La tasca acida nella MRGE: aspetti patogenetici e terapeutici

Transcription

1 La tasca acida nella MRGE: aspetti patogenetici e terapeutici Prof. VINCENZO SAVARINO Professore Ordinario di Gastroenterologia, Università degli Studi di Genova Direttore della Clinica Gastroenterologica IRCCS Azienda Ospedaliera-Universitaria San Martino-IST, Genova

2 Competence of the GE Junction The Sphincter that is a Sphinx Ingelfinger FJ: N Engl J Med, 1971

3 1 Pathophysiology of GERD Impaired esophageal clearance; mucosal hypersensitivity weak anti-reflux barrier: diaphragm LOS increased pressure gradient transient LOS relaxations Delayed gastric emptying excessive acid secretion Savarino E, et al. Curr Opin Otolaryngol Head Neck Surg. 2013; 2:548-56

4 24-hour gastric ph profiles of controls and GERD patients with and without esophagitis Zentilin P et Savarino al, Aliment V Pharmacol et al, APT Ther

5 Schematic diagram of the transient lower esophageal sphincter relaxation reflex Kahrilas P and Boeckxstaens G, Gut 2012

6 Transient Lower Esophageal Sphincter Relaxation Reflex CONVENTIONAL MANOMETRY HIGH RESOLUTION MANOMETRY UES Secondary Peristalsis tlesr with Reflux LES Mittal R et al, NEJM 1997 Savarino E, et al. Curr Opin Otolaryngol Head Neck Surg. 2013; 2:548-56

7 The Anti-Reflux Barrier: Two Sphincters Lower Esophageal Sphincter Diaphragm Hiatus Hernia

8 Pathophysiology of GERD Abnormal esophageal clearing Insufficient antireflux barrier TOO MUCH ACID IN THE WRONG PLACE Altered gastric emptying Diet, drugs overweight, etc Savarino V et al. Digestion 2004

9 Johnson et al, Scand J Gastroenterol 1992 L esposizione esofagea diurna all acido, particolarmente dopo i pasti predomina nella malattia da reflusso gastroesofageo Esposizione intraesofagea all acido (% tempo a ph < 4) ORE Colazione Pranzo Cena

10 2 Example of a ph tracing during pull-through in 1 subject while fasting and again after a meal at the esophagogastric junction Fletcher et al, Gastroenterology 2001

11 Unbuffered acid pocket at Cardia & GE junction Mean of 10 subjects FASTING 6 STOMACH SC-junction ESOPHAGUS ph AFTER 6 MEAL 5 ph ( cm ) ( Fletcher et al Gastroenterology 2001;121: )

12 3 Relating the ph Transition to the SCJ & LES Concurrent HRM, Fluoroscopy & ph-metry 8 ph transition point SCJ -1.5 cm -1.0 cm -0.5 cm 0.0 cm 0.5 cm Acid pocket Respiratory variation Pandolfino JE et al, Am J Gastroenterol 2007

13 Location of the acid pocket in fasting and post prandial conditions in healthy subjects. There is a significant shortening of the high pressure zone after meal (p < 0.05) Clarke AT et al, Gut 2008

14 High Resolution ph metry Proximal margin of the gastric folds antimony ph sensors 8 Hz sampling frequency 12 Polygram net software Custom made by Synectics (Clarke et al Gut 2009;58:904-9 )

15 4 High Resolution ph - Fasting Colour Contour Display Oesophagus Proximal margin of the folds Stomach Clarke At et al, Gut 2009 ph 2 ph 4 ph 6 ph 8

16 High Resolution ph 17 min after meal Oesophagus Proximal margin of the folds Stomach Clarke AT et al, Gut 2009 ph 2 ph 4 ph 6 ph 8

17 5 High Resolution ph 45 min after meal Oesophagus Proximal margin of the folds Stomach Clarke AT et al, Gut 2009 ph 2 ph 4 ph 6 ph 8

18 High Resolution ph Short segment reflux from acid pocket REFLUX EVENT Oesophagus Proximal margin of the folds Stomach Clarke AT et al, Gut 2009 ph 2 ph 4 ph 6 ph 8

19 Acid pocket is frequent source of postprandial reflux Studies with high resolution ph (Clarke et al Gut 2009;58:904-9 )

20 Layering of unbuffered acid in proximal stomach MRI scan Following meal proximal stomach relatively immobile allowing layering of contents Lipid Meal Viscous sucrose liquid meal MRI scan Floating lipid layer Aqueous layer (From Marciani et al Brit J Nutrition 2006;95:331-9) ( From Sauter et al Neurogastroenterol Motil 2012;24: )

21 6 Scintigraphic images of the acid pocket in a normal subject and in a patient with hiatal hernia Beaumont H et al, Gut 2010

22 Median ph and percentage of time at ph < 4.0 in the postprandial period Grigolon A et al, Am J Gastroenterol 2009

23 Position of acid pocket vs acidity of reflux Acidic Weakly acidic 100 Percent of reflux episodes Supradiaphragmatic Intradiaphragmatic Subdiaphragmatic Rohof WO et al. Gut 2012

24 ACID COAT Fundus relaxes after meal so mixing limited, consequently - Acidity will be greatest nearest mucosa i.e. closest to acid source and furthest away from bulk of food buffer Would be consistent with prokinetic agents minimizing acid pocket Mitchell DR et al, J Clin Gastroenterol 2016

25 Relating the ph Transition to the SCJ & LES Normal Control Upright Supine (mmhg) clip 40 clip Fasting EGJ HPZ ph transition ph transition EGJ Esophagus EGJ Esophagus (mmhg) clip 40 clip 40 Postprandial ph transition ph transition EGJ Esophagus EGJ Esophagus Pandolfino JE et al, Am J Gastroenterol 2007

26 Relating the ph Transition to the SCJ & LES Reflux Patient (mmhg) 50 Upright 50 Supine Fasting clip ph transition clip ph transition EGJ Esophagus EGJ Esophagus Postprandial (mmhg) EGJ clip ph transition Esophagus EGJ clip ph transition Esophagus Pandolfino JE et al, Am J Gastroenterol 2007

27 Salient features of the acid pocket pertinent to heartburn/gerd - Following a meal the proximal stomach, very close to EGJ, largely escapes the buffering effect of the food and remains highly acidic acid pocket - Reservoir for acid reflux beginning within 15 minutes of a meal - Can cause proximal migration of the acid interface across the SCJ - Exacerbated by hiatus hernia and low LES pressure

28 The Acid Pocket as a Therapeutic Target

29 Nor placebo nor baclofen significantly affected the proximal extent of acid pockets detected after the meal in GERD patients Scarpellini E et al, Dis Esophagus 2016

30 Pharmacological modification of gastric motility alters acid pocket Placebo Erythromycin Sumatriptan ( Boeckstaens et al APT 2011;33: ) Lack of mixing of acid and food in proximal stomach may contribute to acid pocket

31 Effect of Azithromycin on Gastroesophageal Reflux Prospective Cohort Study N = 47 LTx pts On and Off Azithromycin Crossover, placebo-controlled Trial (Azi 250mg/day) N = 16 pts with GERD and Hiatal Hernia Mertens V et al Dig Dis Sci. 2009;54(5):972-9 Rohof WO et al Gut. 2012;61(12):1670-7

32 7 Preventing formation of the acid pocket Inhibit postprandial acid secretion with PPI Rabeprazole 20 mg vs placebo: day 1 of treatment 50% reduction in detectable acid pocket during ph pull through after standardized meals Reduced length and increased nadir ph of acid pocket Placebo Rabeprazole Vo L, et al Aliment Pharmacol Ther 2005;21:

33 On PPI, the acid pocket was significantly more often located below the diaphragm compared with off PPI (p < 0.05) Rohof WO et al, Clin Gastroenterol Hepatol 2014

34 8 Gaviscon: Mechanism of Action Containing the acid pocket?

35 9 Examples of ph pull-throughs in two GERD patients

36 Gaviscon effect on location of transition (ph<4) to acid pocket (n= 10 GERD patients) Esophagus Distal EGJ cm Fasted +2.3 cm 20 min after meal +1.1 cm EGJ HPZ on HRM Stomach min after Gaviscon -9.5 cm Kwiateck et al, Aliment Pharmacol Ther (1):59-66

37 10 Rohof et al, Clin Gastroenterol Hepatol 2013

38 The mean number of reflux events (A), acid reflux episodes (B) and esophageal acid exposure (C) were reduced by alginate-antacid compared with antacid, but the mean number of weakly acidic reflux episodes was higher than alginate-antacid (D). Rohof et al, Clin Gastroenterol Hepatol 2013

39 Laparoscopic Nissen Fundoplication Peters & DeMeester Minimally Invasive Surgery of the Foregut 1994

40 Conclusions - The acid pocket is a region of high acidity at the gastroesophageal junction after a meal - It appears due to the proximal cardia region of stomach escaping the buffering effect of meal and is visible 15 min after it - The acid pocket measures cm in length in GERD patients - Its presence is exacerbated by hiatus hernia and low LES pressure - There is evidence that it is the source of postprandial reflux - At present, alginate ± antacid seems to be the only drug favoring its complete displacement below the diaphragm

41 GRAZIE PER L ATTENZIONE