Upper Esophageal Sphincter (UES)

The upper esophageal sphincter is a high-pressure area that lies between the pharynx and the upper part of the esophagus. It consists of a mixture of cartilages and muscles that give the sphincter high elastic and tonic properties. The unique composition also allows the sphincter to maintain the capacity to open wide in response to a stimulus. The UES functions to block food from regurgitating back into the airways. It also prevents air from reaching the gastrointestinal tract in significant amounts. The cricoid cartilage and the arytenoid and inter arytenoid muscles make up the anterior parts of the sphincter. The thyropharyngeus and the cricopharyngeus muscles form the majority of the sphincter's posterior and lateral walls, with the former accounting for the upper two-thirds of the sphincter and the latter occupying the lower one-third. Contraction of the hyoid muscle that pulls the larynx forwards, combined with the relaxation of the cricopharyngeus and the thyropharyngeus, causes the sphincter to open wide.[4]

Once the food bolus reaches the oropharynx, it stimulates sensory receptors there. The receptors then transmit the signal to the swallowing center in the brainstem via afferent nerve fibers. In turn, the brainstem processes the message and sends efferent fibers to smooth muscle cells in the UES. The cricopharyngeus and the thyropharyngeus muscles relax in return, and the food bolus passes the UES.[5] In addition to opening the UES, the stimulus also induces swallowing, cessation of breathing, and peristaltic movements down the esophagus. It is worth mentioning that the signals reaching the cricopharyngeus and the thyropharyngeus muscles are inhibitory rather than stimulatory. In other terms, they inhibit the tonic contractions in these muscles leading to LES opening.[4]

Efferent signals also stimulate the hyoid muscle to contract, leading to elevation of the hyoid. Hyoid muscle contraction happens almost simultaneously with the relaxation of the UES. Together, with the propulsion force of the bolus, these three forces allow the food bolus to overcome the pressure in the UES region and pass into the esophagus.[6]

The volume of the bolus also plays an essential role in mediating the physiology of the UES. It dictates the duration between UES opening and pharyngeal movement. A higher volume results in a faster onset of pharyngeal movements. Additionally, increasing the thickness of the bolus increases the time differential between the opening of the UES and pharyngeal movements.[6]

Peristalsis

Once the bolus passes through the UES, it reaches the esophagus. The upper portion of the esophagus mainly consists of striated muscles and is under the control of central control mechanisms. The lower part of the esophagus consists primarily of smooth muscle and is under the control of both central and intrinsic control mechanisms. Central control mechanisms refer to peristaltic movements originating from the brainstem, as in the case of the swallowing reflex. In contrast, peripheral control mechanisms refer to peristaltic movements originating from the esophagus itself and are intrinsic to the smooth muscles owing to their rich nerve plexuses.[7]

The esophagus consists of four different layers: the mucosa, submucosa, muscularis propria, and serosa. The muscle layer, also known as the muscularis propria, further divides into an outer longitudinal and an inner circular muscular layer. The exact role of longitudinal muscles in esophageal physiology is not entirely understood. Recent studies have shown that longitudinal muscles help in reducing the tension associated with circular muscle contractions, which serves to augment peristaltic movements. In contrast, the role of circular muscle fibers in esophageal physiology is well defined. Circular muscles contract radially to provide peristaltic propulsion of the bolus in the distal direction.[8]

As the food bolus enters the esophagus, it triggers primary peristalsis. Primary peristalsis refers to bolus-induced esophageal contractions. In contrast, secondary peristalsis refers to distension-induced contractions. In peristalsis, the area ahead of the bolus relaxes, and the area behind it contracts, enabling the bolus to propel forward. A series of nervous inputs allow for coordinated action between contractions and relaxations, leading to a smooth movement of food along the esophagus.[4]

Primary peristalsis in the esophagus is a complex process mediated by central control mechanisms originating from the brainstem. Upon swallowing, striated muscles in the upper esophagus respond in a slightly different manner than smooth muscles in the lower esophagus. In striated muscles, lower motor neurons in the nucleus ambiguous of the brainstem get activated sequentially to create a peristaltic wave. In smooth muscles, though, inhibitory neurons from the caudal dorsal motor nucleus (cDMN) get activated and cause simultaneous inhibition of all parts of the esophagus. This simultaneous inhibition in the smooth muscle of the esophagus is termed "deglutitive inhibition" and is the first step to generating a peristaltic wave. The inhibition lasts longer in the lower portion of the esophagus than the upper parts. As the inhibition ends, sequential activation of excitatory neurons in the rostral dorsal motor nucleus (rDMN) elicits peristaltic contraction.[7]

The excitatory pathway in smooth muscles originates from vagal preganglionic neurons of the rostral part of the DMN (rDMN). The DMN is a vagal nerve nucleus located in the medulla that lies ventral to the floor of the fourth ventricle. The rDMN preganglionic neurons attach to the excitatory postganglionic neurons that release acetylcholine (ACh) and substance P. The inhibitory pathway, on the other hand, includes preganglionic vagal fibers in the cDMN. These fibers project to postganglionic inhibitory neurons that contain nitric oxide (NO), vasoactive intestinal peptide (VIP), adenosine triphosphate (ATP), and substance P (SP).[7]

Interestingly, the esophagus can also undergo secondary peristalsis, which is a process orchestrated by the intrinsic nervous system and vaso-vagal responses when there is leftover food in the esophagus. Secondary peristalsis usually occurs in the absence of a swallow. It can have the same strength and speed as the primary peristalsis.[5] In skeletal muscles, secondary peristalsis is centrally mediated and occurs in a similar method to primary peristalsis with nerve innervations arising from the nucleus ambiguous. In smooth muscles, a peripheral mechanism regulates secondary peristalsis. The peripheral mechanism starts with the activation of sensory neurons through distention or the presence of a food bolus in the esophagus. The excited sensory neuron transmits the signal to an interneuron, which in turn relays the message to a motor neuron. Subsequently, the motor neuron releases acetylcholine (ACh) proximally and nitric oxide (NO) distally to create a secondary peristaltic wave. This peristaltic wave in smooth muscle is locally contained and generated by the peripheral mechanism.[9]

LES

Once the bolus arrives at the end of the esophagus, it must pass through the LES to reach the stomach. The LES and the crural diaphragm constitute a high-pressure zone separating the esophagus from the stomach. They function as an anti-reflux barrier that protects the esophagus from the acidity and digestive properties of gastric juice. They also allow for the passage of the bolus into the stomach. [10]

The LES consists of smooth muscles that help keep the sphincter tightly closed. In response to direct inhibitory signals, the smooth muscles in the LES relax, allowing the sphincter to open, and the food bolus to pass. The LES does not posses any dilator muscles, though, and opening relies solely on the relaxation of the smooth muscles.[7]

The pressure in the LES depends on a combination of three factors: the myogenic tone of the smooth muscles, the inhibitory nitrergic nerves, and the excitatory cholinergic nerves. The myogenic tone is an intrinsic property of the smooth muscle cells in the LES and is responsible for the tonic contraction of the sphincter. It happens because the LES smooth muscle cells have more depolarized resting membrane potentials, resulting in spontaneous spike-like action potentials and generation of a basal tone. Excitatory cholinergic nerves (ACh) release acetylcholine to activate smooth muscle contraction. As such, they enhance the tonic, myogenic property of the LES, and favor contraction. In contrast, the inhibitory nitrergic (NO) pathway releases NO and favors inhibition. Therefore, it opposes the contractile properties of the LES. The combination of these forces favors contraction over relaxation. Thus, the LES remains contracted even when entirely denervated owing to its myogenic property.[10]

The presence of a bolus in the pharynx induces esophageal peristalsis and LES relaxation by stimulating pharyngeal receptors that relay signals to the brainstem. The sensory stimulus travels to the nucleus tractus solitarius, which connects with the DMN. The vagal efferent nerves from the DMN do not innervate the smooth muscles directly. Instead, they signal the myenteric plexus, which mediates LES relaxation through nitric oxide (NO). The myenteric plexus consists of inhibitory and excitatory motor neurons. The location of the stimulus dictates whether an inhibitory or excitatory action takes place. The inhibitory pathway neurons arise from the caudal DMN, while the excitatory pathway neurons arise from the rostral DMN. Nitric oxide (NO) is the most critical inhibitory postganglionic neurotransmitter. In contrast, ACh and tachykinin are crucial excitatory ones.[10]

In addition to its stimulus-triggered relaxation, the LES also relaxes transiently to allow for gas venting from the stomach. Transient lower esophageal sphincter relaxation (TLESR) is an essential physiological mechanism the LES possesses.[11] Afferent nerves from the pharynx, larynx, and the stomach send information to the brain to mediate the TLESR reflex. The efferent nerves utilize the same pathway as the swallow reflex to trigger LES relaxation.[12]

As mentioned earlier, the high-pressure zone between the esophagus and the stomach consists of a combination of smooth muscles of the LES and the crural diaphragm. The crural diaphragm plays an essential role in allowing for the passage of a food bolus into the stomach just as smooth muscle relaxation does. It also helps in regulating the rate of reflux into the esophagus. It connects to the LES by the phrenoesophageal ligament, meaning that the two structures move together during breathing but can separate during peristalsis and transient LES relaxation.[13] As an essential part of the LES, the crural diaphragm must relax to allow for a food bolus to pass from the esophagus to the stomach, and vice versa. The precise mechanism by which the crural diaphragm relaxes is not fully understood. However, it is well known that diaphragmatic contractions depend on the phrenic nerve through nicotinic acetylcholine receptors.[14]

There are several tests available to assess the function of the esophagus, including upper endoscopy, barium swallow, high-resolution manometry (HRM), pH measurement, and impedance monitoring of the esophagus. Upper endoscopies, barium swallow studies, and high-resolution manometry are more common than the other ones.[15] Upper endoscopies assess the mucosa and submucosa of the esophagus and frequently involve taking biopsies to evaluate esophageal tissue better. A barium swallow study consists of the administration of barium followed by sequential usage of x-rays to determine the movement of barium through the upper gastrointestinal (GI) tract. The test helps to assess the presence of any potential anatomical defects. It also aids in analyzing the physiology of the UES, the esophagus, and the LES. Barium studies, though, are problematic because it is challenging to determine what an average esophageal luminal diameter is.[15] High-resolution manometry involves the use of pressure-sensitive catheters to evaluate both the sphincter and the esophageal motor function. By moving the catheter sequentially down the esophagus and its associated sphincters, the pressure-sensitive catheter picks up the pressure changes as the sphincters open and close, or as peristalsis occurs.[16] Ultrasound is another useful, readily available test that helps evaluate the function of the esophagus. Unfortunately, it has not gained wide popularity for assessing the esophagus yet.[15]

Dysphagia, or difficulty swallowing, is a subjective feeling of an abnormality of difficulty in swallowing. It can occur either while initiating the swallow or shortly thereafter. The former is referred to as oropharyngeal dysphagia and occurs when there is a problem at the level of the oropharynx, as the name implies. The latter happens due to problems in the esophagus, hence the name esophageal dysphagia. There are several mechanisms by which esophageal dysphagia occurs. Physical obstruction and motor problems are the two most common causes of dysphagia. They can occur at the level of the UES, the esophagus itself, or the LES. Diffuse esophageal spasm, achalasia, scleroderma, and diabetes mellitus are common causes of dysphagia owing to a motor problem. Esophageal carcinoma, reflux esophagitis, peptic strictures, or Schatski’s rings, on the other hand, are examples of conditions causing dysphagia due to an obstructive process. Esophageal obstructions cause difficulty swallowing to liquids initially that eventually progresses to dysphagia to both liquids and solids. In contrast, motor diseases cause dysphagia to both solids and liquids from the beginning.[4]

Diffuse Esophageal Spasm

Diffuse esophageal spasm is a condition that causes the esophagus to contract is an irregular, uncoordinated manner leading to dysphagia. An x-ray shows the characteristic "corkscrew" or rosary bead" esophagus. Manometry testing reveals episodes of dysfunctional peristalsis with irregular, repetitive, and ineffective contractions. Patients usually present with dysphagia and chest pain.[17]

Achalasia

Achalasia is a condition characterized by failure of the lower esophageal sphincter to relax and the lower esophagus to contract in response to swallowing. Typically, a food bolus in the pharynx induces esophageal peristalsis and LES relaxation to allow food to pass to the stomach. In achalasia, smooth muscle cells in the LES fail to relax in response to a food bolus, owing to the loss of inhibitory nerve fiber signals. This, along with the failure of lower esophageal peristalsis, prevents the bolus from moving to the stomach. The patient perceives the condition as swallowing difficulty or dysphagia. Barium swallow reveals the classical "Bird's beak" deformity caused by barium hardly passing the contracted sphincter. It also shows a dilated distal esophagus due to the accumulation of barium proximal to the LES. Manometry confirms the diagnosis by showing the characteristic pressure changes in achalasia, i.e., very high pressure in the LES and absent peristalsis in the distal esophagus that fails to improve in response to swallowing.[18]

Scleroderma

Scleroderma is an inflammatory autoimmune disease characterized by a widespread accumulation of collagen and fibrous tissue in various body organs. It typically affects the skin, but can also involve the gastrointestinal tract, especially the esophagus. When fibrosis affects smooth muscle cells in the lower esophagus, atrophy ensures, and the muscles no longer contract as they usually do. Fibrosis results in hypomotility of the esophagus and impaired function of the LES. As such, patients present heartburn and difficulty swallowing. Manometry confirms the diagnosis by showing the characteristic absence of effective peristalsis at the distal esophagus combined with low pressure in the lower esophageal sphincter.[19]

Esophageal carcinoma

Esophageal carcinomas are usually either squamous cell carcinomas or adenocarcinomas. As esophageal cancer expands, the lumen of the esophagus narrows down, and dysphagia occurs due to mechanical obstruction. Upper endoscopy helps with, and biopsy confirms the diagnosis of esophageal cancer.[20]

Peptic Strictures

Peptic strictures are a long-term consequence of chronic reflux esophagitis caused by repeated acid exposure from the stomach. As esophagitis progresses, inflammation and scarring from stomach acid and other irritants ensue, leading to esophageal narrowing and resultant dysphagia. Barium swallow studies and upper endoscopy with biopsy help confirm the diagnosis.[21]

Schatzki's Ring

A Schatzki's ring is a band of excessive mucosa over the normal esophageal mucosa resulting in a decreased luminal diameter of the esophagus. It usually affects the lower esophagus and presents as dysphagia. Diagnosis is generally made based on EGD or barium swallow studies. The condition is often associated with hernias[22].

Zenker's Diverticulum

Lack of UES relaxation can also trigger dysphagia. Any disease that increases the baseline tension of the UES muscles increases the risk of dysphagia. Zenker's diverticulum is an outpouching of mucosa and submucosa occurring just between the cricopharyngeus muscle and the inferior pharyngeal constrictor muscles. It occurs due to excessive pressure in the lower pharynx causing the weakest portion of the pharyngeal wall to balloon out. The inciting event is usually irregular contractions or reduced relaxation of the cricopharyngeus muscle. Besides the dysphagia that most patients with Zenker's diverticulum have, food regurgitation and halitosis (bad breath) also commonly occur.[23]