Definition of adverse reactions to food

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Fig. 1. A classification of adverse reactions to foods.

First of all, adverse reactions to foods are divided into toxic and non-toxic food reactions.

Toxic food reactions derive from the general toxicity to humans, not individual susceptibility, of some substances that contaminate foods or that are naturally present, e.g. poison in non-edible mushrooms. Allergists must be aware of toxic food reactions on account of their prevalence among adverse reactions to foods, to make a correct differential diagnosis.

Non-toxic food reactions depend on an individual’s susceptibility to certain foodstuffs. These reactions are divided into immune-mediated and non immune-mediated reactions. The term food allergy is commonly used for immune-mediated reactions, while non immune-mediated reactions are referred to as food intolerance. Food allergy can be further divided into IgE-mediated and non IgE-mediated reactions.

IgE-mediated reactions affect atopic patients who present IgE antibodies, confirmed by in vivo and/or in vitro tests, specific to foods that significantly correlate with the symptoms and/or provocative tests.

The term non IgE-mediated food allergy includes immune reactions caused by specific food allergen immunoglobulins other than IgE, food immune-complexes and cell-mediated immunity specific to food. In this case too, in order to establish a correct diagnosis, the existence of an immune mediated mechanism (other than IgE) against the suspected food must be proved by means of in vivo and/or in vitro tests and a correlation demonstrated with ingestion of the suspected food and symptoms or provocative tests with this food.

Non immune-mediated food adverse reactions, or food intolerance, are definitions used when the history and/or the provocative tests clearly prove the causative role of a food but there is no evidence of an immunological mechanism. Other mechanisms have been suggested, but rarely demonstrated, to explain these reactions, which are likely to be caused mainly by enzymatic defects or pharmacological actions of drugs or other pharmacologically active substances added to the food or naturally present in it. These reactions are therefore subdivided into enzymatic and pharmacological reactions. When the mechanism of non immune mediated food adverse reactions is not known the reactions are classified in the group of undefined reactions.

Psychosomatic food adverse reactions are not included in the EAACI classification because they are related to a primary mental disorder and are not truly food dependent. However, in clinical practice most patients who believe they are allergic to some food belong to this category (3, 4).

This partially depends on the individual beliefs of patients suffering from vague, recurrent symptoms; when they start to suspect some particular food unfortunately they often find confirmation in the many articles published in magazines and newspapers. Popular medical literature may often attribute a lot of symptoms to food allergy simply on the basis of non-validated hypotheses and anecdotal reports. Then, finally, many of these patients find their assumptions borne out by physicians who apply unorthodox diagnostic procedures that have not been critically analyzed. To avoid this it is sufficient to follow the diagnostic protocols published in the last few years (2, 5) by official international allergy associations.

Characteristics of the different adverse reactions to foods

Toxic reactions
A lot of toxic substances may be present in foodstuffs. However toxic reactions have a low prevalence because the amounts of these toxic substances are generally too small to cause symptoms and habitual dietary variety limits the intake of any single toxin. C. May (6) classified toxic substances in foodstuffs as follows:

• Naturally occurring, both endogenous and exogenous (Table 1)
• Induced in food processing
• Contaminants
• Additives

Table I.
Some examples of naturally occurring toxins in animal and vegetal foods.

Food toxicity mainly affects the CNS (headache, hallucination, incoherence and even convulsions), liver and blood. Toxins induced during food processing, contaminants and additives are the major sources of foodstuff toxicity today. Modern food technology enables us to produce, preserve and distribute large quantities of foods but there enters the frequent risks of breakdown in the food production and distribution chain, exposing many individuals to a high risk of food toxicity. An example of this is the Scombroid syndrome that has become one of the major chemical food-borne illnesses reported in previous years (7, 8).

Non-toxic reactions
Immunological reactions
(food allergy)

IgE-mediated allergy
The role of Type I IgE-mediated reactions in food allergy is the best established. The presence of IgE antibodies directed against an offending food confirms the existence of an IgE mechanism, although clearly this holds only for cases in which a relationship between the ingestion of a particular food and the onset of symptoms is well-established. Double-blind placebo-controlled food challenges (DBPCFC) are frequently necessary to demonstrate this relationship in order to exclude psychological reactions, and to eliminate the physician’s and patient’s bias and prejudice and to obtain objective evidence.

Controlled trials have confirmed a variety of symptoms presumed to be secondary to an IgE-mediated response (9-11). Classical symptoms of allergy are present, i.e. anaphylaxis (associated with exercise in some cases) ; cutaneous manifestations like urticaria-angioedema, atopic dermatitis and contact dermatitis, upper and lower respiratory symptoms like rhinitis (rare), larynx edema and asthma, gastrointestinal disorders like oral allergy syndrome (OAS), infantile colic, nausea, vomiting, diarrhea and abdominal pain and neurological symptoms. However, there is no convincing evidence of a relationship between food and hyperreactivity, depression or migraine. The foods which have been found to cause IgE-mediated food allergy most frequently in series of controlled studies and based on the findings of studies (12) in adults and children after DBPCFC were: egg, milk, peanut, nuts, fish and soy in children, and peanuts, nuts, fish and shellfish in adults.

The prevalence of reactions to specific foods may depend on the eating habits or other peculiarities of a given population; for example soybean allergy is more common in Japan and fish allergies are more prevalent in Scandinavian countries; patients suffering from allergies to certain pollens more often react with OAS to certain fresh fruits and vegetables (13, 14). These patients with pollen allergy present very intense mucosal sensitivity to foods, such that local symptoms are evident within 15 minutes of food contact. OAS is IgE-mediated. The symptoms are generally limited to the oral cavity and pharynx, though they may give way to more serious local manifestations, e.g. angioedema of the oral cavity and pharynx; or distant manifestations such as urticaria, conjunctivitis, orbital angioedema, asthma, and gastrointestinal symptoms. Generalized reactions such as anaphylactic shock may also arise. Apple, peach, cherry, nuts, celery, carrot, tomato and fennel are the main foods likely to induce this IgE-mediated syndrome (13, 14).

The diagnostic protocol for food allergy comprises some fundamental steps:

• Skin prick tests and/or specific IgE test with appropriate antigens
• In case of positivity: Strict avoidance of the allergen for three weeks or more
• If the symptoms disappear: Single blind challenge
• If positive: DBPCFC in hospital.

Non-IgE-mediated allergy
Non-IgE-mediated food allergy provides the evidence that specific food allergen immunoglobulins, belonging to a non-IgE class, or food immune-complexes or cell-mediated immunity specific to foods are directly involved in the mechanism provoking the symptoms. IgG4 anti-food antibodies are frequently found in patients with adverse reactions to foods (15), but they are also seen in normal subjects and the pathogenetic role has not been demonstrated. The presence may be the consequence of prolonged exposure to ubiquitous antigens resulting in an IgG4 restricted response (16). Circulating IgG and IgE immune-complexes containing food antigens may be found in patients with food allergy suffering from asthma and eczema (15, 17), but only rarely has a pathophysiological role unequivocally been demonstrated for these complexes. So far there is also no definitive evidence that either IgG or IgE food immune-complexes cause human disease (15, 17).

There is ample indirect evidence that celiac disease may be provoked by a cell-mediated food allergy to gliadin, a prolamine contained in gluten (18, 19). T cells appear to be involved in the pathogenesis of this disease (20, 21), although exhaustive proof is still lacking that these immune phenomena are directly causative of the human disease. Whether the elevated IgA and IgG antigliadin antibodies play any role in the immunopathogenesis of this disease is also unclear (22, 23).

A clinical picture and histological alterations of the jejunal mucosa mimicking celiac disease are present in some infants with malabsorption syndrome; patchy villous atrophy with cellular infiltrate on jejunal biopsy is associated with the weaning period and cow’s-milk sensitivity is the most frequent cause of this syndrome (24). Sensitivity to soy, egg and wheat have also been reported in this syndrome (25). Serum IgA and IgG antibodies specific to the milk are elevated in cow’s milk-induced malabsorption (26). These abnormalities suggest both type-III (immunocomplexes) and type IV (cell-mediated) immunopathogenesis.

The same mechanisms are suggested for food-induced enterocolitis syndrome in infants (27). The jejunal biopsy shows flattened villi, edema and an increased number of lymphocytes, eosinophils and mast cells. Cow’s milk or soy protein or both are most often responsible. These foods are also involved in food-induced colitis which differs from the above infantile syndromes in its mild clinical picture, generally characterized by the presence of gross or occult blood in the stools and a prominent eosinophilic infiltrate in the colonic mucosa (28). Food-induced pulmonary hemosiderosis is very rare (Heiner’s syndrome), affecting infants with non-IgE-mediated hypersensitivity to cow’s milk, but reactivity to egg and pork has also been reported (29).

Non-immune mediated adverse reactions to foods

Enzymatic food intolerance
Enzymatic food intolerance means an adverse reaction to food or food additives resulting from an enzymatic defect which becomes clinically evident after administration of certain foods. The most common manifestations are:

Conditions Deficiencies

• Disaccharidase lactase, sucrase deficiencies
• Galactosemia galactose 1 phosphate uridyl transferase uridine diphosphate-4 epimerase
• Phenylketonuria phenylalanine hydroxylase
• Alcohol intolerance aldehyde dehydrogenase
• Favism G6PD

Except for lactase deficiency, these are very rare conditions or inborn errors of metabolism. However it is widely held that many undefined food intolerances may result from enzymatic defects. For example, a deficiency of diamine oxidase has been postulated in patients with intolerance to histamine-containing foods (30), but clear evidence of a clinical syndrome due to this enzymatic defect has never been found.

Pharmacological food intolerance
The substances responsible for pharmacological food intolerance are summarized below.

1. Vasoactive amines:
   - monoamines (tyramine, phenylethylamine)
   - histamine
    
2. Indirect pharmacological reactions
   (histamine releasing food stuffs?)
    
3. Food additives

Pharmacological food intolerance may depend on the direct effect of vasoactive amines naturally found in foods. Ingestion of large amounts of a food containing one or more of these amines will be followed by toxic symptoms. Some individuals, however, may have symptoms after eating even a very small amount of one of these substances. In particular, the threshold of susceptibility to histamine maybe lowered in some individuals. Selected foods containing relatively large amounts of histamine or histidine or both can pose problems in these intolerant subjects (31). In scombroid poisoning factors potentiating histamine toxicity are involved and therefore this syndrome must be classified as a toxic food reaction (32).

The largest amounts of histamine and tyramine are found in fermented foods, such as cheese, alcoholic beverages, tinned fish, fish autolysates (Nuoc-Mam), sauerkraut, tuna, dry pork and sausage (33-36).

Some studies indicate that tyramine may play a role in migraine and chronic urticaria, especially in patients treated with a MAO inhibitor (31). In addition certain foods are said to have histamine releasing properties (31, 37). Examples include egg white, shellfish, strawberries, tomatoes, chocolate, citrus fruit, fish and pork. However there is no evidence of this. Studies "demonstrating" histamine release by these foods are non controlled, very old and performed in laboratory animals. More appropriate studies are therefore necessary before this possibility is accepted.

Additive intolerance
Some cases of IgE-mediated additive allergy have been documented (38), but additive intolerance caused by non-toxic reactions does not seem to depend on immune-mediated mechanisms. There are some observations that additive intolerance may depend on an enzymatic inhibition (e.g. sulphites and azo dyes) (39). Other studies show non-specific mediator release in vivo induced by challenge with some additives (ASA, sulphites, etc.) (40, 41). However the mechanisms of additive intolerance remain largely unknown, so it seems more appropriate to list additive intolerance under the heading of undefined food intolerance.

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