Hazelnut

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Code: f17
Latin name: Corylus avellana
Source material: Shelled nuts
Family: Betulaceae (Corylaceae)
Common names: Hazel nut, Hazelnut, Filbert, Cobnut, Cob

The terms "Filbert" and "Hazel nut" are often used interchangeably for nuts from all plants in the genus Corylus, such as C. silvestris, C. maxima and C. colurna.

Allergen Exposure

Geographical distribution
These wild nuts grow in clusters on the Hazel tree in temperate zones around the world. Hazel is an aggressive spreader and is particularly common in Europe as a wild growth, where it has played a significant role in the development of the present forest ecology. Archaeology shows that the nuts were a prehistoric food and the wood a building material, and that tree populations were not adversely affected by land clearance for Neolithic farming.

The tree grows up to 8 m and has a smooth, copper-coloured bark, which peals off in thin papery strips; and twigs covered in thick, reddish, glandular hairs. The fertilised flowers develop into clusters of nuts. The fruit, a 2 cm nut, is surrounded by a leafy bract and ripens in late summer. The fuzzy outer husk opens as the nut ripens, revealing a hard, smooth shell, inside of which is a sweet, rich, grape-size nut within a bitter brown skin that is sometimes removed. Italy, Spain, France and Turkey lead in Hazel nut production. The nuts generally fall in the autumn and are harvested from the ground and then shelled and dried.

Environment
Many Hazel trees grow wild, aggressively forming coppices and scrub. Particularly when cultivated, the nuts (often under the name "Filberts") are used chopped, ground, roasted, blanched, sliced, and as flour and paste in all manner of sweets. They are also eaten whole as a snack (often among "mixed nuts"). During the Western holiday season, bowls of mixed nuts still in their shells are traditionally served, to be cracked with nutcrackers; Hazel nuts are prominent in these mixtures. Hazel nuts also add flavour and texture to savoury items such as salads and main dishes.

Unexpected exposure
Hazel nut is widely used and can be a "hidden" allergen; for example, nougat, an ingredient in secondary products such as confections, is a Hazel nut product.

Allergens
Various allergens have been isolated and characterised in Hazel nut:

  • Cor a 1, a 18 kDa protein, a Bet v 1 homologue and a major Hazel nut allergen (1- 2).
     
  • Cor a 1.04, and variants (3-4).
     
  • Cor a 2, a 14 kDa protein, a profilin (5).
     
  • Cor a 8, a 9,4 kDa protein, a lipid transfer protein (2-3,6-7).
     
  • Cor a 9, a 40 kDa, 11S globulin-like protein, a major protein (8).
     
  • Cor a 11, a 7S vicilin-like globulin
     
  • Cor a Oleosin (9).
     
  • Cor a Heat Shock Protein (10).

The Hazel nut major allergens identified to date are an 18 kDa protein homologous to Bet v 1 and a 14 kDa allergen homologous to Bet v 2. A 47, a 32, and a 35 kDa allergen were detected and reported to be major allergens. The 18 kDa protein was abolished in roasted Hazel nut. The 47 kDa allergen was shown to be a sucrose-binding protein, the 35 kDa allergen a legumin, and the 32 kDa allergen a 2S albumin. Patients with severe anaphylactic reactions to Hazelnut showed IgE reactivity to a 9 kDa allergen that was characterised as a heat-stable lipid transfer protein (LTP) (6,11). The Bet v 1 homologue allergen may have been the allergen now identified as Cor a 1. Roasting of the nuts appears to significantly reduce allergenic activity. Binding of Cor a 1 was severely decreased after heating to 80 °C and higher. No activity of this allergen could be detected in roasted Hazel nut meal.

Three isoforms have been described in Hazel tree pollen, Cor a 1.01, 1.02, and 1.03; and 1, Cor a 1.04, in Hazel nut. Cor a 1.04 shares greater identity with the Birch pollen allergen Bet v 1 (85%) than with its own pollen homologue. A comparison of Birch and Hazel tree pollen extracts and Hazel nut Cor a 1.04 suggests that in some populations, the majority of patients are primarily sensitised by Birch Bet v 1 (13).

Cor a 1 isoforms of Hazel nut display different antigenic and allergenic properties, very likely due to few but significant variations in their amino acid sequences (12). Cor a 1 isoforms appear to represent a complex set of gene products, some of which are more allergenic than others. Cor a 1.04 is a 17.4 kDa protein expressed in at least 4 sub-isoforms, Cor a 1.0401-1.0404, which are 97-99% identical to each other but share only 63% and 71% identity with the Hazel pollen isoforms Cor a 1.0101 and Cor a 1.0301, respectively. Despite the high degree of identity between the 4 nut isoforms, and despite the fact that between 91% and 95% of 43 Hazel nut-allergic patients were reactive with 3 of the 4 versions, 1 form, Cor a 1.0404, reacted with only 74% of the patients (4).

Sensitisation to Cor a 1.04 was demonstrated in 16/17 patients, and to Cor a 2 in 7/17 patients. None of this particular group of patients appeared to be sensitised to the lipid transfer protein Cor a 8 (3). This may indicate that Cor a 8 is a minor allergen in some populations, but a major allergen in others (see below).

Cor a 1.04 has been identified as the major Hazel nut allergen in 65 European patients with positive double-blind, placebo-controlled food challenges to Hazel nut. The 11S globulin Cor a 9 was shown to be a pollen-independent Hazel nut allergen in the United States, whereas the indications were that Cor a 8, a lipid transfer protein (LTP), was an important Birch pollen-unrelated Hazel nut allergen in Europe. Twenty-six Spanish patients allergic to Hazel nut without Birch pollen allergy, including 10 patients with anaphylaxis, were evaluated for sensitisation to Cor a 8. The prevalence of IgE antibody reactivity to this LTP (Cor a 8) was 62% in Hazelnut extract, and 77% to the recombinant LTP. Natural Cor a 8 and rCor a 8 shared identical epitopes. Only 1 patient had positive reactivity to Cor a 1.04, and no patients had positive reactivity to Cor a 2. Two sera bound to high-molecular-weight allergens. Cor a 8 was therefore shown to be a major allergen for a majority of Spanish patients with Hazel nut allergy, and was responsible for severe allergic reactions (2).

Cor a 9 was recognised by IgE antibodies from 86% (12/14) of patients with Hazel nut allergy and systemic reactions (8).

A low-molecular-weight (17 kDa) heat shock protein recognised by IgE from 10 of 14 (71%) Hazel nut-allergic patients is described (10,13).

Potential cross-reactivity

An extensive cross-reactivity among the different individual species of the genus could be expected (14). Cross-reactivity between Hazel nut and Hazel tree pollen may occur. IgE antibodies from all 25 patients displaying type I allergic reactions to the tree pollen as well as allergy to Hazel nuts bound to the major Hazel pollen allergen Cor a 1; and in 16% of the patients the IgE antibodies bound to the 14 kDa Hazel tree pollen profilin. IgE binding to proteins of comparable molecular weights in Hazel nut extracts (18 kDa and 14 kDa) was found, suggesting that proteins similar to Cor a 1 and Hazel profilin might also be expressed in Hazel nuts (5,15).

Indeed, where trees of the family Betulaceae (e.g., Birch, Alder, Hazel and Hornbeam) are prevalent, the cross-reactivity between sensitising pollen and nut allergens can be the leading cause of food allergies (13). Other authors have found a relationship between Birch pollinosis and sensitisation to Hazelnut, Apple, Kiwi, Carrot, Potato and other vegetables (16-17).

Of 196 Birch pollen-hypersensitive patients with Oral Allergy Syndrome, 195 had Apple and/or Hazel nut allergy, and 103 were sensitised to food from the Apiaceae family, suggesting that most Apiaceae allergens cross-react with Apple or Hazel nut allergens, whereas only some Apple or Hazel nut allergens cross-react with Apiaceae allergenic proteins (18).

A 80.5-83% similarity was demonstrated between Cor a 1 isoforms and Bet v 1, the major Birch pollen allergen (12). Allergy to Hazel nuts can therefore be regarded as a common example of Birch pollen-related food allergy (3). Binding to Bet v 1 was abolished in roasted Hazel nut (6).

A similarity of 83.6-85% appears to exist between Cor a 1 isoforms and published sequences of Aln g 1, the major allergen from Alder tree; and a 89.3-95% similarity between Car b 1 (and isoforms), the major allergen from Hornbeam tree. IgE antibodies from tree-pollen-allergic patients reacted with all 4 recombinant isoforms. However, marked differences in the IgE binding patterns of the distinct isoforms were noted (12).

The presence of a Bet v 1-like allergen may explain the association of Hazel nut allergy with other allergies. In individuals with Kiwi allergy, strong reactions to Apple and Hazel nut were reported and moderate reactions to Carrot, Potato and Avocado. RAST inhibition studies revealed cross-reacting antigens between Birch pollen and Kiwi fruit (19).

A 45 and a 30 kDa protein were isolated and shown to have a 60% homology to the conglutin gamma heavy chain from Lupin seed and to a 7S globulin from Soybean, respectively. A 12 kDa protein, probably a 2S albumin, displayed a high degree of homology to the 2S albumin from English walnut (Jug r 1). Immunoblot inhibition and IgE binding to Almond 2S albumin and conglutin gamma were demonstrated in the presence of cross-reacting Walnut or Hazel nut antigens (20).

An important cross-reactivity among the pollen of Platanus acerifolia (London plane tree), Hazel nut and Banana has been reported (21).

Birch may not be the only source of pollen-induced cross-reactivity, as Mugwort (Artemisia vulgaris) pollen has also been shown to be cross-reactive with Hazelnut allergens and may also be a sensitising agent. In a pool of 28 individual sera with IgE antibodies to Mugwort pollen and Hazel nut, IgE antibodies to Hazel nut was inhibited up to 63% by Mugwort pollen. However, the Mugwort pollen-specific IgE was inhibited only up to 36% by Hazel nut. In immunoblotting inhibition experiments, Hazel nut partially inhibited all the Mugwort pollen bands, except that of the 19 kDa protein, whereas Mugwort pollen produced a nearly total inhibition of all the Hazel nut allergens (22).

Besides the major role played by Bet v 1 homologues in cross-reactivity among Birch pollen, Hazel nut and other foods and plants containing these substances, another allergen responsible for cross-reactivity between Birch pollen and Hazel nut is Hazel nut profilin (Cor a 2) – although the clinical relevance of this cross-reactivity has been questioned (15,23).

In some populations, the Hazel nut LTP (Cor a 8) is the major allergen. A Hazel nut LTP allergen has been identified that demonstrated a 62% identity with LTPs from Almond, 59% with Peach, and 59% with Cherry (7). Lipid Transfer Proteins have been reported to be very relevant panallergens, resulting in adverse reactions after the ingestion of botanically unrelated plant-derived foods. It has been suggested that, in view of the high prevalence and severity of the allergic reactions induced, Hazel nut, Walnut and Peanut should be regarded as potentially hazardous to patients sensitised to Lipid Transfer Protein allergens. (6,24-25).

Cor a 9, from Hazel nut, is an 11S globulin seed storage protein family member. This family comprises known food allergens in Peanut (Ara h 3) and Soya bean. The homology among these 3 proteins ranges from 45% to 50%. One known IgE-binding epitope of Ara h 3 shares 67% of homologous amino acid residues with the corresponding area of Cor a 9. The amino acids that differ were previously shown not to be critical for IgE binding in Ara h 3 (8).

Partial cross-reactivity has been reported to occur between Hazel nut and Macadamia nuts (26).

In a study of a patient with anaphylaxis to Coconut and oral symptoms to tree nuts, the presence of cross-reactive allergens between Hazel nut (a tree nut) and Coconut (a distantly related palm family member) was shown (27).

Allergy to Kiwi, Poppy seeds and/or Sesame seeds often occurs in patients with a simultaneous sensitisation to nuts and flour. In a study, the existence of both cross-reacting and unique components was observed; however, the cross-reacting and unique components could be different for different patients (28).

Clinical Experience

IgE-mediated reactions
Hazel nuts are a common cause of food allergy (29-30). In a study of 62 patients (adults and children) with nut allergy, Peanuts were the commonest cause of allergy (47), followed by Brazil nut (18), Almond (14), and Hazel nut (13,31). Allergies to Peanut (a legume) and tree nuts (Walnut, Hazelnut, Brazil nut, Pecan) frequently have an onset in the first few years of life, generally persist, and may account for severe and potentially fatal allergic reactions.

Some patients with allergy to Hazel nut may be allergic to the nut, others to the tree pollen, and still others to both. The type of allergic reaction and the specific allergens recognised can vary considerably from one geographic area to another (13).

Allergic reactions to Hazel nuts range from Oral Allergy Syndrome to severe anaphylactic reactions (8,32). Allergy to Hazel nut is most frequently observed in patients with allergy to Birch pollen. This can be explained largely by cross-reactivity of Bet v 1, the major Birch pollen allergen, with its homologue in Hazel nuts, Cor a 1. In addition, profilin and carbohydrate structures can be involved. Symptoms of food allergy in pollen-allergic patients are usually mild and restricted to the oral cavity, i.e., Oral Allergy Syndrome. Allergy to Hazel nuts without concomitant pollen allergy is less common, but symptoms tend to be more severe and are often systemic (3,11,33-36).

The probability of patients with nut allergy having allergen-specific IgE to a particular combination of Peanut, Hazel nut and Brazil nut is similar, whatever the patients' age and sex. Multiple nut reactivity appears to increase with increasing age and may be due to the exposure of previously unchallenged sensitivity. The risk of a patient being sensitised to multiple nuts is sufficiently high that patients should always be tested for allergy to a range of nuts if they have a history of reacting to any nut (37).

Hazel nut-allergic individuals may react to very low doses of Hazelnut. A study reports that 29 Hazel nut-allergic patients had a positive reaction to increasing-dose challenges with Hazel nut. Itching of the oral cavity and/or lips was the first symptom in all cases. Additional gastrointestinal symptoms were reported in 5 patients, and difficulty in swallowing in 1 patient. Lip swelling was observed in 2 patients, followed by generalised urticaria in 1 of these. Threshold doses for eliciting subjective reactions varied from 1 mg up to 100 mg of Hazel nut protein (which would be found in 6.4 to 640 mg of Hazel nut meal) (38). Similar results have been reported in other studies. A study of a group of Hazel nut-allergic individuals indicated that 50% of the Hazel nut-allergic population will suffer from an allergic reaction after the ingestion of 6 mg (95% CI, 2-11 mg) of Hazel nut protein (8). But roasting of Hazel nuts significantly reduces their allergenic potential (3).

Allergic sensitisation may occur early on in life. In 163 infants aged between 1 and 12 months with symptoms of food allergy, IgE antibodies to Hazel nuts were detected in 68 (41.7%) (39).

In a study of 86 subjects (from Milan, Zurich, and Copenhagen) with a history of symptoms after Hazel nut ingestion, the diagnosis was confirmed in 67 (77.9%) on the basis of a DBPCFC. Of these subjects, 87% also had positive SPT to Birch pollen extract (40). Hazel nut was reported to have resulted in asthma in 2.7% of a study group following DBPCFC oral challenges to Hazel nut (41).

Grass allergy is the most common pollinosis in Northern Italy. Some patients with grass allergy show polysensitisation against other pollens and plant-derived foods. In these patients oral allergic syndrome (OAS) is frequently associated. In a study of 56 children suffering from respiratory allergy due to grass pollens, in the 16 patients with food allergy, Hazel nut was the major triggering food (50%), followed by Peanut (38%), Kiwi (31%), Apple and Walnut (19%) (42).

Severe systemic reactions such as anaphylaxis are possible with allergy to Hazel nut. In contrast to IgE binding patterns that occur in sera from patients with pollen-related Hazel nut allergy, low-molecular-weight (below 10 kDa) heat-stable proteins are responsible, as demonstrated in a young woman who experienced an anaphylactic reaction after the ingestion of Hazel nuts. She was not tree-pollen allergic. Suspect allergens in this size range include LTPs and 2S albumins (43). A Spanish study, evaluating 26 Hazel nut-allergic patients, including 10 who had experienced anaphylaxis, reported the lipid transfer protein to be the major allergen in Hazel nut allergy, including OAS and the more severe symptoms in the majority of patients (2). Food-dependant exercise-induced anaphylaxis has also been reported (44).

Urticaria to commercial Hazel nut skin cream has been reported in a 20-year-old girl who presented with anaphylaxis to String bean (45).

Hidden Hazel nut is a threat to allergic patients. (46) This may take the form of Hazel nut allergens in Hazel nut oil. Hazel nut or other nut oils may be used in chocolate manufacturing. The nut oil may pose a threat to patients with allergy, but this would depend on the method of manufacture and processing (47).

Occupational allergy to Hazel nuts is also a possibility. In a study of workers in candy and pastry manufacturing, SPT with food extracts used in the manufacturing of these products demonstrated that the most frequent positive results occurred with extracts of Cacao (31%), followed by reactions to chocolate (9%), cocoa (6%), Hazel nut (6%), and sugar (2%) (48).

In a study of 37 children with symptoms only of nocturnal enuresis who were investigated for allergy, IgE antibody evaluation showed that there may be a relationship between nocturnal enuresis and Soybean and Hazel nut food allergens. The authors cautioned that further studies were necessary to explain the underlying mechanisms and management of this disorder (49).

Other reactions
Nickel is abundant in Hazel nuts (50).

Compiled by Dr Harris Steinman, harris@zingsolutions.com

References

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