Gastroenterology Hepatology

Gastroesophageal reflux disease

How can I be sure that the patient has gastroesophageal reflux disease?

Heartburn and regurgitation are the two cardinal symptoms of gastroesophageal reflux disease (GERD). While neither symptom is totally specific for the disease, some clinicians have advocated that these symptoms, combined with a response to GERD therapy Some clinicians have advocated that those symptoms, combined with a response of that symptom to GERD therapy (usually acid suppression with a proton pump inhibitor), improves that specificity considerably. This empiric approach is all that is needed for patients presenting with these “typical” GERD symptoms.

In addition to the above noted typical symptoms, there have been many other symptoms attributed to acid reflux. These include chest pain, asthma, cough, hoarseness, and many others. These symptoms are less specific, but if they respond to acid suppression, it is reasonable to assume they are related. On the other hand, none of those symptoms are specific for GERD and objective confirmation (usually using pH testing as below outlined) should be considered in many cases.

A tabular or chart listing of features and signs and symptoms

Symptoms highly suggestive of GERD

  • Heartburn. Most specific symptom, especially when responsive to acid blocking medications.

  • Regurgitation. Also fairly specific for GERD, especially when combined with heartburn. Less likely to improve with acid medications.

Other symptoms frequently associated with GERD

  • Chest pain. After cardiac disease, GERD is the most common cause for chest pain.

  • Cough. After asthma and post nasal drip, GERD is the most common cause for chronic, unexplained cough.

  • Hoarseness and vocal changes.

How can I confirm the diagnosis?

Endoscopy

Endoscopy is indicated in two situations; when the so-called warning symptoms (dysphagia, odynophagia, weight loss, signs of GI blood loss) are present and in patients thought to be at risk for Barrett’s esophagus (BE). These indications are mainly related to identifying complications and not to confirm the diagnosis. On the other hand, when erosive esophagitis (EE) or BE are identified, the diagnosis is confirmed. The absence of EE and/or BE does not exclude GERD as the cause of a patient's symptoms.

An endoscopy for GERD should clearly describe the esophageal mucosa, the esophagogastric junction and biopsy of any area of concern performed. The entire length of the esophagus should be carefully viewed and biopsies obtained if the endoscopic or clinical picture suggests eosinophilic esophagitis or other non-GERD diagnoses. Esophagitis is only diagnosed if there are breaks in the mucosa of the esophagus and should be graded using an accepted scale, preferably the Los Angeles Classification or another well-validated scale.

The extent of columnar replacement of esophageal mucosa should be clearly described and measured (Barrett's esophagus). The distance from the teeth to the esophagogastric junction should be recorded. A retroflexed view is obtained and any hernia should be described and measured.

Ambulatory reflux monitoring

There have been several methods developed to test for reflux from the stomach to the esophagus. Traditionally, these have consisted of a tube with an electrode that measures pH, and which is passed through the nose into the esophagus. Recently, both a tubeless pH monitoring device and impedance-based devices (to evaluate nonacid reflux) have been developed. Ambulatory reflux tests are most useful in patients with GERD symptoms that have not responded to empiric therapy and to confirm GERD in patients under evaluation for endoscopic or surgical therapy.

In patients with excessive acid exposure in the distal esophagus (usually >4.5-5.5% of a 24 hr time period), the diagnosis is confirmed. Some patients will have normal amounts of acid exposure and still may have symptoms produced by reflux. In these patients, current monitoring software is able to calculate indices that help predict the association. The two most common are the symptom index (SI) and the symptom association probability (SAP). An SI higher than 50% or an SAP higher than 95% provide supportive evidence for an association of a given symptom with esophageal reflux.

Other tests

Barium studies do not provide accurate data in the evaluation of GERD and should not be routinely used outside of patients with dysphagia and in some selected patients prior to endoscopic or surgical therapy. While esophageal motility testing will reveal abnormalities in lower esophageal sphincter (LES) pressure and esophageal peristalsis in many GERD patients, the use of this test is restricted to finding the location of the LES to facilitate accurate placement of reflux monitoring probes and, perhaps, to help guide antireflux surgery. Likewise, some patients with GERD will have evidence of delayed gastric emptying with nuclear medicine testing, but testing for this is not routinely recommended. Patients who are at risk for cardiac disease may need additional testing to rule out coronary artery disease. Patients with pulmonary or ear, nose and throat (ENT) symptoms may need structural tests to exclude other pathology (CT scan, nasal endoscopy, etc.).

Therapeutic trials as diagnostic tools

There is no “gold-standard” test to confirm the diagnosis, and most experts believe a trial of medication to be the best diagnostic and therapeutic approach to the majority of patients with symptoms suggestive of GERD. For patients with heartburn or regurgitation, response to high-dose proton pump inhibitors (PPIs) has a sensitivity of 75% and specificity of 55% when compared with ambulatory pH testing. Although using response to acid suppression is not a perfect strategy to diagnose GERD, it is cost-effective and has become the preferred initial approach to patients with GERD-related symptoms. That having been said, although most experts would continue to use empiric acid suppression when an untested patient responds, they would also require confirmatory testing (usually with ambulatory reflux testing) prior to a more invasive endoscopic or surgical approach.

Summary

In summary, if a symptomatic patient has endoscopic evidence of erosive esophagitis or clear evidence of Barrett’s esophagus, then the diagnosis of GERD is confirmed. On the other hand, if neither of these is present, but symptoms are very consistent with GERD, then the patient can be assumed to have GERD. An ambulatory pH test should be performed to confirm the diagnosis (ideally off any acid blocking medication) prior to considering surgical or endoscopic intervention. By using these techniques (endoscopy and pH testing), GERD patients can be subdivided into the following groups:

1. Barrett’s esophagus (BE)

2. Erosive esophagus (EE)

3. Nonerosive reflux with excess esophageal acid exposure

4. Nonerosive reflux with normal acid exposure but a positive symptom association probability (SAP).

5. Functional heartburn (normal endoscopy, normal acid exposure, and negative SAP).

While patients within any of these groups may respond well and be managed medically, there are implications for long-term therapy and for patients with symptoms that do not respond completely. Patients in group 1 and, perhaps, in group 2 should have long-term treatment to prevent development of complications and are probably good candidates for surgical therapy if they have symptoms that are difficult to control. Group 3 may actually behave somewhat like group 2. Groups 4 and 5 are more problematic and care must be taken if surgery or other aggressive long-term therapy is considered.

What other diseases, conditions, or complications should I look for in patients with possible or confirmed GERD?

Although most patients with GERD can be managed with medication, diagnostic testing may be indicated in selected patients.

GERD symptoms leading to early testing

Endoscopy

  • Dysphagia

  • Odynophagia

  • Gastrointestinal blood loss

  • Unintended weight loss

  • Refractory symptoms (?)

Ambulatory pH testing

  • Symptoms refractory to therapeutic trial

Optional initial approach in patients with atypical symptoms

– Confirm disease prior to endoscopic or surgical therapy

Cardiac testing

  • Chest pain

  • Refractory heartburn in patients at risk for cardiac disease

Summary

Complications of GERD may develop and can be at least partially predicted based on symptoms. BE is a metaplastic change in the lining of the esophagus that is the result of chronic GERD and that puts the patient at an increased risk for esophageal adenocarcinoma. It is more common in men and in patients with long-term symptoms. Current guidelines suggest that testing is most beneficial in male patients over the age of 50, with symptoms for at least 5 to 10 years.

Complications of GERD should also be suspected when the so-called warning symptoms are present. These include dysphagia (suggestive of stricture or, less commonly, malignancy), bleeding (overt or occult), and weight loss. Some of the atypical symptoms are nonspecific. For example, cardiac disease should be excluded prior to blaming chest pain on GERD. Mucosal disease of the oropharyngeal region should be considered in patients with proximal symptoms and other pulmonary disease considered in patients with cough and asthma. Recently, the syndrome of eosinophilic esophagitis (EOE) has been widely reported. Classically, this disease is found in patients with dysphagia who often, but not always, have endoscopic findings suggestive of the diagnosis. Some groups have reported EOE in patients with refractory GERD symptoms and even in patients with the atypical symptom of chest pain. While guidelines do not support routine biopsy of all patients with refractory symptoms, this may be a reasonable approach, especially in patients with any hint of mucosal abnormality.

What is the right therapy for the patient with GERD?

The treatment of GERD varies depending on the severity of disease or something as simple as lifestyle changes and as complicated as reflux surgery. All patients with GERD should be given the lifestyle changes that may improve their GERD symptoms. Rather than overwhelm the patient with many suggestions, a simple approach is to ask the patient to avoid foods and activities that trigger their symptoms, lower the volume and fat content of their meals, limit or eliminate caffeine and alcohol consumption, lose weight if appropriate, and avoid late-night meals.

Patients with mild or infrequent symptoms may elect to use over the counter medications, either for short courses or on an as-needed basis. When reflux becomes more frequent or severe and patients present to their health-care providers, PPI therapy is most often initiated. There are several medications available, but, for the most part, a once daily PPI will control symptoms in the majority of patients. Histamine receptor antagonists are another option, but have lower efficacy and may require twice daily dosing.

What is the most effective initial therapy?

The initial therapy for GERD usually depends on the severity and duration of symptoms. Patients with mild, intermittent symptoms can be managed with lifestyle changes, antacids, and other over-the-counter medications. Patients who have persistent symptoms and who seek medical care are usually treated with PPIs. While some of the newer agents (see Table I) may have theoretical advantages, studies to prove these advantages have required vast patient numbers and have resulted in modest and clinically questionable differences. It would seem prudent to choose PPI based on cost to the individual patient and only consider more expensive agents if the initial agent does not provide sufficient control. Histamine receptor blockers are an alternative but offer less complete disease control and require twice daily dosing. There is little reason to use these agents in patients with significant symptoms.

Table I.

Currently available acid suppressants and usual dose
PPI Omeprazole; Prilosec, Zegerid;; 20-40 mg once daily
       
Lansoprazole; Prevacid 15-30 mg once daily
       
Rabeprazole Prevacid 20 mg once daily
       
Pantoprazole Protonix 40 mg once daily
       
Esomeprazole Nexium 20-40 mg once daily
       
Dexlansoprazole Dexilant 30-60 mg once daily
       
H2RA Cimetidine; Tagamet 300-400 mg twice daily
       
Ranitidine; Zantac 150 mg twice daily
       
Famotidine; Pepcid, Pepcid Complete;; 20-40 mg twice daily
       
Nizatidine; Axid 150 mg twice daily

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Lifestyle changes

Education of the patient about factors that may precipitate reflux remains reasonable. Numerous studies have indicated that elevation of the head of the bed, decreased fat intake, cessation of smoking, and avoiding recumbency for 3 hours postprandially all decrease distal esophageal acid exposure although data reflecting the true efficacy of these maneuvers in patients is almost completely lacking. Certain foods (chocolate, alcohol, peppermint, coffee, and, perhaps, onions and garlic) have been noted to lower LES pressure, although randomized trials are also not available to test the efficacy of these maneuvers. Many authors assume the 20% to 30% placebo response rate seen in most randomized trials is due to lifestyle changes, but this has not been rigorously tested. The potential negative effect of lifestyle changes on a patient’s quality of life has also not been examined.

Antacids and antirefluxants

Antacids are better than placebo in achieving relief of heartburn. In certain circumstances, antacids may be preferred to other acid-suppressing medications. They are inexpensive and have a very rapid onset. Alginate-based formulations have been available for the past 30 years and have been marketed under a variety of brand names, the most common of which is Gaviscon®. Alginates act by a unique mechanism in which the alginate precipitates in the presence of gastric acid, forming a gel. The gel then traps carbon dioxide, creating foam that floats on the surface of gastric contents, like a raft on water. It is thought that this “raft” preferentially moves into the esophagus ahead of acidic gastric contents during episodes of reflux and may work as a physical barrier to reduce reflux episodes.

Acid suppression

Acid suppression is the mainstay of GERD therapy. This has evolved quickly over the past few decades. The histamine type-2 receptor antagonists (H2RA) were introduced in the 1980s and, for the first time, provided a specific pharmacological approach to control acid secretion. Eventually, four of these agents were marketed in the United States (cimetidine, ranitidine, famotidine, and nizatidine). H2RAs are relatively effective in treating heartburn symptoms with a rapid onset of action. Although H2RAs offer an improvement over placebo for healing of mild esophagitis, they have limited utility, regardless of dose, in healing more severe esophagitis. Patients who continue to have heartburn after 6 weeks of treatment with H2RAs are unlikely to respond to prolonged courses or increased dosages. These agents have various approved doses and there are small differences in side effects, but, overall, their efficacy is quite similar.

In 1989, the first proton pump inhibitor (omeprazole) was developed. This was followed by the introduction of additional agents (lansoprazole, pantoprazole, and rabeprazole) that, similarly to the H2RAs, were minimally different from the original agent. PPIs are the most potent gastric acid suppressants. A review of 33 randomized trials including over 3000 patients showed that symptomatic relief can be expected in 27% of patients treated with placebo, 60% treated with H2RAs, and 83% treated with PPIs. Of those patients with esophagitis, 24% treated with placebo, 50% treated with H2RAs and 78% treated with a PPI had mucosal healing.

The optimal benefit of PPIs is achieved with appropriate timing of dosages. The best timing for maximum serum concentration is when the largest number of proton pumps are active and meals stimulate proton pumps, so having a high serum concentration of these drugs at the time of a meal results in the most effective acid suppression. Therefore, these drugs should be given prior to meals with enough time for systemic absorption, which is typically 15 to 60 minutes. It has been suggested that patients on once daily PPIs take the dose prior to breakfast. However, a recent study has shown that night-time acid is better controlled if the PPI is taken prior to the evening meal.

PPI therapy does have some limitations. Once daily therapy suppresses gastric acid for 11.2 to 15.3 hours during a 24-hour day. Even a powerful PPI given twice daily still leaves the stomach with a pH below 4.0 for at least 20% of the time, with the majority of this acidity occurring at night. PPI therapy also has a delayed onset of action that achieves optimal acid suppression after 3 to 5 days from initiation of treatment. (SeeTable I.)

Advances in PPI therapy

An optically pure preparation of omeprazole was tested and approved as a different agent (esomeprazole). Esomeprazole has shown some increased efficacy when compared to omeprazole, lansoprazole, and pantoprazole in certain subsets of patients, although huge studies were required in order to achieve statistical significance. An optically pure formulation of lansoprazole was recently developed, which also has a unique small bowel absorption profile resulting in a longer serum concentration. Finally, omeprazole was combined with an antacid in a new formulation that may have some advantages over the parent compound, including the ability to be taken without meals and, perhaps, more rapid onset of action.

Potential adverse effects of long-term acid suppression

There have been proposed adverse effects of long-term acid suppression. In all cases, the data on these interactions are mixed but probably do occur in selected patients. Many of these interactions have been suggested from review of large observational databases and rarely has true causality been proven.

1. Decreased calcium absorption and increased risk of fracture

2. Decline in vitamin B12 stores

3. Decline in serum magnesium

4. Increased risk of Clostridium difficile infection

5. Increased risk of both community and hospital acquired pneumonia

6. Small bowel bacterial overgrowth

7. Increased risk of other enteric infection

8. Drug interactions, most importantly to the antiplatelet drug clopidogrel (Plavix)

9. A small increased risk of chronic kidney disease (based on an observational database)

10. A increased rate of dementia in PPI users (again based on an observational database)

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Prokinetic (motility) therapy

Prokinetic drugs are appealing in the treatment of GERD as they may increase gastric emptying, improve peristalsis, and increase LES pressure. Unfortunately, these agents are typically not effective as monotherapy and their side-effect profiles often limit their use. The prokinetic drugs that have been used in GERD include bethanechol, metoclopramide, cisapride, domperidone, baclofen, and tegaserod.

  • Bethanechol and metoclopramide have poor efficacy, common side effects, and are not recommended for routine use in GERD.

  • Cisapride has been associated with fatal cardiac arrhythmias and significant cardiotoxicity, especially when taken together with protease inhibitors, macrolide antibiotics, and imidazoles and has resulted in its withdrawal from regular availability in the United States. Tegaserod has also been removed form the market, pretty much world-wide.

  • Baclofen is a GABA receptor agonist. It appears to suppress transient LES relaxation and, therefore, reduces the number of reflux episodes and the amount of esophageal acid exposure with a single dose (40 mg). Unfortunately, baclofen has a limiting side-effect profile (e.g., nausea, vomiting, somnolence, seizures, death upon withdrawal).

Endoscopic and surgical approaches

The vast majority of GERD patients will have mucosal disease and the majority of symptoms controlled with medical therapy. There is a small subset with symptoms that either are or appear to be refractory to medical therapy. Of these symptoms, regurgitation seems the most reasonable, since current therapy addresses the acid content of the refluxate, but probably allows continued reflux of neutralized material in a subset of patients.

A trial that randomized 310 patients between surgery and PPIs found surgery to be slightly superior to omeprazole 20 mg per day at the end of 7 years, but if dose titration of up to 40 to 60 mg per day of omeprazole were used, the two treatments were almost equal. Proper selection and preoperative evaluation of patients is very important.

In a study of 100 patients, the best predictors of a good outcome were age less than 50 years and typical reflux symptoms that had completely resolved on medical therapy. It is also clear that these typical reflux symptoms are more likely to resolve after surgery than the other atypical and supraesophageal symptoms. If typical reflux esophagitis is not present endoscopically, ambulatory pH testing should be performed to confirm the disease.

A recent study found significantly lower cost and shorter lengths of hospital stay with the laparoscopic approach, although patient satisfaction was similar between the open and laparoscopic groups. The only adverse effect of switching from an open to laparoscopic approach appears to be an increase in dysphagia in those treated laparoscopically. The decreased post-operative morbidity involved in this approach should not change the indications or evaluations for surgery but does make this option more attractive for some patients whose alternative would be long-term medical therapy. However, post-operative symptoms are common and include dysphagia, difficulty with belching, increased flatulence, and diarrhea. A new implantable LES "prosthesis" (the Linx device) is placed laparoscopically, has been approved and seems to be similar in efficacy to fundoplication. Several endoscopic approaches have been developed, control symptoms in a subset of patients, but overall do not seem to control acid as well as fundoplicartion or "Linx".

Listing of these, including any guidelines for monitoring side effects.

See Figure 1 for an algorithm for managing GERD.

Figure 1.

How should I monitor the patient with GERD?

Once patients' symptoms are under control, their long-term management must be individualized. The more information is known about their original presentation, the more likely there will be success. For example:

Barrett’s esophagus. Patients with BE should be monitored for development of dysplasia using periodic endoscopy with biopsy. Current guidelines suggest that GERD therapy should be directed at symptom control even in those with BE. That having been said, most providers continue acid suppression on these patients regardless of symptoms. In patients who have undergone an upper endoscopy and who do not have BE, additional endoscopy is very unlikely to discover the patient to have developed BE.

Erosive esophagitis. When EE is healed with a PPI and that medication is stopped, EE will return in a high percentage of patients over the ensuing 6-month period. While there is no clear evidence that ongoing EE leads to complications, it seems reasonable to try to control mucosal disease. The subset of patients with reflux-related strictures that have been dilated are an exception in that continued PPI therapy has been demonstrated to extend the period of dysphagia control between dilations.

Nonerosive reflux with excess esophageal acid exposure. Symptom control is key in these patients. Additional investigation is not necessary.

Nonerosive reflux with normal acid exposure but a positive symptom association probability (SAP). Symptom control is key in these patients. Additional investigation is not necessary.

Heartburn (normal endoscopy, normal acid exposure, and negative SAP). Symptom control is key in these patients. Additional investigation is not necessary.

What's the evidence?

Abraham, NS, Hlatky, MA, Antman, DL. "ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use". Am J Gastroenterol. vol. 105. 2010. pp. 2533-49.

(This is an important consensus document on the interaction between PPI and the antiplatelet drug clopidogrel.)

Ali, T, Roberts, DN, Tierney, WM. "Long-term safety concerns with proton pump inhibitors". Am J Med. vol. 122. 2009. pp. 896-903.

(This is a broader review of the potential problems with long-term PPI therapy.)

Katz, PO, Gerson, LB, Vela, MF. " Guidelines for the diagnosis and management of gastroesophageal reflux disease". Am J Gastroenterol. 2013. pp. 108-308.

(These are the most recent American College of Gastroenterology (ACG) guidelines on GERD.)

DeVault, KR, Talley, NJ. "Insights into the future of gastric acid suppression". Nat Rev Gastroenterol Hepatol. vol. 6. 2009. pp. 524-32.

(This review covers the state of the art in acid suppression and reviews several ongoing areas of research that could result in new agents in the future.)

Galmiche, JP, Hatlebakk, J, Attwood, S. "Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD. The Lotus randomized trial". JAMA. vol. 305. 2011. pp. 1969-77.

(This important trial has confirmed that surgery and medical therapy for GERD are roughly equivalent.)

Galmiche, JP, Clouse, RE, Balint, A, Drossman, DA. "Rome III: The Functional Gastrointestinal Disorders". Degnon Associates. 2006. pp. 369-418.

(Reflux symptoms are times functional [e.g., IBS and dyspepsia]. This chapter helps to define an approach to these challenging patients.)

Hirano, I, Richter, JE. "ACG practice guidelines: esophageal reflux testing". AM J Gastroenterol. vol. 102. 2007. pp. 668-85.

(Guideline statement on the use of ambulatory reflux monitoring.)

Jackson, PG, Cleiber, MA, Askari, R, Evans, SRT. "Predictors of outcome in 100 consecutive laparoscopic antireflux procedures". Am J Surg. vol. 181. 2001. pp. 231-5.

(A work that defines which patients would be predicted to do best after reflux surgery.)

Kandulski, A, Malfertheiner, P. "GERD in 2010: diagnosis, novel mechanisms of disease and promising agents". Nature Rev Gastroenterol Hepatol. vol. 8. 2011. pp. 73-4.

(A review paper that updates on some new approaches to GERD including attempts to develop promotility agents.)

Shaheen, NJ, Falk, GW, Iyer, PG, Gerson, L. " Diagnosis and management of Barrett’s esophagus". Am J Gastroenterol. vol. 111. 2016. pp. 30-50.

(Most updated guidelines on the approach to Barrett’s esophagus.)
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