Protein Intolerance

Updated: Oct 20, 2017
  • Author: Agostino Nocerino, MD, PhD; Chief Editor: Carmen Cuffari, MD  more...
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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. [1] 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%).



The major food allergens are water-soluble glycoproteins (molecular weight [MW], 10,000-60,000) that are resistant to heat, acid, and enzymes. Many food allergens have been identified, but milk, eggs, peanuts, tree nuts, fish, soy, wheat, and crustacean shellfishes account for 90% of significant reactions. [2] All these foods contain proteins with a small molecular weight, an abundance of epitopes, water solubility, glycosylation residues, and relative resistance to heat and digestion. [3]

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.

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.

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.

Some antigens can move through intercellular gaps; 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). Antigen uptake has been found to be increased in children with gastroenteritis and with cow's milk allergy.

Numerous studies have implicated the integrity of the skin and mucosal barrier in protecting against sensitization. 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. [4] 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). 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.

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.

A potentially important factor in the response of the immune system to a specific food antigen is microbiota. In humans, differences in the intestinal flora of allergic versus nonallergic children have been observed. [5]

Non–immune-mediated Reactions

Non–immune-mediated reactions include the following:

  • Disorders of digestive-absorptive process

    • 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

Immune-mediated (Food Allergy) Reactions

Immune-mediated (food allergy) reactions include the following:

  • IgE-mediated (positive radioallergosorbent test or skin prick test results)

    • Oral allergy syndrome

    • Immediate GI hypersensitivity

  • Occasionally IgE-mediated

  • Non-IgE-mediated - Food protein–induced entities (eg, enterocolitis, enteropathy, proctocolitis, chronic constipation)

Autoimmune Reactions

Innate and adaptive immunity reactions (ie, Celiac disease) are noted.




United States

In a national survey of pediatric allergists, the prevalence rate of cow's milk allergy in 1997-1999 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. This trend continued in the following years. According to the data from the National Center for Health Statistics, the prevalence of food allergies increased to 5,1% in 2009-2011 and increased with the increase of income level. [6]


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. [7]

Varying incidences of specific intolerances have been reported in different countries. Whether these differences are due to genetic or cultural factors is unclear. [8]

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. [9]


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). [10]


No race predilection has been observed.


No sex predilection is known, but males are slightly more frequently affected with eosinophilic gastroenteritis.


Gastrointestinal food protein intolerance 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. [11] An example is shown in the image below.

Typical atopic dermatitis on the face of an infant 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. [12] 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. [13]