Gastroesophageal reflux disease (GERD) is a condition wherein the gastric contents reflux into the esophagus, causing troublesome symptoms or complications.1 There are numerous individuals diagnosed with GERD worldwide, with the numbers estimated at 20-30% of the population in Western countries and more than 10% of the population in Asia.2,3 Proton pump inhibitors (PPIs) are among the first-line treatments for GERD, which may be effective in about 80% to 90% of patients with reflux esophagitis.4 Contrarily, PPI treatment results in symptom amelioration in only 40-50% of patients with nonerosive disease,5 suggesting that their symptoms may be attributable to several distinct factors.6 As such, if PPI treatment does not have a significant impact on GERD symptoms, pathophysiological evaluation using esophageal multichannel intraluminal impedance–pH testing and esophageal high-resolution manometry (HRM) testing have been recommended.7,8
The pathophysiology of GERD is complex and multifactorial. The results of the combined multichannel intraluminal impedance-pH and HRM testing can provide an accurate diagnosis of GERD and likewise facilitate the detection of pathological mechanisms, including esophageal motility disorders (EMDs) and lower esophageal sphincter dysfunction. Moreover, HRM testing rules out confounding diagnoses, such as achalasia.9 GERD-associated symptoms, such as heartburn and regurgitation, are caused by the reflux of gastric contents into the esophagus. However, some patients experience similar symptoms that are unrelated to reflux.6,10-12 Moreover, some of these patients are ultimately diagnosed with EMDs that include achalasia or jackhammer esophagus requiring a completely different therapeutic approach.11,13,14 Results from previous studies have documented the frequency of EMDs among GERD patients to be 25-76%.14-16 As such, in clinical practice, considering the possibility of EMDs is necessary when symptoms do not improve with PPI treatment. Pathophysiological classifications of EMDs have been described previously.17,18 However, the underlying factors contributing to the pathogenesis of EMDs and their impact on suspected GERD-associated symptoms have not been fully investigated. As such, this study aims to explore clinical features associated with specific types of EMDs in patients with heartburn symptoms.
This retrospective cohort study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Out of the 511 patients who underwent HRM testing at our institution between August 2013 and December 2019, 56 patients without heartburn symptoms and 61 patients who had already been diagnosed with achalasia by other test results (endoscopy and/or barium swallow test) were excluded from this study. The remaining 394 patients who were evaluated for suspected GERD-associated symptoms were analyzed. All patients had heartburn symptoms. Patients who had undergone previous esophageal surgery were not included. Demographic data were recorded, including age, sex, body mass index (BMI), cigarette smoking index (Brinkman index: the number of cigarettes smoked per day multiplied by the number of years of smoking), amount of alcohol consumed, comorbidities (hypertension, diabetes mellitus, scleroderma, and allergy), past history of gastrectomy, and
All study participants completed 3 questionnaires, the frequency scale for symptoms of GERD (FSSG),19 the Gastrointestinal Symptom Rating Scale (GSRS),20 and the Short Form-8 Health Survey (SF-8),21 before undergoing HRM in order to evaluate the differences with respect to their symptoms. The FSSG provides a measure of GERD-related symptoms. Of the 12 FSSG questions, 7 are related to symptoms associated with acid reflux, 5 to symptoms associated with gastrointestinal dysmotility, and 1 to symptoms associated with dysphagia (question 9). The patients answered each question based on a scale ranging from 0 (never) to 4 (always) points.19 The GSRS questionnaire features 15 items and measures gastrointestinal symptoms in 5 categories: acid reflux, abdominal pain, indigestion, diarrhea, and constipation. The score for each item was calculated as an average, and the total GSRS score was calculated as the average of all 15 items. The acid reflux score consists of 2 questions. One is the frequency of heartburn, and the other is the frequency of acid regurgitation. Scoring was performed using a Likert scale ranging from 1 (least severe gastrointestinal symptoms) to 7 (most severe symptoms).20 The SF-8 is a measure of the general health which provides a summary of both physical and mental components. The participants were asked 8 questions about their health in the past 4 weeks; the results include 2 scores between 0 and 100, with higher scores indicative of superior health status.21
All patients underwent upper gastrointestinal endoscopy in order to evaluate the presence and degree of erosive esophagitis, hiatal hernia, and/or gastric mucosal atrophy. Erosive esophagitis was graded according to the Los Angeles classification (A-D).22 Hiatal hernia was defined as an apparent separation of > 1 cm between the lower margin of the esophageal palisade vessels and the diaphragm hiatus on deep inspiration.23 The severity of gastric mucosal atrophy was evaluated according to the Kimura-Takemoto classification (in order of severity: none, C-1, C-2, C-3, O-1, O-2, and O-3).24 The status of infection and eradication of
All HRM studies were conducted employing the Sandhill System (InSIGHT Ultima; Sandhill Scientific Inc, Milwaukee, WI, USA) with the use of 32 pressure sensors and 16 impedance sensors. Patients were asked to swallow 5 mL of water 10 times while in the supine or semi-Fowler’s position; the diagnosis of EMD was made according to the criteria of the Chicago classification, version 3.0.17 The individual HRM metric types included normal motility, outflow obstruction (achalasia and esophagogastric junction [EGJ] outflow obstruction), hypermotility (distal esophageal spasm and jackhammer esophagus), and hypomotility (absence of contractility, ineffective esophageal motility, and fragmented peristalsis).25,26
Baseline data are expressed as mean ± standard deviation and median ± interquartile range. The differences in clinical parameter values between the groups were analyzed using Student’s
HRM test results are presented in Table 1. Of the 394 patients included in this study, 193 (48.9%) were diagnosed with EMDs; of these, 71 (36.7%) patients had outflow obstruction, 15 (7.7%) revealed hypermotility, and 107 (55.4%) were diagnosed with hypomotility. The patients’ clinical characteristics by type of esophageal motility disorder and comparison with the normal motility group are presented in Table 2.
The mean dysphagia symptom score in the outflow obstruction group was significantly higher than that in the normal motility group (
The mean dysphagia symptom score among patients diagnosed with hypermotility was significantly higher than that reported among patients with normal motility (
The mean dysphagia symptom scores among those with esophageal hypomotility were significantly higher than among those with normal motility (
A full analysis of the aforementioned examinations revealed that the mean dysphagia scores of patients in each of the 3 EMD groups were all higher than those of patients with normal motility (Fig. 2). Furthermore, the dysphagia scores of those in the outflow obstruction group were significantly higher than those in the hypomotility group (
This study evaluated the clinical characteristics and symptoms of patients diagnosed with EMDs. Among our findings, we demonstrated that different EMDs have distinct characteristics and symptoms. We also revealed for the first time that cigarette smoking and high BMI are associated with esophageal hypermotility in patients with GERD symptoms. Furthermore, our findings identified dysphagia symptoms as characteristic of all EMDs; as such, an assessment of the dysphagia symptom score on the FSSG questionnaire may be useful with respect to the diagnosis of EMDs.
EMDs include several dysmotility types. In order to evaluate the characteristics of the different EMDs, we categorized them as those with primarily outflow obstruction, those with hypermotility, and those with hypomotility; the responses and characteristics were compared with those with normal motility, as reported in previous studies.25,26 We evaluated the relationship between EMDs and detailed clinical histories of 394 patients presenting with heartburn symptoms; these characteristics included smoking habits, alcohol consumption, comorbidities, past medical histories, and endoscopic findings. In addition, we used 3 questionnaires in order to examine the association between symptoms and EMDs; these questionnaires focused not only GERD symptoms but also on non-GERD-associated symptoms, including irritable bowel syndrome (IBS), and quality of life. Among our results, we revealed that mean acid reflux and dyspepsia scores were significantly lower among those in the outflow obstruction group, whereas mean diarrhea and constipation scores were significantly lower among those with hypomotility. Significantly lower mean scores for acid reflux in the outflow obstruction group may be related to diminish acid reflux due to impaired EGJ relaxation. This result was similar when achalasia and EGJ outflow obstruction groups were separately compared with the normal motility group. On the other hand, the significantly lower score of dysphagia was found only in patients with achalasia. Moreover, the significantly lower mean scores for diarrhea and constipation in the hypomotility group may be due to the fact that more patients were categorized in the normal motility group. In other words, although the relationship between IBS and EMDs is still controversial,27-29 our results suggest the possibility of less EMDs in GERD patients who also experience symptoms associated with IBS.
There are several published studies that have documented the association between EMDs and patient clinical histories and characteristics.30-33 For example, Lee et al30 reported that age was directly associated with esophageal dysmotility. Similarly, Spechler et al31 considered the possibility of an association linking eosinophilic esophagitis with achalasia and other EMDs. With regard to BMI, Tanaka et al32 reported that BMI was negatively associated with the distal contractile integral (DCI) determined by HRM, whereas Côté-Daigneault et al33 reported that 85.0% of EMDs diagnosed in obese patients (BMI > 29 kg/m2) involved hypomotility. Contrarily, Rogers et al26 reported that EMDs were diagnosed less frequently in obese patients (BMI > 30 kg/m2), including the esophageal hypermotility type. In our study, we found no association between BMI and esophageal hypomotility, although there was a distinct association between BMI and esophageal hypermotility. The discrepancies between these sets of results may be related to the differences in the range of BMIs and/or sample sizes; there may be other confounding factors as well. Taken together, the relationship between BMI and EMDs remains unclear; thus, further investigation of this point will be needed.
With regard to cigarette smoking, it is well known that cigarette smoking reduces lower esophageal sphincter pressure and is one of the major risk factors for the development of GERD.34,35 Furthermore, results of a large prospective cohort study indicated that cessation of cigarette smoking was associated with diminished symptoms of reflux in normal-weight individuals.36 Tanaka et al32 reported that the Brinkman index was correlated with DCI. Since patients with normal IRP and high DCI (> 8000 mmHg·sec·cm) are diagnosed with hypermotility, the results of this study are consistent with those previously reported. To the best of our knowledge, previously published reports focusing on the relationship between cigarette smoking and esophageal hypermotility were not found. In the future, it will be necessary to conduct a prospective evaluation in order to determine whether cessation of cigarette smoking and/or weight reduction could improve esophageal motility.
In the present study, the dysphagia score was significantly higher in all EMD groups when compared with that observed among patients with normal esophageal motility. Reddy et al25 examined 211 patients who underwent HRM testing and who were categorized into outflow obstruction, hypermotility, and hypomotility groups, which resulted in a gradient of decreasing dysphagia and increasing reflux burden. Our results were similar to those presented in this study. However, contrary to their methods, we also examined the sensitivity and specificity of dysphagia symptom scores for predicting EMDs. Although the sensitivity and specificity were low, the negative predictive value of a dysphagia score of ≥ 3 was relatively high (82.6%). These results suggest that an assessment of the dysphagia symptom score may be beneficial for excluding a diagnosis of EMD. While various guidelines include recommendations for HRM testing of patients with PPI-refractory GERD, this is not yet a common diagnostic tool; only a few facilities are capable of conducting HRM testing at this time. The opportunity to predict the overall likelihood of EMDs would certainly be clinically useful. The results presented here would assist clinicians with disease-associated predictions.
This study has several limitations. First, although the relationship between EMDs and symptoms was evaluated, reflux monitoring was not performed in all patients, and the relationship between reflux and these symptoms was not explored. As such, EMDs cannot be identified as directly associated with these symptoms. Second, there were only 15 patients in the hypermotility group; as such, this study may have been underpowered with respect to the differences between patients with hypermotility and normal esophageal motility. Esophageal hypermotility is a comparatively uncommon diagnosis; more information on the characteristics of patients with this disorder needs to be collected and verified at multiple centers. Third, all patients in this study exhibited GERD symptoms; no symptom-free individuals were included. Given the reports of peristaltic disorders observed in subjects who report no symptoms,15 it will be necessary to incorporate this group in future studies so as to have an accurate measure of the association between EMDs and associated symptoms.
In conclusion, we demonstrated here that different EMDs present with distinct characteristics and symptoms depending on the type of disorder. The underlying factors associated with the pathogenesis of EMDs remain unknown. Our results may be useful toward a larger understanding of the pathophysiology of EMDs and the development of new treatments for GERD in the future.
The authors would like to thank the staff of the Endoscopy Center of Chiba University Hospital for providing technical assistance and helping in the documentation in this study.
Designed the study, conducted the experiment, collected data, analyzed and interpreted data, and wrote the manuscript: Satsuki Takahashi and Tatsuya Kaneko; designed the study, analyzed and interpreted data, and assisted in writing the manuscript: Tomoaki Matsumura; assisted in conducting the experiment and collecting data: Mamoru Tokunaga, Hirotaka Oura, Tsubasa Ishikawa, Ariki Nagashima, Wataru Shiratori, Naoki Akizue, Yuki Ohta, Atsuko Kikuchi, Mai Fujie, Keiko Saito, Kenichiro Okimoto, Daisuke Maruoka, Tomoo Nakagawa, and Makoto Arai; and assisted in interpreting data and writing the manuscript: Jun Kato and Naoya Kato. All authors approved the final version of the manuscript.