The main esophageal functions are to transport food from the mouth to the stomach and to prevent reflux of gastric contents, so the main manifestations of disease in this organ are either feeding difficulties or regurgitation. Abnormalities of esophageal function occur frequently and can be confined primarily to the esophagus or can occur secondary to systemic illnesses. By interfering with the normal progression of food transit from the mouth to the stomach or by failing to provide adequate protection from gastric contents, esophageal motor disorders can be debilitating and even life threatening. Hence, the esophagus can no longer be regarded as simply a conduit between the pharynx and stomach, and a thorough understanding of the physiology of deglutition and esophageal peristalsis is essential to a better understanding of the varied clinical presentation of esophageal disease.
This chapter provides background for the basic understanding of this structure’s development, anatomy, and physiology to facilitate an understanding of the many clinical presentations of esophageal disease.
Developmental Anatomy of the Foregut/Esophagus
The esophagus develops from a primitive digestive tube through multiple maturational milestones that augment a series of immature reflexes into the complex act of swallowing. The primitive gut forms during the fourth fetal week as the head, tail, and lateral folds incorporate the dorsal part of the yolk sac into the embryo ( Figure 19-1 ). As the embryo develops, mitotic cell division produces three germ layers—ectoderm, mesoderm, and endoderm. It is during this fourth fetal week that the primitive gut forms: the foregut endoderm begins to differentiate into a ventral respiratory section and a dorsal gastrointestinal section through a series of morphogenetic folding movements. The laryngotracheal diverticulum evaginates from the ventral part of the foregut and grows into splanchnic mesenchyme, thereby forming the primitive lung-bud. The endoderm of the lung-bud develops into the epithelium and glands of the future lungs, whereas the splanchnic mesenchyme forms the connective tissue, cartilage, and smooth muscle cells. According to the traditional theory, at 6 to 7 weeks of gestation, separation of the ventral respiratory and dorsal esophageal part is activated by the formation of lateral longitudinal tracheoesophageal folds, which start caudally and end cranially, and fuse in the midline to form the tracheoesophageal septum. Incomplete fusion of these folds may result in the formation of a defective tracheoesophageal septum, and hence, an abnormal connection between the esophagus and trachea.
Multiple theories explaining the partitioning of the trachea have been suggested. One theory suggests that the respiratory system develops as a result of a rapid outgrowth from the original ventral aspect of the foregut tube. The tracheal primordium buds off the ventral foregut and remains separate from the foregut during development. This theory has been described as the “respiratory tap” theory. Another model combines the traditional theory of the mesenchymal septum and the respiratory tap theory to suggest that tracheoesophageal separation is a result of three foregut folds. Models of tracheoesophageal separation are shown in Figure 19-2 .
An abnormal communication, or fistula, connecting the trachea and esophagus can occur (tracheoesophageal fistula; TEF) (once in every 3500 births), owing to incomplete division of the trachea and digestive portion of the foregut during the fourth and fifth weeks of fetal life. There are four main variations of esophageal atresia (EA)/TEF. Although EA probably develops from lack of deviation of the tracheoesophageal septum in a posterior direction, isolated (very rare) EA can develop from failure of recanalization of the esophagus in the embryonic period. TEF and EA are discussed in detail in other chapters.
Once the esophagus separates from the foregut, it undergoes morphogenesis to become a functional tube. It is ensheathed by layers of muscle and lined with stratified squamous epithelium; initially the lumen comprises a ciliated simple columnar epithelium, which is gradually replaced by a stratified squamous epithelium at around 20 weeks of gestation. The striated muscle of the upper esophagus (muscularis externa) is derived from mesenchyme in the caudal branchial arches, whereas the smooth muscle is derived from the surrounding splanchnic mesenchyme.
The development of an effective, safe swallow is dependent on the maturation of aerodigestive organs, which originate from segments adjacent to the primitive foregut. The vocal cords begin as glottal folds. By 6 to 7 weeks of gestation, there is evolution of the epiglottis, aryepiglottic folds, false vocal cords, and laryngeal ventricles, which protect the vocal cords and lower airway. The epiglottis derives from a hypobranchial eminence behind the future tongue, separated from the tongue at around 7 weeks. The larynx originates as a groove in the primitive foregut, folds upon itself to become the laryngotracheal bud, and subsequently divides and forms the bronchopulmonary segments.
Initially the esophagus is very short, but it lengthens rapidly, reaching its final proportionate length by 7 weeks of gestation. This occurs because of cranial body growth and ascent of the pharynx rather than descent of the stomach. Abnormalities in development can result in a shorter esophagus. Congenital stenosis of the esophagus can occur in any area, but is usually present in the distal third as a web or band, or as a long segment of the esophagus with a very narrow lumen. Stenosis typically develops secondary to failure of recanalization of the esophagus in the embryonic period by the eighth week of development. Occasionally, a short esophagus may occur with a portion of the stomach displaced through the diaphragm as a hiatal hernia. Similarly, diverticula, duplication cysts, and other anatomic abnormalities arise owing to failure of proper embryonic development, usually of the proximal esophagus.
Genetic and Molecular Aspects of Tracheoesophageal Development
There are a number of genetic abnormalities and environmental factors associated with the development of EA and/or TEF, but the developmental mechanisms are far from understood. Most likely the development of EA/TEF is multifactorial. The Sonic hedgehog ( Shh ) pathway has been a major focus of animal research. The notochord secretes Shh , which is an important patterning factor; abnormalities in the notochord influence foregut development. Shh -null mutants have severe foregut anomalies, including EA/TEF. Downstream mediators of the Shh pathway, such as genes of the Gli family, which are regulatory transcription factors, have a phenotype associated with EA/TEF. In addition, mutations in Foxf1 and HoxC4 , other transcriptional targets of Shh , are associated with abnormal development of esophagus. HoxD13 mutations have been described in a patient with vertebral, anal, cardiac, TEF, renal, and limb (VACTERL) association. A mouse knockout for EA/TEF, the Nog gene, is a bone morphogenetic protein (BMP) antagonist that exhibits abnormal notochord morphogenesis. It results in EA/TEF in approximately 60% of cases. The transcription factor Nkx2.1 ( Tft-1 ) is critical to the development of the foregut and respiratory system and Nkx2.1 −/− mice demonstrate a common lumen connecting the oropharynx to the lungs and to the stomach. Although a detailed description of all the genes and molecular pathways known to be involved in development of the foregut is beyond the scope of the chapter, a brief description of genes/molecular pathways discovered by knockout studies in mice and chick embryos is presented in Table 19-1 .
|Gene||Function||Human Locus||Foregut Phenotype|
|Shh||Signaling model |
Hedgehog family ligand
|7q36||EA/TEF, lung anomalies|
|FoxF1||Transcription factor||16q24.1||EA/TEF, pulmonary vascular defects|
|Gli2/Gli3||Zinc finger transcription factors||Gli 2: 2q14 |
|EA/TEF, lung agenesis|
|Sox2||HMG type transcriptional regulator||3q26.3||EA/TEF; Anophthalmia-esophageal-genital syndrome (AEG)|
|RAR α/β 2||Retinoic acid receptor||17q21.1||EA/TEF, lung hypoplasia or agenesis|
|TTF-1 (Nkx2.1)||Thyroid transcription factor||14q13||TEF, lung anomalies|
|Hoxc4||Transcription factor||12q13.3||Obstructed esophageal lumen|
EA and/or TEF are commonly associated with other congenital anomalies, but only limited knowledge about a possible genetic predisposition is available. Among them, the VACTERL association is the best known. Currently, the etiology of VACTERL is unknown, and a specific locus has not been identified. EA and/or TEF have been described in at least seven other syndromes and one sequence. Two of these syndromes are Feingold syndrome, with mutations and deletions of the MYCN gene, and Fanconi anemia, with mutations in the FANCC and FANCA genes. Chromosomal abnormalities such as deletions of 22q11, trisomy 18, 13, 21, and mosaic trisomy X, have also been associated with EA/TEF. Recent reports have identified patients with interstitial deletions of chromosome 17 and translocation of 6;15. Single-gene and chromosomal disorders that are associated with tracheoesophageal malformations are also being increasingly described. Environmental factors such as maternal exposure to methimazole, statins, alcohol, and/or smoking have been identified as factors in development of EA/TEF. A more detailed summary of some of the most commonly known congenital anomalies is presented in Table 19-2 .
|Oculo-auriculo-vertebral sequence (OAVS, Goldenhar syndrome)||22q11||EA/TEF|
|Trisomies 13, 18, & 21||EA/TEF|
Anatomy of the Esophagus
The esophagus commences as a downward continuation of the pharynx, at the caudal borders of the cricoid cartilage and the lower margin of the cricopharyngeus (CP) muscle at the level of the sixth vertebra. It descends mostly anterior to the vertebral column, through the superior and posterior mediastina. The esophagus then traverses the diaphragm through the esophageal hiatus around the level of the 10th thoracic vertebra to join the gastric cardia. In general, the esophagus follows the anteroposterior curvature of the vertebral column with two lateral curvatures to assume the style of a reversed “S.” There are several indentations and constrictions of the esophagus: at its commencement at the oropharyngeal junction caused by the CP muscle and cricoid cartilage, where crossed by the aortic arch (aortic constriction), just below where the left main bronchus crosses, and, finally, where it traverses the diaphragm by the inferior esophageal sphincter and esophagogastric vestibule.
The esophagus is a hollow tube comprising the inner circular and outer longitudinal muscle layers with the myenteric plexus in-between. The proximal esophagus has striated muscle, whereas the distal esophagus is composed of smooth muscle. The upper esophageal sphincter (UES), which is a constriction between the pharynx and the proximal esophagus, is characterized by a high pressure zone generated by the CP muscle (primary muscle), proximal cervical esophagus, and inferior pharyngeal constrictor. It is located below the vocal cords, adjacent to fifth and sixth cervical vertebrae, spanning about 2 to 5 cm. The UES is innervated by three major nerves: the vagus nerve via the pharyngoesophageal, superior laryngeal, and recurrent laryngeal branches; the glossopharyngeal nerve; and sympathetic nerve fibers from the superior cervical ganglion. The vagus nerve provides sensory innervation to the vocal cords as well, which ensures that the airway is closed during swallowing and triggers a reflex to eject a bolus if it enters the airway.
The distal end of esophagus is composed primarily of the lower esophageal sphincter (LES), an autonomous contractile apparatus that is tonically active and relaxes periodically to allow bolus transit into the stomach. There is a gradual thickening of the circular and longitudinal muscles at the distal end of the esophagus, commencing about 1 to 2 cm above the diaphragmatic hiatus and extending to the cardia. This region is known as the esophagogastric vestibule. There is a distinct group of muscle fibers at the upper end of the esophagogastric vestibule termed the “inferior esophageal sphincter.” It is believed that the contraction of these muscle fibers is an important factor in the prevention of regurgitation from the stomach.
Because the esophagus emerges from the right crus of the diaphragm slightly left of midline, there is a short intra-abdominal portion ( Figure 19-3 ). The LES is predominantly intrathoracic in neonates and the intra-abdominal part of the sphincter grows in infancy. The lack of the intra-abdominal esophagus in neonates may be part of the reason that infants are more prone to gastroesophageal reflux (GER); the intra-abdominal portion acts as a physiologic sphincter, as it is exposed to the higher pressure of the abdominal cavity, relative to the lower pressure of the thoracic cavity (inspiration). In addition, the insertion position of the esophagus into the stomach may be a contributing factor for GER in infants. In adults and older children, the insertion is much more oblique than the comparatively straight insertion in infants. Important in aiding to prevent GER, neighboring structures, including the oblique sling fibers of the stomach, the musculofascial diaphragmatic sling, and the intra-abdominal esophagus, augment the integrity of the LES. These structures may exert a “physiologic sphincteric” control that may be compromised in the infant as anatomy matures; however, this remains poorly understood, and the main mechanism for infantile GER is thought more likely to be inappropriate relaxation of the gastroesophageal junction.
The esophagus is composed of four layers (inner to outer): mucosa, submucosa, muscularis externa, and adventitia. The mucosa comprises three components (inner to outer): a nonkeratinizing stratified squamous epithelium, a lamina propria, and the muscularis mucosa. The submucosa is composed of loose connective tissue, blood vessels, lymphatics, lymphoid follicles, and submucosal (Meissner) plexus. The muscularis externa has an inner circular muscle layer and an outer longitudinal layer with an intervening myenteric (Auerbach) plexus. The adventitia is the connective tissue fascia layer that surrounds the esophagus.
Esophageal vasculature supply is from regional arteries such as the inferior thyroid branch of the thyrocervical trunk, descending aorta, bronchial arteries, left gastric branch of the celiac artery, and left phrenic artery. Venous drainage follows a longitudinal route similar to that of the inferior thyroid veins, the azygos vein, and left gastric vein. This left gastric vein is the most important of the portosystemic communications, and raised portal pressure can therefore lead to esophageal varices.
Lymphatic drainage is through a longitudinally continuous submucosal system. There are two types of lymphatic vessel plexuses, one that is present in the mucous membrane and the other in the muscular coat.
The esophagus receives dual sensory innervation, traditionally referred to as parasympathetic and sympathetic, that regulates glandular secretion, blood vessel caliber, and the activity of striated and smooth muscle. The parasympathetic nerve supply originates from the nucleus ambiguus and dorsal motor nucleus (DMN) of the vagus nerve and provides motor innervation to the esophageal muscular coat and secretomotor innervation to the glands. The sympathetic nerve supply comes from the cervical and thoracic sympathetic chain (spinal segments T1 to T10) and regulates blood vessel constriction, esophageal sphincter contractions, relaxation of the muscular wall, and increases in glandular and peristaltic activity. The ganglia that lie between the longitudinal and circular layers of the muscularis externa form the myenteric or Auerbach plexus (developed by 9 weeks of gestation), whereas the ganglia that lie in the submucosa form the submucosal or Meissner plexus (developed by 13 weeks of gestation).
Esophageal anatomic variations from normal were discussed with the development of the esophagus. TEF, esophageal stenoses and atresia, and congenital webs were explained previously, but there are other abnormalities that may occur. Rings and webs are common structural abnormalities in the esophagus. An esophageal ring is a concentric, smooth, thin (3 to 5 mm) extension of normal esophageal tissue usually consisting of three anatomic layers of mucosa, submucosa, and muscle. The Schatzki ring (type B) is a mucosal ring at the squamocolumnar junction that results in solid food dysphagia, the severity of which depends on the degree of narrowing. Hiatal hernia, GER, and eosinophilic esophagitis have been associated with Schatzki rings. The muscular ring (type A) is a high-pressure zone of smooth muscle hypertrophy, about 2 cm proximal to the squamocolumnar junction. The type C ring is an indentation caused by the diaphragmatic crura and is not symptomatic. Esophageal webs are thin, 2- to 3-mm membranes of normal esophageal tissue that can protrude or obstruct the esophagus. They are usually located in the upper third of the esophagus and may result from iron deficiency (Plummer-Vinson), in which case they usually resolve with iron replenishment, although many are ruptured at the time of esophagogastroduodenoscopy (EGD). Diverticula incorporate all layers of the esophagus and are of variable etiology. Pulsion (epiphrenic) diverticula occur in the distal third of the esophagus and are usually caused by motor disorders such as diffuse esophageal spasm or achalasia; such a diverticulum is a contraindication to pneumatic dilation. Traction diverticula, due to traction from a mediastinal lymph node usually in tuberculosis or histoplasmosis, occur in the middle third and are rare in childhood. Pseudodiverticula occur rarely, as does Zenker’s diverticulum, which is not a true diverticulum but a pressure-induced outpouching resulting from incoordination between pharyngeal contraction and relaxation of the upper esophageal sphincter as it passes through the cricopharyngeus muscle. The outpouching may become large enough extrinsically to compress the esophageal lumen, and it is important not to enter it accidently on endoscopic esophageal intubation as, unlike other diverticula, it is made up only of mucosa and is therefore easily perforated. Occasionally esophageal polyps can occur, which are either benign or inflammatory.