Novel Technique to Diagnose Gastroesophageal Reflux Disease
Article information
Abstract
Gastroesophageal reflux disease (GERD), which is commonly encountered in clinical practice, has become increasingly prevalent in Asia in recent years. Definitive diagnosis of GERD requires upper gastrointestinal endoscopy and ambulatory pH monitoring and is therefore challenging. Endoscopic lesions are usually not incorporated into the diagnostic criteria, and pH monitoring is expensive, complicated, and uncomfortable for patients. Studies have investigated novel methods for diagnosis of GERD. Mucosal integrity, evaluated by mucosal admittance or impedance, is impaired in GERD owing to microscopic epithelial changes. Measurement of mucosal integrity is simple and can be performed endoscopically. Mucosal impedance has been investigated as a method to differentiate between GERD, non-GERD, and eosinophilic esophagitis, and mucosal admittance provides evidence to support diagnosis of GERD. Further research on these novel techniques is warranted to incorporate these into the diagnostic modalities used for GERD.
INTRODUCTION
Gastroesophageal reflux disease (GERD), a common health concern encountered in clinical practice, results in a significant burden on healthcare expenditure. The worldwide prevalence of GERD ranges from 2.5% to 33.1% and it has been increasing over time [1,2]. Based on the estimated burden in 2021 in the United States, GERD and reflux esophagitis represent the third most common diagnoses among gastrointestinal disorders [3]. Although less common in the Asia-Pacific region, GERD has recently become more prevalent in these countries (6.0%–10.0%) [4-6].
Although GERD shows a broad spectrum of clinical presentation, symptoms are nonspecific. Symptom-based GERD diagnosis shows low sensitivity and specificity, particularly in patients without typical symptoms, including heartburn and regurgitation [7]. Proton pump inhibitor (PPI) trials have limited specificity and are associated with complications of PPI overuse [8]. Endoscopy and ambulatory reflux monitoring are recommended in many guidelines and consensus statements as diagnostic tools to confirm GERD [9-12]. Findings of other investigations, such as esophageal manometry, salivary pepsin level measurements, and histopathology are used as supportive evidence to confirm or exclude diagnosis of GERD. In this review, we describe a novel technique to directly evaluate esophageal mucosal integrity endoscopically. Furthermore, we have summarized the findings of studies that report this technique for evaluation of GERD.
DIAGNOSIS OF GASTROESOPHAGEAL REFLUX DISEASE
Recent guidelines and consensus statements on the diagnosis of GERD recommend endoscopy and 24-hour esophageal pH studies to establish a definitive diagnosis (Table 1). Compared with previous guidelines, the endoscopic criteria for conclusive GERD have significantly changed, and the recommendations for wireless pH monitoring emphasize the accuracy of pH studies in these cases. High-resolution manometry (HRM), salivary pepsin testing, and mucosal integrity evaluation only provide supportive evidence. We present a detailed discussion of these techniques in this report.
Guideline recommendations for diagnostic tests in patients with gastroesophageal reflux disease
Endoscopy
Endoscopy can rule out other diseases or conditions and is therefore essential for accurate diagnosis of GERD, particularly in patients with typical or alarming symptoms. Endoscopy enables direct visualization of the esophageal mucosa to detect GERD-associated lesions and complications [13], including erosive esophagitis (EE), Barrett’s esophagus, peptic strictures, and esophageal cancer, with EE being the most frequently detected lesion [14]. Based on the Lyon consensus 2.0 criteria, EE grades B, C, and D (per the Los Angeles [LA] classification) provide conclusive evidence of GERD [9]. Barrett’s mucosa and peptic esophageal strictures are also diagnostic; however, they are less common. Diagnostic endoscopy is recommended 2–4 weeks after discontinuation of PPIs in patients with unproven GERD based on the rationale that PPIs are associated with a high mucosal healing rate (approximately 80.0%). Therefore, endoscopic diagnosis is challenging in patients who continue to receive PPI or have recently completed PPI therapy [9].
Despite the several benefits of endoscopy, approximately 70.0% of patients with GERD show normal endoscopic findings; this condition is usually referred to as non-erosive reflux disease (NERD) [15]. EE LA grade A is common; however, it may be observed in 5.0%–7.0% of healthy individuals and is therefore considered inconclusive of GERD [16]. GERD is diagnostically challenging in these patients, and other tests such as pH or pH-impedance monitoring are required for diagnostic confirmation.
Ambulatory reflux monitoring
Ambulatory esophageal pH monitoring is considered the “gold” standard for diagnosis of GERD. Using pH and impedance sensors, this method measures the duration of exposure of the esophageal mucosa to gastric acid and can detect airor fluid-induced changes in impedance within the esophageal lumen to identify reflux events. Conventionally, this technique involves the insertion of a transnasal probe into the esophagus, which is removed after 24 hours. Recent studies have reported use of wireless pH probes using a radiotelemetry pH sensing capsule to reduce patients’ discomfort [17]. Monitoring performed over 48–96 hours using the wireless system may be useful to improve diagnostic accuracy [18-20].
The Lyon consensus 2.0 criteria outline the following main changes in the recommendations on ambulatory reflux monitoring: 1) The thresholds for testing of patients off and on antisecretory therapy are discussed separately. 2) Addition of wireless monitoring thresholds with expansion of the discussion of a choice of tests. 3) Addition of thresholds for the mean nocturnal baseline impedance. However, the post-reflux swallow-induced peristaltic wave index is excluded as supportive evidence.
Catheter-based pH monitoring is associated with sensor instability and patient discomfort, and introduction of wireless pH monitoring has facilitated longer monitoring times and better tolerance. Extending the study time increases the likelihood of detection of pathological acid exposure time (AET), symptom presentation, and reflux-symptom association [21]. Scarpulla et al. [22] reported that the sensitivity of GERD diagnosis increased from 63.0% with 24-hour monitoring to 83.0% with 48-hour and 91.0% with 72-hour monitoring compared with the sensitivity findings of a 96-hour study used as the gold standard. Notably, 96-hour pH monitoring can be performed in patients both off and on antisecretory therapy, which serves as an advantage because in addition to its diagnostic value, this method is useful to evaluate the response to PPI treatment. However, there is lack of consensus regarding the number of hours for “off” and “on” therapy in patients who undergo 96-hour pH monitoring.
Despite its superiority in establishing conclusive diagnosis, multichannel intraluminal impedance-pH testing uses an invasive and uncomfortable catheter, which requires patients to alter their daily physical activities and food consumption and may reduce the frequency of GERD symptoms and may therefore affect other associated metrics [23]. Moreover, measuring esophageal mucosal conductivity using this method is unreliable because the liquids, solids, or air within the esophageal lumen can significantly affect the recorded values.
High resolution manometry
Esophageal manometry is the standard diagnostic tool for motility disorders and esophageal sphincter function abnormalities. HRM was introduced in the 1990s, parallel to the revolutionary changes in the Chicago classification from the first to the most recent version (4.0), which was published in early 2021 [24]. Ineffective esophageal motility (IEM) was the most common manometric condition, and approximately 50% of patients with IEM were diagnosed with GERD [25-27]. The diagnostic criteria for IEM were redefined in the latest version of the Chicago classification, which provides more accurate prediction of abnormal acid exposure [28,29]. Patients with GERD who show IEM have a high risk of dysphagia after 360° Nissen fundoplication, and magnetic sphincter augmentation is contraindicated in patients with IEM. Therefore, more rigorous IEM diagnostic criteria are required to expand the potential for antireflux surgery while minimizing the risk of dysphagia [25,30]. HRM can exclude other major motility disorders such as achalasia, esophagogastric junction outflow obstruction, or absent contractility in patients with reflux-like symptoms [31,32].
MEASUREMENT OF MUCOSAL IMPEDANCE AND MUCOSAL ADMITTANCE: NOVEL TECHNIQUES FOR DIAGNOSIS OF GASTROINTESTINAL REFLUX DISEASE
Mucosal impedance measurement
Mechanism
Gastric reflux, which contains gastric acid, pepsin, or bile acids leads to mucosal inflammation, impaired mucosal integrity and GERD symptoms associated with esophageal mucosal epithelial injury in patients with GERD [33,34]. Detection of changes in mucosal integrity may serve as a new approach to conclusively establish diagnosis of GERD [35].
Mucosal integrity can be evaluated both functionally and morphologically. For example, a sample of the esophageal mucosa can be obtained to measure transepithelial electrical resistance (in an Ussing chamber) to evaluate the ability of the mucosa to resist electric current or transfer of ions through the mucosa [36]. However, this technique is complicated, time-consuming, and rarely available in clinical practice. Histopathological examination of tissue samples can identify microscopic epithelial changes; however, this technique is expensive and requires expertise in histopathology, as well as advanced laboratory equipment, such as transmission electron microscopy [35,37].
The direct measurement of mucosal impedance (MI) is proposed as a new method to evaluate mucosal integrity. MI evaluates the resistance of the mucosa to an electric current flowing between neighboring sensors. Theoretically, patients with impaired mucosal integrity, such as those with GERD or eosinophilic esophagitis (EoE), have lower MI than healthy individuals [38]. Although esophageal MI can be recorded based on pH impedance monitoring and is associated with AET [39], the results may be affected by poor mucosal contact, catheter movement, or intraluminal air and fluid. Furthermore, wearing a nasal catheter for at least 24 hours can be challenging for some patients [40].
Endoscopy-guided MI catheters [38] are often small catheters with impedance sensors near their tip. After the catheter is introduced through the biopsy channel of the endoscope, the endoscopist adjusts the distal end of the catheter to establish direct contact between the MI sensors and the mucosa. Subsequently, an electric current flows through the sensors to measure impedance. Compared with pH-impedance monitoring, endoscopy-guided MI catheters show higher accuracy and reliability because patients are sedated during endoscopy, and the endoscopist can directly visualize the measurement site and also clear fluid or foam.
Available systems
In 2012, Vaezi and colleagues introduced the first MI catheter model designed by Sandhill Scientific (now Diversatek Inc., Milwaukee, WI, USA), which facilitates direct endoscopic measurement [38]. The catheter can be inserted through the endoscopy channel and has two MI sensor rings near its tip. The endoscopist initially presses the sensor rings onto the mucosa to maintain stable contact, after which an electric current (frequency 2 kHz) is used for measurement. In this study, MI was measured in the area of esophagitis (in patients with EE) and 2, 5, and 10 cm above the squamocolumnar junction (SCJ) [41]. The mean measurement time was 2 min.
The sensors are wrapped around the catheter; therefore, intraluminal gas and fluid may affect accurate measurement, and the MI catheter design therefore requires further improvement. Catheter movement or differences in the pressure applied to the mucosa can also result in measurement variability. Vaezi and colleagues continued collaboration with Diversatek to design a ballon-based MI catheter system to improve data acquisition [38,42]. The device comprises several columns of impedance sensors (10 cm in length) mounted on an inflatable balloon. The initial design had four columns of sensors, which were subsequently reduced to two columns. Using this design, the catheter was introduced into the biopsy channel, and the farthest sensors were placed directly above the SCJ. Before measurement, the balloon was inflated to stabilize contact between the sensors and mucosa and to push out fluid or gas that may affect the MI values. MI values were measured on a 10-cm section of the esophagus both radially and axially by the sensor columns for over 90 s. The overall duration of the procedure was 2–3 min.
Diversatek introduced a new model called MiVuTM Endo-Cap (Diversatek Inc.) to further simplify the procedure (Fig. 1). This version features an endoscopic cap fitted with four impedance sensors attached to the tip of the endoscope. Using this design, placement of the sensors is directly controlled by the up/down deflection wheels (large wheels) on the endoscope, which simplifies measurement and minimizes variability. This method provides optimal visualization because only the tip of the device is observed in the visual field. The measurement span is 3 cm along the esophageal axis, which necessitates at least four measurements to cover a 10-cm segment. Further studies are required to determine the diagnostic value and accuracy of the new device compared with that of a balloon or standard MI catheter.
Image showing the MiVuTM EndoCap catheter and system. A: MiVuTM EndoCap catheter. B and C: MiVuTM EndoCap attached to the endoscope. D: Endoscopic view of the MiVuTM EndoCap device. E: MiVuTM integrity testing system.
Clinical data
In their first study performed in 2012, Saritas Yuksel et al. [41] investigated 19 patients with EE, 23 without EE but with abnormal pH, and 27 healthy controls. The results showed a significantly lower MI at the lesion site and 2 cm above the SCJ in patients with GERD than in healthy controls. A significant increase in MI was observed along the esophageal axis from the 2 cm to the 10-cm mark. In a larger prospective study in 2015, Ates et al. [43] evaluated MI using the same MI catheters and measurement sites in 61 patients with EE, 81 patients without EE but with abnormal pH, 18 patients with achalasia, 15 patients with EoE, and 93 controls. Comparison of MI measurements between the five groups showed the following findings: 1) MI was significantly lower in patients with GERD and EoE than in those with other conditions (controls or achalasia). 2) Patients with GERD showed a unique pattern of a gradual increase in MI from the distal to proximal esophagus, in contrast to that observed in other conditions in which the MI remained the same along the axis. These findings suggest that based on values and patterns, MI measurements can be useful to distinguish between patients with GERD, EoE, and non-GERD conditions. A cutoff value of 1465 Ω measured 2 cm above the SCJ showed a sensitivity of 70.0% and specificity of 91.0%, and a cutoff value of 2019 Ω measured 5 cm above the SCJ showed a sensitivity of 76.0% and specificity of 95.0%. The authors also performed follow-up endoscopy and MI in patients with esophagitis LA grade C or D after PPI treatment and observed that MI values significantly increased after 6- to 8-week PPI treatment at all locations, which indicates that MI can be used to monitor treatment response. Direct MI measurements may serve as a promising aid to support diagnosis of GERD and reduce the need for ambulatory monitoring [44].
Patel et al. [42] measured MI using balloon catheters in 69 patients (24 patients with GERD, 21 with EoE, and 24 with non-GERD conditions). Patients with EE or abnormal pH were diagnosed with GERD. Similar to findings using the previously described catheter, the results showed significant differences in MI values and patterns between the three groups. MI values were low in the distal esophagus and gradually increased to normal levels in the proximal esophagus in patients with GERD, in contrast to the consistently low MI values observed in patients with EoE. MI values were significantly higher in patients with non-GERD conditions than in patients with GERD and EoE across all measured segments. The prediction model for esophageal diseases using MI values had an area under the receiver operating characteristic curve (AUC) of 0.69 for patients with GERD, 0.89 for patients with EoE, and 0.84 for patients with non-GERD conditions. These results suggest that balloon MI can differentiate between GERD, EoE, and non-GERD conditions [45]. Although this study also included patients with abnormal pH (AET >5.5%), only four patients had abnormal pH and no EE. Therefore, more data are required to confirm the usefulness of MI measurements for diagnosis of patients with NERD. Balloon catheters received Food and Drug Administration approval in the United States in 2021.
Mucosal admittance measurement
Mechanism
Similar to MI catheters, mucosal admittance (MA) measurement is a new system, which is the reciprocal of endoscopically measured impedance. This catheter has an admittance sensor at its tip, and measurements are obtained by gently pressing the sensor against the mucosa. Two electrocardiographic electrodes are attached to the patient’s arms to create a closed circuit. Once stable contact is established between the sensor and the mucosa, the device uses currents with two different frequencies to measure the MA. A high-frequency current of 30.7 kHz measures flow in the intracellular fluid, and a lowfrequency current of 320 Hz measures flow in the extracellular fluid. MA is determined by combining these two measurements [36]. Table 2 shows differences between the MI and MA measurement systems.
Comparison of the mucosal impedance and mucosal admittance measurement systems
Compared with the standard MI catheter, instead of two sensor rings, the MA catheter has a single sensor at its tip. Additionally, the MA system establishes a closed circuit between the catheter tip and the electrodes on the patient’s arm and can evaluate the integrity across the entire mucosal thickness. Therefore, luminal fluid and air have lesser effects on the measurement. Additionally, endoscopists can directly press the tip onto the mucosa, which simplifies the procedure compared with positioning the side of the catheter against the mucosa, as required with use of the MI catheter. Using two frequencies and measurement of the difference between the two currents may minimize the effect of the pressure applied by the sensor on the mucosa.
Available systems
The Tissue Conductance Meter (TCM system, AS-TC100, ASCH JAPAN Co., Ltd., Tokyo, Japan) was developed to measure skin and mucosal MA (Fig. 2). The system includes an endoscope-guided catheter with an MA sensor at its tip, an adapter to control voltage, and a TCM device to control the measurement time and calibration and to record the MA. The recommended settings for mucosal MA measurement include a constant voltage of 12.5 mV and measurement time of 2–3 s.
Image showing the TCM system for MA measurement during endoscopy. MA, mucosal admittance; TCM, Tissue Conductance Meter.
Foam and fluid is cleared from the esophageal lumen before measurement, and the catheter is passed through the working channel of the endoscope. After direct contact is established between the sensor and the mucosa, the endoscopist presses the measurement button or foot pedal to begin measurement. Esophageal measurements are recorded 5 cm and 15 cm above the SCJ. At least five measurements are obtained at each site, and the mean value is used for analysis.
Clinical data
MA measurements have been investigated as a diagnostic and prognostic tool for some gastrointestinal diseases with promising results [46-48]. MA measurement includes recording the esophageal MA for diagnosis of GERD, duodenal MA for diagnosis of functional dyspepsia, and colorectal MA to predict ulcerative colitis relapse.
In a study performed by Matsumura et al. [46] in Japan (2017), MA was measured in 24 patients with EE, 82 patients without EE but with an abnormal pH, and in 14 healthy controls. MA was also measured in 33 patients with refractory heartburn, and the results were compared between GERD and functional heartburn, diagnosed by using 24-hour pH-impedance monitoring. Measurements were obtained 5 cm (distal esophagus) and 15 cm (middle esophagus) above the SCJ. The results showed that the MA in the distal esophagus was higher in patients with EE. The MA cutoff values for diagnosis of GERD (EE or AET >4) were 11.0 for the distal esophagus and 13.1 for the middle esophagus in patients with refractory heartburn.
Clinical data obtained from Vietnam
Dao et al. [49] performed a study in Vietnam (2023) to investigate the role of MA as a diagnostic aid for GERD. The study included 92 patients with reflux symptoms. All patients underwent endoscopy, pH impedance monitoring, and MA measurements. The diagnosis of GERD was established based on the 2018 Lyon Consensus and included esophagitis LA grades C–D and AET >6%. In this study, the median MA recorded at the middle esophagus was significantly higher in the GERD group. The prediction model that integrated MA for GERD diagnosis had a moderate predictive value (AUC=0.704).
“Evaluation of motility and secretion disorders in some upper gastrointestinal diseases” (No. 1846, approved on June 27, 2019—a national-level project funded by the Ministry of Science and Technology, Vietnam) included 120 patients with GERD symptoms who underwent MA measurements, endoscopy, pH-impedance monitoring, and histopathology based on the Esohisto consensus guidelines (biopsies obtained 5 cm above the Z-line). MA values were measured 5 cm and 15 cm above the SCJ (distal and middle esophagus, respectively). Table 3 shows MA measurements at the distal and middle esophagus. The results showed that distal esophageal MA measurements in patients with AET >6% were significantly higher than those recorded in patients with AET ≤6%. No differences in MA values were observed between patients with or without EE, histopathologically documented esophagitis, Barrett’s esophagus, or hiatal hernia.
Intergroup comparison of mucosal admittance
Using abnormal AET as a criterion for GERD diagnosis, a cutoff value of 45.2 at the distal esophagus showed sensitivity of 74.0%, and a cutoff value of 66.8 showed specificity of 89.0% (Fig. 3). A cutoff value of 34.8 at the middle esophagus showed sensitivity of 89.0%, and a cutoff value of 69.3 showed specificity of 89.0%.
Measurement of esophageal MA for diagnosis of GERD based on 24-hour pH-impedance monitoring. GERD, gastroesophageal reflux disease; MA, mucosal admittance; AUC, area under the receiver operating characteristic curve.
These results suggest that MA measurements may be useful to identify patients with abnormal AET. Notably, the cutoff values for GERD diagnosis differed between Japanese and Vietnamese patients, which is perhaps attributable to the fact that the Japanese study differentiated between GERD and functional heartburn in contrast to the Vietnamese study, which differentiated between patients with GERD and non-GERD. Moreover, the diagnostic criteria for GERD differed between the studies (AET ≥4 or positive symptom index in the Japanese study and AET >6 based on the Lyon Consensus in the Vietnamese study). Therefore, further studies are warranted to determine whether the cutoff values for MA for diagnosis of GERD vary across races and countries.
CONCLUSION
Despite its high prevalence, diagnosis of GERD is complicated owing to the unavailability of an accurate but simple diagnostic modality in clinical practice. Current evidence suggests that direct endoscopy-guided MA and MI measurements may be a promising approach; however, multicenter data are unavailable on esophageal diseases other than GERD and EoE. Technical improvements in these methods are required to simplify the measurement process and improve their predictive value for diagnosis and monitoring.
Notes
Availability of Data and Material
Data sharing not applicable to this article as no datasets were generated or analyzed during the study.
Conflicts of Interest
Hang Viet Dao, a contributing editor of the Korean Journal of Helicobacter and Upper Gastrointestinal Research, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.
Funding Statement
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Authors’ Contribution
Conceptualization: Hang Viet Dao. Formal analysis: Hang Viet Dao, Binh Phuc Nguyen, Hue Thi Minh Luu. Investigation: all authors. Methodology: Hang Viet Dao. Supervision: Hang Viet Dao. Validation: Hang Viet Dao. Visualization: Binh Phuc Nguyen. Writing—original draft: Binh Phuc Nguyen, Hue Thi Minh Luu. Writing—review & editing: all authors. Approval of final manuscript: all authors.
Acknowledgements
None