Dianne B. May and Satish SC Rao
KEY CONCEPTS
Gastroesophageal reflux disease (GERD) can be described on the basis of either esophageal symptoms or esophageal tissue injury. The common symptoms include heartburn, acid brash, regurgitation, chest pain, and dysphagia.
Endoscopy is commonly used to evaluate mucosal injury from GERD and to assess for the presence of Barrett’s esophagus or other complications such as bleeding or stricture.
Ambulatory pH monitoring (with or without impedance monitoring) is useful for confirming acid or nonacid reflux in patients with persistent symptoms without evidence of mucosal damage or for patients with atypical symptoms such as hoarseness of voice, chest pain, persistent cough/throat clearing, or erosion of dental enamel; manometry is useful for patients who are candidates for antireflux surgery and for ensuring proper placement of pH probes.
The goals of GERD treatment are to alleviate symptoms, decrease the frequency of recurrent disease, promote healing of mucosal injury, and prevent complications.
GERD treatment is determined by disease severity and includes lifestyle changes and patient-directed therapy, pharmacologic treatment, and antireflux surgery.
Patients with typical GERD symptoms should be treated with lifestyle modifications as appropriate and a trial of empiric acid-suppression therapy. Those who do not respond to empiric therapy or who present with alarm symptoms such as dysphagia, weight loss, anemia, or GI bleeding should undergo endoscopy, or, less commonly, a barium swallow study.
Surgical intervention is a viable alternative treatment for select patients when long-term pharmacologic management is undesirable or when patients have refractory symptoms or complications.
Acid suppression is the mainstay of GERD treatment. Proton pump inhibitors provide the greatest symptom relief and the highest healing rates, especially for patients with erosive disease or moderate to severe symptoms or with complications.
Many patients with GERD will relapse if medication is withdrawn; so long-term maintenance treatment may be required. A proton pump inhibitor is the drug of choice for maintenance of patients with moderate to severe GERD. Both step-up and step-down therapies have been advocated.
Patient medication profiles should be reviewed for drugs that may aggravate GERD. Patients should be monitored for adverse drug reactions and potential drug–drug interactions.
Gastroesophageal reflux disease (GERD) is a common medical disorder. A consensus definition of GERD states it is “a condition that occurs when the refluxed stomach contents lead to troublesome symptoms and/or complications.”1 The key is that these troublesome symptoms adversely affect the well-being of the patient. Episodic heartburn that is not frequent enough or painful enough to be considered bothersome by the patient is not included in this definition of GERD.1
Esophageal GERD syndromes are classified as either symptom-based or tissue injury–based depending on how the patient presents.1 Symptom-based esophageal GERD syndromes may exist with or without esophageal injury and most commonly present as heartburn, regurgitation, or dysphagia. Less commonly, odynophagia (painful swallowing) or hypersalivation may occur. Tissue injury–based syndromes may exist with or without symptoms. The spectrum of injury includes esophagitis (inflammation of the lining of the esophagus), Barrett’s esophagus (when tissue lining the esophagus is replaced by tissue similar to the lining of the intestine), strictures, and esophageal adenocarcinoma.2 Esophagitis occurs when the esophagus is repeatedly exposed to refluxed gastric contents for prolonged periods of time. This can progress to erosion of the squamous epithelium of the esophagus (erosive esophagitis). Complications of long-term reflux may include the development of strictures, Barrett’s esophagus, or possibly adenocarcinoma of the esophagus.
Gastroesophageal reflux symptoms associated with disease processes in organs other than the esophagus are referred to as extraesophageal reflux syndromes. Patients with extraesophageal reflux syndromes may present with chest pain, hoarseness of voice, chronic cough/throat clearing, or asthma. An association between these syndromes and GERD should only be considered when they occur along with esophageal GERD syndrome because these extraesophageal symptoms are nonspecific and have many other causes.1
Many patients suffering from mild GERD do not go on to develop erosive esophagitis and are often managed with lifestyle changes, antacids, and nonprescription histamine-2 (H2) receptor antagonists or nonprescription proton pump inhibitors. Those with more severe symptoms (with or without tissue injury) predictably follow a course of relapsing disease, requiring more intensive treatment with acid-suppression therapy followed by long-term maintenance therapy. Antireflux surgery offers an alternative for select patients in whom prolonged medical management is undesirable or who have refractory symptoms or complications.
EPIDEMIOLOGY
GERD occurs in people of all ages but is most common in those older than age 40 years. Although mortality is rare, GERD symptoms may have a significant impact on quality of life. The true prevalence of GERD is difficult to assess because many patients do not seek medical treatment, symptoms do not always correlate well with the severity of the disease, and there is no standardized definition or universal gold standard method for diagnosing the disease. However, 10% to 20% of adults in Western countries suffer from GERD symptoms on a weekly basis.3
The prevalence of GERD varies depending on the geographic region but appears highest in Western countries and is on the rise.3
Except during pregnancy, there does not appear to be a major difference in incidence between men and women. Although gender does not generally play a major role in the development of GERD, it is an important factor in the development of Barrett’s esophagus. Alarmingly, adenocarcinoma of the esophagus has increased twofold to sixfold over the past two decades.2 The relationship of adenocarcinoma to Barrett’s esophagus, or even just long-standing GERD, which may be an independent risk factor for esophageal adenocarcinoma, remains to be clearly defined.
Other risk factors and comorbidities that may contribute to the development or worsening of GERD symptoms include family history, obesity, smoking, alcohol consumption, certain medications and foods, respiratory diseases, and reflux chest pain syndrome.
PATHOPHYSIOLOGY
The key factor in the development of GERD is the abnormal reflux of gastric contents from the stomach into the esophagus.4 In some cases, gastroesophageal reflux is associated with defective lower esophageal sphincter (LES) pressure or function (see Fig. 19-1). Patients may have decreased gastroesophageal sphincter pressures related to (a) spontaneous transient LES relaxations, (b) transient increases in intraabdominal pressure, or (c) an atonic LES, all of which may lead to the development of gastroesophageal reflux. Problems with other normal mucosal defense mechanisms, such as abnormal esophageal anatomy, improper esophageal clearance of gastric fluids, reduced mucosal resistance to acid, delayed or ineffective gastric emptying, inadequate production of epidermal growth factor, and reduced salivary buffering of acid, may also contribute to the development of GERD. Substances that may promote esophageal damage on reflux into the esophagus include gastric acid, pepsin, bile acids, and pancreatic enzymes. Thus, the composition and volume of the refluxate, as well as duration of exposure, are important aggressive factors in determining the consequences of gastroesophageal reflux. Rational therapeutic regimens in the treatment of gastroesophageal reflux are designed to maximize normal mucosal defense mechanisms and attenuate the aggressive factors.
FIGURE 19-1 Comparison of a normal esophageal high-resolution manometry showing normal upper esophageal sphincter and lower esophageal sphincter (LES) resting pressure and relaxations with a water bolus (A), compared with that seen in a patient with GERD and a weak resting LES (B).
Lower Esophageal Sphincter Pressure
The LES is a specialized thickening of the smooth muscle lining of the distal esophagus with an elevated basal resting pressure. The sphincter is normally in a tonic, contracted state, preventing the reflux of gastric material from the stomach, but relaxes on swallowing to permit the passage of food into the stomach. Mechanisms by which defective LES pressure may cause gastroesophageal reflux are threefold. First, and probably most importantly, reflux may occur following spontaneous transient LES relaxations that are not associated with swallowing. Although the exact mechanism is unknown, esophageal distension, vomiting, belching, and retching cause relaxation of the LES. While not thought to contribute significantly to erosive esophagitis, these transient relaxations, which are normal postprandially, may play an important role in symptom-based esophageal reflux syndromes. Transient decreases in sphincter pressure are responsible for more than half of the reflux episodes in patients with GERD. The propensity to develop gastroesophageal reflux secondary to transient decreases in LES pressure is probably dependent on numerous factors, including the degree of sphincter relaxation, efficacy of esophageal clearance, patient position (more common in recumbent position), gastric volume, and intragastric pressure. Second, reflux may occur following transient increases in intraabdominal pressure (stress reflux). An increase in intraabdominal pressure such as that occurring during straining, bending over, coughing, eating, or a Valsalva maneuver may overcome a weak LES, and thus may lead to reflux. Third, the LES may be atonic, thus permitting free reflux as seen in patients with scleroderma. Although transient relaxations are more likely to occur when there is normal LES pressure, the latter two mechanisms are more likely to occur when the LES pressure is decreased by such factors as fatty foods, gastric distension, smoking, or certain medications (see Table 19-1).5 Various foods aggravate esophageal reflux by decreasing LES pressure or by precipitating symptomatic reflux by direct mucosal irritation (e.g., spicy foods, orange juice, tomato juice, and coffee). Pregnancy is a condition in which reflux is common. There are many postulated reasons for the increased incidence of heartburn during pregnancy, including hormonal effects on esophageal muscle, LES tone, and physical factors (increased intraabdominal pressure) resulting from an enlarging uterus. A decrease in LES pressure resulting from any of the previously mentioned causes is not always associated with gastroesophageal reflux. Likewise, individuals who experience decreases in sphincter pressures and subsequently reflux do not always develop GERD. The other natural defense mechanisms (anatomic factors, esophageal clearance, mucosal resistance, and other gastric factors) must be evoked to explain this phenomenon.
TABLE 19-1 Foods and Medications That May Worsen GERD Symptoms
Anatomic Factors
Disruption of the normal anatomic barriers by a hiatal hernia (when a portion of the stomach protrudes through the diaphragm into the chest) was once thought to be a primary etiology of gastroesophageal reflux and esophagitis. Now it appears that a more important factor related to the presence or absence of symptoms in patients with hiatal hernia is the LES pressure. Patients with hypotensive LES pressures and large hiatal hernias are more likely to experience gastroesophageal reflux following abrupt increases in intraabdominal pressure compared with patients with a hypotensive LES and no hiatal hernia. Although anatomic factors are still considered significant by some, the diagnosis of hiatal hernia is currently considered a separate entity with which gastroesophageal reflux may simultaneously occur.
Esophageal Clearance
In many patients with GERD, the problem is not that they produce too much acid but that the acid produced ends up in the wrong place and spends too much time in contact with the esophageal mucosa. This is not surprising, because the symptoms and/or severity of damage produced by gastroesophageal reflux are partially dependent on the duration of contact between the gastric contents and the esophageal mucosa. This contact time is, in turn, dependent on the rate at which the esophagus clears the noxious material, as well as the frequency of reflux. The esophagus is cleared by primary peristalsis in response to swallowing, or by secondary peristalsis in response to esophageal distension and gravitational effects. Swallowing contributes to esophageal clearance by increasing salivary flow. Saliva contains bicarbonate that buffers the residual gastric material on the surface of the esophagus. The production of saliva decreases with increasing age, making it more difficult to maintain a neutral intraesophageal pH. Therefore, esophageal damage caused by reflux occurs more often in the elderly, and similarly, for patients with Sjögren’s syndrome or xerostomia. In addition, swallowing is decreased during sleep, making nocturnal GERD a problem in many patients.
Mucosal Resistance
Within the esophageal mucosa and submucosa there are mucus-secreting glands that may contribute to the protection of the esophagus. Bicarbonate moving from the blood to the lumen can neutralize acidic refluxate in the esophagus. When the mucosa is repeatedly exposed to the refluxate in GERD, or if there is a defect in the normal mucosal defenses, hydrogen ions diffuse into the mucosa, leading to the cellular acidification and necrosis that ultimately cause esophagitis. In theory, mucosal resistance may be related not only to esophageal mucus but also to tight epithelial junctions, epithelial cell turnover, nitrogen balance, mucosal blood flow, tissue prostaglandins, and the acid–base status of the tissue. Saliva is also rich in epidermal growth factor, stimulating cell renewal.
Gastric Emptying
Delayed gastric emptying can contribute to gastroesophageal reflux. An increase in gastric volume may increase both the frequency of reflux and the amount of gastric fluid available to be refluxed. Gastric volume is related to the volume of material ingested, rate of gastric secretion, rate of gastric emptying, and amount and frequency of duodenal reflux into the stomach. Factors that increase gastric volume and/or decrease gastric emptying, such as smoking and high-fat meals, are often associated with gastroesophageal reflux. This partially explains the prevalence of postprandial gastroesophageal reflux. Fatty foods may increase postprandial gastroesophageal reflux by increasing gastric volume, delaying the gastric emptying rate, and decreasing the LES pressure. Patients with gastroesophageal reflux, particularly infants, may have a defect in gastric antral motility. The delay in emptying may promote regurgitation of feedings, which might, in turn, contribute to two common complications of GERD in infants (e.g., failure to thrive and pulmonary aspiration).6
Composition of Refluxate
The composition, pH, and volume of the refluxate are important aggressive factors in determining the consequences of gastroesophageal reflux. In animals, acid has two primary effects when it refluxes into the esophagus. First, if the pH of the refluxate is less than 2, esophagitis may develop secondary to protein denaturation. In addition, pepsinogen is activated to pepsin at this pH and may also cause esophagitis. Duodenogastric reflux esophagitis, or “alkaline esophagitis,” refers to esophagitis induced by the reflux of bilious and pancreatic fluid. The term alkaline esophagitis may be a misnomer in that the refluxate may be either weakly alkaline or acidic in nature. An increase in gastric bile concentrations may be caused by duodenogastric reflux as a result of a generalized motility disorder, slower clearance of the refluxate, or after surgery.7 Although bile acids have both a direct irritant effect on the esophageal mucosa and an indirect effect of increasing hydrogen ion permeability of the mucosa, symptoms are more often related to acid reflux than to bile reflux. Specifically, the percentage of time that the esophageal pH is <4 is greater for patients with severe disease as compared with that for patients with mild disease. Esophageal pH monitoring in conjunction with 24-hour bile monitoring has shown a higher incidence of Barrett’s esophagus for patients who have both acid and alkaline reflux.7 More study is needed to substantiate this finding. Nevertheless, the combination of acid, pepsin, and/or bile is a potent refluxate in producing esophageal damage.
Complications
Several complications may occur with gastroesophageal reflux, including esophagitis, esophageal strictures, Barrett’s esophagus, and esophageal adenocarcinoma. Strictures are common in the distal esophagus and are generally 1 to 2 cm in length. The use of nonsteroidal antiinflammatory drugs or aspirin is an additional risk factor that may contribute to the development or worsening of GERD complications.3 Although GERD may lead to esophageal bleeding, the blood loss is usually chronic and low grade in nature, but anemia may occur. In some patients, the reparative process leads to the replacement of the squamous epithelial lining of the esophagus by specialized columnar-type epithelium (Barrett’s esophagus), which increases the incidence of esophageal strictures by as much as 30%. Barrett’s esophagus is most prevalent in white males in Western countries. The risk of esophageal adenocarcinoma may be higher for patients with Barrett’s esophagus as compared with that for the general population, although not as high as previously thought. The absolute annual risk of esophageal adenocarcinoma was 0.12% in those with Barrett’s esophagus.8 The pathophysiology of gastroesophageal reflux is a complex cyclic process. It is difficult, if not impossible, to determine which occurs first: gastroesophageal reflux leading to defective peristalsis with delayed clearing or an incompetent LES pressure leading to gastroesophageal reflux. Understanding the factors associated with the development of GERD provides insight into the treatment modalities currently used to manage patients suffering from this disease.
CLINICAL PRESENTATION
GERD can be described on the basis of either esophageal symptoms or esophageal tissue injury. The severity of the symptoms of gastroesophageal reflux does not always correlate with the degree of esophageal tissue injury, but it does correlate with the duration of reflux. Patients with symptom-based esophageal syndromes may have symptoms as severe as those with esophageal tissue injury. It is important to distinguish GERD symptoms from those of other diseases, especially when chest pain or pulmonary symptoms are present.9
CLINICAL PRESENTATION GERD2
Symptom-based GERD Syndromes (With or Without Esophageal Tissue Injury)
Typical symptoms (may be aggravated by activities that worsen gastroesophageal reflux such as recumbent position, bending over, or eating a meal high in fat):
• Heartburn (hallmark symptom described as a substernal sensation of warmth or burning rising up from the abdomen that may radiate to the neck; may be waxing and waning in character)
• Acid brash (hypersalivation)
• Regurgitation/belching
• Chest pain (∼50% with normal electrocardiogram have GERD)9
Alarm symptoms (these symptoms may be indicative of complications of GERD such as Barrett’s esophagus, esophageal strictures, or esophageal adenocarcinoma and require further diagnostic evaluation):
• Dysphagia (common)
• Odynophagia
• Bleeding
• Weight loss
Tissue Injury–based GERD Syndromes (With or Without Esophageal Symptoms)
Symptoms (may present with alarm symptoms such as dysphagia, odynophagia, or unexplained weight loss):
• Esophagitis
• Strictures
• Barrett’s esophagus
• Esophageal adenocarcinoma
Extraesophageal GERD Syndromes
Symptoms (these symptoms have an association with GERD, but causality should only be considered if a concomitant esophageal GERD syndrome is also present):
• Chronic cough
• Laryngitis
• Asthma (∼50% with asthma have GERD)
• Dental enamel erosion
Diagnostic Tests for GERD
Clinical history:
• Generally sufficient to diagnose GERD in patients with typical symptoms
Endoscopy:
• Preferred for assessing for mucosal injury and to assess for other complications, such as bleeding or strictures. Biopsies are necessary to identify Barrett’s esophagus, adenocarcinoma, and eosinophilic esophagitis (a nonacid-related esophageal disorder that generally does not respond well to proton pump inhibitor therapy).
• Noninflammatory GERD and major motor disorders may be missed by endoscopy.
• Absence of erosions does not definitively show symptoms are GERD related.
Ambulatory pH monitoring:
• Identifies patients with excessive esophageal acid exposure and helps determine if symptoms are acid related
• Useful for patients not responding to acid-suppression therapy
• Documents the percentage of time the intraesophageal pH is <4 and determines the frequency and severity of reflux
• Measures only acid reflux (not nonacid reflux)
Combined impedance–pH monitoring:
• Measures both acid and nonacid reflux
Manometry/high-resolution esophageal pressure topography (HREPT):
• Useful in those who have failed twice-daily proton pump inhibitor therapy with normal endoscopic findings to identify motor disorders, to evaluate peristaltic function in those who are candidates for antireflux surgery, and to assure proper placement of pH probes (the recent advancement of the tubeless pH monitoring system using endoscopic landmarks for placement may negate the need for manometry for ensuring proper placement of esophageal pH probes)1
Impedance manometry:
• Evaluates bolus transit esophageal clearance/retention
• Evaluates LES and upper esophageal sphincter pressures and peristalsis
Empiric trial of a proton pump inhibitor as a diagnostic test for GERD:
• Less expensive and more convenient than ambulatory pH monitoring but lacks standardized dosing regimen and duration of the diagnostic trial
Barium radiography:
• Not routinely used to diagnose GERD because it lacks sensitivity and specificity; cannot identify Barrett’s esophagus. Can detect hiatal hernia.
Diagnostic Tests
The most useful tool in the diagnosis of gastroesophageal reflux is the clinical history, including presenting symptoms and associated risk factors. Patients presenting with typical symptoms of reflux, such as heartburn or regurgitation, do not usually require invasive esophageal evaluation. These patients generally benefit from an initial empiric trial of acid-suppression therapy. A clinical diagnosis of GERD can be assumed in patients who respond to appropriate therapy.4 Further diagnostic evaluation is useful to prevent misdiagnosis, identify complications, and assess treatment failures.2 Diagnostic tests should be performed in those patients who do not respond to therapy and in those who present with alarm symptoms (e.g., dysphagia, odynophagia, weight loss), which may be more indicative of complicated disease.
Useful tests in diagnosing GERD include upper endoscopy, ambulatory pH monitoring test or impedance monitoring, and manometry. 
Endoscopy is commonly used to evaluate mucosal injury from GERD and to assess other complications, such as bleeding or stricture. A camera-containing capsule swallowed by the patient offers the newest technology for visualizing the esophageal mucosa via endoscopy. The PillCam ESO is less invasive than traditional endoscopy and takes less than 15 minutes to perform in the clinician’s office. Images of the esophagus are downloaded through sensors placed on the patient’s chest that are connected to a data collector. The camera-containing capsule is later eliminated in the stool. The main disadvantage of the PillCam is that biopsies cannot be obtained. Of note, it is not recommended to use endoscopy as a “screening tool” for Barrett’s esophagus and esophageal adenocarcinoma just because a patient has long-standing GERD.1
Clinical Controversy…
What constitutes refractory GERD is not well defined. Some consider failure to respond to twice-daily proton pump use to be the threshold for refractory GERD. Symptom indexes are available, but their interpretation is controversial.
Unfortunately, the presence or absence of mucosal damage does not prove the patient’s symptoms are reflux related; for that, ambulatory pH monitoring is useful. Ambulatory pH monitoring (with or without impedance monitoring) is useful for confirming acid or nonacid reflux in patients with persistent symptoms without evidence of mucosal damage or for patients with atypical symptoms such as hoarseness of voice, chest pain, persistent cough or throat clearing, or erosion of dental enamel. Ambulatory pH monitoring can be performed by passing a small pH probe transnasally and placing it approximately 5 cm above the LES. Patients are asked to keep a diary of symptoms that later are correlated with the pH measurement corresponding to the time the symptom was reported (see Fig. 19-2). Two developments related to ambulatory reflux monitoring include (a) the use of combined impedance–pH monitoring and (b) the use of a wireless method of pH monitoring.4 Whereas ambulatory pH monitoring only measures acid reflux, combined impedance–pH monitoring measures both acid and nonacid reflux. The wireless pH monitoring involves attaching a radiotelemetry capsule to the esophageal mucosa. The advantages of this method are that a longer period of monitoring is possible (48 hours), it may demonstrate superior recording accuracy compared with some catheter designs, and it is more comfortable for the patient because a nasogastric tube is unnecessary.1 Proton pump inhibitor therapy should be withheld for 7 days prior to performing ambulatory catheter pH, impedance–pH, or wireless pH monitoring when evaluating patients who have failed an initial empiric therapy and who have normal findings on endoscopy and manometry.1 Manometry is also useful and can be performed before ambulatory pH/impedance testing. Reasons for choosing manometry are described in Clinical Presentation of GERD above.
FIGURE 19-2 Graphical representation of a normal 24-hour ambulatory esophageal pH test profile in a healthy subject and a table summarizing key results (A) compared with an abnormal 24-hour ambulatory esophageal pH test (B) showing significant acid reflux (multiple events of pH drop below 4) and abnormal 24-hour profile in the table.
TREATMENT
Therapeutic modalities used in the treatment of gastroesophageal reflux are targeted at reversing the various pathophysiologic abnormalities.
Desired Outcomes
The goals of treatment are to (a) alleviate or eliminate the patient’s symptoms, (b) decrease the frequency or recurrence and duration of gastroesophageal reflux, (c) promote healing of the injured mucosa, and (d) prevent the development of complications. Therapy is directed at augmenting defense mechanisms that prevent reflux and/or decrease the aggressive factors that worsen reflux or mucosal damage (see Fig. 19-3). Therapy is directed at (a) decreasing the acidity of the refluxate, (b) decreasing the gastric volume available to be refluxed, (c) improving gastric emptying, (d) increasing LES pressure, (e) enhancing esophageal acid clearance, and (f) protecting the esophageal mucosa.
FIGURE 19-3 Therapeutic interventions in the management of gastroesophageal reflux disease. Pharmacologic interventions are targeted at improving defense mechanisms or decreasing aggressive factors. (LES, lower esophageal sphincter.)
General Approach to Treatment
GERD treatment is determined by disease severity and includes: (a) lifestyle changes and patient-directed therapy with antacids, nonprescription H2-receptor antagonists, and/or nonprescription proton pump inhibitors; (b) pharmacologic treatment with prescription-strength acid-suppression therapy; (c) and antireflux surgery (see Table 19-2). The initial therapeutic modality used is in part dependent on the patient’s condition (frequency of symptoms, degree of esophagitis, and presence of complications) (see Table 19-3). Historically, a step-up approach was used, starting with noninvasive lifestyle modifications and patient-directed therapy and progressing to pharmacologic management or antireflux surgery. A step-down approach, starting with a proton pump inhibitor instead of an H2-receptor antagonist and then stepping down to the lowest dose of acid suppression (either an H2-receptor antagonist or proton pump inhibitor) needed to control symptoms, has also been advocated. Neither the step-up nor the step-down approach has superior efficacy over the other. The clinician should determine the most appropriate approach for the individual patient. Every attempt should be made to aggressively control symptoms and to prevent relapses early in the course of the patient’s disease in order to prevent the complications. For patients with moderate to severe GERD, especially those with erosive disease, starting with a proton pump inhibitor as initial therapy is advocated because of its superior efficacy over H2-receptor antagonists.
TABLE 19-2 Evidence-Based Treatment Recommendations for GERD 2
TABLE 19-3 Therapeutic Approach to GERD in Adults
While weight loss in obese patients and elevation of the head end of the bed are beneficial for most GERD patients, recommending all lifestyle modifications to all patients is not recommended.1 Instead, education on lifestyle modifications should be tailored to the individual needs of the patient. Table 19-4 lists some of the lifestyle modifications that can be recommended.4
TABLE 19-4 Nonpharmacologic Treatment of GERD with Lifestyle Modifications4
Initially, patients with typical GERD symptoms should be treated with lifestyle modifications and patient-directed therapy. Patients who do not respond to lifestyle modifications and patient-directed therapy after 2 weeks or those with alarm symptoms, such as dysphagia, should seek medical attention and are generally started on empiric therapy consisting of an acid-suppression agent. Those who do not respond to empiric therapy or who present with alarm symptoms should undergo endoscopy or, less commonly, a barium swallow study. Acid-suppression therapy with proton pump inhibitors or H2-receptor antagonists is the mainstay of GERD treatment. Patients presenting with moderate to severe symptoms (with or without esophageal erosions) should be started on a proton pump inhibitor as initial therapy because it provides the most rapid symptomatic relief and healing in the highest percentage of patients.4 H2-receptor antagonists in divided doses are effective for patients with milder GERD symptoms. Standard H2-receptor antagonist doses may be increased to two to four times the normal dose for patients who do not respond to standard doses. However, if this is necessary, it is more cost-effective and efficacious to switch to a proton pump inhibitor.
Promotility agents are not as effective as acid-suppression agents. Combining promotility agents with acid-suppression drugs offers only modest improvements in symptoms over standard doses of H2-receptor antagonists and should not be routinely recommended. In addition, the availability of a promotility agent that has an acceptable adverse-effect profile is lacking. Mucosal protectants, such as sucralfate, have a limited role in the treatment of GERD.
Maintenance therapy is generally necessary to control symptoms and to prevent complications. For patients with more severe symptoms (with or without esophageal erosions) or for patients with other complications, maintenance therapy with a proton pump inhibitor is most effective. Routine use of combination therapy has no role in GERD maintenance therapy. In cases of refractory GERD, the diagnosis should be confirmed through further diagnostic tests before long-term, high-dose therapy or antireflux surgery is considered.4
Nonpharmacologic Therapy
Nonpharmacologic treatment of GERD includes lifestyle modifications and antireflux surgery, which may be viable maintenance modalities in select patients. Endoscopic therapies, such as endoscopic sewing devices and endoluminal application of radio-frequency heat energy, have fallen out of favor and are not routinely recommended.
Lifestyle Modifications
The most common lifestyle modifications that a patient should be educated about include weight loss in obese patients and elevation of the head end of the bed, especially for those patients who have symptoms while in a recumbent position. Other lifestyle modifications should be individualized based on the patient’s specific situation. These include consumption of smaller meals and not sleeping for at least 3 hours after eating, avoidance of foods or medications that exacerbate GERD, smoking cessation, avoidance of tight-fitting clothes, and avoidance of alcohol (see Table 19-4).
Obesity increases the risk of GERD, most likely through increased intraabdominal pressure and possibly by disruption of the esophagogastric junction.10 A high-fat meal will decrease LES pressure for 2 hours or more postprandially. In contrast, a high-protein, low-fat meal will elevate LES pressure. Consequently, weight loss and a low-fat diet may help to improve GERD symptoms. Elevating the head end of the bed by approximately 6 to 8 in (15 to 20 cm) with a foam wedge under the mattress (not just elevating the head with pillows) decreases nocturnal esophageal acid contact time and should be recommended. Many foods may worsen the symptoms of GERD. Fats and chocolate can decrease LES pressure, whereas citrus juice, tomato juice, coffee, and pepper may irritate damaged endothelium.
Patient profiles should be evaluated to identify potential medications that may exacerbate GERD symptoms. Some medications decrease LES pressure, while other medications can act as direct contact irritants to the esophageal mucosa (Table 19-1). Proper patient education can help prevent dysphagia or esophageal ulceration. Patients should be closely monitored for worsening symptoms when any of these medications are started. If symptoms worsen, alternative therapies may be warranted. The clinician must weigh the risks and benefits of continuing a drug known to worsen GERD and esophagitis.
Smoking can cause aerophagia, which leads to increased belching and regurgitation. However, data are lacking to show that symptoms improve for patients who quit smoking. Nevertheless, patients with GERD should be encouraged to quit smoking. Alcohol, although not thought to play a role in severe disease, decreases LES pressure and may exacerbate symptoms such as heartburn.
Many patients are noncompliant with lifestyle modifications, and even those who do comply generally continue to have symptoms that require acid-suppression therapy. Nonetheless, it is important to regularly stress the potential benefits of lifestyle modifications that would benefit each individual patient.
Interventional Approaches
Interventional approaches include antireflux surgery and endoscopic therapies.
Antireflux Surgery Surgical intervention is a viable alternative treatment for select patients when long-term pharmacologic management is undesirable or when patients have refractory symptoms or complications. The goal of antireflux surgery is to reestablish the antireflux barrier, to position the LES within the abdomen where it is under positive (intraabdominal) pressure, and to close any associated defect in the diaphragmatic hiatus by reinforcing the crural muscles. Antireflux surgery should be considered for patients (a) who fail to respond to pharmacologic treatment, (b) who opt for surgery despite successful treatment because of lifestyle considerations, including age, time, or expense of medications, (c) who have complications of GERD (e.g., Barrett’s esophagus, strictures), or (d) who have atypical symptoms and reflux documented with ambulatory pH monitoring. The antireflux surgical procedure chosen depends on the surgeon’s expertise and preference, as well as on anatomic considerations. In general, 90% of patients have symptom resolution following successful Nissen fundoplication. The major complications with antireflux surgery include gas bloat syndrome (inability to belch or vomit), dysphagia, vagal denervation, and splenic trauma. Antireflux surgery is superior to medical management with an H2-receptor antagonist or a promotility agent. In a 7-year followup study of omeprazole compared with antireflux surgery for patients with esophagitis, symptoms (regurgitation and heartburn) were better controlled in the surgical group; however, treatment failures were also higher in the surgical group. In addition, more patients in the surgical group complained of complications, such as inability to belch, flatulence, and dysphagia.11 Long-term effectiveness of antireflux surgery is uncertain.
Endoscopic Therapies Endoscopic approaches for the management of GERD have included endoscopic sewing devices and endoluminal application of radio-frequency heat energy resulting in tissue injury or nerve ablation (the Stretta procedure). Unfortunately, results from these endoscopic therapies have proven disappointing and are not routinely recommended. Currently in their infancy stages, natural orifice transluminal surgery and surgical techniques may evolve.
Pharmacologic Therapy
Pharmacologic treatment consists of (a) patient-directed therapy with nonprescription antacids, H2-receptor antagonists, or proton pump inhibitors and (b) prescription-strength acid-suppression therapy or promotility medications.
Patient-Directed Therapy
Patient-directed therapy, where patients self-treat themselves with nonprescription medications, is appropriate for mild, intermittent symptoms. Patients with continuous symptoms lasting longer than 2 weeks should seek medical attention.
Antacids and Antacid–Alginic Acid Products Patients should be educated that antacids are an appropriate component of treating milder GERD symptoms, even though documentation of their efficacy in placebo-controlled clinical trials is lacking.4 Although the literature is somewhat controversial on the superiority of antacids to placebo, clinicians and patients clearly consider antacids to be effective for immediate symptomatic relief, and antacids are often used concurrently with other acid-suppression therapies. Maintaining the intragastric pH >4 decreases the activation of pepsinogen to pepsin, a proteolytic enzyme. Also, neutralization of gastric fluid leads to increased LES pressure. Patients who require frequent use of antacids for chronic symptoms should be treated with prescription-strength acid-suppression therapy because their illness is considered more significant.
An antacid product combined with alginic acid is not a potent neutralizing agent and does not enhance LES pressure; however, it does form a highly viscous solution that floats on the surface of the gastric contents. This viscous solution is thought to serve as a protective barrier for the esophagus against reflux of gastric contents. It also reduces the frequency of the reflux episodes. The combination product may be superior to antacids alone in relieving the symptoms of GERD.4 Efficacy data indicating endoscopic healing are lacking.
Antacid or antacid combination products interact with a variety of medications by altering gastric pH, increasing urinary pH, adsorbing medications to their surfaces, providing a physical barrier to absorption, or forming insoluble complexes with other medications. Antacids have clinically significant drug interactions with tetracycline, ferrous sulfate, isoniazid, quinidine, sulfonylureas, and quinolone antibiotics. Antacid–drug interactions are influenced by composition, dose, dosage schedule, and formulation of the antacid.
Dosage recommendations for antacids in the management of GERD are somewhat difficult to derive from the literature. Doses range from hourly to an as-needed basis (Table 19-3). In general, antacids have a short duration of action, which necessitates frequent administration throughout the day to provide continuous neutralization of acid. Taking antacids after meals can increase the duration of action from about 1 to 3 hours; however, nighttime acid suppression cannot be maintained with bedtime doses.
Nonprescription H2-Receptor Antagonists and Proton Pump Inhibitors Nonprescription H2-receptor antagonists (cimetidine, famotidine, nizatidine, and ranitidine) are effective in diminishing gastric acid secretion when taken prior to meals and decrease GERD symptoms associated with exercise. Antacids may have a slightly faster onset of action, while the H2-receptor antagonists have a much longer duration of action compared with antacids.
The proton pump inhibitors omeprazole 20 mg (alone or combined with sodium bicarbonate) and lansoprazole 15 mg are available without a prescription for the short-term treatment of heartburn. Patients who do not respond to lifestyle modifications and patient-directed therapy after 2 weeks should be seen by their clinician.
Acid-Suppression Therapy
Acid suppression is the mainstay of GERD treatment. Proton pump inhibitors provide the greatest symptom relief and the highest healing rates, especially for patients with erosive disease or moderate to severe symptoms or with complications.
Proton Pump Inhibitors (Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and Rabeprazole) Proton pump inhibitors are superior to H2-receptor antagonists in treating patients with moderate to severe GERD and should be given empirically to those with troublesome symptoms. This includes not only patients with esophageal tissue injury (e.g., Barrett’s esophagus, strictures, or esophagitis) but also patients with symptom-based GERD syndromes. Twice-daily proton pump inhibitor use is indicated in those not responding to a standard once-daily course of therapy. Further diagnostic evaluation is indicated for patients not responding to twice-daily proton pump inhibitor therapy.
Proton pump inhibitors block gastric acid secretion by inhibiting gastric H+/K+-adenosine triphosphatase in gastric parietal cells. This produces a profound, long-lasting antisecretory effect capable of maintaining the gastric pH >4, even during postprandial acid surges. A correlation exists between the percentage of time the gastric pH remains >4 during the 24-hour period and healing erosive esophagitis.
In general, healing rates at 4 and 8 weeks are similar among proton pump inhibitors. Symptomatic relief is seen in approximately 83% of patients with endoscopic evidence of injury after 8 weeks treated with a proton pump inhibitor, whereas the endoscopic healing rate at 8 weeks is 78%.4
Enteric infections, vitamin B12 deficiency, hypomagnesemia, and bone fractures are potential long-term adverse effects associated with proton pump inhibitors (Table 19-5).1,12–18 It is becoming more apparent that overuse of proton pump inhibitors should be minimized as the clinical implications of chronic therapy are better elucidated.
TABLE 19-5 Drug Monitoring
Drug interactions with the proton pump inhibitors vary slightly with each agent. All proton pump inhibitors can decrease the absorption of drugs such as ketoconazole or itraconazole, which require an acidic environment to be absorbed. Pantoprazole is the least likely to have drug interactions because it undergoes cytosolic sulfotransferase metabolism instead of through the cytochrome P450 (CYP) enzyme system. While no interactions with lansoprazole, pantoprazole, or rabeprazole have been seen with CYP2C19 substrates such as diazepam, warfarin, and phenytoin, concerns have been raised regarding the concomitant use of proton pump inhibitors, particularly omeprazole, with clopidogrel since it is the strongest inhibitor of CYP2C19.19,20 Clopidogrel, a prodrug, is converted to its active metabolite via the CYP2C19 and CYP3A4 enzymes. Inhibition of CYP2C19 by proton pump inhibitors, specifically omeprazole, may decrease the effectiveness of clopidogrel causing cardiovascular adverse events. Careful review of the risk-to-benefit profile regarding the use of proton pump inhibitors for patients on clopidogrel should be considered. Patients with upper GI bleeding or those with multiple risk factors for GI bleeding who require antiplatelet therapy would benefit from proton pump inhibitor therapy. Risk factors for GI bleeding include advanced age, use of anticoagulants, steroids or nonsteroidal antiinflammatory drugs, presence of Helicobacter pylori, or previous history of bleeding or peptic ulcer disease complications.21 Otherwise, using an alternative agent, such as an H2-receptor antagonist, may be prudent in this patient population.
Esomeprazole does not appear to interact with warfarin or phenytoin, and an interaction with diazepam is generally not considered clinically relevant. Although generally not a problem, omeprazole has the potential to inhibit the metabolism of warfarin, diazepam, and phenytoin, and lansoprazole may decrease theophylline concentrations. Patients on potentially interacting drugs, such as warfarin, should be monitored closely for potential problems.
The proton pump inhibitors degrade in acidic environments and are therefore formulated in a delayed-release capsule or tablet formulation. Dexlansoprazole, esomeprazole, lansoprazole, and omeprazole contain enteric-coated (pH-sensitive) granules in a capsule form. Dexlansoprazole is unique in that the capsule is a dual delayed-release formulation, with the first release occurring 1 to 2 hours after the dose and the second release occurring 4 to 5 hours after the dose. The clinical significance of this dual release is to allow the drug to have a longer-lasting benefit, at least 16 to 18 hours. Patients taking pantoprazole or rabeprazole should be instructed not to crush, chew, or split the delayed-release tablets.
For patients who are unable to swallow the capsule or for pediatric patients, there are several alternative administration methods available. The contents of the delayed-release capsules can be mixed in applesauce or placed in orange juice. If a patient has a nasogastric tube, the contents of an omeprazole capsule can be mixed in 8.4% sodium bicarbonate solution. Esomeprazole granules can be dispersed in water. Esomeprazole, omeprazole, and pantoprazole are also available in a delayed-release oral suspension powder packet, and lansoprazole is available as a delayed-release, orally disintegrating tablet. Esomeprazole and pantoprazole are available in an IV formulation, which offers an alternative route of administration for patients who are unable to take an oral proton pump inhibitor. Importantly, the IV product is not more efficacious than oral proton pump inhibitors and is significantly more expensive. Careful patient selection is necessary to avoid the increased cost from the use of the IV product.
The newest dosage form of omeprazole is in a delayed-release tablet; it is also available in a combination product with sodium bicarbonate in an immediate-release capsule and oral suspension (Zegerid®). This is the first immediate-release proton pump inhibitor and it should be taken on an empty stomach at least 1 hour before a meal. Zegerid® offers an alternative to the delayed-release capsules, powder for suspension, or IV formulation in adult patients with a nasogastric tube.
Patients should be instructed to take their proton pump inhibitor in the morning, 15 to 30 minutes before breakfast or before their biggest meal of the day, to maximize efficacy, because these agents inhibit only actively secreting proton pumps. Dexlansoprazole can be taken without regards to meals. Patients with nocturnal symptoms may benefit from taking their proton pump inhibitor prior to the evening meal. If dosed twice daily, the second dose should be administered approximately 10 to 12 hours after the morning dose and prior to a meal or snack.
H2-Receptor Antagonists (Cimetidine, Famotidine, Nizatidine, and Ranitidine) H2-receptor antagonists in divided doses are effective in treating patients with mild to moderate GERD.4 The majority of the trials assessing the efficacy of standard doses of H2-receptor antagonists indicate that symptomatic improvement is achieved in an average of 60% of patients after 12 weeks of therapy.4 However, endoscopic healing rates tend to be lower, an average of 50% of patients at 12 weeks.4
The efficacy of H2-receptor antagonists in the management of GERD is extremely variable and is frequently lower than desired. Response to the H2-receptor antagonists is dependent on the (a) severity of disease, (b) dosage regimen used, and (c) duration of therapy. These factors are important to keep in mind when comparing clinical trials and/or assessing a patient’s response to therapy. The severity of esophagitis at baseline has a profound impact on the patient’s response to H2-receptor antagonists. For symptomatic relief of mild GERD, low-dose, nonprescription H2-receptor antagonists or standard doses given twice daily may be beneficial. Patients who do not respond to standard doses may be hypersecreters of gastric acid and will require higher doses. Although higher doses of H2-receptor antagonists may provide higher symptomatic and endoscopic healing rates, limited information exists regarding the safety of these regimens, and they can be less effective and more costly than once-daily proton pump inhibitors. Unlike duodenal ulcer disease, in which the duration of therapy is relatively short (e.g., 4 to 6 weeks), prolonged courses of H2-receptor antagonists are frequently required in the treatment of GERD.
Because all of the H2-receptor antagonists have similar efficacy, selection of the specific agent to use in the management of GERD should be based on factors such as differences in pharmacokinetics, safety profile, and cost. Patients should be monitored for the presence of adverse effects as well as potential drug interactions, especially when on cimetidine. Cimetidine may inhibit the metabolism of theophylline, warfarin, phenytoin, nifedipine, and propranolol, among others. An alternate H2-receptor antagonist should be selected if the patient is on any of these medications.
Promotility Agents
Promotility agents may be useful as an adjunct to acid-suppression therapy for patients with a known motility defect (e.g., LES incompetence, decreased esophageal clearance, delayed gastric emptying). Unfortunately, all available promotility agents are fraught with undesirable side effects and are not generally as effective as acid-suppression therapy.
Metoclopramide Metoclopramide, a dopamine antagonist, increases LES pressure in a dose-related manner and accelerates gastric emptying in gastroesophageal reflux patients. However, it does not improve esophageal clearance. Metoclopramide provides symptomatic improvement for some patients with GERD; however, substantial data supporting endoscopic healing are lacking. In addition, metoclopramide’s adverse-effect profile, including extrapyramidal effects, tardive dyskinesia, tachyphylaxis, and other CNS effects, limits its usefulness in treating many patients with GERD. The risk of adverse effects is much greater for elderly patients and for patients with renal dysfunction because the drug is primarily eliminated by the kidneys. Contraindications include Parkinson’s disease, mechanical obstruction, concomitant use of other dopamine antagonists or anticholinergic agents, and pheochromocytoma.
Bethanechol Bethanechol, a promotility drug, has limited value in the treatment of GERD because of unwanted side effects, such as urinary retention, abdominal discomfort, nausea, and flushing. It is not routinely recommended for the treatment of GERD.
Other Promotility Drugs Under Investigation Other promotility drugs under investigation include itopride and baclofen. Because domperidone does not cross the blood–brain barrier, it does not cause the CNS effects seen with metoclopramide. However, it is not currently available in the United States. Baclofen, an gamma aminobutyric acid (GABA) receptor type B agonist, may decrease esophageal acid exposure and the number of reflux episodes by decreasing the number of transient relaxations of the LES. However, this agent has many side effects, limiting its usefulness in GERD. Other GABA type B agonists, as well as metabotropic glutamate type 5 (mGluR5) receptor antagonists, macrolide antibiotics, and cannabinoid agonists, are under development as potential prokinetic agents.22
Mucosal Protectants
Sucralfate, a nonabsorbable aluminum salt of sucrose octasulfate, has limited value in the treatment of GERD. It may not be useful in the routine treatment of acid reflux but can be quite useful in the management of radiation esophagitis and bile or nonacid reflux GERD.
Combination Therapy
Combination therapy with an acid-suppression agent and a promotility agent or a mucosal protectant agent would seem logical given the multifactorial nature of the disease, particularly in light of the disappointing results seen with many monotherapy regimens. However, data to support combination therapy are limited, and this approach should not routinely be recommended unless a patient has GERD plus motor dysfunction occurring. The effectiveness of the addition of an H2-receptor antagonist at bedtime to proton pump inhibitor therapy for the treatment of nocturnal symptoms may decrease over time due to tachyphylaxis with H2-receptor antagonists. Using the omeprazole–sodium bicarbonate immediate-release product in addition to once-daily proton pump inhibitors may offer an alternative for nocturnal GERD symptoms.
Maintenance Therapy
Many patients with GERD will relapse if medication is withdrawn; so long-term maintenance treatment may be required. A proton pump inhibitor is the drug of choice for maintenance of patients with moderate to severe GERD. Both step-up and step-down therapies have been advocated.
Although healing and/or symptomatic improvement may be achieved via many different therapeutic modalities, a large percentage of patients with gastroesophageal reflux will relapse following discontinuation of proton pump inhibitor or H2-receptor antagonist therapy, especially those with more severe disease. Patients who have symptomatic relapse following discontinuation of therapy or lowering of drug doses, including patients with complications such as Barrett’s esophagus, strictures, or esophagitis, should be considered for long-term maintenance therapy to prevent complications or worsening of esophageal function.4 The goal of maintenance therapy is to improve quality of life by controlling the patient’s symptoms and preventing complications. These goals cannot generally be achieved by decreasing the dose of the therapeutic modality used for initial healing or switching to a less potent acid-suppression agent. Most patients will require standard doses to prevent relapses. Patients should be counseled on the importance of complying with lifestyle changes and long-term maintenance therapy in order to prevent recurrence or worsening of disease.4
H2-receptor antagonists may be effective maintenance therapy for patients with mild disease.4 The proton pump inhibitors are the drugs of choice for maintenance treatment of moderate to severe esophagitis or symptoms. Low doses of a proton pump inhibitor or alternate-day dosing may be effective in some patients with mild symptoms, thereby allowing titration in some cases. “On-demand” maintenance therapy, by which patients take their proton pump inhibitor only when they have symptoms, may be effective for patients with endoscopy-negative GERD.4 Although not well studied, many patients with only mild to moderate symptoms may decide on their own to take their medication this way for the financial benefit. However, patients with persistent symptoms and/or complications should be maintained on standard doses of proton pump inhibitors.
Long-term chronic use of proton pump inhibitor doses higher than standard treatment doses is not indicated unless the patient has complicated symptoms, has erosive esophagitis per endoscopy, or has had further diagnostic evaluation to determine the level of acid exposure. Metoclopramide is not approved for maintenance therapy, and its use is limited by adverse-effect profile. Antireflux surgery may also be considered a viable alternative to long-term drug therapy for maintenance of healing for patients who are candidates.
Maintenance Therapy with H2-Receptor Antagonists The studies evaluating the efficacy of the H2-receptor antagonists in maintaining GERD patients in remission have been disappointing. Currently, ranitidine 150 mg twice daily is the only H2-receptor antagonist regimen that is FDA approved for maintenance of healing of erosive esophagitis.
Maintenance Therapy with Proton Pump Inhibitors Long-term use of the proton pump inhibitors is associated with adverse effects such as hypomagnesemia, enteric infections, and risk for bone fractures; however, there is no evidence of carcinoid tumors directly linked to their use. Prolonged hypergastrinemia leading to the development of colonic polyps, and potentially adenocarcinoma, was also a concern that has proven unfounded with long-term use. However, the role of H. pylori status for patients with GERD has been questioned. As a consequence of the controversy surrounding H. pylori and GERD, specific guidelines on how to handle patients who are H. pylori positive are lacking. Most clinicians would probably opt to eradicate H. pylori infections once detected. Further studies are needed to determine the role of H. pylori for patients with GERD.
Special Populations
There are several special populations that should be considered when discussing GERD, such as patients with atypical symptoms, pediatric patients, elderly patients, and patients with refractory symptoms.
Patients with Extraesophageal (Atypical) GERD
Patients presenting with atypical symptoms may require higher doses and longer treatment courses as compared with patients with typical symptoms. Patients with suspected reflux chest pain syndrome may benefit from an empiric course of twice-daily proton pump inhibitor therapy for 4 weeks once cardiac workup is known to be negative.1 If symptoms continue, patients should be evaluated with manometry, ambulatory pH, or impedance–pH monitoring to rule out dysmotility or refractory symptoms.1 Because there are many causes of asthma and laryngeal symptoms, a concomitant esophageal GERD syndrome must also be present to associate these symptoms with GERD. In practice, these patients may benefit from twice-daily proton pump inhibitor for 3 to 4 months even though evidence supporting this regimen is not well established.1 This recommendation is based more on pH monitoring data showing normalization of gastric pH with twice-daily dosing.1 For patients not responding to empiric therapy, pH monitoring may be beneficial in determining acid exposure as it relates to symptoms. The optimal dose of proton pump inhibition is not well defined. Maintenance therapy is generally indicated for patients who respond to the therapeutic trial or have endoscopic evidence of reflux. Antireflux surgery may be an option in select patients.
Pediatric Patients with GERD
Many infants have physiologic reflux with little or no clinical consequence. Uncomplicated gastroesophageal reflux usually manifests as regurgitation or “spitting up” and resolves without incident by 12 to 14 months of life.6 It usually responds to supportive therapy, including dietary adjustments, postural management, and reassurance for the parents. Thickened feedings may be useful in milder cases. While this does not decrease the time the pH is <4, it may decrease the incidence of regurgitation.6 Chronic vomiting associated with gastroesophageal reflux must be distinguished from other causes, such as neurologic, metabolic, eating, and rumination disorders. Smaller, more frequent feedings may be beneficial. In formula-fed infants, an extensively hydrolyzed protein may help identify milk protein sensitivity as the cause of unexplained vomiting and crying.6 Developmental immaturity of the LES is one suspected cause of gastroesophageal reflux in infants.6 Like adults, transient LES relaxations seem to be the most common cause of gastroesophageal reflux in children. Other causes include impaired luminal clearance of gastric acid, neurologic impairment, and type of infant formula. Complications, although rare, include distal esophagitis, failure to thrive, esophageal peptic strictures, Barrett’s esophagus, and pulmonary disease. Further diagnostic evaluation is indicated in all who experience apnea or an apparent life-threatening event.
Clinical Controversy…
While the use of proton pump inhibitors in children has increased, there are little safety data in premature infants. Many feel that the proton pump inhibitors are overused in this population.
The benefits of using promotility medications, such as metoclopramide, erythromycin, bethanechol, and baclofen, are outweighed by the potential adverse effects that may occur and, therefore, cannot be routinely recommended.6Careful consideration should be made before medication is recommended, especially in children less than 1 year of age. Overprescribing of acid-suppression therapy may lead to increased risk of infection and other adverse effects in premature infants.23,24 When medication is deemed necessary, ranitidine is commonly used at a dose of 2 to 4 mg/kg twice daily.6 Tachyphylaxis may develop making the effectiveness of H2-receptor antagonists less than optimal. The use of proton pump inhibitor use in children is increasing, especially in those with esophagitis. Most patients will respond to once-daily proton pump inhibitor dosing. Lansoprazole, esomeprazole, and omeprazole are indicated for treating symptomatic and erosive GERD for pediatric patients older than age 1 year. Lansoprazole 15 mg once daily is recommended for children who weigh 30 kg or less, and a dose of 30 mg once daily is recommended for those who weigh more than 30 kg. Esomeprazole may be dosed 10 to 20 mg daily for children 1 to 11 years old and 20 to 40 mg daily for children 12 to 17 years old. Omeprazole 5 mg daily may be used in children weighing between 5 and 10 kg, 10 mg for children weighing between 10 and 20 kg, and 20 mg daily for children weighing >20 kg. Omeprazole has been used off-label for children less than 1 year of age at a dose of 1 mg/kg/day. Long-term use of a proton pump inhibitor without a clear diagnosis of GERD is not recommended.6
Elderly Patients with GERD
Many elderly patients have decreased host defense mechanisms, such as saliva production. In addition, they have more comorbidities, medications, and physiologic changes that put them at higher risk. More aggressive therapy with a proton pump inhibitor may be warranted for patients older than 60 years of age with symptomatic GERD. Often these patients do not seek medical attention because they feel their symptoms are part of the normal aging process. They may also present with atypical symptoms such as chest pain, asthma, poor dentition, or jaw pain. Decreased GI motility is a common problem in elderly patients. Unfortunately, there are no good promotility agents available to these patients. Elderly patients are especially sensitive to the CNS effects of metoclopramide. They may also be sensitive to the CNS effects of H2-receptor antagonists. Proton pump inhibitors appear to be the most useful treatment modality because they have superior efficacy and are dosed once daily, which is beneficial in all patients, but is especially beneficial in the elderly. Long-term risk of bone fractures may be of concern in this population. Patients at risk for bone fractures should be monitored appropriately.
Patients with Refractory GERD
What constitutes refractory GERD is not well defined. It should be considered in patients who have not responded to a standard course of twice-daily proton pump inhibitor therapy.1 In this case, other causes for the patient’s symptoms should be evaluated. The majority of patients with refractory symptoms experience nocturnal acid breakthrough. Other reasons for refractory symptoms may be related to compliance, timing of proton pump inhibitor, and drug metabolism differences in certain patients. Switching to another proton pump inhibitor may be effective for refractory symptoms in some patients. Manometry or ambulatory pH monitoring is useful for patients who are not responding to therapy with normal endoscopic findings. Adding an H2-receptor antagonist at bedtime for nocturnal symptoms has been suggested; however, the effect may be short-lived. Antireflux surgery may also be considered in this patient population. Eosinophilic esophagitis or dysmotility syndromes may be causes of nonacid-related esophageal symptoms.25
PERSONALIZED PHARMACOTHERAPY
Significant liver impairment may result in a sevenfold to ninefold increase in area under the curve and increase half-life of proton pump inhibitors. While clear recommendations are not available, it may be prudent to consider a lower dose in this population.
The hepatic enzyme CYP2C19 is involved in the metabolism of many medications, including proton pump inhibitors, particularly omeprazole. Further evaluation is needed to determine the role of polymorphic gene variation in the hepatic activity of CYP2C19.
Drug interactions with omeprazole are of particular concern for patients who are considered “slow metabolizers” of omeprazole, which is more common in the Asian population but also found in approximately 3% of the white population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers. Like omeprazole, the metabolism of esomeprazole may also be altered for patients with this polymorphic gene variation.
EVALUATION OF THERAPEUTIC OUTCOMES
The long-term benefits of treatment are difficult to assess because of the limited information known about the epidemiology and natural history of GERD. Consequently, successful outcomes are generally measured in terms of three separate end points: (a) relieving symptoms, (b) healing the injured mucosa, and (c) preventing complications.
The short-term goal of therapy is to relieve symptoms such as heartburn and regurgitation to the point at which they do not impair the patient’s quality of life. Patients should be educated regarding specific lifestyle modifications that are applicable to their individual situation including weight loss, raising the head end of the bed, smoking cessation, eating smaller meals, and avoiding eating prior to bedtime. Patients should also be instructed to avoid or limit foods that aggravate GERD symptoms, such as fat and chocolate. 
In addition, patient medication profiles should be reviewed for drugs that may aggravate GERD. Patients should be monitored for adverse drug reactions. Table 19-5 reviews common adverse drug reactions and monitoring of medications used in GERD. Drug–drug interactions should also be assessed and these agents should be avoided if possible. Table 19-6 lists recommendations for providing pharmaceutical care to patients with GERD.
TABLE 19-6 Recommendations for Providing Pharmaceutical Care to Patients with GERD
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 laryngitis asthma or chest pain. These symptoms require further diagnostic evaluation. Longterm maintenance treatment is indicated for patients who have strictures because the strictures commonly recur if reflux esophagitis is not treated.
The second goal is to heal the injured mucosa. Again, individualized lifestyle modifications and the importance of complying with the therapeutic regimen chosen to heal the mucosa should be stressed. Patients should be educated about the risk of relapse and the need for long-term maintenance therapy to prevent recurrence or complications.
The final, long-term goal of therapy is to decrease the risk of complications (esophagitis, strictures, Barrett’s esophagus, and esophageal adenocarcinoma). A small subset of patients may continue to fail treatment despite therapy with high doses of H2-receptor antagonists or a proton pump inhibitor. Patients should be monitored for the presence of continual pain, dysphagia, or odynophagia.
ABBREVIATIONS
REFERENCES
1. The American Gastroenterological Association (AGA) Institute Medical Position Panel. American gastroenterological association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1383–1391.
2. Kahrilas PJ. Gastroesophageal reflux disease. N Engl J Med 2008;359:1700–1707.
3. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut 2005;54:710–717.
4. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100:190–200.
5. DeVault KR. Review article: The role of acid suppression in patients with non-erosive reflux disease or functional heartburn. Aliment Pharmacol Ther 2006;23(Suppl 1):33–39.
6. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49:498–547.
7. Hirano I. Review article: Modern technology in the diagnosis of gastrooesophageal reflux disease—Bilitec, intraluminal impedance and Bravo capsule pH monitoring. Aliment Pharmacol Ther 2006;23(Suppl 1):12–24.
8. Hvid-Jensen F, Pedersen L, Drewes AM, et al. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med 2011;365:1375–1383.
9. Liu JJ, Carr-Lock DL, Osterman MT, et al. Endoscopic treatment for atypical manifestations of gastroesophageal reflux disease. Am J Gastroenterol 2006;101:440–445.
10. Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: A challenge to esophagogastric junction integrity. Gastroenterology 2006;130:639–649.
11. Lundell L, Miettinen P, Myrvold E, et al. Seven-year follow-up of a randomized clinical trial comparing proton-pump inhibition with surgical therapy for reflux oesophagitis. Br J Surg 2007;94:198–203.
12. Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308–2313.
13. Janarthanan S, Ditah I, Phil M, et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: A meta-analysis. Am J Gastroenterol 2012;107:1001–1010.
14. Thomson ABR, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010;16(19):2323–2330.
15. FDA Drug Safety Communication: Possible Increased Risk of Fractures of the Hip, Wrist, and Spine with the Use of Proton Pump Inhibitors. 2010, www.fda.gov.
16. FDA Drug Safety Communication: Possible Increased Risk of Fractures of the Hip, Wrist, and Spine with the Use of Proton Pump Inhibitors. Update. 2011, www.fda.gov.
17. Ngamruengphong S, Leontiadis GI, Radhi S, et al. Proton pump inhibitors and risk of fracture: A systematic review and meta-analysis of observational studies. Am J Gastroenterol 2011;106:1209–1218.
18. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 2010;139:93–101.
19. Ho MP, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937–944.
20. Laine L, Henneken SC. Proton pump inhibitor and clopidogrel interaction: Fact or fiction? Am J Gastroenterol 2010;105:34–41.
21. Abraham NS, Hlatky MA, Antman EM, et al. 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: A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010;122: 2619–2633.
22. Kuo P, Holloway RH. Beyond acid suppression: New pharmacologic approaches for treatment of GERD. Curr Gastroenterol Rep 2010;12:175–180.
23. Hassall E. Over-prescription of acid-suppressing medications in infants: How it came about, why it’s wrong, and what to do about it. J Pediatr 2012;160(2):193–198.
24. Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012;129:e40–e45.
25. Dellon ES, Shaheen NJ. Persistent reflux symptoms in the proton pump inhibitor era: The changing face of gastroesophageal reflux disease. Gastroenterology 2010;139:7–13.