Esophagitis pathophysiology

The esophagus is a part of the gastrointestinal tract which is responsible of moving the food from the mouth to the rectum. Esophagitis is defined as inflammation of mucosal layer of esophagus. Based on the etiology of inflammation esophagitis can be classified into reflux esophagitis and eosinophilic esophagitis. Any condition that lead to the reflux of the gastric acidic contents into the esophagus results in reflux esophagitis. Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens. 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. Characteristic gross pathology findings of esophagitis include fixed esophageal ring, white exudates, longitudinal furrows/ fibrosis, mucosal pallor, Diffuse esophageal narrowing. Characteristic microscopic findings of esophagitis include edema and basal hyperplasia (non-specific inflammatory changes), lymphocytic infiltration, neutrophilic infiltration, eosinophilic infiltration, goblet cell intestinal metaplasia or Barrett’s esophagus and elongation of the papillae.

• The esophagus is a part of the gastrointestinal tract which is responsible of moving the food from the mouth to the rectum.^[1]
• 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.

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

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:^[2][3]

• Transient lower esophageal sphincter relaxations ^[4][5]
• Hypotensive lower esophageal sphincter
• Hiatus hernia.^[6]
• Impaired esophageal acid clearance
• Delayed gastric emptying

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:^{[7][8][9][10][11][12][13][14][15][16]}

• 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.

• 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.

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.

• Endoscopic abnormalities in patients with esophagitis are as follows:^{[17][18][19][20][21]}
  • 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.

On histopathological analysis, based on the type of esophagitis microscopic findings include:^[22]

• Eosinophilic esophagitis
  • > 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

• Reflux esophagitis
  • Edema and basal hyperplasia (non-specific inflammatory changes)
  • Lymphocytic infiltration (non-specific)
  • Neutrophilic infiltration
  • Eosinophilic infiltration
  • Goblet cell intestinal metaplasia or Barrett’s esophagus.
  • Elongation of the papillae
  • Thinning of the squamous cell layer
  • Dysplasia or pre-cancer.

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