ARTICLE IN PRESS

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Disease-a-Month xxx (xxxx) xxx

Contents lists available at ScienceDirect

Disease-a-Month

journal homepage: www.elsevier.com/locate/disamonth

Natural history, pathophysiology and

evaluation of gastroesophageal reflux
diseaseR,✩✩
Ahmed T. Chatila, MD a, Minh Thu T. Nguyen b, Timothy Krill, MD c,
Russell Roark, MD a, Mohammad Bilal, MD c,∗, Gabriel Reep, MD c
a
Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, United States
b
The University of Texas Medical Branch School of Medicine, Galveston, TX, United States
c
Division of Gastroenterology & Hepatology, The University of Texas Medical Branch, Galveston, TX, United States

a r t i c l e i n f o a b s t r a c t

Gastroesophageal reflux disease (GERD) is one of the most

Article history: common diseases encountered by both internists and gas-
Available online xxx troenterologists. GERD can cause a wide variety of symptoms
ranging from heartburn and regurgitation to more atypical
Keywords:
symptoms such as cough, chest pain, and hoarseness. The
Gastroesophageal reflux disease
diagnosis is often times made on the basis of history and
GERD
Heart burn clinical symptomatology. The prevalence of GERD is currently
Evaluation estimated to be 8–33% with the incidence of disease only
expected to increase over time. Although most cases of
GERD can be diagnosed based on symptoms and clinical
presentation, the diagnosis of GERD can be challenging when
symptoms are atypical. In this review, we provide a com-
prehensive summary of the epidemiology, pathophysiology,
evaluation and diagnosis of gastroesophageal reflux disease.
© 2019 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

R
Disclaimers: None.
✩✩
Sources of support/funding: This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
∗
Corresponding author.
E-mail address: mobilal@utmb.edu (M. Bilal).

https://doi.org/10.1016/j.disamonth.2019.02.001
0011-5029/© 2019 Elsevier Inc. All rights reserved.

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
of gastroesophageal reflux disease✰, Disease-a-Month, https://doi.org/10.1016/j.disamonth.2019.02.001
 ARTICLE IN PRESS
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Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Motor anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Anatomical anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Impaired mucosal resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Tobacco smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Hiatal hernia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Clinical manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Typical signs and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Extraesophageal presentation of GERD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Chronic cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Laryngitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Evaluation of GERD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Clinical evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Diagnostic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Diagnosis of GERD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Presumptive diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Diagnostic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
PPI Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Barium swallow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Esophagogastroduodenoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Ambulatory reflux monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Esophageal manometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Introduction

Gastroesophageal reflux disease (GERD) is one of the most common diseases encountered by
both interests and gastroenterologists. The estimated prevalence of disease ranges from 8 to 33%
with the incidence of disease only expected to increase over time.1–7 GERD is a condition that
occurs when the reflux of gastric contents causes troublesome symptoms and complications in
patients. Despite the understanding of numerous risk factors, evaluation modalities, and diag-
nostic tests, GERD continues to affect a large fraction of patients. In this report we provide a
comprehensive review of the epidemiology, pathophysiology, evaluation and diagnosis of GERD.

Epidemiology

GERD is a chronic, commonly encountered disease in both the primary and specialty clinic
settings. The prevalence of GERD in the Western world is estimated to range from 10% to 25%,
while the prevalence in Asia is reported to be <5%.1–4 , 6 , 8 The prevalence of GERD symptoms
had risen about 50% until 1995, but has since remained constant.9 In addition, GERD carries a
significant economic burden with its evaluation and management, and is estimated to be greater
than $10 billion per year.10

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
of gastroesophageal reflux disease✰, Disease-a-Month, https://doi.org/10.1016/j.disamonth.2019.02.001
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GERD can present with a wide variety of symptoms. Typical symptoms of GERD include
heartburn and regurgitation,7 , 8 , 11–13 while atypical symptoms include chronic cough, asthma,
hoarseness, chronic laryngitis, chest pain, dyspepsia, and nausea.6 , 7 , 11 , 13 Weekly GERD like
symptoms were reported in up to 20–28% of patients with clinically troublesome symptomatol-
ogy seen in 6% of the population.7 , 8 , 14 This can further be stratified with 8–54% of patients suf-
fering with GERD reporting upper abdominal symptoms, and 21–59% of patients suffering from
GERD reporting heartburn and/or regurgitation.15 Symptomatic patients report significantly more
lifestyle related problems and decreased health related quality of life (HRQL) including missed
work days, decrease leisurely activities, and increased difficulties with household activities.14 , 16
Although the vast majority of GERD cases (79.2%) were considered uncomplicated, one study
reported up to 20.8% of GERD cases having complications associated with GERD.17
GERD is known to involve both genders, all age groups and all races.5 , 6 A comparison of the
regional and continental prevalence of GERD shows that there is little variations between rates
in North American and Europe, however there was a much lower reported prevalence of GERD
in Asian countries.1 , 18 Factors associated with increase in GERD related symptoms include fe-
male gender, obesity (increased body mass index) and increasing age.19 , 20 Both white and black
individuals have a high prevalence of GERD, with black patients having a lower prevalence and
persistently lower risk of developing esophagitis.21

Pathophysiology

Gastroesophageal reflux disease (GERD) is a chronic relapsing condition that occurs when
the reflux of gastric contents from the stomach causes troublesome symptoms and/or compli-
cations in patients.22–25 The reflux from the stomach provokes symptoms and complications,
which generally includes heartburn and regurgitation.15 , 25 GERD is thought to progress when
factors that are harmful to the esophagus overcome many of the mechanisms that are protec-
tive – the gastroesophageal (GE) junction barrier, acid clearance, and mucosal resistance. When
these protective methods are overcome, refluxate composed of acid, pepsin, duodenal content,
and pancreatic enzymes cause direct damage to the mucosa leading to symptoms and compli-
cations of GERD.6 , 25–28 The mechanisms directly involved in the pathogenesis of GERD include:
(1) motor anomalies, (2) anatomical anomalies, (3) and impaired resistance of the mucosa.

Motor anomalies

Major motor abnormalities that lead to GERD include impairment of the resting tone of the
lower esophageal sphincter (LES), increased frequency/duration of the transient LES relaxation,
impaired acid clearance, and delayed gastric emptying.25 , 27
The LES typically maintains a high-pressure zone that is 15–30 mmHg higher than intragas-
tric pressures in resting conditions, however a minority of patients have a low-pressure LES
permitting the stomach pressure to exceed the LES pressure, hence, leading to reflux.25 Factors
that lead to the decreased LES tone include hormones such as cholecystokinin and progesterone,
medications including nitrates and calcium channel blockers (CCB). Other factors include specific
foods such as chocolate and high fat foods, and alcohol, smoking, and caffeine.25 , 29 , 30
These motor abnormalities can lead to impaired acid clearance. Patients with GERD can have
clearance times that are significantly longer than those without GERD and often can be asso-
ciated with disease states such as scleroderma.28 In addition, a small subset of patients with
delayed gastric emptying may experience GERD, which may be secondary to gastric distention.31

Anatomical anomalies

Patients with hiatal hernias are more susceptible to GERD with a high incidence of GERD
seen in patient with a hiatal hernia.32 The likely cause of this is due to the proximal stomach

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
of gastroesophageal reflux disease✰, Disease-a-Month, https://doi.org/10.1016/j.disamonth.2019.02.001
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being dislocated through the diaphragm hindering the effect of the LES by reducing the LES
pressure and altering its responsiveness.33 , 34

Impaired mucosal resistance

The capability of the esophagus to resist injury is a major element in the development of
GERD. The esophagus contains many structural and functional components to provide a protec-
tive defense to gastric contents including pre-epithelial defenses and epithelial defenses.25

Natural history

The natural history of GERD is difficult to discern despite the increase prevalence of the con-
dition.35 This is due to the lack of longitudinal, prospective studies prior to the universal avail-
ability of proton pump inhibitor (PPI) therapy and ambiguity in the condition’s classification
when overlapped with similar symptoms of other functional gastrointestinal tract disorders.35 , 36
GERD is categorized into two major subtypes: erosive reflux disease (ERD) and non-erosive re-
flux disease (NERD).35 , 36 Up to 70% of GERD patients have the NERD subtype, where there are
no signs of mucosal damage endoscopically.35–37 Retrospective data shows that NERD and mild
esophagitis typically remain unchanged.36 , 38 The annual progression from NERD to ERD ranges
from 0% to 30%, from mild to severe ERD is 10–22%, and from ERD to Barrett’s esophagus is
10–22%.36 , 38 However, further investigation is needed to obtain a better understanding of the
natural history of GERD.

Risk factors

GERD is influenced by both heritable and environmental factors.39 Recognized risk factors
include obesity, genetics, tobacco smoking, pregnancy, hiatal herniation, and certain medications
and foods.40 , 41

Obesity

Lifestyle factors, such as an increased body mass index (BMI) and obesity, are strongly as-
sociated with GERD.39–41 Proposed mechanisms include increased abdominal-thoracic pressure
gradient, greater amount of transient lower esophageal sphincter (LES) relaxation, and upregu-
lated secretion of hormones from adipose tissue.42 In 2009, one study featuring 1659 patients
showed that an increase in BMI correlated with an increase in esophageal acid exposure, with
about 13% of the variation attributable to BMI changes.41 The same study concluded that obese
individuals are more than twice as likely to possess a mechanically defective LES.41 Interestingly,
there are no definite BMI cutoff point linked with development of GERD.41

Genetics

Twin studies show a 30–31% heritability for the disease, with an increased prevalence in
monozygotic twins compared to dizygotic pairs.39 , 43 , 44 Currently, there are no established chro-
mosomal loci connected with GERD.39 However, research points towards single-nucleotide poly-
morphisms in numerous genes, such as anti-inflammatory cytokine and DNA repair genes, NHC,
CCND1, and FOXF1, that have been linked with elevated acid reflux risk.39 , 45–48 Future studies
may illuminate how these genes precisely influence the manifestation of acid reflux.

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
of gastroesophageal reflux disease✰, Disease-a-Month, https://doi.org/10.1016/j.disamonth.2019.02.001
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Tobacco smoking

Smoking is connected to GERD in a dose-dependent manner.39 , 49 Risk is deemed to be ap-

proximately 37% in women and 53% in men.49 Chronic cigarette smokers have significantly lower
LES pressure compared to non-smokers.50 Meanwhile, actively smoking acutely increases rate of
acid reflux events via transient LES relaxation and abrupt increase in intra-abdominal pressure
secondary to deep inspiration or coughing.50

Pregnancy

Heartburn is a common concern during pregnancy, with incidence between 30% and 50%,
and even up to 80% in certain populations.51–53 Many symptomatic pregnant women have new-
onset acid reflux, as opposed to exacerbation of preexisting disease.52 Most women experience
noticeable symptoms after 5 months of gestation, with increasing severity as the pregnancy
progresses.52 , 53 One proposed mechanism involves decreased LES under influence of elevated
estrogen and progesterone.52 Another mechanism is the increased intra-abdominal pressure sec-
ondary to an enlarged gravid uterus.52

Hiatal hernia

A hiatal hernia is a type of hernia where abdominal organ(s), typically the stomach, enters
through an opening in the diaphragm into the thoracic cavity.39 , 54 The most common compli-
cation of hiatal herniation is GERD. Risk factors include any activities that may increase intra-
abdominal pressure (e.g. heavy lifting, recurrent hard coughing, straining), obesity, and older
age.54 The incidence of hiatal hernia in patients with GERD ranges from 0.8% to 43%, with vary-
ing degrees of severity.39 , 55 There is a direct and positive correlation between the size of the
hiatal hernia and severity of the acid reflux, as evident clinically by more frequent coughing and
wheezing spells.54

Medications

Several classes of medications are thought to trigger GERD related symptoms, including cal-
cium channel blockers (CCBs), tricyclic antidepressant (TCAs), anticholinergics, antidepressants,
theophylline, benzodiazepines, among many others.39 , 56 These medications are known to either
damage esophageal mucosa, reduce LES tone, and/or affect esophageal motility, resulting in in-
creased propensity for reflux.39 , 56

Foods

Certain foods have been associated with increased acid reflux events, including beverages
containing caffeine, spicy foods, fatty foods, beer, chocolate, etc.57 , 58 Similar to medications,
pathogenesis is lowered LES pressure and/or manipulation of esophageal motility by the sub-
stances.58 However, studies have shown variable results if these foods can actually lead to GERD.

Clinical manifestations

Typical signs and symptoms

The two most common symptoms associated with GERD are heartburn and regurgitation
(Fig. 1). Heartburn is described as a burning sensation in the retrosternal region of chest, and is

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
of gastroesophageal reflux disease✰, Disease-a-Month, https://doi.org/10.1016/j.disamonth.2019.02.001
 ARTICLE IN PRESS
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Heartburn
Typical
Symptoms
Regurgitaon

Clinical
Comprhensive
Evaluaon of
history
GERD Asthma

Atypical
Chronic Cough
Symptoms

Laryngis

Fig. 1. Clinical evaluation of GERD.

typically postprandial.24 Regurgitation is the feeling of gastric contents refluxing back into the
mouth or throat.24 Other signs include nausea, dysphagia, chest pain, globus sensation, and/or
hypersalivation. Majority of cases of GERD can be diagnosed clinically based on history and
symptomatology, however, it may need to be confirmed with pH monitoring or an esophagogas-
troduodenoscopy (EGD).59

Extraesophageal presentation of GERD

Asthma
GERD is commonly reported in asthmatic patients. One study reports a co-morbidity rate of
approximately 77%.60 A systematic review consisting of 28 studies showed the prevalence of re-
flux symptoms in asthma patients to be 59.2%, as compared to 38.1% in controls.60 , 61 Medical
anti-reflux therapy is shown to improve asthma-related symptoms (e.g., wheezing, cough, dys-
pnea, chest tightness) in approximately 70% of patients.60 , 62 There are three postulated mecha-
nisms for why acid reflux induces bronchoconstriction, thus exacerbating asthma-related symp-
toms: increased bronchial reactivity, micro-aspiration of acid and other gastric contents into
upper airway and increased vagal tone.60 , 61 , 63–65 For those with co-existing asthma and reflux
symptoms, particularly moderate-severe subtypes of asthma, an empiric trial of twice daily PPI
therapy is suggested.61 , 66

Chronic cough
In patients with the chief complaint of a chronic cough (defined as a persistent cough for
more than eight weeks), GERD is reported to be the third leading cause, behind asthma and
postnasal drip.67 , 68 While many patients present with the typical constellation of acid reflux
symptoms (heartburn, sour taste, etc.), over 40% of patients may show no apparent symptoms
other than chronic cough.67 , 69 , 70 Therefore, clinical suspicion for GERD must be high in patients
with upper airway cough syndrome. GERD may induce cough via several mechanisms which
include aspiration of gastric contents, stimulation of receptors in the upper respiratory tract,
or trigger of the esophageal-tracheobronchial cough reflex by the presence of distal esophageal
acid.69 , 71–73 In a study consisting of 22 patients, there was a clinically significant increase in
frequency of cough with acid perfusion in the distal esophagus.73

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
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Laryngitis
Laryngitis and hoarseness are less common extra-esophageal manifestations of GERD. Laryn-
gitis, or the inflammation of the larynx can occur from acidic irritation. It is also commonly
known as laryngopharyngeal reflux disease (LPRD), although LPRD may be a separate and dis-
tinct entity involving the upper esophageal sphincter in the absence of GERD.74 , 75 LPRD presents
with hoarseness, mild dysphagia, globus sensation, and non-productive throating clearing.74 , 75
Interestingly, only approximately 35% of people with confirmed LPRD report of heartburn.76 It is
theorized that GERD causes laryngitis via either a direct or indirect mechanism. For the direct
mechanism, the larynx is irritated by reflux of gastric contents that reach the larynx.75 For the
indirect mechanism, acid reflux in the esophagus triggers laryngeal reflexes that then lead to
activation of vagal tone (e.g., chronic, bronchoconstriction).75 Similar to classic GERD symptoms,
PPI therapy is recommended for those with GERD-induced laryngeal symptoms.77

Evaluation of GERD

The evaluation of GERD can be complicated at times, and requires a combination of subjec-
tive and objective findings. Evaluation of GERD begins with a thorough history regarding pa-
tient’s clinical symptoms, objective findings on physical exam and testing, evaluation of anatom-
ical variances, and exclusion of other common causes of patient’s symptoms.78

Clinical evaluation

The clinical evaluation of a patient begins with a comprehensive history that addresses the
patients problems while paying attention the presence of typical esophageal signs and symp-
toms of GERD (heartburn and regurgitation) as well as atypical or extraesophageal symptoms
(asthma, chronic cough, laryngitis, etc.).24 , 67 , 69 , 74 , 78 The clinical evaluation should also address
the severity of symptoms based on the time of day, any foods or meals that may exacerbate
these symptoms, and the resolution of symptoms with anti-reflux medications (including the
dosage, time, and effect of these medications).78 , 79 Typical symptoms along with the resolution
of reflux symptoms with anti-reflux medications including PPIs can reliably diagnose GERD.79 It
is important to note that not all patients with typical symptom related to GERD actually have
underlying GERD, and many a times these symptoms can be secondary to other functional and
organic diseases.78
Questionnaires and system based surveys have been developed to assist in diagnosing GERD
and include the Reflux Disease Questionnaire and ReQuest symptom scale. These survey’s help
estimate patients’ symptoms, however, they have modest sensitivities and specificities and have
shown to be limited in their diagnostic values.78 , 80 , 81 In current practice, the diagnosis and
treatment of GERD is based on symptomatology alone, and is typically the accepted method-
ology seen in the clinical diagnoses of GERD.6 , 7

Diagnostic evaluation

Current diagnostic modalities for the evaluation and diagnosis of GERD are evolving quickly
in today’s healthcare environment.78 , 82 Since there is not a single gold standard test to diagnose
GERD, the diagnosis falls on the combination of a PPI trial, diagnostic EGD and ambulatory pH
monitoring.6 , 7 , 78 , 82 Other modalities such as barium esophagograms, high resolution esophageal
manometry and gastric emptying studies can help rule out other diseases that might be con-
tributing to, or mimicking GERD related symptoms.

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
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Diagnosis of GERD

As mentioned above, that the diagnosis of GERD is usually a clinical one. However, if the
presumptive diagnosis is insufficient or the patient does not experience resolution of symptoms
after initiation of treatment, other diagnostic modalities are used to confirm the diagnosis of
GERD.6 , 7 Understanding the utility and evidence behind these tests in the diagnosis of GERD is
essential.

Presumptive diagnosis

In routine clinical practice, GERD is routinely diagnosed based on the classic symptoms of
heartburn and regurgitation. This presumptive diagnosis of is based on typical symptoms of
GERD and current societal guidelines strongly recommend initiation of therapy in this setting
with intermediate evidence.7

Diagnostic evaluation

The symptoms related with GERD are neither specific nor sensitive to make a diagnosis of
GERD.83 Therefore, in patients when diagnosis is uncertain or an adequate response to anti-acid
therapy is not achieved, other diagnostic modalities are used for the diagnosis of GERD.

PPI Trial
A PPI trial provides a simple diagnostic evaluation of GERD that is pragmatic, easy to imple-
ment, and provides symptomatic relief to the patient. A PPI trial includes the initiation of PPI
treatment with a symptomatic response to therapy seen in a patient. There are no clear guide-
lines on the length of therapy that must be initiated and no standard as to which PPI or what
dose of PPI should be started during this trial.6 A recent meta-analysis displayed there is a lim-
itation to this approach of testing with a sensitivity of 71% and specificity of 54% even with the
resolution of symptoms.6 , 7 , 84 This report demonstrated that even a successful short term treat-
ment of GERD with a normal/high dose PPI for 1–4 weeks does not confidently establish the
diagnosis of GERD.84

Barium swallow
Barium swallow has become less frequently used in the detection and recognition of anatom-
ical abnormalities that can contribute to GERD or mimic symptoms of GERD.78 It should be un-
derstood however, that there is no diagnostic role barium swallow, and the presence of reflux
during this exam does not correlate with corresponding pH-monitoring.78 , 85

Esophagogastroduodenoscopy
An EGD is needed in patients with typical GERD symptoms who do not respond to empiric
PPI therapy. An EGD can help in the diagnosis of GERD by evaluating for complications of GERD
such as esophagitis, strictures, and Barrett’s esophagus. Biopsies can also be obtained in the
esophagus to look for any alternative diagnoses.6
Confirmatory evidence of GERD upon EGD is very specific. An international consensus group
suggests that the presence of high grade esophagitis (Los Angeles Classification C or D), peptic
strictures, histology proven Barrett’s esophagus of greater than 1 cm, or esophageal acid expo-
sure greater than 6% are appropriate diagnostic findings to define pathological GERD.6 , 7 , 86 It is
important to note that despite this, many times an EGD yields a very low sensitivity in the
diagnosis of GERD.6 While, peptic structuring and high grade esophagitis are considered diag-
nostic and specific for GERD, only about 30% of patients who were treatment naive with typical
symptoms and less than 10% of patients following a PPI trial had these findings.35 , 87 Approxi-
mately, 5–15% of patients with chronic GERD symptoms have endoscopic findings suggestive of

Please cite this article as: A.T. Chatila, M.T.T. Nguyen and T. Krill et al., Natural history, pathophysiology and evaluation
of gastroesophageal reflux disease✰, Disease-a-Month, https://doi.org/10.1016/j.disamonth.2019.02.001
 ARTICLE IN PRESS
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Barrett’s esophagus with histological confirmation shown to be evident in only half of these pa-
tients.6 , 88–90 In summary, it is important to note that endoscopic findings have a high specificity,
but a low sensitivity for diagnosis of GERD.

Ambulatory reflux monitoring

In patients with normal endoscopic findings and/or atypical symptoms (asthma, laryngitis,
and chronic cough), ambulatory reflux monitoring can be used to help provide confirmatory
evidence of GERD.6 , 86 , 91 Ambulatory reflux monitoring can be used on patients who are both
receiving and not receiving treatment for GERD. Patients off medications who may benefit from
ambulatory reflux monitoring include those who have not fully responded to PPI therapy with-
out a previous diagnoses of GERD, those undergoing pre-operative evaluation for endoscopic
anti-reflux procedures, and patients who continue to have GERD symptoms after anti-reflux
surgery. Patients on therapy who may benefit from reflux testing include those needing con-
firmation of acid control in the setting of complicated GERD with strictures and esophagitis and
to assess alternative diagnoses in patients with previously established diagnosis GERD.6 , 7 , 91 , 92
Ambulatory reflux or ambulatory pH monitoring helps to demonstrate GERD through the de-
tection of acid exposure time (AET). It allows to see if reflux episodes occur alongside symptoms
thus confirming and/or excluding GERD.6 The primary outcome of the ambulatory reflux study
over 24 h is the AET with extended recording times being implemented with increasing diag-
nostic yields in patients who have negative tests over 24 h.6 , 93 An abnormal AET is proportional
to the degree of abnormality with the Lyon consensus on the diagnoses of GERD proposing that
an AET of less than 4% be considered normal and an AET of greater than 6% being abnormal and
diagnostic of GERD. Intermediate values are seen as inconclusive.6
Another variant of pH monitoring in the ambulatory is pH-impedance monitoring. This tech-
nique helps characterize reflux events using both a pH electrode and series of impedance elec-
trodes detecting all episodes of reflux – liquid, gas, or mixed.6 , 86 Impedance monitoring is very
helpful in the diagnosis of GERD, but it is cumbersome to perform, and can be challenging to
interpret, and provides limited additional diagnostic yield.94

Esophageal manometry
Esophageal manometry is currently not used specifically in the diagnoses of GERD, but does
play a pivotal role in the evaluation of patients with GERD, since it helps exclude other con-
ditions that could predispose or mimic GERD like symptoms.7 This test is used to evaluate
esophageal motility disorders and is useful in assessing patients for alternative disorders prior to
anti-reflux surgeries or when symptoms do not respond with GERD therapy.6 , 78 Common disor-
ders mimicking GERD include esophageal motility disorders such as achalasia and scleroderma
which can be misdiagnosed as GERD.7 , 78

Conclusion

GERD remains one of the most common conditions encountered in primary care and gas-
troenterology clinics. Despite its increased prevalence, the variation in presentation of GERD can
make the evaluation and diagnosis challenging. There continue to be knowledge gaps in our un-
derstanding of the risk factors, diagnostic modalities, and evaluation of GERD. In majority of the
cases, clinical symptomatology alone is sufficient in making the diagnosis. However, in patients
with atypical symptoms and those who do not respond to anti-acid therapy, other diagnostic
modalities such as esophagogastroduodenoscopy, and ambulatory pH testing can help confirm
the diagnosis. Barium esophagograms and high resolution esophageal manometry can be helpful
to evaluate for conditions that can predispose or mimic GERD like symptoms.

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