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Gastroesophageal Reflux Disease

Gastroesophageal Reflux DiseaseDefinition

Gastroesophageal reflux refers to the retrograde movement of gastric contents from the stomach into the esophagus. Gastroesophageal reflux disease refers to any symptomatic clinical condition or histologic alteration that results from episodes of gastroesophageal reflux. When the esophagus is repeatedly exposed to refluxed material for prolonged periods, inflammation of the esophagus (reflux esophagitis) can occur and in some cases it progresses to erosion of the esophagus (erosive esophagitis).

Pathophysiology

  • In many patients with Gastroesophageal reflux disease, the problem is not excessive acid production but that the acid produced spends too much time in contact with the esophageal mucosa.
  • Gastroesophageal reflux is often caused by defective lower esophageal sphincter  pressure or function. Patients may have decreased lower esophageal sphincter pressures related to spontaneous transient lower esophageal sphincter relaxations, transient increases in intra-abdominal pressure, or an atonic lower esophageal sphincter. A variety of foods and medications may decrease lower esophageal sphincter pressure (Table Foods and Medications that May Worsen Gastroesophageal reflux disease Symptoms).
TABLE. Foods and Medications that May Worsen Gastroesophageal reflux disease Symptoms
Decreased lower esophageal sphincter pressure
Foods
Fatty meal Garlic
Carminatives (peppermint, spearmint) Onions
Chocolate Chili peppers
Coffee, cola, tea  
Medications
Anticholinergics Isoproterenol
Barbiturates Narcotics (meperidine, morphine)
Benzodiazepines (diazepam)
Caffeine Nicotine (smoking)
Dihydropyridine calcium channel blockers Nitrates
Dopamine Phentolamine
Estrogen Progesterone
Ethanol Theophylline
Direct irritants to the esophageal mucosa
Foods
Spicy foods Tomato juice
Orange juice Coffee
Medications
Alendronate Quinidine
Aspirin Potassium chloride
Iron  
Nonsteroidal anti-inflammatory drugs  
  • Problems with other normal mucosal defense mechanisms may also contribute to the development of Gastroesophageal reflux disease, including prolonged acid clearance time from the esophagus, delayed gastric emptying, and reduced mucosal resis- tance.
  • Aggressive factors that may promote esophageal damage upon reflux into the esophagus include gastric acid, pepsin, bile acids, and pancreatic enzymes. The composition and volume of the refluxate and the duration of exposure are the most important aggressive factors in determining the consequences of gastroesophageal reflux.

Clinical presentation

  • The hallmark symptom of gastroesophageal reflux and esophagitis is heartburn, or pyrosis. It is classically described as a substernal sensation of warmth or burning that may radiate to the neck. It is waxing and waning in character and is often aggravated by activities that worsen gastroesophageal reflux (e.g., recumbent position, bending over, eating a high-fat meal). Other symptoms include water brash (hypersalivation), belching, and regurgitation.
  • Atypical symptoms include nonallergic asthma, chronic cough, hoarseness, pharyngitis, dental erosions, and chest pain that mimics angina.
  • Inadequately treated Gastroesophageal reflux disease may lead to complications from long-term acid exposure such as continual pain, dysphagia, and odynophagia. Other severe complications include esophageal strictures, hemorrhage, Barrett’s esophagus, and esophageal adenocarcinoma.

Diagnosis

  • The most useful tool in the diagnosis of gastroesophageal reflux is the clinical history, including both presenting symptoms and associated risk factors.
  • Endoscopy is the preferred technique for assessing the mucosa for esophagitis and complications such as Barrett’s esophagus. It allows visualization and biopsy of the esophageal mucosa, but the mucosa may appear relatively normal in mild cases of Gastroesophageal reflux disease.
  • Barium radiography is less expensive than endoscopy but lacks the sensitivity and specificity needed to accurately determine the presence of mucosal injury or to distinguish Barrett’s esophagus from esophagitis.
  • Twenty-four-hour ambulatory pH monitoring is useful in patients who continue to have symptoms without evidence of esophageal damage, patients who are refractory to standard treatment, and patients who present with atypical symptoms (e.g., chest pain or pulmonary symptoms). The test helps to correlate symptoms with abnormal esophageal acid exposure, documents the percentage of time the intraesophageal pH is low, and determines the frequency and severity of reflux.
  • Omeprazole given empirically as a «therapeutic trial» for diagnosing Gastroesophageal reflux disease may be as beneficial as ambulatory pH monitoring while also being less expensive, more convenient, and more readily available. However, there is no standard dosing regimen; standard doses or double-dose omeprazole have been used.
  • Esophageal manometry to evaluate motility should be performed in any patient who is a candidate for antireflux surgery. It is useful in determining which surgical procedure is best for the patient.

Desired outcome

The goals of treatment are to alleviate or eliminate symptoms, decrease the frequency and duration of gastroesophageal reflux, promote healing of the injured mucosa, and prevent the development of complications.

Treatment

General principles

  • Therapeutic modalities are targeted at reversing the pathophysiologic abnormalities. These include decreasing the acidity of the refluxate, decreasing the gastric volume available to be refluxed, improving gastric emptying, increasing lower esophageal sphincter pressure, enhancing esophageal acid clearance, and protecting the esophageal mucosa.
  • Treatment is categorized into the following modalities:
    • Phase I: lifestyle changes and patient-directed therapy with antacids and/or over-the-counter (OTC) H2-receptor antagonists (H2RA) or proton pump inhibitors (Proton pump inhibitors).
    • Phase II: pharmacologic interventions primarily with standard or high-dose acid-suppressing agents.
    • Phase III: interventional therapies (antireflux surgery or endoluminal therapies).
  • The initial therapeutic modality depends in part on the patient’s condition (symptom frequency, degree of esophagitis, presence of complications). Historically, a step-up approach has been used, starting with phase I and then progressing through phases II and III if necessary. A step-down approach is also effective, starting with a Proton pump inhibitor once or twice daily instead of an H2RA and then stepping down to the lowest acid suppression needed to control symptoms.
  • Lifestyle modifications should be started initially and continued throughout the treatment course.

Antacids and antacid-alginic acid products

  • Antacids provide immediate, symptomatic relief for mild Gastroesophageal reflux disease and are often used concurrently with other acid-suppressing therapies. Patients who require frequent use for chronic symptoms should receive prescription-strength acid-suppressing therapy instead.
  • An antacid with alginic acid (Gaviscon) is not a potent acid neutralizing agent but it does form a viscous solution that floats on the surface of the gastric contents. This serves as a protective barrier for the esophagus against reflux of gastric contents and reduces the frequency of reflux episodes. Efficacy data indicating endoscopic healing are lacking.
  • Antacids have a short duration, which necessitates frequent administration throughout the day to provide continuous acid neutralization. Typical doses are 2 tablets or 1 tablespoonful 4 times daily (after meals and at bedtime). Night-time acid suppression cannot be maintained with bedtime doses of antacids.

RanitidineH2-Receptor Antagonists: Cimetidine, Ranitidine, Famotidine, and Nizatidine

  • The H2RAs in divided doses are effective for treating mild to moderate Gastroesophageal reflux disease. Low-dose OTC products may be beneficial for symptomatic relief of intermittent heartburn and for preventing meal-provoked heartburn in patients with mild disease. For nonerosive disease, H2RAs are given in standard doses twice daily. For nonresponding patients and those with erosive disease, higher doses and/or 4 times daily dosing provide better acid control.
  • The efficacy of H2RAs in Gastroesophageal reflux disease is highly variable; although standard doses produce symptomatic improvement in about 60% of patients, endoscopic healing rates average only about 50%. The more severe the esophageal damage, the poorer the response. Higher doses and prolonged courses (8 weeks or more) are frequently required.
  • The H2RAs are generally well tolerated. The most common adverse effects are headache, somnolence, fatigue, dizziness, and either constipation or diarrhea. Cimetidine may inhibit the metabolism of theophylline, warfarin, phenytoin, nifedipine, and propranolol, among other drugs.
  • Because all of the H2RAs are equally efficacious, selection of the specific agent should be based on differences in pharmacokinetics, safety profile, and cost.

EsomeprazoleProton Pump Inhibitors: Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and Rabeprazole

  • Proton pump inhibitors block gastric acid secretion by inhibiting H+/K+-ATPase in gastric parietal cells, which results in profound and long-lasting antisecretory effects.
  • Proton pump inhibitors are superior to H2RAs in patients with moderate to severe Gastroesophageal reflux disease, including those with erosive esophagitis, complicated symptoms (Barrett’s esophagus, strictures), and nonerosive Gastroesophageal reflux disease with moderate to severe symptoms. Relapse is common in these patients, and long-term maintenance therapy is generally indicated. Symptomatic relief is seen in approximately 83% of patients, and endoscopic healing rates are about 78% at 8 weeks.
  • Proton pump inhibitors are also efficacious in patients refractory to H2RAs and are more cost effective than H2RAs in patients with severe disease.
TABLE. Therapeutic Approach to Gastroesophageal reflux disease
Patient Presentation Recommended Treatment Regimen Comments
Phase I
Intermittent, mild heartburn A. Lifestyle Changes
PLUS
Lifestyle changes should be started initially and continued throughout the course of treatment.
B. Antacids

  • Maalox or Mylanta 30 mL as needed or after meals and at bedtime
  • Maalox TC 5-10 mL as needed or after meals and at bedtime
  • Gaviscon 2 tabs after meals and at bedtime
  • Calcium carbonate (500 mg) 2-4 tablets as needed

AND/OR
C. Low-dose OTC H2-receptor antagonists (each taken up to twice daily)

  • Cimetidine 200 mg
  • Famotidine 10 or 20 mg
  • Nizatidine 75 mg
  • Ranitidine 75 mg

OR
OTC proton pump inhibitor (taken once daily)

  • Omeprazole 20 mg
If symptoms are unrelieved with lifestyle changes and OTC medications after 2 wk, begin pharmacologic therapy (phase II therapy).
Phase II
Symptomatic relief of Gastroesophageal reflux disease
A. Lifestyle modifications
PLUS
For typical symtoms, treat empirically with phase II therapy.
B. Standard doses of H2-receptor antagonists for 6-12 wk

  • Cimetidine 400 mg twice daily
  • Famotidine 20 mg twice daily
  • Nizatidine 150 mg twice daily
  • Ranitidine 150 mg twice daily

OR
B. Proton pump inhibitors for 4-8 wk. All are given once daily.

  • Esomeprazole 20 mg
  • Lansoprazole 15 mg
  • Omeprazole 20 mg
  • Pantoprazole 40 mg
  • Rabeprazole 20 mg
Mild Gastroesophageal reflux disease can usually be treated effectively with H2-receptor antagonists. Patients with moderate to severe symptoms should receive a proton pump inhibitor as initial therapy. If symptoms are relieved, treat recurrences on an as-needed basis.
If symptoms recur frequently, consider maintenance therapy (MT) with the lowest effective dose. Note: Most patients will require standard doses for MT.
 
Healing of erosive esophagitis or treatment of patients presenting with moderate to severe symptoms or complications A. Lifestyle modifications
PLUS
B. Proton pump inhibitors for 4-16 wk (up to twice daily)

  • Esomeprazole 20-40 mg daily
  • Lansoprazole 30 mg daily
  • Omeprazole 20 mg daily
  • Rabeprazole 20 mg daily
  • Pantoprazole 40 mg daily

OR

For atypical symtoms, obtain endoscopy (if possible) to evaluate mucosa. Give a trial of a proton pump inhibitor or an H2-receptor antagonist. If symptoms are relieved, consider MT. Proton pump inhibitors are the most effective maintenance therapy in patients with atypical symptoms, complicated symptoms, and erosive disease.  
B. High-dose H2-receptor antagonist for 8-12 weeks

  • Cimetidine 400 mg four times daily or 800 mg twice daily
  • Famotidine 40 mg twice daily
  • Nizatidine 150 mg 4 times daily
  • Ranitidine 150 mg 4 times daily
Patients not responding to phase II therapy, including those with persistent atypical symptoms, should be evaluated via ambulatory 24-h pH monitoring to confirm the diagnosis of Gastroesophageal reflux disease (if possible). If Gastroesophageal reflux disease is present, consider phase III therapy.  
Phase III Interventional therapies (antireflux surgery or endoluminal therapies) Manometry should be performed in anyone who is a candidate for surgery.  
TABLE. Nonpharmacologic Treatment of Gastroesophageal reflux disease with Lifestyle Modifications
  • Elevate the head of the bed (increases esophageal clearance). Use 6- to 8-inch blocks under the head of the bed. Sleep on a foam wedge
  • Dietary changes
    Avoid foods that may decrease lower esophageal sphincter pressure (fats, chocolate, alcohol, peppermint, and spearmint)
    Avoid foods that have a direct irritant effect on the esophageal mucosa (spicy foods, orange juice, tomato juice, and coffee)
    Include protein-rich meals in diet (augments lower esophageal sphincter pressure)
    Eat small meals and avoid eating immediately prior to sleeping (within 3 h if possible) (decreases gastric volume)
    Weight reduction (reduces symtoms)
  • Stop smoking (decreases spontaneous esophageal sphincter relaxation)
  • Avoid alcohol (increases amplitude of the lower esophageal sphincter, peristaltic waves, and frequency of contraction)
  • Avoid tight-fitting clothes
  • Discontinue, if possible, drugs that may promote reflux (calcium channel blockers, β- blockers, nitrates, theophylline)
  • Take drugs that have a direct irritant effect on the esophageal mucosa with plenty of liquid if they cannot be avoided (tetracyclines, quinidine, and KCl, iron salts, aspirin, nonsteroidal anti-inflammatory drugs)
  • Proton pump inhibitors are usually well tolerated. Potential adverse effects include headache, dizziness, somnolence, diarrhea, constipation, and nausea. All Proton pump inhibitors can decrease the absorption of drugs such as ketoconazole or itraconazole that require an acidic environment for absorption. Other drug interactions vary with each agent.
  • The Proton pump inhibitors degrade in acidic environments and are therefore formulated in delayed-release capsules or tablets. Lansoprazole, esomeprazole, and omeprazole contain enteric-coated (pH-sensitive) granules in a capsule form. In patients unable to swallow the capsules, the contents can be mixed in applesauce or placed in orange juice. In patients with nasogastric tubes, the contents should be mixed in 8.4% sodium bicarbonate solution. Esomeprazole can be mixed with water. Lansoprazole is also available in packets for oral suspension and delayed-release orally disintegrating tablets; neither product should be placed through nasogastric tubes. Patients taking pantoprazole or rabeprazole should be instructed not to crush, chew, or split the delayed-release tablets.
  • Pantoprazole and lansoprazole intravenous (intravenous) injection are indicated for the short-term treatment of Gastroesophageal reflux disease (e.g., up to 7 to 10 days) in patients unable to take oral therapy. However, intravenous formulations are not more effective than oral Proton pump inhibitors and are more expensive.
  • Patients should be instructed to take oral Proton pump inhibitors in the morning 15 to 30 minutes before breakfast to maximize efficacy, because these agents inhibit only actively secreting proton pumps. If dosed twice daily, the second dose should be taken approximately 10 to 12 hours after the morning dose and prior to a meal or snack.
  • All of the Proton pump inhibitors are safe and effective, and the choice of a particular agent is likely to be based on cost.

Prokinetic agents

  • Cisapride has efficacy that is similar to that of the H2RAs in mild esophagitis. However, it costs more than H2RAs and offers no real advantage, especially in patients with normal gastrointestinal motility. It is no longer available for routine use because of life-threatening arrhythmias when combined with certain medications and other disease states. Physicians must register as investigators with the manufacturer (Janssen), and patients must be enrolled just as with any other study protocol.
  • Metoclopramide, a dopamine antagonist, increases lower esophageal sphincter pressure in a dose-related manner and accelerates gastric emptying. Unlike cisapride, it does not improve esophageal clearance.
  • Metoclopramide may provide symptomatic improvement for some patients with Gastroesophageal reflux disease, but substantial evidence of endoscopic healing is lacking.
  • Tachyphylaxis and side effects limit the usefulness of metoclopramide. Commonly reported adverse reactions include somnolence, nervousness, fatigue, dizziness, weakness, depression, diarrhea, and rash.
  • Prokinetic agents have been used as adjunctive therapy with an H2RA. This combination is only appropriate in patients with known or suspected motility disorders or in those who have failed high-dose Proton pump inhibitor therapy.

Mucosal protectants

  • Sucralfate is a nonabsorbable aluminum salt of sucrose octasulfate that has limited value in the treatment of Gastroesophageal reflux disease.
  • It has similar healing rates as H2RAs in mild esophagitis, but it is less effective than higher doses of H2RAs in patients with refractory esophagitis. Based on available data, sucralfate cannot be recommended for treating anything but the mildest cases of Gastroesophageal reflux disease.

Combination therapy

  • Combination therapy with an acid-suppressing agent and a prokinetic agent or mucosal protectant seems logical, but data supporting such therapy are limited. This approach should be reserved for patients who have esophagitis plus concurrent motor dysfunction or for those who have failed high-dose Proton pump inhibitor therapy.
  • Because combination therapy offers only modest improvement over standard doses of H2RAs alone, patients not responding to standard H2RA doses should have the dose increased or be switched to a Proton pump inhibitor instead of adding a prokinetic agent.

Maintenance therapy

  • Although healing and/or symptomatic improvement may be achieved via many different therapeutic modalities, 70% to 90% of patients relapse within 1 year of discontinuation of therapy.
  • Long-term maintenance therapy should be considered to prevent complications and worsening of esophageal function in patients who have symptomatic relapse after discontinuation of therapy or dosage reduction, including patients with complications such as Barrett’s esophagus, strictures, or hemorrhage.
  • Most patients require standard doses to prevent relapses. H2RAs may be an effective maintenance therapy in patients with mild disease. The Proton pump inhibitors are the drugs of choice for maintenance treatment of moderate to severe esophagitis. Usual once-daily doses are omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, or esomeprazole 20 mg. Lower doses of a Proton pump inhibitor or alternate-day regimens may be effective in some patients with less severe disease.

Interventional approaches

  • Antireflux surgery (Nissen, Belsey, Toupet, or Hill fundoplication operations) should be considered in patients who fail to respond to pharmacologic treatment, opt for surgery because of lifestyle considerations, have complications (Barrett’s esophagus, strictures, or grade 3 or 4 esophagitis), or have atypical symptoms and reflux documented on ambulatory pH monitoring.
  • Endoluminal therapies (endoscopic gastroplastic plication, endoluminal application of radiofrequency heat energy, and endoscopic injection of a biopolymer) are FDA-approved therapies, but their precise role in the management of Gastroesophageal reflux disease remains to be determined.

Evaluation of therapeutic outcomes

  • The short-term goals are to relieve symptoms such as heartburn and regurgitation so that they do not impair the patient’s quality of life.
  • The frequency and severity of symptoms should be monitored, and patients should be counseled on symptoms that suggest the presence of complications requiring immediate medical attention, such as dysphagia or odynophagia.
  • Patients should also be monitored for the presence of atypical symptoms such as cough, nonallergic asthma, or chest pain. These symptoms require further diagnostic evaluation.

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