Gastroesophageal Reflux Disease

Gastroesophageal reflux is a normal physiologic phenomenon experienced intermittently by most people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury (ie, esophagitis).

A study by Richter and a Gallup Organization National Survey estimated that 25%-40% of healthy adult Americans experience symptomatic GERD, most commonly manifested clinically by pyrosis (heartburn), at least once a month. Furthermore, approximately 7%-10% of the adult population in the United States experiences such symptoms on a daily basis.[8, 9] (See Epidemiology.)

In most persons with GERD, endogenous defense mechanisms either limit the amount of noxious material that is introduced into the esophagus or rapidly clear the material from the esophagus so that symptoms and esophageal mucosal irritation are minimized. Examples of the defense mechanisms include actions of the lower esophageal sphincter (LES) and normal esophageal motility. When the defense mechanisms are defective or become overwhelmed so that the esophagus is bathed in acid or bile and acid-containing fluid for prolonged periods, GERD can be said to exist. (See Pathophysiology.)

Patients with GERD can exhibit various symptoms, both typical and atypical. Typical symptoms include heartburn, regurgitation, and dysphagia. Atypical symptoms include noncardiac chest pain, asthma, pneumonia, hoarseness, and aspiration.[10, 11] Patients typically have numerous daily episodes of symptomatic reflux, including pyrosis, water brash or sour taste in the mouth, nighttime coughing or aspiration, pneumonia or pneumonitis, bronchospasm, and laryngitis and voice changes, including hoarseness. In addition, objective evidence of esophageal damage can be seen on esophagogastroduodenoscopy as manifested by the incremental grades of esophagitis discussed below. (See Presentation.)

Laboratory tests are seldom useful in establishing a diagnosis of GERD. Esophageal manometry and pH monitoring are considered essential before performing an antireflux operation. Endoscopy reveals that 50% of patients do not have esophagitis. The only way to determine if abnormal reflux is present and if symptoms are actually caused by gastroesophageal reflux is through pH monitoring. Achalasia can present with heartburn. Only esophageal manometry and pH monitoring can be used to distinguish achalasia from GERD. Therapy is completely different for the two conditions. (See Workup.)

GERD is treated via a stepwise approach that is based on lifestyle modifications and control of gastric secretion by means of medical or surgical treatment.[1, 2, 3, 4, 5, 6] (See Treatment.)

GI disorders are some of the most frequent complaints during pregnancy, and gastroesophageal reflux is among these complaints. Some women have certain GI disorders that are unique to pregnancy, and others have chronic GI disorders that require special consideration during pregnancy. Understanding the presentation and prevalence of various GI disorders is necessary in order to optimize care for these patients.

For patient education resources, see Heartburn and GERD Center, as well as Acid Reflux (GERD), GERD FAQs (Gastroesophageal Acid Reflux), and GERD and Heartburn Medications.

The anatomy of the esophagus, stomach, and esophagogastric junction is critical in the understanding of the pathogenesis of reflux.

The esophagus is divided into three parts: cervical, thoracic, and abdominal. The body of the esophagus is made up of inner circular and outer longitudinal muscular layers. The proximal third of the esophagus is striated muscle, which transitions to smooth muscle in the distal two thirds. The proximal esophagus contains the upper esophageal sphincter (UES), which comprises the cricopharyngeus and thyropharyngeus muscles.

The distal thoracic esophagus is located on the left side of midline. As the thoracic esophagus enters the abdomen through the esophageal hiatus in the diaphragm, it becomes the abdominal esophagus. The hiatus is formed by the right crus of the diaphragm, which forms a sling around the esophagus with the right and left pillars, so that the esophagus narrows when the diaphragm contracts.[12, 13, 14] The actual contribution the diaphragm provides in maintaining an adequate length of intra-abdominal esophagus is not clearly understood; however, careful identification and approximation of the pillars during surgical treatment is crucial for preventing recurrence of reflux disease.

At this level, the phrenoesophageal ligament or membrane (see the image below), which is the reflection of the subdiaphragmatic fascia onto the transversalis fascia of the anterior abdominal wall, also encircles the esophagus. A prominent fat pad located on the anterior surface of the esophagus marks the lower limit of the phrenoesophageal ligament, which corresponds to the esophagogastric junction. This junction lies in the abdomen and forms the angle of His. The acute angle and the length of abdominal esophagus both contribute to the normal closure of the esophagus when intragastric and intra-abdominal pressures are high.

Relationship of the phrenoesophageal ligament to the diaphragm and esophagus.

The lower esophageal sphincter—or, more accurately, the distal esophageal high-pressure zone (HPZ)—is the distal most segment of the esophagus (3-5 cm in adults) and can be anywhere from 2-5 cm in length. Maintenance of an adequate intra-abdominal HPZ is crucial in preventing GERD. This HPZ does not correspond to any visible anatomic structure. It is a zone created by a complex architecture of smooth muscle fibers, and it is typically identified during manometry.

Usually, GERD is caused by a malfunction of one or more of these anatomic features. Proper surgical treatment requires complete preoperative and intraoperative evaluation and correction of all defective features.

Blood supply of esophagus and stomach

The blood supply of the esophagus is segmental (see the image below). The inferior thyroid artery supplies the cervical esophagus. Branches of the bronchial arteries and branches directly off of the aorta supply the proximal and distal thoracic esophagus, respectively. Finally, branches of the left gastric and inferior phrenic artery supply the abdominal esophagus. A relatively constant branch connects the left gastric and inferior phrenic arteries, called the Belsey artery.

Arterial blood supply and lymphatic drainage of the esophagus.

The blood supply of the stomach is rich, with overlap among the vessels. The lesser curve is supplied by the left and right gastric arteries, branches of the celiac trunk and hepatic artery, respectively. The greater curve is supplied by the right gastroepiploic artery arising from the gastroduodenal artery and the left gastroepiploic artery and the short gastric arteries originating from the splenic artery. This excellent collateral blood supply of the stomach allows the surgeon to ligate much of the arterial supply (ie, the short gastric arteries during fundoplication) without the risk of ischemia (see the image above).

Schematically, the esophagus, lower esophageal sphincter (LES), and stomach can be envisioned as a simple plumbing circuit as described by Stein and coworkers.[15] The esophagus functions as an antegrade pump, the LES as a valve, and the stomach as a reservoir. The abnormalities that contribute to GERD can stem from any component of the system. Poor esophageal motility decreases clearance of acidic material. A dysfunctional LES allows reflux of large amounts of gastric juice. Delayed gastric emptying can increase the volume and pressure in the reservoir until the valve mechanism is defeated, leading to GERD. From a medical or surgical standpoint, it is extremely important to identify which of these components is defective so that an effective therapy can be applied.

Esophageal defense mechanisms

Esophageal defense mechanisms can be broken down into two categories (ie, esophageal clearance and mucosal resistance). Proper esophageal clearance is an extremely important factor in preventing mucosal injury. Esophageal clearance must be able to neutralize the acid refluxed through the lower esophageal sphincter. (Mechanical clearance is achieved by esophageal peristalsis; chemical clearance is achieved with saliva.) Normal clearance limits the amount of time the esophagus is exposed to refluxed acid or bile and gastric acid mixtures. Abnormal peristalsis can cause inefficient and delayed acid clearance.

Whether peristaltic dysfunction is secondary to esophageal exposure to acids or a primary defect is not understood clearly. In a review by Kahrilas et al, peristaltic dysfunction was progressively more common in patients with greater degrees of esophagitis.[16] Abnormal peristalsis was identified in 25% of patients with mild esophagitis and 48% of patients with severe esophagitis.

Buttar and associates described the importance of esophageal mucosal resistance as a protective mechanism.[17] They classified the factors into pre-epithelial, epithelial, and postepithelial defenses. When the defenses fail, esophagitis and other complications of reflux disease arise.

Dysfunction of the lower esophageal sphincter

The lower esophageal sphincter (LES) is defined by manometry as a zone of elevated intraluminal pressure at the esophagogastric junction. For proper LES function, this junction must be located in the abdomen so that the diaphragmatic crura can assist the action of the LES, thus functioning as an extrinsic sphincter. In addition, the LES must have a normal length and pressure and a normal number of episodes of transient relaxation (relaxation in the absence of swallowing).

LES dysfunction occurs via one of several mechanisms: transient relaxation of the LES (most common mechanism), permanent LES relaxation, and transient increase of intra-abdominal pressure that overcomes the LES pressure.

Delayed gastric emptying

The postulated mechanism by which delayed gastric emptying may cause GERD is an increase in the gastric contents resulting in increased intragastric pressure and, ultimately, increased pressure against the lower esophageal sphincter. This pressure eventually defeats the LES and leads to reflux. However, objective studies have produced conflicting data regarding the role of delayed gastric emptying in the pathogenesis of GERD.

Hiatal hernia

When discussing the mechanisms for GERD, the issue of hiatal hernia must be addressed. Hiatal hernias can be encountered frequently in patients with reflux disease; however, it has been well proven that not all patients with hiatal hernias have symptomatic reflux.

Buttar and coworkers state that a hiatal hernia may contribute to reflux via a variety of mechanisms.[17] (See the image below). The lower esophageal sphincter may migrate proximally into the chest and lose its abdominal high-pressure zone (HPZ), or the length of the HPZ may decrease. The diaphragmatic hiatus may be widened by a large hernia, which impairs the ability of the crura to function as an external sphincter. Finally, gastric contents may be trapped in the hernial sac and reflux proximally into the esophagus during relaxation of the LES. Reduction of the hernias and crural closure are critical to restoring an adequate intra-abdominal length of esophagus and recreating the HPZ.

Hiatal hernia.

Obesity as contributing factor

Some studies have shown that GERD is highly prevalent in patients who are morbidly obese and that a high body mass index (BMI) is a risk factor for the development of this condition.[18, 19, 20, 21, 22, 23] The hypothesis that obesity increases esophageal acid exposure is supported by the documentation of a dose-response relationship between increased BMI and increased prevalence of GERD and its complications. Therefore, the pathophysiology of GERD in patients who are morbidly obese might differ from that of patients who are not obese. The therapeutic implication of such a premise is that the correction of reflux in patients who are morbidly obese might be better achieved with a procedure that first controls obesity.

The mechanism by which a high BMI increases esophageal acid exposure is not completely understood. Increased intragastric pressure and gastroesophageal pressure gradient, incompetence of the lower esophageal sphincter (LES), and increased frequency of transient LES relaxations may all play a role in the pathophysiology of GERD in patients who are morbidly obese.

Excessive retrograde movement of acid-containing gastric secretions or bile and acid-containing secretions from the duodenum and stomach into the esophagus is the etiologic effector of GERD. From a therapeutic point of view, informing patients that gastric refluxate is made up not only of acid but also of duodenal contents (eg, bile, pancreatic secretions) is important.

A functional (frequent transient LES relaxation) or mechanical (hypotensive LES) problem of the LES is the most common cause of GERD. Transient relaxation of the LES can be caused by foods (coffee, alcohol, chocolate, fatty meals), medications (beta-agonists,[24] nitrates, calcium channel blockers, anticholinergics), hormones (eg, progesterone), and nicotine.

Western dietary habits have made GERD a common disease. Richter and associates reported that 25%-40% of Americans experience symptomatic GERD at some point.[19] Approximately 7%-10% of Americans experience symptoms of GERD on a daily basis. Because many individuals control their symptoms with over-the-counter (OTC) medications and without consulting a medical professional, the actual number of individuals with GERD is probably higher.

No sexual predilection exists: GERD is as common in men as in women. However, the male-to-female incidence ratio for esophagitis is 2:1-3:1. The male-to-female incidence ratio for Barrett esophagus is 10:1. White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations.

GERD occurs in all age groups. The prevalence of GERD increases in people older than 40 years.

Most patients with GERD do well with medications, although a relapse after cessation of medical therapy is common and indicates the need for long-term maintenance therapy.

Identifying the subgroup of patients who may develop the most serious complications of GERD and treating them aggressively is important. Surgery at an early stage is most likely indicated in these patients. After a laparoscopic Nissen fundoplication, symptoms resolve in approximately 92% of patients.

The LOTUS trial—a 5-year, exploratory randomized, open, parallel-group trial—demonstrated that with antireflux therapy for GERD, either using drug-induced acid suppression with esomeprazole or laparoscopic antireflux surgery, most patients achieve remission and remain in remission at 5 years.[25]

Most cases of gastroesophageal reflux in infants and very young children are benign and respond to conservative nonpharmacologic treatment (developmental disabilities represent an important diagnostic exception); 80% resolve by age 18 months (55% resolve by age 10 mo). Some patients require a "step-up" to acid-reducing medications, and only a very small minority require surgery. Because symptomatic gastroesophageal reflux after age 18 months likely represents a chronic condition, long-term risks are increased. For patients whose gastroesophageal reflux persists into later childhood, long-term therapy with antisecretory agents is often required.

In refractory cases or when complications related to reflux disease are identified (eg, stricture, aspiration, airway disease, Barrett esophagus), surgical treatment (fundoplication) is typically necessary. The prognosis with surgery is considered excellent. The surgical morbidity and mortality is higher in patients who have complex medical problems in addition to gastroesophageal reflux.

Complications of disease

Esophagitis

Esophagitis (esophageal mucosal damage) is the most common complication of GERD, occurring in approximately 50% of patients (see the images below).

Peptic esophagitis.

Reflux esophagitis is demonstrated on barium esophagram.

Esophagitis may be diagnosed using endoscopy, although it cannot always be appreciated on endoscopy. As many as 50% of symptomatic patients with GERD demonstrate no evidence of esophagitis on endoscopy. Still, documentation of this complication is important in diagnosing GERD. Degrees of esophagitis are described by the Savary-Miller classification as follows.

• Grade I – Erythema

• Grade II – Linear nonconfluent erosions

• Grade III – Circular confluent erosions

• Grade IV – Stricture or Barrett esophagus.

Stricture

Strictures are advanced forms of esophagitis and are caused by circumferential fibrosis due to chronic deep injury. Strictures can result in dysphagia and a short esophagus. Gastroesophageal reflux strictures typically occur in the mid-to-distal esophagus and can be visualized on upper GI tract studies and endoscopy. Presence of a stricture with a history of reflux can also help diagnose GERD. Patients present with dysphagia to solid meals and vomiting of nondigested foods.

As a rule, the presence of any esophageal stricture is an indication that the patient needs surgical consultation and treatment (usually surgical consultation). When patients present with dysphagia, barium esophagography is indicated to evaluate for possible stricture formation. In these cases, especially when associated with food impaction, eosinophilic esophagitis must be ruled out prior to attempting any mechanical dilatation of the narrowed esophageal region.

Barrett esophagus

The most serious complication of long-standing or severe GERD is the development of Barrett esophagus. Barrett esophagus is present in 8%-15% of patients with GERD. Barrett esophagus is thought to be caused by the chronic reflux of gastric juice into the esophagus. It is defined by metaplastic conversion of the normal distal squamous esophageal epithelium to columnar epithelium. Histologic examination of esophageal biopsy specimens is required to make the diagnosis. Varying degrees of dysplasia may be found on histologic examination.

Barrett esophagus with intestinal type metaplasia has malignant potential and is a risk factor for the development of esophageal adenocarcinoma (see the images below), increasing the risk of adenocarcinoma 30-40 times. The incidence of adenocarcinoma of the esophagus is increasing steadily in Western society. Currently, adenocarcinoma accounts for more than 50% of esophageal cancers in the Western industrialized nations.

Gastroesophageal reflux disease (GERD)/Barrett esophagus/adenocarcinoma sequence.

Endoscopy demonstrating intraluminal esophageal cancer.

As with esophageal stricture, the presence of Barrett esophagus indicates the need for surgical consultation and treatment (usually surgical fundoplication).

Gastroesophageal reflux disease (GERD) is associated with a set of typical (esophageal) symptoms, including heartburn, regurgitation, and dysphagia. (However, a diagnosis of GERD based on the presence of typical symptoms is correct in only 70% of patients.) In addition to these typical symptoms, abnormal reflux can cause atypical (extraesophageal) symptoms, such as coughing, chest pain, and wheezing.

The American College of Gastroenterology (ACG) published updated guidelines for the diagnosis and treatment of GERD in 2005. According to the guidelines, for patients with symptoms and history consistent with uncomplicated GERD, the diagnosis of GERD may be assumed and empirical therapy begun. Patients who show signs of GERD complications or other illness or who do not respond to therapy should be considered for further diagnostic testing.[7]

A history of nausea, vomiting, or regurgitation should alert the physician to evaluate for delayed gastric emptying.

Patients with GERD may also experience significant complications associated with the disease, such as esophagitis, stricture, and Barrett esophagus. Approximately 50% of patients with gastric reflux develop esophagitis.

Typical esophageal symptoms

Heartburn is the most common typical symptom of GERD. It is felt as a retrosternal sensation of burning or discomfort that usually occurs after eating or when lying supine or bending over.

Regurgitation is an effortless return of gastric and/or esophageal contents into the pharynx. Regurgitation can induce respiratory complications if gastric contents spill into the tracheobronchial tree.

Dysphagia occurs in approximately one third of patients. Patients with dysphagia experience a sensation that food is stuck, particularly in the retrosternal area. Dysphagia can be an advanced symptom and can be due to a primary underlying esophageal motility disorder, a motility disorder secondary to esophagitis, or stricture formation.

Atypical extraesophageal symptoms

Coughing and/or wheezing are respiratory symptoms resulting from the aspiration of gastric contents into the tracheobronchial tree or from the vagal reflex arc producing bronchoconstriction. Approximately 50% of patients who have GERD-induced asthma do not experience heartburn.

Hoarseness results from irritation of the vocal cords by the gastric refluxate and is often experienced by patients in the morning.

Reflux is the most common cause of noncardiac chest pain, accounting for approximately 50% of cases. Patients can present to the emergency department with pain resembling a myocardial infarction. Reflux should be ruled out (using esophageal manometry and 24-hour pH testing if necessary) once a cardiac cause for the chest pain has been excluded. Alternatively, a therapeutic trial of a high-dose proton pump inhibitor (PPI) can be tried.

Additional atypical symptoms from abnormal reflux include damage to the lungs (eg, pneumonia, asthma, idiopathic pulmonary fibrosis), vocal cords (eg, laryngitis, cancer), ear (eg, otitis media), and teeth (eg, enamel decay).

Mandatory studies include upper GI endoscopy and manometry. Endoscopy can help confirm the diagnosis of reflux by demonstrating complications of reflux (esophagitis, strictures, Barrett esophagus) and can help in evaluating the anatomy (eg, hiatal hernia, masses, strictures). Manometry helps surgical planning by determining the lower esophageal sphincter (LES) pressure and identifying any esophageal motility disorders. Esophageal amplitudes and propagation of esophageal swallows are also evaluated.

Optional studies include 24-hour pH probe test and upper GI series. Use of 24-hour pH testing helps confirm the diagnosis in patients in whom the history is not clear, atypical symptoms dominate the clinical picture, or endoscopy shows no complications of reflux disease. Upper GI series can be ordered to further delineate the anatomy. Hiatal hernias can be evaluated (size) and reflux can be demonstrated. In addition, gastric emptying can be evaluated to a limited extent. If a question exists regarding inadequate gastric emptying or if the patient has a history of nausea and vomiting, a nuclear medicine gastric emptying study can be obtained.

At the authors' institution, endoscopy, manometry, and 24-hour pH studies are obtained routinely. Upper GI series and nuclear medicine gastric emptying studies are ordered only if clinically indicated. Currently, no role exists for CT, MRI, or ultrasonography in the routine evaluation of patients with reflux disease.

Esophagogastroduodenoscopy (EGD) demonstrates the anatomy and identifies the possible presence and severity of complications of reflux disease (esophagitis, Barrett esophagus, strictures). Using the patient's history and pathologic analysis of biopsy specimens obtained during endoscopy, the diagnosis of GERD can be made. EGD also excludes the presence of other diseases (eg, peptic ulcer) that can present similarly to GERD.

Although EGD is frequently performed to help diagnose GERD, it is not the most cost-effective diagnostic study, because esophagitis is present in only 50% of patients with GERD.

Esophageal manometry defines the function of the LES and the esophageal body (peristalsis). Esophageal manometry is essential for correctly positioning the probe for the 24-hour pH monitoring.

Indications for esophageal manometry and prolonged pH monitoring include the following:

• Persistence of symptoms while taking adequate antisecretory therapy, such as PPI therapy

• Recurrence of symptoms after discontinuation of acid-reducing medications

• Investigation of atypical symptoms, such as chest pain or asthma, in patients without esophagitis

• Confirmation of the diagnosis in preparation for antireflux surgery

Ambulatory 24-hour pH monitoring is the criterion standard in establishing a diagnosis of GERD, with a sensitivity of 96% and a specificity of 95%. It quantifies the gastroesophageal reflux and allows a correlation between the symptoms of reflux and the episodes of reflux.

Patients with endoscopically confirmed esophagitis do not need pH monitoring to establish a diagnosis of GERD.

Plain radiographic findings are not useful in evaluating patients for GERD, but they are helpful in evaluating the pulmonary status and basic anatomy. Chest images may demonstrate a large hiatal hernia, but small hernias can be easily missed. Upper GI contrast-enhanced studies are the initial radiologic procedure of choice in the workup of the patient in whom GERD is suggested. Esophageal inflammatory and neoplastic diseases are better detected with double-contrast techniques. Conversely, single-contrast techniques are more sensitive for structural defects such as hiatal hernias and strictures or esophageal rings.[27]

Although delayed gastric emptying is present in as many as 60% of patients with GERD, this emptying defect is usually a minor factor in the pathogenesis of the disease in most patients (except in patients with advanced diabetes mellitus or connective tissue disorders). Patients with delayed gastric emptying typically experience postprandial bloating and fullness in addition to other symptoms. Gastric emptying studies may be worthwhile in the evaluation of patients in whom delayed gastric emptying is believed to contribute to the manifestation of GERD symptoms.

See Gastroesophageal Reflux Disease Imaging for more information.

Gastroesophageal reflux scintigraphy can be performed with acidified orange juice labeled with technetium-99m sulfur colloid. Compared with fluoroscopy, this allows for a longer time of evaluation, a decreased radiation dose, and the ability to semiquantitate the amount of reflux. However, gastroesophageal reflux scintigraphy has little role in the adult patient due to limited sensitivity and the availability of other methods of evaluation.

Gastroesophageal reflux scintigraphy is much more commonly used in infants and children due to the noninvasive nature of the study and relatively low radiation dose. In infants and children, the study is often performed with labeled milk. In addition to evaluating the degree of reflux, pulmonary aspiration can be detected by imaging over the lungs.

Intraluminal esophageal electrical impedance (EEI), a newer test, is useful for detecting both acid reflux and nonacid reflux by measuring retrograde flow in the esophagus. Gastroesophageal reflux episodes as brief as 15 seconds may be measured (see the image below).

The image is a representation of concomitant intraesophageal pH and esophageal electrical impedance measurements. The vertical solid arrow indicates commencement of a nonacid gastroesophageal reflux (GER) episode (diagonal arrow). The vertical dashed arrow indicates the onset of a normal swallow.

In adult studies, impedance measurements have been used in conjunction with 24-hour intraesophageal pH monitoring in order to provide a more complete picture of bolus movement in the esophagus. EEI has not been thoroughly validated, and normal values have not been determined in the pediatric age group.

Treatment of gastroesophageal reflux disease (GERD) involves a stepwise approach. The goals are to control symptoms, to heal esophagitis, and to prevent recurrent esophagitis or other complications. The treatment is based on (1) lifestyle modification and (2) control of gastric acid secretion through medical therapy with antacids or PPIs or surgical treatment with corrective antireflux surgery.[1, 2, 3, 4, 5, 6]

Approximately 80% of patients have a recurrent but nonprogressive form of GERD that is controlled with medications. (See Pharmacologic Therapy.) Identifying the 20% of patients who have a progressive form of the disease is important, because they may develop severe complications, such as strictures or Barrett esophagus. For patients who develop complications, surgical treatment should be considered at an earlier stage to avoid the sequelae of the disease that can have serious consequences. (See Surgical Care.)

Use of a patient management tool such as the self-administered GERD Questionnaire (GerdQ) to stratify patients may improve the management of GERD patients in primary care settings.[28]

Lifestyle modifications include the following:

• Losing weight (if overweight)

• Avoiding alcohol, chocolate, citrus juice, and tomato-based products (2005 guidelines from the American College of Gastroenterology [ACG] also suggest avoiding peppermint, coffee, and possibly the onion family[7] )

• Avoiding large meals

• Waiting 3 hours after a meal before lying down

• Elevating the head of the bed by 8 inches

According to the ACG 2005 guidelines, studies have shown decreased distal esophageal acid exposure after these changes are made, but few data are available to confirm these findings.[7]

Lifestyle modifications are the first line of management in pregnant women with GERD. Advise patients to elevate the head of the bed; avoid bending or stooping positions; eat small, frequent meals; and refrain from ingesting food (except liquids) within 3 hours of bedtime.

Antacids

Antacids were the standard treatment in the 1970s and are still effective in controlling mild symptoms of GERD. Antacids should be taken after each meal and at bedtime.

H2 receptor antagonists and H2 blocker therapy

H2 receptor antagonists are the first-line agents for patients with mild to moderate symptoms and grades I-II esophagitis. Options include cimetidine (Tagamet), famotidine (Pepcid), and nizatidine (Axid). The US Food and Drug Administration announced voluntary recalls of ranitidine (Zantac) from the market between December 2019 and February 2020 after raising major concerns in September 2019 about drug contamination with the impurities of the carcinogenic molecule N-nitrosodimethylamine (NDMA).[29] A total withdrawal of all ranitidine products was requested in April 2020.[30]

H2 receptor antagonists are effective for healing only mild esophagitis in 70%-80% of patients with GERD and for providing maintenance therapy to prevent relapse. Tachyphylaxis has been observed, suggesting that pharmacologic tolerance can reduce the long-term efficacy of these drugs.

Additional H2 blocker therapy has been reported to be useful in patients with severe disease (particularly those with Barrett esophagus) who have nocturnal acid breakthrough.

Proton pump inhibitors

PPIs are the most powerful medications available for treating GERD. These agents should be used only when this condition has been objectively documented. They have few adverse effects. However, data have shown that PPIs can interfere with calcium homeostasis and aggravate cardiac conduction defects. Long-term use of these agents has also been associated with bone fractures in postmenopausal women, chronic renal disease, acute renal disease, community-acquired pneumonia, and Clostridium difficile intestinal infection.[31, 32]

Available PPIs include omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), and esomeprazole (Nexium). In November 2013, the FDA approved the first generic versions of rabeprazole sodium delayed-release tablets for the treatment of GERD in adults and adolescents ages 12 and up. In clinical trials, the most commonly reported adverse reactions to rabeprazole were sore throat, flatulence, infection, and constipation in adults, and abdominal pain, diarrhea, and headache in adolescents.[33]

A research review by the Agency for Healthcare Research and Quality (AHRQ) concluded, on the basis of grade A evidence, that PPIs were superior to H2 receptor antagonists for the resolution of GERD symptoms at 4 weeks and healing of esophagitis at 8 weeks.[34] In addition, the AHRQ found no difference between individual PPIs (omeprazole, lansoprazole, pantoprazole, and rabeprazole) for relief of symptoms at 8 weeks. For symptom relief at 4 weeks, esomeprazole 20 mg was equivalent, but esomeprazole 40 mg superior, to omeprazole 20 mg.[34]

A systematic review and meta-analysis of two randomized trials and four prospective cohort studies on the effects of PPI in obstructive sleep apnea in patients with GERD found a lack of definitive data.[35]

Prokinetic medications and reflux inhibitors

Prokinetic agents are somewhat effective but only in patients with mild symptoms; other patients usually require additional acid-suppressing medications, such as PPIs. The usual regimen in adults is metoclopramide, 10 mg/day orally. Long-term use of prokinetic agents may have serious, even potentially fatal, complications and should be discouraged.

As in many other fields, surgical therapy for gastroesophageal reflux has evolved a great deal. A few historical procedures of note include the Allison crural repair, the Boerema anterior gastropexy, and the Angelchik prosthesis. Both the Allison and the Boerema repairs have high failure rates and are rarely, if ever, used.[36, 37] The Angelchik prosthesis is a silicone ring that is positioned at the gastroesophageal junction and prevents reflux. The Angelchik prosthesis was rarely used in children and has been largely abandoned because of a high rate of complications.[38]

Today, both transthoracic and transabdominal fundoplications are performed, including partial (anterior or posterior) and circumferential wraps. The most commonly performed operation today in both children and adults is the Nissen fundoplication, which is a 360° transabdominal fundoplication (see the image below).[39, 40] First reported in 1991, laparoscopic fundoplication is well studied in adult populations. Laparoscopic fundoplication has also quickly gained acceptance for use in children.[41, 42, 43, 44, 45, 46] However, in one study in which 119 children underwent fundoplication for severe GERD, 7.6% required a redo fundoplication and 53.8% needed to restart their antireflux medications within 6 months of surgery.[47]

Nissen fundoplication.

Indications for fundoplication include the following:

• Patients with symptoms that are not completely controlled by PPI therapy can be considered for surgery; surgery can also be considered in patients with well-controlled GERD who desire definitive, one-time treatment

• The presence of Barrett esophagus is an indication for surgery (whether acid suppression improves the outcome or prevents the progression of Barrett esophagus remains unknown, but most authorities recommend complete acid suppression in patients with histologically proven Barrett esophagus)

• The presence of extraesophageal manifestations of GERD may indicate the need for surgery; these include the following: (1) respiratory manifestations (eg, cough, wheezing, aspiration); (2) ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media); and (3) dental manifestations (eg, enamel erosion)

• Young patients

• Poor patient compliance with regard to medications

• Postmenopausal women with osteoporosis

• Patients with cardiac conduction defects

• Cost of medical therapy

Several randomized clinical trials have challenged the benefits of surgery in controlling GERD. Lundell followed up his cohort of patients for 5 years and did not find surgery to be superior to PPI therapy.[48] Spechler found that, at 10 years after surgery, 62% of patients were back on antireflux medications.[49] A very rigorous, randomized study by Anvari et al reestablished surgery as the criterion standard in treating GERD.[50] The investigators showed that, at 1 year, the outcome and the symptom control in the surgical group was better than that in the medical group.[50]

A British multicenter randomized study conducted by Grant et al also compared surgical treatment versus medical therapy in patients with documented evidence of GERD.[51] The type of laparoscopic fundoplication was decided by the respective surgeons. Individuals who had received medication for their condition had taken them for a median of 32 months before participating in the study. The investigators reported that by 12 months, 38% of those who had undergone surgery were taking reflux medication, compared with 90% of the individuals randomized to medical management.[51]

Long-term results of laparoscopic antireflux surgery have shown that, at 10 years, 90% of patients are symptom free and only a minority still take PPIs.[52]

Long-term follow-up results from a multicenter, randomized trial showed that, relative to pharmacotherapy, fundoplication maintained better symptomatic relief in the management of gastroesophageal reflux disease without evidence of long-term postsurgical adverse symptoms. At 5 years, among patients with a treatment response, almost twice as many of those randomized to medical management (82%) were taking antireflux agents relative to those who had been randomized to surgery (44%).[53]

Laparoscopic fundoplication

Laparoscopic fundoplication is performed under general endotracheal anesthesia. Five small (5-mm to 10-mm) incisions are used (see image below). The fundus of the stomach is wrapped around the esophagus to create a new valve at the level of the esophagogastric junction.

Laparoscopic Nissen fundoplication.

The essential elements of the operation are as follows:

• Complete mobilization of the fundus of the stomach with division of the short gastric vessels

• Reduction of the hiatal hernia

• Narrowing of the esophageal hiatus

• Creation of a 360° fundoplication over a large intraesophageal dilator (Nissen fundoplication)

Laparoscopic fundoplication procedure takes about 2-2.5 hours. The hospital stay is approximately 2 days. Patients resume regular activities within 2-3 weeks. Approximately 92% of patients obtain resolution of symptoms after undergoing laparoscopic fundoplication.

The AHRQ found, on the basis of limited evidence, that laparoscopic fundoplication was as effective as open fundoplication in relieving heartburn and regurgitation, improving quality of life, and decreasing the use of antisecretory medications.[34]

Although a prospective, randomized trial has never been performed to compare PPIs to laparoscopic fundoplication, the authors believe fundoplication is preferable for the following reasons:

• PPIs, although effective in controlling the acid component of the refluxate, do not eliminate the reflux of bile, which some believe to be a major contributor to the pathogenesis of Barrett epithelium

• Patients with Barrett esophagus tend to have lower LES pressure and worse esophageal peristalsis than patients without Barrett esophagus; patients with Barrett esophagus are also exposed to a larger amount of reflux

• A fundoplication offers the only possibility of stopping any kind of reflux by creating a competent LES; however, until the definitive answer is known, the authors recommend that patients with Barrett esophagus should continue to undergo periodic endoscopic surveillance even after laparoscopic fundoplication

Sleeve gastrectomy

In a study that evaluated laparoscopic sleeve gastrectomy for GERD in 71 morbidly obese patients, symptomatic and reflux control improved in most patients following the procedure.[54] However, a systematic review and meta-analysis of 33 studies was unable to determine the effect of sleeve gastrectomy on the prevalence of GERD owing to the high heterogeneity among the available studies and paradoxical outcomes of objective esophageal function tests.[55]

Devices

The US Food and Drug Administration approved the LINX Reflux Management System in March 2012. This device is designed to augment the lower esophageal sphincter. The system is a small flexible band that is placed laparoscopically around the esophagus just above the stomach to create a natural barrier to reflux. The band consists of interlinked titanium beads with magnetic cores. The act of swallowing temporarily breaks the magnetic bond, allowing food and liquid to pass normally.[56]

In a systematic review, magnetic sphincter augmentation appeared to reinforce the lower esophageal sphincter to antireflux, effectively reducing the time percentage of esophageal acid exposure (pH <  4), improving the GERD health-related quality of life score, reducing the operative time (vs Nissen fundoplication), and achieving similar treatment success as that of fundoplication.[57] These findings suggest that magnetic sphincter augmentation may have potential as an alternative surgical option for patients with conservative GERD treatment failure.[57]

Schizas et al conducted a systematic review of 35 studies that evaluated the safety and efficacy of magnetic sphincter augmentation (MSA) using the LINX® Reflux Management System. A total of 2511 patients were included and analyzed; the majority of patients reported complete resolution of their GERD symptoms. All patients discontinued PPI therapy and experienced less bloating and a better ability to blech or vomit compared to laparoscopic fundoplication. Encouraging results were also noted in bariatric patients as well as patients with large hiatal hernias.[58]

The goals of pharmacotherapy are to prevent complications and to reduce morbidity in patients with gastroesophageal reflux disease (GERD). The agents used include antacids, H2 receptor antagonists, proton pump inhibitors, and prokinetic agents.

Class Summary

H2 receptor antagonists are the first-line agents for patients with mild to moderate symptoms and grades I-II esophagitis. Options include cimetidine (Tagamet), famotidine (Pepcid), and nizatidine (Axid).

The H2 receptor antagonists are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. They are highly selective, do not affect the H1 receptors, and are not anticholinergic agents. Although IV administration of H2 blockers may be used to treat acute complications (eg, gastrointestinal bleeding), the benefits are not yet proven.

These agents are effective for healing only mild esophagitis in 70%-80% of patients with GERD and for providing maintenance therapy to prevent relapse. Tachyphylaxis has been observed, suggesting that pharmacologic tolerance can reduce the long-term efficacy of these drugs.

Additional H2 blocker therapy has been reported to be useful in patients with severe disease (particularly those with Barrett esophagus) who have nocturnal acid breakthrough.

Ranitidine (Zantac)

Ranitidine inhibits histamine stimulation of the H2 receptor in the gastric parietal cells, which, in turn, reduces gastric acid secretion, gastric volume, and hydrogen concentrations. As of April 1, 2020, ranitidine was withdrawn from the market due to an increasing number of products containing the contaminant known as N-nitrosodimethylamine (NDMA), a possible carcinogen.

Cimetidine (Tagamet)

Cimetidine inhibits histamine at H2 receptors of the gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Nizatidine (Axid)

Nizatidine competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Class Summary

Proton pump inhibitors (PPIs) inhibit gastric acid secretion by inhibition of the H+/K+ ATPase enzyme system in the gastric parietal cells. These agents are used in cases of severe esophagitis and in patients whose conditions do not respond to H2 receptor antagonist therapy. Options include omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), and esomeprazole (Nexium).

PPIs are the most powerful medications available for treating GERD. These agents should be used only when this condition has been objectively documented. They have few adverse effects. However, data have shown that PPIs can interfere with calcium homeostasis and aggravate cardiac conduction defects. Long-term use of these agents has also been associated with bone fractures in postmenopausal women, chronic renal disease, acute renal disease, community-acquired pneumonia, and Clostridium difficile intestinal infection.[31, 32]

Omeprazole (Prilosec)

Omeprazole is used for up to 4 weeks to treat and relieve the symptoms of active duodenal ulcers. It may be used for up to 8 weeks to treat all grades of erosive esophagitis.

Lansoprazole (Prevacid)

Lansoprazole inhibits gastric acid secretion. It is used for up to 8 weeks to treat all grades of erosive esophagitis.

Rabeprazole (Aciphex)

Rabeprazole is for short-term (4- to 8-wk) treatment and relief of symptomatic erosive or ulcerative GERD. In patients who are not healed after 8 weeks, consider an additional 8-wk course.

Esomeprazole (Nexium)

Esomeprazole is an S-isomer of omeprazole. It inhibits gastric acid secretion by inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Pantoprazole (Protonix)

Pantoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells. Use of the intravenous preparation has only been studied for short-term use (ie, 7-10 d).

Class Summary

Prokinetic agents, such as metoclopramide (Reglan), improve the motility of the esophagus and stomach and increase the lower esophageal sphincter (LES) pressure to help reduce reflux of gastric contents. They also accelerate gastric emptying.

Prokinetic agents are somewhat effective but only in patients with mild symptoms; most patients usually require acid-suppressing medications, such as PPIs. Long-term use of prokinetic agents may have serious, even potentially fatal, complications and should be discouraged.

Metoclopramide (Reglan)

Metoclopramide is a GI prokinetic agent that increases GI motility, increases resting esophageal sphincter tone, and relaxes the pyloric sphincter.

Class Summary

Antacids were the standard treatment in the 1970s and are still effective in controlling mild symptoms of GERD. Antacids should be taken after each meal and at bedtime. These agents are used as diagnostic tools to provide symptomatic relief in infants. Associated benefits include symptomatic alleviation of constipation (aluminum antacids, such as ALternaGEL and Amphojel) or loose stools (magnesium antacids, such as Phillips Milk of Magnesia).

Aluminum hydroxide (ALternaGEL, Amphojel)

Aluminum hydroxide increases gastric pH to greater than 4 and inhibits the proteolytic activity of pepsin, reducing acid indigestion. Antacids can initially be used in mild cases. They have no effect on the frequency of reflux, but they decrease its acidity.

Magnesium hydroxide (Phillips Milk of Magnesia, Phillips Chewable)

Magnesium hydroxide is used as an antacid to relieve indigestion. It also causes osmotic retention of fluid, which distends the colon and increases peristaltic activity that provides a laxative effect. In vivo, it forms magnesium chloride after reacting with stomach hydrochloric acid.