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Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.
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Published in final edited form as:

Am J Gastroenterol. 2022 January 01; 117(1): 27–56. doi:10.14309/ajg.0000000000001538.
ACG Clinical Guideline: Guidelines for the Diagnosis and

Management of Gastroesophageal Reflux Disease
Philip O. Katz, MD, MACG [Professor of Medicine, Director of Motility Laboratories],
Weill Cornell Medical Center, Jay Monahan Center for Gastrointestinal Health, New York, NY
Kerry Dunbar, MD, PhD [Associate Professor of Medicine, Section Chief],

University of Texas Southwestern Medical Center, Gastroenterology and Hepatology, Dallas VA
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Medical Center, Dallas, TX
Felice H. Schnoll-Sussman, MD, FACG [Professor of Clinical Medicine, Director, Director of

Endoscopy],
Jay Monahan Center for Gastrointestinal Health, Weill Cornell Medical Center, New York, NY
Katarina B. Greer, MD, MS, FACG [Associate Professor of Medicine],

Case Western Reserve University School of Medicine, Cleveland Louis Stokes VA Medical
Center, Cleveland, OH
Rena Yadlapati, MD, MSHS [Associate Professor of Clinical Medicine],

Division of Gastroenterology, University of California San Diego, La Jolla, CA
Stuart Jon Spechler, MD, FACG [Chief, Co-Director]

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Division of Gastroenterology, Center for Esophageal Diseases, Baylor University Medical Center
at Dallas, Dallas, TX
Abstract
Gastroesophageal reflux disease (GERD) continues to be among the most common diseases
seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the
varied presentations of GERD, enhancements in diagnostic testing, and approach to patient
management have evolved. During this time, scrutiny of proton pump inhibitors (PPI) has
increased considerably. While PPIs remain the medical treatment of choice for GERD, multiple
publications have raised questions about adverse events, raising doubts about the safety of
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Corresponding author: Philip O. Katz, MD, [email protected].

Specific author contributions:
All authors contributed to the planning, data analysis, writing, and the final version of the manuscript.
Potential competing Interests:
Katz PO: Has served as Consultant for Phathom Pharma and Medtronic
Research support: Diversatek
Royalties: Up to Date
Dunbar K: None currently. Previous research funding from Ironwood.
Schnoll-Sussman FH: Consultant for Ethicon, Interpace Biosciences and Medtronic
Greer KB: None
Yadlapati, R: Consultant thru institutional agreement: Medtronic, Ironwood, Diversatek. Research support: Ironwood. Advisory Board:
Phathom Pharma: Stock Options: RJS Mediagnostics
Spechler SJ: Has served as a consultant for Interpace Diagnostics, Cernostics, Phathom Pharmaceuticals, Takeda and Ironwood
Pharmaceuticals.
Royalties: Up To Date.
Katz et al. Page 2
long-term use and increasing concern about over-prescribing of PPIs. New data regarding the
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potential for surgical and endoscopic interventions have emerged. In this new document, we
provide updated, evidence-based recommendations and practical guidance for the evaluation and
management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management.
The GRADE system was used to evaluate the evidence and the strength of recommendations. Key
concepts and suggestions that as of this writing do not have sufficient evidence to grade are also
provided.
Introduction
A lot has changed, much remains the same. Gastroesophageal reflux disease (GERD)
continues to be among the most common diseases seen by gastroenterologists, surgeons, and
primary care physicians. Since publication of the last American College of Gastroenterology
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guideline on reflux management [1], clinically important advances in surgical and

endoscopic therapy of GERD have emerged. Our understanding of the varied presentations
of GERD, enhancements in diagnostic testing, and approach to patient management
have evolved. During this time, scrutiny of proton pump inhibitors (PPI) has increased
considerably. While PPIs remain the medical treatment of choice for GERD, multiple
publications have raised questions about adverse events, raising doubts about the safety
of long-term use and increasing concern about over-prescribing of PPIs. In this new
document, we provide updated, evidence-based recommendations and practical guidance
for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical,
and endoscopic management. The management of functional heartburn and other functional
upper GI symptoms is beyond the scope of this guideline. Additional detail regarding
esophageal physiologic testing is covered in other guidelines.
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Summary and strength of the recommendations can be found in Table 1 with Key Concepts
summarized in Table 2.
Methods
The guideline is structured in the format of statements that are considered to be clinically
important by the content authors for evaluation and treatment of GERD. The authors
developed PICO questions and performed a literature search for each question with
assistance from a research librarian. The Grading of Recommendations, Assessment,
Development, and Evaluation (GRADE) process was used to assess the quality of evidence
for each statement [2]. The quality of evidence is expressed as high (we are confident in
the effect estimate to support a particular recommendation), moderate, low, or very low (we
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have very little confidence in the effect estimate to support a particular recommendation)
based on the risk of bias of the studies, evidence of publication bias, heterogeneity among
studies, directness of the evidence and precision of the estimate of effect [3]. A strength of
recommendation is given as either strong (recommendations) or conditional (suggestions)
based on the quality of evidence, risks versus benefits, feasibility, and costs taking
into account perceived patient and population-based factors [4]. Furthermore, a narrative

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evidence summary for each section provides important details for the data supporting the
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statements.
Our goal is to showcase a document that offers best practice recommendations for clinicians
caring for patients with GERD.
Diagnosis of GERD
Recommendations
1. For patients with classic GERD symptoms of heartburn and regurgitation who
have no alarm symptoms, we recommend an 8-week trial of empiric proton
pump inhibitor (PPI) once daily before a meal. (Strong recommendation,
moderate level of evidence)
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2. We recommend attempting to discontinue the PPIs in patients whose classic

GERD symptoms respond to an 8-week empiric trial of PPIs. (conditional
recommendation, low level of evidence)
3. We recommend diagnostic endoscopy, ideally after PPIs are stopped for 2 to 4

weeks, in patients whose classic GERD symptoms do not respond adequately
to an 8-week empiric trial of PPIs, or whose symptoms return when PPIs are
discontinued. (Strong recommendation, low level of evidence)
4. In patients who have chest pain without heartburn and who have had adequate
evaluation to exclude heart disease, objective testing for GERD (endoscopy
and/or reflux monitoring) is recommended. (Conditional recommendation, low
level of evidence)
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5. We do not recommend the use of a barium swallow solely as a diagnostic test for
GERD. (Conditional recommendation, low level of evidence)
6. We recommend endoscopy as the first test for evaluation of patients presenting

with dysphagia or other alarm symptoms (weight loss, GI bleeding), and
for patients with multiple risk factors for Barrett’s esophagus. (Strong
7. In patients for whom the diagnosis of GERD is suspected but not clear,
and endoscopy shows no objective evidence of GERD, we recommend reflux
monitoring be performed off therapy to establish the diagnosis. (Strong
8. We recommend against performing reflux monitoring off therapy solely as a

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diagnostic test for GERD in patients known to have endoscopic evidence of

Los Angeles grade C or D reflux esophagitis, or in patients with long-segment
Barrett’s esophagus. (Strong recommendation, low level of evidence)
Key Concept
1. We do not recommend high resolution manometry (HRM) solely as a diagnostic
test for GERD.

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Defining GERD—A single unifying definition of GERD is difficult. In preparing this

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guideline, we have blended the multiple definitions in the literature to create the following:
GERD is the condition in which the reflux of gastric contents into the esophagus results
in symptoms and/or complications. GERD is objectively defined by the presence of
characteristic mucosal injury seen at endoscopy and/or abnormal esophageal acid exposure
demonstrated on a reflux monitoring study.
Pathophysiology of GERD—The pathophysiology of GERD includes a poorly

functioning esophagogastric junction; the antireflux barrier composed of the lower
esophageal sphincter and crural diaphragm, coupled with impaired esophageal clearance
and alterations in esophageal mucosal integrity. Reflux esophagitis develops when refluxed
gastric juice triggers the release of cytokines and chemokines that attract inflammatory
cells, and that also might contribute to symptoms. Other contributors to GERD symptoms
may include decreased salivary production, delayed gastric emptying, and esophageal
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hypersensitivity. As such, GERD can no longer be approached as a single disease, but one
with multiple phenotypic presentations and different diagnostic considerations.
Symptoms—Typical symptoms of GERD include heartburn and regurgitation. Heartburn

is the most common GERD symptom, and is described as substernal burning sensation rising
from the epigastrium up toward the neck. Regurgitation is the effortless return of gastric
contents upward toward the mouth, often accompanied by an acid or bitter taste. While both
heartburn and regurgitation are major symptoms of GERD, the genesis of these symptoms
are not the same, and the diagnostic and management approaches vary depending on which
symptom predominates. Chest pain, indistinguishable from cardiac pain, may present in
conjunction with heartburn and regurgitation, or as the only GERD symptom. The symptoms
of GERD are nonspecific and may overlap or be confused with those of other disorders such
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as rumination, achalasia, eosinophilic esophagitis, reflux hypersensitivity, functional disease,

cardiac or pulmonary disease, and paraesophageal hernia.
Extraesophageal manifestations of GERD can include laryngeal and pulmonary symptoms

such as hoarseness, throat clearing, and chronic cough, and conditions such as laryngitis,
pharyngitis, and pulmonary fibrosis. It also has been proposed that GERD might exacerbate
asthma. These extraesophageal manifestations are challenging for patients and physicians
because, while they may result from GERD, they may also be due to a host of other causes.
Even in patients with established GERD, it can be difficult to establish that GERD is the
cause of these extraesophageal problems.
There is no gold standard for the diagnosis of GERD. Thus, the diagnosis is based on
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a combination of symptom presentation, endoscopic evaluation of esophageal mucosa,

reflux monitoring, and response to therapeutic intervention. Heartburn and regurgitation
remain the most sensitive and specific symptoms for GERD, although not as reliable as
one might believe. A well-done but older systematic review found a variable sensitivity of
heartburn and regurgitation for erosive esophagitis (30-76%), with the specificity ranging
from 62-96% [5]. Most consensus statements and guidelines advocate a trial of therapy with
a proton pump inhibitor (PPI) as a diagnostic “test” in patients with the typical symptoms of
heartburn and regurgitation, with the underlying assumption that a PPI response establishes

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the diagnosis of GERD. While this a practical and efficient approach it is limited by a pooled
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sensitivity of 78% and specificity of only 54% (using endoscopy and pH monitoring as the
reference standard) based on a meta-analysis and prospective study [6, 7].
Chest pain is commonly listed as a symptom of GERD. Similar to heartburn, a PPI trial
has often been used for diagnosis of suspected GERD-related chest pain [8]. However,
a systematic review of PPI treatment of non-cardiac chest pain found that symptom
improvement with a PPI trial was effective only in patients with erosive esophagitis or
abnormal pH monitoring [9]. There was no significant response to PPIs compared with
placebo when endoscopy and pH monitoring were normal, and the symptoms of chest pain
and heartburn did not reliably predict a PPI response [10].
Atypical and extraesophageal symptoms and conditions such as chronic cough, dysphonia,
asthma, sinusitis, laryngitis, and dental erosions have been associated with GERD. However,
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these symptoms and conditions have poor sensitivity and specificity for the diagnosis of
GERD. Diagnoses of GERD by extraesophageal symptoms alone or by their response to
PPIs are unreliable due to poor sensitivity and specificity for GERD and not recommended
(see additional discussion in the Extraesophageal GERD section below).
Barium radiography—Barium radiographs should not be used solely as a diagnostic test

for GERD. The presence of reflux on a barium esophagram or upper GI series has poor
sensitivity and specificity for GERD when compared to pH testing. In a recent prospective
study, only about one-half of patients with abnormal reflux on a barium study were found to
have abnormal pH monitoring [11, 12]. The finding of barium reflux above the thoracic inlet
with or without provocative maneuvers (including the water siphon test) somewhat increases
the sensitivity for reflux, but not sufficiently for barium esophagram to be recommended as a
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diagnostic test for GERD [13].
Endoscopy—Upper endoscopy is the most widely used objective test for evaluating the
esophageal mucosa. For patients with GERD symptoms who also have alarm symptoms
such as dysphagia, weight loss, bleeding, vomiting, and/or anemia, endoscopy should
be performed as soon as feasible. The endoscopic findings of erosive esophagitis (EE)
and Barrett’s esophagus are specific for the diagnosis of GERD. The Los Angeles (LA)
classification of EE is the most widely used and validated scoring system [14]. Recent
expert consensus statements concluded that LA grade A EE is not sufficient for a definitive
diagnosis of GERD, as it is not reliably differentiated from normal [15, 16]. LA B EE can
be diagnostic of GERD in the presence of typical GERD symptoms and PPI response, while
LA grade C is virtually always diagnostic of GERD. In outpatients, LA grade D EE is a
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manifestation of severe GERD, but LA grade D EE might not be a reliable index of GERD
severity in hospitalized patients. The finding of any Barrett’s esophagus segment >3 cm with
intestinal metaplasia on biopsy is diagnostic of GERD and obviates the need for pH testing
merely to confirm that diagnosis. In patients with LA grade C and D EE, endoscopy is
recommended after PPI treatment to ensure healing and to evaluate for Barrett’s esophagus,
which can be difficult to detect when severe EE is present.

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For patients having endoscopy for typical GERD symptoms, normal mucosa is the most
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common finding. There are limited data on the frequency of finding EE in patients
undergoing endoscopy while taking PPIs but, since PPIs are highly effective for healing
EE, underlying EE clearly can be missed in this setting. Consequently, a diagnosis of
non-erosive reflux disease (NERD) should only be made if endoscopy is performed off
PPIs. In order to maximize the yield of GERD diagnosis and assess for EE, diagnostic
endoscopy should ideally be performed after PPIs have been stopped for 2 weeks, and
perhaps as long as 4 weeks if possible. In a small prospective study assessing relapse of
EE in patients with LA C EE that was healed with PPIs, discontinuation of PPI therapy
led to return of EE in as little as one week [17]. Stopping PPIs for 2 to 4 weeks also will
facilitate a diagnosis of eosinophilic esophagitis (EoE), which is a diagnostic consideration
when endoscopy is performed for patients with symptoms that are thought to be due to
GERD but are not eliminated by PPIs [18]. While esophageal biopsies have little value as
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a diagnostic test for GERD, they are required to establish a diagnosis of EoE. Since PPIs
can eliminate the endoscopic and histologic features of EoE, the diagnosis of EoE cannot
be excluded if endoscopy is performed while the patient is taking PPIs [18]. Patients should
be advised that they can take antacids for symptom relief during this period of 2 to 4
weeks off PPIs. Some patients will not be able to tolerate discontinuing their PPI therapy,
but the diagnostic advantages discussed above warrant an attempt at stopping PPIs before
performing diagnostic endoscopy for GERD.
Esophageal Manometry—High resolution manometry (HRM) can be used to assess

motility abnormalities associated with GERD, but HRM is not alone a diagnostic test for
GERD. Weak LES pressure and ineffective esophageal motility often accompany severe
GERD, but no manometric abnormality is specific for GERD. For esophageal impedance-pH
monitoring, HRM is used to locate the LES for positioning of transnasal pH-impedance
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catheters. HRM also has a role in the evaluation of patients considering surgical or
endoscopic antireflux procedures, primarily to evaluate for achalasia. Patients with achalasia
can have heartburn and regurgitation that are mistaken for GERD symptoms, and antireflux
procedures performed for such a mistaken diagnosis of GERD can result in devastating
dysphagia. Thus, HRM should ideally be performed in all patients prior to any antireflux
procedure. Although esophageal manometry has been proposed as a means to “tailor”
antireflux operations, with Nissen (complete) fundoplication reserved for patients with
normal peristalsis and partial fundoplication used for those with ineffective esophageal
motility, studies on this issue have not supported the efficacy of this approach. Nevertheless,
absent contractility is for most a contraindication to fundoplication. Newer developments
in HRM include physiologic assessment of esophagogastric junction morphology and
provocative testing with multiple rapid swallows or the rapid drink challenge. In patients
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undergoing surgical treatment of GERD, reduced contractile reserve documented by

multiple rapid swallows on HRM is associated with post-operative dysphagia [19]. More
data are needed to clarify the role of altered motility on outcomes after magnetic sphincter
augmentation and transoral incisionless fundoplication. Until those are forthcoming, a
preoperative HRM is recommended. HRM is part of the diagnostic work up for patients
unresponsive to PPIs when an etiology for symptoms cannot be demonstrated by impedance

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pH monitoring and in patients with non-cardiac chest pain especially those not responsive to
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a PPI trial to assess for motility abnormalities
Reflux monitoring—Ambulatory reflux monitoring (pH or impedance-pH) allows for

assessment of esophageal acid exposure to establish or refute a diagnosis of GERD, and for
correlating symptoms with reflux episodes using the symptom index or symptom association
probability. The main methods of reflux testing include a wireless telemetry capsule (Bravo
Reflux Capsule, Medtronic, Minneapolis, MN) attached to the esophageal mucosa during
endoscopy and transnasal catheter-based testing, and there are strengths and weaknesses to
each approach. With transnasally-positioned pH and pH/impedance catheters, the monitoring
period generally is limited to 24 hours, while wireless pH telemetry capsule monitoring
can last from 48 to 96 hours. In addition, the capsule avoids the physical discomfort
and embarrassment of a transnasal catheter, and so patients are more likely to carry on
normal daily activities during capsule pH monitoring [20, 21]. There is no capsule system
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available for impedance monitoring, which requires a transnasal catheter. Dual-pH sensor
transnasal catheters and a hypopharyngeal pH probe are also available to document acid
reflux into the proximal esophagus and oropharynx, but the utility of these techniques is
highly questionable with studies reporting widely disparate results (see extraesophageal
section). Several factors are assessed during reflux testing, including acid exposure time,
number of reflux events, and symptom correlation. Impedance pH testing also allows for
measurement of weakly acidic and nonacid reflux, assessment of bolus clearance, and extent
of proximal reflux. Reflux symptom association on impedance pH testing may help predict
symptom response to therapy and may help in diagnosing reflux hypersensitivity [22]. With
both wireless capsule and catheter-based reflux tests, the most consistently reliable variables
include the total acid exposure time and the composite DeMeester score.
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The relationship between symptoms and reflux events can be assessed using the symptom
index (SI) or symptom association probability (SAP). To calculate SI, the total number
of reflux episodes associated with symptom episodes is divided by the total number of
symptom episodes during the entire monitoring period; an SI ≥50% is considered positive.
To determine the SAP, the 24-hour monitoring period is divided into 720 two-minute
increments, and each increment is evaluated for the occurrence of reflux and symptom
episodes. A Fisher’s exact test is performed to determine a p-value for the probability
that reflux and symptom events are randomly distributed, and the SAP is determined by
subtracting the calculated p value from 1, and multiplying the remainder by 100%; an SAP
>95% is considered positive. The validity of both of these indices has been questioned, and
neither has been demonstrated superior to the other for clinical purposes. The sensitivity
and specificity of reflux monitoring is high in GERD patients with erosive esophagitis,
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though perhaps not as accurate in those with a normal endoscopy. Impedance monitoring
that enables detection of weakly acidic and non-acidic reflux has been shown to be useful
in identifying patients with reflux hypersensitivity who might respond to antireflux surgery
[23].
An issue that frequently arises is whether esophageal pH monitoring should be performed

on or off PPI therapy. It is generally recommended to monitor after PPIs are stopped for 7
days if the diagnosis of GERD is not clear, and prior to antireflux surgery or endoscopic

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therapy for GERD to document abnormal acid reflux [16]. This recommendation includes
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testing with either the telemetry capsule (48-96 hours) or impedance-pH catheter. Reflux
monitoring while on PPI therapy is suggested in patients who have had the diagnosis
of GERD established by previous objective evidence (i.e. erosive esophagitis, Barrett’s
esophagus, prior pH testing off PPI) but who have symptoms potentially reflux-related that
have not responded to PPIs. In these patients, impedance/pH testing is recommended to
document reflux hypersensitivity for weakly acidic or non-acidic reflux as well as for acid
reflux. Figure 1 outlines an overall approach to the diagnosis of GERD.
Diagnosis of GERD in Pregnancy—Approximately two-thirds of pregnant women

experience heartburn, which can begin in any trimester [24]. Most patients do not have a
previous diagnosis of GERD [25], though a history of GERD may increase the likelihood
of GERD occurring during pregnancy. Despite its frequent occurrence during pregnancy,
heartburn usually resolves after delivery [26]. Pregnancy and the amount of weight gain
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during pregnancy are risk factors for frequent GERD symptoms one-year post delivery
[26]. Heartburn is the only GERD symptom that has been studied in pregnancy, and the
diagnosis of GERD is almost always symptom based. Endoscopy and pH monitoring are
rarely needed.
New developments—A recently approved device for evaluation of GERD uses a

catheter-based balloon lined by sensors that measure mucosal impedance during endoscopy.
This technique has shown promise for differentiating GERD from EoE and may develop to
be a useful adjunct to endoscopy in the diagnosis of GERD [27].
GERD Medical Management

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Recommendations
1. We recommend weight loss in overweight and obese patients for improvement of
GERD symptoms. (Strong recommendation, moderate level of evidence)
2. We suggest avoiding meals within 2-3 hours of bedtime. (Conditional

3. We suggest avoidance of tobacco products/smoking in patients with GERD

symptoms. (Conditional recommendation, low level of evidence)
4. We suggest avoidance of "trigger foods" for GERD symptom control.

Conditional recommendation, low level of evidence)
5. We suggest elevating head of bed for nighttime GERD symptoms. (Conditional

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6. We recommend treatment with PPI over treatment with H2RA for healing
erosive esophagitis. (Strong recommendation, high level of evidence)
7. We recommend treatment with PPI over H2RA for maintenance of healing from
erosive esophagitis. (Strong recommendation, moderate level of evidence)

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8. We recommend PPI administration 30 to 60 minutes prior to a meal rather than at

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bedtime for GERD symptom control. (Strong recommendation, moderate level of

evidence)
9. For GERD patients who do not have erosive esophagitis or Barrett’s esophagus,
and whose symptoms have resolved with PPI therapy, an attempt should be
made to discontinue PPIs or to switch to on-demand therapy in which PPIs
are taken only when symptoms occur and discontinued when they are relieved.
(Conditional recommendation, low level of evidence)
10. For GERD patients who require maintenance therapy with PPIs, the PPIs should
be administered in the lowest dose that effectively controls GERD symptoms and
maintains healing of reflux esophagitis. (Conditional recommendation, low level
of evidence)
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11. We recommend against routine addition of medical therapies in PPI non-

responders. (Conditional recommendation, moderate level of evidence)
12. We recommend maintenance PPI therapy indefinitely or antireflux surgery for

patients with Los Angeles grade C or D esophagitis. (Strong recommendation,
13. We do not recommend Baclofen in the absence of objective evidence of GERD.

(Strong recommendation, moderate level of evidence)
14. We recommend against treatment with a prokinetic agent of any kind for
GERD therapy unless there is objective evidence of gastroparesis. (Strong
15. We do not recommend sucralfate for GERD therapy except during pregnancy.
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(Strong recommendation, low level of evidence)
16. We suggest on-demand or intermittent PPI therapy for heartburn

symptom control in patients with non-erosive reflux disease. (Conditional
Key Concepts
1. There is conceptual rationale for a trial of switching PPIs for patients who have
not responded to one PPI. For patients who have not responded to one PPI, more
than one switch to another PPI cannot be supported.
2. Use of the lowest effective PPI dose is recommended and logical but must be
individualized. One area of controversy relates to abrupt PPI discontinuation and
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potential rebound acid hypersecretion resulting in increased reflux symptoms.

Although this has been demonstrated to occur in healthy controls, strong
evidence for an increase in symptoms after abrupt PPI withdrawal is lacking.
Management of GERD requires a multifaceted approach, taking into account the symptom
presentation, endoscopic findings, and likely physiological abnormalities. Management
decisions may differ depending on hiatal hernia type and size, on the presence of erosive
esophagitis and/or Barrett’s esophagus, body mass index and on accompanying physiologic

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abnormalities such as gastroparesis or ineffective motility with absence of contractile

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reserve. Medical management includes lifestyle modifications as well as pharmacologic

therapy, principally with medications that reduce gastric acid secretion. Surgical and
endoscopic options are discussed in other sections.
Non-pharmacologic lifestyle modifications include recommendations for diet modification

(content and timing), body positioning with meals and while sleeping, and weight
management (Table 3).
Diet and Lifestyle Changes—Common recommendations include weight loss for

overweight patients, elevating the head of the bed, tobacco and alcohol cessation, avoidance
of late night meals and bedtime snacks, staying upright during and after meals, and cessation
of foods that potentially aggravate reflux symptoms such as coffee, chocolate, carbonated
beverages, spicy foods, acidic foods such as citrus and tomatoes, and foods with high fat
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content [28]. Supporting data for these recommendations are limited and variable, often
involving only small and uncontrolled studies, and rarely as the only intervention, making
interpretation and definitive recommendations difficult. However, multiple studies, including
several randomized controlled trials, have demonstrated improvement in nocturnal GERD
symptoms and nocturnal esophageal acid exposure with head of bed elevation or sleeping on
a wedge. Also, compared to lying left-side down, lying right-side down increases nocturnal
reflux and reflux after meals, presumably because right-sided recumbency places the EGJ in
a dependent position relative to the pool of gastric contents that favors reflux [29, 30].Thus,
patients might be advised to avoid sleeping right side down [31-34].
Several studies have evaluated the effects of various foods on LES pressure to try to
determine which items might lead to GERD. In laboratory studies, coffee, caffeine, citrus,
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and spicy food had little to no effect on LES pressure [35, 36]. However, some of these
items might have irritant effects that could evoke GERD symptoms without influencing
reflux. Alcohol consumption, tobacco smoking, chocolate, peppermint, and high-fat foods
do reduce LES pressure in the laboratory, but few studies document the benefits of avoiding
these foods and practices. Smoking cessation was shown to improve GERD symptoms in
a large cohort study [37]. Patients in a smoking cessation study had GERD symptoms
measured by validated questionnaire, and those who successfully quit smoking for a year
had 44% improvement in GERD symptoms, compared to 18% in those who continued to
smoke [38].
A recent paper, using data collected from the prospective Nurses Health Study, evaluated
women without a known history of GERD for the impact of coffee, tea, soda, milk, water
and juice on reflux symptoms. Six servings of coffee, tea, and soda were associated with
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increased reflux symptoms compared to zero servings per day. In contrast, milk and juice
were not associated with increased reflux symptoms, despite the acidic nature of some
of these beverages [39]. Substituting water for two servings of coffee, tea and soda was
associated with a decrease in GERD symptoms, suggesting that substitution of water for
these beverages might be helpful in the management of GERD.

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The timing of food intake can also affect GERD symptoms. A short interval (<3 hours)
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between eating and bedtime or lying supine is associated with increased GERD symptoms
and need for medication [40]. Weight gain has been associated with new onset of GERD
symptoms [41], even in those with a normal BMI at baseline. Obesity increases the risk
of GERD, possibly due to a combination of eating a diet high in fat and other foods that
promote reflux, increased intra-abdominal pressure that promotes reflux due to increased
intra-abdominal fat, and physiologic changes induced by products of visceral fat [42].
Several studies have examined the role of weight and weight loss on GERD. A population-
based study in Norway assessed weight and GERD symptoms at baseline and 10 years
later, and identified a dose-dependent improvement in GERD symptoms with weight loss
[43]. Prospective and cohort studies also have shown improvement in GERD with weight
loss. One study documented a 40% reduction in frequent GERD symptoms in women who
reduced their BMI by 3.5 or more compared with controls [44]. A meta-analysis suggests
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that weight loss in overweight patients, avoidance of eating prior to going to sleep, and
smoking cessation are effective in relief of GERD symptoms [45].
Medications—The backbone of pharmacologic therapy for GERD are medications that

are directed at neutralization or reduction of gastric acid. Agents in this class include
antacids, histamine H2-receptor antagonists (H2RA), and proton pump inhibitors. Antacids
are used exclusively for on-demand symptom relief with little evidence to favor one type
over another. Studies with an alginic acid preparation manufactured in the United Kingdom
suggest potential efficacy in symptom relief compared to other products, but alginate content
of preparations sold in other countries is variable [46].
Proton Pump Inhibitors—PPIs are the most commonly prescribed medication based on
ample data demonstrating consistently superior heartburn and regurgitation relief, as well
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as improved healing compared to H2RAs. A meta-analysis (published when only two PPIs
were available) provides important insight into PPI efficacy. PPIs showed a significantly
faster healing rate (12%/week) vs. H2RAs (6%/week), and faster, more complete heartburn
relief (11.5%/week) vs. H2RAs (6.4%/week) [47, 48].
Studies on GERD treatment typically last only 8-12 weeks, in part because symptom
relief and healing appear to peak in that time frame. The healing rates of erosive
esophagitis are not linear; thus, clinicians and patients need to understand that symptom
relief and healing may not be rapid. PPIs are associated with a greater rate of “complete”
symptom relief (usually assessed at 4 weeks) in patients with erosive esophagitis (~70-80%)
compared to patients with so called non-erosive reflux disease (NERD) in which symptom
relief approximates 50-60% [49]. Trials in NERD patients are based on symptoms of
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frequent heartburn and the absence of erosions on an index endoscopy without objective
documentation of GERD by reflux monitoring. There are likely many patients included in
NERD who have functional heartburn and thus unlikely to respond to PPI.
Meta-analyses suggest that overall GERD symptom relief and healing rates differ little
among the seven available PPIs, despite studies demonstrating differences in pH control.
A meta-analysis examining efficacy of different PPIs for healing of erosive esophagitis
included 10 studies (15,316 patients) [50]. At 8 weeks, there was a 5% (RR, 1.05; 95%

Katz et al. Page 12
CI, 1.02-1.08) relative increase in the probability of healing of erosive esophagitis with
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esomeprazole, yielding an absolute risk reduction of 4% and number needed to treat (NNT)
of 25, a number unlikely to be clinically meaningful. Although all the PPIs are effective for
healing reflux esophagitis when given in their standard dosages, there are wide variations in
the acid-suppression potency of the different PPI preparations. If relative acid-suppression
potencies of individual PPIs (based on their effects on mean 24-hour intragastric pH)
are standardized to omeprazole to yield ‘omeprazole equivalents’ (OEs, with omeprazole
having an OE of 1.00), the relative potencies of standard-dose pantoprazole, lansoprazole,
omeprazole, esomeprazole and rabeprazole have been estimated at 0.23, 0.90, 1.00, 1.60 and
1.82 OEs, respectively [51] [52].
PPIs can bind only to proton pumps that are actively secreting acid. Since meals stimulate
proton pump activity, enteric-coated PPIs control intra-gastric pH best when given before a
meal (30-60 minutes before breakfast for once-daily dosing, 30-60 minutes before breakfast
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and dinner for twice-daily dosing [53, 54]. Bedtime dosing is discouraged as this is less
effective than a pre-dinner dose in acid control [55]. Dexlansoprazole , a dual delayed
release PPI, in which first absorption is in the duodenum, then partially further down the
small bowel appears to have similar efficacy in pH control regardless of meal timing. An
omeprazole-sodium bicarbonate combination that is not enteric coated provides good control
of intragastric pH in the first four hours of sleep when dosed at bedtime [56]. There appears
to be a wide variation in individual intragastric pH control between PPIs, a rationale for
considering switching PPIs in patients with incomplete response [57]. In a study of 282
patients with persistent heartburn on lansoprazole 30 mg once daily who were randomized
either to double the dose of lansoprazole or to switch to esomeprazole 40 mg once daily,
the two strategies were equally effective, with approximately 55% of patients in both groups
experiencing a decrease in the percentage of heartburn-free days [58]. Studies suggest that
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genetic differences in CYP2C19 metabolism affect PPI response, however genetic testing in
this regard has no established role in practice. If one is considering a PPI switch, changing
to a PPI that does not rely on CYP2C19 for primary metabolism (rabeprazole) might be
considered.
Maintenance PPI therapy should be administered for patients with GERD complications
including severe erosive esophagitis (LA C or D) and Barrett’s esophagus[59]. For patients
without erosive esophagitis or Barrett’s esophagus who continue to have symptoms when
PPI therapy is discontinued, consideration can be given to on-demand therapy in which
PPIs are taken only when symptoms occur and discontinued when they are relieved [60,
61]. Two-thirds of patients with nonerosive disease responsive to PPIs will demonstrate
symptomatic relapse when PPIs are stopped. With LA grade C esophagitis, nearly 100% will
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relapse within 6 months [62]. Recurrence of erosive esophagitis after discontinuation can
occur in as little as 1-2 weeks, particularly in patients with prior LA C erosive esophagitis
[17]. Patients with LA grade C or D erosive esophagitis should remain on long-term PPI
therapy to maintain healing.
In some cases, patients with NERD and otherwise non-complicated GERD can be managed
successfully with on-demand or intermittent PPI therapy. In one randomized controlled trial,
83% of NERD patients randomized to 20 mg of omeprazole on demand were in remission

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at 6 months compared with 56% of patient on placebo [63]. In a systematic review of

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randomized controlled trials comparing on-demand PPI vs placebo, symptom-free days for
NERD patients in the on-demand arm were equivalent to rates for patients on continuous
PPI therapy, and both on-demand and continuous PPI were superior to placebo. On-demand
PPI therapy was not better than continuous PPI therapy for patients with erosive esophagitis.
Step-down therapy to H2RAs is another acceptable option for management, particularly in
NERD patients [64, 65].
Use of the lowest effective dose is recommended and logical but must be individualized.
One area of controversy relates to abrupt PPI discontinuation and potential rebound
acid hypersecretion resulting in increased reflux symptoms. Although rebound acid
hypersecretion has been demonstrated to occur in healthy controls, strong evidence for an
increase in symptoms after abrupt PPI withdrawal is lacking [66-68].
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Histamine-2-Receptor Antagonists Taken at Bedtime—Medical options for GERD

patients with incomplete symptom response on PPI therapy are limited. The addition of
bedtime H2RA has been suggested for patients on PPI with persistent nocturnal symptoms.
This approach gained popularity after several studies demonstrated improved overnight
intragastric pH control with the addition of an H2RA [69], although a well-done study
demonstrated loss of pH control (tachyphylaxis) after a month of bedtime H2RA therapy
[70]. Based on these data, use of a bedtime H2RA may be beneficial if dosed on an as-
needed basis for patients with nocturnal symptoms and for patients with objective evidence
of nocturnal acid reflux on pH monitoring despite PPI treatment.
Prokinetics—There are limited data on the use of prokinetic agents for patients with
GERD. Metoclopramide has been shown to increase lower esophageal sphincter pressure,
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enhance esophageal peristalsis, and augment gastric emptying. However, data on its efficacy
in GERD are scant, and significant adverse events have been reported with long-term
and high-dose metoclopramide use, including central nervous system side effects such as
drowsiness, agitation, irritability, depression, dystonic reactions, and tardive dyskinesia [71,
72]. Thus, we do not recommend using metoclopramide solely for the treatment of GERD.
Prucalopride, a 5 HT agonist FDA-approved for treatment of constipation, was shown in
one off-label use study to improve gastric emptying and reduce esophageal acid exposure in
patients with GERD. In the future, this may be a potential add-on therapy for patients with
GERD on PPIs found to have delayed gastric emptying [73].
Baclofen—Baclofen, a GABAB agonist, reduces the transient LES relaxations that enable
reflux episodes. Baclofen decreases the number of post-prandial acid and non-acid reflux
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events, nocturnal reflux activity, and belching episodes [74-76]. A trial of baclofen at
a dosage of 5-20 mg three times a day can be considered in patients with objective
documentation of continued symptomatic reflux despite optimal PPI therapy. Short-term
randomized controlled trials have demonstrated symptomatic improvement with baclofen
[74-76]. A randomized, placebo-controlled trial of medical therapy (including baclofen)
vs antireflux surgery for PPI-refractory heartburn found no significant benefit for baclofen
compared to placebo at one year, but the study was not sufficiently powered to detect a

Katz et al. Page 14
small but potentially important effect for baclofen [23]. Usage is limited by side effects of
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dizziness, somnolence, and constipation.
Sucralfate—Sucralfate is a mucosal protective agent, but few data document its efficacy
in GERD. Limited studies have suggested similar efficacy to H2RAs, but there are no
comparative data to PPIs, nor any combination studies with these agents. Sucralfate is
largely unabsorbed and has no systemic toxicity. There is little to recommend for this agent
in GERD outside of pregnancy.
Treatment of GERD during Pregnancy—A small randomized controlled trial found

that sucralfate was superior to dietary and lifestyle modifications for relieving heartburn
and regurgitation in pregnant women [77]. Approximately two-thirds of pregnant women
experience heartburn. It has been recommended that treatment of GERD during pregnancy
should start with lifestyle modifications. When lifestyle modifications fail, antacids
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(aluminum-, calcium-, or magnesium-containing), alginates, and sucralfate are the first-line

therapeutic agents. All histamine H2-blockers are FDA Category B, and all PPIs are FDA
Category B except omeprazole, which is FDA Category C.
Extraesophageal GERD Symptoms

Recommendations
1. We recommend evaluation for non-GERD causes in patients with possible
extra-esophageal manifestations before ascribing symptoms to GERD. (Strong
recommendation, moderate level of evidence)
2. We recommend that patients who have extra-esophageal manifestations of

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GERD without typical GERD symptoms (e.g. heartburn, regurgitation) undergo

reflux testing for evaluation prior to PPI therapy. (Strong recommendation,
3. For patients who have both extraesophageal and typical GERD symptoms we
suggest considering a trial of twice-daily PPI therapy for 8 to 12 weeks prior to
additional testing. (Conditional recommendation, low level of evidence)
4. We suggest that upper endoscopy should not be used as the method to establish a
diagnosis of GERD-related asthma, chronic cough, or laryngopharyngeal reflux.
(Conditional recommendation, low level of evidence)
5. We suggest against a diagnosis of laryngopharyngeal reflux based on

laryngoscopy findings alone and recommend additional testing should be
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considered. (Conditional recommendation, low level of evidence)
6. In patients treated for extraesophageal reflux disease, surgical or endoscopic

anti-reflux procedures are only recommended in patients with objective evidence
of reflux. (Conditional recommendation, low level of evidence)

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Key Concepts
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1. While GERD may be a contributor to extraesophageal symptoms in some

patients, careful evaluation for other causes should be considered for patients
with laryngeal symptoms, chronic cough, and asthma.
2. Diagnosis, evaluation, and management of potential extraesophageal symptoms

of GERD is limited by lack of a gold standard test, variable symptoms, and other
disorders which may cause similar symptoms
3. Due to difficulty distinguishing between patient with laryngeal symptoms and

normal controls, salivary pepsin testing is not recommended for evaluation of
patients with extraesophageal reflux symptoms
4. For patients whose extraesophageal symptoms have not responded to a trial of

twice-daily PPIs, we recommend upper endoscopy, ideally off PPIs for 2 to 4
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weeks. If endoscopy is normal, consider reflux monitoring. Demonstration of

erosive esophagitis by endoscopy establishes a diagnosis of GERD, but does not
confirm that GERD is the cause of the extraesophageal symptoms. Confirmation
may require pH/impedance testing.
5. For patients with extraesophageal symptoms, we do not routinely recommend

oropharyngeal or pharyngeal pH monitoring.
Numerous extraesophageal symptoms and conditions have been attributed to GERD,

including chronic cough, throat-clearing, hoarseness, globus, asthma, and laryngitis.
These are vexing for patients as well as physicians, as the symptoms ascribed to extra-
esophageal GERD are often non-specific and overlap with other disorders. Evaluation
by otorhinolaryngology, allergy, and pulmonary specialists should be considered in these
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patients, depending on the constellation of symptoms. Currently available diagnostic tools

to establish GERD as the cause of extraesophageal symptoms have substantial limitations.
PPI treatment is relied upon as both a diagnostic tool and treatment for extraesophageal
GERD symptoms, but is often ineffective and prolonged treatment trials with PPI may delay
diagnosis and care for patients with non-reflux laryngeal and pulmonary disorders.
Symptoms—The association between GERD and extraesophageal symptoms has been

examined in multiple studies. In a case-control study of veterans, patients with esophagitis
or esophageal strictures were more likely to have a diagnosis of laryngitis (OR 2.01),
aphonia (OR 1.81), asthma (OR 1.51), and pharyngitis (OR 1.48) compared to control
patients [78]. In a U.S. survey study, 26% of patients reported both GERD and laryngeal
symptoms [79]. Of this group with both GERD and laryngeal complaints, 38% reported
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voice disorders and 44% had occasional breathing difficulties. Some studies have suggested
that chronic cough may be due to GERD in 21-41% of cases [80]. However, due to the wide
variety of causes of chronic cough, the American College of Chest Physicians guideline for
evaluation of chronic cough suggests looking for other sources before attributing chronic
cough to GERD [81].
GERD may also have a role in asthma, with one systematic review of 28 studies identifying
GERD symptoms in 59% of asthma patients and abnormal pH testing in 51% [82]. However,

Katz et al. Page 16
data from several randomized controlled trials suggest that PPI treatment is ineffective for
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many patients with asthma, which brings in to question the role of acid reflux in asthma
symptoms [83, 84].
Endoscopy—Endoscopy is frequently used for assessing classic symptoms of GERD,

such as heartburn and regurgitation, but its role in assessment of extraesophageal GERD
symptoms is less clear. In patients with extraesophageal GERD symptoms, the reported
frequency of erosive esophagitis ranges from 18% to 52% [85, 86]. However, the presence
of erosive esophagitis does not confirm GERD as a cause of extraesophageal symptoms, as
erosive esophagitis has been found in 16% of patients with no typical or extraesophageal
GERD symptoms in a general population who were undergoing periodic health checkup
[87]. Nevertheless, if LA grade C or D erosive esophagitis is present, this establishes a
diagnosis of severe GERD and justifies a trial of PPI therapy.
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Laryngoscopy—Laryngoscopy performed by an otorhinolaryngologist (ENT) is

commonly used to assess for signs of extraesophageal GERD, in particular,
laryngopharyngeal reflux (LPR). Findings on laryngoscopy that are associated with reflux
include posterior commissure hypertrophy, laryngeal and arytenoid inflammation, vocal cord
edema, and endolaryngeal mucus. Several scoring systems have been developed for grading
the laryngoscopic findings, the most common of which is the reflux finding score (RFS)
[88]. However, correlation between symptoms, laryngoscopic findings, and other objective
testing such as pH and pH-impedance monitoring, is low. In a systematic review evaluating
different reported signs of LPR and relevant clinical outcomes, 29 different LPR signs
and multiple scoring systems were evaluated. LPR signs on laryngoscopy were found to
have low specificity, with validation hampered by the lack of a gold standard for diagnosis
[89]. Inter-rater reliability for laryngeal findings was also found to be low for multiple
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laryngoscopic features attributed to LPR [90]. In one study of patients originally thought to
have LPR, a careful review of laryngoscopic findings by study investigators identified other
causes of the laryngeal complaints including cancer, muscle tension dysphonia, vocal cord
paresis, and benign mucosal lesions [91]. In one recent pediatric study, the laryngoscopic
RFS did not correlate with pH-impedance findings, the presence of erosive esophagitis, or
quality of life [92]. This lack of correlation between laryngoscopic findings and symptoms
also been documented in adults. In one study of 105 normal, asymptomatic volunteers, 86%
had findings associated with reflux on laryngoscopy, with some signs of LPR seen in 70% of
participants [93]. A second study of normal, asymptomatic volunteers found at least one sign
of inflammation in 93% of participants who underwent flexible laryngoscopy [94]. The use
of laryngoscopy for diagnosis of LPR has substantial limitations, with inflammation seen in
asymptomatic volunteers, low reproducibility, and lack of correlation between laryngoscopic
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findings and symptoms. While ENT physicians often treat LPR based on laryngoscopy
findings, a poor response to medical therapy should not be surprising.
Reflux testing—Multichannel pH-impedance testing, traditional catheter-based pH

testing, and wireless pH testing have been used to evaluate patients with extraesophageal
GERD symptoms. Reflux testing using pH-impedance can detect acidic (pH <4), weakly
acidic (pH 4-7), and nonacidic reflux (pH >7), and determine the extent of proximal

Katz et al. Page 17
reflux, which may be important in the evaluation of extra-esophageal GERD symptoms.

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pH-impedance testing in patients with LPR symptoms is abnormal in 40% of cases [95].
pH-Impedance monitoring has been used in several studies of patients with LPR symptoms,
and those with abnormal pH impedance results were found to be more likely to respond to
PPI treatment than patients with normal testing [96, 97]. Studies in which pH-impedance
monitoring was used to identify the relationship between reflux events and cough episodes
have shown that chronic cough can be associated with weakly acidic and nonacidic reflux
events [98, 99]. In a study of 21 patients with globus and 12 with heartburn alone who were
evaluated by pH-impedance testing performed on PPI therapy, proximal reflux was noted to
be more common in the globus patients [100]. Use of pH-impedance in this study increased
the yield of standard pH testing by 28%, and identified proximal esophageal reflux as a
significant predictor of globus.
Presently, the clinical significance of proximal reflux is unclear, and studies have varied in
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their criteria for defining this entity [101]. One study found that extraesophageal symptoms
were not more frequently associated with proximal esophageal reflux than typical GERD
symptoms and that, irrespective of symptoms, half of all reflux events extended to the
proximal esophagus [102]. In a study of 237 patients with extraesophageal symptoms
refractory to medical therapy, traditional reflux parameters were better predictors of
fundoplication outcome than impedance testing, with the presence of heartburn and acid
exposure times >12% increasing the probability of surgical success [103]. In a retrospective
study of 33 patients with refractory reflux symptoms (typical and atypical) evaluated by
pH-impedance monitoring on PPIs, only a positive SAP for heartburn or regurgitation was
associated with improvement after surgery [104]. In the absence of a clear definition of
‘normal’ proximal esophageal reflux, interpretation of impedance results for extraesophageal
GERD is problematic, and surgical outcomes appear to be predicted better by traditional
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reflux parameters.
The choice to test on or off PPI in patients with extraesophageal symptoms has no clear
answer. Testing off PPI can be used to determine whether pathologic esophageal acid
exposure is present and should be considered when the pre-test probability for GERD is
low. Testing on PPI can be considered in patients already known to have pathologic acid
exposure, such as those with Barrett’s esophagus or with LA C or D erosive esophagitis
[105]. One proposed model for determining which patients should undergo pH testing on
or off a PPI was developed using a population of 471 patients with refractory heartburn
or extraesophageal GERD [106]. Risk factors for abnormal esophageal acid exposure
in patients with suspected extraesophageal reflux included BMI >25, hiatal hernia, and
presence of heartburn. In patients with extraesophageal symptoms persistent after 2 months
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of BID PPI, the investigators suggest calculation of the Heartburn, Asthma, and BMI
Extraesophageal Reflux (HAs-BEER) score – 1 point each for BMI >25, asthma, and
heartburn, but no points for cough or hoarseness. pH impedance testing on PPI was
recommended for patients with a HAs-BEER score of 3, whereas testing off PPI was
recommended for those with scores ≤2. Other studies attempting to address the question
of testing on or off PPI have found that the total number of reflux episodes detected by
impedance is similar between testing on and off PPI [107, 108], while one study found that
patients were more likely to have a positive SAP off PPI [107].

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Wireless pH testing also has been used for evaluation of patients with extraesophageal
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symptoms. In one series of patients with extraesophageal GERD who had wireless pH
testing, 81% had abnormal acid exposure, typically mild to moderate reflux, and more often
in the upright position [109]. However, as wireless pH testing focuses on distal acid reflux
only, it is not a reliable index for laryngeal acid exposure. However, if normal over 96 hours
of testing, it provides evidence against acid reflux as a cause of symptoms.
Pharyngeal and Oropharyngeal Reflux Monitoring—Catheter-based pharyngeal pH

monitoring with dual sensor probes, and oropharyngeal pH monitoring have been proposed
as methods to better detect LPR compared to traditional pH monitoring and pH-impedance.
However, the reliability of pharyngeal pH measurement has been questioned, and proximal
sensor data may be unreliable due to placement issues [110-113]. Similar to pH-impedance
testing, the amount of proximal reflux considered abnormal varies by study [114-117].A
systematic review found no significant differences in dual-channel pH testing results
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between normal controls and patients with laryngeal symptoms [118].
Early studies of oropharyngeal pH testing were promising, and appeared to predict

success of antireflux surgery [119, 120]. However, subsequent studies have failed to
identify a significant correlation between oropharyngeal reflux events and pH-impedance
reflux events, suggesting that decreases in oropharyngeal pH may be due to factors
other than gastroesophageal reflux [121-125]. One study of adults with laryngeal
symptoms evaluated patients using the reflux symptom index, video laryngoscopy, and
oropharyngeal pH monitoring, followed by a PPI trial [126]. There were no significant
differences in oropharyngeal acid exposure between PPI responders, partial responders, and
nonresponders. Lack of correlation between oropharyngeal pH events and pH impedance
events was seen in another study of adults with suspected LPR - oropharyngeal pH test
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results were unable in distinguishing asymptomatic volunteers from patients with laryngeal
irritation [127].
Salivary pepsin testing—Salivary pepsin testing has been proposed as a non-invasive

method of detecting LPR. A recent meta-analysis of 11 observational studies examined
the role of salivary pepsin testing in diagnosing LPR [128]. Significant heterogeneity was
found, with varying reference standards for LPR diagnosis (pH monitoring, symptoms,
laryngoscopic signs), different pepsin assays, variable definitions of abnormal tests, and
number of pepsin tests performed. Another study found pooled sensitivity of pepsin testing
for LPR was 64% and specificity was 68%, with an AUC of 0.71 [129]. Another meta-
analysis of pepsin as a marker of LPR reached similar conclusions, and noted that control
patients often had elevated salivary pepsin levels [130]. Salivary pepsin levels also may
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vary by time of day, with higher levels in the morning, which limits interpretation [131]. A
study of children with GERD found no correlation between multichannel pH-impedance and
salivary pepsin testing results [129]. In a study of adults with laryngeal complaints, pepsin
was found in the saliva of 78% of those with laryngoscopic signs of laryngeal inflammation,
but in 47% of patients with normal laryngoscopy [130]. In another study, pepsin testing was
unable to distinguish between healthy adult volunteers and patients with extra-esophageal
reflux symptoms [132].

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PPIs and Extraesophageal Symptoms—A clinical response to PPI therapy has been
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proposed as a method to both diagnose and treat extra-esophageal GERD [133-135], and has
been evaluated in numerous observational studies and randomized controlled trials, with 4
meta-analyses and 1 systematic review compiling the results. The efficacy of PPIs in LPR
remains unclear, as two meta-analyses found no significant benefit of PPIs [136, 137], while
two found some benefit [138, 139]. In one recent meta-analysis of 10 RCTs of PPI treatment
for LPR, the pooled relative risk of improvement with any PPI treatment was 1.31, with
a stronger PPI effect seen in studies that excluded dietary management of LPR (RR 1.42)
[138]. Another meta-analysis found improved symptoms in LPR patients treated with PPI
compared to placebo, with improvements in symptom index, but not in the laryngoscopy
reflux finding score [139]. These analyses showed that the diagnostic criteria for LPR varied
substantially between studies, as did clinical outcomes, treatment regimens, and treatment
duration, making recommendations for use of PPI in LPR challenging [138, 140].
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While PPI treatment is often the first step in the management of LPR, this approach may
need to be reconsidered. One study comparing up-front reflux testing for LPR patients rather
than starting them on empiric PPI therapy found that overall evaluation and treatment costs
were lower with initial pH-impedance and esophageal manometry testing [141]. Also, a
comparison of several algorithms for managing LPR revealed that total costs of therapy were
lower in LPR patients treated with initial twice-daily PPI dosing rather than once-daily PPI
[141].
Recent studies have questioned the role of PPI therapy for patients with asthma. Two
randomized controlled trials, one in adults and one in children, showed no benefit in
controlling asthma symptoms in patients on twice-daily PPIs [83, 84]. One systematic
review on the role of PPIs in asthma found a small improvement in morning peak expiratory
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flow that was unlikely to be clinically meaningful [142]. One RCT did show improved
asthma symptoms in patients on twice-daily PPIs, but only in GERD patients with nocturnal
respiratory symptoms [143]. Chronic cough has also been attributed to GERD, but recent
studies and systematic reviews suggest that PPIs are not effective in treating chronic cough
in the majority of patients [144] [145-147].
Surgery—Antireflux surgery has been used to treat patients with extraesophageal

GERD symptoms, but outcomes are inferior to those of antireflux surgery for patients
with traditional GERD symptoms. Two systematic reviews (involving primarily studies
that were small, retrospective, and uncontrolled) have examined the relationship among
extraesophageal GERD symptoms, esophageal acid exposure, and surgical outcomes, [148,
149]. The range of reported improvement in extraesophageal symptoms was wide, ranging
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from 15% to 95%, with extraesophageal symptoms having poorer response to surgical
treatment than typical GERD symptoms.
In one study, patients for whom PPIs provided only incomplete relief of laryngeal symptoms
despite normalizing esophageal acid exposure were offered antireflux surgery. At one year,
only 10% of patients who underwent surgery and 7% of patients who continued medical
therapy for GERD had improvement in laryngeal symptoms. However, two-thirds of patients
who pursued non-surgical, non-GERD treatments for laryngeal symptoms had improved

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symptoms at 1 year [150]. This study illustrates the importance of pursuing non-GERD
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treatments for unexplained laryngeal symptoms.
Several observational studies and one randomized controlled trial have suggested that
antireflux surgery can improve asthma symptoms. In the one RCT, 74% of surgically-treated
patients (n=16) had improvement in asthma symptoms compared to 9% on H2RAs and 4.2%
in the control group [151]. Observational studies of antireflux surgery for asthma patients
suggest that asthma symptoms can improve, but improvement in pulmonary function
tests and objective parameters is inconsistent [151-153]. Furthermore, heterogeneity in
inclusion criteria and surgical techniques among studies make it difficult to draw meaningful
conclusions about the efficacy of antireflux surgery for treating asthma.
Predicting which patients with extraesophageal symptoms will improve with antireflux
surgery is challenging. In one study of patients with extraesophageal symptoms, predictors
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of symptomatic improvement after surgery included the presence of heartburn with or

without regurgitation, and abnormal acid exposure time on pH testing [103]. Recurrence of
extraesophageal symptoms after surgical therapy is also a concern. One retrospective cohort
study compared adults with extraesophageal GERD (n=36) and typical reflux symptoms
(n=79), all of whom had abnormal distal esophageal acid exposure. Recurrence of symptoms
after surgery was more likely in patients with extraesophageal symptoms and in those
who had a poor response to preoperative PPI therapy [154]. Patients with extraesophageal
symptoms that do not respond to PPI and patients without objective evidence of reflux
should avoid surgical or endoscopic treatment of GERD.
Refractory GERD
Recommendations
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1. We recommend optimization of PPI therapy as the first step in management of

refractory GERD. (Strong recommendation, moderate level of evidence)
2. We suggest esophageal pH monitoring (Bravo, catheter-based, or combined

impedance-pH monitoring) performed OFF PPIs if the diagnosis of GERD has
not been established by a prior pH monitoring study or an endoscopy showing
long-segment Barrett’s esophagus or severe reflux esophagitis (Los Angeles
grade C or D). (Conditional recommendation, low level of evidence)
3. We suggest esophageal impedance pH monitoring performed ON PPIs for

patients with an established diagnosis of GERD whose symptoms have not
responded adequately to twice-daily PPI therapy. (Conditional recommendation,
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low level of evidence)
4. For patients who have regurgitation as their primary PPI-refractory symptom

and who have had abnormal gastroesophageal reflux documented by objective
testing, we suggest consideration of anti-reflux surgery or TIF. (Conditional

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Key Concepts
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1. It is important to stop PPI therapy in patients whose off-therapy reflux testing is

negative, unless another indication for continuing PPI is present.
2. Esophageal manometry should be considered as part of the evaluation for

refractory GERD in patients with a normal endoscopy and pH monitoring study,
and for patients being considered for surgical or endoscopic treatment.
3. If not already performed off PPIs, we recommend diagnostic upper endoscopy

after discontinuing PPI therapy, ideally for two to four weeks. Esophageal
biopsies should be performed even if endoscopy reveals normal mucosa.
4. We recommend performing high-resolution esophageal manometry in patients

with refractory GERD if reflux monitoring and endoscopy are unrevealing.
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It has been suggested that up to 40% of patients treated with PPI will report persistent
symptoms of heartburn and regurgitation, with negative effects on quality of life [155-157].
One systematic review of GERD studies found that persistent GERD symptoms were
present in 32% of patients participating in primary care-based randomized trials of GERD
therapy, with 45% of patients in observational studies having persistent symptoms [156].
Although there is limited data evaluating the benefit of twice-daily PPIs for patients
with GERD symptoms refractory to once-daily PPIs [158], GERD generally has not been
considered “PPI-refractory” unless the patient has been on PPIs BID. The most commonly
accepted definition of refractory GERD is persistent heartburn and/or regurgitation despite
8 weeks of double-dose PPI therapy [159]. Other authorities consider persistent symptoms
after 12 weeks on double-dose PPI to be refractory GERD [160]. These patient-driven
definitions, while pragmatic, are broad. Similarly, the terms “complete relief/response”,
“partial relief/response”, and “no response” have been arbitrarily and poorly defined, and
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duration of symptoms and PPI dosing vary across studies [156, 161]. GERD is a disease
with multiple symptom presentations that respond variably to PPIs. Heartburn is more likely
to respond to PPIs than regurgitation or extraesophageal symptoms. As such, it is clinically
useful to separate refractory heartburn, regurgitation, and extraesophageal symptoms when
thinking about these patients. Table 4 lists four potential mechanisms of refractory GERD.
There are two broad groups of patients with symptoms despite PPI therapy. One group is
patients with symptoms suspected to be GERD-related who have been empirically treated
with a PPI (typically once- then increased to twice-daily) yet remain symptomatic. The
second group of patients have objective evidence of GERD, with endoscopic findings
of erosive esophagitis or Barrett’s esophagus and/or reflux testing showing abnormal
esophageal acid exposure, who have incomplete or no response to PPI. When discussing
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the overall approach to patients with GERD symptoms not relieved by PPIs, it is prudent to
discuss management of these two groups separately.
History and Physical Exam—The evaluation of refractory GERD should begin with
a careful history and physical examination. This will enable the clinician to make a
meaningful assessment of the likelihood that GERD is causing the bothersome symptoms
and may provide clues to the presence of non-esophageal disorders. If no obvious non-

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esophageal disorders are present, then optimization of PPI therapy is recommended. This is
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critical for managing patients with persistent GERD symptoms, regardless of whether the
patient has been empirically treated or carries an objective diagnosis of GERD.
Optimization of PPI Therapy—Optimization of PPI therapy includes verifying

compliance, confirming that the PPI is taken 30 to 60 minutes before the first meal of
the day for daily dosing and before the first and dinner meal for twice daily dosing
[162]. A study analyzing data from randomized trials in which gastric pH monitoring was
performed in patients receiving various PPI formulations concluded that twice-daily PPI
therapy is superior to once-daily double-dose PPI therapy in maintaining gastric pH above
4 during a 24-hour monitoring period [52]. We analyzed data from randomized clinical
trials that performed pH testing in patients receiving solid-dose PPI formulations. In one
study, patients with good symptom control took daily PPI on 84% of days, compared
to patients with poor symptom control, who took PPI on only 55% of days [163], with
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similar findings seen in other studies [80]. In a recent randomized, multicenter trial of
Veterans with heartburn refractory to PPI treatment, 42 of 366 (11.4%) participants had
≥50% improvement in GERD symptoms when omeprazole use was optimized, with dosing
30 minutes before breakfast and dinner[23]. Another study of nonerosive reflux disease
patients with typical GERD symptoms despite PPI use found that 35% responded to daily
esomeprazole when dosed correctly [164]. A smaller trial examined the effects of optimizing
daily omeprazole compared to ad lib dosing, and found improvement in symptoms and
GERD quality of life scores in those receiving education on proper dosing of daily PPI
[165]. Some studies have found that doubling the PPI dose or dosing twice daily can help
with persistent typical symptoms of GERD, as can switching to a different PPI [58, 166].
Regardless of dose, a small, but clinically significant number of patients will have symptom
improvement with the simple, low-cost intervention of optimizing PPI therapy.
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Endoscopy—Endoscopy is the next step to investigate persistent GERD symptoms and

evaluate alternative diagnoses. Performing endoscopy after a PPI holiday might increase
the yield for identifying erosive esophagitis or determine if an alternative diagnosis, such
as eosinophilic esophagitis, is responsible for symptoms. A recent study found that erosive
esophagitis can relapse within two weeks after stopping PPI, with some patients even
developing Los Angeles grade C erosive esophagitis [62]. Eosinophilic esophagitis has been
seen in 1-8% of patients with refractory GERD [23, 167-170]. Temporarily discontinuing
PPIs prior to endoscopy in these patients may unmask the eosinophilic esophagitis histology,
which could be obscured if endoscopy is performed on PPI, missing an opportunity to
identify the cause of ongoing GERD symptoms. In patients with persistent GERD symptoms
on PPIs, there is a low likelihood of finding reflux esophagitis if PPIs are not stopped prior
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to endoscopy [16, 171].
Reflux monitoring—Regardless of symptom presentation, it is imperative to document

the presence of abnormal or ongoing reflux in order to plan treatment options for patients
with persistent GERD symptoms. Reflux monitoring can identify patients with ongoing acid
reflux, weakly acidic, non-acidic reflux, adequate acid control but ongoing symptoms, and
normal reflux parameters. Depending on the clinical situation, performing monitoring off

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PPI for seven days or testing for acid, weakly acidic, and nonacid reflux while on PPI, can
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be considered.
The choice of test and whether to test on or off PPI is dependent on the question being
asked. If the patient has been empirically treated (never had an objective diagnosis of
GERD), or the clinician believes the likelihood that reflux is the cause of symptoms is low,
or for patients considering surgery, an off-therapy study should be considered [16, 159]. A
recent study investigated the utility of 96 hour capsule based pH monitoring off PPI therapy
in patients with persistent typical symptoms despite PPI treatment to determine if PPIs could
be stopped. Patients with two or more days with esophageal acid exposure time >4 percent
were unlikely to be able to stop PPIs. Those with a normal study on all four days were the
group with the highest likelihood of being able to discontinue PPIs [172].
On-therapy monitoring is suggested prior to surgery or endoscopic intervention in patients

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with previous objective findings of GERD (such as Barrett’s esophagus or Los Angeles
grade C/D erosive esophagitis) who have continued symptoms despite PPI treatment [16].
Although retrospective studies suggest that patients with GERD symptoms unresponsive to
PPIs who are proven to have GERD by off-therapy pH monitoring can respond to surgery
[107], and some interventionalists endorse antireflux procedures based on off-therapy pH
monitoring for such patients [173], the documentation of persistent abnormal acid reflux on
PPIs or of a positive association between symptoms and reflux episodes offers “reassurance”
that surgery or endoscopic therapy can be successful in the PPI-refractory patient.
Several studies have attempted to address the question of testing on or off PPI in patients
with persistent GERD. The total number of reflux episodes detected by impedance is similar
between testing on and off PPI [107, 174, 175]. Other studies have used reflux testing
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to guide therapy for patients with refractory GERD symptoms. Reflux testing combined
with other testing, such as esophageal manometry, gastric emptying studies, and endoscopy,
identified a diagnosis of GERD in only 34.5% of cases in one study [176]. In a multicenter
study, only 21% of patients with persistent heartburn on PPIs were found to have truly
refractory GERD [23]. Overall, the balance of data suggests that few patients with refractory
GERD symptoms on PPIs have continued reflux as the cause for symptoms, suggesting
value for a tailored approach using impedance-pH monitoring prior to intervention [23].
For on-therapy reflux monitoring, we recommend that PPIs be taken twice-daily, the
approach used in the randomized trial of medical vs surgical therapy for PPI-refractory
reflux disease [23]. Furthermore, impedance-pH monitoring rather than pH monitoring alone
is recommended for on-therapy reflux monitoring, both because the yield of pH monitoring
in this setting is so low (fewer than 10% of patients on twice-daily PPIs have persistently
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abnormal acid reflux [160]) and because impedance monitoring enables correlation between
symptoms and non-acid reflux episodes. It is important to stop PPI therapy in patients whose
off-therapy reflux testing is negative, unless a previous diagnosis of GERD had been made
or another indication for continuing PPI is present. In one study, 42% of patients reported
continuing PPI treatment after a negative evaluation for refractory GERD, which included
negative endoscopy and pH impedance monitoring [177].

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Esophageal Manometry—Some patients with motility disorders such as achalasia or

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esophageal spasm will report heartburn symptoms. In studies of patients with refractory
GERD, 1-3% of patients are found to have achalasia when manometry is performed [23,
178]. Patients with esophageal aperistalsis are identified in roughly 3% of manometry tests
performed for evaluation of GERD [178]. These patients often report heartburn symptoms
and have a poor response to antireflux surgery. Other disorders, such as rumination and
supragastric belching, may also detected by esophageal manometry.
Surgery—Recent publications have changed the thought process on surgical intervention

for some patients with refractory GERD. Randomized trials compared magnetic sphincter
augmentation to continued medical therapy in patients with regurgitation refractory to PPIs.
MSA improved symptoms more than continued medical therapy in patients with objective
documentation of abnormal reflux [179, 180]. Two randomized trials with transoral
incisionless fundoplication (TIF) also demonstrate better improvement in regurgitation with
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TIF compared to high dose PPI, though the magnitude of improvement was not as great
as with MSA [181]. A recent study illustrates the challenge of managing refractory GERD.
In this study of medical versus surgical treatment for 366 patients with heartburn that
failed to respond to PPIs, extensive evaluation revealed that heartburn symptoms were truly
PPI-refractory and reflux-related in only 78 patients (21%) [23].
Identifying patients with true refractory GERD is crucial as surgery (or endoscopic
treatment) may truly be best in this group. For patients with regurgitation refractory to
PPI therapy, care should be taken to distinguish regurgitation from rumination, a functional
disorder characterized by effortless food regurgitation during or soon after eating, typically
with rechewing, reswallowing, or spitting out of the regurgitated material. Surgical treatment
is not recommended for patients with rumination [182]. A detailed discussion of the
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management of functional heartburn and other functional upper gastrointestinal symptoms

exceeds the scope of this guideline.
Surgical and Endoscopic Options for GERD

Recommendations
1. We recommend antireflux surgery performed by an experienced surgeon as an
option for long-term treatment of patients with objective evidence of GERD,
especially those who have severe reflux esophagitis (LA grades C or D),
large hiatal hernias, and/or persistent, troublesome GERD symptoms. (Strong
recommendation, moderate level of evidence)
2. We recommend consideration of magnetic sphincter augmentation (MSA) as an

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alternative to laparoscopic fundoplication for patients with regurgitation who fail

medical management. (Strong recommendation, moderate level of evidence)
3. We suggest consideration of Roux-en-Y gastric bypass (RYGB) as an option to

treat GERD in obese patients who are candidates for this procedure and who are
willing to accept its risks and requirements for lifestyle alterations. (Conditional

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4. Since data on the efficacy of radiofrequency energy (Stretta) as an antireflux

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procedure is inconsistent and highly variable, we cannot recommend its use

as an alternative to medical or surgical antireflux therapies. (Conditional
5. We suggest consideration of transoral incisionless fundoplication (TIF) for

patients with troublesome regurgitation or heartburn who do not wish to undergo
antireflux surgery and who do not have severe reflux esophagitis (Los Angeles
grades C or D) or hiatal hernias >2 cm. (Conditional recommendation, low level
of evidence)
Key Concepts
1. We recommend high resolution manometry prior to antireflux surgery or
endoscopic therapy to rule out achalasia and absent contractility. For patients
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with ineffective esophageal motility, high resolution manometry should include

provocative testing to identify contractile reserve (e.g. multiple rapid swallows).
2. Prior to performing invasive therapy for GERD, a careful evaluation is required

to ensure that GERD is present and as best as possible determine is the cause
of the symptoms to be addressed by the therapy, to exclude achalasia (which
can be associated with symptoms such as heartburn and regurgitation that can be
confused with GERD), and to exclude conditions that might be contraindications
to invasive treatment such as absent contractility.
In the majority of patients, the symptoms and endoscopic signs of GERD resolve readily
with medical treatment, and invasive antireflux therapies are neither required nor desired by
patients. However, GERD is a chronic disease, and patients often require protracted medical
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treatment, which is inconvenient and carries some risk. Severe reflux esophagitis (LA grades
C and D) does not heal reliably with any medical therapy other than PPIs, and studies
have demonstrated that severe erosive esophagitis returns quickly in the large majority of
patients when PPIs are stopped [17, 183, 184]. It might be possible to reduce or even
eliminate medical therapy for patients with mild forms of GERD (e.g. no reflux esophagitis
worse than Los Angeles grade B), but patients with severe reflux esophagitis (Los Angeles
grades C or D) will require PPI therapy indefinitely to maintain healing. In light of recent
concerns regarding the safety of long-term PPI usage, many patients are uncomfortable
with the prospect of lifelong PPI treatment. Although antireflux procedures have their own
well-established risks, some of which are serious, there are a number of patients who prefer
to opt for those over the putative risks and inconvenience of lifelong PPI therapy.
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GERD that fails to respond to medical therapy is another valid indication for antireflux
procedures, but one that requires meticulous pre-procedure evaluation to achieve good
surgical outcomes. Prior to the advent of PPIs, failure to respond to medical therapy was
the major indication for antireflux surgery. Today, however, PPI therapy is so effective for
treating typical GERD symptoms like heartburn and regurgitation that failure to respond
to PPIs should be regarded as a red flag that GERD may not be the underlying cause.
Indeed, patients who have the best response to antireflux surgery are those with typical
GERD symptoms who respond well to PPIs [185, 186], presumably because these patients

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clearly have abnormal gastroesophageal reflux, and antireflux surgery is highly effective
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at controlling that problem. Although it is claimed that 30% to 40% of patients treated
with PPIs for GERD have persistent “GERD symptoms” [187, 188], in many cases those
PPI-resistant symptoms are mistakenly assumed to be caused by reflux. Symptoms that are
not reflux-related will not respond to antireflux procedures, yet these procedures often have
been used (and failed) in patients who had little or no objective evidence of underlying
GERD. It is critical to establish that “refractory GERD symptoms” are indeed reflux-related
before recommending invasive antireflux treatment.
In a recent study of medical versus surgical treatment for PPI-refractory heartburn that
included 366 patients referred to GI clinics because of heartburn that failed to respond
to PPIs, extensive work-up revealed that the heartburn was truly PPI-refractory and reflux-
related in only 78 patients (21%) [23]. Among the other 288 patients, heartburn was
relieved in 42 (12%) when they were given a trial of twice-daily omeprazole with explicit
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instructions on how to take the medication properly, 70 (19%) were unwilling or unable
to complete the rigorous preoperative work-up required for trial entry, 54 (15%) were
excluded for miscellaneous reasons, 23 (6%) had non-GERD esophageal disorders such as
eosinophilic esophagitis and achalasia, and 99 (27%) had functional heartburn. For the 78
patients in whom rigorous work-up established that the PPI-refractory heartburn was indeed
reflux-related, treatment success (≥50% improvement in GERD Health-Related Quality of
Life symptom scores at one year) for laparoscopic Nissen fundoplication (18/27, 66.7%)
was significantly superior to active medical (7/25, 28.0%, p=.007) and placebo medical
(3/26, 11.5%, p<0.001) treatments.
Even though heartburn is the cardinal symptom of GERD, the aforementioned study
shows that PPI-refractory heartburn is uncommonly due to GERD. As discussed above
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establishing a clear causal relationship with GERD can be even more difficult for so-called
“extraesophageal GERD symptoms” such as throat clearing, hoarseness, and chronic cough.
Surgical treatment of extraesophageal GERD is reviewed in detail in the ‘extraesophageal
GERD section’. Few high-quality data have established the benefit of invasive treatments
for patients with these extraesophageal GERD symptoms, and physicians should be extra
cautious in recommending such treatments for patients with laryngopharyngeal reflux and
other “extraesophageal GERD symptoms. Only persistent abnormal acid reflux and reflux
hypersensitivity are likely to benefit from antireflux procedures.
Fundoplication—Fundoplication, especially Nissen fundoplication, is widely regarded

as the “gold-standard” among the antireflux procedures for its efficacy in improving the
physiologic parameters of GERD such as LES pressure and esophageal acid exposure time
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[189]. Fundoplication creates a barrier to the reflux of all gastric material (acidic and
non-acidic), and therefore should be an effective treatment for any GERD symptom that is
reflux related.
Interest in surgical antireflux therapy intensified in the 1980s when observational studies
described >90% efficacy for fundoplication in controlling GERD symptoms over a 10-
year period [190]. Interest in fundoplication was further fueled by a randomized trial
conducted by the VA in the late 1980s (when antireflux surgery was performed as an open

Katz et al. Page 27
procedure and before PPIs were available) which found that open Nissen fundoplication was
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significantly more effective than ranitidine-based medical therapy in healing the symptoms
and endoscopic signs of complicated GERD for the two-year duration of the study [191].
However, a long-term follow-up investigation published in 2001 showed that after 10 to
13 years, 23 (62%) of 37 surgical patients for whom follow-up was available reported that
they were once again taking antireflux medications on a regular basis to treat their GERD
symptoms, and surgically-treated patients had decreased long-term survival due largely to
excess deaths from heart disease [192]. This report and other developments resulted in a
long decline in the use of operative treatment for GERD.
Laparoscopic antireflux surgery (LARS) was introduced in 1991, and this has since
become the standard operative approach to fundoplication, essentially replacing open
antireflux surgery. Studies focusing on the durability of modern surgical technique have
found a wide range of GERD recurrence rates. Cohort studies often found high rates of
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postoperative antireflux medication usage (up to 43%) [193-197], while several randomized
trials of LARS vs. medical therapy conducted at specialized centers described lower GERD
recurrence rates (10%-27% during follow-up periods of 3 to 5 years) [198-200].
A recent systematic review and meta-analysis focusing on patient-relevant outcomes of

fundoplication versus PPI-based medical management of GERD found that heartburn
and regurgitation were less frequent with surgical than with medical therapy and,
although a considerable proportion of patients still needed antireflux medications after
fundoplication, surgical patients were significantly more satisfied with their treatment in
the short and medium term [201]. However, a more recent Cochrane review concluded
that there is considerable uncertainty in the balance of benefits versus harms of
laparoscopic fundoplication compared to long term PPI therapy, and called for further
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randomized, controlled trials [202]. Compared to Nissen (complete) fundoplication, partial

fundoplications (e.g. Toupet, Dor) appear to have similar efficacy in relieving GERD
symptoms, but result in less postoperative dysphagia, gas-bloat, and inability to belch and
vomit [203-206]. However, partial fundoplication also might have a higher rate of recurrent
GERD [206].
A recent report of a retrospective, population-based cohort study has shed considerable light
on the outcome of LARS performed in a “real-world” setting [207]. The study involved
2,655 patients identified in the Swedish Patient Registry as having had primary LARS
performed between 2005 and 2014. During a mean follow-up period of 5.1 years, 470
patients (17.7%) had a reflux recurrence (i.e., 393 used PPIs/H2RAs for >6 months, 77 had
repeat antireflux surgery). Within 30 days of surgery, 109 patients (4.1%) had complications
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such as infection, bleeding, and esophageal perforation, and there were only 2 deaths
(0.1%), neither of which was directly related to the operation. Postoperative dysphagia was
documented in 21 patients (0.8%), including 14 (0.5%) who required endoscopic dilatation.
This report suggests that LARS can be performed with a relatively low rate of morbidity,
and with a very low mortality rate, considerably lower than that of the old open antireflux
surgery. The study did not assess patient reported outcomes or the use of over-the-counter
medications, and it is well known that LARS occasionally can have catastrophic short- and
long-term complications. Nevertheless, it appears to be well tolerated in the large majority

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of cases, and the observation that >80% of patients did not resume the use of antireflux
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medications suggests that the operation provides long-lasting relief of GERD symptoms for
most patients. How patients and physicians view the 17.7% recurrence rate is a matter of
personal perspective.
In summary, modern medical antireflux therapy and laparoscopic fundoplication appear

to have similar efficacy in healing the symptoms and endoscopic signs of GERD. Recent
concerns about the safety of long-term PPI therapy and refinements in surgical technique
that have substantially decreased its morbidity and mortality have rekindled interest in
fundoplication. Clearly, antireflux surgery is not a permanent cure for GERD in all patients
as it was once touted to be, and the operation occasionally can have severe adverse effects.
Nevertheless, most patients obtain long-term benefit from fundoplication, and patient
satisfaction with successful surgery appears to be greater than that for chronic medical
therapy. The major question for patients considering antireflux surgery is this: Does the
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>80% possibility of long-term freedom from PPIs and their attendant risks warrant the 4%
risk of acute complications of fundoplication and its 17.7% risk of GERD recurrence? [208]
Magnetic sphincter augmentation—Magnetic sphincter augmentation (MSA) with the

LINX® Reflux Management System, a necklace of titanium beads with magnetic cores that
encircles the distal esophagus to bolster the LES and prevent reflux, was developed as a
less invasive and more readily reversible GERD treatment than fundoplication. The initial
target population for MSA was GERD patients with abnormal acid reflux documented by
esophageal pH monitoring (off PPIs) who experienced only partial relief with PPIs, and
who did not have large hiatal hernias or severe reflux esophagitis [209]. For 100 such
patients in an early pilot study with no control group, 92% achieved ≥50% improvement in
quality-of-life scores, 93% reduced their PPI usage by ≥50%, and 64% had ≥50% reduction
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in esophageal acid exposure at one year [209]. Dysphagia was the most frequent adverse
event, experienced by 68% of patients in the postoperative period, by 11% at one year, and
by 4% at three years. Six patients had serious adverse events, and six eventually had the
device removed. In a 5-year follow-up of patients in this study, there were no device erosions
or migrations, 85% of patients had discontinued their use of PPIs, and all patients reported
the ability to belch and vomit [210].
Although large hiatal hernias and severe reflux esophagitis were contraindications to MSA
in early studies of the technique, subsequent studies have found that the short-term clinical
outcomes of MSA for patients with those conditions are similar to those described for
patients with less severe forms of GERD [211-213]. Unlike the minimal surgical dissection
required for implantation of the device in patients with small hiatal hernias, however,
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patients with large hiatal hernias require a more extensive dissection and repair of the crural
diaphragm.
One problem with implantation of the metallic MSA device is that patients cannot have
MRI with scanning systems >1.5 Tesla. An early concern regarding MSA was that the
device would erode into the esophagus. A recent study of data provided by the manufacturer
(Torax Medical, Inc.) and the MAUDE database on 9,453 devices placed between 2007 and
2017 found that the risk of erosion was 0.3% at 4 years [214]. The median time to erosion

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was 26 months, and most occurred between 1 to 4 years after device implantation. Most
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of the eroded devices were removed by a combination of endoscopy and laparoscopy, and
there were no serious complications of device removal. Thus, device erosion appears to be
infrequent and safely managed.
To date, there has been no publication of a randomized trial directly comparing MSA with
the gold-standard surgical treatment of laparoscopic fundoplication. However, observational
cohort studies have compared the techniques, and systematic reviews and meta-analyses
of those reports have arrived at generally similar conclusions [215-218]. Compared to
fundoplication, MSA has shorter operative times and shorter durations of hospital stays.
There appear to be no significant differences between MSA and fundoplication in rates of
GERD symptom control, postoperative PPI usage, major complications including dysphagia,
and rates of reoperation. Most, but not all reports suggest that MSA results in less gas-bloat
and greater ability to belch and vomit than fundoplication.
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A recent randomized trial has established the unequivocal superiority of MSA over twice-
daily PPIs for the control of regurgitation [180]. In this study, 152 patients with moderate
to severe regurgitation despite once-daily PPI therapy were randomly assigned to receive
twice-daily PPIs (n = 102) or MSA (n = 50), and MSA was offered to patients in the
twice-daily PPI group who had persistent regurgitation after 6 months of treatment. At one
year, control of regurgitation was achieved in 72 of 75 patients (96%) in the MSA group,
but in only 8 of 43 patients treated with PPIs (19%). MSA was not associated with any
peri-operative events, device explants, erosions, or migrations.
MSA also appears to have a role in the treatment of GERD that worsens or develops after
bariatric operations such as sleeve gastrectomy and Roux-en-Y gastric bypass [219]. These
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operations alter gastric anatomy in a way that can preclude performance of a standard
fundoplication. Limited data suggest that MSA is safe and effective for treating GERD in
this setting.
In summary, MSA appears to be a safe and effective alternative to laparoscopic

fundoplication. Clinical outcomes of the two procedures are similar, and both have unique
advantages and disadvantages. The minimal surgical dissection required for MSA results in
greater technical ease, shorter operative times, and shorter durations of hospital stays than
for fundoplication. MSA is also easier to reverse, and MSA may result in less gas-bloat
and greater ability to belch and vomit than fundoplication. The MRI restriction after MSA
is a disadvantage and, compared to fundoplication, there is a paucity of long-term data on
MSA outcomes. With no randomized trials comparing the two procedures, it is difficult to
recommend one over the other at this time.
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Roux-en-Y gastric bypass—GERD is strongly associated with obesity. Compared to

individuals with a normal body mass index (BMI), the prevalence of GERD in those whose
BMI exceeds 35 is increased up to six-fold [220]. Obesity poses technical challenges
to the performance of fundoplication surgery. In addition, the elevated intra-abdominal
pressure associated with obesity might put strain on the diaphragmatic hiatus, resulting
in fundoplication disruption and herniation, increased surgical complications, and poor

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outcomes. Roux-en-Y gastric bypass (RYGB) can control GERD in obese patients,
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presumably because the small gastric pouch fashioned during RYGB produces far less acid
than an intact stomach, and because the accompanying long alimentary loop prevents the
reflux of bile. Due to the widespread perception among surgeons that fundoplication has
poor outcomes in obese patients, and the fact that RYGB has been shown both to control
reflux and induce weight loss, RYGB has come to be considered the antireflux surgery of
choice for obese patients, in whom it is used both as a primary antireflux procedure and
as a means for correction of a failed fundoplication [221, 222]. However, there is now
considerable controversy regarding the role of RYGB as an antireflux procedure.
One reason for the controversy is the substantial variability in results of studies on
outcomes and rates of complications for fundoplication in obese patients. Some studies have
documented poorer results of fundoplication in the obese [223], while others have found
no differences in complications and outcomes between obese and non-obese patients [224].
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A recent systematic review and meta-analysis on this issue found no significant differences
between obese and non-obese patients in the rates of perioperative complications, redo
surgery, and conversion from laparoscopic to open surgery, but the recurrence of reflux
after fundoplication was significantly lower in the non-obese patients (OR 0.28, 95% CI
0.13-0.61, p=0.001) [225]. Other reasons for controversy on the role of RYGB include
the lack of randomized trials comparing it directly with fundoplication, and the fact that,
although RYGB can have numerous beneficial effects, it is a technically difficult operation
that produces major alterations in anatomy, which can result in serious early and late
complications [226]. In addition, a recent, nationwide cohort study of all adults with
preoperative reflux who underwent gastric bypass in Sweden between 2006 and 2015 found
that, in 2,454 participants followed for median 4.6 years, reflux recurred in 48.8% (95% CI
46.8-51.0) within 2 years of the operation [227]. The authors concluded that the efficacy of
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gastric bypass for GERD symptoms might have been overestimated. Finally, reports have
documented the occasional new development of GERD after RYGB [219].
With all the above-noted uncertainty, an argument can be made to regard RYGB primarily
as a highly effective weight loss operation that has the added potential benefit of controlling
acid reflux, rather than as an antireflux operation primarily. Obese patients with GERD
should be adequately counseled and willing to accept the risks and lifestyle demands of
bariatric surgery before undergoing RYGB for control of GERD.
Endoscopic antireflux therapies—A number of endoscopic devices for treating GERD

have been introduced over the past two decades, and most have been withdrawn from
the marketplace because of concerns regarding safety and efficacy. Presently, the only
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endoscopic GERD treatments still widely available are radiofrequency antireflux treatment
(Stretta, Restech corporation, Houston Texas) and transoral incisionless fundoplication
(TIF, endogastric solutions). Studies of the endoscopic procedures generally have excluded
patients with hiatal hernias >2 cm, grade C and D erosive esophagitis, esophageal strictures,
and long-segment Barrett’s esophagus. Consequently, if these devices are to be used at all,
based on data their use should be limited to patients with milder forms of GERD.

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The Stretta procedure is difficult to evaluate, in part because it is not totally clear how it
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functions as an antireflux therapy. Initially, it was thought to control reflux by inducing

swelling and mechanical alteration at the esophagogastric junction. However, an early,
sham-controlled trial found that, 6 months after treatment, Stretta had significantly improved
gastroesophageal reflux disease symptoms and quality of life, but it did not decrease
esophageal acid exposure [228]. This raised the possibility that the procedure might alleviate
GERD symptoms by altering sensation in the distal esophagus. Systematic reviews and
meta-analyses have arrived at contradictory conclusions regarding Stretta’s efficacy. One
meta-analysis that evaluated only randomized controlled trials found that Stretta did not
produce significant changes in esophageal acid exposure, quality of life, or the ability to
stop PPIs [229], while another meta-analysis that included both controlled and cohort studies
concluded that Stretta significantly reduced esophageal acid exposure, improved quality
of life, and decreased PPI usage [230]. Nevertheless, in 2013, the Society of American
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Gastrointestinal and Endoscopic Surgeons (SAGES) gave Stretta a strong recommendation

for use in patients who refuse laparoscopic Nissen fundoplication [231].
TIF attempts to create a flap valve involving 180° to 270° of the circumference of the
esophagogastric junction by plicating a portion of the proximal stomach using a series of
T-fasteners. Randomized trials have shown that TIF is effective for treating troublesome
regurgitation [181, 232], but the long-term benefit of TIF is not established and questionable
[218]. One recent systematic review and meta-analysis on the use of TIF for refractory
GERD found that TIF resulted in significant improvements in GERD health-related quality
of life and DeMeester scores, enabling 89% of patients to discontinue PPIs [233]. However,
another systematic review and meta-analysis on the use of TIF for the treatment of GERD
found that although symptoms responded to TIF significantly more often that to PPIs/sham,
TIF did not result in significant improvement in esophageal acid exposure and most patients
Author Manuscript
resumed PPIs at reduced dosages during long-term follow-up. The incidence of serious
adverse events (perforation and bleeding) was 2.4%, and the rate of total satisfaction with
TIF was 69% by 6 months [234].
Long-Term PPI Issues

1. Regarding the safety of long-term PPI usage for GERD, we suggest that
patients should be advised as follows: “Proton pump inhibitors (PPIs) are the
most effective medical treatment for gastroesophageal reflux disease (GERD).
Some medical studies have identified an association between the long-term
use of PPIs and the development of numerous adverse conditions including
intestinal infections, pneumonia, stomach cancer, osteoporosis related bone
Author Manuscript
fractures, chronic kidney disease, deficiencies of certain vitamins and minerals,

heart attacks, strokes, dementia and early death. Those studies have flaws, are
not considered definitive, and do not establish a cause-and-effect relationship
between PPIs and the adverse conditions. High-quality studies have found that
PPIs do not significantly increase the risk for any of these conditions except
intestinal infections. Nevertheless, we cannot exclude the possibility that PPIs
might confer a small increase in the risk of developing these adverse conditions.

Katz et al. Page 32
For the treatment of GERD, gastroenterologists generally agree that the well-
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established benefits of PPIs far outweigh their theoretical risks.”
2. Switching PPIs can be considered for patients who experience minor side
PPI effects including headache, abdominal pain, nausea, vomiting, diarrhea,
constipation and flatulence.
3. For GERD patients on PPIs who have no other risk factors for bone disease, we
do not recommend that they raise their intake of calcium or vitamin D, or that
they have routine monitoring of bone mineral density.
4. For GERD patients on PPIs who have no other risk factors for vitamin B12
deficiency, we do not recommend that they raise their intake of vitamin B12, or
that they have routine monitoring of serum B12 levels.
5. For GERD patients on PPIs who have no other risk factors for kidney disease, we
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do not recommend that they have routine monitoring of serum creatinine levels.
6. For GERD patients on clopidogrel who have Los Angeles grade C or D

esophagitis or whose GERD symptoms are not adequately controlled with
alternative medical therapies, the highest quality data available suggest that
the established benefits of PPI treatment outweigh their proposed but highly
questionable cardiovascular risks.
7. PPIs can be used to treat GERD in patients with renal insufficiency with close
monitoring of renal function or consultation with a nephrologist.
PPIs are widely considered the mainstay of medical treatment for GERD. Side effects of
PPIs that have been identified in clinical trials and listed on FDA labels as the “most
common adverse reactions” include headache, abdominal pain, nausea, vomiting, diarrhea,
Author Manuscript
constipation, and flatulence. These relatively minor side effects occur infrequently and
abate when the medications are stopped. Limited data also suggest that these side effects
sometimes can be PPI preparation-specific and, for patients who experience them, a trial
of switching from one PPI to another is a reasonable management strategy [235]. Of far
more concern to patients and physicians alike are the growing number of serious putative
adverse effects of chronic PPI therapy that have been identified predominantly through weak
associations found in observational studies [236, 237].
Table 5 lists the major putative adverse effects of chronic PPI therapy and the proposed
underlying mechanisms. Some of these effects are assumed to be a consequence of PPI-
induced suppression of gastric acid secretion. For example, gastric acid suppression can
enable ingested pathogens that ordinarily would have been destroyed by gastric acid to
Author Manuscript
survive and cause enteric infections, or to be aspirated and cause pneumonia [237]. Reduced
gastric acidity can impair the uptake of certain vitamins (e.g. B12) and minerals (e.g.
calcium) and can elevate serum levels of gastrin, a growth factor with pro-proliferative
effects that might predispose to carcinogenesis [237]. Mechanisms other than gastric acid
inhibition have been proposed to underlie a number of other adverse effects that have been
associated with PPI usage such as kidney disease and cardiovascular events (Table 5).

Katz et al. Page 33
One area of considerable persistent controversy relates to the association between chronic
Author Manuscript
PPI use and hypomagnesemia. Two meta-analyses on this issue concluded that long-term
PPI use is significantly associated with hypomagnesemia [238, 239], while another two
concluded that the risk of PPI-induced hypomagnesemia was unclear because of significant
heterogeneity among studies [240, 241]. A recent AGA Best Practice Recommendation
concluded that long-term PPI users should not routinely screen or monitor serum
magnesium levels [242], whereas the FDA suggests that health care providers should
consider monitoring magnesium levels prior to initiation of PPI treatment and then
periodically (http://www.fda.gov/Drugs/DrugSafety/ucm245011.htm). We feel that presently
there is insufficient data to make a meaningful recommendation regarding the need for
monitoring of magnesium levels in patients on chronic PPI therapy.
It is important to appreciate that the mere identification of an association between

PPIs and adverse conditions in observational studies cannot establish a cause-and-effect
Author Manuscript
relationship, and that such studies are highly susceptible to biases that can prejudice results.
Observational studies on potential PPI side effects are especially susceptible to the biases
of confounding by indication (in which the medical indication for a PPI, not the PPI itself,
is responsible for the adverse effect) and protopathic bias (in which the PPI does not
cause an adverse condition, but is prescribed to treat symptoms of that already-present yet
unrecognized condition) [243, 244].
The epidemiologist/statistician Sir Austin Bradford Hill, in his Presidential Address to the
Section of Occupational Medicine of the Royal Society of Medicine in 1965, proposed
9 criteria that can strengthen the case for a cause-and-effect relationship in associations
between exposures and diseases identified through observational studies [245]. These so-
called Bradford-Hill criteria include 1) Strength of the association, 2) Consistency of the
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observation, 3) Specificity of the exposure for the disease, 4) Temporality (i.e. exposure
preceded disease), 5) Biological gradient (dose response), 6) Plausibility of the proposed
mechanism for how the exposure might cause disease, 7) Coherence among epidemiologic
and other types of data, 8) Experimental data support a cause-and-effect relationship, and
9) Analogy with the effects of similar types of exposures. In 2017, Vaezi and colleagues
reported that no proposed PPI adverse effect fulfilled all 9 of the Bradford-Hill criteria, and
most fulfilled fewer than 4 [246].
It has been noted that most reported associations in observational clinical research are
spurious, and the minority that are real are often exaggerated [247]. Experts caution that
weak associations found in such studies are more likely to result from bias than from
cause-and-effect relationships and, unless relative risks (RRs) in cohort studies exceed 2-3
Author Manuscript
or odds ratios (ORs) in case-control studies exceed 3-4, the findings generally should not
be considered credible [247]. Reports of observational studies that have identified potential
PPI side effects typically have described weak associations with RRs or ORs <2 [248].
Furthermore, even strong associations in such studies do not establish cause-and-effect
relationships. For example, some observational studies have found a strong association (ORs
>4) between PPI usage and esophageal adenocarcinoma, an association that is likely due to
confounding by indication (i.e., PPIs were prescribed to treat GERD, which was the real
risk factor for the cancer that subsequently developed) [249]. Observational studies also

Katz et al. Page 34
have found a strong association between PPI usage and development of community-acquired
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pneumonia, an association that may well have been the result of protopathic bias (i.e., PPIs
were prescribed for symptoms of cough and chest discomfort that were mistakenly attributed
to GERD but in fact were caused by an unrecognized, early pneumonia) [250].
A recent, large, placebo-controlled randomized trial reported by Moayyedi et al. has shed
considerable light on the issue of PPI safety [251]. In this exceptionally high-quality study,
17,598 patients aged 65 years or older with stable cardiovascular or peripheral artery
disease treated with rivaroxaban and/or aspirin were randomly assigned to receive the
PPI pantoprazole (40 mg daily, n-8,791) or placebo (n=8,807). Following randomization,
data were collected at 6-month intervals over a period of 3 years specifically with
the intent of identifying potential PPI side effects including pneumonia, C. difficile
infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease,
dementia, cardiovascular disease, cancer, and all-cause mortality. The investigators found
Author Manuscript
no significant differences between the PPI and placebo groups in rates of occurrence for
any of those potential side effects except for enteric infections (1.4% vs 1.0% in the PPI
and placebo groups, respectively; OR 1.33; 95% confidence interval 1.01-1.75). Table 5 lists
the hazard ratios (HRs) and ORs for all the putative adverse events evaluated in this study.
The authors concluded that the use of pantoprazole for 3 years was not associated with any
adverse event other than a modestly increased risk of developing enteric infections.
Moayyedi’s report provides high-quality evidence to suggest that most of the associations
between PPI usage and adverse events that have been identified in observational studies
were the result of residual confounding and other biases, and unlikely to represent cause-
and-effect relationships. Reassuring as this study is, it is important to consider several
caveats. First, the trial had a maximum follow-up of five years, which might not be sufficient
Author Manuscript
time for some adverse events to develop (e.g., gastric cancer) [252]. Next, despite the large
size of the study, some adverse events (e.g. gastric atrophy, C. difficile-associated diarrhea)
occurred so infrequently that conclusions regarding possible PPI involvement are limited.
Finally, and perhaps most important, the 95% confidence intervals around some of the
HRs and ORs observed in this prospective trial, large as it is, still are relatively wide. It
is reassuring that the HRs and ORs for some events (pneumonia, fracture, cardiovascular
disease, dementia, and all-cause mortality) are even lower than the lower limits of the 95%
confidence intervals reported in earlier observational studies. Nevertheless, this study cannot
exclude the possibility that PPIs confer a modest risk for any of these adverse events (i.e.,
the upper limit of the 95% confidence intervals all are >1), and even a modest risk for such
serious events is cause for concern. As the authors themselves acknowledge, the possibility
that PPIs confer a modest risk for these putative adverse events can never be excluded no
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matter how large the study sample size [251].
Summary
We have made every effort to review and grade all available evidence to develop this
guideline. Much is new and different compared to the 2013 guideline, particularly as
it relates to approaching extraesophageal symptoms, refractory GERD, and surgical and
endoscopic therapies. Each section provides a separate review of the evidence supporting

Katz et al. Page 35
our recommendations, therefore some repetition was necessary to do this effectively.

Author Manuscript
Our algorithms offer an overall approach to diagnosis and management of the major
presentations of the disease, and reflect our discussion in the body of the manuscript. We
have attempted to address all the key issues in PPI management and adverse events so
clinicians will have a comprehensive, go-to source in the guideline. . We have done our best
to present a thorough review of the evidence for our recommendations and key concepts, and
to provide an evidence-based approach to GERD that can be used effectively in everyday
practice.
We expect that new diagnostic tools and treatments will be developed and those that we have
will be further refined. Mucosal integrity testing, for example, is available commercially but
is not developed sufficiently to warrant discussion in this guideline. Esophageal function
testing is addressed in detail in another guideline, while other extensive reviews focus on
valuable additions to our clinical armamentarium such as magnetic sphincter augmentation
Author Manuscript
and TIF. Potassium-competitive acid blockers (PCABs) are exciting potential new agents
for pharmacologic treatment of GERD. One, currently available in Japan, presently is
undergoing Phase 3 trials in the US as we complete this document, and may well be
approved for clinical use soon after this review is published! Future research with advanced
endoscopic techniques, data on long-term efficacy of surgical intervention, and advances in
artificial intelligence and basic science will almost certainly change the way we manage
GERD going forward.
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Million US Seniors: An Extended Cox Survival Analysis. Clin Gastroenterol Hepatol, 2021.
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Figure 1:
Diagnosis of Gastroesophageal Reflux Disease
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Katz et al. Page 53
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Figure 2:
Diagnostic Algorithm for Extraesophageal Gastroesophageal Reflux Disease symptoms
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Katz et al. Page 54
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Figure 3:
Management Algorithm of Symptoms Suspected Due to GERD Incompletely Responsive to
Proton Pump Inhibitors
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Katz et al. Page 55
Table 1.
Summary and strength of recommendations

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GRADE GRADE strength of

quality recommendation
of evidence
Diagnosis of GERD
For patients with classic GERD symptoms of heartburn and regurgitation who have no alarm Moderate Strong
symptoms, we recommend an 8-wk trial of empiric PPIs once daily before a meal.
We recommend attempting to discontinue the PPIs in patients whose classic GERD symptoms Low Conditional
respond to an 8-wk empiric trial of PPIs.
In patients with chest pain who have had adequate evaluation to exclude heart disease, objective Low Conditional
testing for GERD (endoscopy and/or reflux monitoring) is recommended.
We do not recommend the use of a barium swallow solely as a diagnostic test for GERD. Low Conditional
We recommend endoscopy as the first test for evaluation of patients presenting with dysphagia or Low Strong
other alarm symptoms (weight loss and GI bleeding) and for patients with multiple risk factors for
Barrett’s esophagus.
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In patients for whom the diagnosis of GERD is suspected but not clear, and endoscopy shows no Low Strong
objective evidence of GERD, we recommend reflux monitoring be performed off therapy to establish
the diagnosis.
We suggest against performing reflux monitoring off therapy solely as a diagnostic test for GERD Low Strong
in patients known to have endoscopic evidence of LA grade C or D reflux esophagitis or in patients
known to have long-segment Barrett’s esophagus.
GERD management
We recommend weight loss in overweight and obese patients for improvement of GERD Moderate Strong
symptoms.
We suggest avoiding meals within 2–3 hr of bedtime. Low Conditional
We suggest avoidance of tobacco products/smoking in patients with GERD symptoms. Low Conditional
We suggest avoidance of “trigger foods” for GERD symptom control. Low Conditional
We suggest elevating head of bed for nighttime GERD symptoms. Low Conditional
We recommend treatment with PPIs over treatment with H2RA for healing EE. High Strong
We recommend treatment with PPIs over H2RA for maintenance of healing for EE. Moderate Strong
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We recommend PPI administration 30–60 min before a meal rather than at bedtime for GERD Moderate Strong
symptom control.
For patients with GERD who do not have EE or Barrett’s esophagus, and whose symptoms have Low Conditional
resolved with PPI therapy, an attempt should be made to discontinue PPIs
For patients with GERD who require maintenance therapy with PPIs, the PPIs should be Low Conditional
administered in the lowest dose that effectively controls GERD symptoms and maintains healing
of reflux esophagitis.
We recommend against routine addition of medical therapies in PPI nonresponders. Moderate Conditional
We recommend maintenance PPI therapy indefinitely or antireflux surgery for patients with LA Moderate Strong
grade C or D esophagitis.
We do not recommend baclofen in the absence of objective evidence of GERD. Moderate Strong
We recommend against treatment with a prokinetic agent of any kind for GERD therapy unless Low Strong
there is objective evidence of gastroparesis.
We do not recommend sucralfate for GERD therapy except during pregnancy. Low Strong
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We suggest on-demand/or intermittent PPI therapy for heartburn symptom control in patients with Low Conditional
NERD.
Extraesophageal GERD symptoms
We recommend evaluation for non-GERD causes in patients with possible extraesophageal Moderate Strong
manifestations before ascribing symptoms to GERD.

Katz et al. Page 56
GRADE GRADE strength of

quality recommendation
of evidence
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We recommend that patients who have extraesophageal manifestations of GERD without typical Moderate Strong
GERD symptoms (e.g., heartburn and regurgitation) undergo reflux testing for evaluation before PPI
therapy.
For patients who have both extraesophageal and typical GERD symptoms, we suggest considering Low Conditional
a trial of twice-daily PPI therapy for 8–12 wk before additional testing.
We suggest that upper endoscopy should not be used as the method to establish a diagnosis of Low Conditional
GERD-related asthma, chronic cough, or LPR.
We suggest against a diagnosis of LPR based on laryngoscopy findings alone and recommend Low Conditional
additional testing should be considered.
In patients treated for extraesophageal reflux disease, surgical or endoscopic antireflux procedures Low Conditional
are only recommended in patients with objective evidence of reflux.
Refractory GERD
We recommend optimization of PPI therapy as the first step in management of refractory GERD. Moderate Strong
We recommend esophageal pH monitoring (Bravo, catheter-based, or combined impedance-pH Low Conditional
monitoring) performed OFF PPIs if the diagnosis of GERD has not been established by a previous
pH monitoring study or an endoscopy showing long-segment Barrett’s esophagus or severe reflux
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esophagitis (LA grade C or D).

We recommend esophageal impedance-pH monitoring performed ON PPIs for patients with an Low Conditional
established diagnosis of GERD whose symptoms have not responded adequately to twice-daily PPI
therapy.
For patients who have regurgitation as their primary PPI-refractory symptom and who have had Low Conditional
abnormal gastroesophageal reflux documented by objective testing, we recommend consideration of
antireflux surgery or TIF.
Surgical and endoscopic options for GERD
We recommend antireflux surgery performed by an experienced surgeon as an option for long-term Moderate Strong
treatment of patients with objective evidence of GERD. Those who have severe reflux esophagitis
(LA grade C or D), large hiatal hernias, and/or persistent, troublesome GERD symptoms who are
likely to benefit most from surgery.
We recommend consideration of MSA as an alternative to laparoscopic fundoplication for patients Moderate Strong
with regurgitation who fail medical management.
We recommend consideration of RYGB as an option to treat GERD in obese patients who are Low Conditional
candidates for this procedure and who are willing to accept its risks and requirements for lifestyle
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alterations.
Because data on the efficacy of radiofrequency energy (Stretta) as an antireflux procedure is Low Conditional
inconsistent and highly variable, we cannot recommend its use as an alternative to medical or surgical
antireflux therapies.
We suggest consideration of TIF for patients with troublesome regurgitation or heartburn who do Low Conditional
not wish to undergo antireflux surgery and who do not have severe reflux esophagitis (LA grade C or
D) or hiatal hernias >2 cm.
EE, erosive esophagitis; GERD, gastroesophageal reflux disease; GI, gastrointestinal; GRADE, Grading of Recommendations, Assessment,
Development, and Evaluation; H2RA, histamine-2-receptor antagonists; LA, Los Angeles; LPR, laryngopharyngeal reflux; MSA, magnetic
sphincter augmentation; NERD, nonerosive reflux disease; PPI, proton pump inhibitor; TIF, transoral incisionless fundoplication; RYGB, Roux-en-
Y gastric bypass.
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Katz et al. Page 57
Table 2.
Key concept statements

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Diagnosis of GERD
We do not recommend HRM solely as a diagnostic test for GERD.
GERD management
There is conceptual rationale for a trial of switching PPIs for patients who have not responded to one PPI. For patients who have not
responded to one PPI, more than one switch to another PPI cannot be supported.
Use of the lowest effective dose is recommended and logical but must be individualized. One area of controversy relates to abrupt PPI
discontinuation and potential rebound acid hypersecretion, resulting in increased reflux symptoms. Although this has been demonstrated to
occur in healthy controls, strong evidence for an increase in symptoms after abrupt PPI withdrawal is lacking.
Extraesophageal GERD
Although GERD may be a contributor to extraesophageal symptoms in some patients, careful evaluation for other causes should be
considered for patients with laryngeal symptoms, chronic cough, and asthma.
Diagnosis, evaluation, and management of potential extraesophageal symptoms of GERD is limited by lack of a gold-standard test, variable
symptoms, and other disorders which may cause similar symptoms
Endoscopy is not sufficient to confirm or refute the presence of extraesophageal GERD.
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Because of difficulty in distinguishing between patient with laryngeal symptoms and normal controls, salivary pepsin testing is not
recommended for evaluation of patients with extraesophageal reflux symptoms
For patients whose extraesophageal symptoms have not responded to a trial of twice-daily PPIs, we recommend upper endoscopy, ideally
off PPIs for 2–4 wk. If endoscopy is normal, consider reflux monitoring. If EGD shows EE, that does not confirm that the extraesophageal
symptoms are from GERD. Patients still may need pH-impedance testing
For patients with extraesophageal symptoms, we do not routinely recommend oropharyngeal or pharyngeal pH monitoring.
Refractory GERD
It is important to stop PPI therapy in patients whose off-therapy reflux testing is negative, unless another indication for continuing PPIs is
present. In 1 study, 42% of patients reported continuing PPI treatment after a negative evaluation for refractory GERD, which included negative
endoscopy and pH-impedance monitoring [2].
Esophageal manometry should be considered as part of the evaluation for patients with refractory GERD in patients with a normal endoscopy
and pH monitoring study and for patients being considered for surgical or endoscopic treatment.
If not already performed off PPIs, we recommend diagnostic upper endoscopy with esophageal biopsies after discontinuing PPI therapy,
ideally for 2 to 4 wk
For patients with PPI-refractory symptoms who have a normal pH monitoring test OFF PPIs or a normal impedance-pH monitoring test ON
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PPIs (including a negative SI and SAP), we recommend discontinuation of PPIs unless there is an indication for PPI therapy other than the
refractory symptoms.
Surgical and endoscopic therapy
We recommend HRM before antireflux surgery or endoscopic therapy to rule out achalasia and absent contractility. For patients with
ineffective esophageal motility, HRM should include provocative testing to identify contractile reserve (e.g., multiple rapid swallows).
We recommend a careful evaluation and caution before proceeding with invasive therapy for patients with PPI-refractory GERD symptoms
other than regurgitation.
Before performing invasive therapy for GERD, a careful evaluation is required to ensure that GERD is present and as best as possible
determine is the cause of the symptoms to be addressed by the therapy, to exclude achalasia (which can be associated with symptoms such as
heartburn and regurgitation that can be confused with GERD), and to exclude conditions that might be contraindications to invasive treatment
such as absent contractility.
Long-term PPI issues
Regarding the safety of long-term PPI usage for GERD, we suggest that patients should be advised as follows: “PPIs are the most effective
medical treatment for GERD. Some medical studies have identified an association between the long-term use of PPIs and the development of
numerous adverse conditions including intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney
disease, deficiencies of certain vitamins and minerals, heart attacks, strokes, dementia, and early death. Those studies have flaws, are not
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considered definitive, and do not establish a cause-and-effect relationship between PPIs and the adverse conditions. High-quality studies
have found that PPIs do not significantly increase the risk of any of these conditions except intestinal infections. Nevertheless, we cannot
exclude the possibility that PPIs might confer a small increase in the risk of developing these adverse conditions. For the treatment of GERD,
gastroenterologists generally agree that the well-established benefits of PPIs far outweigh their theoretical risks.”
Switching PPIs can be considered for patients who experience minor PPI side effects including headache, abdominal pain, nausea, vomiting,
diarrhea, constipation, and flatulence.

Katz et al. Page 58
For patients with GERD on PPIs who have no other risk factors for bone disease, we do not recommend that they raise their intake of calcium
or vitamin D or that they have routine monitoring of bone mineral density.
For patients with GERD on PPIs who have no other risk factors for vitamin B12 deficiency, we do not recommend that they raise their intake
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of vitamin B12 or that they have routine monitoring of serum B12 levels.
For patients with GERD on PPIs who have no other risk factors for kidney disease, we do not recommend that they have routine monitoring
of serum creatinine levels.
For patients with GERD on clopidogrel who have LA grade C or D esophagitis or whose GERD symptoms are not adequately controlled with
alternative medical therapies, the highest quality data available suggest that the established benefits of PPI treatment outweigh their proposed
but highly questionable cardiovascular risks.
PPIs can be used to treat GERD in patients with renal insufficiency with close monitoring of renal function or consultation with a
nephrologist.
EE, erosive esophagitis; GERD, gastroesophageal reflux disease; HRM, high-resolution manometry; LA, Los Angeles; PPI, proton pump inhibitor;
SAP, symptom association probability; SI, symptom index.
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Table 3.
Recommendations based on results of a review of studies involving lifestyle modifications
Lifestyle modification Strength of scientific evidence Pathophysiologically conclusive? Recommendable?

Katz et al.
Avoid fatty meals Equivocal Equivocal Yes

Avoid carbonated beverages Moderate Yes Yes
Select decaffeinated beverages Equivocal Equivocal Not generally
Avoid citrus Weak Yes Yes, if citrus triggers symptoms
Eat smaller meals Weak Yes Yes
Lose weight Equivocal Equivocal a
Yes
Avoid alcoholic beverages Weak Mechanisms not understood; different alcoholic beverages have different effects Not generally
Stop smoking Weak Yes a
Yes
Avoid excessive exercise Weak Yes Yes
Sleep with head elevated Equivocal Equivocal Yes
Sleep on the left side Unequivocal Yes Yes
a
Obesity and smoking seem to be risk factors for cancer of the distal esophagus.

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Table 4.
Potential mechanisms underlying symptoms suspected due to GERD but refractory to PPI therapy
Despite PPI therapy abnormal acid reflux persists and is causing symptoms
Katz et al.
There is reflux hypersensitivity, a condition in which PPIs have normalized esophageal acid exposure, but “physiologic” reflux episodes (acidic or nonacidic) nevertheless are strongly associated with
and evoke symptoms
The symptoms are not due to GERD, but are caused by esophageal disorders other than GERD (e.g., EoE and achalasia)
The symptoms are not due to GERD, but are caused by nonesophageal disorders (e.g., gastroparesis, rumination, and heart disease)
The symptoms are functional (i.e., not because of GERD or any other identifiable histopathologic, motility, or structural abnormality).
EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.

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Katz et al. Page 61
Table 5.
Major putative adverse effects of chronic PPI therapy

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a b
Meta- HR or OR (95%
analysis CI)
reference found in recent
Putative adverse effect numbers RCT (94) Major proposed mechanisms
Cardiovascular events (237-240) a PPIs block metabolism of ADMA, which accumulates and inhibits NO
1.04 (0.93–-1.15) synthase, thus blocking endothelial production of NO needed for vascular
(All) MI a homeostasis
0.94 (0.79–1.12)
Stroke a
1.16 (0.94–1.44)
Cardiovascular death a
1.03 (0.89–1.20)
Cardiovascular events in (241-260) NA PPIs are metabolized by the same enzyme needed to activate clopidogrel
c (CYP2C19), so concomitant use of these drugs might decrease the
patients on clopidogrel antiplatelet effect of clopidogrel
Kidney disease (261-265) NA AIN develops as an idiosyncratic drug reaction and progresses to chronic
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kidney disease
(All) AIN NA
Chronic kidney b
disease 1.17 (0.94–1.45)
Enteric infection (other (266,267) b Reduced gastric acid enables ingested enteric pathogens to survive
than Clostridium. 1.33 (1.01–1.75) passage through the stomach
difficile)
C. difficile (268-276) b Reduced gastric acid enables survival of ingested C. difficile vegetative
2.26 (0.70–7.34) forms and prevents conversion of salivary nitrite to ROS that suppress C.
difficile spores; PPIs may enhance C. difficile toxin expression and cause
microbiome alterations that promote C. difficile colitis
SIBO (277,278) NA Reduced gastric acid enables increased bacterial colonization of the UGI
tract
Spontaneous bacterial (279-283) NA Increased bacterial colonization of the UGI tract and PPI-induced
peritonitis in patients increases in UGI tract permeability predispose to bacterial translocation;
with cirrhosis PPIs also might interfere with inflammatory cell functions that ordinarily
would prevent infection
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Pneumonia (284-289) b Reduced gastric acid enables UGI tract colonization with pulmonary
1.02 (0.87–1.19) pathogens that can be aspirated; PPIs also might interfere with
inflammatory cell functions that ordinarily would prevent infection
Dementia (290-293) b
1.20 (0.81–1.78) PPIs block vacuolar H+-ATPase needed to acidify microglial lysosomes,
thereby preventing their degradation of cerebral amyloid-β peptide; PPI-
induced B12 deficiency also might contribute to dementia
Bone fracture (294-302) b Reduced gastric acid causes calcium malabsorption leading to decreased
0.96 (0.79–1.17) bone mineral density; PPIs might reduce bone resorption by blocking
vacuolar H+-ATPase in osteoclasts; PPIs cause hypergastrinemia that
might cause parathyroid hyperplasia
Gastric atrophy (303-305) b PPIs promote corpus-predominant H. pylori gastritis that results in gastric
0.73 (0.40–1.32) atrophy with loss of parietal cells
Gastric cancer (306-308) NA PPIs promote gastric atrophy and inflammation in H. pylori–infected
patients, resulting in intestinal metaplasia predisposed to malignancy;
reduced gastric acid enables overgrowth of bacteria that convert dietary
nitrates to potentially carcinogenic N-nitroso compounds; PPI-induced
hypergastrinemia causes gastric epithelial cell proliferation that promotes
carcinogenesis
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Vitamin B12 deficiency (309) NA Reduced gastric acid results in malabsorption of protein-bound cobalamin;
gastric atrophy results in decreased intrinsic factor production
Hypomagnesemia (310-312) NA PPI effects in elevating intestinal pH may interfere with magnesium
absorption, perhaps because the affinity of the enterocyte magnesium
transporter TRPM6/7 for magnesium decreases in a higher pH
environment

Katz et al. Page 62
a b
Meta- HR or OR (95%
analysis CI)
reference found in recent
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Putative adverse effect numbers RCT (94) Major proposed mechanisms

All-cause mortality (313) a Potentially all of above
1.03 (0.92–1.15)
a
Hazard ratio.
b
Odds ratio
c
The US Food and Drug Administration recommends avoiding the concomitant use of clopidogrel and omeprazole.
ADMA, asymmetric dimethylarginine; AIN, acute interstitial nephritis; ATP, adenosine triphosphate; CI, confidence interval; HR, hazard ratio; MI,
mucosal integrity; NA, not available; NO, nitric oxide; OR, odds ratio; PPI, proton pump inhibitor; RCT, randomized controlled trial (94); ROS,
reactive oxygen species; SIBO, small intestinal bacterial overgrowth; TRPM6/7, transient receptor potential melastatin 6 and 7.
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ACG Clinical Guideline: Guidelines for the Diagnosis and

Kerry Dunbar, MD, PhD [Associate Professor of Medicine, Section Chief],

Medical Center, Dallas, TX

Felice H. Schnoll-Sussman, MD, FACG [Professor of Clinical Medicine, Director, Director of

Katarina B. Greer, MD, MS, FACG [Associate Professor of Medicine],

Rena Yadlapati, MD, MSHS [Associate Professor of Clinical Medicine],

Stuart Jon Spechler, MD, FACG [Chief, Co-Director]

Corresponding author: Philip O. Katz, MD, [email protected].

guideline on reflux management [1], clinically important advances in surgical and

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

2. We recommend attempting to discontinue the PPIs in patients whose classic

3. We recommend diagnostic endoscopy, ideally after PPIs are stopped for 2 to 4

6. We recommend endoscopy as the first test for evaluation of patients presenting

8. We recommend against performing reflux monitoring off therapy solely as a

diagnostic test for GERD in patients known to have endoscopic evidence of

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

Defining GERD—A single unifying definition of GERD is difficult. In preparing this

Pathophysiology of GERD—The pathophysiology of GERD includes a poorly

Symptoms—Typical symptoms of GERD include heartburn and regurgitation. Heartburn

as rumination, achalasia, eosinophilic esophagitis, reflux hypersensitivity, functional disease,

Extraesophageal manifestations of GERD can include laryngeal and pulmonary symptoms

a combination of symptom presentation, endoscopic evaluation of esophageal mucosa,

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

Barium radiography—Barium radiographs should not be used solely as a diagnostic test

diagnostic test for GERD [13].

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

Esophageal Manometry—High resolution manometry (HRM) can be used to assess

undergoing surgical treatment of GERD, reduced contractile reserve documented by

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

a PPI trial to assess for motility abnormalities

Reflux monitoring—Ambulatory reflux monitoring (pH or impedance-pH) allows for

An issue that frequently arises is whether esophageal pH monitoring should be performed

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

Diagnosis of GERD in Pregnancy—Approximately two-thirds of pregnant women

New developments—A recently approved device for evaluation of GERD uses a

GERD Medical Management

2. We suggest avoiding meals within 2-3 hours of bedtime. (Conditional

3. We suggest avoidance of tobacco products/smoking in patients with GERD

4. We suggest avoidance of "trigger foods" for GERD symptom control.

5. We suggest elevating head of bed for nighttime GERD symptoms. (Conditional

recommendation, low level of evidence)

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

8. We recommend PPI administration 30 to 60 minutes prior to a meal rather than at

bedtime for GERD symptom control. (Strong recommendation, moderate level of

11. We recommend against routine addition of medical therapies in PPI non-

12. We recommend maintenance PPI therapy indefinitely or antireflux surgery for

13. We do not recommend Baclofen in the absence of objective evidence of GERD.

(Strong recommendation, low level of evidence)

16. We suggest on-demand or intermittent PPI therapy for heartburn

potential rebound acid hypersecretion resulting in increased reflux symptoms.

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

abnormalities such as gastroparesis or ineffective motility with absence of contractile

reserve. Medical management includes lifestyle modifications as well as pharmacologic

Non-pharmacologic lifestyle modifications include recommendations for diet modification

Diet and Lifestyle Changes—Common recommendations include weight loss for

Am J Gastroenterol. Author manuscript; available in PMC 2023 January 01.

Medications—The backbone of pharmacologic therapy for GERD are medications that