Gastroesophageal Reflux Disease Rajeev Jain, MD November 27, 2006

Outline Definition Epidemiology Pathophysiology Diagnosis Treatment Management

Definition No gold standard Montreal Definition “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications” Montreal Consensus based on expert opinion & systematic review of the literature using a Delphi model for consensus. Vakil N, et al. Am J Gastroenterol 101(8):1900-20.2006.

Classification Endoscopy Symptoms Erosive esophagitis Los Angeles classification Non-erosive reflux disease (NERD) or endoscopy negative reflux disease (ENRD) Symptoms Esophageal Extra-esophageal

LA Classification LA Grade A LA Grade B LA Grade C LA Grade D

Epidemiology Prevalence Incidence Symptoms in western populations 25% monthly 12% weekly 5% daily Incidence 1.5 – 3% develop weekly GERD per yr Moayyedi P, Axon ATR. Aliment Pharmacol Ther 22(S1):11-9.2005.

Risk Factors Demographic Lifestyle & Environmental Genetic Age & gender not a major difference Lifestyle & Environmental Obesity, EtOH, & tobacco have weak associations (OR 1.5 – 2.5) 1 H. pylori has no impact 2 Genetic Higher concordance in mono- than dizygotic twins 1 1. Moayyedi P & Talley NJ. Lancet 367:2086-100.2006. 2. Raghunath AS, et al. Aliment Pharmacol Ther 20:733-44.2004.

Pathophysiology Primary mechanism – impaired function of the lower esophageal sphincter (LES) In most patients with GERD, exposure of the esophagus to refluxate is greater than normal In a minority of patients, exposure is within normal limits; in these patients, GERD may be due to decreased mucosal resistance to refluxate Pathogenesis of GERD – overview Both the ACG guidelines and those resulting from the Genval Workshop state that exposure to refluxed acid and pepsin is the predominant mechanism underlying symptoms and mucosal damage in GERD (1,2). Some reflux of gastric contents occurs in all individuals. Refluxate is returned to the stomach by esophageal peristalsis and neutralized by bicarbonate ions in swallowed saliva and esophageal secretions. Most people with GERD show abnormally prolonged exposure of the distal esophagus to acid and pepsin (2). This disrupts the normal esophageal mucosal defences against acid and pepsin, resulting in the characteristic symptoms of GERD. In a minority of patients, GERD symptoms can be provoked by normal amounts of acid and pepsin (2,3). In these patients, GERD may result from a decreased resistance of the esophageal mucosa to acid refluxate. (1) DeVault et al. Am J Gastroenterol 1999; 94: 1434–42. (2) Dent et al. Gut 1999; 44 (Suppl. 2): S1–S16. (3) Shi et al. Gut 1995; 37: 457–64.

Mechanisms of Acid Reflux Causes of increased exposure of the esophagus to gastric refluxate As described in the previous slide, most people with GERD show abnormal exposure of the esophagus to gastric acid and pepsin. In most cases, this is due to dysfunction of the lower esophageal sphincter (LES). However, exposure can also be increased as a result of increased intra-abdominal pressure, hiatal hernia, inadequate clearance of refluxate from the esophagus, or delayed gastric emptying. These potential causes are described in more detail in the following slides.

Defective Esophageal Clearance Ineffective peristalsis Reduced salivary secretion Reduced secretion from esophageal submucosal glands Defective esophageal clearance Under normal circumstances, refluxed gastric contents are cleared from the esophagus by peristalsis, and residual acid is neutralized by bicarbonate ions in the saliva and secretions from esophageal submucosal glands. In people with GERD, peristalsis may be ineffective, or salivary or esophageal secretion may be reduced. These changes may lead to inadequate clearance or neutralization of refluxate.

LES ‘dysfunction’ Inappropriate and prolonged transient relaxations Reduction in basal LES pressure/tone LES ‘dysfunction’ Gastric reflux can occur as a result of inappropriate, prolonged relaxations of the LES. Such relaxations are responsible for almost all reflux episodes in normal individuals, and up to 80% of episodes in some patients with GERD (1). A second LES-related cause of reflux is a reduction in basal LES pressure or tone. This occurs in approximately 20% of patients with severe erosive esophagitis (1,2). Individuals with low or absent LES tone may suffer from stress reflux (caused by increases in intra-abdominal pressure resulting from abdominal muscle contraction) or from spontaneous free reflux (3). In some patients, LES dysfunction can be caused or exacerbated by lifestyle factors such as cigarette smoking, diet or some medications. However, contrary to commonly held opinion, lifestyle factors are not a dominant factor in the pathogenesis of GERD. (1) Bell et al. Digestion 1992; 51 (Suppl. 1): 59–67. (2) Hunt. Aliment Pharmacol Ther 1995; 9 (Suppl. 1): 3–7. (3) Richter. In: Winawer, Almaty (eds). Management of gastrointestinal diseases. New York, USA: Gower Medical, 1992: 1.1–1.44.

Substances that Decrease LES Pressure Hormones Secretin Cholecystokinin Glucagon Somatostatin Progesterone Foods Fat Chocolate Ethanol Peppermint Medications

Medications that Decrease LES Pressure -adrenergic agonists Theophylline Anticholinergics Tricyclic antidepressants -adrenergic antagonists Diazepam Calcium channel blockers Medications that may aggravate GERD symptoms by impairing LES function A number of medications can aggravate GERD symptoms, either by impairing LES function or by damaging the esophageal mucosa (see next slide). Medications that can impair LES function include -adrenergic agonists, theophylline, tricyclic antidepressants and calcium channel blockers.

Hiatal Hernia May trap a reservoir of gastric contents above the diaphragm, increasing reflux May compromise LES function Hiatal hernia A hiatal hernia occurs when the upper portion of the stomach moves up through the diaphragm. This can trap a portion of the gastric contents above the diaphragm, increasing the likelihood of reflux. The presence of a hiatal hernia can compromise the function of the LES, since the action of the sphincter is no longer reinforced by the diaphragm. This also increases the risk of reflux.

Increased Intra-abdominal Pressure Pregnancy Obesity Bending Straining Coughing Tight clothes Increased intra-abdominal pressure Increases in esophageal exposure to acid and pepsin can also occur as a result of raised intra-abdominal pressure. This can occur during pregnancy, or as a result of changes in posture (bending or straining), obesity, coughing, or wearing tight clothes.

Delayed Gastric Emptying May result in an increase in the volume of gastric contents available for reflux into the esophagus Exact role in GERD remains to be clarified Delayed gastric emptying Delayed gastric emptying may lead to an increase in gastric reflux by increasing the volume of stomach contents available for reflux into the esophagus. However, the exact role of delayed gastric emptying in the pathogenesis of GERD is unclear, as many patients with GERD do not show abnormal gastric emptying (1). (1) Richter. In: Winawer, Almaty (eds). Management of gastrointestinal diseases. New York, USA: Gower Medical, 1992; 1.1–1.44.

Diagnostic Methods History Endoscopy Empiric therapy pH monitoring Radiology Diagnostic methods in GERD Most cases of GERD can be diagnosed on the basis of symptoms alone, although techniques such as endoscopy, pH monitoring, or an empirical trial of therapy, may be useful in some cases. These techniques are described in the following slides.

History History taking is the primary diagnostic ‘tool’ for GERD Heartburn – sensation of discomfort or burning behind the sternum rising up to the neck Regurgitation – effortless return of gastric contents into the pharynx Accuracy of symptoms when compared to endoscopy as gold standard Sensitivity 30-76% Specificity 45-68% History A detailed history of the patient’s symptoms is the primary diagnostic tool for GERD. As described earlier, heartburn is the pivotal symptom for the diagnosis of this disease. Other typical symptoms include acid regurgitation and dysphagia. Symptom analysis offers reasonable sensitivity and specificity for GERD. Most cases of typical GERD can be diagnosed from symptoms alone. Moayyedi P, et al. JAMA 295:1566-76.2006.

Endoscopy Allows direct visualization of the esophageal mucosa and biopsy if necessary Presence and severity of erosive esophagitis Detection of complications such as stricture or Barrett’s esophagus Endoscopy Endoscopy allows the esophageal mucosa to be visualized directly, and is therefore the technique of choice for the detection and assessment of erosive esophagitis (1). An additional advantage of endoscopy is that it permits biopsies to be performed if necessary. Negative findings on endoscopy do not preclude a diagnosis of GERD, as more than 50% of patients with persistent heartburn (twice or more a week for 6 months) do not have endoscopically visible breaks in the esophageal mucosa (2). Endoscopy is the only reliable technique for the diagnosis of Barrett’s esophagus (1,2). Endoscopic biopsy typically shows goblet cells interspersed among columnar mucous cells. (1) DeVault et al. Am J Gastroenterol 1999; 94: 1434–42. (2) Dent et al. Gut 1999; 44 (Suppl. 2): S1–S16. DeVault et al. Am J Gastroenterol 1999

Advances in Endoscopy Ultra-thin endoscopes Magnification endoscopy Transnasal or oral No sedation Magnification endoscopy Capsule endoscopy

Referral for Endoscopy Chronic symptoms requiring continuous acid-suppression therapy Persistent suspected GERD symptoms that fail to respond to acid suppression Any new GERD patient over the age of 40 Warning signs: Weight loss Anemia or Bleeding Dysphagia Gastroesophageal Reflux Disease Slide 10

Empiric Therapy PPI Test Logical as GERD is an acid-related disorder Normal or high-dose PPI for 1-4 wks in the diagnosis of GERD (gold standard was 24 hr ambulatory pH study) Sensitivity 78% (95% CI 66-86%) Specificity 54% (95% CI 44-65%) Empiric therapy An empiric trial of acid-suppressing therapy can be used in patients with suspected GERD to determine whether symptoms are acid-related. Either a standard treatment course or a short, high-dose, course can be used. The evidence currently available suggests that high doses provide the greatest diagnostic sensitivity (1). PPIs are the agents of choice for therapeutic trials, as studies have shown that these agents are significantly more effective in relieving GERD symptoms than other medical treatments (1,2). Numans et al performed a systematic review of 15 studies …. Numans ME, et al. Ann Intern Med 140:518-27.2006.

pH Monitoring Allows investigation of: In general, most useful in: the amount and timing of reflux the correlation between reflux and symptoms the effect of therapy on reflux In general, most useful in: endoscopy-negative patients patients with chest pain or pulmonary/upper respiratory symptoms patients with refractory symptoms pH monitoring pH monitoring involves the introduction of a pH probe into the esophagus via the nose. It allows investigation of the amount and timing of reflux, the correlation between reflux and symptoms, and the effect of therapy on reflux. The AGC guidelines recommend that pH monitoring may be useful in patients with persistent symptoms who do not have endoscopic evidence of erosive esophagitis, patients with atypical symptoms such as chest pain or upper respiratory symptoms, and patients with refractory symptoms (1). The sensitivity of pH monitoring in extra-esophageal GERD and non-erosive disease is not clear. (1) DeVault et al. Am J Gastroenterol 1999; 94: 1434–42.

pH Monitoring 24 hr pH monitoring single best test 50-60% will have abnormalities new device: BRAVO probe 48 hr monitoring

pH Monitoring

Barium Esophagram Now considered to be of very limited practical value in the diagnosis of GERD1 May be helpful in the detection of subtle strictures and hiatal hernias in patients with dysphagia May be helpful in identifying pathologies unrelated to GERD Radiology Radiological techniques are now considered to be of little practical value in the diagnosis of GERD (1). Radiological investigation may be helpful in the detection of esophageal strictures or hiatal hernias in patients with dysphagia. However, hiatal hernia is not consistently associated with GERD, and thus can not be used as a firm criterion for diagnosis (1). Radiology may also be helpful in identifying pathologies unrelated to GERD, such as diverticuli, swallowing dysfunction and motility dysfunction. The radiograph on this slide shows an esophageal stricture. It is reproduced with permission from reference 2. (1) Dent et al. Gut 1999; 44 (Suppl. 2): S1–S16. (2) Lam, Lombard. Crash course: gastroenterology. London, UK: Mosby, 1999. 1Dent et al. Gut 1999

The Pyramid of Diseases Associated with GERD 0% Yes Misc Asthma ENT Need to investigate role of acid Prevalence of GERD Chest pain The pyramid of diseases associated with GERD This is the final slide in the section on the definition and description of GERD. It summarizes the association between GERD and other diseases or symptoms (1). At the base of the pyramid is erosive esophagitis, which has a 95% specificity for GERD (meaning that 95% of cases of erosive esophagitis are due to GERD). Further up the pyramid are other diseases or symptoms with progressively lower specificities for GERD. As the specificity of a disease or symptom for GERD decreases, the need for investigations to determine whether GERD is responsible for that disease or symptom increases. Monitoring of esophageal pH can show whether there is an association between acid reflux and a given complaint, but only an empiric trial of a PPI can demonstrate causality. (See the slides on the diagnosis of GERD for information on different methods of investigation.) (1) Richter. Am J Gastroenterol 2000: 95 (Suppl.): S1–S3. Reproduced with permission from the American College of Gastroenterology. Non-erosive reflux disease Erosive esophagitis 100% No Richter. Am J Gastroenterol 2000

Complications of GERD Esophageal Extra-esophageal Barrett’s esophagus adenocarcinoma stricture ulceration bleeding Extra-esophageal asthma reflux laryngitis vocal cord ulcers subglottic stenosis tracheal stenosis Complications of GERD Erosive esophagitis can lead to complications such as Barrett’s esophagus, adenocarcinoma, esophageal stricture, ulceration or bleeding. Barrett’s esophagus occurs in approximately 10–15% of patients with GERD (1), and esophageal stricture in 1%. In some patients, aspiration of refluxate into the trachea can result in extra-esophageal complications such as asthma, reflux laryngitis, vocal cord ulcers, and subglottal or tracheal stenosis. These complications can lead to patients presenting initially to ear, nose and throat (ENT) or respiratory physicians. (1) Spechler. Digestion 1992; 51 (Suppl. 1): 24–9.

Esophageal stricture Esophageal stricture An esophageal stricture is defined as a narrowing of the esophagus due to inflammation, scar formation, or both. Such strictures occur in approximately 1–2% of patients with GERD.

Barrett’s Esophagus Barrett’s esophagus – definition Barrett’s esophagus can be defined as “a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy” (1). Normally, the esophagus is lined with squamous epithelium (as shown on the left of the slide). Chronic exposure to gastric refluxate may lead to transformation of areas of squamous epithelium into columnar epithelium (as shown on the right of the slide). This tissue type is usually found in the lining of the stomach and intestine – hence the term ‘intestinal metaplasia’. The change from squamous to columnar epithelium represents an adaptive response to the presence of acidic refluxate in the esophagus, as columnar epithelium is more resistant to acid than the squamous type. (1) Sampliner. Am J Gastroenterol 1998; 93: 1028–31.

Barrett’s Esophagus Clinical Significance Premalignant lesion for esophageal adenocarcinoma Patients with Barrett’s esophagus may be 30–60 times more likely to develop this cancer than the general population1 The reported incidence of Barrett’s esophagus is rising Barrett’s esophagus – clinical significance Barrett’s esophagus is an important complication of GERD and requires careful management. This is because it is a premalignant lesion for esophageal adenocarcinoma. As indicated in this slide, patients with Barrett’s esophagus may be 30–60 times more likely to develop this type of cancer than the general population (1). Notably, the reported incidence of Barrett’s esophagus is rising. It should be noted that Barrett’s esophagus is probably not a necessary step in the evolution of adenocarcinoma in patients with GERD. It is certainly true that most esophageal adenocarcinomas arise in Barrett’s metaplasia (1,2). However, data from a large study conducted in Sweden suggest that it is reflux per se, rather than Barrett’s esophagus resulting from reflux, that is the crucial factor in the development of adenocarcinomas (1). (1) Lagergren J et al. N Engl J Med 1999; 340: 825–31. (2) Clark et al. Arch Surg 1994; 129: 609–14. 1Lagergren et al. New Engl J Med 1999

The Risk of Esophageal Adenocarcinoma Increases with: Frequency of reflux symptoms OR 16.7 with > 3/wk Duration of reflux symptoms OR 16.4 with greater than 20 yrs Severity of reflux symptoms OR 20 with most severe score Lagergren et al. N Engl J Med 1999

Treatment Management This is the title slide for a subsection.

Treatment Options Lifestyle measures Pharmacological therapy Initial therapy Maintenance therapy Antireflux surgery Endoscopic techniques Management options in GERD There are four main options for the management of GERD: lifestyle measures, pharmacological therapy, antireflux surgery and newer endoscopic techniques.

Lifestyle Measures Raise the head of the bed, or lie on left side Decrease fat intake Avoid certain foods Avoid lying down for 3 hours after eating Stop smoking Lose weight if appropriate Lifestyle measures Lifestyle measures that are sometimes recommended to GERD patients include avoiding factors that are known to aggravate GERD symptoms, such as certain foods, avoiding lying down after meals, raising the head of the bed to reduce nocturnal reflux, and losing weight.

Aggravating Dietary Factors Caffeinated products Peppermint Fatty foods Chocolate Spicy foods Citrus fruits and juices Tomato-based products Alcohol Dietary factors that may aggravate GERD symptoms A number of dietary factors, including spicy or fatty foods, chocolate, citrus fruits and alcohol, can trigger or aggravate GERD symptoms. The mechanisms by which such foods affect GERD symptoms may include impairment of LES function, increased sensitivity of the esophagus to acid, or both.

Pharmacological Therapy Antacids Prokinetics Acid suppression Histamine 2-receptor antagonists (H2RAs) Proton pump inhibitors (PPIs) Evolution of pharmacological therapy Four types of drug are used in the management of GERD: antacids prokinetic agents histamine H2-receptor antagonists (H2RAs) proton pump inhibitors (PPIs).

Acid Suppression Erosive Esophagitis – Initial Therapy H2RA v placebo (4-8 wks of therapy) 18 trials, 2134 patients NNT 5 (95% CI, 3-22) PPI v placebo 5 trials, 635 patients NNT 2 (95% CI, 1.4-2.5) PPI v H2RA 26 trials, 4064 patients NNT 3 (95% CI, 2.8-3.6) Khan M, et al. Cochrane Database Syst Rev.2006.

Acid Suppression Erosive Esophagitis – Maintenance Therapy 80% relapse after 6-12 months off therapy PPI v H2RA 10 trials, 1583 patients, 24-52 wks of therapy Relapse rate 22% in PPI group 58% in H2RA group NNT 2.5 (95% CI, 2.0-3.4) Donnellan C, et al. Cochrane Database Syst Rev.4:2004.

Antireflux Surgery – Procedures This slide shows the two commonest forms of anti-reflux surgery: Nissen fundoplication (360º wrap) and the Toupet procedure (270° wrap). The latter is indicated in obese patients, those with severe esophageal pathology and those who have undergone previous surgery to the upper abdomen (as it is performed using a transthoracic approach).

Antireflux Surgery – use and efficacy Antireflux surgery is an option as maintenance therapy for patients with well documented GERD1 The efficacy of antireflux surgery is similar to that of chronic PPI therapy2 The outcome of surgery is highly dependent on the skill and experience of the surgeon2 Antireflux surgery – use and efficacy Antireflux surgery is an option for maintenance treatment of some patients with well documented GERD (1). Patient selection is important, however; ambulatory pH monitoring should be performed if erosive esophagitis is not present, and the ACG guidelines recommend that esophageal manometry should be performed routinely before surgery to determine the most appropriate procedure (1). There are no clear-cut indications for antireflux surgery. Indeed, the characteristics that make a patient a good candidate for surgery (namely, a good response to PPIs and the presence of GERD without comorbidities) also makes him or her a good candidate for pharmacological therapy. Because of this, the choice of surgery or pharmacological therapy often depends largely on patient preference. The best long-term (5-year) results are comparable with those achieved with PPIs (2). However, the outcome of antireflux surgery is highly dependent on the skill and experience of the surgeon (2). The most commonly used surgical techniques involve positioning the distal esophagus below the diaphragm and creating a flap or valve to augment LES function. Laparoscopic techniques are being developed, and appear to be comparable, or possibly even superior, in efficacy to the open approach (1). These techniques offer the advantage of decreased postoperative morbidity and a shorter duration of hospitalization, and may make surgery more acceptable to some patients for whom the option would be long-term medical therapy (1). (1) DeVault et al. Am J Gastroenterol 1999; 94: 1434–42. (2) Dent et al. Gut 1999; 44 (Suppl. 2): S1–S16. 1DeVault et al. Am J Gastroenterol 1999 2Dent et al. Gut 1999

Endoscopic Therapy Three FDA approved techniques Stretta: radiofrequency therapy to LES EndoCinch: endoscopic gastroplication Enteryx: 8% ethylene vinyl alcohol copolymer Endoscopic therapy for GERD Two endoscopic therapy techniques have recently been approved for the treatment of GERD: the Stretta procedure and endoscopic gastroplication. These techniques are described in the following two slides. Early results from small, nonrandomized trials in mild GERD suggest that these techniques may have a therapeutic role to play. However, these trials were uncontrolled and the study populations were highly selected. Further research is needed.

Endoscopic Gastroplication Gastroplication can be performed endoscopically using an ‘endoscopic sewing machine’. As shown on the slide, this procedure has four main stages: (A) the endoscope is advanced into the gastric cardia (B) a vacuum is applied, tissue is captured and a stitch is placed (C) the suture material is knotted (D) the knot is drawn tight, forming a gastroplication. Typically, 2–3 plications are performed 1 cm below the Z line, with each plication requiring two stitches. The aim of endoscopic gastroplication in patients with GERD is to tighten the LES and form a barrier to reflux.

Management Goals Provide complete relief from heartburn and other symptoms Heal underlying erosive esophagitis Treat or prevent complications Prevent recurrence Goals in the management of GERD This slide lists the main aims of treatment in GERD.

Management Clinical diagnosis Endoscopy in pts with alarm symptoms PPI once daily taken 30 min before breakfast for 4-8 weeks If symptoms resolve, consider on-demand therapy or step down Relapse is common

Management If symptoms persist despite daily PPI Nonadherence Inadequate dosing or timing Nocturnal acid breakthrough Rare Zollinger-Ellison syndrome Drug resistance Surgery – right patient and right surgeon