vincenzo savarino, prof., md
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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 - PowerPoint PPT PresentationTRANSCRIPT
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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
LE MANIFESTAZIONI EXTRASOFAGEE DELLA MRGE: REALI O IMMAGINARIE ?
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GERD - New Montreal DefinitionGERD is a condition which develops when the reflux
of stomach content causes troublesome symptoms and / or complications
GERD 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
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Abnormal 24-hour pH Monitoring in Patients With Suspected Reflux Laryngitis
Source n pH abnormalityHavas 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
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Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.
Pat
ien
ts w
ith
ab
no
rmal
aci
d r
eflu
x (%
)
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)
100
80
60
40
20
0
55
33
61
82
70
90
53
Abnormal Acid Reflux Linked to Asthma
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Prevalence of reflux-associated chronic cough by esophageal pH monitoring
Vaezi MF, APT 2006
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Dental erosions in GERD patients
Ranjitkar S et al, J Gastroenterol Hepatol 2012
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No.
ref
lux
epis
odes
p<0.001
p<0.001
p<0.001
p<0.001
p<0.05
p<0.05
Savarino E et al, AJRCCM 2009
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.
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p<0.001
p<0.001
No.
ref
lux
epis
odes
15
cm a
bove
LE
S
Savarino E et al, Am J Resp Crit Care Med 2009
Proximal migration of reflux episodes in scleroderma patients and in controls.
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Correlation between proximal migration of refluxes Correlation between proximal migration of refluxes and total number of reflux events and pulmonary and total number of reflux events and pulmonary
fibrosis scorefibrosis score
0 5 10 15 20
140
120
100
80
60
40
20
0
HRCT SCORE
N Re
flux E
pisod
es a
t 15
cm a
bove
the
LES
r2=0.644,p<0.001
0 5 10 15 20
200
150
100
50
0
HRCT SCORE
Tot N
Ref
lux
Episo
des
r2=0.637,p<0.001
Savarino E et al, Am J Respir Crit Care Med 2009
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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 fibrosisBoxplots showing the number of total, acid and non-acidic reflux Boxplots showing the number of total, acid and non-acidic reflux
in patients with IPF and non-IPF and in controlsin patients with IPF and non-IPF and in controls
Savarino E et al, DDW 2012
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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
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5 10 15 20 25 30 35
140
120
100
80
60
40
20
0
IPF_SCORE_HRCT
IPF
_N°R
EF
LU
SSI
5 10 15 20 25 30 35
100
80
60
40
20
0
IPF SCORE HRCT
IPF
Pro
x Ex
t tot
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
r2=0.567,p<0.001
r2=0.632,p<0.001
Savarino E et al, DDW 2012
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Percentages of patients with presence of biliary Percentages of patients with presence of biliary acids and pepsin in IPF, non-IPF and controlsacids and pepsin in IPF, non-IPF and controls
SALIVA BAL
Biliary acids 61% IPF patients 36% non-IPF patients 0% controls
Pepsin:68% IPF patients 39% non-IPF patients 0% controls
Biliary acids: 62% IPF patients 40% non-IPF patients 0% controls
Pepsin:67% IPF patients40% non-IPF patients0% controlsP < 0.01
Savarino E et al, DDW 2012
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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
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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
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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.]
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Katz et al, Am J Med 2000; 108(suppl 4a): 170S-177S.
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
Suggested Regimens for Extra-esophageal Manifestations of GERD
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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
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Usefulness of PPI test in GERD
N° Studies
mg/die
om/lan/eso
duration
daysSens
%
Spec
%Typical symptoms
8 40-60 5-14 27-89 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
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Endoscopy
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It’s not simple to establish a cause-effect relationship between GERD and
extraesophageal manifestations !
Regurgitation or pyrosis : 20%-75%
Erosive Esophagitis : < 30%
Irvin,1993; Ours,1999
GERD and extraesophageal GERD and extraesophageal manifestationsmanifestations
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Ear, nose and throat (ENT) signs in normal volunteers (n = 105)Ear, nose and throat (ENT) signs in normal volunteers (n = 105)
Hicks DM et al, 2002
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pH-Asthma is not GORD-related
Asthma improvedBegin maintenance anti-GORD therapy, which may include: PPIs H2RAs
Prokinetic agents Surgery in selected patients
pH+Increase anti-GORD therapy or refer to gastroenterologist
Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.
Adult asthma patients
Asthma not improvedPerform 24-hour oesophageal pH test while on anti-GORD regimen
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
Therapeutic trial of anti-GORD therapy for asthma patients
Therapeutic trial of anti-GORD therapy for asthma patients
PEF = Peak Expiratory Flow
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24-hour ambulatory pH-impedance
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Episode of acid gastroesophageal reflux
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Episode of weakly acidic GER
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Criteria for selection of patients with chronic cough in whom GERD should be investigated
Galmiche JP et al, APT 2008
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Nonacid reflux episode associated with Nonacid reflux episode associated with coughcough
Rosen and Nurko, 2004
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Relevance of acid and/or weakly acidic reflux in chronic cough
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
3 Non acid Associated2 Acid & Non acid Associated
5 Acid Associated
10 SAP + Reflux-Cough
22 Patients
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Identification of three subgroups with chronic cough
Blondeau et al, APT 2007
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NEG
Proposal of a diagnostic work-up in patients with suspected atypical GERD
Quigley et al, 2008
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Therapeutic results in patients with
atypical symptoms of GERD
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Medical Treatment of Patients with Chronic Cough from Suspected GERD
35PPI
( Ome 40 mg bid )
Double-blind, placebo-controlled
17Ours et al, ‘99
100H2RAs or PPIsUncontrolled11Vaezi et al, ‘97
97H2RAs
prokinetics
Uncontrolled20Smyrnios et al, ‘95
80H2RAs, PPIsUncontrolled25Waring et al, ‘95
70Antacids, Cimetidine, Metoclopramide
Uncontrolled20Fitzgerald et al, ‘89
100Metoclopramide and/or H2RAs
Uncontrolled28Irwin et al, ‘90
100Metoclopramide and/or
H2RAs
Uncontrolled9Irwin et al, ‘89
Asymtomatic patients (%)
TherapyStudy designn
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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
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Medical treatment trials for GERD-related asthmaMedical treatment trials for GERD-related asthma
Richter et al, 2005
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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
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Questionnaire scores and lung function measures at 24 weeks of follow up
Holbrook J et al, JAMA 2012
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Results of Uncontrolled Studies in the Treatment of Patients With Suspected Reflux Laryngitis
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%
Response
(*PPIs were given generally twice daily, before breakfast and dinner)
Vaezi et al, 2003
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Medical antireflux treatment of reflux laryngitis: Medical antireflux treatment of reflux laryngitis: placebo-controlled studiesplacebo-controlled studies
Richter et al, 2005
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Estimates of relative risk for improvement or resolution of laryngeal symptoms in patients treated with PPIs
Gatta et al, APT 2007
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Summary of proton pump inhibitor efficacy for potential manifestations of GORD as assessed in randomised controlled trials.
Kahrilas and Boeckxstaens, Gut 2012
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Surgical therapy of chronic cough due to GORDSurgical therapy of chronic cough due to GORD
60FundoplicatioProspectic,controlled
7Leeder ‘02
56 FundoplicatioProspectic, uncontrolled
16So ‘98
51%(asintom)
31%(migliorati
FundoplicatioProspectic, uncontrolled
20Allen, Anvari‘98
76FundoplicatioProspectic, uncontrolled
40Johnson ‘96
85%FundoplicatioProspectic, uncontrolled
13Giudicelli ‘90
100FundoplicatioProspectic, uncontrolled
17DeMeester ‘90
100FundoplicatioProspectic,uncontrolled
5Pellegrini ‘79
Asymptomatic (%)
TreatmentStudy designno. pts.
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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
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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
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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-than-standard doses of PPIs and for longer-than-usual time periods
• However, both medical and surgical therapies are frequently disappointing in controlled studies
• Our future efforts should be addressed to identify the subgroup of patients who can respond to anti-reflux treatment
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The EndThe End