1. GASTROESOPHAGEAL REFLUX DISEASE (GERD)
Fall 2014

3. Gastroesophageal Reflux Disease (GERD)
Gastroesophageal reflux (GER) is defined as the retrograde passage of gastric contents from the stomach into the esophagus. It is primarily the result of transient relaxation of the LES.
Gastroesophageal reflux is a normal physiologic phenomenon experienced intermittently by most people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury (ie, esophagitis).
LES: Lower Esophageal Sphincter

4. GERD should be defined as symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung. GERD can be further classified as the presence of symptoms without erosions on endoscopic examination (non-erosive disease or NERD) or GERD symptoms with erosions present (ERD).

5. High Prevalence of Gastroesophageal Reflux Symptoms
The symptoms of heartburn and regurgitation NOT the CONFIRMED GERD could be experienced by as many as 59% of the population at least once a month.
Locke et al. Gastroenterology 1997;112:1148.

6. Heartburn is a common problem in the United States and in the Western world. Approximately 7% of the population experience symptoms of heartburn daily. An abnormal esophageal exposure to gastric juice is probably present in 20-40% of this population, meaning 20-40% of the people who experience heartburn do indeed have gastroesophageal reflux disease (GERD). In the remaining population, heartburn is probably due to other causes. Because many individuals control symptoms with over-the-counter (OTC) medications and without consulting a medical professional, the condition is likely underreported.

7. Epidemiology
GERD is a chronic disease that affects patients across all age groups with equal distribution between men and women. The prevalence of GERD appears to be greater in the Western population with patients presenting with more clinically important disease and complications than in Eastern countries (especially Asian populations) where GERD is uncommon.
It has also been estimated that 7% of the U.S. population have complicated GERD associated with erosive esophagitis.
Up to 75% of patients who undergo endoscopic procedures due to symptoms associated with GERD have normal esophageal findings. These patients are identified as having functional heartburn, NERD, or endoscopy-negative reflux disease (ENRD).
Childhood GERD appears to continue into adolescence and adulthood. Although most infants develop physiological regurgitation, or spitting up, the majority (95%) will have abatement of symptoms by 1.0 to 1.5 years of age. infants with persisting symptoms beyond 2 years of age are at risk of developing complicated GERD.

8. Complications associated with GERD include esophageal erosions (5%), strictures (4%–20%), and Barrett's metaplasia (8%–20%). Male gender and advancing age (men and women) are associated with an increase in the prevalence of esophageal complications, presumably due to refluxed acidic contents damaging the mucosa over time. No sexual predilection exists.
The prevalence of GERD increases in people older than 40 years.
Approximately 50% of patients with gastric reflux develop esophagitis.

9. The physiologic and anatomic factors that prevent the reflux of gastric juice from the stomach into the esophagus include the following:
The lower esophageal sphincter (LES) must have a normal length and pressure and a normal number of episodes of transient relaxation (relaxation in the absence of swallowing).
The gastroesophageal junction must be located in the abdomen so that the diaphragmatic crura can assist the action of the LES, thus functioning as an extrinsic sphincter. The presence of a hiatal hernia disrupts this synergistic action and can promote reflux.
Esophageal clearance must be able to neutralize the acid refluxed through the LES. (Mechanical clearance is achieved with esophageal peristalsis. Chemical clearance is achieved with saliva.)
The stomach must empty properly.

10. Pathophysiology
Abnormal gastroesophageal reflux is caused by the abnormalities of one or more of the following protective mechanisms:
1) Transient Relaxations of the Lower Esophageal Sphincter.
The LES, when in a resting state, remains at a high pressure (10–30 mmHg) to prevent the gastric contents from entering into the esophagus.
Pressures are lowest during the day and with meals and highest at night.
Transient relaxations of the LES are short periods of sphincter relaxation that are different from those that occur with swallowing or peristalsis. They occur due to vagal stimulation in response to gastric distension from meals (most common), gas, stress, vomiting, or coughing and can persist >10 seconds. These transient relaxations of the LES are associated with virtually all GER events in healthy individuals but account for 50% to 80% of occurrences in patients with pathogenic GERD

11. 2) Esophageal Acid Clearance and Buffering Capabilities.
Peristalsis is the primary mechanism by which acid refluxate is removed from the esophagus. Other mechanisms include swallowing, esophageal distension in response to refluxate, and gravity (which is only effective when the patient is in an upright position).
Saliva plays an important role in the neutralization of gastric acid within the esophagus. Its bicarbonate-rich content buffers the residual acid that remains in the esophagus after peristalsis
The reduction of swallowing that occurs during sleep is associated with nocturnal GERD. Patients with decreased saliva production (e.g., elderly, patients taking medication with anticholinergic effects, and those with certain medication conditions such as xerostomia or Sjogren's syndrome) may also be at increased risk of developing GERD

12. 3) Anatomic Abnormalities. 4) Gastric Emptying 5) Mucosal Resistance
6) Aggressive Factors Associated With Esophageal Damage
Hiatal hernia (protrusion of the upper portion of the stomach into the thoracic cavity due to weakening in the diaphragmatic muscles) is frequently described as a cause of GERD, but its causal relationship remains uncertain.
Delayed gastric emptying increases the volume of gastric fluid remaining within the stomach that is available for reflux and is associated with gastric distension.
The capability of the esophageal mucosa to endure contact with and withstand injury from gastric refluxate (acid and pepsin) is a substantial determinate for the development of GERD
The gastric refluxate, which is composed primarily of gastric acid and pepsin, is the primary aggressive factor associated with GERD. The development and degree of mucosal damage is dependent on the pH and contents of the refluxate as well as the total exposure time of refluxate with the esophageal mucosa. A pH <4 is usually required to produce injury to the esophageal mucosa, but as the refluxate becomes more acidic, the mucosal damage is accelerated

15. Clinical Presentations of GERD
Classic (Typical) GERD
Extraesophageal (Atypical) GERD
Complicated GERD

16. Dysphagia
Difficulty swallowing: food sticks or hangs up
Odynophagia
Retrosternal pain with swallowing

18. Extraesophageal Manifestations of GERD
Pulmonary
Asthma
Aspiration pneumonia
Chronic bronchitis
Pulmonary fibrosis
Other
Chest pain
Dental erosion
ENT
Hoarseness
Laryngitis
Pharyngitis
Chronic cough
Globus sensation
Dysphonia
Sinusitis
Subglottic stenosis
Laryngeal cancer

19. Potential Oral and Laryngopharyngeal Signs Associated with GERD
Edema and hyperemia of larynx
Vocal cord erythema, polyps, granulomas, ulcers
Hyperemia and lymphoid hyperplasia of posterior pharynx
Interarytenyoid changes
Dental erosion
Subglottic stenosis
Laryngeal cancer
Vaezi MF, Hicks DM, Abelson TI, Richter JE. Clin Gastro Hep 2003;1:

20. Gastroesophageal reflux disease (GERD) can cause typical (esophageal) symptoms or atypical (extraesophageal) symptoms.
However, a diagnosis of gastroesophageal reflux disease (GERD) based on the presence of typical symptoms is correct in only 70% of patients. Therefore, GERD cannot be confirmed solely based on clinical symptoms.

21. Even though diagnosis of GERD cannot be confirmed based on symptoms alone, ACG guidelines recommend empiric treatment to be initiated with the presence of classic symptoms/history of GERD

22. When to Perform Diagnostic Tests
Uncertain diagnosis
Atypical symptoms
Symptoms associated with complications
Inadequate response to therapy
Recurrent symptoms
Prior to anti-reflux surgery

23. Diagnostic Tests for GERD
Barium swallow
Endoscopy
Ambulatory pH monitoring
Esophageal manometry

24. Barium Swallow
A barium esophagogram is particularly important for patients with gastroesophageal reflux disease (GERD) who experience dysphagia due to:
Stricture (location, length)
Mass (location, length)
Bird’s beak
Hiatal hernia (size, type).
Limitations
Detailed mucosal exam for erosive esophagitis, Barrett’s esophagus

25. Endoscopy Indications for endoscopy Alarm symptoms
Empiric therapy failure
Preoperative evaluation
Detection of Barrett’s esophagus

27. Ambulatory 24 hr. pH Monitoring
Physiologic study
Quantify reflux in proximal/distal esophagus
% time pH < 4
DeMeester score
Symptom correlation

28. Ambulatory 24 hr. pH Monitoring
Normal
GERD

29. Wireless, Catheter-Free Esophageal pH Monitoring
Potential Advantages
Improved patient comfort and acceptance
Continued normal work, activities and diet study
Longer reporting periods possible (48 hours)
Maintain constant probe position relative to SCJ

30. Esophageal Manometry Limited role in GERD
Assess LES pressure, location and relaxation
Assist placement of 24 hr. pH catheter
Assess peristalsis
Prior to antireflux surgery

32. Treatment Goals for GERD
Eliminate symptoms
Heal esophagitis
Manage or prevent complications
Maintain remission

36. Step-wise progression of GERD therapy
Phase I: Mild/occasional symptoms. Do not seek medical help. Phase II a: Persistent symptoms, mucosal damage. Phase II b: Severe mucosal damage. Phase III: Refractory disease. The following table summarizes the pharmacologic treatments for the different phases.

37. OTC PPI products are all approved only for either a prn use or daily use for 2 weeks only. Prescription PPI should NEVER be used prn.

39. Phase II a: Persistent symptoms, mucosal damage.
Cimitidine 400 mg bid, ranitidine 150 mg bid, famotidine 20 mg bid, nizatidine 150 mg bid.
Metoclopramide mg ac and HS
Phase II b: severe mucosal damage.
Cimitidine 800 mg bid or 400 mg qid, ranitidine 150 mg qid, famotidine 40 mg bid, nizatidine 150 mg qid
PPI

40. Phase III: refractory disease. Anti-reflux surgery.
PPI bid for a short period of time. If no improvement, consider surgery.
Approximately 80% of patients have a recurrent but nonprogressive form of gastroesophageal reflux disease (GERD) that is controlled with medications. Identifying the 20% of patients who have a progressive form of the disease is important, because they may develop severe complications, such as strictures or Barrett esophagus. For patients who develop complications, surgical treatment should be considered at an earlier stage to avoid the sequelae of the disease that can have serious consequences.

41. Indications for fundoplication include the following:
Patients with symptoms that are not completely controlled by PPI therapy can be considered for surgery. Surgery can also be considered in patients with well-controlled gastroesophageal reflux disease (GERD) who desire definitive, one-time treatment.
The presence of Barrett esophagus is an indication for surgery. Whether acid suppression improves the outcome or prevents the progression of Barrett esophagus remains unknown, but most authorities recommend complete acid suppression in patients with histologically proven Barrett esophagus.

42. The presence of extraesophageal manifestations of gastroesophageal reflux disease (GERD) may indicate the need for surgery. These include the following: (1) respiratory manifestations (eg, cough, wheezing, aspiration); (2) ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media); and (3) dental manifestations (eg, enamel erosion).
Young patients
Poor patient compliance with regard to medications
Postmenopausal women with osteoporosis
Patients with cardiac conduction defects
Cost of medical therapy

43. Laparoscopic fundoplication
Laparoscopic fundoplication is performed under general endotracheal anesthesia. Five small (5- to 10-mm) incisions are used (see image below). The fundus of the stomach is wrapped around the esophagus to create a new valve at the level of the gastroesophageal junction.

47. Treatment
Antacids
Over the counter acid suppressants and antacids appropriate initial therapy
Approx 1/3 of patients with heartburn-related symptoms use at least twice weekly
More effective than placebo in relieving GERD symptoms
Antacids were the standard treatment in the 1970s and are still effective in controlling mild symptoms of gastroesophageal reflux disease (GERD). Antacids should be taken after each meal and at bedtime.

48. Antacids: work within 5-15 minutes. Duration of relief 1-3 hours
Antacids: work within minutes. Duration of relief 1-3 hours. An adult dose is about mEq acid-neutralizing capacity (ANC) taken 4-5 times daily.
Sodium Bicarbonate
Calcium Carbonate
Aluminum Hydroxide
Magnesium Hydroxide
Magnesium-Aluminum Hydroxides
Possible interactions with tetracyclines, quinolone antibiotics, iron supplements, digoxin, azithromycin.

49. Alginic acid: works by forming sodium alginate which is a viscous solution that floats on the surface of gastric contents so that when reflux occurs, sodium alginate rather than acid is refluxed and irritation is minimized.
Tablets should be chewed and taken with a full glass of water.
Should be taken when patients are in an upright position. NOT at bedtime.

50. Common Alginic Acid Products
Advance is double strength and has antacid (1000 mg of Na-alginate and 200 mg of K-HCO3 (potassium bicarbonate) per 5 mL)

53. Treatment: H-2 Blockers
Histamine H2-receptor antagonists are the first-line agents for patients with mild to moderate symptoms and grades I-II esophagitis. Histamine H2 receptor antagonists are effective for healing only mild esophagitis in 70-80% of patients with gastroesophageal reflux disease (GERD) and for providing maintenance therapy to prevent relapse. Tachyphylaxis has been observed, suggesting that pharmacologic tolerance can reduce the long-term efficacy of these drugs.
Additional H2 blocker therapy has been reported to be useful in patients with severe disease (particularly those with Barrett esophagus) who have nocturnal acid breakthrough.
More effective than placebo and antacids for relieving heartburn in patients with GERD
Faster healing of erosive esophagitis when compared with placebo
Can use regularly or on-demand.

54. Treatment AGENT EQUIVALENT DOSAGE DOSAGES
Cimetadine mg twice daily mg twice daily
Tagamet
Famotidine mg twice daily mg twice daily
Pepcid
Nizatidine mg twice daily mg twice daily
Axid
Ranitidine mg twice daily mg twice daily
zantac
--similar clinical efficacy

55. Treatment: PPI Proton Pump Inhibitors
Better control of symptoms with PPIs vs H2RAs and better remission rates
Faster healing of erosive esophagitis with PPIs vs H2RAs

56. Treatment AGENT EQUIVALENT DOSAGE DOSAGES
Esomeprazole mg daily mg daily
Nexium
Omeprazole mg daily mg daily
Prilosec
Lansoprazole mg daily md daily
Prevacid
Pantoprazole mg daily mg daily
Protonix
Rabeprazole mg daily mg daily
Aciphex
--no significant differences in symptomatic tx of GERD or healing of erosive esophagitis (IA) evidence
--works only on active pumps—take 30-60min prior to meals
--long-term tx generally benefits outweigh risks

57. Newest PPI on the market
Dexlansoprazole (trade names Kapidex, Dexilant) is a proton pump inhibitor that is marketed by Takeda Pharmaceuticals. Chemically, it is an enantiomer of lansoprazole. The compound was launched in the US for use in the treatment and maintenance of patients with erosive oesophagitis and non-erosive gastro-oesophageal reflux disease. Dexlansoprazole was approved by the U.S. Food and Drug Administration (FDA) on January 30, 2009

58. OTC PPI Products OTC PPI strengths and dosage forms:
Omeprazole 20 mg delayed release tablets.
Omeprazole and sodium bicarbonate 20/1100 mg immediate release capsules.
Lansoprazole 15 mg delayed release capsules.
All PPI products (OTC and Rx) are delayed release products EXCEPT for ZEGERID. Na-HCO3 provides protection from acid degradation and increases the bioavailability

60. Treatment H2RAs vs PPIs 12 week freedom from symptoms
12 week healing rate
52% vs 84%
Speed of healing
6%/wk vs 12%/wk

61. Effectiveness of Medical Therapies for GERD
Treatment Response
Lifestyle modifications/antacids 20 %
H2-receptor antagonists 50 %
Single-dose PPI %
Increased-dose PPI up to 100 %

62. Summary of Treatment Algorithm for GERD
Figure 26-5 Management of gastroesophageal reflux disease. H2RA, H2-receptor antagonist; PPI, proton pump inhibitor.

63. If Initial Treatment Fails, the Following Should be Considered:
Improve compliance
Optimize pharmacokinetics
Adjust timing of medication to 15 – 30 minutes before meals (as opposed to bedtime)
Allows for high blood level to interact with parietal cell proton pump activated by the meal
Consider switching to a different PPI

64. GERD is a Chronic Relapsing Condition
Esophagitis relapses quickly after cessation of therapy
> 50 % relapse within 2 months
> 80 % relapse within 6 months
Effective maintenance therapy is imperative

65. Brain Storming! (2-slides)
Can PPIs be co-adminstered with antacids / H2 blockers? What should be the patient’s instructions?
Why is omperazole 10 mg capsules Rx only while 20 mg tablets is OTC?
Since 95% of the proton pumps will be permanently inactivated within 5 days of single daily use of a full-dose PPI, what is the rationale for twice daily dosing?

66. Several weeks after daily dosing of a PPI, patients usually complain of breakthrough heartburns. Why is that? How can this be managed?
A patient did not get a full relief with omeprazole 40 mg daily. Should we increase the dose to 80 mg or change into another PPI?
What are the main differences in indications and use instructions between OTC and Rx PPI products?

67. Complications of GERD Erosive/ulcerative esophagitis
Esophageal (peptic) stricture
Barrett’s esophagus
Adenocarcinoma

68. Erosive Esophagitis

69. Peptic Stricture Barium Swallow Endoscopy
Figure Endoscopic appearance of benign strictures. Acid-septic strictures and Schatzki's rings are the most common strictures requiring dilation. Although in most instances endoscopic examination allows obvious distinction between the two, variation in air insufflation and the differences in magnification over short distances between the lower esophageal sphincter and the endoscope can make the assessment of the lower esophagus difficult in some patients. A subtle peptic stricture may be missed endoscopically, or, more precisely, may be confused with a Schatzki's ring. Contrast radiology can be a more sensitive technique for demonstrating subtle rings and strictures and for calibrating the lumen more precisely. A–C, Endoscopic photographs of several Schatzki's rings. D–G, peptic strictures. Note the esophageal pseudodiverticula proximal to the peptic stricture in panels F and G. Their presence increases the risk of unguided dilatation of the esophagus and mandates the use of a guidewire technique. H, Tight anastomotic stricture (suture at 10 o'clock) and “watermelon esophagus” viewed endoscopically. The watermelon seeds and kernel of corn provide a reference for the pinhole quality of this stricture.

70. Esophageal Stricture: Dilating Devices

71. TTS Balloon Dilation of a Peptic Stricture
Figure Types of dilators: balloons. Balloon dilators are an additional option for the endoscopist approaching an esophageal stricture. They may be placed over a guidewire or through the scope (TTS). Theoretically, balloons have the advantage of being safer because of the radial application of force, and elimination of the shearing effect of rigid dilators. Moreover, dilation can be performed under direct visualization using the TTS balloon. Recent balloon innovations facilitating their use include longer balloons that avoid the tendency for slippage with inflation, and high-pressure balloons that should provide a truer diameter for the dilation of more resistant strictures. In the limited number of randomized studies comparing Savory-type dilators with balloon dilators, they appeared equally safe. Efficacy, as assessed by symptom improvement and luminal patency, has been variably reported in the literature favoring either technique [18], [19], [20]. A, Range of available balloons and an inflation gun. B–E, A peptic stricture before and after balloon dilation, thus demonstrating the direct visualization that is possible with the TTS technique.
References:
[18]. Saeed ZA, Winchester CB, Ferro PA, et al. Prospective randomized comparison of polyvinyl bougies and through-the-scope balloons for dilation of peptic strictures of the esophagus. Gastrointest Endosc
[19]. Cox JGC, Winter RK, Maslin SC, et al. Balloon or bougie for dilation of benign oesophageal stricture? An interim report of a randomized controlled trial. Gut
[20]. Shemesh E, Czerniak A, Comparison between Savary-Gilliard and balloon dilatation of benign esophageal strictures. World J Surg

72. Barrett’s Esophagus

73. Esophageal Cancer
Barium Swallow
Endoscopy