Functional Endoscopy

The endoscopic diagnosis of gastroesophageal reflux disease (GERD) traditionally relies on several factors, including the presence or size of hiatal hernia, morphological changes in the mucosal flap valve [1, 2], the presence of esophageal erosions [3], and the existence of Barrett’s esophagus [4]. While cases with obvious esophageal erosion or Barrett’s esophagus are easily diagnosed as classic reflux esophagitis, diagnosing nonerosive reflux disease (NERD), which accounts for approximately 70% of GERD patients, has been a major challenge [5]. Currently, the gold standard for diagnosing GERD is the 24-h impedance pH test [6]. In addition, high-resolution manometry (HRM) is employed to evaluate esophageal motor function, both of which are independent studies from conventional endoscopic examination [7]. However, the 24-h impedance pH test, while indispensable for GERD diagnosis, has limitations. It requires 24 h to complete the test, and the discomfort associated with inserting a catheter through the nose into the esophagus is a notable issue that warrants improvements. An alternative solution to this discomfort is the use of an indwelling capsule-type Bravo pH monitoring system. However, it has its drawbacks, such as concerns about the diagnostic accuracy and the associated high cost [8]. Conversely, in conventional endoscopy, we have observed a variety of findings that are characteristic of GERD patients, extending beyond the morphological changes mentioned earlier. During upper endoscopy, insufflation is carried out in the stomach to identify intragastric lesions. In this process, GERD patients frequently exhibit a persistent and weak burping response following stomach insufflation, resulting in incomplete stomach distention. In such cases, the contraction of the lower esophageal sphincter (LES) becomes insufficient to effectively prevent gastric content reflux, indicating impaired anti-reflux function of the LES. These phenomena can be directly observed through dynamic endoscopic observation. Furthermore, in typical GERD cases, including those involving Barrett’s esophagus, the presence of bile-containing reflux is frequently noted when the endoscope is introduced into the esophagus. Therefore, we believe it is possible to identify several critical findings specific to GERD during the routine endoscopic study. Endoscopic pressure study integrated system (EPSIS), a novel endoscopic assessment tool we have proposed, aims to comprehensively assess LES function by integrating endoscopic findings with intragastric pressure data obtained during endoscopic examination [9].

During a regular gastrointestinal endoscopy, it is possible to measure intragastric pressure externally by simply attaching a connector to the instrumental channel of the endoscope and connecting it to a pressure-measuring device [10]. Initially, intragastric pressure was measured by inserting a catheter into the stomach through the instrumental channel. However, it has since been found that the same results can be obtained without the need for catheter insertion, based on Pascal’s principle. In the EPSIS test, carbon dioxide gas is insufflated into the stomach, which is a standard procedure in regular endoscopic observation. A small microphone is affixed to the patient’s neck to capture burping sounds. The diagnosis relies on the intragastric pressure waveform and the highest recorded intragastric pressure value (IGP max), which is obtained by continuously insufflating the stomach. In cases not related to GERD, insufflation should be halted when the intragastric pressure surpasses 22 mm Hg. Over-insufflation of the stomach may lead to Mallory Weiss tears in the mucosa, highlighting the importance of caution in this regard.

During an endoscopic examination, continuous insufflation of CO₂ is carried out until the gastric lumen is adequately distended. At this point, the LES can be endoscopically observed through holding the scope shaft in the retroflex view, a phenomenon referred to as the positive scope holding sign (SHS) [9]. The LES functions as a one-way valve, primarily tasked with preventing the reflux of gastric contents into the esophagus. The presence of a positive SHS indicates the normal function of the LES’s anti-reflux mechanism. In contrast, observing the contraction of the LES from the esophageal side is challenging because the LES naturally relaxes to facilitate the smooth passage of esophageal contents into the stomach after swallowing. The contraction of the LES that occurs during gastric insufflation is an involuntary reflex prompted by the distention of the stomach. However, when the intragastric pressure reaches a certain threshold, the LES begins to relax, leading to a burping reflex (the expulsion of intragastric gas through the mouth). This relaxation prevents further increases in the intragastric pressure. The highest recorded intragastric pressure during this process is termed IGP max, and its value reflects the LES’s capacity to prevent reflux. Consequently, EPSIS can be considered as a stimulation test for the LES’s response to gastric insufflation. In many GERD cases, IGP max is notably decreased.

The pilot study was conducted to assess the performance of EPSIS for the diagnosis of GERD [9]. The optimal cutoff value for IGP max was determined to be 18.7 mm Hg. In this preliminary study, an IGP max of less than 18.7 mm Hg demonstrated a sensitivity of 74.2% (95% confidence interval [CI] 56.8–86.3) and a specificity of 57.1% (95% CI: 39.1–73.5) for detecting GERD. Similarly, a “flat” pattern showed a sensitivity of 71.0% (95% CI: 53.4–83.9) and a specificity of 82.1% (95% CI: 64.4–92.1) for GERD. When combined, these EPSIS parameters (IGP max ≤18.7 mm Hg and a “flat” pattern) emerged as the most robust predictors for both GERD (odds ratio [OR] 16.05, 95% CI: 3.23–79.7) and NERD (OR 14.7, 95% CI: 2.37–90.8). However, there are cases in which characterizing waveform pattern into either of these two patterns (“uphill” or “flat” pattern) can be challenging and subjective. In addition, categorizing the waveform into two patterns seemed to limit the diagnostic ability. To address this issue and improve the performance of EPSIS, we evaluated additional components of the IGP waveform: the gradient of the waveform (mm Hg/s), which can be calculated as the “pressure difference” (IGP max − IGP min) divided by the “insufflation time.” Additional analysis revealed that the gradient of the waveform showed a high diagnostic yield in the diagnosis of acid reflux (the AUROC of the pressure gradient was 0.81) [11]. Hence, EPSIS showed a positive correlation with GERD when using 24-h impedance pH as the definitive diagnostic criterion for GERD [9, 11]. Furthermore, to distinguish between acid reflux and bile reflux, one can readily estimate the bile acid concentration in the refluxate through narrow band imaging of it [12].

To validate that the positive SHS corresponds to the contraction of the LES, HRM was integrated with a pediatric endoscope. HRM measurements were conducted concurrently with the EPSIS study. This integration allowed the confirmation that the burp observed during the procedure coincides with the release of scope holding, which is accompanied by LES contraction [13]. In the group classified as having a “suspected GERD pattern” according to EPSIS, the LES resting pressure, as assessed by esophageal manometry, was significantly lower compared to the “normal pattern” group (13.2 vs. 25.3 mm Hg, p = 0.002). Additionally, both the expiratory end LES pressure (8.5 vs. 15.5 mm Hg, p = 0.019) and the average integrated relaxation pressure were significantly lower (5.9 vs. 9.8 mm Hg, p = 0.020) in this group. These results suggest that when a “flat pattern” is observed, it can be anticipated that LES function is compromised. Conversely, when an “uphill pattern” is observed, LES function is generally considered to be normal.

In cases with erosive esophagus, as compared to cases without erosions, there was a lower maximum intragastric pressure (16.0 vs. 18.8 mm Hg, p = 0.01), and the “flat pattern” was observed more frequently (82.8% vs. 37.3%, p < 0.001). Similarly, in cases with Barrett’s esophagus, when compared to cases without Barrett’s esophagus, the maximum intragastric pressure was lower (15.7 vs. 19.6 mm Hg, p < 0.001), and the “flat pattern” was observed at a higher frequency (69% vs. 37.1%, p < 0.001). Furthermore, these trends were confirmed in multivariate analysis [14].

The data presented above pertain to the use of EPSIS in diagnosing GERD. In the future, we envision that this procedure could also find utility in evaluating treatment outcomes. Specifically, we aimed to determine whether EPSIS could serve as an assessment tool for the therapeutic efficacy of endoscopic cardioplasty procedures, such as anti-reflux mucosal ablation (ARMA) or anti-reflux mucosectomy. In anti-reflux mucosectomy and ARMA procedures, an ulcer is induced at the gastric cardia level by resecting or ablating the mucosa, subsequently facilitating cardioplasty through the scarring process. In our retrospective study, we evaluated 22 patients who had undergone endoscopic cardioplasty, conducting EPSIS assessments both before and after the endoscopic treatment. These patients were further evaluated via 24-h pH monitoring conducted 2–6 months post-ARMA. The median acid exposure time significantly decreased from 20.4% to 5.4% (p = 0.01), concurrently with an increase in the pressure gradient of the IGP waveform (0.15 vs. 0.25 mm Hg/s, p = 0.001). These changes suggest that the LES function had improved as a result of the endoscopic intervention. It is worth noting that when EPSIS is performed following Nissen’s fundoplication, the IGP max tends to exceed 25 mm Hg. To establish a robust evidence base, it is imperative to conduct several prospective studies involving multiple institutions. When conducting EPSIS, it is essential to exercise caution to prevent excessive insufflation, which can potentially lead to mucosal tears. Based on our experience, insufflation should be discontinued if the IGP exceeds 22 mm Hg.

The successful application of EPSIS in GERD diagnosis suggests the potential for its use in diagnosing other functional disorders within the small intestine and colon. Notably, a pilot study assessing anorectal function during colonoscopy yielded promising results [15]. Furthermore, our prior research has predominantly focused on acid reflux, with limited attention to reflux hypersensitivity and functional heartburn. These are ongoing investigations aimed at determining whether EPSIS can serve as a diagnostic tool in NERD, differentiating reflux hypersensitivity from functional heartburn.

The EPSIS procedure offers a straightforward and promising approach to enhance the diagnosis of functional gastrointestinal diseases during routine endoscopic examinations. Its simplicity and effectiveness in identifying GERD have provided a strong foundation for envisioning its broader application in diagnosing various functional disorders across the gastrointestinal tract. Its future contributions to the field of gastroenterology are certainly worth anticipating as it opens new avenues for improved patient care and management.

Haruhiro Inoue has been a part of Olympus (advisory, educational activities), Top Corporation (advisory), and Takeda Pharmaceutical Company (educational activities) and has provided advisory guidance for endoscopic pressure study integrated system (EPSIS). Yuto Shimamura declares no conflict of interests.

This study was not supported by any sponsor or funder.

Conception and design: Haruhiro Inoue. Data acquisition, interpretation of data, and final manuscript approval: Haruhiro Inoue and Yuto Shimamura. Critical revision of the manuscript for important intellectual content: Yuto Shimamura.