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* Skip to Article Content * Skip to Article Information Search withinThis JournalAnywhere * Search term Advanced Search Citation Search * Search term Advanced Search Citation Search Login / Register * Individual login * Institutional login * REGISTER Alimentary Pharmacology & Therapeutics Volume 20, Issue s9 p. 14-25 Free Access REVIEW ARTICLE: THE PATHOPHYSIOLOGY OF GASTRO-OESOPHAGEAL REFLUX DISEASE − OESOPHAGEAL MANIFESTATIONS D. O. Castell, D. O. Castell Departments of Medicine Search for more papers by this author J. A. Murray, J. A. Murray Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN Search for more papers by this author R. Tutuian, R. Tutuian Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC Search for more papers by this author R. C. Orlando, R. C. Orlando Tulane University Medical School, New Orleans, LA, USA Search for more papers by this author R. Arnold, R. Arnold Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Phillips University, Marburg, Germany Search for more papers by this author D. O. Castell, D. O. Castell Departments of Medicine Search for more papers by this author J. A. Murray, J. A. Murray Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN Search for more papers by this author R. Tutuian, R. Tutuian Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC Search for more papers by this author R. C. Orlando, R. C. Orlando Tulane University Medical School, New Orleans, LA, USA Search for more papers by this author R. Arnold, R. Arnold Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Phillips University, Marburg, Germany Search for more papers by this author First published: 04 November 2004 https://doi.org/10.1111/j.1365-2036.2004.02238.x Citations: 115 Dr Donald O. Castell, Medical University of South Carolina, Clinical Science Bldg, 96 Jonathon Lucas Street, Charleston, SC, 29425, USA. E-mail: castell@musc.edu About * FIGURES * REFERENCES * RELATED * INFORMATION * PDF Sections * Summary * Introduction * Critical factors involved in the pathogenesis of gerd * LES pressure abnormalities * Transient lower oesophageal sphincter relaxations * Hiatal hernia * Gastric emptying abnormalities * Visceral hypersensitivity * Mucosal defensive factors * Damage induced by refluxate * Damage induced by ingested components * Genetic contributions to GERD * Night-time reflux * Conclusions * Acknowledgements * References * Citing Literature PDF Tools * Request permission * Export citation * Add to favorites * Track citation ShareShare Give access Share full text access Close modal Share full-text access Please review our Terms and Conditions of Use and check box below to share full-text version of article. I have read and accept the Wiley Online Library Terms and Conditions of Use -------------------------------------------------------------------------------- Shareable Link Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Copy URL Share a link Share on * Email * Facebook * x * LinkedIn * Reddit * Wechat SUMMARY The pathogenesis of gastro-oesophageal reflux disease (GERD) is multifactorial, involving transient lower oesophageal sphincter relaxations (TLESRs) as well as other lower oesophageal sphincter (LES) pressure abnormalities. GERD is associated with a decrease in LES pressure, which can be provoked by factors such as foods (fat, chocolate, etc.), alcohol, smoking and medications. These factors have also been shown to increase TLESRs. As a result, reflux of acid, bile, pepsin and pancreatic enzymes occurs, leading to oesophageal mucosal injury, which can potentially progress to oesophageal adenocarcinoma in a minority of patients with Barrett's metaplasia. In addition, duodenogastric contents can also contribute to oesophageal injury. Other factors contributing to the pathophysiology of GERD include hiatal hernia, poor oesophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Hiatal hernia has a permissive role in the pathogenesis of reflux oesophagitis by promoting LES dysfunction. Delayed gastric emptying, resulting in gastric distension, can significantly increase the rate of TLESRs, contributing to postprandial GER. The mucosal defensive factors have an important role in GERD. When excessive acid causes a breakdown in oesophageal epithelial defenses, epithelial resistance may be reduced. Nocturnal GERD is associated with prolonged acid exposure and proximal extent of acid contact, which elevates the risk for oesophageal damage and GERD-related complications. In sum, GERD is a complex problem caused by many factors that are exacerbated when the patient is in the supine position. INTRODUCTION The pathophysiology of gastro-oesophageal reflux disease (GERD) is complex, involving many different physiological changes (Figure 1).1 The symptoms, signs and clinical conditions that characterize GERD result primarily from recurrent reflux of gastric contents into the oesophagus. Several mechanisms contribute to the development of GERD. Among them are transient lower oesophageal sphincter relaxations (TLESRs) and other lower oesophageal sphincter (LES) pressure abnormalities.2 LES relaxation can be caused by a variety of factors including hormonal and neural agents, as well as medications and foods.3 Abnormalities in LES pressure often occur during the night-time, increasing the severity of GERD complications.4 Other factors contributing to the pathophysiology of GERD include hiatal hernia, poor oesophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Hiatal hernia has been recognized as a significant pathophysiological factor in the majority of patients with GERD, reducing LES pressure and impairing acid clearance.5 Delayed gastric emptying can trigger TLESRs, further contributing to the pathophysiology of GERD.6 Several mucosal defensive factors also have an important role in GERD. When excessive acid causes a breakdown in the oesophageal epithelial defense system, the result is impaired epithelial resistance.7 The interaction of these pathophysiological factors in the development and progression of GERD will be addressed in this paper. Figure 1 Open in figure viewerPowerPoint Aetiological factors involved in GERD. LES, lower oesophageal sphincter. Adapted from Kahrilas P.J. Cleve Clin J Med 2003; 70(Suppl. 5): S4–S19;1 with permission. CRITICAL FACTORS INVOLVED IN THE PATHOGENESIS OF GERD LES PRESSURE ABNORMALITIES The oesophageal gastric junction is located at the level of the diaphragm (Figure 2).8 At this level, the oesophageal musculature forms the LES, which allows the passage of boluses during food ingestion from the oesophagus into the stomach and prevents the reflux of a significant amount of gastric content back into the oesophagus. The anti-reflux barrier function of the oesophageal gastric junction depends on the competence of both LES and diaphragmatic crura.9, 10 Figure 2 Open in figure viewerPowerPoint Anatomy of the gastro-oesophageal junction. The lower oesophageal sphincter represents the internal, smooth muscle sphincter, whereas the crural diaphragm represents the external, skeletal muscle sphincter. Adapted from Mittal R.K. & Balaban D.H. N Engl J Med 1997; 336: 924;8 with permission. One measure of the anti-reflux barrier is the intraluminal pressure at the level of the LES. The LES resting pressure is influenced by a series of physiological factors (respiration, gastric activity, body position and circadian variations), hormones and medications (Table 1).1 The LES resting pressure has low amplitude variation of 5–10 mmHg from minute to minute. During tidal respiration, the intraluminal pressure may increase with inspiration and decrease with expiration by as much as 30 mmHg,11 increasing to approximately 90 mmHg with deep inspiration.12 Table 1. Factors that affect lower oesophageal sphincter pressure (LESP) Factor Increases LESP Decreases LESP Hormones Gastrin, motilin, substance P Secretin, cholecystokinin, glucagon, gastric inhibitory polypeptide, vasoactive intestinal polypeptide, progesterone Neural agents α-Adrenergic agonists, β-adrenergic antagonists, cholinergic agonists α-Adrenergic antagonists, β-adrenergic agonists, cholinergic antagonists, serotonin Medications Metoclopramide, domperidone, prostaglandin F2α, cisapride* Nitrates, calcium channel blockers, theophylline, morphine, meperidone, diazepam, barbiturates, sildenafil Food Protein Fat, chocolate, ethanol, peppermint * * No longer approved by the Food and Drug Administration due to severe cardiac side-effects. * Adapted from Kahrilas P.J. Cleve Clin J Med 2003; 70(suppl. 5): S4–S19;1 with permission. Other physiological variations of the LES resting pressure are related to changes in body position.13 In an attempt to protect the oesophagus from gastro-oesophageal reflux, the LES pressure rises in the recumbent position.14 Studies have shown that this is a true rise in the LES resting pressure and not just related to a decrease in intra-abdominal pressure during recumbency.15 The influence of certain food constituents on the LES was recognized in the early 1970s.16 Clinical studies found that high-fat meals,17 smoking,18 alcohol,19 chocolate20 and caffeine21 decrease the LES pressure, which increases gastro-oesophageal reflux. Besides certain foods, hormones22 and medication23 influence the LES resting pressure. LES pressure is increased by gastrin,24 cholinergic stimulation,25 insulin-induced hypoglycaemia26 and bombesin,27 whereas cholecystokinin decreases the LES resting pressure.28 Elevated progesterone levels during pregnancy decrease the LES pressure, predisposing pregnant women to GERD.29, 30 However, physiological monthly cycle variations of oestrogen and progesterone do not influence the LES pressure.31, 32 Several studies have addressed the role of impaired oesophageal gastric junction in GERD. Anatomic displacement of the oesophageal gastric junction high pressure zone,33, 34 as seen in hiatus hernias, has an important role in the pathophysiology of GERD and will be discussed below. Decreased LES resting pressure and length have been associated with increased gastro-oesophageal reflux.35, 36 Both medical and surgical studies stress the important role of the LES resting pressure37 and the length of the intra-abdominal portion of the LES38 in the pathogenesis of GERD. TRANSIENT LOWER OESOPHAGEAL SPHINCTER RELAXATIONS Many GERD patients do not have hiatus hernia and have a normal LES resting pressure, therefore a different theory was required to explain the abnormal gastro-oesophageal reflux in this substantial group of patients. Postprandial and sleep studies in healthy volunteers have identified that reflux episodes during these periods are not due to a low steady-state basal LES pressure, but rather to an increased number of inappropriate LES relaxations or TLESRs.2 As defined by these investigators, TLESRs are not swallow-induced and should be distinguished from normal physiological swallow-induced LES relaxations. In normal subjects, gastro-oesophageal reflux occurs only during TLESRs and swallow-induced LES relaxations,39 whereas in patients with GERD, TLESRs account for 48–73% of reflux episodes.40, 41 Thus TLESRs account for the majority of gastro-oesophageal reflux episodes.42 Neurophysiology studies indicate that TLESRs are visceral reflexes with vagal afferent and efferent pathways that transmit information to and from the dorsal nucleus of the vagus (Figure 3).8 There is limited direct information about the central control of TLESRs, so the information on how certain drugs may work has been extrapolated from the knowledge of brain-evoked LES relaxation.43 Gastric distension has been recognized as a major factor inducing TLESRs.6 Neurovisceral mechanisms that lead to the induction of TLESRs include stimulation of proximal gastric tension44–46(Figure 4) and stretch receptors.47 Recently, a study in healthy volunteers suggested that stretch receptors (gastric volume) seem to be more relevant than tension receptors in triggering the TLESR.47 Figure 3 Open in figure viewerPowerPoint Neural pathways coordinating transient lower oesophageal sphincter relaxations. Ach, acetylcholine; NO, nitric oxide; VIP, vasoactive intestinal peptide. Adapted from Mittal R.K. & Balaban D.H. N Engl J Med 1997; 336: 924;8 with permission. Figure 4 Open in figure viewerPowerPoint Relation between gastric distension and number of reflux episodes per hour. *P < 0.05, baseline vs. air infusion. TLESR, transient lower oesophageal sphincter relaxation. Reprinted from Kahrilas P.J. et al. Gastroenterology 2000; 118: 688–95,44 with permission from the American Gastroenterological Association. Similar to LES resting pressure, the frequency of TLESRs is influenced by foods (fat, chocolate, etc.), alcohol and smoking. More recently, baclofen, a GABAB agonist, has been shown to reduce the frequency of TLESRs by inhibiting information transfer between the nucleus tractus solitarius and the dorsal motor nucleus of the vagus.48, 49 Clinical trials have shown the efficacy of baclofen in decreasing both acidic and nonacidic gastro-oesophageal reflux.50, 51 HIATAL HERNIA For many years, the hiatal hernia was considered to be synonymous with reflux.52 Then, in the early 1980s, it was suggested that the LES was more important than the presence of hiatal hernia in the pathogenesis of GERD. Subsequent findings, however, demonstrated the strong link between hiatal hernia and reflux oesophagitis, showing a 94% incidence of hiatal hernia in patients with reflux oesophagitis.53 It was found that hiatal hernia has a permissive role in the pathogenesis of reflux oesophagitis by promoting LES dysfunction. A more recent series of studies have identified that hiatal hernia is associated with an increased severity of reflux, a greater likelihood of Barrett's oesophagus, and substantial impairment of the barrier function of the LES.33, 54, 55 The association between increased reflux severity and hiatal hernia was demonstrated in a stepwise and logistic regression analysis of pathophysiological variables in GERD. This study found that hiatal hernia size was the strongest predictor of oesophagitis severity (P = 0.0001) compared with other significant predictors including LES pressure, oesophageal acid exposure and number of reflux episodes lasting more than 5 min.54 A study assessing the role of hiatal hernia in patients with Barrett's oesophagus found the presence of a 2-cm or longer hernia in 96% of patients studied.55 The investigators concluded that hiatal hernia contributes to the development of Barrett's oesophagus. One of the ways hiatal hernia is believed to affect the chronicity of GERD is by hindering LES function.33 Susceptibility to reflux associated with abrupt increases in intra-abdominal pressure, such as inspiration or coughing, is related to both diminished LES pressure and hiatal hernia.56 Phenomena that reduce LES pressure are more likely to lead to reflux in individuals who have hiatal hernias, due to impairment of the oesophageal junction.56, 57 Another potential mechanism by which hiatal hernia can lead to reflux is by acting as a reservoir for acid-containing material, whereby acid becomes trapped in the hiatal hernia sac during oesophageal acid clearance and subsequently refluxes into the oesophagus during LES relaxation as the patient swallows. This mechanism contributes to the delayed acid clearance associated with GERD.5 GASTRIC EMPTYING ABNORMALITIES It has long been held that delay in gastric emptying results in the extended retention of acidified gastric contents in the stomach during the postprandial period. This availability of material in the stomach to reflux may increase the likelihood of GERD. However, the literature has been quite variable with regard to the potential contribution of gastric emptying in the predisposition to reflux. Some authors have claimed that as many as 40% of patients with reflux disease have delayed gastric emptying, but others have cited rates as low as 6%.58–60 A recent study demonstrated that variability in research methodologies accounted for these differences.61 Using recently established international control values for scintigraphic gastric emptying assessment, the investigators were able to standardize the measurement for gastric emptying and revealed that 33% of patients with GERD had intragastric contents greater than the 95th percentile at 120 min postprandially and that 26% had abnormal results at 240 min postprandially. It was also shown that gastrointestinal symptoms, including dyspepsia and regurgitation, occurred in many patients. These symptoms were not predictive of delayed gastric emptying. Patients frequently complain of heartburn as well as postprandial dyspepsia or epigastric discomfort, and it is often difficult for patients to discriminate between these responses. It is currently believed that delayed gastric emptying contributes to the pathogenesis of GERD in a small proportion of patients, primarily by increasing available amounts of refluxate and causing gastric distension.1 The effects of gastric distension were investigated in a study by inflating an intragastric balloon in patients with GERD and controls.6 In both groups of patients, gastric distension significantly increased the rate of TLESRs, indicating that GERD-associated gastric distension may be a factor in postprandial GERD. VISCERAL HYPERSENSITIVITY A subset of individuals with GERD symptoms has been shown to experience hypersensitivity to pain in the absence of excessive oesophageal acid exposure.62 The mechanisms responsible for this enhanced visceral sensitivity have not been fully elucidated, but are believed to involve altered cerebral processing of sensory input through cortical neural activity.62–65 One study evaluated 20 patients with GERD symptoms who had normal acid exposure times on 24-h oesophageal pH monitoring.62 These patients and a matched control group were tested for tolerance to oesophageal balloon distension. The sensory threshold was significantly lower for oesophageal discomfort (P < 0.0001) and distension (P = 0.002) in the study group than among controls. This finding suggested that a group of patients who have oesophageal acid exposure in the physiological range might experience symptoms of GERD as a result of visceral hypersensitivity. Similar findings were reported in a series of 771 consecutive patients with symptoms suggestive of GERD who underwent 24-h pH monitoring and simultaneous evaluation for reflux symptoms.63 In this report, oesophageal acid exposure was within the normal range in 12.5% of patients, yet there was a significant association between reflux symptoms and episodes of reflux. In this group, the duration of the reflux episode was significantly shorter (average 1.28 min) and the minimum pH was significantly higher than among patients with typical GERD – a finding suggestive of oesophageal hypersensitivity. Another study evaluated subjects complaining of heartburn at least 4 days per week that required antacids for relief. In this study, 43% of individuals were found to have normal acid contact time. A reduced threshold for oesophageal sensation and pain was noted in this group in response to intra-oesophageal balloon distension compared with previously reported healthy subjects.64 The finding that 21% of subjects were found to have mild oesophagitis despite a normal acid contact time (≤6%) led the authors to speculate that this subset of patients may have defective mucosal defense mechanisms. Either medical (omeprazole) or surgical (fundoplication) treatment has shown excellent symptomatic improvement in patients with oesophageal hypersensitivity.66, 67 MUCOSAL DEFENSIVE FACTORS A major determinant for the development of reflux oesophagitis is the status of the oesophageal mucosa. In both erosive and non-erosive oesophagitis, the primary means of presentation is the same, i.e. patients present with heartburn. This is not surprising because heartburn, by definition, is a symptom complex characterized by substernal pain, usually burning in quality, which is relieved by antacids.68 Relief by antacids is essential in this definition because it establishes the primacy of acid in this symptom-driven disease. Given that refluxed gastric content, and specifically gastric acid (and acid-activated pepsin), is key to the symptoms and signs of reflux oesophagitis – a point readily made by noting the effectiveness of potent acid suppression or anti-reflux surgery for its control – it is understandable why the focus of this disorder revolves around acid (and pepsin) production by the stomach and its subsequent reflux into the oesophagus as the ultimate cause of disease.68 Oesophageal pH monitoring, however, tells a different story if one focuses on individual patient data over mean data. Individual data on patients with heartburn show a substantial overlap in distal oesophageal acid exposure for patients with reflux disease and healthy subjects. This is especially true for those with non-erosive reflux disease, in which up to 50% are shown to have acid contact time values within the normal range (up to 10% acid exposure over a 24-h period).69 This cannot be completely accounted for by patients reducing their diet or activity during the study. From the perspective of the oesophageal epithelium, therefore, there are two fundamentally different ways to develop reflux oesophagitis. One is by exposure of the epithelium to the acidic gastric refluxate for a prolonged period of time (abnormal acid contact time on pH monitoring), and the other is by primary damage to the oesophageal mucosa through, for instance, ingestion of noxious substances, such that exposure to even physiological levels of acid reflux results in symptoms and signs of oesophagitis (normal acid contact time on pH monitoring).68 The oesophageal epithelium is damaged in both instances, due to material from either above or below the gastro-oesophageal junction. Mucosal resistance. The existence of mucosal resistance is established by the fact that healthy oesophageal epithelium is not injured despite exposure to HCl (pH 1.1) for up to 30 min during the Bernstein test70 and, based on pH monitoring, exposure to acid and pepsin from physiological reflux amounting to a cumulative ∼1–3 h per day.69 This is because the mucosa contains several dynamic structural and functional components that serve as a protective defense against noxious luminal substances. These include a relatively weak pre-epithelial defense and a strong epithelial defense that is supported by the blood supply.7 The pre-epithelial defense in the oesophagus consists of a small, unstirred water layer with limited buffering capacity, presumably due to the presence of bicarbonate derived from swallowed salivary secretions and secretions from oesophageal submucosal glands.7 The absence of a surface mucous layer, as it exists in the stomach, may be one reason for its limited capacity to buffer backdiffusing luminal acid.71 Consequently, when the oesophagus is acid perfused with HCl (pH 2.0), the pH at the epithelial surface falls to ∼pH 3.0 while the same exposure in the mucus-covered stomach results in a fall in surface pH to ∼6.0.72 Nevertheless, despite the modest change in surface pH in the acid-exposed oesophagus, this layer may still serve a protective function by changing the surface pH from one that supports pepsin activity to one that negates pepsin activity. For instance, it has been shown experimentally that pepsin is relatively inactive at pH 3.0 as an injurious agent for oesophageal epithelium.73 In the event that the pre-epithelial defense proves inadequate, i.e. luminal acidity reduces surface pH to < 3.0, the major defense of the epithelium falls to the epithelium itself. In the oesophagus, the epithelial defense against acid injury consists of three major components (Figure 5): (1) the barriers to hydrogen ion diffusion (i.e. cell membranes and the intercellular junctional complex), which limit the rate at which luminal acid can penetrate into the intercellular space or cell cytosol; (2) the presence of cellular and intercellular buffers (i.e. bicarbonate, proteins and phosphate) to neutralize acid as it enters the cellular or intercellular (cytosolic) space; and (3) the presence of cell membrane ion transporters (i.e. the Na+/H+ exchanger and the Na+-dependent Cl–/HCO3– exchanger), which serve to extrude acid from the cell cytosol when intracellular pH falls to acidic levels.7, 74, 75 It is these three factors that work in combination with and are supported by the postepithelial defense (i.e. blood supply) that ultimately enable the oesophageal epithelium to withstand the daily acid-pepsin assaults without incurring injury.76 However, these defenses – as the final determinants of health or disease – also have their limits, which can be reached either by refluxates containing high levels of luminal acidity or by ingestion of substances high in alcohol, heat, osmolality or smoke-derived chemicals.77–80 Figure 5 Open in figure viewerPowerPoint Some of the recognized epithelial defenses against acid injury are illustrated. Structural barriers to H+ diffusion include the cell membrane and intercellular junctional complex. Functional components include intracellular buffering by negatively charged proteins and HCO3– and H+ extrusion processes (Na+/H+ exchange and Na+-dependent Cl–/HCO3– exchange) for regulation of intracellular pH. CA, carbonic anhydrase; ICS, intercellular space. Adapted from Orlando R.C., ed. Gastro-oesophageal Reflux Disease. New York: Marcel Dekker, 2000: 165–192;7 with permission. DAMAGE INDUCED BY REFLUXATE There is compelling evidence that acid and acid-pepsin are the major damaging factors in the refluxate that initially attack and damage the intercellular junctions.7 This damage results in an increase in paracellular permeability, which is reflected functionally by increases in transepithelial dextran flux and reflected morphologically by the presence of dilated intercellular spaces.81 Moreover, this lesion, which is best seen by transmission electron microscopy, has been shown on both light and electron microscopy to be present in the oesophageal epithelium of patients with both erosive and nonerosive oesophageal reflux disease (Figure 6).82, 83 Figure 6 Open in figure viewerPowerPoint Dilated intercellular spaces. Transmission electron photomicrographs of an oesophageal biopsy from three human patients. (A) No symptoms or signs of reflux or other oesophageal disease. (B) Heartburn and erosive oesophagitis on endoscopy. (C) Symptomatic reflux (heartburn) but a grossly normal oesophagus on endoscopy. Note: the biopsy from the patient with erosive oesophagitis, as with biopsies from the other patients, was taken from an area of endoscopically normal oesophageal mucosa (original magnification × 3000). GERD, gastro-oesophageal reflux disease. Reprinted from Tobey N.A. et al. Gastroenterology 1996; 111: 1200–1205,82 with permission from the American Gastroenterological Association. Ultimately, dilated intercellular spaces are important because they are markers of defective epithelial barrier function that can help explain the symptoms and signs of reflux disease. The symptoms (heartburn) are explained by the presence of sensory neurones within the intercellular space that can generate impulses for central transmission (the latter required for pain perception).84 The signs (erosions) are explained by luminal acid diffusing into the tissue in sufficient quantities to acidify the intercellular space. This, in turn, results in acidification of the cell cytosol and, ultimately, cell oedema and necrosis.7 Additionally, epithelial repair is another defense that prevents necrosis from producing erosions: it is a process dependent to some extent on the presence of salivary epidermal growth factor. Patients with reflux oesophagitis have reduced salivary epidermal growth factor secretion, which may result in defective repair.85 This occurs because in the presence of dilated intercellular spaces, swallowed salivary epidermal growth factor has the capacity to diffuse into the tissue and gain access to otherwise inaccessible epidermal growth factor receptors on the cell membranes of the basal cell layer, which are the only cells capable of replication in oesophageal epithelium.81 As indicative of stimulated repair in non-erosive reflux disease, the oesophageal epithelium on biopsy exhibits a characteristic histological finding referred to as basal cell hyperplasia.86 DAMAGE INDUCED BY INGESTED COMPONENTS As noted above, patients with both erosive and non-erosive oesophageal reflux disease have morphological defects in the oesophageal epithelium that are indicative of a broken epithelial barrier at either the macroscopic (erosions) or the microscopic (dilated intercellular spaces) level. These defects, specifically at the microscopic level, do not have to result from excessive acid or acid-pepsin exposure as indicated by the common occurrence of normal acid contact times on pH monitoring in patients with nonerosive oesophageal reflux disease.69 Indeed, it has been shown experimentally in rabbit oesophageal epithelium that defects in the epithelial barrier can result directly from exposure to alcoholic, hot (temperature) or hypertonic solutions.77, 78, 80 For instance, the junctional barrier is broken by alcohol at concentrations of ≥ 10% (comparable to that found in wine and distilled spirits),77 hot beverages at temperatures ≥ 49 °C80 and hypertonicity at values above 525 mOsm/kg H2O for salt solutions and above 750 mOsm/kg H2O for small nonionic molecules such as urea.87 Oesophageal exposure to swallowed components in cigarette smoke such as nicotine and water-soluble tars that can be readily extracted from smoke as it passes through saliva are also damaging, but not to the junctions.79 Instead, they impair epithelial defense by inhibiting active ion (sodium) transport, which increases cell vulnerability to an acid or volume stress by inhibiting cell pH and volume regulation. In effect, junctional or cellular defects in epithelial defense can accrue from ingested material just as they can from refluxed material. The end result is that physiological reflux – not pathological reflux – is the means by which the symptoms and signs of reflux disease develop in this instance. The signs and symptoms of reflux disease result from contact of a defective oesophageal epithelium with refluxed acid-pepsin. These defects, however, may accrue either from a primary breakdown in epithelial defense from contact with noxious ingested materials or secondarily from defective anti-reflux and luminal clearance mechanisms that prolong the contact of the epithelium with noxious materials (acid-pepsin) within the refluxate. The former most likely explains heartburn (when relieved by antacids) in patients with non-erosive oesophageal reflux disease who have normal acid contact time on pH monitoring and the latter explains heartburn (when relieved by antacids) in patients with erosive or non-erosive oesophageal reflux disease and abnormal acid contact time on pH monitoring. GENETIC CONTRIBUTIONS TO GERD Recent work in twin studies has suggested an aggregation of GERD symptoms in monozygotic (genetically identical) twins as compared to dizygotic (fraternal) twins.88 It was calculated that genetic influences comprised almost 30% of attributable risk for GERD in those affected. Another line of study showed that relatives of Barrett's or adenocarcinoma patients were more likely to have GERD symptoms than relatives of their spouses, again suggesting an important role for genetics in the risk for reflux.89 NIGHT-TIME REFLUX The pathophysiology of night-time GERD differs from daytime GERD in several respects. Oesophageal acid exposure is prolonged at night due to a reduced ability to clear acid during sleep.4, 90 When 13 patients with GERD and an equal number of controls received acid infusion during sleep, acid clearance times were significantly longer during sleep than during wakeful states (P < 0.01).90 This demonstrated that individuals with GERD, who have a greater potential to reflux during sleep than controls,4 are at increased risk for prolonged oesophageal contact with acid reflux that leads to oesophagitis and other complications of GERD. Duration of acid exposure and proximal extent of acid contact have been associated with increased severity of complications in night-time GERD. Twenty-five patients with GERD complications, including oesophageal strictures, ulcers and Barrett's oesophagus, were compared with an equal number of patients with uncomplicated GERD using 24-h pH monitoring. The mean duration of nocturnal acid reflux was 15.4 min in the group with complicated GERD vs. 2.1 min in the group without complications (P < 0.001).91 Night-time reflux was also associated with longer periods of acid exposure. Intra-oesophageal pH < 4 occurred in patients with complications 36% of the time and in patients with uncomplicated GERD 5.2% of the time (P < 0.001).91 GERD severity is influenced by patterns of oesophageal acid exposure, with more severe forms of GERD associated with supine and bipositional reflux and less severe forms associated with postprandial and upright reflux.92 In a study of 401 patients with GERD, mucosal injury increased in relation to the pattern of reflux. Risk of oesophageal injury, including oesophagitis, oesophageal strictures, ulcers and Barrett's oesophagus, increased progressively from postprandial to upright to supine to bipositional reflux (P < 0.001).92 The presence of a structurally defective LES was higher among patients with supine or bipositional reflux. The investigators postulated that in patients with early reflux disease who experience postprandial or upright reflux, the LES is structurally intact and reflux episodes may be associated primarily with TLESRs. However, with more advanced reflux disease, as seen with supine or bipositional reflux, the LES may become chronically incompetent with impaired oesophageal clearance, leading to increased mucosal injury.92 Finally, nocturnal GERD is a period of increased risk for proximal migration of refluxed gastric contents, potentially leading to respiratory complications.93–95 Migration of acid to the proximal oesophagus and prolonged acid clearance time during sleep have been reported to occur in 40% of patients vs. 1% of those tested when awake.93 Impaired clearance mechanisms can lead to aspiration of pharyngeal secretions during sleep, which can in turn lead to bacterial pneumonia.94 Proximal acid exposure has been reported to be increased, especially at night, in GERD patients experiencing laryngeal symptoms, such as dysphonia, cough, frequent throat clearing, persistent sore throat and globus.95 However, other studies have failed to replicate this finding.96 CONCLUSIONS The pathophysiology of GERD is multifactorial, involving TLESRs, LES pressure abnormalities, hiatal hernia, delayed gastric emptying, and impaired oesophageal acid clearance and mucosal resistance. 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FASS, Alimentary Pharmacology & Therapeutics * Review article: supra‐oesophageal manifestations of gastro‐oesophageal reflux disease and the role of night‐time gastro‐oesophageal reflux R. Fass, S. R. Achem, S. Harding, R. K. Mittal, E. Quigley, Alimentary Pharmacology & Therapeutics * Gastro‐oesophageal reflux disease and hiatus hernias Paul Burton, Geraldine J. Ooi, Textbook of Surgery, [1] * Review article: the pathophysiology of gastro‐oesophageal reflux disease G. E. E. 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