Practical pointers for grappling with GERD

Heartburn gnaws at quality of life for many patients

Lawrence A. Szarka, MD; Giles R. Locke, MD

VOL 105 / NO 7 / JUNE 1999 / POSTGRADUATE MEDICINE

CME learning objectives

• To become familiar with causes of heartburn and gastroesophageal reflux disease (GERD)
• To learn common signs of more serious consequences of GERD
• To understand various treatment options available for GERD and its possible complications

This is the first of three articles on esophageal diseases

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Preview: Gastroesophageal reflux disease (GERD) seriously impairs quality of life for millions of people and consumes huge amounts of medical resources. The typical symptoms of heartburn and acid regurgitation are considered reasonably specific for GERD, but the exact mechanisms involved in causing these symptoms are still not clear. In this article, Drs Szarka and Locke review the current concepts about the causes, recognition, and treatment of this disorder.

About 18% of the adult population in the United States have heartburn at least once a week, and 6% have weekly episodes of acid regurgitation (1). Heartburn, the primary symptom of gastroesophageal reflux disease (GERD), is a fairly consistent problem for about 15% of the population worldwide (figure 1: not shown) (2). At least 40% of the US population experiences heartburn on a monthly basis (3).

Quality-of-life scores for patients with GERD are lower than for patients with congestive heart failure, symptomatic coronary artery disease, and diabetes mellitus (4,5). The cost of GERD is high in terms of medical resources because it is common and chronic and may be associated with serious complications.

Terminology

A number of terms have been used to describe the manifestations of reflux. Gastroesophageal reflux simply describes the movement of gastric acid into the esophagus, and some degree of reflux is found in most people. This "physiologic reflux" is characterized by rapid clearance from the distal esophagus and is usually asymptomatic. Some people have excessive esophageal acid exposure with typical symptoms of heartburn or acid regurgitation. Others have chest pain, dysphagia, dyspepsia, or other "atypical" symptoms, including asthma, cough, and other respiratory complaints. Complications, such as strictures, bleeding, Barrett's esophagus, or adenocarcinoma of the esophagus, occur in a minority of patients. GERD is now the term used to encompass the entire spectrum of conditions related to gastroesophageal reflux.

Mechanisms

The major antireflux barrier is the lower esophageal sphincter (LES), located at the esophagogastric junction. The action of the LES is augmented by extrinsic compression from the diaphragm. Contrary to previous beliefs, the majority of patients with GERD have completely normal LES tone; only a minority of these people have pathologically weak LES tone or a large hiatal hernia.

In experiments where LES pressure and esophageal pH are simultaneously determined, the majority of reflux episodes are due to spontaneous complete relaxations of the otherwise normal LES (6). This phenomenon of transient LES relaxations has the distinctive pattern of being unrelated to swallowing or peristalsis and of lasting significantly longer than the relaxation associated with a single swallow (7).

The physiologic process of transient LES relaxations is controlled through vagal sensory and motor nerves in response to gastric distention. The transient relaxations are responsible for physiologic reflux, but in GERD patients, they occur more often and may last longer (8). It remains unclear whether the long list of endogenous hormones, medications, and specific foods that have been shown to decrease LES tone have any important impact on transient LES relaxations.

In addition to having LES dysfunction, some patients with GERD have impaired esophageal acid clearance. After a reflux episode, the restoration of normal esophageal pH depends on the combination of effective peristalsis and swallowed saliva (which contains salivary bicarbonate). Patients with disordered esophageal motility from connective-tissue diseases or primary motility disorders and those with hyposalivation from chronic xerostomia, cigarette smoking, or anticholinergic medications are therefore predisposed to increased severity of GERD.

The primary cause of symptoms and tissue injury associated with GERD is duration of esophageal exposure to acid and other digestive juices. Except for the rare cases of Zollinger-Ellison syndrome, the typical patient with GERD has qualitatively and quantitatively normal secretion of gastric acid and digestive juices. The enzymatic activity of pepsin is dependent on acid pH; pepsin does not cause any tissue damage at neutral pH. The relative role of acid and bile salts as mediators of tissue injury is controversial.

A recent study involving simultaneous esophageal measurements of acid and bilirubin (9) has shown that isolated bile reflux does not result in esophagitis. Therefore, while both pepsin and bile may augment tissue injury in the presence of acid, the major therapeutic principle remains minimizing esophageal exposure to acid.

To summarize, the most common mechanism for GERD is prolonged esophageal acid exposure due to transient LES relaxations. Other mechanisms, such as pathologically weak LES tone, large hiatal hernia, esophageal motility disorders, Zollinger-Ellison syndrome, and delayed gastric emptying, are less common.

Symptoms

Heartburn, defined as a retrosternal burning sensation radiating to the pharynx, and acid regurgitation, referring to effortless return of acid gastric contents to the pharynx, are classic symptoms of GERD. They usually occur postprandially, especially after large meals. Less common symptoms associated with GERD include water brash (hypersalivation associated with episode of esophageal acid exposure), globus sensation, and dysphagia. The typical symptoms may be exacerbated by recumbency, straining, and bending over and are usually improved by antacids. These symptoms are specific enough that their presence establishes the diagnosis of GERD without confirmatory tests (10).

Complications

Esophageal complications are not unusual with GERD and may include esophagitis, esophageal peptic stricture, and Barrett's esophagus. Slightly less than 50% of patients seeking care who have typical reflux symptoms have endoscopic evidence of esophageal inflammation (11).

Esophagitis
The extent of esophagitis can be graded according to endoscopic findings (table 1). Severe esophagitis with ulceration may result in gastrointestinal hemorrhage, which is reported in about 2% of patients with reflux esophagitis (12). Even severe forms of esophagitis can be effectively managed with aggressive acid-suppression therapy.

Table 1. System for grading esophagitis
Grade 1.	Linear, nonconfluent lesions with erythema or exudate
Grade 2.	Confluent, noncircumferential erosions and exudative lesions
Grade 3.	Circumferential erosions and exudative lesions
Grade 4.	Chronic mucosal lesions including ulceration, metaplasia (Barrett's esophagus), or stricture
Adapted from Kahrilas and Hogan (21).

Strictures
Benign esophageal strictures form in about 10% of patients with GERD who undergo endoscopic examinination (13). These patients are managed with periodic dilations and acid suppression with proton pump inhibitors, which have been shown to decrease frequency and severity of stricture recurrences (14).

Barrett's esophagus
Metaplastic changes in the esophageal mucosa that result from GERD are referred to as Barrett's esophagus. The precise definition of Barrett's esophagus and its true incidence are controversial. However, the presence of columnar-appearing epithelium more than 3 cm above the proximal gastric folds is a reasonable endoscopic criterion for diagnosis. Microscopically, the normal squamous epithelium is replaced by a specialized columnar epithelium characterized by goblet cells and a villous structure resembling intestinal epithelium.

The reported incidence of adenocarcinoma in patients with Barrett's esophagus, which is considered a premalignant condition, ranges from 1 in 52 patient-years to 1 in 441 patient-years (15). In population-based studies, the prevalence of Barrett's esophagus is 400 per 100,000 (16). As already noted, 20% (or 20,000 per 100,000) of the general population have weekly reflux symptoms. Thus, only 2% (400 per 20,000) of the general population with reflux symptoms are likely to have Barrett's esophagus. These figures makeit unlikely that endoscopy-based screening for Barrett's esophagus is cost-effective.

About 20% of the population having endoscopy, with or without reflux symptoms, have less than 3 cm of intestinal metaplasia (short-segment Barrett's) (17). Management of short-segment Barrett's is controversial. However, the increasing incidence of adenocarcinoma of the esophagus has created interest in early identification of Barrett's esophagus. The problem is that it is impractical to identify and follow the one fifth of this population with intestinal metaplasia for possible adenocarcinoma of the esophagogastric junction, which occurs at a rate of only 2 to 4 per 100,000 people per year (18). Adenocarcinoma of the esophagus may be increasing, but it is still much less common than colon, pancreas, stomach, liver, or biliary cancer.

Currently, Barrett's esophagus is managed by acid-suppression therapy to alleviate reflux symptoms and inflammation. Neither surgery nor acid suppression is effective in causing regression of Barrett's esophagus and a return to normal squamous epithelium. Surveillance endoscopy every 2 to 3 years is currently recommended for patients with Barrett's esophagus in an attempt to identify high-grade dysplasia and early carcinoma. However, only patients who can withstand major surgery should undergo surveillance.

Other complications
Extraesophageal complications of GERD are widely recognized. The most common symptoms are noncardiac chest pain, chronic hoarseness and cough, and asthma. Pneumonia, vocal cord ulcer and granuloma, sinusitis, dental erosions, pharyngitis, otalgia, and subglottic stenosis have also been reported (19).

Various mechanisms could explain the association between these disorders and GERD. Among them are gross aspiration, microaspiration, and distal esophageal acid-induced vagal reflexes. No currently available test reliably detects the presence of refluxate at the site of possible organ damage, which would prove or disprove the association between GERD and these complications. In many cases, the diagnosis rests on the outcome of a trial of empirical treatment.

Diagnosis

A number of tests facilitate diagnosis of GERD and its complications, but no single test currently provides all the information necessary for definitive evaluation in patients with complicated symptoms.

Esophageal endoscopy is the most popular test for initial evaluation of GERD symptoms. The magnified endoscopic view of the esophageal lining, in conjunction with biopsy confirmation, is the "gold standard" for diagnosis of esophagitis and staging of its severity as well as for diagnosis of Barrett's esophagus. Endoscopy is also very sensitive for detecting significant peptic stricture.

The opportunity to perform therapeutic dilation makes this procedure even more useful. The major shortcoming of endoscopy is the frequent (50%) lack of visible esophageal findings in patients with typical GERD symptoms and those with presumed extra-esophageal GERD complications. The practice of biopsying endoscopically normal-appearing mucosa to look for microscopic evidence of reflux esophagitis has not proved sensitive or specific enough to be clinically helpful (20). Nonetheless, endoscopy remains the best test to exclude esophageal complications of GERD, provide information on the severity of esophagitis, and allow for biopsy and therapeutic stricture dilation.

Barium swallow modified by a barium-coated test meal is the most sensitive test for evaluation of dysphagia (21). In addition, the observation of reflux of free barium into the esophagus, or reflux with provocative maneuvers, establishes the diagnosis of GERD (22). The major deficiencies of barium swallow are that lower grades of erosive esophagitis and the presence of Barrett's esophagus can easily be missed. Also, any stricture seen radiographically requires endoscopic evaluation for possible biopsy and therapeutic dilation. Thus, the best role for barium swallow is to exclude a subtle stricture, or ring, in a patient with persistent dysphagia but negative findings at endoscopy.

Ambulatory esophageal pH monitoring is the best test to establish the presence of abnormal acid esophageal reflux, although it provides no information about the esophageal structure or mucosa. Monitoring involves transnasal placement of a pH probe in the lower esophagus. The probe is attached to an external recording monitor. The patient is asked to maintain a symptom diary for the study period. This test can quantify the amount of esophageal acid exposure and correlate the patient's symptoms with esophageal pH events. The main indications are to establish or exclude the diagnosis of GERD in patients with atypical or equivocal symptoms and to provide objective documentation of GERD in patients considering antireflux surgery.

Other tests, including the Bernstein test (provocative esophageal acid infusion), gastroesophageal scintigraphy, and manometry, have also been used to evaluate GERD symptoms. However, these tests often are not practical in a primary care setting.

Treatment

Since GERD generally is chronic and relapsing, most patients require a long-term management plan designed to alleviate symptoms and prevent complications. Lifestyle modification is often mentioned as the sole therapy for uncomplicated mild reflux or as an adjunct to pharmacologic and surgical therapy for patients with more severe reflux.

Lifestyle modification
The specifics of lifestyle modification involve a long list of behavior changes (table 2). Aside from the difficulty of implementing even a single behavior modification (eg, sustained weight loss), there is no clinical evidence that any or all of these interventions are effective treatments for GERD. However, lifestyle modification is appropriate for most patients, especially those with uncomplicated GERD who wish to avoid medication.

Table 2. Lifestyle modifications recommended for all stages of GERD

Stop smoking cigarettes Lose excess weight Eat small meals Reduce consumption of caffeine, chocolate, fatty foods, alcohol, onions, peppermint, and spearmint Elevate head of bed 6 to 9 in. Avoid tight-fitting garments

Antacids
Antacids work by neutralizing gastric acid and are indicated for treatment of occasional heartburn, as well as for managing some gastric and duodenal ulcers. Thevarious antacids have a wide range of acid-neutralizing capacity, but all have a very short duration of action, necessitating frequent dosing. At therapeutic doses, side effects include constipation (aluminum hydroxide), diarrhea (magnesium hydroxide), and gastric acid rebound (calcium carbonate). None of the antacids heal reflux esophagitis or prevent nocturnal acid reflux. Thus, they are a poor therapeutic choice for treatment of frequent GERD symptoms.

Histamine antagonists
Histamine2 (H2) receptor antagonists are moderately effective for treating GERD. This class includes cimetidine (Tagamet), ranitidine hydrochloride (Zantac), famotidine (Pepcid), and nizatidine (Axid Pulvules). These drugs block the H2 receptors on parietal cells and thereby inhibit the intracellular accumulation of cyclic adenosine monophosphate. This effect reduces basal acid output by 90% and nocturnal acid output by 67% (23).

The overall reduction in acid production is responsible for the efficacy seen in GERD patients. As a class, these drugs are remarkably safe, with rare side effects. However, cimetidine may cause mental status changes, antiandrogenic activity (which sometimes results in gynecomastia), and inhibition of the cytochrome P-450 system, which may alter levels of drugs metabolized by this pathway (eg, theophylline, warfarin sodium [Coumadin], diazepam [Valium, Valrelease, Zetran], phenytoin [Dilantin]).

The indicated oral doses for the treatment of reflux esophagitis are cimetidine, 800 mg twice daily; ranitidine, 150 mg two to four times daily; famotidine, 20 mg to 40 mg twice daily; and nizatidine, 150 mg twice daily (24). At these doses, the efficacy of all the H2 receptor antagonists is equivalent: esophagitis classified as grade 1 or 2 (figure 2: not shown) heals in 75% to 90% of patients, while esophagitis categorized as grade 3 or 4 heals in only 40% to 50% of patients (25). Low-dose, over-the-counter H2 receptor antagonists are appropriate for treating occasional GERD symptoms.

Proton pump inhibitors
The proton pump inhibitors (PPIs), omeprazole (Prilosec) and lansoprazole (Prevacid), are the most effective acid-suppressing medications available. These drugs inhibit the H+/K+ adenosine triphosphatase proton pump, which is the final common pathway for gastric acid secretion. Basal, nocturnal, and stimulated acid secretions are therefore equally inhibited. Omeprazole is absorbed in the small intestine and accumulates in the parietal cells. Peak inhibitory effect occurs 2 to 4 hours after a single dose. The biological half-life of its effect is 18 to 24 hours.

As gastric acid is reduced, the bioavailability of omeprazole improves. Therefore, maximum acid suppression may require 3 to 5 days. The usual dosage for treatment of reflux esophagitis is 20 to 40 mg of omeprazole daily or 30 mg of lansoprazole daily. At these doses, reflux symptoms are abolished in most patients. Complete healing of even severe ulcerative (grade 4) esophagitis occurs after 8 weeks in 80% of patients (26).

PPIs are safe and well tolerated. The theoretical risk of gastric carcinoids has not materialized with extensive use in Europe and the United States. Both omeprazole and lansoprazole can be used for long-term maintenance therapy; therefore, treatment does not have to be stopped after 3 months.

The side effects of headache, abdominal pain, and diarrhea do not occur more often in patients treated with PPIs than in those receiving placebo (27), and dosage does not need to be adjusted in patients with hepatic or renal impairment. The success of the PPIs has captured the attention of managed care organizations because these drugs tend to be expensive. Undoubtedly, some patients with GERD require PPIs and benefit from using them. Nevertheless, the majority of GERD patients could very well be treated with less expensive H2 receptor antagonists.

Promotility drugs
The promotility medication cisapride (Propulsid) has been approved for the treatment of symptomatic GERD. This drug probably increases acetylcholine release at the myenteric plexus, which results in accelerated gastric emptying, increased LES tone, and increased production of saliva. At doses of 10 to 20 mg four times daily, cisapride is comparable to the H2 receptor antagonists in efficacy of symptom relief and healing of mild reflux esophagitis (28). Side effects are minimal and include diarrhea, headache, and abdominal pain. However, cisapride has been associated with torsade de pointes, both singly and in combination with other medications, especially the imidazoles (eg, fluconazole [Diflucan], metronidazole [Flagyl, Protostat]) and the macrolides (eg, erythromycin, clarithromycin [Biaxin]) (29). Cisapride should not be used in patients with a history of cardiac arrhythmias or in those with long Q-T intervals.

Metoclopramide also has been used for treatment of GERD, but it is impractical for long-term use because of tachyphylaxis and serious side effects, including fatigue, lethargy, and psychotropic and extrapyramidal effects.

Other management considerations

Most patients with GERD have chronic, relapsing disease. Those with classic symptoms who are less than 40 years old and who have had symptoms for less than 10 years do not require diagnostic studies. Treatment may be adjusted from antacids for occasional symptoms to full-dose H2 receptor antagonists. Lifestyle modifications are appropriate for all patients with GERD. Indications for upper gastrointestinal endoscopy include onset of new symptoms in older patients with long-standing GERD, the presence of alarm symptoms (table 3), atypical or equivocal symptoms, and failure of full-dose H2 receptor antagonist therapy.

Table 3. Alarm symptoms in patients with suspected GERD

Hematemesis Melena Dysphagia Unexplained weight loss Frequent vomiting

Endoscopic examination in this setting provides staging of GERD severity, treatment of complications (stricture or bleeding), or an alternative diagnosis (eg, peptic ulcer disease, malignancy). In patients with suspected GERD but negative endoscopic findings, ambulatory esophageal pH monitoring may confirm or exclude the diagnosis.

Patients with severe (grade 3 or 4) reflux esophagitis or an esophageal GERD complication (eg, stricture, Barrett's esophagus) should be treated with the indicated dose of a PPI. Those with lower-grade esophagitis should be treated with an H2 receptor antagonist or cisapride.

Once the diagnosis of GERD is established, the degree of acid suppression required should be adjusted to effect. This means that sometimes patients require higher-dose PPI therapy for symptom control alone. Despite the efficacy of PPIs, a full 25% of patients need more than 20 mg of omeprazole or 30 mg of lansoprazole to eliminate their symptoms or to heal their esophagitis (30). Alternatively, after the initial reflux esophagitis is treated for 8 weeks, the dose of the PPI or H2 receptor antagonist may be decreased, provided the patient remains asymptomatic.

Antireflux surgery
Antireflux operations are now commonly performed laparoscopically. They involve reduction of the hiatal hernia and wrapping of the proximal stomach around the distal esophagus (Nissen fundoplication, figure 3 [not shown]). Antireflux surgery was originally reserved for patients who did not respond to medical therapy. Now, however, laparoscopic fundoplication is appropriate in otherwise healthy patients who prefer surgical treatment to long-term medication use.

Gastrointestinal evaluation before surgery requires only objective documentation of GERD. Esophageal manometry or gastric emptying scans are indicated only if there is a strong suspicion of a motility disorder.

After antireflux surgery, about 90% of patients are symptom-free at 1 year, and 60% to 80% remain asymptomatic at long-term follow-up (31). Patients who are young and otherwise healthy but require high doses of medications are the best candidates for antireflux surgery. Those who have milder disease, are older, or have other significant health problems probably are better managed with medical therapy.

When treatment fails

Not everyone with heartburn or esophagitis has GERD. Pill esophagitis should always be considered in an elderly patient with new onset of GERD symptoms. Esophagitis caused by Candida albicans, Herpes simplex virus, and cytomegalovirus are common causes of esophageal pain in immunocompromised patients. Patients who complain of excessive nausea, vomiting, or bloating may have delayed gastric emptying. Pain and regurgitation with achalasia may also mimic GERD. Finally, in some patients, GERD may be the only manifestation of Zollinger-Ellison syndrome.

Summary

GERD is a common condition, generally caused by transient LES relaxations. The spectrum of disease due to GERD is wide, ranging from symptoms alone to esophagitis, Barrett's esophagus, and respiratory tract complications. Excellent diagnostic tests are available to confirm the diagnosis and stage the disease, and medications can predictably relieve symptoms and heal even the most severe forms of esophagitis. Finally, surgical therapy is an effective option for patients with truly refractory disease or for those patients with significant disease who prefer not to use drug treatment.

References

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Dr Szarka is a fellow and Dr Locke is a consultant in the department of gastroenterology and hepatology, Mayo Clinic, Rochester, Minnesota. Correspondence: Lawrence A. Szarka, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Symposium Index

• ESOPHAGEAL DISEASES: Commentary on a three-article symposium by Joseph A. Murray, MD
• PRACTICAL POINTERS FOR GRAPPLING WITH GERD: Heartburn gnaws at quality of life for many patients by Lawrence A. Szarka, MD, Giles R. Locke, MD
• ESOPHAGEAL CANCER AND BARRETT'S ESOPHAGUS: How to approach surveillance, treatment, and palliation by Wael Shahin, MBBS, Joseph A. Murray, MD
• WHEN IT'S HARD TO SWALLOW: What to look for in patients with dysphagia by Victor R. Mujica, MD, Jeffrey Conklin, MD

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