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1.3.2 Characteristics ofComplications
Major complications of GERD include dysphagia (including digestive stricture, sar-
coid ring), erosive esophagitis bleeding, and esophageal adenocarcinoma. In three
population-based studies, patients received endoscopy examination regardless of
their symptoms, and the prevalence of erosive esophagitis was 6.4% in China and
15.5% in Sweden [14–16]. The prevalence of erosive esophagitis in individuals
without symptoms of GERD was 6.1% in China and 9.5% in Sweden. Erosive
esophagitis is often a transient phenomenon. In one prospective longitudinal study,
26% of patients with baseline non-erosive reux disease were found to have erosive
esophagitis by endoscopic reexamination 2years later; in another similar study,
10% of patients were found to have erosive esophagitis 5years later [17, 18]. Of
those diagnosed with grade A erosive esophagitis with Los Angeles grading system,
21% had more severe symptoms 5years later.
Although mortality attributable to erosive esophagitis is rare, the mortality rate
in the United States rose from 1.0 per million person-years during the period
1968–1972 to 2.1 per million person-years during 1988–1992 [19]. However, the
number of patients with recurrent stenosis requiring repeated endoscopic expansion
dropped from 16% in 1992 to 8% in 2000; these results may be associated with the
use of proton pump inhibitors [20]. From 2003 to 2006, the hospitalization rate of
erosive esophagitis was about 10,570 per year, and that of esophageal stenosis was
14,000 per year [12]. Esophageal adenocarcinoma is the most terrible complication
of GERD, and its precancerous lesion Barrett’s esophagus is also the sequela of
GERD [21].
1.4 Symptoms ofGERD
According to the Montreal consensus, the clinical manifestations of GERD include
uncomfortable symptoms and complications, which can be divided into esophageal
symptomatic syndrome (the former includes symptomatic syndrome and syndromes
with esophageal injury) and extra-esophageal symptomatic syndrome (the latter
includes two categories: proven related syndromes and possibly related syndromes)
[1]. Symptomatic syndromes include classic reux syndrome and reux chest pain
syndrome, while syndromes with esophageal injury include reux esophagitis,
reux stenosis, Barrett’s esophagus, and esophageal adenocarcinoma. The proven
correlating manifestations in the extra-esophageal syndrome include cough, laryn-
gitis, asthma, and dental erosion, while the possible correlating manifestations
include pharyngitis, sinusitis, idiopathic pulmonary brosis, and recurrent otitis
media [11].
Heartburn and reux are typical symptoms of gastroesophageal reux disease.
Patients usually report a burning sensation in the posterior sternum area, which rises
to the chest and radiates to the neck, throat, and occasionally to the back [19]. These
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5
symptoms usually occur after meals—especially after heavy fat meals and spicy
foods, citrus products, lipids, chocolate, or alcohol. Heartburn may be aggravated
by lying on your back and bending over. Night heartburn may cause difculty in
sleeping and affect the state of the next day [22]. Lack of sleep and perceived stress
of psychological or auditory symptoms can lower the threshold [23]. GERD can be
diagnosed based on symptoms, such as heartburn for at least 2days a week or more,
although symptoms that are troublesome and decrease happiness may not be as
frequent [1]. The frequency and severity of heartburn are not consistent with the
extent of esophageal injury.
In GERD’s clinical trials and epidemiological studies, the descriptions of reux
were even more inconsistent. According to the Montreal Consensus statement,
reux is dened as “the sensation of gastric contents regurgitation into the mouth or
down the throat” [12]. In patients with daily reux, the pressure in the lower esopha-
geal sphincter is usually lower. Many patients have gastroparesis and esophagitis is
common, making it more difcult to treat than traditional heartburn [24].
Due to the lack of diagnostic criteria for gastroesophageal reux disease, the
accuracy of typical heartburn and/or reux is difcult to dene. A study from the
UK Diamond tries to solve the problems of patients who report the above upper
gastrointestinal symptoms to their family doctors [25]. About 203/308 (66%) of the
patients diagnosed with GERD were diagnosed according to the association proba-
bility of positive symptoms suggested by endoscopic esophagitis manifestations
and/or abnormal acid exposure or 24h pH monitoring. Only 49% of people with
GERD listed heartburn or reux as their most troublesome symptom, followed by
indigestion, bloating, reux, and abdominal pain or discomfort not called indiges-
tion. The sensitivity and specicity of family physicians to diagnose GERD accord-
ing to symptoms were 63% and 63%, respectively, and that of gastroenterologists
was 67% and 70%. Questionnaires about reux symptoms did not do much better—
their sensitivity and specicity for diagnosing GERD were only 62% and 67%,
respectively. PPI diagnostic treatment also failed to increase the accuracy of diagno-
sis, and it was observed that 69% of patients with GERD and 51% of patients with-
out GERD in PPI test were actively treated [26]. Similarly, a well-performed
meta-analysis suspected PPI diagnostic accuracy test found that the sensitivity and
specicity of GERD patients accounted for 78% and 54%, respectively [27].
Less common symptoms of GERD include difculty swallowing, chest pain,
stomach heat, swallowing pain, hiccups, nausea, and vomiting. Dysphagia is con-
sidered an alarm symptom in GERD patients, indicating the need for upper gastro-
intestinal endoscopy [28]. Dysphagia usually occurs in patients with chronic
heartburn and is usually a slowly progressive solid dysphagia. Because patients
have a good appetite, weight loss is usually not noticeable. The most common cause
is ulcerative stenosis and severe inammation, but dysphagia may be the rst symp-
tom of Barrett’s esophagus with esophageal cancer. Reux chest pain is often indis-
tinguishable from ischemic heart pain. Gastroesophageal reux is a more common
cause of non-cardiac chest pain than esophageal motility disorders [1].
The most problematic and controversial symptoms associated with GERD are
chronic cough, chronic laryngitis (including hoarseness, globules, and
1 Epidemiology andPathophysiology ofGastroesophageal Reux Disease
6
laryngectomy), asthma, and dental erosion. Although the possible pathogenesis has
been identied, medical and surgical trials of antireux therapy have not yielded
denitive and consistent results [1]. Some people with GERD have no symptoms,
and this is especially true in older patients—possibly because the reux material is
less acidic or the patient’s own pain is less intense. Gastroesophageal reux disease
(GERD) is the rst complication in many elderly patients due to the long-term exis-
tence of the disease and mild symptoms. This is a particular concern for patients
with Barrett’s esophagus. Studies in the European population have found that
44%–46% of patients have no symptoms of GERD [29, 30].
1.5 Anatomic Characteristics ofEsophagus andStomach
1.5.1 Esophageal Anatomy
1.5.1.1 Esophageal Local Anatomy
The esophagus is a hollow tubular structure, measuring about 25cm from the phar-
ynx to the stomach (Fig.1.3). The pharynx is a muscular tube about 12cm long that
serves as the entrance to the esophagus and the respiratory tract. The oropharynx is
Fig. 1.3 Anatomy of the esophagus
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at the back of the mouth, and the nasopharynx is behind the nasal cavity. They are
separated by the soft palate, which is lifted up when swallowed to close the naso-
pharynx [31]. The esophagus consists of three parts: the neck, chest, and abdomen.
Cervical esophagus: The cervical esophagus is located to the left of the midline
behind the larynx and the trachea. The entrance into the cervical segment of the
esophagus is called the cricopharyngeal or superior esophageal sphincter. Thoracic
esophagus: The upper part of the thoracic esophagus passes behind the bifurcation
of the trachea (carina) and the left main bronchus, and the lower thoracic esophagus
lies behind the left lung. It enters the abdomen (the opening in the diaphragm)
through a hiatus in the esophagus. The abdominal esophagus is an area about 2–4cm
long. Also known as the lower esophageal sphincter (LES), it connects the esopha-
gus with the stomach [31]. The esophagus has three luminal strictures: the upper
esophageal sphincter near the cricoid cartilage (UES); the left main bronchus and
the aortic arch pass through the compressed esophagus of the esophageal structure,
and the LES region of the esophagus across the diaphragm [10].
The narrowest part of the esophagus is the upper esophageal sphincter (UES).
The esophagus at this point is about 14mm in diameter and is a weak area that is
relatively prone to forming esophageal diverticulum and perforation during esopha-
goscopic examination. Dysphagia and circumpharyngeal dysfunction describe the
difculty of transporting solids from the oropharynx to the upper esophagus. Causes
of the disorder include central and peripheral nervous system abnormalities and
inammatory myopathy, as well as other unknown factors. A lump in the throat is
sometimes attributed to peripheral dysphagia, although it is not always due to neu-
rological causes [31].
The aortobronchial constriction measures approximately 15–17 mm in diameter;
this is a common anatomical predilection site for stenosis. While oral medications
can induce luminal injury leading to stenosis, tetracyclines, potassium chloride for-
mulations, and nonsteroidal anti-inammatory drugs (NSAIDs) are the most preva-
lent etiological agents. The phrenic constriction represents the third stricture site,
with a diameter of 16–19 mm. The dilated segments proximal and distal to these
constriction sites are designated as the upper and lower segmental dilatations,
respectively. The upper dilated segment (adjacent to the aortobronchial constric-
tion) has a diameter of 19 mm, and the lower dilated segment (adjacent to the
phrenic constriction) measures 22 mm in diameter [2].
1.5.2 Stomach Dissection
In terms of appearance, the stomach has ve regions (Fig.1.4): the cardia and gas-
troesophageal junction (GE), the bottom, the gastric body, the gastric antrum, and
the pylorus [32–35]. The fundus and body of the stomach contain acid-secreting
glands, while the antrum contains alkaline-secreting surface epithelium and endo-
crine and gastrin G cells. The sharp angle between the circular dome of the lower
esophagus and the vertical esophagus at the GE junction can be observed by
1 Epidemiology andPathophysiology ofGastroesophageal Reux Disease
8
Fig. 1.4 Anatomy of the
stomach
laparotomy or laparoscopy. The pylorus has no visible mark, but the muscular ring
between the stomach and the duodenum is easily observed. When viewed exter-
nally, the concave border formed by the junction of the stomach’s anterior and pos-
terior walls is dened as the lesser curvature. The angular incisure—a distinct notch
located on the lesser curvature—serves as the anatomical boundary between the
acid-secreting gastric body and the non-acid-secreting gastric antrum.
In the elderly, the non-secreting acid mucosa in the gastric antrum may migrate
to the cephalic side to replace the acid-secreting mucosa, resulting in up to 30% loss
of functional acid-secreting ability. Necrosis of gastric mucosa may be due to the
presence of chronic gastritis [36–38], which increases the secretion of gastrin in the
mucosa and also reduces the resistance of local mucosa, making gastric ulcer prone
to appear (within 2–3cm of the gastric body/antrum) [39]. These are important
considerations when selecting the boundaries of distal gastrectomy for peptic ulcer.
Despite more than 200years of intense interest, there are still no satisfactory
answers to the question posed by William Beaumont [40]: Why does the stomach
fail to digest itself? And in the last 200years to understand the conditions and
mechanisms of acid secretion, new interventions and procedures may challenge our
understanding of mucosal resistance to luminal damage acidity and other adverse
luminal conditions. Over the years, several paradoxes have arisen from each of the
hypothetical gastro-protection dimensions proposed by experimental work. For
example, considerable interest is expressed in changes in the physical properties of
gastric juices in the ambient pH [41]. From the gastric mucosal interface and lumen,
mucin resists a large ow of acid, but does not diffuse protons [42]. Gastric mucin
is a complex structure characterized by cysteine-rich clusters and non-covalent
binding of protein, lipid, and carbohydrate components [43]. Mucin components are
also believed to play a role in mucosal proliferation, growth, and renewal [44], and
have been identied as factors hypothesized to promote chronic peptic ulcer healing
and malignant pathogenesis [45].
G. Wang
9
1.6 The Structural andFunctional Basis
ofGastroesophageal Reux
1.6.1 The Occurrence ofGERD
The occurrence of GERD is related to various external factors and the structure of
the gastro-esophagus itself. Among them, the structure of the gastroesophageal
junction (GEJ) is considered the initial site of GERD occurrence and the most
important anatomical basis for reux occurrence (Fig.1.5).
The normal structure of the gastroesophageal junction (GEJ) confers anti-reux
function, and its structural underpinnings include the following: the compliance and
luminal pressure of the lower esophageal sphincter (LES); the compliance and lumi-
nal pressure of the crural diaphragm (at the esophageal hiatus); the integrity of the
phrenoesophageal membrane (which anchors the esophagus within the esophageal
hiatus); the presence of an abdominal segment of the esophagus; and the acute angle
of His formed by the esophagus and gastric fundus—these components collectively
form a reux-resistant barrier. Any structural or functional abnormalities can impair
anti-reux capability, thereby increasing the incidence of gastroesophageal reux [46].
Intermittent proximal GEJ displacement into an abnormally large hiatal hernia
(HH) results in a hiatal hernia that leads to a disturbance in a variety of anti-reux
structures (Fig.1.6). GERD patients are more likely to have HH than non-GERD
patients. It is estimated that 50%–90% of GERD patients have HH, while non-
GERD patients have decreased rates of HH [47]. Transient anti-reux loss is a com-
mon cause of occasional reux symptoms, and this transient sexual dysfunction is
usually reversible. Irreversible anti-reux function and/or structural disorders, such
as signicant cardiac relaxation and HH, are the most common causes of
chronic GERD.
Fig. 1.5 The structural and functional basis of gastroesophageal reux
1 Epidemiology andPathophysiology ofGastroesophageal Reux Disease
10
Fig. 1.6 Disorder in the area of the LES: hiatal hernia
1.6.2 Gastroesophageal Hypodynamic State andGERD
Transient lower esophageal sphincter relaxation (TLESR), decreased transient esoph-
ageal peristalsis function and clearance ability, and LES stress are common patho-
logical states of GERD. Transient lower esophageal sphincter relaxation (TLESR),
impaired esophageal peristaltic function, reduced esophageal clearance capacity, and
abnormal LES pressure are common pathophysiological mechanisms of GERD [48].
UES is a high-pressure region, similar to a “nozzle” in the pharynx that acts as a
barrier between the pharynx and the esophagus, preventing air from entering the
digestive tract and reux from the esophagus into the throat. However, when high
reux breaks UES high pressure zone, different forms of hypo-physial spraying
phenomenon can be formed, namely, 3S phenomenon (surging, spraying, and spurt-
ing), participating in the formation of external esophageal reux [49, 50].
Low UES pressure is common in GERD patients (about 50%), while UES pres-
sure in patients with throat reux is signicantly lower than that in typical GERD
patients [51]. Increased and decreased UES protective function may result in laryn-
gopharyngeal reux and micro-inhalation, contributing to the development of extra-
esophageal symptoms and complications [52]. Gastroesophageal reux may also be
secondary to gastrointestinal drainage disorders [53, 54]. Functional gastrointesti-
nal diseases often overlap with GERD, further leading to a decline in patients’ qual-
ity of life and an increase in the need for medical intervention [55].
1.6.3 Reduced Visceral Threshold (Hypersensitivity)
andEnhanced Tissue Reactivity
Patients with signicant reux exposure but no obvious symptoms have increased
sensory tolerance, which may easily lead to reux complications, such as reux
esophagitis and aspiration pneumonia. Patients with normal reux load, but with
G. Wang
11
obvious correlation between symptoms and reux events, are those with visceral
hypersensitivity, which can lead to multiple reux symptoms, such as acid hyper-
sensitivity esophagus, non-acid hypersensitivity esophagus, reux pharyngitis,
GERC, and GERA [56, 57].
In most cases, acid exposure in the back circulation (digestive tract, airways,
etc.) is the primary cause of symptoms and signs. In some cases, especially in non-
erosive reux disease (NERD) and extra-esophageal syndrome, weak acid reux,
alkali reux, gas reux, and bile, digestive enzymes, and chyme in reux are both
etiological and aggravating factors of GERD [58, 59].
Anxiety, depression, and other psychological states can enhance the patients’
perception of GERD symptoms and further reduce their quality of life, forming a
vicious circle [60], which is more common in NERD patients [61, 62]. There were
also differences in the tissue reactivity of the reux canal: there were differences
between the esophageal mucosa and the airway mucosa; the same site also has dif-
ferences under the same reux exposure (whether erosion occurs, whether inam-
matory hyperplasia, metaplasia, dysplasia, or cancer ration occurs) [63].
1.6.4 Exo-esophageal Symptoms
The resistance and clearance ability of the external esophageal organs (such as the
throat and airway) to the reux is weaker than the esophagus, and the reaction
threshold of the reux is usually lower than the esophagus.
Possible mechanisms of exo-esophageal symptoms include direct effects of
reux (usually trace or gaseous) on the airway, or indirect involvement of the exo-
esophageal organs (neuro-reex or immune-mediated) [64]. The highly sensitive or
susceptible state of the backow channel signicantly reduces the threshold for
GERD symptoms and complications resulting from reux events [65]. For extra-
esophageal symptoms, reux is one of the causes (as an aggravating factor) or the
only cause. Clinically, the former is more common [66, 67].
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