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.