Circle in the center T represents the ultrasound transducer. Images were obtained in resting state. Note the asymmetry of the LES and esophagus. Source: Liu et al. Anatomic descriptions of the LES are limited by the fact that the LES is best identified functionally on manometry, and the anatomic dissections can only guess the identity of the LES.
Nonetheless, anatomic studies suggest that LES muscle cells are not completely circular and in the lower part of the LES they are arranged in the form of incomplete "C-shaped" fibers arising from the left and the right sides that clasp each other. On the left side, the "C-shaped" fibers intermingle with the gastric sling fibers. The gastric sling fibers form the oblique muscle layer of the stomach and may play an important role in the formation and modulation of angle of His.
The excitatory and inhibitory motor neurons for the control of gastric oblique fibers are located in the stomach. On the other hand, fibers that constitute the LES are innervated by the inhibitory motor neurons located either locally within the LES or in the esophagus.
Studies in cats and humans show functional differences between clasp fibers on the right side of the LES and the gastric sling fibers. In addition to acetylcholine, there are differences in the sensitivity between clasp and the sling fibers to dopamine and other pharmacologic agents.
Ultrastructural studies of the sphincter muscle in the opossum suggest that muscle cells from the LES are of larger diameter and form fewer gap junctions than do those of the esophageal body. The sphincter muscle cells also have irregular surfaces and evaginations that are not seen in the esophageal body.
These evaginations are likely to be related to the tonically contracted state of the sphincter muscle. Mitochondria and the smooth endoplasmic reticulum mass are greater in the LES than in the esophageal body.
The difference between LES and esophageal muscle is that the former maintains higher basal tone than the latter, and in the in vivo situation the LES in humans is recognized as a zone of high pressure, 2 to 4 cm in length. What is responsible for this tone?
A multitude of myogenic, neural, and neurohumoral factors can either increase or decrease LES tone 16, 17 Table 1. The myogenic elements responsible for LES tone maintenance may be due to differences in the structural protein as described by Szymanski et al. There are also distinct intracellular signaling pathways in the LES as compared to the esophageal body.
The unique signaling pathway may contribute to the tonic contraction of the LES. From an electrophysiologic point of view, the LES muscle is in a state of greater depolarization than the esophageal muscle, as evidenced by a higher resting membrane potential than the esophageal muscle. Tonic LES contraction is both spike dependent and spike independent.
The relative contribution of myogenic tone to the LES pressure differs in different species. In the opossum, administration of tetrodotoxin a nerve poison does not affect LES pressure in vivo, suggesting that the basal LES tone is entirely myogenic.
Immunohistochemical staining of the myenteric plexus of the LES shows the presence of acetylcholine and substance P, the two likely candidates for excitatory neurotransmissions. These nerve cells are likely to be located in the parasympathetic pathway to the LES. Electrical stimulation of the sympathetic nerves also results in LES contraction that is mediated by -adrenergic receptors.
It has been suggested that interstitial cells of Cajal ICCs that are present in the LES and may serve as intermediary to amplify actions of neurotransmitters on the LES smooth muscle cells.
Slow phasic contractions in concert with the gastric component of the migrating myoelectrical complex MMC occur in the LES of humans and animals. The MMC -related contractions are abolished by atropine and anesthesia. Postrelaxation contraction is coordinated with esophageal peristalsis and is atropine sensitive. A similar behavior is seen in the muscle strips in vitro. Human LES circular muscle strips show prominent after-contraction when basal tone is low, but as tone increases the after-contraction is diminished.
The LES pressure increases in response to increases in intraabdominal pressure. However, considerable controversy exists as to whether the rise in LES pressure during abdominal compression is due to reflex LES contraction or merely a passive transmission of the increased intraabdominal pressure.
The brainstem contains the central control mechanism for the LES , which is closely integrated with the swallow pattern generator. The afferent information from the sensory nucleus of the tractus solitarius NTSs is relayed to the DMV motor neurons via the interneurons. Glutamate is the neurotransmitter of the sensory afferents. The motor neurons of the DMV contain acetylcholine, nitric oxide, dopamine, and epinephrine.
The swallow pattern generator, located in the reticular formation or the interneurons, is under the influence of GABA , and stimulation of the GABA -B receptor results in a reduction in its threshold and therefore of the swallow frequency.
The mammalian diaphragm is primarily a respiratory muscle. However, it should be considered as two separate muscles consisting of the crural and the costal diaphragms. Respiratory function relates to ventilation, and gastrointestinal to the sphincter like action at the lower end of the esophagus.
During human development myoblasts originating in the body wall and derived from the cervical segments invade two pleuroperitoneal membranes and form the costal diaphragm.
On the other hand, the two crura develop in the mesentery of the esophagus. According to Delattre et al. The central fibers have a relatively circular arrangement, but the peripheral fibers are oriented in a craniocaudal direction. The unique arrangement of its muscle fibers results in two different types of actions on the esophagus when it contracts: a vertical or craniocaudal motion, and a circumferential squeeze.
Phrenic nerves formed by the branches of C5, C6, and C7 nerve roots provide both motor and sensory innervation to the crural and costal diaphragm. In the dog, the C5 root has been reported to innervate almost exclusively the costal diaphragm, whereas the C7 root innervates the crural diaphragm. However, later more refined topographic mapping studies in the cat showed that there was no such simple segmental organization, but that generally the ventral region of both muscles is innervated by the C5 neurons, and the dorsal portions are innervated by the C6 neurons.
Therefore, although there is a highly delineated strip-like peripheral projection to muscle fibers, the motoneurons in the spinal cord are relatively intermingled rostrocaudally, dorsoventrally, and mediolaterally.
The proprioception function transduced by the muscle spindles located in the crural diaphragm is likely to be important in the reflex contraction of the diaphragmatic sphincter secondary to stretch exerted on it during increases in intraabdominal pressure. Measuring the contribution of diaphragmatic sphincter pressure to the EGJ is problematic in humans for three reasons: 1 The LES and diaphragmatic sphincter are anatomically superimposed on each other, and therefore it is difficult to discern whether the intraluminal pressure is related to LES or diaphragmatic sphincter contraction.
It contributes to both tonic sustained and phasic pressure increases at the level of the LES. It is widely believed that end-expiratory pressure at the lower end of the esophagus is due to tonic contraction of the LES , and the increase in pressure with inspiration is due to the contribution from the diaphragmatic sphincter.
In the cat, paralysis of the diaphragmatic sphincter by curare results in the loss of inspiratory pressure oscillations or phasic contraction at the LES. In humans, tidal inspirations cause a to mmHg increase in the LES pressure, and with forceful inspiration the increase in LES pressure can be to mmHg 63 Figure 3. The diaphragmatic sphincter also contracts reflexively during all those physiologic maneuvers that are associated with an increase in intraabdominal pressure Figure 4.
Studies in normal subjects as well as patients with an absent LES demonstrate increases in pressure at the lower end of the esophagus, with an increase in intraabdominal pressure as a result of abdominal compression, straight leg raise maneuver, coughing, and Valsalva maneuver. Diaphragmatic contraction was induced by standardized inspiratory efforts standardized Muller maneuver of different durations, 1, 2, 4, and 6 seconds.
Contractions of the inspiratory muscles of respiration produce negative intrathoracic and negative intraesophageal pressure, thus increasing the pressure gradient between the stomach and esophagus in favor of GER. Contraction of the abdominal wall and diaphragm also increases the pressure gradient between the stomach and esophagus.
All of the maneuvers accompanied by contraction of the inspiratory and the abdominal wall muscles that increase gastroesophageal pressure gradients are accompanied by contraction of diaphragmatic sphincter. Thus the rapid changes in pressure gradients between esophagus and stomach, caused by skeletal muscle contraction of the chest and abdomen, are antagonized by rapidly contracting skeletal sphincter muscles of the diaphragmatic sphincter. Originally described by Winan, several investigators have noticed that the LES pressure is circumferentially asymmetric.
Axial asymmetry means that the pressure in the LES is asymmetric along its length. The LES pressure is distributed in a bell-shaped curve, with the highest pressure somewhere in the middle. The highest LES pressure is in the leftward direction.
Richardson and Welch 68 found that atropine caused a greater reduction in the leftward pressure as compared to the pressure on the right. Preiksaitis et al. Ultrasound images of the LES show that the shape of the LES is relatively more circular toward the left, 66 which could be due to either a stronger contraction of the sling fibers in vivo or to the crus of diaphragm, 69 which compresses LES from the left side.
From the physics point of view Laplace's law , asymmetry in the shape of LES Figure 2 could account for the circumferential asymmetry of the LES pressure. Loose areolar tissue surrounds the esophagus from the level of mediastinum to the upper abdomen. Toward the periphery, the loose areolar tissue condenses to form the phrenoesophageal ligament, which anchors the esophagus and LES to the undersurface of the diaphragmatic sphincter.
Some feel that phrenoesophageal ligament originates from the undersurface of the diaphragm, and as it gets closer to the esophagus it forms two leaflets. The upper leaflet is inserted above the squamocolumnar junction and the lower leaflet is attached several centimeters below the upper leaflet.
The phrenoesophageal ligament is a relatively compliant and elastic structure because it allows the esophagus and the LES to slide in and out of the hiatus several centimeters. During a swallow, the lower end of the esophagus moves approximately 2 cm in the cranial direction, 70 and during TLESR the movement is even greater, 3 to 4 cm or even more.
The weakening of the phrenoesophageal ligament, as may occur with age, results in a sliding hiatal hernia, which may be reducible or nonreducible. Nonreducible hiatal hernias are strongly associated with severe GER disease.
For the transport of ingested contents into the stomach, relaxation of both the LES and the diaphragmatic sphincter is essential. Deglutition and distention of the esophagus are the two major stimuli that induce EGJ relaxation. Deglutition-induced LES relaxation starts within 2 seconds of the onset of swallowing and lasts 6 to 10 seconds Figure 5.
Lower esophageal sphincter relaxation is terminated by the arrival of esophageal peristaltic contraction at the LES and is followed by an after-contraction that may last up to 10 seconds.
After-contraction is seen only in the upper part of the LES ; in the lower part, LES pressure simply returns to the resting pressure level. Electrical recordings show that swallow-induced LES relaxation is associated with cessation of spike activity when present. The LES normally relaxes to a pressure very close to the intragastric pressure.
Besides relaxation, the LES also opens to allow passage of the bolus into the stomach. It is important to understand the difference between relaxation and opening because manometry only measures relaxation and not the opening function of the LES.
However, for the bolus to pass through the LES the latter must also open to the diameter of the bolus. Lower esophageal sphincter relaxation is an active process that is mediated by neurotransmitters, but the opening is related to passive or viscoelastic properties of the LES. Bolus pressure is responsible for the opening of the LES. To the left of the dark vertical line are normal swallow-associated events: submental EMG , pharyngeal contraction, and esophageal peristaltic contraction.
The gray vertical line represents the onset of the transient relaxation. Note the associated event, that is, esophageal contractions at the onset of the relaxation. Reflux occurs during transient relaxation of the LES and results in a fall of esophageal pH from 5 to 1.
Also note the difference in the duration between swallow induced and transient LES relaxation. Swallow is normally associated with LES relaxation followed by esophageal peristalsis, and as the esophageal contraction arrives at the LES , the latter recovers to baseline pressure. However, the two components i. Relaxation of the LES is the more sensitive component of the swallow reflex, and it is possible to have LES relaxation without any other motor evidence of the swallow reflex.
Isolated LES relaxation can be induced experimentally by applying pharyngeal tactile stimulation, which is subthreshold for producing a full swallow response. Low-intensity stimulation of the swallow center in the brain stem can also cause isolated LES relaxation. During a swallow, stimuli from the oropharyngeal region traverse via the vagal afferent pathways into the nucleus tractus solitarius, which then relays information into groups of cells, rather loosely organized reticular formation.
These cells are felt to be the pattern generator for the deglutition reflex and communicate with the premotor neurons of the DMV. Nitric oxide and acetylcholine are the neurotransmitter involved in the neurotransmission at the DMV. It appears that there is a tonic inhibition of the swallow reflex by GABA. It seems that the deglutition pattern generator has a certain threshold, which can be manipulated pharmacologically.
GABA -B agonist and antagonist, for example, can decrease and increase the spontaneous swallow frequency 50 by altering this threshold. Lower esophageal sphincter relaxation induced by electrical stimulation of vagal efferent nerves and esophageal distention is blocked by tetrodotoxin, which indicates that the motor neuron for LES relaxation is located with in the myenteric plexus.
Further studies reveal that M 1 receptors are responsible for the transmission at the level of the myenteric neuron. Deglutition-induced, vagal efferent stimulation—induced, esophageal distention—induced, and direct myenteric neuron stimulation—induced relaxation are all blocked by NO antagonists. Distention of the striated and smooth muscle portion of the esophagus produces LES relaxation that is associated with secondary peristalsis in the esophagus.
During prolonged esophageal distention, the LES recovers from relaxation despite ongoing distention. As with primary peristalsis, LES relaxation is also the most sensitive component of secondary peristalsis. Thus, isolated LES relaxation without esophageal contraction occurs with distentions that are subthreshold for activation of secondary peristalsis.
Intramuscular intercellular cells of Cajal ICC-IM may play a role in transducing the effects of neurotransmitters released from nerve ending to smooth muscle cells. At the intracellular level, LES relaxation is due to suppression of a resting chloride conductance by NO or activation of a potassium conductance resulting in smooth muscle hyperpolarization electromechanical coupling. These signaling molecules can cause smooth muscle relaxation without causing membrane hyperpolarization pharmacomechanical coupling.
Deglutition and esophageal distention, besides causing LES relaxation, also induces selective inhibition of the diaphragmatic sphincter muscle. Deglutition-induced inhibition of diaphragmatic sphincter is usually not complete, and as a result flow across the EGJ is interrupted if the subject inspires during the period of deglutition-induced LES relaxation.
In fact, alteration in the breathing pattern can cause complete arrest of the bolus in the esophagus above the EGJ. Vagotomy abolishes esophageal distention—mediated inhibition of the diaphragmatic sphincter, 99 suggesting that vagal afferents inhibit the brainstem medullary neurons responsible for diaphragmatic sphincter contraction vagophrenic inhibitory reflex.
Altschuler et al. Oyer et al. Liu et al. Diaphragmatic sphincter inhibition is temporally correlated with the longitudinal muscle contraction of the esophagus, and it may be that stretch of the diaphragmatic sphincter is important in its relaxation.
Manometric recordings were made with an electrode sleeve sensor inset at pressure recording ports at various locations from the pharynx to the stomach. The vertical arrow indicates the onset of relaxation, which occurs in the absence of a swallow as shown by the absence of a pressure wave or contraction in the pharynx. Relaxation is associated with inhibition of the crural diaphragm, as indicated by the loss of inspiratory pressure oscillations at the level of the sphincter and loss of inspiratory DEMG.
The contribution of the LES is shown in pink, and that of the crural diaphragm in brown. Reflux indicated by a decrease in esophageal pH occurs after complete relaxation of the sphincter and crural diaphragm and is associated with an increase in intraesophageal pressure. Source: Adapted from Mittal et al , with permission from American Gastroenterological Association. As stated earlier, the LES and diaphragmatic sphincter relaxation and opening are quite distinct processes.
Although relaxation is an active process and dependent on normal neural circuit and neurotransmitters, the LES and diaphragmatic sphincter opening is a passive process related to the viscoelastic properties of the LES , the diaphragmatic sphincter, and possibly the phrenoesophageal ligament and the surrounding abdominal viscera. Following relaxation, the LES and diaphragmatic sphincter needs to open to the size of the swallowed bolus.
Under normal physiologic conditions the entire LES opening occurs following its relaxation. But LES and diaphragmatic sphincter distensibilty is increased in reflux disease. For a given distention pressure, the diaphragmatic sphincter opening is greater in patients with reflux disease as compared to normal subjects.
Under normal circumstances, in humans an opening of 13 mm is required for the solid and liquid bolus to pass freely into the stomach. Our understanding of the distensibilty at the lower end of the esophagus and its role in esophageal transit abnormality is relatively limited because the routinely used technique to study LES function i. Atropine reduces LES pressure but does not affect distensibilty or the opening functioning at the lower end of the esophagus, and therefore may not improve dysphagia related to poor distensibilty.
Fundoplication, an effective surgical procedure to treat reflux disease, reduces distensibilty of the lower end of the esophagus and causes dysphagia. Intuitively, one would think that weakness of either the LES or the diaphragmatic sphincter is the cause of GER disease.
Indeed, some patients with reflux disease have a weak LES , some have a weak diaphragmatic sphincter, and some have both. In the majority, however, especially in mild to moderate reflux disease, the LES and diaphragmatic sphincter pressure is normal. In fact, similar to deglutition-induced LES relaxation being a physiologic mechanism for the antegrade flow, gastric distention—induced TLESR is a physiologic mechanism for the retrograde flow of stomach contents into the esophagus.
Initially described as inappropriate LES relaxation, the name was later changed to TLESR because the phenomenon occurs in normal healthy situation. McNally et al. Dent and colleagues first described in the exact phenotypic description and its association with GER. Transient LES relaxation is seen as an abrupt fall in LES pressure to the level of intragastric pressure that is not triggered by deglutition, as manifested by the distinctive pattern of pharyngeal or mylohyoid muscle contraction.
Transient LES relaxation is typically of longer duration than the swallow-induced LES relaxation, lasting 10 to 45 seconds. Distal esophageal contractions occur often at the onset of TLESRs, and when recorded at more than one site usually have a synchronous onset.
During the period of LES inhibition, there is also inhibition of the esophageal body as manifested by inhibition of primary peristalsis. This pattern of inhibition during TLESR is consistent with a coordinated pattern of activity generated in the pattern generator in the brainstem. Approximately 15 mL of air is delivered to the stomach with each swallow, and without an in-built venting mechanism, uncontrolled gastrointestinal bloating would occur.
Studies in which the stomach was partitioned surgically show that the subcardiac region of the stomach is primarily responsible for triggering TLESR. Although distention of other parts of the stomach can increase the rate of TLESR , the thresholds for distention is substantially higher in these regions and the response is less marked. In some studies, a similar effect has been reported after meals. Lower esophageal sphincter relaxation without swallow can be induced by instillation of minute amounts of liquid into the hypopharynx in humans , and light stroking of the pharynx or low-frequency stimulation of the superior laryngeal nerve in the opossum.
In both healthy humans and dogs, the stimulation of TLESRs produced by gaseous gastric distension is almost totally suppressed in the supine posture. Transient LES relaxation does not occur during stable sleep ; reflux episodes that do occur during the nighttime sleep periods are totally confined to periods of arousal during sleep that may last for only 10 seconds.
In patients with reflux disease, the presence or absence of endoscopically visible esophagitis does not influence the rate of TLESRs after meals.
However, the effect of healing of esophagitis with acid suppressants on the rate of TLESRs is controversial; omeprazole has been reported to have no effect, whereas H2 antagonists seem to decrease the rate of TLESRs.
The mechanisms underlying this effect include a possible a reduction in the degree of distention of the gastric cardia by the gastric wrap, which may reduce the gastric distention—induced stimulation of TLESRs.
Transient LES relaxation is a neural reflex with afferent and efferent pathways and a pattern generator located in the swallow center of the brainstem. Penagini et al. The afferents from the gastric mechanoreceptors traverse through the vagus nerve, via nodose ganglion into the NTSs and to the DMV via interneurons. In the opossum, intrinsic gastric nerves independent of extrinsic nerves can induce LES relaxation. Selective inhibition of the diaphragmatic sphincter, which is characteristic of TLESRs, also occurs during vomiting and is coordinated through the brainstem.
The basic element is a vagal reflex pathway triggered by gastric distention or pharyngeal stimulus and integration that occurs in the brainstem. Slightly above the junction of the esophagus and the stomach is another band of muscle called the lower esophageal sphincter. When the esophagus is not in use, these sphincters close so that food and stomach acid do not flow back up the esophagus from the stomach to the mouth.
During swallowing, the sphincters open so food can pass to the stomach. With aging, the strength of esophageal contractions and the pressure in the sphincters decrease. This condition makes older people more prone to backflow of acid from the stomach gastroesophageal reflux or GERD Gastroesophageal Reflux Disease GERD In gastroesophageal reflux disease, stomach contents, including acid and bile, flow backward from the stomach into the esophagus, causing inflammation in the esophagus and pain in the bottom Two of the most common symptoms of esophageal disorders are dysphagia an awareness of swallowing difficulty Difficulty Swallowing Some people have difficulty swallowing dysphagia.
People feel as though food or liquids become Symptoms may be similar. Gastroesophageal reflux Dysphagia and chest or back pain may occur in any esophageal disorder, the most serious of which is esophageal cancer Esophageal Cancer Esophageal cancers develop in the cells that line the wall of the esophagus the tube that connects the throat to the stomach.
Tobacco and alcohol use, human papillomavirus infections, and Abnormal propulsion of food Abnormal Propulsion of Food The movement of food from mouth to stomach requires normal and coordinated action of the mouth and throat, propulsive waves of muscular contractions of the esophagus called peristalsis , and Achalasia Achalasia Achalasia is a disorder in which the rhythmic contractions of the esophagus called peristalsis are missing or impaired, the lower esophageal sphincter does not relax normally, and the resting Dysphagia lusoria Dysphagia Lusoria Dysphagia lusoria is difficulty swallowing dysphagia caused by compression of the esophagus by an abnormally formed blood vessel that is present at birth.
See also Overview of Esophageal Eosinophilic esophagitis Eosinophilic Esophagitis Eosinophilic esophagitis is an inflammatory disorder in which the wall of the esophagus becomes filled with large numbers of eosinophils, a type of white blood cell.
This disorder may be caused Esophageal laceration Mallory-Weiss syndrome Esophageal Laceration Mallory-Weiss Syndrome An esophageal laceration Mallory-Weiss syndrome is a tear that does not penetrate the wall of the esophagus. The tear can be caused by forceful vomiting. Symptoms include blood in vomit. Esophageal pouches diverticula Esophageal Pouches Diverticula Esophageal diverticula are abnormal pouches or pockets in the esophagus. Rarely, they cause swallowing difficulties and regurgitation the spitting up of food without nausea or forceful contractions Esophageal ruptures Esophageal Ruptures Esophageal ruptures are tears that penetrate the wall of the esophagus.
In addition to eating, we use this part of the esophagus while simply breathing. It also comes into play during unpleasant bodily functions, such as burping or throwing up, that serve to expel gas or harmful materials from the body. The cluster of muscles that make up the upper esophageal sphincter prevents food from traveling down the trachea , or windpipe.
This is known as aspiration and refers to foreign materials in the airway. Aspiration can lead to choking or even pneumonia if food journeys to the lungs. When food goes down the "wrong pipe," the best advice is to cough, which helps the food go down the esophagus instead. It is also known as the inferior pharyngeal sphincter since it's positioned at the lower end of the pharynx and protects the opening into the esophagus. If the upper esophageal sphincter doesn't function properly, an acid that has flowed back into the esophagus is allowed into the throat.
This can lead to painful medical conditions, such as heartburn or gastroesophageal reflux disease GERD , the term used to describe repeated cases of heartburn. The UES plays a special role in regulating the passage of food and liquid down the throat, but it and the LES are not the only sphincters in the body. There's also the anal sphincter, the muscle group near the anus that regulates the passage of stool out of the body.
Then, there's the sphincter of Oddi, which regulates the passage of bile and pancreatic secretions into the small intestine. While sphincters appear in different areas of the body, they all function to control the flow of substances through organs and to open and shut different body parts. Sphincters play an important role in keeping the body sound and healthy. While learning about the body parts that play key roles in the development of acid reflux won't make your discomfort disappear, it can turn you into an informed patient, knowledgeable enough to pursue a variety of options to find the right treatment.
Chronic heartburn or GERD can seriously affect one's quality of life. If you're having repeated episodes of acid reflux, consult your healthcare provider about how to remedy the problem. Antacids, surgery or even home remedies and lifestyle changes can alleviate your symptoms. Get nutrition tips and advice to make healthy eating easier.
Functional anatomy and physiology of the upper esophageal sphincter.
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