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Zhang N, Han M, Zheng QW, Zhang MY, Zhi WL, Li JJ, Cui LX, Tian JL, Wang Y, Fang SQ. A scientometrics analysis and visualization of refractory gastroesophageal reflux disease. Front Pharmacol 2024; 15:1393526. [PMID: 39139634 PMCID: PMC11319146 DOI: 10.3389/fphar.2024.1393526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/18/2024] [Indexed: 08/15/2024] Open
Abstract
Background Refractory gastroesophageal reflux disease (refractory GERD) is a heterogeneous disease characterized by unresponsiveness or poor efficacy to proton-pump inhibitors (PPIs). This chronic disorder substantially weakens patients' mental wellbeing and quality of life, increasing the financial burden on society. Multiple articles have been reported in this area. However, literature involving scientometric analysis of refractory GERD is absent. Therefore, it is necessary to understand the evolution of research themes and the main hotspots of refractory GERD through bibliometric methods. Methods All documents related to refractory GERD based on the WOS Core Collection from January 2000 to November 2023 were selected for analysis. Citespace V 6.1 R6, VOSviewer V 1.6.20, and Scimago Graphica V 1.0.38 were used to perform bibliometric analysis. Results We collected a total of 241 research articles from 36 countries and 322 institutions, contributed by over 1,000 authors. Over the last 20 years, the number of articles in this field has increased year by year, and since 2011, the number of publications has increased dramatically, with 85.89% of the papers. These countries are led by the United States and Japan. GUT had the highest number of citations and DIGESTION had the highest number of publications. Research on standardized diagnosis and management, mechanisms, novel monitoring methods, and innovative drugs and procedures for refractory GERD are the main topics and hotspots in this field. This study also found that neuroimmune interaction is closely related to refractory GERD, which may be a new direction for future mechanism research. Conclusion Our study is the first bibliometric analysis of the global literature on refractory GERD. This research provides valuable insights for researchers, enabling them to quickly understand the research frontier and hot topics of this field.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Sheng-Quan Fang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Davis TA, Gyawali CP. Refractory Gastroesophageal Reflux Disease: Diagnosis and Management. J Neurogastroenterol Motil 2024; 30:17-28. [PMID: 38173155 PMCID: PMC10774805 DOI: 10.5056/jnm23145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/16/2023] [Indexed: 01/05/2024] Open
Abstract
Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett's esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.
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Affiliation(s)
- Trevor A Davis
- Division of Pediatric Gastroenterology, Washington University School of Medicine, Saint Louis Children’s Hospital, St. Louis, MO, USA
| | - C Prakash Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
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Gyawali CP, Yadlapati R, Fass R, Katzka D, Pandolfino J, Savarino E, Sifrim D, Spechler S, Zerbib F, Fox MR, Bhatia S, de Bortoli N, Cho YK, Cisternas D, Chen CL, Cock C, Hani A, Remes Troche JM, Xiao Y, Vaezi MF, Roman S. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut 2024; 73:361-371. [PMID: 37734911 PMCID: PMC10846564 DOI: 10.1136/gutjnl-2023-330616] [Citation(s) in RCA: 149] [Impact Index Per Article: 149.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/30/2023] [Indexed: 09/23/2023]
Abstract
The Lyon Consensus provides conclusive criteria for and against the diagnosis of gastro-oesophageal reflux disease (GERD), and adjunctive metrics that consolidate or refute GERD diagnosis when primary criteria are borderline or inconclusive. An international core and working group was assembled to evaluate research since publication of the original Lyon Consensus, and to vote on statements collaboratively developed to update criteria. The Lyon Consensus 2.0 provides a modern definition of actionable GERD, where evidence from oesophageal testing supports revising, escalating or personalising GERD management for the symptomatic patient. Symptoms that have a high versus low likelihood of relationship to reflux episodes are described. Unproven versus proven GERD define diagnostic strategies and testing options. Patients with no prior GERD evidence (unproven GERD) are studied using prolonged wireless pH monitoring or catheter-based pH or pH-monitoring off antisecretory medication, while patients with conclusive GERD evidence (proven GERD) and persisting symptoms are evaluated using pH-impedance monitoring while on optimised antisecretory therapy. The major changes from the original Lyon Consensus criteria include establishment of Los Angeles grade B oesophagitis as conclusive GERD evidence, description of metrics and thresholds to be used with prolonged wireless pH monitoring, and inclusion of parameters useful in diagnosis of refractory GERD when testing is performed on antisecretory therapy in proven GERD. Criteria that have not performed well in the diagnosis of actionable GERD have been retired. Personalisation of investigation and management to each patient's unique presentation will optimise GERD diagnosis and management.
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Affiliation(s)
- C Prakash Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Rena Yadlapati
- Division of Gastroenterology, University of California in San Diego, La Jolla, California, USA
| | - Ronnie Fass
- Medicine/Section of Gastroenterology, Case Western Reserve University, Cleveland, Ohio, USA
| | - David Katzka
- Gastroenterology and Hepatology, Columbia University, New York, New York, USA
| | - John Pandolfino
- Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, Department of Medical and Surgical Specialties, University of Padua, Padova, Italy
| | - Daniel Sifrim
- Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK
| | - Stuart Spechler
- Division of Gastroenterology, Baylor Scott and White North Texas, Dallas, Texas, USA
| | - Frank Zerbib
- Gastroenterology, CHU de Bordeaux, Bordeaux, France
| | - Mark R Fox
- Gastroenterology, University of Zurich, Zurich, Switzerland
| | | | | | - Yu Kyung Cho
- Gastroenterology, Catholic University of Korea - Songsin Campus, Seoul, Korea (the Republic of)
| | - Daniel Cisternas
- Digestive System Research Unit, Universidad del Desarrollo Facultad de Medicina Clínica Alemana, Las Condes, Chile
| | - Chien-Lin Chen
- Department of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Charles Cock
- Department of Gastroenterology and Hepatology, Flinders University, Adelaide, South Australia, Australia
| | - Albis Hani
- Gastroenterology Unit, Department of Medicine, Pontificia Universidad Javeriana, Bogota, Colombia
| | | | - Yinglian Xiao
- Department of Gastroenterology, Sun Yan-sen University of Medical Sciences, Guangzhou, China
| | - Michael F Vaezi
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Sabine Roman
- Department of Digestive Physiology, Universite de Lyon, Lyon, France
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Gorgulu V, Ergun P, Kipcak S, Doganavsargil B, Sifrim D, Bor S. Revisiting the Role of Esophageal Mucosal Dilated Intercellular Spaces in the Diagnosis and Pathophysiology of Heartburn. J Neurogastroenterol Motil 2023; 29:436-445. [PMID: 37814434 PMCID: PMC10577464 DOI: 10.5056/jnm22142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/01/2022] [Accepted: 02/12/2023] [Indexed: 10/11/2023] Open
Abstract
Background/Aims Dilated intercellular spaces (DISs) facilitate the diffusion of noxious agents into the deep layers of the esophageal epithelium. The role of DIS in heartburn pathogenesis is still controversial. Therefore, we aim to reinvestigate DIS in an extensively evaluated group of patients and healthy controls (HCs). Methods We classified 149 subjects into the following groups: 15 HC, 58 mild erosive reflux disease (ERD), 17 severe ERD, 25 nonerosive reflux disease (NERD), 15 reflux hypersensitivity (RH), and 19 functional heartburn (FH). A total of 100 length measurements were performed for each patient's biopsy. Results The overall intercellular spaces (ISs) value of gastroesophageal reflux disease (GERD) patients was higher than that of HC (P = 0.020). In phenotypes, mild ERD (vs HC [P = 0.036], NERD [P = 0.004], RH [P = 0.014]) and severe ERD (vs HC [P = 0.002], NERD [P < 0.001], RH [P = 0.001], FH [P = 0.004]) showed significantly higher IS. There was no significant difference between the HC, NERD, RH, and FH groups. The 1.12 μm DIS cutoff value had 63.5% sensitivity and 66.7% specificity in the diagnosis of GERD. There was a weak correlation (r = 0.302) between the IS value and acid exposure time, and a weak correlation (r = -0.359) between the IS value and baseline impedance. A strong correlation was shown between acid exposure time and baseline impedance (r = -0.783). Conclusions Since the IS length measurement had better discrimination power only in erosive groups, it is not feasible to use in daily routine to discriminate other nonerosive phenotypes and FH. The role of DIS in heartburn in nonerosive patients should be reconsidered.
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Affiliation(s)
- Volkan Gorgulu
- Departments of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Pelin Ergun
- Departments of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, Turkey
- Division of Gastroenterology, Faculty of Medicine, Ege Reflux Study Group, Ege University, Izmir, Turkey
| | - Sezgi Kipcak
- Division of Gastroenterology, Faculty of Medicine, Ege Reflux Study Group, Ege University, Izmir, Turkey
- Departments of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Basak Doganavsargil
- Departments of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Serhat Bor
- Division of Gastroenterology, Faculty of Medicine, Ege Reflux Study Group, Ege University, Izmir, Turkey
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Layne SJ, Lorsch ZS, Patel A. Novel Diagnostic Techniques in the Evaluation of Gastroesophageal Reflux Disease (GERD). Dig Dis Sci 2023; 68:2226-2236. [PMID: 37071244 DOI: 10.1007/s10620-023-07901-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/21/2023] [Indexed: 04/19/2023]
Abstract
In our present clinical paradigm, patient symptoms and presentation in the setting of traditional findings from endoscopy (erosive esophagitis, Barrett's esophagus, reflux-mediated stenosis), esophageal high-resolution manometry, and/or ambulatory reflux monitoring (distal esophageal acid exposure time, numbers of reflux events, reflux-symptom association) guide the care of patients with suspected GERD. However, novel metrics and techniques acquired from or performed at endoscopy, manometry, or pH-impedance monitoring, beyond conventional evaluation, are of great interest to the gastroenterology community given the frequent (and sometimes challenging) presentation of suspected GERD. These novel and evolving diagnostic approaches have the potential to enhance the evaluation of these patients and optimize their management. In this invited review, we discuss the present evidence and potential clinical utility of selected GERD metrics and techniques of interest at endoscopy (dilated intercellular spaces, mucosal impedance), manometry (contractile integral, impedance analysis, straight leg raise, multiple rapid swallow maneuvers), and reflux monitoring (mean nocturnal baseline impedance, post-reflux swallow-induced peristaltic wave indices), and how these tools may be most optimally adopted and utilized for clinical care (Fig. 1).
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Affiliation(s)
- Sabrina J Layne
- Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA
| | - Zachary S Lorsch
- Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA
| | - Amit Patel
- Division of Gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Box 3913, Durham, NC, 27710, USA.
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Zhang T, Zhang B, Tian W, Wei Y, Wang F, Yin X, Wei X, Liu J, Tang X. Trends in gastroesophageal reflux disease research: A bibliometric and visualized study. Front Med (Lausanne) 2022; 9:994534. [PMID: 36250094 PMCID: PMC9556905 DOI: 10.3389/fmed.2022.994534] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/06/2022] [Indexed: 11/19/2022] Open
Abstract
Background Gastroesophageal reflux disease (GERD), a disorder resulting from the retrograde flow of gastric contents into the esophagus, affects an estimated 10-30% of the Western population, which is characterized by multifactorial pathogenesis. Over the past few decades, there have been many aspects of uncertainty regarding GERD leading to an ongoing interest in the field as reflected by a large number of publications, whose heterogeneity and variable quality may present a challenge for researchers to measure their scientific impact, identify scientific collaborations, and to grasp actively researched themes in the GERD field. Accordingly, we aim to evaluate the knowledge structure, evolution of research themes, and emerging topics of GERD research between 2012 and 2022 with the help of bibliometric approaches. Methods The literature focusing on GERD from 2012 to 2022 was retrieved from the Science Citation Index Expanded of the Web of Science Core Collection. The overall publication performance, the most prolific countries or regions, authors, journals and resources-, knowledge- and intellectual-networking, as well as the co-citation analysis of references and keywords, were analyzed through Microsoft Office Excel 2019, CiteSpace, and VOSviewer. Results A total of 8,964 publications were included in the study. The USA published the most articles (3,204, 35.74%). Mayo Clin ranked first in the number of articles published (201, 2.24%). EDOARDO SAVARINO was the most productive author (86, 0.96%). The most productive journal in this field was SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES (304, 3.39%). AMERICAN JOURNAL OF GASTROENTEROLOGY had the most co-citations (4,953, 3.30%). Keywords with the ongoing strong citation bursts were transoral incision less fundoplication, eosinophilic esophagitis, baseline impedance, and functional heartburn. Conclusion For the first time, we obtained deep insights into GERD research through bibliometric analysis. Findings in this study will be helpful for scholars seeking to understand essential information in this field and identify research frontiers.
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Affiliation(s)
- Tai Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Beihua Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wende Tian
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuchen Wei
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaolan Yin
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiuxiu Wei
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiali Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xudong Tang
- Traditional Chinese Medicine Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Wu Y, Guo Z, Zhang C, Zhan Y. Mean nocturnal baseline impedance, a novel metric of multichannel intraluminal impedance-pH monitoring in diagnosing gastroesophageal reflux disease. Therap Adv Gastroenterol 2022; 15:17562848221105195. [PMID: 35983222 PMCID: PMC9379274 DOI: 10.1177/17562848221105195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 05/18/2022] [Indexed: 02/04/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) is a common disease with increasing prevalence worldwide. However, the diagnosis of GERD is challenging because there are no definite gold standard criteria. Recently, a novel impedance parameter, namely mean nocturnal baseline impedance (MNBI), has been proposed, which reflects the burden of longitudinal reflux and the integrity of esophageal mucosa. MNBI has shown an immense promise for increasing the diagnostic rate of multichannel intraluminal impedance-pH (MII-pH) monitoring and predicting the response to proton pump inhibitor (PPI) or anti-reflux intervention in patients with reflux symptoms. The present paper reviews the association between baseline impedance and esophageal mucosal integrity, the acquisition of MNBI in 24-h MII-pH monitoring, the clinical utilization of MNBI in improving the diagnosis rate of GERD in patients with typical reflux symptoms, predicting the response to PPI or anti-reflux treatment in these patients, the utilization of MNBI in diagnosing patients with atypical symptoms or extra-esophageal symptoms, and the correlation between reflux burden and MNBI. MNBI should be routinely assessed using MII-pH monitoring.
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Affiliation(s)
| | | | | | - Yutao Zhan
- Department of Gastroenterology, Beijing Tong Ren Hospital, Capital Medical University, No.1, Dongjiaominxiang, Dongcheng District, Beijing 100730, P. R. China
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Iwamuro M, Urata H, Tanaka T, Okada H. Application of electron microscopy in gastroenterology. World J Gastrointest Pathophysiol 2022; 13:41-49. [PMID: 35433095 PMCID: PMC8976235 DOI: 10.4291/wjgp.v13.i2.41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 10/26/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Electron microscopy has long been used in research in the fields of life sciences and materials sciences. Transmission and scanning electron microscopy and energy-dispersive X-ray spectroscopy (EDX) analyses have also been performed in the field of gastroenterology. Electron microscopy and EDX enable (1) Observation of ultrastructural differences in esophageal epithelial cells in patients with gastroesophageal reflux and eosinophilic esophagitis; (2) Detection of lanthanum deposition in the stomach and duodenum; (3) Ultrastructural and elemental analyses of enteroliths and bezoars; (4) Detection and characterization of microorganisms in the gastrointestinal tract; (5) Diagnosis of gastrointestinal tumors with neuroendocrine differentiation; and (6) Analysis of gold nanoparticles potentially used in endoscopic photodynamic therapy. This review aims to foster a better understanding of electron microscopy applications by reviewing relevant clinical studies, basic research findings, and the state of current research carried out in gastroenterology science.
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Affiliation(s)
- Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Haruo Urata
- Central Research Laboratory, Okayama University Medical School, Okayama 700-8558, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Hospital, Okayama 700-8558, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Franciosi JP, Mougey EB, Dellon ES, Gutierrez-Junquera C, Fernandez-Fernandez S, Venkatesh RD, Gupta SK. Proton Pump Inhibitor Therapy for Eosinophilic Esophagitis: History, Mechanisms, Efficacy, and Future Directions. J Asthma Allergy 2022; 15:281-302. [PMID: 35250281 PMCID: PMC8892718 DOI: 10.2147/jaa.s274524] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/14/2022] [Indexed: 12/11/2022] Open
Abstract
Over the past decade, the role of proton pump inhibitor (PPI) medication has evolved from a diagnostic tool for Eosinophilic Esophagitis (EoE), by excluding patients with PPI responsive esophageal eosinophilia (PPI-REE), to a therapy for EoE. This transition resulted from the Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the Appraisal of Guidelines for Research and Evaluation II (AGREE) Conference to support PPI therapy for EoE in children and adults. Additional recent advances have suggested a role for genetic variations that might impact response to PPI therapy for EoE. This review article will explore a brief background of EoE, the evolution of PPI therapy for EoE and its proposed mechanisms, efficacy and safety in children and adults, and considerations for future PPI precision medicine in patients with EoE.
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Affiliation(s)
- James P Franciosi
- Division of Gastroenterology, Nemours Children’s Hospital, Orlando, FL, USA
- College of Medicine, University of Central Florida, Orlando, FL, USA
- Correspondence: James P Franciosi, Division of Gastroenterology, Nemours Children’s Hospital, 6535 Nemours Parkway, Orlando, FL, 32827, USA, Email
| | - Edward B Mougey
- Center for Pharmacogenomics and Translational Research, Nemours Children’s Health System, Jacksonville, FL, USA
| | - Evan S Dellon
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Carolina Gutierrez-Junquera
- Pediatric Gastroenterology Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Autonomous University of Madrid, Madrid, Spain
| | | | - Rajitha D Venkatesh
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, Columbus, OH, USA
| | - Sandeep K Gupta
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine and Community Health Network, Indianapolis, IN, USA
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10
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Nikaki K, Sifrim D. Pathophysiology of Pediatric Gastroesophageal Reflux Disease: Similarities and Differences With Adults. J Clin Gastroenterol 2022; 56:99-113. [PMID: 34560757 DOI: 10.1097/mcg.0000000000001604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Gastroesophageal reflux (GOR) is defined as "the passage of gastric contents into the esophagus with or without regurgitation and vomiting" and gastroesophageal reflux disease (GORD) is defined "when GOR leads to troublesome symptoms affecting the daily functioning and/or complications." This definition was first developed in 2006 by the Montreal consensus group (1) and later on adopted by pediatric gastroenterology societies such as ESPGHAN and NASPGHAN in 2009 (2). The definition of gastroesophageal reflux reveals little about its pathophysiology and is focused on symptomatology. In this way, it acts as an umbrella term for the multifactorial causes of the disease and the various phenotypes encountered; from functional heartburn to hypersensitive esophagus and nonerosive reflux disease, to erosive esophagitis and Barrett's esophagus. This article is devoted to the pathophysiology of pediatric GORD in comparison to adult GORD and is divided in 2 parts. In the first part, we will systematically describe the different mechanisms for the generation and clearance of reflux events, while on the second part we will discuss the mechanisms involved in symptoms generation. Finally, we will discuss the similarities and differences between pediatric and adult GORD.
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Affiliation(s)
- Kornilia Nikaki
- Gastroenterology Department, Great Ormond Street Hospital for Children
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, The Blizard Institute, QMUL, London, UK
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11
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Effects of Central Obesity on Esophageal Epithelial Barrier Function. Am J Gastroenterol 2021; 116:1537-1541. [PMID: 33955725 PMCID: PMC8243777 DOI: 10.14309/ajg.0000000000001196] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/22/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION We assessed if obesity perturbs the esophageal epithelial barrier function independent of promotion of gastroesophageal reflux (GER). METHODS Thirty-eight participants were divided into 4 groups: Obesity-/GER-, Obesity+/GER-, Obesity-/GER+, and Obesity+/GER+. Esophageal intercellular space and desmosome density (structural integrity) and fluorescein leak (functional integrity) were measured. RESULTS The Obesity+/GER- group demonstrated increased intercellular space, reduced desmosome density, and increased fluorescein leak compared with control subjects. These changes were similar but not additive to findings seen in Obesity-/GER + and Obesity+/GER+ patients. DISCUSSION Central obesity impairs structural and functional integrity of the esophageal barrier independent of GER, likely predisposing to esophageal injury.
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12
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Zerbib F, Bredenoord AJ, Fass R, Kahrilas PJ, Roman S, Savarino E, Sifrim D, Vaezi M, Yadlapati R, Gyawali CP. ESNM/ANMS consensus paper: Diagnosis and management of refractory gastro-esophageal reflux disease. Neurogastroenterol Motil 2021; 33:e14075. [PMID: 33368919 DOI: 10.1111/nmo.14075] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 11/11/2020] [Accepted: 12/13/2020] [Indexed: 02/08/2023]
Abstract
Up to 40% of patients with symptoms suspicious of gastroesophageal reflux disease (GERD) do not respond completely to proton pump inhibitor (PPI) therapy. The term "refractory GERD" has been used loosely in the literature. A distinction should be made between refractory symptoms (ie, symptoms may or may not be GERD-related), refractory GERD symptoms (ie, persisting symptoms in patients with proven GERD, regardless of relationship to ongoing reflux), and refractory GERD (ie, objective evidence of GERD despite adequate medical management). The present ESNM/ANMS consensus paper proposes use the term "refractory GERD symptoms" only in patients with persisting symptoms and previously proven GERD by either endoscopy or esophageal pH monitoring. Even in this context, symptoms may or may not be reflux related. Objective evaluation, including endoscopy and esophageal physiologic testing, is requisite to provide insights into mechanisms of symptom generation and evidence of true refractory GERD. Some patients may have true ongoing refractory acid or weakly acidic reflux despite PPIs, while others have no evidence of ongoing reflux, and yet others have functional esophageal disorders (overlapping with proven GERD confirmed off therapy). In this context, attention should also be paid to supragastric belching and rumination syndrome, which may be important contributors to refractory symptoms.
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Affiliation(s)
- Frank Zerbib
- CHU de Bordeaux, Centre Medico-chirurgical Magellan, Hôpital Haut-Lévêque, Gastroenterology Department, Université de Bordeaux, INSERM CIC 1401, Bordeaux, France
| | | | - Ronnie Fass
- Digestive Health Center, MetroHealth System, Cleveland, OH, USA
| | - Peter J Kahrilas
- Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, USA
| | - Sabine Roman
- Hospices Civils de Lyon, Hôpital E Herriot, Digestive Physiology, Université de Lyon, Inserm U1032, LabTAU, Lyon, France
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University Hospital of Padua, Padua, Italy
| | - Daniel Sifrim
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Michael Vaezi
- Division of Gastroenterology, Vanderbilt University, Nashville, TN, USA
| | - Rena Yadlapati
- Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, CA, USA
| | - C Prakash Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
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13
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Fabisiak A, Bartoszek A, Talar M, Binienda A, Dziedziczak K, Krajewska JB, Mosińska P, Niewinna K, Tarasiuk A, Mokrowiecka A, Wierzchniewska-Ławska A, Małecka-Panas E, Salaga M, Fichna J. Expression of FFAR3 and FFAR4 Is Increased in Gastroesophageal Reflux Disease. J Clin Med 2020; 9:jcm9124111. [PMID: 33419235 PMCID: PMC7766740 DOI: 10.3390/jcm9124111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 12/12/2022] Open
Abstract
Background: The negative impact of a high-fat diet on the course of gastroesophageal reflux disease (GERD) has been previously reported. Free fatty acid receptors (FFARs) may be mediators of this phenomenon. The aim of this study was to characterize the role of FFARs in the course of nonerosive (NERD) and erosive (ERD) reflux disease. Methods: Collectively, 73 patients (62 with GERD and 11 healthy controls (HCs)) were recruited to the study. Esophageal biopsies were drawn from the lower third of the esophagus and kept for further experiments. Quantitative, real-time polymerase chain reaction was used to assess the expression of FFAR1, FFAR2, FFAR3, and FFAR4 in biopsies. Histological evaluation of dilated intracellular spaces (DISs) was also performed. Results: FFAR3 exhibited the highest expression, and FFAR4 exhibited the lowest expression in all esophageal samples. Higher relative expression of FFAR1 and FFAR2 and significantly higher expression of FFAR3 (p = 0.04) was noted in patients with GERD compared to respective HCs. Patients with nonerosive GERD (NERD) presented higher expression of all FFARs compared to patients with erosive GERD (ERD) and respective HCs. Interestingly, in patients with ERD, the expression of FFAR3 was lower than in HCs. Significant, weak, positive correlation was found for FFAR3 and FFAR4 expression and DIS scores (r = 0.36, p < 0.05 for FFAR 3, and r = 0.39, p < 0.05 for FFAR4). Conclusions: In this study, we show that FFARs may play a role in GERD pathogenesis, particularly in the NERD type. It may be assumed that FFARs, in particular FFAR3 and FFAR4, may have diagnostic and therapeutic potential in GERD.
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Affiliation(s)
- Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.M.); (E.M.-P.)
| | - Adrian Bartoszek
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Marcin Talar
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Agata Binienda
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Katarzyna Dziedziczak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Julia B. Krajewska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Paula Mosińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Karolina Niewinna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Aleksandra Tarasiuk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.M.); (E.M.-P.)
| | | | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.M.); (E.M.-P.)
| | - Maciej Salaga
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (A.F.); (A.B.); (M.T.); (A.B.); (K.D.); (J.B.K.); (P.M.); (K.N.); (A.T.); (M.S.)
- Correspondence: ; Tel.: +48-42-272-57-07; Fax: +48-42-272-56-94
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14
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Savarino V, Marabotto E, Zentilin P, Demarzo MG, Pellegatta G, Frazzoni M, De Bortoli N, Tolone S, Giannini EG, Savarino E. Esophageal reflux hypersensitivity: Non-GERD or still GERD? Dig Liver Dis 2020; 52:1413-1420. [PMID: 33097427 DOI: 10.1016/j.dld.2020.10.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
The most recent iteration of the classifications for functional esophageal disorders, Rome IV, proposed relevant modifications of the previous definitions for Rome III. They specifically considered increased esophageal acid exposure as the marker of gastroesophageal reflux disease (GERD), including the remaining part of non-erosive reflux disease patients with normal acid in the group with functional alterations, considering both reflux hypersensitivity and functional heartburn. However, recent pathophysiological and therapeutic data suggest the need for a return to including reflux hypersensitivity in the GERD spectrum. Indeed, physiologic alterations in esophageal mucosal integrity and chemical clearance, the presence of microscopic esophagitis, and strict symptom-reflux association support the concept that reflux hypersensitivity pertains to GERD. Surgical anti-reflux therapy has resulted in positive outcomes, even in the long term, in patients with reflux hypersensitivity and not in those with functional heartburn. Moreover, clinical trials using neuromodulators have been scarce and provided conflicting results. As a result, the real progress of the Rome IV classifications is in dispute. This article aims to summarize the most recent knowledge of non-erosive reflux disease and reflux hypersensitivity to discuss the utility of Rome IV criteria in the identification and management of functional esophageal disorders.
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Affiliation(s)
- Vincenzo Savarino
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Patrizia Zentilin
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Maria Giulia Demarzo
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Gaia Pellegatta
- Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas, Rozzano, Milan, Italy
| | - Marzio Frazzoni
- Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy
| | - Nicola De Bortoli
- Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Salvatore Tolone
- General and Bariatric Surgery Unit, Department of Surgery, Università della Campania Luigi Vanvitelli, Naples, Italy
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Edoardo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
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15
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Clarke JO, Ahuja NK, Chan WW, Gyawali CP, Horsley-Silva JL, Kamal AN, Vela MF, Xiao Y. Mucosal impedance for esophageal disease: evaluating the evidence. Ann N Y Acad Sci 2020; 1481:247-257. [PMID: 32588457 DOI: 10.1111/nyas.14414] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/21/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022]
Abstract
Impedance has traditionally been employed in esophageal disease as a means to assess bolus flow and reflux episodes. Recent and ongoing research has provided new and novel applications for this technology. Measurement of esophageal mucosal impedance, via either multichannel intraluminal impedance catheters or specially designed endoscopically deployed impedance catheters, provides a marker of mucosal integrity. Mucosal impedance has been shown to segregate gastroesophageal reflux disease (GERD) and eosinophilic esophagitis from non-GERD controls and may play a role in predicting response to reflux intervention. More data are needed with regard to other esophageal subgroups, outcome studies, and functional disease. Our paper reviews the history of impedance in esophageal disease, the means of assessing baseline and mucosal impedance, data with regard to the newly developed mucosal impedance probes, the clinical utility of mucosal impedance in specific clinical conditions, and limitations in our existing knowledge, along with suggestions for future studies.
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Affiliation(s)
- John O Clarke
- Department of Medicine, Stanford University, Redwood City, California
| | - Nitin K Ahuja
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Walter W Chan
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | | | | | - Afrin N Kamal
- Department of Medicine, Stanford University, Redwood City, California
| | - Marcelo F Vela
- Gastroenterology Division, the Mayo Clinic, Scottsdale, Arizona
| | - Yinglian Xiao
- Department of Gastroenterology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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16
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Ofer F, Custon N, Scott S, Abraham K. Functional esophageal chest pain, functional heartburn and reflux hypersensitivity. CLINICAL AND BASIC NEUROGASTROENTEROLOGY AND MOTILITY 2020:247-262. [DOI: 10.1016/b978-0-12-813037-7.00017-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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17
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Zhang M, Pandolfino JE, Zhou X, Tan N, Li Y, Chen M, Xiao Y. Assessing different diagnostic tests for gastroesophageal reflux disease: a systematic review and network meta-analysis. Therap Adv Gastroenterol 2019; 12:1756284819890537. [PMID: 31803253 PMCID: PMC6876191 DOI: 10.1177/1756284819890537] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The aim of the current systematic review and network meta-analysis (NMA) was to assess the diagnostic characteristics of the gastroesophageal reflux disease questionnaire (GERDQ), proton-pump inhibitor (PPI) test, baseline impedance, mucosal impedance, dilated intercellular spaces (DIS), salivary pepsin, esophageal pH/pH impedance monitoring and endoscopy for gastroesophageal reflux disease (GERD). METHODS We searched PubMed and the Cochrane Controlled Trial Register database (from inception to 10 April 2018) for studies assessing the diagnostic characteristics of the GERDQ, PPI test, baseline impedance, mucosal impedance, DIS, or salivary pepsin and esophageal pH/pH impedance monitoring/endoscopy in patients with GERD. Direct pairwise comparison and a NMA using Bayesian methods under random effects were performed. We also assessed the ranking probability. RESULTS A total of 40 studies were identified. The NMA found no significant difference among the baseline impedance, mucosal impedance, and esophageal pH/pH impedance monitoring and endoscopy in terms of both sensitivity and specificity. It was also demonstrated that the salivary pepsin detected by the Peptest device had comparable specificity to esophageal pH/pH impedance monitoring and endoscopy. Results of ranking probability indicated that esophageal pH/pH impedance monitoring and endoscopy had highest sensitivity and specificity, followed by mucosal impedance and baseline impedance, whereas GERDQ had the lowest sensitivity and PPI test had the lowest specificity. CONCLUSIONS In a systematic review and NMA of studies of patients with GERD, we found that baseline impedance and mucosal impedance have relatively high diagnostic performance, similar to esophageal pH/pH impedance monitoring and endoscopy.
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Affiliation(s)
- Mengyu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | | | - Xuyu Zhou
- Medical Information Research Institute, Sun Yat-sen University, Guangzhou, China
| | - Niandi Tan
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuwen Li
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yinglian Xiao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
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18
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Why differences between New York and New Delhi matter in approach to gastroesophageal reflux disease. Indian J Gastroenterol 2019; 38:371-377. [PMID: 31768894 DOI: 10.1007/s12664-019-00987-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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19
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Nikaki K, Woodland P, Lee C, Ghisa M, Marinelli C, Savarino E, Sifrim D. Esophageal mucosal innervation in functional heartburn: Closer to healthy asymptomatic subjects than to non-erosive reflux disease patients. Neurogastroenterol Motil 2019; 31:e13667. [PMID: 31225933 DOI: 10.1111/nmo.13667] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 05/29/2019] [Accepted: 06/12/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mucosal innervation in non-erosive reflux disease (NERD; pathological esophageal acid exposure, normal macroscopic mucosa) is clearly distinct from that of healthy volunteers (HV) and from patients with esophagitis or Barrett's esophagus: The nerves in NERD are situated much closer to the luminal surface of the mucosa. Patients with functional heartburn (FH) have a similar symptom profile to patients with NERD and indistinguishable macroscopic appearances. However, they have physiological acid exposure and no reflux-symptom association. The aim of our study was to delineate the position of esophageal mucosal nerve fibers in patients with FH and compare it with that in NERD and HV. METHODS Distal esophageal biopsies from patients with FH were immunohistochemically stained for CGRP. CGRP-positive nerve fibers were identified, and their position relative to the lumen was determined. These results were compared to our previously published cohort of HV and NERD. RESULTS Eleven patients were included in the FH group with a mean age of 46 years (range 33-69); 7F:4M. Nine patients had visible nerve fibers. The location of the afferent nerve fibers in the distal esophageal mucosa (median of 22, range 10.4-28) was similar to the HV group (median 25.5) and significantly deeper than the superficial nerves seen in NERD (median 9.5). CONCLUSIONS The mucosal innervation pattern in FH is more alike that of healthy individuals than that of NERD, with afferent nerves lying deep in the mucosa, away from the luminal surface. This supports the theory that heartburn in FH has a distinct nociceptive pathophysiology.
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Affiliation(s)
- Kornilia Nikaki
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, UK.,Gastroenterology Department, Royal London Hospital, London, UK
| | - Philip Woodland
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, UK.,Gastroenterology Department, Royal London Hospital, London, UK
| | - Chung Lee
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, UK
| | - Matteo Ghisa
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Carla Marinelli
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, UK
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20
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Ribolsi M, Giordano A, Guarino MPL, Tullio A, Cicala M. New classifications of gastroesophageal reflux disease: an improvement for patient management? Expert Rev Gastroenterol Hepatol 2019; 13:761-769. [PMID: 31327288 DOI: 10.1080/17474124.2019.1645596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/12/2019] [Indexed: 12/18/2022]
Abstract
Introduction: Gastroesophageal reflux disease (GERD) is a very common and often debilitating disease. In the broad spectrum of GERD phenotypes, three main groups may be traditionally distinguished: 1) patients only affected by esophageal and/or extra-esophageal symptoms; 2) patients with erosive esophagitis and 3) patients with further complications. Areas covered: This review provides an overview on the current classifications of GERD patients, and their impact on their management. Expert opinion: In 2017, the GERD Consensus Working Group focused the attention on patients unresponsive to PPIs. In this scenario, a diagnosis of GERD might be confirmed by evident signs of erosive esophagitis and the finding of pH or multichannel intraluminal impedance-pH tests, such as more than 6%. The 'Lyon Consensus' panel of experts confirmed that positive indices of reflux-symptom association, without other altered parameters, represent reflux hypersensitivity. GERD requires a customized management; it is crucial to assess frequency and severity of symptoms and their response to an optimal course of therapy as well as to explore the endoscopic alterations and consider other diagnoses responsible for persistent symptoms.
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Affiliation(s)
- Mentore Ribolsi
- a Unit of Gastroenterology and Digestive Endoscopy, University Campus Bio Medico , Rome , Italy
| | - Antonio Giordano
- a Unit of Gastroenterology and Digestive Endoscopy, University Campus Bio Medico , Rome , Italy
| | | | - Alessandro Tullio
- a Unit of Gastroenterology and Digestive Endoscopy, University Campus Bio Medico , Rome , Italy
| | - Michele Cicala
- a Unit of Gastroenterology and Digestive Endoscopy, University Campus Bio Medico , Rome , Italy
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21
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Hungin APS, Molloy-Bland M, Scarpignato C. Revisiting Montreal: New Insights into Symptoms and Their Causes, and Implications for the Future of GERD. Am J Gastroenterol 2019; 114:414-421. [PMID: 30323266 PMCID: PMC6434899 DOI: 10.1038/s41395-018-0287-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 08/13/2018] [Indexed: 12/11/2022]
Abstract
The Montreal definition of gastroesophageal reflux disease (GERD) provided a rationale for acid suppression medication without investigation, thus enhancing the management of the substantial symptom burden in these patients. Increased proton-pump inhibitor use has also highlighted their limitations, with one third of "typical" symptoms known to be refractory. Most refractory symptoms are ascribed to reflux hypersensitivity (RH) and functional heartburn (FH). RH may be caused by impaired esophageal mucosal barrier function and sensitization of peripheral esophageal receptors. Central sensitization may also contribute to the perception of non-pathologic reflux in RH, and the perception of physiological stimuli in FH. Importantly, mechanisms underlying GERD, RH, and FH are (in theory) not mutually exclusive, further complicating patient management. Methods used to distinguish GERD from RH and FH are impractical for use in epidemiological studies and pragmatic care and may have limited diagnostic accuracy. This is impeding accurate prevalence estimates and risk factor determination and the identification of new therapies. Direct assessment of mucosal barrier function by measuring impedance is a promising candidate for improved diagnosis. Ultimately though the concept of GERD as a composite, symptom-based entity needs re-evaluation, so that new understandings of upper GI symptoms can direct more precise management.
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Affiliation(s)
- A. Pali S. Hungin
- The Institute of Health and Society, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | - Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Parma, Italy
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22
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Duricek M, Nosakova L, Zatko T, Pecova R, Hyrdel R, Banovcin P. Cough reflex sensitivity does not correlate with the esophageal sensitivity to acid in patients with gastroesophageal reflux disease. Respir Physiol Neurobiol 2018; 257:25-29. [DOI: 10.1016/j.resp.2018.03.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 03/17/2018] [Accepted: 03/21/2018] [Indexed: 01/23/2023]
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23
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Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJPM, Vaezi M, Sifrim D, Fox MR, Vela MF, Tutuian R, Tack J, Bredenoord AJ, Pandolfino J, Roman S. Modern diagnosis of GERD: the Lyon Consensus. Gut 2018; 67:1351-1362. [PMID: 29437910 PMCID: PMC6031267 DOI: 10.1136/gutjnl-2017-314722] [Citation(s) in RCA: 921] [Impact Index Per Article: 131.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 01/11/2018] [Accepted: 01/14/2018] [Indexed: 12/12/2022]
Abstract
Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett's mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET <4% and <40 reflux episodes on pH-impedance monitoring off proton pump inhibitors. Reflux-symptom association on ambulatory reflux monitoring provides supportive evidence for reflux triggered symptoms, and may predict a better treatment outcome when present. When endoscopy and pH or pH-impedance monitoring are inconclusive, adjunctive evidence from biopsy findings (histopathology scores, dilated intercellular spaces), motor evaluation (hypotensive lower oesophageal sphincter, hiatus hernia and oesophageal body hypomotility on high-resolution manometry) and novel impedance metrics (baseline impedance, postreflux swallow-induced peristaltic wave index) can add confidence for a GERD diagnosis; however, diagnosis cannot be based on these findings alone. An assessment of anatomy, motor function, reflux burden and symptomatic phenotype will therefore help direct management. Future GERD management strategies should focus on defining individual patient phenotypes based on the level of refluxate exposure, mechanism of reflux, efficacy of clearance, underlying anatomy of the oesophagogastric junction and psychometrics defining symptomatic presentations.
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Affiliation(s)
- C Prakash Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Peter J Kahrilas
- Division of Gastroenterology, Department of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Frank Zerbib
- Department of Gastroenterology, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
| | - Francois Mion
- Digestive Physiology, Hopital E Herriot, Hospices Civils de Lyon, Université de Lyon, Lyon, France,Digestive Physiology, Université de Lyon, Lyon I University, Lyon, France,Université de Lyon, Inserm U1032, Lyon, France
| | - André J P M Smout
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Michael Vaezi
- Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Daniel Sifrim
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mark R Fox
- Gastroenterology, St. Claraspital, Kleinriehenstrasse 30, Basel, Switzerland,Zürich Neurogastroenterology and Motility Research Group, Clinic for Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland
| | - Marcelo F Vela
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Radu Tutuian
- Division of Gastroenterology, University Clinics for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
| | - Jan Tack
- Department of Gastroenterology, Catholic University of Leuven, Leuven, Belgium
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - John Pandolfino
- Division of Gastroenterology, Department of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Sabine Roman
- Digestive Physiology, Hopital E Herriot, Hospices Civils de Lyon, Université de Lyon, Lyon, France,Digestive Physiology, Université de Lyon, Lyon I University, Lyon, France,Université de Lyon, Inserm U1032, Lyon, France
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24
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Bill J, Rajagopal S, Kushnir V, Gyawali CP. Diagnostic yield in the evaluation of dysphagia: experience at a single tertiary care center. Dis Esophagus 2018; 31:5003024. [PMID: 29800269 DOI: 10.1093/dote/doy013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Evaluation of dysphagia typically starts with esophagogastroduodenoscopy (EGD); further testing is pursued if this is negative. When no mucosal, structural, or motor esophageal disorders are identified with persisting symptoms, functional dysphagia is considered. We evaluated outcomes in patients undergoing EGD for dysphagia, and estimated prevalence of functional dysphagia. The endoscopy database at single tertiary care center was interrogated to identify EGDs performed for an indication of 'dysphagia' over a 12-month period (2008-09). Electronic medical records were reviewed over the next 8 years to assess if an etiology was identified. Data were analyzed to assess the diagnostic yield of endoscopy and subsequent tests in the evaluation of dysphagia. Of 5486 EGDs, 822 (15.0%) were performed for dysphagia in 694 patients (58.4 ± 0.6 year, range: 18-95 year, 55.8% female). Of these, 529 (76.2%) had EGD findings that explained dysphagia; another 22 (3.2%) had findings on histopathology. Of the remainder 143 patients (20.6%) with normal index EGD, 38 (26.6%) patients underwent barium esophagram with 15 (39.5%) having abnormal studies. 19 patients (13.3%) underwent esophageal high resolution manometry with 12 (63.2%) being abnormal, and 7 had a mechanism for dysphagia on alternate testing. A repeat EGD was abnormal in 6 patients, while 45 patients were lost to follow-up. 42 patients had complete resolution of symptoms despite normal endoscopy, of which 30 were treated empirically with a proton pump inhibitor (PPI). Only 16 patients had no findings on evaluation, and had continued dysphagia symptoms, representing true functional dysphagia in 2.3% of all dysphagia patients and 11.2% of patients with normal EGD. Endoscopy remains the test with the highest yield (over 75%) for a diagnosis in patients presenting with dysphagia; secondary tests are useful when endoscopy does not provide a diagnosis. Benign strictures and GERD-related etiologies are leading causes; PPI therapy is useful even when testing is negative. Functional dysphagia is extremely rare, accounting for <2.5% of all dysphagia.
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Affiliation(s)
- J Bill
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - S Rajagopal
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - V Kushnir
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - C P Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
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25
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Blevins CH, Iyer PG, Vela MF, Katzka DA. The Esophageal Epithelial Barrier in Health and Disease. Clin Gastroenterol Hepatol 2018; 16:608-617. [PMID: 28652128 DOI: 10.1016/j.cgh.2017.06.035] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 06/15/2017] [Accepted: 06/19/2017] [Indexed: 02/07/2023]
Abstract
Dysfunction in the esophageal epithelial barrier function is a major source for morbidity. To better understand the pathophysiologic pathways of the diseases associated with barrier dysfunction, including gastroesophageal reflux disease, eosinophilic esophagitis, Barrett's esophagus, and obesity, it is important to understand the esophageal epithelial embryologic development, microscopic anatomy with a special focus on the barrier structure and function, extraepithelial defense mechanisms, and how these change in the diseased state. In recent years, significant progress has been made in elucidating the esophageal barrier structure and function both in vitro and in vivo. This has enhanced the understanding of mechanisms of disease, and may also allow identification of therapeutic targets that can help in the management of these diseases. This review provides a detailed discussion regarding the esophageal epithelial barrier structure and function, the current and historical techniques used to study the barrier, and how it is affected by common esophageal diseases.
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Affiliation(s)
- Christopher H Blevins
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota.
| | - Marcelo F Vela
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona
| | - David A Katzka
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota
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26
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Mermelstein J, Chait Mermelstein A, Chait MM. Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions. Clin Exp Gastroenterol 2018; 11:119-134. [PMID: 29606884 PMCID: PMC5868737 DOI: 10.2147/ceg.s121056] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist.
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Affiliation(s)
- Joseph Mermelstein
- Gasteroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alanna Chait Mermelstein
- Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maxwell M Chait
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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27
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Frazzoni L, Frazzoni M, de Bortoli N, Tolone S, Martinucci I, Fuccio L, Savarino V, Savarino E. Critical appraisal of Rome IV criteria: hypersensitive esophagus does belong to gastroesophageal reflux disease spectrum. Ann Gastroenterol 2018; 31:1-7. [PMID: 29333061 PMCID: PMC5759602 DOI: 10.20524/aog.2017.0199] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 09/17/2017] [Indexed: 12/12/2022] Open
Abstract
The Rome IV Committee introduced a major change in the classification of functional gastrointestinal disorders, proposing a more restrictive definition of gastroesophageal reflux disease (GERD). It was suggested that hypersensitive esophagus (HE) may sit more firmly within the functional realm. It was suggested that GERD diagnosis should be based upon abnormal acid exposure time (AET) only, implying no advantage of impedance-pH over pH monitoring. Symptom association probability (SAP), symptom index (SI) and heartburn relief with proton pump inhibitor (PPI) therapy were regarded as unreliable, whereas a lack of response to PPI was considered as evidence of functional heartburn. These assumptions are contradicted by numerous studies showing the clinical relevance of weakly acidic refluxes and the diagnostic utility of SAP, SI and new impedance parameters, namely the post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI). The PSPW index and MNBI provide significant diagnostic advantage, particularly in patients with normal AET who can be classified as HE when both parameters are abnormal, even though SAP and SI are negative. Visceral pain modulators are recommended by the Rome IV Committee despite scanty evidence of efficacy, but a positive outcome with medical or surgical anti-reflux treatment has been reported by several studies of HE patients. Therefore, we believe that patients with endoscopy-negative heartburn should be investigated by means of impedance-pH monitoring with analysis of PSPW index and MNBI: such an approach provides accurate identification of HE cases, who remain, in our opinion, within the realm of GERD and should be treated accordingly.
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Affiliation(s)
- Leonardo Frazzoni
- Department of Medical and Surgical Sciences, University of Bologna (Leonardo Frazzoni, Lorenzo Fuccio), Italy
| | - Marzio Frazzoni
- Digestive Pathophysiology Unit, Baggiovara Hospital, Modena (Marzio Frazzoni), Italy
| | - Nicola de Bortoli
- Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa (Nicola de Bortoli, Irene Martinucci), Italy
| | - Salvatore Tolone
- General and Bariatric Surgery Unit, Department of Surgery, 2 University of Napoli (Salvatore Tolone), Italy
| | - Irene Martinucci
- Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa (Nicola de Bortoli, Irene Martinucci), Italy
| | - Lorenzo Fuccio
- Department of Medical and Surgical Sciences, University of Bologna (Leonardo Frazzoni, Lorenzo Fuccio), Italy
| | - Vincenzo Savarino
- Gastroenterology Unit, Department of Internal Medicine, University of Genova (Vincenzo Savarino), Italy
| | - Edoardo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova (Edoardo Savarino), Italy
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28
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Savarino E, Bredenoord AJ, Fox M, Pandolfino JE, Roman S, Gyawali CP. Expert consensus document: Advances in the physiological assessment and diagnosis of GERD. Nat Rev Gastroenterol Hepatol 2017; 14:665-676. [PMID: 28951582 DOI: 10.1038/nrgastro.2017.130] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
GERD is a common condition worldwide. Key mechanisms of disease include abnormal oesophagogastric junction structure and function, and impaired oesophageal clearance. A therapeutic trial of acid-suppressive PPI therapy is often the initial management, with endoscopy performed in the setting of alarm symptoms and to exclude other conditions. If symptoms persist and endoscopy does not reveal evidence of GERD, oesophageal function tests are performed, including oesophageal manometry and ambulatory reflux monitoring. However, reflux episodes can be physiological, and some findings on endoscopy and manometry can be encountered in asymptomatic individuals without GERD symptoms. The diagnosis of GERD on the basis of functional oesophageal testing has been previously reported, but no updated expert recommendations on indications and the interpretation of oesophageal function testing in GERD has been made since the Porto consensus over a decade ago. In this Consensus Statement, we aim to describe modern oesophageal physiological tests and their analysis with an emphasis on establishing indications and consensus on interpretation parameters of oesophageal function testing for the evaluation of GERD in clinical practice. This document reflects the collective conclusions of the international GERD working group, incorporating existing data with expert consensus opinion.
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Affiliation(s)
- Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 35128 Padova, Italy
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands
| | - Mark Fox
- Abdominal Center: Gastroenterology, St. Claraspital, Kleinriehenstrasse 30, 4016 Basel, Switzerland
| | - John E Pandolfino
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 St. Clair Street, Chicago, Illinois 60611, USA
| | - Sabine Roman
- Digestive Physiology, Hopital Edouard Herriot - Pavillon L, 5 Place d'Arsonval, 69437 Lyon Cedex 03, Lyon, France
| | - C Prakash Gyawali
- Division of Gastroenterology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA
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29
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Abstract
Functional heartburn (FH) is defined as a functional esophageal disorder characterized by symptoms of chronic heartburn with no apparent correlation to acid or nonacid reflux. In addition, its symptoms persist despite the lack of organic abnormalities or inflammation, esophageal motility disorders, or metabolic disorders. Although conditions presenting with esophageal symptoms without endoscopic abnormalities were previously categorized as nonerosive reflux disease, such conditions are now classified into 3 categories under Rome IV criteria: nonerosive reflux disease, reflux hypersensitivity, and FH. Although many aspects of FH remain unclear, its onset mechanism is considered to be strongly associated with peripheral or central sensitization, given the fact that its symptoms seem to be unrelated to gastroesophageal reflux. In addition, the cause of such hypersensitivity is an interesting topic in itself, and psychological factors, such as stress followed by increasing esophageal permeability are gaining attention as factors that can potentially influence this condition. There is a great unmet clinical need for therapeutic drugs that can be used to treat FH, and the development of novel drugs, diagnostic tests and biomarkers is eagerly awaited.
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30
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Frazzoni M, de Bortoli N, Frazzoni L, Tolone S, Savarino V, Savarino E. Impedance-pH Monitoring for Diagnosis of Reflux Disease: New Perspectives. Dig Dis Sci 2017; 62:1881-1889. [PMID: 28550489 DOI: 10.1007/s10620-017-4625-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 05/19/2017] [Indexed: 12/17/2022]
Abstract
Heartburn is the most specific symptom of gastroesophageal reflux disease (GERD). In clinical practice, heartburn relief by a proton pump inhibitor (PPI) trial does suffice to confirm GERD. However, an objective diagnosis of GERD is required before anti-reflux endoscopic or surgical interventions, independently from PPI response. Thus, since normal findings at upper endoscopy are detected in the majority of patients with heartburn, reflux monitoring is often required. When traditional catheter-based or wireless pH tests are used, reflux episodes are conventionally identified by pH drops below 4.0 units. Combined impedance-pH monitoring has the advantage to provide a comprehensive assessment of both physical and chemical properties of refluxate and the distinction between acid and weakly acidic refluxes, both proven to cause heartburn. Unfortunately, the conventional impedance-pH parameters, namely acid exposure time and number of reflux events, are characterized by suboptimal diagnostic sensitivity, and the reliability of symptom-reflux association indexes remains questionable. Therefore, novel impedance parameters, namely the post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI), have recently been proposed in order to achieve a better diagnostic yield. In fact, they proved to be highly accurate in distinguishing reflux-related from reflux-unrelated heartburn, off- as well as on-PPI therapy. Currently, manual review of impedance-pH tracings is needed because of the modest accuracy of available software tools for automated analysis. PSPW index and MNBI are highly applicable and reproducible, and their calculation requires a few additional minutes during the manual review of impedance-pH tracings. So far, we believe that PSPW index and MNBI are ready for prime time and should become part of the standard analysis of impedance-pH tracings for GERD diagnosis in patients with endoscopy-negative heartburn.
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Affiliation(s)
- Marzio Frazzoni
- Digestive Pathophysiology Unit, Baggiovara Hospital, Viale Giardini 1355, 41100, Modena, Italy.
| | - Nicola de Bortoli
- Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Leonardo Frazzoni
- Digestive Pathophysiology Unit, Baggiovara Hospital, Viale Giardini 1355, 41100, Modena, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Salvatore Tolone
- General and Bariatric Surgery Unit, Department of Surgery, 2nd University of Napoli, Naples, Italy
| | - Vincenzo Savarino
- Gastroenterology Unit, Department of Internal Medicine, University of Genova, Genoa, Italy
| | - Edoardo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
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31
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Ambulatory 24-hour multichannel intraluminal impedance-pH monitoring and high resolution endoscopy distinguish patients with non-erosive reflux disease from those with functional heartburn. PLoS One 2017; 12:e0175263. [PMID: 28384225 PMCID: PMC5383280 DOI: 10.1371/journal.pone.0175263] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 03/23/2017] [Indexed: 12/13/2022] Open
Abstract
AIMS To assess the contribution of 24-h esophageal multichannel intraluminal impedance and pH (MII-pH) monitoring and high resolution endoscopy (HRE) with i-scan imaging in differentiating non erosive reflux disease (NERD) from functional heartburn (FH). METHODS This is a retrospective cohort study of patients with heartburn from the Endoscopy Unit. NERD patients and FH patients were defined by 24-h MII-pH monitoring and white light endoscopy. Minimal mucosal changes were assessed by HRE with i-scan imaging. RESULTS Total of 156 consecutive patients with heartburn but without esophageal mucosal erosions were studied. Forty-eight of these subjects had NERD, with increased acid exposure time (AET) and positive SAP and/or SI. Eighteen had FH with normal AET and negative SAP and SI. When compared to FH patients and healthy controls, NERD patients had significantly increased number of total acid reflux episodes, as well as increased number of weakly acidic reflux episodes (p<0.01). The rate of proximal reflux episodes in NERD patients was higher than that of FH patients and healthy controls (p<0.01). Irregular or blurring of the Z-line (58.3%) and white mucosal turbidity (47.9%) were the most common endoscopic findings of minimal mucosal changes observed in this study. NERD patients had more prevalent minimal changes than FH patients and the controls (87.5%vs. 66.6%vs. 61.9%; p = 0.004) with sensitivity of 87.5%. Histopathological evaluation showed that NERD patients had significantly higher average scores of intercellular spaces dilation (2.82±0.9 vs. 1.2±0.6, p = 0.005) and papillae elongation (2.65±1.0 vs. 1.5±0.8, p = 0.014), but not for basal cell proliferation (1.6±1.3 vs. 1.0±0.9, p = 0.070). The histological scores of the NERD patients were 7.1±1.2, which were higher than those of FH patients (3.4±1.0, p = 0.004). CONCLUSIONS Minimal mucosal changes could be useful markers to support clinical diagnosis of NERD. Combination of 24-h MII-pH monitoring and i-scan high resolution endoscopy can distinguish patients with NERD from those with FH.
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32
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Kawai T, Hirayama Y, Oguchi A, Ishii F, Matushita M, Kitayama N, Morishita S, Hiratsuka N, Ohata K, Konishi H, Kishino M, Nakamura S. Effects of rikkunshito on quality of life in patients with gastroesophageal reflux disease refractory to proton pump inhibitor therapy. J Clin Biochem Nutr 2017. [PMID: 28366995 DOI: 10.3164/jcbn.16.77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6-8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.
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Affiliation(s)
- Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Yoji Hirayama
- Department of General Medicine and Primary Care, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Aiko Oguchi
- Shinjuku NS Building Clinic, 2-4-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0820, Japan
| | - Fumi Ishii
- Shinjuku Mitsui Building Clinic, 2-1-1 Nishishinjuku, Shinjuku-ku, Tokyo 183-0410, Japan
| | - Masanao Matushita
- Department of Internal Medicine, International Catholic Hospital, 2-5-1 Nakaochiai, Shinjuku-ku, Tokyo 161-8521, Japan
| | - Naoya Kitayama
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Shinji Morishita
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Noboru Hiratsuka
- Hiratsuka Gastroenterological Hospital Shinjuku Center Clinic, 1-25-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0690, Japan
| | - Ken Ohata
- Department of Gastroenterology, NTT Medical Center Tokyo, 5-9-22 Higashi-gotanda, Shinagawa-ku, Tokyo 141-8625, Japan
| | - Hiroyuki Konishi
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Maiko Kishino
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Shinichi Nakamura
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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33
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Kawai T, Hirayama Y, Oguchi A, Ishii F, Matushita M, Kitayama N, Morishita S, Hiratsuka N, Ohata K, Konishi H, Kishino M, Nakamura S. Effects of rikkunshito on quality of life in patients with gastroesophageal reflux disease refractory to proton pump inhibitor therapy. J Clin Biochem Nutr 2017; 60:143-145. [PMID: 28366995 PMCID: PMC5370532 DOI: 10.3164/jcbn.16-77] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 09/14/2016] [Indexed: 12/24/2022] Open
Abstract
We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6–8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.
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Affiliation(s)
- Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Yoji Hirayama
- Department of General Medicine and Primary Care, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Aiko Oguchi
- Shinjuku NS Building Clinic, 2-4-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0820, Japan
| | - Fumi Ishii
- Shinjuku Mitsui Building Clinic, 2-1-1 Nishishinjuku, Shinjuku-ku, Tokyo 183-0410, Japan
| | - Masanao Matushita
- Department of Internal Medicine, International Catholic Hospital, 2-5-1 Nakaochiai, Shinjuku-ku, Tokyo 161-8521, Japan
| | - Naoya Kitayama
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Shinji Morishita
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Noboru Hiratsuka
- Hiratsuka Gastroenterological Hospital Shinjuku Center Clinic, 1-25-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0690, Japan
| | - Ken Ohata
- Department of Gastroenterology, NTT Medical Center Tokyo, 5-9-22 Higashi-gotanda, Shinagawa-ku, Tokyo 141-8625, Japan
| | - Hiroyuki Konishi
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Maiko Kishino
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Shinichi Nakamura
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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34
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Dulery C, Lechot A, Roman S, Bastier PL, Stoll D, de Gabory L, Zerbib F. A study with pharyngeal and esophageal 24-hour pH-impedance monitoring in patients with laryngopharyngeal symptoms refractory to proton pump inhibitors. Neurogastroenterol Motil 2017; 29. [PMID: 27424517 DOI: 10.1111/nmo.12909] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/22/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND The role of gastroesophageal reflux in chronic laryngeal symptoms is difficult to establish. The aim of this study was to characterize pharyngeal and esophageal pH-impedance reflux patterns in a group of patients with suspected laryngopharyngeal reflux and to determine predictive factors of response to proton pump inhibitors. METHODS Patients with chronic pharyngolaryngeal symptoms were evaluated with a symptom score questionnaire, laryngoscopy, and 24-hour pharyngeal and esophageal pH-impedance monitoring at baseline and after 8-week treatment with esomeprazole 40 mg b.i.d. Response to treatment was defined by a diminution of more than 50% of the score for the primary symptom. Reflux patterns and baseline impedance values were compared to those obtained in 46 healthy subjects. KEY RESULTS Twenty-four patients were included (17 women, median age 54 years), all previously refractory to antisecretory therapy. Symptom scores were 46 (32-62) and 40 (27-76) off and on therapy, respectively (P=.1). There was no significant difference between patients and controls for pH-impedance reflux parameters and baseline values off and on therapy in distal and proximal esophagus and in the pharynx. Median numbers of pharyngeal reflux were 0 and 0 off and on therapy, respectively. Only two patients were responders to treatment, both with excessive distal reflux but no pharyngeal reflux. Only one patient had abnormal pharyngeal reflux but did not respond to proton pump inhibitors. CONCLUSIONS Patients with suspected laryngopharyngeal reflux refractory to therapy do not exhibit abnormal pharyngeal or esophageal pH-impedance reflux. In these patients, laryngopharyngeal reflux is unlikely.
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Affiliation(s)
- C Dulery
- Gastroenterology Department, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
| | - A Lechot
- ENT Department, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
| | - S Roman
- LabTAU, Inserm U1032, Univ Lyon, Lyon, France.,Digestive Physiology Department, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - P-L Bastier
- ENT Department, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
| | - D Stoll
- ENT Department, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
| | - L de Gabory
- ENT Department, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
| | - F Zerbib
- Gastroenterology Department, Bordeaux University Hospital, Université de Bordeaux, Bordeaux, France
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Patel A, Sayuk GS, Gyawali CP. Prevalence, characteristics, and treatment outcomes of reflux hypersensitivity detected on pH-impedance monitoring. Neurogastroenterol Motil 2016; 28:1382-90. [PMID: 27061427 PMCID: PMC5002267 DOI: 10.1111/nmo.12838] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/17/2016] [Indexed: 01/15/2023]
Abstract
BACKGROUND Positive symptom association probability (SAP) with physiologic esophageal acid exposure time (AET) on pH-impedance monitoring defines reflux hypersensitivity (RH), a correlate of acid sensitivity on pH monitoring. We evaluated prevalence, clinical characteristics, and symptomatic outcomes of RH in a prospective observational cohort with reflux symptoms undergoing pH-impedance monitoring. METHODS Reflux hypersensitivity was diagnosed when SAP was positive with pH- and/or impedance-detected reflux events with physiologic AET. Symptom burden was assessed using dominant symptom intensity (DSI, product of symptom severity and frequency on 5-point Likert scales) and global symptom severity (GSS, global esophageal symptoms on 100-mm visual analog scales) by questionnaire, both at baseline and on prospective follow-up. Clinical characteristics and predictors of symptomatic improvement were assessed with univariate and multivariate analyses. KEY RESULTS Seventy-seven patients (29%) met criteria for RH, of which 53 patients (53.7 ± 1.8 years, 66% F) were contacted after 3.3 ± 0.2 years for follow-up. Reflux hypersensitivity was detected on pH-impedance testing both on and off antisecretory therapy; pH alone missed 51% of RH. About 57% reported ≥50% GSS improvement. Sixteen patients undergoing antireflux surgery (ARS) reported better symptom improvement compared to 37 patients treated medically (GSS change: p = 0.005; DSI change: p = 0.04). Hiatus hernia (p = 0.03) and surgical management (p ≤ 0.04) predicted symptom improvement on univariate analysis, while acid sensitivity was a negative predictor for outcome on both univariate (p = 0.02) and multivariate analyses (p ≤ 0.04). CONCLUSIONS & INFERENCES Reflux hypersensitivity is a mechanism for persistent reflux symptoms in almost one-third of patients undergoing pH-impedance testing. While acid sensitivity predicts suboptimal symptom improvement, antireflux therapy may improve RH in select settings.
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Affiliation(s)
- A Patel
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO, USA
| | - G S Sayuk
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO, USA
| | - C P Gyawali
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO, USA
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Abstract
The gastrointestinal mucosal barrier plays an essential role in the separation of the inside of the body from the outside environment. Tight junctions (TJs) are the most important component for construction of a constitutive barrier of epithelial cells, and they regulate the permeability of the barrier by tightly sealing the cell-cell junctions. TJ proteins are represented by claudins, occludin, junctional adhesion molecules, and scaffold protein zonula occludens. Among these TJ proteins, claudins are the major components of TJs and are responsible for the barrier and the polarity of the epithelial cells. Gastrointestinal diseases including reflux esophagitis, inflammatory bowel disease, functional gastrointestinal disorders, and cancers may be regulated by these molecules, and disruption of their functions leads to chronic inflammatory conditions and chronic or progressive disease. Therefore, regulation of the barrier function of epithelial cells by regulating the expression and localization of TJ proteins is a potential new target for the treatment of these diseases. Treatment strategies for these diseases might thus be largely altered if symptom generation and/or immune dysfunction could be regulated through improvement of mucosal barrier function. Since TJ proteins may also modify tumor infiltration and metastasis, other important goals include finding a good TJ biomarker of cancer progression and patient prognosis, and developing TJ protein-targeted therapies that can modify patient prognosis. This review summarizes current understanding of gastrointestinal barrier function, TJ protein expression, and the mechanisms underlying epithelial barrier dysregulation in gastrointestinal diseases.
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Gastroesophageal reflux disease-related and functional heartburn: pathophysiology and treatment. Curr Opin Gastroenterol 2016; 32:344-52. [PMID: 27206157 DOI: 10.1097/mog.0000000000000282] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Patients who continue to experience heartburn symptoms despite adequate-dose proton pump inhibitor therapy have unmet clinical needs. In this review, we focus on the most recent findings related to the mechanism of heartburn symptom generation, and on the treatment of gastroesophageal reflux disease-related and functional heartburn. RECENT FINDINGS The immunological mechanism in the esophageal mucosa has been addressed as a potential mechanism of the onset of esophageal mucosa damage and the generation of heartburn symptoms. Peripheral or central hypersensitivity in viscera is a potentially unifying pathophysiological concept in functional heartburn. Vonoprazan, a novel and potent first-in-class potassium-competitive acid blocker, is expected to prove useful in the treatment of reflux disease. SUMMARY New findings in the mechanisms of heartburn symptom generation are emerging, including the immunological mediation of esophageal mucosal damage and the development of visceral hypersensitivity in functional heartburn. In the future, we anticipate the emergence of new and specific therapeutic options based on these mechanisms, with less dependence on acid-suppressing agents.
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Kim JH, Kim BJ, Kim SW, Kim SE, Kim YS, Sung HY, Oh TH, Jeong ID, Park MI. [Current issues on gastroesophageal reflux disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2016; 64:127-32. [PMID: 25252860 DOI: 10.4166/kjg.2014.64.3.127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gastroesophageal reflux disease (GERD) is one of the most common problems in gastrointestinal disorders. With the increase in our understanding on the pathophysiology of GERD along with the development of proton pump inhibitors, the diagnostic and therapeutic approaches to GERD have changed dramatically over the past decade. However, GERD still poses a problem to many clinicians since the spectrum of the disease has evolved to encompass more challenging presentations such as refractory GERD and extraesophageal manifestations. This has led to significant confusion regarding the optimal approach to these patients. This article aims to discuss current issues on GERD.
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Affiliation(s)
- Jie-Hyun Kim
- Department of Internal Medicine, Kosin University College of Medicine, Seoul, Korea
| | - Beom Jin Kim
- Chung-Ang University College of Medicine, Seoul, Korea
| | - Sang Wook Kim
- Chonbuk National University Medical School, Jeonju, Korea
| | - Sung Eun Kim
- Kosin University College of Medicine, Busan, Korea
| | - Yeon Soo Kim
- Hallym University College of Medicine, Chuncheon, Korea
| | | | - Tae-Hoon Oh
- Inje University College of Medicine, Seoul, Korea
| | - In Du Jeong
- University of Ulsan College of Medicine, Ulsan, Korea
| | - Moo In Park
- Kosin University College of Medicine, Busan, Korea
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Bile Salts at Low pH Cause Dilation of Intercellular Spaces in In Vitro Stratified Primary Esophageal Cells, Possibly by Modulating Wnt Signaling. J Gastrointest Surg 2016; 20:500-9. [PMID: 26715559 PMCID: PMC7202037 DOI: 10.1007/s11605-015-3062-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 12/14/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND The presence of dilated intercellular spaces in the stratified squamous lining of the esophagus is the pathognomonic feature of reflux esophagitis secondary to gastroesophageal reflux disease (GERD). In addition to stomach acid, bile salts are major constituents of gastroesophageal refluxate. The aim of our study was to determine the effect of bile salts cocktail at different pHs on epithelial junctions in an in vitro transwell model of stratified esophageal squamous epithelium. DISCUSSION Human telomerase reverse transcriptase (hTERT) immortalized primary esophageal EPC1 cells were grown on polyester transwell surfaces in calcium-enriched media. The cells exhibited gradual stratification into an 11-layered squamous epithelium over 7 days, together with epithelial barrier function as indicated by increased transepithelial electrical resistance (TEER). This stratified epithelium demonstrated well-formed tight junctions, adherens junctions, and desmosomes as visualized by immunofluorescence and electron microscopy. When exposed to short pulses of bile salts at pH 5, but not either condition alone, there was loss of stratification and decrease in TEER, concomitant with disruption of adherens junctions, tight junctions, and desmosomes, leading to the appearance of dilated intercellular spaces. At the cellular level, bile salts at pH 5 activated the Wnt pathway (indicated by increased β-catenin Ser552 phosphorylation). CONCLUSION In conclusion, in our in vitro transwell model bile salts at pH 5, but not bile salts or media at pH 5 alone, modulate Wnt signaling, disrupt different junctional complexes, and cause increased permeability of stratified squamous esophageal epithelium. These changes approximate the appearance of dilated intercellular space similar to that found in GERD patients.
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Established and Emerging Treatment Options for Functional Heartburn and Chest Pain. ACTA ACUST UNITED AC 2016; 14:19-27. [DOI: 10.1007/s11938-016-0081-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Herregods TVK, Bredenoord AJ, Smout AJPM. Pathophysiology of gastroesophageal reflux disease: new understanding in a new era. Neurogastroenterol Motil 2015; 27:1202-13. [PMID: 26053301 DOI: 10.1111/nmo.12611] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 05/05/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND The prevalence of gastroesophageal reflux disease (GERD) has increased in the last decades and it is now one of the most common chronic diseases. Throughout time our insight in the pathophysiology of GERD has been characterized by remarkable back and forth swings, often prompted by new investigational techniques. Even today, the pathophysiology of GERD is not fully understood but it is now recognized to be a multifactorial disease. Among the factors that have been shown to be involved in the provocation or increase of reflux, are sliding hiatus hernia, low lower esophageal sphincter pressure, transient lower esophageal sphincter relaxation, the acid pocket, obesity, increased distensibility of the esophagogastric junction, prolonged esophageal clearance, and delayed gastric emptying. Moreover, multiple mechanisms influence the perception of GERD symptoms, such as the acidity of the refluxate, its proximal extent, the presence of gas in the refluxate, duodenogastroesophageal reflux, longitudinal muscle contraction, mucosal integrity, and peripheral and central sensitization. Understanding the pathophysiology of GERD is important for future targets for therapy as proton pump inhibitor-refractory GERD symptoms remain a common problem. PURPOSE In this review we provide an overview of the mechanisms leading to reflux and the factors influencing perception, in the light of historical developments. It is clear that further research remains necessary despite the recent advances in the understanding of the pathophysiology of GERD.
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Affiliation(s)
- T V K Herregods
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - A J Bredenoord
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - A J P M Smout
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
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Kandulski A, Weigt J, Caro C, Jechorek D, Wex T, Malfertheiner P. Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn. Clin Gastroenterol Hepatol 2015; 13:1075-81. [PMID: 25496815 DOI: 10.1016/j.cgh.2014.11.033] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/15/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Mucosal integrity can be assessed in patients with gastroesophageal reflux disease (GERD) by measuring intraluminal baseline impedance (BI). However, it is not clear whether BI is abnormal in patients with functional heartburn (FH), or can be used to distinguish them from patients with GERD. We compared differences in BI between patients with FH vs GERD. METHODS We performed a prospective study of 52 patients (16 men; mean age, 55 y; range, 23-78 y) seen at a tertiary university hospital from February 2009 through December 2012. Thirty-five patients had GERD (19 had nonerosive reflux disease [NERD], 16 had erosive reflux disease [ERD]) and 17 had FH. All patients discontinued proton pump inhibitor therapy and then underwent esophagogastroduodenoscopy and multichannel intraluminal impedance and pH monitoring. BI was assessed at 3, 5, 7, 9, 15, and 17 cm proximal to the lower esophageal sphincter in recumbent patients. Biopsy specimens were taken from 3 cm above the gastroesophageal junction; histology analysis was performed to identify and semiquantitatively score (scale, 0-3) dilated intercellular spaces. RESULTS Baseline impedance in the distal esophagus was significantly lower in patients with NERD or erosive reflux disease (ERD) than FH (P = .0006). At a cut-off value of less than 2100 Ω, BI measurements identified patients with GERD with 78% sensitivity and 71% specificity, with positive and negative predictive values of 75%. Also in the proximal esophagus, reduced levels of BI levels were found only in patients with ERD. There were negative correlations between level of BI and acid exposure time (r = -0.45; P = .0008), number of acidic reflux episodes (r = -0.45; P = .001), and proximal extent (r = -0.40; P = .004). Biopsy specimens from patients with NERD or ERD had significant increases in dilation of intercellular spaces, compared with those from patients with FH; there was an inverse association between dilated intercellular spaces and BI in the distal esophagus (r = -0.28; P = .06). CONCLUSIONS Measurement of BI in the lower esophagus can differentiate patients with ERD or NERD from patients with FH (78% sensitivity and 71% specificity), and therefore should be considered as a diagnostic tool for patients with proton pump inhibitor-refractory reflux. Low levels of BI are associated with increased exposure to acid and dilation of intercellular spaces, indicating that BI is a marker of mucosal integrity.
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Affiliation(s)
- Arne Kandulski
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
| | - Jochen Weigt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Carlos Caro
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Doerthe Jechorek
- Institute of Pathology, Otto-von-Guericke University, Magdeburg, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany; Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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Triantos C, Koukias N, Karamanolis G, Thomopoulos K. Changes in the esophageal mucosa of patients with non erosive reflux disease: How far have we gone? World J Gastroenterol 2015; 21:5762-5767. [PMID: 26019440 PMCID: PMC4438010 DOI: 10.3748/wjg.v21.i19.5762] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 03/13/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
The normal esophageal mucosa creates a protective epithelial barrier that constrains the acidic reflux in the esophageal lumen. Microscopic findings and functional studies indicate that this barrier might be impaired in patients with non erosive reflux disease (NERD) but not in patients with functional heartburn (FH). Whereas endoscopy and pH monitoring are the most important diagnostic tools in the diagnosis of NERD, recent studies suggest that esophageal biopsies might have a complementary role. Particularly in the differential diagnosis between NERD and FH, the application of histological severity scores showed very promising results. Further evaluation of the scores could lead to routine application of histology in specific NERD populations.
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Penagini R, Sweis R, Mauro A, Domingues G, Vales A, Sifrim D. Inconsistency in the Diagnosis of Functional Heartburn: Usefulness of Prolonged Wireless pH Monitoring in Patients With Proton Pump Inhibitor Refractory Gastroesophageal Reflux Disease. J Neurogastroenterol Motil 2015; 21:265-72. [PMID: 25843078 PMCID: PMC4398246 DOI: 10.5056/jnm14075] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 12/01/2014] [Accepted: 12/07/2014] [Indexed: 12/13/2022] Open
Abstract
Background/Aims The diagnosis of functional heartburn is important for management, however it stands on fragile pH monitoring variables, ie, acid exposure time varies from day to day and symptoms are often few or absent. Aim of this study was to investigate consistency of the diagnosis of functional heartburn in subsequent days using prolonged wireless pH monitoring and its impact on patients’ outcome. Methods Fifty proton pump inhibitotor refractory patients (11 male, 48 years [range, 38–57 years]) with a diagnosis of functional heart-burn according to Rome III in the first 24 hours of wireless pH monitoring were reviewed. pH variables were analysed in the following 24-hour periods to determine if tracings were indicative of diagnosis of non-erosive reflux disease (either acid exposure time > 5% or normal acid exposure time and symptom index ≥ 50%). Outcome was assessed by review of hospital files and/or telephone interview. Results Fifteen out of 50 patients had a pathological acid exposure time after the first day of monitoring (10 in the second day and 5 in subsequent days), which changed their diagnosis from functional heartburn to non-erosive reflux disease. Fifty-four percent of non-erosive reflux disease vs 11% of functional heartburn patients (P < 0.003) increased the dose of proton pump inhibitors or underwent fundoplication after the pH test. Outcome was positive in 77% of non-erosive reflux disease vs 43% of functional heartburn patients (P < 0.05). Conclusions One-third of patients classified as functional heartburn at 24-hour pH-monitoring can be re-classified as non-erosive reflux disease after a more prolonged pH recording period. This observation has a positive impact on patients’ management.
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Affiliation(s)
- Roberto Penagini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy
| | - Rami Sweis
- University College London Hospital, London, United Kingdom
| | - Aurelio Mauro
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy
| | | | - Andres Vales
- Esophageal Lab, Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Daniel Sifrim
- Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Restoring mucosal integrity: "closing the gap" in the treatment of esophageal eosinophilia. Clin Gastroenterol Hepatol 2014; 12:1830-1. [PMID: 25086196 DOI: 10.1016/j.cgh.2014.07.046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 07/25/2014] [Accepted: 07/28/2014] [Indexed: 02/07/2023]
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Frazzoni M, Bertani H, Manta R, Mirante VG, Frazzoni L, Conigliaro R, Melotti G. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis 2014; 46:596-602. [PMID: 24709005 DOI: 10.1016/j.dld.2014.03.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 02/11/2014] [Accepted: 03/11/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The pathophysiological mechanisms underlying proton pump inhibitor-refractory reflux oesophagitis has been scarcely studied. AIMS To assess impedance-pH parameters relevant to the pathogenesis of refractory reflux oesophagitis. METHODS Cases referred for heartburn/regurgitation refractory to high-dosage proton pump inhibitors between January 2008 and December 2012 were reviewed and subdivided into refractory oesophagitis (29 patients, 72% males, median age 50 years), healed oesophagitis (18 patients, 67% males, median age 54 years), and non-erosive reflux disease (49 patients, 53% males, median age 42 years). On-therapy impedance-pH tracings were blindly re-analysed by one observer to assess gastric and oesophageal acid exposure time and chemical clearance as expressed by the post-reflux swallow-induced peristaltic wave index. RESULTS The median gastric and oesophageal acid exposure time did not differ among the three groups (35%, 34%, 41% and 1.2%, 0.7%, 0.8%, respectively; P>0.05 for all comparisons). A normal oesophageal acid exposure time was found in two thirds of patients with refractory oesophagitis. The post-reflux swallow-induced peristaltic wave index was significantly lower in refractory oesophagitis (16%) than in healed oesophagitis (30%) and non-erosive reflux disease (29%) (P=0.003). CONCLUSIONS Refractory reflux oesophagitis is characterized by impairment of chemical clearance. Adequate acid suppression is found in the majority of patients who would likely not benefit from further proton pump inhibitor dose escalation.
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Affiliation(s)
- Marzio Frazzoni
- Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy.
| | - Helga Bertani
- Digestive Endoscopy Unit, Baggiovara Hospital, Modena, Italy
| | - Raffaele Manta
- Digestive Endoscopy Unit, Baggiovara Hospital, Modena, Italy
| | | | - Leonardo Frazzoni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rita Conigliaro
- Digestive Endoscopy Unit, Baggiovara Hospital, Modena, Italy
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Woodland P, Sifrim D. Oesophageal mucosal barrier: a key factor in the pathophysiology of non-erosive reflux disease (NERD) and a potential target for treatment. Gut 2014; 63:705-6. [PMID: 23831781 DOI: 10.1136/gutjnl-2013-305101] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Philip Woodland
- Center for Digestive Diseases, Wingate Institute for Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, , London, UK
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Martinucci I, de Bortoli N, Savarino E, Piaggi P, Bellini M, Antonelli A, Savarino V, Frazzoni M, Marchi S. Esophageal baseline impedance levels in patients with pathophysiological characteristics of functional heartburn. Neurogastroenterol Motil 2014; 26:546-55. [PMID: 24433456 DOI: 10.1111/nmo.12299] [Citation(s) in RCA: 182] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 12/06/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recently, it has been suggested that low esophageal basal impedance may reflect impaired mucosal integrity and increased acid sensitivity. We aimed to compare baseline impedance levels in patients with heartburn and pathophysiological characteristics related to functional heartburn (FH) divided into two groups on the basis of symptom relief after proton pump inhibitors (PPIs). METHODS Patients with heartburn and negative endoscopy were treated with esomeprazole or pantoprazole 40 mg daily for 8 weeks. According to MII-pH (off therapy) analysis, patients with normal acid exposure time (AET), normal reflux number, and lack of association between symptoms and refluxes were selected; of whom 30 patients with a symptom relief higher than 50% after PPIs composed Group A, and 30 patients, matched for sex and age, without symptom relief composed Group B. A group of 20 healthy volunteers (HVs) was enrolled. For each patient and HV, we evaluated the baseline impedance levels at channel 3, during the overnight rest, at three different times. KEY RESULTS Group A (vs Group B) showed an increase in the following parameters: mean AET (1.4 ± 0.8% vs 0.5 ± 0.6%), mean reflux number (30.4 ± 8.7 vs 24 ± 6.9), proximal reflux number (11.1 ± 5.2 vs 8.2 ± 3.6), acid reflux number (17.9 ± 6.1 vs 10.7 ± 6.9). Baseline impedance levels were lower in Group A than in Group B and in HVs (p < 0.001). CONCLUSIONS & INFERENCES Evaluating baseline impedance levels in patients with heartburn and normal AET could achieve a better understanding of pathophysiology in reflux disease patients, and could improve the distinction between FH and hypersensitive esophagus.
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Affiliation(s)
- I Martinucci
- Division of Gastroenterology, University of Pisa, Pisa, Italy
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Abstract
The mainstay of pharmacological therapy for GERD is gastric acid suppression with proton pump inhibitors (PPIs), which are superior to histamine-2 receptor antagonists for healing erosive esophagitis and achieving symptomatic relief. However, up to one-third of patients may not respond to PPI therapy, creating the need for alternative treatments. Potential approaches include transient lower esophageal sphincter relaxation inhibitors, augmentation esophageal defense mechanisms by improving esophageal clearance or enhancing epithelial repair, and modulation of sensory pathways responsible for GERD symptoms. This review discusses the effectiveness of acid suppression and the data on alternative pharmacological approaches for the treatment of GERD.
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Affiliation(s)
- Marcelo F Vela
- Division of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, 2002 Holcombe Boulevard, Houston, TX 77030, USA.
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Cicala M, Emerenziani S, Guarino MPL, Ribolsi M. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. World J Gastroenterol 2013; 19:6529-6535. [PMID: 24151377 PMCID: PMC3801364 DOI: 10.3748/wjg.v19.i39.6529] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 07/31/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023] Open
Abstract
Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.
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