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

Ingelfinger FJ: N Engl J Med, 1971

“The Sphincter that is a Sphinx”

Competence of the GE Junction

1

excessive acid secretion

increased

pressure

gradient

transient LOS

relaxations

weak anti-reflux barrier:

• diaphragm

• LOS

Impaired esophageal clearance; mucosal hypersensitivity

Delayed gastric

emptying

Pathophysiology of GERD

Savarino E, et al. Curr Opin Otolaryngol Head Neck Surg. 2013; 2:548-56

24-hour gastric pH profiles of controls and GERD patients with

and without esophagitis

Savarino V et al, APT 1998Zentilin P et al, Aliment Pharmacol Ther 2003

Schematic diagram of the transient lower

esophageal sphincter relaxation reflex

Kahrilas P and Boeckxstaens G, Gut 2012

Mittal R et al, NEJM 1997

Savarino E, et al. Curr Opin Otolaryngol Head Neck Surg. 2013; 2:548-56

Transient Lower Esophageal Sphincter

Relaxation Reflex

LES

UES

tLESR with

Reflux

Secondary

Peristalsis

CONVENTIONAL MANOMETRY HIGH RESOLUTION MANOMETRY

Diaphragm

Hiatus Hernia

Lower

Esophageal

Sphincter

The Anti-Reflux Barrier: Two Sphincters

TOO MUCH

ACID IN THE

WRONG PLACE

Diet, drugsoverweight, etc

Abnormalesophageal

clearing

Insufficientantireflux

barrier

Alteredgastric

emptying

Savarino V et al. Digestion 2004

Pathophysiology of GERD

0

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4

6

8

10

12

14

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6

Colazione Pranzo Cena

ORE

Esposizione intraesofagea all’acido

(% tempo a pH < 4)

Johnson et al, Scand J Gastroenterol 1992

L’esposizione esofagea diurna all’acido, particolarmente dopo i

pasti predomina nella malattia da reflusso gastroesofageo

2Example of a pH tracing during pull-through in 1 subject

while fasting and again after a meal at the esophago-

gastric junction

Fletcher et al, Gastroenterology 2001

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1

2

3

4

5

6

Unbuffered acid pocket at Cardia & GE junction

0

1

2

3

4

5

6

ESOPHAGUSSTOMACH SC-junction

pH

pH

FASTING

AFTER

MEAL

( cm )( Fletcher et al Gastroenterology 2001;121:775-783 )

Mean of 10 subjects

3Relating the pH Transition to the SCJ & LES

Concurrent HRM, Fluoroscopy & pH-metry

Pandolfino JE et al, Am J Gastroenterol 2007

-1.5 cm -1.0 cm -0.5 cm 0.0 cm 0.5 cmSCJpH transition point

0

2

4

6

8

‘Acid pocket’

Respiratory variation

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

Proximal margin of

the gastric folds

1

2

3

45 6 7

9

10

11

8

12

12 antimony pH sensors

8 Hz sampling frequency

Polygram net software

High Resolution pH metry

Custom made by Synectics(Clarke et al Gut 2009;58:904-9 )

4 High Resolution pH - Fasting

Colour Contour Display

Clarke At et al, Gut 2009pH 2 pH 4 pH 6 pH 8

Oesophagus

Proximal margin of the folds

Stomach

High Resolution pH – 17 min after meal

Oesophagus

Proximal

margin of the

folds

Stomach

pH 2 pH 4 pH 6 pH 8Clarke AT et al, Gut 2009

5 High Resolution pH – 45 min

after meal

Clarke AT et al, Gut 2009pH 2 pH 4 pH 6 pH 8

Oesophagus

Proximal margin of the folds

Stomach

Oesophagus

StomachProximal

margin of the

folds

High Resolution pH

Short segment reflux from acid

pocket

REFLUX

EVENT

pH 2 pH 4 pH 6 pH 8Clarke AT et al, Gut 2009

Acid pocket is frequent source of

postprandial reflux

(Clarke et al Gut 2009;58:904-9 )

Studies with high resolution pH

Layering of unbuffered acid in

proximal stomach

Following meal proximal stomach relatively immobile

allowing layering of contents

Floating

lipid layer

Aqueous

layer

MRI scan

(From Marciani et al

Brit J Nutrition 2006;95:331-9)

Lipid Meal Viscous sucrose liquid meal

( From Sauter et al

Neurogastroenterol Motil 2012;24:632-40 )

MRI scan

6Scintigraphic images of the acid pocket

in a normal subject

and in a patient with hiatal hernia

Beaumont H et al, Gut 2010

Median pH and percentage of time at pH < 4.0 in the postprandial period

Grigolon A et al, Am J Gastroenterol 2009

Position of acid pocket vs acidity of refluxAcidic Weakly acidic

Percent of reflux

episodes

Rohof WO et al. Gut 2012

100

80

60

40

20

0Sub-

diaphragmaticSupra-

diaphragmaticIntra-

diaphragmatic

ACID COAT

- Acidity will be greatest nearest mucosa – i.e. closest to acid

source and furthest away from bulk of food buffer

Fundus relaxes after meal so mixing limited, consequently

Would be consistent with prokinetic agents minimizing acid pocket

Mitchell DR et al, J Clin Gastroenterol 2016

36 34 32 30 28 26 24 22 20-50

10

20

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40

50

EGJ Esophagus

36 34 32 30 28 26 24 22 20-50

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20

30

40

50

EGJ Esophagus

clip

clip

36 34 32 30 28 26 24 22 20-50

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20

30

40

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EGJ Esophagus

36 34 32 30 28 26 24 22 20-50

10

20

30

40

50

EGJ Esophagus

clipclip

(mmHg)

Relating the pH Transition to the SCJ & LESNormal Control

Pandolfino JE et al, Am J Gastroenterol 2007

pH transitionEGJ HPZ

pH transition

pH transitionpH transition

Fasting

Post-

prandial

(mmHg)

Upright Supine

36 34 32 30 28 26 24 22 20-50

10

20

30

40

50

EGJ Esophagus

36 34 32 30 28 26 24 22 20-50

10

20

30

40

50

EGJ Esophagus

clip clip

Relating the pH Transition to the SCJ & LESReflux Patient

Pandolfino JE et al, Am J Gastroenterol 2007

Fasting

(mmHg)

Upright Supine

pH transitionpH transition

36 34 32 30 28 26 24 22 20-50

10

20

30

40

50

EGJ Esophagus

36 34 32 30 28 26 24 22 20-50

10

20

30

40

50

EGJ Esophagus

clip clip

(mmHg)

Post-

prandial

pH transition pH transition

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

The Acid Pocket as a Therapeutic Target

Nor placebo nor baclofen significantly affected the proximal extentof acid pockets detected after the meal in GERD patients

Scarpellini E et al, Dis Esophagus 2016

( Boeckstaens et al APT 2011;33:1370-7 )

Pharmacological modification of gastric motility

alters acid pocket

Placebo SumatriptanErythromycin

Lack of mixing of acid and food in proximal stomach

may contribute to acid pocket

Effect of Azithromycin on Gastroesophageal Reflux

Mertens V et al Dig Dis Sci. 2009;54(5):972-9 Rohof WO et al Gut. 2012;61(12):1670-7

Crossover, placebo-controlled Trial (Azi 250mg/day)

N = 16 pts with GERD and Hiatal Hernia

Prospective Cohort Study

N = 47 LTx pts On and Off Azithromycin

7

Vo L, et al Aliment Pharmacol Ther 2005;21:1321-30

Preventing formation of

the acid pocketInhibit 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 pocketPlacebo Rabeprazole

On PPI, the acid pocket was significantly more often locatedbelow the diaphragm compared with off PPI (p < 0.05)

Rohof WO et al, Clin Gastroenterol Hepatol 2014

8Gaviscon: Mechanism of Action

Containing the acid pocket?

9Examples of pH pull-throughs in

two GERD patients

Aliment Pharmacol Ther 2011 34(1):59-66

-15

-12.5

-10

-7.5

-5.0

-2.5

0

+2.5

+5.0

Distal EGJ20 min

after meal+1.1 cm

Gaviscon effect on location of transition (pH<4) to “acid pocket” (n= 10 GERD patients)

Fasted+2.3 cm

Stomach

EsophagusEGJ HPZon HRM

20 min after Gaviscon-9.5 cm

cm

Kwiateck et al,

10

Rohof et al, Clin Gastroenterol Hepatol 2013

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

Laparoscopic Nissen Fundoplication

11 2 3

4 5 6

Peters & DeMeester Minimally Invasive Surgery of the Foregut 1994

Conclusions

- The acid pocket is a region of high acidity at the gastro-

esophageal 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 3.0-6.5 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

GRAZIE PER

L’ATTENZIONE