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„GRIGORE T. POPA” UNIVERSITY OF MEDICINE AND PHARMACY IAŞI

EXTRADIGESTIVE MANIFESTATIONS OF

GASTROESOPHAGEAL REFLUX DISEASE

Ph. D. Thesis Summary

Scientific coordinator:

Prof. MD. Ph.D. GHEORGHE BĂLAN

Ph. D. Candidate:

OANA-BOGDANA LEONTE (BĂRBOI)

2016

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SUMMARY

LIST OF ABBREVIATIONS……………………………………………………………….i

INTRODUCTION…………………………………………………………………………..ii

GENERAL PART

I. GENERAL INFORMATION. HISTORY. DEFINITIONS 1

II. EPIDEMIOLOGY 3 II.1. Gastroesophageal reflux disease 3

II.2. Gastroesophageal reflux disease with extradigestive manifestations 5

III. ETHIO-PHYSIO-PATHOGENICITY 7

III.1. Physio-pathogenic mechanisms 7

III.1.1. Incompetence of the anti reflux barrier 7

III.1.2. Imbalance between the factors of aggression and defense of the

esophageal lining 9

III.2. Ethio-pathogenic factors 9

III.2.1. Nitric oxide 9

III.2.2. Behavioral factors 9

III.2.3. Helicobacter pylori infection 10

III.2.4. Mental stress 11

III.2.5. Genetic factors 11

III.3. Gastroesophageal reflux disease with extradigestive manifestations 11

III.3.1. Gastroesophageal reflux disease and chronic laryngitis 12

III.3.2. Gastroesophageal reflux disease and chronic cough 12

III.3.3. Gastroesophageal reflux disease and asthma 13

III.3.4. Gastroesophageal reflux disease and dental erosions 13

III.3.5. Gastroesophageal reflux disease and pseudo-angina 13

IV. DIAGNOSIS 13

IV.1. Clinical diagnosis 13

IV.1.1. Gastroesophageal reflux disease and chronic laryngitis 14

IV.1.2. Gastroesophageal reflux disease and asthma 15

IV.1.3. Gastroesophageal reflux disease and chronic cough 15

IV.1.4. Gastroesophageal reflux disease and pseudo-angina 15

IV.1.5. Gastroesophageal reflux disease and dental erosions 16

IV.1.6. Gastroesophageal reflux disease and sleep disorders 16

IV.1.7. Other symptoms 16

IV.1.8. Impaired quality of life 16

IV.2. Para-clinical diagnosis 17

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IV.2.1. Diagnosis techniques 17

IV.2.2. Gastroesophageal reflux disease and chronic laryngitis 24

IV.2.3. Gastroesophageal reflux disease and asthma 26

IV.2.4. Gastroesophageal reflux disease and chronic cough 27

IV.2.5. Gastroesophageal reflux disease and pseudo-angina 28

IV.2.6. Gastroesophageal reflux disease and dental erosions 29

V. TREATMENT 29

V.1. Lifestyle changes 29

V.2. Medical treatment 30

V.2.1. Antiacids 30

V.2.2. Alginates 30

V.2.3. H2 histamine receptor antagonists 30

V.2.4. Prokinetics 30

V.2.5. Proton pump inhibitors 31

V.2.6. New agents 31

V.3. Endoscopic treatment 32

V.4. Surgery treatment 32

V.5. Treatment of gastroesophageal reflux disease associated with chronic laryngitis 32

V.6 Treatment of gastroesophageal reflux disease associated with asthma 34

V.7 Treatment of gastroesophageal reflux disease associated with chronic cough 35

V.8. Treatment of gastroesophageal reflux disease associated with pseudo-angina 35

V.9. Treatment of gastroesophageal reflux disease associated with dental erosion 36

VI. GASTROESOPHAGEAL REFLUX DISEASE AND ATRIAL FIBRILLATION 36

VI.1. Patho-physiological mechanisms 37

VI.1.1. Sympatico-vagal imbalance 37

VI.1.2. Hiatal hernia 37

VI.1.3. Inflammation 38

VI.1.4. Other possible mechanisms 38

VI.2. Evidence of association between gastroesophageal reflux disease and atrial

fibrillation 38

VI.3. Treatment of gastroesophageal reflux disease associated with atrial fibrillation 39

PERSONAL CONTRIBUTION

VII. PERSONAL RESEARCH MOTIVATION. STRUCTURE OF THE PERSONAL

STUDY. GENERAL OBJECTIVES 40

VIII. EVALUATION OF PATIENTS WITH CHRONIC LARYNGITIS

WITH AN ETHIOLOGIC POTENTIAL OF GASTRO ESOPHAGEAL REFLUX

DISEASE 42

VIII.1. Purpose 42

VIII.2. Material and Method 42

VIII.2.1. Patients 42

VIII.2.2. Study protocol 43

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VIII.2.3. Statistical processing 46

VIII.3. Results 47

VIII.4. Discussions 80

VIII.5. Conclusions 93

IX. EVALUATION OF PATIENTS WITH ASTHMA WITH AN ETHIOLOGIC

POTENTIAL OF GASTRO ESOPHAGEAL REFLUX DISEASE 95

IX.1. Purpose 95

IX.2. Material and Method 95

IX.2.1. Patients 95

IX.2.2. Study protocol 96

IX.2.3. Statistical processing 97

IX.3. Results 97

IX.4. Discussions 127

IX.5. Conclusions 136

X. EVALUATION OF PATIENTS WITH CHRONIC COUGH WITH AN

ETHIOLOGIC POTENTIAL OF GASTRO ESOPHAGEAL REFLUX DISEASE 138

X.1. Purpose 138

X.2. Material and Method 138

X.2.1. Patients 138

X.2.2. Study protocol 138

X.2.3. Statistical processing 139

X.3. Results 139

X.4. Discussions 167

X.5. Conclusions 175

XI. COMPARATIVE EVALUATION OF EXTRA DIGESTIVE

MANIFESTATIONS POSSIBLY INDUCED BY GASTROESOPHAGEAL

REFLUX DISEASE 176

XI.1. Purpose 176

XI.2. Material and Method 176

XI.3. Results 176

XI.4. Discussions 183

XI.5. Conclusions 185

XII. GASTRO ESOPHAGEAL REFLUX DISEASE AND ATRIAL FIBRILLATION 186

XII.1. Purpose 186

XII.2. Material and Method 186

XII.2.1. Patients 186

XII.2.2. Study protocol 187

XII.2.3. Statistical analysis 188

XII.3. Results 188

XII.4. Discussions 202

XII.5. Conclusions 206

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XIII. DIFFICULTIES AND LIMITATIONS OF RESEARCH 208

XIV. ORIGINALITY OF THE STUDY 208

XV. PERSPECTIVES OPEN BY PERSONAL RESEARCH AND FUTURE

DIRECTIONS OF STUDY 209

XVI. GENERAL CONCLUSIONS

211

XVII. BIBLIOGRAPHIC REFERENCES 212

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LIST OF ABBREVIATIONS

BA – bronchitis asthma

Ao - aorta

LA - left atrium

CVA – cerebrovascular stroke

PAD - peripheral arterial disease

CAD - coronary artery disease

GERD – gastroesophageal reflux disease

CRP - C-reactive protein

SD - standard deviation

DM – diabetes mellitus

E - velocity peak of the early diastolic filling wave of the mitral flow

Ea – early diastolic velocity peak of the mitral ring longitudinal movement

EB – Barrett esophagus

UGE - upper gastrointestinal endoscopy

AF - atrial fibrillation

H pylori - Helicobacter pylori

HH - hiatal hernia

AHT – arterial hypertension

MII-pH - multichannel intra-luminal pH- impedance

PPI - proton pump inhibitors

LA - Los Angeles classification of esophagitis

LF / HF - ratio of low frequency / high frequency power

ENT - ear, nose and throat

proBNP - B-type natriuretic peptide

LFR – laryngopharyngeal reflux

SR - sinus rhythm

SAP - symptom association probability

SDNN - standard deviation of the mean of all ranges of normal R-R in 24 hours

SI - symptom index

VRR - R-R variability

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INTRODUCTION

The gastroesophageal reflux disease (GERD) is a chronic complex clinical condition,

which is also recurrent, multi-factorial, with risk of complications and a significant morbidity

level.

The gastroesophageal reflux disease has become undoubtedly the most commonly

diagnosed disease by the gastroenterologist in the specialized ambulatory care, being one of the

most common diseases of modern civilization. It is considered that GERD negatively affects the

patient’s quality of life as much as osteoarthritis or acute coronary events, representing a public

health problem, with important socio-economic and psychological impact. In many cases,

requiring long-term therapy, this pathology involves periods of absenteeism, repeated

hospitalizations, explorations and costly treatments, unnecessarily burdening the health system

budget.

The gastroesophageal reflux disease with extradigestive manifestations remains a

controversial issue in terms of epidemiology, diagnosis and treatment, the literature on this

pathology being contradictory. GERD with extradigestive manifestations remains an important

issue for diagnosis and treatment for both gastroenterologists and other physicians: ENT,

cardiology, pulmonology, dentistry, as evidenced by the growing number of patients with

suspected reflux disease who are referred to Gastroenterologists from these services. Numerous

articles published in international medical literature devoted to this subject reflect growing

concerns over scientific researchers of this pathology, still incompletely understood.

Since GERD has become in recent decades one of the most widespread diseases in the

world, an algorithm for diagnosis and treatment must be unanimously accepted immediately.

Despite a wide range of diagnostic tests available, none is so far considered "gold standard" in

the diagnosis of GERD with extradigestive manifestations, making it difficult for clinicians.

The doctoral thesis contains a number of 171 figures, 52 tables and 529 references. The

thesis summary retains the original numbering of the chapters and subchapters, as well as figures

and tables.

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GENERAL PART

I. GENERAL INFORMATION. HISTORY. DEFINITIONS

This chapter provides general information related to GERD, a brief history of the

evolution of this pathology over time and definitions that have been issued by experts in recent

decades to describe GERD or GERD with extradigestive manifestations.

II. EPIDEMIOLOGY

This chapter reveals epidemiological data known to date, in the medical international and

national literature on GERD, with and without extradigestive manifestations.

III. ETHIO-PHYSIO-PATHOGENICITY

This chapter addresses the patho-physiological mechanisms and etiologic factors

involved in triggering GERD.

IV. DIAGNOSIS

This chapter addresses, according to literature, the role of clinical symptoms in the

diagnosis of GERD with extradigestive manifestations, as well as the contribution of the latest

laboratory techniques for obtaining a proper diagnosis.

V. TREATMENT

Chapter V presents the principles of treatment used in GERD with extradigestive

manifestations and the response to various therapies of patients presenting associations of GERD

with chronic laryngitis, asthma, chronic cough, pseudo-angina, erosions dental, according to the

latest studies published in literature.

VI. GASTRO ESOPHAGEAL REFLUX DISEASE AND ATRIAL

FIBRILLATION

The chapter analyses the most relevant and current scientific evidence on the association

between GERD and atrial fibrillation (AF) in terms of epidemiology, diagnosis and treatment.

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PERSONAL CONTRIBUTION

VII. PERSONAL RESEARCH MOTIVATION

GERD has progressed in the last decades from a seemingly trivial disease status to a

prevalent disease, dominating today the pathology diagnosed in the gastroenterology ambulatory

care.

Increasing prevalence could be explained by the increased medical interest and by the

degree of recognition of GERD with extradigestive manifestations, not only of the

gastroenterology specialists, but also by other physicians, and also by the increased accuracy and

availability of diagnosis methods.

As a disease of modern civilization, GERD has become a public health problem, with

socio-economic and psychological implications, in that it adversely affects the quality of life of

the working population, generating periods of absenteeism from work, with lower work

productivity. Repeated need healthcare, costly explorations conducted in order to establish the

correct diagnosis or testing multiple therapies to achieve disease symptom resolution generate

high costs, which are detrimental to the health system budget.

Although this topic is widely discussed in international medical literature, the

epidemiology, diagnosis and treatment of GERD with extradigestive manifestations remain

controversial; moreover, in Romania, the existing data so far are limited. The lack of a

standardized national protocol for diagnosis and treatment, and the diagnosis methods with, often

exceeded, which are available in health centers in our country, make the task of clinicians more

difficult.

Starting from these premises and with the help of the data in literature, I decided to

evaluate prospectively the association between GERD and certain extradigestive manifestations

(chronic laryngitis, chronic cough and asthma) and to analyze the possibility of grouping atrial

fibrillation as an extradigestive manifestation of GERD.

STRUCTURE OF THE PERSONAL STUDY

The thesis section dedicated to personal contribution included five studies, with the first

four studies pursuing the same objectives and the same study protocol, while the fifth study has

different research objectives and a different protocol.

GENERAL OBJECTIVES

The main objectives of this doctoral research were as follows:

assessment of the association between GERD and chronic laryngitis, asthma, chronic

cough

assessment of the usefulness of Gastrointestinal investigations in patients showing extra

digestive manifestations (chronic laryngitis, asthma and chronic cough) possibly induced

by GERD

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evaluation of the effect of treatment with proton pump inhibitors on extradigestive

manifestations (chronic laryngitis, asthma, chronic cough) with a potential GERD

etiology

assessing the relationship between GERD and paroxysmal non-valvular atrial fibrillation

and verifying the possibility of classification of atrial fibrillation as an extradigestive

manifestation of GERD.

The secondary objectives were represented by:

determining the demographic, clinical, biological and endoscopic characteristics of

patients that associate GERD with chronic laryngitis, bronchitis asthma poorly controlled

therapeutically, chronic cough, and paroxysmal non-valvular atrial fibrillation and

analyzing the correlations between them

assessment of the risk factors involved in the association between GERD and chronic

laryngitis, asthma, chronic cough or paroxysmal non-valvular atrial fibrillation

research on the impact of GERD associated with chronic laryngitis, asthma or chronic

cough, on sleep and daily activities of patients

assessment of the structural, electrical and mechanical remodeling of the left atrium in

patients with GERD and atrial fibrillation.

Ethical considerations

All patients enrolled in the study have expressed verbal and written informed consent for

participation in the study, after they were explained the details regarding the purpose and

methodology of the study, the risks and benefits involved in the study and after they were offered

information on the confidential results. The present doctoral study was approved by the Ethics

Committee of "Grigore T. Popa" University of Medicine and Pharmacy and the Ethics

Committee of "Sf. Spiridon" Hospital.

VIII. EVALUATION OF PATIENTS WITH CHRONIC LARYNGITIS

WITH AN ETHIOLOGIC POTENTIAL OF GASTROESOPHAGEAL

REFLUX DISEASE

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VIII.1. The aim of this study was to evaluate the association between GERD and chronic

laryngitis.

VIII.2. MATERIAL AND METHOD

VIII.2.1. Patients

We conducted a prospective case-control study over a period of 37 months (November 1,

2012 - November 30, 2015) at the Institute of Gastroenterology and Hepatology of "St. Spiridon"

Hospital, in collaboration with the ENT Clinic of "St. Spiridon" Hospital in Iaşi.

Inclusion criteria:

patients older than 18 who have signed the informed consent

patients diagnosed with chronic laryngitis and suggestive lesions of GERD in ENT

examination:

edema and erythema of the posterior commissure - arytenoids and the

interarytenoid area

edema and erythema of the posterior pharyngeal wall

arytenoidian granuloma

diffuse congestion of the endolarynx or of the vocal cords.

Exclusion criteria:

refusal from patient/uncooperative patient/patient with documented psychiatric

pathology

presence of laryngeal formations or other ENT injuries that may explain laryngitis

oropharyngeal infections of bacterial, viral or fungal causes

history of laryngeal surgery or oro-tracheal intubation maneuvers

chronic exposure to toxic or allergic environmental factors

patients with alarm symptoms (unexplained weight loss, upper gastrointestinal bleeding,

dysphagia)

history of gastric or esophageal surgery

pathological personal history of movement disorders (achalasia cardia, scleroderma,

myopathies)

pregnant or lactating women

patients on chronic medications that can impair motor function of the esophagus and SEI

(anticholinergics, NSAIDs, calcium channel blockers, beta-blockers, nitrates,

barbiturates, progesterone)

patients receiving treatment with PPIs in the last 8 weeks prior to enrollment.

VIII.2.2. Study protocol

Chronic laryngitis possible deriving from GERD was considered by the ENT specialist

for patients who have:

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Clinically: dysphonia (especially in the morning), globus, hemming, foreign body

sensation in the throat or sore throat, lasting at least 8 weeks, with or without typical

symptoms of GERD (heartburn and / or regurgitation).

ENT exam (which consisted of indirect laryngoscopy and videofibrolaryngoscopy):

lesions suggestive of GERD - edema and erythema of the posterior commissure

(arytenoids and interarytenoidian area), edema and erythema of the rear wall of the

pharynx, arytenoidian granuloma, diffuse congestion of vocal cords or of the endolarynx.

Each patient included in the study was compiled a data sheet that recorded information

related to: personal data (name, age, gender, environment, BMI), personal history and family

history, history of their disease, living and working conditions (using voice for vocational

purposes, behaviors towards the environment: smoker / non-smoker, consumption of coffee,

alcohol and drugs, how the symptoms of the disease influenced the sleep of patients and

therefore everyday work, biological data (Ac anti-Helicobacter pylori, cholesterol and

triglycerides)).

In our clinic, patients with possibly GERD-induced chronic laryngitis have been

evaluated differently depending on the presence or absence of typical symptoms of reflux

(heartburn and / or regurgitation occurred with a frequency of at least 2-3 times / week and

considered "troublesome" by the patient). All patients included in the study were clinically

evaluated every month and 3 months, in IGH Iasi Ambulatory Hospital.

All patients who complained exclusively of laryngitis symptoms (i.e. in the absence of

heartburn and / or regurgitation) were evaluated by upper gastrointestinal endoscopy (fig.VIII.1).

If no esophageal lesions were identified, patients were further explored by esophageal

impedance-pH metry, over 24 hours, which revealed the diagnosis of GERD, characterized the

type of reflux and established a temporal relationship between the symptoms of laryngitis and the

reflux episode. If the course of the impedance-pH metry was within normal parameters, GERD

has been excluded. Patients with esophageal lesions were treated with double dose PPI and

monitored over the two periods.

PATIENTS WITH NO TYPICAL GERD

SYMPTOMS

UGE

WITH ESOPHAGITIS

BRGE DIAGNOSIS

DOUBLE DOSE PPI TREATMENT

CLINICAL EVALUATION

AFTER 30 AND 90 DAYS

WITHOUT ESOPHAGITIS

IMPEDANT-PHMETRY

GERD VALIDATION

DOUBLE DOSE PPI TREATMENT

CLINICAL EVALUATION


GERD

INVALIDATION

Figure VIII.1. Protocol of evaluation for patients without typical GERD symptoms

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Patients who accused manifestations of chronic laryngitis and typical symptoms of reflux

were randomized into two groups in the ratio 1:1, in chronological order, following the study

entry (fig.VIII.2). A subset of patients has been investigated by UGE, and further, depending on

the presence / absence of esophageal inflammatory lesions, the protocol described above was

followed. The second subset of patients receiving empiric trial with double dose PPI

(pantoprazole 40mgx2/day) and the diagnostic of GERD-induced laryngitis was considered when

the therapeutic test was positive, that means improvement by at least 50 % (measured

subjectively by the patient) of the clinical manifestations of laryngitis after 3 months of

treatment.

PATIENTS WITH GERD TYPICAL SYMOPTOMS

THERAPEUTIC TEST

CLINICAL EVALUATION


NO PPI RESPONSE

INVALIDATION

PPI RESPONSE

CONFIRMED

UGE

INVALIDATED ESOPHAGITIS

IMPEDANȚ-PHMETRY

GERD VALIDATION

GERD INVALIDATION

VALIDATED ESOPHAGITIS

DOUBLE DOSE PPI

TREATMENT

VALIDATION

CLINICAL EVALUATION


All patients who have confirmed the association of GERD and chronic laryngitis were

further treated with double dose pantoprazole of 40 mg x 2 / day for 3 months. A significant

improvement was defined as improvement of laryngitis symptoms by at least 50% and a slight

improvement as improving manifestations of laryngitis in a smaller percentage of 50%.

In patients with Helicobacter pylori infection, the triple eradication therapy (pantoprazole

40 mg x 2 / day, amoxicillin 1g x 2 / day, clarithromycin 500 mg x 2 / day) for 14 days, was

applied. The check of the eradication was performed by fecal Helicobacter pylori antigen, 6

weeks after the end of the treatment.

VIII.2.3. Statistical processing

Data were loaded and processed using SPSS 18.0 (SPSS Inc., Chicago, IL, SUA)

statistical functions, the materiality threshold of 95%. The following indicators derivatives were

used, described by ANOVA test: indicators of the mean (simple arithmetic mean, median, mode,

minimum and maximum values); indicators of dispersion (standard deviation, coefficient of

variation). 2 Test - qualitative non-parametric test, comparing frequency distributions. Student t-

Test - parametric test, comparing the means observed in 2 groups with normal distributions.

Kruskall - Wallis Correlation comparing ordinal variables of 3 or more groups. ROC curve was

used to draw the balance specificity / sensitivity.

Figure VIII.2. Protocol of evaluation for patients with typical GERD symptoms

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VIII.3. RESULTS

VIII.3.1. General characteristics of the group of patients with chronic laryngitis

We included 112 patients who met the selection criteria, which were characterized by the

predominance of males and of urban origin, with ages between 20-83 years and an average age

of about 50 years. Most patients did not show typical symptoms of GERD.

VIII.3.2. Diagnosis protocol for possibly GERD-induced chronic laryngitis

Following established protocol diagnosis, we identified an association between chronic

laryngitis and GERD of 80.4%, a percentage that is much higher than that reported in literature

(fig.VIII.9).

Figure VIII.9. Distribution of chronic laryngitis possibly GERD-induced cases

By randomizing patients with laryngitis and typical reflux symptoms and by their

different investigation, using either the therapeutic test or UDE, we assessed the sensitivity and

specificity of these two techniques for the diagnosis of laryngitis with GERD etiologic potential.

By plotting the ROC curve, we found a sensitivity of 57% and a specificity of 60% for UDE and

a much lower sensitivity and specificity, of only 42% and 40% for empiric PPI trial (Fig.

VIII.10).

Figure VIII.10. The balance sensitivity/specificity for

UDE and the therapeutic test in the diagnosis of GERD-induced laryngitis

With symptoms, therapeutic test +

17.9%With symptoms,

UDE with esophagitis 15.2%

With symptoms, IIM-pH+

0.9%Without symptoms,

UDE with esophagitis 34.8%

Without symptoms,IIM-pH+11.6%

No GERD19.6%

Area Under the Curve

.601 .091 .540 .378 .734

.444 .091 .540 .266 .622

Test Result Variable(s)

EDS

TestTerapeutic

Area Std. Errora

Asy mptotic

Sig.b

Lower Bound Upper Bound

Asy mptotic 95% Conf idence

Interv al

The test result v ariable(s): EDS, TestTerapeutic has at least one tie between the posit iv e actual

state group and the negativ e actual state group. Stat istics may be biased.

Under the nonparametric assumptiona.

Null hy pothesis: t rue area = 0.5b.

1.00.80.60.40.20.0

1 - Specificity

1.0

0.8

0.6

0.4

0.2

0.0

Se

ns

itiv

ity

TestTerapeutic

EDS

Source of the Curve

ROC Curve

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Of all the diagnostic methods used in this study, the esophageal impedance-pH metry had

the highest yield of diagnosis, regardless of the presence or absence of typical reflux

manifestations, with a sensitivity of 100% and a specificity of 75% (fig. VIII. 12).

VIII.3.3. Evaluation of demographic characteristics of patients with potentially

etiologic GERD chronic laryngitis

In the group of 90 patients who had confirmed the association, gender distribution of

patients was relatively smooth, with a slight predominance of males, the major provenance being

urban with ages of patients ranging between 20 and 76, with a the average age of diagnosis of 50,

representing young active people, a fact that may have socio-economic implications.

VIII.3.4. Evaluation of risk factors in patients with chronic laryngitis and GERD

None of the analyzed variables (demographic characteristics, behavioral habits, intense

voice use, obesity, dyslipidemia, Helicobacter pylori infection, hiatal hernia) did in any way

have a significant statistical effect on the association of the two pathologies.

VIII.3.5. Evaluation of clinical characteristics of patients with potentially etiologic

GERD chronic laryngitis

Regarding clinical characteristics, only 42.2% of the patients had typical manifestations

of GERD. Typical symptoms of GERD were not good predictors for the presence and severity of

esophagitis and hiatal hernia in our study, noticing that erosive esophagitis caused a relative risk

44% increased that patients without typical symptoms of reflux could present GERD and chronic

laryngitis, a result that confirms the data in the literature (table VIII.5).

1.00.80.60.40.20.0

1 - Specificity

1.0

0.8

0.6

0.4

0.2

0.0

Sen

sit

ivit

y

ROC Curve

Figure VIII.12. The balance sensitivity/ specificity for the

esophageal impedance-pH metry in the diagnosis of GERD

induced laryngitis according to the therapeutical response

within 3 months

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Table VIII.5. Prognosis of the pathology associated in the determinism of typical GERD

symptomatology in patients with typical chronic laryngitis

Characteristics

With symptoms

(n=38)

Without symptoms

(n=52)

p

OR

Esimated

risk

IC95%

n % n %

H pylori (+) 19 50,0 31 59,6 0,365 0,68 0,80 a)

1,18 b) 0,49-1,29 0,82-1,70

Esophagită 17 44,8 39 75,0 0,007 0,27 0,60 a)

1,44 b)

0,41-0,88

1,01-2,04

Esophagitis A 14 36,8 28 53,8 0,167 0,50 0,58 a)

1,34 b)

0,42-1,11

0,93-1,94

Esophagitis B 3 7,9 11 21,2 0,157 0,44 0,59 a)

1,34 b)

0,25-1,41

0,93-1,94

Barrett

Esophagus 1 2,6 2 3,8 0,748 0,68

0,78 a)

1,16 b)

0,16-3,96

0,51-2,64

Hiatal hernia 10 26,3 26 50,0 0,022 0,36 0,54 a)

1,50 b) 0,30-0,96 1,06-2,11

a) relative risk in patients with symptoms; b) relative risk in patients without symptoms

b)

VIII.3.6. Evaluation of the biological characteristics of patients with potentially


The role of Helicobacter pylori in the etio-pathogeny of GERD is controversial, some

studies supporting the protective role of the bacteria, while others recommended its eradication.

In our study, the Helicobacter pylori infection was identified in approximately 56% of patients,

who were characterized by the predominance of the male sex, age over 50, of urban origins and

absence of typical reflux manifestations. The statistical analysis noticed that this parameter has

not influenced in any sense (positively or negatively) the lrisk of association between the two

diseases.

VIII.3.7. Evaluation of the endoscopic characteristics of patients with potentially


Although most studies in the literature indicate that the lesions of esophagitis are absent

in up to 85-95% of cases, our findings contradict this hypothesis, as esophagitis was diagnosed in

62.2% of the patients studied, with predominance of mild esophagitis of grade A Los Angeles.

The study did not identify any case of severe esophagitis (grade C or D), while Barrett's

esophagus was confirmed only in 3 cases (fig.VIII.30).

Figure VIII.30. Distribution of cases with erosive esophagitis

Esophagitis

A

46.7%

Esophagitis

B 15.6%

Barrett esophagus

3.3%

Without esophagitis

34.4%

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Hiatal hernia, which was identified in 40% of patients, correlated significantly with the

presence of reflux esophagitis, inducing a risk of association of chronic laryngitis with erosive

GERD 67% higher, a result that is consistent with the data in the medical literature.

VIII.3.8. Assessing the impact of the disease on sleep and on daily activities in

patients with chronic laryngitis and GERD

Regarding the impact of the disease on sleep and on daily activities of patients, 56.7% of

patients reported sleep disorders that caused them intense fatigue and negatively influencing their

daily work, the most affected being patients with jobs requiring intensive use of voice (teachers,

opera singers, actors, priests and teachers), a result that is consistent with the data in the medical

literature (fig.VIII.39).

Figure VIII.39. Impaired sleep and daily activities by using professional voice

VIII.3.9. Assessment of PPI therapy response of patients with GERD and chronic

laryngitis

Regarding the response to PPI therapy in patients with reflux laryngitis, 91% of the

patients studied responded within a month, of which 54.4% showed a significant improvement of

laryngitis manifestations, 36.7% declared a slight improvement and approximately 9% did not

respond at all. After 3 months of treatment with PPIs in double dose, the response rate was

higher, approx. 97%, 76% of patients had a significant improvement in the ENT manifestations,

21% of them had a slight improvement, while only 3.3% were still non-responders.

Comparing the response rates of one month to 3 months, it has been noticed that by

prolonging the treatment with PPI, the response rate increases. This result confirms the literature,

patients with GERD and laryngitis requiring a more aggressive treatment with a higher dose of

PPI and for a longer period of time.

Statistically, there were no significant differences between the 3 categories of response in

terms of demographical, biological or clinical data, but it was noted that all obese and

dyslipidemic patients responded to PPIs. The therapeutic response was inversely proportional to

the severity degree of the esophageal inflammatory lesions, the worst response coming from

patients with Barrett's esophagus or grade B esophagitis, a result that confirms the data in the

literature (fig.VIII.48).

0%

20%

40%

60%

80%

100%

21.65.1

Nu

Folosirea profesională a vocii

Affected Not affected

No

Professional use

of voice

19

Figure VIII.48. The response within 3 months depending on associated comorbidity

VIII.4. DISCUSSIONS

The relationship between GERD and chronic laryngitis continues to be a subject of

debate among gastroenterologists and ENT-ists. Although the evidence of the association of the

two pathologies exists, a cause-effect relationship between them could not be determined clearly

until now. It is very difficult to assess whether GERD induces manifestations of laryngitis or if

these conditions coexist independently of each other, since there is no gold standard so far for the

diagnosis of reflux laryngitis.

In our study, based on the established diagnostic protocol, we found an association of

GERD with chronic laryngitis in 80.4% of cases, a percentage that is much higher than that

reported in literature. One possible explanation could be linked to the rigorous selection of

patients included in this study because we selected only patients showing clinical signs and

laryngoscope lesions considered by most studies as the most common and highly suggestive for

GERD and we excluded patients with other pathologies which could explain laryngitis.

Although upper gastrointestinal endoscopy had superior performance parameters to the

therapeutic test in patients with laryngitis who have typical reflux symptoms associated, this

diagnosis technique was not a good predictor for the diagnosis of laryngitis reflux, requiring

further investigation. This result contradicts the literature, indicating therapeutic PPI test as a

sensitive and specific method, the first step in the diagnosis of typical symptoms of reflux

laryngitis of GERD. UDE has proven useful, however, in the selection of patients undergoing

evaluation by impedance-pH metry. Esophageal impedance-pH metry was the only method that

materialized as a good predictor, providing the information necessary for a treatment appropriate

to the reflux type, but has the disadvantage of high cost, which limits its use.

The increased percentage of reflux esophagitis identified on the studied cases could be

explained, on the one hand, by the fact that the boundary detection of esophagitis grade A

compared to normal esophageal lining is very fine (to increase diagnostic accuracy we needed

UDE with high resolution magnification) and, on the other hand, by a good tolerance of these

patients to refluxate.

The treatment response was much higher than that reported in literature. The possibility

of a placebo effect should be taken into discussion, as in the present study we did not apply an

0% 20% 40% 60% 80% 100%

Fumat

Alcool

Cafea

H pylori (+)

Esofagită A/B

Esofagită A

Esofagită B

Esofag Barrett

Hernie hiatală

Gastrită

Dislipidemie

Obezitate

Ameliorare uşoară

Ameliorare semnificativă

Fără răspuns

Obesity Dyslipidemia

Gastritis Hiatal hernia

Barrets’s esophagus Esophagitis B

Esophagitis A/B H pylori (+)

Coffee Alcohol

Smoking

Slight improvement Significant improvement No response

20

objective method for quantifying this response (laryngoscopy exam, validated questionnaire), the

degree of improvement of laryngitis symptoms being appreciated in a subjective way by the

patient. In addition, this study was not a double-blind trial placebo-controlled.

VIII.5. CONCLUSIONS

The diagnosis of GERD induced-laryngitis is a difficult task, requiring a close

interdisciplinary collaboration between the gastroenterologist and the ENT-ist. The increased

percentage identified for the association between GERD and chronic laryngitis reflects the

importance of gastroenterological evaluation in patients with chronic laryngitis without a clear

etiology. Contrary to previous research data reported, the present study did not show therapeutic

test with proton pump inhibitors as a sensitive and specific method for the diagnosis of reflux

laryngitis with typical GERD symptoms. The esophageal impedance-pH metry proved an

important diagnosis tool in patients with normal endoscopy and laryngitis; it has identified and

characterized the type of reflux, stating a correct diagnosis, provided the information necessary

for appropriate treatment of reflux type and hasset a temporal relationship between the reflux

episode and the extradigestive manifestation. However, impedance-pH metry remains a difficult

method to reach in local hospitals in Romania.

Helicobacter pylori infection did not influence the risk of association, the role of

Helicobacter pylori in the etiopathogeny of GERD with ENT manifestations remaining

controversial still. Esophagitis lesions were objectified in a much higher percentage than that

reported in literature, all cases being mild esophagitis. The typical symptoms of GERD, found in

more than half of the cases, were not good predictors of the presence and severity of esophagitis

and hiatal hernia in our study.

GERD manifestations of chronic laryngitis had negative consequences for patients by

developing sleep disorders and by altering their daily activity, patients with professions that

require use of the voice intensively (teachers, opera singers, actors, priests, teachers) with

preference being affected, a result that is consistent with the data in the medical literature.

The resolution of symptoms of GERD-induced chronic laryngitis requires a more

aggressive treatment with PPIs, with a higher dose and for a longer period of time. The

therapeutic response to PPI was inversely proportional to the degree of severity of esophageal

lesions, results confirmed by numerous studies in the literature.

21

IX. ASSESSMENT OF ASTHMA PATIENTS WITH POTENTIALLY

ETIOLOGIC GASTROESOPHAGEAL REFLUX DISEASE

IX.1. THE AIM of the second study was to evaluate the association between poorly

controlled / uncontrolled asthma and GERD, as a clinical condition may induce other.

IX.2. MATERIAL AND METHOD

IX.2.1. Patients

We conducted a prospective case-control study over a period of 37 months (November 1,

2012 - November 30, 2015), at the Institute of Gastroenterology and Hepatology of "St.

Spiridon" Hospital, in collaboration with Iasi Pneumology Hospital.

Inclusion criteria:

patients older than 18 who have signed informed consent

patients diagnosed with asthma according to GINA 2015 guideline (Global Initiative for

Asthma) at least 6 months with significant reversibility inhaled bronchodilator (FEV1

(forced expiratory volume in one second) > 200 ml and > 12%)

uncontrolled or partially controlled asthma patients with maximal therapeutic dose of

inhaled corticosteroids (CIS) and beta2-agonists long-acting (BDLA)

CSI treatment and / or BDLA initiated at least 3 months prior to enrollment

patients who had at least one exacerbation of symptoms of asthma in the past year.

Exclusion criteria:

patient refusal / uncooperative patient / patient with documented psychiatric pathology

active tuberculosis or other acute lower respiratory tract infection

chronic bronchitis or lung cancers

use of oral corticosteroids 30 days prior to study entry

patients with alarm symptoms (unexplained weight loss, upper gastrointestinal bleeding,

dysphagia)


pathological personal history of motility disorders (achalasia cardia, scleroderma,

myopathies)





patients receiving treatment with PPIs in the last 8 weeks.

22

IX.2.2. Study protocol

We included patients diagnosed with bronchial asthma at least 6 months prior to the

study, according to GINA criteria 2015.

The diagnosis of GERD induced- asthma was considered under the following conditions:

• historically positive for respiratory symptoms (particularly nocturnal or postprandial):

wheezing, shortness of breath , tightness of the chest.

• alteration objectified in spirometry lung function by lowering FEV1 (forced expiratory volume

in one second) and the ratio FEV1 / FVC (forced vital capacity) and was reversible inhaled

bronchodilators.

• lack of therapeutic or partial therapeutic control of asthma treatment with maximum doses of

anti-asthma properly.

• irrespective of the presence or absence of typical symptoms of reflux (heartburn and / or

regurgitation).

Patients with possibly GERD-induced asthma have been investigated following the same

protocol as in the previous study (fig.VIII.1 and VIII.2) .

IX.2.3. Statistical processing

The results were centralized in a SPSS 18.0 database (SPSS Inc., Chicago, IL, USA) and

processed with statistical functions to which they report, to the materiality threshold of 95%. In

the statistical analysis, we used descriptive as well as analytical methods.

IX.3. RESULTS

IX.3.1. General characteristics of patients with asthma

The present study included 44 patients diagnosed with asthma suspected of GERD origin.

This group of patients revealed the clear predominance of male sex and urban provenance, aged

between 18 and 77, with an average age of approx. 50 years. Most patients did not have typical

symptoms of GERD.

IX.3.2. Diagnosis protocol for asthma with potentially etiologic GERD

Following the same protocol as for the diagnosis of chronic laryngitis, we have identified

an association between the prevalence of GERD and asthma 88.6%, falling in the range of

variance of the prevalence reported by the international literature, but superior to that reported in

our country (fig.IX.7).

23

Figure IX.7. Distribution of asthma possibly GERD-induced cases

By plotting ROC curve, it was found that both the therapeutic test, and UDE are

ineffective for diagnosis of GERD-induced asthma. UDE had a sensitivity of 55% and a

specificity of 45%, while therapeutic test had a lower sensitivity and specificity of 50% and,

respective, 40% (fig.IX.8).

Only 3 patients were tested by esophageal impedance-pH metry. Of these, in 2 patients

the association between GERD and asthma was established.

IX.3.3. Evaluation of the demographic characteristics of patients with potentially

etiologic GERD asthma

In the group of 39 patients with uncontrolled or partially therapeutically controlled

asthma and GERD, there was noted a slightly higher percentage of males and the clear

predominance of urban provenance. The age of the patients ranged between 23 and 77, with an

average value of 51 years in the study group.

IX.3.4. Evaluation of risk factors in patients with asthma and GERD

Of all risk factors analyzed, only alcohol consumption and hiatal hernia induced a

statistically significant risk of association between GERD and asthma.

With symptoms, therapeutic

test+17.9%

With symptoms,UDE with

esophagitis15.2%

With symptoms,

IIM-pH+0.9%

Without symptomsUDE with

esophagitis34.8%

Without symptoms,

IIM-pH+11.6%

Without GERD

confirmation10.4%

1.00.80.60.40.20.0

1 - Specificity

1.0

0.8

0.6

0.4

0.2

0.0

Se

ns

itiv

ity

TestTerapeutic

EDSSource of the Curve

ROC Curve


.545 .088 .606 .374 .717

.455 .088 .606 .283 .626


EDS

TestTerapeutic

Area Std. Errora

Asy mptotic

Sig.b



Interv al





Figure IX.8. The balance

sensitivity/ specificity for UDE

and the therapeutic test in the

diagnosis of the association

between GERD and asthma

24

IX.3.5. Evaluation of clinical characteristics of patients with potentially etiologic

GERD asthma

The majority of patients with asthma and GERD have shown typical reflux symptoms.

The typical symptoms of reflux were not significantly correlated with the presence or with the

severity of the lesions of the esophagus; in the presence of esophageal lesions, AB relative risk

of association with GERD without typical symptoms was 5.68 times higher, the highest risk

being given esophagitis of grade A (table IX.4). This result supports the literature.

Table IX.4. Prognosis of the pathology associated in the determinism of typical GERD

symptomatology in patients with asthma

Characteristics

With typical

symptoms

(n=16)

Without typical

symptoms

(n=23)

p

OR

Estimated

risk

IC95%

n % n %

H pylori (+) 10 62,5 13 56,5 0,708 1,28 1,16 a)

0,90 b)

0,53-2,54

0,54-1,52

Esophagitis 9 56,3 22 95,7 0,002 0,06 0,33 a)

5,68 b) 0,18-0,61 0,90-36,0

Esophagitis A 6 37,5 14 60,9 0,086 0,32 0,51 a)

1,61 b)

0,23-1,14

0,90-2,88

Esophagitis B 2 12,5 5 21,7 0,452 0,51 0,65 a)

1,27 b) 0,19-2,25 0,73-2,22

Esophagitis C/D 1 6,3 3 13,0 0,776 0,70 0,80 a)

1,14 b)

0,15-4,15

0,49-2,66

Barrett’s Esophagus 2 12,5 5 21,7 0,452 0,51 0,65 a)

1,27 b) 0,19-2,25 0,73-2,22

Hiatal hernia 6 37,5 15 65,2 0,050 0,32 0,51 a)

1,61 b)

0,23-1,14

0,90-2,88

Gastritis 6 37,5 10 43,5 0,708 0,78 0,86 a)

1,11 b) 0,39-1,89 0,66-1,86

Dyslipidemis 6 37,5 7 30,4 0,646 1,37 1,20 a)

0,88 b)

0,56-2,57

0,49-1,58

Obesity 4 25,0 7 30,4 0,709 0,76 0,85 a)

1,11 b) 0,35-2,07 0,64-1,93


IX.3.6. Evaluation of biological characteristics of patients with potentially etiologic

GERD asthma

Helicobacter pylori infection was serologically objectified in 59% of the patients; the age

over 50 and the use of alcohol induced a risk of infection by about 30% higher. Helicobacter

pylori infection was significantly correlated with lesions of the esophagus and hiatal hernia. In

the presence of esophagitis, the relative risk of infection was 2.71 times higher, a result that is

contrary to the data reported by previous studies that Helicobacter pylori infection may play a

protective role in patients with erosive GERD.

25

IX.3.7. Evaluation of the endoscopic characteristics of patients with potentially

etiologic GERD asthma

Esophageal lesions were identified in 79.5% of patients, the highest recurrence being

mild esophagitis. The percentage obtained by us is 2-3 times higher than that reported in

literature (fig.IX.25).

Figure IX.25. Distribution of reflux esophagitis in the study group

In more than 50% of cases we identified hiatal hernia endoscopically. This result is in

agreement with the literature, which indicates that hiatal hernia is a common condition in

patients with asthma and / or GERD.

IX.3.8. Assessing the impact of disease on sleep and daily activities in patients with

GERD and asthma

GERD associated with asthma caused a negative impact on sleep and daily activities in

more than half of patients. Female patients (fig. IX.33) and those who accused typical GERD

symptoms were more affected in this regard (fig.IX.35).

Esophagitis

A51.3%

Esophagitis

B17.9%

Esophagitis

C7.7%

Esophagitis

D26% Barrett

17.9%

No

esophagitis

2.6%

0%

20%

40%

60%

80%

100%

Cu afectare

Fără afectare

57.1

22.2

Fără simptome tipice de BRGE

Cu simptome tipice de BRGE

0

30

60

90

Masculin Feminin < 50 ani > 50 ani Urban Rural

33.3

66.7

28.6

71.476.2

23.8

83.3

16.7

55.6

44.4

83.3

16.7

%

Cu afectare

Fără afectare

Male Female <50years >50years Urban Rural



With typical GERD symptoms Without typical GERD symptoms

Figure IX.33. Impact on sleep and daily activity according to

demographic data Figure IX.35. Impact on sleep and daily activity

according to the presence of typical GERD

symptomatology

26

IX.3.9. PPI therapy response assessment of patients with GERD and asthma

One month after the treatment with double dose PPI, 82% of the patients with GERD and

asthma responded; 43.6% of them showed a significant improvement in symptoms of asthma,

while 38.5% reported a slight improvement and about 18% of the patients did not respond after

one month.The response rate after a month of PPI treatment in patients with GERD and asthma

analyzed in this study was similar to that reported in literature.

After 3 months of treatment with double dose PPI, the response rate was significantly

increased, 56.4% and only 12.8% remained non-responsive. As in the case of laryngitis, the

prolongation of the treatment period determined an increase in the rate of response to PPI, thus

confirming that patients with GERD and asthma require higher doses and a longer time to

control the symptoms of asthma.

The profile of patients who showed a significant improvement after 3 months of PPI

treatment was outlined as follows: male, typical symptoms of GERD, consumer of coffee, with

severe esophagitis injuries or Barrett's esophagus; while women of a younger age, without

typical GERD symptoms, smokers with mild esophagitis lesions were more likely not to respond

to PPI (Table IX.12, fig.IX42).

Table IX.12. Response to double dose PPI therapy within 3 months

Response after 3

months

Slight

improvement

(n=12)

Significant

improvement

(n=22)

No response

(n=5)

Kruskal Wallis test

p

Sex

Male 6 (50,0%) 14 (63,6%) 2 (40,0%) 0,979

Female 6 (50,0%) 8 (36,4%) 3 (60,0%)

Age group

< 50 years 8 (66,7%) 11 (50,0%) 4 (80,0%) 0,948

≥ 50 years 4 (33,3%) 11 (50,0%) 1 (20,0%)

Environment

Urban 9 (75,0%) 19 (86,4%) 3 (60,0%) 0,788

Rural 3 (25,0%) 19 (13,6%) 2 (40,0%)

Typical GERD symptomatology

Yes 2 (16,7%) 12 (54,5%) 2 (40,0%) 0,146

No 10 (83,3%) 10 (45,5%) 3 (60,0%)

Figure IX.42. Response report 3 months after depending on associated comorbidity

27

IX.4. DISCUSSIONS

The present study identified a prevalence of GERD associated with poorly controlled

asthma (with maximal treatment) of 88.6%, a percentage that falls in the range of variation in the

prevalence reported by the international literature, but it is significantly higher than that reported

in our country.

The diagnosis of GERD-induced asthma is very challenging, especially when typical

symptoms of GERD are absent. A case of asthma difficult to control with maximal doses of

specific therapy should raise suspicion of GERD secondary asthma, limiting the chance of

diagnosis and therapeutic error. Here lies the importance of the interdisciplinary approach to this

pathology, which can save lives or at least improve the quality of life of affected patients.

Although the current guidelines indicate the therapeutic test with inhibitors of proton

pump as a first stage of diagnosis in patients with asthma possibly secondary to GERD, in the

present study the PPI test was shown to be an effective technique for diagnosis in patients with

typical symptoms of reflux. UDE performance parameters were superior to those of therapeutic

PPI test, but they confirmed literature, reaffirming that UDE is not a method efficient enough to

diagnose GERD-induced asthma in patients with typical symptoms of reflux. Esophageal

impedance-pH metry is the diagnosis technique that can establish a temporal relationship

between symptoms of asthma and the production of the reflux episode, acid or non-acid.

Unfortunately, the number of patients who were evaluated by impedance-pH metry was very

small and did not allow calculating performance parameters for this method.

Studies show that the presence of esophagitis is not common in patients with GERD and

asthma. This study contradicts this result, identifying a rate 2-3 times higher of esophagitis

lesions, with mild esophagitis prevalence. A possible explanation is similar to the case of chronic

laryngitis.

Multiple controversies have been reported in literature also for the case of the efficacy of

PPI in patients with GERD-induced asthma. In our study, the response rate in patients with

GERD and asthma to PPI was similar to that reported in literature. Extending the duration of

treatment to 3 months we noticed an increase in the percentage of patients that reported

improvement of the manifestations of asthma.

IX.5. CONCLUSIONS

Establishing a relationship of cause-effect between GERD and asthma is an extremely

difficult task, given that there is no gold standard method for diagnosis, to prove the meaning of

the link between events in this two-way relationship or if the two clinical conditions coexist

independently of each other. The prevalence of the association between asthma and GERD was

placed in the range of variation in the prevalence reported by the international literature, but was

higher than that reported in our country. Patients with uncontrolled/ partially controlled asthma

with maximal therapeutic anti-asthma treatment require gastroenterological assessment by

excluding other possible factors of exacerbation of asthma symptoms, the interdisciplinary

approach being essential.

Both the therapeutic test and EDS are ineffective methods for the diagnosis of GERD-

induced asthma. Although the very small number of patients evaluated by esophageal

impedance-pH metry did not allow calculation of performance parameters for this method, the

esophageal impedance-pH metry had an important role in revealing the diagnosis and

28

establishing a temporal relationship between the episode of reflux and the manifestations of

asthma in patients without endoscopic GERD mark.

From a demographic perspective, patients with GERD and asthma were characterized by

the predominance of males and urban origin, with a mean age segment of the population that is

active in working with the socio-economic repercussions not insignificant.

The typical symptoms of GERD were absent in more than half of the cases, suggesting

the important role of silent reflux and did not correlate with the presence or severity of lesions of

the esophagus, a result which is consistent with the medical literature.

More than half of patients reported sleep disturbances and decreased yield due to socio-

occupational disease manifestations, female patients and those who have typical reflux

symptoms charged with being more affected.

The response to PPI therapy was similar to that reported in literature, patients requiring

higher doses and a longer time to resolution of symptoms of asthma.

X. ASSESSMENT OF PATIENTS WITH POTENTIALLY ETIOLOGIC

CHRONIC COUGH GERD

X.1. THE AIM of the third study was to evaluate the association between chronic cough

and GERD, in order to analyze the possibility of GERD involvement in the etiology of chronic

cough.

X.2. MATERIAL AND METHOD

X.2.1. Patients

The prospective case-control study was conducted over a period of 37 months (November

1, 2012 - November 30, 2015) at the Institute of Gastroenterology and Hepatology of "St.

Spiridon" Hospital in collaboration with the Iaşi Pneumology Hospital.

Inclusion criteria:

patients older than 18 who have signed informed consent

patients diagnosed with chronic cough (cough, lasting at least 8 weeks) without a clear

etiology.

Exclusion criteria:

patient refusal / uncooperative patient / patient with documented psychiatric pathology

active tuberculosis or other acute respiratory tract infection

history of asthma, chronic bronchitis or lung cancers

postnasal syndrome or rhinosinusitis

smokers

chronic exposure to toxic or allergic environmental factors

treatment with angiotensin-converting inhibitors

history of left ventricular failure or mitral stenosis

alarm symptoms (unexplained weight loss, gastrointestinal bleeding upper dysphagia)


29

pathological personal history of motiliyy disorders (achalasia cardia, scleroderma,

myopathies)





patients receiving treatment with PPI in the last 8 weeks.

X.2.2. Study protocol

The present study included patients with chronic cough which were excluded from

possible breathing etiologies (clinical examination, chest radiography, spirometry and sputum

examination normal), ENT etiologies (indirect and direct laryngoscopy without change), allergic

etiologies (skin tests for allergies negative) and heart etiologies (echocardiography normal in the

absence of angiotensin converting enzyme inhibitor therapies).

Once these causes of chronic cough were excluded, patients were evaluated in our

service, following the same protocol for diagnosis, treatment and monitoring as in previous

studies (fig.VIII.1 and VIII.2) and GERD was considered under the same criteria.

X.2.3. Statistical processing

In the statistical analysis we used descriptive and analytical methods. The data were

collected in the SPSS 18.0 database (SPSS Inc., Chicago, IL, USA) and processed to materiality

threshold 95% (CI 95%).

X.3. RESULTS

X.3.1. General characteristics of the group of patients with chronic cough

The study group comprised 35 patients diagnosed with chronic cough suspected of

GERD otigin, which were characterized by the predominance of males and urban origin. The age

of patients with chronic cough varying widely, with extremes of 28 and 81 years old and with an

average of about 48 years. In contrast to the above mentioned extradigestive manifestations, the

cough patients included in the study had their most typical symptoms of reflux.

X.3.2. Diagnosis protocol for possibly GERD-induced chronic cough

According to the established study protocol, we found an association between GERD and

chronic cough in 85.7% of cases, a percentage that is higher than estimated literature (fig.X.7).

30

Figure X.7. Distribution of cases with chronic cough and GERD

Comparing the performance parameters of UDE versus the therapeutic test, by plotting

ROC curve it was found that both methods are less sensitive for the diagnosis of GERD as an

etiological substrate of chronic cough. For UDE, we have achieved a sensitivity of 53% and a

specificity of 50%, while the therapeutic test had a sensitivity and specificity slightly lower, only

45% and 50% respectively (Fig. X.8).

There were 3 patients rated by impedance pH metry, of which only one male, 54 years

old, of urban origin, confirmed the diagnosis of GERD.

X.3.3. Evaluation of demographic characteristics of patients with potentially

etiologic GERD chronic cough

In the group of 30 patients who confirmed the association between chronic cough and

GERD there was noted a clear predominance of males and urban origin. The ages of the patients

ranged between 29 and 81 years with an average of about 47 years in the study group.

X.3.4. Evaluation of risk factors in patients with chronic cough and GERD

Among the analyzed risk factors, coffee consumption, obesity and dyslipidemia induced

a statistically significant increased risk of associating GERD with chronic cough, results that are

in line with data reported by a number of previous studies.

With symptoms,therapeutic

test+17.9%

With symptoms, UDE with

esophagitis15.2%

With symptoms,

IIM-pH+0.9%

Without symptoms,,

UDE with esophagitis

34.8%

Without symptoms,

IIM-pH+11.6%

Without GERD conformation

14.3%

1.00.80.60.40.20.0

1 - Specificity

1.0

0.8

0.6

0.4

0.2

0.0

Sen

sit

ivit

y

TestTerapeutic

EDS

Source of the Curve

ROC Curve


.527 .103 .794 .325 .730

.473 .103 .794 .270 .675


EDS

TestTerapeutic

Area Std. Errora

Asy mptotic

Sig.b



Interv al





Figure X.8. Balance

sensitivity/specificity for EDS vs

Therapeutic test in GERD

diagnosis associated to chronic

cough

31

X.3.5. Evaluation of clinical characteristics of patients with potentially etiologic GERD

chronic cough

Typical symptoms were present in over half of patients falling within the ranges reported

in the literature. The same inverse relationship was noticed between typical reflux symptoms the

and presence of esophagitis, like in the case of the other extradigestive manifestations (Table

X.4).

Table X.4. The prognosis pathology associated with typical GERD symptoms determinism in

patients with chronic cough

Characteristics

With typical

symptoms

(n=17)

Without typical

symptoms

(n=13)

p

OR

Estimated

risk

IC95%

n % n %

H pylori (+) 12 70,6 9 69,2 0,936 1,07 1,03 a)

0,96 b)

0,52-2,05

0,40-2,33

Esophagitis 10 58,8 12 92,3 0,030 0,12 0,52 a)

4,36 b)

0,31-0,88

0,67-28,4

Esophagitis A 5 29,4 4 30,8 0,936 0,94 0,97 a)

1,04 b)

0,49-1,94

0,43-2,51

Esophagitis B 4 23,5 4 30,8 0,658 0,69 0,85 a)

1,22 b)

0,39-1,84

0,52-2,88

Esophagitis C 1 5,9 2 15,4 0,391 0,34 0,56 a)

1,64 b)

0,11-2,87

0,65-4,11

Esophagitis D 0 0 2 15,4 0,060 NC 2,55 b) 1,61-4,03

Barrett’s esophagus 3 17,6 3 23,1 0,713 0,71 0,86 a)

1,20 b)

0,36-2,04

0,47-3,04

Hiatal hernia 7 41,2 6 46,2 0,765 0,82 0,92 a)

1,12 b)

0,48-1,74

0,50-2,54

Gastritis 8 47,1 6 46,2 0,961 1,04 1,02 a)

0,98 b)

0,54-1,90

0,43-2,23

Dyslipidemia 7 41,2 4 30,8 0,556 1,58 1,21 a)

0,77 b)

0,65-2,24

0,31-1,92

Obesity 6 35,3 4 30,8 0,794 1,23 1,09 a)

0,89 b)

0,57-2,08

0,36-2,19


NC-not computed (incalculable)

X.3.6. Evaluation of the biological characteristics of patients with potentially

etiologic GERD chronic cough

Helicobacter pylori infection was serologically objectified in 70% of patients. As a

particularity of the group, female gender was statistically significantly correlated with

Helicobacter pylori infection, causing a 4.63 times higher risk of infection.

X.3.7. Endoscopic evaluation of the characteristics of patients with potentially etiologic

GERD chronic cough

The prevalence of esophageal lesions identified on the studied cases was very high in

comparison with the literature, with predominant mild esophagitis, the possible explanation

being the same as in the case of other extradigestive manifestations (fig.X.24).

32

The esophagitis risk was higher in young patients with urban origin and those who

associate hiatal hernia and / or chronic gastritis.

One fifth of the patients studied had Barrett metaplasia, which is similar to the results

reported in the literature in patients with GERD and in 43.3% of patients hiatus hernia was

identified, which did not induce a significant risk of GERD association with chronic cough.

Figure X.24. Distribution of cases with esophageal lesions in the study group

X.3.8. Assessing the impact of disease on sleep and daily activities in patients with

GERD and chronic cough

Sleep disorders and impaired daytime activity were reported by two thirds of patients

who were characterized by the predominance of the male sex, older age, and urban area

provenance. Also, patients with esophagitis or Barrett's esophagus had a worse sleep quality

compared to non-erosive GERD, supporting data in literature.

X.3.9. PPI therapy response assessment of patients with GERD and chronic cough

After one month of double dose PPIs, 80% of patients responded, 40% showing

significant improvement of chronic cough, mild improvement in 40% and 20% did not respond.

After 3 months, the response rate was higher, but similar to that shown in literature;

76.7% of patients experienced significant improvement in cough, 13.3% had mild improvement,

and 10% did not answer to PPI. Both after one month and after three months, the response rate to

treatment was inversely proportional to the severity of esophagitis, ie. severe esophagitis had the

weakest responders. Of all the variables analyzed, obesity and dyslipidemia caused the increased

percentage of response to PPI therapy, after 3 months all obese patients and / or dyslipidemic

patients being responsive (fig.X.38, fig.X.41).

X.4. DISCUSSIONS

As with the other extradigestive manifestations above, in the diagnosis of GERD

associated with chronic cough the test commonly used to detect typical GERD are less useful, as

the classic symptoms are present only to a quarter of the patients with cough reflux and

esophagitis is detected endoscopically at less than 20% of patients (120).

Esphagitis

A30.0%

Esophagitis

B26.7%

Esophagitis

C10.0%

Esophagitis

D6.7%

Barret's

Esophagus

20.0%

No

esophagitis

6.7%

33

The percentage of association between GERD and chronic cough we found is higher than

that estimated in literature. This may be due to the study methodology, selection of patients for

enrollment being very rigorous. We excluded the most common etiologies possible that could

explain chronic cough and factors that could influence the association between GERD and

cough. Also, this percentage reflects the prevalence of the association between GERD and cough

and not the temporal relationship between them, which was established by esophageal

impedance-pH metry, according to the protocol, in only one patient.

In front of a patient with unexplained chronic cough, the doctor should suspect GERD as

etiologic substrate of cough and refer the patient to accurately assess and establish the

gastroenterology therapeutic conduct.

Comparing the performance parameters of the therapeutic test versus UDE, it was found

that both methods are less sensitive for the diagnosis of GERD as an etiologic substrate of

chronic cough.

As a feature of our casuistry, female gender increased the risk of infection with

Helicobacter pylori in patients studied. The explanation of this difference can only be

speculated, possibly due to the different hormonal status of the two sexes, knowing that oxytocin

plays an important role in gastric emptying.

Treatment of chronic cough suspected to be GERD induced remains a controversial topic

in literature, although it has been widely studied in numerous clinical trials. The results reported

by are more varied and inconsistent, because of important limitations and methodological

problems, the most common being the small number of patients included and the lack of placebo

control group.

After 3 months, the response rate was higher than that in a month, but similar to that

shown by the literature. The response to PPI was inversely proportional to the severity of

esophagitis, ie severe esophagitis had the weakest responders. Of all the variables analyzed,

obesity and dyslipidemia caused the increased percentage of response to PPI therapy, after 3

months all obese patients and / or dyslipidemic patients being responsive.

X.5. CONCLUSIONS

GERD-induced chronic cough is a true diagnostic challenge, the usual tests commonly

applied to detect typical GERD being less useful in this case; the therapeutic test with PPI and

UDE proved not sufficiently efficient for the diagnosis of reflux cough. The asociation between

GERD and chronic cough was identified in our study in a high percentage of patients,

emphasizing the importance of gastroenterological evaluation of patients with chronic cough

who were excluded from other causes (ENT, respiratory, allergic or cardiac).

Most patients was characterized by the following traits: male, average age under 50 years

and urban origin. Coffee consumption, obesity and dyslipidemia are factors which induced an

increased risk of GERD with the combination of a chronic cough, respectively, which are in

agreement with data reported by a number of previous studies.

Typical symptoms were present in over half of patients falling within the range of values

reported in literature. An inverse relationship was noted between the presence of typical

symptoms of GERD and reflux esophagitis.

Helicobacter pylori infection has been objectified in an increased number of patients,

female gender increased the risk of infection, which is a feature of the study group.

34

The prevalence of esophageal lesions was very high in comparison with the literature, the

majority of cases falling within the degrees of mild esophagitis. Esophagitis risk was higher in

patients with younger age, urban origin or hiatus hernia.

Sleep disorders and impaired daytime activity were declared by two thirds of patients,

mostly males, of older age and of urban origin. Also, patients with esophagitis or Barrett's

esophagus had a worse sleep quality compared to non-erosive GERD.

PPI therapy was followed by an increased response rate after 3 months, similar to the data

presented by the literature. Extending treatment with PPI to 90 days increased the response rate

of the patients studied. The response rate to treatment was inversely proportional to the severity

of esophagitis, severe esophagitis having the weakest responders, while obesity and dyslipidemia

caused the highest percentage of increased response to therapy with PPI.

XI. COMPARATIVE ASSESSMENT OF EXTRADIGESTIVE

MANIFESTATIONS POSSIBLY INDUCED BY THE

GASTROESOPHAGEAL REFLUX DISEASE

XI.1. The aim of this study was the comparative analysis in demographic, clinical,

biological, endoscopic and therapeutic terms of the patients with extradigestive manifestations

(chronic laryngitis, asthma and chronic cough respectively) supposedly induced by GERD.

XI.2. MATERIAL AND METHOD

We performed a prospective descriptive case-control study comparing patients with

extradigestive manifestations to which we confirmed the diagnosis of GERD according to the

previously established protocol. Patients were analyzed in demographic data, clinical, biological,

endoscopic and therapeutic response terms.

Statistical analysis

The data were statistically analyzed using a centralized SPSS 18.0 database (SPSS Inc.,

Chicago, IL, USA) F ANOVA -test and the correlation Kruskall-Wallis.

XI.3. RESULTS

Study groups were constituted as follows:

• Group I - 90 patients with GERD and chronic laryngitis, which represents 80.4% of the 112

patients who were suspected of GERD etiologic substrate laryngitis

• Group II - 39 patients, representing 88.6% of the 44 patients known to have bronchial asthma

which confirmed suspicion of GERD

• Group III - 30 patients, representing 85.7% of the 35 patients known to have chronic cough,

which confirmed suspicion of GERD.

35

Demographic characteristics

The gender distribution of study groups showed homogeneity, registering slightly higher

frequency of male patients in all groups.

With a wide variation, the age of patients with chronic laryngitis ranged between 20-76

years, with a mean of 49.94 ± 14.36 years and a median of 50 years. In the group of patients with

asthma, the average age was slightly higher (51 ± 13.43 years), with a median of 50 years. In

patients with chronic cough, age ranged from 28-81 years, with a median of 49 years and a mean

of 47.37 ± 13.06 years, which was slightly lower compared to other study groups (p = 0.546)

(table XI.1).

Table XI.1. Statistical indicators, descriptive of age (years) by study groups

Study group N

Median

St.

deviation

St. error

Confidence interval Min Max

p

FANOVA

test - 95%CI +95%CI

Group I 90 49,94 14,36 1,51 46,94 52,95 20 76

0,546 Group II 39 51,00 13,43 2,15 46,65 55,35 23 77

Group III 30 47,37 13,06 2,38 42,49 52,24 28 81

Total 159 49,72 13,87 1,10 47,54 51,89 20 81

Depending on the area of origin, the structure of the groups was homogenous, the urban

origin being predominant in all groups (74.4%, 79.5% and 76.7%; p = 0.694).

Clinical characteristics

Depending on the presence of typical GERD symptoms, the structure of the groups was

fairly homogeneous, however it should be noted that in the group with GERD and chronic

cough, typical reflux manifestations were more frequent (p = 0.337) (Fig. XI.5).

Group 1 Group 2 Group 3

Figure XI.5. Structure of groups depending on the presence of typical GERD symptoms

The share of smokers was relatively small in the groups with laryngitis and asthma, while

in the group with chronic cough smoking was an exclusion criterion for the group (23.3%;

17.9%; p = 0.490 0% respectively). The proportion of patients that were coffee consumers was

increased in all study groups, without statistical significance (55.6%; 59%; 68.7% respectively p

= 0.296).

Obesity was significantly more frequent in patients with chronic cough versus the other

groups (15.6%, 28.2% and 33.3%; p = 0.025).

36

Biological features

Helicobacter pylori infection has been objectified in the highest percentage (70%) in

patients with chronic cough; differences between groups did not reach statistical significance

(55.6% and 59%; p = 0.184) (fig.XI.10).

Figure XI.10. The distribution of patients with Helicobacter pylori by study groups

The distribution of cases with dyslipidemia showed a share of 36.7% in patients with

chronic cough, but the percentage was not significantly increased compared to that of the group

with laryngitis (26.7%) or asthma (33.3% ) (p = 0.260).

Endoscopic characteristics

Esophagitis was more frequently observed in patients with chronic cough (73.3%), but

the percentage differences were not significant compared with other study groups (62.2% and

71.5%) (p = 0.154) (Fig.XI.12).

Figure XI.12. The distribution of patients with esophagitis by study groups

Barrett's esophagus was noted in 20% of patients with chronic cough and 17.9% in those

with poorly controlled asthma therapy, a significantly higher frequency of chronic laryngitis

compared to group (p = 0.002). Hiatal hernia was more frequently observed in patients with

asthma (53.8%), but the percentage differences were not statistically significant compared with

other study groups (40.0% and 43.3%) (p = 0.094).

Impact of the disease on sleep and daily activities of patients

The share of impaired sleep and impact on daily activity was increased in all study

groups (56.7%; 53.8%; 66.7% respectively p = 0.531).

0

20

40

60

80

55.6 59

70

%

Lot I

Lot II

Lot III

0

20

40

60

80

55.6 59

70

%

Lot I

Lot II

Lot III

37

Response to treatment with PPI

The response after a month was generally the same in the groups analyzed, being

dominated by the significant improvement with shares of 40% in patients with chronic cough and

54.4% in those with laryngitis (p = 0.519). After 3 months of treatment with PPI significant

improvements were noted in 75.6% of patients with laryngitis and in 76.7% of those with

chronic cough, slightly higher frequencies compared to the lot with asthma, where significant

improvement was observed only in 56.4% of patients. However, percentage distributions did not

statistically differ significantly.

XI.4. DISCUSSIONS

Comparing confirmation percentages of GERD in patients with extradigestive

manifestations, it was noticed that the most increased percentage was recorded in the group of

patients with asthma, followed by the group with chronic cough, the group of patients with

chronic laryngitis having the lowest rate of diagnosis confirmation.

Depending on the presence of typical symptoms of GERD, the groups with laryngitis and

asthma were homogeneous, with predominance patients without classic manifestations of GERD,

but the group with chronic cough distinguished by a higher percentage of patients who accused

heartburn and/ or regurgitation. Maybe this was why confirmatory diagnostic rate of GERD in

patients with cough was increased, the diagnosis being relatively easy.

Esophagitis lesions were endoscopically identified with an increased frequency in the

group of patients with chronic cough, followed by the group with asthma and finally the group of

patients with GERD and laryngitis. Relating to the severity of esophagitis, it was observed that

mild esophagitis was found at an increased proportion in patients with asthma, laryngitis

respectively, while severe esophagitis was significantly more frequent in the group with chronic

cough.

If in the group with laryngitis the prevalence of Barrett's esophagus was lower than that

reported in literature, in the other two groups, this complication of GERD was above the value

indicated by data from other studies. It seems therefore that patients with GERD and chronic

cough are more likely to develop severe lesions of esophagitis and Barrett's esophagus compared

with patients showing one of the other extra-digestive manifestations.

Hiatal hernia was most often diagnosed in patients with GERD and asthma versus those

with GERD and cough or GERD and laryngitis, but the percentage differences were not

significant in statistical terms, a result that is consistent with previously published data in the

literature.

Over 50% of patients of all three groups have declared a bad sleep quality and thus an

impairment of their daily activities because of chronic fatigue. In the group with chronic cough

the highest percentage of affected patients was noted, cough is therefore the extra-digestive

manifestation that prompted the most frequent awakenings from sleep with major socio-

professional consequences.

Response rates after one month of treatment with PPI in patients in the three study groups

were comparable. The increased rate of significant improvement was noted in patients with

chronic laryngitis, and the highest percentage of non-responsive patients had GERD and chronic

cough. Patients with GERD and laryngitis, and those with GERD and cough had the highest

percentages of significant improvement (75%) after 3 months of therapy with PPI.

38

XI.5. CONCLUSIONS

Extradigestive manifestations associated with GERD were common and generally

homogeneous in our study; similar to the literature, the groups were marked by the

predominance of males. Although the group of patients who associated GERD and chronic

cough recorded the highest share of young people, and the group with asthma included most

elderly patients, all three categories of extradigestive manifestations affected mostly the young,

representing the active population segment. The diagnosis of GERD with extradigestive

manifestations was established much more in males versus females. Like in the literature data,

we identified a high prevalence of patients with GERD and extradigestive manifestations from

urban areas.

Typical symptoms of GERD were met with preference in patients with GERD and

chronic cough, unlike those with GERD and laryngitis or asthma who were mostly asymptomatic

from a digestive point of view..

Behavioral habits (alcohol, coffee, tobacco) have not resulted in significant differences

between the study groups, while obesity was more common in patients with GERD and cough

compared to other groups. Also, Helicobacter pylori infection and dyslipidemia were noted more

in the group with chronic cough.

The most increased frequency of esophageal lesions overall, and the most severe of them

(C and D grade esophagitis, Barrett's esophagus) was found in the group with chronic cough, and

the lowest in the group with chronic laryngitis. Hiatal hernia was found especially in patients

with GERD and asthma, while chronic gastritis in patients with GERD and cough.

Although more than half the patients in each group declared a bad sleep quality, and

impaired social and professional activities, patients with GERD and cough were the most

affected.

After one month of treatment with double dose PPI, patients with GERD and chronic

cough had the lowest rate of significant improvement, after 3 months these patients had

increased the percentage of significant improvement or complete resolution of extradigestive

manifestations. Of all extradigestive manifestations studied, asthma had the weakest response to

PPI therapy.

XII. GASTRO-ESOPHAGEAL REFLUX DISEASE AND ATRIAL

FIBRILLATION

XII.1. The aim of this study was to evaluate the association between GERD and

paroxysmal non-valvular atrial fibrillation, to investigate whether atrial fibrillation can be

classified as an extradigestive manifestation of GERD.

XII.2. MATERIAL AND METHOD

We conducted a prospective case-control trial, with the inclusion of consecutive patients

over a period of 13 months (July 1, 2014 - July 31 2015), at the Institute of Gastroenterology and

Hepatology Iasi, in collaboration with 3 rd

Medical Clinic from "St. Spiridon" Hospital.

39

XII.2.1. Patients

Inclusion of patients in the study was carried out by a joint team: gastroenterologist and

cardiologist based on the inclusion and exclusion criteria agreed.

Inclusion criteria:

We included patients older than 18 years diagnosed with paroxysmal non-valvular AF

from the Medical Clinic III of the Hospital "St. Spiridon ", to which we confirmed (GERD + AF)

or disproved (non-GERD + AF) the diagnosis of GERD, at the Institute of Gastroenterology and

Hepatology of “St. Spiridon” Hospital, as well as patients without AF, but diagnosed with GERD

(GERD + RS) or without GERD (non-GERD + RS), who gave their consent for consensual

enrollment.

Exclusion criteria:

patients aged under 18

documented valvular AF

persistent or permanent AF

hemodynamically unstable patients with acute coronary syndrome / aortic dissection,

sick sinus syndrome, pericarditis, myocarditis, endocarditis, congenital heart disease,

cardiac surgery, cardiac pacemaker or defibrillator, Wolff-Parkinson-White pre-

excitation syndrome

chronic pulmonary heart, pulmonary embolism, pneumonia

endocrine disorders (hyperthyroidism, pheochromocytoma)

dyselectrolytemia (hypokalemia, hypomagnesemia, hypocalcemia)

neoplasia

psychiatric and neurological pathology (subarachnoid haemorrhage)

history of esophageal surgery

abuse of alcohol or other stimulants (cocaine)


uncooperative patients / patients who refused enrollment

treatment with PPI in the last 8 weeks.

XII.2.2. Study protocol

All patients were investigated in the cardiology service by history and physical

examination, ECG, Holter ECG, echocardiography and biological dosages and in the

gastroenterology service by history, clinical examination and UDE. Paroxysmal non-valvular

atrial fibrillation was defined according to the current guidelines as paroxysmal AF (ECG

presence of three elements: irregular RR intervals, the absence of P waves and fibrillation

irregular activity, with a frequency of 400-600/ minute, with spontaneous remission or under

antiarrhythmic medication in less than 7 days), without rheumatic mitral stenosis, prosthetic

valve or mitral valve repair (475). The diagnosis of GERD was determined on the basis of

clinical symptoms (according to the Montreal Consensus) (7): heartburn and/ or regurgitation of

at least 2-3 times / week, perceived as "troublesome" by patients.

40

Each patient included in the study was compiled a data sheet that recorded information

about the evaluated parameters: clinical, biological, endoscopic, electrocardiographic and

echocardiographic.

Clinical parameters: age, sex, body mass index. presence of comorbidities: hypertension,

dyslipidemia, coronary heart disease, heart failure, peripheral arterial disease (PAD), diabetes,

history of stroke, aortic atheroma, chronic myocardial infarction.

Biological parameters: At study entry, all patients were taken blood samples for the

determination of cholesterol and triglyceride levels. proBNP (brain natrium peptide), troponin I,

CRP and Ac anti-Helicobacter pylori.

Endoscopic parameters: esophagitis lesions, Barrett's esophagus and hiatal hernia.

Echocardiographic parameters: area and volume of left atrium, in apical 4 and 2 rooms,

an expression of left ventricular diastolic dysfunction, assessed by the type of the evaluated

mitral pattern in pulsated and tissue Doppler (E / A, E / Ea).

Electrocardiographic parameters followed by Holter ECG for 24 hours was the RR

variability using parameters from time domain (SDNN - standard deviation of the mean of all

normal RR intervals in 24 hours) and in the frequency domain (LF / HF ratio - power of low

frequencies / power of high frequencies).

Antiarrhythmic medication was not suspended during the course of the study.

XII.2.3. Statistical processing

The statistical analysis was performed with SPSS 18.0 software (SPSS Inc., Chicago, IL,

USA), materiality threshold of 95%. The following indicators derivatives were used, described

by ANOVA test: indicators of the mean (simple arithmetic mean, median, mode, minimum and

maximum values) and indicators of dispersion (standard deviation, coefficient of variation), 2

test and t-Student test.

XII.3. RESULTS

This study included 135 patients, where 61 patients (45.2%) had GERD and 74 (54.8%)

did not have GERD. Study groups constituted are illustrated in figure XII.1.

Figure XII.1. Distribution of patients by study groups

Following statistical analysis, we found that the percentage of patients with AF was

increased in patients with GERD compared to non-GERD patients, but the difference did not

reach statistical significance (59% vs 47.3%; p = 0.575).

41

Clinical parameters

AF patients with GERD and AF were characterized by the predominance of females, at

an average age of 60 years and overweight status.

Regarding comorbidities, heart failure was significantly more prevalent in patients with

GERD and AF, entailing a risk of association estimated 1.65 times higher. In patients with AF,

aortic atheroma statistically significantly increased relative risk of GERD, 42%, making the

aortic atheroma a possible risk factor for the combination of the two pathologies.

Biological parameters

In the studied cases, we found the most increased medium values of proBNP in patients

with AF, irrespective of the presence of GERD.

By analyzing the relationship between the average value of troponin I and the presence of

AF in patients with GERD, we found that structural remodeling of the left atrium through atrial

fibrosis was not influenced by the presence of GERD.

We found no statistically significant differences between patients with GERD and AF

versus other study groups regarding CRP value.

Although the literature indicates that Helicobacter pylori infection increases the risk of

GERD association with AF, our study did not confirm this hypothesis.

Dyslipidemia, a risk factor for AF and GERD, increased the risk of association solely on

the basis of hypertriglyceridemia, a relationship that could not also be established in the case of

serum cholesterol.

Endoscopic parameters

Half of the patients with GERD + AF showed esophagitis lesions in endoscopic

examination, the risk that patients with GERD develop AF in the presence of esophagitis was 2.5

times higher (Table XII.7).

Hiatal hernia was found in a small percentage of patients with GERD + AF and there was

no significant difference compared with the group with AF and without GERD.

Table XII.7. Endoscopic parameters by study groups

Endoscopic

result

BRGE+FiA non-BRGE+FiA χ

2 p RR IC95%

n % N %

Esophagitis 18 50,0 3 7,7 17,88 0,001 2,57 1,70-3,90

Barrett’s

esophagus

2 5,6 1 2,6 0,44 0,506 1,41 0,61-3,26

Hiatal hernia 7 19,4 6 15,4 0,22 0,643 1,15 0,65-2,03

Echocardiographic parameters

Of all the echocardiographic parameters analyzed, the area and the average volume of

AS, as markers of LA structural remodeling, and the parameters of velocity, E / A and E / Ea, as

markers of diastolic dysfunction of the left ventricle, only in the case of AS volume was there

registered an average higher in patients with GERD + AF compared to other study groups, but

the differences did not reach statistical significance (fig.XII.14).

42

Figure XII.14. LA averages volume by study groups

Electrocardiographic parameters

SDNN average values were significantly higher in non-GERD + AF group compared

with GERD + AF group (182.14 vs 109.33; p = 0.024) and in group GERD + AF compared to

GERD+ RS (109,33vs 69.60; p = 0.05), aspect that also stands between the groups RS and / or

GERD (123.56 vs 69.6; p = 0.043) (fig.XII.17). This means a lower variability R-R in the

presence of GERD, regardless of the existence or RS or AF.

XII.4. DISCUSSIONS

GERD association with AF is a topic which continues to provoke controversy in the

literature. There is evidence of this association published as case studies and some observational

studies (419-422, 424, 462-464). But this evidence is inconsistent, part of the studies being

retrospective with important limitations related to how GERD diagnosis was established.

Kunz et al. (424) found that GERD induces a relative risk 1.39 times greater than atrial

fibrillation. The results of the largest epidemiological study conducted to date (1,000,000

subjects analyzed) showed that patients with GERD carry a significantly higher risk of

developing AF than those without GERD; moreover, GERD is associated independently with an

increased risk of atrial fibrillation (464).

This study identified a higher proportion of patients with AF between patients with

GERD than in those without GERD, but the difference did not reach statistical significance. This

study is the second in the literature, after the study by Bunch et al. (423), which has not

confirmed this association. Our results cannot be extrapolated to the general population and are

valid only in the group of patients selected according to specific criteria for inclusion in the

study.

0

20

40

60

45.2 43.61 43.59 42.34 BRGE+FiA

BRGE+RS

non-BRGE+FiA

non-BRGE+RS

0

100

200

109.33

69.6

182.14

123.56BRGE+FiA

BRGE+RS

non-BRGE+FiA

non-BRGE+RS

43

Although it is unclear whether the link between GERD and AF is a cause-effect link or an

association, there is evidence that the two clinical entities have common patho-physiological

pathways and are favored by predisposing factors (456-460).

A number of published studies in the literature support the idea that local inflammation is

both involved in GERD physiopatogeny and in the AF physiopatogeny (442, 443). The

inflammation can be assessed by measuring serum levels of C-reactive protein. In the present

study we found no statistically significant differences between patients with GERD and AF

versus other study groups, regarding CRP value. Our results therefore do not confirm the role of

CRP as a marker of inflammation in patients with GERD and AF, requiring dosing of high-

sensitive CRP (hs-CRP), which is a biochemical parameter with superior accuracy for assessing

inflammation in cardiovascular diseases.

proBNP is a protein-hormone produced by cardiac myocytes in response to increased

volume and pressure overload of heart cavities, the most powerful predictor for developing AF.

We found in our cases, the most increased mean values of proBNP in patients with AF,

irrespective of the presence of GERD. This result means that the association of GERD in patients

with atrial fibrillation does not significantly influence structural remodeling of the left atrium (by

the pressures that lead to increased secretion of proBNP).

Troponin I represents an AF marker of structural remodeling of the left atrium. Analyzing

the relationship between the average value of troponin I and the presence of AF in patients with

GERD, we found that structural remodeling of the left atrium through atrial fibrosis (troponin is

correlated with destruction of atrial myocardium and development of fibrosis respectively) is not

influenced by the presence of GERD.

Helicobacter pylori, the Gram-negative bacteria mostly known to infect the stomach,

appears to be associated to cardio-vascular pathologies, being involved in atrial chronic

inflammation, which is the substrate for development of atrial fibrillation. Our results are similar

to the latter, as we have not found any statistically significant relationship between AF and

Helicobacter pylori infection.

As I mentioned, chronic inflammation is one of the main mechanisms involved in the

physiopathogeny of the association between GERD and AF. Even if we did not managed to

prove the role of inflammation in the pathogenesis of GERD association with AF through RPC,

the inflammatory mechanism is supported by the presence of esophagitis lesions in a proportion

higher in patients diagnosed with both diseases.

Developing atrial fibrillation is closely related to electrical and mechanical structural remodeling

of the left atrium. Left atrial dilation as a marker of structural remodeling, it is strongly

associated with the occurrence of atrial fibrillation and is also a marker of severity and chronicity

of diastolic dysfunction (489).

Of all the echocardiographic parameters analyzed, the area and the average volume of

AS, as markers of LA structural remodeling, and the parameters of velocity, E / A and E / Ea, as

markers of diastolic dysfunction of the left ventricle, only in the case of the LA volume was there

registered an average higher in patients with GERD + AF compared to other study groups, but

the differences did not reach statistical significance. But these results do not support the

hypothesis that left atrial dilation (as a result of left ventricular diastolic dysfunction) by

mechanical effect could alter pressures at the esophageal gastric junction and thus favoring the

occurrence of GERD.

Sympatico-vagal imbalance is considered one of the main mechanisms suspected to be

involved in the association between GERD and FA. R-R cycle variability is a noninvasive tool

44

useful for assess the balance between the two components of the autonomic nervous system: the

sympathetic and parasympathetic, and for assessing vulnerability and arythmogenicity

fibrillation. VRR decreases when there is a predominance of sympathetic activity and

conversely, increases when the parasympathetic prevails, a lower value of VRR signifying an

increase of atrial vulnerability and arythmogenicity.

According to the European Society of Cardiology, the most used methods for

determining VRR are those in time and frequency domain in Holter ECG monitoring. In the time

domain, we analyzed the SDNN parameter (standard deviation of the mean R-R normal intervals

within 24 hours) and in the frequency domain, we calculated the ratio between the powers of low

and high frequencies, LF / HF. We obtained statistically significant differences only in the case

of the variable of time. SDNN value was statistically significantly lower in patients with GERD

than in those without GERD, regardless of the presence of AF. This shows a greater

arythmogenicity given by GERD and supports the theory of autonomic system imbalance as a

mechanism of association of GERD with AF.

XII.5. CONCLUSIONS

Atrial fibrillation was more common in patients with GERD, but without statistically

significant difference compared with patients without GERD. The present study is the second

study that does not demonstrate a statistically significant association relationship between GERD

and AF.

A feature of the sample studied was the predominance of females in patients with GERD

and AF, contrary to data reported by most studies published so far, which might suggest that the

female population in the region of N-E Romania is more prone to develop this association.

Inclusion criteria for this study could still create biases in data interpretation. Similar to the

literature, the average age of patients with GERD and AF in our study was 60 years, indicating

the older age as factor for the combination of the two pathologies.

Overweight status was not found to be a risk factor for GERD association with AF, but a

feature of the study is the absence of obesity in patients of the study group. Dyslipidemia on the

basis of hypertriglyceridemia was correlated in our study with the presence of GERD and AF.

Regarding associated comorbidities, heart failure induced an increased risk of developing

a paroxysm of AF in patients with GERD, while aortic atheroma increased risk of GERD in

patients with AF, results that are consistent with the literature. Helicobacter pylori infection has

not been shown to be a risk factor for the combination of GERD and AF.

The theory of inflammation as a pathophysiological mechanism involved in the

association between GERD and AF was sustained in our study by the presence of esophagitis

lesions identified in a higher percentage in patients with GERD and AF, but could not be

supported by CRP, as a marker of biological inflammation of the left atrium. The theory of the

mechanical effect of dilatation of the left atrium on the esophagus has not proven to be one of the

pathophysiological mechanisms involved in the association of the two pathologies in terms of

biological or echocardiographic parameters analyzed. Patients with GERD showed a reduced R-

R cycles variability, regardless of the presence of AF, which reflects an increased

arythmogenicity induced by GERD and supports the theory of the autonomic system imbalance

as a mechanism of association of GERD with AF.

45

XVI. GENERAL CONCLUSIONS

1. Our study revealed an increased prevalence of the association between GERD and

extradigestive manifestations, stressing the importance of gastroenterological evaluation in

patients with chronic laryngitis, poorly controlled asthma, chronic cough, potentially etiologic

GERD.

2. The diagnosis of GERD with extradigestive manifestations was an extremely difficult

task, challenging, given that at present there is no gold standard method to demonstrate the

causality of these clinical conditions.

3. Of all the diagnosis methods used in the present study, the esophageal impedance-pH

metry has proven to be the tool with the best diagnostic yield, being a good predictor regardless

of the presence or absence of typical symptoms of reflux.

4. Helicobacter pylori infection did not significantly influenced the risk of association

between GERD and extradigestive manifestations.

5. Typical GERD symptoms were met with preference in patients with GERD and

chronic cough, unlike those with GERD and laryngitis or asthma who were mostly asymptomatic

from a digestive point of view and were not good predictors for the presence and severity of

reflux esophagitis and hiatal hernia.

6. In our study, esophagitis lesions were identified in a percentage much higher than that

reported in literature, with mild esophagitis being predominant. The presence of hiatal hernia

was statistically significantly associated with GERD and asthma, GERD and laryngitis

respectively, while chronic gastritis was statistically significantly more frequently associated

with GERD and cough.

7. GERD with extra-digestive manifestations caused a negative impact on sleep and

consequently on daily activities due to decreased professional efficiency and labor productivity,

which is why GERD currently represents a major public health problem, burdening state budget.

8. The rate of favorable response to treatment with double dose PPI was increased in

patients with GERD, regardless of the extra-digestive manifestation, while prolonging therapy

for 3 months resulted in an increased responsiveness to treatment. The therapeutic response to

PPI was inversely proportional to the degree of esophagitis lesions severity.

9. Atrial fibrillation was a clinical condition more common in patients with GERD, but

the association did not reach statistical significance.

10. The results of our study confirmed the theory of inflammation as a pathophysiological

mechanism involved in the association between GERD and AF and also the theory of the

autonomic nervous system imbalance, but did not support the theory of the mechanical effect of

the left atrial dilation on the esophagus.

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