GASTROESOPHAGEAL REFLUX DISEASE. William M. Brady

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1 Drugs of Today 1998, 34(1): Copyright PROUS SCIENCE GASTROESOPHAGEAL REFLUX DISEASE William M. Brady Section of General Internal Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA CONTENTS Summary Definition Physiology Etiology Diagnosis Treatment References Summary Gastroesophageal reflux disease is a common disorder in which irritant gastric contents enter the esophagus, most commonly via transient lower esophageal sphincter relaxation. The diagnosis of gastroesophageal reflux disease may be made on clinical grounds alone or may be confirmed with studies including esophagogastroduodenoscopy or ambulatory ph monitoring. There are a number of different medications to treat reflux disease, including histamine-2 receptor antagonists, promotility agents and the proton pump inhibitors. Reflux disease often requires chronic maintenance therapy. Definition Gastroesophageal reflux disease (GERD) is an episodic or chronic disorder of impaired esophageal motor activity and mucosal defense affecting up to 60 million Americans on a monthly basis. The key pathophysiologic event of GERD is the exposure of the esophageal mucosa to irritant gastric contents, Correspondence: William M. Brady, Section of General Internal Medicine, Temple University School of Medicine, 3401 N. Broad Street (508-92), Philadelphia, PA 19140, USA. most frequently by transient relaxations of the lower esophageal sphincter. Although patients with GERD may be asymptomatic, heartburn, regurgitation, nausea, water brash and belching are typical. Less commonly asthma, chronic cough, chronic hoarseness, dysphagia, globus and chest pain can occur. Patients with GERD commonly have normal appearing esophageal mucosa on endoscopy, but may develop complications including esophagitis, esophageal erosions, strictures or Barrett s metaplasia. The incidence of GERD increases with age and does not differ appreciably among ethnic groups. GERD does not affect longevity, but impairs quality of life (1). Physiology The normal esophagus has three elements of defense against the reflux of gastric contents: a pressure barrier formed by the lower esophageal sphincter and crural diaphragm which prevents gastric juice from entering the esophagus, efficient neutralization and clearance of refluxed contents from the esophagus, and tissue-level resistance to the digestive effects of gastric refluxate. In a normal individual, the lower esophageal sphincter (LES) and crural diaphragm prevent the

2 reflux of gastric contents into the distal esophagus by maintaining a resting high pressure zone between the esophagus and stomach that, in general, relaxes only with peristalsis as a food bolus is passed. The important role of the crural diaphragm in maintaining this high pressure zone has been appreciated only recently. The crural diaphragm helps prevent reflux at the time of inspiration when the esophagus is experiencing negative intrathoracic pressure and the stomach the positive pressure of the abdomen as the diaphragm contracts and compresses abdominal contents. The crural diaphragm is also important in maintaining a high pressure zone in other instances of increased intraabdominal pressure, such as coughing or straight-leg raising. The loss of the effectiveness of the crural diaphragm in individuals with hiatal hernia helps explain the increased frequency with which these individuals experience GERD. Efficient clearance of gastric refluxate from the esophagus by peristalsis and gravity is an important protective mechanism for the esophagus. The role of gravity, in part, explains why reflux symptoms worsen for many in the supine position. Salivary bicarbonate helps neutralize gastric acid following a reflux episode. Tissue resistance to the digestive elements of gastric refluxate is the result of many factors. Preepithelial defenses include a mucus layer, unstirred water layer and local bicarbonate production. Epithelial barriers include cell membranes and intracellular junctions that block acid invasion, intracellular buffering and ion transport systems that remove hydrogen ions. The esophageal blood supply also helps buffer any gastric acid that penetrates the epithelium. Etiology Gastroesophageal reflux is a normal event in healthy individuals. The development of disease depends on the duration and frequency of reflux episodes (2), which, in turn, depend on the rate of clearance of the refluxate from the esophagus. The principal mechanism responsible for disease in patients who suffer from GERD is the failure of the barriers that prevent reflux, most commonly by transient lower esophageal sphincter relaxation (TLESR). Only recently has the critical role of TLESR been appreciated. TLESR is an abrupt decrease in LES pressure below the pressure of the stomach not caused by swallowing. These relaxations occur more commonly following meals, especially when fat is present in the duodenum, helping explain some of the characteristics of GERD observed clinically. Although normal individuals have TLESRs, patients with GERD have a higher frequency of TLESRs and a higher frequency of reflux episodes per TLESR than do patients without disease (3). The TLESRs are considered the primary pathologic element for the majority of patients with GERD. In patients with the more severe forms of GERD, other methods of reflux become important, including a low resting LES tone that is easily overcome by gastric pressure (3). The presence of hiatal hernia predisposes to GERD because the pressure barrier normally provided in part by the crural diaphragm is lost. Also, the herniated portion of the stomach provides a reservoir of gastric contents which can pass more easily into the esophagus during any episodes of LES relaxation. GERD is exacerbated at night because the refluxate has a longer contact time with the esophageal mucosa due to decreased esophageal clearance and because salivary secretions are reduced at night (4). The vast majority of patients with GERD have normal gastric acid secretion. There appears to exist a threshold intraesophageal ph below which reflux symptoms can occur, but above which symptoms are rare. Raising intraesophageal ph above 4.0 effectively eliminates reflux symptoms and explains the effectiveness of many medications commonly used to treat GERD. The presence of this threshold phenomenon is thought to relate, at least in part, to the substantially increased activity of the pepsin found in gastric juice at ph values less than 4.0. Diagnosis GERD is a diagnosis most commonly made clinically. A patient who presents with symptoms typical of uncomplicated GERD does not require any confirmatory testing prior to initiating therapy. The recognized indications for testing for GERD are atypical symptoms, typical symptoms that do not respond to medical therapy, suspicion for a complication of GERD (e.g., esophageal stricture), evaluation prior to antireflux surgery, and possibly to estimate prognosis or evaluate response to therapy in severe disease (5). A number of diagnostic modalities are available for the workup of GERD, including barium radiographs, esophagogastroduodenoscopy (EGD), ambulatory ph monitoring and an acid perfusion test. Esophageal manometry, previously investigated as a diagnostic tool, presently has no role in the workup of GERD (6). Barium studies of the esophagus have limited sensitivity in detecting GERD. The two principal indications for this mode of testing are to rule out an esophageal stricture or mass lesion and to help diagnose hiatal hernia. Despite its limitations, EGD is considered a firstline test in the diagnosis of GERD because of its specificity, availability and ability to diagnose other

3 upper gastrointestinal pathology. EGD is insensitive for the detection of GERD because the vast majority of patients with GERD have no visible esophagitis (5). Interestingly, the grade of esophagitis noted on EGD often does not correlate with the severity of a particular patient s symptoms. EGD can diagnose complications of GERD including esophageal erosions, esophageal stricture and Barrett s esophagus. The exact role of EGD remains controversial, with a few experts who propose that all patients treated for reflux undergo EGD, but most recommend a more conservative application of testing (7). Ambulatory ph monitoring, in which a small ph probe is introduced via the nose into the distal esophagus and a 24-hour ph recording is obtained, is both sensitive (85%) and specific (>95%) for the diagnosis of GERD (5). One of the principal advantages of ph monitoring is that it allows correlation of reflux symptoms with reflux episodes. Ambulatory ph monitoring is particularly useful in patients with atypical reflux symptoms or in patients who do not respond to medical therapy. Although the sensitivity of ph monitoring in patients without esophagitis on EGD is lower than the figure quoted above, there remains an additional role for ph monitoring in patients in whom EGD is not diagnostic. One limitation of ambulatory ph monitoring is that it is technically demanding. The acid perfusion test, also known as the Bernstein test, involves instillation of an acid solution into the mid-esophagus via a nasogastric tube. A positive test occurs when the infusion of the acid replicates the patient s symptoms. The acid perfusion test is specific but not sensitive. It is most useful in the workup of a patient with chest pain of unclear etiology. Treatment Because it may be an episodic or chronic disease, the treatment of GERD has two phases. Initial healing can be considered to occur over the first 8-12 weeks of treatment, and is in many cases followed by chronic management. The earliest treatment of GERD often occurs without the advice of a physician. Initial nonpharmacologic management includes measures to avoid the precipitants of GERD or to reduce the severity of reflux episodes (Table I). Some commonly prescribed medications can exacerbate reflux (Table II). A number of over-the-counter medications are available to treat reflux symptoms. Antacids are commonly used to lower gastric ph. Alginic acid preparations produce a floating raft of precipitated alginate that forms a physical barrier between the esophageal mucosa and gastric fluid. Alginic acid is of principal benefit in the upright position (8). Over-the-counter histamine-2 receptor antagonists (H 2 RAs) are also commonly used to relieve reflux symptoms. Symptoms that fail to respond satisfactorily to the above therapies are often brought to the attention of a physician. The mainstay of GERD therapy remains the H 2 RAs. H 2 RAs block gastric acid secretion and raise intraesophageal ph. H 2 RAs are proven to be safe and superior to placebo in improving reflux symptoms and healing esophagitis (9). The four H 2 RAs available in the U.S. (cimetidine, ranitidine, famotidine and nizatidine) are equally efficacious in the treatment of GERD. Healing rates with H 2 RAs improve as the dose and duration of treatment are increased, presumably reflecting the degree of acid suppression (10). Importantly, the success of H 2 RA therapy varies inversely with the severity of esophagitis (9). A number of alternatives to H 2 RAs for the treatment of GERD exist. Medications that promote gut motility, such as metoclopramide and especially cisapride, have a role in treating reflux. Metoclopramide shows benefit when compared to placebo, but is limited in usefulness by side effects including extrapyramidal symptoms, fatigue and confusion. Cisapride increases LES pressure and augments peristalsis. Cisapride improves symptoms and heals esophagitis with an efficacy equal to that of H 2 RAs (11). Additionally, the combination of cisapride and an H 2 RA may be superior to each used alone (12). Cisapride is generally well tolerated, with side effects limited principally to diarrhea, abdominal pain and constipation. The role of sucralfate in the treatment of GERD remains unclear. The data from studies of sucralfate are conflicting. At best, it is comparable in efficacy to H 2 RAs in mild disease. Proton pump inhibitors (PPIs), similarly to H 2 RAs, reduce intraesophageal acidity to treat reflux disease. However, by directly blocking the Table I: The nonpharmacologic management of gastroesophageal reflux disease. Small meals Avoidance of late evening meals Elevation of the head of the bed Discretion in the intake of fatty foods, acidic foods, alcohol, caffeine and mints Smoking cessation Weight loss

4 Table II: Some medications that precipitate or worsen gastroesophageal reflux disease. Anticholinergics β-adrenergic agonists Calcium channel blockers Narcotics Nicotine Nitrates Progestins Theophylline H + /K + enzymatic pump of the gastric mucosa, PPIs reduce gastric acid secretion much more profoundly than do H 2 RAs and therefore offer the potential to treat reflux symptoms and heal esophagitis more reliably. Omeprazole has been shown to be superior to even high-dose H 2 RAs in the healing of esophagitis and is especially advantageous in the treatment of severe disease (9). Patients with reflux disease resistant to H 2 RA therapy are reliably healed with omeprazole (9, 13). Lansoprazole, the other PPI available in the U.S., is similarly effective. The standard dose of omeprazole for treating GERD is 20 mg once a day and of lansoprazole 30 mg once a day. Some patients respond to PPIs in a dose-dependent fashion, so failure of standard PPI therapy should prompt a doubling of the dose. Standard PPI therapy has the advantage of once-daily administration, but is a little more expensive than H 2 RA therapy per daily dose. Algorithms for the initial treatment of GERD are shown in Figures 1-3. GERD is often a chronic disease. In patients with esophagitis, 50-80% will relapse within 6-12 months of initial healing if left untreated (6). Patients with mild disease or infrequent episodes can be treated as needed for recurrences. However, patients with esophagitis, complications of GERD or frequent recurrences should be considered for chronic suppressive maintenance therapy. Despite their effectiveness in the initial treatment of GERD, H 2 RAs are less useful for chronic maintenance therapy. For patients with reflux esophagitis, H 2 RAs given chronically will maintain remission in only one-half to two-thirds of patients at 1 year (9, 14). Nevertheless, some patients will benefit from Typical symptoms of uncomplicated GERD Lifestyle modification Reassessment of medications that worsen reflux Over-the-counter medications Treat as needed Prescription dose H 2 RA or cisapride Consider esophagogastroduodenoscopy PPI or? H 2 RA plus cisapride Frequent recurrences Perform esophagogastroduodenoscopy if not already done Consider ambulatory ph monitoring High dose PPI Consider maintenance therapy Fig. 1. Algorithm for the initial management of uncomplicated gastroesophageal reflux disease.

5 Symptoms suggesting a complication of GERD Perform esophagogastroduodenoscopy Prescription dose H 2 RA or cisapride Mild esophagitis Moderate to severe esophagitis or complication of GERD PPI Consider maintenance therapy Maintenance therapy High dose PPI Consider ambulatory ph monitoring Maintenance therapy or surgery Fig. 2. Algorithm for the management of complicated gastroesophageal reflux disease. Atypical symptoms of GERD Consider esophagogastroduodenoscopy and/or ambulatory ph monitoring versus Empiric therapy with lifestyle modification, reassessment of medications that worsen reflux and prescription dose H 2 RA or cisapride Treat as needed Perform esophagogastroduodenoscopy and/or ambulatory ph monitoring Fig. 3. Algorithm for the management of atypical presentations of gastroduodenal reflux disease. chronic H 2 RA therapy, so it can be considered for chronic disease. Cisapride may have a role in preventing relapse in mild GERD. Additionally, cisapride in combination with an H 2 RA is more effective than an H 2 RA used alone (14). The PPIs are the most effective medical treatment for chronic reflux. When compared directly to H 2 RAs or cisapride, PPIs are superior in preventing symptoms and maintaining healing of esophagitis (14). There are, however, theoretical concerns about the long-term use of PPIs. Prolonged hypergastrinemia, as with pernicious anemia or Zollinger-Ellison syndrome, causes enterochromaffin-like cell hyperplasia and carcinoids. The PPIs so effectively abolish acid secretion that in both animals and humans a secondary hypergastrinemia develops, although not to the degree

6 observed in the aforementioned conditions. In rats given very high, lifelong doses of omeprazole, an increased rate of carcinoid tumors has been observed. To date, however, no human studies show an increased risk of carcinoids with chronic use. Therefore, although the risk of long-term PPI use remains theoretical, for any individual patient this risk must be weighed against the drug s potential benefit. Surgical techniques have been developed as an alternative to chronic medical therapy for GERD. In general, these techniques increase the pressure barrier of the gastroesophageal junction by wrapping the proximal gastric fundus around the distal esophagus and thereby prevent gastroesophageal reflux from occurring. At present, only patients who have failed medical therapy, who have complications of reflux (e.g., esophageal stricture) despite medical therapy, or who are young and face lifelong treatment should be considered for antireflux surgery. The most popular antireflux surgery is the Nissen fundoplication, which can now be performed laparoscopically in the hands of an experienced surgeon. Direct comparisons of the outcomes of surgical versus medical therapy for GERD are limited. In one study, Nissen fundoplication was shown to be superior to ranitidine in maintaining remission (10), but to date no studies comparing surgery to PPIs have been published. Complications of fundoplication include an inability to belch or vomit (4-11% of patients), caused by creation of a gastroesophageal junction that is too tight, splenectomy (1-8.5%) and rarely, death (15). References 1. Spechler, S.J. Epidemiology and natural history of gastro-oesophageal reflux disease. Digestion 1992, 51 (Suppl. 1): Dent, J. Roles of gastric acid and ph in the pathogenesis of gastro-oesophageal reflux disease. Scand J Gastroenterol 1994, 29 (Suppl. 201): Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J. Transient lower esophageal sphincter relaxation. Gastroenterology 1995, 109 (2): Galmiche, J.P., Janssens, J. The pathophysiology of gastro-oesophageal reflux disease: An overview. Scand J Gastroenterol 1995, 30 (Suppl. 211): Richter, J.E. Typical and atypical presentations of gastroesophageal reflux disease. Gastroenterol Clin North Am 1996, 25 (1): Fennerty, M.B., Castell, D., Fendrick, A.M. et al. The diagnosis and treatment of gastroesophageal reflux disease in a managed care environment: Suggested disease management guidelines. Arch Intern Med 1996, 156 (5): Boyce, H.W. Therapeutic approaches to healing esophagitis. Am J Gastroenterol 1997, 92 (4, Suppl.): 22-9S; discussion 27-9S. 8. Castell, D.O., Dalton, C.B., Becker, D., Sinclair, J., Castell, J.A. Alginic acid decreases postprandial upright gastroesophageal reflux: Comparison with equal-strength antacid. Dig Dis Sci 1992, 37 (4): Johnson, D.A. Medical therapy for gastroesophageal reflux disease. Am J Med 1992, 92 (Suppl. 5A): 88-97S. 10. Brady, W.M., Ogorek, C.P. Gastroesophageal reflux disease: The long and the short of therapeutic options. Postgrad Med 1996, 100 (5): 76-80, 85-6, Galmiche, J.P., Fraitag, B., Filoche, B. et al. Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis. Dig Dis Sci 1990, 35 (5): Richter, J.E. Efficacy of cisapride on symptoms and healing of gastro-oesophageal reflux disease: A review. Scand J Gastroenterol 1989, 24 (Suppl. 165): Hixson, W., Kelley, C.L., Jones, W.N., Tuohy, C.D. Current trends in the pharmacotherapy for gastroesophageal reflux disease. Arch Intern Med 1992, 152 (4): Vigneri, S., Termini, R., Leandro, G. et al. New Engl J Med 1995, 333 (17): Dehn, T.C. Surgery for uncomplicated gastroesophageal reflux. Gut 33 (3):

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