A missing sphincteric component of the gastro-oesophageal junction in patients with GORD

Authors


Dr Larry Miller, Section of Gastroenterology, Department of Medicine, 8th Floor Parkinson Pavillion, Temple University Hospital, Philadelphia, PA 19140, USA.
Tel: +1 215 707 9985; fax: +1 215 707 2684; e-mail: vivi@temple.edu

Abstract

Abstract  It was recently shown that the tonic pressure contribution to the high-pressure zone of the oesophago-gastric segment (OGS) contains the contributions from three distinct components, two of which are smooth muscle intrinsic sphincter components, a proximal and a distal component [J Physiol 2007; 580.3: 961]. The aim of this study was to compare the pressure contributions from the three sphincteric components in normal subjects with those in gastro-oesophageal reflux disease (GORD) patients. A simultaneous endoluminal ultrasound and manometry catheter was pulled through the OGS in 15 healthy volunteers and seven patients with symptomatic GORD, before and after administration of atropine. Pre-atropine (complete muscle tone), postatropine (non-muscarinic muscle tone plus residual muscarinic tone) and subtracted (pure muscarinic muscle tone) pressure contributions to the sphincter were averaged after referencing spatially to the right crural diaphragm and the pull-through start position. In the normal group, the atropine-resistant and atropine-attenuated pressures identified the crural and two smooth muscle sphincteric components respectively. The subtraction pressure curve contained proximal and distal peaks. The proximal component moved with the crural sling between full inspiration and full expiration and the distal component coincided with the gastric sling-clasp fibre muscle complex. The subtraction curve in the GORD patients contained only a single pressure peak that moved with the crural sphincter, while the distal pressure peak of the intrinsic muscle component, which was previously recognized in the normal subjects, was absent. We hypothesize that the distal muscarinic smooth muscle pressure component (gastric sling/clasp muscle fibre component) is defective in GORD patients.

Abbreviations:
AUC

area under the curve

CD

crural diaphragm

FI

full inspiration

FE

full expiration

GORD

gastro-oesophageal reflux disease

HPZ

high-pressure zone

LOS

lower oesophageal sphincter

OGS

oesophago-gastric segment

PTS

pull-through start

RCd

right crural diaphragm distal

RCp

right crural diaphragm proximal

Introduction

The gastro-oesophageal junction contains intrinsic smooth muscle and extrinsic skeletal crus muscles that create a high-pressure zone (HPZ) and regulate the flow of fluid between the oesophagus and stomach. In addition to controlling oesophageal emptying, these muscles provide an antireflux barrier to gastric content and control physiological air venting (belching) and retrograde ejection of gastric contents (vomiting).

The oesophago-gastric segment (OGS) HPZ is a complex and dynamic structure that is subjected to different forces including active muscle tone and passive elastic stress that resists hiatal opening, intraluminal pressure driving hiatal opening, and a pressure gradient between gastric and intra-thoracic fluid content that drives reflux after hiatal opening. The relationship between the forces is made more complex because:

  • 1 The components of the gastro-oesophageal junction HPZ overlap and move in relationship to each other with respiration.
  • 2 The tone within the sphincter components change in time along with intra-abdominal pressure.
  • 3 The sphincters may relax spontaneously either as a transient lower oesophageal sphincter relaxation or with swallowing.
  • 4 The forces that drive reflux events are constantly changing with respiration and change with strain.

Numerous investigators have proposed the existence of various components of the gastro-oesophageal junction HPZ. Ingelfinger1 argued for skeletal muscle crural diaphragmatic contraction as important to the antireflux barrier. This crural barrier has been confirmed by a number of other investigators.2–6

Code et al.7 reported an intrinsic smooth muscle intraluminal HPZ in the segment between the oesophageal body and the gastric cardia. Partial in vivo suppression of sphincteric pressure in humans by atropine,8–13 and studies in which the HPZ was quantified after removal of the gastro-oesophageal segment during oesophagogastrectomy in humans5 led to the proposal that this second intrinsic sphincteric component overlaps spatially with the crural diaphragm (CD).14,15 Because no anatomic correlate could be found, it has been necessary to assume a purely physiological circular smooth muscle ‘lower oesophageal sphincter’ (LOS) intrinsic to the smooth muscle fibres of the oesophagus.16,17

Liebermann-Meffert et al.18,19 measured a thickened wall of smooth muscle at the gastric sling/clasp muscle fibre groups in cadavers. ‘Sling’ muscle fibres surround the junction of the oesophagus and the greater curvature side of the gastric cardia. Opposing these are ‘clasp’ muscle fibres on the lesser curvature junction. Stein et al.15 argued for an anatomic smooth-muscle LOS defined by the gastric sling/clasp muscle fibre group at the locally thickened oesophago-cardiac junction.

In a recent study, Brasseur et al.20 reconciled these contrasting models by applying simultaneous ultrasound/manometry with pharmacological attenuation of the intrinsic muscarinic smooth muscle components of the high pressure zone. By the use of atropine with deep inspiration and expiration, they stabilized the sphincter area allowing the non-muscarinic pressure profile to be subtracted from the entire pressure profile of this area after referencing to the crural sphincter leaving only the muscarinic smooth-muscle sphincter contribution. With these subtraction curves Brasseur et al.20 showed that the gastro-oesophageal junction HPZ can be separated into three components: two atropine attenuated intrinsic muscarinic smooth muscle components and an atropine resistant skeletal muscle component (the external CD). The intrinsic and extrinsic components move relative to one another during inspiration and expiration. The two components separate and the OGS lengthens during expiration. The proximal component and the CD move together in lock step during respiration, while the distal component moves relatively independently. However, it should be noted that the distal component also moves with respiration in the same direction that the proximal component moves, just not as far.

This study compares and contrasts patients with gastro-oesophageal reflux disease (GORD) to the normal control subject group previously described by Brasseur et al.20 using the same methodology to evaluate the gastro-oesophageal junction HPZ. The purpose of this study was to determine if there were any significant differences in the strength or relative positioning of the three sphincteric components in GORD patients. If so, these differences might point to an anatomic or physiological abnormality that may underlie the pathophysiology of GORD. The data from the GORD patients in this study were collected at the same time as the normative data reported in Brasseur et al.,20 therefore, the GORD group was compared with the previously presented study of the normal volunteer group.

Materials and methods

Subjects

Fifteen normal volunteer subjects were evaluated (eight male, seven female, 23–47 years, mean age 34 ± 8.5 years) in the study published previously by Brasseur et al.20 Seven patients (three male and four female) with GORD (33–66 years, mean age 45 ± 10.7 years) were evaluated over the same time period with the same procedure as the normal subjects. All GORD patients complained of heartburn and/or regurgitation, which were relieved with high dose proton pump inhibitors. All subjects gave IRB approved informed consent to take part in the studies, and all subjects were tested in accordance with the policies of the National Institute of Health and Temple University School of Medicine. Exclusion criteria for all subjects included subjects on any medication, which could affect the gastro-oesophageal junction HPZ. This included prokinetic agents, erythromycin type antibiotics and anticholinergics. The following medical problems were also considered exclusion criteria: abdominal surgery involving the stomach or oesophagus, diabetes, scleroderma, achalasia and current pregnancy. In addition normal volunteers were excluded if they used antacids, H2 blockers, proton pump inhibitors, had any gastrointestinal symptoms, conditions and disorders including a history of oesophagitis, gastrointestinal symptoms such as abdominal pain, heartburn, reflux, regurgitation, chest pain, difficulty swallowing, pain on swallowing, dysphagia, nausea or vomiting, oesophageal motility disorders or non-cardiac chest pain (see Brasseur et al.20 for more details).

Endoscopy

All study subjects underwent upper endoscopy using a Pentax 2900 video endoscope (Pentax, Orangeburg, NY, USA) using topical oral anaesthesia with Cetacaine (Getylite Industries, Pennsauken, NJ, USA), with or without sedation. Subjects found to have a hiatal hernia were excluded from the normal group. Hiatal hernia was not an exclusion criterion in the GORD study group.

Equipment

A custom assembly was constructed which combined a 20 MHz ultrasound transducer (Microvasive; Boston Scientific, Watertown, MA, USA) with a water perfused manometry catheter. The manometry catheter consisted of a three French angiography catheter with a small side hole port at the same level as the ultrasound transducer, to simultaneously obtain gastro-oesophageal junction HPZ musculature cross-section images and corresponding intraluminal pressures at the same location. The transducer rotated at 15–30 Hz to provide 360° oesophageal cross-section imaging with 0.1-mm axial slice thickness and a typical penetration of about 2 cm. Images were recorded on VHS videotape at 30 frames s−1 on a Kay Elemetrics swallowing workstation (Kay-Elemetrics, Lincoln Park, NJ, USA) to provide temporal synchronization of the two data sources (Fig. 1).

Figure 1.

 Screen of the Kay-Elemetrics workstation showing the ultrasound image and the corresponding manometric pressure (46.0 mmHg). The ultrasound image on the left is shown at the time indicated by the vertical line on the manometry tracing (right). The arrows point to the crural diaphragm.

A custom made pull-through machine provided a calibrated, constant retraction of the simultaneous ultrasound and manometry catheter in a proximal direction through the stomach and the oesophagus at 0.5 cm s−1. The pressure data were saved to a computer file and the ultrasound images digitized into 256 grey levels, 640 × 480 lossless TIFF files.

Procedure and data collection

Prior to insertion of the simultaneous ultrasound and manometry assembly into the proximal stomach, the back of each subject’s throat was numbed with Cetacaine and the nose numbed with Lidocaine to reduce discomfort during the catheter’s passage through the nostril. An intravenous line was prepared to allow for the later administration of atropine.

Ultrasound images were collected and co-localized with manometric pressure in the 15 healthy volunteer subjects and seven GORD patients with breath holding under full inspiration (FI) and full expiration (FE) during a machine pull-through of the catheter assembly at 5 mm s−1 from the stomach into the thoracic oesophagus. The subject lay supine with his or her back at approximately a 35° angle. Subject movement was minimized during the duration of the study. Ultrasound imaging verified that the initial transducer position was in the proximal stomach at both FI and FE. After ensuring the catheter’s position was correct, the catheter was marked at the nares to ensure accurate repositioning of the transducer assembly in the stomach at the pull-through start (PTS) reference location.

Sphincteric contributions to pressure were measured with the costal diaphragm in the extreme inferior and superior positions. For maximal inferior positioning, the subject was instructed to inhale as deeply as possible and hold his/her breath during ‘FI’ pull-throughs. For maximal superior positioning, the subject exhaled as far as possible and held his/her breath during ‘FE’ pull-throughs. Each pull-through began in the stomach at the premarked start location of the transducer (PTS position) and ended well into the oesophageal body. At least three pull-throughs were recorded for each FI and FE respiratory state. Swallowing was monitored, and if the subject swallowed at any time during the pull-through, the entire pull-through was discarded. Subjects were asked to hold their breath after deep inspiration or exhalation to quantify the changes in axial pressure variation associated with changes in alignment of smooth vs skeletal muscle sphincteric tone from inferior vs superior displacement of the costal diaphragm.

Pull-throughs were repeated after injection and intravenous administration of atropine. For each pull-through, the axial locations of the distal margin of the right crus muscle (RCd) were quantified to use as a spatial reference when averaging pressures over the 15 normal and seven GORD patient subjects. In addition to the RCd, the initiation of the PTS was also used as a spatial reference to determine absolute displacement of the pressure peaks. For this reason, great care was taken to return the catheter assembly to its original position by marking the position of the nares on the catheter with a Sharpie pen. The PTS reference was not used to evaluate shifts between the pre- to postatropine pull-throughs, as the extended passage of time between data collection led to reference drift. All analysis was carried out with in-house computer software or image pro plus software (Image Pro plus version 6; Media Cybernetics, Bethesda, MD, USA).

After collecting data in FI and FE, the intrinsic muscarinic smooth muscle contribution to the sphincter was attenuated using a pharmaceutical protocol developed by Mittal et al.11,12 and Fang et al.,21 based on the previous studies by Dodds et al.8 and Holloway et al.,9 these studies showed dose-dependent partial suppression of the resting sphincteric pressure by atropine. Following the Mittal et al.11,12 protocol, an initial bolus of atropine (15 μg kg−1) was administered intravenously, followed by continuous intravenous atropine infusion at 4 μg kg−1 h−1 during the remainder of the study. After waiting 30 min and determining that there was an appropriate increase in heart rate to assure maximal suppression of muscarinic smooth-muscle tone (approximately 40% or greater over baseline heart rate), the data were collected for the same positions and respiratory states as done in the absence of atropine with three additional assembly pull-throughs.

Each subject had multiple insertions of the transducer assembly into the stomach and subsequent data collection during a constant speed retraction with the pull-through machine. Each of these insertions and retractions is defined as a ‘pull through’.

Data analysis

The crural sling could be clearly identified on the ultrasound images. The crus muscles impinging on the oesophageal wall appear as hypoechoic muscle bundles. The proximal (right crural diaphragm proximal, RCp) and distal (RCd) margins of the crural sling adjacent to the oesophageal wall were identified by L.M., and checked independently by Q.D., as the first and last extrinsic crus muscle bundles imaged during each pull-through. The ‘width’ of the crural sling was defined as the axial separation between RCd and RCp. To quantify relative anatomic shifts in crural sling location, both proximal and distal crus locations were used as references. There were no statistical differences in the results when using either reference. Therefore, all results use the distal marker (RCd) as the spatial reference for the crural sling. The spatial excursions of the anatomic crus and the pressure signatures between FI and FE were determined by referencing to the location of the transducer assembly in the stomach at the initiation of each pull-through (PTS). This was done both pre- and postatropine. To quantify relative anatomical shifts in CD location, the RCd and PTS were used.

From the three (or more) pull-throughs per subject for each case, one pull-through was chosen based on best quality of high frequency ultrasound images for determining the anatomic crural sling spatial references. After data collection, separate gastric baseline pressures were determined by Q.D. for each pull-through by averaging the pressure signal 5–10 s just prior to the start of each pull-through, with cough and other obvious artefacts excluded. All pressures were referenced to time averaged gastric baseline pressure.

Reconstructing the muscarinic smooth-muscle (atropine attenuated) pressure distribution

As described above, the administration of atropine partially attenuates the muscarinic components of smooth muscle tone in the gastro-oesophageal HPZ segment. Brasseur et al.20 showed that the atropine-resistant pressure distribution is associated with the skeletal crural sling and that any residual smooth muscle non-muscarinic or myogenic tonic contributions are relatively minor in comparison. The intrinsic muscarinic smooth muscle contribution to pressure was reconstructed by subtracting the postatropine pressures from the full pre-atropine pressures after spatial referencing to the RCd. This subtraction process leaves the purely muscarinic contribution to pressure as the pressure profile from the CD and any residual intrinsic non-muscarinic pressure is removed in the subtraction process. In this way, the full pressure distribution, the atropine-resistant and the atropine attenuated intrinsic muscarinic smooth muscle pressure distributions were obtained. These pressures were averaged relative to the inferior margin of the anatomic crural sling when the costal diaphragm was in its extreme superior (FE) and inferior (FI) positions. As done with the normal subjects in Brasseur et al.20 in the GORD group the individual pressure profiles were linearly interpolated onto a grid with time increment of 1/250 s before ensemble averaging (Fig. 2A,B).

Figure 2.

 (A) The full expiratory pressure curve of an individual normal control subject. The red curve is the pre-atropine pressure curve, the green curve is the postatropine pressure curve and the blue curve is the subtraction curve (red curve minus green curve). The vertical line at zero on the X-axis represents the start of the right crural diaphragm (RCd). Note that there are two pressure peaks in the subtraction curve (blue). The distal peak represents the lower LOS and the proximal peak represents the upper LOS. (B) The full expiratory pressure curve of an individual GORD patient. Note that there is only one pressure peak within the subtraction curve (blue), which corresponds with the proximal peak in the normal control subjects.

Measurement of area under the curve

To quantify the pressure contributions from each component of the gastro-oesophageal junction HPZ, the area under the ensemble averaged pressure curve was measured for the GORD patients and reanalysed for the normal controls using image pro-plus software. The area under the CD (atropine resistant) pressure curve was measured from the beginning of the upslope of the pressure curve to the point where the downslope of the pressure curve crossed the zero pressure baseline. The lower intrinsic muscarinic smooth muscle (atropine attenuated) area under the pressure curve was measured from the beginning of the upslope of the subtraction curve to the first minimum. The upper intrinsic muscarinic smooth muscle (atropine attenuated) area under the pressure curve was measured from the beginning of the upslope of the pressure curve after the first minimum to the tubular oesophagus above the HPZ (Fig. 3).

Figure 3.

 Panels (A) and (B) show the ensemble averaged inspiratory and expiratory pressure curves in 15 normal volunteers respectively. The red curve is the pre-atropine pressure curve in both full inspiration (FI) and full expiration (FE). The green curve is the postatropine pressure curve in both FI and FE. The blue curve is the subtraction curve (red curve minus green curve). The vertical line at zero on the X-axis represents the start of the right crural diaphragm (RCd). The box labelled crus represents the extent of the crural diaphragm on ultrasound imaging. There are two pressure peaks in the subtraction curves in both FI and FE. The upper or more proximal peak reflects an ‘upper LOS’ or proximal intrinsic muscarinic component. The distal peak reflects a ‘lower LOS’ or distal intrinsic muscarinic component. The area under the pressure curve form the atropine resistant crural diaphragm was measured from the beginning of the upslope to the point where the downslope of the pressure curve crossed the zero pressure baseline (area not shaded in the above graphs). The lower intrinsic muscarinic smooth muscle (atropine attenuated) area under the pressure curve was measured from the beginning of the upslope of the subtraction curve to the first minimum. The upper intrinsic muscarinic smooth muscle area under the pressure curve was measured from the beginning of the upslope of the pressure curve after the first minimum to the tubular oesophagus above the high-pressure zone. The area under the graphs of the pressure curves of the GORD patients was performed in a similar manner.

Statistics

All statistical tests were performed using the paired Student’s t-test with 95% confidence level and assuming equal variances. Ensemble plots are presented from all 15 normal subjects and all seven GORD patients. Data analysis included the per cent contribution of the area under the curve (AUC) from intrinsic muscarinic smooth muscle pressure profiles and the atropine resistant pressure profiles. The means and SD of these values were reported. The above data were evaluated to determine the intrinsic muscarinic smooth muscle (atropine attenuated) pressure profiles and the CD (atropine resistant) contributions to the OGS and to determine the effects of respiration on the position and pressure relationships of these pressure profiles.

Results

Analysis of normal control subjects

As described previously by Brasseur et al.,20 all 15 normal volunteer subjects had normal oesophageal and gastro-oesophageal segment HPZ function. The width of the longitudinal segment of the oesophageal wall in contact with the crural sling averaged 2.0–2.3 cm, as measured from ultrasound imaging. The lower margin of the crural sling was displaced by 1.9 cm as the costal diaphragm shifted from its inferior-most (FI) to its superior-most (FE) respiratory positions. The ensemble averaged full pressure profiles of the HPZ were compared with the averaged pressure profiles after administering atropine, in FI and FE. These plots were lined up relative to the distal margin of the RCd (Fig. 3).

In normal volunteer subjects, the distal intrinsic muscarinic smooth muscle pressure component contributes 34% of the AUC of the entire pressure profile to the gastro-oesophageal junction HPZ in FI and 31% in FE (Table 1) (Fig. 3).

Table 1.   Sphincteric contribution in normal volunteers
 Full inspirationFull expiration
% of total area under the pressure curve% of intrinsic area under the pressure curve% of total area under the pressure curve% of intrinsic area under the pressure curve
  1. This table demonstrates per cent contribution of each sphincteric component to the area under the pressure curve.

  2. LOS, lower oesophageal sphincter; CD, crural diaphragm.

Upper LOS25 (14.1)66 (13.2)43 (21.7)69 (26.0)
CD62 (13.2)na39 (21.5)na
Lower LOS13 (7.9)34 (13.2)20 (9.1)31 (26.0)

Analysis of GORD patients

Two of the GORD patients were found to have hiatal hernia at endoscopy (one small and one moderate sized hiatal hernia). The other five GORD patients showed no sign of hiatal hernia. The preminus the postatropine subtraction curves in the GORD patients demonstrated distinctly different pressure profiles from the subtraction curves in the normal volunteer subjects in both FI and FE (Fig. 3B).

In the GORD patients, the subtraction curve, demonstrated that the distal intrinsic muscarinic smooth muscle pressure peak (lower LOS), which was present in the normal volunteer subjects, was absent in both the inspiratory and expiratory phases in the GORD patients, while the proximal intrinsic muscarinic smooth muscle pressure peak (upper LOS), seen previously in the normal volunteer subjects, was present and at the same axial position relative to the RCd as in the normal volunteer subjects.

In the GORD group, the width of the gastro-oesophageal junction HPZ during FI was 2.5 ± 0.7 cm and the width during FE was 2.5 ± 0.7 cm (P = 0.9). Unlike the normal volunteer subjects, there was no significant change in the width of the HPZ between FI and FE. The width of the CD during FI was 2.1 ± 0.8 and during FE was 2.1 ± .6 (P = 0.9). Like the normal control subjects, the width of the CD did not change between FI and FE. These results indicate that there was no lengthening of the gastro-oesophageal junction HPZ from FI to FE in the GORD patients as opposed to the normal volunteer subjects. The beginning of the RCd moved 1.4 cm proximally relative to the initiation of the PTS position between FI and FE; the intrinsic muscarinic smooth muscle pressure profile moved approximately the same distance in concert with the CD. This is also approximately the same distance that the RCd moved between FI and FE in the normal volunteer subjects.

In the GORD patients, the distal intrinsic muscarinic smooth muscle pressure component (lower LOS) made no contribution to the pressure of the gastro-oesophageal junction HPZ pressure profile (Table 2).

Table 2.   Sphincteric contribution in GORD patients
 Full inspirationFull expiration
% of total area under the pressure curve% of intrinsic area under the pressure curve% of total area under the pressure curve% of intrinsic area under the pressure curve
  1. This table demonstrates per cent contribution of each sphincteric component to the area under the pressure curve. Note that there is no distal intrinsic muscarinic pressure component in the GORD patients.

  2. GORD, gastro-oesophageal reflux disease; LOS, lower oesophageal sphincter; CD, crural diaphragm.

Upper LOS62.9 (21.1)100 (13.9)26 (14.46)100 (17.2)
CD37.1 (17.0)na74 (18.8)na
Lower LOS0 (0)0 (0)0 (0)0 (0)

Discussion

The intrinsic sphincter (oesophageal smooth muscle sphincter) and the CD (external skeletal muscle sphincter) are anatomically superimposed in normal individuals. The intraluminal pressure is a summation of pressures from all of these muscle groups.20 Distinguishing the components of the distal oesophageal HPZ is important because these pressures reflect anatomic and/or physiological components of the sphincter and because these pressures combine to equal the closure forces that contribute to and maintain the function of the antireflux barrier.

This study compared the gastro-oesophageal junction HPZ pressure profile in GORD patients to the gastro-oesophageal junction HPZ pressure profile in normal volunteer subjects. In our previous work in normal control subjects, we administered cis-atracurium and completely abolished the skeletal crural muscle without affecting the smooth muscle sphincter. The smooth muscle contribution to the HPZ was measured directly. The post-cis-atracurium pressure distribution displayed the same double-peaked patterns as was seen using the atropine subtraction method in normal volunteers. The fact that the same double-peaked pattern, of approximately the same magnitude in pressure, was demonstrated with the use of cis-atracurium as in the atropine subtraction curves is strong evidence that the atropine subtraction curves account for most of the muscarinic tone within the two intrinsic oesophageal smooth muscle components.

However, when designing this study we took into account the fact that atropine does not eliminate all of the muscarinic tone. We therefore designed this study, from the outset, with that fact in mind. When we subtract the pre-atropine pressure from the postatropine pressure, the subtraction process eliminates all of the pressure that is due to non-muscarinic tone. Even though atropine does not eliminate all of the muscarinic tone, what is left after the subtraction process, is pure muscarinic tone (pressure). Pressure due to anything non-muscarinic has been subtracted away. When designing the study we also took into account the fact that atropine may have variable effects on different individuals. We therefore used each individual subject as their own internal control pre-atropine and subtracted each individual subject’s postatropine pressure curve from the pre-atropine pressure curve. Thus, we were able to eliminate the problem of the variable effect of atropine between subjects.

Although the manometric technique, that was used in this study, is somewhat limited by having only one pressure port, we believe that it is more than sufficient to prove the main hypothesis of this manuscript, that the distal pressure profile is present in normal control subjects and absent in GORD patients. The manometric analysis was limited by the fact that the investigators had to design and build the technology to perform these studies. Nevertheless, even though the HPZ is known to be asymmetric, we strongly believe that what we have demonstrated in this study does not need sophisticated vector volume manometry. We demonstrated that the distal intrinsic oesophageal muscarinic pressure component is absent in GORD subjects and it is unnecessary to show the symmetry or asymmetry of a pressure profile that is absent.

The three HPZ components in normal subjects consist of a proximal intrinsic muscarinic smooth muscle pressure component (the upper LOS), a distal intrinsic muscarinic smooth muscle component (the lower LOS) and an atropine resistant pressure component (the external CD). Each pressure component was localized spatially with respect to the other pressure components, and the per cent contribution of each pressure component to the antireflux barrier gastro-oesophageal junction HPZ was quantified by measuring the area under the ensemble averaged pressure curves. It was determined that the intrinsic proximal muscarinic smooth muscle component and the CD move in lock step with each other during respiration and move away from the distal intrinsic muscarinic smooth muscle pressure component during FE, thus accounting for the lengthening of the high pressure zone between FI and FE. It should be noted that both the proximal and distal smooth muscle pressure components move in the same direction during respiration, but that the distal component moves less than the proximal component.

The HPZ in GORD patients (Fig. 4A) differs dramatically from the HPZ in normal control subjects (Fig. 4B). The distal intrinsic muscarinic smooth muscle pressure profile that was demonstrated in the normal control subjects is absent in GORD patients whether or not a hiatal hernia is present. In the normal volunteer subjects, the gastro-oesophageal junction HPZ pressure profile lengthens due to the proximal intrinsic muscarinic smooth muscle pressure component moving proximally away from the relatively fixed distal intrinsic muscarinic smooth muscle pressure component. While the results in the GORD patients also demonstrate respiratory movement of the intrinsic muscarinic smooth muscle pressure component and the CD in lock step, the width of the gastro-oesophageal junction HPZ pressure profile remained unchanged between FI and FE. The explanation for this is that there is no distal intrinsic muscarinic smooth muscle pressure component. Therefore, when the intrinsic muscarinic smooth muscle pressure component and CD move it does not lengthen the HPZ (no distal component to move away from).

Figure 4.

 (A) The ensemble averaged pressure curve in full expiration from seven GORD patients, referenced to right crural diaphragm (RCd). (B) The ensemble averaged pressure curve in full expiration from 15 normal control subjects. The red curve is the pre-atropine pressure curve, the green curve is the postatropine pressure curve and the blue curve is the subtraction curve (red curve minus green curve). The vertical line at zero on the X-axis represents the start of the RCd. Note that in the subtraction curve (blue), the proximal intrinsic muscarinic pressure peak is present in the GORD patients and is in the same axial position relative to the RCd as in the normal volunteers as demonstrated by the rose coloured vertical line on the right. The subtraction curve between the pre- and postatropine pressure curves in GORD patients shows that the distal intrinsic muscarinic peak is absent, as demonstrated by the light turquoise coloured line and box on the left.

In normal volunteer subjects, the distal intrinsic muscarinic smooth muscle pressure component contributes 34% of the AUC of the entire pressure profile to the gastro-oesophageal junction HPZ in FI and 31% in FE (Table 1). In the GORD patients, the distal intrinsic muscarinic smooth muscle pressure component (lower LOS) made no contribution to the pressure of the gastro-oesophageal junction HPZ pressure profile (Table 2) (Fig. 4).

The proximal intrinsic muscarinic smooth muscle pressure profile appears to be a physiological sphincter of oesophageal circular smooth muscle.20 Given the close correspondence of the pressure contribution defining the upper LOS in the normal group with the single pressure contribution in the GORD group, we propose that these two pressure contributions arise from the same intrinsic muscarinic smooth muscle sphincteric component in both normal subjects and GORD patients. We base this conclusion on two observations. Firstly, the location of this intrinsic muscarinic smooth muscle pressure component relative to the RCd in both the normal volunteer subjects and GORD patients is the same. Secondly, this intrinsic muscarinic smooth muscle component moves in lock step with the CD during respiration in both the normal subjects and GORD patients. Thus, in both the normal and GORD groups, the CD is rigidly attached to this intrinsic muscarinic smooth muscle pressure component by the phreno-oesophageal ligament.

The distal muscarinic pressure peak normally constitutes one-third of the gastro-oesophageal junction HPZ pressure profile as measured by the AUC in normal subjects. This pressure profile may be important to the antireflux barrier, as it is the most distal component at the OGS and therefore the first line of defence against reflux of gastric contents into the oesophagus in the resting state. From the normal volunteer data, this distal muscarinic pressure profile complex remains relatively stationary while the CD and proximal intrinsic muscarinic smooth muscle pressure components move proximally about 2 cm during FE. Without the distal muscarinic pressure profile, the distal oesophagus is unprotected and may be exposed to gastric pressure, increasing the probability of opening during the resting state. It is not clear what causes the loss of pressure of the distal muscarinic muscle fibre complex in GORD patients. However, there are no apparent sonographic abnormalities in this region, as the loss of this distal pressure profile appears to be present in GORD patients with and without hiatal hernia. The loss of this lower contribution to the sphincter may account for the abnormal pressure profile reconstructed in hiatal hernia patients by Kahrilas et al.,22 as discussed in Brasseur et al.20

Anatomical changes of a hiatal hernia may explain the loss of the third distal intrinsic oesophageal muscarinic component as the so called Hill valve is effaced. However, the loss of this component in GORD patients without hiatal hernias was also noted. Even if this pressure loss in GORD patients with hiatal hernias is due to effacement of the Hill valve we believe that this loss of pressure is likely an underlying cause of GORD.

The results of this study provide new knowledge and understanding of the anatomy and physiology of the gastro-oesophageal junction HPZ and insight into the abnormalities associated with GORD. We hypothesize that the distal intrinsic muscarinic pressure profile is due to the gastric sling/clasp fibre muscle complex. We hypothesize that the lack of contribution from the gastric sling/clasp muscle fibre complex at the junction between the oesophagus and gastric cardia is an underlying pathophysiological abnormality associated with GORD. The underlying cause of the absence of the distal intrinsic muscarinic smooth muscle pressure profile implies either a weak gastric sling/clasp muscle fibre complex, or a distended oesophagus/cardia region, or both. If there is a weak sling/clasp muscle fibre complex, then this is either due to a myogenic or a neurogenic defect of either the gastric sling muscle fibres, the gastric clasp muscle fibres or both. If there is a distended oesophagus/cardia region, then this is either due to a hiatal hernia or due to an anatomic (conformational) abnormality such that the gastric clasp muscle fibres do not oppose the gastric sling muscle fibres. Future studies should be directed at determining the aetiology and pathophysiology of the absence of the distal intrinsic muscarinic smooth muscle pressure profile.

Acknowledgments and disclosures

Grant support – NIH, BARD.

Financial disclosures

None.

Ancillary