Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal
      Reflux Disease
      Kenneth R. DeVault, M.D., F.A.C.G., Donald O. Castell, M.D., F.A.C.G., and
      The Practice Parameters Committee of the American College of
      Gastroenterology

      Preamble
      Guidelines for the diagnosis and treatment of gastroesophageal reflux
      disease (GERD) were published by the American College of Gastroenterology
      in 1995 (1). These and other guidelines undergo periodic review.
      Significant advances have been made in the area of GERD over the past
      several years, leading us to review and revise our previous guidelines
      statements. These advances have included an increase in our comfort with
      the chronic use of proton pump inhibitors and an increased acceptance of
      laparoscopic antireflux surgery, among other factors. These and the
      original guidelines are intended to apply to all physicians who address
      GERD and are intended to indicate the preferable, but not only acceptable,
      approach. Physicians must always choose the course best suited to the
      individual patient and the variables that exist at the moment of the
      decision. These guidelines are intended to apply to adult patients with
      the symptoms, tissue damage, or both that result from the reflux of
      gastric contents into the esophagus. For the purpose of these guidelines
      GERD is defined as chronic symptoms or mucosal damage produced by the
      abnormal reflux of gastric contents into the esophagus.
      Both these and the original guidelines were developed under the auspices
      of the American College of Gastroenterology and its Practice Parameters
      Committee, and approved by the Board of Trustees. The world literature was
      reviewed extensively for the original guidelines and was once again
      reviewed using the National Library of Medicine database. All appropriate
      studies were reviewed and any additional studies found in the reference
      list of these papers were obtained and reviewed. Evidence was evaluated
      along a hierarchy, with randomized controlled trials given the greatest
      weight. Abstracts presented at national and international meetings were
      only used when unique data from ongoing trials were presented. When
      scientific data were lacking, recommendations were based on expert
      consensus. During preparation, the guidelines were reviewed by the
      American Gastroenterological Association and the American Society for
      Gastrointestinal Endoscopy. Recommendations and comments obtained from
      these reviews were incorporated into the final document whenever possible.

      Empiric Therapy for GERD
      Old
      If the patient's history is typical for uncomplicated GERD, an initial
      trial of empirical therapy (including lifestyle modification) is
      appropriate. Patients in whom empirical therapy is unsuccessful or who
      have symptoms suggesting complicated disease should have further
      diagnostic testing.
      New
      If the patient's history is typical for uncomplicated GERD, an initial
      trial of empirical therapy (including lifestyle modification) is
      appropriate. Patients in whom empirical therapy is unsuccessful, or who
      have symptoms suggesting complicated disease, should have further
      diagnostic testing. Selected individuals who have longstanding symptoms or
      who require continuous therapy may need endoscopic screening for Barrett's
      esophagus.
      Symptoms that are highly specific for GERD (when the predominant or only
      symptoms) include heartburn (pyrosis), regurgitation, or both, which often
      occur after meals (especially large or fatty meals) (2). These symptoms
      are often aggravated by recumbency or bending and are relieved by
      antacids. The combination of symptoms and endoscopic changes are highly
      specific (97%) for GERD (confirmed with pH testing) (3). Expert opinion
      holds that it is appropriate to offer empirical therapy for GERD to
      patients with symptoms consistent with GERD. It is also reasonable to
      assume a diagnosis of GERD in patients who respond to appropriate therapy.
      Further diagnostic testing should be considered under four circumstances:
      lack of response to therapy, warning symptoms (Table 1), chronic symptoms
      in a patient at risk for Barrett's esophagus, or need for continuous
      chronic therapy. Patients who do not respond to therapy often have another
      cause for their symptoms, but this lack of response does not always
      exclude reflux as a possibility. Even when the most effective therapy for
      GERD is prescribed, some patients will continue to reflux acid (4). The
      purpose of evaluating patients who have warning symptoms is to exclude
      complications of GERD (esophageal strictures, carcinomas, etc). Other
      guidelines have been published that examine Barrett's esophagus in detail
      (5). In brief, certain patients with long-term symptoms (either with or
      without therapy) are at an increased risk for the development of Barrett's
      esophagus. Because we cannot be assured that partial (or even complete)
      control of acid changes this progression, the number of years of
      antireflux therapy may need to be considered in the calculation of when to
      search for Barrett's esophagus. The concept of symptoms predicting the
      presence of Barrett's esophagus has been challenged by reports suggesting
      that both the frequency and severity of reflux symptoms are poorly
      predictive of the presence of Barrett's esophagus (6).
        Table 1.
        Warning Symptoms Suggesting Complicated GERD

              Dysphagia
              Bleeding
              Weight loss
              Choking (acid causing coughing, shortness of breath , or
              hoarsness)
              Chest pain

      Endoscopy in GERD
      Old
      Endoscopy with biopsy is the primary technique for evaluating mucosal
      integrity. If unavailable, double-contrast radiography may be used.
      New
      Endoscopy is the technique of choice for evaluating the mucosa for
      esophagitis. The diagnosis of Barrett's esophagus requires biopsy to
      search for intestinal metaplasia.
      Endoscopy allows direct visualization of the esophageal mucosa. This is
      the only reliable method for the diagnosis of Barrett's esophagus. A
      reticular pattern on barium esophagram is neither sensitive (26%) nor
      specific (50%) when compared with endoscopy with biopsy (7). Barium
      radiography is reasonably accurate in cases of severe (98.7%) or moderate
      (81.6%) esophagitis, but is much less accurate with mild esophagitis
      (24.6%) (8, 9, 10, 11). Finally, reflux of barium during radiographic
      evaluation is only positive in 25-75% of symptomatic patients and is
      falsely positive in as many as 20% of normal controls (12, 13). Patients
      with hiatal hernias or who reflux barium at fluoroscopy have more acid
      exposure by ambulatory pH testing, but these findings have poor
      specificity and sensitivity and should not be used as a screening test for
      GERD (14). These factors limit the usefulness of barium radiography in the
      routine diagnosis of GERD.
      Endoscopic biopsy is needed to determine the presence of Barrett's
      epithelium. The issues surrounding both routine and short-segment
      Barrett's are covered in another guidelines statement (5). Patients with
      both typical and atypical manifestations of GERD will often have
      normal-appearing esophageal mucosa. These cases must be confirmed with
      other methods (pH testing or therapeutic trial). There is little value for
      histological examination of normal-appearing squamous mucosa to either
      confirm or exclude pathological acid reflux (15, 16).

      pH and Provocative Testing
      No Change
      Ambulatory pH testing helps to confirm gastroesophageal reflux in patients
      with persistent symptoms without evidence of mucosal damage and with
      noncardiac chest pain or reflux-associated pulmonary and upper respiratory
      symptoms, and to monitor the esophageal acid exposure of a patient with
      refractory symptoms. Provocative tests have a limited usefulness in the
      routine diagnosis and therapy of GERD.
      Although endoscopy allows for the evaluation of esophageal mucosa, the
      presence or absence of mucosal injury does not provide proof that the
      patient's symptoms are or are not related to GERD. Many patients with
      typical GERD symptoms and increased esophageal acid exposure do not have
      esophagitis (17). Patients with symptomatic, but not excessive,
      gastroesophageal reflux have persistence of symptoms and requirements for
      therapy similar to patients with excessive reflux, but are less likely to
      have endoscopic findings (18, 19). This endoscopic-negative form of GERD
      produces symptoms and illness behavior identical to that of GERD with
      endoscopic findings (20). Ambulatory pH testing allows the identification
      of patients with excess esophageal acid exposure and those with symptoms
      that correlate with esophageal acid (with either normal or abnormal total
      acid exposure). Good reproducibility (84-93%) and sensitivity and
      specificity (96%) have been reported (21, 22). Some additional papers have
      provided cause for concern. Normal acid exposure was reported in as many
      as 29% of patients with documented esophagitis and differences were found
      in the simultaneous acid exposure recorded by two attached probes (23,
      24). Despite these limitations, ambulatory pH testing remains the best
      method to study the actual amount of reflux occurring in a given patient.
      Patients with typical reflux symptoms and a normal endoscopy, but who
      respond to antireflux therapy, will not benefit greatly from a pH study.
      Ambulatory pH testing while taking reflux therapy may also be of benefit
      in the patient with refractory symptoms (25).
      The most commonly used provocative test of the esophagus is the Bernstein
      test of mucosal sensitivity to acid. If the subject's symptoms are
      provoked by acid and not by a normal saline control, the test is highly
      specific for GERD, but unfortunately much less sensitive (26). The
      Bernstein test may therefore establish that a patient's symptoms are
      related to GERD, but cannot exclude reflux and also cannot differentiate
      between degrees of reflux or esophagitis.
      An empirical trial of therapy with full- or double-dose proton pump
      inhibitor (PPI) has been suggested as a "test" for GERD. Relief of
      symptoms with 1 wk of omeprazole 20 mg twice daily had a sensitivity of
      75% and a specificity of 55% when compared with endoscopy and ambulatory
      pH testing (27). In another study, using pH as the gold-standard, an
      omeprazole trial had a positive and negative predictive value of 68% and
      63%, respectively, and when the omeprazole trial was considered the
      standard, the pH test had identical positive and negative predictive
      values (28). Neither a PPI trial nor ambulatory pH testing should be
      considered to provide absolute proof or disproof of GERD and in difficult
      cases both may be needed for the highest diagnostic certainty. An
      empirical trial of PPI has also been advocated as a diagnostic test in
      patients with atypical symptoms or signs such as chronic laryngitis (29)
      or unexplained chest pain (30).

      Esophageal Manometry
      Old
      Esophageal manometry is indicated and in certain complicated cases may be
      helpful before an antireflux procedure is performed.
      New
      Esophageal manometry should be used to facilitate placement of ambulatory
      pH probes and to guide antireflux surgery.
      The accurate placement of esophageal pH probes requires knowledge of the
      location of the lower esophageal sphincter (LES) (31, 32). This usually
      requires intubation with a manometry catheter and provides an opportunity
      for full manometry. There now have been several reports that show adequate
      placement of pH tubes using a combined pH/pressure measurement system,
      which negates the need for full manometry (33, 34). Esophageal manometry
      to document the presence of effective esophageal peristalsis is useful in
      patients in whom antireflux surgery is being considered (35). Patients who
      have ineffective peristalsis may need to either avoid surgery or undergo
      an alternative (i.e., less tight) procedure (36). In a series of 107
      patients, manometry changed the therapy offered in 10% of patients
      referred for antireflux surgery (37). Surgeons will often elect to perform
      a partial fundoplication in patients who have peristaltic dysfunction of
      the esophagus by manometry (38). These reports suggest, but do not prove,
      that better reflux control is achieved with a complete (Nissen)
      fundoplication than with a partial (Toupet) and that in a patient with
      less effective esophageal peristalsis, the risk of dysphagia is higher
      with the complete fundoplication. If these assumptions are true, manometry
      should be mandatory before fundoplication to choose the best surgery for
      the individual patient. Absolute LES pressure has been suggested to
      inversely correlate with esophageal acid exposure. This has been
      challenged by more recent reports suggesting esophageal body dysfunction
      to be a better predictor of abnormal acid exposure (39).

      Lifestyle Modification
      No Change
      Lifestyle modification should be initiated and continued throughout the
      course of GERD therapy.
      Numerous studies have indicated that elevation of the head of the bed (40,
      41), decreased fat intake (42), cessation of smoking (43), and avoiding
      recumbency for 3 h postprandially (44) decrease distal esophageal acid
      exposure, although data reflecting the true efficacy of these maneuvers in
      patients is almost completely lacking. Certain foods [chocolate (45),
      alcohol (46), peppermint (47), coffee (48), and perhaps onions and garlic
      (49)] have been noted to increase esophageal reflux and should be avoided,
      although randomized trials are also not available to test the efficacy of
      these maneuvers. Weight loss has been suggested to improve reflux, but
      studies have not been able to provide objective evidence of this
      association (50). Many authors assume the 20-30% placebo response rate
      seen in most randomized trials is due to lifestyle changes, but this has
      not been tested. Neither the efficacy nor the potential negative effect of
      lifestyle changes on a patient's quality of life have been adequately
      examined for any of the maneuvers. Despite this lack of data, expert
      opinion holds that education of the patient about factors that may
      precipitate reflux is reasonable.

      Patient-Directed Therapy
      New
      Antacids and over-the-counter acid suppressants are appropriate, initial
      patient-directed therapy for GERD. If symptoms persist while on therapy or
      warning signs develop (Table 1), the patient should undergo a diagnostic
      evaluation (see earlier diagnostic guidelines).
      Antacids and antirefluxants such as alginic acid are useful in the
      treatment of milder forms of GERD. Antacids (51) and alginic acid (52, 53)
      have been shown to be more effective than placebo in the relief of
      symptoms induced by a heartburn-promoting meal. In addition, combined
      antacid/alginic acid therapy may be superior to antacids alone in the
      control of symptoms (54, 55). There are two long-term trials that suggest
      effective symptom relief in approximately 20% of patients using
      over-the-counter agents (56, 57).
      All four of the histamine type-2 receptor antagonists (H2RAs) approved for
      use in the United States are now available in an over-the-counter (OTC)
      form at a dose that is usually one-half of the standard prescription dose.
      These doses have been shown to decrease gastric acid, particularly after a
      meal. Though there are some differences in potency, duration, and rapidity
      of action, they may generally be used interchangeably. The OTC H2RAs are
      particularly useful when taken before an activity that may potentially
      result in reflux symptoms (heavy meal or exercise in some patients). Many
      patients can predict when they are going to suffer from reflux and can
      premedicate with the OTC H2RAs. Famotidine 10 mg taken before an evening
      meal has been demonstrated to prevent reflux and restore sleep in patients
      who are usually awakened by GERD (58).
      Comparisons between OTC H2RAs and antacids are limited. It has been
      suggested that antacids provide a more rapid response, but gastric pH
      begins to rise less than 30 min after taking a dose of H2RA so this does
      not seem to be a major factor. The peak potency of OTC H2RAs and antacids
      are similar, but the H2RAs have a much longer duration of action (up to 10
      h).

      Acid Suppression for GERD
      Old
      Acid suppression is the mainstay of therapy for GERD. Histamine2-receptor
      blockers given in divided doses are effective treatment in many patients.
      Proton pump inhibitors provide rapid symptomatic relief and healing of
      esophagitis in the highest percentage of patients.
      New
      Acid suppression is the mainstay of therapy for GERD. Proton pump
      inhibitors provide rapid symptomatic relief and healing of esophagitis in
      the highest percentage of patients. Histamine2-receptor blockers given in
      divided doses may also be used and are effective treatment in many
      patients with less severe GERD.
      In the original guideline statement, the results of 33 randomized trials
      with more than 3000 patients are presented. Symptomatic relief can be
      expected in 27% of placebo-treated, 60% of H2RA-treated, and 83% of
      PPI-treated patients. Esophagitis healed in 24% of placebo-treated, 50% of
      H2RA-treated, and 78% of proton pump inhibitor-treated patients. We will
      not readdress those studies here, but it is clear that whereas some
      patients will have relief of symptoms and improvement or healing of
      esophagitis with H2RAs, PPIs eliminate symptoms and heal esophagitis more
      frequently and more rapidly than the other agents. Both higher doses and
      more frequent dosing of H2RAs appear to be more effective in the treatment
      of reflux symptoms and healing of esophagitis, but these agents are still
      inferior to proton pump inhibitors and more costly at higher dosages (59,
      60, 61).
      Concerns about the use of PPIs surround the profound decrease in gastric
      acid secretion produced by these medications (62). This leads to an
      increase in gastrin production from the antral-G cells and sustained
      increases in serum gastrin, usually to a mild degree (two to four times
      basal) (63). The question of whether these changes in serum gastrin might
      produce dangerous trophic effects on the gastric mucosa with long-term use
      of PPIs remains to be completely resolved, although both omeprazole and
      lanzoprazole are now approved for 1 yr of continuous usage. The experience
      with PPIs is approaching a decade in the United States and much longer in
      Europe and Australia. There has not been a reported case of gastric
      carcinoid type tumor in a patient receiving a PPI, with the exception of
      cases who had a multiple endocrine neoplasia syndrome not felt to be
      related to the drug. Atrophic gastritis has been reported with long-term
      omeprazole therapy. It was recently reported that these patients were
      often infected with Helicobacter pylori (64), but the clinical relevance
      of these findings has been questioned and essentially discounted (65).
      Cobalamin absorption may be decreased with chronic PPI therapy, but no
      change in serum levels have been reported after as many as 7 yr of therapy
      (66). There has also been no evidence of bacterial overgrowth after
      long-term acid suppression (67). It is becoming increasingly clear that
      the potential benefit of chronic PPI therapy in patients with chronic or
      complicated GERD outweighs any theoretical risk.
      There is much debate over the role of H2RAs and PPIs in the initial
      treatment of GERD. One approach, the so called step-up therapy, is to
      start with a standard or even OTC dose of H2RA and titrate to symptom
      control. The other approach, step-down therapy, starts with once- or
      perhaps twice-daily proton pump therapy and decreases the therapy to the
      lowest form of acid suppression that controls the symptoms. There have
      been models constructed to evaluate both the efficacy and
      cost-effectiveness of these approaches and neither has been proven
      superior, therefore the approach is best left to the choice of the
      individual practitioner in consultation with the patient (68, 69).

      Promotility Therapy for GERD
      Old
      Promotility agents such as cisapride and domperidone have an efficacy
      similar to standard-dose histamine receptor blockers.
      New
      The available promotility agents (cisapride and metoclopramide) have an
      efficacy similar to standard-dose histamine receptor blockers.
      Defects in esophagogastric motility (LES incompetence, poor esophageal
      clearance, and delayed gastric emptying) are central to the pathogenesis
      of GERD (70). If these defects could be corrected, then GERD would be
      controlled, making suppression of normal amounts of gastric acid
      unnecessary. Bethanechol may increase LES pressure to a small degree, but
      has limited efficacy in GERD. The frequent central nervous system side
      effects of metoclopramide (drowsiness, irritability, extrapyramidal
      effects, etc.) have, appropriately, decreased the regular use of this
      medication (71). Cisapride (10 mg q.i.d.) can provide effective
      symptomatic relief and healing of esophagitis, with results comparable to
      cimetidine 400 mg q.i.d. or ranitidine 150 mg b.i.d., and superior to
      placebo (72, 73, 74). Combined therapy with cimetidine and either
      metoclopramide (10 mg q.i.d.) (75) or cisapride (10 mg q.i.d.) (76) have
      been shown to result in improved healing of esophagitis, compared with
      cimetidine alone. Cisapride may also be an effective maintenance therapy
      for GERD (77, 78). A combination of cisapride and ranitidine was superior
      to ranitidine alone in the maintenance therapy of GERD, but inferior to
      omeprazole alone (79). Contrary to the positive studies cited,
      postprandial reflux as measured with ambulatory pH monitoring was not
      decreased in patients treated with cisapride, compared with controls (80).

      There have been reports of fatal cardiac dysrhythmias associated with the
      combination of cisapride and several agents that are metabolized by the
      cytochrome P-450 system (particularly antifungal agents and some
      antimicrobials) (81, 82). The widespread use of this medication throughout
      the world suggests that these important side effects must be relatively
      rare. Although cisapride may be useful in certain patients with a
      combination of symptoms (nausea and constipation, among others), PPIs
      provide greater control of acid reflux, without the risk, albeit small, of
      cardiac rhythm disturbances.

      Maintenance Therapy for GERD
      Old
      Because GERD is a chronic condition, therapy with acid suppression or
      promotility agents or both at the lowest dose needed to control symptoms
      and prevent complications is appropriate. This may include chronic proton
      pump inhibitor therapy.
      New
      Because GERD is a chronic condition, continuous therapy to control
      symptoms and prevent complications is appropriate. Chronic proton pump
      inhibitor therapy is an effective and appropriate form of maintenance
      therapy in many patients.
      Many, perhaps most, patients with GERD require long-term, possibly
      life-long, therapy. Therefore, maintenance therapy becomes a major
      concern. Effective maintenance therapy should keep the patient's symptoms
      comfortably under control and prevent complications. This will vary in
      each patient and may require only antacids and lifestyle modifications in
      as many as 20% of patients. Other patients with chronic reflux (50%) have
      frequent symptomatic relapses despite appropriate therapy. Patients whose
      disease has been controlled with PPIs often will have symptomatic relapses
      and failure of healing of esophagitis with a standard dose, or even
      higher-dose H2RA or prokinetic therapy (83). A full dose of H2RA given
      once daily, although effective for peptic ulcer disease, is not
      appropriate for GERD. Reduced doses of PPIs have not been shown
      consistently to be effective long-term in the therapy of GERD. This
      includes alternate-day omeprazole (84) or so-called weekend therapy (85).
      A daily dose of 10 mg may be superior to standard-dose ranitidine (86).
      The frequent marked improvement in GERD symptoms noted with the acid
      suppression produced by full-dose PPI is usually followed by a rapid
      return of symptoms once it is discontinued (87).
      There are clear data that acid suppression decreases the recurrence of
      peptic esophageal strictures. Cimetidine 400 mg four times a day did not
      affect the frequency of the need for dilation (88), but several studies
      have found that full-dose PPIs will lengthen the interval between
      symptomatic relapses (89, 90). There are no similar data in regards to the
      prevention or prevention of progression of Barrett's esophagus. It does
      not appear that Barrett's esophagus will regress with either medical or
      surgical therapy (91, 92). There have been reports of occasional islands
      of squamous epithelium appearing with chronic PPI therapy, but the
      significance of this is not known (93). Abnormalities of esophageal
      peristalsis have long been thought to predispose to reflux, but recent
      studies suggest that at least a portion of these motility disorders are in
      fact a consequence of the reflux and may improve while taking antireflux
      therapy (94).

      Surgical Therapy for GERD
      Old
      Surgery should be considered if medical therapy fails or is deemed
      appropriate in individual cases.
      New
      Antireflux surgery, performed by an experienced surgeon, is a maintenance
      option for the patient with well-documented GERD.
      Considerable controversy exists over the long-term effectiveness of
      surgical intervention in GERD and whether it is superior to chronic
      medical therapy. In the two published trials of medical versus surgical
      therapy, surgery has been shown to be more effective. The initial
      comparison favored surgical over a rather modest medical therapy
      (essentially antacids and lifestyle changes) over a 36-month period (95).
      A comparison of surgery versus ranitidine and metoclopramide indicated
      superiority for the surgical approach (96). Preliminary results of a
      similar comparison between surgery and PPIs were recently presented. This
      randomized trial of 310 patients, who initially had their disease
      controlled with omeprazole 40 mg per day, found surgery to be slightly
      superior (maintenance of esophagitis healing and symptoms) to omeprazole
      20 mg per day at the end of 3 yr (97). If dose titration up to 40-60 mg
      per day of omeprazole was used the two treatments were equal. Proper
      selection and preoperative evaluation of patients is very important. If
      typical reflux esophagitis is not present endoscopically, ambulatory pH
      testing should be performed. Esophageal manometry may alter the surgical
      decision in as many as 10% and should be a routine procedure before
      antireflux surgery. Delayed gastric emptying has been reported to increase
      the rate of complication after an antireflux surgery, but the utility of
      the routine preoperative use of these tests is not clear (98).
      The medical therapy of GERD has focused on the neutralization of refluxed
      acid from the stomach. It is clear that there are other injurious factors
      involved. The possibility of duodenogastroesophageal reflux (alkaline
      reflux) has been raised as an additional indication for the surgical
      repair of the LES in patients with GERD (99). Although it appears that
      control of acid decreases the injury in patients who reflux duodenal
      contents (100, 101), certain of these patients may benefit from antireflux
      surgery although objective evidence of this type of reflux is difficult to
      obtain preoperatively.
      A laparoscopic approach to antireflux surgery is rapidly evolving and
      appears to be equal or perhaps even superior to the open approach (102,
      103, 104). A recent study found significantly lower cost and shorter
      lengths of hospital stay with the laparoscopic approach, although patient
      satisfaction was similar between the open and laparoscopic groups (105).
      This approach may not be possible in some patients who have had previous
      surgery and in the very obese. The decreased postoperative morbidity
      involved in this approach should not change the indications or evaluations
      for surgery, but does make this option more attractive for some patients
      whose alternative would be long-term medical therapy (106). The long-term
      durability of laparoscopic antireflux surgery remains incompletely
      defined, but several studies of the open technique have reported adequate
      control of disease for as long as 20 yr (107, 108). Another study
      suggested a deterioration in both LES pressure and endoscopic histology
      back toward the presurgical level 5-6 yr postoperatively (109).

      GERD Refractory to Therapy
      New
      GERD refractory to medical therapy is very rare. The diagnosis should be
      carefully confirmed before chronic high-dose acid suppression or
      antireflux surgery.
      The vast majority of patients will have their symptoms and mucosal disease
      controlled with medical therapy for GERD. When a patient presents with
      either typical or atypical symptoms of GERD refractory to therapy, the
      diagnosis, current therapy, or both should be reconsidered. This may
      involve an ambulatory pH study, either with or without therapy, additional
      endoscopic and manometric evaluations, and consideration of testing and
      therapeutic trials for other conditions that may produce symptoms similar
      to GERD. Although PPIs provide outstanding acid control in the vast
      majority of patients, there has been a recent report of two patients who
      had refractory reflux (by pH study and symptoms) while taking omeprazole,
      who had better acid suppression with high-dose H2-receptor therapy (110).
      These cases are rare, but emphasize the need for individualized therapy
      and testing when symptoms consistent with GERD are refractory to therapy.

      Extraesophageal Manifestations of GERD
      New
      GERD should be considered in the differential diagnosis of unexplained
      cases of chronic chest pain, cough, hoarseness, and asthma.
      Several other symptoms may be related to GERD and are usually referred to
      as atypical or extraesophageal symptoms of GERD. An association with GERD
      may occur in as many as 50% of patients with noncardiac chest pain (111),
      78% of patients with chronic hoarseness (112), and 82% of patients with
      asthma (113). Chronic cough has also been associated with GERD (114, 115).
      Gastroesophageal reflux may be induced by exercise and can either be
      asymptomatic or present with typical or atypical symptoms (116, 117).
      Dental erosions have been associated with asymptomatic gastroesophageal
      reflux as well (118). These patients may or may not have typical symptoms
      of GERD and are often best diagnosed with either an empirical trial of
      therapy, ambulatory pH testing, or, in some cases, both. It has been
      suggested that these patients may require higher doses of acid suppression
      and longer therapeutic trials than patients with more typical symptoms of
      GERD. Finally, when these symptoms are refractory to medical therapy, the
      diagnosis of GERD needs to be carefully reconsidered before recommending
      surgical therapy.

      References
      1. DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of
      gastroesophageal reflux disease. Arch Intern Med 1995;155:2165-73.
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