A. Case study
A 40-year old man experienced a couple of episodes of acute, generalized urticaria within minutes of having a meal that included tuna. He had eaten tuna before on many occasions without any adverse reactions and therefore assumed that it was something else in the meal that caused the reaction. He continued to eat tuna after that and did not experience urticaria every time. In total, he reacted 3 times after the initial reaction and twice failed to react. This occurred over a period of 20 months and involved more or less the same amount of tuna every time. He did not react to physical contact with fish and did not eat canned tuna.

The patient had never shown any type of reaction to any other fish species. His wife, being a dietitian, monitored his dietary intake carefully, trying to determine whether there was a correlation between his dietary intake and the reactions.

THOUGHT PROCESS:
What could be the possible causes for his reaction?
a. He was reacting to the tuna.
b. He was reacting to something else in the meal.
c. He was reacting to something in the environment while he was eating the meal.

The wife could not pick up any other element than tuna in the meal that was consistently associated with the reaction. Also, the environment could not give any clues. Three out of the 4 reactions occurred after eating tuna in a specific restaurant, but he also ate tuna there without any reaction.

THOUGHT PROCESS:
Could one react to tuna on one occasion and not the next? What type of reaction could it be? An allergy, intolerance or toxic reaction?

POSSIBILITIES:
Allergy:
a. He was reacting to a heat-labile allergen in tuna. The fish may not have been cooked through on the occasions that he reacted to it.
b. The fish he was eating was not always tuna (although he thought it was), i.e., he was truly allergic to tuna, but at the times he did not react to the "tuna", he was eating another type of fish.
c. The preparation method was not always the same (e.g., on some occasions spices were added, and these caused his reaction).

Intolerance:
d. He reacted to histamine in tuna, as histamine intolerance can present with allergy-like symptoms. The fish may not have been stored properly on the occasions that he reacted to the tuna, so as to have increased levels of histamine.

Toxic reaction:
e. Whatever induced his reaction (e.g., bacteria or toxin) was "contaminating" the fish and would therefore not always be present in all tuna.

RESULTS:
a. This could be possible. To determine if it was the case, a serum-specific IgE test to tuna could be done.
b. This was not the case.
c. This was not relevant.
d. If the patient was sensitive to histamine and he had not reacted to other histamine-containing foods before, it would indicate that he reacts to a high dose of histamine. On the occasions that he reacted to tuna, the fish could have contained high levels of histamine (indicating that it had been improperly stored). But the restaurant owner claimed that the fish that he served were freshly caught and served. This possibility was thus excluded.
e. If he were reacting to a contaminant, then others eating the same meal in the restaurant would also have been affected.

It was decided to measure his total IgE and serum-specific IgE test to tuna. The total IgE was increased, but the IgE to tuna was normal.

What did this indicate?
He was definitely sensitized to something, but it was not tuna. The wife decided to contact specialists in the field and was told to consider an allergy to Anisakis simplex. Allergy to this fish parasite is quite common and is difficult to distinguish from regular allergy to fish. A serum-specific IgE test to this parasite was performed and confirmed the diagnosis.

TIP for Allergy Advisor users: Allergy Advisor would been useful in the assessment of this patient. Entering "fish" into the search function of Allergy Advisor will bring up information, for example that Anasakis simplex and other contaminants may be present and could be the cause of a reaction. Looking under "tuna" specifically, the following information could be obtained: "Possible additional constituents" indicate that there is an association with tuna and histamine/scromboid poisoning, tartrazine can be present in canned tuna even though it is not labeled as such and reactions are possible to raw and cooked tuna. From there one could find more information on histamine, etc.

B. More information:
Many people associate adverse reactions to fish only with allergy. But there are in fact many types of reactions to fish, including (see lettered sections, here indicated in parentheses, for more information):

• Allergy:


• Allergy to allergens inherent in the flesh of fish


• Allergy to parasites present in fish, e.g., Anisakis simplex (a)


• Allergy to iodine, of which fish is a rich source of (b)


• Intolerance:


• Histamine sensitivity/scromboid poisoning (c)


• Unabsorbable substances, e.g., wax esters in certain species of fish (d)


• Toxic reactions:


• Ciguetera poisoning (e)


• Heavy metal toxicity, e.g., methyl mercury (f)


• Parasitic infestation, e.g., Anisakis simplex (a)


• Bacterial and viral contamination, e.g., salmonella (g)

This newsletter will give a brief overview of some of these reactions other than the regular fish allergy. Some of the topics are discussed in more detail, according to how common the problems are and how much is known about them.

a. ADVERSE REACTIONS TO ANISAKIS SIMPLEX
Anisakis simplex or cod worm is a seafood-borne parasite that can cause two major problems in humans: infection (anisakiasis) and allergic reactions. Various studies have shown that 5-80 % of fish samples are infested by Anisakis (mainly freshwater fish). It first inhabits the gut of the fish, but migrates into other tissues when the fish's temperature rises as a result of storage conditions.^1,2

1. Allergy:
Adverse reactions have been recorded to ingesting or inhaling the Anisakis allergen(s) due to an IgE-mediated allergic reaction.³ A study in Spain found that allergy to Anisakis was more frequent than fish allergy and sensitization much higher.⁴ Allergic reactions to this parasite should be suspected when allergic-like reactions occur after eating seafood, yet the results of serum-specific tests to seafood are normal. Reactions often occur intermittently after eating seafood rather than on every occasion.

Deep-freezing at -20 degrees Celsius for more than 48 hours and cooking at temperatures higher than 60 degrees Celsius for 10 minutes is important in protecting against infection with live parasites, but may not protect against reactions to their allergens.^5,6 The heat-stability of Anisakis allergens has been demonstrated,⁷ even though there have been reports of sensitized individuals (with a history of severe allergic disease to the parasite) who did not react to the dead larvae.² The clinical reality is that sensitized individuals may react to cooked, frozen or canned fish.⁷

IgE-mediated reactions that have been reported include urticaria, angiodema, anaphylaxis, asthma,^4,7,8,9 and eczema.¹⁰ Occupational exposure upon inhaling particles of Anisakis simplex (through cutting fish and inhaling fish flour) have been recorded to cause conjunctivitis (perennial itching, burning and redness of eyes with increased tearing)¹¹ and asthma.¹²

2. Infestation:
If an individual is infected by this parasite, it can lead to anisakiasis or anisakidosis (herring or cod worm disease)¹³, an acute or chronic disease involving mainly the digestive tract. It only affects those who consume raw or undercooked parasitized fish.³ As noted, deep-freezing or cooking infected fish at appropriate temperatures is necessary to protect against infection.⁶

b. IODINE ALLERGY
Fish is a good dietary source of iodine. Fish allergy and iodine allergy are independent of each other.

c. HISTAMINE SENSITIVITY
Histamine is a vasoactive amine that can induce allergy-like symptoms in sensitive individuals. The reactions, however, are not IgE-mediated, but of an intolerance type reaction.¹⁴

Histamine may occur naturally at different concentrations in some foods such as fish, wine and cheese. The level present in fish can increase when fish is improperly refrigerated or refrigeration is delayed (even though the fish is not rancid). Histidine (naturally present in fish) is converted by histidine decarboxylase to histamine at an optimal temperature of 20-30 degrees Celsius. The longer fish is improperly stored and remains ungutted, the higher the histamine content.^15,16,17 Fish involved include mackerel, tuna, herring, sardines, marlin, anchovies and bluefish. Affected fish often have a metallic or peppery taste.¹⁸

Histamine levels in freshly-caught fish are less than 1mg/100g of fish, but if the fish is left at room temperature can increase to up to 100mg histamine/100g of fish within 12 hours.¹⁷ Hazardous levels are thought to be 50mg histamine/100g or more.¹⁶ But it is important to note that high levels of histamine do not necessarily occur in fish that are rancid.

The term "scromboid poisoning" originates from the fact that spoiled fish from the family Scombridae (e.g., tuna, mackerel and bonito) were originally implicated in incidents of this type of poisoning. But it is not the only fish that can cause histamine reactions.^16,17,19

Some studies have shown that histamine-intolerant individuals have a deficiency of the enzyme, diamine oxidase, in the jejunal mucosa, resulting in diminished histamine degradation and absorption in the gastrointestinal tract. In pregnancy, diamine oxidase levels are known to be about 500-fold elevated.²⁰ Up to 94 drugs have been shown to inhibit diamine oxidase, including dihydralazine, isoniazid, clavulanic acid, promethazine, verapamil and metoclopramide. Alcohol is seen as a histamine liberator, i.e., it can enhance the effect of histamine in sensitive individuals.²¹

The onset of the symptoms usually occurs within a few minutes after ingestion of the food, and the duration of symptoms ranges from a few hours to 24 hours. Reactions that have been recorded to histamine are flushing, headache, dizziness, burning sensation in the mouth and throat, peppery taste, abdominal cramps, nausea, vomiting, diarrhoea, urticaria, generalised pruritis, sneezing, bronchospasm, asthma, respiratory distress, hypotension and eczema.^17,22 Histamine has also been implicated as an important mediator in certain types of headaches that are thought to differ from migraine and tend to be located to one side of the head and face.¹⁵

d. UNABSORBABLE WAX ESTERS IN FISH
The passage of oil through the rectum has been observed following the ingestion of "butterfish": a food idiosyncrasy. There have only been a few articles in the literature on this subject: 1 in a South African journal²³ and 3 in one issue of Communicable Diseases Intelligence in 2002^24,25,26. The latter journal's articles reported 3 "outbreaks" in Victoria. There has also been one similar communication from New South Wales in October 2001. Following media reports on this issue in Australia, there have been numerous additional reports (60 before 2002).²⁷

Dr. Harris Steinman (one of the editors of this newsletter) has, while lecturing, asked his audience on several occasions how many of them have experienced this before. Around half would put up their hands. There is probably a significant under-reporting of this condition, as the symptoms can be mild and short-lived.²⁷ But for some affected individuals, they can be quite dramatic and embarrassing (as discussed below). Also, the incidence is likely to be increasing as butterfish is eaten more commonly.

In the studies, there is some confusion about the correct names of the fish that cause this passage of oil per rectum. The following points have to be considered:

To illustrate the similarities between Ruvettus pretiosus, Lepidocybium flavobrunneum, Centrolophus niger and Tubbia sp. (provided by Don Nichols of the West Australian Seafood Quality Management Initiative):

Figure 1. Oilfish, Ruvettus pretiosus	Figure 2. Escolar, Lepidocybium flavobrunneum
Figure 3. Rudderfish, Centrolophus niger	Figure 4. Rudderfish, Tubbia sp.

In one article, a study was performed in which two of the authors consumed about 500g each of the baked flesh of the fish. After 12 symptom-free hours, oil began to be passed per rectum. It was difficult to contain the oil that was pooling in substantial quantities in the lower rectum, and therefore frequent evacuation was required. These calls of nature were generally prophylactic visits to avoid soiling of clothing, and were not for the most part caused by sheer inability to retain rectal contents. Or this was, at any rate, the testimony of the subjects.²³

Approximately 10ml of pure oil was passed per occasion. The oil was a clear orange or green in colour. It was inoffensive and mostly not contaminated significantly by faecal material. Because most experiences occurred in the absence of any bowel cramps or abdominal discomfort, this would imply that the frequent calls to stool were caused by the lubricant effect of the oil, and not by an irritant action. This could therefore not be diarrhoea, theoretically. Diarrhoea is defined as a more rapid passage and fluidity of faecal material. The name keriorrhoea was given (the greek word, keras, meaning "wax" and diarrhein meaning "to flow through").²³

The symptoms described in other articles show wide variation. Symptoms ranged from mild and rapid passage of oily yellow or orange droplets, to severe diarrhoea with abdominal pain, nausea, headache and vomiting. In those who are susceptible, the onset of symptoms occurs at a median of 2.5 hours and within a range of 1 to 90 hours after consumption. Most people recovered within 24 hours.^24,26,27

Why does this occur?
Escolar (this name may refer to oilfish as well: see above) and true rudderfish contain very high levels of oil (generally between 14 to 25% of wet mass) in the fillet. Escolar oil contains mainly wax ester (>90% of oil). The oil from rudderfish contained mainly diacylglyceryl ether (DAGE, >80% of oil) or hydrocarbon (>80% of oil, predominately squalene).²⁸

The oil composition of fish fillet samples was consistent with culprit foods being escolar rather than rudderfish species. Even though rudderfish species contain similar proportions of oil, they do not contain the indigestible wax ester seen in escolar and oilfish.²⁷ The high proportion of wax esters in the flesh of the fish, their resistance to digestive enzymes, and their low melting point all contribute to the pooling in the rectum of significant volumes of oil. And it is the oil's lubricant quality that then causes the frequency of stooling.²³

Wax esters consist of fatty acids esterified to similarly long-chain alcohols. Such compounds are found in animal, plant and microbial tissues and they have a variety of functions, such as energy storage, waterproofing and even echo-location. The ultimate source of the wax esters (or at least the fatty alcohol component) is likely to be zoöplankton. Most predators of zoöplankton such as the herring, sardine and baleen whale do not accumulate wax esters. It has been presumed that these animals cannot metabolise the wax esters. Other wax-accumulating vertebrates are the coelacanth (Latimeria chalumnae) and the sperm whale.²³

There are little data available to identify people susceptible to this type of oily diarrhoea. One study could find no association between the development of the symptom and body mass index, age or general health status. Researchers found, however, that individuals with bowel problems, malabsorption or pregnancy may be at increased risk. It is also possible that seasonal and geographic differences may influence the level of indigestible wax ester content in fish.^26,27

Despite the majority of effects being mild, warnings have been released in some jurisdictions indicating that these fish are not suited for catering and should be avoided by those in the high-risk category. Those eating the fish for the first time should be advised to, initially, consume small portions to determine their susceptibility.²⁷

There have been reports of toxic effects in experimental animals but not in humans. Although many who experience this phenomenon are concerned by its effects (including social embarrassment and having to throw away clothes soiled with the oil), the condition appears to be medically harmless with the quantities that are normally consumed.²³

e. CIGUETERA POISONING
Ciguetera poisoning is triggered by eating tropical reef fish that have fed on toxic algae, which produce a neurotoxin. This poisoning causes more human illnesses than any other seafood toxicity. As larger reef fish feed on smaller ones, the toxin concentrates in the organs of larger fish such as red snapper, barracuda, sea bass, eels and kingfish. Because the toxin is heat-stable, it is unaffected by cooking. Symptoms of this neurotoxin present primarily as an acute neurologic disease with gastrointestinal symptoms. Most people recover within a few days or weeks with supportive treatment, but ongoing disability has occasionally been described.^13,18

f. HEAVY METAL TOXICITY
Although several metals can accumulate in fish, mercury is the most common. Mercury is a naturally occurring element, found in soil and rocks and also in lakes, streams and oceans. It is also released into the environment by human activities. The mercury in lakes, streams and oceans can be transformed by bacteria into methyl mercury, an organic and more toxic form. This form of mercury is the predominant form present in the flesh of fish, and humans are exposed to it when ingesting the fish. High levels of mercury can damage the nervous system, but the effects of trace amounts are not known. Long-term studies are being conducted to determine the effects of low levels of mercury, especially in young children.^29,30

Since methyl mercury tends to concentrate or "bioaccumulate" through the food chain, predator fish species tend to have higher levels than non-predator fish species. In some countries the public is advised to limit consumption of shark, marlin, swordfish and fresh and frozen tuna. Pregnant women, women of childbearing age and young children should limit their intake even more.29,30

g. BACTERIAL CONTAMINATION
Seafood poisoning outbreaks have frequently been associated with bacterial contamination (such as Salmonella) of shellfish harvested in waters containing untreated sewage.¹³

compiled by Karen du Plessis B.Sc. Diet. karen@allergyadvisor.com Food & Allergy Consulting & Testing Services (FACTS) PO Box 565 Milnerton 7435 South Africa

C. Comments by our editor

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D. References
1. Ikeda K, Humashio R, Kifune T. Nine cases of acute gastric anisakiasis. Gastrointest Endosc 1989;35:304-8.
2. Valinas B, Lorenzo S, Eiras A, Figueiras A, Sanmartin ML, Ubeira FM. Prevalence of and risk factors for IgE sensitization to Anisakis simplex in a Spanish population. Allergy 2001;56(7):667-71.
3. Moneo I, Caballero ML, Gomez F, Ortega E, Alonso MJ. Isolation and characterization of a major allergen from the fish parasite Anisakis simplex. J Allergy Clin Immunol 2000;106(1):177-82.
4. Del Pozo MD, Audicana M, Diez JM, Munoz D, Ansotegui IJ, Fernandez E, et al. Anisakis simplex, a relevant etiologic factor in acute urticaria. Allergy 1997;52(5):576-9.
5. Audicana L, Audicana MT, Fernandez de Corres L, Kennedy MW. Cooking and freezing may not protect against allergenic reactions to ingested Anisakis simplex antigens in humans. Vet Rec 1997;140(9):235.
6. Audicana MT, Fernandez de Corres L, et al. Recurrent anaphylaxis caused by Anisakis simplex parasitizing fish. J Allergy Clin Immunol 1995;96:558-60.
7. Montoro A, Perteguer MJ, Chivato T, Laguna R, Cuellar C. Recidivous acute urticaria caused by Anisakis simplex. Allergy 1997;52(10):985-91.
8. Estrada Rodriguez JL, Gozalo Reques F. Sensitization to Anisakis simplex: an unusual presentation. Allergologia et Immunopathologia 1997;25(2):95-7.
9. Fernandez de Corres L, Audicana M, et al. Anisakis simplex induces not only anisakiasis: report on 28 cases of allergy. J Investig Allergol Clin Immunol 1996;6(5):315-9.
10. Conde-Salazar L, Gonzalez MA, Guimaraens D. Type I and Type IV sensitization to Anisakis simplex in 2 patients with hand eczema. Contact Dermatitis 2002;46(6):361.
11. Anibarro B, Seoane FJ. Occupational conjunctivitis caused by sensitisation to Anisakis simplex. J Allergy Clin Immunol 1998;102:331-2.
12. Armentia A, Lombardero M, Callejo A, Martin Santos JM, et al. Occupational asthma by Anisakis simplex. J Allergy Clin Immunol 1998;102(5):831-4.
13. http://www.scienceinafrica.co.za/2001/november/allergy.htm
14. Taylor SL. Histamine food poisoning: toxicology and clinical aspects. Crit Rev Toxicol 1986;17(2):91-128.
15. Joneja JV. Dietary management of food allergies and intolerances - a comprehensive guide 2nd edition. J.A. Hall Publications Ltd., USA, 1998.
16. Sanchez-Guerrero IM, Vidal JB, Escudero AI. Scromboid fish poisoning: A potentially life-threateninng allergic-like reaction. J Allergy Clin Immunol 1997;100(3):433-4.
17. Muller GJ, Lamprecht JH, Barnes JM, et al. Scombroid poisoning. Case series of 10 incidents involving 22 patients. S Afr Med J 1992;81(8):427-430.
18. http://www.allergycapital.com.au/Pages/seafood.html
19. Taylor S, Stratton J, Nordlee J. Histamine poisoning (scromboid fish poisoning): An allergy-like intoxication. Clin Toxicol 1989;27:225-240.
20. Jarisch R, Wantke F. Wine and headache. Int Arch Allergy Immunol 1996;110(1):7-12.
21. Serghini-Idrissi N, Ravier I, Aucouturier H, Ait Tahar H, Sonneville A. Food allergy in the chronic alcoholic and alcohol in food allergy: apropos of 38 cases. [French] Allerg Immunol (Paris) 2001;33(10):378-82.
22. Wantke F, Hemmer W, et al. Histamine in wine. Bronchoconstriction after a double-blind placebo-controlled red wine provocation test. Int Arch Allergy Immunol 1996;110(4):397-400.
23. Berman P, Harley EH, Spark AA. Keriorrhoea - the passage of oil per rectum - after ingestion of marine wax esters. S Afr Med J 1981;59(22):791-2.
24. Gregory J. Outbreaks of diarrhoea associated with butterfish in Victoria. Commun Dis Intell 2002;26:439-440.
25. Givney RC. Illness associated with rudderfish/escolar in South Australia. Commun Dis Intell 2002;26:440.
26. Yohannes K, Dalton CB, Halliday L, Unicomb LE, Kirk M. An outbreak of gastrointestinal illness associated with the consumption of escolar fish. Commun Dis Intell 2002;26:441-445.
27. http://www.health.gov.au/pubhlth/cdi/cdi2603/html/cdi2603i.htm
28. Nichols P, Mooney B, Elliot N. Unusually high levels of non-saponifiable lipids in the fishes escolar and rudderfish: identification by gas and thin-layer chromatography. J Chromatography 2001;936:183-191.
29. http://www.hc-sc.gc.ca/english/protection/warnings/2002/2002_41e.htm
30. www.cfia-acia.agr.ca/english/corpaffr/foodfacts/mercurye.shtml

E. CPD Questions (South Africa, Australia)

This CPD session is now closed. Please contact karen@allergyadvisor.com for more information.

PLEASE ANSWER ALL THE QUESTIONS
(There is only one correct answer per question.)
1. How can one become exposed to Anisakis simplex?
(a.) Ingesting raw fish containing Anisakis simplex.
(b.) Ingesting cooked fish containing Anisakis simplex.
(c.) Inhaling the allergen when cutting fish.
(d.) All of the above.

2. Which of the following will not protect against human infestation with Anisakis simplex?
(a.) Deep-freezing at -20 degrees Celsius for more than 48 hours
(b.) Cooking at temperatures higher than 60 degrees Celsius for 10 minutes
(c.) Keeping sushi at fridge temperature until it is served
(d.) None of the above

3. Which of the following is true?
(a.) All histamine-sensitive individuals will react to the normal level of histamine that is normally found in foods
(b.) No histamine-sensitive individual will react to a histamine dose of lower than 50mg histamine/100g fish
(c.) Some histamine-sensitive individuals may react to only large doses of histamine
(d.) None of the above

4. Which of the following does not have an effect on the level of histamine that affects a sensitive individual?
(a.) Pregnancy
(b.) Age
(c.) Drugs such as dihydralazine, isoniazid, clavulanic acid, promethazine, verapamil and metoclopramide
(d.) Alcohol

5. Which of the following fish are truly responsible for inducing keriorrhoea?
(a.) Escolar, oilfish and rudderfish
(b.) Escolar and oilfish
(c.) Escolar and rudderfish
(d.) Oilfish and rudderfish

6. To what in the flesh of the fish can kerriorrhoea be attributed?
(a.) The high levels of oil content
(b.) The indigestible wax ester content
(c.) The fact that the oil in the fish mainly comprises diacylglyceryl ether or hydrocarbon
(d.) The presence of parasites

7. True or false: The main feature of Ciguetera poisoning in humans is acute nephrotic syndrome.
(a.) True
(b.) False

8. For what reason is the intake of shark, marlin, swordfish and tuna restricted in pregnant women, women of childbearing age and young children specifically?
(a.) Histamine content
(b.) The risk of Ciguetera poisoning
(c.) Methyl mercury content
(d.) Iodine content

1. a [ ] b [ ] c [ ] d [X]		2. a [ ] b [ ] c [X] d [ ]		3. a [ ] b [ ] c [X] d [ ]
4. a [ ] b [X] c [ ] d [ ]		5. a [ ] b [X] c [ ] d [ ]		6. a [ ] b [X] c [ ] d [ ]
7. a [ ] b [X]		8. a [ ] b [ ] c [X] d [ ]

1. d. All of the above
2. c. Keeping sushi at fridge temperature until it is served.
3. c. Some histamine-sensitive individuals may react to only large doses of histamine
4. b. Age
5. b. Escolar and oilfish
6. b. The indigestible wax ester content
7. b. False
8. c. Methyl mercury content