This document discusses gastroesophageal reflux disease (GERD). It defines GERD and describes the mechanisms involved in normal gastroesophageal reflux versus pathological reflux in GERD. Risk factors, epidemiology, clinical presentation, complications, and treatment goals are summarized. The pathophysiology of GERD is explained in detail, focusing on transient lower esophageal sphincter relaxation, acid clearance, mucosal resistance, and the role of gastric acid and pepsin in esophageal damage.
2. Definitions
GERD is a common acid-related GI disorder associated
with a wide array of symptoms, the most frequent of which
is heartburn, and acid regurgitation.
Gastroesophageal reflux (GER) is defined as the
retrograde passage of gastric contents from the
stomach into the esophagus. It is primarily the result of
transient relaxation of the LES.
When the LES is relaxed, the esophagus is exposed to
small amounts of acidic stomach contents. This normal
physiological event occurs many times throughout the day
3.
4. Protective mechanisms such as esophageal
peristalsis and bicarbonate-rich saliva quickly
return the acidic pH to normal.
GERD develops when alterations in reflux
result in symptoms, mucosal injury, or both.
Esophageal injury occurs with continued exposure
of the mucosa to gastric acid and results in
inflammation that can progress to ulceration
(erosive esophagitis).
5. Epidemiology
GERD is a chronic disease that affects patients
across all age groups with equal distribution
between men and women.
The prevalence of GERD appears to be greater
in the Western population with patients
presenting with more clinically important disease
and complications than in Eastern countries
(especially Asian populations) where GERD is
uncommon.
6. When considering the symptoms of GERD, such
as heartburn and acid regurgitation,
the overall prevalence in the United States is
approximately 45%.
In Western populations, 25% of patients report
heartburn monthly, 12% weekly, and 5%
describe daily symptoms.
It has also been estimated that 7% of the U.S.
population have complicated GERD
associated with erosive esophagitis
7. Up to 75% of patients who undergo endoscopic
procedures due to symptoms associated with
GERD have normal esophageal findings.
These patients are identified as having functional
heartburn, nonerosive reflux disease (NERD),
or endoscopy-negative reflux disease (ENRD).
Other patients with GERD have symptoms that
occur outside of the esophagus which are
considered atypical or extraesophageal
manifestations of GERD.
8. Extraesophageal manifestations may be
present with or without accompanying typical
symptoms (e.g., heartburn).
Extraesophageal manifestations have been
estimated to occur in about 80% of patients
with at least weekly symptoms of GERD.
10. Etiology and Risk Factors
increased contact of the acidic refluxate with the
esophageal mucosa.
dietary and lifestyle factors, drugs, and certain medical
and surgical conditions.
lowering the LES pressure (e.g., nitrates, progesterone,
foods high in fat, mint, chocolate) or having a direct
irritating effect on the esophageal mucosa (e.g., citrus,
tomatoes, bisphosphonates).
increased intra-abdominal pressure has been
associated with overeating, coughing, and bending or
straining to lift heavy objects as well as tight-fitting
11. Lifestyle
Smoking – Inhibits saliva, may also increase acid
production & weaken the LES.
Certain exercising & bending – that may increase
the abdominal pressure.
Wearing of tight clothing – increases the
abdominal pressure.
Lying flat after a meal – relaxes the muscles
making susceptibility for reflux.
12. Diet
Fatty, greasy foods - take longer to digest keeping
food in the stomach longer.
Peppermint, spearmint, and chocolate weaken the
LES.
Carbonated and alcoholic beverages increase the
acidity in the stomach.
Large meal portions – produce large acid levels.
Citrus, onions, and acid from tomatoes can be
irritating to the esophagus.
14. Childhood GERD appears to continue into
adolescence and adulthood.
Although most infants develop physiological
regurgitation, or spitting up, the majority
(95%) will have abatement of symptoms by
1.0 to 1.5 years of age.
However, infants with persisting symptoms
beyond 2 years of age are at risk of
developing complicated GERD.
15. Pregnancy has also been associated with an
increased incidence of GERD with 30% to 50%
of pregnant women complaining of heartburn;
however, in patients without a previous diagnosis
of GERD, the symptoms resolve when the child
is born.
The mechanisms for GERD in pregnancy are
related to
a) the hormonal effects of progesterone and
estrogen, which lower LES pressure, and
16. Certain medical and surgical conditions such as
gastroparesis,
scleroderma,
ZES, and
long-term placement of nasogastric tubes may also be
associated with GERD.
the eradication of H. pylori infection may
increase the risk of GERD symptoms and
esophagitis (????)
17. Quality Of Life (QOL)
Patients with GERD may have a decrease in
quality of life.
When comparing quality of life in patients with
GERD to those with other chronic medical
diseases, the quality of life in GERD
patients was between patients with
psychiatric disorders and patients with
mild heart failure.
18. Pathophysiology
The pathophysiology of GERD is associated with
defects in transient relaxations of the LES,
esophageal acid clearance and buffering capabilities,
anatomy,
gastric emptying,
mucosal resistance and
with exposure of the esophageal mucosa to aggressive
factors (gastric acid, pepsin, and bile salts) leading to
esophageal damage.
19. Transient Relaxations of the Lower
Esophageal Sphincter
The LES, when in a resting state, remains at a high
pressure (10–30 mmHg) to prevent the gastric
contents from entering into the esophagus.
Pressures are lowest during the day and with
meals and highest at night.
Transient relaxations of the LES are short periods of
sphincter relaxation that are different from those that
occur with swallowing or peristalsis.
They occur due to vagal stimulation in response to
gastric distension from meals (most common), gas,
stress, vomiting, or coughing and can persist >10
seconds.
20. A small percentage of patients may also have a
continuously weak and hypotensive LES
(decreased LES resting tone).
Stress reflux increases intra-abdominal pressure
and may blow open the hypotensive LES.
When LES pressures remain constantly low, the
risk for serious complications (e.g., erosive
esophagitis) increase dramatically.
Scleroderma, which is related to fibrosis of
smooth muscle, may reduce LES tone and
21. Esophageal Acid Clearance and
Buffering Capabilities
Although the number of reflux events and quantity of
refluxate are notable, it is the duration of time the
mucosa is in contact with these noxious
substances that determines esophageal damage
and complications.
More than 50% of patients diagnosed with severe
esophagitis have decreased acid clearance from the
esophagus.
Peristalsis is the primary mechanism by which acid
refluxate is removed from the esophagus.
Other mechanisms include swallowing, esophageal
distension in response to refluxate, and gravity (which
22. Saliva plays an important role in the neutralization
of gastric acid within the esophagus.
Its bicarbonate-rich content buffers the residual
acid that remains in the esophagus after
peristalsis.
However, saliva is only effective on small
amounts of gastric acid, as patients with larger
volumes of acid refluxate may not have the
neutralizing capacity in saliva necessary to protect
the esophagus.
23. The reduction of swallowing that occurs during
sleep is associated with nocturnal GERD.
Patients with decreased saliva production (e.g.,
elderly, patients taking medication with
anticholinergic effects, and those with certain
medication conditions such as xerostomia or
Sjogren's syndrome) may also be at increased
risk of developing GERD.
24. Anatomic Abnormalities
Hiatal hernia (protrusion of the upper portion of the
stomach into the thoracic cavity due to weakening in the
diaphragmatic muscles) is frequently described as a cause
of GERD, but its causal relationship remains uncertain.
Although hiatal hernia is associated with a greater degree of
esophagitis, strictures, and Barrett's metaplasia, not all
patients with hiatal hernia develop symptoms or
complications.
This may be related to the size of the hiatal hernia and its
effect on LES pressure.
Hypotensive LES in combination with hiatal hernia
increases the likelihood of reflux and complicated
25. Gastric Emptying
Delayed gastric emptying increases the volume of
gastric fluid remaining within the stomach that is
available for reflux and is associated with gastric
distension.
Although delayed gastric emptying is present in up to
15% of patients with GERD, a causal relationship has
not been established.
Because some patients such as those with diabetic
gastroparesis also have GERD, the association between
delayed gastric emptying and GERD cannot be
26. Mucosal Resistance
The capability of the esophageal mucosa to endure
contact with and withstand injury from gastric refluxate
(acid and pepsin) is a substantial determinate for the
development of GERD.
When considering the mucosal resistance within the
esophagus compared with that of the stomach and
duodenum, the esophagus is less resistant to damage
from gastric acid.
However, mucosal resistance in the esophagus is
composed of many defensive factors working in tandem
27. The esophagus also secretes a protective mucous
layer and bicarbonate.
This creates an environment in the esophagus of a higher
pH than that of the stomach. The pH in the esophagus is
normally about 7-8, whereas the pH in the stomach is
generally 2-4.
Enhanced blood flow in response to an acidic
environment within the esophagus improves tissue
oxygenation, provides nutrients, and helps to maintain a
normal acid–base balance.
Esophageal injury also occurs when the concentration
of acid and pepsin exceed the protection afforded by
28. Aggressive Factors Associated With
Esophageal Damage
The gastric refluxate, which is composed primarily of
gastric acid and pepsin, is the primary aggressive
factor associated with GERD.
The development and degree of mucosal damage is
dependent on the pH and contents of the refluxate as
well as the total exposure time of refluxate with the
esophageal mucosa.
A pH <4 is usually required to produce injury to the
esophageal mucosa, but as the refluxate becomes more
acidic, the mucosal damage is accelerated.
The addition of pepsin (which is converted from secreted
pepsinogen in an acidic pH) to the acidic refluxate will
markedly increase the propensity of the refluxate to
compromise mucosal resistance and increases the
29. Duodenogastric reflux or alkaline reflux containing
bile acids and pancreatic juices may also contribute
to esophagitis.
Because gastric and duodenogastric reflux are often
concomitantly present, their actions may be additive
in causing esophageal damage.
The duration of total exposure time of the esophagus
to the refluxate is the primary mechanism involved in
the development of GERD and its complications.
The longer the duration of exposure time, the greater
the possibility of severe disease, including
progression to Barrett's metaplasia.
30. Eradication of Helicobacter pylori
The relationship between H. pylori infection and GERD
remains controversial.
Early studies suggest that H. pylori eradication is
associated with increased gastric acidity and subsequent
development of erosive esophagitis.
In contrast, it appears that H. pylori may be protective
against GERD symptoms and related complications.
This is presumably due to the microorganisms ability to
decrease the acidity of the refluxate, as it does not
appear to affect the functional defense mechanisms of
the esophagus.
Although H. pylori testing in patients with GERD is not
standard practice, if the patient is tested and found to be
H. pylori positive, eradication is recommended
31. The 3 mechanisms of the lower esophageal
sphincter (LES) which prevent backflow
are:
Pressure in the LES is greater than that of the
stomach.
High levels of Acetylcholine, a neurotransmitter
increases constriction of the LES.
Gastrin, a hormone also increases constriction of
the LES.
32. Some conditions that can interfere with the
mechanisms of the Lower Esophageal
Sphincter (LES):
OBESITY - excess weight puts extra pressure on the
stomach & diaphragm.
Pregnancy – results in greater pressure on the stomach &
also has a higher level of progesterone. This hormone
relaxes many muscles, including the LES.
ASTHMA – it is unsure why, but, is believed that the
coughing leads to pressure changes on the diaphragm.
HIATAL HERNIA – which is the following topic.
33. There are specialized cells deep in the stomach lining that
affect the rate of acid production.
The primary cells which contribute to acid production are
known as parietal cells.
Each gastric parietal cell contains about 1 million acid
pumps.
The primary function of the activated pumps are to
exchange hydrogen ions from the parietal cells to
potassium using energy derived from splitting ATP.
The stomach produces an average of 2 liters of HCL a
day, which in combination with the protein-splitting
enzyme pepsin, breaks down chemicals in food.
34. The binding of these 3 receptors in
the parietal cells initiates the
process of acid production.
PARIETAL
CELLS
Acetylcholine Gastrin Histamine
35. Complications
Complications of long-term reflux may
include the development of
erosive esophagitis (up to 47%)
Strictures (>30%),
Barrett’s esophagus (10% to 15% ), or
adenocarcinoma of the esophagus.
38. The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
GRADE A:
One or more mucosal breaks no longer than 5
mm, non of which extends between the tops of
the mucosal folds
39. The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
GRADE B:
One or more mucosal breaks more than 5 mm
long, none of which extends between the tops of
two mucosal folds
40. The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
GRADE C:
Mucosal breaks that extend between the tops of two or more
mucosal folds, but which involve less than 75% of the
oesophageal circumference
41. The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
GRADE D:
Mucosal breaks which involve at least 75% of
the oesophageal circumference
43. Treatment
Therapeutic Goals
to alleviate symptoms, promote esophageal
healing, prevent recurrence, provide cost-
effective pharmacotherapy, and avoid long-term
complications.
One long-term consequence is Barrett's esophagus,
or Barrett's metaplasia, which is identified in 10% to
15% of GERD patients on endoscopic evaluation.
This premalignant condition may predispose the patient
to esophageal adenocarcinoma.
Patients with Barrett's esophagus have a 30- to 125-
fold greater risk of developing esophageal cancer
than an age-matched population.
44. Nonpharmacologic Measures and
Self-Directed Treatment
Lifestyle and dietary modifications comprise the initial
step in managing patients with GERD
Lifestyle modifications are aimed at reducing acid
exposure within the esophagus by increasing LES
pressure, decreasing intragastric pressure, improving
esophageal acid clearance, and avoiding specific
agents that irritate the esophageal mucosa.
There is evidence to support several modifications that
reduce esophageal gastric acid exposure and
symptoms.These include
raising the head of the bed 6 to 8 inches by using blocks
sleeping in a left lateral decubitus position; and
weight loss, which also decreases intra-gastric pressure.
Avoiding large meals within 3 hours of bedtime or lying
down in the supine position may also decrease symptoms.
45. Pharmacotherapy
Antacids
Antacids are useful only in the relief of mild
symptoms associated with GERD.
Because of their short duration of action and
inability to heal erosive esophagitis, they are
not an option for treating moderate to severe
GERD.
46. H2-Receptor Antagonists
The H2RAs are effective in treating patients with mild to
moderate GERD,
but response rates vary with the severity of disease, the
dose of the drug, and the duration of therapy.
The H2RAs are considered equally effective when used in
equipotent doses for symptomatic relief and
esophageal healing.
They are effective in reducing nocturnal symptoms but
only modestly effective in relieving meal-related
symptoms, as they only block one mechanism of parietal
cell activation (the H2 receptor).
The H2RAs relieve symptoms in about 50% to 60% of
47. Increasing the H2RA dose may not improve
symptoms in some patients.
Esophageal healing requires higher doses
Esophageal healing rates with the H2RAs are
reported to be about 50% after 8 to 12 weeks of
treatment, but rates will vary depending on the degree
of esophagitis.
For example, endoscopic healing rates in trials with
high-dose H2RAs were approximately 60% to 90% in
patients with grades I and II esophagitis but were
only 30% to 50% in patients with more severe disease
(grades III and IV esophagitis).
48. Proton Pump Inhibitors
The PPIs are the drugs of choice for patients with
frequent moderate to severe GERD symptoms and
esophagitis because they provide more rapid relief of
symptoms and esophageal healing than do the H2RAs.
Act by Inhibits the gastric acid pump, H+/K+
ATPase & are prodrugs
When used in recommended dosages, all of the PPIs
provide similar rates of symptom relief and esophageal
healing.
Their superior efficacy, when compared with the
H2RAs, is related to their ability to maintain an
intragrastric pH >4 for a long duration time (up to 24
hours/day vs. up to 10 hours with a H2RA).
49. Typically, PPIs are taken once daily 30 to 60
minutes before breakfast, but if a second dose is
required, it should be taken prior to the evening
meal.
A large meta-analysis of 16 trials confirms that
PPIs are superior to the H2RAs for achieving
rapid and complete relief of GERD symptoms.
Complete symptom relief (within 4–12 weeks)
was achieved in 77.4% of patients taking a PPI
versus 47.6% of those taking and H2RA (p
50. Healing also occurred more quickly with PPI
therapy in that by week two, 63.4% of patients
had healed with the PPI, while it took 12 weeks
with the H2RAs for 60.2% of patients to heal.
Another large meta-analysis, which evaluated
over 33 randomized trials, demonstrated similar
results with 81.7% of patients healed at 8 weeks
with a PPI versus 52.0% with a H2RA.
51. Esophageal healing among the five PPIs appears to
be equivalent, as about 85% to 90% of patients
achieve complete healing at 8 weeks in numerous
head-to-head trials with equivalent doses.
One meta-analysis, which compared esophageal
healing rates among omeprazole 20 mg,
lansoprazole 30 mg, pantoprazole 40 mg, and
rabeprazole 20 mg (each given once daily), reported
no statistical difference.
However, all of the PPIs were superior to ranitidine
300 to 600 mg/day.
52. The ability of a high-dose PPI to reverse
Barrett's metaplasia remains controversial.
Although studies have demonstrated islands of
normal squamous epithelium returning, no data
have determined that this is associated with a
risk reduction in adenocarcinoma.
In fact, others have suggested that this return of
normal mucosa may actually mask carcinogenic
changes occurring deeper in the gastric mucosa.
53. Improvement of quality of life has also been
evaluated in patients receiving PPI therapy in
the management of GERD.
A recent study comparing esomeprazole with
ranitidine over a period of 6 months showed a
significant improvement in both physical
functioning and sleep with the PPI therapy.
54. Prokinetic Agents
Two prokinetic agents, metoclopramide and
bethanechol, may be effective in the
management of GERD.
Both drugs stimulate the motility of the upper GI
tract without altering gastric acid secretion and
increase LES pressure.
Although these drugs may provide relief of
symptoms, they are ineffective in healing
erosive esophagitis unless they are combined
55. Prokinetics are not widely used to treat GERD,
because they are not as effective as other
treatments and are associated with numerous
side effects.
Prokinetics are reserved for patients who are
refractory to other available treatment options or
who have delayed gastric emptying.
56. Sucralfate
Sucralfate appears to be effective in treating mild
cases of GERD and possibly mild esophagitis
but is not effective in the management of severe
disease.
Given better options at this time, sucralfate is
rarely used in the management of GERD.
The PPIs are considered the drugs of choice
for patients with frequent or severe GERD
symptoms, or who have complicated disease,
57. Maintenance Therapy
GERD is chronic disease. Up to 80% of patients with
severe esophagitis and 15% to 30% with less severe
disease have a symptomatic relapse within 6 months
after discontinuing treatment.
The goal of maintenance therapy is to keep the patient
symptom-free and prevent potentially life-threatening
complications.
Continuous maintenance therapy with a daily PPI is
more effective than a H2RA, with reported relapse rates
of 25% and 50%, respectively.
Thus, PPIs are the drugs of choice for maintaining
remission in patients with healed esophagitis.
58. On-Demand Pharmacotherapy
The use of intermittent (on-demand) courses of PPI
therapy (2–4 weeks) have been suggested as being
potentially beneficial in patients with GERD.
One trial, which compared continuous maintenance
therapy with esomeprazole 20 mg daily versus on-
demand therapy with the same drug and dose in
patients with healed erosive esophagitis, reported that
continuous therapy was superior to on-demand
therapy (81% vs. 58%, respectively) in maintaining
endoscopic remission at 6 months.
59. Although numerous studies with a variety of
PPIs have demonstrated patient satisfaction with
on-demand therapy, systemic review of 17 trials
evaluating the use of on-demand therapy
indicates that intermittent therapy should only
be considered in patients with mild,
nonerosive disease.
60. Combination of a Proton Pump Inhibitor
and H2-Receptor Antagonists
The addition of a H2RA at bedtime to a once or twice
daily PPI regimen is sometimes used for patients who
continue to have nocturnal symptoms, although the
evidence to support this combination remains
inconclusive.
The rational for this practice is based on evidence that
suggests a period of nocturnal acid breakthrough
(defined as intragastric pH <4 for longer than 1 hour
during the night) in a significant number of patients
despite twice-daily PPI therapy, suggesting that
histamine release may have an important function in
61. One study suggests that the addition of a H2RA to a
twice-daily PPI regimen resulted in a statistically
significant reduction in nocturnal acid breakthrough
during the sleeping hours.
This trial, however, evaluated only a single bedtime
dose of a H2RA and did not consider the tachyphylaxis
that can occur with continuous use.
A more recent trial using a twice-daily PPI regimen
with continuous use of a H2RA for 4 weeks
demonstrated no difference in nocturnal acid
suppression, suggesting that tolerance does play an
62. Nonerosive Reflux Disease
Up to 75% patients with typical GERD symptoms who
undergo endoscopy will not have evidence of esophagitis
or complicated disease.
These patients are described as having functional
heartburn, NERD or ENRD and usually undergo 24-hour
ambulatory pH monitoring to determine whether abnormal
reflux is present despite a negative endoscopy.
A trial of a PPI is usually indicated despite no esophageal
findings, as many patients will respond to this therapy.
Further medical evaluation is usually required if a patient
63. Asthma and Gastroesophageal Reflux
Disease
GERD may play a role in the pathophysiology of
asthma.
Reports suggest that concomitant GERD occurs in
34% to 89% of the asthmatic population.
Two theoretical mechanisms exist as to how GERD
can potentially exacerbate asthma symptoms.
The reflex theory proposes that symptoms result from
the direct irritation of the vagus nerve when refluxate
comes into contact with the esophageal mucosa,
64. In contrast, the reflux theory proposes that
aspiration of refluxed acid into the lungs causes
caustic injury of tissue within the bronchial tree,
resulting in asthmatic symptoms.
An important meta-analysis of trials that
evaluated the effects of antireflux therapy on
patients with asthma indicates that asthma
symptoms improved in 69% of patients, that the
use of asthma medications was reduced by 62%,
and that only 26% of the subjects showed
65. All other pulmonary function tests (PFTs) showed little
or no change with antireflux therapy.
However, this meta-analysis only evaluated studies of
up to 8 weeks in duration.
A recent trial with esomeprazole 40 mg daily for 3
months demonstrated improvements in PFTs and a
decreased use of short-acting rescue bronchodilators
in asthmatics with GERD compared with asthmatics
without GERD.
One-third of the patients in the GERD group were
69. Potassium competitive acid blockers (P-
CABs)
Target H+/K+ ATPase
Ionically binds to the proton pump
Specific for the K+ binding region and
prevents acid secretion
Binds reversibly
Still in clinical trials
Extraesophageal manifestations of gastroesophageal reflux disorder (GERD) are frequent, and consist broadly of
Zollinger Ellison Syndrome
Systemic Sclerosis (Scleroderma)
Systemic sclerosis, also called scleroderma (skleros, meaning hard; derma, meaning skin), is a multisystem disorder of connective tissues characterized by inflammation, fibrosis, and degenerative changes in the blood vessels, skin, synovium, skeletal muscle, and some internal organ systems (e.g., gastrointestinal tract, lung, heart, kidney).
Odynophagia=Severe pain on swallowing due to a disorder of the esophagus
