Current Otorhinolaryngology Reports (2018) 6:196–202

https://doi.org/10.1007/s40136-018-0192-6

LARYNGOLOGY: DYSPHAGIA (A AL-HUSSAINI, SECTION EDITOR)

Laryngopharyngeal Reflux: Current Concepts on Etiology

and Pathophysiology and Its Role in Dysphagia
Sandra Stinnett 1 & Vaninder Dhillon 1 & Lee Akst 1

Published online: 1 May 2018

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Laryngopharyngeal reflux (LPR) is one of the most commonly encountered chronic inflammatory conditions
of the larynx. The lack of a unifying consensus regarding diagnosis and management makes it difficult to relate laryngeal
disorders and dysphagia to this disease entity, particularly for an otolaryngologist. This article reviews diagnosis and management
of LPR from an otolaryngological and gastroenterological perspective by reconciling current trends in the literature.
Recent Findings More sophisticated testing via multichannel pH probes as well as the implementation of pepsin assays has
potential in diagnosing LPR. This will hopefully more clearly delineate this disease entity, in the setting of dysphagia.
Summary Dysphagia and LPR both have significant overlap with numerous disease entities. Though there is little literature to
address outcomes in treatment and management of dysphagia in the setting of LPR, few studies show that managing LPR-related
dysphagia may improve with surgical intervention if there is no improvement with conservative management.

Keywords Laryngopharyngeal reflux . (LPR) reflux . Laryngoscopy . pH probe . Empiric treatment . Proton pump inhibitor .
Pepsin . Gastroesophageal reflux . Reflux laryngitis . Heartburn . Dysphagia . Swallowing

Introduction
Extraesophageal manifestations of reflux are estimated to cost
$5438 per patient in direct medical expenses in the initial year
after presentation and $137,000 for 5 years. Economic burden
estimates of extraesophageal reflux (EER) have shown that
expenditures for this disease entity could surpass $50 billion,
86% of which may be attributed to pharmaceutical costs [1].
Laryngopharyngeal reflux (LPR) is considered an
extraesophageal manifestation of gastroesophageal reflux dis-
ease (GERD). LPR is described as reflux of gastric contents
into the larynx, pharynx, and upper aerodigestive tract. As a
result of exposure to acid reflux, some patients present with
‘typical symptoms’ such as heartburn and acid regurgitation
This article is part of the Topical Collection on LARYNGOLOGY:
Dysphagia
* Sandra Stinnett
Ssaintv1@jhmi.edu
1
Department of Otolaryngology – Head and Neck Surgery, Johns
Hopkins University, 601 North Caroline Street,
Baltimore, MD 21287, USA
at one end of the spectrum and others present with “atypical
symptoms.” Still, others may present with a combination of
both types of symptoms [2]. ‘Atypical’ LPR symptoms com-
monly result in several otolaryngologic inflammatory disorders
as well as potentially neoplastic diseases of the
laryngopharynx. Many of these complaints include dysphonia,
and cough. LPR has also been linked to specific disease states
of the aerodigestive tract including otitis media, sinusitis,
cough, sleep-disordered breathing, laryngitis, laryngospasm,
and airway stenosis [3]. LPR often times results in inflamma-
tion, edema, and subsequent decreased sensation of the larynx
and pharynx, which can cause dysphagia with or without
globus sensation [4]. The underlying mechanism for this broad
clinical presentation is unclear but is suspected to involve upper
esophageal sphincter (UES) abnormalities and underlying
esophageal motility disorders, with the potential mechanism
being dysmotility of the esophagus resulting in stasis [5, 6].
LPR has also been implicated as a probable etiology for
Zenker’s diverticulum [7], and this emphasizes importance of
considering other head and neck etiologies in suspected LPR.
As of late, there is no gold standard for diagnosis or therapy
for this condition. As a result, there is an increasing trend towards
LPR being potentially over-diagnosed and over-treated [8]. This
review addresses the current state of laryngopharyngeal reflux
Curr Otorhinolaryngol Rep (2018) 6:196–202
with regard to knowledge about diagnosis and pathophysiology,
treatment recommendations, and practice patterns, with a partic-
ular focus on reflux and dysphagia.
Pathophysiology
The consensus in the otolaryngology community is that LPR
can exist even in the absence of GERD symptoms. The laryn-
geal mucosa is suspected to have a different susceptibility to
injury compared to gastric mucosa [7]. Additionally, esopha-
geal tissue may benefit from mucosal defense mechanisms
that are not available to the larynx, such as peristalsis to clear
the refluxate as well as carbonic anhydrase production to
which buffers acid content. This, in addition to the presence
of pepsin receptors on the larynx, results in laryngopharyngeal
inflammation from reflux even at pH of 5.5, supporting LPR
as a separate entity from GERD [9, 10].
A study performed by Johnston et al. confirmed LPR pa-
tients had a decreased carbonic anhydrase level in the vocal
fold epithelium. E-cadherin levels were absent in 37% of LPR
specimens as well. This implied that the larynges lack a key
transmembrane cell surface molecule that potentially helps in
epithelial defense, making it more susceptible to injury from
reflux [11]. Additionally, when compared to healthy controls
and patients with GERD, LPR patients had impaired UES
contractile reflexes and abnormal UES relaxation in response
to simulated liquid reflux events [5], potentially further per-
petuating noxious exposure.
Nonacid reflux is a newly understood type of reflux that
has been identified through the use of impedance-pH (MII-
pH) monitoring. Though its symptoms manifest similarly to
those with reflux disease, nonacid reflux is usually refractory
to treatment with proton pump inhibitors (PPIs) [12]. There
are two proposed major pathophysiologic mechanisms for this
entity. The reflex theory, also known as the esophago-tracheo-
bronchial reflex theory, proposes that receptors on the mucosa
are stimulated by the refluxate, resulting in activation of in-
flammatory mediators causing extraesophageal symptoms
[13]. The second theory is the proximal reflux, or micro/mac-
ro-aspiration, theory, which proposes that gastric contents
flow retrograde into the throat due to structural and functional
abnormalities of the lower esophagus. The refluxate may di-
rectly stimulate cough receptors or increase production of mu-
cus through the vagal reflex. This activates the cough recep-
tors resulting in other laryngopharyngeal symptoms [14].
Diagnosis
The diagnosis of LPR is particularly challenging due to its
vast and nonspecific symptomatology. The otolaryngologic
197
approach to diagnosing LPR is multifactorial and contingent
upon clinical presentation. Clinical exam plays a role in eval-
uation of laryngopharyngeal complaints, but by itself cannot
confirm presence or absence of LPR. Thus, LPR diagnoses are
often tentative, and initial treatment with antacid may be more
accurately considered a therapeutic trial rather than definitive
therapy. As a corollary to this point, this also creates the situ-
ation in which presumed LPR patients may not benefit from
anti-reflux treatment—in which case, broad differential diag-
nosis beyond reflux alone is encouraged.
Initially, patients with voice or swallowing complaint will
most likely present to their primary care physician for care.
Ruiz et al. surveyed primary care providers in their treatment
of dysphonia. Three hundred fourteen (12.9%) of the surveyed
physicians responded. From the survey, most of these physi-
cians preferred to treat hoarse patients before referring to an
otolaryngologist and without direct visualization of the larynx.
Reflux medications and antihistamines were the most common-
ly used medications for empiric treatment. 79.2% of these phy-
sicians would treat chronic hoarseness with reflux medications
in the absence of GERD [15]. If symptoms did not improve
after 3 months or resolve after 6 months, of anti-reflux treat-
ment, Ford et al. recommended evaluation with impedance and
pH monitoring (MII-pH), esophageal manometry as well as
endoscopy to guide possible operative intervention [16].
The tendency to blame reflux first may delay appropriate
evaluation and treatment of laryngeal disorders where LPR is
not the cause. According to Position Statement published in
2002, Koufman et al. described the most common LPR symp-
toms as hoarseness, globus pharyngeus, dysphagia, cough,
chronic throat clearing, and sore throat [17]. Because each
symptom associated with reflux is also related to various other
head and neck pathologies, diagnosis of reflux based on
symptoms is best suited in combinations to create a score
which may more accurately reflect the presence or absence
of LPR. One particular tool previously used is the Belafsky
Reflux Symptoms Index (RSI), which asks about associated
LPR symptoms, and scores > 10 suggest LPR [18]. However,
recent studies have found the RSI alone to be of little utility in
diagnosing LPR, alone as well as in conjunction with pH
probe [19, 20]. Thus, history alone is inadequate in providing
a definitive diagnosis of LPR [21].
Physical exam and laryngoscopy had initially been consid-
ered useful in determining the presences of pathophysiologic
reflux changes, though recent evidence has called the ability
of laryngopharyngoscopy to be reliable and specific into ques-
tion—limited evidence is found for each mucosal finding in
LPR [22]. Belafsky et al. reported the Reflux Findings Scale
(RFS), which is a standardized scoring system that consists of
an 8-item clinical severity score based on laryngoscopic ex-
amination. Patients with an RFS of ≥ 7 had a 95% chance of
having LPR based on their analysis [23]. However, RFS has
198
been shown to have poor inter-rater and intra-rater reliability
in clinical practice [24]. Hicks et al. assessed pharyngeal signs
of LPR in normal controls and showed how prevalent they
were in this population that was screened against any head and
neck complaints [19]. One hundred five adults had a flexible
videolaryngoscopic exam, reviewed by two laryngologists at
different times. There was presence of at least one LPR find-
ing 86% of the time in the healthy individuals; inter-arytenoid
bar was present 70% of the time. Other common findings seen
were arytenoid erythema, pharyngeal wall cobblestoning,
inter-arytenoid bar erythema, posterior cricoid wall edema,
and vocal fold edema.
Stroboscopic examination provides increased illumination
and magnification, which allows for meticulous assessment of
glottic closure and mucosal wave. In a study by Fritz et al.,
stroboscopy was invaluable in identifying laryngeal pathology
when LPR is suggested as the referral diagnosis [25], espe-
cially in the setting of hoarseness. Often, stroboscopy can
reveal etiology for hoarseness beyond initial diagnosis of re-
flux. Sulica published a retrospective study that looked at 381
new patients presenting with hoarseness [26]. Of them, 26
patients carried a diagnosis of reflux as the primary cause of
their dysphonia. Using stroboscopy, he identified diagnoses
other than LPR in every patient, which included
phonotraumatic lesions, neurologic disorders, age-related
changes, and infectious causes. He concluded that hoarse pa-
tients that fail to improve with empiric anti-reflux treatment
would benefit from further laryngeal investigation.
The gastrointestinal literature debates the need to screen the
larynx as part of the upper gastrointestinal endoscopy. In a
study by Katsinelos et al., 1130 patients underwent upper
gastrointestinal (UGI) endoscopy who were asymptomatic in
the laryngopharyngeal area but who underwent a structured
examination of this area before insertion of the UGI scope into
the esophagus. They discovered a rate of 3.89% of pathology
suspected by the endoscopist, which was then confirmed by
an otolaryngologist colleague. Their most significant findings
on exam were leukoplakia, posterior laryngitis, and Reinke’s
edema. It was concluded that a screen of the
laryngopharyngeal area should be performed as part of the
UGI endoscopy prior to insertion to the esophagus even in
the absence of symptoms in the area [27].
Empiric treatment with PPI based on history and physical
exam suggestive of LPR has resulted in the rising cost in
treatment of this disease entity [28], despite GI recommenda-
tions that do not support starting PPI treatment in the absence
of GERD symptom [29•]. The 2013 American College of
Gastroenterology guidelines recommend initial ambulatory
testing in cases of suspected LPR in the absence of GERD
symptoms [30]. The gold standard for diagnosing reflux con-
sists of 24-h double-probed pH monitoring. There is no con-
sensus as to what type of probe is relative for diagnosing
Curr Otorhinolaryngol Rep (2018) 6:196–202
extra-esophageal reflux and at what pH threshold parameters
or what anatomic position of the upper probe works best.
Pharyngeal probes have been developed in addition to the
dual esophageal probe, which addresses laryngopharyngeal
acid exposure via a probe just beneath the upper esophageal
sphincter. With 24-h dual-probed pH monitoring, pharyngeal
reflux episodes below pH 4.0 are considered diagnostic for
LPR. Distal esophageal probe data are considered abnormal
if the pH is lower than 4.0, 8.1% of the time in the upright
position and 2.9% of the time in the supine position.
Abnormalities greater than 5.5% of the total time are also
considered abnormal results [31].
Multichannel intraluminal impedance and pH monitoring
(MII-pH) has been useful in the identification and quantifica-
tion of nonacid refluxate, particularly in patients who remain
symptomatic despite aggressive acid-suppression therapy. It is
also useful in detecting liquid as well as gaseous refluxate.
However, no established normative values exist for parame-
ters acquired during MII-pH. Additionally, the clinical signif-
icance of abnormal findings with LPR awaits further study
[32, 33].
It was initially hypothesized that increased number of prox-
imal reflux events would correlate with degree of reflux lar-
yngitis [21]; however, this is not the case. This may be due to
the laryngopharyngeal epithelium’s increased sensitivity to
reflux-related injury in comparison to the esophageal epithe-
lium. As a result, smaller amounts of acid and fewer episodes
of reflux may cause damage as well as laryngeal symptoms.
It remains to be elucidated whether up-front objective reflux
testing could be more cost-effective than currently employed
empiric suppression trials. Up-front testing could identify pa-
tients in whom acid reflux is not the primary cause of LPR,
avoiding 3–9 months of unnecessary medication. A study by
Carroll et al. showed that normal test results could save over
50% in cost compared to a patient who is started on an empiric
trial [34•]. Additionally, the cost to undergo up-front MII-pH
and with high-resolution manometry testing (HRM) is estimat-
ed to be 37% lower than average per-patient cost of treatment
with up-front BID PPI dosing. This is the first study of its kind
to address an alternative treatment regimen as well as evaluation
for managing and diagnosing LPR.
Other technologies such as an artificial neural network
(ANN) pattern recognition tool which objectively addresses
laryngopharyngeal reflux color and texture recognition have
been used to study LPR by Witt et al. [35]. The study demon-
strated that ANN-based pattern recognition of hue and texture
features objectively distinguished between non-LPR and LPR
laryngoscope imaging. Another study by Du et al. sought to
compare ANN analysis to MII-24 pH and showed that various
textures and hue values were classifiable as positive for LPR
based on MII-24 pH, providing a method in which its scale
relies on objective data [36].
Curr Otorhinolaryngol Rep (2018) 6:196–202
There is strong evidence for the use of pepsin as a marker
of LPR; however, the role it plays is still unclear. Pepsin is a
proteolytic enzyme that is activated in an acidic environment.
It is secreted by the gastric chief cells in the form of pepsino-
gen. It is present in all refluxate, as opposed to other gastric
components such as bile or acid, which may or may not al-
ways be present [37]. In a meta-analysis published by Calvo-
Henriquez et al. [38•], 10 out of 12 studies were found to show
statistically significant differences for pepsin in diagnosed
cases of LPR compared to healthy control. It is known that
some degree of reflux is physiologic; thus, in most studies,
there was a noticeably lesser concentration of pepsin levels in
healthy controls. There is not a uniform pepsin assay available
and in the literature, there is significant variability in the cutoff
point to consider pepsin as pathologic. Additionally, there are
various mechanisms by which samples can be obtained, which
include saliva and sputum as well as pharyngeal and laryngeal
biopsies, where sedation is often required for the latter.
Dysphagia
Dysphagia is defined often used to describe a symptom that
manifests as awareness of swallowing difficulty during pas-
sage of liquid or solid bolus or perception of obstruction dur-
ing swallowing. It is reported to have significant impact on the
quality of life of patients [39], posing profound social, emo-
tion, and socioeconomic implications as well as significant
morbidity and mortality. Patients reporting “swallowing prob-
lems” could be experiencing a variety of symptoms which
include dysphagia, but also odynophagia, globus sensation,
and/or heartburn [40].
Dysphagia is often mentioned in the literature as one of the
presenting symptoms of LPR; however, it has significant over-
lap with many various laryngeal disorders. Stroboscopic ex-
amination is important for patients with concurrent voice com-
plaints. Modified barium swallow may provide valuable in-
formation regarding potential structural as well as functional
abnormalities, which is useful in diagnosis as well as treat-
ment. Other tests may include esophagogastroduodenoscopy
to further assess for structural abnormalities and manometry to
assess for motility disorders.
There are multiple postulated mechanisms by which reflux
causes dysphagia: by inducing esophageal dysmotility sec-
ondary to prolonged exposure to refluxate, via
pharyngoesophageal mucosal inflammation and esophageal
stricture formation, or through circopharyngeal dysfunction
and pharyngeal outlet obstruction [41]. Etiologies for dyspha-
gia include head and neck cancer, neuromuscular disease,
structural as well as function abnormalities, and LPR/
GERD; however, there are few studies that address patient
outcomes in treatment and management of dysphagia [42].
199
Treatment
Of the many treatment modalities available for LPR, therapeu-
tic lifestyle modifications with dietary changes is one of the
first treatments implemented clinically, though there is a lack
of evidence that these modifications can improve esophageal
pH profiles or reflux symptoms [43]. There is evidence how-
ever that elevating the head of the bed, lying in the left lateral
decubitus position, and weight loss improved pH profiles as
well as symptoms in patients.
The generally recommended medical management for pa-
tients with LPR is once- or twice-daily dosing of a proton
pump inhibitor (PPI) for 3–6 months. There are numerous
studies that report PPIs as providing adequate treatment in
improving LPR complaints, and there is an equal amount of
studies that show that either PPIs may not be predictive of the
presence or absence of LPR or that there is no significant
change in symptoms with PPI treatment [44–46]. A meta-
analysis performed by Qadeer et al., summarized randomized
controlled trials on PPI for suspected GERD-related chronic
laryngitis, concluded that there was no difference statistically
between PPI and placebo [47].
There are substantial side effects associated with long-term
exposure to PPI therapy. In a recent systematic review, observ-
ing adverse events from PPI usage, community-acquired
pneumonia (CAP), C. difficile infection, and bone fractures
were most significantly associated with PPI usage, though
these events are relatively uncommon. Other risks include
possible modulation of risk for heart attack and kidney disease
and poor B12 absorption. Therefore, it is recommended that
the data should be used to guide the use of medication in high-
risk groups, especially in the setting of empiric utilization as a
diagnostic challenge [48]. In light of this, Lin et al. assessed
factors that affected weaning off of PPI in patients on empiric
therapy for LPR, and notably, BMI was found to have the
unifying factor in patients that failed weaning [49].
The dosing regimen of twice-daily PPI, before breakfast
and before dinner, is often times difficult for patients to adhere
to, making compliance an issue. Carroll et al. was the first
study to investigate empiric once-daily, high-dose pre-break-
fast PPI (QD) and a bedtime high-dose ranitidine (QHS) in
treatment of LPR [34•]. They found that if acid-suppression
therapy is going to work, the majority of patients will respond
to the QD/QHS regimen, providing an alternative to twice-
daily PPI’s.
Other treatment modalities utilized for LPR and its related
symptoms include a variety of medical and surgical manage-
ments that have been suggested in the literature. Liquid algi-
nate suspension has been shown to be one alternative for tra-
ditional PPI and H2 blockers. A randomized control trial
showed significant improvement in RFS and RSI scores in
the liquid alginate therapy group compared to controls [50].
For patients that are refractory to all medical management,
200
pa rtic ularly h igh-d ose PPI, la paro scopic Nisse n
fundoplication (LNF) has been shown to manage patient
symptoms. Sataloff et al. in 2014 revealed that 90% of symp-
toms were improved postoperatively, 60% were able to dis-
continue anti-reflux medications, and 24% took less medica-
tion postoperatively [51]. Another study examined the post-
operative symptoms of patients that underwent LNF with LPR
had a statistically significant improvement in dysphagia,
3 months after surgery [52]. A new treatment recently ap-
proved by the FDA is the magnetic sphincter augmentation
(MSA), also known by the trade name of LINX. Many pa-
tients with GERD and LPR symptoms have undergone MSA
implantation with results that parallel those seen in
fundoplication for LPR [53].
Dysphagia symptoms are often times ameliorated with em-
piric PPI treatment; however, further intervention may be war-
ranted. Cricopharyngeal muscle hypertrophy, secondary to re-
flux, may become severe enough that surgery may be indicat-
ed. The cricopharyngeal muscle may be addressed via multi-
ple mechanisms, which include dilation, chemical paralysis,
or permanent surgical division. Balloon dilation may also be
considered, though less effective in comparison to surgical
management [54]. It has been hypothesized that manipulation
of the cricopharyngeal muscle may worsen symptoms of gas-
troesophageal and LPR due to loss of upper esophageal
sphincter tone resulting in increased refluxate into the hypo-
pharynx. However, there are several studies that show an im-
provement in RSI and Eat Assessment Tool-10 (EAT-10)
scores postoperatively.
The Role of the Otolaryngologist
in Dysphagia and LPR
LPR as seen in the otolaryngologist office can come in many
forms, with symptoms of throat clearing, mouth burning,
globus, dysphagia,, hoarseness, cough, paroxysmal
laryngospasm, and dental erosion. A diagnosis of LPR should
be made after a thorough history of dysphonia and dysphagia.
The adopted empiric treatment of LPR with PPI trial may be
useful initially; however, new methods of implementing H2-
blockers have proven useful in the empiric management of
LPR with less side effects and improved compliance. After
4–6 weeks of treatment, if symptoms have not been resolved,
pH probe may be used to qualify the type and severity of
reflux. If patient’s with suspected LPR report dysphagia, that
is, refractory to empiric treatment or with significant weight
loss and/or aspiration, further investigation is warranted. MBS
evaluation should be considered with speech pathology to
provide diagnosis as well as treatment if warranted. With ex-
tensive knowledge of nasal anatomy, otolaryngologists are
familiar with passing endoscopes via the nose, which is led
to the emergence of transnasal esophagoscopy (TNE),
Curr Otorhinolaryngol Rep (2018) 6:196–202
particularly in laryngology and head and neck oncology.
This in conjunction with MBS may be useful in diagnosing
and treating diseases of the upper esophagus such as
cricopharyngeal hypertonicity or strictures. If other etiologies
for dysphagia are suspected, such as lower esophageal dis-
eases, spasm, or dysmotility issues, further evaluation via a
gastroenterologist is recommended.
Conclusion
In conclusion, this article reviews the various etiologies and
pathophysiologies of LPR as well as how the otolaryngologist
may approach dysphagia in the setting of LPR. Advancements
in diagnosis and treatment are changing with an attempt to
better characterize the behavior of LPR. To date, there is no
overarching consensus or gold standard. Ultimately, the role
of the otolaryngologist, in alignment with gastroenterologists
as well as the primary care physicians, should be able to re-
view EER in relationship to other causes, rule in or rule out
other diagnoses as it relates to dysphonia and dysphagia, with
the appropriate diagnostic tests, and refrain from empiric treat-
ment alone.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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