Esophagogastric Junction Opening Parameters are Consistently Abnormal in Untreated Achalasia

Introduction:

Achalasia is a disorder of impaired lower esophageal sphincter (LES) relaxation and failed peristalsis traditionally characterized by manometry.¹ As impaired LES relaxation is a mechanism of reduced EGJ opening, abnormally reduced EGJ-distensibility assessed with functional luminal imaging probe (FLIP) was reported among patients with untreated achalasia.^2–5 We therefore aimed to describe the performance characteristics of EGJ opening parameters on FLIP panometry among a large cohort of treatment-naïve achalasia patients.

Methods:

Subjects

An esophageal motility registry of patients that completed FLIP during sedated endoscopy between November 2012 and September 2019 was retrospectively evaluated to identify patients with a corresponding high-resolution manometry (HRM) diagnosis of achalasia. Achalasia was diagnosed per Chicago Classification (CC) v3.0.¹ Patients with previous foregut surgery (including LES myotomy), previous pneumatic dilation, or mechanical esophageal obstruction were excluded. Patients were compared to 42 asymptomatic volunteers (controls). Portions of these cohorts have been previously described.^{4, 6, 7}

Study Protocol and Analysis

During sedated endoscopy, 16-cm FLIP balloons were positioned across the EGJ and distal esophagus during stepwise balloon distension from 20 ml to 70 ml. FLIP panometry studies were performed and analyzed using a customized program as previously described (Supplemental material).^{4, 6–8} EGJ-distensibility index (DI) was calculated by dividing the median EGJ-midline cross-sectional area by the median intraballoon pressure measured over the duration of the 60-ml distension volume. The maximum EGJ-diameter achieved over the span of the entire FLIP study was also identified. HRM studies involved ten 5-ml liquid swallows performed in the supine position and were analyzed per CCv3.0.¹ Statistical comparisons between achalasia and controls were performed using Mann-Whitney U tests.

Results:

240 patients with achalasia, mean (SD) age 54 (17) years, 45% female and 42 controls, mean (SD) age 31 (6) years, 69% female were included. HRM achalasia subtypes included 54 (22%) type I, 126 (52%) type II, and 62 (26%) type III achalasia.

The median (5-95^th CI) EGJ-DI was 0.88 (0.34–2.7) mm²/mmHg in achalasia and 5.6 (2.9–9.3) mm²/mmHg in controls; P <.0.001. 219/240 (91%) achalasia patients had an EGJ-DI ≤2.0 mm²/mmHg and 233/240 (97%) had an EGJ-DI ≤3.0 mm²/mmHg. None of the controls had an EGJ-DI ≤2.0 mm²/mmHg and 3/42 (7%) had an EGJ-DI ≤3.0 mm²/mmHg; Figure. The 60-ml median EGJ-diameter was <12mm in all of the achalasia patients; only 1 control (2%) had a 60-ml median EGJ diameter <12mm.

Figure. Esophagogastric junction (EGJ) opening in achalasia and asymptomatic volunteers.

Values reflect measures obtained over the course of the 60ml fill volume during the functional luminal imaging probe (FLIP) panometry study. Median EGJ-diameter was transformed from median CSA via assumption of a circular lumen. In achalasia, the median (5-95th CI) EGJ-diameter was 6.0 (4.8–9.7) mm and median intraballoon pressure was 32 (16–69) mmHg. In controls, the median (5–95th CI) EGJ-diameter was 18.1 (12.9–21.9) mm and median intraballoon pressure was 44 (31–64) mmHg; P-values <0.001. Figure used with permission from the Esophageal Center at Northwestern.

The median (5-95^th CI) maximum EGJ-diameter was 9.2 (5.3–15.5) mm in achalasia and 23.0 (17.7–30.4) mm in controls, P<0.001. 202/240 (84%) achalasia patients had a maximum EGJ-diameter of <12mm and 231/240 (96%) had a maximum EGJ-diameter <16mm. All 7 of the patients with EGJ-DI > 3.0 mm²/mmHg had a maximum EGJ-diameter <16mm. All of the controls had a maximum EGJ-diameter >16mm.

Discussion:

In a retrospective analysis of 240 patients with achalasia diagnosed by HRM, we demonstrated that abnormal EGJ opening parameters on FLIP panometry are nearly ubiquitous in patients with achalasia. Our results are consistent with previous studies that EGJ-DI on FLIP is reduced in achalasia, though in a substantially larger cohort than previous studies.^{2, 3, 5} Even among the small group (9%; 21/240) of achalasia patients with a borderline or normal EGJ-DI (i.e. EGJ-DI >2.0 mm²/mmHg), examination of the individual DI components (pressure or EGJ-diameter), or application of a maximum EGJ-diameter, demonstrated consistent differentiation of achalasia from controls. Thus, using a combination of EGJ-DI and maximum EGJ-diameter can essentially rule out achalasia when abnormal EGJ-DI (<3.0 mm²/mmHg) and abnormal maximum EGJ-diameter (<16mm) are not observed. Thereby, unnecessary treatments targeting the LES can be avoided.

The approach of using multiple measurements to define EGJ opening contrasts to the flawed approach utilized with HRM whereby the diagnosis of abnormal LES relaxation is reliant on the integrated relaxation pressure (IRP) as a single discriminator.^{1, 8} Thus, false positives and false negatives related to both IRP on HRM and EGJ-DI on FLIP can be better adjudicated using additional measures to help determine whether the patient has achalasia. However, it is important to note that although almost all achalasia patients have abnormal EGJ opening on FLIP panometry, abnormally reduced EGJ opening parameters can also be observed among patients without achalasia.⁴ Unfortunately, the specificity of using the above cut-off values to diagnose achalasia cannot be gleaned from this study as this would require a more heterogeneous population that was not preselected. This will be the focus of future studies and we hypothesize that this approach could help define a non-achalasia disease state that exhibits abnormal EGJ opening without impaired LES relaxation.