Etiology
The primary etiologic factor involved in Barrett esophagus is gastroesophageal reflux. However, there is evidence that combined acid and bile reflux are the primary causative agents. In one study of patients with gastroesophageal reflux disease, more than 50% had abnormal levels of bile in the esophagus.[12] The highest level of esophageal bile was in patients with Barrett esophagus, and about one half of patients with Barrett esophagus with abnormal esophageal bile exposure had normal bile levels in the stomach. Barrett esophagus, and esophageal mucosal injury overall, was most common in patients exposed to a combination of acid and bile, and uncommon in patients exposed only to bile. Mucosal injury was less common in those exposed to acid alone, but still significantly higher than normal.[13]
Pathophysiology
The American College of Gastroenterology defines Barrett esophagus as a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia.[14] However, not all intestinal metaplasia is endoscopically visible. Non-goblet epithelium can be intestinalized.[15] Gradually we are are developing a better understanding of the complex molecular mechanisms that are implicated in the conversion of normal squamous esophageal epithelium to intestinal metaplasia, dysplasia, and carcinoma.[16]
For Barrett esophagus to develop, environmental factors must interact with genetically determined characteristics. Because Barrett esophagus is rarely familial (although there are some "multiplex" families with Barrett esophagus which places them at substantial risk of adenocarcinoma) it is likely that these characteristics are normal variations (polymorphism) in multiple genes, rather than a single gene mutation.[17]
The more commonly accepted pathogenetic mechanism involves metaplastic columnar stem cell development from a local (squamous epithelium stem cell) or bone marrow (bone marrow derived stem cell) source. The stem cell origin of Barrett esophagus can explain its persistence and the predisposition to developing adenocarcinoma. The proposed origins of these altered metaplastic stem cells are:
the basal cell layer of the squamous epithelium
stem cells originating from the gastroesophageal junction proliferating in response to acid and duodenogastroesophageal reflux
stem cells from the neck of the esophageal submucosal glands migrating and proliferating in the surface of the distal esophagus after squamous mucosa injury
bone marrow stem cell migration to the injured epithelium.
These changes may be mediated by activation or inactivation of transcription factors and modulation of signaling pathways at the cellular level. Gastroesophageal reflux can produce genetic alterations, which result in increased production of transcription factors promoting intestinal cell differentiation (metaplasia) and decreased production of transcription factors promoting squamous cell differentiation.[18]
There are several candidate genes whose alteration may lead to development of intestinal metaplasia.[19] Expression of the cyclo-oxygenase-2 gene in the esophageal squamous epithelium seems to be increased as a result of reflux, and downregulated as a result of antireflux surgery.[20] In addition, the homoeotic transcription factor Cdx2 (Caudal-type homeobox 2) has been discovered to be the "master switch" gene for intestinal epithelium. Its loss or deletion is associated with the development of metaplasia.[21]
Ultimately, the importance of intestinal metaplasia is in its malignant potential. Although the exact genetic and molecular mechanisms have not been elucidated, it seems that the intraluminal refluxate acts as a proproliferative driver leading to the genetic and, more important, biologic characteristics of malignancy. These include activation of cell surface pH controllers (e.g., sodium-hydrogen exchangers), which lead to cell signaling changes (e.g., transforming growth factor-beta, mitogen-activated protein kinase, and protein kinase C), resulting in disruption of the p53 gene, leading to evasion of apoptosis. These hyperproliferating cells will eventually require angiogenesis to maintain growth. This is usually mediated by the cyclo-oxygenase-2 gene. Eventually, it is hoped that an understanding of the molecular events that occur in the metaplasia-dysplasia-carcinoma sequence will lead to biomarkers to identify patients who are destined to develop adenocarcinoma.[19] Although it is clear that Barrett esophagus increases the risk of esophageal adenocarcinoma, quantifying the risk has been difficult. One systematic review set the risk as 6.3/1000 person-years, with a 95% confidence interval of 4.7 to 8.4/1000 people and substantial heterogeneity of the data.[22][Figure caption and citation for the preceding image starts]: Barrett esophagus; note salmon-colored mucosa extending superior to the gastroesophageal junction as a continuous columnFrom the personal collection of Dr Vic Velanovich; used with permission [Citation ends].
[Figure caption and citation for the preceding image starts]: Barrett esophagus; note salmon-colored mucosa extending superior to the gastroesophageal junction with marked irregular borderFrom the personal collection of Dr Vic Velanovich; used with permission [Citation ends].
[Figure caption and citation for the preceding image starts]: Barrett metaplasia without dysplasia, demonstrating columnar epithelium with goblet cells from superior to the gastroesophageal junctionCourtesy of Adrian Ormsby, MD, Henry Ford Hospital, Detroit, MI [Citation ends].
[Figure caption and citation for the preceding image starts]: Barrett metaplasia with low-grade dysplasia; note the more irregular cells and nucleiCourtesy of Adrian Ormsby, MD, Henry Ford Hospital, Detroit, MI [Citation ends].
[Figure caption and citation for the preceding image starts]: Barrett metaplasia with high-grade dysplasia; note more advanced irregularity of the cellsCourtesy of Adrian Ormsby, MD, Henry Ford Hospital, Detroit, MI [Citation ends].
[Figure caption and citation for the preceding image starts]: Barrett metaplasia with high-grade dysplasia associated with a focus of intramucosal carcinoma; note the frankly malignant cells beyond the confines of the basement membrane to involve the lamina propriaCourtesy of Adrian Ormsby, MD, Henry Ford Hospital, Detroit, MI [Citation ends].
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