See “Elevated Serum Tissue Transglutaminase Antibodies in Children With Eosinophilic Esophagitis” by Le Fevre et al on page 69 and See “The Association Between Celiac Disease and Eosinophilic Esophagitis: Mayo Experience and Meta-analysis of the Literature” by Hommeida et al on page 58.
Although the possible relationship between eosinophilic esophagitis (EoE) and celiac disease (CD) has been previously suggested, they are 2 clinically and histologically distinct disorders of upper gastrointestinal tract involving different anatomy and physiology (1). Immunologically, CD is a TH1-mediated response, triggered by gluten-derived peptides, that is activated in genetically susceptible individuals, whereas EoE has been shown to be a TH2-mediated disorder that is associated with immunoglobulin E– and non–immunoglobulin E-mediated food allergies. Traditionally, TH1 and TH2 immune responses have been considered mutually antagonistic, but recent molecular studies have suggested that autoimmune and atopic diseases share risk factors that increase the propensity of the immune system to generate both TH1- and TH2-mediated inappropriate responses to nonpathological antigens. These findings seem to suggest a more generalized defect of immune regulation than a casual association between CD and EoE (2,3).
According to one theory, increased intestinal permeability secondary to CD may facilitate the exposure of the intestinal immune system to various antigens and an upregulated immune response, which, in turn, causes intestinal inflammation and damage (4,5). There are several food antigens that have been implicated in EoE, similar to the role gluten plays in CD, which is why the question exists of whether these 2 conditions are associated. And, because wheat can also trigger EoE, several studies have investigated the relationship between these 2 disease entities (6). It has been suggested that eosinophilic infiltration of the esophagus may be a manifestation associated with gluten exposure in a small population of patients with CD and could also be caused by CD itself (7). Reported observations of an association have been based on the increased prevalence of EoE in those with CD. It is not clear whether this is secondary to an increasing awareness and detection of the disease or whether it is a true phenomenon (8). In a study by Jensen et al, (9) children with CD who were treated with a gluten-free diet (GFD) exhibited symptomatic and histologic improvement of their EoE, suggesting a possible shared pathogenic trigger between the 2 diseases. A study by Lucendo et al (10), did not find an increased human leukocyte antigen (HLA) DQ2 and DQ8 in those with EoE when compared with controls.
Shah et al first described the coexistence of EoE and CD in the same patient in 2006. Since then, several case reports and cohort studies have suggested an association between EoE and CD (11). Although this association was initially reported for pediatric patients, it has since been reiterated in adult patients, but not universally confirmed in large population-based studies (10). A systematic review of studies showed the prevalence of CD in EoE varied between 0.16% and 57.1%, whereas the prevalence of EoE in CD ranged from 0% to 10.7%. A significant bias exists in favor of short studies reporting positive associations, whereas large cohorts show no support for any relation between CD and EoE (10,12,13).
Hommeida et al retrospectively reviewed 10,201 children who underwent endoscopic evaluation and found that the prevalence of EoE in children with CD was 1.83% compared with 5.83% in all children who had EoE. They also concluded that there was no increased risk of EoE in children with CD supporting other published large cohorts (14). Le Fevre et al concluded that tissue transglutaminase (tTG) antibody was elevated in 23% of their EoE cohort. They examined total tTG antibody level rather than separate tTG IgA and IgG. Only 3 patients had lymphocytic inflammation in the duodenum and no concomitant villous atrophy. The tTG level in 1 patient improved even without an intervening elimination diet. A second patient had a negative HLA DQ2/DQ8 status. Only 1 patient with type 1 diabetes and positive HLA status was included (15). Elevated tTG antibody titers are not specific to CD, which can explain the elevated levels in EoE. A significant increase in duodenal eosinophils in tTG-positive patients can be related to duodenal inflammation. Although the present study did not show any correlation between EoE and CD, they recommended routine esophageal and duodenal biopsies.
The major shortcoming in all the studies is the diagnosis of EoE. The correct term should be esophageal eosinophilia because the diagnosis of EoE can only be made after exclusion of other causes of eosinophilic inflammation. The use of a high-dose proton pump inhibitor at the time of initial diagnosis is not mentioned in any of the 3 studies published this month, which makes the diagnosis unclear.
Wallach et al described the importance of adhering to biopsy guidelines when diagnosing either condition. When they retrospectively reviewed 9171 children, only 35% of cases were biopsied according to the American College of Gastroenterology (ACG) guidelines for CD diagnosis and 8% were biopsied according to the 2007 ACG EoE consensus recommendations (16). NASPGHAN guidelines recommend to obtain 1 to 2 biopsies from the duodenal bulb and more than 4 biopsies from distal duodenum (17). EoE guidelines by ACG and NASPGHAN recommend multiple biopsy specimens should be obtained from different esophageal locations (18).
There is a high degree of confusion regarding whether EoE is a representative pattern associated with CD alone or whether there is a true association between both diseases (19). In the 3 studies featured, 2 studies (Le Fevre et al and Hommeida et al) did not show a true association between CD and EoE (14,15). And, the third study, by Wallach et al (16), described the importance of adhering to biopsy guidelines when diagnosing either condition (20). To add to the confusion, some studies have shown improvements in both diseases with a gluten-free diet, as wheat can also trigger EoE. The higher incidence of EoE in those with CD may be due to a selection bias, as biopsies are usually taken in those with symptoms suggestive of EoE, such as feeding difficulties, poor weight gain, dysphagia, and esophageal food impaction. In pediatrics, it is very common to have a grossly normal appearing esophagus, but obtaining biopsies may be necessary when considering an association between the 2 diseases. Unfortunately, the association does not seem to be strong enough to recommend obtaining esophageal biopsies in all patients with CD. Nonetheless, the question remains whether screening for CD is required in those with biopsy-proven EoE, and the elimination of gluten from those with EoE, because there may be a risk for CD. The recognition that EoE does occur in patients with CD may help guide us in learning about the complex interplay between environmental factors and host immunity that occurs commonly in these specific gastrointestinal disorders and can also assist us in finding concerted treatments of both conditions. The particular subset of patients with CD is, however, still unknown in regards to developing esophageal eosinophilia. Although a connection between the 2 disorders seems likely, further studies with correct definition of EoE are needed with a larger sample size.
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