Pathogenesis and current treatment

of gastroesophageal reflux disease

Georgios P. Karamanolis

Assistant Professor in Gastroenterology

Aretaieion Hospital

GERD - definitionGERD is a condition which develops when the reflux of stomach content causes troublesome symptoms

and / or complications

Symptomatic Syndromes

Typical reflux syndrome

Reflux chest pain syndrome

Syndromes with Esophageal Injury

Reflux esophagitis

Reflux stricture

Barrett's esophagus

Adenocarcinoma

Esophageal Syndromes

Established Association

Reflux cough

Reflux laryngitis

Reflux asthma

Reflux dental erosions

Proposed Association

Sinusitis

Pulmonary fibrosis

Pharyngitis

Recurrent otitis media

Extra-esophageal Syndromes

Vakil et al. Am J Gastroenterol 2006

pathophysiology

impaired clearance

hiatal herniaTLESRs

hypotensive sphincterdelayed gastric

emptying

anti-reflux barrier

CD LES

failure

l low basal LESP

l transient LES relaxations

l hiatal hernia

LES pressure

*

(98)

**

0

10

20

30

40

50

60

70

80

NormalVolunteers GERD

Mildesoph

Severeesoph

PatientControls

LESPressure(mmHg)

Kahrilas et al., 1986

swallow

LES

stomach

7

1

20

40

40

40

40

20

3

7

11

15

pH

mm Hg

Manometry

cm

ab

ove

LE

S

20

transient LES relaxations

pathways mediating

Inhibitory

Motor Neuron

--

-

NO

+ +

InterneuronVagal

efferent

CNS

Vagal

afferent

Fundic

mechanoreceptors

transient LES relaxations

TLESRs

No. / h5

10

15

0

80

100

Controls GERD

60

40

20

%TLESRswith

acid reflux

Controls GERD

Sifrim et al., 2001

transient LES relaxations

Transient LESrelaxation

Swallow-induced LES

relaxation

LES pressuredrift

Absent basalLES pressure

pHPharynx

LOS

Stomach

100

80

60

40

20

0

%Reflux

episodes

reflux mechamisms in GERD

– ambulatory study

Penagini et al., 1996

hiatal hernia

lower threshold for

triggering TLESRs

retention in hernia

with re-reflux

low LESPsusceptible to intra-

abdominal pressure rises

Sivri and Mittal, 1991

Kahrilas et al., 2000

Van Herwaarden et al., 2000

initialmanagement

long-term management

GERD: clinical management

non-erosive reflux disease (NERD) : 60-70%

reflux esophagitis (RE): 30-40%

GERD phenotypes

reflux symptoms

normal endoscopy

reflux symptoms

endoscopic criteria

Lundell et al. Gut 1999

LA Grade C

1 mucosal

breaks bridging

the tops of folds

but involving

<75% of the

circumference

LA Grade D

1 mucosal

breaks bridging

the tops of folds

and involving

>75% of the

circumference

LA classification

1 isolated

mucosal breaks

>5 mm long

LA Grade B1 isolated

mucosal breaks

5 mm long

LA Grade A

? x2 daily PPI + H2RA

x2 daily PPI

x1 daily PPI

x1 daily ½ PPI

Prokinetic + H2RA

Prokinetic*

Antacids + lifestyle

Antacids

Lifestyle

H2RA*OR

*no clear dose-response established

highest efficacy

lowest efficacy

Recommended

Should beabandoned

Current

guidelines

mainstream options for therapy of

GERD

Dent et al. Gut 1999 (Suppl 2)

hours / day

gastric pH > 4

lifestyle advices

stop smoking

reduce alcohol intake

weight loss in obese patients

elevation of the head of the bed

eat 3-4 hrs before sleeping

4 weeks PPIs

Dent et al. Gut 1999 (Suppl 2)

non-erosive reflux disease (NERD)

PPIs vs. placebo

NERD - cochrane 2006

NERD - cochrane 2006

PPIs vs. H2RAs

Α/Β LA

Dent et al. Gut 1999 (Suppl 2)

C/D LA

4 weeks PPIs 8 weeks PPIs

90-95% 5-10%

reflux esophagitis (RE)

esophagitis - cochrane 2007

PPIs vs. placebo

4 weeks

PPIs vs. H2RAs

8 weeks

esophagitis - cochrane 2007

0

20

40

60

80

100

0 1 2 3 4 5 6

patients without esophagitis

patients with esophagitis

25%

10%

monthstime since treatment cessation

Carlsson et al 1998

repalse of symptomsp

atients

in s

ym

pto

ma

tic r

em

issio

n %

maintenance therapy

sustain satisfactory symptom control

maintain endoscopic remission

prevention of complications

MAINTENANCE THERAPY

medical therapy

surgical therapy

endoscopic therapy

Medical therapy

initial

therapy

successful

step down

to the lowest PPIs

efficient dose

Dent & Talley. Aliment Pharmacol Ther 2003 ( Suppl 1)Dent et al. Gut 2004 (Suppl 4)

MAINTENANCE THERAPY

continuous long-term PPIs therapy

Dent et al. Gut 1999 (Suppl 2)

MAINTENANCE THERAPY

C / D LA esophagitis

s = symptom recurrence

continuous (months)

intermittent (weeks)

S S

“on demand” (days)

S S S S S S

NERD and A / B LA esophagitis

on demand vs. continuous

maintenance therapy

Bour et al. APT 2005

NSP=0.065

on demand continuous

18

12

% failures

75 86

% symptom free

0.31

0.96

Nb units / day

drawbacks of PPIs

daily administration

incomplete symptom relief

need to chronically consume drugs

not address the pathophysiology of GERD

baclofen (GABA agonist) in GERD

Van Herwaarden et al., 2002

** ** *

0

5

10

15

20

25

30

35

N TLESRs N acid reflux events % time pH < 4

Nu

mb

er

Placebo

Baclofen

surgical therapy

indications for surgical

treatment of GERD

reflux patients who need long-term medical

treatment with standard or increased

dose of PPIs

candidates for surgical treatment

good response to PPIs

predicts good response

to surgical therapy

SO JB, et al. Surgery 1998

nissen fundoplication

long-term outcomes of

laparoscopic Nissen

No of pts f/p (yrs) efficacy (%) revised (%)

Lafullarde et al 178 5-8 87 13

Booth et al 175 2-8 90 6

Bammer et al 171 5-8 94 nr

Dallemange et al 86 10 90 5

limitations of surgical therapy

surgical expertise

hospitalization / post-operative recovery

efficacy may wane over time

up to 50% of patients require acid antisecretory therapy to control symptoms

new symptoms following the procedure

dysphagia 35%

inability to belch 20%

flatulence 41%

dyspepsia 30%

Freston & Triantafilopoulos. APT 2004

dysphagia after Nissen

0

5

10

15

20

25

30

Early dysphagia Late dysphagia Dilation

Nu

mb

er

of

pa

tie

nts

(%

)

Perdikis, et al.Surg Laparosc Endosc 1997

meta-analysis in 2453 patients

with laparoscopic Nissen

endoscopic therapy

10

implantation

radiofrequency endoscopic suturing

deviceinjection of bulking agents

endoscopic fundoplication

esophyx

conclusions

multifactorial disease

TLERs are the most predominant mechanism

chronic disease with relapses

PPIs are the corn stone medical treatment

antireflux surgery is an effective alternative treatment

ΚΑΛΗ ΕΠΙΤΥΧΙΑ ΣΤΟ Κ.Ε.Ε.Λ