The function of the esophagus, the first organ of the digestive tract, seems very simple: it is an antero-posteriorly flattened hollow tube organ that transports material from the mouth into the stomach. This apparently simple task is accomplished successfully by a host of complex mechanisms.
In carrying out its function, the esophagus is exposed to a variety of potentially noxious substances. These substances, contained in ingested foods, beverages and medications, and refluxed gastric and duodenal contents, may be acid or alkaline, hyper- or hypo-osmolar, hot or cold, and may include bile salts, alcohol, and tobacco smoke. Despite these physical and chemical challenges to its integrity and function, the organ remains healthy and functional in most humans, due to a variety of complex physiologic defenses. In this paper, the mechanisms by which the esophagus carries out its physiological function are described.
The major challenge to the integrity of esophageal function is gastroesophageal reflux (GER). When this occurs, and the forces overcome the defense, the esophagus may be damaged, with significant consequences for the affected individual.
In this paper, the nature of the most common and most important offense, GER, is examined, as is that of the defense mechanisms, in an attempt to explain the mechanisms by which GER occurs, and by which the esophagus may be compromised.
The normal functions of mastication and swallowing are discussed, as are the anatomy and physiology of the esophagus. Following this the disruptions of normality which result in pathologic GER and gastroesophageal reflux disease (GERD) are addressed. The pathophysiology of extraintestinal manifestations of reflux disease such as respiratory or laryngeal disease has been reviewed elsewhere (1–3), and is not addressed in detail here. The North American Society of Pediatric Gastroenterology and Nutrition published recently a detailed review on the diagnostic procedures and treatment recommendations (4).
For the purpose of this review, the terms “reflux,” “gastroesophageal reflux,” and “GER” are used synonymously; and while many manifestations of GER or GERD are both symptoms and signs, in general the word “symptoms” is used.
Many factors influence the incidence of GER and occurrence of complications. These are summarized in Table 1, and discussed in detail in this article.
Gastroesophageal reflux (GER) is defined as the involuntary passage of gastric contents into the esophagus, is a normal physiologic process that occurs throughout the day in healthy infants, children, and adults. GER contents may include ingested food and drink, in addition to saliva, gastric, pancreatic, and biliary secretions. Most episodes of reflux are into the distal esophagus, are brief, and asymptomatic. Regurgitation is defined as passage of refluxed gastric contents into the oral pharynx. Vomiting is defined as expulsion of the refluxed gastric contents from the mouth (4,5). GER occurs during episodes of transient relaxation of the lower esophageal sphincter or inadequate adaptation of the sphincter tone to changes in abdominal pressure.
PRIMARY AND SECONDARY GASTROESOPHAGEAL REFLUX (GER)
Primary GER results from a primary disorder of function of the upper gastrointestinal tract. In secondary GER, reflux results from dysmotility occurring in systemic disorders such as neurologic impairment or systemic sclerosis. It may also result from mechanical factors at play in chronic lung disease or upper airway obstruction such as in chronic tonsillitis. Other causes include systemic or local infections (e.g., urinary tract infection, gastroenteritis), food allergy, metabolic disorders, intracranial hypertension, and medications such as chemotherapy. In some cases, secondary reflux results from stimulation of the vomiting centre in the dorsolateral reticular formation by afferent impulses from circulating bacterial toxins, and stimulation from a variety of sites such as the eye, olfactory epithelium, labyrinths, pharynx, gastrointestinal and urinary tracts, and testes (4,5); these stimuli usually cause vomiting.
The symptoms and signs of primary and secondary reflux are similar, but a distinction is conceptually helpful in determining a therapeutic approach. Mechanisms of “secondary” GER are not discussed in this paper.
The most typical, although nonspecific, symptoms of esophageal dysfunction are GER, regurgitation, and vomiting (4–6). Sometimes GER is a normal esophageal function, serving a protective role, e.g., during meals, or in the immediate postprandial period; if the stomach is overdistended, GER serves to decompress it. When GER occurs, natural protective mechanisms serve to remove refluxed material that is noxious to the esophageal mucosa as rapidly and effectively as possible, by antegrade peristalsis toward the stomach, or retrograde peristalsis, resulting in vomiting.
Regurgitation may be physiological in healthy, thriving, happy infants. While reflux does occur physiologically at all ages, there is a continuum between physiological GER and GERD leading to significant symptoms and complications. GERD is a spectrum of disease that can best be defined as the symptoms and/or signs of esophageal or adjacent organ injury secondary to the reflux of gastric contents into the esophagus or, beyond, into the oral cavity or airways (4–6).
Presenting symptoms/signs of GERD are detailed elsewhere (4–6), but one less commonly recognized presentation is worthy of mention, that being unexplained “feeding problems”. Presentation may be with decreased food intake and aversive behavior around feeds. There is often clearly abnormal sucking and swallowing. Not surprisingly, the mother-child interaction is affected, making the situation less easily treated (7). There may be poor weight gain. These infants have no apparent malformations, and may be diagnosed as “non-organic failure to thrive” or “NOFTT” (8), a “disorder” that sometimes is attributed to social/sensory deprivation, socio-economic, or primary maternal-child problems. Primary GERD is but one root cause of “feeding problems” in infancy, others being structural abnormalities of the mouth/pharynx/upper gastrointestinal tract, neurologic conditions, primary behavior disorders, cardiorespiratory problems, or metabolic dysfunction; however, no matter what the cause, so-called “feeding problems” are bio-behavioral conditions, i.e., disorders in which biologic and behavioral causes interact (9).
ESOPHAGEAL DEFENSES: OVERVIEW
Three major tiers of defense serve to limit the degree of GER, and to minimize the risk of reflux-induced injury to the esophagus. The first line of defense is the “antireflux barrier”, consisting of the lower esophageal sphincter (LES), and the diaphragmatic pinchcock and angle of His; this barrier serves to limit the frequency and volume of refluxed gastric contents. When this line of defenses fails, the second, esophageal clearance, assumes greater importance, to limit the duration of contact between luminal contents and esophageal epithelium. Gravity and esophageal peristalsis serve to remove volume from the esophageal lumen, while salivary and esophageal secretions (the latter from esophageal submucosal glands), serve to neutralize acid. The third line of defense, “tissue or esophageal mucosal resistance” comes into play when acid contact time is prolonged, such as when esophageal clearance is defective or not operative (e.g., motility disorders, sleep). These mechanisms are discussed below.
THE MOUTH: MASTIFICATION AND SECRETION OF SALIVA
The major function of mastication is to prepare food mechanically for transport and to initiate the process of digestion. Mastication is poorly developed in infants but increases in importance when solids are introduced. There are few data on the influence of mastication on GER, but mastication is known to stimulate the parasympathetic nerves that regulate salivary, gastric, and pancreatic secretion. Saliva has different functions. The larger the volume of saliva, the more that food is lubricated, resulting in easier esophageal transport. In adults, the secreted volume is 1000 to 1500 ml per day. It is largely composed of water (99.5%), but also contains enzymes, salts, especially bicarbonate, and growth factors, of which epidermal growth factor (EGF) has been the best studied. Saliva secretion is decreased during sleep, as is swallowing—normal adults swallow 600 times during 24 hours, but only 50 times during sleep (9). Acetylcholine stimulates salivary gland secretion, as does cisapride, a prokinetic drug that stimulates acetylcholine release in the myenteric plexus; cisapride produces a 45% increase in salivary volume secreted in basal conditions, a 32% increase during mastication, a 53% increase during mechanical stimulation by inflation of esophageal balloons, and a 51% increase during stimulation with a mixture of HCl and pepsin (10). Others report that cisapride increases salivary secretion during the postprandial phase but not during fasting (11). Cisapride also changes saliva qualitatively—it increases the non-organic buffers (bicarbonate, inorganic phosphate), and increases organic protective components (protein, glycoconjugates, and epidermal growth factor content) (10,12).
`Water brash,' a phenomenon in which the mouth suddenly fills with saliva, is experienced by some patients with GER. It tends to occur with prolonged episodes of acid reflux, and is due to an “esophago-salivary reflex” (13). Salivary flow can be doubled by gum chewing, as non-pharmacological treatment for some patients with GERD (10). In either case, the relatively large volumes of saliva contribute to the neutralization of refluxed acid by alkalinity, and by inducing wet swallows, and thus primary peristalsis. However, decreased salivary secretion has also been demonstrated in patients with esophagitis (14). While the degree of the role of saliva in GER remains unknown, it may be limited, as shown by a study in which a 90% reduction of saliva secretion in a rat model did not increase the incidence of development of esophagitis (15).
ANATOMY OF THE ESOPHAGUS AND THE ANTIREFLUX BARRIER
In adults, the body of the esophagus is 18 to 22 cm long. The upper level of the esophageal body begins about 18 cm from the incisors and ends at 40 cm (range 26–50 cm) in men, and 37 cm (22–41 cm) in women (16). In children, these lengths vary with body length/height (17). The esophagus consists of four layers, as do all parts of the hollow digestive tract (18). However, in contrast to the rest of the gastrointestinal tract, esophageal mucosal is stratified squamous epithelium of the non-keratinizing type, a continuation of pharyngeal mucosa. This type of epithelium protects against rough food material that is swallowed, but its integrity is compromised by recurrent, chronic exposure to strong acid or alkali. The dense connective tissue of the submucosa layer, together with the muscularis mucosa, forms numerous longitudinal mucosal folds, which result in an irregularly outlined lumen in cross-section. Owing to the elasticity of the connective tissue of the submucous layer, these folds are flattened when the esophageal lumen is distended by air, liquids, or solids.
In the upper one-third of the esophagus (unlike in the remainder of the GI tract), both outer and inner layers of the muscularis propria consist of striated muscle. In contrast, in the distal one-third, the muscularis propria consists of smooth muscle in outer longitudinal and inner circular layers (with a myenteric nerve plexus between). In fact, the inner so-called “circular” layer has many spiral or oblique bundles, while “longitudinal” muscularis bundles of the outer layer are irregularly arranged. In the body of the esophagus, there is an extensive system of neural elements between the longitudinal and the circular muscle layers, known as the myenteric plexus of Auerbach. Similarly, in the submucosa, the neural elements form the submucous plexus of Meissner, which appears at about 13 weeks of fetal life. Both plexuses are part of the intrinsic neural structure. Extrinsic vagal and sympathetic fibers are also present.
In some animals, such as the dog and cat, which spend a great part of their life horizontal, the LES is an anatomically discrete sphincter. In contrast, in humans, the upper and lower esophageal sphincters (UES, LES) are anatomically not distinct muscles (18)—the LES is an extension of the circular muscle of the esophageal body. The sphincter is identified surgically by its thickened nature, endoscopically by the narrowing of the esophagus, and manometrically as a high-pressure zone. The LES and gastric fundus are held in place by a prominent phreno-esophageal membrane, a tough fibroelastic layer attached to the thoracic and abdominal diaphragm as well as the esophagus within the hiatus. The anti-reflux barrier consists of the LES and the crural portion of the diaphragm. The esophagogastric angle or angle of His is the angle between esophagus and the great curvature of the stomach, and is normally acute (further discussed below). On the mucosal side, the macroscopic junction of the tubular esophagus with the stomach is the somewhat jagged “Z-line”; this marks the abrupt transition from stratified squamous (shiny, pearly white in its normal state) to columnar epithelium (“salmon” pink).
SWALLOWING AND PERISTALSIS
Swallowing is a complex, integrated act involving somatic and visceral afferent and efferent nerves, and their associated striated and smooth muscles. An effective sucking-swallowing mechanism does not appear before 35 weeks of gestation. Non-nutritive sucking develops first, and is characterized by its rapidity, exceeding two sucks per second, which is approximately twice that seen in nutritive sucking (19). In older children and adults, the initiation of deglutition is under conscious control though it still occurs involuntarily as well.
For simplicity, swallowing can be divided in two distinct phases, an oropharyngeal or pharyngeal and an esophageal phase (20). In the former, following initiation of a swallow, the upper esophageal sphincter (UES) relaxes, respiration is inhibited, and the glottis closes as the larynx is drawn forward and upward. The muscles of the esophagus relax and respiration resumes as the UES contracts to separate the bolus in the esophagus from the pharynx and the airways. Activation of the swallowing center influences the activities of other centers, most notably the respiratory center, as is evidenced by a physiologic apneic pause of 0.5 to 3.5 seconds that accompanies every swallow (21). Apnea occurs also during belching and vomiting. In the relationship between swallowing and airway protective mechanisms, the exquisite temporal coordination in normal adults may be disrupted by the presence of dysphagia or by the presence of pulmonary disease, an area that is not fully clarified (22). The integration of functions is more “fragile” in infants, in whom patterns of swallow and airway protection may not be fully mature. For example, during the early part of oral feeding, healthy term infants show a significant reduction in ventilation during which cyanosis and bradycardia may develop in some; there is recovery with continued feeding. The changes occur with continuous feeding, and to a lesser degree with intermittent sucking (23). Add GER into the mix, and the processes become more disrupted—hence irregular, immature breathing patterns in infants with GERD (24,25).
Esophageal contractions are classified as primary, secondary, and tertiary.Primary esophageal contractions are propagated peristaltic waves initiated by a pharyngeal swallow. Pharyngeal swallows which are not followed by propagated peristalsis are known as “dropped swallows”. Secondary peristalsis is induced by GER, and starts at the highest level that refluxed material reaches in the esophagus. It contributes to esophageal clearance of any remains of refluxed material that were not cleared by a primary wave. Secondary waves can be produced experimentally by inflation and deflation of an esophageal balloon; they are unaffected by cisapride, but have a higher amplitude with larger volumes of refluxate (26). Except for their (afferent) origin, secondary waves are similar to primary, but are inhibited by swallowing (27). Tertiary contractions occur spontaneously in the mid and lower smooth muscle segment, unrelated to swallows or reflux. They are simultaneous, nonpropagated waves, and do not depend on extrinsic innervation.
Swallowing induces contractions waves that begin at the superior constrictor muscle of the pharynx and sweep through the striated and smooth muscle to the cardia without interruption. In the adult, this primary peristaltic contraction propels a solid bolus down the esophagus into the stomach, and takes about 8 to 12 seconds, with a propagation speed of about 2 cm/s (28–30). These parameters are not known in children. In the upright position, due to gravity, fluids ingested reach the esophago-gastric junction before the primary peristaltic wave arrives. But in the head-down position, fluids reach the stomach because they are propelled by the primary contractions induced by deglutition. Pain delays esophageal clearance. In adults, normal esophageal transit time increases to 25 to 102 seconds if the subject's hand is plunged in iced water (30). Ingested substances that are hot increase the speed and amplitude of contractions, whereas cold swallows have the opposite effect.
In the resting state, between swallows, the esophagus is closed at both ends by the upper and lower esophageal sphincters. Both the UES and LES relax secondary to deglutition. When a subject takes a series of swallows, such as when drinking a glass of water, the UES opens and closes at each swallow, while the LES opens when the first peristaltic wave enters the sphincter, and only closes when the last contraction has passed it. Transient relaxations of the UES occur, and when these occur simultaneously with a transient relaxation of the LES, a “common cavity” is created, resulting in a direct connection between the outside world and the stomach (31). The pressure of the UES is lower during infancy and disappears during sleep, but increases with inspiration, glossopharyngeal breathing, gagging, and during straining (32). The response of the UES differs in relation to the kind of material that is present in the esophagus—its pressure disappears when there is air in the esophagus, as in belching; but, when ingested material or acid refluxes in the esophagus, the pressure of the UES increases (33). The vigor of straining, estimated as an increase of gastric pressure, correlates significantly with the degree of augmentation of UES pressure (34). Inspiratory strain is the most common strain spontaneously occurring in children (34).
In adults, pharyngeal swallowing frequency increases three-fold over baseline during daytime reflux episodes, and this primary peristalsis is the most effective mechanism for esophageal acid clearance. In one study (35), clearance of acid occurred after primary peristalsis in 83% of reflux episodes, while secondary waves were rare, usually disorganized (only 19% were peristaltic), and cleared fewer than 1% of reflux episodes. During sleep, swallowing frequency in response to nighttime reflux episodes is lower than during the day; hence mechanisms protective against reflux are less effective during sleep (35). In active sleep, term infants more clear GER by increasing swallowing and secondary peristalsis (36). The important reduction of swallowing rate during quiet sleep may contribute to a delayed esophageal clearance of nocturnal reflux episodes. As we know, infants sleep a lot more than adults; therefore, esophageal clearance may be more compromised in infants. However, preterm infants at term-equivalent age clear acid GER faster as fully propagated peristaltic waves carry neutralizing saliva down the length of the esophagus. In contrast, term infants have a significantly higher proportion of dropped swallows during GER; therefore, when they are supine, saliva does not readily reach the lower third of the esophagus. Reports in adults and older children indicate that secondary peristalsis does not play an important role in esophageal acid clearance. Data suggest that healthy term infants may use pharyngeal swallowing and secondary peristalsis to clear spontaneous GER, a pattern similar to that in adults. Preterm infants by term-equivalent age respond differently and rely on swallowing followed by propagated peristalsis. These mechanisms may explain why preterm infants at term have significantly shorter episodes of reflux than term infants (37). However, the incidence of spontaneous swallowing in term and preterm infants, during sleep and unrelated to GER, is similar if sleep-state related, and is ten-fold more frequent than in adults.
Connective tissue diseases, such as mixed connective tissue disease and scleroderma frequently involve the esophagus (38). In patients with familial amyloidosis, it is unlikely that amyloid deposits in the mucosal wall increase the esophageal “stiffness”, but an autonomic, predominantly vagal, denervation probably best explains the disturbed function (39). Similarly, there is a correlation between esophageal dysmotility and cardiovascular autonomic dysfunction (40).
Esophageal clearance is influenced by at least three factors: esophageal peristaltic waves, gravity, and saliva (41–43). Esophageal clearance mechanisms are well developed by at least 31 weeks postmenstrual age (44), and are fully functional in premature infants with chronic lung disease (45). Delayed or poor clearance of acid from the esophagus is one of the major mechanisms involved in the development of esophagitis (46,47). The pH of saliva varies from neutral to alkaline. Swallowed saliva contributes to the neutralization of the refluxed acid. Moreover, the bolus-effect of swallowed saliva will help in clearing the esophagus from the refluxed material. There is a decreased salivary function in patients with GERD (14). Although poorly studied, it seems logical to suppose that gravity helps also to clear the esophagus. The efficacy of positional treatment may partially be related to gravity (48–50). The esophagus tends to function normally in healthy controls to water swallows when not assisted by gravity (51). On the contrary, more abnormal contractions (simultaneous, retrograde, non-transmitted) occur in the upright position when compared to supine (51). GER occurs most in the seated position, followed by the supine position and is at the lowest in prone position (48–50). The amplification of peristaltic clearing may be considered the initial protective process against acid reflux (52).
Esophageal glands are small, irregularly distributed, and contain only mucous cells (53). These glands can be more frequently detected just distal to the UES and just proximal to the LES. They lubricate the swallowed bolus during its passage from pharynx to stomach. However, esophageal secretions are very important as pre-epithelial factors in GERD. The bicarbonate secretory capacity of the human esophagus is small and the clinical relevance of intrinsic esophageal bicarbonate for mucosal defense is thought to be negligible (54). However, the esophagus also secretes other substances, as illustrated by the observation that patients with an endoscopy-negative GERD have a higher esophageal secretory potential, in term of protein and glycoconjugates, than asymptomatic controls (55). Unlike cisapride, neither omeprazole nor ranitidine affect esophageal bicarbonate secretion (54).
ESOPHAGEAL MUCOSAL RESISTANCE AND DEVELOPMENT OF ESOPHAGITIS
The esophageal mucosal resistance is determined by different factors (Table 3). The innermost layer or the pre-epithelial defense layer provides some mechanical protection, but little or no effective barrier to H+-penetration (56). The human esophagus is lined by a moist, partially keratinized, stratified squamous epithelium, one important property of which is to serve as a barrier between the outside (luminal) world and the internal world of the organisms (57). Knowledge about the nature of the intracellular junctional complex in esophageal epithelium is limited, though there are data to suggest that it is composed of both tight junctions and an intercellular “cement”, the latter depending on species comprised of either lipid or mucinous material (56). Tight junctions act as a barrier to molecules passing between the cells from lumen to blood and vice versa. Tight junctions, however, are neither impermeable nor equally permeable to all ions, and they are generally more permeable to cations than anions (56). However, as H+ enters the junction, it can titrate the negatively charged ions and so change its selective permeability from cation-selective to anion-selective (56). The protective mechanisms of esophageal mucosa operate within the pre-epithelial, epithelial, and post-epithelial compartments. Since refluxed acid and pepsin always act from the luminal side of the mucosa, protective factors like the epidermal growth factor operating as a part of the pre-epithelial defense, are essential in the maintenance of the integrity of the esophageal mucosa (58). The net movement of Na+ from luminal to serosal surface is accomplished relatively rapidly by the expenditure of cellular energy, the accompanying anion, usually Cl−, moves passively and more slowly in the same direction along its electrical gradient. This process creates a measurable potential difference. Understanding the factors that determine this potential difference are of more than theoretical interest since the transmural potential difference has been used to study the pathogenesis of acid injury to the esophageal epithelium and to identify patients with esophagitis and Barrett's esophagus (59,60). The resistance of the mucosa to the noxious effect of the refluxed material (acid, pepsin, chymotrypsin and trypsin, bile, etc.) is different from person to person, and is genetically determined.
Prostaglandin E2 and nitric oxide (NO) are said to be protective (in low concentrations) and detrimental (in high concentrations) for esophageal mucosal integrity (61). Prostaglandin E2 is the major arachidonic acid metabolite secreted (62). Esophageal perfusion with saline stimulates the secretion of prostaglandin E2, whereas the infusion of acid decreases prostaglandin E2 secretion, and HCL/pepsin infusion is related to a further increase of prostaglandin E2 secretion in comparison to saline infusion (62–64). Prostaglandins are only secreted in case of esophageal inflammation (63). Prostaglandin E2 shortens the duration of esophageal contractions in healthy volunteers (64). An increase in secretion of epidermal growth factor and prostaglandin E2 in saliva during mastication or following mechanical of chemical stimulation was demonstrated (12,58). Acetyl salicylic acid renders the esophageal mucosa more permeable to acid and pepsin (65). These effects are in part pH-dependent and might be practically reversed by prostaglandin E2 cotherapy (65). The decline in the rate of luminal PGE2 release in healed reflux esophagitis indicates that its elevated value in active esophageal disease should be considered an implication of mucosal damage induced by HCl and/or pepsin (65). Inhibition of the rate of luminal release of PGE2 under the impact of HCl and pepsin may play a role in the development and/or progression of mucosal damage (66). Nonsteroid anti-inflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins, and since NSAIDs also are reported to have positive effects in animal models on reflux esophagitis, it is proposed that prostaglandins exert a deleterious effect during esophagitis (67). This hypothesis can explain the relation between inflammation and dysmotility (67). But, in the rabbit, prostaglandin E2 has no effect on esophageal mucosa repair (68), although HGF, IGF-I, epidermal growth factor (stimulation), and TGF-beta 1 (inhibition) have a major effect (68). Among PGE2, PGF2 alpha, PGI2, and TXB2 content in esophageal mucosa biopsies in healthy controls and patients with esophagitis, only a difference in PGI2 was noticed (69). The presence of a murine calcium-sensitive chloride channel in esophageal mucosa testifies for the presence of exocrine secretory cells and suggests transepithelial ion transport (70). All the above can probably be summarized as follows. Prostaglandin E2 and nitric oxide are, in low concentrations, protective, whereas, at high doses, they can be harmful (71). Moreover, release of prostaglandin differs for the subtypes and in function of the composition of the refluxed material (63).
Last but not least, the duration of reflux symptoms and of GERD is likely to contribute to the incidence and severity of reflux esophagitis. A large epidemiologic study concluded that the correlation between reflux symptoms and endoscopy-positive GERD is poor and that most GERD patients younger than 50 years have endoscopy-negative GERD (72).
ESOPHAGEAL INNERVATION AND RECEPTORS
Esophageal peristalsis is mediated by central and peripheral stimuli. Medullary circuits comprising premotor neurons of the nucleus tractus solitarii are intrinsically capable of generating rhythmic esophageal motor output, but are subject to a powerful modulation by peripheral sensory feedback (73). Different types of receptors in the esophagus have been identified in animals: mechanical, chemical, temperature, and osmolarity sensitive receptors (74). Although these receptors have not all been convincingly anatomically identified, daily life experience testifies that they exist. That mechanical receptors are present in the human esophagus is illustrated by clinical studies in which the ingestion of large volumes of fluid, or inflation of an intra-esophageal balloon is perceived by the test individual (75). In addition, sudden rapid stretch of the mechanoreceptors in the proximal esophagus can trigger the hiccup reflex in normal subjects (76). Esophageal distention also elicits spike activity in single vagal and splanchnic afferent fibers (77,78). The existence of chemical receptors is also experienced frequently by humans. Many people experience “pyrosis” or “heartburn”, the burning sensation associated with acid reflux. Similarly, when very hot or ice-cold substances are swallowed, these differences in temperatures are felt by the individual. In pathologic conditions, these receptors become “nociceptive”, meaning that they have an increased sensitivity, thus responding with the sensation of pain to (physiologic) stimuli that normally do not cause pain. These nociceptors inform the patient about the existence of tissue damage, and nociceptive responses vary between individuals. Distinct afferent units transduce different sensations, which supports the theory of pain specificity (79). Esophageal distention and acid perfusion induces spatially and temporally distinct cortical activation. Painful and non-painful stimuli induce activation in the same cortical area and cause activation of anterior cingulate gyri (80).
Afferent neurons serve to transmit information acquired at the level of the esophageal receptors to the brain. In the ferret, at least three types of esophageal afferent fibers exist, namely mucosal, tension, and tension/mucosal fibers (81). In the human, two different types of afferent neurons have been identified: C-unmyelinated fibers, responsible for a deep, burning pain, and A-delta fibers, responsible for a sharp, abrupt pain. Repeated noxious stimuli or one very strong stimulus can sensitize both types of fibers to respond to typical non-noxious stimuli as very painful. This hypothesis explains the fact that in some specific clinical situations, a relatively small esophageal distention such as occurs in belching, minimal regurgitation, or even the passage of a swallowed food bolus, may be experienced as very painful. Visceral hyperalgesia may result in a disordered motility, causing more reflux. All this suggests the following hypothesis: in some patients, acid GERD may initially be caused by abnormal motility and cause pain which in turn may induce abnormal motility phenomena. Although vagal nerve endings are involved in the neuronal pathways, their exact role is still poorly understood. Vagal efferent neurons respond to gastroesophageal mechanical inputs, and also receive convergent input from esophageal acid-sensitive and gastrointestinal bradykinin- and capsaicin-sensitive afferents.
In addition to neuronal pathways, neurotransmitters are required for transmission of information between periphery and brain. The sensation of pain is transported to the brain via calcitonin gene-related peptide (CCRP) and substance P (82). Substance P has been best studied—it causes smooth muscle contractions and vasodilatation, and therefore increased mucosal permeability. Substance P is released when there is tissue damage—therefore, in esophagitis for example, the more substance P released, the greater the noxious effect of the refluxed material feeding a vicious cycle (83). Substance P also causes histamine release from mast cells in the alveoli, thus contributing to bronchospasm (84). The latter is one illustration of the complexity of the relationship between GERD and chronic respiratory disease (see section entitled “GERD and respiratory disease”).
Pain sensation in reflux esophagitis can be compared to pain due to skin burns. It is well recognized that third-degree skin burns are not painful because the receptors for pain have been burned. By analogy, the sensation of pain in reflux esophagitis seems limited to the less severe forms of reflux disease. In the extreme form of reflux injury, Barrett's esophagus, mucosal pain sensitivity is decreased (85) (see “Barrett's esophagus” section). This observation leads to the speculation that self-medication and temporary relief may result in only partial healing of tissue damage, leading to chronic esophagitis and perhaps the development of Barrett's esophagus; in the latter case, the patient may believe the reflux esophagitis to have healed because pain has disappeared.
LOWER ESOPHAGEAL SPHINCTER (LES)
Cohen and Harris (86) introduced the concept of a defective LES as a predominant etiology of GER in 1971. The LES is a functional barrier, and represents a zone with an intraluminal pressure that is greater than that of the stomach and esophagus. In adults, this high-pressure zone has a length of 3 to 6 cm, and has a pressure of about 20 mmHg, ranging between 10 to 40 mmHg. An absolute pressure of less than 6 mmHg is required for GER (87). In infants, its length is only a few millimeters. The LES relaxes 2.5 seconds after the initiation of a swallow, well before the arrival of the bolus at the level of the LES, and remains open during 10 to 12 seconds, until the bolus has passed through the region. Increased abdominal pressure is, in the main, associated with increased sphincter pressure (88). Dodds et al. (89) first described the phenomenon of transient LES relaxations (TLESRs), and so the defective LES had given way to the era of the dysfunctional LES. However, gastric distension that is not associated with an increased intragastric pressure, is accompanied by a fall in LES-pressure or by inappropriate TLESRs, that can last for 10 up to 17 seconds (90). It is believed that that these responses are mediated via vagal reflexes. Stimulation of mechanoreceptors in the gastric fundus, or stretching of the gastric fundus, initiates vagosympathetic-mediated reflexes resulting in these TLESRs (91).
The LES pressure constitutes one of the most classically reported and relevant defense mechanisms to prevent GER, although only 20% of all reflux episodes occur in relation to a decreased basal low resting LES pressure (46). The LES pressure decreases postprandially, as well in normals as in patients. Gastric contractions, gastric alkalinization, and proteins increase the LES pressure. Gastrin, motilin, and substance P increase the pressure of the LES. The effect of some hormones is listed in Table 2. Cord blood gastrin levels are much higher than adult levels (92). During the first days and weeks of life gastrin levels are decreased in comparison to adult levels. The role of gastrin in infantile regurgitation has not been evaluated. Esophageal balloon dilatation, the presence of fat in the duodenum, progesterone, atropine (in cats), cholecystokinin, glucagon, vasoactive intestinal peptide (VIP), nitric oxide (NO), dopamine, secretin, estrogen, nicotine, alcohol, mint, and chocolate all decrease the pressure of the LES. Although the anticholinergic agent atropine decreases the LES-pressure, it also decreases reflux by inhibiting the TLESRs (93). GER is most likely to be mediated through a central cholinergic blockade (94). L-arginine, the endogenous source of NO, prolongs TLESRs (94). While fat and chocolate do increase the number of reflux episodes and severity of heartburn, this effect is much greater with red wine and chili (95). Onions increase reflux variables as measured with pH monitoring in patients with heartburn but not in controls (96). Glucagon and cholecystokinin are increased in renal insufficiency, and downregulate hunger and sense of satiety. VIP, NO, and cholecystokinin induce TLESRs (97,98). NO also delays gastric emptying (99) and is increased in infants with H. pyloric stenosis (100), suggesting that TLESRs are a protective mechanism for gastric over-distension. NO controls several esophageal neuromuscular functions, including relaxation of the LES (101), although nitric oxide levels were equal in biopsies of normal and inflamed esophageal mucosa (102). However, on the contrary again, nitric oxide synthetase and cyclooxygenase-2 are reported to be involved early and often in Barrett's neoplastic progression, since they were increased in 4/5 and 5/5 patients, respectively (103).
Most reflux episodes occur in relation to TLESRs, also in children (104). TLESRs are also the predominant mechanism of GER in healthy preterm infants and those with chronic lung disease (44,45). TLESRs are more frequent in the seated position than in supine position. Reflux episodes can also occur during periods of prolonged LES hypotonia or drifts of LES-pressure, especially in patients with severe esophagitis (105). Gastric distension and partial or incomplete swallowing induce TLESRs, which are also the normal mechanism for burping and belching (106). The larger the meal, the more TLESRs. Equally, the greater the gastric secretory volume and the higher the intragastric osmolarity, the more TLESRs. Part of the efficacy of proton pump inhibitors and H2-receptor antagonists may be related to a decreased secretory gastric volume, independent from its pH. During sleep, there are normally no TSLESs. All physiologic GER episodes are related to TLESRs, but in patients with severe reflux esophagitis many GER-episodes are not related to a TLESR (107). In “chalasia” there is a chronic relaxation of the LES. In “achalasia”, there is a complete absence of TLESR. Achalasia is a complex motor disorder of the entire esophagus with primary and secondary motility abnormalities of the esophageal body (108), and is characterized by a hypertonicity of the sphincter with lack or incompleteness of relaxation (109). Achalasia is associated with extra-esophageal autonomic nervous dysfunction that involves cardiovascular function as well as regulation of mesenteric arterial blood flow (110). A lack of NO-synthetase in the LES, cardia, and gastric fundus is involved in the pathophysiology of cardiac achalasia in children (111). In patients with achalasia, esophageal tonic activity is impaired (112).
The antireflux effects of Nissen fundoplication and the Belsey Mark IV procedure may be based on changes of LES motor patterns that result in incomplete LES relaxation and reduction of the number of TLESRs (113,114). GER is related to a low LES pressure, but the resting LES pressure is not necessarily decreased. If there is a relationship between TLESRs and regurgitation, the volume and speed of feeding and regurgitation is a topic for further research. TLESRs are the major mechanism causing GER and GERD. However, it is not clear if a decreased resting LES pressure should be considered as a cause or a consequence of GER. It is very likely that both phenomena occur and contribute to pathologic GER.
INTRA-ABDOMINAL ESOPHAGUS: HIATAL HERNIA
For many years when the main method of investigating reflux was contrast radiology, the hiatal hernia was considered almost synonymous with reflux and a necessary element to explain reflux disease (115). Hiatal hernia is a common finding in healthy adults (116). In general terms, hiatus hernia refers to herniation of elements of the hollow gastrointestinal tract through the esophageal hiatus of the diaphragm. With type I or sliding hiatal hernia, there is a widening of the muscular hiatal tunnel and circumferential laxity of the phreno-esophageal membrane, allowing a portion of the gastric cardia to herniate upward. Largely because of the inherent subjectivity in defining type I hiatal hernia, estimates of prevalence vary enormously, from 10% to 80% (117). In all probability, most type I hiatal hernias are asymptomatic. The likelihood to developing reflux disease is directly related to the size of the herniation. The less common types II, III, and IV, all varieties of paraesophageal hernias, account for at most 5% of all hiatal hernias (118). The crural diaphragm bolsters the LES during inspiration, straining, etc. The resurgence to prominence of the hiatal hernia started with an appreciation of the role of the crural diaphragm in augmenting LES pressure, especially its role in preventing reflux in the face of abrupt increases in abdominal pressure (119–121). The intra-abdominal part of the esophagus is shorter during the first weeks of life. Hiatal hernia is more frequent within an affected family, and is likely to have an at least partially genetic inheritance pattern. Severe hiatal hernia may in some cases even be an autosomal dominant inherited disorder (122). However, (sliding) hiatal hernia is more prominent in different conditions that all have severe GER in common, such as neurologic impairment, chronic lung disease (especially cystic fibrosis), esophageal atresia, etc. (123). There are no data on the prevalence of hiatal hernia in children. However, the important role of hiatus hernia in children with severe GERD is suggested by the observation that children with Barrett's esophagus have hiatal hernias (124). Hiatal hernia is associated with the more severe degrees of reflux esophagitis, especially Barrett's esophagus (125,126).
The incidence of reflux symptoms in a population with hiatal hernia type I is rather low, but there is a high prevalence of hiatal hernia in adults with reflux symptoms (116,127). In a prospective trial including 930 (adult) patients undergoing endoscopy because of reflux symptoms, 14% had esophagitis and 17% hiatal hernia (127). Forty-nine percent of the patients with hiatal hernia had endoscopic esophagitis, and 60% of those with esophagitis had hiatal hernia (127). The severity of the esophagitis was dependent on both the presence and the size of the hiatal hernia (127). The mechanism to explain this seems evident: the length of the intra-abdominal esophagus is shortened or non-existent in patients with a hiatal hernia. As a consequence, the LES region is located in the thorax, surrounded by a negative pressure. The gastric content is “aspirated” back into the esophagus because of the pressure differences between abdomen (positive pressure) and thoracic cavity (negative pressure, enforced during inspiration). During the first year of life, the length of the intra-abdominal esophagus is physiologically very short, which contributes to the increased incidence of regurgitation in this age group. The understanding now has come that severe reflux disease is likely to be associated to anatomic malformations such as hiatal hernia, and that in patients with less severe reflux disease, functional abnormalities such as TLESRs are more likely to be the culprit (128–130).
ESOPHAGOGASTRIC ANGLE: ANGLE OF HIS
Normally there is an acute angle between the great curvature of the stomach and the esophagus. It is speculated that in some patients, as in those with hiatal hernia, this angle is obtuse, and favors GER episodes. The function of the “acute angle” is comparable to the function of a valve. It has been hypothesized (but not demonstrated) that this angle is less acute, perhaps even obtuse in young infants, and only becomes acute after the age of one year.
Although extremely little is known about the anatomy of the esophago-gastric angle in infants, its position does seem relevant since certain positions or postures seem to promote the incidence of GER. Esophageal acid exposure is greater in the right side sleeping position than in the left position (131,132). Esophageal clearance is delayed in the right side position (132). The esophagogastric junction is submerged in the right side posture in a majority of (adult) patients in a barium-pool (thus liquid) below the air-barium interface in the stomach (131). This does not occur in the left posture or upright (131).
GASTRIC VOLUME AND GASTRIC EMPTYING
It is logical to relate gastric volume to the incidence of GER: if the stomach is empty, there is absence of material to reflux into the esophagus. Delayed gastric emptying is present in 10% to 15% of adults with GER disease (87). Gastric electrical abnormalities underlying delayed gastric emptying have been documented in children with severe GER disease (133). To accommodate the intake of food or liquid, gastric reservoir functions, adaptive and receptive relaxations, are important as a physiological reflex (134). Adaptive relaxation is a reflex in which the fundus of the stomach dilates in response to small increases in intragastric pressure when food enters the stomach. Receptive relaxation is a reflex in which the gastric fundus dilates when food passes down the esophagus. Nitric oxide is involved in both pathways (134). Stretch of the gastric wall activates the mechanoreceptors in gastric mucosa, inducing the release of NO which causes a relaxation of the circular muscle and thus of the fundus. Receptive relaxation is mediated by vagal motor fibers. In contrast with the pressure-induced adaptive relaxation, ganglionic nicotinic transmission is essential in the vagally mediated receptive relaxation (134). Phasic relaxations of the LES are induced through afferent vagal pathways by stimulation of mechanoreceptors in the fundus of the stomach (135). The tone of the proximal gastric region is of major importance (136). Children with central nervous disorders who vomit often have abnormal GER as abnormal gastric motility (137). However, also in neurologic normal children, gastric dysrhythmias may play a major role in the pathogenic components of GER disease (138).
Children with delayed gastric emptying, who do not have gastric emptying procedures, have twice the risk of development of pathologic reflux following antireflux surgery (139). However, there do appear to be reliable methods of preoperative selection of these patients for gastric emptying procedures (140). The role of the vagal nerve endings in the esophagus could possibly be involved in this mechanism: the esophageal nerve endings are very rapidly “irritated” once GER occurs, which increases the local prostaglandin tissue levels, and the irritated vagal nerve endings also cause pylorospasm. The nitric oxide donor nitroglycerin inhibits pyloric motility, alters the organization but not the number of antral pressure waves, and slows gastric emptying (100). Patients with GER and chronic respiratory disease and patients with GER and failure to thrive present with delayed gastric emptying. The frequency of postprandial GER is related to the meal size, and gastric bolus feeding is related to a greater intragastric pressure increase and causes more TLESRs. Increased osmolarity and volume of the meal contents slow gastric emptying and increase postprandial GER (141). Mechanoreceptors are present in the fundus, near the gastric part of the cardiac region. When these are stimulated because of gastric distension, they induce TLESRs.
There is a genetic predisposition to the development of reflux in families of patients with Barrett's esophagus and esophageal carcinoma (142). Barrett's esophagus is a premalignant condition in which metaplastic specialized columnar epithelium with gobble cells is present in the tubular esophagus (143). Barrett has a male predominance (144), and increases with age (72). In uncomplicated reflux esophagitis, environmental factors such obesity and smoking appear more important (142). The main determining factor to develop Barrett's esophagus is the severity of reflux (145,146). Children with neurologic impairment, chronic lung disease (especially cystic fibrosis), esophageal atresia, and chemotherapy, have the most severe pathologic reflux and are at high risk for the development of complications of GERD, such as Barrett's esophagus (146). In pediatric reflux, there is no genetic difference in young infants presenting with uncomplicated reflux disease, although severe pediatric reflux may have a genetic component (147)(see section entitled “Genetic and Environmental Factors”). Although the evidence for a purely congenital cause of Barrett's esophagus can be refuted, a congenital component in combination with severe mucosal injury cannot be ruled out (143). Patients with short segments of columnar-lined esophagus and intestinal metaplasia have similar esophageal acid exposure but significantly higher frequency of abnormal bilirubin exposure and longer median duration of reflux symptoms than patients without intestinal metaplasia (148). The rise in prevalence of Barrett's esophagus (in adults) over a short time interval again raises the question about the importance of environmental factors such as obesity and smoking in addition to genetic etiological factors (61).
“The more acid, the more acid GER,” seems logical. Although reflux patients are infrequently hypersecretors of acid, subgroups of GERD patients with gastric hypersecretion have been identified, including children and patients with Barrett's esophagus (149–151). Studies find acid combined with pepsin to be the most injurious agents to the esophageal mucosa. There is a very large variation in the secretion of gastric acidity during a 24-hour period. The vagal nerve regulates gastric acid secretion (152). Moreover, the volume secreted may be more relevant than the pH: proton pump inhibitors are very potent in the treatment of esophagitis, despite the nocturnal break-through of acid secretion.
HELICOBACTER PYLORI INFECTION AND ERADICATION
During the past three decades, hospital discharges and mortality rates of gastric cancer, gastric ulcer, and duodenal ulcer have declined, while those of esophageal adenocarcinoma and GERD have markedly risen (144). The opposing time trends suggest that corpus gastritis secondary to Helicobacter pylori (H. pylori) infection protects against GERD (144). The influence of gastric colonization by H. pylori and its eradication of GERD are a matter of controversy (153). Provocative studies suggested that H. pylori colonization, especially with the more virulent cagA-positive strains, may be protective against severe esophagitis and Barrett's esophagus (154,155). Increased intragastric ammonia production and pangastritis with gastric atrophy and intestinal metaplasia, both promoting hypoacidity, are the most likely mechanisms (153). Thus, it is suggested that eradication of H. pylori may aggravate GER in some susceptible subjects (156,157). However, rather than increase GER, H. pylori eradication is more likely to bring GER back to a normal incidence, since it was suppressed by the hypoacidity caused by the chronic H. pylori gastritis.
PEPSIN, TRYPSIN, AND BILE SALTS
The noxious effect of pepsin and trypsin on the esophageal mucosa is clearly related to the proteolytic properties of these enzymes. Both promote detachment of the surface cells from the epithelium, presumably by digesting the intercellular substances and surface structures that contribute to the maintenance of cohesion between cells (158,159). Each agent causes the most damage at its optimal pH activity range, pH 2 to 3 for pepsin and pH 5 to 8 for trypsin (160). The exact role of bile reflux or duodeno-gastric reflux is still poorly understood (161). Although bile salts increase the permeability of the esophageal mucosa to acid (162), they are only toxic for the esophageal mucosa in the presence of acid (59,60). Bile salts are hypothesized to gain entrance across the mucosa because of their lipophilic state, causing intramucosal damage primarily by disorganizing membrane structure or interfering with cellular function (163,164). The effect of bile salts is influenced by the pH of the refluxed material: conjugated bile salts are noxious at acid pH-, whereas deconjugated bile salts and trypsin are noxious at neutral pH (165). Recent studies show increased amounts of bile acids in the refluxate in adults with reflux disease, especially in those with Barrett's esophagus (148). For this reason, “mixed” refluxate can be more noxious to the mucosa than pure acid GER. Endogenous and exogenous cholecystokinin decrease the LES pressure and increase the number of TLESRs (166). Cholestyramine increases the gallbladder emptying and the number of TLESRs (166).
The “intra-abdominal pressure” is probably an important, yet very poorly studied mechanism favoring GER. In adults, 17% of the GER episodes are related to transient increases in intra-abdominal pressure (167). At least in adults, there is a significant association between weight loss and improvement in symptoms of reflux (168,169). However, the relation between body mass index and GER symptoms is also contradicted in a Swedish population-based interview study (170). However, the authors defined reflux-symptoms to occur only when the patient has symptoms at least once a week for more than 5 years, and body mass index was based on data provided by the interview and not on real measurements (170).
The pressure of the UES increases significantly during inspiratory strain during the postprandial period in infants with GERD-like symptoms (34). Reflux-specific behavioral criteria, as established for older infants, are inappropriate as diagnostic criteria for GERD in premature infants (171,172). The maintenance of a laryngeal mask covering the airways during awakening after general anesthesia until the patient can open his mouth on command increases the incidence of reflux in comparison to when the mask is withdrawn more rapidly when the patients shows signs of rejection (173). The role of crying and straining is thought to decrease sharply after the age of 4 months, although convincing data does not exist. The role of increased intra-abdominal pressure in children, as occurs in constipation or with a tight diaper, has not been evaluated.
GASTROESOPHAGEAL REFLUX CAUSING GASTROESOPHAGEAL REFLUX
GER itself is an important mechanism favoring GER, and this is because of the effect of GER on the esophageal mucosa, inducing several vicious circles. GER frequently contains acid. As a result of the contact of the acid with the esophageal mucosa, there is an increase in the regional blood flow, increasing the local tissue content in prostaglandin E2. Prostaglandin increases the permeability of the mucosa to acid, which enhances the susceptibility of the mucosa for inflammation. Inflammation of the mucosa of the lower part of the esophagus causes an impairment of the LES (favoring GER), causing a dysmotility of the LES (favoring GER), finally causing esophagitis. Nitric oxide delays gastric emptying (48). A subpopulation of nitric oxide synthase-containing vagal preganglionic neurons innervate the upper gastrointestinal tract and mediate relaxation (174,175).
The contact of acid on the esophageal mucosa causes an irritation, dysfunction and inflammation of the local vagal nerve endings, causing an impairment of the LES and a pylorospasm. Both pylorospasm and impaired function of the LES favor GER. As said before, the presence of trypsin, pepsin, and bile may aggravate the toxicity of reflux episodes for the esophageal mucosa.
GENETIC AND ENVIRONMENTAL FACTORS
It has been demonstrated that severe GER disease is more frequent in men than in women (116,144). However, males also have significantly more physiologic reflux than women (176). Prevalence of heartburn and acid regurgitation are more frequent in men than women, but there is no sex-related difference regarding the incidence of the symptoms (177). Barrett's esophagus is at least partially genetically determined (142,144,178). There are many data (in adults) demonstrating the aggravating effects of alcohol, smoking, drugs, dietary components, etc. on the incidence of GER. A detailed discussion on these environmental factors is beyond the scope of this review. Changes in lifestyle in men and women may result in the fact that the differences in incidence in GERD between both sexes may be disappearing. Mild reflux tends to be more common in women than men, while severe GERD characterized by erosive esophagitis, esophageal ulcer, stricture or Barrett's metaplasia are far more common in men (144). We could not demonstrate a male predominance in children with abnormal pH monitoring (179). All forms of GERD affect Caucasians more often than African Americans or Native Americans (144). However, the importance of the genetic background was hypothesized by demonstrating that esophagitis and hiatus hernia were more common in a population with dyspeptic symptoms in England than in Singapore (180). Race, sex, body mass index, and age were independently associated with hiatus hernia and esophagitis, race being the most important risk factor (180). However, over-the-counter use of low-dose aspirin and nonsteroidal anti-inflammatory drugs have a greater impact on severe GERD such as esophageal stricture than age (181). Carre described autosomal-dominant inheritance of hiatal hernia by discovering familial hiatal hernia in a large, five-generation family, but without demonstrating the link to GERD (122). No individual with a hiatal hernia was born to unaffected parents (122). Meanwhile, a gene has been mapped from affected and unaffected members of five families with severe GERD that may be responsible for severe reflux in children (147). From the last two studies (122,147), it seems quite likely that severe GERD in selected families has a strong genetic component. However, whether this genetic component is also relevant for all the children with GERD remains to be determined, although this seems unlikely to be the case.
GASTROESOPHAGEAL REFLUX DISEASE AND RESPIRATORY DISEASE
Reflux may be causing respiratory symptoms through different pathways, such as (micro-)aspiration or vagally mediated. Many patients with chronic cough have gastrohypopharyngeal reflux (182). A consequence of pulmonary aspiration of refluxed material may be the presence of an increased number of lipid-laden macrophages. Although simply observing the presence of lipid-laden alveolar macrophages is likely to be nonspecific, it has been suggested that quantification would be a useful marker of silent aspiration (183). Children with chronic chest disease suspected to be caused by silent aspiration secondary to GER had a significantly higher number of lipid-laden macrophages (median 117; range 10–956) than children with recurrent pneumonia due to their reasons (median 29, range 5–127) and healthy controls (median 37, range 5–188)(183). However, in another study, the overlap was even more important: in children with aspiration the range of lipid-laden macrophages was 94 to 236 (mean 157) and in the group without aspiration the range was 0 to 303 (mean 46)(184). An index of more than 100 lipid-laden macrophages had a sensitivity of 94% and a negative predictive value of 98% (184). The specificity was 89% and the positive predictive value only 71% (184). Since there is obvious overlap between the groups, it is likely that a high number of lipid-laden macrophages is related to aspiration, but a low number does not rule out this hypothesis. Moreover, a high number of lipid-laden macrophages is not specific for (micro)aspiration since this is also found in other conditions such as lipoid pneumonia, in prematures receiving intravenous lipid. We agree with Knauer-Fisher that an elevated index of lipid-laden macrophages can be found in a variety of pulmonary diseases in which there is no clinical evidence of aspiration and is therefore unlikely to be a specific marker for silent pulmonary aspiration (185). Data are lacking and thus needed on the diagnostic accuracy, sensitivity, and specificity of the detection and quantification of other substances in tracheal aspirates, such as lactose, pepsin, intrinsic factor, and others.
But, in some patients it may not be GER that is causing respiratory disease, but the reverse. Respiratory difficulties cause greater respiratory breathing efforts and thus more pronounced negative intrathoracic pressures, and thus respiratory symptoms may provoke GER. However, the incidence of a direct temporal relation between reflux and cough episodes is relatively low (182).
The relation between respiratory disease and GER may also be neurogenic, and is in this case designated as “gastric asthma” (186). The tracheobronchial tree and the esophagus have common embryonic foregut origins and share autonomic innervation through the vagus nerve (1,187). In a dog model, Mansfield and Stein (188) noted that esophageal acid increased respiratory resistance, which was ablated with bilateral vagotomy. In other words, it can be speculated that GER increases the irritability of the vagal nerve endings in the esophagus, and that as a result these nerve endings hyper-react together with the nerve endings in the airways because they have the same embryonic origin.
Some individuals may be more susceptible to the development of GER disease because of a genetic predisposition or a condition provoking severe reflux. Lack of mucus and bicarbonate secretion by surface epithelial cells, lack of defensive enhancement by prostaglandin release, lack of an effective mucus cap after injury, and an apparent lack of capacity to rapidly heal erosions by the process of epithelial restitution, all may play a role in the development of esophageal lesions. The function of the UES is not well understood. The role and function of the UES in patients with GERD and chronic respiratory disease will be an interesting area of future research. If direct contact of the laryngeal structures and mucosal is important in this condition, it may well be that the pressure of the UES in patients with GERD and otorhinolaryngeal lesions is lower than in other GER patients. The most plausible hypothesis is that individuals will develop esophagitis if exposed to reflux of sufficient duration and severity. In some other cases, the following offers an attractive speculation and may be an area of future research (Fig. 1). The starting phenomenon could be delayed gastric emptying (e.g., because of overfeeding, overweight, increased intra-abdominal pressure, postviral gastritis). The gastric distension stimulates mechanoreceptors in the gastric wall near the cardia, causing a vago-vagal mechanism resulting in an abnormal neural control of the LES(pressure) by the central nervous system. As a consequence, there is a defective LES-motility and increase in TLESRs, finally resulting in a defective basal LES tone, favoring GER. In the presence of a (sliding) hiatal hernia, GER will be even more facilitated. Ineffective acid clearance (neutralization of the pH by saliva, and inefficient volume clearance by inefficient motility) enhances the noxious effect of the refluxed material. The mucosal resistance, which is partially genetically determined, contributes to the development of reflux esophagitis. Since so many factors all contribute to the severity of reflux and the development of esophagitis, it seems very plausible that in clinical situations the relative importance of contributing factors differ. GER disease is not a “yes” or “no” situation, but a result of a complex interaction between protective and noxious factors.
Future research should concentrate on better understanding of the neuronal pathways mediating the function of the upper and lower esophageal sphincter and of the complex interaction of the many factors determining the mucosal resistance. All these are crucial in the development of reflux disease, but are today rather poorly understood. It is likely that this improved understanding will subsequently result in the improvement of medical therapy. A better understanding of the mechanisms of GERD will likely result in improved diagnosis and treatment.
1. Vandenplas Y. Asthma and gastro-oesophageal reflux. J Pediatr Gastroenterol Nutr 1997; 24:89–99.
2. Wong RK, Hanson DG, Waring PJ, Shaw G. ENT manifestations of gastroesophageal reflux. Am J Gastroenterol 2000; 95(Suppl 8):S15–22.
3. Richter JE. Extraesophageal presentations of gastroesophageal reflux disease: an overview. Wam J Gastroenterol 2000; 95(Suppl):S1–3.
4. Rudolph CD, Mazur LJ, Liptak GS, baker RD, Boyle JT, Coletti RB, Gerson WT, Werlin SL. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children. Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001; 32(Suppl2):S1–31.
5. Vandenplas Y. Oesophageal pH monitoring for gastro-oesophageal reflux in infants and children. John Wiley and Sons, Chichester, England. 1992;pp. 27–36.
6. Vandenplas Y, B. Hegar. Diagnosis and treatment of gastro-oesophageal reflux disease in infants and children. J Gastroenterol Hepatol 2000; 15:593–603.
7. Mathisen B, Worall L, Masel J, Wall C, Shepherd RW. Feeding problems in infants with gastro-oesophageal reflux disease: a controlled study. J Pediatr Child Health 1999; 35:163–9.
8. Black MM, Dubowitz H, Huctheson J. A randomized clinical trial of home intervention for children with failure to thrive. Pediatrics 1995; 95:807–14.
9. Burklow KA, Phelps AN, Schultz JR, Mc Connel K, Rudolph C. Classifying complex pediatric feeding disorders. J Pediatr Gastroenterol Nutr 1998; 27:143–7.
10. Kapila YV, Dodds WJ, Helm JF, Hogan WJ. Relationship between swallow rate and salivary flow. Dig Dis Sci 1984; 29:528–33.
11. Goldin GF, Marcinkiewicz M, Zbroch T, Bityutskiy LP, McCallum RW, Sarosiek J. Esophagoprotecive potential of cisapride. An additional benefit for gastroesophageal reflux disease. Dig Dis Sci 1997; 42:1362–9.
12. Chen SD, Kao CH, Chnag CS, Chen GH. Salivary function in patients with reflux esophagitis: effect of cisapride. J Nucl Med 1998; 39:1449–52.
13. Bouchoucha M, Callais F, Renard P, Ekindjian OG, Cugnenc PH, Barbier JP. Relationship between acid neutralization capacity of saliva and gasto-oesophageal reflux. Arch Physiol Biochem 1997; 105:19–26.
14. von Schonfeld J, Hector M, Evans DF, Wingate DL. Oesophageal acid and salivary excretion: is chewing gum a treatment option for gastro-oesophageal reflux? Digestion 1997; 58:111–4.
15. Kao CH, Ho YJ, ChangLai SP, Liao KK. Evidence for decreased salivary function in patients with reflux esophagitis. Digestion 1999; 60:191–5.
16. Aldazabal P, Lopez de Torre B, Uriarte S, Elizaguirre I, San Vincente MT, Tovar JA. Saliva in experimental gastroesophageal reflux. Chir Pediatr 1998; 11:19–4.
17. Vantrappen, Hellemans J. Diseases of the esophagus. New York: Springer Verlag, 1974.
18. Strobel CT, Byrne WJ, Ament ME, Euler AR. Correlation of esophageal lengths in children with height: application to the Tuttle test without prior esophageal manometry. J Pediatr 1979; 94:81–4.
19. Vandenplas Y. Development of the upper gastrointestinal tract. In: Oesophageal pH monitoring for gastro-oesophageal reflux in infants and children. Ed. Y. Vandenplas, John Wiley & Sons, Chichester 1992;pp. 3–12.
20. Wolff PH. The serial organisation of sucking in the young infant. Pediatrics 1968; 42:943–56.
21. Goyal RK, Sivaro DV. Functional anatomy and physiology of swallowing and esophageal motility. In: The Esophagus. 3rd
Ed. Eds. Castell DO, Richter JE. Lippincott Williams & Wilkins, Philadelphia 1999.
22. Martin BJ, Logemann JA, Shaker R, Dodds WJ. Coordination between respiration and swallowing: respiratory phase relationships and temporal integration. J Appl Physiol 1994; 76:714–23.
23. Mathew OP, Clark ML, Pronske ML, Luna-Solaorzano HG, Pertson MD. Breathing, pattern and ventilation during oral feeding in term newborn infants. J Pediatr 1985; 106:810–3.
24. Suys B, De Wolf D, Vandenplas Y. Bradycardia and gastroesophageal reflux in term and preterm infants: is there any relation? J Pediatr Gastroenterol Nutr 1994; 19:187–90.
25. Sacré L, Vandenplas Y. Gastroesophageal reflux associated with respiratory abnormalities during sleep. J Pediatr Gastroenterol Nutr 1989; 9:28–33.
26. Holloway RH, Penagini R, Schoeman MN, Dent J. Effect of cisapride on secondary peristalsis in patients with gastroesophageal reflux disease. Am J Gastroenterol 1999; 94:799–803.
27. Cook IJ, Dodds WJ, Dantas RO, Massey B, Kern MK, Lang IM, Brasseur JG, Hogan. Opening mechanisms of the human upper esophageal sphincter. Am J Physiol 1989; 257:G748–59.
28. Kahrilas PJ, Dodds WJ, Dent J, Logemann JA, Shaker R Upper esophageal sphincter function during deglutition. Gastroenterology 1988; 95:52–62.
29. Goyal RK, Paterson WG. Esophageal motility. In Wood JD, Schultz SG, eds. Handbook of Physiology. The gastrointestinal system. Washington DC: AM Physiol Soc 1987;865–67.
30. Kendall KA, McKenzie S, Leonard RJ, Goncalves MI, Walker A. Timing of events in normal swallowing: a videofluroscopic study. Dysphagia 2000; 15:74–83.
31. Kahrilas PJ, Dodds WJ, Dent J, Wyman JB, Hogan WJ, Arndorfer. Upper esophageal sphincter function during belching. Gastroenterology 1986; 91:133–40.
32. Kahrilas PJ, Dodds WJ, Dent J, Haeberle B, Hogan WJ, Arndorfer. Effect of sleep, spontaneous gastroesophageal reflux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology 1987; 92:466–71.
33. Torrico S, Kern M, Aslam M, Narayanan S, Kannappan A, Ren J, Sui Z, Hofmann C, Shaker R. Upper esophageal sphincter function during gastroesophageal reflux events revisited. Am J Physiol Gastrointest Liver Physiol 2000; 279:G262–7.
34. Willing J, Furukawa Y, Davidson GP, Dent J. Strain induced augmentation of upper oesophageal sphincter pressure in children. Gut 1994; 35:159–64.
35. Jeffery HE, Ius D, Page M. The role of swallowing during active sleep in the clearance of reflux in term and preterm infants. J Pediatr 2000; 137:545–8.
36. Arad-Cohen N, Cohen A, Tirosh E. The relationship between gastroesophageal reflux and apnea in infants. J Pediatr 2000; 137:321–6.
37. Jeffery HE, Page M. Developmental maturation of gastro-oesophageal reflux in preterm infants. Acta Paediatr 1995; 84:245–50.
38. Lock G, Strozter M, Straub RH, Scholmerich J, Feuerbach S, Holstege A, Lang B. Air oesophagram: a frequent, but not a specific sign of oesophageal involvement in connective tissue disease. Br J Rheumatol 1998; 37:1011–4.
39. Bjerle P, EK B, Linderholm H, Steen L. Oesophageal dysfunction in familial amyloidosis with polyneuropathy. Clin Physiol 1993; 13:57–69.
40. Jermendy G, Fornet B, Koltai MZ, Pogatsa G. Correlation between oesophageal dysmotility and cardiovascular autonomic dysfunction in diabetic patients without gastrointestinal symptoms of autonomic neuropathy. Diabetes Res 1991; 16:193–7.
41. Helm JF, Dodds WJ, Hogan WJ. Salivary responses to esophageal acid in normal subjects and patients with reflux esophagitis. Gastroenterology 1982; 93:1393.
42. Helm JF. Determinants of esophageal acid clearance in normal subjects. Gastroenterology 1987; 85:607–12.
43. Kahrilas PJ. Effect of peristaltic dysfunction on esophageal volume clearing. Gastroenterology 1988; 94:73–80.
44. Omari TI, Barbett C, Snel A, Goldswarthy W, Haslam R, Davidson G, Kirubakaran C, Bakewell M, Fraser R, Dent J. Mechanisms of gastroesophageal reflux in healthy premature infants. J Pediatr 1998; 133:650–4.
45. Omari T, Barnett C, Snel A, Davidson G, Haslam R, Bakewell M, Dent J. Mechanism of gastroesophageal reflux in premature infants with chronic lung disease. J Pediatr Surg 1999; 34:1795–8.
46. Cadiot G, Bruhat A, Rigaud D, Coste T, Vuagnat A, Benyedder Y, Vallot T, Le Guludec D, Mignon M. Multivariate analysis of pathophysiological factors in reflux oesophagitis. Gut 1997; 40:167–74.
47. Holloway RH. Esophageal body motor response to reflux events: secondary peristalsis. Am J Med 2000; 108(Suppl14a):S20–6.
48. Orenstein SR. Effects on behavior state of prone versus seted positioning for infants with gastroesophageal reflux. Pediatrics 1990; 85:765–7.
49. Orenstein SR, Whitington PF, Orenstein DM. The infant seat as treatment for gastroesophageal reflux. N Engl J Med 1983; 309:760–3.
50. Vandenplas Y, Sacre-Smits L. Seventeen-hour continuous esophageal pH monitoring in the newborn: evaluation of the influence of position in asymptomatic and symptomatic babies. J Pediatr Gastroenterol Nutr 1985; 4:356–61.
51. Allen ML, Zamani S, Dimarino Jr. AJ The effect of gravity on oesophageal peristalsis in humans. Neurogastroenterol Motil 1997; 9:71–6.
52. Cuomo R, Sarnelli G, Grasso R, Alfieri M, Botiglieri ME, Paternuosto M, Budillon G. Manometric study of hiatal hernia and its correlation with esophageal peristalsis. Dig Dis Sci 1999; 44:1747–53.
53. Long JD, Orlando RC. Esophageal submucosal glands: structure and function. Am J Gastroenterol 1999; 94:2818–24.
54. Mertz-Nielsen A, Hillingso J, Bukhave K, Rask-Madsen J. Reappraisal of bicarbonate secretion by the human oesophagus. Gut 1997; 40:582–6.
55. Marcinkiewicz M, Han K, Zbroch T, Poplawski C, Gramley W, Goldin G, Sarosiek J. The potential role of the esophageal pre-epithelial barrier components in the maintenance of integrity of the esophageal mucosa in patients with endoscopically negative gastroesophageal reflux disease. Am J Gastroenterol 2000; 95:1652–60.
56. Orlanco RC. Pathophysiology of gastroesophageal reflux disease. In The Esophagus, 3rd
ed. Eds DO Castell, JE Richter. Lippincott, Williams & Wilkins 1999,pp.409–19.
57. Orlando RC. Review article: oesophageal mucosal resistance. Aliment Pharmacol Ther 1998; 12:191–7.
58. Marcinkiewicz M, Grabwska SZ, Czyzewska E. Role of epidermal growth factor (EGF) in oesophageal mucosal integrity. Curr Med Res Opin 1998; 14:145–53.
59. Orlando RC, Powell DW, Bryson JC, Kinard 3d, HB Carney CN, Jones JD, Bozymski EM. Esophageal potential difference measurements in esophageal disease. Gastroenterology 1982; 83:1026–32.
60. Orlando RC, Bryson JC, Powell DW. Mechanisms of HCl injury in rabbit esophageal epithelium. Am J Physiol 1984; 246:G718–24.
61. Ransford RA, Jankowski JA. Genetic versus environmental interactions in the oesophagitis-metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus. Acta Gastroenterol Belg 2000; 63:18–21.
62. Jimenez P, Lanas A, Piazuelo E, Bioque G, Esteva F. Prostagladin E2 is the major arachidonic acid metabolite secreted by esophageal mucosal cells in rabbits. Inflammation 1997; 21:419–29.
63. Sarosiek J, Yu Z, namiot Z, Rourk RM, Hetzel DP, McCallum RW. Impact of acid and pepsin on human esophageal prostaglandins. Am J Gastroenterol 1994; 89:588–94.
64. Holtmann G, Kolbel CB, Ewers M, Giese A, Mayer P. Effect of prostaglandin E2 analog nocloprost on motility and acid clearance of the tubular esophagus in man. Med Klin 1993; 88:S2–4.
65. Lanas AI, Sousa FL, Ortego J, Esteva F, Blas JM, Soria J, Sainz R. Aspirin renders the oesophageal mucosa more permeable to acid and pepsin. Eur J Gastroenterol Hepatol 1995; 7:1065–72.
66. Marcinkiewicz M, Sarosiek J, Edmunds M, Scheurich J, Weiss P, McCallum RW. Monophasic luminal release of prostaglandin E2 in patients with reflux esophagitis under the impact of acid and acid/pepsin solutions. Its potential pathogenic significance. J Clin Gastroenterol 1995; 21:268–74.
67. Morgan G. Deleterious effects of prostaglandin E2 in reflux oesophagitis. Med Hypotheses 1996; 46:42–4.
68. Jimenez P, Lanas A, Piazuelo E, Esteva F. Effect of growth factors and prostaglandin E2 on restitution and proliferation of rabbit esophageal epithelial cells. Dig Dis Sci 1998; 43:2309–16.
69. Tihanyi K, Rozsa I, Banai J, Dobo I, Bajtai A. Tissue concentrations and correlations of prostaglandins in healthy and inflamed human esophageal and jejunal mucosa. J Gastroenterol 1996; 31:149–52.
70. Gruber AD, Gandhi R, Pauli B. The murine calcium-sensitive chloride channel (mCaCC) is widely expressed in secretory epithelia and in other select tissues. Histochem Cell Biol
71. Zicari A, Corrado G, Cavaliere M, Frandina G, Rea P, Pontieri G, Cardi E, Cucchiara S. Increased levels of prostaglandins and nitric oxide in esophageal mucosa of children with reflux esophagitis. J Pediatr Gastroenterol Nutr 1998; 26:194–9.
72. Voutilainen M, Sipponen P, Macklin JP, Juhola M, Farkkila M. Gastroesophageal reflux disease: prevalence, clinical, endoscopic and histopathological findings in 1,128 consecutive patients referred for endoscopy due to dyspeptic and reflux symptoms. Digestion 2000; 61:6–13.
73. Lu W, Zhang M, Neuman RS, Bieger D. Fictive oesophageal peristalsis evoked activation of muscarinic acethylcholine receptors in rat nucleus tractus solitarii. Neurogastroenterol Motil 1997; 9:247–56.
74. El Ouzzani T, Mei N. Elcetrophysiologic properties and role of the vagal thermoreceptors of lower esophagus and stomach of cat. Gastroenterology 1982; 83:995–9.
75. Rodrigo J. Hernandez J, Vidal MA, Pedrosa JA. Vegetative innervation of the esophagus. II. Intranganglionic laminar endings. Acta Anat (Basel) 1975; 92:79–100.
76. Fass R, Higa L, Kodner A, Mayer EA. Stimulus and site specific induction of hiccups in the oesophagus of normal subjects. Gut 1997; 41:590–3.
77. Sengupta JN, Kauvar D, Goyal RK. Characteristics of vagal esophageal tension-sensitive afferent fibers in the opposum. J Neurophysiol 1989; 61:1001–10.
78. Sengupta JN, Saha JK, Goyal RK. Stimulus-response function studies of esophageal mechanosensitive nociceptors in sympathetic afferents of opposum. J Neurophysiol 1990; 64:796.
79. Cervero F, Janig W. Visceral nociceptors: a new world order? Trends Neurosci 1992; 15:374–8.
80. Aziz Q, Thompson DG. Brain-gut axis in health and disease. Gastroenterology 1998; 115:559–78.
81. Page AJ, Blackshaw LA. An in vitro study of the properties of vagal afferent fibres innervating the ferret oesophagus and stomach. J Physiol Lond 1998; 512:907–16.
82. Yoshida Y, Tanaka Y, Hirano M, Nakashima. Sensory innervation of the pharynx and larynx. Am J Med 2000; 108 (Suppl 4a):S51S–61.
83. Smid SD, Page AJ, O'Donnell T, Langman J, Rowland R, Blackshaw LA. Oesophagitis-induced changes in capsaicin-sensitive tachykininergic pathways in the ferret lower oesophageal sphincter. Neurogastroenterol Motil 1998; 10:403–11.
84. Patterson PE, Harding SM. Gastroesophageal reflux disorders and asthma. Curr Opin Pulm Med 1999; 5:63–7.
85. Niemantsverdriet EC, Timmer R, Breumelhof R, Smout AJ. The role of excessive gastro-oesophageal reflux, disordered oesophageal motility and decreased mucosal sensitivity in the pathogenesis of Barrett's oesophagus. Eur J Gastroenterol Hepatol 1997; 9:515–9.
86. Cohen S, Harris LD. Does hiatus hernia affect competence of the gastroesophageal sphincter? N Engl J Med 1971; 284:1053–6.
87. Richter J. Do we know the causes of reflux disease? Eur J Gastroenterol Hepatol 1999; 11(Suppl1):S3–9.
88. Cohen S, Harris ID. The lower esophageal sphincter. Gastroenterology 1972; 63:1066–73.
89. Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R, Patel GK, Egide MS. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982; 307:1547–52.
90. McNally EF. Mechanisms of belching: effects of gastric distension with air. Gastroenterology 1964; 46:254–9.
91. Holloway RH. Gastric distension: a mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985; 89:778–84.
92. Zarate A, Ochoa R, Fonseca E, Moran C. Hypergastrinemia of newborns and infants during breast-feeding. J Soc Gynecol Investig 1995; 2:531–4
93. Fang JC, Sarosiek I, Yamamoto Y, Liu J, Mittal RK. Cholinergic blockade inhibits gastro-oesophageal reflux and transient lower oesophageal sphincter relaxation through a central mechanism. Gut 1999; 44:603–7.
94. Luiking YC, Weusten BL, Portincasa P, Van Der Meer R, Smout AJ, Akkermans LM. Effects of long-term oral L-arginine on esophageal motility and gallbladder dynamics in healthy humans. Am J Physiol 1998; 274:G984–91.
95. Rodriguez S, Miner P, Robinson M, Greenwood B, Maton PN, Pappa K. Meal type affects heartburn severity. Dig Dis Sci 1998; 43:485–90.
96. Allen ML, Mellow MH, Robinson MG, Orr WC. The effect of raw onions on acid reflux and reflux symptoms. Am J Gatsroenterol 1990; 85:679–80.
97. Hirsch DP, Holloway RH, Tytgat GN, Boeckxstaens GE. Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis. Gastroenterology 1998; 115:1374–80.
98. Boulant J, Mathieu S, D'Amato M, Abergel A, Dapoigny M, Bommelaer G. Cholecystokinin in transient lower oesophageal sphincter relaxation due to gastric distension in humans. Gut 1997; 40:575–81.
99. Sun WM, Doran S, Jones KL, Ooi E, Boeckxstaens G, Hebbard GS, Lingenfelser T, Morley JE, Dent J, Horowitz M. Effects of nitroglycerin on liquid gastric emptying and antropyloroduodenal motility. Am J Physiol 1998; 275:G1173–8.
100. Vanderwinden JM, Mailleaux P, Schiffmann SN, Verhaeghen JJ, De Laet MH. Nitric oxide synthase activity in infantile hypertrophic pyloric stenosis. N Engl J Med 1992; 327:511–5.
101. Zicari A, Corrado G, Cavaliere M, Frandina G, Rea P, Pontieri G, Cardi E, Cucchiara S. Increased levels of prostaglandins and nitric oxide in esophageal mucosa of children with reflux esophagitis. J Pediatr Gastroenterol Nutr 1998; 26:194–9.
102. Gupta SK, Fitzgerald JF, Chong SK, Croffie JM, Garcia JG. Expression of inducible nitric oxide synthase (iNOS) mRNA in inflamed esophageal and colonic mucosa in a pediatric population. Am J Gastroenterol 1998; 93:795–8.
103. Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res 1998; 58:2929–34.
104. Kawahara H, Dent J, Davidson G. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology 1997; 113:399–408.
105. Dent J, Holloway RH, Toouli J. Mechanism of lower esophageal sphincter incompetence in patients with symptomatic gastroesophageal reflux. Gut 1988; 29:1020–8.
106. Sifrim D, Silny J, Holloway RH, Janssens JJ. Patterns of gas and liquid reflux during tarnsient lower esophageal sphincter relaxation: a study using intraluminal electrical impedance. Gut 1999; 44:47–54.
107. Hart JJ. Pediatric gastroesophageal reflux. Am Fam Physician 1996; 54:2463–72.
108. Kalicinski P, Dluski E, Drewniak T, Kaminski W. Esophageal manometric studies in children with achalasia before and after operative treatment. Pediatr Surg Int 1997; 12:571–5.
109. Tovar KA, Prieto G, Molina M, Arana J. Esophageal function in achalasia: preoperative and postoperative manometric studies. J Pediatr Surg 1998; 33:834–8.
110. von Herbay A, Heyer T, Olk W, Kiesewalter B, Auer P, Enck P, Haussinger D, Frieling T. Autonomic dysfunction in patients with achalasia of the oesophagus. Neurogastroenterol Motil 1998; 10:387–93.
111. Lui H, Vanderwinden JM, Ji P, De laet MH. Nitric oxide synthase distribution in the enteric nervous system of children with cardiac achalasia. Chin Med J Engl 1997; 110:358–61.
112. Gonzalez M, Mearin F, Vasconez C, Armengol JR, Malagelada JR. Oesophageal tone in patients with achalasia. Gut 1997; 41:291–6.
113. Kawahara H, Imura K, Yagi M, Soh H, Tazuke Y, Okada A. Mechanisms underlying the antireflux effect of Nissen fundoplication in children. J Pediatr Surg 1998; 33:1618–22.
114. Masclee AA, Horbach JM, Ledboer M, Lamers CB, Gooszen HG. Prospective study of the effect of the Belsey Mark IV fundoplication on reflux mechanisms. Scand J Gastroenterol 1998; 33:905–10.
115. Zaino C. Hiatal insufficiency and hiatal hernia. In: Zaino C, ed. The lwoer esophageal vestibular complex. Springfield: Thomas, 1963:173–218.
116. Stal P, Lindberg G, Ost A, Iwarzon M, Seensalu R. Gastroesophageal reflux in healthy subjects. Signficance of endoscopic findings, histology, age, and sex. Scand J Gastroenterol 1999; 34:121–8.
117. Skinner DB. Hernias (hiatal, traumatic and congenital). In Berk JE, ed, Gastroenterology (4th
ed). Philadelphia: WB Saunders, 1985:705–32.
118. Peridikis G, Hinder RA. Paraesophageal hiatal hernia. In Nyhus LM, Condon RE, eds, Hernia; Philadelphia: JB Lippincott Co, 1995:544–65.
119. Mittal RK, Rochester DF, McCallum RW. Effect of the diaphragmatic contraction on lower esophageal sphincter pressure in man. Gut 1987; 28:1564–8.
120. Sloan S, Rademaker AW, kahrilas PJ. Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both? Ann Int Med 1992; 117:977–82.
121. Kasapidis P, Vassilakis JS, Tzovaras G, Chrysos E, Xynos E. Effect of hiatal hernia on esophageal manometrie and pH-metry in gastroesophageal reflux disease. Dig Dis Sci 1995; 40:2724–30.
122. Carre IJ, Johnston BT, Thomas PS, Morrisson PJ. Familial hiatal hernia in a large five generation family confirming true autosomal dominant inheritance. Gut 1999; 45:649–52.
123. Hassall E. Wrap session: is the Nissen slipping? Can medical treatment replace surgery for severe gastroesophageal reflux disease in children? Am J Gastroenterol 1995; 90:1212–20.
124. Hassall E. Barrett's esophagus: new definitions and approaches in children. J Pediatr Gastroenterol Nutr 1993; 16:345–64.
125. Wiright RA, Hurwitz AL. Relationship of hiatal hernia to endoscopically proved reflux esophagitis. Dig Dis Sci 1979; 24:311–3.
126. Ben rejeb M, Bouche O, Zeiton P. Study of 47 consecutive patients with peptic esophageal stricture comapred with 3880 cases of reflux esophagitis. Dig Dis Sci 1992; 37:733–6.
127. Petersen H, Johannessen T, Sandvik AK, Kleveland PM, Brenna E, Waldum H, Dybdahl JD. Relationship between endoscopic hiatus hernia and gastroesophageal reflux symptoms. Scan J Gastroenterol 1991; 26:921–6.
128. Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients. Gastroenterology 2000; 118:688–95.
129. van Herwaaarden MA, Samsom M, Smout AJPM. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000; 119:1439–46.
130. Murray JA, Camillieri M. The fall and ris of teh hiatal hernia. Gastroenterology 2000; 119:1779–81.
131. Shay SS, Conwell DL, Mehindru V, Hertz B. The effect of posture on gastroesophageal reflux event frequency and composition during fasting. Am J Gastroenterol 1996; 91:54–60.
132. Katz LC, Just R, Castell DO. Body position affects recumbent postprandial reflux. J Clin Gastroenterol 1994; 18:280–3.
133. Cucchaira S, Salvia G, Borelli O. Gastric electrical dysrhythmias and delayed gastric emptying in gastroesophageal reflux disease. Am J Gastroenterol 1997; 92:1103–8.
134. Arakawa T, Uno H, Fukuda T, Higuchi K, Kobayashi K, Kuroki T. New aspects of gastric adaptive relaxation, reflex after food intake for more food: involvement of capsaicin-sensitive sensory nerves and nitric oxide. J Smooth Muscle Res 1997; 33:81–8.
135. Martin CJ, Patrikios J, Dent J. Abolition of gas reflux and transient lower esophageal sphincter relaxation by vagal blockage in the dog. Gastroenterology 1986; 91:890–6.
136. Zerbib F, Bruley des Varannes S, Ropert A, Lamouliatte H, Quinton A, Galmiche JP. Proximal gastric tone in gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 1999; 11:511–15.
137. Ravelli AM, Milla PJ. Vomiting and gastroesophageal motor activity in children with disorders of the central nervous system. J Pediatr Gastroenterol Nutr 1998; 26:56–63.
138. Cucchiara S, Salvia G, Borrelli O, Ciccimarra E, Az-Zeqeh N, Rapagiolo S, Minella R, Campanozzi A, Riezzo G. Gastric electrical dysrhythmias and delayed gastric emptying in gastroesophageal reflux disease. Am J Gastroenertol 1997; 92:1103–8.
139. Bustorff Silva J, Fonkalsrud EW, Perez CA, Quintero R, Martin L, Villasenor E, Atkinson JB. Gastric empying procedures decrease the risk of postoperative recurrent reflux in children with delayed gastric emptying. J Pediatr Surg 1999; 34:79–82.
140. Johnson DG, reid BS, Meyers RL, Fry MA, Nortmann CA, Jackson WD, Marty TL. Are scintiscans accurate in the selection of reflux patients for pyloroplasty? J Pediatr Surg 1998; 33:573–9.
141. Tolia V, Lin CH, Kuhns LR. Gastric emptying using three different formulas in infants with gastroesophageal reflux: J Pediatr Gastroenterol Nutr 1992; 15:297–301.
142. Romero Y, Cameron AJ, Locke 3rd, GR Schaid DJ, Slezak JM, Branch CD, Melton 3rd. LJ Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal carcinoma. Gastroenterology 1997; 113:1449–56.
143. Hassall E. Barrett's esophagus: congenital or acquired? Am J Gastroenterol 1993; 88:819–24.
144. Sonnenberg A, El-Serag HB. Clinical epidemiology and natural history of gastroesophageal reflux disease. Yale J Biol Med 1999; 72:81–92.
145. Krug E, Bergmeijer JH, Dees J, de Krijger R, Mooi WJ, Hazebroek FW. Gastroesophageal reflux and Barrett's esophagus in adults born with esophageal atresia. Am J Gastroenterol 1999; 94:2825–8.
146. Hassall E. Co-morbidities in childhood Barrett's esophagus. J Pediatr Gastroenterol Nutr 1997; 25:255–260.
147. Hu FZ, Preston RA, Post JC, White GJ, Kikuchi LW, Wang X, Leal SM, Levenstien MA, Ott J, Self TW, Allen G, Stiffler RS, McGraw C, Pulsifer-Anderson EA, Ehrlich GD. Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14. JAMA 2000; 284:325–34.
148. Oberg S, Peters JH, DeMeester TR, Lord RV, Johansson J, DeMeester SR, Hagen JA. Determinants of intestinal metaplasia within the columnar-lined esophagus. Arch Surg 2000; 135:651–6.
149. Colen MJ, Lewis JH, Benjamin SP. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. Gastroenterology 1990; 98:654–61.
150. Colen MJ, Ciarleglio CA, Stanczak VJ, Treem WR, Lewis JH. Basal gastric acid secretion in children with atypical epigastric pain. Am J Gastroenterol 1988; 83:923–6.
151. Mulholland MW, Reid BJ, Levine DS, Rubin CE. Elevated gastric acid secretion in patients with Barrett's metaplastic epthelium. Dig Dis Sci 1989; 34:1329–34.
152. Please provide reference info for reference 152.
153. McNamara D, O'Morain C. Gastro-oesophageal reflux disease and Helicobacter pylori
: an intricate relation. Gut 1999; 45(Suppl 1):I13–7.
154. Graham DY, Yamaoka Y. Disease-specific Helicobacter pylori
virulence factors: the unfulfilled promise. Helicobacter 2000; 5(Suppl 1):S3–9.
155. Wu JC, Sung JJ, Chan FK, Ching JY, Ng AC, Go MY, Wong SK, Ng EK, Chung SC. Helicobacter pylori
infection is associated with milder gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000; 14:427–32.
156. De Koster E. Adverse events of HP eradication: long term negative consequences of HP eradication. Acta Gastroenterol Belg 1998; 61:350–1.
157. Fallone CA, Barkin AN, Friedman G, Mayrand S, Loo V, Beech R, Best L, Joseph L. Is Helicobacter pylori eradication associated with gastroesophageal reflux disease? Am J Gastroenterol 2000; 95:914–20.
158. Mistry FP, Sreenivasa D, Narawane NM, Abraham P, Bhatia SJ. Vagal dysfunction following endoscopic variceal sclerotherapy. Indian J Gastroenterol 1998; 17:22–3.
159. Salo JA, Lehto VP, Kivilaakso E. Morphological alteration in experimental esophagitis. Dig Dis Sci 1983; 28:440–8.
160. Vaezi MF. Duodenogastric reflux. In: The Esophagus (3rd
ed). Eds DO Castell, Richter JE. Lippincott Willimas & Wilkins, Philadelphia 1999;421–36.
161. Szarszewski A, Korzon M, Kaminska B, Lass P. Duodenogastric reflux: clinical and therapeutic aspects. Arch Dis Child 1999; 81:16–20.
162. Safaie-Shirazi S. Effect of bile salts on the ionic permeability of the esophageal mucosa and their role in the production of esophagitis. Gastroenterology 69:728–33; 1975.
163. Batzri S, Harmon JW, Schweitzer EJ, Toles R. Bile acid accumulation in gastric mucosal cells. Proc Soc Exp Biol Med 1991; 197:393–9.
164. Schweitzer EJ, Bass BL, Batzri S, Young PM, Huesken J, Harmon JW. Lipid solubilization during bile salt-induced esophageal mucosal barrier disruption in the rabbit. J Lab Clin Med 1987; 110:172–9.
165. Harmon JW. Effects of acid and bile salts on the rabbit esophageal mucosa. Dig Dis Sci 1981; 26:65–72.
166. Clave P, Gonzalez A, Moreno A, Lopez R, Farre A, Cusso X, D'mato M, Azpiroz F, Lluis F. Endogenous cholecystokinin enhances postprandial gastroesophageal reflux in humans through extrasphincteric receptors. Gastroenterology 1998; 115:597–604.
167. Dodds WJ, Stef JJ, Hogan WJ. Factors determing pressure measurement accuracy by intraluminal esophageal manometry. Gastroenterology 1976; 70:117–23.
168. Dodds WJ Hogan WJ, Helm JF, Dent J. Pathogenesis of reflux esophagitis. Gastroenterology 1981; 81:376–94.
169. Fraser-Moodie CA, Norton B Gornall C, Magnango S, Weale AR, Holmes GK. Weight loss has an independent beneficial effect on symptoms of gastro-oesophageal reflux in patients who are overweight. Scand J Gastroenterol 1999; 34:337–40.
170. Lagergren J, Bergstrom R, Nyren O. No relation between body mass and gastro-oesophageal reflux symptoms in a Swedish population based study. Gut 2000; 47:26–9.
171. Snel A, Barnett CP, Cresp TL, Haslam RR, Davidson GP, Malbert TH, Dent J, Omari TI. Behavior and gastroesophageal reflux in the premature neonate. J Pediatr Gastroenterol Nutr 2000; 30:18–21.
172. Feranchak AP, Orenstein SR, Cohn JF. Behaviors associated with onset of gastroesophageal reflux episodes in infants. Prospective study using split-screen video and pH probe. Clin Pediatr (Phila) 1994; 33:654–62.
173. Cheong YP, Park SK, Son Y, Lee KC, Song YK, Yoon JS, Kim TY. Comparison of incidence of gastroesophageal reflux and regurgitation associated with timing of removal of the laryngeal mask airway: on appearance of signs of rejection versus after recovery of consciousness. J Clin Anesth 1999; 11:657–62.
174. Sun WM, Doran S, Jones KL, Ooi E, Boeckxstaens G, Hebbard GS, Lingenfelser T, Morley JE, Dent J, Horowitz M. Effects of nitroglycerin on liquid gastric emptying and antropyloroduodenal motility. Am J Physiol 1998; 275:G1173–8.
175. Hornby PJ; Abrahams TP. Central control of lower esophageal sphincter relaxation. Am J Med 2000; 108 Suppl 4a:90S–98S.
176. Ter RB, Johnston BT, Castell DO. Influence of age and gender on gastroesophagel reflux in symptomatic patients. Dis Esophagus 1998; 11:106–8.
177. Kay L, Jorgensen T, Jensen KH. Epidemiology of abdominal symptoms in a random population: prevalence, incidence, and natural history. Eur J Epidemiol 1994; 10:559–66.
178. Cameron AJ, Henriksson C, Nyren O, Locke GR, Pederson NL. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 2002; 122:55–9.
179. Peeters S, Vandenplas Y. Sex ratio of gastroesophagael reflux in infancy. J Pediatr Gastro Nutr 1991; 13:314–5.
180. Kang JY, Ho KY. Different prevalences of reflux oesophagitis and hiatus hernia among dyspeptic patients in England and Singapore. Eur J Gastroenterol Hepatol 1999; 11:845–50.
181. Kim SL, Hunter JG, Wo JM, Davis LP, Waring JP. NSAIDs, aspirin, and esophageal strictures: are over-the-counter medications harmful to the esophagus? J Clin Gastroenterol 1999; 29:32–4.
182. Paterson WG, Murat BW. Combined ambulatory esophageal manometry and dual-probe pH metry in the evaluation of patients with chronic unexplained cough. Dig Dis Sci 1994; 39:1117–5.
183. Ahrens P, Noll C, Kitz R, Willigens P, Zielen S, Hofmann D. Lipid-laden alveolar macrophages: a useful marker of silent aspiration in children. Pediatr Pulmonol 1999; 28:83–8.
184. Adams R, Ruffin R, Campbell D. The value of the lipid-laden macrophage index in the assessment of aspiration pneumonia. Aust N Z J Med 1997; 27:550–3.
185. Knauer-Fischer S, Ratjen F. Lipid-laden macrophages in bronchoalveolar lavage fluid as a marker for pulmonary aspiration. Pediatr Pulmonol 1999; 27:419–22.
186. Bruno G, Graf U, Andreozzi P. Gastric asthma: an unrecognized disease with an unsuspected frequency. J Asthma 1999; 36:315–25.
187. Cunningham Jr, ET Ravich WJ, Jones B, Donner MW. Vagal reflexes referred from the upper aerodigestive tract: an infrequently recognized cause of common cardiorespiratory responses. Ann Int Med 1992; 116:575–82.
188. Mansfield LE, Stein MR. Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978; 41:424–6.