Food Intolerance and Allergy

According to some surveys, 20 to 25% of people in the U.S. are allergic to certain foods. Self-reported information based on changes in dietary habits to accommodate a food problem is likely to be mostly erroneous. Often, patients who say they have a food allergy avoid a food and never seek medical advice. Diagnosis of food allergies is overworked, poorly defined, and misused. There are many misconceptions about food allergies, such as understanding of the causes of food allergies and their symptoms. A minority of practitioners who have overemphasized the magnitude of the role of food allergies in human illness have greatly contributed to this misconception. The American Academy of Allergy and Immunology has sharply criticized their concepts and questioned their practices.

Double-blind placebo-controlled studies indicate that food allergies occur in 2 to 2.5% of the population. It has been estimated that 1 to 3% of children under the age of 6 years have allergies to foods. The frequency of food allergies is highest in infancy and early childhood, but decreases with age. Childhood allergies to egg and cow's milk usually disappear, but allergies to nuts, legumes, fish, and shellfish tend to linger throughout life. Prevalence of childhood allergies is related to the gastrointestinal epithelial membrane barrier, which is immature during infancy. Thus, the barrier allows more proteins into the circulation, which can sensitize infants to ingested allergens. The mucosal barrier becomes less absorptive and more efficient for digestion as the child matures, and cow's milk and eggs become less offending.

Food allergies can be influenced by culture and eating habits. In Scandinavia, fish can be responsible for food allergies. In Japan, both fish and rice can cause food-induced allergies. In the U.S., the prevalent food that causes allergies is peanuts. Because of the internationalization of food supply, there is an increase in food allergies due to exotic foods, e.g., kiwi. Genetic influence is very strong for food-induced allergies. If one parent is allergic, then the risk of the same allergy occurring in offspring is increased by 50%. If both parents show food allergies, the chance of offspring having similar problems increases to 67 to 100%.

For a small population, the problem of allergies can be life threatening. Allergies cause more than 100 deaths/year in the U.S. Anaphylactic episodes due to food account for a third of all cases, with twice the incidence and three times the mortality compared with those by bee stings.

Allergy can be defined as a disease state caused by exposure to a particular chemical to which certain individuals have a heightened sensitivity (hypersensitiv-

TABLE 10.1 Food Sensitivities

Primary Food Sensitivity

Immunological (Food Allergies)

IgE-mediated Non-IgE-mediated

Nonimmunological (Food Intolerance)

Anaphylactoid reactions Metabolic reactions Idiosyncratic reactions

Secondary Food Sensitivity

Secondary to GI disorders Secondary to drug treatment ity), which has an immunological basis. Foods are not the only substances to which people can be allergic. Bee stings, insect bites, pollen, dander, mold spores, house dust, and drugs can also initiate allergies. For such allergens, the symptoms are identical to those found for food allergies, and many individuals suffer multiple sensitivities from food or other sources.

allergy and types of hypersensitivity

Many people eat a variety of foods and show no ill effects; however, a few people exhibit adverse reactions to certain foods. Food sensitivities refer to the broad concept of individual adverse reactions to foods. Food sensitivities are reproducible, unpleasant reactions to specific food or food ingredients. There are many types of adverse reactions to foods, e.g., hives, headaches, asthma, and gastrointestinal complaints. Food sensitivities can be divided into primary and secondary sensitivities (Table 10.1).

Primary Food Sensitivity

Primary food sensitivities can be divided into immunological and nonimmunological reactions. The basis of an abnormal immunological response after food consumption is a true food allergy or hypersensitivity. Primary sensitivities involving immuno-logical reactions are further divided into IgE-mediated and non-IgE-mediated food allergies. Individuals who have IgE-mediated food allergy reactions to certain components (allergens) constitute only a small part of food sensitivities. The reactions are often noted as immediate hypersensitivity reactions, because the symptoms occur soon after ingesting the offending foods. Food allergens are defined as common food proteins which, in certain individuals, produce substances that induce allergic symptoms and can be life threatening. As in all people, the allergens are ingested, pass through the gut epithelium, and circulate in the blood; however, the immune system of some individuals reacts to these food allergens by manufacturing immunoglobulin E (IgE).

Foods contain many proteins, but only a few of them are allergens. Virtually all allergens are proteins, but not all proteins are food allergens. Allergens tend to be the most abundant protein found in a particular food. Overall, in most people, major muscle proteins in beef, pork, and chicken do not cause allergic reactions. Important

TABLE 10.2

Properties of Major Immunoglobulin (Ig) Classes

Half-Life Percent of Total Ig Class (d) Circulating Ig Structure

Tissue in Which Found and Properties

7-21

Monomer

Blood and lymph, attaches to phagocytes,complementfixation Blood and lymph, secretory antibody Blood and lymph, attaches to phagocytes Surface of B-cells Blood and lymph, attaches to mast cells and basophils, allergic response

IgA IgM

6 10

15 5-10

Monomer, dimer Pentamer

Monomer Monomer allergens of the legumes are storage proteins,whichmakeupthemajorityofthe protein content of the seed, whereas the major allergenic protein from codfish is present in a small amount in the fish. Mostallergenicfoodscontainmultiplealler-gens; for example, egg white contains 20 proteins, of which 5 or 6 are allergenic. Most allergens are stable to digestion andprocessing, e.g.,acid-resistantglycopro-teins. Fruits and vegetables are the exceptions; however, there might be oral signs related to allergic reactions. Heat and processingtendtochangethetertiarystructure of food proteins, but this may be minimallyimportanttotheir allergenicity.

IgE is one of five antibody systems thathumanshavetofightinfectionandresist disease, the other immunoglobulins being IgG,IgA,IgM,andIgD. Table10.2defines some properties of major immunoglobulinclasses.

A particular role of IgE is in fighting parasiticinfection.Usually,mosthumans have a low level of circulating IgE antibodies, butsomeindividualspredisposedto developing allergies produce IgE antibodies that are specific for and recognize certain antigens.

The IgE and other immunoglobulins areproducedbyplasmacells derivedfrom B cells, or B lymphocytes. IgEs have the abilitytorecognizefoodallergens. The B lymphocytes are mainly derived from lymphoidtissueofthebone marrowinhigher animals and from the bursa of Fabricius in birds. The other major components of the immune system are the T lymphocytes, which are of thymic lymphoid tissue origin. The lymphoid tissues of the bone and thymus are referred to as primary lymphoid tissues. Secondary lymphoid tissues include the spleen, lymph nodes, tonsils, and adenoids. There are also some lymphoid aggregates at the three major portals of entry for environmental agents, the lung, gut, and skin: the bronchus-associated lymphoid tissue (BALT), gut-associated lymphoid tissue (GALT), and skin-associated lymphoid tissue (SALT). Thus, B cells are responsible for the synthesis of circulating humoral antibodies or immunoglobins, and T cells are involved in a variety of important cell-mediated processes, such as graft rejection, hypersen-sitivity reactions, and defense against malignant cells and many viruses.

IgE molecules are secreted out of the B cells and are distributed through the circulatory system, where they can find a mast cell. Mast cells are ubiquitous and

Allergen

Stimulates Production of

Stimulates Production of

Mast cells Basophils

Sensitized Cell

Mast cells Basophils

Sensitized Cell

Histamine

Allergen

Heparin

Allergen

Histamine

Platelet-aggregating factor

Heparin

FIGURE 10.1 IgE-mediated allergic reaction.

in the blood stream are called basophils. Basophils and mast cells contain granules filled with active chemicals (mediators) thatcanbereleasedduringanallergicor inflammatory response. The mechanism ofIgE-mediatedallergicreaction,orimme-diate hypersensitivity (Type I; Figure 10.1), is composed of two major events. The first event or sensitization is when an allergen(antigen)isconsumed.Otherroutes of exposure can be portals for sensitization,i.e.,therespiratorytractortheskin. Serum concentration of IgE is low comparedwiththatofotherimmunoglobulins, and its serum half-life is relatively short (Table ).Once theallergenisconsumed, the individual become sensitized. Sensitization results in production of allergen-specific IgE antibodies, which then bind to local tissue mast cells and on entering the circulation bind to circulating mast cells, basophils, and other tissue mast cells distal to the original site of entrance. The second event occurs after subsequent exposures or reexposure to the allergenic material, whereupon the allergen crosslinks two IgE antibodies on the surface ofthemastcellorbasophilmembranevia sites called Fc receptors. This cross-link resultsinachangeinthemembrane (degranulation) and stimulates the release of chemicalmediatorssuch ashistamine,heparin, and platelet aggregating factor. These mediatorspromote vasodilation,inflammation, and bronchial constriction. Clinical manifestations vary from urticarial skin reactions (wheals and flares) to rhinitis and conjuctivitis to asthma and anaphylaxis.

The mechanism of IgE-mediated sensitivity is identical to that of allergic reactions to various environmental substances, such as pollen, pet dander, drugs, penicillin, and insect stings. The food allergen must be small enough to gain access through the body's barrier (GI membrane, skin, lungs) but large enough for the immune system to recognize. Some structural characteristics of allergens may be shared by similar foods and be biologically related, and sensitive people may consequently have IgEs that cross-react with the related foods.

Non-IgE-mediated primary food sensitivities are usually manifested by 6- to 24-h delayed hypersensitivity reactions following ingestion of food material. The allergic reactions develop slowly and peak at 48 h, subsiding 72 to 96 h later. Mounting evidence suggests that the allergic response involves the interaction between specific allergens from the food and sensitized, tissue-bound T cells, releasing inflammatory mediators. Celiac disease or celiac sprue is an example of a non-IgE-mediated immunological primary food sensitivity. Celiac disease sufferers are sensitive to glutens, particularly the gliadin fraction of wheat and related crops. Gliadin is a simple protein found in the gluten, consisting of 43% glutamine. Following ingestion of glutens, the absorptive epithelial cells in the small intestine become damaged by an inflammatory process. The intestinal damage results in a severe malabsorption syndrome, i.e., diarrhea, bloating, weight loss, anemia, fatigue, and muscle and bone pain. In children, celiac disease can cause failure to gain weight and growth retardation. Celiac disease is an inherited trait affecting people of European backgrounds and is very rare in Asians and Africans. Some believe that the affected population lacks an enzyme necessary to digest gliadin. Celiac disease is treated by avoiding gliadin foods, which restores the absorptive function and resolves the disease. Celiac disease sufferers can exhibit symptoms by ingesting even small amounts of gluten grains.

Nonimmunological Primary Food Sensitivities

These reactions have been referred to as food intolerances and involve nonimmu-nological mechanisms. Like true food allergies, food intolerances affect some people only, and usually they can tolerate small amounts of the offending food without adverse effects. Nonimmunological primary food sensitivities can be categorized as anaphylactoid reactions, metabolic food disorders, and idiosyncratic illnesses (Table 10.3).

Anaphylactoid reactions are adverse reactions caused by foods or food components that produce a spontaneous release of histamine and related mediators from tissue mast cells. Thus, except the IgE-mediated response, the reaction to foods or food components is identical to that for true food allergies. Substances found in the offending food may react with and destabilize the membrane of mast cells, releasing

TABLE 10.3

Nonimmunological Reactions

Anaphylactoid Metabolic Idiosyncratic

Strawberry

Cheese

Chocolate

Lactose Sulfite

Favism Tartrazine

Cabbage MSG Licorice BHT/BHA

histamine and other mediators. The mechanism is well established for certain drugs; however, no histamine-releasing substances have been isolated from such offending foods, e.g., strawberry allergy. Individuals affected by the ingestion of strawberries exhibit true food allergy symptoms, such as hives, but the symptoms are not IgE-mediated. One symptom mimics anaphylaxis.

Metabolic food disorders can be either due to inherited defects in the metabolism of a food or food component or due to genetically linked enhanced sensitivity to some food chemical. For example, individuals with lactose intolerance lack the enzyme lactase or b-galactosidase in the intestinal mucosa. As a result, such individuals cannot hydrolyze lactose or milk sugar into its monosaccharides, galactose and glucose. The undigested lactose cannot be absorbed, so it passes down the small intestine to the colon, where bacteria ferment it. Fermentation of lactose to carbon dioxide, water, and acetic acid results in gas, abdominal cramping, and diarrhea. Lactose intolerance is prevalent in some ethnic groups, such as Greeks, Arabs, Jews, African Americans, Hispanics, and Asians. In susceptible individuals, the activity of intestinal b-galactosidase is usually enough at birth to provide sufficient digestion of mothers' milk. With time, such individuals lose enzyme activity, and lactose intolerance can begin at any age. The condition can be very severe in the elderly.

Individuals who lack the red cell enzyme glucose-6-phosphate dehydrogenase (G6PDH) are susceptible to favism, a metabolic food disorder to ingested fava beans. Fava beans contain vicine and convicine, which are naturally occurring oxidants. These oxidants damage the red cell membranes of G6PDH-deficient individuals, resulting in erythrocyte hemolysis, causing individuals to suffer from hemolytic anemia. G6PDH is a critical red blood cell enzyme responsible for maintaining glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), which help prevent oxidative damage. G6PDH deficiency is common, affecting approximately 100 million people worldwide, with highest prevalence among populations of Jews, Greeks, and African Americans.

Individuals sensitive to cabbage exhibit goiter, because isothiocyanates present in cabbage interfere with the utilization of iodine. Some people are sensitive to licorice because the glycyrrhizic acid found in licorice mimics mineralocorticoids, resulting in hypertension and cardiac enlargement following sodium retention.

Idiosyncratic Reactions

Individuals who display idiosyncratic reactions to foods show a link between ingestion of such foods and their illness but without any defined mechanisms. The symptoms associated with idiosyncratic reactions can be from trivial to life threatening. For many cases, the role of specific food ingredients in causing idiosyncratic reactions remains to be determined. The cause-and-effect relationship can only be established through carefully controlled double-blind food challenges.

An example of a well-established idiosyncratic reaction is sulfite-induced asthma. Sulfites are widely used as food ingredients to control nonenzymatic and enzymatic browning and to prevent bacterial growth. Sulfites also are useful anti-oxidants and can condition dough and bleach certain foods. In some asthmatic populations, sulfite ingestion initiates an asthmatic reaction, which can be severe, and, on occasions, life threatening. The prevalence of sulfite sensitivity among asthmatics ranges from 1 to 10%. The most severe asthmatics seem to be the individuals who are most sulfite sensitive. Sulfite sensitivity is diagnosed by subjecting individuals to a sulfite challenge test, with the sulfite administered in a doubleblind fashion.

Sulfite sensitivity may be due to a partial deficiency of sulfite oxidase in sulfitesensitive asthmatics. Inhalation of sulfur dioxide vapors during the ingestion of foods and beverages may trigger an irritative reaction in the lungs of sensitive asthmatics. Some sulfite-sensitive asthmatics exhibit a positive skin test to sulfites, indicating a possible IgE-mediated mechanism.

Tartrazine sensitivity has been reported to cause asthma in some children, and such reports have been verified by double-blind studies. A high dose of monosodium glutamate (MSG) affects small populations. There have been a few isolated reports suggesting that butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) elicit sensitivity, but this has not yet been proven.

Secondary Food Sensitivity

Secondary food sensitivities are adverse reactions to food that occur as a consequence of other conditions. Examples include secondary sensitivities to gastrointestinal disorders or to drug treatment. Lactose intolerance is an adverse effect to lactose and occurs secondarily to a gastrointestinal disorder. Individuals who take antide-pressant drugs have an increased sensitivity to tyramine. Secondary food sensitivities often disappear within a few weeks after recovery from the illness or discontinuation of drug therapy. A variety of gastrointestinal illnesses can enhance the chance of developing food allergies, such as bacterial or viral gastroenteritis, cystic fibrosis, Crohn's disease, and ulcerative colitis.

symptoms and diagnosis

Usually, individuals prone to food allergies suffer only a few symptoms. Symptoms can vary among individuals, ranging from the common gastrointestinal symptoms to severe anaphylaxis. Table 10.4 summarizes the symptoms experienced during allergic reactions to foods. Rhinitis is runny nose, asthma is difficulty breathing, laryngeal edema is constriction of the throat, angioedema is swelling, urticaria is hives, and eczema/atopic dermatitis is skin rash. The potentially fatal form of food-

TABLE 10.4

Symptoms of IgE-Mediated Food Allergies

Respiratory Cutaneous Gastrointestinal Systemic

Rhinitis Angioedema Abdominal cramps Anaphylactic shock

Asthma Urticaria Diarrhea

Laryngeal edema Eczema/atopic dermatitis Nausea

Vomiting allergic response, anaphylaxis, is rare, but may begin with mild symptoms (tongue swelling and itching, throat tightening, wheezing and cyanosis) and develop rapidly, resulting in cardiorespiratory arrest and shock. Death may occur rapidly if the individual cannot obtain medications.

In some individuals, exercise before or just after ingesting the offending food can induce symptoms of food allergies, including severe anaphylaxis. Certain foods, such as shellfish, wheat, and celery, produce symptoms provoked by exercise. The mechanism of action is unknown, but may involve enhanced mast cell responsiveness to physical stimuli.

The first step in the diagnosis of IgE-mediated food allergies is to establish an association between the ingestion of one or more offending foods and the elicitation of an adverse reaction. An allergist should be consulted, because self-diagnosis or parental diagnosis of children can be problematic, leading to erroneous findings. Careful history-taking, which includes a food diary by an experienced allergist, can often identify problem foods. This can be confirmed by using elimination diets of the suspected problem food, followed by challenges. The double-blind placebo-controlled food challenge (DBPCFC) is often used in clinical situations to document the existence of a food-associated adverse reaction. However, DBPCFC is not used in cases involving serious, life-threatening adverse reactions because of the risk to the patient. After the role of the specific offending food has been established, the involvement of the IgE mechanism can be documented through skin-prick tests by using extracts of the suspected foods. Alternatively, radioallergosorbent tests (RASTs) can be done to test for the presence of food-specific IgE antibodies in the blood of patients. A summary of steps in the diagnosis of IgE-mediated food allergies is shown in Table 10.5.

treatment

Approaches for treating food allergies include (1) specific avoidance diet, (2) overall elimination diet, (3) pharmacological treatment, and (4) prophylactic treatment.

In a specific avoidance diet, the problem food or foods containing the offending substances are eliminated from the diet. Careful scrutiny of labels and considerable knowledge of food composition are important. Even with such knowledge, difficulties may be encountered because of the presence of allergenic residues that do not appear on a label and because labeling is inadequate in restaurant and eating establishments away from home. A patient must have considerable knowledge of possible hidden sources of the allergen in the diet. The potential problem with specific avoidance diets is that such diets could lead to nutritional deficiencies. Specific avoidance diets

TABLE 10.5

Steps in the Diagnosis of IgE-Mediated Food Allergies

Food diary

Double-blind placebo-controlled food challenge (DBPCFC) Skin prick test (SPT) or radioallergosorbent test (RAST)

can be a successful treatment approach; however, it is important that such diets be based on solid data from patients' history and skin tests and food challenge tests. Unfortunately, very few medical foods are available for those with food allergies. Infants allergic to cow's milk can be given soybean and hydrolyzed casein products, but for the many other types of food allergies, very few substitutes are available.

The overall elimination diet is used in situations where a variety of possible allergenic foods have to be removed from the diet at one time. Such diets are used for patients with severe, chronic cases of an allergy, often due to multiple foods. Although this technique may resolve chronic symptoms of such individuals, the diets become unpalatable if used for long.

Pharmacological treatments include various antihistamines, which are used to treat the symptoms following an allergy episode, and epinephrine-filled syringes for life-threatening reactions. Physicians often advise individuals with a lifelong history of acute allergic reactions to carry antihistamines or epinephrine products to be rapidly administered. Prior treatment of some individuals with antihistamines allows some to tolerate offending foods, particularly patients allergic to cow's milk. Although immunotherapy has been useful in treating insect-sting and pollen allergies, no definitive evidence has been obtained for their use against food allergies.

Many studies have been done to address the usefulness of breast-feeding as a prophylactic treatment in preventing food allergies. The results have been mixed, with the edge given in favor of the benefits of breast-feeding. Many allergists are recommending exclusive breast-feeding for at least 6 months, particularly to infants with a family history of allergies. Some have recommended breast-feeding for even longer than 6 months because some studies have demonstrated that allergies to cow's milk can develop in infants exclusively breast-fed for 6 months. Others have suggested that if the infant's diet is well managed for the introduction of other foods early on, breast-feeding for beyond 6 months is not necessary. Little is known regarding the mechanism of prophylactic action of breast milk; however, the presence of secretory IgA antibodies in breast milk may play a role. Some infants even after being fed breast milk develop food allergies. It is likely that transmission of protein allergens occurs through breast milk or even via in utero sensitization. Both egg and soybean proteins have been identified in both human colostrum and mature breast milk.

study questions and exercises

1. Describe, in words and with an illustration, IgE-mediated sensitivities.

2. What are the major types of immunoglobulins? Describe their properties.

3. Describe food allergies, sensitivities, and intolerances. What are idiosyncratic reactions?

recommended readings

Bruggink, T., Food allergy and food intolerance, in Food Safety and Toxicity, deVries, J., Ed., CRC Press, Boca Raton, FL, 1997, pp. 183-193.

Metcalfe, D.D., Food allergens, Clin. Rev. Aller., 3, 331-349, 1985.

Selgrade, M.K., Germolec, D.R., Luebke, R.W., Smialowicz, R.J., Ward, M.D., and Sailstad,

D.M., Immunotoxicity, in Introduction to Biochemical Toxicology, 3rd ed., Hodgson,

E. and Smart, R.C., Eds., Wiley-Interscience, New York, 2001, pp. 561-598. Sampson, H.A., Mechanisms in adverse reactions to food, Allergy, 50, 46-51, 1995. Sampson, H.A., Food allergy: from biology toward therapy, Hosp. Pract., pp. 67-83, May

Taylor, S.L. and Hefle, S.L., Food allergies and other food sensitivities, Food Techn., 55, 6883, 2001.

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