Rhonda Souza M.D.

Souza, R. F. and S. J. Spechler (2017). “Oesophagus: A new candidate for the progenitor cell of barrett metaplasia.” Nat Rev Gastroenterol Hepatol: 2017 Nov [Epub ahead of print].

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In Barrett oesophagus, the distal oesophagus is lined by an abnormal columnar epithelium that has both gastric and intestinal features and is predisposed to malignant transformation1. Barrett oesophagus develops through metaplasia, the process in which one adult tissue type replaces another in response to injury, and its pathogenesis typically begins with oesophageal injury from GERD1. With ongoing GERD, damaged stratified squamous epithelium is replaced by metaplastic, single-layer, columnar epithelium which, presumably, is more resistant to GERD injury. This process must involve GERD-induced molecular reprogramming of key developmental transcription factors (transcommitment) in the progenitor cells giving rise to the metaplastic epithelium2.

Souza, R. F. (2017). “Reflux esophagitis and its role in the pathogenesis of barrett’s metaplasia.” J Gastroenterol 52(7): 767-776.

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Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barrett’s esophagus, the precursor of esophageal adenocarcinoma. Therefore, to prevent the development of Barrett’s metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2alpha, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury. In some individuals, reflux esophagitis heals with Barrett’s metaplasia. A number of possibilities exist for the origin of the progenitor cells that give rise to this intestinal metaplasia including those of the esophagus, the proximal stomach, or the bone marrow. However, intestinal cells are not normally found in the esophagus, the stomach, or the bone marrow. Thus, the development of Barrett’s intestinal metaplasia must involve some molecular reprogramming of key developmental transcription factors within the progenitor cell, a process termed transcommitment, which may be initiated by the noxious components of the gastric refluxate. This review will highlight recent studies on the pathogenesis of reflux esophagitis and on reflux-related molecular reprogramming of esophageal squamous epithelial cells in the pathogenesis of Barrett’s metaplasia.

Spechler, S. J., J. L. Merchant, T. C. Wang, P. Chandrasoma, J. G. Fox, R. M. Genta, J. R. Goldenring, Y. Hayakawa, E. J. Kuipers, P. K. Lund, F. McKeon, J. C. Mills, R. D. Odze, R. M. Peek, Jr., T. Pham, J. Que, A. K. Rustgi, N. J. Shaheen, R. A. Shivdasani, R. F. Souza, P. Storz, A. Todisco, D. H. Wang and N. A. Wright (2017). “A summary of the 2016 james w. Freston conference of the american gastroenterological association: Intestinal metaplasia in the esophagus and stomach: Origins, differences, similarities and significance.” Gastroenterology 153(1): e6-e13.

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Robert Genta reviewed the histologic features of intestinal metaplasia, and Jason Mills provided a historical overview, noting that Rudolph Virchow coined the term “metaplasia” at the VIIIth International Medical Congress in Copenhagen in 1884. In 1900, the pathologist George Adami presciently contended that there are “mother” (stem) cells that regenerate normal tissue and, “under abnormal conditions, the fully differentiated functioning cells of certain tissues are capable of proliferation and giving rise to cells of like nature, but this is only after a preliminary reversion to a simpler, more embryonic type.” Adami proposed that this process of dedifferentiation leading to increased proliferation might result in “glandular cancer.”2 During the 1930s, developmental biologists largely abandoned Adami’s concepts, instead embracing Conrad Waddington’s notion that stem cell differentiation was unidirectional. However, recent evidence vindicates Adami, showing that differentiated cells can indeed contribute to metaplasia.

Dunbar, K. B. and R. F. Souza (2017). “Beyond dysplasia grade: The role of biomarkers in stratifying risk.” Gastrointest Endosc Clin N Am 27(3): 447-459.

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Gastroenterology society guidelines recommend endoscopic surveillance as a means to detect early stage cancer in Barrett’s esophagus. However, the incidence of esophageal adenocarcinoma in Western countries continues to increase, suggesting that this strategy may be inadequate. Current surveillance methods rely on the endoscopist’s ability to identify suspicious areas of Barrett’s esophagus to biopsy, random biopsies, and on the histopathologic diagnosis of dysplasia. This review highlights the challenges of using dysplasia to stratify cancer risk and addresses the development and use of molecular biomarkers and in vivo molecular imaging to detect early neoplasia in Barrett’s esophagus.

Nguyen, A. D., S. J. Spechler, M. N. Shuler, R. F. Souza and K. B. Dunbar (2017). “Unique clinical features of los angeles grade d esophagitis suggest that factors other than gastroesophageal reflux contribute to its pathogenesis.” J Clin Gastroenterol: 2017 Jun [Epub ahead of print].

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BACKGROUND: The Los Angeles (LA) grade of reflux esophagitis (A to D) is assumed to reflect severity of the underlying gastroesophageal reflux disease (GERD). Thus, LA-D esophagitis patients might be expected to have the most conditions predisposing to GERD (eg, obesity, hiatal hernia), and the highest frequency of GERD symptoms. GOALS: The main goal of this study is to compare clinical features of patients with the most severe (LA-D) and mildest (LA-A) grades of esophagitis. STUDY: For this comparative study, we searched our endoscopy database for patients diagnosed with LA-D or LA-A esophagitis, reviewed their endoscopic images, and reviewed medical records of the first 100 we confirmed to have LA-D or LA-A esophagitis. RESULTS: Compared with LA-A patients, LA-D patients were older (mean age, 65+/-13.4 vs. 56+/-13.4 y; P<0.001), had lower body mass index (25.9+/-5.6 vs. 29.4+/-5.3; P<0.001), were more frequently hospitalized (70% vs. 3%; P<0.001), and in the intensive care unit (15% vs. 0%; P<0.001), and had significantly more serious cardiopulmonary disorders and gastrointestinal bleeding. Conversely, a GERD history was more common in LA-A than LA-D patients (67% vs. 45%; P=0.002). Hiatal hernia was more frequent in LA-A patients than LA-D patients, but not significantly (48% vs. 36%; P=0.09). CONCLUSIONS: LA-D esophagitis primarily affects hospitalized, older, nonobese patients who often have serious comorbidities, and no history of GERD or hiatal hernia. In contrast, LA-A patients are generally younger, obese outpatients who often have a history of GERD and hiatal hernia without serious comorbidities. These profound differences between LA-A and LA-D patients suggest that factors other than typical GERD contribute to LA-D esophagitis pathogenesis.