Section 4
I Esophageal DisordersMichael F. Vaezi, MD, PHD, MSC(EPI)
Vanderbilt University Medical Center
Normal Esophageal Anatomy and Physiology
The esophagus is a muscular tube that connects the pharynx to the stomach and acts as a channel for the transport of food. The details of its structure and function are much more complex, however. Understanding the anatomy and physiology of the esophagus is essential in understanding esophageal disease states.
The proximal margin of the tubular esophagus is the upper esophageal sphincter (UES), the functional unit correlating anatomically with the junction of the inferior pharyngeal constrictor and cricopharyngeus muscles. The esophagus extends distally 18 to 26 cm within the posterior mediastinum as a hollow muscular tube to the lower esophageal sphincter (LES). The LES is a 2 to 4 cm long segment of tonically contracted thickened circular smooth muscle that lies within the diaphragmatic hiatus.
The esophageal wall has four layers: mucosa, submucosa, muscularis propria, and adventitia. Unlike the rest of the gastrointestinal tract, the esophagus has no serosa. The mucosa is normally composed of stratified squamous epithelium, lamina propria, and the muscularis mucosa. Lymphatic drainage begins in the lamina propria. The muscularis propria consists of both skeletal and smooth muscle. The proximal 5% to 33% is skeletal muscle, the middle 35% to 40% is a mixture of skeletal and smooth muscle, and the distal 50% to 60% is smooth muscle. The muscles are arranged into inner circular and outer longitudinal layers.
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| Figure 1. Anatomy of the Esophagus |
The smooth muscle portions of the esophageal body are innervated by the vagus nerve, which controls peristalsis under physiologic conditions. Neural innervation of the esophagus is from the myenteric (Auerbach) plexus, located between the two muscle layers; and the submucosal Meissner plexus [see Figure 1]. The myenteric plexus is responsible for esophageal peristalsis, whereas the Meissner complex is the site of afferent sensory input. Although the precise interaction between morphology and function of the nerve plexuses is not entirely clear, there are two main neurotransmitters within the myenteric plexus. Excitatory neurons release acetylcholine (ACh), which mediates contraction of both the circular and longitudinal muscle layers. Inhibitory neurons predominately affect the circular muscle layer via release of nitric oxide (NO). Excitatory stimulation from ACh has its largest effect proximally, whereas the inhibitory effect of NO is seen distally.
Functionally, the UES, the esophageal body, and the LES act in a coordinated manner to allow normal swallowing. Swallowing begins when a food bolus is propelled into the pharynx from the mouth. This initial oropharyngeal phase of swallowing is voluntary; the esophageal phase that follows is involuntary. The mechanical effect of esophageal peristalsis is a wave that strips the esophagus clean from its proximal to distal end.
LES relaxation occurs in response to swallowing; it may also occur in response to esophageal distention (secondary peristalsis), or it may even occur without peristalsis. Transient lower esophageal sphincter relaxation (TLESR) triggered by gastric distention is a vagally mediated reflex that is a part of normal digestion. TLESR represents the primary mechanism for gastro-esophageal reflux in normal individuals and those with mild gastroesophageal reflux disease (GERD).
DiagnosisClinical Manifestations
Primary symptoms suggesting the presence of an underlying esophageal disorder typically include heartburn, dysphagia, odynophagia, and regurgitation.
Heartburn
Heartburn, or pyrosis, is classically described as a substernal burning sensation usually occurring within 30 minutes to 2 hours after meals and that is made worse by lying down or bending over. Large meals, especially those containing fat, chocolate, coffee, or alcohol, are particularly likely to precipitate heartburn. Relieving factors often include drinking milk or taking an antacid. The presence of recurrent heartburn, as an isolated symptom, strongly suggests GERD as the diagnosis.
Dysphagia
Dysphagia refers to the sensation of food being delayed in its normal passage from mouth to stomach. Patients often complain of a sensation of food “sticking.” Clinically, dysphagia may be classified as either oropharyngeal or esophageal. Oropharyngeal (or transfer) dysphagia is difficulty in initiating a swallow—that is, in moving a food bolus from the hypopharynx to the esophagus. Oropharyngeal dysphagia arises from disease of the upper esophagus, pharynx, or UES. Esophageal dysphagia results from difficulty transporting food down the esophagus secondary to structural or neuromuscular defects in the smooth muscle portion of the esophagus.
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| Figure 2. Evaluation of Dysphagia |
Further history can often establish the diagnosis in patients with esophageal dysphagia [see Figure 2]. Patients with primarily solid food dysphagia typically have a structural lesion, such as a peptic stricture, ring, or malignancy. Esophageal rings tend to cause intermittent solid food dysphagia, whereas strictures and cancer cause persistent and often progressive dysphagia. Patients with both solid and liquid dysphagia are more likely to have a motility disorder such as achalasia or scleroderma.
The site at which a patient senses dysphagia is of limited value in determining the type of dysphagia. Although patients with oropharyngeal dysphagia accurately identify the location of the obstruction as being in the cervical or throat region, patients with esophageal dysphagia secondary to distal esophageal obstruction indicate the same area in up to 30% of cases.1 Dysphagia that is felt in the retrosternal or epigastric area frequently corresponds to the actual site of obstruction, however.
The distinction between oropharyngeal and esophageal dysphagia is crucial, because the conditions have distinctly different causes [see Figure 2]. A careful history may be adequate to make this distinction. Patients with oropharyngeal dysphagia typically experience the immediate onset of coughing, choking, gagging, or nasal regurgitation when attempting to swallow, especially with liquids.
Oropharyngeal dysphagia is most commonly caused by neuromuscular dysfunction that disrupts the finely coordinated act of swallowing. Consequently, the history and physical examination should concentrate on neurologic signs and symptoms. Any disease that affects the sensory or motor nerves, or the muscles, can produce oropharyngeal dysphagia, but the more common associations include cerebrovascular accidents, amyotrophic lateral sclerosis, Parkinson disease, myasthenia gravis, and tardive dyskinesia. Rarely, structural abnormalities such as cervical osteophytes, hypopharyngeal diverticulum (Zenker diverticulum), tumors, or postcricoid webs can cause oropharyngeal dysphagia. These patients typically have difficulty when attempting to swallow a solid food bolus. Although these structural abnormalities occur rarely, it is important that they be identified because they may be treatable with endoscopic or other surgery.
The oropharyngeal swallow is best assessed by videofluoroscopy; this procedure is also known as the modified barium swallow. Videofluoroscopy serves not only to confirm the presence of oropharyngeal dysfunction but also to assess the degree of aspiration. It is helpful to have an experienced speech pathologist present at the time of videofluroscopy to identify these abnormalities and to assist with specific swallow therapies. Assessment of aspiration risk and its treatment are essential in the management of these patients because aspiration carries a high risk or morbidity and mortality.
Odynophagia
Dysphagia must be distinguished from odynophagia, which refers to pain caused by swallowing. This symptom indicates a pharyngeal or esophageal problem. Most often, the source of odynophagia is an inflammatory condition of the esophagus such as erosive, pill-induced, or infectious esophagitis.
Regurgitation
Regurgitation is the effortless appearance of an acidic or bitter taste in the mouth. Regurgitation may be particularly severe at night and may awaken a patient from sleep with coughing and choking. Although esophageal problems do not cause true vomiting, patients may complain of vomiting when they are experiencing regurgitation. Regurgitation should be differentiated from water brash, which is the sudden filling of the mouth with clear, slightly salty fluid. This fluid represents salivary secretions, not regurgitated gastric contents. Water brash is vagally mediated.
Ancillary Symptoms
Chest pain Chest pain is a common symptom of esophageal disorders. Esophageal disorders are probably the most common causes of noncardiac chest pain. This pain can be indistinguishable from angina, but chest pain of esophageal origin tends to be of longer duration, related to meals and to position, and associated with other gastrointestinal symptoms. Esophageal causes of chest pain include GERD and motility disorders.
Globus Globus sensation, defined as feeling of a lump, fullness, or “tickle” in the throat, is a frequently encountered esophageal symptom. Globus may result from psychological factors or be related to increased visceral sensation; a thorough investigation of the pharynx, larynx, neck, and esophagus should be pursued. Physiologic and structural causes should be treated in order to assess their relationship with globus.
Other symptoms Hiccups may be associated with esophageal reflux or obstruction. Asthma, cough, hoarseness, sore throat, and repetitive throat clearing may be secondary to reflux of gastroduodenal contents and should be treated aggressively.
Laboratory Testing
Endoscopy
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| Figure 3. Anatomy of Gastroesophageal Junction |
Endoscopy is the technique of choice to evaluate the mucosa of the esophagus and detect structural abnormalities. Collection of biopsy specimens and treatment of selected disorders can also be accomplished endoscopically. Esophageal mucosa normally appears smooth and light pink. Visual inspection can reveal mucosal breaks, ulcers, strictures, or lesions such as Barrett esophagus and hiatal hernia [see Figure 3]. The current indications for endoscopy include warning symptoms such as weight loss, upper gastrointestinal bleeding, dysphagia, odynophagia, and chest pain; and partial or no response to empirical antisecretory therapy. Endoscopy is also performed in the monitoring of Barrett esophagus.
Esophageal Manometry
Esophageal manometry measures intraluminal pressures and coordination of the pressure activity of the three functional regions of the esophagus: the LES, esophageal body, and the UES. Manometry is commonly used in the assessment of patients with symptoms suggestive of esophageal motor dysfunction, such as dysphagia and noncardiac chest pain. A manometric study is also indicated for the evaluation of esophageal peristalsis before antireflux surgery.
Manometry is the standard test for the diagnosis of motor disorders of the esophageal body and LES. Manometric evaluation of the LES can accurately assess basal pressure and relaxation of the sphincter during swallowing. The esophageal body can be assessed for amplitude and duration of contractions and peristalsis. Peristalsis is defined by a coordinated contraction sequence and is quantified by recording the percentage of swallows associated with peristalsis. Using these characteristics of the LES and esophageal body, a number of esophageal manometric disorders can be diagnosed [see Table 1].
Ambulatory 24-Hour Esophageal pH Monitoring
Ambulatory 24-hour esophageal pH monitoring is an important tool in the diagnosis and management of GERD. Esophageal pH monitoring can detect and quantify gastro-esophageal reflux and correlate symptoms temporally with reflux. The primary indications for ambulatory 24-hour esopha geal pH monitoring are as follows: (1) to document excessive acid reflux in patients suspected of having GERD in the absence of endoscopic evidence of esophagitis, and (2) to evaluate the efficacy of medical or surgical therapy.2,3
Standard pH monitoring measures distal esophageal acid exposure by use of a single pH electrode catheter that is passed through the nose and positioned 5 cm above the superior margin of the manometrically determined LES. After the catheter placement, the patients are encouraged to have a typical day, without dietary or activity limitations. The pH is recorded every 6 to 8 seconds, and the data are transmitted to an ambulatory device for logging. Most devices have an event marker that the patient can activate to indicate the timing of symptoms, meals, and recumbence. At the end of the study, data are downloaded to a computer, which generates a pH tracing and a data summary.
A reflux episode is considered to have occurred when the esophageal pH drops below 4.0. A pH of less than 4.0 best distinguishes between symptomatic patients and asymptomatic control subjects.4 Some gastroesophageal reflux is physiologic and may be seen in normal individuals, especially after meals. Although many scoring systems and parameters have been evaluated, the percentage of time that the pH is less than 4.0 is the single most important parameter to measure and is calculated in most software programs used in the analysis of data from pH monitoring. Results of ambulatory pH monitoring studies are generally considered abnormal when the pH is below 4.0 for more than 4.2% of the total time, or approximately 1 hour a day. Stratification of pH results by supine and upright time is also reported by all software programs.
One potential advantage of ambulatory pH monitoring is the ability to correlate symptoms with reflux episodes. However, even in patients with well-documented GERD, fewer than 20% of reflux episodes are associated with symptoms. This discrepancy has prompted the development of several scoring systems. The symptom index score is defined as the percentage of symptom episodes related to reflux events during the study period. Good correlation is considered to be 50%. The symptom association probability (SAP) score is a statistical probability calculation in which the entire pH tracing is separated into 2-minute intervals and each segment is evaluated for reflux and symptom episodes. A modified chi-square test is used to calculate the probability that the observed distribution could have occurred by chance. Unfortunately, no clinical trials prove that either of these symptom scores predicts a cause-and-effect relationship. Cause and effect can be confirmed only by the response to appropriate antireflux therapy.
pH monitoring may be performed with the patient on or off medical therapy. When the study is performed with the patient off medical therapy, use of proton pump inhibitors (PPIs) is suspended for at least 1 week, H2 receptor blockers for 48 hours, and antacids for 2 hours. The decision to perform a study on or off therapy depends on what information the clinician desires to gain. A pH study off therapy simply documents whether acid reflux is present, such as in a patient considering antireflux surgery or with atypical GERD symptoms. The study performed on therapy helps determine whether patients who have had a poor or incomplete response to therapy are experiencing symptoms as a result of continued acid reflux.
With multiple-probe catheters, additional pH electrodes are located more proximally in the esophagus or the hypopharynx. These electrodes allow the detection of proximal esophageal or pharyngeal acid reflux events, which may be useful in the evaluation of extraesophageal GERD symptoms, particularly laryngitis, chronic cough, and asthma. The conventional location for the proximal esophageal pH probe is 15 to 20 cm above the LES; at this site, the pH should be lower than 4.0 for less than 1% of the time (i.e., for less than 15 minutes a day). The hypopharyngeal probe is usually placed 2 cm above the manometrically determined UES. Although normal values are not clearly defined, more than two or three episodes of hypopharyngeal reflux (i.e., pH below 4) are considered abnormal. Again, it is critical to review the pH tracings to be sure that proximal esophageal or hypopharyngeal reflux events are accompanied by distal esophageal reflux and are not secondary to artifacts.
Ambulatory 24-Hour Bile Monitoring
Bile reflux refers to regurgitation of duodenal contents through the pylorus into the stomach, with subsequent reflux into the esophagus. It may be important because factors other than acid—namely, bile and pancreatic enzymes—may play a role in mucosal injury and symptoms in patients with GERD. For these tests, the presence of bilirubin is used as a surrogate marker for bile reflux, independent of pH. Bilirubin has a characteristic spectrophotometric absorption band at 450 nm; absorption near this wavelength implies the presence of bilirubin and is therefore assumed to represent bile reflux. It should be emphasized that this technique does not directly measure reflux of bile acids or pancreatic enzymes.
As with pH monitoring, data from bile monitoring are usually interpreted by measuring the percentage of time that bilirubin is present at spectrophotometric absorption levels above 0.14; the data can be analyzed separately for total, upright, and supine periods. Several reports have indicated a good correlation between bile monitoring readings and bile acid concentration as measured by duodenogastric aspiration studies.5,6 A variety of substances may result in false positive readings, however, because the equipment indiscriminately records any substance with an absorption of around 450 nm. Patients must eat a modified diet to avoid interference and false readings.6 The clinical role of bile monitoring is limited, especially with the advent of new technologies for ambulatory monitoring.
New Technologies
Because of the limitations of standard 24-hour pH monitoring, several new diagnostic modalities for GERD are under investigation. These include a wireless pH probe and a multichannel intraluminal impedence (MII) monitor.2
Wireless pH probe The wireless pH probe (Bravo, Medtronic Inc, Minneapolis) is a catheter-free monitoring system in which a pH monitoring probe approximately the size of a medication capsule is placed endoscopically. The capsule probe, which is clipped onto the esophageal lining 6 cm above the gastroesophageal junction, transmits pH data to a recording device on the patient's waist. Besides being catheter free, the wireless system has the advantage of recording 48 hours of pH data. The capsule probe falls off the esophageal lining after 4 to 10 days and is passed in the stool. Emerging data suggest that this device may be more sensitive for GERD detection than are conventional catheter-based pH probe systems. It is also clear that patients prefer this device to the catheter-based system, because of reduced discomfort.
Multichannel intraluminal impedence The MII monitor is a relatively new device that measures both acidic and nonacidic refluxates of liquid or gas consistencies.7 This device is capable of measuring characteristics of gastroesophageal reflux that are not detectable by the pH probe, which is currently the gold standard for assessing reflux. Impedence is a measure of the total resistance to current flow between adjacent electrodes; it is capable of differentiating between liquid and gas refluxates on the basis of their inherent current and resistance properties. Combined MII-pH monitoring has an advantage over standard pH monitoring, which cannot detect nonacidic reflux. Clinically, therefore, MII monitoring may be most useful for further evaluation of typical or atypical reflux symptoms that are refractory to acid suppression therapy, for assessment of possible nonacid or nonliquid reflux, or both. Although MII-pH monitoring may be more sensitive than pH monitoring alone for detecting esophageal or hypopharyngeal reflux of gastroduodenal contents, long-term outcome studies are needed to evaluate the clinical relevance of nonacid reflux in patients with persistent symptoms.
Provocative Testing
Provocative testing for esophageal disorders are the Bernstein and the edrophonium tests. These tests are mostly of historical value.
Bernstein test In the Bernstein test, saline and then a 0.1 N hydrochloric acid solution are infused into the esophagus; if the hydrochloric acid infusion reproduces the patient's chest pain and the saline does not, the test is considered positive. Because of its low sensitivity, especially as compared with pH monitoring, the Bernstein test is now rarely used.
Edrophonium test The edrophonium test is a provocative test designed to implicate esophageal motility disorders as a cause of chest pain. Edrophonium, a parasympathomimetic, increases the amplitude and duration of esophageal contractions. The test consists of an intravenous injection of 80 µg of edrophonium, which will produce esophageal manometric changes and cause chest pain in 20% to 30% of patients who have noncardiac chest pain. The sensitivity of edrophonium testing is low and varies widely in the literature. Also, studies have shown poor correlation between increased esophageal contraction amplitude and duration and the patient's symptoms of chest pain.
Disease States Causing DysphagiaEsophageal Motility Abnormalities
A new classification system for esophageal motility disorders categorizes such disorders according to four major patterns of esophageal manometric abnormalities: inadequate LES relaxation, uncoordinated contraction, hypercontraction, and hypocontraction [see Table 1].8 Most esophageal motility abnormalities fall predominantly into one of these four major categories, although there can be considerable overlap.
Processes that affect the inhibitory innervation of the LES (e.g., achalasia) can interfere with LES relaxation and thereby delay esophageal clearance. In the body of the esophagus, abnormal motility is characterized by uncoordinated contraction, hypercontraction, and hypocontraction. Uncoordinated esophageal contractions (i.e., contractions that are not peristaltic and not directed toward the stomach) can delay esophageal clearance. Such uncoordinated contractions are the hallmark of diffuse esophageal spasm. Hypercontraction abnormalities are those that are characterized by contractions that are of high amplitude, long duration, or both. The putative disorders of hypercontraction (e.g., nutcracker esophagus, isolated hypertensive LES) are perhaps the most controversial of the abnormal esophageal motility patterns because it is not clear whether esophageal hypercontraction has any pathophysiologic significance. In contrast, hypocontraction abnormalities that result from weak (i.e., low-amplitude) muscle contractions can cause ineffective esophageal motility that delays esophageal clearance. In addition, LES hypotension can result in GERD.
Achalasia
Achalasia is a primary esophageal motility disorder of unknown etiology characterized by insufficient LES relaxation and loss of esophageal peristalsis. Available data suggest hereditary, degenerative, autoimmune, and infectious factors as possible causes.9 Pathologic changes in the myenteric plexus consist of a patchy inflammatory infiltrate of T cells, eosinophils, and mast cells; loss of ganglion cells; and myenteric neural fibrosis.10 These changes result in selective loss of postganglionic inhibitory neurons, which contain both nitric oxide and vasoactive intestinal polypeptide (VIP). The postganglionic cholinergic neurons of the myenteric plexus are spared, leading to unopposed cholinergic stimulation. The resulting high basal LES pressures and loss of inhibitory input lead to insufficient LES relaxation. Aperistalsis is related to the loss of the latency gradient along the esophageal body—a process mediated by nitric oxide.
The most common symptoms of achalasia include dysphagia for solids and liquids, regurgitation, and chest pain. Most patients are symptomatic for years before seeking medical attention. Achalasia patients tend to localize their dysphagia to either the cervical or xiphoid areas. Initially, dysphagia may be for solids only, but most patients have dysphagia for solids and liquids by the time of presentation.9 Patients tend to accommodate for their problem by using various maneuvers, including lifting the neck or drinking carbonated beverages to help empty the esophagus. Regurgitation occurs in 75% of achalasia patients and becomes a greater problem as the esophagus dilates with progression of the disease. Regurgitation occurs most commonly in the recumbent position and may awaken the patient from sleep because of choking and coughing. Chest pain is experienced by approximately 40% of achalasia patients. Weight loss occurs in 60% but is usually minimal.11
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| Figure 4. Esophagram of Patient with Achalasia |
When the diagnosis of achalasia is suspected, a barium esophagram with fluoroscopy is the best initial diagnostic study. This test will reveal loss of primary peristalsis in the distal two-thirds of the esophagus. In the upright position, there will be poor esophageal emptying, with retained food and saliva often producing a heterogeneous air-fluid level at the top of the barium column. The esophagus may be dilated; in early disease, this is often minimal, but in chronic disease, it can be massive, with a sigmoidlike tortuosity [see Figure 4]. There is a smooth tapering of the lower esophagus leading to the closed LES, resembling a bird's beak. The presence of an epiphrenic diverticulum may also suggest the diagnosis of achalasia.
Esophageal manometry may also be used to establish the diagnosis.12 In the body of the esophagus in patients with achalasia, aperistalsis is always present; all swallows are followed by simultaneous contractions, typically with low contraction amplitudes. Abnormal LES relaxation is also seen in all achalasia patients. About 70% to 80% of patients have absent or incomplete LES relaxation with swallows; in the remainder, the relaxations are complete but are of short duration. The baseline LES pressure is usually elevated but may be normal in up to 45% of patients; however, a low LES pressure is never seen in untreated patients with achalasia.
All patients with achalasia should undergo upper endoscopy to exclude pseudoachalasia arising from a tumor at the gastro-esophageal junction. Pseudoachalasia may mimic classic achalasia both clinically and manometrically. This diagnosis should be suspected in older patients, those with a short duration of symptoms, and those with more significant weight loss. At endoscopy, the esophageal body in classic achalasia often appears dilated and tortuous. Retained secretions and food debris may be encountered. The LES region usually appears puckered and remains closed with air insufflation; however, with gentle pressure, the endoscope will traverse this area. The gastroesophageal junction and gastric cardia need to be examined closely for the presence of tumors to rule out pseudoachalasia.
There is no cure for achalasia, but most patients can obtain relief of symptoms and improvement in esophageal emptying. The two most effective treatments are graded pneumatic dilation and surgical myotomy. All patients considered for pneumatic dilation should be surgical candidates, because the procedure is associated with a 2% to 5% risk of perforation.9
Pneumatic dilation, performed endoscopically, uses a graded series of balloon dilators to dilate and disrupt the circular muscle fibers of the LES. After pneumatic dilation, all patients should undergo a Gastrografin study followed by a barium swallow to exclude esophageal perforation. Studies to date indicate good to excellent relief of symptoms in 50% to 93% of patients using the graded dilators.9 The clinical response improves with increasing size of the balloon diameter.13
Surgical myotomy for achalasia involves performing an anterior incision of the LES (Heller myotomy), usually in combination with an antireflux procedure such as gastric fundoplication. Myotomies are commonly performed by laparoscopy, with 80% to 94% of patients showing a good to excellent response.9 A potential complication of myotomy is GERD, which occurs in 10% to 20% of patients.14
Alternative treatments for patients in whom pneumatic dilation or surgery poses high risk include endoscopic injection of the LES with botulinum toxin and pharmacologic treatment with nitrates or calcium channel blockers. Injection of botulinum toxin, which inhibits the release of acetylcholine from nerve terminals, is initially effective in about 85% of patients.9 Symptoms recur in more than 50% of patients within 6 months, however.15 Therefore, botulinum toxin injection is reserved for elderly patients who are at high surgical risk. Calcium channel blockers and long-acting nitrates are effective in reducing LES pressure and temporarily relieving dysphagia, but they do not improve peristalsis or LES relaxation with swallowing.16 The clinical effect is of short duration, symptom relief is usually incomplete, and clinical efficacy decreases over time. Given these limitations, pharmacologic therapy is recommended only for patients who are not candidates for pneumatic dilation or surgical myotomy and in whom botulinum toxin injections fail.
Other Motility Disorders
In addition to achalasia, a number of other primary motility disorders of the esophagus have been described.8 These disorders are defined in terms of specific manometric criteria, and for the most part, their clinical relevance is questionable.17 These disorders are typically noted on manometry performed in patients with chest pain or dysphagia.
Diffuse esophageal spasm
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| Figure 5. Esophagram in Diffuse Esophageal Spasm |
Nutcracker esophagus Nutcracker esophagus is another common manometric diagnosis in noncardiac chest pain patients. This disorder is defined by high-amplitude peristalsis. Nutcracker esophagus is unlikely to be a true primary motility disorder; more likely, it is a marker for increased visceral pain perception.
Ineffective esophageal motility Ineffective esophageal motility (IEM) is a hypocontractile disorder that has relevant clinical associations. IEM is defined by a distal esophageal contraction amplitude of less than 30 mm Hg in 30% or more of wet swallows. The prevalence of IEM is higher in patients with GERD, especially those who have respiratory symptoms.18
Secondary motility disorders Secondary motility disorders characteristically result from systemic conditions, most commonly scleroderma. Other systemic conditions that can result in esophageal hypomotility include hypothyroidism, diabetes mellitus, and amyloidosis [see Esophageal Manifestations of Systemic Disease, below].
Strictures
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| Figure 6. Endoscopic Views of Esophageal Strictures |
An esophageal stricture is defined as any loss of lumenal area within the esophagus. The normal esophageal lumen measures 20 mm in diameter; reduction of the diameter to less than 15 mm predictably results in dysphagia. Less severe strictures can cause intermittent dysphagia to large food pieces such as meat and bread. Esophageal strictures have multiple intrinsic and extrinsic causes [see Table 2]. Intrinsic strictures are most common, with acid/peptin accounting for the majority of cases [see Figure 6].
Regardless of etiology, the foundation for treatment of benign stricture disease is esophageal dilation. Although mild reflux-related strictures may respond to PPI therapy, most will require endoscopic dilation. Operators can choose from a variety of dilators, depending on the characteristics of the stricture. Complications of esophageal dilation include perforation (0.5% of cases), bleeding (0.3%), and transient bacteremia (20% to 50%).19,20 Patients with radiation-induced or malignant strictures are at higher risk for perforation. To minimize the risk of perforation, the so-called rule of three applies: no more than three dilations with dilators of progressively higher size are to be performed per session, once heme is noted or resistance to dilation is encountered. The goal of esophageal dilation is to obtain a lumen diameter of greater than 15 mm. Approximately 90% of patients whose esophagus is dilated to a diameter of 15 mm have no recurrence at 24 months.21
Refractory esophageal strictures are defined by a lack of response to two or more dilations. The causes for refractory strictures may include ongoing insults from swallowed medication [see Pill-Induced Injury, below], uncontrolled acid reflux, and inadequate lumen diameter with dilations. PPIs are superior to H2 blockers in preventing recurrence of acid-related strictures.22 Treatment of refractory strictures includes eliminating offending agents (e.g., pills or acid) and gentle dilation to 15 mm. Intralesional steroids injected before dilation are safe and probably effective for refractory strictures. Surgery is now extremely rarely performed for benign strictures, but it may be considered for patients with strictures that fail to respond to aggressive medical therapy and dilation.
Rings and Webs
Esophageal rings and webs are common findings on upper endoscopy. Although many of these structural abnormalities are clinically silent, some result in intermittent solid food dysphagia, aspiration, or regurgitation.
Although the terms esophageal ring and web have been used interchangeably, there are subtle differences between the two entities. Rings are circumferential, can consist of mucosa or muscle, and most commonly occur in the distal esophagus.23 Webs occupy only part of the esophageal lumen, are always mucosal, and usually are located in the proximal esophagus.
Esophageal webs can be found in as many as 5% of asymptomatic persons.23 When symptomatic, they usually cause dysphagia. The triad of proximal esophageal webs, iron deficiency anemia, and dysphagia was reported independently by Plummer and Vinson in the United States and by Paterson and Kelly in the United Kingdom; consequently, it has been termed Plummer-Vinson or Paterson-Kelly syndrome.24 Barium radiography is the most sensitive test for diagnosing esophageal webs [see Figure 7]. Endoscopic visualization is also possible; on endoscopy, the web will appear as a thin, eccentric lesion with normal-appearing mucosa. Some webs are located so far proximally that routine passage of the endoscope through the UES fractures the web before its presence becomes apparent.
Treatment of symptomatic esophageal webs consists of mechanical disruption. This can be accomplished with bougie or balloon dilators.
Esophageal rings are of two types: Schatzki, or B, rings; and A rings. Schatzki rings occur at the gastroesophageal junction at the distal margin of the LES and are the most common cause of intermittent solid-food dysphagia and food impaction. The presence of symptoms depends on the luminal diameter. If the ring diameter is less than 13 mm, the patient will have symptoms; if it is greater than 20 mm, the patient will almost never have symptoms.25 With rings between 13 mm and 20 mm, which account for the majority of Schatzki rings, symptoms are variable. Possible causes of Schatzki rings include congenital lesions and GERD.
The most sensitive test for detecting a Schatzki ring is the barium swallow. However, most Schatzki rings can also be identified on endoscopy, with patience and the use of air insufflation.
Treatment is required only in symptomatic patients and is usually accomplished with mechanical bougienage. Recurrence of symptoms requiring repeat dilation is not uncommon, and some authors recommend maintaining the patient on acid suppression, given the possible association with GERD.26
The A ring is a muscular ring most commonly detected on barium swallow. These rings occur at the proximal margin of the LES, approximately 2 cm proximal to the squamocolumnar junction. They rarely cause symptoms.
Eosinophilic Esophagitis
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| Figure 8. Endoscopic View in Eosinophilic Esophagitis |
In recent years, eosinophilic esophagitis (also known as ringed, feline, or corrugated esophagus) has rapidly gained recognition as a cause of dysphagia and, often, of food impaction in young adults.27,28 Most cases are recognized when endoscopy in a patient with dysphagia discloses the presence of multiple esophageal rings [see Figure 8]. The etiology is unclear, but GERD, a congenital abnormality, and allergic conditions have been implicated.
Eosinophilic esophagitis is characterized by the presence of eosinophils in the esophageal mucosa at higher levels than those found in patients with acid reflux. The eosinophil density required for the diagnosis of eosinophilic esophagitis is more than 15 eosinophils per high-power field; a further criterion is that the eosinophilia does not clear after appropriate treatment with a PPI.27 Features that support an allergic etiology are that patients with eosinophilic esophagitis often have other atopic diseases and may have a family history of atopy.27
Despite the limitations in knowledge of the natural history of eosinophilic esophagitis and the lack of consensus on the therapeutic goal, a number of dietary, medical, and endoscopic therapies have been reported. Dietary modification and elimination have been effective in the pediatric population, suggesting that certain foods may serve as environmental triggers for the eosin ophilic infiltration. Pharmacologic treatment with oral or topical corticosteroids or leukotriene receptor antagonists has been shown to improve clinical symptoms and histology in the majority of patients with eosinophilic esophagitis. Although current studies do not support a significant role for GERD in most cases of eosinophilic esophagitis, peptic acid suppression is clearly indicated in patients complaining of GERD symptoms. Because many adults present with strictures, endoscopic esophageal dilation is another management modality. Several treatment sessions are often required to obtain a desired esophageal lumen size of 15 mm. These patients are also at higher risk for painful, deep mucosal tears. Alternatively, dilation with bougienage can be performed.
Esophageal Manifestations of Systemic Disease
Connective tissue diseases, diabetes mellitus, thyroid disease, amyloidosis, and Behçet disease are the more common systemic disorders that may involve the esophagus. The severity and frequency of esophageal symptoms varies both within and between these diverse disorders.
Scleroderma
Gastrointestinal involvement, which may manifest as heartburn, regurgitation, or dysphagia, occurs in 90% of patients with scleroderma; approximately 50% of these patients experience serious symptoms.29 Scleroderma is characterized by a small-vessel vasculopathy and proliferation of connective tissue with fibrosis of multiple organs. The fibrosis predominately affects smooth muscle in the gastrointestinal tract, leading to motility abnormalities. In scleroderma patients, there is progressive loss of peristalsis in the esophagus and eventual ablation of the LES pressure. This leads to the classic manometric findings of aperistalsis in the distal two thirds of the esophagus and very low LES pressure. Barium esophagrams typically demonstrate a dilated esophagus, a patulous gastroesophageal junction, and free reflux into the proximal esophagus. Because of the disruption of the antireflux barrier and the inability to clear reflux from the esophagus, scleroderma patients are often afflicted with severe, complicated GERD. The sequelae of severe GERD are common in these patients and include Barrett esophagus, esophagitis, and strictures. Dysphagia may result from impaired peristalsis or from acquired peptic strictures. Treatment consists of aggressive acid suppression; dilation of strictures, if necessary; and surveillance of Barrett esophagus, if present. Control of the underlying scleroderma is important, but currently available treatments are often unsatisfactory.
Other Connective Tissue Diseases
Esophageal involvement may be a minor manifestation of other connective tissue diseases, including mixed connective tissue disease, inflammatory myopathies, systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome. The myopathies are distinct in that they affect striated muscle with resultant dysfunction in the oropharynx and proximal esophagus and thus may cause oropharyngeal dysphagia [see Figure 2]. The other rheumatologic disorders can be manifested by hypomotility and, rarely, dysphagia.
Diabetes Mellitus
Esophageal symptoms in diabetes mellitus typically result from decreased peristalsis and esophageal emptying. In addition, diabetes can lead to gastroparesis, resulting in secondary GERD symptoms. Both the gastric and esophageal changes likely have a neurologic basis. Treatment with prokinetic agents (e.g., metoclopramide) has been tried; such agents are largely ineffective for the esophageal dysmotility but may help patients with gastroparesis.
Behçet Disease
Behçet disease, an idiopathic inflammatory disorder typified by recurrent oral and genital aphthous ulceration, can infrequently involve the esophagus. Esophageal manifestations include ulcerations, erosions, esophagitis, and perforation. When the esophagus is involved, there is usually small bowel or colonic ulceration as well, making Behçet disease difficult to distinguish from Crohn disease.
Hypothyroidism
Hypothyroidism is a rare cause of dysphagia. Manometry has documented decreased amplitude and velocity of peristalsis that improves with thyroid replacement therapy.
Amyloidosis
Esophageal manometric abnormalities may be seen in up to 60% of patients with amyloidosis.30 Aperistalsis, hypomotility, incompletely relaxing LES, and decreased LES pressure have all been reported. This dysmotility is thought to result from neurogenic dysfunction rather than amyloid deposition in the esophageal wall. Despite the frequency of these manometric findings, esophageal symptoms are rarely prominent in amyloidosis.
Cutaneous Diseases and the Esophagus
Several dermatologic diseases have esophageal manifestations. The most important are the blistering skin diseases: epidermolysis bullosa, bullous pemphigoid, cicatricial pemphigoid, and pemphigus vulgaris.
Epidermolysis Bullosa
Epidermolysis bullosa consists of several disorders typified by blister formation after minor trauma. Dystrophic epidermolysis bullosa (epidermolysis bullosa dystrophica [EBD]) is an inherited disorder with both autosomal dominant and autosomal recessive forms. Esophageal involvement is more frequent in the recessive form of EBD, which manifests during childhood and features the development of blisters of the skin, mouth, and esophagus. Esophageal bullae result from minor trauma from food and can lead to severe dysphagia and odynophagia. The lesions heal with fibrosis; this leads to constriction of the mouth and to esophageal strictures. Both of these conditions may result in malnutrition. Endoscopy is relatively contraindicated in EBD patients because it may cause bullae to form, but endosocpy may be necessary for the gentle dilation of strictures. Some patients require esophageal resection and replacement, whereas others need lifelong parenteral nutrition.
Bullous Pemphigoid
Bullous pemphigoid is the most common bullous skin disease. Patients have antibodies to skin basement membrane; histologically, subepidermal bullae are present. The skin lesions consist of pruritic plaques than evolve into bullae. Esophageal involvement is rare and consists of bullae. Glucocorticoid treatment is effective. Both bullous pemphigoid and cicatricial pemphigoid (see below) may predispose to esophageal carcinoma.
Cicatricial Pemphigoid
Cicatricial pemphigoid is a bullous disorder involving mucosal surfaces, with minimal or absent cutaneous lesions. The esophagus is involved in fewer than 5% of cases, but this disorder is less responsive to treatment than bullous pemphigoid. Because these bullae heal by fibrosis, endoscopic findings include not only bullae but also webs and strictures, usually in the proximal esophagus. Although steroids may be effective, stricture dilation is often required.
Pemphigus Vulgaris
Pemphigus vulgaris is characterized by intraepidermal bullous formation in the skin and mucous membranes. It is an autoimmune disease characterized by antibodies to the cell adhesion molecule desmoglein 3, which is expressed in stratified squamous epithelia. The esophagus is frequently involved, along with the mouth, with bullae and erosions. Glucocorticoid treatment is usually effective.
Lichen Planus
Lichen planus is characterized by skin papules, mucosal hyperkeratosis, and mucosal erosions. Esophageal involvement is unusual, but patients can present with strictures and dysphagia.
Esophageal Diverticula
An esophageal diverticulum is a sac that protrudes from the esophageal wall. As in the rest of the gastrointestinal tract, a true diverticulum is one that contains all layers of the wall. A false diverticulum contains only mucosa and submucosa that have herniated through a defect in the muscular wall. These diverticula are most practically classified into four categories on an anatomic basis: Zenker diverticula, midesophageal diverticula, epiphrenic diverticula, and intramural pseudodiverticulosis.
Zenker Diverticulum
Zenker diverticulum is often referred to as an esophageal diverticulum. However, its location is in fact proximal to the esophagus, above the UES, and it therefore should be considered a hypopharyngeal diverticulum. Zenker diverticula are believed to form as a result of an area of weakness in the Killian triangle, between the cricopharyngeal sphincter and the inferior pharyngeal constrictor muscle. The primary abnormality that leads to the development of the diverticula is incomplete relaxation of the UES. An association between Zenker diverticula and gastroesophageal reflux has been suggested but not confirmed. Typical symptoms include oropharyngeal dysphagia, regurgitation of undigested food, halitosis, cough, and aspiration pneumonia. Barium swallow is an excellent test for the diagnosis of Zenker diverticulum.
Many small diverticula are asymptomatic, but symptomatic patients with large diverticula should be offered treatment. The classic treatment is an open surgical resection of the diverticulum with division of the cricopharyngeus muscles. Another option for extremely large diverticula is diverticulopexy, or suspension of the diverticulum in a cranial direction. In addition, recent advances in endoscopic stapling and carbon dioxide laser technologies have added new therapeutic possibilities.31
Midesophageal Diverticula
Diverticula in the midesophageal area are of two types: traction and pulsion. Both are most commonly asymptomatic.
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| Figure 9. Midesophageal Traction Diverticulum |
Midesophageal traction diverticula are the only true diverticula in the esophagus. Traction diverticula are located in the middle third of the esophagus and result from external pulling of the esophageal wall by neighboring inflammatory or fibrotic tissue, such as adjacent tuberculous mediastinitis [see Figure 9].
Pulsion diverticula result from internal forces applied to a portion of the esophageal wall. They are often associated with motility disorders. Their pathogenesis is similar to Zenker and epiphrenic diverticula.
Epiphrenic Diverticula
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| Figure 10. Multiple Epiphrenic Diverticula |
Epiphrenic diverticula, which are located near the diaphragmatic hiatus, occur in the distal esophagus near the LES [see Figure 10]. These diverticula are often the result of a motility disorder such as achalasia or diffuse esophageal spasm.32 It is imperative to obtain manometric studies in patients with an epiphrenic diverticulum to rule out an associated motility disorder. Most epiphrenic diverticula are asymptomatic, but chest pain or regurgitation occur occasionally. Treatment consists of managing the underlying motility disorder and diverticulotomy with or without myotomy for symptomatic diverticula.
Intramural Pseudodiverticula
Esophageal intramural pseudodiverticula are multiple small outpouchings apparent on barium swallow or endoscopy. These rare outpouchings are not acutual diverticula; rather, they are ducts draining dilated submucosal glands. The etiology is not clear, but they are associated with acid reflux, alcoholism, diabetes mellitus, esophageal strictures, and esophageal cancer.
Esophageal Foreign Bodies
Ingestion of foreign bodies occurs most commonly in children, the mentally ill, and prison inmates. Elderly persons with loose-fitting dentures are also at increased risk. The esophagus has several areas of physiologic narrowing where a foreign body may become impacted: the UES, the level of the aortic arch, and the diaphragmatic hiatus/LES. The management of esophageal foreign bodies varies according to the type of foreign body. To begin with, true foreign bodies must be differentiated from food impaction.
Food impactions tend to occur in adults with benign structural abnormalities of the esophagus. Patients usually present with the sudden onset of dysphagia after swallowing a large piece of beef, hot dog, or bread. Patients may complain of chest pain and difficulty swallowing their own saliva. Typically, the patient has a history of intermittent solid food dysphagia. Management includes obtaining anteroposterior and lateral chest radiographs to assess for free air and to look for bones in the food bolus. A trial of pharmacologic therapy with glucagon, 1 to 2 mg intravenously, which relaxes the LES, can be given; however, glucagon is rarely successful in relieving a food impaction. The primary therapy for food impaction is prompt endoscopy. If the patient is able to manage his or her own saliva and is comfortable, this can be done on a nonurgent basis, but preferably within 12 hours.33 There is no role for barium studies, unless to confirm disimpaction. Endoscopic intervention involves pushing the bolus into the stomach or, if that cannot be done safely, extracting it. After removal of the foreign body, the esophagus should be assessed for underlying pathology, which is present in approximately 90% of patients.34 This assessment can be difficult, because some inflammation, edema, and erythema are usually present. If a benign structural abnormality is found, dilation should be arranged at a later date. If only minimal inflammatory change is present, dilation may be performed safely in the same session.
True foreign bodies are classified on the basis of their physical characteristics: small and blunt, sharp or pointed, or long. Plain radiographs of the neck, chest, and abdomen are essential to evaluate for perforation and to attempt to localize the foreign body. Any foreign body in the esophagus must be removed, because pressure necrosis with resultant perforation may occur. Sharp or long objects carry a 15% to 35% risk of perforation and should be removed regardless of location.35 Conversely, most small blunt objects that have passed the esophagus will traverse the remainder of the gastrointestinal tract without incident.
Small blunt objects, such as coins, can become lodged at areas of physiologic or pathologic narrowing, even if they are smaller than the usual esophageal diameter of 20 mm. Small objects can be removed endoscopically from the esophagus, using a variety of specialized forceps designed for foreign body extraction. In children, the procedure is usually performed under general anesthesia with endotracheal intubation to protect the airway.
Sharp and long foreign bodies in the esophagus are emergencies, whereas those that have passed into the stomach can be addressed urgently. If the object is not within reach of the endoscope, the patient should be followed closely with radiographs. Many sharp objects will pass through the gastrointestinal tract without difficulty, but surgery may be indicated if there is evidence of perforation, obstruction, or nonprogression.
Gastroesophageal Reflux DiseaseGERD can manifest as chronic symptoms or as esophageal mucosal damage secondary to the abnormal reflux of gastric contents.36 Reflux esophagitis refers to a subgroup of patients with GERD who have endoscopic or histopathologic changes in the esophageal mucosa. The term nonerosive reflux disease (NERD) refers to a condition in which patients have typical GERD symptoms, but findings on endoscopy are normal. In the spectrum of GERD, NERD accounts for approximately 60% of patients, reflux esophagitis for 30%, and Barrett esophagus for the remaining 10%.37
Pathogenesis
GERD occurs when the normal antireflux barrier between the stomach and the esophagus is impaired, either transiently or permanently. Therefore, defects in the esophagogastric barrier, such as LES incompetence, TLESR, and hiatal hernia, are the primary factors involved in the development of GERD.38 TLESRs are short relaxations of the LES that do not occur in response to swallowing [see Normal Esophageal Anatomy and Physiology, above]. Studies have demonstrated that TLESR is the primary mechanism for gastroesophageal reflux in normal persons and those with mild GERD. Conversely, severe GERD with complications is more likely to develop in persons who have a permanent functional or structural alteration, such as low basal LES pressure or a large hiatal hernia.39 Delayed gastric emptying can also be a contributing factor to the development of GERD.
Symptoms of GERD develop when the offensive factors in the gastroduodenal contents (e.g., acid, pepsin, bile acids, and trypsin) overcome several lines of esophageal defense, including esophageal acid clearance and mucosal resistance. As more components of esophageal defense break down, the severity of symptoms increases.
Diagnosis
Clinical Manifestations
Classic symptoms of GERD are heartburn and acid regurgitation. Symptoms often occur after meals and may increase when a patient is recumbent. Although these classic symptoms are specific for GERD, they are not sensitive for the diagnosis, as determined by abnormal results on 24-hour pH monitoring. Other typical ancillary symptoms are dysphagia, odynophagia, and belching. Patients with GERD may also present with atypical symptoms, including asthma, chest pain, cough, laryngitis, and dental erosions [see Extraesophageal GERD, below].
There is no gold standard for confirming the presence of GERD. Therefore, it is reasonable to consider an initial empirical trial of antisecretory therapy in a patient with classic GERD symptoms in the absence of alarm signs. Further diagnostic testing should be considered if the symptoms fail to respond to an empirical course of antisecretory therapy or the patient develops alarm signs, such as dysphagia, odynophagia, weight loss, chest pain, or choking.
Laboratory Studies
Endoscopy is the technique of choice to evaluate the mucosa in patients with symptoms of GERD. Reflux esophagitis is present when erosions or ulcerations are present at the squamocolumnar junction. There are many grading systems for characterizing the severity of reflux esophagitis; the one most commonly used is the Los Angeles (LA) classification [see Table 3].40
Although ambulatory 24-hour pH monitoring has long been considered the gold standard for the diagnosis of GERD, this test has limitations that remain underappreciated. Results are normal in 25% of patients with erosive esophagitis and in approximately 33% of patients with NERD.41 Nevertheless, 24-hour pH testing can be useful to quantitate esophageal acid exposure and to correlate symptom timing with reflux events. Given the lack of a reliable diagnostic test, a clinical response to acid suppression is a good indication that a patient's symptoms may be from GERD.
Treatment
The goals of treatment in GERD are to relieve symptoms, heal esophagitis, prevent recurrence of symptoms, and prevent complications. A variety of lifestyle modifications are recommended in the treatment of GERD. These include avoidance of precipitating foods (e.g., fatty foods, alchohol, caffeine), avoidance of recumbency for 3 hours postprandially, elevation of the head of the bed, smoking cessation, and weight loss.42 Although these measures make sense physiologically, few data are available to support them. Additionally, with the availability of potent acid-suppressive agents, dietary modification as the primary therapy for GERD is no longer strongly emphasized.
Antacids and alginic acid can provide temporary relief of episodic heartburn. Despite the wide use of these over-the-counter products, surprisingly few data are available on their utility for healing reflux esophagitis or for the long-term management of GERD symptoms. Sucralfate, a complex metal salt of sulfated sucrose, is an exceptionally safe medication that has some demonstrated efficacy in the treatment of mild reflux esophagitis. Few published data are available on the use of sucralfate in GERD, however.
In theory, prokinetic agents may decrease gastroesophageal reflux by increasing LES pressure and by enhancing esophageal and gastric clearance. Currently, metoclopramide is the only prokinetic agent available in the United States for the treatment of GERD. Metoclopramide is a dopamine antagonist; its use is limited by side effects such as agitation, restlessness, somnolence, and extrapyramidal symptoms, which occur in up to 30% of patients. Cisapride, a serotonin-4 receptor agonist, demonstrated efficacy in mild GERD, but this agent was withdrawn when it was found to cause lethal cardiac arrhythmias in patients with a number of predisposing conditions.
The cornerstone of GERD therapy is the administration of agents that decrease gastric acid secretion, thereby decreasing esophageal acid exposure. H2 receptor antagonists in standard divided doses achieve complete symptom relief in approximately 60% of patients and heal esophagitis in about 50%.43 The H2 blockers are most useful for patients with GERD of mild to moderate severity, in whom the highest rates of healing can be anticipated. However, healing rates with these agents are poor in patients who have severe reflux esophagitis. High doses of H2 blockers (up to eight times the conventional dose) have been used effectively to treat esophagitis in severe cases of GERD, but this approach generally is not recommended. Few data document the long-term efficacy of H2 receptor blockers used in any dosage, and many patients develop tolerance to the antisecretory effects of these agents.
For patients with severe GERD, most authorities prescribe PPIs rather than high-dose H2 receptor blocker therapy. PPIs are superior to H2 blockers both for relieving symptoms and for healing erosive esophagitis, with response rates approaching 90%.43
GERD is a chronic relapsing disease with almost universal recurrence of symptoms after treatment withdrawal; thus, it requires maintenance therapy in many patients. Long-term therapy with PPIs is again superior to long-term therapy with H2 blockers; 80% of patients taking PPIs maintain remission, compared with 50% of patients taking H2 blockers.44 After more than a decade of experience with PPIs in the United States, initial concerns regarding the long-term safety of these agents remain unsubstantiated.45 Nevertheless, in clinical practice, step-down therapy is recommended for patients suspected of having GERD. Patients are initially treated with PPIs until clinical response is achieved and are then treated with H2 blockers or PPIs on an as-needed basis.
Antireflux surgery, now performed primarily by the laparoscopic approach, remains an option for carefully selected patients with well-documented GERD.46 Patients who choose surgery typically do so because of concerns about the cost or potential adverse effects associated with long-term PPI therapy. Patients with large hiatal hernias with predominant regurgitation symptoms are also good candidates. In patients with GERD that is refractory to high-dose PPI therapy, any consideration of surgery must be guarded; to justify operative treatment in such cases, evidence of ongoing esophageal acid exposure or damage despite continuing use of medication should be documented. Studies of impedance pH monitoring showing persistent nonacid reflux in some patients with GERD that is refractory to PPI therapy suggest a possible benefit from surgery, but controlled studies are needed before surgery can be recommended in this group.47 At this time, surgery is not advised in patients unresponsive to PPIs who have no evidence of esophageal acid exposure or nonacid regurgitation.
Endoscopic techniques for treating GERD have been developed and are undergoing clinical trials.48,49 These techniques include endoscopic suturing and delivery of radiofrequency energy to the gastroesophageal junction. All have been shown to result in improved LES pressure; however, most studies of endoscopic therapy have included only limited follow-up data for a relatively small number of patients. Therefore, the durability of these approaches is unknown. Serious adverse events were reported with one form of endoscopic therapy—injectable agents for bulking the gastroesophageal junction—and such agents are no longer available. A number of other endoscopic antireflux procedures are under investigation. Small studies report promising results, but the safety and efficacy of these procedures are not yet known, and their role in the treatment of GERD is not clear.
Extraesophageal GERD
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| Figure 11. Treatment for GERD |
Atypical manifestations of GERD include asthma, chest pain, chronic cough, laryngitis, and dental erosions. Although the relationship between each of these manifestations and GERD varies, there are some common themes. GERD patients with atypical symptoms tend not to have the classic symptoms of heartburn and regurgitation, and they often do not have esophagitis or Barrett esophagus. Additionally, the response to antireflux therapy in this group of patients is often less predictable. In general, an empirical trial of a PPI twice daily is indicated initially, because there is no diagnostic gold standard for GERD. If PPI treatment fails, ambulatory pH testing is recommended to ensure that medical therapy has been intensive enough [see Figure 11]. The diagnosis of GERD can be confirmed only when specific antireflux therapy provides consistent symptom relief.
Laryngitis
There is increasing evidence that GERD can cause laryngeal signs and symptoms. This is often referred to as reflux laryngitis or laryngopharyngeal reflux. In fact, it is estimated that 4% to 10% of patients presenting to otolaryngologists do so because of symptoms in part related to GERD.50,51 Symptoms of reflux laryngitis can include hoarseness, throat clearing, dysphagia, increased phlegm, and globus sensation.
GERD may be responsible for causing significant laryngeal changes, including erythema, edema, ulcerations, vocal cord nodules and polyps, granulomas, or even leukoplakia and cancer. Although some experts believe that these laryngeal signs are specific for acid-related problems, others suggest that these changes may be secondary to smoking, excessive use of alcohol, allergies, asthma, viral illnesses, or voice abuse. A 2002 study investigated the baseline prevalence of laryngeal signs in 105 healthy subjects who were without reflux or laryngeal complaints. The majority of these normal subjects (87%) had at least one abnormal finding in the larynx.52 The three most common laryngeal findings included interarytenoid bar, arytenoid medial wall erythema, and posterior pharyngeal wall cobblestoning, all of which had previously been considered pathognomonic for GERD. Importantly, these signs in healthy subjects were associated with the presence of other upper airway irritants, including chronic nasal congestion, postnasal drip, alcohol use, or asthma. Therefore, this study suggests the potential for overdiagnosis of GERD as a result of the poor specificity of some of the laryngeal signs currently considered to indicate GERD. Other studies comparing laryngeal signs in normal volunteers with those in GERD patients suggest that two laryngeal findings may be more specific for GERD-induced laryngeal injury: vocal cord lesions and arytenoid medial wall erythema and edema.53,54 This suggests the possibility of identifying more specific laryngeal findings in patients with GERD.
There is still controversy about the prevalence of GERD-related laryngeal signs and symptoms, partially related to the lack of consensus about the utility of 24-hour esophageal pH monitoring in diagnosing this disorder. Studies have clearly shown that 24-hour esophageal pH monitoring may not be ideal for diagnosing atypical GERD. Overall, only 50% of patients with laryngoscopic signs of GERD have abnormal esophageal acid exposure, irrespective of the location of the pH probe (distal or proximal esophagus or hypopharyngeal). This low rate may reflect either overdiagnosis of GERD as the cause of laryngeal pathology or the lack of sensitivity of the pH probes in diagnosing acid-related disease in this group of patients. Distal and proximal esophageal pH probes are at best 75% and 50% sensitive, respectively, in detecting acid reflux in a group of patients with classic acid reflux disease.55 Furthermore, studies using distal, proximal or hypopharyngeal probes in patients with laryngeal pathology yielded conflicting data on their ability to predict clinical improvement on the basis of abnormal findings for each of the pH probes.
Because of the unpredictable response of laryngeal manifestations to acid suppression and negative results in placebo-controlled studies,56 there are currently no accepted treatment protocols for these cases. The negative placebo-controlled studies reflect the lack of a reliable method for identifying patients whose laryngeal signs and symptoms result from GERD. Nonetheless, open-label studies suggest that PPIs may be more effective than H2 receptor blockers and should be the first line of therapy in patients suspected of having reflux-related laryngeal signs and symptoms.51 Clinical response rates ranging from 60% to 98% have been reported with medical therapy. However, there is a lack of consensus on dose, dosing frequency, and length of therapy in this group of patients. Initial aggressive therapy with twice-daily doses followed by tapering to once-daily dosing in responders is the approach currently recommended [see Figure 11].51
Asthma
There is a clear association between asthma and GERD. Approximately 70% to 80% of asthma patients have GERD.57 Two main pathophysiologic mechanisms of acid-induced asthma have been proposed: (1) proximal esophageal reflux leading to microaspiration and bronchospasm, and (2) a vagally mediated esophageal-bronchial reflex resulting in bronchospasm.58 Features that suggest GERD-related asthma are adult onset of asthma; no family history of asthma or atopy; and heartburn, especially if it precedes the onset of asthma. Similarly, wheezing that is exacerbated by meals, exercise, or the supine position, as well as nocturnal wheezing may be GERD related.59 As with laryngitis, diagnostic testing with ambulatory pH monitoring is controversial, especially because vagally mediated bronchospasm may not be associated with proximal reflux. Meta-analysis of clinical data suggests that treatment of GERD in asthma patients improves respiratory symptoms in 69% of patients and reduces asthma medication use by 62%.59,60 However, objective improvements in pulmonary function have not been consistently reported. In clinical practice, most adult patients with GERD-related asthma are treated with a PPI to suppress GERD and possibly help control GERD and asthma symptoms. This is an off-label use of PPIs.
Chest Pain
Patients with esophageal disease may present with recurring anginalike, substernal chest pain and have a negative cardiac workup. Noncardiac chest pain may also result from pulmonary or musculoskeletal disorders, but the most common esophageal cause of noncardiac chest pain is GERD, which accounts for 40% to 60% of cases.61,62 Once cardiac disease has been ruled out, the most cost-effective initial therapy in patients with noncardiac chest pain is a trial of PPIs for 2 to 3 months [see Figure 11]. In one study, 92% of patients with noncardiac chest pain who received PPI therapy showed a positive response, defined as a greater than 50% improvement in symptoms.63 Another prospective placebo-controlled study in 36 patients with noncardiac chest pain and GERD demonstrated a reduction of chest pain scores in 81% of patients in the treated group, as compared with 44% in the placebo group.64
Endoscopy has a limited role in noncardiac chest pain. The prevalence of erosive esophagitis in this population is less than 10%.65 Endoscopy is indicated only in patients with symptoms such as dysphagia, odynophagia, weight loss, or chronic reflux symptoms.
Chronic Cough
Chronic cough is defined as a cough that persists for more than 3 months. Postnasal drip, asthma, and GERD are the leading causes of chronic cough, with GERD accounting for 21% of cases.66 The pathophysiology of GERD-related cough includes both irritation of the upper respiratory tract (with or without aspiration) and stimulation of an esophageal-bronchial cough reflex. Chronic cough from GERD should be suspected in patients who have normal chest radiographs, are nonsmokers, are not on medications known to cause cough (e.g., angiotensin-converting enzyme inhibitors), and have had no response to treatment for postnasal drip and asthma. Between 43% and 75% of patients with GERD-related cough have no typical reflux symptoms.66,67 As with GERD-related asthma, the best initial evaluation is a trial of PPIs, although patients should be advised that treatment may need to be maintained for as long as 3 months for GERD-related cough to resolve [see Figure 11].68
Despite its limited accuracy, 24-hour pH monitoring may be helpful in the management of GERD-related cough. If GERD is responsible, the cough should should occur simultaneously with a drop in pH, or within 5 minutes after a reflux episode.67,69 On the other hand, cough that precedes a drop in pH suggests reflux secondary to the cough. Normal results on an ambulatory pH study and poor correlation between pH decreases and symptoms excludes GERD-related cough; such patients will not respond to acid suppression therapy. Alternatively, a positive pH study result does not adequately predict response to therapy. In one study of patients with chronic cough and abnormal pH testing, only 35% had relief with sustained acid suppression.70
Dental Erosions
Dental erosion is a loss of tooth structure from a chemical rather than bacterial cause. The reported prevalence of dental erosions in GERD patients has varied from 17% to 68%.71 The pathophysiology is simple: chronic exposure to acid can lead to loss of enamel and tooth substance. This complication of GERD is important to recognize because treatment can limit the damage. In addition, referral to a dentist can lead to prompt diagnosis and treatment of dental lesions and institution of preventive dental therapy.
Barrett Esophagus
In Barrett esophagus, the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal columnar metaplasia.72 Barrett esophagus is a significant complication of chronic GERD, because it predisposes to the development of esophageal adenocarcinoma [see 12:VI Pancreatic, Gastric, and Other Gastrointestinal Cancers].
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| Figure 12. Long-segment Barrett Esophagus |
Barrett esophagus is suspected endoscopically when salmon-pink columnar mucosa can be seen extending beyond the gastroesophageal junction into the distal esophagus, displacing the pale pink squamous epithelium [see Figures 6 and 12]. The diagnosis of Barrett esophagus is confirmed by the finding of intestinal metaplasia on biopsy specimens from the distal esophagus.
In the past, Barrett esophagus was classified as either short segment (SSBE) or long segment (LSBE), depending on whether the metaplasia extended for less or more than 3 cm past the gastroesophageal junction. It is now known that although dysplasia or cancer is more common in patients with LSBE, patients with SSBE are also at increased risk.
It is estimated that Barrett esophagus will be found in 6% to 12% of patients undergoing endoscopy for GERD.72 The risk is highest in older white men. Unfortunately, for every known case of Barrett esophagus, as many as 20 cases may go undetected.73 Although there are no specific symptoms related to Barrett esophagus, it is clearly associated with more severe gastro-esophageal reflux. Barrett patients tend to develop reflux at a younger age and to have a long duration of reflux symptoms; in addition, they are more likely to have nocturnal symptoms, hiatal hernias, and complications of GERD such as esophagitis and strictures. However, some patients have impaired sensitivity to acid and have symptoms no worse than those typical of uncomplicated GERD. Thus, it is recommended that patients with prolonged GERD symptoms, especially middle-aged white men, undergo endoscopic screening for Barrett esophagus.74
Patients with confirmed Barrett esophagus require endoscopic surveillance for the development of dysplasia and adenocarcinoma. The risk of esophageal adenocarcinoma in Barrett esophagus is approximately 0.5% annually.75 The goal of surveillance is to detect cancer at an earlier and potentially curable stage. Several retrospective studies demonstrate that in patients with Barrett esophagus in whom adenocarcinoma was detected in a surveillance program, cancers are detected at an earlier stage and 5-year survival is better than in similar patients who did not undergo routine surveillance.76–78 Current endoscopic surveillance guidelines suggest four-quadrant biopsies at 2-cm intervals along the entire length of Barrett esophagus every 3 years.74 Special attention should be paid to mucosal abnormalities. Even with this extensive biopsy protocol, there is potential for sampling error, because the distribution of dysplasia and cancer is variable. Surveillance endoscopy should not be performed until any active inflammation of GERD is controlled with PPI therapy, because landmarks are more difficult to identify and reparative changes make interpretation of biopsies for dysplasia difficult.
Surveillance biopsies are examined for the presence and degree of dysplasia. Dysplasia should be categorized into one of the following categories: (a) negative for dysplasia, (b) indefinite for dysplasia, (c) low-grade dysplasia, (d) high-grade dysplasia, or (e) carcinoma.79,80 Surveillance intervals for Barrett esophagus are determined on the basis of the presence and degree of dysplasia, as outlined in the updated practice guidelines of the American College of Gastroenterology [see Table 4].74 Patients with no evidence of dysplasia on two consecutive biopsies can be followed every 3 years. Those with low-grade dysplasia as the highest grade found on follow-up endoscopy with concentrated biopsies in the area of dysplasia should be followed annually until there is no dysplasia. The natural history of low-grade dysplasia is variable, but this may in part reflect interobserver variability in establishing the diagnosis. In one study of patients with low-grade dysplasia who were followed for a mean of 26 months, 28% experienced progression to high-grade dysplasia or adenocarcinoma, 62% had regression of dysplasia, and 12% continued to have low-grade dysplasia.81
High-grade dysplasia is a finding that requires further investigation. Unsuspected carcinoma has been detected in esophagectomy specimens in approximately 40% of patients with high-grade dysplasia.82 On the other hand, progression to adenocarcinoma can take many years and is not inevitable. Studies have shown variable rates of progression to cancer, with rates as high as 59% at 5 years and as low as 20% at 7 years.83,84 Given these facts, the treatment of high-grade dysplasia is controversial. It is essential that a pathologist with expertise in gastrointestinal histology confirm that high-grade dysplasia is present.74 Patients with focal high-grade dysplasia may be followed with intensive 3-month surveillance, and intervention should be considered in those with multifocal disease. Intervention measures may include esophagectomy, mucosal ablation with photodynamic therapy, or endoscopic mucosal resection for mucosal irregularities.
Pill-Induced Injury
Over 70 drugs may be capable of producing injury to the esophagus.85 Drugs commonly associated with pill-induced injury include nonsteroidal anti-inflammatory drugs, doxycycline, iron, quinidine, potassium chloride, iron, and alendronate [see Table 5]. Pills can damage the esophagus by various mechanisms, including acidity, size, and contact time with esophageal mucosa. There is a wide spectrum of injury, from acute self-limited esophagitis to refractory strictures. Pill-induced injury typically occurs at sites of anatomic narrowing, which are at the level of the aortic arch and the distal esophagus. Most patients do not have other esophageal pathology such as strictures or motility disorders.
Patients typically present with chest pain and odynophagia, often severe. Dysphagia typically reflects stricture within the inflammatory changes. In symptomatic patients, the diagnosis is often made by endoscopy. Mucosal changes at endoscopy can also vary widely and include ulcer formation, plaques resembling Candida, and strictures.
Management can be difficult and includes repeat dilations for strictures and avoidance of the offending agent. To prevent further damage, all medicines should be taken in liquid form, if possible. All medications should be taken with sufficient fluids and the patient should remain upright for 15 to 30 minutes after swallowing pills. Symptoms and endoscopic findings usually resolve within weeks after the culprit pill is stopped.85 Local anesthetics (e.g., viscous lidocaine) may be used to provide symptom relief in patients with severe odynophagia.
Infectious Esophagitis
Infectious esophagitis is common, especially in immunosuppressed hosts such as patients with HIV infection, transplant recipients, and those receiving chemotherapy. The cardinal symptom of infectious esophagitis is pain with swallowing. However, immunodeficient patients can present with a variety of symptoms, including heartburn, nausea, fever, or bleeding. The three most common causes of infectious esophagitis are Candida albicans, cytomegalovirus (CMV), and herpes simplex virus (HSV).
 |
| Figure 13. Endoscopic View: Severe Esophagitis |
C. albicans, which is normally found in oral flora, is the most frequent cause of infectious esophagitis in immunocompromised hosts, including those with diabetes mellitus, alcoholism, and glucocorticoid use.86 Other predisposing factors are advanced age, hypochlorhydria, and motility disorders. Oral thrush, if present, is a helpful clue to diagnosis in patients with concurrent esophageal symptoms; 75% of such patients will have candidal esophagitis.87,88 Many patients at risk can be treated empirically with antifungal medications, but a definitive diagnosis can be made by endoscopy with biopsy and brushings. The classic endoscopic appearance is adherent white to pale yellow plaques [see Figure 13]. It should be noted, however, that this finding is not pathognomomic for Candida; it can occur with esophagitis from any cause. Brushings of the plaques will reveal hyphae and budding yeast in the presence of Candida. Treatment consists of antifungal therapy, most commonly with fluconazole, 100 to 200 mg a day for 10 to 14 days. In patients with only mild immunologic deficiencies, the topical antifungals clotrimazole and nystatin are reasonable alternatives. These agents are virtually devoid of side effects but must be taken four to five times a day. Patients who have granulocytopenia and more severe immune compromise may need treatment with amphotericin B to prevent disseminated disease.
CMV infects the submucosal fibroblasts and endothelial cells rather than the squamous epithelium of the esophagus. Because CMV may be a systemic infection, patients often present not only with odynophagia but with other gastrointestinal symptoms, including abdominal pain, nausea, and vomiting. The typical endoscopic findings are serpiginous erosions and ulcers, which may coalesce and form deep, larger ulcers. Histologic examination of biopsy specimens taken from the base of the ulcer is needed for diagnosis89; specimens should also be sent for viral culture, which is more sensitive than histology alone. Both ganciclovir and foscarnet are treatment options. Most immunocompromised patients require maintenance therapy for several weeks after an initial 2-week full-dose regimen, at least until their immune function returns to normal.
HSV esophagitis occurs in both immunocompetent and immunocompromised hosts. Most often this represents reactivation of latent viral infection, but it can occur with primary HSV infection, as well. As with other forms of infectious esophagitis, the diagnosis is best made by endoscopy. Characteristic early finds include esophageal vesicles, which will rupture to create ulcers with raised edges. Unlike CMV, HSV infects epithelial cells. Therefore, biopsies must be taken from the ulcer margins where squamous mucosa is present. Histologic examination can reveal multinucleated giant cells and ground glass intranuclear inclusion bodies, but viral culture is more sensitive. Treatment consists of intravenous acyclovir, 5 to 10 mg/kg every 8 hours until the patient is able to tolerate oral therapy. Duration of acyclovir treatment should be 7 to 10 days.
Other pathogens can rarely cause esophagitis. These include varicella-zoster virus, Epstein-Barr virus, and human papillomavirus; esophagitis may also be a feature of diphtheria, syphilis, and primary HIV infection. Of these, HIV is the most common and can lead to ulceration in the absence of any pathogens. After other infectious causes are ruled out, these patients are treated with prednisone, with good response.
Caustic Injury
Caustic ingestion can result in severe injury to the esophagus and stomach. Most ingestions occur accidentally in children; the remainder occur in suicidal, psychotic, and alcoholic adults. More than 5,000 caustic ingestions are estimated to occur annually in the United States, and the incidence is rising.90 Of all ingested chemicals, strong alkali and acids are most likely to produce injury. Strong alkali are contained in drain cleaners and other household cleaning products. Lye is a generic term for the strong alkali used in these cleansing agents, usually sodium or potassium hydroxide. In the esophagus, alkaline materials produce liquefactive necrosis and result in rapid and deep tissue injury.91 In the stomach, partial neutralization of the ingested alkali by gastric acid results in a more limited injury. Acidic agents produce a coagulation necrosis that may somewhat limit penetration and injury. Recent data suggest, however, that acid-induced ingestion injury may be more severe than alkaline-induced injury.92,93
The clinical features of caustic ingestions vary widely. Early signs and symptoms often do not correlate with the severity and extent of tissue injury.94,95 Patients may complain of orpharyngeal, retrosternal or epigastric pain; dysphagia; odynophagia; or hypersalivation. Persistant severe chest pain may indicate esophageal perforation and mediastinitis. Hoarseness, stridor, and respiratory difficulties are uncommon but can result from burns of the epiglottis and larynx. All patients should be examined for evidence of oropharyngeal injury; if airway compromise is present, intubation may be necessary. The absence of oropharyngeal burns does not preclude the presence of esophageal or gastric injury. Thus, in the absence of clinical signs of perforation, upper endoscopy should be performed during the first 24 to 48 hours after ingestion to evaluate the extent of esophageal and gastric damage, which will establish prognosis and guide therapy.
A grading system to predict clinical outcome in patients with esophageal injury has been developed [see Table 6].96 Patients with grades 1 and 2A injury have an excellent prognosis, without acute morbidity or chronic stricture formation. These patients can be started on a liquid diet and advanced to a regular diet in 1 to 2 days. Patients with grades 2B/3A develop strictures in 70% to 100% of cases. Grade 3B carries a 65% early mortality and a high need for esophageal resection; there is no evidence that medical therapy, such as antibiotics and glucocorticoids, is of any benefit. In-hospital observation for symptoms and signs of perforation is recommended. If the patient is able to swallow without pain or vomiting, liquids can be started after 48 hours.
If esophageal strictures form, the patient will require esophageal dilation. Esophageal strictures are usually located where caustic agents pool, at the cricopharyngeus, the level of the aortic arch, and the LES. These caustic strictures tend to be longer and tighter than strictures from other benign causes. Thus, they are often refractory and have a higher rate of complications with dilation. In fact, a significant portion (10% to 50%) of these patients may require surgery because of refractory strictures.
Another late complication of caustic ingestion is squamous cell carcinoma of the esophagus. Caustic injury may increase the risk of squamous cell carcinoma more than a thousandfold.97 The mean time to formation of cancer is approximately 40 years after caustic ingestion. This risk has led some groups to suggest endoscopic surveillance for squamous cell cancer in patients with a distant history of caustic ingestion (e.g., ingestion that occurred 15 to 20 years ago).98
The author has received research funding from Astrazeneca, TAP Pharmaceutical Products Inc., and Respiratory Technology Corporation, participates in the speakers bureau of AstraZeneca and TAP Pharmaceutical Products Inc., and is a consultant for AstraZeneca and Santarus, Inc.
AcknowledgmentFigures 1 and 3 Seward Hung.
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