Pathophysiology of gastroesophageal acid reflux (gerd)

Pathophysiology:

 GER is a multifactorial process where gastric contents are allowed to re-enter the esophagus. Three main etiological processes have been described:  – transient relaxation of the lower esophageal sphincter (TRLES);  – hypotonic or incompetent LES; and – anatomic disruption of the esophagogastric junc-tion (EGJ) [as in hiatal hernia]. The consequence of these processes is reflux of gastric contents into the esophagus; in-sufficient esophageal clearance and buffering of the refluxate; and abnormalities in epithelial restitution and repair. By its very nature, the physical barrier between the esophagus and stomach is imperfect and multiple episodes of reflux occur in healthy subjects every day. However, the protective function of this specialized area of digestive anatomy exists in its ability to limit the frequency of reflux episodes, to modulate the circumstances in which acidic gastric content is allowed to reflux back into the esophagus, and to minimize esophageal acid contact time.( Orlando RC.,2001)

1-Transient Relaxation of the Lower Esophageal Sphincter (LES) The LES is a band of specialized smooth muscle found in the terminal few centimeters of the esophagus. Unlike the esophagus, which contracts briefly during swallowing, the LES maintains a sustained state of contraction, acting as a physical barrier and preventing reflux of gastric contents.( Harnett KM, , et al  2005)

The resting tone of the LES is approximately 10–30 mmHg above gastric and esophageal luminal pressures TRLESs are sponta-neous, vagally induced, abrupt decreases in LES pressure un-related to the act of swallowing. In contrast to swallow-induced relaxations of the LES, which usually last 6–8 seconds, TRLESs are longer in duration, typically lasting more than 10 seconds. Furthermore, they are generally defined as having a nadir pressure £2 mmHg. TRLESs are primarily triggered by gastric distension and are therefore seen more frequently in the postprandial state. Overall, TRLES constitutes the major mechanism under-lying GER.( Mittal RK,, 1995)

In GERD, studies show that not only is there an increase in the frequency of TRLES, but there is also an increase in the amount of reflux during these episodes and an increase in the duration of the reflux episode.This prolonged period of reflux allows for longer contact time of acidic gastric contents with the esophageal epithelium resulting in tissue injury. Emerging evidence shows that as the severity of GERD increases, TRLES progressively gives way to other mechanisms that further potentiate LES dysfunction and disease progression.( Orlando RC,2001)

2 Hypotensive or Incompetent LES The neuromuscular mechanisms that regulate the LES are not well understood. The LES maintains a contracted state at rest, transiently relaxing to allow passage of a bolus from the esoph-agus. It is postulated that the LES tone is spontaneous and myogenically regulated, whilst LES relaxation and esophageal contraction are neurally induced (Biancani P, et al ,2006) Orlando describes a hypotensive LES as having a pressure of <10 mmHg, and an in-competent sphincter as having a pressure of <4 mmHg. Episodes of abrupt increases in intra-abdominal pressure, such as that which occur during physical activity, coughing or bending over, result in free reflux if the LES has abnormally low tone. Dys-function of the LES in this setting is now considered to be a secondary motor abnormality that occurs because of impaired neural signaling.( Rieder F,, et al , 2007)

Two distinct intracellular pathways are involved in LES circular smooth muscle contraction. The first is a protein kinase C-dependent pathway activated by exposure to low levels of agonists, such as arachidonic acid, prostaglandin F2, and thromboxane A2, that is dominant during maintenance of spontaneous tone. The second is a Ca++-calmodulin-myosin light chain kinase-dependent pathway that is activated in response to maximally effective doses of agonists, such as acetylcholine, during the initial phase of esophageal contraction. (Biancani P, et al ,2006)

It is the amount of intracellular Ca++ available for contraction, mediated in part by agonist-induced activity of phospholipase C, that de-termines which pathway will be activated.Damage to the esophageal epithelium initially results in the release of specific inflammatory mediators such as substance-P and platelet-activating factor (PAF).( Cheng L, 2005)These mediators diffuse into the surrounding smooth muscle and induce an overproduction of additional inflammatory mediators and re-active oxygen species, such as interleukin (IL)-6, IL-8, and hydrogen peroxide (H2O2). In animal models, PAF has been shown to reduce LES tone and stimulate further release of H2O2. H2O2 appears to affect esophageal neurons and signal transduction, resulting in impairment of LES-sustained con-traction. Furthermore, H2O2 increases production of PAF and inhibits Ca++ adenosine triphosphatase (ATPase) activity, de-pleting releasable intracellular Ca++ stores and further im-pairing LES contractile ability. ( Cheng L, 2005) This establishes a pro-inflammatory feedback loop resulting in further mucosal injury and reduction in esophageal sphincter tone. This spiral of events may lead to permanent impairment of LES tone and lower esophageal peristalsis.( Rieder F,2010)

3 The Esophagogastric Junction The EGJ represents an anatomical distinction separating the esophagus from the stomach and provides a physical barrier to reflux of gastric contents. Structural components that are in-tegral to this barrier include the LES, the crural diaphragm, the phrenoesophageal ligament, the acute angle of His, the mucosal rosette (the circumferential clustering of mucosal folds at the EGJ) and the intra-abdominal segment of the EGJ (the portion situated below the diaphragmatic plane). (Rieder F,2010) Anatomical dis-ruption of the EGJ has been considered a risk factor for the development of GERD, although the exact relationship of these anatomical factors and how they affect TRLES has not been thoroughly explored. The most common abnormality of the EGJ that has been associated with GERD is a hiatus hernia. Hiatal herniae are re-ported to increase the frequency of reflux events through reduc-tions in LES pressure and increases in strain-associated episodes of reflux. Moreover, they have also been shown to delay esophageal clearance of refluxate.( Kahrilas PJ,2000) It is postulated that a hiatal hernia alters the angle of the cardia and allows the gastric wall tension to pull open the LES even if the LES is itself anatomically normal.Adult studies have further shown that the size of the hiatal hernia has a strong correlation with LES dysfunction and impaired EGJ barrier function and that there is an increase in TRLES frequency induced by gastric distension.  Another possible cause of EGJ disruption is esophageal shortening, which has been shown in animal models to occur as a result of increased contractility of esophageal longitudinal smooth muscle.( Dunne DP,,2000) Mucosal acid-induced injury appears to trigger mast-cell degranulation and histamine release that re-sults in this smooth muscle contraction. These findings raise the possibility that the hiatal hernia may occur secondary to acid-related mucosal injury and progressive esophageal shortening. However, over time, the development of the hernia could clearly contribute to the worsening of GERD. In children, special consideration needs to be given to individuals with other conditions that have the potential to disrupt normal esophageal and EGJ function, such as neuro-logical impairment, obesity, and repaired esophageal atresia or diaphragmatic hernia. (Ruigo´ mez A,,2010)