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 ?

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

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

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

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

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.

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.

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

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

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

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

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

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.]

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

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

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

Endoscopy

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

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

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

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 Nonacid reflux episode associated with coughcough

Rosen and Nurko, 2004

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

Identification of three subgroups with chronic cough

Blondeau et al, APT 2007

NEG

Proposal of a diagnostic work-up in patients with suspected atypical GERD

Quigley et al, 2008

Therapeutic results in patients with

atypical symptoms of GERD

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

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 asthmaMedical 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

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

Medical antireflux treatment of reflux laryngitis: Medical antireflux treatment of reflux laryngitis: placebo-controlled studiesplacebo-controlled 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 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.

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-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

The EndThe End