GASTROESOPHAGEAL REFLUX DISEASE (GERD)

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Gastroesophageal reflux disease (GERD) is a motility disorder of the lower esophageal sphincter (LES). The definition of this disease has evolved over time, reflecting better understanding of the roles that transient LES relaxations and acid/pepsin contact with esophageal mucosa play, as well as the ability to identify these events. The diagnosis of GERD has changed from identification of a hiatal hernia, to identification of erosive esophagitis, to the currently accepted patient-centered definition: any symptom or injury to esophageal mucosa resulting from reflux of gastric contents into the esophagus.

GERD should not be confused with physiologic gastroesophageal reflux, which is not associated with symptoms or esophageal mucosal injury.

The prevalence of GERD is difficult to ascertain, although several studies have indicated it to be as high as 50% of adults in Western countries, with 10% to 18% experiencing heartburn on a daily basis. Studies using health care utilization data may underestimate the prevalence because of self-treatment by individuals in the community, whereas population surveys may overestimate it because of inaccurate assessment of symptoms and absence of objective data. Regardless of the real number, the management of this disease costs more than $10 billion annually in the United States. GERD has been called a disease of white males, although recent data suggest increasing prevalence in Asia and Pacific regions.

  1. 1
    Pathophysiology

    GERD is a motility disorder of the LES characterized by inappropriate or transient relaxations that allow gastric contents to reflux into the esophagus. The LES is a tonically contracted ring of smooth muscle fibers innervated by the vagus nerve. Vagal stimulation during swallowing produces physiologic LES relaxation and is a likely source for transient LES relaxations. Gastroesophageal reflux occurs most frequently during postprandial periods, at a rate of 6 reflux episodes per hour, but averages 2 episodes per hour over the entire day.

    Increasing frequency of reflux in the postprandial period results from gastric distention after a meal and stimulation of tension receptors in the proximal stomach leading to transient LES relaxations (Box 1). A chronically hypotensive LES is not a major mechanism for GERD in most patients but can be seen in cases of severe erosive esophagitis.

    Box 1  
    Factors That Modulate Transient Lower Esophageal Sphincter Relaxation

    Stimulants

    •   Gastric distention

    •   Pharyngeal intubation

    •   Upright orientation

    •   Foods (fatty foods, caffeine, alcohol)

    •   Tobacco

    Inhibitors

    •   Recumbency

    •   Lateral decubitus (left side)

    •   Anesthesia

    • Sleep

    Reflux of acidic gastric contents can lead to injury of the esophageal mucosa, including inflammation, ulceration, stricturing, Barrett’s metaplasia, and adenocarcinoma. Peristaltic clearance, tissue resistance, and salivary bicarbonate make up host defense mechanisms that work by clearing reflux and neutralizing the acid residue on the mucosa. Erosive esophagitis or strictures result in the most severe form of GERD, which includes nocturnal reflux with longer acid contact times, decreased salivary production, and lower frequency of swallowing during sleep.

  2. 2
    Complications

    Acid reflux can lead to significant morbidity if it is not recognized and treated appropriately. Habitual contact of acid and activated pepsin with the stratified squamous epithelium, along with impaired defense mechanisms, results in tissue injury (Box 2). The end result of this process can be ulceration, fibrosis with stricture formation, Barrett’s esophagus, or adenocarcinoma. These complications can produce alarm symptoms (Box 3). Patients presenting with alarm symptoms should undergo immediate diagnostic evaluation with an esophagogastroduodenoscopy (EGD).

    Box 2  
    Esophageal Tissue Defense Mechanisms

    Preepithelial

    • Mucous layer
    • Unstirred water layer
    • Surface bicarbonate concentration

    Epithelial Structures

    • Cell membranes
    • Intercellular junctional complexes (tight junctions, glycoconjugates/lipid)

    Cellular

    • Epithelial transport (Na+/H+ exchanger, Na+-dependent Cl−/ HCO3- exchanger)
    • Intracellular and extracellular buffers
    • Cell restitution
    • Cell replication

    Postepithelial

    • Blood flow
    • Tissue acid-base status
    Box 3  
    Alarm Symptoms of Gastroesophageal Reflux Disease

    Presence of any of the following symptoms requires immediate evaluation:

    •   Dysphagia

    •   Odynophagia

    •   Weight loss

    •   Spontaneous resolution of GERD symptoms

    •   Iron deficiency anemia

    •   Gastrointestinal bleeding

    Erosive Esophagitis

    The endoscopic finding of erosive esophagitis is seen in fewer than 50% of patients with heartburn. The severity is stratified according to the Los Angeles Classification of Esophagitis. Treatment with a proton pump inhibitor (PPI) for 4 to 12 weeks heals erosive esophagitis in

    78% to 95% of cases. The healing effect of antisecretory therapy, and particularly PPIs, demonstrates the important role of acid reflux in causing tissue injury. The recurrence rates for erosive esophagitis are high after discontinuation of PPI maintenance therapy (75%–92%), necessitating continuation of gastric acid suppression.

    Strictures

    Most strictures caused by GERD are peptic in origin and are located at the squamocolumnar junction. Patients with GERD and strictures, compared to those without strictures, are more likely to have a hypotensive LES, abnormal peristalsis, and prolonged acid clearance time. Stricture formation decreases the luminal diameter, resulting in solid food dysphagia. Dysphagia in these patients is often a combination of decreased luminal diameter and dysmotility of the distal esophageal body with low-amplitude peristalsis. Patients with GERD who develop dysphagia should have immediate barium radiography and an endoscopic evaluation.

    Barrett’s Esophagus

    Barrett’s esophagus (BE) is a premalignant condition that may evolve into esophageal adenocarcinoma. The histologic abnormality involves intestinal-like metaplasia of the stratified squamous epithelium.

    Epidemiologic studies show Barrett’s to be more common among Caucasians, males, and the elderly (mean age, 60 years). The relative risk of esophageal adenocarcinoma (EAC) in BE patients was thought to be 30- to 125-fold with an incidence of 0.5% per patient year; however, recent population studies have shown a lower incidence of 0.12% to 0.13%. Despite the prevalent use of PPIs in the treatment of GERD, the incidence of adenocarcinoma has been increasing. Current guidelines encourage endoscopic surveillance for patients with Barrett’s esophagus, yet there are sparse data showing the cost- effectiveness or mortality benefit of this strategy.

    Adenocarcinoma

    Approximately 50% of esophageal cancers are adenocarcinomas. Since the 1970s, the incidence has been rising for reasons that are still unknown. GERD is a risk factor for esophageal adenocarcinoma, and the risk increases with the duration and severity of GERD symptoms. There is a suggestion that cagA strains of Helicobacter pylori are protective against development of Barrett’s esophagus and adenocarcinoma. The declining incidence of H. pylori may be a possible explanation for the rising incidence of adenocarcinoma.

  3. 3
    Diagnosis

    GERD is largely a clinical diagnosis under the current definition (i.e., any symptom or tissue injury resulting from reflux of gastric contents into the esophagus). Patients with the typical symptoms of heartburn and regurgitation most often associated with meals have a high pretest probability of having GERD. A well-obtained history and symptom questionnaire are usually sufficient to form a presumptive diagnosis and are more cost-effective than ambulatory reflux testing or EGD. An empiric trial of PPI therapy that leads to a significant reduction or resolution of symptoms likely confirms the diagnosis.

    The pathophysiology of GERD is much more complex than previously thought. It involves more than acid reflux, because nonacid reflux with a pH greater than 4 can be a common source of symptoms. This entity is unmasked when PPI therapy is found to control gastric acid secretion and impedance-pH testing identifies a temporal relationship between symptoms and episodes of nonacid reflux.

    Direct-to-consumer marketing and the availability of over-the- counter PPI medications (Prilosec OTC) have led to self-treatment of GERD-type symptoms and a consequent change in the type of patients seeking medical care for their symptoms. Patients with typical GERD symptoms that do not completely respond to therapy with PPIs, including over-the-counter and prescription PPIs, warrant a more detailed evaluation of their symptoms. A separate population requiring earlier diagnostic evaluation includes patients with exclusively atypical GERD symptoms such as cough, hoarseness, throat clearing, asthma attacks, and chest pain. Less commonly, patients presenting with signs or symptoms of tissue injury, such as solid food dysphagia, should also be more rigorously tested for GERD (Box 4).

    Box 4  
    Clinical Spectrum of Gastroesophageal Reflux Disease–Related Symptoms and Tissue Injury

    Esophageal

    Symptomatic Syndromes

    •   Typical reflux syndrome

    •   Reflux chest pain syndrome

    Syndromes with Tissue Injury

    •   Reflux esophagitis

    •   Reflux stricture

    •   Barrett’s esophagus

    •   Adenocarcinoma

    Extraesophageal Established Association

    •   Reflux cough

    •   Reflux laryngitis

    •   Reflux dental erosions

    Proposed Association

    •   Sinusitis

    •   Reflux asthma

    •   Pulmonary fibrosis

    •   Pharyngitis

    •   Recurrent otitis media

    Patients who have symptoms associated with GERD, whether typical or atypical, are frequently treated empirically with PPI therapy. With a lack of discrimination regarding symptom types, this population is very heterogeneous and comprises patients with symptoms that are truly associated with GERD, not at all associated with GERD, and a combination of both. The pretest probability of GERD in this group is diluted, and nonresponders to empiric therapy are numerous. Partial responders and nonresponders to PPI therapy should undergo ambulatory reflux testing using combined multichannel intraluminal impedance (MII)-pH or standard pH. MII- pH catheters measure both esophageal pH changes and impedance changes that occur as an ion-rich refluxate passes a pair of ring electrodes, resulting in a drop in the resistance to a low-voltage current between the electrodes. The change in impedance can detect gastroesophageal reflux regardless of the acid content and can distinguish reflux types as liquid, gas, or mixed.

    The goals of ambulatory reflux testing are to determine whether the esophageal acid contact time is abnormal, whether there are an abnormal number of reflux episodes, and whether a relationship between reflux and symptoms exists. The advantage of combined MII- pH is its ability to identify both acid and nonacid reflux, so that

    testing can be done while the patient is on acid-suppression therapy and the artifact of acidic food or beverage ingestion is eliminated; pH- only testing is affected by both of these conditions. The major disadvantage is that MII-pH testing is less available than conventional pH testing.

    EGD is specific for detecting reflux-related tissue injury but is not sensitive, because fewer than 50% of patients with GERD-related heartburn have endoscopic findings of reflux. If erosive esophagitis or Barrett’s esophagus is found on endoscopy, aggressive antisecretory therapy with a PPI is warranted.

    A barium esophagram is unlikely to add useful diagnostic information in patients with GERD symptoms without dysphagia. It is a useful tool in distinguishing obstructive from nonobstructive dysphagia and may even be more sensitive than EGD in detecting causes of obstructive dysphagia. Achalasia is often mistaken for GERD during the onset of symptoms, and early use of esophagography may help make this diagnosis.

  4. 4
    Management

    GERD is predominantly a postprandial event involving transient LES relaxations. The primary focus in management of this disease is to eliminate or improve symptoms and prevent tissue injury. In most patients with recurrent GERD symptoms, this can be accomplished by controlling gastric acid secretion with antisecretory therapy. PPIs are the most effective pharmacologic therapy for improving symptoms and preventing tissue injury from acid reflux. Individuals with only occasional heartburn may successfully treat symptoms with a combination of lifestyle modifications and over-the-counter antacids, histamine 2 receptor antagonists, or a PPI.

    Patients presenting with typical symptoms and a history consistent with GERD should be given a trial of PPI once daily for at least 4 weeks. A validated GERD symptom assessment questionnaire such as the Reflux Disease Questionnaire should be used as an initial screening tool, because symptom response is the primary outcome measure and subsequent questionnaire responses are useful in comparison with the initial responses for measuring treatment efficacy. If symptoms have not responded or have responded only partially after this trial, then the dosing or frequency of the PPI should be increased over another 4-week period. If the response is still unsatisfactory, diagnostic testing with ambulatory combined MII-pH or pH-only monitoring is indicated.

    PPIs are an effective maintenance therapy for most patients with GERD and may be stepped down or used on demand, but GERD is a chronic condition with a high recurrence rate of symptoms without some form of maintenance therapy. This creates a large population of patients on antisecretory therapy for a disease with a low mortality rate, which raises the question of drug safety. There are insufficient data available that would warrant a recommendation against long- term PPI therapy. Clinical judgment in specific patient populations should be used to determine the optimal PPI regimen.

    At present, pharmacologic reflux reduction therapy consists solely of the use of baclofen (Lioresal),1 which has been shown to reduce transient LES relaxations and associated gastroesophageal reflux. The drawback of this medication is its unwanted side effects, which include somnolence and dizziness, limiting its tolerability and clinical utility as a stand-alone therapy.

    Antireflux surgery is another alternative that is effective in limiting GERD symptoms in patients with a positive reflux-symptom relationship. Candidates for surgery include younger patients who do not want to continue chronic PPI therapy and patients with symptomatic nonacid reflux. Today, most antireflux surgery is performed laparoscopically with a 360-degree Nissen fundoplication. The associated mortality rate is small (0.5%–1%), and this approach is preferred to open laparotomy. Traditional predictors for surgical success have included the presence of typical symptoms (heartburn and regurgitation), symptom response to a trial of PPIs, and an abnormal ambulatory pH study. These criteria exclude the important group of patients with atypical symptoms or symptoms related to nonacid reflux. However, such patients should be considered candidates for antireflux surgery if a positive reflux-symptom relationship can be demonstrated.

    Patients with alarm symptoms and those who are partial responders to PPI therapy should also undergo EGD to aid in determining the cause of the symptoms, such as obstructive dysphagia from peptic strictures, adenocarcinoma, and bleeding esophageal ulcers (which can cause anemia). EGD findings that suggest GERD are a result of acid reflux. However, the incidence of these findings has declined with the use of PPIs.

    Nonerosive reflux disease is increasingly common as more patients are converted from acid refluxers to nonacid refluxers with PPI therapy. By definition, these patients have no findings on endoscopy to suggest ongoing GERD. Absence of endoscopic findings does not exclude GERD, however, because tissue injury can occur at the microscopic as well as the macroscopic level. Patients with either erosive esophagitis or nonerosive reflux disease have dilated intercellular spaces on electron microscopy.

    As previously discussed, patients with GERD may develop Barrett’s esophagus. The metaplastic transformation from normal stratified squamous epithelium to an intestinal-type, columnar-lined epithelium creates a premalignant lesion with a 0.5% per year risk of progression to adenocarcinoma. Screening for Barrett’s esophagus remains controversial. There is no evidence that screening results in a mortality benefit due to early detection of esophageal adenocarcinoma. Screening of all patients with GERD for Barrett’s esophagus is clearly not cost-effective, but it is reasonable to target the highest-risk populations, such as Caucasian men older than 50 years of age with chronic reflux symptoms. Current American College of Gastroenterology guidelines recommend surveillance endoscopy in patients with known Barrett’s esophagus at intervals determined by the degree of dysplasia. Because there have been no long-term, controlled studies, it is a grade C recommendation.

  5. 5
    References

    Bonino J., Sharma P. Barrett’s esophagus. Curr Opin Gastroenterol. 2005;21:461–465.

    Castell D.O., Richter J.E. The Esophagus. ed 4 Philadelphia: Lippincott Williams & Wilkins; 2003.

    Frye J., Vaezi M. Extraesophageal GERD. Gastroenterol Clin North Am. 2008;37:845–858.

    Hila A., Agrawal A., Castell D. Combined multichannel intraluminal impedance and pH esophageal testing compared to pH alone for diagnosing both acid and weakly acidic gastroesophageal reflux. Clin Gastroenterol and Hepatol.

    2007;5:172–177.

    Hvid-Jensen F., Funch-Jensen P., et al. Incidence of adenocarcinoma among patients with Barrett’s esophagus. NEJM. 2011;365:1375–1383.

    Katz P.O., Gerson L.B., Vela M.F. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308–328.

    Mainie I., Tutuian R., Agrawal A., et al. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg. 2006;93:1483–1487.

    Mainie I., Tutuian R., Castell D. Comparison between the combined analysis and the DeMeester score to predict response to PPI therapy. J Clin Gastroenterol. 2006;40:602–605.

    Mainie I., Tutuian R., Shay S., et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: A multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;55:1398–1402.

    Savarino E., Zentilin P., Tutuian R., et al. The role of nonacid reflux in NERD: Lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol. 2008;103:2685–2693.

    Vakil N., Van Zanten S.V., Kahrilas P., et al. The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–1920.

    Vakil N. Review article: Test and treat or treat and test in reflux disease. Aliment Pharmacol Ther. 2003;17(Suppl. 2):57–59.

    Verbeek R.E., Siersema P.D., et al. Surveillance and follow-up strategies in patients with high-grade dysplasia in Barrett’s esophagus: a Dutch population-based study. Am J Gastroenterol. 2012;107:534–542.

    Wang K.K., Sampliner R.E. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol. 2008;103:788–797.

    1  Not FDA approved for this  indication.

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