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.
Food protein intolerance can be immunoglobulin E (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.
Several clinical reactions to food proteins have been reported in children and adults. Only a few of these
have a clear allergic 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.
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 ; 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. [2] 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 (T reg)
cells and a possible delay in the progression to an optimal balance between TH 1 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.
Many immunologic reactions to food allergens are IgE-mediated and usually target several different
epitopes. Certain epitopes are homologous in different foods.
Non-IgE mediated food allergies involve T-cell mediated immunity to certain food proteins. and large
amounts of inflammatory cytokines such as TNF- are produced by T cells in an antigen-specific manner.
TNF- increases intestinal permeability, which facilitates the uptake of undigested food antigens.
In both IgE-mediated and non-IgE-mediated food allergies, Th2 cytokines (such as IL-4, IL-5 and IL-13)
are produced by T cells in response to specific food antigens. However, the precise mechanisms and
pathogenesis of GI allergy remain unclear.[4]

Eosinophilic gastrointestinal diseases (EGIDs) have been classified as a combined IgE-mediated and
cell-mediated disease because many patients have detectable food-specific IgE antibodies. However, the
roles of IgE antibodies in the pathogenesis of EGID remain unclear. [5, 5]
Morphologic studies have demonstrated the role of GI T lymphocytes (ie, intraepithelial lymphocytes) in
the pathogenesis of GI food allergy. The pathogenic 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 proteins

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.
Antigen uptake has been found to be increased in children with gastroenteritis and with cow's milk allergy.
The classification of different clinical presentations of food intolerance in children based on their
presumptive underlying pathophysiological mechanisms is below.

Nonimmune-mediated reactions

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
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 proteininduced entities (eg, enterocolitis, enteropathy, proctocolitis, chronic
constipation)

Autoimmune

Innate and adaptive immunity - Celiac disease

History
Numerous symptoms can be a consequence of food protein intolerance. GI manifestations are the most
common clinical presentation, usually without involvement of other organ systems. Most cases of food
protein intolerance in the pediatric population occur in the first months of life as a consequence of cow's
milk protein intolerance.
The typical history is that of an infant younger than 6 months who is fed for a few weeks with formula and
who then develops diarrhea and, eventually, vomiting. In the case of the common enterocolitis syndrome,
the infant can become dehydrated and lose weight. In the rare instance of cow's milk enteropathy,
amalabsorption syndrome develops, with growth failure and hypoalbuminemia. On the other hand, the
common food-induced proctocolitis syndrome is characterized by diarrhea in a healthy infant without any
weight loss.
Food allergic reactions may be divided into quick-onset reactions, which occur within an hour of food
ingestion and are usually immunoglobulin E (IgE)-mediated (eg, skin rashes, urticaria, angioedema,
wheezing, anaphylaxis), and slow-onset reactions, which take hours or days to develop and are usually
nonIgE-mediated.
The most common and specific symptoms of food protein intolerance are as follows:

GI symptoms
Oral allergy syndrome: Oral allergy syndrome is a form of IgE-mediated contact allergy that is almost
exclusively confined to the oropharynx and is most commonly associated with the ingestion of various
fresh fruits and vegetables. Oral allergy syndrome mainly affects adults who have pollen allergy
(especially to ragweed, birch, and mugwort) and is caused by cross-reactivity of pollen IgE antibodies
with proteins in some fresh fruits and vegetables. Symptoms include itching; burning; and angioedema
of the lips, tongue, palate, and throat. The clinical picture is usually short-lived, but symptoms may be
more prominent after the ragweed season.
o Immediate GI hypersensitivity: GI anaphylaxis is defined as an IgE-mediated GI reaction that often
accompanies allergic manifestations in other organs, such as the skin or lungs. Bioptic samples show
a significant decrease in stainable mast cells and tissue histamine after the challenge. The reaction
usually occurs within minutes to 2 hours of food ingestion. Within 1-2 hours, the patient develops
nausea, abdominal pain, and vomiting. After 2 hours, diarrhea ensues. In children with atopic eczema
and food allergy, subclinical reactions have been described. Poor appetite, poor weight gain, and
intermittent abdominal pain are frequent symptoms.
o Eosinophilic esophagitis
Esophageal eosinophilia that persists despite traditional antireflux therapy may represent a sign of
allergic esophagitis.
Eosinophilic esophagitis was described in early 1990s in adults suffering from dysphagia and in
children complaining of severe reflux symptoms refractory to therapy, both associated with an
eosinophil-predominant infiltration.
o

o
o

Eosinophilic esophagitis occurs in children and adults but rarely occurs in infants and is
characterized by chronic esophagitis, with or without reflux. Affected children present with a wide
range of symptoms, which are largely age dependent.[13]
Children younger than 2 years often present with food refusal, irritability, vomiting, and abdominal
pain.
Older children, adolescents, and adults present with intermittent vomiting, heartburn, dysphagia for
solids, or spontaneous food impaction and failure to respond to conventional reflux medications.
In older children, dysphagia, anorexia, and early satiety can help distinguish eosinophilic
gastroenteritis from gastroesophageal reflux and correlates with the severity of histologic and
endoscopic findings.[14]
Occasionally, esophageal strictures develop, apparently due to an esophageal dysmotility. [15]
Eosinophilic esophagitis is a chronic disease, with less than 10% of the population developing
tolerance to food allergies.[16]
Numerous studies have suggested that eosinophilic esophagitis has a strong genetic inheritability.
Polymorphisms in a locus at 5q22 appear to be strongly associated with eosinophilic esophagitis. [17]
Eosinophilic gastritis: Eosinophilic gastritis that is responsive to elimination diets has occasionally
been reported. Symptoms and signs are those usual for gastritis of different etiologies, such as
postprandial vomiting, abdominal pain, anorexia, early satiety, and failure to thrive. Approximately half
of these patients have atopic features.
Eosinophilic gastroenteritis: Eosinophilic gastroenteritis is an ill-defined disease that is pathologically
characterized by the infiltration of eosinophils in the mucosa of the GI tract. The syndrome has been
reported in children of all ages. Diagnosis requires symptoms related to the GI tract and a bioptic
sample showing an eosinophilic infiltration. Unfortunately, no clear-cut line can be drawn to distinguish
eosinophilic gastroenteritis from other GI diseases and from nonpathologic eosinophilic infiltration of
the lower intestine.
Food proteininduced enterocolitis syndrome (FPIES)
Food proteininduced enterocolitis syndrome describes a symptom complex of profuse vomiting and
diarrhea diagnosed in infancy, involving both the small and the large intestine.
Food-induced enterocolitis syndrome occurs most frequently in the first months of life. Most cases
are observed in infants younger than 3 months.
Cow's milk and soy protein are most often responsible.
Symptoms include protracted vomiting and diarrhea. Vomiting generally occurs 1-3 hours after
feeding, and diarrhea occurs 5-8 hours after feeding.
Specific descriptions of the histologic findings are not available because the diagnosis can be made
clinically. Some small bowel specimens show mild villous injury with inflammatory infiltration,
whereas colonic specimens reveal crypt abscesses and a diffuse inflammatory infiltrate.
A similar enterocolitis syndrome has been reported in older infants and children as a consequence of
intolerance to different food proteins (eg, eggs, fish, nuts, peanuts, other proteins). Rice can induce
severe cases of enterocolitis.[18]
Food-specific IgE test findings are typically negative[19] ; atopy patch testing is under investigation.
The oral food challenge remains the diagnostic standard in this disorder. [20] Gastric juice analysis can
help with diagnosis.[21]
During a prospective long-term follow-up study, most patients with infantile food proteininduced
enterocolitis syndrome lost intolerance to cows milk at age 14-16 months (tolerance rate, 72.7%).[22]
Food protein-induced enteropathy: Cow's milk proteins and soy proteins can cause an uncommon
syndrome of chronic diarrhea, weight loss, and failure to thrive, similar to that appearing in celiac
disease. Vomiting is present in up to two thirds of patients. Small bowel biopsy findings reveal an
enteropathy of variable degrees with villous hypotrophy. Total mucosal atrophy, histologically
indistinguishable from celiac disease, is a frequent finding. Intestinal protein and blood losses can
aggravate the hypoalbuminemia and anemia that are frequently observed in this syndrome. The
nonceliac food-induced enteropathy has been less frequent and less severe in the last 25 years. More
recent cases described patients who presented with patchy intestinal lesions. Usually, the syndrome
affects infants in the first months of life.
Gluten-sensitive enteropathy: See Celiac Disease.
Protein-losing enteropathy: Protein-losing enteropathy is a common finding in children with cow's milk
protein intolerance. Some infants can present with pronounced protein-losing symptoms after

introduction of cow's milk. It has been suggested that mast cell infiltration is related to increased
intestinal permeability and protein loss.[23]
o Food-induced proctocolitis: Food-induced proctocolitis usually occurs in the first few months of life.
Cow's milk and soy proteins are most often responsible, but 60% of reported infants were exclusively
breastfed. In most of the latter cases, a strict maternal diet (including the elimination of all cow's milk
based products from their diets) can resolve the problem. Symptoms include diarrhea and blood in the
stools. Affected infants generally appear healthy and have normal weight gain. The onset of bleeding
is gradual and initially erratic over several days. It then progresses to streaks of blood in most stools
that can elicit suspicion of an internal anal tear. Bowel lesions are generally confined to the distal large
bowel. This entity, even if untreated, usually resolves in 6 months to 2 years. In older children,
eosinophilic colitis is a loosely defined diagnosis, without any correlation with symptoms, history of
atopy, inflammatory markers, or clinical outcome.[24]
o Chronic constipation due to cow's milk intolerance: Chronic constipation as the sole symptom of
intolerance to cow's milk was described in 1993. However, chronic constipation was not considered a
feature of cow's milk intolerance until 1998, when an Italian study hypothesized that intolerance to
cow's milk can cause severe perianal lesions with pain upon defecation and subsequent constipation
in young children.[25] An allergic colitis, with resolution of the symptoms after removal of milk from the
diet, was subsequently demonstrated in 4 newborns with constipation. Therefore, in a small subgroup
of children with constipation, cow's milk protein intolerance can be the cause of symptoms.
o Infantile colic
Infantile colic is the usual name given to a prolonged pattern of crying or fussing in infants, even if
the pathophysiology of this distressing behavior has not yet been elucidated. Numerous theories on
the pathogenesis have been published, and many, often conflicting, therapeutic approaches have
been suggested.
Cow's milk intolerance has been implicated as a cause of colic, at least in some formula-fed infants.
Some studies have suggested that an elimination diet that substitutes cow's milk formula with a soybased formula or a protein-hydrolysate can relieve the symptoms of infantile colic in a significant
percentage of cases. In these infants, challenge with cow's milk proteins usually causes a
recrudescence of the crying crises. The infants who respond to the elimination diet are usually those
with more prolonged crying crises, and they often have a familial history of allergy. Most often, other
signs of cow's milk protein intolerance develop in the following weeks or months.
Studies including a selected population of infants report percentages of responses to the elimination
diet to be as high as 89%. One blind study showed that 18% of infants with colic improved with soy
formula, whereas 0% improved in another blind study. Moreover, in most of the responsive infants,
the duration of the effect is not sustained, despite an ongoing elimination diet. In any case, true food
protein intolerance can only be demonstrated in a small subgroup of infants with colic.
o Allergic dysmotility: In older children, milk protein intolerance can induce chronic abdominal pain, with
an endoscopic finding of lymphonodular hyperplasia.[26]
o Multiple food protein intolerance of infancy: Some infants are intolerant to cow's milk proteins, soy,
extensively hydrolyzed formulas, and a wide range of other food proteins. Most of these children
develop symptoms while they are receiving only breast milk. Symptoms remit after feeding with an
elemental amino acidbased complete infant formula.
Dermatologic symptoms
o Symptoms include urticaria, angioedema, rashes, and atopic eczema.
o Atopic dermatitis is one of the most common symptoms of protein intolerance. Approximately one third
of children with atopic dermatitis have a diagnosis of cow's milk protein allergy and cow's milk protein
intolerance, according to elimination diet and challenge tests, and about 20-40% of children younger
than 1 year with protein intolerance have atopic dermatitis. Most children with atopic dermatitis and
protein intolerance develop a complete tolerance in a few years.
o Umbilical and periumbilical erythema has been related to cows milk protein intolerance in a group of
384 Italian infants; this bizarre sign was observed in 36 cases (9.4%), disappeared within the second
week on elimination diet, and reappeared within 24 hours after challenge.[27]
Respiratory symptoms: These symptoms include rhinitis and asthma.
General symptoms: Anaphylaxis due to cow's milk protein intolerance is a rare but well-described event.
The child, usually a young infant, suddenly becomes pale and cold and sweats. The child usually
presents with urticaria or angioedema and goes into shock within minutes after milk ingestion.

Anaphylaxis following ingestion of soy protein is exceptionally rare, even though a survey in Sweden
identified 4 cases of death caused by soy protein anaphylaxis.[28]
Nonspecific symptoms: Many more nonspecific GI reactions have been ascribed to food allergy,
including oral aphthae, pyloric stenosis, and bowel edema and obstruction. For most of these
manifestations, a clear correlation with an immune reaction to foods has never been established.

Differential Diagnoses

Crohn Disease
Gastroenteritis
Gastroesophageal Reflux
Ulcerative Colitis