Lesson 2, Volume 16—Gastroesophageal Reflux Disease

By John K. DiBaise, MD

Objectives

1. Understand the epidemiology of gastroesophageal reflux disease (GERD).
2. Know the pathophysiologic derangements responsible for GERD.
3. Recognize the proper evaluation of patients with classical GERD symptoms.
4. Recognize the proper evaluation of patients with suspected atypical GERD symptoms.
5. Determine the proper therapeutic strategy for patients with GERD.

Key words

diagnosis; epidemiology; gastroesophageal reflux disease; pathogenesis; therapy

Abbreviations

GERD = gastroesophageal reflux disease; H₂RA = histamine₂-receptor antagonist; LES = lower esophageal sphincter; PPI = proton pump inhibitor; TLESR = transient lower esophageal sphincter relaxation

Gastroesophageal reflux disease (GERD) reflects a spectrum of disease that is the most common condition affecting the esophagus and probably the most prevalent disorder originating from the entire GI tract. Indeed, GERD may be the most common problem seen in general clinical practice. Its importance, however, lies not only in its prevalence but also in the diversity of its clinical presentations, the potential for morbidity and mortality, and the high rate of health-care utilization.

Epidemiology

The prevalence of GERD in the general population has been assessed in several epidemiologic studies that have typically used the classic symptoms of GERD—namely, heartburn and acid regurgitation—as markers of the disease. In the most recent of these studies, Locke and colleagues¹ surveyed the community of Olmsted County, Minnesota and found that the prevalence of heartburn or regurgitation occurring on a yearly and weekly basis was about 60% and 20%, respectively. No significant differences were found relative to sex or age, although a trend was noted for an inverse association with increasing age. It is important to keep in mind that the actual prevalence is probably even higher if those patients with GERD but without heartburn or regurgitation are taken into account. GERD is not unique to the United States, as similar findings have been reported in Europe. Interestingly, GERD is fairly uncommon in persons of Asian origin compared with Caucasians, suggesting an influence of cultural factors.² A familial relationship for GERD has also been suggested as the prevalence of GERD increases substantially in persons who have first-degree relatives with Barrett’s esophagus or esophageal adenocarcinoma, two complications of GERD.³ Finally, in a large case-control study in Sweden, Lagergren and colleagues⁴ recently showed that there is a strong and probably causal relationship between GERD and esophageal adenocarcinoma with an odds ratio of 43.5 (95% confidence interval, 18.3 to 103.5) in individuals with long-standing and severe symptoms of reflux. Because of the dramatic increase in the incidence of esophageal adenocarcinoma, these data underscore the importance of early recognition and appropriate management of GERD.

Diagnosis

GERD is defined as symptoms or tissue injury resulting from exposure of the esophagus to gastric contents. There is currently no diagnostic gold standard for reflux disease. Although the diagnosis of GERD is usually straightforward when classical symptoms are present, uncertainty and confusion may result when a patient presents with so-called "atypical" symptoms, as both classical symptoms and esophagitis frequently are absent. Remember that the patient may not clearly understand the nature of the sensation of heartburn; thus, a description to the patient is often necessary for it to be recognized with any sensitivity. Therefore, while symptom evaluation is extremely important for diagnosis of GERD, its sensitivity falls far short of a gold standard.⁵ Similarly, the role of endoscopy in the diagnosis of GERD is limited because as many as two thirds of reflux patients, even those with classical symptoms, will have normal findings on endoscopy, both grossly and microscopically.^1,6 Ambulatory esophageal pH testing, while frequently considered to be the gold standard, is also not so. Its use is particularly problematic in patients with atypical symptoms of suspected GERD and in patients without esophagitis on endoscopy.⁶ Recently, a short course of high-dose proton pump inhibitor (PPI) therapy has been evaluated as a diagnostic test for GERD.⁷ While seemingly more cost-effective than pH testing, it does not appear to offer any diagnostic superiority. Lastly, some patients with GERD, such as elderly patients and those with Barrett’s esophagus, may be completely asymptomatic until they present with a complication. This may be a consequence of reduced sensitivity or insensitivity to esophageal acid⁸ and highlights the point that reflux symptoms do not necessarily correlate with the presence or absence of esophagitis.

Evaluation

The evaluation of GERD depends upon the patient’s presentation. Those who have classical symptoms and no alarm symptoms (eg, dysphagia, weight loss, bleeding) usually require no confirmatory testing and should be treated empirically. Further testing should be performed in the following situations: presence of alarm symptoms, lack of symptom response to medical therapy, atypical presentations of suspected GERD, and prior to antireflux surgery. Additionally, a more aggressive approach in the elderly is warranted because their disease presentation is typically more severe despite milder symptoms. Several tests are available to aid in the evaluation of GERD, including endoscopy, barium esophagography, esophageal manometry, and esophageal pH testing. These tests should be applied selectively to the individual based upon the information desired (Table 1). The barium esophagogram is useful when evaluating dysphagia, particularly with suspected oropharyngeal or nonobstructive esophageal (esophageal dysmotility) types. True esophageal dysphagia is best evaluated by endosocopy because, in addition to its higher diagnostic sensitivity and ability to obtain a biopsy specimen, endoscopy allows therapeutic intervention. Esophageal manometry is most helpful to localize the lower esophageal sphincter before esophageal pH testing and, possibly, to evaluate peristalsis prior to antireflux surgery. Esophageal pH testing is most useful to confirm GERD prior to antireflux surgery in endoscopy-negative patients and to evaluate patients who are not responding to medical therapy or have recurrent/persistent symptoms after antireflux surgery. An abnormal test while receiving medical treatment suggests the need for more aggressive therapy, while a normal test points toward an alternative diagnosis. A therapeutic trial with a PPI, as opposed to initial pH testing, seems to be more useful in identifying a causal relationship between acid reflux and extraesophageal/atypical presentations. Esophageal pH testing while the patient is receiving medical therapy can then be limited to those patients who are not responding.

Pathogenesis

The pathophysiology of GERD is multifactorial and consists primarily of both esophageal and gastric factors (Table 2). The major factor responsible for reflux is a defect in the antireflux barrier, which is composed of the lower esophageal sphincter (LES), diaphragm, and supporting ligaments. The occurrence of inappropriate, nonswallow-related LES relaxations, also known as transient LES relaxations (TLESRs), rather than low resting LES pressure, is the most common cause of reflux events in both healthy individuals and patients with GERD.⁹ The major stimulus for TLESRs is gastric distension. The diaphragm participates in the antireflux barrier by contributing resting tone to the LES and augmenting tone during inspiration, when intra-abdominal pressure is increased. Recently, it has been shown that the susceptibility to reflux correlates with both weak LES pressure and with hiatal hernia size¹⁰; however, a hiatal hernia is neither necessary nor sufficient for the development of reflux esophagitis. Defects in esophageal acid clearance mechanisms and altered esophageal mucosal resistance also play a role in the pathogenesis of GERD. Indeed, poor peristalsis and/or reduced salivation can result in significant esophageal injury. The contribution of altered mucosal sensitivity remains unclear. Of course, the presence of gastric contents (acid, pepsin, bile, pancreatic enzymes) in the esophagus is necessary for esophageal injury to occur. Although acid is clearly important, there is no evidence of gastric acid hypersecretion in the vast majority of GERD patients. The role of pepsin and bile, in particular, is controversial.¹¹ Delayed gastric emptying exists commonly in patients with GERD¹² but probably is of pathogenetic importance in only about 10% of patients. Lastly, there has been considerable interest recently on the potential role of Helicobacter pylori in the pathogenesis of GERD. While there appears to be no excess of H pylori infection in GERD patients when compared with age-matched control subjects, theory and accumulating circumstantial evidence suggest that this infection may be relatively protective against reflux when it produces gastritis severe enough to cause a major reduction of gastric acid secretion.^13,14 Similarly, when H pylori infection is cured, a significant component of gastritis resolves, acid secretion increases, and, at least in theory, GERD may be provoked or worsened in the setting of antireflux barrier dysfunction.¹⁵

Clinical Presentations and Complications

The spectrum of GERD symptoms is diverse and ranges from classical heartburn and acid regurgitation to the less common esophageal symptoms of dysphagia, odynophagia, belching, and chest pain. In addition, a multitude of extraesophageal symptoms/conditions that seem to be related to reflux disease increasingly are being recognized (Table 3).

Esophageal complications of GERD include varying degrees of esophagitis, peptic stricture, and Barrett’s esophagus. Noncardiac chest pain is also sometimes considered in this category. Esophagitis will be seen in 40 to 60% of patients with GERD who undergo endoscopy; however, brisk bleeding as a consequence is rare (Fig 1). Benign peptic strictures may occur in up to 20% of patients with erosive esophagitis and can usually be effectively managed by aggressive antireflux therapy combined with intermittent dilatation as needed (Fig 2). One curious aspect of peptic strictures is that they often develop in patients who have few, if any, classical GERD symptoms. This further emphasizes the point that there is little correlation between the severity of GERD symptoms and severity of findings on endoscopy.

Figure 1. Endoscopic photograph of severe reflux esophagitis. Note the circumferential involvement and several linear erosions with overlying exudate and surrounding erythema extending upward from the gastroesophageal junction.

Figure 2. Endoscopic photograph of a peptic stricture. Note the circumferential ulceration and narrowing at the gastroesophageal junction.

Barrett’s esophagus is a condition in which specialized columnar epithelium (with goblet cells), also referred to as intestinal metaplasia, replaces the damaged squamous epithelium in the distal esophagus (Fig 3). It is now generally accepted that this results from long-standing, severe GERD and is the single most important risk factor for esophageal adenocarcinoma.¹⁶ The frequency of this lesion varies depending upon the population studied but usually ranges from 10 to 20%. There is a strong male and Caucasian predominance with an average age at diagnosis of about 55. The prevalence of adenocarcinoma in Barrett’s esophagus is approximately 10%, while the annual incidence rate in those with known Barrett’s esophagus undergoing surveillance is about 0.5%.¹⁷ Endoscopic surveillance for cancer and dysplasia, the precursor to cancer, is currently considered the standard of care; however, its usefulness and cost-effectiveness remain highly controversial. Surveillance is unlikely to be effective for the GERD population as a whole, and endoscopic screening of all persons with GERD is infeasible and cost-prohibitive. Recent recommendations suggest endoscopy for all persons with typical GERD symptoms for at least 5 years, particularly middle-aged Caucasian men, to screen for Barrett’s esophagus.¹⁸ The usefulness of cytologic sampling via a transoral, balloon-tipped catheter in an unsedated patient, much as is done in China when screening for squamous cell esophageal cancer, is currently being investigated for Barrett’s esophagus screening.¹⁹ Finally, it remains controversial whether aggressive antireflux therapy, medical or surgical, will lead to regression of Barrett’s esophagus and/or dysplasia. The available evidence is contradictory and usually drawn from retrospective or anecdotal reports.

Figure 3. Endoscopic photograph of Barrett’s esophagus. Note the salmon-colored mucosa extending upward from the gastroesophageal junction. Islands of squamous mucosa are also apparent.

The esophagus may be implicated in almost half of those patients with noncardiac chest pain. Several mechanisms have been postulated including GERD, dysmotility, ischemia, and abnormal esophageal sensation/perception. Primary esophageal motor disorders are very uncommon in these patients.²⁰ While recent studies suggest that GERD is by far the most common cause of noncardiac chest pain, opinion seems to be shifting more toward sensory/perception dysfunction. In general, after exclusion of a cardiac source, which is usually not possible based upon historical information alone, it may be reasonable to proceed with an empirical trial of high-dose antisecretory therapy in these patients, particularly if they have typical reflux symptoms.²¹ Further evaluation can then be reserved for those without improvement.

Physicians are becoming increasingly aware that GERD may have respiratory and ear, nose, and throat manifestations (Table 3). Approximately 40% of these patients will deny any typical reflux symptoms, and reflux esophagitis is generally absent.^22,23 Indeed, the high prevalence of absence of concomitant classical GERD symptoms or esophagitis in patients with these "atypical" manifestations has led some individuals to refer to this condition not as GERD, but rather as laryngopharyngeal reflux. Two mechanisms have been implicated in the pathogenesis of these extraesophageal presentations: direct acid contact as a consequence of reflux of gastric contents through the upper esophageal sphincter (reflux theory) or a vagally mediated reflex initiated by acid exposure in the esophagus (reflex theory). The degree of importance each of these proposed mechanisms plays in causing the various extraesophageal manifestations remains unclear but probably differs depending upon the symptom. Furthermore, evidence supporting these mechanisms is rather scanty and generally indirect. Data from our motility laboratory do not support the hypothesis that the nature of the clinical presentation of GERD is related to different patterns of esophageal acid exposure or esophageal motility as measured by conventional manometry and dual-channel pH testing.²⁴

Treatment

The major acute goals of GERD therapy are to relieve symptoms and to heal esophagitis, thereby preventing complications. However, GERD is a chronic condition, and as such, the long-term goal is to maintain the acute goals. Treatment options include lifestyle modifications, pharmacologic agents, and antireflux surgery (Table 4). The traditional step-up approach has been to start with lifestyle modifications and progress to medications and then surgery for persistent symptoms. A more recent alternative approach (step-down) is to start with the most potent medical therapy and, when symptoms are controlled, to attempt to change therapy to a less potent/less costly agent. The most cost-effective approach has yet to be determined.

Lifestyle modifications that minimize reflux and maximize acid clearance include elevating the head of the bed 4 to 6 inches when sleeping, weight reduction, avoiding large and late-night meals, and avoiding substances known to reduce LES pressure (caffeine, cigarettes, alcohol, certain medications, etc). While the scientific evidence supporting these adaptations is generally weak, there may be some patients who benefit and do not require any pharmacologic therapy. In addition, many of these measures are useful in treating other diseases and in maintaining overall body health.

Antacids, which briefly neutralize acid, and alginic acid, which mixes with saliva to form a viscous layer that floats on the surface of the gastric pool acting as a mechanical barrier, are useful for treating mild and infrequent reflux symptoms. They do not heal esophagitis. When approved in the late 1970s, histamine₂-receptor antagonists (H₂RAs) achieved the first real breakthrough in the treatment of GERD. All four available H₂RAs are equally effective and act to decrease gastric acid production. Although symptomatic improvement can be achieved in up to 60% of patients, healing of esophagitis is less common with these agents. The over-the-counter dosages of H₂RAs, although longer-lasting, are generally equivalent to antacids. Higher doses of H₂RAs do not seem to be more effective than standard doses in improving the severely symptomatic patient²⁵ and become less cost-effective than a single daily dose of PPIs. Prokinetic agents work by increasing LES pressure, improving esophageal peristalsis, increasing salivary flow, and improving gastric emptying. A prokinetic agent may be most useful in patients with typical reflux symptoms plus associated bloating and early satiety, suggesting dysmotility. Cisapride, a 5-HT₄ agonist that exerts its prokinetic action through the indirect release of acetylcholine in the myenteric plexus, has a similar efficacy to H₂RAs. However, due to concerns over its safety, specifically because of several reports of fatal cardiac dysrhythmias associated with the combination of cisapride and several medications and medical conditions, cisapride was removed from the market by the Food and Drug Administration in July 2000. As a consequence, there is currently no suitable prokinetic agent available for long-term use. Metoclopramide, a dopamine antagonist, is currently the only prokinetic agent available for use in the United States, but it has modest efficacy in relieving symptoms, no proven efficacy in healing esophagitis, and a significant incidence of side effects. We eagerly await the results of ongoing clinical trials evaluating the efficacy and safety of new prokinetic agents. PPIs profoundly diminish acid secretion by inhibiting H⁺-K⁺ ATPase (proton pump). All five available PPIs seem to be equally effective with regard to symptom improvement and healing of esophagitis. In several trials, PPIs have been shown to be highly effective in both symptom reduction and healing rates of esophagitis (up to 90%). They are the first choice in complicated GERD cases. Acute side effects include headache, abdominal cramping, and diarrhea. Side effects of long-term use are uncommon; concerns over development of gastric carcinoid tumors and atrophic gastritis have not been realized in studies following patients taking high-dose omeprazole for > 12 years. While the use of a prokinetic agent in combination with an H₂RA has recently been shown to have an additive effect on maintenance of healing of reflux esophagitis, the combination of a prokinetic agent and a PPI does not seem to provide much advantage over a PPI alone.²⁶

GERD can by cured only by surgery. Indications for antireflux surgery include the patient with refractory GERD, those who will not or cannot afford to take daily medications long-term, and the young patient who would otherwise require a very long course of medical treatment. It should be kept in mind that the availability of potent antisecretory therapy (ie, PPIs) has made the patient with truly refractory GERD rare. Therefore, a search for an alternative diagnosis in such patients should be entertained. With the availability of the laparoscopic approach, the morbidity of antireflux surgery is greatly reduced compared to open fundoplication. In experienced hands, this procedure is safe and highly effective; however, the long-term success rate for the laparoscopic approach is unknown and certain side effects, such as dysphagia and the gas-bloat syndrome, may be more frequent. The cost-effectiveness of antireflux surgery as a long-term therapy for GERD remains to be shown.

There is now substantial interest in the development of therapies that target the principal defect resulting in reflux episodes, namely, TLESRs. Several recent reports indicate that various pharmacologic agents can reduce rates of TLESRs in healthy individuals and patients with GERD.²⁷ While none of the agents tested thus far is suitable for long-term clinical use, this remains an intriguing area likely to offer major developments in the treatment of GERD. Lastly, two novel transoral endoluminal approaches to the treatment of GERD have recently been approved by the Food and Drug Administration. One utilizes a suturing system attached to the tip of the endoscope, while the other delivers thermocouple-controlled radiofrequency energy to the region of the gastroesophageal junction via a bougie catheter delivery system. Preliminary studies have demonstrated encouraging results for both techniques.^28,29 Where these therapies will fit into the overall treatment strategy remains to be determined.

Practical Approach to Evaluation and Management

Figure 4 illustrates a suggested approach for managing the patient with classical GERD symptoms. Initially, these patients should be evaluated for the presence of alarm symptoms. If present, further diagnostic evaluation, usually endoscopy, is necessary. If absent, empiric therapy guided by symptom severity should be commenced. Endoscopy should be considered in patients who require long-term therapy for severe symptoms, even in those who experience good symptom relief and have no alarm symptoms, in order to evaluate for the presence of Barrett’s esophagus. If the patient responds poorly to therapy, further diagnostic testing should be considered. In this setting, endoscopy may be useful to evaluate for other potential etiologies of the symptoms; esophageal pH testing may be useful while the patient is taking medication in order to assess the adequacy of therapy. The management of esophagitis without Barrett’s esophagus, endoscopy-negative GERD, and Barrett’s esophagus is based primarily on symptom relief. Patients with Barrett’s esophagus should be enrolled in an endoscopic surveillance program.

Figure 4. Algorithm for the acute and long-term management of the patient with classical GERD symptoms. Alarm symptoms include dysphagia, weight loss, and bleeding.
*Guided by symptom severity.
†To evaluate for Barrett's esophagus.
‡PPI.

A similar approach to the management of patients with atypical manifestations of GERD, including chest pain, pulmonary symptoms, and ear, nose, and throat symptoms, is illustrated in Figure 5. At this time, there are insufficient data to declare any one approach best. Previously, particularly in those patients who did not have concomitant classical GERD symptoms, early esophageal pH testing was recommended as the best initial test for identifying abnormal esophageal acid exposure (ie, acid reflux) and correlating these symptoms with reflux episodes. However, as alluded to earlier, several problems arise when esophageal pH testing is used to identify the potential role of reflux in patients with suspected atypical GERD-related conditions. Controversy exists relating to the need for single- vs dual-channel pH monitoring and the proper position of the proximal probe (pharyngeal vs upper esophagus), if used. In addition, there are problems relating to a lack of well-established normal values, reproducibility, and the occurrence of artifacts involving the proximal pH sensor. There also seems to be a tendency for false-negative tests; thus, a negative test may not confidently exclude the diagnosis. Lastly, a positive test confirms only that an abnormal amount of gastroesophageal reflux is present and does not prove a causal relationship. This can be assured with confidence only when an atypical symptom of suspected GERD shows sustained, dramatic improvement following aggressive treatment of GERD.

Figure 5. Algorithm for the management of the patient with suspected atypical GERD symptoms with or without concomitant classical GERD symptoms.
*To evaluate for Barrett's esophagus.

As a result of this complex relationship among symptoms, presence of GERD, and causality, the use of aggressive therapeutic trials, typically with a twice-daily PPI, has been advocated to identify patients with true GERD-related atypical symptoms. This approach has been supported by recent reports suggesting that an empiric trial of a twice-daily PPI for 2 to 3 months may be more cost-effective than early testing.^21,30 If no response is seen after this extended therapeutic trial, esophageal pH testing while the patient continues therapy is suggested in order to assess its adequacy. For those who do respond, gradual titration of the therapy downward is recommended. Keep in mind that, unlike reflux-related chest pain, management of reflux-related pulmonary and ear, nose, and throat conditions tends to require higher doses of antisecretory agents for prolonged periods of time.

Conclusion

GERD is a common condition with diverse clinical presentations, the potential for morbidity and mortality, and a high rate of health-care utilization. On the basis of its pathophysiology, GERD is most appropriately considered to be an upper gut motility disorder. While patients who have classical symptoms and no alarm symptoms may be treated empirically, endoscopy may be useful to identify Barrett’s esophagus even in those who respond well to therapy. Patients who have atypical symptoms that fail to respond to PPI therapy or who have classical symptoms that respond poorly are best evaluated by ambulatory esophageal pH testing while continuing therapy. The goals of GERD therapy are to relieve symptoms, heal esophagitis, and prevent complications. The principal treatment of GERD relies on pharmacologic agents combined with lifestyle modifications and antireflux surgery, in selected circumstances. Further study regarding the optimal cost-effective diagnostic and therapeutic strategies in GERD is needed.

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