1. Ronnie Fass, MD. Professor of Medicine Case Western Reserve University
The Role of Stress in Gastroesophageal Reflux Disease – What Do We Know?
Ronnie Fass, MD.
Professor of Medicine
Case Western Reserve University
Pathophysiology and Treatment of GERD, Atlanta, March 2008

2. MetroHealth Medical Center

3. Case Western Reserve University
Pathophysiology and Treatment of GERD, Atlanta, March 2008

4. Chronic Vs. Acute

5. The Effect of Life Stress on Symptoms of Heartburn
Sixty subjects with current heartburn symptoms were recruited by community advertisement
All assessed for presence of stressful life events retrospectively over the preceding 6 months and prospectively for 4 months.
Symptom severity by daily diary, quality of life, and psychological symptoms of anxiety, depression, and vital exhaustion were also measured.

6. The Effect of Life Stress on Symptoms of Heartburn
Naliboff BD Psychosom Med 2004 May-Jun;66(3):

7. The Effect of Life Stress on Symptoms of Heartburn
The presence of a severe, sustained life stress during the previous 6 months significantly predicted increased heartburn symptoms during the following 4 months
Naliboff BD Psychosom Med 2004 May-Jun;66(3):

8. Acute Stress and GERD
Up to 64% of GERD patients reported that stress exacerbated their reflux symptoms (Gallup survey, 1988)
What is the mechanism?

9. Does Stress Increase Intra – Esophageal Acid Exposure?
Stressful tasks in normal subjects - no change in pH measurements (Cook, 1986)
Prolonged stressors in GERD patients - no change in intra-esophageal acid exposure post prandially (Bradley, 1993)
No!

10. Stress and GERD
Highly anxious patients reported increased reflux symptoms during stress despite no change in intra-esophageal pH (Bradley, 1993)

12. Aim
To determine the effect of an established acute psychologic stress condition on perceptual and emotional responses in healthy controls and patients with established GERD, subclassified as nonerosive reflux disease (NERD) and erosive esophagitis (EE).

13. Study Design
Fass et al. Gastroenterology 2008;134:

14. Stress Induction
Psychologic stress was achieved by using dichotic listening, which involves 2 conflicting types of music delivered simultaneously at 30 dB, via separate headphone channels.
Folk music in a foreign language was heard by the subject in one ear and “heavy metal” music in the other ear.
Objectively, increased autonomic function was documented during stress induction. Subjectively, by using the SRR, subjects scored higher as compared with baseline on the stress scale.
During the control period, background instrumental music was delivered through both headphone channels. All patients and normal controls were exposed to the same music.
Fass et al. Gastroenterology 2008;134:

15. Dual Chamber Harvard Apparatus
Fass & Eslick. Noncardiac Chest Pain–A Growing Medical Problem. Plural Publishing, San Diego, 2007.

16. Fass et al. Gastroenterology 2008;134:696-706

17. Auditory Stress and Esophageal Sensitivity
† ‡ * + ** ++
* P = ** P = P < P = † P = NS ‡P = NS
Fass et al. Gastroenterology 2008;134:

18. Effect of Stress on Acute Mood Rating
Fass et al. Gastroenterology 2008;134:

19. Conclusions
Auditory stress can enhance perceptual responses to intra-esophageal acid stimuli (esophageal hypersensitivity)
Increased perceptual response to intraluminal acid was associated with increased emotional responses to the stressor but was not related to the presence or absence of esophageal mucosal injury
Fass et al. Gastroenterology 2008;134:

20. Anxiety Increases Acid – Induced Esophageal Hyperalgesia
Sharma A et al. Psychosom Med.2010 Oct;72(8):802-9.

21. Esophageal Hypersensitivity
The perception of non-painful esophageal stimuli as being painful and painful esophageal stimuli as being more painful
Remes and Fass, Handbook of GI Motility and Functional Disorders textbook 2015

22. Esophageal hypersensitivity Reflux hypersensitivity
Acid exposure
Figure 2 (QA 1)
Roles of acid exposure and esophageal hypersensitivity in overlapping GERD and functional esophageal syndromes. Acid exposure and response to proton pump inhibitors decreases from erosive esophagitis to functional heartburn while esophageal hypersensitivity increases across the same spectrum. (Adapted from Galmiche et al, UEG Journal 2013).
Erosive
esophagitis
NERD
Reflux hypersensitivity
Functional heartburn
QA 1
Galmiche et al, UEG 2013

23. Esophageal Pain Sensation “Think Outside of the Lumen”
Heartburn
Central Stress
Intraesophageal Stimulus
Pathological Physiological
Esophageal hypersensitivity
Fass & Tougas Gut 2002;51(6):

24. Stress and Mechanisms of Heartburn
Ang, Sifrim & Tack, Nat Clin Pract Gastroenterol Hepatol 2008;5(7):

25. The Effect of Psychological Distress on Response to PPI Treatment (Rabeprazole 20mg/d for 8 weeks)
Nojkov B et al. Aliment Pharmacol Ther 2008:27;

26. Factors Associated with Partial Response to PPI Treatment of GERD Patients in Primary care
-The health improvement network – UK -Partial responders – 120/6453 (18.6%) - New tx, increase dose, switching PPI
Factor OR
95% CI
Female
1.25
1.05 – 1.37
Anxiety or Depression
1.15
1.00 – 1.31
Prescription > 6 drugs before GERD
1.42
Ruigomez et al. Scand J Gastroenterol. 2012 Jul;47(7):751-61

27. Prediction of Response to PPI Therapy and Factors Influencing Treatment Outcome in Patients with GORD
-1888 GERD patients - A multicentre, multinational, prospective, open study of 8 weeks pantoprazole treatment, 40 mg daily
Heading RC et al. BMC Gastroenterol. 2011 May 11;11:52

29. Aim
To determine whether sleep deprivation by itself can exacerbate GERD by evaluating stimulus response functions to acid in GERD patients vs healthy controls, who experience sleep deprivation and sufficient sleep conditions.

30. Methods
Ten healthy controls and 10 patients with erosive esophagitis (grades B–D) were included in the study.
All subjects were randomized to either sleep deprivation (1 night with <3 hours of sleep) or sufficient sleep (3 days with >7 hours sleep/night).
Patients crossed over to the other arm after a washout period of 1 week.
To ensure proper sleep time, we objectively monitored subjects with an actigraph.
The morning after sufficient sleep or sleep deprivation, patients underwent stimulus response functions to esophageal acid perfusion.

31. Acid Perfusion Sensitivity Score
The Relationship Between Acid Perfusion Sensitivity Score and Sleep Deprivation During an Acid Perfusion Test 0.1 N HCl 10 cc/min
Acid Sensitivity *
Acid Perfusion Sensitivity Score
*p < 0.05
Sleep Groups
Schey R et al. Gastroenterology 2007;133:
Sleep & GERD--An Eye-Opening Experience,Israel_Dec2011

32. Conclusions Sleep deprivation is hyperalgesic in patients with GERD
This is a potential mechanism for increase in GERD symptom severity in sleep-deprived patients.
Schey R et al. Gastroenterology 2007;133:

33. The Bidirectional Relationship Between Sleep and GERD
Increase
Alter
Esophageal physiology
Sleep
GERD
Increase
Decrease
Decrease
Increase
Fass R. J Gastroenterol Hepatol 2010:25;S41 – S44
Sleep & GERD--An Eye-Opening Experience,Israel_Dec2011

35. Aims
To determine if esomeprazole 40 mg daily, given over a period of 8 weeks, may attenuate the effect of acute stress on symptom perception of patients with GERD as compared with placebo
To determine the clinical predictive factors for response to esomeprazole 40 mg daily in GERD patients undergoing stressful stimulus.
Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e  

36. Study Design
Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e  

37. Comparison of Mean Acid Perfusion Sensitivity Score Between the Esomeprazole Group and Those Who Received Placebo Once Daily
Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e  

38. Conclusions
Treatment with a PPI significantly reduced esophageal perceptual responses to acid even during a stressful stimulus.
Interpersonal sensitivity was the sole predictor for response to antireflux treatment during acute stress.
Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e  

39. Chernivtsi

40. Conclusions Chronic and acute stress exacerbate GERD symptoms
Acute stress exacerbates GERD symptoms through centrally induced esophageal hypersensitivity to intra-luminal stimuli
Chronic stress affects response to PPI treatment
PPI treatment attenuates the effect of acute stress on esophageal hypersensitivity

41. The Early Gastroenterologist
The End
The Early Gastroenterologist