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

2. 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):

3. 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 %
nonerosive reflux disease (NERD), if the mucosal breaks are absent %
Esophageal complications of erosive esophagitis are:
ulceration
stricture
Barrett’s esophagus
adenocarcinoma of the esophagus.

4. 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.

5. 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.

6. 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.

7. GERD -OBESITY Obesity is associated with:
fold increase risk for GERD symptoms and erosive esophagitis
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)

8. 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):

9. PATHOGENESIS
DYSFUNCTION OF THE LES
HIATAL HERNIA

10. 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.

11. HIATAL HERNIA

12. 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

13. 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

14. PATHOLOGY

15. OTHER CAUSES OF EROSIVE ESOPHAGITIS

16. 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.

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

18. 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.

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

20. 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%.

21. 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%.

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

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

24. 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

25. 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.

26. 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

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

28. 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.

29. 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.

30. Management algorithm

31. 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.

32. 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

33. 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

34. 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

35. 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:

36. 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:

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

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

39. 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:
Refractory GERD_Mechanisms and Management_Boston_April 2010

40. 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

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

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

43. 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

44. 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.