Reference Section
a report by
George Triadafilopoulos, MD, DSc, FACP, FACG
Clinical Professor of Medicine, Stanford University School of Medicine
Clinical Case
A 57-year-old woman presents to her primary care
physician with heartburn for the past three to six
months. She describes this as a severe, retro-sternal
burning discomfort intermittently occurring
throughout the day and occasionally awakening her at
night. Use of antacids provides her with temporary
complete relief. She denies dysphagia, abdominal pain,
weight loss, or gastrointestinal bleeding, but reports
weekly nocturnal regurgitation. The patientýs past
medical history is significant for erosive esophagitis,
treated with H2-receptor antagonists (H2RAs) and
eventually proton pump inhibitors (PPIs). Eventually,
because of persistent symptoms, she underwent an
uneventful laparoscopic fundoplication that completely
eliminated her symptoms for at least five years.


Attributing her heartburn to recurrent gastroesophageal
reflux (GER), her physician prescribes lansoprazole
30mg daily.When seen on follow-up four weeks later,
the patient reports that her heartburn is 20% to 30%
improved but her regurgitation nearly unchanged. Her
physician advises her to increase the dosage of
lansoprazole to 30mg twice-daily 30 minutes before
meals, and schedules a return office visit for four weeks
later. At that office visit, the patient reports a 60% to
70% improvement in her heartburn and regurgitation,
a nearly complete elimination of her nocturnal
symptoms, but some post-prandial bloating and
occasional headaches. Esomeprazole 40mg once daily is
substituted and ý in view of her prior fundoplication ý
the patient is referred to a gastroenterologist for further
evaluation and treatment. During her initial visit to the
gastroenterologist, the patient reports no significant
improvement of her symptoms after one month of
esomeprazole therapy.


Discussion
The Genval Working Group defined gastroesophageal
reflux disease (GERD) as the condition that affects
ý...individuals who are exposed to the risk of physical
complications from gastroesophageal reflux or who
experience clinically significant impairment of health-
related well being (quality of life) due to reflux-related
symptoms... 1 The patient above presents mostly with a
ýfunctionalý symptom complex such as heartburn and
regurgitation, and has no clinical evidence of
ýcomplicatedý disease, such as peptic stricture, ulceration
or Barrettýs adenocarcinoma that would be expected to
present with ýstructuralý symptoms, such as dysphagia,
anemia, and gastrointestinal bleeding. Nevertheless, her
prior history of erosive esophagitis, her initial response
to medical therapy with antisecretory drugs, and
eventually her initial response to fundoplication strongly
suggests GERD. However, at this point we have only a
ýfailed surgeryý, a ýpartially successfulý medical therapy
and no diagnosis.Are her new symptoms due to GER?
Is her fundoplication intact? Have the patientýs
heartburn and regurgitation impaired her quality of life?
The Genval Working Group states that ýhealth-related
well being is impaired in proportion to the frequency of
heartburn. 1 Further, the group notes that when
heartburn occurs on two or more days per week it
impairs an individualýs quality of life enough to be
considered a ýdiseaseý. Because this patient has sought
medical attention and received therapy for her condition
both in the past and presently, the main question is
whether or not her disease is currently due to GER.


Could the patientýs heartburn and regurgitation not be
attributable to GER? The most characteristic and
frequently encountered GERD symptoms are
heartburn and regurgitation.2 Heartburn is an
intermittent symptom, most commonly experienced
within 60 minutes of eating, during exercise, and while
lying recumbent. The discomfort is relieved with
antacids but can occur frequently and interfere with
normal activities. In this case, her heartburn was treated
earlier with a fundoplication with excellent early results
and subsequently re-appeared. Although the patient
reports the typical exacerbating and alleviating factors
for GER, she has failed the ýPPI testý.3
The physicianýs decision to empirically treat her with
lansoprazole, the subsequent increase of that therapy to
twice-daily, and the eventual trial of esomeprazole,
amounted to his performing a therapeutic trial.A PPI is
an ideal agent for a therapeutic trial because of impressive
efficacy in treating all acid-related disorders (including
GERD) and a superb safety profile.4 In this case, the
GERD ý The Potential for Endoscopic Intervention
George Triadafilopoulos, MD, DSc,
FACP, FACG, is Clinical Professor of
Medicine, Stanford University School
of Medicine, CA. He is a fellow of
the American College of
Gastroenterology and the American
College of Physicians, and a
member of numerous other
professional societies, including the
American Gastroenterological
Association, and the American
Society for Gastrointestinal
Endoscopy. Dr Triadafilopoulosý
research has covered many areas of
gastroenterology, including
gastroesophageal reflux disease,
Barrettýs esophagus, colorectal
polyps and cancer, inflammatory
bowel disease, irritable bowel
syndrome, Barrettýs esophagus and
adenocarcinoma, and NSAID-related
effects on the gastrointestinal tract.


The author over 180 original
articles, monographs, and book
chapters, Dr Triadafilopoulos is the
Editor-in-Chief of Gastrointestinal
Endoscopy and a reviewer for many
other professional journals, including
the New England Journal of
Medicine, Gastroenterology, and the
American Journal of
Gastroenterology. He earned his
medical degree at the Aristotelian
University Medical School in
Thessaloniki, Greece. He completed
his internship and residency at
Wayne State University Affiliated
Hospitals in Michigan, and a clinical
and research fellowship in
gastroenterology at Boston
University Medical Center in
Boston, MA.


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Reference Section
patient reports a 60% to 70% response,a ýpartialýresponse,
but develops new symptoms, such as bloating and
headaches. A change to another PPI is made without
significant improvement of her GER complaints but
with some improved tolerance.Potential explanations for
her inadequate clinical response include:
ý inadequate therapy;
ý disruption of the prior fundoplication;
ý non-reflux causes of esophagitis;
ý esophageal hyperalgesia;
ý non-acid reflux; or
ý functional heartburn.5
Potential Management Strategies
Endoscopy would be helpful at this point,since it might
reveal peptic esophagitis, a disrupted fundoplication
with herniation, or could detect infectious or pill-
induced esophagitis.6 Because esophagitis would
potentially no longer be evident after four to six weeks
of PPI treatment, some would argue that pH
monitoring should be performed if endoscopy were
negative or equivocal. Where do we go from here?
Broadly speaking, there are three management options:
ý increase the potency of GERD therapy or offer an
alternative GERD therapy (medical, surgical, or
endoscopic) without further testing;
ý pursue diagnostic testing with endoscopy, pH
monitoring, etc; and
ý empirically treat the patient with a low-dose
tricyclic antidepressant on the presumption that she
is experiencing ýfunctionalý heartburn.7
Figure 1
Abnormal intra-esophageal pH profile on PPI.The 24-hour pH study was performed on esomeprazole (40mg orally daily) and showed per cent time intra-esophageal pH <4.0: 8.3;
DeMeester score: 28.8. Despite PPI, this patient has achieved an inadequate intra-gastric/esophageal pH control, resulting in persistent symptomatic GERD.


Normal intra-esophageal pH profile on PPI after Stretta.The 24-hour pH study was performed on esomeprazole (40mg orally daily) and showed per cent time intra-esophageal pH
<4.0: 1.1; DeMeester score: 3.7.This patient has now achieved control of intra-esophageal pH and is asymptomatic.


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Reference Section
Recommended Management Strategy
Escalating GERD therapy at this point is unlikely to
work. Twice-daily PPI therapy is a very effective
treatment for heartburn,generally 80% to 85%.Empiric
therapy with a tricyclic agent for presumptive
ýfunctional heartburný would be premature. Thus, an
upper endoscopy is arranged. It is advisable to
simultaneously arrange an ambulatory esophageal pH
monitoring with the caveat that it would be cancelled
should the endoscopy yield definitive findings. An
esophageal manometry is also helpful, to look for lower
esophageal sphincter (LES) hypotension, intra-
abdominal LES segment shortening, and defective
peristalsis, all of which would predispose to reflux and
potentially poor esophageal clearance.


One question that emerges with respect to the
ambulatory pH monitoring study is whether it should be
done with the patient on or off PPI therapy.There is a
rationale for doing the test either way. On one hand, one
wants objective evidence of quantitatively abnormal acid
exposure or significant reflux-heartburn association, and
on the other hand one wishes to see whether or not the
esomeprazole is effectively controlling esophageal acid
exposure. In fact, in some particularly difficult cases, the
test ends up being done twice to accommodate both
needs. Because testing for PPI-refractory reflux in this
case is conceptually appealing, the pH monitoring study
is done with the patient taking esomeprazole 40mg daily
(see Figure 1 and 2).


Case Evolution
An endoscopy is performed and the esophageal mucosa
appears normal. The squamocolumnar junction is
sharply demarcated, yet relatively patulous.There is no
evidence of a disrupted fundoplication and there are no
mucosal erosions or hiatal hernia noted.An esophageal
manometry shows a short (<1cm) intra-abdominal LES
length, an LES pressure of 10mmHg (normal
10ý30mmHg), and mean amplitude of esophageal
contractility of 44mmHg (normal 50ý100mmHg) with
episodes of failed peristalsis. Esomeprazole is increased
to 40mg orally twice-daily but is poorly tolerated; the
patient decides to continue with only once-daily
therapy, which achieves the maximum GER symptom
control with minimum side effects.


A dual-sensor pH monitoring is performed while the
patient is receiving esomeprazole 40mg orally once-
daily.The proximal sensor is placed 5cm above the LES,
Figure 2: New Paradigm for the Long-term Management of GERD Utilizing Multi-modality Approach
As symptoms become refractory to one modality, another modality is added, ultimately aiming at normalization of the patientýs quality of life (EndoRx: Endoscopic therapy).


GERD ý The Potential for Endoscopic Intervention
B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
4
recording distal esophageal acid exposure, and the
proximal sensor is placed 10cm below the LES,
recording pH activity in the proximal stomach. The
patient tolerates the test well, being able to eat normally
and conduct her usual activities during the study.


Evaluation of the tracing reveals that the per cent distal
esophageal acid exposure (pH<4.0) is 8.3% and a
DeMeester score of 28.8, mostly during the night.The
proximal gastric sensor reveals significant persistence of
gastric acidity despite PPI therapy (see Figure 1).


However, there is no symptom correlation with acid
reflux events.This data indicates that the patient does
have GERD despite her prior surgery and subsequent
maximization of acid suppression with esomeprazole
therapy and her syndrome is categorized as ýPPI-
refractory heartburný.


Is this Functional or PPI-refractory
Heartburn?
This question is frequently raised because a patient with
functional heartburn is unlikely to respond to any
treatment for GERD, whereas a patient with refractory
heartburn will only respond partially and inadequately.


According to the Rome II definitions, ýfunctionalý
heartburn is defined as ýepisodic burning in the absence
of pathological reflux, pathology-based motility
disorders, or structural explanationsý.8 Therefore,
because the patientýs symptoms are consistent with
reflux, the esophageal motility is abnormal, and the pH
study on PPI therapy is abnormal, this is not a case of
functional heartburn. This patient best fits the
description of having endoscopy-negative reflux
disease, refractory to PPI and surgical therapy.


Refractory heartburn is very rarely related to refractory
esophagitis because PPIs and surgery are quite effective
in healing esophagitis of any degree of severity.


However, PPIs are not as good in heartburn relief, be it
in the setting of endoscopy-positive or endoscopy-
negative disease.9ý11 The endoscopy-negative group
accounts for an increasing number of consultations. In
this patient, endoscopy was negative, either because of
the intermittent nature of the erosions in GERD, or
because of prior or on-going treatment that has healed
her esophagitis. As it did in this case, esophageal pH
monitoring can be used to detect GERD and guide
therapy. Alternatively, quantitative histopathologic
methods or measurement of mucosal potential
difference have revealed abnormalities of the esophageal
epithelium in patients who did not meet ýesophagitisý
criteria using the Los Angeles grading system.12ý14
Subsequent Management
Given the persistence of GERD symptoms and the
associated compromise in her GERD-related quality of
life, despite a maximum possible PPI therapy as well as
the past history of fundoplication that would make
repeat surgery technically challenging, the patient is
offered endoscopic therapy using the Stretta procedure
(radiofrequency energy delivery to the muscle of the
gastroesophageal junction).The procedure is performed
uneventfully. Six months later, patient continues daily
esomeprazole 40mg orally, but her symptoms have been
eliminated.A repeat pH study is performed and reveals
an esophageal 24-hour pH<4.0 of 1.1% and a
DeMeester score of 3.7 (see Figure 1).


A New GERD Treatment Paradigm
Figure 2 diagrammatically depicts a proposed model for
the management of GERD in 2005. Such a model is
based on the fact that there are several modalities to
treat GERD (medications, endoscopic therapies,
surgery) and that such therapies can be used either
singly, or in conjunction with others aiming at
ýnormalizationý of the patientýs GERD-related quality
of life and, if possible, esophageal acid exposure. The
traditional model of single modality therapy has
practically failed in the long-term management of
GERD.The proposed model is in many ways similar to
the long-term management of coronary artery disease
where pharmacotherapy, angioplasty, and bypass surgery
are frequently used in tandem or in combination.


In this model, patients who have not normalized their
GERD-related quality of life with once- or twice-
daily PPI mono-therapy undergo functional
esophageal evaluation with pH testing and esophageal
motility study, and they are evaluated by both an
endoscopist and a surgeon.At this point, a decision to
proceed with either of the two modalities is made
based on the criteria for endoscopic therapy and
surgery, availability of local expertise and patientsý
preference. If, several months (up to one year) later,
GERD-related quality of life has not normalized,
combination therapy with PPI is instituted. If this again
fails, combination with either a repeat endoscopic
procedure or another endoscopic procedure (different
than the first), or surgery could be tried. For example,
in the case of a failed fundoplication, an endoscopic
therapy can be applied; conversely, in case of a failed
endoscopic procedure, the same (or another)
endoscopic procedure or fundoplication may be
offered. Because of its technical complexity, repeat
fundoplication can thus be reserved for failures of
combination therapy (see Figure 3). It is important to
emphasize that this model has not been validated in
clinical trials yet, mostly because there are no sensitive
instruments to measure GERD-related quality of life
under these circumstances. Nevertheless, the model
provides a conceptual framework on how to manage
patients who fail conventional GERD therapy.


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Reference Section
Conclusions ý The Potential for
Endoscopic GERD Therapy
The concept of using endoscopic therapy for the
treatment of symptomatic GERD is new and exciting.


Currently,three basic techniques are approved for use in
the US:
ý radiofrequency-induced thermal therapy (Stretta);
ý gastric plication or suturing (Endocinch, NDO
plicator); and
ý injection therapy (Enteryx) in the area of the lower
esophageal sphincter.15ý18
So far, the trials for each type of endoscopic therapy have
varied in methodology and data analysis, and it is
important to recognize these differences when comparing
their relative efficacy and outcomes. In addition, the
risk/benefit profile must be carefully evaluated for each of
these interventions before considering it a viable
treatment strategy.19 In 2005, there are several modalities
to treat GERD (medications, endoscopic therapies,
surgery), and such therapies can be used either singly, or
in conjunction with the others.20ý23 This case exemplifies
that multi-modality therapy aiming at normalization of
quality of life is an option today and describing a patient
as a ýfailureý of one or another therapy (pharmacologic,
endoscopic, or surgical) is not only patient-centered, but
may be incorrect and pessimistic.24 a73
References
1. An evidence-based appraisal of reflux disease management-the Genval Workshop Report, Gut (1999), 44: pp. S1ýS16.


2. Klauser A G, Schindlebeck N E, Muller-Lissner S A,ýSymptoms in gastroesophageal reflux diseaseý, Lancet (1990), 335: pp.


205ý208.


3. Fass R,ýEmpirical trials in treatment of gastroesophageal reflux diseaseý, Dig. Dis. (2000), 18: pp. 20ý26.


4. Dekel R, Morse C, Fass R,ýThe role of proton pump inhibitors in gastro-oesophageal reflux diseaseý, Drugs (2004), 64: pp.


277ý295.


5. Kahrilas P J,ýRefractory heartburný, Gastroenterology (2003), 124: pp. 1,941ý1,945.


6. Triadafilopoulos, G, ýGastroesophageal reflux disease (GERD)ý, In: Endoscopy Practice and Safety, Peter Cotton (ed.),
Advanced Digestive Endoscopy E-books Series Peter Cotton (ed.),Website: GastroHep , ISSN: (2004),
pp. 1,478ý1,239. Blackwell Publishing, Oxford.


7. Fass R,Tougas G,ýFunctional heartburn: the stimulus, the pain, and the brainý, Gut (2002), 51: pp. 885ý892.


8. Clouse R E, Richter J E, Heading R C, Janssens J,Wilson J A, ýFunctional esophageal disordersý, Gut (1999), 45: pp.


II31ýII36.


9. Chiba N, DeGara C J,Wilkinson J M, ýendoscopic therapy al. Speed of healing and symptom relief in grade II-IV gastro-
esophageal reflux disease:A meta-analysisý, Gastroenterology (1997), 112: pp. 1,798ý1,810.


10.Lind T, Havelund T, Carlsson R,Anker-Hansen O, Glise H, Hernqvist H, Junghard O, Lauritsen K, Lundell L, Pedersen S A,
Stubberod A, ýHeartburn without oesophagitis: efficacy of omeprazole therapy and features determining therapeutic responseý,
Scand. J. Gastroenterol. (1997), 32: pp. 974ý979
11.Richter J E, Peura D, Benjamin S B, Joelsson B,Whipple J,ýEfficacy of omeprazole for the treatment of symptomatic acid reflux
disease without esophagitisý, Arch. Intern. Med. (2000), 160: pp. 1,810ý1,816.


12.Kahrilas P J,ýDiagnosis of symptomatic GERDý, Am. J. Gastroenterol. (2003), 98: pp. S15ýS23.


13.Veith M, Haringsma J, Delarive J,Wiesel P H,Tam W, Dent J,Tytgat G M, Stolte M, Lundell L,ýRed streaks in the oesophagus
in patients with reflux disease: is there a histomorphological correlate?ý, Scand. J. Gastroenterol. (2001), 36: pp. 1,123ý1,127.


14.Carlsson R, Fandricks L, Jonsson C, Lundell L, Orlando R C,ýIs the esophageal squamous epithelial barrier function impaired
in patients with gastroesophageal reflux disease?ý, Scand. J. Gastroenterol. (1999), 34: pp. 454ý458.


15.Triadafilopoulos G,ýStretta: an effective, minimally invasive treatment for gastroesophageal reflux diseaseý, Am. J. Med. (2003),
pp. 115 (Suppl 3A): pp. 192Sý200S.


16.Rothstein R I, Filipi C J,ýEndoscopic suturing for gastroesophageal reflux disease: clinical outcome with the Bard EndoCinchý,
Gastrointest. Endosc. Clin. N.Am. (2003), 13: pp. 89ý101.


17.Pleskow D, Rothstein R, Lo S, Hawes R, Kozarek R, Haber G, Gostout C, Lembo A,ýEndoscopic full-thickness plication for
the treatment of GERD: a multicenter trialý, Gastrointest. Endosc. (2004), 59: pp. 163ý171.


18.Johnson D A, Ganz R, Aisenberg J, Cohen L B, Deviere J, Foley T R, Haber G B, Peters J H, Lehman G A,ýEndoscopic
implantation of enteryx for treatment of GERD: 12-month results of a prospective, multi-center trialý, Am. J. Gastroenterol.


(2003), 98: pp. 1,921ý1,930.


19.Contini S, Scarpignato C,ýEndoscopic treatment of gastro-oesophageal reflux disease (GORD): a systematic reviewý, Dig. Liver
Dis. (2003), 35: pp. 818ý838.


20.Lundell L, Mietinnen P, Myrvold H E, et al.,ýContinued (5-year) follow-up of a randomized clinical study comparing anti-reflux
surgery and omeprazole in gastro-esophageal reflux diseaseý, J. Am. Coll. Surg. (2001), 192: pp. 172ý179.


GERD ý The Potential for Endoscopic Intervention
B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
6
21.Spechler S J, Lee E,Ahnen D, et al.,ýLong-term outcome of medical and surgical therapies for gastro-esophageal reflux disease.


Follow-up of a randomized controlled trialý, JAMA (2001), 285: pp. 2,331ý2,338.


22.Richards W O, Houston H L,Torquati A, Khaitan L, Holzman M D, Sharp K W,ýParadigm shift in the management of gastro-
esophageal reflux diseaseý, Ann. Surg. (2003), 237: pp. 638ý647
23.Chadalavada R, Lin E, Swafford V, Sedghi S, Smith C D, ýComparative results of endoluminal gastroplasty and laparoscopic
antireflux surgery for the treatment of GERDý, Surg. Endosc. (2004), 18: pp. 261ý265.


24.Kamolz T, Pointner R,Velanovich V,ýThe impact of gastroesophageal reflux disease on quality of lifeý, Surg. Endosc. (2003),
17: pp. 1,193ý1,199.