Published: August 2010
Acid peptic disorders include a number of conditions whose pathophysiology is believed to be the result of damage from acid and pepsin activity in the gastric secretions. This chapter focuses on gastroesophageal reflux disease (GERD) and peptic ulcer disease, the two most common and well-defined disease states.
GERD is defined as chronic symptoms of heartburn, acid regurgitation, or both, or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus.1 Reflux esophagitis occurs in a subgroup of GERD patients with histopathologically demonstrated characteristic changes in the esophageal mucosa.
Nonerosive reflux disease, also known as endoscopy-negative reflux disease, occurs in patients who have typical GERD symptoms caused by intraesophageal acid but who do not have visible mucosal injury at endoscopy. Functional heartburn is defined as episodic retrosternal burning without evidence of increased esophageal acid exposure or other structural esophageal abnormalities.
GERD is generally considered to be one of the most prevalent conditions affecting the gastrointestinal (GI) tract; however, figures on the precise prevalence and incidence of GERD are based more on estimates than on actual data. A population-based study, using a validated questionnaire, found that 58.7% of the population has heartburn or acid regurgitation at least once during the course of a year and that 19.8% experience symptoms at least once weekly. 2 It is estimated that approximately 50% of patients with typical reflux symptoms have erosive esophagitis (Fig. 1).
GERD occurs when the normal antireflux barrier between the stomach and esophagus is impaired, either transiently or permanently. Therefore, defects in the esophagogastric barrier, such as lower esophageal sphincter incompetence, transient lower esophageal sphincter relaxation, and hiatal hernia, are the primary factors involved in the development of GERD. Symptoms develop when the offensive factors in the gastroduodenal contents, such as 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 the reflux increases.
Classic symptoms of GERD are heartburn, defined as a retrosternal burning discomfort, and acid regurgitation. Symptoms often occur after meals and can increase when a patient is recumbent. Other ancillary symptoms seen in typical reflux are dysphagia, odynophagia, and belching. Atypical GERD symptoms include chest pain, asthma, cough, hoarseness, sore throat, globus, and repetitive throat clearing.
Although 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 empirical 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 empirical trial of proton pump inhibitor (PPI) therapy in the diagnosis of GERD. However, recent meta-analyses have shown that successful PPI therapy may be useful in the diagnosis of GERD-related noncardiac chest pain, but it is not very useful in the diagnosis of GERD; the sensitivity and specificity are 0.78 (95% confidence interval [CI], 0.66-0.86) and 0.54 (95% CI, 0.44-0.65), respectively. 3 Endoscopic evaluation should be performed under the following conditions 1 :
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. However, Barrett's epithelium must be confirmed by a biopsy revealing intestinal metaplasia. When mucosal breaks are present, the patient is classified as having erosive esophagitis. The Los Angeles (LA) classification is used to grade the severity of the esophagitis.
Unfortunately, in the absence of mucosal breaks, there is no definitive standard for the diagnosis of GERD. Although ambulatory 24-hour pH monitoring has long been believed to be the most useful 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 symptoms to be correlated to acid reflux events. Determining how long the pH is lower than 4 (expressed as a percentage of total recording time) is the single most important parameter in these studies. At present, the barium esophagram has no role in the routine evaluation of GERD. This test demonstrates reflux in only 25% to 75% of symptomatic patients and it can yield false-positive results 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 not only of acid reflux but also of nonacid reflux. The Bravo pH probe is a catheter-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. In addition to being catheter free, the Bravo system has the advantage of recording 48 hours of pH data. This allows improved evaluation of the relation of symptoms to reflux events.
The goals of treatment in GERD are to relieve symptoms, heal esophagitis, prevent recurrence of symptoms, and prevent complications.
Various lifestyle modifications are recommended for the treatment of GERD. However, although all these measures make sense physiologically, few data are available in the literature to support them. Lifestyle measures include avoiding precipitating foods (e.g., fatty foods, alcohol, caffeine), avoiding recumbency for 3 hours postprandially, elevating the head of the bed, quitting smoking, and losing weight. 6
The cornerstone of GERD therapy is the administration of agents that decrease gastric acid secretion, thereby decreasing esophageal acid exposure. 7 An antacid, which only neutralizes acid that is already secreted, and antirefluxants such as alginates may be used for patient-directed immediate symptom relief, but they are not recommended as chronic therapy. Approximately 20% of patients experience symptom relief with these therapies. Administration of histamine-2 (H2) receptor antagonists (H2RAs) 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 Over-the-counter H2RAs are particularly useful when taken before any reflux. The peak potency of antacids and H2RA is identical, but H2RAs have a much longer duration of action, up to 10 hours. PPIs are superior to H2RAs in regard to healing erosive esophagitis and relieving symptoms, with healing rates approaching 90% and symptom relief in 83%. 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 H2RAs, with remission maintained in 80% compared with 50% of patients, respectively. 9 PPIs should always be given before meals; a single dose may be given in the morning to patients with daytime symptoms and in the evening to those with nighttime symptoms. PPIs are generally well tolerated, with the most common side effects being diarrhea and headache. 10 Observational studies have raised concerns about the possibility of an increased risk of community-acquired pneumonia, Clostridium difficile infections, and hip fractures in patients on long-term PPI therapy. 11-13
Because of their superiority in 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 patients who do not respond to a standard dosing regimen. On the other hand, patients whose GERD is well controlled on PPI therapy may consider step-down therapy to an 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 who 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, are also good candidates. However, because patients refractory to medical therapy are 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. Evidence indicates that fundoplication works better than low-dose PPIs but in a manner similar to that of high-dose PPIs; however, 10-year follow-up results have indicated that up to 62% of patients initially treated with surgery go back on reflux medications. 1
Barrett's esophagus (Fig. 2) is a potentially serious complication of chronic GERD. It 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; the odds of developing Barrett's epithelium increase by about sixfold after 10 years of symptoms. 14 It is estimated that 6% to 12% of patients undergoing endoscopy for GERD have Barrett's esophagus. 15 The most dreaded complication of Barrett's epithelium is esophageal adenocarcinoma. However, the incidence rate for developing esophageal carcinoma is still low, approximately 0.5% annually. 16 Unfortunately, symptoms do not predict the development of Barrett's epithelium in patients with chronic GERD. 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). 17 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.
|Two EGDs with biopsy within 1 year||Endoscopy every 3 years|
|Highest grade on repeat EGD with biopsies within 6 months||1 year interval until no dysplasia × 2|
|Expert pathologist confirmation|
|Repeat EGD with biopsies to rule out EAC within 3 months||Continued 3-month surveillance or intervention based on results and patient|
|Expert pathologist confirmation|
EAC, esophageal adenocarcinoma; EGD, esophagogastroduodenoscopy; ER, endoscopic resection.
Wang KK, Sampliner RE: Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 103(3):788-797.
The role of chemoprevention is also being actively investigated. A systematic review has demonstrated a protective association between any use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and esophageal cancer (odds ratio, 0.67; 95% CI, 0.51 to 0.87).18 Use of this class of medications was protective against adenocarcinoma and squamous cell carcinoma, and there was a dose-related effect. The mechanism may be related to the inhibition of cyclooxygenase (COX)-2 enzyme, which is induced in the development of esophageal maligancies.19 Additionally, studies have demonstrated that administration of a selective COX-2 inhibitor decreases cell growth and increases apoptosis in esophageal adenocarcinoma lines.20
Peptic ulcers (gastric and duodenal) are defects in the GI mucosa that extend through the muscularis mucosa.
The lifetime prevalence of peptic ulcer disease is approximately 5% to 10%. 21 In Helicobacter pylori–positive subjects, the lifetime prevalence is significantly higher, 10% to 20%. 22 In patients with dyspepsia, a positive urea breath test for H. pylori was found to be associated with duodenal ulcer in 40% and gastric ulcer in 13% of patients, whereas a negative test result was associated with duodenal and gastric ulcers in only 2% and 3% of patients, respectively. 23
Peptic ulcer disease is the end result of an imbalance between aggressive and defensive factors in the gastroduodenal mucosa. H. pylori infection, NSAIDs, and acid secretory abnormalities are the major factors that disrupt this equilibrium. Although acid peptic injury is necessary for ulcers to form, acid secretion is normal in almost all patients with gastric ulcers (Fig. 3) and increased in only one third of patients with duodenal ulcers. A defect in bicarbonate production and, in turn, acid neutralization in the duodenal bulb is also seen in patients with duodenal ulcer disease. This abnormality resolves with eradication of H. pylori infection when it is present. However, a small percentage of ulcers is not related to H. pylori infection or NSAID use. These are classified as idiopathic and may be related to defective mucosal defense mechanisms, tobacco use, genetics, rapid gastric emptying, or psychological stress.
Dyspepsia, the classic symptom of peptic ulcer disease, is defined as pain centered in the upper abdomen or discomfort characterized by fullness, bloating, distention, or nausea.24 Symptoms may be chronic, recurrent, or new.
Dyspepsia is a common clinical problem that may be seen in 25% to 40% of adults. Only 10% of patients with upper GI symptoms are found to have a gastric or duodenal ulcer. 24 Up to 60% of patients have no definitive diagnosis and are classified as having functional dyspepsia, a condition probably related to visceral hypersensitivity. When ulcers are present, they may be asymptomatic, especially in patients ingesting NSAIDS. Patients might also present with complications of ulcer disease: Hemorrhage can develop in 20%, perforation in 5%, and gastric outlet obstruction in 2%.
There are several possible diagnostic approaches to the patient with dyspepsia 24 :
These approaches are outlined in the American Gastroenterological Association's medical position statement on the evaluation of dyspepsia. 24
Early endoscopic evaluation is indicated for patients older than 55 years with new-onset dyspepsia. It is also indicated for younger patients with alarm features such as unintended weight loss, bleeding, dysphagia, odynophagia, iron-deficiency anemia, persistent vomiting, palpable mass or lymphadenopathy, jaundice, or family history of gastric cancers. If a gastric ulcer is found at endoscopy, multiple biopsies and a brush cytologic examination are required to exclude malignancy. Endoscopy is also indicated for patients whose disease does not respond to empirical therapy. There is no longer any role for barium radiography in the evaluation of dyspepsia because of its poor sensitivity and specificity.
In patients younger than 55 years without alarm features, an initial H. pylori test-and-treat strategy is a reasonable approach if the population prevalence of H. pylori is higher than 10%. The rationale for this is that H. pylori eradication helps in peptic ulcer healing, improves symptoms of nonulcer dyspepsia, and prevents any potential future complications. At the same time, empirically treating dyspepsia patients with antibiotics for only presumed H. pylori infection is not supported by any model to date and should not be done. In H. pylori–negative patients, an empirical trial of acid suppression for 4 to 8 weeks should be instituted. Empirical PPI therapy as the initial choice is a most cost-effective approach when the H. pylori prevalence in a population is lower than 10%. Patients who respond to an H. pylori test-and-treat strategy or PPI therapy may be managed without further investigations. Initial concerns about exacerbating GERD symptoms following H. pylori eradication have remained unsubstantiated.
H. pylori testing is essential for 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 detecting H. pylori are subdivided into nonendoscopic and endoscopic techniques. Enzyme-linked immunosorbent assay (ELISA) serologic tests, formerly the cornerstone of H. pylori testing, are no longer recommended because of the poor performance characteristics of these tests: a sensitivity rate of 85% and specificity rate of 79%. 25 Furthermore, serologic test results can remain positive for up to 3 years after bacteria are eradicated, 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 rate of 89% to 98% and a specificity of more than 90%. 26 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 diagnostic yield of both these biopsy tests.
A subset of patients also requires post-treatment testing to confirm the eradication of H. pylori infection. Post-treatment testing is mandatory for patients with complicated peptic ulcer disease, in which there is bleeding, perforation, or obstruction. Such post-treatment 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.
A number of treatment options are available for the healing of peptic ulcers. These include antacids, H2RAs, and PPIs. Antacids are potentially effective agents for healing ulcers and controlling symptoms; however, because they neutralize only acid that is already secreted, their greatest buffering capacity is active when they are taken 1 hour after eating. From a practical perspective, this inconvenient dosing frequency and the adverse effects of therapy, such as diarrhea, limit the use of antacids to symptom control only.
H2RAs are better than antacids for ulcer healing. Acid secretion is decreased by competitive and selective inhibition of the H2 receptor of the parietal cell. The four available H2RAs are cimetidine, ranitidine, famotidine, and nizatidine. All these compounds act by the same mechanism but have different relative potencies for inhibiting gastric acid secretion. The inhibition of acid secretion results in an increase of the 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 P-450, causing increased drug-drug interactions. H2RAs 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+-ATPase (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. PPIs are generally well tolerated and effective; they achieve duodenal ulcer healing rates at 4 weeks (90%-100%) typically seen at 8 weeks with H2RAs. Additionally, PPIs relieve symptoms more rapidly than H2RAs. 27 Gastric ulcer healing is also more rapid with PPIs, but an 8-week course of therapy is still needed to achieve healing rates higher 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 use.
|Duodenal Ulcer||Gastric Ulcer|
|Agent||Dose (mg)||Duration (wk)||Dose (mg)||Duration (wk)|
|H2 Receptor Antagonists|
|Proton Pump Inhibitors|
© 2002 The Cleveland Clinic Foundation.
Eradication of H. pylori infection 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. Recent meta-analyses have confirmed that for duodenal ulcer healing, H. pylori eradication therapy is superior to ulcer-healing drugs (relative risk [RR] = 0.66; 95% CI, 0.58-0.76) and no treatment (RR = 0.37; 95% CI, 0.26-0.53). 29 Eradication therapy was also superior to no treatment for preventing recurrent duodenal ulcers (RR = 0.20; 95% CI, 0.15-0.26) and recurrent gastric ulcers (RR = 0.29; 95% CI, 0.20-0.42). However, there was no significant difference between eradication therapy and ulcer-healing drugs for gastric ulcer healing or preventing recurrent gastric and duodenal ulcers. Because eradication therapy is much more cost effective than ulcer-healing drugs and is better tolerated by patients, it should be routinely instituted whenever feasible.
The in vivo activity of antibiotics is variable, so combinations of two antibiotics plus a PPI are used to maximize the chance of eradication. Usually, the efficacy of these regimens is approximately 90%. Current treatments are shown in Box 1. 30 A reasonable approach is to use a metronidazole- or clarithromycin-based triple-therapy regimen as first-line therapy. If that fails, second-line therapy involves the antimicrobial not used initially, with quadruple therapy reserved as the third-line option. Because resistance to metronidazole is approximately 35% and resistance to clarithromycin is 11% in the United States, using these two agents together in the initial treatment of H. pylori is not recommended. Recent reports have documented clarithromycin resistance in up to 24% of patients, believed to be related to a gene mutation (A2143G). Therefore, sequential therapy with four medications (PPI, bismuth, metronidazole, and tetracycline) for 10 to 14 days, rather than typical 1-week therapy, has been suggested in such patients. This regimen successfully eradicated H. pylori infection in 85% of patients who live in areas of high metronidazole resistance and in 95% of patients with clarithromycin resistance.
|Box 1: Preferred Therapies for Helicobacter pylori Infection
|Twice-Daily Proton Pump Inhibitor (PPI) or Ranitidine Bismuth Citrate Triple Therapies|
Adapted from Graham DY: Therapy of Helicobacter pylori: Current status and issues. Gastroenterology 2000;118(Suppl 1):S2-S8.
For patients who develop ulcers while ingesting NSAIDs, NSAID therapy should be stopped, if possible, and the patient placed on conventional doses of 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. 31 Therapy with a nonaspirin antiplatelet agent such as clopidogrel carries a similar risk as low-dose aspirin. In a meta-analysis of aspirin and clopidogrel for peptic ulcer bleeding, it was noted that low-dose aspirin doubles the risk of major GI bleeding compared with placebo, but the absolute increase was only 1.2 in 1000 patients. Aspirin increases major GI bleeding by 1.5-fold compared with clopidogrel. However, switching to clopidogrel is not cost effective compared with adding a PPI to aspirin. In fact, the risk of recurrent peptic ulcer bleeding is significantly higher with clopidogrel compared with aspirin and a PPI.32 Therefore, patients with aspirin-related peptic ulcer bleeding should not be switched to clopidogrel; instead, a PPI needs to be added to aspirin.
Even though COX-2 inhibitors have a lower incidence of peptic ulcers than nonselective NSAIDs, the combination of a COX-2 inhibitor and low-dose aspirin has the same risk as a nonselective NSAID. Conversely, the combination of a PPI and an NSAID has a similar incidence of peptic ulcers as COX-2 inhibitors. Evidence indicates that the combination of a PPI and COX-2 inhibitor is superior to using COX-2 inhibitors alone for reducing peptic ulcers. However, concerns continue to be raised about cardiovascular adverse events with COX-2 inhibitors and, therefore, these agents should be used judiciously, if at all.
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. Because prophylactic medications are expensive and NSAID use is common, ulcer prophylaxis should be considered only for high-risk patients. Misoprostol is a prostaglandin E1 analogue that is effective for the prophylaxis of NSAID-induced ulcers and decreases the incidence of serious GI 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.33
|Box 2: Risk Factors for NSAID-Induced GI Ulceration
|Age older than 60 years|
|Prior history of peptic ulcer disease or GI hemorrhage|
|Concurrent use of NSAIDs and corticosteroids|
|Concurrent use of NSAIDs and anticoagulants|
|High dosage of NSAIDs or use of more than one NSAID|
GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drugs.
For more information on the diagnosis and treatment of gastroesophageal reflux disease and gastric and duodenal ulcers, please refer to the following guidelines: