DEFINITION

GERD is defined as chronic symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus.¹ Reflux esophagitis refers to a subgroup of GERD patients with histopathologically demonstrated characteristic changes in the esophageal mucosa.

Nonerosive reflux disease, also know as endoscopy-negative reflux disease, refers to patients with typical GERD symptoms caused by intraesophageal acid who do not have visible mucosal injury at endoscopy. On the other hand, functional heartburn is defined as episodic retrosternal burning without evidence of increased esophageal acid exposure or other structural esophageal etiology.

GERD is generally considered to be one of the most prevalent conditions affecting the gastrointestinal tract; however, figures on the precise prevalence and incidence of GERD are based more on estimates than actual data. A population-based study, using a valid questionnaire, found that 58.7% of the population had heartburn or acid regurgitation at least once during the course of a year and that 19.8% experienced symptoms at least once weekly.² It is estimated that approximately 50% of patients with typical reflux symptoms have erosive esophagitis (Figure 1).

Despite the fact that GERD is a common clinical problem, there is no diagnostic gold standard for this disease. Classic symptoms of acid regurgitation and heartburn are specific but not sensitive for the diagnosis of GERD, as determined by abnormal 24-hour pH monitoring. It is reasonable to consider an empiric trial of antisecretory therapy in a patient with classic symptoms of GERD in the absence of alarm signs.¹ Considerable attention has been given to the role of an empiric trial of proton pump inhibitor (PPI) therapy in the diagnosis of GERD. A therapeutic trial of omeprazole (40 mg in the morning, 20 mg in the evening) has a sensitivity of 80% with a specificity of 57% in patients with GERD, as documented by endoscopy or 24-hour pH monitoring.³ Further diagnostic testing should be considered in the following settings:

• failure to respond to an empiric course of antisecretory therapy
• alarm signs suggestive of complicated reflux disease (such as dysphagia, odynophagia, bleeding, weight loss, chest pain, and choking)
• chronic symptoms in a patient at risk for Barrett's esophagus
• patients requiring chronic antisecretory therapy¹

Endoscopy is the technique of choice to evaluate the mucosa in patients with symptoms of GERD. Erosions or ulcerations at the squamocolumnar junction as well as the findings of Barrett's esophagus are diagnostic of GERD. When mucosal breaks are present, the patient is classified as having erosive esophagitis. The LA classification is used to grade the severity of the esophagitis (Figure 2).

Unfortunately, in the absence of mucosal breaks, there is no gold standard for the diagnosis of GERD. Although ambulatory 24-hour pH monitoring has long been thought to be 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 nonerosive reflux disease.⁴ Nevertheless, 24-hour pH testing is useful to document acid exposure and allows for the correlation of symptoms to acid reflux events. The percent time that pH is less than 4 is the single most important parameter to measure in these studies. The barium esophagram has no role at present in the routine evaluation of GERD. This test demonstrates reflux in only 25% to 75% of symptomatic patients and may be falsely positive in 20% of normal controls.⁵

Because of the limitations of standard 24-hour pH monitoring, several new diagnostic modalities for GERD are under investigation. These include multichannel intraluminal impedance (MII) and the Bravo pH probe. Impedance uses changes in resistance to alternating current between two metal electrodes to detect the presence of a bolus in the esophageal lumen. When combined with 24-hour pH monitoring, this system allows the detection of not only acid reflux, but non-acid reflux as well. The Bravo pH probe is a catherer-free monitoring system in which a pH monitoring probe approximately the size of a medication capsule is placed endoscopically. The pH data are then transmitted to a recording device worn on the patient's waist (Figure 3). Besides being catheter free, the Bravo system has the advantage of recording 48 hours of pH data. However, at this point, it is unclear if there is any additional diagnostic benefit to the Bravo system compared to convential pH recording systems.

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. However, although all of these measures make sense physiologically, little data are available in the literature to support them. Lifestyle measures include avoidance of precipitating foods (fatty foods, alcohol, caffeine), avoidance of recumbency for three hours postprandially, elevation of the head of the bed, smoking cessation, and weight loss.⁶ The cornerstone of GERD therapy is the administration of agents that decrease gastric acid secretion, thereby decreasing esophageal acid exposure.⁷ Antacids, which neutralize only acid that is already secreted, may be used for immediate symptom relief, but are not recommended as chronic therapy. Administration of histamine H₂-receptor antagonists in standard divided doses achieves complete symptom relief in approximately 60% of patients and heals esophagitis in about 50%.⁷ Doubling the dose does not further improve the response.⁸ PPIs are superior to histamine H₂-receptor antagonists in both healing erosive esophagitis and symptom relief, with healing rates that approach 90% (Figure 4).⁷

For most patients, GERD is a chronic relapsing disease with almost universal recurrence of symptoms after treatment withdrawal; thus, it requires maintenance therapy. Long-term therapy with PPIs is again superior to histamine H₂-receptor antagonists, with remission maintained in 80% compared with 50% of patients, respectively.⁹ With over a decade of experience in the United States, initial concerns regarding the long-term safety of PPIs remain unsubstantiated.¹⁰

Because of their superiority in both healing esophagitis and maintaining symptom relief, PPIs are the treatment of choice in patients with frequent reflux symptoms or complications from reflux disease. Dose escalation may be necessary in those rare individuals who do not respond to a standard dosing regimen. On the other hand, patients who are well controlled on PPI therapy may consider step-down therapy to a H₂-receptor blocker.

Antireflux surgery, now performed primarily by the laparoscopic approach, remains an option for carefully selected patients with well-documented GERD.¹¹ The ideal candidate is the patient with typical symptoms that responds completely to antisecretory therapy. Patients in this category who opt for surgery typically have concerns regarding the cost or potential adverse effects associated with long-term PPI therapy. Patients with predominant regurgitation symptoms, which are often nocturnal and may be accompanied by pulmonary complications, are also good candidates. However, because patients refractory to medical therapy are extraordinarily uncommon with the use of high-dose PPI therapy, any consideration of surgery in this group must first document continued evidence of ongoing acid exposure or esophageal damage while PPIs are being used.

In the past several years, several endoscopic therapies for the treatment of GERD have been approved by the FDA. These include endoscopic suturing, radiofrequency ablation, and bulking techniques, all of which target the gastresophageal junction. There is a paucity of controlled clinical trials of these techniques. Thus, until further information regarding the efficacy of these procedures is available, they should all be considered investigational and used only in the setting of a clinical trial.

Barrett's esophagus (Figure 5) is a potential serious complication of chronic GERD. Barrett's esophagus is present when the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal columnar metaplasia. It is the most significant histologic outcome of long-standing GERD and predisposes to the development of esophageal adenocarcinoma. It is estimated that 6% to 12% of patients undergoing endoscopy for GERD will have Barrett's esophagus.¹² The risk of esophageal adenocarcinoma in Barrett's esophagus is approximately 0.5% annually.¹³ Thus, these patients require not only acid suppression with PPIs to control symptoms but also continued endoscopic surveillance to detect the development of dysplasia and adenocarcinoma.

Surveillance intervals for Barrett's esophagus are based on the presence and degree of dysplasia (Table 1), as outlined in the updated practice guidelines of the American College of Gastroenterology (ACG).¹⁴ Because endoscopic surveillance is cumbersome and imperfect, risk stratification to make surveillance more efficient is desirable. Biomarkers and genomic profiles have promise in this regard.

The role of chemoprevention is also being actively investigated. A recent systematic review demonstrated a protective association between any use of aspirin or nonsteroidal antiflammatory medication and esophageal cancer (Odd ratio 0.57).²⁴ Medication usage was protective against both adenocarcinoma and squamous cell carcinoma and there was a dose-related effect. The mechanism may be related to inhibition of cyclooxygenase (COX)-2 enzyme, which is induced in the development of esophageal maligancies.²⁵ Additionally, studies have demonstrated that administration of a selective COX-2 inhibitor decreases cell growth and increases apoptosis in esophageal adenocarcinoma lines.²⁶ Based on these preliminary results, it is hypothesized that administration of COX-2 inhibitors could therefore decrease the risk of esophageal cancer in Barrett's esophagus patients. However, this strategy is not yet ready for routine clinical practice.

Dyspepsia is a common clinical problem that may be seen in 25% to 40% of adults. Only 15% to 25% of patients with dyspepsia are found to have a gastric or duodenal ulcer.¹⁷ Up to 60% of patients have no definite diagnosis and are classified as having functional dyspepsia, a condition most likely related to visceral hypersensitivity. Furthermore, when ulcers are present, they may be asymptomatic, especially in patients ingesting NSAIDS. Patients may also present with complications of ulcer disease; hemorrhage may develop in 20%, perforation in 5%, and gastric outlet obstruction in 2%.

There are several possible diagnostic approaches to the patient with dyspepsia are:

• instituting a short trial of empiric antisecretory therapy
• performing immediate endoscopy
• conducting noninvasive testing for H. pylori infection followed by antibiotic treatment of patients with positive test results

These approaches are outlined in the American Gastroenterological Association's medical position statement on evaluation of dyspepsia.¹⁷

Immediate endoscopic evaluation without a trial of empiric antisecretory therapy is indicated for individuals with obvious systemic symptoms, such as weight loss, bleeding, nausea, and vomiting, as well as for individuals older than 45 to 50 years with new-onset dyspepsia in whom gastric neoplasia is a consideration. If a gastric ulcer is found at endoscopy, multiple biopsies and brush cytologic examination are required to exclude malignancy. Endoscopy is also indicated in patients whose disease does not respond to empiric therapy. There is no longer any role for barium radiography in the evaluation of dyspepsia because of its poor sensitivity and specificity. Initial noninvasive testing for H. pylori followed by antimicrobial therapy in patients with a positive test result is a reasonable approach for patients younger than 45 years with uncomplicated dyspepsia. The rationale for this is that, if ulcer disease is present, it will heal, and any future ulcer diathesis will be eliminated. However, empirically treating dyspepsia patients with antibiotics for simply presumed H. pylori infection is not supported by any model to date and should not be done.

H. pylori testing is essential in patients with peptic ulcer disease. A negative test result will focus subsequent diagnostic evaluation on ruling out other causes of peptic ulcer disease. However, an initial negative test result in patients with newly diagnosed peptic ulcer disease should be confirmed by a second test, given the importance of diagnosing H. pylori infection. Diagnostic tests for the detection of H. pylori are subdivided into nonendoscopic and endoscopic techniques. Enzyme-linked immunosorbent assay serologic tests, formerly the cornerstone of H. pylori testing, are no longer recommended because of the poor performance characteristics of these tests—a sensitivity of 85% and specificity of 79%.¹⁸ Furthermore, serologic test results may remain positive for up to 3 years after bacterial eradication, which limits the role of such testing in the documentation of response to therapy. Urea breath tests are more accurate than serologic tests and are now the noninvasive test of choice for diagnosing H. pylori infection and documenting successful H. pylori eradication after antibiotic therapy. Patients should not receive PPIs for at least 14 days before administration of breath tests to avoid false-negative results. Stool antigen tests are an acceptable alternative to the urea breath test, with a sensitivity of 89 to 98 percent and a specificity of over 90 percent.²⁷ If endoscopy is performed, the diagnosis is made by the rapid urease test or histologic examination of biopsy specimens. Recent treatment with antibiotics or proton pump inhibitors decreases the yield of both of these biopsy tests.

A subset of patients also requires posttreatment testing to confirm the eradication of H. pylori. Posttreatment testing is mandatory in patients with complicated peptic ulcer disease, in which there is bleeding, perforation, or obstruction. Such testing may also be performed in all patients with newly diagnosed peptic ulcer disease or when persistent infection is a particular concern. Because antibiotic treatment suppresses the organism even if it is not eradicated, testing to confirm cure should not be done until 4 weeks after completion of therapy.

Histamine H₂-receptor antagonists remain a mainstay of ulcer therapy. Acid secretion is decreased by competitive and selective inhibition of the histamine H₂-receptor of the parietal cell. The four available histamine H₂-receptor antagonists are cimetidine, ranitidine, famotidine, and nizatidine. All of these compounds act by the same mechanism but have different relative potencies for inhibiting gastric acid secretion. The inhibition of acid secretion results in a rise of gastric pH and a decrease of pepsin activity. This class of drugs is uniformly safe and well tolerated, although the risk of adverse effects is slightly increased with cimetidine because it interacts with cytochrome P450, causing increased drug interactions. Histamine H₂-receptor antagonists heal 90% to 95% of duodenal ulcers and 88% of gastric ulcers within 8 weeks. Given as a single full dose at bedtime, each of the available compounds has a comparable efficacy for ulcer healing.

The PPIs are substituted benzimidazoles that bind irreversibly to the H+/K+-adenosine triphosphatase enzyme of the gastric parietal cell. This blocks the final step of gastric acid secretion in response to any type of stimulation and results in long-lasting inhibition of gastric acid secretion. For gastric secretory activity to be restored, new enzymes need to be resynthesized, a process that normally takes 2 to 5 days. The PPIs are all remarkably well tolerated and effective; they achieve duodenal ulcer healing rates at 4 weeks (90% to 100%) typically seen at 8 weeks with H₂-receptor antagonists. Additionally, PPIs relieve symptoms more rapidly than H₂-receptor antagonists.¹⁹ Gastric ulcer healing is also more rapid with PPI's, but an 8 week course of therapy is still needed to achieve healing rates greater than 90%.²⁸ Table 2 outlines the dosing and duration of therapy of agents used to treat peptic ulcer disease. Maintenance antisecretory therapy is rarely needed, except in circumstances such as unsuccessful H. pylori eradication or chronic NSAID usage.

Eradication of H. pylori accelerates the rate of duodenal and gastric ulcer healing, approximating the rate obtained with omeprazole at 4 weeks, and essentially cures them. Therefore, eradication should be attempted in all patients with current or past documented peptic ulcer disease and evidence of infection. The in vivo activity of antibiotics is variable, thus, combinations of two antibiotics plus either a PPI or ranitidine bismuth citrate are used to maximize the chance of eradication. The efficacy of these regimens is typically approximately 90%. Current treatments are shown in Table 3.²⁰ A reasonable approach is to use either a metronidazole- or clarithromycin-based triple therapy regimen as first-line therapy. Should that fail, second-line therapy would use the antimicrobial initially not used, with quadruple therapy reserved as the third-line option. Because resistance to metronidazole is approximately 35% and to clarithromycin 11% in the United States, using these two agents together in the initial treatment of H. pylori is not recommended.

For patients who develop ulcers while ingesting NSAIDS, therapy should be stopped, if possible, and the patient placed on conventional doses of H₂-receptor antagonists or PPIs. It is important to realize that even low-dose aspirin used for cardiac prophylaxis is a risk factor for bleeding from peptic ulcer disease. Patients should be tested for H. pylori infection and treated, if infection is confirmed. For patients who need continued NSAID therapy, the NSAID dosage should be reduced as much as possible. Small ulcers (5 mm or less) will heal with coadministration of histamine H₂-receptor antagonists, whereas large ulcers require coadministration of a PPI for healing. Given the fact that prophylactic medications are expensive and NSAID use is common, ulcer prophylaxis should be considered only in high-risk individuals. Table 4 lists such risk factors, based on the guidelines for the treatment and prevention of NSAID-induced ulcers of the American College of Gastroenterology.²¹

There are two options for ulcer prevention: coadministration of agents that protect the gastroduodenal mucosa or use of cyclo-oxygenase-2 (COX-2)-selective agents. Misoprostol is a prostaglandin E1 analog that is effective for the prophylaxis of NSAID-induced ulcers and decreases the incidence of serious gastrointestinal complications such as bleeding, perforation, and gastric outlet obstruction. Although misoprostol at a dose of 200 µg three or four times daily is effective for ulcer prevention, adverse events such as diarrhea and abdominal cramps are common and limit its use. More recent data suggest PPIs are effective and better tolerated than either histamine H₂-receptor antagonists or misoprostol for the prevention of NSAID-induced ulcers.^22,23

For more information on the diagnosis and treatment of gastroesophageal reflux disease and gastric and duodenal ulcers, please refer to the following guidelines:

ACG guidelines for the diagnosis and treatment of gastroesophageal reflux disease (www-east.elsevier.com/ajg/issues/9406/
ajg1123fla.htm)

AGA medical position statement: evaluation of dyspepsia

ACG guidelines for the management of Helicobacter pylori infection
(www-east.elsevier.com/ajg/issues/9312/ajg684fla.htm)

ACG guidelines for the treatment and prevention of NSAID-Induced Ulcers (www.acg.gi.org/acg-dev/staging/members/guides/
nsaid_ulcer.html)

ACG Updated Guidelines for the Diagnosis, Surveillance, and Therapy of Barrett's Esophagus.
(www.acg.gi.org/acgdev/staging/members/
guides/barretts.html)

ACG guidelines for the management of peptic ulcer disease
(www.acg.gi.org/acg-dev/staging/members/guides/pudabs.html)

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