eMedicine Feature Series

Gastroesophageal Reflux Disease Newsletter _________ Series 1, Issue 7, 2007

PATHOPHYSIOLOGY OF REFLUX ESOPHAGITIS

Samy A Azer, MD, PhD, FACG
Universiti Teknologi, Mara, Malaysia

INTRODUCTION

Gastroesophageal reflux is the movement of gastric contents into the distal esophagus. This is usually not associated with symptoms and is considered normal or physiological. However, gastroesophageal reflux can be associated with symptoms such as heartburn, dysphagia, cough, asthma, and atypical chest pain. Damage to the esophagus, oropharynx, larynx, bronchial tree, and lungs may occur in association with these symptoms. When the reflux is symptomatic and associated with these complications, it is referred to as gastroesophageal reflux disease (GERD).^1,2 This usually evolves from an imbalance in the mechanisms that prevent excessive entrance of the gastric contents (mainly acid and pepsin, though bile salts may be involved) into the distal esophagus. Based on the endoscopic appearance of the esophageal mucosa, GERD falls into the following 3 main categories: (1) reflux esophagitis (RE), characterized by the presence of mucosal erosions or ulcers; (2) nonerosive reflux disease (NERD), also known as negative-endoscopy reflux disease, in which no mucosal changes are present;^2,3 and (3) Barrett esophagus, in which squamous epithelium is replaced with a metaplastic columnar epithelium. Therefore, patients who present with GERD usually remain within 1 of these 3 groups, with a tendency for transition, over time, into another group. The aim of this article is to discuss the pathophysiology of reflux esophagitis.

REFLUX ESOPHAGITIS

Reflux esophagitis is characterized by the presence of GERD symptoms with endoscopically visible erosions and ulcers in the esophageal mucosa.⁴ In severe cases of reflux esophagitis, patients may develop iron deficiency anemia, dysphagia (due to stricture formation), and Barrett esophagus.^5,6 Those who develop Barrett esophagus are at increased risk of developing esophageal adenocarcinoma.⁷ To understand the pathophysiological mechanisms underlying the development of reflux esophagitis, one should first discuss the different components of the normal esophageal defense mechanisms.

Normal esophageal defense mechanisms

The esophagus is protected from gastric refluxate by numerous physiological mechanisms that can be grouped into 3 lines of defense. These mechanisms aim at minimizing gastroesophageal reflux (anti-reflux mechanisms) and esophageal injury (anti-injury mechanisms).

The first line of defense comprises numerous anatomical structures. These include the lower esophageal sphincter (LES), which is a thickened ring of circular smooth muscle located at the distal 2-3 cm of the esophagus that serves as a mechanical barrier; the right crus of the diaphragm, which encircles the lower esophageal sphincter and potentates its mechanical barrier; the acute angle of His, an acute anatomical angle that is formed between the cardia of the stomach and the distal esophagus and functions as a flap; and the intra-abdominal segment of the esophagus. These structures together form the esophagogastric junction (EGJ), the primary defense mechanisms. However, the first line of defense is not perfect. To maximize the physiological defense, second and third lines are needed.

The second line of defense comprises numerous clearance mechanisms, such as gravity, esophageal peristalsis, swallowed salivary secretions, and esophageal submucosal gland secretions. When functional, these mechanisms clear esophageal acid and decrease the mean esophageal acid contact time.

The third line of defense comprises cellular and molecular mechanisms responsible for epithelial and tissue resistance, such as surface bicarbonate, epithelial ultrastructures, the buffer capacity of epithelial cytosol and intercellular space, and basolateral epithelial membrane acid transporters.^8,9,10 The rich blood supply of the esophageal mucosa helps in the removal of acids and the secretion of bicarbonate, minimizing any damage that may be caused by gastric acid.

Weaknesses in the defense mechanisms

Generally, GERD is not related to excess gastric acid, pepsin secretion, or any other offensive substance in the refluxate; rather, it is a disease related to the breakdown of the defense mechanisms.¹¹ Numerous weaknesses of the defense mechanisms may result. These weaknesses contribute to the development of GERD.

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Delayed acid clearance and poor bolus clearance are usually due to incompetence of the lower esophageal sphincter, a disturbance in esophageal motility, or the presence of a hiatal hernia.¹² These pathological changes, which may often occur in combination, are responsible for the development of reflux esophagitis.¹³

Transient lower esophageal sphincter relaxation (TLESR) can result in excessive exposure of the esophagus to acid and pepsin.¹⁴ The TLESR is mediated by the vagal nerve and is precipitated by gastric fundal distension, which is caused by gas accumulated in the fundus and abnormality of the motor function of the proximal gastric region. The TLESR is responsible for acid and pepsin reflux and the development of NERD. Patients with NERD usually have a larger fraction of TLESR associated with reflux than do people with normal esophageal defenses and usually experience longer durations of esophageal acid and pepsin exposure.¹⁵

PATHOGENESIS OF REFLUX ESOPHAGITIS

Numerous studies have demonstrated that the main factors underlying the development of reflux esophagitis are incompetence of the lower esophageal sphincter¹⁶ and the presence of a hiatal hernia.¹³ These 2 factors, together with increased intra-abdominal pressure (stress reflux), produce a weakness in the normal defense mechanisms. This results in prolonged mean esophageal acid contact time, delayed acid clearance, and poor bolus clearance, all of which contribute to the development of reflux esophagitis.¹¹ The presence of a hiatal hernia is associated with increased severity of GERD, particularly when the hernia is large. A hernia, particularly when nonreducible, disrupts the integrity of the sphincter mechanism and interferes with esophageal clearance.¹⁷

The cause of lower esophageal sphincter incompetence in reflux esophagitis was studied by Shafik and colleagues.¹⁸ The authors investigated the hypothesis that the EGJ incompetence results from failure of the gastric distention to produce the contraction of the lower esophageal sphincter and disordered crural diaphragm. In an elegant study, the authors examined 19 subjects (11 male, 8 female) who had reflux esophagitis and hiatal hernia and were scheduled for a fundoplication operation. Eight control volunteers (5 male, 3 female) who had no reflux esophagitis or hiatal hernia were also studied. The authors recorded the electromyographic activity and pressure response of the lower esophageal sphincter and crural diaphragm to separate esophageal and gastric distention.

The authors reported that, in the control group, esophageal distention decreased the electromyographic activity of both the crural diaphragm and lower esophageal sphincter. On the other hand, gastric distention increased the electromyographic activity of the crural diaphragm and lower esophageal sphincter. In the patients with GERD, the crural diaphragm and lower esophageal sphincter either did not respond to gastric or esophageal distention or showed a paradoxical response; this raises the possibility of a neurogenic dysfunction.¹⁸

Dysfunction of the autonomic nervous system in patients with GERD was the basis of a research project reported by Chen and colleagues.¹⁹ The authors examined the role of the autonomic nervous system in 2 groups: patients with GERD (17 subjects with NERD and 18 with erosive esophagitis) and healthy controls (20 subjects). Patients with GERD were allocated into their groups on the basis of typical reflux symptoms, endoscopic findings, and 24-hour esophageal pH level measurements. The authors also measured the heart rate variability and calculated the low-frequency (LF) band, the high-frequency (HF) band, and the LF/HF ratio. Compared to patients with NERD, a lower HF band power was found in patients with erosive esophagitis (P <.01) and controls (P <.05). On the other hand, LF band power and LF/HF ratio were significantly lower in the patients with NERD compared to the patients with erosive esophagitis (P <.05) and controls (P <.05). Other parameters, such as age, gender, body mass index, or current tobacco use, were not different in the reflux patients and controls. Taking these results together, the authors concluded that patients with erosive esophagitis and NERD may display similar degrees of symptom severity, but they may differ significantly in regard to the pattern of the autonomic dysfunction.¹⁹

These 2 studies^18,19 show that the lower esophageal sphincter and diaphragm dysfunction play an important role in the development of reflux esophagitis. A neuromuscular and/or autonomic dysfunction may contribute to the development of lower esophageal sphincter malfunction. However, further research is needed to assess the exact nature of the neuromuscular defect and whether the lower esophageal sphincter disorder is a primary problem (ie, precedes GERD) or a secondary change (ie, a consequence of GERD).

Development of reflux esophagitis at cellular and molecular levels

According to a 2003 study, dilated intercellular space is an extremely sensitive marker of damage in gastroesophageal reflux disease, duodenal gastroesophageal reflux, and nonerosive reflux disease.²⁰ Additionally, the dilated intercellular space serves as the most appropriate marker of damage evaluation in nonerosive reflux disease. A mean dilated intercellular space of 0.74 痠 provides a cut-off score for damage. When dilated intercellular space scores of pure and mixed acid reflux were compared, no quantitative or qualitative differences were found.²⁰ These findings may indicate that dilated intercellular space is a change that precipitates both NERD and reflux esophagitis.

Yoshida and colleagues²¹ studied the changes in esophageal mucosal levels attributed to interleukin-8 (IL-8) and the role of IL-8 in the pathogenesis of reflux esophagitis. In this study, they tested whether bile acids play a role in the IL-8 expression in normal human esophageal epithelial cells. They also examined the underlying molecular mechanisms. Using unconjugated bile acids, conjugated bile acids, and inflammatory cytokines to stimulate esophageal epithelial cells, they measured the protein and messenger RNA (mRNA) of IL-8. In addition, they examined protein kinases and transcription factors involved in IL-8 synthetic pathways, using protein kinase inhibitors and luciferase expression vectors, respectively. They found that unconjugated bile acids were able to induce IL-8 production from human esophageal epithelial cells at higher levels than conjugated bile acids. Conjugated bile acids, however, induced a remarkable increase in IL-8 production in acidic media. This work supports the hypothesis that bile acids induce IL-8 expression from the esophageal epithelial cells and indicate a possible role for IL-8 expression in the pathogenesis of reflux esophagitis.¹⁹

The role of IL-8 in the progress of reflux esophagitis was also studied by Isomoto and colleagues.²² In this study, 2 distinct receptors (CXC receptors CXCR-1 and CXCR-2) were examined, and their mRNA expression levels in reflux esophagitis were measured. The research is based on the fact that IL-8 mediates neutrophil trafficking via its receptors. Patients with reflux esophagitis (26 subjects) and asymptomatic controls (15 subjects) were included in the study. Paired biopsy samples were taken from the esophagus 3 cm above the gastroesophageal junction; one biopsy was snap frozen for measurement of CXCR-1 and CXCR-2 mRNA levels and another was formalin-fixed for histopathological evaluation. Compared to normal controls, the relative expression levels of CXCR-1 and CXCR-2 mRNA were decreased in the esophageal mucosa of patients with reflux esophagitis. However, no significant differences were found in the relative mRNA expression levels of CXCR-1 and CXCR-2 among endoscopic grades of reflux esophagitis as per the Los Angeles classification. This study demonstrated that the overexpression of IL-8 in patients with reflux esophagitis is associated with lower than expected levels of CXCR-1 and CXCR-2 mRNA in the affected esophageal mucosa.²²

To further elaborate on the roles of cytokines, neutrophils, and reactive oxygen species (ROS) in the pathogenesis of reflux esophagitis, Yamaguchi and colleagues²³ studied their roles in a rat model. Esophagitis was produced in male rats by ligation at the limiting ridge of the stomach and lower part of the duodenum; the esophagus was then removed. In addition to an esophageal histological examination, several esophageal mucosal parameters were studied, including the lesion index, wet weight, thiobarbituric acid-reactive substances (an index of lipid peroxidation), myeloperoxidase activity (an index of neutrophil accumulation), tumor necrosis factor-alpha (TNF-α), and cytokine-induced neutrophil chemoattractant (CINC)-1. The mRNA expressions of tumor necrosis factor TNF-α and CINC-1 were analyzed. The values of all inflammatory markers increased. The mRNA expressions of both cytokines were observed at 3 hours and at 6 hours after induction. Histological study revealed the presence of neutrophil infiltration and edema in mucosa and submucosa at 12 hours and 18 hours after induction. The authors concluded that the ROS and lipid peroxidation mainly derived from neutrophils, which are stimulated and mobilized by TNF-α and CINC-1, are implicated in the pathogenesis of esophageal inflammation induced by reflux.

These studies show that esophageal epithelial cells and leukocyte-derived products, such as ROS and superoxide anions, play a significant role in the development of reflux esophagitis.²⁴ IL-8 is a prototype of CXC chemokines, secreted by esophageal epithelial cells. It mediates the recruitment of neutrophils into sites of inflammation.²⁵ Fitzgerald and colleagues reported significantly higher expressions of IL-8 mRNA levels in biopsy specimens obtained from patients with reflux esophagitis.²⁶ The findings from the studies by Yoshida and colleagues²¹ and Isomato and colleagues²² support the role of IL-8 in the pathogenesis of reflux esophagitis. Furthermore, a significantly positive correlation has been reported between mucosal IL-8 levels and endoscopic reflux esophagitis grade of the Los Angeles classification system.²⁵ IL-8 acts on neutrophils and stimulates the release of various reaction oxygen species, which leads to tissue damage and mucosal injury.²⁷ Some of these inflammatory mediators are relaxant to the circumferential smooth muscles, which accounts for the lower pressures in the lower esophageal sphincter and peristalsis that are involved in the pathogenesis of reflux esophagitis.

Progression of nonerosive reflux disease to reflux esophagitis

Numerous studies have shown that patients with symptomatic reflux disease (SGERD) with no associated endoscopic changes can develop reflux esophagitis later in their lives. For example, Kawanishi²⁸ examined this hypothesis. For 5 years, 497 subjects underwent annual endoscopic examination. Of these subjects, 47 were symptomatic and 450 did not have GERD symptoms. Hiatal hernia was found in 31.9% of the SGERD group and 10.9% of the group without GERD. The development of esophagitis was higher in the SGERD group (11.3%) compared to the negative GERD group (36.2%). The authors concluded that the risk factors for developing esophagitis are the presence of SGERD (P <.01), the absence of Helicobacter pylori infection (P <.01), the absence of gastric mucosa atrophy (P <.01), an elevated body mass index (P <.05), and smoking and drinking alcohol.²⁸

These findings indicate that lifestyle and exposure to cigarette smoke and alcohol can increase the risk of progression from NERD to reflux esophagitis.

FUTURE DIRECTIONS

Many questions have not yet been answered. For example, what role do genetics and inheritance play in the development of reflux esophagitis? A large twin study demonstrated that monozygotic twins exhibit an increased concordance for GERD compared to dizygotic twins. This suggests that genetic factors are responsible for about one third of GERD cases in a population like that of the United States.²⁹ Further studies are needed to highlight the genetic linkage and determine whether it is responsible for the incompetence of the esophageal sphincter in patients with GERD and reflux esophagitis. More studies are also needed to examine, at a molecular level, the esophageal mucosal defense mechanisms, the role of cell membranes and intracellular junction complexes, and the role of mucosal blood flow and epithelial transporters in the pathogenesis of reflux esophagitis.

SUMMARY

The pathogenesis of reflux esophagitis is mainly related to a breakdown of the normal physiological defense mechanisms rather than due to excess gastric acid or pepsin secretion. This involves a combination of defects in the antireflux and esophageal clearance mechanisms. Understanding the mechanisms underlying the pathogenesis of reflux esophagitis at structural, functional, cellular, and molecular levels could help clinicians provide better management options and delay the progression of NERD to reflux esophagitis.

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AUTHOR SPOTLIGHT

Samy A Azer, MD, PhD, FACG
Chair and Professor of Medical Education
Universiti Teknologi, MARA, Malaysia
Visiting Professor, University of Toyama, Japan
Formerly Chair and Senior Lecturer in Medical Education, University of Melbourne, Australia