High prevalence of esophagitis in patients with severe ineffective esophageal motility: need for a new diagnostic cutoff.

Background: A new classification criterion for diagnosing ineffective esophageal motility (IEM) was proposed at the 2018 Stanford symposium, but limited data exists about the utility of this criterion.
Methods: We conducted a cross-sectional study among 3826 patients treated at the Institute of Gastroenterology and Hepatology, Hanoi, Vietnam, between March 2018 and May 2020. Patients were classified as having normal motility, mild IEM, severe IEM, or absent contractility based on the Chicago classification version 3.0 and the new IEM criterion (severe IEM was defined as having >70% ineffective swallows). We examined the association between these 4 motility subgroups and the presence of erosive esophagitis and Barrett's esophagus, using multivariate logistic regression analysis.
Results: The mean age of the study sample was 44.7 years and 66.3% were women. The prevalence of symptoms, hiatal hernia, and Helicobacter pylori-positive patients was similar in the 4 study groups. The 4-second integrated relaxation pressures and lower esophageal sphincter resting pressures were lower in patients with severe IEM and absent contractility. Severe IEM and absent contractility, but not mild IEM, were significantly associated with Los Angeles (LA) grade B-D esophagitis (relative risk ratio [RRR] for severe IEM 1.81, 95% confidence interval [CI] 1.17-2.80; and RRR for absent contractility 2.37, 95%CI 1.12-5.04). None of the hypomotility subgroups were associated with LA grade A esophagitis and Barrett's esophagus. Conclusions: Patients with severe IEM have a high prevalence of severe erosive esophagitis. These findings suggest the need for a more meaningful classification criterion for IEM. Copyright: © Hellenic Society of Gastroenterology.

Introduction

In the past decade, high-resolution manometry has become an important tool for the study of esophageal motility disorders. The most commonly utilized criterion for determining the presence of esophageal motility disorders is the Chicago Classification version 3.0 [1]. In this classification system, hypomotility disorders include ineffective esophageal motility (IEM), fragmented peristalsis, and absent contractility. While absent contractility (complete loss of esophageal peristalsis) is clearly associated with an increased risk of gastroesophageal reflux disease (GERD) [2,3], IEM appears to have less clinical significance because the findings concerning its association with GERD are inconclusive [4]. The 2018 Stanford symposium suggested that the IEM population might be heterogeneous, including both healthy individuals and persons at higher risk for GERD [4], reinforcing the need for a more detailed classification schema for those with hypomotility disorders. These investigators proposed a new classification criterion for IEM, which separates the condition into mild (having ≥50% to ≤70% ineffective swallows), and severe IEM (having >70% ineffective swallows) [4]. The Chicago Classification version 4.0 proposed in 2020 also modified the diagnostic criteria for IEM as having >70% ineffective swallows or ≥50% failed swallows [5]. It has been suggested that patients with severe IEM have more abnormal reflux exposure and dysphagia [6,7]. Since significant hypomotility is associated with impairment of normal bolus clearance [7], patients with severe hypomotility may be at higher risk for developing erosive esophagitis [8] and Barrett’s esophagus [9].

In this cross-sectional study of patients with normal motility or hypomotility, we examined the relationship between motility categories and endoscopic findings, including erosive esophagitis and Barrett’s esophagus. We combined the conventional Chicago Classification version 3.0 with the IEM criterion proposed in the Stanford symposium to separate IEM into 2 entities (severe or mild). Our hypothesis is that patients with severe IEM would have a greater burden of these esophageal injuries compared to those with mild IEM. Such findings, if present, suggest the need to expand the diagnostic paradigm for hypomotility disorders in the Chicago Classification version 3.0.

Patients and methods

We conducted a cross-sectional study among patients who had a diagnosis of normal motility, IEM, or absent contractility based on the Chicago Classification version 3.0 on high-resolution manometry (HRM) at the Institute of Gastroenterology and Hepatology, Hanoi, Vietnam, between March 2018 and May 2020. To exclude changes in esophageal motility due to the use of various treatment practices, only the first HRM measurements of those who had not received any treatment for motility disorders in the past 3 months were analyzed.

Data collection

Demographic information was obtained from electronic medical records. Body mass index (BMI) and clinical symptoms were collected in a routine patient form completed before patients underwent HRM. Clinical symptoms relevant to motility disorders and GERD were categorized into 3 main groups: typical symptoms (heartburn, regurgitation), obstructive symptom (dysphagia), and other atypical symptoms. The clinical severity of GERD was assessed using the GERD Questionnaire (GERDQ) [10] and the Frequency Scale from the Symptoms of GERDQ (FSSG) [11]. A clinical diagnosis of GERD was made when the GERDQ or FSSG total score was ≥8 [10,11]. We also collected data on the history of systemic diseases, such as systemic sclerosis, mixed connective tissue disorder or CREST syndrome, and performed a thorough clinical examination. Patients with symptoms that suggested these conditions would be referred to a dermatologist for more specialized investigations.

HRM

Indications for HRM included suspected esophageal motility disorders, refractory GERD, extraesophageal reflux symptoms, systemic disease with esophageal symptoms, and the need for determining the location of the lower esophageal sphincter (LES) prior to 24-h pH-impedance monitoring. HRM would be canceled or delayed if the patient had a history of gastroesophageal surgery or esophageal tumors, had active upper gastrointestinal bleeding on endoscopy, or had taken medications that affect esophageal motility (e.g., prokinetics, calcium channel blockers, nitrates, opiates, anticholinergics) during the past 48 h [12].

We used the Solar GI (Laborie) HRM system with 22-channel water-perfusion catheters. The results were interpreted based on the Chicago Classification version 3.0, with a 4-sec integrated relaxation pressure (IRP4s) of <19 mmHg being considered normal (according to the specification of the manufacturer). An esophageal swallow was classified into either normal, ineffective, failed, or fragmented swallow. The normal range of LES resting pressure was 10-45 mmHg; values below 10 mmHg were considered as LES hypotension [13]. The peristaltic reserve was assessed using the distal contractile integral (DCI) ratio, calculated by dividing the multi-rapid swallow DCI by the average DCI of single wet swallows [14].

After excluding patients with either a hypermotility disorder or impaired relaxation capacity (LES resting pressure ≥45 mmHg or IRP4s ≥19 mmHg), we categorized patients into those with normal motility, mild IEM (≥50% to ≤70% ineffective swallows), severe IEM (>70% ineffective swallows), and absent contractility (100% failed peristalsis). The criteria for mild and severe IEM were adopted from the 2018 Stanford symposium [4]. Patients with fragmented peristalsis were too few to be included in the analysis.

Esophagogastroduodenoscopy (EGD) and Helicobacter pylori (H. pylori) testing

Endoscopic results were collected from patient’s electronic medical records. We collected data on the presence of erosive esophagitis, Barrett’s esophagus, and hiatal hernia. The severity of erosive esophagitis was evaluated using the Los Angeles (LA) classification [15]. According to the 2021 American College of Gastroenterology guidelines, LA grade B in the presence of typical symptoms and proton-pump inhibitor response, and LA grade C-D are diagnostic of GERD, whereas LA grade A is not sufficient for a definitive diagnosis of GERD [16]. Therefore, we grouped patients with LA grades B to D esophagitis into a single subgroup, making up 3 subgroups of patients with esophagitis (no esophagitis, LA grade A esophagitis, and LA grades B-D esophagitis). Barrett’s esophagus on endoscopy was categorized as either short-segment (<3 cm in length) or long-segment (≥3 cm in length), and hiatal hernia was diagnosed on EGD if a Hill grade III or IV gastroesophageal flap valve was found in the retroflex view [17,18]. All of the procedures were performed and evaluated by endoscopists who had more than 5 years of experience. We reviewed the images of several categories of endoscopic results, including LA grades C-D esophagitis, long-segment Barrett’s esophagus, and results without LA classification.

Per routine practice, H. pylori was tested for during endoscopy using the rapid urease test. Patients who tested negative were then tested again using the urea breath test to avoid false-negative urease test results. Patients were considered to be H. pylori-positive when at least one test result was positive and H. pylori-negative when both tests were negative.

Statistical analysis

The study population characteristics were expressed as percentages for categorical variables and means (standard deviation) or medians (interquartile range/min–max) for continuous variables. We compared differences in several patient characteristics between the 4 motility subgroups (normal, mild IEM, severe IEM, and absent contractility) using the chi-square test, one-way analysis of variance (ANOVA), or Kruskall-Wallis test where appropriate. The primary outcomes of the study were erosive esophagitis and Barrett’s esophagus. To examine the association of hypomotility subgroups (mild IEM, severe IEM, and absent contractility) with erosive esophagitis, we used multinominal logistic regression. To examine the association with Barrett’s esophagus, we used binary logistic regression. All the regression models were adjusted for potentially confounding characteristics, including male sex, older age, higher BMI, lower LES resting pressures [19-23], positive H. pylori state [19,24], and abnormal multiple rapid swallows [25]. Data were cleaned and analyzed using the Python programming language version 3.8.6.

Results

Study population characteristics

Between March 2018 and May 2020, a total of 3826 eligible patients were recruited and included in our analysis. The mean age of this study population was 44.7 years, two-thirds were women, and more than one-third were overweight (BMI ≥23 kg/m2). The proportion of patients with normal motility, mild IEM, severe IEM and absent contractility were 41.8%, 21.7%, 32.4% and 4.1%, respectively. The prevalences of typical symptoms and dysphagia were higher in patients with absent contractility than in the IEM and normal groups, but not significantly different. Erosive esophagitis was present in 44.4% of patients (41.0% LA grade A and 3.4% LA grade B-D).

All 4 groups were similar in terms of clinical GERD severity and the prevalence of symptoms (Table 1), as well as the prevalence of hiatal hernia and H. pylori infection (Table 2). However, the mean IRP4s and LES resting pressure were lower in patients with severe IEM and absent contractility. In addition, fewer patients in the hypomotility subgroups had DCI ratio >1. LA grade B-D esophagitis and short-segment Barrett’s esophagus were more common in patients with severe IEM and absent contractility.

Table 1

Study population characteristics according to the presence of motility disorders

Table 2

Characteristics on endoscopy and high-resolution manometry according to the presence of motility disorders

Association of hypomotility with erosive esophagitis and Barrett’s esophagus

In examining the association between hypomotility disorders and the presence of erosive esophagitis, severe IEM and absent contractility were not associated with LA grade A esophagitis but were significantly associated with LA grade B-D esophagitis (relative risk ratio (RRR) for severe IEM 1.81, 95% confidence interval (CI) 1.17-2.80; and RRR for absent contractility 2.37, 95%CI 1.12-5.04) (Table 3). Mild IEM was not associated with any grade of esophagitis. None of the hypomotility disorders was associated with Barrett’s esophagus (Table 3).

Table 3

Differences in the risk of esophagitis and Barrett’s esophagus among patients with motility disorders

Discussion

In this large observational study, we examined the association between esophageal lesions and the 4 HRM subgroups (normal motility, mild IEM, severe IEM, and absent contractility). Severe IEM and absent contractility were associated with more severe (LA grade B-D) esophagitis, independently of LES hypotension, hiatal hernia and impaired contraction reserve, but were not associated with LA grade A esophagitis and Barrett’s esophagus.

We found that there was a relationship between the severity of hypomotility and the prevalence of LA grade B-D esophagitis: the RRR was higher in patients with severe IEM and absent contractility. A 2018 study of 188 patients who underwent HRM and pH monitoring examined the cutoff to classify IEM using the Chicago Classification version 3.0, showing that patients with a higher proportion of ineffective and failed swallows were associated with higher total acid exposure time on pH monitoring [26]. Other studies have failed to find an association between IEM and GERD, although IEM was associated with prolonged acid exposure time and impaired esophageal clearance capacity [27-29]. Therefore, the observed higher prevalence of esophagitis in patients with severe IEM could be due to more impaired reflux clearance, suggesting that severe IEM should be distinguished from mild IEM because the patients might have different risks of developing esophagitis.

We also found that, compared with normal patients, the mean LES resting pressure and IRP4s, and the percentage of those with contraction reserve, were lower in patients with hypomotility, with a trend towards being lower in patients with more severe conditions. The adequacy of LES pressure and esophageal motility are major mechanisms that prevent reflux events. The combination of LES hypotension and esophageal hypomotility, as well as hiatal hernia, could predispose to the development of GERD [30].

The Chicago Classification version 4.0 has changed the working definition of IEM recommended for use in the Chicago Classification version 3.0 from ≥50% ineffective swallows to ≥70% ineffective swallows or ≥50% failed swallows [5]. Although the value of the new classification criteria will need to be evaluated in different populations, these changes reflect the current opinion that the earlier cutoff might be too low to detect clinically meaningful changes [4]. It is also noteworthy that the percentage of ineffective or failed single swallows on HRM is not the only diagnostic criteria for IEM. Different protocols for HRM, such as multi-rapid swallows, rapid drink challenges, or use of a single wet swallow in other positions, as well as use of the findings from other diagnostic techniques, such as functional luminal imaging probes, have been proposed to more systematically identify disorders of hypomotility that are clinically relevant [4,5].

This is one of the first studies that has explored the association between different severity levels of hypomotility and esophagitis. The large sample size of our study provided precise estimates of this association. However, our results should be interpreted within certain limitations. Data on erosive esophagitis and Barrett’s esophagus were collected retrospectively; therefore, there might be inconsistency in the ascertainment of these outcomes. We attempted to minimize this bias by independently reviewing the endoscopic images to the extent possible. Our HRM system did not use an integrated impedance catheter, so we could not provide further information about bolus transport and esophageal clearance in the study sample. We did not perform pH-impedance monitoring, a better method for diagnosing GERD, and thus did not have the gold standard criteria for diagnosing patients with nonerosive reflux disease. However, the pH-impedance study is an expensive and resource-intensive approach and cannot be utilized in all patients with suspected GERD.

In conclusion, patients with severe IEM detected on HRM had a higher rate of severe erosive esophagitis compared to patients with mild IEM. Our findings suggest the use of a new cutoff, such as >70% ineffective swallows, to distinguish between mild and severe IEM, or another modification of the definition of IEM to make it a more clinically meaningful diagnosis.

What is already known:

Hypomotility disorders are common; ineffective esophageal motility (IEM) is the most prevalent, but its clinical relevance is unclear

The 2018 Stanford symposium and subsequent Chicago classification version 4.0 proposed new cutoff values for diagnosing IEM

Severe hypomotility is associated with impaired bolus clearance and a higher risk for developing erosive esophagitis and Barrett’s esophagus

What the new findings are:

Severe IEM and absent contractility, but not mild IEM, were associated with Los Angeles (LA) grade B-D esophagitis, currently considered as a finding of gastroesophageal reflux disease on endoscopy

None of the hypomotility subgroups were associated with LA grade A esophagitis and Barrett’s esophagus