Gastroesophageal Reflux Disease (GERD)

Etiology

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 lower esophageal sphincter, the diaphragm, the intra-abdominal portion of the esophagus, the angle of His, and the phrenoesophageal membrane.

• Lower esophageal sphincter: This physiological sphincter measures 3 to 5 cm in length. 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 support 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.
• 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.[6]

Physiologic mechanisms also protect against gastroesophageal reflux. These mechanisms include but are not limited to, esophageal peristalsis, saliva production, and inherent esophageal mucosal protection.

• Esophageal motility: Esophageal peristalsis promotes the return of regurgitated acid to the stomach.
• 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 distal esophageal mucosa from acidic stomach contents.[7][8]

Etiologies and Risk Factors 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 or produce protective physiological mechanisms. The underlying etiologies of GERD include but are not limited to:

• Transient relaxation of the lower esophageal sphincter or a low resting lower esophageal sphincter pressure
• Hiatal hernia
• Extrinsically increased intra-abdominal pressure, as in obesity
• 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 [9][10][11][12][13] 

In addition to the above etiologies, certain individuals are at increased risk of developing GERD. These risk factors include but are not limited to:

• Male sex
• White ethnicity
• Age 50 or older
• Tobacco use
• Alcohol consumption
• Delayed gastric emptying
• Metabolic dysfunction-associated steatotic liver disease
• Chronically decreased thoracic pressure
• Psychosocial stress [14][15][16][17][18][19]

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%.[13][20] GERD is equally prevalent among men and women.[21] However, the predominance of esophagitis and Barrett esophagitis is notably higher in men than women, with ratios of 3:1 and 10:1, respectively. The results of some studies report a higher frequency of reflux esophagitis in men, whereas others report an increased frequency in women.[22][23] The incidence of reflux esophagitis is greatest in individuals aged 60 to 70 and slightly decreases thereafter. Similar to 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.[24] GERD exists universally in preterm infants.[25]

Genetic variations, environmental factors, and lifestyle all contribute to the development of esophageal reflux. During pregnancy, approximately half of women complain about 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.[26] Typically, these patients do not have symptoms such as heartburn before pregnancy; only 14% may have infrequent mild heartburn. 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.[27] Several medications have been associated with symptoms of GERD, including drugs that modulate the lower esophageal sphincter pressure, including nitrates, calcium channel blocker agents, anticholinergics, α-adrenergic agonists, theophylline, and morphine. Patients with nonalcoholic fatty liver disease also exhibit an increased incidence of GERD independent of any confounders.[17]

Pathophysiology

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

• Transient relaxation of the lower esophageal sphincter: 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.

• Hiatus hernia: A hernia disturbs the anatomical relationship between the crural diaphragm and the lower esophageal sphincter function. Also, hernias are a reservoir for gastric contents, which can reflux into the esophagus when swallowing due to relaxation of the lower esophageal sphincter.

• Increased intra-abdominal fat: This change increases the gastroesophageal pressure gradient and the frequency of the transient lower esophageal sphincter relaxation phase, which results in the reflux of the stomach contents 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 are as follows:
  • 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 comprise tight intercellular junctions, cellular and intercellular buffers, and cell membrane transporters.
  • Reduced post-epithelial line of defense, including blood supply to the esophagus.

• The pathogenesis of GERD and the development of complications such as Barrett esophagus are mediated by cytokines rather than the results of chemical injury. Reflux esophagitis activates hypoxia-inducible factor (HIF)-2 alpha and nuclear factor kappa-light-chain-enhancer of activated B cells, causing increased levels of pro-inflammatory cytokines and the migration of inflammatory cells, particularly T cells, and damage to the esophagus.[28][29][30][31][32][33][34][35][36]

Histopathology

Reflux esophagitis occurs in patients with GERD when toxic substances such as 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 through endoscopy in 30% to 40% of patients. The histology of GERD is not specific, as the histological changes may also be present in other pathological states, such as adjacent mucosa in esophageal cancer.[37] The histological changes associated with reflux esophagitis secondary to GERD include the following.

• Epithelial injury and neutrophilic infiltration of the epithelium
• Changes confined to the mucosa, lamina propria, and muscularis mucosa
• Longstanding and untreated patients develop peptic strictures, chronic inflammation, and Barrett metaplasia
• Papillae proliferation of basal cells in the distal esophagus
• Dilated intercellular spaces within the squamous epithelium [38]

In patients with nonerosive disease, 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 it is more commonly found in the proximal esophagus of patients with eosinophilic esophagitis. Therefore, distinguishing between these conditions is crucial.[39] 

Confocal laser endomicroscopy in patients with nonerosive disease is characterized by more intrapapillary capillary loops per image compared to that in control individuals.[40] 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

The most common symptoms of GERD are heartburn and acid regurgitation. 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. A sour or burning fluid in the throat or mouth typically characterizes acid regurgitation. Maneuvers that increase intra-abdominal pressure, such as bending forward, may also provoke the regurgitation of gastric acid.[41] Dysphagia is reported in 30% of patients with reflux esophagitis associated with peptic strictures, Schatzki rings, weak peristalsis, or mucosal inflammation. 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.[42] However, without heartburn and acid regurgitation, less common symptoms such as hoarseness, globus, nausea, abdominal pain, and dyspepsia are unlikely due to GERD.[5] 

Conversely, some patients with severe esophagitis or Barrett esophagus are asymptomatic. Patients may also experience 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, diffuse esophageal spasms, or hypertensive peristalsis (nutcracker esophagus), may be considered in the evaluation. However, reflux esophagitis is more common compared to these esophageal disorders.
• Chronic cough: GERD is one of the causes of chronic cough. Other causes include post-nasal discharge, asthma, and certain medications, such as angiotensin-converting enzyme inhibitors. The underlying pathogenesis of cough in reflux esophagitis can be explained based on the acid stimulation of nerve endings in the lower esophagus, causing activation of the cough center and response.
• Asthma: An association between asthma and GERD exists. However, whether this relationship is an association or a cause-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.
• Extraesophageal symptoms: Pathological changes secondary to GERD other than esophagitis, including dental erosions, dysphonia (voice disorder), sore throat, and laryngospasm, may be present.[43][44][45][46][47][48]

Evaluation

The diagnosis of GERD is imprecisely based on clinical features, patient response to a PPI trial regimen, and diagnostic studies. GERD can be initially presumptively diagnosed in most patients presenting with typical symptoms of heartburn and regurgitation. This diagnosis may be confirmed by a trial of PPIs, as this provides supportive evidence of GERD. However, diagnostic testing is recommended instead of empiric therapy if atypical symptoms such as chest pain or alarm symptoms are present.

Proton Pump Inhibitor Trial Therapy

Unless alarm symptoms such as dysphagia, odynophagia, significant weight loss, gastrointestinal bleeding, or anorexia are present, patients should be initiated on empiric therapy with PPIs for 8 weeks; a response to treatment may support a diagnosis of GERD.[49] 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 such as upper-endoscopy and ambulatory reflux monitoring should be performed to confirm GERD and exclude differential diagnoses according to the international Lyon Consensus.[5][50][51] Furthermore, patients presenting with chest pain should be investigated to exclude cardiac causes before the commencement of gastrointestinal evaluation. Furthermore, patients presenting with dysphagia should undergo an endoscopic examination to rule out reflux complications such as esophageal strictures, peptic ulcerations, and malignancy. 

Esophageal Manometry

Esophageal manometry is of limited value in the primary diagnosis of GERD and is not recommended as a solitary diagnostic test. 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 anti-reflux surgery to rule out achalasia or severe hypomotility, as in the scleroderma-like esophagus where Nissen fundoplication is contraindicated.[52]

Ambulatory Esophageal Reflux Monitoring

Ambulatory reflux monitoring is the only test determining abnormal esophageal acid reflux and frequency. In patients with PPI-resistant symptoms, ambulatory 24-hour pH-impedance monitoring can assess the relationship between symptoms and reflux episodes. This test can help exclude GERD, but the test should be carried out after the cessation of PPI therapy.[53] Medically refractory GERD is increasingly common, and patients often have normal findings on endoscopy evaluation as PPIs are incredibly 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 indicating GERD. Ambulatory reflux pH with or without impedance monitoring employs the utility of a telemetry pH capsule or a transnasal catheter. 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. Current practice guidelines recommend mandatory preoperative ambulatory pH monitoring in patients without evidence of erosive esophagitis.

Esophagogastroduodenoscopy

Patients presenting with typical GERD symptoms associated with any of the alarm symptoms or atypical symptoms should be examined with an esophagogastroduodenoscopy and pH monitoring before a PPI trial to rule out complications of GERD. Performing endoscopy may be indicated in high-risk groups, particularly overweight, aged 50 and above, and with chronic esophageal reflux for >5 years. Also, esophagogastroduodenoscopy is indicated in patients at high risk of complications, including patients with Barrett esophagus, dysphagia, gastrointestinal bleeding, esophageal stricture, esophageal adenocarcinoma, peptic ulcer disease, and significant weight loss.[54] According to the current ACG guidelines, distal esophageal biopsies are not routinely recommended to diagnose GERD. Patients with a high index of suspicion for coronary artery disease presenting with GERD symptoms should undergo evaluation for underlying cardiovascular disease. In contrast, patients presenting with noncardiac chest pain suspected due to GERD should undergo a diagnostic assessment with an esophagogastroduodenoscopy and pH monitoring before initiation of PPIs.[55] Current ACG guidelines recommend against screening for Helicobacter pylori infection in patients with symptoms of GERD. Los Angeles classification includes the following 4 grades of reflux esophagitis severity with esophagogastroduodenoscopy.

• Grade A: ≥1 esophageal mucosal breaks less than 5 mm long.
• Grade B: ≥1 mucosal breaks greater than 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.[56]

Imaging Studies

Radiographic studies such as barium radiographs can detect moderate to severe esophagitis, esophageal strictures, hiatal hernia, and tumors. However, their role in evaluating GERD is limited and should not be performed to diagnose GERD.[57] Barium studies to diagnose GERD are of limited value. 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 are not useful in diagnosing GERD.[58]

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.[51](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.[59] Patients should also be counseled about avoiding meals at least 3 hours before bedtime and maintaining good sleep hygiene, as minimal disturbances in sleep are associated with decreased reflux episodes.[60][61] Studies have also shown improvement in symptoms of GERD and pH monitoring studies with the elevation of the head end 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.
• Elevate the head of the bed during sleep and avoid meals 2 to 3 hours before sleep to reduce reflux at night.
• To reduce stomach acidity, avoid trigger foods and beverages such as chocolate, caffeine, alcohol, and spicy food.
• Avoid tobacco products and smoking.[52][62][63][64]
(B2)

Pharmacologic Therapy

Patients should be treated with a PPI for 8 weeks daily before the day's first meal. If a partial response is elicited, the dose should be increased to twice daily. PPIs are safe in pregnant women if clinically indicated. PPIs should be administered at the lowest effective dose to control symptoms of GERD and maintain the healing of reflux esophagitis. Chronic use of PPI is associated with complications, including an increased risk of bone fractures, electrolyte deficiencies, and renal insufficiency. Clinicians should decrease PPI treatment to an as-needed basis in patients without Barrett esophagus who are responsive to a PPI trial. Medical therapy is also indicated in patients who do not respond to lifestyle modifications and includes antacid antisecretory agents such as histamine (H2) receptor antagonists (H2RAs) or PPI therapy and prokinetic agents in select patients. However, these additional medical therapies are not recommended for PPI nonresponders. PPI nonresponders should be evaluated for differential diagnoses, including eosinophilic esophagitis, delayed gastric emptying, irritable bowel syndrome, achalasia, and psychological disorders.

Currently, 2 US Food and Drug Administration (FDA)-approved H2RAs, famotidine and cimetidine, are available over-the-counter. The other commonly used H2RA, ranitidine, has been recalled as a potential health hazard or safety risk due to an unexpected impurity in the active ingredient. The less commonly known prescription-only H2RA, nizatidine, has also been recalled due to similar concerns. In the United States, 6 PPIs are currently available, of which omeprazole, lansoprazole, and esomeprazole are available over-the-counter. The remaining 3 medications, pantoprazole, dexlansoprazole, and rabeprazole, are prescription-only. Of the available medical options, PPI therapy is considered the most effective for both erosive and nonerosive GERD based on multiple large-scale studies. The results of these studies have also shown improved symptom control, healing of underlying esophagitis, and decreased relapse rates compared to H2RAs.[65][66] If needed, bedtime administration of H2RAs is recommended for patients with nighttime symptoms not optimized with maximal PPI therapy.[57] (A1)

For patients with Los Angeles grade C or D esophagitis, continued maintenance of PPI therapy or antireflux surgery is recommended. Baclofen has been found to decrease the number of postprandial acid reflux episodes; however, the therapy is not advised in patients without the results of diagnostic studies confirming the diagnosis. For patients that do have evidence of GERD on diagnostic studies, baclofen 5 to 20 mg 3 times daily may be considered. Prokinetic agents such as metoclopramide and domperidone in patients with GERD are not recommended unless gastroparesis is present due to a lack of evidence and their profound adverse effects on the central nervous and cardiovascular systems.[52] Furthermore, sucralfate for patients with GERD is only recommended during pregnancy. 

Surgical Therapy

Patients who have medically refractory GERD, chronic reflux esophagitis, noncompliance or adverse effects with medical therapy, underlying large hiatal hernia, or who desire to discontinue long-term medical treatment can be considered for surgical management. The available surgical options for GERD are laparoscopic Nissen fundoplication, laparoscopic anterior 180° fundoplication, or bariatric surgery for obese patients. Laparoscopic Nissen fundoplication has been the gold-standard surgical treatment in the management of GERD. However, given the rapid prevalence of obesity in the United States, gastric bypass surgery is the most common surgical treatment for GERD. Gastric bypass may be considered in patients who are obese with symptoms of GERD who prefer surgical therapy.[60] 

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 therapy with surgical therapy reported contrary conclusions, with one reporting improvement of symptoms of GERD after surgery compared with medical therapy and the other reporting considerable uncertainty in the benefits of surgical therapy compared to medical therapy.[67] 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. The most common bariatric surgeries are Roux-en-Y gastric bypass, laparoscopic adjustable gastric banded plication, and sleeve gastrectomy. Studies have shown that weight loss resulting from the surgical management of obesity has a positive impact on patients with GERD. Of all the bariatric surgeries that are options, Roux-en-Y gastric bypass is the most effective bariatric surgery for reducing the symptoms of GERD. The bariatric procedure of choice is recommended in patients with severe GERD preoperatively.[14](A1)

In the era of minimally invasive surgery techniques, many different types of endoscopic therapies have been developed for the management of GERD. Most of them were discontinued after failing to demonstrate long-term efficacy. Endoluminal therapies include magnetic sphincter augmentation and transoral incision-less fundoplication.[57] A recent meta-analysis conducted by Gerson et al that incorporated data from 233 patients demonstrated that subjects who underwent transoral incision-less fundoplication procedure had improved esophageal pH, decreased need for PPIs, and significant improvement in the quality of life 3 years following the procedure.[68] Another prospective study by Testoni et al demonstrated transoral incision-less fundoplication as an effective long-term treatment option for patients with symptomatic GERD with associated hiatal hernias less than 2 cm. A meta-analysis comparing Nissen fundoplication and magnetic sphincter augmentation that 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.[69](A1)

Differential Diagnosis

The differential diagnoses of GERD include coronary artery disease, infectious esophagitis, eosinophilic esophagitis, peptic ulcer disease, biliary colic, esophageal motor disorders, esophageal stricture, esophageal cancer, dyspepsia, dysphagia, rumination syndrome, radiation- and chemotherapy-induced esophagitis, achalasia, gastroparesis, and esophageal and gastric neoplasm.[70]

Prognosis

Many patients with GERD have a positive 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, such as stricture, aspiration, airway disease, and Barrett esophagus, are identified, surgical intervention such as fundoplication is typically necessary. The prognosis with surgery 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.[71]

Complications

Complications associated with GERD are listed below.

• Esophagitis: Patients with Grade C and D esophagitis in the Los Angeles classification are characterized by severe reflux. These patients have the lowest healing rate with PPIs. Patients with severe reflux esophagitis typically relapse after treatment and are more likely to develop Barrett esophagus. These patients should undergo endoscopy 8 to 10 weeks after PPI therapy to monitor healing progress and assess for complications.
• Lower esophageal rings (Schatzki): This complication correlates with GERD. Dilatation is the mainstay of management, followed by treatment with PPI.
• Barrett esophagus: Barrett esophagus occurs in 5% to 15% of patients with reflux esophagitis. This complication is more likely to occur in White male patients with severe reflux esophagitis who have had the symptoms for a longer duration and are older than 50.
• Peptic stricture: This complication tends to occur in older patients with GERD for a longer duration, with abnormal esophageal motility and not receiving treatment for reflux symptoms.
• Esophageal adenocarcinoma: Occurs more commonly in men with a ratio of 8 to 1 in males to females.
• Other complications: Peptic ulceration, gastric cardia cancer, dysphagia, upper gastrointestinal bleeding, anemia due to chronic blood loss, laryngitis, cough, sinusitis, bronchial asthma, idiopathic pulmonary fibrosis, and dental erosions.[72][73]