Gastroesophageal Reflux Disease (GERD)

Etiology

Gastroesophageal Anatomy

Anatomical structures regulate esophageal function and minimize gastroesophageal reflux. A complex valvular mechanism at the esophagogastric junction antagonizes positive abdominal pressure and negative thoracic pressure. This anatomical mechanism comprises the following structures:

• Lower esophageal sphincter: This physiological sphincter measures 3 to 5 cm long. The high resting tone of the smooth muscle in the lower esophageal sphincter prevents regurgitation of gastric contents into the esophagus.
• Diaphragm: The esophagus enters the abdominal cavity through the diaphragmatic hiatus. The diaphragm provides extrinsic reinforcement to the lower esophageal sphincter.
• Abdominal portion of the esophagus: This esophageal segment is exposed to positive intra-abdominal pressure and collapses without a bolus. This collapse provides further support to the lower esophageal sphincter.
• The angle of His: This is the acute angle between the esophagus and the gastric fundus, which enhances the function of the lower esophageal sphincter.
• Phrenoesophageal membrane: This is a fibroelastic ligament that continues the transversalis fascia, which leaves the diaphragm and surrounds the esophagus.[9]

Gastroesophageal Physiological Mechanisms

Physiological mechanisms also protect against gastroesophageal reflux, including:

• Esophageal motility: Esophageal peristalsis promotes the return of regurgitated acid to the stomach.[10]
• Saliva production: Swallowed saliva contains bicarbonate and is slightly alkaline; salivary mucins also act as lubricants.
• Esophageal epithelial protection: Esophageal submucosal glands also secrete bicarbonate and mucin to protect the distal esophageal mucosa from acidic stomach contents.

Etiologies of Gastroesophageal Reflux Disease

The reflux of gastric contents into the esophagus in healthy individuals is limited, and the refluxed contents are cleared through esophageal peristalsis. However, patients with GERD cannot clear these refluxed contents adequately or produce protective physiological mechanisms. Some of the underlying etiologies of GERD include:

• Transient relaxation of the lower esophageal sphincter or a low resting lower esophageal sphincter pressure [11]
• Hiatus hernia
• Extrinsically increased intra-abdominal pressure, as in obesity [12]
• Intrinsically increased intra-abdominal pressure, as observed during pregnancy or in patients with high-volume ascites
• Impaired esophageal motility
• Impaired saliva production 
• Impaired esophageal mucosal defense mechanisms [12] 

Gastroesophageal Reflux Disease Risk Factors 

Additionally, certain individuals are at an increased risk of developing GERD. These risk factors include:

• Male sex [12]
• White ethnicity
• Age 50 or older
• Tobacco use [12]
• Alcohol consumption [12]
• Delayed gastric emptying
• Metabolic dysfunction-associated steatohepatitis (MASH) [13]
• Chronically decreased thoracic pressure
• Use of aspirin and other non-steroidal anti-inflammatory drugs [14]
• Use of drugs that reduce the lower esophageal sphincter pressure, including nitrates, calcium channel blocker agents, anticholinergics, α-adrenergic agonists, theophylline, and morphine
• Anxiety and depression, although the relationship with GERD may be bidirectional [15]

Epidemiology

Geographical variations are present in the distribution of the diagnosis of GERD. In Western countries, the prevalence of the disease is approximately 10% to 20%, and severe disease is observed in 6% of the population. In Asian countries, the prevalence is approximately 5%.[16][17] GERD is equally prevalent among men and women.[18] However, the predominance of Barrett esophagitis is notably higher in men than women, with a ratio of approximately 3:1.[19] The results of some studies report a higher frequency of reflux esophagitis in men, whereas others report an increased frequency in women.[20][14] The incidence of reflux esophagitis is greatest in individuals aged 60 to 70 and slightly decreases thereafter. Like its prevalence in adults, GERD is also increasingly observed in the pediatric population. Nelson et al reported an incidence of GERD ranging from 12% to 50% in children aged 0 to 18 between 2000 and 2005.[21] Gastroesophageal reflux exists universally in preterm infants.[22]

Genetic variations, environmental factors, and lifestyle all contribute to the development of esophageal reflux. During pregnancy, approximately half of women experience reflux. The prevalence of GERD increases throughout pregnancy, affecting 20% to 30% of women in the first trimester, 40% to 45% in the second trimester, and 60% in the third trimester.[23] Reflux esophagitis and Barrett esophagus are associated with higher body mass index. The association of GERD with overweight patients has an odds ratio of 1.33 and 95% confidence intervals of 1.07 to 1.64; the association with obese individuals has an odds ratio of 1.70 and a 95% confidence interval of 1.36 to 2.12.[24]

Pathophysiology

The following pathophysiological mechanisms underlying GERD are related to the etiological causes:

• Transient lower esophageal sphincter relaxation (TRLES): This change results in regurgitation of the gastric acid, peptic enzymes, and bile acids into the esophagus. The effect is enhanced in patients with increased intra-abdominal pressure, such as patients with ascites and pregnant women. TRLES is the most common mechanism explaining reflux in normal individuals and those with GERD.

• Hiatal hernia: A hiatal hernia disturbs the anatomical relationship between the crural diaphragm and the lower esophageal sphincter function. Also, hernias can act as a reservoir for gastric contents, which can reflux into the esophagus when the lower esophageal sphincter relaxes during swallowing.

• Increased intra-abdominal fat: This change increases the gastroesophageal pressure gradient and the frequency of the TRLES phase, leading to the reflux of gastric content into the esophagus.

• Impaired physiological defense mechanisms: Dysregulation of esophageal peristalsis could lead to ineffective clearance of acids from the lower esophagus.

• Impaired saliva production: The process of neutralizing the acids refluxed into the esophagus decreases.

• Impaired esophageal mural defense mechanisms 
  • A compromised pre-epithelial barrier comprises an unstirred water layer combined with bicarbonate from swallowed saliva and the secretion of submucous glands.
  • Impaired epithelial defense mechanisms typically include tight intercellular junctions, cellular and intercellular buffers, and cell membrane transport proteins.
  • Reduced blood supply to the esophagus and other postepithelial lines of defense [25]

Additionally, the pathogenesis of GERD and the development of complications (eg, Barrett esophagus) are mediated by cytokines rather than the result of chemical injury.[26] Reflux esophagitis activates hypoxia-inducible factor (HIF) 2 alpha and nuclear factor kappa-light-chain-enhancer of activated B cells, leading to increased levels of pro-inflammatory cytokines, the migration of inflammatory cells, particularly T cells, and damage to the esophagus.[27]

Histopathology

Reflux esophagitis occurs in patients with GERD when toxic substances, including gastric acid, pepsin, and bile salts, come into contact with the esophageal mucosa, resulting in damage to the distal esophageal mucosa and mucosal breaks that can be detected by endoscopy. The histology of GERD is not specific, as the histological changes may also be present in other pathological states, eg, adjacent mucosa in esophageal cancer.[28] The histological changes associated with reflux esophagitis secondary to GERD include:

• Epithelial injury and neutrophilic infiltration of the epithelium
• Changes confined to the mucosa, lamina propria, and muscularis mucosa
• Longstanding and untreated patients may develop chronic inflammation, peptic strictures, and Barrett metaplasia
• Papillae proliferation of basal cells in the distal esophagus
• Dilated intercellular spaces within the squamous epithelium [29][25][29]

In patients with NERD, the most consistent histological finding is dilatation of the intercellular spaces. Basal hyperplasia and papillary elongation may also be present. Eosinophilic infiltration can occur, but is more commonly found in the distal esophagus in patients with NERD, while eosinophilic infiltration is more likely to be found in the proximal esophagus of patients with eosinophilic esophagitis.[30] 

Confocal laser endomicroscopy demonstrates more intrapapillary capillary loops per image in patients with NERD than in control individuals.[31] In addition, the diameter of intrapapillary capillary loops and intercellular spaces is greater in patients with reflux esophagitis compared to that in controls.

History and Physical

Clinical History

The most common symptoms of GERD are heartburn, regurgitation, and chest pain. Heartburn is a burning sensation primarily felt behind the sternum within 60 minutes of eating, typically precipitated by exercising or lying in a recumbent position. The pain commonly starts in the epigastrium and radiates towards the neck. Sour or burning fluid in the throat or mouth typically characterizes acid regurgitation. By increasing intra-abdominal pressure, the Valsalva maneuver may also provoke the regurgitation of gastric acid.[32] 

Dysphagia is reported in 30% of patients with reflux esophagitis associated with peptic strictures, Schatzki rings, weak peristalsis, or mucosal inflammation, including that found in eosinophilic esophagitis, which is often found concurrently with reflux esophagitis. Esophageal food impactions may be due to any of these causes.[33] Other symptoms of GERD can sometimes include a globus sensation or a lump in the throat and water brash, which involves increased salivary secretions in response to the acidity of the esophagus.[34] 

However, without heartburn and acid regurgitation, less common symptoms such as hoarseness, globus, nausea, abdominal pain, and dyspepsia are unlikely due to GERD.[8] Accordingly, diagnostic evaluation should be considered in those individuals with suspected extraesophageal GERD who do not have typical symptoms of GERD.[35] Some patients with severe esophagitis or Barrett esophagus are asymptomatic.

Patients may also present with the following atypical symptoms:

• Chest pain: Esophageal reflux may mimic cardiac pain, and patients should be evaluated to exclude cardiac causes. Other causes of esophageal chest pain, including esophageal motility disorders, eg, achalasia, diffuse esophageal spasm, hypercontractile esophagus (including but not limited to jackhammer esophagus), or hypertensive peristalsis (nutcracker esophagus), may be considered in the evaluation. However, reflux esophagitis is more common than these esophageal motility disorders.
• Chronic cough: GERD may cause a chronic cough, but it should be distinguished from upper respiratory or pulmonary conditions. Chronic cough can also be an adverse effect of certain medications, eg, angiotensin-converting enzyme inhibitors. The underlying pathogenesis of cough in reflux esophagitis can be explained by stimulation of an esophageal-bronchial reflux.[36] Alternatively, chronic cough may be due to pharynx or larynx acid irritation.
• Asthma: An association between asthma and GERD exists. However, whether this relationship is an association or a cause-and-effect change is unclear. However, the underlying relationship could be explained based on autonomic dysregulation that typically occurs in patients with asthma, resulting in an increased vagal tone. This change, together with the increased negative intrathoracic pressure during asthma, could enhance the tendency for reflux. Another contributing factor is medications used to manage asthma, such as theophylline and α-2 adrenergic receptor agonists, which may promote reflux by lowering the pressure across the lower esophageal sphincter.[35]
• Extraesophageal symptoms: Pathological changes secondary to GERD other than esophagitis may be present, including dysphonia (vocal hoarseness), sore throat, and laryngospasm.[37]

Physical Examination

Physical findings are nonspecific, many attributable to extraesophageal manifestations of GERD. Moreover, patients with no abnormal findings related to GERD at physical examination are not unusual. Findings may include epigastric abdominal tenderness, wheezing or rhonchi on a pulmonary exam, pharyngitis or laryngitis on laryngoscopy, and dental erosions.

Evaluation

The diagnosis of GERD is based on clinical features, patient response to a PPI trial regimen, and diagnostic studies.[38] When the presenting symptom is chest pain, cardiac disease must first be excluded before performing gastrointestinal evaluation or planning for a prolonged trial of medication for GERD. Patients with relatively mild symptoms of GERD should be advised to make appropriate lifestyle modifications (Please refer to the Treatment/Management section for more information) and to begin a trial of a standard-dose PPI once daily. However, if alarm symptoms such as dysphagia, odynophagia, significant weight loss, gastrointestinal bleeding, or anorexia are present, diagnostic testing is recommended instead of empiric therapy.

Proton Pump Inhibitor Trial Therapy

Unless alarm symptoms are present, patients should be initiated on empiric therapy with a PPI at either standard or high dose (Please refer to the Treatment/Management section for more information) before the first meal of the day for 8 weeks. A response to treatment supports the diagnosis of GERD.[39] PPIs should then be discontinued in responsive patients after the 8-week trial period. If alarm or atypical symptoms are present, a patient has a suboptimal response to pharmacological treatment, indicating long-term therapy may be required, or the patient does not improve, or symptoms reoccur following an 8-week PPI trial, further diagnostic studies, eg, upper-endoscopy and ambulatory reflux monitoring should be performed to confirm GERD and exclude differential diagnoses according to the International Lyon Consensus.[8][40][38]

Esophageal Manometry

Esophageal manometry is of limited value in the primary diagnosis of GERD. Neither a decrease in lower esophageal sphincter pressure nor the presence of a motility abnormality is specific to the diagnosis of GERD. However, manometry is recommended before antireflux surgery to rule out achalasia or severe dysmotility, as in the scleroderma-like esophagus, where Nissen fundoplication is contraindicated.[41]

Ambulatory Esophageal pH Monitoring

Ambulatory esophageal pH monitoring is the only test that determines abnormal esophageal acid reflux and frequency. Ambulatory pH-impedance monitoring can assess the relationship between symptoms and reflux episodes in patients with PPI-resistant symptoms. This test can help exclude GERD, but the test should be carried out after the cessation of PPI therapy.[42] Medically refractory GERD is increasingly common, and patients often have normal findings on endoscopy evaluation, as PPIs are very effective in healing esophagitis caused by the refluxate. Ambulatory esophageal reflux monitoring is indicated in cases of medically refractory GERD and patients with extraesophageal symptoms suggestive of GERD.[43][44][43] Ambulatory reflux pH with or without impedance monitoring can be done in the following 3 ways:

• A 24-hour transnasal catheter measuring distal esophageal pH
• A 48-hour (or up to 96-hour) wireless pH monitoring, utilizing a small capsule endoscopically pinned to the distal esophageal mucosa. The patient is given a hand-held recording device with which symptoms can be documented and timed. The recorder is returned, and the esophageal pH correlates with the symptoms' recording. If the esophageal pH is lower at the time of 1 or more of these symptoms, this would indicate that the symptoms are due to acid reflux.
• Combined multichannel intrauminal impedance and pH testing (MII-pH) utilizes a 24-hour transnasal catheter. Impedance testing identifies mild acidic reflux that pH monitoring may not diagnose when used alone. Ambulatory esophageal reflux monitoring is the only available test that detects pathological acid exposure, frequency of reflux episodes, and correlation of symptoms with reflux episodes.

Testing is performed off PPI therapy for at least 1 week if the goal is to diagnose reflux as the cause of symptoms, while a high-dose PPI course is continued if the testing is being conducted to look for nonacid reflux by impedance testing or refractory acid reflux.

Esophagogastroduodenoscopy (EGD)

Patients presenting with typical GERD symptoms associated with any of the alarm symptoms or atypical symptoms should be examined with an esophagogastroduodenoscopy (EGD) and, in some cases, with pH monitoring before a PPI trial to rule out complications of GERD. Performing endoscopy may be indicated in high-risk groups, particularly in patients who are overweight, aged 50 and older, or who have had chronic esophageal reflux for >5 years. EGD is also indicated in patients at high risk of complications, including those with Barrett esophagus.[45] 

According to the current ACG guidelines, distal esophageal biopsies are not routinely recommended to diagnose GERD. Patients presenting with noncardiac chest pain that is suspected of being due to GERD should undergo a diagnostic assessment with an esophagogastroduodenoscopy and pH monitoring before initiation of PPIs.[46] Current ACG guidelines recommend against screening for Helicobacter pylori infection in patients with symptoms of GERD. The Los Angeles classification includes the following grades of reflux esophagitis severity with EGD:

• Grade A: ≥1 esophageal mucosal breaks <5 mm long
• Grade B: ≥1 mucosal breaks >5 mm but with continuity across mucosal folds
• Grade C: Continuous mucosal breaks between the tops of ≥2 mucosal folds but involving <75% of the esophageal circumference
• Grade D: Mucosal breaks involving >75% of the esophageal sphincter [47]

Imaging Studies

Radiographic studies, eg, barium radiographs, can detect moderate to severe esophagitis, esophageal strictures, hiatus hernia, and tumors. However, their role in evaluating uncomplicated reflux is limited.[48] The presence or absence of reflux during barium esophagography does not correlate with the incidence or extent of reflux observed during 24-hour pH impedance monitoring; therefore, barium studies do not help diagnose GERD.[49]

Treatment / Management

In patients with minimal to moderate symptoms of GERD, management typically involves implementing lifestyle modifications and PPI therapy with additional pharmacologic treatment when indicated. Patients with severe GERD or those who do not respond to initial strategies may require long-term treatment or invasive procedures such as laparoscopic fundoplication or magnetic sphincter augmentation.[38](B3)

LIFESTYLE MODIFICATIONS

Lifestyle modifications are considered the cornerstone of any therapy for patients with GERD. Counseling should be provided about the importance of weight loss, given that underlying obesity is a significant risk factor for the development of GERD, and studies have shown that weight gain in individuals with a normal body mass index has been associated with the development of symptoms.[50] Patients should also be counseled to avoid meals at least 3 hours before bedtime and to maintain good sleep hygiene, as minimal sleep disturbances are associated with decreased reflux episodes.[51][52] Studies have also shown improvements in symptoms of GERD and pH monitoring studies with elevating the head of the bed. Therefore, patients with GERD should be counseled to implement the following changes: (B2)

• Lose excessive weight to reduce the severity and frequency of symptoms. Even a small amount of weight loss can improve symptoms.
• Elevate the head of the bed during sleep and avoid eating 2 to 3 hours before bedtime to reduce nighttime reflux.
• Avoid trigger foods and beverages, eg, chocolate, caffeine, alcohol, and spicy foods.
• Avoid tobacco products and smoking[53][54] 
(B2)

PHARMACOLOGICAL THERAPY

Medications used to treat GERD include antacids that neutralize gastric acid, as well as several classes of drugs that reduce gastric acid production: Histamine-2-receptor antagonists (H₂RA), PPIs, and potassium-competitive acid blockers (P-CAB). Antacids are used on an as-needed basis to treat symptoms of dyspepsia or reflux, including heartburn.

Histamine type 2 receptor antagonists

H2RAs currently available over-the-counter include famotidine and cimetidine. The other commonly used H₂RAs, ranitidine and nizatidine, were withdrawn from the market due to NDMA (N-nitrosodimethylamine), a probable carcinogen, being found in some samples of these drugs.[55] Based on multiple large-scale studies, PPI therapy is considered the most effective for both erosive and nonerosive GERD. The results of these studies have also shown improved symptom control, healing of underlying esophagitis, and decreased relapse rates compared to H₂RAs.[56][57] If needed, bedtime administration of H₂RAs is recommended for patients with nighttime symptoms that are not optimized with maximum PPI therapy.[48](A1)

Proton pump inhibitors

Omeprazole was the first PPI to be approved in the US in 1989 after being used successfully in Europe for many years, and the PPIs as a class (also including lansoprazole, pantoprazole, rabeprazole, esomeprazole, omeprazole-sodium bicarbonate, and dexlansoprazole) are the recommended medication for the treatment and maintenance of erosive esophagitis.[41] PPIs irreversibly block the exchange of protons and potassium cations on proton pumps in parietal cells of the stomach. They have a half-life of approximately 1 to 2 hours and are converted to sulfonamides in the presence of acid.[38](B3)

Patients with suspected GERD or documented LA Grade A or B reflux esophagitis should first be treated with a daily PPI dose for 8 to 12 weeks, taken 30 minutes to 1 hour before the day's first meal (see Table. Standard and High Doses of Proton Pump Inhibitors). This timing has proven most effective because PPIs only bind to proton pumps secreting acid, and meals promote acid secretion.[38] If a partial response is elicited, the dose can be increased to twice the initial dose once daily, or the initial dose should be taken twice daily, before breakfast and dinner. PPIs should be administered at the lowest effective dose to control symptoms of GERD and maintain the healing of reflux esophagitis.(B3)

Adverse effects are unusual and minor, but they are consistent for all PPIs in a particular patient. Patients with mild or no esophagitis (or those who were not endoscoped before treatment) whose symptoms have resolved should discontinue the PPI. All patients who require maintenance PPI therapy should be treated with the lowest effective dose in terms of controlling symptoms and maintaining resolution of esophagitis. Those individuals with severe reflux esophagitis (LA Grades C and D) or who have Barrett esophagus or concurrent eosinophilic esophagitis require long-term maintenance PPI therapy.[41] 

Chronic use of PPI drugs has been associated with a long list of potential complications, but high-quality studies have shown that none of these occur with any significant frequency except for intestinal infections. These infections include Clostridioides difficile, norovirus, other viral causes of gastroenteritis, and some multidrug-resistant bacteria. The risk is increased due to the acid suppression effect on the microbiome.[38] Deficiencies of vitamins D and B12, calcium, magnesium, and iron may be theoretically associated with the need for gastric acid to be present for proper absorption. Other reported complications include pneumonia, gastric cancer, bone fractures related to osteoporosis, dementia, renal disease, heart attacks, strokes, and early death. Studies examining the risks of these complications are not considered definitive and fail to demonstrate a cause-and-effect relationship between PPIs and these conditions. Experts have obtained a consensus that the benefits of PPI drugs substantially outweigh these potential risks.[58](B3)

Table. Standard and High Doses of Proton Pump Inhibitors (PPIs)

 * - The relative potency of standard dose PPIs compared to omeprazole 20 mg is based on the % of 24 hours that the gastric pH is > 4.[60]

** - Relative potency of once-daily dose of dexlansoprazole compared to twice-daily doses of the other PPIs (Med Lett Drugs Ther. 2022 May 16;64(1650):79-80.

Symptoms should be reassessed after a 4- to 8-week trial of PPI. For patients with Los Angeles grade C or D esophagitis (Please refer to the Evaluation section for more information), continued maintenance of PPI therapy is recommended, with antireflux surgery being an alternative. Options for those patients who don't tolerate or fail to respond to PPIs include:

• Evaluation for other diagnoses such as eosinophilic esophagitis, achalasia, other esophageal motility disturbances, delayed gastric emptying, nonulcer dyspepsia, and psychological disorders
• Increasing the dose of the same PPI from standard to high dose (see Table. Standard and High Doses of Proton Pump Inhibitors)
• Switching to a different PPI that is either more potent[60], less metabolized through the CYP2C19 pathway (eg, rabeprazole or esomeprazole), or to dexlansoprazole, which is a delayed-release formulation
• Adding an evening dose of an H2RA to once or twice daily use of the PPI
• Switching to a potassium-competitive acid blocker (P-CAB) such as vonoprazan

Potassium-competitive acid blockers

The newest class of medications for GERD is the potassium-competitive acid blockers (P-CABs), which may provide a more potent means of suppressing gastric acid production. These drugs reversibly prevent potassium from binding to H+/K+ ATP-ase proton pumps, stopping gastric acid production. Moreover, 7 medications of this type have been developed, and vonoprazan was the first approved by the US FDA in late 2023. Revaprazan has been approved for clinical use in South Korea since 2006. Tegoprazan is marketed in South Korea, China, and other parts of Asia, as well as in Central America and South America. Tegoprazan is now in phase 3 trials in the US. The P-CABs are acid-stable and have a much longer half-life than the PPIs, so they can be taken at any time during the day, regardless of meal times.

Vonoprazan is available in 10 mg and 20 mg oral tablets. The higher dose is prescribed to treat acid-induced erosive esophagitis, and the lower dose is used for maintaining a healed esophagitis. Vonoprazan is currently recommended as a second-line treatment for patients with documented acid-related reflux who have failed to respond to high-dose PPI therapy. This agent is an option for the healing and maintenance of severe erosive esophagitis (Los Angeles grades C and D); however, vonoprazan has not been proven in a randomized trial against high-dose PPIs to be superior to and is much more expensive than PPI therapy, so this medication is not routinely used as first-line therapy in this setting.[61] Vonoprazan and lansoprazole were compared in a 5-year prospective maintenance trial in over 200 patients with healed erosive esophagitis in Japan. Because both PPIs and P-CABs suppress acid production, they cause hypergastrinemia and elevated chromogranin A levels, both of which are shown to be greater with vonoprazan than with lansoprazole. However, no patient in either group developed a malignant alteration of gastric epithelial cells. Other adverse effects with P-CABs were similar to those with PPIs and were similarly rare. This study showed good safety profiles for both drugs over 5 years.[62](A1)

Other medications

Baclofen has been found to decrease the number of postprandial acid reflux episodes by reducing TLESRs; however, its benefit when added to a PPI in refractory GERD is marginal at best.[62] Prokinetic agents, eg, metoclopramide and domperidone, are not recommended for the treatment of GERD unless gastroparesis is a concurrent problem, due to the risk of tardive dyskinesia and other neurologic adverse effects with metoclopramide and prolongation of the Q-Tc interval with both prokinetic drugs.[41] Domperidone is not approved by the FDA for use in the United States. Sucralfate is only recommended for GERD treatment during pregnancy and is comparably effective when compared to H2RAs. However, sucralfate has not been compared to PPIs or studied in combination with any of these drugs.(A1)

ENDOSCOPIC AND SURGICAL THERAPY

Patients who have medically refractory GERD, noncompliance or adverse effects with medical therapy, a large hiatus hernia, or who do not wish to discontinue long-term medical treatment should be considered for endoscopic or surgical management. The available surgical options for GERD are laparoscopic Nissen fundoplication, laparoscopic anterior 180° fundoplication, and bariatric surgery for obese patients. Laparoscopic Nissen fundoplication has been the gold standard surgical treatment for managing GERD. However, given the high prevalence of obesity in the United States, gastric bypass surgery is being performed much more frequently for GERD than in the past. Gastric bypass may be considered in patients who are obese with symptoms of GERD who prefer surgical therapy.[51] 

Current ACG guidelines recommend performing preoperative ambulatory pH monitoring in patients without erosive esophagitis and esophageal manometry to rule out achalasia or undiagnosed scleroderma-like esophagus before surgical therapy. Two large meta-analyses comparing medical treatment with surgical treatment reported contradictory conclusions. One found improvement in symptoms of GERD after surgery compared to medical treatment, while the other reported considerable uncertainty in the benefits of surgical treatment compared to medical treatment.[63](A1)

However, patients undergoing fundoplication are at risk for developing postoperative adverse events that include bloating, which is observed in 15% to 20% of patients, dysphagia, and belching. Roux-en-Y gastric bypass is the most effective operation when GERD is an additional indication for bariatric surgery.[15] Studies have shown that weight loss resulting from the surgical management of obesity has a positive impact on patients with GERD.

Several types of minimally invasive endoscopic and surgical techniques have been developed for managing GERD, including:

• The Stretta endoscopic procedure: A catheter with 4 needles is endoscopically placed at the level of the lower esophageal sphincter. A balloon is inflated within the catheter, allowing the needles to break through the mucosal barrier. Then, radiofrequency is applied through the needles. This results in an increase in LES pressure and a reduction in TLESRs, which improves symptoms of GERD. Stretta is used for patients with refractory GERD who have Los Angeles grade A or B esophagitis and normal esophageal peristalsis and LES relaxation, as determined by manometric evaluation. They should not have a hiatal hernia larger than 2 cm or long-segment Barrett esophagus.[48]

• Magnetic sphincter augmentation: A laparoscopic operation in which an approximately 2.5 cm titanium ring of metallic beads is permanently placed around the LES that allows most foods to pass into the stomach freely, but significantly reduces gastroesophageal reflux.[64] A meta-analysis comparing Nissen fundoplication and magnetic sphincter augmentation concluded that the procedure was effective for GERD.[48]

• Transoral incisionless fundoplication: This procedure is indicated for patients with refractory mild to moderate esophagitis (LA grades A or B) who experience problematic heartburn or regurgitation, do not have a hiatal hernia >2 cm, and do not wish to undergo traditional antireflux surgery. A recent meta-analysis showed that subjects who underwent the transoral incisionless fundoplication procedure experienced improved esophageal pH, a decreased need for PPIs, and significantly improved quality of life 3 years after the procedure.[65] Another prospective study by Testoni et al demonstrated transoral incisionless fundoplication as an effective long-term treatment option for patients with symptomatic GERD with associated hiatus hernias <2 cm. A meta-analysis comparing Nissen fundoplication and magnetic sphincter augmentation, which included data from 688 patients who underwent magnetic sphincter augmentation and the rest who were treated with Nissen fundoplication, concluded that the procedure was effective for GERD.[66]
(A1)

Differential Diagnosis

The differential diagnoses of GERD include coronary artery disease, infectious esophagitis, eosinophilic esophagitis, radiation- and chemotherapy-induced esophagitis, esophageal motility disorders, benign esophageal strictures, esophageal cancer, peptic ulcer disease, nonulcer dyspepsia, gastroparesis, gastric cancer, rumination, and biliary colic.[67]

Prognosis

The majority of patients with GERD have a good prognosis with medications, but relapse after ceasing medical treatment is common and indicates the need for long-term maintenance therapy. In refractory cases or when complications related to GERD, eg, stricture, aspiration, airway disease, and Barrett esophagus, are identified, surgical or endoscopic therapeutic intervention is typically necessary. The prognosis with these interventions is considered excellent.

Surgical morbidity and mortality are higher in patients who have complex medical problems in addition to esophageal reflux. Approximately 10% of patients with reflux develop Barrett esophagus, a precursor for adenocarcinoma of the esophagus.[68] Superficial esophageal adenocarcinoma may be curable with endoscopic therapy[69], but more advanced malignancy has a poorer prognosis.

Complications

Complications associated with GERD include:

• Esophagitis: Patients with Grade C and D esophagitis in the Los Angeles classification are characterized as having severe reflux. These patients have the lowest healing rate with PPIs and lifestyle modification. Patients with severe reflux esophagitis are more likely to relapse after treatment and have a greater risk of developing Barrett esophagus. These patients should undergo endoscopy 8 to 10 weeks after PPI therapy to monitor healing progress and assess for complications.
• Esophageal stricture development: Dilatation is the mainstay of management if the stricture persists despite improvement or resolution of esophagitis.
• Peptic stricture: This complication tends to occur in older patients with GERD who have had the condition for a longer duration, have abnormal esophageal motility, and do not receive or maintain treatment for their reflux symptoms.
• Barrett esophagus: This occurs in 5% to 15% of patients with reflux esophagitis. This complication is most likely to occur in White male patients over the age of 50 with severe reflux esophagitis who have had the symptoms for a longer duration.
• Esophageal adenocarcinoma: This occurs in 5% of patients with Barrett esophagus, especially when it involves a long segment of the esophagus. It is approximately 8-fold more common in men than in women.
• Other complications: Peptic ulceration, gastric cardia cancer, upper gastrointestinal bleeding, iron deficiency anemia due to chronic blood loss, laryngitis, cough, sinusitis, bronchial asthma, idiopathic pulmonary fibrosis, and dental erosions.[70][71]