DIAGNOSTIC EVALUATION
Many tests are available for evaluating patients with suspected GERD. These tests are often unnecessary because the classical symptoms of heartburn and acid regurgitation are sufficiently specific to identify reflux disease and to begin medical treatment. However, this may not always be the case, and the clinician must decide which test to choose to arrive at a diagnosis in a reliable, timely, and cost-effective manner, depending on the information desired.
The simplest and most definitive method for diagnosing GERD and assessing its relation to symptoms (either classical or atypical) is the empiric trial of acid suppression. Unlike other tests that only suggest an association (e.g., esophagitis at endoscopy or positive symptom index on pH testing), the response to antireflux therapy ensures a cause-and-effect relationship between GERD and symptoms. Therefore, it has become the “first” test used in patients with classical or atypical reflux symptoms without “alarm” complaints. The popularity of this approach was aided by the introduction of the PPIs, which, unlike the histamine 2 receptor antagonists (H 2RAs), could drastically reduce the amount of acid reflux into the esophagus. Symptoms usually respond to a PPI trial in 7 to 14 days. If symptoms disappear with therapy and then return when the medication is stopped, GERD may be assumed.
In the reported empiric trials with heartburn, the initial dose of PPI was high (e.g., omeprazole 40 to 80 mg/d) and was given for not less than 14 days. A positive response is defined as at least 50% improvement in heartburn. Using this approach, the PPI empiric trial had a sensitivity of 68% to 83% for determining the presence of GERD. Empiric trials using a 2- to 4-month regimen of PPIs taken twice a day also are commonly used in patients with suspected GERD-associated asthma and GERD complaints related to the ear, nose and throat.
An empiric trial of PPIs for diagnosing GERD has many advantages. The test is office based, is easily performed, is relatively inexpensive, is available to all physicians, and avoids many needless procedures. Disadvantages are few, including a placebo response and uncertain symptomatic end point if symptoms do not resolve totally with extended treatment.
Extraesophageal Manifestations
It has been suggested that GER may be the cause of a wide spectrum of conditions including noncardiac chest pain, asthma, posterior laryngitis, chronic cough, recurrent pneumonitis, and even dental erosion. Some of these patients have classical reflux symptoms, but many are “silent refluxers,” contributing to problems in making the diagnosis. Furthermore, it may be difficult to establish a causal relationship even if GER can be documented by testing (e.g., pH studies), because patients may simply have two common diseases without a cause-and-effect relationship.
Chest Pain
GER-related chest pain may mimic angina pectoris. The chest pain is usually described as squeezing or burning, substernal in location, and radiating to the back, neck, jaw, or arm. It often is worse after meals, awakens the patient from sleep, and may worsen during periods of emotional stress. Heavy exercise, even treadmill testing, may provoke
Asthma and Other Pulmonary Diseases
The association of GERD and pulmonary diseases was recognized by Sir William Osler, who recommended that asthmatic patients should “learn to take their large daily meal at noon to avoid nighttime asthma which occurred if they ate a full supper.” More recent studies suggest the coexistence of the two diseases in up to 80% of asthmatic patients, irrespective of the use of bronchodilators. GERD should be considered in asthmatic patients who present in adulthood, those without an intrinsic component, and those not responding to bronchodilators or steroids. Up to 30% of patients with GERD-related asthma have no other esophageal complaints. Other pulmonary diseases associated with GERD include aspiration pneumonia, interstitial pulmonary fibrosis, chronic bronchitis, bronchiectasis, and possibly cystic fibrosis, neonatal bronchopulmonary dysplasia, and sudden infant death syndrome. Proposed mechanisms of reflux-induced asthma are either aspiration of gastric contents into the lungs with secondary bronchospasm or activation of a vagal reflex from the esophagus to the lungs causing bronchoconstriction. Animal and human studies report bronchoconstriction after esophageal acidification, but the response tends to be mild and unpredictable. In contrast, intratracheal infusion of even small amounts of acid induces profound and reproducible bronchospasm in cats. The reflux of acid into the trachea as compared with the esophagus alone predictably caused marked changes in peak expiratory flow rates in asthmatic patients. Although either mechanism may be responsible for reflux-induced asthma, most patients probably suffer from intermittent microaspiration.
Ear, Nose, and Throat Diseases
GERD may be associated with a variety of laryngeal conditions and symptoms, of which reflux laryngitis is perhaps the most common. These patients present with hoarseness, globus sensation, frequent throat clearing, recurrent sore throat, and prolonged voice warmup. Ear, nose, and throat signs attributed to GERD include posterior laryngitis with edema and redness, vocal cord ulcers and granulomas, leukoplakia, and even carcinoma. These changes usually are limited to the posterior third of the vocal cords and interarytenoid areas, both in close proximity to the upper esophageal sphincter. GERD is the third leading cause of chronic cough (after sinus problems and asthma), accounting for 20% of cases. Dental erosion, defined as the loss of tooth structure by chemical processes not involving bacteria, can be caused by GER in healthy persons and in patients with bulimia. Despite the association between ear, nose, and throat diseases and GERD, overt esophagitis usually is absent, and most patients have only mild reflux symptoms, if any. Microaspiration of gastric contents is the most likely cause of these complaints. Animal studies find that the combination of acid and pepsin is very injurious to the larynx. Human studies report that proximal esophageal acid exposure, especially at night while sleeping, is significantly increased in patients with laryngeal symptoms and signs.
Classical Reflux Symptoms
Heartburn is the classical symptom of GERD, with patients generally reporting a burning feeling, rising from the stomach or lower chest and radiating toward the neck, throat, and occasionally the back. Usually, it occurs postprandially, particularly after large meals or the consumption of spicy foods, citrus products, fats, chocolates, and alcohol. Recumbency and bending over may exacerbate heartburn. When heartburn dominates the patients’ complaints, it has very high specificity (89%), but low sensitivity (38%) for GERD as diagnosed by abnormal 24-hour esophageal pH testing. The diagnosis of GERD usually is based on the occurrence of heartburn on 2 or more days a week, although less frequent symptoms do not preclude the disease. Although this symptom is an aid to diagnosis, the frequency and severity of heartburn do not predict the degree of esophageal damage. Heartburn is caused by acid stimulation of sensory nerve endings in the deeper layers of the esophageal epithelium. These nerve endings are normally protected by a relatively impermeable epithelium, but with epithelial changes caused by reflux, they may be stimulated by H + or spicy foods.
Other common symptoms of GERD are acid regurgitation and dysphagia. The effortless regurgitation of acidic fluid, especially after meals and exacerbated by stooping or recumbency, is highly suggestive of GERD. Among patients with daily regurgitation, the LES pressure usually is low, many have associated gastroparesis, and esophagitis is common. For these reasons, acid regurgitation may be more difficult to control medically then classical heartburn complaints. Dysphagia is reported by more than 30% of patients with GERD. It usually occurs in the setting of long-standing heartburn, with slowly progressive dysphagia primarily for solids. Weight loss is uncommon because patients have good appetites. The most common causes are a peptic stricture or Schatzki ring, but other causes include severe esophageal inflammation alone, peristaltic dysfunction, and esophageal cancer arising from Barrett esophagus.
Less common reflux-associated symptoms include water brash, odynophagia, burping, hiccups, nausea, and vomiting. Water brash is the sudden appearance in the mouth of a slightly sour or salty fluid. It is not regurgitated fluid, but rather secretions from the salivary glands in response to acid reflux. Odynophagia, pain on swallowing, can occasionally be seen with severe ulcerative esophagitis. However, its presence should raise the suspicion of an alternative cause of esophagitis, especially infections (candidiasis, herpes) or pills (tetracycline, potassium chloride, quinine, vitamin C, alendronate).
In contrast to the previously described symptomatic presentations, some patients with GERD are asymptomatic. This is particularly true in elderly patients because of decreased acidity of the reflux material or decreased pain perception. Many elderly patients present first with complications of GERD because of long-standing disease with minimal symptoms. For example, up to one third of patients with Barrett esophagus are insensitive to acid at the time of presentation.
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.
The term acid reflux disease or (GERD) describes any symptomatic condition or histopathologic alteration resulting from episodes of acid reflux. Reflux esophagitis is a condition experienced by a subset of GERD patients with endoscopically evident lesions in the esophageal mucosa. However, acid reflux often causes symptoms in the absence of esophagitis, and 24-hour esophageal pH monitoring can be helpful in identifying this subset of GERD patients. Nonerosive, or endoscopy-negative, GERD patients have reflux symptoms and abnormal esophageal acid exposure during ambulatory 24-hour pH monitoring, but no endoscopic evidence of esophagitis. The acid sensitive esophagus patient is in a subset of the endoscopy-negative GERD population characterized by normal esophageal acid exposure but nonetheless a strong correlation between reflux symptoms and acid reflux events.
Acid reflux disease (GERD) results from the failure of the normal antireflux mechanism to protect against frequent and abnormal amounts of acid reflux (GER), that is, the effortless movement of gastric contents from the stomach to the esophagus. GER is not itself a disease, but a normal physiological process. It occurs in virtually everyone, multiple times everyday, especially after large meals, without producing either symptoms or signs of mucosal damage. In contrast, GERD is a spectrum of disease usually producing symptoms of heartburn and acid regurgitation. Most patients have no visible mucosal injury at the time of endoscopic examination (nonerosive GERD), whereas others have esophagitis, peptic strictures, Barrett esophagus, or evidence of extraesophageal diseases such as chest pain, pulmonary symptoms, or ear, nose, and throat symptoms. GERD is a multifactorial process, one of the most common human diseases, and of economic importance, contributing to the expenditure in the United States of 4 to 5 billion dollars per year for antacid medications.
In this videoclip, you get an idea of what the doctor sees at esophagoscopy in a case of severe acid reflux. This patient has a hiatal hernia and his LES "valve" is wide open allowing acid to splash upward. Over time, this acid reflux has damaged the lower esophagus creating inflammation and ulcers.
Watch the laparoscopic Nissen procedure for hiatal hernia.
Acid Reflux Causes
Acid Reflux natural course
Acid Reflux Complications
Acid Reflux Progress
Parietal cell receptors for acid secretiom
Proton Pump Inhibitors Mechanism of Action
Proton Pump Inhibitors Mechanism of Action
Parietal cell receptors for acid secretiom
H2 Receptor Antagonists Mechanism of Action
Acid Reflux Surgery
Barrett's Esophagus
Barrett's Esophagus
Esophageal Manometry
Esophageal manometry allows accurate assessment of LES pressure and relaxation, as well as peristaltic activity including contraction amplitude, duration, and velocity. However, esophageal manometry is generally not indicated in the evaluation of the patient with uncomplicated GERD because most of these patients have a normal resting LES pressure. It is an integral component of pH testing to define the LES location accurately, a task poorly performed by endoscopy, fluoroscopy, or the pH pull-through technique. Esophageal manometry is an essential test in the preoperative evaluation of patients for antireflux surgery. A normal LES pressure does not preclude surgery for the reasons discussed, yet occasionally an alternative diagnosis such as achalasia or scleroderma is made, which may change the clinical approach. Most importantly, the presence of ineffective peristalsis characterized by either low-amplitude (<30>
Bile reflux can be measured using ambulatory esophageal bilirubin monitoring (Bilitec: Medtronics,
Symptoms associated with GERD may be mimicked by other esophageal and extraesophageal diseases including achalasia, Zenker diverticulum, gastroparesis, gallstones, peptic ulcer disease, functional dyspepsia, and angina pectoris. These disorders usually can be identified by failure to respond to aggressive antisecretory therapy and by diagnostic tests such as endoscopy, barium esophagram, esophageal manometry, ultrasound, nuclear emptying studies, and various cardiac tests. Although GERD is the most common cause of esophagitis, other causes (esophagitis, infections, or radiation esophagitis) need to be considered in cases that are difficult to manage cases and in older or immunocompromised patients.
Barium Esophagram
The barium esophagram is an inexpensive, readily available, and noninvasive esophageal test. It is most useful in demonstrating structural narrowing of the esophagus and in assessing the presence and reducibility of a hiatal hernia. Subtle findings such as Schatzki rings, webs, or minimally narrowed peptic strictures are often seen only with an esophagram; they are missed by endoscopy, which may not adequately distend the esophagus. This test, which involves consuming a 13-mm radiopaque pill or marshmallow along with the barium liquid, is the most sensitive for detecting esophageal narrowing, with values reported between 95% and 100%. By giving the patient in the prone oblique position swallows of barium, the barium esophagram also allows good assessment of peristalsis and is helpful preoperatively in identifying a weak esophageal pump.
The ability of the barium esophagram to detect esophagitis varies considerably. Although sensitivities of 79% to 100% have been reported with moderate to severe esophagitis, mild esophagitis is usually missed. Barium testing also falls short when addressing the presence of Barrett esophagus. Barium studies can identify GER when contrast moves in a retrograde fashion from the stomach into the esophagus. If this occurs spontaneously, repeatedly, or to a significant degree into the middle or proximal esophagus, the test is positive, but it has a sensitivity of only about 40% for defining GERD. Provocative maneuvers such as leg lifting, coughing, the Valsalva maneuver, or the water-siphon test can be used to elicit stress reflux. Although these tests can improve the sensitivity of the barium esophagram, some argue that they also decrease its specificity.
The barium esophagram is primarily used in evaluating the patient with GERD with new-onset dysphagia because it can define subtle strictures and rings as well as assess motility. Conversely, endoscopy is preferred in the patient with recurrent dysphagia known to have a stricture or for the assessment of esophagitis or Barrett esophagus.
Esophageal pH Monitoring
Ambulatory intraesophageal pH monitoring is now the standard for establishing pathological reflux. The test is performed with a pH probe passed nasally and positioned 5 cm above the manometrically determined LES. The probe is connected to a battery-powered data logger capable of collecting pH values every 4 to 6 seconds. An event marker is activated by the subject in response to symptoms, meals, and body position changes. Patients are encouraged to eat normally and to pursue regular daily activities. Monitoring is carried out usually for 18 to 24 hours. Reflux episodes are detected by a drop in pH to less than 4. Commonly measured parameters include the percentage of total time that the pH is less than 4, the percentage of time upright and supine that the pH is less than 4, the total number of reflux episodes, the duration of longest reflux episode, and the number of episodes longer than 5 minutes. The total percentage of time that the pH is less than 4 is the most reproducible measurement for GERD, with reported upper limits of normal values ranging from 4% to 5.5%. Ambulatory pH testing can discern positional variations in GER, meals, and sleep-related episodes and helps to relate symptoms to reflux events. As the result of its reliability for measuring GER across normal activities, ambulatory pH testing has replaced other older studies, such as the standard acid reflux (Tuttle) test and radionuclide scintigraphy.
One important problem with esophageal pH monitoring is that there exists no absolute threshold value that reliably identifies pathological GER. Validation studies comparing the presence of esophagitis with abnormal pH test report sensitivities ranging from 77% to 100% with specificities from 85% to 100%. However, these patients rarely need pH testing; rather, the patients with normal endoscopic findings and suspected reflux symptoms should benefit most from ambulatory pH monitoring. Unfortunately, the data are much less conclusive in this group, with considerable overlap between controls and patients with nonerosive reflux. Other drawbacks of pH testing include possible equipment failure, the pH probe’s missing a reflux event because it is buried in a mucosal fold, and false-negative studies resulting from dietary or activity limitations from poor tolerability of the nasal probe.
An important advantage of ambulatory esophageal pH monitoring is its ability to record and correlate symptoms with reflux episodes over extended periods. For this indication, it has essentially replaced the shorter acid perfusion (Bernstein) test. Because only about 10% to 20% of reflux episodes are associated with reported symptoms, different statistical analyses have evolved attempting to define a significant association between these two variables including the symptom index, symptom sensitivity index, and symptom association probability. Unfortunately, no studies to date have defined the accuracy of any of these symptom scores in predicting response to therapy. Therefore, pH testing and symptom correlation can define an association between complaints and GER, but only treatment trials address the true definition of a causal relationship.
Definite clinical indications for ambulatory pH monitoring have been established. Before fundoplication, pH testing should be performed in patients with normal endoscopic findings to identify the presence of pathological reflux. If esophagitis is present, pH testing is not necessary because the disease has been established. After antireflux surgery, persistent or recurrent symptoms warrant repeat pH testing. In these situations, pH monitoring is performed with the patient discontinuing all antireflux medications (PPIs for 1 week, H 2RAs for 2 days). Esophageal pH testing is particularly helpful in the evaluation of patients with reflux symptoms resistant to treatment with normal or equivocal endoscopic findings. For this indication, pH testing is usually done in patients receiving therapy to define two populations: those with and those without continued abnormal esophageal acid exposure times. The group with persistent GER needs intensification of the medical regimen, whereas those patients with symptoms and adequate acid control have another cause of their complaints. Finally, ambulatory pH testing may help in defining patients with extraesophageal manifestations of GERD. In this situation, pH testing is usually done with additional pH probes placed in the proximal esophagus or pharynx. Initially, most of these studies were done when patients were not taking antireflux medications, to confirm the coexistence of GERD; however, this does not guarantee symptom causality. Therefore, the current approach is to treat the patients aggressively with PPIs first and to reserve pH testing only for those patients not responding after 4 to 12 weeks of therapy.
Endoscopy
Upper endoscopy is the current standard for documenting the type and extent of mucosal injury to the esophagus. It identifies the presence of esophagitis and excludes other causes of the patient’s complaints. However, only 40% to 60% of patients with abnormal esophageal reflux by pH testing have endoscopic evidence of esophagitis. Thus, the sensitivity of endoscopy for GERD is 60% at best, but it has excellent specificity, at 90% to 95%.
The earliest endoscopic signs of acid reflux include edema and erythema. Neither finding is specific for GERD, and both are very dependent on the quality of endoscopic visual images. More reliable are the findings of friability, granularity, and red streaks. Friability (easy bleeding), occurring with gentle pressure on the mucosa, results from the development of enlarged capillaries near the mucosal surface in response to acid. Red streaks may extend upward from the esophagogastric junction along the ridges of the esophageal folds. In studies evaluating these stigmata, nearly all patients had GERD. With progressive acid injury, erosions develop. These are characterized by shallow thinning of the mucosa associated with a white or yellow exudate surrounded by erythema. Commonly located just above the esophagogastric junction, erosions may be either single lesions or coalesced regions. Typically, they occur along the tops of mucosal folds, areas most prone to acid exposure. Erosions may also be caused by nonsteroidal antiinflammatory drug use, heavy smoking, and infectious esophagitis. Ulcers reflect more severe esophageal damage. They penetrate the mucosa, tend to have either a white or yellow discolored base, and may be seen either isolated along a fold or surrounding the esophagogastric junction.
Endoscopic grading of GERD depends on the endoscopist’s interpretation of these visual images. Unfortunately, there exists no standard classification scheme for endoscopic findings. Instead, several grading systems are available, but none are completely satisfactory. In
Most patients with GERD are treated initially without endoscopy. The important exception is the patient experiencing alarm symptoms: dysphagia, odynophagia, weight loss, and gastrointestinal bleeding. With such symptoms, endoscopy should be performed early to rule out other entities such as infections, ulcers, cancer, or varices.
The role of endoscopy in GERD in the absence of alarm symptoms is more controversial and is evolving in the era of PPI therapy. Initially, endoscopy was used to place patients into two groups—those with nonerosive or mild disease and those with severe erosive disease—and to direct their treatment more precisely. However, this practice is now less popular with the use of PPIs as the first line of therapy for GERD. Because these drugs treat both groups equally well, early endoscopy has less impact on the choice of therapy. Currently, the most important reason for performing endoscopy in patients with GERD is to identify peptic strictures or Barrett esophagus. Using this rationale, most patients with chronic GERD need only one endoscopic examination while they are receiving therapy.
Esophageal Biopsy
The ability to obtain tissue during endoscopy is very important. Biopsies of the esophagus help to identify reflux injury, exclude other esophageal diseases, and confirm the presence of complications, especially Barrett esophagus. Microscopic changes indicative of reflux may occur even when the mucosa appears normal endoscopically. In patients with classical esophagitis, biopsies are usually not taken unless they are needed to exclude other diagnoses such as neoplasm, infection, pill injury, or bullous disease. When Barrett esophagus is suspected, biopsies are mandatory and are best done when esophagitis is healed.
The most sensitive histological markers of GERD are reactive epithelial changes characterized by an increase in the basal cell layer greater than 15% of the epithelium thickness or papilla elongation into the upper third of the epithelium. These changes represent increased epithelial turnover of the squamous mucosa. Papilla, or rete peg, height increases as a result of loss of surface cells from acid injury, whereas basal cell hyperplasia is indicative of mucosal repair. Unfortunately, these changes are also noted in up to 50% of healthy persons when biopsies are taken from the distal 2 to 3 cm of the esophagus. Hence, the changes are sensitive markers for GERD but have poor specificity.
Acute inflammation characterized by the presence of neutrophils and eosinophils is very specific for esophagitis. Acid reflux injury to the vascular bed of the esophagus releases vasoactive substances that promote edema and migration of neutrophils and eosinophils into the area. Neutrophils are specific for acute esophagitis but are an insensitive marker, being present in only 15% to 40% of patients with GERD. Eosinophils are found more often on biopsy (19% to 63% of subjects) but are less specific, present in up to 33% of healthy adults. Interestingly, the sensitivity and specificity of eosinophils in children are much stronger, reflecting the lack of eosinophils in the juvenile inflammatory response.
