Eosinophilic Esophagitis: An IgG4 Disorder that Food Sensitivity Testing Can Help
Allergy-related digestive disorders are recognized and diagnosed more and more frequently in modern society. One disorder, eosinophilic esophagitis (EoE), was not recognized as a distinct disease until 1993. Since its first description, the diagnosis and prevalence of EoE has been steadily increasing. [1] One of the cornerstones of EoE treatment is the identification of food antigens and their elimination from the diet. There is no currently no consensus in the conventional medical world on how to identify such foods, as conventional medicine does not acknowledge IgG food sensitivity testing. [2] However, IgG4 evaluations are being used in research, and a recent study has shown that IgG4 food sensitivity testing may play an important role in designing elimination diets for adults with eosinophilic esophagitis. [3] Meridian Valley Lab has been using immunoglobulin subclass 4 (IgG4) testing to provide such information to clinicians and their patients for over 40 years. The available evidence suggests that adding IgG4 food sensitivity testing to the evaluation of EoE patients may provide a time-saving and cost-effective method of determining inflammatory trigger foods. [4]
Eosinophilic esophagitis is a chronic inflammatory disease found in both children and adults. In both children and adults there are increased numbers of eosinophil immune cells in the esophageal tissues. Patients with EoE often have a history of atopic disease, such as allergic rhinitis, asthma or atopic dermatitis. [5] EoE presents as an upper digestive disorder; in infants and toddlers the symptoms may include feeding difficulties, choking, refusal of food, and vomiting. [6] In adults and older children symptoms may include epigastric or abdominal pain, reflux, nausea and vomiting. While the most common differential diagnosis is gastro-esophageal reflux disease (GERD), there are other conditions that may need to be ruled out such as achalasia, infection, connective tissue disorders, Crohn’s disease, “pill esophagitis”, drug sensitivity, or very rarely a systemic hyper-eosinophilic syndrome. In addition, EoE is not the only condition that presents with increased levels of IgG4; a variety of IgG4-associated autoimmune disorders affect different organs in the body, including the pancreas, biliary tree, salivary glands, kidneys, lymph nodes, thyroid gland, and blood vessels. [7] Both genetics and environment have been shown to influence the expression and severity of EoE. [8] The disease occurs primarily in Caucasians (90%), and the incidence of disease is much higher in developed countries. [9] Alterations of the esophageal microbiota have also been documented in EoE patients. [10]
Eosinophilic esophagitis has a Th-2 inflammatory pattern with elevated levels of CD4 T-helper cells and high circulating levels of interleukin 5 (IL-5) and other inflammatory cytokines. [4] Transcriptional analysis of esophageal tissue from biopsies demonstrates a correlation between interleukins 4, 10 and 13 (IL-4, IL-10, IL-13) and IgG4 levels. The cytokines IL-4 and IL-13 are known to induce the production of both IgE and IgG4 from B-cell lymphocytes, mast cells and eosinophils. Both cytokines are associated with chronic inflammatory responses. [11] The conventional treatment strategy for EoE involves suppression with corticosteroid inhalers, oral steroids and IV interleukin blockers.
In pediatric cases there is often evidence of IgE-mediated food reactions. [5] There are higher rates of food anaphylaxis in pediatric EoE, and IgE reactivity to inhalant allergens (insect dust, molds, pollens, etc). IgE has been demonstrated in large pediatric cohorts using very expensive and cumbersome techniques that require both serial endoscopies and combination skin-prick and atopy patch testing (the “wearing” of a food against the skin for one week’s time to evaluate dermal responses). The positive predictive value of IgE for specific food allergens is low. [5,9] Neither skin-prick testing nor the atopy patch test has a positive-predictive value much better than chance. [12] The two tests combined have a better positive-predictive value, but the combination test is not considered an ideal test for food sensitivity in EoE, and most allergists resort to eliminating the most common allergens, which is not effective for all patients. [9] Tolerance to a trigger food may not be achieved in pediatric EoE populations, as only 8% of patients may regain tolerance to triggers. Of interest, when an antigenic food is re-introduced, the esophageal food reaction develops slowly, over the course of 3-7 days, which is consistent with an IgG-mediated delayed-type hypersensitivity reaction. This has been confirmed by studies in children that demonstrate increased IgG4 levels in esophageal B-cells and in serum. [4] One study found a strong association between serum IgG4 response to cow’s milk and EoE symptoms. [13]
In adults, the levels of IgG4 are highly elevated in the mucosal layer of the esophagus, up to 45 times the IgG4 levels of controls. [2] Serum IgG4 appears to increase slightly (compared to controls), but a recent study has made an important discovery: serum IgG4 responses to food antigens helped predict which trigger foods were causing the EoE inflammation. [4] It is likely that EoE begins as an IgE-mediated reaction that eventually, through cellular signaling, switches cytokine production to a chronic inflammatory Th-2 response. [13] IgG4 levels will increase if there is prolonged exposure to high levels of protein antigens. [14] Such exposures are fairly common if the intestinal mucosal barrier is compromised (“leaky gut”) and there is an increased level of undigested food proteins in circulation. [15] IgG4 levels are also known to increase if there are high levels of IgE; the IgG4 proteins inhibit IgE activity. [16]
While further large-scale studies need to be done, the available evidence suggests that adding IgG4 food sensitivity testing to the evaluation of EoE patients may provide a time-saving and cost-effective method of determining inflammatory trigger foods. [4] Once trigger foods have been identified by IgG4 testing, other strategies may be considered to reduce symptoms and speed mucosal healing:
Elemental diets are liquid diets that eliminate all antigenic foods. The use of such a diet while awaiting IgG4 and other test results may speed healing and decrease immune reactivity. [8,17]
Eliminate processed foods, trans-fats and known food antigens, increase fruit and vegetable consumption, rotate foods to reduce the likelihood of food sensitization. [18, 19]
Evaluate and treat inhalant allergies that may induce food-antigen cross reactions. [20, 21] Treatment strategies may include:
Monitor pollen counts if there is a seasonal exacerbation or comorbid seasonal inhalant allergies. [22, 23, 24]
Identify and eliminate environmental mold exposures that may contribute to antigen sensitization and inflammation. [25]
Evaluate digestion, gastric pH and the gastrointestinal microbiome and treat per results; consider the use of probiotics and fiber to improve the gut microbiome. [26, 27, 28, 29]
Anti-inflammatory therapies to modulate the immune system – resveratrol, curcumin, glutamine, vitamins A and D. [30, 31, 32, 33]
Trace elements – selenium, copper, zinc and iron may all influence the composition of the microbiome, modulate immune cell function, and affect production of cytokines and prostaglandins. [34]
Pre- and post-prandial demulcent herbs, such as marshmallow (Althaea officinalis L.), deglycyrrhizinated licorice (Glycyrrhiza glabra L.), etc. [35]
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