Background: The last 40 years have seen a remarkable change in our understanding of reflux disease. Summary: These changes encompass disease definition and impact, pathophysiology, diagnostic testing, regulatory oversight of clinical trials, pharmacotherapy, endoscopic, and surgical treatment. We have also seen a number of promising therapies fail. Key Messages: The future holds the promise of further advances. Adaptive artificial intelligence will take over diagnostics in manometry and pH impedance testing and patient-driven outcomes may be changed by interactions with artificial intelligence rather than humans. Changes in chip technology will allow higher resolution chips to be carried on smaller devices making extra-esophageal areas where reflux may play a role more accessible to prolonged observation and testing.

On the 40th anniversary of the journal, this qualitative review considers the progress that has been made over the past 40 years in the pathophysiology, diagnostic strategies, pharmacological management, endoscopic, and surgical treatment of GERD. Conceptually, the greatest change over this period of time is an evolution of our thinking regarding this disease from an inconvenience to a disease state with a major impact on the patients’ quality of life.

In 1983, the pathogenesis of reflux disease was thought to be related to a number of mechanisms including changes in lower esophageal sphincter pressure, gastric volume, composition of the refluxate, esophageal acid clearance, and mucosal resistance [1]. Transient sphincter relaxations had become recognized in a study of 10 patients that was published in the New England Journal of Medicine [2]. In the diagnostic arena, the Bernstein acid perfusion test was still in use and was being evaluated as a diagnostic test for chest pain [3, 4]. A questionnaire-based approach to the diagnosis of reflux disease was described for the first time [5]. Ambulatory pH testing using a radiotelemetry capsule and a portable recording system had just been described [6]. An automated computer-based system to read pH recordings had been described [7].

With regard to pharmacological therapy, a stepwise management strategy had developed [8]. Phase 1 consisted of lifestyle modification, elevation of the head end of the bed and antacids and alginates. Phase 2 consisted of drug therapy with drugs that were not approved by the FDA for reflux disease. These drugs consisted of cimetidine, metoclopramide and bethanechol [4]. Phase 3 consisted of anti-reflux surgery. The success of phase 1 treatment was thought to be 75%. Ninety percent of nonresponders to phase 1 treatment were thought to respond to phase 2 leaving a minority of patients for phase 3. The success of phase 1 treatments was thought to be 75% and only a minority of patients were thought to need drugs in phase 2 [6]. Surgeons were still placing the Angelchik prosthesis, a C-shaped, silicone-filled device that was surgically secured around the lower esophagus, and it was considered a promising treatment for refractory patients [9]. Reports of complications had begun to appear and this device was later withdrawn from the market because of serious complications related to migration or erosion into the esophagus [10]. Open surgical fundoplication was performed for refractory patients and long-term results for fundoplication began to recognize that symptoms could recur long after initial surgery [11]. Infants with reflux disease were being positioned in an infant seat called a “chalasia chair” until a randomized controlled trial showed that it was detrimental rather than beneficial when compared to placing the infant prone [12].

Disease Definition and Impact

Consensus on Terminology and Definition of GERD and NERD

Table 1 The Genval consensus was the first international attempt to resolve some of the complex problems with the diagnosis and management of GERD [13]. The disease was defined by this consensus by the presence of esophageal mucosal breaks or by the occurrence of reflux induced symptoms severe enough to impair quality of life. Endoscopy negative patients were recognized as the most common subgroup; most of these patients can be diagnosed by a well-structured symptom analysis. The consensus members recognized a consistent hierarchy of effectiveness of available initial and long-term therapies that applies for all patient subgroups. Lifestyle measures were judged to be of such low efficacy that they were rejected as a primary therapy for all patient subgroups. Proton-pump inhibitor therapy was considered the initial medical treatment of choice because of its clearly superior efficacy which results in the rapid achievement of desirable outcomes at the lowest overall medical cost (Tables 1, 2; Fig. 1).

Table 1.

Major developments in GERD in the last 40 years

Disease Definition and Impact 
 Consensus on terminology and definition of GERD 
 Impact of GERD on quality of life 
 Los Angeles and Prague Classification 
 Economic impact 
Pathophysiology of GERD 
 Transient sphincter relaxation 
 Acid pocket 
 Duodeno-gastroesophageal reflux 
 Gaseous reflux (acid cloud) 
 Esophageal and cortical sensitization and hypervigilance 
Diagnostic techniques 
 Wireless pH testing and pH/impedance testing 
 High-resolution manometry and endoluminal impedance 
 High-resolution endoscopy and narrow-band imaging 
Regulatory oversight of trials 
 Patient reported outcomes 
Pharmacological Interventions 
 Prokinetic agents 
 PPI therapy 
 Potassium competitive acid inhibitors 
 Safety and toxicity of pharmacotherapy 
Endoscopic treatments 
 Stretta Procedure 
 Transoral incisionless fundoplication 
 Endoscopic suturing with and without mucosal ablation 
Surgical techniques 
 Laparoscopic fundoplication 
 Magnetic Sphincter augmentation 
 Electrical stimulation of the lower esophageal sphincter 
Promising therapies that failed, were withdrawn or failed  to live up to the promise 
 Baclofen 
 Lesogaberan 
 Vanilloid Receptor antagonists 
 Tegaserod 
 Endoscopic stitching treatments: Endocinch and NDO Plicator 
 Endoscopic injection/prosthesis: Enteryx and Gatekeeper 
 Reza/reflux band 
Disease Definition and Impact 
 Consensus on terminology and definition of GERD 
 Impact of GERD on quality of life 
 Los Angeles and Prague Classification 
 Economic impact 
Pathophysiology of GERD 
 Transient sphincter relaxation 
 Acid pocket 
 Duodeno-gastroesophageal reflux 
 Gaseous reflux (acid cloud) 
 Esophageal and cortical sensitization and hypervigilance 
Diagnostic techniques 
 Wireless pH testing and pH/impedance testing 
 High-resolution manometry and endoluminal impedance 
 High-resolution endoscopy and narrow-band imaging 
Regulatory oversight of trials 
 Patient reported outcomes 
Pharmacological Interventions 
 Prokinetic agents 
 PPI therapy 
 Potassium competitive acid inhibitors 
 Safety and toxicity of pharmacotherapy 
Endoscopic treatments 
 Stretta Procedure 
 Transoral incisionless fundoplication 
 Endoscopic suturing with and without mucosal ablation 
Surgical techniques 
 Laparoscopic fundoplication 
 Magnetic Sphincter augmentation 
 Electrical stimulation of the lower esophageal sphincter 
Promising therapies that failed, were withdrawn or failed  to live up to the promise 
 Baclofen 
 Lesogaberan 
 Vanilloid Receptor antagonists 
 Tegaserod 
 Endoscopic stitching treatments: Endocinch and NDO Plicator 
 Endoscopic injection/prosthesis: Enteryx and Gatekeeper 
 Reza/reflux band 
Table 2.

Time-line of major developments in GERD

1980s 
 Introduction of H2 receptor antagonists (e.g., cimetidine, ranitidine) in the early 1980s 
1990s 
 Emergence of proton pump inhibitors (PPIs) in the 1990s transformed GERD treatment 
 Advancements in endoscopy techniques during this decade allowed for the visualization of esophageal mucosa and identification of erosive esophagitis. Endoscopy became an essential tool for diagnosing GERD and assessing its severity 
2000s 
 Introduction of wireless pH monitoring and impedance-pH monitoring in the early 2000s revolutionized the evaluation of acid and non-acid reflux episodes 
 Development of minimally invasive endoscopic therapies, such as radiofrequency ablation (RFA), provided a promising approach to manage Barrett’s esophagus 
2010s 
 FDA approval of transoral incisionless fundoplication (TIF) using the EsophyX device in 2010 offered a less invasive alternative to traditional surgical fundoplication for select GERD patients 
 Introduction of magnetic sphincter augmentation (LINX) in the early 2010s provided another novel surgical option for GERD patients 
2020s 
 Continued research into potential new pharmacological treatments, including novel reflux inhibitors and prokinetic agents, with improved safety and efficacy profiles 
 Advancements in endoscopic suturing techniques for the management of gastroesophageal reflux in patients who are not responsive to PPI therapy 
 Ongoing development of digital health technologies, such as mobile apps and wearable devices, for better monitoring and management of GERD symptoms and treatment adherence 
1980s 
 Introduction of H2 receptor antagonists (e.g., cimetidine, ranitidine) in the early 1980s 
1990s 
 Emergence of proton pump inhibitors (PPIs) in the 1990s transformed GERD treatment 
 Advancements in endoscopy techniques during this decade allowed for the visualization of esophageal mucosa and identification of erosive esophagitis. Endoscopy became an essential tool for diagnosing GERD and assessing its severity 
2000s 
 Introduction of wireless pH monitoring and impedance-pH monitoring in the early 2000s revolutionized the evaluation of acid and non-acid reflux episodes 
 Development of minimally invasive endoscopic therapies, such as radiofrequency ablation (RFA), provided a promising approach to manage Barrett’s esophagus 
2010s 
 FDA approval of transoral incisionless fundoplication (TIF) using the EsophyX device in 2010 offered a less invasive alternative to traditional surgical fundoplication for select GERD patients 
 Introduction of magnetic sphincter augmentation (LINX) in the early 2010s provided another novel surgical option for GERD patients 
2020s 
 Continued research into potential new pharmacological treatments, including novel reflux inhibitors and prokinetic agents, with improved safety and efficacy profiles 
 Advancements in endoscopic suturing techniques for the management of gastroesophageal reflux in patients who are not responsive to PPI therapy 
 Ongoing development of digital health technologies, such as mobile apps and wearable devices, for better monitoring and management of GERD symptoms and treatment adherence 
Fig. 1.

Time-line for consensus documents in GERD.

Fig. 1.

Time-line for consensus documents in GERD.

Close modal

The next major development in GERD was a consensus definition of GERD that laid out the framework for a clinical diagnosis of GERD and separation of minor symptoms of heartburn from a disease state that has a major impact on the patient’s quality of life [14]. Gastroesophageal reflux disease was defined as GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications. The consensus group also laid out a framework that divided typical GERD patients presenting with heartburn and regurgitation into two categories: conditions with evidence of esophageal mucosal injury and symptomatic syndromes without evidence of mucosal injury. Extra-esophageal disorders were categorized as established (e.g., reflux-induced cough) and proposed (e.g., reflux-related otitis media). Nonerosive disease (NERD) was addressed in another consensus (Vevey Consensus) [15]. NERD was defined as a condition with reflux symptoms in the absence of mucosal lesions or breaks detected by conventional endoscopy, and without prior effective acid-suppressive therapy. Evidence supporting a diagnosis of NERD included [1] responsiveness to acid suppression therapy [2], abnormal reflux monitoring or [3] identification of specific novel endoscopic, and histological findings. Functional heartburn was considered a separate entity not related to acid reflux. Proton-pump inhibitors are the definitive therapy for NERD, with efficacy best evaluated by validated quality-of-life instruments. Another recent consensus addressed the problem of refractory GERD [16]. The consensus paper proposed using the term “refractory GERD symptoms” only in patients with persisting symptoms and previously proven GERD by either endoscopy or esophageal pH monitoring. Objective evaluation, including endoscopy and esophageal physiologic testing, was deemed requisite to provide insights into mechanisms of symptom generation and evidence of true refractory GERD. The authors also recommended that attention should also be paid to supra-gastric belching and rumination syndrome, which may be important contributors to refractory symptoms.

The Impact of GERD on Quality of Life

A major development in our understanding of reflux disease has been the patient’s perspective of the disease and the impact of reflux on quality of life. In the early 1980s, GERD was still considered a lifestyle disease that could improve with dietary modification, antacids, and alginates. Formal studies on the quality of life have been performed in populations and also in different cohorts of patients with established GERD. Population-based studies showed a meaningful decline in quality of life when GERD symptoms occur 2 or more times a week [17, 18]. Over the time-period of this review, a number of questionnaires have been developed that measure the impact of GERD on quality of life (disease-specific instruments) that are widely used in research studies[19, 20]. Some of these questionnaires were translated and validated in other languages creating a framework for international studies on GERD and comparative studies in different populations across the world [21]. The relationship between sleep and GERD was described during this period. Reflux events that occur during the day are typically brief and acid clearance times are short due to swallowing and of bicarbonate rich saliva and mechanical clearing of the esophagus [22]. Nocturnal reflux events tend to be prolonged due to decreased saliva production, reduced swallowing frequency, and decreased perception of heartburn. Night-time reflux is associated with poor sleep quality and frequent arousals and reduces quality of life.

Los Angeles and Prague Classification

The lack of a generally accepted, reproducible, and validated tool to describe endoscopic findings in GERD was a significant limitation until the Los Angeles Classification of erosive esophagitis was developed [23]. The Los Angeles Classification was developed and validated to provide an endoscopic classification of GERD [24]. It has become a widely accepted tool that now forms the basis of regulatory studies in Europe and the USA. Additional developments were the development of an endoscopic classification and description of Barrett’s esophagus [25]. These classification systems allow objective measurements of healing of esophagitis and also allow long-term studies of Barrett’s esophagus and the impact of treatment measures over long periods of time (Table 2; Fig. 1).

Economic Impact of GERD

A major development in the understanding of reflux disease and its implications was the development of economic studies that measured the cost of GERD management. A review in 2002 found that there were 47 studies on economic evaluations in GERD most of which were centered on the cost of GERD treatment from the perspective of the third-party payor [26]. Over subsequent years, the patients perspective and the employers perspective began to be considered in economic analyses. These studies demonstrated that GERD has a significant effect on work-life leading to reduced productivity at work and increased absenteeism leading to major economic impacts in the workplace [27]. These studies were reproduced in other countries demonstrating the international impact of GERD on quality of life and work impact [28].

Pathophysiology of GERD

Although there have been a number of developments in the pathophysiology of reflux disease over the past 4 decades, many aspects of the disease remain unclear. Major developments in the pathophysiology of GERD were the recognition of inappropriate transient lower esophageal sphincter relaxation and sphincter incompetence as a possible mechanism of GERD. Transient sphincter relaxations were related to a unique finding of longitudinal muscle contraction in the esophagus [29]. There was a resurgence of interest in the hiatus hernia and recognition of its importance in sphincter dysfunction causing GERD. Small hiatus hernias are present in many patients with reflux disease and the role of these hiatus hernias in sphincter incompetence and the development of erosive esophagitis [30, 31]. In 2001, the concept of an acid pocket close to the gastroesophageal junction was developed. The acid pocket is an unbuffered layer of acid thatfloats on the surface of the gastric contents close to lower esophageal sphincter and has a very acidic pH [32]. Acid from this pocket forms a source for recurrent reflux into the distal esophagus. A therapeutic option of an alginate with an antacid was developed [33].

Dilated intercellular channels were described in patients with nonerosive reflux disease and the concept of mucosal integrity and its relationship to symptoms developed [34]. Duodeno-gastroesophageal reflux was described and the effects of bile on the mucosal integrity of the esophagus were described [35, 36]. Our understanding of the perception of symptoms in reflux disease improved over the last 40 years. Heartburn and regurgitation symptoms were more likely to be evoked when the drop was large and proximal extent of the refluxate was high [37]. The concept of an acidic cloud consisting of a gaseous bubble with micro-droplets of acid was developed. It can be perceived as heartburn and regurgitation [33]. Sensitization of the esophageal mucosa by acid was described and these mechanistic studies offered an explanation for esophageal hypersensitivity to other stimuli such as balloon distention in patients with GERD [38]. Obesity was described as an important independent risk factor for GERD [39]. The effects of obesity on the integrity of the esophagogastric junction were elucidated [40]. A large study that evaluated all these factors in a large cohort of patients found that a hiatus hernia was present in 95.4%; incompetence of the lower esophageal sphincter in 88%, duodeno-gastroesophageal reflux in 55%, obesity in 25.6%, impaired esophageal clearance due to poor motility in 8.8%, delayed gastric emptying in 6.8% [41].

Diagnostic Testing in GERD

In the early 1980s, physiologic studies of esophageal function were performed with cumbersome polygraphs with water perfused catheters that provided line tracings of pressure measurements. pH studies were performed with transnasal electrodes and ambulatory recordings were possible for 24 h [42]. Developments in technology, microprocessors, and electronics led to a new wave of instrumentation and diagnostics that made physiologic testing easier. A major development was an international consensus on diagnostic testing in reflux disease [43] (Tables 1, 2).

pH Testing and pH Impedance Testing

Measurements of acid reflux into the esophagus were revolutionized by a small California Company (Endonetics) that developed a catheter-free pH sensor with an ingenious fixation device in the esophagus that allowed 48 h continuous and 72 h measurements of distal esophageal pH [44, 45]. This device has made pH testing accessible in clinical practice settings in a way that transnasal catheters never did. A development on pH testing was the addition of impedance sensors to the catheter to detect liquid, gas, or weakly acidic reflux. In addition to pH monitoring, catheters with a series of impedance electrodes were developed. The pH electrode characterizes acid-related reflux events while the impedance electrodes detect liquid, gas, or mixed reflux episodes [46, 47]. The technique added knowledge about different types of reflux but has limited availability in clinical practice.

High-Resolution Manometry and Endoluminal Impedance

High-resolution esophageal manometry uses catheters with multiple pressure sensors along its length. This in effect creates a continuous measurement of pressure along the length of the esophagus. When the pressure measurements are converted to color topographic plots, the pressure characteristics of the entire esophagus and sphincter can be evaluated, and pattern recognition of motility disorders can be performed [48]. A Endoluminal functional lumen imaging probe has also developed that can evaluate esophageal motility. In the context of reflux disease, these devices have an important role in the assessment of patients before surgery and patients who have complications after surgery [49].

High-Resolution Endoscopy and Narrow-Band Imaging

High-resolution endoscopy and narrow-band imaging endoscopes developed in the last 2 decades have increased visualization of small erosions and enhanced mucosal imaging making both the endoscopic diagnosis of GERD and demonstration of healing more reliable [50].

Regulatory Oversight of Trials

Forty years ago, clinical trials in reflux disease evaluated mucosal healing by endoscopy and symptoms were assessed by the physician by patient interview [51]. While the focus on healing remains in regulatory trials of erosive esophagitis, major changes have taken place in the assessment of symptoms in patients with erosive esophagitis and patients with nonerosive reflux disease. Regulatory agencies now require a direct report of symptoms from the patient rather than interpretations by a nurse or physician. This created a large output of work on patient reported outcomes in reflux disease and increased our understanding of symptom measurement and the perspective of the patient [52]. Simultaneously the arrival of cellular technology made it possible to improve the accuracy of symptom assessment that could be performed daily or twice daily removing the errors caused by recall bias. A consensus on methodology for trials in reflux disease was reached and still forms the basis for clinical trials [53] (Tables 1, 2; Fig. 1).

Pharmacotherapy for Reflux Disease

In the early 1980s, prokinetic drugs, H2 receptor antagonists alginates and antacids were the treatment modalities combined with lifestyle modifications. The approval of omeprazole in Europe in 1989 and in the USA in 1990 was a watershed moment in the management of reflux disease. Trials comparing omeprazole to H2 receptor antagonists and cisapride both in initial treatment and also in maintenance therapy demonstrated the superiority of proton pump inhibitors in the management of reflux disease [54, 55]. A series of additional proton-pump inhibitors followed designed to improve potency or increase the duration of action [56, 57]. Potassium competitive acid inhibitors are a new class of acid inhibitors. They block the K+, H+-ATPase K+ channel, are not affected by food ingestion and therefore do not need to be timed with a meal [58]. They have a rapid onset of action and have a long consistent elevation of intragastric pH. Trials in Asia and the USA suggest that vonoprazan may be of benefit in patients with severe grades of esophagitis, but the benefit on symptom improvement is less clear [59, 60] (Tables 1, 2).

Safety and Toxicity

Cisapride is a serotonin 5-HT4 agonist that stimulates the release of acetylcholine from postsynaptic neurons in the gastrointestinal tract stimulating gastric emptying and augmenting lower esophageal sphincter tone that was approved by the FDA for nocturnal heartburn and was used in the early 1980s in combination with H2 receptor antagonists and proton-pump inhibitors for the treatment of GERD [61]. The drug was shown to cause QT prolongation and ventricular arrhythmias and initially had a boxed warning regarding interactions with other drugs but was eventually withdrawn worldwide. Concern regarding the long-term use of proton-pump inhibitors gained intensity over the last decade and a number of potential side effects have been suggested based on observational studies with considerable risk of residual confounding [62]. Randomized controlled trials have not confirmed these observational studies [63]. A major change over the past 15 years has been the strategy to de-escalate and minimize the long-term use of PPI therapy in patients who do not need it [64].

Endoscopic Treatments for GERD

Endoscopic treatment for GERD consists of three devices: Stretta for radiofrequency therapy Esophyx-Z® for Transoral Incisionless Fundoplication (TIF), and overstitch for endoscopic suturing [65]. In the Stretta procedure, radiofrequency energy is applied to the muscle layer of the lower esophageal sphincter and the gastric cardia by four needle electrodes that are mounted on a balloon catheter. It results in an improvement of reflux symptoms, but its mechanism is unknown. Transesophageal incisionless fundoplication is currently in its second generation and is designed to mimic a fundoplication with serosa-to-serosa plications using fasteners to create a functional sphincter up to 3 cm in length. A meta-analysis of randomized controlled trials demonstrated that TIF subjects at 3 years had improved esophageal pH, a decrease in PPI utilization, and improved quality of life [66]. Endoscopic suturing devices are designed to place sutures in the proximal stomach to reduce reflux. To improve and preserve tissue apposition with the sutures, mucosal ablation with argon plasma coagulation is combined with suturing or with mucosal resection with suturing [62]. Crescentic mucosal resection of the proximal gastric mucosa may also be an effective technique [67]. The body of evidence for these procedures is smaller than for the TIF procedure (Tables 1, 2).

Surgical Treatment

Laparoscopic fundoplication became very popular during the period of this survey and replaced open fundoplication. Early results in community settings were poor with significant adverse outcomes [68]. A long-term study compared esomeprazole treatment to laparoscopic fundoplication in a randomized controlled trial and found the results of both treatments to be similar [69]. A recent study addressed the growing group of patients who present with heartburn refractory to PPI therapy and found that only a minority of these patients had heartburn related to reflux and those that did benefited from surgery [70] (Tables 1, 2).

Magnetic Sphincter Augmentation

The magnetic sphincter is a small device made of interlinked titanium beads with magnetic cores placed laparoscopically around the lower esophageal sphincter [71]. The magnetic attraction between the beads increases the existing LES barrier function to prevent reflux. Reflux is a low-pressure event and the magnets are able to prevent reflux from taking place while allowing food, propelled by more vigorous contractions to traverse the sphincter. A meta-analysis of 3 trials found this technique to be comparable to surgery [72].

Electrical Stimulation of the Lower Esophageal Sphincter

Electrical stimulation of the lower esophageal sphincter using surgically implanted electrodes has been approved for patients with symptoms refractory to medical therapy and has been successful in cohort studies up to 3 years [73].

Promising Treatments that Failed to Achieve Success or Were Withdrawn

Baclofen

Baclofen, a gamma-aminobutyric acid receptor agonist, has been shown to reduce the episodes of gastroesophageal reflux (GER) by reducing the incidence of transient lower esophageal sphincter relaxations. Its use was limited by side effects and the lack of robust scientific data until a placebo-controlled randomized controlled trial failed to show significant benefit in heartburn relief compared to placebo [74].

Lesogaberan

Lesogaberan was a novel γ-aminobutyric acid B-type receptor agonist. It was also inhibiting transient lower esophageal sphincter relaxations and was tested in patients with GERD who had an incomplete response to PPI therapy. It failed to show significant benefit over placebo, and its development was halted.

Vanilloid Receptor Antagonists

The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is a receptor activated by high temperatures and chemical agonists such as the vanilloids and protons. Antagonists of the transient receptor potential vanilloid 1 (TRPV1) were postulated as a treatment for GERD by decreasing the sensitivity of the esophageal mucosa to protons. Initial studies showed promise, but subsequent studies failed to show benefit over placebo and development of this class was halted [75].

Tegaserod

Tegaserod a partial 5HT-4 agonist showed promise in reducing postprandial reflux events [76]. Cisapride, described earlier was a 5HT-4 agonist. Given the history of Cisapride, tegaserod was carefully studied to see if it had effects on the QT interval before being introduced into the market. It was approved for use in constipation predominant IBS in 2002 and was undergoing study for dyspepsia and GERD [77]. The product was withdrawn in 2007 based on post-marketing analysis of earlier clinical trials that showed a higher rate of serious cardiovascular events (including angina, myocardial infarction, and stroke) in patients who took tegaserod compared to placebo [78].

Endoscopic Treatments for GERD: Endocinch and NDO Plicator

The Endocinch was an endoscopic plication device that created mucosal plications that were designed to create pleats at the lower esophageal sphincter. After initial enthusiasm, the sutures tended to separate and the effect of the plication disappeared, and it is no longer in use. The NDO plicator was designed to create full thickness plications and showed efficacy in clinical trials but was withdrawn for unknown reasons.

Endoscopic Treatments: Enteryx and Gatekeeper

Enteryx was an injectable agent that was used to augment the lower esophageal sphincter by mechanical bulking, preventing reflux. It received approval and was in use in the USA when it was withdrawn due to the risk of perforation through the esophagus. The gatekeeper was an implantable inert biogel that also received approval and was in general use. It was designed to restrict the lumen of the distal esophagus. After reports of perforation, pleural effusion the device was withdrawn.

Upper Sphincter Assist Device: Reza Band/Reflux Band

This device also known as an upper esophageal sphincter assist device is a collar with a pressure sensor that is placed around the neck in the region of the upper esophageal sphincter to augment pressure in the UES. It showed some promise in uncontrolled trials and was approved by the FDA [79]. It was initially made available by prescription and then over the counter but has failed to achieve significant success.

The last 40 years have seen remarkable changes in the understanding of reflux disease and its treatment. There have been a number of notable successes particularly in the treatment of erosive esophagitis, but many challenges still remain. Many patients continue to have symptoms despite mucosal healing, esophageal cancer as a consequence of reflux remains a problem despite advances in therapy and the side effects of long-term therapy are still of concern.

We can already recognize disruptive technologies that will change the landscape of GERD in the future. Adaptive artificial intelligence will take over diagnostics in manometry and pH impedance testing and patient-driven outcomes may be changed by interactions with artificial intelligence rather than humans. Changes in chip technology will allow higher resolution chips to be carried on smaller devices making extra-esophageal areas where reflux may play a role more accessible to prolonged observation and testing. Wearable devices and smart phone technology already allow capture of real-time symptoms but will be further developed to enhance compliance, individualize treatment based on the individuals reflux parameters. Genetic and individual profiles will allow targeting of dose and choice of medical treatment.

The authors have no conflicts of interest to declare.

No funding was received for this study.

Nimish Vakil is the sole author and was responsible for the concept, organization writing, and proof reading of this review article.

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