Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Gastroesophageal Reflux: Diagnosis and Management Joel E. Richter To cite this article: Joel E. Richter (1992) Gastroesophageal Reflux: Diagnosis and Management, Hospital Practice, 27:1, 59-66, DOI: 10.1080/21548331.1992.11705342 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705342
Published online: 17 May 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [University of Saskatchewan Library]
Date: 20 September 2016, At: 22:36
Gastroesophageal Reflux: Diagnosis and Management J 0 E L E. RICHTER
University of Alabama
The pathologic potential of chronic esophagitis cannot be overemphasized. Persistent reflux causing cycles of mucosal damage followed by healing may eventually lead to end-stage disease, with development of peptic stricture. The most effective drugs available are those that inhibit acid production. Drugs that will enhance lower esophageal function are still in the future.
Reflux of gastric contents into the esophagus is probably the most common disorder originating in the gastrointestinal tract. Most people experience occasional heartburn as a result of reflux. In arecent Gallup poll, 45% of 800 randomly queried adults reported having heartburn at least once a month. Such episodes of"physiologic" reflux usually occur soon after eating, are short-lived, and, although troubling to some patients, seldom herald more serious symptoms. However, heartburn can also represent a spectrum of disease from reflux esophagitis to cancer of the esophagus. Gastroesophageal reflux disease is present when any symptomatic condition or histologic change is the result of excessive acid reflux from the stomach into the esophagus. Reflux esophagitis is present when there is mucosal injury to the esophagus, such as epithelial erosions, ulcerations, hyperplasia, or inflammation. The concept of reflux disease has been evolVing since 1935, when William Winklestein first suggested that the disease was due to the action of gastric acid on esophageal mucosa. In the 1940s and '50s, the cause of reflux was generally thought to be mechanical, i.e., a sliding hiatal hernia. Although it is true that many patients with severe reflux disease have a hiatal hernia, many others with small hernias do not have reflux disease. In the 1960s. the popular view held that a weak or atonic lower esophageal sphincter permitted reflux. Currently, there is a consensus that both of these factors, as well as others-including the refluxed material, the motility of the esophagus and the resistance ofits epithelium to injury, and the function of the stom-
ach in terms of gastric secretion, volume, distention, and emptying time-may play roles, weighted in any given case by individual characteristics (Table 1). Heartburn and esophagitis are often considered to be synonymous, but only 30% to 40% of patients who complain of heartburn have mucosal injury of the esophagus. Conversely, reflux disease can occur without heartburn as the primary symptom. We do not know just how common atypical presentations are, but gastroesophageal reflux disease has been diagnosed in patients who had presented with chest pain suggesting a heart attack. It has also been diagnosed in patients with primarily pulmonary symptoms, particularly asthma, and in patients whose chief complaint was hoarseness, coughing, sort! throat, or bad breath. In addition, it has been found in patients with laryngeal cancer who were nonsmokers and nondrinkers. Taken together, the classic and the atypical presentations represent a sizable medical problem, one that most physicians see in their practices and should be comfortable treating.
Diagnosis The diagnosis of esophageal reflux disease can often be made on the basis of the history alone. If a patient gives a history of heartburn or gastric regur-
Dr. Richter is Professor of Medicine and Director of Clinical Research, Gastroenterology Division, University of Alabama School of Medicine, Birmingham. Hospital Practice January 15, 1992
59
Table 1. Proposed Factors in the Pathogenesis of Gastroesophageal Reflux Disease Reduced lower esophageal sphincter pressure or inappropriate relaxation Defective esophageal clearance mechanisms (peristalsis, saliva) Heightened gastric secretion (acid, pepsin) and delayed gastric emptying Impaired esophageal epithelial resistance (mucus, unstirred water layer, bicarbonate ions) Hiatal hernia
gitation and lacks signs or symptoms of dysphagia or recent weight or blood loss, there is little doubt about the diagnosis. In nearly half of cases, the history is probably sufficient to indicate treatment with an appropriate antacid or H2 blocker. further evaluation is needed if heartburn persists on treatment or recurs when treatment is stopped. It is also required if a patient complains of episodes occurring several times a week, withorwithoutdysphagta, weight loss, or loss of blood. Patients with dysphagia or atypical symptoms should be investigated before treatment is started. When the presenting symptom is chest pain, other causes must be ruled out. Chest wall disease usually can be detected by eliciting tenderness over the thoracic cage. Since ischemic heart disease is a possibility in any patient with risk factors and in any patient over the age of 40, those who fall into either or both categories should be referred to a cardiologist for evaluation and possible coronary angiography. According to various studies, 10% to 30% of patients undergoing elective coronary artery evaluation for chest pain have normal or nearly normal coronary arteries. Among those referred to gastroenterologists after the exclusion of coronary artery disease, 20% to 60% have esophageal disease as the source of their chest pain. On the other
Figure 1. Barium esophagogram of a patient with severe reflux disease shows a large hiatal hernia, distal stricture, and esophageal ulcer (arrow). In general, the procedure is one of the most useful means for diagnosing reflux. It will also provide information about esophageal motility in the presence or absence of reflux disease and demonstrate tumors or severe mucosal damage.
60
Hospital Practice January 15, 1992
hand, in a recent prospective study of patients undergoing coronary angiography for suspected myocardial disease (rather than merely to rule out the diagnosis), Gaston Vantrappen and associates at the University of Leuven, Belgium, found the esophagus to be the source of chest pain in up to 50% of those whose angiograms were normal. Noncardiac chest pain originating in the esophagus can, of course, be due to either a motility disorder or gastroesophageal reflux. However, our studies as well as those of others suggest that chest pain is more often related to episodes of acid reflux. The most useful tests we have for diagnosing reflux disease are barium esophagography, endoscopy, and 24-hour pH monitoring. The acid perfusion (Bernstein) test has been largely supplanted by pH monitoring, but it is still used in certain circumstances. Barium esophagography. The barium esophagogram will reveal severe grades of mucosal damage and the presence of reflux, strictures, and tumors, as well as provide information about esophageal motility. It should be the first study done in any patient who complains of difficulty swallowing or of food sticking in the throat, because it will usually show the source of the problem. If the barium study shows a normal esophagus, giving the patient a solid challenge (such as a 12.5-mm tablet, a marshmallow, or a food that the patient has characterized as difficult to swallow) may define mildly obstructing rings or strictures. Demonstration of reflux is not particularly helpful unless the reflux is truly striking-that is, into the mid-esophagus or higher. The finding of a hiatal hernia
is also of little consequence since, as noted, it is common in most patients with esophagitis. On the other hand, the absence of a hiatal hernia on the barium swallow will exclude esophagitis with 95% accuracy. The addition of a complete upper GI series to the barium esophagography aids in the diagnosis of other gastroduodenal lesions, such as ulcers or tumors, that may be contributing to the patient's symptoms (Figure 1). Endoscopy. If the patient has no dysphagia, the preferred initial study is endoscopy. It provides a direct view of the esophageal mucosa and permits immediate biopsy when needed. The major advantage of endoscopy is the detection of even mild. nonerosive esophagitis, which cannot be identified reliably with radiography (endoscopy also permits diagnosis of Barrett's esophagus, which may be present in up to 10% of patients with reflux disease). The finding of esophagitis is significant because patients who have it tend to have more severe reflux disease than patients without evidence of mucosal injury. However, a negative finding on endoscopy does not rule out reflux disease (Figure 2). Twenty-four-hour pH monitoring. When there is no evidence of esophagitis despite the clinical suspicion that the patient has reflux disease, the best way to approach the problem is 24-hour pH monitoring. A very small tube with a pH electrode at the tip is passed through the nose and down the esophagus to 5 em above the lower esophageal sphincter. Data from the probe are recorded in a small, lightweight box worn on a belt around the waist and later analyzed by computer. Patients are
Figure 2. In patients with no dysphagia in whom reflux di!l88se is suspected, endoscopy is the preferred initial study. Its direct view of esophageal mucosa enables detection of esophagitis, whether mild and nonM"osive or, as shown, severely erosive with stricture. Although negative findings do not rule out reflux disease, patients with esophagitis tend to have more severe reflux disease than those without such evidence of mucosal damaae.
encouraged to maintain their normal routine during monitoring. They can eat, drink alcoholic beverages. and smoke, but they are asked to avoid foods with a pHbelow5. The box has one or more buttons, depending on the sophistication of the system, that the patient can push to indicate episodes of pain, heartburn, belching, or wheezing. The record will show whether these events coincide with episodes of acid reflux. which are considered to occur whenever the pH drops below 4; normal esophageal pH is 6. The device measures the total amount of acid reflux into the esophagus over the 24-hour period. Several other variables can
be measured also. including the lengths of time the pH is below 4 in the supine, upright, and combined positions, the number of reflux episodes lasting more than five minutes, and the single longest reflux episode in 24 hours (Figure 3). Monitoring is the most sensitive and specific test for diagnosing reflux disease. It has a sensitivity of about 85% and a specificity of about 90%. However, it is moderately expensive and timeconsuming to use, and the results are sometimes thwarted by technical problems. Nevertheless. it is very useful for diagnosing patients with intractable reflux symptoms and negative endoscopic exams, as well as paHospital Practice January 15. 1992
61
tients with atypical presentations, such as noncardiac chest pain, asthma, and ENT complaints. The 24-hour pH test not only reveals excessive acid reflux but also patterns of reflux that often correlate with severity of the disease. Physiologically, almost everyone has a little acid reflux. particularly after meals. Such reflux episodes occur almost exclusively during waking hours, representing no more than about 5.5% of the 24-hour day. This physiologic process is the reason why we belch and have occasional attacks of heartburn. In some patients with excessive acid reflux, most episodes also occur during the day. and consequently in the upright position. These patients tend to have frequent heartburn, belching, and sometimes chest pain, but there is little damage to the esophagus. There are probably several reasons for the relatively benign nature of this pattern. In the upright position, gravity
drains the esophagus, aided by active peristalsis. The symptoms of regurgitation may also provoke swallowing, saliva production, and fluid intake, which tend to neutralize the acid and wash it out of the esophagus. Other patients have reflux only during sleep. They have the supine pattern. which is commonly associated with some degree of esophagitis, because acid remains in the esophagus for prolonged periods in the absence of any of the normal mechanisms for removing it. There are also patients who have reflux during the day and at night; about 75% of them have esophagitis. The most severe disease is seen in patients with esophageal strictures or Barrett's esophagus. a potentially malignant lesion associated with chronic inflammation. These patients tend to have markedly decreased lower esophageal sphincter pressures. Bernstein test. This is a simple screening test that identifies
:r:a.
:r:a.
Treatment 11:00 P.M.
11:20 P.M. Night (Supine Gastroesophageal Reflux)
11:40 P.M.
Figure 3. When there is clinical suspicion of reflux disease but no evidence of esophagitis, 24-hour pH monitoring may confirm the diagnosis, as these representative daytime and nighttime tracings illustrate. During the day, acid reflux episodes, defined as falls in pH to less than 4, are brief and frequently associated with symptoms such as heartburn or belching (top). At night, reflux episodes may last for long periods and be poorly resolved because the patient is supine and both peristalsis and saliva production are minimal (bottom).
62
patients with an acid-sensitive esophagus. It is performed by infusion ofO.l N hydrochloric acid into the distal esophagus at a minimum rate of 7 mVmin, with the patient preferably in the supine position. A positive test replicates the patient's symptoms of heartburn or chest pain. The control is a saline infusion. In theory. the test should be most useful in patients with noncardiac chest pain and a normalappearing esophagus on endoscopy, but we have found it unreliable, especially in such patients. We compared it with 24-hour pH monitoring in 75 consecutive patients with noncardiac chest pain who had an acid perfusion test immediately before pH monitoring. The Bernstein test was positive in 15 patients (20%). whereas 24-hour pH monitoring indicated abnormal reflux episodes in 34 patients (45%). Only nine of the 34 (26%) had a positive acid perfusion test, but pH monitoring correlated acid reflux episodes with symptoms in 45 patients (59%). Although the Bernstein test had excellent specificity in our study (up to 94%), it had poor sensitivity (46% at best). Prolonged pH monitoring is superior for identifying reflux disease in patients with noncardiac chest pain, but if it is not available, the acid perfusion test should be used-with the caution that a negative result does not rule out the diagnosis of gastroesophageal reflux.
Hospital Practice January 15, 1992
Once the diagnosis is made, patients usually can be classified into one of three groups: reflux disease without esophagitis, reflux disease with esophagitis, and severe esophagitis. These diagnostic distinctions have an important bearing on treatment.
Life-style changes. Therapy is dictated by the severity of the disease and the patient's response to treatment. The first step in treatment is to institute some simple but effective lifestyle modifications, which include elevating the head by at least six inches during sleep and altering eating habits. Elevating the head during sleep is best accomplished by placing blocks under the head of the bed or by using a wedge-shaped bolster to support the head and shoulders. The purpose is to help gravity clear any gastric acid regurgitated during sleep. The most important dietary changes include eating smaller meals, eating more frequently, and not eating for at least two hours before bedtime, as well as losing, or at least not gaining, weight. Large meals take longer to pass from the stomach and stimulate more acid production and therefore increase the likelihood of reflux. Going to bed on an empty stomach also helps to reduce the amount of acid in the stomach. A low-fat diet is desirable because fats tend to slow gastric emptying. If certain foods or beverages are associated with symptoms, they should be avoided. The most frequent offenders are chocolate, citrus products, tomatoes, coffee, and alcohol. Smoking reduces lower esophageal sphincter pressure and thus can promote acid reflux, and a number of frequently prescribed medications have the same effect. In addition, some drugs, because of their dosage form, tend to get trapped in the esophagus in patients with reflux disease and may injure the epithelium (Table 2). These life-style modifications are helpful for any patient with reflux disease, regardless of severity. For patients with mild dis-
ease, who may represent nearly one half of all patients with reflux, life-style changes may be sufficient to prevent symptoms in many cases. Antacids and alginic acid. Pharmacologic therapy with antacids or combinations of antacids and alginic acid are also recommended for mild disease, but these agents have not been shown to be consistently effective. Theoretically, antacids neutralize acid in the stomach if taken one to three hours after meals, but in placebo-controlled studies, antacids have not been superior to placebo in preventing symptoms. Alginic acid produces foam when it comes in contact with gastric acid. If reflux occurs, presumably the foam rather than the acid rises into the esophagus (Figure 4). While alginic acid may act in this manner, controlled studies suggest that combinations with antacids are not more effective than antacids alone. Nevertheless, the use of an antacid alone or combined with alginic acid in patients with mild disease without esophagitis on an as-needed basis may be beneficial. These patients do not require constant medication and only occasionally need a more potent drug, such as an H2 blocker, to inhibit gastric acid secretion, or a promotility drug, such as metoclopramide, that strengthens the lower esophageal sphincter to prevent reflux symptoms. Patients with stage I or II (mild or moderate) esophagitis constitute about 30% of all patients with reflux disease, although they may or may not have symptomatic reflux. Treatment of esophagitis has three goals: The first is to relieve symptoms. the second to bring about resolution of the esophagitis, and the third to prevent recurrence. Esophagi-
Table 2. Drugs That May Contribute to Esophageal Disease Agents That Decrease Lower Esophageal Sphincter Pressure Progesterone Theophylline Anticholinergic agents Tricyclic antidepressants fJ-Adrenergic agonists a-Adrenergic antagonists Diazepam Meperidine Calcium channel blockers Agents That Cause Esophageal Injury Tetracycline, doxycycline Quinidine Slow-release potassium chloride Iron salts Nonsteroidal anti-inflammatory drugs
tis tends to recur, each time causing more damage to the esophagus. Adequate treatment. therefore, may be thought of as having both acute and chronic, or maintenance, phases. H 2 blockers are probably the single most effective class of drugs in the treatment of gastroesophageal reflux disease. Four are available, and all are equally effective when used in the right dosages. My recommendations are as follows: cimetidine, 400 mg twice a day; ranitidine, 150 mg twice a day; famotidine, 20 mg twice a day; or nizatidine, 150 mg twice a day. Most physicians are familiar with the use of H2 blockers in peptic ulcer disease. They are customarily prescribed once a day at bedtime to prevent acid Hospital Practice January 15. 1992
63
secretion during the night. In reflux disease, a single bedtime dose usually is not as effective as in peptic ulcer disease. Since the H2 blockers are effective for eight to 12 hours. a single bedtime dose tends to wear off by morning. Furthermore, most acid reflux occurs after the evening meal and before bedtime. Consequently, I prescribe H2 blocker therapy on a twice-a-day schedule, with the first dose in the morning to inhibit acid production after breakfast and lunch and the second dose about 30 minutes after the evening meal. On this schedule, most patients with mild esophagitis have complete resolution in eight to 12 weeks. The promotility drugs bethanechol and metoclopramide are also used for the acute therapy of mild reflux disease. These drugs increase lower esophageal sphincter pressure to some degree and promote acid clearance; metoclopramide also promotes gastric emptying. Neitherdrugaffects gastric acid production. Several studies have shown that they reduce reflux symptoms. but the drugs do not seem to have any predictable effect on esophagitis. Metoclopramide has caused such side effects as lethargy. fatigue, and psychotropic and extrapyramidal symptoms in 10% to 30% of patients. Cisapride is another promotility drug that increases lower esophageal sphincter pressure and gastric emptying. Its effects are due to facilitation of acetylcholine release by myenteric nerves. Clinical trials in Europe indicate that cisapride is very effective as primary therapy in mild esophagitis and is also relatively free of side effects. It is not yet available in the United States. Various combinations of an H2 blocker with a promotility drug 64
Hospital Practice January 15. 1992
or sucralfate, or both, have been used in the acute therapy of esophagitis-but with variable results. Therefore, the mainstay of therapy is prescription of an H 2 blocker. After eight to 12 weeks of drug therapy. most patients should have a repeat endoscopy to ascertain that their esophagitis has resolved. Unfortunately, many patients relapse within several months of sfopping their medication. To maintain remission, an H2 blocker can be given twice daily, although in some cases a single dose after the evening meal may be sufficient. If cisapride is approved for use in the United States. it may become the preferred drug for maintenance therapy in patients with resolved mild esophagitis. Several recent reports suggest that it prevents relapses. For the 10% to 15% of patients with gastroesophageal reflux disease who have severe (grade III or IV) esophagitis, H2 blockers are not effective in the usual doses. Fortunately, we have two therapeutic alternatives. One is prescription of an H2 blocker at double or triple the usual dose, which will achieve healing in perhaps 75% of patients with severe esophagitis. However, the cost of treatment will also double or triple, rising to $200 to $300 a month, and the patient will have to take pills three or four times a day. The other alternative is prescribing omeprazole, the first of the proton-pump-inhibitor drugs. Omeprazole inhibits hydrogen-potassium-ATPase, which is the active transport mechanism for hydrogen ion secretion in the stomach and the final pathway for all acid secretion. Omeprazole is the most powerful agent we have at present for blocking production of gastric acid (Figure 4).
H2 blockers, given in usual doses, reduce gastric acid by 60% to 70%. Omeprazole, in a single daily dose of 20 mg. reduces acid secretion by 90%. In clinical trials, more than 80% of patients with severe esophagitis have had healing after eight to 12 weeks on omeprazole. In contrast to the H2 blockers, which are usually taken at bedtime, omeprazole is taken in the morning. As noted, the recommended dose is 20 mg. but clinical experience suggests that some patients need 40 to 60 mg per day. When prescribing at the higher doses, it is probably advisable to specify 20 mg in the morning and 20 mg in the evening. or 40 mg in the morning and 20 mg in the evening. Despite the high cure rate for severe esophagitis achieved with omeprazole (or, for that matter. with high-dose H2 ) therapy, 80% of patients relapse within six months of stopping treatment. In the United States, omeprazole can be given only for three months at a time because of doubts about its safety in longterm use; it has been found to cause carcinoid tumors in rats. My approach is to continue omeprazole in older patients with severe disease and in those in whom anti-reflux surgery would be very risky. On the other hand, if the patient is young and otherwise healthy. surgery is probably preferable to a lifetime on medication at a cost of $1.000 to $1,500 a year. However, thecaveats for good surgical results are that an experienced surgeon and a thorough evaluation of esophageal function are required. Otherwise, surgery can make the condition worse. Complications. The importance of preventing chronic esophagitis cannot be overemphasized. Persistent reflux caus-
Figure 4. Drugs used to treat reflux disease act at various sites. The promotility agents bethanechol, metoclopramide, and cisapride not only increase lower esophageal sphincter pressure but also improve peristalsis; in addition, bethanechol stimulates saliva production, whereas metoclopramide and cisapride promote gastric emptying. Alginic acid reacts with gastric acid to produce
ing a cycle of mucosal damage followed by healing may eventually lead to end-stage disease. signified by development of peptic stricture. Strictures appear to be caused by a combination offi-
a foam, which presumably provides a protective barrier for the esophagus when reflux occurs. Antacids are believed to neutralize acid in the stomach. H2 blockers and proton pump inhibitors target acid secretion itself. The latter drug class is represented by omeprazole, which blocks acid secretion by inhibiting the H-K-ATPase pump, the final common pathway to acid secretion.
brosis. spasm. and edema. They are usually 2 to 4 em in length but may be longer. and they invariably cause dysphagia if the lumen narrows to less than 13 mm in diameter. Stricture devel-
opsin only about 10% of patients with severe reflux esophagitis, but the incidence increases with age (Figure 5). Barrett's esophagus is another complication of severe recurrent Hospital Practice January 15. 1992
65
Figure 5. The end stage of chronic esophagitis is signified by the development of peptic stricture, which apparently results from a combination of fibrosis, spasm, and
mucosal injury and healing. It represents a reparative process in which the squamous mucosa of the esophagus is gradually replaced with columnar epitheli-
edema. Most peptic strictures are short (A), but some of them involve much or all of the thoracic portion of the esophagus (B) and may be cancerous (C).
urn typical of the intestinal lining. Barrett's esophagus has been described in 5% to 12% of patients with symptomatic gastroesophageal reflux disease un-
Selected Reading Dodds WJ et al: Mechanisms of gastroesophageal reflux In patients with reflux esophagitis. N Eng! J Med 307:1547, 1982 Klauser AG, Schlndlbeck NE. Miiller-Lissner SA: Symptoms of gastroesophageal reflux disease. Lancet 335:205, 1990 Hewson EG et al: 1\venty-four-hour esophageal pH monitoring: The most useful test for evaluating non cardiac chest pain. Am J Med 90:576, 1991 Ott DJ et al: Current status of radiology In evaluating gastroesophageal reflux disease. J Clin Gastroenterol4: 365, 1982 Monnier PH et al: Contribution of endoscopy to gastroesophageal reflux disease. Scand J Gastroenterol 106:26, 1984 Mattox HE, Richter JE: Prolonged ambulatory esophageal pH monitoring In the evaluation of gastroesophageal reflux disease. Am J Med 89:345, 1990 Richter JE et al: Acid perfusion test and 24-hour esophageal pH monltorlngwtth symptom index: Comparison of tests for esophageal acid sensitivIty. DlgDisSci36:565, 1991 Kitchen L. Castell DO: Rationale and efficacy of conservative therapy for gastroesophageal reflux disease. Arch Intern Med 151:440, 1991 Maton PN: Omeprazole. N Eng! J Med 324:965, 1991
66
Hospital Practice January 15. 1992
dergoing endoscopy. Why it occurs is not known, but the observation that it develops in patients with the most severe forms of reflux disease suggests that it is related to the severity of acidic mucosal damage. The heightened risk of adenocarcinoma of the esophagus in patients with Barrett's esophagus mandates follow-up.
Summary Most patients with reflux disease do not generate more gastric acid than normal people. The problem in reflux disease is that the acid is in the esophagus instead of the stomach. The most effective drugs currently available are those that inhibit acid production. It is hoped that the future will see development of drugs that will enhance lower esophageal sphincter function, and thus prevent reflux. D
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Gastroesophageal Reflux: Diagnosis and Management Joel E. Richter To cite this article: Joel E. Richter (1992) Gastroesophageal Reflux: Diagnosis and Management, Hospital Practice, 27:1, 59-66, DOI: 10.1080/21548331.1992.11705342 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705342
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [University of Saskatchewan Library]
Date: 20 September 2016, At: 22:36
Gastroesophageal Reflux: Diagnosis and Management J 0 E L E. RICHTER
University of Alabama
The pathologic potential of chronic esophagitis cannot be overemphasized. Persistent reflux causing cycles of mucosal damage followed by healing may eventually lead to end-stage disease, with development of peptic stricture. The most effective drugs available are those that inhibit acid production. Drugs that will enhance lower esophageal function are still in the future.
Reflux of gastric contents into the esophagus is probably the most common disorder originating in the gastrointestinal tract. Most people experience occasional heartburn as a result of reflux. In arecent Gallup poll, 45% of 800 randomly queried adults reported having heartburn at least once a month. Such episodes of"physiologic" reflux usually occur soon after eating, are short-lived, and, although troubling to some patients, seldom herald more serious symptoms. However, heartburn can also represent a spectrum of disease from reflux esophagitis to cancer of the esophagus. Gastroesophageal reflux disease is present when any symptomatic condition or histologic change is the result of excessive acid reflux from the stomach into the esophagus. Reflux esophagitis is present when there is mucosal injury to the esophagus, such as epithelial erosions, ulcerations, hyperplasia, or inflammation. The concept of reflux disease has been evolVing since 1935, when William Winklestein first suggested that the disease was due to the action of gastric acid on esophageal mucosa. In the 1940s and '50s, the cause of reflux was generally thought to be mechanical, i.e., a sliding hiatal hernia. Although it is true that many patients with severe reflux disease have a hiatal hernia, many others with small hernias do not have reflux disease. In the 1960s. the popular view held that a weak or atonic lower esophageal sphincter permitted reflux. Currently, there is a consensus that both of these factors, as well as others-including the refluxed material, the motility of the esophagus and the resistance ofits epithelium to injury, and the function of the stom-
ach in terms of gastric secretion, volume, distention, and emptying time-may play roles, weighted in any given case by individual characteristics (Table 1). Heartburn and esophagitis are often considered to be synonymous, but only 30% to 40% of patients who complain of heartburn have mucosal injury of the esophagus. Conversely, reflux disease can occur without heartburn as the primary symptom. We do not know just how common atypical presentations are, but gastroesophageal reflux disease has been diagnosed in patients who had presented with chest pain suggesting a heart attack. It has also been diagnosed in patients with primarily pulmonary symptoms, particularly asthma, and in patients whose chief complaint was hoarseness, coughing, sort! throat, or bad breath. In addition, it has been found in patients with laryngeal cancer who were nonsmokers and nondrinkers. Taken together, the classic and the atypical presentations represent a sizable medical problem, one that most physicians see in their practices and should be comfortable treating.
Diagnosis The diagnosis of esophageal reflux disease can often be made on the basis of the history alone. If a patient gives a history of heartburn or gastric regur-
Dr. Richter is Professor of Medicine and Director of Clinical Research, Gastroenterology Division, University of Alabama School of Medicine, Birmingham. Hospital Practice January 15, 1992
59
Table 1. Proposed Factors in the Pathogenesis of Gastroesophageal Reflux Disease Reduced lower esophageal sphincter pressure or inappropriate relaxation Defective esophageal clearance mechanisms (peristalsis, saliva) Heightened gastric secretion (acid, pepsin) and delayed gastric emptying Impaired esophageal epithelial resistance (mucus, unstirred water layer, bicarbonate ions) Hiatal hernia
gitation and lacks signs or symptoms of dysphagia or recent weight or blood loss, there is little doubt about the diagnosis. In nearly half of cases, the history is probably sufficient to indicate treatment with an appropriate antacid or H2 blocker. further evaluation is needed if heartburn persists on treatment or recurs when treatment is stopped. It is also required if a patient complains of episodes occurring several times a week, withorwithoutdysphagta, weight loss, or loss of blood. Patients with dysphagia or atypical symptoms should be investigated before treatment is started. When the presenting symptom is chest pain, other causes must be ruled out. Chest wall disease usually can be detected by eliciting tenderness over the thoracic cage. Since ischemic heart disease is a possibility in any patient with risk factors and in any patient over the age of 40, those who fall into either or both categories should be referred to a cardiologist for evaluation and possible coronary angiography. According to various studies, 10% to 30% of patients undergoing elective coronary artery evaluation for chest pain have normal or nearly normal coronary arteries. Among those referred to gastroenterologists after the exclusion of coronary artery disease, 20% to 60% have esophageal disease as the source of their chest pain. On the other
Figure 1. Barium esophagogram of a patient with severe reflux disease shows a large hiatal hernia, distal stricture, and esophageal ulcer (arrow). In general, the procedure is one of the most useful means for diagnosing reflux. It will also provide information about esophageal motility in the presence or absence of reflux disease and demonstrate tumors or severe mucosal damage.
60
Hospital Practice January 15, 1992
hand, in a recent prospective study of patients undergoing coronary angiography for suspected myocardial disease (rather than merely to rule out the diagnosis), Gaston Vantrappen and associates at the University of Leuven, Belgium, found the esophagus to be the source of chest pain in up to 50% of those whose angiograms were normal. Noncardiac chest pain originating in the esophagus can, of course, be due to either a motility disorder or gastroesophageal reflux. However, our studies as well as those of others suggest that chest pain is more often related to episodes of acid reflux. The most useful tests we have for diagnosing reflux disease are barium esophagography, endoscopy, and 24-hour pH monitoring. The acid perfusion (Bernstein) test has been largely supplanted by pH monitoring, but it is still used in certain circumstances. Barium esophagography. The barium esophagogram will reveal severe grades of mucosal damage and the presence of reflux, strictures, and tumors, as well as provide information about esophageal motility. It should be the first study done in any patient who complains of difficulty swallowing or of food sticking in the throat, because it will usually show the source of the problem. If the barium study shows a normal esophagus, giving the patient a solid challenge (such as a 12.5-mm tablet, a marshmallow, or a food that the patient has characterized as difficult to swallow) may define mildly obstructing rings or strictures. Demonstration of reflux is not particularly helpful unless the reflux is truly striking-that is, into the mid-esophagus or higher. The finding of a hiatal hernia
is also of little consequence since, as noted, it is common in most patients with esophagitis. On the other hand, the absence of a hiatal hernia on the barium swallow will exclude esophagitis with 95% accuracy. The addition of a complete upper GI series to the barium esophagography aids in the diagnosis of other gastroduodenal lesions, such as ulcers or tumors, that may be contributing to the patient's symptoms (Figure 1). Endoscopy. If the patient has no dysphagia, the preferred initial study is endoscopy. It provides a direct view of the esophageal mucosa and permits immediate biopsy when needed. The major advantage of endoscopy is the detection of even mild. nonerosive esophagitis, which cannot be identified reliably with radiography (endoscopy also permits diagnosis of Barrett's esophagus, which may be present in up to 10% of patients with reflux disease). The finding of esophagitis is significant because patients who have it tend to have more severe reflux disease than patients without evidence of mucosal injury. However, a negative finding on endoscopy does not rule out reflux disease (Figure 2). Twenty-four-hour pH monitoring. When there is no evidence of esophagitis despite the clinical suspicion that the patient has reflux disease, the best way to approach the problem is 24-hour pH monitoring. A very small tube with a pH electrode at the tip is passed through the nose and down the esophagus to 5 em above the lower esophageal sphincter. Data from the probe are recorded in a small, lightweight box worn on a belt around the waist and later analyzed by computer. Patients are
Figure 2. In patients with no dysphagia in whom reflux di!l88se is suspected, endoscopy is the preferred initial study. Its direct view of esophageal mucosa enables detection of esophagitis, whether mild and nonM"osive or, as shown, severely erosive with stricture. Although negative findings do not rule out reflux disease, patients with esophagitis tend to have more severe reflux disease than those without such evidence of mucosal damaae.
encouraged to maintain their normal routine during monitoring. They can eat, drink alcoholic beverages. and smoke, but they are asked to avoid foods with a pHbelow5. The box has one or more buttons, depending on the sophistication of the system, that the patient can push to indicate episodes of pain, heartburn, belching, or wheezing. The record will show whether these events coincide with episodes of acid reflux. which are considered to occur whenever the pH drops below 4; normal esophageal pH is 6. The device measures the total amount of acid reflux into the esophagus over the 24-hour period. Several other variables can
be measured also. including the lengths of time the pH is below 4 in the supine, upright, and combined positions, the number of reflux episodes lasting more than five minutes, and the single longest reflux episode in 24 hours (Figure 3). Monitoring is the most sensitive and specific test for diagnosing reflux disease. It has a sensitivity of about 85% and a specificity of about 90%. However, it is moderately expensive and timeconsuming to use, and the results are sometimes thwarted by technical problems. Nevertheless. it is very useful for diagnosing patients with intractable reflux symptoms and negative endoscopic exams, as well as paHospital Practice January 15. 1992
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tients with atypical presentations, such as noncardiac chest pain, asthma, and ENT complaints. The 24-hour pH test not only reveals excessive acid reflux but also patterns of reflux that often correlate with severity of the disease. Physiologically, almost everyone has a little acid reflux. particularly after meals. Such reflux episodes occur almost exclusively during waking hours, representing no more than about 5.5% of the 24-hour day. This physiologic process is the reason why we belch and have occasional attacks of heartburn. In some patients with excessive acid reflux, most episodes also occur during the day. and consequently in the upright position. These patients tend to have frequent heartburn, belching, and sometimes chest pain, but there is little damage to the esophagus. There are probably several reasons for the relatively benign nature of this pattern. In the upright position, gravity
drains the esophagus, aided by active peristalsis. The symptoms of regurgitation may also provoke swallowing, saliva production, and fluid intake, which tend to neutralize the acid and wash it out of the esophagus. Other patients have reflux only during sleep. They have the supine pattern. which is commonly associated with some degree of esophagitis, because acid remains in the esophagus for prolonged periods in the absence of any of the normal mechanisms for removing it. There are also patients who have reflux during the day and at night; about 75% of them have esophagitis. The most severe disease is seen in patients with esophageal strictures or Barrett's esophagus. a potentially malignant lesion associated with chronic inflammation. These patients tend to have markedly decreased lower esophageal sphincter pressures. Bernstein test. This is a simple screening test that identifies
:r:a.
:r:a.
Treatment 11:00 P.M.
11:20 P.M. Night (Supine Gastroesophageal Reflux)
11:40 P.M.
Figure 3. When there is clinical suspicion of reflux disease but no evidence of esophagitis, 24-hour pH monitoring may confirm the diagnosis, as these representative daytime and nighttime tracings illustrate. During the day, acid reflux episodes, defined as falls in pH to less than 4, are brief and frequently associated with symptoms such as heartburn or belching (top). At night, reflux episodes may last for long periods and be poorly resolved because the patient is supine and both peristalsis and saliva production are minimal (bottom).
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patients with an acid-sensitive esophagus. It is performed by infusion ofO.l N hydrochloric acid into the distal esophagus at a minimum rate of 7 mVmin, with the patient preferably in the supine position. A positive test replicates the patient's symptoms of heartburn or chest pain. The control is a saline infusion. In theory. the test should be most useful in patients with noncardiac chest pain and a normalappearing esophagus on endoscopy, but we have found it unreliable, especially in such patients. We compared it with 24-hour pH monitoring in 75 consecutive patients with noncardiac chest pain who had an acid perfusion test immediately before pH monitoring. The Bernstein test was positive in 15 patients (20%). whereas 24-hour pH monitoring indicated abnormal reflux episodes in 34 patients (45%). Only nine of the 34 (26%) had a positive acid perfusion test, but pH monitoring correlated acid reflux episodes with symptoms in 45 patients (59%). Although the Bernstein test had excellent specificity in our study (up to 94%), it had poor sensitivity (46% at best). Prolonged pH monitoring is superior for identifying reflux disease in patients with noncardiac chest pain, but if it is not available, the acid perfusion test should be used-with the caution that a negative result does not rule out the diagnosis of gastroesophageal reflux.
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Once the diagnosis is made, patients usually can be classified into one of three groups: reflux disease without esophagitis, reflux disease with esophagitis, and severe esophagitis. These diagnostic distinctions have an important bearing on treatment.
Life-style changes. Therapy is dictated by the severity of the disease and the patient's response to treatment. The first step in treatment is to institute some simple but effective lifestyle modifications, which include elevating the head by at least six inches during sleep and altering eating habits. Elevating the head during sleep is best accomplished by placing blocks under the head of the bed or by using a wedge-shaped bolster to support the head and shoulders. The purpose is to help gravity clear any gastric acid regurgitated during sleep. The most important dietary changes include eating smaller meals, eating more frequently, and not eating for at least two hours before bedtime, as well as losing, or at least not gaining, weight. Large meals take longer to pass from the stomach and stimulate more acid production and therefore increase the likelihood of reflux. Going to bed on an empty stomach also helps to reduce the amount of acid in the stomach. A low-fat diet is desirable because fats tend to slow gastric emptying. If certain foods or beverages are associated with symptoms, they should be avoided. The most frequent offenders are chocolate, citrus products, tomatoes, coffee, and alcohol. Smoking reduces lower esophageal sphincter pressure and thus can promote acid reflux, and a number of frequently prescribed medications have the same effect. In addition, some drugs, because of their dosage form, tend to get trapped in the esophagus in patients with reflux disease and may injure the epithelium (Table 2). These life-style modifications are helpful for any patient with reflux disease, regardless of severity. For patients with mild dis-
ease, who may represent nearly one half of all patients with reflux, life-style changes may be sufficient to prevent symptoms in many cases. Antacids and alginic acid. Pharmacologic therapy with antacids or combinations of antacids and alginic acid are also recommended for mild disease, but these agents have not been shown to be consistently effective. Theoretically, antacids neutralize acid in the stomach if taken one to three hours after meals, but in placebo-controlled studies, antacids have not been superior to placebo in preventing symptoms. Alginic acid produces foam when it comes in contact with gastric acid. If reflux occurs, presumably the foam rather than the acid rises into the esophagus (Figure 4). While alginic acid may act in this manner, controlled studies suggest that combinations with antacids are not more effective than antacids alone. Nevertheless, the use of an antacid alone or combined with alginic acid in patients with mild disease without esophagitis on an as-needed basis may be beneficial. These patients do not require constant medication and only occasionally need a more potent drug, such as an H2 blocker, to inhibit gastric acid secretion, or a promotility drug, such as metoclopramide, that strengthens the lower esophageal sphincter to prevent reflux symptoms. Patients with stage I or II (mild or moderate) esophagitis constitute about 30% of all patients with reflux disease, although they may or may not have symptomatic reflux. Treatment of esophagitis has three goals: The first is to relieve symptoms. the second to bring about resolution of the esophagitis, and the third to prevent recurrence. Esophagi-
Table 2. Drugs That May Contribute to Esophageal Disease Agents That Decrease Lower Esophageal Sphincter Pressure Progesterone Theophylline Anticholinergic agents Tricyclic antidepressants fJ-Adrenergic agonists a-Adrenergic antagonists Diazepam Meperidine Calcium channel blockers Agents That Cause Esophageal Injury Tetracycline, doxycycline Quinidine Slow-release potassium chloride Iron salts Nonsteroidal anti-inflammatory drugs
tis tends to recur, each time causing more damage to the esophagus. Adequate treatment. therefore, may be thought of as having both acute and chronic, or maintenance, phases. H 2 blockers are probably the single most effective class of drugs in the treatment of gastroesophageal reflux disease. Four are available, and all are equally effective when used in the right dosages. My recommendations are as follows: cimetidine, 400 mg twice a day; ranitidine, 150 mg twice a day; famotidine, 20 mg twice a day; or nizatidine, 150 mg twice a day. Most physicians are familiar with the use of H2 blockers in peptic ulcer disease. They are customarily prescribed once a day at bedtime to prevent acid Hospital Practice January 15. 1992
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secretion during the night. In reflux disease, a single bedtime dose usually is not as effective as in peptic ulcer disease. Since the H2 blockers are effective for eight to 12 hours. a single bedtime dose tends to wear off by morning. Furthermore, most acid reflux occurs after the evening meal and before bedtime. Consequently, I prescribe H2 blocker therapy on a twice-a-day schedule, with the first dose in the morning to inhibit acid production after breakfast and lunch and the second dose about 30 minutes after the evening meal. On this schedule, most patients with mild esophagitis have complete resolution in eight to 12 weeks. The promotility drugs bethanechol and metoclopramide are also used for the acute therapy of mild reflux disease. These drugs increase lower esophageal sphincter pressure to some degree and promote acid clearance; metoclopramide also promotes gastric emptying. Neitherdrugaffects gastric acid production. Several studies have shown that they reduce reflux symptoms. but the drugs do not seem to have any predictable effect on esophagitis. Metoclopramide has caused such side effects as lethargy. fatigue, and psychotropic and extrapyramidal symptoms in 10% to 30% of patients. Cisapride is another promotility drug that increases lower esophageal sphincter pressure and gastric emptying. Its effects are due to facilitation of acetylcholine release by myenteric nerves. Clinical trials in Europe indicate that cisapride is very effective as primary therapy in mild esophagitis and is also relatively free of side effects. It is not yet available in the United States. Various combinations of an H2 blocker with a promotility drug 64
Hospital Practice January 15. 1992
or sucralfate, or both, have been used in the acute therapy of esophagitis-but with variable results. Therefore, the mainstay of therapy is prescription of an H 2 blocker. After eight to 12 weeks of drug therapy. most patients should have a repeat endoscopy to ascertain that their esophagitis has resolved. Unfortunately, many patients relapse within several months of sfopping their medication. To maintain remission, an H2 blocker can be given twice daily, although in some cases a single dose after the evening meal may be sufficient. If cisapride is approved for use in the United States. it may become the preferred drug for maintenance therapy in patients with resolved mild esophagitis. Several recent reports suggest that it prevents relapses. For the 10% to 15% of patients with gastroesophageal reflux disease who have severe (grade III or IV) esophagitis, H2 blockers are not effective in the usual doses. Fortunately, we have two therapeutic alternatives. One is prescription of an H2 blocker at double or triple the usual dose, which will achieve healing in perhaps 75% of patients with severe esophagitis. However, the cost of treatment will also double or triple, rising to $200 to $300 a month, and the patient will have to take pills three or four times a day. The other alternative is prescribing omeprazole, the first of the proton-pump-inhibitor drugs. Omeprazole inhibits hydrogen-potassium-ATPase, which is the active transport mechanism for hydrogen ion secretion in the stomach and the final pathway for all acid secretion. Omeprazole is the most powerful agent we have at present for blocking production of gastric acid (Figure 4).
H2 blockers, given in usual doses, reduce gastric acid by 60% to 70%. Omeprazole, in a single daily dose of 20 mg. reduces acid secretion by 90%. In clinical trials, more than 80% of patients with severe esophagitis have had healing after eight to 12 weeks on omeprazole. In contrast to the H2 blockers, which are usually taken at bedtime, omeprazole is taken in the morning. As noted, the recommended dose is 20 mg. but clinical experience suggests that some patients need 40 to 60 mg per day. When prescribing at the higher doses, it is probably advisable to specify 20 mg in the morning and 20 mg in the evening. or 40 mg in the morning and 20 mg in the evening. Despite the high cure rate for severe esophagitis achieved with omeprazole (or, for that matter. with high-dose H2 ) therapy, 80% of patients relapse within six months of stopping treatment. In the United States, omeprazole can be given only for three months at a time because of doubts about its safety in longterm use; it has been found to cause carcinoid tumors in rats. My approach is to continue omeprazole in older patients with severe disease and in those in whom anti-reflux surgery would be very risky. On the other hand, if the patient is young and otherwise healthy. surgery is probably preferable to a lifetime on medication at a cost of $1.000 to $1,500 a year. However, thecaveats for good surgical results are that an experienced surgeon and a thorough evaluation of esophageal function are required. Otherwise, surgery can make the condition worse. Complications. The importance of preventing chronic esophagitis cannot be overemphasized. Persistent reflux caus-
Figure 4. Drugs used to treat reflux disease act at various sites. The promotility agents bethanechol, metoclopramide, and cisapride not only increase lower esophageal sphincter pressure but also improve peristalsis; in addition, bethanechol stimulates saliva production, whereas metoclopramide and cisapride promote gastric emptying. Alginic acid reacts with gastric acid to produce
ing a cycle of mucosal damage followed by healing may eventually lead to end-stage disease. signified by development of peptic stricture. Strictures appear to be caused by a combination offi-
a foam, which presumably provides a protective barrier for the esophagus when reflux occurs. Antacids are believed to neutralize acid in the stomach. H2 blockers and proton pump inhibitors target acid secretion itself. The latter drug class is represented by omeprazole, which blocks acid secretion by inhibiting the H-K-ATPase pump, the final common pathway to acid secretion.
brosis. spasm. and edema. They are usually 2 to 4 em in length but may be longer. and they invariably cause dysphagia if the lumen narrows to less than 13 mm in diameter. Stricture devel-
opsin only about 10% of patients with severe reflux esophagitis, but the incidence increases with age (Figure 5). Barrett's esophagus is another complication of severe recurrent Hospital Practice January 15. 1992
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Figure 5. The end stage of chronic esophagitis is signified by the development of peptic stricture, which apparently results from a combination of fibrosis, spasm, and
mucosal injury and healing. It represents a reparative process in which the squamous mucosa of the esophagus is gradually replaced with columnar epitheli-
edema. Most peptic strictures are short (A), but some of them involve much or all of the thoracic portion of the esophagus (B) and may be cancerous (C).
urn typical of the intestinal lining. Barrett's esophagus has been described in 5% to 12% of patients with symptomatic gastroesophageal reflux disease un-
Selected Reading Dodds WJ et al: Mechanisms of gastroesophageal reflux In patients with reflux esophagitis. N Eng! J Med 307:1547, 1982 Klauser AG, Schlndlbeck NE. Miiller-Lissner SA: Symptoms of gastroesophageal reflux disease. Lancet 335:205, 1990 Hewson EG et al: 1\venty-four-hour esophageal pH monitoring: The most useful test for evaluating non cardiac chest pain. Am J Med 90:576, 1991 Ott DJ et al: Current status of radiology In evaluating gastroesophageal reflux disease. J Clin Gastroenterol4: 365, 1982 Monnier PH et al: Contribution of endoscopy to gastroesophageal reflux disease. Scand J Gastroenterol 106:26, 1984 Mattox HE, Richter JE: Prolonged ambulatory esophageal pH monitoring In the evaluation of gastroesophageal reflux disease. Am J Med 89:345, 1990 Richter JE et al: Acid perfusion test and 24-hour esophageal pH monltorlngwtth symptom index: Comparison of tests for esophageal acid sensitivIty. DlgDisSci36:565, 1991 Kitchen L. Castell DO: Rationale and efficacy of conservative therapy for gastroesophageal reflux disease. Arch Intern Med 151:440, 1991 Maton PN: Omeprazole. N Eng! J Med 324:965, 1991
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dergoing endoscopy. Why it occurs is not known, but the observation that it develops in patients with the most severe forms of reflux disease suggests that it is related to the severity of acidic mucosal damage. The heightened risk of adenocarcinoma of the esophagus in patients with Barrett's esophagus mandates follow-up.
Summary Most patients with reflux disease do not generate more gastric acid than normal people. The problem in reflux disease is that the acid is in the esophagus instead of the stomach. The most effective drugs currently available are those that inhibit acid production. It is hoped that the future will see development of drugs that will enhance lower esophageal sphincter function, and thus prevent reflux. D
