In eosinophilic esophagitis (EoE), remodeling changes are manifest histologically in the epithelium and subepithelium where lamina propria fibrosis, expansion of the muscularis propria, and increased vascularity occur. The clinical symptoms and complications of EoE are largely consequences of esophageal remodeling. Available therapies have demonstrated variable ability to reverse existing remodeling changes of the esophagus. Systemic therapies have the potential of addressing subepithelial remodeling. Esophageal dilation remains a useful, adjunctive therapeutic maneuver in symptomatic adults with esophageal stricture. As novel treatments emerge, it is essential that therapeutic end points account for the fundamental contributions of esophageal remodeling to overall disease activity.
Key points
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Remodeling changes in eosinophilic esophagitis include epithelial basal zone hyperplasia, lamina propria fibrosis, expansion of the muscularis propria, and increased vascularity.
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Esophageal inflammation in eosinophilic esophagitis drives the remodeling process with mediators that include IL-5, IL-13, TGFβ1, mast cells, fibroblasts, and eosinophils.
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Recent studies have provided increasing evidence that the primary symptoms of esophageal dysfunction in children and adults as well as clinical complications of eosinophilic esophagitis are consequences of esophageal remodeling and fibrostenosis.
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Esophageal remodeling in eosinophilic esophagitis can be demonstrated using widely available tests, such as histopathology, barium esophagram, upper endoscopy, and endoscopic ultrasonography.
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Clinical trials need to account for the presence and reversibility of esophageal remodeling to fully elucidate the potential benefits and limitations of therapeutic interventions.
Introduction
Since the initial case descriptions 2 decades ago, eosinophilic esophagitis (EoE) has emerged as an important clinical entity with steadily rising prevalence. In children, EoE is an increasingly recognized etiology for feeding disorders and manifests with poor weight gain, anorexia, vomiting, regurgitation, abdominal pain, and dysphagia. In adult patients, EoE is one of the most common causes of dysphagia. An increasing number of studies have shown that the primary symptoms in children and adults, as well as clinical complications of EoE, are consequences of esophageal remodeling and fibrostenosis. This article focuses on the current understanding of the pathogenesis, clinical detection, and therapeutic implications of esophageal remodeling in EoE.
Introduction
Since the initial case descriptions 2 decades ago, eosinophilic esophagitis (EoE) has emerged as an important clinical entity with steadily rising prevalence. In children, EoE is an increasingly recognized etiology for feeding disorders and manifests with poor weight gain, anorexia, vomiting, regurgitation, abdominal pain, and dysphagia. In adult patients, EoE is one of the most common causes of dysphagia. An increasing number of studies have shown that the primary symptoms in children and adults, as well as clinical complications of EoE, are consequences of esophageal remodeling and fibrostenosis. This article focuses on the current understanding of the pathogenesis, clinical detection, and therapeutic implications of esophageal remodeling in EoE.
Definition of esophageal remodeling
The concept of eosinophil-associated tissue remodeling stems from diseases such as the hypereosinophilic syndrome and asthma. Remodeling can be defined as tissue changes in target organs that result in end organ dysfunction. Remodeling is associated with histologic alterations, such as fibrosis and angiogenesis, which are caused by changes in cellular function, phenotype, and products. Remodeling itself may not be a pathogenic process, as it could be considered to represent a protective mechanism akin to wound healing. However, when remodeling is not controlled, presumably due to unbridled inflammation, there are negative consequences for organ function. Indeed, the natural history of untreated EoE is to progress to stricture formation, at least in adults.
In EoE, remodeling changes are seen histologically in both the epithelium and subepithelium ( Fig. 1 ). Epithelial changes include basal zone hyperplasia and increased length of the vascular papillae. The papillae are intrusions of the subepithelium into the epithelial space and, as such, are likely a further reflection of subepithelial expansion. Subepithelial changes include lamina propria fibrosis with increased collagen deposition and thickness and increased vascularity with vascular activation. Muscularis remodeling changes include smooth muscle hypertrophy and hyperplasia. Together these tissue changes are the likely mechanisms for the esophageal dysfunction that characterizes EoE and underlies the clinical complications of dysphagia, strictures, food impactions, esophageal rigidity, and dysmotility. Ultimately it is the potential control of the clinical consequences of remodeling that motivates practitioners to treat EoE. In this vain, the assumption is that control of inflammation is equated to control of remodeling. However, this has yet to be systematically proven.
Although it is recommended that there is recurrent tissue procurement for EoE management, this is not the case in other eosinophil-associated diseases. This paucity of repeatedly acquired human tissue has limited our understanding of the true clinical implications of tissue remodeling. For this reason, EoE provides a unique opportunity to understand the clinical complications, natural history, and reversibility of eosinophil-associated tissue remodeling. This is further underscored by the fact that young children have recurrent tissue assessments, allowing us to investigate the long-term effects of tissue architectural changes on esophageal function and EoE progression. If EoE is akin to asthma, a person’s fibrotic phenotype may be defined very early in life.
For the purposes of this review, tissue remodeling as it relates to EoE is considered to be composed of epithelial changes, including basal cell hyperplasia and epithelial mesenchymal transition, subepithelial changes of fibrosis and angiogenesis, and smooth muscle hypertrophy. We provide a summary of the current molecular and clinical data that support the hypothesis that esophageal tissue remodeling (1) is driven by EoE-associated esophageal inflammation, and (2) is the underlying etiology for major EoE clinical symptoms and complications.
Pathogenesis of esophageal remodeling in EoE
Inflammatory mediators and cells clearly play a role in driving esophageal remodeling ( Table 1 , Fig. 2 ). Animal models demonstrate that mice lacking eosinophils or the eosinophilopoetic cytokine interleukin (IL)-5, have significantly less collagen deposition and fibronectin expression than their wild-type littermates. In addition, mice that have decreased esophageal eosinophils also have decreased basal zone hyperplasia. Importantly, a lack of eosinophils, even in the presence of IL-5 overexpression, leads to decreases in stricture formation. In contrast, there is no effect of eosinophil loss on esophageal dysmotility. Overexpression of IL-13 causes esophageal stricture that is not reversible by the subsequent removal of IL-13. This underscores a number of important concepts. First, there is a dependence on eosinophilic inflammation to drive strictures. Second, interleukins in the absence of subsets of cellular inflammation can have distinct effects. Third, various esophageal remodeling features can be uncoupled and can use distinct mechanistic pathways (see Fig. 2 ).
| Mediator | Remodeling Effects | Evidence |
|---|---|---|
| IL-5 | Increased collagen | Animal models |
| Increased smooth muscle contraction force | Animal models | |
| Increased epithelial TGFβ1 | Human anti–IL-5 trials | |
| Increased tenascin C | Human anti–IL-5 trials | |
| IL-13 | Increased collagen deposition Increased esophageal thickness Stricture formation | Animal models |
| Periostin | Increased periostin deposition in lamina propria Increased eosinophil trafficking | Human in vitro studies |
| Siglec-8 | Increased fibronectin Increased angiogenesis | Animal models |
| Smad3 | Increased fibronectin Increased angiogenesis | Animal models |
| TGFβ1 | Increased fibrosis Smooth muscle cell contraction | Human in vitro studies |
| TSLP | Increased food impactions | Animal models |
| Eosinophils | Increased fibrosis | Animal models |
| Strictures | ||
| Increased tenascin | Human anti–IL-5 studies | |
| Increased epithelial TGFβ1 | ||
| Mast cells | Smooth muscle hypertrophy and hyperplasia | Animal studies |
| Basophils | Increased food impactions | Animal studies |
Esophageal eosinophils in EoE produce the profibrotic factor, transforming growth factor beta-1 (TGFβ1), which can increase the production of collagen, fibronectin, and other extracellular matrix proteins. TGFβ1 mRNA and protein levels are elevated in the epithelium and subepithelium of pediatric and adult subjects with EoE when compared with control subjects. In addition to TGFβ1, other profibrotic molecules, including CC chemokine ligand 18 (CCL-18) and fibroblast growth factor 9 (FGF-9) are increased in subjects with EoE, suggesting that there are also TGFβ1 independent pathways to fibrosis. Increased numbers of lamina propria (LP) cells that express phosphorylated Smad2/3, part of the canonical TGFβ1 transcription factor complex, are also found in the LP of pediatric subjects with EoE. Profibrotic factors, such as FGF-9 and TGFβ1, also can have effects on the function of epithelial cells, including proliferation and epithelial mesenchymal transformation.
Mast cells are important in EoE pathogenesis. Indeed, the numbers of mast cells infiltrating the deeper esophageal layers, such as the muscularis mucosa, can exceed the numbers of eosinophils. Both eosinophils and mast cells also provide a source of TGFβ1 in EoE and a distinct mast cell transcript signature is present in both pediatric and adult subjects with EoE. Mast cells are found in couplets with eosinophils in the esophagus of subjects with EoE and eosinophils produce the mast cell survival and recruitment factor, IL-9, suggesting that there is an intricate balance between eosinophilia and mastocytosis in EoE. Animal studies have shown that mast cells and eosinophils travel together in EoE models. There is a decrease in smooth muscle hypertrophy and proliferation in mast cell–deficient mice. As such, it is likely that mast cells not only promote fibrosis but also alter smooth muscle function during the process of esophageal remodeling.
IL-13 is a master regulator in EoE, functioning to increase both IL-5 and eotaxin-3 in the esophagus. Pulmonary overexpression of IL-13 using a Clara cell promoter demonstrates increased fibrosis and esophageal circumference. The effects of IL-13 can be independent of eosinophils and can promote the formation of irreversible strictures. Both IL-13 and TGFβ1 increase the levels of periostin, an extracellular matrix protein that promotes the migration and adherence of eosinophils, thus propagating inflammation in EoE.
Subepithelial angiogenesis is present in EoE. Consistent with this, there are elevated levels of proangiogenic factors, including vascular endothelial growth factor (VEGF) and angiotensin in the esophagus of pediatric subjects with EoE. Increased vascularity provides elevated numbers of conduits for the transport of inflammatory cells into the esophagus. Elevated levels of vascular activation factors described in EoE, such as vascular cell adhesion molecule 1, allow vessels to have increased tethering and transmigration of inflammatory cells. Indeed, mice deficient in eosinophils have diminished levels of angiogenesis.
Human studies using endoscopic ultrasound demonstrate increased esophageal thickness through all the esophageal layers, including the concentric and longitudinal muscle layers, in pediatric and adult subjects with EoE. Subsets of subjects with EoE have altered esophageal motility on manometric studies that assess concentric muscle function and studies that analyze both concentric and longitudinal muscle layers demonstrate significant changes in the coordination between these smooth muscle layers. Functionally, TGFβ1 can cause direct contraction of primary esophageal smooth muscle cells in culture, suggesting that inflammatory cell–derived growth factors can alter esophageal muscle cell function. In addition, transgenic mice that overexpress IL-5 have increased longitudinal and circular smooth muscle contraction force. Interestingly, these IL-5 transgenic mice that lack eosinophils continue to have increased contraction force, demonstrating that although strictures depend on the presence of eosinophils, dysmotility uses other inflammatory cells and/or factors. Human data demonstrate that there is transmural inflammation with both eosinophilia and mastocytosis of the muscularis propria. It is likely that the presence of such inflammatory cells and their chemical mediators would have functional consequences in EoE. Consistent with this concept, mice deficient in thymic stromal lymphopoietin (TSLP) or basophils are protected from food impactions in an experimental EoE model, demonstrating that TSLP and basophils play significant roles in esophageal dysfunction.
Relationship of esophageal remodeling with clinical manifestations and complications
The clinical presentations of EoE reflect esophageal dysfunction. These functional changes in the esophagus likely reflect esophageal remodeling. In adults, EoE is dominated by symptoms of dysphagia and food impaction, whereas in children symptoms more commonly mimic gastroesophageal reflux disease (GERD) with dysphagia and food impactions becoming more prominent in adolescence. In adult subjects, there are 2 determinants for esophageal food impaction risk: (1) a reduction in luminal diameter and (2) limitation in esophageal mural distensibility. These features can occur concurrently or separately. Esophageal strictures, defined as a reduction of normal caliber, can be identified in 30% to 80% of adults with EoE, whereas decreased distensibility is reported in more than 70% of adults with EoE. It is important to note that the rates of esophageal mural rigidity have not been defined in pediatric EoE and, as such, the disease duration of EoE that causes decreased esophageal compliance in children is not clear. Certainly, esophageal strictures are uncommonly identified in children (<5% of subjects with EoE), even though food impactions occur in up to 30% of subjects. In adults, strictures defined as a reduction in luminal diameter to less than 10 mm have been reported in 38%. The strictures can involve any portion of the esophagus, with many patients demonstrating diffusely compromised esophageal diameter, a condition termed “narrow or small-caliber” esophagus. It is possible that lower-grade esophageal stenosis is underreported in the literature because of a lack of sensitivity for such luminal narrowing using the currently available endoscopic and radiographic techniques. Duration of untreated disease has been associated with increased risk of esophageal stricture, supporting the concept of progressive esophageal remodeling in EoE that may explain phenotypic differences between children and adults ( Fig. 3 ).
Both food impactions and strictures have significant complications. For example, food impactions that require emergency room visits and urgent endoscopic extraction is reported in 30% to 55% of adult cohorts with complications that include chest pain, as well as the risks of aspiration, esophageal tears, and esophageal perforation. Esophageal perforation is also a recognized complication of endoscopic extraction of food impactions, particularly when food extraction is performed using rigid endoscopy. Furthermore, several reports of esophageal perforation related to esophageal dilation of strictures have led to reluctance in performing this therapy in EoE.
Additional potential complications of EoE as they relate to esophageal remodeling include impaired quality of life and risk of nutritional deficiency because of dietary restriction. Most aspects of diminished quality of life in adults with EoE are related to the need for dietary modification and social embarrassment, as well as anxiety created by choking episodes. Nutritional concerns in EoE can be related to food aversion that may be secondary to the inflammatory response to specific food antigens. In adults, decreased esophageal mural compliance and distensibility may limit the tolerability of specific foods due to texture, most commonly meat.
Clinical methods to assess remodeling in EoE
Barium Radiography
A variety of methods have been used in clinical practice and investigative studies to demonstrate the remodeling consequences of EoE ( Table 2 ). One of the oldest methods to evaluate the structure of the gastrointestinal tract is barium radiography. Early case series demonstrated the association of marked restriction of the esophageal luminal caliber with EoE, characterized as a narrow caliber or small-caliber esophagus. Fig. 4 illustrates the diffuse nature of this finding. The multiple, ringlike stenoses spanning lengths of the esophagus were initially confused with congenital esophageal stenosis but were subsequently recognized to be a characteristic feature of EoE. Most recently, Alexander characterized restriction of the esophageal diameter in a cohort of adults with EoE, demonstrating a reduction in both the maximum and minimum diameters compared with controls. Radiologic assessment of esophageal remodeling is clinically feasible but does not assess for variations in diameter as a function of intraluminal distension forces. A small volume of barium with low intrabolus distension pressure will have a tendency to provide falsely low estimates of the diameter of an esophageal stricture, as the stiffness of the esophageal wall limits the ability of the wall to expand. Limited studies have used cross-sectional imaging modalities, such as computed tomography or magnetic resonance imaging, to characterize the intramural effects of EoE ( Fig. 5 ).
| Method | Findings | Advantages | Disadvantages |
|---|---|---|---|
| Barium esophagram | Esophageal rings, strictures, narrow caliber esophagus | Availability, ease of testing, cost | Radiation exposure, 2-dimensional imaging, measures diameter but not distensibility or compliance |
| Upper endoscopy | Esophageal rings, strictures, narrow-caliber esophagus | Availability, routine use in management of EoE, capability of therapeutic dilation, validated classification, biopsy evaluation of histologic remodeling | Cost, limited accuracy in determination of stricture diameter |
| Esophageal manometry | Esophageal motor dysfunction including peristaltic integrity, esophageal pressurization, and esophagogastric junction function | Availability, cost, potential physiologic biomarker of esophageal remodeling | Patient tolerance, limited sensitivity and specificity of identified abnormalities, limited to measurement of circular and not longitudinal smooth muscle function |
| Esophageal biopsy | Lamina propria fibrosis, basal zone hyperplasia, rete peg elongation | Availability, routine use in management of EoE | Limited sensitivity for evaluable lamina propria, validation of methodology used for procurement and analysis needed, potential for sampling variability |
| Endoscopic ultrasonography | Increased thickness of mucosa, submucosa, muscularis propria | Availability, assessment of esophageal intramural remodeling | Cost, endoscope diameter may exceed esophageal diameter, validation of methodology needed, nonfunctional/nonquantifiable output |
| Functional luminal imaging | Reduction in esophageal distensibility and compliance | Objective quantification of organ-level esophageal remodeling consequences with demonstrated correlation with clinical outcomes | Limited availability, utility in pediatric patients unknown |
| Tissue biomarkers | TGFβ1, periostin, tenacin C, fibronectin | Potential increased sensitivity for remodeling, potential predictor of targeted therapies, may correlate with TGFβ1 genotypes/pharmacogenomics responses | Validation of methodology needed |
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