Gastroesophageal Reflux Disease - very detailed technical article

Gastroesophageal reflux disease (GERD) results from the failure of the normal antireflux mechanism to protect against frequent and abnormal amounts of gastroesophageal reflux (GER), that is, the effortless movement of gastric contents from the stomach to the esophagus. GER is not itself a disease, but a normal physiological process. It occurs in virtually everyone, multiple times a day, especially after large meals, without producing either symptoms or signs of mucosal damage. In contrast, GERD is a spectrum of disease usually producing symptoms of heartburn and acid regurgitation. Most patients have no visible mucosal injury at the time of endoscopic examination (nonerosive GERD), whereas some have esophagitis, peptic strictures, Barrett esophagus, or evidence of extraesophageal diseases such as chest pain, pulmonary symptoms, or ear, nose, and throat symptoms. GERD is a multifactorial process, one of the most common human diseases, and of economic importance, contributing to the expenditure in the United States of US$4–5 billion per year for antacid medications.

Epidemiology

The prevalence of GERD differs depending on whether the analysis is based on symptoms (primarily heartburn) or signs (i.e., esophagitis) of disease. When based on symptoms, GERD is common in Western countries. For example, in a nationwide population-based study by the Gallup Organization in the United States [1], 44% of the population reported having heartburn at least once a month. More convincing data were obtained by Locke and colleagues [2], who mailed out 2200 validated self-report questionnaires to a predominantly white population residing in Olmsted County, Minnesota. The prevalence of heartburn and acid regurgitation in the previous 12 months were noted to be 42% and 45% respectively. Frequent symptoms (at least weekly) were reported by 20% of respondents, with an equal gender distribution across all ages. The majority reported that heartburn was of moderate severity and had a duration of 5 years or more, and only 5.4% reported a physician visit for reflux complaints within the previous year. More variable prevalence rates for symptomatic GERD have been reported from Europe, ranging from 5% in Switzerland to 27% in Finland [3].

Conversely, the true prevalence of esophagitis is very difficult to define because healthy persons rarely undergo endoscopic procedures. Studies suggest that 7% of persons in the United States have erosive esophagitis, whereas European studies identify prevalence rates ranging from 2% to 10% [4]. Analyses of the gender ratio of GERD show nearly equal proportions of affected men and women, but a male predominance occurs in esophagitis and Barrett esophagus [4]. Increasing age is an important factor in the prevalence of GERD complications, probably the result of cumulative acid injury to the esophagus over time [5].

In contrast, the prevalence of GERD and its complications is relatively low among residents of Africa and Asia. For example, a cross-sectional study in Singapore reported prevalence rates for reflux symptoms of 7.5% in Indian people, 0.8% in Chinese people, and 3.0% in Malay people [6]. Possible reasons for the lower prevalence of GERD include low dietary fat, lower body mass index, and lower maximal acid output related to infection with Helicobacter pylori [7,8].

The prevalence of GERD is increasing in Western countries. El-Serag and Sonnenberg [9] observed opposing time trends in the prevalence of peptic ulcer disease and GERD in the United States: rates of peptic ulcer disease and gastric cancer fell between 1970 and 1995, whereas the prevalence of GERD and esophageal adenocarcinoma rose significantly.

The authors speculated that the decreasing prevalence of H. pylori may be playing a contributory role in the increasing prevalence of GERD. Data suggest that H. pylori-induced gastritis involves both the antrum and corpus, affecting the parietal cells and thus reducing acid secretion and elevating gastric pH [8]. This may have a protective influence on the esophageal mucosa in patients susceptible to GERD. Longterm epidemiological studies will be required to address this question more appropriately.

Other noteworthy epidemiological observations about GERD are that it is more common in white populations than in African American or Native American populations [4], family clustering has been reported [10], and it is rarely the cause of death [4]. GERD, however, is associated with considerable morbidity and with complications such as esophageal ulcerations (5%), peptic stricture (4%–20%), and Barrett esophagus (8%–20%). Furthermore, GERD as a chronic disease significantly impairs quality of life. Compared with other chronic medical conditions, the impairment of quality of life resulting from GERD is similar to, or even greater than, that resulting from arthritis, myocardial infarction, heart failure, or hypertension (Figure 1) [11].

Pathophysiology

The pathophysiology of GERD is complex and results from an imbalance between defensive factors protecting the esophagus (antireflux barriers, esophageal acid clearance, tissue resistance) and aggressive factors from the stomach contents (gastric acidity and volume and duodenal contents). The intermittent nature of symptoms and esophagitis in many patients suggests that the aggressive and defensive forces are part of a delicately balanced system.

Antireflux barriers

The first tier of the three-tiered esophageal defense against acid damage consists of the antireflux barriers. This is an anatomically complex region that includes the intrinsic lower esophageal sphincter (LES), the diaphragmatic crura, the intraabdominal location of the LES, the phrenoesophageal ligaments, and the acute angle of His.

The LES is a tonically contracted segment of distal esophagus about 3.0–4.0 cm in length [12]. It is the major component of the antireflux barrier and is capable of preventing reflux even when it is completely displaced from the diaphragmatic crura because of a hiatus hernia [12]. The proximal margin of the LES is normally about 1.5–2.0 cm above the squamocolumnar junction, whereas the distal segment, about 2.0 cm in length, lies within the abdominal cavity [13]. This location of the distal LES contributes to the maintenance of gastroesophageal competence during intraabdominal pressure events. Resting LES pressure ranges between 10 and 30 mmHg and includes a generous reserve capacity, because a minimal basal LES pressure in the range of 5–10 mmHg usually prevents GER [14]. The LES maintains a high-pressure zone by the intrinsic tone of its muscle and by the action of cholinergic excitatory neurons [15]. There is considerable diurnal variation in basal LES pressure; it is lowest after meals and highest at night. It is also influenced by certain circulating peptides and hormones, foods (particularly fat), and numerous drugs, the most clinically relevant of which include theophylline, calcium channel blockers, estrogen/progesterone, and narcotics. During swallowing, LES relaxation (LESR) occurs for 5–10 s, thus permitting esophageal peristalsis to sweep the swallowed bolus into the stomach.

Anatomically, the LES lies within the hiatus created by the right crus of the diaphragm, and it is anchored by the phrenoesophageal ligaments, which insert at about the level of the squamocolumnar junction [16]. Developmentally, the crural diaphragm arises from the dorsal mesentery of the esophagus and is innervated separately from the costal part of the diaphragm. It is inhibited by esophageal distention, during vomiting, and in association with transient LESRs, but not during swallowing. The crural diaphragm provides extrinsic squeeze to the intrinsic LES, contributing to resting pressure during inspiration and also augmenting LES pressure during periods of increased abdominal pressure such as coughing, sneezing, or bending [17]. Crural contractions impose rhythmic pressure increases of about 5–10 mmHg on the LES pressure recording [18]. During deep inspirations and some periods of increased abdominal straining, these changes may reach 50–150 mmHg [19].

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 [20].

Mechanisms of reflux

Transient lower esophageal sphincter relaxations

This is the most common mechanism underlying GER and also accounts for the reflux of gases during belching. Figure 2 illustrates an example of a transient LESR and highlights differences from swallow-induced LESRs: transient LESRs are not associated with antecedent pharyngeal contractions, are unaccompanied by esophageal peristalsis, persist for longer periods than swallow-induced LESRs (> 10 s), and are always accompanied by inhibition of the crural diaphragm [21]. Transient LESRs account for nearly all reflux episodes in healthy persons and for 50%–80% of episodes in patients with GERD, depending on the severity of associated esophagitis (Fig. 3) [22]. However, one study suggested that low basal LES pressure, rather than transient LESRs, may be the primary mechanism of GER in patients with nonreducible hernias [23]. Transient LESRs are not always associated with GER. In healthy persons, about 40%–60% of transient LESRs are accompanied by reflux episodes, compared with 60%–70% in patients with GERD [15,22,24,25].

The rate of transient LESRs is increased by gastric distention, whether by gas or a meal, by stress, and, to a lesser extent, by subthreshold (for swallowing) stimulation of the pharynx [26]. Under normal circumstances, meals are the major stimuli for transient LESRs, but the importance of specific foods is unknown [27]. Transient LESRs are inhibited by the supine position, sleep, general anesthesia, and vagal cooling [26]. Various drugs also impair transient LESRs including cholecystokinin A antagonists, anticholinergic drugs, morphine, somatostatin, nitric oxide inhibitors, 5-hydroxytryptamine 3 (5-HT3) antagonists, and δ-aminobutyric acid B (GABA-B) agonists [28]. Current evidence indicates that transient LESRs are mediated through vagal pathways [26]. Gastric distention activates mechanoreceptors in the proximal stomach adjacent to the gastric cardia, which send signals to the brainstem center through vagal afferent pathways. The structured sequence of motor events including LESR, inhibition of the crural diaphragm, and contractions of the esophageal body suggest that this process occurs in a programmed manner, probably controlled by a pattern generator within the vagal nuclei. The motor arm is in the vagus nerve and shares common elements with swallow-induced LESRs [29].

Swallow-induced lower esophageal sphincter relaxations

About 5%–10% of reflux episodes occur during swallowinduced LESRs. Most of these episodes are associated with defective or incomplete peristalsis [22,30]. During a normal swallow-induced LESR associated with normal peristalsis, reflux is uncommon because of the absence of concomitant crural diaphragm relaxation, the relatively short duration of LES relaxation (5–10 s), and the prevention of reflux by the oncoming peristaltic wave (see Fig. 2). Reflux during a swallow-induced LESR is more common in the presence of a hiatus hernia because of pooling of gastric liquids in the hernia sac and the absence of any residual diaphragmatic support during the LESR [31].

Hypotensive lower esophageal sphincter pressure

Stress reflux and free reflux are two mechanisms by which GER can be associated with diminished LES pressure [14,22]. Stress reflux results when a relatively hypotensive LES is overcome and is “blown open” by an abrupt increase in intraabdominal pressure from coughing, straining, or bending. Stress reflux is unlikely when the LES pressure is greater than 10 mmHg. Free reflux is characterized by a fall in intraesophageal pH without an identifiable change in intragastric pressure, and it usually occurs when the LES pressure is 0– 4 mmHg. Reflux as the result of low or absent LES pressure is uncommon. It is found mostly in patients with severe esophagitis, in whom it may account for up to 23% of reflux episodes (see Fig. 32.3), and rarely in patients without endoscopic evidence of esophagitis [14,22,24,25]. The mechanisms resulting in a low LES pressure are poorly understood. The presence of a hiatus hernia reduces LES pressure because the intrinsic support of the crural diaphragm is lost [12]. Some LES weakness may be secondary to impairment of the excitatory cholinergic pathways to the LES as a result of esophagitis. Induction of experimental esophagitis in cats affects the release of acetylcholine and lowers LES pressure, changes that are reversible on healing of the esophagitis [32]. However, healing of esophagitis in humans is rarely accompanied by an increase in LES pressure [33].

Hiatus hernia

The relationship between hiatus hernia and GERD remains controversial. Mainstream opinion has shifted widely from one that virtually equated hiatus hernia with GERD to one that denied it a causal role. Currently, both epidemiological and physiological data confirm the importance of the hiatus hernia in patients with more severe esophagitis, peptic stricture, or Barrett esophagus. Hiatus hernias, identified endoscopically or radiologically, are reported in 54%–94% of patients with reflux esophagitis, a rate that is strikingly higher than that in the healthy population [34].

The functional impact of the hiatus hernia has been clarified by elegant combined manometry and videofluoroscopic studies, which show that hiatus hernia impairs LES function through several mechanisms as well as impairing esophageal clearance (Fig. 4) [31,35,36]. Reflux is worse in patients who have a nonreducible as opposed to a reducible hiatus hernia. Nonreducing hernias are those in which the gastric rugal folds remain above the diaphragm between swallows [36]. Furthermore, statistical modeling has revealed a significant interaction between hiatus hernia and LES pressure, such that the likelihood of GER is increased as basal LES pressure decreases, an effect that is substantially amplified by the presence of a hiatus hernia and as hernia size increases [12].

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 because of the loss of the intraabdominal LES segment [35]. Both of these effects are caused by the loss of the extrinsic support of the diaphragmatic crura resulting in increased GER [23]. Hiatus hernia virtually eliminates the increase in LES pressure that occurs during straining and may increase the triggering of transient LESRs during gastric insufflation with gas [35,37]. 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 [31,36].

The origin of hiatus hernia remains unclear. Familial clustering of GERD [10] suggests the possibility of inherited muscle weakness in this area. Animal studies propose that reflux itself causes esophageal shortening, promoting the development of a hiatus hernia [38]. Other studies find an association with obesity [39] and lifting of heavy weights [40], raising the possibility that, over time, chronic intraabdominal stressors may weaken the esophageal hiatus and may cause the development of a hiatus hernia. This theory is attractive because it helps to reconcile the increased prevalence of hiatus hernias as the population ages [34].

Esophageal acid clearance

The second tier of the esophageal defense against reflux damage is esophageal acid clearance. Reflux events determine the frequency with which and extent to which gastric contents enter the esophagus, but esophageal acid clearance time determines the duration that the mucosa is exposed to acid and probably the severity of acid damage. Esophageal acid clearance 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 pH in the esophagus after acid exposure through titration with base, rather than true removal of the refluxed material.

Volume clearance

Esophageal peristalsis operates to clear the acid volume in both the upright and supine positions, but it is inoperative during deep rapid eye movement sleep [41]. Helm and colleagues [42] showed that one or two primary peristaltic contractions will completely clear a 15-mL fluid bolus from the esophagus. Primary peristalsis is elicited by swallowing, which occurs at a frequency of once per minute in awake subjects, regardless of whether reflux occurs. Secondary peristalsis, initiated by esophageal distention from acid reflux, is much less effective in promoting clearance of refluxate, thus offering only an ancillary protective role.

Peristaltic dysfunction, that is, failed peristaltic contractions and hypotensive (< 30 mmHg) peristaltic contractions that incompletely empty the esophagus, increases in frequency with the severity of esophagitis. Kahrilas and colleagues [43] found that the prevalence of peristaltic dysfunction rose from 25% in patients with mild esophagitis to more than 50% patients with severe esophagitis (Fig. 32.5).

Failed peristalsis results in very poor volume clearance because the foci of feeble contractions clear most, but not all, of the refluxate from the esophagus. Whether esophagitis leads to peristaltic dysfunction or whether an underlying motility disorder predisposes to the development of reflux disease is not clear. Animal studies find that esophageal dysmotility associated with active esophagitis is reversible, but that associated with stricture or extensive fibrosis is not [32]. Clinical observations suggest that impaired motor function does not revert to normal after either effective medical or effective surgical therapy [33].

Gravity contributes to bolus clearance when reflux occurs in the upright position. At night, when patients are supine, this mechanism is not operative unless the head of the bed is elevated. This time-honored treatment of GERD markedly improves acid clearance time and is most beneficial in those patients with aperistalsis (i.e., scleroderma) [44].

Salivary and esophageal gland secretions

Saliva is the second essential factor required for normal esophageal clearance of acid. Saliva has a pH of 6.4–7.8 and therefore is a weak base compared with the acidic gastric contents [45]. The high rate of spontaneous swallowing results in saliva production at a rate of approximately 0.5 mL/min. Although saliva is ineffective in neutralizing large volumes of acid (5–10 mL), it can neutralize small residual amounts of acid remaining in the esophagus after the volume of refluxed material has been cleared by severalperistaltic contractions [42]. The importance of swallowed saliva is supported by findings that increased salivation induced by oral lozenges or bethanechol is associated with a significant decrease in acid clearance time. In contrast, suction aspiration of saliva is accompanied by a marked prolongation of esophageal clearance, despite the presence of normal peristaltic contractions [45].

Physiological or pathological compromise of salivation may contribute to GERD. Diminished salivation during sleep explains why nocturnal reflux episodes are associated with markedly prolonged acid clearance times [41]. Similarly, chronic xerostomia is associated with prolonged esophageal acid exposure and esophagitis [46]. Cigarette smoking may promote GER. This was originally attributed to the effects of nicotine on lowering LES pressure, but more recent studies suggest that cigarette smokers have hyposalivation, which may also prolong esophageal acid clearance [47]. Finally, the esophagosalivary reflex may be impaired in patients with reflux esophagitis. This is a vasovagal reflex demonstrated by perfusing acid into the esophagus, thereby stimulating increased salivation [48]. This reflex may explain the symptoms of water brash (copious salivation) observed in some patients with reflux disease. The esophagosalivary reflex is very active in healthy persons, with a doubling or tripling of the salivary flow rate on exposure to acid. However, this reflex is diminished in patients with esophagitis and in those with strictures [48].

In addition to the role of saliva, dilution and neutralization of residual acid are achieved by the aqueous bicarbonate (HCO3 −)-rich secretions of the esophageal submucosal glands. These glands have been identified in the opossum as well as in the human esophagus [49]. Reflux of acid into the esophageal lumen stimulates these glands and helps to neutralize the acid, even if swallowing does not occur [50].

Tissue resistance

Although clearance mechanisms minimize acid contact time with the epithelium, even healthy persons may have their esophagus exposed to acid for 1–2 h during the day and sometimes at night. Nevertheless, only a few persons experience symptomatic GER, and even fewer suffer GERD. This is the result of the third tier of esophageal defense, known as tissue resistance. Tissue resistance is not a single factor but a group of dynamic mucosal structures and functions that interact to minimize mucosal damage from the noxious gastric refluxate [51]. Conceptually, tissue resistance can be subdivided into preepithelial, epithelial, and postepithelial factors. The preepithelial defense in the esophagus, in contrast to that in the stomach and duodenum, is poorly developed. There is neither a well-defined mucous layer nor a buffering capacity of the surface cells to secrete HCO3 − into the unstirred water layer. This results in a lumen-to-surface pH gradient in the esophagus of 1:10, in contrast to the stomach and duodenum where the gradient can range from 1:1000 to 1:10 000 [52].

The epithelial defenses in the esophagus consist of both structural and functional components. Structural components include the cell membranes and intercellular junctional complexes of the esophageal mucosa. This structure is a 25- to 30-cell-thick, 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 with resistance to ionic movement at the intercellular as well as the cellular level as a result of both tight junctions and the matrix of lipidrich glucoconjugates in the intercellular space [53].

The functional components of epithelial tissue resistance include the ability of the esophageal epithelium to buffer and extrude H+ ions. Intracellular buffering is accomplished by negatively charged phosphates and proteins, as well as HCO3 −. When the buffering capacity of the cell is exceeded and intracellular pH falls, the cell has the capacity to actively remove H+ ions. This occurs possibly by the action of two transmembrane proteins, a Na+/H+ exchanger and a Na+- dependent Cl−/HCO3 − exchanger [54,55]. 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 a transmembrane Na+- independent Cl−/HCO3 − exchanger that extrudes HCO3 − from the cytoplasm when the intracellular pH is too high [54]. When the epithelial cells are no longer able to maintain intracellular pH, they lose their ability to regulate volume, edema occurs, and balloon cells develop.

The postepithelial defense is provided by the esophageal blood supply. Blood flow delivers oxygen, nutrients, and HCO3 − and removes H+ and carbon dioxide, thereby maintaining a normal tissue acid–base balance. Blood flow to the esophageal mucosa increases in response to the stress of lumenal acid [56]. Cellular injury also stimulates cell proliferation [57], which results in thickening of the basal cell layer of the epithelium. Unlike the stomach, in which superficial mucosal injury is repaired in hours, the esophagus repairs itself more slowly over days to weeks.

Gastric factors

Gastric factors (particularly gastric volume and certain aggressive factors found in the refluxate) are potentially important in the production of reflux esophagitis. Gastric volume is determined by the basal acid secretion rate, concomitant H. pylori infection, duodenogastric reflux, and the rate of gastric emptying. Increased gastric volume not only results in more gastric contents being available for reflux but also increases the rate of transient LESRs.

Gastric acid secretion

The primary importance of gastric acid in the production of reflux esophagitis is indisputable, but its mechanism of action may involve activation of pepsin rather than direct damage from acid alone. In animal studies, acid causes minimal injury at a pH of less than 3.0, primarily by protein denaturation. However, the combination of acid and even small amounts of pepsin disrupts the mucosal barrier resulting in increased H+ ion permeability, histological changes, and gross hemorrhage [58]. Complementing the animal studies, a series of clinical reports showed that patients with various grades of esophagitis, including Barrett esophagus, have an increased frequency and duration of esophageal exposure to gastric refluxate of pH lower than 4.0 [59,60]. Conversely, perfusing the esophagus of animals with a pepsin solution of pH 7.5 produces minimal mucosal disruption or changes in permeability [58]. These observations are the cornerstone of acid suppressive therapy in the treatment of GERD.

Some studies have suggested that patients with reflux, especially those responding poorly to conventional antisecret- PART 2 Gastrointestinal diseases 778 ory therapy, may have higher rates of acid secretion than control subjects [61]. However, most evidence finds no abnormality of gastric acid secretion in patients with GERD. For example, Hirschowitz [62] compared gastric secretion in 115 patients with esophagitis with that in 508 age-, gender-, and disease-matched control patients without esophagitis. Fasting basal or maximal secretion of either acid or pepsin was the same in both groups, and the severity of esophagitis was not related to any of these factors.

Factors that reduce gastric acid secretion naturally, for example concomitant infection with H. pylori, especially if it is the cagA+ virulent strain, may protect from the development of severe esophagitis and Barrett esophagus [63,64]. H. pylori, particularly this virulent strain, is a biological antisecretory agent that lowers gastric acidity. It produces severe corpus gastritis and accelerates the progression to multifocal atrophic gastritis and intestinal metaplasia, with concomitant lower acid output (Fig. 32.6).

In addition, the bacteria produce ammonia, which acts as a powerful neutralizing agent under elevated pH conditions [8,65]. The corpus mucosa returns to normal when the H. pylori infection is cured, increasing acid secretion and possibly contributing to the reports of esophagitis after successful treatment of H. pylori infection [66,67]. The consequences of long-term normalization of parietal cell function and return to higher intragastric acidity are unknown, but they could promote the development of more severe GERD, Barrett esophagus, and adenocarcinoma in Western populations [8].

Duodenogastric reflux

Bile acids have been implicated in the development of esophagitis, especially in the presence of increased duodenogastric reflux. Studies in animals demonstrate that conjugated bile acids produce their greatest injury in the presence of acid and pepsin, whereas trypsin, deconjugated bile salts, and the conjugated bile salt taurodeoxycholate are more damaging in the absence of acid [68]. Several surgical reports have suggested that duodenogastric reflux into the esophagus is frequent and may predispose to complications of GERD [59,69]. However, accurate measurement of duodenogastric reflux is difficult. Duodenogastric reflux may be indirectly estimated by ambulatory pH studies using an esophageal pH of less than 7.0 to indicate alkaline reflux [70]. However, the reliability of this indirect marker is now questioned by newer techniques, which either spectrophotometrically measure bilirubin, the most common pigment in bile [71], or measure esophageal impedance to the flow of liquids and gases independently of pH [72]. These studies show that acid reflux and bile reflux increase together across the spectrum of GERD, making it nearly impossible to incriminate one agent over the other in the development of esophagitis [73]. In addition, aggressive acid suppression with proton pump inhibitors (PPIs) decreases both acid and duodenogastric reflux, probably by decreasing the volume of gastric contents available to reflux into the esophagus [74]. Finally, the absence of membrane microvesiculation and intracellular bile deposits in human esophageal biopsies, two distinctive morphological features of experimental acid–bile salt injury, also argue against an important role for bile salts in GERD [75].

Delayed gastric emptying

The importance of delayed gastric emptying in the pathogenesis of GERD is controversial. Early studies observed a delay in the gastric emptying of solids in up to 50% of patients with reflux [76]. However, methodological problems with these studies including conducting them with the patients supine, scanning only in the anterior position, and the use of unstable radioisotopes may have influenced the results. More recent studies of patients in the upright position, in whom scanning was done both anteriorly and posteriorly, found only a 6%–38% rate of delayed gastric emptying, regardless of the severity of the esophagitis [77,78]. Nevertheless, delayed gastric emptying may be a major factor contributing to GERD in some groups, such as diabetic patients with autonomic peripheral neuropathy.

Associated conditions

Certain medical and surgical conditions can predispose a person to GERD. The most common is pregnancy: 30%–50% of pregnant women complain of heartburn, especially in the first trimester. Pregnancy increases the risk of reflux because of the relaxing effects of circulating estrogens and progesterones on LES pressure [79]. Although symptoms may be severe, esophagitis is uncommon, and this type of “situational” GERD is cured with childbirth.

Up to 90% of patients with scleroderma have GERD as the result of smooth muscle fibrosis causing low LES pressure and weak or absent peristalsis. Severe disease is common: up to 70% of patients have esophagitis, many have peptic strictures, and Barrett esophagus and carcinoma of the esophagus have been reported [80].

Unlike the previous two conditions, which are characterized by LES dysfunction, hypersecretion of acid and increased gastric volume are the major factors causing GERD in patients with the Zollinger–Ellison syndrome. In these patients, the esophagitis and complications may be more difficult to treat than the ulcer disease [81]. After Heller myotomy, 10%–20% of patients may develop GERD [82]. Finally, prolonged nasogastric tube intubation may contribute to the development of reflux esophagitis, in part because acid tracks orad along the tube and because the tube mechanically interferes with LES barrier function [83].

Clinical manifestations

Classical reflux symptoms

Heartburn is the classical 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 [84]. Usually it occurs postprandially, particularly after large meals or the consumption of spicy foods, citrus products, fats, chocolates, and alcohol. Recumbency and bending over may exacerbate heartburn. Nighttime heartburn interferes with restful sleeping and may impair next-day work performance. When heartburn dominates the patient’s complaints, it has very high specificity (89%), but low sensitivity (38%), for GERD as diagnosed by abnormal 24-h esophageal pH testing [85]. The diagnosis of GERD is usually based on the occurrence of heartburn on 2 or more days a week, although less frequent symptoms do not preclude the disease [86]. Although this symptom is an aid to diagnosis, the frequency and severity of heartburn do not predict the degree of esophageal damage. Heartburn is caused by acid stimulation of sensory nerve endings in the deeper layers of the esophageal epithelium. These nerve endings are normally protected by a relatively impermeable epithelium but, with epithelial changes caused by reflux, they may be stimulated by H+ ions or spicy foods [87].

Other common symptoms of GERD are acid regurgitation and dysphagia. The effortless regurgitation of acidic fluid, especially after meals and exacerbated by stooping or recumbency, is highly suggestive of GERD [85]. Among patients with daily regurgitation, the LES pressure usually is low, many have associated gastroparesis, and esophagitis is common. For these reasons, acid regurgitation may be more difficult to control medically then classical heartburn complaints. Dysphagia is reported by more than 30% of patients with GERD [88]. It usually occurs in the setting of longstanding heartburn, with slowly progressive dysphagia primarily for solids. Weight loss is uncommon because patients have good appetites. The most common causes are a peptic stricture or Schatzki ring, but other causes include severe esophageal inflammation alone, peristaltic dysfunction, and esophageal cancer arising from Barrett esophagus.

Less common reflux-associated symptoms include water brash, odynophagia, burping, hiccups, nausea, and vomiting [89]. 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 [45]. Odynophagia, pain on swallowing, can occasionally be seen with severe ulcerative esophagitis. However, its presence should raise the suspicion of an alternative cause of esophagitis, especially infections (candidiasis, herpes) or pills (tetracycline, potassium chloride, quinine, vitamin C, alendronate).

In contrast to the previously described symptomatic presentations, some patients with GERD are asymptomatic. This is particularly true in elderly patients because of decreased acidity of the reflux material or decreased pain perception [5]. Many elderly 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 esophagus are insensitive to acid at the time of presentation [90].

Extraesophageal manifestations

It has been suggested that GER may be the cause of a wide spectrum of conditions including noncardiac chest pain, asthma, posterior laryngitis, chronic cough, recurrent pneumonitis, and even dental erosion [91]. Some of these patients have classical 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 patients may simply have two common diseases without a cause-and-effect relationship.

Chest pain

GER-related chest pain may mimic angina pectoris. The chest pain is usually described as squeezing or burning, substernal in location, and radiating to the back, neck, jaw, or arm. It often is worse after meals, awakens the patient from sleep, and may worsen during periods of emotional stress. Heavy exercise, even treadmill testing, may provoke GER [92]. Reflux-related chest pain may last minutes to hours, often resolves spontaneously, and may be eased with antacids. Most patients with GERD-induced chest pain have heartburn symptoms [93]. 

Early studies suggested that spastic motility disorders were the most common esophageal cause of chest pain. However, studies using ambulatory esophageal pH and pressure monitoring suggest that about 25%–50% of patients with noncardiac chest pain have GERD [94]. Overall, these series of reports found that 41% of patients had abnormal 24-h pH test results, whereas 32% had chest pain that was clearly associated with acid reflux. Patients with coronary artery disease commonly have coexisting esophageal diseases, but the evidence that GER causes ischemic pain is controversial [95]. The mechanism for GERD-related chest pain is not clearly understood and probably is multifactorial, related to H+ ion concentration, volume and duration of acid reflux, and secondary esophageal spasm.

Asthma and other pulmonary diseases

The association of GERD and pulmonary diseases was recognized by Sir William Osler [96], who recommended that asthmatic patients should “learn to take their large daily meal at noon to avoid nighttime asthma which occurred if they ate a full supper.” More recent studies suggest the coexistence of the two diseases in up to 80% of asthmatic patients, irrespective of the use of bronchodilators [97,98]. GERD should be considered in asthmatic patients who present in adulthood, those without an intrinsic component, and those not responding to bronchodilators or steroids [99]. Up to 30% of patients with GERD-related asthma have no other esophageal complaints. Other pulmonary diseases associated with GERD include aspiration pneumonia, interstitial pulmonary fibrosis, chronic bronchitis, bronchiectasis, and possibly cystic fibrosis, neonatal bronchopulmonary dysplasia, and sudden infant death syndrome.

Proposed mechanisms of reflux-induced asthma are either aspiration of gastric contents into the lungs with secondary bronchospasm or activation of a vagal reflex from the esophagus to the lungs causing bronchoconstriction. Animal [100] and human [101] studies report bronchoconstriction after esophageal acidification, but the response tends to be mild and unpredictable. In contrast, intratracheal infusion of even small amounts of acid induces profound and reproducible bronchospasm in cats [100]. The reflux of acid into the trachea compared with the esophagus alone predictably caused marked changes in peak expiratory flow rates in asthmatic patients [102]. Although either mechanism may be responsible for reflux-induced asthma, most patients probably suffer from intermittent microaspiration.

Ear, nose, and throat diseases

GERD may be associated with a variety of laryngeal conditions and symptoms, of which reflux laryngitis is perhaps the most common [103,104]. 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, vocal cord ulcers and granulomas, leukoplakia, and even carcinoma. These changes usually are limited to the posterior third of the vocal cords and interarytenoid areas, both in close proximity to the upper esophageal sphincter. GERD is the third leading cause of chronic cough (after sinus problems and asthma), accounting for 20% of cases [105]. Dental erosion, defined as the loss of tooth structure by chemical processes not involving bacteria, can be caused by GER in healthy persons and in patients with bulimia [106].

Despite the association between ear, nose, and throat diseases and GERD, overt esophagitis usually is absent, and most patients have only mild reflux symptoms if any [103]. Microaspiration of gastric contents is the most likely cause of these complaints. Animal studies find that the combination of acid and pepsin is very injurious to the larynx [103]. Human studies report that proximal esophageal acid exposure, especially at night while sleeping, is significantly increased in patients with laryngeal symptoms and signs [107].

Diagnostic evaluation

Many tests are available for evaluating patients with suspected GERD. These tests are often unnecessary because the classical symptoms of heartburn and acid regurgitation are sufficiently specific to identify reflux disease and to begin medical treatment. However, this may not always be the case, and the clinician must choose which test to use to arrive at a diagnosis in a reliable, timely, and cost-effective manner, depending on the information desired (Table 32.1).

Empiric trial of acid suppression

The simplest and most definitive method for diagnosing GERD and assessing its relationship to symptoms (either classical or atypical) is the empiric trial of acid suppression. 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 causeand- effect relationship between GERD and symptoms. Therefore, it has become the first test used in patients with classical or atypical reflux symptoms without “alarm” complaints. The popularity of this approach was aided by the introduction of the PPIs, which, unlike the histamine type 2 receptor antagonists (H2RAs), can drastically reduce the amount of acid reflux into the esophagus. Symptoms usually respond to a PPI trial within 7–14 days. If symptoms disappear with therapy and then return when the medication is stopped, GERD may be assumed.

In the reported empiric trials with heartburn, the initial dose of PPI was high (e.g., omeprazole 40–80 mg/day) and was given for not less than 14 days. A positive response was defined as at least 50% improvement in heartburn. Using this approach, the PPI empiric trial had a sensitivity of 68%–83% for determining the presence of GERD [108,109]. In noncardiac chest pain, Fass and colleagues [110] found that a 7-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 colleagues [111] found omeprazole, 40 mg twice a day for 2 weeks, to be a very reliable method for identifying acid-related cough. Empiric trials using a 2- to 4-month regimen of PPIs taken twice a day are commonly used in patients with suspected GERD-associated asthma and GERD complaints related to the ear, nose and throat.

An empiric trial of PPIs for diagnosing GERD has many advantages. The test is office based, is easily performed, is relatively inexpensive, is available to all physicians, and avoids many needless procedures. For example, Fass and associates [110] showed a saving of more than US$570 per average patient because of a 59% reduction in the number of diagnostic tests performed for noncardiac chest pain. Disadvantages are few, including a placebo response and an uncertain symptomatic end point if symptoms do not resolve totally with extended treatment.

Endoscopy

Upper endoscopy is the current standard for documenting the presence of esophagitis and its extent and excluding other etiologies. However, only 40%–60% of patients with abnormal esophageal reflux by pH testing have endoscopic evidence of esophagitis. Thus, the sensitivity of endoscopy for GERD is 60% at best, although it has excellent specificity, at 90%–95% [112].

The earliest endoscopic signs of acid reflux include edema and erythema. Neither finding is specific for GERD, and both are very dependent on the quality of the endoscopic visual images [112]. More reliable are the findings of friability, granularity, and red streaks. Friability (easy bleeding), occurring with gentle pressure on the mucosa, results from the development of enlarged capillaries near the mucosal surface in response to acid. Red streaks may extend upward from the esophagogastric junction along the ridges of the esophageal folds. In studies evaluating these stigmata, nearly all patients had GERD [113]. With progressive acid injury, erosions develop (Fig. 32.7a), characterized by shallow thinning of the mucosa associated with a white or yellow exudate surrounded by erythema.

Commonly located just above the esophagogastric junction, erosions may be either single lesions or coalesced regions and occur along the tops of mucosal folds, areas most prone to acid exposure. Erosions may also be caused by nonsteroidal antiinflammatory drugs (NSAIDs), heavy smoking, and infectious esophagitis [113]. Ulcers reflect more severe esophageal damage. They penetrate the mucosa, tend to have either a white or yellow discolored base, and may be seen either isolated along a fold or surrounding the esophagogastric junction.

Multiple classification systems for esophagitis have been proposed; some are confusing and none has worldwide acceptance [114,115] (Table 32.2). In Europe, the most popular scheme is the Savary–Miller classification [114]. In the United States, the Hetzel [116] and Los Angeles [115] systems are most popular, with the latter gaining the most acceptance.

Most patients with GERD are treated initially without endoscopy. The important exception is the patient experiencing alarm symptoms: dysphagia, odynophagia, weight loss, and gastrointestinal bleeding. With such symptoms, endoscopy should be performed early to rule out other entities such as infections, ulcers, cancer, or varices. The role of endoscopy in GERD without alarm symptoms has changed dramatically in the PPI era. Previously, the degree of esophagitis helped direct management but this is less of an issue with PPIs, which effectively heal all grades of esophagitis. Currently, the most important reason for performing endoscopy in patients with GERD is to identify peptic strictures or Barrett esophagus. Using this rationale, most patients with chronic GERD need only one endoscopic examination while they are receiving therapy.

Esophageal biopsy

Similar to endoscopy, the role of esophageal biopsies in evaluating GERD has evolved over the years. Microscopic changes indicative of reflux may occur even when the mucosa appears normal endoscopically [117]. These classical findings are reactive epithelial changes characterized by an increase in the basal cell layer of greater than 15% of the epithelium thickness or papilla elongation into the upper third of the epithelium (see Fig. 32.7b), both changes representing increased epithelial turnover of the squamous mucosa. Unfortunately, these changes are also noted in up to 50% of healthy persons when biopsies are taken from the distal 2–3 cm of the esophagus [118]. Hence, the changes are sensitive markers for GERD but have poor specificity.

Acute inflammation characterized by the presence of neutrophils and eosinophils is very specific for esophagitis [118]; however, the sensitivity is low, in the range of 15%– 40% [119]. Eosinophils are found more often on biopsy (19%–63% of subjects) but are less specific, present in up to 33% of healthy adults [120]. Interestingly, the sensitivity and specificity of eosinophils in children are much stronger, reflecting the lack of eosinophils in the juvenile inflammatory response [118,121].

In clinical practice, the primary indication for esophageal biopsy is to determine the presence of Barrett epithelium and possible eosinophilic esophagitis. When the former diagnosis is suspected, a biopsy is essential and should be carried out when all visual evidence of esophagitis is healed.

Esophageal pH monitoring

Ambulatory intraesophageal pH monitoring is the standard for establishing pathological reflux [122,123]. The test is performed with a pH probe passed nasally, positioned 5 cm above the manometrically determined LES and connected to a battery-powered data logger capable of collecting pH values every 4–6 s. An event marker is activated by the subject in response to symptoms, meals, and body position changes. Patients are encouraged to eat normally and to pursue regular daily activities. Monitoring is carried out usually for 18–24 h. Reflux episodes are detected by a pH drop below 4.0. Commonly measured parameters include the percentage of total time that the pH is below 4.0, the percentage of time upright and time supine that the pH is below 4.0, the total number of reflux episodes, the duration of the longest reflux episode, and the number of episodes that last for longer than 5 min [122]. The total percentage of time that the pH is below 4.0 is the most reproducible measurement for GERD, with reported upper limits of normal ranging from 4% to 5.5% [123]. Ambulatory pH testing can discern positional variations in GER, meal- and sleep-related episodes, and help to relate symptoms to reflux events (Fig. 32.8).

As the result of its reliability for measuring GER across normal activities, ambulatory pH testing has replaced other older studies such as the standard acid reflux (Tuttle) test and radionuclide scintigraphy.

One important problem with esophageal pH monitoring is that there exists no absolute threshold value that reliably identifies pathological GER. Validation studies comparing the presence of esophagitis with an abnormal pH test report sensitivities ranging from 77% to 100% with specificities of 85%–100% [123]. However, these patients rarely need pH testing; rather, patients with normal endoscopic findings and suspected reflux symptoms should benefit most from ambulatory pH monitoring. Unfortunately, the data are much less conclusive in this group, with considerable overlap between control subjects and patients with nonerosive reflux [123]. Other drawbacks of pH testing include possible equipment failure, the pH probe missing a reflux event because it is buried in a mucosal fold, and false-negative studies resulting from dietary or activity limitations because of poor tolerability of the nasal probe.

An important advantage of ambulatory esophageal pH monitoring is its ability to record and correlate symptoms with reflux episodes over extended periods. For this indication it has essentially replaced the shorter acid perfusion (Bernstein) test. Because only about 10%–20% of reflux episodes are associated with reported symptoms, different statistical analyses have evolved in an attempt to define a significant association between these two variables, including the symptom index, symptom sensitivity index, and symptom association probability [124]. However, one study found none of these statistical relationships to be superior to a high-dose trial of a PPI in establishing the causal relationship between symptoms and GER [124].

Definite clinical indications for ambulatory pH monitoring have been established [123]. Before fundoplication, pH testing should be performed in patients with normal endoscopic findings to identify the presence of pathological reflux. If esophagitis is present, pH testing is not necessary because the disease has been established. After antireflux surgery, persistent or recurrent symptoms warrant repeat pH testing. In these situations, pH monitoring is performed with the patient discontinuing all antireflux medications (PPIs for 1 week, H2RAs for 2 days). Esophageal pH testing is particularly helpful in the evaluation of patients with reflux symptoms resistant to treatment and with normal or equivocal endoscopic findings. For this indication, pH testing is usually also carried out in patients receiving therapy to define two populations: those with and those without continued abnormal esophageal acid exposure times. The group with persistent GER needs intensification of the medical regimen, whereas those patients with symptoms and adequate acid control have another cause of their complaints. Finally, ambulatory pH testing may help in defining patients with extraesophageal manifestations of GERD. In this situation, pH testing is usually carried out with additional pH probes placed in the proximal esophagus or pharynx [125]. Initially, most of these studies were carried out when patients were not taking antireflux medications, to confirm the coexistence of GERD; however, this does not guarantee symptom causality. Therefore, the current approach is to treat the patients aggressively with PPIs first and to reserve pH testing only for those patients not responding after 4–12 weeks of therapy [126].

Two advancements have made pH testing more userfriendly and capable of measuring nonacid reflux. The Bravo pH capsule is a tubeless method of acid monitoring that uses a radiotelemetry capsule attached directly to the esophageal mucosa. This is more tolerable to the patient, allows 48 h of monitoring, and may improve test accuracy by allowing patients to more comfortably carry out their usual activities [127]. The second improvement combines impedance and pH testing, allowing the measurement of both acid and nonacid reflux. This test may be helpful in patients with regurgitation or those with persistent symptoms despite an adequate medical trial of a PPI [128].

Barium esophagram

The barium esophagram is an inexpensive, readily available, and noninvasive esophageal test. It is most useful in demonstrating structural narrowing of the esophagus and in assessing the presence and reducibility of a hiatal hernia. Schatzki rings, webs, or minimally narrowed peptic strictures are often seen only with an esophagram, 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 [129]. By giving the patient in the prone oblique position swallows of barium, the barium esophagram also allows good assessment of peristalsis and is helpful preoperatively in identifying a weak esophageal pump [130]. The ability of a barium esophagram to detect esophagitis varies considerably, with sensitivities of 79%–100% for moderate to severe esophagitis, with mild esophagitis usually missed [130]. Barium testing also falls short when addressing the presence of Barrett esophagus. The spontaneous reflux of barium into the proximal esophagus usually suggests reflux but is infrequent [129]. Provocative maneuvers such as leg lifting, coughing, the Valsalva maneuver, or the watersiphon test can be used to elicit stress reflux. Although these tests can improve the sensitivity of the barium esophagram, some argue that they also decrease its specificity [131,132].

Esophageal manometry

Esophageal manometry allows accurate 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 patients with uncomplicated GERD because most of these patients have a normal resting LES pressure [43]. It is an integral component of pH testing to define the LES location accurately, a task poorly performed by endoscopy, fluoroscopy, or the pH pullthrough technique. Esophageal manometry is traditionally recommended before antireflux surgery to document adequate esophageal peristalsis [133]. If ineffective peristalsis (low amplitude or frequent failed peristalsis) is identified [134], then a complete fundoplication may be contraindicated. However, several studies have challenged this physiological premise, finding that reflux control was better and dysphagia no more common in patients with weak peristalsis after a complete, compared with a partial, fundoplication [135]. Using impedance combined with traditional manometry, one study found that fewer than 50% of patients with manometric “ineffective” peristalsis have poor esophageal bolus clearance [136]. Thus, this new technology helps to better define a weak esophageal pump and limits the use of the less effective partial fundoplication.

Differential diagnosis

Symptoms associated with GERD may be mimicked by other esophageal and extraesophageal diseases including achalasia, Zenker diverticulum, gastroparesis, gallstones, peptic ulcer disease, functional dyspepsia, and angina pectoris. These disorders can usually be identified by their failure to respond to aggressive antisecretory therapy and by diagnostic tests such as endoscopy, barium esophagram, esophageal manometry, ultrasound, nuclear emptying studies, and various cardiac tests. Although GERD is the most common cause of esophagitis, other causes (pill injury, infections, or radiation esophagitis) need to be considered in cases that are difficult to manage and in older or immunocompromised patients.

Clinical course

The clinical course of reflux esophagitis depends to a great extent on whether the patient has erosive or nonerosive GERD on initial presentation. Furthermore, patients tend not to cross over from one group to another unless they are treated medically or surgically: in follow-up ranging from 6 months to more than 5 years, only 15% of patients with nonerosive disease evolved over time to having esophagitis or complications of GERD [137,138].

Nonerosive reflux disease

Although early studies from tertiary referral centers suggested that nearly half of patients with GERD had esophagitis [139], studies carried out in community practices reveal that up to 70% of the patients with GERD had a normal endoscopic examination [140,141]. Furthermore, another community- based study of antacid users found that 53% of patients with GERD had nonerosive disease, and two-thirds of the remaining had only minimal erosive changes at endoscopy [142]. Endoscopy-negative patients with GERD are more likely to be female, younger, thin, and without hiatal hernia. Despite their mild mucosal damage, these patients demonstrate a chronic pattern of symptoms with periods of exacerbation and remission [143]. Studies suggest that dilation of intercellular spaces is a histological marker of this disease, irrespective of esophageal acid exposure [144].

Nonerosive GERD is suspected by the presence of typical reflux symptoms with a normal endoscopic examination and is confirmed by the patient’s response to antisecretory therapy. When performed, 24-h esophageal pH monitoring identifies three distinct subsets of patients with nonerosive disease. First, there are the patients with abnormal acid exposure times who are usually responsive to antisecretory therapy. Second are the patients with normal reflux parameters but a good relationship between acid reflux episodes and symptoms. This group represents 30%–50% of patients with nonerosive GERD [145] and has “functional heartburn” [143]. These patients probably have heightened esophageal sensitivity to acid and are less likely to respond to antireflux therapy [146]. The third group is characterized by normal acid exposure times and poor symptom correlation. Despite sometimes having classical reflux symptoms, other diseases such as achalasia, gastroparesis, bile reflux, or functional dyspepsia are the cause of their symptoms. Overall, patients with nonerosive GERD do not respond to antireflux treatments as well as patients with erosive GERD, probably because these three subsets are not carefully defined before treatment [143].

Erosive reflux disease

The clinical course of patients with erosive esophagitis is more predictable and is associated with complications of GERD. Controlled studies have shown that, in the absence of ongoing maintenance therapy, up to 85% of patients with erosive GERD will have a relapse within 6 months, and the relapse rate is highest in those with the more severe grades of esophagitis [147,148]. This observation, however, should not prevent at least one attempt to withdraw medication, because 20% of patients remain in remission for up to 1 year, especially those with milder esophagitis grades. Although the natural history of untreated erosive GERD is well studied, two European studies suggest that these patients are more prone to reflux complications. In a Finnish study, 20 patients with erosive GERD treated with lifestyle changes, antacids, and prokinetic drugs were followed up for a median of 19 years. In total, 14 patients continued to have erosions, and six new cases of Barrett esophagus were detected [149]. Similarly, a large retrospective European study with 6.5 years of follow-up found a high rate of complications (21%) including 13 patients with esophageal ulcers, 15 with strictures, and 45 with Barrett epithelium [150]. However, these data must be contrasted with other studies, for example a 2- year trial in the United States [151] in which no patients with erosive esophagitis developed Barrett esophagus, and a study over a 12-year period of 3800 French patients [152] in whom the development of stricture was reported in only 0.26%.

Complications

Hemorrhage and perforation

Hemorrhage and esophageal perforation are rare complications of reflux esophagitis and are usually associated with deep esophageal ulcers or severe diffuse esophagitis. Clinically important hemorrhage has been reported in 7%–18% of patients with GERD [153]. Esophageal perforations are very rare in the PPI era, but they can result in mediastinitis and can be fatal if they are not rapidly recognized and treated.

Peptic esophageal strictures

Strictures occur in 7%–23% of patients with untreated reflux esophagitis, especially in older men [154]. They usually evolve over many years and may be linked to the long-term use of NSAIDs [155]. The mechanism of stricture formation is complex, starting as a reversible inflammatory process with edema, cellular infiltration, and vascular congestion, progressing to deposition of connective tissue and collagen, and ending in irreversible fibrosis. With the onset of dysphagia there is often less heartburn, reflecting the fact that the stricture is acting as a barrier to reflux. Dysphagia is usually limited to solids but it may progress to liquids. Unlike malignant strictures, patients with peptic strictures have a good appetite, alter their diet, and lose little weight.

Radiographically, peptic strictures are smooth-walled, tapered, circumferential narrowings in the lower esophagus; they are usually less than 1 cm long but can occasionally extend to 8 cm in length (Fig. 32.9).

In these unusual cases the clinician should suspect a predisposing condition, such as the Zollinger–Ellison syndrome, superimposed pill esophagitis, or prolonged nasogastric intubation [154]. A stricture in the middle to upper esophagus should raise the suspicion of Barrett esophagus or malignant disease. Although once controversial, most data suggest that a Schatzki ring is a forme fruste of an early peptic stricture [156]. In all cases, the nature of a peptic stricture needs to be confirmed by endoscopy with biopsies because some patients may have Barrett esophagus or unsuspected cancer.

Barrett esophagus

In some patients with GERD, the squamous epithelium of the distal esophagus is replaced by specialized columnar epithelium resembling that of the intestine and containing goblet cells. Although Dr. Norman Barrett thought that this lesion was a congenitally shortened esophagus [157], studies consistently show that these patients have severe GERD with low LES pressures, poor esophageal motility, large hiatal hernias, and extensive acid and bile reflux [158]. Furthermore, most patients have had chronic reflux symptoms for at least 10 years [159]. Animal experiments show that, if the mucosal lining of the distal esophagus is excised in the setting of free acid reflux, columnar epithelium will regenerate in the area previously occupied by squamous epithelium [160]. If reflux is controlled, the mucosal lining will regenerate with squamous epithelium. Pluripotential stem cells derived from the stratified squamous epithelium are the origin of the specialized columnar epithelium [161].

Barrett esophagus was once considered an uncommon condition, but estimates of its frequency at autopsy (1 in 57 to 1 in 105 cases), on general endoscopy survey (1 in 100 cases), and on endoscopic surveys of patients with GERD (10 in 100 to 15 in 100 cases) indicate that it is not uncommon and that it affects nearly 700 000 adults in the United States [157]. An autopsy series from Olmsted County, Minnesota found that most cases of Barrett esophagus go undetected during life and thus are not accessible for cancer surveillance programs [162]. Barrett esophagus is principally a disorder of white men; it is three times more frequent in men than in women and is rare in African American and Asian populations [163]. It is found predominantly in middle-aged and older adults; the mean age at diagnosis is approximately 55 years, but it has been reported in children older than 5 years of age [164]. The prevalence of Barrett esophagus increases with age, paralleling that of reflux esophagitis, but the length of the columnar-lined segment remains remarkably stable, even over years of endoscopic follow-up [163]. This finding suggests that it arises rapidly in the susceptible reflux-damaged esophagus and early in the course of disease. Families have been reported with multiple members having Barrett esophagus, some with cancer affecting more than one generation [10,165]. Although the columnar-lined esophagus in itself does not cause symptoms, most patients complain of heartburn and regurgitations. Approximately 25% of patients with Barrett esophagus discovered at endoscopy have no esophageal symptoms [90].

Barrett esophagus is suspected at endoscopy and is confirmed by biopsy and histological examination. The columnar epithelium of the stomach is reddish pink, and the junction between the glossy white squamous mucosa and the columnar mucosa (Z-line) is normally found at the lower end of the tubular esophagus, just above the proximal folds of a hiatal hernia if present. In Barrett esophagus, the distal esophagus is lined with columnar epithelium, extending upward for a variable distance, often 3–10 cm, but occasionally involving most of the esophagus.

The proximal margin may be horizontal or there may be irregular, often tongue-shaped upward extensions of columnar mucosa. Some patients have pale islands of regenerative or residual squamous epithelium, whereas others have punched-out benign ulcers in the columnar area. Strictures and esophagitis may be seen at the new squamocolumnar junction. The endoscopist should especially look for evidence of adenocarcinoma, such as nodularity or masses [166].

The characteristic histological finding in Barrett esophagus is a distinctive specialized intestinal epithelium. This is a glandular epithelium with mucin-type cells and the distinguishing presence of goblet cells (see Fig. 32.10b).

These are easily seen on hematoxylin and eosin-stained sections and can be demonstrated more prominently in sections stained with Alcian blue. It occupies most or all of the columnarlined area and is the type of epithelium in which adenocarcinoma arises [167]. Other types of epithelia seen with Barrett esophagus include gastric fundic and cardia-type epithelia, but these alone do not make the diagnosis of Barrett esophagus nor are they associated with adenocarcinoma.

There is some controversy over the classification of Barrett esophagus [157,166]. The classical or long-segment Barrett esophagus requires at least 3 cm of esophagus to be lined with columnar epithelium. This is the best-studied subset of Barrett esophagus, with traditional demographic features and a definite increased risk of becoming adenocarcinoma. Short-segment Barrett esophagus refers to shorter lengths or tongues of columnar epithelium, less than 3 cm, in the distal esophagus, with intestinal metaplasia on biopsy. This entity is three to five times more common than the long-segment variant, but, based on anecdotal reports, the risk of cancer appears to be lower [168]. Intestinal metaplasia at the esophagogastric junction refers to microscopic findings on biopsy but no visible columnar epithelium in the esophagus at endoscopy [157]. This finding has been reported in 10%– 32% of biopsies from unselected patients, many of whom have no reflux symptoms [168]. The percentage of woman and African American people with this lesion is also higher than the percentage with either long- or short-segment Barrett esophagus. The cause is controversial; some investigators suggest that this is the earliest form of GERD [169], whereas others believe that these changes are secondary to H. pylori infection [170]. Cancer risk is minimal, if it exists at all.

Patients with long-segment Barrett esophagus have an estimated 30–125 times increased risk of developing esophageal cancer compared with the general population [171]. Early studies suggested that the median cancer incidence was 1 per 100 patient-years of follow-up [157], but subsequent studies with longer follow-up suggest a lower cancer incidence of 1 per 200–250 patient-years [172,173]. This represents an annual incidence of approximately 0.5%, with about 500 cases of adenocarcinoma diagnosed annually. However, since the early 1980s, the incidence of squamous cell carcinoma has stayed constant, whereas the incidence of adenocarcinoma of the esophagus and esophagogastric junction has risen fivefold – a growth rate exceeding that of any other cancer [174]. Adenocarcinoma accounts for more than half of all esophageal cancers in the United States. Despite this cancer risk, most patients with Barrett esophagus die of unrelated causes [173]. More than 95% of patients who develop cancer present with symptoms caused by the tumor itself and are unaware of their antecedent Barrett esophagus [175]. Epidemiological data suggest that the mean interval from developing Barrett esophagus to evolution of cancer may be 20–30 years [163].

Medical and surgical therapy

The rationale for GERD therapy depends on a careful definition of specific aims. In patients without esophagitis, the therapeutic goals are simply to relieve the acid-related symptoms and to prevent frequent symptomatic relapses. In patients with esophagitis, the goals are to relieve symptoms and to heal the esophagitis while attempting to prevent further relapses and the development of complications. These goals are set against a complex background: GERD is a chronic disease that may wax and wane in intensity, and relapses are common.

Nonprescription therapy

Although GERD is common in the United States, very few persons seek medical care for their complaints, instead choosing to change their lifestyles and self-medicate with over-the-counter (OTC) antacids and low doses of H2RAs. These observations have led to the “iceberg” model of the GERD population. Most heartburn sufferers 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 [176].

Lifestyle modifications

Sensible changes in lifestyle, especially if their rationale is explained to the patient, should be part of the initial management of all subjects. These include head of the bed elevation, avoidance of tight-fitting clothes, weight loss, restriction of alcohol consumption, elimination of smoking, dietary therapy, refraining from lying down after meals, and avoidance of evening snacks before bedtime. Physiological studies show that these maneuvers enhance esophageal acid clearance, minimize acid reflux-related events, or ease heartburn symptoms, but their therapeutic efficacy in controlled trials usually has not been evaluated [176,177]. The head of the bed can be elevated either by putting 6- to 8-inch blocks under the legs of the bed or by using a Styrofoam wedge under the mattress to elevate the upper torso. Eating several hours before retiring and avoiding evening snacks keep the stomach empty at bedtime, thereby decreasing the number of nocturnal reflux episodes. These three lifestyle changes are recommended for patients with nocturnal GERD symptoms or laryngeal complaints. One study found that head of the bed elevation was nearly as effective as ranitidine therapy in healing esophagitis [178]. Avoidance of tight-fitting clothes and weight loss are interventions aimed at reducing the incidence of reflux by the abdominal stress mechanism. Although obesity is now well established as a risk factor for GERD, esophagitis and esophageal adenocarcinoma, the efficacy of weight reduction is controversial [179]. Targeted weight loss may be helpful when discrete periods of weight gain can be associated with exacerbation of reflux symptoms. Cessation of smoking and elimination of alcohol are valuable because both agents lower LES pressure, reduce acid clearance, and impair intrinsic squamous epithelial protective functions [47,180,181]. Dietary changes for GERD include reducing the sizes of meals and the intake of fats, carminatives, and chocolate, to reduce the frequency of reflux by decreasing gastric distention and by reducing the episodes of transient LESRs, and avoiding foods that lower basal LES pressure [176,179]. Additionally, some patients complain of heartburn after consuming citrus drinks, spicy foods, tomato-based products, coffee, tea, or cola drinks. Stimulation of gastric acid secretion or esophageal sensitivity to low pH or hyperosmolar liquid solutions may account for these symptoms [145]. However, the indiscriminate prohibition of food products should be avoided; rather, to promote dietary compliance, prohibition should be tailored to those foods that bring on individual symptoms. Finally, if possible, patients should avoid drugs that lower LES pressure or which can promote localized esophagitis.

Over-the-counter medications

Over-the-counter antacids, Gaviscon, and H2RAs are useful in treating mild and infrequent heartburn symptoms, especially when symptoms are brought on by lifestyle indiscretions. Antacids increase LES pressure but work primarily by buffering gastric acid in the esophagus and stomach, albeit for relatively short periods. Heartburn symptoms are rapidly relieved, but patients need to take antacids frequently, usually 1–3 h after meals and at bedtime, depending on symptom severity. Gaviscon, containing alginic acid and antacids, mixes with saliva to form a highly viscous solution that floats on the surface of the gastric pool and acts as a mechanical barrier. Both antacids [182] and Gaviscon [183] are more effective than placebo in relieving symptoms induced by a heartburn-promoting meal. However, these agents do not heal esophagitis, and long-term trials suggest effective symptom relief in only 20% of patients using antacids [184]. H2RAs are available in an OTC form at doses that are usually one-half of the standard prescription dose. Although their onset of relief is not as rapid as that of antacids, the OTC H2RAs have a longer duration of action, up to 6–10 h. Therefore, they are particularly useful when taken before a potentially refluxogenic activity, such as a heavy meal or exercise. Similar to antacids, the OTC H2RAs are ineffective in healing esophagitis [185]. In the summer of 2003, the US Food and Drug Administration (FDA) approved omeprazole (20 mg) as the first OTC PPI. Drug labeling suggested daily use for only 2 weeks and recommended physician follow-up for persistent symptoms. Despite initial fears that patients might abuse this drug and not see a physician, early consumer data suggest that individuals accurately self-select if OTC omeprazole is appropriate to use, comply with a 2-week regimen, and seek physician care for long-term management of frequent heartburn [186].

Prescription medication therapy

Patients with frequent heartburn, esophagitis, or complications of GERD usually see a physician and receive prescription medications for their disease. Although prokinetic drugs attempt to correct the motility disorder associated with GERD, the most clinically effective medications for short- and longterm reflux treatment are the acid-suppressive drugs.

Prokinetic drugs

Until recently, three prokinetic drugs were available for the treatment of GERD: bethanechol, a cholinergic agonist; metoclopramide, a dopamine antagonist; and cisapride, a serotonin (5-HT4) receptor agonist, which increases acetylcholine release in the myenteric plexus. These drugs improve reflux symptoms by increasing LES pressure, acid clearance, or gastric emptying [187]. However, none alters the frequency of transient LESRs, and their physiological activity decreases as the disease severity worsens [188]. Therefore, all of the current prokinetics provide modest benefit in controlling heartburn but they have little efficacy in healing esophagitis unless they are combined with an acid-inhibiting drug [187].

The use of prokinetic drugs is limited by their sideeffect profiles. Bethanechol commonly causes flushing, blurred vision, headaches, abdominal cramps, and urinary frequency. Metoclopramide, which crosses the blood–brain barrier, has a 20%–50% incidence of fatigue, lethargy, anxiety, and restlessness, and rarely causes tremor, parkinsonism, or tardive dyskinesia. It is possible to decrease the frequency of these side effects by dose reduction, by increasing the dosing regimen to twice a day, by taking a larger single dose before dinner or at bedtime, or by using a sustained-release tablet. Although cisapride was the best prokinetic drug for treating GERD, with an excellent safety profile, it was withdrawn from the US market because of increased reports of serious cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation), with associated cardiac arrest and deaths related to possible drug interactions [189].

Histamine type 2 receptor antagonists

Cimetidine, ranitidine, famotidine, and nizatidine reduce acid secretion by competing for histamine receptors on parietal cells. They are more effective in controlling nocturnal than meal-related acid secretion because parietal cells may also be stimulated postprandially by acetylcholine and gastrin [190]. All of the H2RAs are equally effective when used in proper doses, usually twice a day before meals. Clinical GERD trials show that heartburn, both day and night, can be significantly decreased by H2RAs compared with placebo, although symptoms are rarely abolished (Fig. 32.11a) [191]. Trials and a metaanalysis found that the overall esophagitis healing rates with H2RAs rarely exceeded 60% after up to 12 weeks of treatment, even when higher than standard doses were used (see Fig. 32.11b) [191,192]. Healing rates differ in individual trials, depending primarily on the degree of esophagitis being treated: grade I and II esophagitis heals in 60%–90% of patients, whereas grade III and IV heals in 30%–50% of patients despite high-dose regimens [192].

Reflux symptoms associated with nocturnal gastric acid breakthrough during PPI therapy have been recognized [193]. At bedtime, H2RAs successfully eliminated this problem, suggesting a new indication for H2RAs in the PPI era [194]. 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 [195]. This may impair the ability of chronic long-term nocturnal dosing of H2RAs to eliminate acid breakthrough symptoms [196], but it suggests an important clinical role as medications to be used on an as-needed basis when lifestyle indiscretions may promote nocturnal symptoms.

The H2RAs are very safe, with a side-effect rate (most of which are minor and reversible) of about 4% [190]. Serum concentrations of phenytoin, procainamide, theophylline, and warfarin are altered after the administration of cimetidine and, to a lesser degree, ranitidine, whereas this interaction is not reported with the other two H2RAs. The concern that these agents could alter blood ethanol levels has been discounted [190].

Proton pump inhibitors

This class of drugs markedly diminishes gastric acid secretion by inhibiting the final common pathway of acid secretion, the H+,K+-ATPase pump. PPIs inhibit daytime, nocturnal, and meal-stimulated acid secretion to a significantly greater degree than H2RAs [197], but they rarely make patients achlorhydric. Unlike H2RAs, the degree of acid inhibition by PPIs does not correlate with plasma concentration, but is related to the concentration and duration (area under the curve). After oral ingestion, acid inhibition is delayed because PPIs need to accumulate in the secretory canaliculus of the parietal cell to bind irreversibly to actively secreting proton pumps [198]. Therefore, the slower a PPI is cleared from the plasma, the more of it is available for delivery to the proton pumps. PPIs are best taken before the first meal of the day, when most proton pumps are active. Because not all pumps are active at any given time, a single PPI dose does not inhibit all pumps. A second dose, if needed, can be taken before the evening meal.

The five available PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole, the S-isomer of the racemic omeprazole. Their superior efficacy compared with H2RAs is based on their ability to maintain an intragastric pH higher than 4.0 between 15 and 21 h daily compared with approximately 8 h daily for the H2RAs [199]. PPIs are superior to H2RAs in completely relieving heartburn symptoms in most patients with severe GERD, usually within 1–2 weeks (see Fig. 32.11a) [192]. Symptom relief is better in patients with erosive than nonerosive disease [200]. Controlled studies and a large metaanalysis report complete healing of even severe ulcerative esophagitis after 8 weeks in more than 80% of patients taking PPIs compared with 51% of patients taking H2RAs and 28% receiving placebo (see Fig. 32.11b) [201–205]. In those patients not healing initially, prolonged therapy with the same dose or an increased dose usually resulted in 100% healing [206]. Therapeutic efficacy between PPIs was similar; however, large studies have found that the newest PPI, esomeprazole (40 mg), is superior to omeprazole (20 mg) and lansoprazole (30 mg) in healing esophagitis [207]. The therapeutic advantage is minimal with mild esophagitis (number to treat, 20–40 patients) and greatest with severe esophagitis (number to treat, 7–10 patients). This superiority is related to higher systemic bioavailability and less interpatient variability with esomeprazole. Several PPIs are now available in the United States for intravenous use.

All of the PPIs are well tolerated with headaches and diarrhea described as the most common side effects in clinical trials. Although increased gastrin levels are reported with all of the PPIs, the elevations generally do not exceed the normal range for gastrin and levels return to normal values within 1 week of stopping the drug. Omeprazole may decrease the clearance of diazepam and warfarin because of competition for the cytochrome P450 isoenzyme P2C19 [208]. The four newer PPIs have minimal or no important drug–drug interactions.

Maintenance therapy

GERD tends to be a chronic relapsing disease, especially in patients with low LES pressure, severe grades of esophagitis, and difficult to manage symptoms [185]. Although almost all patients with severe esophagitis can be healed with PPI treatment, recurrence can be anticipated in more than 80% of patients within 6 months of drug discontinuation [147]. The chronicity of less severe forms of GERD is less certain, but relapses probably occur in 15%–30% of patients over 6 months [209]. Therefore, maintenance therapy is needed for many patients.

One-year maintenance studies always find that the PPIs are superior to the H2RAs or prokinetics, with remission rates higher than 75% [148,210,211]. H2RAs and prokinetic drugs have lower overall remission rates (20%–50%) and are most useful in patients with mild or no esophagitis [148,212]. The FDA has approved all of the PPIs, sometimes at half the short-term dose, for maintenance therapy, but only ranitidine, 150 mg twice daily, has maintenance indications for mild esophagitis. Conversely, clinicians are now placing their patients with severe erosive esophagitis on long-term PPI therapy indefinitely. The efficacy of this approach is supported by open, compassionate use data, primarily from the Netherlands and Australia [213,214]. In a study of 230 patients with severe esophagitis healed initially with 40 mg of omeprazole, all subjects were kept 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 needed in only 12% of patients, suggesting a lack of tolerance to PPIs. Relapses were rare (1 per 9.4 years of follow-up), strictures did not occur, and Barrett esophagus did not progress [214].

There was concern about the long-term safety of PPIs because of their profound acid suppression. Evidence suggests that this fear is unjustified, as sufficient gastric acid is produced, allowing for normal protein and carbohydrate digestion, iron and calcium absorption, and the prevention of bacterial overgrowth. The clinical effect of omeprazole on vitamin B-12 absorption is controversial [215]. Therefore, it may be prudent to monitor vitamin B-12 levels in patients receiving long-term PPI therapy, especially elderly patients or those with poor or unusual diets. The main concern over the long-term safety of PPIs stemmed from reports that omeprazole causes hypergastrinemia and gastric carcinoid tumors in rats, changes also subsequently demonstrated with long-term ranitidine therapy and subtotal resection of the gastric fundus [216]. However, the rat has a high density of enterochromaffin-like cells and an exaggerated response to achlorhydria; long-term omeprazole therapy in species with lower densities of enterochromaffin-like cells (mice, dogs, humans) has not caused carcinoid tumors. Furthermore, other groups with massive hypergastrinemia (five to ten times the gastrin values seen with omeprazole), such as patients with pernicious anemia or Zollinger–Ellison syndrome, rarely develop carcinoid tumors [216]. Finally, one study suggested that patients taking 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 [217]. Nevertheless, a subsequent FDA panel determined that the available data were insufficient for recommending screening and treatment of H. pylori infection in patients receiving long-term PPI therapy [218].

Treatment in elderly or pregnant patients

Older patients often complain of less severe reflux symptoms than their younger cohorts; however, because of prolonged acid exposure over many years, the elderly may have more complicated disease [5]. Treatment of older patients with GERD follows the same principles as treatment of other adults, although they may require more aggressive acidsuppression therapy [219]. Pill-induced esophagitis may complicate treatment. Metoclopramide must be used with caution because of frequent side effects in the elderly. H2RAs can be associated with mental changes in older patients, and doses need to be decreased in patients with renal insufficiency. Fewer drug interactions are seen with famotidine and nizatidine. Alternative methods of administering PPIs may be necessary in debilitated older patients who cannot swallow intact omeprazole or lansoprazole capsules. Both capsules can be opened and the granules taken with water, a HCO3 −-based suspension, or apple or orange juice; alternatively, the granules can be sprinkled onto apple sauce or yogurt [220].

Teratogenicity or fetal harm from absorption of medications across the placenta is the foremost consideration in the treatment of GERD during pregnancy [221]. Lifestyle modifications and the use of antacids or Gaviscon remain the cornerstones of treatment, providing adequate relief to the majority of women with mild symptoms. Although rarely used in adults, sucralfate is a nonabsorbable mucosal binder that has been found to be superior to lifestyle changes in a controlled study in pregnant women [222]. Metoclopramide, H2RAs, and most PPIs (except omeprazole) have a category B FDA safety profile for use during pregnancy, which is based on animal studies showing no risk, as well as on small case series and anecdotal human reports. Ranitidine is the only one of these drugs that has been shown to be effective during pregnancy [223]. PPIs may be safe for aspiration prophylaxis before anesthesia for elective cesarean sections. Antacids, sucralfate, and most H2RAs (except nizatidine) are safe to use during lactation, even though H2RAs are excreted in breast milk. PPIs are not recommended for use during breastfeeding, based on safety concerns in animal studies [221].

Treatment of complications

Extraesophageal presentations

Acid reflux-related chest pain is easily treated by H2RAs or PPIs, with efficacy substantiated by placebo-controlled studies [224]. The efficacy of acid-suppression therapy in asthma, cough, and other pulmonary complications of GERD is more mixed [98]. Medical antireflux therapy improves asthma symptoms and reduces the need for asthma medications in more than 60% of patients, but objective improvement of peak expiratory flow rates is observed in only 25% of patients. Best results are found with higher doses of PPIs (usually twice-daily administration) given for 2–3 months. Potential positive predictors of PPI response include asthma that is difficult to control, associated acid regurgitation, proximal reflux on pH testing, and healing of esophagitis with antireflux therapy. Case studies report that 60%–96% of patients with suspected acid-related ear, nose, and throat symptoms and signs improve with acid suppression, but the results of placebo-controlled studies are inconsistent and much less encouraging [126]. Here again, PPIs are more effective than H2RAs, and extended therapy for up to 3 months may be required. Predictors of response have not been identified, although patients with milder laryngeal signs show better symptom improvement. In all of these possible extraesophageal presentations of GERD, failure to respond to aggressive PPI therapy, confirmed by adequate acid control on pH testing, suggests a cause of these complaints other than acid.

Esophageal strictures

Dysphagia in patients with esophageal strictures is related to stricture diameter and severity of esophagitis [225]. When the esophageal lumen diameter is less than 13 mm, dysphagia is a major complaint and esophageal dilation is required. Simple short strictures can be dilated by blind peroral passage of rubber Hurst (round ends) or Maloney (tapered ends) mercury-filled dilators of increasing sizes (16–60 French, 3 French = 1 mm) to disrupt the fibrous bands producing the obstruction. 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. Before and after dilation, medical therapy with PPIs is indicated; PPIs have been shown to be superior to H2RAs in relieving symptoms and in reducing the need for repeat dilations [227]. Maintenance PPI therapy for patients with strictures has dramatically reduced the incidence of repeat esophageal dilations and the cost of treating these patients [154]. Recalcitrant strictures requiring surgery are now very uncommon and suggest another aggravating factor such as chronic pill injury.

Barrett esophagus

Esophagitis in the presence of Barrett esophagus can be easily healed with PPI therapy; however, regression of Barrett epithelium, except for small squamous islands, is rarely reported, even with high-dose PPI therapy [228]. Recent ex vivo studies [229] have suggested that intermittent “pulses” of acid enhance Barrett epithelial cell proliferation, possibly increasing the risk of dysplasia and cancer. The clinical relevance of this data is supported by a 20-year follow-up study of 236 veteran patients by a single endoscopist. In multivariate analysis, the use of PPIs after the diagnosis of Barrett esophagus was independently associated with a reduced risk of dysplasia (hazard ratio 0.25, 95% confidence interval 0.13–0.47) [230]. Therefore, all Barrett patients should be on chronic PPI therapy.

Esophageal resection of Barrett esophagus can prevent the progression to cancer; however, this requires a total esophagectomy, which has a high mortality rate except in selected surgical centers. Therefore, ablation of Barrett epithelium in the setting of strict PPI anacidity has been proposed. Photodynamic therapy, laser, multipolar electrocoagulation, argon plasma coagulation, and endoscopic mucosal resection have been used for this purpose [231]. In these studies, Barrett mucosa can be reversed completely in 70%–80% of patients, but intestinal metaplasia underlying the new squamous mucosa is reported in almost all series, with the occasional residual foci of metaplasia developing adenocarcinoma [232]. Adverse effects of ablation therapy have ranged from mild chest pain, sore throat, or odynophagia to esophageal perforation and death. The incidence of adenocarcinoma in patients with Barrett esophagus without dysplasia is probably so low that endoscopic ablation cannot be advocated outside of study protocols. Endoscopic therapy for patients with high-grade dysplasia or early cancer holds more promise, especially in the older patients with comorbid illnesses [233].

Because there is no way of eliminating the malignant risk of Barrett esophagus, regular endoscopic surveillance is recommended. Biopsies should be taken from each quadrant every 2 cm axially within the metaplastic tissue. The rationale is that dysplasia within Barrett epithelium is often multifocal, and obtaining fewer tissue samples increases the risk of missing dysplastic areas [234]. Brush cytology can complement endoscopic biopsies [235]. Biomarkers [236], such as p53, and flow cytometry [237] may augment the yield of histological examination of biopsy specimens. Although prospective studies are not available, case series confirm that esophageal adenocarcinomas detected by endoscopic surveillance are at an earlier stage and have a more favorable survival outcome than cancers detected at the time of diagnosis of Barrett esophagus, typically when patients present with dysphagia [238].

The appropriate surveillance interval for patients with Barrett esophagus has not been studied prospectively. However, current programs, such as proposed by the American College of Gastroenterology, are based on the grade of dysplasia [239]. In these recommendations, the management of high-grade dysplasia remains most controversial. Some groups suggest that high-grade dysplasia may regress to lesser grades, and that an intensive biopsy protocol every 3 months will differentiate high-grade dysplasia from cancer [240,241]. The surgical literature contrasts with this experience. Of 126 cases with high-grade dysplasia alone on endoscopic biopsy, 41% had cancer, although usually an early stage, at the time of esophagectomy [239]. Nevertheless, most patients with Barrett esophagus never progress to important degrees of dysplasia. Predictors of cancer progression at the initial diagnosis of Barrett esophagus are needed to define individual surveillance programs more appropriately. One study suggested that patients whose baseline biopsies are negative or show only low-grade dysplasia without increased 4N or aneuploidy on flow cytometry may have surveillance deferred for up to 5 years [241]. Another prospective multivariate analysis revealed that progression to high-grade dysplasia or cancer was significantly and independently associated with dysplasia at diagnosis or at any time during follow-up, hiatal hernia size, and Barrett esophagus length [242]. These patients may warrant more frequent surveillance programs.

Other unresolved issues in Barrett esophagus include the role of screening endoscopy and chemoprevention in dysplasia [243]. As the majority of Barrett patients remain undiagnosed, screening endoscopy has been recommended for older men with chronic long-standing heartburn [157]. A recent mathematical model [244] found that screening a 50-year-old man with GERD was cost-effective (US$10 000 per quality-adjusted life-year of survival gained) if followup endoscopies were carried out only in the subset of Barrett patients with dysplasia at initial biopsy. Two studies [244,245] of patients referred for colon cancer screening who agreed to upper endoscopy demonstrated Barrett esophagus (usually short segment) in 10%–25%, regardless of the presence of reflux symptoms, suggesting a practical method to address this issue. Chemoprevention is a rapidly emerging option that can be used to reduce the risk of developing adenocarcinoma in Barrett esophagus. A metaanalysis of previous cohort studies showed that low-dose aspirin and NSAIDs led to a significant risk reduction in esophageal cancer [246]. These drugs block the up-regulation of cyclooxygenase 2 (COX-2) enzyme activity, which is serially increased along the metaplasia–dysplasia–cancer cascade [247].

Surgical treatment

Antireflux surgery reduces GER by increasing basal LES pressure, decreasing episodes of transient LESR, and inhibiting complete LESR [248]. This is accomplished by reducing the hiatal hernia back into the abdomen and thereby restoring an adequate length of intraabdominal sphincter, reconstructing the diaphragmatic hiatus, and reinforcing the LES [249]. Since the advent of minimally invasive surgery, the two most popular operations are the Nissen fundoplication and the Toupet partial fundoplication.

The former is a superior operation with more long-term durability, but it has a higher frequency of postoperative dysphagia and gas bloat symptoms [250,251]. Both are now routinely performed laparoscopically through the abdomen. The hospital stay is 1–2 days, and many patients return to normal activity within 7–10 days. Patients with more severe disease and a short esophagus manifested by a large nonreducible hernia, a tight stricture, or a long-segment Barrett esophagus require a Collis lengthening procedure creating a 3- to 5-cm neoesophagus so that the fundoplication can be placed in the abdomen under minimal tension [252].

In the PPI era, the resolution of symptoms on treatment helps to predicate the success of antireflux surgery for both classical and atypical symptoms [253]. Antireflux surgery is a reasonable option in the following situations: (1) healthy patients with GERD well controlled on PPIs who want alternative therapy because of drug expense, poor medication compliance, or a fear of unknown long-term side effects; (2) patients with atypical GERD symptoms responding to PPIs; and (3) patients with volume regurgitation and aspiration symptoms not controlled on PPIs. Patients recalcitrant to PPI therapy need to be approached cautiously with surgery because there may be another cause of their disorder (i.e., pill esophagitis, gastroparesis, functional heartburn).

Extensive physiological testing should be carried out before antireflux surgery is performed. All patients need to undergo endoscopy to exclude strictures, Barrett esophagus, and dysplasia. A barium esophagram can help define a nonreducible hernia, shortened esophagus, and poor esophageal motility. Esophageal manometry combined with impedance testing will identify ineffective esophageal peristalsis and previously misdiagnosed achalasia or scleroderma. In addition, 24-h pH testing is needed in all patients with nonerosive GERD or in those with esophagitis not responding to PPI therapy. Gastric analysis and gastric emptying studies may be indicated in selected patients. Careful testing will result in modification of the original operation or an alternative diagnosis in approximately 25% of patients [131].

Antireflux surgery relieves reflux symptoms and reduces the need for stricture dilation in more than 90% of patients [251], but Barrett esophagus rarely regresses and there is insufficient evidence that surgery reduces the risk of esophageal cancer [254]. Comparison studies have found that antireflux surgery is superior to lifestyle changes, the use of antacids, and H2RA and prokinetic therapy [151,184], but not to PPI therapy, especially when dose titration is permitted [255]. Mortality is rare (< 1%) after antireflux surgery, but new postoperative complaints can occur in up to 25% of patients, including dysphagia, gas bloat, diarrhea, and increased flatus [256]. Most symptoms improve over a year, but persistent complaints suggest too tight a wrap, a displaced fundoplication, or inadvertent damage to the vagus nerve. Successful antireflux surgery, however, does not guarantee a permanent cure. The best surgical results are obtained by experienced surgeons in high-volume centers who report long-term symptom recurrence in only 10%– 15% of patients [250]. However, most operations are performed by community or Veterans Affairs hospital surgeons. Here the results are not as good, with studies finding relapse of symptoms after 2 years in 32% of patients, with 7% requiring repeat surgery [257], and a return to regular use of antireflux medications in 62% of patients (one-half on PPIs) 10–15 years after fundoplication [258]. Potential factors contributing to these high relapse rates include inexperienced surgeons, low numbers of operations performed yearly per surgeon, and persistence of abdominal stressors (i.e., obesity, heavy isometric exercise or work) that gradually weaken the fundoplication. A suboptimal operation or severe symptom relapse may necessitate a second operation, which has less likelihood of a successful outcome [249]. Because optimal medical therapy is available to all patients with GERD, the risk and benefits of both long-term medical treatment and antireflux surgery must be carefully discussed with patients so that they can take part in this important decision.

New treatments

The future medical treatment of GERD involves drugs that interfere with transient LESRs but which do not cause dysphagia. Baclofen, a GABA-B agonist, has been shown to decrease reflux symptoms and to improve pH studies in healthy persons and in patients with GERD [259]. Newer endoscopic treatments of GERD have been approved by the FDA. These techniques include an endoscopic suturing system, radiofrequency energy delivery to the gastroesophageal junction, and the injection of nonabsorbable polymers into the submucosa surrounding the LES [260–262]. These procedures decrease the frequency of transient LESRs, but LES pressure is unchanged and less than 40% of patients have normal pH tests. To date, these techniques have been applied only to patients with small (< 2 cm) or no hernias and mild esophagitis. The results are encouraging, with improvement of symptoms and decreased medication requirements, but the cost-effectiveness and durability of the procedures is suspect (usually > 50% failure by 1–2 years) and reported complications include perforation, hemorrhage, pain, and death. Controlled studies using the radiofrequency energy delivery and injectable polymer techniques show consistent symptom improvement over the sham procedure, inconsistent reduction in the use of PPIs, and no significant improvement in LES pressure or pH profiles [263,264]. Serious adverse effects after using the injectable techniques, including several deaths, led to the voluntary withdrawal of Enteryx by the manufacturer in September 2005, and suspension of the Gatekeeper clinical program in 2005. An American Gastroenterological Association (AGA) Institute medical position statement recommended that “current data suggests that there are no definite indications for endoscopy therapy for GERD at this time” [265].

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