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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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Esophageal Reflux Hypersensitivity: A Comprehensive Review

Akinari Sawada1 , Daniel Sifrim2 , Yasuhiro Fujiwara1

1Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan, and 2Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Correspondence to: Akinari Sawada
ORCID https://orcid.org/0000-0002-0590-3693
E-mail a.sawada@omu.ac.jp

Received: August 24, 2022; Revised: October 1, 2022; Accepted: October 18, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver.

Published online January 2, 2023

Copyright © Gut and Liver.

Reflux hypersensitivity (RH) is one of the phenotypes of gastroesophageal reflux disease. The latest Rome IV defines RH as a condition with typical reflux symptoms and positive reflux-symptom association despite normal acid exposure. Subsequently, the Lyon consensus proposed detailed cutoff values for the criteria on the basis of experts’ consensus. Rome IV brought a clear-cut perspective into the pathophysiology of gastroesophageal reflux disease and the importance of esophageal hypersensitivity. This perspective can be supported by the fact that other functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia often overlap with RH. Although several possible pathophysiological mechanisms of esophageal hypersensitivity have been identified, there is still unmet medical needs in terms of treatment for this condition. This review summarizes the current knowledge regarding RH.

Keywords: Reflux hypersensitivity, Gastroesophageal reflux disease, Functional esophageal disorders, Impedance-pH monitoring, Behavioral disorders

Reflux hypersensitivity (RH) is one of the functional esophageal disorders in Rome IV.1 RH is defined as patients with typical reflux symptoms having normal acid exposure and positive reflux symptom association. The definition of RH, formerly called hypersensitive esophagus, changed with the revision of the Rome criteria. In the previous criteria (Rome III), RH and patients with abnormal acid exposure were encompassed within the same entity (i.e., nonerosive reflux disease [NERD]) in spite of inconsistency in response to acid suppression therapy and mechanisms of reflux symptom generation.2 Subsequently, Rome IV introduced a new classification of gastroesophageal reflux disease (GERD) including a specific category called RH on the basis of the balance between two main pathophysiological parameters: esophageal acid exposure and esophageal hypersensitivity. For acid exposure, highly effective therapeutic options are available such as acid suppressive therapy and anti-reflux surgery (ARS). The healing of erosive esophagitis (EE) can be achieved in more than 90% of the cases by proton pump inhibitors (PPIs) or potassium-competitive acid blockers (PCABs).3-5 However, these treatments cannot alleviate reflux symptoms enough in up to 48% of reflux patients.6,7 The difference of treatment outcome between mucosal healing and reflux symptoms is probably attributable to esophageal hypersensitivity since there is poor correlation between the severity of mucosal damage and the severity of symptoms.8-10 The process of symptom generation starts from the esophageal sensory nerve fibers stimulated by gastroesophageal reflux, followed by the transmission of the simulation to the central nervous system via vagal afferent nerves or spinal nerves. Although many studies found that there are multitude of central and peripheral factors related to esophageal hypersensitivity, this extremely complex process has not been completely elucidated, and makes the treatment for this condition challenging.

In this comprehensive review, we summarized the current knowledge about RH from epidemiology to treatment.

RH affects a relatively small proportion of patients with GERD. However, the number of RH patients is not negligible considering the high global prevalence of GERD (14.8%).11 Martinez et al.12 studied patients with heartburn who were not yet treated with PPIs. They found that 9% of the reflux patients had RH, which accounts for 20% of patients with normal upper endoscopy (Fig. 1). This study could not identify nonacid reflux because of the lack of impedance sensors, then Savarino et al.8 investigated patients with typical reflux symptoms using off-PPI impedance-pH monitoring. The study showed similar proportion of RH, NERD, and functional heartburn (FH) in endoscopy-negative patients to the previous study when calculating reflux-symptom association only for acid reflux episodes. However, incorporation of nonacid reflux episodes into reflux-symptom association increased the prevalence of RH by approximately 10%. A similar diagnostic yield was seen in other off-PPI impedance-pH monitoring studies (Fig. 1).13,14

Figure 1.Prevalence of each reflux phenotype in all patients with heartburn (A) and in endoscopy-negative patients with heartburn and/or regurgitation (B). The patients in both studies were phenotyped after at least a 14-day discontinuation of acid suppressive therapy. Only pH monitoring was used in (A), while impedance-pH monitoring was used in (B) so that the reflux-symptom association could be calculated for both acid and nonacid reflux episodes.
NERD, nonerosive reflux disease; RH, reflux hypersensitivity; FH, functional heartburn.

On-PPI impedance-pH monitoring showed that the RH prevalence in endoscopy-negative patients was similar to that observed in studies performed off-PPI. Roman et al.15 reported 36% of PPI nonresponder patients was diagnosed as RH on PPI. Patel et al.16 also found similar prevalence of RH between on- and off-PPI studies. However, part of NERD patients diagnosed off PPI can be converted into RH when tested on-PPI.17 Thus, RH cohort defined by off-PPI study is not necessarily same as those by on-PPI study.

The regional difference influences the RH prevalence. Several large Japanese on-PPI studies report that the prevalence of RH is up to 44%, which is higher than in Western countries.18-20

The two experts’ consensuses, Rome IV criteria and the Lyon consensus, are the bedrock of RH diagnosis. Their proposed criteria for RH require dedicated esophageal physiology testing (i.e., manometry and impedance-pH monitoring). Thus, RH is normally diagnosed at tertiary centers due to the availability of such techniques. The Lyon consensus complements Rome IV criteria providing detailed cutoff values, specifically for impedance-pH monitoring (Fig. 2).

Figure 2.Diagnostic algorithm of PPI/PCAB refractory reflux patients.
PPI, proton pump inhibitor; PCAB, potassium-competitive acid blocker; SGB, supragastric belching; RS, rumination syndrome; EGD, esophagogastricduodenoscopy; HRM, high-resolution manometry; HRIM, high-resolution impedance manometry; RS, rumination syndrome; EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; LA, Los Angeles classification; LSBE, long segment Barrett’s esophagus; AET, acid exposure time.

1. Rome IV criteria

The latest Rome IV criteria classifies GERD into four phenotypes as follows: (1) EE, (2) NERD, (3) RH, (4) FH.1 It is suggested that acid exposure predominantly accounts for esophageal symptoms in EE and NERD whilst esophageal hypersensitivity overrides acid reflux in RH and FH.

The diagnostic criteria of RH are as follows: (1) retrosternal symptoms including heartburn and chest pain; (2) normal endoscopy and absence of evidence that eosinophilic esophagitis is the cause for symptoms; (3) absence of major esophageal motor disorders (achalasia/esophagogastric junction outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent peristalsis); and (4) evidence of triggering of symptoms by reflux events despite normal acid exposure on pH only or impedance-pH monitoring.

The last condition has been amended from Rome III as response to antisecretory therapy is no longer required for the diagnosis. All of the four items must be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis with a frequency of at least twice a week. In clinical practice, regurgitation is often seen as one of the typical symptoms in RH in spite of the criteria.

The diagnostic work-up incudes multiple biopsies from different levels of the esophagus to exclude eosinophilic esophagitis during endoscopy, high-resolution manometry and pH only or impedance-pH monitoring. High-resolution manometry is essential to exclude motility disorders and locate the upper edge of the lower esophageal sphincter to position esophageal pH sensor precisely.21 Typical reflux symptoms such as heartburn and/or regurgitation can be presented by up to 75%, 35% and 20% of patients with achalasia, hypercontractile esophagus and distal esophageal spasm respectively.22-25

Rome IV also introduces the concept that RH and FH can overlap with proven GERD (i.e., Los Angeles classification grade B/C/D or long segment Barrett’s esophagus) as some patients still suffer from reflux symptoms after the mucosal healing.1,26 This concept seems to be supported by the similar psychological profiles and the prevalence of other functional gastrointestinal disorders such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) between RH/FH with and without proven GERD.27 This kind of overlap between functional and organic disorders is also seen in bowel disorders as some patients with inflammatory bowel diseases suffer from IBS-like symptoms even in remission.28

2. Lyon consensus

Although the Rome IV criteria defines RH, there was lack of concrete cutoff values for two conditions, (1) normal esophageal acid exposure and (2) positive symptom reflux association. The Lyon consensus addressed this issue where normal and pathological acid exposure time (AET) were proposed as <4% and >6%, respectively.29 Concerning reflux-symptom association, symptom index (SI) and symptom association probability (SAP) are the two most common indices. In many cases, a symptom is considered related to reflux when the symptom is marked within 2 minutes after a reflux episode. SI is the proportion of reflux-related symptoms to the total number of reflux symptoms which considered positive when ≥50%. SAP uses a Fisher exact test for the presence or absence of reflux and/or symptoms for each 2 minutes segment of the entire tracings. A p<0.05 indicates the probability of chance association between reflux symptoms and reflux episodes is <5%, corresponding to a positive SAP (>95%).

The diagnosis of RH can be inconclusive with AET between 4% and 6% and/or only SI or SAP positive. There would be two options to make a robust diagnosis for RH as follows: (1) performing prolonged wireless pH monitoring, or (2) using other MII-pH parameters as a complement. The choice largely depends on local institutional expertise and availability of the techniques.

Wireless pH monitoring can record up to 96 hours, which decreases the influence of day-to-day variability of AET.30 As even healthy subjects have pathological AET at times, RH patients can be diagnosed as NERD if tested with 24-hour pH metry on the worst reflux day. Hasak et al.31 found that longer recording time (e.g., 72 or 96 hours) can provide diagnostic yield especially when AET in the first 2 days are discordant or borderline. The complementary metrics include the number of reflux episodes, mean nocturnal baseline impedance (MNBI) and post-reflux swallow peristaltic wave (PSPW) index. The Lyon consensus proposes that >80 reflux episodes per 24 hours is conceivably abnormal whereas <40 is physiological. Recently <40 and <35 reflux episodes have been validated as physiological for heartburn and regurgitation respectively.32,33 MNBI reflects cumulative damage of the mucosa, which is known as a surrogate marker for mucosal integrity (MI). Thus, little influence of day-to-day variability of acid reflux. PSPW index is the proportion of reflux episodes followed by saliva swallowing within 30 seconds from the end of reflux episode, which reflects the ability of esophageal chemical clearance.34 In fact, several studies showed lower PSPW index in acid reflux predominant GERD phenotypes (i.e., EE and NERD) compared to esophageal hypersensitivity predominant.34 Frazzoni et al.33 showed 50% for PSPW index and 2,000 Ω for MNBI at 3 cm above the lower esophageal sphincter as optimal cutoff values to predict PPI-dependent heartburn compared to asymptomatic subjects. On the other hand, the largest healthy subjects’ data (n=391) of 24-hour off-PPI impedance-pH monitoring calculated a cutoff value of MNBI and PSPW index as 1,384 Ω and 15%, respectively.35 These studies suggest that patients with >50% PSPW index and/or >2,000 Ω MNBI probably have normal acid exposure on average even when AET is inconclusive in 24-hour impedance-pH monitoring.

Several studies demonstrated esophageal hypersensitivity to noxious stimuli in GERD patients. Trimble et al.36 showed that patients with RH had a lower sensory threshold for esophageal balloon distension compared to those with NERD, Barrett’s esophagus or asymptomatic healthy subjects. Although the entire mechanism of esophageal hypersensitivity remains to be elucidated, several potential factors have been reported so far (Fig. 3).

Figure 3.Mechanism underlying esophageal reflux hypersensitivity. Exogenous stimuli perceived by the esophageal sensory nerves are transmitted to the central nervous system via two ways; vagal afferent nerves via the nodose ganglion and spinal nerves via dorsal root ganglion. Several factors contribute to reflux hypersensitivity influencing peripheral sensors in the esophagus or the central nervous system. Some mechanisms such as mucosal integrity, cytokines and prostaglandin E2, sensory receptors (TRPV1 and ASIC3) and superficial mucosal afferent nerves are associated with peripheral hypersensitivity. Other mechanisms such as esophageal hypervigilance along with anxiety and sleep disturbance mainly affect the processing of the conveyed stimuli in the central nervous system, which results in amplification of the sensation. These factors also might enhance peripheral sensitivity by impairing the mucosal integrity.
TRPV1, transient receptor potential vanilloid receptor-1; ASIC3, acid-sensing ion channel 3.

1. Mucosal integrity

Reflux symptoms can occur when the refluxate comes in contact with the esophageal mucosa. In EE, such stimuli including acid, bile, and pepsin can reach sensory afferent nerve endings in the esophageal wall via the mucosal deficit.37 On the other hand, microscopic mucosal damage impairs MI in NERD. MI reflects barrier function of the mucosa, which can be measured in vivo (e.g. impedance monitoring) or in vitro (e.g. transepithelial electrical resistance, molecule permeability using ushing chamber, and transmission electron microscopy).38 Impaired MI lets noxious substances pass through the mucosa, and MI inversely correlates to acid sensitivity in patients with NERD (i.e., lower MI more hypersensitive).10,39 However, Weijenborg et al.40 found no difference in MI between NERD and FH even though NERD had the shorter perception time in the acid perfusion test. These findings indicate that MI is not a sole factor to explain acid sensitivity.

Esophageal mucosal dilated intercellular space (DIS) is a histological condition associated with impaired MI. There is a causal link between DIS and MI as acid and bile perfusion cause both conditions simultaneously.38,41 DIS can be found not only in EE and NERD but also in patients with normal AET.37,42,43 Thus, DIS could explain the mechanism of symptom perception in RH. However, it should be noted that DIS can be found in up to 30% of asymptomatic subjects.44 On top of that, the DIS is predominantly located in the basal layer, which questions whether it truly increases epithelial permeability for noxious substances from the luminal side.

2. Cytokines and prostaglandin E2

Despite the orthodox hypothesis that reflux damages esophageal mucosa directly from the luminal side, Souza et al.45 suggests the opposite way of the development of esophageal inflammation by reflux (i.e., from inside the mucosa via cytokines). Their animal study found that acid reflux causes the epithelium to secrete proinflammatory cytokines such as interleukin (IL)-8 and IL1-b, and subsequently mainly IL-8 induces the migration of T cells and neutrophils to the submucosal layer, finally extending to the epithelial surface. Isomoto et al.46 showed increased IL-8 expression in the esophageal epithelium of NERD patients, which lowered after 8-week PPI treatment in line with reflux symptom resolution. This implies the involvement of IL-8-induced mucosal inflammation in symptom generation.

Prostaglandin E2 (PGE2) also plays an important role in visceral hypersensitivity both at central and peripheral levels via the prostaglandin E2 receptor-1 (EP-1). Kondo et al.47 showed that the level of PGE2 in the esophageal mucosa increased after acid perfusion which correlated to intensity of heartburn. EP1 receptor expressed in the mucosa and co-localized on protein gene product 9.5 immunoreactive nerve specifically in the muscularis mucosae and submucosa. In line with the results, EP-1 receptor antagonists and diclofenac (nonsteroidal anti-inflammatory drug) attenuated acid infusion induced heartburn or visceral hypersensitivity.48-50

3. Superficial mucosal afferent nerves

Esophageal afferent sensory nerves are distributed in the esophageal mucosa and are likely to play an important role on perceiving noxious stimuli from the luminal surface. The afferent nerves are normally located closer to the lumen in the proximal esophagus compared to the distal esophagus.51 It might explain acid hypersensitivity in the proximal esophagus.52 Additionally, proximal reflux is one of the determinants triggering reflux symptoms.53,54 Given these findings, the sensitivity of mucosal afferent nerves presumably depends on its proximity to the lumen. Our previous study found that NERD patients show more superficial mucosal afferent nerve (i.e., closer to the lumen) compared to healthy subjects.55 Thus, the superficial nerve may partly underlie the mechanism of esophageal hypersensitivity. Interestingly, FH patients had mucosal afferent nerve at the similar depth to healthy subjects.56 Esophageal hypersensitivity in FH might be predominantly formed by central factors rather than peripheral factors. Further study is warranted to investigate esophageal mucosal innervation of RH patients.

4. Sensory receptors (TRPV1 and ASIC3)

Transient receptor potential vanilloid receptor-1 (TRPV1) is a polymodal, nociceptive cation channel. TRPV1 can be activated by several exogenous factors including protons (H+), capsaicin and high temperature.57 The expression of TRPV1 can be seen in not only afferent nerve fibers but also non-neural cells.58-60 Guarino et al.61 found NERD and EE patients have higher mRNA and protein expression levels of TRPV1 in esophageal mucosal biopsies than healthy control. Besides, our recent study showed that TRPV1 is frequently expressed on superficial afferent nerves in the esophageal epithelium whereas occasional expression was seen on deep nerves around basal layer.62 On the other hand, a randomized controlled study by Krarup et al.63 showed no inhibitory effect of TRPV1 antagonist on chest pain induced by heat, distension or electronic current in the esophagus. With regard to other TRPs receptors, transient receptor potential melastatin 8 (TRPM8) might be involved in esophageal hypersensitivity as menthol (i.e., TRPM8 agonists) infusion into the esophagus triggers different sensation in healthy subjects (cold sensation) and GERD patients (heartburn).64

A few studies have reported the role of acid-sensing ion channels (ASICs) in human GERD. ASICs are voltage-insensitive epithelial Na+ channels responding to extracellular acidification, which function as nociceptor as well as mechanoreceptor.65 Immunohistochemistry shows increased expression of ASIC3 in NERD compared to FH.62 On the other hand, mRNA expression level of ASIC3 in the esophageal mucosa does not differ between NERD and control.62,66

Proteinase-activated receptor-2 (PAR-2) is a tethered ligand G protein-coupled receptor with seven transmembrane domains. Serine proteases including mast cell tryptase and pancreatic trypsin can activate PAR-2, which leads to visceral hypersensitivity and pain as a result of inflammatory and neuroinflammatory epithelial response via the secretion of IL-8, substance P and calcitonin gene-related peptide.67,68 Kandulski et al.67 found that PAR-2 and IL-8 expressed in the esophageal epithelium markedly in NERD and EE compared to control. Furthermore, these expressions correlated to histological changes such as DIS, basal cell hyperplasia and papillary elongation.

Wu et al.69 studied the link between TRPV1, ASIC3 and PAR-2 using human esophageal epithelial cells and found that activation of PAR-2 enhances a pain-related substance release (i.e., acid-induced adenosine triphosphate) from the esophageal epithelium through TRPV1 and ASIC3.

5. Sleep disturbance

Sleep disturbance is one of the common coexisting conditions in GERD. In a U.S. nationwide survey of 1,000 patients with at least once-a-week heartburn, 79% of the patients reported nighttime heartburn, and 75% of whom considered the reflux symptoms affected their sleep.70 As for a Japanese nationwide survey, 56.3% of 2,426 patients with heartburn had sleep disorders which was significantly higher than those without (40.7%), and there was a positive correlation between frequency of heartburn and the prevalence of sleep disturbance.71

GERD and sleep disturbance are likely to affect each other bidirectionally. Nighttime reflux provokes heartburn, which leads to difficulty in falling asleep, nocturnal and/or early morning awakening.72 Contrarily, sleep deprivation sensitizes the esophagus to acid and capsaicin (TRPV1 agonist).73,74 It is of interest that this effect was seen in GERD patients, however not in healthy volunteers.73 Sleep disturbance probably affects not only the processing of sensation in the central nervous system but also peripheral sensitivity since acute stress impaired mucosa integrity with DIS in animal study.75 GERD and sleep disturbance can be exacerbated each other in a “vicious cycle” where GERD deteriorates sleep quality which in turn sensitizes the esophagus.73 Our previous study found endoscopy-negative GERD was a significant risk factor of sleep disturbance compared to EE (odds ratio, 2.18; 95% confidence interval, 1.05 to 4.53),76 which might underscore the influence of sleep disturbance towards RH rather than the opposite direction.

6. Esophageal hypervigilance and anxiety

It is well known that psychological factors such as anxiety and depression contribute to symptom generation as well as its intensity in many conditions. This is the case in reflux symptoms as there is a higher level of visceral hypersensitivity, anxiety and depression across endoscopy-negative reflux phenotypes (i.e., RH, FH, and NERD) compared to healthy control.77 Moreover, Kessing et al.78 showed anxiety level positively correlates to severity of heartburn and chest pain.

Hypervigilance is a mental condition which encompasses several thoughts that drives attention to body sensations, anxiety and expectation about symptoms and fear for the consequences of the symptoms. This condition lowers a threshold to stimuli, that is to say, the patients can perceive no or subtle stimuli which most people cannot (i.e., allodynia), and symptoms can be intensified (i.e., hyperalgesia).79 Taft et al.79 have recently developed and validated a questionnaire called esophageal hypervigilance and anxiety scale (EHAS) to assess hypervigilance and anxiety, specifically for esophageal sensations. So far several studies demonstrated close relationship between EHAS and esophageal symptom severity in GERD, esophageal motility disorders, and eosinophilic esophagitis.80-83 Wong et al.80 found that EHAS positively correlated to reflux symptom severity regardless of GERD phenotypes. While Guadagnoli et al.81 demonstrated that only hypervigilant component in EHAS was a significant factor associated with reflux symptom severity.

1. IBS and function dyspepsia

Common functional gastrointestinal disorders such as FD and IBS often overlap with GERD.84,85 Our previous study found that FD and IBS coexist with 31% and 29% of GERD patients respectively, and more importantly the overlap worsens health-related quality of life compared to having either one condition.84 In a meta-analysis, IBS patients are more likely to have reflux symptoms compared to non-IBS patients (odds ratio, 4.17; 95% confidence interval, 2.85 to 6.09).86 de Bortoli et al.87 further scrutinized this relationship for each GERD phenotype and found that the prevalence of IBS in RH was 48.2% situating between true NERD (17%) and FH (77%). This tendency was similar in the prevalence of anxiety and depression diagnosis between the three groups. With regard to FD, Savarino et al.14 found that clinically relevant dyspeptic symptoms in 37% of RH as well as NERD patients, which was lower than FH (63%). These findings suggest that RH shares the mechanism of visceral hypersensitivity with other functional gastrointestinal disorders.

2. Behavioral disorders (supragastric belching and rumination syndrome)

Excessive supragastric belching (SGB) and rumination syndrome (RS) are functional gastroduodenal disorders in Rome IV.88 Their impact on PPI refractory GERD has been increasingly recognized recently. In a study by Yadlapati et al.,89 postprandial high-resolution impedance manometry revealed the high prevalence of excessive SGB (42%) and RS (20%) in 94 PPI nonresponders. Our study evaluating the prevalence of the behavioral disorders in each reflux phenotype found that approximately 40% and 10% of RH patients had excessive SGB and RS respectively. Of which, 40% of typical reflux episodes (i.e., heartburn and regurgitation) recorded in impedance-pH monitoring was associated with SGB or rumination events.90

Belching can be classified into two types, gastric belching and SGB. Gastric belching is a physiological phenomenon to eliminate accumulated air in the proximal stomach through the mouth via transient lower esophageal relaxation. On the other hand, SGB is a behavioral disorder where a patient subconsciously swallows or sucks air from the mouth into the esophagus, then immediately followed by evacuating the air through the mouth using abdominal straining. SGB can cause reflux symptoms in two ways (1) triggering gastroesophageal reflux within a few seconds after the onset of SGB91 or (2) distending the esophagus. In fact, esophageal balloon distension can trigger heartburn sensation.92 Notably, some patients with excessive SGB predominantly complain about reflux symptoms rather than belching symptom.91

RS is defined as the repetitive, effortless regurgitation of recently ingested food into the mouth followed by rechewing and re-swallowing or expulsion of the food bolus.88 Typical RS patients are young female with low body mass index suffering from regurgitation.90 RS uses voluntary, but unconscious abdominal straining to bring up the gastric content into the mouth generating high intragastric pressure.93

SGB and RS patients are often referred to a gastroenterologist as PPI refractory GERD since reflux symptoms due to these conditions do not respond to acid suppression. Therefore, careful medical interview and impedance-pH monitoring would be required to avoid overlooking them.

1. Proton pump inhibitors

RH is often diagnosed after unsuccessful PPI/PCAB treatment. However, several studies evaluated the efficacy of PPI on PPI-naïve RH patients. Watson et al.94 found that omeprazole (40 mg/day) relieved 67% of GERD patients with normal endoscopy and physiological acid exposure in which positive SI was related to better outcome. de Bortoli et al.87 found that 56% of 218 RH patients experienced >50% symptom relief by PPIs, which is lower than NERD (68%), however, much better than FH (0%). Besides, Taghavi et al.95 showed the good association between positive SAP and symptomatic response to omeprazole (60 mg/day). Given the high efficacy of high-dose PPIs, maximizing the acid suppression (e.g., double-dose PPIs or vonoprazan 20 mg/day) should be considered for RH patients naïve to such treatments. However, PPIs/PCAB should be stopped especially for hypersensitivity to nonacid reflux in off-PPI impedance-pH monitoring.26

2. Histamine2-receptor antagonists

Histamine2-receptor antagonists are known to have analgesic effects on visceral nociception.96 Rodriguez-Stanley et al.96 showed ranitidine ameliorated esophageal acid sensitivity measured by acid perfusion test in RH or FH patients even after single administration of the drug. It is also the case in famotidine for NERD patients.97 Due to the small sample size in these studies, the pain modulating effect of histamine2-receptor antagonists needs to be evaluated for a large RH cohort.

3. ARS (fundoplication)

There are some evidences to support ARS for RH patients. Broeders et al.98 found that Nissen fundoplication improved or resolved reflux symptoms in 85% of RH patients even at 5 years after the surgery, which was similar to patients with pathological acid exposure. Patel et al.16 found the preferable outcome of ARS to medical therapy in RH. Although ARS achieved >50% symptoms improvement in about 90% of RH patients, the presence of hiatus hernia was associated with positive outcome. Besides, Rengarajan et al.99 found that patients with normal AET could be a candidate for ARS when MNBI is abnormal (<2,292 Ω). It implicates that part of these RH patients might be NERD with false negative AET. Spechler et al.100 conducted a randomized controlled study having three treatment arms (i.e., ARS [Nissen fundoplication], PPI plus baclofen and desipramine, and PPI plus placebo baclofen and desipramine) for refractory heartburn patients with positive SAP in on-PPI impedance-pH monitoring. They showed that the ARS group (67%) had better treatment success rate at 1 year after surgery than other groups, and the outcome in the ARS group did not differ regardless of coexisting abnormal acid exposure. Desjardin et al.101 also showed that positive SAP could predict successful outcome of ARS.

Taking these findings into consideration, RH is likely to be a good candidate for ARS as recommended in the ICARUS guidelines.102 Concomitant condition related to abnormal reflux (i.e., hiatus hernia or low MNBI) can further justify its application. However, there is still not enough evidence to support the indication. Furthermore, it should be noted that RH patients in several studies above are diagnosed by on-PPI impedance-pH monitoring. Given that PPIs/PCAB can normalize AET in most patients, RH should be diagnosed off PPI. Thus, we should be very careful about application of ARS to true RH phenotyped off PPI.

4. Pain modulators

Antidepressants are recommended as pain modulators for functional esophageal disorders. Several randomized controlled studies tested the effect of tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRIs) for well-phenotyped RH patients refractory to PPIs. Limsrivilai et al.103 showed once-daily imipramine 25 mg (TCA) had no effect on reflux symptoms despite a marginal improvement of QOL. On the other hand, Viazis et al.104 found that citalopram 20 mg/day (SSRI) resolved reflux symptoms in 61.5% of the RH patients superior to placebo (33.3%). Another study including both RH and FH patients also showed a better effect of fluoxetine (SSRI) over omeprazole and placebo.105

5. Cognitive behavioral therapy

Excessive SGB and/or RS require dedicated intervention due to their unignorable impact on reflux symptom burden.90 Although some studies reported the efficacy of baclofen and pregabalin on such behavioral disorders,106,107 cognitive behavioral therapy using diaphragmatic breathing should be attempted first because of the equal or greater efficacy without any adverse effect than the drugs.91,108-110 We reported that cognitive behavioral therapy reduces excessive SGB sufficiently in almost half of the patients.91 Our cognitive behavioral therapy program is composed of 5 sessions during 10 weeks. In brief, it helps patients to understand the mechanism of SGB in cognitive part and learn slow diaphragmatic breathing and mouth opening/tongue position to physically prevent SGB in behavioral part.91,111 In RS, pain modulators (e.g., TCA) might be an additional option if refractory to the diaphragmatic breathing.112

Since the Montreal definition,113 our understanding of GERD has been extended by a great deal of studies. Especially impedance monitoring and prolonged wireless pH metry have contributed to better understanding of RH. This progress led to a new perspective of GERD proposed by Rome IV and the Lyon consensus so that more pathophysiology-focused diagnosis can be made for the four reflux phenotypes including RH. The discovery of fairly high impact of behavioral disorders on reflux symptoms would be another novel finding contributing to identification of true RH. More precise diagnosis is essential for better management. However, treatment modalities for esophageal hypersensitivity are still limited. Further study will be required to understand the pathophysiology of esophageal hypersensitivity and develop new treatments.

  1. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional esophageal disorders. Gastroenterology 2016;150:P1368-P1379.
    Pubmed CrossRef
  2. Galmiche JP, Clouse RE, Bálint A, et al. Functional esophageal disorders. Gastroenterology 2006;130:1459-1465.
    Pubmed CrossRef
  3. Ashida K, Sakurai Y, Hori T, et al. Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther 2016;43:240-251.
    Pubmed KoreaMed CrossRef
  4. Xiao Y, Zhang S, Dai N, et al. Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis. Gut 2020;69:224-230.
    Pubmed KoreaMed CrossRef
  5. Iwakiri K, Fujiwara Y, Manabe N, et al. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021. J Gastroenterol 2022;57:267-285.
    Pubmed KoreaMed CrossRef
  6. Cicala M, Emerenziani S, Guarino MP, Ribolsi M. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. World J Gastroenterol 2013;19:6529-6535.
    Pubmed KoreaMed CrossRef
  7. Okuyama M, Nakahara K, Iwakura N, et al. Factors associated with potassium-competitive acid blocker non-response in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. Digestion 2017;95:281-287.
    Pubmed CrossRef
  8. Savarino E, Zentilin P, Tutuian R, et al. The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol 2008;103:2685-2693.
    Pubmed CrossRef
  9. Kohata Y, Fujiwara Y, Machida H, et al. Pathogenesis of proton-pump inhibitor-refractory non-erosive reflux disease according to multichannel intraluminal impedance-pH monitoring. J Gastroenterol Hepatol 2012;27 Suppl 3:58-62.
    Pubmed CrossRef
  10. Weijenborg PW, Smout AJ, Verseijden C, et al. Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis. Am J Physiol Gastrointest Liver Physiol 2014;307:G323-G329.
    Pubmed CrossRef
  11. Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Dodaran M, Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut 2018;67:430-440.
    Pubmed CrossRef
  12. Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Non-erosive reflux disease (NERD): acid reflux and symptom patterns. Aliment Pharmacol Ther 2003;17:537-545.
    Pubmed CrossRef
  13. Savarino E, Marabotto E, Zentilin P, et al. The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease. Dig Liver Dis 2011;43:542-547.
    Pubmed CrossRef
  14. Savarino E, Pohl D, Zentilin P, et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut 2009;58:1185-1191.
    Pubmed KoreaMed CrossRef
  15. Roman S, Keefer L, Imam H, et al. Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux. Neurogastroenterol Motil 2015;27:1667-1674.
    Pubmed KoreaMed CrossRef
  16. Patel A, Sayuk GS, Gyawali CP. Prevalence, characteristics, and treatment outcomes of reflux hypersensitivity detected on pH-impedance monitoring. Neurogastroenterol Motil 2016;28:1382-1390.
    Pubmed KoreaMed CrossRef
  17. Hemmink GJ, Bredenoord AJ, Weusten BL, Monkelbaan JF, Timmer R, Smout AJ. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: 'on' or 'off' proton pump inhibitor? Am J Gastroenterol 2008;103:2446-2453.
    Pubmed CrossRef
  18. Sawada A, Itami H, Nakagawa K, et al. Supragastric belching in Japan: lower prevalence and relevance for management of gastroesophageal reflux disease compared to United Kingdom. J Gastroenterol 2020;55:1046-1053.
    Pubmed KoreaMed CrossRef
  19. Tamura Y, Funaki Y, Izawa S, et al. Pathophysiology of functional heartburn based on Rome III criteria in Japanese patients. World J Gastroenterol 2015;21:5009-5016.
    Pubmed KoreaMed CrossRef
  20. Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J Gastroenterol 2009;44:518-534.
    Pubmed CrossRef
  21. Yadlapati R, Kahrilas PJ, Fox MR, et al. Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©. Neurogastroenterol Motil 2021;33:e14058.
    Pubmed KoreaMed CrossRef
  22. Pandolfino JE, Gawron AJ. Achalasia: a systematic review. JAMA 2015;313:1841-1852.
    Pubmed CrossRef
  23. Wahba G, Bouin M. Jackhammer esophagus: a meta-analysis of patient demographics, disease presentation, high-resolution manometry data, and treatment outcomes. Neurogastroenterol Motil 2020;32:e13870.
    Pubmed CrossRef
  24. Hosaka H, Kawami N, Manabe N, et al. Clinical presentation and therapeutic outcome of patients with jackhammer esophagus: a multicenter cohort study in Japan. Esophagus 2022;19:393-400.
    Pubmed KoreaMed CrossRef
  25. Tutuian R, Mainie I, Agrawal A, Gideon RM, Katz PO, Castell DO. Symptom and function heterogenicity among patients with distal esophageal spasm: studies using combined impedance-manometry. Am J Gastroenterol 2006;101:464-469.
    Pubmed CrossRef
  26. Yadlapati R, Gyawali CP, Pandolfino JE; CGIT GERD Consensus Conference Participants. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: expert review. Clin Gastroenterol Hepatol 2022;20:984-994.
    Pubmed CrossRef
  27. Rengarajan A, Pomarat M, Zerbib F, Gyawali CP. Overlap of functional heartburn and reflux hypersensitivity with proven gastroesophageal reflux disease. Neurogastroenterol Motil 2021;33:e14056.
    Pubmed CrossRef
  28. Piche T, Ducrotté P, Sabate JM, et al. Impact of functional bowel symptoms on quality of life and fatigue in quiescent Crohn disease and irritable bowel syndrome. Neurogastroenterol Motil 2010;22:626-e174.
    Pubmed CrossRef
  29. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut 2018;67:1351-1362.
    Pubmed KoreaMed CrossRef
  30. Sifrim D, Gyawali CP. Prolonged wireless pH monitoring or 24-hour catheter-based pH impedance monitoring: who, when, and why? Am J Gastroenterol 2020;115:1150-1152.
    Pubmed CrossRef
  31. Hasak S, Yadlapati R, Altayar O, et al. Prolonged wireless pH monitoring in patients with persistent reflux symptoms despite proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2020;18:2912-2919.
    Pubmed KoreaMed CrossRef
  32. Rogers BD, Valdovinos LR, Crowell MD, Bell R, Vela MF, Gyawali CP. Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation. Gut 2021;70:450-455.
    Pubmed CrossRef
  33. Frazzoni L, Frazzoni M, De Bortoli N, et al. Application of Lyon Consensus criteria for GORD diagnosis: evaluation of conventional and new impedance-pH parameters. Gut 2022;71:1062-1067.
    Pubmed CrossRef
  34. Frazzoni M, Manta R, Mirante VG, Conigliaro R, Frazzoni L, Melotti G. Esophageal chemical clearance is impaired in gastro-esophageal reflux disease: a 24-h impedance-pH monitoring assessment. Neurogastroenterol Motil 2013;25:399-406.
    Pubmed CrossRef
  35. Sifrim D, Roman S, Savarino E, et al. Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world. Gut 2021;70:1441-1449.
    Pubmed CrossRef
  36. Trimble KC, Pryde A, Heading RC. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut 1995;37:7-12.
    Pubmed KoreaMed CrossRef
  37. van Malenstein H, Farré R, Sifrim D. Esophageal dilated intercellular spaces (DIS) and nonerosive reflux disease. Am J Gastroenterol 2008;103:1021-1028.
    Pubmed CrossRef
  38. Farré R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011;60:885-892.
    Pubmed CrossRef
  39. Woodland P, Al-Zinaty M, Yazaki E, Sifrim D. In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut 2013;62:1256-1261.
    Pubmed CrossRef
  40. Weijenborg PW, Smout AJ, Bredenoord AJ. Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn. Neurogastroenterol Motil 2016;28:1649-1654.
    Pubmed CrossRef
  41. Farré R, van Malenstein H, De Vos R, et al. Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces. Gut 2008;57:1366-1374.
    Pubmed CrossRef
  42. Caviglia R, Ribolsi M, Maggiano N, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol 2005;100:543-548.
    Pubmed CrossRef
  43. Hopwood D, Milne G, Logan KR. Electron microscopic changes in human oesophageal epithelium in oesophagitis. J Pathol 1979;129:161-167.
    Pubmed CrossRef
  44. Zentilin P, Savarino V, Mastracci L, et al. Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol 2005;100:2299-2306.
    Pubmed CrossRef
  45. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 2009;137:1776-1784.
    Pubmed CrossRef
  46. Isomoto H, Saenko VA, Kanazawa Y, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol 2004;99:589-597.
    Pubmed CrossRef
  47. Kondo T, Oshima T, Tomita T, et al. Prostaglandin E(2) mediates acid-induced heartburn in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2013;304:G568-G573.
    Pubmed CrossRef
  48. Kondo T, Sei H, Yamasaki T, et al. A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial. J Gastroenterol 2017;52:1081-1089.
    Pubmed CrossRef
  49. Kondo T, Oshima T, Tomita T, et al. The nonsteroidal anti-inflammatory drug diclofenac reduces acid-induced heartburn symptoms in healthy volunteers. Clin Gastroenterol Hepatol 2015;13:1249-1255.
    Pubmed CrossRef
  50. Sarkar S, Hobson AR, Hughes A, et al. The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans. Gastroenterology 2003;124:18-25.
    Pubmed CrossRef
  51. Woodland P, Aktar R, Mthunzi E, et al. Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa. Am J Physiol Gastrointest Liver Physiol 2015;308:G525-G531.
    Pubmed KoreaMed CrossRef
  52. Thoua NM, Khoo D, Kalantzis C, Emmanuel AV. Acid-related oesophageal sensitivity, not dysmotility, differentiates subgroups of patients with non-erosive reflux disease. Aliment Pharmacol Ther 2008;27:396-403.
    Pubmed CrossRef
  53. Bredenoord AJ, Weusten BL, Curvers WL, Timmer R, Smout AJ. Determinants of perception of heartburn and regurgitation. Gut 2006;55:313-318.
    Pubmed KoreaMed CrossRef
  54. Zerbib F, Duriez A, Roman S, Capdepont M, Mion F. Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 2008;57:156-160.
    Pubmed CrossRef
  55. Woodland P, Shen Ooi JL, Grassi F, et al. Superficial esophageal mucosal afferent nerves may contribute to reflux hypersensitivity in nonerosive reflux disease. Gastroenterology 2017;153:1230-1239.
    Pubmed CrossRef
  56. Nikaki K, Woodland P, Lee C, et al. Esophageal mucosal innervation in functional heartburn: closer to healthy asymptomatic subjects than to non-erosive reflux disease patients. Neurogastroenterol Motil 2019;31:e13667.
    Pubmed CrossRef
  57. Gouin O, L'Herondelle K, Lebonvallet N, et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 2017;8:644-661.
    Pubmed KoreaMed CrossRef
  58. Blackshaw LA. Transient receptor potential cation channels in visceral sensory pathways. Br J Pharmacol 2014;171:2528-2536.
    Pubmed KoreaMed CrossRef
  59. Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 2004;16:897-902.
    Pubmed CrossRef
  60. Bhat YM, Bielefeldt K. Capsaicin receptor (TRPV1) and non-erosive reflux disease. Eur J Gastroenterol Hepatol 2006;18:263-270.
    Pubmed CrossRef
  61. Guarino MP, Cheng L, Ma J, et al. Increased TRPV1 gene expression in esophageal mucosa of patients with non-erosive and erosive reflux disease. Neurogastroenterol Motil 2010;22:746-751.
    Pubmed CrossRef
  62. Ustaoglu A, Sawada A, Lee C, et al. Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors. Am J Physiol Gastrointest Liver Physiol 2021;320:G804-G815.
    Pubmed CrossRef
  63. Krarup AL, Ny L, Gunnarsson J, et al. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain. Scand J Gastroenterol 2013;48:274-284.
    Pubmed CrossRef
  64. Banovcin P, Duricek M, Zatko T, Liptak P, Hyrdel R, Kollarik M. The infusion of menthol into the esophagus evokes cold sensations in healthy subjects but induces heartburn in patients with gastroesophageal reflux disease (GERD). Dis Esophagus 2019;32:doz038.
    Pubmed CrossRef
  65. Chen CC, Wong CW. Neurosensory mechanotransduction through acid-sensing ion channels. J Cell Mol Med 2013;17:337-349.
    Pubmed KoreaMed CrossRef
  66. Yoshida N, Kuroda M, Suzuki T, et al. Role of nociceptors/neuropeptides in the pathogenesis of visceral hypersensitivity of nonerosive reflux disease. Dig Dis Sci 2013;58:2237-2243.
    Pubmed CrossRef
  67. Kandulski A, Wex T, Mönkemüller K, et al. Proteinase-activated receptor-2 in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol 2010;105:1934-1943.
    Pubmed CrossRef
  68. Yoshida N, Katada K, Handa O, et al. Interleukin-8 production via protease-activated receptor 2 in human esophageal epithelial cells. Int J Mol Med 2007;19:335-340.
    Pubmed CrossRef
  69. Wu L, Oshima T, Shan J, et al. PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2015;309:G695-G702.
    Pubmed CrossRef
  70. Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487-1493.
    Pubmed CrossRef
  71. Kusano M, Kouzu T, Kawano T, Ohara S. Nationwide epidemiological study on gastroesophageal reflux disease and sleep disorders in the Japanese population. J Gastroenterol 2008;43:833-841.
    Pubmed CrossRef
  72. Fujiwara Y, Arakawa T, Fass R. Gastroesophageal reflux disease and sleep disturbances. J Gastroenterol 2012;47:760-769.
    Pubmed CrossRef
  73. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787-1795.
    Pubmed CrossRef
  74. Yi CH, Lei WY, Hung JS, Liu TT, Orr WC, Chen CL. Sleep disturbance and enhanced esophageal capsaicin sensitivity in patients with gastroesophageal reflux disease. J Gastroenterol Hepatol 2016;31:1940-1945.
    Pubmed CrossRef
  75. Farré R, De Vos R, Geboes K, et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 2007;56:1191-1197.
    Pubmed KoreaMed CrossRef
  76. Fujiwara Y, Kohata Y, Kaji M, et al. Sleep dysfunction in Japanese patients with gastroesophageal reflux disease: prevalence, risk factors, and efficacy of rabeprazole. Digestion 2010;81:135-141.
    Pubmed CrossRef
  77. Losa M, Manz SM, Schindler V, Savarino E, Pohl D. Increased visceral sensitivity, elevated anxiety, and depression levels in patients with functional esophageal disorders and non-erosive reflux disease. Neurogastroenterol Motil 2021;33:e14177.
    Pubmed CrossRef
  78. Kessing BF, Bredenoord AJ, Saleh CM, Smout AJ. Effects of anxiety and depression in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2015;13:1089-1095.
    Pubmed CrossRef
  79. Taft TH, Triggs JR, Carlson DA, et al. Validation of the oesophageal hypervigilance and anxiety scale for chronic oesophageal disease. Aliment Pharmacol Ther 2018;47:1270-1277.
    Pubmed KoreaMed CrossRef
  80. Wong MW, Liu TT, Yi CH, et al. Oesophageal hypervigilance and visceral anxiety relate to reflux symptom severity and psychological distress but not to acid reflux parameters. Aliment Pharmacol Ther 2021;54:923-930.
    Pubmed CrossRef
  81. Guadagnoli L, Yadlapati R, Taft T, Pandolfino JE, Tye M, Keefer L. Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations. Neurogastroenterol Motil 2021;33:e14081.
    Pubmed KoreaMed CrossRef
  82. Taft TH, Carlson DA, Simons M, et al. Esophageal hypervigilance and symptom-specific anxiety in patients with eosinophilic esophagitis. Gastroenterology 2021;161:1133-1144.
    Pubmed KoreaMed CrossRef
  83. Carlson DA, Gyawali CP, Roman S, et al. Esophageal hypervigilance and visceral anxiety are contributors to symptom severity among patients evaluated with high-resolution esophageal manometry. Am J Gastroenterol 2020;115:367-375.
    Pubmed KoreaMed CrossRef
  84. Kaji M, Fujiwara Y, Shiba M, et al. Prevalence of overlaps between GERD, FD and IBS and impact on health-related quality of life. J Gastroenterol Hepatol 2010;25:1151-1156.
    Pubmed CrossRef
  85. Vakil N, Stelwagon M, Shea EP, Miller S. Symptom burden and consulting behavior in patients with overlapping functional disorders in the US population. United European Gastroenterol J 2016;4:413-422.
    Pubmed KoreaMed CrossRef
  86. Lovell RM, Ford AC. Prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. Am J Gastroenterol 2012;107:1793-1801.
    Pubmed CrossRef
  87. de Bortoli N, Frazzoni L, Savarino EV, et al. Functional heartburn overlaps with irritable bowel syndrome more often than GERD. Am J Gastroenterol 2016;111:1711-1717.
    Pubmed CrossRef
  88. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. Gastroenterology 2016;150:1380-1392.
    Pubmed CrossRef
  89. Yadlapati R, Tye M, Roman S, Kahrilas PJ, Ritter K, Pandolfino JE. Postprandial high-resolution impedance manometry identifies mechanisms of nonresponse to proton pump inhibitors. Clin Gastroenterol Hepatol 2018;16:211-218.
    Pubmed KoreaMed CrossRef
  90. Sawada A, Guzman M, Nikaki K, et al. Identification of different phenotypes of esophageal reflux hypersensitivity and implications for treatment. Clin Gastroenterol Hepatol 2021;19:690-698.
    Pubmed CrossRef
  91. Glasinovic E, Wynter E, Arguero J, et al. Treatment of supragastric belching with cognitive behavioral therapy improves quality of life and reduces acid gastroesophageal reflux. Am J Gastroenterol 2018;113:539-547.
    Pubmed CrossRef
  92. Takeda T, Nabae T, Kassab G, Liu J, Mittal RK. Oesophageal wall stretch: the stimulus for distension induced oesophageal sensation. Neurogastroenterol Motil 2004;16:721-728.
    Pubmed CrossRef
  93. Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001;121:526-535.
    Pubmed CrossRef
  94. Watson RG, Tham TC, Johnston BT, McDougall NI. Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux: the "sensitive oesophagus". Gut 1997;40:587-590.
    Pubmed KoreaMed CrossRef
  95. Taghavi SA, Ghasedi M, Saberi-Firoozi M, et al. Symptom association probability and symptom sensitivity index: preferable but still suboptimal predictors of response to high dose omeprazole. Gut 2005;54:1067-1071.
    Pubmed KoreaMed CrossRef
  96. Rodriguez-Stanley S, Ciociola AA, Zubaidi S, Proskin HM, Miner PB Jr. A single dose of ranitidine 150 mg modulates oesophageal acid sensitivity in patients with functional heartburn. Aliment Pharmacol Ther 2004;20:975-982.
    Pubmed CrossRef
  97. Marrero JM, de Caestecker JS, Maxwell JD. Effect of famotidine on oesophageal sensitivity in gastro-oesophageal reflux disease. Gut 1994;35:447-450.
    Pubmed KoreaMed CrossRef
  98. Broeders JA, Draaisma WA, Bredenoord AJ, et al. Oesophageal acid hypersensitivity is not a contraindication to Nissen fundoplication. Br J Surg 2009;96:1023-1030.
    Pubmed CrossRef
  99. Rengarajan A, Savarino E, Della Coletta M, Ghisa M, Patel A, Gyawali CP. Mean nocturnal baseline impedance correlates with symptom outcome when acid exposure time is inconclusive on esophageal reflux monitoring. Clin Gastroenterol Hepatol 2020;18:589-595.
    Pubmed CrossRef
  100. Spechler SJ, Hunter JG, Jones KM, et al. Randomized trial of medical versus surgical treatment for refractory heartburn. N Engl J Med 2019;381:1513-1523.
    Pubmed CrossRef
  101. Desjardin M, Luc G, Collet D, Zerbib F. 24-hour pH-impedance monitoring on therapy to select patients with refractory reflux symptoms for antireflux surgery: a single center retrospective study. Neurogastroenterol Motil 2016;28:146-152.
    Pubmed CrossRef
  102. Pauwels A, Boecxstaens V, Andrews CN, et al. How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery). Gut 2019;68:1928-1941.
    Pubmed CrossRef
  103. Limsrivilai J, Charatcharoenwitthaya P, Pausawasdi N, Leelakusolvong S. Imipramine for treatment of esophageal hypersensitivity and functional heartburn: a randomized placebo-controlled trial. Am J Gastroenterol 2016;111:217-224.
    Pubmed CrossRef
  104. Viazis N, Keyoglou A, Kanellopoulos AK, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study. Am J Gastroenterol 2012;107:1662-1667.
    Pubmed CrossRef
  105. Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil 2014;26:670-678.
    Pubmed CrossRef
  106. Blondeau K, Boecxstaens V, Rommel N, et al. Baclofen improves symptoms and reduces postprandial flow events in patients with rumination and supragastric belching. Clin Gastroenterol Hepatol 2012;10:379-384.
    Pubmed CrossRef
  107. Kunte H, Kronenberg G, Fink K, Harms L, Hellweg R. Successful treatment of excessive supragastric belching by combination of pregabalin and baclofen. Psychiatry Clin Neurosci 2015;69:124-125.
    Pubmed CrossRef
  108. Hemmink GJ, Ten Cate L, Bredenoord AJ, Timmer R, Weusten BL, Smout AJ. Speech therapy in patients with excessive supragastric belching: a pilot study. Neurogastroenterol Motil 2010;22:24-28.
    Pubmed CrossRef
  109. Murray HB, Juarascio AS, Di Lorenzo C, Drossman DA, Thomas JJ. Diagnosis and treatment of rumination syndrome: a critical review. Am J Gastroenterol 2019;114:562-578.
    Pubmed KoreaMed CrossRef
  110. Hoshikawa Y, Fitzke H, Sweis R, et al. Rumination syndrome: assessment of vagal tone during and after meals and during diaphragmatic breathing. Neurogastroenterol Motil 2020;32:e13873.
    Pubmed CrossRef
  111. Sawada A, Anastasi N, Green A, et al. Management of supragastric belching with cognitive behavioural therapy: factors determining success and follow-up outcomes at 6-12 months post-therapy. Aliment Pharmacol Ther 2019;50:530-537.
    Pubmed CrossRef
  112. Robles A, Romero YA, Tatro E, Quezada H, McCallum RW. Outcomes of treating rumination syndrome with a tricyclic antidepressant and diaphragmatic breathing. Am J Med Sci 2020;360:42-49.
    Pubmed CrossRef
  113. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-1920.
    Pubmed CrossRef

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Gut and Liver

Published online January 2, 2023

Copyright © Gut and Liver.

Esophageal Reflux Hypersensitivity: A Comprehensive Review

Akinari Sawada1 , Daniel Sifrim2 , Yasuhiro Fujiwara1

1Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan, and 2Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Correspondence to:Akinari Sawada
ORCID https://orcid.org/0000-0002-0590-3693
E-mail a.sawada@omu.ac.jp

Received: August 24, 2022; Revised: October 1, 2022; Accepted: October 18, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Reflux hypersensitivity (RH) is one of the phenotypes of gastroesophageal reflux disease. The latest Rome IV defines RH as a condition with typical reflux symptoms and positive reflux-symptom association despite normal acid exposure. Subsequently, the Lyon consensus proposed detailed cutoff values for the criteria on the basis of experts’ consensus. Rome IV brought a clear-cut perspective into the pathophysiology of gastroesophageal reflux disease and the importance of esophageal hypersensitivity. This perspective can be supported by the fact that other functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia often overlap with RH. Although several possible pathophysiological mechanisms of esophageal hypersensitivity have been identified, there is still unmet medical needs in terms of treatment for this condition. This review summarizes the current knowledge regarding RH.

Keywords: Reflux hypersensitivity, Gastroesophageal reflux disease, Functional esophageal disorders, Impedance-pH monitoring, Behavioral disorders

INTRODUCTION

Reflux hypersensitivity (RH) is one of the functional esophageal disorders in Rome IV.1 RH is defined as patients with typical reflux symptoms having normal acid exposure and positive reflux symptom association. The definition of RH, formerly called hypersensitive esophagus, changed with the revision of the Rome criteria. In the previous criteria (Rome III), RH and patients with abnormal acid exposure were encompassed within the same entity (i.e., nonerosive reflux disease [NERD]) in spite of inconsistency in response to acid suppression therapy and mechanisms of reflux symptom generation.2 Subsequently, Rome IV introduced a new classification of gastroesophageal reflux disease (GERD) including a specific category called RH on the basis of the balance between two main pathophysiological parameters: esophageal acid exposure and esophageal hypersensitivity. For acid exposure, highly effective therapeutic options are available such as acid suppressive therapy and anti-reflux surgery (ARS). The healing of erosive esophagitis (EE) can be achieved in more than 90% of the cases by proton pump inhibitors (PPIs) or potassium-competitive acid blockers (PCABs).3-5 However, these treatments cannot alleviate reflux symptoms enough in up to 48% of reflux patients.6,7 The difference of treatment outcome between mucosal healing and reflux symptoms is probably attributable to esophageal hypersensitivity since there is poor correlation between the severity of mucosal damage and the severity of symptoms.8-10 The process of symptom generation starts from the esophageal sensory nerve fibers stimulated by gastroesophageal reflux, followed by the transmission of the simulation to the central nervous system via vagal afferent nerves or spinal nerves. Although many studies found that there are multitude of central and peripheral factors related to esophageal hypersensitivity, this extremely complex process has not been completely elucidated, and makes the treatment for this condition challenging.

In this comprehensive review, we summarized the current knowledge about RH from epidemiology to treatment.

EPIDEMIOLOGY

RH affects a relatively small proportion of patients with GERD. However, the number of RH patients is not negligible considering the high global prevalence of GERD (14.8%).11 Martinez et al.12 studied patients with heartburn who were not yet treated with PPIs. They found that 9% of the reflux patients had RH, which accounts for 20% of patients with normal upper endoscopy (Fig. 1). This study could not identify nonacid reflux because of the lack of impedance sensors, then Savarino et al.8 investigated patients with typical reflux symptoms using off-PPI impedance-pH monitoring. The study showed similar proportion of RH, NERD, and functional heartburn (FH) in endoscopy-negative patients to the previous study when calculating reflux-symptom association only for acid reflux episodes. However, incorporation of nonacid reflux episodes into reflux-symptom association increased the prevalence of RH by approximately 10%. A similar diagnostic yield was seen in other off-PPI impedance-pH monitoring studies (Fig. 1).13,14

Figure 1. Prevalence of each reflux phenotype in all patients with heartburn (A) and in endoscopy-negative patients with heartburn and/or regurgitation (B). The patients in both studies were phenotyped after at least a 14-day discontinuation of acid suppressive therapy. Only pH monitoring was used in (A), while impedance-pH monitoring was used in (B) so that the reflux-symptom association could be calculated for both acid and nonacid reflux episodes.
NERD, nonerosive reflux disease; RH, reflux hypersensitivity; FH, functional heartburn.

On-PPI impedance-pH monitoring showed that the RH prevalence in endoscopy-negative patients was similar to that observed in studies performed off-PPI. Roman et al.15 reported 36% of PPI nonresponder patients was diagnosed as RH on PPI. Patel et al.16 also found similar prevalence of RH between on- and off-PPI studies. However, part of NERD patients diagnosed off PPI can be converted into RH when tested on-PPI.17 Thus, RH cohort defined by off-PPI study is not necessarily same as those by on-PPI study.

The regional difference influences the RH prevalence. Several large Japanese on-PPI studies report that the prevalence of RH is up to 44%, which is higher than in Western countries.18-20

DIAGNOSIS OF RH

The two experts’ consensuses, Rome IV criteria and the Lyon consensus, are the bedrock of RH diagnosis. Their proposed criteria for RH require dedicated esophageal physiology testing (i.e., manometry and impedance-pH monitoring). Thus, RH is normally diagnosed at tertiary centers due to the availability of such techniques. The Lyon consensus complements Rome IV criteria providing detailed cutoff values, specifically for impedance-pH monitoring (Fig. 2).

Figure 2. Diagnostic algorithm of PPI/PCAB refractory reflux patients.
PPI, proton pump inhibitor; PCAB, potassium-competitive acid blocker; SGB, supragastric belching; RS, rumination syndrome; EGD, esophagogastricduodenoscopy; HRM, high-resolution manometry; HRIM, high-resolution impedance manometry; RS, rumination syndrome; EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; LA, Los Angeles classification; LSBE, long segment Barrett’s esophagus; AET, acid exposure time.

1. Rome IV criteria

The latest Rome IV criteria classifies GERD into four phenotypes as follows: (1) EE, (2) NERD, (3) RH, (4) FH.1 It is suggested that acid exposure predominantly accounts for esophageal symptoms in EE and NERD whilst esophageal hypersensitivity overrides acid reflux in RH and FH.

The diagnostic criteria of RH are as follows: (1) retrosternal symptoms including heartburn and chest pain; (2) normal endoscopy and absence of evidence that eosinophilic esophagitis is the cause for symptoms; (3) absence of major esophageal motor disorders (achalasia/esophagogastric junction outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent peristalsis); and (4) evidence of triggering of symptoms by reflux events despite normal acid exposure on pH only or impedance-pH monitoring.

The last condition has been amended from Rome III as response to antisecretory therapy is no longer required for the diagnosis. All of the four items must be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis with a frequency of at least twice a week. In clinical practice, regurgitation is often seen as one of the typical symptoms in RH in spite of the criteria.

The diagnostic work-up incudes multiple biopsies from different levels of the esophagus to exclude eosinophilic esophagitis during endoscopy, high-resolution manometry and pH only or impedance-pH monitoring. High-resolution manometry is essential to exclude motility disorders and locate the upper edge of the lower esophageal sphincter to position esophageal pH sensor precisely.21 Typical reflux symptoms such as heartburn and/or regurgitation can be presented by up to 75%, 35% and 20% of patients with achalasia, hypercontractile esophagus and distal esophageal spasm respectively.22-25

Rome IV also introduces the concept that RH and FH can overlap with proven GERD (i.e., Los Angeles classification grade B/C/D or long segment Barrett’s esophagus) as some patients still suffer from reflux symptoms after the mucosal healing.1,26 This concept seems to be supported by the similar psychological profiles and the prevalence of other functional gastrointestinal disorders such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) between RH/FH with and without proven GERD.27 This kind of overlap between functional and organic disorders is also seen in bowel disorders as some patients with inflammatory bowel diseases suffer from IBS-like symptoms even in remission.28

2. Lyon consensus

Although the Rome IV criteria defines RH, there was lack of concrete cutoff values for two conditions, (1) normal esophageal acid exposure and (2) positive symptom reflux association. The Lyon consensus addressed this issue where normal and pathological acid exposure time (AET) were proposed as <4% and >6%, respectively.29 Concerning reflux-symptom association, symptom index (SI) and symptom association probability (SAP) are the two most common indices. In many cases, a symptom is considered related to reflux when the symptom is marked within 2 minutes after a reflux episode. SI is the proportion of reflux-related symptoms to the total number of reflux symptoms which considered positive when ≥50%. SAP uses a Fisher exact test for the presence or absence of reflux and/or symptoms for each 2 minutes segment of the entire tracings. A p<0.05 indicates the probability of chance association between reflux symptoms and reflux episodes is <5%, corresponding to a positive SAP (>95%).

The diagnosis of RH can be inconclusive with AET between 4% and 6% and/or only SI or SAP positive. There would be two options to make a robust diagnosis for RH as follows: (1) performing prolonged wireless pH monitoring, or (2) using other MII-pH parameters as a complement. The choice largely depends on local institutional expertise and availability of the techniques.

Wireless pH monitoring can record up to 96 hours, which decreases the influence of day-to-day variability of AET.30 As even healthy subjects have pathological AET at times, RH patients can be diagnosed as NERD if tested with 24-hour pH metry on the worst reflux day. Hasak et al.31 found that longer recording time (e.g., 72 or 96 hours) can provide diagnostic yield especially when AET in the first 2 days are discordant or borderline. The complementary metrics include the number of reflux episodes, mean nocturnal baseline impedance (MNBI) and post-reflux swallow peristaltic wave (PSPW) index. The Lyon consensus proposes that >80 reflux episodes per 24 hours is conceivably abnormal whereas <40 is physiological. Recently <40 and <35 reflux episodes have been validated as physiological for heartburn and regurgitation respectively.32,33 MNBI reflects cumulative damage of the mucosa, which is known as a surrogate marker for mucosal integrity (MI). Thus, little influence of day-to-day variability of acid reflux. PSPW index is the proportion of reflux episodes followed by saliva swallowing within 30 seconds from the end of reflux episode, which reflects the ability of esophageal chemical clearance.34 In fact, several studies showed lower PSPW index in acid reflux predominant GERD phenotypes (i.e., EE and NERD) compared to esophageal hypersensitivity predominant.34 Frazzoni et al.33 showed 50% for PSPW index and 2,000 Ω for MNBI at 3 cm above the lower esophageal sphincter as optimal cutoff values to predict PPI-dependent heartburn compared to asymptomatic subjects. On the other hand, the largest healthy subjects’ data (n=391) of 24-hour off-PPI impedance-pH monitoring calculated a cutoff value of MNBI and PSPW index as 1,384 Ω and 15%, respectively.35 These studies suggest that patients with >50% PSPW index and/or >2,000 Ω MNBI probably have normal acid exposure on average even when AET is inconclusive in 24-hour impedance-pH monitoring.

PATHOPHYSIOLOGY OF ESOPHAGEAL HYPERSENSITIVITY

Several studies demonstrated esophageal hypersensitivity to noxious stimuli in GERD patients. Trimble et al.36 showed that patients with RH had a lower sensory threshold for esophageal balloon distension compared to those with NERD, Barrett’s esophagus or asymptomatic healthy subjects. Although the entire mechanism of esophageal hypersensitivity remains to be elucidated, several potential factors have been reported so far (Fig. 3).

Figure 3. Mechanism underlying esophageal reflux hypersensitivity. Exogenous stimuli perceived by the esophageal sensory nerves are transmitted to the central nervous system via two ways; vagal afferent nerves via the nodose ganglion and spinal nerves via dorsal root ganglion. Several factors contribute to reflux hypersensitivity influencing peripheral sensors in the esophagus or the central nervous system. Some mechanisms such as mucosal integrity, cytokines and prostaglandin E2, sensory receptors (TRPV1 and ASIC3) and superficial mucosal afferent nerves are associated with peripheral hypersensitivity. Other mechanisms such as esophageal hypervigilance along with anxiety and sleep disturbance mainly affect the processing of the conveyed stimuli in the central nervous system, which results in amplification of the sensation. These factors also might enhance peripheral sensitivity by impairing the mucosal integrity.
TRPV1, transient receptor potential vanilloid receptor-1; ASIC3, acid-sensing ion channel 3.

1. Mucosal integrity

Reflux symptoms can occur when the refluxate comes in contact with the esophageal mucosa. In EE, such stimuli including acid, bile, and pepsin can reach sensory afferent nerve endings in the esophageal wall via the mucosal deficit.37 On the other hand, microscopic mucosal damage impairs MI in NERD. MI reflects barrier function of the mucosa, which can be measured in vivo (e.g. impedance monitoring) or in vitro (e.g. transepithelial electrical resistance, molecule permeability using ushing chamber, and transmission electron microscopy).38 Impaired MI lets noxious substances pass through the mucosa, and MI inversely correlates to acid sensitivity in patients with NERD (i.e., lower MI more hypersensitive).10,39 However, Weijenborg et al.40 found no difference in MI between NERD and FH even though NERD had the shorter perception time in the acid perfusion test. These findings indicate that MI is not a sole factor to explain acid sensitivity.

Esophageal mucosal dilated intercellular space (DIS) is a histological condition associated with impaired MI. There is a causal link between DIS and MI as acid and bile perfusion cause both conditions simultaneously.38,41 DIS can be found not only in EE and NERD but also in patients with normal AET.37,42,43 Thus, DIS could explain the mechanism of symptom perception in RH. However, it should be noted that DIS can be found in up to 30% of asymptomatic subjects.44 On top of that, the DIS is predominantly located in the basal layer, which questions whether it truly increases epithelial permeability for noxious substances from the luminal side.

2. Cytokines and prostaglandin E2

Despite the orthodox hypothesis that reflux damages esophageal mucosa directly from the luminal side, Souza et al.45 suggests the opposite way of the development of esophageal inflammation by reflux (i.e., from inside the mucosa via cytokines). Their animal study found that acid reflux causes the epithelium to secrete proinflammatory cytokines such as interleukin (IL)-8 and IL1-b, and subsequently mainly IL-8 induces the migration of T cells and neutrophils to the submucosal layer, finally extending to the epithelial surface. Isomoto et al.46 showed increased IL-8 expression in the esophageal epithelium of NERD patients, which lowered after 8-week PPI treatment in line with reflux symptom resolution. This implies the involvement of IL-8-induced mucosal inflammation in symptom generation.

Prostaglandin E2 (PGE2) also plays an important role in visceral hypersensitivity both at central and peripheral levels via the prostaglandin E2 receptor-1 (EP-1). Kondo et al.47 showed that the level of PGE2 in the esophageal mucosa increased after acid perfusion which correlated to intensity of heartburn. EP1 receptor expressed in the mucosa and co-localized on protein gene product 9.5 immunoreactive nerve specifically in the muscularis mucosae and submucosa. In line with the results, EP-1 receptor antagonists and diclofenac (nonsteroidal anti-inflammatory drug) attenuated acid infusion induced heartburn or visceral hypersensitivity.48-50

3. Superficial mucosal afferent nerves

Esophageal afferent sensory nerves are distributed in the esophageal mucosa and are likely to play an important role on perceiving noxious stimuli from the luminal surface. The afferent nerves are normally located closer to the lumen in the proximal esophagus compared to the distal esophagus.51 It might explain acid hypersensitivity in the proximal esophagus.52 Additionally, proximal reflux is one of the determinants triggering reflux symptoms.53,54 Given these findings, the sensitivity of mucosal afferent nerves presumably depends on its proximity to the lumen. Our previous study found that NERD patients show more superficial mucosal afferent nerve (i.e., closer to the lumen) compared to healthy subjects.55 Thus, the superficial nerve may partly underlie the mechanism of esophageal hypersensitivity. Interestingly, FH patients had mucosal afferent nerve at the similar depth to healthy subjects.56 Esophageal hypersensitivity in FH might be predominantly formed by central factors rather than peripheral factors. Further study is warranted to investigate esophageal mucosal innervation of RH patients.

4. Sensory receptors (TRPV1 and ASIC3)

Transient receptor potential vanilloid receptor-1 (TRPV1) is a polymodal, nociceptive cation channel. TRPV1 can be activated by several exogenous factors including protons (H+), capsaicin and high temperature.57 The expression of TRPV1 can be seen in not only afferent nerve fibers but also non-neural cells.58-60 Guarino et al.61 found NERD and EE patients have higher mRNA and protein expression levels of TRPV1 in esophageal mucosal biopsies than healthy control. Besides, our recent study showed that TRPV1 is frequently expressed on superficial afferent nerves in the esophageal epithelium whereas occasional expression was seen on deep nerves around basal layer.62 On the other hand, a randomized controlled study by Krarup et al.63 showed no inhibitory effect of TRPV1 antagonist on chest pain induced by heat, distension or electronic current in the esophagus. With regard to other TRPs receptors, transient receptor potential melastatin 8 (TRPM8) might be involved in esophageal hypersensitivity as menthol (i.e., TRPM8 agonists) infusion into the esophagus triggers different sensation in healthy subjects (cold sensation) and GERD patients (heartburn).64

A few studies have reported the role of acid-sensing ion channels (ASICs) in human GERD. ASICs are voltage-insensitive epithelial Na+ channels responding to extracellular acidification, which function as nociceptor as well as mechanoreceptor.65 Immunohistochemistry shows increased expression of ASIC3 in NERD compared to FH.62 On the other hand, mRNA expression level of ASIC3 in the esophageal mucosa does not differ between NERD and control.62,66

Proteinase-activated receptor-2 (PAR-2) is a tethered ligand G protein-coupled receptor with seven transmembrane domains. Serine proteases including mast cell tryptase and pancreatic trypsin can activate PAR-2, which leads to visceral hypersensitivity and pain as a result of inflammatory and neuroinflammatory epithelial response via the secretion of IL-8, substance P and calcitonin gene-related peptide.67,68 Kandulski et al.67 found that PAR-2 and IL-8 expressed in the esophageal epithelium markedly in NERD and EE compared to control. Furthermore, these expressions correlated to histological changes such as DIS, basal cell hyperplasia and papillary elongation.

Wu et al.69 studied the link between TRPV1, ASIC3 and PAR-2 using human esophageal epithelial cells and found that activation of PAR-2 enhances a pain-related substance release (i.e., acid-induced adenosine triphosphate) from the esophageal epithelium through TRPV1 and ASIC3.

5. Sleep disturbance

Sleep disturbance is one of the common coexisting conditions in GERD. In a U.S. nationwide survey of 1,000 patients with at least once-a-week heartburn, 79% of the patients reported nighttime heartburn, and 75% of whom considered the reflux symptoms affected their sleep.70 As for a Japanese nationwide survey, 56.3% of 2,426 patients with heartburn had sleep disorders which was significantly higher than those without (40.7%), and there was a positive correlation between frequency of heartburn and the prevalence of sleep disturbance.71

GERD and sleep disturbance are likely to affect each other bidirectionally. Nighttime reflux provokes heartburn, which leads to difficulty in falling asleep, nocturnal and/or early morning awakening.72 Contrarily, sleep deprivation sensitizes the esophagus to acid and capsaicin (TRPV1 agonist).73,74 It is of interest that this effect was seen in GERD patients, however not in healthy volunteers.73 Sleep disturbance probably affects not only the processing of sensation in the central nervous system but also peripheral sensitivity since acute stress impaired mucosa integrity with DIS in animal study.75 GERD and sleep disturbance can be exacerbated each other in a “vicious cycle” where GERD deteriorates sleep quality which in turn sensitizes the esophagus.73 Our previous study found endoscopy-negative GERD was a significant risk factor of sleep disturbance compared to EE (odds ratio, 2.18; 95% confidence interval, 1.05 to 4.53),76 which might underscore the influence of sleep disturbance towards RH rather than the opposite direction.

6. Esophageal hypervigilance and anxiety

It is well known that psychological factors such as anxiety and depression contribute to symptom generation as well as its intensity in many conditions. This is the case in reflux symptoms as there is a higher level of visceral hypersensitivity, anxiety and depression across endoscopy-negative reflux phenotypes (i.e., RH, FH, and NERD) compared to healthy control.77 Moreover, Kessing et al.78 showed anxiety level positively correlates to severity of heartburn and chest pain.

Hypervigilance is a mental condition which encompasses several thoughts that drives attention to body sensations, anxiety and expectation about symptoms and fear for the consequences of the symptoms. This condition lowers a threshold to stimuli, that is to say, the patients can perceive no or subtle stimuli which most people cannot (i.e., allodynia), and symptoms can be intensified (i.e., hyperalgesia).79 Taft et al.79 have recently developed and validated a questionnaire called esophageal hypervigilance and anxiety scale (EHAS) to assess hypervigilance and anxiety, specifically for esophageal sensations. So far several studies demonstrated close relationship between EHAS and esophageal symptom severity in GERD, esophageal motility disorders, and eosinophilic esophagitis.80-83 Wong et al.80 found that EHAS positively correlated to reflux symptom severity regardless of GERD phenotypes. While Guadagnoli et al.81 demonstrated that only hypervigilant component in EHAS was a significant factor associated with reflux symptom severity.

CONDITIONS ASSOCIATED WITH RH

1. IBS and function dyspepsia

Common functional gastrointestinal disorders such as FD and IBS often overlap with GERD.84,85 Our previous study found that FD and IBS coexist with 31% and 29% of GERD patients respectively, and more importantly the overlap worsens health-related quality of life compared to having either one condition.84 In a meta-analysis, IBS patients are more likely to have reflux symptoms compared to non-IBS patients (odds ratio, 4.17; 95% confidence interval, 2.85 to 6.09).86 de Bortoli et al.87 further scrutinized this relationship for each GERD phenotype and found that the prevalence of IBS in RH was 48.2% situating between true NERD (17%) and FH (77%). This tendency was similar in the prevalence of anxiety and depression diagnosis between the three groups. With regard to FD, Savarino et al.14 found that clinically relevant dyspeptic symptoms in 37% of RH as well as NERD patients, which was lower than FH (63%). These findings suggest that RH shares the mechanism of visceral hypersensitivity with other functional gastrointestinal disorders.

2. Behavioral disorders (supragastric belching and rumination syndrome)

Excessive supragastric belching (SGB) and rumination syndrome (RS) are functional gastroduodenal disorders in Rome IV.88 Their impact on PPI refractory GERD has been increasingly recognized recently. In a study by Yadlapati et al.,89 postprandial high-resolution impedance manometry revealed the high prevalence of excessive SGB (42%) and RS (20%) in 94 PPI nonresponders. Our study evaluating the prevalence of the behavioral disorders in each reflux phenotype found that approximately 40% and 10% of RH patients had excessive SGB and RS respectively. Of which, 40% of typical reflux episodes (i.e., heartburn and regurgitation) recorded in impedance-pH monitoring was associated with SGB or rumination events.90

Belching can be classified into two types, gastric belching and SGB. Gastric belching is a physiological phenomenon to eliminate accumulated air in the proximal stomach through the mouth via transient lower esophageal relaxation. On the other hand, SGB is a behavioral disorder where a patient subconsciously swallows or sucks air from the mouth into the esophagus, then immediately followed by evacuating the air through the mouth using abdominal straining. SGB can cause reflux symptoms in two ways (1) triggering gastroesophageal reflux within a few seconds after the onset of SGB91 or (2) distending the esophagus. In fact, esophageal balloon distension can trigger heartburn sensation.92 Notably, some patients with excessive SGB predominantly complain about reflux symptoms rather than belching symptom.91

RS is defined as the repetitive, effortless regurgitation of recently ingested food into the mouth followed by rechewing and re-swallowing or expulsion of the food bolus.88 Typical RS patients are young female with low body mass index suffering from regurgitation.90 RS uses voluntary, but unconscious abdominal straining to bring up the gastric content into the mouth generating high intragastric pressure.93

SGB and RS patients are often referred to a gastroenterologist as PPI refractory GERD since reflux symptoms due to these conditions do not respond to acid suppression. Therefore, careful medical interview and impedance-pH monitoring would be required to avoid overlooking them.

TREATMENT

1. Proton pump inhibitors

RH is often diagnosed after unsuccessful PPI/PCAB treatment. However, several studies evaluated the efficacy of PPI on PPI-naïve RH patients. Watson et al.94 found that omeprazole (40 mg/day) relieved 67% of GERD patients with normal endoscopy and physiological acid exposure in which positive SI was related to better outcome. de Bortoli et al.87 found that 56% of 218 RH patients experienced >50% symptom relief by PPIs, which is lower than NERD (68%), however, much better than FH (0%). Besides, Taghavi et al.95 showed the good association between positive SAP and symptomatic response to omeprazole (60 mg/day). Given the high efficacy of high-dose PPIs, maximizing the acid suppression (e.g., double-dose PPIs or vonoprazan 20 mg/day) should be considered for RH patients naïve to such treatments. However, PPIs/PCAB should be stopped especially for hypersensitivity to nonacid reflux in off-PPI impedance-pH monitoring.26

2. Histamine2-receptor antagonists

Histamine2-receptor antagonists are known to have analgesic effects on visceral nociception.96 Rodriguez-Stanley et al.96 showed ranitidine ameliorated esophageal acid sensitivity measured by acid perfusion test in RH or FH patients even after single administration of the drug. It is also the case in famotidine for NERD patients.97 Due to the small sample size in these studies, the pain modulating effect of histamine2-receptor antagonists needs to be evaluated for a large RH cohort.

3. ARS (fundoplication)

There are some evidences to support ARS for RH patients. Broeders et al.98 found that Nissen fundoplication improved or resolved reflux symptoms in 85% of RH patients even at 5 years after the surgery, which was similar to patients with pathological acid exposure. Patel et al.16 found the preferable outcome of ARS to medical therapy in RH. Although ARS achieved >50% symptoms improvement in about 90% of RH patients, the presence of hiatus hernia was associated with positive outcome. Besides, Rengarajan et al.99 found that patients with normal AET could be a candidate for ARS when MNBI is abnormal (<2,292 Ω). It implicates that part of these RH patients might be NERD with false negative AET. Spechler et al.100 conducted a randomized controlled study having three treatment arms (i.e., ARS [Nissen fundoplication], PPI plus baclofen and desipramine, and PPI plus placebo baclofen and desipramine) for refractory heartburn patients with positive SAP in on-PPI impedance-pH monitoring. They showed that the ARS group (67%) had better treatment success rate at 1 year after surgery than other groups, and the outcome in the ARS group did not differ regardless of coexisting abnormal acid exposure. Desjardin et al.101 also showed that positive SAP could predict successful outcome of ARS.

Taking these findings into consideration, RH is likely to be a good candidate for ARS as recommended in the ICARUS guidelines.102 Concomitant condition related to abnormal reflux (i.e., hiatus hernia or low MNBI) can further justify its application. However, there is still not enough evidence to support the indication. Furthermore, it should be noted that RH patients in several studies above are diagnosed by on-PPI impedance-pH monitoring. Given that PPIs/PCAB can normalize AET in most patients, RH should be diagnosed off PPI. Thus, we should be very careful about application of ARS to true RH phenotyped off PPI.

4. Pain modulators

Antidepressants are recommended as pain modulators for functional esophageal disorders. Several randomized controlled studies tested the effect of tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRIs) for well-phenotyped RH patients refractory to PPIs. Limsrivilai et al.103 showed once-daily imipramine 25 mg (TCA) had no effect on reflux symptoms despite a marginal improvement of QOL. On the other hand, Viazis et al.104 found that citalopram 20 mg/day (SSRI) resolved reflux symptoms in 61.5% of the RH patients superior to placebo (33.3%). Another study including both RH and FH patients also showed a better effect of fluoxetine (SSRI) over omeprazole and placebo.105

5. Cognitive behavioral therapy

Excessive SGB and/or RS require dedicated intervention due to their unignorable impact on reflux symptom burden.90 Although some studies reported the efficacy of baclofen and pregabalin on such behavioral disorders,106,107 cognitive behavioral therapy using diaphragmatic breathing should be attempted first because of the equal or greater efficacy without any adverse effect than the drugs.91,108-110 We reported that cognitive behavioral therapy reduces excessive SGB sufficiently in almost half of the patients.91 Our cognitive behavioral therapy program is composed of 5 sessions during 10 weeks. In brief, it helps patients to understand the mechanism of SGB in cognitive part and learn slow diaphragmatic breathing and mouth opening/tongue position to physically prevent SGB in behavioral part.91,111 In RS, pain modulators (e.g., TCA) might be an additional option if refractory to the diaphragmatic breathing.112

CONCLUSION

Since the Montreal definition,113 our understanding of GERD has been extended by a great deal of studies. Especially impedance monitoring and prolonged wireless pH metry have contributed to better understanding of RH. This progress led to a new perspective of GERD proposed by Rome IV and the Lyon consensus so that more pathophysiology-focused diagnosis can be made for the four reflux phenotypes including RH. The discovery of fairly high impact of behavioral disorders on reflux symptoms would be another novel finding contributing to identification of true RH. More precise diagnosis is essential for better management. However, treatment modalities for esophageal hypersensitivity are still limited. Further study will be required to understand the pathophysiology of esophageal hypersensitivity and develop new treatments.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig 1.

Figure 1.Prevalence of each reflux phenotype in all patients with heartburn (A) and in endoscopy-negative patients with heartburn and/or regurgitation (B). The patients in both studies were phenotyped after at least a 14-day discontinuation of acid suppressive therapy. Only pH monitoring was used in (A), while impedance-pH monitoring was used in (B) so that the reflux-symptom association could be calculated for both acid and nonacid reflux episodes.
NERD, nonerosive reflux disease; RH, reflux hypersensitivity; FH, functional heartburn.
Gut and Liver 2023; :

Fig 2.

Figure 2.Diagnostic algorithm of PPI/PCAB refractory reflux patients.
PPI, proton pump inhibitor; PCAB, potassium-competitive acid blocker; SGB, supragastric belching; RS, rumination syndrome; EGD, esophagogastricduodenoscopy; HRM, high-resolution manometry; HRIM, high-resolution impedance manometry; RS, rumination syndrome; EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; LA, Los Angeles classification; LSBE, long segment Barrett’s esophagus; AET, acid exposure time.
Gut and Liver 2023; :

Fig 3.

Figure 3.Mechanism underlying esophageal reflux hypersensitivity. Exogenous stimuli perceived by the esophageal sensory nerves are transmitted to the central nervous system via two ways; vagal afferent nerves via the nodose ganglion and spinal nerves via dorsal root ganglion. Several factors contribute to reflux hypersensitivity influencing peripheral sensors in the esophagus or the central nervous system. Some mechanisms such as mucosal integrity, cytokines and prostaglandin E2, sensory receptors (TRPV1 and ASIC3) and superficial mucosal afferent nerves are associated with peripheral hypersensitivity. Other mechanisms such as esophageal hypervigilance along with anxiety and sleep disturbance mainly affect the processing of the conveyed stimuli in the central nervous system, which results in amplification of the sensation. These factors also might enhance peripheral sensitivity by impairing the mucosal integrity.
TRPV1, transient receptor potential vanilloid receptor-1; ASIC3, acid-sensing ion channel 3.
Gut and Liver 2023; :

References

  1. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional esophageal disorders. Gastroenterology 2016;150:P1368-P1379.
    Pubmed CrossRef
  2. Galmiche JP, Clouse RE, Bálint A, et al. Functional esophageal disorders. Gastroenterology 2006;130:1459-1465.
    Pubmed CrossRef
  3. Ashida K, Sakurai Y, Hori T, et al. Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther 2016;43:240-251.
    Pubmed KoreaMed CrossRef
  4. Xiao Y, Zhang S, Dai N, et al. Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis. Gut 2020;69:224-230.
    Pubmed KoreaMed CrossRef
  5. Iwakiri K, Fujiwara Y, Manabe N, et al. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021. J Gastroenterol 2022;57:267-285.
    Pubmed KoreaMed CrossRef
  6. Cicala M, Emerenziani S, Guarino MP, Ribolsi M. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. World J Gastroenterol 2013;19:6529-6535.
    Pubmed KoreaMed CrossRef
  7. Okuyama M, Nakahara K, Iwakura N, et al. Factors associated with potassium-competitive acid blocker non-response in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. Digestion 2017;95:281-287.
    Pubmed CrossRef
  8. Savarino E, Zentilin P, Tutuian R, et al. The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol 2008;103:2685-2693.
    Pubmed CrossRef
  9. Kohata Y, Fujiwara Y, Machida H, et al. Pathogenesis of proton-pump inhibitor-refractory non-erosive reflux disease according to multichannel intraluminal impedance-pH monitoring. J Gastroenterol Hepatol 2012;27 Suppl 3:58-62.
    Pubmed CrossRef
  10. Weijenborg PW, Smout AJ, Verseijden C, et al. Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis. Am J Physiol Gastrointest Liver Physiol 2014;307:G323-G329.
    Pubmed CrossRef
  11. Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Dodaran M, Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut 2018;67:430-440.
    Pubmed CrossRef
  12. Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Non-erosive reflux disease (NERD): acid reflux and symptom patterns. Aliment Pharmacol Ther 2003;17:537-545.
    Pubmed CrossRef
  13. Savarino E, Marabotto E, Zentilin P, et al. The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease. Dig Liver Dis 2011;43:542-547.
    Pubmed CrossRef
  14. Savarino E, Pohl D, Zentilin P, et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut 2009;58:1185-1191.
    Pubmed KoreaMed CrossRef
  15. Roman S, Keefer L, Imam H, et al. Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux. Neurogastroenterol Motil 2015;27:1667-1674.
    Pubmed KoreaMed CrossRef
  16. Patel A, Sayuk GS, Gyawali CP. Prevalence, characteristics, and treatment outcomes of reflux hypersensitivity detected on pH-impedance monitoring. Neurogastroenterol Motil 2016;28:1382-1390.
    Pubmed KoreaMed CrossRef
  17. Hemmink GJ, Bredenoord AJ, Weusten BL, Monkelbaan JF, Timmer R, Smout AJ. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: 'on' or 'off' proton pump inhibitor? Am J Gastroenterol 2008;103:2446-2453.
    Pubmed CrossRef
  18. Sawada A, Itami H, Nakagawa K, et al. Supragastric belching in Japan: lower prevalence and relevance for management of gastroesophageal reflux disease compared to United Kingdom. J Gastroenterol 2020;55:1046-1053.
    Pubmed KoreaMed CrossRef
  19. Tamura Y, Funaki Y, Izawa S, et al. Pathophysiology of functional heartburn based on Rome III criteria in Japanese patients. World J Gastroenterol 2015;21:5009-5016.
    Pubmed KoreaMed CrossRef
  20. Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J Gastroenterol 2009;44:518-534.
    Pubmed CrossRef
  21. Yadlapati R, Kahrilas PJ, Fox MR, et al. Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©. Neurogastroenterol Motil 2021;33:e14058.
    Pubmed KoreaMed CrossRef
  22. Pandolfino JE, Gawron AJ. Achalasia: a systematic review. JAMA 2015;313:1841-1852.
    Pubmed CrossRef
  23. Wahba G, Bouin M. Jackhammer esophagus: a meta-analysis of patient demographics, disease presentation, high-resolution manometry data, and treatment outcomes. Neurogastroenterol Motil 2020;32:e13870.
    Pubmed CrossRef
  24. Hosaka H, Kawami N, Manabe N, et al. Clinical presentation and therapeutic outcome of patients with jackhammer esophagus: a multicenter cohort study in Japan. Esophagus 2022;19:393-400.
    Pubmed KoreaMed CrossRef
  25. Tutuian R, Mainie I, Agrawal A, Gideon RM, Katz PO, Castell DO. Symptom and function heterogenicity among patients with distal esophageal spasm: studies using combined impedance-manometry. Am J Gastroenterol 2006;101:464-469.
    Pubmed CrossRef
  26. Yadlapati R, Gyawali CP, Pandolfino JE; CGIT GERD Consensus Conference Participants. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: expert review. Clin Gastroenterol Hepatol 2022;20:984-994.
    Pubmed CrossRef
  27. Rengarajan A, Pomarat M, Zerbib F, Gyawali CP. Overlap of functional heartburn and reflux hypersensitivity with proven gastroesophageal reflux disease. Neurogastroenterol Motil 2021;33:e14056.
    Pubmed CrossRef
  28. Piche T, Ducrotté P, Sabate JM, et al. Impact of functional bowel symptoms on quality of life and fatigue in quiescent Crohn disease and irritable bowel syndrome. Neurogastroenterol Motil 2010;22:626-e174.
    Pubmed CrossRef
  29. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut 2018;67:1351-1362.
    Pubmed KoreaMed CrossRef
  30. Sifrim D, Gyawali CP. Prolonged wireless pH monitoring or 24-hour catheter-based pH impedance monitoring: who, when, and why? Am J Gastroenterol 2020;115:1150-1152.
    Pubmed CrossRef
  31. Hasak S, Yadlapati R, Altayar O, et al. Prolonged wireless pH monitoring in patients with persistent reflux symptoms despite proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2020;18:2912-2919.
    Pubmed KoreaMed CrossRef
  32. Rogers BD, Valdovinos LR, Crowell MD, Bell R, Vela MF, Gyawali CP. Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation. Gut 2021;70:450-455.
    Pubmed CrossRef
  33. Frazzoni L, Frazzoni M, De Bortoli N, et al. Application of Lyon Consensus criteria for GORD diagnosis: evaluation of conventional and new impedance-pH parameters. Gut 2022;71:1062-1067.
    Pubmed CrossRef
  34. Frazzoni M, Manta R, Mirante VG, Conigliaro R, Frazzoni L, Melotti G. Esophageal chemical clearance is impaired in gastro-esophageal reflux disease: a 24-h impedance-pH monitoring assessment. Neurogastroenterol Motil 2013;25:399-406.
    Pubmed CrossRef
  35. Sifrim D, Roman S, Savarino E, et al. Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world. Gut 2021;70:1441-1449.
    Pubmed CrossRef
  36. Trimble KC, Pryde A, Heading RC. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut 1995;37:7-12.
    Pubmed KoreaMed CrossRef
  37. van Malenstein H, Farré R, Sifrim D. Esophageal dilated intercellular spaces (DIS) and nonerosive reflux disease. Am J Gastroenterol 2008;103:1021-1028.
    Pubmed CrossRef
  38. Farré R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011;60:885-892.
    Pubmed CrossRef
  39. Woodland P, Al-Zinaty M, Yazaki E, Sifrim D. In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut 2013;62:1256-1261.
    Pubmed CrossRef
  40. Weijenborg PW, Smout AJ, Bredenoord AJ. Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn. Neurogastroenterol Motil 2016;28:1649-1654.
    Pubmed CrossRef
  41. Farré R, van Malenstein H, De Vos R, et al. Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces. Gut 2008;57:1366-1374.
    Pubmed CrossRef
  42. Caviglia R, Ribolsi M, Maggiano N, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol 2005;100:543-548.
    Pubmed CrossRef
  43. Hopwood D, Milne G, Logan KR. Electron microscopic changes in human oesophageal epithelium in oesophagitis. J Pathol 1979;129:161-167.
    Pubmed CrossRef
  44. Zentilin P, Savarino V, Mastracci L, et al. Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol 2005;100:2299-2306.
    Pubmed CrossRef
  45. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 2009;137:1776-1784.
    Pubmed CrossRef
  46. Isomoto H, Saenko VA, Kanazawa Y, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol 2004;99:589-597.
    Pubmed CrossRef
  47. Kondo T, Oshima T, Tomita T, et al. Prostaglandin E(2) mediates acid-induced heartburn in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2013;304:G568-G573.
    Pubmed CrossRef
  48. Kondo T, Sei H, Yamasaki T, et al. A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial. J Gastroenterol 2017;52:1081-1089.
    Pubmed CrossRef
  49. Kondo T, Oshima T, Tomita T, et al. The nonsteroidal anti-inflammatory drug diclofenac reduces acid-induced heartburn symptoms in healthy volunteers. Clin Gastroenterol Hepatol 2015;13:1249-1255.
    Pubmed CrossRef
  50. Sarkar S, Hobson AR, Hughes A, et al. The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans. Gastroenterology 2003;124:18-25.
    Pubmed CrossRef
  51. Woodland P, Aktar R, Mthunzi E, et al. Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa. Am J Physiol Gastrointest Liver Physiol 2015;308:G525-G531.
    Pubmed KoreaMed CrossRef
  52. Thoua NM, Khoo D, Kalantzis C, Emmanuel AV. Acid-related oesophageal sensitivity, not dysmotility, differentiates subgroups of patients with non-erosive reflux disease. Aliment Pharmacol Ther 2008;27:396-403.
    Pubmed CrossRef
  53. Bredenoord AJ, Weusten BL, Curvers WL, Timmer R, Smout AJ. Determinants of perception of heartburn and regurgitation. Gut 2006;55:313-318.
    Pubmed KoreaMed CrossRef
  54. Zerbib F, Duriez A, Roman S, Capdepont M, Mion F. Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 2008;57:156-160.
    Pubmed CrossRef
  55. Woodland P, Shen Ooi JL, Grassi F, et al. Superficial esophageal mucosal afferent nerves may contribute to reflux hypersensitivity in nonerosive reflux disease. Gastroenterology 2017;153:1230-1239.
    Pubmed CrossRef
  56. Nikaki K, Woodland P, Lee C, et al. Esophageal mucosal innervation in functional heartburn: closer to healthy asymptomatic subjects than to non-erosive reflux disease patients. Neurogastroenterol Motil 2019;31:e13667.
    Pubmed CrossRef
  57. Gouin O, L'Herondelle K, Lebonvallet N, et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 2017;8:644-661.
    Pubmed KoreaMed CrossRef
  58. Blackshaw LA. Transient receptor potential cation channels in visceral sensory pathways. Br J Pharmacol 2014;171:2528-2536.
    Pubmed KoreaMed CrossRef
  59. Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 2004;16:897-902.
    Pubmed CrossRef
  60. Bhat YM, Bielefeldt K. Capsaicin receptor (TRPV1) and non-erosive reflux disease. Eur J Gastroenterol Hepatol 2006;18:263-270.
    Pubmed CrossRef
  61. Guarino MP, Cheng L, Ma J, et al. Increased TRPV1 gene expression in esophageal mucosa of patients with non-erosive and erosive reflux disease. Neurogastroenterol Motil 2010;22:746-751.
    Pubmed CrossRef
  62. Ustaoglu A, Sawada A, Lee C, et al. Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors. Am J Physiol Gastrointest Liver Physiol 2021;320:G804-G815.
    Pubmed CrossRef
  63. Krarup AL, Ny L, Gunnarsson J, et al. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain. Scand J Gastroenterol 2013;48:274-284.
    Pubmed CrossRef
  64. Banovcin P, Duricek M, Zatko T, Liptak P, Hyrdel R, Kollarik M. The infusion of menthol into the esophagus evokes cold sensations in healthy subjects but induces heartburn in patients with gastroesophageal reflux disease (GERD). Dis Esophagus 2019;32:doz038.
    Pubmed CrossRef
  65. Chen CC, Wong CW. Neurosensory mechanotransduction through acid-sensing ion channels. J Cell Mol Med 2013;17:337-349.
    Pubmed KoreaMed CrossRef
  66. Yoshida N, Kuroda M, Suzuki T, et al. Role of nociceptors/neuropeptides in the pathogenesis of visceral hypersensitivity of nonerosive reflux disease. Dig Dis Sci 2013;58:2237-2243.
    Pubmed CrossRef
  67. Kandulski A, Wex T, Mönkemüller K, et al. Proteinase-activated receptor-2 in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol 2010;105:1934-1943.
    Pubmed CrossRef
  68. Yoshida N, Katada K, Handa O, et al. Interleukin-8 production via protease-activated receptor 2 in human esophageal epithelial cells. Int J Mol Med 2007;19:335-340.
    Pubmed CrossRef
  69. Wu L, Oshima T, Shan J, et al. PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2015;309:G695-G702.
    Pubmed CrossRef
  70. Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487-1493.
    Pubmed CrossRef
  71. Kusano M, Kouzu T, Kawano T, Ohara S. Nationwide epidemiological study on gastroesophageal reflux disease and sleep disorders in the Japanese population. J Gastroenterol 2008;43:833-841.
    Pubmed CrossRef
  72. Fujiwara Y, Arakawa T, Fass R. Gastroesophageal reflux disease and sleep disturbances. J Gastroenterol 2012;47:760-769.
    Pubmed CrossRef
  73. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787-1795.
    Pubmed CrossRef
  74. Yi CH, Lei WY, Hung JS, Liu TT, Orr WC, Chen CL. Sleep disturbance and enhanced esophageal capsaicin sensitivity in patients with gastroesophageal reflux disease. J Gastroenterol Hepatol 2016;31:1940-1945.
    Pubmed CrossRef
  75. Farré R, De Vos R, Geboes K, et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 2007;56:1191-1197.
    Pubmed KoreaMed CrossRef
  76. Fujiwara Y, Kohata Y, Kaji M, et al. Sleep dysfunction in Japanese patients with gastroesophageal reflux disease: prevalence, risk factors, and efficacy of rabeprazole. Digestion 2010;81:135-141.
    Pubmed CrossRef
  77. Losa M, Manz SM, Schindler V, Savarino E, Pohl D. Increased visceral sensitivity, elevated anxiety, and depression levels in patients with functional esophageal disorders and non-erosive reflux disease. Neurogastroenterol Motil 2021;33:e14177.
    Pubmed CrossRef
  78. Kessing BF, Bredenoord AJ, Saleh CM, Smout AJ. Effects of anxiety and depression in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2015;13:1089-1095.
    Pubmed CrossRef
  79. Taft TH, Triggs JR, Carlson DA, et al. Validation of the oesophageal hypervigilance and anxiety scale for chronic oesophageal disease. Aliment Pharmacol Ther 2018;47:1270-1277.
    Pubmed KoreaMed CrossRef
  80. Wong MW, Liu TT, Yi CH, et al. Oesophageal hypervigilance and visceral anxiety relate to reflux symptom severity and psychological distress but not to acid reflux parameters. Aliment Pharmacol Ther 2021;54:923-930.
    Pubmed CrossRef
  81. Guadagnoli L, Yadlapati R, Taft T, Pandolfino JE, Tye M, Keefer L. Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations. Neurogastroenterol Motil 2021;33:e14081.
    Pubmed KoreaMed CrossRef
  82. Taft TH, Carlson DA, Simons M, et al. Esophageal hypervigilance and symptom-specific anxiety in patients with eosinophilic esophagitis. Gastroenterology 2021;161:1133-1144.
    Pubmed KoreaMed CrossRef
  83. Carlson DA, Gyawali CP, Roman S, et al. Esophageal hypervigilance and visceral anxiety are contributors to symptom severity among patients evaluated with high-resolution esophageal manometry. Am J Gastroenterol 2020;115:367-375.
    Pubmed KoreaMed CrossRef
  84. Kaji M, Fujiwara Y, Shiba M, et al. Prevalence of overlaps between GERD, FD and IBS and impact on health-related quality of life. J Gastroenterol Hepatol 2010;25:1151-1156.
    Pubmed CrossRef
  85. Vakil N, Stelwagon M, Shea EP, Miller S. Symptom burden and consulting behavior in patients with overlapping functional disorders in the US population. United European Gastroenterol J 2016;4:413-422.
    Pubmed KoreaMed CrossRef
  86. Lovell RM, Ford AC. Prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. Am J Gastroenterol 2012;107:1793-1801.
    Pubmed CrossRef
  87. de Bortoli N, Frazzoni L, Savarino EV, et al. Functional heartburn overlaps with irritable bowel syndrome more often than GERD. Am J Gastroenterol 2016;111:1711-1717.
    Pubmed CrossRef
  88. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. Gastroenterology 2016;150:1380-1392.
    Pubmed CrossRef
  89. Yadlapati R, Tye M, Roman S, Kahrilas PJ, Ritter K, Pandolfino JE. Postprandial high-resolution impedance manometry identifies mechanisms of nonresponse to proton pump inhibitors. Clin Gastroenterol Hepatol 2018;16:211-218.
    Pubmed KoreaMed CrossRef
  90. Sawada A, Guzman M, Nikaki K, et al. Identification of different phenotypes of esophageal reflux hypersensitivity and implications for treatment. Clin Gastroenterol Hepatol 2021;19:690-698.
    Pubmed CrossRef
  91. Glasinovic E, Wynter E, Arguero J, et al. Treatment of supragastric belching with cognitive behavioral therapy improves quality of life and reduces acid gastroesophageal reflux. Am J Gastroenterol 2018;113:539-547.
    Pubmed CrossRef
  92. Takeda T, Nabae T, Kassab G, Liu J, Mittal RK. Oesophageal wall stretch: the stimulus for distension induced oesophageal sensation. Neurogastroenterol Motil 2004;16:721-728.
    Pubmed CrossRef
  93. Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001;121:526-535.
    Pubmed CrossRef
  94. Watson RG, Tham TC, Johnston BT, McDougall NI. Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux: the "sensitive oesophagus". Gut 1997;40:587-590.
    Pubmed KoreaMed CrossRef
  95. Taghavi SA, Ghasedi M, Saberi-Firoozi M, et al. Symptom association probability and symptom sensitivity index: preferable but still suboptimal predictors of response to high dose omeprazole. Gut 2005;54:1067-1071.
    Pubmed KoreaMed CrossRef
  96. Rodriguez-Stanley S, Ciociola AA, Zubaidi S, Proskin HM, Miner PB Jr. A single dose of ranitidine 150 mg modulates oesophageal acid sensitivity in patients with functional heartburn. Aliment Pharmacol Ther 2004;20:975-982.
    Pubmed CrossRef
  97. Marrero JM, de Caestecker JS, Maxwell JD. Effect of famotidine on oesophageal sensitivity in gastro-oesophageal reflux disease. Gut 1994;35:447-450.
    Pubmed KoreaMed CrossRef
  98. Broeders JA, Draaisma WA, Bredenoord AJ, et al. Oesophageal acid hypersensitivity is not a contraindication to Nissen fundoplication. Br J Surg 2009;96:1023-1030.
    Pubmed CrossRef
  99. Rengarajan A, Savarino E, Della Coletta M, Ghisa M, Patel A, Gyawali CP. Mean nocturnal baseline impedance correlates with symptom outcome when acid exposure time is inconclusive on esophageal reflux monitoring. Clin Gastroenterol Hepatol 2020;18:589-595.
    Pubmed CrossRef
  100. Spechler SJ, Hunter JG, Jones KM, et al. Randomized trial of medical versus surgical treatment for refractory heartburn. N Engl J Med 2019;381:1513-1523.
    Pubmed CrossRef
  101. Desjardin M, Luc G, Collet D, Zerbib F. 24-hour pH-impedance monitoring on therapy to select patients with refractory reflux symptoms for antireflux surgery: a single center retrospective study. Neurogastroenterol Motil 2016;28:146-152.
    Pubmed CrossRef
  102. Pauwels A, Boecxstaens V, Andrews CN, et al. How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery). Gut 2019;68:1928-1941.
    Pubmed CrossRef
  103. Limsrivilai J, Charatcharoenwitthaya P, Pausawasdi N, Leelakusolvong S. Imipramine for treatment of esophageal hypersensitivity and functional heartburn: a randomized placebo-controlled trial. Am J Gastroenterol 2016;111:217-224.
    Pubmed CrossRef
  104. Viazis N, Keyoglou A, Kanellopoulos AK, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study. Am J Gastroenterol 2012;107:1662-1667.
    Pubmed CrossRef
  105. Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil 2014;26:670-678.
    Pubmed CrossRef
  106. Blondeau K, Boecxstaens V, Rommel N, et al. Baclofen improves symptoms and reduces postprandial flow events in patients with rumination and supragastric belching. Clin Gastroenterol Hepatol 2012;10:379-384.
    Pubmed CrossRef
  107. Kunte H, Kronenberg G, Fink K, Harms L, Hellweg R. Successful treatment of excessive supragastric belching by combination of pregabalin and baclofen. Psychiatry Clin Neurosci 2015;69:124-125.
    Pubmed CrossRef
  108. Hemmink GJ, Ten Cate L, Bredenoord AJ, Timmer R, Weusten BL, Smout AJ. Speech therapy in patients with excessive supragastric belching: a pilot study. Neurogastroenterol Motil 2010;22:24-28.
    Pubmed CrossRef
  109. Murray HB, Juarascio AS, Di Lorenzo C, Drossman DA, Thomas JJ. Diagnosis and treatment of rumination syndrome: a critical review. Am J Gastroenterol 2019;114:562-578.
    Pubmed KoreaMed CrossRef
  110. Hoshikawa Y, Fitzke H, Sweis R, et al. Rumination syndrome: assessment of vagal tone during and after meals and during diaphragmatic breathing. Neurogastroenterol Motil 2020;32:e13873.
    Pubmed CrossRef
  111. Sawada A, Anastasi N, Green A, et al. Management of supragastric belching with cognitive behavioural therapy: factors determining success and follow-up outcomes at 6-12 months post-therapy. Aliment Pharmacol Ther 2019;50:530-537.
    Pubmed CrossRef
  112. Robles A, Romero YA, Tatro E, Quezada H, McCallum RW. Outcomes of treating rumination syndrome with a tricyclic antidepressant and diaphragmatic breathing. Am J Med Sci 2020;360:42-49.
    Pubmed CrossRef
  113. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-1920.
    Pubmed CrossRef
Gut and Liver

Vol.17 No.1
January, 2023

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