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3. Gastroesophageal reflux disease
INTRODUCTION: Gastroesophageal reflux disease (GERD) is a condition which develops when the reflux of gastric contents causes troublesome symptoms or complications. The prevalence of GERD in Western societies has been estimated at 10-20%, making it one of the commonest encountered disorders in Primary Care. The spectrum of GERD encompasses typical symptoms of esophageal reflux (heartburn or regurgitation), esophageal injury (erosive esophagitis, stricture, Barrett’s esophagus and rarely adenocarcinoma) and extra-esophageal symptoms, such as chronic cough, asthma and laryngitis. Proper diagnosis and treatment is aimed at excluding other illnesses, avoiding overuse of medications and invasive testing, reducing symptoms, and minimizing complications.

4. What causes GERD? Prolonged exposure to reflux of gastric contents
Transient relaxations of lower esophageal sphincter expose esophagus to stomach acid and contents
Factors that increase exposure
Increased intra-abdominal pressure (obesity, pregnancy)
Decreased esophageal or gastric motility
Xerostomia
Hiatal hernia
Increased esophageal sensitivity may predispose to more severe symptoms or tissue damage
Increased acid production is not an important cause of GERD
Zollinger-Ellison syndrome the rare exception
What causes GERD?
Although intermittent movement of gastric contents into the esophagus is a normal physiologic occurrence, prolonged exposure or increased sensitivity to this exposure leads to GERD. The barrier between esophagus and stomach is made up of the lower esophageal sphincter (LES; specialized esophageal muscle fibers) and the crural diaphragm through which the esophagus passes from the chest into the abdomen. Transient relaxations of the LES (tLESRs) occur with equal frequency in GERD patients and healthy controls, probably as a venting reflex due to meal-related gastric distention. However, acid exposure in the esophagus may be increased in GERD patients due to a variety of factors including increased intraabdominal pressure such as from obesity or pregnancy, decreased esophageal or gastric motility, xerostomia, or presence of a hiatal hernia (with loss of the normal anatomic barrier mentioned above). In addition, there is variation in esophageal visceral sensitivity and mucosal integrity which may predispose to more severe symptoms or tissue damage. Increased acid production is not an important cause of GERD (Zollinger-Ellison syndrome being the rare exception). In terms of extraesophageal manifestations, the reflux theory holds that gastric contents are aspirated and directly damage bronchial or laryngeal areas, whereas the reflex theory proposes bronchoconstriction due to a vagally-mediated reflex.  
Boeckxstaens GE, Rohof WO. Pathophysiology of gastroesophageal reflux disease. Gastroenterol Clin North Am Mar;43(1):15-25.

5. What symptoms and signs should prompt clinicians to consider GERD?
Typical esophageal symptoms
Heartburn
Regurgitation
Atypical esophageal symptoms
Epigastric discomfort
Noncardiac chest pain
Nausea, satiety, dysphagia, globus, eructation, hematemesis
Extraesophageal symptoms
Cough, wheezing
Sore throat, hoarseness
Dental erosions
What symptoms and signs should prompt clinicians to consider GERD?
GERD may present with typical, atypical or extraesophageal symptoms (see box below). Typical esophageal symptoms are heartburn (retrosternal burning) and regurgitation (the perception of flow of gastric contents into the oropharynx). Although the sensitivity and specificity are not ideal, typical symptoms are considered sufficient to make a presumptive diagnosis of GERD in the absence of other concerning symptoms or signs.
In the DIAMOND study of 308 patients presenting to family practitioners with various upper gastrointestinal complaints, all subjects were evaluated by symptom questionnaire, visit with a gastroenterologist, endoscopy, pH testing and Proton Pump Inhibitor (PPI) trial. The sensitivity and specificity of heartburn and regurgitation for GERD was 69% and 62% respectively, if either was the first or second most bothersome symptom.
BOX – Symptoms of GERD
Typical esophageal symptoms: Heartburn, regurgitation
Atypical esophageal symptoms: Epigastric discomfort, noncardiac chest pain, nausea, satiety, dysphagia, globus, eructation, hematemesis
Extraesophageal symptoms: Cough, wheeze, sore throat, hoarseness, dental erosions
Attempts to standardize and validate symptom reporting has led to the development of self-administered questionnaires designed for the Primary Care setting. These have an advantage of focusing on patient-reported outcomes,. An example is the Reflux Disease Questionnaire (RDQ) (Figure 1), a 12-question instrument which has been validated for use in the primary care setting and has also been used for quantifying outcomes in intervention trials.
In the above mentioned DIAMOND study, investigators demonstrated a sensitivity of 62% and specificity of 67% for the RDQ compared to diagnosis of GERD based on a gold standard of either erosive changes by endoscopy or positive symptom correlations during a pH monitoring study. 88% of patients with a RDQ score of had GERD based on these confirmatory tests.6
In terms of extra-esophageal manifestations of GERD, an association is well established for cough, laryngitis, asthma and dental erosions (OR ), but less so for sinusitis, pulmonary fibrosis, pharyngitis and recurrent otitis media  

6. When should clinicians try an empirical therapeutic trial of acid suppression therapy to support a preliminary diagnosis?
When upper GI complaints are vague and symptom questionnaire is suggestive of GERD
Reflux Disease Questionnaire: 12-question instrument
When esophageal & extraesophageal symptoms present
Trial of PPI: take once or twice daily for 1 to 2 weeks
Assure proper dosing and compliance
If only partial improvement occurs, consider twice-daily dosing or switch to another PPI before declaring non- responder
When should clinicians consider an empirical therapeutic trial of acid suppression therapy to support a preliminary diagnosis of GERD?
As a diagnostic tool, the accuracy of the so-called “PPI Test” (any available PPI given once or twice daily for 1-2 weeks) is not significantly better than symptom-based diagnosis. For example, a meta-analysis in 2004 of 15 studies comparing empiric PPI use to the gold-standard pH measurement for diagnosis yielded a sensitivity of 78% and specificity of 54% . Another study showed that over 50% of patients without GERD felt improved after a course of PPIs compared to 69% of those with GERD proven by pH test or erosive esophagitis on endoscopy. For patients with somewhat vague upper GI complaints, a symptom questionnaire (as described above) may help to select patients for a trial of PPIs and therefore improve its specificity.
An empiric trial of PPIs should be considered as part of the diagnostic workup for suspected extraesophageal GERD in patients who exhibit both esophageal and extraesophageal symptoms. An AGA technical review found evidence to support an 8-week trial of twice daily PPI dosing for patients with laryngitis or asthma (USPSTF grade B) as well as for chronic cough (though graded USPSTF insufficient) when esophageal symptoms were also present.
When evaluating a patient’s response to PPIs, proper dosing (see Treatment section) and compliance must be assured, and if only partial improvement is seen, there is some data to support using twice-daily dosing or switching to another PPI before declaring the patient a “non-responder”.  

7. When should clinicians consider upper endoscopy in evaluating patients with possible GERD?
Indications for EGD in Known or Suspected GERD
Typical GERD symptoms that persist after a PPI trial
Alarm symptoms (dysphagia, bleeding, unexplained iron deficient anemia, weight loss, vomiting, epigastric mass)
Atypical GERD symptoms (epigastric pain, early satiety, food impaction): to exclude other upper GI diseases
Confirm healing after severe erosive esophagitis
Screen for Barrett esophagus in men >50 years with chronic GERD and additional risk factors
Surveillance of known Barrett esophagus
When should clinicians consider upper endoscopy in evaluating patients with possible GERD?
Roughly two thirds of patients with GERD have normal results on upper endoscopy (esophago-gastroduodenoscopy [EGD]) (14 –15). As a result, it is more useful for diagnosing complications and excluding other diseases. In an effort to limit unnecessary use of EGD, several professional societies have issued guidelines, which are summarized in the Box.
The 2012 American College of Physicians (ACP) clinical guidelines recommend EGD in patients reporting heartburn together with alarm symptoms (dysphagia, bleeding, anemia, weight loss or recurrent vomiting), patients with persistent symptoms after a PPI trial, and in patients with prior severe esophagitis to assess healing. The guidelines further state that EGD may be indicated as a screening test in men over 50 years old with >5 years of symptoms as well as any risk factors for dysplasia (nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use, and intra-abdominal distribution of fat).
2013 American College of Gastroenterology (ACG) guidelines and 2008 American Gastroenterological Association (AGA) guidelines vary slightly from this due to different interpretations of the available evidence.  
BOX: Indications for Upper Endoscopy in Known or Suspected GERD
Typical GERD symptoms that persist after a proton-pump inhibitor trial
Alarm symptoms (dysphagia, bleeding, unexplained iron deficiency anemia, weight loss, vomiting, or epigastric mass)
Atypical GERD symptoms, to exclude other upper gastrointestinal diseases (e.g., epigastric pain, early satiety, food impaction)
Confirmation of healing after documented severe erosive esophagitis
Screening for Barrett esophagus in men older than 50 years with chronic GERD and additional risk factors (see text)
Surveillance of known Barrett esophagus

8. What other diagnoses should clinicians consider in patients with suspected GERD?
Esophageal disorders
Cancer (squamous or adenocarcinoma)
Eosinophilic esophagitis
Functional heartburn
Motility disorders (achalasia, spastic disorders, hypotensive lower esophageal sphincter)
Nonreflux esophagitis (infectious, pill- or radiation- induced)
The rumination syndrome
Strictures, webs, or rings
Zenker’s diverticulum
Continued
What other diagnoses should clinicians consider in patients with suspected GERD?
The breadth of differential diagnosis in patients with symptoms suggestive of GERD depends on the nature of the symptoms and the patient’s history. Importantly, patients with a primary complaint of chest pain must first be investigated for cardiac causes. When ischemic heart disease has been ruled out, GERD should be considered as the next most likely etiology.
In a retrospective study of almost 14,000 patients complaining of new-onset chest pain compared to 20,000 matched controls without chest pain, the OR for cardiac ischemia was 14.9 and for GERD was 3.0.
In a questionnaire study of 2200 residents of Olmsted county, Minnesota, non-cardiac chest pain was reported by 37% of people who experienced frequent heatburn symptoms compared with 7.9% of those reporting no GERD symptoms.
Patients with heartburn may have chest wall pain if there is no association with food intake and tenderness on exam. Where regurgitation is prominent, rumination syndrome or underlying gastroparesis could be considered in the proper circumstance. In those with dysphagia, investigation into achalasia or eosinophilic esophagitis might be pursued. Patients with globus or odynophagia may have an extra-esophageal throat or neck condition, infectious esophagitis, or pill-related esophagitis. For patients presenting with dyspepsia (discomfort in the upper abdomen) one might consider peptic ulcer disease, functional dyspepsia, biliary colic, pancreatitis, medication side effects, and malignancies. Finally, extraesophageal symptoms including cough, asthma, laryngitis and other sinus and pulmonary problems should be appropriately considered in the context of their own differential diagnoses.
BOX: Differential Diagnosis of Suspected Esophageal GERD
Esophageal disorders
Cancer (squamous or adenocarcinoma)
Eosinophilic esophagitis
Functional heartburn
Motility disorders (achalasia, spastic disorders, hypotensive lower esophageal sphincter)
Nonreflux esophagitis (infectious, pill- or radiation-induced)
The rumination syndrome Strictures, webs, or rings Zenker diverticulum Other gastrointestinal disorders
Biliary colic
Gastritis
Gastroparesis
Hiatal hernia
Nonulcer dyspepsia
Peptic ulcer disease
Nongastrointestinal disorders
Chest wall pain
Coronary artery disease
Oropharyngeal and laryngeal disorders

9. Other gastrointestinal disorders
Biliary colic
Gastritis
Gastroparesis
Hiatal hernia
Nonulcer dyspepsia
Peptic ulcer disease
Nongastrointestinal disorders
Chest wall pain
Coronary artery disease
Oropharyngeal and laryngeal disorders
What other diagnoses should clinicians consider in patients with suspected GERD?
The breadth of differential diagnosis in patients with symptoms suggestive of GERD depends on the nature of the symptoms and the patient’s history. Importantly, patients with a primary complaint of chest pain must first be investigated for cardiac causes. When ischemic heart disease has been ruled out, GERD should be considered as the next most likely etiology.
In a retrospective study of almost 14,000 patients complaining of new-onset chest pain compared to 20,000 matched controls without chest pain, the OR for cardiac ischemia was 14.9 and for GERD was 3.0.
In a questionnaire study of 2200 residents of Olmsted county, Minnesota, non-cardiac chest pain was reported by 37% of people who experienced frequent heatburn symptoms compared with 7.9% of those reporting no GERD symptoms.
Patients with heartburn may have chest wall pain if there is no association with food intake and tenderness on exam. Where regurgitation is prominent, rumination syndrome or underlying gastroparesis could be considered in the proper circumstance. In those with dysphagia, investigation into achalasia or eosinophilic esophagitis might be pursued. Patients with globus or odynophagia may have an extra-esophageal throat or neck condition, infectious esophagitis, or pill-related esophagitis. For patients presenting with dyspepsia (discomfort in the upper abdomen) one might consider peptic ulcer disease, functional dyspepsia, biliary colic, pancreatitis, medication side effects, and malignancies. Finally, extraesophageal symptoms including cough, asthma, laryngitis and other sinus and pulmonary problems should be appropriately considered in the context of their own differential diagnoses.
BOX: Differential Diagnosis of Suspected Esophageal GERD
Esophageal disorders
Cancer (squamous or adenocarcinoma)
Eosinophilic esophagitis
Functional heartburn
Motility disorders (achalasia, spastic disorders, hypotensive lower esophageal sphincter)
Nonreflux esophagitis (infectious, pill- or radiation-induced)
The rumination syndrome Strictures, webs, or rings Zenker diverticulum Other gastrointestinal disorders
Biliary colic
Gastritis
Gastroparesis
Hiatal hernia
Nonulcer dyspepsia
Peptic ulcer disease
Nongastrointestinal disorders
Chest wall pain
Coronary artery disease
Oropharyngeal and laryngeal disorders

10. What other lab tests should clinicians consider when the diagnosis is uncertain?
Ambulatory reflux monitoring
Esophageal manometry
For refractory cases
For pre-op testing for anti-reflux surgery
Barium radiography (esophagram &/or upper GI series)
For primary complaint of dysphagia
For pre-op or post-op testing for anti-reflux surgery
Laryngoscopy
Presence of laryngeal erythema, edema, or other abnormalities not specific for GERD
Which other laboratory tests should clinicians consider in evaluating patients when the diagnosis of GERD is uncertain?
Ambulatory reflux monitoring is the only available test that can document the presence and frequency of esophageal exposure to gastric refluxate. Patient reporting during the test allows correlation as to whether this exposure is symptomatic. 24-hour transnasal catheter based systems for measuring pH and combined pH-impedance (thus including non-acid reflux events) are available, as well as 48-hour wireless pH telemetry probes. The ACG recommends ambulatory reflux testing as part of the evaluation of patients with suspected GERD who are refractory to PPIs and prior to surgical or endoscopic therapy when erosive changes are not present (strong recommendation, low level of evidence). The AGA recommends ambulatory reflux testing, preferably after esophageal manometry, for patients with persistent symptoms despite a PPI trial and with a negative EGD (USPSTF grade B, fair quality). Expert opinion also suggests reflux testing as a first-line test for patients with suspected extra-esophageal GERD who do not also display typical esophageal symptoms17.
Esophageal manometry should not be used to diagnose GERD initially, but rather is reserved for refractory cases to rule out primary motility disorders and as part of pre-operative testing for anti-reflux surgery.
Barium radiography (esophagram and/or upper GI series) has good specificity (77-85%) but poor sensitivity (26-50%) for the diagnosis of GERD,, as well as interoperator variability, such that its use is generally reserved for a primary complaint of dysphagia, or as part of the pre- or post-operative evaluation of patients undergoing antireflux surgery.
Finally, the laryngoscopic presence of laryngeal erythema, edema, or other abnormalities is not specific for GERD and, as such, a diagnosis of “reflux laryngitis” should not be based on laryngoscopy alone (AGA strong recommendation, moderate level of evidence) (16).
In a study of 41 consecutive patients with laryngoscopic diagnosis of reflux, only 41% were shown to have demonstrable reflux by impedance-pH testing. Another prospective study of 52 asymptomatic controls found at least one laryngoscopic abnormality associated with laryngopharyngeal reflux (LPR) in over 90% of cases.

11. Is there any connection between GERD and Helicobacter pylori infection?
Diagnose and manage as separate entities
Both may present with dyspepsia
No reason to test for H. pylori in patients with typical symptoms of heartburn or regurgitation
Patients with H. pylori gastritis may experience increased GERD symptoms even when H. pylori is eradicated
Long-term PPI use may increase risk for atrophic gastritis in patients with undiagnosed H. pylori infection
Routinely checking H. pylori status in patients on long- term PPIs is not recommended
Is there any connection between GERD and Helicobacter pylori infection?
Although both GERD and Helicobacter pylori-related ulcer or gastritis may present with dyspepsia, there is no reason to test patients who present only with typical GERD symptoms of heartburn or regurgitation for H. pylori. H. pylori gastritis can lead to gastric atrophy and hypochlorhydria or reduced acid production. As a result, patients might experience increased GERD symptoms when H. pylori is eradicated. However, the bacteria should still be done due to the their well-documented ulcerogenic and carcinogenic properties. Finally, a concern that long-term use of PPIs in the setting of undiagnosed H. pylori infection may increase risk for atrophic gastritis has been raised. However, this has not yet been proven, and at least in the United States, routinely checking H. pylori status in patients receiving long-term PPI prescriptions is not recommended. Therefore, despite considerable controversy, clinicians can diagnose and manage GERD and H. pylori as separate entities.

12. When should clinicians consider gastroenterology consultation during the evaluation of GERD?
Typical symptoms do not respond to an empiric PPI trial
Atypical symptoms overlap with those of other esophageal or gastric disorders
Alarm symptoms
High risk of Barrett esophagus and adenocarcinoma
When should clinicians consider gastroenterology consultation during the evaluation of GERD?
During the initial evaluation of patients where GERD is suspected, several circumstances should lead to referral. First, patients with typical symptoms who do not respond to an empiric PPI trial can be considered for further evaluation and testing. For patients who have atypical symptoms that overlap with those of other esophageal or gastric disorders, an evaluation may also be warranted. Despite poor specificity, alarm symptoms should prompt referral to consider EGD and alternate diagnoses. As mentioned above, patients at high risk of Barrett esophagus and adenocarcinoma when first diagnosed with GERD can be considered for screening EGD. Figure 2 suggests a management algorithm for GERD outlining diagnostic and treatment strategies.

13. CLINICAL BOTTOM LINE: Diagnosis...
Empiric diagnosis of GERD is based on
Presence of typical esophageal symptoms
Response to a PPI trial
Use of patient-reported questionnaires
If no response to PPI trial or if symptoms are extraesophageal or atypical: consider other disease possibilities
Consider EGD when alarm signs are present (dysphagia, bleeding, weight loss, vomiting or epigastric mass)
Don’t use barium radiography or laryngoscopy for GERD Dx
Reserve other tests for refractory or complex cases
Clinical Bottom Line: Diagnosis… Empiric diagnosis of GERD is made based on the presence of typical esophageal symptoms (heartburn and/or regurgitation), response to a PPI trial, or use of patient-reported questionnaires. Those who do not respond to a PPI trial or who have atypical or extraesophageal symptoms should be evaluated for other disease processes in addition to GERD. When alarm signs of dysphagia, bleeding, weight loss, vomiting or epigastric mass are present, an EGD should be considered. Barium radiography and laryngoscopy are considered inaccurate in the diagnosis of GERD. Other testing including pH monitoring and esophageal manometry are typically reserved for refractory or diagnostically complex cases.

14. What is the role of dietary modification in the treatment of GERD?
Dietary modifications may improve symptoms or reduce complications, but evidence isn’t strong
Some foods may lower LES tone (carminatives)
Other foods may irritate inflamed esophageal mucosa (citrus)
Patients may report improvement when avoiding particular substances
May control uncomplicated GERD without medical therapy
What is the role of dietary modification in the treatment of GERD?
Despite a theoretical basis and anecdotal reports, there is no strong evidence that dietary modifications can improve GERD symptoms or reduce complications. Certain foods such as carminatives are thought to lower LES tone, whereas others such as citrus are thought to further irritate already inflamed esophageal mucosa. However, controlled studies have not demonstrated a significant clinical effect when these are withheld.
A 2006 systematic review of 100 studies from identified 16 cohort or case-control trials which studied physiologic and clinical responses to dietary agents. Although chocolate and carbonated beverages were shown to reduce LES pressure, cessation of intake did not improve any important clinical outcome. Neither caffeinated or alcoholic beverages, nor fatty, spicy or acidic foods were shown to reduce LES pressure or worsen GERD symptoms in the controlled trials reviewed.
Given the lack of evidence, the ACG and AGA recommend against routine avoidance of these so-called triggers (conditional recommendation, low level of evidence; USPSTF grade insufficient). Of course, on a case-by-case basis, patients may report improvement when avoiding particular substances and if there are no nutritional consequences this may allow control of uncomplicated GERD without the addition of medical therapy.

15. Are behavioral interventions effective in the treatment of GERD?
Weight loss
Smoking cessation
Elevating head by 6-8 inches when in bed
Avoiding meals in the last 2-3 hours before bed
Are behavioral interventions effective in the treatment of GERD?
Obesity is associated with increased incidence of GERD symptoms and complications, whereas significant weight loss in the obese has been associated with improved symptoms in some (though not all) studies. As such, weight loss is recommended in overweight GERD patients (AGA recommendation with a USPSTF B grade).
A prospective population-based cohort study of almost 30,000 Norwegians showed that each unit increase of BMI had an OR of 1.3 for new-onset GERD. In a random sample of 10,545 women completing a questionnaire as part of the Nurses’ Health Study, the odds ratio for frequent heartburn symptoms increased with higher BMI range, from 0.67 at a BMI less than 20, to 2.93 for BMI above 35. A 40% reduction in GERD symptoms occurred in patients who decreased their BMI by 3.5 or more.
Tobacco has been shown to lower LES pressure, increase esophageal acid exposure, and is associated with increased risk of esophageal cancer (both squamous cell and adenocarcinoma), but smoking cessation has not been shown to improve GERD symptoms.
Elevation of the head of the bed at night (by 6-8 inches using blocks or foam wedges) and avoidance of meals in the last 2-3 hours before bedtime have been shown to improve GERD symptoms and esophageal acid exposure in some studies, although the benefit may be limited to patients with significant nighttime acid exposure and those with moderate to severely erosive disease  

16. Which medications cause or exacerbate GERD, and how should clinicians counsel patients regarding their use?
Medications that exacerbate GERD
By decreasing LES pressure and/or slowing esophageal clearance
CCBs, nitrates, anticholinergics, α-adrenergic antagonists, prostaglandins, theophylline, sedatives
Medications that irritate already inflamed tissue
Aspirin, NSAIDs, bisphosphonates
Which medications cause or exacerbate GERD? How should clinicians counsel patients regarding the use of these medications?
A number of medications can theoretically exacerbate GERD by decreasing LES pressure and/or slowing esophageal clearance. These include calcium channel blockers, nitrates, anticholinergic agents, α-adrenergic antagonists, prostaglandins, theophylline and sedatives. Other medications are thought to irritate already inflamed tissue, such as aspirin, NSAIDs and bisphosphonates. Whether GERD can be controlled by avoiding these medications rather than by active treatment as described here should be made on a case-by-case basis.
Decide whether to avoid these medications on a case by case basis

17. Which non-prescription medications are effective in the management of GERD?
Antacids neutralize stomach acid to relieve heartburn
Best used “on-demand” for infrequent symptoms
Regular or frequent use a marker of uncontrolled GERD
H2-receptor antagonists (H2RAs)
Inhibit histamine binding on gastric parietal cell receptor
Help heal erosive esophagitis and improve symptoms
Best used “on-demand” for infrequent symptoms in patients with symptoms after stopping initial PPI therapy
Use when PPIs not tolerated or contraindicated
Use limited by tachyphylaxis
Which non-prescription medications are effective in the management of GERD?
Antacids describe a variety of agents which neutralize stomach acid after it is secreted. Some are combined with H2RAs, anti-gas agents, alginate or other substances; form and concentration of the active ingredients vary considerably. Most can buffer stomach acid within minutes and yield an effect over 1-2 hours. Studies have demonstrated improved relief of heartburn versus placebo, though antacids do not provide prophylaxis of frequent symptoms and probably do not prevent complications. They are best used “on-demand” for infrequent symptoms. Regular or frequent use of antacids can be considered a marker of uncontrolled GERD.
In a study randomly assigning 565 patients with heartburn to self-directed treatment as needed with famotidine, antacid or placebo, the proportion of heartburn episodes relieved was 60-70% with famotidine and 62% with antacids, which were both statistically superior to 41% with placebo.
H2RAs, which are also available without prescription, work by competitively inhibiting histamine binding on the gastric parietal cell receptor. Their onset of action is within 1 hour, while duration is typically less than 12 hours. H2RAs have been shown to be inferior to PPIs, but superior to placebo, in healing erosive esophagitis and improving symptoms. The addition of a nighttime H2RA dose to an ongoing PPI regimen may incrementally reduce nighttime acid exposure, however has been shown to be limited by tachyphylaxis. Therefore the use of H2RAs is best limited to infrequent, on-demand dosing for patients without erosive or complicated disease who continue to have symptoms after stopping initial PPI therapy. They are also used when available PPIs are not tolerated or contraindicated due to drug interactions.
Several PPIs are now available over-the-counter, approved by the FDA for short-term use. As a class, they are discussed in the next section (See Table 2).  

18. When should clinicians consider prescription medications?
PPIs
First-line agents for patients with erosive disease or with typical esophageal symptoms
Irreversibly inhibit parietal cell proton pump
Most efficacious when taken 30 to 60 minutes before eating
More potent acid suppressors than H2RAs
Initial therapy: 8-week course of once daily PPI
Maintenance therapy indicated if GERD symptoms persist
Continued
When should clinicians consider prescription medications, and which medications are available?
PPIs work by irreversibly inhibiting the parietal cell proton pump (H+/K+ ATPase) and are most efficacious when taken minutes before eating, due to meal-stimulated increases in the number of pumps available for inhibition (with the exception of dexlansoprazole). With continued regular dosing, additional pumps will be inhibited, and a maximal drug effect is reached after several days. Because the proton pump is the final common pathway of gastric acid secretion, PPIs are more potent acid suppressors than H2RAs.
PPIs have demonstrated clear superiority to H2RAs and as such are recommended as first-line agents for patients with erosive disease, or with typical esophageal symptoms as empirical therapy (AGA grade A). An eight week course of a once daily PPI is recommended as initial therapy by the ACG (Strong recommendation, high level of evidence). Maintenance therapy with PPIs is also indicated for patients who continue to have GERD symptoms after the PPI is discontinued, as well as for those with erosive disease or other complications of GERD such as peptic stricture or Barrett esophagus (see following section).
Numerous studies have demonstrated that compared to H2RAs, PPIs have shown better efficacy and speed in healing erosive disease and relieving heartburn symptoms. For example, a Cochrane analysis demonstrated a RR of 0.51 for persistent erosive esophagitis while on PPIs compared to H2RA (as well as RR of 0.22 versus placebo). PPIs have also been found superior to H2RAs in symptom control for patients with nonerosive disease, with a relative risk of 0.66 as compared to H2RAs for persistent heartburn.
Several other classes of medications have putative benefit in GERD but less data to support their use (See Table 2). Baclofen is a GABA-B agonist which can increase LES tone and reduce tLESR-related reflux events, but limited proof of clinical efficacy. The ACG states that although not FDA approved for GERD and carrying possible adverse effects, baclofen can be considered in patients with documented continued reflux despite PPI use, but not without diagnostic evaluation. Prokinetic agents such as metoclopramide benefit specific subsets of patients either alone or in combination with antisecretory medications. By Cochrane analysis metoclopramide almost reached significance in controlling heartburn compared with placebo, but was given a grade D rating by the AGA as harm is thought to outweigh benefit. Sucralfate, a mucosal protectant which binds to inflamed mucosa, did not demonstrate superiority to placebo by Cochrane analysis. Antidepressants such as selective serotonin reuptake inhibitors and tricyclic antidepressants may modulate visceral pain sensation due to acid exposure especially in patients who are thought to be hypersensitive, but have not demonstrated an important clinical effect in large studies. In general, these agents are considered on a case-by-case basis after consultation with a gastroenterologist.  

19. tLESR inhibitors (baclofen)
GABA-B agonist increases lower esophageal sphincter tone
Prokinetic agents (metoclopramide)
Promote gastric emptying
Mucosal protectant (sucralfate)
Binds to inflamed mucosa
Antidepressants (SSRIs, tricyclic antidepressants)
May modulate visceral pain sensation due to acid exposure especially in hypersensitive patients
When should clinicians consider prescription medications, and which medications are available?
PPIs work by irreversibly inhibiting the parietal cell proton pump (H+/K+ ATPase) and are most efficacious when taken minutes before eating, due to meal-stimulated increases in the number of pumps available for inhibition (with the exception of dexlansoprazole). With continued regular dosing, additional pumps will be inhibited, and a maximal drug effect is reached after several days. Because the proton pump is the final common pathway of gastric acid secretion, PPIs are more potent acid suppressors than H2RAs.
PPIs have demonstrated clear superiority to H2RAs and as such are recommended as first-line agents for patients with erosive disease, or with typical esophageal symptoms as empirical therapy (AGA grade A). An eight week course of a once daily PPI is recommended as initial therapy by the ACG (Strong recommendation, high level of evidence). Maintenance therapy with PPIs is also indicated for patients who continue to have GERD symptoms after the PPI is discontinued, as well as for those with erosive disease or other complications of GERD such as peptic stricture or Barrett esophagus (see following section).
Numerous studies have demonstrated that compared to H2RAs, PPIs have shown better efficacy and speed in healing erosive disease and relieving heartburn symptoms. For example, a Cochrane analysis demonstrated a RR of 0.51 for persistent erosive esophagitis while on PPIs compared to H2RA (as well as RR of 0.22 versus placebo). PPIs have also been found superior to H2RAs in symptom control for patients with nonerosive disease, with a relative risk of 0.66 as compared to H2RAs for persistent heartburn.
Several other classes of medications have putative benefit in GERD but less data to support their use (See Table 2). Baclofen is a GABA-B agonist which can increase LES tone and reduce tLESR-related reflux events, but limited proof of clinical efficacy. The ACG states that although not FDA approved for GERD and carrying possible adverse effects, baclofen can be considered in patients with documented continued reflux despite PPI use, but not without diagnostic evaluation. Prokinetic agents such as metoclopramide benefit specific subsets of patients either alone or in combination with antisecretory medications. By Cochrane analysis metoclopramide almost reached significance in controlling heartburn compared with placebo, but was given a grade D rating by the AGA as harm is thought to outweigh benefit. Sucralfate, a mucosal protectant which binds to inflamed mucosa, did not demonstrate superiority to placebo by Cochrane analysis. Antidepressants such as selective serotonin reuptake inhibitors and tricyclic antidepressants may modulate visceral pain sensation due to acid exposure especially in patients who are thought to be hypersensitive, but have not demonstrated an important clinical effect in large studies. In general, these agents are considered on a case-by-case basis after consultation with a gastroenterologist.  

20. How should clinicians select from among available antireflux medications?
No real efficacy differences within same medication class
Modest superiority for esomeprazole vs. other PPIs
Dexlansoprazole can be dosed at any time of day
Immediate release omeprazole-sodium bicarbonate may improve nighttime gastric pH compared to other PPIs
Few data to support high- or double-dose of any PPI other than acute healing of esophagitis
Idiopathic side effects (diarrhea, constipation, headache) may occur with one PPI but not another
Pregnancy may affect medication selection
How should clinicians select from among available antireflux medications?
In general, there are no major differences in efficacy within the same class of medication. A 2006 meta-analysis did show statistical superiority for esomeprazole as compared to other PPIs available at that time, although the RR for improved healing of esophagitis and symptom control at 8 weeks was modest at 5% and 8% respectively, with NNT of Dexlansoprazole is a dual delayed release PPI which can be dosed at any time of day. Immediate release omeprazole-sodium bicarbonate may improve nighttime gastric pH compared to other PPIs, though the clinical impact of this is unproven.
Importantly, there is little data to support use of high- or double-dose of any PPI other than acute healing of esophagitis. One situation is during a “PPI test” where patients are only partial responders, and another is during evaluation of extraesophageal symptoms (see earlier section). On the other hand, a common reason to switch PPIs is due to idiopathic side effects such as diarrhea, constipation, headache or abdominal pain which may occur with one PPI but not another.
For the pregnant patient with GERD, although omeprazole carries a “C” rating, multiple studies have supported its safe use in humans. The remainder of the PPIs as well as all H2RAs are class “B”. Sucralfate, also category “B” is sometimes recommended due to lack of systemic absorption. The reader is referred elsewhere for a more complete discussion  

21. How long should patients continue pharmacologic therapy for GERD?
Complicated GERD
Erosive disease, stricture, or Barrett esophagus
Indefinite PPI maintenance therapy avoids relapse
Decreases risk of dysplasia development
Uncomplicated GERD
Consider maintenance therapy if symptoms recur
Make every attempt to taper and minimize medication use
Manage with intermittent or on-demand PPI therapy
Consider ‘step-down’ approach by using H2RAs on-demand
Balance symptom control against cost, inconvenience, and potential side effects of chronic PPI use
How long should patients continue pharmacologic therapy for GERD?
Indefinite maintenance therapy with a PPI is recommended for patients with complications including erosive disease, stricture or Barrett esophagus. Patients with moderate to severe erosive disease will demonstrate nearly universal relapse by 6 months off of treatment and therefore generally are maintained on PPIs indefinitely. Similarly, stricture has a high rate of recurrence and should prompt continuation of PPI therapy. The recommendation for ongoing PPI use in Barrett esophagus is based on retrospective studies showing a decreased risk of dysplasia development among Barrett patients taking PPIs regularly, along with expert opinion17.
In the more common situation of uncomplicated GERD, patients whose symptoms recur after cessation of initial PPI therapy should consider maintenance therapy, but every attempt should be made to taper and minimize medication use. Studies have shown that these patients can be managed with intermittent or on-demand PPI therapy, which by systematic review was found to be equivalent to continuous PPI therapy and superior to placebo. Studies have also demonstrated acceptable symptom control with a ‘step-down’ approach by using H2RAs in an on-demand fashion in such patients. For patients unable to taper, symptom control is balanced against the cost, inconvenience and potential side effects of chronic PPI use.
A systematic review of PPI discontinuation in GERD and non-ulcer dyspepsia found in analyzing six studies (heterogeneous and of varying quality) that dose reduction could be achieved in 30-50% of patients and discontinuation in 14-64% of patients, without loss of symptom control. Tapering appeared more effective than abrupt discontinuation.  

22. What are the adverse effects of long-term acid suppression therapy?
Gastric acid aids in vitamin and mineral absorption
PPIs may increase iron deficiency or pernicious anemia risk
PPIs may increase hip fracture risk
Gastric acid aids in destruction of ingested potentially pathogenic bacteria
PPIs may increase risk for enteric infections (C. difficile)
Pneumonia may be more common during sh-term PPI use
PPI + clopidogrel may increase cardiovascular risk
Long-term PPI use could predispose to intestinal metaplasia or gastric malignancy
What are the adverse effects of long-term acid suppression therapy?
Normal gastric acid plays a role in the absorption of various vitamins and minerals as well as in the destruction of ingested potentially pathogenic bacteria. This theoretical basis has led to several large studies which have helped to clarify the actual clinical risk for longterm PPI users. Studies have not found an increased risk of iron deficiency or pernicious anemia, except for elderly institutionalized patients where B12 deficiency was slightly more common. Meta-analyses have demonstrated a measurable increase in hip fracture risk (OR 1.2) in PPI users and not in H2RA users; however, the results are limited by heterogeneity and the lack of studies showing increased rates of osteoporosis in PPI users. Most experts recommend skeletal evaluation or alteration of therapy only if additional risk factors exist for hip fracture.
PPI use has been shown to increase the risk of Clostridium difficile (RR ) and other enteric infections, although elderly patients or those with significant comorbidities may already be at increased risk. Community-acquired pneumonia may be more common during short-term PPI use, though meta-analyses have shown mixed results and there is no proven long-term risk 17.
Clopidogrel requires activation by the cytochrome p450 CYP2C19 enzyme which also metabolizes omeprazole, lansoprazole and esomeprazole. In 2009 the FDA warned against increased cardiovascular events in patients using clopidogrel with PPIs based on in vitro data as well as initial retrospective studies. Since then, two randomized trials failed to demonstrate an increased risk of adverse cardiovascular events, and meta-analyses have demonstrated that previous work was limited by heterogeneity. Current guidelines do not support any change in PPI therapy for clopidogrel users (ACG strong recommendation, high level of evidence).
Finally, altered hormonal feedback due to acid suppression leads to increased gastrin production, and therefore the concern that long term use could predispose patients to intestinal metaplasia or gastric malignancy. A recent Cochrane analysis did not find evidence to support an increased chance of metaplasia or dysplasia, although so-called “simple” or “linear” ECL cell hyperplasia was found to be more common. 

23. When should clinicians consider surgical therapy for GERD?
Surgical anti-reflux therapy: laparoscopic fundoplication
Long-term treatment option with similar efficacy to medical Rx for some
Those with typical symptoms who respond to PPIs but wish to discontinue use
Those with continued symptoms / damage despite PPIs
Evidence doesn’t support surgery for other patients
Those with atypical symptoms or who don’t respond to PPIs
Those with Barrett esophagus who wish to prevent cancer
Bariatric surgery may be a treatment option for morbidly obese patients with GERD
When should clinicians consider surgical therapy for GERD?
Surgical therapy can be viewed as a long-term treatment option for GERD, with an efficacy similar to medical therapy for a selected group of patients. Surgical antireflux therapy typically refers to laparoscopic fundoplication, which includes variability in approach, technique and completeness of the “wrap”. For patients with typical esophageal symptoms of GERD who respond to PPIs, surgery can be considered for those who wish to discontinue PPI use due to pill burden, cost, side effects or compliance issues. In this setting, when performed by an experienced surgeon, surgical therapy is as effective as medical therapy (ACG strong recommendation, high level of evidence; AGA grade A).
In a Cochrane review of surgical versus medical therapy for GERD, data from four trials including over 1200 randomized patients demonstrated improved symptoms and quality of life scores for laparoscopic fundoplication versus medical therapy. Short-term costs were higher and serious adverse events (though rare) were more common for surgical patients.
In 5-year outcomes reported from the REFLUX trial including 357 patients randomized to surgical versus medical therapy, 26% of the surgical group compared to 82% in the medical group were taking PPIs. 7% of surgical patients went on to have additional surgical intervention either for complication or revision. Economic analysis suggested that surgical management may be more cost-effective in the longterm.
Another group of patients who may benefit from surgery are those with continued symptoms or damage despite PPIs, such as persistent erosive esophagitis associated with a large hiatal hernia. Patients with continued bothersome regurgitation despite PPI use, due to non-acid reflux confirmed by impedance testing, may also be considered for antireflux procedures. Lastly, there is some evidence to support bariatric surgery rather than antireflux surgery for morbidly obese patients with GERD (ACG conditional recommendation, moderate level of evidence).
For patients who do not respond to PPIs or have atypical symptoms, there is not enough data to support surgical therapy. In addition, there is no evidence to support antireflux surgery for patients with Barrett esophagus to prevent progression to cancer. Although some studies have shown a benefit to surgical fundoplication in selected patients with extraesophageal GERD, reviews have not demonstrated a clear overall benefit.
Other emerging invasive treatments for GERD include endoscopic therapy using radiofrequency augmentation of the LES; transoral incisionless fundoplication; implanted magnetic sphincter augmentation; and implanted electrical stimulation devices. Although certain high-quality trials have demonstrated improved outcomes for some of these ,, other evaluations have been less positive., We do not yet know whether these less invasive strategies will approach the success of traditional surgical fundoplication while minimizing side effects and adverse events. Long-term data is still accumulating for each technique and there remains no broad recommendation for their use in GERD at this time.  

24. Is it necessary to evaluate for Barrett esophagus periodically?
Estimated to occur in up to 10% with chronic GERD
Annual risk of esophageal adenocarcinoma is low (≈ 0.12%) even in patients with Barrett esophagus
Consider endoscopy for men >50 who have had GERD ≥5 yrs and who are overweight or have other risk factors
No role for periodic screening endoscopy in patients with uncomplicated GERD
No role for periodic screening endoscopy in patients with normal index endoscopy performed for above indications
Is it necessary to evaluate for Barrett esophagus periodically?
Although Barrett esophagus is estimated to occur in as many as 10% of patients with chronic GERD, the USPSTF makes no statement regarding esophageal cancer screening, and the AGA found insufficient evidence to recommend for or against screening to prevent death from cancer. This may be due in part to the fact that the incidence of esophageal adenocarcinoma in the general population is still low (4.4/100,000) despite a rise over the last few decades. In addition, the annual risk of esophageal adenocarcinoma even in patients with Barrett esophagus was recently estimated at 0.12%, rather than previous estimates of 0.5%. Given the available epidemiological evidence, both the ACP and the ACG state that endoscopy can be considered as a screening test in men over 50 years old with at least 5 years of GERD symptoms who are overweight or have other potential risk factors (see earlier section). However, there is no role for periodic screening EGDs in patients with uncomplicated GERD or in those who have had a normal index endoscopy performed for the above indications.
A large retrospective multicenter VA study examined a cohort of 68,610 patients who had a negative EGD within 1 year of GERD diagnosis. During a mean followup of 3.2 years, 29 patients developed any upper gastrointestinal malignancy, of which 10 were esophageal adenocarcinoma. Patients who developed cancer in this interval tended to be older and had more comorbidities. The incidence of subsequent esophageal adenocarcinoma in this group of veterans with mean age 55.5 and a negative index EGD was 4.6/100,000 patient-years.  

25. How should clinicians manage patients once Barrett esophagus is present?
Periodic surveillance can lead to earlier cancer Dx
In absence of dysplasia, use endoscopy every 3-5 years
Continue PPIs
Document presence of absence of dysplasia
Risk of progression to adenocarcinoma 0.1% to 0.5% per patient-year for non-dysplastic Barrett esophagus
Risk of progression to adenocarcinoma 5%-20% for dysplastic tissue
Data support endoscopic eradication therapy with radio- frequency ablation for high- and low-grade dysplasia
How should clinicians manage patients once Barrett esophagus is present?
Most professional societies recommend periodic surveillance of Barrett esophagus based on multiple retrospective studies showing that patients undergoing surveillance tended to be diagnosed with cancer at earlier stages and had longer survival compared with those diagnosed symptomatically.
Of critical importance is the documentation of the presence of absence of dysplasia when Barrett esophagus is present. This is due to the fact that the risk of progression to adenocarcinoma is 0.1% to 0.5% per patient-year for non-dysplastic Barrett esophagus, compared to 5%-20% for dysplastic tissue. A full discussion of the management of patients with dysplastic Barrett esophagus is outside the scope of this article. Briefly, there is growing data to support the use of endoscopic eradication therapy using radiofrequency ablation (RFA) or other techniques for patients with both high- and low-grade dysplasia. However, significant controversy exists and patients must be adequately informed during the decision making process.
In the absence of dysplasia, most professional societies recommend surveillance endoscopy every 3-5 years. PPIs are continued indefinitely based on retrospective evidence of benefit (see above). Although aspirin may decrease the incidence of esophageal adenocarcinoma, there is no clear evidence that the benefit outweighs risk at this time.

26. How frequently should clinicians see patients with GERD and what are the components of good follow-up?
At least annually if chronically taking PPIs or H2RAs
Assess symptom character, frequency, and severity
Check for alarm signs
Provide counseling to reduce exacerbating factors
Taper medical therapy to lowest effective dose
Reassure patients that risk for developing complicated disease is very low in uncomplicated GERD
Even with continued symptoms of heartburn and reflux
How frequently should clinicians see patients with GERD and what are the components of good follow-up?
There is no proven interval at which patients with GERD should be monitored once the diagnosis is established and the patient is appropriately treated as above, though one expert group recommended at least annual assessment for patients who are taking PPIs or H2RAs chronically. Periodic assessment should include symptom character, frequency and severity, and presence of “alarm” signs such as dysphagia, weight loss, vomiting or blood loss. Counseling should occur to reduce exacerbating factors as mentioned previously, including especially weight loss for overweight or obese patients. For uncomplicated GERD, medical therapy should be tapered to the lowest effective dose including intermittent or on-demand dosing when possible. Patients and doctors should be reassured that those with uncomplicated disease and no alarm signs or increased risk for Barrett esophagus are at very low risk of going on to develop complicated disease, even if they have continued symptoms of heartburn and reflux.

27. When should clinicians consider gastroenterology referral for treatment of a patient with GERD?
Alarm symptoms develop in context of previously well- managed GERD
Patients are interested in anti-reflux procedures
Patients are at high risk of Barrett esophagus and adenocarcinoma
Patients have prior documented severe esophagitis or Barrett esophagus
Most gastroenterologists happy to assist in all aspects of care
When should clinicians consider gastroenterology referral for the treatment of a patient with GERD?
Internists and other providers should consider referring established GERD patients to a gastroenterologist in a number of settings. Patients who develop alarm symptoms in the context of previously well-managed GERD should be referred for endoscopic evaluation. Patients interested in antireflux procedures are typically referred to gastroenterologists at least for pre-operative testing prior to surgery, or for endoscopic anti-reflux procedures performed by some practitioners (see above). As mentioned above, patients at high risk of Barrett esophagus and adenocarcinoma can be considered for screening EGD, and those with prior documented severe esophagitis or Barrett esophagus should be surveilled. Although diagnosis, initial treatment, and longterm management of uncomplicated GERD can certainly be accomplished alone by the motivated internist, most gastroenterologists are happy to assist in all aspects of care and may if nothing else provide useful reassurance to both the patient and referring doctor.

28. CLINICAL BOTTOM LINE: Treatment...
Nonmedication treatment
Weight loss for obese persons
Head-of-bed elevation for people with reflux at night
Dietary changes not universally recommended
Medication treatment
Initial Rx: PPIs once daily (30-60 mins before meal) for 8 wks
For those responsive to PPIs, taper to lowest effective dose
For those unable to taper or with significant erosive disease, Barrett esophagus, or peptic stricture Hx: Continue PPIs
H2RAs and antacids may be used for occasional symptoms
Surgery is an effective option for some patients with GERD
Refer for specialty evaluation when alarm symptoms develop
Clinical Bottom Line: Treatment…. Treatment... Proven nonmedication treatment for GERD includes weight loss for obese persons and possibly head-of-bed elevation for people who experience reflux at night. Dietary changes are not universally recommended due to a lack of evidence. PPIs should be used once daily (30-60 minutes before a meal for traditional PPIs) for 8 weeks as initial therapy; if a response is achieved, they should be tapered to the lowest effective dose, including “on-demand” dosing. Maintenance PPI treatment should be continued for patients unable to taper and those with Barrett esophagus, significant erosive disease, or history of peptic stricture. H2RAs and occasionally antacids can be used intermittently for occasional symptoms. Patients who develop alarm symptoms, and possibly those at higher risk for Barrett esophagus, should be referred for evaluation and EGD. Surgery is effective for PPI responders who wish to avoid or cannot tolerate long-term PPIs.