Eosinophilic gastroenteritis (EGE) represents one member within the spectrum of diseases collectively referred to as eosinophilic gastrointestinal disorders, which includes eosinophilic esophagitis (EoE), gastritis, enteritis, and colitis. EGE is less common than EoE and involves a different site of disease but otherwise shares many common features with EoE. The clinical manifestations of EGE are protean and can vary from nausea and vomiting to protein-losing enteropathy or even bowel obstruction requiring surgery. Although systemic corticosteroids are an effective treatment for EGE, their use results in substantial corticosteroid toxicity. Accordingly, there is a great need for improved therapies for these patients.
Key points
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Eosinophilic gastroenteritis (EGE) is diagnosed by the presence of gastrointestinal symptoms, biopsies showing predominant eosinophilic infiltration, and the absence of allergic, parasitic, or other diseases that may cause eosinophilia.
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EGE is a rare disease affecting approximately 22 to 28 per 100,000 persons.
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Because EGE may vary by both the site of involvement (stomach, duodenum, jejunum) and the depth of involvement (mucosal, muscularis, or serosal disease), its manifestations are protean.
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Dietary therapy is effective in allergic EGE.
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Systemic and topical corticosteroids are effective treatments for EGE, but are limited by long-term corticosteroid side effects.
Clinical presentation of EGE
Eosinophilic gastroenteritis (EGE) represents one member within the spectrum of diseases collectively referred to as eosinophilic gastrointestinal disorders (EGIDs), which includes eosinophilic esophagitis (EoE), gastritis, enteritis, and colitis. Although some patients present with EGID limited to the stomach (eosinophilic gastritis, EG) or duodenum (eosinophilic duodenitis), it is often simplest to refer to the combined entity of EGE. EoE as a clinical entity is effectively limited to “solitary EoE”; patients having coexistent EoE and EGE are a small minority. EoE and EGE are closely related disease entities, the relationship of which is discussed below. The diagnosis of EG is confirmed by a characteristic biopsy and/or eosinophilic ascitic fluid in the absence of other causes of gut eosinophilia.
The disease can affect patients of any age, but case series have noted a dominance of presentations starting in the third through fifth decade. As the prevalence of EoE has increased and there is an overall greater appreciation of EGID, it is likely that a second peak of incidence in the first decade of life will become better appreciated. As with EoE, there is a clear male predominance. An electronic survey sent to North American Allergists and Pediatric Gastroenterologists indicate prevalence for EGE of 22 to 28 per 100,000 persons. Although no large longitudinal study has been performed, EGE is largely understood to be a chronic disease with few remissions after the first year.
The clinical features of EGE are protean and are related to the organs, tissue layers affected, and the intensity of eosinophilic inflammation. Some patients present with dominant gastric or duodenal disease, whereas others have involvement of both organs. Dominant gastric disease often presents with nausea, vomiting, and early satiety. In contrast, dominant duodenal disease may present with malabsorption and protein-losing enteropathy. Both forms of EGE often have crampy abdominal pain and bloating as additional features. Because jejunal and ileal biopsies are not routinely obtained on endoscopy, it is not known how much these gut segments contribute to disease. Patients can variably present with either diarrhea or constipation.
In addition to the varying distribution of eosinophils along the length of the gastrointestinal (GI) tract, multiple reports have cited EGE subtypes based on differing depth of eosinophilic infiltration. The 3 well-described subtypes include dominant involvement of the mucosal, muscularis, and subserosal layers, respectively. Whether these actually represent different diseases or simply different presentations of the same disease is not known. The prevalence of each subtype is unknown because of reporting and referral biases. For example, surgical series report a predominance of muscularis disease with obstruction, whereas medical series primarily describe patients with mucosal involvement. Serosal disease is associated with eosinophilic ascites, but it is not known whether this reflects isolated serosal involvement or simply intense transmural eosinophilic inflammation.
In addition to the common presentations noted above, EGE can present with a variety of unusual manifestations. Patients may have gastric ulcer disease as a feature of their EGE. Typically these ulcers do not respond well to proton pump inhibitor therapy, but do respond to either topical or systemic corticosteroids. There is a case report of ulcer disease responding to an elemental diet.
In contrast to EoE, stricture formation is not a common feature of EGE. That said, a subset of perhaps 5% to 10% of EGE patients do have clinically significant strictures at some point. Such cases will typically present as an acute bowel obstruction with nausea, vomiting, crampy abdominal pain, and bloating. Such bowel obstructions appear to be a combination of both mechanical obstruction due to stricture and functional obstruction due to inflammation, edema, and decreased GI motility. Most of the time these obstructions are reversible with corticosteroid treatment, suggesting that in many cases there is a functional component that can be reversed with treatment. As such, clinically stable EGE patients presenting with bowel obstruction should generally first be treated with parenteral corticosteroid therapy, such as methyl prednisolone 1 to 2 mg/kg/d, and carefully observed.
EGE can occasionally involve the hepatobiliary tree. Pancreatitis is the best described hepatobiliary complication of EGE. It is not clear if this is due to eosinophilic infiltration of the pancreas, gall bladder, or hepatobiliary ducts or to a secondary cause. In addition, EGE can rarely present with eosinophilic cholangitis.
Clinical presentation of EGE
Eosinophilic gastroenteritis (EGE) represents one member within the spectrum of diseases collectively referred to as eosinophilic gastrointestinal disorders (EGIDs), which includes eosinophilic esophagitis (EoE), gastritis, enteritis, and colitis. Although some patients present with EGID limited to the stomach (eosinophilic gastritis, EG) or duodenum (eosinophilic duodenitis), it is often simplest to refer to the combined entity of EGE. EoE as a clinical entity is effectively limited to “solitary EoE”; patients having coexistent EoE and EGE are a small minority. EoE and EGE are closely related disease entities, the relationship of which is discussed below. The diagnosis of EG is confirmed by a characteristic biopsy and/or eosinophilic ascitic fluid in the absence of other causes of gut eosinophilia.
The disease can affect patients of any age, but case series have noted a dominance of presentations starting in the third through fifth decade. As the prevalence of EoE has increased and there is an overall greater appreciation of EGID, it is likely that a second peak of incidence in the first decade of life will become better appreciated. As with EoE, there is a clear male predominance. An electronic survey sent to North American Allergists and Pediatric Gastroenterologists indicate prevalence for EGE of 22 to 28 per 100,000 persons. Although no large longitudinal study has been performed, EGE is largely understood to be a chronic disease with few remissions after the first year.
The clinical features of EGE are protean and are related to the organs, tissue layers affected, and the intensity of eosinophilic inflammation. Some patients present with dominant gastric or duodenal disease, whereas others have involvement of both organs. Dominant gastric disease often presents with nausea, vomiting, and early satiety. In contrast, dominant duodenal disease may present with malabsorption and protein-losing enteropathy. Both forms of EGE often have crampy abdominal pain and bloating as additional features. Because jejunal and ileal biopsies are not routinely obtained on endoscopy, it is not known how much these gut segments contribute to disease. Patients can variably present with either diarrhea or constipation.
In addition to the varying distribution of eosinophils along the length of the gastrointestinal (GI) tract, multiple reports have cited EGE subtypes based on differing depth of eosinophilic infiltration. The 3 well-described subtypes include dominant involvement of the mucosal, muscularis, and subserosal layers, respectively. Whether these actually represent different diseases or simply different presentations of the same disease is not known. The prevalence of each subtype is unknown because of reporting and referral biases. For example, surgical series report a predominance of muscularis disease with obstruction, whereas medical series primarily describe patients with mucosal involvement. Serosal disease is associated with eosinophilic ascites, but it is not known whether this reflects isolated serosal involvement or simply intense transmural eosinophilic inflammation.
In addition to the common presentations noted above, EGE can present with a variety of unusual manifestations. Patients may have gastric ulcer disease as a feature of their EGE. Typically these ulcers do not respond well to proton pump inhibitor therapy, but do respond to either topical or systemic corticosteroids. There is a case report of ulcer disease responding to an elemental diet.
In contrast to EoE, stricture formation is not a common feature of EGE. That said, a subset of perhaps 5% to 10% of EGE patients do have clinically significant strictures at some point. Such cases will typically present as an acute bowel obstruction with nausea, vomiting, crampy abdominal pain, and bloating. Such bowel obstructions appear to be a combination of both mechanical obstruction due to stricture and functional obstruction due to inflammation, edema, and decreased GI motility. Most of the time these obstructions are reversible with corticosteroid treatment, suggesting that in many cases there is a functional component that can be reversed with treatment. As such, clinically stable EGE patients presenting with bowel obstruction should generally first be treated with parenteral corticosteroid therapy, such as methyl prednisolone 1 to 2 mg/kg/d, and carefully observed.
EGE can occasionally involve the hepatobiliary tree. Pancreatitis is the best described hepatobiliary complication of EGE. It is not clear if this is due to eosinophilic infiltration of the pancreas, gall bladder, or hepatobiliary ducts or to a secondary cause. In addition, EGE can rarely present with eosinophilic cholangitis.
Pathogenesis of EGE
The many similarities between EGE and EoE suggest they share a common pathogenesis. Shared features include tissue eosinophilic inflammation, coexisting allergic disease, peripheral eosinophilia, and polysensitization to food allergens. The most compelling clinical feature of EoE is its responsiveness to elemental and highly restricted diets. Several case series suggest that at least a subpopulation of EGE is also responsive to elemental and 6-food elimination diets. These findings underscore the concept that both EoE and EGE are food allergen–driven eosinophilic inflammatory bowel diseases.
In an early report, Jaffe and colleagues noted increased interleukin (IL)-5 expression in peripheral blood mononuclear cells from EGE patients. Consistent with in vivo activation by food allergen, this IL-5 message was constitutively produced by CD4 T cells in the peripheral blood mononuclear cell. A role for IL-5 in driving the peripheral eosinophilia has been further established by the use of therapeutic monoclonal anti-IL-5, which potently decreases peripheral eosinophils in EGE.
In the author’s work, food allergen-specific CD4 T-cell responses in EGE, peanut allergies, and healthy control subjects were examined and differing Th2 responses in these eosinophilic versus anaphylactic forms of food allergy were found. Notably, EGE is uniquely associated with an IL-5+ Th2 (IL-5+, IL-13+) response to foods; conversely, in peanut allergy, the Th2 response is almost entirely IL-5− (IL-5−, IL-13+). This IL-5+ Th2 response is highly correlated to peripheral blood eosinophil count, further establishing a link between this Th2 subpopulation and eosinophilia. In recent work these IL-5+ Th2 cells have been further characterized as highly differentiated Th2 cells that require multiple rounds of antigen exposure to attain the IL-5+ Th2 phenotype. These data suggest that in EGE these pathogenic proeosinophilic IL-5+ Th2 cells are the product of multiple rounds of food allergen stimulation in vivo.
EGE and EoE are defined by their respective sites of clinical disease. Despite these differences, their similarities far outweigh the differences and suggest the pathogenesis of these 2 forms of EGID have common mechanisms. The differences in site of disease may be due to local effects that may favor esophageal versus gastric eosinophilic inflammation. For example, EoE may be influenced by high concentrations of swallowed aeroallergen impacting the esophagus, or by gastroesophageal reflux. Alternatively, there may be specific homing signals or receptors that favor esophageal versus gastric homing.
Diagnosis of EGE
Unlike EoE, there are no consensus guidelines for the diagnosis of EGE. The diagnosis is based on typical symptoms coupled with increased gastric or intestinal eosinophils, in the absence of other potential causes of GI eosinophilia. There is no consensus on the requisite number of eosinophils needed for the diagnosis. As detailed in the accompanying article, “Histopathologic Features,” based on studies of healthy controls, peak eosinophil counts of 30 eos/hpf in the stomach and 50 eos/hpf (eosinophils per high powered field) in the duodenum have been proposed for the diagnosis of EG and duodenitis, respectively. Additional features, such as epithelial eosinophils, intraglandular eosinophils, and eosinophils in the muscularis, also weight toward the diagnosis of EGE. The intensity of eosinophilic inflammation is quite variable within an affected organ and can reach almost confluent density in some cases ( Fig. 1 ). Accordingly, endoscopic biopsies should be obtained from 5 to 6 sites per affected organ, in a similar manner to the consensus procedures in EoE.
Given the association of EGE with allergic disease, in clinical studies of “allergic” EGE, additional criteria have been used, such as immunoglobulin E (IgE) sensitization to multiple food allergens and peripheral blood eosinophilia. These added criteria identify a subpopulation of EGE patients with more homogeneous immunologic findings and add to the specificity of diagnosis. However, such criteria should not be used as an absolute requirement for the diagnosis because there is a large fraction of EGE patients lacking these.
The gross endoscopic findings are often normal. Gastritis or ulcers may be present. The one observation that is relatively typical for EG is the presence of pseudopolyps. These sessile lesions are not true polyps in that they are largely composed of dense collagen deposits with epithelium heaped on top. As such, they do not represent true polyps and do not contain hyperplastic glandular or epithelial components. Gastric pseudopolyps are the most common presentation ( Fig. 2 ) and may occur in as many as 25% of EGE subjects (Calman Prussin, personal observation, 2014). Small bowel pseudopolyps may occur, but are less frequent ( Fig. 3 ).
