C. Prakash Gyawali and Amit Patel
GENERAL PRINCIPLES
· Gastroesophageal reflux disease (GERD) is a condition characterized by symptoms or tissue damage from reflux of gastric contents into the esophagus or beyond.
· Population surveys indicate that GERD is very common, with 10% to 20% of the general population reporting at least weekly symptoms.1,2
· There are several barriers to reflux of gastric contents into the esophagus.3,4
o Resting tone in the lower esophageal sphincter (LES) keeps the gastroesophageal junction closed in between swallows.
o The diaphragmatic crura, normally aligned with the LES, pinch the gastroesophageal junction during inspiration to prevent reflux when intrathoracic pressure is negative relative to the atmosphere.
o Any refluxed material is promptly returned back into the stomach by secondary peristaltic waves initiated by local esophageal neural reflexes.
o Residual acidic material in the mucosa is neutralized by saliva, which is alkaline.
· Despite these measures, physiologic reflux occurs in most individuals, typically after meals.
· Inappropriate transient LES relaxation (TLESR) is the most frequent mechanism of reflux, in healthy people as well as patients with GERD.3,4
o The LES is designed to relax immediately at the initiation of a swallow.
o A TLESR is said to occur inappropriately when the LES relaxes in between swallows.
o Several triggers, including a full stomach and the presence of a hiatus hernia, may precipitate frequent TLESRs, which in turn can lead to reflux of gastric contents into the esophagus.
· Low tone in the LES is seen in approximately a quarter of reflux patients, wherein the barrier to gastroesophageal reflux is weak.3,4
o A prototype condition associated with extremely low LES tone is scleroderma, where fibrosis of the esophageal smooth muscle leads to near-absent tone in the LES and hypomotility or aperistalsis in the esophageal body.
o Certain medications and food items that lower LES tone include the following anticholinergics, smooth muscle relaxants, caffeine, theophylline, alcohol, and fatty or greasy foods.
· A hiatus hernia results when the diaphragmatic crura are not snug against the gastroesophageal junction, allowing a pouch of stomach to prolapse proximal to the crura.3,4
o The typical axial hiatus hernia slides up and down through the diaphragmatic hiatus. The presence of a hiatus hernia disrupts the physiologic barrier to gastroesophageal reflux by several mechanisms. First, the anatomic integrity of the barrier formed by close alignment of the diaphragmatic crura and the closed LES is lost. A pouch of gastric mucosa is now above the level of the diaphragmatic pinch, which can serve as a reservoir for gastric (acidic) secretions that can easily reflux when the patient lays supine. Finally, local neural reflexes may be affected by the presence of the hiatus hernia, allowing for a higher frequency of inappropriate LES relaxations.
o The larger the hiatus hernia, the higher the likelihood for reflux.
o However, not every patient with a hiatus hernia has GERD, and not every patient with GERD has a hiatus hernia.
DIAGNOSIS
Clinical Presentation
· Heartburn is the most frequent reflux symptom, described by patients as a retrosternal or epigastric burning sensation.4 The discomfort may radiate upward to the neck, to the shoulders, or even to the back.
· Acid reflux often occurs in the postprandial state but can sometimes occur at night and awaken the patient from sleep.
· Eating or taking an antacid promptly relieves the symptom by neutralizing refluxed acid.
· Heartburn may be associated with regurgitation of a sour, bitter liquid with an acidic taste.
· Bending over, laying supine, and wearing tight garments over the abdomen may provoke both heartburn and regurgitation in some instances.
· Mucosal inflammation in the esophagus from acid reflux can also prompt the sensation of dysphagia in some patients, which may improve with acid-suppressive therapy.
· Atypical presentations can occur.
o Over the past few decades, several atypical reflux symptoms have been identified. It is important to recognize atypical symptoms, as they may occur even when typical symptoms are absent.5
o The most significant atypical symptom is chest pain, which is important because chest pain may indicate concomitant cardiac disease. Conversely, cardiac disease needs careful exclusion before chest pain is attributed to GERD in appropriate age groups. In older patients, both GERD and coronary artery disease can coexist. Despite documenting correlation of reflux with chest pain, many patients continue to worry about cardiac disease, making noncardiac chest pain an important cause for health care expenditure.
o Wheezing and asthma have also been linked to reflux, especially adult-onset symptoms in the absence of an allergic component. There are two mechanisms by which reflux can result in asthma. Regurgitation of gastric contents to the pharynx and tracheal microaspiration. Triggering of a reflex bronchospasm in susceptible individuals by smaller amounts of acid in the distal esophagus. When correlation between bronchospastic symptoms and reflux exists, adequate management of GERD can lead to better treatment outcomes. Other pulmonary symptoms and disorders linked to reflux include cough, interstitial fibrosis, and aspiration pneumonia.
o Other supraesophageal manifestations of reflux disease include hoarseness, throat clearing, dental erosions, and posterior laryngitis. Dyspeptic symptoms, nausea, and back pain may also have etiologic links to GERD in certain situations.
Differential Diagnosis
Eosinophilic Esophagitis
· Eosinophilic esophagitis (EoE) is a chronic condition characterized by eosinophil infiltration of the esophageal mucosa and submucosa, leading to mucosal inflammation, fibrosis, and luminal narrowing.6,7
· Annual incidence rates vary between 0.1 and 1.2 per 10,000. It is seen most often in young men.8
· Presenting manifestations can be obstructive (dysphagia, recurrent food bolus impactions) or perceptive (heartburn, chest pain). Solid food dysphagia is the most common presenting symptom.9
· On endoscopy, the esophageal lumen may be narrowed with a corrugated trachea-like appearance.10 However, similar endoscopic features have been described in other esophageal disorders and are not pathognomonic for EoE.
· Esophageal biopsies should therefore be obtained whenever EoE is suspected, regardless of esophageal endoscopic appearance.10 With few exceptions, biopsies should demonstrate >15 eosinophils/high-power field to establish a diagnosis of EoE.9
· Topical steroids should be considered for both initial and maintenance therapy in EoE patients. Topical treatment is available in both inhaled and viscous forms. Recommended initial dose of inhaled treatment is 440 to 880 μg of fluticasone puffed and swallowed through metered dose inhaler twice daily. Viscous treatment consists of mixing 1 g of budesonide with ten 1-g packets of sucralose. The mixture is then swallowed, and patients should not eat or drink for 30 minutes after drug ingestion.9,11–13
· Proton pump inhibitors (PPIs) are effective adjunctive treatment options for EoE.9
· Esophageal dilation is a treatment option in healthy adult patients with anatomic esophageal narrowing, followed by a course of topical steroids to reduce inflammation and decrease remodeling. Patients with EoE are not at greater risk for perforation when compared to patients with other causes of esophageal stricture undergoing dilatation.14,15
· Patients with EoE have high rates of concurrent asthma, allergic rhinitis, eczema, and food allergy. A thorough evaluation by an allergist or immunologist is recommended for diagnosis and treatment of concurrent atopic diseases.9
Infectious Esophagitis
· Candida esophagitis is the most frequent infectious esophagitis seen in immunocompromised individuals.16
o Other risk factors include esophageal stasis (strictures, achalasia, and neoplasia), antibiotic use, steroid use, diabetes, and malnutrition.
o Endoscopic evaluation reveals whitish exudates and plaques in the esophagus; fungal hyphae can be seen on cytology.
o If an immunocompromised patient has esophageal symptoms (dysphagia and odynophagia) and oropharyngeal thrush is encountered, empiric therapy with fluconazole (100 mg daily for 14 days) or nystatin (100,000 units/mL, 5 mL tid for 14 to 21 days) can be empirically initiated, reserving endoscopy for refractory symptoms.
· Herpes esophagitis can occur in both immunocompetent and immunocompromised hosts.16
o A history of cold sores is frequently elicited.
o Patients present with severe odynophagia, resulting in food aversion.
o Endoscopic evaluation may reveal grouped vesicles or ulcers, biopsies from which may reveal intracytoplasmic inclusions.
o Therapy consists of acyclovir for 10 to 14 days.
· Cytomegalovirus esophagitis is only seen in immunocompromised hosts, typically after solid organ transplants and in advanced AIDS with low CD4 counts.16 Endoscopy typically reveals deep ulcers, and biopsies demonstrate typical intranuclear inclusions.
Pill Esophagitis
· Pill esophagitis is usually seen in conjunction with esophageal stasis, strictures, and hypomotility disorders.17
· Presentation may include heartburn, chest pain, and odynophagia.
· Frequent locations for pill esophagitis are the aortic arch and the LES.
· Usual culprits include quinidine, tetracycline, doxycycline, nonsteroidal anti-inflammatory drugs, and alendronate.
Functional Heartburn and Chest Pain
Perceptive esophageal symptoms similar to that seen with GERD can be encountered in patients with visceral hyperalgesia.18 Symptoms may overlap with nonerosive reflux disease, functional heartburn, and functional chest pain.
Diagnostic Testing
Proton Pump Inhibitor Trial
· The most convenient and cost-effective approach for diagnosis of GERD is by initiating a therapeutic trial of PPI therapy.19
· This approach has been studied using omeprazole (40 mg before breakfast and 20 mg before supper) for 1 week in patients with typical symptoms.
· Symptom resolution predicts good diagnostic accuracy with a sensitivity of 78% and specificity of 54% in meta-analyses.20
· Patients with atypical symptoms require double doses of PPIs and longer therapeutic trials, as long as 1 month for atypical chest pain and 3 to 6 months for supraesophageal symptoms.5
Endoscopy
· Esophagitis is visualized in only 50% to 60% of GERD patients with typical symptoms if endoscopy is performed prior to initiation of antireflux therapy; the number goes down to <10% if adequate antireflux therapy has already been initiated.21,22
· The frequency of finding visible esophagitis is lower in patients with atypical symptoms (30% for asthma, 15% to 20% for atypical chest pain, and ≤15% for laryngeal symptoms) even under ideal circumstances.
· Therefore, the best use of endoscopy is to evaluate for complications and to screen for Barrett esophagus.19,21
· Patients with alarm symptoms (dysphagia, weight loss, anemia, or family history of esophageal cancer) or with a long history of reflux symptoms (>5 years), older patients (>45 years), or those failing to respond adequately to antisecretory therapy are offered endoscopy, typically performed after the patient has been taking a PPI for 8 to 12 weeks. The purpose of the procedure is, therefore, to evaluate for ongoing erosive esophagitis, alternate causes of esophagitis (e.g., EoE and infectious esophagitis), strictures, Barrett esophagus, and esophageal neoplasia.
Ambulatory pH Monitoring
· Ambulatory pH monitoring is considered the gold standard for quantifying esophageal acid exposure.19,23 The test is not used to diagnose GERD but rather to quantify the degree of acid exposure in patients referred for antireflux surgery, patients with atypical symptoms, and patients not responding to seemingly adequate antireflux measures. Ambulatory pH monitoring allows not just measurement of acid exposure time, but also correlation of symptoms to reflux events.
· There are two techniques of pH monitoring, catheter-based monitoring with one or two pH sensors and wireless monitoring, where a pH sensor capsule attached to the esophageal mucosa communicates recorded pH to a receiver worn by the patient.
· The test is performed off antireflux therapy (off PPIs for a week, H2 receptor blockers for 3 days, and antacids for 24 hours) to quantify acid exposure time, to correlate symptoms to reflux events, for preoperative evaluation prior to antireflux procedures, and in patients with persistent GERD despite antireflux surgery.24
· Testing on twice a day PPI therapy allows assessment of adequacy of treatment in patients with persistent symptoms despite therapy. This indication is now served best by esophageal impedance-pH testing as described below.
· The wireless pH system allows for longer duration of pH monitoring and better patient tolerability, without loss of accuracy.25 Longer monitoring improves sensitivity of symptom-reflux association tests and addresses day-to-day variation in acid exposure.26 The capsule is placed 6 cm above the squamocolumnar junction following upper endoscopy. Contraindications include stricture, severe esophagitis, varices, history of bowel obstruction, and pacemakers or defibrillators.
· Ambulatory pH monitoring only measures acidic elements in the refluxate, but impedance monitoring assesses reflux irrespective of the pH of the refluxate.23,27 Impedance is measured by passing minute electrical currents through pairs of electrodes implanted on a catheter. Changes in the resistance to flow of current indicate presence of liquid refluxate or air (e.g., belch), and direction of movement of the change distinguishes swallows from reflux events. Impedance catheters typically have a pH sensor for distal esophageal pH measurement. Impedance-pH monitoring is an attractive option for patients with ongoing symptoms despite antireflux therapy, especially if symptoms are regurgitation predominant.
Esophageal Manometry
· Esophageal manometry contributes little to the diagnosis of GERD but may define pathophysiologic mechanisms in patients with impaired esophageal peristalsis or low LES resting tone.19,23,28
· Manometry is often performed prior to antireflux surgery to assess adequacy of esophageal peristaltic performance and to exclude potentially confounding diagnoses such as achalasia.
· Esophageal manometry is used to locate the LES for placement of catheter-based pH and impedance-pH probes (placed 5 cm proximal to the LES).
Barium Esophagogram
Barium contrast esophagograms provide accurate anatomic information and delineate even subtle strictures or narrowings. Barium studies are not accurate for the diagnosis of GERD and should not be used for this indication.21,29
Other Diagnostic Procedures
Other specialized esophageal investigative studies used in the research setting include the Bernstein test, balloon distension studies, esophageal planimetry, high-definition ultrasound, and transit time measurements.
TREATMENT
Medications
Acidic gastric contents are corrosive to the esophageal mucosa. The basis of pharmacologic treatment is to reduce gastric acidity and render the refluxate less corrosive.
Proton Pump Inhibitors
· The standard of acid-suppressive therapy is the PPI.19,30
· PPIs are administered 30 to 60 minutes before a meal to allow the agent to circulate in the blood stream when the proton pumps are activated by a meal. PPIs then bind to the proton pump and render them inactive, thereby lowering gastric acidity for 12 to 18 hours. For continued efficacy, these agents have to be administered daily, prior to breakfast if used once a day and additionally prior to supper if used twice a day.
· PPIs are remarkably safe; minor side effects include abdominal pain and diarrhea. Fundic gland polyps may develop in some patients on long-term acid suppression.31 Concern for rare side effects arises from prolonged continued use, but reports are limited, and long-term studies continue to establish overall safety of these agents.32
· These rare side effects include small intestinal bacterial overgrowth, Clostridium difficile colitis, vitamin B12 malabsorption, and calcium malabsorption leading to osteopenia and hip fractures in susceptible individuals.33–35
· Commonly available PPIs are listed in Table 29-1.
Table 29-1 Typical Doses of Antisecretory Medications for GERD
Histamine-2 Receptor Antagonists
· H2 receptor antagonists also lower gastric acid secretion and may be effective in patients with intermittent or mild symptoms.
· H2 receptor antagonists have been used in addition to PPI therapy in patients with nocturnal breakthrough symptoms.
· These agents may be subject to tachyphylaxis, which may affect continued efficacy.
· Side effects include drug interactions and rarely thrombocytopenia and confusion.
GABA Agonists
· GABA agonists such as baclofen reduce TLESRs, the most common mechanism of reflux in both healthy individuals and GERD patients.
· Baclofen has been associated with decreased upright acid exposure times as well as significant improvement in belching, regurgitation, and overall reflux symptoms.
· Baclofen has also been shown to be a useful adjunct therapy in patients with nighttime heartburn and/or sleep complaints despite PPI therapy.36,37
Promotility Agents
· There are no effective promotility agents appropriate for management of GERD symptoms currently on the market.19
· Metoclopramide is sometimes prescribed to improve LES tone and enhance gastric emptying but is associated with frequent side effects, including irritability and extrapyramidal dysfunction. Benefit for reflux has not been systematically demonstrated.
Surgical Management
· Antireflux surgery performed by an experienced surgeon is an alternate option to pharmacologic management in patients with well-documented GERD.19
· Patients with large hiatus hernias, low LES resting tone, and regurgitation-predominant symptoms appear to benefit most from this approach.
· Good to excellent results can be expected in patients who respond to PPI therapy, especially when there is good symptom-reflux correlation on ambulatory pH monitoring. Antireflux surgery can also be considered in patients intolerant of PPIs.
· Antireflux surgery has similar efficacy to PPI therapy when considering remission rates at 5 years. Breakthrough reflux symptoms may develop in some, especially after 5 to 10 years, and supplemental antisecretory therapy may be required.38 It is estimated that the cost of antireflux surgery compares with that of pharmacologic therapy in approximately 10 years.
· Benefits of surgery must also be weighed against the possible adverse effects. New symptomatic postoperative dysphagia occurs in approximately 6% of patients undergoing antireflux surgery. However, early postoperative dysphagia is not associated with poorer long-term reflux control after surgery.39,40
Lifestyle Modification
· Lifestyle modification measures make physiologic sense but are not considered adequate by themselves for management of symptomatic reflux disease. Rather, these measures are recommended in conjunction with pharmacologic therapy.19
· These measures include the following:
o Avoid large meals.
o Avoid eating 2 to 3 hours before lying down.
o Avoid foods and beverages that can decrease the lower esophageal sphincter pressure (e.g., chocolate, peppermint, caffeine, and alcohol).
o Individual patients should avoid foods that worsen their symptoms—common examples include acidic foods, spicy foods, and fatty foods, but this is not necessarily consistent from patient to patient.
o Avoid tight-fitting garments.
o Lose weight.
o Elevate the head of the bed (placement of four to six in blocks underneath the front legs of the bed is preferred to propping the head up with pillows).
o Quit smoking and decrease alcohol use.
COMPLICATIONS
Mucosal Erosion/Strictures
· Mucosal erosions are seen in the esophagus in approximately 60% of patients with typical reflux symptoms prior to initiation of antireflux therapy. These erosions can be circumferential and associated with ulcerations in 10% to 15%. Healing of ulcerated areas can lead to luminal narrowing and stricture formation.
· When dysphagia results, esophageal dilation is of value.41 Continued acid suppression with a PPI may delay recurrence of peptic esophageal strictures.
· Dilation can be performed with through-the-scope endoscopic balloons or bougies, either passed blindly (Maloney dilators) or over a guide wire (Savary dilators).
· Refractory strictures that recur within short intervals may benefit from steroid injection into the rents created by dilation, which may prolong intervals between dilations.
Barrett Esophagus
· In genetically susceptible individuals, acid reflux can trigger a change in the distal esophageal mucosal lining from the normal squamous cell lining to incomplete intestinal metaplasia, termed Barrett esophagus.19,42,43
· This is characterized visually as a change in color from normal pearly white to salmon pink, either in a circumferential fashion or as slivers of changed mucosa (also called “tongues”) extending proximally from the gastroesophageal junction.
· Barrett esophagus is seen most frequently in middle-aged Caucasian males who are obese, smoke, and consume alcohol.44
· The overall prevalence of Barrett esophagus is thought to be about 5% to 15% in the GERD population and about 1% to 2% in the general population.44,45
· The significance of Barrett esophagus is the small but real risk of progression to high-grade dysplasia and esophageal adenocarcinoma. The risk of progression from high-grade dysplasia to esophageal adenocarcinoma is approximately 10% per year.46
· The incidence of esophageal adenocarcinoma has been rising over the past few decades and has overtaken squamous cell cancer as the most frequent esophageal cancer in Caucasian males.
· Although Barrett esophagus is asymptomatic, erosive disease and adenocarcinoma both can lead to symptoms of dysphagia, anemia, and rarely weight loss, making these alarm symptoms necessitating endoscopic evaluation of the esophagus.
· Most authorities agree that patients with established Barrett esophagus should undergo surveillance high-resolution endoscopy with biopsies every 1 to 3 years to assess for dysplastic changes that are suggestive of degeneration toward malignancy.42
· At least two experienced gastrointestinal pathologists should evaluate all biopsies when diagnosis of dysplasia is considered. Extent of dysplasia can correlate with progression to cancer.46
· If high-grade dysplasia is encountered, intervention is needed:
o Esophagectomy remains an option but is not the only therapy available.
o Endoscopic options include photodynamic therapy, radiofrequency ablation, endoscopic mucosal resection, endoscopic thermal, and cryotherapy.
o Endoscopic mucosal resection should treat all suspected areas of high-grade dysplasia and early esophageal adenocarcinoma.
o Any mucosal irregularity, including nodularity or ulceration, requires intense biopsy and endoscopic mucosal resection if possible, to exclude adenocarcinoma. Endoscopic ultrasound may help further characterize mucosal nodules.
o Radiofrequency ablation is the best ablative technique for treating flat high-grade dysplasia and residual Barrett esophagus mucosa after focal endoscopic mucosal resection.46,47 Follow-up screening endoscopies are required at suggested intervals of 2, 5, and 10 years.46
o When high-grade dysplasia is unifocal, repeat surveillance after 3 months of aggressive PPI therapy can be an option, as mucosal inflammation can rarely lead to histopathologic findings mimicking dysplasia. The risk of development of adenocarcinoma is 30% with high-grade dysplasia.
· Low-grade dysplasia is monitored with more frequent endoscopic biopsy surveillance, typically every 6 months initially, which can subsequently be extended to every 12 months in the absence of progression.
· All patients with Barrett esophagus are maintained on PPI therapy, mainly to heal esophagitis proximal to the Barrett segment, but also because Barrett esophagus is an accurate indicator of abnormal acid exposure times.
Extraesophageal Complications
Extraesophageal complications of GERD include laryngitis, tracheal stenosis, interstitial pneumonitis, aspiration pneumonia, dental erosions, worsening of asthma, and chronic cough. It is not completely clear if reflux of gastric contents can contribute to laryngeal cancer.
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