GASTROESOPHAGEAL REFLUX DISEASE Tiberiu Hershcovici, MD Director, Gastrointestinal Motility Lab Hadassah University Hospital

DEFINITION According to the Montreal International Consensus Group1: GERD is defined as a condition that develops when the reflux of stomach contents causes troublesome reflux-associated symptoms. While GERD is commonly diagnosed in clinical practice based on symptoms alone, it has been demonstrated that esophageal symptoms are not stimulus specific and thus heartburn could result from non-reflux related stimuli. Vakil N, et al. The American Journal of Gastroenterology 2006;101(8):1900-20

CLASSIFICATION Patients with GERD are further classified based on upper endoscopy results, into: erosive esophagitis, if visible mucosal breaks in the distal esophagus are present- 20-30% nonerosive reflux disease (NERD), if the mucosal breaks are absent- 60-70% Esophageal complications of erosive esophagitis are: ulceration stricture Barrett’s esophagus adenocarcinoma of the esophagus.

EPIDEMIOLOGY Population-based studies suggest that GERD is a common condition with a prevalence of 10–30% in Western Europe and North America. GERD is less commonly seen in the Asia-Pacific region.

EPIDEMIOLOGY The prevalence of GERD and GERD-related disorders has been steadily increasing in the US, Western Europe, Australia and Asia. An opposing trend time was observed between 1970 and 1995 in the prevalence of peptic ulcer disease and GERD. The rates of peptic ulcer and gastric cancer fell while at the same time the rates of GERD and esophageal adenocarcinoma rose significantly.

CAUSES AND RISKS FACTORS Age: prevalence of GERD increases with age, older patients are more likely to develop less symptomatic but more severe disease Cigarette smoking Alcohol Coffee High fat diet Food products such as chocolate, peppermint, citrus juices but not carbonated beverages Medications: narcotics, calcium channel blockers etc.

GERD -OBESITY Obesity is associated with: 1.5- 2-fold increase risk for GERD symptoms and erosive esophagitis 2- 2.5-fold increase risk for esophageal adenocarcinoma Mechanisms proposed to explain the close relationship between increased BMI and GERD include: increased gastroesophageal pressure gradient increased prevalence of hiatal hernia increased prevalence of transient lower esophageal sphincter relaxations (TLESR)

RELATIONSHIP BETWEEN HELICOBACTER PYLORI AND GERD Some studies suggested that H. pylori infection conferred protection from GERD and its eradication was associated with an increased risk of developing GERD. A more recent meta analysis of twelve trials revealed no association between H. pylori eradication in patients with duodenal ulcer and: development of erosive esophagitis, appearance of new symptomatic GERD, worsening of symptoms in patients with pre-existing GERD. Laine L, et al. The American Journal of Gastroenterology 2002;97(12):2992-7.

PATHOGENESIS DYSFUNCTION OF THE LES HIATAL HERNIA

DYSFUNCTION OF THE LES GER occurs predominantly during transient lower esophageal sphincter relaxation (TLESR), TLESR is a spontaneous (not preceded by a swallow), prolonged relaxation of the LES (>10 sec). It is triggered primarily by gastric fundic relaxation and mediated by a vago-vagal reflex. Although recent trials found no increased rate of TLESR’s in patients with GERD, TLESR was more likely to be associated with an acid reflux event in patients with GERD as compared to healthy controls. This may be caused by increased compliance of the esophago-gastric junction in GERD patients.

HIATAL HERNIA

HIATAL HERNIA The presence of a hiatal hernia, particularly if it is large (≥5 cm) is associated with increased severity of GERD . The prevalence of hiatal hernia increases with the severity of esophageal mucosal involvement. 20-30% in NERD patients 95% in patients with long segment Barrett’s esophagus Displacement of LES from the crural diaphragm into the chest: reduces LES basal pressure loss of the intra-abdominal LES segment reduced threshold for TLESR in response to gastric distension

PATHOGENESIS –OTHER FACTORS Esophageal mucosal defense mechanisms Esophageal clearance – peristaltic dysfunction Gastric acid secretion Duodenogastroesophageal (bile) reflux Acid pocket –related to hiatal hernia Gastric dysmotility

PATHOLOGY

OTHER CAUSES OF EROSIVE ESOPHAGITIS

CLINICAL PRESENTATION- TYPICAL SYMPTOMS Heartburn: a sensation of discomfort or burning behind the sternum rising up to the neck, made worse after meals and eased by antacids. Acid Regurgitation: the perception of flow of refluxed gastric content into the mouth or hypopharynx.

CLINICAL PRESENTATION- ATYPICAL SYMPTOMS Angina-like chest pain-non cardiac chest pain Globus sensation Chronic cough Hoarseness Asthma

CLINICAL PRESENTATION GERD symptom frequency or severity does not correlate with the extent of esophageal mucosal involvement in patients with erosive esophagitis. Heartburn severity and intensity are similar in patients with erosive esophagitis and NERD. In the elderly patient with GERD, heartburn and acid regurgitation are less frequent than in younger subjects. In contrast, atypical symptoms such as vomiting, anorexia, dysphagia, respiratory symptoms, belching, dyspepsia, hoarseness, and postprandial fullness are more common presentations in elderly.

DIAGNOSTIC METHODS Clinical evaluation The proton pump inhibitor (PPI) test Upper endoscopy Ambulatory 24-hour esophageal pH monitoring

DIAGNOSTIC METHODS Clinical evaluation The proton pump inhibitor (PPI) test: a short course (1–4 weeks) of high-dose PPI given twice daily for the diagnosis of GERD in patients with typical, atypical or extraesophageal manifestations of GERD. If symptoms disappear with therapy and then return when medication is stopped, GERD can be assumed and no further testing is required. Sensitivity: from 66% to 89%, Specificity: from 35% to 73%.

UPPER ENDOSCOPY The gold standard procedure for diagnosing erosive esophagitis, GERD complications, and Barrett’s esophagus. Allows an assessment of the degree of esophageal mucosal injury, and tissue sampling can be performed if necessary. Sensitivity: 30–50% in patients with typical symptoms of GERD, as most patients with GERD have NERD. Specificity: 9095%.

AMBULATORY 24-HOUR ESOPHAGEAL pH MONITORING Allows assessment of : 24-hour esophageal acid exposure the temporal relationship between patient symptoms and acid reflux events

TREATMENT-GOALS Adequate relief of GERD symptoms Healing of erosive esophagitis if present Maintenance of mucosal healing Improvement of quality of life

LIFESTYLE MODIFICATIONS Adequate for patients with mild and infrequent reflux symptoms Weight loss Cessation of smoking Elevation of head of the bed Avoidance of aggravating foods

PROTON PUMP INHIBITORS For patients with erosive esophagitis :effective control of reflux symptoms (77%) and a high rate of healing of esophagitis (84%). The proportion of NERD patients responding to a standard dose of PPI is approximately 2030% lower than in patients with erosive esophagitis. A once-daily morning dosing of PPI, half an hour before a meal, is generally the most appropriate initial therapy, but may fail in up to 30% of patients.

HISTAMINE TYPE 2 RECEPTOR ANTAGONISTS Standard doses have been proven to be effective in controlling symptoms and in healing mild to moderate erosive esophagitis. Tachyphylaxis develops quickly with H2RAs, limiting their regular use in clinical practice. The main appeal of H2RAs is their rapid effect on GERD symptoms, unsurpassed by any of the currently available PPIs. Nighttime use for refractory symptoms-currently unproven

TLESR REDUCERS Gamma-aminobutyric acid B (GABAB ) receptor agonists: Baclofen Arbaclofen placarbil Lesogaberan Metabotropic glutamate receptor 5 (mGluR5) antagonists ADX10059

PROMOTILITY AND PROKINETIC DRUGS May improve gastroesophageal reflux by: increasing LES basal pressure restoring esophageal peristalsis facilitating gastric emptying The benefit of these compounds in controlling heartburn and in healing erosive esophagitis has been very modest, primarily because of lack of effect on TLESR.

ANTIREFLUX SURGERY Laparoscopic Nissen fundoplication remains the most commonly performed operation and consists of a 360° wrap of the gastric fundus around the distal esophagus Results in augmentation of LES basal pressure and a decrease in the rate of TLESR. Relieves reflux symptoms and heals erosive esophagitis. However: Barrett’s esophagus does not regress.

Management algorithm

CLINICAL STRATEGIES The step-up approach initiates patients on the least effective antireflux modality and upgrades treatment if satisfactory control of symptoms is not achieved. The step-down approach initiates patients on the most potent antireflux modality and downgrades patients to a therapeutic modality that still controls their symptoms effectively. The step-in approach initiates and maintains patients on the most potent antireflux modality. It is the most popular therapeutic strategy in clinical practice. On-demand or intermittent PPI therapy: in patients with NERD and potentially in those with mild erosive esophagitis.

REFRACTORY GERD Patients who failed to obtain satisfactory symptomatic response after a course of standard-dose PPI. Any attempt to narrow the definition of refractory GERD might exclude many true sufferers

The PPI Failure Dilemmas What Constitutes PPI Failure? Failure of PPI once a day – No GERD indications for PPI twice daily – Drug development – Third-party payers and institutions Failure of PPI twice daily – Clinically relevant Symptoms cutoff  Complete  Partial

Nonerosive reflux disease The Reported Rate of Symptomatic Failure in Therapeutic Trials of GERD Patients Nonerosive reflux disease 40%–50% Erosive esophagitis 25%–30% Barrett’s esophagus 20% PPI Failure Refractory GERD_Mechanisms and Management_Boston_April 2010

Putative Underlying Mechanisms for PPI Failure Psychological comorbidity Compliance Improper dosing time Weakly acidic reflux Duodenogastroesophageal reflux Residual acid reflux Delayed gastric emptying Concomitant functional bowel disorder Reduced PPI bioavailability Rapid PPI metabolism PPI resistance Others Functional heartburn (esophageal hypersensitivity) Eosinophilic esophagitis (?) Fass & Sifrim. Gut 2009;58:295-309

Putative Underlying Mechanisms for PPI Failure Psychological comorbidity Compliance Improper dosing time Weakly acidic reflux Duodenogastroesophageal reflux Residual acid reflux Delayed gastric emptying Concomitant functional bowel disorder Reduced PPI bioavailability Rapid PPI metabolism PPI resistance Others Functional heartburn (esophageal hypersensitivity) Eosinophilic esophagitis (?) Fass & Sifrim. Gut 2009;58:295-309

Distribution of Adherence to Proton Pump Inhibitor Treatment Over Time Van Soest et al. Aliment Pharmacol Ther 2006;24:377-385)

Suboptimal Proton Pump Inhibitor Dosing in PPI Failure Patients Gunaratnam et al. Aliment Pharmacol Ther 2006;23(10):1473-1477

The Persistent Reflux Hypothesis Psychological comorbidity Compliance Improper dosing time Weakly acidic reflux Duodenogastroesophageal reflux Residual acid reflux Delayed gastric emptying Concomitant functional bowel disorder Reduced PPI bioavailability Rapid PPI metabolism PPI resistance Others Functional heartburn (esophageal hypersensitivity) Eosinophilic esophagitis (?) Fass & Sifrim. Gut 2009;58:295-309 Refractory GERD_Mechanisms and Management_Boston_April 2010

Terms You Need to Know  Acidic Reflux – Reflux pH <4  Nonacidic reflux – Reflux pH  4  Weakly acidic reflux – 4  reflux pH <7  Neutral reflux – Reflux pH = 7  Alkaline reflux – Reflux pH > 7

How Common is Residual Acid Reflux in Patients Who Failed PPI Once or Twice Daily? Charbel et al. Am J Gastroenterol 2005;100(2):283-289.

Results of Combined pH and Bilitec Monitoring in Symptomatic GERD Patients While on PPI Therapy 33% 40% 5% 22% Karamanolis et al. Dig Dis Sci 2008;53:2387-2393

Hershcovici and Fass. Best Prac Res Clin Gastroenterol (in press) Upper endoscopy Treat mucosal findings Alarm symptoms PPI once daily (2 months) Failure Switch to another PPI (2 months) PPI twice daily (am & pm) for 2 months Review proper PPI dosing time and compliance Pain modulators Tricyclics SSRIs Trazodone Review again PPI dosing time and compliance TLESR Reducers Pain modulators Antireflux surgery Esophageal impedance + pH Negative Positive for acid reflux Positive for weakly acidic reflux Hershcovici and Fass. Best Prac Res Clin Gastroenterol (in press) H2RA qhs TLESR reducers Pain modulators

EPIDEMIOLOGY 7% of the US adult population has erosive esophagitis whereas in Europe and Asia the prevalence has been estimated to range between 2–10%. Furthermore, erosive esophagitis is usually milder in Asia (predominantly Los Angeles grade A and B) and complications are relatively uncommon.