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Volume: Barrett's Esophagus
Chapter: Etiology and origins of Barrett's epithelium

What is the role of an inadequate control of the lower esophageal sphincter (structure, position, innervation, hormonal control)?

O. Korn, A. Csendes, I. Braghetto (Santiago)

Anatomy of the lower esophageal sphincter

There are few structures in the human anatomy more debated than the existence of an anatomical sphincter at the level of the gastroesophageal junction (GEJ) [1]. However, manometric studies have shown a clear sphincterian mechanism at GEJ [2, 3], which constitutes a mayor barrier against reflux of gastric content into the esophagus [4]. The main problem until recent years was to demonstrate an anatomical structure on distal esophagus that matched to the classical concept of a sphincter, that is, a distinct ring of a thickened circular muscle separated from the adjoining muscles by connective tissue septums [1, 5]. Such a structure has not been demonstrated at GEJ. Winans challenged the classic concept of a circular sphincter in 1977, when he demonstrated a manometric asymmetry of the lower esophageal sphincter (LES) [6]. Anatomical studies from Liebermann et al. [7], have demonstrated a particular disposition and an increment in the amount of the fibers of the internal muscular sheath at the GEJ. This internal muscular coat does not form a ring or circular muscle, instead, it forms a layer of semicircular fibers or clasps oriented transversally, which are open at the anterior and posterior aspect of the esophagus. At the GEJ, these clasps fibers are inserted firmly into the submucous connective tissue at the margin of contact with the oblique fibers. On the opposite side, the oblique fibers replace progressively the short transverse muscle bundles of the esophagus at the greater curvature and they build a muscular sling structure that covers the anterior and posterior wall of the stomach, the so-called "gastric sling fibers" (Figure 1). These oblique fibers are a muscular bundle of 3 cm width and cover an area that starts 1.5 cm above the angle of His and ascends forming part of the distal end of the esophagus. In this way they surround the GEJ at the greater curvature and its two arms run parallel to the lesser curvature in direction to the antrum. The end of the clasp fibers border at almost a right angle at the lateral margin of the sling fibers. The muscular fibers of both clasps and sling fibers increase in number and concentration across the GEJ determining a subtle thickening of the wall at this level. This thickening is asymmetric and is more prominent at the greater curvature side at approximately 1 cm above the angle of His. A recent study has shown that the manometric three-dimensional pressure images of the lower esophageal high-pressure zone correlates with the radial and longitudinal asymmetry of muscular structures at the GEJ [8].

Therefore, the LES is not an annular sphincter, but rather formed by two muscles bundles, which are acting complementary: the "clasp" and the "oblique" muscular fibers (Figure 2).

Figure 1. The arrangement of the clasp fibers and the oblique sling fibers at the gastroesophageal junction of the human stomach. The stomach was opened on both curvatures (the dorsal wall is shown). After fixation, the mucosa was stripped off and the muscular fibers of the inner coat exposed.

Figure 2. A. Radial manometric pressure profile (top) at the level of the respiratory inversion point (RIP), and longitudinal manometric pressure profile (bottom) of the cardia in the right anterior (RA) and left posterior (LP) direction showing highest pressure at the level of the RIP, which is front-tofront despite the obliquity of the cardia. Figures constructed based on data from Stein et al. [9]. B. Circular and parallel forces exerted over the perfused catheter, explaining the symmetry of highest pressure shown in A. C. Anatomy required to support the concept of the action of circular forces around the oblique cardia. D. Perpendicular forces exerted over the catheter based on the arrangement of the oblique sling fibers and clasp fibers. E. Muscular anatomy.

Mechanism of action of the lower esophageal sphincter

By manometric studies, the radial sphincter pressures in a cross section (at the level of RIP) or at longitudinal section demonstrate the asymmetry of the pressure in each side, which is in correlation with the muscular structure of the zone [8]. In addition, the highest pressure zones are front-to-front, although both zones are anatomically in different levels due to the obliquity of the cardia (Figure 3). Therefore, for both sides to be able to contact it is necessary that the greater curvature descends and advances medially by the action of the oblique fibers (sling fibers), to the encounter with the lesser curve which can only move transversely towards the center, being limited by the shortness of the semicircular fibers (clasps). These geometrical changes can be seen clearly in Figure 4, where the normal situation is demonstrated with the intersection of the displacement areas of each curvature and their contact zone, producing a sphincteric closure and a mucosal seal, with an optimum length and pressure. This mechanism was satisfactorily tested in a mechanical model [9].

Figure 3. Three-dimensional representation of the lower esophageal sphincter.

Figure 4. Schematic representation of the mechanism of action of the LES in the normal state. A. Arrangement of the muscular fibers around the cardia. B. An oblique fiber and its force vector. C. The mucosal seal is reached in the intersection of the displacement of each curvature. D. Sphincter closure area with normal length, pressure, and competence.


In resting condition the sphincter is closed and lies at the level of the diaphragmatic hiatus, its upper portion is partially above this and the length of the distal or abdominal portion (1.5-2 cm) is variable, depending on the respiratory movements [10]. In a combined endoscopic and manometric studies in 109 control subjects and 778 patients with gastroesophageal reflux (GER) [11] we have demonstrated that the distal limit of the LES is located 41.5 cm from the incisors and the proximal end at 37.5 cm from the incisors (normal LES length is 4 cm). The squamous-columnar junction is located at 40 cm from the incisors, that is, near in the middle portion of the LES. As GER increases as well as the injury at the esophageal mucosa, this squamous-columnar junction ascends to proximal, while the distal limit of the LES remains almost in normal position.


The radial asymmetry in pressure profile of the LES also is reflected in the cholinergic distribution in the resting LES. The atropine-sensitive component represent 80% of the resting pressure in the leftward direction (which includes the oblique sling fibers) and 53% in the rightward direction [12]. Also there are differences in the tension response to cholinergic stimulation of the left and right half of the LES musculature in vitro. The physiological role of the oblique sling fibers as part of the LES and antireflux mechanism is very important. It is possible that a reduction in cholinergic excitation as occurs in GER disease [13] may have its greatest effect in enhancing reflux because of dysfunction of the sling fibers. Also, augmentation of the intrinsic cholinergic mechanisms by action of extrinsic nerves could produce an asymetrical pressure profile showing the greater cholinergic responsiveness of the left side of the LES [12]. The innervation of the distal esophagus and LES originates in the dorsal motor nucleus of the vagus and terminates in ganglia at the myenteric plexuses. This plexus lies between the muscular layers, receives afferent impulses from the brainstem and esophagus. The main types of effector neurons are found within the esophageal plexuses [14]:
a) excitatory neurons mediate contraction of the muscle layers via cholinergic receptors,
b) inhibitory neurons that affects the muscle layers via vasoactive intestinal polypeptide, a nonadrenergic noncholinergic neurotransmitter.

Sympathetic innervation is provided by branches of the superior and inferior cervical ganglia in the neck and by splachnic nerves in the chest. They do not have motor function but rather modulate the activity of the others neurons at the plexuses. However, LES pressure is mainly of intrinsic myogenic origin because it persists even after neural input is abolished by tetradotoxiny, a neurotoxin.

Immunohistochemical studies could distinguish excitatory motor neurons that contain cholin acetyltransferase at the myenteric plexus from inhibitory motor neurons that contains nitric oxide syntethase. This enzyme produces nitric oxide which induces relaxation and hyperpolarization of smooth muscle of many gastrointestinal organs [15]. Nerve-induced relaxation is also mediated by nitric oxide. The relaxation of LES is thought to be mediated by nitric oxide response. These conclusions have been based on two main evidences:
a) exogenous nitric oxide mimics some events produced by nerve stimulation (relaxation of LES and hyperpolarizes circular smooth muscle from the esophagus) [16],
b) inhibitors of nitric oxide syntethase antagonize all neuromuscular events resulting from nerve stimulation.

Recent studies have proved that nitric oxide is released by stimulation of intrinsic nerves of the LES [16].

Hormonal control

There is a list of neural hormones that either contract or relax the LES, but none has importance on the resting LES pressure. Rather these hormones regulate or modulate LES response. Actually vasoactive intestinal peptide is considered to be the most important neurotransmitters for the inhibitory response at the LES. Other hormones such as secretin, CCK, glucagon, GIP and somatostatine are also potential relaxing neurotransmitter. On the contrary hormones such as, gastrin, neurotensin and substance P promote the function of LES.

Recently, it seems that one of the most important hormone which plays a significant role in the contraction of LES is motilin [17, 18]. Motilin is involved in the development of interdigestive migrating motor complex in gastrointestinal tract of humans. LES contracts in response to the development of this motor complex in order to prevent GER. Motilin acts by releasing acetylcholine and also directly on receptors at the LES muscle. In Table I the hormones that affect LES pressure are shown, and in Table II, other agents affecting LES pressure are also detailed.

Table I. Hormones affecting LES pressure.

Table II. Other agents affecting LES pressure.

Mechanical dysfunction of the lower esophageal sphincter

The mechanical incompetence of the LES in patients with gastroesophageal reflux disease (GERD) and Barrett's esophagus has been extensively pointed out [19], however its cause until now, it has not been quite clear. Recently our group have postulate a hypothesis based on the progressive anatomic dilatation of the gastroesophageal junction or cardia, clinically observed and objectively documented in patients with GERD and Barrett's esophagus [20, 21]. The dilatation of the cardia is the anatomic expression of an irreversible change in the architecture or arrangement of the muscular bands that shape the LES and therefore its function is compromised also. The dilatation of the cardia implies elongation of the muscular fibers, and alterations in its angulation and arrangements. A schematic view of this phenomenon and its consequences is shown in Figure 5 (see normal situation in Figure 4). The angle of the cardia changes (Figure 5A), the angle of His becomes more obtuse, and the oblique fibers are separated, elongated, and angulated (Figure 5B). The greater curvature is more distant and by displacing for closure, the displacement is now no more coincidental with that of the lesser curvature (Figure 5C). The contact area (mucosal seal) is smaller and the pressure zone is shortened. Thus the closing pressure is impaired and weak (Figure 5D), in other words, a mechanically defective sphincter results.

Despite of these concepts were satisfactorily tested in a mechanical model [21], we agree that all of this is just a hypothesis, however it provides substantial evidences to establish a correlation between anatomical and functional findings that until now has no been considered in the literature.

Figure 5. Schematic diagram of the proposed gastroesophageal sphincter dysfunction when the cardia is anatomically dilated. A. The oblique angle of the cardia changes, and the angle of His becomes obtuse. B. The oblique fiber are elongated and angulated modifying their lengthtension properties. C. The mucosal seal is smaller and the pressure zone is shortened. D. The sphincter is mechanically incompetent.


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Publication date: August 2003 OESO©2015