Continuing Education Activity

Reflux esophagitis is considered one of the most common diseases encountered by gastroenterologists and contributes to a large proportion of cases treated by primary care providers. It 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 complications. This activity reviews the evaluation and management of esophageal reflux and highlights the role of the interprofessional team in evaluating and improving care for patients suffering from esophageal reflux.

Objectives:

• Identify the etiology of reflux esophagitis.
• Describe the options to diagnose reflux esophagitis.
• Outline the current management options used in reflux esophagitis.
• Identify interprofessional team strategies for improving care coordination and outcomes in patients with reflux esophagitis.

Introduction

Reflux esophagitis is considered one of the commonest diseases encountered by gastroenterologists and primary care providers. Reflux esophagitis is defined as inflammation of the esophageal mucosa secondary to gastroesophageal reflux disease (GERD), a condition in which the stomach contents reflux into the esophagus or beyond (oral cavity, larynx, or the lungs), causing troublesome symptoms and complications.

The American College of Gastroenterology defines GERD as “chronic symptoms or mucosal damage incurred by the abnormal reflux of gastric contents into the esophagus.”[1][2] It contributes to a large proportion of cases treated by primary care providers. 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%.[3][4] 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 channel blocker agents, and 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. It can be classified based 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, it is more likely to be NERD when it occurs in women. 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.[5] 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.[6] The reflux may also result in extra-gastrointestinal complications, including dental erosions, laryngitis, cough, asthma, sinusitis, and idiopathic pulmonary fibrosis.[7] 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:

• Reduction of weight in patients with obesity and changes in dietary habits to decrease the effects of reflux
• Treatment of reflux with PPI
• Exploring alternative management plans for patients not responding to PPI
• Management of esophageal reflux complications

Etiology

To understand the etiology of reflux esophagitis, the physiological mechanisms that regulate esophageal functions and minimize esophageal reflux should be understood first. These factors can be summarized as follows:

1. The complex valvular mechanism at the esophagogastric junction antagonizes the positive abdominal pressure and the negative thoracic pressure and acts together to prevent the reflux of gastric acid contents into the esophagus. This complex valvular mechanism comprises the following components:[8][9]
   • The lower esophageal sphincter: This physiological sphincter is composed of different muscle fibers spinning 3 to 5 cm in length and coordinating the passage of food into the stomach and preventing the regurgitation of gastric contents into the esophagus.
   • Diaphragm: The diaphragm plays an essential role as the esophagus enters the abdomen through the hiatus. The diaphragm works as an extrinsic component to support the lower esophageal sphincter function.[10]
   • Abdominal part of the esophagus: This part of the esophagus is exposed to the positive intra-abdominal pressure causing a collapse of this part of the esophagus and thus supporting the lower esophageal sphincter.
   • The angle of His: This is the acute angle between the esophagus and the gastric fundus. Such design enhances the function of the lower esophageal sphincter.
   • Phreno-esophageal membrane: This is a fibroelastic ligament that is a continuation of the transversalis fascia that leaves the diaphragm and surrounds the esophagus.
2. Protective physiological mechanisms include:
   • Esophageal motility: The peristaltic movement of the esophagus enables the movement of any regurgitated acid to return to the stomach.[11][12]
   • Saliva production: Swallowed saliva (alkaline) helps neutralize any acids at the lower esophagus.
   • Esophageal epithelial protection: This mechanism comprises pre-epithelial, epithelial, and post epithelial mechanisms (the three mechanisms are discussed later).

Reflux of gastric contents into the esophagus occurs in healthy individuals, but the amounts refluxed are normally cleared through two main mechanisms:

1. Clearance by esophageal peristaltic movement
2. Neutralization of the small acidic residue by weakly alkaline swallowed saliva

Therefore, the causes of reflux esophagitis could be discussed as follows:[8][9][13][14][15]

• Transient relaxation of the lower esophageal sphincter or a low resting lower esophageal sphincter pressure
• Presence of a hiatus hernia
• Increased intra-abdominal fat, as is the case in obesity, and increased intra-abdominal pressure, such as in pregnancy and patients with ascites
• Impairment of the normal defense mechanisms, including esophageal peristalsis (dysregulation of esophageal peristalsis)
• Impairment of saliva production due to several causes, including chronic inflammation of the salivary glands
• Impairment of esophageal mural defense mechanisms

 The factors that increase the risk of development of esophageal reflux include:[16][17][18][19]

• White males over the age of 50 and a family history of reflux esophagitis
• Central obesity: This is associated with ERD and complications, including Barrett esophagus and adenocarcinoma[18]
• Tobacco smoking is considered an etiological factor of reflux esophagitis, while alcohol consumption is considered a triggering factor of reflux[20]
• Delayed gastric emptying
• Esophageal dysmotility
• Increased abdominal pressure
• Hiatus hernia
• Non-alcoholic fatty liver disease[19]
• Decreased thoracic pressure, such as in chronic chest problems
• Psychosocial stress and the severity of reflux esophagitis correlate with the degree of stress[21]

Epidemiology

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%.[15][22] Reflux esophagitis is equally prevalent among men and women.[23] However, the predominance of esophagitis and Barrett esophagitis in men compared to women is 3:1 and 10:1, respectively. Some studies report a higher frequency of reflux esophagitis in men, whereas others report an increased frequency in women.[24][25] The incidence of reflux esophagitis is greatest at the age of 60 to 70 years and decreases slightly thereafter. As observed in adults, GERD is also increasingly seen in the pediatric population. Nelson et al. reported incidence of GERD ranging between 12% and 50% in children aged 0-18 years from the year 2000 to 2005.[26] Gastroesophageal reflux exists universally in preterm infants.[27] Genetic variations, environmental factors, and lifestyle play a role in developing 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.[28] 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 an odds ratio of 1.33, 95% confidence intervals of 1.07-1.64, and the association with obesity has an odds ratio of 1.70, 95% confidence intervals 1.36 to 2.12.[29]

Several medications have been associated with reflux esophagitis symptoms, including drugs acting by modulating the lower esophageal sphincter pressure, including nitrates, calcium channel 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.[19]

Pathophysiology

The pathophysiological mechanisms underlying reflux esophagitis are related to the etiological causes and will be discussed in more detail below.[30][31][32][33]

• Transient relaxation of the lower esophageal sphincter: This change results in regurgitation of the gastric acid, peptic enzymes, and bile acids into the esophagus. In patients with increased intra-abdominal pressure (patients with ascites and pregnant women), this effect is enhanced.

• Hiatus hernia: The presence of a hernia disturbs the anatomical relationship between the crural diaphragm and the lower esophageal sphincter function. Also, hernias act as a reservoir for gastric contents, which can reflux into the esophagus during swallowing (relaxation of the lower esophageal sphincter).

• Increased intra-abdominal fat: The change increases the gastroesophageal pressure gradient and increases the frequency of transient lower esophageal sphincter relaxation phase. These changes result in the reflux of the stomach contents into the esophagus.[34][35]

• Impairment of the physiological defense mechanisms: For example, dysregulation of esophageal peristalsis could result in ineffective clearance of acids from the lower esophagus.

• Impairment of saliva production could impair the role of saliva in neutralizing the acids refluxed into the esophagus.

• Impairment of esophageal mural defense mechanisms: This comprises three different mechanisms:
  • A pre-epithelial barrier (unstirred water layer combined with bicarbonate from swallowed saliva and the secretion of submucous glands).
  • Epithelial defense mechanisms include tight intercellular junctions, cellular, intercellular buffers, and cell membrane transporters.
  • Post-epithelial line of defense, including blood supply to the esophagus.

• The pathogenesis of reflux esophagitis 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 (NF), causing increased pro-inflammatory cytokines and migration of T cells inflammatory cells, causing damage to the esophagus.[36][37][38]

Histopathology

In reflux esophagitis, toxic substances (gastric acid, pepsin, and bile salts) are brought in contact with esophageal mucosa causing damage to the distal esophageal mucosa and mucosal breaks that can be detected by endoscopy in 30% to 40% of these patients. The histology of reflux esophagitis is not specific, as the histologic changes may also be present in other pathologic states, such as in adjacent mucosa in esophageal cancer.[39] The histological changes of reflux esophagitis include:[40]

• 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

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.[41]

Confocal laser endomicroscopy in patients with NERD is characterized by more intrapapillary capillary loops per image than in control individuals.[42] Also, the diameter of intrapapillary capillary loops and intercellular spaces are greater in reflux esophagitis compared to controls.

History and Physical

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. It is usually precipitated by exercising and lying in a recumbent position. The pain usually starts in the epigastrium and radiates towards the neck. However, some patients with severe esophagitis or Barrett esophagus may be symptom-free and have no heartburn.[43]

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.[44]

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:

• Globus sensation (a sense of a lump in the throat)
• Water brash (increased salivary secretions in response to the acidity of the esophagus)[45]

Atypical Symptoms

These include the following:[46]

• Chest pain: The esophageal reflux may mimic cardiac pain, and patients should be evaluated to exclude cardiac causes.[47] 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.
• Chronic cough: Reflux esophagitis is one of the causes of chronic cough.[48] Other causes of chronic cough include post-nasal discharge, asthma, and some medications such as angiotensin-converting enzyme inhibitors. The underlying pathogenesis of cough in reflux esophagitis can be explained based on acid stimulation of nerve endings in the lower esophagus causing activation of the cough center and cough response.
• Asthma: There is an association between asthma and reflux esophagitis.[49] However, it is unclear whether this relationship is an association or a cause-effect change. However, the underlying relationship could be explained based on 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 medications used to manage asthma, such as theophylline, and alpha-2 adrenergic receptor agonists, which may promote reflux by lowering the pressure across the lower esophageal sphincter.
• Dental erosions, dysphonia (voice disorder), sore throat, and laryngospasm may be present.[50]

Evaluation

The diagnosis of reflux esophagitis is usually made based on a combination of presenting symptoms, objective testing with endoscopy, ambulatory reflux monitoring, and response to a PPI therapy.[51] 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.[52] 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, and 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 an adjunct to endoscopic examination, particularly in patients with non-erosive changes and those suspected to have eosinophilic esophagitis.[53]

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 considering 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 exclude reflux esophagitis, but the test should be carried out after the cessation of PPI therapy.[54]

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 is of no value in the diagnosis of reflux esophagitis.[55]

Los Angeles classification of severity of reflux esophagitis-four grades:[56]

• Grade A: One or more esophageal mucosal breaks less than 5 mm in length.
• Grade B: One or more mucosal breaks greater than 5 mm but with continuity across mucosal folds.
• Grade C: Continuous mucosal breaks between the tops of two or more mucosal folds but involving less than 75% of the esophageal circumference.
• Grade D: Mucosal breaks involving more than 75% of the esophageal sphincter.

Response to therapy with PPI (twice daily) in patients suspected of reflux esophagitis confirms the diagnosis. However, the PPI test is sensitive but has less specificity.[57]

Treatment / Management

Recommendations for the management of reflux esophagitis include the following:[58]

• Weight loss, particularly in overweight patients and patients with obesity, will help in reducing the severity and frequency of symptoms.[59]
• Elevating the head of the bed during sleep and avoiding meals two to three hours before sleep will reduce reflux at night.[60]
• Avoiding certain foods such as chocolate, caffeine, alcohol, and spicy food may help.[61]
• Treatment of patients with a proton pump inhibitor for eight weeks is recommended. Usually, initiated once daily before the first meal of the day. If there is a partial response, the dose should be increased to twice daily. PPIs are safe in pregnant women if clinically indicated.
• Maintain PPI therapy for patients who continue to have symptoms and patients with erosive esophagitis and Barrett esophagus.
• Patients who need PPI therapy for longer durations or life because of recurrence of symptoms should be placed on the lowest dose required for maintenance. Chronic use of PPI is associated with complications, including increased risk of bone fractures, electrolyte deficiencies, and renal insufficiency.
• Patients not responding to PPIs treatment should be evaluated by the provider. In addition, other disorders should be considered, including eosinophilic esophagitis, delayed gastric emptying, irritable bowel syndrome, achalasia, and psychological disorders.
• Surgical therapy is as effective as medical therapy in patients with chronic reflux esophagitis. It offers long-term treatment. Patients should be investigated (preoperative manometry) for surgery to rule out achalasia and scleroderma-like esophagus.
• Vonoprazan fumarate tablet (a new synthesized potassium-competitive acid blocker), used on-demand, is an effective alternative maintenance therapy for mild reflux esophagitis.[62]
• In patients with obesity, bariatric surgery- gastric bypass is usually recommended.
• Management of reflux complications such as Schatzki rings by esophageal dilatation followed with PPI treatment; esophageal adenocarcinoma; laryngitis; and idiopathic pulmonary fibrosis.

Differential Diagnosis

 The differential diagnoses of reflux esophagitis may include:[63]

• 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

Prognosis

Many patients with esophageal reflux do well with medications, but relapse after stopping medical treatment is common and indicates the need for long-term maintenance therapy. In refractory cases or when complications related to reflux disease are identified (e.g., stricture, aspiration, airway disease, Barrett esophagus), surgical treatment (fundoplication) is typically necessary. The prognosis with surgery is considered excellent. The surgical morbidity and mortality are higher in patients who have complex medical problems in addition to esophageal reflux. About 10% of patients with reflux develop Barrett esophagus, a precursor for adenocarcinoma of the esophagus.[64]

Complications

Complications associated with reflux esophagitis include:

• Esophagitis varies in severity. Patients with Grade C and D in LA classification are characterized by severe reflux. These patients have the lowest healing rate with PPIs. Patients with severe reflux esophagitis usually relapse after treatment and are more likely to develop Barrett esophagus. These patients should undergo endoscopy 8 to 10 weeks after PPI therapy to check on healing and assess for complications.[65][66]
• Lower esophageal rings (Schatzki)- This complication correlates with reflux esophagitis. Dilatation is the mainstay of management, followed by PPI treatment.
• Barrett esophagus: This complication presents in 5% to 15% of patients with reflux esophagitis. It is more likely to occur in White male patients with severe reflux esophagitis, who have the symptoms for a longer duration, and are over the age of 50.
• Peptic stricture tends to occur in older patients who have reflux for a longer duration, with abnormal esophageal motility and not receiving treatment for the reflux symptoms.
• Esophageal adenocarcinoma (8 to 1 male to a female)
• Peptic ulceration, gastric cardia cancer, dysphagia, and upper gastrointestinal bleeding.
• Other complications include anemia (due to chronic blood loss), laryngitis, cough, sinusitis, bronchial asthma, idiopathic pulmonary fibrosis, and dental erosions.

Deterrence and Patient Education

Lifestyle modifications are an important part of treatment for esophageal reflux. Patients are counseled to make the following changes in their lifestyle:

• Weight loss (if overweight)
• Avoid alcohol, chocolate, citrus juice, peppermint, and coffee
• Avoid large meals
• Wait three hours after a meal before lying down
• Elevate the head of the bed by 8 inches
• Avoid bending or stooping

Pearls and Other Issues

The diagnosis of esophageal reflux is usually based on symptoms, objective testing with endoscopy, ambulatory reflux monitoring, and response to a PPI therapy. However, upper endoscopy is not required in patients presenting typical esophagitis symptoms. In addition, patients presenting with chest pain require investigation to exclude cardiac causes of chest pain.

Enhancing Healthcare Team Outcomes

The majority of patients with reflux esophagitis may present to the primary care provider. The public and patients require education about common presenting symptoms of reflux esophagitis and preventive measures. Because patients may present with atypical symptoms or complications, healthcare workers, including providers, gastroenterologists, pulmonologists, 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 pulmonologists and otolaryngologists, not aware that esophageal reflux is the primary disease. Performing endoscopy may be indicated in high-risk groups, particularly overweight, over 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 improve patient management.[67][68]

While the providers listed above will drive therapeutic interventions, they should enlist the pharmacist's assistance. Pharmacists can help determine which agents would best suit the patient's presentation and counsel the patient regarding appropriate administration and dosing and what adverse effects might occur. Nursing can answer patient questions, assess compliance, evaluate treatment progress, and inform the provider staff of any concerns they encounter. This type of interprofessional teamwork will improve patient outcomes with reflux esophagitis. [Level 5]