Gastroesophageal Reflux Symptoms in

Typical and Atypical GERD

Tanisa Patcharatrakul, Sutep Gonlachanvit
J Gastroenterol Hepatol.

Abstract and Introduction

Abstract
Background/Aim: To determine the roles of gastroesophageal acid reflux (GER)
and esophageal dysmotility on typical and atypical GERD symptoms.
Methods: Two hundred thirty-six patients (159 females, age 47 14 years) with
typical and atypical GERD symptom(s) for > 3 months underwent standard water
perfused esophageal manometry (EM) and 24 h esophageal pH studies during off
therapy.
Results: Eighty seven and 93 patients had positive lower esophageal pH tests and
abnormal EM, respectively. Patients with positive lower esophageal pH test were
significantly older (50 13 vs 45 13 years, P < 0.005) and had higher prevalence
of acid regurgitation symptoms than patients with negative test (56/87 vs
72/149, P < 0.05). Patients with positive upper esophageal pH test (n = 67) also had
significantly higher prevalence of acid regurgitation symptoms (43/67 vs
74/152, P < 0.05). Prevalence of other upper gastrointestinal and respiratory
symptoms were similar between patients with positive and negative upper and
lower pH test. Patients with abnormal EM were significantly older (49 14 vs 45
13 years, P < 0.05) and had higher prevalence of chronic cough than patients with
normal EM(30/93 vs 26/143, P < 0.05). In patients with positive pH tests, the
prevalence of dysphagia, chronic cough, and hoarseness of voice were significantly
higher in patients with abnormal than those with normal EM (18/31 vs 18/56, P <
0.05; 12/31 vs 6/56, P < 0.005 and 19/31 vs 18/56, P < 0.01, respectively). Whereas
in patients with negative lower pH tests, only the prevalence of heartburn was
significantly lower in patients with normal than those with abnormal EM (26/87 vs
30/62, P < 0.05).
Conclusions: Acid regurgitation but not heartburn was associated with GER.
Esophageal dysmotility had no significant effect on acid regurgitation symptom but
associated with chronic cough, hoarseness of voice, and dysphagia only in patients
with abnormal esophageal acid exposure.
Introduction
Gastroesophageal reflux disease (GERD) is common in the general population
worldwide. The heartburn and acid regurgitation symptoms have been considered
as typical and specific symptoms for gastroesophageal reflux disease. [1] However,

not only these typical GERD symptoms but also atypical symptoms such as
noncardiac chest pain, chronic cough, hoarseness of voice, throat irritation, globus
sensation, and increase throat secretion have been reported to be associated with
GERD.[25]
Esophageal motility disorders have been reported to be present in 2548% of GERD
patients[68] and increasing prevalence with increasing severity of reflux esophagitis.
[7]
The disorders were found to be associated with delayed clearance of
gastroesophageal reflux contents[9,10] and may increase a prevalence of
laryngopharyngeal refluxes.[11] Although the gastroesophageal acid refluxes and
ineffective esophageal contractions have been considered as a major
pathophysiologic mechanism of gastroesophageal reflux disease, the interplay
between abnormal gastroesophageal acid refluxes and esophageal dysmotility with
typical and atypical GERD symptoms have not been well explored. Previous studies
in western countries suggested that the increased acid exposure in the esophagus is
associated with heartburn and/or acid regurgitation, [12,13] noncardiac chest pain,
[14]
chronic cough,[15]and chronic laryngo-pharyngeal symptoms, [16] but the effect of
esophageal dysmotility on the development of these symptoms was not clearly
shown.
Therefore, the aim of this study was to determine the roles of abnormal esophageal
acid exposure and ineffective esophageal motility on the presence of typical and
atypical GERD symptoms in patients who were suspected of having GERD.
Materials and Methods
Subjects
Consecutive patients with clinical symptoms suggestive of GERD who underwent
esophageal manometry and 24-hr esophageal pH monitoring off therapy were
included. The indications for 24-hr esophageal pH monitoring in our center were; (i)
uncertain diagnosis in patients with atypical GERD symptoms (noncardiac chest
pain, chronic cough, or chronic ear-nose-throat (ENT) symptoms; (ii) uncertain
diagnosis in patients with overlapping typical GERD and functional dyspepsia
symptoms; and (iii) patients with typical GERD symptoms who were refractory to
treatment.
The inclusion criteria were patients who were 1880 years-old, having at least one
of these following clinical symptoms for more than 3 months; (i) heartburn and/or
acid regurgitation, (ii) chronic idiopathic ENT symptoms including hoarseness of
voice, throat clearing problem, sore throat, burning throat, mucous in the throat,
and choking, (iii) chronic cough with unknown etiology, and (iv) angina-like chest
pain with negative cardiologic evaluation(s). All patients who had dysphagia or
other alarm features including age > 50 years old, anemia, or weight loss
underwent upper endoscopy within 6 months prior to the studies. The exclusion
criteria were: (i) patients with a previous history of esophageal or gastrointestinal
surgery except appendectomy and cholecystectomy, (ii) patients who could not stop
the medications that affect gastric acid secretion, gut motility and sensation
including proton pump inhibitors (PPIs). H2 receptor antagonists, tricyclic
antidepressants, selective serotonin reuptake inhibitors (SSRI), domperidone,

metoclopramide, cisapride, itopride, antihistamine, and macrolide antibiotics for 7

days prior to the studies, (iii) pregnant women, (iv) patients with clinical symptoms
suggestive of gut obstruction, (v) patients with history of advanced underlying
medical/psychological conditions such as ischemic heart disease, heart failure,
diabetes mellitus, chronic kidney disease, cirrhosis, chronic pancreatitis, a major
neurological or psychological disease, and chronic obstructive pulmonary disease
(COPD), and (vi) patients with peptic ulcer disease, cancer of the esophagus,
stomach, or pancreas, gastric outlet obstruction, achalasia, and systemic sclerosis.
This study was approved by institution review board and all participants provided
written informed consent before participating in this study.
Methods
All patients underwent esophageal manometry and 24 h esophageal pH monitoring
at the Gastrointestinal Motility Research Unit, Division of Gastroenterology,
Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok,
Thailand during January 2005 to January 2006.
On the testing date, all patients were interviewed regarding the following
information using a symptom questionnaire: (i) patient characteristics including age,
sex, occupation, underlying medical conditions, previous history of surgery, current
use of medications, symptom duration, weight, and height, (ii) the presence of
esophageal and upper gastrointestinal symptoms including chest pain, dysphagia,
acid regurgitation, heartburn, upper abdominal pain, upper abdominal burning,
upper abdominal fullness, abdominal bloating, early satiety, nausea, and vomiting,
(iii) the presence of chronic ENT and respiratory symptoms including hoarseness of
voice, throat clearing problem, sore throat, burning throat, mucous in the throat,
and choking as well as chronic cough. Each symptom was scored 03 according to
its influence on patients' daily activities: 0, absent; 1, mild (symptoms presented
but not interfere with daily activities); 2, moderate (symptoms presented and
interfere with but not preclude daily activities); 3, severe (symptoms interfere with
daily activities markedly enough to urge modification). [17] This questionnaire has
been validated and used in our previous study. [8] The patients who had heartburn
and/or acid regurgitation as their main problem were classified as typical reflux
symptom, and the patients who had upper abdominal pain or discomfort as their
main problem, accompanying with any severity of heartburn and/or acid
regurgitation, were classified as reflux-like dyspepsia.
After fasting for at least 8 h, each patient underwent an esophageal manometry to
evaluate the esophageal motor functions and to locate the location of the upper
border of the lower esophageal sphincter followed by a 24 h esophageal pH testing.
Esophageal Manometry
The esophageal manometry was performed using an eight channel-water perfused
esophageal manometry catheter with a Dentsleeve (Dentsleeve's manometry
catheter, Mui Scientific Inc., Ontario, Canada) and the state of the art manometry
system (Medtronic Inc., Minneapolis, Minnesota, USA). During esophageal
manometry study, the resting lower esophageal sphincter (LES) pressure,

esophageal contractions in response to 10 swallows of 5 mL water were evaluated.

The position of the proximal border of the LES was determined.
The esophageal manometry results was determined as described by S.J. Spechler
and D.O. Castell.[18]
24h Esophageal pH Monitoring
After esophageal manometry study, a single or dual channel esophageal pH probe
was passed through the nose into the esophagus. The distal and proximal pH sensor
was positioned at 5 cm and 20 cm above the proximal border of the LES,
respectively. The pH catheter was connected to the pH data logger (Digitrapper pH,
Medtronic Inc., Minneapolis, MN, USA). The patients were instructed to record the
time of meal ingestions, the time when the patients were in the supine or upright
position, and the time when they experienced any symptoms during the study into
a study diary. All patients were allowed to have their regular meals except acidic
foods/drinks. The time of actual meal ingestions was recorded both on the pH data
logger and on the study diary page. All patients reported at the GI Motility Research
Unit, King Chulalongkorn Memorial Hospital on the following day in the fasting
condition for removal of the pH catheter. The positive pH tests of the lower and
upper esophagus were defined as the percent time pH less than 4 at the distal
esophagus > 4.5%[19]and at the upper esophagus > 1.0%, respectively. [20]
Statistical Analysis
Data were expressed as mean SD or median (interquartile range). Unpaired t-test
or 2 test was used as appropriate to determine significant difference between two
parameters. Stepwise regression analysis was used to determine factor(s) which
associated with a positive pH testing result and abnormal esophageal manometry.
The data were analyzed using SPSS software for Windows (version 17.0, SPSS Inc,
Chicago, IL)
Results
Two-hundred and thirty six patients with GERD-related symptoms (159 females, age
47 14 years, body mass index [BMI] 23.2 3.7 kg/m 2) were included. All patients
completed standard water perfused esophageal manometry and 24 h lower
esophageal pH studies during off therapy. Two hundred and nineteen patients had
both upper and lower esophageal pH studies. Seventeen patients had only distal
esophageal pH monitoring due to nonavailability of the dual pH catheter at the time
of the studies. The patient characteristics and esophageal manometry findings of all
patients and the patients with positive and negative 24 h esophageal pH test were
demonstrated inTable 1.
Five, 61, 33, 122, and 15 patients had typical GERD, reflux like dyspepsia,
noncardiac chest pain, chronic ENT symptoms, and chronic cough as their main
problem, respectively. The duration of symptoms was 12(536) months. Among 66
patients who had typical reflux or reflux-like dyspepsia as their main problem, 59
patients (89%) previously used acid suppressions, and 80% (47/59) of these
patients had unsatisfied response. All of patients with atypical GERD symptoms

(noncardiac chest pain, chronic ENT symptoms, and chronic cough) had esophageal
manometry and 24 h pH monitoring because of uncertain diagnosis.
Eighty seven and 67 patients had positive pH tests of the lower and upper
esophagus, respectively (Table 1). Patients with positive lower esophageal pH test
were significantly older than patients with negative lower esophageal pH test (50
13 vs 45 13 years, P < 0.005). Gender and BMI were not significantly different
between patients with positive and negative either lower or upper esophageal pH
test (P > 0.05) (Table 1).
Abnormal esophageal manometry studies were presented in 93 patients, including
ineffective esophageal motility disorders (n = 82), nutcracker esophagus (n = 8),
and diffuse esophageal spasm (n= 3). Patients with abnormal esophageal motility
were significantly older than patients with normal esophageal manometry (49
14 vs 45 13 years, P < 0.05). Prevalence of esophageal dysmotility between
patients with positive and negative lower as well as upper esophageal pH test was
similar (P > 0.05).
Among 123 patients who had upper endoscopy within 6 months prior to esophageal
manometry and pH monitoring, 111 patients showed no esophagitis. Nine and three
patients had esophagitis LA grade A and grade B, respectively. No Barrett's
esophagus was found. There was no significant difference of the prevalence of
esophagitis in patients with normal and abnormal pH tests (P > 0.05) or patients
with normal and abnormal esophageal manometry (P > 0.05).
Associations Between Upper Gastrointestinal/Respiratory Tract Symptoms
and 24 h Lower Esophageal pH Monitoring/Esophageal Manometry Results
Patients with positive and negative pH tests of the lower esophagus had similar
prevalence of upper gastrointestinal and respiratory tract symptoms (P > 0.05),
except acid regurgitation symptom was significantly more prevalent in the pH
positive group (56/87 vs 72/149, P < 0.05) (Fig. 1). Prevalence of heartburn
symptom was similar between the patients with positive and negative pH tests of
lower esophagus (P > 0.05).
Patients with normal and abnormal esophageal manometry results had similar
upper gastrointestinal and respiratory symptom profile. Although patients with
abnormal esophageal manometry had higher prevalence of dysphagia symptom
than patients with normal esophageal manometry, it did not reach the statistical
significant difference (46/93 vs 53/143, P > 0.05) (Fig. 2). Only prevalence of chronic
cough symptom was significantly higher in patients with abnormal esophageal
manometry than in patients with normal manometry (30/93 vs 26/143, P < 0.05).
Logistic regression analysis also showed that age more than 45 years and the
presence of acid regurgitation symptom were the independent factors that were
significantly associated with positive lower esophageal pH result (odds ratio [OR] =
1.2(1.11.4), P < 0.005 for age; OR = 1.1(1.0041.3), P< 0.05 for acid regurgitation
symptom). In addition, age more than 45 years old and the presence of chronic
cough symptom were the independent factors that were significantly associated

with abnormal esophageal manometry (OR = 1.2(1.0021.3), P < 0.05 for age; OR =
1.2(1.0031.4), P < 0.05 for chronic cough symptom).
To determine the role of gastroesophageal acid refluxes and esophageal dysmotility
on upper gastrointestinal and respiratory tract symptom, the prevalence of each
symptom in patients with positive or negative pH tests of the lower esophagus was
compared between patients with or without abnormal esophageal manometry tests.
In patients with positive pH tests, the prevalence of dysphagia, chronic cough, and
hoarseness of voice symptom were significantly higher in patients with abnormal
esophageal manometry than in patients with normal esophageal manometry
(18/31 vs 18/56, P < 0.05; 12/31 vs 6/56, P < 0.005 and 19/31 vs 18/56, P < 0.01,
respectively). The prevalence of acid regurgitation and heartburn symptom were not
significantly different between patients with normal and abnormal manometry in
patients with positive lower esophageal pH test (P > 0.05). Whereas in patients with
negative lower esophageal pH tests, the prevalence of heartburn symptom was
significantly lower in patients with normal esophageal manometry than in patients
with abnormal esophageal manometry (26/87 vs 30/62, P < 0.05). The prevalence
of acid regurgitation and other upper GI as well as respiratory symptoms were not
significantly different between patients with normal and abnormal manometry in
patients with positive (Fig. 3a) or negative (Fig. 3b) lower esophageal pH test (P >
0.05).
Discussion
The typical GERD symptoms including heartburn and acid regurgitation have been
shown to be associated with abnormal esophageal acid exposure. [1] Although little
information on the association of gastroesophageal acid refluxes and laryngopharyngeal symptoms is available, the reflux symptom index (RSI) which includes
typical reflux, respiratory and pharyngeal symptoms has been used for the
diagnosis of laryngopharyngeal reflux disease. [21]
The interplay between esophageal motility disorders and gastroesophageal refluxes
on the development of GERD symptoms has not been clearly known. It has been
reported that ineffective esophageal motility disorder associated with prolonged
esophageal volume clearance and retrograde bolus escape, [22,23] theoretically, may
produce more regurgitation, cough, and other ENT or respiratory symptoms. In
addition, ineffective esophageal dysmotility itself can produce heartburn or chest
pain irrespective of gastroesophageal acid refluxes in previous studies [2427] possibly
due to sustained longitudinal esophageal contractions and reduced esophageal wall
blood flow. Therefore, evaluation of the association between gastroesophageal acid
refluxes and these symptoms should be evaluated together with esophageal motor
functions.
In our study, we found that acid regurgitation symptom was associated with
abnormal gastroesophageal acid refluxes with no significant effect of esophageal
dysmotility on the symptom. This may suggest that there is usually no esophageal
contraction during the occurrence of regurgitation. Patients with abnormality of
either esophageal manometry or pH study had similar prevalence of dysphagia and
hoarseness of voice symptoms compared to patients with normal results of both

tests, whereas prevalence of dysphagia, chronic cough and hoarseness of voice

symptoms were increased in patients with both abnormal gastroesophageal acid
refluxes and abnormal esophageal motility test results. This suggested that
gastroesophageal acid reflux may enhance the expression of dysphagia in patients
with esophageal dysmotility, and esophageal dysmotility may contribute to the
development of hoarseness of voice and cough symptom in patients with positive
pH tests. We observed that most patients with chronic cough who were refractory to
PPI but had low amplitude segmental simultaneous esophageal contraction or
diffuse spasm responded well to smooth muscle relaxant (nitrate) (data were not
shown). This finding not only demonstrate the interplay of esophageal motility and
esophageal acid exposure but also encourage further evaluations by esophageal
manometry and pH testings in the patients with extraesophageal symptoms
especially who have chronic cough or hoarseness of voice symptoms refractory to
acid suppression. Due to the fact that our hospital is a referral center, esophageal
dysmotility and extraesophageal symptoms were presented in quite high
prevalence. Among the 93 patients who had abnormal esophageal manometry
results in our study, 88.2% were diagnosed as ineffective esophageal motility. Eight
patients had nutcracker esophagus, and three patients had diffuse esophageal
spasm. All of these 11 patients had symptoms suggestive of GERD that fulfilled our
inclusion criteria (typical reflux, eight; noncardiac chest pain, two; chronic ENT
symptom, one), and four of these patients also had positive either upper or lower
pH test. This supported previous findings that ineffective esophageal motility is the
most common esophageal dysmotility in GERD, and other esophageal dysmotility
including nutcracker esophagus and diffuse esophageal spasm can also be found,
[6,10,28]
and we therefore included all patients with these esophageal dysmotilities for
analysis. However, after only the patients with ineffective esophageal motility were
analyzed, the outcomes did not change from described above. This suggests that
the association between esophageal dysmotility and dysphagia or ENT symptoms in
our study was the effect of ineffective esophageal contractions. A previous study in
Korean patients by Lee et al. suggested that there was no significant effect of
ineffective esophageal motility on typical GERD and laryngopharyngeal symptoms.
[29]
They found that only heartburn symptoms were associated with concurrently
abnormal esophageal acid exposure and ineffective esophageal motility. However,
the sample size of patients with ineffective esophageal motility in their study was
too small (n = 32), which may lead to type II error of their conclusions.
The acid regurgitation symptom was associated with both significant upper and
lower esophageal acid exposure. The higher prevalence of acid regurgitation
symptom compare to the prevalence of heartburn symptom in our patients suggests
that certain episodes of gastroesophageal acid reflux are not perceived as burning
sensation by the esophagus which is different from the data of western countries.
Heartburn and acid regurgitation were developed by different pathophysiologic
mechanisms. Heartburn has been reported to be induced by chemical stimulation
such as acid or capsaicin in the esophagus and sustained contractions or thickening
of the esophageal wall,[2427] but acid regurgitation developed when the regurgitated
gastric content moves up to the throat or oral cavity. We hypothesized that
capsaicin in chili may mask heartburn symptom because Thais generally consumed

spicy foods, and capsaicin mediate painful and burning sensation in gastrointestinal
tract via TRPV1 receptors. A preliminary study in our laboratory also suggested that
chronic ingestion of chili can decrease heartburn symptoms. [30,31] We do not think
Thai patients misunderstand the meaning of "heartburn" because we also found
that acid perfusion tests (data were not reported in this study) did not induce any
symptoms in most of the patients in our study which correlated with the low
prevalence of heartburn. The term "heartburn" and "acid regurgitation" in Thai
language are easy to describe by the patients, and our finding was not due to the
language issue. These may explain why there was no correlation of heartburn
symptoms and pH test results in our patients. Moreover, we found that prevalence
of heartburn symptoms in the patients with either abnormal results of esophageal
manometry or pH test were similar but significantly higher than in patients with
normal of both esophageal manometry and pH test. This finding supports the
previous reports on the mechanism of heartburn symptom other than esophageal
acid exposure, which probably is the role of esophageal dysmotility. [2427]
Ineffective esophageal contractions can be associated with cough symptoms by
contribution to higher refluxes of gastric contents leading to more prevalence of
micro-aspiration and cough. In addition, esophageal dysmotility has been reported
to be associated with bronchial hyperresponsiveness to methacholine. [32] Thus,
patients with esophageal dysmotility may also have airway hyperresponsiveness to
micro-aspiration of reflux contents and explains the results of our study.
Old age, obesity, and male patients were previously reported to be associated with
more reflux symptoms and esophagitis.[3336] Although we found that older age was
significantly associated with more prevalence of positive lower esophageal pH test,
subgroup analysis showed that this association was demonstrated only in patients
with abnormal esophageal manometry but not in patients with normal manometry.
Thus, the association between older age and higher prevalence of significant lower
esophageal acid exposure possibly depends on the presence of esophageal
dysmotility. Aging is associated with many esophageal physiologic changes that
could exacerbate refluxes. Previous studies reported the age-related impairment of
esophageal motility including low amplitude esophageal contraction as well as
ineffective esophageal peristalsis, which were associated with prolonged
esophageal acid clearance.[37,38] BMI was not significantly associated with
esophageal pH and esophageal motility test results in our study. This finding could
result from most of our patients having relatively normal BMI (less than 25 kg/m 2).
Since most GERD patients in our study had non-erosive GERD, the results in our
study should not be applied to erosive reflux disease. Further investigations are
needed to demonstrate the interplay between abnormal gastroesophageal acid
reflux and esophageal dysmotility on typical and atypical GERD symptoms in
erosive reflux disease patients.
In conclusion, acid regurgitation, dysphagia, hoarseness of voice, and chronic cough
were associated with gastroesophageal acid refluxes in our patients with typical and
atypical gastroesophgeal reflux symptoms. Acid regurgitation symptom but not
heartburn was associated with gastroesophageal acid reflux in our patients.
Esophageal dysmotility had no significant effect on the development of acid

regurgitation symptom, whereas chronic cough, hoarseness of voice, and dysphagia

symptom were associated with esophageal dysmotility only in patients with
abnormal esophageal acid exposure. This study demonstrated the interplay
between ineffective esophageal motility and gastroesophageal acid refluxes on the
pathogenesis of typical and atypical GERD symptoms.