Introduction

Gastroesophageal reflux disease (GERD) is a common clinical condition that can evolve into a debilitating chronic illness and be associated with complications, including the development of esophageal cancer. It is a heterogeneous condition and has been globally classified as an erosive or non-erosive disease¹. It is increasing in prevalence and incidence worldwide (clinically defined as the presence of symptoms and complications, related to the reflux of gastric contents into the esophagus¹-³. GERD is a common disorder that affects the quality of life and is responsible for a high resource expenditure for both patients and payors. In the US, the annual expenditure on diagnosing and treating the disease exceeds 9 billion dollars⁴,⁵. The increasing prevalence and incidence of GERD appear to be closely related to aging, obesity, tobacco use, certain medications such as calcium channel blockers, and tricyclic antidepressants¹-⁵.

GERD can occur in normal individuals without representing disease. Pathologic GERD occurs primarily due to an inappropriate transient relaxation of the lower esophageal sphincter, and this can be further enhanced by the presence of a hiatal hernia which can be associated with LES incompetence, displacement of the acid pocket closer to the esophageal mucosa as well as shortening of the esophagus⁶-⁸. Other contributing factors include a balance of protective factors: adequate saliva production, esophageal elimination of luminal contents, integrity of the natural antireflux barrier, acid clearance from the esophageal lumen, esophageal mucosa resistance to acid, and non-esophageal components such as degree of gastric acidity, volume of regurgitant and, in specific instances, duodenal contents⁶-⁸.

The mainstay of treatment of GERD is symptom relief and resolution and prevention of complications. A multimodal approach is needed in all patients. The management is always started with medical therapy, including pharmacologic and non-pharmacologic interventions. Endoscopic and surgical treatments aim to improve or normalize the mechanical component of GERD. Independent of what intervention is carried out; patients require lifestyle changes including dietary habits, avoiding eating late at night or lying recumbent soon after eating, prandial postural modifications, weight loss, and tobacco abstinence. The use of proton pump inhibitors and potassium channel modifiers is the first line. Acid suppression with Proton pump inhibitor (PPI) is quite effective and easy to follow, with very good response and efficacy and limited adverse events⁹. There are patients that appear to develop a less effective response overtime and may respond to either a different PPI or changing to a potassium channel modifier. Best responders include patients with typical symptoms of GERD, whereas those with more visceral or functional components and those with extraesophageal symptoms do not fare so well. There is increased awareness in the public for potential PPI-related long-term side effects that prefer an alternative therapy. There is a sub-group of patients (approximately 40%) that may not have an appropriate response to adequate dosing and duration of therapy with PPI and are classified as refractory GERD¹⁰,¹¹.

In surgical anti-reflux procedures, main objectives include increasing the LES basal pressure, repair of the hiatal hernia, fixation the LES to the hiatus, augmentation the intra-abdominal segment of the esophagus, decrease the amount of gastric reflux into the esophagus, and improve esophageal clearance¹²-¹⁴. Usual indications for surgical intervention include patients not responding to appropriate trials of medications, the development of side effects, the concern of long-term use of medications and the unwillingness to do so, contraindications to PPIs, large volume refluxate, or the presence of non-responsive complications such as strictures and Barrett’s esophagus. The most frequent surgical procedures performed include laparoscopic 360° fundoplication (Nissen) and partial fundoplication (Toupet), with an expected efficiency in the 90% range as well as a reduction in the use of medications, in the high 80% range¹²-¹⁴. Short-term outcomes show that approximately 10% of patients do not respond, and that increases to approximately 30% long-term, and a significant number of patients may remain on medications. Because of that, being more invasive, and the possible side effects including inability to belch, vomit, dysphagia, gas bloat, diarrhea, increased flatus, incisional hernia, and need for revision surgeries, an increasing number of patients opt for endoscopic therapies.

Endoscopic correction of GERD is not new, now spanning over 3 decades of various attempts with mixed results. Some of those therapies were designed as a definitive treatment whereas others were conceptualized as a bridge therapy between medications and definitive surgery. The appropriate selection of patients is of paramount importance for endoscopic approaches. An important determinant is the gastroesophageal flap valve (GEFV). Grading of the GEFV is according to Hill´s classification¹⁵: Grade I: fold of tissue tightly surrounds the endoscope; Grade II: fold is prominent but there is intermittently opening and closing around the scope; Grade III: fold is not obvious and the diaphragmatic hiatus is freely open, with no or minimal sliding hiatal hernia visible; Grade IV: fold disappeared, and the diaphragmatic hiatus increased significantly, showing a well-defined sliding hiatal hernia.

Over the years, there have been endoscopic therapies that have now disappeared include the silicon prosthesis¹⁶, endo-plication¹⁷, and injection of bulking agents¹⁸. While success was reported, the long-term results were not favorable, and some were associated with increased morbidity and mortality. Endoscopic therapies now have evolved to include different forms of plication, ablation, tissue removal, and ligation. Ablative therapies include radiofrequency (Stretta), and other thermal therapies (ARMS, ARMA). Ligation therapy includes Peroral endoscopic cardial constriction with band (PECC-B). Plication therapies include MUSE, TIF-1, TIF-2, and GERD-X. Tissue removal includes mucosectomy.

The development of endoscopic techniques has gone from requiring relatively inexpensive devices, easy to use, to requiring expensive add-on devices and technically difficult, to back to less expensive, easy-to-apply techniques that include those used for other purposes in the gastrointestinal tract. While some of these techniques are relatively new, their technical feasibility and familiarity with endoscopists make them very attractive for immediate use. There is also an impetus in combining techniques (ablative and plication) (plication and laparoscopic hiatal hernia repair) considering the various mechanisms of GERD¹⁹ or TIF with laparoscopic HH repair²⁰. The current endoscopic methods also offer benefits as a complementary intervention in reducing PPI intake and improving quality of life, especially since the causes of GERD are so variable. This makes anti-reflux endoscopy not only an alternative to PPIs but also a complementary tool that can reduce their consumption help improve quality of life, and improve the GERD-HRQL score²¹,²².

Offering endoscopic therapy should be carried out equally to offering surgical intervention. At the present time, when appropriately selected, endoscopic therapies have not shown inferiority to surgery, and offer advantages including fewer complications acutely and fewer symptom side effects in the long-term, shorter procedural time, less cost, and, importantly, do not preclude future surgery if needed.

Endoscopic therapies

ARMS and ARMA

ARMS involves mucosectomy of the cardias which then develops a deep scar that strengthens the gastroesophageal junction: this can be performed using endoscopic submucosal dissection and endoscopic mucosal resection techniques. ARMA utilizes a triangular-tipped knife J connected to an electrocautery generator in a spray coagulation mode (Figs. 1A-C). Mucosal ablation is performed around the cardia after the creation of a submucosal cushion with saline and Indigo Carmine in a butterfly shape, leaving two areas of normal mucosa (approximately the width of the endoscope) to avoid stenosis²⁷-³⁶. ARMA can also be used with Argon Plasma Coagulation (Figs. 2A-C) forced mode 100W or spray coagulation 50 W, effect 2. ARMS can be performed in a 180° and 270° fashion, both showing a significant improvement in the GERD-Q and decreased use of medications at 6 and 12 months. The overall safety profile is excellent for both ARMS and ARMA, with side effects perhaps being more common with 270° ARMS, and mostly related to dysphagia from stricture formation. While the initial observation of reduction in GERD symptoms after mucosectomy for Barrett’s esophagus was noted, the mechanism of action is not well known but may relate to suppression of backflow of gastric content, enhancement of the GEJ flap valve, increasing the integrated relaxation pressure and LES resting pressure and reduction of GEJ distensibility.

Figure 1 A: endoscopic retrograde appearance of the cardias showing a hiatal hernia and a cap on the endoscope. B: the endoscopic image of the area ablated to the side of the cardias. C: endoscopic view of the ablated area by the cardias. 

Figure 2 A: endoscopic retrograde appearance of the cardias showing a hiatal hernia. B: the endoscopic image of the area ablated to the side of the cardias with Argon plasma coagulator. C: endoscopic view of the ablated area by the cardias. 

Both ARMS and ARMA, especially the latter, offer technical simplicity, do not require costly add-on devices, and can be performed in a standard endoscopy room. While the procedure is not standardized, most authors do not involve the esophageal mucosa, only the gastric cardia and spare 1 cm of normal mucosa along the greater and lesser curvature.

There have been multiple non-randomized studies with varying follow-up from 2 months to 3 years²⁸-³⁴. The clinical success varies from 60 to 100% in the short term (< 6 months) and around 75% at 3 years. The overall safety of the procedure has been high. The most common adverse event has been dysphagia (5-10%). Perforation has been the most severe adverse event (ARMS only) occurring in <2% of patients. Chest pain, odynophagia, and epigastric pain have also been reported. All studies have reported statistically significant improvement in the GERD-HRQL scores, median Hill flap grade, and pH median DeMeester score.

This procedure, especially ARMA, is very attractive considering its simplicity, familiarity with the technology, time and cost of procedure, safety, and efficacy. While randomized studies are lacking, it is a very promising technique.

Aplication

Medigus ultrasonic surgical endostapler (MUSE), Medigus, Omer, Israel is a transoral fundoplication using a video-guided surgical stapler³⁷-³⁹. It combines visual, ultrasonic, and surgical stapling capabilities into one device, which enables a single endoscopist to perform a transoral anterior fundoplication. This flexible surgical endostapler resembles an endoscope with a rigid section holding a cartridge with five standard 4.8-mm titanium surgical staples. The distal tip contains an anvil for bending the staples, two small 21-gauge screws, and an ultrasonic transducer to measure the distance to the cartridge. MUSE is a three-step procedure that includes: (1) Advancing the device into the stomach through an overtube and retroflex; (2) Retraction of the device to 3 cm proximal to the GEJ for clamping when the tissue thickness measurement reaches 1.4-1.6 mm and actuating the stapler; and (3) The procedure is repeated 5 times to create an anti-reflux barrier. The results of various prospective studies have been compared favorably with Stretta and TIF-2 (see below). Overall patients report symptomatic improvement and reduction of PPI use. Long-term follow-up includes data to 5 years. Significant improvement in GERD-HRQL score and reduction in the number of patients taking PPIs daily, 69-92% and 64%, respectively, have been reported. Limited functional analysis of the impact on pH monitoring has been positive for reduction in acid exposure. The safety profile of the device is robust, with reported complications including gastrointestinal bleeding, perforation, pneumothorax, and empyema, all < 3%. Most studies have included patients with GERD with a hiatal hernia < 3 cm.

TIF involves the use of EsophyX EndoGastric Solutions, Inc., Redmond, WA, United States. The EsophyX is a device inserted through the mouth and positioned in the esophagus and stomach and creates folds of tissue held together by plications, creating a mechanical antireflux barrier. The device has evolved, along with the technique, in creating circumferential plications rather than longitudinal. The circumferential plication encompasses 200° to 300° in circumference and ~3-cm length wrap over the distal esophagus below the diaphragm to create full-thickness plications. The current version of EsophyX is easier to use and more automated with a result that mimics a Toupet surgical fundoplication (Figs. 3A-C)⁴⁰-⁴².

Figure 3 A: endoscopic retrograde appearance of the cardias showing a hiatal hernia and a cap on the endoscope. B: endoscopic view showing TIF-2 device plicating. C: endoscopic view of a completed TIF-2 plication. 

Best candidates for TIF are patients with a Hill Grade II LES incompetence without a concomitant HH. Patients with a hiatal hernia > 2 cm and a Hill grade 3-4 can be treated with concomitant hernia repair and TIF. Most studies, randomized and non-randomized, have included patients with small to no hiatal hernia, absent severe erosive disease, or Barrett’s epithelium. Rates of success range from 50% at 1 year to 92% at 10 years. Overall, improvement in GERD-HRQL score, reduction in heartburn and regurgitation is observed in ~70% of patients, and a reduction in PPI use of approximately 63% at 1 year. Studies randomized to TIF versus sham have included responses up to a year, with a primary endpoint being an equal or > 50% reduction in GERD-HRQL. Data at 5 years have shown improvement in 80-86% of patients. Performing a combined endoscopic plication with TIF and laparoscopic fundoplication may provide a greater insight into the most desired intervention and actional mechanisms⁴³.

Acid measurement and lowering of acid reflux episodes have been documented at 3 months but not at a year follow-up point. Adverse events are uncommon, occurring in < 3%. TIF has been favorably compared to antireflux surgery in reducing symptoms and decreasing PPI use with a better safety profile and fewer adverse events long-term.

GERDx (G-SURG GmbH, Seeon–Seebruck, Germany) involves performing a full-thickness plication with the GERDx system, which creates a plication with a pretied transmural suture. It uses hydraulic elements for control and requires a slim gastroscope that works as a light source. Symptomatic improvement is achieved in 93.3% of patients and 63% were able to discontinue PPI⁴⁴. However, almost 20% required surgical anti-reflux procedures at 3 months. Improvement in DeMeester score was reduced with ~60.0%) achieving normal levels. Reduction in PPI use was reported with most being on demand or off medication, ~80%. The complication rate is around 10%, including a suture passing through the left hepatic lobe, GE junction hematoma, a Mallory–Weiss tear, and empyema.

Ligation

PECC-B ligation involves ligating GEJ mucosa with a band⁴⁵,⁴⁶. After a routine esophagogastroduodenoscopy is performed, the endoscope is then loaded with a standard ligating device advanced to the gastric fundus, and retroflexed. The mucosa around the cardia opening of the gastric fundus is suctioned and a ligation is performed. This is repeated up to 4 times, depending on the degree of cardial incompetence. The first band is placed ~ 1 cm above the cardia along the lesser curvature and the second band is ~ 1 cm above the greater curvature. A clip may be placed at the base of the bands to minimize the risk of band slippage. This procedure can be performed in patients with all Hill grades. Statistically significant reduction in the GERD-Q scores at 1, 3, 6, and 12 months was statistically significantly decreased, with apparent better results in patients with Hill Type III. Randomized controlled trials of patients with refractory GERD have shown significant improvement in GERD-HRQL score and the number of reflux episodes at 1 year. The overall safety profile of the technique is good, with only minor side effects reported, including transient dysphagia and epigastric pain, in 25% and 40%, respectively. Overall, data are limited and lack proper follow-up and randomization. Advantages include simplicity of technique, use of familiar equipment and devices, safe profile, and reported efficacy.

Conclusion

GERD is a complex and chronic condition. Symptoms can be caused by multiple factors and not necessarily only from reflux of gastric contents. The management should be multimodal, always starting with the least invasive and effective treatment, medical. For patients with an inappropriate response or those not wanting to take long-term medications, endoscopic and surgical interventions are warranted. The selection of patients is important to determine the most appropriate therapeutic route. Endoscopic therapies have evolved to include easier techniques, simpler, widely available, effective, and safe, that do not require cumbersome add-on devices. Independent of technique, the clinical success, and reduction of medication intake are similar across all techniques. The appropriate selection will be made after a thorough discussion with the patient.