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A. Introduction and Symptoms [1]navigator

  1. Epidemiology
    1. Heartburn affects ~30% of US adult population at least once per month
    2. Some 33% of these (10% of adult US population overall) has endoscopic esophagitis
    3. 40% of patients with esophagitis resolve spontaneously
    4. 50% of patients with esophagitis have chronic disease
    5. 10% of patients with esophagitis progress to Barrett's Esophagus (see below)
  2. Sour taste in mouth
  3. Substernal burning and tightness ("dyspepsia")
    1. Unexplained or atypical chest pain, often at night
    2. Substernal chest pain without radiation
    3. Patients with non-cardiac chest pain should be evaluated for reflux esophagitis
    4. Omeprazole (proton pump inhibitor, PPI) challenge is cost-effective in these patients [2]
    5. PPI test to rule in GERD is not sufficient for establishing diagnosis [3]
  4. Symptoms increased on lying down and with meals
  5. Presence of dysphagia or bleeding should prompt initial urgent endoscopy
  6. Supraesophageal symptoms may be prominant
    1. Bronchoconstriction (asthma), presenting with cough and wheezing (see below)
    2. Hoarseness, Laryngitis, Vocal Cord Ulcers, Subglottic Stenosis
    3. Cough-syncope
    4. Chronic sinusitis and/or cough with pneumonia
    5. Tooth Erosion

B. Risk Factorsnavigator

  1. Alcohol
  2. Smoking [4]
  3. Medications
    1. Aspirin and NSAIDs - unclear if these are significant risk factors for GERD [4]
    2. Nitrates - reduces lower esophageal sphincter tone
    3. Calcium channel antagonists - reduces lower esophageal sphincter tone
    4. Alendronate (Fosamax®): >1:2400 cases develops chemical esophagitis [5]
    5. Estrogen replacement therapy (ERT) may increase risk [6]
  4. Hiatal Hernia - sliding versus paraesophageal
  5. Obesity [5,6,27]
    1. Obesity associated most often with severely symptomatic GERD
    2. Risk for GERD is 2.8X for BMI>30kg/m2 versus general population
    3. Risk for GERD is 3.3X for men and 6.3X for women with BMI>35kg/m2
    4. Unknown if weight loss improves symptoms, though this is likely
    5. Obesity also associated with increased risk for erosive esophagitis and adenocarcinoma
  6. Helicobacter pylori
    1. Not a risk factor for reflux esophagitis
    2. Eradication of CagA+ strains of H. pylori associated with increase [7] in esophagitis
    3. Eradication of H. pylori had no overall effect on heartburn or esophagitis [15]

C. Etiologynavigator

  1. Mainly due to regurgitation of gastric contents into the esophagus
    1. The lower esophageal sphincter (LES) normal prevents reflux of these gastric contents
    2. GERD occurs with prolonged esophageal exposure to acid and other gastric materials
    3. Abnormal LES function and abnormal gastroesophageal junction anatomy contribute
    4. Bile acids from duodenum may also play a critical role in GERD development
  2. Determinants of Lower Esophageal Sphincter (LES) Function
    1. The LES is composed of internal (esophageal muscle) and external (diaphragm) parts
    2. Intrinsic LES muscular tone may be reduced by vasodilatory medications
    3. These include nitrates and calcium channel blockers
    4. Diaghragmatic musculature (crural portion) may dilate, especially in times of stress
    5. Most cases are associated with transient LES relexations (TLESRs) which reduce sphincter tone
    6. In patients with reflux, most have abnormal TLESRs and normal basal LES tone
    7. GABA, glutamate, serotonin, acetylcholine, and other receptors are involved in these TLESRs
  3. Hiatal Hernia
    1. Defined as acquired herniation of part of the stomach through the diaphragm
    2. With herniation, the LES loses its external (diaphragmatic) component
    3. That is, the esophageal LES muscle does not align with the external crural diaphragm
    4. Thus, diaphragmatic muscle will prevent complete washout of stomach contents from the part of stomach above the diaphragm
    5. Therefore, the LES frequently exposed to stomach contents without external sphincter
    6. So a hiatal hernia contributes mainly to severity and chronicity of disease
  4. Esophageal dysmotility - delayed emptying of esophageal contents may increase risk
  5. Hyperacidity in stomach probably increases risk of GERD also

D. Diagnosisnavigator

  1. Presence of Symptoms and Risk Factors
  2. Response to anti-reflux and/or anti-acid therapy (including omeprazole)
  3. Proton Pump Inhibitor (PPI) Challenge [2,3]
    1. Empiric trial of omeprazole 60mg per day x 7 days with symptom evaluation [2]
    2. Patients with good reduction / elimination of symptoms are very likely to GERD
    3. This evaluation is cost-effective and avoids the need for invasive testing
    4. However, in meta-analysis, sensitivity ~78%, specificity ~54% suggest the test is unreliable
  4. pH Probe in esophagus
    1. Gold standard diagnostic method
    2. pH <4.0 for >4% of a 24 hour monitoring period leads to GERD
  5. Esophageal Manometry
    1. Normal tone is ~20mm Hg
    2. LES tone usually <10mm
    3. Most patients however have inappropriate relaxation of LES
  6. Upper Endoscopy [10]
    1. Definitely indicated for evaluation of chronic dyspepsia
    2. Evaluation for mucosal abnormalities, Barrett's metaplasia, complications (see below)
    3. Early endoscopy may be more cost-effective than H-2 blockers for dyspepsia evaluation
    4. Upper endoscopy should be considered in all patients with poorly controlled reflux symptoms, particularly those >50 years old [11]

E. Complicated Disease [11]navigator

  1. Occurs in 10-20% of persons with GERD
  2. Esophageal Ulceration
  3. Esophageal Stricture
  4. Barrett's Esophagus (see below)
  5. Distal Erosive Esophagitis
  6. Esophageal Adenocarcinoma [12]
    1. Absolute risk in moderate to severe GERD is 0.02% per year
    2. Lower risk in patients with mild or asymptomatic GERD
    3. Very low risk of developing adenocarcinoma over 10-13 years of followup [13]
    4. General screening in patients with GERD only with severe reflux, obesity, possibly male sex []
  7. Carcinoma of the Gastric Cardia
  8. Reflux Induced Asthma [14]
    1. May be due to aspiration of gastric contents to lung leading to bronchospasm
    2. In addition, activation of vagal reflex from esophagus to lung causing bronchocontriction
    3. May represent a normal protective mechanism against aspiration induced lung injury
    4. Proton-pump inhibitors (PPI) may be effective for this syndrome
    5. Must distinguish patients with asthma and GERD from those with asthma from GERD
    6. Empiric trial of high dose H2-blockers or PPIs with new astha is often reasonable
  9. Reflux Induced Chronic Cough [3]
    1. Associated with posterior laryngitis
    2. Sinusitis, pneumonia, syncope (with cough), tooth erosion, subglotic stenosis also seen
    3. Generally responds to PPI

F. Treatment [25]navigator

  1. Therapeutic Classes [13,21]
    1. Non-pharmacologic therapy generally not effective
    2. Trial of H-2 blockers (available without prescription)
    3. PPI are mainstay of therapy and are very safe
    4. PPI are more effective than H-2 blockers, promotility agents, antacids
    5. For severe erosive esophagitis, PPI should be continued >1 year to indefinitely
    6. Laparoscopic surgery is generally as effective as high dose PPI [21]
    7. Surgery may provide minimal or no benefit over continued medical therapy [12,13,21]
  2. Efficacy Overview [22]
    1. <25% of patients will have improved symptoms with placebo
    2. H2-blockers provide symptomatic relief in ~60%; about 30% are healed
    3. PPI provide relief and healing in >90% of patients (low to moderate doses)
    4. High dose PPI (such as omeprazole 60mg qd) procides relief in nearly all patients
  3. Non-Pharmacologic Therapy
    1. Reduce risk factors: smoking, alcohol, NSAIDS, late night eating (see above)
    2. Elevate head of bed when sleeping
    3. Weight loss
    4. maller meals with less fat
  4. Consider changing or reducing medications that relax LES
    1. Nitrates
    2. Ca2+ channel antagonists
    3. Anticholinergic agents
  5. Antacids
    1. Used for intermittent (1-2 episodes per week) GERD
    2. Magnesium based agents (may precipitate diarrhea): Maalox®, Milk of Magnesia®
    3. Calcium based agents (TUMS®, others) - also effective for osteoporosis prophylaxis
    4. Gaviscon® - potent antacid, decreases reflux episodes and better coating (foam agent)
  6. PPI - see below
  7. H2 Blocking agents
    1. Initial treatment should be high dose oral drugs, at least twice daily
    2. Begin at ranitidine 150mg bid, famotidine 20mg bid, cimetidine 300mg tid
    3. May double above doses or increase to tid or qid
    4. Twice daily dosing for 4 weeks, then decrease to once daily (qhs) for 6-8 weeks
  8. Sucralfate
    1. Aluminum salt of sulfated polysaccharide
    2. Coats esophagus, stomach
    3. Minimal side effects, but consider aluminum accumulation in brain and bones
    4. Dosing: 1gm qid orally (slurry now available)
    5. Good for short term, especially in patients with drug reactions
  9. Metoclopramide (Reglan®)
    1. Increases Gastric emptying and promotes intestinal motility
    2. Extra-pyramidal side effects due to dopamine blocking action
    3. May be useful in patients who eat late at night
    4. Dose is 10mg po bid to qid
    5. May cause dystonic reactions at high dose
  10. Cisapride (Propulsid®) - prokinetic (5HT4 agonist) agent, withdrawn from market
  11. Endoluminal Therapies [26]
    1. Radiofreqency energy to cardia and distal esophagus - reduced need for PPI
    2. Endoscopic sutering - reduced need for PPI
    3. These early methods are under development and may provide long term improvement
  12. Surgery (see below) [21]
    1. Nissen Fundoplication is most common operation, may be done laparoscopically
    2. Hiatal Hernia Repair
    3. Surgical treatment is rarely indicated
    4. Consider in young patients with severe reflux, patients with medication intolerance

G. Proton Pump Inhibitors (PPI) navigator

  1. More effective than H-2 blockers, promotility agents, coating agents, antacids
  2. Effective in intractable cases and complicated esophagitis
    1. Barrett Esophagus
    2. Esophageal Ulceration
    3. Esophageal Stricture
  3. Chronic PPI Treatment
    1. If PI must be used for long term, endoscopy should generally confirm diagnosis
    2. Long term treatment with PPI safe and effective for refractory reflux esophagitis
    3. Check gastrin levels and H. pylori titers initially and gastrin after 1 year
    4. Some patients (~10%) will develop very high (>500ng/L) gastrin level on PPI
    5. This suggests atrophic gastritis
    6. PPI can probably be stopped in patients with very high gastrin levels
    7. Biannual upper endoscopy may not be required as Barrett progression is very low [12]
    8. Gastric carcinoid development has not been reported in humans on omprazole >5 years
    9. Omeprazole, esomeprazole, lansoprazole approved by FDA for pediatric use [38]
  4. Healing of Erosive Esophagitis
    1. Esomeprazole (Nexium®) is no more effective than omeprazole (Prilosec®) [28,29]
    2. Lansoprazole (Prevacid®) 15mg qd maintains healing of erosive esophagitis for 1 year [30]
  5. H. pylori Infection
    1. Omeprazole use in patients with H. pylori infection can lead to atrophic gastritis
    2. Biopsy or other test for H. pylori should probably be done before long term PPI therapy
    3. Omeprazole or lansoprazole + antibiotics effectively eradicate H. pylori
  6. Agents and Dosing
    1. Omeprazole (Prilosec® and OTC) 20-40mg po qd; 20mg now available over the counter [31]
    2. Lansoprazole (Prevacid®) 15-30mg qd [30]
    3. Rabeprazole (AcipHex®) 20mg po qd [32]
    4. Pantoprazole (Protonix®) 40 mg qd (least expensive) [33]; 40-80mg IV qd-bid also [34]
    5. Esomeprazole (Nexium®) - S isomer of omeprazole, 20-40mg po qd [28]
    6. No clear benefits of esomeprazole over omeprazole [29]
  7. Vitamin B12
    1. Vitamin B12 absorption is dependent on intrinsic factor made by gastric parietal cells
    2. Suppression of acid production by parietal cells appears to reduce intrinsic factor
    3. Long term acid suppression causes Vitamin B12 malabsorption [35]
    4. Vitamin B12 levels should be monitored in patients on long term acid suppression

H. Endoscopic Stretta Anti-Reflux Procedure [8]navigator

  1. Endoscopically guided radiofrequency energy delivery system (Stretta®)
  2. FDA approved for GERD treatment
  3. Endoscopically guided catheter with baloon at end
    1. Balloon has 4 needle electrodes which insert in LES when balloon inflated
    2. Generator delivers RF energy through catheter to needles to target tissue for ~90 seconds
    3. After delivery, balloon deflated and needles withdrawn, then rotate 45° and repeat
    4. Repeat procedure overy 0.5cm from 1cm agove to 1cm below gastroesophageal junction
  4. Believed to work by stimulating collagen deposition in LES, tightening it
  5. Significant improvement in symptom scores, quality of life; little effect on medication use
  6. Unclear if definitively reduces exposure of LES to acid
  7. Retrosternal chest pain, transient dysphagia, nausea, vomiting, reported
  8. Perforation very rare
  9. Unclear how effective procedure is in severe patients

I. Anti-Reflux Surgery [11,12,13,21]navigator

  1. Effective means of controlling chronic reflux
  2. May now be done as a laparoscopic procedure
  3. Types of Procedures [12,21,36]
    1. Nissen fundoplication - laparoscopic is now standard
    2. Toupet partial fundoplication
    3. Goal is reduction of hiatal hernia and construction of valve mechanism at GE Junction
  4. Surgical Outcomes Similar to PPI Therapy [12,13,21]
    1. About 35% of surgical patients still had to take PPI to control symptoms
    2. Surgery more effective than omeprazole 20mg qd but similar to 40-60mg qd
    3. Very low rates of progression to esophageal adenocarcinoma with surgery or PPI
    4. Increased mortality in patients undergoing surgical versus medical treatment of GERD
    5. Laparoscopic has shorter hospital stay, pain medications, work lost, than open surgery
  5. Risks of Surgery [9,11,21,37]
    1. Currently, 1-2% require repeat surgeries
    2. Esophageal dilatation may be required for stenosis (11%)
    3. Excessive gas, abdominal bloating, dysphagia are fairly common after surgery
    4. Diarrhea in up to 15% may occur, and can be long term
  6. May be useful in patients with complicated disease or reactions to therapies
  7. Surgery is curative in minority of patients and complications do occur

J. Barrett's Esophagus [16,17,18]navigator

  1. Pathophysiology
    1. Exposure of squamous cells to both acid and bile salts induces cell damage and repair
    2. Generation and selection of specific epithelial cell clones (mainly columnar) that resist inorganic acids and bile salts
    3. Mucosal inflammation with T cell infiltration may be required for progression
    4. Increased expression of IL-1ß and TNFa are found in metaplastic areas
    5. Recent data suggest that chronic inflammation is essential for progression of Barrett's
    6. Eventually, squamous epithelium is replaced by columnar epithelium
    7. This initial cell type transition, which is not neoplastic, is called metaplasia
    8. Metaplasia of the esophageal squamous cell lining is called Barrett's Esophagus
    9. Metaplastic tissue (columnar epithelium) is at high risk for developing dysplasia
    10. Low grade dysplasia can become high grade
    11. High grade dysplasia has >30% risk for developing frank adenocarcinoma
  2. Epidemiology
    1. Overall risk for developing cancer with Barrett's is <5% over lifetime [12] or ~1 per 200-300 patient years (0.3-0.5% per year) [19]
    2. Length of segment of metaplasia has a correlation with adenocarcinoma risk [20]
    3. Metaplasia >3cm is considered "long-segment" and probably has highest risk
    4. Metaplasia <3cm is short-segment and may have lower risk for carcinoma
    5. Endoscopy of patients with GERD shows ~4% have long- and ~15% have short-segment
    6. Grade of dysplasia is much better predictor of carcinoma development than segment
    7. Short- and long-segment disease is managed similarly
    8. PPI or surgical therapy may slow progression of Barrett's [12,13]
    9. PPI or surgical therapy do not induce frank regression of Barrett's [16,21]
  3. Risk Factors for Barrett's
    1. Male > Female
    2. Age >45-50
    3. White >> Black or Asian
    4. Long history or GERD (>5 years)
    5. Severe Esophagitis
    6. Esophageal Stricture
    7. Esophageal Ulceration
    8. Reticular pattern or pseudomembranes on barium esophagram
    9. Patients with dysphagia
    10. Scleroderma
    11. GERD related hoarseness or cough
    12. Very long-segments involved (>8cm)
    13. Presence of Helicobacter pylori associated with reduced GERD risk [22]
  4. Molecular Changes in Barrett's Esophagus
    1. Mutations in p53
    2. Overexpression of p16 and cyclin D1 levels
    3. Decreased E-cadherin expression
    4. Loss of heterozygosity of Adenomatous Polyposis Coli (APC) gene
  5. Histology
    1. Continuum of progression from esophagitis to metaplasia to dysplasia to neoplasia
    2. Barrett's is specifically simple columnar epithelium folded to form glandular invaginations
    3. Metaplasia and dysplasia of distal esophagus is most common
    4. Three histologic subtypes of columnar epithelium are found
    5. Specialized columnar epithelium
    6. Junctional-type epithelium
    7. Gastric-Fundic Type Epithelium
    8. Level of dysplasia is classified from 1 (none) to 5 (submucosal adenocarcinoma)
    9. Any area, regardless of segment length, of high grade dysplasia is very concerning [20]
    10. Once Barrett's transformation is initiated, mucosal colonization occurs quickly
  6. Dysplasia within Barrett's
    1. Dysplasia is considered premalignant or frankly malignant (levels 4 and 5)
    2. Risk of developing adenocarcinoma is about 1 case per 100 patient-years
    3. Overall risk of cancer with Barrett's is about 40 fold higher than general population
    4. High grade dysplasia has 30-100% risk of carcinoma development over 8 years
    5. Low grade dysplasia has low risk of carcinoma development
  7. Screening [23,24]
    1. No study has yet shown reduced death by screening GERD patients for Barrett's
    2. Persistent moderate to severe GERD should undergo baseline endoscopy with biopsy
    3. Screening 50 year old men with GERD for Barrett esophagus is cost effective [24]
    4. If no dysplasia, continue suveillance endoscopy at >5 year intervals [24]
    5. If dysplasia present, confirm diagnosis and grade by experienced pathologist
    6. Low grade dysplasia is treated as for GERD but with frequent endoscopy (see below)
    7. High grade dysplasia is treated aggressively
  8. Treatment Overview
    1. Depends on grade of dysplasia and presence of intramucosal neoplasia
    2. Low grade dysplasia can be treated with standard GERD therapy and intermittent biopsies
    3. High grade dysplasia can be treated with high dose anti-refulx agents and surveillance biopsies every 3 months [16]
    4. Any patient with intramucosal cancer, or multiple high grade lesions, should be treated with mucosal ablation
  9. Treatment of Low Grade Dysplasia [16]
    1. Treat patients with low grade dysplasia as for standard GERD
    2. Biopsy low grade dysplastic lesions every 6-12 months then yearly if no progression
    3. This frequency for low grade lesions based on annual progression of ~0.5%
    4. In patients who progress, treat as high grade dysplasia
  10. Treatment of High Grade Dysplasia
    1. Fit patients may undergo esophagectomy, ablation of high grade area, or surveillance
    2. High dose PPI therapy leads to reversal of high grade dysplasia in <40% of cases
    3. Various methods for endoscopic mucosal ablation are available (below)
    4. Mucosal ablation can also be used with intramucosal neoplasia
    5. Esophagectomy is a very difficult operation with 3-12% mortality and 40% complications
  11. Mucosal Ablation [16]
    1. Endoscopic ablation techniques are well tolerated and none appears superior
    2. Photosensitization with 5-aminolevulinic acid can eradicate dysplastic tissue
    3. Porfimer sodium an aproved photosensitizer in USA
    4. Main side effects are photosensitive skin, which can last for 2-3 months
    5. Successful eradication of 77% of cancers, 90% of dysplasias
    6. Electrocoagulation, laser coagulation, or photodynamic therapy all followed by acid suppression therapy can lead to reversal of Barrett's metaplasia [10]
    7. Endoscopic submucosal resection can also be performed, especially with nodules present
  12. Overall, <0.02% risk / year of progression to adenocarcinoma in patients with GERD
  13. Guidelines are also provided by American College of Gastrogenerology www.acg.gi.org

References navigator

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