Chapter 135

Gastroesophageal Reflux Disease

Michelle Freshman

Definition and Epidemiology

Gastroesophageal reflux refers to the retrograde movement of gastric contents from the stomach to the esophagus. This occurs in the general population approximately once per hour, followed by rapid clearance of refluxed material from the distal esophagus, without injury.¹ Swallowing initiates primary peristalsis; distention of the esophagus or acidification promotes secondary peristalsis. When the capacity of the esophageal mucosa to tolerate caustic refluxate is overwhelmed, this normal physiologic process can produce pathologic signs and symptoms in the oropharynx, larynx, esophagus, and respiratory tract. An individual is said to have gastroesophageal reflux disease (GERD) in the setting of chronic symptom distress with or without mucosal damage.

GERD is one of the most prevalent¹ clinical conditions of the gastrointestinal tract, affecting 10% to 20% of adults at least weekly in Western countries, although these accounts are subjective.² Prevalence among American (15% to 20%), British (10% to 15%), Swedish (5% to 10%), and Chinese citizens (0.1% to 5.0%) is variable,³ and estimates of U.S. expenditure range from $9.3 billion to $12.3 billion per year.⁴ Whereas body mass index (BMI) may be a factor, sex and older age appear to be less so.³ Some 4% to 7% of patients with GERD experience progressive disease associated with aspiration (most often related to age, comorbidities, or large hiatal hernia).²

The most common symptoms of GERD are heartburn (retrosternal area pain, pyrosis) and acidic regurgitation. Although their sensitivity is high,⁵ the sensitivity of either symptom is lower than originally thought.⁶ Thoracic pain has been offered as a consideration in the definition.² Aside from typical symptoms, atypical and extraesophageal symptoms (EESs) are frequently reported.⁵ Atypical symptoms include epigastric fullness, epigastric pressure, epigastric pain, dyspepsia, nausea, bloating, and belching, which may suggest GERD but actually represent microaspirations and overlap with other entities.⁵ Symptomatic GERD affects quality of life, may contribute to tissue injury, and is associated with EESs such as dental erosions, sore throat, laryngitis, hoarseness, chronic cough, wheezing, asthma, and bronchospasm, to which some add burning of mouth and tongue, globus sensation, or shortness of breath.³ As proposed with atypical symptoms of GERD, in cases of EESs, microaspirations or a vagally mediated response triggered by the distal esophagus has been theorized, although GERD may not be involved at all.⁵

Nevertheless, severity of symptoms is not a reliable indicator of mucosal damage or prognosis. There are three main types of GERD: nonerosive, erosive, and functional heartburn. Nonerosive, endoscopically negative GERD is the most prevalent type. In fact, 50% to 85% of patients have nonerosive reflex disease.³ Although it is defined as heartburn in the absence of esophageal mucosal damage, a significant proportion of individuals with endoscopically negative GERD have been shown to have pH testing abnormalities on impedance testing. Esophageal damage is marked by erosions, ulcers, or strictures in the esophagus, exclusive of malignant disease. A small percentage of endoscopically negative, symptomatic GERD will progress to erosive GERD.⁷ In patients with no findings on EDG or pH monitoring, functional GERD is suspected, which still may be responsive to standard GERD therapy.

Alarm symptoms include gastrointestinal bleeding, anemia, dysphagia, odynophagia, unintentional weight loss, early satiety, age older than 55 at presentation, and recurrent vomiting.³^,⁶

Pathophysiology

No single mechanism explains all cases of symptomatic GERD; however, multiple factors are thought to be involved in the pathogenesis of reflux²:

• Transient lower esophageal sphincter (LES) relaxations (TLESRs)

• Low resting LES pressure

• Poor esophageal acid clearance, with increased volume and causticity

• Defects in esophagogastric motility or peristalsis

• Impaired mucosal resistance and other protective defenses

• Altered hiatal and gastroesophageal anatomy (involving hiatal crura, phrenoesophageal ligament, esophageal shortening)

• Hypersensitivity to gastric acid

TLESRs, the first factor, have been shown to be the cause of most reflux events. Intervals of LES relaxation, which allow the gastric contents to reflux into the esophagus, result in esophageal damage. It is not necessarily the more frequent TLESRs but the higher percentage of relaxations that is associated with acid migration (often closer to a meal), leading to more discomfort and damage.¹ TLESRs account for over 90% of reflux events⁸ and can occur when a patient lies flat or performs a Valsalva maneuver. Anatomic variations such as hiatal hernia, shortened abdominal length or obesity can contribute.³

The second factor, low resting pressure of the sphincter (normally 10 to 20 mm Hg), has been demonstrated in a minority of patients with reflux esophagitis.¹ A shorter LES (<2 to 5 cm) has been indicated as a potential contributor.¹ In addition, the absolute minimal pressure is 4 mm Hg (other cutoffs are <6 mm Hg)¹; the normal range is 10 to 30 mm Hg higher than the gastric pressure. The pressure is lowest in the daytime and during the postprandial period and highest at night.¹ It remains unclear whether low LES pressure is a cause or consequence of esophagitis because chronic inflammation may also reduce the sphincter’s ability to close.¹

LES pressure is maintained or increased by acetylcholine; relaxation of the LES occurs in response to nitric oxide, as seen in response to swallowing, often augmented by the crural diaphragm and phrenoesophageal ligament⁷ when intra-abdominal pressure increases.¹ Patients with chronic symptoms usually have a hiatal hernia, which reflects movement of the proximal stomach upward through the diaphragm into the chest, where the crural diaphragm becomes separated from the LES. This separation is highly correlated with severe esophagitis, especially in the setting of esophageal stricture or Barrett esophagus.¹ However, the presence of a hiatal hernia alone does not confirm the presence of reflux esophagitis because the majority of patients with hiatal hernias do not have any symptoms. Other conditions increase intra-abdominal pressure and cause retrograde movement of refluxate. In pregnancy there is an increased prevalence of reflux, especially in the final trimester, which results from the relaxant effects of circulating estrogen and progesterone on the LES.

A third factor is intensity of acid exposure. The proton pump ultimately drives the production of acid in the stomach.¹ This acidification pathway results from gastric parietal cells in response to histamine, acetylcholine, and gastrin,³ using hydrogen-potassium adenosine triphosphate molecules in the secretory canaliculi to dislodge hydrogen ions, which in turn acidifies the stomach pH to 1.5 to 3.5.¹^,³ Once acid reflux has occurred, impaired acid clearance prolongs exposure of the mucosa to the damaging effects of the reflux. Evidence suggests that the acid component of the refluxate is the primary cause of heartburn and subsequent erosion. Other factors include the duration of the acid reflux event on the esophageal mucosa and the extent and composition of refluxate. Secondary causes of GERD involving heightened acid exposure include rare hypersecretory disorders. The most common of these disorders, Zollinger-Ellison syndrome, is caused by gastrin-producing tumors of the duodenum, pancreas, or both. In this disease, an overproduction of gastrin-driven acid output refluxes upward, causing severe GERD pain or peptic stricture.

A fourth pathogenic factor is the inability of the esophagus to clear itself of reflux material, resulting in longer exposure to gastric contents. This is more common in patients with severe esophagitis.¹ Abnormalities in peristalsis increase the risk for esophagitis. This includes delayed gastric emptying when gastric contents wash back into the esophagus as a result of their increased time in the stomach. Connective tissue disorders, gastric outlet obstruction caused by ulceration and stricture, and delayed gastric emptying from a variety of causes (such as postviral infections, gastric stasis, neuromuscular disease, vagal nerve disorders, idiopathic gastroparesis, pyloric dysfunction, duodenal dysmotility, duodenogastroesophageal bile reflux, and functional disorders of the gut) may account for up to half of the inadequate refluxate clearance.¹ A decrease in esophageal peristalsis can be more pronounced in patients with scleroderma, diabetes mellitus, hypothyroidism, amyloidosis, and eating disorders.¹

A fifth factor is the integrity of the protective barrier of the mucosal lining. The inability of the mucosa to resist breakdown in the face of excessive refluxed gastric acid, along with pepsin, bile, trypsin, and pancreatic enzymes of the small intestine, may lead to erosive esophagitis in the majority of patients and ulcers and strictures in the minority.¹ Saliva, along with alkaline secretion from the esophageal glands, serves as a potent buffer in neutralizing acid. Salivation decreases during sleep, which in turn prolongs acid clearance and may correlate with increased symptom severity at night. Reduced salivary secretion, such as in Sjögren disease or sicca syndrome, can lead to esophagitis. Eosinophilic esophagitis, both proton pump inhibitor (PPI) responsive and non–PPI responsive, is an allergy-mediated disease. Altered structural anatomy is also a factor in establishing an accurate diagnosis.

Finally, there is evidence to support the prevalence of GERD in individuals evaluated for excessive acid exposure despite normal findings on 24-hour pH monitoring studies. Of 128 patients in one study, 55% had confirmed normal acid exposure, but within 4 to 6 years 87% of these subjects continued to complain of GERD, leading to the suspicion that hypersensitivity plays a significant role.³

Clinical Presentation

The most common symptom of GERD is heartburn, which is usually described as a burning, retrosternal discomfort. Other terms for heartburn include indigestion, acid regurgitation, sour stomach, and bitter belching. A hot sensation usually begins inferiorly and radiates up the entire retrosternal area to the neck, occasionally to the back, and rarely into the arms. The sensation may become so intense that it is described as pain. Heartburn is usually relieved with antacids, baking soda, or milk, but these remedies are often short-lived.

Heartburn is frequently precipitated by food intake and occurs within 1 hour of eating, particularly after a large fatty meal. Other foods that precipitate heartburn are foods high in fat or sugar, chocolate, coffee, and onions, because they lower pressure in the LES. Alcohol may also lower LES pressure. Tobacco smoking may have a dual role in causing harm: promoting bile movement from the intestine to the stomach while prolonging effective neutralization by delaying saliva secretion.¹ Other foods that commonly cause heartburn are citrus products, tomato-based foods, and spicy foods. These foods do not affect LES pressure but instead are direct mucosal irritants. Other direct irritants include aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), potassium, and even swallowing of large tablets. The prevalence of GERD is higher in patients on benzodiazepines, calcium antagonists, and aspirin, but GERD is less often seen in patients on oral contraceptives and hormone replacement therapy.³ Patients may also report heartburn or acid regurgitation that increases after going to bed, especially after eating late in the evening. This pain usually occurs within 1 to 2 hours of bedtime and may awaken a patient from sleep. Several other maneuvers, including bending over, lifting, straining, and exercising, or even sleeping position¹ may also precipitate heartburn because of increased intra-abdominal pressure.

Other symptoms of GERD, outside of esophageal burning and regurgitation, are termed extraesophageal symptoms, involve the respiratory and oropharyngeal tracts, and may be associated with other entities as well. A subset, extraesophageal reflux (EER), involves the respiratory tract.² Another subset is laryngopharyngeal reflux (LPR).⁴ Because these conditions may relate to GERD, they are included in the workup and treatment. Some variations of cough, sore throat, hoarseness, postnasal drainage, globus sensation, asthma, water brash, dysphagia, odynophagia, chest pain, sleep disturbance, nausea, and vomiting are described as EESs, but a consensus has not emerged.²^–⁴ The cost of investigating and treating this disparate group of patients is substantially higher than in PPI-controlled GERD.⁴

Acid regurgitation, bitter acidic fluid in the mouth, usually occurs at night or when bending over. Acid regurgitation may be associated with extraesophageal complications should the refluxate extend beyond the esophagus to the lungs, larynx, pharynx, or oral cavity. This symptom should be differentiated from vomiting. Water brash is the appearance of salty-tasting fluid in the mouth because of stimulated saliva secretion. If delayed gastric emptying is the cause of GERD, abdominal fullness, nausea, and early satiety may be present.

Dysphagia, which may affect up to 30% of patients with GERD,¹ and odynophagia are more predictive of severe disease and should be considered alarm symptoms. Dysphagia, an impairment of swallowing food into the stomach, is experienced immediately after swallowing. Patients may say that the food “sticks,” “hangs up,” or “stops.” This may be stemming from the oropharynx in the upper esophageal area or lower in the esophagus and reflects peristaltic dysfunction, inflammation, peptic stricture, or a Schatzki ring.¹ Esophageal strictures are highly correlated with hiatal hernia.⁹ Dysphagia and food impaction are hallmarks of eosinophilic esophagitis, which may be driven by reflux as a precursor and is thought to depend on the role of impaired esophageal mucosa and immune activation.¹⁰ Alternatively, GERD may be associated with a globus sensation, which is considered a heightened perception of something stuck like a “lump” in the throat, despite the lack of a diagnosable artifact. A recent onset of severe dysphagia might reflect esophageal cancer¹ (see Chapter 143). Odynophagia is sharp pain on swallowing and usually occurs under the sternum. Odynophagia is more commonly associated with infectious esophagitis (fungal, viral, or bacterial) or pill ulceration¹ (see Chapter 134).

Chest pain can mimic angina, which may be explained by shared neural pathways. Esophageal disorders are considered the most common cause of noncardiac chest pain.¹ Symptoms that are more suggestive of esophageal problems include pain that continues for hours, interrupts sleep, or is retrosternal without lateral radiation and pain that is meal related or relieved with antacids. Some association of GERD symptoms with obstructive sleep apnea has been observed, but causal direction with respect to reflux and apnea has yet to be determined. Obesity may be a confounder in both. Pain that is not exercise induced is also suggestive of an esophageal disorder.¹

When GERD is overlooked as a factor, many of these atypical GERD symptoms can be refractory to treatment. As described earlier, some conditions, such as dyspepsia, may overlap with GERD; erosive esophagitis and nonerosive esophagitis are said to be present in 20% of patients with dyspepsia, the most common finding, followed by peptic ulcer.⁷ However, symptom control in response to standard GERD treatment, including surgery, may serve to uncover reflux as a factor. Co-management, especially in respiratory illnesses such as asthma, pulmonary fibrosis, and aspiration pneumonia, increasingly is standard practice.

Medications may contribute to GERD by decreasing salivation, esophageal motility, LES tone, or a combination of these factors.¹ Decreased LES pressure results from the administration of nitrates, tricyclic antidepressants, benzodiazepines among other sedatives, anticholinergics, bronchodilators, and methylxanthine derivatives (such as caffeine, aminophylline, and theophylline) as well as a wide assortment of cardiac medications including alpha-adrenergic blockers, beta blockers, and calcium channel blockers.¹^,³

Physical Examination

A careful history is likely to be more important than the physical findings. Because there is an association between dental erosions and GERD, an oral examination may suggest GERD in a patient with extensive loss of enamel and exposed dentin. Halitosis might also be a sign. Cutaneous evidence of smoking can be associated with GERD, as well as scleroderma, evidenced as thickened, tight, shiny skin or sclerodactyly as well as facial telangiectasia. Weight loss is a concern, particularly in patients who have dysphagia; by contrast, obesity can lead to symptoms. Respiratory wheezes and cough may be seen if there is associated asthma. Epigastric tenderness or Hemoccult-positive stool may be the result of esophageal erosions, ulcerations, or even severe inflammation. Any abdominal mass would suggest malignant neoplasia.

Diagnostics

Further diagnostic testing should be considered in patients with a failed empirical trial suggesting an alternative diagnosis, with sudden onset of symptoms in a patient aged 50 years or older, with alarm symptoms suggesting complicated disease (anemia, dysphagia, bleeding, odynophagia), and with long-standing symptoms of sufficient duration to put patients at risk for Barrett esophagus. The purpose of evaluating patients with long-term symptoms is to exclude complications of GERD.

Although barium radiography will help characterize mechanical obstructions such as strictures, hiatal hernia, and esophageal shortening to inform surgical approach, it has poor sensitivity and specificity and should not be used as a screening test. However, it may be used in refractory GERD along with high-definition, high-resolution, flexible video esophagogastroduodenoscopy (EGD) and mucosal biopsy.⁸^,¹¹

EGD is appropriate for patients with long-standing or poorly controlled GERD or in the presence of alarm features. In fact, a rise in the prevalence of GERD and an older population correlate with a 40% rise in the number of screening EGDs among Medicare beneficiaries.⁶ The American College of Physicians EGD Clinical Guidelines Committee members published best practices in 2012. Because EGD is notoriously problematic as a screening tool in those with reflux symptoms, it is better used (1) to examine patients who have breakthrough symptoms despite 4 to 8 weeks of twice-daily PPI therapy; (2) to monitor severe erosive esophagitis after 2 months of PPI therapy to assess healing or rule out Barrett esophagus; (3) to monitor patients with a history of esophageal stricture who have recurrent dysphagia; (4) to screen high-risk individuals with chronic GERD or to survey high-risk individuals with GERD and Barrett esophagus with or without dysplasia; and (5) to screen atypical or extraesophageal presentations as part of a presurgical evaluation or to perform stricture dilation.³^,⁹

Because heartburn and regurgitation lead the clinician to GERD above other diagnoses, patients are commonly treated with PPI therapy without EGD. This risks missing a potential case of Barrett esophagus, eosinophilic esophagitis, and PPI-responsive eosinophilia, because they may overlap.⁶^,¹⁰ Barrett esophagus is an important diagnosis to be made; it represents a change in typically observed esophageal mucosa and may develop into esophageal adenocarcinoma within a rare, unfortunate group of patients with GERD. The Montreal consensus definition for classification of Barrett’s esophagus includes all three types of columnar metaplasia (specialized intestinal, characterized by goblet cells; gastric junctional type, also known as cardiac type; and gastric fundic type), but the presence of metaplasia (goblet cells) in the columnar epithelial lining of the distal esophagus is the only type of esophageal columnar epithelium known to predispose to malignancy, so it is a preferred diagnosis.²

In cases of dysphagia, EGD is always indicated initially because dilation of a possible stricture can occur at the same time as the diagnostic procedure. Biopsy specimens of the gastric mucosa obtained during EGD may reveal gram-negative Helicobacter pylori, which affects 20% to 50% of the industrialized world’s population and 80% of the developing world’s.¹² Opinion is divided as to whether patients should be tested and treated for H. pylori before long-term PPI therapy. There is some association with the location of H. pylori and gastric and duodenal ulcers (in 1% to 10%), gastric carcinoma (0.1% to 3%, a sixfold increased risk), and gastric mucosa–associated lymphoid tissue lymphoma (rare); the majority will develop symptoms.¹² It is also linked to vitamin B₁₂ and iron deficiency. In general, patients treated for H. pylori have a decrease in GERD symptoms.³ Although H. pylori is associated with some protective effects with respect to developing GERD, esophageal carcinoma, pediatric allergies, and asthma, on the whole it is thought better eradicated in cases of peptic ulcer disease, carcinoma of the stomach, and functional dyspepsia, given that its cost-effectiveness is not established in broad testing and treatment.¹²

Gastric emptying scans are useful for early satiety, nausea, and vomiting symptoms. Dynamic barium videography is useful to examine swallowing irregularities and look for structural defects.

Ambulatory pH testing (24-hour catheter based or ≥48-hour wireless) and high-resolution esophageal manometry are of benefit to patients with refractory symptoms and before reflux surgery. Esophageal pH testing can be performed with or without PPI and H₂ receptor antagonist acid suppression therapy. Esophageal pH testing with a single- or dual-sensor pH probe positioned above the LES (and below the upper esophageal sphincter, if the second sensor is used) for 24 hours contributes to the composite DeMeester score.⁸

Diagnostics

Gastroesophageal Reflux Disease (GERD)

Laboratory