Physiology and

Pathogenesis of
G a s t ro e s o p h a g e a l R e f l u x D i s e a s e
a b,
Dean J. Mikami, MD , Kenric M. Murayama, MD *

KEYWORDS
 Gastroesophageal reflux disease  GERD  Heartburn  Pathology of GERD
 Pathogenesis of GERD

KEY POINTS
 Gastroesophageal reflux disease (GERD) represents a wide range of pathologic
conditions that are poorly understood.
 Reflux of gastric acid most commonly presents as heartburn, but GERD can also be asso-
ciated with bile (alkaline) reflux, gastric or esophageal distention, and motility disorders.
 Pain associated with gastroesophageal reflux is secondary to the stimulation and activa-
tion of mucosal chemoreceptors by acid; the lower esophageal sphincter (LES) plays a
vital role in the frequency and severity of GERD.
 Development of Barrett esophagus is believed to be due to repeated and uncontrolled
acid exposure of the distal esophagus resulting in metaplasia, which can progress to
dysplasia of the epithelium of the distal esophagus.

INTRODUCTION: NATURE OF THE PROBLEM

GERD is a common problem treated by primary care physicians. It is estimated that up

to 20% of Americans experience symptomatic GERD weekly and that an even higher
percentage of people have heartburn monthly.1 The cost of managing a disease of this
prevalence is substantial, with estimates of direct and indirect costs exceeding $14
billion in the United States, 60% of which is accounted for by medication costs.2
Although the physiology and pathogenesis of GERD are poorly understood, heartburn,
the most common symptom, occurs in most patients and is thought to be due to the
stimulation and activation of mucosal chemoreceptors in the distal esophagus.3 The

a
Center for Minimally Invasive Surgery, Division of Gastrointestinal Surgery, The Ohio State
University Wexner Medical Center, N717 Doan Hall, 410 West 10th Avenue, Columbus, OH
43210, USA; b Department of Surgery, Abington Memorial Hospital, 1245 Highland Avenue,
Price Building, Suite 604, Abington, PA 19001, USA
* Corresponding author. Department of Surgery, Abington Memorial Hospital, 1245 Highland
Avenue, Price Building, Suite 604, Abington, PA 19001.
E-mail address: [email protected]

Surg Clin N Am - (2015) -–-

http://dx.doi.org/10.1016/j.suc.2015.02.006 surgical.theclinics.com
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2 Mikami & Murayama

pain associated with heartburn is usually due to gastric acid present in the esophagus,
but it can also be due to bile salt irritation of the esophagus, esophageal distention,
and motility disorders of the distal esophagus.4 There has been an alarming increase
in the prevalence of GERD in the United States over the past 2 decades, and although
the cause is likely multifactorial and our understanding of GERD has improved, 2
factors that seem to have contributed most are the obesity epidemic and improve-
ments in diagnostic techniques, with the routine use of endoscopy becoming more
commonplace.5,6
The wide range of symptoms from mild to severe heartburn with or without acid
exposure in combination with the multifactorial nature of GERD makes understanding
this disease challenging. GERD and its associated symptoms occur as the end prod-
uct of a collection of anatomic and/or physiologic abnormalities. Under normal circum-
stances, the intra-abdominal pressure is positive, whereas the intrathoracic pressure
is negative, a physical principle that should promote reflux of gastric contents into the
esophagus. Not surprisingly, small amounts of reflux occur throughout the day in
everyone, but pathologic GERD is prevented by the normal anatomy and physiology
of the esophagus, LES, diaphragm muscles at the hiatus, and the stomach. In general,
pathologic reflux is most commonly a consequence of the breakdown of the normal
reflux barrier of the LES, but it can also result from factors that increase the pressure
gradient between the abdomen and thorax (eg, morbid obesity and pregnancy) or
dysmotility of the esophagus, hiatus musculature, and/or the stomach. This article
examines the physiology of GERD and the pathologic conditions resulting from it.

PHYSIOLOGY OF THE DISTAL ESOPHAGUS

The distal esophagus and LES are dynamic and interrelated (Fig. 1). The antireflux
mechanism of the esophagus consists of the LES, the angle of His, and the muscle
fibers of the diaphragm. The LES is 2 to 4 cm in length of the distal esophagus and
is composed of tonically contracted circular smooth muscle located within the dia-
phragm hiatus.7,8 Gastroesophageal reflux occurs when there is inappropriate relax-
ation of the LES permitting gastric acid to enter the distal esophagus, stimulating
the chemoreceptors and causing irritation, leading to the manifestation of symptoms.
In addition, several drugs can alter the LES tone (Table 1) and affect the natural de-
fenses of the esophagus to induce heartburn; however, more commonly, many
different foods can trigger heartburn (Box 1). As mentioned, other key contributors
to reflux in addition to the drugs and foods listed are factors that increase intra-
abdominal pressure, overcoming the antireflux barrier, such as pregnancy or obesity.9
The LES is a circular muscle layer of the distal esophagus that generates a resting
pressure higher than the intra-abdominal pressure.7 The LES resting pressure is nor-
mally sufficient to prevent reflux of gastric contents into the esophagus thereby pre-
venting symptomatic heartburn, but during times of increased abdominal pressure
(ie, Valsalva maneuver, lifting, Trendelenburg position, and pregnancy) other mecha-
nisms aid in preventing reflux.10 The left and right crural muscles of the diaphragm
constitute the second mechanism of defense to protect the esophagus from reflux.
The crural muscles and the LES are anatomically connected by the phrenoesophageal
ligament (Fig. 2) and give the esophagus 2 distinct but interactive mechanisms to pre-
vent reflux of stomach contents into the esophagus.11
Swallowing is a complex physiologic process that results in the propulsion of the
food bolus from the pharynx into the esophagus and then into the stomach. This pro-
cess can be started consciously or reflexively by stimulation of areas of the mouth or
pharynx. Pharyngeal activity during swallowing stimulates the esophageal phase and
 Physiology and Pathogenesis of GERD 3

Fig. 1. Schematic view of the esophagus. The esophagus is approximately 40 cm from the
incisors to the bottom of the LES. UES, upper esophageal sphincter. (From Patel D, Vaezi
MF. Normal esophageal physiology and laryngoesophageal reflux. Otolaryngol Clin North
Am 2013;46:1025; with permission.)

Table 1
Effect of drugs on the lower esophageal sphincter tone

Increase Decrease No Change

Metoclopramide Atropine Propranolol
Domperidone Glycopyrrolate Oxprenolol
Prochlorperazine Dopamine Cimetidine
Cyclizine Sodium nitroprusside Ranitidine
Edrophonium Ganglion blockers Atracurium
Neostigmine Thiopental ?Nitrous oxide
Succinylcholine Tricyclic antidepressants
Pancuronium b-Adrenergic stimulants
Metoprolol Halothane
a-Adrenergic stimulants Enflurane opioids
Antacids ?Nitrous oxide
Propofol

? indicates possibly.
Data from Sharma VK. Role of endoscopy in GERD. Gastroenterol Clin North Am 2014;43(1):
39–46.
4 Mikami & Murayama

Box 1
Foods that are commonly associated with heartburn

Alcohol, particularly red wine

Black pepper
Garlic
Raw onions
Spicy foods
Chocolate
Citrus fruits
Coffee
Tea
Soda
Peppermint
Tomatoes

Data from Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association
Medical Position Statement on the management of gastroesophageal reflux disease. Gastro-
enterology 2008;135:1383–91; and Vaezi MF. The Esophagus: Anatomy, Physiology, and Dis-
eases. In: Flint PW, Haughey BH, Lund VJ, et al., editors. Cummings Otolaryngology: Head
and Neck Surgery. 5th edition. Philadelphia: Mosby Elsevier; 2010. p. 953–80.

because of the helical arrangement of the circular smooth muscle, the esophageal
body functions as a “worm drive” propulsive pump. The esophageal phase of swal-
lowing moves food from the esophagus into the stomach and accomplishes this
against a pressure gradient of 12 mm at rest ( 6 mm Hg pressure in the thoracic cavity
and 16 mm Hg pressure in the abdominal cavity).11 The upper esophageal sphincter
(UES) closes rapidly after the initiation of a swallow, and the contraction that follows
relaxation of the UES proceeds down the esophagus as a peristaltic wave.11 When
present, defects in primary and secondary peristalsis contribute to GERD, so under-
standing the physiology in a patient with GERD is essential.
The symptoms resulting from GERD are because of mucosal injury and are directly
related to the frequency of reflux events, the duration of mucosal acidification, and the

Fig. 2. Attachments of the phrenoesophageal membrane. (From Peters JH, Watson TJ,
DeMeester TR. Esophagus: anatomy, physiology and gastroesophageal reflux disease. In:
Greenfield LJ, editor. Surgery: scientific principles and practice. 3rd edition. Philadelphia:
Lippincott Williams and Wilkins; 2001. p. 660; with permission.)
 Physiology and Pathogenesis of GERD 5

caustic potency of the refluxate.12 The esophageal mucosa in normal individuals ex-
ists in a milieu that constantly fluctuates between damaging and protective forces.
The main mechanism that leads to most physiologic reflux events is termed transient
lower esophageal sphincter relaxations (TLESRs).13 TLESRs are the normal gastric
venting mechanism of the stomach, and a normal TLESR event is activated by
different stimuli such as distension of the stomach. In patients with GERD there is
an increased percentage of TLESRs predisposing to symptomatic heartburn. The
main relaxation is mediated through the vagus nerve, which inhibits the crural fibers
of the diaphragm (Fig. 3).14–16 The overexaggeration of this phenomenon is seen in pa-
tients with a hiatal hernia and can contribute to significant heartburn symptoms.

HIATAL HERNIA

There are 4 types of hiatal hernias (Fig. 4). Type 1 hiatal hernias are called sliding hiatal
hernias with upward migration of the LES. Type 2 hiatal hernias are called paraesopha-
geal hiatal hernias and have a normal gastroesophageal junction (GEJ) location below
the diaphragmatic hiatus with migration of gastric fundus through the hiatus. Type 3
hiatal hernias represent a combination of type 1 and 2 hernias with both the GEJ
and gastric fundus migrating through the diaphragmatic hiatus. The last and rarest
is the type 4 hiatal hernia, which involves herniation of other abdominal organs such
as the colon or the spleen. The most common type of hiatal hernia is type 1, which
is seen in 90% of patients with a hiatal hernia.15 The disruption of the crural muscle
and the phrenoesophageal ligament secondary to the hiatal hernia creates a proximal
pouch in the distal esophagus. This pouch has been termed an acid pocket and can
cause an increased environment for acid exposure.16 Development of a hiatal hernia is

Fig. 3. Neural pathway involved in TLESRs. DMV, dorsal motor nucleus of the vagus nerve;
NTS, nucleus of the solitary tract. (From Boeckxstaens GE, Rohof WO. Pathophysiology of
gastroesophageal reflux disease. Gastroenterol Clin North Am 2014;43(1):17; with
permission.)
6 Mikami & Murayama

Fig. 4. Types of hiatal hernias. (A) Type I (sliding hiatal hernia); (B) type II (paraesophageal
hernia). (C) type III (mixed type); (D) type IV (complex with other organs in hernia). (From
Laparoscopic paraesophageal hernia repair. In: Jones DB, Maithel SK, Schneider BE, editors.
Atlas of minimally invasive surgery. 1st edition. Woodbury (CT): Cine-Med, Inc; 2006. p. 129;
with permission.)

poorly understood but is more common in obese patients,17 and a hiatal hernia greater
than 2 cm is associated with a greater incidence of erosive esophagitis and Barrett
esophagus. Repeated shortening of the esophagus as a result of swallowing or retch-
ing and loss of elasticity of the phrenoesophageal ligaments are thought to be primary
contributors to the formation of a hiatal hernia.
Hiatal hernias disrupt the normal anatomic and physiologic mechanisms of the LES
and TLESRs. There is a reduction in LES length and pressure and alterations of esoph-
ageal peristalsis that can result in increased acid exposure at the distal esophagus
contributing to mucosal injury.15 In sliding hiatal hernias (type I), there is a circumfer-
ential weakness of the phrenoesophageal ligament leading to migration of the esoph-
agogastric junction in a craniad direction into the lower mediastinum. Type II
(paraesophageal) hernias result from local weakness of the phrenoesophageal liga-
ment laterally resulting in migration of the fundus into the lower mediastinum.18

GASTRIC FUNCTION

The third and often overlooked component of GERD is the contribution of gastric func-
tion. Delay in gastric emptying can cause prolonged gastric retention of food, which in
turn increases the propensity for GERD. With this phenomenon, there is an increase in
the gastroesophageal pressure gradient, gastric volume, and the volume of potential
refluxate.16 Normal peristaltic movement in the stomach is important for the clearance
and propulsion of liquids and solids toward the pylorus. Patients with gastroparesis
often feel bloated and full because of the resultant poor emptying of the stomach,
and this may lead to heartburn symptoms. It is important to distinguish between gas-
troparesis and gastric outlet obstruction because the treatment algorithm is different
 Physiology and Pathogenesis of GERD 7

for both groups and a preoperative upper endoscopy should be done in the workup of
these patients.19 Gastric outlet obstruction can be caused by ulcer disease, large
gastric polyps, or cancer, and the subsequent poor gastric emptying can lead to
gastric distention pressures that overcome the LES closing pressure and result in
GERD. Gastric emptying studies should be carried out in any patient with a history
of abdominal bloating before antireflux surgery or a preoperative esophageal manom-
etry that is incongruous with the diagnosis of GERD. A scintigraphy test of a
solid-phase meal rather than a liquid meal is the gold standard for the diagnosis of
gastroparesis.20 Gastric emptying of liquids may seem normal even in patients with
advanced gastroparesis, and gastroparesis is seen more often in patients with
GERD than in those without GERD.21

TREATMENT OPTIONS

While the surgical treatment of GERD is comprehensively addressed in the remainder

of this article, it is essential to remember that nonsurgical therapy is the mainstay of
initial treatment. However, several published trials have supported the premise that
surgery results in similar resolution of GERD symptoms as medical therapy. In a recent
study by Rossetti and colleagues22 comparing medical versus surgical therapy for
GERD in 301 patients, there was not a significant improvement of quality of life scores
(36-Item Short Form Health Survey and Health Related Quality of Life) in the medical
versus the surgical group at 1 year in patients with documented acid reflux.
In the LOTUS (Long-Term Usage of Esomprazole versus Surgery) trial, one of the
largest prospective randomized trials, 554 patients with documented GERD were
randomly assigned to receive either esomeprazole (20–40 mg/d) or laparoscopic anti-
reflux surgery. The conclusion from this multicenter trial was that both medical and
surgical antireflux therapies result in most patients remaining in symptom remission
at 5 years.23
The long-term use of proton pump inhibitors has been shown to increase the risk of
hip fractures, community-acquired pneumonia, diarrhea, and drug interactions espe-
cially in patients taking clopidogrel.24 Patients with refractory GERD despite high-dose
protein pump inhibitor therapy remain a treatment dilemma, and a pH study is indi-
cated to provide clarity regarding whether symptoms are related to acid reflux. Talaie
and colleagues25 studied 48 patients with refractory GERD, and they had a mean
DeMeester score of 10.06 (standard deviation 5 10.48). The study demonstrated
that most of patients with refractory GERD did not have acid reflux. Patients with re-
fractory heartburn should undergo impedance pH monitoring while on acid suppres-
sive therapy to best clarify the relationship between symptoms and acid or nonacid
reflux. Patients with acid or nonacid reflux that either fails or does not respond to med-
ical therapy may benefit from an antireflux operation. Unfortunately, unlike acid reflux
for which there is effective medical therapy, options are limited for patients with
nonacid reflux and antireflux surgery may be the best option.

SPECIAL CIRCUMSTANCES
Barrett Esophagus
Barrett esophagus is the most feared consequence of longstanding GERD because
there is a small but real risk of conversion to adenocarcinoma. The progression to
Barrett esophagus (metaplastic columnar mucosa) from the normal esophageal strat-
ified squamous epithelium is seen with repeated and untreated acid exposure of the
distal esophagus. The prevalence of Barrett esophagus varies between studies, but
it has been estimated that 5.6% of the adult population in the United States has the
8 Mikami & Murayama

disease.26 The risk of developing esophageal adenocarcinoma in patients with non-

dysplastic Barrett esophagus is only 0.1% to 0.3% per year, but male sex and the
presence of long-segment Barrett esophagus increases this risk. The standard
workup of a patient suspected of having Barrett esophagus starts with a standard
esophagogastroduodenoscopy and a systematic biopsy protocol with the finding of
columnar epithelium proximal to the GEJ. Esophageal biopsies should demonstrate
intestinal metaplasia with the presence of goblet cells to make the diagnosis of Barrett
esophagus. The proximal extent of the columnar metaplasia above the GEJ deter-
mines whether there is long-segment (3 cm) or short-segment (<3 cm) Barrett
esophagus.26 To prevent the progression to Barrett esophagus, the 3 main patho-
physiologic causes of GERD (ie, dysfunctional esophageal motility, a weakened
LES, and impaired gastric emptying) discussed previously need to be evaluated and
treated if present. Interestingly, routine screening of patients with GERD symptoms
may have a low yield because most patients with short-segment Barrett esophagus
have no GERD symptoms and up to 40% of patients with esophageal adenocarci-
noma have no history of symptomatic GERD. The rate of progression to adenocarci-
noma is estimated to be approximately 6% per year if high-grade dysplasia is present.
Traditionally, esophagectomy was the recommended treatment for patients with high-
grade dysplasia, but more recently endoscopic resection and ablation have become
more commonplace to eradicate dysplasia. The mainstay of treatment is the use of
proton pump inhibitors and modulation of the proinflammatory mechanisms. Antireflux
surgery for Barrett esophagus has been shown to be equally effective in the LOTUS
trial.27 The current recommendation for patients with low-grade dysplasia is endo-
scopic surveillance at 6- to 12-month intervals or endoscopic ablative therapy. Pa-
tients with nondysplastic metaplasia should undergo routine surveillance, but
currently ablation therapy is not indicated.26

Upright Versus Supine Reflux

Upright versus supine GERD symptoms differ in presentation, pathophysiology, and
management options. Patients who have upright reflux generally reflux during the
day, whereas those who have supine reflux generally have GERD symptoms at
night.28 Relaxation pressure, distal latency, and distal contractility are significantly
lower in the upright position when compared with supine.29 In general, patients with
supine reflux tend to have weakness of the LES, can have bipositional GERD (upright
and supine), and tend to have more severe GERD. Patients with upright daytime GERD
tend to have reflux primarily because of the TLESRs discussed earlier and, generally,
have less severe disease. Interestingly, TLESRs are decreased in the supine position,
so patients with normal LES function tend not to reflux in the supine position; however,
if the LES is defective as in patients with supine reflux, TLESRs are a nonfactor.28

Extraesophageal Manifestations of gastroesophageal reflux disease

Some of the more common extraesophageal complications of GERD include aspira-
tion pneumonia, reflux-induced asthma, reflux cough syndrome, and laryngitis.30
Asthma, chronic cough, and laryngitis have been shown to have a direct correlation
with GERD, whereas aspiration pneumonias are usually multifactorial.31 The usual
management is medical therapy with the mainstay of treatment being proton pump in-
hibitors. Antireflux surgery should be offered if medical therapy is ineffective, if pa-
tients cannot or will not take medications, or if complications of reflux worsen in
spite of adequate medical therapy (ie, volume regurgitation and aspiration). Unfortu-
nately, treatment outcomes and benefits for these extraesophageal manifestations
of GERD are less predictable than for heartburn or esophagitis symptoms.
 Physiology and Pathogenesis of GERD 9

Laryngopharyngeal reflux (LPR) is an extraesophageal variant of GERD, because

the main symptomatic region involves the larynx and the pharynx. Heartburn and
regurgitation are the hallmark symptoms of GERD in contrast to the symptoms of
LPR, which often include hoarseness, chronic cough, sore throat, globus pharyngeus
(“lump in the throat”), and frequent throat clearing. Recognition of LPR as an extrae-
sophageal variant of GERD has increased, and approximately 10% of all otolaryn-
gology clinic patients overall and 50% of patients with voice complaints have been
diagnosed with LPR.32

Eosinophilic Esophagitis
Eosinophilic esophagitis (EOE) is a chronic, immune-antigen-mediated disease recog-
nized with increasing frequency that is often confused with GERD. This disease is
characterized by symptoms of esophageal dysfunction clinically and by eosinophil-
predominant inflammation on endoscopic biopsy. EOE can cause dysphagia and
food impaction in both adults and children, and the diagnosis requires an esophageal
biopsy of the esophageal epithelium with 15 or more eosinophils per high-power field
(HPF).33 Eosinophils are not present in normal mucosa, but eosinophilic infiltration can
occur from various diseases, such as GERD, eosinophilic gastroenteritis, collagen
vascular disease, achalasia, and parasitic infections. Eosinophils can be observed
in the mucosa in small numbers (4 per HPF) in GERD, but the characteristic appear-
ance of EOE such as longitudinal furrows is not seen in GERD.34 The importance of
EOE in the discussion of GERD is that it occurs with increasing frequency and patients
with EOE are often treated for GERD and fall into the category of patients with “GERD
unresponsive to medical therapy.” Therefore, any patient who is refractory to medical
therapy who has dysphagia should be evaluated for EOE.

SUMMARY

GERD remains one of the most common gastrointestinal problems. The heartburn a
patient feels is related to multiple factors of which fluctuations in LES pressures is
the most important. The diagnosis, treatment, and follow-up of these patients with
GERD are significant burdens to our health care system, as is evident from the fact
that some of the most costly and commonly prescribed medications in the United
States are proton pump inhibitors. There are many options to treat GERD including
medical and surgical options, but it is unlikely that one option will be best for every pa-
tient. More studies are being conducted in this field to improve understanding of this
complex disease process.

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