Aetiology

Food allergy is a broad term that indicates an abnormal immunological response to a food antigen. The allergy results from a loss of tolerance to specific foods.[11] This loss of tolerance can result in abnormal IgE production against a particular food antigen. Loss of tolerance or sensitisation to a food allergen may occur via the gastrointestinal tract, via the epidermis (in which barrier function is impaired), or via the respiratory tract (to pollen homologous to food allergens).[12] When the food is ingested, broken down, and absorbed, it can bind to IgE located on mast cells, leading to mast-cell degranulation (type I hypersensitivity reaction).[11] Mast cells release mediators that cause the signs and symptoms of anaphylaxis. Although some diseases, such as food-induced anaphylaxis, seem to be solely mediated by IgE, other diseases involve both IgE- and cell-mediated responses; for example, atopic dermatitis and eosinophilic gastrointestinal diseases.[11] The underlying mechanisms that drive the development of food-specific IgE responses, as opposed to food-specific cell-mediated responses, are still under investigation.

Non-immune food intolerances often result from either acquired or congenital deficiencies in key enzymes that break down specific carbohydrates ingested in food. The inability to break down these carbohydrates into absorbable substrates results in transit of the undigested carbohydrate into the colon which leads to the symptoms of pain, diarrhoea, and flatulence, which are often experienced by patients with these deficiencies.[7][13]

Non-immune food sensitivities such as migraines after tyramine ingestion and reactions to monosodium glutamate are an area of controversy in the literature.[8][9] However, there is a well-reported association between ingestion of sulfites and bronchospasm in sulfite-sensitive patients.[10]

Food-induced anaphylaxis

Type I hypersensitivity reaction is mediated by food proteins binding to food-specific IgE, leading to mast-cell degranulation. Mast cells release mediators such as tryptase and histamine, which give rise to the sudden onset and rapid progression of symptoms of anaphylaxis: life-threatening airway and/or breathing and/or circulation problems with or without skin and/or mucosal changes (e.g., erythema, urticaria, angio-oedema, rhinitis, pruritus).[14]​[15]​ Symptoms usually develop within 2 hours of ingestion of the inciting food.[16]​ Generalised urticaria, angio-oedema, and rhinitis without life-threatening airway, breathing, or circulation problems do not meet the criteria for anaphylaxis, however if in doubt, give intramuscular adrenaline and seek expert help.[15]

The most common food allergens in adults are peanuts, tree nuts, shellfish, and fish. In children, milk, eggs, soya, wheat, peanuts, and tree nuts are usually responsible.[1] History is key to the diagnosis of food-induced anaphylaxis, as well as to the identification of the inciting food. The history narrows the focus of the diagnostic evaluation from a list of many possible foods to one of several likely foods. These foods can be further evaluated through skin prick tests, in vitro IgE assay (such as the immunoCAP system capsulated hydrophilic carrier polymer fluorescent enzyme immunoassay), and food challenges.

Food-dependent exercise-induced anaphylaxis

This is characterised by the symptoms of anaphylaxis (urticaria, angio-oedema, throat tightness, wheezing, hoarseness, pruritus, vomiting, diarrhoea, hypotension, and respiratory distress) after ingestion of a particular food followed by exercise.[17] Anaphylaxis to the food allergen occurs only in the setting of exercise; generally, the food allergen is tolerated when ingested in the absence of exercise, and exercise alone does not provoke symptoms.[18] The condition is due to a type I hypersensitivity reaction. Exercise within 45 minutes to 2 hours after ingestion of the causal food leads to the symptoms of anaphylaxis. The exercise may be mild or strenuous. Ingestion of the causal food at the same time as aspirin may also provoke anaphylaxis. It has been suggested that exercise and aspirin facilitate absorption of the food allergen from the gastrointestinal tract.

Common food allergens provoking food-dependent exercise-induced anaphylaxis include wheat (most common), shellfish, vegetables, and nuts.[17][18] While other forms of food allergy usually require constant dietary avoidance, with food-dependent exercise-induced anaphylaxis avoidance can be limited to 4 hours before exercise.

Oral allergy syndrome

This is a type I hypersensitivity reaction resulting from IgE to pollen or latex antigens cross-reacting with homologous food allergens.[19] It is more common in adults than children. The initial event is sensitisation to pollen or latex, with subsequent development of cross-reactivity to food allergens.[19] The condition is considered a class 2 food allergy, as the sensitiser is pollen or latex and the elicitor of symptoms is a food allergen, with the reactions normally limited to the mouth.[20] This contrasts with class 1 food allergies such as peanut, egg white, and cows' milk, which induce allergic sensitisation via the gastrointestinal tract and cause systemic reactions. Oral allergy syndrome develops as a consequence of shared epitopes in the primary and tertiary structures of pollen, latex, and food allergens. Symptoms are classically localised to the oropharynx and may include pruritus and angio-oedema of the lips, oral mucosa, and soft palate.[21] Although rare, it may occasionally progress to anaphylaxis.[21]

Atopic dermatitis

Food allergy plays a pathological role in a small subset of young children and infants with atopic dermatitis. The mechanism is a type I hypersensitivity reaction and/or type IV delayed-type reaction.[22] Approximately one third of children with severe atopic dermatitis have IgE-mediated food allergies that exacerbate their underlying eczema.[22][23] For adults, the evidence of an effect of food allergy on eczema is less clear.[22][23] Food-specific IgE and food-specific T-cell responses to the most common food allergens have been implicated.

Eosinophilic oesophagitis (EoE)

This is a type I hypersensitivity reaction and/or type IV delayed-type hypersensitivity reaction that results in an inappropriate accumulation of eosinophils in the oesophagus. The incidence has increased markedly over the last decade across patients of all ages.[23] The pathophysiology seems to be related to both T-cell responses and food-specific IgE antibody; >50% of patients with EoE have other allergic diseases.[23][24] Therefore, patients with EoE should undergo evaluation for specific IgE to foods.[25]

Infants and young children with EoE may present with failure to thrive, vomiting, or regurgitation, while children and adolescents often suffer from heartburn, abdominal pain, or dysphagia.[24] Adult patients typically present with food impaction as well as dysphagia.[26] Patients with these symptoms should be treated with medications for gastro-esophageal reflux initially. Any patient with food impaction, dysphagia, or failure to respond to anti-reflux therapy should be evaluated for EoE.[27]

Food protein-induced enterocolitis/proctocolitis

Food protein-induced enterocolitis is a severe type IV delayed-type food hypersensitivity reaction, generally seen in young infants and usually in response to milk or soya.[28][29] Less commonly, it may be a response to grains, vegetables, or poultry.[29] Often enterocolitis to solid food is likely to involve more than one food, is typically to grains, and may also involve milk and soya.[29][30] These infants usually present 2 hours after milk or soya ingestion with profuse vomiting, diarrhoea, irritability, and lethargy that may progress to dehydration and shock.[28][29] Repeat exposures to the inciting food agent elicit similar responses, and continued exposure may result in bloody diarrhoea and failure to thrive.[16] Diagnosis is based primarily on history, as evidence of food-specific IgE is often negative.[30]

In food protein-induced proctocolitis, healthy, thriving young infants typically present with intermittent blood-streaked, loose stools.[1] Food protein-induced proctocolitis is usually caused by immune responses to cows' milk or soya-based formulas in infants aged 1 to 4 months.[31] However, 50% of infants with proctocolitis are breastfed and may be responding to a food antigen in the maternal diet.[16] Diagnosis is based on history. Symptoms resolve once the offending food is removed from the infant's diet, or from the maternal diet if the mother is breastfeeding.[32]

Coeliac disease

A disease of chronic inflammation in the small intestine that occurs due hypersensitivity to cereal gluten proteins in wheat, rye, and barley.[33][34]​​​​ In Europe and the US, the mean frequency of coeliac disease in the general population is approximately 1%.[35]​ Coeliac disease can present at any age. About 95% of patients are positive for HLA-DQ2; coeliac disease is also associated with HLA-DQ8.[36]​ 

​​​​Chronic inflammation of the mucosa leads to villous atrophy. Although antibodies against auto-antigens are present in some coeliac patients, not all have autoantibodies.[34] Coeliac disease may, however, be associated with autoimmune disorders such as type I diabetes and autoimmune thyroiditis.[33]​​[34][37]​​

Lactose intolerance

Lactose intolerance is a fairly common condition that results from a deficiency of the enzyme lactase.[7][13] Lactose is the primary carbohydrate in mammalian milk and is a disaccharide that requires breakdown by lactase into glucose and galactose in order for absorption to occur.[7][13] When the lactase enzyme is deficient, lactose travels from the small intestine undigested into the colon. Undigested lactose generates an osmotic load that draws fluid into the colon leading to loose stools.[7] Furthermore, colonic bacteria may metabolise lactose into volatile fatty acids and gases, thereby causing abdominal pain, bloating, and flatulence.[13] Infants with congenital lactase deficiency are extremely rare. These infants develop diarrhoea in response to ingestion of formula from birth. The most common form of lactose intolerance results from the loss of lactase with age.[7][13]

Congenital sucrase isomaltase deficiency

Sucrase isomaltase deficiency is an autosomal dominant disorder resulting from congenital deficiencies in the enzymes sucrase and isomaltase, which are responsible for digestion of sucrose.[38] Because sucrose is not broken down in the small intestine, it travels undigested to the colon. In the colon, it causes osmotic load and fluid influx, which results in diarrhoea and, possibly, failure to thrive.[38]

Tyramine reactions

Tyramine is a biogenic amine, which acts to release noradrenaline from sympathetic nerve terminals. Tyramine is degraded by monoamine oxidase.[39] It has been proposed to trigger headaches through the release of noradrenaline, which may then act on alpha-adrenergic receptors.[39] This proposed mechanism of action was derived from observations that patients taking monoamine oxidase inhibitors developed headaches when they ingested aged cheese, which has a high tyramine content.[39] However, more rigorous studies involving tyramine challenges in patients with food-induced migraines have failed to find an association between tyramine ingestion and the development of migraines.[8]

Monosodium glutamate (MSG) reactions

MSG is a flavour enhancer that is added to many foods, as well as being found naturally in food.[7] Reports of MSG sensitivity have existed for many years.[7][40] However, numerous controlled trials in self-reported MSG-sensitive patients have failed to confirm any reactions to MSG.[7][40] Therefore, MSG reactions may not be a true food sensitivity.

Sulfite sensitivity

Sulfites are added to food to prevent browning, to control microbial growth, and to modify textures.[41] Sulfite sensitivity is a problem in some asthmatic patients, particularly in those who are dependent on corticosteroids.[10][41] Three potential mechanisms of action to explain sulfite sensitivity have been described: bronchospasm secondary to inhalation; IgE-mediated reactions to sulfites; and some patients have been found to have less sulfite oxidase activity in their fibroblasts.[10]

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