Background
Many food proteins can act as antigens in humans. Cow's milk proteins are most frequently implicated as a cause of food intolerance during infancy. Soybean protein ranks second as an antigen in the first months of life, particularly in infants with primary cow's milk intolerance who are placed on a soy formula. From school age on, egg protein intolerance becomes more prevalent.
Several clinical reactions to food proteins have been reported in children and adults. Only a few of these have a clear allergic immunoglobulin E (IgE)–mediated pathogenesis. For this reason, the term "food protein intolerance" is usually preferred to "food protein allergy," in order to include all offending specific reactions to food proteins, no matter the pathogenesis. In children, GI symptoms are generally most common, with a frequency ranging from 50-80%, followed by cutaneous symptoms (20-40%), and respiratory symptoms (4-25%).
Pathophysiology
The major food allergens are water-soluble glycoproteins (molecular weight [MW], 10,000-60,000) that are resistant to heat, acid, and enzymes.
Cow's milk contains more than 20 protein fractions. In the curd, 4 caseins (ie, S1, S2, S3, S4) can be identified that account for about 80% of the milk proteins. The remaining 20% of the proteins, essentially globular proteins (eg, lactalbumin, lactoglobulin, bovine serum albumin), are contained in the whey. Casein is often considered poorly immunogenic because of its flexible, noncompact structure. Historically, lactoglobulin has been accepted as the major allergen in cow's milk protein intolerance. However, polysensitization to several proteins is observed in about 75% of patients with allergy to cow's milk protein.
The proteins most frequently and most intensively recognized by specific IgE are the lactoglobulin and the casein fraction. However, all milk proteins appear to be potential allergens, even those that are present in milk in trace amounts (eg, serum bovine albumin, immunoglobulins, lactoferrin). In each allergen, numerous epitopes can be recognized by specific IgE presence. Cow's milk proteins introduced with maternal diet can be transferred to the human milk. Many studies have focused on the presence of bovine lactoglobulin throughout human lactation. The GI tract is permeable to intact antigens. The antigen uptake is an endocytotic process that involves intracellular lysosomes.
Studies have demonstrated that food allergens are transported in large quantities across the epithelium by binding to cell surface IgE/CD23, which opens a gate for intact dietary allergens to transcytose across the epithelial cells that protect the antigenic protein from lysosomal degradation in enterocytes.[1]
Some antigens can move through intercellular gaps;[2] however, the penetration of antigens through the mucosal barrier is not usually associated with clinical symptoms. Under normal circumstances, food antigen exposure via the GI tract results in a local immunoglobulin A (IgA) response and in an activation of suppressor CD8+ lymphocytes that reside in the gut-associated lymphoid tissue (oral tolerance).
In some children who are genetically susceptible, or for other as-of-yet-unknown reasons, oral tolerance does not develop, and different immunologic and inflammatory mechanisms can be elicited. Whether nonimmunologic mechanisms can have a role in the development of specific intolerances to food proteins is still disputed.
Some evidence suggests that reduced microbial exposure during infancy and early childhood result in a slower postnatal maturation of the immune system through a reduction of the number of T regulatory (Treg) cells and a possible delay in the progression to an optimal balance between TH1 and TH2 immunity, which is crucial to the clinical expression of allergy and asthma (hygiene hypothesis).[3] Genetic variations in receptors for bacterial products are likely to be related to allergic sensitizations. On the other hand, intestinal infections may increase paracellular permeability, allowing the absorption of food proteins without epithelial processing. As a consequence, infectious exposures can be an important contributory factor in the pathogenesis of food protein allergies.
Antigen uptake has been found to be increased in children with gastroenteritis and with cow's milk allergy.
Food protein intolerance can be IgE-mediated or non-IgE-mediated. Local production and systemic distribution of specific reaginic IgE plays a significant role in IgE-mediated reactions to food proteins.
Morphologic studies have demonstrated the role of GI T lymphocytes (ie, intraepithelial lymphocytes) in the pathogenesis of GI food allergy. The pathogenetic role of the eosinophils in food-induced eosinophilic GI diseases has not been defined. Vast evidence describes the occurrence of immunoglobulin G (IgG) food protein antibodies. However, their actual role in the pathogenesis of clinically relevant symptoms is, at best, doubtful.
Cow's milk contains more than 20 protein fractions. In the curd, 4 caseins (ie, S1, S2, S3, S4) can be identified that account for about 80% of the milk proteins. The remaining 20% of the proteins, essentially globular proteins (eg, lactalbumin, lactoglobulin, bovine serum albumin), are contained in the whey. Casein is often considered poorly immunogenic because of its flexible, noncompact structure. Historically, lactoglobulin has been accepted as the major allergen in cow's milk protein intolerance. However, polysensitization to several proteins is observed in about 75% of patients with allergy to cow's milk protein.
The proteins most frequently and most intensively recognized by specific IgE are the lactoglobulin and the casein fraction. However, all milk proteins appear to be potential allergens, even those that are present in milk in trace amounts (eg, serum bovine albumin, immunoglobulins, lactoferrin). In each allergen, numerous epitopes can be recognized by specific IgE presence.
Cow's milk proteins introduced with maternal diet can be transferred to the human milk. Many studies have focused on the presence of bovine lactoglobulin throughout human lactation.
The table below reports a classification of different clinical presentations of food intolerance in children, based on their presumptive underlying pathophysiological mechanisms.
Table. Classification of Main Adverse Reactions to Food (Open Table in a new window)
| Type of Reaction | Pathogenesis | Clinical Entities |
| Non–immune-mediated | Disorders of digestive-absorptive processes | Glucose-galactose malabsorption, lactase deficiency, sucrase-isomaltase deficiency, enterokinase deficiency |
| Pharmacological reactions | Tyramine in aged cheeses, histamine (eg, in strawberries, caffeine) | |
| Idiosyncratic reactions | Food additives, food colorants | |
| Inborn errors of metabolism | Phenylketonuria, hereditary fructose intolerance, tyrosinemia, galactosemia, lysinuric protein intolerance | |
| Immune-mediated (food allergy) | IgE-mediated (positive radioallergosorbent test or skin prick test results) | Oral allergy syndrome, immediate GI hypersensitivity |
| Occasionally IgE-mediated | Eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis | |
| Non–IgE-mediated | Food protein–induced entities, such as enterocolitis, enteropathy, proctocolitis, chronic constipation | |
| Autoimmune | Innate and adaptive immunity | Celiac disease |
Epidemiology
Frequency
United States
In a national survey of pediatric allergists, the prevalence rate of cow's milk allergy was reported to be 3.4%, whereas the prevalence rate of soy protein allergy was 1.1%. During the 10-year period of 1997-2006, food allergy rates significantly increased among both preschool-aged and older children.[4] In 2007, the reported food allergy rate among all children younger than 18 years was 18% higher than in 1997.
International
Incidence of food allergy in children has been variously estimated at 0.3-8%, and the incidence decreases with age. Food allergies affect 6-8% of infants younger than 2 years. In a cohort of 1,749 newborns from the municipality of Odense in Denmark who were prospectively monitored for the development of cow's milk protein intolerance during the first year of life, a 1-year incidence of 2.2% was reported.[5]
Varying incidences of specific intolerances have been reported in different countries. Whether these differences are due to genetic or cultural factors is unclear.[6]
To evaluate the prevalence of food allergy among different countries in Europe, the EuroPrevall project was launched in June 2005. Subsequently, the EuroPrevall-INCO project has been developed to evaluate the prevalence of food allergies in China, India, and Russia.[7]
Mortality/Morbidity
Most of the cases of food protein intolerance can be resolved with dietary management. A few cases of severe anaphylactic reactions to food proteins have been reported. A report from the United Kingdom suggests an incidence of 0.22 severe cases per 100.000 children per year (15% of cases were fatal or near fatal).[8]
Race
No race predilection has been observed.
Sex
No sex predilection is known, but males are slightly more frequently affected with eosinophilic gastroenteritis.
Age
Food allergy is mainly a problem in infancy and early childhood. Cow's milk allergy or intolerance usually develops in early infancy. In most of the cases, the onset of symptoms is closely related to the time of introduction of formula based on cow's milk.
In a prospective study from Norway, the prevalence of atopic dermatitis in the first 2 years was 18.6% with no significant difference between preterm and term children. Adverse reactions to food were found in 15.8% (a similar prevalence in premature and term children). Mode of delivery did not affect prevalence of atopic dermatitis.[9] An example is shown in the image below.
Typical atopic dermatitis on the face of an infant. An unselected prospective study indicated that 42% of infants who developed cow's milk protein intolerance were symptomatic within 7 days (70% within 4 wk) following the introduction of cow's milk.[4] Cow's milk protein intolerance has been diagnosed in 1.9-2.8% of general populations of infants aged 2 years or younger in different countries of northern Europe, but incidence fell to approximately 0.3% in children older than 3 years.
Protein intolerance is generally believed to remit by age 5 years, when the infant's mucosal immune system matures and the child becomes immunologically tolerant of milk proteins; in most affected children, symptoms resolve by age 1-2 years. However, cow's milk protein intolerance may persist or may initially manifest in older children, demonstrating characteristic endoscopic and histopathologic features; it occasionally recurs in adults.
Studies have suggested increased persistence of food allergies (albeit ones possibly affected by selection bias); possible explanations have been primarily focused on peanut intolerance.[10]
Yu LC. The epithelial gatekeeper against food allergy. Pediatr Neonatol. Dec 2009;50(6):247-54. [Medline].
Hong X, Tsai HJ, Wang X. Genetics of food allergy. Curr Opin Pediatr. Dec 2009;21(6):770-6. [Medline].
Sironi M, Clerici M. The hygiene hypothesis: An evolutionary perspective. Microbes Infect. Feb 21 2010;[Medline].
Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief. Oct 2008;(10):1-8. [Medline].
Assa'ad A. Eosinophilic gastrointestinal disorders. Allergy Asthma Proc. Jan-Feb 2009;30(1):17-22. [Medline].
Hill DJ, Hosking CS, Heine RG. Clinical spectrum of food allergy in children in Australia and South-East Asia: identification and targets for treatment. Ann Med. Aug 1999;31(4):272-81. [Medline].
Wong GW, Mahesh PA, Ogorodova L, et al. The EuroPrevall-INCO surveys on the prevalence of food allergies in children from China, India and Russia: the study methodology. Allergy. Nov 4 2009;[Medline].
Colver AF, Nevantaus H, Macdougall CF, Cant AJ. Severe food-allergic reactions in children across the UK and Ireland, 1998-2000. Acta Paediatr. Jun 2005;94(6):689-95. [Medline].
[Best Evidence] Kvenshagen B, Jacobsen M, Halvorsen R. Atopic dermatitis in premature and term children. Arch Dis Child. Mar 2009;94(3):202-5. [Medline].
Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. Feb 2010;125(2 Suppl 2):S116-25. [Medline].
Aceves SS, Newbury RO, Dohil MA, Bastian JF, Dohil R. A symptom scoring tool for identifying pediatric patients with eosinophilic esophagitis and correlating symptoms with inflammation. Ann Allergy Asthma Immunol. Nov 2009;103(5):401-6. [Medline].
Binkovitz LA, Lorenz EA, Di Lorenzo C, Kahwash S. Pediatric eosinophilic esophagitis: radiologic findings with pathologic correlation. Pediatr Radiol. May 2010;40(5):714-9. [Medline].
Ozdemir O, Mete E, Catal F, Ozol D. Food intolerances and eosinophilic esophagitis in childhood. Dig Dis Sci. Jan 2009;54(1):8-14. [Medline].
Rothenberg ME, Spergel JM, Sherrill JD, Annaiah K, Martin LJ, Cianferoni A. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. Apr 2010;42(4):289-91. [Medline].
Mehr SS, Kakakios AM, Kemp AS. Rice: a common and severe cause of food protein-induced enterocolitis syndrome. Arch Dis Child. Mar 2009;94(3):220-3. [Medline].
Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol. Aug 2006;17(5):351-5. [Medline].
Sicherer SH. Food protein-induced enterocolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol. Jan 2005;115(1):149-56. [Medline].
Hwang JB, Song JY, Kang YN, et al. The significance of gastric juice analysis for a positive challenge by a standard oral challenge test in typical cow's milk protein-induced enterocolitis. J Korean Med Sci. Apr 2008;23(2):251-5. [Medline].
Hwang JB, Sohn SM, Kim AS. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome. Arch Dis Child. Jun 2009;94(6):425-8. [Medline].
Behjati S, Zilbauer M, Heuschkel R, et al. Defining eosinophilic colitis in children: insights from a retrospective case series. J Pediatr Gastroenterol Nutr. Aug 2009;49(2):208-15. [Medline].
Host A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol. 2002;13 Suppl 15:23-8. [Medline].
Kokkonen J, Tikkanen S, Karttunen TJ, Savilahti E. A similar high level of immunoglobulin A and immunoglobulin G class milk antibodies and increment of local lymphoid tissue on the duodenal mucosa in subjects with cow's milk allergy and recurrent abdominal pains. Pediatr Allergy Immunol. Apr 2002;13(2):129-36. [Medline].
Walker WA. Cow's milk protein-sensitive enteropathy at school age: a new entity or a spectrum of mucosal immune responses with age. J Pediatr. Dec 2001;139(6):765-6. [Medline].
Iacono G, Cavataio F, Montalto G, et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med. Oct 15 1998;339(16):1100-4. [Medline].
[Guideline] Plaut M, Sawyer RT, Fenton MJ. Summary of the 2008 National Institute of Allergy and Infectious Diseases-US Food and Drug Administration Workshop on Food Allergy Clinical Trial Design. J Allergy Clin Immunol. Oct 2009;124(4):671-8.e1. [Medline].
Frew AJ. Sublingual immunotherapy. N Engl J Med. May 22 2008;358(21):2259-64. [Medline].
Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy. Nov 2007;62(11):1261-9. [Medline].
Wang J, Sampson HA. Food allergy: recent advances in pathophysiology and treatment. Allergy Asthma Immunol Res. Oct 2009;1(1):19-29. [Medline].
Lack G. Clinical practice. Food allergy. N Engl J Med. Sep 18 2008;359(12):1252-60. [Medline].
Kull I, Bergstrom A, Lilja G, Pershagen G, Wickman M. Fish consumption during the first year of life and development of allergic diseases during childhood. Allergy. Aug 2006;61(8):1009-15. [Medline].
[Guideline] Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. Jan 2008;121(1):183-91. [Medline].
Iacono G, Di Prima L, D'Amico D, Scalici C, Geraci G, Carroccio A. The "red umbilicus": a diagnostic sign of cow's milk protein intolerance. J Pediatr Gastroenterol Nutr. May 2006;42(5):531-4. [Medline].
Foucard T, Malmheden Yman I. A study on severe food reactions in Sweden--is soy protein an underestimated cause of food anaphylaxis?. Allergy. Mar 1999;54(3):261-5. [Medline].
AAP. Food allergy. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 5th ed. Elk Grove, IL: American Academy of Pediatrics; 2004:593-607.
Zutavern A, Brockow I, Schaaf B, et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. Jan 2008;121(1):e44-52. [Medline].
Nwaru BI, Erkkola M, Ahonen S, et al. Age at the introduction of solid foods during the first year and allergic sensitization at age 5 years. Pediatrics. Jan 2010;125(1):50-9. [Medline].
[Guideline] Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. Jan 2008;121(1):183-91. [Medline].
[Best Evidence] Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. Oct 18 2006;CD003741. [Medline].
[Guideline] Allen KJ, Davidson GP, Day AS, et al. Management of cow's milk protein allergy in infants and young children: an expert panel perspective. J Paediatr Child Health. Sep 2009;45(9):481-6. [Medline].
Axelsson I, Jakobsson I, Lindberg T, Benediktsson B. Bovine beta-lactoglobulin in the human milk. A longitudinal study during the whole lactation period. Acta Paediatr Scand. Sep 1986;75(5):702-7. [Medline].
Blackshaw AJ, Levison DA. Eosinophilic infiltrates of the gastrointestinal tract. J Clin Pathol. Jan 1986;39(1):1-7. [Medline].
Bock SA. Evaluation of IgE-mediated food hypersensitivities. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S20-7. [Medline].
[Guideline] Caffarelli C, Baldi F, Bendandi B, et al. Cow's milk protein allergy in children: a practical guide. Ital J Pediatr. Jan 15 2010;36(1):5. [Medline].
Carroccio A, Montalto G, Custro N, et al. Evidence of very delayed clinical reactions to cow's milk in cow's milk-intolerant patients. Allergy. Jun 2000;55(6):574-9. [Medline].
[Guideline] Darsow U, Wollenberg A, Simon D, et al. ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol. Aug 31 2009;[Medline].
Dupont C, Heyman M. Food protein-induced enterocolitis syndrome: laboratory perspectives. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S50-7. [Medline].
[Guideline] Ebisawa M. Management of food allergy in Japan "food allergy management guideline 2008 (revision from 2005)" and "guidelines for the treatment of allergic diseases in schools". Allergol Int. Dec 2009;58(4):475-83. [Medline].
[Guideline] Garcia BE, Gamboa PM, Asturias JA, et al. Guidelines on the clinical usefulness of determination of specific immunoglobulin E to foods. J Investig Allergol Clin Immunol. 2009;19(6):423-32. [Medline].
Hill DJ, Firer MA, Shelton MJ, Hosking CS. Manifestations of milk allergy in infancy: clinical and immunologic findings. J Pediatr. Aug 1986;109(2):270-6. [Medline].
Hill DJ, Heine RG, Cameron DJ, Francis DE, Bines JE. The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance. J Pediatr. Jul 1999;135(1):118-21. [Medline].
Kalliomaki M, Salminen S, Poussa T, Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol. Apr 2007;119(4):1019-21. [Medline].
Kelly KJ. Eosinophilic gastroenteritis. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S28-35. [Medline].
Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. Nov 1995;109(5):1503-12. [Medline].
Kokkonen J, Haapalahti M, Laurila K, Karttunen TJ, Maki M. Cow's milk protein-sensitive enteropathy at school age. J Pediatr. Dec 2001;139(6):797-803. [Medline].
Kokkonen J, Karttunen TJ, Niinimäki A. Lymphonodular hyperplasia as a sign of food allergy in children. J Pediatr Gastroenterol Nutr. Jul 1999;29(1):57-62. [Medline].
Kukkonen K, Savilahti E, Haahtela T, et al. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. Jan 2007;119(1):192-8. [Medline].
Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S58-60. [Medline].
Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast-fed infants. J Pediatr. Dec 1982;101(6):906-10. [Medline].
Leung AK. Food allergy: a clinical approach. Adv Pediatr. 1998;45:145-77. [Medline].
Liacouras CA, Ruchelli E. Eosinophilic esophagitis. Curr Opin Pediatr. Oct 2004;16(5):560-6. [Medline].
Lindberg T. Infantile colic: aetiology and prognosis. Acta Paediatr. Jan 2000;89(1):1-2. [Medline].
Lowichik A, Weinberg AG. A quantitative evaluation of mucosal eosinophils in the pediatric gastrointestinal tract. Mod Pathol. Feb 1996;9(2):110-4. [Medline].
Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics. Mar 2009;123(3):e459-64. [Medline].
Murch S. Food allergies. In: Guandalini S. Ed. Textbook of pediatric gastroenterology and nutrition. London: Taylor & Francis; 2004.
Niggemann B, Beyer K. Pitfalls in double-blind, placebo-controlled oral food challenges. Allergy. Jul 2007;62(7):729-32. [Medline].
Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. Aug 26 2004;351(9):940-1. [Medline].
Novembre E, Vierucci A. Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy. 2001;56 Suppl 67:105-8. [Medline].
Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 2003;CD003664. [Medline].
[Guideline] Plaut M, Sawyer RT, Fenton MJ. Summary of the 2008 National Institute of Allergy and Infectious Diseases-US Food and Drug Administration Workshop on Food Allergy Clinical Trial Design. J Allergy Clin Immunol. Oct 2009;124(4):671-8.e1. [Medline].
[Guideline] Rance F, Deschildre A, Villard-Truc F, et al. Oral food challenge in children: an expert review. Eur Ann Allergy Clin Immunol. Apr 2009;41(2):35-49. [Medline].
Sampson HA, Anderson JA. Summary and recommendations: Classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S87-94. [Medline].
Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S45-9. [Medline].
Szajewska H, Setty M, Mrukowicz J, Guandalini S. Probiotics in gastrointestinal diseases in children: hard and not-so-hard evidence of efficacy. J Pediatr Gastroenterol Nutr. May 2006;42(5):454-75. [Medline].
Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol. Jan 2007;119(1):184-91. [Medline].
Tlaskalova-Hogenova H, Tuckova L, Lodinova-Zadnikova R, et al. Mucosal immunity: its role in defense and allergy. Int Arch Allergy Immunol. Jun 2002;128(2):77-89. [Medline].
| Type of Reaction | Pathogenesis | Clinical Entities |
| Non–immune-mediated | Disorders of digestive-absorptive processes | Glucose-galactose malabsorption, lactase deficiency, sucrase-isomaltase deficiency, enterokinase deficiency |
| Pharmacological reactions | Tyramine in aged cheeses, histamine (eg, in strawberries, caffeine) | |
| Idiosyncratic reactions | Food additives, food colorants | |
| Inborn errors of metabolism | Phenylketonuria, hereditary fructose intolerance, tyrosinemia, galactosemia, lysinuric protein intolerance | |
| Immune-mediated (food allergy) | IgE-mediated (positive radioallergosorbent test or skin prick test results) | Oral allergy syndrome, immediate GI hypersensitivity |
| Occasionally IgE-mediated | Eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis | |
| Non–IgE-mediated | Food protein–induced entities, such as enterocolitis, enteropathy, proctocolitis, chronic constipation | |
| Autoimmune | Innate and adaptive immunity | Celiac disease |
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