibited by aminoguanidine.

• Isoniazid(anti-tuberculosis) is inhibitor of both MAO

and DAO.

• Antihistamines taken, may protect from HFP.

DIAGNOSIS

• Attention should be given to the type of fish ingested,

whether the fish was cooked or raw, whether these reactions

have occurred in the past, and the time frame between fish

ingestion and the onset of symptoms.

• An assessment of spoiled fish based on appearance and odor

alone does not aid in diagnosis. Instead, it is necessary to

test the histamine levels directly.

• In the allergy clinic, where in vitro testing for tissue levels of

histamine in fish is not available, skin prick testing (SPT)

can help diagnose HFP.

SKIN PRICK TEST

TREATMENT • Antihistamines are the mainstay of treatment.

• For mild to moderate symptoms, effective oral H1 antagonists include

diphenhydramine, cetirizine, and chlorphenarimaine

• Cetirizine is preferred because it is less sedating.

• H2 blockers such as cimetidine, famotidine, or ranitidine can also be

added.

• If nausea is present, intravenous promathazine can be used and

intravenous fluids are indicated for diarrhea.

• Intravenous diphenhydramine and ranitidine or famotidine are the

drugs of choice in case intensity is serious.

• Intravenous fluids are indicated in treatment of hypotension.

FACTORS AFFECTING CHANCES OF OCCURRENCE

OF HISTAMINE POISONING

1. POST CATCHING CONTAMINATION

• At several levels: aboard the fishing vessel, at processing plant,

distribution system and at the consumer level.

• Subburaj et al.(1984)investigated fish market environment of

Mangalore.

2. TEMPERATURE ABUSE ON FISHING VESSELS

3. INADEQUATE CHILL-STORAGE TEMPERATURES

4. INADEQUATE FREEZING AND THAWING PROCEDURES

5. TEMPERATURE ABUSE IN PREPARING DRIED AND

SMOKED PRODUCTS.

6. POOR CANNING PROCEDURES

7. LOW-QUALITY FERMENTED PRODUCTS.

8. TEMPERATURE ABUSE OF RAW TUNA FOR SUSHI

MARKETS.

CONTROLLING SCOMBROTOXIN

FORMATION

Rapid chilling of scombrotoxin- forming fish

immediately after death is the most important

element in the strategy to control HFP,

especially for fish that are exposed to warm

waters of air, and for tunas which generate heat

in their tissues.

FDA, 1999

Time required to lower the internal temperatures of fish after

capture depends on:

1. The harvest method

2. The size of the fish

3. The chilling method.

Once chilled, the fish must be maintained at freezing

till consumption.

Exposures to temperature more than 40°F should be

minimised.

• This time limit depends on whether the fish had been

previously frozen properly, or heat-processed

sufficiently.

Heat processed fish are at low risk for formation of toxin(provided they

are handled in a proper manner that eliminates further contamination).

(FDA,1999)

HEALTH POLICY INITIATIVES

• In 1996, FDA implemented the HACCP Program, a set of rules that

governs time and temperature requirements at critical control points

along the entire supply chain.

• However, it is difficult to ensure that boats are adhering to HACCP

and the compliance rates were low.

• Several histamine fish poisoning outbreaks have been traced back to

fish caught on private boats.

• Healthcare providers must be made aware of this under-recognized

disease.

• Physicians should report histamine fish poisoning cases to local and

state health agencies for monitoring.

HAZARD ANALYSIS AND CRITICAL CONTROL POINTS(HACCP)

Aims to identify steps in the supply chain of fish where human intervention is needed to

control histamine poisoning: each concerned step is termed as a CCP.

LIKELY CCPs UNLIKELY CCPs

Receiving Continuous brief steps like filleting

Processing, such as: Processing brief steps such as:

1.Thawing 1. Date code stamping

2. Brining 2. Case packing

3. Smoking 3. Assembly for distribution

4. Drying Frozen product storage

5. Mixing (salad preparation)

Packaging

Final chilling

Storing raw material, in-process product

and finished product under refrigeration

QUESTIONS POSED FOR FURTHER RESEARCH • What are the exact role of potentiators, urocanic acid and other biogenic

amines in the disease? How do these work, both singly and in combination?

• Can elevation in histamine be detected by faster and portable methods?

• Can microbes be commercially used for detoxification of histamine? If yes

then which ones can? And how can they be utilised?

• How true is the hypothesis that HDB arise from post-catching

contamination?

• How to properly differentiate it from allergy?

• How does greater histidine content of these fish help in their physiology?

• How to develop faster, more efficient control strategies in compliance with

HACCP to eliminate HFP?

So on and so forth…….

THANK

YOU