What is acid reflux?

Pathogenesis.
The extent and severity of esophageal injury due to GER depend on the frequency and the duration of esophageal exposure to the refluxed material, the volume and potency of gastric juice available for reflux, and the ability of the esophageal mucosa to withstand injury and to repair itself.
The pathogenesis of reflux esophagitis or GERD is a multifactorial process. The following factors all contribute to the development of GERD:
Antireflux mechanisms. A positive pressure gradient exists between the abdomen and the thorax. If there were no physiologic barrier at the area of the gastroesophageal junction, GER would occur continuously, especially with increases in intraabdominal pressure or changes in gravitational position and during events associated with abdominal muscle contraction, such as coughing, sneezing, straining, bending, turning in bed, and exercise. The antireflux barrier can be divided into two categories.
Anatomic factors extrinsic to the lower esophageal sphincter (LES) that augment the LES to prevent GER include a distal esophageal mucosal flap, the acute esophagogastric angle, compression of the esophagogastric junction by gastric sling fibers, the diaphragmatic crus acting as pinchcock, a hiatal tunnel, the sling action of the right diaphragmatic crus, and the intraabdominal junction of the esophagus. The longer the intraabdominal segment, the less likely reflux is to occur.
The presence of hiatal hernia with loss of the abdominal esophageal segment supported by the diaphragm and the normal acute esophagogastric angle may lead to GER. However, a direct causal relationship has not been found between hiatal hernia and GER. Nevertheless, a hiatal hernia generally (90%) accompanies reflux esophagitis. It is possible that hiatal hernia enhances the likelihood of LES dysfunction due to the loss of angulation at the esophagogastric junction and the direct transmission of intragastric pressure to the infrathoracic LES. Also, the hiatal hernia may act as a reservoir of refluxate and impair esophageal clearance in the recumbent position, thus promoting esophageal injury.
The closure strength and efficacy of LES
LES corresponds to the 2- to 4-cm zone of asymmetrically thickened smooth muscle at the esophagogastric junction.
LES maintains a high-pressure tone during resting conditions and relaxes with swallowing, esophageal distention, and vagal stimulation. These properties are independent of the diaphragm and persist even when the LES is in the thorax, as in patients with hiatal hernia.
LES is innervated by both excitatory and inhibitory autonomic nerves carried in the vagi to the esophageal plexuses. The major function of the LES inhibitory nerves is to mediate sphincter relaxation in response to swallowing.
LES pressure (LESP) is controlled by neural (most likely cholinergic), hormonal, and myogenic factors.
Resting LES pressure is not constant and varies from minute to minute in the awake state. During sleep, this variability is diminished.
The intrinsic tone (the resting LESP) is one of the major factors that prevent spontaneous GER.
In general, patients with GER have lower LESPs than controls. A minimum resting LESP in the range of 6 to 10 mm Hg prevents GER even during transient increases in intraabdominal pressure.
Changes in resting LES pressure occur throughout the day, especially during the postprandial period. In addition, transient episodes of LES relaxation occur not only in response to swallowing but also spontaneously, a process referred to as inappropriate LES relaxation or transient LES relaxation (TLESR). In physiologic refluxers, most reflux events occur during the relaxation events. In pathologic refluxers (i.e., patients with reflux disease), other mechanisms of reflux also occur, including gradual decreases in resting pressure and episodes of increased intragastric pressure. However, most reflux events continue to occur during TLESR.
TLESR appears to represent a physiologic response to increased gastric distention to relieve intragastric pressure.
Some GER occurs in all individuals with normal or lower-than-normal LESP throughout the day. The frequency of GER increases for 2 hours postprandially. However, patients with esophagitis have significantly more and longer episodes of GER than controls.
Low resting LESP seen in patients with esophagitis may be primary or secondary to injury from reflux and inflammation.
LESP is affected by various drugs and hormones. Avoidance of agents that decrease the LESP and use of agents that increase LESP can be helpful in diminishing GER symptoms and esophageal damage.

Gastric factors
Gastric volume
The occurrence of GER depends on an available reservoir of gastric fluid.
The probability and rate of GER are related to gastric volume.
The rate of reflux and the volume of the refluxate increase with incremental increases in gastric volume, intragastric pressure, and the pressure gradient between the stomach and the esophagus.
Gastric volume is determined by several factors.
Volume and composition of ingested materials.
Rate and volume of gastric secretion.
Rate and efficiency of gastric emptying.
Frequency and volume of duodenogastric reflux.
One or more of the factors in d that favor an increase in gastric volume also favor the occurrence of GER.
Pyloric channel or duodenal ulcers may result in delayed gastric emptying and predispose to increased GER and GERD.
Delayed gastric emptying due to neuromuscular abnormalities such as in collagen vascular diseases, diabetes mellitus, and hypothyroidism or mechanical gastric outlet obstruction may also predispose to GERD.

Irritant potency of the refluxed material
The composition of the material refluxed into the esophagus is important in determining the nature and extent of esophageal injury.
Gastric acid causes esophageal injury by protein denaturation and back diffusion of hydrogen ion into deeper layers of the esophageal wall to cause deeper injury.
Pepsin, a protease, digests esophageal epithelial intercellular substance, causing shedding of epithelial cells.
Duodenogastric reflux, especially postprandially, introduces bile salts and pancreatic enzymes into the stomach, which may then reflux into the esophagus. Bile salts may result in micellar dissolution of the lipids in the esophageal epithelial cell membranes and increase the permeability of the esophageal mucosa to hydrogen ion back diffusion. Pancreatic enzymes may cause proteolytic injury.
Pancreatic digestive enzymes and bile salts may be the significant agents of esophageal injury in patients with gastric hypochlorhydria and near-neutral pH.

Esophageal clearance
The severity of esophageal injury from GER depends on the irritant potency of the refluxed material and its contact time with the esophagus.
The rate of esophageal clearance determines the duration of the exposure of the esophageal mucosa to the refluxed material.
Esophageal clearance of the refluxed material involves three mechanisms:
Volume clearance involves the emptying out of the esophagus of the volume of the refluxed material. It is facilitated by gravity, esophageal motor activity, and salivation.
Normal esophageal motor activity (peristalsis) is required for esophageal clearance.
Primary peristalsis is initiated by swallowing, and the contraction wave progresses in a sequential fashion throughout the entire length of the esophagus, resulting in esophageal emptying into the stomach. Normally, primary peristalsis occurs about once a minute while an individual is awake. It is the main esophageal motor event that clears the esophagus of refluxed material. The absence of swallowing and esophageal peristalsis during sleep impedes esophageal clearance of refluxed material and predisposes to esophageal injury. Similarly in patients with abnormal esophageal motility, increased nonperistaltic contractions lead to increased reflux injury to the esophagus.
Secondary peristalsis is elicited with distention of the esophagus by a bolus of food or refluxed fluid. It has a limited effect on volume clearance, because it does not result in a complete stripping peristaltic wave.
Acid clearance involves the disappearance of the hydrogen ion from the esophageal mucosa after the reflux of acid fluid. It is accomplished by a neutralizing action of swallowed saliva.
Saliva is the third factor that contributes to esophageal clearance.
Normal awake individuals generate 0.5 mL of saliva per minute.
Salivation stops during sleep.
Salivation stimulates swallowing.
Stimuli that increase salivary secretion include sucking, eating, intubation, and cholinergic agents.
Under basal conditions, saliva has a pH of 6 to 7 due to the presence of bicarbonate ion as the major buffer.
During stimulation, both the salivary volume and the bicarbonate ion concentration increase.
Normal salivary flow effectively neutralizes small volumes (-1 mL) of refluxed acid.
Salivation, by promoting swallowing and primary stripping peristalsis, clears the esophagus of the main volume of the refluxed material. Subsequently saliva itself clears the acid from the esophageal mucosa by its neutralizing action.
Diminished salivation, primary (e.g., in Sjogren's syndrome) or secondary (e.g., due to anticholinergic drugs), causes delayed acid clearance and promotes esophageal injury.

Tissue resistance of the esophageal mucosa.
The esophageal mucosa itself has intrinsic protective mechanisms that resist and limit mucosal injury.
Preepithelial defenses
The luminal surface of esophageal epithelium is lined by a layer of mucus that serves as both a lubricant and a protective barrier against noxious and irritant luminal contents. This viscous gel layer prevents large protein molecules like pepsin from contacting the underlying epithelium directly and slows down hydrogen ion back diffusion.
Underneath the mucous layer, there is an area of low turbulence called the unstirred water layer, which is rich in bicarbonate. This layer establishes a protective alkaline microenvironment on the epithelial surface, neutralizing the hydrogen ion that penetrates the mucous layer.
Mucus and bicarbonate are secreted by salivary glands and submucosal glands located just below the upper esophageal sphincter and near the esophagogastric junction. The rate of secretion of these glands increases with vagal stimulation and with prostaglandins.
Postepithelial defenses. As in all tissues, adequate blood flow and normal tissue acid-base status are essential for the maintenance of a healthy epithelium. Blood flow provides the epithelium with oxygen, nutrients, and bicarbonate (HCO3-) as buffer and removes injurious waste products.

Epithelial regeneration.
Despite the intrinsic ability of the esophageal mucosa to resist injury, prolonged exposure to noxious substances results in epithelial cell necrosis. Cell death further increases epithelial permeability, setting up a vicious circle for further damage. The replicating cells of the stratum basale along the basement membrane need to be protected for epithelial regeneration. The destruction of this layer appears to be necessary for the development of esophageal ulcers, strictures, and Barrett's epithelium. There is evidence that epithelial cell turnover and replication is increased after hydrogen (H+) injury. Basal cell hyperplasia seen in mucosal biopsies of patients with reflux esophagitis lends further support to this finding. Normal turnover rate for esophageal epithelium is 5 to 8 days. This rate seems to be increased to 2 to 4 days with injury. This will allow for epithelial renewal and repair in a short time if further injury is prevented.

Prevention of retrograde flow of gastrointestinal contents is a major function of the lower esophageal sphincter (LES) . Retrograde flow is prevented by the lower esophageal sphincters, which remain closed between swallows.
The lower esophageal sphincter is composed of smooth muscle and is innervated by parallel sets of parasympathetic excitatory and inhibitory pathways. It remains closed because of its intrinsic myogenic tone, which is modulated by the excitatory and inhibitory nerves. It opens in response to the activity of the inhibitory nerves. The neurotransmitters of the excitatory nerves are acetylcholine and substance P, and those of the inhibitory nerves are vasoactive intestinal peptide (VIP) and nitric oxide. The function of the LES is supplemented by the striated muscle of the diaphragmatic crura, which surrounds the LES and acts as an external LES. Relaxation of the LES without esophageal contraction occurs during belching and gastric distention. Gastric distention-evoked transient lower esophageal sphincter relaxation (tLESR) is a vasovagal reflex. Fatty meals, smoking, and beverages with a high xanthine content (tea, coffee, cola) also cause a reduction in sphincter pressure. Many hormones and neurotransmitters can modify LES pressure. Muscarinic M2 and M3receptor agonists, a-adrenergic agonists, gastrin, substance P, and prostaglandin F2acause contraction. Nicotine, b-adrenergic agonists, dopamine, cholecystokinin, secretin, VIP, calcitonin gene-related peptide (CGRP), adenosine, prostaglandin E, and nitric oxide donors such as nitrates reduce sphincter pressure.

Several factors must work in concert to produce clinical effects of esophageal reflux. Normal subjects may have a few short-duration reflux episodes postprandially and in the upright position. Those in whom reflux has produced symptoms or pathologic changes will demonstrate more frequent and prolonged episodes of reflux, which also tend to occur at night. The factor or factors that cause this difference are not entirely known. However, important differences between persons with and without reflux might help explain these findings.

The LES is a specialized bundle of circular muscle at the lower end of the esophagus with different physical and pharmacologic characteristics when compared with the circular muscle above and below it. Although mean LES pressure is significantly lower in subjects with GERD than in normal persons, much overlap occurs between the groups; LES pressure is not very useful in predicting whether reflux is present in an individual patient unless the pressure is very low. The most common event associated with reflux appears to be a transient relaxation of the LES unassociated with either swallowing or the distention of the esophageal body by refluxed fluid. Thus, two abnormalities of LES may be associated with reflux: a sphincter with very low tone, as measured by LES pressure, or inappropriate relaxation of a normally competent sphincter.

Several factors are important in removing refluxed material from the esophagus. The upright position facilitates esophageal emptying by gravity. Peristaltic waves initiated by swallowing or by esophageal distention help remove the refluxed material. Acid placed within the esophagus is cleared less well by patients with GERD than by normal subjects, although the manometric tracings seen in both groups seem identical. Clearing of acid regurgitation occurs in two phases: the bulk of the fluid is returned to the stomach by a peristaltic contraction, and the remaining acid film clinging to the esophageal wall is neutralized by swallowed saliva.

The composition and perhaps the quantity of the refluxed material also play a role in the production of GERD. Gastric acid and pepsin seem clearly important in the pathogenesis of GERD. Bile salts, and possibly pancreatic enzymes, may be responsible in patients in whom acid is absent. The combination of bile salts plus acid is more injurious to the esophagus than either agent alone. Other less well-studied factors, such as altered or abnormal esophageal mucus, swallowed saliva of high bicarbonate content, and diminished resistance of the esophageal mucosa to digestion, may be important in determining the amount of mucosal damage in GERD.

Esophageal squamous epithelium reacts to reflux by an increase in the basal cell or germinative layer. The dermal pegs are increased in height and may become more vascular. If the process becomes more severe, the epithelial layer is destroyed, with the appearance of micro-ulcers and classic signs of inflammation in the lamina propria, such as infiltration with polymorphonuclear leukocytes and edema. Even deeper lesions cause first submucosal and then muscular inflammation and fibrosis, resulting in an esophageal stricture. Why reflux is so common, yet inflammation and stricture formation are relatively uncommon, is not known.

Reflux during pregnancy, once thought to be due to the increased abdominal pressure from the fetus, may be due mainly to diminished LES strength caused by increased estrogen and progesterone. Weight gain also tends to aggravate reflux through an unknown mechanism. Resection of the lower esophageal area for cancer or myotomy for achalasia can lead to severe postoperative reflux. Gastroesophageal reflux with stricture formation is especially severe in patients with progressive systemic sclerosis.

The crural diaphragm usually wraps around the gastroesophageal junction to augment the intrinsic LES. In a hiatal hernia, an anatomic displacement of the LES and crural diaphragm is seen. Although hiatal hernias may be associated with reflux, the presence of a hiatal hernia is now considered to be much less of a factor in GERD than previously thought, because it is present in a large percentage of normal subjects. It is not appropriate to spend time trying to define whether a hiatal hernia is present or absent in dealing with most patients with GERD; rather, the focus should be on the symptoms of reflux.

Factors related to the Stomach:
Stomach factors (particularly stomach content's volume and certain aggressive factors found in the refluxate) are potentially important in the production of reflux esophagitis. Stomach volume is determined by the basal acid secretion rate, concomitant H pylori infection, duodenogastric reflux, and the rate of stomach emptying. Increased stomach volume not only provides more stomach contents available for reflux, but also increases the rate of transient LESRs.

Stomach Acid Secretion

The primary importance of stomach acid is indisputable in the production of reflux esophagitis, but its mechanism may involve activation of pepsin rather than direct damage from acid alone. In animal studies, acid causes minimal injury at a pH of less than 3.0, primarily by protein denaturation. However, the combination of acid and even small amounts of pepsin disrupts the mucosal barrier resulting in increased H + permeability, histological changes, and gross hemorrhage. Complementing the animal studies, a series of clinical reports showed that patients with various grades of esophagitis, including Barrett esophagus, have increased frequency and duration of esophageal exposure to Stomach refluxate of pH lower than 4. Conversely, perfusing the esophagus of animals with a pepsin solution of pH 7.5 produces minimal mucosal disruption or changes in permeability. These observations are the cornerstone of acid suppressive therapy in the treatment of GERD.

Some studies have suggested that patients with reflux, especially those responding poorly to conventional antisecretory therapy, may have higher rates of acid secretion than controls. However, most evidence finds no abnormality of Stomach acid secretion in patients with GERD. Factors that reduce Stomach acid secretion naturally, for example, concomitant infection with H pylori, especially if it is the cagA + virulent strain, may protect from the development of severe esophagitis and Barrett esophagus. H pylori infection, particularly infection with this virulent strain, is a biologic antisecretory agent that lowers Stomach acidity. It produces severe corpus gastritis and accelerates the progression to multifocal atrophic gastritis and intestinal metaplasia, with concomitant lower acid output. In addition, the bacteria produce ammonia that acts as a powerful neutralizing agent at elevated pH conditions. The corpus mucosa returns to normal when the H pylori infection is cured, increasing acid secretion and possibly contributing to the reports of esophagitis after successful treatment of H pylori infection. The consequences of long-term normalization of parietal cell function and return to higher intragastric acidity is unknown, but they could promote the development of more severe GERD, Barrett esophagus, and adenocarcinoma in Western populations.

Duodenogastric Reflux

Bile acids have been implicated in the development of esophagitis, especially in the presence of increased duodenogastric reflux. Studies in animals demonstrate that conjugated bile acids produce their greatest injury in the presence of acid and pepsin, whereas trypsin, deconjugated bile salts, are more damaging in the absence of acid. Several surgical reports have suggested that duodenogastric reflux into the esophagus is frequent and may predispose to complications of GERD. However, accurate measurement of duodenogastric reflux is difficult. Duodenogastric reflux may be indirectly estimated by ambulatory pH studies using an esophageal pH of less than 7 to indicate alkaline reflux. However, the reliability of this indirect marker is now questioned by newer techniques, which either spectrophotometrically measure bilirubin, the most common pigment in bile, or measure esophageal impedance of the flow of liquids and gases independent of pH. These studies show that acid reflux and bile reflux increase together across the spectrum of GERD, making it nearly impossible to incriminate one agent over the other in the development of esophagitis. In addition, aggressive acid suppression with proton pump inhibitors (PPIs) decreases both acid and duodenogastric reflux probably by decreasing the volume of Stomach contents available to reflux into the esophagus. Finally, the absence of membrane microvesiculation and intracellular bile deposits in human esophageal biopsies, two distinctive morphologic features of experimental acid-bile salt injury, also argue against an important role for bile salts in GERD.

Delayed Stomach Emptying

The importance of delayed Stomach emptying in the pathogenesis of GERD is controversial. Early studies observed a delay in the Stomach emptying of solids in up to 50% of patients with reflux. More recent studies found only a 6% to 38% rate of delayed Stomach emptying, regardless of the severity of the esophagitis. Nevertheless, delayed Stomach emptying may be a major factor contributing to GERD in some groups, such as diabetic patients with autonomic peripheral neuropathy.

Associated Conditions

Certain medical and surgical conditions can predispose a person to GERD. The most common is pregnancy; 30% to 50% of pregnant women complain of heartburn, especially in the first trimester. Pregnancy increases the risk for reflux by the relaxing effects of circulating estrogens and progesterones on LES pressure. Although symptoms may be severe, esophagitis is uncommon, and this type of “situational” GERD is cured with childbirth.

Up to 90% of patients with scleroderma have GERD as the result of smooth muscle fibrosis causing low LES pressure and weak or absent peristalsis. Severe disease is common; up to 70% of patients have esophagitis, many have peptic strictures, and Barrett esophagus and carcinoma of the esophagus have been reported.

Unlike the previous two conditions that are characterized by LES dysfunction, hypersecretion of acid and increased Stomach volume are the major factors causing GERD in patients with the Zollinger-Ellison syndrome. In these patients, the esophagitis and complications may be more difficult to treat than the ulcer disease. After Heller myotomy, 10% to 20% of patients may develop GERD. Finally, prolonged nasogastric intubation may contribute to the development of reflux esophagitis, in part because acid tracks orad along the tube and because the tube mechanically interferes with LES barrier function.

Esophageal Acid Clearance
The second tier against reflux damage is esophageal acid clearance. Reflux events determine the frequency and extent that gastric contents enter the esophagus, but esophageal acid clearance time determines the duration the mucosa is exposed to acid and probably the severity of acid damage. Esophageal acid clearance involves two related but separate processes: volume clearance, which is the actual removal of the reflux material from the esophagus, and acid clearance, which is the restoration of normal pH in the esophagus after acid exposure through titration with base, rather than true removal of the refluxed material.
Volume Clearance
Esophageal peristalsis operates to clear the acid volume in both the upright and supine positions, but it is inoperative during deep rapid eye movement sleep. Primary peristalsis is elicited by swallowing, which occurs with a frequency of once per minute in awake subjects, regardless of whether reflux occurs. Secondary peristalsis, initiated by esophageal distention from acid reflux, is much less effective in promoting clearance of refluxate, thus offering only an ancillary protective role. Peristaltic dysfunction, that is, failed peristaltic contractions and hypotensive (<30 style="font-style: italic;">Salivary and Esophageal Gland Secretions
Saliva is the second essential factor required for normal esophageal clearance of acid. Saliva has a pH of 6.4 to 7.8 and therefore is a weak base compared with the acidic gastric contents. The high rate of spontaneous swallowing results in saliva production of approximately 0.5 mL per minute. Although saliva is ineffective in neutralizing large volumes of acid (5 to 10 mL), it can neutralize small residual amounts of acid remaining in the esophagus after the volume of refluxed material has been cleared by several peristaltic contractions The importance of swallowed saliva is supported by findings that increased salivation induced by oral lozenges or bethanechol is associated with a significant decrease in acid clearance time. In contrast, suction aspiration of saliva is accompanied by a marked prolongation of esophageal clearance, despite the presence of normal peristaltic contractions. Physiological or pathological compromises of salivation may contribute to GERD. Diminished salivation during sleep explains why nocturnal reflux episodes are associated with markedly prolonged acid clearance times. Similarly, chronic xerostomia is associated with prolonged esophageal acid exposure and esophagitis. Cigarette smoking may promote GER. This was originally attributed to the effects of nicotine on lowering LES pressure, but more recent studies suggest that cigarette smokers have hyposalivation, which may also prolong esophageal acid clearance. Finally, the esophagosalivary reflex may be impaired in patients with reflux esophagitis. This is a vasovagal reflex demonstrated by perfusing acid into the esophagus, thereby stimulating increased salivation. This reflex may explain the symptoms of water brash (copious salivation) observed in some patients with reflux disease. The esophagosalivary reflex is very active in healthy persons, with a doubling or tripling of the salivary flow rate on exposure to acid. However, this reflex is diminished in patients with esophagitis and in those with strictures. In addition to the role of saliva, dilution and neutralization of residual acid are achieved by the aqueous bicarbonate (HCO 3 -)-rich secretions of the esophageal submucosal glands. These glands have been identified in the opossum as well as in the human esophagus. Reflux of acid into the esophageal lumen stimulates these glands and helps to neutralize the acid, even if swallowing does not occur.

Tissue Resistance
Although clearance mechanisms minimize acid contact time with the epithelium, even healthy persons may have their esophagus exposed to acid 1 to 2 hours during the day and sometimes at night. Nevertheless, only a few persons experience symptomatic GER, and even fewer suffer GERD. This is the result of a third tier for esophageal defense, known as tissue resistance. Tissue resistance is not a single factor, but a group of dynamic mucosal structures and functions that interact to minimize mucosal damage from the noxious gastric refluxate. Conceptually, tissue resistance can be subdivided into preepithelial, epithelial, and postepithelial factors.
The preepithelial defense in the esophagus, in contrast to the stomach and duodenum, is poorly developed. There is neither a well-defined mucous layer nor a buffering capacity by the surface cells to secrete HCO 3 - into the unstirred water layer. This results in a lumen-to-surface pH gradient in the esophagus of 1:10, in contrast to the stomach and duodenum, where the gradient can range from 1:1000 to 1:10,000.
The epithelial defenses in the esophagus consist of both structural and functional components. Structural components include the cell membranes and intercellular junctional complexes of the esophageal mucosa. This structure is a 25- to 30-cell-thick, nonkeratinized squamous epithelium functionally divided into a proliferating basal cell layer (stratum basalis), a midzone layer of metabolically active squamous cells (stratum spinosum), and a 5- to 10-cell-thick layer of dead cells (stratum corneum). The esophageal mucosa is a relatively “tight” epithelium with resistance to ionic movement at the intercellular as well as the cellular level as the result of both tight junctions and the matrix of lipid-rich glucoconjugates in the intercellular space. The functional components of tissue resistance include the ability of the esophageal epithelium to buffer and extrude hydrogen ions (H +). Intracellular buffering is accomplished by negatively charged phosphates and proteins, as well as HCO 3 -. When the buffering capacity is exceeded and intracellular pH falls, it has the capacity actively to remove H + from the cells. This is possibly by the action of two transmembrane proteins, one a sodium (Na +)/H + exchanger and the other a Na +-dependent chloride (Cl -)/HCO 3 - exchanger. After reflux-induced cell acidification, these transporters restore the intracellular pH to neutrality by exchanging H + for extracellular Na + or by exchanging Cl - for extracellular HCO 3 -, respectively. Additionally, esophageal cells contain within their membrane a Na +-independent Cl -/HCO 3 - exchanger that extrudes HCO 3 - from the cytoplasm when the intracellular pH is too high. When the epithelial cells are no longer able to maintain intracellular pH, they lose their ability to regulate volume, edema occurs, and balloon cells develop.
The postepithelial defense is provided by the esophageal blood supply. Blood flow delivers oxygen, nutrients, and HCO 3 - and removes H + and carbon dioxide, thereby maintaining normal tissue acid-base balance. Blood flow to the esophageal mucosa increases in response to the stress of lumenal acid. Cellular injury also stimulates cell proliferation, which results in thickening of the basal cell layer of the epithelium. Unlike the stomach, in which superficial mucosal injury is repaired in hours, the esophagus repairs itself more slowly over days to weeks.

The relationship between hiatal hernia and GERD remains controversial. Mainstream opinion has shifted widely from one that virtually equated hiatal hernia with GERD to one that denied it a causal role. Currently, both epidemiologic and physiological data confirm the importance of the hiatal hernia in patients with more severe esophagitis, peptic stricture, or Barrett esophagus. Hiatal hernias, identified endoscopically or radiologically, are reported in 54% to 94% of patients with reflux esophagitis; a rate strikingly higher than in the healthy population.
The functional impact of the hiatal hernia has been clarified by elegant combined manometry and videofluoroscopic studies that show that hiatal hernia impairs LES function through several mechanisms as well as impairing esophageal clearance. Reflux is worse in patients who have a nonreducible as opposed to a reducible hiatal hernia. Nonreducing hernias are those in which the gastric rugal folds remain above the diaphragm between swallows. Furthermore, statistical modeling has revealed a significant interaction between hiatal hernia and LES pressure, such that the likelihood of GER is increased as basal LES pressure decreases, an effect that is substantially amplified by the presence of a hiatal hernia and as hernia size increases.
Displacement of the LES from the crural diaphragm into the chest reduces basal LES pressure and shortens the length of the high-pressure zone primarily because of the loss of the intra-abdominal LES segment. Both these effects are caused by the loss of the extrinsic support of the diaphragmatic crura resulting in increased GER. Hiatal hernia virtually eliminates the increase of LES pressure that occurs during straining and may increase the triggering of transient LESRs during gastric insufflation with gas. , Large, nonreducible hernias also impair esophageal acid clearance because of increased tendency for reflux to occur from the hernia sac during swallow-induced LESRs.
The origin of hiatal hernia remains unclear. Familial clustering of GERD suggests the possibilities of inherited muscle weakness in this area. Animal studies propose that reflux itself causes esophageal shortening promoting the development of a hiatal hernia. Other studies find an association with obesity and lifting of heavy weights, raising the possibilities that over time, chronic intra-abdominal stressors may weaken the esophageal hiatus and may cause the development of a hiatal hernia. This theory is attractive because it helps to reconcile the increased prevalence of hiatal hernias as the population ages.

Mechanisms of Reflux
Transient Lower Esophageal Sphincter Relaxations
This is the most common mechanism underlying GER and also accounts for the reflux of gases during belching. Transient LESRs are not associated with antecedent pharyngeal contractions, are unaccompanied by esophageal peristalsis, persist for longer periods (>10 seconds) than swallow-induced LESRs, and are always accompanied by inhibition of the crural diaphragm. Transient LESRs account for nearly all reflux episodes in healthy persons and for 50% to 80% in patients with GERD, depending on the severity of associated esophagitis. However, one study suggested that low basal LES pressure, rather than transient LESRs, may be the primary mechanism of GER in patients with nonreducible hernias. Transient LESRs are not always associated with GER. In healthy persons, about 40% to 60% of transient LESRs are accompanied by reflux episodes, compared with 60% to 70% in patients with GERD. The rate of transient LESR is increased by gastric distention, whether by gas or a meal, by stress, and, to a lesser extent, by subthreshold (for swallowing) stimulation of the pharynx. Under normal circumstances, meals are the major stimuli for transient LESRs, but the importance of specific foods is unknown. Transient LESRs are inhibited by the supine position, sleep, general anesthesia, and vagal cooling. Various drugs also impair transient LESRs including cholecystokinin A antagonists, anticholinergic drugs, morphine, somatostatin, nitric oxide inhibitors, 5-hydroxytryptamine 3 (5-HT 3) antagonists, and d-aminobutyric acid B (GABA B) agonists. Current evidence indicates that transient LESRs are mediated through vagal pathways. Gastric distention activates mechanoreceptors in the proximal stomach adjacent to the gastric cardia that send signals to the brainstem center through vagal afferent pathways. The structured sequence of motor events including LESR, inhibition of the crural diaphragm, and contractions of the esophageal body suggest that this process occurs in a programmed manner, probably controlled by a pattern generator within the vagal nuclei. The motor arm is in the vagus nerve and shares common elements with swallow-induced LESR.
Swallow-Induced Lower Esophageal Sphincter Relaxations
About 5% to 10% of reflux episodes occur during swallow-induced LESRs. Most of these episodes are associated with defective or incomplete peristalsis. During a normal swallow-induced LESR associated with normal peristalsis, reflux is uncommon because of the absence of concomitant crural diaphragm relaxation, the relatively short duration of LES relaxation (5 to 10 seconds), and the prevention of reflux by the oncoming peristaltic wave (see Reflux during swallow-induced LESR is more common in the presence of a hiatus hernia because of pooling of gastric liquids in the hernia sac and the absence of any residual diaphragmatic support during the LESR.
Hypotensive Lower Esophageal Sphincter Pressure
Stress reflux and free reflux are two mechanisms by which GER can be associated with diminished LES. Stress reflux results when a relatively hypotensive LES is overcome and is “blown open” by an abrupt increase in intra-abdominal pressure from coughing, straining, or bending. Stress reflux is unlikely when the LES pressure is greater than 10 mm Hg. Free reflux is characterized by a fall in intraesophageal pH without an identifiable change in intragastric pressure, and it usually occurs when the LES pressure is 0 to 4 mm Hg. Reflux as the result of low or absent LES pressure is uncommon. It is found mostly in patients with severe esophagitis, in whom it may account for up to 23% of reflux episodes, and rarely in patients without endoscopic evidence of esophagitis. The mechanisms of a low LES pressure are poorly understood. The presence of a hiatus hernia reduces LES pressure because the intrinsic support of the crural diaphragm is lost. Some LES weakness may be secondary to impairment of the excitatory cholinergic pathways to the LES as a result of esophagitis. Induction of experimental esophagitis in cats affects the release of acetylcholine and lowers LES pressures; changes that are reversible on healing of the esophagitis. However, healing of esophagitis in humans is rarely accompanied by an increase in LES pressure.

PATHOPHYSIOLOGY
The pathophysiology of GERD is complex and results from an imbalance between defensive factors protecting the esophagus (antireflux barriers, esophageal acid clearance, tissue resistance) and aggressive factors from the stomach contents (gastric acidity and volume and duodenal contents). The intermittent nature of symptoms and esophagitis in many patients suggests that the aggressive and defensive forces are part of a delicately balanced system.
Antireflux Barriers
The first tier of the three-tiered esophageal defense against acid damage consists of the antireflux barriers. This is an anatomically complex region that includes the intrinsic lower esophageal sphincter (LES), the diaphragmatic crura, the intra-abdominal location of the LES, the phrenoesophageal ligaments, and the acute angle of His.
The LES is a tonically contracted segment of distal esophagus about 3 to 4 cm in length. It is the major component of the antireflux barrier and is capable of preventing reflux even when it is completely displaced from the diaphragmatic crura because of a hiatus hernia. The proximal margin of the LES is normally about 1.5 to 2.0 cm above the squamocolumnar junction, whereas the distal segment, about 2 cm in length, lies within the abdominal cavity. This location of the distal LES contributes to the maintenance of gastroesophageal competence during intra-abdominal pressure events. Resting LES pressure ranges between 10 to 30 mm Hg and includes a generous reserve capacity, because a minimal basal LES pressure in the range of 5 to 10 mm Hg usually prevents GER. The LES maintains a high-pressure zone by the intrinsic tone of its muscle and by cholinergic excitatory neurons. There is considerable diurnal variation in basal LES pressure; it is lowest after meals and highest at night. It is also influenced by certain circulating peptides and hormones, foods (particularly fat), and numerous drugs. During swallowing, LES relaxation (LESR) occurs for 5 to 10 seconds, thus permitting esophageal peristalsis to sweep the swallowed bolus into the stomach.
Anatomically, the LES lies within the hiatus created by the right crus of the diaphragm, and it is anchored by the phrenoesophageal ligaments, which inserts at about the level of the squamocolumnar junction . Developmentally, the crural diaphragm arises from the dorsal mesentery of the esophagus and is innervated separately from the costal part of the diaphragm. It is inhibited by esophageal distention, during vomiting, and in association with transient LESRs, but not during swallowing. The crural diaphragm provides extrinsic squeeze to the intrinsic LES, contributing to resting pressure during inspiration and also augmenting LES pressure during periods of increased abdominal pressure such as coughing, sneezing, or bending. Crural contractions impose rhythmic pressure increases of about 5 to 10 mm Hg on the LES pressure recording. During deep inspirations and some periods of increased abdominal straining, these changes may reach 50 to 150 mm Hg.
The oblique entrance of the esophagus into the stomach creates a sharp angle on the greater curve aspect of the gastroesophageal junction, the angle of His. This angle has been shown in cadavers to create a flap valve effect that contributes to gastroesophageal junction competency.