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EXPLORING THE PATHOPHYSIOLOGY AND TREATMENT STRATEGIES FOR GASTROESOPHAGEAL REFLUX DISEASE: BEYOND ACID CONTROL
Nazarov Nodirbek Nomozboy ogli
Assistant lecturer at the Alfraganus University Email address: [emailprotected] https://doi.org/10.5281/zenodo.14992278
ABSTRACT
Received: 01st March 2025 Accepted: 06th March 2025 Online: 07th March 2025 KEYWORDS
Pepsin, esophageal ambulatory monitoring,
bile
acids, motility, reflux potassium-
competitive acid blocker.
Gastroesophageal reflux disease (GERD) is a complex condition characterized by the backward flow of refluxate into the esophagus. Despite its prevalence and frequent clinical diagnosis, the pathogenesis of GERD is multifaceted. Many patients continue to experience persistent symptoms of GERD even after extended treatment with proton pump inhibitors (PPIs) for acid suppression. The development of GERD involves a dynamic interaction of chemical, mechanical, psychological, and neurological factors, all of which influence symptom manifestation, diagnosis, and treatment approaches. Consequently, GERD should be considered a condition that extends beyond simple acid reflux. This review will explore the key contributors to GERD pathogenesis, including aspects related to the refluxate, esophageal defense mechanisms, and factors that facilitate pathological reflux into the esophagus. Additionally, this paper will discuss recent therapeutic advancements and highlight potential future research directions in the management of GERD.
Introduction
Gastroesophageal reflux disease (GERD) is defined by the presence of bothersome reflux symptoms or erosive complications in the esophagus resulting from the backward flow of gastric contents. Traditionally considered a disease of excess acid, up to 50% of patients with GERD report minimal to no relief with pharmacologic acid suppression therapies. As research advances, it has become increasingly evident that the pathogenesis of GERD extends beyond the acidity of the refluxate. Variations in symptom presentation and treatment response can be attributed not only to the composition of the refluxate but also to factors at the esophageal level, including structural, mechanical, biochemical, and physiological aspects (Figure 1). This review will delve into the pathophysiological mechanisms of GERD, focusing on emerging diagnostic tools and treatment approaches that target the diverse mechanisms of GERD beyond traditional acid suppression strategies.
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Figure 1. Pathways contributing to the development of GERD.
Composition of Refluxate
In gastroesophageal reflux disease (GERD), the primary factor contributing to esophageal mucosal damage is the refluxate. The refluxate's ability to overcome the natural defenses of the esophageal epithelium is influenced by its potency, composition, and the duration of its exposure to the esophageal lining. Refluxate consists of varying levels of acid, bile, pepsin, food particles, and normal gut microbiota. Each component of the refluxate impacts the esophageal mucosa through distinct mechanisms, leading to different etiological pathways of GERD depending on the predominant component and its specific mode of action (Figure 2).
Figure 2. Impact of Individual Refluxate Components on Esophageal Mucosa Acid
Gastroesophageal reflux disease (GERD) is often synonymous with "acid reflux," emphasizing the central role of acid in the disease process. Acid, primarily in the form of hydrochloric acid (HCl), is a potent component of gastric juice and a key contributor to esophageal irritation and reflux symptoms. The pathophysiology of acid-induced mucosal injury is well-established. At the cellular level, HCl damages the esophageal mucosa by altering the electrochemical gradient, known as the potential difference, across the esophageal lining. Under normal conditions, the esophageal epithelium maintains this gradient, but increased luminal HCl, as demonstrated in animal models, significantly raises the potential difference. This shift impairs cell volume regulation, leading to cellular edema, loss of cellular integrity, and necrosis within the epithelial lining.
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In addition to direct cellular damage, acid exposure triggers indirect inflammatory responses in the esophageal epithelium. Studies in both animal and human models have identified proinflammatory mediators such as interleukin (IL)-8, platelet-activating factor, and interferon-gamma as key players. The release of these mediators recruits immune cells to the esophageal mucosa and initiates inflammatory cascades that produce reactive oxygen species (ROS), causing further cell damage.
Several chemical and mechanical factors can exacerbate acid-induced mucosal damage. One such factor is the "acid pocket," a highly acidic, unbuffered zone located just distal to the gastric cardia. This phenomenon, observed in both GERD patients and healthy individuals, is associated with increased reflux events, particularly postprandially when food buffering temporarily raises gastric pH. However, the presence and size of the acid pocket are more pronounced in GERD patients. Conditions like a hiatal hernia can increase the size of the acid pocket, leading to greater acid pooling and enhanced esophageal acid exposure.
Gastric acid also amplifies reflux symptom perception by increasing esophageal sensitivity. Research indicates that acid-induced hypersensitivity is more pronounced in the proximal esophagus compared to distal regions. This heightened sensitivity is likely due to acid's damaging effects on the mucosal barrier, which exposes afferent nerves to the toxic components of the refluxate. The anatomical and pathophysiological mechanisms underlying reflux-related hypersensitivity will be explored further in this review.
Bile Acid
While acid is a well-recognized driver of cellular injury in gastroesophageal reflux disease (GERD), not all GERD cases involve acidic refluxate. During esophageal pH monitoring, some GERD patients exhibit transient increases in pH above 7.0, indicating the presence of an alkalinizing agent, such as bile acid. Studies have shown a correlation between higher bile acid concentrations and these alkaline pH events.
Bile acids, as detergent molecules, possess the ability to solubilize cell membranes. However, their permeability through cell membranes depends on their lipophilic state. In an acidic environment, bile acids become protonated, losing their charge and allowing them to pass through cell membranes. This interaction suggests that bile acids may exert enhanced cytotoxic effects in acidic conditions, supporting their role in GERD associated with duodenogastroesophageal reflux. Additionally, bile acids have been shown to increase hydrogen ion absorption in the esophagus, potentially explaining the link between bile acid concentration and the severity of reflux symptoms. Prolonged exposure to higher bile acid concentrations correlates with progressive esophageal mucosal injury, with certain bile acids demonstrating greater esophageal toxicity.
The interaction between bile and gastric acids in GERD pathophysiology is complex. While studies indicate that duodenogastroesophageal and gastric reflux coexistence is associated with increased mucosal injury, the effects of bile and gastric acids might occur through distinct mechanisms. Interestingly, bile acid reflux does not consistently correlate with esophageal acid exposure as measured by pH monitoring, nor does a poor response to proton pump inhibitor (PPI) therapy necessarily indicate bile reflux. However, bile acid reflux may predict a reduced response to PPI therapy, highlighting the need for alternative treatment approaches. The simultaneous exposure to both bile and gastric acids is linked to
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more severe GERD, though whether these effects are synergistic or independent remains unclear. Further research into bile acid detection and treatment could lead to improved symptom management, particularly in severe or refractory GERD cases.
In conditions such as erosive esophagitis and Barrett's esophagus (BE), bile acids have been associated with increased expression of proinflammatory cytokines, including IL-6, IL-8, COX-2, and TNF-a, which promote inflammatory cell recruitment. This proinflammatory response is not observed in acid-only exposure, underscoring a distinct role for bile acids in esophageal damage. Moreover, in an acidic environment, bile acids can increase oxidative stress by inducing the release of reactive oxygen species (ROS), which may lead to DNA damage and a higher risk of cellular metaplasia.
The role of bile acids in GERD pathogenesis positions them as potential diagnostic biomarkers and therapeutic targets. A recent multicenter, placebo-controlled trial involving 280 GERD patients found that adding a bile acid sequestrant (IW-3718) to PPI therapy significantly reduced heartburn and regurgitation. Despite promising results, the diverse mechanisms by which bile acids contribute to esophageal injury require further investigation to optimize the use of bile acid sequestrants in treating refractory GERD.
Pepsin
The exact role of pepsin in esophageal mucosal injury remains less clearly defined compared to acid and bile acids. Pepsin, a proteolytic enzyme, breaks down proteins into smaller peptides, facilitating protein absorption or further digestion in the intestines. Its enzymatic activity is optimal at a pH of approximately 2.0, but it can remain partially active between pH 2.0 and 6.5. At higher pH levels (6 to 8), pepsin enters a "dormant phase" where it is inactive but can reactivate if the surrounding environment becomes more acidic.
Although pepsin is involved in less than 20% of protein digestion within the gastrointestinal tract, its broad substrate specificity allows it to hydrolyze a variety of proteins. When pepsin is released into the esophagus or nearby structures, it can cause tissue damage since the esophagus lacks a protective mucus layer, unlike the stomach. In the small intestine, the alkaline environment quickly deactivates pepsin, providing a natural defense not present in the esophagus. Upon reflux into the esophagus and extraesophageal tissues, pepsin binds to and damages the surface epithelial cells lining these organs.
Pepsin can become activated through two primary mechanisms: (1) exposure to acidic refluxate and (2) intracellular activation after being taken up by epithelial cells. Once active, pepsin can induce direct cellular damage by degrading extracellular proteins and disrupting intercellular junctions. It can also cause indirect damage by interfering with cellular defenses. For example, a study by Johnston et al. (2006) demonstrated that exposure of laryngeal epithelial cells to both acid and pepsin resulted in the depletion of critical stress proteins, Sep70 and Sep53, an effect not observed with acid exposure alone. Additionally, pepsin may inhibit intracellular defense enzymes, contributing to oxidative stress, inflammation, and apoptosis. Pepsin has also been shown to directly damage intracellular organelles, including disrupting mitochondrial and Golgi apparatus functions.
The diverse mechanisms by which pepsin contributes to epithelial damage and cell death suggest that its impact on GERD may persist despite acid-suppressive therapies. Pepsin's ability to remain dormant and reactivate under acidic conditions highlights its
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potential as a diagnostic and therapeutic target in GERD management. Current studies on salivary pepsin as a diagnostic marker have shown mixed results, indicating the need for further research to clarify its clinical utility. In terms of therapy, previous studies suggest that alginates, which are commonly used in GERD treatment, may reduce pepsin activity, offering a potential approach to managing pepsin-related mucosal injury.
Esophageal Defenses Against Gastric Refluxate
Structural Integrity of the Esophageal Epithelium
The esophageal mucosa is composed of nonkeratinized squamous epithelium with three functionally distinct layers: the proliferative stratum basalis, the metabolically active stratum spinosum, and the enucleated stratum corneum. Despite its 20-30 cell layers, the esophageal mucosa lacks certain protective characteristics that make it vulnerable to damage from noxious components of gastric refluxate. Unlike the stomach, the esophagus does not contain mucus-secreting cells or bicarbonate production, which are critical for creating a biochemical barrier to neutralize acidic or toxic refluxate.
As previously discussed, acid can create an optimal environment for the caustic activities of pepsin and the absorption of bile acids. Without adequate neutralization mechanisms, the esophageal lining is more susceptible to damage from these harmful agents. However, the absence of neutralization alone does not fully explain the variable symptom presentations seen in gastroesophageal reflux disease (GERD). The interplay between the properties of the refluxate and the esophageal epithelium significantly influences GERD pathogenesis and symptom presentation.
The esophageal epithelium comprises intercellular junctional complexes that help maintain epithelial integrity and facilitate cell-to-cell communication and transport. When these junctions are disrupted by harmful stimuli, the resulting increase in intercellular permeability weakens the esophageal wall. This loss of integrity not only exposes the deeper esophageal structures to toxic refluxate but also enhances the risk of noxious stimulation of neurochemical pathways in the lamina propria.
Refluxate components, such as pepsin and acid, gain access to esophageal afferent neuron chemoreceptors primarily through dilated intercellular spaces (DIS). Electron microscopy has identified DIS as a potentially sensitive marker for GERD-related esophageal damage. However, studies present mixed findings on the correlation between DIS and GERD, including its subtypes like nonerosive reflux disease (NERD). Some studies suggest that DIS may not be specific to GERD, as similar findings have been reported in asymptomatic individuals. Additionally, while DIS resolution has been observed following proton pump inhibitor (PPI) therapy, other stressors—including physical, chemical, and psychological factors—have also been linked to DIS development.
Given the inconsistent evidence surrounding DIS as a diagnostic marker, the role of endoscopic biopsy in GERD is currently limited to specific scenarios such as erosive and eosinophilic esophagitis and Barrett's esophagus (BE) surveillance. However, emerging research indicates that more subtle changes in junctional integrity may contribute to GERD development.
A novel approach to assessing esophageal mucosal integrity involves mucosal impedance technology, which can evaluate the structural and functional integrity of the
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esophageal lining during endoscopy. Preliminary studies show promise in distinguishing GERD from other esophageal conditions, including eosinophilic esophagitis and achalasia, in real-time. As research into these molecular and ultrastructural changes progresses, this technology could enhance GERD diagnosis and help refine targeted treatment strategies.
Neuronal Afferents in the Esophageal Mucosa
When gastric acid penetrates the esophageal mucosa through dilated intercellular spaces (DIS), it activates specific sensory receptors embedded within the esophageal wall. These acid-sensitive receptors belong primarily to three major families: acid-sensing ion channels (ASICs), P2X receptors, and transient receptor potential (TRP) channels. Among the TRP receptors, the transient receptor potential vanilloid 1 (TRPV1) receptor plays a critical role in mediating the perception of acid-induced esophagitis.
Upon activation by noxious stimuli, afferent neurons transmit signals as action potentials along two primary pathways:
1.Vagal Stimulation Pathway: Signals travel to the central nervous system (CNS) through the nodose and jugular ganglia, with synapses occurring at the nucleus of the solitary tract.
2.Spinal Afferent Pathway: Pain signals are relayed to the thalamus via the dorsal root ganglion, spanning spinal levels C1 to L2.
These neuronal pathways present potential therapeutic targets for treating gastroesophageal reflux disease (GERD), particularly in cases where traditional acid suppression therapy is ineffective.
Neuronal Sensitivity in Nonerosive Reflux Disease (NERD)
GERD encompasses two main subtypes: nonerosive reflux disease (NERD) and erosive reflux disease, differentiated by the presence or absence of structural esophageal damage. Erosive reflux disease can be identified endoscopically by visible inflammation, erosive mucosal breaks, and the transformation of squamous epithelium to columnar epithelium (a hallmark of Barrett's esophagus). In contrast, NERD is characterized by classic GERD symptoms without endoscopic evidence of esophageal irritation.
Studies suggest that in NERD, symptoms may result from hypersensitivity of esophageal sensory neurons to refluxed contents. Sensory neurons in NERD patients are often positioned more superficially in the esophageal wall compared to those with erosive esophagitis or Barrett's esophagus (BE). This superficial positioning may explain why NERD patients experience heightened symptoms such as heartburn despite an intact epithelial lining. Conversely, patients with BE or esophagitis often exhibit nociceptor desensitization, contributing to hyposensitivity to noxious stimuli.
Reflux Hypersensitivity and Treatment Approaches
Reflux hypersensitivity has gained recognition as one of the five functional esophageal disorders under the Rome IV criteria. Unlike NERD, patients with reflux hypersensitivity exhibit normal physiological levels of reflux, suggesting that their symptoms are more related to altered sensory perception than to the frequency or volume of reflux events.
Given the diverse presentations of reflux-related symptoms, effective treatment strategies must address both acid exposure and sensory hypersensitivity. Advances in therapy have focused on modulating the neuronal pathways associated with symptom perception.
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•Esophageal Neuromodulators: Medications such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) have demonstrated efficacy in managing PPI-refractory heartburn by altering pain perception pathways.
•Psychological Interventions: Therapies like esophageal-directed hypnotherapy and cognitive behavioral therapy (CBT) offer promising results in managing functional esophageal disorders, including reflux hypersensitivity. These approaches aim to reduce visceral hypersensitivity and improve symptom management through cognitive and behavioral strategies.
Reduced Esophageal Clearance of Refluxate
When the forward movement (anterograde flow) of esophageal and gastric contents is impaired, the esophageal mucosa is exposed to refluxate for prolonged periods. This increased exposure heightens the risk of mucosal damage due to the caustic nature of refluxate components. Effective esophageal clearance relies on both chemical and mechanical mechanisms, including glandular secretions and proper esophageal motility patterns. Disruptions in these processes can diminish esophageal clearance and contribute to the pathogenesis of gastroesophageal reflux disease (GERD).
Salivary Gland Secretions
Saliva plays a crucial role in promoting esophageal clearance primarily through acid neutralization. Salivary secretion is triggered by a specific esophagosalivary reflex, where the presence of acid in the esophagus activates esophageal chemoreceptors, prompting the salivary glands to release saliva. While saliva does not directly influence esophageal motility, its buffering capacity enhances acid clearance, as demonstrated in animal models.
The importance of saliva in esophageal clearance is further illustrated by the phenomenon of nocturnal GERD. During sleep, salivary secretion significantly decreases, which correlates with a higher frequency of nighttime reflux events and increased esophageal acid exposure. Additionally, chronic medical conditions and medications that reduce salivary flow have been linked to increased reflux episodes and a higher risk of developing esophageal reflux disease.
Esophageal Dysmotility
The link between esophageal dysmotility and gastroesophageal reflux disease (GERD) is well-established, with research suggesting a bidirectional relationship. Many GERD patients exhibit impaired esophageal motility, including disrupted peristalsis and lower esophageal sphincter (LES) dysfunction. These motility abnormalities can slow the movement of esophageal contents, reducing refluxate clearance and increasing mucosal exposure to harmful components.
Esophageal dysmotility can result from both intrinsic and extrinsic factors. Intrinsic causes include neuromuscular and autoimmune disorders, while extrinsic factors involve mechanical influences such as a hiatal hernia. Impaired esophageal motility not only contributes to prolonged exposure to toxic refluxate but also exacerbates GERD progression and symptom severity. Studies have demonstrated a direct correlation between the extent of esophageal mucosal injury, increased acid exposure, and worsening esophageal motor function. This dysfunction can reduce LES pressure and impair acid clearance, creating a vicious cycle that perpetuates GERD symptoms and mucosal damage.
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Manometric studies of GERD patients often reveal specific metrics of esophageal dysmotility, including decreased distal contractile integrity, greater peristalsis breaks, lower LES pressure, reduced peristaltic wave amplitudes, and ineffective esophageal motility. These parameters highlight the intricate relationship between esophageal motility and GERD, where each condition may contribute to the development and progression of the other.
Therapeutic Challenges and Potential of Prokinetic Agents
Despite the recognized role of esophageal dysmotility in GERD, effective treatment options targeting motility remain limited. Traditional prokinetic agents, such as dopamine receptor antagonists, GABAB receptor agonists, 5-hydroxytryptamine (5-HT) agonists, and acetylcholine receptor agonists, generally show inconsistent symptom improvement in GERD. Additionally, these medications often produce significant side effects.
For example, cisapride was once considered an effective prokinetic therapy for GERD but was withdrawn from the market due to severe cardiac side effects. Similarly, metoclopramide, known for enhancing gastric motility in delayed gastric emptying, is associated with adverse effects such as restlessness, dystonia, and tardive dyskinesia due to its central action on D2 receptors.
However, some newer prokinetic agents show promise in managing GERD with a more favorable safety profile. Mosapride, a selective 5-HT4 receptor agonist, has shown potential to enhance proton pump inhibitor (PPI) therapy in certain patients, particularly those with erosive esophagitis. Nevertheless, the evidence remains mixed, with many studies unable to replicate significant benefits when using mosapride alongside PPIs.
Rikkunshito, a traditional Japanese medicine that stimulates gastric motility by promoting ghrelin release, may also offer therapeutic benefits in refractory GERD. It has shown synergistic effects with PPIs and could serve as a monotherapy for some GERD patients.
Reversed Gastroesophageal Gradient
A critical factor contributing to the development of gastroesophageal reflux disease (GERD) is the concept of a reversed gastroesophageal pressure gradient. Under normal physiological conditions, the esophagus resides within the thoracic cavity, meaning intraesophageal pressure is aligned with intrathoracic pressure and remains lower than intraabdominal pressure. To push contents into the stomach (a higher-pressure environment), the lower esophageal sphincter (LES) must sustain tonic contraction to counteract this pressure gradient.
When the LES fails to maintain its tone—whether due to an inherently hypotonic LES, the presence of a hiatal hernia, or increased intra-abdominal pressure as seen in obesity or pregnancy—refluxate can flow backward from the stomach into the esophagus.
The role of the LES in facilitating retrograde flow is also influenced by a physiological process known as transient LES relaxations (TLESRs). TLESRs occur when gastric distention triggers spontaneous, vagally-mediated relaxation of both the LES and the crural diaphragm, allowing gas to escape from the stomach without preceding peristalsis. Studies present mixed findings regarding TLESR frequency in GERD, with some research indicating similar rates in GERD patients and healthy individuals, while others suggest a higher frequency in GERD cases.
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The uncertain relationship between TLESRs and GERD has spurred the development of pharmacologic agents aimed at enhancing LES function and reducing TLESR episodes. These include:
•GABAB Receptor Agonists (e.g., Baclofen)
•Metabotropic Glutamate Receptor 5 (mGluR5) Agonists
•Cholecystokinin (CCK) Receptor Agonists
•Cannabinoid Receptor Agonists
•Nitric Oxide Synthase Inhibitors
Of these, Baclofen, a GABAB receptor agonist, has shown the most efficacy in reducing reflux events by improving LES tone and decreasing TLESR frequency. However, its use is limited due to potential central nervous system (CNS) side effects, including fatigue, nausea, vomiting, and dizziness.
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Surgical and Endoluminal Treatments for GERD
When pharmacological treatments prove insufficient, surgical and endoluminal interventions can effectively enhance LES function and reduce retrograde flow:
1.Laparoscopic Nissen Fundoplication (LNF): This procedure, which wraps the stomach around the LES, is highly effective in cases with a hiatal hernia and weakened LES.
2.Laparoscopic Toupet Fundoplication: An alternative to LNF, especially for patients with esophageal hypomotility, offering symptom relief by repairing hiatal hernias and improving LES function.
3.Magnetic Sphincter Augmentation (MSA): MSA involves placing a magnetic ring around the LES to reinforce its closure, suitable for patients with or without a hiatal hernia.
4.Transoral Incisionless Fundoplication (TIF): TIF is a minimally invasive endoscopic option that strengthens the antireflux barrier, particularly effective when there is no major anatomical disruption.
5.Bariatric Surgery: Primarily for GERD patients with obesity, bariatric procedures reduce the stomach's size, decrease acid production by limiting parietal cell area, and lower intra-abdominal pressure through weight loss.
Future Opportunities and Conclusion
Gastroesophageal reflux disease (GERD) is a multifaceted condition with a complex and often multifactorial pathogenesis. A deeper understanding of the mechanisms underlying GERD can drive significant advancements in both diagnostic strategies and therapeutic approaches (Table 1). Effective management of GERD involves looking beyond acid exposure to address the broader impact of refluxate on esophageal health. Non-invasive diagnostic techniques, such as measuring salivary pepsin, could become a valuable tool in identifying gastric refluxate biomarkers and enhancing the diagnostic paradigm of GERD.
Innovative therapeutic options, including bile acid sequestrants and alginates, may offer a complementary approach to acid suppression by specifically targeting bile and pepsin components. For patients who experience inadequate relief or cannot tolerate proton pump inhibitors (PPIs), potassium competitive acid blockers (P-CABs) present a promising alternative with potentially superior acid suppression. Concurrently, new diagnostic and therapeutic modalities are being developed to reinforce the esophageal mucosa's natural
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defenses. Real-time assessment of mucosal integrity may provide a practical method for detecting compromised esophageal epithelial integrity in GERD patients.
Pharmacological and psychological interventions continue to expand, offering effective means to manage esophageal hypersensitivity and reduce nociception. However, current treatments aimed at enhancing esophageal clearance are still limited, highlighting the need for further research into selective prokinetic agents and other innovative therapies.
Additionally, advanced surgical and endoluminal techniques such as magnetic sphincter augmentation and transoral incisionless fundoplication (TIF) show considerable potential in restoring the antireflux barrier, particularly for patients with refractory GERD. Continued exploration and development in these areas hold promise for delivering more targeted, personalized, and effective treatment options for managing GERD and improving patient outcomes.
Table 1.
Current and future diagnostic tools and therapy for GERD personalized to mechanistic factor
Factors in GERD developmentDiagnostic toolTreatment option
Refluxate compositionAcidAmbulatory reflux monitoringProton pump inhibitor H2 receptor antagonist Potassium competitive acid blockers
BileBilitecBile acid sequestrant
PepsinSalivary pepsinAlginates
Esophageal defensesReduced integrity of the esophageal epitheliumDilated intracellular space on biopsy Mucosal impedance/integrityAlginates
Heightened nociception via neuronal afferentsPharmacologic neuromodulators Esophageal-directed hypnotherapy Cognitive behavioral therapy
Reduced esophageal clearanceHigh-resolution manometry with impedance Multichannel intraluminal impedance and pH monitoring (MII-pH) Barium esophagramProkinetic agents
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Factors in GERD developmentDiagnostic toolTreatment option
Reversed gastroesophageal gradientEsophageal manometry Barium esophagramGABA agonist Surgical fundoplication Transoral incisionless fundoplication Magnetic sphincter augmentation
Note: Italics represent novel options and/or opportunities for future investigation.
In conclusion, while gastroesophageal reflux disease (GERD) is often perceived primarily as a condition related to acid reflux, it is, in fact, a complex and multifactorial disease. GERD involves a delicate balance between the aggressive components of the refluxate and the defensive mechanisms of the esophagus. The clinical presentation of GERD is diverse, with symptoms ranging from typical and atypical to extraesophageal manifestations. Diagnostic classification further differentiates GERD through endoscopy and biopsy findings.
Effective treatment begins with a thorough assessment of the patient's specific symptoms, complemented by diagnostic studies to identify contributing factors. It is noteworthy that nearly half of patients with heartburn do not achieve full relief with standard proton pump inhibitor (PPI) therapy, underscoring the need for a broader approach to GERD management. As our understanding of GERD pathogenesis expands, new therapeutic targets related to esophageal motility, hypersensitivity, and non-acid reflux components could transform our strategies for managing GERD, moving beyond the traditional focus on acid suppression alone.
References:
1.Vakil N, van Zanten SV, Kahrilas K, et al. 2006. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am. J. Gastroenterol 101: 1900-1920. [DOI] [PubMed] [Google Scholar]
2.Ang D, How CH & Ang TL 2016. Persistent gastrooesophageal reflux symptoms despite proton pump inhibitor therapy. Singapore Med. J 57: 546-551. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Castell DO, Murray JA, Tutuian OR, et al. 2004. Review article: the pathophysiology of gastro-oesophageal reflux disease-oesophageal manifestations. Aliment. Pharmacol. Ther 20(Suppl. 9): 14-15. [DOI] [PubMed] [Google Scholar]
4.Tack J & Pandolfino JE 2018. Pathophysiology of gastroesophageal reflux disease. Gastroenterology 54:277-288. [DOI] [PubMed] [Google Scholar]
5.Orlando RC, Powell DW & Carney CN 1981. Pathophysiology of acute acid injury in rabbit esophageal epithelium. J. Clin. Invest 68: 286-293. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliot M, et al. 2002. Diversity in oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut 50: 451459. [DOI] [PMC free article] [PubMed] [Google Scholar]
EURASIAN JOURNAL OF MEDICAL AND NATURAL SCIENCES
Innovative Academy Research Support Center IF = 7.921www.in-academy.uz
7.Ma J, Altomare A, de la Monte S, et al. 2010. HCl-induced inflammatory mediators in esophageal mucosa increase migration and production of H2O2 by peripheral blood leukocytes. Am. J. Physiol. Gastrointest. Liver Physiol 299: G791-G798. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Isomoto H, Wang A, Mizuta Y, et al. 2003. Elevated levels of chemokines in esophageal mucosa of patients with reflux esophagitis. Am. J. Gastroenterol 98: 551-556. [DOI] [PubMed] [Google Scholar]
9.Kahrilas PJ, McColl K, Fox M, et al. 2013. The acid pocket: a target for treatment in reflux disease?Am. J. Gastroenterol 108:1058-1064. [DOI] [PubMed] [Google Scholar]
10.Mitchell DR, Derakhshan MH, Robertson EV, et al. 2016. The role of the acid pocket in gastroesophageal reflux disease. J. Clin. Gastroenterol 50: 111-119. [DOI] [PubMed] [Google Scholar]
11.Emerenziani S, Ribolsi M, Guarino MPL, et al. 2014. Acid reflux episodes sensitize the esophagus to perception of weakly acidic and mixed reflux in non-erosive reflux disease patients. Neurogastroent. Motil26:108-114. [DOI] [PubMed] [Google Scholar]
12.Zerbib F, Duriez A, Roman S, et al. 2008. Determinants of gastro-esophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 57: 156160. [DOI] [PubMed] [Google Scholar]
13.Lin KM, Ueda RK, Hinder RA, et al. 1991. Etiology and importance of alkaline esophageal reflux. Am. J. Surg 162: 553-557. [DOI] [PubMed] [Google Scholar]
14.Stein HJ, Feussner H, Kauer W, et al. 1994. Alkaline gastroesophageal reflux: assessment by ambulatory esophageal aspiration and pH monitoring. Am. J. Surg 167: 163-168. [DOI] [PubMed] [Google Scholar]
15.Kauer WK, PetersJH, DeMeester TR, et al. 1997. Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease. Surgery 122: 874881. [DOI] [PubMed] [Google Scholar]
16.Siddiqui A, Rodriguez-Stanley R, Zubaidi S, et al. 2005. Esophageal visceral sensitivity to bile salts in patients with functional heartburn and in health control subjects. Dig. Dis. Sci 50: 81-85. [DOI] [PubMed] [Google Scholar]
17.Nehra D, Howell P, Williams CP, et al. 1999. Toxic bile acids in gastroesophageal reflux disease: influence of gastric acidity. Gut 44: 598-602. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Pace F, Sangaletti O, Pallotta S, et al. 2007. Biliary reflux and non-acid reflux are two distinct phenomena: a comparison between 24-hour multichannel intraesophageal impedance and bilirubin monitoring. Scand. J. Gastroenterol 42: 1031-1039. [DOI] [PubMed] [Google Scholar]
19.Gasiorowska A, Navarro-Rodriguez T, Wendel C, et al. 2009. Comparison of the degree of duodenogastroesophageal reflux and acid reflux between patients who failed to respond and those who were successfully treated with a proton pump inhitibor once daily. Am. J. Gastroenterol 104:2005-2013. [DOI] [PubMed] [Google Scholar]
20.de Bortoli N, Gyawali CP, Frazzoni M, et al. 2020. Bile reflux in patients with nerd is associated with more severe heartburn and lower values of mean nocturnal base-line impedance
EURASIAN JOURNAL OF MEDICAL AND NATURAL SCIENCES
Innovative Academy Research Support Center IF = 7.921www.in-academy.uz
and chemical clearance. Neurogastroenterol. Motil e13919. 10.1111/nmo.13919 [DOI] [PubMed]
21.Vaezi MF & Richter JE 1996. Role of acid and duo-denogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 111: 1192-1199. [DOI] [PubMed] [Google Scholar]
22.Sun D, Wang X, Gai Z, et al. 2015. Bile acids but not acidic acids induce Barrett's esophageal. Int. J. Clin. Exp. Pathol 8:1384-1392. [PMC free article] [PubMed] [Google Scholar]
23.McQuaid KR, Laine L, Fennerty MB, et al. 2011. Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment. Pharmacol. Ther 34:146-165. [DOI] [PubMed] [Google Scholar]
24.Dvorak K, Payne CM, Chavarria M, et al. 2007. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett's oesophagus. Gut 56: 763-771. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Vaezi MF, Fass R, Vakil N, et al. 2020. IW-3718 reduces heartburn severity in patients with refractory gastroesophageal reflux disease in a randomized trial. Gastroenterology 158: 20932103. [DOI] [PubMed] [Google Scholar]
