Review of the regulatory management of food allergens

5.3 Gluten containing cereals

Gluten containing cereals are subject to the mandatory declaration requirements in Standard 1.2.3 of the Code. The specified cereals (i.e. wheat, barley, oats, spelt and their hybridised strains) and their products must be declared when present in food. The requirements address two distinct types of immunologically mediated adverse reactions caused by dietary intake of cereals, i.e. coeliac disease, and immunoglobulin (Ig) E-mediated food allergy. The pathogenic mechanisms underlying these types of adverse reactions are different.

Stakeholder submissions to FSANZ highlighted the difficulty in interpreting the Standard in the context of the two different adverse reactions to gluten-containing cereals. For example, the stakeholders indicated that it is not clear whether all wheat ingredients must be declared if an ingredient has no detectable gluten but is derived from wheat. Also, some stakeholders are concerned that triticale grain, which is a a hybrid of wheat and rye, is used in products labelled as ‘wheat free’, even though triticale is covered by the current declaration requirements in Standard 1.2.3. The stakeholders suggest it may be clearer to food manufacturers if triticale was specifically listed along with other cereals containing gluten.

5.3.1 Gluten

The term ‘gluten’ refers to the rubbery mass that remains when wheat dough is washed to remove starch granules and water-soluble constituents. Gluten also generically refers to the protein fraction from cereals known to trigger coeliac disease. The cereals are wheat (including spelt and kamut), barley, rye, cross-bred hybrids (e.g. triticale), and possibly oats. Gluten can be separated into gliadin and glutenin proteins according to their solubility in aqueous alcohol.

The soluble gliadin is a heterogenous mixture of single-chained polypeptides with molecular weights of around 28–55 kDa that can be classified according to their different primary structures into: α-, β-, γ-, and ω-gliadins. The glutenin fraction comprises aggregated proteins linked by interchain disulphide bonds. After reduction of disulphide bonds, the resulting glutenin subunits show solubility in aqueous alcohols similar to gliadins (Bietz et al., 1977; Shewry et al., 2002).
The predominant protein type is low molecular weight (LMW) glutenin subunits; while the high molecular weight (HMW) glutenin subunits are minor components (Wieser, 2007). Prolamins, the alcohol soluble fractions of storage proteins found in wheat, barley and rye, are known as gliadins, hordeins and secalins, respectively. The prolamins of these closely related cereals have a higher composition of proline and glutamine than oats and other distantly related cereals. The glutamine-rich peptide sequences in prolamins of wheat, barley and rye appear to be responsible for their toxicity in coeliac disease (Fraser and Ciclitira, 2001).

5.3.2 Coeliac disease

Coeliac disease (CD) is an immune-mediated gastrointestinal disease triggered by the ingestion of gluten in genetically susceptible persons. The abnormal immune response is characterised by an inflammatory reaction in the small intestine leading to flattening of the mucosa. As a result, affected individuals absorb food and nutrients poorly. This can result in bowel symptoms and deficiencies of vitamins, minerals and other nutrients. CD has several autoimmune features, including the production of highly disease-specific IgA and IgG autoantibodies when patients are on a gluten containing diet (Kaukinen et al., 2010).

Tissue transglutaminase (tTG) appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Clinical manifestations of CD are commonly associated with various skin and mucosal disorders. Most common and typical among them is dermatitis herpetiformis, which is characterised by skin lesions that may affect several body areas. Comorbidity between CD and other autoimmune disorders has been established. Failure to diagnose and manage CD can lead to serious complications including osteoporosis and malignancy (Fraser and Ciclitira, 2001; Fasano, 2006; West, 2004; Anderson et al., 2007; Barton and Murray, 2008).
The gliadin fraction of cereal protein has been demonstrated to trigger CD with symptoms including mucosal flattening. Although all gliadins are toxic to coeliac patients, the most severe effects are caused by α-gliadins (Ensari et al., 1998; Fraser and Ciclitira, 2001; Hischenhuber et al., 2006).
CD is now recognised as a significant health issue worldwide. Currently, the only effective treatment for CD is a life-long strict avoidance of dietary gluten (Rodrigo-Sáez, 2006; Faulkner-Hogg et al., 2009; Cummins and Roberts-Thomson, 2009; Kaukinen et al., 2010).
Although strict dietary avoidance of gluten is recommended to CD patients, it is probably impossible to maintain. Many food products on the market may contain trace amounts of gluten due to cross contamination (Storsrud et al., 2003). A safe threshold for gluten has recently been under investigation. Based on several studies, a daily intake of 10–20 mg gluten appears to be harmless, whereas daily gluten intake over 200–500 mg is likely to induce small bowel villous damage and inflammation (Hischenhuber et al., 2006; Catassi et al., 2007; Akobeng and Thomas, 2008).

Oats are genetically different from wheat, rye and barley, and the prolamine content in oats is lower than that of other cereals (Shewry and Halford, 2002). Despite evidence that oats are well-tolerated by the majority of patients with coeliac disease, the inclusion of oats in the diet for CD patients is still a matter of debate (Selby et al, 1999; Arentz-Hansen et al., 2004; Haboubi et al., 2006; Kaukinen et al., 2010). Gluten contamination in commercially available oats has been reported (Thompson 2004; Storsrud et al., 2003).

5.3.3 Allergy to wheat and other cereals

Wheat is the dominant cereal crop in temperate countries and is one of the most commonly consumed cereal crops in many parts of the world (Shewry, 2009). Wheat proteins can be classified into: water-soluble albumins, salt-soluble globulins, ethanol-soluble prolamins, which include gliadins and acid-soluble glutenins. The gliadins and glutenins form the gluten fraction (discussed above).

Both respiratory and food allergies to wheat have been reported in the medical literature. However, reports of food allergy to wheat and related cereals, are relatively infrequent considering the vast dietary exposure.
Wheat allergy develops most commonly in infants, affecting up to 1%, but it tends to disappear within five years (Poole et al., 2006). The main symptoms in children are hives and atopic dermatitis (AD). Occasionally delayed reactions occur after the food is eaten regularly over several days, resulting in eczema or sometimes diarrhoea, or poor weight gain (Hischenhuber et al., 2006; ASCIA, 2010b). Wheat allergy among adults is infrequent, however, reported manifestations include food-dependent exercise-induced anaphylaxis (FDEIA), angiooedema and irritable bowel syndrome (Simonato et al., 2001; Morita et al., 2003; Hischenhuber et al., 2006). FDEIA is a rare but well-defined syndrome where the ingestion of food followed by physical exercise can result in an anaphylactic reaction. Anaphylaxis does not occur if exercise is delayed by several hours.
The allergenicity of cereal proteins was initially recognised for its role in the occupational respiratory disease known as bakers’ asthma. A number of proteins in the water/salt-soluble fraction (albumins and globulins) have been identified as major allergens associated with the condition (Sanchez-Monge et al., 1992; Baur and Posch, 1998; Amano et al., 1998). In particular, the role of α-amylase inhibitors is considered important but other wheat proteins have been shown to bind IgE from patients with bakers' asthma, including gliadin (Constantin et al., 2008; Bittner et al., 2008). Patients with bakers’ asthma reportedly tolerate the ingestion of bread (Armentia, 2009).
A number of studies investigated the profile of allergenic wheat proteins with IgE from patients with various manifestations of wheat allergy (Hischenhuber et al., 2006; Tatham and Shewry, 2008).
Varjonen et al (2000) investigated wheat allergens recognized by IgEs from a group of AD patients suspected of wheat food allergy. Their results suggest that gliadins could be important allergens in this type of allergy to wheat. Palosuo et al. (2001a) studied a group of children with a history suggestive of wheat allergy. Open or double bind oral wheat challenge resulted in immediate symptoms in 48% and delayed symptoms in 20%.The major allergenic protein was identified as the ω-gliadin. IgE antibodies to gliadin were not detected in the children with delayed symptoms.
In a study of 28 children and adults with wheat allergy, confirmed by DBPCFC, Ig E antibodies to various wheat proteins were detected. Seventy two percent showed IgE antibodies against the albumin/globulin protein fraction.

IgE antibodies against α- and β-gliadins and LMW weight glutenin subunits were detected in 60% of patients, while IgE against lipid transfer proteins (LTP) were detected in 28% of patients (Battais et al., 2003).

In a more extensive study with 60 patients, different antigenic profiles were observed in food allergy to wheat, as a function of age and symptoms (Battais et al., 2005a). Gliadins (α, β and γ) and albumins/globulins appeared to be more important allergens for children with AD with or without asthma, while ω-gliadins were major allergens for adults with WDEIA and/or anaphylaxis (100%), or urticaria (55%).
LMW glutenin subunits also featured in anaphylaxis cases in adults. Only 23% of patients with AD and 8% of those with AD and asthma reacted to ω -gliadins (Battais et al., 2005b).
A study by Daengsuwan et al. (2005) showed that gliadins were also the major allergens in children with wheat-induced anaphylaxis. These studies suggest that differences exist between children and adults in the pattern of response to major wheat allergens and in disease outcome.
In recent years, wheat-dependent exercise-induced anaphylaxis (WDEIA) has been increasingly recognised. Several studies clearly established that for wheat this condition is mainly associated with a group of gliadins, called ω5-gliadins (Morita et al., 2003; Matsuo et al., 2005). A number of other proteins have also been shown to react with IgE from patients with WDEIA, including glutenin subunits, and related proteins from barley and rye but their clinical significance is unknown (reviewed by Tatham and Shewry, 2008). Mechanisms of eliciting anaphylactic symptoms by exercise were postulated by Inomata (2009). One mechanism is the activated tissue transglutaminase increases the allergenicity of the protein and another is the increased absorption of allergens through the gastrointestinal tract.
In relation to the amount of wheat required to trigger reactions in wheat allergic individuals, a review of the clinical studies suggest that the amount is higher than that for coeliac patients (Hischenhuber et al., 2006).

5.3.4 Cross reactivity among cereal food allergens

Information on clinically significant cross-reactivity among cereals in wheat allergic patients is limited. A study of 145 paediatric patients suffering from AD with a positive skin test to one or more cereals was reported (Jones et al., 1995). Only 21% of patients had symptomatic reactivity as determined by DBPCFC performed using up to 10 g of cereal proteins, and 80% of reactions occurred in response to only one cereal grain (76% wheat). Palosuo et al. (2001b) demonstrated that the γ-70 secalin of rye and the γ-3 hordein of barley cross-react with ω5-gliadin, a major allergen in WDEIA.

5.3.5 Conclusions

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  Wheat allergy and coeliac disease are immunologically mediated adverse reactions to dietary gluten. Wheat allergy in children commonly develops during infancy and is usually outgrown by the age of five.
  

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  Wheat allergy is not common in adolescents and adults but is more likely to persist.
  

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  Gluten triggers coeliac disease and also appears to be a major source of allergens in wheat food allergy.
  

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  It is now widely accepted that small amounts of gluten daily intake of 10–20 mg are tolerated by the majority of coeliac patients. It has also been suggested that most wheat allergic individuals can tolerate the same, or higher, amounts of wheat protein.
  

5.3.6 Recommendation

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  FSANZ to consult with allergy experts on the current state of knowledge in relation to wheat allergy, including cross-reactivity with other cereals, and if necessary, develop options to improve the clarity of the declaration requirements in relation to coeliac and wheat allergic patients.