LE MANIFESTAZIONI EXTRASOFAGEE
DELLA MRGE: REALI O IMMAGINARIE ?
Vincenzo Savarino, Prof., MD
Head of the Department of Internal Medicine and
Medical Specialties, University of Genoa, Italy
Head of the Gastroenterology-Hepatology Unit,
IRCCS Azienda Ospedaliera-Universitaria San
Martino - IST, Genoa, Italy
GERD - New Montreal Definition
GERD is a condition which develops when the reflux
of stomach content causes troublesome symptoms
and / or complications
Esophageal
Syndromes
Extra-esophageal
Syndromes
Symptomatic
Syndromes
Syndromes with
Esophageal Injury
Established
Association
Proposed
Association
Typical reflux
syndrome
Reflux esophagitis
Reflux cough
Sinusitis
Reflux stricture
Reflux laryngitis
Reflux chest
pain syndrome
Pulmonary
fibrosis
Barrett's
esophagus
Reflux asthma
Adenocarcinoma
Reflux dental
erosions
Pharyngitis
Recurrent otitis
media
Vakil et al., Am J Gastroenterol 2006
Abnormal 24-hour pH Monitoring in Patients
With Suspected Reflux Laryngitis
Source
n
pH abnormality
Havas et al, 1999
15
53%
Metz et al, 1997
10
60%
Little et al, 1996
222
76%
Chen et al, 1998
735
50%
Wiener et al, 1989
15
80%
Katz et al, 1990
10
70%
Ulualp et al, 1999
20
75%
McNally et al, 1989
11
55%
Shaker et al, 1995
12
100%
Ossakow et al, 1988
38
68%
Koufman et al, 1988
32
75%
Wilson et al, 1989
97
18%
Cumulative
1217
54%
Vaezi et al, 2003
Patients with abnormal acid reflux (%)
Abnormal Acid Reflux Linked
to Asthma
100
90
82
80
70
61
60
55
40
53
33
20
0
Ducolone
et al.
(n=51)
Nagel
et al.
(n=44)
Giudicelli
et al.
(n=140)
Sontag
et al.
(n=104)
DeMeester
et al.
(n=77)
Larrain
et al.
(n=105)
Kiljander
et al.
(n=107)
Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.
Prevalence of reflux-associated chronic cough
by esophageal pH monitoring
Vaezi MF, APT 2006
Dental erosions in GERD patients
Ranjitkar S et al, J Gastroenterol Hepatol 2012
Boxplots showing the total number and the chemical composition of reflux episodes in the two
subgroups of SSC patients with and without pulmonary fibrosis and healthy volunteers.
p<0.001
p<0.001
No. reflux episodes
p<0.001
p<0.001
p<0.05
p<0.05
Savarino E et al, AJRCCM 2009
Proximal migration of reflux episodes in scleroderma patients and in controls.
p<0.001
No. reflux episodes 15 cm above LES
p<0.001
Savarino E et al, Am J Resp Crit Care Med 2009
Correlation between proximal migration of refluxes
and total number of reflux events and pulmonary
fibrosis score
140
200
r2=0.644,p<0.001
r2=0.637,p<0.001
120
150
Tot N Reflux Episodes
100
80
60
40
100
50
20
0
0
0
5
10
HRCT SCORE
15
20
0
5
10
15
20
HRCT SCORE
Savarino E et al, Am J Respir Crit Care Med 2009
N° REFLUX EVENTS
Number and types of gastro-esophageal reflux in IPF (n=40) and non-IPF
patients (n=40) and in healthy controls (n = 50). Bars indicate median
values. IPF= idiopathic pulmonary fibrosis
Boxplots showing the number of total, acid and non-acidic reflux
in patients with IPF and non-IPF and in controls
Savarino E et al, DDW 2012
N° PROXIMAL REFLUX EVENTS
Median number of reflux episodes reaching the proximal esophagus in
IPF (n=40) and non-IPF patients (n=40) and in healthy controls (n = 50).
Bars indicate median values. IPF= idiopathic pulmonary fibrosis
Savarino E et al, DDW 2012
Correlation between the grade of pulmonary fibrosis (HRCT score)
and the number of total reflux episodes at both the distal (on the
left) and proximal (on the right) esophagus
140
100
r2=0.567,p<0.001
r2=0.632,p<0.001
120
80
IPF Prox Ext tot
100
80
60
60
40
40
20
20
0
0
5
10
15
20
IPF_SCORE_HRCT
25
30
35
5
10
15
20
25
30
IPF SCORE HRCT
Savarino E et al, DDW 2012
35
Percentages of patients with presence of biliary
acids and pepsin in IPF, non-IPF and controls
SALIVA
P < 0.01
BAL
Biliary acids
61% IPF patients
36% non-IPF patients
0% controls
Biliary acids:
62% IPF patients
40% non-IPF patients
0% controls
Pepsin:
68% IPF patients
39% non-IPF patients
0% controls
Pepsin:
67% IPF patients
40% non-IPF patients
0% controls
Savarino E et al, DDW 2012
PREVALENCE OF
ATYPICAL SYMPTOMS
•Prevalence of atypical symptoms concerning
upper airways:
– Sporadic manifestations between 7% and
15%
– Frequent manifestations : 5 %
Locke GR Gastroenterology 1997; 112:1448-56.
•In more than 50% of patients with atypical
symptoms, typical symptoms are lacking
Koufmann JH. Laringoscope 1991
GERD and respiratory symptoms
PATHOPHYSIOLOGY
• Microaspiration of gastric contents into
the larynx or airways with consequent
mucosal reaction
• Vagal reflex stimulated by refluxate in
the distal esophagus with the production
of cough and/or bronchospasm
DIAGNOSTIC STRATEGY
(search for GERD in patients with
extraesophageal symptoms)
• Clinical features
• Trial of aggressive acid suppression
(PPI test)
• Endoscopy
• 24-h pH-metry
[the choice of the diagnostic work-up should be
based on test sensitivity, prevalence of the
disease, cost-effectiveness, etc.]
Suggested Regimens for Extraesophageal Manifestations of GERD
Symptom
Medication and dose
Duration
Chest pain
PPI b.i.d.
1-8 weeks
Asthma
PPI b.i.d.
≤3 month
Cough
PPI b.i.d.
1-3 months
Upper airway
PPI b.i.d.
1-3 months
Katz et al, Am J Med 2000; 108(suppl 4a): 170S-177S.
Cough scores dramatically decrease after the
introduction of omeprazole 40 mg bid and the patient
remains free of cough 1 yr after PPI withdrawal
Ours T et al, Am J Gastroenterol 1999
Usefulness of PPI test in GERD
duration
mg/die
days
Studies om/lan/eso
8
40-60
5-14
N°
Typical
symptoms
Sens
%
27-89
Spec
%
6-73
NCCP
3
40-80
7-30
69-80
75-90
Cough
Laryngitis
3
40-80
7-90
63-81
55-90
 Gold standard: pH-metry and/or endoscopy
De Vault et al, 2000
Endoscopy
GERD and extraesophageal
manifestations
It’s not simple to establish a causeeffect relationship between GERD
and extraesophageal manifestations !
Regurgitation or pyrosis : 20%-75%
Erosive Esophagitis : < 30%
Irvin,1993; Ours,1999
Ear, nose and throat (ENT) signs in normal volunteers (n = 105)
Hicks DM et al, 2002
Therapeutic trial of anti-GORD therapy
for asthma patients
Adult asthma patients
Monitor baseline asthma symptom, PEF, asthma
medication use and spirometry
3-month trial with omeprazole 20 mg twice daily,
lansoprazole 30 mg twice daily,
or rabeprazole 20 mg twice daily
Continue monitoring as above
Asthma improved
Begin maintenance anti-GORD
therapy, which may include:
 PPIs
 H2RAs
 Prokinetic agents
 Surgery in selected patients
PEF = Peak Expiratory Flow
Asthma not improved
Perform 24-hour oesophageal pH
test while on anti-GORD regimen
pH+
Increase anti-GORD
therapy or refer to
gastroenterologist
pHAsthma is not
GORD-related
Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.
24-hour
ambulatory
pH-impedance
Episode of acid gastroesophageal reflux
Episode of weakly acidic GER
Criteria for selection of patients with chronic
cough in whom GERD should be investigated
Galmiche JP et al, APT 2008
Nonacid reflux episode associated with cough
Rosen and Nurko, 2004
Relevance of acid and/or weakly acidic reflux in chronic cough
22 Patients
10 SAP + Reflux-Cough
5 Acid Associated
2 Acid & Non acid
Associated
3 Non acid Associated
Weakly Acidic Reflux in Patients with Chronic Unexplained Cough During 24 Hour Pressure, pH and
Impedance Monitoring; D. Sifrim et al; GUT; 2005; 54;449-454
Identification of three subgroups with chronic cough
Blondeau et al, APT 2007
Proposal of a diagnostic work-up in patients with suspected atypical GERD
NEG
Quigley et al, 2008
Therapeutic results in patients with
atypical symptoms of GERD
Medical Treatment of Patients with Chronic Cough from Suspected GERD
n
Study design
Therapy
Asymtomatic
patients (%)
Irwin et al, ‘89
9
Uncontrolled
Metoclopramide and/or
H2RAs
100
Irwin et al, ‘90
28
Uncontrolled
Metoclopramide and/or
H2RAs
100
Fitzgerald et al,
‘89
20
Uncontrolled
Antacids, Cimetidine,
Metoclopramide
70
Waring et al, ‘95
25
Uncontrolled
H2RAs, PPIs
80
Smyrnios et al,
‘95
20
Uncontrolled
H2RAs
 prokinetics
97
Vaezi et al, ‘97
11
Uncontrolled
H2RAs or PPIs
100
Ours et al, ‘99
17
Double-blind,
placebo-controlled
PPI
( Ome 40 mg bid )
35
Results of Seven Randomized, Controlled Trials of
PPIs in Subjects with GERD-related Asthma
Authors
Year
Pts no.
RX
Response
Ford et al
1994
10
Ome 20, 4 wks
- sympts, - PEF
Meier et al
1994
15
Ome 40, 6 wks
- FEV1
Teichtahl et al
1996
20
Ome 40, 4 wks
- sympts, - FEV1, + PEF
Levin et al
1998
9
Ome 20, 8 wks
+ sympts, + PEF, - FEV1
Boeree et al
1998
30
Ome 80, 12 wks
-day + night sympts,
- FEV1, - PEF
Kiljander et al
1999
52
Ome 40, 8 wks
-Day + night symptoms,
- FEV1,
- PEF
Jiang et al
2003
30
Ome 20,
Domperidone
10 TID, 6 wks
+ FEV1, + PEF
Shaheen N, DDW 2004
Medical treatment trials for GERD-related asthma
Richter et al, 2005
Treatment difference (95% CI) in change in morning and evening PEF rate
(L/min), classified according to GERD and nocturnal symptoms in asthmatic
subjects receiving esomeprazole 40 mg twice daily or placebo
Kiljander et al, AJRCCM 2006
Questionnaire scores and lung function measures at 24 weeks of follow up
Holbrook J et al, JAMA 2012
Results of Uncontrolled Studies in the Treatment of
Patients With Suspected Reflux Laryngitis
Response
Source
n
Therapy
Duration
(mo)
Symptoms
Larynx
Koufman et al,
1991
33
H2RAs
6
85%
85%
Metz et al, 1997
10
PPI (80 mg)*
1
60%
Hanson et al,
1995
182
H2RA/PPI
1-3
98%
98%
Kamel et al, 1994
16
PPI (40 mg)*
1-6
92%
56%
Shaw et al, 1997
68
PPI (40 mg)*
3
60%
Wo et al, 1997
21
PPI (40 mg)*
2
67%
50%
Vaezi et al, 2001
45
PPI*± H2RA
4
67%
62%
Cumulative
375
3.6
83%
85%
(*PPIs were given generally twice daily, before breakfast and dinner)
Vaezi et al, 2003
Medical antireflux treatment of reflux laryngitis: placebocontrolled studies
Richter et al, 2005
Estimates of relative risk for improvement or resolution of laryngeal
symptoms in patients treated with PPIs
Gatta et al, APT 2007
Summary of proton pump inhibitor efficacy for potential manifestations
of GORD as assessed in randomised controlled trials.
Kahrilas and Boeckxstaens, Gut 2012
Surgical therapy of chronic cough due to GORD
no.
pts.
Study design
Treatment
Asymptomatic
(%)
5
Prospectic,
uncontrolled
Fundoplicatio
100
DeMeester
‘90
17
Prospectic,
uncontrolled
Fundoplicatio
100
Giudicelli ‘90
13
Prospectic,
uncontrolled
Fundoplicatio
85%
Johnson ‘96
40
Prospectic,
uncontrolled
Fundoplicatio
76
Allen, Anvari
‘98
20
Prospectic,
uncontrolled
Fundoplicatio
51%(asintom)
31%(migliorat
i
So ‘98
16
Prospectic,
uncontrolled
Fundoplicatio
56
7
Prospectic,
controlled
Fundoplicatio
60
Pellegrini ‘79
Leeder ‘02
Preoperative and postoperative voice frequency (CFx) and
amplitude (CFa) are compared in patients with documented
irregularity in their preoperative electroglottography (n = 6).
p < 0.0012 and p < 0.0415
Ayazi S et al, J Clin Gastroenterol 2012
Shortcomings Shared by Studies on
Extra-esophageal Reflux Disease
• Most studies feature small number of subjects
• Case definition is variable (also 24-hour pH data are
of limited utility)
• In patients with abnormal pH data, a simple
association instead of causation between reflux and
laryngeal-respiratory symptoms may be present
• In a subgroup of patients with chronic cough acid
and/or weakly acidic gastroesophageal reflux can be
present
• Study outcome measures are not standardized and
may vary considerably across studies
• Treatment amount and duration may be inadequate
Atypical GERD: key messages
• GERD can manifest with atypical symptoms
• Their prevalence ranges between 5% and 20%
• There is no diagnostic method of adequate reliability
• It is mandatory to distinguish simple association from
causality between GERD and extra-esophageal disorders
• It is recommended to treat these patients with higher-thanstandard doses of PPIs and for longer-than-usual time
periods
• However, both medical and surgical therapies
frequently disappointing in controlled studies
are
• Our future efforts should be addressed to identify the
subgroup of patients who can respond to anti-reflux
treatment
The End