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Management of gastroesophageal reflux disease.

Abstract: Gastroesophageal reflux disease is the most common and expensive digestive disease with complex and multi-factorial pathophysiologic mechanisms. Transient inappropriate relaxation of the lower esophageal sphincter is the predominant mechanism in the majority of patients with mild to moderate disease. Hiatal hernias and a reduced lower esophageal sphincter pressure have a significant role in patients with moderate to severe disease. Typical manifestations of gastroesophageal reflux disease include heartburn, regurgitation, and dysphagia. Atypical symptoms, such as noncardiac chest pain, pulmonary manifestations of asthma, cough, aspiration pneumonia, or ENT manifestations of globus and laryngitis, can be seen in patients with or without typical symptoms of gastroesophageal reflux disease. Endoscopy and ambulatory pH tests are best to evaluate the anatomic and physiologic impact of gastroesophageal reflux disease. Complications of chronic gastroesophageal reflux disease include peptic strictures and Barrett metaplasia. Barrett esophagus is a major risk factor for esophageal adenocarcinoma, and upper endoscopy with surveillance biopsies is recommended for patients with Barrett esophagus. Medical therapy with anti-secretory agents ([H.sub.2] blockers and proton pump inhibitors) is effective for most patients with gastroesophageal reflux disease. Surgical fundoplications and endoscopic treatment modalities are mechanical treatment options for patients with gastroesophageal reflux disease.

Key Words: gastroesophageal reflux disease, Barrett esophagus


Gastroesophageal reflux disease (GERD) is due to the symptoms or tissue injury resulting from refluxed gastric contents into the esophagus. Gastroesophageal reflux disease is the most expensive digestive disease in the United States with an estimated direct cost of more than 10 billion dollars per year. A Gallop poll survey (1) revealed that 7% of the population experienced heartburn symptoms daily, 14% weekly, and 44% monthly. Most sufferers self medicate with over-the-counter antacids and antisecretory agents. Nonerosive reflux disease (also known as endoscopy negative reflux disease) is seen in the majority of patients with GERD. Only one in four people have discussed their symptoms with a physician. In the past decade, antisecretory agents, such as [H.sub.2] blockers and proton pump inhibitors, have been made available over the counter.

Clinical Manifestations

The typical manifestations of gastroesophageal reflux disease are heartburn, regurgitation, and dysphagia. Heartburn is defined as a retrosternal burning discomfort located in the epigastric area that may radiate up toward the neck, which may occur in the postprandial period, especially after a high fat or large volume meal. Patients often note that postural changes, such as bending over, will exacerbate their symptoms. In addition, symptoms can be aggravated by ingestion of certain foods or beverages, such as tomato sauce, peppermint, chocolate, coffee, tea, and alcohol. Patients will experience transient relief with the use of antacids. Atypical manifestations of GERD refer to symptoms that are extra-esophageal (pulmonary or ENT manifestations) in origin or esophageal in nature but not typical GERD symptoms (non-cardiac chest pain). The atypical symptoms of GERD include ENT manifestations of the laryngitis and globus, pulmonary manifestations of chronic cough, asthma, and aspiration pneumonia, and noncardiac chest pain.


Physiologic reflux of gastric contents into the esophagus occurs in the postprandial state. Pathologic reflux occurs when the refluxate overcomes the antireflux barriers. The antireflux barrier at the gastroesophageal junction (GEJ) is anatomically and physiologically complex and vulnerable to a number of potential mechanisms of reflux. The two main patterns of lower esophageal sphincter (LES) dysfunction are hypotensive LES and pathologic transient LES relaxations (tLESRs). (2,3) Anatomic disruption of the GEJ, commonly associated with a hiatal hernia, is another mechanism that contributes to the pathogenesis of reflux disease by impairing LES function. Transient LES relaxations account for the majority of reflux events in individuals with a normal LES pressure and clinically mild reflux disease. Low LES pressures and hiatal hernias are the predominant mechanisms for patients with severe reflux disease. (4)

It is important to recognize that gastric factors can play a significant role in gastroesophageal reflux disease due to delayed gastric emptying or gastroparesis. (5) Increased gastric distention can cause an increase in transient LES relaxations and volume of refluxate, particularly in patients with GERD and hiatal hernias. (6) Delayed gastric emptying may be present in approximately 15% of patients with GERD and gastroparesis is underdiagnosed.

Patients with gastroparesis and GERD often present with concomitant nausea, vomiting, or early satiety symptoms. These patients may not respond to antisecretory agents alone, as the refluxate can contain bile and other digestive enzymes in addition to gastric acid. Gastroparesis should be suspected in patients with the acute or subacute symptom onset of gastroesophageal reflux disease, particularly after an episode of viral upper respiratory infection or gastroenteritis. The natural history of GERD with gastroparesis is that the majority of patients will achieve symptomatic resolution, although some will need treatment with prokinetic agents. Antisecretory agents may offer some symptomatic relief and reduce gastric volume. Dietary changes such as low fat, frequent, and small meals may also be helpful in controlling symptoms.

There are other factors that decrease LES pressure and contribute to gastroesophageal reflux disease. These include medications such as theophylline, calcium channel blockers, estrogens, progesterone, anticholinergics, diazepam, narcotics, and [beta]-agonists including inhalers (Table 1). Certain foods, beverages, and behaviors will cause heartburn by reducing LES pressure. Fatty foods, peppermint, chocolate, caffeinated beverages, and alcohol, as well as smoking, can all lead to decreased LES pressure.


Complications from chronic GERD include bleeding from esophageal erosions or ulceration, stricture formation, and Barrett esophagus. However, frequent, severe GERD is a major risk factor for esophageal adenocarcinoma (7)--the second fastest growing cancer in the United States.

Barrett esophagus is the most important risk factor for the development of esophageal adenocarcinoma. Barrett esophagus is defined as the development of a specialized columnar epithelium that replaces the normal squamous epithelium of the esophagus. (8) Approximately 8% of patients have adenocarcinoma at the time of the initial diagnosis of Barrett esophagus. Most new cases of esophageal cancer have not had a previous diagnosis of Barrett esophagus, suggesting the need for more effective screening strategies. (9)

Barrett esophagus is initiated by GERD, leading to reflux esophagitis with injury of the squamous epithelium. There is healing of this injured epithelium with specialized columnar epithelium and intestinal metaplasia (Barrett epithelium). This epithelium may be more protective than esophageal epithelium against further injury by gastric acid. However, this metaplastic epithelium is associated with an increased risk for esophageal carcinoma.

The epidemiology of Barrett esophagus shows a male to female ratio of approximately 3:1. The average age of patients at the time of diagnosis is 55 years. (10) Barrett esophagus is more likely to be found in patients with more severe GERD. In patients who undergo routine endoscopy, approximately 1 to 2% of patients will have Barrett esophagus. In contrast, the prevalence of Barrett esophagus in patients with erosive esophagitis is approximately 10%; in patients with peptic strictures of the esophagus, the prevalence is almost 30%.

Barrett esophagus cannot be detected on clinical grounds, as there are no specific symptoms of Barrett esophagus that distinguish this condition clinically from patients with GERD without Barrett esophagus. In addition, this condition cannot be detected by radiologic studies such as a barium swallow. The gold standard for the diagnosis of Barrett esophagus is upper endoscopy with biopsy of the gastroesophageal junction. Barrett esophagus is a histopathologic diagnosis in the appropriate endoscopic appearance. The current recommendation for patients who have long standing (five to ten years) gastroesophageal reflux disease is to undergo upper endoscopic surveillance, (11) even if GERD symptoms are controlled. In addition, patients over the age of 50 with GERD should have screening for Barrett esophagus. In patients with good symptom control and a negative Barrett esophagus screen, further endoscopic surveillance is not recommended.

In patients who have the findings of Barrett esophagus but no evidence of dysplasia, an upper endoscopy and biopsy should be repeated in one year to confirm negative dysplasia (Fig.). If the findings are stable, the interval can be lengthened to three and five years. At the current time, the exact recommendation for an optimal follow-up interval is debated, as follow-up endoscopies and biopsies in patients without dysplasia have not been proven to be an overall cost-effective screening technique. (11-13)

Patients who have low-grade dysplasia at the time of endoscopy are recommended to undergo yearly surveillance endoscopies. Some patients who have initial findings of low-grade dysplasia may turn out to have regenerative changes and not true dysplasia, whereas others may advance to high-grade dysplasia.

In patients with findings of high-grade dysplasia, the histopathologic diagnosis should be confirmed by an expert pathologist and a repeat endoscopy with multiple biopsies. If high-grade dysplasia is confirmed, it is recommended to proceed with esophagectomy. In patients with endoscopic findings of high-grade dysplasia, up to 30% of patients will have adenocarcinoma present at the time of surgical resection. This remains a controversial area, as some physicians prefer to perform endoscopies every three months in these patients and only proceed to surgery if cancer is found. The difficulty with this management strategy is that it is possible that cancer will not be recognized by the surveillance endoscopy program and there may be a delay before definitive therapy. (14)


The treatment goals of patients with Barrett esophagus are to eliminate the symptoms of GERD and prevent GERD complications. (15) If GERD is well controlled, then progression to malignancy may be prevented. (16) Patients with Barrett esophagus may require higher than usual doses of medication to control their symptoms, as they tend to have more severe degrees of GERD. Because of the severity of the GERD symptoms, patients may require antireflux surgery to control their symptoms. It is important to note that antireflux surgery does not reduce the risk of adenocarcinoma in patients who have Barrett esophagus and continued surveillance of the Barrett esophagus after surgery is required, even if the surgery is successful and the patient is asymptomatic. (17-19)

There have recently been attempts to reverse the changes of Barrett esophagus by endoscopically applying ablative therapies. These therapies reverse Barrett esophagus by injuring the Barrett lining and promoting repair of the injured lining with normal squamous epithelium. There have been various techniques used to date, including use of cautery, laser, and photodynamic therapy. (20,21) Although short-term results are promising and regeneration of normal squamous epithelium can be achieved, long-term results are lacking. There has not been proven to be a decrease in incidence in the development of esophageal cancer in patients who have undergone ablative therapies, although squamous epithelium can replace the Barrett epithelium. In addition, there have been a few worrisome reports of squamous epithelium growing on top of Barrett columnar epithelium and an inability to provide surveillance postablative therapy. (22) Thus, at the current time, this technique should be primarily performed in clinical trials.


Classic GERD can be diagnosed by symptomatic history and confirmed by a complete response to medical therapy. (23) In general, diagnostic testing is reserved for patients who fail to respond to a trial of adequate medical therapy or for patients who have alarm symptoms of GERD. (24) The alarm symptoms in GERD are weight loss, dysphagia, advanced age, gastrointestinal bleeding, anemia, occult blood in the stool, or those patients with an atypical presentation. The current diagnostic tests for GERD include x-ray studies, upper endoscopy, pH probe studies, and esophageal manometry testing (Table 2).

Radiologic studies can detect moderate to severe esophagitis, strictures, hiatal hernias, and tumors. The x-ray studies that are most commonly used are the barium swallow that only examines the esophagus, and the upper GI series that examines the esophagus, stomach, and upper small intestine. The primary utility of x-ray studies in GERD is to rule out the presence of other diseases in patients in whom a low clinical suspicion of significant disease is present. These studies can help exclude peptic ulcer disease and tumors. In addition, x-ray studies can be helpful in the evaluation of a patient with dysphagia, although most patients will subsequently need upper endoscopy. Overall, radiologic studies are noninvasive, widely available, and relatively inexpensive compared with endoscopy. However, they are less sensitive and specific than upper endoscopy and require operator skill (which may be reduced with advances in this era of cross-sectional imaging). In addition, patients without GERD will at times have evidence of reflux of barium from the stomach into the esophagus during the examination, and this finding by itself is of little clinical significance. (25)

Upper endoscopy involves the insertion of an endoscope into the mouth and direct inspection of the esophagus, stomach, and proximal duodenum. In addition to excluding the presence of other diseases such as tumors and peptic ulcers, it can detect and grade the severity of esophagitis. (26) It allows for the detection and biopsy of possible Barrett esophagus (which would not be seen on x-ray studies). If a patient has dysphagia and a stricture is detected, dilation of the stricture can be performed during the same procedure. Upper endoscopy is the best test in the evaluation of patients with GERD who need anatomic studies due to its high accuracy rate. Upper endoscopy is the test of choice in patients with alarm symptoms; however, it is relatively invasive and expensive compared with x-ray studies.

Intraesophageal ambulatory pH monitoring utilizes a probe that can record the distal esophageal pH continuously for 24 hours. This technique allows for a correlation of symptoms with reflux episodes. It records the timing, length, and number of reflux episodes. The results are compared with a normal range of nonpathological reflux: there is normally a small amount of acid reflux, such that the percentage of time that the pH is less than 4.0 in the distal esophagus should be less than 4%. Intraesophageal pH probe monitoring is the most sensitive test to detect the presence of intraesophageal acid. (27)

Monitoring by pH probes is useful in patients who have typical GERD symptoms but are unresponsive to therapy (to determine if the diagnosis is correct or if additional medical therapy is required). It is extremely helpful in patients with atypical GERD symptoms, such as noncardiac chest pain, laryngitis, asthma, and chronic cough, to determine whether these symptoms are due to GERD. Patients with extraesophageal manifestations of GERD do not always have the typical manifestations of GERD (heartburn or regurgitation), making this diagnosis challenging. It is also an important test to be done in the preoperative evaluation of a patient who is considering surgery for GERD, unless erosive esophagitis is seen on endoscopy.

The discomfort associated with a nasal probe prompted the development of a wireless pH monitoring system. A system called the Bravo pH system (Medtronic Inc.) allows for a wireless capsule to be attached to the distal esophageal mucosa during an upper endoscopy. The pH monitoring lasts for 48 hours, compared with 24 hours with the conventional pH probe. Patients typically have less discomfort, as there is no need for a tube to be maintained in place. The main disadvantage of this system is that up to 10% of patients will experience some discomfort due to the presence of the pH capsule or may feel that the capsule is present. Capsule loss can occur with the capsule becoming displaced before the pH study is complete.

Esophageal manometry measures the pressure within the lumen of the esophagus with a nasal catheter. The primary use of this technique is to diagnose esophageal motility disorders, such as achalasia, diffuse esophageal spasm, or scleroderma. However, the test is useful in the preoperative assessment of esophageal motility in patients undergoing fundoplication surgery. Manometry is not indicated for the diagnosis and management of most patients who have GERD. (28)


The goals of treatment for GERD are to resolve symptoms, heal esophagitis, and prevent any complications. Once in remission, the goal is to maintain remission from symptoms and prevent further tissue injury.

A cornerstone of GERD treatment is lifestyle modifications. (29) Patients are instructed to avoid foods that can exacerbate their symptoms. Patients should avoid lying down for two to three hours after eating, as ingested food may remain in the stomach and contribute to reflux. Smaller and frequent meals are also recommended. Elevation of the head of the bed by six inches (blocks underneath the front feet of the bed) uses gravity to reduce reflux. Patients should be instructed to stop smoking and reduce weight, which can be critical to reduce or eliminate symptoms. The current epidemic of obesity is a major contributing factor to the increasing number of persons with GERD.

Medical treatment is characterized by antisecretory agents. [H.sub.2] blockers, taken twice daily, are approximately 75% effective in patients with mild to moderate degrees of esophagitis. However, in patients with moderate to severe degrees of esophagitis, these medications are only 50% effective in healing esophagitis. (30) [H.sub.2] blockers are appropriate for patients with mild to moderate GERD and remain a major treatment modality for GERD.

The proton pump inhibitors act by blocking the hydrogen potassium ATPase on the apical surface of the parietal cell and are typically given once a day. Side effects can occur in up to 5% of patients, which include headaches and diarrhea. Proton pump inhibitors are indicated as initial therapy in patients with moderate to severe GERD and in patients with complications of GERD such as bleeding and strictures. They are also effective for the treatment of mild GERD.

The safety of long-term proton pump inhibitor (PPI) therapy has been shown with the treatment of millions of patients for the past twenty years. During initial tests, gastric carcinoids were seen in animal models. (31) This has not subsequently been demonstrated to occur in humans. (32) There is also a theoretical concern about interference with nutrient absorption (especially calcium, iron and protein) due to a significant decrease in gastric acid production; however, there has not been a demonstrable reduction in these nutrients. (33) There has been a modest reduction of vitamin [B.sub.12] levels with long term PPI use, which may be due to decrease in protein-bound vitamin [B.sub.12] absorption. (34,35) Therefore, vitamin [B.sub.12] levels should be periodically monitored in patients who are on continuous PPI therapy for years. Clinically insignificant bacterial overgrowth of the small bowel has been noted to occur with chronic PPI use. (36) However, the bacterial overgrowth can become significant if there is an underlying motility disorder of the small intestine or surgical alteration of anatomy. Recently, the use of PPIs has been associated with increased rates of community-acquired pneumonias (37) and Clostridium difficile infection. (38)

Once patients have achieved remission from clinical symptoms, most should have a trial of medication withdrawal. (39,40) Symptom relief should first be sustained for two to three months before medications are attempted to be withdrawn. If a patient is on a proton pump inhibitor, the medication can either be tapered to every other day, to a reduced dose (if possible), or switched to a [H.sub.2] blocker. Most patients who are treated with [H.sub.2] blockers are on twice daily medications and the initial tapering should be to once a day. If a patient tolerates a taper for two to four weeks without an increase in symptoms, the dosage can be further decreased or the medication can be discontinued. However, if a patient experiences recurrent symptoms, the medication regimen should be resumed until symptom resolution is achieved.

Therapy for gastroesophageal reflux disease is chronic and long term in most patients as the underlying disorder is dysfunction of the lower esophageal sphincter, which is not directly affected by current available therapies. More than 80% of patients with erosive esophagitis will relapse if their therapy is stopped. Thus, the same medication that induces remission is usually required in the same dosage to maintain remission. (41-43)

Mechanical Treatment Options

Although most patients with GERD will be successfully managed with lifestyle modifications and medical therapy, some patients may have persistent symptoms despite treatment. Antireflux surgeries and endoscopic treatment modalities can be used as primary therapy for patients who achieve a good clinical response but wish to discontinue medications, or for the treatment of patients who have failed medical therapy.

Gastroesophageal reflux surgery has been performed since the early 50s. The most widely performed procedure is the Nissen fundoplication. Other procedures such as Hill, Belsy, and Toupe repairs have all been devised to offer antireflux surgeries for specific patient populations. There have been a number of studies that have found a symptomatic response of 80 to 90% with the open fundoplication procedure. For laparoscopic fundoplication, a similar success rate of 85 to 90% has been reported. When patients are carefully selected, control of symptoms at 10-year follow-up after surgery can be as high as 90%. However, it has been noted that 62% of patients are back on medications 10 years after antireflux surgery. (44) Complications following fundoplication include dysphagia, chest pain, gas-bloat syndrome, postoperative flatulence, and vagal nerve injuries leading to gastroparesis and diarrhea. The prevalence of these postoperative complications ranges between 5 to 20%. Postoperative dysphagia ranges from 0 to 18% with early dysphagia occurring in approximately 20% of patients and late dysphagia occurring in 6% of patients at two years. For those patients who fail fundoplication initially, a second antireflux surgery can be performed. However, if the second fundoplication fails there is no benefit from additional surgery.

For endoscopic antireflux treatments, there are two available types of therapy: radio frequency energy and suturing of the gastroesophageal junction. The Stretta catheter is a radio-frequency ablation device (Curon Medical, Freemont, CA). (45,46) The EndoCinch device (Bard Inc., Billerica, MA) is an endoscopic suturing device. (47-49) Patients initially have an 85 to 90% complete response rate to these therapies and at 12 months, 66% of patients are off proton pump inhibitors and 62% of patients are off all medications. These procedures offer a nonsurgical alternative to patients with gastroesophageal reflux disease. An injectable treatment called Enteryx (Boston Scientific, Natick, MA) was approved by the FDA in 2003, but was recently withdrawn from the market due to safety concerns.

Complications associated with these endoscopic procedures include aspiration pneumonia, perforation, mediastinitis, and rarely, death. For injectable bulking material there have been reports of death due to aortic injection of the bulking material. Two to three year follow-up results of these endoscopic procedures have varied from a 40% success rate to a 60 to 70% success rate. Future studies are needed to further understand the mechanism of these endoscopic reflux treatments and improve the efficacy and durability of these procedures.

Mechanical treatment of gastroesophageal reflux disease can be curative for patients provided the antireflux effects are achieved. Surgical or endoscopic approaches can be offered to patients; however, the determination of the optimal approach for patients needs to be individualized.


Gastroesophageal reflux disease is the most common gastrointestinal disorder. It is predominantly due to dysfunction of the lower esophageal sphincter, although other factors including medications, diet, and gastric emptying are important. Clinical manifestations may be typical or atypical. Barrett esophagus is due to GERD and the replacement of squamous epithelium with a specialized columnar epithelium. Barrett esophagus is the most important risk factor for esophageal adenocarcinoma, and surveillance with biopsy is recommended for diagnosis and to detect dysplasia. Endoscopy and ambulatory pH monitoring are the best diagnostic modalities for gastroesophageal reflux disease. Medical therapy is effective but patients need to be treated with medications that are sufficiently powerful to relieve their symptoms. Surgical fundoplications and endoscopic therapies are treatment options, but the long-term efficacy of these therapies is unclear at this time.


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Destroy the family, you destroy the country.
--Vladimir Ilyich Lenin

Julia J. Liu, MD, and John R. Saltzman, MD

From the Harvard Medical School, Brigham and Women's Hospital, Boston, MA.

Reprint requests to John R. Saltzman, MD, Gastroenterology Division, Brigham and Women's Hospital, 75 Francis Street. Boston, MA 02115. Email:

Accepted March 15, 2006.

Drs. Liu and Saltzman have no disclosures to declare.


* Understanding the pathophysiology of gastroesophageal reflux disease leads to improved patient management through the identification and treatment of contributing factors.

* Gastroesophageal reflux disease may have typical symptoms of heartburn and regurgitation or may present in an atypical manner with ENT symptoms, pulmonary manifestations or noncardiac chest pain.

* Screening for Barrett esophagus should be considered in patients with long-standing gastroesophageal reflux disease, as it is the most important risk factor for esophageal adenocarcinoma.

* Testing is not required in most patients with suspected gastroesophageal reflux disease, but patients with alarm symptoms or persistent symptoms despite medical therapy should undergo upper endoscopy and/or ambulatory pH studies.

* Medical therapy is safe and effective in most patients with gastroesophageal reflux disease.
Table 1. Common medications that decrease lower esophageal sphincter

[beta]-agonists including inhalers
Calcium channel blockers

Table 2. Relative value of diagnostic tests in GERD

 Ambulatory pH
 Barium swallow Endoscopy monitoring Manometry

Dysphagia ++ +++ - +
Mucosal injury + +++ - -
Quantitate reflux + - +++ -
Atypical symptoms + ++ +++ -
Presurgery + +++ +++ +++
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Title Annotation:CME Topic; medical research; includes related article "Key Points" and statistical tables
Author:Saltzman, John R.
Publication:Southern Medical Journal
Geographic Code:1U600
Date:Jul 1, 2006
Previous Article:Southern Medical Journal CME topic: management of gastroesophageal reflux disease.
Next Article:CME questions: management of gastroesophageal reflux disease.

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