Esophageal reflux is considered the most common disease encountered by gastroenterologists and general practitioners. It contributes to a large proportion of cases treated by general practitioners (primary care physicians). 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%. Esophageal reflux disease is defined as a condition in which the stomach contents reflux into the esophagus or beyond (oral cavity, larynx, or the lungs), causing troublesome symptoms and or complications. Risk factors contributing to the development of esophageal reflux include age over 50, body mass index above 30, smoking, anxiety, depression, and decreased physical activity. Medicines that modulate the lower esophageal sphincter pressure, including nitrates, calcium blocker agents, anticholinergics, play a role. Recently, non-alcoholic fatty liver disease has been reported to increase the risk of developing reflux esophagitis. The disease is primarily a disorder of the lower esophageal sphincter and can be classified on the presence of symptoms without erosions on endoscopic examination (non-erosive disease, NERD) or symptoms plus esophageal erosions (erosive reflux disease, ERD). While the disease is particularly more common in men, when it occurs in women, it is more likely to be NERD. The diagnosis is usually established based on a combination of presenting symptoms, objective testing with endoscopy, ambulatory reflux monitoring, and response to a proton pump inhibitor (PPI) therapy. Based on the clinical picture, particularly when patients are presenting with typical symptoms, investigations are not needed in these patients. Investigations are usually recommended in patients presenting with atypical symptoms and patients developing complications. Esophageal reflux may result in several complications, including esophagitis, upper gastrointestinal bleeding, anemia, peptic ulcer, peptic stricture, dysphagia, cancer of gastric cardia, and Barrett esophagus. The reflux may also result in extra-gastrointestinal complications, including dental erosions, laryngitis, cough, asthma, sinusitis, and idiopathic pulmonary fibrosis. Reflux esophagitis frequently occurs during pregnancy at any trimester. Usually, these patients do not have heartburn before pregnancy, and in these patients, reflux and heartburn usually resolve after the delivery. The management goals are (i) reduction of weight in patients with obesity and changes in dietary habits to decrease the effects of reflux, (ii) treatment of reflux with PPI, (iii) exploring alternative management plans for patients not responding to PPI, and (iv) management of esophageal reflux complications.
To understand the etiology of reflux esophagitis, we should first discuss the physiological mechanisms that regulate the esophageal functions and minimize esophageal reflux. These factors can be summarized as follows:
First: The complex valvular mechanism at the esophagogastric junction antagonizes the positive abdominal pressure and the negative thoracic pressure and acts together on preventing the reflux of gastric acid contents into the esophagus. This complex valvular mechanism comprises the following components[1][2]:
Second: Protective physiological mechanisms including:
Reflux of gastric contents into the esophagus occurs in healthy individuals, but the amounts refluxed are normally cleared through two main mechanisms (i) Clearance by esophageal peristaltic movement, and (ii) Neutralization of the small acidic residue by weakly alkaline swallowed saliva.
Therefore, the causes of reflux esophagitis could be discussed as follows[1][2]][3][4][5]:
There are a number of factors that increase the risk of development of esophageal reflux including[6][7][8][9]:
There are geographical variations in the distribution of reflux esophagitis. In Western countries, the prevalence of the disease is approximately 10% to 20%, and severe disease is observed in 6% of the population, while in Asian countries, the prevalence is approximately 5%.[5][12]
Reflux esophagitis is equally prevalent among men and women. However, the predominance of esophagitis and Barrett esophagitis in men compared to women is 3:1 and 10:1, respectively.
The incidence of reflux esophagitis is greatest at the age of 60 to 70 years old and decreased slightly thereafter. Genetic variations, environmental factors, and lifestyle play a role in the development and prevalence of esophageal reflux.
Approximately half of the pregnant women complain of reflux during pregnancy: 20% to 30% in the first trimester, 40% to 45% in the second trimester, and 60% in the third trimester.[13] Usually, these patients do not have symptoms such as heartburn before their pregnancy. Only 14% may have infrequent mild heartburn.
Reflux esophagitis and Barrett esophagus are associated with higher body mass index: The association with overweight has odds ratio 1.33, 95% confidence intervals 1.07-1.64, and the association with obesity has odds ratio 1.70, 95% confidence intervals 1.36 to 2.12.[14]
Several medications have been associated with reflux esophagitis symptoms, including drugs acting by modulating the lower esophageal sphincter pressure, including nitrates, calcium blocker agents, anticholinergics, alpha-adrenergic agonists, theophylline, and morphine.
Patients with nonalcoholic fatty liver disease exhibit an increased incidence of reflux esophagitis independent of any confounders.[9]
The pathophysiological mechanisms underlying reflux esophagitis are related to the etiological causes and will be discussed in more detail below.[15][16][17][18][2][1][3]
In reflux esophagitis, toxic substances (gastric acid, pepsin, and bile salts) are brought in contact with esophageal mucosa causing damages to the distal esophageal mucosa, mucosal breaks (can be detected by endoscopy in 30% to 40% of patients with reflux). The histological changes in patients include:
In patients with NERD, dilatation of the intercellular spaces (the most consistent microscopic finding), basal hyperplasia, and papillary elongation may be present.
Eosinophilic infiltration can be present. However, eosinophilic infiltration, particularly of the proximal esophagus, is present in eosinophilic esophagitis, and these two conditions should be differentiated.[22]
Confocal laser endomicroscopy in patients with NERD is characterized by more intrapapillary capillary loop per image compared to control individuals.[23] Also, the diameter of intrapapillary capillary loops and intercellular spaces are greater in reflux esophagitis compared to controls.
1. Typical symptoms: The typical symptoms of reflux esophagitis may include heartburn and acid regurgitation. Heartburn is a burning sensation felt behind the sternum within 60 minutes of eating, precipitated by exercising, and while lying recumbent. The pain usually starts in the epigastrium and radiates towards the neck. However, some patients with severe esophagitis or Barrett's esophagus may be symptom-free and have no heartburn.
Acid regurgitation where the patient may notice a sour or burning fluid in the throat or mouth may be present. Maneuvers increasing intra-abdominal pressure and bending forward could provoke regurgitation of gastric acid.[24]
Some dysphagia may be reported in 30% of patients with reflux esophagitis (usually present in the presence of peptic strictures, Schatzki rings, weak peristalsis, or mucosal inflammation).
Other symptoms include (i) Globus sensation (a sense of a lump in the throat) and (ii) Water brash (increased salivary secretions in response to the acidity of the esophagus).
2. Atypical symptoms: These include the following[25]:
(i) Chest pain: The esophageal reflux pain may mimic cardiac pain, and patients should be evaluated to exclude cardiac causes. Other causes of esophageal causes of 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 than these esophageal disorders.(ii) Chronic cough: Reflux esophagitis is one of the causes of chronic cough. Other causes of chronic cough include post-nasal discharge, asthma, some medications such as angiotensin-converting enzyme inhibitors. The underlying pathogenesis cough in reflux esophagitis can be explained on the basis of acid stimulation of nerve endings in the lower esophagus causing activation of the cough center and cough response.(iii) Asthma: There is an association between asthma and reflux esophagitis. However, it is not clear if this relationship is an association or a cause-effect change. However, the underlying relationship could be explained on the basis of autonomic dysregulation that usually 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 related to medications used in managing asthma such as theophylline, alpha-2 adrenergic receptor agonists may promote reflux by lowering the pressure across the lower esophageal sphincter. (iv) Dental erosions, dysphonia (voice disorder), sore throat, and laryngospasm may be present.
The diagnosis of esophageal reflux is usually made based on a combination of presenting symptoms, objective testing with endoscopy, ambulatory reflux monitoring, and response to a PPI therapy. A good percentage of patients present with typical symptoms of heartburn and gastric regurgitation and do not need investigations to make the diagnosis. Patients presenting with chest pain should be investigated to exclude cardiac causes of chest pain before the commencement of gastrointestinal evaluation.
Patients with atypical symptoms should undergo a diagnostic evaluation with endoscopy and pH monitoring before a PPI trial. Patients presenting with dysphagia should undergo an endoscopic examination to rule out reflux complications (esophageal strictures, peptic ulcerations, malignancy).
Performing endoscopy may be indicated in high-risk groups, particularly overweight, over the age of 50, with chronic esophageal reflux for more than five years. Also, it is indicated in patients at high risk of complications, including Barrett esophagus, dysphagia, anemia, bleeding, and weight loss. Esophageal biopsies should be taken as an adjunct to endoscopic examination, particularly in patients with non-erosive changes and those suspected to have eosinophilic esophagitis.
Esophageal manometry is of limited value in the primary diagnosis of reflux esophagitis disease.
Neither a decrease in lower esophageal sphincter pressure nor the presence of a motility abnormality is specific for the diagnosis of reflux esophagitis disease. However, manometry is recommended before the consideration of anti-reflux surgery (to rule out achalasia or severe hypomotility as in scleroderma-like esophagus where Nissen fundoplication is contraindicated).
Ambulatory reflux monitoring is the only test that allows the determination of abnormal esophageal acid reflux and reflux frequency. In patients with PPI-resistant symptoms, ambulatory 24-h pH-impedance monitoring can be used to assess whether there is a relationship between symptoms and reflux episodes. This test can help to exclude reflux esophagitis, but the test should be carried out after the cessation of PPI therapy.[26]
Patients with atypical symptoms should undergo a diagnostic evaluation with endoscopy and pH monitoring before a PPI trial. Barium studies to diagnose reflux esophagitis 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 and of no value in the diagnosis of reflux esophagitis.[27]
Los Angeles classification of severity of reflux esophagitis- four grades[28]:
Response to therapy with PPI (twice daily) in patients suspected of reflux esophagitis confirms the diagnosis. However, the PPI test is a sensitive but less specific test.[29]
Recommendations for the management of reflux esophagitis include the following [30]:
The differential diagnosis of reflux esophagitis may include[32]:
Complications associated with reflux esophagitis include:
The diagnosis of esophageal reflux is usually made based on a combination of symptoms, objective testing with endoscopy, ambulatory reflux monitoring, and response to a PPI therapy. However, upper endoscopy is not required in patients presenting with typical esophagitis symptoms. Patients presenting with chest pain require investigation to exclude cardiac causes of chest pain.
The majority of patients with reflux esophagitis may present to the general practitioner. The public and patients require education about common presenting symptoms of reflux esophagitis and preventive measures. Because patients may present with atypical symptoms or with complications, healthcare workers, including doctors, gastroenterologists, pulmonary physicians, otolaryngologists, nurses, and pharmacists, all operating as an interprofessional team, need to be aware of the diagnosis, sequelae, and complications. Dentists should be aware of dental changes associated with reflux esophagitis. Patients presenting with atypical symptoms such as chronic cough, asthma, laryngitis, or dysphonia may seek medical advice from pulmonary physicians and otolaryngologists, not aware that esophageal reflux is the primary disease. Performing endoscopy may be indicated in high-risk groups, particularly overweight, over the age of 50, with chronic esophageal reflux. Also, it is indicated in patients at high risk of complications, including Barrett esophagus, dysphagia, and weight loss. Using new classifications to stage reflux esophagitis patients should aim at improving patient management.[35][36]
While the clinicians listed above will drive therapeutic interventions, they should enlist the assistance of the pharmacist. Pharmacists can help determine which agents would best suit the patient presentation, and counsel the patient regarding appropriate administration and dosing, as well as what adverse effects might occur. Nursing can answer patient questions, assess compliance, evaluate treatment progress, and inform the clinician staff of any concerns they encounter. This type of interprofessional teamwork will improve patient outcomes with reflux esophagitis. [Level 5]
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