Reference Section
a report by
Michael F Vaezi, MD, PhD
Associate Professor of Medicine, Center for Swallowing and Esophageal Disorders,
Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation
Abstract
Gastroesophageal reflux disease (GERD) may manifest
as laryngitis, asthma, cough, or non-cardiac chest pain.


The diagnosis of these supraesophageal manifestations
by primary care physicians may be difficult because most
patients do not have heartburn or regurgitation.


Diagnostic tests have low specificity and cause-and-
effect association between GERD and supraesophageal
symptoms is difficult to establish. Response to aggressive
acid suppression is often the best indication of GERD
etiology in patients with extraesophageal symptoms.


Presenting Symptoms of GERD
Gastroesophageal reflux disease (GERD) causes
heartburn and regurgitation, which may be
experienced daily by 7% and monthly by up to 40% of
the US population.1 This pattern of presentation is
often referred to as ýtypical GERDý. In addition to
heartburn and regurgitation, GERD may present with
other less typical symptoms. Most common ýatypicalý or
extraesophageal manifestations may include ear, nose,
throat (ENT),pulmonary (chronic cough or asthma),or
cardiac (non-cardiac chest pain) symptoms (see Figure
1).2 Patients with extraesophageal manifestations often
do not complain of the ýtypcialý GERD symptoms.


Classic reflux symptoms are absent in 40% to 60% of
asthmatics, in 57% to 94% of patients with ENT
complaints and in 43% to 75% of patients with chronic
cough.This ýsilentý nature of reflux contributes to the
difficulty in establishing the diagnosis. Thus, GERD
should be in the differential diagnosis of patients
presenting with extraesophageal symptoms, especially
when alternative diagnoses are excluded.


Two possible mechanisms may be responsible for
GERD-related extraesophageal symptoms:3 microaspi-
ration of gastric contents or vagally mediated
mechanisms. A disturbance in any of the normal
protective mechanisms may allow direct contact of
noxious gastroduodenal contents with the larynx or the
airway, resulting in laryngitis, chronic cough, or asthma.


As to the indirect mechanisms,embryologic studies show
that the esophagus and bronchial tree share a common
embryologic origin, and neural innervation via the vagus
nerve.Acidification of the distal esophagus can stimulate
acid-sensitive receptors resulting in non-cardiac chest
pain, cough, bronchoconstriction or asthma.


Asthma
Many pulmonary conditions have been associated with
GERD (see Figure 1). However, the strongest association
appears to be with asthma.6,7 Over 15 million Americans
suffer from asthma and 50% to 80% of these patients
may also have GERD. Most patients with asthma
complain of co-existing heartburn and up to 75% of
patients have excess acid reflux into the esophagus.7 The
most common reason for improvement of refractory
asthma may be treating GERD. However, the cause and
effect relationship between asthma and GERD is
difficult to establish since either condition may induce
the other.Asthma attack can cause esophageal reflux of
gastric contents by creating a negative intrathoracic
pressure that overcomes the LES barrier. On the other
hand, GERD, either by direct aspiration mechanism or
indirectly by stimulating the distal esophageal sensory
vagal nerve, may induce bronchospasm and asthma.


Additionally, asthma may also promote GERD by
having an adverse effect on esophageal physiology by
Extraesophageal Manifestations of Gastroesophageal Reflux Disease
Michael F Vaezi, MD, PhD, is an
Associate Professor of Medicine and
Full Staff member at the Cleveland
Clinic Foundation in the Department
of Gastroenterology and Hepatology
ý Center for Swallowing and
Esophageal Disorders. He completed
his fellowship in Gastroenterology at
the Cleveland Clinic Foundation
where he was elected as the Chief
Fellow. Dr Vaezi is an associate
member of the American
Gastroenterological Association, a
Fellow member of the American
College of Gastroenterology, and an
associate member of the American
Medical Association. He completed a
four-year academic residency in
internal medicine in a program
focused on clinical research at the
University of Alabama Hospitals in
Birmingham. Dr Vaezi attended the
University of Alabama School of
Medicine where he received his MD
degree in 1992.


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B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
1. Locke G R,Talley N J, Fett S L, Zinsmeister A R, Melton L J,ýPrevalence and clinical spectrum of gastroesophageal reflux: a
population based study in Olmstead County, Minnesotaý, Gastroenterology (1997), 112: pp. 1,448ý1,456.


2. Richter J E,ýExtraesophageal presentation of gastroesophageal reflux diseaseý, Semin. Gastrointest. Dis. (1997), 8: pp. 75ý89.


3. Shaker R,ýProtective mechanisms against supraesophageal GERDý, Clin. Gastroenterol. (2000), 30: pp. S3ýS8.


4. Vaezi M F, Hicks D M,Abelson T I, Richter J E,ýLaryngeal signs and symptoms and GERD: a critical assessment of cause
and effect associationý, Clin. Gastroenterol. Hepatol. (2003), :1, pp .333ý344.


5. Koufman J A,ýThe otolaryngologic manifestation of gastroesophageal reflux diseaseý, Laryngoscope (1991), 101: pp. 1ý78.


6. Sontag S J,ýGastroesophageal reflux disease and asthmaý, J. Clin. Gastroenterol. (2000), 30: pp. S9ýS30.


7. Harding S M, ýRecent clinical investigations examining the association of asthma and gastroesophageal refluxý, Am. J. Med.


(2003), 115: pp. S39ýS44.


medications used by asthma patients. Theophylline,
beta2-antagonists, and even prednisone, may increase
esophageal exposure to acid reflux by affecting the
protective mechanisms of GERD.


The history is the most important clue in diagnosing
GERD in asthmatics. Certain clues can be helpful in
identifying GERD-related asthma. Nocturnal cough
and worsening asthma symptoms after eating big
meals, drinking alcohol, or being in the supine
position; asthma presenting initially in adulthood, or
those with poor control with their usual asthma
medications, should be suspected of having GERD.


Additionally, symptoms of heartburn and
regurgitation before the onset of asthma may suggest
reflux as the causal agent.


Chronic Cough
Chronic cough, defined as cough duration greater than
three weeks, accounts for up to 38% of referrals to
pulmonary physicians and is one of the most common
clinical presentations to primary care physicians.


GERD, along with postnasal drip and asthma, is among
the three most common causes of chronic cough in all
age groups.8,9 Importantly, chronic cough may be
caused by more than one etiology in up to one-third of
patients. Similar to asthma, chronic cough can induce
GERD as well as be caused by it.Therefore, cause-and-
effect association is often difficult to establish.


GERD-related cough occurs predominantly during the
day and in the upright position. It is often non-
productive and long-standing in nature. Cough may be
the sole manifestation of GERD in more than 50% of
patients with many denying heartburn or regurgitation.


GERD should be suspected in patients with cough
whose symptoms have been chronic and who are not
smokers, on any cough inducing medications such as
ACE inhibitors, and have normal CXR and no
evidence of asthma or post-nasal drip.


Reflux Laryngitis
There is increasing evidence that GERD causes
laryngeal signs and symptoms.4,5 This is often referred
to as ýreflux laryngitisý, ýENT refluxý or recently as
ýlaryngopharyngeal reflux (LPR)ý. Many laryngeal
symptoms are associated with GERD, including
hoarseness, throat-clearing, cough, sore or burning
throat, dysphagia, and globus. Hoarseness is caused by
GERD in an estimated 10% of all cases. Studies,
particularly using 24-hour pH monitoring, in patients
with unresponsive hoarseness found that up to 55%
have acid reflux. Chronic laryngitis and difficult-to-
treat sore throat are associated with acid reflux in as
many as 60% of patients. GERD is the third leading
cause of chronic cough (after sinus problems and
asthma), accounting for 20% of cases. Globus
sensation (a feeling of choking or a lump in the throat
more prominent between meals and generally
disappearing at night) may be caused by GERD in
25% to 50% of cases. Finally, laryngeal cancer has
recently been associated with GERD. The most
common mechanism for laryngeal irritation from
GERD is direct contact with the gastroduodenal
contents. Recent studies show that pepsin and
conjugated bile acids result in laryngeal tissue
inflammation, while non-acid exposure of any
gastroduodenal agents do not cause injury.


Clinically, patients are initially evaluated by primary
care physicians and subsequently referred to ENT
physicians for laryngoscopy. Laryngoscopic evaluation
is usually the initial test when GERD is suspected.


Normal laryngeal tissue is often smooth and
glistening in nature ý GERD may be responsible for
causing laryngeal pathology, such as ulcerations, vocal
cord nodules, granuloma, or even leukoplakia and
cancer. Many laryngeal signs have been attributed to
GERD including erythema and edema of the
posterior larynx, vocal cord polyps and granuloma,
and subglottic stenosis. However, most signs are not
specific for GERD and may also occur as a result of
other laryngeal irritants, such as smoking, alcohol,
post-nasal drip, viral illness, voice overuse, or
environmental allergens.This may explain why many
patients with laryngeal signs do not respond to
GERD therapy. Recent studies suggest that laryngeal
abnormalities involving the vocal cords and medial
arytenoid walls may be more specific for GERD.This
suggests that the subjective laryngeal signs of
erythema and edema currently in common use
should be abandoned in order to increase confidence
in GERD diagnosis.


Chest Pain
Approximately 20% to 30% of patients with chest pain
have normal or insignificant cardiac catherization
findings and are classified as having ýnon-cardiac chest
painý.10,11 Earlier studies suggested that spastic
esophageal motility disorders, such as nutcracker
esophagus or diffuse esophageal spasm, were the most
common esophageal cause of chest pain. However,
recent data suggest that GERD may account for 25% to
55% of patients with non-cardiac chest pain. Direct
contact of the esophageal mucosa with gastroduodenal
Gastroesophageal Reflux Disease
8. Irwin R S, Richter J E,ýGastroesophageal reflux and chronic coughý, Am. J. Med. (2000), 95: pp. S9ýS14.


9. Irwin R S, Curley F J, French C L,ýChronic coughý, Am. Rev. Respir. Dis. (1990), 141: pp. 640ý647.


agents, such as acid and pepsin, are the most likely
etiology for the development of symptoms.


Clinically, GERD-related chest pain may mimic angina
pectoris. It can be squeezing or burning, substernal in
location, and may radiate to the back, neck, jaws, or arms.


It may be worse after meals and wake the patient from
sleep.Exercise may induce GERD,resulting in chest pain,
which can be indistinguishable from chest pain due to
coronary disease.Symptoms may last for minutes or hours
and are often relieved by antacids or acid suppressive
agents. Similar to GERD-related asthma patients, many
may also give a history of heartburn and regurgitation,
however, up to 20% may have silent reflux. Given the
dilemma in distinguishing GERD-related chest pain from
coronary disease, the clinician should always rule out the
latter before considering the former.


Diagnostic Tests
Diagnostic tests available to detect GERD include
barium swallow, endoscopy, and 24-hour pH
monitoring. In most patients with typical GERD,
history is sufficient to diagnose and initiate empiric
therapy without the need for the any testing.12 Testing
is usually indicated in patients with persistent symptoms
despite therapy, those with warning symptoms (i.e.


dysphagia, weight loss, bleeding) prior to surgical
fundoplication or in those with long-standing GERD
to rule out Barrettýs esophagus.


Patients with supraesophageal GERD typically have
low prevalence of endoscopic esophagitis. Most studies
report only mild esophagitis in 10% to 30% of patients
with supraesophageal GERD.2,4 This is in contrast to
typical GERD, where the reported prevalence may
range from 47% to 79%. Twenty-four-hour pH
monitoring,once considered to be the gold standard for
detecting esophageal acid exposure, suffers from poor
sensitivity (70% to 80%).The false negative rate for this
test may range from 20% to 50%.Therefore, a negative
test may not exclude the diagnosis of GERD in patients
with supraesophageal complaints. To make matters
more complicated, a positive test does not confirm that
GERD is the etiology for the supraesophageal
symptoms.The cause and effect relationship is usually
best established with sustained response to acid-
suppressive therapy.Therefore, diagnostic tests in extra-
esophageal GERD should usually be reserved for
those unresponsive to therapy or have other indications
for testing. Recent development of impedance
monitoring allows for detection of acid as well as non-
acid liquid or gas reflux events and may increase the
sensitivity of GERD diagnosis in this group of patients.


However, the over-diagnosis of GERD in many
patients with extraesophageal symptoms may be the
most important limitation for any of the currently
available diagnostic tests.


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B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
Reference Section
Figure 2:Treatment Algorithm for Extraesophageal
GERD
Ensure compliance
Change PPIs
Increase PPI dose
Suspected Supraesophageal GERD
BID PPI x 3ý4 months
Sx better
24-hour pH test Titrate Down
Normal Abnormal
Other dx
Less likely on BID PPI therapy
10. Richter J E,ýChest pain and gastroesophageal reflux diseaseý, J. Clin. Gastroenterol. (2000), 30: pp. S39ýS41.


11. Ockene I S, Shay M T,Alpert J S, et al.,ýUnexplained chest pain in patients with normal coronary arteriograms.A follow-up
study of functional statusý, N. Engl. J. Med. (1980), 30: pp. 1,249ý1,252.


12. Devault K R, Castell D O,ýUpdated guidelines for the diagnosis and treatment of gastroesophageal reflux diseaseý, The Practice
Parameters Committee of the American College of Gastroenterology (1999), 94: pp. 1,434ý1,442.


Figure 1: Extraesophageal GERD
Extraesophageal Manifestations of GERD
ENT Pulmonary Cardiac Other
laryngitis
sinusitis
otitis
ulcers
granuloma
polyps
laryngeal CA
(hoarseness, throat
clearing, globus, sore
or burning throat)
asthma
chronic cough
pneumonia
bronchitis
interstitial fibrosis
chest pain
sinus arrhythmia
dental erosions
halitosis
Treatment
The dilemma in treating patients suspected of having
supraesophageal GERD is their unpredictable response
to acid-suppressive therapy. Response to acid
suppression is usually less predictable in this group of
patients. This is most likely a reflection of the true
prevalence of GERD among this group of patients;
GERD may be only one of several etiologies causing
the patientýs symptoms and signs.Thus, given the poor
specificity of diagnostic testing, response to empiric
therapy is currently the ýgold standardý in diagnosing
GERD in this group of patients.


Due to their unpredictable response to acid suppression,
there are currently no accepted protocols for the most
cost-effective treatment of patients with supraesophageal
GERD. H2 receptor antagonists (H2RAs) usually
produce only mild to moderate improvements, at best.


Although not FDA-approved in supraesophageal
GERD, recent studies recommend using the more
effective proton-pump inhibitors (PPIs).13ý15 Clinical
response rate ranging from 60% to 98% has been
reported with medical therapy.Most studies now suggest
using twice-daily (BID) dosing of PPIs.2,4 Surgical
intervention is usually less effective in supraesophageal
GERD than patients with typical GERD symptoms of
heartburn and regurgitation. This again, reflects the
multifactorial nature of supraesophageal GERD
symptoms in many patients.


A potential treatment algorithm for supraesophageal
GERD is shown in Figure 2. Initial empiric therapy
with BID PPIýs for two to four months is generally
recommended. In patients with laryngitis, longer
treatment duration may be needed for resolution of
all laryngeal inflammation. In patients with asthma, it
may take up to three months to see improvement in
bronchial symptoms. However, many patients may
report a partial response of the supraesophageal
symptoms by six to eight weeks. In those who have
minimal or no improvement by four months of BID
PPI therapy, 24-hour pH monitoring on therapy may
identify the small subgroup of patients who continue
to have abnormal esophageal acid exposure. However,
in majority of patients, lack of response is an
indication that GERD is most likely not an etiologic
factor in patients supraesophageal symptoms. In this
group other causes for patientsý symptoms should
be investigated. a73
Extraesophageal Manifestations of Gastroesophageal Reflux Disease
13. Shaw G Y, Searl J P,ýLaryngeal manifestations of GER before and after treatment with omeprazoleý, South Med. J. (1997),
90: pp. 1,115ý1,122.


14. Wo J M, Grist W J, Gussack G et al.,ýEmpiric trial of high-dose omeprazole in patients with posterior laryngitis:A prospective
studyý, Am. J. Gastro (1997), 92: pp. 2,160ý2,165.


15. Vaezi M F, Hicks D M, Ours T M, Richter J E,ýENT manifestation of GERD:A large prospective study assessing treatment
outcome and predictors of responseý, Gastroenterology (2001), 120: p.A636.


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