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Wu B, Ciren Y, Peng S, Wu Z, Zhang Y, Liu Y, Yu X, Shen L. QX-314 inhibits acid-induced esophageal hypersensitivity by regulating TRPV1/NaV1.8 receptor pathway. Int Immunopharmacol 2025; 157:114767. [PMID: 40334629 DOI: 10.1016/j.intimp.2025.114767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 04/12/2025] [Accepted: 04/27/2025] [Indexed: 05/09/2025]
Abstract
Gastroesophageal reflux disease (GERD) is characterized by the reflux of stomach contents, leading to discomfort and potential complications. The intractable discomfort may be related to esophageal hypersensitivity. TRPV1 plays an important role in acid -induced esophageal hypersensitivity, and QX-314 can produce sensory-selective blocked by TRPV1 channels. The present study aims to investigate the role of QX-314 in inhibiting esophageal sensory conduction by constructing GERD guinea pig model. GERD guinea pig model was evaluated by the expression of inflammatory markers and the inflammation scores in the esophagus. The co-localization of TRPV1 and NaV1.8 in the esophagus, nodose ganglion, and jugular ganglion was examined using immunofluorescence, while their expression levels were quantified through Western Blot and RT-qPCR. Inflammatory infiltration was observed in acid-induced guinea pig esophagitis, and the expression levels of inflammatory factors (IL-1β, IL-6, and TNF-α) decreased after QX-314 intervention, while the anti-inflammatory factor (IL-10) increased. Furthermore, the expression and co-localization of TRPV1 and NaV1.8 in the esophagus and jugular ganglion were markedly up-regulated in the GERD group compared to the control group. Compared to GERD group, QX-314 suppressed the expression of TRPV1 and NaV1.8. No substantial alterations were observed in the nodose ganglion. Our results showed that QX-314 can block NaV1.8 channels and consequently exert an inhibiting effect of esophageal sensory conduction by entering cells of jugular ganglion through TRPV1, and then reduce acid-induced esophageal hypersensitivity. Moreover, QX-314 is effective only in the context of acid exposure in the esophagus, enabling the selective inhibition of esophageal hypersensitivity.
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Affiliation(s)
- Baixin Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yuzhen Ciren
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Shuai Peng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zunan Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yuling Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yashi Liu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoyun Yu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Lei Shen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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Ribolsi M, Marchetti L, Olmi LM, Cicala M, Savarino E. Esophageal chest pain resembles heartburn in reflux metrics and response to proton pump inhibitor therapy. Neurogastroenterol Motil 2025; 37:e14953. [PMID: 39485991 DOI: 10.1111/nmo.14953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/14/2024] [Accepted: 10/19/2024] [Indexed: 11/03/2024]
Abstract
BACKGROUND Gastro-esophageal reflux disease (GERD) is the most common cause for noncardiac chest pain (NCCP), with an estimated prevalence rate ranging between 30% and 60%. Heartburn and NCCP may share common mechanisms. AIMS/METHODS To assess whether particular patterns of impedance-pH variables characterize patients with dominant heartburn, regurgitation, or NCCP and their ability to predict proton pump inhibitor (PPI) response for each symptom, GERD patients, evaluated with high-resolution manometry (HRM) and impedance-pH, were included. RESULTS In total, 109 NCCP, 68 heartburn, and 64 regurgitation patients were included. Pathological reflux episodes were observed in 28%, 19%, and 56% (p < 0.001). Pathological mean nocturnal baseline impedance (MNBI) values were observed in 55%, 53%, and 34% (p < 0.05). Hypomotility was more frequent in NCCP compared to heartburn patients (p < 0.05). When comparing NCCP with heartburn, hypomotility was associated with NCCP perception (OR: 2.34, 95% CI: 1.23-4.43; p < 0.01). When comparing NCCP with regurgitation, >80 refluxes and type 2/3 esophagogastric junction (EGJ) were associated with regurgitation perception (OR: 0.31, 95% CI: 0.16-0.59; p < 0.001, and OR: 0.5, 95% CI: 0.27-0.93; p < 0.05), while pathological MNBI was associated with NCCP perception (OR: 2.34, 95% CI: 1.23-4.43; p < 0.01). 45.5% NCCP patients, 45.6% with heartburn, and 36% with regurgitation responded to PPIs (p < 0.05). At multivariate analysis, pathological MNBI or PSPW index were associated with PPI responsiveness in patients with NCCP or heartburn, while in patients with regurgitation, pathological MNBI was associated with PPI responsiveness and a reflux number >80 to PPI refractoriness. CONCLUSIONS We highlight the usefulness of an accurate clinical and functional evaluation of GERD patients, allowing to discriminate particular characteristics in patients with dominant heartburn, NCCP, or regurgitation, which may benefit of distinct therapeutic strategies.
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Affiliation(s)
- Mentore Ribolsi
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Lorenzo Marchetti
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Lucrezia Maria Olmi
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Michele Cicala
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
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Han X, Zhang Y, Lee A, Li Z, Gao J, Wu X, Zhao J, Wang H, Chen D, Zou D, Owyang C. Upregulation of acid sensing ion channels is associated with esophageal hypersensitivity in GERD. FASEB J 2021; 36:e22083. [PMID: 34918385 PMCID: PMC8715981 DOI: 10.1096/fj.202100606r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 11/03/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022]
Abstract
Proton pump inhibitors (PPIs) are the mainstay of therapy for gastroesophageal reflux disease (GERD) but up to 60% of patients have inadequate response to therapy. Acid sensing ion channels (ASICs) play important roles in nociception. This study aimed to investigate whether the increased expression of ASICs results in neuronal hyperexcitability in GERD. Esophageal biopsies were taken from GERD patients and healthy subjects to compare expression of ASIC1 and 3. Next, gene and protein expression of ASIC1 and 3 from esophageal mucosa and dorsal root ganglia (DRG) neurons were measured by qPCR, Western‐blot and immunofluorescence in rodent models of reflux esophagitis (RE), non‐erosive reflux disease (NERD), and sham operated groups. Excitability of DRG neurons in the GERD and sham groups were also tested by whole‐cell patch‐clamp recordings. We demonstrated that ASIC1 and 3 expression were significantly increased in patients with RE compared with healthy controls. This correlated positively with symptom severity of heartburn and regurgitation (p < .001). Next, ASIC1 and 3 gene and protein expression in rodent models of RE and NERD were similarly increased in esophageal mucosa as well as T3–T5 DRG neurons compared with sham operation. DRG neurons from RE animals showed hyperexcitability compared with sham group. However, intrathecal injection of ASIC specific inhibitors, PcTx1 and APTEx‐2, as well as silencing ASIC1 and 3 genes with specific siRNAs prevented visceral hypersensitivity. Overall, upregulation of ASIC1 and 3 may lead to visceral hypersensitivity in RE and NERD and may be a potential therapeutic target for PPI non‐responsive patients.
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Affiliation(s)
- Xu Han
- Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yawen Zhang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Allen Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Zhaoshen Li
- Division of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jun Gao
- Division of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xiaoyin Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jiulong Zhao
- Division of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hui Wang
- Division of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Di Chen
- Division of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chung Owyang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Oldfield EC, Parekh PJ, Johnson DA. Diagnosis and Treatment of Esophageal Chest Pain. THE ESOPHAGUS 2021:18-37. [DOI: 10.1002/9781119599692.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zachariah RA, Goo T, Lee RH. Mechanism and Pathophysiology of Gastroesophageal Reflux Disease. Gastrointest Endosc Clin N Am 2020; 30:209-226. [PMID: 32146942 DOI: 10.1016/j.giec.2019.12.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Gastroesophageal reflux (GER) describes a process in which gastric contents travel retrograde into the esophagus. GER can be either a physiologic phenomenon that occurs in asymptomatic individuals or can potentially cause symptoms. When the latter occurs, this represents GER disease (GERD). The process by which GER transforms into GERD begins at the esophagogastric junction. Impaired clearance of the refluxate also contributes to GERD. Reflux causes degradation of esophageal mucosal defense. The refluxate triggers sensory afferents leading to symptom generation.
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Affiliation(s)
- Robin A Zachariah
- H.H. Chao Comprehensive Digestive Disease Center, 333 City Boulevard West, Suite 400, Room 459, Orange, CA 92868, USA
| | - Tyralee Goo
- Tibor Rubin Veterans' Affairs Medical Center, 5901 E. Seventh Street, Long Beach, CA 90822, USA
| | - Robert H Lee
- H.H. Chao Comprehensive Digestive Disease Center, 333 City Boulevard West, Suite 400, Room 459, Orange, CA 92868, USA; Tibor Rubin Veterans' Affairs Medical Center, 5901 E. Seventh Street, Long Beach, CA 90822, USA.
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6
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Abstract
Non-cardiac chest pain (NCCP) is defined as recurring, angina-like, chest pain of non-cardiac origin. Studies have estimated that gastroesophageal reflux disease (GERD) is the most common contributing factor for NCCP. In patients with non-GERD related NCCP, esophageal motility disorders, and functional chest pain of presumed esophageal origin are the main underlying mechanisms for symptoms. Epidemiologic studies show a high prevalence of panic disorder, anxiety and major depression in NCCP patients. The diagnostic esophageal workup starts only after that cardiac and pulmonary diseases have been ruled out. NCCP patients with typical reflux symptoms are more likely to have GERD-related NCCP than those without typical reflux symptoms. High-dose proton pump inhibitor trial (PPI test) can be used to confirm the diagnosis of GERD-related NCCP. Negative upper endoscopy is quite common. For patients unresponsive to antireflux treatment and with negative endoscopy, impedance-pH monitoring should be done. Treatment of patients with non-GERD-related NCCP has focused on esophageal (hypercontractile or spastic) motility disorders and esophageal visceral hypersensitivity. In the first case, several trials using calcium channel blockers, nitrates, anticholinergics, or botulinum toxin injection and recent trials with endoscopic myotomy have been conducted. In case of visceral hypersensitivity, studies found that the amelioration, when compared to placebo, was significant with venlafaxine, sertraline, and imipramine. In this context, also cognitive behavioral therapy has been proposed.
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Affiliation(s)
- Marilena Durazzo
- Department of Medical Sciences, University of Turin, Turin, Italy -
| | | | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza di Torino, Turin, Italy
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7
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Gregersen H, Lo KM. What Is the Future of Impedance Planimetry in Gastroenterology? J Neurogastroenterol Motil 2018; 24:166-181. [PMID: 29605974 PMCID: PMC5885717 DOI: 10.5056/jnm18013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/09/2018] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal (GI) tract is efficient in transporting ingested material to the site of delivery in healthy subjects. A fine balance exists between peristaltic forces, the mixing and delivery of the contents, and sensory signaling. This fine balance is easily disturbed by diseases. It is mandatory to understand the pathophysiology to enhance our understanding of GI disorders. The inaccessibility and complex nervous innervation, geometry and mechanical function of the GI tract make mechanosensory evaluation difficult. Impedance planimetry is a distension technology that assesses luminal geometry, mechanical properties including muscle dynamics, and processing of nociceptive signals from the GI tract. Since standardized models do not exist for GI muscle function in vivo, models, concepts, and terminology must be borrowed from other medical fields such as cardiac mechanophysiology. The review highlights the impedance planimetric technology, muscle dynamics assessment, and 3 applied technologies of impedance planimetry. These technologies are the multimodal probes that assesses sensory function, the functional luminal imaging probe that dynamically measures the geometry of the lumen it distends, and Fecobionics that is a simulated feces providing high-resolution measurements during defecation. The advanced muscle analysis and 3 applied technologies can enhance the quality of future interdisciplinary research for gaining more knowledge about mechanical function, sensory-motor disorders, and symptoms. This is a step in the direction of individualized treatment for GI disorders based on diagnostic subtyping. There seems to be no better alternatives to impedance planimetry, but only the functional luminal imaging probe is currently commercially available. Wider use depends on commercialization of the multimodal probe and Fecobionics.
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Affiliation(s)
- Hans Gregersen
- GIOME, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong.,California Medical Innovations Institute, San Diego, California, USA
| | - Kar Man Lo
- GIOME Doublecove, Wu Kai Sha, New Territories, Hong Kong
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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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9
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Ribolsi M, Balestrieri P, Biasutto D, Emerenziani S, Cicala M. Role of Mixed Reflux and Hypomotility with Delayed Reflux Clearance in Patients with Non-cardiac Chest Pain. J Neurogastroenterol Motil 2016; 22:606-612. [PMID: 27095707 PMCID: PMC5056569 DOI: 10.5056/jnm15182] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 02/06/2016] [Accepted: 03/05/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Gastroesophageal reflux disease (GERD) is the most common cause of non-cardiac chest pain (NCCP). Currently available data reveal a weak relationship between NCCP and dysmotility. Moreover, it is unclear why some refluxes are perceived as heartburn and others as NCCP. We aimed to evaluate the role of the reflux pattern and the esophageal motility in patients with NCCP. METHODS Forty-eight patients with NCCP (Group 1) and 50 only typical GERD symptoms (Group 2) were included and underwent high-resolution manometry (HRM) and multichannel intraluminal impedance-pH monitoring. RESULTS Impaired peristalsis was found in 60% of patients with NCCP and in 24% of patients with typical symptoms (P < 0.05). In patients belonging to Group 1, the majority of reflux episodes associated with chest pain were acid and mixed. The proportion of mixed refluxes was higher than that in Group 2. In Group 1, the reflux clearing time at 5, 9, and 15 cm, measured in reflux episodes associated to NCCP was longer than in reflux episodes associated to typical symptoms (mean ± 95% CI: 27.2 ± 5.6, 23.3 ± 4.4, and 14.6 ± 2.3 seconds vs 18.3 ± 3.5, 13.3 ± 2.2, and 11.1 ± 1.8 seconds; P < 0.01). CONCLUSIONS The presence of gas in the refluxate seems to be associated with NCCP. The impaired motility observed in NCCP patients may play a relevant role in delaying reflux clearing, hence increasing the time of contact between refluxate and esophageal mucosa.
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Affiliation(s)
- Mentore Ribolsi
- Digestive Disease Unit, Campus Bio Medico University, Rome,
Italy
| | | | - Dario Biasutto
- Digestive Disease Unit, Campus Bio Medico University, Rome,
Italy
| | - Sara Emerenziani
- Digestive Disease Unit, Campus Bio Medico University, Rome,
Italy
| | - Michele Cicala
- Digestive Disease Unit, Campus Bio Medico University, Rome,
Italy
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10
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Min YW, Rhee PL. Esophageal hypersensitivity in noncardiac chest pain. Ann N Y Acad Sci 2016; 1380:27-32. [PMID: 27496289 DOI: 10.1111/nyas.13182] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/13/2016] [Accepted: 06/20/2016] [Indexed: 01/04/2025]
Abstract
Noncardiac chest pain (NCCP) is an often-encountered clinical problem. Although many patients suffer from persistent or recurrent chest pain, treatment remains a challenge owing to its various possible etiologies. Gastroesophageal reflux disease (GERD) is the most common cause of NCCP. In GERD-related NCCP, proton pump inhibitor treatment appears to be effective. However, the pathophysiology remains to be fully elucidated in NCCP patients without GERD. Treatment for non-GERD-related NCCP has been aimed at esophageal motility disorders and visceral hypersensitivity. As there is growing evidence that esophageal visceral hypersensitivity plays a role in NCCP, pain modulators have become the mainstay of therapy in patients with non-GERD-related NCCP. However, there is an unmet need for the treatment of esophageal hypersensitivity in NCCP due to modest evidence for the benefit of pain modulators, including antidepressants, in non-GERD-related NCCP. Recent studies have demonstrated that esophageal mast cell infiltration and impaired mucosal integrity are related to visceral hypersensitivity in patients with NCCP. Thus, esophageal mast cell stabilization and restoration of esophageal mucosal integrity could be considered potential therapeutic targets in selected NCCP patients with hypersensitivity. However, further observations are necessary to shed light on esophageal hypersensitivity in NCCP.
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Affiliation(s)
- Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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11
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Farmer AD, Franchina M, Gregersen H, Penagini R, Shaker A, Soffer E. Provocative testing of the esophagus and its future. Ann N Y Acad Sci 2016; 1380:33-47. [DOI: 10.1111/nyas.13109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 04/21/2016] [Accepted: 04/25/2016] [Indexed: 12/25/2022]
Affiliation(s)
- Adam D. Farmer
- Centre for Digestive Diseases, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine & Dentistry; Queen Mary University of London; London United Kingdom
- Department of Gastroenterology; University Hospitals of North Midlands; Stoke on Trent Staffordshire United Kingdom
| | - Marianna Franchina
- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi of Milan and Gastroenterology and Endoscopy Unit; Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico; Milan Italy
| | - Hans Gregersen
- GIOME, College of Bioengineering; Chongqing University; Chongqing China
- Department of Surgery; Prince of Wales Hospital; Shatin Hong Kong SAR
| | - Roberto Penagini
- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi of Milan and Gastroenterology and Endoscopy Unit; Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico; Milan Italy
| | - Anisa Shaker
- Department of Medicine; University of Southern California; Los Angeles California
| | - Edy Soffer
- Department of Medicine; University of Southern California; Los Angeles California
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Gesualdo M, Scicchitano P, Carbonara S, Ricci G, Principi M, Ierardi E, Di Leo A, Cortese F, Ciccone MM. The association between cardiac and gastrointestinal disorders: causal or casual link? J Cardiovasc Med (Hagerstown) 2016; 17:330-338. [PMID: 26702598 DOI: 10.2459/jcm.0000000000000351] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases are the leading cause of death worldwide: among them, coronary artery disease and arrhythmias represent the most frequent pathological conditions. Similarly, the gastrointestinal disorders, that is, gastroesophageal reflux and inflammatory bowel diseases, have a high incidence in the general population. Several pieces of evidence have documented a link between cardiac and gastrointestinal disorders as they often share similar risk factors and symptoms. Furthermore, both can simultaneously occur in the same patient, thus creating problems in the correct clinical diagnosis. It is well known that gastrointestinal disorders may present with chest pain and mimic angina pectoris. In contrast, they can also unmask heart disease, such as in the case of the angina-linked ischemia. The aim of this review was to elucidate the mechanisms underlying the relationship between cardiac and gastrointestinal diseases to better understand the causal or casual character of such a linkage.
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Affiliation(s)
- Michele Gesualdo
- aCardiovascular Diseases Section bDivision of Gastroenterology, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy
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14
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Emerenziani S, Ribolsi M, Guarino MPL, Balestrieri P, Altomare A, Rescio MP, Cicala M. Acid reflux episodes sensitize the esophagus to perception of weakly acidic and mixed reflux in non-erosive reflux disease patients. Neurogastroenterol Motil 2014; 26:108-114. [PMID: 24118616 DOI: 10.1111/nmo.12239] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 08/29/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Non-erosive reflux disease (NERD) patients are more sensitive than erosive esophagitis patients to weakly acidic reflux and to the presence of gas in the refluxate. Intra-esophageal acid perfusion sensitizes esophageal receptors to mechanical and chemical stimuli. METHODS To establish whether acid sensitization plays a role in the perception of weakly acidic and mixed reflux episodes, 29 NERD patients, responders and 14 non-responders to proton pump inhibitors (PPIs), underwent pH-impedance monitoring. Non-responders repeated the study while on PPIs. To assess the effect of acid exposure on symptom perception, the time period with pH below 4 was measured in 15- and 30-minute time-windows preceding the onset of each reflux episode. KEY RESULTS Considering weakly acidic and mixed refluxes, both in responder and non-responder patients (off PPIs), the symptomatic refluxes were preceded by a significantly higher cumulative acid exposure than the asymptomatic refluxes. In all patients, following acid reflux, the percentage of symptomatic weakly acidic reflux episodes was significantly higher than that of asymptomatic refluxes. Non-responder patients, off-treatment, were characterized by a lower proportion of weakly acidic reflux and mixed reflux episodes. In the non-responder patients on PPI, only mixed and weakly symptomatic reflux episodes were preceded by a higher cumulative acid exposure. CONCLUSIONS & INFERENCES In NERD patients, spontaneous acid reflux enhances subsequent reflux perception, regardless of acidity or liquid/mixed composition of episodes; in non-responder patients on PPIs, only the perception of mixed and weakly acidic reflux episodes seems to be mediated by a preceding acid exposure.
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Affiliation(s)
- S Emerenziani
- Unit of Digestive Disease, Campus Bio Medico University, Roma, Italy
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16
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Altomare A, Luca Guarino Sara Emerenziani MP, Cicala M, Drewes AM, Krarup AL, Brock C, Lottrup C, Frøkjaer JB, Souza RF, Nardone G, Compare D. Gastrointestinal sensitivity and gastroesophageal reflux disease. Ann N Y Acad Sci 2013; 1300:80-95. [PMID: 24117636 DOI: 10.1111/nyas.12236] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This paper reports on gastrointestinal sensitivity, including on the role of refluxate volume on the perception of reflux symptoms; experimental pain models that mimic mechanisms and symptoms of pain associated with esophageal diseases; the potential role of the acid receptor TRPV1 in the genesis of gastroesophageal reflux disease (GERD) symptoms; and roles for ATP and the purine and pyrimidine receptor subfamilies P1, P2X, and P2Y in the pathogenesis of GERD symptoms.
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Affiliation(s)
- Annamaria Altomare
- Department of Digestive Disease, Campus Bio-medico University, Rome, Italy
| | | | - Michele Cicala
- Department of Digestive Disease, Campus Bio-medico University, Rome, Italy
| | - Asbjørn Mohr Drewes
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Anne Lund Krarup
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Christian Lottrup
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Rhonda F Souza
- Departments of Medicine, University of Texas Southwestern Medical Center and the VA North Texas Health Care System, Dallas, Texas
| | - Gerardo Nardone
- Department of Clinical and Experimental Medicine, Gastroenterology Unit, University "Federico II,", Naples, Italy
| | - Debora Compare
- Department of Clinical and Experimental Medicine, Gastroenterology Unit, University "Federico II,", Naples, Italy
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Effect of age and correlation between esophageal visceral chemosensitivity and mechanosensitivity in healthy Japanese subjects. J Gastroenterol 2013; 48:360-5. [PMID: 23001250 DOI: 10.1007/s00535-012-0665-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 08/12/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to examine the impact of age on esophageal sensation, and to determine whether esophageal mechanosensitivity and chemosensitivity are correlated in healthy Japanese subjects. METHODS To evaluate chemosensitivity, a catheter was inserted and placed 10 cm above the upper border of the lower esophageal sphincter (LES), which was determined with an esophageal manometric catheter. After saline had been infused into the esophagus at a rate of 10 mL/min for 2 min, 0.1 N hydrochloric acid, instead of saline-without the subjects' knowledge-was infused for 10 min at the same rate. The acid perfusion sensitivity score (APSS) was assessed. To evaluate mechanosensitivity, a barostat test was performed, with a balloon being placed 10 cm above the upper border of the LES. The initial perception threshold (IPT), pain threshold (PT), and maximal pain were quantified. RESULTS The APSS was significantly inversely correlated with age. IPT, PT, and mean maximal pain were significantly correlated with age. Body mass index, drinking, and smoking habits were not correlated with the esophageal perception threshold. The correlation of chemosensitivity and mechanosensitivity was also assessed, and the APSS was inversely correlated with IPT, PT, and maximal pain. CONCLUSIONS The thresholds of esophageal visceral chemosensitivity and mechanosensitivity in same individuals were significantly correlated and both of these thresholds were inversely correlated with age.
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18
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Almansa C, Achem SR. The Role of Acid Reflux in Non‐Cardiac Chest Pain. PRACTICAL MANUAL OF GASTROESOPHAGEAL REFLUX DISEASE 2013:132-153. [DOI: 10.1002/9781118444788.ch9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Acid-suppressive therapy with esomeprazole for relief of unexplained chest pain in primary care: a randomized, double-blind, placebo-controlled trial. Am J Gastroenterol 2013; 108:56-64. [PMID: 23147520 DOI: 10.1038/ajg.2012.369] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES High-quality data regarding the efficacy of acid-suppressive treatment for unexplained chest pain are lacking. The aim of this study was to evaluate the efficacy of esomeprazole in primary-care treatment of patients with unexplained chest pain stratified for frequency of reflux/regurgitation symptoms. METHODS Patients with a ≥ 2-week history of unexplained chest pain (unrelated to gastroesophageal reflux) who had at least moderate pain on ≥ 2 of the last 7 days were stratified by heartburn/regurgitation frequency (≤ 1 day/week (stratum 1) vs. ≥ 2 days/week (stratum 2)) and randomized to 4 weeks of double-blind treatment with twice-daily esomeprazole 40 mg or placebo. Chest pain relief during the last 7 days of treatment (≤ 1 day with minimal symptoms assessed daily using a 7-point scale) was analyzed by stratum in keeping with the predetermined analysis plan. RESULTS Overall, 599 patients (esomeprazole: 297, placebo: 302) were randomized. In stratum 1, more esomeprazole than placebo recipients achieved chest pain relief (38.7% vs. 25.5%; P=0.018); no between-treatment difference was observed in stratum 2 (27.2% vs. 24.2%; P=0.54). However, esomeprazole was superior to placebo in a post-hoc analysis of the whole study population (combined strata; 33.1% vs. 24.9%; P=0.035). CONCLUSIONS A 4-week course of high-dose esomeprazole provided statistically significant relief of unexplained chest pain in primary-care patients who experienced infrequent or no heartburn/regurgitation, but there was no such significant reduction in patients with more frequent reflux symptoms.
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20
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Fass R, Herschcovici T. Non‐Cardiac Chest Pain. THE ESOPHAGUS 2012:14-41. [DOI: 10.1002/9781444346220.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ford AC, Suares NC, Talley NJ. Meta-analysis: the epidemiology of noncardiac chest pain in the community. Aliment Pharmacol Ther 2011; 34:172-80. [PMID: 21615436 DOI: 10.1111/j.1365-2036.2011.04702.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Prevalence of, and risk factors for, noncardiac chest pain in the community have not been well studied. AIMS To conduct a systematic review and meta-analysis to examine these issues. METHODS MEDLINE, EMBASE and EMBASE Classic were searched (up to March 2011) to identify population-based studies reporting prevalence of noncardiac chest pain in adults (≥15 years) according to self-report, questionnaire or specific symptom-based criteria. Prevalence of noncardiac chest pain was extracted for all studies, and according to study location and certain other characteristics including presence or absence of gastro-oesophageal reflux disease (GERD) symptoms, where reported. Pooled prevalence overall, as well as odds ratios (OR), with 95% confidence intervals (CIs) were calculated. RESULTS Of 18 articles evaluated, 16 reported prevalence of noncardiac chest pain in 14 separate populations, containing 24 849 subjects. Pooled prevalence of noncardiac chest pain in all studies was 13% (95% CI 9-16). The prevalence of noncardiac chest pain was higher in Australian studies and in studies using a questionnaire to define its presence, compared with those using Rome I or II criteria. Prevalence was no different in women vs. men (OR 0.99; 95% CI 0.82-1.20). The prevalence was markedly higher in subjects who also reported GERD (OR 4.71; 95% CI 3.32-6.70) and increased according to frequency of GERD symptoms. CONCLUSIONS Pooled prevalence of noncardiac chest pain in the community was 13%, but there were few studies. Rates did not appear to differ according to gender or age. Presence of GERD was strongly associated with noncardiac chest pain.
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Affiliation(s)
- A C Ford
- Leeds Gastroenterology Institute, Leeds General Infirmary, Leeds, UK.
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22
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Fass R, Achem SR. Noncardiac chest pain: epidemiology, natural course and pathogenesis. J Neurogastroenterol Motil 2011; 17:110-23. [PMID: 21602987 PMCID: PMC3093002 DOI: 10.5056/jnm.2011.17.2.110] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Revised: 03/17/2011] [Accepted: 03/28/2011] [Indexed: 12/24/2022] Open
Abstract
Noncardiac chest pain is defined as recurrent chest pain that is indistinguishable from ischemic heart pain after a reasonable workup has excluded a cardiac cause. Noncardiac chest pain is a prevalent disorder resulting in high healthcare utilization and significant work absenteeism. However, despite its chronic nature, noncardiac chest pain has no impact on patients' mortality. The main underlying mechanisms include gastroesophageal reflux, esophageal dysmotility and esophageal hypersensitivity. Gastroesophageal reflux disease is likely the most common cause of noncardiac chest pain. Esophageal dysmotility affects only the minority of noncardiac chest pain patients. Esophageal hypersensitivity may be present in non-GERD-related noncardiac chest pain patients regardless if esophageal dysmotility is present or absent. Psychological co-morbidities such as panic disorder, anxiety, and depression are also common in noncardiac chest pain patients and often modulate patients' perception of disease severity.
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Affiliation(s)
- Ronnie Fass
- Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System, Tucson, Arizona, USA.
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23
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Arora AS, Katzka DA. How do I handle the patient with noncardiac chest pain? Clin Gastroenterol Hepatol 2011; 9:295-304; quiz e35. [PMID: 21056690 DOI: 10.1016/j.cgh.2010.10.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 10/12/2010] [Accepted: 10/16/2010] [Indexed: 02/07/2023]
Affiliation(s)
- Amindra S Arora
- Division of Gastroenterology and Hepatology, Mayo Foundation, Rochester, Minnesota 55905, USA
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Wang K, Duan LP, Zeng XZ, Liu JY, Xu-Chu W. Differences in cerebral response to esophageal acid stimuli and psychological anticipation in GERD subtypes--an fMRI study. BMC Gastroenterol 2011; 11:28. [PMID: 21439078 PMCID: PMC3073936 DOI: 10.1186/1471-230x-11-28] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 03/26/2011] [Indexed: 12/14/2022] Open
Abstract
Background To evaluate whether there are differences in the cerebral response to intraesophageal acid and psychological anticipation stimuli among subtypes of gastroesophageal reflux disease (GERD). Methods Thirty nine patients with GERD and 11 healthy controls were enrolled in this study after gastroscopy and 24 hr pH monitoring. GERD subjects were divided into four subgroups: RE (reflux esophagitis), NERD+ (non-erosive reflux disease with excessive acid reflux), NERD-SI+ (normal acid exposure and positive symptom index) and NERD-SI+ (normal acid exposure and negative symptom index, but responded to proton pump inhibitor trial). Cerebral responses to intraesophageal acid and psychological anticipation were evaluated with fMRI. Results During intraesophageal acid stimulation, the prefrontal cortex (PFC) region was significantly activated in all subgroups of GERD; the insular cortex (IC) region was also activated in RE, NERD+ and NERD-SI- groups; the anterior cingulated cortex (ACC) region was activated only in RE and NERD-SI- groups. The RE subgroup had the shortest peak time in the PFC region after acid was infused, and presented the greatest change in fMRI signals in the PFC and ACC region (P = 0.008 and P = 0.001, respectively). During psychological anticipation, the PFC was significantly activated in both the control and GERD groups. Activation of the IC region was found in the RE, NERD-SI+ and NERD-SI- subgroups. The ACC was activated only in the NERD-SI+ and NERD-SI- subgroups. In the PFC region, the NERD-SI- subgroup had the shortest onset time (P = 0.008) and peak time (P < 0.001). Compared with actual acid infusion, ACC in RE and IC in NERD+ were deactivated while additional areas including the IC and ACC were activated in the NERD-SI+ group; and in NERD-SI- group, onset-time and peak time in the PFC and IC areas were obviously shorter in induced anticipation than in actual acid infusion. Conclusions The four subgroups of GERD patients and controls showed distinctly different activation patterns and we therefore conclude GERD patients have different patterns of visceral perception and psychological anticipation. Psychological factors play a more important role in NERD-SI+ and NERD-SI- groups than in RE and NERD+ groups.
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Affiliation(s)
- Kun Wang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, PR China
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25
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Quantitative assessment and characterization of visceral hyperalgesia evoked by esophageal balloon distention and acid perfusion in patients with functional heartburn, nonerosive reflux disease, and erosive esophagitis. Clin J Pain 2010; 26:326-31. [PMID: 20393268 DOI: 10.1097/ajp.0b013e3181c8fc83] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES The role of esophageal hypersensitivity in functional heartburn (FH) with negative pH test, negative symptom index, and the proton pump inhibitor (PPI) failure has not been established. The aim of this study was to investigate the characterization of visceral hyperalgesia evoked by esophageal balloon distention and acid perfusion in patients with FH, nonerosive reflux disease, and erosive esophagitis and further characterize the pathophysiologic mechanism of FH. METHODS A total of 21 FH patients (with esophageal acid exposure <3.1% and a symptom index<50% and nonresponse to a therapeutic trial with proton pump inhibitors, 25 Nonerosive reflux disease (NERD) patients (with esophageal acid exposure>4%), 23 erosive esophagitis (EE) patients (LA grade B to D), and 18 healthy controls were recruited in the study. Mechanosensitivity including the initial perception threshold (IPT) and pain threshold (PT) was evaluated by using a Barostat with a double-random staircase distension protocol. Chemosensitivity was graded along a visual analog scale after perfusion of saline and 0.1 N HCl. RESULTS The baseline IPTs and PTs were all lower in patients with FH, NERD, and EE than in the controls (all P<0.01). In addition, the baseline PT in FH patients was significantly lower than those in NERD (P=0.015) and EE patients (P<0.001). After acid perfusion, the mean symptom intensity scores were significantly greater in patients with FH, NERD, and EE than those in the controls (all P<0.001). The postacid perfusion IPTs in patients with FH, NERD, and EE were all significantly lower than the corresponding baseline values (all P<0.01). The PTs in FH (P=0.026) and EE patients (P<0.001) were significantly lower than the corresponding baseline values. Moreover, the postacid perfusion PT was significantly lower in FH patients than in NERD patients (P<0.001). CONCLUSIONS FH patients are more sensitive to mechanical or chemical stimuli than NERD patients. Sensitization of esophageal acid-sensitive chemoreceptors may exert a significant influence on the pressure-sensitive mechanoreceptors, and there is the cooperative interaction in the process of esophageal visceral hyperalgesia.
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Lopez-Alvarenga JC, Vargas JA, Lopez LH, Fass R, Sobrino-Cossio S, Higgins P, Comuzzie A. Effect of body weight and esophageal damage on the severity of gastroesophageal reflux symptoms. Mexican GERD working group. Arch Med Res 2010; 40:576-81. [PMID: 20082872 DOI: 10.1016/j.arcmed.2009.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2008] [Accepted: 07/27/2009] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Several studies have demonstrated overweight and obesity are strong independent risk factors of GERD symptoms and esophageal erosions. Our aim was to analyze the joint effect of BMI with the grade of esophageal damage over symptoms' intensity of GERD. METHODS We used a questionnaire with a Likert scale for severity of symptoms related to GERD. The distal portion of the esophagus was evaluated to determine the presence of mucosal injury, classified by Los Angeles criteria (LA). RESULTS We included 917 subjects (53.76% females) with average age 36.8+/-7 years. Males had higher BMI than females (26.8+/-3.5 vs. 25.2+/-4.5, p<0.001). Severe damage (C-D ulcers) was associated with overweight (BMI 25-30), severity of heartburn,retching, halitosis, regurgitation, and chest oppression. BMI >30 had high score for heartburn and retching, but low score for nausea, compared with lower weight. The model with interaction showed a non-linear association between BMI and LA. Overweight (but not obese) patients with damage scored C-D had the highest score for intensity of heartburn and retching. CONCLUSIONS BMI and LA do not have additive effects on the severity of symptoms of GERD. Those with BMI between 25 and 30 had severe symptoms score, but those with BMI >30 showed lower scores. These findings could explain controversial results found in other studies.
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Abstract
Noncardiac chest pain (NCCP) is not only a difficult disorder to define but is also complex in characterization and treatment. Patients with NCCP are a challenge to primary care and subspecialty services such as cardiology and gastroenterology. NCCP is often a heterogeneous disorder with many potential causes including gastroenterologic diagnoses. This article presents the current evidence for gastroesophageal reflux disease as a cause of NCCP and highlights the best currently available tests for this group of patients.
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Affiliation(s)
- Amanke C Oranu
- Division of Gastroenterology, Hepatology and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, TVC 1660, Nashville, TN 37232-5280, USA
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Banerjee B, Medda BK, Schmidt J, Zheng Y, Zhang Z, Shaker R, Sengupta JN. Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats. Histochem Cell Biol 2009; 132:585-97. [PMID: 19784665 DOI: 10.1007/s00418-009-0639-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2009] [Indexed: 11/28/2022]
Abstract
Purinergic P2X(3) receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X(3) receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X(3) receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT-PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X(3) mRNA expressions in DRGs (T1-T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X(3) mRNA in DRGs (T6-T12) and in the esophageal muscle. At protein level, P2X(3) exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X(3) and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X(3) and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X(3) expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux-induced esophagitis.
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Affiliation(s)
- Banani Banerjee
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Olesen AE, Staahl C, Brock C, Arendt-Nielsen L, Drewes AM. Evoked Human Oesophageal Hyperalgesia: A Potential Tool for Analgesic Evaluation? Basic Clin Pharmacol Toxicol 2009; 105:126-36. [DOI: 10.1111/j.1742-7843.2009.00422.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Peles S, Medda BK, Zhang Z, Banerjee B, Lehmann A, Shaker R, Sengupta JN. Differential effects of transient receptor vanilloid one (TRPV1) antagonists in acid-induced excitation of esophageal vagal afferent fibers of rats. Neuroscience 2009; 161:515-25. [PMID: 19324074 DOI: 10.1016/j.neuroscience.2009.03.040] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Revised: 02/17/2009] [Accepted: 03/17/2009] [Indexed: 12/17/2022]
Abstract
Gastro-esophageal acid reflux can stimulate esophageal vagal sensory afferents by activating proton-sensitive ion channel transient receptor vanilloid one (TRPV1). The objective of this study was to investigate the response characteristics of vagal afferent fibers of rats to acid (0.1 N HCl) and capsaicin (CAP) following esophagitis and differential effects of two classes of TRPV1 antagonists on responses of vagal afferent fibers. The chronic reflux was induced by ligating the fundus of the stomach and partial constriction of pylorus. Extracellular single fiber recordings were made from the cervical vagal afferent fibers from naive control and fundus-ligated (FL) esophagitis rats. Innervations of fibers were identified to esophageal distension (ED) and subsequently tested to CAP and acid before and after injection of TRPV1 antagonist JYL1421 or AMG9810 (10 micromol/kg i.v.). Seventy-five vagal afferent fibers from 70 rats were identified to ED. Intra-esophageal CAP (0.1 ml of 1 mg/ml) excited 39.5% (17/43, 5/22 from naive and 12/21 from FL rats) fibers. In contrast, i.v. injection of CAP (0.03-0.3 micromol/kg) dose-dependently excited 72% (42/58) fibers. Responses to CAP were significantly greater for fibers from FL rats (n=32) than naive rats (n=25). TRPV1 antagonists JYL1421 and AMG9810 (10 micromol/kg) significantly blocked response to CAP. Intra-esophageal acid infusion stimulated 5/17 (29.4%) fibers from naive rats and 12/28 (42%) from FL rats. Effect of acid was significantly blocked by AMG9810, but not by JYL1421. Results indicate that following esophagitis the number of fibers responsive to CAP and acid is greater than noninflamed esophagus, which may contribute to esophageal hypersensitivity. Acid-induced excitation of vagal sensory afferents can be differentially attenuated by different classes of TRPV1 antagonists. Therefore, TRPV1 antagonists play a key role in attenuation of hypersensitivity following reflux-induced esophagitis. The use of TRPV1 antagonists could be an alternative to the traditional symptoms-based treatment of chronic acid reflux and esophageal hypersensitivity.
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Affiliation(s)
- S Peles
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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Affiliation(s)
- Sebastien Kindt
- Department of Gastroenterology, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium
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Qin C, Farber JP, Foreman RD. Intraesophageal chemicals enhance responsiveness of upper thoracic spinal neurons to mechanical stimulation of esophagus in rats. Am J Physiol Gastrointest Liver Physiol 2008; 294:G708-16. [PMID: 18187515 DOI: 10.1152/ajpgi.00477.2007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Esophageal hypersensitivity is one of the most common causes of noncardiac chest pain in patients. In this study, we investigated whether exposure of the esophagus to acid and other chemical irritants affected activity of thoracic spinal neurons responding to esophageal distension (ED) in rats. Extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital sodium-anesthetized, -paralyzed, and -ventilated male rats. ED (0.2 or 0.4 ml, 20 s) was produced by water inflation of a latex balloon placed orally into the middle thoracic region of the esophagus. The chemicals were administered via a tube that was passed through the stomach and placed in the thoracic esophagus. To irritate the esophagus, 0.2 ml of HCl (0.01 N), bradykinin (10 microg/ml), or capsaicin (10 microg/ml) were injected for 1-2 min. Only neurons excited by ED were included in this study. Results showed that intraesophageal instillation of HCl, bradykinin, and capsaicin increased activity in 3/20 (15%), 7/25 (28%), and 9/20 (45%) neurons but enhanced excitatory responses to ED in 9/17 (53%), 8/15 (53%), and 7/11 (64%) of the remaining spinal neurons, respectively. Furthermore, intraesophageal chemicals were more likely to enhance the responsiveness of low-threshold neurons than high-threshold neurons to the esophageal mechanical stimulus. Normal saline (pH 7.4, 0.2 ml) or vehicle instilled in the esophagus did not significantly affect activity or ED responses of neurons. We conclude that enhanced responses of thoracic spinal neurons to ED by the chemically challenged esophagus may provide a possible pathophysiological basis for visceral hypersensitivity in patients with gastroesophageal reflux and/or esophagitis.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
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Lawal A, Kern M, Sanjeevi A, Antonik S, Mepani R, Rittmann T, Hussaini S, Hofmann C, Tatro L, Jesmanowicz A, Verber M, Shaker R. Neurocognitive processing of esophageal central sensitization in the insula and cingulate gyrus. Am J Physiol Gastrointest Liver Physiol 2008; 294:G787-94. [PMID: 18187518 DOI: 10.1152/ajpgi.00421.2007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The cingulate and insular cortices are parts of the limbic system that process and modulate gastrointestinal sensory signals. We hypothesized that sensitization of these two limbic area may operate in esophageal sensitization. Thus the objective of the study was to elucidate the neurocognitive processing in the cingulate and insular cortices to mechanical stimulation of the proximal esophagus following infusion of acid or phosphate buffer solution (PBS) into the esophagus. Twenty-six studies (14 to acid and 12 to PBS infusion) were performed in 20 healthy subjects (18-35 yr) using high-resolution (2.5 x 2.5 x 2.5 mm(3) voxel size) functional MRI (fMRI). Paradigm-driven, 2-min fMRI scans were performed during randomly timed 15-s intervals of proximal esophageal barostatically controlled distentions and rest, before and after 30-min of distal esophageal acid or PBS perfusion (0.1 N HCl or 0.1 M PBS at 1 ml/min). Following distal esophageal acid infusion, at subliminal and liminal levels of proximal esophageal distentions, the number of activated voxels in both cingulate and insular cortices showed a significant increase compared with before acid infusion (P < 0.05). No statistically significant change in cortical activity was noted following PBS infusion. We conclude that 1) acid stimulation of the esophagus results in sensitization of the cingulate and insular cortices to subliminal and liminal nonpainful mechanical stimulations, and 2) these findings can have ramifications with regard to the mechanisms of some esophageal symptoms attributed to reflux disease.
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Affiliation(s)
- Adeyemi Lawal
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Banerjee B, Medda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN. Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil 2007; 19:681-91. [PMID: 17640184 DOI: 10.1111/j.1365-2982.2007.00947.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A possible mechanism of oesophageal hypersensitivity is the acid-induced activation of transient receptor potential vanilloid receptor 1 (TRPV1) in the primary sensory neurons. We investigated TRPV1 expression and its colocalization with substance P (SP) and isolectin B4 (IB4)-positive cells in the thoracic dorsal root ganglia (DRGs) and nodose ganglia (NGs) of rats with reflux-induced oesophagitis (RO). RO was developed by fundus ligation and partial obstruction of the pylorus of Sprague-Dawley rats. Four groups of rats were used; fundus ligated acute (RO 48 h), chronic 7 days (RO 7D), RO 7D + omeprazole (7D + Omz, 40 mg kg(-1), i.p.) and sham-operated controls. Immunohistochemical analysis of TRPV1, SP and IB4 expression were carried out in spinal cord (SC), DRGs and NGs. RO rats exhibited significant inflammation and increase in TRPV1-ir and SP-ir expressions in the SC, DRGs and NGs. The maximum colocalization of TRPV1 and SP was observed in RO 7D rats, but Omz prevented inflammation and over expression of TRPV1 and SP. TRPV1-ir significantly increased in IB4-positive cells in DRGs and SC, but not in the NGs. Results document that acid-induced oesophagitis increases TRPV1 expression in both SP- and IB4-positive sensory neurons. The over expression of TRPV1 may contribute to oesophageal hypersensitivity observed in gastro-oesophageal reflux disease (GORD).
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Affiliation(s)
- B Banerjee
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Hammer J, Vogelsang H. Characterization of sensations induced by capsaicin in the upper gastrointestinal tract. Neurogastroenterol Motil 2007; 19:279-87. [PMID: 17391244 DOI: 10.1111/j.1365-2982.2007.00900.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Intraluminal capsaicin induces perception in the jejunum, but chemosensitivity of proximal gastrointestinal regions is unclear. Our aim was to evaluate the quality of perception induced by intraluminal capsaicin in different regions of the upper gastrointestinal tract. Healthy volunteers received either an oral tube for distension and capsaicin perfusion of the mid-duodenum or jejunum or swallowed a capsule containing 0.75 mg capsaicin powder. Graded questionnaires evaluated quality and severity of sensations during distensions, capsaicin infusion and 30 min after ingestion of capsaicin capsules respectively. Duodenal capsaicin induced sensations at lower doses than jejunal capsaicin (P < 0.05). Most prominent sensations evoked by capsaicin infusion were pressure, cramps, pain and nausea; nausea and warmth were more intense during capsaicin infusion than distension (P < 0.05,for the duodenum and jejunum), pain was more intense during distension (P < 0.05, duodenum only). Gastric ingestion of capsaicin capsules mainly induced sensations of pressure, heartburn and warmth. Capsaicin application into the upper gastrointestinal tract reproducibly induced upper abdominal sensation. Qualitative features distinguished chemically from mechanically induced sensations, but both sensitivity for chemical and mechanical stimulation decreased along the intestine. Activation of chemical pathways could be a useful human pain model activating nociceptors apart from mechanical stimulation.
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Affiliation(s)
- J Hammer
- Abteilung für Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria.
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Lamb K, Gebhart GF, Bielefeldt K. Luminal stimuli acutely sensitize visceromotor responses to distension of the rat stomach. Dig Dis Sci 2007; 52:488-94. [PMID: 17216335 DOI: 10.1007/s10620-006-9621-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2006] [Accepted: 09/14/2006] [Indexed: 12/09/2022]
Abstract
Inflammation can enhance responses to different stimuli consistent with the development of hypersensitivity. To determine whether sequentially applied stimuli interact, we determined visceromotor responses (VMR) to gastric distension, measured at baseline and 60 min after instillation of saline, glycocholic acid (GCA) or ethanol through a gastrostomy in controls and rats with gastric ulcers. In another series of experiments, chemicals were administered before and 60 min after repeated distension of the stomach. Ethanol, but not saline or GCA, increased VMR in controls with a more significant rise in rats with gastric ulcerations. GCA increased responses to gastric distension in controls, whereas GCA and ethanol enhanced responses to gastric distensions in rats with gastric ulcers. Responses to saline, GCA, or ethanol were not affected by repeated noxious distension of the stomach. Luminal stimuli can trigger visceromotor responses and sensitize gastric afferents to mechanical stimulation, thus potentially contributing to dyspeptic symptoms.
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Affiliation(s)
- K Lamb
- Department of Pharmacology, University of Iowa, Iowa City, IA, USA
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Remes-Troche JM, Maher J, Mudipalli R, Rao SSC. Altered esophageal sensory-motor function in patients with persistent symptoms after Nissen fundoplication. Am J Surg 2007; 193:200-5. [PMID: 17236847 DOI: 10.1016/j.amjsurg.2006.10.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Revised: 10/30/2006] [Accepted: 10/30/2006] [Indexed: 01/27/2023]
Abstract
BACKGROUND The pathophysiology of persistent gastroesophageal reflux disease (GERD) symptoms after antireflux surgery is unclear. We assessed esophageal sensorimotor function in patients with GERD before and after Nissen fundoplication (NF). METHODS Sensory and biomechanical properties were evaluated before surgery using impedance planimetry in 17 GERD patients and 16 healthy volunteers. All patients underwent standard laparoscopic NF. Eight GERD patients with persistent symptoms after surgery underwent repeat evaluations at least 12 months after surgery. RESULTS At baseline, GERD patients had lower thresholds for first perception (P < .001), discomfort (P < .001), and pain (P < .001) compared with controls. The esophagus was more reactive (P = .001) and less distensible (P = .04) in patients than controls. After NF, in patients with persistent symptoms, the sensory thresholds were unchanged (P > .05) but esophageal wall reactivity decreased (P = .001), and distensibility improved (P = .025). CONCLUSIONS NF improves esophageal biomechanical dysfunction but not the underlying hypersensitivity. Visceral hypersensitivity of the esophagus may explain persistent symptoms after NF.
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Affiliation(s)
- Jose M Remes-Troche
- Section of Neurogastroenterology, Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr, 4612 JCP, Iowa City, IA 52242, USA
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Dimcevski G, Schipper KP, Tage-Jensen U, Funch-Jensen P, Krarup AL, Toft E, Thorsgaard N, Arendt-Nielsen L, Drewes AM. Hypoalgesia to experimental visceral and somatic stimulation in painful chronic pancreatitis. Eur J Gastroenterol Hepatol 2006; 18:755-64. [PMID: 16772833 DOI: 10.1097/01.meg.0000223903.70492.c5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES To gain more information of the pain mechanisms in chronic pancreatitis we applied standardized experimental pain stimulation of the duodenum, oesophagus and the skin in 12 healthy controls and 13 patients with chronic pancreatitis and typical pain attacks. METHODS Using endoscopy a guide wire was positioned into the horizontal part of the duodenum, and a probe with a distal balloon was introduced over the guide wire. Mechanical stimuli were given as tonic (38 ml/min) or phasic (increasing volume steps of 5 ml delivered for 60 s) distensions of the balloon. After stimulation of the duodenum, the distal oesophagus was stimulated with the same protocol. Finally, the skin was stimulated with 'single and repeated burst' electrical stimuli reflecting activation of peripheral and central pain mechanisms. RESULTS The stimuli reliably evoked both painful and non-painful local and referred sensations. The patients had hyposensitivity to both tonic and phasic mechanical stimuli of the duodenum and the oesophagus (P=0.001). Hypoalgesia was also observed to single and repeated electrical skin stimuli in the patients, most evident for repeated stimuli (P=0.001). The evoked referred pain did not differ between the groups, but the patients used on average more words from the McGill Pain Questionnaire to describe the pain evoked in the duodenum (P=0.02). CONCLUSIONS Generalized hypoalgesia to experimental visceral and somatic stimulations was found in chronic pancreatitis. The findings suggest that the activation and modulation of central mechanisms is fundamental in pancreatic pain, and future studies should address the effect of analgesics with central effects in the treatment of these patients.
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Affiliation(s)
- Georg Dimcevski
- Centre for Visceral Biomechanics and Pain, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
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Drewes AM, Arendt-Nielsen L, Funch-Jensen P, Gregersen H. Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain. World J Gastroenterol 2006; 12:2806-17. [PMID: 16718803 PMCID: PMC4087795 DOI: 10.3748/wjg.v12.i18.2806] [Citation(s) in RCA: 15] [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] [Indexed: 02/06/2023] Open
Abstract
Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Center for Visceral Biomechanics and Pain, Department of Medical Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
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Sami SAK, Rössel P, Dimcevski G, Nielsen KD, Funch-Jensen P, Valeriani M, Arendt-Nielsen L, Drewes AM. Cortical changes to experimental sensitization of the human esophagus. Neuroscience 2006; 140:269-79. [PMID: 16631315 DOI: 10.1016/j.neuroscience.2006.02.031] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Revised: 01/17/2006] [Accepted: 02/05/2006] [Indexed: 12/24/2022]
Abstract
Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.
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Affiliation(s)
- S A K Sami
- Center for Sensory-Motor Interactions, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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Yang M, Li ZS, Xu XR, Fang DC, Zou DW, Xu GM, Sun ZX, Tu ZX. Characterization of cortical potentials evoked by oesophageal balloon distention and acid perfusion in patients with functional heartburn. Neurogastroenterol Motil 2006; 18:292-9. [PMID: 16553584 DOI: 10.1111/j.1365-2982.2006.00761.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Oesophageal visceral hypersensitivity is thought to be important in generating symptoms in functional heartburn (FH). However, the neurophysiological mechanisms involved are poorly understood. The aim of this study was to compare the characteristics of oesophageal cortical evoked potentials (CEPs) induced by balloon distension and acid perfusion in FH and controls. We studied 21 FH patients and 12 healthy volunteers. Oesophageal mechanical stimulation was performed using the specially constructed mechanical pump. CEPs were recorded using the 10-20 international system of electroencephalogram recording. Oesophageal distention elicited recognizable, reproducible and muti-peak CEPs. CEP latencies for N1, P1 and N2 components were significantly shorter (P = 0.016, P = 0.003 and P = 0.031, respectively) in FH than in controls before perfusion. Acid perfusion significantly decreased the latencies of N1, P1 and N2 (P = 0.022, P = 0.007 and P = 0.041, respectively) and significantly increased the amplitude of P1-N2 components (P = 0.020) in FH patients, but not in controls. In conclusion, cortical evoked potential responses evoked by oesophageal distention and acid perfusion were greater in FH than in controls, suggesting that dysfunction of visceral neural pathways and/or alterations in cortical processing may produce and mediate oesophageal hypersensitivity in FH. These findings provide the evidence that central sensitization contributes to the development and maintenance of oesophageal hypersensitivity.
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Affiliation(s)
- M Yang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Abstract
Various underlying mechanisms have been described in patients with non-cardiac chest pain (NCCP). By far, gastroesophageal reflux disease (GERD) is the most common cause and thus requires initial attention when patients with NCCP are managed. Esophageal dysmotility can be demonstrated in 30% of the NCCP patients, but appears to play a very limited role in symptom generation. A significant number of patients with NCCP lack any evidence of GERD and have been consistently shown to have reduced perception thresholds for pain. Peripheral and/or central sensitization have been suggested to be responsible for visceral hypersensivity in NCCP patients. Further understanding of the underlying mechanisms for pain in patients with NCCP will likely improve our current therapeutic approach.
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Affiliation(s)
- Daniel Van Handel
- The Neuro-Enteric Clinical Research Group, Department of Medicine, Section of Gastroenterology, Southern Arizona VA Health Care System and University of Arizona Health Sciences Center, Tucson, AZ 85723-0001, USA
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Hungin APS, Raghunath AS, Wiklund I. Beyond heartburn: a systematic review of the extra-oesophageal spectrum of reflux-induced disease. Fam Pract 2005; 22:591-603. [PMID: 16024554 DOI: 10.1093/fampra/cmi061] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastro-oesophageal reflux disease (GORD) is a chronic condition affecting up to one-quarter of the Western population. GORD is characterized by heartburn and acid regurgitation, but is reported to be associated with a spectrum of extra-oesophageal symptoms. OBJECTIVE The aim of this systematic review was to critically evaluate postulated extra-oesophageal symptoms of GORD. METHODS Extra-oesophageal symptoms were identified from population-based studies evaluating their association with GORD (either defined as heartburn and/or acid regurgitation, or diagnosed in general practice). The response of these symptoms to acid-suppressive therapy was investigated using randomized, double-blind, placebo-controlled studies. Pathogenic mechanisms were evaluated using clinical and preclinical studies. RESULTS An association between GORD and symptoms or a diagnosis of chest pain/angina, cough, sinusitis and gall-bladder disease was evident from three eligible population-based studies of GORD. Randomized placebo-controlled studies (n=20) showed that acid-suppressive therapy provides symptomatic relief of chest pain, asthma and, potentially, chronic cough and laryngitis. Mechanistic models, based on direct physical damage by refluxate or vagally mediated reflexes, support a causal role for GORD in chest pain and respiratory symptoms, but not in gall-bladder disease. CONCLUSION GORD is likely to play a causal role in chest pain and possibly asthma, chronic cough and laryngitis. Further investigation is desirable, particularly for other potential extra-oesophageal manifestations of GORD such as chronic obstructive pulmonary disease, sinusitis, bronchitis and otitis. Acid-suppressive therapy is likely to benefit patients with non-cardiac chest pain, but further placebo-controlled studies are needed for other symptoms comprising the extra-oesophageal spectrum of GORD.
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Affiliation(s)
- A Pali S Hungin
- Cetre for Integrated Health Care Research, University of Durham--Stockton Campus, Wolfson Research Institute, Stockton-on-Tees TS176BH, UK.
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Drewes AM, Reddy H, Staahl C, Pedersen J, Funch-Jensen P, Arendt-Nielsen L, Gregersen H. Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid. World J Gastroenterol 2005; 11:4367-74. [PMID: 16038036 PMCID: PMC4434664 DOI: 10.3748/wjg.v11.i28.4367] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization.
METHODS: Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine.
RESULTS: The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change.
CONCLUSION: Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.
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Affiliation(s)
- Asbjørn-Mohr Drewes
- Center for Biomechanics and Pain, Department of Medical Gastroenterology, Aalborg Hospital, DK-9000 Aalborg, Denmark.
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Abstract
Heartburn is a symptom complex that has traditionally been accepted as an acid-mediated event and a reliable indicator of gastroesophageal reflux disease. Recently, however, these concepts have been questioned because patients with endoscopy-negative "heartburn" have lower response rates to acid suppression with proton pump inhibitors than do patients with endoscopy-positive "heartburn," ie, erosive esophagitis. As explanation for this, 3 different mechanisms have been proposed to explain the occurrence of heartburn in the endoscopy-negative setting. They are: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. In this report, we review the observations in support of each concept and propose a means for reconciling them under one hypothesis: abnormal tissue resistance. Essential to this review and to the conclusions drawn about the pathogenesis of heartburn in nonerosive reflux disease is a reaffirmation of the definition of reflux-associated "heartburn" as an acid-mediated event requiring "relief by antacids" as a necessary component of the history.
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Affiliation(s)
- William J Barlow
- Tulane University Health Sciences Center, Department of Medicine SL-35, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA
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Medda BK, Sengupta JN, Lang IM, Shaker R. Response properties of the brainstem neurons of the cat following intra-esophageal acid–pepsin infusion. Neuroscience 2005; 135:1285-94. [PMID: 16165290 DOI: 10.1016/j.neuroscience.2005.07.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Revised: 06/24/2005] [Accepted: 07/01/2005] [Indexed: 11/16/2022]
Abstract
Studies in humans have documented that acute acid infusion into the esophagus leads to decrease in threshold for sensations to mechanical distension of the esophagus. It is not known whether acid infusion leads to sensitization of brainstem neurons receiving synaptic input from vagal afferent fibers innervating the esophagus. The aim of this study was to investigate the correlation of responses of vagal afferents and brainstem neurons after acute infusion of acid (0.1 N HCl)+pepsin (1 mg/ml) into the esophagus of cats. The vagal afferent fibers (n=20) exhibited pressure-dependent increase in firing to graded esophageal distension (5-80 mm Hg). Infusion of acid+pepsin into the esophagus produced a significant increase in ongoing resting firing of five of 16 fibers (31%) tested. However, their responses to graded esophageal distension did not change when tested 30 min after infusion. Pepsin infusion did not change the resting firing and response to esophageal distension (n=4). Twenty-one brainstem neurons were recorded that responded in an intensity-dependent manner to graded esophageal distension. Responses of 12 excited neurons were tested after intra-esophageal acid+pepsin infusion. Neurons exhibited a decrease in threshold for response to esophageal distension and increase in firing after acid+pepsin infusion. The sensitization of response after intra-esophageal acid remained unaffected after cervical (C1-C2) spinal transection (n=3). Results indicate that the esophageal distension-sensitive neurons in the brainstem exhibit sensitization of response to esophageal distension after acute acid+pepsin exposure. The sensitization of brainstem neurons is possibly initiated by increased spontaneous firing of the vagal afferent fibers to acid+pepsin, but not to sensitized response of vagal distension-sensitive afferent fibers to esophageal distension. Results also indicate that spinal pathway does not contribute to sensitization of brainstem neurons.
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Affiliation(s)
- B K Medda
- MCW Dysphagia Institute and Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
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Abstract
OBJECTIVE To describe factors influencing chest pain expression in patients with cardiac or noncardiac disease. METHODS The authors conducted a case presentation and review of literature. RESULTS Causes of chest pain are diverse. Psychologic factors influence chest pain expression commonly in patients with or without cardiac disease. CONCLUSIONS Physicians and other therapists must be aware of psychologic influences on chest pain expression to provide optimal treatment to their patients.
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Affiliation(s)
- David S Sheps
- University of Florida and the Malcom Randall VA Medical Center, P.O. Box 100181, Gainesville, FL 100181-0181, USA.
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Abstract
Originally, sensory testing of the esophagus included the acid perfusion test and the edrophonium test, which were developed to assess patients with non-cardiac chest pain. In the last 2 decades interest in functional esophageal disorders has increased and thus further understanding of the underlying mechanisms of esophageal pain required development of new sensory testing techniques. Balloon distension using a computerized electronic device, electrical stimulation and impedance planimetry have generated important information about esophageal sensory thresholds for pain in different disease states. Intraluminal ultrasonography has been used to determine the physiologic changes of the muscle wall of the esophagus during perception of typical esophageal symptoms. Central evaluation of patients undergoing esophageal stimulation has recently been introduced to assess cerebral activation in different esophageal disorders. However, many studies using esophageal sensory testing are afflicted with significant design flaws, making interpretation of the results very difficult. This is primarily due to lack of recognition of factors that can modulate esophageal sensation.
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Affiliation(s)
- Ronnie Fass
- Neuro-Enteric Clinical Research Group, Department of Medicine, Section of Gastroenterology, Southern Arizona VA Health Care System, Tucson, Arizona 85723, USA.
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Clouse RE. Central nervous system approaches for treating functional disorders: how, when, and why? J Pediatr Gastroenterol Nutr 2004; 39 Suppl 3:S763-5. [PMID: 15167380 DOI: 10.1097/00005176-200406003-00023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Ray E Clouse
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8124, St. Louis, MO 63110, USA.
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Abstract
NCCP is a common condition in Asia. The diagnostic approach of NCCP in Asians is similar to the Western population. GERD is the most common etiology. PPI therapy is an attractive alternative to other invasive diagnostic tests for NCCP and is equally effective for the Asian population.
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Affiliation(s)
- Wai-Man Wong
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong, China
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