eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Protein Intolerance: Differential Diagnoses & Workup

Author: Agostino Nocerino, MD, PhD, Chief of Pediatric Oncology, Department of Pediatrics, University of Udine, Italy
Coauthor(s): Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Contributor Information and Disclosures

Updated: Aug 25, 2009

Differential Diagnoses

Crohn Disease
Gastroenteritis
Gastroesophageal Reflux
Ulcerative Colitis

Other Problems to Be Considered

Enteropathy
Celiac disease
Autoimmune enteropathy
Intractable diarrhea of infancy
Intestinal infections

Enterocolitis syndrome
Intestinal infections
Inflammatory bowel diseases

Proctocolitis
Anal fissures
Meckel diverticulum
Intestinal duplication
Intestinal hemangiomas
Intestinal infections
Inflammatory bowel disease

Workup

Laboratory Studies

The following tests are indicated in assessing food protein intolerance:

• Radioallergosorbent test (RAST): RAST is often used to screen for antigen-specific IgE in the patient's serum.
• Enzyme-linked immunosorbent assay (ELISA): ELISAs have been replacing methods that use radiation. Unfortunately, determination of specific IgE involves the same problems as the skin test. A negative test result has a high predictive accuracy with a low sensitivity, whereas a positive test result has a low predictive value.
• Fecal leukocytes: Fecal eosinophils are a significant clue to the diagnosis of allergic colitis. However, although eosinophils predominate after a single acute challenge, the findings on fecal smears at diagnosis are more likely of the inflammatory type, with a predominant population of lymphocytes and neutrophils and a small number of eosinophils.
• Allergic eosinophilic esophagitis
  • Total serum IgE is within the reference range or slightly elevated.
  • Peripheral eosinophilia is uncommon.
  • Skin test and RAST results are frequently negative.
  • Results of pH testing can be pathologic or normal.
  • Esophageal biopsy reveals infiltration of the mucosa and submucosa with eosinophils.
• Allergic eosinophilic gastritis
  • The IgE level is elevated in approximately half of patients.
  • Peripheral eosinophilia is present in approximately half of patients.
  • Gastric biopsy findings reveal marked infiltration of the mucosa and submucosa with eosinophils (especially in the gastric antrum).
• Allergic eosinophilic gastroenteritis
  • Peripheral eosinophilia is commonly found but is not reliable as a diagnostic criterion.
  • Diagnosis requires a biopsy specimen showing an eosinophilic infiltration of the mucosa and submucosa.
  • Unfortunately, no standards for making the histologic diagnosis are recognized. In infants and children without GI symptoms, eosinophilic counts in the gastric fundus and antrum are consistently low, but in the terminal ileum, cecum, and proximal colon, an eosinophil count as high as 30 per high-power field can be detected.
• Immediate GI hypersensitivity
  • Prick tests and RAST results are usually positive.
  • Fluoroscopy studies show gastric hypotonia, prominent pylorospasm, and subsequent increased or decreased peristaltic activity of the intestine.
• Enterocolitis syndrome
  • Prick tests and RAST results are usually negative.
  • Stools generally contain occult blood, neutrophils, and eosinophils. The jejunal biopsy findings reveal villous atrophy and infiltration by lymphocytes, eosinophils, and mast cells.
• Nonceliac food-induced enteropathy
  • The results of both IgE-specific tests (ie, prick, RAST) are usually normal.
  • The findings of the jejunal biopsy are similar to those in celiac disease but usually are less pronounced. A varying degree of villous atrophy is present, with crypt hyperplasia and lymphocytic infiltration of the lamina propria. Often, the lesions have a patchy distribution, observed especially in the last few years. Several studies have detected increased numbers of IgE plasmocytes in biopsy specimens of patients with cow's milk protein intolerance.
• Food-induced proctitis
  • Fecal leukocytes are usually positive for neutrophils.
  • Eosinophils can be absent.
  • For colonoscopic findings, see Procedures.

Other Tests

• Skin test responses to cow's milk or other food proteins and detection of food-specific IgE antibodies are usually positive in children with IgE-mediated food allergy. However, most of the food protein intolerances are not IgE-mediated. A double-blind placebo-controlled oral food challenge is the ideal method for definitely confirming histories of adverse reactions to food proteins. However, this approach is rarely used in clinical practice. In addition, even double-blind placebo-controlled challenges can have pitfalls.
• Skin testing with food extracts is often used to screen patients with suspected IgE-mediated food allergies.
  • Skin testing is usually completed by the prick technique, which is a reliable means of detecting IgE antibodies to food in children.
  • A positive skin test result merely implies the presence of food-specific IgE antibodies. A negative skin test result has a high predictive accuracy (estimated to be >95%).
  • Unfortunately, a positive prick test result is a poor predictor of clinical symptoms during food challenges. The positive predictive accuracy widely varies but has been estimated to be lower than 50%. In children younger than 2 years, the negative predictive accuracy of the skin test result is not as good as in older children, but, on the other hand, a positive test result is more likely to be significant. Composition and quality of the extracts are also a significant consideration. Sometimes, testing a drop of the milk that is used to feed the child (eg, formula milk, soy milk, others) is preferable.
• A position statement issued by the American Academy of Allergy, Asthma, and Immunology considered cytotoxic testing, provocative subcutaneous testing, and provocative sublingual tests to be of unproven value.
• Elimination diets involve the following:
  • The simplest type of elimination diet is elimination of suspected food antigens from the diet for 2-4 weeks or longer.
  • When no specific allergens can be incriminated, the common food allergens are eliminated from the diet.
  • In severe and unresponsive cases, consider the use of an elemental diet.
• Food challenge tests involve the following:
  • An elimination diet for 10-14 days should precede a food challenge test.
  • Perform a food challenge under medical supervision. A history of food-related anaphylaxis is a relative contraindication to food challenge.
  • An open food challenge (both the physician and the patient are aware of the food) can be accepted when the resulting symptoms can be objectively observed. Use a double-blind placebo-controlled food challenge (both the physician and the patient are unaware of the food) if the resulting symptoms are only subjective.
  • The oral food challenge has been established as the criterion standard for the diagnosis of adverse food reactions caused by any mechanism. The test is diagnostic of food intolerance when symptoms subside following dietary elimination of the offending food or when symptoms recur within 48 hours after milk provocation. Reactions must be reproducible with repeated elimination/challenge tests. Delayed-onset reactions, a common cause of GI reactions, cause symptoms hours or days after the ingestion, with a timing pattern. In cow's milk protein intolerance, the same original clinical picture tends to recur after the challenge.
  • Very delayed clinical reactions to food challenge including constipation, wheezing, dermatitis plus constipation, and dermatitis alone have been reported in a small subgroup of patients. The mean time between the challenge and the onset of a clinical symptom was 13.3 days (range, 4-26 d).

Procedures

• Upper and lower GI endoscopies: Usually, the clinical picture and the history are clear, and the recommended diagnostic process (see Lab Studies above) does not require performance of endoscopic procedures. However, endoscopy may be part of the differential diagnostic workup in cases in which clinical doubt is acknowledged.
  • Upper endoscopy
    • In cases with eosinophilic esophagitis, various degrees of hyperemia are macroscopically observed. In addition, furrowing of the mucosa, rings, and plaques have been described. Microscopically, eosinophils are observed infiltrating the esophageal wall. Although no pathognomonic histologic characteristics are associated with eosinophilic esophagitis, an eosinophilic count of more than 20 cells per high-power field is considered diagnostic of this recently described entity. Patchy lymphonodular hyperplasia of the GI tract, at any site from the duodenum to the colon, has been suggested to be related to food allergy.
    • In patients presenting with signs or symptoms of enteropathy, an upper endoscopy with duodenal biopsies may be indicated in the diagnostic workup. The microscopic picture of enteropathy can totally overlap with that of celiac disease (ie, partial to total villous atrophy, crypt hyperplasia), possibly with a more common occurrence of a patchy lesion rather than continuous lesion.
  • Lower GI endoscopy (colonoscopy): This procedure is completed in the presence of signs or symptoms of colitis or proctitis (mainly lower GI bleeding) and whenever the diagnosis of food-induced colitis is not obvious. In food-induced colitis, the procedure macroscopically reveals linear erosions and mucosal edema. Bowel lesions are generally confined to the distal large bowel. Microscopically, focal erythema and frequent nodularity with superficial erosions are observed. Eosinophilic infiltration, most prominent in the lamina propria, can be observed in the biopsy specimens but is by no means a constant finding.
• Biopsy
  • In allergic eosinophilic esophagitis, esophageal biopsy reveals infiltration of the mucosa and submucosa with eosinophils.
  • In allergic eosinophilic gastritis, gastric biopsy reveals marked infiltration of the mucosa and submucosa with eosinophils (especially in the gastric antrum).
  • In allergic eosinophilic gastroenteritis, diagnosis requires a biopsy specimen that reveals an eosinophilic infiltration of the mucosa and submucosa. Unfortunately, no standards for making the histologic diagnosis are available. In infants and children without GI symptoms, eosinophilic counts in the gastric fundus and antrum are consistently low, but in the terminal ileum, cecum, and proximal colon, eosinophil counts as high as 30 per high-power field can be detected.
  • In enterocolitis syndrome, the jejunal biopsy reveals villous atrophy and infiltration by lymphocytes, eosinophils, and mast cells.
  • In nonceliac food-induced enteropathy, the findings of the jejunal biopsy are similar to those in celiac disease but usually are less pronounced. A varying degree of villous atrophy is present with crypt hyperplasia and lymphocytic infiltration of the lamina propria. Often, the lesions have a patchy distribution, observed especially in the last few years. Several studies have detected increased numbers of IgE plasmocytes in biopsy specimens of patients with cow's milk protein intolerance.

Histologic Findings

See Procedures.

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