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:
  
  
  
  • Avoid large meals.
    
  • Avoid eating 2 to 3 hours before lying down.
    
  • Avoid foods and beverages that can decrease the lower esophageal sphincter pressure (e.g., chocolate, peppermint, caffeine, and alcohol).
    
  • 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.
    
  • Avoid tight-fitting garments.
    
  • Lose weight.
    
  • 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).
    
  • 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:
  
  
  
  • Esophagectomy remains an option but is not the only therapy available.
    
  • Endoscopic options include photodynamic therapy, radiofrequency ablation, endoscopic mucosal resection, endoscopic thermal, and cryotherapy.
    
  • Endoscopic mucosal resection should treat all suspected areas of high-grade dysplasia and early esophageal adenocarcinoma.
    
  • 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.
    
  • 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
    
  • 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.

REFERENCES

1. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastroesophageal reflux disease: a systematic review. Gut 2005;54:710–717.

2. Locke GR III, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastro-esophageal reflux: a population based study in Olmstead County, Minnesota. Gastroenterology 1997;112:1448–1456.

3. Galmiche JP, Janssens J. The pathophysiology of gastro-oesophageal reflux disease: an overview

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