Current state of knowledge
There are currently two schools of thought concerning the smooth-muscle intrinsic contribution to the gastro-oesophageal sphincter. One argument places the intrinsic component within the circular muscle of the abdominal oesophagus at roughly the same axial location as the crural sphincter. In this model the gastro-oesophageal sphincter is maintained by two overlapping additive components, one intrinsic and one extrinsic, above the junction between the oesophageal body and gastric cardia. This model has evolved primarily from studies in which sphincteric pressure was measured using the Dent sleeve before and after administering atropine (Dodds et al. 1981; Holloway et al. 1986; Mittal et al. 1990, 1991, 1995a; Fung et al. 1999). These studies could not spatially localize the source of intrinsic sphincteric tone since the Dent sleeve measures only the highest pressure along its length. Nevertheless, this overlapping two-component model of the gastro-oesophageal sphincter is assumed in many studies and reviews (Boyle et al. 1985; Christensen, 1987; Goyal & Paterson, 1989; Martin et al. 1992; Klein et al. 1993; Heine et al. 1993; Mittal et al. 1995a, 1997; Kahrilas, 1997, 1999).
Two studies of the normal gastro-oesophageal sphincter provide important anatomic information relevant to the overlapping two-component model. Using manometric pull-throughs in 50 volunteers, Stein et al. (1991) found that the peak HPZ pressure was spatially close to the pressure inversion point (PIP), with 38% of the integrated pressure above and 62% below the PIP, on average. This places the peak sphincteric pressure well within the abdominal oesophagus and spatially near the oesophageal attachments of the phreno-oesophageal ligaments. Since the sleeve sensor responds to the highest pressure along its length, the Dent sleeve studies showing clear attenuation of sphincteric pressure with atropine (above) and with removal of the smooth-muscle sphincter by oesophagogastrectomy (Klein et al. 1993) combined with the Stein et al. (1991) result leads one to conclude that the attenuated intrinsic smooth-muscle component must overlap the extrinsic skeletal crural component.
This conclusion is more convincingly shown in a study by Kahrilas et al. (1999) in which the HPZ was measured by manometry pull-through concurrent with fluoroscopic imaging of metal clips placed at the squamo-columnar junction and on the build-up of tissue that localizes the gastric sling muscles at the oesophago-cardiac junction (Friedland, 1978; Stein et al. 1995). As shown in Fig. 8A, Kahrilas et al. (1999) measured the peak end-expiratory HPZ pressure (minimizing crural tone) to be 2 cm above the oesophago-cardiac junction (OCJ), 1 cm above the squamo-columnar junction, and 0.5 cm above the hiatus, placing the overlapping extrinsic and intrinsic HPZ sphincteric pressures well within the abdominal oesophagus. They repeated their measurements in patients with hiatal hernia and symptomatic reflux disease and found a two-peaked pressure structure with the proximal contribution displaced axially along with the squamo-columnar junction (Fig. 8B). These results support the model of overlapping extrinsic and intrinsic sphincters with additive pressure contributions that normally sum to create the normal HPZ. Because, the LOS component is attached to the costal/crural diaphragm by elastic phreno-oesophageal ligaments (Friedland, 1978; Kwok et al. 1999), disrupted ligaments in hiatal hernia separate the intrinsic and extrinsic in sphincteric components.
Figure 8. Sphincteric pressures Sphincteric pressures from Kahrilas et al. (1999) with permission from the BMJ Publishing Group. A, average normal sphincteric pressure from eight volunteers. B, average sphincteric pressure distribution in patients with severe hiatal hernia. C, reconstituted pressure distribution from hiatal hernia patients where, for each individual, the upper pressure in B was ‘telescoped’ to overlay the lower pressure by aligning the squamo-columnar junction to the same average position as in A for normals, relative to the hiatus. In the figure, the distal clip (added) marks the location of the oesophago-cardiac junction and the proximal clip marks the squamo-columnar junction. Averages are referenced spatially to the hiatus, determined fluoroscopically.
Download figure to PowerPoint
A difficulty with the overlapping two-component model is the lack of research showing clear neurophysiological differentiation of smooth muscle fibres localized spatially to the abdominal oesophagus (Christensen, 1975, 1987). The search for an anatomical LOS has lead to a second school of thought stimulated by measurements in human cadavers of a thickening of the muscularis at the oesophago-cardiac junction (Liebermann-Meffert et al. 1979). Repeating these measurements, Stein et al. (1995) proposed that the observed thickening reflects a pair of specialized smooth-muscle fibres that mark the transition between the tubular oesophagus and gastric cardia at the OCJ. Surrounding the OCJ there are two opposing sets of fibres that do not encircle the lumen (Fig. 1). Gastric ‘sling’ fibres wrap over the greater curvature side and open toward the lesser curvature side. Roughly opposing the sling fibres, wrapping over the lesser curvature side and opening toward the greater curvature side are smooth-muscle fibres often called ‘clasp’ fibres (Tian et al. 2004). From a mechanical perspective the ‘sling-clasp’ complex might form a functional unit of opposing fibres that, when both are in tension, would act together to close the OCJ.
More is understood about the pharmaco-physiology of the smooth-muscle sling and clasp fibres at the oesophago-cardiac junction from in vitro muscle strip studies (Preiksaitis & Diamant, 1997; Tian et al. 2004; González et al. 2004; Heureux et al. 2006). Preiksaitis & Diamant (1997) and Tian et al. (2004) found that human sling fibres were much more sensitive to carbachol and acetylcholine-induced cholinergic stimulation than were clasp fibres, and that neither fibres responded to atropine after stretch. Heureux et al. (2006) found, from in vitro studies of feline muscle strips, a strong nitrergic response in the gastric clasp fibres to l-NG-nitroarginine (l-NNA; a nitric oxide antagonist inhibitor), but not in the sling fibres. However, the gastric sling fibres were strongly suppressed by atropine after electric field stimulation, and the clasp fibres responded significantly to atropine after l-NNA induction of muscle contraction. Thus, it has been proposed that the sling fibres may maintain tone through continual cholinergic stimulation (Preiksaitis & Diamant, 1997).
The cholinergic contribution to sphincter tone from the current study
To clarify the functional components of the gastro-oesophageal sphincter we pharmacologically suppressed the cholinergic smooth-muscle contribution with atropine, and then subtracted the atropine-resistant contribution from the full pressure to obtain the cholinergic smooth-muscle contribution to sphincteric pressure after spatially referencing to the distal margin of the crural sling, identified from concurrent endoluminal ultrasound. The post-atropine pressures were therefore a consequence of the additive contribution from the crural sphincter, and pressure from myogenic and residual cholinergic or non-cholinergic tone within the smooth muscle of the gastro-oesophageal segment.
By subtracting pressures post atropine from pre-atropine pressures, the myogenic and residual smooth-muscle contributions were removed in addition to crural tone, leaving only the atropine-sensitive, or cholinergic smooth-muscle contributions to pressure. To further discover the extent to which the atropine-resistant and cholinergic smooth-muscle pressure contributions approximated the skeletal and smooth-muscle sphincteric contributions, respectively, we carried out a second protocol in which skeletal crural muscle tone was suppressed with the drug cisatracurium and the complete smooth-muscle component was measured directly, with the lungs inflated to approximate full inspiration in the atropine protocol. The cholinergic smooth-muscle contribution to pressure (from the atropine study) and full smooth-muscle pressures (from the cisatracurium study), each referenced to the anatomic crural sling, compared very well (Fig. 7) in most details, including the same two-peaked pressure structure with the same relative separation and magnitudes of the peaks. We conclude that the smooth muscle contribution to the gastro-oesophageal segment pressure profile is, to a large extent, functionally cholinergic. The atropine protocol removed sufficient smooth-muscle tone to suggest that the pressure measured within the atropine-resistant sphincter is largely from the crural sling.
The extrinsic skeletal-muscle sphincteric component
Figure 5A shows that the central atropine-resistant sphincter pressure is virtually identical in the full inspiration and expiration positions of the costal diaphragm when referenced to the lower margin of the crural sphincter, indicating that the atropine-resistant pressure was dominated by the skeletal crus muscles external to the oesophageal wall. Furthermore, the atropine-resistant pressure profile is centred over the anatomic crus, and the shift in the positioning of the anatomic crural sphincter from respiratory-induced movement of the costal diaphragm is strongly correlated to the shift in the atropine-resistant pressure profile (Fig. 5B). We conclude that the atropine-resistant contribution to the HPZ reflects, to a large degree, the anatomic crus muscles and define the extrinsic component of the sphincter. The external crural sphincter covers approximately 2.1 cm of the abdominal oesophagus (Table 1).
The peak crural sphincter pressure (Fig. 5A) and total pressure (Fig. 4) did not significantly change between FE and FI, consistent with Christensen (1975, p. 249), who reported that ‘on deep inspiration, sphincter closure tension, recorded manometrically in humans, falls below the tension recorded in the normal respiratory cycle…’ and with Boyle et al. (1985) and Klein et al. (1993) who report that the phasic respiratory contribution to pressure from the crural sling disappears with sustained breath-holding.
Structure of the cholinergic and intrinsic smooth muscle sphincter pressures
From mechanical principles, it can be argued that the HPZ reflects additive contributions from external skeletal-muscle and internal smooth-muscle sphincteric components of the gastro-oesophageal segment. As the costal diaphragm moved from its inferior-most to its superior-most positions, the crural muscles surrounding the abdominal oesophagus shifted proximally by about 2 cm (Fig. 3B), and the tonic HPZ widened considerably (Fig. 4). Because the width of the crural component was unaffected by its axial displacement (Fig. 5A), widening of the HPZ requires either a widening of the smooth muscle contribution to the sphincter, or a relative displacement of the internal and external sphincteric components.
We discover, however, that both the cholinergic and the complete intrinsic smooth-muscle sphincter have a more complex pressure signature than does the external skeletal-muscle contribution. Figures 6 and 7 show that the pressure signatures associated with these components have a two-peaked structure. The very high structural correlation between the smooth muscle pressure signature obtained by subtraction in the atropine study, and obtained directly in the cisatracurium study, is strong support for the claim that the cholinergic smooth-muscle component is a good approximation of the full smooth muscle sphincter, and allows us to conclude with a high degree of certainty that the cholinergic and complete smooth-muscle contributions to the HPZ are similar in configuration and magnitude and contain two peaks that separate with superior displacement of the diaphragm.
Interestingly, the proximal peak of the smooth-muscle pressure remained fixed relative to the crural sphincter even as the crus shifted >2 cm with respiration (Fig. 6). We conclude that the component of the smooth-muscle sphincter responsible for the proximal pressure peak is as rigidly attached to the costal diaphragm as is the crural sphincter. Since the normal oesophagus is under global longitudinal tension (Liebermann-Meffert et al. 1979; Stein et al. 1995), the portion of the oesophageal body associated with the proximal sphincteric component must be dragged distally by the inferior displacement of the costal diaphragm. The only anatomic structures available to generate a drag force to counter the basal longitudinal force on the abdominal oesophagus are the phreno-oesophageal ligaments that connect the costal diaphragm and the oesophageal wall. We conclude that in the normal oesophago-gastric segment these ligaments are relatively stiff, at least as stiff as the skeletal crural sling.
In contrast to the upper component of the smooth muscle sphincter, responsible for the proximal pressure peak in Figs 6 and 7 and rigidly coordinated with the crural sphincter, the component of the smooth muscle sphincter responsible for the distal pressure peak moves separately from the crural sphincter and costal diaphragm. Figure 6 indicates that the distal peak shifts distally by about 1.1 cm relative to the upper peak as the crural sphincter moves ∼2 cm from its inferior to superior positions. Thus, since the upper component of the smooth-muscle sphincter moves rigidly with the crural sphincter, the lower smooth-muscle component must shift a little under 1 cm proximally as the crural sling and upper sphincteric component shift superiorly by 2 cm and the two sphincteric components separate by 1.1 cm.
Three sphincteric components of the gastro-oesophageal segment
As discussed above, Kahrilas et al. (1999) used hiatal hernia as a model to separate the smooth and skeletal muscle components of the sphincter within the oesophago-gastric segment (see Fig. 8). They went on to hypothesize that the normal HPZ can be reconstructed from the hernia groups by appropriately realigning the proximal and distal pressure contributions in each individual. To realign the intrinsic and extrinsic sphincteric contributions to the HPZ, they assumed (a) that the two sphincteric components are approximately in the same position relative to the hiatal indentation determined fluoroscopically, and (b) that the squamo-columnar junction is positioned approximately the same in each individual relative to the intrinsic sphincter. With these assumptions, the squamo-columnar junctions with attached proximal high pressure contributions were shifted to a position 0.5 cm distal to the hiatal indentation, the average relative position of the squamo-columnar junction in normals. Their result is shown in Fig. 8C. Interestingly, whereas the remodelled pressure distribution approximated reasonably well the normal pressure distribution proximal to the hiatus, the normal HPZ below the hiatus was 2–3 times more extended and at higher pressure in normals than in the reconstructed hiatal hernia group.
Figure 6 suggests a third, smooth-muscle component of the HPZ that probably explains the incomplete reconstruction obtained by Kahrilas et al. (1999) with hiatal hernia. We summarize the three-sphincter model in Fig. 9. We find that the HPZ of the oesophago-gastric segment has three components: one external component associated with the skeletal muscle right crus muscle surrounding the abdominal oesophagus, and two internal components associated with the smooth muscle intrinsic to the oesophageal wall. Figure 5 clearly identified the atropine-resistant (skeletal) component with the external crural sphincter. The proximal smooth-muscle component we propose to identify with the classical intrinsic LOS. This component, we find, overlaps and moves with the crural sling (see Fig. 9), apparently due to rigid attachment of the abdominal oesophagus to the costal diaphragm from relatively stiff phreno-oesophageal ligaments.
Figure 9. Illustration of the upper and lower internal sphincter components The upper, physiological, lower oesophageal sphincter (LOS) remains centred on the upper margin of the crural sling and moves with the crus as the costal diaphragm displaces between its inferior-most position during FI, and its superior-most position during full expiration (FE). We suggest that the lower LOS reflects the gastric sling-clasp fibre muscle groups at the oesophago-gastric junction. When the diaphragm is in its inferior-most position (full inspiration, FI) the lower margin of the crural sling overlaps the lower LOS-sling/clasp group; when in its superior-most position (FE) the sling and lower LOS separate. (The figures to the left were adapted from Netter (2000) with copyright approval from the publisher.)
Download figure to PowerPoint
In contrast to the upper smooth-muscle sphincteric component of the oesophago-gastric segment (what we shall refer to as the ‘upper LOS’), the distal smooth-muscle component remains more locally in place, shifting slightly less than 1 cm proximally during the superior excursion of the costal diaphragm, while separating from the proximal component by slightly more than 1 cm. We suggest that the distal smooth-muscle component is a ‘lower LOS’ created by sling and clasp fibres within the muscularis propria at the junction between the gastric cardia and tubular abdominal oesophagus (Fig. 9). We propose that the transitional muscle fibres at the OCJ form a third sphincteric component that, like the abdominal oesophagus overall, moves superiorly and inferiorly, but less so than the LOS due to elastic stretch between the two smooth-muscle sphincteric components as gastric ligaments resists the axial motion induced by the rigidly attached phreno-oesophageal ligaments at the upper LOS. We suggest that in the hiatal hernia group described by Kahrilas et al. (1999), the pressure from the lower LOS component was absent, explaining the shorter and lower pressure distal to the reconstructed pressure profile in the hiatal hernia patients relative to the normal HPZ.
Anatomically, it is likely that the lower LOS is associated with the thickened junction between the tubular oesophageal and stomach identified by Stein et al. (1995) as the LOS from measurements in human cadavers. The differences in cholinergic, nitregic and related neurophysiological responses of the sling versus clasp fibres at the OCJ (Preiksaitis & Diamant, 1997; Tian et al. 2004; Heureux et al. 2006) suggest that the gastric sling and clasp fibres may both respond to atropine if in initially stimulated states. Asymmetry of sphincteric pressure, and the asymmetrical effect of atropine on sphincteric pressure, has been reported by Richardson & Welch (1981). However, the measurements are not specific enough to know if the measured asymmetry reflected the asymmetry in forces applied to the oesophageal wall by the crural sling (Fig. 1B), or the asymmetrical structure and neurophysiological response of the gastric sling/clasp combination (Preiksaitis et al. 1994). (Pressure asymmetry was not evaluated in the current study that used only one pressure transducer.)
As summarized in Fig. 9, we hypothesize that the sphincter within the gastro-oesophageal segment has three distinct components, each of which are controlled by different neurophysiology, and which work functionally together and separately in different ways and at different times to both maintain the reflux barrier as well as to allow antegrade or retrograde transport, as the physio-mechanical state of the gastro-oesophageal environment varies. One of these components, the crural sphincter, is extrinsic and composed of skeletal muscle. The other two components are intrinsic to the oesophageal-gastric wall smooth muscle. The proximal component, we argue, is the physiologically mediated LOS (Christensen, 1987), while the distal component is associated with the gastric sling and clasp muscle unit (Stein et al. 1995), each muscle fibre group having a very different physiology (Heureux et al. 2006).
The functional significance of a three-component gastro-oesophageal sphincter follows from the mechanics of sphincter opening and flow. Sphincter opening from below, for example, is a consequence of a change in the balance of forces at the distal-most point of the closed oesophageal lumen, where gastric fluid meets closed lumen. Opening is driven by an increase in gastric fluid (liquid or gas) pressure relative to the pressure external to the gastric wall at this point. The summation of active and passive tension force within the muscle wall at the junction point resists this pressure opening force. Thus, the existence of tension within the sling-clasp complex of a ‘lower LOS’ would act as a barrier to reflux. If this barrier were overcome, then tension forces within the ‘upper LOS’, together with the extrinsic muscles of the crural sphincter provide the next level of protection. Only when all three barriers are overcome will reflux occur. It follows that a complete understanding of the anatomy, physiology and mechanics underling the complex protective functions of the gastro-oesophageal sphincter, and especially the complex interactions that underlie chronic dysfunction, requires a complete understanding of the interactions of the three sphincteric components over a wide range of physiological and mechanical states of the gastro-oesophageal environment.