Stuart Spechler M.D.

Spechler, S. J. (2020). “Medical versus Surgical Treatment for Refractory Heartburn. Reply.”
New England Journal of Medicine 382(3): 297-298.

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Our trial, sponsored by the Department of Veterans Affairs, spanned more than a decade from planning to publication and presented numerous challenges that threatened its successful completion. We agree with Yadlapati and Pandolfino that future RCTs that compare interventional therapies for patients with GERD will encounter similarly daunting obstacles. A rigid requirement for such difficult and expensive RCTs to validate new endosurgical techniques will delay their implementation and may well discourage investigators and their industry partners from developing new devices. On the other hand, there is considerable potential for harm in using invasive treatments whose efficacy is substantiated only by low-quality evidence. Pragmatic yet valid alternatives to RCTs are highly desirable and would facilitate the introduction of sorely needed new treatments for GERD. We also agree with Nicolaides et al. that ensuring patient compliance with PPI dosing is a simple clinical maneuver that works in a substantial minority of patients with PPI-refractory heartburn. Since PPIs bind only to gastric proton pumps that are actively secreting acid, patients should take PPIs 30 to 60 minutes before meals to ensure that the drugs are in the bloodstream when the greatest number of proton pumps are activated by food. Switching PPIs may also be effective, since PPI potencies vary widely, and individual patients can exhibit considerable variability in response to different PPIs. These simple maneuvers can spare many patients the expense, inconvenience, and risk of invasive tests and alternative treatments. Patients in our medical treatment groups were given instructions to avoid lying down for 3 hours after meals and to avoid bedtime snacks. We did not specifically mandate other lifestyle modifications intended to address reflux, such as weight loss, avoidance of foods that may induce heartburn, elevation of the head of the bed, and smoking cessation. The body-mass index (the weight in kilograms divided by the square of the height in meters) in 86% of our patients with reflux-related heartburn was greater than 25, and we agree with Gardner that there are high-quality data showing that weight loss can ameliorate GERD symptoms in obese persons. However, evidence supporting the efficacy of the other lifestyle modifications for patients with GERD is far less robust, and none (including weight loss) have been shown to be effective in patients with heartburn that is refractory to twice-daily PPI therapy, the subject of our trial. The health benefits of smoking cessation and weight loss for obese persons go far beyond any reduction in GERD symptoms, and we certainly support those recommendations. However, our trial was designed specifically to compare the effectiveness of antireflux surgery with that of medications for PPI-refractory heartburn. (Text of author’s reply to commentators on: Spechler SJ, Hunter JG, Jones KM, et al. Randomized trial of medical versus surgical treatment for refractory heartburn. N Engl J Med 2019;381:1513-1523.)

Spechler, S. J., J. G. Hunter, K. M. Jones, R. Lee, B. R. Smith, H. Mashimo, V. M. Sanchez, K. B. Dunbar, T. H. Pham, U. K. Murthy, T. Kim, C. S. Jackson, J. M. Wallen, E. C. von Rosenvinge, J. P. Pearl, L. Laine, A. W. Kim, A. M. Kaz, R. P. Tatum, Z. F. Gellad, S. Lagoo-Deenadayalan, J. H. Rubenstein, A. A. Ghaferi, W. K. Lo, R. S. Fernando, B. S. Chan, S. C. Paski, D. Provenzale, D. O. Castell, D. Lieberman, R. F. Souza, W. D. Chey, S. R. Warren, A. Davis-Karim, S. D. Melton, R. M. Genta, T. Serpi, K. Biswas and G. D. Huang (2019). “Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.” New England Journal of Medicine 381(16): 1513-1523.

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BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Spechler, S. J. (2019). “Eosinophilic Esophagitis: Novel Concepts Regarding Pathogenesis and Clinical Manifestations.” J Gastroenterol 54(10): 837-844.

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This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.

Que, J., K. S. Garman, R. F. Souza and S. J. Spechler (2019). “Pathogenesis and Cells of Origin of Barrett’s Esophagus.” Gastroenterology 157(2): 349-364.e341.

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In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications.

Spechler, S. J. (2019). “Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations.” J Gastroenterol Jul 24. [Epub ahead of print].

Full text of this article.

This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.