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 rGad c 1

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Code: f3
Latin name: Gadus morhua
Source material: Fish muscle
Family: Gadidae

Atlantic Cod - Gadus morhua
Baltic Cod - Gadus callarias

Allergen Exposure

The Atlantic cod, Gadus morhua, is a well-known food fish belonging to the family Gadidae. It grows to two metres in length, with sexual maturity being reached between ages 2 and 4. Its colouring is brown to green on the dorsal side, shading to silver ventrally.

The Atlantic cod is one of the world's most important food fish. It is sold fresh, frozen, smoked, salted or canned. The cod family, Gadidae, contains many important species. Several are internationally marketed as frozen fish meat under a variety of names. Walleye pollack (Theragra chalcogramma) is a major constituent of surimi.

Cod is sold fresh, frozen, smoked, salted and canned.

Cod may be an undeclared ingredient in industrially-prepared food, such as cured meat products.

It may occur as a contamination of cooking oil, utensils and containers.

Allergen Description

Several IgE-reactive allergens spanning a wide molecular-weight range have been detected in Cod extracts. Storage conditions and other factors may influence the relative distribution of IgE-reactive protein bands. IgE-reactive protein bands of 104 and 130 kDa have been detected and may correspond to aggregates, as EDTA was shown to increase the relative amount of the 60, 67, 104, and 130 kDa IgE-reactive protein bands. (1) Other IgE-reactive proteins of 41 and 80 kDa were detected. An 18 kDa protein was detected only in fish stored for several days. In short, EDTA and storage conditions may influence the relative distribution of IgE-reactive protein bands. (1)

The following allergens have been identified to date:

Gad m 1, a 12.3 kDa protein, a parvalbumin and a calcium-binding protein. (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

Gad m 45kD, a 45 kDa protein of unknown function. (13)

From the related Baltic cod, Gadus callarias, the following allergens have been identified to date:

  • Gad c 1, a 12.3 kDa protein, a parvalbumin and a calcium-binding protein. (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
  • Gad c 41kD, a 41 kDa protein. (25, 26) 

Although specific IgE is often directed mainly at parvalbumin (Gad m 1), the antibody response is heterogenous; as demonstrated by a Spanish study, where fish allergy occurred in 22% of all patients with a diagnosis of food hypersensitivity. In a study comparing the allergen patterns of commonly consumed fish species – Whiff, Tuna, Swordfish and Cod – using sera of 16 Spanish patients with type I allergy to fish: for Whiff, 13 patients' sera had IgE specific for a protein around 12 kDa, and 6 patients recognised a 17 kDa and a 33 kDa double band. High-molecular-weight Whiff proteins between 40 and 90 kDa were recognised by more than 80% of patients' sera. For Tuna, 13 patients recognised a 12 kDa band, and the same 13 patients displayed IgE to a protein of approximately 12 kDa in Swordfish; one also recognised a band around 40 kDa. For Cod, 15 patients showed IgE specific for a protein around 12 kDa, and 3 patients to a band around 50 kDa. Eighty-one percent of the patients' sera had IgE specific for purified Cod parvalbumin. The 12 kDa proteins recognised in all four fish extracts could be parvalbumin. (27)

Gad m 1 is a parvalbumin. The parvalbumin content of most commonly consumed fish species has been shown to vary considerably (being very low in tuna) and is 20-60% lower in processed samples (cooked/commercial). (28) Incomplete digestion of Cod has been shown to be a risk factor for anaphylaxis in patients with allergy to Cod. In subjects without allergy, absorption of biologically active fish allergens occurs 10 minutes after ingestion, with maximal serum levels after 1 to 2 hours. Digestive enzymes were shown to cause protein fragmentation, leading to reduced biological activity. However, raising the pH to 3.0 for digestion resulted in reactivity patterns comparable to those of undigested extracts. (29)

Gad c 1 is a 12.3 kDa protein, a parvalbumin (a calcium-binding protein) and a major Cod allergen. The frequency of sensitisation to Gad c 1 in Cod-allergic individuals is estimated to be up to 100%. (9, 30) Gad c 1 (Allergen M) from Cod was the first fish allergen isolated as a pure fraction. (18) This allergen has served as a model for fish allergy. It is a calcium-binding protein belonging to the parvalbumins found only in the muscle tissue of fish and amphibians. These major allergens of most fish are small, acidic, calcium-buffer sarcoplasmic proteins that are described as cross-reactive. Parvalbumins are proteins found in fast muscle of lower and higher vertebrates, and are thought to be involved in the relaxation process in fast-twitch muscle.

Teleost fish such as Cod, Whiff and Swordfish have 2 types of muscle: fast-twitching white muscles, and dark (or red) muscles for continuous swimming. White muscles have a higher content of parvalbumin than dark muscles. Hence in active fish (such as Swordfish) – which have more dark muscles – the parvalbumin content is lower, and patients can probably tolerate them better than they can tolerate Cod, Salmon, Carp, and Whiff. (31)

Calcium-binding proteins (CBPs) are important food allergens in fish and amphibians, and are ubiquitous pollen allergens. (32) The first calcium-binding allergen characterised was parvalbumin from fish (Cod), then others were discovered in pollens of trees, grasses and weeds; and recently, as autoallergens in man. Calcium-binding proteins from pollens are described as polcalcins because their expression is restricted to pollen grains. (33) Although there is cross-reactivity described within the subfamilies of calcium-binding allergens, there are no strong indications for IgE cross-reactivity among CBPs from plants, fish, and humans. (32) Not all calcium-binding proteins are cross-reactive. (34)

Potential Cross-Reactivity

Species within groups of fish such as Gadiformes (examples: Cod and Hake) and Scombroid fishes (examples: Mackerel and Tuna) seem to share allergenic components.

Although cross-reactivity between the parvalbumin Gad m 1 in Atlantic Cod (Gadus morhua) and Gad c 1 in Baltic Cod (Gadus callarias) would be expected to be very high because of the close species relationship, it has been reported that Gad m 1 shares greater amino acid sequence homology with Sal s 1 from Salmon (75%) than with Gad c 1 (62.3%). It was suggested that Gad m 1 and Gad c 1 may correspond to 2 distinct genes of the Gadus species. (11)

Fish-hypersensitive patients can probably tolerate some fish species while being allergic to others. Nonetheless, cross-reactivity is a strong possibility between fish species if a parvalbumin allergen is involved. A study evaluated the cross-reactivity among 9 common edible fish – Cod, Salmon, Pollack, Mackerel, Tuna, Herring, Wolffish, Halibut, and Flounder – using sera from 10 fish-allergic patients. Cod (Gad c 1), Salmon (Sal s 1), Pollack (The c 1), Herring, and Wolffish were shown to share antigenic and allergenic determinants, whereas Halibut, Flounder, Tuna, and Mackerel displayed the lowest cross-reactivities. (10)

Carp parvalbumin (Cyp c 1) has been shown to contain 70% of the IgE epitopes present in natural extract of Cod, Tuna and Salmon (Sal s 1). (35,)  (36) High cross-reactivity occurs between Cod and Carp parvalbumins. (12) Other studies have also reported the presence and cross-reactivity of parvalbumins from different fish species (Cod, Tuna, Salmon, Perch, Carp, and Eel). (9, 37) Sco j 1, Sco a 1, and Sco s 1 from Mackerel have been reported to have very similar IgE-binding epitopes, and they showed a high degree of cross-reactivity with Sco j 1, and homologies of 58% with Gad c 1, 65-75% with the parvalbumins from Salmon, and 75% with the parvalbumins Cyp c 1.01 and Cyp c 1.02 from Carp. (38) A parvalbumin immunochemically similar to Gad c 1 was also detected in Catfish and Snapper, but not in Tuna. (39)

There have been conflicting reports regarding parvalbumin in Tuna. Previous studies have reported the absence (or very low levels) of parvalbumin in Tuna. (10, 39, 40) However, others have reported the presence of parvalbumin in Tuna, and found it to be allergenic. (9, 41) In a study with the purpose of evaluating the reasons for these inconsistencies, parvalbumin was shown to be present in the white muscle of Tuna and absent in the red. It was unequally distributed in further ways, with the ventral white muscle containing slightly more parvalbumin than the dorsal white muscle. These findings were replicated. The amount of parvalbumin decreased from the rostral region to the caudal region. (42) This observation has also been reported for Cod. (43) The authors suggested that this observation was likely to be unique to fish with large portions of red muscle in sections of the torso. Although the white meat of Tuna is favoured when eaten raw (as in sashimi), both white and red meat of the fish are consumed in the cooked form. Therefore, these findings have significant implications for preparing Tuna fish diagnostic allergen extracts from raw material. (42)

Tropical fish may also be commonly consumed, in certain populations. The allergenicity of 4 commonly consumed tropical fish, the threadfin (Polynemus indicus), Indian anchovy (Stolephorus indicus), Pomfret (Pampus chinensis) and Tengirri (Scomberomorus guttatus) was assessed in 10 patients, 9 of whom were allergic to multiple fish. All patients exhibited detectable specific IgE to Cod, despite lack of previous exposure. The major allergen of the 4 tropical fish was the 12-kDa parvalbumin, and IgE cross-reactivity to Gad c 1 was observed to be moderate to high in the tropical fish studied. (44)

Parvalbumin is also highly conserved across fish species and amphibians and is the major cross-reactive allergen associated with both fish and frog allergy. Cod parvalbumin has been shown to share IgE binding epitopes with frog parvalbumin, and this appeared to be clinically relevant. (45) However, species-specific differences in proteins that appear to represent various isoforms of parvalbumin may occur, as demonstrated in Carp, Catfish, Cod and Tilapia. No parvalbumin was detected in Tuna. The study concluded that parvalbumin isoforms may have slight differences in the epitope region recognised by anti-frog parvalbumin antibody. (46)

In an American study on Catfish, Bass, Perch, Mackerel (f206), Tuna (f40), Salmon (f41), Trout (f204), Cod (f3), Flounder and Sardine (f308), among other species, it was found that patients allergic to one fish may tolerate other fish species. (78) This confirmed the results of an Italian study on Cod-sensitive children, which also included Eel (f 364), Anchovy (f 313), Sole (f 337), and other species. (18) Results will depend on whether the allergic individual is allergic to a species-specific Cod allergen, or the cross-reactive parvalbumin allergen.

Generalised dermatitis and itch induced by a possible drug-food interaction was reported in a 33-year-old woman who was taking the drug clomipramine. About a month after starting treatment, she developed a severe generalised urticaria with intense itch, which followed having ingested Cod the day preceding the rash. A re-challenge with the drug one month later did not induce any adverse event. In contrast, when the re-challenge of Cod was combined with clomipramine, urticaria was observed. (47)

Clinical Experience

IgE-mediated reactions

Sensitisation to fish allergen is common. Fish, and especially Cod, is a common cause of food allergy and atopic dermatitis, in particular in countries of the Northern Hemisphere (48, 49, 50, 51, 52, 53) and Asian countries. (54)

Contact with Cod through ingestion or through the inhalation of cooking vapours has resulted in allergic symptoms, including oral allergy syndrome, generalised urticaria, facial angioedema and anaphylaxis. (55, 56, 57) Wheezing and life-threatening bronchospasm have been reported. (58) Oropharyngeal itching and swelling occur as the first symptom, always preceding the onset of any accompanying symptom. Contact with fresh raw Cod has also resulted in allergic dermatitis, urticaria and anaphylaxis. (59, 60, 61 )Immediate allergic reactions may follow ingestion of minute amounts of Cod. (62 )Patients allergic to fish often have dramatic symptoms, and severe asthmatic attacks can be triggered by the smell of fish. Extremely sensitive patients have suffered anaphylactic shock after eating foods cooked in reused cooking oil, or when utensils and containers have been used earlier for cooking fish. (63, 64) Sensitisaton to Cod may occur through the inhalation of Cod allergens present in the dust of homes. (65, 66)

Prevalence figures vary from approx. 10% to approx. 40% in atopic populations. In Norway, fish allergy was found in 1 in 1 000 of the general population. A nationwide, cross-sectional, random telephone survey performed in the USA found that seafood allergy is reported by 3.3% of the general population, and by at least one member of 5.9% of US households. (67) In another report, allergy to some type of seafood was reported for 0.6% of US children younger than 18 years, and 2.8% of adults. In the US, fish allergy accounts for an estimated 0.1% and 0.4% of food allergies in children and adults respectively. (68)

A European study estimated the prevalence of food hypersensitivity (FHS) to the most common allergenic foods in an unselected population of 1272 young adults. In patients with primary FHS (not concomitantly allergic to pollen), the most common allergenic food was peanut (0.6%), followed by additives (0.5%), shrimp (0.2%), Cod (0.1%), Cow's milk (0.1%), octopus (0.1%) and soy (0.1%). (69) In a German study of 419 adults referred for suspected food allergies, 214 patients (51.1%) were found to have an IgE-mediated food allergy, of which 15 patients were allergic to Cod compared with 18 for shrimp, 9 for egg and 5 for Cow's milk. (70)

In a UK study of 76 Caucasian and non-Caucasian children, a total of 125 reactions to 23 different food allergens were documented. The top five food allergens were egg, peanut, tree nut, Cow milk and Cod, in that order. Together these five foods accounted for almost 90% of all the reactions. (71)

In a group of Italian children with food allergy, about 18% had IgE antibodies to Cod and two-thirds had clinical manifestations upon inhalation or ingestion of the fish. (18) A fatal anaphylactic reaction occurred in a fish-allergic patient who ate fried potatoes cooked in the same oil in which fish had been cooked. (72) Allergy to Cod may play a role in children with atopic dermatitis. (73)

In Portugal, allergic reactions to fish are reported to be common among patients diagnosed with food hypersensitivity. In a study of 13 patients aged between 3 and 24 years who reported being allergic to fish, 10 of the 13 (85%) experienced allergic symptoms within 30 minutes after ingestion of fish: urticaria/angioedema (54%), vomiting (23%), itching (23%) and wheezing (15%). Twenty-three percent reported eczema worsening after fish ingestion. Subjects were tested for Cod, Pollack, Salmon, Tuna, Sole, Sardine and Anisakis simplex: 12 of the 13 patients (92%) were skin-prick-test positive to at least one of the 6 fish extracts tested, 7 patients had positive SPT and sIgE to all extracts, 5 had negative SPT and specific IgE to tuna. The highest mean sIgE of 13 sera was caused by Cod (58.7KU/L), followed by Sardine (48.4), Salmon (31.8), Pollack (16.2), Sole (11.8) and Tuna (5.6). A major protein (12-14 kD) was present in all fish extracts and was recognised by serum IgE from 12 out of 13 patients (92%). (74)

Occupational allergy (in particular, allergic dermatitis) to Cod has been reported. (75) A 48-year-old woman, who had worked for several years as a cook in a grill bar where she fried meat and fish on a hob, developed a severe itching on the forearms and face 11 years later. The eczema healed after 3 weeks off work, but returned within 1-2 days when work was resumed. When she fried cod by itself for one hour, a vigorous itching of the forearms developed, followed by papular urticaria on the forearms. Open tests with small pieces of fresh cod and plaice (which were applied to the skin of the back for 5 minutes) gave a positive reaction, in the shape of wheals and erythema on the test area. Serum-specific IgE for fish was positive. Although she had previously eaten fish without trouble, following onset of the dermatitis she began to experience swelling in the mouth and throat after very small portions of fish. (76)

Because patients react to both cooked and raw fish, it is assumed the allergens are heat-resistant. However, more recent studies indicate that patients may react differently to processed food (77) and that allergic reactions may be species-specific. (18, 78)

Because of the good correlation between reactions in in vivo and in vitro tests, it has been suggested that food challenges are not necessary. (30) The clinical sensitivity and specificity of serum-specific IgE testing were reported to be 93% and 87% respectively. (79)

Other reactions

Acute anisakiasis as a result of the larvae of the fish parasite Anisakis simplex may occur following ingestion of undercooked or raw Cod. Patients may develop violent abdominal pain within a few hours. Individuals sensitised to the protein of the larvae may develop an allergic reaction which may manifest as urticaria. In these instances, the seafish-induced urticaria might be an allergic response to Anisakis larval antigens rather than to the fish itself. (80, 81)

Compiled by Dr Harris Steinman, 


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Updated: 2010


As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.