1024941

book-review2021
GUTXXX10.1177/26345161211024941ForegutKamal et al

Solicited Book Review

Foregut

Assessing the Merits of a PPI

1­–5
© The Author(s) 2021
Article reuse guidelines:
Trial-Based Diagnosis for sagepub.com/journals-permissions
DOI: 10.1177/26345161211024941
https://doi.org/10.1177/26345161211024941

Gastroesophageal Reflux Disease: journals.sagepub.com/home/gut

Speculations on Efficacy and Pitfalls

Afrin N. Kamal1, Thomas A. Zikos1, and John O. Clarke1

Abstract
Gastroesophageal reflux disease is a highly prevalent condition which can lead to complications in affected individuals.
Given the economic implications of widespread testing, there has been interest in a symptom-based approach to
diagnosis and use of short-term empiric acid suppressive therapy as a diagnostic modality. This review will highlight
the background with regards to these clinical questions, the data regarding performance characteristics of establishing
a symptom-based reflux diagnosis (focusing on typical, atypical, and extra-esophageal symptoms), the merits of the
so-called “PPI Trial” and potential pitfalls to consider when seeing patients with suspected reflux symptoms.

Keywords
gastroesophageal reflux disease, proton pump inhibitor, heartburn, regurgitation, chest pain

Introduction achalasia, eosinophilic esophagitis, rumination—or

Gastroesophageal reflux disease (GERD) is a common
condition in the United States, believed to affect approxi-
mately 20% of American adults on a weekly basis, and
over half the population of the United States on an annual
basis.1 In addition to significant symptoms affecting
quality of life, GERD can also lead to numerous compli-
cations including esophagitis, esophageal strictures,
Barrett’s esophagus, and esophageal adenocarcinoma.2
Data suggest that both GERD and esophageal adenocar-
cinoma have increased over the past decades and are on
the rise.3 While this increase is likely multifactorial in the
context of a changing American diet, microbiome altera-
tions, the obesity epidemic, and other unidentified fac-
tors—the fact remains that we are in a GERD epidemic
that is unlikely to abate anytime soon. In this context, the
societal and economic implications of GERD are stagger-
ing, with cost estimates of up to $20 billion annually in
the United States alone.4,5
Given these factors, medical professionals are faced
with the question of how to approach patients with
GERD symptoms? Does the presence of associated
symptoms confirm a diagnosis of GERD and should
treatment be instituted before diagnostic tests are per-
formed? On one hand, one could argue that symptoms
alone are nonspecific and that lack of formal diagnostic
testing may miss clinically relevant conditions such as
even potentially ominous diagnoses such as esophageal
cancer. On the other hand, however, it is simply not fea-
sible to subject 20% of the American population to inva-
sive and costly procedures such as endoscopy when
well-established data suggest the yield of these proce-
dures to be <10% in patients already taking a proton
pump inhibitor (PPI).6,7 This review will address these
questions, highlighting the pros and cons of making a
symptom-based diagnosis of GERD, and the merits of
empiric medication trials. We will incorporate data
where available but also speculate from our personal
experience on the value of these approaches.
The Diagnosis of GERD
The modern diagnosis of GERD begins with the Montreal
Consensus, which defined GERD as gastric reflux caus-
ing either troublesome symptoms or complications.8 The
authors separated symptoms of GERD into esophageal
1
Stanford University School of Medicine, Stanford, CA, USA
Corresponding Author:
John O. Clarke, Division of Gastroenterology and Hepatology,
Stanford University School of Medicine, 300 Pasteur Drive, MC 5244,
Stanford, CA 94305, USA.
Email: john.clarke@stanford.edu
2 Foregut 00(0)
and extraesophageal subtypes, and went on to further
separate esophageal symptoms into “typical” and “atypi-
cal” buckets. Typical symptoms were classified as heart-
burn and regurgitation, with other potential esophageal
symptoms including chest pain and dysphagia classified
as atypical.8 This consensus dominated the landscape of
GERD-related publications over the next decade. In more
recent years, other key GERD consensus statements have
emerged, including the Rome IV Foundation which char-
acterized the functional aspects of GERD,9 and the Lyon
Consensus which approached the physiologic attributes
of GERD.7 These varied approaches have led to the rec-
ognition that reflux is a heterogeneous process with mul-
tiple phenotypes leading to a common set of symptoms.
For example, heartburn could relate to erosive esophagi-
tis, reflux hypersensitivity, non-erosive reflux disease, or
functional heartburn—all would result in the same symp-
tom and yet the clinical course and treatment approaches
would differ for each. This has led to an interest in a pre-
cision medicine concept for GERD, which we expect to
dominate GERD diagnosis and treatment for the next
several years.10,11 However, it is worth noting that while
we fully embrace this precision medicine concept for
GERD, we believe that this approach is best served for
those patients with either atypical symptoms or typical
symptoms that do not respond to initial treatment mea-
sures. For example, patients with classic symptoms that
respond to lifestyle modification and intermittent acid-
suppressive therapy certainly do not need formal reflux
monitoring—whether they have non-erosive reflux,
reflux hypersensitivity, or functional heartburn is only an
academic distinction if their symptoms respond to safe
intermittent therapy and they have an excellent quality of
life. As such, the approach of the tertiary specialist when
seeing a refractory patient is by definition going to differ
significantly from that of a more front line provider.
The Symptom-Based Diagnosis of
GERD
Given the prevalence of GERD, a symptom-based
approach to diagnosis has an intuitive appeal and data
suggest it to be economically pragmatic.4,12 For typical
reflux symptoms—namely, heartburn and regurgita-
tion—there seems to be general agreement that this is a
reasonable approach for the uncomplicated patient. The
Montreal Consensus reported a strong level of agreement
(100% A−, A, or A+) that “the typical reflux syndrome
can be diagnosed on the basis of the characteristic symp-
toms, without diagnostic testing.”8 The American College
of Gastroenterology “Guidelines for the Diagnosis and
Management of Gastroesophageal Reflux Disease” con-
curred with this sentiment giving a strong recommenda-
tion with moderate level of evidence to the following
statement: “A presumptive diagnosis of GERD can be
established in the setting of typical symptoms of heart-
burn and regurgitation.”13 However, due to challenges in
the definition of GERD and the heterogeneity of the dis-
order, it should be acknowledged that the evidence to
support this recommendation is somewhat limited.
Perhaps the largest study to address this question was the
Diamond Study, which assessed the accuracy of a symp-
tom-based GERD diagnosis when compared to endos-
copy with wireless pH monitoring and a dedicated PPI
trial in a large international population. In their evalua-
tion, GERD was present in 2/3 of patients but only 49%
of GERD patients selected either heartburn or regurgita-
tion as their most troublesome symptom. The sensitivity
and specificity, respectively, of the symptom-based diag-
nosis of GERD was 62%/67% for formal reflux question-
naires, 63%/63% for assessment by a family practitioner,
and 67%/70% for assessment by a gastroenterologist.14
Similarly, a large systematic review assessed the accu-
racy of reflux symptoms in the diagnosis of esophagitis in
7 studies with over 5000 patients, and reported the sensi-
tivity and specificity of symptoms for prediction of
esophagitis to be suboptimal (30%-76% and 62%-96%
respectively).15 Finally, over a dozen studies have evalu-
ated the role of questionnaires to diagnose reflux given a
constellation of symptoms, also with generally subopti-
mal performance characteristics.16
Despite these limitations, we believe a symptom-
based diagnosis of GERD is very reasonable for an
uncomplicated patient with typical symptoms and this is
endorsed by current societal recommendations—and we
believe that this symptom-based diagnosis of GERD can
be reasonably implemented in clinical practice for the
purpose of initial treatment attempts. While performance
characteristics of this approach are suboptimal, it makes
sense on a practical approach given the relatively safety
of initial measures and the societal and economic impact
of more widespread initial testing. If patients do not
respond to initial therapy or are under consideration for
potential endoscopic or surgical anti-reflux therapies,
then we strongly favor formal testing given the limita-
tions in the data above and the only-moderate sensitivity
and specificity for a symptom-based diagnosis in the con-
text of typical symptoms.
Atypical reflux symptoms are myriad and include dys-
phagia, chest pain, water brash, odynophagia, burping, hic-
cups, nausea, vomiting, hoarseness, sore throat, and
cough—amongst others. While some of these patients
undoubtedly have GERD, there are no good data to suggest
that a reliable diagnosis of GERD can be made based on the
presence of these symptoms in the absence of more typical
symptoms such as heartburn and regurgitation. In addition,
many of these symptoms including dysphagia and chest
pain are alarm findings which should prompt further
Kamal et al 3
investigation and should not lead to a diagnosis of GERD in
the absence of such. For atypical symptoms, we strongly
recommend further investigation before concluding that
reflux is the etiology and there are not data to our knowl-
edge to show that a reliable diagnosis of GERD can be
established from the presence of atypical symptoms alone.
Utilization of Empiric Medical
Therapies to Establish a Diagnosis of
GERD
If reflux is mediated by the movement of gastric contents
into the esophagus then it makes intuitive sense that acid
suppression would play both a diagnostic and therapeutic
role. This concept in tandem with the availability of PPI
therapy led to the concept of the “PPI Trial,” wherein
empiric acid suppressive therapy is provided for a period
of time to determine whether symptoms believed to be
from reflux improve. While this trial can be employed
with less potent acid suppressive therapies, the relative
efficacy and availability of PPI therapy has made these
agents the usual first choice for empiric therapy. The PPI
trial is commonly employed in clinical practice as an ini-
tial measure to treat reflux symptoms in uncomplicated
patients and has been endorsed by several major societ-
ies.13,17 There is a lack of consensus as to what constitutes
appropriate PPI dosing and treatment length. Published
studies evaluating the efficacy of the PPI trial have ranged
from less than a week to periods as long as 12 weeks, and
the potency/dosing interval of PPIs employed has also
varied similarly.18,19 As a general rule, once daily dosing
for shorter durations is generally employed for typical
reflux symptoms (where suspicion for reflux is high) and
higher doses for longer durations are generally employed
for atypical symptoms (eg, non-cardiac chest pain and
potential laryngopharyngeal reflux) where the underlying
diagnosis is more uncertain. The goal in each case, how-
ever, is to see if symptoms improve, to taper to the lowest
dose or off entirely if that is the case, and to stop therapy
entirely if symptoms do not change.
When one evaluates the efficacy of PPI therapy for
reflux symptoms and/or esophagitis in published clinical
trials, there is not surprisingly a wide range reported. On
one end of the spectrum, PPIs have demonstrated response
in >80% of patients with erosive esophagitis, 70% of
patients with uninvestigated heartburn, and 64% of
patients with regurgitation. On the other hand, however,
PPIs have been shown in randomized controlled trials to
improve non-cardiac chest pain with negative GERD
testing, chronic cough and laryngeal symptoms in only
23%, 18%, and 14% of patients, respectively.2
Formal evaluation of the PPI test has shown mixed
results. A meta-analysis of 15 studies that evaluated a
short-term PPI trial in patients with typical reflux
symptoms reported an overall sensitivity of 78% but
specificity of only 54%.18 Subsequent to that publication,
a well-done study from the Netherlands compared
response to a 2 weeks esomeprazole course to formal pH-
monitoring and reported the sensitivity of the PPI test to
be excellent (91%) but specificity was poor (26%).20 In
post-hoc analysis of the previously-mentioned Diamond
Study, a positive response to the PPI test was observed in
69% of patients with GERD as compared to 51% of
patients without GERD, and the authors concluded that
“the PPI test has limited ability to identify patients with
GERD, diagnosed by current standard tests.”21
While the performance characteristics of the PPI trial
may be suboptimal for patients with typical reflux symp-
toms, the diagnostic yield may increase in situations
where the likelihood of symptoms being attributable to
reflux is low. This has been examined extensively in the
context of non-cardiac chest pain. In a meta-analysis of 8
studies evaluating the role of PPI therapy for treatment of
patients with chest pain in whom a cardiac etiology had
been excluded, the pooled sensitivity, specificity, and
diagnostic odds ratio for the PPI test versus 24-hour pH
monitoring and endoscopy were 80%, 74%, and 13.8,
respectively.22 Perhaps not surprisingly given the absence
of a true gold standard for diagnosis, the data with regards
to a PPI trial for potential extra-esophageal reflux symp-
toms are murky. For potential LPR symptoms, a recent
systematic review reported success rates of empiric medi-
cation trials to range from 17% to 87%—and in aggregate
slightly >50% response rate.23,24
When thinking of the concept of the PPI trial in broad
terms, the more likely it is that symptoms are derived
from acid and the lower the incidence of those symp-
toms in the baseline population, the higher the yield of
the PPI trial will be. In this context, non-cardiac chest
pain is potentially an ideal symptom for which to con-
sider a PPI trial as it is potentially acid-mediated and not
as frequently reported as heartburn. Conversely, bland
regurgitation or extra-esophageal symptoms such as
hoarseness are in theory more problematic as it is less
established that these symptoms stem from acid-related
effects even in the context of documented reflux. It is
also worth note that the rising concerns regarding PPI
safety in the lay press have tempered enthusiasm for
empiric PPI use for both primary care providers and
patients and is often a point of discussion with patients
in our individual practices.
Diagnostic Considerations and
Potential Pitfalls
When seeing a patient with potential reflux, it is always
important to keep a wide differential diagnosis and spe-
cifically to consider other diagnoses that could present
4 Foregut 00(0)
with similar symptoms. Perhaps most pressing, it is
important to keep in mind any potential ominous diagno-
ses and investigate any alarm findings that may be pres-
ent. Chest pain should not be assumed to be reflux-related
until cardiac etiologies have been excluded and all
patients with warning signs such as weight loss, dyspha-
gia, or bleeding should undergo diagnostic evaluation
before empiric medication trials. In addition, there are
also a few other key diagnoses to consider when seeing
these patients in evaluation; namely, achalasia, eosino-
philic esophagitis, functional dyspepsia, gastroparesis,
and rumination.
Achalasia is a rare disorder characterized by loss of
esophageal inhibitory neurons resulting in aperistalsis
and tonic contraction of the lower esophageal sphincter.
Heartburn is reported in approximately 40% of cases and,
particularly early in the clinical course, the presence of
heartburn in tandem with the relative incidence of
reflux:achalasia may lead to misdiagnosis. As treatment
of reflux and achalasia are divergent it is important to
keep this diagnosis in mind when seeing patients with
atypical reflux symptoms, particularly when dysphagia is
reported.25
Eosinophilic esophagitis (EoE) is a clinicopathologic
syndrome characterized by esophageal eosinophilia and
characteristic endoscopic findings in the context of asso-
ciated symptoms. Similar to achalasia, dysphagia is often
the dominant symptom in adults; however, more classic
reflux symptoms are also reported—and symptoms
improve in a distinct subgroup of patients treated with
PPI therapy.26,27 To compound this situation, reflux and
EoE may co-exist and the presence of 1 diagnosis may
increase the likelihood of the other.28
Gastroparesis is defined by impaired gastric empty-
ing in the presence of associated symptoms, including
nausea, vomiting, and pain. Functional dyspepsia con-
sists of similar symptoms in the absence of delayed gas-
tric emptying. Both of these entities can be associated
with upper abdominal discomfort, postprandial bloat-
ing, and vomiting—and in practice these patients can
often be referred for potential reflux given the wide
overlap of symptoms. To compound this situation,
patients with GERD often have overlap with gastric
dysmotility29,30 and approximately a quarter of patients
with gastroparesis will relate moderate-to-severe GERD
symptoms.31 In our practice, we always assess gastric
emptying before recommending any mechanical inter-
vention for reflux given this concern.
Finally, rumination is always worth keeping in the
back of your mind when seeing these patients. Rumination
Syndrome consists of a functional disorder wherein
ingested material is regurgitated during or soon after eat-
ing and then usually reswallowed. It can often be con-
fused for reflux given the associated symptoms; however,
it is a learned behavior and responds well to behavioral
therapy and non-medical intervention in most cases.32
Conclusions
The diagnosis of GERD can be challenging and the
absence of a true gold standard compounds this issue.
Based on the Montreal Consensus, absence of a true gold
standard, the significant prevalence of GERD in the com-
munity and the potential economic/societal impact of
widespread diagnostic testing, we support an evidence-
based diagnosis of GERD in the context of typical reflux
symptoms (heartburn and acid regurgitation). In our opin-
ion and on review of the data, we believe that patients
with atypical esophageal symptoms (including chest pain
and dysphagia) and potential extra-esophageal symptoms
cannot be diagnosed with GERD in the absence of typical
esophageal symptoms and warrant additional investiga-
tion. An empiric trial of acid suppressive therapy is very
reasonable as a first step, in particular given societal
endorsement for this approach and the relative efficacy of
PPI therapy; however, it should be recognized that the
performance characteristics of this approach for typical
esophageal symptoms are relatively low and a negative
response should not preclude further evaluation. In con-
trast, performance characteristics of the PPI test may be
highest in the context of atypical esophageal symptoms
such as chest pain where symptoms are believed to be
acid-mediated but the prevalence of these symptoms in
the baseline population is low. One should be careful to
not miss cases of achalasia, eosinophilic esophagitis,
functional dyspepsia, gastroparesis, and rumination.
While the trend now is toward “precision medicine” for
GERD, it is important to keep in mind that up to half of
American adults experience GERD symptoms on at least
an annual basis and proceeding to endoscopy and formal
reflux testing in all affected patients would be a financial
disaster and colossal waste of resources. From a prag-
matic standpoint, beginning with symptom-based diag-
noses where feasible and empiric PPI trials makes
practical sense in the uncomplicated patient.
Guarantor of the Article
John O. Clarke
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Kamal et al 5
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