The Evaluation and Treatment of Adults with Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage that results from the abnormal reflux of gastric contents into the esophagus. A systematic review of population-based studies estimates that heartburn or regurgitation symptoms occur in 21% to 59% of the population during a given year.¹ The frequency of GERD in specific populations is provided in Table 1. Although only 1 in 5 patients with upper intestinal symptoms that occur at least weekly seeks medical attention,² nearly 1% of all visits to a family physician’s office are for GERD or related conditions.³

GERD significantly affects the quality of patients’ lives. In a survey of patients presenting for upper endoscopy with symptoms of at least 3 months’ duration, those with a diagnosis of GERD reported low scores at baseline for general wellbeing. Fortunately, follow-up data reported 4 weeks after treatment note improvement in gastrointestinal symptoms, general well-being, general health, vitality, and depression.⁴

Pathophysiology

The pathogenesis of GERD is multifactorial and is thought to involve lower than normal esophageal sphincter pressures. This allows gastric acidic content to reflux into the distal esophagus, which lacks a protective barrier, causing esophagitis. Inflamed tissue impairs the normal clearance of acid, worsening the esophagitis, which inhibits normal motility.

Although Helicobacter pylori is clearly associated with peptic ulcer disease, its association with GERD is still debated. Data from case control studies actually suggest an inverse association; that is, that the presence of H pylori may be protective against the development of GERD.⁵

Because of the anatomical location of the esophagus, GERD should be considered in the differential diagnosis for presenting complaints other than regurgitation or dyspepsia. For example, approximately 50% of patients with chest pain in whom cardiac etiology is ruled out will ultimately be given a diagnosis of GERD.⁶ Similarly, 10% of patients with chronic cough⁷ and 78% of patients with laryngitis have GERD.⁸ Clear associations between GERD and asthma have been demonstrated, but data from meta-analyses fail to show improvement of asthma symptoms when GERD is appropriately treated.⁹

Diagnosis

The diagnosis of GERD can usually be made without the use of invasive tests. The accuracy of key tests, including clinical history, is outlined in Table 2. One study of patients presenting with dyspepsia (signs and symptoms referable to the upper gastrointestinal tract) found that 56% also have GERD.¹⁰ Another showed that 60% of patients referred for pH monitoring had GERD.¹¹ Since reasonable prevalence estimates for GERD in the family practice setting may be slightly lower, calculations in Table 2 assume that between 40% and 60% of patients with suspected GERD actually have the condition.

Individual symptoms of GERD such as heartburn, regurgitation, belching, or dyspepsia are of limited usefulness in diagnosis. In a survey of patients referred for pH monitoring likelihood ratios hovered near 1, meaning that the presence or absence of the symptom had little impact on the diagnosis.¹¹ The clinician’s overall impression that a patient has GERD, however, is much more useful to rule in disease than any individual symptoms.¹¹ Assuming that half of patients with suspected GERD have the disease, if a clinician suspects GERD, that probability increases to 77%. Most clinicians would find a trial of empiric therapy appropriate at that probability.

The omeprazole test is also helpful in confirming a diagnosis of GERD. It consists of the patient taking 40 mg omeprazole in the morning and 20 mg at night for 1 week. If the symptoms resolve, the test is considered diagnostic of GERD.¹² Some consider this approach to be therapeutic, as well as diagnostic. Beginning with an omeprazole test and reserving invasive testing for those not responding to the medication was cost-effective for patients with noncardiac chest pain.¹³ In a decision analysis, empiric treatment with omeprazole was a cost-effective approach to the management of GERD.¹⁴ Of course, initial endoscopy is indicated for patients with “red flags”: signs and symptoms consistent with obstruction, bleeding, or perforation, and those older than 50 years who are at a higher risk of malignancy.

Upper endoscopy, however, is not very accurate in diagnosing GERD. Among patients with GERD, only 22% have esophageal erythema, and only 48% have erosions or ulcerations. Therefore, because of costs and limited resources, the American Society for Gastrointestinal Endoscopy recommends that endoscopy be reserved for patients presenting with possible GERD who also have symptoms of more serious disease (dysphagia, weight loss, gastrointestinal bleeding) and for those not responding to a reasonable trial of therapy.¹⁵ The goal is to rule out more serious conditions.

Twenty-four–hour pH monitoring, while more accurate than endoscopy, is also reserved as a second-line test. According to the American Gastro-enterological Association guidelines, pH recording is indicated when endoscopy is normal and reflux symptoms persist despite acid suppression therapy or to evaluate extra-esophageal symptoms that may be GERD (ie, atypical chest pain or chronic cough).¹⁶ The goal here is to rule in GERD as the etiology of the patient’s symptoms.

Numerous other tests have been proposed to evaluate the patient with suspected GERD: manometry, scintigraphy, esophograms (as part of upper gastrointestinal series), and the Bernstein test (a provocative challenge with hydrochloric acid infusion). Data on the accuracy of these tests are limited by the lack of an accepted reference standard, and most have fallen out of favor because of their inconvenience or limited accuracy. None are more helpful than pH monitoring or endoscopy, and they are therefore not recommended.

Treatment

Pharmacologic

Treatments for GERD address the pathophysiology of the disease; they tend to target the removal of precipitating factors, using gravity or medications to improve acid clearance, lower the acidity of gastric contents, or improve the esophageal sphincter tone. Short-term treatment goals are to relieve symptoms and heal esophagitis; long-term goals are to prevent relapses and sequelae, such as esophageal stricture formation or adenocarcinoma.

Recommendations for lifestyle modifications to lessen GERD symptoms are extensive and mostly based on pathophysiologic data. Possible triggers for GERD include obesity, tight clothing, fatty foods, alcohol, tobacco, caffeine, onions, peppermint, and chocolate.^17-21 Because symptoms are typically worse at night, elevating the head of the bed or avoiding postprandial recumbency is recommended.^22,23 Eliminating these factors has been shown to decrease the amount of acid in the distal esophagus or improve the pressure readings on manometry. This is disease-oriented evidence; it does not necessarily translate into reduced symptoms for patients. The only patient-oriented evidence that supports lifestyle modification is a small crossover trial in which subjects had less heartburn and belching following a hamburger meal compared with the same meal with onions on the burger.¹⁸ Despite the lack of high-quality evidence of effectiveness, guidelines recommend lifestyle modification as the first-line therapy or adjunct to additional medication.^24,25 Because these lifestyle changes are not thought to be harmful and may have other possible health benefits it is reasonable to recommend them to patients until better studies are published.

Promotility agents are a possible treatment of GERD because they improve acid clearance from the esophagus. Older agents such as metoclopramide and bethanecol have little data to support their use^26,27 and are further limited by their central nervous system side effects. A meta-analysis of trial data found that cisapride heals esophagitis and decreases symptoms of GERD²⁸ but was taken off the market because of problems with cardiac arrhythmias.

Acid suppression strategies available over-the-counter include antacids, alginates, and H2-blockers (H2Bs). Small, short-term trials have demonstrated mixed results with regard to symptom relief and lessened acid exposure from both antacids and alginates.^29,30 Longer follow-up in cohort studies suggests a modest benefit from antacids.³¹ More than 24 randomized controlled trials (RCTs) have demonstrated the benefits of H2Bs in the treatment of GERD for both healing esophagitis and symptom relief. The number needed to treat (NNT) is 5; that is, for every 5 GERD patients treated with H2Bs instead of placebo, 1 patient benefits.³² H2Bs also prevent the long-term recurrence of symptoms (NNT =15).³³ There is no clear benefit of one H2B agent over another. Proton pump inhibitors (PPIs) are also well supported by meta-analyses of RCTs in the short term (NNT = 2) and long term (NNT = 3) treatment of GERD.³³ As with H2Bs, no clear advantage is found between different PPI medications.

STEPS. Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare H2Bs and PPIs is one way to help guide management of GERD. H2Bs are not associated with any serious long-term complications. PPIs are theoretically linked to malignancy through 2 mechanisms: proliferation of endocrine cells leading to endocrine neoplasia and atrophic gastritis caused by chronic acid suppression as a precursor to gastric adenocarcinoma. However, studies have not borne out these concerns.³⁴ Thus, both H2Bs and PPIs seem equally safe. The best measure of tolerability is the pooled dropout rate, which is the number of patients dropping out of a study for any reason. Dropout rates are about the same for H2Bs and PPIs.³⁵ Meta-analyses of trials comparing the efficacy of H2Bs to PPIs in the short- and long-term treatment of GERD consistently favor PPIs.^33,35 Of 100 patients with GERD, approximately 25 will benefit from treatment with an H2B, and 75 to 80 will benefit from treatment with a PPI.³³ An interesting comparison of trials suggests that the therapeutic gain of PPIs is greatest in those patients with more severe GERD.³⁶ Little data exist about the prevention of complications of GERD with acid suppression. However, 1 small trial found a decreased rate of esophageal stricture recurrence at 1 year in patients with reflux esophagitis (NNT =7) treated with 30-mg lansoprazole compared with those treated with 300-mg ranitidine.³⁷ These data seem to suggest that high-risk patients are more apt to benefit from PPIs than H2Bs.

Because H2Bs are now available in generic forms, price tips the scales greatly in their favor. The average cost for PPIs is nearly 10 times that of generic H2Bs (3020-mg omeprazole tablets cost $105.55 and 60 150-mg ranitidine tablets cost $10.98 as of 11/0/00). Simplicity is a toss-up: most PPIs are dosed once daily, while H2Bs are given once or twice daily. A general approach is to start patients with GERD on a reasonable dose of H2Bs, and move on to PPIs if symptoms do not resolve in 2 to 4 weeks.^25,54 Some insurance companies require documentation of H2B failure before covering the increased costs of PPIs, despite their efficacy advantage.

Surgery

For patients with chronic or recurrent GERD, surgery offers an additional treatment option. Prospective cohort studies note that open Nissen fundoplication produces an 80% to 93% success rate at 10-year follow-up. Laproscopic procedures are producing similar short-term results, but long-term data are pending.³⁸ One randomized trial demonstrated equivalent 3-year outcomes for those undergoing Nissen fundoplication and those taking 40 mg omeprazole daily.³⁹ Decision analysis data favor the cost effectiveness of open Nissen⁴⁰ if medical treatment will be required for more than 4 years, and laproscopic procedure if medical treatment will be needed for more than 10 years.⁴¹

Prognosis

GERD may be a short-term intermittent problem or may be severe and chronic in nature. Untreated, approximately 15% of patients will have symptom relief.³² Antacids can raise that rate to an estimated 20%,^31,25 while H2Bs are associated with symptom-free rates of approximately 25%.³⁰ The best outcomes are found with PPIs, where recurrence of GERD symptoms is suppressed in 75% to 82% of patients at 1-year follow-up.^33,35

Although many patients will experience recurrences, chronic medications may not be necessary. In 1 study, 677 patients with heartburn and mild esophagitis were randomized to treatment with omeprazole or ranitidine for 2 weeks. If symptoms persisted, the dose of medication was doubled. If symptoms resolved, medication was stopped. Recurrences were treated for 2 to 4 weeks at the previously effective dose. Nearly half the patients were successfully treated with intermittent medication, and nearly 40% of initial responders required no further treatment.⁴²

GERD is associated with esophageal strictures, Barrett esophagus (metaplasia of the distal esophageal columnar cells, thought to be a precursor of dysplasia and cancer) and adenocarcinoma. Limited data are available for the actual incidence of stricture in GERD patients. One retrospective cohort study of patients discharged from veterans’ administration hospitals found that 8.4% of patients with GERD had strictures, and the association between esophageal ulcers and stricture was significant.⁴³ This study likely suffered from significant selection bias, however, and the rate in primary care practice is almost certainly much lower. Barrett was noted in 11.6% of 662 patients with GERD referred from general practice settings for endoscopy.⁴⁴ Again, though, patients with GERD referred for endoscopy are likely to have more severe disease, and a recent meta-analysis suggests that the actual risk of Barrett in unselected patients is closer to 3% to 4%.⁴⁵ A longer duration of symptoms was associated with an increase risk. Patients with Barrett esophagus; negative, low-grade, or indefinite dysplasia; and neither aneuploidy or increased 4N on flow cytometry are at very low risk of esophageal cancer (<2% over 5 years). Only approximately 4% of patients with Barrett go on to develop esophageal cancer.⁴⁶

In a well-conducted case control study in Sweden, reflux symptoms were associated with a 7- to 10-fold increase in the risk of esophageal adenocarcinoma. A dose-response risk was noted for symptom frequency, severity, and duration.⁴⁷ However, because adenocarcinoma of the esophagus is so rare, the authors note that a family physician would need to perform endoscopy on more than 1400 men older than 40 years who have severe GERD symptoms to identify 1 case of cancer. Further, there are no data to suggest that treating GERD will reduce the likelihood of these more serious sequelae.

Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage that results from the abnormal reflux of gastric contents into the esophagus. A systematic review of population-based studies estimates that heartburn or regurgitation symptoms occur in 21% to 59% of the population during a given year.¹ The frequency of GERD in specific populations is provided in Table 1. Although only 1 in 5 patients with upper intestinal symptoms that occur at least weekly seeks medical attention,² nearly 1% of all visits to a family physician’s office are for GERD or related conditions.³

GERD significantly affects the quality of patients’ lives. In a survey of patients presenting for upper endoscopy with symptoms of at least 3 months’ duration, those with a diagnosis of GERD reported low scores at baseline for general wellbeing. Fortunately, follow-up data reported 4 weeks after treatment note improvement in gastrointestinal symptoms, general well-being, general health, vitality, and depression.⁴

Pathophysiology

The pathogenesis of GERD is multifactorial and is thought to involve lower than normal esophageal sphincter pressures. This allows gastric acidic content to reflux into the distal esophagus, which lacks a protective barrier, causing esophagitis. Inflamed tissue impairs the normal clearance of acid, worsening the esophagitis, which inhibits normal motility.

Although Helicobacter pylori is clearly associated with peptic ulcer disease, its association with GERD is still debated. Data from case control studies actually suggest an inverse association; that is, that the presence of H pylori may be protective against the development of GERD.⁵

Because of the anatomical location of the esophagus, GERD should be considered in the differential diagnosis for presenting complaints other than regurgitation or dyspepsia. For example, approximately 50% of patients with chest pain in whom cardiac etiology is ruled out will ultimately be given a diagnosis of GERD.⁶ Similarly, 10% of patients with chronic cough⁷ and 78% of patients with laryngitis have GERD.⁸ Clear associations between GERD and asthma have been demonstrated, but data from meta-analyses fail to show improvement of asthma symptoms when GERD is appropriately treated.⁹

Diagnosis

The diagnosis of GERD can usually be made without the use of invasive tests. The accuracy of key tests, including clinical history, is outlined in Table 2. One study of patients presenting with dyspepsia (signs and symptoms referable to the upper gastrointestinal tract) found that 56% also have GERD.¹⁰ Another showed that 60% of patients referred for pH monitoring had GERD.¹¹ Since reasonable prevalence estimates for GERD in the family practice setting may be slightly lower, calculations in Table 2 assume that between 40% and 60% of patients with suspected GERD actually have the condition.

Individual symptoms of GERD such as heartburn, regurgitation, belching, or dyspepsia are of limited usefulness in diagnosis. In a survey of patients referred for pH monitoring likelihood ratios hovered near 1, meaning that the presence or absence of the symptom had little impact on the diagnosis.¹¹ The clinician’s overall impression that a patient has GERD, however, is much more useful to rule in disease than any individual symptoms.¹¹ Assuming that half of patients with suspected GERD have the disease, if a clinician suspects GERD, that probability increases to 77%. Most clinicians would find a trial of empiric therapy appropriate at that probability.

The omeprazole test is also helpful in confirming a diagnosis of GERD. It consists of the patient taking 40 mg omeprazole in the morning and 20 mg at night for 1 week. If the symptoms resolve, the test is considered diagnostic of GERD.¹² Some consider this approach to be therapeutic, as well as diagnostic. Beginning with an omeprazole test and reserving invasive testing for those not responding to the medication was cost-effective for patients with noncardiac chest pain.¹³ In a decision analysis, empiric treatment with omeprazole was a cost-effective approach to the management of GERD.¹⁴ Of course, initial endoscopy is indicated for patients with “red flags”: signs and symptoms consistent with obstruction, bleeding, or perforation, and those older than 50 years who are at a higher risk of malignancy.

Upper endoscopy, however, is not very accurate in diagnosing GERD. Among patients with GERD, only 22% have esophageal erythema, and only 48% have erosions or ulcerations. Therefore, because of costs and limited resources, the American Society for Gastrointestinal Endoscopy recommends that endoscopy be reserved for patients presenting with possible GERD who also have symptoms of more serious disease (dysphagia, weight loss, gastrointestinal bleeding) and for those not responding to a reasonable trial of therapy.¹⁵ The goal is to rule out more serious conditions.

Twenty-four–hour pH monitoring, while more accurate than endoscopy, is also reserved as a second-line test. According to the American Gastro-enterological Association guidelines, pH recording is indicated when endoscopy is normal and reflux symptoms persist despite acid suppression therapy or to evaluate extra-esophageal symptoms that may be GERD (ie, atypical chest pain or chronic cough).¹⁶ The goal here is to rule in GERD as the etiology of the patient’s symptoms.

Numerous other tests have been proposed to evaluate the patient with suspected GERD: manometry, scintigraphy, esophograms (as part of upper gastrointestinal series), and the Bernstein test (a provocative challenge with hydrochloric acid infusion). Data on the accuracy of these tests are limited by the lack of an accepted reference standard, and most have fallen out of favor because of their inconvenience or limited accuracy. None are more helpful than pH monitoring or endoscopy, and they are therefore not recommended.

Treatment

Pharmacologic

Treatments for GERD address the pathophysiology of the disease; they tend to target the removal of precipitating factors, using gravity or medications to improve acid clearance, lower the acidity of gastric contents, or improve the esophageal sphincter tone. Short-term treatment goals are to relieve symptoms and heal esophagitis; long-term goals are to prevent relapses and sequelae, such as esophageal stricture formation or adenocarcinoma.

Recommendations for lifestyle modifications to lessen GERD symptoms are extensive and mostly based on pathophysiologic data. Possible triggers for GERD include obesity, tight clothing, fatty foods, alcohol, tobacco, caffeine, onions, peppermint, and chocolate.^17-21 Because symptoms are typically worse at night, elevating the head of the bed or avoiding postprandial recumbency is recommended.^22,23 Eliminating these factors has been shown to decrease the amount of acid in the distal esophagus or improve the pressure readings on manometry. This is disease-oriented evidence; it does not necessarily translate into reduced symptoms for patients. The only patient-oriented evidence that supports lifestyle modification is a small crossover trial in which subjects had less heartburn and belching following a hamburger meal compared with the same meal with onions on the burger.¹⁸ Despite the lack of high-quality evidence of effectiveness, guidelines recommend lifestyle modification as the first-line therapy or adjunct to additional medication.^24,25 Because these lifestyle changes are not thought to be harmful and may have other possible health benefits it is reasonable to recommend them to patients until better studies are published.

Promotility agents are a possible treatment of GERD because they improve acid clearance from the esophagus. Older agents such as metoclopramide and bethanecol have little data to support their use^26,27 and are further limited by their central nervous system side effects. A meta-analysis of trial data found that cisapride heals esophagitis and decreases symptoms of GERD²⁸ but was taken off the market because of problems with cardiac arrhythmias.

Acid suppression strategies available over-the-counter include antacids, alginates, and H2-blockers (H2Bs). Small, short-term trials have demonstrated mixed results with regard to symptom relief and lessened acid exposure from both antacids and alginates.^29,30 Longer follow-up in cohort studies suggests a modest benefit from antacids.³¹ More than 24 randomized controlled trials (RCTs) have demonstrated the benefits of H2Bs in the treatment of GERD for both healing esophagitis and symptom relief. The number needed to treat (NNT) is 5; that is, for every 5 GERD patients treated with H2Bs instead of placebo, 1 patient benefits.³² H2Bs also prevent the long-term recurrence of symptoms (NNT =15).³³ There is no clear benefit of one H2B agent over another. Proton pump inhibitors (PPIs) are also well supported by meta-analyses of RCTs in the short term (NNT = 2) and long term (NNT = 3) treatment of GERD.³³ As with H2Bs, no clear advantage is found between different PPI medications.

STEPS. Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare H2Bs and PPIs is one way to help guide management of GERD. H2Bs are not associated with any serious long-term complications. PPIs are theoretically linked to malignancy through 2 mechanisms: proliferation of endocrine cells leading to endocrine neoplasia and atrophic gastritis caused by chronic acid suppression as a precursor to gastric adenocarcinoma. However, studies have not borne out these concerns.³⁴ Thus, both H2Bs and PPIs seem equally safe. The best measure of tolerability is the pooled dropout rate, which is the number of patients dropping out of a study for any reason. Dropout rates are about the same for H2Bs and PPIs.³⁵ Meta-analyses of trials comparing the efficacy of H2Bs to PPIs in the short- and long-term treatment of GERD consistently favor PPIs.^33,35 Of 100 patients with GERD, approximately 25 will benefit from treatment with an H2B, and 75 to 80 will benefit from treatment with a PPI.³³ An interesting comparison of trials suggests that the therapeutic gain of PPIs is greatest in those patients with more severe GERD.³⁶ Little data exist about the prevention of complications of GERD with acid suppression. However, 1 small trial found a decreased rate of esophageal stricture recurrence at 1 year in patients with reflux esophagitis (NNT =7) treated with 30-mg lansoprazole compared with those treated with 300-mg ranitidine.³⁷ These data seem to suggest that high-risk patients are more apt to benefit from PPIs than H2Bs.

Because H2Bs are now available in generic forms, price tips the scales greatly in their favor. The average cost for PPIs is nearly 10 times that of generic H2Bs (3020-mg omeprazole tablets cost $105.55 and 60 150-mg ranitidine tablets cost $10.98 as of 11/0/00). Simplicity is a toss-up: most PPIs are dosed once daily, while H2Bs are given once or twice daily. A general approach is to start patients with GERD on a reasonable dose of H2Bs, and move on to PPIs if symptoms do not resolve in 2 to 4 weeks.^25,54 Some insurance companies require documentation of H2B failure before covering the increased costs of PPIs, despite their efficacy advantage.

Surgery

For patients with chronic or recurrent GERD, surgery offers an additional treatment option. Prospective cohort studies note that open Nissen fundoplication produces an 80% to 93% success rate at 10-year follow-up. Laproscopic procedures are producing similar short-term results, but long-term data are pending.³⁸ One randomized trial demonstrated equivalent 3-year outcomes for those undergoing Nissen fundoplication and those taking 40 mg omeprazole daily.³⁹ Decision analysis data favor the cost effectiveness of open Nissen⁴⁰ if medical treatment will be required for more than 4 years, and laproscopic procedure if medical treatment will be needed for more than 10 years.⁴¹

Prognosis

GERD may be a short-term intermittent problem or may be severe and chronic in nature. Untreated, approximately 15% of patients will have symptom relief.³² Antacids can raise that rate to an estimated 20%,^31,25 while H2Bs are associated with symptom-free rates of approximately 25%.³⁰ The best outcomes are found with PPIs, where recurrence of GERD symptoms is suppressed in 75% to 82% of patients at 1-year follow-up.^33,35

Although many patients will experience recurrences, chronic medications may not be necessary. In 1 study, 677 patients with heartburn and mild esophagitis were randomized to treatment with omeprazole or ranitidine for 2 weeks. If symptoms persisted, the dose of medication was doubled. If symptoms resolved, medication was stopped. Recurrences were treated for 2 to 4 weeks at the previously effective dose. Nearly half the patients were successfully treated with intermittent medication, and nearly 40% of initial responders required no further treatment.⁴²

GERD is associated with esophageal strictures, Barrett esophagus (metaplasia of the distal esophageal columnar cells, thought to be a precursor of dysplasia and cancer) and adenocarcinoma. Limited data are available for the actual incidence of stricture in GERD patients. One retrospective cohort study of patients discharged from veterans’ administration hospitals found that 8.4% of patients with GERD had strictures, and the association between esophageal ulcers and stricture was significant.⁴³ This study likely suffered from significant selection bias, however, and the rate in primary care practice is almost certainly much lower. Barrett was noted in 11.6% of 662 patients with GERD referred from general practice settings for endoscopy.⁴⁴ Again, though, patients with GERD referred for endoscopy are likely to have more severe disease, and a recent meta-analysis suggests that the actual risk of Barrett in unselected patients is closer to 3% to 4%.⁴⁵ A longer duration of symptoms was associated with an increase risk. Patients with Barrett esophagus; negative, low-grade, or indefinite dysplasia; and neither aneuploidy or increased 4N on flow cytometry are at very low risk of esophageal cancer (<2% over 5 years). Only approximately 4% of patients with Barrett go on to develop esophageal cancer.⁴⁶

In a well-conducted case control study in Sweden, reflux symptoms were associated with a 7- to 10-fold increase in the risk of esophageal adenocarcinoma. A dose-response risk was noted for symptom frequency, severity, and duration.⁴⁷ However, because adenocarcinoma of the esophagus is so rare, the authors note that a family physician would need to perform endoscopy on more than 1400 men older than 40 years who have severe GERD symptoms to identify 1 case of cancer. Further, there are no data to suggest that treating GERD will reduce the likelihood of these more serious sequelae.

Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage that results from the abnormal reflux of gastric contents into the esophagus. A systematic review of population-based studies estimates that heartburn or regurgitation symptoms occur in 21% to 59% of the population during a given year.¹ The frequency of GERD in specific populations is provided in Table 1. Although only 1 in 5 patients with upper intestinal symptoms that occur at least weekly seeks medical attention,² nearly 1% of all visits to a family physician’s office are for GERD or related conditions.³

GERD significantly affects the quality of patients’ lives. In a survey of patients presenting for upper endoscopy with symptoms of at least 3 months’ duration, those with a diagnosis of GERD reported low scores at baseline for general wellbeing. Fortunately, follow-up data reported 4 weeks after treatment note improvement in gastrointestinal symptoms, general well-being, general health, vitality, and depression.⁴

Pathophysiology

The pathogenesis of GERD is multifactorial and is thought to involve lower than normal esophageal sphincter pressures. This allows gastric acidic content to reflux into the distal esophagus, which lacks a protective barrier, causing esophagitis. Inflamed tissue impairs the normal clearance of acid, worsening the esophagitis, which inhibits normal motility.

Although Helicobacter pylori is clearly associated with peptic ulcer disease, its association with GERD is still debated. Data from case control studies actually suggest an inverse association; that is, that the presence of H pylori may be protective against the development of GERD.⁵

Because of the anatomical location of the esophagus, GERD should be considered in the differential diagnosis for presenting complaints other than regurgitation or dyspepsia. For example, approximately 50% of patients with chest pain in whom cardiac etiology is ruled out will ultimately be given a diagnosis of GERD.⁶ Similarly, 10% of patients with chronic cough⁷ and 78% of patients with laryngitis have GERD.⁸ Clear associations between GERD and asthma have been demonstrated, but data from meta-analyses fail to show improvement of asthma symptoms when GERD is appropriately treated.⁹

Diagnosis

The diagnosis of GERD can usually be made without the use of invasive tests. The accuracy of key tests, including clinical history, is outlined in Table 2. One study of patients presenting with dyspepsia (signs and symptoms referable to the upper gastrointestinal tract) found that 56% also have GERD.¹⁰ Another showed that 60% of patients referred for pH monitoring had GERD.¹¹ Since reasonable prevalence estimates for GERD in the family practice setting may be slightly lower, calculations in Table 2 assume that between 40% and 60% of patients with suspected GERD actually have the condition.

Individual symptoms of GERD such as heartburn, regurgitation, belching, or dyspepsia are of limited usefulness in diagnosis. In a survey of patients referred for pH monitoring likelihood ratios hovered near 1, meaning that the presence or absence of the symptom had little impact on the diagnosis.¹¹ The clinician’s overall impression that a patient has GERD, however, is much more useful to rule in disease than any individual symptoms.¹¹ Assuming that half of patients with suspected GERD have the disease, if a clinician suspects GERD, that probability increases to 77%. Most clinicians would find a trial of empiric therapy appropriate at that probability.

The omeprazole test is also helpful in confirming a diagnosis of GERD. It consists of the patient taking 40 mg omeprazole in the morning and 20 mg at night for 1 week. If the symptoms resolve, the test is considered diagnostic of GERD.¹² Some consider this approach to be therapeutic, as well as diagnostic. Beginning with an omeprazole test and reserving invasive testing for those not responding to the medication was cost-effective for patients with noncardiac chest pain.¹³ In a decision analysis, empiric treatment with omeprazole was a cost-effective approach to the management of GERD.¹⁴ Of course, initial endoscopy is indicated for patients with “red flags”: signs and symptoms consistent with obstruction, bleeding, or perforation, and those older than 50 years who are at a higher risk of malignancy.

Upper endoscopy, however, is not very accurate in diagnosing GERD. Among patients with GERD, only 22% have esophageal erythema, and only 48% have erosions or ulcerations. Therefore, because of costs and limited resources, the American Society for Gastrointestinal Endoscopy recommends that endoscopy be reserved for patients presenting with possible GERD who also have symptoms of more serious disease (dysphagia, weight loss, gastrointestinal bleeding) and for those not responding to a reasonable trial of therapy.¹⁵ The goal is to rule out more serious conditions.

Twenty-four–hour pH monitoring, while more accurate than endoscopy, is also reserved as a second-line test. According to the American Gastro-enterological Association guidelines, pH recording is indicated when endoscopy is normal and reflux symptoms persist despite acid suppression therapy or to evaluate extra-esophageal symptoms that may be GERD (ie, atypical chest pain or chronic cough).¹⁶ The goal here is to rule in GERD as the etiology of the patient’s symptoms.

Numerous other tests have been proposed to evaluate the patient with suspected GERD: manometry, scintigraphy, esophograms (as part of upper gastrointestinal series), and the Bernstein test (a provocative challenge with hydrochloric acid infusion). Data on the accuracy of these tests are limited by the lack of an accepted reference standard, and most have fallen out of favor because of their inconvenience or limited accuracy. None are more helpful than pH monitoring or endoscopy, and they are therefore not recommended.

Treatment

Pharmacologic

Treatments for GERD address the pathophysiology of the disease; they tend to target the removal of precipitating factors, using gravity or medications to improve acid clearance, lower the acidity of gastric contents, or improve the esophageal sphincter tone. Short-term treatment goals are to relieve symptoms and heal esophagitis; long-term goals are to prevent relapses and sequelae, such as esophageal stricture formation or adenocarcinoma.

Recommendations for lifestyle modifications to lessen GERD symptoms are extensive and mostly based on pathophysiologic data. Possible triggers for GERD include obesity, tight clothing, fatty foods, alcohol, tobacco, caffeine, onions, peppermint, and chocolate.^17-21 Because symptoms are typically worse at night, elevating the head of the bed or avoiding postprandial recumbency is recommended.^22,23 Eliminating these factors has been shown to decrease the amount of acid in the distal esophagus or improve the pressure readings on manometry. This is disease-oriented evidence; it does not necessarily translate into reduced symptoms for patients. The only patient-oriented evidence that supports lifestyle modification is a small crossover trial in which subjects had less heartburn and belching following a hamburger meal compared with the same meal with onions on the burger.¹⁸ Despite the lack of high-quality evidence of effectiveness, guidelines recommend lifestyle modification as the first-line therapy or adjunct to additional medication.^24,25 Because these lifestyle changes are not thought to be harmful and may have other possible health benefits it is reasonable to recommend them to patients until better studies are published.

Promotility agents are a possible treatment of GERD because they improve acid clearance from the esophagus. Older agents such as metoclopramide and bethanecol have little data to support their use^26,27 and are further limited by their central nervous system side effects. A meta-analysis of trial data found that cisapride heals esophagitis and decreases symptoms of GERD²⁸ but was taken off the market because of problems with cardiac arrhythmias.

Acid suppression strategies available over-the-counter include antacids, alginates, and H2-blockers (H2Bs). Small, short-term trials have demonstrated mixed results with regard to symptom relief and lessened acid exposure from both antacids and alginates.^29,30 Longer follow-up in cohort studies suggests a modest benefit from antacids.³¹ More than 24 randomized controlled trials (RCTs) have demonstrated the benefits of H2Bs in the treatment of GERD for both healing esophagitis and symptom relief. The number needed to treat (NNT) is 5; that is, for every 5 GERD patients treated with H2Bs instead of placebo, 1 patient benefits.³² H2Bs also prevent the long-term recurrence of symptoms (NNT =15).³³ There is no clear benefit of one H2B agent over another. Proton pump inhibitors (PPIs) are also well supported by meta-analyses of RCTs in the short term (NNT = 2) and long term (NNT = 3) treatment of GERD.³³ As with H2Bs, no clear advantage is found between different PPI medications.

STEPS. Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare H2Bs and PPIs is one way to help guide management of GERD. H2Bs are not associated with any serious long-term complications. PPIs are theoretically linked to malignancy through 2 mechanisms: proliferation of endocrine cells leading to endocrine neoplasia and atrophic gastritis caused by chronic acid suppression as a precursor to gastric adenocarcinoma. However, studies have not borne out these concerns.³⁴ Thus, both H2Bs and PPIs seem equally safe. The best measure of tolerability is the pooled dropout rate, which is the number of patients dropping out of a study for any reason. Dropout rates are about the same for H2Bs and PPIs.³⁵ Meta-analyses of trials comparing the efficacy of H2Bs to PPIs in the short- and long-term treatment of GERD consistently favor PPIs.^33,35 Of 100 patients with GERD, approximately 25 will benefit from treatment with an H2B, and 75 to 80 will benefit from treatment with a PPI.³³ An interesting comparison of trials suggests that the therapeutic gain of PPIs is greatest in those patients with more severe GERD.³⁶ Little data exist about the prevention of complications of GERD with acid suppression. However, 1 small trial found a decreased rate of esophageal stricture recurrence at 1 year in patients with reflux esophagitis (NNT =7) treated with 30-mg lansoprazole compared with those treated with 300-mg ranitidine.³⁷ These data seem to suggest that high-risk patients are more apt to benefit from PPIs than H2Bs.

Because H2Bs are now available in generic forms, price tips the scales greatly in their favor. The average cost for PPIs is nearly 10 times that of generic H2Bs (3020-mg omeprazole tablets cost $105.55 and 60 150-mg ranitidine tablets cost $10.98 as of 11/0/00). Simplicity is a toss-up: most PPIs are dosed once daily, while H2Bs are given once or twice daily. A general approach is to start patients with GERD on a reasonable dose of H2Bs, and move on to PPIs if symptoms do not resolve in 2 to 4 weeks.^25,54 Some insurance companies require documentation of H2B failure before covering the increased costs of PPIs, despite their efficacy advantage.

Surgery

For patients with chronic or recurrent GERD, surgery offers an additional treatment option. Prospective cohort studies note that open Nissen fundoplication produces an 80% to 93% success rate at 10-year follow-up. Laproscopic procedures are producing similar short-term results, but long-term data are pending.³⁸ One randomized trial demonstrated equivalent 3-year outcomes for those undergoing Nissen fundoplication and those taking 40 mg omeprazole daily.³⁹ Decision analysis data favor the cost effectiveness of open Nissen⁴⁰ if medical treatment will be required for more than 4 years, and laproscopic procedure if medical treatment will be needed for more than 10 years.⁴¹

Prognosis

GERD may be a short-term intermittent problem or may be severe and chronic in nature. Untreated, approximately 15% of patients will have symptom relief.³² Antacids can raise that rate to an estimated 20%,^31,25 while H2Bs are associated with symptom-free rates of approximately 25%.³⁰ The best outcomes are found with PPIs, where recurrence of GERD symptoms is suppressed in 75% to 82% of patients at 1-year follow-up.^33,35

Although many patients will experience recurrences, chronic medications may not be necessary. In 1 study, 677 patients with heartburn and mild esophagitis were randomized to treatment with omeprazole or ranitidine for 2 weeks. If symptoms persisted, the dose of medication was doubled. If symptoms resolved, medication was stopped. Recurrences were treated for 2 to 4 weeks at the previously effective dose. Nearly half the patients were successfully treated with intermittent medication, and nearly 40% of initial responders required no further treatment.⁴²

GERD is associated with esophageal strictures, Barrett esophagus (metaplasia of the distal esophageal columnar cells, thought to be a precursor of dysplasia and cancer) and adenocarcinoma. Limited data are available for the actual incidence of stricture in GERD patients. One retrospective cohort study of patients discharged from veterans’ administration hospitals found that 8.4% of patients with GERD had strictures, and the association between esophageal ulcers and stricture was significant.⁴³ This study likely suffered from significant selection bias, however, and the rate in primary care practice is almost certainly much lower. Barrett was noted in 11.6% of 662 patients with GERD referred from general practice settings for endoscopy.⁴⁴ Again, though, patients with GERD referred for endoscopy are likely to have more severe disease, and a recent meta-analysis suggests that the actual risk of Barrett in unselected patients is closer to 3% to 4%.⁴⁵ A longer duration of symptoms was associated with an increase risk. Patients with Barrett esophagus; negative, low-grade, or indefinite dysplasia; and neither aneuploidy or increased 4N on flow cytometry are at very low risk of esophageal cancer (<2% over 5 years). Only approximately 4% of patients with Barrett go on to develop esophageal cancer.⁴⁶

In a well-conducted case control study in Sweden, reflux symptoms were associated with a 7- to 10-fold increase in the risk of esophageal adenocarcinoma. A dose-response risk was noted for symptom frequency, severity, and duration.⁴⁷ However, because adenocarcinoma of the esophagus is so rare, the authors note that a family physician would need to perform endoscopy on more than 1400 men older than 40 years who have severe GERD symptoms to identify 1 case of cancer. Further, there are no data to suggest that treating GERD will reduce the likelihood of these more serious sequelae.