Gastroesophageal Reflux Disease (GERD)☆

Kenneth K Wang and Juan Reyes Genere, Mayo Clinic, Rochester, MN, United States
© 2020 Elsevier Inc. All rights reserved.

Glossary
Ambulatory pH monitoring A test considered a gold standard for diagnosing GERD by directly measuring physiologic
gastroesophageal reflux events over 24–48 h via a trans-nasal catheter system or via a tethered capsule.
Barrett’s esophagus A precancerous condition that develops when the normal esophageal squamous mucosa is repopulated
by a specialized intestinal columnar epithelium due to chronic acid exposure.
Cardiac stress test A noninvasive test assessing for coronary artery disease by stimulating cardiac activity pharmacologically or
with exercise.
Dysphagia Describes difficulty with either initiating a swallow or passing a food bolus into the stomach without getting stuck
with the esophagus.
Epigastrium Refers to the area of the middle upper abdomen, just below the rib cage and located over the stomach.
Esophagogastroduodenoscopy (EGD, upper endoscopy, or endoscopy) A diagnostic and therapeutic procedure whereby the
esophagus, stomach, and second part of the duodenum can be directed inspected with a flexible fiber optic camera. Tissue
sampling and therapy may be performed with instruments that fit through a specified channel in the scope.
Foregut Refers to the segment of the gastrointestinal tract between the esophagus and second part of the duodenum and
associated structures, including liver, gallbladder, biliary system, and pancreas.
Fundoplication Surgical or endoscopic procedure to treat GERD in which the fundus of the stomach is mobilized or folded to
create a wrap around the distal esophagus and reinforce the gastroesophageal junction.
Gas-bloat syndrome Describes abdominal bloating and intestinal gas accumulation resulting from inability of the stomach to
release swallowed air or digestive gases by belching, due to a tight surgical fundoplication.
Gastroesophageal junction (GEJ) Connection where the distal esophagus meets with the proximal stomach.
Gastroesophageal reflux Retrograde flow of acidic gastric contents into the esophagus.
H2 receptor antagonists (H2RA) Antiacid medications that work by blocking the histamine receptor on the acid producing
parietal cells located in the stomach.
Hiatal Hernia A condition where a portion of the proximal stomach bulges passed the diaphragm and into the thoracic cavity,
through the esophageal hiatus.
Odynophagia Describes chest pain associated with swallowing solid or liquid food.
Postprandially Referring to a state after eating a meal.
Proton pump inhibitors (PPI) Potent acid suppressing medications that block acid secretion by inhibiting the Hþ, Kþ-ATPase
pump in parietal cells of the stomach.
Reflux esophagitis Inflammatory changes (linear mucosal breaks and ulcers) in the distal esophagus resulting from
gastroesophageal reflux injury.

Nomenclature
Electrocardiogram (ECG)
Over-the-counter (OTC)
Upper endoscopy
Tracing of cardiac electrical activity.
Refers to medications that can be purchased without a prescription from a medical provider.
For the purposes of this review, upper endoscopy used interchangeably with both
esophagogastroduodenoscopy (EGD) and endoscopy.

Introduction

Gastroesophageal reflux disease (GERD) is a spectrum of disease resulting from the backflow of gastric acid into the esophagus,
leading to esophageal injury or persistent symptoms. GERD is a prevalent medical problem encountered worldwide and associated

☆
Change History: June 2019, J. Reyes Genere and K.K. Wang updated the sections ‘Pathophysiology’, ‘complications’, ‘medical therapy’, ‘References’, and ‘Further
reading’. The remaining sections and all figures are new in this edition.
This is an update of J. Patrick Waring, Gastroesophageal Reflux Disease (GERD), In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier,
New York, 2004, Pages 203–210.

672 Encyclopedia of Gastroenterology, 2nd Edition https://doi.org/10.1016/B978-0-12-801238-3.65937-8

 Gastroesophageal Reflux Disease (GERD) 673

with high healthcare burden, including substantial cost of therapy and serious effects on quality of life. This article will discuss
GERD in detail from the scope of the problem, pathophysiology, and the clinical management.

Epidemiology

The prevalence of GERD has been increasing over the last 2–3 decades and is over represented in the developed world. Recent
studies have reported that GERD affects 2.5–33% of the population worldwide, with an incidence of 5 per 1000 person-years. The
Middle East, the United States, and Europe have the highest prevalence (8.7–33%. 18.1–27.8%, and 8.8–25.9% respectively), while
Asia has the lowest (2.5–7.8%). Particularly in western countries, these numbers are about 10–20% higher than previous
estimations in the late 1990s and likely reflect the rising obesity epidemic (Chang and Friedenberg, 2014). Given these figures, it
is no surprise that GERD results in high healthcare burden. In the United States GERD has become the most common indication for
outpatient medical visits and approximately $10 billion per year are spent on acid reducer therapy, suggesting high direct and
indirect economic burden. People with uncontrolled reflux symptoms may lose up to 2 h of work weekly and have lower quality of
life scores compared to mild chronic heart failure or ischemic heart disease. The genetics of GERD are poorly understood and the
clinical implications are unclear. There may be links to hereditary smooth muscle disorders leading to impaired esophageal motility
and predisposition of hiatal hernia, both which can lead to gastroesophageal reflux. However, these conditions do not affect the
majority of patients with GERD. Single nucleotide polymorphisms have been of interest as predictors of GERD, but the clinical
significance of these observations remains unclear.

Pathophysiology

Gastroesophageal reflux is the result of an imbalance of protective and provoking factors and can involve various mechanisms. The
gastroesophageal barrier (GB) is an anatomic unit that has a central role in preventing gastroesophageal reflux. The lower
esophageal sphincter (LES) is the primary component of the GB and it is supported by interactions with the crural diaphragm,
phrenoesophageal ligaments, and the angle of His. The LES is made of smooth muscle fibers that remain contracted at rest with
a basal pressure ranging between 10 and 30 mmHg. At least 1 cm (or more) of the LES is located within the abdominal cavity in
order to take advantage of positive pressures in this environment and help it remain closed at rest. The crural diaphragm wraps
around the LES and anchors it in position via phrenoesophageal ligament attachments. This gives the LES an additional
5–10 mmHg at rest and even greater supportive pressures during periods of exertion and breathing. These phrenoesophageal
attachments also help anchor the LES in position to prevent it from sliding into the negative pressure environment of the chest.
Lastly, the angle of His describes the acute entrance of the esophagus into the stomach which forms an intrinsic valve structure.
The GB can be broken down through several mechanisms. Impaired LES tone can lead to reflux events from reduced basal
contractility and increased episodes of transient lower esophageal sphincter relaxations. Healthy people without GERD experience
LES relaxations normally with swallowing and transiently through neurohormonal pathways (tLESR). Reflux occurs physiologically
by these pathways in healthy people to a degree, but it is more significant, or more frequent, in GERD sufferers. The LES muscles
may also be impaired by underlying disease. Connective tissue disease such as scleroderma may cause LES tone impairment and
secondarily allow more reflux events. A Hiatal hernia is an anatomic breakdown of the GB and is thought to be an important risk
factor for GERD. This occurs when increased laxity of the phrenoesophageal ligaments allow displacement of the GEJ above the
diaphragm, into the chest (Fig. 1). A portion of the proximal stomach will generally follow and bulge (or herniate) through the
esophageal hiatus. This proves to be an unfavorable situation for the LES as it loses the external support from the crural diaphragm
and becomes exposed to negative thoracic pressure that would facilitate reflux into the hernia. In addition, food or gastric juices
retained within the hernia sac form an “acid pocket” which cannot be buffered by normal mechanisms. The acid pocket is thought
to lead to more frequent reflux events and increase esophageal acid exposure.
Factors external to the GB are also important in gastroesophageal reflux disease. Esophageal muscle contraction and peristalsis
facilitates refluxate clearance, to reduce esophageal acid exposure time and potential for injury. The esophageal mucosa has intrinsic
mechanisms for acid-base regulation via apical Naþ/Hþ and HCO–3/CL-exchangers, tight-junctions, and buffering from salivary
secretions as well. On the other hand, the stomach is a primary driver for gastroesophageal reflux. First, stomach filling occurs
postprandially and this increases the gastric pressure gradient and stimulates tLESR to promote reflux. Refluxate itself contains
digestive secretions generated by specialized cells in the gastric body called parietal cells. These cells express Hþ, Kþ ATPase pumps
to acidify gastric juices to a of pH 1 after eating a meal. In addition, pepsin, an enzyme important for protein digestion, is activated
in stomach acid, both which are stimulated postprandially. Gastric acid and pepsin work synergistically to degrade esophageal
epithelial tight junction proteins, causing the intercellular connections to widen and disrupt the delicate acid-base microenviron-
ment. Evidence of esophageal mucosa injury at the cellular level can be seen early after acid exposure in pathologic gastroesophageal
reflux. E-cadherins, among other tight junction molecules, denature with pepsin and acid exposure, leading to epithelial tight
junctions swelling. Tight junction permeability increases, in turn, deregulating intercellular pH and compromising intracellular
buffering capacity. This cascade of events ultimately leads to pH autoregulatory failure and apoptosis, or cell death. Associations
between obesity and GERD have centered on mechanical factors such as central adiposity increasing intra-abdominal pressure and
GEJ gradient. In addition it has been found that obese patients may also have widened intracellular spaces, regardless of presence or
674 Gastroesophageal Reflux Disease (GERD)

Fig. 1 Barium esophagram of a large hiatal hernia. Contrast can be seen throughout the esophagus, gastroesophageal junction (GE jct. arrows), and stomach.
The stomach is mostly in the chest, above the esophageal hiatus (as indicated by arrows) with only the distal stomach remaining in the abdomen and emptying
into the duodenum.

absences of gastroesophageal reflux exposure. Increased permeability of tight junctions in obese patients with reflux is thought
explain why erosive reflux disease is more prevalent in this population.
Finally, the perception of pain or discomfort from reflux is an important element of GERD. These sensations are facilitated by
activation of esophageal pain receptors by various stimuli including heat, acid, esophageal distention and contractions secondary to
refluxate exposure. The absence of erosive changes in a large subset of GERD patients may be explained by volumetric reflux and
afferent nervous system activation from these various stimuli, in the setting of intact protective mechanisms from mucosal injury.

Clinical Manifestations

GERD has multiple clinical manifestations with different types of symptoms, pathologic findings, and complications. Typical
symptoms will present with either retrosternal burning (heartburn) or effortless regurgitation of gastric fluid. Classically these
symptoms will occur after eating meals and with specific foods (coffee, chocolate, or spicy foods), over-eating, and bending or
recumbent position changes. Dysphagia and odynophagia are considered alarm symptoms and may suggest complications of
GERD or an underlying sinister cause, such as esophageal cancer. Other alarm symptoms include new onset symptoms at >60 years
old, iron deficiency anemia, unintentional weight loss, persistent vomiting, or a first degree relative with a history of gastrointestinal
cancer. Atypical GERD symptoms may include epigastric pain, nausea, bloating, belching, and may often overlap other functional
gut disorders. Extra-gastrointestinal manifestations of GERD are also common and may be result of gastric acid irritation to
respiratory tract structures. These include sleep disturbance from nocturnal reflux symptoms, sore throat, voice hoarseness,
cough, frequent throat clearing, and exacerbation of pulmonary diseases such as asthma, COPD, or interstitial lung disease.
Erosive reflux esophagitis (ERD) and nonerosive reflux esophagitis (NERD) are the two main types of GERD (Fig. 2). ERD is only
present in about 13–15% percent of patients with symptoms of GERD and is explained by acidic refluxate leading to esophageal
mucosal injury. ERD is associated with hiatal hernias, obesity, and more commonly seen in older, white males. Upper endoscopy
examination is required to diagnose ERD (Fig. 3). The Los Angeles Classification system is used to standardize the degree of ERD
severity seen on endoscopy and is based on the degree of damage seen in the distal esophagus (Table 1). The majority of patients
with GERD will have NERD, characterized by either weak acid refluxate or afferent hypersensitivity to normal reflux events. NERD
patients will generally require ambulatory pH monitoring in order to diagnose and guide clinical management. Patients who do not
have objective evidence of gastroesophageal reflux may be subclassified into functional heart burn or require further upper
respiratory tract evaluation if atypical symptoms are predominant.
GERD complications occur secondary to chronic mucosal injury. The most common complications include strictures and
ulcerations, which occur in less than a quarter of untreated ERD patients (Fig. 3, right and Fig. 4). Barrett’s Esophagus (BE) is
another complication of GERD that is the only known precursor to esophageal adenocarcinoma (EAC) (Fig. 5). This is especially
 Gastroesophageal Reflux Disease (GERD) 675

Fig. 2 Summary of GERD Clinical Manifestations.  Indications to perform upper endoscopy are typical GERD symptoms with alarm symptoms or PPI
nonresponders.

Fig. 3 Endoscopic images of erosive reflux disease (ERD). The left image shows mild esophagitis with a small (<5 mm) mucosal break noted above the
gastroesophageal junction (arrow). The right image demonstrates severe esophagitis with circumferential involvement and ulceration.

Table 1 Los Angeles classification: A classification system to standardize the degree of esophagitis seen endoscopically.

Grade Endoscopic findings

A One or more distal esophageal mucosal breaks 5 mm, that do not extend between mucosal folds
B One or more distal esophageal mucosal breaks ˃5 mm, that do not extend between mucosal folds
C Distal esophageal mucosal breaks extending between 2 folds, but ˂75% circumference
D Distal esophageal mucosal breaks extending between 2 folds and  75% circumference

Sami, S., and Ragunath, K. (2013). The Los Angeles classification of gastroesophageal reflux disease. Video Journal and Encyclopedia of
GI Endoscopy 1 (1), 103–104.
676 Gastroesophageal Reflux Disease (GERD)

Fig. 4 Peptic stricture from erosive reflux disease. This patient presented with progressive dysphagia and developed a food impaction. The patient had
an endoscopic dilation and started on a PPI, which resulted in symptom resolution.

Fig. 5 Barrett’s esophagus and esophageal adenocarcinoma. The characteristic salmon colored mucosa of Barrett’s esophagus extending above the
gastroesophageal junction can be seen on the left image. On the right a mass can be seen in the background of Barrett’s esophagus, which can be partially
appreciated as a linear tongue extending up the 12 o’clock position. This mass was resected endoscopically and revealed invasive adenocarcinoma.

important seeing as very early EAC can have a good prognosis, but advanced disease is universally fatal. The prevalence of BE in
patients with GERD is about 5% and 5–15% of patients with chronic GERD develop BE. Patients at higher risk are Caucasian males,
>50 years old with at least 5 years of GERD symptoms. Other risk factors include central obesity and tobacco use. BE develops from
chronic esophageal acid exposure and injury, which triggers compensatory mucosal changes that replace normal esophageal
squamous epithelium with specialized columnar intestinal epithelium. Endoscopically BE is seen as salmon-colored mucosa,
extending  1 cm above the gastroesophageal junction into the esophagus, and confirmed histologically with biopsies showing
intestinal metaplasia. BE progresses to EAC by step-wise cellular changes starting from nondysplastic BE, then low-grade (LGD) to
high-grade dysplasia (HGD), followed by EAC. Overall, people with BE have about a 0.33% per year chance of developing EAC. This
rate increases modestly in people who progress LGD (0.54–0.7% per year), but substantially in those with HGD (5–7% per year).
Patients with BE are usually followed by a surveillance endoscopy program every 3-years in effort to detect dysplasia or EAC early
and allow for early intervention.

Diagnosis

There are various presentations of gastroesophageal reflux symptoms and developing a differential diagnosis is based on the
patient’s primary complaint. Cardiac disease should be considered in every patient presenting with chest discomfort and cardiac
testing is mandated for patients with worsening chest discomfort on physical exertion or with risk factors for coronary artery disease.
Patients presenting with respiratory tract ailments may be having extra-intestinal manifestations of GERD, but primary pulmonary
or sinus disease should be considered as well. A broad differential diagnosis exists also when symptoms are suspected to be from the
gastrointestinal tract. Inflammatory conditions affecting the esophagus such as eosinophilic esophagitis, Crohn’s disease, infections
 Gastroesophageal Reflux Disease (GERD) 677

(fungal, cytomegalovirus or herpes simplex virus), radiation injury, or pill induced esophagitis can all lead to chest pain, burning, or
discomfort with eating. Esophageal motility disorders, such as achalasia, or structural abnormalities, like Zenker’s diverticulum or
obstructing masses, can lead to regurgitation. Other conditions referring pain to the epigastrium or sternum include peptic ulcers,
Helicobacter pylori gastritis, functional dyspepsia, gallbladder disease, biliary obstruction, or gastroparesis.
The clinical assessment of a patient’s presenting illness will guide the clinician to further testing, including blood tests,
electrocardiogram, chest X-ray, abdominal ultrasound, cardiac stress test, upper endoscopy or laryngoscopy (Fig. 6). If GERD is
suspected and there is low concern of alternative diagnosis then starting a proton pump inhibitor (PPI) trial is a reasonable
approach. GERD can be affirmed if patient’s symptoms improve with PPI. Patients who do not respond to a PPI trial will need to be
further evaluated for alternative diagnoses or GERD complications, given true GERD unresponsive to high dose PPI trials are quite
uncommon. Patients with chest pain and a negative cardiac evaluation may be treated with a PPI trial, although some advocate
objective testing for reflux to confirm the diagnosis first.
Upper endoscopy is an excellent tool to evaluate complications of GERD, alternative diagnosis, or other sinister process such as
malignancy. Endoscopy allows for high definition and magnified direct visualization of the gastrointestinal mucosa. Passage of
biopsy forceps or endoscopic brush through a working channel in the scope can be used to obtain tissue and culture samples for
laboratory analysis when needed. Routine upper endoscopy for GERD is not recommended by current guidelines. Indications for
endoscopic examination include the presence of alarm symptoms (as described in Clinical Manifestations section), GERD refractory
to PPI therapy, or when dyspeptic symptoms are suspected. Upper endoscopy visualizes the esophagus, stomach, and second
portion of the duodenum. The full examination may be helpful to not only evaluate alternative esophageal disease (i.e. eosinophilic
esophagitis), but also other foregut disease such as peptic ulcer disease.
Ambulatory pH monitoring measures physiologic esophageal acid exposure over a prolonged period and is the gold standard for
diagnosing GERD. In clinical practice this test is useful to evaluate patients with GERD symptoms and normal endoscopy, to
confirm reflux is actually occurring. Ambulatory pH monitoring is required to diagnose patients NERD and also to subclassify these
patients to determine benefit from ongoing acid suppressing treatment. There are two types of ambulatory pH monitoring systems.
A pH impedance system measures both pH and physical reflux events over a 24-h time period. This system requires placement of
a trans nasal catheter into the esophagus with a distal tip in the stomach that remains in-situ through the testing period. The other
system uses a capsular pH monitor, which is sutured endoscopically above the GEJ. The capsule then wirelessly records acid reflux
events over a 48-h time period. This device is easier to tolerate, records a longer time period, but it only measures acid reflux events
which limits its use. The information collected from either type of pH ambulatory monitoring system includes the number of acid
(and nonacid with impedance systems) reflux events and correlation of these events with symptoms. Symptom correlation is
an important marker for determining a causal relationship between reflux and the presenting complain.
Barium esophagram and esophageal manometry have been used for evaluating GERD in the past, but are not recommended for
routine use. A barium esophagram is a contrast enhanced X-ray study of the esophagus that is performed taking multiple X-rays of
the chest during and after swallowing barium contrast fluid (Fig. 1). This provides an anatomic survey of the esophagus and
stomach. In clinical practice a barium esophagram may be helpful when evaluating for structural esophageal deformities, such as
a hiatal hernia, which may contribute to reflux. It may also give a gross view of esophageal function and may be helpful for
evaluation of swallowing disorders in conjunction with GERD. Esophageal manometry is a physiologic measurement of esophageal
muscle contraction and peristalsis. This test may be helpful in select patients when esophageal motility disorders, such as
scleroderma or achalasia, are suspected. Esophageal manometry is also routinely done prior to considering antireflux surgery.

Fig. 6 GERD Diagnostic Algorithm.  Consultation to ENT, pulmonary, or allergy may be indicated depending on the predominant presenting symptom.
678 Gastroesophageal Reflux Disease (GERD)

Treatment

The treatment options for GERD include lifestyle changes, medical therapy, endoscopic treatments, and surgery. Severity of
symptoms is the first indication for what level of treatment is needed. Most people experience mild and infrequent GERD symptoms
that respond to nonmedical interventions or with over-the-counter drugs, avoiding the need to seek medical care at all. Frequent or
severe symptoms will necessitate PPI therapy of which dosing and duration of treatment will depend on the degree of GERD and
presence of complications. Endoscopic and surgical procedures targeted to reinforcing an incompetent GB may be used when
medical therapy fails or by patient preference.

Lifestyle Modification
Many patients will identify triggers and engage in lifestyle changes before seeking medical care. Dietary indiscretions and behavioral
factors are believed to be associated with GERD. Lifestyle modifications alone may be effective for patients with mild, infrequent
GERD. These patients may never seek medical consultation if symptom control is satisfactory. The majority of patients presenting to
the medical office for GERD will need co-administration of medical therapy, along with lifestyle changes. Fatty, spicy, and citrus
foods, as well chocolate, alcohol, and smoking are thought to increase reflux via reducing LES tone. Behavioral factors associated
with GERD may result secondary to physical mechanisms. Gastric distention from overeating stimulates tLESR and increases GEJ
pressure gradient. Nighttime meals taken shortly before bedtime may reflux due to position changes in the recumbent position.
Lastly, central obesity is a major contributor to reflux by increasing intra-abdominal pressures. The evidence for lifestyle intervention
is limited. Only weight loss of 10–15 lbs. and utilizing head of bed elevation when nocturnal symptoms are present have been
shown to improve GERD. There is no evidence that excluding dietary trigger foods leads to improved symptoms or objective end-
points of GERD. Furthermore, complying with a restrictive diet can be frustrating for patients and difficult to adhere to when there is
little to gain. If there are discrete food triggers for substantial reflux symptoms, however, it would seem reasonable to eliminate these
on a case-by-case basis. Smoking cessation and avoiding excessive alcohol intake can be recommended to all patients for general
health promotion, not necessarily for GERD.

Medical Therapy
The goal of medical therapy is to alleviate gastroesophageal reflux symptoms by neutralizing refluxate acidity. Resolution of
esophagitis in ERD is an important marker of drug efficacy, yet it is important to note these medications do not reduce nonacid
reflux events. Patients with predominate heartburn symptoms are likely to gain the most benefit from medical therapy, while
regurgitation or NERD are less responsive.
The two main classes of drugs available to treat GERD are antacids and antisecretory medications. Antacids are oldest, more
commonly used, and available over-the-counter (OTC). Antacids exist in various oral forms including calcium carbonate, sodium
bicarbonate, phosphate binders, and magnesium and aluminum salts. These medications function to immediately neutralize gastric
acid and pepsin activity, lasting up to 1–3 h if taken postprandially. Studies evaluating the efficacy of antacids have failed to show
superiority over placebo for treating esophagitis, however there may be a small signal towards improvement of GERD symptoms in
20% of patients. Gaviscon with alginic acid is an OTC agent that neutralizes acid and creates a floating viscous layer over gastric fluid
to mechanically reduce reflux. Gaviscon is best taken after meals to displace the postprandial acid pocket and evidence has shown
superior symptom benefit of 8% versus 26% compared to other antacids. The side effect profile of antacid medications is favorable;
however, electrolyte disturbances can occur with prolonged, high doses (especially in the setting underlying kidney disease).
Antacids may impair absorption of other medications if co-administered and separating times of intake is generally advised.
Antisecretory agents are much better at suppressing gastric acid and have revolutionized the treatment of many foregut diseases.
Proton pump inhibitors (PPIs) and Histamine-2 receptor antagonists (H2RA) are both available OTC, however a prescription from
a medical provider is needed for stronger formulation or prolonged therapy. The mechanism of action for both antisecretory drugs
involves inhibiting parietal cell function. H2RA bind to histamine receptors on the parietal cells to inhibit acid secretion, while PPIs
bind directly to the Hþ, Kþ ATPase pump on the apical cell surface. H2RAs are taken twice daily before meals and are generally safe,
with infrequent side effects. The rate of healing esophagitis is may depend on extent of disease and ranges anywhere from 30% to
90%, though a randomized control trial comparing H2RAs to PPIs found about 52% healing in the H2RA group. Improvement, but
not elimination, of reflux symptoms occur in the majority of patients and it may be more effective in managing nocturnal
symptoms. Long-term H2RA use may result in medication tolerance, owing to neurohormonal pathway adaptation. It is often
advocated to use H2RA either on an as needed basis due to tolerance or in mild-moderate reflux disease without esophagitis. H2RA
may also be indicated when breakthrough nocturnal symptoms are present through twice daily PPI, however there is controversy
about the duration of effect.
PPIs are the most effective agents for acid suppression and treating GERD. PPIs are best taken 30 min before breakfast to
maximize the number of proton pump inhibition, which are expressed postprandially after a prolonged fast. The evidence for PPI
use in GERD has shown superior healing of esophagitis compared to placebo (90% versus 15%) and H2RA (83% versus 52%)
(Chiba et al., 1997). Long-term efficacy of maintenance therapy has also been shown in controlled trials and an uncontrolled
observational study to maintain esophageal healing over 7 years. Symptom response is excellent with PPI, especially for patients
with typical reflux symptoms. Side effects of PPI are infrequent, but may include altered bowel habits, abdominal pain, headache,
 Gastroesophageal Reflux Disease (GERD) 679

and idiosyncratic interstitial kidney disease. However, a major concern with PPI use have been in regards to long-term safety of
chronic acid suppression and antiplatelet drug–drug interactions. Biologically it is believed that chronic acid suppression may result
in untamed exposure or growth of enteric bacteria by allowing more habitable environment for these organisms. Acid suppression
also impairs absorption of calcium and other nutrients that dependent on acidic metabolism. These concerns were highlighted by
population based studies reporting association with increased hip fracture rates, intra-abdominal and enteric infections, kidney
disease, as well as pneumonias in chronic PPI users. Other studies have even implicated PPIs in dementia and cardiovascular events
such as heart attack and stroke. However, there is no convincing evidence proving PPIs are actually causing these adverse events and
this remains a theoretical risk. These associative studies have not led to studies that have found a biological foundation for these
potential side effects. In addition, the degree of risk has not been very high. Similarly, drug-drug interactions with a cardiac
medication essential for treating and preventing heart attacks have not been substantiated clinically. Clopidogrel is a commonly
used antiplatelet pro-drug for preventing coronary stent blockage, or thrombosis after placement. Clopidogrel is converted to active
metabolite via CYP2C19 enzyme activity in the liver. Several PPIs use a similar pathway and it is thought that antiplatelet activity
may be reduced with coadministration of PPI. However, a meta-analysis of 27 studies did not show any increase cardiovascular
events within patients administered both PPI and clopidogrel; indicating coadministration is likely safe even in this case. In clinical
practice, patients with proven benefit from PPI (ERD or symptom relief ) may be continued on long-term therapy. However,
growing awareness for selective PPI discontinuation in patients who have weak indications is often practiced and recommended.
Other agents such as prokinetics and tLESR inhibitors have been used to treat GERD refractory to acid suppression therapy.
However, the data supporting these medications is limited and the side effect profile is unfavorable. Both prokinetics and tLESR
inhibitors are not recommended for the general treatment of GERD, except in select cases.

Endoscopic Treatment and Surgery

Despite the success of medical therapy managing GERD, 20% of patients may be nonresponsive to maximal medical therapy.
Endoscopic and surgical strategies reinforce the gastroesophageal barrier to obstruct physiologic reflux by wrapping the gastric
fundus around the distal esophagus—this is called a fundoplication. Surgical fundoplication has been performed since the mid-
1900s and has evolved into several types including total and partial, which is further subtyped into anterior or posterior. Total
fundoplication (also known as Nissen fundoplication) is most commonly done in North America and now is usually done
laparoscopically. Patients with typical reflux symptoms who are PPI responsive or experience prominent regurgitation symptoms
are most likely to benefit from antireflux surgery, with up to 90% resolution in the short-term. Long-term follow-up has shown
durability of symptom relief, though the antireflux effects may decay in 33% of patients over 7 years. Additionally, 25–62% of
patients may return to needing medical therapy about 5–15 years after surgery. Atypical symptoms have a variable response, ranging
from 67% to 92% improvement including symptoms of hoarseness, sore throat, bronchitis, aspiration, and wheezing. GERD related
cough, on the other hand, has a very high short and long-term response relative to other atypical symptoms. Complication rate of
antireflux surgery in terms of mortality is very low (<1%). However, adverse symptoms postoperatively may result from a tight
fundoplication and lead to trouble swallowing, diarrhea, inability to vomit, and gas-bloat syndrome in 25–80% of cases. In the last
decade a new surgical approach has been introduced using a ring of magnetic beads, placed surgically around the distal esophagus.
The magnetic attraction between the beads provides external closure pressure onto the LES to prevent reflux. Clinical trials have
shown substantial improvement in reflux symptoms from 50% to 80%, down to <10–12% at 5 years follow-up. Eighty-five percent
of patients remained off PPI medications over the same time period. No mortalities have been reported, but similar side effects to
fundoplication have been reported. A meta-analysis comparing fundoplication and magnetic sphincter augmentation showed
comparable effectiveness for GERD and development of postoperative dysphagia, but gas-bloat syndrome and inability to vomit
occurred significantly less in the magnetic sphincter augmented group. This device has not been studied in patients with hiatal
hernias or Barrett’s esophagus, however, and use in these cases would be investigational.
Endoscopic antireflux therapies have been recently regaining traction. After first generation devices were found ineffective and
unsafe, the success of newer devices appears to be promising. The advantages to endoscopic therapy include minimally invasive,
shorter recovery period, and infrequent long-term side effects. Endoscopic plication systems appear to have the most potential, with
the ability create a 270 fundoplication using durable plicating anchors. The device may reduce small hiatal hernias, but larger ones
would require laparoscopic assistance for reduction. The clinical trial results show endoscopic therapy is efficacious. In one study,
90% of patients with regurgitation and 62% with atypical symptoms had complete symptom resolution over 6-month period.
Ninety percent of patients were off PPIs at the 6-month follow-up period as well. The antireflux effects of endoscopic fundoplication
may decrease over time in 20% of patients over 5 years. There have been no direct comparisons between endoscopic therapy and
surgery, but surgery appears to result in superior improvements in objective reflux measures despite the comparable subjective and
satisfaction scores. The complication rate of endoscopic therapy may be <2.4% with new generation systems and no long-term
postprocedure side effects have been reported, including gas-bloat syndrome.

Treating GERD Complications

Endoscopic therapy has key roles in treating GERD complications. Through-the-scope balloon or bougie dilators can be used to treat
peptic strictures quite effectively (up to 95% success), though it may require multiple sessions. Dilating peptic strictures is safe, with
a perforation and bleeding rate as low as 0.1–0.4%. PPI therapy is continued and optimized after dilation to prevent recurrence.
680 Gastroesophageal Reflux Disease (GERD)

Nondysplastic BE requires a surveillance endoscopy every 3–5 years. This is done with high definition, white light examination and
biopsies taken every 2 cm throughout the length of Barrett’s mucosa. The addition of advanced imaging techniques may improve
detection of mucosal irregularities. Dysplastic BE is managed endoscopically to reduce the risk of progression to EAC and the
available ablative treatments are very effective. Current guidelines recommend both confirmed LGD and HGD undergo endoscopic
therapy, although the former could also be monitored if the patient elects to do so. Radiofrequency ablation is the choice modality
for treating dysplastic BE. This technique uses thermal energy to ablate dysplastic tissue and promote generation of a new squamous
epithelial layer. In cases of dysplastic BE with suspected mass or neoplasia, then endoscopic resection of the visible lesion is
recommended to rule out EAC, followed by ablation of remaining BE. In patients with low risk early EAC limited to the mucosal
layer, endoscopic resection with BE eradication can achieve long-term cancer remission. Select, low risk EAC cases with invasion into
the submucosa may also be candidates for endoscopic resection; however advanced disease will generally require multidisciplinary
engagement involving a thoracic surgeon and medical oncologist to assure the most successful treatment plan.

Prognosis

The prognosis for GERD is good, owing the availability and success of PPI therapy in suppressing stomach acid. In most patients,
GERD symptoms are mild and do not significantly increase risks of death compared to the general population. The disease remains
stable or improves over time spontaneously. Patients with significant GERD, however, will have severe impact on quality of life if
left untreated. Observations have found that GERD can impact sleep, vitality, and general physical and mental wellbeing. This can
lead to decreased work productivity and health-related quality of life scores similar or worsen then those seen with arthritis,
diabetes, heart failure or ischemic heart disease. Fortunately, the majority of patients with significant symptoms or objective signs of
reflux disease will respond to antisecretory therapy and will not develop complications. GERD related deaths rare, but when they
occur it is due to complications of peptic ulcers, such as bleeding or perforation. People who develop Barrett’s esophagus have
a higher risk for acquiring esophageal cancer, but the rate of developing cancer and related mortality remains very low.

Guidelines

There are several guidelines published for GERD from various medical and surgical groups worldwide including North and South
America, Asia, Europe, and Australia. These guidelines offer a comprehensive clinical overview of GERD management and
sometimes provide specific insight to their region. Guidelines have been changing with the influx of new information in the area
of GERD, yet currently many of these guidelines are several years old and updates are anticipated in the near future.

See Also: Barrett’s Esophagus. Esophageal Cancer Surveillance and Screening: Barrett’s Esophagus and GERD. Esophageal Strictures.
Gastroesophageal Reflux Disease (GERD) in Children. Hiatal Hernias. Surgery for Benign Esophageal Disorders. Surgery for Gastroesophageal Reflux
Disease

References
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Chiba N, De Gara C, Wilkinson J, and Hunt R (1997) Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: A meta-analysis. Gastroenterology 112(6):
1798–1810.

Further Reading
Dean BB, Gano AD, Knight K, Ofman JJ, and Fass R (2004) Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clinical Gastroenterology and Hepatology 2(8):
656–664.
El-Serag HB, Sweet S, Winchester CC, and Dent J (2014) Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut 63(6): 871–880.
Floch NR (2010) Gastroesophageal junction and diaphragm. In: Floch MH and Floch NR (eds.) Netter’s gastroenterology, 2nd ed., pp. 18–20. Philadelphia, PA: Elsevier/Saunders.
Ford AC, Forman D, Bailey AG, Axon ATR, and Moayyedi P (2013) The natural history of gastro-oesophageal reflux symptoms in the community and its effects on survival: A longitudinal
10-year follow-up study. Alimentary Pharmacology & Therapeutics 37(3): 323–331.
Herregods TVK, Bredenoord AJ, and Smout AJPM (2015) Pathophysiology of gastroesophageal reflux disease: New understanding in a new era. Neurogastroenterology and Motility
27(9): 1202–1213.
Kahrilas PJ (2008) Clinical practice. Gastroesophageal reflux disease. The New England Journal of Medicine 359(16): 1700–1707.
Katz PO, Gerson LB, and Vela MF (2013) Guidelines for the diagnosis and management of gastroesophageal reflux disease. The American Journal of Gastroenterology 108(3):
308–328. quiz 329.
Kuipers EJ and Spaander MC (2018) Natural history of Barrett’s esophagus. Digestive Diseases and Sciences 63(8): 1997–2004.
Maton PN and Burton ME (1999) Antacids revisited: A review of their clinical pharmacology and recommended therapeutic use. Drugs 57(6): 855–870.
Moayyedi P and Talley NJ (2006) Gastro-oesophageal reflux disease. Lancet 367(9528): 2086–2100.
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Oelschlager BK, Quiroga E, Parra JD, et al. (2008) Long-term outcomes after laparoscopic antireflux surgery. The American Journal of Gastroenterology 103(2): 280–287. quiz 288.
Ofman JJ (2003) The economic and quality-of-life impact of symptomatic gastroesophageal reflux disease. The American Journal of Gastroenterology 98(3): S8–14. Supplement.
Pereira-Lima JC, Ramires RP, Zamin I, et al. (1999) Endoscopic dilation of benign esophageal strictures: Report on 1043 procedures. The American Journal of Gastroenterology 94(6):
1497–1501.
Richter JE and Friedenberg FK (2016) Gastroesophageal reflux disease. In: Qayed E, Srinivasan S, and Shahnavaz N (eds.) Sleisenger and Fordtran’s gastrointestinal and liver disease,
10th ed., pp. 733–754. Philadelphia, PA: Elsevier/Saunders.
Reyes Genere J and Wang KK (2018) Endoscopic techniques for treating gastroesophageal reflux. Current Opinion in Gastroenterology 34(5): 288–294.
Ronkainen J, Aro P, Storskrubb T, et al. (2005) High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish
population: A Kalixanda study report. Scandinavian Journal of Gastroenterology 40(3): 275–285.
Sami S and Ragunath K (2013) The Los Angeles classification of gastroesophageal reflux disease. Video Journal and Encyclopedia of GI Endoscopy 1(1): 103–104.
Sethi S and Richter JE (2017) Diet and gastroesophageal reflux disease: Role in pathogenesis and management. Current Opinion in Gastroenterology 33(2): 107–111.
Shaheen NJ, Hansen RA, Morgan DR, et al. (2006) The burden of gastrointestinal and liver diseases, 2006. The American Journal of Gastroenterology 101(9): 2128–2138.
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Zadeh J, Andreoni A, Treitl D, and Ben-David K (2018) Spotlight on the Linx™ reflux management system for the treatment of gastroesophageal reflux disease: Evidence and research.
Medical Devices (Auckland, N.Z.) 11: 291–300.