Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is a chronic condition in which stomach contents flow back into the esophagus, causing irritation to the mucosa. Reflux is primarily caused by an inappropriate, transient relaxation of the lower esophageal sphincter (LES). Risk factors include obesity, stress, certain eating habits (e.g., heavy meals or lying down shortly after eating), and changes in the anatomy of the esophagogastric junction (e.g., hiatal hernia). Typical symptoms are retrosternal burning pain (heartburn) and regurgitation, but the presentation is variable and may also include symptoms like chest pain and dysphagia. Most patients with suspected GERD should receive empirical treatment with proton pump inhibitors (PPIs). Diagnostic studies, e.g., esophagogastroduodenoscopy (EGD) and/or 24-hour pH test, may be indicated to confirm the diagnosis or to rule out other causes of symptoms. Management involves lifestyle modifications, medication, and, in some cases, surgery. Treating esophagitis is especially important because chronic mucosal damage can cause Barrett esophagus, a premalignant condition that can progress to adenocarcinoma.

• Gastroesophageal reflux: regurgitation of stomach contents into the esophagus (can also occur in healthy individuals, e.g., after consuming greasy foods or wine)
• Gastroesophageal reflux disease (GERD)
  • A condition in which reflux causes troublesome symptoms (typically including heartburn or regurgitation) and/or esophageal injury/complications
  • The most common endoscopic finding associated with esophageal mucosal injury is reflux esophagitis. ^[1]
    • NERD (non-erosive reflux disease): characteristic symptoms of gastroesophageal reflux disease in the absence of esophageal injury, such as reflux esophagitis, on endoscopy (50–70% of GERD patients) ^[2]
    • ERD (erosive reflux disease): gastroesophageal reflux with evidence of esophageal injury, such as reflux esophagitis, on endoscopy (30–50% of GERD patients) ^[2]

• Prevalence: ∼ 15–30% in the US (increases with age) ^[3]
• Sex: ♀ = ♂ ^[3]

References:^[3][4]

Epidemiological data refers to the US, unless otherwise specified.

GERD develops when reflux-promoting factors, such as corrosiveness of the gastric juice, overcome protective mechanisms, such as the gastroesophageal junction and esophageal acid clearance.

Mechanisms

• Gastroesophageal junction dysfunction can occur due to the following factors:
  • Increased frequency of transient lower esophageal sphincter relaxations (TLESRs) ^[5]
    • Normally, TLESRs allow for the exit of accumulated gases, which distend the stomach.
    • In individuals with GERD ^[6]
      • About two-thirds of TLERS are also accompanied by reflux of gastric content.
      • The frequency of TLESRs increases.
  • Imbalance between intragastric and lower esophageal sphincter (LES) pressures ^[6]
    • Reflux occurs when the intragastric pressure is higher than that created by the LES.
    • LES tone can be decreased by substances such as caffeine and nitroglycerin, as well as by conditions that cause denervation of the muscle layer, such as scleroderma (see “Risk factors/associations” below).
    • Intragastric pressure is increased in pregnancy, delayed gastric emptying, and obesity, among other conditions.
  • Anatomic abnormalities of gastroesophageal junction (e.g., hiatal hernia, tumors)
• Impaired esophageal acid clearance ^[7]
  • Normally, acid reflux is neutralized by salivary bicarbonate and evacuated back to stomach via esophageal peristalsis.
  • Clearance can be disrupted by reduced salivation (e.g., due to smoking) and/or decreased peristalsis (e.g., due to inflammation).

Risk factors/associations

• Smoking; caffeine and alcohol consumption ^{[7][8] [9]}
• Stress ^[2]
• Obesity ^[10]
• Pregnancy ^[7]
• Angle of His enlargement (> 60°) ^[11]
• Iatrogenic (e.g., after gastrectomy)
• Inadequate esophageal protective factors (i.e., saliva, peristalsis) ^[7]
• Gastrointestinal malformations and tumors: gastric outlet obstruction, gastric cardiac carcinoma
• Scleroderma ^[7]
• Sliding hiatal hernia: ≥ 90% of patients with severe GERD ^[7]
• Asthma

References:^[10][11]

• Typical symptoms
  • Retrosternal burning pain (heartburn)
  • Regurgitation
• Atypical symptoms
  • Pressure sensation in the chest/noncardiac chest pain
  • Belching, bloating
  • Dyspepsia, epigastric pain
  • Nausea
  • Halitosis
• Extraesophageal symptoms
  • Chronic nonproductive cough and nighttime cough
  • Hoarseness
  • Dental erosions
• Aggravating factors
  • Lying down shortly after meals
  • Certain foods/beverages

References:^{[3][4][10][12]}

The histopathological findings include the following (may vary depending on the severity of mucosal damage): ^[13]

• Superficial coagulative necrosis in the nonkeratinized squamous epithelium
• Thickening of the basal cell layer
• Elongation of the papillae in the lamina propria and dilation of the vascular channels at the tip of the papillae (leading to hyperemia)
• Inflammatory cells (granulocytes, lymphocytes, macrophages)
• Transformation of squamous into columnar epithelium leads to Barrett metaplasia ^[14]

Other forms of esophagitis

• Infectious esophagitis: generally in immunocompromised patients
  • Esophageal candidiasis; : Endoscopy shows white or yellow adherent plaques (pseudomembranes).
  • Herpes esophagitis (mainly HSV-1); : Endoscopy shows superficial, punched-out ulcers in the upper or mid esophagus in the absence of plaques.
  • CMV esophagitis; : Endoscopy shows distal mucosal erosions, linear ulcers, and viral inclusion bodies in cell nuclei on biopsy.
• Drug-induced esophagitis: Some medications may cause esophageal mucosal irritation, leading to erosions and ulcers.^[16]
  • Causes
    • Antibiotics (e.g., tetracycline, doxycycline, and clindamycin)
    • Anti-inflammatory drugs, NSAIDs (e.g., aspirin)
    • Bisphosphonates (e.g., alendronate)
    • Others (e.g., potassium chloride, iron compounds, quinidine)
  • Endoscopic findings: punched-out ulcers with mild inflammatory changes of the surrounding mucosa
• Eosinophilic esophagitis
  • Often associated with atopy (e.g., in individuals with allergic asthma, allergic rhinitis, food allergies)
    • Ingestion of food containing allergens may lead to dysphagia and bolus obstruction.
  • Endoscopic findings
    • Circumferential mucosal lesions (rings/corrugations)
    • Longitudinal furrows
    • Mucosal fragility
    • Biopsy: Histological findings include an increased number of eosinophils.
  • Usually does not respond to GERD therapy

The differential diagnoses listed here are not exhaustive.

Approach ^[10][17]

• Typical symptoms: Presume GERD diagnosis and start an empiric PPI trial.
  • Good response: often used to confirm GERD diagnosis
  • Symptoms persist: EGD is indicated.
• Atypical symptoms or alarm features: consider endoscopic evaluation (see “Indications for EGD”).
  • Start treatment based on EGD findings.
  • Consider other studies if inconclusive (e.g., ambulatory esophageal pH monitoring, barium swallow if dysphagia is present).
  • See also “Diagnostic approach for suspected peptic ulcer disease”.
• Extraesophageal symptoms: Rule out other diagnoses first.

If the presenting symptom is chest pain, other diagnoses should be ruled out first. (See “Diagnostics” in “Chest pain” for a comprehensive workup.)

EGD ^{[10][17][18][19]}

• Indications
  • Alarm features
    • Dysphagia, odynophagia
    • Early satiety
    • Anemia or evidence of GI bleeding
    • Persisting vomiting
    • Unintentional weight loss
    • Aspiration pneumonia
  • Risk factors for Barrett esophagus
  • No symptomatic improvement after PPI trial
• Supportive findings (typically in the lowest third of the esophagus) ^[20]
  • Erythema, edema, friability
  • Erosions, mucosal breaks, ulcerations
  • Peptic strictures and rings
  • Salmon-pink mucosa (suggestive of Barrett esophagus)
  • Proximal migration of the gastroesophageal junction (Z line), e.g., in Barrett esophagus or hiatal hernia ^[21]
• Biopsies
  • Not routinely indicated for the diagnosis of GERD
  • Consider for exclusion of other diagnoses or complications (e.g., eosinophilic esophagitis, Barrett esophagus).
  • See “Pathology” for histological findings.

Esophageal pH monitoring ^[10][20]

Esophageal pH monitoring is the gold standard and can be used to objectively identify abnormal reflux of gastric content into the esophagus. It is not a routine diagnostic test. ^[10]

• Indications
  • Refractory GERD symptoms despite PPI therapy
  • Confirmation of suspected NERD
  • Evaluation before surgical or endoscopic antireflux procedure
• Procedure
  • Measurement of esophageal pH over 24–48 hours using a telemetry capsule or a transnasal catheter
  • Documentation of relevant events by the patient
• Supportive finding: Drops in esophageal pH to 4 or less that correlate with symptoms of acid reflux and precipitating activities. ^[23]

Further diagnostic studies ^[10][20]

Not routinely indicated, as they play a limited role in the diagnosis of GERD; useful if endoscopy is inconclusive.

• Esophageal barium swallow: Consider if the main symptom is dysphagia or if there is suspicion of structural abnormalities or motility disorders (see “Diagnostics” in “Dysphagia”).
• Esophageal manometry: Consider if achalasia or esophageal hypermotility disorders are suspected. ^[24]

The initial management of GERD consists of implementing lifestyle changes and initiating acid suppression therapy, preferably with PPIs. Surgical therapy is not routinely indicated and should only be considered in select cases, e.g., patients who develop complications despite receiving optimal medical therapy.

Pharmacological therapy ^[10][19]

See “Antacids and acid suppression medications” for agents, detailed dosages, and pharmacological considerations.

• PPIs: : standard dose of PPI for 8 weeks
  • Indications
    • Empiric PPI trial in patients with typical symptoms
    • After EGD: ERD or presumed NERD
  • Continuous management (based on the clinical response after 8 weeks) ^[25]
    • Good response and no complications: Discontinue PPI.
    • Good response in patients with complications : Continue PPI at maintenance dose.
    • Partial response: Increase dose (to twice daily therapy), adjust timing, or switch to a different PPI.
    • Recurrence of symptoms after discontinuation of PPI or during weaning: Consider confirming the diagnosis (e.g., with ambulatory esophageal pH monitoring) prior to continuing maintenance therapy.
    • No response: further diagnostic evaluation
  • There is controversy surrounding the risks of long-term PPI therapy ^{[26][27][28][29]}
• H₂ receptor antagonists: Consider as alternate maintenance therapy for NERD, or in addition to PPIs to control nighttime symptoms
• Maintenance therapy: lowest effective dose of acid suppression medication
• Adjunctive therapy: Consider adding in patients with partial response to PPIs; Not recommended without confirmatory diagnostic studies
  • Prokinetic medication for patients with gastroparesis: e.g., metoclopramide
  • Baclofen (off-label) for refractory symptoms

Lifestyle changes ^{[10][19][30][31][32]}

There is conflicting evidence as to which lifestyle modifications confer a significant benefit. The following recommendations are commonly mentioned in the literature but should be approached on a case-by-case basis, as they may offer relief only for some patients.

• Dietary recommendations
  • Small portions
  • Avoid eating at least 3 hours before bedtime.
  • Avoid foods/beverages that appear to trigger symptoms. ^[33]
• Physical recommendations
  • Weight loss in patients with obesity
  • Elevate the head of the bed (10–20 cm) for patients with nighttime symptoms.
• Reduce or avoid triggering substances
  • Nicotine, alcohol, caffeine if the patient experiences a correlation with symptoms
  • Medications that may worsen symptoms (e.g., CCBs, diazepam) ^[8]

Surgical therapy ^[10][19][34]

Antireflux surgery may be considered for select patients after careful evaluation. Predictors of successful outcomes include: ^[35][36]

Indications

• Discontinuation of medical therapy (e.g., due to nonadherence or side effects)
• Symptoms refractory to medical therapy
• Complications despite optimal medical therapy, e.g., severe esophagitis, strictures, recurrent aspiration

Fundoplication

• Definition: an antireflux procedure in which the gastric fundus is wrapped around the lower esophagus and secured with stitches to form a cuff; results in a narrowing of the distal esophagus and the gastroesophageal junction (GEJ), preventing reflux
• Approach: Laparoscopic and open fundoplication are possible.
• Techniques ^[35]
  • Partial fundoplication (fewer complications)
    • 180° (Dor fundoplication)
    • 270° (Toupet fundoplication)
  • Complete fundoplication (Nissen fundoplication): 360°
• Complications ^[35]
  • Gas bloat syndrome: inability to belch, leading to bloating and an increase in flatulence
  • Dysphagia
  • Recurrence of reflux esophagitis
• Considerations for patients with comorbidities
  • Patients with obesity and reflux undergoing bariatric surgery: Consider Roux-en-Y.
  • Hiatal hernias: Combine fundoplication with hiatoplasty and, in some cases, gastropexy.

Barrett esophagus ^[19][37][38]

• Definition: intestinal metaplasia of the esophageal mucosa induced by chronic reflux.
  • Histopathological examination of the mucosa shows a columnar epithelium instead of the normal squamous epithelium.
  • A premalignant change that requires close surveillance. ^[37][39]
• Incidence: up to 15% of patients with GERD
• Risk factors for Barrett esophagus ^[10]
  • Male sex
  • European descent
  • Age ≥ 50 years
  • Obesity
  • Symptoms ≥ 5 years
• Pathophysiology
  • Reflux esophagitis → stomach acid damages mucosa of distal esophagus → nonkeratinized stratified squamous epithelium is replaced by nonciliated columnar epithelium and goblet cells (intestinal metaplasia, Barrett metaplasia) ^[14]
  • The physiological transformation zone (Z line) between squamous and columnar epithelium is shifted upwards.
• Pathology
  • Short-segment (< 3 cm of columnar epithelium between Z line and GEJ)
  • Long-segment (> 3 cm of columnar epithelium between Z line and GEJ): higher cancer risk
• Complications: esophageal adenocarcinoma (see “Esophageal cancer”)
• Management and surveillance
  • PPI therapy ^[25]
    • Consider if asymptomatic.
    • Continue maintenance therapy long-term if symptomatic.
  • Endoscopy with four-quadrant biopsies at every 2 cm of the suspicious area (salmon-colored mucosa)
    • If no dysplasia: Repeat endoscopy every 3–5 years.
    • If indefinite for dysplasia: Repeat endoscopy with biopsies after 3–6 months of optimized PPI therapy.
    • If low-grade dysplasia:
      • Endoscopic therapy of mucosal irregularities
      • Alternatively: surveillance every 6-12 months with biopsies every 1 cm
    • If high-grade dysplasia: endoscopic treatment of mucosal irregularities, e.g., radiofrequency ablation
  • Consider antireflux surgery or resection of the segment based on a specialist's evaluation. ^[35][36]

Additional complications

• Reflux esophagitis: most common complication of GERD ^[40]
• Iron deficiency anemia: mucosal erosions and ulcerations → chronic bleeding → anemia
• Esophageal stricture
  • Etiology: most common sequela of reflux esophagitis; or ingestion of caustic substances ^[40]
  • Clinical features: solid food dysphagia
  • Diagnostics
    • Barium esophagram (best initial test): narrowing of the esophagus at the gastroesophageal junction
    • Endoscopy with biopsies: to rule out malignancy and eosinophilic esophagitis
  • Treatment
    • First-line treatment: dilation with bougie dilator/balloon dilator and PPIs in patients with reflux
    • In refractory cases (multiple recurrences): steroid injection prior to dilation; endoscopic electrosurgical incision
  • Recurrence occurs in the majority of patients; multiple treatment attempts are often necessary.
• Esophageal ring ^[41]
  • Schatzki rings: narrowing of the esophagus
    • Most commonly seen at the squamocolumnar junction
    • Usually caused by chronic acid reflux
    • Can lead to dysphagia
• Complications due to aspiration of gastric contents
  • Aspiration pneumonia
  • Chronic bronchitis
  • Asthma (exacerbation)
• Reflux laryngitis: hoarseness (due to laryngopharyngeal reflux)

We list the most important complications. The selection is not exhaustive.