Gastroesophageal reflux disease (GERD) refers to a condition where the reflux of gastric and duodenal contents into the esophagus causes discomfort and/or complications. The most common symptoms are heartburn and regurgitation, although damage to adjacent esophageal tissues and extra-esophageal symptoms may also occur. Based on the presence or absence of esophageal mucosal erosion or ulcers, GERD is classified into reflux esophagitis (RE) and nonerosive reflux disease (NERD).
GERD is a common clinical condition, with its prevalence increasing with age and showing no significant difference between genders. In Western countries, the prevalence of GERD is approximately 10% to 20%, while in Asian regions, it is about 5%. NERD is more commonly observed in both populations.
Pathogenesis
GERD is primarily a motility disorder of the gastroesophageal junction, characterized by dysfunction of the lower esophageal sphincter (LES). The main damaging factors are refluxed gastric acid, pepsin, unconjugated bile salts, and pancreatic enzymes.
Abnormalities in the Structure and Function of the Anti-Reflux Barrier
Increased intra-abdominal pressure (e.g., due to obesity, pregnancy, or constipation), hiatal hernia, prolonged gastric pressure (e.g., from delayed gastric emptying or gastric distension), and post-surgical complications like achalasia can damage the LES structure. Additionally, certain hormones (e.g., cholecystokinin, glucagon, vasoactive intestinal peptide), foods (e.g., high-fat diets, chocolate), and medications (e.g., calcium channel blockers, diazepam) can impair LES function or prolong transient relaxation. When the esophageal mucosa is exposed to refluxate under these conditions, GERD may develop.
Reduced Esophageal Clearance
This is often seen in conditions that cause abnormal esophageal motility or reduced saliva production, such as Sjögren's syndrome. In cases of hiatal hernia, part of the stomach enters the thoracic cavity through the esophageal hiatus, altering the LES structure and reducing the esophagus's ability to clear refluxate, thereby contributing to GERD.
Damage to the Esophageal Mucosal Barrier
Long-term smoking, alcohol consumption, and the intake of irritant foods or medications can impair the esophageal mucosal barrier.
Pathology
The gross pathological changes of RE are detailed in the endoscopic examination section. Histopathological changes include epithelial necrosis, inflammatory cell infiltration, mucosal erosion, and ulcer formation. In NERD, histopathological changes include:
- Basal cell hyperplasia,
- Elongation of lamina propria papillae with vascular proliferation,
- Inflammatory cell infiltration,
- Widened intercellular spaces in squamous epithelial cells.
When the squamous epithelium of the distal esophagus is replaced by metaplastic columnar epithelium, the condition is referred to as Barrett's esophagus.
Clinical Manifestations
Esophageal Symptoms
Typical Symptoms
Heartburn and regurgitation are the most common and characteristic symptoms of GERD. Heartburn refers to a burning sensation behind the sternum or below the xiphoid process, often radiating upward from the lower sternum. Regurgitation refers to the sensation of gastric or duodenal contents flowing into the throat or mouth without nausea or retching, often with a sour taste. These symptoms typically occur within one hour after meals and may worsen in a supine position, when bending forward, or with increased intra-abdominal pressure. Some patients may also experience symptoms during nighttime sleep.
Atypical Symptoms
Chest pain caused by refluxate irritating the esophagus is located behind the sternum and can be severe, presenting as sharp pain radiating to the precordium, back, shoulders, neck, or behind the ears, sometimes mimicking angina pectoris. GERD is one of the common causes of non-cardiac chest pain. For patients with chest pain not accompanied by typical heartburn or regurgitation, cardiac disease should first be ruled out before evaluating GERD. Dysphagia or a sensation of a foreign body behind the sternum may result from esophageal spasms or functional disorders, often intermittent. In rare cases, dysphagia may be caused by esophageal strictures, presenting as persistent or progressively worsening difficulty swallowing.
Extra-Esophageal Symptoms
These symptoms are caused by refluxate irritating or damaging tissues or organs outside the esophagus, such as chronic cough, laryngitis, or asthma. For patients with unexplained and recurrent cases of these conditions, especially when accompanied by heartburn and regurgitation, GERD should be considered. Severe cases may result in aspiration pneumonia or even pulmonary interstitial fibrosis.
Complications
Barrett's Esophagus
This condition results from severe damage to the esophageal mucosa and carries a risk of malignant transformation to adenocarcinoma.
Esophageal Stricture
Recurrent esophagitis can lead to fibrosis and subsequent scar formation, causing strictures.
Upper Gastrointestinal Hemorrhage
Mucosal erosion and ulcers can result in hematemesis and/or melena.
Auxiliary Examinations
Endoscopy
Endoscopy is the most accurate method for diagnosing reflux esophagitis (RE). It allows for the assessment of the severity and presence of complications and, when combined with histopathological examination, helps differentiate RE from other causes of esophagitis and esophageal diseases, such as esophageal cancer. The Los Angeles (LA) classification system for grading RE is as follows:
- Normal: No mucosal damage in the esophagus.
- Grade A: One or more mucosal breaks, each no longer than 5 mm.
- Grade B: At least one mucosal break longer than 5 mm, without confluence.
- Grade C: Confluent mucosal breaks involving less than 75% of the esophageal circumference.
- Grade D: Confluent mucosal breaks involving at least 75% of the esophageal circumference.
Normal esophageal mucosa consists of stratified squamous epithelium, appearing uniformly pink under endoscopy. Barrett's esophagus is characterized by the replacement of the squamous epithelium with metaplastic columnar epithelium, appearing orange-red and often located proximal to the gastroesophageal junction at the dentate line, presenting as islands, tongues, or rings.
Esophageal Reflux Monitoring
This includes esophageal pH monitoring and impedance-pH monitoring, which are used to evaluate the relationship between symptoms and reflux, providing objective evidence of reflux. These methods are considered the gold standard for diagnosing GERD.
Esophageal Manometry
This test assesses esophageal motility and is useful for preoperative evaluation before anti-reflux surgery.
Esophageal Barium Swallow
The sensitivity and specificity of this method for diagnosing GERD are relatively low, and it is no longer a routine diagnostic tool for GERD. However, it can help exclude other esophageal diseases, such as esophageal cancer.
Diagnosis and Differential Diagnosis
For patients with typical symptoms of heartburn and regurgitation, a provisional diagnosis of GERD can be established. If symptoms significantly improve after a trial of proton pump inhibitor (PPI) therapy, a preliminary diagnosis can be established.
The diagnostic approaches differ between RE and NERD:
RE Diagnosis:
- Presence of heartburn and/or regurgitation symptoms.
- Endoscopic findings of RE.
NERD Diagnosis:
- Presence of heartburn and/or regurgitation symptoms.
- Negative findings on endoscopy.
- Objective evidence of reflux provided by esophageal reflux monitoring.
- Effective response to PPI therapy.
GERD should be differentiated from other esophageal conditions, such as infectious esophagitis, eosinophilic esophagitis, drug-induced esophagitis, achalasia, and esophageal cancer, as well as from peptic ulcers and biliary diseases. Chest pain caused by GERD needs to be distinguished from cardiac chest pain and other causes of non-cardiac chest pain. GERD should also be differentiated from functional disorders, such as functional heartburn and functional dyspepsia.
Treatment
The goals of treatment include symptom control, mucosal healing, prevention of recurrence, and avoidance of complications.
Patient Education
Patients with structural damage or functional abnormalities of the LES are advised to avoid lying down immediately after meals. To reduce reflux during sleep or when lying down, it is recommended to avoid eating within two hours of bedtime and to elevate the head of the bed.
Factors that increase intra-abdominal pressure, such as obesity and constipation, should be minimized. Foods that may trigger GERD symptoms, such as high-fat foods, chocolate, and coffee, should be avoided. Medications that lower LES pressure or delay gastric emptying, such as nitrates, calcium channel blockers, and anticholinergics, should be used with caution.
Smoking cessation and alcohol avoidance are encouraged.
Pharmacological Treatment
Acid-Suppressing Medications
Gastric acid and pepsin are the primary damaging factors in GERD, making acid suppression the cornerstone of treatment.
- Proton Pump Inhibitors (PPIs): PPIs irreversibly bind to the H+-K+-ATPase enzyme, providing strong acid suppression and proven efficacy. They are the first-line treatment for GERD, with a typical course lasting 4-8 weeks. For patients with severe esophagitis (LA-C and LA-D grades) or GERD associated with hiatal hernia, the treatment duration can be extended or the dosage increased.
- Potassium-Competitive Acid Blockers (P-CABs): P-CABs have a treatment duration similar to PPIs. As a newer class of acid-suppressing drugs, P-CABs offer advantages such as rapid onset of action, prolonged effect, and reliable nighttime acid suppression. Their efficacy in mucosal healing and symptom relief is comparable to PPIs, but long-term clinical efficacy and safety require further validation.
- H2-Receptor Antagonists (H2RAs): These drugs have weaker acid-suppressing effects and are suitable for patients with mild to moderate symptoms, with a treatment course of 8-12 weeks. Increasing the dosage can improve efficacy but may also lead to more adverse effects.
Prokinetic Agents
These medications work by increasing lower esophageal sphincter (LES) pressure, improving esophageal motility, and promoting gastric emptying, thereby reducing reflux of gastric and duodenal contents and shortening their exposure time in the esophagus. They are suitable for patients with mild symptoms or as adjunctive therapy to acid-suppressing drugs.
Antacids
Antacids are used for temporary symptom relief in patients with mild and intermittent symptoms.
Refractory GERD
Refractory GERD refers to cases where symptoms such as heartburn and/or regurgitation show no significant improvement after 8 weeks of double-dose PPI therapy. Various factors can contribute to refractory GERD. Reflux-related factors include insufficient acid suppression, obesity, and hiatal hernia, while non-reflux-related factors include esophageal motility disorders, other types of esophagitis, and psychological factors. Treatment plans should be adjusted based on the specific causes in individual patients.
Maintenance Therapy
Maintenance therapy can be classified into on-demand treatment and long-term treatment. Patients with NERD or mild esophagitis may undergo on-demand treatment, taking medication when symptoms occur and stopping once symptoms resolve. Patients who experience rapid and persistent symptom recurrence after stopping medication, as well as those with severe esophagitis, esophageal strictures, or Barrett's esophagus, require long-term treatment. PPIs, P-CABs, and H2RAs can all be used for maintenance therapy, with PPIs being the preferred option. The dosage for maintenance therapy should be individualized, aiming for the lowest dose that effectively controls symptoms.
Anti-Reflux Surgery
Anti-reflux surgery can be considered for patients whose symptoms remain poorly controlled despite adequate acid-suppressing treatment, for those who require long-term maintenance therapy despite effective acid suppression, and for cases where symptoms are clearly caused by reflux.
Anti-reflux surgery includes endoscopic and surgical approaches. Endoscopic treatments include radiofrequency ablation and transoral incisionless fundoplication. Surgical treatment primarily involves laparoscopic fundoplication, which has efficacy comparable to PPIs but carries certain risks.
Management of Complications
Barrett's Esophagus
Maintenance therapy is recommended, and regular follow-up is important for the early detection of dysplasia and malignant transformation. Endoscopic or surgical treatment should be performed if high-grade dysplasia or early esophageal cancer is detected.
Esophageal Stricture
Most cases of esophageal stricture can be managed with endoscopic esophageal dilation, except for rare cases of severe scar-related strictures that may require surgical treatment. Long-term maintenance therapy is necessary to prevent recurrence after dilation. Anti-reflux surgery may also be considered for younger patients.
Upper Gastrointestinal Hemorrhage
The management of upper gastrointestinal hemorrhage can be seen in the guidelines on gastrointestinal hemorrhage.
Prognosis
The severity of RE is an important factor in determining the prognosis. Patients with mild esophagitis (LA-A and LA-B grades) typically achieve mucosal healing after 4 weeks of treatment, while those with severe esophagitis (LA-C and LA-D grades) often require 8 weeks or longer for mucosal healing.
Prevention
Establishing a three-tier prevention system for GERD is crucial for reducing its occurrence, progression, and recurrence.
- Primary Prevention: Aimed at the general population, this focuses on preventing the onset of GERD through measures such as public education on disease prevention.
- Secondary Prevention: Targeting high-risk groups, this aims to identify GERD at an early stage and control its progression through regular community screening and other measures.
- Tertiary Prevention: Directed at patients, this seeks to reduce the risk of complications and recurrence through therapeutic lifestyle interventions and other strategies.