Stuart Spechler M.D.

Spechler, S. J. (2019). “Proton Pump Inhibitors: What the Internist Needs to Know.” Med Clin North Am 103(1): 1-14.

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This report reviews the physiology of gastric acid suppression by proton pump inhibitors (PPIs) and anti-inflammatory effects of PPIs that are independent of their acid-suppressive effects. Valid indications for PPI use are discussed, as are putative adverse effects of PPIs that have been identified through weak associations in observational studies that cannot establish cause-and-effect relationships. Although evidence supporting the validity of these adverse effects is weak, there is also insufficient evidence to dismiss the risks. The report emphasizes how PPIs frequently are prescribed inappropriately and encourages physicians to carefully consider the indication for PPI therapy in their patients.

Nguyen, A. D., S. J. Spechler, M. N. Shuler, R. F. Souza and K. B. Dunbar (2019). “Unique Clinical Features of Los Angeles Grade D Esophagitis Suggest That Factors Other Than Gastroesophageal Reflux Contribute to its Pathogenesis.” J Clin Gastroenterol 53(1): 9-14.

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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.

Spechler, S. J., V. Konda and R. Souza (2018). “Can Eosinophilic Esophagitis Cause Achalasia and Other Esophageal Motility Disorders?” Am J Gastroenterol Oct 12. [Epub ahead of print].

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Eosinophilic esophagitis (EoE), a disorder identified by its esophageal mucosal features, often is associated with esophageal motility abnormalities, which are manifestations of esophageal muscle dysfunction. Those motility abnormalities sometimes normalize with treatments that reduce esophageal eosinophilia, suggesting that eosinophils can cause reversible esophageal motility disturbances, perhaps by releasing myoactive and neuroactive eosinophil products. Although achalasia uncommonly is associated with EoE as currently defined, most achalasia patients have evidence of an abnormal accumulation of eosinophils and/or their degranulation products in the esophageal muscularis propria, a location inaccessible to routine endoscopic evaluation. Achalasia is an idiopathic condition resulting from destruction of neurons in the myenteric plexus of the esophagus, and degranulating eosinophils release toxic proteins capable of destroying those neurons, thereby causing the irreversible motility abnormalities of achalasia. This report reviews data on the association of esophageal eosinophilia with achalasia and other esophageal motility abnormalities. Based on this review, we propose that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms with different clinical manifestations. A muscle-predominant form of EoE could underlie a variety of reversible and irreversible esophageal motility disorders, including achalasia. The concept that esophageal motility abnormalities might develop from a muscle-predominant form of EoE warrants serious consideration and further investigation.

Zhang, Q., A. T. Agoston, T. H. Pham, W. Zhang, X. Zhang, X. Huo, S. Peng, M. Bajpai, K. Das, R. D. Odze, S. J. Spechler and R. F. Souza (2018). “Acidic Bile Salts Induce Epithelial to Mesenchymal Transition via VEGF Signaling in Non-Neoplastic Barrett’s Cells.” Gastroenterology Sep 27. [Epub ahead of print].

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BACKGROUND & AIMS: Metaplastic glands buried under squamous epithelium are frequently detected in patients with Barrett’s esophagus (BE). This sub-squamous intestinal metaplasia (SSIM) might be responsible for cancers that develop despite endoscopic surveillance, and for metaplasia recurrences after endoscopic ablation. To determine whether reflux induces BE cells to undergo epithelial to mesenchymal transition (EMT) that produces SSIM, we assessed EMT in BE cells exposed to acidic bile salts, and in rat and human esophageal tissues. METHODS: We compared markers of EMT and cell motility in transwell and 3-dimensional organotypic culture systems among dysplastic BE epithelial cell lines, nondysplastic telomerase-immortalized BE cell lines (BAR-T), and BAR-T cells exposed acutely or for 20 weeks (BEC-20W) to acidic bile salts. VEGFA was inhibited with a neutralizing antibody or CRISPR-Cas9n and VEGFR2 was inhibited with SU1498 or shRNA, and cells were analyzed by immunohistochemistry, quantitative PCR, or immunoblotting for markers of VEGF signaling and EMT; cell motility was assessed by transwell. We used immunohistochemistry and quantitative PCR to assess EMT markers in the columnar-lined esophagus of rats with surgically induced reflux esophagitis and in esophagectomy specimens from patients with BE. RESULTS: We detected features of EMT (decreased cadherin 1 [CDH1]; increased fibronectin 1, vimentin, and MMP2; and increased motility) in dysplastic BE epithelial cell lines and in BEC-20W cells, but not in unexposed BAR-T cells. Acute acidic bile salt exposure induced expression of the zinc finger E-box binding homeobox 1/2 (ZEB1/2) in BAR-T cells, which reduced their expression of CDH1 and increased motility; inhibitors of VEGF signaling blocked these effects. Columnar-lined esophagus of rats with reflux esophagitis had increased expression of ZEB1/2 and decreased expression of CDH1 compared with controls. Dysplastic BE tissues also had significantly increased levels of ZEB1 and significantly decreased levels of CDH1 compared with non-dysplastic BE tissues. CONCLUSIONS: In BE cell lines, acidic bile salts induce EMT via VEGF signaling, which increases expression of ZEB1/2, repressors of CDH1. These observations suggest that reflux induces EMT in metaplastic BE tissues, which promotes development of SSIM.

Dellon, E. S., C. A. Liacouras, J. Molina-Infante, G. T. Furuta, J. M. Spergel, N. Zevit, S. J. Spechler, S. E. Attwood, A. Straumann, S. S. Aceves, J. A. Alexander, D. Atkins, N. C. Arva, C. Blanchard, P. A. Bonis, W. M. Book, K. E. Capocelli, M. Chehade, E. Cheng, M. H. Collins, C. M. Davis, J. A. Dias, C. . . . et al., and A. J. Bredenoord (2018). “Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference.” Gastroenterology Sep 6. [Epub ahead of print].

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BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm(2)) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.