Supraesophageal manifestations Supraesophageal manifestations of GERDof GERD

Symptoms and signs of LPRSymptoms and signs of LPR

Hoarseness 71% Hoarseness 71%

Chronic cough 51%Chronic cough 51%

Globus pharyngeus 47%Globus pharyngeus 47%

Heart burn/regurgitation 43%Heart burn/regurgitation 43%

Chronic throat clearing 42%Chronic throat clearing 42%

Difficulty swallowing 35%Difficulty swallowing 35%

Symptoms and signs

Cummings(III) ch.126 Gastroesophageal reflux disease P2426Cummings(III) ch.126 Gastroesophageal reflux disease P2426

Treatment of Chronic Throat Symptoms with PPIs Should Treatment of Chronic Throat Symptoms with PPIs Should Be Preceded by pH MonitringBe Preceded by pH Monitring

Am J Gastroenterol 2006;101:6-11Am J Gastroenterol 2006;101:6-11

Chronic Throat SymptomsChronic Throat Symptoms

Empiric treatment with PPIs

pH Monitoring

PROPRO::Empiric treatment with PPIs is not Empiric treatment with PPIs is not appropriate without testingappropriate without testing

PPIs are not innocent drugsPPIs are not innocent drugs• Side effects: Headache, diarrhea, Side effects: Headache, diarrhea,

constipation, flatulence, abdominal pain, constipation, flatulence, abdominal pain, dry mouth. dry mouth.

• Less common: anaphylactic shock, Less common: anaphylactic shock, Stevens-Johnson syn., pancreatitis, Stevens-Johnson syn., pancreatitis, nephritis, toxic epidermal necrolysis.nephritis, toxic epidermal necrolysis.

Predispose treated individuals to Predispose treated individuals to pneumoniapneumonia

PPIs are not innocent drugsPPIs are not innocent drugs

PPIs interfere with neutrophil function PPIs interfere with neutrophil function by increasing intracellular calciumby increasing intracellular calcium leading to immunoedeficiency.leading to immunoedeficiency.

In hospitalized patients more CD In hospitalized patients more CD enteritis. enteritis.

Mask and delay the diagnosis of Mask and delay the diagnosis of esophageal AdenoCa. esophageal AdenoCa.

PPIs are not innocent drugsPPIs are not innocent drugs

Rebound and hypersecretion after Rebound and hypersecretion after PPIs withdrawal. PPIs withdrawal. • HypergastrinemiaHypergastrinemia• Increased parietal cell massIncreased parietal cell mass• Increase ECL cells activityIncrease ECL cells activity

Rebound might last more than 2 Rebound might last more than 2 months months ( Fossmark et al. ) ( Fossmark et al. )

A successful empirical trial with PPIs A successful empirical trial with PPIs does not necessarily confirm the does not necessarily confirm the diagnosis of refluxdiagnosis of reflux

• Meta-analysis by Numans et al: Meta-analysis by Numans et al: • Sensitivity – 78%Sensitivity – 78%• Specificity -54%Specificity -54%• Predictive value in LPR should be even Predictive value in LPR should be even

lowerlower

PPIs are overusedPPIs are overused Placebo effect in LPR is highPlacebo effect in LPR is high

• Steward et al: Steward et al: • Rabeprazole bid + lifestyle modificationRabeprazole bid + lifestyle modification 53% response 53% response • Vs. Placebo bid + lifestyle modificationVs. Placebo bid + lifestyle modification 50% response 50% response Noordzij et al: placebo response of 50%Noordzij et al: placebo response of 50%

PPI trial in LPR has the predictive value of PPI trial in LPR has the predictive value of a coin flipa coin flip

We are creating PPI addictsWe are creating PPI addicts

Ambulatory pH testing Ambulatory pH testing complemented by laryngoscopycomplemented by laryngoscopy

Dual-probe pH testing is the gold Dual-probe pH testing is the gold standard for LPRstandard for LPR

The proximal pH sensor is placed The proximal pH sensor is placed 1cm above the UES in the 1cm above the UES in the hypopharyngshypopharyngs

Proximal esophageal acid exposure Proximal esophageal acid exposure can not be relied upon to diagnose can not be relied upon to diagnose extraesophageal disease!!!extraesophageal disease!!!

Ambulatory pH testingAmbulatory pH testing

Merati et al. Meta-analysis of 790 Merati et al. Meta-analysis of 790 extraesophageal pH reports in 16 extraesophageal pH reports in 16 studies for LPRstudies for LPR

Hypopharyngeal pH study does Hypopharyngeal pH study does appear to be able to discriminate LPR appear to be able to discriminate LPR patients from normal. patients from normal.

Sensitivity of 80%Sensitivity of 80%

Laryngoscopy as adjunct testLaryngoscopy as adjunct test

Laryngoscopy alone cannot be relied upon Laryngoscopy alone cannot be relied upon to make the diagnosis of LPRto make the diagnosis of LPR

Tobacco, environmental pollutants, Tobacco, environmental pollutants, infections, excessive voice use and allergy infections, excessive voice use and allergy can all cause laryngeal inflammation.can all cause laryngeal inflammation.

Combination of laryngoscopy and dual-Combination of laryngoscopy and dual-probe pH testing should be considered the probe pH testing should be considered the gold standard in the diagnosis of LPR gold standard in the diagnosis of LPR

Treatment with PPIs should not preceded Treatment with PPIs should not preceded with pH monitoring in suspected LPRwith pH monitoring in suspected LPR

Prolonged pH monitoring is Prolonged pH monitoring is considered the gold standard in the considered the gold standard in the

diagnosis of GERD diagnosis of GERD HoweverHowever pH monitoring is not likely to help in pH monitoring is not likely to help in

the diagnosis or treatment of LPRthe diagnosis or treatment of LPR

The important questions:The important questions:

Does the presence of esophageal acid Does the presence of esophageal acid reflux suggest a casual association reflux suggest a casual association between throat symptoms and GERD?between throat symptoms and GERD?

Does the absence of abnormal acid Does the absence of abnormal acid exposure in the esophagus or even in the exposure in the esophagus or even in the hypopharyngs suggest lack of such an hypopharyngs suggest lack of such an association?association?

Should the pH test be performed on or off Should the pH test be performed on or off therapy and does it matter?therapy and does it matter?

NO!!!

pH monitoringpH monitoring

The overall pre-therapy prevalence of an The overall pre-therapy prevalence of an abnormal pH test us 53%abnormal pH test us 53%

The prevalence of excessive distal, The prevalence of excessive distal, proximal and hypopharyngeal acid proximal and hypopharyngeal acid exposure is 42%, 44% and 38%exposure is 42%, 44% and 38%

No established casual relationshipNo established casual relationship Number and duration of hypopharyngeal Number and duration of hypopharyngeal

reflux events are similar between controls reflux events are similar between controls and LPR patients and LPR patients ( Bilgen et al)( Bilgen et al)

pH testing is a poor predictor of pH testing is a poor predictor of response to therapyresponse to therapy

28/39 patients with posterior 28/39 patients with posterior laryngitis were found to have laryngitis were found to have abnormal pharyngeal refluxabnormal pharyngeal reflux

However, both groups had However, both groups had improvement in symptoms and improvement in symptoms and laryngeal findings with PPIs. laryngeal findings with PPIs. (Ulualp et al)(Ulualp et al)

The dichotomy in the literature The dichotomy in the literature regarding pH monitoring is a result of:regarding pH monitoring is a result of:

Probe positioningProbe positioning Lack of consensus regarding duration Lack of consensus regarding duration

and amount of reflux to denote and amount of reflux to denote abnormal acid refluxabnormal acid reflux

Poor sensitivity of pH monitoring: Poor sensitivity of pH monitoring: 70%, 55% and 40% for distal, 70%, 55% and 40% for distal, proximal and hypopharyngeal proximal and hypopharyngeal probes. probes.

Intermittent nature of reflux eventsIntermittent nature of reflux events

pH testing in patients under pH testing in patients under treatmenttreatment

Was not found to be clinically helpfulWas not found to be clinically helpful Among 115 pts with extraesophageal Among 115 pts with extraesophageal

symptoms while on BID therapy only symptoms while on BID therapy only 2% had abnormal acid exposure. 2% had abnormal acid exposure.

Impedance studies did not reveal a Impedance studies did not reveal a significant role for non-acid reflux.significant role for non-acid reflux.

Posterior laryngitisPosterior laryngitis

Specificity of laryngoscopySpecificity of laryngoscopy

The laryngeal signs are nonspecific. The laryngeal signs are nonspecific. In a study o 105 healthy subjects without In a study o 105 healthy subjects without

any symptoms, the majority had abnormal any symptoms, the majority had abnormal laryngeal findings. laryngeal findings.

91/105 (87%) had at least one abnormal 91/105 (87%) had at least one abnormal findingfinding

3 abnormal findings have been identified:3 abnormal findings have been identified:• Posterior cricoid awall erythemaPosterior cricoid awall erythema• Vocal cord erythema and edemaVocal cord erythema and edema• Arytenoid medial wall erythema and edemaArytenoid medial wall erythema and edema

The role of empiric therapyThe role of empiric therapy Aggressive acid suppression would identify Aggressive acid suppression would identify

those whose laryngeal signs and those whose laryngeal signs and symptoms are related to GERDsymptoms are related to GERD

An overall response rate of 50-70% could An overall response rate of 50-70% could be expected. be expected.

The lack of response among the The lack of response among the remaining patients is most likely related to remaining patients is most likely related to an overlap between GERD and other an overlap between GERD and other causescauses

The suggestion that PPI therapy is not safe The suggestion that PPI therapy is not safe even for a short time period is not based even for a short time period is not based on any solid data. on any solid data.

Medical antireflux treatment of reflux laryngitis: placebo-Medical antireflux treatment of reflux laryngitis: placebo-

controlled studiescontrolled studies Havas Havas et alet al 1515 Lansoprazole Lansoprazole

30 mg 30 mg

b.d. × 3 monthsb.d. × 3 months L: 35%; L: 35%; P: 33%P: 33%

L: 43%; P: L: 43%; P:

54%54%

El-Serag El-Serag et alet al.. 2020 Lansoprazole Lansoprazole 30 mg 30 mg

b.d. × 3 monthsb.d. × 3 months L: 50%L: 50% P: P:

10%*10%* L: 58% L: 58%

P: 30%P: 30%

No No a prioria priori predictors of predictors of

responseresponse

Noordzij Noordzij et alet al. . 3030 Omeprazole Omeprazole 40 mg 40 mg

b.d. × 2 monthsb.d. × 2 months

O: 48%; O: 48%;

P: 19%P: 19% O: NC;O: NC;

P: NCP: NC

Mild hoarseness Mild hoarseness and throat and throat clearing better clearing better

with omeprazole with omeprazole

Eherer Eherer et alet al.. 1414 Pantoprazole 40 mg Pantoprazole 40 mg

b.d. × 3 monthsb.d. × 3 months Pan: 43%; Pan: 43%;

P: 41%P: 41% Pan: N.S.Pan: N.S.

P: N.S. P: N.S.

Patients on Patients on placebo did as placebo did as well as well as

pantoprazolepantoprazole

Vaezi Vaezi et alet al.. 145145 Esomerprazole Esomerprazole 40 mg 40 mg

b.d. × 4 monthsb.d. × 4 months

Eso: 42%; Eso: 42%;

P: 46%P: 46% Eso: N.S.; P: Eso: N.S.; P:

N.S.N.S. Enrolled patients Enrolled patients had either no or had either no or minimal classic minimal classic GERD symptomsGERD symptoms

Symptoms LaryngoscopySymptoms Laryngoscopy

תודה רבהתודה רבה

אפידמיולוגיה של תופעות על וושטיות אפידמיולוגיה של תופעות על וושטיות GERDGERDב-ב-

בנבדקים עם צרבת קלהבנבדקים עם צרבת קלה נמצאה לפחות תופעה על-ושטית אחת נמצאה לפחות תופעה על-ושטית אחת80%80%ב- ב- •

בנבדקים ללא צרבתבנבדקים ללא צרבת נמצאו תופעות על ושטיות נמצאו תופעות על ושטיות 49%49% ב- ב-•

נבדקים נבדקים101,366101,366 על על VAVAבמחקר במחקר מהנבדקים עם אזופגיטיס היו תופעות על- מהנבדקים עם אזופגיטיס היו תופעות על- 17%17%ב-ב-

ושטיותושטיות

Lock GR et al. Gastroenterology. 1997

Prevalence of extra-oesophageal manifestations in GERD:Prevalence of extra-oesophageal manifestations in GERD: an analysis based on the ProGERD Studyan analysis based on the ProGERD Study..

0

5

10

15

20

25

30

35

Total

NCCP

ch. C

ough

lary

ngeal d

is.

asth

ma

62156215 נבדקים עם נבדקים עם GERDGERD-תופעות תופעות 32.8%32.8%ס"ה ב-ס"ה ב

ע"וע"ו34.9%34.9%עם אזופגיטיס- עם אזופגיטיס- •30.5%30.5%ללא אזופגיטיס – ללא אזופגיטיס – •

%%

Aliment Pharmacol Ther. 2003 Jaspersen D et al

Prevalence and clinical spectrum of gastroesophageal Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, reflux: a population-based study in Olmsted County,

Minnesota. (2200 individuals)Minnesota. (2200 individuals)

0

5

10

15

20

25

Pne

umon

ia

NC

CP

Hoa

rsne

ss

Bro

nchi

tis

Ast

hma

Glo

bus

Lock GR et al. Gastroenterology. 1997

%

ComparisionComparision of the GERD Symptoms of the GERD Symptoms of the Typical Esophagitis Patient, the “Atypical” Otolaryngology of the Typical Esophagitis Patient, the “Atypical” Otolaryngology

Patient, and Pediatric PatientPatient, and Pediatric Patient..

SymptomsSymptoms

Heartburn Heartburn RegurgitationRegurgitation DysphagiaDysphagia CoughCough Pulmonary infectionPulmonary infection HoarsenessHoarseness Throat irritation (soreness, Throat irritation (soreness,

clearing)clearing)

Typical Typical

(%)(%)

8383

2323

4040

4747

1616

1212

33

Introduction

Koufman JA, Laryngoscope 1991Koufman JA, Laryngoscope 1991

AtypicalAtypical

(%)(%)

2020

--

1212

2626

--

4444

8787

PediatricPediatric

(%)(%)

1616

6868

3030

--

3636

--

--

ComparisionComparision of History, Laryngeal Examination, and of History, Laryngeal Examination, and Diagnostic Testing in Otolaryngology Patient With Cervical Diagnostic Testing in Otolaryngology Patient With Cervical

Symptoms(n=63) or Esophagitis(n=36), and in Controls(n=10)Symptoms(n=63) or Esophagitis(n=36), and in Controls(n=10)

A. SymptomsA. Symptoms Heartburn and/or regurgitationHeartburn and/or regurgitation Hoarseness, dysphagia, globus, throat Hoarseness, dysphagia, globus, throat

clearing and coughclearing and cough

B. Laryngeal ExaminationB. Laryngeal Examination NormalNormal ErythemaErythema Contact ulcer or granulationContact ulcer or granulation

C. Diagnostic StudiesC. Diagnostic Studies Upper esophageal sphincter pressure Upper esophageal sphincter pressure

(mmHg)(mmHg) Positive standard acid reflux testPositive standard acid reflux test Positive Bernstein acid perfusion testPositive Bernstein acid perfusion test Abnormal esophageal manometryAbnormal esophageal manometry Esophageal dysmotilityEsophageal dysmotility Abnormal esophageal acid clearanceAbnormal esophageal acid clearance

6%6%

100%100%

50%50%

25%25%

25%25%

144144±±121121

68%68%

5%5%

10%10%

60%60%

78%78%

89%89%

0%0%

100%100%

0%0%

0%0%

7171±±4040

100%100%

89%89%

8%8%

10%10%

80%80%

Otolaryngology Pt.Otolaryngology Pt. Esophagitis Pt.Esophagitis Pt.

Introduction

Koufman JA, Laryngoscope 1991Koufman JA, Laryngoscope 1991

Upper GI Endoscopy

Left Vocal Fold Granuloma:Left Vocal Fold Granuloma: Pre and Post anti-acid therapyPre and Post anti-acid therapy

Schnatz et al., Am J Gastroenterol 1996; 91: 1715–18.

Normal22%

(n=12)

Reflux78%

(n=42)

54 patients with chronic persistent cough possibly due to reflux

GORD in patientsGORD in patientswith pulmonary symptomswith pulmonary symptoms

GORD in patientsGORD in patientswith pulmonary symptomswith pulmonary symptoms

Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.

Pat

ien

ts w

ith

ab

no

rmal

aci

d r

eflu

x (%

)

Ducolone Ducolone et alet al. . (n=51)(n=51)

Nagel Nagel et alet al. . (n=44)(n=44)

Giudicelli Giudicelli et alet al. .

(n=140)(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 Abnormal acid reflux linked to asthmato asthma

Abnormal acid reflux linked Abnormal acid reflux linked to asthmato asthma

Asthmatics with gastroesophageal reflux

Long term results of a randomized trial of medical and surgical antireflux therapies

Asthmatics with gastroesophageal reflux

Long term results of a randomized trial of medical and surgical antireflux therapies

Asthmatics with gastroesophageal reflux

Long term results of a randomized trial of medical and surgical antireflux therapies

Sontag SJ, O'Connell S, Khandelwal S, Sontag SJ, O'Connell S, Khandelwal S, et al.et al. Asthmatics Asthmatics with gastroesophageal reflux: long term results of a with gastroesophageal reflux: long term results of a randomized trial of medical and surgical anti-reflux randomized trial of medical and surgical anti-reflux therapies. therapies. Am J GastroenterolAm J Gastroenterol 2003; 2003; 9898: 987–99.: 987–99.

Mucosal healingMucosal healing

Poe RH, Kalloy MC. Chronic cough and gastroesophageal Poe RH, Kalloy MC. Chronic cough and gastroesophageal reflux disease. Experience with specific therapy for reflux disease. Experience with specific therapy for

diagnosis and treatment. diagnosis and treatment. ChestChest 2003; 2003; 123123: 679–84: 679–84..

. Cumulative Response to GERD Therapy

Weeks of anti-reflux RxWeeks of anti-reflux Rx Patients Responding, No Patients Responding, No (%) (%)

22 16 (41)16 (41)

44 38 (86)38 (86)

66 42 (95)42 (95)

88 43 (99)43 (99)

1212 (44 (100(44 (100

2424hr double probe pH-metryhr double probe pH-metry Diagnosis

dietary & life style dietary & life style modification plusmodification plus

ranitidine 1 tablet(150mg) ranitidine 1 tablet(150mg) twice dailytwice daily After 8weeks After 8weeks

improve improve (-)(-)

ranitidine 300mg bid or tidranitidine 300mg bid or tid

After 6 After 6 monthsmonths

improve (-)improve (-)Consider surgical managementConsider surgical management

AfterAfter 8weeks 8weeks improve improve (+)(+)

persistent persistent medication for 6 medication for 6 monthsmonths

Cummings(III) ch.126 Gastroesophageal reflux disease P2419Cummings(III) ch.126 Gastroesophageal reflux disease P2419

Management of LPRDManagement of LPRD

Cummings(III) ch.126 Gastroesophageal reflux disease P2426

Typical symptomsTypical symptoms(Heartburn/regurgitation)(Heartburn/regurgitation)

Atypical symptomsAtypical symptoms ComplicationsComplications

With With oesophagitisoesophagitis

Without Without oesophagitisoesophagitis

Chest painChest pain(visceral (visceral

hyperalgesia)hyperalgesia)

Asthma, Asthma, chronic cough, chronic cough,

wheezing wheezing

HoarsenessHoarseness(‘reflux (‘reflux

laryngitis’)laryngitis’)

Oesophageal Oesophageal erosions erosions

and/or ulcersand/or ulcers

StrictureStricture

Barrett’s Barrett’s oesophagusoesophagus

Oesophageal Oesophageal adenocarcinomaadenocarcinomaDental erosionsDental erosions

Nathoo, Int J Clin Pract 2001; 55: 465–9.

Range of presentations of GERDRange of presentations of GERDRange of presentations of GERDRange of presentations of GERD

Common signs•  Interarytenoid bar 70•  Arytenoid medial wall edema 29•  Posterior pharyngeal wall

cobblestoning21

• Intererytenoid bar erythema 15•  Posterior cricoid wall edema 10•  True vocal cord edema 10

Table 1. Ear, nose and throat (ENT) signs in Table 1. Ear, nose and throat (ENT) signs in normal volunteersnormal volunteers

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