0 GERD Abstractbook 11FINAL 67833

PARMA, April 16-18, 2015
CHAMBER OF COMMERCE OF THE PARMA COUNTY
HONORARY PRESIDENT Emilio Marangio, MD
POST-GRADUATE COURSE & INTERNATIONAL CONGRESS
EXTRA-DIGESTIVE GERD:
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SCIENTIFIC PROGRAM
ABSTRACT BOOK
PRESIDENTS Carmelo Scarpignato, MD, DSc, PharmD, MPH Francesco Di Mario, MD

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PRESIDENTS CME ACCREDITATION

Carmelo Scarpignato, MD, DSc, PharmD, The Post-graduate Course and the Con-
MPH, FRCP (London), FACP, FCP, FACG, AGAF gress have been accredited for Health Pro-
Professor of Clinical Pharmacology, fessionals: Physicians (Gastroenterology,
University of Parma, Italy Pneumology, Otolaringology, Cardiology,
Associate Professor of Gastroenterology,
University of Nantes, France Neurology, Primary Care, Anesthesiology,
General Secretary, World Organization for Internal Medicine, Palliative Medicine),
Esophageal Diseases (OESO), Paris, France Dentistry and given 7.5 CME credits by
Planning Congressi (CME Provider n. 38).
Francesco Di Mario, MD
Professor of Gastroenterology,
University of Parma, Italy An effective presence to all meeting sessions
Director, Postgraduate School of as well as a correct answer to at least 75% of
Gastroenterology & Digestive Endoscopy the MCQs are needed to get the CME credits.
No exception will be considered.
HONORARY PRESIDENT
Emilio Marangio, MD
Professor of Respiratory Medicine,
CONGRESS VENUE
University of Parma
Head, Division of Respiratory Diseases, PARMA CHAMBER OF COMMERCE
Maggiore University Hospital, Parma Via Verdi, 2
43121 Parma (Italy)
SCIENTIFIC SECRETARIAT
Anna Bertel, MD
Clinical Pharmacology
& Digestive Pathophysiology Unit,
Department of Clinical &
Experimental Pharmacology
University of Parma, Italy
E-mail: GI.Pharmacology@gmail.com
This abstract book has been printed

thanks to an unrestricted educational
grant from: The official language of the Congress is
English and all the presentations will be
delivered in English. A translation into and
from Italian will be provided for the atten-
dants.
2 PRESIDENTS Carmelo Scarpignato, MD, DSc, PharmD, MPH (Parma, Italy) Francesco Di Mario, MD (Parma, Italy)
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FACULTY
Lars Erik Agrus (Stockholm, Sweden) Robert C. Heading (Durham, UK)
Piero Amodio (Padova, Italy) Pali Hungin (Durham, UK)
Antonio Balzano (Naples, Italy) Richard H. Hunt (Hamilton, ON, Canada)
Giovanni Barbara (Bologna, Italy) Wolfgang Issing (Newcastle upon Tyne, UK)
Gabrio Bassotti (Perugia, Italy) Peter Kahrilas (Chicago, IL, USA)
Corrado Blandizzi (Pisa, Italy) Peter Malfertheiner (Magdeburg, Germany)
Stanislas Bruley des Varannes (Nantes, France) Gerardo Nardone (Naples, Italy)
Giuseppina Campisi (Palermo, Italy) Ambrogio Orlando (Palermo, Italy)
Alfredo A. Chetta (Parma, Italy) Fabio Pace (Milan/Seriate, Italy)
Rosario Cuomo (Naples, Italy) Liborio Parrino (Parma, Italy)
John de Caestecker (Leicester, UK) Franco Radaelli (Como, Italy)
Peter W. Dettmar (Kingston upon Hull, UK) Edoardo Savarino (Padua, Italy)
Carlo Di Mario (London, UK) Vincenzo Savarino (Genoa, Italy)
Francesco Di Mario (Parma, Italy) Carmelo Scarpignato (Parma, Italy)
Ronnie Fass (Cleveland, OH, USA) Jaclyn A. Smith (Manchester, UK)
Antonio Gasbarrini (Rome, Italy) Dino Vaira (Bologna, Italy)
Majid Hashemi (London, UK) Mark Watson (Doncaster, UK)
PRESIDENTS Carmelo Scarpignato, MD, DSc, PharmD, MPH (Parma, Italy) Francesco Di Mario, MD (Parma, Italy) 3
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POST-GRADUATE COURSE
THURSDAY, April 16, 2015
ADVANCES IN GASTROINTESTINAL PHARMACOLOGY & THERAPEUTICS

Chairpersons: Antonio Gasbarrini (Rome, Italy) Fabio Pace (Milan/Seriate, Italy)
09:00 Opening Lecture:

Generics & Biosimilars: Therapeutic Challenges of the Third Millenium
Corrado Blandizzi (Pisa, Italy)
09:30 Therapy of Refractory GERD: Beyond the PPIs

Vincenzo Savarino (Genoa, Italy)
10:00 Addressing H. pylori Eradication Challenges

Dino Vaira (Bologna, Italy)
10:30 Gastropanel as Non Invasive Tool to Assess Drug Effects on Human

Gastric Mucosa
Francesco Di Mario (Parma, Italy)
11:00 Coffee Break
11:30 Management of Small Intestine Bacterial Overgrowth

Carmelo Scarpignato (Parma, Italy)
12:00 New Pharmacological Approaches to the Treatment of IBS

Giovanni Barbara (Bologna, Italy)
12:30 Drug Therapy of Chronic Constipation: Whats New

Gabrio Bassotti (Perugia, Italy)
13:00 Working Lunch
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15:00 Management of the Colonic Diverticular Disease: Lessons from the

Italian Consensus Conference
Rosario Cuomo (Naples, Italy)
15:30 Management of Inflammatory Bowel Disease: Where Are We going?

Ambrogio Orlando (Palermo, Italy)
16:00 From Laxation to Bowel Cleansing: the Ideal Preparation for

Colonoscopy
Franco Radaelli (Como, Italy)
16:30 Coffee Break
17:00 Gut Microbiota in Health & Disease

Gerardo Nardone (Naples, Italy)
17:30 Management of GI Disease with Probiotics: When and How

Fabio Pace (Milan/Seriate, Italy)
18:00 Microbiota-directed Therapies for Liver Diseases

Piero Amodio (Padova, Italy)
18:30 End of the Post-graduate Course
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FRIDAY, April 17, 2015 Morning
OPENING CEREMONY
08:30 Welcome Address

Regional Academic & Health Authorities
Congress Presidents
SESSION I: EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Chairpersons: Gerardo Nardone (Naples, Italy) Vincenzo Savarino (Genoa, Italy)
09:30 Opening Lecture The Genval, Montreal and Vevey Consensus on

GERD: Where Are We Now? Open Questions and a Look to the Future
Richard H. Hunt (Hamilton, ON, Canada)
10:00 Epidemiology of Extra-digestive GERD

Lars Erik Agrus (Stockholm, Sweden)
10:30 Typical versus Atypical GERD: Similarities and Differences

Robert C. Heading (Durham, UK)
11:00 Coffee Break
SESSION II: NEW DIAGNOSTIC MODALITIES

11:30 Pepsin Detection in Digestive and Respiratory Fluids: An Update
Peter W. Dettmar (Kingston upon Hull, UK)
12:00 pH-impedance and Airway pH Recording

Edoardo Savarino (Padua, Italy)
12:30 Extra-digestive GERD: Is Upper GI Endoscopy Always Indicated?

Peter Malfertheiner (Magdeburg, Germany)
13:00 Working Lunch
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FRIDAY, April 17, 2015 Afternoon
SESSION III: EXTRA-DIGESTIVE MANIFESTATIONS OF GERD

Chairpersons: Alfredo A. Chetta (Parma, Italy) Liborio Parrino (Parma, Italy)
15:00 Respiratory Manifestations of GERD

Stanislas Bruley des Varannes (Nantes, France)
15:30 ENT Manifestations of Laryngopharyngeal Reflux

Wolfgang Issing (Newcastle upon Tyne, UK)
16:00 GERD-related Non Cardiac Chest Pain and Arrhythmias

John de Caestecker (Leicester, UK)
16:30 Coffee Break
17:00 GERD and Sleep Disturbances

Ronnie Fass (Cleveland, OH, USA)
17:30 Dental Erosions and Halitosis as Oral Manifestations of GERD

Giuseppina Campisi (Palermo, Italy)
18:00 Globus and Its Complexities

Peter Kahrilas (Chicago, IL, USA)
18:30 End of the First Day
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SATURDAY, April 18, 2015 Morning
SESSION IV: THERAPEUTIC APPROACH TO EXTRA-DIGESTIVE GERD

Chairpersons: Corrado Blandizzi (Pisa, Italy) Antonio Balzano (Naples, Italy)
09:00 Is There an Effective Medical Therapy for Extra-digestive GERD?

Facts and Fiction
09:30 Indications and Selection for Surgery of Patients

with Extra-digestive GERD
Majid Hashemi (London, UK)
10:00 Coffee Break
SESSION V: Round table HOT TOPICS IN THERAPY
10:30 PPI Long-term Use and Misuse:

Who Is Responsible for?
11:15 Are There Better Alternatives to PPIs

for Treatment of Extra-digestive GERD?
12:00 Extra-digestive GERD: Which Medications

in Addition to Anti-reflux Therapy?
Primary Care Physician: Pali Hungin (Durham, UK)

Respirologist: Jaclyn A. Smith (Manchester, UK)
ENT Physician: Mark Watson (Doncaster, UK)
Cardiologist: Carlo Di Mario (London, UK)
Gastroenterologist: Francesco Di Mario (Parma, Italy)
12:45 Closing Remarks

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Notes
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Notes
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SESSION I:
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
CHAIRED BY:
Gerardo Nardone, MD
Federico II University, Naples
Director, Division of Gastrointestinal Oncology,
Department of Clinical and Experimental Medicine,
University Hospital of Naples, Italy
Gerardo Nardone
Vincenzo Savarino, MD
University of Genoa, Italy
Chairman, Department of Internal Medicine,
President, Italian Society of Gastroenterology (SIGE)
Vincenzo Savarino
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09:30 Opening Lecture

The Genval, Montreal and Vevey Consensus on GERD:
Where Are We Now? Open Questions and a Look to
the Future
Richard H. Hunt, MB ChB, FRCP, FRCPEd, FRCPC, AGAF,
MACG, MWGO
Emeritus Professor of Medicine, Department of Medicine,
Division of Gastroenterology and Farncombe Family Digestive
Richard H. Hunt Health Research Institute, McMaster University,
Hamilton, ON, Canada
Introduction
Gastro-esophageal reflux disease (GERD) has changed substantially over the past 50
years with respect to both epidemiology and clinical expression. Our awareness of this
condition came to the fore with the widespread introduction of upper gastrointesti-
nal endoscopy into clinical practice. Erosive esophagitis was found more commonly
than, and was not as closely related, to symptomatology as was expected with the
knowledge and perceptions of the time. We now have the benefits of more than four
decades of careful observation and research.
Today GERD is increasingly common, with studies showing an estimated 20% to 44%
of Western populations reporting symptoms at least once a month and 20% with
GERD symptoms weekly [1]. When weekly heartburn or acid regurgitation are the
objective endpoint, the prevalence of GERD ranges from 10% to 20% in Western
countries, although in Asia prevalence is still less than 5% [2].
GERD invariably presents with a spectrum of symptoms, which include esophageal

and extra-esophageal components. Symptoms may be frequent or infrequent, mild or
severe and can adversely affect the patients quality of life [3] even when no mucosal
injury is observed at the time of endoscopy [4].
The pathophysiology of symptoms and mucosal damage is explained primarily by

the increased exposure of the distal esophageal mucosa to refluxed gastric contents.
These are invariably acidic in nature and also contain pepsin, bile acids, and pancreatic
enzymes etc. all of which can contribute to mucosal damage. In general, the degree of
acidity correlates with the severity of erosive esophagitis. Hiatus hernia is also important
in reflux disease, since it can disrupt the barrier function at the esophago-gastric
junction, it is associated with increased frequency of transient LES relaxations (TLESRs)
[5] and can act as a reservoir for gastric juice above the diaphragm from where it may
reflux more frequently [6].
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Heartburn is a symptom complex traditionally accepted as acid mediated and a reliable

indicator of GERD [7]. However, these concepts have been questioned based on the
false observation that patients with endoscopy-negative heartburn appeared to show
a lower response rate to acid suppression with proton pump inhibitors (PPIs) than did
patients with heartburn and changes of erosive esophagitis [8, 9].
The Three Consensus Meetings, Genval, Montreal and Vevey

With this background, accurate definition of the disease has been considered key to
optimal diagnosis and treatment of patients presenting with reflux symptoms. Con-
sequently a series of consensus workshops has been undertaken to understand the
pathophysiology and implications for diagnosis and treatment strategies. The first of
these was the 1999 Genval Workshop [10], which included international representation
and forms a reference point with respect to the disease definition. The methodology
was based on a critical evaluation of the evidence and this was followed by transla-
tion of this evidence to clinical practice. The consensus recognized the importance of
physiological gastro-esophageal reflux (GER), which is a normal phenomenon and
efficient esophageal clearance mechanisms return most of the refluxed material to the
stomach and symptoms do not occur [11]. However, when reflux volume is large or
aggressive enough, it causes troublesome symptoms and / or complications adversely
affecting quality of life and giving rise to gastro-esophageal reflux disease (GERD). The
consensus did not consider extra-esophageal syndromes. The consensus concluded by
defining the disease as The presence of esophageal mucosal breaks or the occurrence
of reflux induced symptoms severe enough to impair quality of life. Endoscopy
negative reflux patients were recognized as the most common subgroup. There was
emphasis on the effective use of symptom analysis for the initial assessment with
participants concluding that this was a practical and inexpensive approach to diagnosis,
which identified most patients with endoscopically negative disease as well as those
with erosive esophagitis. Moreover, initial symptom assessment should separate
patients with dyspepsia from those with heartburn to determine the primary decision
pathway. Interestingly, sleep disturbance was not considered important.
The consensus concluded that the hierarchy of treatment effectiveness was the same
for initial and long-term treatment but there was little information for endoscopy
negative patients on long-term treatment. The conclusions for treatment in patients
with erosive esophagitis were clear-cut but for the management of patients not endo-
scoped, with endoscopy-negative or mild esophagitis was based more on experience
than on evidence, which was largely lacking.
Importantly, the authors concluded that the Genval workshop had highlighted important
areas for research, which included how symptom patterns could improve management
and minimize costs, critical evaluation of the timing and roles of endoscopy in the
majority of patients with reflux disease. They also advocated development of strategies
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for cost-effective medical and surgical treatments. The thorny question of functional
heartburn was not addressed or even mentioned in this manuscript.
The 2005 Montreal international consensus [12] was organized to provide definition
and classification to assist patients, aid primary care physicians in clinical practice and
embrace the needs of researchers and regulatory agencies. The consensus considered
both esophageal and extra-esophageal syndromes. The consensus defined GERD as a
condition, which develops when the reflux of stomach contents causes troublesome
symptoms and/or complications. They emphasized that in erosive esophagitis, injury
of the esophageal mucosa is endoscopically evident, whereas non-erosive reflux disease
(NERD) is defined by the presence of troublesome reflux-associated symptoms and
the absence of mucosal breaks at endoscopy [12].
The workshop placed considerable emphasis on symptoms and concluded that reflux
symptoms, which are not troublesome should not be diagnosed as GERD and that,
in practice, the patient should determine if their symptoms are troublesome. While
agreeing that GE reflux is the most common cause of heartburn, this consensus noted
that heartburn can have a number of non-reflux related causes but the prevalence of
these was not known. The consensus went further in delineating symptoms related to
reflux including the fact that epigastric pain can be a major symptom of GERD. More-
over, sleep disturbance was discussed extensively and considered more frequent and
relevant than at Genval. Both sleep and nighttime heartburn could be substantially
improved by PPI treatment.
Importantly for this Parma meeting considering extra-digestive GERD, the consensus
concluded that chest pain, which is indistinguishable from cardiac pain can be caused
by GERD and this can occur without heartburn or regurgitation. Esophageal motor
disorders can also cause pain that resembles ischemic cardiac pain separate from
reflux but that reflux is a more frequent cause than esophageal motor disorders.
Heartburn frequency and intensity correlate with the severity of mucosal injury but
neither will accurately predict the severity of injury in the individual patient. There
were lower levels of agreement for the association of chronic cough, chronic laryngitis
and asthma with GERD but more agreement that these conditions are complex and
multifactorial where reflux can be an aggravating factor. Furthermore, there was similarly
modest agreement that in the absence of heartburn or regurgitation unexplained
asthma or laryngitis were unlikely to be related to GERD.
The conclusions of Montreal helped to delineate some of the more specific issues
around symptoms and initiated the recognition of extra-esophageal syndromes. They
also addressed heartburn due to non-reflux related causes but the only use in the
manuscript of the term functional is in relation to functional dyspepsia.
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The Vevey International Consensus [13] focused on non-erosive reflux disease (NERD),
which by then was considered to be the dominant form of reflux disease in the deve-
loped world. NERD was defined as a subcategory of GERD characterized by trouble-
some reflux-related symptoms in the absence of esophageal mucosal erosions/breaks
at conventional endoscopy and without recent acid-suppressive therapy. This definition
was qualified by a further statement based on the discussions on pathobiology and
diagnosis and stated that Evidence in support of this diagnosis includes, but is not
limited to, responsiveness to acid suppression, positive 24h pH monitoring (positive
Symptom Association) or identification of specific novel endoscopic, morphological
or physiological findings.
Important debate centered on the ability of endoscopy to provide objective assess-

ment of mucosal injury. This led to the important qualifying statement (vide supra)
based on the controversial observations of basal cell hyperplasia and papillary elonga-
tion and the dilated intercellular spaces studied by electron microscopy. The consensus
agreed that symptom severity did not allow confident differentiation between NERD
and erosive reflux disease (ERD) and that there is no specific symptom pattern that
reliably predicts the diagnosis of NERD as compared with ERD. The prevalence of
concomitant functional dyspepsia and / or IBS is higher in patients with NERD than
in ERD. This consensus addressed, in contrast to Genval and Montreal, functional
heartburn (FH) emphasizing this is a separate symptom complex which is unrelated to
reflux of gastric contents and is therefore excluded from the definition of NERD [13].
Thus, association of symptoms with reflux episodes is crucial to evaluating pH-metry
and impedance studies in patients with NERD, who are poorly responsive to acid
suppression [13, 14].
All three consensus groups placed emphasis on the importance of symptoms which
was echoed by Sharma et al. [15], who questioned whether clinicians were losing
sight of symptoms by choosing endoscopy as their first step in management rather
than pursuing a careful history. Moreover, characterizing the patient on the basis of
their presenting symptoms rather than the endoscopic findings is the reality in most
healthcare systems. This can provide a practical approach to identifying those patients
whose symptoms are most likely associated with acidic reflux, not related to acid at
all, or some combination.
Hiatus hernia (HH) was only briefly discussed in each of the three consensus meetings. At
Genval it was considered that HH could not be used as a firm criterion for the diagnosis
of reflux disease because it was not consistently associated with this problem [10].
At Montreal [12, 16] it was considered as one risk factor, while at Vevey [13] there was
little evidence to suggest an association and prevalence of HH in NERD, which was
numerically lower than in erosive esophagitis [17].
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Clinical trial design and the impact of the conclusions of the three consensus meetings
were not discussed at Genval, were commented on at Montreal and increasingly con-
sidered for NERD trials at Vevey. However, a clinical trials methodological workshop,
employing a modified Delphi technique, was published in 2008 [18] and the EMA
Guideline for the evaluation of drugs for the treatment of GERD was published in
2011 [19]. These two papers have helped to refine the conduct of recent trials in
reflux disease and improved quality, comparability and also helped frame more critical
regulatory requirements.
Future Perspective
The three consensus publications reflect the evolution of understanding about gastro-
esophageal reflux and the implications for clinical practice. The Vevey consensus was
the first to consider patho-biological mechanisms and serves to highlight areas of
research need. There is increasing availability of novel endoscopic and biopsy based
objective assessments of both structure and function. These include chromo-endo-
scopy, narrow band imaging (NBI), confocal endo-microscopy, electron-microscopy
and pH-impedance recording, etc.
Thus, several important new research directions have evolved over the decade of the
consensus meetings. These include better definition of disease and better trial design,
the impact of reflux on sleep disturbance (rather less of sleep disturbance on reflux),
patterns of reflux and the importance of the volume and extent of both gas and
liquid reflux.
Despite this, there is no universal definition for success in treatment trials in GERD
[20] and, indeed, definitions of treatment failure are controversial with little or no
agreement.
Despite the extensive discussion on symptoms, many simple questions remain. For
example, how should reflux symptoms be evaluated objectively and how should
response to therapy be monitored? Should we focus on healing and maintenance of
healing or on adequate symptom relief? How long should maintenance treatment be
continued to be considered successful?
Diagnosis and management of GERD patients is closely linked to their symptom

response to acid lowering drugs. However, there is no good evidence for a gastric
acid secretory abnormality in GERD and there is no magic to the intra-esophageal
pH 4 threshold in pH-metry evaluation. Acid-mediated reflux symptoms may last
minutes or longer, even when the JohnsonDeMeester score is normal (% time
of pH <4 for >4.2% of the time) [21, 22]. This gives equal weight for solutions of
pH 4 and pH 1 despite a 1000-fold difference in H + concentration. Indeed, pain is
significantly associated with infusion of weakly acidic solutions >pH 4 in patients
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with GERD symptoms [23]. A re-evaluation of these criteria and the concepts will
improve understanding and precision in diagnosis, especially in patients responding
poorly to acid suppression. The combination of pH-metry and impedance measure-
ment are helping to address many of these questions. Moreover, this is also relevant
to a better understanding of the role of pepsin in both esophageal and extra-esophageal
syndromes.
GERD continues to be considered primarily a motor disorder with multiple factors

involved. Impaired LES function, abnormal esophageal clearing and delayed gastric
emptying and the presence of hiatal hernia are all motility abnormalities, which increase
the dwell time of acidic reflux in the distal esophagus [24]. Reflux increases markedly
after meals in both healthy subjects and in patients with GERD, almost exclusively due
to the inappropriate and transient LES relaxations from food-induced gastric accom-
modation. These mechanisms may increase the severity of mucosal damage in GERD
but are not related to functional heartburn (FH), where further studies of autonomic
function in relation to esophageal disease and hypersensitivity are needed.
For the clinician first seeing a patient with reflux symptoms, the challenge is to determine
whether he is experiencing acid-related symptoms or not. This becomes more chal-
lenging with atypical or extra-esophageal symptoms. In any event, most patients will
be started on acid suppression with a PPI. The proportion of patients with sympto-
matic GERD who fail to respond only partially or completely to standard dose PPI is
1040% and more than 50% of reflux patients are dissatisfied with their treatment
[25]. With no accepted definition of treatment success, an important challenge remains
the treatment of patients who fail PPI therapy.
The three consensus meetings together with the clinical trials methodology workshop
and the EMA guidelines have made enormous contributions to clarifying the complex
problem of gastro-esophageal disease, the underlying pathophysiology, symptom
presentation, diagnosis and treatment. However, there remain many unanswered
questions and the time is right to consider a further consensus to address the challenges
of this capricious condition.
References
1) Fass R. Erosive esophagitis and non-erosive reflux disease (NERD): comparison of epidemiologic,
physiologic, and therapeutic characteristics. J Clin Gastroenterol 2007; 41: 131-137.
2) Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease:
a systematic review. Gut 2005; 54: 710-717.
3) Bruley Des Varannes S, Marek L, Humeau B, Lecasble M, Colin R. Gastroesophageal reflux disease
in primary care: prevalence, epidemiology and quality of life of patients. Gastroenterol Clin Biol
2006; 30: 364-370.
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4) Labenz J, Jaspersen D, Kulig M, Leodolter A, Lind T, Meyer-Sabellek W, Stolte M, Vieth M, Willich S,

Malfertheiner P. Risk factors for erosive esophagitis: a multivariate analysis based on the ProGERD
study initiative. Am J Gastroenterol 2004; 99: 1652-1656.
5) Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increased frequency of transient lower esophageal sphincter
relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology
2000; 118: 688-695.
6) Sloan S1, Kahrilas PJ. Impairment of esophageal emptying with hiatal hernia. Gastroenterology 1991;
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7) Barlow WJ, Orlando RC. The pathogenesis of heartburn in non-erosive reflux dis-ease: a unifying
hypothesis. Gastroenterology 2005; 128: 771-778.
8) Tack J, Fass R. Review article: approaches to endoscopic-negative reflux disease: part of the GERD
spectrum or a unique acid related disorder? Aliment Pharmacol Ther 2004; 19 (Suppl 1): 18-34.
9) Weijenborg PW, Cremonini F, Smout AJ, Bredenoord AJ. Poor effectiveness of proton pump
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758-769.
10) Dent J, Brun J, Fendrick AM, Fennerty MB, Janssens J, Kahrillas PJ, Lauritsen K, Reynolds JC, Shaw
M, Talley NJ. An evidence-based appraisal of reflux disease management: the Genval workshop
report. Gut 1999; 44: S1-S16.
11) Kahrilas PJ. GERD pathophysiology: the importance of acid control. Rev Gastroenterol Mex 2003;
68: 14-19.
12) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. Global Consensus Group. The Montreal definition
and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J
Gastroenterol 2006; 101: 1900-1920.
13) Modlin IM, Hunt RH, Malfertheiner P, Moayyedi P, Quigley EM, Tytgat GN, Tack J, Heading RC,
Holtman G, Moss SF; Vevey NERD Consensus Group. Diagnosis and Management of Non-Erosive
Reflux Disease The Vevey NERD Consensus Group. Digestion 2009; 80: 74-88.
14) Scarpignato C. Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth
in the end! Neurogastroenterol Motil 2012; 24: 697-704.
15) Sharma P, Chey W, Hunt R, Laine L, Malfertheiner P, Wani S. Endoscopy of the esophagus in gastro-
esophageal reflux disease: are we losing sight of symptoms? Another perspective. Diseases of the
Esophagus 2009; 22: 461-466.
16) Avidan B, Sonnenberg A, Schnell TG, Chejfec G, Metz A, Sontag SJ. Hiatal hernia size, Barretts
length, and severity of acid reflux are all risk factors for esophageal adenocarcinoma. Am J Gastro-
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17) Sgouros SN, Mpakos D, Rodias M, Vassiliades K, Karakoidas C, Andrikopoulos E, Stefanidis G,
Mantides A. Prevalence and axial length of hiatus hernia in patients, with nonerosive reflux disease:
a prospective study. J Clin Gastroenterol 2007; 41: 814-818.
18) Dent J, Kahrilas PJ, Vakil N, Van Zanten SV, Bytzer P, Delaney B, Haruma K, Hatlebakk J, McColl E,
Moayyedi P, Stanghellini V, Tack J, Vaezi M. Clinical trial design in adult reflux disease: a methodo-
logical workshop. Aliment Pharmacol Ther 2008; 28: 107-126.
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19) EMA Guideline on the evaluation of drugs for the treatment of gastro-oesophageal disease. EMA/
CHMP/EWP/342691/2009 and EMA/131448/2011
20) Sharma P, Wani S, Romero Y, Johnson D, Hamilton F. Racial and geographic issues in gastro-
esophageal reflux disease. Am J Gastroenterol 2008; 103: 2669-2680.
21) Johnson LF, Demeester TR. Twenty-four-hour pH-monitoring of the distal esophagus. A quantitative
measure of gastroesophageal reflux. Am J Gastroenterol 1974; 62: 325-332.
22) Hunt R. Acid suppression for reflux disease: off-the-peg or a tailored approach? Clin Gastroenterol
Hepatol 2012; 10: 210-213.
23) Smith JL, Opekun AR, Larkai E, Graham DY. Sensitivity of the esophageal mucosa to pH in gastro-
esophageal reflux disease. Gastroenterology 1989; 96: 683-689.
24) Boeckxstaens GE, Rohof WO. Pathophysiology of gastroesophageal reflux disease. Gastroenterol
Clin North Am 2014; 43: 15-25.
25) Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009;
58: 295-309.
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10:00 Epidemiology of Extra-digestive GERD

Lars Erik Agrus, MD, PhD, AGAF
Professor and Chair,
Center for Family and Community Medicine,
Department of Neurobiology,
Care Sciences and Society,
Karolinska Institutet, Stockholm, Sweden
Lars Erik Agrus The extra-digestive GERD conditions have been classified by the
Montreal definition [1]. In this State of the Art publication from
2006, the extra-digestive GERD conditions are divided into:
Established conditions Proposed conditions

Reflux Cough Syndrome Pharyngitis
Reflux Laryngitis Syndrome Sinusitis
Reflux Asthma Syndrome Idiopathic Pulmonary Fibrosis
Reflux Dental Erosion Syndrome Recurrent Otitis Media
There area also some Non-Montreal proposed conditions in the literature, e.g.
Non Cardiac Chest Pain

Globus
Pneumonia
Idiopathic pulmonary fibrosis
Sleep disorders
The Spectrum of GERD

In order to understand if extra-digestive symptoms or diseases are caused by or as-
sociated with GERD, it is important to understand the spectrum GERD. GERD may
progress from gastresophageal reflux symptoms (GERS) without histological change
(probably true functional GERD), non-erosive reflux disease (NERD) as seen by only
histological change, and to endoscopically detectable erosive esophagitis (EE). GERD
may also progress to a (distal) columnar lined esophagus, called Barretts esophagus
(BE), and to esophageal adenocarcinoma (EA). The spectrum of GERD is shown in
(Figure 1).
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GERD
% with
Reflux Symptoms 100% ?%* 70% 60% 60%
(GERD)
Esophagitis Barretts Adeno

Normal histo cancer
Functional Non-erosive Erosive
microscopic visible
NERD
Non Erosive Reflux Disease
Figure 1: Spectrum of GERD. Proportions of subject with reflux symptoms at different stages
of distal esophageal pathology.
*not known in the population
The extra-digestive GERD conditions can occur with or without concomitant GERS,
and with or without EE or BE visible on an upper endoscopy. GERS per se occurs in
25-40% of the adult general population, and GERS is often fluctuating [2-4]. It is to
be pointed out from an epidemiological point of view that in population based studies
esophagitis might very well be asymptomatic. In a study from Northern Sweden, the
Kalixanda Study [5], about a quarter of those with GERS had an EE, and that among
those with an EE about a third had no GERS! An Italian population based study [4]
showed approximately the same patterns. In both studies only about 55% those with
Barretts esophagus reported GERS. What complicates the estimation of the epide-
miology/prevalence of extra-digestive GERD is that most of the time histology from
the esophagus is not available, and when it is, there is no consensus on how an histo-
logical NERD shall be defined. If 24 h. pH-monitoring in the esophagus was used in
epidmiology it would probably the best way to define acid dependent GERD/GERS/
extra-digestive GERD, but it is not. This also reflects that a PPI response to GERS and/
or the supposed GERS associated extra-digestive symptoms/diseases often is required.
However, as there most probably is an association at least in some extent wit true
functional heartburn, with doubtful association with both 24 h pH-monitoring and
PPI response, the reality is even more problematic, both from an epidemiological and
clinical point of view. An overview of the literature is shown in Table 1.
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Table 1: Overview of prevalence and association in the adult population or in

patients with atypical GERD symptoms or diseases versus GERS/GERD
Symptom/disease Proposed cause or association with GERD Reference

Cough 10-41% [7, 8]
Asthma/COPD GERS 59% (range 45.0-71.0%), [12]
Abnormal 24 h Ph: 51% (range 14.8-81.8%)
Laryngitis No significant outcomes [16]

Dental erosions 32.5% (range 21-83% [17]
Proposed Significantly associated atypical symptoms in the
Montral and population 14.8-67.7%. [18]
non-Montral No solid prevalence data on objective
disorders measurements except for non-cardiac chest pain
with 40-50% having abnormal 24 h Ph [7]
Established conditions
Cough
Cough is one of the most prevalent symptoms, but when defined as a disease it
should persist for 8 weeks. On the basis of epidemiological data from cohort studies
it has been estimated that chronic unspecific cough is common [6]. GERD is supposed
to be the third common cause of chronic cough (after asthma and postnasal drip) [7],
estimated to be associated in 1041% of the cases [7, 8]. Interestingly, in one study as
many as 64% of the patients with presumed reflux cough based on esophageal func-
tion testing (esophageal manometry and/or 24 h esophageal pH-monitoring) did not
complain of any typical reflux symptoms [9]. In another study on patients in specialist
care with cough or asthma with a clinical suspicion (not specified) of causally related
GERD, 78% had a pathological proximal and/or distal 24 h pH-monitoring, with no
significant difference between proximal and distal monitoring, but with 67% having a
pathological proximal (only 12%, combined 55%) measuring [10]. In a Cochrane report
on pooled data from five studies in adults, a PPI course to treat cough associated with
GERD has some effect: number needed to treat (NNT) was 5 [11].
Asthma/COPD
In a systemic review on 28 studies, the prevalence of GERD symptoms in asthma
patients was 59% (range 45-71%), while in controls it was 38%. In patients with
asthma, the average prevalence of abnormal esophageal pH, esophagitis and hiatus
hernia was 50.9% (range 14.8-81.8%), 37.3% (range 27.8-47.48%) and 51.2%
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(range 37.1-61.7%), respectively. On the other hand, the prevalence of asthma in

GERD patients was 4.6%, compared to 3.9% in the controls. Overall the pooled odds
ratio for asthma patients having GERD symptoms was 5.5 (95% CI 1.915.8), and 2.3
(95% CI 1.82.8) for GERD patients having asthma. However, the review shed doubts
on the aetiology: One longitudinal study showed a significant association between
a diagnosis of asthma and a subsequent diagnosis of GERD (relative risk 1.5; 95%
CI 1.21.8), whereas two studies, which assessed whether GERD precedes asthma,
gave inconsistent results [12]. One third of asthma patients with GERS have no other
GERD related symptoms [10]. Some asthma drugs may also be potentially harmful for
GERD [13]. Presently data fail to confirm that acid (or other compounds like bile etc.)
in the esophagus exerts a direct influence on bronchopulmonary function, while it
may increase bronchial hyper-reaction [14]. Maybe the concept of functional heart-
burn co-exists with bronchial hyper-reactability, but studies on the epidemiology of
this concept are to my knowledge lacking. An association with COPD has though also
been proposed [6].
Laryngitis
There are studies showing that reflux esophagitis and hiatus hernia is associated with
laryngopharyngeal reflux (LR) [6, 15], but in a systematic review on 11 studies, the
prevalence of LR events was compared between normal controls and patients with
laryngitis by means of 24-hour double-probe (pharyngeal and esophageal) pH-monito-
ring in patients with symptoms and/or signs of reflux laryngitis. There was no significant
difference between the groups (p = 0.079). Only a minority of patients with clinical
reflux laryngitis showed LR events, and there was no significant difference between
patients with reflux laryngitis and healthy controls [16]. Moreover, most studies on
acid suppression drugs versus placebo have failed to show any difference, but the
quality of the studies can be discussed from different views.
Dental Erosions
Dental erosions (DE) seem to be associated with GERD. In a meta-analysis on 17 studies,
the median prevalence of GERD in DE adult patients was 32.5%. (range: 21-83%),
and the median prevalence of DE in GERD patients was 24%, with a large range
(5-47.5%) [17].
Proposed Montral and non-Montral Disorders

Epidemiological data on the conditions proposed by the Montreal group to be associa-
ted with GERD, and the proposed non-Montral disorders are scarce. In a population
based study on 2200 Olmsted County residents, there was a significant association
between GERD symptoms (prevalence in the population 19.8%, 95% CI 17.7-21.9%)
and non-cardiac chest pain (23% in the population, 67.7% of them having frequent
or infrequent GERS), dysphagia (13.5%, 47.6%, having GERS), globus sensation
(7.0%, 22.9% having GERS), bronchitis (14%, 37.4% having GERS) and hoarseness
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(14.8, 38.5% having GERS) (all p<0.01), but not to asthma or pneumonia [18]. A
review [7] stated that 40-50% of those with non-cardiac chest pain had a pathological
24 h pH-monitoring. The eventual association with sinusitis, otalgia, otitis media and
other otolaryngeal disorders is discussed in reviews by Malfertheiner et al. and Rathod
[6, 7]. The latter conclude that at least 25% of patients with GERD also present oto-
laryngeal symptoms or diseases. Rathod [7] made a short literature review on GERD
and idiopathic pulmonary fibrosis also indicating an association. Due to small studies,
sometime only case reports, the data are not conclusive. An exception is sleep disor-
ders, where in a systematic literature review of 22 trials on symptomatic GERD the
mean prevalence of nocturnal heartburn was 54% (SD+/- 22%), affecting quality of
life both at night and in daytime. The effect of PPI treatment confirmed the aetiology
[19]. The effect on sleep has also been pointed out in the review by Malfertheiner et al.
[6], where 50-80% of those with GERD symptoms are affected in one way or the
other.
References
1) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of
gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;
101: 1900-1920.
2) Agrus L, Svrdsudd K, Talley NJ, Jones MP, Tibblin G. Natural history of gastroesophageal reflux
disease and functional abdominal disorders: a population-based study. Am J Gastroenterol 2001;
96: 2905-2914.
3) Ronkainen J, Aro P, Storskrubb T, Lind T, Bolling-Sternevald E, Junghard O, Talley NJ, Agrus L.
Gastro-oesophageal reflux symptoms and health-related quality of life in the adult general popu-
lation the Kalixanda study. Aliment Pharmacol Ther 2006; 23: 1725-1733.
4) Zagari RM, Fuccio L, Wallander MA, Johansson S, Fiocca R, Casanova S, Farahmand BY, Winchester CC,
Roda E, Bazzoli F. Gastro-oesophageal reflux symptoms, oesophagitis and Barretts oesophagus in
the general population: the Loiano-Monghidoro study. Gut 2008; 57: 1354-1359.
5) Ronkainen J, Aro P, Storskrubb T, Johansson SE, Lind T, Bolling-Sternevald E, Graffner H, Vieth M,
Stolte M, Engstrand L, Talley NJ, Agrus L. High prevalence of gastroesophageal reflux symptoms
and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda
study report. Scand J Gastroenterol 2005; 40: 275-285.
6) Malfertheiner P, Hallerback B. Clinical manifestations and complications of gastroesophageal reflux
disease (GERD). Int J Clin Pract 2005; 59: 346-355.
7) Rathod NR. Extra-oesophageal presentation of gastro-oesophageal reflux disease. J Indian Med
Assoc 2010; 108: 18-20.
8) Morice AH. Epidemiology of cough. Pulm Pharmacol Ther 2002; 15: 253-259.
9) Everett CF, Morice AH. Clinical history in gastroesophageal cough. Respir Med 2007; 101: 345-348.
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10) Schnatz PF, Castell JA, Castell DO. Pulmonary symptoms associated with gastroesophageal reflux:
use of ambulatory pH-monitoring to diagnose and to direct therapy. Am J Gastroenterol 1996; 91:
1715-1718.
11) Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gastro-oesophageal reflux treatment
for prolonged non-specific cough in children and adults. Cochrane Database Syst Rev 2006; 18:
CD004823.
12) Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux
disease and asthma: a systematic review. Gut 2007; 56: 1654-1664.
13) Labenz J. Facts and fantasies in extra-oesophageal symptoms in GORD. Best Pract Res Clin Gastro-
enterol 2010; 24: 893-904.
14) Galmiche JP, Zerbib F, Bruley des Varannes S. Review article: respiratory manifestations of gastro-
oesophageal reflux disease. Aliment Pharmacol Ther 2008; 27: 449-464.
15) Lai YC, Wang PC, Lin JC. Laryngopharyngeal reflux in patients with reflux esophagitis. World J
Gastroenterol. 2008; 14: 4523-4528.
16) Joniau S, Bradshaw A, Esterman A, Carney AS. Reflux and laryngitis: a systematic review. Otolaryngol
Head Neck Surg 2007; 136: 686-692.
17) Pace F, Pallotta S, Tonini M, Vakil N, Bianchi Porro G. Systematic review: gastro-oesophageal reflux
disease and dental lesions. Aliment Pharmacol Ther 2008; 27: 1179-1186.
18) Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton III LJ. Prevalence and clinical spectrum of gastro-
esophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology
1997; 112: 1448-1456.
19) Gerson LB, Fass R. A systematic review of the definitions, prevalence, and response to treatment
of nocturnal gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2009; 7: 372-378.
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10:30 Typical versus Atypical GERD:

Similarities and Differences
Robert C. Heading, MB ChB, MD, FRCP (Lond),
FRCP (Ed)
Honorary Clinical Professor of Medicine, School of Medicine,
Pharmacy and Health, Durham University, UK
If heartburn and regurgitation are considered to represent typical

Robert C. Heading gastro-esophageal reflux disease (GERD), atypical patients are
those with sore throat, globus, hoarseness, throat clearing, un-
explained cough or asthma. This categorisation and the difficulties
it creates are of course man-made, arising from our wish to classify patients and
their diseases. Typical and atypical GERD are the concepts of physicians rather than
fundamental biological differences and the relationships between typical and atypical,
common and uncommon, can change over time. For example, esophagitis was
common before acid suppressing drugs became available but today is relatively rare.
Rarity does not equate with atypical, however.
Heartburn and regurgitation are the symptoms of typical GERD. Regrettably, however,
our ability to diagnose GERD clinically in patients with upper GI symptoms is far from
perfect: it has a sensitivity and specificity no greater than 60 70% [1]. The accuracy
of a GERD clinical diagnosis in the atypical patients remains uncertain, because the
accuracy of available reference tests such pH recording, endoscopy, impedance mea-
surement and others is unquantified. However, it is clear that extra-esophageal
symptoms are common among patients presenting with typical GERD symptoms [2]
and, with the possible exception of asthma, are more frequent than in controls [3].
Conversely, increased esophageal acid exposure is common in patients presenting
with extra-esophageal reflux (EER) symptoms, irrespective of whether they have con-
current heartburn or regurgitation [4]. Consequently, the obvious inference is that
direct contact between refluxate and the airway mucosa is the cause of the EER
symptoms but of course neither the association of heartburn and EER symptoms nor
the association of abnormal acid exposure with EER symptoms proves conclusively
that gastro-esophageal reflux is the cause of these symptoms. In this context, the
occurrence of abdominal symptoms, notably dyspepsia and irritable bowel syndrome
(IBS), in patients with typical GERD must be considered, given that these occur more
often than may be explained by chance. Is dyspepsia in GERD patients a simple con-
sequence of contact between refluxate and the distal esophageal mucosa or is the
mechanism of symptom generation more complex? It is hard to understand how
IBS symptoms can be explained as a direct consequence of esophageal contact with
gastric acid. Thus there is a need to consider how visceral hypersensitivity or psycholo-
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gical factors such as anxiety may contribute to the perception of heartburn, dyspepsia
and IBS. Both have undoubted relevance to the perception of classical reflux symptoms
and possibly to perception of atypical reflux symptoms also. Observed associations of
typical GERD symptoms with EER symptoms might thus be explained without implica-
ting direct contact of refluxate with airway mucosa to explain the latter.
Consideration of visceral sensory processes immediately highlights the potential

relevance of reflexes with afferent inputs triggered by gastro-esophageal reflux.
Abnormality of cardiac vagal reflexes in GERD has been recognised for many years
[5] and vagally mediated reflexes initiated by acid in the esophagus are thought to
explain broncho-constriction, increased airway sensitivity to histamine and decreased
airway response to methacholine in asthmatics [6-8]. There is also evidence that
autonomic reflexes may mediate an increased liability to cardiac arrthymias in some
GERD patients and that the occurrence of some arrhythmias may be reduced by GERD
treatment [9-11]. These observations invite revision of some of the established ideas
of typical and atypical GERD so as to focus on the fact that a core aspect of the
pathophysiology of GERD is that neural mechanisms give rise to potentially variable
perception of symptoms ranging from classic retrosternal heartburn through non-
cardiac chest pain to sore throat. The same neural mechanisms may also reflexly influence
other physiological processes including airway constriction, cardiac rhythm and bowel
function. While direct contact between refluxate and the tissue is the obvious expla-
nation for tissue damage, such as esophageal mucosal erosion or erosion of dental
enamel, the extent to which neural modulation of sensory processes affects the
perception of various symptoms is unclear. Some patients with abnormal acid reflux
experience no heartburn whereas others with troublesome heartburn have a normal
magnitude of gastro-esophageal acid reflux. At present we do not know the extent
to which neural mechanisms responding to refluxate in the lower esophagus contribute
to EER symptoms.
For these reasons, therefore, the categorisation of GERD into typical and atypical is
possibly a flawed concept. Typical and atypical GERD are of course both encompassed
by the Montreal assertion that the term GERD is appropriate when troublesome
symptoms or complications are attributable to gastro-esophageal reflux. All manife-
stations of GERD arise directly or indirectly from contact between refluxate and the
esophagus, oro-pharynx or airway. All symptomatic manifestations are nevertheless
influenced by sensory processes and some manifestations are reflex responses to those
sensory processes.
Diagnostic Issues
There is general agreement that a clinical diagnosis of GERD will be correct in most
patients presenting with heartburn and acid regurgitation. Correct in this context
is founded on the fact that some such patients have esophagitis observable at
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endoscopy and some have excess esophageal acid exposure, perhaps with a positive
symptom-reflux correlation demonstrable on ambulatory pH-recording. However the
words to which attention should be drawn here are that the diagnosis is likely to be
correct. It is accepted that not every patient with heartburn has reflux disease: the
entity functional heartburn is now acknowledged.
For patients with typical GERD, tests may be sometimes be desirable to confirm
the diagnosis. Endoscopy is usually undertaken first because of the diagnostic utility
of finding esophagitis, even though esophagitis is nowadays found in less than one
third of patients with heartburn who are not on medication [12]. Ambulatory pH
monitoring, possibly with measurement of SI or SAP, may be helpful and impedance
monitoring may be undertaken, especially in a patient who is still symptomatic on acid
suppressing medication. Not surprisingly, all these procedures are best documented
in the context of typical reflux symptoms, though the reliability of SI and SAP measu-
rements both in pH and impedance recording remains disturbingly uncertain [13].
For patients with EER symptoms, reliable confirmatory tests are few. Esophagitis
would certainly establish a GERD diagnosis but is uncommon in patients presenting
with EER symptoms and the interpretation of findings at laryngeal endoscopy is con-
strained by the fact that observed abnormalities correlate poorly with esophageal
and pharyngeal pH recordings. As noted above, there is an association between EER
symptoms and increased esophageal acid exposure but this does not prove cause
and effect. Although classical heartburn may be attributed to gastro-esophageal
reflux when a convincing temporal coincidence of heartburn episodes and reflux
events is demonstrated, temporal correlation of symptoms and reflux events cannot
be sought for symptoms such as sore throat or hoarseness. In theory, a correlation
might be demonstrable for chronic cough but it is unreliable in practice unless acou-
stical detection of coughing is undertaken [14].
Thus so far as diagnostic issues are concerned, the differences between typical and
atypical GERD are differences of degree. In some cases of typical reflux, a clinical
diagnosis can be made with fair accuracy on the basis of symptoms alone whereas this
is less frequent in most cases of atypical GERD. Confirmatory tests can be conclusive
in typical GERD; less often so in atypical GERD.
Therapeutic Issues
The PPI test as a means of confirming a GERD diagnosis is now considered to be of
little value, being no better than clinical diagnosis made in the conventional way [1].
Empirical treatment with a PPI is widely accepted for typical uncomplicated GERD
symptoms and empirical treatment using twice daily PPI symptoms is often recom-
mended for EER symptoms. The fact that almost all controlled clinical trials of PPI
therapy both for classical reflux symptoms and for EER symptoms show symptom
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reduction in the patients given placebo makes interpretation of symptom response to

a PPI in an individual patient hard to interpret.
An important similarity of typical and atypical GERD symptoms lies in this difficulty
of assessing response to therapy, especially in the individual patient seen in clinical
practice. The question of what constitutes a good therapeutic response in not yet one
for which an easy answer can be given. In the typical GERD patient, for example, not
only does the symptom of regurgitation respond notably less well than heartburn
to a PPI [15], representing a potential cause for an incomplete therapeutic response,
but because the overall symptom burden of the typical GERD patient is much wider
than just heartburn and regurgitation. Full symptom control is not achieved in some
35% of patients after 8 weeks of a PPI [16] and continuing symptoms despite the PPI
are a real problem in the longer term [17]. For atypical GERD, there is still controversy
about the efficacy of PPI therapy, arising in part from the fact that the best recognized
measure of EER symptoms, the Reflux Symptom Index (RSI), includes an assessment
of heartburn. Some patients with EER symptoms have heartburn too, so there is the
possibility that use of the RSI to study the effect of therapy in a clinical trial will show
an active drug is better than placebo simply because the active drug successfully alle-
viates heartburn. Similar conflating of symptom improvements will be true in everyday
clinical practice, given that many patients with EER symptoms also have heartburn.
The close association of typical GERD symptoms with other abdominal symptoms
and with the EER symptoms is reflected in many studies of therapy. For example, the
symptom response of GERD patients that has been documented with the ReQuest
questionnaire has shown that bowel symptoms improve on PPI treatment, albeit to a
lesser extent than the classical reflux symptoms [18]. Similarly, patients who experience
both typical reflux symptoms and laryngeal symptoms or cough show improvement
in both the typical symptoms and the EER symptoms on PPI therapy: interestingly, it
is the patients with the most severe typical symptoms before treatment that gain the
least improvement in EER symptoms on the PPI [19].
Thus describing reflux symptoms as typical or atypical is simply a product of our

expectations that in some respects is at variance with reality. Figure 1 shows the
percentage of patients with endoscopic esophagitis or Barretts esophagus who
reported each of the symptoms specified in response to specific enquiry, together with
the frequency of the symptoms similarly reported by control subjects. Estimates of the
frequency with which gastroenterologists believed these same symptoms occurred in
their own GERD patients are also shown. From the standard deviations, it is apparent
that gastroenterologists varied considerably in their estimates of the frequency with
which some symptoms occurred. Overall, they tended to overestimate the occurrence
of heartburn and, to a lesser degree, regurgitation in GERD and to underestimate
bloating, early post-prandial fullness and poor appetite. Interestingly, the gastroente-
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rologists tended to overestimate the occurrence of globus and hoarseness but under-
estimate some other EER symptoms in these patients. The main message to be taken
from the figure, however, is that typical and atypical reflux symptoms very often
co-exist.

heartburn
Heartburn
stomach acid
Stomach acid coming
coming up up
regurgitaion
Regurgitation
indigesion
Indigestion
acid/sour taste
Acid/sour taste inin mouth
mouth
belching
Belching
pressure in
Pressure in chest
chest
Diffi diculty swallowing food
culty swallowing food
nausea
Nausea
pressure/lump in
Pressure/lump in throat
throat
vomiing
Vomiting
atulence
Flatulence
bloaing
Bloating
Rush rush of
of saliva
saliva into
into mouth
mouth
feeling ofof things
Feeling things stuck
stuck in in throat
throat
Coughing coughing when when lying
lying down
down
gurgling stomach
Gurgling stomach
Bad breath heartburn
bad breath
stomach
pain in
Pain tahroat
cid coming
in throat up
hoarseness
Hoarseness regurgitaion
fullness too
Fullness too early
early after
ajer eating
eaing indigesion

acid/sour taste in
wheezing
Wheezing mouth
Diffidiculty swallowing liquids
culty swallowing liquids belching
pressure in chest
choking
Choking
diculty swallowing
throat clearing
Throat clearing food
coughing when
Coughing when eating eaing nausea
pressure/lump
hiccups in throat
Hiccups
decreased appetite
Decreased appeite vomiing
diculty
Diffi breathing atulence
culty breathing
coughing when
Coughing upright bloaing
when upright
rush of saliva
excess
Excess mucus
mucus into mouth
feeling of things
back spain
Back ptuck
ain in throat
mucus dripping
Mucus coughing
dripping down wthroat
down then
hroat lying
down
gurgling stomach
headache
Headache
bad breath
00
pain in throat
20
20 40
40 60
60 80
80 100
100
hoarseness
fullness too early ajer eaing
Figure
Fig 1: Percentages
1. Percentages of 1of 100
00 heartburn control
wheezing
control subjects
subjects ( ) ( and
) and of 1of
36 136 patients
patients with
with esophagitisoor
oesophagitis r
Barretts
esophagus diculty
stomach ( as)wallowing
reporting
cid coming liquids uthe p symptoms indicated and estimated percentage
Barretts
of GERD patients experiencing o esophagus ( ) r eporting
regurgitaion choking
each t he s ymptoms i ndicated
symptom given by 259 gastroenterologists (mean + 1 SD)
(from Drinnan et al. [20]). throat indigesion clearing

and coughing
acid/sour taste w in hen
mouth eaing
belching hiccups
decreased
pressure in cao ppeite
hest
estimated percentage f GERD patients experiencing each symptom given by 259
30 PRESIDENTS Carmelo diculty sdiculty
wallowing
Scarpignato, bMD, reathing
food DSc, PharmD, MPH (Parma, Italy) Francesco Di Mario, MD (Parma, Italy)
gastroenterologists
( mean
coughing when + 1
nausea S D).
upright
pressure/lump excess
in throat mucus
back pain
vomiing

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ablation in patients with gastroesophageal reflux disease or irritable bowel syndrome-the heart to
gut connection! J Interv Card Electrophysiol 2013; 37: 259-265.
12) Poh CH, Gasiorowska A, Navarro-Rodriguez T, Willis MR, Hargadon D, Noelck N, Mohler J, Wendel CS,
Fass R. Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treat-
ment failed versus those not receiving antireflux treatment. Gastrointest Endosc 2010; 71: 28-34.
13) Slaughter JC, Goutte M, Rymer JA, Oranu AC, Schneider JA, Garrett CG, Hagaman D, Vaezi MF.
Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastro-
esophageal reflux disease. Clin Gastroenterol Hepatol 2011; 9: 868-874.
14) Kavitt RT, Higginbotham T, Slaughter JC, Patel D, Yuksel ES, Lominadze Z, Abou-Ismail A, Pasricha
T, Garrett CG, Hagaman D, Vaezi MF. Symptom reports are not reliable during ambulatory reflux
monitoring. Am J Gastroenterol 2012; 107: 1826-1832.
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15) Kahrilas P, Howden C, Hughes N. Response of regurgitation in proton pump inhibitor therapy in
clinical trials of gastroesophageal reflux disease. Am J Gastroenterol 2011; 106: 1419-1425.
16) Heading R, Mnnikes H, Tholen A, Schmitt H. Prediction of response to PPI therapy and factors
influencing treatment outcome in patients with GORD: a prospective pragmatic trial using panto-
prazole. BMC Gastroenterol 2011; 11: 52.
17) El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump
inhibitor therapy in primary care and community studies. Pharmacol Ther 2010; 32: 720-737.
18) Bardhan K, Stanghellini V, Armstrong D, Berghofer P, Gatz G, Monnikes H. Evaluation of GERD
symptoms during therapy. Digestion 2004; 69: 229-237.
19) Jaspersen D, Labenz J, Willich SN, Kulig M, Nocon M, Leodolter A, Lind T, Meyer-Sabellek W, Vieth M,
Stolte M, Malfertheiner P. Long-term clinical course of extra-oesophageal manifestations in
patients with gastro-oesophageal reflux disease. A prospective follow-up analysis based on the
ProGERD study. Dig Liver Dis 2006; 38: 233-238.
20) Drinnan M, Powell J, Nikkar-Esfahani A, Heading RC, Doyle J, Griffin SM, Leslie P, Bradley PT,
James P, Wilson JA. Gastroesophageal and extraesophageal reflux symptoms: Similarities and
differences. Laryngoscope 2015; 125: 424-430.
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SESSION II:
NEW DIAGNOSTIC MODALITIES
CHAIRED BY:
Gerardo Nardone, MD
Federico II University, Naples
Director, Division of Gastrointestinal Oncology,
Department of Clinical and Experimental Medicine,
University Hospital of Naples, Italy
Gerardo Nardone
Vincenzo Savarino, MD
Chairman, Department of Internal Medicine,
President, Italian Society of Gastroenterology (SIGE)
Vincenzo Savarino
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11:30 Pepsin Detection in Digestive and Respiratory Fluids:

An Update
Peter W. Dettmar, PhD, CBiol, FSB, FRSPH
Honorary Professor of Pharmaceutics,
University of Nottingham and Managing Director,
RD Biomed Ltd, Castle Hill Hospital, Kingston Upon Hull, UK
Introduction
Peter W. Dettmar PeptestTM is the Worlds first non-invasive test for reflux. PeptestTM
is a rapid diagnostic test that utilises two unique monoclonal anti-
bodies to human pepsin 3. It is designed to be used by a medical
professional to objectively identify the presence of pepsin in the saliva of a patient
with suspected reflux disease as pepsin has become well established as a good clinical
marker for recent prior reflux.
Pepsin
Pepsin is a digestive enzyme secreted in the stomach by chief cells and is responsible
for the initial crude digestion of protein in the diet within the stomach. Pepsin is an
aspartic proteinase and is the major enzyme in gastric juice and the concentration in
the stomach can reach 1 mg/ml [1]. Pepsin is secreted as the precursor pepsinogen
and there are several pepsin isoforms (1, 3a, 3b, 3c and 5) of which pepsin 3b accounts
for 70% [2-4]. Each pepsin isoenzyme has its own optimal pH range when its action
is at a maximum, thus ensuring digestion across a wide range of gastric pH [3, 5].
However the pH profile is substrate dependent and it is important to be aware that
pepsin remains active up to pH 6.5 and is not irreversibly denatured until pH 8.0 [6, 7].
It is clear that pepsin is a damaging component of the gastric refluxate. It is a large
protein (34500 Da) that is structurally unchanged over the pH range of reflux. That is
in direct contrast with acidity since H + is the smallest biological entity and it is readily
neutralised by bicarbonate and food. The detection of pepsin as a marker for reflux
would appear to be more appropriate marker than pH.
There is an extensive scientific and clinical literature describing the role of pepsin in
esophageal damage [8-11] and laryngeal damage [12, 13] and pepsin plays a key role
in the aetiology and pathology of GERD [3, 14, 15].
PeptestTM
PeptestTM (www.peptest.co.uk) is specific for human pepsin 3 but due to high homo-
geneity of amino acid structure there is some cross reactivity to human pepsin 1 and
porcine pepsin A. There is very little cross reactivity to pepsin 5 (gastricsin). PeptestTM is
sensitive down to 16 ng/ml with a maximal quantifiable limit of 500 ng/ml. PeptestTM
WHATS NEXT ?
provides a visual result as to the presence or absence of pepsin within 5 minutes and
with digital quantification the level of pepsin can be quantified within 15 minutes.
Clinical Evaluation
A number of clinical evaluation studies are ongoing or have recently been completed
with the current marketed version of PeptestTM . These studies have generated many
conference abstracts [16-25] and a recent full peer-reviewed article [26]. Two studies
will be discussed in detail here, the published study by Hayat et al. (2014) [26] and a re-
cently completed clinical study performed in GERD and patients with laryngopharyngeal
reflux (LPR). Brief discussion of small studies in respiratory disease will also be discussed.
Control Subjects
The recent published study is the optimal investigation of true controls and the extent
of pepsin found in saliva generally [26]. Data was obtained for 87 healthy asympto-
matic controls that underwent multichannel intraluminal impedance pH-monitoring
(MII-pH) and were confirmed to not have abnormal levels of reflux. Each subject pro-
vided three saliva samples (on waking, 1 hr after lunch and 1 hr after evening meal)
whilst they were being assessed by MII-pH. Out of the 87 healthy controls 37.9%
exhibited at least 1 positive PeptestTM result.
Figure 1 and Table 1 show additional interpretation of the healthy population control
data.
35
mean (95% CI) pepsin [ng/ml]
30
25
20
15
10
5
0

waking after lunch after dinner
time
Figure 1: Pepsin concentration measured by PeptestTM in 87 healthy asymptomatic controls that

provided 3 saliva samples at defined times. Data are mean ( 95% CI).
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Table 1: Pepsin prevalence and mean pepsin concentration in 87 healthy control

subjects by sample time and as a whole
Time N. Positive % Positive Mean Pepsin

Subjects/Total (ng/ml)
Waking 13/87 14.9% 10.6
After lunch 24/87 27.6% 22.3
After dinner 20/87 23.0% 18.0
Total 33/87 37.9% 17.0
(subjects at least 1 positive sample)
There was a distinction between the morning/waking samples and postprandial samples
and so the normal range for the two time points was determined based on 95% CI
of the mean. In the morning 95% CI was 3-18 ng/ml and in the postprandial period
95% CI was 13-27 ng/ml. Therefore the normal level of pepsin in saliva is 27 ng/ml
which is represented by only a faint line on the PeptestTM device.
Gastro-esophageal Reflux Disease (GERD)

GERD (and Hypersensitive Esophagus) patients were recruited into the study descri-
bed by Hayat et al. [26 ] confirmed to have GERD symptoms and MII-pH documented
reflux. There was a total of 84 patients in this population. Each patient provided three
saliva samples (on waking, 1 hr after lunch and 1 hr after evening meal) whilst they
were being assessed by MII-pH. Table 2 shows our additional interpretation of the
GERD data.
Table 2: Pepsin prevalence and mean pepsin concentration in 82 GERD subjects

by sample time and as a whole
Time N. Positive % Positive Mean Pepsin

Subjects/Total (ng/ml)
Waking 16/80 20.0% 28.6
After lunch 53/82 64.6% 112.8
After dinner 47/82 57.3% 108.9
Total 65/82 79.3% 83.9
(subjects at least 1 positive sample)
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In a recent study GERD patients were recruited at Rotherham General Hospital Endo-
scopy clinic with GERD symptoms and scoring 8 on the GERDQ questionnaire [27]
or either exhibiting erosive esophagitis. Each patient provided saliva samples with 3
different protocols (single at anytime, every 2 hours, or at set times). The final analysis
included 59 GERD patients comprising 283 samples (ranging from 1-10 samples per
patient). 79.7% of GERD patients had a least 1 positive sample with a mean pepsin
concentration of 94.4 ng/ml. This data was very comparable to the published data of
Hayat et al. [26] and statistical analysis showed that there was no significant differences
between the 2 studies (all data, t-test P=0.6647). Therefore the GERD data from both
studies was combined (total 141 GERD patients).
GERDwas
samples were
low on collated
first waking according
in GORD to definable
patients but time
high points. These included
postprandially, on and when
at bedtime
waking, 1 hour after meals, at bedtime and also when symptomatic. The concentra-
symptomatic (Figure 2).
tion of pepsin was low on first waking in GERD patients but high postprandially, at
bedtime and when symptomatic (Figure 2).

GORD (n=141)
GERD (n=141)
500
500
400
400
Pepsin [ng/ml]
Pepsin [ng/ml]
300
300
200
200
100
100
0 0

waking
waking PP
PP bedtime
bedtime symptoms
symptoms all
Figure 2: Pepsin concentration measured by Peptest in 141 GORD patients that provided
Figure 2: Pepsin
saliva samples at defined
concentration times. by
measured Data
Peptestare TMraw
in 141 data
GERD + mpatients
ean. Pthat
P = provided
postprandial
saliva
samples at defined times. Data are raw data + mean. PP = postprandial

Laryngopharyngeal Reflux
Laryngopharyngeal
Patients diagnosed with LPR were Reflux (LPR) from ENT clinics at Rotherham General
recruited
Hospital and Voice clinics at Queens Medical
Patients diagnosed with LPR were recruited Centre,
from Nottingham
ENT clinics aift they scored G
Rotherham 14
eneral Hospital
on the RSI questionnaire [28]. Each patient provided saliva samples with 3 different
and Voice clinics at Queens Medical Centre, Nottingham if they scored 14 on the RSI
protocols (single at anytime,
28
every 2 hours, or at set times).
questionnaire . Each patient provided saliva samples with 3 different protocols (single at
anytime, every 2 hours, or at set times).
The final analysis included 77 LPR patients comprising 336 samples (ranging from 1-9
samples per patient). 89.6% of LPR patients had a least 1 positive sample with a mean
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The final analysis included 77 LPR patients comprising 336 samples (ranging from 1-9
samples per patient). 89.6% of LPR patients had a least 1 positive sample with a mean
pepsin concentration of 120.7 ng/ml.
LPR samples were collated according to definable time points. These included on wa-
king, 1 hour after meals, at bedtime and also when symptomatic. The concentration
of pepsin was high and similar at all time points (Figure 3).
LPR(n=77)
LPR (n=77)
500
500
400
400
pepsin [ng/ml]
Pepsin [ng/ml]
300
300
200
200
100
100
0 0

waking
waking PP
PP bedtime
bedtime symptoms
symptoms all
all
Figure 3: Pepsin concentration measured by Peptest in 77 LPR patients that provided

saliva samples at defined times.
Data 3:
Figure are raw d
Pepsin ata + mean. measured
concentration PP = postprandial
by Peptest in 77 LPR patients that provided saliva
TM
samples at defined times. Data are raw data + mean. PP = postprandial.
Peptest Profile: Control, GORD, LPR

The data
Peptest TM
Profidescribed above GERD,
le: Control, has been extensively analysed to create Peptest generated pepsin
LPR
Theconcentration
data describedprofiles
above has on been
first extensively
waking, 1 analysed to create Peptest
hour postprandially and generated
TM
when experiencing
pepsin concentration profiles on first waking, 1 hour postprandially and when experien-
symptoms (Figure 4) which clearly shows low values
cing symptoms (Figure 4) which clearly shows low values only for controls but signifi only for controls but -significantly
elevated pepsin concentrations for GORD postprandially and with symptoms while for LPR
cantly elevated pepsin concentrations for GERD postprandially and with symptoms
while for LPRall sufferers
sufferers samples allhad
samples
elevated hadpepsin
elevated pepsin
with with symptomatic
symptomatic samples
samples significantly higher
significantly higher than for GERD (p=0.0205).
than for GORD (p=0.0205).
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Pespin level by time and group
225

200
mean (SE) pepsin [ng/ml]
175

LPR (n=77)

150
*

GERD (n=141)
125 *

control (n=87)
100
*

75
50 * significantly
different
25 to control
0

LPR significantly

waking postprandial symptoms different
to GERD
+ 1 hr
Figure 4: PeptestTM determined pepsin concentration profiles seen for healthy controls, GERD
and LPR patients according to timing of saliva sample. Data are mean (SE). Significance when
p<0.05, t-test.
Respiratory Reflux
An array of pilot studies have been performed in respiratory medicine related to
airways reflux and are briefly described. This PeptestTM data indicates the importance
of reflux in the aetiology and exacerbation of pulmonary disease and justifies further
investigation.
Idiopathic Pulmonary Fibrosis (IPF)

Repetitive injury to the pulmonary epithelium, including microaspiration of gastric
refluxate, with failed healing is the proposed mechanism of IPF. IPF patients (n=21)
collected 3 saliva samples and pepsin, measured by PeptestTM , was detected in 81%
of patients [20].
Chronic Obstructive Pulmonary Disease (COPD)

Reflux occurs concurrently in 50-60% of COPD patients and is very strongly linked
to the acute exacerbations of COPD. COPD patients (n=12) provided a single saliva
sample and 67% had detectable pepsin, measured by PeptestTM , in the saliva sample
with a mean concentration of 72.2 ng/ml.
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Cystic Fibrosis (CF)

Reflux is common in CF and may be associated with deteriorating lung function. CF
patients (n=25) provided 4 saliva samples (after physiotherapy, 1 hour postprandially,
with symptoms and at bedtime) and 80% had detectable pepsin, measured by
PeptestTM , in at least one sample but the greatest pepsin positivity prevalence was
seen when symptoms were noted.
References
1) Ten Kate RW, Tuynman HA, Festen HP, Pals G, Meuwissen SG . Effect of high dose omeprazole on
gastric pepsin secretion and serum pepsinogen levels in man. Eur J Clin Pharmacol 1988; 35 (2):
176-176.
2) Pearson JP, Parikh S . Nature and properties of gastro-oesophageal and extra-oesophageal reflu-
xate. Aliment Pharmacol Ther 2011; 33 (Suppl 1): 2-7.
3) Pearson JP, Ward R, Allen A, Roberts NB, Taylor WH. Mucus degradation by pepsin, comparison
of mucolytic activity of human pepsin 1 and pepsin 3: implications in peptic ulceration. Gut 1986;
27: 243-248.
4) Roberts NB. Human pepsin their multiplicity, function and role in reflux disease. Aliment Pharmacol
Ther 2006; 24 (Suppl 2): 2-9.
5) Walker V, Taylor WH. Pepsin 5 in gastric juice: determination and relationship to the alkalistable
peptic activity. Gut 1979; 20: 977-982.
6) Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human
pepsin: implications for reflux attributed laryngeal disease. Laryngoscope 2007; 117: 1036-1039.
7) Tasker A, Dettmar PW, Pearson JP. Can acid reflux be considered among the causes of middle
ear effusions? In The Duodenogastroesophageal Reflux 2006; Giuli R, Scarpignato C, Collard JM,
Richter JE (Eds): 164-168. John Libbey Eurotext. Paris.
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experimental esophagitis. Gastroenterology 1969; 56: 223-230.
9) Gotley DC, Flaks B, Cooper MJ . Bile acids do not modify the effects of pepsin on the fine structure
of human oesophageal epithelium. Aust N Z J Surg 1992; 62: 569-575.
10) Nagahama K, Yamato M, Nishio H, Takeuchi K. Essential role of pepsin in pathogenesis of acid
reflux esophagitis in rats. Dig Dis Sci 2006; 51: 303-309.
11) Tobey NA, Hosseini SS, Caymaz-Bor C, Wyatt HR, Orlando GS, Orlando RC. The role of pepsin in
acid injury to esophageal epithelium. Am J Gastroenterol 2001; 96: 3062-3070.
12) Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a
clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental
investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope
1991; 101 (Suppl 53): 1-78.
13) Ludemann JP, Manoukian J, Shaw K, Bernard C, Davis M, al-Jubab A. Effects of simulated gastro-
esophageal reflux on the untraumatized rabbit larynx. J Otolaryngol 1998; 27: 127-131.
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14) Bardhan KD, Strugala V, Dettmar PW. Review article. Reflux revisited: advancing the role of pepsin.
Int J Otolaryngol 2012; (doi:10.1155/2012/646901).
15) Tack J. Review article: the role of bile and pepsin in the pathophysiology and treatment of gastro-
oesophageal reflux disease. Aliment Pharmacol Ther 2006; 24 (Suppl 2): 10-16.
16) Hayat JO, Yazaki E, Kang J-Y, Woodcock A, Dettmar PW, Mabery J, Sifrim D. Pepsin in saliva and
gastroeophageal reflux monitoring in 100 healthy asymptomatic controls. Gastroenterology 2013;
144 (Suppl 1): S-118.
17) Hayat JO, Woodcock A, Dettmar P, Yazak E, Kang JY, Sifrim D . Is pepsin detected in saliva of
healthy individuals? Gut 2013; 62 (Suppl 1): A108-109.
18) Hayat JO, Gabieta-Gomez S, Yazaki E, Kang JY, Woodcock A, Dettmar P, Mabery J, Sifrim D.
Pepsin in saliva and gastroesophageal reflux monitoring in 100 healthy asymptomatic subjects
and 65 patients with significant heartburn/regurgitation. UEG Journal 2013; 1 (Suppl 1): A112.
19) Faruqi S, Woodcock AD, Dettmar PW, Morice AH. Pepsin detection in expectorated saliva: a useful
marker of airway reflux? Thorax 2013; 68 (Suppl 3): A19-20.
20) Dudziak JM, Crooks MG, Woodcock AD, Dettmar PW, Morice AH, Hart SP. Salivary pepsin as a
biomarker of airway reflux in idiopathic pulmonary fibrosis an observational study. Thorax 2013;
68 (Suppl 3): A18-19.
21) Crossfield GL, Jackson W, Burke J, Woodcock AD, Strugala V, Pearson JP, Dettmar PW, Morice AH.
Pepsin detection despite the use of acid suppressant medication in patients with airway reflux
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22) Hayat JO, Yazaki E, Moore AT, Hicklin LAC, Dettmar PW, Kang J-Y, Sifrim D. Novel techniques for
assessing oesophagopharyngeal reflux in patients with hoarseness and suspected laryngopharyn-
geal reflux. Gut 2012; 61 (Suppl 2): A260.
23) Hayat JO, Kang J-Y, Dettmar PW, Moore AT, Hicklin LC, Yazaki E, Sifrim D. Do patients with
hoarseness and endoscopic signs of LPR have abnormal esophago-pharyngeal reflux? A study
using simultaneous impedance-pHmetry, oro-pharyngeal pH monitoring (Restech) and pepsin
measurement in saliva. Gastroenterology 2012; 142 (Suppl 1): S-411-S-412.
24) de Bortoli N, Savarino E, Furnari M, Martinucci I, Russo S, Bertani L, Bellini M, Savarino V, Marchi S.
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series of suspected NERD patients. A pilot study. Gut 2012; 61 (Suppl 3): A199.
25) Bor S, Capanoglu DS, Yildirim E, Vardar R, Woodcock A, Dettmar PW. The validation of Peptest
a new non-invasive technology for the diagnosis of laryngopharyngeal reflux (LPR). Gut 2012; 61
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26) Hayat JO, Gabieta-Somnez S, Yazaki E, Kang JY, Woodcock A, Dettmar P, Mabary J, Knowles CH,
Sifrim D. Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease. Gut 2014; 64:
373-380.
27) Jones R, Junghard O, Dent J, Vakil N, Halling K, Wernersson B, Lind T. Development of the GerdQ,
a tool for the diagnosis and management of gastro-oesophageal reflux disease in primary care.
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Journal of Voice. 2002; 16: 274-277.
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12:00 pH-impedance and Airway pH Recording

Edoardo V. Savarino, MD, PhD
Assistant Professor of Gastroenterology, Gastroenterology Unit,
Department of Surgery, Oncology and Gastroenterology,
University of Padua, Italy
In the past decade we have witnessed a progressively increased

emphasis on the association between gastro-esophageal reflux
Edoardo V. Savarino disease (GERD) and extra-esophageal disorders [1, 2]. In fact, we
have realized that GERD may also present atypically and is referred
to as extra-esophageal syndrome in agreement with the Montreal
classification [3]. Common extra-esophageal manifestations include reflux cough syn-
drome, reflux asthma syndrome and reflux laryngitis syndrome. Population-based
surveys from the westernized countries show that the overall prevalence of extra-
esophageal complaints associated with GERD is approximately 10%-15% [4]. The
mechanisms put forward to explain how GER may contribute to atypical respiratory
symptoms are represented by direct (aspiration) and indirect (neutrally mediated)
factors [5]. In other words, reflux may cause symptoms by direct contact of gastro-
duodenal contents with the larynx or airways or may stimulate a vagal reflex producing
cough and/or bronchospasm.
The establishment of a clear relationship between reflux and extra-esophageal symp-

toms can be challenging. The diagnosis is based on an empiric trial of proton pump
inhibitor (PPI) therapy, which can be positive in 50%-60% of cases, and in further dia-
gnostic testing such as upper GI endoscopy, laryngoscopy and 24-hour pH (-impedance)
monitoring, for those who do not respond to PPI therapy. The limitations of these tests
are well known because they are rather inaccurate in selecting those patients where
GERD is causally related to the extra-esophageal symptoms [6]. In particular, upper
GI endoscopy has been demonstrated to have low sensitivity given that the majority
of suspected GERD patients present a normal endoscopy without any sings of erosive
esophagitis and/or Barretts esophagus [7-9]. Moreover, the pre-endoscopy PPI usage
may significantly contribute to the misclassification of GERD patients, further reducing
the sensitivity of upper endoscopy in identifying GERD [10]. Laryngoscopic findings
potentially reflux-related such as erythema, edema, ventricular obliteration, post-cricoid-
hyperplasia and pseudosulcus are often detected by ENT surgeons during laryn-
goscopy examinations and are used to diagnose laryngo-pharyngeal reflux [11].
However, these laryngoscopic findings are also common in healthy volunteers (in up
to 50% of the cases), and this largely limits their diagnostic value [12]. Finally, the
sensitivity and specificity of ambulatory pH monitoring in diagnosing reflux in patients
with extra-esophageal GERD symptoms have been challenged by several studies given
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the poor correlation between pH-metry findings and outcomes after medical and/or
surgical therapy [3]. Advances
in Diagnosis
and Therapy
In last years, new diagnostic
of GERDmodalities haveBergamo,
been developed February 24-25,
and applied 2012
in patients
with atypical manifestations of GERD in order to understand their utility and potential
application in clinical practice. In particular, the availability of multichannel intraluminal
impedance and pH monitoring (MII-pH) has modified the diagnostic approach towards
atypical manifestations of GERD [13-15]. Indeed, MII-pH is able to detect not only
OESO Post-graduate Course

acid but also non-acid reflux (Figure 1) and proximal migration of the refluxate and
Baseline impedance in ohms is dependent on the presence of the esophageal mucosa
can correlate symptoms with both types of reflux. A temporal relationship between
and muscle wall surrounding the recording electrodes. Subsequent to the swallow, there
cough and acid or non-acid reflux has been demonstrated in approximately 45% of
is a rapid increase in impedance (decreased conductance) as swallowed air moves past
patients by MII-pH monitoring especially by using esophago-gastric manometry [16]
the recording segment. This is quickly followed by a large and longer decrease in im-
or an acoustic cough recording device [17] instead of events marker activation by
pedance as the liquid bolus distends the esophagus and passes the recording segment.
the patient. Furthermore, laparoscopic Nissen fundoplication led to disappearance
of symptoms in six patients with cough associated with nonacid reflux (positive SI)
Finally, impedance returns to a level slightly above and then back to baseline as the
during pH-impedance monitoring on therapy, with a median follow up of 17 months
esophageal contraction wave closes the esophageal lumen and clears the bolus. By
[14]. More recently, in patients with LPR diagnosed based on laryngoscopic findings,
using a catheter with a series of ring electrodes spaced at 2 cm intervals throughout
MII-pH impedance monitoring was able to detect the presence of pathological GERD
the esophagus (Figure 2), segmental changes in impedance allow accurate recording
in about 40% of the patients, confirming the very low specificity of laryngoscopic
of the transit of ingested material down the esophagus or, conversely, the passage of
signs in diagnosing GERD and, on the other hand, highlighting the ability of MII-pH
refluxed material up the esophagus.
Acid Reflux Non-acid Reflux
17 cm
15 cm
Impedance
9 cm
7 cm
5 cm
3 cm
pH 5 cm
30 sec 30 sec
Figure 1: Gastroesophageal reflux episodes identified by combined impedance-pH monitoring.

Figure 2: Gastroesophageal
Impedance reflux episodes
detects reflux episodes as a dropidentified by combined
in intraluminal impedance-pH
impedance progressingmonitoring.
over time
Impedance
from the LESdetects reflux
towards theepisodes
proximalasesophagus.
a drop in intraluminal
Data from impedance progressing
the pH sensor is used toover timerefl
classify fromux
the
intoLES towards
acid the<proximal
(nadir pH esophagus.
4) and non-acid Data from the pH sensor is used to classify reflux into
reflux.
acid (nadir pH < 4) and non-acid reflux.
Ambulatory 24-h impedance-pH monitoring has become the gold-standard for investi-
gating gastro-esophageal reflux. The ability of impedance-pH monitoring to detect
and characterize gastroesophageal reflux represents an important advance for clinical
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monitoring in identifying those patients who have more probability to respond to

medical or surgical therapy [18]. It is important to bear in mind that these approaches
require further validation by appropriate controlled outcome studies. However, if testing
with impedance monitoring off therapy is normal, a strong negative predictive value
for baseline abnormal esophageal reflux can be established and other causes for extra-
esophageal symptoms should be searched [19]. Overall, the most recent studies
suggest that GER may play a role in chronic cough, while the role of reflux in chronic
laryngitis and asthma is far less clear.
The association between GERD and other respiratory diseases such as pharynigitis or
sinusitis is less consistent, in particular with pulmonary fibrosis. However, our group
has recently published the results of a prospective study performed with 24-hour
pH-impedance testing off-therapy in a consistent group of consecutive patients with
systemic sclerosis, in whom severity of lung involvement in terms of interstitial lung
disease was graded on the basis of high-resolution computed tomography [20].
We have found that the number of reflux episodes, both acid and weakly acidic, and
their proximal migration along the esophagus were significantly higher in scleroderma
patients with most severe disease than in those with mild or moderate disease and
in controls. Moreover, there was a good correlation between the severity of reflux
expressed by the number of proximal and distal reflux episodes and the severity of
lung fibrosis as assessed by a previously validated radiologic score (i.e. Best score).
More recently, we evaluated 40 consecutive patients with biopsy-proven idiopathic
pulmonary fibrosis (IPF) who underwent pulmonary high-resolution computed tomo-
graphy scan and impedance-pH monitoring while off antisecretory therapy [21].
The presence of pulmonary fibrosis was assessed using validated HRCT scores. Forty
consecutive patients with interstitial lung disease other than IPF (non-IPF patients) and
50 healthy volunteers were also enrolled. IPF patients had significantly higher esopha-
geal acid exposure, number of acid and proximal reflux events compared to non-IPF
patients and healthy volunteers, respectively. Pulmonary fibrosis HRCT scores correlated
well with reflux episodes in both the distal and proximal esophagus. Finally, patients
with IPF had more bile acids and pepsin in broncho-alveolar lavage fluid and saliva
than non-IPF patients and controls. These findings seem to reinforce the role of GER
in the pathogenesis of pulmonary fibrosis, although they do not show the existence
of causality.
Recently, a new technology able to detect aerosols of acid and gaseous clouds of acid
has been described: the Dx-pH measurement system (Dx-pH) (Respiratory Technology
Corp., San Diego, CA). Dx-pH is a highly sensitive and minimally invasive device for the
detection of acid reflux in the posterior oropharynx (Figure 2).
Advances
in Diagnosis
and Therapy
of GERD Bergamo, February 24-25, 2012

Advances
Course
in Diagnosis EXTRA-DIGESTIVE GERD:
and Therapy Figure 2a: A patient wearing THE Dx-pH probe with its
of GERD Bergamo, WHATS February NEXT24-25,
? 2012
solid state memory for data recording.
Figure 2b: Dx-pH probe with its light emitting diode
OESO Post-graduate
positioned in the oropharynx.
Course
Figure 2a: A patient wearing THE Dx-pH probe with its
solid state memory for data recording.
Figure 2b: Dx-pH probe with its light emitting diode
OESO Post-graduate
positioned in the oropharynx.
Figure 2a: A patient wearing THE Dx-pH probe

with its solid state memory for data recording.
Figure 2b: Dx-pH probe with its light emitting

diode positioned in the oropharynx.
It uses a nasopharyngeal catheter with a sensor that is able to measure pH in either

liquid or aerosolised droplets [22]. A number of preliminary studies have suggested
that this technique may have a role in identifying patients with extra-esophageal
symptoms caused by reflux disease (Figure 3) [23-25], although there are also recent
investigations in which the clinical utility of Dx-pH has been questioned because of
the very poor agreement between its findings and those observed during concurrent
MII-pH monitoring off-medication [26].
Treatment trials with PPIs in patients with extra-esophageal symptoms possibly related
to GERD have provided little insight into a causal relationship between these two con-
ditions. Several critical literature reviews and many negative, randomized, controlled
trials have clearly shown that the link between reflux and extra-esophageal symptoms
hasFigure
been3:overestimated [27]. However,
Restech laryngo-pharyngeal refluxthere is aevidence
study in that
patient with subgroups of
extra-esophageal patients
GERD.
may gain benefit from antireflux therapy, but it is difficult to predict responders [28].
As the success of PPI or surgical therapy depends on the cause-effect relation between
Course Directors:
GER and Fabio
symptoms, PACE
our (Milan/Seriate)
future Carmelo
efforts must SCARPIGNATO
be addressed (Parma)
to identify the subgroups 17
of individuals who can respond to antireflux treatment.
Figure 3: Restech laryngo-pharyngeal reflux study in a patient with extra-esophageal GERD.
Course Directors: Fabio PACE (Milan/Seriate) Carmelo SCARPIGNATO (Parma) 17
OESO Post-
WHATS NEXT ?
Figure3:3:Restech
Figure Restech laryngo-pharyngeal
laryngo-pharyngeal reflux
reflux study
study in in a patient
a patient with
with extra-esophageal
extra-esophageal GERD.
GERD.
Course Directors: Fabio PACE (Milan/Seriate) Carmelo SCARPIGNATO (Parma)

References 17
1) Del Negro R, Pomari C, Micheletto C, Turco p; Tognella S. Prevalence of gastro-oesophageal reflux in

asthmatics: an Italian study. Ital J Gastroenterol Hepatol 1999; 31: 371-375.
2) El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with oeso-
phagitis in United States military veterans. Gastroenterology 1997; 113: 755-760.
3) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The Montreal definition
and classification of gastroesophageal reflux disease. Am J Gastroenterol 2006; 101: 1900-1920.
4) Vaezi M, Hicks DM, Abelson TI, Richter JE. Laryngeal signs and symptoms and gastroesophageal
reflux disease (GERD): a critical assessment of cause and effect association. Clin Gastroenterol
Hepatol 2003; 1: 333-344.
5) Moore JM, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease: real or
imagined? Curr Opinion Gastroenterol 2010; 26: 389-394.
6) Penagini R. Extra-oesophageal manifestations of gastro-oesophageal reflux disease: Good news
in the long-term! Dig Liver Dis 2006; 38: 238-239.
WHATS NEXT ?
7) Savarino E, Zentilin P, Savarino V. NERD: an umbrella term including heterogeneous subpopula-

tions. Nat Rev Gastroenterol Hepatol 2013; 10: 371-380.
8) Lacy BE, Weiser K, Chertoff J, Fass R, Pandolfino JE, Richter JE, Rothstein RI, Spangler C, Vaezi MF.
The diagnosis of gastroesophageal reflux disease. Am J Med 2010; 123: 583-592.
9) Giannini EG, Zentilin P, Dulbecco P, Vigneri S, Scarlata P, Savarino V. Management strategy for
patients with gastroesophageal reflux disease: a comparison between empirical treatment with
esomeprazole and endoscopy-oriented treatment. Am J Gastroenterol 2008; 103: 267-275.
10) Gaddam S, Wani S, Ahmed H, Maddur P, Hall SB, Gupta N, Puli SR, Higbee A, Rastogi A, Bansal A,
Sharma P. The impact of pre-endoscopy proton pump inhibitor use on the classification of non-
erosive reflux disease and erosive oesophagitis. Aliment Pharmacol Ther 2010; 32: 1266-1274.
11) Vaezi MF, Hicks DM, Abelson TI, Richter JE. Laryngeal signs and symptoms and gastroesophageal
reflux disease (GERD): a critical assessment of cause and effect association. Clin Gastroenterol
Hepatol 2003; 1: 333-344.
12) Milstein CF, Charbel S, Hicks DM, Abelson TI, Richter JE, Vaezi MF. Prevalence of laryngeal irrita-
tion signs associated with reflux in asymptomatic volunteers: impact of endoscopic technique rigid
vs. flexible laryngoscope. Laryngoscope 2005; 115: 2256-2261.
13) Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with
chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut 2005;
54: 449-454.
14) Tutuian R, Mainie I, Agrawal A, Adams D, Castell DO. Nonacid reflux in patients with chronic cough
on acid suppressive therapy. Chest 2006; 130: 386-391.
15) Mainie I, Tutuian R, Agrawal A, Hila A, Highland KB, Adams DB, Castell DO. Fundoplication elimi-
nates chronic cough due to non-acid reflux identified by impedance pH monitoring. Thorax 2005;
60: 521-523.
16) Blondeau K, Dupont LJ, Mertens V, Tack J, Sifrim D. Improved diagnosis of gastro-oesophageal
reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther 2007; 25: 723732.
17) Smith JA, Decalmer S, Kelsall A, McGuinness K, Jones H, Galloway S, Woodcock A, Houghton LA.
Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroe-
nterology 2010; 139: 754762.
18) de Bortoli N, Nacci A, Savarino E, Martinucci I, Bellini M, Fattori B, Ceccarelli L, Costa F, Mumolo
MG, Ricchiuti A, Savarino V, Berrettini S, Marchi S. How many cases of laryngopharyngeal reflux
suspected by laryngoscopy are gastroesophageal reflux disease-related? World J Gastroenterol
2012; 18: 43634670.
19) Richter JE. Review article: extraoesophageal manifestations of gastro-oesophageal reflux disease.
Aliment Pharmacol Ther 2005; 22(Suppl 1): 70-80.
20) Savarino E, Bazzica M, Zentilin P, Pohl D, Parodi A, Cittadini G, Negrini S, Indiveri F, Tutuian R,
Savarino V, Ghio M. Gastroesophageal reflux and pulmonary fibrosis in scleroderma. A study using
pH-impedance monitoring. Am J Respir Crit Care Med 2009; 179: 408-413.
21) Savarino E, Carbone R, Marabotto E, Furnari M, Sconfienza L, Ghio M, Zentilin P, Savarino V. Gastro-
oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J
2013; 42: 1322-1331.
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22) Sun G, Muddana S, Slaughter JC, Casey S, Hill E, Farrokhi F, Garrett CG, Vaezi MF. A new pH
catheter for laryngopharyngeal reflux: Normal values. Laryngoscope 2009; 119: 1639-1643.
23) Vailati C, Mazzoleni G, Bondi S, Bussi M, Testoni PA, Passaretti S. Oropharyngeal pH monitoring
for laryngopharyngeal reflux: is it a reliable test before therapy? J Voice 2013; 27: 84-89.
24) Becker V1, Graf S, Schlag C, Schuster T, Feussner H, Schmid RM, Bajbouj M. First agreement
analysis and day-to-day comparison of pharyngeal pH monitoring with pH/impedance monitoring
in patients with suspected laryngopharyngeal reflux. J Gastrointest Surg 2012; 16: 1096-1101.
25) Worrell SG, DeMeester SR, Greene CL, Oh DS, Hagen JA. Pharyngeal pH monitoring better predicts
a successful outcome for extraesophageal reflux symptoms after antireflux surgery. Surg Endosc
2013; 27: 4113-4118.
26) Hayat JO, Yazaki E, Moore AT, Hicklin L, Dettmar P, Kang JY, Sifrim D. Objective detection of
esophagopharyngeal reflux in patients with hoarseness and endoscopic signs of laryngeal inflam-
mation. J Clin Gastroenterol 2014; 48: 318-327.
28) Gibson PG, Henry RL, Coughlan JL. Gastrooesophageal reflux treatment for asthma in adults and
children. Cochrane Database Syst Rev 2003; 2: CD001496.
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Notes
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12:30 Extra-digestive GERD: Is Upper GI Endoscopy

Always Indicated?
Peter Malfertheiner, MD, PhD
Professor of Medicine and Director,
Department of Gastroenterology,
Hepatology & Infectious Diseases,
Otto-von-Guericke-University, Magdeburg, Germany
Chairman, EAGEN Educational Committee
with the cooperation of Arne Kandulski, MD, PhD

Peter Malfertheiner
Associate Professor
Background
The diagnosis of gastroesophageal reflux disease (GERD) as underlying condition of
atypical (extra-digestive) symptoms has an enormous impact on the individual patient
management. Moreover, the economic burden of medical therapies prescribed for
extra-digestive GERD is enormous.
According to the 2013 Consumer Report1, in the US, more than 120 million prescrip-
tions of proton pump inhibitors (PPI) are documented, which result in PPI sale of
more than $ 9.5 billion in 2012 for the indication GERD. By the analysis of health care
expenses in different clinical subgroups of GERD, the highest cost for PPI consum-
ption was calculated in patients with suspected extra-esophageal manifestations of
GERD. The cost for these patients is more than 5-fold higher as compared to patients
with typical symptoms [1].
A careful diagnostic work-up of patients with extra-digestive symptoms potentially

related to GERD is helpful in guiding the therapeutic management and is cost-saving
as it will identify those patients for whom a long term PPI therapy will be ineffective.
Chronic cough, asthma, laryngitis are frequent manifestations of extra-digestive GERD

according to the Montreal classification [2]. These symptoms as well as hoarseness,
postnasal drainage and globus occur in the context of GERD but frequently as well
without any association to GERD in general population [3-6]. A firm diagnosis of
GERD is essential for the definition of an extra-digestive GERD manifestation. This is
a diagnostic challenge in patients with atypical symptoms potentially related to GERD
but in the absence of heartburn and regurgitation.
1
https://www.consumerreports.org/health/resources/pdf/best-buy-drugs/PPIsUpdate-FINAL.pdf
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Role of Endoscopy in Typical GERD and Advancement in the Endoscopic

Diagnosis of Non-erosive Reflux Disease (NERD)
Endoscopic examination of the esophagus is not generally recommended for all patients
with typical reflux symptoms in the absence of alarm symptoms. However upper GI
endoscopy should be considered for all patients with relapsing or long-lasting symp-
toms and in case of insufficient response to therapy with PPI [7, 8].
Upper GI endoscopy is the gold standard in the diagnosis of erosive reflux disease,
allows to detect mucosal breaks and to define their severity. Furthermore endoscopy
allows to assess esophageal abnormalities such as Barrett esophagus and turns to
guide individual therapies. Japanese endoscopists attempted to implement minimal
endoscopic changes such as mucosal erythema, edema and red streaks in the endo-
scopic diagnosis of NERD and to establish the M- & N-classification using standard
white light endoscopy [9, 10]. However because abnormal acid exposure was associated
only with the appearance of red streaks, and moreover because of a high interobserver
variability with low kappa-values [9], a general use of this classification was not intro-
duced into clinical practice.
In case of the normal appearing mucosa with standard white light endoscopy tech-
nologically advanced endoscopic imaging including high definition, high resolution,
zoom as well as contrast-enhancing techniques [narrow band imaging (NBI, Olympus),
Flexible Spectral Imaging Colour Enhancement (FICE, Fujifilm) and Blue Laser Imaging
(BLI, Fujifilm)] allow to reveal abnormal mucosal findings in patients with GERD.
Sharma and colleagues using zoom endoscopy and NBI in the diagnosis of NERD,
reported the appearance of more dense, elongated and tortuous intrapapillary loops
(IPCLs) as endoscopic features for NERD with comparable fair test criteria [11]. Similar
to endoscopes with the optical filter system in NBI endoscopes, contrast enhancement
obtained by FICE enables the detection of IPCLs [12]. We are currently studying the
potential of BLI in the detection of minor abnormalities in the context of NERD. The
mucosal changes of IPCLs visualized by advanced imaging endoscopy correlate best
with the histomorphological appearance of papillary elongation by visual enhance-
ment of the small vessels within the papilla [13, 14].
Endoscopy Based Histological Assessment

An important add-on to the endoscopic visualization is the option of taking esophageal
biopsies in the presence of macroscopic mucosal abnormalities. Targeted biopsies of
endoscopically detected abnormalities, as in the presence of columnar lined epithelium
(i.e. Barretts esophagus) diagnosis are mandatory.
In the histopathological assessment of the esophageal mucosa, microscopic changes

are detectable in erosive as well as non-erosive reflux disease. Distinct changes of the
WHATS NEXT ?
esophageal mucosa in response to excessive exposure to acidic luminal contents have

first been described 1970 by Ismail-Beigi [15]. Hopwood and Tobey extended these
findings with the description of dilated intercellular spaces of the esophageal mucosa
by electron-microscopy. Dilated intercellular spaces of the esophageal mucosa have
since become defined as a characteristic mucosal feature in the esophagus of patients
with NERD [16, 17].
Microscopic morphological changes have been further characterized in different sub-

categories of GERD and were found to be positively correlated with parameters of
functional parameters (pH-impedance, MII-pH) indicating impaired mucosal integrity
[18-22].
Different proposals have been made to implement histopathological scoring systems

in the diagnostic algorithm of GERD [23]. Although not recommended for the initial
diagnosis and risk evaluation of GERD, esophageal biopsies should be encouraged in
case of PPI-refractory symptoms. In case of refractory symptoms, patients with true
NERD present with typical features of microscopic esophagitis and this is of great help
especially for the distinction from patients with functional heartburn [19, 21].
The Role of Endoscopy in Extra-digestive GERD

The management of patients with extra-digestive manifestations of GERD poses an
important challenge.
There is very limited information about the endoscopic evaluation of patients presen-
ting exclusively with extra-digestive symptoms in the absence of concomitant typical
reflux symptoms. A prospective study conducted in the US included 128 patients
with extra-digestive symptoms being the chief complaint mainly cough in some
with associated typical GERD symptoms. In this patient group, erosive changes of
the esophageal mucosa were detected in 18% of the cases, mainly mild to moderate
according to Los Angeles classification A and B [24]. The prevalence of abnormal acid
exposure documented by wireless pH-metry was higher in patients with concomitant
typical reflux symptoms and was detected in 66% of the patients with extra-digestive
symptoms without concomitant typical symptoms.
In the ProGERD study, with a large population initially of more than 6,000 patients,
GERD-related extra-digestive symptoms were reported in about 30% of these patients
[3, 4]. While extra-digestive symptoms may persist over two years they eventually
became less prevalent and may even disappear during the follow-up of 5 years [5].
The current developments in high definition endoscopy with NBI, FICE, BLI and other
modalities, including histology, should also consider the measurement of mucosal
integrity. The development of a catheter for direct measurement of mucosal impedance
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1112 SARITAS YUKSEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 10
A
10cm
Endoscope
5cm Distances above SCJ

measurements obtained
Mucosal impedance (MI)
catheter 2cm
Esophagitis
Impedance sensors spaced 2 mm site
apart
B
Traditional multichannel
Mucosal impedance (MI) catheter impedance/pH catheter:
9 cm
2-mm diameter catheter 2-mm diameter catheter
Impedance sensors: Impedance sensors:
Length = 2mm Length = 4mm
Sensor separation = 2mm 7 cm Sensor separation = 1.6cm
4 Distal esophageal segments
centered at:
3, 5, 7, 9cm Figure 1. Schematic represen-
5 cm pH sensor at 5cm tation of MI catheter. (A) Two
2-mm long impedance sensing
electrodes positioned 1 mm
from the tip of a 2-mm soft cath-
eter advanced through an upper
3 cm endoscope. MI measurements
obtained by direct mucosal con-
tact of sensors at the site of
esophagitis (if present) and 2, 5,
and 10 cm above the SCJ. (B)
Photograph of the MI catheter
(inset photo) and schematic
0.4 cm comparison of the MI catheter
with the traditional multichannel
impedance-pH catheter.
model was 1201 (at the site of esophagitis), 1223 (2 cm above on this model, 60 patients (20 patients in each group) provided
Figure 1: Schematic representation of MI catheter. (A) Two 2-mm
the SCJ), and 1513 (5 cm above the SCJ). To determine the
long impedance sensing electro-
80% power to detect a difference of 1400 in impedance values
des positionedappropriate
1 mm from samplethe
size,tip of athe
we used 2-mm soft catheter
most conservative estimateadvanced
between through
the groupsan( upper
.025). endoscope.
Subject characteristics were
of the standard
MI measurements obtained deviation, 1513 , mucosal
by direct while holding power con-
contact describedat
of sensors using
themedians
site ofand esophagitis
interquartile ranges
(if for continu-
stant at 80% and using a significance level of 0.025. Thus, based ous variables and proportions for categoric variables. Statistical
present) and 2, 5, and 10 cm above the SCJ. (B) Photograph of the MI catheter (inset photo) and
schematic comparison of the MI catheter with the traditional multichannel impedance-pH catheter.
WHATS NEXT ?
during the endoscopic examination (Figure 1) would greatly facilitate the diagnostic
assessment (one stop shop) [25].
Therefore, the indication for endoscopy in extra-digestive symptoms suspected for

GERD should always be performed and should be considered at any early stage in the
diagnostic algorithm (Figure 2). Early diagnosis or exclusion of GERD in patients with
extra-digestive diseases will contribute to minimize consultations with specialists and
the use of inappropriate medical therapy. Prospective investigations aiming at these
specific questions are lacking and are mandatory for extra-digestive GERD.
Extra-digestive Symptoms
Alarm Symptoms With Typical Symptoms Without Typical Symptoms

age > 55 years
Exclusion of other
Upper GI Endoscopy Empiric PPI Therapy 1 reasons by ENTs and
pneumologists
Relapsing / 2 upper GI endoscopy

Persisting Symptoms + Histology
+ pH-metry / MII-pH
Figure 2: Algorithm for extra-digestive symptoms and suspected GERD.
Challenging Clinical Scenario in GERD: Hoarseness

Several studies have been performed with the aim to correlate specific laryngoscopical
images and findings with GERD. The results generally failed to prove that laryngeal
inflammatory changes could indicate GERD as the underlying cause. Therefore, laryngo-
scopy is not a diagnostic tool by itself to guide anti-reflux based therapeutic management.
The recent American guidelines state that extra-digestive GERD cannot be diagnosed
solely on laryngoscopy [26, 27]. The diagnosis of extra-esophageal GERD deserves a
close interdisciplinary cooperation between gastroenterologists and ENT physicians.
This needs to be extended to pneumologists in case of lung disease (e.g. asthma).
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Although a specific diagnostic algorithm for extra-digestive GERD has not been pro-
posed in recent guidelines, the diagnostic modalities in patients with chronic laryngitis
should include upper GI endoscopy laryngoscopy, pH-metry/ pH-impedance [7, 8].
Practice Points
1) Patients with extra-digestive symptoms in GERD associated with typical symptoms
should be managed according to the usual guidelines in GERD. Endoscopy is man-
datory and most beneficial in all patients with chronic or relapsing symptoms. Our
personal philosophy goes with the tradition of once in a life-time endoscopy in all
patients with suspected GERD.
2) Patients with extra-digestive disease and no concomitant typical symptom,

heartburn and regurgitation should first be explored by either ENT specialists
or pneumologists and after exclusion of a specific organ disease referred to the
gastroenterologist for upper GI endoscopy with/without the need of complemen-
tary function tests.
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N, Frigo AC, Fiocca R, Savarino V. Microscopic esophagitis distinguishes patients with non-erosive
reflux disease from those with functional heartburn. J Gastroentero 2013; 48: 473-482.
20) Kandulski A, Weigt J, Caro C, Jechorek D, Wex T, Malfertheiner P. Esophageal Intraluminal Baseline
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21) Kandulski A, Jechorek D, Caro C, Weigt J, Wex T, Monkemuller K, Malfertheiner P. Histomor-
phological differentiation of non-erosive reflux disease and functional heartburn in patients with
PPI-refractory heartburn. Aliment Pharmacol Ther 2013; 38: 643-651.
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22) Martinucci I, de Bortoli N, Savarino E, Piaggi P, Bellini M, Antonelli A, Savarino V, Frazzoni M,

Marchi S. Esophageal baseline impedance levels in patients with pathophysiological characteristics
of functional heartburn. Neurogastroenterol Motil 2014; 26: 546-555.
23) Fiocca R, Mastracci L, Riddell R, Takubo K, Vieth M, Yerian L, Sharma P, Fernstrom P, Ruth M.
Development of consensus guidelines for the histologic recognition of microscopic esophagitis in
patients with gastroesophageal reflux disease: the Esohisto project. Hum Pathol 2010; 41: 223-231.
24) Fletcher KC, Goutte M, Slaughter JC, Garrett CG, Vaezi MF. Significance and degree of reflux in
patients with primary extraesophageal symptoms. Laryngoscope 2011; 121: 2561-2565.
25) Saritas Yuksel E, Higginbotham T, Slaughter JC, Mabary J, Kavitt RT, Garrett CG, Vaezi MF.
Use of direct, endoscopic-guided measurements of mucosal impedance in diagnosis of gastro-
esophageal reflux disease. Clin Gastroenterol Hepatol 2012; 10: 1110-1116.
26) Milstein CF, Charbel S, Hicks DM,. Abelson TI, Richter JE, Vaezi MF. Prevalence of laryngeal
irritation signs associated with reflux in asymptomatic volunteers: impact of endoscopic technique
(rigid vs. flexible laryngoscope). Laryngoscope 2005; 115: 2256-2261.
27) Powell J, H.C. Cocks HC. Mucosal changes in laryngopharyngeal refluxprevalence, sensitivity,
specificity and assessment. Laryngoscope 2013; 123: 985-991.
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Notes
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FRIDAY, April 17, 2015 Afternoon
SESSION III:
EXTRA-DIGESTIVE MANIFESTATIONS OF GERD
CHAIRED BY:
Alfredo A. Chetta, MD, PhD

Professor of Respiratory Medicine and Director,
Post-graduate School of Respiratory Medicine,
Alfredo A. Chetta
Liborio Parrino, MD, PhD

Associate Professor of Neurology and
Director, Post-graduate School of Neurology,
University of Parma
Director, Center for Sleep Disorders,
Maggiore University Hospital, Parma, Italy
Liborio Parrino
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15:00 Respiratory Manifestations of GERD

Stanislas Bruley des Varannes, MD, PhD
Professor of Gastroenterology, University of Nantes
Head, Division of Gastroenterology and Hepatology,
Hotel-Dieu University Hospital and Director of the Institute for
Digestive Diseases (IMAD), Nantes, France
Stanislas Respiratory manifestations of GERD represent one of the most

Bruley des Varannes
prevalent extra-esophageal syndromes such as described in the
Montreal classification. The main respiratory disorders associated
with GERD are indicated in table 1 [1]. In fact the relationship between reflux and such
a manifestations remain difficult to establish with a high degree of certainty. In addition
considering that respiratory manifestations, and especially chronic cough, and GERD
are both frequently encountered in clinical conditions the simple association is also
possible. If some significant epidemiological associations and pathophysiological
mechanisms support for a causal relationship, at the individual level only the demon-
stration of a temporal relationship between symptom occurrence and reflux episodes
and at a lesser extent the improvement with therapeutic interventions can be consi-
dered.
Table 1: Main Respiratory Manifestations Associated with GERD

(from Galmiche et al. [1])
Chronic persistent cough

Bronchial asthma
Chronic bronchitis
Pulmonary aspiration complications
Idiopathic pulmonary fibrosis
Chronic obstructive pulmonary disease
Obstructive sleep apnea syndrome
Among reflux related respiratory syndromes two have to be predominantly considered:

asthma and chronic cough.
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Asthma and GERD

Asthma and GERD are very frequently associated with a high prevalence of GERD in
asthmatics, estimated in average around 60% [2]. Likewise studies measuring distal
esophageal acidity have reported abnormal exposure in up to 80% of asthmatics
[3, 4]. In fact difficulties are increased by the poor adequation between symptoms
and true GERD as using pH monitoring allows to detect clinical silent acidic reflux in
25-60% of asthmatics, whereas it has been reported that only 50% of asthmatics
with typical reflux symptoms did have an abnormal acidic reflux on pH monitoring
[5]. It is not clear which pathological condition is occurring first. Some studies suggest
that nocturnal reflux would be associated with asthma or with difficult to control
asthma. This association has been considered as possibly related to a lesser efficacy
of protective mechanisms against reflux such as reduction in clearance, and weak
upper esophageal sphincter pressure. In addition increased acid secretion during night
period may account for a more injurious refluxates.
The main mechanisms by which reflux may trigger asthma are microaspiration and
vagally mediated bronchospasm. In fact the effect of esophageal acidification are
far from being established. Despite extensive experimental studies there is no clear
evidence to consider that spontaneous reflux or esophageal acidifcation has an
effect on lung function in asthmatics, maybe excepting a sub-group of patients with
nocturnal GERD symptoms [6]. The involvement of a bronchial hyperresponsiveness
is suggested by the decrease in the concentration of cholinergic agonist required to
decrease respiratory conductance. It appears also that reflux may be the consequence
of asthma itself, especially by the induced-increase of transdiaphragmatic pressure.
Thus Zerbib et al. were able to confirm the bronchospasm-induced increased reflux
frequency. This was associated with an increase in the rate of transient lower esopha-
geal sphincter relaxations [7]. In addition asthma could facilitate reflux through
the effects of medications reducing the lower esophageal sphincter tone and the
contractile activity of the esophagus.
Although numerous clinical trials have reported positive effects of antireflux therapy
in asthmatics, recent well conducted placebo-controlled studies did not show clear
improvement in asthma following treatment for GERD. Thus in a large series of more
than 400 patients with no symptoms of GERD, the rate of episodes of poor asthma
control was not different between asthmatics receiving 40 mg of esomeprazole twice
daily and those receiving matching placebo after 6 months follow-up [8]. Importantly,
the presence of asymptomatic gastroesophageal reflux, which was noted in nearly
half of participants, was not predictive of a treatment effect. In addition neither the
body mass index nor the presence or absence of night awakening identified a group
of patients who had a response to proton-pump inhibitors [8]. In another large study
including more than 900 asthmatic patients with GERD symptoms, if esomeprazole
40 mg (o.d or b.i.d.) improved morning Peak Expiratory Flow (PEF) and asthma related
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quality of life, other parameters were not changed and it was concluded that these
changes were minor and of small clinical significance [9, 10].
Overall it appears that relationships between asthma and GERD are more complex
than initially thought. It is of importance to consider that despite a high prevalence
of reflux in asthmatics there is a limited efficacy of antireflux therapy on asthma out-
come. As more data support that asthma may also induce reflux and if reflux induce
asthma a vicious circle probably could arise with an increase in the severity of asthma.
However clinical experience shows that antireflux treatments are appropriate in some
patients, but the target populations have to be more precisely defined in the future.
Chronic Cough and GERD

GERD is considered as a frequent cause of chronic cough in addition to asthma and
post-nasal drip accounting for approximately 20% of cases of chronic cough. As for
other GERD-related respiratory manifestations, pathogenesis involves both reflux
(micro-aspiration), reflex mechanisms and possibly a low tussive threshold. In fact the
role of aspiration remains poorly established even if some indirect mechanisms could
suggest such a relationship. Until now monitoring pH in proximal esophagus have
produced contradictory results on the real occurrence of cough induced by proximal
reflux. An alteration of esophago-glottal reflex or laryngeal sensitivity increasing the
risk of microaspiration is not established.
The role of reflex mechanisms in explaining the relationship between cough and reflux
is supported by an inhibition of acid-induced cough by distal esophageal anaesthesia
associated with the fact that distal exposure is better correlated than proximal expo-
sure to reflux-associated cough. In fact multiple central and peripheral mechanisms
may be involved. In this aspect a recent study determined cough-reflux relationships
by using an acoustic device and 24-h esophageal pH-impedance monitoring in 71
consecutive patients with chronic cough [11]. The rate of association (using Symptom
Analysis Probability SAP) was high, with 70% of patients with temporal associa-
tions. Positive SAP for cough preceded by reflux was present in 48% of patients and
these patients had a more sensitive cough reflex (using citric acid). The similar incidence
of cough preceding reflux points suggests that cough and reflux may precipitate each
other resulting in a self-perpetuating cycle maintaining chronic cough.
Results of randomized controlled therapeutic trials in patient with coughassociated

reflux are not decisive. When considering meta-analysis comparing PPI treatment
(2-3 months) with placebo no significant difference was reported on the resolution
of cough [12, 13] (Figure 1). In fact better designed studies including carefully selected
patients are required before conlcuding that GERD treatment is not effective in a sub-
group of patients with reflux-related cough.
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Papers
Standard mean difference Weight Standard mean difference

Study or subcategory (fixed) (95% CI) (%) (fixed) (95% CI)
Studies using omeprazole 24.23 -1.09 (-2.03 to -0.15)

Kijander 2000 40.31 -0.48 (-1.21 to 0.25)
Noordzij 2001 64.55 -0.71 (-1.29 to -0.14)
Subtotal (95% CI)
Test for heterogeneity: 2=1.01, df=1, P=0.32, I 2=0.7%
Test for overall effect: z=2.42, P=0.02
Studies using other PPI (lansoprazole, pantoprazole)

Eherer 2003 14.72 0.39 (-0.81 to 1.59)
Havas 1999 20.74 0.01 (-1.00 to 1.03)
Subtotal (95% CI) 35.45 0.17 (-0.61 to 0.94)
Test for heterogeneity: 2=0.22, df=1, P=0.64, I 2=0%
Total (95% CI) 100.00 -0.40 (-0.86 to 0.06)

Test for heterogeneity: 2=4.41, df=3, P=0.22, I 2=32.0%
-4 -2 0 2 4
Favours PPI Favours placebo
Fig 3 Meta-analysis of standardised cough scores at end of intervention (77 participants included in meta-analysis)
Figure 1: Meta-analysis of standardised cough scores at end of intervention (77 participants

SD units (fixed) Weight SD units (fixed)
included
Study in meta-analysis) (from Chang et al. [12]).(95% CI) (%) (95% CI)
Eherer 2003 38.68 -0.34 (-0.88 to 0.20)

Kijander 2000 61.32 -0.45 (-0.88 to -0.02)
100.00 -0.41 (-0.75 to -0.07)
In Test
clinical practice the question is to establish 1) the diagnosis of GERD and 2) the link
for heterogeneity: =0.10, df=1, P=0.76, I =0%
2 2
between
Test for overallGERD and
effect: z=2.37, respiratory -1manifestations.
P=0.02 -0.5 0 The empiric
0.5 strategy
1 with PPI (usually
double dose) for at least 3 months is largely used despite
Favours PPI
the lack of strong evidence
Favours placebo
of its relevance. In usual conditions

Fig 4 Meta-analysis of data from the two crossover trials
investigations are proposed after failure of empirical
assessing mean change in symptoms (subanalysis). Using generic inverse variance for crossover studies,
13 14
use of proton pump inhibitors was significantly more likely than placebo to reduce cough scores at end of intervention, 0.41 SD units (0.75 to 0.07)
approach. This approach is reinforced by the results of a recent retrospective analysis
GORD,ofand previous
most, but studies
not all, had suggesting
cough. GORD that there
criteria alsocould be with
junction a subgroup
proton pump ofinhibitors.
responders amongst
In children, the absence of
varied patients
between studies, withwhich highermay havelevels of esophageal
influenced results. Most acid exposure
data makes specific[14]. pH or pH-impedance
recommendations impossible, and other
studies did not use criteria for GORD specified by international causes of cough should be considered in children before any
monitoring is better performed off therapy
guidelines. There are no data from randomised controlled tri-
3 24 to document pathological esophageal
empirical treatment with a prolonged course of GORD medica-
als on acid exposure
the efficacy of GORDand with
treatment special
for chronic emphasis
cough in the given
tions to the analysis
or interventions. of theparallel
Sufficiently powered temporalplacebo con-
absence correlations
of GORD symptoms. between In view of cough bursts
the possibility and refl
of period ux randomised
trolled episodes. However
controlled when
trials that includepatients
an examination
fail to respond to PPI despite documentedof
or placebo effect leading to misdiagnosis of chronic non-specific
cough as due to GORD, we believe that objective confirmation of
time to response, optimal duration of treatment, effects after
refl ux it maybe useful to perform pH-
treatment, and valid cough outcomes (objective and validated
GORDimpedance
is preferable monitoring
to empirical therapy while in thepatients
patient withis on therapy
subjective to are
scales) determine
required tothe potential
justify roleguide-
international
chronicof residualcough
non-specific acidand reflnouxgastrointestinal
or non acid refluxInrelated
symptoms. lines. with the occurrence
Examinations
4 5
of differentoftreatments
cough. for acid and
those with gastrointestinal symptoms, however, an empirical trial non-acid GOR are also required.
of proton pump inhibitors may be justified.
Conclusion
Proton pump inhibitors are currently the most potent
What is already known on this topic
Definitive
non-surgical studies
intervention establishing
for acid-GORD, and noaadverse
causal effect between reflux and respiratory manife-
events
were reported in these studies. The use of these drugs as a trial of Gastroesophageal reflux disease (GORD) is common in
therapystations
is probablyare
low still lacking.
risk but It appears
rational prescription that a8 varietyadults
is required. of triggers might be involved making
with chronic cough
Protonpatients moremay
pump inhibitors sensitive
also causeto some
cough andinternal
the packagevagal stimuli such as esophageal reflux events.
insert In
foraddition
omeprazole includes cough as an adverse International guidelines on cough recommend empirical
a central sensitization mayevent
contribute to a larger syndrome inducing such a
treatment for GORD in those with chronic cough, though
(1.1%).9 In contrast with pharmaceutical interventions, we found
cough
no studies hypersensitivity
on surgical exceeding
intervention, which thewith
is associated single
a relationship between
evidence for an respiratory diseases
effect is conflicting
and
small but reflux. rate of serious adverse events.
measurable
What this study adds
Conclusion and future research Drugs to reduce the effect of gastric acid in GORD are
From this systematic review and meta-analysis we conclude that beneficial in some adults with cough associated with GORD
proton pump inhibitors for cough associated with GORD prob-
PRESIDENTS
ably have someCarmelo Scarpignato,
effect in MD, DSc,
some adults, though the PharmD, MPH (Parma,
effect is less Italy)isless
The effect Francesco Di Mario,
universal than MD
suggested (Parma,
in cohort Italy)
studies 63
universal than reported in cohort studies. There are insufficient and international guidelines on chronic cough, and the
data to support or refute common recommendations to change magnitude of the clinical effect is uncertain
the diet or use motility agents either as a single agent or in con-
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References
2) Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux
disease and asthma: a systematic review. Gut 2007; 56: 1654-1664.
3) Sontag SJ, OConnell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, Serlovsky R. Most
asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology
1990; 99: 613-620.
4) Harding SM, Guzzo MR, Richter JE. 24-h esophageal pH testing in asthmatics: respiratory symptom
correlation with esophageal acid events. Chest 1999; 115: 654-659.
5) Kiljander TO, Laitinen JO. The prevalence of gastroesophageal reflux disease in adult asthmatics.
Chest 2004; 126: 1490-1494.
6) Kiljander TO, Harding SM, Field SK, Stein MR, Nelson HS, Ekelund J, Illueca M, Beckman O,
Sostek MB. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled
trial. Am J Respir Crit Care Med 2006; 173: 1091-1097.
7) Zerbib F, Guisset O, Lamouliatte H, Quinton A, Galmiche JP, Tunon-De-Lara JM. Effects of bronchial
obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with
asthma. Am J Respir Crit Care Med 2002; 166: 1206-1211.
8) American Lung Association Asthma Clinical Research Centers, Mastronarde JG, Anthonisen NR,
Castro M, Holbrook JT, Leone FT, Teague WG, Wise RA. Efficacy of esomeprazole for treatment of
poorly controlled asthma. N Engl J Med 2009; 360: 1487-1499.
9) Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole 40 mg once or twice daily on
asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2010; 181: 1042-1048.
10) Chan WW, Chiou E, Obstein KL, Tignor AS, Whitlock TL. The efficacy of proton pump inhibitors for
the treatment of asthma in adults: a meta-analysis. Arch Intern Med 2011; 171: 620-629.
Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroente-
rology 2010 ; 139: 754-762.
12) Chang AB, Lasserson TJ, Kiljander TO, Connor FL, Gaffney JT, Garske LA. Systematic review and meta-
analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough
associated with gastro-oesophageal reflux. Br Med J 2006; 332: 11-17.
13) Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gastro-oesophageal reflux treatment for
prolonged non-specific cough in children and adults. Cochrane Database Syst Rev 2011; CD004823.
14) Kahrilas PJ, Howden CW, Hughes N, Molloy-Bland M. Response of chronic cough to acid-suppressive
therapy in patients with gastroesophageal reflux disease. Chest 2013; 143: 605-612.
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Notes
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15:30 ENT Manifestations of Laryngopharyngeal Reflux

Wolfgang Issing, MD, PhD, FRCS
Consultant ENT Surgeon, Freeman Hospital,
Newcastle-upon-Tyne, UK
Associate Professor of Otolaryngology, Ludwig-Maximilian
University, Munich, Germany
We live in the golden era of laryngology, with laryngopharyngeal

Wolfgang Issing reflux (LPR) being perhaps the most extensively researched ENT
topic of the past decade. The H + /K+ -adenosine triphosphatase
(proton) pump has been found in serous cells and ducts of sub-
mucosal glands in the human larynx, representing a potential site for proton pump
inhibitor action, with possible relevance for the treatment of patients with chronic
laryngitis with or without LPR disease. Laryngopharyngeal reflux is here to stay. Despite
advances in the role of pepsin, better drugs, and less invasive tests, diagnosis is still
difficult and is still in many places based on empiric treatment rather than robust
evidence.
Over the last 30 years, otolaryngologists have reported an increasing number of

patients suffering from non-specific laryngeal and respiratory disorders attributed to
laryngopharyngeal reflux (LPR). An estimated 4 to 10 per cent of ENT patient consul-
tations are prompted by LPR-related symptoms. In the three year period 1990-1993,
annual visits to otolaryngologists by patients suffering from reflux-related problems
averaged 89,000; this average increased to 421,000 annual visits during the three-
year time span 1998-2001. Therefore in-depth knowledge of diagnostic methods and
treatment options for LPR is becoming more important. Laryngopharyngeal reflux is
a manifestation of extra-esophageal gastro-oesophageal reflux disease. Its proposed
mechanisms of injury include direct contact of the larynx with low pH irritant stomach
contents and vagally mediated reflex responses to exposure to low pH in the distal
oesophagus. Symptoms of laryngopharyngeal reflux are variable and include throat
clearing, sore throat, troublesome cough, and hoarseness. The Reflux Symptom Index
is a validated symptom questionnaire that can support establishing a diagnosis. Never-
theless many symptoms of laryngopharyngeal reflux do not fall within the realm of
the Reflux Symptom Index or the gastro-oesophageal reflux disease (GERD) Symptom
Assessment Scale and can make diagnosis challenging. Laryngoscopy findings in
patients with laryngopharyngeal reflux similarly show great variability. They may include
subglottic oedema, ventricular obliteration, erythema and hyperaemia, vocal cord
oedema, laryngeal oedema, posterior commissure hypertrophy, granuloma, and thick
endolaryngeal mucus (Figure 1). These findings are represented by the Reflux Finding
Score, a tool to assist in the evaluation of laryngopharyngeal reflux and the efficacy of
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its treatment. Laryngoscopic signs of reflux can also be found in up to 70% of healthy
volunteers and are therefore not sensitive or specific for laryngopharyngeal reflux.
Signs on Laryngoscopy
Erythema (arrow)
Edema
Ventricular Obliteration
Postcricoid Hyperplasia
Normal Pseudosulcus
Vestibular Vocal Cord Ventricular

Fold Edema Obliteration
(Ventricle)
Vocal Cords
Trachea
Esophagus
Figure 1: Laryngo-pharyngeal reflux: signs on laryngoscopy (from Barry & Vaezi [2010]).
The issue of chronic cough, postnasal drip, and reflux is quite a controversial topic and
remains a therapeutic challenge. Troublesome cough can often be the only symptom
of laryngopharyngeal reflux, and some patients will consult respiratory physicians and
undergo respiratory investigations for some time before a diagnosis of laryngopharyn-
geal reflux is established. Chronic cough can be associated with many diseases that
often overlap more than one medical specialty. A detailed assessment of the patient
with chronic cough relies on a multidisciplinary approach and close cooperation
between pulmonary medicine, gastroenterology, and otolaryngology. Gastro-esopha-
geal reflux (GERD) and postnasal drip syndrome account for a significant number of
cases of chronic non-productive cough seen in otolaryngology practice. Each may,
alone or in combination, contribute to cough even when clinically silent and failure
to recognise their contribution may lead to unsuccessful treatment. Many of these
patients are notoriously difficult to diagnose and treat but the literature suggests that
a systematic and thorough approach in a multidisciplinary setting can lead to successful
diagnosis and treatment in the majority of patients.
Proton pump inhibitors (PPIs) suppress gastric acid production and have been shown
to be efficient in treating GERD, but their value of treating the symptoms of laryngo-
pharyngeal reflux is controversial.
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Alginate suspensions act by forming a raft on top the gastric contents, producing a
mechanical barrier preventing reflux outside the stomach, thus possibly reducing or
preventing the contact of gastric contents with the oesophageal and laryngeal mucosa.
Alleviation of symptoms of laryngopharyngeal reflux has been achieved with an alginate
suspension (Gaviscon Advance) in an uncontrolled study. Studies on healthy individuals
have shown that there is no negative impact on the bioavailability of proton pump
inhibitors when co-prescribed with alginates, and neither does treatment with proton
pump inhibitors affect the formation of alginate rafts. Gaviscon Advance is the only
alginate compound licensed for the treatment of laryngopharyngeal reflux.
Gastroesophageal reflux during sleep is thought to be an important mechanism for

the development of certain supra-esophageal complications of laryngopharyngeal
reflux, such as asthma and idiopathic pulmonary fibrosis. While some patients with
laryngopharyngeal reflux have been described as experiencing daytime or upright
reflux other patients have reported supra-esophageal symptoms, most notably asthma
and laryngospasm, shown to have an association with night-time, or supine, reflux.
There are several proposed mechanisms believed to support the significance of night-
time reflux in the pathogenesis of certain reflux-related laryngeal disorders. During
waking hours, several protective responses defend the esophageal and supra-esopha-
geal structures against injury due to exposure to gastric contents. These protective
Figure
responses2 -areDeterminants of Nocturnal
absent or less effective Esophageal
during sleep (Figure 2). Exposure to Gastric
Refluxate (from Orr [2005])
Contact time of gastric refluxate is greater
during sleep and supine positioning than
when awake and upright
Esophageal Physiology During Sleep
Esophageal acid clearance
Gravity-mediated drainage of refluxate
Swallowing and primary peristalsis
Salivary flow
Heartburn awareness
Upper and lower esophageal sphincter pressure
Cough reflex
Upright Supine
Figure 2: Determinants of nocturnal esophageal exposure to gastric refluxate (from Orr [2005]).
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In addition, during sleep several mechanisms act to slow oesophageal acid clearance
and to prolong the contact time of gastric acid in the oesophagus. These mechanisms
include: slower gastric emptying; decreased saliva production; decreased swallowing
frequency; and a reduction in voluntary clearance behaviours, due to a lower aware-
ness of heartburn. During deep sleep upper oesophageal sphincter pressure dimini-
shes significantly. This drop in sphincter pressure weakens the barrier, which prevents
movement of gastric refluxate from the esophagus to the larynx or pharynx during
sleep. Furthermore, basal acid output increases in the late evening and the early mor-
ning hours, allowing for the possibility of a more injurious gastric refluxate.
Eosinophilic esophagitis (EE) is a great reflux mimic and often presents with dysphagia,
recurrent food bolus obstruction and GERD-like symptoms (Figure 3).
Prox Esophagus at 25 cm
Allergic esophagus
infiltrative eosinophilia
Increasing incidence vs
underrecognized
Signs/symptoms:
Dysphagia, food impaction,
abdominal/chest pain,
vomiting, regurgitation
Eos
Clinical characteristics
Male predominance
(70%-80% of cases)
Family or personal history
of allergy/atopy
- Asthma, rhinitis, eczema,
food allergy
Endoscopic Features
GERD of Eosinophilic Esophagitis
and Reflux Esophagitis
Figure 3: Eosinophilic esophagitis can mimic GERD (from Arora & Amazaki [2004]).
Despite higher awareness, the literature suggests that EE remains a commonly misdia-
gnosed condition especially in the otolaryngology community. The treatment though
differs than the LPR treatment and EE should be part of the differential diagnosis
when faced with difficult to treat LPR or GERD. The introduction of Transnasal
Esophagoscopy (TNO) in the ENT office over the last decade has meant that increa-
singly more laryngologists become accustomed in recognising esophageal pathology
including EE.
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The role of surgery in management of laryngo-pharyngeal reflux is also a matter of

debate in the literature. Results of laparoscopic fundoplication for the treatment of
classic GERD are well established. In theory, surgery for persistent LPR after failure of
medical treatment should be equally as effective, if we agree on the notion that LPR
and GERD share common pathophysiology. Many studies have demonstrated symp-
tomatic improvement after surgical fundoplication. However, current knowledge does
not allow this conclusion. Large multicentre, randomized control trials are needed,
focusing on diagnostic tools to improve selection criteria, presenting standard end-
points and long-term follow-up.
Suggested Readings
Altman KW, Haines GK, Hammer ND, Radosevich JA. The H +/K+ -ATPase (proton) pump is expressed
in human laryngeal sumucosal galnds. Laryngoscope 2003; 113: 1927-1930.
Arora AS, Yamazaki K. Eosinophilic esophagitis: asthma of the esophagus? Clin Gastroenterol
Hepatol 2004; 2: 523-530.
Barry DW, Vaezi MF. Laryngopharyngeal reflux: More questions than answers. Cleve Clin J Med
2010; 77: 327-334.
Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS).
Laryngoscope 2001; 111: 1313-1317.
Dettman PW, Hampson FC, Jain A. Administration of an alginate based gastric reflux suppressant
on the bioavailability of omeprazole. Ind J Med Res 2006; 123: 517-524.
Dettmar PW, Little SP, Baxter T. The effects of omeprazole pre-treatment on rafts formed by reflux
suppressant tablets containing alginates. J Int Med Res 2005; 33: 301-308.
Fass R, Achem SR, Mittal RK, Quigley E: Supraoesophageal manifestations of gastro-oesophageal
reflux disease and the role of night-time gastro-oesophageal reflux. Aliment Pharmacol Ther 2004;
20: 26-38.
Karkos PD, Benton J, Leong SC, Karkanevatos A, Badran K, Srinivasan VR, Temple RH, Issing WJ.
Trends in laryngopharyngeal reflux: a British ENT survey. Eur Arch Otorhinolaryngol 2007; 264:
513-517.
Karkos PD, Leong SC, Benton J, Sastry A, Assimakopoulos DA, Issing WJ. Reflux and sleeping
disorders: a systemic review. JLO 2009; 1-3.
Koufman JA. Laryngopharygeal reflux: a new paradigm airway disease. Ear Nose Throat J 2002;
81: 2-6.
Lieder A, Issing W. Treatment for resilient cough owing to laryngopharyngeal reflux with a combina-
tion of proton pump inhibitor and Gaviscon Advance: how we do it. Clin Otolaryngol 36: 583-587.
McGlashan JA, Johnstone LM, Sykes J. The value of a liquid alginate suspension (Gaviscon Advance)
in the management of laryngopharyngeal reflux. Eur Arch Otorhinolaryngol 2008; 266: 243-251.
Orr WC. Night-time gastro-oesophageal reflux disease: prevalence, hazards, and management.
Eur J Gastroenterol Hepatol 2005; 17: 113-120.
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Reichel O, Dressel H, Wiederaenders K, Issing WJ. Double-blind, placebo-controlled trial with

esomeprazole for symptoms and signs associated with laryngopharyngeal reflux. Head Neck Surg
2008; 139: 414-420.
Reichel O, Issing WJ. Impact of different pH thresholds for 24-hour dual probe pH monitoring in
patients with suspected laryngopharyngeal reflux. JLO 2007; 1-5.
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16:00 GERD-related Non Cardiac Chest Pain

and Arrhythmias
John de Caestecker, MD, FRCP
Consultant Gastroenterologist, Digestive Diseases Centre,
University Hospitals of Leicester, UK
Honorary Professor, Department of Health Sciences,
DeMontfort University, Leicester
John de Caestecker Introduction and Epidemiology

Having previously been regarded as an extra-esophageal manife-
station of GERD, non-cardiac chest pain (NCCP) is now grouped
among the esophageal syndromes by the Montreal classification (2006). NCCP is re-
cognised to be prevalent in Western communities: a recent meta-analysis of community
surveys found a prevalance of 13% [1]. Interestingly, NCCP was found to be far more
prevalent in individuals also reporting heartburn [1], demonstrating that the esophagus
is a common source of NCCP. Of those that present to physicians, non-cardiac causes
of chest pain are the commonest diagnoses among patients seen in general practice
[2] and those referred to cardiologists [3, 4]. Half or more of such patients do not
appear to have a cardiac diagnosis; however, these patients often continue to have
symptoms and disability [1, 2 ]. In the more highly selected group undergoing coronary
angiography, disability persists even 10 years after the demonstration of normal
coronary arteries [5]. It is clearly desirable to identify these patients early in the hope
of preventing the false perception that symptoms arise from the heart (which can be
very difficult to dispel) [6]. Patients prefer to have an explanation for their symptoms,
and in this context it is well recognised that the esophagus is a likely site of origin for
symptoms: indeed gastro-esophageal reflux (GER) is by far the commonest abnormality
identified but the question is whether GER is causally related to the symptoms.
It should be appreciated that other causes such as musculoskeletal disorders are also
common in NCCP patients and should also be considered by physicians, including
gastroenterologists [7]. It may be that there is more than one trigger for chest pain
which the patient then misinterprets as being cardiac and of serious import, probably
as a result of psychosocial factors [6, 8]. An understanding of the underlying neuro-
physiology of nociception from the esophagus [9] (considered below) shows how
multiple minor stimuli from different sources within the chest, chest wall or upper
abdomen can result in changes in central pain pathways which result in perception
of pain. Preconceptions, psychological state and hypervigilance [8] cause patients to
focus on and misinterpret this pain: the longer this situation persists, the more likely
that the pain pathways will remain permanently altered and the more difficult it
becomes to reverse these changes.
Hiroto Miwa, et al

quantify; and patients do not necessarily use the same words to EXTRA-DIGESTIVE is felt. These are esophageal
GERD:sensations. A substantial
describe the same sensations. As a site for research on visceral WHATS knowledge NEXThas ?accumulated about the stimuli resp
sensation, the esophagus offers a number of advantages; for ex- such sensations, the pathways by which those stimuli
ample, determination of the sites where esophageal symptoms mitted to the central nervous system, and the receptors
originate is comparatively easy, and the esophagus has the com- ate that transmission.
Patients
parativelywith established
specific coronary
symptom heartburn. artery even
However, disease,
in theincludingIt isthosethought whothat, have hadnoxious stimuli - che
generally,
interventions (surgery or coronary stenting) also commonly have chest pain which
esophagus, research on the manifestation of symptoms is not easy. chanical, thermal and etc - in the esophageal mucos
is not always clearly cardiac in origin. Patients find it difficult to distinguish between
In this article,
heartburn and weangina
review findings
[9, 10],related
so it to
is esophageal sensation
not surprising verted to action
that cardiologists oftenpotentials by nociceptive receptors on
empirically
and hypersensitivity in the hope of contributing to the under- nerves
prescribe acid suppression in this context, once persisting cardiac ischaemia has been and are then transmitted to the central nervous
standing of the mechanisms by which visceral symptoms are
excluded. either spinal nerves or vagal nerves (Fig. 1). Via the s
manifested. pathway, the signals are transmitted to laminae I and
Aetiology dorsal horn of the spinal cord via dorsal root ganglia,
The inter-relationships between esophageal and cardiac pain are readily
cell bodies understood
of the primary sensory neurons are located
byBasis of Esophageal
considering Sensationof Pathway
the neurophysiology visceral pain. Nociceptor informationpathways
arriving at from bothhorn is then transmi
the dorsal
esophagus and heart, as well as those from
After being swallowed, food and beverages are automatically other organs such as gallbladder and
ondary neurons by neurotransmitter-mediated syna
pleura, converge on the same 2nd order spinothalamic neurones within the spinal cord
conveyed to the stomach through the esophagus. Normally, this mission, and then directly or interneuronally transmi
[9] (Figure 1). These neurones also receive input from cutaneous and somatic structures,
process occurs
explaining theunconsciously, but if from
referral of pain the food
bothor beverage
heart and is ex-gullet thalamus. The axons
to the anterior of theneck
chest, dorsal horn neurons i
cessively hot or cold, the person will perceive the process.
and arms and the difficulty patients have in distinguishing between different sourcesthought to ascend th
transmission to the thalamus are
2-4
Furthermore,
and types of whenchesta large
pain.amount of material is swallowed, pain lamic tract in the contralateral lateral funiculus.
nerves are also thought to play an important role in co
tion between the gastrointestinal (GI) tract and brain.
gal pathway, noxious information is thought to be tran
the nucleus of the solitary tract via the nodose gangli
the significance of these two sensory pathways is still n
derstood, it is possible that a specific transmission pa
be selected depending upon the type of noxious stimu
cific receptors are associated with different types
Nodose ganglion stimuli. In the stomach, vagus and spinal nerves have b
Nucleus tractus solitari to be involved in transmission of signals from chemic
5-7
Vagus nerve chanical stimuli, respectively, while in the esopha
been inferred that perception of noxious stimuli invol
Spinal nerve spinal nerves.
8
Esophagus Identification of the receptors for noxious stimuli

Dorsal root ganglion Figure 1: Sensoryesophageal
for understanding pathway sensation and hypersen
from esophagus
the field of somatic topain,
brain.proteins and receptors expres
Spinal cord Esophageal nociceptive
cally in primary stimuli have been discovere
sensory neurons
are conveyed to the brain via
another, and their roles in the transmission of pain se
2 major sensory pathways a
being investigated.
sympathetic pathway Receptors
and vagalof the transient recepto
9
pathway (from Miva et al. [9]). typical. The TRP f
(TRP) cation channel family are
Stomach sists of six subfamilies, each of which has addition
channels. Many other nociceptive receptors, includin
the acid-sensing ion channel (ASIC) family and the P
Figure 1. Sensory pathway from esophagus to brain. Esophageal a family of ligand-gated ion channels responsive to A
nociceptive stimuli are conveyed to the brain via 2 major sensory been cloned, but in regard to the esophagus, the tr
pathways - a sympathetic pathway and vagal pathway. ceptor potential vanilloid 1 (TRPV1) receptor has at
354 Journal of Neurogastroenterology and Motility

WHATS NEXT ?
Furthermore, it is clear that acid perfusion of the esophagus can lead to neurally
mediated coronary artery narrowing and cardiac ischaemia [11, 12]: indeed, sponta-
neously occurring GER has been shown to be associated with ECG evidence of cardiac
ischaemia [10], indicating the potential of GER to cause ischaemia in patients with
proven coronary artery disease. The potential mechanisms by which arrythmias may
be initiated by stimuli arising from the gullet (such as swallow syncope) [13] are less
well studied but are likely to arise through vagal mechanisms. These are rare and have
been shown to be initiated by oesophageal distension in studies now over 50 years
old, but treatment is usually directed towards preventing the arrythmia (eg by cardiac
pacing) rather than to the gullet [13]. There are some interesting but contraversial
data linking AF to GERD the GERD may predate the AF [14]. If the association exists,
the mechanism is unclear but may be related to vagal mechanisms.
NCCP is likely to be a range of disorders, similar to GERD, where the classical con-
dition of endoscopic esophagitis accompanied by excess GER is only one part of a
spectrum: non-erosive reflux disease (NERD) patients are acid sensitive without neces-
sarily having excess acid reflux while patients with functional heartburn (FH) have
neither excess acid nor esophagitis and their symptoms do not coincide with reflux
events. These FH patients have hypersensitivity to a wide variety of esophageal stimuli
[13]. Among patients with NCCP, a similar spectrum is evident, although endosco-
pic esophagitis is rare in these patients, found in 30% or less. Rome III recognises
functional chest pain as a distinct category with similarities to FH [15, 16] but it is
clear that both functional chest pain patients and NCCP patients with acid sensitive
esophagus (similar to NERD) both have abnormal sensitivity to intra-esophageal acid.
In this context it is helpful to review current understanding of the effects of intra-
esophageal acid on esophageal sensation. Peripheral sensitisation of the esophagus
to balloon stretch has been demonstrated in response to acid in healthy volunteers
[17]: in this study, as had been recognised previously, patients with NCCP already had
a lowered threshold to balloon stretch, raising the posibility that acid reflux may have
caused this. Further studies have shown that spinal neurones can be sensitised by
repeated esophageal acid perfusion [18]. This is called central sensitisation: this dif-
fers from peripheral sensitisation at the site of the stimulus since recruitment occurs of
sensory fields distant from the original acid exposure, in the more proximal esophagus
(secondary hyperalgesia). The time pattern of this sensitisation is dependent on the
duration and frequency of the initial noxious acid stimulus such that repeated and/
or long lasting acid infusion results in prolonged central sensitisation outlasting the
original stimulus by hours [18]. Further human experiments have shown that blockade
of PGE1 [19] or NMDA [20] receptors attenuates or abolishes this central sensitisation.
Furthermore, in patients with noncardiac chest pain the fact that prolonged treat-
ment with proton pump inhibitors (PPIs) appears to partially reverse central sensitisa-
tion [21] argues that occult acid GER may be an important trigger of NCCP in clinical
practice. Patients in whom a non cardiac trigger for chest pain is not recognised and
WHATS NEXT ?
treated early become difficult to treat probably because the central sensitisation
becomes permanent.
Investigation
In terms of investigation, a reasonable first choice investigation is a short therapeutic
trial of high dose PPI: a recent meta-analysis has demonstrated a pooled sensitivity of
80% and specificity of 74% for this therapeutic trial [22]. It should be noted that for
most of these studies, a 50% reduction in chest pain was required to define a postive
response. The relatively low specificity reflects the fact that a high placebo response
rate can be expected in this patient group, reflecting the heterogeneity of NCCP sub-
groups as mentioned above. The relatively poor sensitivity likely reflects the fact that
even with long 3 month courses of PPI, esophageal hypersensitivity to acid is not fully
reversed [21] so a short therapeutic trial of PPI may not identify all NCCP patients
with GER-induced pain. Indeed, one recent study has suggested an advantage to a
longer therapeutic trial [23]. While endoscopy will usually be carried out, it rarely
shows esophagitis in NCCP patients. Prolonged esophageal pH monitoring is the best
available test to diagnose NCCP secondary to GER. In my view, it is best carried out
in patients with a normal endoscopy in whom the PPI test is negative or in whom
continued PPI treatment has lost efficacy. There is some evidence that prolonged
(48 hour or more) monitoring using the BRAVO pH sensor detects more patients with
GER-related NCCP [24] and it may be that 24-hour pH and impedence monitoring is
a more sensitive test as suggested by one recent study [25], but this remains unclear.
The most important aspect of esophageal pH/impedence monitoring is to demonstrate
a symptom-reflux association (either using the Symptom Index [SI] with a threshold
of > 50% or the Symptom Association Probability [SAP]) between chest pain (not
heartburn if the patient complains of both symptoms) and reflux events, whether
detected by pH or impedence. My own experience, in a trial recruiting patients with
pH monitoring proven GER and NCCP, was that PPIs were surprisingly ineffective in
comparison to placebo treatment. The only patients likely to respond to esomeprazole
in this small trial were those with a positive symptom index for chest pain [26].
Treatment
There has been a recent meta-analysis of RCTs of treatment of acid-related NCCP with
PPIs, demonstrating RR for improvement versus placebo of 4.3 for a 50% improve-
ment in chest pain (Figure 2). This meta-analysis also showed that patients without
objective evidence of GER rarely responded to PPIs, and that the additional presence
of heartburn did not predict a response to PPI therapy [27]. In my opinion, calculation
of the SI or SAP for chest pain is more useful than quantitating acid or non-acid GER
[26]. Although there is no strong evidence to support particular dosing schedules of
PPIs, I prefer to use a twice-daily PPI (making sure it is taken 30-60 minutes before
meals) because this provides superior 24-hour suppression of gastric acid secretion
[28].
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100
+
Therapeutic gain with PPI (%)
90 Lansoprazole 30 mg daily
Upper limit of potential
80
therapeutic gain Lansoprazole 60 mg
70 AM and 30 mg PM
60
Omeprazole 40 mg
50 AM and 20 mg PM
40 Omeprazole 40 mg
30
twice daily
20 Rabeprazole 20 mg
AM and 20 mg PM
10
0 Global average
0 10 20 30 40 50 60 70 80 90 100 (error bars represent range)
Placebo response (%)
Figure 2: Therapeutic gain in randomised placebo-controlled trials of proton pump inhibitor

treatment for unexplained chest pain. All five clinical trials used a threshold of >50% improve-
ment in chest pain to define a positive treatment response. (+) indicates GERD-positive patients
(abnormal esophageal acid exposure and/or reflux esophagitis); () indicates GERD-negative
patients (no objective evidence of GERD); PPI, proton pump inhibitor. The upper limit of potential
therapeutic gain (diagonal line) is 100 minus the placebo response rate (from Kahrilas et al. [27]).
In patients not responding to a PPI, it is worth considering a tricyclic antidepressant

(TCA) such as imipramine or nortryptiline, as NCCP patients are commonly hypersen-
sitive to acid and other stimuli as explained above [29]. Indeed, there may be benefit
in combining PPI treatment with TCA in patients with an incomplete response to PPI
alone [30]. My own practice is to use nortryptiline or imipramine in preference to ami-
tryptiline, as many patients find the latter too sedating even at small doses of 10-20
mg at night. I titrate the dose from 25 mg at night, increasing by 25 mg every 2 weeks
and aiming for a dose of between 50-100 mg. Many patients are not able to tolerate
these doses and indeed one study found that although chest pain was improved by
imipramine, quality of life was not, due to adverse drug effects [31]. For patients
unable to tolerate TCAs, sertraline may be effective [32, 33] but it has not been used
in combination with PPIs. Both citalopram [34] and pregabalin [35] have been shown
to attenuate the hyperalgesic effect of esophageal acid perfusion in healthy controls,
so these agents offer the potential to be used as alternatives to TCAs. Having said
all this, a recent well conducted meta-analysis of RCTs using SSRIs in NCCP failed to
demonstrate any significant benefit of these agents [36].
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Finally, among patients with ischaemic heart disease (IHD), the few clinical studies
which have been reported suggest that GER is common in patients with IHD and that
not only can GER trigger angina but the pain of reflux can be mistaken for angina by
patients [10]. It has recently been shown in a RCT in IHD patients that prescription
of a PPI reduces the amount of angina episodes experienced, probably by the latter
mechanism [37]. However, while this supports the empirical use of PPI therapy among
such patients when cardiological investigation suggests that pain is non-ischaemic,
enthusiasm for this may be tempered by the potential of interaction between some
PPIs and clopidogrel although evidence suggests that this potential interaction is not
of clinical significance [38, 39].
GERD-associated Atrial Arrhythmias

GERD-induced atrial arrhythmias have described long ago. Gerson et al. [40] reported
3 patients with symptoms of both palpitations and GERD, who underwent simultaneous
Holter and 24-hour ambulatory pH-monitoring while not taking any acid-lowering
drug. All of the patients reported a reduction in arrhythmia symptoms on PPI therapy.
These findings suggested a potential relationship between GERD and atrial arrhythmias
that might improve with anti-reflux therapy. A study evaluating 32 patients with GERD
and arrhythmias found in 56% of them a statistically significant correlation between
the esophageal pH and heart rate variability [41]. PPI therapy was effective also in
these patients with a significant reduction of cardiac symptoms, suggesting that patients
with GERD and arrhythmias, in whom esophageal acid stimulus induced cardiac auto-
nomic reflexes, acid suppression is able to achieve symptom relief.
A recent systematic review [42], including 8 papers, found - in patients with GERD a
prevalence of atrial fibrillation (AF), of 0.6-14%, a figure higher than that observed
in subjects without reflux disease. Observational studies showed that patients with
GERD, especially those with more severe symptoms, have also an increased risk of
developing AF compared with those without.
However, a causal relationship between GERD and AF could not be established. The
mechanisms of GERD-associated AF remain largely unknown, with inflammation
and vagal stimulation playing a possible role in the development of these disorders.
Treatment with PPIs improve symptoms related to AF and may facilitate conversion to
sinus rhythm.
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References
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presumed gastro-oesophageal reflux in coronary artery disease controlled study of lansoprazole
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38) Chen J, Yuan YC, Leontiadis GI, Howden CW. Recent safety concerns with proton pump inhibitors.
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39) Johnson DA, Chilton R, Liker HR. Proton-pump inhibitors in patients requiring antiplatelet therapy:
new FDA labeling. Postgrad Med 2014; 126: 239-245.
40) Gerson LB, Friday K, Triadafilopoulos G. Potential relationship between gastroesophageal reflux
disease and atrial arrhythmias. J Clin Gastroenterol 2006; 40: 828-832.
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42) Roman C, Bruley des Varannes S, Muresan L, Picos A, Dumitrascu DL. Atrial fibrillation in patients
with gastroesophageal reflux disease: a comprehensive review. World J Gastroenterol 2014; 20:
9592-9599.
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Notes
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17:00 GERD and Sleep Disturbances

Ronnie Fass, MD, FACP, FACG
Professor of Medicine, Case Western Reserve University,
Chairman, Division of Gastroenterology & Hepatology
and Director, Esophageal & Swallowing Center,
MetroHealth Medical Center, Cleveland, OH, USA
Introduction
Gastroesophageal reflux disease (GERD) is a chronic disorder and
Ronnie Fass
the most common disease that affects the esophagus. A popu-
lation-based study estimated that 20% of the U.S. adult popu-
lation experience GERD-related symptoms at least once a week [1]. GERD can lead to
esophageal mucosal injury in a subset of patients as well as bothersome symptoms, such
as heartburn and acid regurgitation that may affect patients reported quality of life.
The epidemiology of nocturnal gastroesophageal reflux is not well studied. According

to a Gallup Poll from 1988 in which 1000 GERD patients completed a survey, 79% of
the respondents reported nocturnal heartburn [2]. In a study by Farup et al. 74% of the
subjects with frequent GERD symptoms reported nocturnal symptoms [3]. In contrast,
Locke et al. found in a community-based survey that 47% and 34% of the GERD
sufferers reported nocturnal heartburn and nocturnal acid regurgitation, respectively
[1]. Fass et al. in a large prospective, cohort study of subjects evaluated for sleep
disturbances demonstrated that 24.9% reported heartburn during sleep [4].
Acid reflux episodes are divided into daytime reflux and nighttime reflux. However,
because there is no clear definition of nighttime reflux some prefer the separation to
reflux during awake period and reflux during sleep period. The latter division under-
scores the impact of sleep physiology on gastroesophageal reflux. Acid reflux during
awake time tends to be more frequent, but of shorter duration. In contrast, acid reflux
during sleep is commonly less frequent, but of a significant longer duration [5].
Nocturnal gastroesophageal reflux has been demonstrated to be an important under-

lying mechanism for the development of complicated GERD and extra-esophageal
manifestations of GERD. The latter may include oropharyngeal, laryngeal and pulmonary
manifestations [6, 7]. The former may include erosive esophagitis, peptic stricture,
esophageal ulcerations, Barretts esophagus and adenocarcinoma of the esophagus.
Furthermore, recent reports demonstrated that nocturnal GERD is associated with
poor quality of sleep and a variety of sleep disturbances [8, 9].
Nocturnal reflux is also associated with further decrease in health related quality of
life (HRQL) as compared with the general population. In addition, patients with night-
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time symptoms of GERD have a substantially diminished quality of life as compared

with individuals without GERD symptoms during nighttime [3].
Definition of Nocturnal GERD

Presently, we are still devoid of an accepted definition for nocturnal GERD. Interestingly,
studies that assessed either prevalence or therapeutic response of patients with night-
time heartburn, lacked clear definition of nocturnal GERD [1, 2, 10]. Farup et al. offered
the following definition of nighttime GERD: nocturnal awakening by GERD symptoms;
nocturnal awakening caused by coughing or choking, regurgitation of fluid or food,
and acidic/bitter taste; GERD symptoms while in the supine position; and morning
awakening secondary to GERD symptoms [3]. This is an inclusive definition that may
include patients that experience GERD-related symptoms in the supine position while
still awake. In contrast, Fass et al. suggested that nighttime heartburn should be defined
as heartburn that awakens patients from sleep during the night [Fass, NIH study, DDW
2003] [4]. While this is a much more restrictive definition, it underscores the impor-
tance of having GERD-related symptoms during sleep physiology.
In any case, nighttime heartburn and GER are a symptom and a condition that occur
while sleeping or attempting to fall asleep. This period refers to the time between
going to bed and getting out of bed [5]. Therefore, events during this period strongly
affect the sleep of individuals. GER or symptoms that occur when sleeping during the
day are excluded, although napping is a type of shallow sleep. These concepts are
presented in Figure 1.
Midnight
0
Bedtime Nighttime or
Nocturnal
Recumbent Heartburn/GER
Nighttime
Sleep
Dinner
Evening
18 6 Figure 1:
Arousal Morning Nighttime
heartburn or
Upright Nap Breakfast gastroesopha-
Daytime Sitting geal reflux
Standing
Walking
(from Fujiwara
et al. [11]).
12
Lunch Noon
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Pathophysiology of Nocturnal GERD

Normal sleep physiology results in many changes of gastroesophageal function that
contribute to the pathogenesis of GERD. Sleep may alter physiological mechanisms
responsible for normal esophageal clearance, resulting in impairment of esophageal
acid clearance. Rate of swallowing is reduced during sleep leading to decrease in primary
peristalsis, a pivotal defense mechanism that is responsible for volume clearance of
refluxate from the esophagus [11]. Diminished salivary production during sleep as
well as reduced delivery of saliva to the distal esophagus due to decreased primary
peristalsis delay alkalization and thus normalization of esophageal pH after acid reflux
has occurred. The upper esophageal sphincter basal pressure is significantly reduced,
resulting in an increased risk for aspiration, which may lead to upper airways exposure
to gastroesophageal reflux and consequently extra-esophageal manifestations (Table1).
In addition, gastric acid secretion is increased and gastric emptying is delayed during
nighttime. Moreover, there is less conscious awareness of gastroesophageal reflux
during sleep, resulting in reduction in symptom perception and thus in alteration in
conscious dependent defensive behavior against gastroesophageal reflux (antacid
consumption, assuming the upright position, initiating a swallow, etc.) [12].
Table 1: Extra-esophageal Manifestations of GERD
Pulmonary Pharyngo-laryngeal
Asthma Pharyngitis
Aspiration pneumonia Vocal cord granuloma
Chronic bronchitis Subglottic stenosis
Bronchiectasis Laryngitis
Interstitial pulmonary fibrosis Stridor
Oral Hoarseness
Halitosis Globus
Dental caries Laryngeal cancer
Poor oral hygiene Chronic cough
The overall weakening in esophageal defense mechanisms during sleep leads to pro-
longed esophageal acid exposure during nighttime, resulting in a more serious injury
to the esophageal mucosa. Several studies have demonstrated that nocturnal GERD
is associated with increased risk of having severe gastroesophageal disease, such as
WHATS NEXT ?
erosive esophagitis, peptic stricture, Barretts esophagus and even adenocarcinoma of

the esophagus [13]. DeMeester et al. [14] studied GERD manifestations in 100 patients
with reflux-related symptoms and demonstrated that patients with supine reflux had a
higher incidence of erosive esophagitis than those with predominantly upright reflux.
Robertson et al. [15] compared pH testing results of patients with uncomplicated versus
complicated GERD. The authors concluded that complicated GERD is associated with
prolonged nocturnal acid exposure of the esophagus. They further stipulated that
nocturnal acid exposure may be the cause of peptic stricture, esophageal ulceration
or Barretts metaplasia. Another study has demonstrated a significant nocturnal acid
exposure in patients with Barretts esophagus as compared to those with erosive
esophagitis or non-erosive reflux disease [16]. Furthermore, patients with long-segment
Barretts esophagus ( 3 cm) demonstrated a significantly higher nighttime acid expo-
sure as compared to those with short-segment Barretts esophagus (< 3 cm) [17, 18].
Overall, there was an increase in total as well as supine esophageal acid exposure, as
documented by pH testing, from non-erosive reflux disease to erosive esophagitis and
then to Barretts esophagus [16].
Lastly, the risk of esophageal adenocarcinoma is eight times higher among patients
with weekly reflux symptoms in comparison with asymptomatic subjects. The risk is
even higher in patients reporting nocturnal heartburn [13].
GERD and Sleep Disturbances

There is some data supporting close association between nocturnal GERD and sleep
disturbances. Sleep disturbances in patients with GERD are poorly recognized and
rarely elicited during clinic visits. Despite the significant impact of these disturbances
on patients quality of life and, probably, on their perception of the severity of their
disease, sleep disturbance is not usually asked about in the routine history taken from
patients with reflux disease. When 759 patients with endoscopy-negative reflux disease,
who were enrolled in the esomeprazole (Nexium) clinical trial program, [19] were
assessed by a quality of life tool for sleep disturbances for at least some of the time
(score 4), 50% reported that symptoms of GERD were responsible for difficulties in
getting a good nights sleep. Other indicators of sleep disturbance were feeling tired/
worn out due to lack of sleep (42%), failure to wake up feeling fresh/rested (41%),
having trouble falling asleep (40%), and heartburn/acid regurgitation waking the
patient and preventing him/her from falling asleep (35%) [19].
In a national survey of 1000 subjects with GERD, 75% of the participants reported
that GERD symptoms affected their sleep, 63% believed that heartburn negatively
affected their ability to sleep well [2]. The prevalence of sleep disturbances among
respondents increased with increase in frequency of the nighttime heartburn episodes
during the week. Additionally, 42% could not sleep through the night and 39% took
naps whenever possible. Green et al. reported, in an abstract form, that GERD patients
WHATS NEXT ?
that sleep less during the night are more likely to have symptoms that correlate with
acid reflux events [20]. Additionally, the extent of distal esophageal acid exposure has
a significant effect on patients reported sleep experience [8]. The higher the acid
exposure, the lower the overall reported quality of sleep (supine) and the higher the
number of nocturnal awakenings (total and supine). Dekel et al. demonstrated that
the frequency and severity of GERD symptoms were correlated with patients quality
of sleep. Patients with erosive esophagitis reported more nocturnal awakenings due
to heartburn than those with non-erosive reflux disease, but otherwise reported simi-
lar sleep abnormalities and quality of sleep. Other investigators have demonstrated
that nighttime gastroesophageal reflux may result in anamnestic short awakenings
that lead to sleep fragmentation and feeling unrefreshed the next morning, dozing
off and daytime sleepiness [9].
Obstructive sleep apnea (OSA) is a breathing disorder that occurs during sleep in which
the patient experiences respiratory pauses lasting at least 10 seconds and occurring
at least 5 times per hour of sleep [21]. OSA is characterized by excessive daytime
sleepiness, snoring, repeated episodes of upper airway obstruction during sleep, and
nocturnal hypoxemia leading to memory problems, irritability, and depression. The
exact association between OSA and GERD remains controversial. In one study, OSA
was not influenced by severity of GERD. Additionally, objective measures of disordered
sleep had stronger association with age, smoking and alcohol use than GERD in men
and stronger association with age and body mass index than GERD in women [22].
Kerr et al. have demonstrated that precipitous droops in pH were frequently prece-
ded by arousal (98.4%), movement of the patient (71.9%), and swallowing (80.4%)
[23]. In this case, arousal is theorized to be caused by increased ventilatory effort
[24]. Arousal and movement may trigger gastroesophageal reflux by causing transient
alteration in the pressure gradient across the lower esophageal sphincter (LES). Additio-
nally, the lowered intrathoracic pressure that accompanies OSA may itself predispose
the patient to gastroesophageal reflux by exacerbating the LES pressure gradient.
Treatment with nasal continuous positive airway pressure (CPAP) showed dramatic
reduction in the frequency of gastroesophageal reflux by elevating intrathoracic
pressure [23].
Investigators have suggested that GERD causes OSA, and OSA has been linked to
GERD [22]. Other studies could not demonstrate a causal relationship between OSA
and GERD. In a study by Penzel et al. 37 of 52 reflux events that occurred during
sleep, involving either apnea or hypopnea, were found prior to the reflux event [25].
The sequence in time did not prove a causal relationship between the respiratory and
reflux events. Patients subjectively report that the quality of sleep is affected by the
severity of GERD; however, objective correlation between OSA and GERD is lacking,
which may suggest that both are common entities sharing similar risk factors but may
not to be causally linked [22].
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Diagnostic Evaluation and Initial Treatment

Upper endoscopy should be performed in all patients with classic symptoms of GERD
who also report alarm symptoms (dysphagia, odynophagia, weight loss, anorexia,
evidence of gastrointestinal bleeding or iron deficiency anemia). All patients with
chronic symptoms of GERD, particularly those who are 50 years and older, are at in-
creased risk for Barretts esophagus and thus should undergo an upper endoscopy at
least once during their lifetime to rule out the presence of Barretts mucosa. Patients
who are found to have Barretts esophagus should undergo regular surveillance using
a standard esophageal mucosal biopsy protocol.
Presently, the sole presence of nocturnal heartburn is not an indication for an upper
endoscopy, unless alarm symptoms are also elicited. Similarly, pH testing should be
reserved only for individuals who are not responding to potent anti-reflux treatment
(on therapy).
Patients with symptoms of nocturnal GERD may be treated with diet, lifestyle modi-
fications and medications without prior endoscopic evaluation. A step-up approach
may be adopted, starting with an H2 receptor antagonist and upgrading to a proton
pump inhibitor if nocturnal symptoms are not improved. Others may elect either a
step-in or a step-down approach. The former suggests initiating and maintaining
subjects on a proton pump inhibitor, while the latter proposes initiating patients on
a proton pump inhibitor and then tapering them down to the least potent anti-reflux
modality that can still control patients symptoms.
References
1) Locke G, III, Talley NJ, Fett S, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of
gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroentero-
logy 1997; 112: 1448-1456.
2) Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated
clinical problem that impacts sleep and daytime function: The results of a Gallup Survey conducted
on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003; 98: 1487-
1493.
3) Farup C, Kleinman L, Sloan S, Ganoczy D, Chee E, Lee C, Revicki D. The impact of nocturnal symp-
toms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern
Med 2001; 161: 45-52.
4) Fass R, Quan SF, OConnor GT, Ervin A, Iber C. Predictors of heartburn during sleep in a large
prospective cohort study. Chest 2005; 127: 1658-1666.
5) Orr WC, Johnson LF, Robinson MG. Effect of sleep on swallowing, esophageal peristalsis, and acid
clearance. Gastroenterology 1984; 86: 814-819.
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6) Cuttitta G, Cibella F, Visconti A, Peralta G, Cuttitta G, Trizzino A, Giannone G, Bonsignore G.

Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics.
Am J Respir Crit Care Med 2000; 161: 177-181.
7) Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pH-metry in patients with reflux laryngitis.
8) Green C, Dekel R, Quan S, Stephen G, Fass R. The relationship between the extent of esophageal
acid exposure and reported quality of sleep [abstract]. Gastrointest Endosc 2003; 57: AB133.
9) Dekel R, Green C, Quan S, Stephen G, Fass R. The relationship between severity and frequency
of symptoms and quality of sleep (QOS) in patients with gastroesophageal reflux disease (GERD).
Gastroenterology 2003; 124: A-414.
10) Castell DO, Richter JE, Robinson M, Sontag SJ, Haber MM. Efficacy and safety of lansoprazole in
the treatment of erosive reflux esophagitis. The Lansoprazole Group. Am J Gastroenterol 1996; 91:
1749-1757.
11) Fujiwara Y, Arakawa T, Fass R. Gastroesophageal reflux disease and sleep disturbances. J Gastro-
enterol 2012 ; 47: 760-769.
12) Schoeman MN, Holloway RH. Integrity and characteristics of secondary oesophageal peristalsis in
patients with gastro-oesophageal reflux disease. Gut 1995; 36: 499-504.
13) Pasricha PJ. Effect of sleep on gastroesophageal physiology and airway protective mechanisms.
Am J Med 2003; 115: 114S-118S.
14) Lagergren J, Bergstrom R, Lindgren A, Nyrn O. Symptomatic gastroesophageal reflux as a risk
factor for esophageal adenocarcinoma. N Engl J Med 1999; 340: 825-831.
15) DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastro-
esophageal reflux in health and disease. Ann Surg 1976; 184: 459-470.
16) Robertson D, Aldersley M, Shepherd H, Smith CL. Patterns of acid reflux in complicated oesophagitis.
Gut 1987; 28: 1484-1488.
17) Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Nonerosive reflux disease (NERD) acid reflux
and symptom patterns. Aliment Pharmacol Ther 2003; 17: 537-545.
18) Fass R, Hell RW, Garewal HS, Martinez P, Pulliam G, Wendel C, Sampliner RE. Correlation of oesopha-
geal acid exposure with Barretts oesophagus length. Gut 2001; 48: 310-313.
19) Brandt MG, Darling GE, Miller L. Symptoms, acid exposure and motility in patients with Barretts
esophagus. Can J Surg 2004; 47: 47-51.
20) Fass R. Poorly recognized reflux-induced symptoms. Eur J Gastroenterol Hepatol 2001; 13: S32-S34.
21) Green C, Dekel R, Quan S, Stephen G, Fass R. The effect of sleep duration on symptoms perception
of patients with gastroesophageal reflux disease (GERD). Gastroenterology 2003; 124: A-255.
22) Farmer W, Yaffe J, Santiago T. Managing sleep disorders in military personnel. Federal Practitioner
2002; 19: 21-39.
23) Morse CA, Quan SF, Mays MZ, Green C, Stephen G, Fass R. Is there a relationship between
obstructive sleep apnea and gastroesophageal reflux disease? Clin Gastroenterol Hepatol 2004;
2: 761-768.
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24) Kerr P, Shoenut JP, Millar T, Buckle P, Kryger MH. Nasal CPAP reduces gastroesophageal reflux in
obstructive sleep apnea syndrome. Chest 1992; 101: 1539-1544.
25) Gleeson K, Zwillch CW, White DP. The influence of increasing ventilatory effort on arousal from
sleep. Am Rev Respir Dis 1990; 142: 295-300.
26) Penzel T, Becker HF, Brandenburg U, Labunski T, Pankow W, Peter JH. Arousal in patients with
gastro-oesophageal reflux and sleep apnoea. Eur Respir J 1999; 14: 1266-1270.
WHATS NEXT ?
17:30 Dental Erosions and Halitosis as Oral

Manifestations of GERD
Giuseppina Campisi, DMD, PhD
Professor of Dentistry, Department of Surgery,
Oncology & Stomatology, University of Palermo, Italy
with the cooperation of Giuseppe Pizzo DMD, PhD
Associate Professor & Olga Di Fede, DMD, PhD
Research Fellow
Giuseppina Campisi
Gastro-esophageal reflux disease (GERD) refers to reflux of gastric

contents into the esophagus leading to esophagitis, reflux symptoms capable to im-
pair quality of life, or long-term complications [1, 2]. Heartburn and regurgitation
are the typical clinical manifestations of GERD; in addition, several pulmonary, ear,
nose and throat and oral manifestations are linked to GERD. These are called as extra-
esophageal manifestations of GERD [3] and include symptoms such as dysphagia,
odynophagia, globus (lump in the throat), sore throat, laryngitis, water brash (increased
salivary flow) and cough, among many others [3].
With regard to GERD-associated manifestations in the oral cavity, dental erosions [4] ,
halitosis [5], non-specific burning sensation, mucosal ulcerationerosion, loss of taste
and both xerostomia and increased salivary flow have been reported [6-8].
Dental erosion is the loss of dental hard tissue, due to action of gastric acids with a
high frequency in patients with GERD and a strict association with reflux characteristics
(Figure 1). Moreover, the presence and degree of dental erosions are predominant
in female patients, over 70 years old, in the palatal surfaces of anterior sector. GERD
symptoms as acid regurgitation and acid taste could be important indicators for the
presence of dental erosions [6, 8].
Another extraesophageal manifestation in GERD patients is halitosis. A strong positive

association between GERD-related symptoms and halitosis was found in denture-
wearing subjects (Table 1) and a moderate, positive association in dentate subjects
(Table 2), with a clear dose-effect relationship [9].
The origin of halitosis is mostly oral (8090 %) and caused by anaerobic bacteria on
the dorsal surface of the tongue [9-11]. These anaerobic bacteria produce compounds,
called volatile sulfur compounds (VSCs). Tongue coating (43.4%) is the most frequent
associated factor, followed by a combination of tongue coating, periodontitis, and
gingivitis (18.2%).
osion lesion has a clean

osion
osion lesion has aa clean
lesion has clean EXTRA-DIGESTIVE GERD:
appearance,
sion lesion haswith loss of
ppearance,
ppearance, withaloss
with clean
loss of
of WHATS NEXT ?
e. grooves and
ppearance, pits)
withpits) as
lossasofaaa
e.
e. grooves andand pits) as
on.grooves
e. (b) Non-eroded teeth
and pits)teeth
as a
n. (b) Non-eroded
on. Non-eroded teeth
of pronounced
n. occlusal
of(b)
of Non-eroded
pronounced
pronounced teeth
occlusal
occlusal
centre
of of the teeth.
pronounced occlusal
entre
centre of the
the teeth.
teeth.
entre of the teeth.
a b
hallow erosion
hallow erosion withthin- thin-
hallow erosion with with thin-
llallow
haserosion
has
has
resulted
resulted
resulted in
with in thin-an
in an an
y of has
of theresulted
the incisalregion
incisal in an
region ofof
y of the incisal region of
ycentral
of the incisal
central incisors,
incisors, region
associ-
associ- of
central incisors, associ-
central
raynessincisors,
rayness (Courtesy
(Courtesy associ-
DrA.
Dr A.
ayness
ayness
(Courtesy
(Courtesy
Dr
Dr A.
A.
er enamel
enamel inthe
in thecervical
cervical
er
er enamel
enamel in
in the cervical
neck)
neck) of
of the thethe cervical
teeth
teeth has
has
neck) of
neck) of the the teethteeth has has
g degrees,
degrees, accentuating
accentuating
gg degrees,
nce
nce
degrees, accentuating
of
of the
accentuating
the underlying
underlying
ceresulted
ssce of the
of the in underlying
underlying c d
resulted in the
the loss
lossofof
smel resulted
resulted in the loss ofof
mel of
of thethein the loss
maxillary
maxillary inci-
inci-
mel
mel
ng of
of the maxillary
the maxillary inci-
inci-
ng erosion
erosion has
has caused
caused
ng erosionand hasdentincaused
alg enamel
al erosion
enamel has
and caused
dentin ofof
alesulting
enamel and
l enamel and dentin
dentinofof
esulting in in cupping
cupping ofof
esulting in
esulting
mple in cupping
cupping ofof
mple there there isis aa severe severe
mple
mple
sal surface there of
there isis athe
a severe
severe
man-
sal surface of the man-
al
thal surface
surface of
adjacent to the
of the man-man-
resin
th adjacent to the resin
th h(black
adjacent
adjacentarrow). to
to thetheresin
resin
(black arrow).
(black
(black arrow).
arrow).
40
40 Each of these wear processes has a specific of GERD with erythema of the palatal mucosa and uvula.28 And, 28 a
Eachofofthese thesewear wear processeshas has a specific ofof GERD with erythema of the palatal mucosa andaand uvula. And, a
n400 beEach
Eachgenerally
of these wearprocesses
identified processes hasa aspecific
at both macroscopic specific histologic GERD
of GERD with erythema
examination
with erythema ofofpalatal
the
of thepalatal
mucosa
palatalmucosafound
mucosa uvula.
greater
and
28
uvula. And,28 a
preva- And, a
nels. be
be generally
generally identified
identified atat both
both macroscopic
macroscopic histologic
histologic
lence of
examination
examination
epithelial atrophy, of of palatal
palatal
deepening
mucosa
mucosa of found found
epithelial a a greater
greater
crests in preva-
con-
preva-
Figure
n be generally identified at both macroscopic 1: (a) Broad shallow erosion with thinning of the enamel
histologic examination of palatal mucosa found a greater preva- has resulted in an increased
els.
ls.
erosion from acid regurgitation involves the lence
lence
nective of of
tissueepithelial
epithelial
and a atrophy,
atrophy,
higher deepening
deepening
prevalence of of epithelial
epithelial
fibroblasts crests
in crests
31 in
GERD in con-
con-
els. translucency of the incisal region lence of oftheepithelial
anterior maxillary central incisors,
atrophy, deepening associated
of epithelial crests with increased
in con-
erosion
erosion from
from acid the
acid regurgitation involves the nectivenective tissue and a higher prevalence of35fibroblasts in 31 GERD
entin
erosion
entin
from
from from acidregurgitation
initially
initially regurgitation
the palatal
(b)involves
palatal surfaces
grayness. The of
involves
surfaces of
the
thinner
the
the
patients
enamel
nective
patients
intissue
compared
the
tissue andand
cervical
compared
awith
higher
awith14 prevalence
regions
higher control
14
(around
prevalence
control
of the
subjects. fibroblasts
But,
neck)
of35fibroblasts
subjects. 35
in the
these
of
But,
31in
these
GERD
changes
teeth
31changes
GERD has been
entin
ng
entin from
several
fromyears initially
initially the
thepalatal
to become
eroded palatal
to surfaces
clinically
surfaces
varying of ofthe
obvious patients
were
the accentuating
degrees, notcompared
patients visible
compared with
thetoyellow
the with14
naked control
14 eye,
appearance subjects.
unlike
control the
subjects.
of thethe But,
mucosal35 these
underlyingBut,changes changes
these
dentin. that
changes
(c) Erosion
ng several
g several years
years to become clinically obvious were not visible to the naked eye, unlike mucosal changes that
anding
ngandingseveral yearstotoerosion
instances,
instances,
become
become
has resulted
erosion
clinically
can clinically
can also
obvious
alsoinaffect
theobvious
affect loss
were
the of palatal
maywere notnot
be and
visible
more visible to the
readily
incisal
naked
observed
toenamel
the nakedeye,eye,
ofinthe
unlike
esophagitis the the
unlike
maxillary
mucosal
and mucosal
incisors.
changes
laryngitis (d) where
changes that that
Long-standing
nding instances,
urfaces of maxillary erosion
teeth as canwellalsoas affect
mandibu- thethe may themay bebe
pH more
of more readily
thereadily
gastric observed
observed
refluxate in esophagitis
inatesophagitis
these sites and and laryngitis
laryngitis
is lower than in wherethewhere
nding instances,
urfaces of maxillary erosion
erosion
teethasas can
has
wellalso
causedaffect the loss
severe may be
of 23,25 more
occlusal readily
enamelobserved and dentin inatesophagitis
of lower and
molar laryngitis where
teeth, resulting in
rfaces of
xisting maxillary
non-eroded teeth
restorations well asasmandibu-
appear mandibu-
raised the the
mouth. pHpH of ofthe the
Other gastric
gastric
studies refluxate
refluxate
have notatfound
thesethese
sites
any sites is
is lower
abnormal lowerthanthan
appearances in the in the
rfaces of
xisting maxillarycupping
non-eroded teeth as well
restorations of these as mandibu-
appear teeth.
raised the
For example
mouth.pH23,25 of
there
23,25 the
Other isgastric
astudies
severe refluxate
cupping
have not atfound
these
of the sites
any is lower
occlusal
abnormal surfacethanof
appearances inthethe man-
xisting
oded tooth non-eroded
surfaces.restorations
The patternappear of erosionraised is mouth.
of the oral Other
mucosa
23,25 studies have not found
or associated any abnormal
oral symptoms appearances
in patients with
xisting non-eroded restorations
dibular first appear
molar raised
tooth mouth. Other studies haverestoration
not found any abnormal appearances
roded
oded and
ence tooth
tooth surfaces.
surfaces.
distribution The
The pattern
of pattern
oral of
biofilm oferosion
erosion
(dental is isadjacent
of of
confirmed to
thetheoral the
oral resin
mucosa
mucosa
GERD. composite
41,42 or associated
orHowever,
associated acid oral
oralregurgitation
symptoms (black
symptoms inarrow).
maypatients (from
inexacerbate
patients withwith Ranjitkar
oded
ence tooth surfaces.
and distribution
distribution etTheal. pattern
[7]).
oforal
oralbiofilm of erosion is of the oral mucosa or
41,42 associated oral symptoms in patients with
ence and andquality of saliva of (which isbiofilm
protective (dental
(dental of confirmed
oral
confirmedmucosal GERD.
GERD.changes 41,42 However,
associated
However,
41,42
acid
with
acid regurgitation
co-existing
regurgitation may
hyposalivation,
may exacerbate
exacerbate
ence
ior
and
and
andteeth
quality indistribution
quality ofofsaliva
particular), of
theoral
saliva(which
(whichnumberbiofilm and (dental
isisprotective
protective ofof oral
posi- confirmed
oral
which mucosal
can arise
mucosal
GERD.changes
changes
However,
associated
from associated
systemic acid
with
conditions,
with
regurgitation
co-existing
co-existing
may exacerbate
hyposalivation,
local hyposalivation,
salivary gland
ior and
dior otherquality
teethconditions
teeth of saliva
ininparticular),
particular), (which
(suchthe the
asnumber is
mouth protective
numberand andposi-
breathing of
posi- which oral
conditions mucosal
whichcancan and
arise changes
arise
intake
from from associated
systemic
ofsystemic
drugs including with co-existing
conditions,
conditions, PPIs.local local hyposalivation,
salivary
salivary gland gland
dd ior
mpetentteethconditions
other
other in particular),
lips,
conditions facial(such
(such the
paralysis number
and
asasmouth
mouth and
major posi- conditions
sali-
breathing
breathing which
conditions can arise
andand from
intake
intake of of systemic
drugs
drugs conditions,
including
including PPIs. PPIs. local salivary gland
In a few cases, periodontitis (7.4%) and gingivitis (3.8%) could be the sole responsible
dy). other
mpetent
mpetentlips, conditions
lips,facial (such
paralysis
facialcauses. as mouth
and
andmajor
paralysisXerostomia breathing
majorsali- sali- conditions and intake of drugs including PPIs.
mpetent lips, facial paralysis and major sali-
is another one of the most important other oral source (2.5%) [11].
y).).
y). Sleep bruxism and GERD
esions When oral halitosis origin Sleep
Sleep bruxism
is left(tooth
Bruxism bruxism
out, malodour and and
grinding or clenching)
GERD
may GERDalso be due to extraoral origins
is defined as contact of teeth
esions Sleep bruxism and GERD
s may result from by
esions GERD thebyrespiratory
direct acid or tract,Bruxism
or
for pharyngo-tonsilar
reasons other
(tooth than
grinding eating
or diseases,
and
clenching)
Bruxism (tooth grinding or clenching) is defined is a or the
common
is defined asgastrointestinal
cause ofcontact
contact
as tooth of wear
teeth
of teeth
tract.
esions In particular, GERD has been increasingly considered as a possible extraoral source
sin the
may oral
result cavity.
from However,
GERD
s may result from GERD by direct acid or there
by is
direct a paucity
acid or in
for Bruxism
humans.
reasons (tooth
43
It
other can grinding
than occur
eating or
bothclenching)
and during
is a is
the
common
for reasons other than eating and is a common cause of44tooth wear defined
awake
cause as contact
state
of as
tooth tooth
wearof teeth
sin
en may
effect
the
theoral result
ofcavity.
oral GERD from
cavity. of
onGERD
However,
However,halitosis.
oral by
mucosal
there
theredirect acid
isisachanges.
apaucity
paucity or in for reasons
clenching,
inhumans.
humans. and other
43 43
Itduring
cancan
It than
sleep
occur eating
occur and
as tooth
both both duringis a common
grinding
duringthe the cause
or clenching.
awake awake ofastooth
statestate Sleep
tooth wear
as tooth
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gy and Hepatology 27 (2012) 2127 23
enterology
gy and PRESIDENTS
Hepatology
and Hepatology
Carmelo
27 (2012)Foundation
2127
Scarpignato,
and Blackwell MD,
Publishing DSc,
Asia PharmD,
Pty Ltd MPH (Parma, Italy) Francesco Di Mario, MD
23 (Parma, Italy) 91
gy and Hepatology 27 (2012) 2127 23
enterology
gy and Hepatology
and Hepatology Foundation
27 (2012) 2127 and Blackwell Publishing Asia Pty Ltd 23
enterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
enterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
WHATS NEXT ?
Table 1: Association Between Gastroesophageal Reflux Related Symptoms and

Halitosis in Dentate Subjects (n=2588) . (from Struch et al. [9]).
Model Symptom: heartburn or acid regurgitation Referent: absent

Mild (n=838) Moderate (n=330) Severe (n=65)
OR (95%-CI) OR (95%-CI) OR (95%-CI)
1 1.49 (1.211.84) 1.92 (1.452.52) 3.32 (1.995.54)
2 1.53 (1.241.90) 1.94 (1.472.57) 3.33 (1.985.59)
3 1.40 (1.121.74) 1.75 (1.322.32) 2.71 (1.604.60)
4 1.37 (1.101.70) 1.70 (1.272.26) 2.67 (1.574.55)
5 1.31 (1.051.64) 1.62 (1.212.17) 2.47 (1.444.23)
6 1.31 (1.051.63) 1.60 (1.192.14) 2.49 (1.444.31)
7 1.29 (1.031.61) 1.56 (1.162.09) 2.45 (1.424.25)
8 1.28 (1.021.60) 1.48 (1.091.99) 2.24 (1.273.92)
Logistic regression analysis (dependent variable halitosis). Model 1: unadjusted. Model 2: adjusted
for age and sex. Model 3: adjusted for variables in model 2 and depressive symptoms. Model 4:
adjusted for variables in model 3, chronic gastritis, and history of gastric or duodenal ulcer. Model
5: adjusted for variables in model 4 and difficulty in swallowing. Model 6: adjusted for variables in
model 5, spirits consumption during the past weekend, coffee consumption, and smoking status.
Model 7: adjusted for variables in model 6, living together, and school education. Model 8:
adjusted for variables in model 7, number of periodontal pockets, and gingival bleeding while
tooth brushing OR = odds ratio, CI = confidence interval.
Several mechanisms could be responsible of halitosis in GERD patients:

1) acidic contents of the stomach can reach the nasopharynx and cause irritation of
its walls, resulting in postnasal drip with a consequent malodour;
2) impaired lower esophageal sphincter function allows intestinal gas and stomach
contents to reflux into the esophagus;
3) direct acid-peptic injury to susceptible supraesophageal tissue [7].
Clinical surveys of dental erosions and halitosis can be considered the most important
biomarkers in order to discover and treat GERD.
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Table 2: Association Between Gastroesophageal Reflux Related Symptoms and

Self-reported Halitosis in Edentulous Subjects (n = 417) . (from Struch et al. [9]).
Model Symptom: heartburn or acid regurgitation Referent: absent

Mild (n=101) Moderate (n=61) Severe (n=12)
OR (95%-CI) OR (95%-CI) OR (95%-CI)
1 1.86 (0.824.20) 2.29 (0.925.69) 7.60 (2.0528.14)
2 2.09 (0.894.90) 2.87 (1.107.48) 11.22 (2.7146.49)
3 1.79 (0.754.29) 2.45 (0.926.54) 10.44 (2.4843.96)
4 2.02 (0.844.87) 2.71 (1.017.32) 14.19 (3.0965.13)
5 2.08 (0.865.02) 2.73 (1.017.39) 15.03 (3.2669.38)
6 2.01 (0.834.90) 2.68 (0.987.31) 13.75 (2.9364.55)
7 2.04 (0.835.01) 2.78 (1.007.65) 13.58 (2.8464.91)
8 2.06 (0.845.08) 2.74 (0.997.62) 12.94 (2.6663.09)
Logistic regression analysis (dependent variable: self-reported halitosis). Model 1: unadjusted.

Model 2: adjusted for age and sex. Model 3: adjusted for variables in model 2 and depressive
symptoms. Model 4: adjusted for variables in model 3, chronic gastritis, and history of gastric or
duodenal ulcer. Model 5: adjusted for variables in model 4 and difficulty in swallowing. Model 6:
adjusted for variables in model 5, spirits consumption during the past weekend, coffee consump-
tion, and smoking status. Model 7: adjusted for variables in model 6, living together, and school
education. Model 8: adjusted for variables in model 7, complete denture upper jaw, and complete
denture lower jaw OR = odds ratio, CI = confidence interval.
References
1) Dent J, Brun J, Fendrick AM, et al. An evidence-based appraisal of reflux disease management: the
Genval workshop report. Gut 1999; 44: S116.
2) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. Global Consensus Group. The Montreal definition
Gastroenterol 2006; 101: 1900-1920.
3) Hom C, Vaezi MF. Extra-esophageal manifestations of gastroesophageal reflux disease: diagnosis
and treatment. Drugs 2013; 73: 1281-1295.
4) Roesch-Ramos L, Roesch-Dietlen F, Remes-Troche JM, Romero-Sierra G, Mata-Tovar CJ, Azamar-Jcome
AA, Barranca-Enrquez A. Dental erosion, an extraesophageal manifestation of gastroesophageal
reflux disease. The experience of a center for digestive physiology in Southeastern Mexico. Rev Esp
Enferm Dig 2014; 106: 92-97.
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5) Kim JG, Kim YJ, Yoo SH, Lee SJ, Chung JW, Kim MH, Park DK, Hahm KB. Halimeter ppb Levels as
the Predictor of Erosive Gastroesophageal Reflux Disease. Gut Liver 2010; 4: 320-325.
6) Pace F, Pallotta S, Tonini M, Vakil N, Bianchi Porro G. Systematic review: gastro-oesophageal reflux
disease and dental lesions. Aliment Pharmacol Ther 2008; 27: 1179-1186.
7) Ranjitkar S, Smales RJ, Kaidonis JA. Oral manifestations of gastroesophageal reflux disease. J Gastro-
enterol Hepatol 2012; 27: 21-27.
8) Marsicano JA, de Moura-Grec PG, Bonato RC, Sales-Peres Mde C, Sales-Peres A, Sales-Peres SH.
Gastroesophageal reflux, dental erosion, and halitosis inepidemiological surveys: a systematic
review. Eur J Gastroenterol Hepatol 2013; 25: 135-141.
9) Struch F, Schwahn C, Wallaschofski H, Grabe HJ, Vlzke H, Lerch MM, Meisel P, Kocher T. Self-
reported Halitosis and Gastro-esophageal Reflux Disease in the General Population. J Gen Intern
Med 2008; 23: 260-266.
10) Torres Vargas L, Torres Vargas N, Vargas Crdenas G. Dental erosions in patients with gastro-
esophageal reflux disease in National Hospital Arzobispo Loayza [Spanish]. Rev Gastroenterol Peru
2012; 32: 343-350.
11) Kislig K, Wilder-Smith CH, Bornstein MM, Lussi A, Seemann R. Halitosis and tongue coating in
patients with erosive gastroesophageal reflux disease versus nonerosive gastroesophageal reflux
disease. Clin Oral Investig 2013; 17: 159-165.
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Notes
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18:00 Globus and Its Complexities

Peter J. Kahrilas, MD, FACG, AGAF
Marquardt Professor of Medicine, Northwestern University,
Chicago, IL, USA
Definition and Epidemiology

Globus is defined as a sense of a lump, retained food, mucus,
or tightness in the throat [1]. The symptom is non-painful, fre-
Peter J. Kahrilas quently improves with eating, is often episodic, and is distinct
from dysphagia or odynophagia that may or may not be accom-
panying symptoms [2]. Other commonly associated symptoms
are cough [3] and heartburn. Functional globus as defined by Rome III is a functional
disorder characterized by globus sensation that is unexplained by structural lesions,
GERD, or histopathology-based esophageal motility disorders [4]. Globus is common,
reported to occur at some point in their life by 46% of healthy individuals [5], and
has a peak incidence in middle age [6]. The symptom is equally prevalent in men and
women, but affected women are more likely to seek health care [7].
Pathogenesis
As suggested above, globus can occur in association with a myriad of other identifiable
disease processes (tumors, diverticuli, osteophytes, etc) or in isolation [8]. The symptom
has variably been attributed to upper esophageal sphincter (UES) dysfunction, gastro-
esophageal reflux (GER, Table 1), and visceral hypersensitivity, although there is currently
no consensus as to etiology and psychological factors have also been invoked. Termi-
nology varies across medical specialities with globus hystericus often appearing in
the psychiatric literature and globus pharyngeus favored amongst otorhinolaryn-
gologists. Owing to innumerable reports of ENT lesions or inflammatory conditions
potentially associated with globus, a routine ENT exam is indicated as part of the
initial evaluation. Significant findings on that exam will then lead to specifc therapy
directed at those findings.
Table 1: Globus and GERD: Evidence for Relationship (from Selleslagh et al. [8])
Association of globus with typical reflux symptoms

Association of globus with reflux esophagitis or esophageal minimal change lesions
Association of globus with hiatal hernia
Reflux monitoring results in relation to globus
Globus symptom response after GERD therapy
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In the absence of pharyngeal structural lesions, abnormalities of UES function have

received the most attention as a potential cause of globus. Proposed abnormalities
have included increased UES pressure, sphincter discoordination, heightened sphincter
reactivity, and incomplete deglutitive relaxation. Among these possibilities, augmenta-
tion of UES pressure, detectable by manometry and sensed as globus is very attractive
in principle. However, while some studies have reported increased UES pressure in
globus patients [9], others have not confirmed these findings [10]. More consistent,
has been the notion of heightened reactivity of the UES, either in response to emo-
tional stress [10], esophageal acid infusion [11], or respiration [12]. Augmented UES
reactivity is a particularly appealing hypothesis because of the inherent hyper-reactivity
of the sphincter to any intraluminal stimulation [13], including the manometric instru-
mentation requisite for recording the pressure [14]. Indeed, in the absence of exogenous
stresses and during sleep or anesthesia, UES pressure is negligible, on the order of
5-10 mmHg [15]. Notably, in one of the largest physiological studies of globus patients,
involving 131 patients and 68 normal controls Kwiatek et al. found that the mean re-
spiratory fluctuation in UES pressure averaged 37 mmHg in globus patients compared
to 11 mmHg in controls (p<0.0001) [12]. A respiratory fluctuation >27 mmhg was
found in >60% of globus patients compared to <15% of controls.
As with the pharynx, a myriad of esophageal structural abnormalities (webs, strictures,

tumors, polyps, inflammation, etc) have been associated with globus [8]. Hence, an
endoscopic exam of the esophagus is indicated even though it will be normal far more
often than not. One potential finding of particular interest is a cervical esophageal inlet
patch of heterotopic acid-secreting gastric mucosa. Across the board, inlet patches
are more common in patients with globus than without, but particularly intriguing
are recent case series in which globus symptoms have resolved after ablation of inlet
patches [16]. Hence, although the evidence base is not robust, it does favor offering
ablation therapy to a globus patient found to have an inlet patch and no other expla-
nation for globus.
Motor disorders of the esophagus have also been associated with globus. Several
manometric series have been published, although there is no common theme or ob-
servation that emerges from these. Typical of these is a recent large case series of 119
globus patients resistant to PPI therapy that reported finding 52 normal, 32 ineffective
esopahgeal motility, 8 achalasics, 5 diffuse esophageal spasm, 5 nutcracker esophagus
and 1 case of LES hypercontraction [17]. In fact, those numbers would be fairly typical
of any consecutive series of patients undergoing motility testing for standard clinical
indications. Hence, manometry is certainly indicated as part of the evaluation if globus
is accompanied by chest pain or dysphagia, but not necessarily otherwise.
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GERD
Globus occurs in 15-28% of patients with typical reflux symptoms and most studies
have found globus to be more prevalent in patients with typical reflux symptoms than
in asymptomatic controls [8]. Conversely, the prevalence of GERD in patients with globus
is similar to GERD prevalence in patients presenting with other laryngopharyngeal
symptoms such as hoarseness or cough [18]. The mechanism by which this occurs is
uncertain. Certainly, the studies of Tokashiki suggest that acid reflux causes reflexive
contraction of the UES associated with perceived globus. However, those studies were
done in normal controls and one could argue that the intensity of the stimulus ge-
reatly exceeded what is commonly experienced by GERD patients [11]. Supporting
that contention, prolonged manometric recordings of the UES in both GERD patients
and control subjects during spontanteous reflux demonstrated no reflexive UES con-
traction [15, 19]. Regardless of the mechanism, however, the association between
GERD and globus is clear and treatment trials with PPI therapy have generally had a
favorable response on the globus symptom [18]. Hence, from a management per-
spective a trial of PPI therapy is warranted.
Therapy
Optimally, treatment of globus targets the associated syndrome, be that laryngitis,
GERD, or achalasia. However, a number of cases will prove refractory to that approach,
then gaining the label of functional globus. In many, but not all, instances, functional
globus is associated with psychiatric comorbidities such as anxiety, depression, so-
matization, or catrastrophizing. Interventions targeting these comorbidities or even
hypnotherapy [20] have proven effective in such circumstances.
Conclusions
In summary, globus can occur as an isolated symptom or as one element of a syndrome.
The Rome III criteria for functional globus clearly apply to only a small subgroup of
patients with globus encountered in clinical practice where many patients also have
comorbidities such as dysphagia, odynophagia, anxiety/depression, or GERD. In all
likelihood the mechanism of symptom development is also heterogenneous, depen-
ding on the associated conditions. In terms of diagnostic evaluation, the schematic
of Figure 1 provides a reasonable approach, progressing down a hierarchy designed
to detect the most morbid and most common associated conditions as expeditiously
as possible.
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Patient with non-painful sensation

of a lump in the throat
Voice dysfunction, yes

ENT evaluation
H&N cancer risks?
no no yes
Abnormality? Treat as indicated
Dysphagia, yes
esophageal EGD, dysphagia evaluation
cancer risks?
no yes
Abnormality? Treat as indicated
Reflux yes
symptoms? PPI trial
no
no Globus yes GERD with globus:
improved? titrate PPI Rx
Functional globus
Amenable to
Cognitive-Behavioral yes
CBT trial
Therapy?
no
Reassurance
Figure 1: Management Algorithm for Globus.
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References
1) Chevalier JM, Brossard E, Monnier P. Globus sensation and gastroesophageal reflux. Eur Arch
Otorhinolaryngol 2003; 260: 273-276.
2) Kahrilas PJ, Smout AJPM. Esophageal disorders. Am J Gastroenterol 2010; 105: 747-756.
3) Everett CF, Morice AH. Clinical history in gastroesophageal cough. Respir Med 2007; 101: 345-
348.
4) Galmiche JP, Clouse RE, Balint A, Cook IJ, Kahrilas PJ, Paterson WG, Smout AJ. Functional esopha-
geal disorders. Gastroenterol 2006; 130: 1459-1465.
5) Thompson WG, Heaton KW. Heartburn and globus in apparently healthy people. Can Med Assoc
J 1982; 126: 46-48.
6) Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson JG, Whitehead WE, Janssens J,
Funch-Jensen P, Corazziari E, Richter JE, Koch GG. U.S. householders survey of functional gastro-
intestinal disorders. Prevalence, sociodemography and health impact. Dig Dis Sci 1993; 38: 1569-
1580.
7) Batch AJG. Globus pharyngeus (part I). J Laryngol Otol 1988; 102: 152-158.
8) Selleslagh M, van Oudenhove L, Pauwels A, Tack J, Rommel N. The complexity of globus: a multi-
disciplinary perspective. Nat Rev Gastroenterol Hepatol 2014; 11: 220-233.
9) Watson WC, Sullivan SN. Hypertonicity of the cricopharyngeal sphincter: a cause of globus sensa-
tion. Lancet 1974; 2: 1417-1419.
10) Cook IJ, Dent J, Collins SM. Upper esophageal sphincter tome and reactivity to stress in patients
with a history of globus sensation. Dig Dis Sci 1989; 34: 672-676.
11) Tokashiki R, Funato N, Suzuki M. Globus sensation and increased upper esophageal sphincter
pressure with distal esopahgeal acid perfusion. Eur Arch Otorhinolaryngol 2010; 267: 737-741.
12) Kwiatek MA, Mirza F, Kahrilas PJ, Pandolfino JE. Hyperdynamic upper esophageal sphincter pressure:
A manometric observation in patients reporting globus sensation. Am J Gastroenterol 2009; 104:
289-298.
13) Shaker R, Ren J, Xie P, Lang IM, Bardan E, Sui Z. Characterization of the pharyngo-UES contractile
reflex in humans. Am J Physiol 1997; 273: G854 -G858.
14) DiRe C, Shi G, Manka M, Kahrilas PJ. Manometric characteristics of the upper esophageal sphincter
recorded with a microsleeve. Am J Gastroenterol 2001; 96: 1383-1389.
15) Kahrilas PJ, Dodds WJ, Dent J, Haeberle B, Hogan WJ, Arndorfer RC. The effect of sleep, spontaneous
gastroesophageal reflux and a meal on UES pressure in humans. Gastroenterology 1987; 92: 466-
471.
16) Bajbouj M, Becker V, Eckel F, Miehlke S, Pech O, Prinz C, Schmid RM, Meining A. Argon plasma
coagulation of cervical heterotopic gastric mucosa as an alternative treatment for globus sensations.
17) Tsutsui H, Manabe N, Uno M, Imamura H, Kamada T, Kusunoki H, Shiotani A, Hata J, Harada T,
Haruma K. Esophageal motor dysfunction plays a key role in GERD with globus sensation analysis
of factors promoting resistance to PPI therapy. Scand J Gastroenterol 2012; 47: 893-899.
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18) Sinn DH, Kim JH, Kim S, Son HJ, Kim JJ, Rhee JC, Rhee PL. Response rate and predictors of response
in a short-term empirical trial of high-dose rabeprazole in patients with globus. Aliment Pharmacol
Ther 2008; 27: 1275-1281.
19) Vakil NB, Kahrilas PJ, Dodds WJ, Vanagunas A. Absence of an upper esophageal sphincter response
to acid reflux. Am J Gastroenterol 1989; 84: 606-661.
20) Kiebles JL, Kwiatek MA, Pandolfino JE, Kahrilas PJ, Keefer L. Do patients with globus sensation
respond to hypnotically assisted relaxation therapy? A case series report. Dis Esoph 2010; 23: 545-
553.
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Notes
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SESSION IV:
THERAPEUTIC APPROACH TO EXTRA-DIGESTIVE GERD
CHAIRED BY:
Corrado Blandizzi, MD, PhD

Professor of Pharmacology & President,
School of Medicine, University of Pisa
Director, Center for Clinical Pharmacology,
University Hospital, Pisa, Italy
Corrado Blandizzi
Antonio Balzano, MD
Former Director, Division of Gastroenterology
& Digestive Endoscopy
A. Cardarelli National Hospital, Naples, Italy
President, Italian Association of Hospital
Gastroenterologists (AIGO)
Antonio Balzano
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09:00 Is There an Effective Medical Therapy for

Extra-digestive GERD? Facts and Fiction
Carmelo Scarpignato, MD, DSc, PharmD (h.c.),
MPH, FRCP (Hon), FACP, FCP, FACG, AGAF
Professor of Clinical Pharmacology, University of Parma, Italy
University of Nantes, France
General Secretary, World Organization for Esophageal
Diseases (OESO), Paris, France
Carmelo Scarpignato Governor for Italy, American College of Gastroenterology (ACG)
with the cooperation of Anna Bertel, MD
Consultant Physician & Gastroenterologist
Introduction
Gastro-esophageal reflux disease (GERD) is a common condition. The prevalence has
been increasing worldwide, with the highest rates (up to 30%) in Western Europe,
North America, and South America [1].
Typical GERD symptoms include heartburn and acid regurgitation. However, extra-
esophageal manifestations of GERD, such as cough, laryngitis, asthma and even dental
erosions also occur. Over the last 2 decades, these conditions, often called extra-
esophageal, or better, extra-digestive manifestations of GERD, have gained increasing
attention. In the ProGERD study, involving 6215 patients with heartburn, the preva-
lence of extra-esophageal symptom was 32.8%. Chest pain was the most frequent
complaint (14.5%), followed by chronic cough (13%), laryngeal disorders (10.4%)
and asthma (4.8%) [2]. It is worth mentioning that the costs of managing patients
with suspected extra-digestive GERD has been estimated to be over 5 times that of
patients with typical GERD symptoms [3].
During the Montreal Consensus [4], four key principles were adopted to identify the
extra-esophageal syndromes:
1. An association between GERD and the manifestations of these syndromes exists;

2. These syndromes rarely occur in isolation, without concomitant manifestations of
the typical esophageal syndrome;
3. These syndromes are usually multifactorial, with GERD as one of several potential
aggravating factors;
4. Data supporting a significant benefit of anti-reflux therapy for these syndromes
are weak.
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Although some symptoms may well be related to extra-digestive GERD, there is currently
an overdiagnosis of GERD as the major contributing factor to the extra-esophageal
syndromes. Patients with suspected extra-digestive GERD are usually referred to gastro-
enterologists often without other manifestations of GERD from ENT physicians,
respirologists, cardiologists and primary care physicians.
The diagnosis of extra-digestive GERD is difficult due to the lack of gold standard
diagnostic criteria. Functional investigations and upper GI endoscopy are not always
adequate diagnostic tools to definitively establish a causal link between reflux patterns
and patients chronic symptoms [5-7]. For this reason, empirical PPI therapy is recom-
mended as an initial approach to diagnose and treat the potential underlying cause
of these extra-esophageal symptoms. Diagnostic testing with naso-laryngoscopy,
esophago-gastro-duodenoscopy and 24-hour esophageal pH-impedance monitoring
is usually reserved for those who continue to be symptomatic despite an initial empiric
trial of PPI therapy. The current approach to the extra-digestive manifestations of
GERD discussed in this meeting will be outlined below.
Non-cardiac Chest Pain

Despite being included in the esophageal syndromes by the Montreal Classification [4],
non-cardiac chest pain (NCCP) was long considered an extra-esophageal symptom
of GERD. Chest pain, of a burning or squeezing nature, is a symptom of non-cardiac
origin and often related to GERD. Semantically, it could be considered in the so-called
extra-digestive GERD and will therefore be discussed here.
Undoubtedly, acid (as well as non-acid) reflux can cause NCCP, but it represents only
one of the many components (including esophageal dysmotility and esophageal visceral
hypersensitivity to mention a few) of a complex, multifactorial disorder [8, 9]. An
early meta-analysis by Moayyedis group [10], including 7 studies with 232 patients,
reported a pooled risk ratio for continued chest pain after PPI therapy of 0.54 (95%
CI 0.41-0.71), with an overall number needed to treat (NNT) of only 3 (95% CI 2-4).
Similar results were obtained by Gerson & Fass [11] in a later meta-analysis, which
included one more trial. A further systematic review [12] included RCTs, which used
24 h pH-monitoring and/or endoscopy to define GERD-positive patients. Compared
to placebo, the therapeutic gain of >50% improvement with PPIs was 56-85% in
GERD-positive and 0-17% in GERD-negative patients, while the RR of >50% improve-
ment in chest pain with PPI versus placebo was 4.3 (95% CI 2.8 to 6.7; p<0.0001) and
0.4 (95% CI 0.3 to 0.7; p=0.0004) for GERD-positive and GERD-negative patients,
respectively (Figure 1).
More than 30% of patients with coronary artery disease (CAD) suffer from persistent
chest pain, which is due to extra-cardiac sources, overlapping or mimicking precordial
symptoms originating in the heart [13, 14]. These are mainly due to the coexistence
WHATS NEXT ?
of GERD, low-dose aspirin-induced GI tract damage, and musculoskeletal or panic

disorders [15]. In this connection, PPIs are able to improve symptoms (by increasing
pain-free days and reducing rest nocturnal pain) [16-18] and health-related quality of
life (HRQL) [19]. Since PPIs do not affect episodes of ST segment depression on Holter
monitoring, their benefit may be due to suppression of GER-induced pain, misinterpreted
as angina, rather than acid-provoked ischaemia [17].
A B
RR meta-analysis plot (fixed effects) RR meta-analysis plot (fixed effects)
Fass 3.60 (1.76 to 8.28) Fass 0.17 (0.05 to 0.49)
Pandak 18.00 (3.77 to 101.72) Pandak 0.50 (0.23 to 0.99)
Xia 2.75 (1.40 to 6.71) Xia 0.95 (0.43 to 2.17)
Bautista 3.50 (1.59 to 8.86) Bautista 0.25 (0.06 to 0.90)
Dickman 4.00 (1.60 to 11.70) Dickman 0.50 (0.12 to 2.08)
Combined 4.29 (2.77 to 6.66) Combined 0.44 (0.28 to 0.69)

(fixed) (fixed)
1 2 5 10 100 1000 0.01 0.1 0.2 0.5 1 2 5

RR (95% CI) RR (95% CI)
Figure 1: RR meta-analysis plot (fixed effects) of proton pump inhibitor symptomatic response
for patients with chest pain and with (Panel A) and without (Panel B) objective evidence of GERD
(from Kahrilas et al. [12]).
When esophageal motility disorders (e.g. diffuse esophageal spasm, nutcracker

esophagus, achalasia or non-specific disorders) are implicated in the pathogenesis
of NCCP, smooth muscle relaxants (e.g. nitrates and calcium channel blockers) are
indicated [20], although the evidence for their effectiveness is fair or poor [21, 22].
Botulinum toxin A (BoTox) has also been used, here again with poor evidence [21,
22]. However, its efficacy in relieving chest pain appears to markedly diminished if
repeated doses are required. Thus, with every repeated dose, the duration of the effect
may be shortened.
In addition to pathologic GER, many patients with NCCP show hypersensitivity to

acid or mechanical stimuli, or both [23]. The first-line treatment for patients with
hypersensitive esophagus is acid suppression [24]. This may be a difficult task in these
patients because their esophageal sensitivity mandates almost complete suppression
of gastric acid secretion. Even a drop of acid in contact with esophageal mucosa could
be indeed enough to trigger pain. Moreover, acid suppression will not relieve those
symptoms associated with nonacidic reflux and fundoplication may be indicated in
this setting [25].
WHATS NEXT ?
Esophageal hypersensitivity is a key neurobiological mechanism underlying pain.

Compared to healthy controls, patients with NCCP demonstrate a 50% lower sensory
threshold, together with a hyperreactive and poorly compliant esophagus, suggesting
that esophageal hypersensitivity is more important than motor dysfunction [8, 9].
After the seminal paper of Cannon et al. [26], antidepressants have been widely em-
ployed in the pharmacological treatment of NCCP. Two recent systematic reviews
[27, 28] confirmed that esophageal pain thresholds do increase after antidepressant
therapy and chest pain is reduced by 23-61%. The improvement in NCCP symptoms
appears to be independent of improvement in depression scores. It is worth mentioning,
however, that adverse effects are relatively common with this kind of therapy and
they were the reported reason for discontinuation of trials in 53% of patients taking
antidepressants, compared to 29% of those receiving placebo [27].
In summary, NCCP is a heterogeneous condition for which diagnosis and treatment

are challenging. After excluding a cardiac source for chest pain, GERD being the most
important cause of NCCP, it is reasonable to begin with aggressive anti-reflux therapy
(e.g. a PPI twice daily), which may also represent a useful diagnostic test [10, 29].
In patients in whom a PPI trial is successful in improving symptoms, tapering the PPI
dose to once daily and subsequently to the lowest effective dose is recommended.
Esophageal dysmotility is relatively uncommon and smooth muscle relaxants are often
ineffective. Pain modulators can offer significant symptom improvement in patients
with non GERD-related NCCP, where PPIs are obviously ineffective.
Reflux Cough Syndrome

Reflux cough syndrome has a well-established association with GERD. GERD is im-
plicated as the primary etiologic factor in 10% of patients with chronic cough and is
considered the third leading cause of chronic cough, behind sinus problems and asthma
[30]. Chronic cough and bronchitis are documented symptoms in 30-50% of patients
suffering from GERD [31]. Although placebo-controlled studies do not support a
benefit of acid suppression, in reflux cough syndrome an empiric treatment with twice
daily PPIs is widely adopted, mainly on the basis of an early, successful open trial [32].
Although a meta-analysis of five placebo controlled studies [33, 34] found no benefit
of PPI therapy compared to placebo, a recent review [35] concluded that a therapeutic
benefit for acid-suppressive therapy in patients with chronic cough cannot be dismis-
sed, suggesting that rigorous patient selection could allow identification of patients
likely to be responsive (Figure 2).
To summarize, in patients with chronic cough and normal chest X-ray, not taking
angiotensin-converting enzyme (ACE) inhibitors once postnasal drip and asthma are
excluded a short course of PPI therapy is a reasonable initial approach. However, a
close follow-up is needed to evaluate the patients response and avoid unnecessary
long-term acid suppression.
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100
Patients with pathological esophageal
acid exposure
90
Omeprazole 40 mg once daily for 8 weeks
(n=21; first period of crossover study)
80 Upper limit of potential
Omeprazole 40 mg twice daily for 8 weeks
therapeutic gain
Therapeutic gain (%)
(n=53)
70
Omeprazole 40 mg twice daily for 12 weeks
(n=23)
60
Esomeprazole 40 mg twice daily for 12 weeks
50 (n=17; mean of severity and frequency score)
Ranitidine 150 mg once daily for 8 weeks
40 (n=24; first period of crossover study)
Global average (not weighted according to
30 sample size contributions; bars represent range)
20 Patients with normal esophageal

acid exposure
10 Esomeprazole 40 mg twice daily for 16 weeks
(n=19: most were pH-metry negative)
0 Esomeprazole 40 mg twice daily for 12 weeks
0 10 20 30 40 50 60 70 80 90 100 (n=23: all pH-metry negative; mean of severity
and frequency score)
Placebo response (%) Global average (not weighted according to
sample size contributions; bars represent range)
Figure 2: Efficacy of PPI therapy in patients with chronic cough. Calculated therapeutic gain
for datasets derived from patients with pathologic esophageal acid exposure and populations
including patients with normal esophageal acid exposure. aPercentage change in symptom score;
b
Percentage change in proportion of responders. (from Kahrilas et al. [35]).
Reflux Asthma Syndrome

In asthmatics, the prevalence of GERD is generally reported to be higher than in controls,
but with a wide range, probably due to patient selection [36]. In a minority of asthmatics,
GERD aggravates or triggers asthma. Moreover, asthma itself and anti-asthmatic medi-
cations (i.e. theophylline, beta-agonists, steroids) facilitate GERD [37, 38]. Selecting
those who are likely to respond to anti-reflux measures is important: those with diffi-
cult to treat asthma, non-allergic asthma, adult-onset asthma with GERD symptoms
should be screened for reflux, especially if they complain of nocturnal symptoms. To this
end, functional investigations and upper GI endoscopy are advisable.
There is a discrepancy between the high prevalence of reflux in asthmatics and the
limited efficacy of anti-reflux therapies [38]. This has been highlighted in a 2003
Cochrane review, which includes 12 RCTs with 432 subjects in whom the effects of
GERD therapy on asthma outcomes were reported [39]. While this early meta-analysis
showed no benefit of PPI therapy on nocturnal symptom score and lung function, a
more recent study [40] by selecting the morning peak expiratory flow (PEF) rate as
primary outcome found a benefit of PPIs over placebo, which was larger in patients
WHATS NEXT ?
with proven GERD (Figure 3). The magnitude of the improvement (below the minimal
range perceived by the patients), however, is unlikely to be clinically meaningful. There
is insufficient evidence to recommend empirical use of PPIs for routine treatment
of asthma. However, when nocturnal GERD symptoms are present, twice daily PPI
therapy results in improvement of both morning and evening PEF [41]. In a highly
selective group of patients (with idiopathic chronic cough and abnormal proximal
exposure to gastro-duodenal contents documented by hypopharyngeal pH-impedance
recording) anti-reflux surgery is highly effective [42].
GERD Source No. Difference Standard P

Diagnosis in Means Error Value Favors Placebo Favors PPI
No Kiljander et al., 2006 770 6.30 3.36 .06
No Mastronarde et al., 2009 393 6.00 5.10 .24
No Subgroup Overall 1163 6.21 2.80 .03
Yes Ford et al., 1994 20 7.00 38.46 .86

Yes Teichtahl et al., 1996 40 14.00 30.68 .65
Yes Levin et al., 1998 18 37.80 12.67 .003
Yes Boeree et al.,1998 28 13.80 39.44 .74
Yes Littner et al.,2005 207 6.00 12.51 .63
Yes dos Santos et al., 2007 44 60.00 23.83 .01
Yes Kiljander et al., 2010 647 5.50 3.41 .11
Yes Subgroup Overall 1004 16.90 8.19 .04
Overall Overall 2167 7.33 2.65 .006
100.00 50.00 0 50.00 100.00
Difference in Means and 95% CI
Figure 3: Meta-analysis of morning peak expiratory flow rate. Subgroup analysis of patients
with asthma based on GERD diagnosis. CI indicates confidence interval; GERD, gastroesophageal
reflux disease; PPI, proton pump inhibitor. (from Chan et al. [40]).
Reflux Laryngitis Syndrome

Reflux of gastro-duodenal contents in a patient with chronic laryngitis is often refer-
red to as laryngo-pharyngeal reflux (LPR), where presenting symptoms typically include
dysphonia, globus pharyngeus (sensation of lump in throat), mild dysphagia, hoarse-
ness, chronic cough, and nonproductive throat clearing [43]. Since both acid and
pepsin can cause direct mucosal injury [44], PPIs, which display antisecretory and
(indirect) antipeptic activity, have been considered the cornerstone of the therapy for
patients suspected of having GERD-related laryngeal symptoms [45]. As for other
extra-digestive manifestations of GERD, the benefits of acid suppression have been
inconsistent, with high symptomatic and laryngoscopic responses in open trials [46]
and lack of benefit on both symptoms and signs of LPR in the largest, randomized,
WHATS NEXT ?
placebo controlled, multicenter trial with esomeprazole (40 mg twice daily for 4 months)
[47]. Two meta-analyses of placebo-controlled, RCTs did not demonstrate a signifi-
cant effect of PPI therapy on chronic laryngitis [48] or laryngeal symptoms (Figure 4)
[49]. Both analyses emphasized that it is mandatory to identify the characteristics of
patients that may respond to acid suppression therapy. Recent investigations have
shown that patients with moderate to severe reflux parameters at baseline, moderate
sized (larger than 4 cm) hiatal hernia and concomitant heartburn and/or regurgitation
(in addition to their chief laryngeal symptoms) may be the most likely subgroup to
respond to anti-reflux therapy [50]. Patients unresponsive to aggressive acid suppression
are unlikely to benefit from surgical treatment [51].
Study Risk ratio (95% CI) % Weight

Ours (1999) 3.33 (0.15 71.90) 1.6
El-Serag (2001) 5.00 (0.72 34.92) 3.9
Eherer (2003) 1.36 (0.77 2.43) 44.2
Steward (2004) 0.89 (0.43 1.85) 27.2
Vaezi (2006) 0.92 (0.41 2.05) 23.1
Overall 1.18 (0.81 1.74) 00.0
0.1 1 100
RR 5 RCTs
Favors Placebo Favors PPI 247 Patients
Heterogeneity =3.76 (d.f.=4) P=0.439

2
Figure 4: Efficacy of PPIs on GERD-related laryngeal symptoms: A meta-analysis. (from Gatta et al.
[49]).
LPR can be prevented through augmentation of the upper esophageal sphincter (UES)
pressure barrier. A recent investigation found that application of 20 to 30 mm Hg
cricoid pressure significantly increases the UES intraluminal pressure and prevents
pharyngeal reflux induced by esophageal slow liquid infusion [52]. This can be achieved
with a newly developed medical device, the so-called Reza-Band (Figure 5), which
is typically worn while sleeping. This physiologically sound approach has been eva-
luated in preliminary trials [53, 54] and results look very promising: 86% of patients
had a successful outcome with significant reduction in symptoms after two weeks.
Physicians reported being satisfied with the device 92% of the time and patients were
satisfied 75% of the time, with 59% being very satisfied.
of stomach contents into the throat and lungs. LPR causes
many challenging symptoms that constitute a spectrum
of disorders including chronic throat irritation and cough,
hoarse voice, difficulty swallowing, postnasal drip, sleep
disruption and pneumonia.
The REzA BAnd was created to improve the quality of
life forOF
CHAMBER millions of patients OF
COMMERCE suffering
THE from LPR symptoms
PARMA COUNTY
due to acid reflux into the throat and lungs. This simple,
revolutionary medical device safely and effectively reduces
the symptoms associated with this widespread condition EXTRA-DIGESTIVE GERD:
with few mild and short side effects. See Instructions for Use WHATS NEXT ?
for full prescribing, safety and effectiveness information at
www.rezaband.com/instructions.
REzA BAnd Features
Small ergonomically-shaped The soft Comfort Band fits

Cushion applies a slight, easily around the neck.
controlled pressure to a
persons dysfunctional UES.
The easy-to-use Clasp

makes the REzA BAnd durable and attractive
a snap to put on and lightweight Frame.
take off.
Remarkably Simple Relief from Acid Reflux

Patients suffering from laryngopharyngeal reflux (LPR) have
Comfort Dial provides
in common a dysfunctional upper esophageal sphincter
easy adjustments for(UES). A poorly functioning UES can result in regurgitation
of stomach contents into the throat and lungs. LPR causes
patient comfort. many challenging symptoms that constitute a spectrum
of disorders including chronic throat irritation and cough,
hoarse voice, difficulty swallowing, postnasal drip, sleep
disruption and pneumonia.
How the REzA BAnd works

The REzA BAnd was created to improve the quality of
life for millions of patients suffering from LPR symptoms
Figure 5: Reza-Band and its features.

due to acid reflux into the throat and lungs. This simple,
revolutionary medical device safely and effectively reduces
The REzA BAnd is designed to apply a small the symptoms associated with this widespread condition
pressure at the cricoid cartilage, right below themild and short side effects. See Instructions for Use
with few
for full prescribing, safety and effectiveness information at
Adams apple. The REzA BAnd slightly increases
www.rezaband.com/instructions.
Ininside
the summary, suspected
pressure of the LPR from
UES to stop reflux patients without warning signs should initially be treated
REzA BAnd Features
with
going empiric
above the UES. PPI therapy
The REzA BAnd isforused1-2 to months. If symptoms improve, the therapy may need
reduce reflux symptoms in people that have been
to be prolonged
diagnosed up toworn
with LPR and is typically 6 months to allow healing of laryngeal tissue,
while Small ergonomically-shaped after which the
The soft Comfort Band fits
dose should be tapered to theCushion

sleeping. lowest pressure toeffective
applies a slight,
controlled a dose [45]. In unresponsive
easily around the neck.
patients,
persons dysfunctional UES.
functional evaluation and laryngoscopy may identify other causes for patients conti-
nued symptoms. It is important to remember
The easy-to-use Clasp that the role of diagnostic testing in LPR
makes the REzA BAnd
is not to rule reflux in but rule it aout,
snap to putwhich
on and is the most common scenario
lightweight Frame. [5].
durable and attractive
take off.
GERD-related Sleep Disturbances Comfort Dial provides

easy adjustments for
GERD and sleep disturbances are both common health problems. There is a significant
patient comfort.
association between disturbed sleep and GERD, and this is likely to be bidirectional.
How the REzA BAnd works
Nighttime reflux can leadTheto sleep
REzA BAnd disturbance
is designed to apply a small and sleep disturbance may further
pressure at the cricoid cartilage, right below the
aggravate GERD by prolongedAdams apple.acid
The REzAcontact time and heightened sensory perception
BAnd slightly increases
the inside pressure of the UES to stop reflux from
[55]. Among GERD patients, upthe UES.
going above toThe79% REzA BAnd report
is used to
reduce reflux symptoms in people that have been
nocturnal symptoms, resulting in si-
gnificant impairment in HRQOL and sleep quality [56]. The continued presence of
diagnosed with LPR and is typically worn while
sleeping.
nocturnal heartburn despite routine medical treatment is strongly associated with a

decrease in HRQOL, whereas treatment of nocturnal heartburn can provide relief of
related sleep disturbances and improvements in functioning and productivity [57-59].
Being reflux-related, subjective, but not objective, measures of sleep can improve
with anti-reflux (both medical and surgical) therapy. Elevation of the head of bed,
PPI therapy, H2-receptor antagonists, and Nissen fundoplication all alleviate nocturnal
heartburn and associated sleep disturbances [56]. A systematic review [60], which
included 8 studies, concluded that the existing evidence supports the use of PPIs as
WHATS NEXT ?
a GERD treatment to improve quality-of-life and sleep disturbance-related outcomes.

While confirming that esomeprazole significantly reduces esophageal acid exposure
during nighttime, a very recent study [61] showed no impact of acid suppression on
the duration of recumbent-awake periods and frequency or duration of conscious
awakenings in GERD patients. It is therefore likely that acid reflux occurs primarily
because patients experience awakenings from other reasons (noise, snoring spouse,
need to urinate, light, periodic leg movements, etc.) rather than specifically triggered
by acid reflux. Besides adopting sleep hygiene principles, administration of a hypnotic
may potentially reduce conscious awakenings from sleep during the night, and thus
may improve control of nighttime gastro-esophageal reflux. However, at the present
time, not data are available to support this therapeutic strategy [61].
GERD-related Dental Erosions and Halitosis

In patients with either distal or proximal gastro-esophageal reflux, oral manifestations
including dental erosions and halitosis are common. This association is usually observed
by dentists, but is given cursory mention or omitted entirely when extra-esophageal
manifestations of GERD are described [62].
Repeated or prolonged exposure of teeth to any acid (but particularly refluxed gastric
acid) leads to selective dissolution of specific components of the tooth surface, with
eventual loss of tooth substance, hypersensitivity, functional impairment, and even
tooth fracture [62]. Besides conservative treatment of the affected teeth, treatment
of the underlying disease with anti-reflux medications is mandatory. A recent study
[63], using optical coherence tomography (OCT), was able to detect and quantify a
significantly diminished progression of dental tissue demineralization and enamel loss
after only 3 weeks of treatment with esomeprazole (20 mg b.i.d.) in comparison with
placebo, suggesting that gastric acid suppression is useful in counteracting progres-
sion of GERD-related dental erosions.
Preventive measures may involve the stimulation or substitution of salivary secretions

(after assessing their quantity and quality) [64] neutralizing the effects of endogenous
and exogenous acids, reducing tooth sensitivity, providing dietary advice (regarding
dental erosion, dental caries and oral mucosal sensitivity), enhancing tooth surface
integrity (using acidulated phosphate fluoride, metallic ions), and placing adhesive
physical barriers on susceptible tooth surfaces.
Treatment of halitosis relies on dental hygiene, including tooth brushing and tongue
cleaning [65], in addition to anti-reflux therapy. Acid regurgitation may exacerbate
oral mucosal changes associated with co-existing reduced salivation, which can arise
from systemic conditions, local salivary gland conditions and intake of drugs, including
PPIs [66].
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Preventive management should involve restoration of the host defense, primarily sali-
vary secretion. The importance of adequate fluid intake should be reinforced in GERD
sufferers, especially in the elderly living in hot and dry conditions. Since salivary flow
decreases during sleep, a humidifier may be required to relieve symptoms of sleep-related
xerostomia [67]. Cooperation between gastroenterologists and dental practitioners
during the management of patients with GERD is also strongly advocated.
GERD-related Globus Sensation

The hypothesis that globus is an extra-esophageal manifestation of GERD has been
investigated on the basis of the following clinical evidence: the co-occurrence of globus
and typical reflux symptoms (heartburn and/or regurgitation); reflux esophagitis or
esophageal minimal change lesions; results from 24 h pH monitoring; globus symptom
response after anti-reflux therapy [68].
Although few specific studies are available, the best clinical approach to GERD-related
globus sensation relies like that for the other extra-digestive manifestations of reflux
disease on gastric acid suppression [69, 70]. Globus symptoms in patients with LPR
treated with PPIs resolve more slowly (up to 6 months) than typical reflux symptoms in
patients with GERD [71]. Short-term treatment will benefit only a minority of patients
[70].
In unresponsive patients, pH-impedance recording (while not taking a PPI) and high-
resolution esophageal manometry, together with naso-laryngoscopy are indicated to
rule out GERD and identify other associated GI causes (e.g. achalasia, UES dysfunction,
laryngitis, etc.). Functional globus, for which no apparent cause can be found, is as-
sociated with psychiatric comorbidities such as anxiety and depression. Interventions
addressing these comorbidities [68] or even hypnotherapy [72] have proven effective
in such circumstances.
Management of Extra-digestive GERD: The Way Forward

While PPIs represent the mainstay of medical treatment of esophageal manifesta-
tions of GERD, their benefit in extra-digestive GERD is still uncertain. The complexity
of patient presentation is matched only by the challenge in making an appropriate
diagnosis of reflux as the cause for the patients complaints. Upper GI endoscopy
and pH-impedance monitoring suffer from poor sensitivity while laryngoscopy suffers
from poor specificity in diagnosing reflux in this group of patients [5]. An empiric trial
of PPIs could be the initial approach to diagnose and treat the potential underlying
cause of these extra-digestive symptoms. Symptom resolution usually needs a higher
PPI dose and longer treatment time than those adopted in patients with typical GERD
[71]. However, it is important to highlight that in extra-digestive GERD PPI therapy
and twice daily dosing are both unapproved indications for these agents but one that
is recommended by both GI [73, 74] and other specialty guidelines [75-77].
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For patients, who improve with PPIs, GERD is presumed to be the most important
etiological factor, but for those who do not respond, diagnostic testing with pH-im-
pedance monitoring is reasonable to typically exclude continued acid or weakly acidic
reflux. If this is the case, etiologies other than GERD should be pursued. However,
there is increasing evidence suggesting that in patients with proven GERD PPIs
alone may not suffice and the use of add-on medications can achieve a higher success
rate. Even with higher PPI doses and a longer duration of therapy, the response of
patients with extra-digestive symptoms can be substantially less than that seen in
patients with typical GERD symptoms. This may be due to the inclusion in the study
cohorts of non-GERD patients or related to the exquisite sensitivity of the supra-
esophageal structures to damage from even a small amount of acid. As argued by Hunt
[78], the currently adopted criteria for mucosal acid exposure are too insensitive with
respect to symptoms. The JohnsonDe Meester criteria (% time of pH<4 for >4.2%
of the time) give equal weight to solutions of pH 4 and pH 1, despite a 1000-fold
difference in H + concentration. In addition, at the cut-off of pH 4, the H + concentration
can still be sufficient to damage supra-esophageal tissues while being less harmful for
the distal esophageal mucosa. Last but not least, the pathogenesis of extra-digestive
GERD is multifactorial and hence isolated acid suppression may not be effective,
relegating the underlying cause(s) as being non-GERD related.
Although a recent systematic review does not recommend prokinetics as a treat-

ment option for LPR [79], some studies found a better symptomatic improvement in
patients with LPR [80, 81] or in those with GERD-related chronic cough [32] when a
prokinetic agent was added to PPI therapy.
A randomized, placebo-controlled, doubleblinded study [82] evaluated the effect of

N-acetylcysteine (NAC, 600 mg daily), a mucolytic agent, combined with omeprazole
(20 mg twice daily) in patients with LPR. After 3-month treatment, combined treat-
ment achieved a significantly better improvement of objective (laryngoscopic findings)
and subjective (both reflux symptom index, RSI, and reflux symptom score, RSS)
findings.
In patients with LPR, alginate-containing formulations (e.g. Gaviscon Advance)

achieve a significant improvement in symptom scores and clinical findings either alone
[83] or in combination with PPIs [84]. Compared to acid suppression alone, the
combination of esomeprazole and Gaviscon Advance attained a significantly better
reduction of the RSI [85]. The efficacy of alginates in extra-esophageal manifestations
of GERD are likely due to its barrier effect, which translates into a reduction of the
proximal migration of the refluxed gastric contents [86] and into binding and inacti-
vation of pepsin [87]. The concentration and mucosal damaging activity of pepsin
are potentially very high in the (acidic or non-acidic) refluxate that can reach the
upper airways [44]. A mucosal protection from pepsin (and acid as well) is exerted
WHATS NEXT ?
also by Esoxx One (a mixture of hyaluronic acid and chondroitin sulfate in a bio-
adhesive carrier) [88]. This class 3 medical device proved to be effective in patients
with refractory GERD symptoms either alone [89] or in combination with PPIs [Savarino
et al., personal communication]. A trial in patients with extra-esophageal manifestations
of GERD is ongoing and results are eagerly awaited.
A suggested algorithm for the management of extra-digestive GERD is presented

in Figure 6, where anti-reflux surgery is also considered. Fundoplication could be a
reasonable choice in patients with moderate-to-severe reflux (both gastro-esophageal
and duodeno-gastro-esophageal) and a large hiatal hernia as well as regurgitation
despite PPI therapy, in whom volume reflux may be the cause for patients continued
symptoms.
Conclusions
Diagnosis and management of extra-digestive GERD is a difficult and challenging
task and leaves the clinical practitioner with several dilemmas, for the dogma has
been to try aggressive acid suppression as a means of diagnosis and/or treatment in
these patients. Although acid (as well as non-acid) reflux gives rise to symptoms in
both digestive and extra-digestive GERD, the underlying mechanism of injury may be
different as is the case for patients with erosive and non erosive reflux disease [90]. A
better understanding of the precise role of each component of the refluxate will allow
a more pathophysiologically sound approach. Moreover, the response to therapeutic
intervention still lacks serious well-controlled studies to permit drawing reasonable
conclusions. In this topic more is said than done, with so many reviews perpetuating
concepts without objective criticism.
Overall, there is room for improvement in the current approach to extra-esophageal

reflux disease and larger and better-designed clinical trials [91] are needed. First,
definitions need to be standardized. Extra-digestive GERD needs to be defined with
functional and endoscopic criteria and other modalities. Outcome measures need to
be standardized as well. Cohorts of a sufficient size need to be analyzed, and analysis
must include intention to treat. Only then could the empiricism be left behind and
management of extra-digestive GERD become evidence-based. In this connection,
time is now ripe for a new consensus to address the still unmet therapeutic needs of
this chellenging clinical condition.
WHATS NEXT ?
Suspected
Extra-digestive GERD
PPI Therapy
(Twice daily for 1-3 months)
Symptom Symptom
Persistence Improvement or Relief
Add-on Continue Therapy

Medications or Down Titrate
Symptom Symptom
Persistence Improvement or Relief
Functional Investigation Continue Therapy

& Endoscopy or Down Titrate
Normal Abnormal
Alternative Check Compliance

Diagnoses Discuss Surgery
Figure 6: Suggested algorithm for management of extra-digestive GERD.
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Notes
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09:30 Indications and Selection for Surgery of Patients

with Extra-digestive GERD
Majid Hashemi, MB ChB, FRCS
Senior Lecturer and Consultant Esophago-Gastric Surgeon,
University College Hospital, London, UK
Introduction
At present, surgery for extra-digestive GERD is usually only consi-
Majid Hashemi dered when all other therapies have failed. The cautious approach
adopted by the majority of surgeons is due to uncertainty about
the benefits of surgery in this population. The evidence base though broad and histori-
cal, presents widely varying results of surgical treatment in a heterogeneous population,
where the classification and reporting of symptoms vary, and where selection criteria
for surgery and the outcome measures are not always clearly defined. This contrasts
with the more clearly established role of surgery in typical GERD, where surgical inter-
ventions are often considered alongside medical therapies as an alternative approach
in management.
The role of surgery for the comprehensive group of extra-digestive GERD manifesta-
tions that are defined and discussed in this Congress will be considered, but reflecting
the practical and scientific data available, these manifestations will not necessarily all
be addressed separately.
Outcomes and Selection

Reflux-Cough and Reflux-Asthma
The success of surgery depends on identifying those patients who will most likely bene-
fit from surgery. Extra-digestive GERD patients usually do not have typical heartburn
and identifying GERD as a cause of their symptoms requires a high index of suspicion.
Even if gastro-esophageal reflux (GER) is the cause of chronic cough, it may be silent in
up to 75% of patients [1]. Once suspected, the workup will yield many results which are
not easy to reconcile. Many patients with extra-digestive GERD do not have esophagitis
and many do not have increased lower esophageal acid exposure and single probe pH-
monitoring would underestimate the presence of proximal reflux [2].
Extra-digestive GERD manifestations have often been reported together as atypical

symptoms and this in itself is a potential source of confusion when interpreting the
literature. Outcomes measures for anti-reflux surgery are not well defined and though
some papers use tools such as the Reflux Symptom Index (RSI) to quantify the symptom
response, this is not uniformly applied. Furthermore, the surgical series often use
widely differing outcome measures. This is partly what underlies the wide range of
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response to surgery from 15 95%. However, when looked at individually, there is

some consistency with certain more reliable predictors.
In a series of 44 patients who had undergone fundoplication for laryngopharyngeal

reflux and its severe sequelae 23/44 patients, who underwent dual probe testing had
normal lower esophageal acid exposure whilst off medication. Despite this, 19 of those
23 with normal distal acid exposure still had abnormal pharyngeal acid exposure by the
criteria applied in that study and 84% patients achieved significant symptomatic impro-
vement by 14 months after floppy 360 degree fundoplication [3]. Therefore, a normal
esophageal pH without proximal testing is insufficient to rule out proximal reflux in
patients with extra-digestive GERD. Furthermore, pharyngeal pH studies when testing
just for acid exposure are not sufficient to identify reflux related EDR disease [2] and it
may be non-acid refluxate that is the cause of the mucosal damage at the supra or extra-
esophageal level.
The belief that a good response to medication predicts a good response to surgery
derives from 2 sources. One is extrapolating from the observation in GERD patients
where indeed poor response of GERD symptoms leads to increased likelihood of
patient dissatisfaction post-surgery [4]. The other is from the studies available on
the outcome of surgery in extra-digestive GERD. In one prospective trial, 72 patients
were treated with aggressive medical therapy. Of the 25 non responders (35%) 10
patients with sore throat, hoarseness and cough elected to undergo surgery. Only
one patient out of the 10 reported improvement in laryngeal symptoms despite all 10
having resolution of laryngeal physical signs and normalisation of pH [5]. Although
failure to respond to medical therapy should prompt investigation for other causes,
there are pitfalls with over reliance on a positive response to medical therapy as a basis
for selection for surgery. Though the refluxate is less acidic in patients treated with
PPIs it may continue nonetheless, particularly if there are anatomical derangements
associated with a hiatus hernia.
A later study from the same group on patients with medically refractory extra-
esophageal reflux and physiological evidence of GERD (less than 50% response after
12 weeks) showed symptomatic improvement in 59% of them after surgery. In this
study a hiatal hernia was present in 63% of the surgical group and in almost half of
these the hernia was larger than 4 cm. In the final analysis, the presence of a hernia
greater than 4 cm was associated with a response to surgery whilst those with hernias
smaller than 4 cm were all in the surgical non responder group [6]. Others have also
reported resolution of chronic cough in 83-85% after surgery in patients who had
failed to respond to medical therapy [7, 8, 9].
Therefore patients who do not respond to medication should not be ruled out for
surgery but instead need more intensive workup. With multi-channel intraluminal
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impedance pH monitoring non-acid reflux events are also identified. When used with
the symptom index that records symptoms within 5 minutes after a reflux event it can
help identify those patients who are non-responsive to medical treatment but who
may respond to surgery [10]. More recently, Hoppo et al identified 81 patients with
chronic cough of unknown cause on whom they had performed hypopharyngeal
multi-channel impedance together with an assessment of the symptom association.
Patients with abnormal proximal exposure had a higher prevalence of long term cough,
objective findings of GERD and defective lower esophageal sphincter. From this popu-
lation, 16 patients were subsequently submitted to tailored anti-reflux surgery. They
achieved resolution of symptoms in 13 and improvement in 3 (100% improvement) [11].
When surgery is performed for pulmonary symptoms and objective baseline and
post-operative parameters are carefully measured, there is at least an overall pattern of
improvement. Sontag et al. [12] assessed pulmonary symptoms, peak expiratory flow
rates, bronchodilator and steroid use before and after surgery in a randomised control
trial of 75 patients with three arms (control, medical and surgical treatments, Figure 1).
Screened
359
235 Qualified (GER + Asthma)

Did Not Qualify
124
7 42
Lacked Full Not interested
Unterstanding
Randomized
75
Requested Surgery 26 Lost to F/U 24 25 Refused Surgery

2 2 9
Control Medical Surgical

24 22 16
12.1 19.1 years 12.1 18.6 years 11.9 19.0 years
Figure 1: Randomisation of treatment for pulmonary symptoms. Recruitment, randomization

and enrollment. After randomization, nine patients in the surgical group changed their minds
and withdrew (six because of resistance to the study by their attending physician, two patients
in the control group because of severe heartburn; two patients in the medical group were drop-
ped (one disappeared without a trace and one had a stroke) (from Sontag et al. [12]).
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The numbers are small and although there was minimal effect on pulmonary function,
by the end of 2 years there was nearly 80% improvement in asthma symptoms in
the surgical group compared to 9% in the medical group. The medical group did
not improve significantly, although treatment was with ranitidine only (Figure 2) [12].
80
70
with >40% improvement
Improved
Percentage of Patients
60
Worsened
50
40
30
20
10
0
Control Medical Surgical
p=0.008 (surgical) versus (medical/control)
Figure 2: Effect of anti-reflux surgery on GERD-related pulmonary symptoms. For asthma

symptoms, 75% of the surgical group compared with 20% and 0% of the control and medical
groups, respectively had improvement (p<0.05). No patient in the surgical group had worse-
ning of asthma symptoms versus 7% and 18% of the control and medical groups, respectively. In
the control group 28.6% (versus 0% in the medical and surgical groups) had worsening of reflux
symptoms (from Sontag et al., [12]).
In another study in 74 patients, operated on primarily for GERD but with prominent
pulmonary symptoms and using similarly defined end points, bronchospasm was
reduced from 60% to 9% and bronchodilator use and steroid use from 14 to 4% [13].
Others show similar rates of improvement with 82% improvement in cough after anti-
reflux surgery but without further quantification other than the reported symptoms
[7]. Those patients with more severe symptoms may show less improvement [14].
Those with weak esophageal body motility may also have less improvement of their
extra-digestive GERD symptoms after surgery [15, 14].
The ACCP guidelines emphasise the importance of vigilance for reflux as an underlying
cause in patients presenting with cough and advise that the absence of endoscopic
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signs does not necessarily exclude GERD. An initial detailed history and assessment,
followed by a trial of empiric acid suppression therapy, is recommended once other
potential non GERD pathology has been ruled out but failure of medical therapy and
even a non-supportive esophageal physiology test should not be regarded as conclusive
as non-acid reflux should be considered as well [1].
Laryngopharyngeal Reflux
70% of patients with refractory ENT symptoms have GERD [16]. Laryngopharyngeal
reflux (LPR) has a massive impact on the patients quality of life, with scores for social
functioning and vitality even being worse than those seen in symptomatic typical GER
[17].
Hoarseness has been shown to improve after anti reflux surgery [18, 39]. Notable is
the series by Lindstrom et al. [9] where amongst 29 patients with pulmonary symp-
toms and LPR symptoms, hoarseness was identified as the most common symptoms
(70% of the patients) and where 8/21 of these patients had laryngeal stenosis and
2/21 had laryngeal cancer and where 93% of their patients gained symptomatic relief
after fundoplication. This distribution is likely an indication of referral pathways, but
nevertheless this and another series [3] describe the severe end of the spectrum of
laryngopharyngeal reflux.
Improvements in voice quality can be measured and quantified, even if not overtly
detected clinically. A prospective study measuring the impedance across the vocal
cords before and after surgery showed that there was a significant improvement in
all parameters in 16 patients, who underwent laparoscopic anti-reflux surgery for
symptomatic GERD [19].
Failure of Surgery for Extra-esophageal GERD

As in surgery for typical GERD, the reasons for failure are incorrect patient selection,
incomplete patient preparation, the allocation of the wrong procedure and errors in
surgical technique. Contributing to poor results is the difficulty in the management
of patient expectations, particularly so given that, by the time of anti-reflux surgery,
some patients with extra-esophageal GERD may have structural changes, for example
subglottic stenosis. In these patients the changes may be irreversible and voice impro-
vements may be minimal or absent [3].
What Is Available The Surgical Options

Hiatus Hernia Repair
In patients attending respiratory clinics with chronic cough or asthma, 40 60% have
hiatus hernias. Most are of the type I or sliding variety, but many of these patients
who present with extra-esophageal GERD have type III hernias where both the gastro
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esophageal junction and a portion of the stomach have migrated up through the
hiatus (Figure 3).
Herniated portions
of the stomach
Esophagus Herniated portion

of the stomach
Diaphram
Stomach
Normal Stomach Sliding Type III

Hiatal Hernia Hiatal Hernia
Figure 3: A Comparison of the normal stomach and sliding as well as type III hiatal hernia.
Patients with the larger hernias are often older and frail (Figure 4). It is worthwhile consi-
dering the treatment of the patient with the larger hiatal hernia greater than 4 cm, type
III hernia, or giant hernia, separately since they represent a different group of patients
and the surgical technique is very different from that applied in the more common
laparoscopic fundoplication and hernia repair. Preoperatively, the patient requires
more aggressive workup with pre-optimisation that will include physiotherapy and
treatment of pulmonary symptoms with bronchodilators to improve any reversible
airway restrictive disease. They may require a longer period of fasting, without solid
foods due to the hold up in the herniated stomach, which may even be intermittently
incarcerating, and the induction for anaesthesia needs special attention to reduce
the risk of aspiration. There are additional considerations when undertaking surgery
to repair the type III hiatal hernia. The objective is primarily restoration of normal
anatomy, with tension free reduction of the stomach, back into the abdominal cavity.
This requires dissection in the mediastinum, excision or at least circumcision of the
mediastinal hernia sac. There is an increased risk of pneumothorax, and increased
risk of visceral injury. The esophagus is often shortened and this adds to the risk of
recurrence: sufficient mobilisation of the esophagus is therefore essential. The crura
may be repaired if not too attenuated and biological mesh can be used if the hiatal
defect is too wide. A fundoplication is then fashioned. In these giant hiatal hernias
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Number of Patients
12
10
0
0-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80
Age
Sliding hiatal hernia (n=34)
Paraesophageal hernia (n=18)
Figure 4: Age distribution of 18 patients with paraesophageal hernia compared with that of 34
patients with sliding hiatal hernia.
radiological recurrence after laparoscopic repair can be as high as 40% but does
not necessarily indicate symptomatic recurrence and most of these recurrences can
be managed conservatively. New strategies to improve the durability of the repair
with absorbable mesh and Collis gastroplasty to overcome the tension in a shortened
esophagus have reduced the recurrence rates to 18% [20, 21].
The presence of strictures, obesity and pre-existing esophageal shortening is a major

contributor to these recurrences hence the importance of careful mobilisation of the
lower esophagus, up as far as the aortic arch [22].
Laparoscopic hiatal hernia repair and fundoplication

Just as in the surgical treatment of GERD, most surgical options for extra-esophageal
GERD are aimed at restoring the mechanical barrier at the lower esophageal sphincter
using the fundus of the stomach. In those without an obvious hiatal hernia, the pro-
cedure focuses more on restoration of the lower esophagus into the abdominal cavity
and reinforcement with a fundoplication.
The laparoscopic approach is well established. Briefly, the procedure is carried out
through four or five ports, involves circumferential mobilisation at the GEJ taking care
to protect the vagal trunks. The hepatic branches of the vagus should also be preserved.
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The short gastric vessels may be taken down but they may also be left. The essence of
the procedure is restoration of the lower esophageal sphincter into the positive pres-
sure zone of the abdominal cavity in a tension free manner. Whether the wrap itself is
360 or 270 or 180 degree seems to be less important. There is in fact good evidence
that those with slightly weaker esophageal body function in the setting of severe
reflux have better outcomes with a full 360 fundoplication and in support of this
are also data that indicate the 180 degree Toupet is not as effective as an anti-reflux
barrier [23]. The fundoplication needs to be fashioned from the upper most part of
the stomach and leaving redundant portions can lead to pooling, and this in turn may
lead to post-operative regurgitation and symptoms such as a bad taste, mimicking the
LPR symptoms that existed preoperatively.
The recognised side effects after fundoplication are bloating, dysphagia, and the
inability to belch or vomit. In the treatment of symptomatic GERD the drawback from
these side effects are outweighed by the benefits obtained by relieving the symptoms
of GERD. The side effect-benefit balance is altered when the preoperative symptoms
are diverse and less easily quantified or atypical.
For all the hernia repairs pooled together revision rates of as high as 20% are reported
in longer term series.
Magnetic Sphincter Augmentation Device (MSAD)

Another problem with the laparoscopic fundoplication is that it is not a standardised
operation and the tightness and configuration of the wrap that is fashioned is down
to the judgement and experience of the surgeon. The magnetic sphincter augmen-
tation device (MSAD) is a new alternative to the fundoplication. The MSAD is placed
around the gastro-esophageal junction (Figure 5). This allows uniform standardisa-
tion of the procedure, and significantly reduces the dissection required. There is no
longer the need to dissect or mobilise the upper stomach. The short gastrics can be
left undivided. The vagal nerves are precisely identified and the MSAD device is placed
between the outer esophageal wall and the posterior vagus nerve. By using a dedi-
cated measuring instrument, the size of the MSAD can be tailored to the esophageal
circumference to the nearest 4 mm. To date over 1000 cases have been placed in 82
institutions worldwide. It has been proved safe with few post-operative complications.
Erosion has occurred in 1 patient (0.1%) and there has been a removal rate of 3.4%
and post-operative endoscopic dilatation in 5.35% the latter results have shown
a trend of improvement with progression along the learning curve [24]. Sympto-
matic response so far appears good and comparable to that for the fundoplication
with 93% reduction in medication by 50% or more with 81% reduction in PPIs and
with greater than 50% improvement HRQOL in the short term. Over 90% of patients
are able to vomit and fewer patients suffer from bloating when compared to the
traditional fundoplication [25, 26].
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Figure 5: The Lynx Reflux Management System.
Bypass Surgery
Not all cases of extra-digestive GERD are simply due to a weak lower esophageal
sphincter. Patients with gastroparesis, idiopathic, or diabetic may have extra-digestive
GERD symptoms and even if they have a co-existing weak lower esophageal sphincter
a fundoplication will lead to bloating and abdominal discomfort. Occasionally, a pa-
tient with a hiatus hernia can have a repair of the hernia in isolation to restore normal
anatomy without a fundoplication. However, this is often an incomplete remedy and
a formal bypass may have a role here.
Scleroderma affects esophageal motility and the integrity of the lower esophageal
sphincter as well as causing gastric emptying delay. All of this combined leads to
massive extra-digestive GERD, as well as other sequelae of intractable reflux including
strictures which can in turn further exacerbate the extra-digestive GERD [27]. Traditio-
nally, the recommendation after conservative management and medical management
has been a fundoplication, tailored as a partial 180 [28]. The fundoplication however
will often be ineffective if loose and problematic as a source of dysphagia is more
effective for the reflux. A modified laparoscopic gastric bypass provides an effective
diversion without these drawbacks and achieves good symptom resolution. There is
then no need to reinforce the LES but care needs to be taken to avoid hold up at the
newly fashioned anastomosis and attention given to fashion a vertical pouch or small
micro pouch where no hold up can occur.
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Those patients with extra-digestive and typical GERD who are obese have a higher
chance of recurrence and failure of hiatal hernia repair and fundoplication. The sur-
gery in these obese patients is also technically more difficult. Furthermore, the obesity
itself contributes to the mechanisms predisposing to the GERD and increases the likeli-
hood of erosive esophagitis. The bypass provides an effective remedy for the reflux
related symptoms, whilst also addressing the obesity and its related co-morbidities [29].
Who Will Benefit: Tools for the Selection of Patients

Pre-operative Selection
The preoperative work-up for patients undergoing anti-reflux surgery for typical GERD
symptoms of heartburn, regurgitation and dysphagia is standardised, though still evol-
ving [30]. The principles are the same when selecting and preparing a patient for anti-
reflux surgery for extra-digestive GERD. Although the extra-digestive manifestations
will be the drivers for referral, the majority of these patients will have some gastro-
esophageal symptoms too. The reflux symptom index (RSI) and the reflux finding
score (RFS) are already established as part of the routine workup of many clinics,
together with the GERD-HRQOL. An upper GI endoscopy will be indicated even if
GERD symptoms are not predominant.
Laryngoscopy is recommended in all patients with laryngitis symptoms or laryngo-

pharyngeal symptoms being considered for surgery (and before) to rule out primary
laryngeal pathology and to quantify any reflux induced laryngeal injury. However, in
practice, the findings can be subjective and varying from clinician to clinician and some
physical signs of inflammation are not specific to reflux [31].
Salivary pepsin testing is cheap and easy to apply in the clinic setting. In isolation it
lacks specificity but it can be useful to provide some reassurance that the association
between reflux and the extra-digestive symptoms is real, thereby improving the accu-
racy of the preoperative selection. Wassener et al. [32] analysed data on 9 patients,
seven who went on to have Nissen fundoplication, and two who had endoluminal
fundoplication. Pepsin was detected in 8/9 patients preoperatively but in only 1/9 post-
operatively. All eight patients who were positive for pepsin preoperatively improved
after surgery, whilst the single patient who was negative preoperatively and negative
post operatively had no symptom improvement.
Multi-channel intraluminal impedance HRM combined with concurrent assessment of

symptom association with reflux episodes identifies abnormal pharyngeal acid exposure
and provides good support for whether the extra-esophageal symptoms are caused by
reflux [10, 33, 11].
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Summary and Recommendations

From the information available, the following patients with extra-digestive GERD will
likely benefit from anti-reflux surgery:
1. Those with a hiatus hernia, particularly with a type III hernia;

2. Those patients with extra-digestive GERD who also have typical GERD symptoms,
together with supportive impedance-manometry testing, whether or not there
has been a response to medical treatment;
3. The extra-digestive GERD patient with NO typical GERD symptoms but who is posi-
tive for abnormal acid exposure or non-acid reflux events on intraluminal impedance
testing in the distal and proximal esophagus, or just positive in the proximal esopha-
gus. If the extra-digestive symptoms are mainly pulmonary with cough or asthma,
then it is likely that the patient will benefit. If it is primarily with throat symptoms that
the patient has presented, then I would proceed more cautiously and counsel the
patient carefully to ensure expectations are realistic.
In the absence of confirmed proximal reflux episodes on impedance and particularly

in a patient with normal lower esophageal acid exposure without a hiatus hernia, the
outcome of surgery is likely to be poor. In such a case one should review the symp-
toms and presentation together with the endoscopy and laryngoscopy findings to
further question the cause of the extra-digestive symptoms. The threshold for surgery
could be adjusted according to the pattern of symptoms those that have nocturnal
asthma, which worsens when lying down, where the GER symptoms appeared before
the pulmonary symptoms are likelier to improve after anti-reflux surgery.
If the lower esophageal sphincter resting pressure is low, then there would be a ratio-
nale for surgery in the symptomatic patient. If resting sphincter pressures are normal,
then there would be a risk of inviting side effects postoperatively whilst not correcting
the presenting symptoms.
For patients with extra-digestive GERD the time to resolution of symptoms after
surgery will be longer than after surgery for typical GERD and patients need to be
counselled accordingly.
The Way Ahead

Surgical remedies for reflux disease have continued to become less invasive and more
standardised. In parallel, multi-channel intraluminal impedance and high-resolution
manometry, together with other new technologies have enhanced our confidence
and ability in identifying patients where suspected extra-digestive manifestations are
attributable to gastro-esophageal reflux. In such carefully selected patients, particu-
larly those with severe or progressive disease, timely anti-reflux surgery performed
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within a specialist multi-disciplinary setting has a major role to play alongside medical
therapies.
References
1) Irwin RS. Chronic Cough Due to Gastroesophageal Reflux Disease: ACCP Evidence-Based Clinical
Practice Guidelines. Chest 2006; 129 (Suppl): 80S-94S.
2) Oelschlager BK, Chang L, Pope CE, Pellegrini C a. Typical GERD symptoms and esophageal pH-
monitoring are not enough to diagnose pharyngeal refl ux. J Surg Res 2005; 128: 55-60.
3) Westcott CJ, Hopkins MB, Bach K, Postma GN, Belafsky PC, Koufman J a. Fundoplication for laryngo-
pharyngeal reflux disease. J Am Coll Surg 2004; 199: 23-30.
4) Csendes a. Multivariate analysis of factors predicting outcome after laparoscopic Nissen fundopli-
cation. J Gastrointest Surg. 1998; 4: 650. Available from: http://www.ncbi.nlm.nih.gov/pubmed/
11351961.
5) Swoger J, Ponsky J, Hicks DM, Richter JE, Abelson TI, Milstein C, et al. Surgical Fundoplication in
Laryngopharyngeal Reflux Unresponsive to Aggressive Acid Suppression: A Controlled Study. Clin
6) Francis DO, Goutte M, Slaughter JC, Garrett CG, Hagaman D, Holzman MD, et al. Traditional reflux
parameters and not impedance monitoring predict outcome after fundoplication in extraesopha-
geal reflux. Laryngoscope 2011; 121: 1902-1909.
7) Allen CJ, Anvari M. Does laparoscopic fundoplication provide long-term control of gastroesopha-
geal reflux related cough? Surg Endosc Other Interv Tech 2004; 18: 633-637.
8) Lugaresi M, Aramini B, Daddi N, Baldi F, Mattioli S Effectiveness of Antireflux Surgery for the Cure of
Chronic Cough Associated with Gastroesophageal Reflux Disease. World J Surg 2015; 39: 208-15.
9) Lindstrom DR, Wallace J, Loehrl T a, Merati AL, Toohill RJ. Nissen fundoplication surgery for extra-
esophageal manifestations of gastroesophageal reflux (EER). Laryngoscope 2002; 112: 1762-1765.
10) Mainie I, Tutuian R, Agrawal a., Adams D, Castell DO. Combined multichannel intraluminal impe-
dance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic
Nissen fundoplication. Br J Surg 2006; 93: 1483-1487.
11) Hoppo T, Komatsu Y, Jobe BA. Antireflux surgery in patients with chronic cough and abnormal
proximal exposure as measured by hypopharyngeal multichannel intraluminal impedance. JAMA
Surg [Internet]. 2013; 148: 608-615. Available from: http://archsurg.jamanetwork.com/article.
aspx?articleID=1688807\nhttp://www.ncbi.nlm.nih.gov/pubmed/23700139
12) Sontag SJ, OConnell S, Khandelwal S, Greenlee H, Schnell T, Nemchausky B, Chejfec G, Miller T,
Seidel J, Sonnenberg A. Asthmatics with gastroesophageal reflux: long term results of a randomi-
zed trial of medical and surgical antireflux therapies. Am J Gastroenterol 2003; 98: 987-999.
13) Fernando HC, El-Sherif A, Landreneau RJ, Gilbert S, Christie NA, Buenaventura PO, Close JM,
Luketich JD. Efficacy of laparoscopic fundoplication in controlling pulmonary symptoms associated
with gastroesophageal reflux disease.Surgery 2005; 138: 612-617.
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14) Brown SR, Gyawali CP, Melman L, Jenkins ED, Bader J, Frisella MM, Brunt LM, Eagon JC,
Matthews BD. Clinical outcomes of atypical extra-esophageal reflux symptoms following laparosco-
pic antireflux surgery. Surg Endosc Other Interv Tech 2011; 25: 3852-3858.
15) DeMeester TR, Bonavina L, Iascone C, Courtney J V, Skinner DB. Chronic respiratory symptoms and
occult gastroesophageal reflux. A prospective clinical study and results of surgical therapy. Ann
Surg 1990; 211: 337-345.
16) Poelmans J, Feenstra L, Tack J. Determinants of long-term outcome of patients with reflux-related
ear, nose, and throat symptoms. Dig Dis Sci 2006; 51: 282-288.
17) Carrau RL, Khidr A, Crawley J a, Hillson EM, Davis JK, Pashos CL. The impact of laryngopharyngeal
reflux on patient-reported quality of life. Laryngoscope 2004; 114: 670-674.
18) Iqbal M, Batch a. J, Moorthy K, Cooper BT, Spychal RT. Outcome of surgical fundoplication for
extra-oesophageal symptoms of reflux. Surg Endosc Other Interv Tech 2009; 23: 557-561.
19) Ayazi S, Pearson J, Hashemi M. Gastroesophageal Reflux and Voice Changes Objective Assessment
of Voice Quality and Impact of Antireflux Therapy 2012; 46: 119-123.
20) Zehetner J, Demeester SR, Ayazi S, Kilday P, Augustin F, Hagen JA, Lipham JC, Sohn HJ, Demeester TR.
Laparoscopic versus open repair of paraesophageal hernia: The second decade. J Am Coll Surg
2011; 212: 813-8220. Available from: http://dx.doi.org/10.1016/j.jamcollsurg.2011.01.060.
21) Hashemi M, Peters JH, DeMeester TR, Huprich JE, Quek M, Hagen JA, Crookes PF, Theisen J,
DeMeester SR, Sillin LF, Bremner CG. Laparoscopic repair of large type III hiatal hernia: Objective
followup reveals high recurrence rate. J Am Coll Surg 2000; 190: 553-561.
22) Gastal OL, Hagen JA, Peters JH, Campos GM, Hashemi M, Theisen J, Bremner CG, DeMeester TR.
Short esophagus: analysis of predictors and clinical implications. Arch Surg 1999; 134: 633-636.
23) Horvath KD, Jobe B a, Herron DM, Swanstrom LL. Laparoscopic Toupet fundoplication is an inade-
quate procedure for patients with severe reflux disease. J Gastrointest Surg 1999; 3: 583-591.
24) Lipham JC, Taiganides PA, Louie BE, Ganz RA, Demeester TR. Safety analysis of first 1000 patients
treated with magnetic sphincter augmentation for gastroesophageal reflux disease. Dis Esophagus.
2014; [Epub ahead of print].
25) Riegler M, Schoppman SF, Bonavina L, Ashton D, Horbach T, Kemen M. Magnetic sphincter
augmentation and fundoplication for GERD in clinical practice: one-year results of a multicenter,
prospective observational study. Surg Endosc 2014; [Epub ahead of print] Available from: http://
link.springer.com/ 10.1007/s00464-014-3772-7.
26) Bonavina L, Saino G, Bona D, Sironi A, Lazzari V. One hundred consecutive patients treated with
magnetic sphincter augmentation for gastroesophageal reflux disease: 6 years of clinical expe-
rience from a single center. J Am Coll Surg 2013; 217: 577-585. Available from: http://dx.doi.
org/10.1016/j.jamcollsurg. 2013.04.039.
27) Ntoumazios SK, Voulgari P V., Potsis K, Koutis E, Tsifetaki N, Assimakopoulos DA. Esophageal Invol-
vement in Scleroderma: Gastroesophageal Reflux, the Common Problem. Semin Arthritis Rheum
2006; 36: 173-181.
28) Mansour K a., Malone CE. Surgery for scleroderma of the esophagus: A 12-year experience. Ann
Thorac Surg 1995; 60: 227.
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29) Pag MP, Kastenmeier A, Goldblatt M, Frelich M, Bosler M, Wallace J, Gould J. Medically refractory
gastroesophageal reflux disease in the obese: what is the best surgical approach? Surg Endosc
Other Interv Tech 2014; 28: 1500-1504.
30) Jobe BA, Richter JE, Hoppo T, Peters JH, Bell R, Dengler WC, DeVault K, Fass R, Gyawali CP, Kahrilas
PJ, Lacy BE, Pandolfino JE, Patti MG, Swanstrom LL, Kurian AA, Vela MF, Vaezi M, DeMeester TR.
Preoperative diagnostic workup before antireflux surgery: An evidence and experience-based
consensus of the esophageal diagnostic advisory panel. J Am Coll Surg 2013; 217: 586-597. Available
from: http://dx.doi.org/10.1016/j.jamcollsurg.2013. 05.023.
31) Branski RC, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal
findings associated with laryngopharyngeal reflux disease. Laryngoscope 2002; 112: 1019-1024.
32) Wassenaar E, Johnston N, Merati A, Montenovo M, Petersen R, Tatum R,Pellegrini C, Oelschlager B.
Pepsin detection in patients with laryngopharyngeal reflux before and after fundoplication. Surg
Endosc Other Interv Tech 2011; 25: 3870-3876.
33) Hoppo T, Sanz AF, Nason KS, Carroll TL, Rosen C, Normolle DP, Shaheen NJ,Luketich JD, Jobe BA.
How Much Pharyngeal Exposure Is Normal? Normative Data for Laryngopharyngeal Reflux Events
Using Hypopharyngeal Multichannel Intraluminal Impedance (HMII). J Gastrointest Surg 2012; 16:
16-25.
34) Worrell SG, DeMeester SR, Greene CL, Oh DS, Hagen JA. Pharyngeal pH-monitoring better predicts
a successful outcome for extraesophageal reflux symptoms after antireflux surgery. Surg Endosc
Other Interv Tech 2013; 27: 4113-4118.
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SESSION V: ROUND TABLE

HOT TOPICS IN THERAPY
CHAIRED BY:
Corrado Blandizzi, MD, PhD

Professor of Pharmacology & President,
School of Medicine, University of Pisa
Director, Center for Clinical Pharmacology,
University Hospital, Pisa, Italy
Corrado Blandizzi
Antonio Balzano, MD
Former Director, Division of Gastroenterology
& Digestive Endoscopy
A. Cardarelli National Hospital, Naples, Italy
President, Italian Association of Hospital
Antonio Balzano
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SESSION V: ROUND TABLE

HOT TOPICS IN THERAPY
10:30 12.45
PPI Long-term Use and Misuse:

Are There Better Alternatives to PPIs

for Treatment of Extra-digestive GERD?
Extra-digestive GERD: Which Medications

in Addition to Anti-reflux Therapy?
The Primary Care Physicians Point of View: Pali Hungin (Durham, UK)
The Respirologists Point of View: Jaclyn A. Smith (Manchester, UK)
The ENT Physicians Point of View: Mark Watson (Doncaster, UK)
The Cardiologists Point of View: Carlo Di Mario (London, UK)
The Gastroenterologists Point of View: Francesco Di Mario (Parma, Italy)
followed by a Panel Discussion
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The Primary Care Physicians Point of View
Pali Hungin, OBE, DL, MD, FRCGP, FRCP, FRSA
Professor of Primary Care and General Practice,
Centre for Integrated Health Care Research & Dean
of Clinical Medicine, School of Medicine,
Pali Hungin
A substantial proportion of the total population is on long-term
acid suppression, mainly PPIs. This ranges between 2-15% of the
population depending on definitions of long term [1, 2]. When first released PPIs
were considered suitable for peptic ulcer disease but the volumes prescribed soon
overtook the prevalences of ulcers and it was clear that they had a broader indication.
Recognition of gastro-esophageal reflux disease (GERD) as an entity necessitating
management guidelines [3] placed PPIs firmly within the clinical arena, followed by
indications for H. pylori eradication, and even for non-ulcer dyspepsia. Arguments
about the initial management of dyspepsia (essentially between early endoscopy,
test and treat for H. pylori and empirical PPI therapy) led to differing attitudes
about the use of PPIs, with a large number of patients remaining on them for the
long term, whether intermittently or continuously. Over the last ten years the role
of PPIs has been reinforced through their use as prophylactics against GI bleeding
in patients on NSAIDs and aspirin, and this group had grown considerably as the
population ages and more people have rheumatologic and cardiovascular problems.
Despite being generally safe, there have been questions about problems from PPIs,
such as hypomagnesia, increased fracture risk and lung infections as well as the prospect
of rebound acid hyper-secretion after stopping [4].
The majority of long term PPI prescribing is in primary care. Here, the clinician has
to make a judgment about the initial management of dyspepsia, the treatment of
GERD symptoms, which constitute a chronic problem and which have a community
prevalence of 10-20% and increasing [5]. This is against a backdrop of an increasing
population on NSAIDs, and particularly, aspirin, taken for cardiovascular reasons. There-
fore, whilst there is certainly some over-prescribing of PPIs, it is difficult to quantify
the size of this inappropriate prescribing unless detailed data are available on the
prevalence the various clinical entities for each country. We also need a better under-
standing of the reasons for patient consultations and why patients seek medications.
In the past many arguments about the appropriate prescribing of PPIs have centered
on their costs but with the availability of cheap generics the economic arguments
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have reduced alternatives, such as gastroscopy are recognized as being much more
costly.
Perhaps the one sector where over-prescribing can be quantified is from studies in
patients on long-term prescriptions where the initial indications have been ascertained.
In one such primary care study on patients on long term PPIs in the UK [1] moderate or
severe dyspepsia symptoms occurred in 61% and reflux symptoms in 59%. Average
symptom scores and PPI usage was lower in patients with non-ulcer dyspepsia and
gastro-protection than in those with GERD or uninvestigated dyspepsia. These data
point to a group of people in whom PPIs were not appropriate essentially some with
presumed GERD and those with uninvestigated dyspepsia. In short, if PPIs do not
seem to work, there is no need for them.
Two other factors merit consideration: the majority of patients with GERD are adherent
to their medication, even if symptom control is variable; severe symptoms and Barretts
increases adherence [6]. Secondly, there is almost certainly under prescribing of PPIs
in patients who fall into categories where gastro-protection is recommended, especially
in relation to aspirin.
The overall message is that appropriate use and misuse are not easily defined or quanti-
fied and that better awareness of the benefits of PPIs is more important than some
sort of policing for primary care. There is probably no need to get so worked up about
it and the answer to the initial question is that we are all responsible!
References
1) Raghunath AS, Hungin AP, Mason J, Jackson W. Symptoms in patients on long-term proton pump
inhibitors: prevalence and predictors. Aliment Pharmacol Ther 2009; 29: 431-439.
2) Murie J, Allen J, Simmonds R, de Wet C. Glad you brought it up: a patient-centred programme to re-
duce proton-pump inhibitor prescribing in general medical practice. Qual Prim Care 2012; 20: 141-148.
3) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group.The Montreal defini-
tion and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am
J Gastroenterol 2006; 101: 1900-1920.
4) Haastrup P, Paulsen MS, Begtrup LM, Hansen JM, Jarbl DE. Strategies for discontinuation of proton
pump inhibitors: a systematic review. Fam Pract 2014; 31: 625-630.
5) Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Changes in prevalence, incidence and spontaneous
loss of gastro-oesophageal reflux symptoms: a prospective population-based cohort study, the
HUNT study. Gut 2012; 61: 1390-1397.
6) Hungin AP, Hill C, Molloy-Bland M, Raghunath A. Systematic review: Patterns of proton pump
inhibitor use and adherence in gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2012;
10: 109-116.
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The Respirologists Point of View
Jaclyn A. Smith, MB ChB, PhD, FRCP
Centre for Respiratory Medicine and Allergy,
University of Manchester and Honorary Consultant,
University Hospital of South Manchester, Manchester, UK
Jaclyn A. Smith
The interest in the potential impact of gastro-esophageal reflux
on respiratory disease has been steadily growing in recent decades, as has the wide-
spread use of proton pump inhibitors (PPIs). In one study of patients on respiratory
hospital wards, over 40% were treated with these therapies [1]. The precise reasons
for clinical decisions to initiate and then continue PPI treatment can be difficult to
establish, but surveys suggest their use frequently seems to be outside the appropria-
te national prescribing guidelines [2].
Possible rationales for the high levels of use of PPIs by respiratory physicians are as
follows:
1) Many patients with respiratory diseases complain of both typical symptoms of reflux
(e.g. heartburn, regurgitation) but also symptoms such as chronic cough, throat
clearing, dysphonia which are often specifically attributed to gastro-esophageal
reflux disease (GERD).
2) Oral corticosteroids are often used for exacerbations of respiratory diseases such
as asthma and Chronic Obstructive Pulmonary Disease (COPD), and sometimes
chronically prescribed. Protection from gastric ulceration may therefore also be a
concern.
3) Concerns that GERD may exacerbate the symptoms of respiratory diseases and
perhaps also hasten disease progression have received a lot of attention. These
factors, combined with the general notion that PPIs are relatively safe probably
account for their widespread use.
More recent data would suggest that chronic PPI use may add to the risks of osteopo-
rosis [3], Clostridium difficile infection [4, 5] and pneumonia. Corticosteroid treatments
already confer a significant risk of osteoporosis in respiratory disease patients. Many
respiratory conditions are also punctuated by infective exacerbations requiring anti-
biotic treatment and hospital admission, both factors increasing the risk of C. difficile
infections without the additional contribution of PPI use. Furthermore, PPI treatment
may increase the risk of community-acquired pneumonia (CAP) perhaps as a result of
altering oropharyngeal or upper gastro-intestinal flora [6].
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The evidence that PPI use has benefit in patients with chronic respiratory disorders is
less compelling than the evidence they may do harm. In patients presenting with iso-
lated chronic cough, where GERD has been thought to be one of the main aetiological
factors, randomised controlled trials have struggled to show a benefit. Similarly results
in asthma have been inconsistent and little evidence is available in other conditions
such as COPD and idiopathic pulmonary fibrosis. Thus the risk benefit ratio of PPI use
needs to be more carefully considered, especially in older respiratory patients.
References
1) van Vliet EP, Otten HJ, Rudolphus A, Knoester PD, Hoogsteden HC, Kuipers EJ, Siersema PD.
Inappropriate prescription of proton pump inhibitors on two pulmonary medicine wards. Eur J
2) Heidelbaugh JJ, Goldberg KL and Inadomi JM. Magnitude and economic effect of overuse of
antisecretory therapy in the ambulatory care setting. Am J Manag Care 2010; 16: e228-234.
3) Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z. Proton pump inhibitor
use, hip fracture, and change in bone mineral density in postmenopausal women: results from the
Womens Health Initiative. Arch Intern Med 2010; 170: 765-771.
4) Howell MD, Novack V, Grgurich P, Soulliard D, Novack L, Pencina M, Talmor D. Iatrogenic gastric
acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010;
170: 784-790.
5) Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent
Clostridium difficile infection. Arch Intern Med 2010; 170: 772-778.
6) Meijvis SC, Cornips MC, Voorn GP, Souverein PC, Endeman H, Biesma DH, Leufkens HG, van de
Garde EM. Microbial evaluation of proton-pump inhibitors and the risk of pneumonia. Eur Respir J
2011; 38: 1165-1172.
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The ENT Physicians Point of View
Mark G. Watson, MB ChB, FRCS
Consultant ENT Surgeon, Royal Infirmary and Bassetlaw
Hospital, Doncaster & Lead Clinician for Head
and Neck Cancer in the NHS Foundation Trust, UK
Mark G. Watson
Laryngopharyngeal reflux (LPR) has been recognised as a cause of
laryngeal symptoms and disease since the original work of James
Koufman in the USA [1]. LPR is thought to be a common problem in ENT clinics in
the Western world [2]. Whilst there is a profusion of basic science knowledge of the
underlying disease processes [3], in clinical practice, diagnosis and treatment can be
more problematic [4].
Whilst in classical GERD the underlying disease is related to acid exposure and the
response to PPI therapy is generally good, it is increasingly recognised that patients
with non-erosive reflux disease (NERD) do not respond as well as those with erosive
esophagitis. In LPR, the underlying disease is thought to be related to pepsin exposure
[3], and so PPIs are at best an indirect treatment, exerting their effect by preventing
the cleavage of pepsinogen to active pepsin in a highly acid environment.
The use of PPIs in LPR remains controversial, with some studies recommending their
use [5], and other authors suggesting that there is little evidence to support their
use [6]. In the UK, they are commonly used to treat a range of throat symptoms.
If they are to be useful, it is strongly recommended that they are prescribed twice daily
before meals, and continued for at least 2-3 months before assessing response. The
use of a structured symptom score such as the Reflux Symptom Index (RSI) is strongly
recommended [7].
In the UK, PPI therapy for LPR is begun either by the primary care physician (GP) or the
ENT specialist in a hospital clinic setting. The responsibility for long-term maintenance
prescribing lies with the GP. Both have a responsibility for the correct use of PPI in the
long term, as do patients themselves.
The role of the ENT specialist in PPI use for LPR firstly lies in making the correct diagno-
sis. In most cases the diagnosis is a clinical one, with specialist investigations usually
being reserved for difficult cases [2]. LPR is often over-diagnosed, for example in a
patient with globus but no other LPR symptoms and a low RSI score. In such as a si-
tuation use of a PPI, especially in the long term, is probably inappropriate. For patients
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with more classical LPR, it is the duty of the ENT specialist to report improvement on
treatment to the GP, and make a recommendation on long-term management, as
most patients will not have long-term follow-up in the ENT clinic.
The GP needs to monitor the long-term prescriptions supplied to the patients on his
caseload. Several UK schemes have helped GPs to reduce long-term polypharmacy,
and some have used PPI prescription rates as a marker.
One of the reasons that patients may be reluctant to stop their PPI treatment is the
phenomenon of acid rebound, especially if therapy is terminated abruptly [8]. One
approach to dealing with this is for the ENT specialist to provide the GP with a PPI
step-down schedule at the point of discharge from the hospital clinic [2].
References
1) Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a
clinical investigation of 225 patients using ambulatory 24hr pH monitoring and an experimental
investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope
1991; 101 (Suppl 53): 1-78.
2) Watson MG. Whats new in LPR? The Otorhinolaryngologist 2011; 4: 21-27.
3) Dettmar PW, Castell DO, Heading RC (Eds) Review article: Reflux and its consequences the laryn-
geal, pulmonary and oesophageal manifestations. Aliment Pharmacl Ther 2011; 33 (Suppl 1): 1-71.
4) Powell J, OHara J, Wilson JA. Are persistent throat symptoms atypical features of gastric reflux and
should they be treated with proton pump inhibitors? BMJ 2014; 349: g5813
5) Reichel O, Dressel H, Wiederanders K, Issing WJ. Double blind, placebo-controlled trial with esome-
prazole for symptoms and signs associated with Laryngopharyngeal reflux. Otolaryngol Head
Neck Surg 2008; 139: 414-420.
6) Vaezi MF, Richter JE, Stasney CR, Spiegel JR, Iannuzzi RA, Crawley JA, Hwang C, Sostek MB, Shaker
R. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope 2006; 116: 254-260.
7) Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS).
The Laryngoscope 2001; 111: 1313-1317.
8) Gillen D, Wirz AA, Ardill JE, McColl KEL. Rebound hypersecretion after omeprazole and its relation
to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999; 116:
239-247.
WHATS NEXT ?

The Cardiologists Point of View
Carlo Di Mario, MD, PhD, FRCP, FSCAI, FESC, FACC
Professor of Clinical Cardiology,
Imperial College and Consultant Cardiologist,
Royal Brompton Hospital, London, UK
Theme Leader, Complex Coronary Artery Disease,
RRU Brompton, National Institute of Health Research, UK
Carlo Di Mario
Cardiologists are certainly responsible of many inappropriate long-

term prescriptions of PPIs prompted by the need to protect patients at risk of gastro-
intestinal bleeding during treatment with antiplatelet and anticoagulant agents [1].
The first issue to address is the gastrotoxicity of many cardiac drugs and the preven-
tion of secondary damage. Before the development of interventional cardiology as the
prevalent modality of treatment of patients with acute coronary syndromes, aspirin
was the only gastrotoxic drug recommended in the presence of established evidence
of coronary artery disease or after CABG [2-4]. With the universal use of stents during
PCI, thienopyridines have been added to aspirin, with prasugrel and ticagrelor replacing
clopidogrel, especially in STEMI patients and diabetic patients [5-7]. Before the year
2000 dual combination treatment was given for one month only. In the last decade,
bare metal stents have been substituted by drug eluting stents, effective in drama-
tically reducing restenosis but also delaying strut coverage and responsible of late
stent thrombosis, a phenomenon which is rare but associated with death and myo-
cardial infarction in more than 2/3 of cases. In the last 10 years more biocompatible
polymers in second generation drug eluting stents have nearly eliminated this severe
complication and suggested the limitation of DAPT to 3-6 months. A large US trial
also called DAPT [8], enrolling patients after one year of uncomplicated use of aspirin
and clopidogrel, has observed a significant reduction of ischemic events in the group
prolonging treatment up to 3 years, with of the events prevented caused by un-
treated lesions. This advantage was sufficient to compensate the increased bleeding
risk [9-11].
At present, decisions for practising cardiologists are difficult because of these conflicting
results. On one hand a multitude of small-scale trials has confirmed the safety of early
withdrawal of these drugs, but this evidence is in conflict with the nearly 20,000
patient experience of DAPT. The low cost of clopidogrel, now a generic drug, has
reduced the pressure to reduce the duration of treatment with this drug.
WHATS NEXT ?
The second field of wide application of PPI is in patients with permanent of paroxysmal
atrial fibrillation [12-15] and the many other cardiovascular indications to anticoagu-
lation (mechanical heart valves, cavity thrombosis, pulmonary embolism, etc). With
larger indications to the initiation of anticoagulants in patients with arrhythmias at
risk of thrombus formation (CHAD2VASC2 score 1) elderly patients at high risk of
bleeding become the target for a combination with warfarin or the new oral anticoa-
gulants (NOACs) with PPI [1]. The difficulties in maintaining a constant INR level with
warfarin explain the lower bleeding risk and adverse events observed in the seminal
studies comparing enoxaparin with dabigatran, rivaroxibam, apixabam [16]. These
powerful anticoagulants, however, also have very high inherent bleeding risk and gastric
protection is almost uniformly applied [1].
The most frequently asked questions cardiologists address to gastroenterologists and

clinical pharmacologists are the following:
PPI are nearly always started in patients admitted with acute myocardial infarction or
NSTEMI because the need of offering a prompt revascularisation treatment often limit
the time to investigate the patients history in search of evidence of previous gastric
problems or bleeding. After the acute phase when and for whom is withdrawal of PPI
safe? Catastrophic bleedings or progressive anemia remain frequent despite the use
of PPI in patients with high bleeding risk. How can we identify this small group with a
risk of severe or fatal bleeding and how to handle them? How to treat patients with
chronic blood loss but no evidence of focal GI bleeding (ulcer, polyps)?
The second issue of common interest for gastroenterologists and cardiologists is the
presence of gastroesophageal reflux (or other upper GI pathologies) as a confounder
mimicking symptoms of angina or, viceversa, as the real cause of symptoms wrongly
addressed with complex and often invasive diagnostic and therapeutic cardiological
investigations. In modern medicine, with history relegated among the least relevant
medical activities and great emphasis on the routine performance of multiple tests,
the problem has become more common and probably is a leading cause of inappropria-
te investigations and treatments in both disciplines. The specialist to blame is often
dictated by the referring physician, often the GP, who may be rightly confused by the
many similarities of the symptoms or by elements in the history (previous episodes,
risk factors), suggestive of one or the other pathology. The main difficulty is the inci-
dence of both problems is so high that often patients with symptoms due to severe
life-threatening coronary stenosis are falsely reassured by the presence of minor ab-
normalities in upper endoscopy and patients with symptoms due reflux are wrongly
labeled as coronary patients because of pseudo-ischemic changes demonstrated by
false positive non-invasive tests or, worse, because of true pathological coronary
changes demonstrated with MSCT or coronary angiography that are only innocent
bystanders. Investigations and treatments in the wrong direction are obvious cases
WHATS NEXT ?
of frustration or, worse, dire medico-legal consequences if the attention to the real
problem comes too late, after an acute heart attack or a bleeding precipitated by the
inappropriate use of aspirin or other gastrotoxic drugs administered based on a wrong
diagnosis.
Questions to answer are many, starting from the rules to follow to avoid falling into
the trap of mistaking the detection of coronary atherosclerotic changes or benign
long-standing upper GI pathologies as the cause of the symptoms. Maybe the first
advice can be to good back to the practice of the old days when doctors had fewer
sophisticated techniques of analysis and imaging and more time to listen to their
patients.
References
1) Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW, Huber K, Grove EL, Morais J,
Husted S, Wassmann S, Rosano G, Atar D, Pathak A, Kjeldsen K, Storey RF; ESC Working Group on
Cardiovascular Pharmacology and Drug Therapy and ESC Working Group on Thrombosis. Expert
position paper on the use of proton pump inhibitors in patients with cardiovascular disease and
antithrombotic therapy. Eur Heart J 2013; 34: 1708-1713.
2) Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101: 1206-1218.
3) Patrono C, Garca Rodrguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of
atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
4) Hennekens CH, Dalen JE. Aspirin in the treatment and prevention of cardiovascular disease: past
and current perspectives and future directions. Am J Med 2013; 126: 373-378.
5) Norgard NB, Dinicolantonio JJ. Clopidogrel, prasugrel, or ticagrelor? A practical guide to use of
antiplatelet agents in patients with acute coronary syndromes. Postgrad Med 2013; 125: 91-102.
6) Pilgrim T, Windecker S. Antiplatelet therapy for secondary prevention of coronary artery disease.
Heart 2014; 100: 1750-1756.
7) Warren J, Baber U, Mehran R. Antiplatelet therapy after drug-eluting stent implantation. J Cardiol
2015; 65: 98-104.
8) Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E,
Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari
DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study Investigators.
Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371:
2155-2166.
9) Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Genereux P, Branzi A, Stone GW. Stent
thrombosis with drug-eluting stents: is the paradigm shifting? J Am Coll Cardiol 2013; 62: 1915-
1921.
10) Rha SW. Duration of dual antiplatelet treatment in the era of next generation drug-eluting stents.
World J Cardiol 2014; 6: 148-153.
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11) Park SJ, Kang SM, Park DW. Dual antiplatelet therapy after drug-eluting stents: defining the proper
duration. Coron Artery Dis 2014; 25: 83-89.
12) Steinberg BA, Piccini JP. Anticoagulation in atrial fibrillation. BMJ 2014; 348: 2116.
13) Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial
fibrillation? J Thorac Dis 2015; 7: 165-167.
14) Jalota A, Scarabelli TM, Saravolatz L, Bakhsh MU, Agrawal P, Jalota R, Chen-Scarabelli C, Fuster V,
Halperin J. Novel anticoagulants for stroke prevention in patients with atrial fibrillation. Cardiovasc
Drugs Ther 2014; 28: 247-262.
15) Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial
fibrillation? J Thorac Dis 2015; 7: 165-171.
16) Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin
Haematol. 2013; 26:191-202.
17) Tran H, Joseph J, Young L, McRae S, Curnow J, Nandurkar H, Wood P, McLintock C. New oral
anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding
management. Australasian Society of Thrombosis and Haemostasis. Intern Med J 2014; 44: 525-
536.
18) Fenger-Eriksen C, Mnster AM, Grove EL. New oral anticoagulants: clinical indications, monitoring
and treatment of acute bleeding complications. Acta Anaesthesiol Scand 2014; 58: 651-659.
WHATS NEXT ?

The Gastroenterologists Point of View
Professor of Gastroenterology and Director,
Post-graduate School of Gastroenterology,
with the cooperation of Elisabetta Goni, MD,
Francesco Di Mario Research Fellow
Gastro-esophageal reflux disease (GERD) is generally considered as an acid-related

disorder. The Montreal consensus classified different presentations of GERD, e.g.
esophageal and extra-esophageal syndromes, where the prevalence of mucosal damage
is very different. In particular, patients with heartburn and/or regurgitation display
esophagitis more frequently than those experiencing extra-esophageal symptoms, in
whom the non erosive disease is more common [1].
Interestingly enough, when extra-esophageal symptoms (chronic cough, laryngitis,

asthma, non-cardiac chest pain, obstructive sleep apnea syndrome, arrhythmias, etc)
are present, the typical symptoms are usually absent, making the correct diagnosis
more difficult [2].
Once the (often presumptive) diagnosis is made, the majority of patients are treated
with proton pump inhibitors (PPIs), usually in a symptom-driven fashion. The reasons
for giving a PPI is not only to suppress acid but also to decrease the volume of gastric
secretions, an important factor in the pathophysiology of reflux disease. However,
acid hypersecretion is rare in GERD patients while the defective lower esophageal
sphincter (LES) and impaired esophageal clearance are common [3]. Therefore, the
current extensive use of PPIs in patients with extra-digestive GERD may be inappro-
priate.
By using 24 h pH-impedance recording, were are now able to characterize the com-
position (acidic, weakly acidic or non acid) and nature (liquid or gaseous) of the
refluxate and should be able to tailor drug treatment accordingly, limiting PPI therapy to
patients, where gastro-esophageal reflux is predominantly acidic. Other drug classes
(e.g. prokinetics or barrier drugs) should be more suitable to target symptoms related
to non-acidic reflux.
WHATS NEXT ?
pH-impedance monitoring, which represents the best functional investigation for

diagnosis of GERD and GERD-related symptoms, is clearly not widely available and
this could be one of the plausible reasons for PPI misuse in patients with extra-digestive
GERD by both GPs and other non GI specialists.
In addition to PPI misuse, their underuse is common. A standard (single) dose of PPIs
for 4-8 weeks is commonly used while experience does show that in patients with
extra-esophageal manifestations of GERD higher (double, twice daily) doses and
longer treatments are needed to achieve a consistent symptom resolution.
Finally, 25 years after the introduction of the first PPI (i.e. omeprazole) in clinical
practice, this class of drugs is perceived as extremely safe. Although these compounds
are usually well tolerated in the short-term, long-term acid suppression has a dark
side [4], with some potential adverse events that should be duly taken into account,
especially in the elderly [5]. These findings suggest a close follow-up of PPI users in
order to evaluate the need for continuous therapy and the evaluation of its benefit-
to-risk ratio.
References
1) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal defini-
tion and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am
J Gastroenterol 2006; 101: 1900-1920.
2) Hom C, Vaezi MF. Extra-esophageal manifestations of gastroesophageal reflux disease: diagnosis
and treatment. Drugs 2013; 73: 1281-1295.
3) Naik RD, Vaezi MF. Extra-esophageal manifestations of GERD: who responds to GERD therapy?
Curr Gastroenterol Rep 2013; 15: 318.
4) Nealis TB, Howden CW. Is there a dark side to long-term proton pump inhibitor therapy? Am J Ther
2008; 15: 536-542.
5) Maggio M, Corsonello A, Ceda GP, Cattabiani C, Lauretani F, Butt V, Ferrucci L, Bandinelli S,
Abbatecola AM, Spazzafumo L, Lattanzio F. Proton pump inhibitors and risk of 1-year mortality
and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med
2013; 173: 518-523.
WHATS NEXT ?
11:15 Are There Better Alternatives to PPIs for Treatment

of Extra-digestive GERD?
Pali Hungin
This is a difficult topic. Primary care physicians are frequently faced
by patients whose problems do not seem to respond to the treatments apparently
indicated and it is natural therefore to seek alternative explanations. Such conditions
include recurrent ENT symptoms seemly not responsive to ENT directed treatments,
respiratory complaints such as asthma-like symptoms or chronic cough, upper respi-
ratory symptoms, dental erosions and non-cardiac chest pain. Whereas GPs are used
to the concept of functional problems such as IBS or fibromyalgia, the prospect of
treating other difficult to manage problems like extra-esophageal complications raises
hopes for better targeted management. Around a third of patients with GERD may
have extra-digestive manifestations [1] and the cost of extra-digestive GERD problems
has even been estimated as being five times that of GERD alone [2].
However, there has been much confusion in deciding what constitutes an extra-digestive
problem related to GERD; data have been conflicting and there has been confusion
as to whether the treatment should relate to acid suppression or the reduction and
prevention of reflux.
It is thought that GERD contributes to extra-digestive manifestations through two

mechanisms: direct (aspiration) or indirect (vagally mediated) mechanisms. The
direct mechanism may be associated with the cough reflex, laryngitis or asthma and
the indirect mechanism is related to cough, non-cardiac chest pain and bronchial
spasm mediated by vagal stimulation.
For the direct mechanism the reflux of gastroduodenal contents is classified as high
or distal and the presence of an intact lower esophageal sphincter and the upper
esophageal sphincter barrier usually prevents reflux and is considered an effective
barrier. In the indirect mechanism, as the esophagus and bronchial tree share a com-
mon embryonic origin they also share a common innervation via the vagus. Pressure
gradient changes, such as through a vicious cycle of cough and reflux can contribute
to respiratory symptoms.
WHATS NEXT ?
Therapeutic options are geared to the tentative mechanisms. Empirical, usually high
dose PPI therapy has been used in most cases although it is recognized that other
agents such as pepsin and possibly, bile, are also important. However, placebo con-
trolled studies with high dose PPIs have shown contradicting results [3].
Treatment beyond PPIs is normally out of the remit of primary care and suggestions
have included the use of agents to tighten the lower esophageal sphincter (such as
by using baclofen to inhibit transient lower esophageal sphincter relaxations), enhan-
cement of the anti-reflux barrier (such as with alginates) or surgical treatments such
as fundoplication. The effectiveness of these, again, is variable and the selection of
patients best suited to such approaches has proved a problem for example, it has
been held that patients poorly responsive to PPIs will do badly with fundoplication.
Specific, laboratory based tests, such as pH and impedance monitoring, are required
to select patients for high-level interventions but there is little in routine use that can
be recommended easily.
References
2003; 17: 1515-1520.
3) Richter JE. Review article: extraoesophageal manifestations of gastro-oesophageal reflux disease.
Aliment Pharmacol Ther 2005; 22 (Suppl 1): 70-80.
WHATS NEXT ?

Jaclyn A. Smith
There are two main mechanisms via which gastro-esophageal
reflux is thought to be able to impact upon respiratory disease. Firstly, via the shared
vagal innervation of the esophagus and airways, refluxate within the esophagus may
be capable of evoking respiratory reflexes such as cough or bronchoconstriction.
Experimental studies infusing acid into the esophagus provide evidence that such me-
chanisms exist [1, 2], along with studies assessing the temporal associations between
symptoms and reflux events [3, 4], however the latter suggest the degree of acidity
of the refluxate may not be important, especially in patients with chronic cough.
Secondly, respiratory physicians are often concerned that refluxate may escape the
esophagus and enter the larynx and lower airways of their patients, leading to increased
symptoms and perhaps worsening of disease through the damaging effects of com-
ponents such as pepsin, bile acids and perhaps also the introduction of infection. This
process of micro-aspiration, however, is extremely challenging to measure and assess.
Importantly, PPI treatment, which primarily reduces the acidity of refluxate, may well
not address either of these mechanisms. Indeed, in the case of micro-aspiration, if the
refluxate is rendered less irritant, it may be more readily micro-aspirated and the loss
of acidity may increase the microbial content.
In the case of symptoms being provoked by reflux events within the esophagus, an
important question is whether the amount of reflux the esophagus is exposed to is
excessive or not. In patients presenting with chronic cough we have found this may not
be the case [5], rather these patients seemed to be coughing in response to physio-
logical numbers of distal reflux events [4], suggesting that neuronal sensitisation of
the vagal pathways may be the main underlying etiology. Moreover, in such patients
treatments targeting neuronal sensitivity such as gabapentin and P2X3 inhibitors may
be most effective, by blocking the sensitivity of esophageal as well as airway vagal
afferents provoking cough [6, 7].
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In other respiratory conditions, such as cystic fibrosis and interstitial lung disease, there
is accumulating evidence that esophageal reflux is excessive, and extends to the proxi-
mal esophagus, increasing the risks of micro-aspiration [8, 9]. Currently treatments
know to reduce the number and proximal extent of reflux events in such patients are
lacking. The vast majority of reflux events are thought to result from transient lower
esophageal sphincter relaxations (TLESRs). Novel therapies that reduce the number of
TLOSRs have been developed, including GABAB and metabotropic Glutamate Receptor
5 (mGluR5) agonists. Whilst these therapies seem to have failed to have sufficient
efficacy in patients with typical GERD [10], a role in patients with respiratory diseases
needs exploration. Reductions in the number of TLESRs and hence reflux events may
explain some of the reported successes in uncontrolled studies of reflux surgery in
respiratory patients, although the risk of complications and dysphagia can be high.
References
1) Wu DN, Yamauchi K, Kobayashi H, Tanifuji Y, Kato C, Suzuki K, Inoue H. Effects of esophageal acid
perfusion on cough responsiveness in patients with bronchial asthma. Chest 2002; 122: 505-509.
2) Ing AJ, Ngu MC and Breslin AB. Pathogenesis of chronic persistent cough associated with gastro-
esophageal reflux. Am J Respir Crit Care Med 1994; 149: 160-167.
3) Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with
chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut 2005;
54: 449-454.
Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastro-
enterology 2010; 139: 754-762.
5) Ryan NM, Birring SS, Gibson PG. Chronic cough: relationship between microaspiration, gastro-
esophageal reflux, and cough frequency. Chest 2012; 142: 958-964.
6) Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA. P2X3 receptor antago-
nist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2
study. Lancet 2014; ii: S0140-6736(14)61255-1. [Epub ahead of print]
7) Ryan NM, Birring SS and Gibson PG, Gabapentin for refractory chronic cough: a randomised, double-
blind, placebo-controlled trial. Lancet 2012 380: 1583-1589.
8) Pauwels A, Blondeau K, Dupont LJ, Sifrim D. Mechanisms of increased gastroesophageal reflux in
patients with cystic fibrosis. Am J Gastroenterol 2012; 107: 1346-1353.
9) Savarino E, Carbone R, Marabotto E, Furnari M, Sconfienza L, Ghio M, Zentilin P, Savarino V. Gastro-
oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J
2013; 42: 1322-1331.
10) Kahrilas PJ, Boeckxstaens G. Failure of reflux inhibitors in clinical trials: bad drugs or wrong patients?
Gut 2012; 61: 1501-1509.
WHATS NEXT ?

Mark G. Watson
LPR is a disease, which is clearly related to lifestyle, and it is clearly
logical to include lifestyle advice in the management of patients
with this condition [1]. In Doncaster we provide every patient with oral and written
advice on lifestyle issues including smoking, alcohol, fizzy drinks, fruit juices, sleeping
position and other matters.
A reflux advice session from a trained speech and language therapist (SLT) can improve
treatment compliance, and therefore hopefully improve outcomes in LPR patients. An
audit carried out in Doncaster on 37 consecutive LPR patients showed that a single
advice session covering voice care and reflux management increased compliance from
an average of 66% to 88%. Before SLT intervention 0/37 achieved 100% compliance
compared to 12/37 afterwards, and the number only managing <50% compliance
fell from 8/37 to 0/37 after intervention [2]. Specialist voice therapy for those patients
with hoarseness and LPR has been shown to improve outcomes [3].
One study has suggested that drinking alkaline water may improve LPR symptoms,
although a proper clinical trial is needed [4].
Alginate treatment is frequently used in the UK for the treatment of LPR, either alone
or in combination with PPIs. One prospective controlled trial showed clearly positive
results [5]. In Doncaster, our standard treatment regime includes low-dose PPI twice
daily, 30 minutes before food, along with alginate (Gaviscon Advance) just before
retiring at night.
Antireflux surgery can be effective in controlling LPR, but results are best when the
diagnosis is confirmed by appropriate physiological testing [6].
WHATS NEXT ?
References
1) Steward DL, Wilson KM, Kelly DH, Patil MS, Schwartzbauer HR, Long JD, Welge JA. Proton pump
inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Otolaryngol
Head Neck Surg 2004; 131: 342-350.
2) Watson MG. Whats new in LPR? The Otorhinolaryngologist 2011; 4: 21-27.
3) Vashani K, Murugesh M, Hattiangadi G, Gore G, Keer V, Ramesh VS, Sandur V, Bhatia SJ. Effective-
ness of voice therapy in reflux-related voice disorders. Dis Esophagus 2010: 23: 27-32.
4) Koufman JA, Johnston N. Potential benefits of pH 8.8 drinking water as an adjunct in the treatment
of reflux disease. Ann Otol Rhinol Laryngol 2012; 121: 431-434.
5) McGlashan JA, Johnston LM, Sykes J, Strugala V, Dettmar PW. The value of a liquid alginate suspen-
sion (Gaviscon Advance) in the management of laryngopharyngeal reflux. Eur Arch Otorhinolaryngol
2009; 266: 243-251.
6) Francis DO, Goutte M, Slaughter JC, Garrett CG, Hagaman D, Holzman MD, Vaezi MF. Traditional
reflux parameters and not impedance monitoring predict outcome after fundoplication in extra-
esophageal reflux. Laryngoscope 2011; 121: 1902-1909.
WHATS NEXT ?

Carlo Di Mario
In the management of GERD-related non-cardiac chest pain

(NCCP), PPIs are highly effective [1, 2] with an NNT of only 3. Their benefits are more
evident in patients where the diagnosis of GERD could be established by functional
investigation [3]. In these patients the therapeutic gain of >50% improvement with
acid suppression can reach some 85%.
According to a recent systematic review [4] PPI treatment is also effective to improve
symptoms related to atrial fibrillation (AF) in patients with concomitant GERD and may
actually facilitate conversion to sinus rhythm.
For the cardiologist therefore there is no need for a treatment alternative to PPIs.
References
patients with non-cardiac chest pain (NCCP): systematic review and meta-analysis. Gastroentero-
logy 2014; 146 (Suppl 1): S-128.
Gut 2011; 60: 1473-1478.
9592-9599.
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Notes
WHATS NEXT ?

with the cooperation of Elisabetta Goni, MD,
In patients, where extra-digestive symptoms are related to non-acidic reflux (as

evidenced by pH-impedance recording), PPI use is clearly ineffective and therefore
inappropriate. Two drug classes more suitable in such patients are prokinetics and
the so-called barrier drugs, like alginate-containing formulations.
Unfortunately, cisapride, a prokinetic agent long used in the treatment of GERD, has
been withdrawn from the market because of its cardiac adverse events. The same
holds true for tegaserod. Metoclopramide is endowed with important neurologic
untoward reactions, which allowed both the US Food and Drug Administration (FDA)
and European Medicine Agency (EMA) to issue a black box. Finally, domperidone is
currently under review by EMA (Article 31 referall) because the concerns about cardiac
adverse events, previously evaluated by the PhV Working Party. In summary, we are
being left without prokinetics, with the exception of levosulpiride.
Levosulpiride, a neuroleptic with mild prokinetic activities available in Italy and some
other few European Countries, is more effective in functional dyspepsia rather than in
GERD [1] and its long-term administration is associated with significant hyperprolacti-
nemia and its consequences (galactorrhea, amenorrhea, etc) [2].
Prucalopride, approved for laxative-resistant constipation in women, has recently

been shown to accelerate gastric emptying and reduce esophageal exposure to acid
[3]. Some case reports do show its effectiveness in GERD [4].
Barrier compounds represent a very interesting class of drugs, thanks to both a

virtually complete absence of adverse effects (even at the level of intestinal micro-
biota) and their capability to counterbalance the reflux of any gastric content into
the esophagus. Alginate-based, raft-forming formulations have been marketed word-
wide for over 30 years under various brand names, the most widely prescribed being
Gaviscon. Several studies demonstrated that the alginate raft can preferentially move
into the esophagus in place, or ahead, of gastric contents during episodes of gastro-
WHATS NEXT ?
esophageal reflux [5]; some studies further suggest that the raft can act as a physical
barrier to reduce the number and the proximal extent of reflux episodes [6]. Gaviscon
does represents therefore a reliable alternative to PPIs in patients with documented
supra-esophageal (acid and non-acid) reflux. Its administration at bedtime represents
an effective mean to counterbalance nocturnal gastro-esophageal reflux, whose poten-
tial damaging effect on supra-esophageal tissues is very high [7]
References
1) Mansi C, Borro P, Giacomini M, Biagini R, Mele MR, Pandolfo N, Savarino V. Comparative effects of
levosulpiride and cisapride on gastric emptying and symptoms in patients with functional dyspepsia
and gastroparesis. Aliment Pharmacol Ther 2000; 14: 561-569.
2) Mucci A, Nolfe G, Maj M. Levosulpiride: a review of its clinical use in psychiatry. Pharmacol Res
1995; 31: 95-101.
3) Kessing BF, Smout AJ, Bennink RJ, Kraaijpoel N, Oors JM, Bredenoord AJ. Prucalopride decreases
esophageal acid exposure and accelerates gastric emptying in healthy subjects. Neurogastroenterol
Motil 2014; 26: 1079-1086.
4) Nennstiel S, Bajbouj M, Schmid RM, Becker V. Prucalopride reduces the number of reflux episodes
and improves subjective symptoms in gastroesophageal reflux disease: a case series. J Med Case
Rep 2014; 8: 34.
5) Mandel KG, Daggy BP, Brodie DA, Jacoby HI. Review article: alginate-raft formulations in the treat-
ment of heartburn and acid reflux. Aliment Pharmacol Ther 2000; 14: 669-690.
6) Zentilin P, Dulbecco P, Savarino E, Parodi A, Iiritano E, Bilardi C, Reglioni S, Vigneri S, Savarino V.
An evaluation of the antireflux properties of sodium alginate by means of combined multichannel
intraluminal impedance and pH-metry. Aliment Pharmacol Ther 2005; 21: 29-34.
7) Nocon M, Labenz J, Jaspersen D, Leodolter A, Meyer-Sabellek W, Stolte M, Vieth M, Lind T,
Malfertheiner P, Willich SN. Nighttime heartburn in patients with gastroesophageal reflux disease
under routine care. Digestion 2008; 77: 69-72.
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12:00 Extra-digestive GERD: Which Medications in

Addition to Anti-reflux Therapy?
Pali Hungin
There have been few advances in the management of difficult
GERD in the last few years but possibly the rediscovery of an old, previously well-used
remedy, the alginates, may have potential. Previously well known to primary care phy-
sicians, especially before the advent of the acid-suppression drugs, these fell into di-
suse until recent research uncovered the concept of the acid pocket and the potential
benefits of reduced acid exposure and mucoprotection of the lower esophagus. These
factors may be of importance as we seek additional products for managing extra-di-
gestive manifestations of GERD, particularly where the direct mechanism of gastro-
duodenal reflux is concerned (see above; under Are there better alternatives to
PPIs for the treatment of extra-digestive symptoms?). The mainstay of mana-
gement here is lifestyle advice, PPIs, frequently at high doses, and medications or
interventions to tighten the lower esophageal sphincter.
The concept of the acid pocket was illustrated by Beaumont et al. [1] as a physical
space where post-prandial acid accumulated above the gastric contents, below the
gastro-esophageal sphincter. The position of the pocket is largely determined by
the presence of a hiatus hernia and entrapment of the pocket above the diaphragm
was found to be a major risk factor in the increased presence of acidic reflux during
transient lower esophageal sphincter relaxation (TLOSR) in patients with GERD. Ma-
naging this acid pocket, which is essentially related to the post-prandial situation,
offers possibilities for reducing or eliminating, with concurrent PPIs, the level of reflux
into the esophagus. These acid, pepsin and other fluids (possibly bile) when refluxing
may also be tied in with hyper-sensitization of the lower esophagus, with heartburn
exerting a centrally, neuronally mediated reaction. This is one possible explanation
for lower esophageal hypersensitivity and mediation of sensation to elsewhere via
the vagus (the indirect mechanism, referred to above). Nocturnal reflux may also
have a role here [2].
An antacid-alginate formulation has been shown to displace or eliminate the acid

pocket in GERD patients. Utilizing measurements with pH pull-thoughts, and high
resolution manometry and fluoroscopy [3] this effect was attributed to the alginate
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raft displacing gastric contents away from then gastro-esophageal area. In another
study [4], a similar, raft-forming alginate was comparted with a non-raft forming
antacid in volunteers, 30 minutes after a meal. Observed using MRI the alginate-
acid combination formed a barrier mass at the gastro-esophageal junction and the
number of post-prandial reflux events was also reduced. This effect was confirmed
in a RCT of upper GI symptoms by using an alginate-antacid versus placebo where
dyspeptic symptoms were reduced in GERD patients [5].
These data do not, of course, apply directly to the extra-digestive problems thought
to be associated with GERD. However, the modes of action of the alginate-antacid
studied and the tentative mechanisms postulated for extra-digestive problems do tie
up and these products may offer an adjunctive role in clinical management.
References
1) Beaumont H, Bennink RJ, de Jong J, Boeckxstaens GE. The position of the acid pocket as a major
risk factor for acidic reflux in healthy subjects and patients with GORD. Gut 2010; 59: 441-451.
2) Boeckxstaens GE. Review article: the pathophysiology of gastro-oesophageal reflux disease. Aliment
Pharmacol Ther 2007; 26: 149-160.
3) Kwiatek MA, Roman S, Fareeduddin A, Pandolfino JE, Kahrilas PJ. An alginate-antacid formulation
(Gaviscon Double Action Liquid) can eliminate or displace the postprandial acid pocket in sympto-
matic GERD patients. Aliment Pharmacol Ther 2011; 34: 59-66.
4) Sweis R, Kaufman E, Anggiansah A, Wong T, Dettmar P, Fried M, Schwizer W, Avvari RK, Pal A,
Fox M. Post-prandial reflux suppression by a raft-forming alginate (Gaviscon Advance) compared
to a simple antacid documented by magnetic resonance imaging and pH-impedance monitoring:
mechanistic assessment in healthy volunteers and randomised, controlled, double-blind study in
reflux patients. Aliment Pharmacol Ther 2013; 37: 1093-1102.
5) Thomas E, Wade A, Crawford G, Jenner B, Levinson N, Wilkinson J. Randomised clinical trial: relief
of upper gastrointestinal symptoms by an acid pocket-targeting alginate-antacid (Gaviscon Double
Action) a double-blind, placebo-controlled, pilot study in gastro-oesophageal reflux disease.
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Jaclyn A. Smith
Treatment options for patients thought to have extra-digestive
GERD are very limited beyond acid-suppression, with very little evidence available to
support the use of other licensed therapies. Measurement of the number, acidity and
proximal extent of reflux events via esophageal pH/impedance studies may suggest
which treatments may help individual patients. For example, in patients with chronic
cough, those with heartburn and increased esophageal acid exposure may be most
likely to respond to PPI treatment [1]. Other strategies that might help minimize the
number of reflux events and their proximal extent in patients with respiratory disease
include improvement of esophageal dysmotility, promotion of gastric emptying, and
dietary and lifestyle modifications.
Some studies suggest that esophageal peristalsis may be impaired in up to a third of

patients presenting with chronic cough [2, 3]; how often this is encountered in other
respiratory diseases is less clear. The failure of peristalsis to adequately clear material
from the esophagus may well have consequences for the impact of reflux events on
respiratory disease. If clearance of reflux by swallowing and peristalsis is delayed,
proximal events may be at greater risk of micro-aspiration and intra-esophageal events
may provide a more prolonged vagal stimulus. Unfortunately efficacious pro-kinetic
therapies such as cisapride have been discontinued due to safety issues, and metoclo-
pramide and domperidone have to be used with caution due to their safety and side
effect profiles but may improve esophageal peristaltic amplitude and increase lower
esophageal sphincter pressure [4]. These treatments also promote gastric emptying
which may be delayed in patients with cystic fibrosis and complicating diabetes and
following lung transplantation.
Although lifestyle and dietary modifications to improve reflux have not been specifi-
cally evaluated in patients with extra-digestive GERD, it is our experience that they can
be effective in some patients. Weight reduction and smoking cessation are known to
be beneficial in reducing GERD symptoms. Anecdotally we find modification of meal
size and timing, avoiding alcohol and certain dietary ingredients such as carbonated
drinks, caffeine, fat, spicy foods is reported as helpful by some patients.
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References
2) Almansa C, Smith JA, Morris J, Crowell MD, Valdramidou D, Lee AS, DeVault KR, Houghton LA.
Weak peristalsis with large breaks in chronic cough: association with poor esophageal clearance.
Neurogastroenterol Motil 2015; 27: 431-442.
3) Houghton LA. Weak peristalsis with large breaks in chronic cough: association with poor esopha-
geal clearance. Neurogastroenterol Motil 2015; 27: 431-442.
4) Kastelik JA, Redington AE, Aziz I, Buckton GK, Smith CM, Dakkak M, Morice AH. Abnormal
oesophageal motility in patients with chronic cough. Thorax 2003; 58: 699-702.
5) Dilawari JB, Misiewicz JJ. Action of oral metoclopramide on the gastrooesophageal junction in
man. Gut 1973; 14: 380-382.
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Mark G. Watson
As mentioned in the previous section, alginate therapy can be very
effective in the treatment of LPR patients. As well as its role in
preventing reflux episodes by forming a raft on the surface of the gastric contents, in
the region of the so-called acid pocket, evidence is emerging of its role as a mucosal
protectant [1]. Pepsin has been shown to bind to alginate molecules so that it cannot
attack the underlying mucosa [2].
As well as being an effective treatment in its own right, alginate has been shown to
be a useful addition to PPI therapy [3].
GABAB agonists and metabotropic glutamate receptor 5 (mGlu5) antagonists are said
to improve lower esophageal sphincter tone and may be helpful [4]. The antibiotic
azithromycin has also been used for this purpose.
As yet, there is no commercially available antipepsin drug. Amylopectin sulphate

and pepstatin have been tried in peptic ulcer disease, without success [5], but to my
knowledge they have not been used in LPR.
References
1) Woodland P, Lee C, Duraisamy Y, Farr R, Dettmar P, Sifrim D. Assessment and protection of
esophageal mucosal integrity in patients with heartburn without esophagitis. Am J Gastroenterol
2013; 108: 535-543.
2) Strugala V, Avis J, Jolliffe IG, Johnstone LM, Dettmar PW. The role of an alginate suspension on
pepsin and bile acids key aggressors in gastric refluxate. J Pharm Pharmacol 2009; 61: 1021-1028.
3) Strugala V, Dettmar PW. Alginate in the treatment of extra-oesophageal reflux, in Effects, Diagnosis
and Management of Extra-Esophageal Reflux, N. Johnson and R. J. Toohill, Eds., Nova Science
Publishers, New York, NY, USA, 2010; pp. 145-168.
4) Watson MG. Review article: laryngopharyngeal reflux: the ear, nose and throat patient. Aliment
Pharmacol Ther 2011; 33 (Suppl 1): 53-57.
5) Bardhan KD, Strugala V, Dettmar PW. Reflux revisited: Advancing the role of pepsin. Int J Otolaryngol
2012; 646901.
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Notes
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Carlo Di Mario
The efficacy of PPI treatment in GERD-related NCCP [1-3] and

arrhythmias [4] is very high, as attested by meta-analyses and everyday clinical practice.
In GERD patients with post-prandial arrhythmias, refluxed acidic content into the
esophagus can induce cardiac autonomic reflexes [5]. In these patients, in addition
to acid suppression, alginate-containing formulations (especially Gaviscon Double
Action) can be useful since they target the acid pocket [6] and reduce esophageal
exposure to acid [7].
References
patients with non-cardiac chest pain (NCCP): systematic review and meta-analysis. Gastroentero-
logy 2014; 146 (Suppl 1): S-128.
Gut 2011; 60: 1473-1478.
9592-9599.
and idiopathic cardiac dysrhythmias. Aliment Pharmacol Ther. 2006; 24: 361-370.
6) Thomas E, Wade A, Crawford G, Jenner B, Levinson N, Wilkinson J. Randomised clinical trial: relief
of upper gastrointestinal symptoms by an acid pocket-targeting alginate-antacid (Gaviscon Double
Action) a double-blind, placebo-controlled, pilot study in gastro-oesophageal reflux disease.
7) De Ruigh A, Roman S, Chen J, Pandolfino JE, Kahrilas PJ. Gaviscon Double Action Liquid (antacid
& alginate) is more effective than antacid in controlling post-prandial oesophageal acid exposure
in GERD patients: a double-blind crossover study. Aliment Pharmacol Ther 2014; 40: 531-537.
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Notes
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with the cooperation of Elisabetta Goni, MD
In addition to the three drug classes (namely PPIs, prokinetics and alginate-containing
formulations) already discussed, some old and new add-on medications can be use-
ful in patients with extra-digestive GERD.
Baclofen, a GABAB agonist widely used in the treatment of spastic disorders [1], can
relieve GERD symptoms by reducing the incidence of transient lower esophageal
sphincter relaxations (TLESRs). A recent meta-analysis [2], including 9 studies with 283
GERD patients and healthy subjects, provided high quality data supporting the ability
of baclofen to promote a short-term decrease in the number of reflux episodes per
patient, the average length of reflux episodes, and the incidence of TLESRs. All reported
adverse effects of baclofen were of mild-to-moderate intensity. An early study [3]
found the drug capable of reducing duodeno-gastro-esophageal reflux (DGER) and
associated reflux symptoms that persisted during PPI therapy and a recent one [4]
showed that a combination of a slow-release formulation of baclofen and omeprazole
is more effective treatment for heartburn and regurgitation than the PPI alone.
Stimulation of esophageal mucosal defence, an often forgotten therapeutic target, could

be an alternative avenue in the treatment of extra-digestive GERD. A recently developed,
class 3, medical device (namely Esoxx One) is able to counterbalance the increased mu-
cosal permeability induced by noxious agents in the swine esophagus [5]. The device
is based on a mixture of hyaluronic acid and chondroitin sulfate in a bioadhesive
carrier (poloxamer 407 or Lutrol), which facilitates the adhesion of both compounds
on the esophageal mucosa. A recent trial [Savarino et al., unpublished observations]
found Esoxx One in combination with PPIs effective in patients with refractory
GERD symptoms. The device could therefore be suitable as add-on treatment for patients
with extra-esophageal manifestations of GERD. In this connection, a study is ongoing.
Visceral hypersensitivity, present in some NERD patients, is involved in neurogenic

inflammation showing an increase in both substance P release and neurokinin (NK1)
receptor expression, which may be associated with the activation of transient receptor
potential vanilloid 1 (TRPV1) and protease activated receptor-2 (PAR2) [6].
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To target neurogenic inflammation, caused by acidic and non-acid components of the

refluxate, a TPV1 receptor antagonist (namely AZD1386) was tried. Despite the patho-
physiologic background, the compound showed no analgesic effect on experimental
esophageal pain in patients with NERD and a partial PPI response, whereas it increased
cutaneous heat tolerance [7]. However, curcumin, a yellow coloring agent extracted from
turmeric (Curcuma longa) [8] is a promising lead for the treatment of functional gastro-
intestinal diseases, including GERD. Indeed, this compound, which we found capable
of reducing antral inflammation [9], inhibits visceral nociception by antagonizing
TRPV1 [10].
References
1) Brogden RN, Speight TM, Avery GS. Baclofen: a preliminary report of its pharmacological properties
and therapeutic efficacy in spasticity. Drugs 1974; 8: 1-14.
2) Li S, Shi S, Chen F, Lin J. The effects of baclofen for the treatment of gastroesophageal reflux disease:
a meta-analysis of randomized controlled trials. Gastroenterol Res Pract 2014; 2014: 307805.
3) Koek GH, Sifrim D, Lerut T, Janssens J, Tack J. Effect of the GABA(B) agonist baclofen in patients
with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut
2003; 52: 1397-1402.
4) Abbasinazari M, Panahi Y, Mortazavi SA, Fahimi F, Valizadegan G, Mohtashami R, Pourhoseingholi
MA, Shirvani Bakhtiari K. Effect of a Combination of Omeprazole Plus Sustained Release Baclofen
Versus Omeprazole Alone on Symptoms of Patients with Gastroesophageal Reflux Disease (GERD).
Iran J Pharm Res 2014; 13: 1221-1226.
5) Di Simone MP, Baldi F, Vasina V, Scorrano F, Bacci ML, Ferrieri A, Poggioli G. Barrier effect of Esoxx
on esophageal mucosal damage: experimental study on ex-vivo swine model. Clin Exp Gastroenterol
2012; 5: 103-107.
6) Yoshida N, Kuroda M, Suzuki T, Kamada K, Uchiyama K, Handa O, Takagi T, Yoshikawa T, Kuramoto H.
Role of nociceptors/neuropeptides in the pathogenesis of visceral hypersensitivity of nonerosive
reflux disease. Dig Dis Sci 2013; 58: 2237-2243.
7) Krarup AL, Ny L, Gunnarsson J, Hvid-Jensen F, Zetterstrand S, Simrn M, Funch-Jensen P, Hansen MB,
Drewes AM. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive
gastroesophageal reflux disease and a partial response to PPI treatment is not associated with
analgesia to esophageal experimental pain. Scand J Gastroenterol 2013; 48: 274-284.
8) Shehzad A, Rehman G, Lee YS. Curcumin in inflammatory diseases. Biofactors 2013; 39: 69-77.
9) Zhi L, Dong L, Kong D, Sun B, Sun Q, Grundy D, Zhang G, Rong W. Curcumin acts via transient
receptor potential vanilloid-1 receptors to inhibit gut nociception and reverses visceral hyperalgesia.
Neurogastroenterol Motil 2013; 25: e429-440.
10) Di Mario F, Cavallaro LG, Nouvenne A, Stefani N, Cavestro GM, Iori V, Maino M, Comparato G,
Fanigliulo L, Morana E, Pilotto A, Martelli L, Martelli M, Leandro G, Franz A. A curcumin-based
1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from
failure? Helicobacter 2007; 12: 238-243.
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Notes
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ORGANIZING SECRETARIAT UNDER THE AUSPICES OF

CME PROVIDER
The University of Parma

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Phone +39 051 300100 Ext. 157
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MULTIMEDIA SERVICE Gastroenterology (SIGE)
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ACCREDITED FOR CONTINUING The Italian Society of

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General Practitioners
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PRESIDENTS Carmelo Scarpignato, MD, DSc, PharmD, MPH (Parma, Italy) Francesco Di Mario, MD (Parma, Italy)

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PARMA, April 16-18, 2015

CHAMBER OF COMMERCE OF THE PARMA COUNTY

HONORARY PRESIDENT Emilio Marangio, MD

POST-GRADUATE COURSE & INTERNATIONAL CONGRESS

PRESIDENTS Carmelo Scarpignato, MD, DSc, PharmD, MPH Francesco Di Mario, MD

PRESIDENTS CME ACCREDITATION

This abstract book has been printed

Lars Erik Agrus (Stockholm, Sweden) Robert C. Heading (Durham, UK)

Piero Amodio (Padova, Italy) Pali Hungin (Durham, UK)

Antonio Balzano (Naples, Italy) Richard H. Hunt (Hamilton, ON, Canada)

Gabrio Bassotti (Perugia, Italy) Peter Kahrilas (Chicago, IL, USA)

Corrado Blandizzi (Pisa, Italy) Peter Malfertheiner (Magdeburg, Germany)

Giuseppina Campisi (Palermo, Italy) Ambrogio Orlando (Palermo, Italy)

Alfredo A. Chetta (Parma, Italy) Fabio Pace (Milan/Seriate, Italy)

Rosario Cuomo (Naples, Italy) Liborio Parrino (Parma, Italy)

John de Caestecker (Leicester, UK) Franco Radaelli (Como, Italy)

Carlo Di Mario (London, UK) Vincenzo Savarino (Genoa, Italy)

Francesco Di Mario (Parma, Italy) Carmelo Scarpignato (Parma, Italy)

Ronnie Fass (Cleveland, OH, USA) Jaclyn A. Smith (Manchester, UK)

Antonio Gasbarrini (Rome, Italy) Dino Vaira (Bologna, Italy)

Majid Hashemi (London, UK) Mark Watson (Doncaster, UK)

THURSDAY, April 16, 2015

ADVANCES IN GASTROINTESTINAL PHARMACOLOGY & THERAPEUTICS

09:00 Opening Lecture:

09:30 Therapy of Refractory GERD: Beyond the PPIs

10:00 Addressing H. pylori Eradication Challenges

10:30 Gastropanel as Non Invasive Tool to Assess Drug Effects on Human

11:00 Coffee Break

11:30 Management of Small Intestine Bacterial Overgrowth

12:00 New Pharmacological Approaches to the Treatment of IBS

12:30 Drug Therapy of Chronic Constipation: Whats New

13:00 Working Lunch

15:00 Management of the Colonic Diverticular Disease: Lessons from the

15:30 Management of Inflammatory Bowel Disease: Where Are We going?

16:00 From Laxation to Bowel Cleansing: the Ideal Preparation for

16:30 Coffee Break

17:00 Gut Microbiota in Health & Disease

17:30 Management of GI Disease with Probiotics: When and How

18:00 Microbiota-directed Therapies for Liver Diseases

18:30 End of the Post-graduate Course

FRIDAY, April 17, 2015 Morning

08:30 Welcome Address

SESSION I: EPIDEMIOLOGY AND PATHOPHYSIOLOGY

09:30 Opening Lecture The Genval, Montreal and Vevey Consensus on

10:00 Epidemiology of Extra-digestive GERD

10:30 Typical versus Atypical GERD: Similarities and Differences

11:00 Coffee Break

SESSION II: NEW DIAGNOSTIC MODALITIES

12:00 pH-impedance and Airway pH Recording

12:30 Extra-digestive GERD: Is Upper GI Endoscopy Always Indicated?

13:00 Working Lunch

FRIDAY, April 17, 2015 Afternoon

SESSION III: EXTRA-DIGESTIVE MANIFESTATIONS OF GERD

15:00 Respiratory Manifestations of GERD

15:30 ENT Manifestations of Laryngopharyngeal Reflux

16:00 GERD-related Non Cardiac Chest Pain and Arrhythmias

16:30 Coffee Break

17:00 GERD and Sleep Disturbances

17:30 Dental Erosions and Halitosis as Oral Manifestations of GERD

18:00 Globus and Its Complexities

18:30 End of the First Day

SATURDAY, April 18, 2015 Morning

SESSION IV: THERAPEUTIC APPROACH TO EXTRA-DIGESTIVE GERD

09:00 Is There an Effective Medical Therapy for Extra-digestive GERD?