Eosinophilic gastroenteritis is an infrequently diagnosed condition that is characterized by prominent eosinophilic infiltration of the stomach or small intestine, generally localized to one level of the intestinal wall; the variable organ locus and wall depth produce heterogeneous clinical presentations. A strong association with atopy is present in most cases, supported by circumstantial evidence and the demonstration of Th-2 proinflammatory cytokine profiles in animal studies. A high degree of suspicion is required to establish the diagnosis, which must be based on intense gastrointestinal eosinophilia. Management is directed toward removal of offending allergens and use of anti-inflammatory agents. Novel and emerging treatments on the horizon are biologic therapies and selective anti-eosinophil agents.
Eosinophilic gastroenteritis (EG) is commonly regarded as a synonym for eosinophilic gastrointestinal disorders (EGID), referring to a broad spectrum of clinical presentations produced by prominent eosinophilic infiltration through a variable depth of one or more gastrointestinal sites, and thus including eosinophilic esophagitis, gastritis, enteritis, and proctocolitis. Alternatively, the term has been used to refer to eosinophilic inflammation limited exclusively to the stomach and small intestine. To avoid redundancy in this issue of Gastroenterology Clinics of North America , this article is restricted to a focused and updated review of eosinophilic gastroenteritis as limited to the latter definition.
Epidemiology
Because of a notable scarcity of published data on the epidemiology, it is difficult to determine the true burden of EG. An English language literature review does not reveal a well-analyzed published case series describing primary EG in the last 3 years, suggesting that it is an uncommon and perhaps difficult-to-diagnose disorder. Nevertheless, several case reports of EG have emerged recently in different parts of the world . The diagnosis affects most ethnicities, and all ages of both genders . It is diagnosed most frequently in the third decade of life . A personal or family history of allergic disorders, such as asthma, hay fever, or eczema, is present in 60% to 70% of patients .
A report from India on EG documented only 7 young adults during a 10-year period , and a hospital in China identified 15 patients who had EG, including 2 children, during 18 years . Talley and colleagues reported one of the largest case series of EG by characterizing 40 patients diagnosed during a 30-year period.
Pathogenesis
EG may be primary, also known as allergic, or secondary to one of many conditions that provoke eosinophilic inflammation (see later section on differential diagnosis), with parasitic infections being the leading cause. The cause cannot be precisely determined in a small but important minority of patients, who are regarded as having idiopathic EG.
Eosinophils and Key Mediators
EG, like other allergic diseases, is characterized predominantly by a Th-2 type of inflammatory response. This response, in concert with eosinophils and their granular proteins and eotaxin-1, a selective chemoattractant, are all critical to the pathogenesis of EG.
Eosinophils, the hallmark of the pathology of EG, normally reside in the gastrointestinal tract lining beyond the esophagus, and are believed to have a role in host defense (eg, against parasitic infections). Reported normal densities of eosinophils vary throughout the length and depth of the gastrointestinal tract (see later discussion of diagnostic evaluation).
Eosinophils function as antigen-presenting cells and mediate inflammatory effects by releasing preformed granular proteins, such as eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), eosinophil peroxidase, and major basic protein (MBP) . Extracellular deposits of ECP and MBP have been demonstrated in the small intestine of patients who have EG; electron microscopy has provided further evidence for eosinophil degranulation in duodenal mucosal samples from patients who have EG . Eosinophils also secrete Th-2–type proinflammatory cytokines, such as interleukin (IL)–3, IL-4, IL-5, IL-18, and transforming growth factor, and lipid mediators that are cytotoxic to human intestinal epithelium .
Further new and exciting insights into the mechanism of intestinal mucosal eosinophilia have been made possible through the study of the BioBreeding (BB) lymphopenic (lyp) rat model . The lyp gene encodes a molecule known as GTPase of the immunity-associated protein, which may protect lymphocytes against apoptosis. Homozygosity of the lyp gene mutation in this murine model is associated with intense eosinophilia of the small and large intestinal mucosa, an overall Th-2 phenotype expressed by cell cultures derived from lymph nodes and spleen, with increased levels of IL-4, IL-5, and IL-13 RNA, and increased serum levels of IgE. Furthermore, the rats develop clinical features of wasting, bloating, intestinal distention, splenomegaly, and mesenteric adenopathy. An interesting feature observed even before the histopathology findings was the presence of an autoantibody, BB rat serum IgG, bound to intestinal cells that resembled fibroblasts. This finding has led to the speculation that a novel autoantigen in the subepithelial layer may provoke mucosal eosinophilic invasion.
Allergy
Excess circulating eosinophils are considered a hallmark of atopy, and hence it is no surprise that the frequency of allergies in patients who have EG is 25% to 75%. Peripheral eosinophilia is present in 50% of those who have both EG and atopic diseases, such as asthma, eczema, and hay fever . EG-associated allergies are reported variably as mediated by either IgE or non-IgE mechanisms. Mice challenged by oral antigens produce correlates of human EG disease: antigen-specific serum antibodies, prominent eosinophilic intestinal infiltrates, and clinical manifestations, including diarrhea, gastromegaly, dysmotility, and cachexia .
Genetics/Familial
Genetic susceptibility is also now being implicated in the pathogenesis, as evidenced by the presence of a family history of an EGID in 10% of patients .
Pathogenesis
EG may be primary, also known as allergic, or secondary to one of many conditions that provoke eosinophilic inflammation (see later section on differential diagnosis), with parasitic infections being the leading cause. The cause cannot be precisely determined in a small but important minority of patients, who are regarded as having idiopathic EG.
Eosinophils and Key Mediators
EG, like other allergic diseases, is characterized predominantly by a Th-2 type of inflammatory response. This response, in concert with eosinophils and their granular proteins and eotaxin-1, a selective chemoattractant, are all critical to the pathogenesis of EG.
Eosinophils, the hallmark of the pathology of EG, normally reside in the gastrointestinal tract lining beyond the esophagus, and are believed to have a role in host defense (eg, against parasitic infections). Reported normal densities of eosinophils vary throughout the length and depth of the gastrointestinal tract (see later discussion of diagnostic evaluation).
Eosinophils function as antigen-presenting cells and mediate inflammatory effects by releasing preformed granular proteins, such as eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), eosinophil peroxidase, and major basic protein (MBP) . Extracellular deposits of ECP and MBP have been demonstrated in the small intestine of patients who have EG; electron microscopy has provided further evidence for eosinophil degranulation in duodenal mucosal samples from patients who have EG . Eosinophils also secrete Th-2–type proinflammatory cytokines, such as interleukin (IL)–3, IL-4, IL-5, IL-18, and transforming growth factor, and lipid mediators that are cytotoxic to human intestinal epithelium .
Further new and exciting insights into the mechanism of intestinal mucosal eosinophilia have been made possible through the study of the BioBreeding (BB) lymphopenic (lyp) rat model . The lyp gene encodes a molecule known as GTPase of the immunity-associated protein, which may protect lymphocytes against apoptosis. Homozygosity of the lyp gene mutation in this murine model is associated with intense eosinophilia of the small and large intestinal mucosa, an overall Th-2 phenotype expressed by cell cultures derived from lymph nodes and spleen, with increased levels of IL-4, IL-5, and IL-13 RNA, and increased serum levels of IgE. Furthermore, the rats develop clinical features of wasting, bloating, intestinal distention, splenomegaly, and mesenteric adenopathy. An interesting feature observed even before the histopathology findings was the presence of an autoantibody, BB rat serum IgG, bound to intestinal cells that resembled fibroblasts. This finding has led to the speculation that a novel autoantigen in the subepithelial layer may provoke mucosal eosinophilic invasion.
Allergy
Excess circulating eosinophils are considered a hallmark of atopy, and hence it is no surprise that the frequency of allergies in patients who have EG is 25% to 75%. Peripheral eosinophilia is present in 50% of those who have both EG and atopic diseases, such as asthma, eczema, and hay fever . EG-associated allergies are reported variably as mediated by either IgE or non-IgE mechanisms. Mice challenged by oral antigens produce correlates of human EG disease: antigen-specific serum antibodies, prominent eosinophilic intestinal infiltrates, and clinical manifestations, including diarrhea, gastromegaly, dysmotility, and cachexia .
Genetics/Familial
Genetic susceptibility is also now being implicated in the pathogenesis, as evidenced by the presence of a family history of an EGID in 10% of patients .
Clinical Presentations
Patients who have EG have heterogeneous clinical presentations, some of which overlap with more familiar diagnoses, such as functional GI disorders and inflammatory bowel disease. Presenting symptoms may be vague and nonspecific (eg, recurrent abdominal pain ) or dramatic (eg, gastric ulcer perforation ). Symptom onset may be at any age, but most patients are diagnosed as young adults, between the third and fifth decades of life. Often patients experience symptoms for many months and undergo an elaborate evaluation before the diagnosis of EG is correctly established. The natural history of EG is not well studied, although the course is usually characterized by waxing and waning symptoms.
Patients who have EG have selective involvement of the stomach (26%–81%) and small intestine (28%–100%) . As alluded to earlier, however, EG is popularly used to refer to those cases of prominent gastric or small intestinal eosinophilia that may have concurrent, although less prominent, eosinophilia of the esophagus, large intestine, or rectum. It is debated, for example, whether the occasional patient presenting with apparent eosinophilic esophagitis (EE) and marked eosinophilic inflammation extending to other segments of the gastrointestinal tract represents primary EE or EE as part of EGID.
The most common presenting complaint is abdominal pain, reported by two thirds of patients in most case series, followed by the symptoms of nausea, vomiting, and diarrhea .
Classification
The Klein classification describes EG clinical presentations in terms of the variable depth of eosinophilic infiltration: mucosal, submucosal, and serosal subtypes .
Mucosal
The mucosal subtype is the most common one (25%–100%), perhaps because of the accessibility to diagnosis by routine endoscopy and biopsies. Patients who have mucosal EG present with common, albeit nonspecific, complaints of abdominal pain, nausea, vomiting, diarrhea, occult gastrointestinal bleeding, anemia, weight loss, or protein-losing enteropathy . Because of their nonspecific nature, these clinical presentations may be confused with irritable bowel syndrome, dyspepsia, pancreatitis, acute appendicitis, or inflammatory bowel disease. Intestinal loss of blood and protein is a unique presentation in children who have allergic EG, and is suspected to be attributable to increased intestinal permeability induced by eosinophilic inflammation. Frequent coexisting findings in patients who have mucosal EG are atopy and high serum IgE levels.
Muscular
This subtype of EG is diagnosed in 13% to 70% of all EG cases, and is best known to present with a clinical picture of gastric outlet or intestinal obstruction . Abdominal pain is usually characterized as colicky. EG presenting as gastric outlet obstruction can mimic hypertrophic pyloric stenosis, and has been successfully managed with a hypoallergenic formula rather than surgery . Intestinal obstruction attributable to enteric strictures, although rare, occurs most frequently at the level of the jejunum, and has been described in children and adults .
Serosal
The serosal layer is involved in 12% to 40% of cases of EG. Most commonly affected are adults who present classically with ascites. Other notable findings in these patients are significant bloating, a higher level of peripheral eosinophilia, and a better response to steroids .
Differential Diagnosis
A broad range of conditions are associated with gastrointestinal mucosal eosinophilia and the following is a brief review of some of the important differential diagnoses.
Infections
Parasitic infestations
Among parasites, helminths are most characteristically associated with peripheral eosinophilia, probably as a reflection of an immunologic response to their tissue migration. Tissue eosinophilia also may be found with several other parasites, including hookworms ( Ancylostoma caninum ), pinworms ( Enterobius vermicularis ), Eustoma rotundatum , Giardia lamblia , Anisakis , Trichinella spiralis , Ascaris , Trichuris , Schistosomiasis , Toxocara canis , and Strongyloides stercoralis . Diagnosis should be pursued in the appropriate clinical situation using studies such as stool for ova and parasites, stool giardia antigen, serology, paracentesis (in the case of ascites), duodenal aspirate, and endoscopy with biopsies .
Helicobacter pylori
H pylori gastritis has been observed in patients who have diffuse intestinal eosinophilia in the absence of food allergies. The significance of these coexisting findings, beyond coincidence, is not clear .
Cytomegalovirus
Cytomegalovirus (CMV) gastroenteritis evident by serology and pathology, the latter also consistent with EG, has been reported in an immunocompetent child presenting with protein-losing enteropathy . Whether the allergic mucosa predisposed to reactivation of latent CMV or CMV triggered prominent intestinal eosinophilia could not be elucidated from this report. Interestingly, this patient had complete resolution of clinicopathologic features without specific antiviral or antiallergy therapy within 4 weeks.
Medications
Several medications have been implicated in producing gastrointestinal eosinophilia as an allergic response. Examples include interferon , gemfibrozil , enalapril , carbamazepine , clofazimine and co-trimoxazole . Tissue eosinophilia is usually reversible with cessation of the medication.
Connective Tissue Disease and Vasculitis
Various connective tissue disorders (eg, scleroderma, dermatomyositis, lupus) and vasculitis (eg, Churg-Strauss syndrome, polyarteritis nodosa) are associated with fluctuating peripheral and gastrointestinal eosinophilia . The presence of specific clinicopathologic and autoimmune markers is helpful in their differentiation from primary EG.
Inflammatory Fibroid Polyps
Rarely diagnosed, these benign localized polyps, also known as fibroma, inflammatory pseudotumor, submucosal granuloma, or localized EG, originate in the submucosa and are accompanied by a variable eosinophilic infiltrate. These lesions are most commonly located in the stomach (∼35% of cases) and the small bowel (∼50%), and come to attention because of obstructive presentations. Surgical excision is a cure for symptomatic patients .
Hypereosinophilia Syndrome
Hypereosinophilia syndrome is a rare heterogeneous disorder with features of unexplained marked peripheral hypereosinophilia (>1500 cells/μL for more than 6 consecutive months) despite an extensive evaluation, and presence of organ damage or dysfunction related to hypereosinophilia . The heart, skin, and central nervous system are the major targets, whereas occasional intestinal involvement is reported. Recently, hypereosinophilia syndrome has been classified as either myeloproliferative or lymphocytic indicating an underlying hematologic basis for these variants.
Inflammatory Bowel Disease
Peripheral and intestinal eosinophilia is often noted in patients who have irritable bowel disease, in the context of classic clinicopathologic features that allow differentiation from primary EG and other conditions.
Transplantation
Recipients of solid organ transplantation may develop intestinal eosinophilia as a consequence of immunosuppression, an imbalance of Th-1/Th-2 lymphocytes, and de novo food allergies. A substantial number of patients are on immunosuppressive regimens composed of tacrolimus, a calcineurin inhibitor that is strongly implicated in inducing intestinal eosinophilia. A high total IgE and food allergen–specific IgE levels are observed in this subgroup of patients and dietary therapy has proved to be satisfactory .
Diagnostic Evaluation
Diagnosis of EG requires suspecting the disease, excluding other disorders in the differential diagnoses, confirming the definitive diagnosis, and assessing for potential complications. Currently accepted diagnostic criteria are the presence of gastrointestinal symptoms, an intense eosinophilic infiltrate on histopathologic examination, and exclusion of other causes of intestinal eosinophilia. Tests considered useful in the evaluation of EG and its differentials are presented in Table 1 .
| Evaluation | Significance |
|---|---|
| Complete blood count with differential | Anemia, absolute eosinophilia |
| Total protein and albumin | Hypoalbuminemia, edema, protein-losing enteropathy, ascites, malnutrition |
| Quantitative immunoglobulins | Protein-losing enteropathy |
| Stool α-1 antitrypsin | Protein-losing enteropathy |
| Stool eosinophils | EG diagnosis and follow-up |
| Stool for eosinophil-derived granular proteins (eg, ECP) | EG diagnosis and follow-up |
| Stool giardia antigen, ova and parasite | Exclusion of parasite-induced EG |
| Radiology | |
| Barium contrast studies | Thickening of folds, stenoses/strictures, inflammation, lymphadenopathy; exclusion of differentials (eg, appendicitis) |
| Computerized tomography | |
| Ultrasound | Ascites |
| Food Allergy | |
| Serum CAP-FEIA | IgE-mediated allergies |
| Skin prick tests | IgE-mediated allergies |
| Skin patch tests | Non–IgE-mediated allergies |
| Endoscopy | |
| Gross | Erythema, erosions, ulcers, polyps, nodules |
| Microscopy | Dense eosinophilic infiltrates, epithelial and glandular invasion, abscesses; exclusion of differentials |
| Surgery and pathology | Establishing diagnosis, relief of obstruction |
| Paracentesis | Eosinophilia in serosal EG |
| Miscellaneous | |
| Liver enzymes | Evaluation of differentials and multi-organ involvement |
| Pancreatic enzymes | |
| Erythrocyte sedimentation rate | |
| C-reactive protein | |
| Tissue transglutaminase antibody | |
| Autoimmune antibodies | |
| Stool calprotectin, lactoferrin | |
A single diagnostic algorithm may not be universally applicable, because, for example, the screening evaluation may follow the demonstration of tissue eosinophilia. The following aspects of evaluation usually complement each other.
History and Physical Examination
The history and physical examination should be aimed at eliciting information pertaining to food-related adverse effects, stigmata of atopic diseases (wheezing, eczema, rhinitis), and evidence of malnutrition (edema, anemia, failure to thrive).
Laboratory
In the context of gastrointestinal symptoms, peripheral eosinophilia, present in 50% to 100% of those who have EG, is indeed a useful clue to EG, but is not definitive. Peripheral eosinophil concentrations fluctuate and may reflect the effects of circadian rhythms. Tests on stool and duodenal aspirates for parasites (particularly helminths) are strongly recommended to exclude secondary causes of EG, particularly in high-risk geographic areas. Other potentially useful laboratory investigations are directed toward evaluation for anemia (complete blood count), hypoalbuminemia (serum albumin), enteric protein losses (stool α-1 antitrypsin), autoimmune associations (autoantibodies), the eosinophilic intestinal inflammatory process (eosinophils and their remnants—ie, Charcot-Leyden crystals in stools), and eosinophilic ascites (paracentesis). In the near future, serum, stool, and urine assays of active eosinophil inflammation (eg, ECP, EDN) may be used for follow-up and response to therapy.
Allergy Evaluation
Commonly available tests for allergy include skin prick tests (SPT) and in vitro quantitative CAP-fluorescent enzyme immunoassay (CAP-FEIA), formerly known as radioallergosorbent test (RAST), which detects allergen-specific IgE antibody. The results of both should be interpreted with caution because of low sensitivity and a high rate of false-positive results . It has also been shown that the probability of a true positive food challenge, and hence the positive predictive value, is high if allergen-specific IgE to a few select foods (milk, soy, egg, wheat, peanut, and fish) exceeds certain values . The high negative predictive value of SPT is useful in confirming the absence of IgE-mediated reactions, if good quality food extracts are used.
In the evaluation of non–IgE-mediated food allergies, patch testing is now available in Europe and North America, but has not been studied specifically in EG, and remains of limited usefulness because of lack of standardized criteria . Double-blind placebo-controlled food challenges are not practical in the clinical setting, and may also have limited usefulness in EG, because delayed hypersensitivity reactions may not be apparent for a few days. In children strongly suspected to have allergic EG, therefore, the clinician is often faced with the challenge of balancing the benefits of eliminating offending foods against the risks of unnecessarily restricted diets caused by the institution of time-limited dietary trials.
Radiographic Evaluation
Barium contrast studies in patients who have EG may reveal irregular gastric or small intestinal folds, a string sign in gastric outlet obstruction, or strictures . Ultrasound of the abdomen is useful in detecting serosal EG and ascites . Deep layer infiltration and intestinal wall thickening may also be appreciated on computerized tomography . White blood cell Tc-99m scintigraphy may demonstrate inflammation in EG, but without differentiating EG from other inflammatory causes .
Endoscopy and Pathology
The macroscopic features of EG are few, but include erythema, whitish specks, focal erosions, ulcerations, thickening of folds, polyps, nodules ( Fig. 1 ), and friability . A fair number of cases are not associated with any visible mucosal abnormalities ( Fig. 2 A).
Related posts:
Eosinophilic Esophagitis in Children: Clinical Manifestations
Functional Gastrointestinal Disorders and the Potential Role of Eosinophils
Pediatric Anorectal Disorders
Autoimmune Pancreatitis
Diagnosis and Treatment of Autoimmune Hepatitis
Antimitochondrial Antibody–Negative Primary Biliary Cirrhosis
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