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.

A history of recurrent heartburn along with a positive response to antacids or acid-suppressing medication is adequate to diagnose Acid Reflux Disease. Specific testing is reserved for patients who have (1) Acid Reflux Disease plus alarm symptoms of dysphagia, weight loss, or gastrointestinal bleeding; (2) Acid Reflux Disease of sufficient chronicity (e.g., 5 years) to raise concern for Barrett's esophagus; and (3) suspected Acid Reflux Disease with atypical symptoms, such as chest pain or oropharyngeal, laryngeal, or airway symptoms.

Establishing Acid Reflux Disease as a Cause of Nonheartburn Symptoms

Currently, the preferred method for establishing Acid Reflux Disease as the cause of symptoms (e.g., chest pain, wheezing) is an empirical trial of acid suppression with a PPI (e.g., omeprazole, 20 mg twice daily), which normalizes esophageal acidity in approximately 95% of subjects. In some instances, a bedtime dose of a histamine H2-receptor antagonist (e.g., ranitidine, 300 mg) is added to reduce the possibility of nocturnal acid breakthrough. The treatment period in which to expect a satisfactory response is 2 to 4 weeks for chest pain and 2 to 3 months for inflammatory disease of the airway. Resolution of the symptoms supports Acid Reflux Disease as possibly causal. Confirmation may be obtained by relapse when medication is withdrawn and by a subsequent positive response to re-treatment, as confirmed by documenting control of esophageal acidity on pH monitoring while undergoing PPI therapy. Failure of symptoms to improve with PPI therapy is not generally an indication for antireflux surgery (see later) but rather an indication to search for another disease. A rarely used alternative is the Bernstein test, in which acid (0.1 N HCl, pH 1.1) or saline (control) is perfused through a catheter positioned in the midesophagus. If symptoms typical of those that occur spontaneously develop with acid but not saline, the test is considered positive for Acid Reflux Disease.

Tests for Reflux

Documenting acid reflux is not necessary except when symptoms fail to respond to PPI therapy or when surgery is being considered. Esophageal pH monitoring, the “gold standard” for identifying acid reflux, is performed by fixing a small pH probe in the esophagus, 5 cm above the LES, and recording all episodes in which esophageal pH drops to less than 4 over a 24- to 48-hour period. The number and duration of each acidic event, when combined, yield a value for total esophageal acid contact time. Total acid contact times of greater than 5% are abnormal and consistent with a diagnosis of Acid Reflux Disease. An event marker activated by the patient also allows symptoms to be related to episodes of esophageal acidity. An upper gastrointestinal series can detect grossly abnormal reflux by observing movement of barium from the stomach to the esophagus with the patient in the head-down position. It has low sensitivity but, when positive, has high predictive value. The positive predictive value is much lower, however, if reflux is induced by having the subject sip water through a straw in the head-down position. This test is rarely useful for therapeutic decisions.

Tests for Esophageal Injury
Endoscopic signs.

Tests of Esophageal Motor Function

An upper gastrointestinal series or barium swallow is valuable for identifying gross reflux and marked abnormalities in esophageal anatomy (e.g., hiatal hernia, diverticulum) and peristaltic and sphincter function. More subtle abnormalities, however, require esophageal manometry. Low mean LES pressure (<10 mm Hg) is a specific but insensitive marker of Acid Reflux Disease, with 60% of patients having normal values. Currently, the major uses of esophageal manometry in Acid Reflux Disease are to (1) position the pH probe for reflux testing, (2) exclude motor disease (achalasia, scleroderma), and (3) quantify peristaltic amplitudes before surgical fundoplication. If contraction amplitudes average less than 30 mm Hg, a partial (Toupet) rather than complete (Nissen) wrap may be preferable to avoid postoperative dysphagia.

Recurrent heartburn, when properly defined, is the hallmark of Acid Reflux Disease and enables the diagnosis to be made by the history alone. The heartburn associated with Acid Reflux Disease typically occurs once or twice per day and lasts from a few minutes to an hour or more if untreated. This pattern recurs, but with considerable variation in frequency and severity. However, neither the frequency, severity, nor duration of heartburn predicts disease severity on endoscopy. Acid Reflux Disease can also be associated with dysphagia, an alarm symptom because it raises concern for the presence of a peptic stricture or adenocarcinoma arising in Barrett's esophagus. For this reason, dysphagia is an indication for early endoscopy.

The damage in Acid Reflux Disease is best assessed by upper endoscopy and esophageal biopsy. Endoscopy may reveal friability, erosions, ulcers, strictures, or Barrett's esophagus in a third of subjects. In the other two thirds, endoscopic findings are normal but esophageal biopsy may show basal cell hyperplasia, elongation of the rete pegs, inflammatory cell infiltrates, cell edema, dilated intercellular spaces in squamous epithelium, or any combination of these findings. “Dilated intercellular spaces” is the earliest detectable lesion in NERD and correlates with heartburn because it reflects “leakiness” of the paracellular pathway to refluxed gastric acid. A barium swallow or upper gastrointestinal series may also detect ulcers, strictures, and hiatal hernias, but it does not reliably detect inflammation, erosions, or Barrett's esophagus.

Although Acid Reflux Disease is often used synonymously with reflux damage to the esophagus, Acid Reflux Disease includes reflux damage to the oropharynx, larynx, and respiratory tract. Consequently, symptoms and signs of Acid Reflux Disease can include sore throat/pharyngitis, earache/otitis, eroded tooth enamel, hoarseness/laryngitis, bronchitis/chronic cough, asthma/wheezing, and aspiration pneumonia. With the exception of pneumonia, which occurs as a result of gross regurgitation and aspiration of mixed gastric content, damage to the oropharynx, larynx, and airways is mediated by refluxed gastric acid. Asthma (wheezing) and bronchitis (chronic cough) can be triggered either directly by contact of acid with airway epithelium (microaspiration) or indirectly through an esophagopulmonary vagal reflex initiated by contact of acid with esophageal epithelium. The frequency with which Acid Reflux Disease causes, as opposed to being caused by, wheezing/asthma, chronic cough/bronchitis, and hoarseness/laryngitis is unknown.

Associated Conditions
Acid Reflux Disease can develop as a consequence of other conditions, such as Zollinger-Ellison syndrome, scleroderma, diabetes mellitus, nasogastric intubation, and pregnancy.

Gastroesophageal reflux is a physiologic process that refers to the effortless movement of stomach contents from the stomach to the esophagus. It occurs in everyone, multiple times every day, usually without producing symptoms or signs of damage. Reflux can also be pathologic and produce symptoms and signs of injury to the esophagus, oropharynx, larynx, and respiratory tract. Reflux damage to the esophagus (reflux esophagitis) is the most common form of Acid Reflux Disease and is most often recognized by recurrent heartburn. In almost all patients with heartburn, esophageal mucosal pathology is identifiable, although only about 40% have endoscopically detectable erosions. The remaining 60% of patients with heartburn have endoscopically undetectable (microscopic) pathology—termed nonerosive reflux disease (NERD).

Acid Reflux Disease is one of the most common diseases in the Western world based on the prevalence of heartburn. In the United States, about 45% of adults have heartburn at least once a month, about 20% once a week, and about 10% daily. Heartburn affects men two- to threefold more often than it affects women and is more common in whites than blacks. Although Acid Reflux Disease rarely causes death, it reduces quality of life and has a morbidity rate of 10 to 15% secondary to ulceration, bleeding, stricture, Barrett's esophagus, and adenocarcinoma. The overall risk for esophageal adenocarcinoma in patients with heartburn is very low, with estimates of 1 in 2500 cases per year for those with daily heartburn to 1 in 10,000 cases per year for those with monthly heartburn.

Acid Reflux Disease develops when acidic stomach contents reflux into the esophagus and remain there long enough to overcome the resistance of the esophageal epithelium. Based on 24-hour esophageal pH monitoring, Acid Reflux Disease develops in at least two fundamentally different ways: (1) under conditions in which there is prolonged contact of the esophageal epithelium with refluxed stomach acid and (2) under conditions in which the esophageal epithelium is damaged despite a normal duration of contact with refluxed stomach acid. Prolonged acid contact results from defects in the antireflux barriers or luminal clearance mechanisms (or both), with transient LES relaxations accounting for more than 50% of acid reflux events in NERD. These relaxations are non–swallow-induced, reflex relaxations of the LES caused by stomach fundic distention. They are associated with acid reflux because they are twice as long as relaxations with swallowing and, unlike swallow-induced LES relaxations, are accompanied by inhibition of diaphragmatic contraction and unaccompanied by lumen-obliterating esophageal peristalsis. The cause of the increase in the frequency of acid reflux episodes associated with transient relaxations in patients with Acid Reflux Disease is unclear but is unrelated to delayed stomach emptying or infection with Helicobacter pylori. A diet rich in nonabsorbable carbohydrates may be one possible provocateur. In erosive esophagitis, transient LES relaxations account for less than 50% of acid reflux events, with most occurring across a mechanically weak LES. Whether LES weakness causes erosive esophagitis or is a consequence of it remains unclear because products released during inflammation can impair LES contractility. Similarly, hiatal hernias and impaired peristalsis are common in erosive esophagitis, but whether they are cause or consequence is also unclear because esophagitis can result in both esophageal shortening (by sustained contraction of the longitudinal muscle) and peristaltic dysfunction (by weakening circular muscle contractility). Patients with heartburn despite normal acid contact time presumably have primary defects in tissue resistance, with these defects probably being acquired by dietary indiscretions such as excess exposure to alcoholic, hypertonic, or hot-temperature products.

Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage resulting from reflux of gastric acid into the esophagus and more proximal structures.
The predominant symptoms of GERD are heartburn and regurgitation.
Atypical symptoms include cough, asthma, hoarseness, chest pain, hiccups, and dental erosions.
Symptom response to a therapeutic trial of PPIs can be diagnostic.
Endoscopic evaluation is recommended for patients with warning symptoms of dysphagia, odynophagia, early satiety, weight loss, or bleeding, and atypical symptoms (cough, asthma, hoarseness, chest pain, aphthous ulcers, hiccups, dental erosions).
Patients with symptoms refractory to empiric acid suppression or requiring continuous medication for prolonged periods should also undergo endoscopy.
Ambulatory pH monitoring is used to establish elevated esophageal acid exposure and symptom-reflux correlation in patients with ongoing symptoms despite acid suppression (especially if endoscopy is negative) or those with atypical symptoms. It is also used to determine adequacy of acid suppression in patients with established GERD and ongoing symptoms.
Lifestyle Modification
The basics of lifestyle modification include eating small meals; refraining from eating for 2-3 hours before lying down; elevating the head of the bed 4-6 in.; decreasing intake of fatty foods, chocolate, coffee, cola, and alcohol; and smoking cessation.
Lifestyle modification also includes avoiding medications such as calcium channel blockers, theophylline, sedatives/tranquilizers, and anticholinergics, as they may potentiate reflux.
Lifestyle modifications alone are unlikely to resolve symptoms in the majority of GERD patients, but should be recommended in conjunction with medications.
Medications
In patients with mild or intermittent symptoms, over-the-counter antacids and H2RAs can be used intermittently or prophylactically if necessary.
PPIs have been demonstrated to be more effective than placebo or standard-dose H2RA in symptomatic relief as well as endoscopic healing of GERD. Higher doses (omeprazole, 20–40 mg PO bid or equivalent) may be required in severe esophagitis or persistent symptoms. Continuous long-term PPI therapy is safe and effective in maintaining remission of GERD symptoms, and is recommended for patients with erosive esophagitis, Barrett's esophagus, and severe symptoms.
Standard doses of H2RAs can result in symptomatic benefit in up to 60% of patients and endoscopic healing in 50%. Higher doses of H2RAs (equivalent to ranitidine, 600 mg daily) improve the healing rate to 75% at a higher cost. Dosage adjustments are required in renal insufficiency.
Surgery
Indications for fundoplication include the need for continuous or increasing doses of medication in patients who are good surgical candidates. Patients who require aggressive long-term medical therapy should be offered the surgical option. Other indications include patient preference for surgery and noncompliance with medical therapy.
The success rate of laparoscopic fundoplication in controlling GERD symptoms exceeds 90%, with fewer complications compared to the open technique. Elevated esophageal acid exposure and correlation of symptoms to reflux events on ambulatory pH monitoring predict a higher likelihood of a successful outcome.
Patients with medical treatment failures need careful evaluation to determine whether symptoms are indeed related to acid reflux before surgical options are considered; these patients often have other diagnoses including visceral hypersensitivity and functional heartburn.
Complications
Esophageal ulceration and stricture formation can occur in patients with GERD. Iron-deficiency anemia is less common.
GERD can contribute to laryngitis, laryngeal ulcers, asthma, and dental caries.
Barrett's esophagus is a change in the esophageal mucosa from normal squamous epithelium to specialized intestinal metaplastic epithelium due to longstanding acid related injury. It carries a small risk of progression to esophageal adenocarcinoma. Endoscopic surveillance for Barrett's esophagus should be considered in patients with a symptom history that exceeds 5 years.