Gastroesophageal reflux disease (GERD) is one of the most common disorders seen in the general population. Approximately 10% of all people experience heartburn daily, 15% in any given week, and about half the population in any given year.1 The spectrum of disease ranges from occasional postprandial substernal discomfort to the development of peptic stricture or even carcinoma in the setting of Barrett esophagus. It is important for physicians to identify and select appropriate treatments for patients at risk of developing complications. This chapter reviews the etiology, diagnosis, complications, and treatment of GERD.
The esophagus is lined with a stratified nonkeratinizing squamous epithelium consisting of three layers: superficial, intermediate, and basal. The basal cell layer comprises 15% of the total epithelial thickness and is the only layer that normally contains mitotic figures. The lamina propria, which lies deep to the squamous epithelium, contains glandular structures similar to those found in the gastric cardia. The epithelium is covered by a protective layer of mucin and surface bicarbonates that are produced by salivary glands located in the proximal esophagus and in the region adjacent to the gastroesophageal junction (GEJ). The mucus produced in these glands reaches the intervening sections of the esophagus through peristalsis. Unlike the stomach, the mucus layer that lines the esophagus is rudimentary and provides little protection against prolonged acid exposure.
The sensations of heartburn or discomfort from reflux are transmitted from the esophagus by the spinal splanchnic afferent nerves. These sensations may be modulated by vagal afferent nerves. A series of high-pressure zones, or sphincters, and zones of complex neural interaction propel the forward movement of food and liquid into the stomach and retard the return or reflux of gastric contents back into the esophagus. The intrinsic lower esophageal sphincter (LES), along with its extrinsic components, is the mechanism chiefly responsible for preventing gastric reflux back into the esophagus (Fig. 37-1). The LES is identified on intraluminal manometry as a 2- to 4-cm-long zone of high pressure at the GEJ. A ringed circular muscle is also present at this junction. The vessel density and amount of connective tissue are greater in LES muscle than in the remainder of the esophagus. This region is also rich in mitochondria and smooth endoplasmic reticulum.
The LES exerts a resting basal pressure in normal individuals. The tonic muscular contraction that is the hallmark of the LES contributes to the resting tone, distinguishing this region from the esophageal body. Inhibition of LES contraction is mediated largely through nitric oxide, whereas excitation is mediated through acetylcholine. Even with ablation of all neural input, the LES maintains its intrinsic basal smooth muscle tone. This muscular tone is distributed unevenly throughout the sphincter. The pressure is greatest in the lowest 2 cm of the LES and on the left side, where the left crus and sling fibers of the stomach exert force on the LES. The basal pressure also varies according to the respiratory cycle. During inspiration, the pressure in the upper half of the LES decreases, whereas the pressure in the lower half increases. This finding may be related to the respiratory contractions of the diaphragmatic crural fibers or relative intrathoracic and intra-abdominal pressures. A small shift in the position of the LES can have dramatic effects on these pressure gradients.
Relaxation of the LES occurs naturally during deglutition, about 2 seconds after the initiation of swallowing. At this time, the pressure in the LES decreases to a level approximating the intragastric pressure. This period of decreased pressure may last as long as 8 to 10 seconds. Distention of the esophagus produces a reflex relaxation of the LES that is distinct from the relaxation elicited during initiation of swallowing, such as that produced from tactile pharyngeal stimulation. A number of hormones and neurotransmitters also can produce LES relaxation. These include gastric inhibitory peptide, glucagon, cholecystokinin, nitric oxide, progesterone, vasoactive intestinal peptide, and prostaglandin E. Conversely, hormones that stimulate contraction include gastrin, bombesin, motilin, serotonin, and somatostatin (Table 37-1).
The two components of the extrinsic portion of the LES are the transmitted intra-abdominal pressure and the crural fibers. As long as the LES is situated below the diaphragm (the normal anatomic position), increases in intra-abdominal pressure are exerted equally on the LES and stomach. The crural fibers serve as a redundant means of maintaining LES pressure. A normal LES should be able to resist most increases in intragastric pressure. For this reason, many individuals with a hiatal hernia have no reflux. The crural fibers exert increased pressure on the LES when the tendency toward reflux is greatest (i.e., during inspiration and with increases in intra-abdominal pressure). During inspiration, the intrathoracic pressure decreases, and the intra-abdominal pressure increases. Crural fibers contract along with the diaphragm, causing an increase in LES pressure. Pressure from the crural fibers also increases during independent increases in intra-abdominal pressure.
The anatomy of the proximal stomach and its angle of attachment to the LES (angle of His) counteract the tendency for reflux to occur. The esophagus joins the stomach not at its apex but farther down along the lesser curvature. It is believed that the lateral fold of the gastric mucosa acts as a flap valve, helping to close the entrance to the LES during episodes of raised intra-abdominal and intragastric pressure. The fundus and cardia of the stomach act as a reservoir to minimize the increase in intragastric pressure associated with meals. The anatomic significance of the angle of His and its relationship to the fundic reservoir is apparent in studies showing a larger degree of reflux when individuals lie on the right side as opposed to the left.
Normal esophageal motility and clearance are important to minimizing the effects of gastric refluxate. Reflux into the esophagus is normally followed by waves of secondary peristalsis that move the contents back into the stomach. This secondary wave of peristalsis also brings bicarbonate-rich saliva into the esophagus to neutralize the remaining gastric acid. Although impaired esophageal motility occasionally may result from severe reflux esophagitis, it also may contribute to it, such as occurs in patients with scleroderma.
Factors that affect the degree of gastroesophageal reflux include esophageal motility, the amount and composition of the saliva and other protective esophageal factors, the intrinsic LES, alterations in the transthoracic—transabdominal pressure gradient, the extrinsic LES (including the crural muscles), the integrity of the angle of His, gastric emptying, and the nature of the refluxate.
The LES is the most important component of the antireflux apparatus. Decreased resting LES tone and transiently decreased LES tone both may contribute to reflux. Transient relaxation is induced by gastric distention and pharyngeal stimulation. The former condition allows eructation with relief of gastric pressure, whereas the latter is important in swallowing. Transient relaxation is inhibited in the supine position and during sleep. The consumption of inappropriately large meals not only provides a pressure gradient favoring reflux but also induces transient relaxation of LES tone. Inappropriately low transient LES pressure is believed to be the most common cause of reflux and may account for 60% to 70% of episodes of heartburn. Pathologic transient decreases in LES tone occur when the LES pressure decreases by more than 5 mm Hg in the absence of a swallow. Reflux in patients with mild to moderate disease and no endoscopic evidence of esophagitis most often occurs as a consequence of transient decreases in LES pressure, whereas patients with severe reflux typically also have deficits in resting LES tone. Normal LES tone is 10 to 30 mm Hg above gastric pressure. Less than 2.5% of the population has a resting LES pressure of less than 6 mm Hg. Most patients with mild reflux have normal LES tone. Patients with erosive esophagitis usually have a low resting LES tone, and the degree of esophagitis typically correlates with the lack of LES tone. There is evidence in animals that repeated exposure of the LES to acid via transient relaxation may damage the sphincter, leading to a lower resting LES tone.
A hiatal hernia is defined as the separation and cranial displacement of the GEJ from the diaphragmatic hiatus. In normal individuals, the GEJ is anchored to the crus by the phrenoesophageal ligament, which is composed of a reflection of peritoneum fused with fibrous tissue (Fig. 37-2). When there is a hiatal hernia, the crura are often stretched and thin, and the phrenoesophageal ligament is lax. The redundant tissue is termed the hernia sac. In normal individuals, increased intra-abdominal pressure does not lead to reflux. In patients with hiatal hernia, however, the contribution of the diaphragmatic crura and effects of increased intra-abdominal pressure on the intra-abdominal esophagus are lost, leading to increased susceptibility to strain-induced reflux. Whether prolonged reflux leads to fibrosis and shortening of the esophagus with development of a hiatal hernia, or if the primary laxity in the crura and phrenoesophageal membrane leads to the development of reflux is unknown. As the hiatal hernia enlarges, the resting LES tone diminishes.
Deficits in esophageal peristalsis are seen commonly in individuals with moderate-to-severe GERD. An esophageal contraction of 30 mm Hg or greater is usually adequate to clear an acid bolus in the supine patient. Poor contractility, with a decreased number or amplitude of contractions, leads to acid retention in the esophagus. Repeated exposure of the esophagus to acid is believed to injure the intrinsic muscles of the esophagus and may lead to further deficits in esophageal motility and clearance. Twenty-five percent of patients with mild and 50% of patients with severe esophagitis have evidence of severe dysfunction.2 Individuals with decreased salivary volume (e.g., patients with Sjögren’s syndrome and smokers) have increased acid exposure in the esophagus owing to decreased clearance.
Most individuals with symptomatic GERD have normal gastric emptying. It is evident, however, that a delay in gastric emptying will increase gastric volume and pressure and exacerbate GERD in patients predisposed to the condition. This can be seen after any surgery on the GEJ if the vagus nerves are injured, and it must be considered in any patient who has reflux despite fundoplication. Patients with gastroduodenoesophageal reflux and GERD may be more susceptible to erosive esophagitis than those with GERD alone. Pepsin and bile salts from the duodenum have proteolytic and detergent effects that exacerbate the damaging effects of gastric acid.
Most individuals experience the typical symptoms of heartburn, that is, regurgitation or midline chest discomfort, at some point during their lifetime (Table 37-2). The burning pain or pressure associated with heartburn is caused by reflux of acid into the esophagus. Frequently, symptoms are more prevalent after meals or in the supine position. Certain foods associated with decreased LES tone, such as high-fat meals, caffeine, chocolate, peppermint, and alcohol, may exacerbate these symptoms. In general, individuals who experience heartburn only after certain foods tend to have higher resting LES pressures than those who experience heartburn with almost all types of foods. Patients with daily symptoms are more likely to have resting LES pressures of less than 10 mm Hg.1 Relief of symptoms immediately after ingestion of water or antacids supports the diagnosis of GERD. Substernal pressure may be related to esophageal spasm caused by esophagitis or exposure to acid. If the pain is related to exertion and stops on cessation of activity, cardiac ischemia should be considered, although a significant number of these patients also may have reflux. The severity and frequency of symptoms do not necessarily reflect the severity of the underlying esophagitis. One-quarter of all patients with severe reflux and Barrett esophagus have no symptoms at all.3 Likewise, a significant number of patients with frequent and severe complaints are not found to have esophagitis by endoscopy.
Respiratory symptoms such as hoarseness, cough, asthma, and recurrent pneumonia are referred to as atypical symptoms (Table 37-2). Although a significant number of patients with chronic asthma or cough also may have GERD, these symptoms are less specific than typical symptoms, and surgical fundoplication is, in general, less effective for symptom control. A randomized controlled trial by Larrain et al.4 treated 94 intrinsic asthma patients with reflux documented by either barium swallow or pH probe analysis. The patients were randomized to placebo, cimetidine, or surgery. The surgery and cimetidine groups had roughly 75% improvement in wheezing and respiratory function versus only 34% in the control group. Long-term follow-up showed that 50% of the surgical group was asthma-free compared with only 5% of the control group. Individuals with respiratory symptoms who may be more likely to respond to GERD treatment are those with nonallergic asthma, nocturnal symptoms, abnormal proximal esophageal acid exposure, and those who had reflux symptoms before developing asthma.
Patients with odynophagia (i.e., pain on swallowing) or dysphagia (i.e., difficulty swallowing) are more likely to have severe esophagitis, abnormal motility, or structural abnormalities of the esophagus. Odynophagia may be associated with severe esophagitis or esophageal spasm. Dysphagia may be related to motor diseases (typically, dysphagia to both solids and liquids) or to a narrowing caused by a peptic stricture, ring, or tumor (dysphagia more with solids than with liquids).
