We report the case of a patient, among a group of five, in a small outbreak of histamine fish poisoning (HFP). The epidemic character of the ailment led us to the correct diagnosis. In this case, the diagnosis was also associated with a Kounis syndrome (KS). Literature concerning this subject is reviewed, reporting recent physiopathological data

Botteldoorn, N.

Daube, G.

Denayer, S.

Ghuysen, A.

Gobert, S.

Marissiaux, L.

Scholtes, B.

Scippo, M.-L.

Open Marine Archive

© Acta Anæsthesiologica Belgica, 2018, 69, n° 2
Abstract : We report the case of a patient, among a 
group of five, in a small outbreak of histamine fish 
poisoning (HFP). The epidemic character of the ailment 
led us to the correct diagnosis. In this case, the diagnosis 
was also associated with a Kounis syndrome (KS).
Literature concerning this subject is reviewed, reporting 
recent physiopathological data.
Key words : histamine fish poisoning ; Kounis syn-
drome.
Case report
 A 50 years-old woman was admitted to 
the emergency department (ED) complaining of 
dizziness and discomfort experienced during a 
business lunch at a restaurant with four colleagues. 
The meal included a piece of tuna, grilled on one 
side. The fish was served with lettuce, tomatoes and 
white wine. Except from being slightly too spicy, 
the patient and her colleagues had no complaint 
regarding the taste of the meal. Ten minutes after 
starting to eat, the patient presented brutal facial 
flushing, with palpitations, headache, dizziness, and 
diffuse thoracic oppression. Curiously, the other 
participants developed concomitant symptoms at 
the same time, but to a lesser extent. The patient 
had no relevant past medical history, in particular, 
no known allergies and was not under any treatment 
at that time.
 At admission to the emergency department, 
the patient was quite anxious, had marked facial 
erythema and oedema (Fig. 1). She suffered from 
mild arterial hypertension with a heart rate of 150/
min. Arterial oxygen saturation was under normal 
range and lung examination was clear. She rapidly 
developed diffuse erythema, spreading downward 
without other cutaneous lesion, and her blood 
pressure fell to 85/40 mmHg.
 Arterial blood gas revealed respiratory 
alkalosis and mild increase in lactates at 170 mg/L. 
The electrocardiogram at admission (mild arterial 
hypertension) was abnormal with a sinus tachycardia 
and altered repolarization phases: ST segment 
depression in the inferior leads (Fig. 2). Point-
of-care ultrasound showed a small hyperkinetic 
left ventricle and collapsed inferior vena cava. 
Biologic blood tests remained normal except for a 
discrete troponin T elevation from < 5 ng/L to 14 
ng/L. The tryptase level remained normal. Urinary 
N-methylhistamine (a metabolite of histamine) 
could not be obtained by our laboratory.
 Hemodynamic recovery was rapidly obtained 
under treatment 0.5 mg intramuscular epinephrine, 
intravenous methylprednisolone and fluid-chal-
lenge. Oral cetirizine was also provided and, six 
hours later, the patient felt asymptomatic. Skin 
flushing and tachycardia disappeared and ECG 
abnormalities relieved. 
(Acta Anaesth. Belg., 2018, 69, 119-122)
(*) Emergency Department, Liège University Hospital, Liège, 
Belgium
 (**) Department of Food Sciences, FARAH, University of 
Liège, Liège, Belgium
 (***) National Reference Laboratory of foodborne pathogens, 
Scientific Institute of Public Health, Brussels, Belgium
 (****) Laboratoire d’Océanographie Biologique, MARE, 
FOCUS, STARESO, University of Liège, Liège, Belgium
 (*****) Researcher, Department of Public Health, Nutrition, 
Environment and Health, University of Liège, Liège, 
Belgium
Corresponding author : Laurent Marissiaux, MD, Emergency 
Department, CHU de Liège, av. de l’Hôpital, 1, 4000 Liège, 
Belgium.
E-mail : laurent.marissiaux@chuliege.be
An awkward fishing expedition
L. Marissiaux (*) , M.-L. scippo (**), G. Daube (**), s. Denayer (***), n. botteLDoorn (***), 
s. Gobert (****), b. schoLtes (*****), a. Ghuysen(*)
Fig. 1. — Facial erythema, downward diffusing.
Marissiaux.indd   119 2/07/18   12:08
© Acta Anæsthesiologica Belgica, 2018, 69, n° 2
120 L. Marissiaux et al. 
receptors leads to the release of neurotransmitters 
in the central nervous system, responsible for 
headaches and vomiting. H4 receptors are the 
immune system’s histamine receptors and their role 
in HFP is undetermined (2).
 While the precise physiopathological mecha-
nisms of HFP remain incompletely understood, 
several mechanisms of toxicity have been proposed 
in the literature (2). HFP is not simply a pure 
histamine intoxication. Scombroid food poisoning 
has a higher toxicity than equivalent dose-related 
pure histamine (2). Additionally, other biogenic 
amines derived from spoiled fish, may play a 
role as facilitating agents, potentiating histamine 
absorption in the gut and preventing its metabolism. 
Agents such as putrescine and cadaverine have been 
implicated but others may also be involved (3).
 Several authors have argued that another 
hypothesis explaining the dose/response abnorma-
lities of scombroid poisoning could be the presence 
of unknown histamine receptors agonists in spoiled 
fish (1, 2). Furthermore, individual HFP sensitivity 
appears variable, resulting in a wide range of clinical 
presentations among patients sharing the same 
meal (2). Such variety could arise from differences 
in the catabolism rate of histamine, affecting the 
duration and severity of symptoms. It must be 
noted that several drugs may exhibit inhibiting 
effects on histamine-metabolizing enzymes, such 
as mono-amine oxidase inhibitors and isoniazide 
(1). Alcoholic beverages may also increase the 
severity of the episode by enhancing the absorption 
of histamine contained in the meal (4).
 Small amounts of histamine are present in a 
large number of foodstuffs. In healthy individuals, a 
normal amount of dietary histamine is well tolerated 
and metabolized in the gut (11). Some patients 
have reduced gut enzymatic barriers and may 
develop histamine-related symptoms with peculiar 
ailments. Table 1 shows the most common sources 
of histamine.
Diagnosis
 The diagnosis of HFP in the emergency 
department is mainly based on clinical features. 
Symptoms usually occur 10 to 60 minutes after meal 
ingestion, the most common being facial flushing, 
abdominal pain, diarrhoea and headache (2). Other 
symptoms may include vomiting, dyspnea, flushing 
of the torso or the whole body. In rare cases, 
symptoms may even become more severe, with 
bronchospasm, respiratory distress, hypotension 
and shock, mainly in patients with pre-existing 
Further bacteriological cultures and analyses from 
samples of the tuna fish revealed Enterobacteriaceae 
(5.8 103 CFU/g) and Pseudomonas (> 1.5 107 
CFU/g) colonisation, together with high histamine 
level at 4400 mg/kg (4400 parts per million, 
ppm), 44 times the authorized European upper 
limit (COMMISSION REGULATION (EC) No 
2073/2005 of 15 November 2005 on microbiological 
criteria for foodstuffs)
DisCussion
Physiopathology
 Although histamine Fish Poisoning (HFP), or 
Scombroid Fish Poisoning, was initially described 
in 1799, it remains under-recognized and often 
misdiagnosed as IgE-mediated fish allergy (1). This 
condition is the result of an ingestion of histamine-
contaminated fish of the Scombroidae and 
Scomberesocidae families, such as mackerel, tuna, 
bonito or skipjack. Other families of fish (herring, 
anchovies, sardines) have been also implicated, and, 
in rare cases, cheese (1). Most of these contain high 
levels of free histidine, a natural amino acid (2). Due 
to poor freezing conditions, bacteria from the gills 
and gastrointestinal tracts or from the surrounding 
environment may appear to grow, while some 
types, such as Morganella, Proteus, Enterobacter, 
Serratia, Citrobacter, Pseudomonas… present 
histidine-decarboxylase activities, responsible for 
converting histidine into histamine, that further 
accumulates in fish’s flesh. Once histamine is 
formed, the compound is very resistant to cooking, 
freezing, and smoking (1).
 Histamine can be absorbed via the patient’s 
gastro-intestinal tract and binds to four different 
receptor subtypes (H1 to H4) leading to pathological 
effects (2).
 H1 and H2 receptors mediate cutaneous and 
cardiovascular symptoms while activation of H3 
Fig 2. — First ECG.
Marissiaux.indd   120 2/07/18   12:08
© Acta Anæsthesiologica Belgica, 2018, 69, n° 2
 an awkwarD fishing expeDition 121
(carcinoid tumors, …) or rare conditions like IgE 
mediated anaphylaxis to Anisakia larvae (a parasite 
infesting a fish’s flesh and transmitted to humans via 
the ingestion of raw fish) (1).
Prevention and treatment
 The main issue concerning HFP relies on 
prevention measures and food safety. In that per-
spective, fish destined for human consumption 
should imperatively be stored at low temperatures, 
uninterrupted from fishing to cooking, to prevent 
bacterial growth and histamine-decarboxylase acti-
vity (1). Complete cooking of fish or shellfish is the 
only way to avoid Anisakiasis. The best prevention 
of Ig-E mediated fish allergy is avoidance (6).
 With regards to HFP therapy, oral H1 
blockers are effective against mild to moderate 
cases (5). For more severe symptoms, intravenous 
treatment is preferred, if available. Should the 
patient present hypotension, intravenous fluids 
and methylprednisolone may be used, but in more 
severe reactions with shock, epinephrine (IM or IV) 
could be needed (1).
Kounis Syndrome
 Kounis Syndrome (KS), is an acute coronary 
syndrome related to coronary vasospasm in the 
setting of an allergic or hypersensitivity reaction.
Cerebrovascular and mesenteric vascular events 
have also been reported (6). This syndrome is 
consecutive to an inflammatory cascade involving 
several mediators such as histamine, PAF, cytokines 
and chemokines… (6). 
 There is a possible overlap in the mechanism 
between vasospasms and other coronary related 
ischemic cardiac events. Kounis syndrome with 
plaque rupture and/or stent thrombosis have been 
described and need to be considered in the event of 
coronary events during hypersensitivity reactions. 
Histamine and others inflammatory mediators are 
found to be elevated in both acute allergic reactions 
and in patients with acute, non-allergic, coronary 
syndrome (9).
 Various triggers have been recognized that have 
the potential to prompt this cascade. Among these, 
food intake (fruits, vegetables, canned food, shellfish 
and fish) is certainly the most frequent condition 
associated with the syndrome (7). Other triggers 
have been described, such as drugs (gelofulsine, 
vaccines with gelatine, antibiotics, anaesthetic 
agents, NSAIDs, anti-cancer drugs, lozartan and 
corticosteroids) (6), but also environmental:  insect 
bites (8), latex, etc.
asthma or heart diseases (1). Clinical suspicion 
should be confirmed through biological dosage, 
revealing normal tryptase levels, no elevation in 
urinary PGD-M excretion (a metabolite of the mast 
cell activation, releasing histamine) but elevated 
urinary histamine, and N-methyl histamine, its 
metabolite (5). N-methylhistamine (NMH) is the 
major metabolite of histamine. Because of its longer 
half-life, its urinary measurements have superior 
sensitivity and specificity than histamine, the 
parent compound, notably in patients with urticarial 
pigmentosa, systemic mastocytosis, or mast cell 
activation. While average diet has no effect on 
urinary NMH, elevations may be observed in case 
of histamine-rich meal. It should also be mentioned 
that patients taking monoamine oxydase inhibitors 
may also have increased levels of urinary NMH. 
 However, the definitive confirmatory test 
remains the dosage of histamine in the suspected 
piece of fish. The higher the level of histamine, 
the higher the probability that the patient develops 
HFP symptoms. The European permitted cut-
off is 100 ppm. In most studies focussing on this 
poisoning, levels of histamine as high as 1000 
ppm were found (4), but symptoms may develop 
at lower concentrations, due to the heterogeneity of 
individual sensibilities. 
 In Belgium, over the last seven years (2010-
2016), 51 cases of confirmed HFP were reported, 
for a total number of foodborne outbreaks patients 
of 13,997.  During that period, only 10 patients 
were hospitalized due to HFP and no deaths were 
attributed to this condition (National Reference 
Laboratory of foodborne pathogens, scientific 
institute of public health, WIV-ISP). 
 When managing cases of HFP, several dif-
ferential diagnoses should be considered.  Distinction 
between HFP and IgE-mediated allergic reaction to 
fish (or to other ingredients of the meal) may be 
challenging. Apart from the epidemic aspect of HFP, 
usually affecting several patients simultaneously, in 
allergic reactions the patient frequently has a history 
of allergies. Symptoms tend to be more prolonged 
and serum tryptase level is elevated. 
 HFP is related to the ingestion of fish conta-
minated by (usually a large amount of) histamine. 
Other foodstuffs may induce non-allergic adverse 
food reactions, like tomatoes, chocolate or berries, 
causing less severe symptoms, related to histamine-
like or histamine-releasing compounds. Alcohol may 
also be the cause of flushing disorders by individuals 
with Alcohol Deshydrogenase deficiency (10). 
 Other conditions should also be considered, 
such as myocardial infarction, flushing disorders 
Marissiaux.indd   121 2/07/18   12:08
© Acta Anæsthesiologica Belgica, 2018, 69, n° 2
122 L. Marissiaux et al. 
ConClusions
Although HFP is a common food-related poisoning, 
its diagnosis appears to be frequently ignored and 
underestimated as it may present like a classical 
food-allergy. First line practitioners should be 
aware of this specific condition and should alert 
food hygiene public services whenever it occurs in 
order to address the root cause and prevent further 
cases.
References
1. Feng C, Teubert S. and Gershwin M.E. 2016. Histamine 
(scromboid) Fish Poisoning : a comprehensive review. 
Clinic Rev. Allerg. Immunol. 50 : 64-69.
2. Hungerford JM. 2010.  Scombroid poisoning: a review. 
Toxicon. 56 : 231-243.
3. Anastasius M. and Yannikas J. 2015.  Scombroid fish 
poisoning illness and coronary artery vasospasm. Astralas 
Med. J. 8 : 96-99. 
4. Colombo F.M., Cattaneo P., Confalonieri E. and Bernadi C. 
2018. Histamine food poisonings: A systematic review and 
meta-analysis . Crit. Rev. Food Sci. Nutr., 58 : 1131-1151.
5. Morrow J.D, Margolies G.R., Rowland J. and Roberts L.J. 
1991. Evidence that histamine is the causative toxin of 
scombroid-fish poisoning. NEJM 32  : 716-719.
6. Kounis N.G. 2016. Kounis syndrome: an update on 
epidemiology, pathogenesis, diagnosis and therapeutic 
management. Clin. Chem. Lab. Med.,  54 : 1545-1559.
7. Kounis N.G., Patsouras N., Grapsas N. and Hahalis G. 
2015. Histamine induced coronary artery spasm, fish 
consumption and Kounis syndrome. Int. J. Cardiol. 193 : 
39–41.
8. Abdelghany M., Subedi R., Shah S. and Kozman H. 
2017. Kounis Syndrome: A review article on epidemioly, 
diagnostic findings, management and complications of 
allergic acute coronary syndrome. Int. J. Cardiol. 232 : 1-4.
9. Kounis N.G. 2006 Kounis syndrome (allergic angina and 
allergic myocardial infarction): A natural paradigm? Int. J. 
Cardiol. 11 : 7-14.
10. Sampson H.A. 1986. Differential diagnosis in adverse 
reactions to foods. J. Allergy Clin. Immunol.78 : 212-219.
11. Kovacova-Hanuskova E., Buday T., Gavliakova S. and 
Plevkova J..2015. Histamine, histamine intoxication and 
intolerance. Allergol. Immunopathol . 43 : 498-506.
 The diagnosis of Kounis syndrome is usually 
based on a clinical examination and further 
confirmed using various technical exams. The main 
presenting symptom is chest pain (86%) which 
may be associated with palpitations and dyspnea 
and, often, allergic manifestations (8), while ECGs 
and biological testing reveal cardiac ischemic 
abnormalities. 
 Three variants of the Kounis syndrome have 
sometimes been proposed, and, in that perspective, 
the occurrence of a Kounis syndrome including 
histamine food poisoning by fish and food in 
general, might interrogate the existence of a type IV 
variant. However, the classical description of Kounis 
syndrome only stands for a coronary vasospasm in 
the setting of an allergy or hypersensitivity reaction.
 The variant of KS, proposed by Kounis, are the 
following (8) :
1. Type I is the most common and is characterized 
by coronary artery spasm. Cardiac biomarkers may 
remain normal. There is no underlying coronary 
artery disease
2. Type II is associated with vasospasm and 
plaque erosion or rupture, in patients with known 
coronary artery disease or risk factors.
3. Type III is associated with coronary artery 
stent thrombosis.
 The best practice treatment for type I is the 
management of the associated allergic disorders. 
Calcium channel blockers or nitrates can be useful 
in order to release the vasospasm. In type II variant, 
treatment should associate classical management 
of the acute coronary syndrome, with coronary 
angiography and angioplasty if required, and anti-
allergic drugs. Intra-stent thrombus aspiration is 
very important in type III variant. Indeed, apart 
from coronary artery reperfusion, this approach 
allows the histological examination of the thrombus, 
confirming its allergic origin.
Naturally occurring histamine in 
larger quantities
Tomatoes, eggplant, spinach, fish, chicken and every stored meat. All fermented food (cheeses, sausages, 
sauerkraut, wine, beer, champagne).
Natural histamine liberators  Pineapple, bananas, citrus fruits, strawberries, nuts, papaya, liquorice, spices, legumes, cocoa, seafood, pork, 
egg white.
Histamine liberators of artificial 
origin 
Additives (food coloring, preservatives, stabilisers, taste enhancers, flavourings …).
Natural histamine liberator and 
inhibitor of its metabolism
Alcohol.
Scombroid poisoning Spoiled finfish from the Scombroidae and Scomberesocidae families, such as tuna, mackerel, skip-jack, and 
bonito. Other types of fish, such as mahi-mahi (dolphin fish), bluefish, amberjack, swordfish, marlin, herring, 
sardines, anchovies, salmon, tilapia, and trout and contaminated Swiss cheese.
Table 1.
The most common sources of histamine [adapted from . E. Kovacova-Hanuskova et al. (11)].
Marissiaux.indd   122 2/07/18   12:08


An awkward fishing expedition

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