Eosinophilic Gastroenteritis

Background

Eosinophilic gastroenteritis (EGE) is an uncommon inflammatory gastrointestinal (GI) disease affecting both children and adults. This condition is characterized by the following:

• Eosinophilic infiltration in one or more areas of the GI tract, mainly the stomach and duodenum and, in some cases, the esophagus and colon, defined as 20 or more eosinophils per high-power field (HPF)
• The presence of abnormal GI symptoms, most often abdominal pain, nausea, vomiting, diarrhea, and weight loss
• The absence of an identified cause of eosinophilia
• The exclusion of eosinophilic involvement in organs other than the GI tract

A history of atopy or food allergies is often present.

Clinical symptoms are determined by the anatomic locations of eosinophilic infiltrates and the depth of GI involvement: mucosal, muscularis, or serosal.^[1]

Kaijser was probably the first to report a patient with eosinophilic gastroenteritis in 1937; since then, the number of case reports has increased. Treatments are often unsatisfactory, and long-term outcomes are uncertain.

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Pathophysiology

The underlying molecular mechanism predisposing to the clinical manifestation of eosinophilic gastroenteritis is unknown. Eosinophilic gastritis, enteritis, and gastroenteritis are diseases characterized by the selective infiltration of eosinophils in the stomach, small intestine, or both.^[2] The disorders are classified into primary and secondary subtypes. The primary subtypes, which have also been called idiopathic or allergic gastroenteritis, include the atopic, nonatopic, and familial subtypes.

In patients, manifestations of their diseases are based on histologic involvement: mucosal, muscularis, or serosal forms.^[1] Any layer of the GI tract can be involved. The secondary subtypes may be divided into two groups: systemic eosinophilic disorders (ie, hypereosinophilic disorders) and noneosinophilic disorders (eg, celiac disease, inflammatory bowel disease, vasculitis).

Although these diseases are idiopathic, recent investigations support the role of eosinophils, T helper 2 (Th2) cytokines (interleukin [IL]-3, IL-4, IL-5, and IL-13), and eotaxin as the critical factors in the pathogenesis of eosinophilic gastroenteritis. Eosinophils function as antigen presenting cells as they express major histocompatibility complex (MHC) class II molecules.

Eosinophils can mediate proinflammatory effects, including the up-regulation of adhesion systems, modulation of cell trafficking, and cellular activation states by releasing cytokines (IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-16, IL-18, and transforming growth factor [TGF]-alpha/beta), chemokines (RANTES and eotaxin), and lipid mediators (platelet activating factor [PAF] and leukotriene C4).

Finally, eosinophils can serve as major effector cells, inducing tissue damage and dysfunction by releasing toxic granule proteins (major basic protein [MBP], eosinophilic cationic protein [ECP], eosinophil peroxidase [EPO], and eosinophil-derived neurotoxin [EDN]) and lipid mediators, which are cytotoxic.

Atopy is present in a subset of patients, as these patients demonstrate increased total immunoglobulin E (IgE) on food-specific IgE radioallergosorbent assay test (RAST) or skin tests. Furthermore, lamina propria T cells from the duodenum of these patients proliferated in response to milk proteins and secreted Th2 cytokines (IL-13).

However, other studies suggest a non–IgE-mediated mechanism. Upregulation of thymic stromal lymphopoietin (TSLP) has been observed in these patients.

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Etiology

The cause or mechanism of eosinophilic infiltration is not known.

Patients with eosinophilic gastroenteritis have elevated IgE and eosinophilia of tissue and blood. An imbalance in the T-cell paradigm causing an increase in the production of IL-13, IL-4, and IL-5 and cytokines has been postulated as the cause of IgE synthesis and eosinophilia.

In one study, immunohistochemistry detected IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 in the granule matrix of eosinophils, the release of which is thought to be involved in the perpetuation of intestinal eosinophil infiltration and inflammation.

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Epidemiology

United States data

The disease is rare, and the incidence is difficult to estimate. However, since the description of eosinophilic gastroenteritis by Kaijser in 1937, without an accurate database registry, the incidence is estimated to be 1 case per 100,000 and a prevalence of 28 per 100,000 in the United States.

International data

Although cases have been reported worldwide, the exact incidence of eosinophilic gastroenteritis is unclear. A confounding factor is lack of diagnostic precision.

A systematic review that evaluated the racial differences in eosinophilic gastrointestinal disorders between white and Asian populations found that eosinophilic gastroenteritis more commonly affects Asian patients (72%), whereas eosinophilic esophagitis is more common in white patients (94%).^[3] Asian patients with eosinophilic esophagitis exhibited significantly fewer symptoms of heartburn and dysphagia but more vomiting and abdominal pain compared to white patients. In addition, Asian patients with eosinophilic gastroenteritis were significantly more likely to have eosinophil infiltration of the colon, but the stomach was less likely to be affected.^[3]

Kim et al reported 31 new cases of eosinophilic gastroenteritis in Seoul, Korea, between January 1970 and July 2003.^[4]

Chen et al reported on 15 patients, including 2 children, with eosinophilic gastroenteritis who were evaluated over an 18-year period at a hospital in China in 2003.^[5]

Venkataraman et al reported 7 new diagnoses of eosinophilic gastroenteritis over a 10-year period in India.^[6]

Race-, sex-, and age-related demographics

Cases of eosinophilic gastroenteritis are reported mostly in white individuals, with some cases occurring in Asians.

A slight male preponderance has been reported.

Patients present clinically in the third to fifth decades of life, but the disease can affect any age group, from infancy through the seventh decade.

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Prognosis

The natural history of eosinophilic gastroenteritis (EGE) has not been well documented. Eosinophilic gastroenteritis is a chronic, waxing and waning condition. Mild and sporadic symptoms can be managed with reassurance and observation, whereas disabling gastrointestinal (GI) symptom flare-ups can often be controlled with oral corticosteroids. When the disease manifests in infancy and specific food sensitization can be identified, the likelihood of disease remission by late childhood is high.

There are very few published studies on the natural progression of EGE. In a retrospective study of 43 patients over a mean duration of 13 years, De Chambrun et al noted three patterns: 42% of patients suffered a single outbreak of EGE shorter than 3 months, 37% patients experienced intermittent flares, and 21% had persistent active symptoms.^[7]

Morbidity/mortality

Morbidity includes malnutrition and intestinal obstruction and perforation​. Fatal outcomes are rare, GI obstruction is the most common complication, and the risk of cancer is not increased.

Complications

Some patients with EGE may present with bloody diarrhea, mimicking inflammatory bowel disease. Another complication includes intestinal perforation, which usually requires surgical repair. Extraintestestinal presentations can also occur, such as eosinophilic hepatitis, cholecystopancreatitis with bile duct dilatation obstruction and jaundice.

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History

Patients with eosinophilic gastroenteritis may have various clinical presentations depending on the region of the gastrointestinal (GI) tract involved and the depth of the bowel wall involvement. The disease most often involves the and the small bowel. A history of atopy and allergies is present in many of the cases.^{[8, 9]}

Rarely, eosinophilic gastrointestinal disease may be associated with autoimmune connective tissue disease.^[10]

Note the following:

• The mucosal form of eosinophilic gastroenteritis is characterized by vomiting, dyspepsia, abdominal pain, diarrhea, blood loss in the stools, iron deficiency anemia, malabsorption, protein-losing enteropathy, and failure to thrive.
• The muscularis form, characterized by infiltration of eosinophils predominantly in the muscularis layer, may present with gastrointestinal obstructive symptoms mimicking pyloric stenosis or gastric outlet syndrome.
• The serosal form, which is less common, presents with significant bloating, exudative ascites, and higher peripheral eosinophil counts.

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Physical Examination

The heterogeneity in the clinical presentation of eosinophilic gastroenteritis is determined by the site and depth of eosinophilic intestinal infiltration.

Approximately 50% of patients have a history of atopy (eg, hay fever, asthma, food allergy). In children, a history of allergy is even more common.

Children and adolescents can present with growth retardation, failure to thrive, delayed puberty, or amenorrhea. Adults have abdominal pain, diarrhea, or dysphagia.

Patients with muscle layer involvement typically present with pyloric or intestinal obstruction. The eosinophilic involvement often is localized to the stomach but can involve the small bowel. Cramping and abdominal pain associated with nausea and vomiting occur frequently. Food allergy and past history of allergy are less common in these patients than in patients with mucosal layer disease.

Involvement of the serosal layer is the least common form of the disease. The entire GI wall usually is involved. These patients typically present with eosinophilic ascites. Serosal and visceral peritoneal inflammation leads to leakage of fluids.

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Approach Considerations

The evaluation starts with a comprehensive history and physical examination. The diagnosis of eosinophilic gastrointestinal conditions, including eosinophilic gastroenteritis, is one of exclusion and requires the presence of gastrointestinal symptoms, the presence of gastrointestinal eosinophilia on biopsy specimens, and the exclusion of other known causes of tissue eosinophilia.^{[1, 11]}

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Laboratory Studies

General workup includes a complete blood cell (CBC) count and differential. Peripheral blood eosinophilia is found in 20-80% of cases. The average count is 2000 eosinophils (eos)/µL in patients with mucosal layer involvement, 1000 eos/µL in patients with muscular layer involvement, and 8000 eos/µL in patients with serosal involvement.

Mean corpuscular volume measurements may reveal iron-deficiency anemia, and serum albumin levels may be low, especially in patients with mucosal layer involvement.

Also note the following:

• Although usually unnecessary, fecal protein loss can be measured by measuring alpha1-antitrypsin in a 24-hour feces collection. This test is used to identify the inability to digest and absorb proteins in the GI tract. The normal value is 0-54 mg/dL. Patients with eosinophilic gastroenteritis have elevated alpha1-antitrypsin in their feces. Obtain a stool sample (minimum 2-g portion), and keep it refrigerated.
• Protein loss also can result in a low level of quantitative immunoglobulins.
• The erythrocyte sedimentation rate (ESR) and serum IgE level can be elevated.
• Obtain three separate stool specimens to rule out parasitic infection. Perform a wet mount or stain smear.
• Mild-to-moderate steatorrhea is present in approximately 30% of patients. This can be measured by qualitative and quantitative stool tests.
• Skin prick tests to inhalant allergens and food help identify sensitization to specific allergens.
• The diagnosis of eosinophilic gastroenteritis depends on microscopic evaluations of endoscopic biopsy specimens. Examine specimens from each intestinal segment with particular attention to the following: (1) eosinophil quantification; (2) the location of eosinophils especially if present in the intraepithelial, superficial mucosal, and intestinal crypts; (3) the presence of extracellular eosinophilic granules; (4) associated pathologic abnormalities; and (5) the absence of other primary disorders (ie, vasculitis).

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Imaging Studies

Radiography

Radiographically, eosinophilic gastroenteritis does not have a pathognomic appearance. Radiographic changes are variable, nonspecific, and/or absent in at least 40% of patients. Note the following:

• Gastric folds can be enlarged, with or without nodular filling defects.
• Valvular conniventes may be thickened and flattened. Strictures, ulceration, or polypoid lesions may occur.
• In eosinophilic gastroenteritis involving the muscle layer, localized involvement of the antrum and pylorus may occur, causing narrowing of the distal antrum and gastric retention. The small intestine also may be dilated, with an increase in the thickness of the folds. Prominent mucosal folds also may be observed in the colon.
• Rarely, diffuse esophageal narrowing or achalasia-like motor abnormalities may occur.

Ultrasonography and computed tomography (CT) scanning

Abdominal ultrasonographic images and CT scans may show thickened intestinal walls and, sometimes, localized lymphadenopathy.^[12] Ascitic fluid usually is detected in patients with serosal layer involvement.

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Procedures

Endoscopy and biopsy

Note the following:

• When eosinophilic gastroenteritis is suspected, obtain biopsy samples from the gastric antrum and duodenum.^{[13, 14]} It is not recommended that biopsy samples be placed in Bouin preservative, as this can cause difficulty in identifying eosinophils.^[14]
• Because of possible sampling error, when performing endoscopy, obtain at least 6 biopsy specimens from normal and abnormal areas of the bowel.
• Grossly prominent mucosal folds, hyperemia, ulceration, or nodularity may be apparent.
• In patients with esophageal or colonic symptoms, obtain additional biopsy specimens from the relevant sites to aid in the diagnosis. Gastroesophageal reflux can cause tissue eosinophilia in the distal esophagus. See the images below.

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  Biopsy specimen of eosinophilic gastroenteritis.

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  Biopsy specimen of eosinophilic gastroenteritis.

   

  

   

Paracentesis

Patients with serosal disease present with ascites. Abdominal paracentesis demonstrates a sterile fluid with a high eosinophil count. Pleural effusion also may be present. Laparoscopy may show hyperemia and/or nodularity of the GI wall.

Laparotomy

Exploratory laparotomy may be indicated, especially in patients with serosal eosinophilic gastroenteritis.

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Histologic Findings

Histopathology usually demonstrates increased numbers of eosinophils (often >50 eos per high-power field) in the lamina propria. Large numbers of eosinophils often are present in the muscularis and serosal layers. The localized eosinophilic infiltrates may cause crypt hyperplasia, epithelial cell necrosis, and villous atrophy. The gross appearance of eosinophilic gastroenteritis upon endoscopy shows erythematous, friable, nodular, and, often, ulcerated mucosa. Diffuse enteritis with complete loss of villi, submucosal edema, infiltration of the GI wall, and fibrosis may be apparent. Mast cell infiltrates and hyperplastic mesenteric lymph nodes infiltrated with eosinophils may be present. Because of errors in sampling or to mucosal sparing, 10% of mucosal biopsies are not helpful to establish a diagnosis.

Histologic analysis of the small intestine reveals increased deposition of extracellular major basic proteins (MBPs) and eosinophilic cationic proteins (ECPs).

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Approach Considerations

Most patients with eosinophilic gastroenteritis respond to conservative measures, empiric dietary elimination of six foods or an elemental diet, and oral glucocorticosteroids.^[11] Patients can be monitored every 6 months. Biologic therapy with humanized IL-5 treatment has been associated with a reduced eosinophil count but not with improved clinical symptoms.^[15] Treatment with omalizumab has shown a reduction in eosinophil count as well as clinical improvement of symptoms; however, the results were not clinically significant.^[16] A 2016 case report showed treatment with clarithromycin resulted in both improvement in clinical symptoms and a decrease in eosinophil count.^[17]

Avoid surgery if at all possible, unless it is necessary to relieve persistent pyloric or small bowel obstruction. Reoccurrence is possible, even after surgical excision.^[18]

Consultations

Refer patients with persistent abdominal symptoms and peripheral eosinophilia to a gastroenterologist for workup, endoscopy, and biopsies.

Refer patients to an allergy/immunology specialist for food skin testing and evaluation of eosinophilia and high IgE levels.

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Medical Care

Elimination of foods implicated by skin testing has variable effects, but resolution of symptoms can sometimes be achieved with amino acid based elemental diets. Supportive treatment with pharmacotherapy, mainly oral glucocorticosteroids, (20-40 mg per day) followed by a rapid taper, is indicated for those with obstructive symptoms.

Patients with mucosal layer involvement may benefit from anti-inflammatory medications (eg, oral glucocorticoids, oral cromolyn) and/or diet elimination therapy, particularly if they report a history of food intolerance or allergy.

Drugs, such as montelukast, ketotifen, suplatast tosilate, and mycophenolate mofetil (inosine monophosphate dehydrogenase inhibitor), and alternative Chinese medicines have been advocated but are generally not successful.

Dietary considerations

Educate patients to avoid foods that they cannot tolerate and to seek medical care when needed. Initially, a trial elimination diet that excludes milk, eggs, wheat and/or gluten, soy, and beef may be helpful. RAST or skin testing can identify food hypersensitivity. If a prohibitive number of food reactions are found, an amino–acid-based diet or elemental diet may be considered.

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Diet

The strong association of eosinophilic gastroenteritis with food allergies has prompted the use of restrictive or elemental diets.^[11] However, there is a lack of good, high-quality clinical data regarding the efficacy of dietary interventions.^[19]

On the basis of the available studies, an attempt may be made with an empiric elimination of six foods, including milk, soy, wheat, egg, peanuts/tree nuts, and fish/shellfish.

The American Partnership For Eosinophilic Disorders (APFED) provides educational resources and support for patients and caregivers. For additional patient education resources, see Digestive Disorders Center, as well as Gastroenteritis.

The absolute eosinophil count can be checked 4-6 weeks after implementation of empiric dietary treatment. A reduction of 50% in the peripheral eosinophil count can be considered a response to treatment. Although food hypersensitivity plays a role in eosinophilic gastroenteritis pathophysiology, no food allergy test has been shown to effectively identify specific culprit foods leading to clinical improvement in these patients’ symptoms.

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Long-Term Monitoring

No official guidelines for long-term follow-up exist in patients with eosinophilic gastroenteritis (EGE) because the disease evolution is so variable. Patients may present with a single outbreak, intermittent flares, and/or prolonged a protracted disease course. Yearly follow-up may be of benefit. The American Partnership For Eosinophilic Disorders (APFED) established an online patient database registry that may have the potential to provide more insights to the disease course.

Endoscopy and radiologic findings in EGE may reveal a normal appearance. These may be used for follow-up on a case-by-case basis.

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Medication Summary

Oral glucocorticosteroids with anti-inflammatory properties are the primary therapy, especially for patients with obstructive symptoms and eosinophilic ascites. Most patients with eosinophilic gastroenteritis respond dramatically to oral glucocorticosteroids within 2 months. Successful treatment with other anti-inflammatory medications, such as leukotriene modifiers (eg, montelukast), macrolides, and mast cell stabilizers (eg, cromolyn), has been reported.

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Fluticasone inhaled (Flovent)

• Dosing, Interactions, etc.

Clinical Context:  Decreases recruitment of inflammatory cells including eosinophils and decreases the release of eotaxins and other inflammatory mediators. Dosage required is higher than dosage used in asthma.

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Budesonide (Pulmicort Respule) oral viscous suspension

• Dosing, Interactions, etc.

Clinical Context:  Decreases inflammation, reduces capillary permeability.

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Prednisolone (AK-Pred, Delta-Cortef)

• Dosing, Interactions, etc.

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Equivalent dosages of prednisone or methylprednisolone may be used.

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Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

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Cromolyn (Intal, Gastrocrom)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits release of histamine, leukotrienes, and other mediators from sensitized mast cells. It also inhibits the influx of neutrophils, as well as the formation of the active form of NADPH oxidase which in turn prevents tissue damage caused by oxygen radicals.

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Class Summary

Inhibit degranulation of sensitized mast cells following exposure to allergens.

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Montelukast (Singulair)

• Dosing, Interactions, etc.

Clinical Context:  Potent and selective antagonist of leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT1.

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Class Summary

Prevent or reverse some of the pathologic features associated with the inflammatory process mediated by leukotrienes C₄, D₄, and E₄. Successful treatment of eosinophilic gastroenteritis has been reported.

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Clarithromycin (Biaxin, Biaxin XL)

• Dosing, Interactions, etc.

Clinical Context:  Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, thereby inhibiting bacterial growth.

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