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Gastroesophageal Reflux Disease (GERD): A Review of Conventional and Alternative Treatments

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Gastroesophageal reflux disorder (GERD), a common disorder in the Western world, can lead to complications that include esophageal stricture and esophageal adenocarcinoma. Multiple challenges are associated with GERD treatment. First, lack of symptoms does not correlate with the absence of or the healing of esophageal lesions. Second, proton pump inhibitors, the current standard of care for GERD, are ineffective for the majority of GERD patients who have non-erosive disease. This article discusses these challenges, investigates the mechanisms of damage in GERD, and explores the existing data on unconventional forms of treatment, including melatonin, acupuncture, botanicals, and dietary interventions.
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Review Article
Abstract
Gastroesophageal reux disorder (GERD), a common disorder
in the Western world, can lead to complications that include
esophageal stricture and esophageal adenocarcinoma.
Multiple challenges are associated with GERD treatment. First,
lack of symptoms does not correlate with the absence of or
the healing of esophageal lesions. Second, proton pump
inhibitors, the current standard of care for GERD, are
ineective for the majority of GERD patients who have
non-erosive disease. This article discusses these challenges,
investigates the mechanisms of damage in GERD, and explores
the existing data on unconventional forms of treatment,
including melatonin, acupuncture, botanicals, and dietary
interventions.
(Altern Med Rev 2011;16(2):116-133)
Introduction
GERD is defined as a “condition that develops
when the reflux of stomach contents causes
troublesome symptoms and/or complications.1
Heartburn, estimated to occur daily in seven
percent of the U.S. population, is the most
common symptom of GERD.2 Between 20 and 40
percent of those experiencing common heartburn
are predicted to actually have a diagnosis of GERD.
In addition to heartburn, regurgitation and
diculty swallowing are common GERD symptoms.
GERD also includes subcategories of diagnosis:
non-erosive esophageal reflux disease (NERD) and
the additional pathologies that result as GERD
progresses, including esophageal ulcer, esophageal
stricture, Barrett’s esophagus, and Barrett’s
carcinoma (esophageal adenocarcinoma).1
In the United States, GERD is the most common
diagnosis of all presenting gastrointestinal (GI)-
related complaints and accounts for about four
percent of all visits in family practice.3 An esti-
mated 14-20 percent of all U.S. adults have some
degree of gastroesophageal reflux.3 Although
symptoms are only considered clinically significant
if they occur at least twice weekly, in Europe and
North America an estimated 10-30 percent of the
population complains of symptoms related to
GERD at least once weekly.1,4 Evidence for the
prevalence of GERD symptoms also comes indi-
rectly from the use of proton pump inhibitors
(PPIs), a first-line therapy for GERD. Americans
spend in excess of 10 billion dollars yearly on PPIs,
while two PPIs were reported as being among the
top five selling pharmaceuticals in a 2006 study.5
Despite the use of PPIs, the incidence of esopha-
geal adenocarcinoma, a complication of erosive
esophagitis, has been increasing significantly in the
past 20 years, with an estimated increase of
200-600 percent.6
GERD-Associated Symptoms
While heartburn, regurgitation, and diculty
swallowing are the most common GERD-related
complaints, GERD can manifest a variety of other
symptoms. is recognition has led to a broader
definition of GERD-related symptomology, which
can include laryngitis, cough, asthma, and dental
erosions, for example.1
Regurgitation or aspiration of gastric juice in
GERD can cause chronic cough, dental erosion,
recurrent pneumonitis, or idiopathic pulmonary
fibrosis. In one cohort of patients with idiopathic
pulmonary fibrosis, 67 percent were later diag-
nosed with GERD.7 GERD can also manifest as
chronic sinusitis, posterior laryngitis, nocturnal
choking, chronic hoarseness, otitis media, idio-
pathic pulmonary fibrosis, and asthma.8
Epidemiological evidence suggests that 34-89
percent of asthmatics have GERD (irrespective of
the use of bronchodilators).9
Gastroesophageal Reux Disease (GERD):
A Review of Conventional and Alternative
Treatments
Lyn Patrick, ND
Lyn Patrick, ND – 1984
graduate of Bastyr University;
consulting practice in chronic
hepatitis C; Board Consultant
for the American College for
the Advancement of Medicine
and on the faculty of ACAM
Environmental Medicine and
Metal Toxicology courses
and lectures internationally
on chronic hepatitis C, and
Environmental Medicine;
Contributing Editor for
Alternative Medicine Review.
Email: lpatrick@frontier.net
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Review Article
GERD is a common cause of unexplained sleep
disturbance. It can also manifest as angina-like
pain radiating to the back, neck, jaw, or arms,
hypersalivation, globus sensation (perception of a
constant lump in the throat), nausea, or
dysphagia.8
Eosinophilic esophagitis, often diagnosed in
GERD, may be a separate entity or may arise as a
feature of GERD. As a separate entity, it is related
to a histological finding of high eosinophil counts
(>15 eosinophils per high-powered field) and
eosinophil degranulation on biopsy and is more
commonly found in younger patients without
hiatal hernia. Symptoms include dysphagia, chest
pain, and food impaction.10 Eosinophilic esophagi-
tis responds to elemental diets and elimination of
food allergens.11
Conditions Associated with GERD
Hiatal Hernia
Hiatal hernia is associated with an increased risk
for GERD. Estimates suggest that 75 percent of
those with esophagitis have a hiatal hernia, while
the incidence of hiatal hernia increases to 90
percent in persons with Barrett’s esophagus. Hiatal
hernia can produce a separation of the lower
esophageal sphincter (LES) from the crural
diaphragm, causing a weakening of the gastro-
esophageal barrier. e result is a degree of
functional incompetence at this barrier. is has
been demonstrated in hiatal hernia patients with
GERD.12
Obesity and Metabolic Syndrome
Obesity in general, and abdominal obesity
specifically, is associated with an increased risk for
GERD. In a meta-analysis, being categorized as
overweight (BMI >25-30 kg/m2) or obese (BMI >30
kg/m2) was associated with GERD symptoms,
erosive esophagitis, and esophageal carcinoma.13
ere is also a relationship between visceral
adiposity and GERD. Presumably the increased
visceral fat leads to increased intra-abdominal and
intragastric pressure, resulting in a predisposition
for hiatal hernia.14 Obese individuals reportedly
have an increased number of transient lower
esophageal sphincter relaxation (TLESR) episodes
secondary to gastric distention.15
Metabolic syndrome is a risk factor for GERD
and its progression. Subjects with hypercholester-
olemia, hyperuricemia, enlarged waist circumfer-
ence, hypertension, low HDL-cholesterol level,
hypertriglyceridemia, and a diagnosis of metabolic
syndrome were more likely to progress from a
nonerosive esophagitis to erosive disease and less
likely to regress from erosive to nonerosive states.16
Diagnosis
e diagnostic guidelines for GERD depend on
whether the symptoms are complicated or uncom-
plicated. An uncomplicated presentation (heart-
burn, regurgitation, or both, often occurring after
meals and aggravated by lying down or bending
over, with relief obtained from antacids) is treated
empirically with single daily-dose PPI.17 If no relief
is obtained, the dosage is doubled. Lack of
response to a PPI necessitates further diagnostic
workup (upper GI endoscopy, esophageal biopsy,
ambulatory esophageal pH monitoring, impedance
monitoring, and esophageal Bilitec for bile detec-
tion). Current U.S. treatment guidelines recom-
mend treatment without invasive diagnostic
testing unless dysphagia, weight loss, gastrointesti-
nal blood loss, or anemia is present. Details are
provided in the treatment guidelines of the
American College of Gastroenterology.17
Endoscopy is used to identify Barrett’s esopha-
gus and esophagitis in patients with long-term
symptoms or alarm symptoms. A negative endos-
copy does not rule out GERD; in fact, the majority
of GERD patients have negative endoscopic
findings. ere is a non-linear, and at times
paradoxical, relationship between the severity of
symptoms and the severity of endoscopic findings.
It is possible to have severe symptoms of GERD
with negative endoscopic findings, while it is also
possible to have no GERD symptoms and positive
endoscopic findings. erefore, the absence of
symptoms does not indicate the absence of
pathology. In one study of 1,000 northern
Europeans, only 40 percent of patients with
Barrett’s esophagus and only 30 percent with
GERD esophagitis were symptomatic.18 Barrett’s
esophagus (which occurs in only 0.25-3.9 percent
of all cases of GERD but in 6-12 percent of all
GERD patients referred for endoscopy), hemor-
rhagic esophageal stricture, and esophageal
adenocarcinoma are also often asymptomatic.19
Self-assessment questionnaires can mimic the
diagnostic accuracy of gastroenterology practices.
For example, the GERDQ is a self-assessment
questionnaire that was shown to have 65-percent
sensitivity and 71-percent specificity in a sample of
300 patients, similar to the diagnostic accuracy
achieved by gastroenterologists.20 e question-
naire (Table 1) is a six-question, easy-to-score list
that assesses frequency of symptoms during the
previous week. A symptom score of 8 or higher
Keyword: GERD, esophagus,
gastroesophageal, reux,
iberogast
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Review Article
indicates a high likelihood of the presence of GERD.
is questionnaire was also determined to be a
predictor of response to PPI. Individuals who had
no single question receiving a score of more than 1
were most likely to have a positive response to
treatment.20
Abnormal Physiology Involved in GERD
Some reflux is normal. Reflux is diluted with
saliva and the esophagus clears the diluted refluxed
acid with peristaltic action. Having a properly
functioning LES with normal pressure and a
normal number of episodes of transient relaxation
(in the absence of swallowing) is also part of the
physiological mechanism that protects against
damage from stomach acid reflux. For the LES to
perform this function properly, the gastroesopha-
geal junction must be positioned in the abdomen
so the diaphragmatic crura can assist the LES, in
essence functioning as an external sphincter. e
common defects in the pathogenesis of GERD are
delayed gastric emptying, reduced pressure in the
LES, increase in transient LES relaxations, ineec-
tive clearance of reflux from the esophagus, and
impaired esophageal mucosal defense.21
Reuxate: The Damaging Eect of Acid, Pepsin, Bile,
and Pancreatic Secretions
Most reflux events do not produce symptoms of
GERD. In a study of a combined total of 1,807
reflux episodes in GERD patients, only 203
episodes produced symptoms.22 In this study,
reflux occurred routinely and was involved in the
mechanism of belching. e symptom-producing
reflux events of GERD patients in the study were
related to lower pH, longer acid clearance time, and
higher total acid exposure. Reflux with higher pH
(4-7) produced symptoms only 15 percent of the
time.22
Bile acid and pancreatic secretions (termed
duodeno-gastric-esophageal reflux or DGER) are
also commonly found in the refluxate of GERD
patients. Both are related to an increased risk of
esophageal damage and the presence of DGER is
associated with heartburn. One study of 65
patients with reflux who were non-responsive to
PPI found that, while only 37 percent had acid
reflux, 64 percent had DGER. e most severe
esophagitis occurred in the 26 percent with both
acid- and bile-based reflux.23 Another study of the
eect of DGER in GERD patients with active reflux
found that 51 percent had DGER present in
refluxate. Symptoms of reflux were related to
higher levels of DGER and higher levels of DGER
Table 1. GERDQ Symptoms are Scored for the Previous Seven Days
How often did you have a burning feeling behind your breastbone (heartburn)?
How often did you have stomach contents (liquid or food) moving upwards to
your throat or mouth (regurgitation)?
How often did you have pain in the center of your stomach?
How often did you have nausea?
How often did you have diculty getting a good nights sleep because of
heartburn and/or regurgitation
How often did you take additional medication for your heartburn and/or
regurgitation, other than what the physician told you to take (such as Tums,
Rolaids or Maalox)?
Question
Frequency score (points) for symptom
0 days 1 day
1
1
2
2
1
1
2-3 days
2
2
1
1
2
2
4-7 days
3
3
0
0
3
3
0
0
3
3
0
0
Adapted from: Jones R, Junghard O, Dent J, et al. Development of the GerdQ, a tool for the diagnosis and management of gastro-oesophageal
reux disease in primary care. Aliment Pharmacol Ther 2009;30:1030-1038.
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Review Article
increased risk for the severity of esophageal
damage and Barrett’s esophagus.24
In vitro studies show bile acids alone, in a low pH
environment, can induce oxidative damage in a
model of Barrett’s esophagus and that oxidative
damage can lead to esophageal inflammation.25
Although the use of PPI therapy has been shown to
reduce DGER, this eect is not consistent or
predictable. e use of promotility agents (e.g.,
baclofen 20 mg) has been shown to reduce symp-
toms in patients with DGER who were not respon-
sive to PPI, suggesting that motility problems in
these patients might be the source of DGER.23
Lower Esophageal Sphincter Relaxation
e majority of cases of GERD involve resting
LES pressures that are within the normal range.21,26
Reflux occurs instead during TLESR, which is part
of the normal function of the LES. is relaxation
is not related to swallowing or peristaltic action,
but is responsible for the occurrence of belching in
normal stomach function. In GERD, the relaxation
of this sphincter is directly related to reflux
episodes. Gastric distention is believed to be the
trigger for reflux during transient relaxation and
may be the reason that postprandial reflux,
triggered by stretch receptors in the stomach, is
more common than at any other time.21
Another cause of TLESR involves colonic
fermentation of carbohydrate. Between two and 20
percent of all ingested carbohydrate is metabolized
into short-chain fatty acids by intestinal flora in
the colon.27 Lactose is known to be one of the most
poorly absorbed disaccharides. When healthy
human subjects were given colonic infusions of 30
g of lactose along with short-chain fatty acids
(SCFA), the numbers of TLESR and acid reflux
episodes that followed were significantly elevated.
e SCFA infusions also lowered LES pressure and
increased the number of reflux episodes more
significantly than lactose itself.28 e amount of
lactose used in this study was a relatively large dose
(30 g lactose is equivalent to 1 liter of cow’s milk or
2.5 cups of ice cream). e dose was chosen in an
attempt to duplicate what might occur if lactose
was given to a lactose-intolerant individual. is
amount of lactose would lead to 135 mmol of SCFA,
the amount infused in the study. is research
agrees with other studies where lactose and SCFA
administration has resulted in delayed gastric
emptying and gastric distention.29, 30
Esophageal Involvement
Esophageal erosion is a result of both the time
that esophageal tissue is exposed to stomach
contents and the sensitivity of the esophageal
tissue to those fluids. Reflux of the stomach
contents occurs as part of normal physiology.
Normal mechanisms for removing and diluting
refluxed stomach contents include esophageal
peristalsis to eliminate the reflux and salivary
bicarbonate to neutralize it.31 Although it is known
the ability of the esophagus to clear reflux contents
is delayed in GERD, it is not clear which comes first
– esophageal injury or slowed peristalsis.32
Gastric Emptying
Delayed gastric emptying is a risk factor for
GERD. In studies of gastric emptying rates, approx-
imately 10-40 percent of GERD patients demon-
strate delayed gastric emptying.33 e relationship
between delayed emptying times and esophageal
acid exposure is complex; delayed gastric emptying
results in less acidic refluxate, but does not
increase the number of reflux events.33 Slower
gastric emptying does, however, induce gastric
distension and results in a greater volume of
refluxate. is may be why GERD patients with
both gastric and esophageal motility problems tend
to have increased damage. Studies, however, have
failed to find a direct connection between delayed
gastric emptying and esophageal acid exposure.34
GERD and Acidity
e mechanisms that allow episodes of reflux to be
felt by patients are complex. ey include the time
the reflux remains in the esophagus, the volume of
reflux, the ability of the esophagus to neutralize the
reflux with bicarbonate from saliva, and the acidity of
the reflux fluid.22,35 A consensus definition of
diering levels of acidity in reflux contents has been
established: “Acid reflux” (pH<4), “weakly acid reflux”
(pH 4-7), and “weakly alkaline reflux” (pH7).36 It is
estimated that in GERD patients not taking PPIs,
approximately 50 percent of all reflux episodes have a
weakly acidic pH above 4.37
In a study evaluating the acidity of reflux and its
symptom-provoking eects, both weakly acidic and
acidic reflux were able to generate symptoms of
heartburn.35 In patients with GERD who do not
respond to PPIs, weakly acidic reflux may be
responsible for 30-40 percent of symptoms.38 In
one group, a strong positive association between
symptoms and weakly acidic reflux was found in 37
percent of 168 patients who did not respond to PPI
therapy, but were still on medication.39 In another
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Review Article
study of 200 patients who were PPI non-respond-
ers, 50 percent had weakly acidic reflux and the
other 50 percent had weakly acidic reflux mixed
with acidic reflux.40 One proposed theory to
explain why weakly acidic reflux can cause esopha-
geal damage is that the gas in weakly acidic reflux
may cause distension of the proximal esophagus,
leading to dilation of the intercellular spaces (DIS),
a known mechanism in esophagitis that increases
mucosal permeability and heartburn. Increased
esophageal DIS leading to heartburn has been
shown to occur in persons who are exposed to
weakly acidic bile-containing solutions.41
Non-erosive Reux Disease: The Paradox
In a European study, 66 percent of those
reporting symptoms had no evidence of erosive
esophagitis – classified as non-erosive reflux
disease (NERD).19 NERD accounts for 50-85
percent of all GERD diagnoses.42 NERD is referred
to as functional heartburn, defined as “retrosternal
burning in the absence of pathological gastro-
esophageal reflux, pathology-based motility
disorders or structural explanations.” Because only
50 percent of NERD diagnoses respond to PPI
therapy, research is expanding to understand the
complex etiology of NERD.43
NERD is dicult to assess. Negative endoscopic
findings of NERD patients do not generally
correlate with symptom severity.44 In other words,
a NERD patient may have a negative endoscopy
and severe symptoms of heartburn, theoretically
explained by esophageal hypersensitivity. is
hypersensitivity is believed to result from lowered
mucosal immunity and inflammation, allowing
refluxate eective access to intercellular spaces,
causing DIS and resulting in symptoms of esopha-
geal pain or heartburn. Psychological stress has
also been shown to result in increased perception
of esophageal pain in NERD.45
NERD patients are less likely to have abnormal
esophageal exposure to gastric contents (acid,
pepsin, and bile) and lower nighttime esophageal
acid exposure than those with erosive esophagi-
tis.46 Although NERD patients have decreased
peristalsis, it is less severe than those with erosive
esophagitis. NERD patients also have only mildly
reduced LES pressure.47 Hiatal hernia, a major risk
factor for reflux esophagitis, only occurs in 29
percent of NERD diagnoses compared to 71
percent of those with erosive esophagitis.48
Regardless of the presence or absence of symp-
toms, NERD does not generally appear to progress
to erosive esophagitis. e largest
population-based
study of 12,374 GERD patients, taken from a pool
of patients seen from 1977 to 2001, found that
only 4.4 percent progressed from NERD to esopha-
geal lesions within a five-year period.49 As many as
25 percent of NERD patients also appear to have
esophagitis that resolves and reoccurs, according to
an investigation of two-year follow-ups.50
Treatment of GERD: Lifestyle
Interventions
Avoidance of tobacco, alcohol, chocolate, and
citrus juice is typically recommended for GERD
treatment.51 While published GERD trials provide
evidence that smoking, alcohol, carbonated
beverages, coee, and chocolate ingestion lead to
decreased LES pressures, there is disagreement
regarding whether dietary and lifestyle changes can
result in actual clinical improvement in GERD. A
review of the literature included 2,039 studies on
lifestyle factors, including weight loss, timing of
meals, elevation of head during sleep, and avoid-
ance of alcohol, smoking, coee, citrus, and
chocolate. Of the 100 relevant studies, no evidence
was found for the ecacy of dietary measures or
smoking or alcohol cessation in improving sympto-
mology, LES pressure, or esophageal pH profiles.
e only ecacious factors were elevation of the
head of the bed and lifestyle interventions that led
to weight loss (mean loss of 12.4 kg in 13 weeks).51
Although spearmint intake has been shown to
lower LES tone in one double-blind randomized
controlled trial of GERD patients, it was not shown
to worsen GERD symptoms.52
e Geneva Workshop Report, a consensus group
of 35 gastroenterologists from 16 countries, agreed
that most reflux is postprandial and avoidance of
any foods and beverages that provoke reflux is
therapeutic.53 is group also agreed, contrary to
the meta-analysis cited above, that nocturnal reflux
is only a problem in a small subgroup of patients,
that only these individuals benefit from bed head
elevation, and that it is not eective as a first line of
treatment in most patients.53
Medications Used to Treat GERD
Antacids
Over-the-counter (OTC) antacids oer rapid,
short-term relief from GERD symptoms. In one
study that included 1,009 GERD patients, antacids
were commonly used to treat break-through
symptoms not eectively treated by standard PPI
medication. While oering symptomatic relief,
antacids have not been shown to contribute to the
healing of erosive esophagitis.54
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Review Article
Histamine H2-receptor Antagonists
Histamine H2-receptor antagonists (ranitidine,
famotidine, cimetidine, nizatidine), like antacids,
provide temporary relief, albeit with a slower onset
of action than antacids. Long-term use of these
medications for GERD is not recommended
because the body develops tolerance within 1-2
weeks, and they are not as eective as PPIs for
healing erosive esophagitis.55
Prokinetics
Prokinetic medications (cisapride, metoclo-
pramide) activate serotoninergic or dopaminergic
receptors to increase esophageal and gastric
peristalsis, which addresses the delayed esophageal
clearance seen in GERD patients.32 Prokinetic
medication results in approximately 70-percent
acid suppression in the gut, but the symptom relief
is both slow in onset and short-term (4-8 hours).56
ese medications have not been shown to be
eective in healing high-grade esophagitis. e side
eect profile of prokinetics, which includes tremor,
tardive dyskinesia, fatigue, and increased risk for
cardiac events, limits their use for GERD.54
Proton Pump Inhibitors
PPIs (pantoprazole, lansoprazole, esomeprazole,
omeprazole, rabeprazole) are the standard of care
for the treatment of GERD. e number of yearly
prescriptions for PPIs has doubled in the last 10
years.5 Currently, 21 percent of all PPI prescrip-
tions in the Netherlands are written specifically for
gastro-protection of patients on non-steroidal
anti-inflammatory drugs or aspirin. e mecha-
nism of action of PPIs involves blocking the gastric
acid pump of the parietal cells in the stomach. is
pump, commonly known as hydrogen/potassium
ATPase (H+/K+-ATPase) is the last step necessary
for the release of hydrochloric acid from the
parietal cell into the stomach lumen (Figure 1).56
PPIs provide faster relief than prokinetics or
H2-blocking agents and have good evidence for
long-term healing of esophageal erosion (including
Barrett’s esophagus). Side eect profile includes
nausea, diarrhea, headache, insomnia, and
anaphylaxis.54
Concerns associated with PPI use for GERD
include failure to respond, rebound gastritis,
atrophic gastritis, Helicobacter pylori or Clostridium
dicile infection, and other drug-induced side
eects.
A recent article assessing the need for manage-
ment of PPI failure states, “e failure of PPI to
resolve GERD symptoms has become the most
commonly seen patient scenario in gastroenterol-
ogy practices.”57 A meta-analysis of GERD patients
on a once daily dosage of a PPI reported that 25-40
percent of these patients continued to have
symptoms.58 While the standard of care with PPI
involves doubling the dose if an initial single dose
is ineective, only 20-25 percent of patients who
fail initial treatment respond to doubling the
dose.59 e majority of non-responders most likely
have NERD.56 Reasons for the lack of clinical
response to PPI in persons with NERD include
weakly acidic reflux, delayed motility, reflux that
contains bile, and increased esophageal pain
sensitivity.14 Regardless of the reason, PPI therapy
appears to be only partially eective for addressing
the underlying issues in NERD patients.
Evidence indicates that when patients discon-
tinue PPIs after long-term treatment, they eventu-
ally relapse.60 PPIs can induce parietal cell prolifera-
tion, which leads to a state of hyperacidity after
discontinuation. is rebound hyperacidity can
create a dependence on continued PPI use, an issue
that has become a concern among researchers and
clinicians. A study reported that 33 percent of
Figure 1. Gastric Acid Secretion Occurs via Hydrogen/Potassium ATPase
Adapted from: Vesper BJ, Altman KW, Elseth KM, et al. Esophageal Reux Disease
(GERD): Is there more to the story? Chem Med Chem 2008;3:552-559.
Basolateral
Membrane
Apical
Membrane
Parietal Cell
Lining of Stomach
HCO3-
Na+
K+
K+
K+
H+
CI -
CI -
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Review Article
patients given PPIs, supposedly for short-term use,
renew the prescription.61 On interview, primary
care clinicians viewed reduction or withdrawal of
long-term PPI medication as dicult.62 A recent
review of the long-term use of PPIs states,
“Profound acid suppressive therapy leads to
hypergastrinaemia in nearly all patients.”63 Serum
gastrin levels (clinically used to evaluate parietal
cell hyperplasia and to predict the rebound acidity
that occurs with long-term use of PPI) are com-
monly increased to four times the upper limit of
normal while on PPI medication. In some patients,
levels can be elevated to 40 times the upper limit of
normal (4,000 ng/L). ese elevated levels normal-
ize very slowly after PPI withdrawal.63
In 120 healthy volunteers, rebound acid hyperse-
cretion occurred after as little as eight weeks of PPI
treatment. Forty-four percent of those in the study
who were on a PPI for eight weeks experienced
acid-related symptoms 9-12 weeks after discon-
tinuing the PPI. e authors of this study sug-
gested that patients taper o PPIs more gradually
than is commonly suggested, due to the observa-
tion that symptoms lasted up to four weeks
post-discontinuation.64 Two additional studies
report increased acid production can continue
more than eight weeks post PPI discontinua-
tion,65,66 lending credence to the concerns about
rebound hyperacidity and the need to taper o
slowly.
Persons who experience rebound acidity as a
result of PPI withdrawal are more likely to be
infected with H. pylori and to develop atrophic
gastritis.67 Atrophic gastritis has been seen in 30
percent of patients infected with H. pylori on
long-term PPI therapy.68,69 Findings of an increased
incidence of atrophic gastritis in GERD patients on
long-term PPI therapy have been confirmed in
multiple studies.70,71 One 12-month study of PPI
therapy did not find increased atrophic gastritis,
although they did report increased levels of
inflammation in the corpus of the stomach.72 Other
studies report that, although H. pylori infection
increases the risk for atrophic gastritis in GERD, it
might be protective for severe reflux esophagitis,
Barrett’s esophagus, and esophageal adenocarci-
noma.73 Erosive reflux esophagitis occurs signifi-
cantly more often in the absence of H. pylori
infection.74 e “protective eect” of H. pylori is
apparent in the most virulent strain (cagA+). e
risk of developing Barrett’s esophagus with
dysplasia or adenocarcinoma is decreased two-fold
in individuals infected with the cagA+ strain when
compared with H. pylori-negative esophagitis
patients.75 is protective eect of H. pylori is
presumably due to H. pylori-induced atrophy of the
parietal cells. e atrophied cells produce less acid
which reduces the acid load on the esophagus. is
hypochlorhydric eect is lost when H. pylori is
successfully treated.74,75 Further evidence in
support of this protective relationship has been
shown when treatment of H. pylori has promoted
the development of esophagitis in both patients
with GERD and otherwise healthy patients.76,77
Concern has been raised about the risk for
nosocomial and outpatient Clostridium dicile
infection in long-term PPI users. Studies have
found a dosage-related risk for PPI users as well as
increased risk for reinfection.78 In one prospective
study of inpatient C. dicile cases, 64 percent of
patients were on a PPI when the infection devel-
oped. e authors could find no valid indication for
PPI therapy in 63 percent of the cases.79
PPI use is also linked to a significant increased
risk for hospital-acquired pneumonia80 and a
doubling of risk for reinfection with community-
acquired pneumonia.81
ere is also a modest increased risk for fractures
of the hip, spine, and lower arm, and increased risk
for the number of total fractures in menopausal
women on a PPI.82
Surgical Intervention for GERD
e primary surgical intervention for the
treatment of GERD is laparoscopic fundoplication,
a procedure where the fundus of the stomach is
wrapped around the esophagus to create a new
cardiac valve-equivalent at the gastroesophageal
junction. It is often recommended for patients who
have diagnosed erosive GERD, Barrett’s esophagus,
or cardiac conduction defects, for postmenopausal
women with osteoporosis, patients who have poor
compliance with medication, and for those with
serious respiratory or oral manifestations of GERD.
An examination of the data available on the
comparison of medication to surgical intervention
by the Agency for Healthcare Research and Quality
revealed that 10-65 percent of patients undergoing
surgical intervention still require medication. e
analysis also found that PPIs appear to be as
eective as surgery for improving symptoms and
decreasing esophageal acid exposure.83
Alternative Treatments for GERD
Low-Carbohydrate Diet
Although there have been no large scale trials of
GERD and low-carbohydrate diets, a case series84
and two small trials85,86 provide evidence that
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Review Article
low-carbohydrate diets may be related
to symptom improvement. In the first
small case series, five individuals
followed the standard Atkins diet,
which restricts carbohydrates to 20 g
daily, while allowing unlimited access
to protein and fat. According to patient
self-reports, all five patients had a
remission of GERD symptoms within
one day to two weeks from the time
they started the diet, and symptoms
reoccurred when it was discontinued.
ree of the five individuals restricted
caeine or coee, and alcohol was not
eliminated in all cases. Because dietary
change in these cases included
reduction or elimination of caeine in three cases
or elimination of other potentially bothersome
foods (e.g., tomato sauce, fruit juices), it is not clear
whether reduction of dietary carbohydrate was the
only factor involved in the elimination of GERD
symptoms.84
In an older, non-randomized, crossover study, 41
participants with diagnosed severe dyspepsia were
placed on either a low-carbohydrate diet or a
“gastric diet” (defined as a low-fat diet that elimi-
nated caeine and alcohol) for three months, then
crossed over to the alternate, low-carbohydrate
diet. Sixty-eight percent of the participants had
improvement on the low-carbohydrate diet
compared to the “gastric diet,” 27 percent did not
notice any dierence between diets, and five
percent had a worsening of symptoms on the
low-carbohydrate diet.85
A recent study assessed eight obese individuals
with GERD on a diet that, like the Atkins diet, was
restricted to 20 g carbohydrate daily. Participants
underwent esophageal pH monitoring and com-
pleted the GERD Symptom Assessment Scale-
Distress Subscale (GSAS-ds) pre-initiation of the
diet and six days later. e authors concluded that
after six days on the diet, the symptom scale
improved and esophageal acid exposure dropped
significantly.86
Acupuncture
Standard of care in patients who do not respond to
a single dose (20 mg once daily) of a PPI is to double
the dose (20 mg bid). A recent U.S. trial looked at the
ecacy of acupuncture versus doubling the PPI dose
in patients who failed single-dose PPI treatment.
irty patients with endoscopy-diagnosed NERD
were randomized to receive their original PPI dose
(omeprazole 20 mg once daily) plus acupuncture, or a
double PPI dose (omeprazole 20 mg twice daily).
Acupuncture treatment consisted of five points
(Table 2) and was administered in 10 sessions over a
four-week period. e acupuncture point Spleen 9
was either included or omitted based on a traditional
Chinese medicine (TCM) evaluation conducted by the
practitioner. At week 4, symptom assessments from
both groups were compared to pretrial symptom
ratings. Improvement in the symptom survey of
those in the double-dose PPI group was only statisti-
cally improved for the symptom of daytime heart-
burn (Table 3). All symptoms in the acupuncture plus
single dose PPI group improved significantly (Table
4).87 e authors concluded that suppression of
gastric acid secretion alone is an unlikely reason the
acupuncture group improved significantly; more
Table 2. Acupuncture versus
Omeprazole: Points Used in
the Study
Per 6
St 36
CV 12
CV 17
Liv 3
Sp 9
Neiguan
Zusanli
Zhangwan
Shanzhong
Taichong
Yinlingquan
Table 3. Symptom Ratings after Four Weeks of Double-dose Omeprazole
Compared to Baseline
Adapted from: Dickman R, Schi E, Holland A, et al. Clinical trial: acupuncture vs.
doubling the proton pump inhibitor dose in refractory heartburn. Aliment
Pharmacol Ther 2007;26:1333-1344.
Symptom value
Daytime heartburn
Night-time heartburn
Acid regurgitation
Dysphagia
Chest pain
Baseline
12.867 ± 1.816
12.800 ± 1.694
8.993 ± 2.226
6.333 ± 2.267
6.000 ± 1.813
4 weeks
16.400 ± 1.632
15.667 ± 1.305
7.400 ± 1.712
7.200 ± 1.996
5.800 ± 1.529
P-value
0.030
0.065
0.299
0.495
0.920
Table 4. Symptom Ratings after Four Weeks of Acupuncture Plus Single-
dose Omeprazole Compared to Baseline
Adapted from: Dickman R, Schi E, Holland A, et al. Clinical trial: acupuncture vs.
doubling the proton pump inhibitor dose in refractory heartburn. Aliment
Pharmacol Ther 2007;26:1333-1344.
Symptom value
Daytime heartburn
Night-time heartburn
Acid regurgitation
Dysphagia
Chest pain
Baseline
18.333 ± 1.816
18.067 ± 1.694
14.867 ± 2.226
6.600 ± 2.267
7.200 ± 1.813
4 weeks
3.267 ± 1.632
3.600 ± 1.305
3.733 ± 1.712
2.933 ± 1.996
1.267 ± 1.529
P-value
<0.001
<0.001
<0.001
0.007
0.006
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Review Article
probable mechanisms involved increased gastric and
esophageal motility and decreased
pain perception.87
Studies suggest other potential mechanisms
associated with symptom improvement with
acupuncture treatment. Acupuncture increases
gastric peristalsis and accelerates gastric emptying
in patients with dyspepsia.88,89 Perhaps more
importantly, acupuncture improves esophageal
peristalsis, limits lower esophageal sphincter
relaxation, and reduces esophageal pain
perception.90,91
Melatonin
Up to 500 times more melatonin is synthesized
in the mammalian intestinal tract than in the
pineal gland.92 Although production is highest in
the stomach, small intestine, and distal colon,
evidence also exists for some production in the
mouth and esophagus.93,94 Melatonin is produced
by the enterochroman cells in the stomach and
intestinal tract, which also produce serotonin.92
After feeding, levels of melatonin in the mucosa of
the mammalian gut are 100-400 times higher than
in peripheral blood. is increase in intestinally-
derived melatonin appears to be in response to
diet-derived tryptophan.95 Melatonin manufac-
tured in the gut is then delivered to the liver and
gall bladder where concentrated levels in the portal
vein are higher than in the peripheral
circulation.93,96
Melatonin has been identified as an important
gut motility signal and an eective signaling
molecule for communication between the gut and
the liver.97 Both significant amounts of melatonin
and melatonin-binding sites are present in the
esophageal mucosa.98 Orally administered melato-
nin has a local eect on the esophageal mucosa in
animal models, increasing microcirculation and
modulating nitric oxide production.99 Melatonin
stimulates the production of nitric oxide and
prostaglandin E2, both of which protect the
esophageal mucosa from damage induced by stress
and excessive free radical production.99 Melatonin
also inhibits gastric acid secretion, while increasing
gastrin release.99 Gastrin then stimulates the
contractile activity of the LES; both actions protect
the esophagus by minimizing contact with reflux-
ate. Melatonin has also been shown to prevent
acid-pepsin-induced esophagitis in animals.100
In experimentally-induced reflux esophagitis,
melatonin reversed inflammatory lesions and
reduced lipid peroxidation that occurs as a result of
gastric juice and bile-containing duodenal contents.
Melatonin was also found to reduce inflammatory
cytokine levels of tumor necrosis factor-alpha
(TNF-Į), interleukin (IL) -1β, and -6 and to
normalize levels of glutathione and superoxide
dismutase, the latter two of which are antioxidants
depleted in experimental models of reflux
esophagitis.101
Human trials of melatonin for GERD are limited,
but the results are significant. One study compared
176 patients on a nutrient/melatonin combination
with 175 patients on 20 mg omeprazole.102 e
nutrients provided included tryptophan, vitamin
B6, vitamin B12, methionine, betaine, and folic acid.
e nutrients were selected to promote the
synthesis of s-adenosyl-L-methionine (SAMe), an
increase of which might increase serotonin and
noradrenaline and act as an analgesic (Table 5).
Melatonin was selected due to its ecacy in animal
models of GERD. Treatment eect was measured
by the length of time to become asymptomatic
(defined as no heartburn or regurgitation) for 24
hours.
Ninety percent of patients taking the nutrient/
melatonin combination experienced relief after
seven days, while 66 percent of those on omepra-
zole had similar relief after nine days. After 40 days,
100 percent of the patients in the melatonin/
nutrient group reported relief of symptoms
compared to 66 percent of the omeprazole group.
At the end of the 40-day trial, the 60 patients in
Table 5. Daily Dosage of Melatonin/
Nutrient Supplement
Melatonin
L-Trytophan
Vitamin B12
Methionine
Betaine
Folic acid
Vitamin B6
6 mg
200 mg
50 μg
100 mg
100 mg
10 mg
25 mg
Pereira RS. Regression of gastroesophageal reux
disease symptoms using dietary supplementation
with melatonin, vitamins and amino acids:
comparison with omeprazole. J Pineal Res
2006;41:195-200.
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125 Alternative Medicine Review Volume 16, Number 2 Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Review Article
the omeprazole group who still reported symptoms
were given the melatonin/nutrient combination for
another 40 days. At the end of this treatment
period 100 percent of these PPI non-responders
(omeprazole) reported that all symptoms had
resolved. Side eects reported in the omeprazole
group (n=175) were diarrhea (7 patients), headache
(2 patients), hypertension (3 patients), and
somnolence (4 patients). e single side eect
experienced by those in the melatonin/nutrient
group was somnolence, which occurred in 159 of
176 subjects.102
Another smaller human study consisted of 60
symptomatic GERD patients diagnosed by endos-
copy and compared to a control group comprised of
persons without GERD.103 All GERD patients in the
study had decreased LES pressure, increased LES
relaxation duration, lowered esophageal pH,
lowered serum gastrin levels, and elevated gastric
basal acid output. GERD patients were treated with
3 mg melatonin alone, 20 mg omeprazole alone, or
melatonin and omeprazole. Repeat symptom
survey and all other indices of GERD were mea-
sured at four and eight weeks.
e eect of melatonin and omeprazole and the
dierences among the three groups are detailed in
Table 6. Heartburn and epigastric pain were
decreased after four weeks and completely resolved
after eight weeks in all treatment groups. One of
the primary dierences among the treatment
groups was that only the two groups that included
melatonin as part of the protocol had significant
improvements in LES function; the omeprazole-
alone group did not. All treatment groups experi-
enced an increase in serum gastrin (reflecting
improved gastric motility) and a significant
decrease in basal acid output. Treatment with
omeprazole or omeprazole plus melatonin resulted
in a significant improvement in esophageal pH and
gastrin in addition to a decrease in gastric acid
output compared to the melatonin-only group after
four and eight weeks. Measurements at the
beginning of the trial revealed that patients with
GERD had about half the daytime serum melatonin
levels compared to controls. Both nighttime and
daytime melatonin levels increased to near normal
in both groups on melatonin, but did not change in
the omeprazole-only group.103
Table 6. Results of GERD Study Comparing Melatonin with Omeprazole
Heart burn
control
pretreatment:
yes
duration
4 weeks
8 weeks
Epigastric pain
control
pretreatment:
yes
duration
4 weeks
8 weeks
LES pressure (mmHg)
control
pretreatment
4 weeks
8 weeks
Relaxation duration (seconds)
control
pretreatment
4 weeks
8 weeks
control
pretreatment
4 weeks
8 weeks
control
pretreatment
4 weeks
8 weeks
control
pretreatment
4 weeks
8 weeks
control
pretreatment
4 weeks
8 weeks
0
7
1.3 ± 0.4
3(57.1%)
0(100%)
0
6
1.4 ± 0.5
3(50%)
1(83%)
22.8 ± 1.3
10 ± 1.58
14.5 ± 1.58
20.2 ± 1.56
5.0 ± 0.1
6.8 ± 0.12
5.9 ± 0.16
5.3 ± 0.12
7.8 ± 0.4
2.3 ± 0.36
5.2 ± 0.5
6.7 ± 0.65
2.6 ± 0.6
24.7 ± 0.5
20.1 ± 0.4
16.6 ± 0.6
41.8 ± 7.1
22.1 ± 4.2
27.2 ± 2.3
32.3 ± 2.1
36.1 ± 2.3
18.2 ± 5.54
28.26 ± 2.26
34.5 ± .35
Melatonin
0
7
1.2 ± 0.3
2(71.4%)
0(100%)
0
6
1.3 ± 0.4
2(66.7%)
0(100%)
22.8 ± 1.36
10.5 ± 2.86
10.4 ± 4.05
10.5 ± 2.85
5.0 ± 0.1
6.5 ± 2.74
6.3 ± 2.7
6.3 ± 2.65
7.8 ± 0.4
2.1 ± 0.38
5.9 ± 0.48
7.2 ± 0.32
2.6 ± 0.6
25.1 ± 0.6
17.2 ± 0.7
11.5 ± 0.6
41.8 ± 7.1
21.5 ± 4.6
32.1 ± 2.1
35.9 ± 1.8
36.1 ± 2.3
18.5 ± 3.75
19.2 ± 3.47
17.9 ± 3.72
Omeprazole
0
8
1.4 ± 0.4
1(87.5%)
0(100%)
0
6
1.3 ± 0.4
1(83.3%)
0(100%)
22.8 ± 1.3
10.3 ± 1.68
14.5 ± 1.26
20.5 ± 1.22
5.0 ± 0.1
6.8 ± 0.16
5.8 ± 0.13
5.2 ± 0.12
7.8 ± 0.4
1.98 ± 0.37
6.1 ± 0.55
7.5 ± 0.31
2.6 ± 0.6
24.9 ± 0.7
15.8 ± 0.9
10.2 ± 0.9
41.8 ± 7.1
21.9 ± 4.7
33.6 ± 2.7
36.8 ± 2.1
36.1 ± 2.3
18.3 ± 3.8
28.83 ± 1.82
34.5 ± 2.35
Melatonin &
Omeprazole
Symptoms
LES Study
pH (at 5 cm above
the LES)
BAO(mmol/h)
Serum Gastrin(pg/ml)
Melatonin level at
day time (pg/ml)
Adapted from: Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential therapeutic eect of melatonin in
gastro-esophageal reux disease. BMC Gastroenterol 2010;10:7.
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Review Article
Botanicals for GERD
Lonicerae: Chinese Honeysuckle Flower
e flower of Lonicerae (jin yin jua, Chinese
honeysuckle) was evaluated in an animal model of
GERD. When rats were pretreated with a powdered
water-extract preparation at a dose of 125-, 250-,
or 500 mg/kg and sacrificed nine hours later, there
were significant improvements in esophageal
lesion scores and thickness of the esophageal
mucous membrane. e mechanism of action was
believed to be an antioxidant eect. e gastric
mucosa of treated animals had significantly higher
levels of glutathione and lower levels of myeloper-
oxidase; the antioxidant, tissue-protective eects
were similar to animals given alpha-tocopherol.
ere have been no published human studies of
Chinese honeysuckle and GERD.104
Spearmint/Peppermint
While ingesting spearmint does not appear to
improve or worsen GERD symptoms,52 peppermint
oil might have some benefits. Peppermint oil is
reported to accelerate the early phase of gastric
emptying, increase relaxation time of the pyloric
valve, and decrease the resting lower esophageal
sphincter pressure.105
Iberogast®
STW 5 (Iberogast) is a commercial ethanolic
extract formula that includes nine botanicals:
Iberis amara, Matricaria chamomilla, Carum carvi,
Mentha piperita, Glycyrrhiza glabra, Melissa
ocinalis, Chelidonium majus, Silybum marianum,
and Angelica archangelica (Table 7). Iberogast has
been shown to both inhibit the function of the
proximal stomach (through the actions of the
botanicals chamomile flowers, licorice root
(Glycyrrhiza), and garden Angelica root), while
greater celandine (Chelidonium), lemon balm leaf
(Melissa), caraway fruit (Carum), and bitter
candytuft (Iberis) increased the motility of the
distal stomach.106 While these mechanisms
theoretically improve gastric motility, Iberogast
has not been shown to increase gastric emptying
in human trials.107
Iberogast has been evaluated in six randomized
controlled trials for the treatment of functional
dyspepsia. In three trials that were selected for
meta-analysis, 273 patients classified as having
“functional dyspepsia” had symptoms of GERD
(acid regurgitation, epigastric pain, or dysmotility
symptoms). e trial dosages were consistent – 1
mL three times daily for four weeks. At the end of
the trials 83/138 treated patients reported that
their symptoms had changed from severe to either
mild or absent, while only 33/135 in the placebo
group had the same response. At the end of
treatment only seven percent of the treatment
group said their symptoms remained “severe” or
“very severe,” while 26 percent of the placebo group
still complained of the “severe” or “very severe”
nature of their symptoms. STW 5 was most
eective for the specific complaints of epigastric
pain, retrosternal pain, and acid regurgitation.
Adverse events using the botanical combination of
STW 5 during the trials were similar to placebo.
e adverse events reported during the 14 years of
these trials are seven cases of dermatitis that
included both disseminated neurodermatitis and
angioedema, six cases of digestive intolerance and
one case of allergic asthma.106
While STW 5 appears to be eective in treating
some of the symptoms associated with GERD,
trials have not attempted to measure factors such
as changes in LES pressure or esophageal healing.
Further research with endoscopic evaluations to
determine whether Iberogast influences the
healing of esophageal ulceration is warranted. STW
5 has been on the German market for 40 years, has
a good safety profile,106 and might be appropriate
for symptomatic relief in persons with GERD.
Table 7. Herbal Constituents of Iberogast
Latin Name
Matricaria recutita
Iberis amara
Angelica archangelica
Carum carvi
Melissa ocinalis
Chelidonium majus
Glycyrrhiza glabra
Silybum marianum
Mentha piperita
Common Name
German chamomile
clown's mustard
(or bitter candy)
garden angelica
caraway
lemon balm
greater celandine
licorice
milk thistle
peppermint
Part Used
ower
tuft
root and rhizome
fruit
leaf
aerial part
root
fruit
leaf
Amount
(per 100 mL)
20 mL
15 mL
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
5 mL
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Review Article
Raft-forming Agents
Raft-forming agents, the constituents of which
are natural substances including alginate, pectin,
and carbenoxolone (a synthetic derivative of
glycyrrhizin), have been used in the symptomatic
treatment of GERD. Alginate-based raft-forming
agents have been used for treating heartburn and
esophagitis for over 30 years. Alginate, in the
presence of gastric acid, forms a gel. e bicarbon-
ates added to the alginate formula are converted to
carbon dioxide in the presence of gastric acid,
which becomes trapped within the gel as bubbles
and converts it to a lighter substance that can rise
to the surface of gastric contents and float (thus
the name “raft-forming agent”). is combination
has been shown to move into the esophagus and
provide a barrier to reduce acid contact with the
esophageal mucosa.108
Pectin-based raft-forming agents are eective for
reducing esophageal pH and preventing reflux of
food and gastric contents.109 Trials in GERD
patients with hiatal hernia and reflux have shown
benefit symptomatically and endoscopically with
carbenoxolone-based raft-forming agents.110
Alginate-based raft-forming agents have been
demonstrated to prevent relapse of healed reflux
esophagitis.111 Pectin-based raft-forming agents
have been tested in a comparison trial with PPIs
and found to be faster acting and as eective at
reducing reflux of both food and acid, although the
PPI (esomeprazole) was significantly more eective
based on the patient satisfaction reports (92
percent versus 58 percent on the pectin-based
raft-forming agent).112 Pyrogastrone is a raft-form-
ing antacid that contains alginate, magnesium
trisilicate, aluminum hydroxide, sodium bicarbon-
ate, and carbenoxolone. Pyrogastrone has been
Table 8. Summary of Studies on Raft-forming Agents for GERD
Outcome
Pyrogastrone: 82%
improvement in 8 weeks vs.
63% on antacid/alginate
Pyrogastrone:
89% symptom remission in 8
weeks; 95% endoscopy
conrmed esophageal ulcer
remission compared with 67%
controls (antacid/alginate
alone)
Addition of either metoclo-
pramide or cimetidine did not
improve outcome; pyrogastrone
alone resulted in symptom relief
in 85% of 96 patients in 4-8
weeks; endoscopic healing in
76% of 55 patients in 4-8 weeks
Pyrogastrone: 40% healed at 6
weeks vs. 37% on cimetidine;
both equivalent at 12 weeks
Indicators
Symptom
rating scale,
endoscopy
Symptom
rating scale,
endoscopy
Symptom
rating scale,
endoscopy
Symptom
rating scale,
endoscopy
Dosage
1 tid after
meals and 2
at bedtime
same
same
same
Length
8 weeks
8 weeks
42 months
12 weeks
Design
DBRC in endoscopy-
conrmed GERD;
pyrogastrone vs. alginate
raft
DBRC in endoscopy-
conrmed GERD;
pyrogastrone vs. alginate
raft
Endoscopy conrmed
GERD;
Retrospective analysis in
three groups: pyrogas-
trone, pyrogastrone plus
metoclopramide,
both with cimetidine
Endoscopy conrmed
GERD;
randomized to
pyrogastrone or
cimetidine
n
29/30
37
104
80
Study
Young et al
Reed et al
Markham et al
Maxton et al
DBRC= double-blind, randomized, control trial
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Review Article
compared to alginate formulations, motility agents
(metoclopramide), and histamine H2-receptor
antagonists (cimetidine). In comparison studies,
pyrogastrone was more eective for improving
endoscopic findings and symptom rating scales
than alginate alone, and as eective as both
metoclopramide and cimetidine together (Table
8).113-116 Raft-forming agents lack major side eects
and are considered useful in treating mild-to-
moderate forms of GERD.113
D-Limonene
D-limonene is found in citrus oils and used as a
fragrance and flavoring agent in body products and
beverages. As such it is considered safe for inges-
tion and generally recognized as safe (GRAS).
Clinical trials have determined no toxicity or side
eects in humans at 100 mg/kg.117 In unpublished
data, 19 patients with GERD or chronic heartburn
were given 1,000 mg d-limonene daily or every
other day. After 14 days, 89 percent of patients
reported a complete remission of symptoms.
Following this pilot trial, 13 participants with
GERD or chronic heartburn were randomized to
1,000 mg d-limonene once daily or every other day
or placebo. By day 4, 29 percent of participants on
treatment experienced significant relief and by day
14, 86 percent experienced complete relief of all
symptoms, compared to 29 percent on placebo.118
e mechanism of action of d-limonene in GERD
and chronic heartburn is unknown, although in
vitro research suggests it may protect mucosal
surfaces from gastric acid and support normal
peristalsis.118,119
Esophagitis and Oxidant Stress
Because the severity of esophageal damage
cannot be predicted based on the amount of time
acid contacts the esophageal mucosa, nor can the
pH of esophageal refluxate predict the severity of
symptoms, researchers have proposed that factors
other than the acidity of refluxate or the amount
and duration of exposure to refluxate might
determine esophageal damage. Several studies
demonstrate mucosal resistance, inflammation,
and free radical damage are major determinants in
the progression of reflux esophagitis.120-122 e
esophageal epithelium is morphologically and
embryologically related to skin epithelium, and
skin epithelium is recognized as a major immuno-
logical organ. e esophagus has similar keratino-
cytes and epithelial cells that are able to secrete
proinflammatory cytokines (e.g., IL-8, IL-10,
nuclear factor-kappaB [NF-κB], IL-6, and platelet
adhesion factors).123 Esophageal biopsies demon-
strate elevated levels of these cytokines in GERD,
with significantly higher levels in Barrett’s esopha-
gus and adenocarcinoma than patients with erosive
GERD.123
Artemisia asiatica
Higher levels of reactive oxidant species are
found in the esophageal tissue of patients with
GERD, especially in Barrett’s esophagus and
esophageal adenocarcinoma.124 In an animal model,
oxidative stress was found to be more important
than acid exposure in development of esophageal
ulcerations.125 In this animal model, the use of
ethanol-extracted Artemisia asiatica, given at two
dosages of 30 mg/kg or 100 mg/kg, acted as an
antioxidant and was more eective in preventing
esophageal erosion than ranitidine (Zantac®).125
Curcumin, Quercetin, and Vitamin E
In a study designed to simulate acid exposure
experienced by GERD patients, curcumin pre-
vented the expression of inflammatory cytokines
in human esophageal tissue.126 In another animal
model, rats with experimentally-induced reflux
esophagitis were given quercetin (100 mg/kg) or
alpha-tocopherol (16 IU/kg) and compared with
rats on omeprazole. Both quercetin and alpha-
tocopherol lowered the level of esophageal inflam-
mation and decreased acid and pepsin production
in the stomach. Both antioxidants also raised levels
of glutathione and other antioxidant enzymes
while decreasing collagen production, indicating an
anti-inflammatory and antifibrotic eect.127
Conclusion
Current conventional approaches to GERD
management rely extensively on the use of PPIs.
While these medications can be eective in
treating non-erosive GERD, their utility for many
GERD patients is less evidence-based. Over-
reliance on PPIs is also potentially problematic
because they are often used not only as a means of
treating GERD, but as a means of diagnosis, with
the response to a trial of a PPI routinely relied
upon as the primary method of GERD diagnosis. If
a patient responds favorably to a PPI, it is pre-
sumed that GERD has been eectively addressed.
However, a remission of symptoms subsequent to
PPI treatment does not always reflect healing of
underlying pathology. e simplistic model of
GERD, in which acid exposure equals degree of
erosion, does not bear out in the literature. Animal
models and in vitro research linking oxidative
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129 Alternative Medicine Review Volume 16, Number 2 Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Review Article
stress to esophageal damage continue to challenge
the current model of pathogenesis. ese underly-
ing issues need more investigation and will ideally
be considered in future research designed to
prevent and treat GERD.
While older medications, like raft-forming agents
based upon alginates, pectins, and glycyrrhizin
analogs have been proven to be eective and safe in
mild-to-moderate disease, they have fallen out of
favor, replaced by newer, more expensive agents.
Melatonin is a potentially attractive alternative
therapy for GERD. It might directly address several
underlying mechanisms (oxidative stress, inflam-
mation, motility, and gastrointestinal signaling).
Its primary side eect is, not surprisingly, somno-
lence, which occurs in a majority of persons. While
it has not been investigated, it is at least possible
that the increased quality of sleep that occurs
because of this side eect contributes in part to the
therapeutic response to melatonin in GERD
patients.
e use of compounds such as curcumin and
quercetin has not been explored in human GERD
trials, but the existing in vitro and animal data
suggest these compounds warrant further investi-
gation. e botanical combination Iberogast has
shown ecacy in existing trials and has a low side
eect profile. Further research on this botanical
combination is warranted.
Evidence suggests acupuncture might play a
therapeutic role in combination with PPIs for
treatment of GERD. Its ecacy as a stand-alone
treatment for this condition has not been investi-
gated. More research on acupuncture in combina-
tion with other therapies and as a stand-alone
approach should be conducted.
ere is insucient evidence to make any
definitive dietary recommendations for persons
with GERD. Limited evidence suggests potential
benefits from consuming a low-carbohydrate diet.
Evidence also suggests that dietary changes that
produce weight loss might benefit GERD.
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... Other symptoms are bloating, feeling of fullness in the stomach, chest pain, difficulty swallowing, cough, and hoarseness (2). In endoscopy, pathological findings are seen in just 30-40% of patients with GER, and no pathological findings are seen in the endoscopy of the remaining (5). Complications such as erosive esophagitis, esophageal stricture, Barrett's esophagus and cancer of the esophagus can be seen in endoscopy, depending on the duration and intensity of the symptoms (2,5). ...
... In endoscopy, pathological findings are seen in just 30-40% of patients with GER, and no pathological findings are seen in the endoscopy of the remaining (5). Complications such as erosive esophagitis, esophageal stricture, Barrett's esophagus and cancer of the esophagus can be seen in endoscopy, depending on the duration and intensity of the symptoms (2,5). ...
Article
Full-text available
Objective: Gastroesophageal reflux (GER) is the migration of stomach contents to the lower part of the oesophagus, which is a physiological phenomenon that can usually be detected 10-15 times a day. It can occur after meals and during sleep. This study was conducted to investigate the nutritional behaviour of patients diagnosed as having GER disease (GERD). Methods: In this research, among patients who were admitted to the gastroenterology outpatient clinic in a training and research hospital in İstanbul between June and December 2019, 104 patients aged 18-65 and diagnosed as having GERD as the study group, and 104 individuals not diagnosed as having GERD as the control group were included. Results: Of both patient and control groups, 49% were male and 51% were female. It was determined that those diagnosed as having the disease frequently experienced pyrosis and regurgitation with acidity. The average body mass index (BMI) of the patient group was 30.40 kg/m2, and of the control group, it was 25.41 kg/m2 (p<0.05). In this study, nutritional habits were assessed, and statistically significant variations were found in the number of meals, meal skipping, eating speeds, and food temperatures. It was determined that most people with GERD symptoms ate more chocolate, fatty foods, acidic foods, spicy foods, and sodas than the control group. It was found that most individuals diagnosed as having GERD were overweight and their physical activities were significantly lower than the control group (p<0.05).
... Lifestyle factors like consumption of tea, coffee and use of tobacco products like bidis and cigarettes can also account for the higher presence of GERD symptoms in the present study. These factors have also been shown to be associated with increased incidence of GERD [12] . In the present study, though almost 62% patients had reflux symptoms, only 41% of patients had significant GERD-Q score. ...
... Non asthmatic patients included patients with allergic rhinitis, upper respiratory tract infection, pharyngitis, etc. It has been a known fact that these non-asthmatic conditions can also be aggravated by GERD [12] . This could be the reason for the higher prevalence of GERD in the control group. ...
... Proton pump inhibitors (PPIs) are commonly used to treat GORD; however, not all patients benefit from them, as such agents are ineffective in 30% and 40% of GORD patients with Erosive Reflux Disease (ERD) and with Non-Erosive Reflux Disease (NERD), respectively. [3][4][5][6][7][8][9][10] In recent years, attention has been focused on the mechanism that impairs oesophageal barrier function, [11][12][13][14] and the development of new products that adhere to the oesophageal mucosa to form a stable film with a barrier effect. Such an effect aims to protect the oesophageal mucosa, enhancing its physiological defence mechanisms against the damaging action of gastro-oesophageal reflux (GOR) and thus preventing the GORD-related symptoms of heartburn and retrosternal and epigastric pain. ...
Article
Full-text available
Purpose: A novel experimental design based on a human-reconstructed oesophageal epithelium (HO2E) model has been applied to quantitively assess the properties of a set of liquid formulations, Device A (Gerdoff® Protection), Device B (Esoxx® One), and Device C (Marial® gel) developed to form a temporary physical barrier on the oesophageal epithelium and modify epithelial permeability so to protect the oesophageal mucosa from refluxate components. Methods: The formulations were applied to a prewetted HO2E model for 15 min. Then, a 0.5% caffeine solution was applied, and its penetration kinetics was assessed at 1 h and 2 h in acidic environments (pH= 3.3) to mirror exposure of the oesophageal mucosa to acidic reflux in GORD patients. Caffeine permeated into the basolateral compartment (evaluated by HPLC-UV) and Lucifer yellow (LY) permeability were quantified 15 min after application of the caffeine in acidic environments. Results: At the 15 min timepoint, Device A reduced caffeine permeation by 77.2% and LY flux by 30.4% compared to the untreated control and with a faster mode of action than that of the other liquid formulations. Transepithelial caffeine flux was reduced, albeit with different timing and efficiency, by all three compounds up to the end of the 2 hour experiment. At 1 h, Device A reduced the caffeine flux by 79.2%; Device B, by 67.2%; and Device C, by 37%. Conclusion: These results confirm the ability of the medical devices tested to interact with the oesophageal epithelium and create a temporary physical protective film for up to 2 hours after their application. The results underline differences in the mechanism of action of the three medical devices, with Device A performing faster than the other formulations. The overall results support the relevance of the reconstructed mucosal model to investigate oesophageal epithelium-product interactions and precisely differentiate liquid formulation performance.
... More recent research employed similar methods for examining preterm birth, gastroesophageal reflux disease, and periodontitis [21]. Previous research made independent hypotheses on a positive linkage between gastroesophageal reflux disease and periodontitis and on a positive relationship between periodontitis and preterm birth [34][35][36][37][38][39][40]. In a similar context, one would hypothesize a positive association between gastroesophageal reflux disease and preterm birth. ...
Article
This study reviews recent advances on the application of artificial intelligence for the early diagnosis of various maternal-fetal conditions such as preterm birth and abnormal fetal growth. It is found in this study that various machine learning methods have been successfully employed for different kinds of data capture with regard to early diagnosis of maternal-fetal conditions. With the more popular use of artificial intelligence, ethical issues should also be considered accordingly.
... Biofeedback therapy, a technique which employs visual and audio signals or direct verbal feedback to gain a greater awareness of bodily functions, could be interesting (162). Finally, also acupuncture is reported to improve GERD symptoms, although the exact mechanisms are not known (163). However, studies evaluating the clinical efficacy of these approaches in patients with rGERD are scarce. ...
Article
Full-text available
Gastroesophageal reflux disease (GERD) is one of the most frequent gastrointestinal disorders. Proton pump inhibitors (PPIs) are effective in healing lesions and improving symptoms in most cases, although up to 40% of GERD patients do not respond adequately to PPI therapy. Refractory GERD (rGERD) is one of the most challenging problems, given its impact on the quality of life and consumption of health care resources. The definition of rGERD is a controversial topic as it has not been unequivocally established. Indeed, some patients unresponsive to PPIs who experience symptoms potentially related to GERD may not have GERD; in this case the definition could be replaced with “reflux-like PPI-refractory symptoms.” Patients with persistent reflux-like symptoms should undergo a diagnostic workup aimed at finding objective evidence of GERD through endoscopic and pH-impedance investigations. The management strategies regarding rGERD, apart from a careful check of patient’s compliance with PPIs, a possible change in the timing of their administration and the choice of a PPI with a different metabolic pathway, include other pharmacologic treatments. These include histamine-2 receptor antagonists (H2RAs), alginates, antacids and mucosal protective agents, potassium competitive acid blockers (PCABs), prokinetics, gamma aminobutyric acid-B (GABA-B) receptor agonists and metabotropic glutamate receptor-5 (mGluR5) antagonists, and pain modulators. If there is no benefit from medical therapy, but there is objective evidence of GERD, invasive antireflux options should be evaluated after having carefully explained the risks and benefits to the patient. The most widely performed invasive antireflux option remains laparoscopic antireflux surgery (LARS), even if other, less invasive, interventions have been suggested in the last few decades, including endoscopic transoral incisionless fundoplication (TIF), magnetic sphincter augmentation (LINX) or radiofrequency therapy (Stretta). Due to the different mechanisms underlying rGERD, the most effective strategy can vary, and it should be tailored to each patient. The aim of this paper is to review the different management options available to successfully deal with rGERD.
... Antacids are known to be effective in gastric and duodenal ulcer and GERD for several decades. Although they have not been proven to directly act on the erosive lesions, they are able to neutralize the excess of HCl in the gastric juice and therefore, reduce the activity of pepsin, enhance the healing process, and offer rapid relief of heartburn and acid reflux [12][13][14][15]. Antacids are alkaline drugs that neutralize gastric acidity and exert a buffering effect to stabilize the pH of the gastric juice. ...
Article
Full-text available
Aim: The aim of this study was to evaluate the acid-neutralizing capacity (ANC) and other properties of antacid drugs marketed in Morocco. Methods: Samples of 12 antacids were collected from pharmacies and were subjected to the test described in the US Pharmacopoeia in order to measure their ANC. Other properties such as price and sodium content were also studied. Results: All the tested brands met the minimal requirement of 5 mEq. However, Aluminum hydroxide/Magnesium hydroxide combinations showed a superior acid-neutralizing capacity over other products and oral suspensions showed better results compared to other pharmaceutical forms. Regarding the cost of antacids, Aluminum hydroxide/Magnesium hydroxide combinations and calcium carbonate/magnesium carbonate combinations showed the most favorable ANC/price ratio. Some of the antacids studied contain a high amount of sodium. Conclusion: All the antacids marketed in Morocco meet the USP requirement regarding their ANC. However, the ANC value should be included in the antacids' labels so that both patients and physicians can choose the most appropriate product. The ANC value should be evaluated according to the dose of the active substance instead of the minimum labeled dosage in order to allow a better result interpretation.
... In another study, melatonin was found to have potential suppressive efficacy against esophageal carcinoma. Gastroesophageal reflux disease (GERD) includes a chronic disorder with several complications [112] as well as a risk factor of esophageal carcinoma [113]. Reports in in vivo animal models demonstrated that treatment with melatonin inhibited esophageal damage from acid-pepsin and acid-pepsin-bile exposure [38]. ...
Article
Gastrointestinal cancer is one of the most common cancers globally. Melatonin, a natural endogenous body hormone, has been of interest for years, due to its anti-cancer characteristics, such as antiproliferative, antimetastatic, and cytotoxic as well as apoptotic induction. Through regulating several proteins such as melatonin upregulated mRNAs and proteins of downregulated Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), as well as cytoplasmic protein such as calcium-binding proteins calmodulin or tubulin, and nuclear receptors, including RORα/RZR, and acts by non-receptor-regulated mechanisms, melatonin can exert anti-cancer efficacy. Moreover, melatonin modulates angiogenesis by targeting mRNA and protein expression of endothelin-converting enzyme (ECE-1) protein. In the present review, we address in vivo, in vitro and clinical reports on its anti-cancer efficacies, and the molecular mechanisms of action responsible for these effects. We advance the possibility of therapeutic melatonin administration for cancer therapy.
Chapter
Alternative medicine interventions to decrease gastro-esophageal reflux has been poorly studied. Therefore, no recommendations can be made. There is some evidence for an impact of lifestyle and over-weight, especially dietary habits, in children. The impact of positional treatment and dietary changes are not considered to be part of “alternative medicine” in infants since they have been well studied, making these interventions part of the recommended first-line approach. More research on the impact of alternative medicine interventions in adolescents is needed.
Article
Full-text available
Background: Irritable bowel syndrome (IBS) affects 9,2% of the global population and places a considerable burden on healthcare systems. Most medications for treating IBS, including spasmolytics, laxatives, and antidiarrheals, have low efficacy. Effective and safe therapeutic treatments have yet to be developed for IBS. Purpose: This study assessed the efficacy and safety of a food supplement containing standardized menthol, limonene, and gingerol in human participants with IBS or IBS/functional dyspepsia (FD). Design: A double-blind, randomized, placebo-controlled trial. Methods: We randomly assigned 56 patients with IBS or IBS/FD to an intervention group (Group 1) or control group (Group 2) that were given supplement or placebo, respectively, in addition to the standard treatment regimen for 30 d. Three outpatient visits were conducted during the study. Symptom severity was measured at each visit using a 7×7 questionnaire. Qualitative and quantitative composition of the intestinal microbiota were assessed at visits 1 and 3 based on 16S rRNA gene sequencing. Results: At visit 1 (before treatment), the median total 7×7 questionnaire score was in the moderately ill range for both groups, with no difference between the groups (p = 0.1). At visit 2, the total 7×7 score decreased to mildly ill, with no difference between the groups (p = 0.4). At visit 3, the total score for group 1 indicated borderline illness and for group 2 remained indicated mild illness (p = 0.009). Even though we observed some variations in gut microbiota between the groups, we did not find any statistically significant changes. Conclusion: The food supplement with standardized menthol, limonene, and gingerol content increased the efficacy of standard therapy in IBS and FD patients. The use of the supplement did not cause any obvious side effects. Registration: ClinicalTrials.gov Identifier: NCT04484467.
Article
Background: This study used machine learning and population data for testing the associations of preterm birth with gastroesophageal reflux disease (GERD) and periodontitis. Methods: Retrospective cohort data came from Korea National Health Insurance Service claims data for all women who aged 25-40 years and gave births for the first time as singleton pregnancy during 2015-2017 (405,586 women). The dependent variable was preterm birth during 2015-2017 and the independent variables were GERD (coded as no vs. yes) for each of the years 2002-2014, periodontitis (coded as no vs. yes) for each of the years 2002-2014, age (year) in 2014, socioeconomic status in 2014 measured by an insurance fee, and region (city) (coded as no vs. yes) in 2014. Random forest variable importance was adopted for finding main predictors of preterm birth and testing its associations with GERD and periodontitis. Results: Based on random forest variable importance, main predictors of preterm birth during 2015-2017 were socioeconomic status in 2014, age in 2014, GERD for the years 2012, 2014, 2010, 2013, 2007 and 2009, region (city) in 2014 and GERD for the year 2006. The importance rankings of periodontitis were relatively low. Conclusion: Preterm birth has a stronger association with GERD than with periodontitis. For the prevention of preterm birth, preventive measures for GERD would be essential together with the improvement of socioeconomic status for pregnant women. Especially, it would be vital to promote active counseling for general GERD symptoms (neglected by pregnant women).
Article
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Enantiomers of limonene, which are often used in conjunction with other terpenes in medicinal products for the treatment of gallstones and ureteric stones, were assessed for their bioactivity in vitro. There was a substantial difference in the activity of the two enantiomers: the (+) enantiomer exhibited the higher activity against 19 of 25 different bacterial species and showed higher activity against 13 of the 20 different varieties of Listerin monocytogenes; the two isomers behaved differently against six of the eight species of fungi and against different pharmacological tissue preparations in vitro including rat vas deferens, phrenic nerve - diaphragm, caecum and uterus and guinea-pig ileum. The results indicate that the proportion of enantiomers could drastically affect the potency of the drugs in vivo.
Article
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The abnormally high postprandial rate of transient lower oesophageal sphincter relaxations seen in patients with reflux disease may be related to altered proximal gastric motor function. Heightened visceral sensitivity may also contribute to reporting of symptoms in these patients. To assess motor function of the proximal stomach and visceral perception in reflux disease with a barostat. Fasting and postprandial proximal gastric motility, sensation, and symptoms were measured in nine patients with reflux disease and nine healthy subjects. Gastric emptying of solids and liquids was assessed in six of the patients on a different day (and compared to historical controls). Minimal distending pressure and gastric compliance were similar in the two groups, whereas the patients experienced fullness at lower pressures (p < 0.05) and discomfort at lower balloon volumes (p < 0.005) during isobaric and isovolumetric distensions respectively. Maximal gastric relaxation induced by the meal was similar in the two groups. Late after the meal, however, proximal gastric tone was lower (p < 0.01) and the score for fullness higher (p < 0.01) in the reflux patients, in whom the retention of both solids and liquids in the proximal stomach was greater (p < 0.05). Reflux disease is associated with delayed recovery of proximal gastric tone after a meal and increased visceral sensitivity. The former may contribute to the increased prevalence of reflux during transient lower oesophageal sphincter relaxations and the delay in emptying from the proximal stomach, whereas both may contribute to symptom reporting.
Article
Full-text available
Noxious stimuli in the esophagus activate nociceptive receptors on esophageal mucosa, such as transient receptor potential, acid-sensing ion channel and the P2X family, a family of ligand-gated ion channels responsive to ATP, and this generates signals that are transmitted to the central nervous system via either spinal nerves or vagal nerves, resulting in esophageal sensation. Among the noxious stimuli, gastric acid and other gastric contents are clinically most important, causing typical reflux symptoms such as heartburn and regurgitation. A conventional acid penetration theory has been used to explain the mechanism of heartburn, but much recent evidence does not support this theory. Therefore, it may be necessary to approach the causes of heartburn symptoms from a new conceptual framework. Hypersensitivity of the esophagus, like that of other visceral organs, includes peripheral, central and probably psychosocial factor-mediated hypersensitivity, and is known to play crucial roles in the pathoegenesis of nonerosive reflux disease, functional heartburn and non-cardiac chest pain. There also are esophagitis patients who do not perceive typical symptoms. This condition is known as silent gastroesophageal reflux disease. Although the pathogenesis of silent gastroesophageal reflux disease is still not known, hyposensitivity to reflux of acid may possibly explain the condition.
Article
In summary, the strength of agreement was also very high, with the vast majority of the consensus group agreeing strongly, or with only minor reservations, with over 90% of the statements. Only the Barrett's classification led to some discussion and dissent; most of the other areas met with uniform consensus. This activity was sponsored by AstraZeneca Research & Development. In blind votes on bias and industry influence, 90% of the audience agreed that the voting process was fair and that they had a chance to input adequately, and 92% agreed that the sponsor had not in any way influenced their voting.
Article
Oesophagitis arises when reflux of acid from the stomach into the oesophagus causes mucosal inflammation. It is a common problem and a systematic review on the optimum treatment would be useful. To assess the effectiveness of proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), prokinetic therapy, sucralfate and placebo in healing oesophagitis or curing reflux symptoms or both. To compare adverse effects with the different treatments. We searched MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and the National Research Register until December 2004 and reference lists of articles. We also contacted manufacturers and researchers in the field. Randomised controlled trials assessing the healing of oesophagitis or reflux symptoms or both. Treatment involving PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another treatment regimen or to placebo for 2 and 12 weeks. Two reviews independently assessed trial quality and extracted data. We included 134 trials involving 35,978 oesophagitis participants. Five RCTs evaluated standard dose of PPI versus placebo in 965 participants. There was a statistically significant benefit of taking standard dose PPI therapy compared to placebo in healing of oesophagitis (RR = 0.22; 95% CI 0.15 to 0.31). Ten RCTs reported on the outcome for H2RA versus placebo evaluating 1241 participants. There was statistically significant benefit of taking H2RA compared to placebo in healing of oesophagitis (RR 0.74,95% CI = 0.66 to 0.84). Three RCTs evaluated prokinetic therapy versus placebo in 198 participants. There was no statistically significant benefit of taking prokinetic therapy compared to placebo in healing of oesophagitis (RR 0.71, 95% CI 0.46 to 1.10). Twenty six RCTs reported the outcome for PPI versus H2RA or H2RA plus prokinetics, evaluating 4032 participants. There was statistically significant benefit of taking PPI therapy compared to H2RA or H2RA plus prokinetics in healing of oesophagitis (RR 0.51, 95% CI 0.44 to 0.59). PPI therapy is the most effective therapy in oesophagitis but H2RA therapy is also superior to placebo. There is a paucity of evidence on prokinetic therapy but no evidence that it is superior to placebo.
Article
Drugs that inhibit gastric acid might increase the risk of hip fracture. However, little long-term exposure data exist and no large studies have been conducted in the United States. We conducted a case-control study using data from an integrated health services organization. We evaluated 33,752 patients with incident diagnoses of hip/femur fractures (cases), 130,471 matched members without fractures (controls), prescription data for use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) (up to 10 years' cumulative duration), and confounders. Patients with hip fractures were more likely than controls to have previously received a > or =2-year supply of PPIs (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.21-1.39) or H2RAs (OR, 1.18; 95% CI, 1.08-1.29). The risk was reduced after discontinuation of medication (OR of 1.30 [95% CI, 1.21-1.41] for current PPI users vs OR of 1.09 [95% CI, 0.64-1.85] for patients who received their last prescription 2-2.9 years ago). Higher dosages (but not increasing cumulative durations) were associated with increased risk (eg, > or =1.5 pills/day: OR, 1.41 [95% CI, 1.21-1.64]; <0.74 pills/day: OR, 1.12 [95% CI, 0.94-1.33]). Excess fracture risk for PPI use was only present among persons with at least one other fracture risk factor. Use of drugs that inhibit gastric acid is associated with an increased risk of hip fracture; however, this association was only found among persons with at least one other risk factor for hip fracture. Acid inhibition might therefore be associated with fracture risk in persons already at risk for osteoporosis, although other confounding cannot be excluded.
Article
Gastroesophageal reflux disease (GERD) is one of the most common problems in clinical practice today. It is widely believed that functional and structural abnormalities of the gastroesophageal junction as well as an abnormal exposure to gastroduodenal contents are the main contributors to its pathogenesis. Novel findings of the inflammatory process in GERD suggest a far more complex process involving multifaceted inflammatory mechanisms. This review summarizes knowledge about the expression of inflammatory mediators in GERD and their potential cellular sources and provides an integrated concept of disease pathogenesis. In addition we evaluate the contribution of inflammatory mediators to well-known complications of GERD, namely motility abnormalities, fibrosis, and carcinogenesis. Novel findings regarding the pathophysiology of esophageal inflammation should enhance our understanding of GERD and its complications and provide new treatment insights.