Protein Intolerance Clinical Presentation

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 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 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) 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.

• 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. Subclinical reactions have been described in children with atopic eczema and food allergy. Poor appetite, poor weight gain, and intermittent abdominal pain are frequent symptoms.

• 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.

  • 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. ^[14]

  • 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. ^[15]

  • Occasionally, esophageal strictures develop, apparently due to an esophageal dysmotility. ^[16]

  • Eosinophilic esophagitis is a chronic disease, with less than 10% of the population developing tolerance to food allergies. ^[17]

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  • Numerous studies have suggested that eosinophilic esophagitis has a strong genetic inheritability. 

• Eosinophilic gastritis

  • Eosinophilic gastritis that is responsive to elimination diets has occasionally been reported.
  • In children it is usually localized in the antrum and/or fundus, ^[18] with eosinophilia elsewhere in the GI tract. ^[19]
  • Symptoms and signs vary, but they are the usual ones 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. The disease is highly responsive to dietary restriction therapies in children.

• 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. Eosinophilic gastrointestinal disease seems to precede inflammatory bowel disease in some subsets of children. ^[20]

• Food protein–induced enterocolitis syndrome (FPIES)

  • Food protein–induced enterocolitis syndrome describes a complex symptom 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. The typical presentation is acute. Vomiting generally occurs 1-3 hours after feeding, and diarrhea occurs 5-8 hours after feeding. However, some children have a chronic course, characterized by protracted diarrhea, failure to thrive, and intermittent vomiting. ^[21]

  • 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. ^[22]

  • Food-specific IgE test findings are typically negative ^[23] ; atopy patch testing is under investigation. The oral food challenge remains the diagnostic standard in this disorder. ^[24] Gastric juice analysis can help with diagnosis. ^[25]

  • During a prospective long-term follow-up study, most patients with infantile food protein–induced enterocolitis syndrome lost intolerance to cow’s milk at age 14-16 months (tolerance rate, 72.7%). ^[26]  In a cohort of 160 children, the median age for tolerance was 4.7 years for rice, 5.1 years for milk in the absence of milk-specific IgE, and 6.7 years for soy; none of the subjects with detectable milk specific IgE became tolerant to milk during the study. ^[27]

• 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. ^[28]

• Food-induced proctocolitis: Food-induced proctocolitis usually occurs in the first few months of life; it is usually considered a delayed non IgE-mediated allergic reaction to food proteins, even if some studies have proposed different pathogenetic mechanisms. ^{[29, 30, 31]}  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. Other allergens, mainly eggs, can be the causative agent in nonresponding infants. ^[32] 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, which 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. Endoscopy is not recommended, unless severe symptoms are present. The duration of the allergic proctocolitis does not seem to induce worsening of the infant's nutritional status. ^[33]  

• 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. ^[34] 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.

• Allergic dysmotility: In older children, milk protein intolerance can induce chronic abdominal pain, with an endoscopic finding of lymphonodular hyperplasia. ^[35]

• 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. ^[36]

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. ^[37]

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.

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.

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.