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Development of Columnar Lined Esophagus in Man: Role of BMP-4 & CDX2.

17.11.2011 by Reflux Medical

Reflux Medical
Endoscopically visible columnar lined esophagus (CLE). The Biopsy forceps straddles the squamocolumnar junction (SCJ).

Activation of the BMP-4 pathway and early expression of CDx2 characterize non-specialized columnar metaplasia in a human model of Barrett‘s esophagus.

Castillo D, Puig S, Iglesias M, et al.

J Gastrointest Surg 2011; ahead print (11. Nov. 2011)

Background:
The normal esophagus is lined by a columnar Epithelium. During Gastroesophageal reflux disease ( GERD), a columnar lining replaces the the Squamous epithelium, this is cardiac Mucosa. By the inclusion of goblet cells, the cardiac Mucosa may progress towards intestinal metaplasia, this is Barrett‘s esophagus without Dysplasia. Via low- and high grade Dysplasia the non-dysplastic Barrett‘s esophagus may progress to Esophageal adenocarcinoma (0.5% annual incidence). The development of columnar lined esophagus (CLE) seems to be mediated via the BMP-4 pathway and CDX2. BMP-4 is suggested to foster the development of CLE, whereas CDX2 represents a marker of intestinal differentiation (i.e. goblet cell formation, the hallmark of Barrett‘s esophagus)

Following the surgical subtotal resection of the esophagus, the surgeon creates an anastomosis between the proximal esophagus and the gastric tube (=gastric pull up procedure). Therefore, after the end of the procedure, the Squamous epithelium fuses to the Oxyntic mucosa of the Stomach. This condition has been used by the authors of this study to model Gastroesophageal reflux disease ( GERD).

Using modern histopathology ( Chandrasoma classification) the authors examined the morphologic and genetic changes at the neo-squamo-columnar junction.

After 6 months, 2.5 and 3 years after the operation, neo-columnar lined esophagus (CLE) developed in 33%, 43% and 50% of the individuals, respectively (5-30 mm length; mean: 15.5 mm). These changes were paralleled by Esophagitis in 50%-60% of the cases after 6 months and 3 years, respectively. Until 2 years after the operation, 2 of 18 patients (11.1 %) developed non-dysplastic Barrett‘s esophagus. These changes were paralleled by the nuclear expression of CDX2 within the neo-CLE, but not within normal Squamous epithelium. Both Squamous epithelium and CLE expressed nuclear staining for BMP-4.

Taken together, columnar lined esophagus commences to develop 6 months after the creation of an anastomosis between the squamous lined proximal esophagus and the gastric tube, lined by Oxyntic mucosa. The observation models the morphology of Gastroesophageal reflux disease.

iGERD comment:
The authors are to be congratulated for this outstanding study. The data are of profound clinical relevance and improve our understanding regarding the genesis of GERD related morphology. The paper nicely demonstrates how Reflux drives the formation of CLE and Barrett‘s esophagus, and that the changes occur after 6 months of gastro-esophageal Reflux. Furthermore, the histopathology is paralleled by genetic changes. Most importantly, the normal appearing, squamous lined esophagus expresses the genetic information for CLE development, i.e. BMP-4. This indicates, that the information already sits there and waits to be turned on by the Reflux. The genetic changes and CLE developed under proton pump inhibitor therapy. Taken together these data indicate that CLE is a response of the esophagus to gastroesophageal Reflux which is formatted within the genetic information and „switched on“ by the exposure to the Reflux. Since both medical therapy (as in this paper) and effective anti- Reflux surgery can not prevent CLE formation, others than the so called luminal factors seem to tfoster the genetics leading to the development of CLE. Remains the possibility, that the formation of CLE is somehow connected to the metabolism. Future studies will have to elicit these issues.

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Histopathology of non-dysplastic Barrett's esophagus. Note the presence of goblet cells within the columnar lining, this is the hallmark of non-dysplastic Barrett's esophagus (H&E, courtesy of Dr. Ildiko Mesteri & Prof. Dr. Fritz Wrba, Vienna).

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