eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology
Protein Intolerance
Updated: Jan 17, 2008
Introduction
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. The GI tract is permeable to intact antigens. The antigen uptake is an endocytotic process that involves intracellular lysosomes. 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. 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 and delay in the progression to an optimal balance between TH 1 and TH 2 immunity (hygiene hypothesis). The TH 1/TH 2 imbalance is crucial to the clinical expression of allergy and asthma. 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.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.
Classification of Main Adverse Reactions to Food
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Table
| 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 |
| 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 |
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%.
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.1
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.
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.
An unselected prospective study indicated that 42% of infants who developed cow's milk protein intolerance were symptomatic within 7 days (and 70% within 4 wk) following the introduction of cow's milk.2 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.
Clinical
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, a malabsorption 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 IgE-mediated (eg, skin rashes, urticaria, angioedema, wheezing, anaphylaxis), and slow-onset reactions, which take hours or days to develop and are usually non–IgE-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). 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.
- 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.
- Esophageal eosinophilia: Esophageal eosinophilia that persists despite traditional antireflux therapy may represent a sign of allergic esophagitis. Allergic eosinophilic esophagitis is characterized by chronic esophagitis, with or without reflux. Affected children present with intermittent vomiting, food refusal, abdominal pain, and failure to respond to conventional reflux medications. Occasionally, esophageal strictures develop.
- 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 protein–induced enterocolitis syndrome
- Food protein–induced 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).
- Food-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.
- 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.
- 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.3 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.
- 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 soy-based 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.
- 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 acid–based complete infant formula.
- Dermatologic symptoms
- Symptoms include urticaria, angioedema, rashes, and atopic eczema.
- 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.
- Umbilical and periumbilical erythema has been related to cow’s 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.4
- 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.5
- 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.
Physical
Usually, the GI manifestations are isolated, without any sign of atopic dermatitis, urticaria, rhinitis, conjunctivitis, or wheezing.
- In proctocolitis syndrome, the child (usually a young infant) appears healthy, without any weight loss or other physical problems.
- In food-induced GI anaphylaxis, these symptoms (eg, atopic dermatitis, urticaria, rhinitis, conjunctivitis, wheezing) can occur, and, therefore, the child must be checked for the presence of systemic signs of allergic reaction.
- The infant with enterocolitis syndrome can be dehydrated as a consequence of diarrhea, vomiting, or both. Signs of dehydration include blunted eyes, dry mucous membranes, and hypoelastic skin.
- In the unusual instances of nonceliac food-induced enteropathy, infants present with signs and symptoms of malabsorption syndrome. Dystrophy, growth failure, edema (hypoalbuminemia), rickets (vitamin D malabsorption), and hemorrhages (vitamin K malabsorption) can all be present.
Causes
Many food proteins can act as an antigen in humans. Cow's milk proteins are most frequently implicated as a cause of food intolerance during infancy. Soybean protein is the second most frequent antigen in the first months of life, particularly in infants with primary cow's milk intolerance.
More on Protein Intolerance |
 Overview: Protein Intolerance |
| Differential Diagnoses & Workup: Protein Intolerance |
| Treatment & Medication: Protein Intolerance |
| Follow-up: Protein Intolerance |
| References |
| Next Page » |
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Further Reading
Keywords
protein intolerance, food allergy, food-protein intolerance, food protein intolerance, food-protein allergy, cow's milk intolerance, cow's milk allergy, egg intolerance, egg allergy, soy intolerance, soy allergy, cow's milk protein, food allergens, immunoglobulin E–mediated pathogenesis, asthma, gastroenteritis, eosinophilic gastroenteritis, enterocolitis syndrome, cow's milk enteropathy, malabsorption syndrome, growth failure, hypoalbuminemia, proctocolitis syndrome, urticaria, angioedema, pollen allergy, oral allergy syndrome, GI anaphylaxis, esophageal eosinophilia, allergic esophagitis, chronic esophagitis, esophageal strictures, eosinophilic gastritis, celiac disease, protein-losing enteropathy, infantile colic, atopic dermatitis, oral aphthae, pyloric stenosis, bowel edema, bowel obstruction
