Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

Section II ESOPHAGUS

CHAPTER 13. Gastroesophageal Reflux Disease

Rajeev Vasudeva, MD, FACG

Image True/False: Patients with gastroesophageal reflux disease (GERD) usually seek medical attention.

False. While an extremely common problem, the majority of patients with GERD do not seek medical attention.

Image How often is endoscopic evidence of erosive esophagitis and Barrett’s esophagus seen in patients with symptoms suggestive of GERD?

Up to one-half of patients with reflux symptoms and not receiving antisecretory medication will have erosive esophagitis, albeit usually mild, and about 11% will have Barrett’s esophagus.

Image What are the major physiologic mechanisms that protect against esophageal acid injury?

Esophageal clearance mechanisms (peristalsis/saliva), esophageal mucosal/epithelial integrity, antireflux barrier (lower esophageal sphincter [LES]) competence, and gastric emptying are the four major physiologic mechanisms.

Image What are the three mechanisms of LES incompetence and how often is each primarily responsible for GERD?

Image

Image What factors are associated with severe esophagitis?

Low LES pressure, esophageal motor abnormalities, and recumbent reflux are the most important determinants of severe endoscopic esophagitis. The presence of a hiatal hernia is also important.

Image What esophageal histologic abnormalities are typical of GERD?

The basal zone occupying more than 15% of the total thickness of the epithelium and the papillae extending more than two-thirds of the distance to the surface. Eosinophils and neutrophils are also commonly present. Unfortunately, the sensitivity and specificity of these findings, either individually or in combination, is only fair at best.

Image What role does the hiatal hernia play in the pathogenesis of GERD?

This has been a controversial issue for the past 4 decades. Initially thought to be the only mechanism by which reflux occurred, later it was considered to be unimportant. However, recently it has been shown that the right crus of the diaphragm contributes significantly to the antireflux barrier, thereby stressing the importance of a normally placed gastroesophageal junction. Some studies have shown that the hernia sac acts as a reservoir for gastric contents (acid trap) and is associated with complicated forms of GERD such as severe esophagitis and peptic strictures, suggesting that it is a major contributory factor.

Image True/False: There is a clear correlation between abnormal esophageal acid exposure on ambulatory pH monitoring, clinical symptoms, and severity of esophagitis.

False. It appears that all three are independent although related aspects of GERD. No clear relationship exists between symptom severity, amount of reflux, and presence of esophagitis.

Image What is the cancer risk in Barrett’s esophagus?

Barrett’s esophagus is the major risk factor for esophageal adenocarcinoma whose incidence has been rising dramatically over the past two decades. A recent meta-analysis suggests that patients develop esophageal adenocarcinoma at a rate of < 0.5% per year (annual incidence rate). These patients have a 30 to 125 times increased risk of developing esophageal cancer compared to the general population.

Image What are similarities and differences in demographics between patients with long-segment Barrett’s esophagus (LSBE) and short-segment Barrett’s esophagus (SSBE)?

• In general, the prevalence of LSBE is 3 to 5 times less than that of SSBE.

• The mean age of diagnosis is similar (55 to 65 years) with a strong propensity for males in LSBE (> 90%) and slightly less for SSBE (70%).

• Predominance of Caucasians is noted for both although more striking in LSBE.

• Both smoking and alcohol ingestion are more prevalent in LSBE than in SSBE.

Image What are similarities and differences in pathophysiology and clinical presentation between patients with LSBE and SSBE?

• Symptoms of heartburn are similar but duration of heartburn greater than 5 years appears to be a distinguishing feature of LSBE.

• The pathophysiology and degree of acid reflux is different. Patients with LSBE typically have a large hiatal hernia, very low LES pressure, and decreased distal esophageal amplitude as compared with SSBE patients. Additionally, patients with LSBE have a combination of upright and supine reflux and more proximal esophageal acid reflux, while SSBE have predominantly upright and distal esophageal reflux.

Image What is the difference in dysplasia risk between patients with LSBE and SSBE?

The dysplasia prevalence is 15%–24% in LSBE or 2 to 3 times higher than that in SSBE. The adenocarcinoma prevalence is 15% in LSBE or 7 to 15 times higher than that in the SSBE population.

Image True/False: Intestinal metaplasia of the gastric cardia has the same malignant potential as SSBE.

False.

Image True/False: There is universal agreement among practice guidelines from the major GI societies in the developed nations that endoscopic screening for Barrett’s esophagus is indicated for patients with chronic symptoms of GERD.

False.

Image True/False: Intestinal metaplasia is required for the diagnosis of Barrett’s esophagus.

True. This is the only of esophageal columnar epithelium that clearly predisposes to malignancy.

Image What is the Prague classification system?

This is a simple endoscopic method of recording the circumferential (C) and maximal extent (M) of metaplasia in centimeters that has been developed in hopes of promoting more uniformity in the reporting of Barrett’s esophagus.

Image True/False: Antireflux surgery has been repeatedly demonstrated to lead to a reversal of Barrett’s esophagus and risk of esophageal adenocarcinoma.

False. To date, no nonablative medical or surgical therapy has been convincingly shown to lead to reversal of Barrett’s esophagus or the risk of esophageal adenocarcinoma.

Image What are recommended guidelines for endoscopic surveillance in Barrett’s esophagus?

Although it is not clear that Barrett’s esophagus adversely influences survival or that endoscopic surveillance can reliably detect early curable neoplasia, the following practice guidelines have been published:

• GERD should be treated aggressively prior to surveillance in order to minimize confusion due to inflammation.

• Random, four-quadrant biopsies taken with a large capacity forceps every 2 cm for standard histologic evaluation is recommended in those without dysplasia and every 1 cm in those with dysplasia. Specific biopsy sampling of mucosal irregularities should also be performed.

• For patients with no dysplasia at two endoscopies (at unspecified intervals), subsequent surveillance endoscopy is recommended at 3- to 5-year intervals.

• For patients with low grade dysplasia, the diagnosis should be confirmed by an expert pathologist and endoscopy should be repeated in 3–6 months and at yearly intervals thereafter if dysplasia has not progressed.

• For patients with high-grade dysplasia, the diagnosis should first be confirmed by an expert pathologist. Although esophageal resection is one option, given the morbidity and mortality of surgical approach is significant, an intensive endoscopic surveillance may also be considered depending on patient comorbidities and/or preference. A repeat endoscopy should be performed with special attention to any mucosal irregularity and multiple biopsies (or endoscopic mucosal resection) should be obtained with a large capacity forceps. Focal high-grade dysplasia (< 5 crypts) may be followed with 3-month intervals. Surgical intervention should be more strongly considered when multifocal high-grade dysplasia is confirmed. Ablative therapeutic modalities including radiofrequency ablation, photodynamic therapy, and endoscopic mucosal resection may also be considered; however, the completeness of their reversal and their durability remains uncertain.

Image True/False: Chromoendoscopy is currently recommended for use during the routine surveillance of Barrett’s esophagus.

False.

Image What is the natural history of high-grade dysplasia in Barrett’s esophagus?

The natural history is poorly defined and therefore management of this condition is disputed. On the one hand, some studies have shown that progression to cancer is frequent and rapid while other studies have shown no apparent progression to cancer and even regression. Therefore, management varies between esophageal resection, continued surveillance, and endoscopic ablative therapies.

Image True/False: There is a relationship between GERD and a multitude of pulmonary and otorhinolaryngology symptoms.

True. A number of uncontrolled studies and anecdotal reports link GERD with several symptoms including laryngitis, hoarseness, globus, laryngeal cancer, chronic cough, asthma, aspiration, bronchitis, sinusitis, and dental erosions; however, the association appears to be the strongest for chronic cough, hoarseness, and asthma.

Image In patients with noncardiac (unexplained) chest pain, what percentage is due to GERD and how effective is treatment?

Several studies show nearly 50% of patients may have underlying GERD. Uncontrolled studies reveal an improvement of 65%–100% in symptomatology utilizing proton pump inhibitors.

Image What are the mechanisms by which GERD is thought to produce respiratory symptoms?

Two mechanisms have been suggested: 1) microaspiration of refluxed gastric contents into the airway (reflux theory) and 2) reflux of gastric contents into the distal esophagus initiating a vagally-mediated reflex arc (reflex theory).

Image In what way is the response to antireflux therapy in patients with extraesophageal symptoms different from classical GERD?

Despite the lack of adequate controlled data, the therapeutic response appears to be less. Therefore, high-dose proton pump inhibitors and a longer duration (several months) of treatment are required. Additionally, remission may be more difficult to maintain. The optimal management strategy remains to be defined.

Image What are the therapeutic recommendations in the management of confirmed or suspected reflux-related extraesophageal symptoms?

A twice-daily proton pump inhibitor for at least 3 months should be attempted before considering a patient to have failed medical therapy or not to have GERD. Antireflux surgery may be considered as an alternative therapeutic modality in patients with documented GERD who have failed medical therapy. The efficacy of antireflux surgery in patients with extraesophageal GERD is unclear based on the published literature.

Image In what situations should you consider diagnostic testing in patients with suspected GERD?

• Uncertain diagnosis.

• Suspected atypical or extraesophageal symptoms (chest pain, ENT, pulmonary).

• Symptoms associated with complications (dysphagia, odynophagia, unexplained weight loss, bleeding, anemia).

• Inadequate response to therapy.

• Recurrent symptoms.

• Prior to antireflux surgery.

Image What are the differences between the various diagnostic tests used in GERD?

Diagnostic tests should be performed in individual patients to answer specific questions. While somewhat controversial, a barium swallow is the test of choice for evaluation of dysphagia given that its sensitivity is superior to endoscopy in identifying subtle mucosal rings and evaluating esophageal motility. Endoscopy with biopsy is the best study for evaluating mucosal injury as well as identifying Barrett’s esophagus. Ambulatory pH monitoring is the best study to confirm GERD, quantify reflux, and allow symptom correlation. Combined impedance and acid testing can identify both acid and nonacid (volume) reflux, thereby identifying a subset of patients that do not respond to conventional acid suppression and may potentially benefit from alternative treatments. Esophageal manometry has a limited role but may be useful prior to antireflux surgery in order to identify severe esophageal peristaltic abnormalities.

Image What are the indications for ambulatory esophageal pH monitoring?

• Typical symptoms that do not respond to proton pump inhibitor therapy (on therapy).

• Atypical symptoms (noncardiac chest pain, ENT/pulmonary manifestations).

• Prior to antireflux surgery if confirmation of GERD is necessary (endoscopy-negative patients).

• Recurrent symptoms following antireflux surgery.

Image True/False: A tubeless (ie, catheter-free) method of ambulatory esophageal pH monitoring is available for clinical use.

True. A pH capsule that can be attached directly to the esophageal mucosa is available. This device may be more accurate than the catheter-based system due to its increased recording time (48 hours versus 24 hours) and comfort.

Image True/False: Lifestyle modifications are extremely effective in the treatment of GERD.

False. Lifestyle modifications are helpful in relieving symptoms in only about 20% of patients. No studies exist that demonstrate efficacy of lifestyle modifications in healing esophagitis, managing or preventing complications, or maintaining remission.

Image True/False: An initial trial of empiric antisecretory therapy is appropriate in a patient with symptoms suggestive of uncomplicated GERD.

True. It is also reasonable to assume a diagnosis of GERD in patients who respond to this therapy.

Image Which class of drugs provides the best long-term remission rate in erosive esophagitis?

Proton pump inhibitors. Of note, the maintenance dose requirement may increase with time.

Image True/False: Large, population-based, epidemiological studies have demonstrated an association between proton pump inhibitor use and an increased risk of hip fracture and a decreased risk of infectious diarrhea including Clostridium difficile infection.

False. While these studies have shown an increase in hip fracture risk, they have also shown an increased risk of infectious diarrhea including a doubling of the risk of C. difficile. Importantly, a causal relationship remains to be proven.

Image How effective are promotility agents in GERD therapy?

They are not ideal as monotherapy agents but can be used in selected patients as an adjunct to acid suppression.

Their benefit comes mainly from enhancing gastric emptying rather than an effect on esophageal peristalsis or LES function.

Image True/False: Agents targeting transient lower esophageal sphincter relaxation (tLESR) have been clearly shown to have clinical benefit in patients with GERD.

False. Although baclofen, a gamma butyric acid (GABA-B) agonist, has been shown to have benefit in terms of reducing the frequency of tLESRs and acid reflux events, its symptomatic benefit in GERD patients has not been clearly demonstrated. Furthermore, it has significant side effects prohibiting its widespread use in clinical practice. Recent clinical trials using longer-acting, better tolerated agents targeting tLESRs are ongoing but, to date, have not shown convincing benefit.

Image How effective are H2 receptor antagonists as GERD therapy?

They eliminate symptoms in up to 50% with twice-daily dosing. Healing of mild-to-moderate esophagitis requires at least twice-daily dosing and usually more frequent and higher dosing is often required. Remission of esophagitis healing occurs in only about 15%–25%. Although the addition of a nocturnal dose of these medications to twice-daily proton pump inhibitors received some popularity on the basis of pharmacodynamic studies, this practice has not been supported by studies using clinical endpoints.

Image What is the recurrence rate of GERD on discontinuation of therapy?

GERD is a chronic relapsing condition and, in one study, 80% of patients were symptomatic 6 months after discontinuation of antisecretory therapy.

Image Where are peptic esophageal strictures usually located?

The distal esophagus involving the squamocolumnar junction. Other etiologies should be considered if strictures are located elsewhere.

Image True/False: Medical therapy is effective in preventing the need for subsequent stricture dilatation.

True. While treatment with H2 receptor antagonists and promotility agents does not decrease the need for subsequent dilatations, several studies have shown that proton pump inhibitors are effective in not only healing associated esophagitis but also decreasing the need for stricture dilatation.

Image True/False: Medical intractability remains a major indication for antireflux surgery in the era of proton pump inhibitors.

False. Although once the most frequent reason for antireflux surgery, it is currently not a major indication for surgery. True intractability is uncommon in the era of proton pump inhibitors and the physician should reconsider the diagnosis of GERD in those who do not respond to these drugs. Antireflux surgery today is best reserved for patients who respond well to medical therapy. However, there is a small group of high-volume, nonacid refluxers identified by impedance testing that may benefit from antireflux surgery.

Image Describe potential postoperative gastrointestinal complications following antireflux surgery.

Dysphagia, flatulence, inability to belch, gas-bloat, and diarrhea. These are usually mild and self-limited and rarely require surgical revision. Interestingly, many (if not the majority of) patients will require proton pump inhibitors on a daily basis for the management of postoperative dyspeptic complaints.

Image True/False: Titrated dosing of proton pump inhibitor is equivalent to antireflux surgery in the long-term management of GERD.

True.

Image What are some of the reasons why proton pump inhibitors may fail to control gastric acidity?

• Nonadherence to the medication regimen is likely the most common reason.

• There is significant intersubject variability in the bioavailability of proton pump inhibitors, which may be decreased even further when taken with food.

• The acid suppressive effect of proton pump inhibitors tends to be reduced in Helicobacter pylori–negative patients.

• Although uncommon, hypersecretors of acid may have a decreased effect.

• Rapid metabolizers, based on cytochrome P450 2C, show a decreased effect on acid control.

• True proton pump inhibitor resistance (rare).

• Incorrect diagnosis.

• Nonacid reflux.

• Factors including significant gastric stasis, LES dysfunction, or ineffective peristalsis may contribute to persisting symptoms.

• Many patients with GERD often have symptoms including bloating, distention, and nausea which may be unmasked by proton pump inhibitors even though the classic reflux symptoms have improved.

Image What diagnostic study should be considered in patients with medically refractory GERD?

Twenty-four hour simultaneous intraesophageal and intragastric pH-metry while on antisecretory medication. A similar study off medication may be considered if the diagnosis of GERD is in doubt.

Image What are the best predictors of a good outcome after antireflux surgery?

Age < 50 years and typical reflux symptoms that are resolved completely with medical therapy. The experience of the surgeon is also important for a good outcome.

Image What are the indications for antireflux surgery?

• Patient with severe GERD who are unwilling to accept life-long medical therapy.

• Patients with severe GERD who cannot tolerate proton pump inhibitors due to allergy or intolerable side effects.

• Patients who have GERD manifestations that require long-term high-dose proton pump inhibitor therapy.

• Patients who are young and require chronic proton pump inhibitor therapy for control of symptoms and complications of GERD.

• Patients with nonacid reflux and good symptom correlation unresponsive to aggressive medical treatment.

Image True/False: Several endoscopic modalities to control GERD are clinically available and have shown comparable effectiveness as antireflux surgery.

False. Several techniques have been developed but, for a variety of reasons, most are no longer available (eg, radiofrequency energy application, endoscopic sewing techniques, and injection of various substances into the LES region) and none are commonly used. Nevertheless, the development of endoscopic approaches to manage reflux continues.

• • • SUGGESTED READINGS • • •

Altman KW, Prufer N, Vaezi MF. A review of clinical practice guidelines for reflux disease: toward creating a clinical protocol for the otolaryngologist. Laryngoscope. 2011;121(4):717-723.

Stefanidis D, Hope WW, Kohn GP, Reardon PR, Richardson WS, Fanelli RD. SAGES Guidelines Committee. Guidelines for surgical treatment of gastroesophageal reflux disease. Surg Endosc. 2010;24(11):2647-2669.

Kahrilas PJ, Shaheen NJ, Vaezi M. AGAI technical review: management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1392-1413.

Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. AGA. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):e18-e52.