Pathophysiology of Gastroesophageal Reflux

Embryology of the Aerodigestive Apparatus

Embryologic origins and the neuroanatomic relationships between the airway and foregut are intricate and develop from adjacent segments of the primitive foregut ( Fig. 161.1 ). The tracheobronchial diverticulum, the pharynx, the esophagus, the stomach, and the diaphragm are all derived from the primitive foregut and/or its mesenchyme and share similar control systems. By 4 weeks of embryonic life, tracheobronchial diverticulum appears at the ventral wall of the foregut, with left vagus nerve being anterior and right vagus being posteriorly located. The stomach is a fusiform tube with the dorsal side growth rate greater than the ventral side, thus creating greater and lesser curvatures. At 7 weeks of embryonic life, the stomach also rotates 90 degrees clockwise, with the greater curvature displaced to the left. The left vagus innervates the stomach anteriorly, and the right vagus innervates the posterior aspect. At 10 weeks, the esophagus and the stomach are properly positioned; the circular and longitudinal muscle layers and the ganglion cells are in place. The true vocal cords begin as glottal folds. By the sixth or seventh week of gestation, a structure superior to the true vocal cords evolves to protect the vocal cords and lower airway. This superior structure consists of the epiglottis, aryepiglottic folds, false vocal cords, and the laryngeal ventricles. The epiglottis starts as a hypobranchial eminence behind the future tongue and by week 7, the epiglottis is separated from the tongue. At the same time, two lateral folds connect to the base of the epiglottis, which develop into the arytenoids cartilages at the distal end. The larynx begins as a groove in the primitive foregut, which folds upon itself to become the laryngotracheal bud, the subsequent divisions of which form the bronchopulmonary segments. From this phase, 20 generations of conducting airways form. The first 8 generations constitute bronchi and acquire cartilaginous walls; the next 9 to 20 generations comprise the nonrespiratory bronchioles, which are not cartilaginous and contain smooth muscle. Subsequent divisions form the bronchopulmonary segments.

Thus, congenital anomalies of the aerodigestive tract and gastroesophageal junction can result in situations predisposing to GER. Such conditions may include but are not limited to craniofacial anomalies, airway anomalies, esophageal atresia and tracheoesophageal fistula, congenital diaphragmatic hernia, hiatal hernia, abdominal wall defects, malrotation, atresias, and duplication of the small intestine.

Neuromuscular Components of Gastroesophageal Junction

The pharynx, upper esophageal sphincter (UES), and proximal esophagus are composed of striated muscle. The distal esophagus and the lower esophageal sphincter (LES) are composed of smooth muscle with an inner layer consisting of circular muscle cells and an outer layer consisting of longitudinal muscle cells with a myenteric plexus in between. The UES high-pressure zone is a constriction between the pharynx and the proximal esophagus generated by the cricopharyngeus (the principal muscle), proximal cervical esophagus, and inferior pharyngeal constrictor. The LES is an autonomous sphincter composed chiefly of circular smooth muscle; the integrity of the gastroesophageal junction is further augmented by (1) diaphragmatic crural fibers and (2) the intraabdominal part of esophagus and sling fibers of the stomach. The UES is innervated by (1) the vagus via the pharyngoesophageal, superior laryngeal, and recurrent laryngeal branches; (2) the glossopharyngeal nerve; and (3) sympathetic nerve fibers via the cranial cervical ganglion. The LES is an autonomous contractile apparatus that is tonically active and relaxes periodically to facilitate bolus transit. Although the LES is considered to be an important functional segment in preventing GER, other neighboring structures including oblique sling fibers of the stomach, the musculofascial diaphragmatic sling, and intraabdominal esophagus also contribute to this function.

The musculature of the larynx is derived from the mesenchyme of the fourth and sixth pharyngeal arches. Laryngeal muscles are innervated by branches of the tenth cranial nerve. The superior laryngeal nerve innervates the derivatives of the fourth pharyngeal arch (cricothyroid, levator palatini, and constrictors of pharynx), and the recurrent laryngeal nerve innervates derivatives of the sixth pharyngeal arch (intrinsic muscles of the larynx).

The airways and esophagus share common innervations. ^{, ,} Foregut afferents are derived from both vagal and dorsal root ganglions with cell bodies in the nodose ganglion. This afferent apparatus conveys signals to the neurons in the nucleus tractus solitarius, located in the dorsomedial medulla oblongata. These signals are integrated in a specific terminal site of the nucleus tractus solitarius, the subnucleus centralis, which is the sole point of termination of esophageal afferents. After sensory integration in the nucleus tractus solitarius, the signals in turn activate airway motor neurons in the nucleus ambiguus and the dorsal motor nucleus of the vagus, producing an efferent parasympathetic response and or nonadrenergic, noncholinergic response mediated via vasoactive intestinal polypeptide or nitric oxide.

Thus anomalies of the aerodigestive tract and anomalies of the neuromuscular apparatus predispose one to GER and/or its consequences.

Physiology of Gastroesophageal Junction, Esophagus, and Stomach

Normally, intragastric pressure is higher and is highly variable; the gastric contractility is dependent on the phases of interdigestive motility cycle, feeding intervals, and antral contractions. This occurs regardless of the activity or sleep states. On the other hand, basal intraesophageal pressures during normal breathing reflect intrathoracic pressures; pressures are negative or more negative during inspiration and less negative or positive during expiration. Thus at rest, a pressure gradient exists between the stomach and the esophagus. In the absence of other factors, this pressure difference should propel gastric contents into the esophagus. However, the gastroesophageal junction, a tonically active high-pressure zone, acts as a protective barrier and regulates to-and-fro bolus movement between the esophagus and stomach. This high-pressure zone at the gastroesophageal junction reflects the combined activities of two sphincter subsystems: the LES and the crural diaphragm. The activities of these two subsystems are constantly changing to prevent reflux despite changes in gastric, abdominal, and thoracic pressures. The LES muscle is thicker than muscle in the more proximal esophagus or adjoining stomach and has specialized neural innervation. The myocytes of LES have unique mechanical, electrical, and neurotransmitter-related response characteristics. ^, In contrast to the adjacent esophagus, in which the plexus lies only between the circular and longitudinal muscle layers, the innervation of the LES is unique in that the myenteric plexus occupies multiple muscle planes. As shown in Fig. 161.2 , at normal tidal breathing, the high-pressure zone is characterized by a tonically elevated basal pressure contributed by intrinsic LES and respiratory-induced pressure oscillations contributed by active contractions in the diaphragmatic crura, both of which are of greater magnitude than the pressure simultaneously found in the adjacent stomach and esophagus. ^,

The crural diaphragm is distinguished from the costal diaphragm by its attachment to the vertebral column rather than the rib cage. Because the esophagus passes through the crural diaphragm, diaphragmatic contractions create an external sphincter mechanism at the gastroesophageal junction. The activity of the crural diaphragm varies with the respiratory cycle, thereby compensating for variations in thoracic and abdominal pressure that would otherwise favor GER during inspiration (see Fig. 161.2 ). Another important contributory factor to the integrity of the gastroesophageal junction comes from the smooth muscle fibers of the stomach, constituting a sling around the greater curvature of the stomach. Although they are not strictly part of the LES, the sling fibers help to prevent reflux by acting as a flap valve during fundal distension, pressing the closed end of the sling against the distal esophagus.