Esophagitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens. The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE. The documented cytokine expression profile in the esophageal tissue of EoE patients is that of a TH2 inflammatory response. IL-5 and IL-13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation. IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue. IL-5 prolongs the survival of the eosinophils. The activated TH2 response leads to the recruitment and activation of Mast cells degranulate and cause tissue damage and repair. Cytokines produced by TH-1 cells are tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, TNF-α is expressed by the epithelial cells of the esophagus whereas the INF-γ is upregulated by the peripheral T cells. Delayed or type- IV hypersensitivity is the mechanism is involved in the EoE rather than the non-IgE. It is postulated that the EoE-defining endoscopic and histologic manifestations are a culmination of the disease process which, may have debilitating long-term effects including strictures and food impactions in untreated or poorly managed cases of EoE. CD34+ myeloid precursor cells in the bone marrow produce eosinophils and then the eosinophils develop granulation and migrate to vascular spaces. The preformed granule proteins of the eosinophils are ECP- Eosinophil Cationic Protein, MBP- Major Basic Protein, EPO- Eosinophil Peroxidase, EDN- Eosinophil Derived Neurotoxin. Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues. Eosinophils synthesize and release cytokines such as IL-5, IL-13, Transforming growth factor (TGF)-α and -β, Chemokines (eotaxins and RANTES), Lipid mediators such as platelet activating factor (PAF) and leukotriene C4. IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause the maturation and migration of the eosinophils. Eosinophils cause inflammation in the EoE patients by the following mechanisms Angiogenic molecules from the eosinophils recruits the inflammatory cells and the increase the vascularity. Fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9 causes the airway remodeling. MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophageal through their involvement in smooth muscles, fibroblasts, and cell-adhesion molecules. The above-mentioned processes lead to tissue remodeling eventually causing an overall esophageal dysfunction.Pathophysiology of reflux esophagitis depends on several mechanisms that lead to the retrograde movement of the acidic content of the stomach to the esophagus. These mechanisms include transient lower esophageal sphincter relaxation, hypotensive lower esophageal sphincter, hiatal hernia, and prolongedesophageal acid clearance.

Pathophysiology

Normal physiology of the food motility through the esophagus

• The esophagus is a part of the gastrointestinal tract which is responsible of moving the food from the mouth to the rectum.
• The esophagus has anti-reflux barrier which prevents the return of the acidic contentof the stomach back to the esophagus. The anti-reflux barrier consists of the lower esophageal sphincter (LES) and the related part of the diaphragm.
• The lower esophageal sphincter is contracting smooth muscle at the end of the esophagus responsible for the food passage to the stomach. LES has high pressure tone which helps keeping it a strong barrier between the esophagus and the stomach.

Pathogenesis

Esophagitis is defined as inflammation of mucosal layer of esophagus. Based on the etiology of inflammation esophagitis can be discussed under two categories

• Reflux esophagitis
• Eosinophilic esophagitis

Reflux Esophagitis

Pathogenesis of reflux esophagitis depends on various mechanisms that lead to the reflux of the gastric acidic contents into the esophagus. Several mechanisms impair the anti-reflux barrier and cause esophageal dysmotility. These mechanisms include the following:

• Transient lower esophageal sphincter relaxations
• Hypotensive lower esophageal sphincter
• Hiatus hernia.
• Impaired esophageal acid clearance
• Delayed gastric emptying

Eosinophilic Esophagitis

Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens. The pathophysiology of the EoE is as follows:

• The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE.
• They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions.

Production of eosinophils

• TH2 inflammatory cell response play a major role in the production of eosinophils.
• Activated TH2 response leads to the recruitment and activation of eosinophils and mast cells.
• T cells (Th2) cell response also stimulates production of IL-5 and IL-13.
• IL-13 stimulates the epithelial cells of the esophagus to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue.
• IL-5 prolongs the survival of the eosinophils.

Granule proteins of the eosinophils
ECP	Eosinophil Cationic Protein
MBP	Major Basic Protein
EPO	Eosinophil Peroxidase
EDN	Eosinophil Derived Neurotoxin

Role of eosinophils in inflammation

Eosinophils cause inflammation in the EoE patients by the following mechanisms

• Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues.
• Granule proteins from eosinophils recruits the inflammatory cells and increase the vascularity.
• Increased vascularity stimulates fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9.
• TGF-β and eosinophilic granule proteins MBP and EPO are the key eosinophil effector proteins.
• MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophagus through their involvement in the smooth muscles, fibroblasts, and cell-adhesion molecules.
• Eventually resulting in tissue remodeling and esophageal dysfunction.

Gross Pathology

• Endoscopic abnormalities in patients with esophagitis are as follows:
  • Fixed esophageal ring
  • White exudates
  • Longitudinal furrows/ fibrosis
  • Mucosal pallor
  • Diffuse esophageal narrowing
  • Mucosal fragility leading to esophageal lacerations during the endoscopy
• However, because these endoscopic features have been described in other esophageal disorders, none can be considered pathognomonic for esophagitis.

File:File:Eosinophilic esophagitis endo.jpg

Endoscopy of the esophagus: Eosinophilic esophagitis
Source: Wikimedia

Histopathology

• Characteristic features are as follows:
  • > 20 eosinophils/0.24 mm2.
  • Papillae are elongated
  • Papillae reach into the top 1/3 of the epithelial layer
  • Basal cell hyperplasia; > 3 cells thick or >15% of epithelial thickness

H&E stain of esophagus biopsy showing eosinophilic esophagitis, manifested by an infiltration of eosinophils in the lamina propria

• The most common cause is gastroesophageal reflux disease (GERD). If caused by GERD, the diseases is also called reflux esophagitis.
• Other causes of esophagitis include infections (most commonly candida, herpes simplex and cytomegalovirus). These infections are typically seen in immunocompromised people, such as those with HIV.
• Food allergies have also been known to cause esophagitis
• Chemical injury by alkaline or acid solutions may also cause esophagitis, and is usually seen in children or in adults who attempt suicide.
• Physical injury resulting from radiation therapy or by nasogastric tubes may also be responsible.

Pathological Findings

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Images

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  Herpes esophagitis 100 x

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  Herpes esophagitis 400 x

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  Herpes esophagitis 600 x

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  Reflux esophagitis 100 x

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  Reflux esophagitis 400 x

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  Necrotizing esophagitis and gastritis, sulfuric acid ingested as suicide attempt

Histopathological Findings: Herpes Esophagitis

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