ANTIREFLUX BARRIERS

The first tier of the three-tiered esophageal defense against acid damage, the antireflux barriers, is an anatomically complex region including the intrinsic lower esophageal sphincter (LES), diaphragmatic crura, the intra-abdominal location of the LES, the phrenoesophageal ligaments, and the acute angle of His (Fig. 43-3).

Figure 43-3. Anatomy of the gastroesophageal junction illustrating the major elements of the antireflux barrier.

The LES involves the distal 3 to 4 cm of the esophagus and at rest is tonically contracted.⁴² It is the major component of the antireflux barrier, being capable of preventing reflux even when completely displaced from the diaphragmatic crura by a hiatal hernia.⁴³ The proximal portion of the LES is normally 1.5 to 2 cm above the squamocolumnar junction, whereas the distal segment, about 2 cm in length, lies within the abdominal cavity. This location maintains gastroesophageal competence during intra-abdominal pressure excursions. Resting LES pressure ranges from 10 to 30 mm Hg with a generous reserve capacity because only a pressure of 5 to 10 mm Hg is necessary to prevent GER.⁴⁴ The LES maintains a high-pressure zone by the intrinsic tone of its muscle and by cholinergic excitatory neurons.^45,46 There is considerable diurnal variation in basal LES pressure; it is lowest after meals and highest at night, and large increases occur with phase III of the migrating motor complex. It is also influenced by circulating peptides and hormones, foods (particularly fat), as well as a number of drugs (Table 43-1) (see also Chapter 48).

Table 43-1 Modulators of Lower Esophageal Sphincter Pressure

LES, lower esophageal sphincter; VIP, vasoactive intestinal peptide.

The LES lies within the hiatus created by the right crus of the diaphragm and is anchored by the phrenoesophageal ligaments, which insert at the level of the squamocolumnar junction (see Fig. 43-3). Developmentally, the crural diaphragm arises from the dorsal mesentery of the esophagus and is innervated separately from the costal diaphragm. It is inhibited by esophageal distention, vomiting, and during transient LES relaxations (tLESRs), but not during swallowing. The crural diaphragm provides extrinsic squeeze to the intrinsic LES, contributing to resting pressure during inspiration and augmenting LES pressure during periods of increased abdominal pressure, such as with coughing, sneezing, or bending.⁴⁷ Crural contractions impose rhythmic pressure increases of about 5 to 10 mm Hg on the LES pressure recording. During deep inspirations and some periods of increased abdominal straining, these changes may lead to pressures of 50 to 150 mm Hg.⁴⁸

The oblique entrance of the esophagus into the stomach creates a sharp angle on the greater curve aspect of the gastroesophageal junction, the angle of His. This angle has been shown in cadavers to create a flap valve effect that contributes to gastroesophageal junction competency.⁴⁹

MECHANISMS OF REFLUX

Transient Lower Esophageal Sphincter Relaxations

tLESRs are the most frequent mechanism for reflux in patients with healthy sphincter pressures. Figure 43-4 illustrates a transient LESR and highlights differences from swallow-induced LESRs. tLESRs occur independently of swallowing, are not accompanied by esophageal peristalsis, persist longer (>10 seconds) than swallow-induced LESRs, and are accompanied by inhibition of the crural diaphragm.⁵⁰ tLESRs account for nearly all reflux episodes in healthy subjects and 50% to 80% of episodes in GERD patients, depending on the severity of associated esophagitis (Fig. 43-5).⁵¹ However, one study suggests that low basal LES pressure, rather than tLESRs, may be the primary mechanism of GER in patients with nonreducible hiatal hernias.⁵²

Figure 43-4. Example of a transient lower esophageal sphincter (LES) relaxation (tLESR) on an esophageal manometry study. LES pressure is referenced to gastric pressure, which is indicated by the horizontal dashed line. Note that the tLESR persisted for almost 30 seconds, whereas the swallow-induced LES relaxation (LESR) to the right (Sw) persisted for only 5 seconds. Also note the absence of a submandibular electromyographic (EMG) signal during the tLESR, which indicates absence of a pharyngeal swallow. Finally, the associated esophageal motor activity is different in the two types of LESR: the swallow-induced relaxation is associated with primary peristalsis, whereas the tLESR is associated with a vigorous, repetitive “off contraction” throughout the esophageal body.

(From Kahrilas PJ, Gupta RR. Mechanisms of reflux of acid associated with cigarette smoking. Gut 1990; 31:4.)

Figure 43-5. Proportion of reflux episodes in control subjects and in patients with gastroesophageal reflux disease (GERD) occurring by the following mechanisms: transient lower esophageal sphincter relaxation (tLESR), swallow-induced lower esophageal sphincter relaxation (LESR), absent basal LES pressure, and straining in the presence of low LES pressure.

(From Holloway RH. The anti-reflux barrier and mechanisms of gastro-oesophageal reflux Ballieres Clin Gastroenterol 2000; 14:681.)

tLESRs are not always associated with GER. In normal subjects 40% to 60% of tLESRs are accompanied by reflux episodes, compared with 60% to 70% in GERD patients.^45,51,53 Possible factors determining whether reflux occurs include abdominal straining, presence of a hiatal hernia, degree of esophageal shortening, and duration of tLESRs. The dominant stimulus for tLESR is distention of the proximal stomach by either food or gas,^54,55 which is not surprising given that a tLESR is the mechanism of belching. More varying stimuli are fat, stress, and subthreshold (for swallowing) stimulation of the pharynx.⁴⁹ Various drugs may impair tLESRs including cholecystokinin A (CCK-1) receptor antagonists, anticholinergic drugs, morphine, somatostatin, nitric oxide inhibitors, 5-hydroxytryptamine (5-HT)₃ antagonists, and γ-aminobutyric acid (GABA_B) agonists.⁵⁶

Evidence indicates that tLESRs are mediated through vagal pathways.⁵⁴ Gastric distention activates mechanoreceptors (intraganglionic lamellar endings) adjacent to the gastric cardia, sending signals to the brainstem center via vagal afferent pathways.⁵⁷ The structured sequence of motor events including LESR, crural diaphragm inhibition, and secondary esophageal peristalsis suggests that this process occurs in a programmed manner, probably controlled by a pattern generator within the vagal nuclei. The motor arm is the vagus nerve sharing common elements with swallow-induced LESR.⁵⁶

HIATAL HERNIA

The contribution of the hiatal hernia to GERD is controversial. Opinion has shifted widely from one that virtually equated hiatal hernia with reflux disease to one that denied it a causal role. Epidemiologic and physiologic data confirm the importance of the hiatal hernia in patients with more severe esophagitis, peptic stricture, or Barrett’s esophagus.⁶² Hiatal hernia occurs in 54% to 94% of patients with reflux esophagitis, a rate strikingly higher than that in the healthy population.⁶³ Two studies have also found that in individuals with reflux symptoms, the presence of hiatal hernia confers a significantly increased risk of erosive esophageal injury.⁶⁴

The hiatal hernia impairs LES function through several mechanisms, as well as impairing esophageal acid clearance (Fig. 43-6).⁶⁵ Reflux is worse in patients having a “nonreducible” as opposed to a “reducible” hiatal hernia. Nonreducing hernias are those in which the gastric rugal folds remain above the diaphragm between swallows.⁶² Statistical modeling has revealed a significant interaction between hiatal hernia and LES pressure, such that the likelihood of GER is increased as basal LES pressure decreases, an effect substantially amplified by the presence of a hernia and as the hernia size increases.⁴³

Figure 43-6. Schematic diagram showing the effect of a hiatal hernia on the antireflux barrier. LES, lower esophageal sphincter.

Displacement of the LES from the crural diaphragm into the chest reduces basal LES pressure and shortens the length of the high-pressure zone primarily due to the loss of the intra-abdominal LES segment.⁶² Hiatal hernia eliminates the increase of LES pressure that occurs during straining and increases tLESRs during gastric distention with gas.^65,66 Large, nonreducible hernias also impair esophageal acid clearance because of an increased tendency for reflux to occur from the hernia sac during swallow-induced LESRs.⁵³ Finally, an alteration of esophagogastric junction compliance, especially in GERD patients with hiatal hernia, has been identified.⁵⁹ For the same degree of intragastric pressure, the esophageal junction opens at a lower pressure and the cross-sectional area is greater and more symmetrical as intragastric pressure increases. These changes in compliance simulated a 10-fold increase in air and 6-fold increase in liquid reflux across the esophageal junction.

The etiology of a hiatal hernia remains unclear. Familial clustering of GERD suggests the possibilities of an inherited smooth muscle disorder. Animal studies propose that reflux itself causes esophageal shortening promoting the development of a hiatal hernia.⁶⁷ Other studies find an association with obesity⁶⁸ and heavy lifting,⁶⁹ raising the possibilities that over time chronic intra-abdominal stressors may weaken the esophageal hiatus, causing the development of a hiatal hernia. This theory is attractive as it helps to reconcile the increased prevalence of hiatal hernias as the population grows older.⁶³

ESOPHAGEAL ACID CLEARANCE

The second tier against reflux damage is esophageal acid clearance. This phenomenon involves two related but separate processes: volume clearance, which is the actual removal of the reflux material from the esophagus, and acid clearance, which is the restoration of normal esophageal pH following acid exposure through titration with base from saliva and esophageal gland secretions. Although the competency of the antireflux barrier determines the frequency and volume of GER, esophageal acid clearance determines the duration of acid exposure to the mucosa and probably the severity of mucosal damage.

Volume Clearance

Esophageal peristalsis clears acid volume in the upright and supine positions but is inoperative during deep rapid-eye-movement (REM) sleep. Helm and colleagues⁷⁰ showed that one or two primary peristaltic contractions completely clear a 15-mL fluid bolus from the esophagus (Fig. 43-7). Primary peristalsis is elicited by swallowing. Secondary peristalsis, initiated by esophageal distention from acid reflux, is much less effective in clearing the refluxate, thus offering only an ancillary protective role.

Figure 43-7. Relationship between esophageal peristalsis, distal esophageal pH, esophageal emptying, and esophageal acid clearance during an acid clearance test performed with radiolabeled 0.1 N hydrochloric acid. Bolus volume within the esophagus is derived from scintiscanning over the chest. Note that, although all but 1 mL of the infused fluid is cleared from the esophagus by the first peristaltic contraction, the distal esophageal pH remains low for at least 3 minutes. Stepwise increases in distal esophageal pH occur with subsequent swallows. DS, dry swallow.

(From Helm JF, Dodds WJ, Pek LR, et al. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1984; 310:284.)

Peristaltic dysfunction (i.e., failed peristaltic contractions and hypotensive [<30 mm Hg] peristaltic contractions that incompletely empty the esophagus) increases in frequency with the severity of esophagitis. Kahrilas and colleagues⁷¹ found that the prevalence of peristaltic dysfunction rose from 25% in individuals with mild esophagitis to more than 50% in patients with severe esophagitis. Whether esophagitis per se leads to peristaltic dysfunction or whether an underlying smooth muscle motility disorder of the esophagus predisposes to the development of reflux disease is not clear. Animal studies have found that esophageal dysmotility associated with active esophagitis is reversible, but esophageal dysmotility associated with stricture or extensive fibrosis is irreversible.⁶⁰ Clinical observations suggest that impaired motor function does not revert to normal following either effective medical or surgical therapies.⁶¹

Gravity contributes to bolus clearance when reflux occurs in the upright position. At night when supine, this mechanism is not operative unless the head of the bed is elevated. This important lifestyle change markedly improves acid clearance time and is most beneficial in patients with aperistalsis (i.e., scleroderma).⁷²

Tissue Resistance

Although clearance mechanisms minimize acid contact time with the epithelium, even healthy subjects have acid reflux during the day and sometimes at night. Nevertheless, only a few subjects experience symptomatic GER and even fewer suffer GERD. This is due to a third tier for esophageal defense, known as tissue resistance. Conceptually, tissue resistance can be subdivided into pre-epithelial, epithelial, and postepithelial factors, which act together to minimize mucosal damage from the noxious gastric refluxate.⁸⁰

The pre-epithelial defense in the esophagus is poorly developed. There is neither a well-defined mucous layer nor buffering capacity by the surface cells to secrete bicarbonate ions into the unstirred water layer. This results in a lumen-to-surface pH gradient in the esophagus of only 1 : 10, in contrast with the stomach and duodenum, where the gradient can range from 1 : 1000 to 1 : 10,000.⁸¹

The epithelial defenses consist of structural and functional components. Structural components include the cell membranes and intercellular junctional complexes of the esophageal mucosa. As reviewed in Chapter 41, this structure is a 25- to 30-cell-thick layer of nonkeratinized squamous epithelium functionally divided into a proliferating basal cell layer (stratum basalis), a midzone layer of metabolically active squamous cells (stratum spinosum), and a 5- to 10-cell-thick layer of dead cells (stratum corneum). The esophageal mucosa is a relatively “tight” epithelium that resists ionic movement at the intercellular, as well as the cellular, level as the result of tight junctions and the matrix of lipid-rich glycoconjugates in the intercellular space.⁸² Luminal acid attacks the epithelial defenses by damaging the intercellular junction, allowing hydrogen ions to enter and acidify the intercellular space. As documented by transmission electron microscopy, the intercellular spaces expand and eventually the buffering capacity of this space is overwhelmed, leading to acidification of the adjacent cytosol via the basolateral membrane.⁸⁰ The functional components of tissue resistance include the ability of the esophageal epithelium to buffer and extrude hydrogen ions. Intracellular buffering is accomplished by negatively charged phosphates and proteins, as well as bicarbonate ions. When the mucosal buffering capacity is exceeded and intracellular pH falls, the epithelium has the capacity to actively remove or neutralize H⁺. This is possibly by the action of two transmembrane proteins, one an Na⁺/H⁺ exchanger and the other an Na⁺-dependent Cl⁻/HCO₃⁻ exchanger.^83,84 After reflux-induced cell acidification, these transporters restore the intracellular pH to neutrality by exchanging H⁺ for extracellular Na⁺ or by exchanging Cl⁻ for extracellular HCO₃⁻, respectively. Additionally, esophageal cells contain within their membrane an Na⁺-independent Cl⁻/HCO₃⁻ exchanger that extrudes HCO₃⁻ from the cytoplasm when the intracellular pH is too high.⁸³ When the epithelial cells are no longer able to maintain intracellular pH, they lose their ability to volume regulate, edema occurs, balloon cells develop, and cell death follows. Additional contributors to the epithelial defense include salivary epidermal growth factor, transforming growth factor-α, and prostaglandin E₂. These factors enhance epithelial cell turnover, enhance esophageal mucin production, and modulate bicarbonate secretion.⁸⁵

Data suggest that dilated intercellular spaces are the earliest markers of esophageal epithelial cellular damage (Fig. 43-8). These alterations arise with exposure to acid and pepsin during gastroesophageal reflux, but the exact pathway of damage to the intercellular junctions remains unclear and seems to be multifactorial.⁸⁶ Other noxious contents of the refluxate, such as bile acids, are harmful, and dilated intercellular spaces can be induced by acute psychological stress.⁸⁷ Dilated intercellular spaces can be assessed quantitatively with electron microscopy (EM), but they also are recognizable with light microscopy (LM). In studies by Calabrese and colleagues,^88,89 all controls had intercellular spaces less than 1.69 µm. Symptomatic patients had a mean intercellular space value and a mean value of the maximum dilated intracellular space at least three times greater than controls. Statistical differences were not observed between esophagitis patients and nonerosive GERD patients. The authors speculated that increased paracellular permeability could partly explain the development of heartburn in the absence of overt esophagitis. This hypothesis is supported by the presence of sensory neuron receptors within the intercellular space, only a few cell layers from the esophageal lumen.⁹⁰ Importantly, aggressive acid inhibition with proton pump inhibitors leads to complete resolution of the dilated intercellular spaces in nearly all patients over three to six months. These changes correlated closely with the resolution of heartburn.⁸⁹

Figure 43-8. Micrographs of esophageal epithelium, obtained during transmission electron microscopy. Normal subjects (A) do not have dilated intercellular spaces. In contrast, patients with “bile” reflux (B), nonerosive gastroesophageal reflux disease (GERD) (C), and erosive gastroesophageal reflux disease (D) have dilated intercellular spaces (irregular white spaces). This dilation appears to be the earliest cellular marker of GERD and is independent of the degree of esophagitis.

(From Calabrese C, Fabbri A, Bortolotti M, et al. Dilated intercellular spaces as a marker of oesophageal damage: Comparative results in gastro-oesophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther 2003; 18:525.)

The postepithelial defense is provided by the esophageal blood supply. Blood flow delivers oxygen, nutrients, and bicarbonate and removes H⁺ and CO₂, thereby maintaining normal tissue acid-base balance. Blood flow to the esophageal mucosa increases in response to the stress of luminal acid.⁹¹ Cellular injury also stimulates cell proliferation, which results in thickening of the basal cell layer of the epithelium. Unlike the stomach, where superficial mucosal injury can be repaired in hours, the esophagus repairs itself more slowly, over days to weeks. Acid suppression with proton pump inhibitors has been shown to reverse the characteristic histologic changes of esophageal reflux including basal layer thickening and dilation of intercellular spaces.^77,92

GASTRIC FACTORS

Gastric factors (volume and components of the gastric refluxate) are potentially important in the production of reflux esophagitis. Gastric acidity determines the degree of potential mucosal damage of the refluxate. Increases in gastric volume augment the rate of tLESRs, making more gastric contents available for reflux.

CLASSIC REFLUX SYMPTOMS

Heartburn is the classic symptom of GERD, with patients generally reporting a burning feeling, rising from the stomach or lower chest and radiating toward the neck, throat, and occasionally the back.¹¹⁴ It occurs postprandially, particularly after large meals or after ingesting spicy foods, citrus products, fats, chocolates, and alcohol. The supine position and bending over may exacerbate heartburn. Recent studies have suggested that sleep deprivation as well as psychological or auditory stress may lower the threshold for symptom perception.^115–117 Nighttime heartburn may cause sleeping difficulties and impair next-day function.¹¹⁸ When heartburn dominates a patient’s complaints, it has high specificity (89%) but low sensitivity (38%) for GERD as diagnosed by 24-hour esophageal pH testing.¹¹⁹ GERD is usually diagnosed symptomatically by the occurrence of heartburn two or more days a week, although less frequent symptoms do not preclude the disease.^120,121 Although an aid to diagnosis, the frequency and severity of heartburn do not predict the degree of esophageal damage.⁵

Heartburn symptoms can arise from acid reflux, weakly acidic reflux, bile reflux, and mechanical stimulation of the esophagus. The receptor that mediates the sensation of heartburn during acid perfusion has not been identified, although the capsaicin or vanilloid receptor 1 (TRPV1) is a leading candidate. TRPV1 is a cation channel that is expressed by sensory neurons, and its activation by heat, acid pH, or ethanol may trigger burning pain.^122–126 Weakly acidic reflux, as detected by combined pH and impedance technology, appears to produce symptoms when there is a large proximal extent reached by the refluxate, large reflux volumes, and prolonged acid-clearance times.¹²⁷ The mechanism that underlies bile-acid–induced esophageal symptoms is unknown. Bile acids are postulated to induce the release of intracellular mediators via damage to lipid membranes.¹²⁸ In addition to acid-induced and bile-acid–induced esophageal damage, pepsin can cause direct damage to the esophageal mucosa, leading to dilated intercellular spaces and increased esophageal mucosal permeability.¹²⁹ Esophageal distention and sustained esophageal contractions are other mechanisms proposed to explain the symptom of heartburn. Balaban and associates used high-frequency endoluminal ultrasound to demonstrate a correlation between spontaneous chest pain or chest pain induced by edrophonium chloride and sustained esophageal longitudinal muscle contractions.¹³⁰ Esophageal hyperalgesia (lowered pain threshold) and psychological comorbidity have also been postulated to contribute to heartburn symptoms.¹³¹

Other common symptoms of GERD are acid regurgitation and dysphagia. The effortless regurgitation of acidic fluid, especially after meals and worsened by stooping or the supine position, is highly suggestive of GERD.¹¹⁹ Among patients with daily regurgitation, LES pressure is usually low; many have associated gastroparesis, and esophagitis is common, making this symptom more difficult to treat medically than classic heartburn. Dysphagia is reported by more than 30% of individuals with GERD.¹³² It usually occurs in the setting of long-standing heartburn with slowly progressive dysphagia for solids. Weight loss is uncommon, because patients have good appetites. The most common causes are a peptic stricture or Schatzki’s ring, but other etiologies include severe esophageal inflammation alone, peristaltic dysfunction, and esophageal cancer arising from Barrett’s esophagus (see Chapter 44).

Less common symptoms associated with GERD include water brash, odynophagia, burping, hiccups, nausea, and vomiting.¹³³ Water brash is the sudden appearance in the mouth of a slightly sour or salty fluid. It is not regurgitated fluid, but rather secretions from the salivary glands in response to acid reflux.⁷³ Odynophagia may be seen with severe ulcerative esophagitis. However, its presence should raise the suspicion of an alternative cause of esophagitis, especially infections or injury from impacted pills (see Chapter 45).

Some patients with GERD are asymptomatic. This is particularly true in the older adults, perhaps because of decreased acidity of the reflux material in some or decreased pain perception in others.⁵ Many older adult patients present first with complications of GERD because of long-standing disease with minimal symptoms. For example, up to one third of patients with Barrett’s esophagus are insensitive to acid at the time of presentation.¹³⁴

EXTRAESOPHAGEAL MANIFESTATIONS

GER may cause a wide spectrum of conditions including noncardiac chest pain, asthma, posterior laryngitis, chronic cough, recurrent pneumonitis, and even dental erosion.¹³⁵ Some of these patients have classic reflux symptoms, but many are “silent refluxers,” contributing to problems in making the diagnosis. Furthermore, it may be difficult to establish a causal relationship even if GER can be documented by testing (e.g., pH studies) because individuals may simply have two common diseases without a cause-and-effect relationship.

Ear, Nose, and Throat Diseases

GERD may be associated with a variety of laryngeal symptoms and signs, of which “reflux laryngitis” is the most common.^147,148 These patients present with hoarseness, globus sensation, frequent throat clearing, recurrent sore throat, and prolonged voice warm-up. Ear, nose, and throat signs attributed to GERD include posterior laryngitis with edema and redness (Fig. 43-9), vocal cord ulcers and granulomas, leukoplakia, and even carcinoma. These changes are usually limited to the posterior third of the vocal cords and interarytenoid areas, both in proximity to the upper esophageal sphincter. Animal studies find that the combination of acid, pepsin, and conjugated bile acids is very injurious to the larynx.¹⁴⁹ Human studies report that proximal esophageal acid exposure, especially while sleeping, is significantly increased in patients with laryngeal symptoms and signs.¹⁵⁰

Figure 43-9. Characteristic laryngeal findings of “reflux laryngitis” in a 31-year-old man with hoarseness whose symptoms and signs resolved after proton pump inhibitor treatment for three months. Black arrows: bilateral erythema of medial arytenoid walls. White arrows: red streaks on the true vocal folds. Reflux changes in the larynx are usually confined to the posterior portion nearest the upper esophageal sphincter (bluish gray slit behind the arytenoid complex).

GERD has been postulated to be a leading cause of chronic cough (after sinus problems and asthma).¹⁵¹ GER increases the cough sensitivity reflex (i.e., reduces the cough threshold) in patients with chronic cough.¹⁵² However, the importance of this association in humans has not been shown in treatment studies, which, in sum, have not demonstrated a superiority of proton pump inhibitors over placebo.¹⁵³ Dental erosion, the loss of tooth structure by nonbacterial chemical processes, can be caused by GER in healthy subjects and patients with bulimia.¹⁵⁴ Microaspiration of gastric contents is the most likely etiology of these complaints.

EMPIRICAL TRIAL OF ACID SUPPRESSION

An empirical trial of acid suppression is the simplest and most definitive method for diagnosing GERD and assessing its relationship to symptoms. Unlike other tests that only suggest an association (e.g., esophagitis at endoscopy or positive symptom index on pH testing), the response to antireflux therapy ensures a cause-and-effect relationship between GERD and symptoms. With the advent of PPIs, it has become the first test used in patients with classic or atypical reflux symptoms without alarm complaints. Symptoms usually respond to a PPI trial in one to two weeks. If symptoms disappear with therapy and then return when the medication is discontinued, GERD has been established.

In empirical trials for heartburn, the initial PPI dose was high (e.g., omeprazole 40 to 80 mg/day), usually given for at least two weeks, and a positive response was defined as at least 50% improvement in heartburn. Using this approach, the PPI empirical trial has a sensitivity of 68% to 83% for determining the presence of GERD.^161,162 In noncardiac chest pain, Fass and colleagues¹⁶³ found that a seven-day trial of omeprazole 40 mg in the morning and 20 mg at night had a sensitivity of 78% and specificity of 86% for predicting GERD when compared with traditional tests. Likewise, Ours and colleagues¹⁶⁴ found omeprazole 40 mg twice daily for two weeks to be a very reliable method for identifying acid-related cough.

An empirical PPI trial for diagnosing GERD offers many advantages: the test is office based, easily done, relatively inexpensive (especially with use of over-the-counter [OTC] PPIs), available to all physicians, and avoids many needless procedures. For example, Fass and colleagues¹⁶³ showed a savings of greater than $570 per patient due to a 59% reduction in the number of diagnostic tests performed for noncardiac chest pain. Disadvantages are few, including a placebo response and uncertain symptomatic endpoint if symptoms do not totally resolve with extended treatment.

ENDOSCOPY

Upper endoscopy is the standard for documenting the presence and extent of esophagitis and excluding other etiologies for the patient’s symptoms. However, only 20% to 60% of patients with abnormal esophageal reflux by pH testing have esophagitis at endoscopy. Thus, the sensitivity of endoscopy for GERD is poor, but it has excellent specificity at 90% to 95%.¹⁶⁵

The earliest endoscopic signs of acid reflux include edema and erythema, but these findings are nonspecific and dependent on the quality of endoscopic visual images.¹⁶⁶ More reliable signs are friability, granularity, and red streaks. Friability (easy bleeding) results from the development of enlarged capillaries near the mucosal surface in response to acid. Red streaks extend upward from the esophageal junction along the ridges of the esophageal folds.¹⁶⁷ Erosions develop with progressive acid injury, characterized by a shallow break in the mucosa with a white or yellow exudate surrounded by erythema. Typically, erosions begin at the gastroesophageal junction, occurring along the tops of esophageal mucosal folds, where acid injury is most prone, and they may be single or multiple. Erosions can also be caused by nonsteroidal anti-inflammatory drugs, heavy smoking, and infectious esophagitis.¹⁶⁵ Ulcers reflect more severe esophageal damage, being deeper into the mucosa or submucosa and either isolated along a fold or surrounding the esophageal junction. Multiple classification systems for esophagitis have been proposed; some are confusing and none has worldwide acceptance. In Europe the most popular scheme is the Savary-Miller classification.¹⁶⁸ The most thoroughly evaluated esophagitis classification is the Los Angeles (LA) system, which is gaining acceptance in the United States and Europe (Table 43-3) (Fig. 43-10A to D).¹⁶⁹

Table 43-3 Endoscopic Grading Systems for Esophagitis

Figure 43-10. Endoscopic photographs of the four grades of esophagitis (A to D) using the Los Angeles classification system as outlined in Table 42-3.

Esophageal capsule endoscopy for the evaluation of reflux symptoms has thus far been disappointing. The capsule is 11 by 26 mm and acquires video images at 14 frames per second. After swallowing images are transmitted to a portable receiver via digital radiofrequency. In one study, compared with standard upper endoscopy, the capsule has a sensitivity of 50% for erosive esophagitis, 54% for the presence of a hiatal hernia, and 79% for the presence of Barrett’s esophagus.¹⁷⁰

As mentioned, most patients with GERD are treated initially with PPIs and without endoscopy. The important exception is the patient experiencing “alarm” symptoms: dysphagia, odynophagia, weight loss, and gastrointestinal bleeding. Here endoscopy should be performed early to diagnose complications of GERD (e.g., strictures) and to rule out other entities such as infections, ulcers, cancer, or varices. Current guidelines suggest the major role of endoscopy is to diagnose and treat GERD complications, especially peptic strictures, and to define Barrett’s esophagus.¹⁷¹ Using this rationale, the majority of patients with chronic GERD need only one endoscopy while on therapy.

ESOPHAGEAL BIOPSY

Like endoscopy, the role of esophageal biopsies in evaluating GERD has evolved over the years. Microscopic changes of reflux may occur even when the mucosa endoscopically appears normal.¹⁷² These classic changes of basal cell hyperplasia and increased height of the rete peg, both representing increased epithelial turnover of the squamous mucosa, are sensitive but not specific histologic findings for GERD.¹⁷³ Acute inflammation characterized by the presence of neutrophils and often eosinophils (Fig. 43-11) is very specific for esophagitis; however, the sensitivity is low, in the range of 15% to 40%.¹⁷⁴ Thus, there is little value for histologic examination of normal-appearing squamous mucosa to either confirm or exclude pathologic acid reflux.¹⁷⁵ In patients with classic esophagitis, biopsies are usually not taken unless necessary to exclude neoplasm, infection, pill injury, or bullous skin disease. Therefore, the current primary indication for esophageal biopsies is to determine the presence of Barrett’s epithelium.¹⁷¹ When this diagnosis is suspected, biopsies are mandatory and best done when esophagitis is healed (see Chapter 44).

Figure 43-11. Histopathology of gastroesophageal reflux disease. Inflammatory cells (eosinophils and neutrophils) are interspersed between squamous epithelial cells.

(Courtesy Edward Lee, MD, Washington, D.C.)

ESOPHAGEAL pH MONITORING

Ambulatory intraesophageal pH monitoring is the standard test for establishing pathologic reflux.^176,177 For catheter-based pH testing, the probe is passed nasally, positioned 5 cm above the manometrically determined LES, and connected to a battery-powered data logger capable of collecting pH values every four to six seconds. An event marker is activated by the patient when symptoms, meals, and body position changes occur. Patients are encouraged to eat normally and engage in regular daily activities, with monitoring carried out for 18 to 24 hours. Reflux episodes are defined by a pH drop of less than 4. Conventionally measured parameters include percent of total time when pH is less than 4; percent of time, upright and supine when pH is less than 4; total number of reflux episodes; duration of longest reflux episode; and number of episodes greater than five minutes.¹⁷⁶ The percent of total time pH is less than 4 is the most reproducible measurement for GERD, with reported upper limits of normal ranging from 4% to 5.5%.¹⁷⁶ Ambulatory pH testing discerns positional variations in GER, meals, and sleep-related episodes and helps relate symptoms to reflux events (Fig. 43-12).

Figure 43-12. Common patterns of 24-hour esophageal pH monitoring. A, The physiologic pattern of gastroesophageal reflux (GER) seen in healthy subjects. Reflux is noted after meals (M) but not during sleep (S). A reflux episode is defined as a pH drop to less than 4. B, Upright reflux pattern with extensive GER during the day but not at night. These patients have frequent symptoms, but esophagitis is uncommon. C, Combined pattern with GER during the day and at night. Most of these patients have esophagitis.

A critical limitation of esophageal pH monitoring is that there exists no absolute threshold value that reliably identifies GERD patients. Studies comparing patients with endoscopic esophagitis who underwent pH tests report sensitivities from 77% to 100% with specificities from 85% to 100%.¹⁷⁸ However, these patients with esophagitis rarely need pH testing; rather, patients with normal endoscopy and suspected GERD might benefit most from this test. Unfortunately, data on these patients are less conclusive, with considerable overlap between controls and nonerosive refluxers.¹⁷⁷ Other drawbacks of pH testing include possible equipment failure, pH probe missing reflux events because the probe is buried in a mucosal fold, and false-negative studies due to dietary or activity limitations from poor tolerability of the nasal probe.¹⁷⁸

A major advance in esophageal pH testing has been the development of a catheter-free system.¹⁷⁹ This system uses a wireless pH capsule that is affixed to the esophageal mucosa with a delivery system that drives a small needle into the epithelium. The capsule then transmits pH data to a portable receiver using radiofrequency signals. Catheter-free testing is rapidly becoming the preferred method of pH testing because monitoring can be extended beyond 24 hours and limitations on normal daily activities and meals are negligible.¹⁷⁹

Ambulatory esophageal pH monitoring is the only test that records and correlates symptoms with reflux episodes over extended periods of time. However, because only 10% to 20% of reflux episodes are associated with symptoms, different statistical analyses have evolved, attempting to define a significant association between symptoms and reflux episodes, including the symptom index, symptom sensitivity index, and symptom association probability.¹⁴⁶ Unfortunately, no studies have defined the accuracy of these symptom scores in predicting response to therapy. Therefore, pH testing can define an association between complaints and GER, but only treatment trials address the critical clinical issue of causality.

Clinical indications for ambulatory pH monitoring are established.¹⁷¹ Before fundoplication, pH testing should be done in patients with normal endoscopy to ensure the presence of pathologic acid reflux. After antireflux surgery, persistent or recurrent symptoms warrant repeat pH testing. In these situations, pH monitoring is performed with the patient off antireflux medications. Esophageal pH testing is particularly helpful in evaluating patients with reflux symptoms who are resistant to treatment and who have normal or equivocal endoscopic findings. For this indication, pH testing is usually done on PPI therapy to define two populations: those with and those without continued abnormal acid exposure times. The group with persistent GER needs intensified medical therapy, whereas patients with symptoms and good acid control have another etiology for their complaints. Finally, ambulatory pH testing may help in defining patients with extraesophageal manifestations of GERD. In this situation, pH testing is often done with additional pH probes in the proximal esophagus or pharynx.¹⁴⁷ Initially most of these studies were done off antireflux medications to confirm the coexistence of GERD; however, this does not guarantee symptom causality. Therefore, one approach is to first treat aggressively with PPIs, reserving pH testing for those patients not responding after 4 to 12 weeks of therapy.¹⁶⁴

A relatively new method of evaluating GERD has been combined impedance and acid testing, which allows the measurement of acid and nonacid (volume) reflux. Nonacid reflux is measured by the detection of a retrograde bolus of ion-rich fluid in the esophagus. Refluxates that are a mixture of liquid and air are also readily detected. In a large group of normal subjects, roughly 40% of reflux episodes were either weakly acidic (pH 4 to 6.5) or alkaline (nadir esophageal pH during episode >6.5).¹⁸⁰ In a multicenter study using impedance, 37% of patients experienced continued reflux symptoms despite twice-daily PPI therapy due to nonacid reflux.¹⁸¹ These patients would have been interpreted as negative for reflux had they been studied using conventional pH only. Another study using 24-hour ambulatory pH impedance found a temporal relationship between symptoms and nonacid reflux in 4.1% and 16.7% of subjects off and on PPI therapy, respectively.¹⁸² Regurgitation and cough were the most prevalent symptoms associated with nonacid reflux.

BARIUM ESOPHAGOGRAM

The barium esophagogram is an inexpensive, readily available, and noninvasive esophageal test. It is most useful in demonstrating anatomic narrowing of the esophagus and assessing the presence and reducibility of a hiatal hernia. Schatzki’s rings, webs, or minimally narrowed peptic strictures may only be seen with an esophagogram, being missed by endoscopy, which may not adequately distend the esophagus. Giving a 13-mm radiopaque pill or marshmallow along with the barium liquid can help to identify these subtle narrowings.¹⁸³ The barium esophagogram allows good assessment of peristalsis and is helpful preoperatively in identifying a weak esophageal pump.¹⁸⁴ The ability of barium esophagogram to detect esophagitis varies, with sensitivities of 79% to 100% for moderate to severe esophagitis, whereas mild esophagitis is usually missed.^185,186 Barium testing also falls short when addressing the presence of Barrett’s esophagus. The spontaneous reflux of barium into the proximal esophagus is very specific for reflux, but it is not sensitive. Provocative maneuvers (e.g., leg lifting, coughing, Valsalva, or water siphon) can elicit stress reflux and improve the sensitivity of the barium esophagogram, but some argue that these maneuvers also decrease its specificity.^185,186

ESOPHAGEAL MANOMETRY

Esophageal manometry allows assessment of LES pressure and relaxation, as well as peristaltic activity, including contraction amplitude, duration, and velocity. However, esophageal manometry is generally not indicated in the evaluation of the uncomplicated GERD patient because most have a normal resting LES pressure.⁵¹ (It is an integral component of pH testing to accurately define LES location; see earlier.) Esophageal manometry to document adequate esophageal peristalsis is traditionally recommended before antireflux surgery.¹⁸⁷ If the study identifies ineffective peristalsis (low amplitude or frequent failed peristalsis),¹⁸⁸ then a complete fundoplication may be contraindicated. However, this assumption has recently been challenged by several studies finding that reflux control was better and dysphagia no more common in patients with weak peristalsis after a complete, as opposed to a partial, fundoplication.¹⁸⁹ An improvement of traditional manometry, combining it with impedance testing, is helping to clarify this controversy. Using this technique, a study found that less than 50% of patients with ineffective peristalsis had a significant delay in esophageal bolus transit measured by impedance.¹⁹⁰ Therefore, potentially only these patients with a significant physiologic defect in motility will require a modified fundoplication.

NONEROSIVE REFLUX DISEASE

Early studies from tertiary referral centers suggested that the majority of GERD patients had esophagitis.¹⁹⁵ However, studies carried out in community practices reveal that up to 70% of GERD patients had a normal endoscopic examination.^196–198 Endoscopy-negative GERD patients are more likely to be female, younger, thin, and without hiatal hernia, and they have a higher prevalence of functional GI disorders.¹⁹⁹ Despite their mild mucosal damage, these patients demonstrate a chronic pattern of symptoms with periods of exacerbation and remission.²⁰⁰ Nonerosive GERD is suspected in the patient with typical reflux symptoms and a normal endoscopy and confirmed by the patient’s response to antisecretory therapy. Esophageal pH testing identifies three distinct subsets of nonerosive GERD patients. First are the patients with excessive acid reflux who usually respond to PPI therapy. Second are the patients with normal reflux parameters but a good correlation between symptoms and acid reflux episodes. This group represents 30% to 50% of nonerosive GERD patients and has “functional heartburn.”²⁰⁰ These patients probably have heightened esophageal sensitivity to acid and are less likely to respond to antireflux therapy.²⁰¹ The third group is characterized by normal acid exposure times and poor symptom correlation. Whether they truly represent a subset of nonerosive GERD is questionable.

EROSIVE REFLUX DISEASE

Patients with erosive esophagitis tend to be male, older, and overweight and are more likely to have hiatal hernias.¹⁹⁹ The clinical course of these patients with erosive esophagitis is more predictable and associated with complications of GERD. Longitudinal studies have shown that up to 85% of patients with erosive GERD, on no maintenance reflux therapy, will relapse within six months of stopping PPI therapy, and the relapse rate is highest in patients with more severe grades of esophagitis (see Table 43-3).^202,203 Several studies confirm that erosive esophagitis patients are prone to reflux complications, including ulcers, strictures, and Barrett’s esophagus. In a Finnish study, 20 patients with erosive GERD treated with lifestyle changes, antacids, and prokinetic drugs were followed for a median of 19 years. Fourteen patients continued to have erosions, and six new cases of Barrett’s esophagus were detected.¹⁹² In another more recent European study¹⁹³ over two years, patients with LA grade C/D esophagitis developed Barrett’s esophagus at a rate of 5.8% compared with only 1.4% for LA grade A/B and 0.5% for nonerosive GERD. However, these data must be contrasted with a two-year U.S. trial in which no patient with erosive esophagitis developed Barrett’s esophagus²⁰⁴ and in another study in which stricture was reported in only 0.9% of 957 patients over 7.6 years of symptom driven antireflux treatment.¹⁹⁴

HEMORRHAGE, ULCERS, AND PERFORATION

GERD-related non-cancer deaths are rare (0.46 per 100,000 persons). The most common fatal causes are hemorrhagic esophagitis, aspiration pneumonia, ulcer perforation, and rupture with severe esophagitis.²⁰⁵ Major hemorrhage and esophageal perforation are usually associated with deep esophageal ulcers or severe esophagitis.²⁰⁶ Esophageal perforations are very rare in the PPI era but can result in mediastinitis and death. Clinically important hemorrhage has been reported in 7% to 18% of GERD patients²⁰⁷ and may result in iron deficiency anemia.

PEPTIC ESOPHAGEAL STRICTURES

Strictures occur in 7% to 23% of patients with untreated reflux esophagitis, and are especially seen in older men.²⁰⁸ They may be linked to chronic nonsteroidal anti-inflammatory drug (NSAID) use.²⁰⁹ Stricture formation is complex, starting as reversible inflammation with edema, cellular infiltration, and vascular congestion, progressing to collagen deposition and ending in irreversible fibrosis. As dysphagia progresses, heartburn often decreases, reflecting the stricture acting as a barrier to further reflux. Dysphagia is usually limited to solids. Unlike malignant strictures, patients with peptic strictures have a good appetite, alter their diet, and lose little weight.

Peptic strictures are smooth-walled, tapered, circumferential narrowings in the lower esophagus, usually less than 1 cm long but occasionally extend to 8 cm (Fig. 43-13). In these unusual cases, the clinician should suspect a predisposing condition, such as Zollinger-Ellison syndrome, or another condition such as pill esophagitis or a stricture from prolonged nasogastric intubation.²⁰⁸ A mid- to upper esophageal stricture should raise concern for Barrett’s esophagus or malignancy. Although once controversial, today a Schatzki’s ring is considered a forme fruste of an early peptic stricture.²¹⁰ All stricture patients should undergo endoscopy, at least initially, to confirm the benign nature of the lesion and, if necessary, take biopsies to exclude cancer and Barrett’s esophagus.

Figure 43-13. Classic peptic stricture demonstrated by barium esophagogram (A) and endoscopy (B). The film shows a large hiatal hernia (HH) common to all GERD strictures. Dark arrow points to short thick fibrous stricture with multiple pseudodiverticula (white arrows). Although not seen on barium examination, the endoscopic view also demonstrates circumferential esophagitis (Los Angeles grade D). GERD, gastroesophageal reflux disease.

BARRETT’S ESOPHAGUS

(see Chapter 44)

NONPRESCRIPTION THERAPIES

Although GERD is common, many sufferers do not seek medical care, instead choosing to change their lifestyles and self-medicate with OTC antacids, histamine-2 receptor antagonists (H₂RAs), and even PPIs. These observations have led to the “iceberg” model of the GERD population. The vast majority of heartburn suffers are invisible because they self-medicate and do not seek professional help; only those at the tip of the iceberg, typically patients with severe symptoms or reflux complications, are seen by physicians.²¹¹

PRESCRIPTION MEDICATIONS

Patients with frequent heartburn, esophagitis, or complications usually see a physician and receive prescription medications. Prokinetic drugs attempt to correct the GERD-related motility disorders associated with GERD. However, the most clinically effective drugs for short- and long-term reflux treatment are acid suppressive drugs.

Histamine-2 Receptor Antagonists (H₂RAs) (see also Chapter 53)

These drugs (cimetidine, ranitidine, famotidine, and nizatidine) are more effective in controlling nocturnal, as compared with meal-related, acid secretion because the parietal cell is stimulated postprandially by gastrin acting via histamine and by acetylcholine (see Chapter 49).²²⁵ The four H₂RAs are equally effective when used in proper doses, usually twice a day before meals. GERD trials find that heartburn can be significantly decreased by H₂RAs, when compared with placebo, although symptoms are rarely abolished (Fig. 43-14). A comprehensive meta-analysis found that the overall esophagitis healing rates with H₂RAs rarely exceeded 60% after up to 12 weeks of treatment, even when higher doses were used.^226,227 Healing rates differ in individual trials depending primarily on the severity of esophagitis being treated: grades I and II esophagitis heal in 60% to 90% of patients, whereas grades III and IV heal in only 30% to 50% despite high-dose regimens.²²⁷

Figure 43-14. A, Symptom relief time curve over 8 weeks for a proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H₂RA) corrected for patients free of heartburn at baseline. By week 2, more patients treated with a PPI were asymptomatic compared with those treated with a H₂RA, even after a much longer duration of treatment with the H₂RA. B, Esophagitis healing time curve for PPI, H₂RA, and placebo over 12 weeks. By 4 weeks treatment with a PPI healed esophagitis in more patients than the other two drug classes over 12 weeks, implying a substantial therapeutic gain. The numbers of studies included for each time point and treatment are shown in parentheses.

(Data based on meta-analysis from Chiba N, Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: A meta-analysis. Gastroenterology 1997; 112:1798.)

Although PPIs are more effective than H₂RAs (Fig. 43-15; discussed following), nocturnal gastric acid breakthrough while on PPI therapy may cause reflux symptoms in some patients. H₂RAs given at bedtime successfully eliminated this problem in one study, suggesting a new indication for H₂RAs in the PPI era.²²⁸ However, this study used only a single evening dose and did not account for the tolerance that frequently develops to H₂RAs over weeks to months.²²⁹ This tolerance impairs the effectiveness of chronic nocturnal dosing of H₂RAs to eliminate nocturnal acid breakthrough,²³⁰ but suggests a useful role in as-needed medications in situations in which lifestyle indiscretions may promote nocturnal complaints.

Figure 43-15. The most common surgical fundoplications used during antireflux surgery. A, The most popular worldwide is the 360-degree Nissen fundoplication. B, An anterior wrap (e.g., Thal, Dor) is commonly used to prevent gastroesophageal reflux after a Heller myotomy for achalasia. The experience with this repair is limited in patients with classical gastroesophageal reflux disease. C, The posterior wrap (Toupet) is popular in patients with poor esophageal motility because postoperative dysphagia is less frequent than after other operations. This is a 220- to 250-degree wrap.

(From Oelschlager BK, Eubanks TR, Pellegrini CA. Hiatal hernia and gastroesophageal reflux disease. In: Townsend CM, Beauchamp RD, Foshee JC, et al, editors. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 18th ed. Philadelphia: Saunders; 2007.)

The H₂RAs are very safe with a side effect rate (most of which are minor and reversible) of about 4%.²²⁵ Serum concentrations of phenytoin, procainamide, theophylline, and warfarin are higher after the administration of cimetidine and, to a lesser degree, ranitidine, whereas these interactions are not reported with the other two H₂RAs.

MAINTENANCE THERAPIES

GERD may be a chronic relapsing disease, especially in patients with low LES pressure, severe grades of esophagitis, and difficult-to-manage symptoms.²¹⁷ After esophagitis is healed, recurrence within six months of stopping medication occurs in more than 80% of patients with severe esophagitis and in 15% to 30% of those with milder esophagitis.^202,247

Cochrane reviews have identified the superiority of PPIs over H₂RAs in maintaining the remission of esophagitis over 6 to 12 months.²⁴⁸ Among 10 randomized trials, the relapse rate for esophagitis was 22% on PPIs versus 58% with H₂RAs, with a number-to-treat of 2.5. The FDA has approved all the PPIs, sometimes at one half the acute dose, for maintenance therapy, but only ranitidine 150 mg twice a day among the H₂RAs has maintenance indications for mild esophagitis. Many clinicians now place their patients with severe disease (daily symptoms, severe esophagitis, or complications) on chronic PPI therapy indefinitely. The efficacy of this approach is supported by open, compassionate use data primarily from the Netherlands and Australia.²⁴⁹ In a study of 230 patients with severe esophagitis healed with 40 mg omeprazole, all subjects remained in remission for up to 11 years. More than 60% were maintained on omeprazole 20 mg a day, whereas higher doses of 60 mg or more were necessary in only 12% of patients, confirming a lack of tolerance to PPIs. Relapses were rare (one per 9.4 years of follow-up), strictures did not occur, and Barrett’s esophagus did not progress.²⁴⁵

Although PPIs offer the best symptom relief and esophagitis healing, many patients do well long term on lesser treatments after having their complaints initially alleviated with PPIs. Using this “step-down approach,” a recent Veterans Affairs study reported that 58% of 71 patients on chronic PPIs could be switched to H₂RAs and/or prokinetics or taken off medication completely.²⁵⁰ Younger age and severe heartburn symptoms predicted PPI requirement. Overall, this approach saved money for the health care system. A similar study by the same investigators found that 80% of patients using multiple-dose PPIs could be stepped down to single-dose PPI, remaining symptom free for six months with considerable cost savings.²⁵¹ Hence the adage “once on a PPI, always on a PPI” is not true.

The initial safety concerns with the PPIs was the potential to develop stomach or other cancers with long-term use. This was initiated by reports of omeprazole producing hypergastrinemia and gastric carcinoid tumors in rats, changes also subsequently demonstrated with chronic ranitidine therapy and subtotal resection of the gastric fundus.²⁵² However, rats have a high density of enterochromaffin-like (ECL) cells and an exaggerated gastrin response to achlorhydria; chronic omeprazole therapy in other species with lower densities of ECL cells (mice, dog, man) has not caused carcinoid tumors. Another review found no evidence of an increased risk of colon cancer with chronic PPI use.²⁵³

Fundic gland polyps are the most common gastric polyp found at endoscopy. Their association with chronic PPI use has been a topic of debate since these drugs were first described. A recent study evaluated 599 patients of whom 322 used PPIs and 107 had fundic gland polyps.²⁵⁴ Long-term PPI use was associated with up to a four-fold increase in the risk of fundic gland polyps. Low-grade dysplasia was found in one fundic gland polyp. Etiologically, these polyps seem to arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression.

Recent studies confirm that chronic acid suppression may be associated with an increased risk of community-acquired pneumonias and enteric infections. In a large Scandinavian population-based study,²⁵⁵ the adjusted relative risk for pneumonia among current PPI users, compared with those who stopped using PPIs, was 1.89. Current users of H₂RAs had a 1.63-fold increased risk of pneumonia compared with those who stopped. A significant positive dose-response relationship was observed in the PPI users. Likewise, a recent systematic review found an increased risk of enteric infections with acid suppression.²⁵⁶ The correlation was stronger with Salmonella, Campylobacter, and other enteric infections, compared with Clostridium difficile, and greater with PPI compared with H₂RA therapy.

Chronic high-dose use of PPIs may also affect the absorption of calcium and vitamin B₁₂. A nested case-controlled study from the United Kingdom among 13,556 patients found that the risk of hip fractures increased with chronic PPI use over one year (adjusted odds ratio, 1.44), especially in those patients receiving high-dose PPIs (adjusted odds ratio, 2.65). A smaller but still significant risk was observed in chronic H₂RA users.²⁵⁷ A large Canadian study²⁵⁸ reached similar conclusions, but found the risk for hip fractures became apparent after five years of treatment (adjusted odds ratio, 1.62) and after seven years for all osteoporotic fractures (adjusted odds ratio, 1.92). The mechanism for this association is unknown and cause-and-effect is not proven as yet. It has been suggested that if PPIs cause osteoporosis, they may interfere with insoluble calcium absorption or possibly inhibit the osteoclastic proton transport system, potentially reducing bone resorption. PPIs could retard the absorption of vitamin B₁₂ by decreasing gastric acidity; reducing the release of cobalamin from dietary protein; or by promoting small bowel bacterial overgrowth, thereby increasing luminal cobalamin consumption. However, cohort and case-control studies have not shown a convincing link between PPI use and vitamin B₁₂ deficiency.²⁵⁹

Finally, a study suggested that patients on long-term omeprazole who are infected with H. pylori develop atrophic gastritis, a precursor to gastric adenocarcinoma, at a more rapid rate than noninfected patients.²⁶⁰ Nevertheless, a subsequent FDA panel determined that the available data were insufficient for recommending screening and treatment of H. pylori infection in patients on long-term PPI therapy.²⁶¹

SURGICAL THERAPY

Only surgical fundoplication can correct the physiologic factors contributing to GERD and potentially eliminate the need for long-term medications. Antireflux surgery reduces GER by increasing basal LES pressure, decreasing episodes of tLESRs, and inhibiting complete LESR.²⁶² This is done by reducing the hiatal hernia into the abdomen, reconstructing the diaphragmatic hiatus, and reinforcing the LES.²⁶³ Before laparoscopic surgery, the three most common operations were the Nissen fundoplication, Belsey Mark IV repair, and Hill posterior gastropexy. Since the introduction of minimally invasive surgery, the two most popular procedures, performed laparoscopically through the abdomen are the Nissen 360-degree fundoplication and the Toupet partial fundoplication (see Fig. 43-15).²⁶⁴ The former is a superior operation with better long-term durability, but it causes more postoperative dysphagia and gas bloat symptoms.^265,266 The typical hospital stay is 1 to 2 days, and many patients return to normal activity in 7 to 10 days. Patients with more severe disease and a short esophagus suggested by a large nonreducible hernia, tight stricture, or long-segment Barrett’s esophagus will require a Collis lengthening procedure to create a 3- to 5-cm neoesophagus that allows the fundoplication to be placed in the abdomen under minimal tension.²⁶⁷

The popularity of antireflux surgery has undergone an explosion since the advent of the laparoscopic operation. The numbers of antireflux operations performed in the United States nearly tripled from 11,000 per year in 1985 (open surgery) to a peak of nearly 32,000 in 1999 but have leveled off at around 24,000 cases per year (11 cases per 100,000 adult population).^268,269 A systematic review identified six randomized controlled trials involving 449 patients that compared open and laparoscopic fundoplication.²⁷⁰ There was no significant difference in recurrence rates between the procedures, and laparoscopic fundoplication was associated with lower operative morbidity (number-to-treat to prevent complication, 8) and shorter hospital stay.

In the PPI era, symptom resolution on treatment helps predicate the success of antireflux surgery for classic as well as atypical symptoms.²⁷¹ Antireflux surgery is a reasonable option in (1) the healthy patient with typical or atypical GERD symptoms well controlled on PPIs desiring alternative therapy because of drug expense, poor medication compliance, or fear of unknown long-term side effects; (2) patients with volume regurgitation and aspiration symptoms not controlled on PPIs; and (3) recurrent peptic strictures in younger patients.²⁶⁵ Patients recalcitrant to PPI therapy may well have another etiology for their complaints (e.g., pill esophagitis, gastroparesis, functional heartburn) and should be approached cautiously with surgery.

Testing must be done before antireflux surgery. Endoscopy is necessary to exclude stricture, Barrett’s esophagus, and dysplasia or carcinoma. A barium esophagogram can help define a nonreducible hiatal hernia, a shortened esophagus, and poor esophageal motility. Esophageal manometry, possibly combined with impedance if available, will identify ineffective esophageal peristalsis and previously misdiagnosed achalasia or scleroderma. Twenty-four-hour pH testing is necessary in patients with nonerosive GERD or those with esophagitis not responding to PPI therapy. Gastric analysis and gastric emptying studies may be indicated in select patients. Careful testing will result in modification of the original operation or an alternative diagnosis in approximately 25% of patients.¹⁸⁷

Antireflux surgery relieves reflux symptoms and reduces the need for stricture dilation in more than 90% of patients,²⁷² but Barrett’s esophagus rarely regresses and the risk of developing esophageal cancer is unchanged.²⁷³ Older studies found antireflux surgery superior to antacids, H₂RA, and prokinetic therapy,²⁰⁴ but not PPI therapy, especially when dose titration is permitted.²⁷⁴ Mortality is rare (<1%) after antireflux surgery, but new postoperative complaints occur in up to 25% of patients including dysphagia, gas bloat, diarrhea, and increased flatus.²⁷² Most symptoms improve over 1 year, but persistent complaints suggest too tight a wrap, a displaced fundoplication, or inadvertent damage to the vagus nerve. Successful antireflux surgery does not guarantee a permanent cure. Best surgical results are obtained by experienced surgeons in high-volume centers who report long-term symptom recurrence in only 10% to 15% of patients.²⁶⁵ However, many operations are performed in lower-volume community hospitals where the results are more variable. A study from community hospitals in a midsize Midwest city²⁷⁵ found that 32% of patients had symptom relapses after two years and 7% required repeat surgery. In contrast, a review of more than 3000 patients undergoing antireflux surgery at VA medical centers between 1990 and 2001 was more reassuring.²⁶⁹ Postoperative dysphagia was recorded in 19.4% of patients, 6.4% required esophageal dilations, and a repeat antireflux operations was needed in only 2.3% of patients. There seems to be increasing consensus from long-term follow-up studies that 25% to 62% of patients are back on some type of acid suppressive medication 5 to 15 years after their antireflux surgery.^{269,275–277} However, the evidence for recurrent GERD by pH testing is infrequent.

Tertiary specialized centers are seeing an increased rate of fundoplication failures. The most common reason for failure are herniation of the intact fundoplication into the chest, “slipped” fundoplication with a recurrent hiatal hernia possibly due to a short esophagus, paraesophageal hernia through an intact fundoplication, too tight a fundoplication, and malpositioned fundoplication usually on the cardia of the stomach. Total breakdown of the fundoplication is now rare.²⁷⁸ Revisional antireflux surgery needs to be performed by very experienced surgeons and can be done laparoscopically, although many prefer an open approach. Reoperation has increased morbidity and mortality compared with the initial operation.

ENDOSCOPIC THERAPY

A variety of endoscopic techniques for the treatment of GERD have been developed as alternatives to antisecretory therapy or antireflux surgery.^279–281 These techniques include the delivery of radiofrequency energy to the gastroesophageal junction (Stretta), injection of bulking agents (Enteryx), or implantation of a bioprosthesis (Gatekeeper) into the LES, and suture plication of the proximal gastric folds (EndoCinch endoscopic plication system). Studies to date have primarily enrolled PPI-dependent patients without severe esophagitis or large hiatus hernia.

All of these techniques decrease reflux symptoms, improve quality of life, and decrease the need for antisecretory medications. However, physiologic studies are much less impressive, with LES pressure rarely increasing, pH normalizing in only 30% of patients, and even mild esophagitis infrequently healing.^279–281 Controlled studies with Stretta,²⁸² Enteryx,²⁸¹ and the Plication²⁸³ system likewise show a decrease in heartburn symptoms and improved quality of life after the active therapy compared with the sham-treated group after three to six months. Only the Plication study showed a significant decrease in pH values, but only by 18%, whereas the other techniques observed no change in pH or LES parameters.²⁸³

Most studies of endoscopic therapy have only limited follow-up information on a relatively small number of patients. The durability of these techniques beyond one to two years remains unclear and seems to gradually decrease over time. The cost-effectiveness of these techniques is difficult to define. Most importantly, safety issues have haunted these procedures, especially when used in the broader community of gastroenterologists. Chest pain, bleeding, esophageal perforations, mediastinitis, and at least eight deaths to date have been attributed to these endoscopic techniques. Serious adverse events, including deaths, led to the voluntary withdrawal of Enteryx by the manufacturer in September 2005 and suspension of the Gatekeeper clinical program in late 2005. A recent AGA Institute medical position statement recommended that “current data suggest that there are no definite indications for endoscopic therapy for GERD at this time.”²⁸⁴

CHEST PAIN AND EXTRAESOPHAGEAL MANIFESTATIONS

The efficacy of acid suppression, especially by PPI treatment, in the extraesophageal presentations of GERD is variable. There are two systemic reviews,^285,286 both suggesting that patients with noncardiac chest pain respond to PPIs better than placebo. These reports identified eight randomized controlled trials that assessed 321 patients, with a pooled relative risk for continued chest pain after PPI therapy compared with placebo of 0.54, with a number-to-treat of 3. Systematic reviews and randomized trials, however, do not support the efficacy of aggressive acid suppression, particularly with PPIs, in other extraesophageal disorders, such as chronic cough,²⁸⁷ asthma,²⁸⁸ or ear, nose, and throat disorders.²⁸⁹ Some patients definitely respond, usually over several months, but the heterogeneous etiology of these groups and the lack of pretreatment predictors of response confound any treatment approach to these patients.

Sleep disturbances may occur in up to 75% of patients with GERD, impairing quality of life. In a large multicenter study, patients with GERD-associated sleep disturbances and nighttime heartburn were randomized to two doses of esomeprazole (40 mg and 20 mg) or placebo for four weeks.²⁹⁰ GERD-related sleep disturbances resolved in significantly more patients on esomeprazole 40 mg (73.7%) or 20 mg (73.2%) than those who received placebo (41.2%). These changes were associated with improved sleep quality and daytime productivity.

PEPTIC ESOPHAGEAL STRICTURES

Dysphagia in patients with esophageal strictures and rings is related to stricture diameter and severity of esophagitis.²⁹¹ When the esophageal lumen diameter is less than 13 mm, dysphagia is common and esophageal dilation is required. Simple short strictures can be dilated by blind peroral passage of rubber Hurst (rounded ends) or Maloney (tapered ends) mercury-filled dilators of increasing sizes (16 to 60 French, 3 French equals 1 mm). Complicated longer, tighter, or more irregular strictures will require bougienage over a guidewire using hollow-centered, Savary, plastic-covered polyvinyl dilators or balloon (Gruentzig) dilators.²⁹² The extensive use of PPIs has markedly impacted our treatment of peptic strictures and esophageal rings. PPIs are superior to H₂RAs in relieving the symptoms of heartburn and dysphagia experienced by stricture patients while reducing the frequency of repeat dilations and the cost for treating these patients.²⁹³ Several studies in community and veterans hospitals note an approximate 33% decline in the incidence of recurrent strictures. The timeline for this decrease parallels the marked increase in PPI use since 1995.²⁹⁴ Another study convincingly shows that in patients with symptomatic Schatzki’s rings, maintenance PPI therapy after bougienage markedly decreases future relapses of the rings.²⁹⁵ In a randomized study, 30 patients with symptomatic rings without esophagitis were dilated and randomized to placebo or omeprazole 20 mg per day. In the treated group, one patient relapsed after 13 months, whereas seven patients relapsed on placebo after a mean of 20 months.