The current conception of GERD is to encompass a family of conditions with the commonality that they are caused by gastroesophageal reflux resulting in either troublesome symptoms or an array of potential esophageal and extraesophageal manifestations. It is estimated that 15% of adults in the United States are affected by GERD, although such estimates are based only on population studies of self-reported chronic heartburn. With respect to the esophagus, the spectrum of injury includes esophagitis, stricture, Barrett’s esophagus, and adenocarcinoma (Fig. 347-9). Of particular concern is the rising incidence of esophageal adenocarcinoma, an epidemiologic trend that parallels the increasing incidence of GERD. There were about 8000 incident cases of esophageal adenocarcinoma in the United States in 2013 (half of all esophageal cancers); it is estimated that this disease burden has increased two- to sixfold in the last 20 years.
Endoscopic appearance of (A) peptic esophagitis, (B) a peptic stricture, (C) Barrett’s metaplasia, and (D) adenocarcinoma developing within an area of Barrett’s esophagus.
The best-defined subset of GERD patients, albeit a minority overall, have esophagitis. Esophagitis occurs when refluxed gastric acid and pepsin cause necrosis of the esophageal mucosa causing erosions and ulcers. Note that some degree of gastroesophageal reflux is normal, physiologically intertwined with the mechanism of belching (transient LES relaxation), but esophagitis results from excessive reflux, often accompanied by impaired clearance of the refluxed gastric juice. Restricting reflux to that which is physiologically intended depends on the anatomic and physiologic integrity of the esophagogastric junction, a complex sphincter comprised of both the LES and the surrounding crural diaphragm. Three dominant mechanisms of esophagogastric junction incompetence are recognized: (1) transient LES relaxations (a vagovagal reflex in which LES relaxation is elicited by gastric distention), (2) LES hypotension, or (3) anatomic distortion of the esophagogastric junction inclusive of hiatus hernia. Of note, the third factor, esophagogastric junction anatomic disruption, is both significant unto itself and also because it interacts with the first two mechanisms. Transient LES relaxations account for about 90% of reflux in normal subjects or GERD patients without hiatus hernia, but patients with hiatus hernia have a more heterogeneous mechanistic profile. Factors tending to exacerbate reflux regardless of mechanism are abdominal obesity, pregnancy, gastric hypersecretory states, delayed gastric emptying, disruption of esophageal peristalsis, and gluttony.
After acid reflux, peristalsis returns the refluxed fluid to the stomach and acid clearance is completed by titration of the residual acid by bicarbonate contained in swallowed saliva. Consequently, two causes of prolonged acid clearance are impaired peristalsis and reduced salivation. Impaired peristaltic emptying can be attributable to disrupted peristalsis or superimposed reflux associated with a hiatal hernia. With superimposed reflux, fluid retained within a sliding hiatal hernia refluxes back into the esophagus during swallow-related LES relaxation, a phenomenon that does not normally occur.
Inherent in the pathophysiologic model of GERD is that gastric juice is harmful to the esophageal epithelium. However, gastric acid hypersecretion is usually not a dominant factor in the development of esophagitis. An obvious exception is with Zollinger-Ellison syndrome, which is associated with severe esophagitis in about 50% of patients. Another caveat is with chronic Helicobacter pylori gastritis, which may have a protective effect by inducing atrophic gastritis with concomitant hypoacidity. Pepsin, bile, and pancreatic enzymes within gastric secretions can also injure the esophageal epithelium, but their noxious properties are either lessened without an acidic environment or dependent on acidity for activation. Bile warrants attention because it persists in refluxate despite acid-suppressing medications. Bile can transverse the cell membrane, imparting severe cellular injury in a weakly acidic environment, and has also been invoked as a cofactor in the pathogenesis of Barrett’s metaplasia and adenocarcinoma. Hence, the causticity of gastric refluxate extends beyond hydrochloric acid.
Heartburn and regurgitation are the typical symptoms of GERD. Somewhat less common are dysphagia and chest pain. In each case, multiple potential mechanisms for symptom genesis operate that extend beyond the basic concepts of mucosal erosion and activation of afferent sensory nerves. Specifically, hypersensitivity and functional pain are increasingly recognized as cofactors. Nonetheless, the dominant clinical strategy is empirical treatment with acid inhibitors, reserving further evaluation for those who fail to respond. Important exceptions to this are patients with chest pain or persistent dysphagia, each of which may be indicative of more morbid conditions. With chest pain, cardiac disease must be carefully considered. In the case of persistent dysphagia, chronic reflux can lead to the development of a peptic stricture or adenocarcinoma, each of which benefits from early detection and/or specific therapy.
Extraesophageal syndromes with an established association to GERD include chronic cough, laryngitis, asthma, and dental erosions. A multitude of other conditions including pharyngitis, chronic bronchitis, pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias, sleep apnea, and recurrent aspiration pneumonia have proposed associations with GERD. However, in both cases, it is important to emphasize the word association as opposed to causation. In many instances, the disorders likely coexist because of shared pathogenetic mechanisms rather than strict causality. Potential mechanisms for extraesophageal GERD manifestations are either regurgitation with direct contact between the refluxate and supraesophageal structures or via a vagovagal reflex wherein reflux activation of esophageal afferent nerves triggers efferent vagal reflexes such as bronchospasm, cough, or arrhythmias.
Although generally quite characteristic, symptoms from GERD need to be distinguished from symptoms related to infectious, pill, or eosinophilic esophagitis, peptic ulcer disease, dyspepsia, biliary colic, coronary artery disease, and esophageal motility disorders. It is especially important that coronary artery disease be given early consideration because of its potentially lethal implications. The remaining elements of the differential diagnosis can be addressed by endoscopy, upper gastrointestinal series, or biliary tract ultrasonography as appropriate. The distinction among etiologies of esophagitis is usually easily made by endoscopy with mucosal biopsies, which are necessary to evaluate for infection or eosinophilic inflammation. In terms of endoscopic appearance, infectious esophagitis is diffuse and tends to involve the proximal esophagus far more frequently than does reflux esophagitis. The ulcerations seen in peptic esophagitis are usually solitary and distal, whereas infectious ulcerations are punctate and diffuse. Eosinophilic esophagitis characteristically exhibits multiple esophageal rings, linear furrows, or white punctate exudate. Esophageal ulcerations from pill esophagitis are usually singular and deep at points of luminal narrowing, especially near the carina, with sparing of the distal esophagus.
The complications of GERD are related to chronic esophagitis (bleeding and stricture) and the relationship between GERD and esophageal adenocarcinoma. However, both esophagitis and peptic strictures have become increasingly rare in the era of potent antisecretory medications. Conversely, the most severe histologic consequence of GERD is Barrett’s metaplasia with the associated risk of esophageal adenocarcinoma, and the incidence of these lesions has increased, not decreased, in the era of potent acid suppression. Barrett’s metaplasia, endoscopically recognized by tongues of reddish mucosa extending proximally from the gastroesophageal junction (Fig. 347-9) or histopathologically by the finding of specialized columnar metaplasia, is associated with a substantially increased risk for development of esophageal adenocarcinoma.
Barrett’s metaplasia can progress to adenocarcinoma through the intermediate stages of low- and high-grade dysplasia (Fig. 347-10). Owing to this risk, areas of Barrett’s and especially any included areas of mucosal irregularity should be extensively biopsied. The rate of cancer development is estimated at 0.1–0.3% per year, but vagaries in definitional criteria and of the extent of Barrett’s metaplasia requisite to establish the diagnosis have contributed to variability and inconsistency in this risk assessment. The group at greatest risk is obese white males in their sixth decade of life. However, despite common practice, the utility of endoscopic screening and surveillance programs intended to control the adenocarcinoma risk has not been established. Also of note, no high-level evidence confirms that aggressive antisecretory therapy or antireflux surgery causes regression of Barrett’s esophagus or prevents adenocarcinoma.
Histopathology of Barrett’s metaplasia and Barrett’s with high-grade dysplasia. H&E, hematoxylin and eosin.
Although the management of Barrett’s esophagus remains controversial, the finding of dysplasia in Barrett’s, particularly high-grade dysplasia, mandates further intervention. In addition to the high rate of progression to adenocarcinoma, there is also a high prevalence of unrecognized coexisting cancer with high-grade dysplasia. Nonetheless, treatment remains controversial. Esophagectomy, intensive endoscopic surveillance, and mucosal ablation have all been advocated. Currently, esophagectomy is the gold standard treatment for high-grade dysplasia in an otherwise healthy patient with minimal surgical risk. However, esophagectomy has a mortality ranging from 3–10%, along with substantial morbidity. That, along with increasing evidence of the effectiveness of endoscopic therapy with purpose-built radiofrequency ablation devices, has led many to favor this therapy as a preferable management strategy.
TREATMENT Gastroesophageal Reflux Disease (GERD)
Lifestyle modifications are routinely advocated as GERD therapy. Broadly speaking, these fall into three categories: (1) avoidance of foods that reduce LES pressure, making them “refluxogenic” (these commonly include fatty foods, alcohol, spearmint, peppermint, tomato-based foods, and possibly coffee and tea); (2) avoidance of acidic foods that are inherently irritating; and (3) adoption of behaviors to minimize reflux and/or heartburn. In general, minimal evidence supports the efficacy of these measures. However, clinical experience dictates that subsets of patients are benefitted by specific recommendations, based on their unique history and symptom profile. A patient with sleep disturbance from nighttime heartburn is likely to benefit from elevation of the head of the bed and avoidance of eating before retiring, but those recommendations are superfluous for a patient without nighttime symptoms. The most broadly applicable recommendation is for weight reduction. Even though the benefit with respect to reflux cannot be assured, the strong epidemiologic relationship between body mass index and GERD and the secondary health gains of weight reduction are beyond dispute.
The dominant pharmacologic approach to GERD management is with inhibitors of gastric acid secretion, and abundant data support the effectiveness of this approach. Pharmacologically reducing the acidity of gastric juice does not prevent reflux, but it ameliorates reflux symptoms and allows esophagitis to heal. The hierarchy of effectiveness among pharmaceuticals parallels their antisecretory potency. Proton pump inhibitors (PPIs) are more efficacious than histamine2 receptor antagonists (H2RAs), and both are superior to placebo. No major differences exist among PPIs, and only modest gain is achieved by increased dosage.
Paradoxically, the perceived frequency and severity of heartburn correlate poorly with the presence or severity of esophagitis. When GERD treatments are assessed in terms of resolving heartburn, both efficacy and differences among pharmaceuticals are less clear-cut than with the objective of healing esophagitis. Although the same overall hierarchy of effectiveness exists, observed efficacy rates are lower and vary widely, likely reflecting patient heterogeneity.
Reflux symptoms tend to be chronic, irrespective of esophagitis. Thus, a common management strategy is indefinite treatment with PPIs or H2RAs as necessary for symptom control. The side effects of PPI therapy are generally minimal. Vitamin B12 and iron absorption may be compromised and susceptibility to enteric infections, particularly Clostridium difficile colitis, increased with treatment. Population studies have also suggested a slight increased risk of bone fracture with chronic PPI use suggesting an impairment of calcium absorption, but prospective studies have failed to corroborate this. Nonetheless, as with any medication, PPI dosage should be minimized to that necessary for the clinical indication.
Laparoscopic Nissen fundoplication, wherein the proximal stomach is wrapped around the distal esophagus to create an antireflux barrier, is a surgical alternative to the management of chronic GERD. Just as with PPI therapy, evidence on the utility of fundoplication is strongest for treating esophagitis, and controlled trials suggest similar efficacy to PPI therapy. However, the benefits of fundoplication must be weighed against potential deleterious effects, including surgical morbidity and mortality, postoperative dysphagia, failure or breakdown requiring reoperation, an inability to belch, and increased bloating, flatulence, and bowel symptoms after surgery.