GERD

1
GERDWhats really up?

• Dr Michael Byrne
• Clinical Associate Professor
• Vancouver General Hospital

2
Definition
The term gastroesophageal reflux disease
should be used to include all individuals who
are exposed to the risk of physical
complications from gastro- esophageal reflux, or
who experience clinically significant impairment
of health-related well-being (quality of life),
due to reflux-related symptoms, after adequate
reassurance of the benign nature of their
symptoms.
Genval statement 1, accepted with some reservation
Dent et al 1999
3
GERD two main categories
Patients with GERD100
Patients with ENRD60
Patients with esophagitis40
Patients without complications 35
Patients with complications 5
Adapted from Quigley 2001
4
Endoscopic assessment and classification of
esophagitis

• Endoscopic esophageal changes caused by reflux
  are helpful diagnostically.
• Several systems are used to classify esophagitis.
• The LA Classification system is the newest
  system, and is based on changes that can be
  reliably and consistently assessed.
• Because of improved reproducibility, it is likely
  that the LA Classification system will supersede
  the SavaryMiller and other classification
  systems.

Lundell et al 1999
5
The LA Classification system for theendoscopic
assessment of reflux esophagitis
Grade A
Grade B
One (or more) mucosal break, no longer than 5 mm,
that does not extend between the tops of two
mucosal folds
One (or more) mucosal break, more than 5 mm long,
that does not extend between the tops of two
mucosal folds
Grade C
Grade D
One (or more) mucosal breakthat is continuous
between the topsof two or more mucosal
folds,but which involves less than 75 of the
circumference
One (or more) mucosal break that involves at
least 75 of the esophageal circumference
Lundell et al 1999
6
Heartburn the primary symptom of GERD
Heartburn is the most common symptom of reflux
disease, occurring in at least 75 of patients.
Genval statement 14, accepted with some
reservation
Heartburn that occurs in the absence of definite
endoscopic reflux esophagitis is most likely
due to gastroesophageal reflux.
Genval statement 15, accepted completely
Dent et al 1999
7
The GERD symptom pattern is similar in patients
with and without esophagitis
Heartburn(100)
Regurgitation
Epigastric pain
without esophagitis
with esophagitis
Nausea
Belching
Bloating
Abdominal pain
Scale of patients with symptom
Carlsson et al 1998b
8
Severity of heartburn is similar in patients with
different grades of esophagitis
Patients with heartburn ()
60
no heartburn
50
mild heartburn
moderate heartburn
40
severe heartburn
30
n4283
20
10
0
A
B
C
D
LA Grade of esophagitis
Levine et al 1999
9
Chronic cough may be a frequent symptom of GERD

• 4375 of patients with GERD-related cough have
  no reflux symptoms.
• GERD-related cough may respond to
  acid-suppressive therapy.
• Up to 40 of cases of chronic cough are caused by
  GERD.

Brightling et al 1999 Irwin et al 1990 Irwin et
al 1993 Kiljander et al 2000 Mello et al 1996
10
Cough can be caused by acid refluxate entering
the lung and/or stimulating the vagus nerve
Esophagealbronchial transmission via cough
centre
Aspiration to lowerrespiratory tree
Stimulation of vagus nerve
Cough response
Gastric refluxate
Gastric refluxate
Irwin et al 1993 Irwin et al 2000
11
GERD may be associated with unexplained chest pain
Patients with unexplained chest pain ()
100
80
60
40
n123
20
0
Reflux
Motility
Pain perception
Esophageal abnormalities
Cherian et al 1995
12
Pathogenesis
13
Increased exposure to gastric acid is the
principal cause of GERD
The dominant mechanism of symptom production
in reflux disease is by contact of the esophageal
mucosa with acid and pepsin.
Genval statement 3, accepted completely
In the majority of people with reflux disease,
there is abnormally prolonged exposure of the
distal esophagus to acid and pepsin.
Genval statement 4, accepted completely
Dent et al 1999
14
Causes of increased exposure of the esophagus to
gastric refluxate
Defectiveesophagealclearance
LESdysfunction
Hiatal hernia
Delayed gastric emptying
Increased intra-abdominalpressure
Katzka DiMarino 1995
15
Reflux disease can be present when acid exposure
is within the normal limits
In a minority of people with reflux disease,
normal levels of reflux of acid and pepsin
trigger reflux- induced symptoms.
Genval statement 5, accepted completely Dent et
al 1999
3350 of patients with non-erosive GERD have
normal esophageal pH levels when measured with
current diagnostic tests.
Fass et al 2001
16
Lifestyle factors have little influence on the
pathogenesis of GERD
Lifestyle factors are not the dominant factor in
the pathogenesis of reflux esophagitis.
Genval statement 6, accepted completely
There is insufficient objective evidence to
determine the importance of lifestyle factors
in the pathogenesis of endoscopy-negative reflux
disease.
Genval statement 7, accepted completely
Dent et al 1999
17
There is only weak evidence that lifestyle
factors aggravate GERD symptoms

• Obesity
• severity of esophagitis correlates with weight
  only when BMI gt30 kg/m2
• contradictory studies into weight loss indicate
  no effect/improvement in GERD.
• Smoking
• lowers LES pressure and the acid-neutralising
  effect of saliva.
• Physical activity
• running might provoke GERD by increasing TLESRs.

Meining Classen 2000
18
Some dietary factors may aggravate GERD symptoms

• Citrus fruits and juices
• Carbonated drinks
• Caffeine
• Heavy meals
• Fatty foods
• Spicy foods weak evidence
• Alcohol

Meining Classen 2000
19
The role of H. pylori in GERD is questionable

• In general, infection with H. pylori
  causesgastric disease.
• But is H. pylori infection protectiveagainst
  GERD?

20
H. pylori eradication does not increase the
development of esophagitis or GERD symptoms
Patients ()
20
H. pylori-remaining
H. pylori-eradicated
10
0
Esophagitisdeveloped n1165
GERD symptoms developed n127
GERD symptoms worsened n406
Status 4 weeks after completion of therapy
Laine Sugg 2002
21
Complications
22
Complications of GERD

• Esophageal
• prolonged exposure of the esophagus to gastric
  refluxate can cause metaplasia, malignancy,
  ulceration or strictures.
• Extra-esophageal
• movement of gastric refluxate through the
  esophageal/pharyngeal/laryngeal/pulmonary axis
  can cause, or exacerbate, several disorders.

23
Metaplasia of the esophagus Barretts esophagus
Definition a change in the esophageal
epithelium of any length that can be recognised
at endoscopy and is confirmed to have intestinal
metaplasia by biopsy of the tubular esophagus and
excludes intestinal metaplasia of the cardia.
Squamous epithelium
Columnar epithelium
Sampliner 2002
24
Barretts esophagus endoscopic appearance
25
The prevalence of Barretts esophagus increases
with the duration of reflux symptoms
Prevalence of endoscopic Barrett's esophagus ()
25
20
15
10
5
0
lt1
15
510
gt10
Duration of symptoms (years)
Lieberman et al 1997
26
Barretts esophagus is associated with
adenocarcinoma

• Patients with Barretts esophagus are at
  increased risk of developing adenocarcinoma of
  the esophagus relative to the general public or
  those with similar reflux symptoms without
  Barretts esophagus.
• Estimates of cancer risk range from 40-
  to125-fold higher than the general population.

Shaheen et al 2000 Shaheen Ransohoff 2002
27
Esophageal adenocarcinoma endoscopic appearance
28
The incidence of esophageal adenocarcinoma is
increasing
Incidence/100,000person-years
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1950
1960
1980
1970
1990
Year
Bytzer et al 1999
29
Esophageal stricture endoscopic appearance
30
Esophageal ulceration endoscopic appearance
31
Possible extraesophageal manifestations of GERD

• Asthma
• Sinusitis
• Dental erosions
• Reflux laryngitis
• Vocal cord ulcers
• Subglottal/tracheal stenosis
• Laryngospasm

Jailwala Shaker 2000 Richter 2000 Ulualp et
al 1999
32
Diagnosis
33
Diagnostic methods in GERD

• Symptom analysis
• Treatment trial with acid-suppressive therapy
• Endoscopy
• pH-monitoring
• Radiology

34
Symptom analysis by questionnaire may be
sufficient for the diagnosis of GERD
Simple, self-administered symptom questionnaires
can substantially facilitate the diagnosis of
reflux disease.
Genval statement 19, accepted with some
reservationDent et al 1999

• Most questionnaires ask patients about
• the presence of heartburn (and describe the
  sensation)
• the presence of an acid taste in the mouth
• the timing of symptoms
• the responsiveness to antacids.

Carlsson et al 1998b Shaw et al 2001
35
Treatment trial of acid-suppressive therapy
PPIs are the agents of choice for a diagnostic
trial.
Genval statement 35, accepted with some
reservation
Trials of PPI therapy are most sensitive for the
diagnosis of reflux disease when a high dose is
used.
Genval statement 36, accepted with some
reservation
Dent et al 1999
36
Indications for additional investigations

• Atypical history.
• Symptoms are frequent and long-standing or do not
  respond to therapy.
• Alarm symptoms are present
• severe dysphagia
• weight loss
• bleeding
• haematemesis
• mass in the upper abdomen
• anaemia.

37
Direct visualisation of the esophageal mucosa by
endoscopy

• Optimal technique for determining the presence
  and severity of esophagitis.
• The only reliable technique for detecting
  Barretts esophagus.
• Allows biopsy to be performed if necessary.

38
Investigation of reflux by 24-hour pH-monitoring

• Investigate the degree and timing of reflux.
• Correlate reflux events with symptoms.
• Potentially unreliable 27 of patients(6/22)
  changed diagnosis from normal to pathological
  reflux when tested 6 weekslater under identical
  conditions.

Franzén Grahn 2002
39
Radiology very limited value in the diagnosis
of GERD

• May be helpful for
• detecting subtle strictures and large hiatal
  hernias in patients with dysphagia
• identifying pathologies unrelated to GERD.

40
Management
41
Goals in the management of GERD

• Provide complete relief from heartburn and other
  symptoms.
• Heal underlying esophagitis.
• Maintain symptomatic and endoscopic remission.
• Treat or prevent complications.
• Achieving these treatment goals significantly
• improves patient quality of life.
• Control of acid secretion is the most effective
• means to achieve these treatment goals.

Dent et al 1999
42
Genval recommendations on first-lineinitial
therapy for GERD
For initial therapy of patients with
esophagitis, the best medical strategy is to
start with a proton pump inhibitor, with
subsequent trial of step down of the intensity
of therapy.
Genval statement 59, accepted with some
reservation
For initial therapy of endoscopy-negative reflux
disease there is an ascending level of efficacy
from either H2-receptor antagonist or cisapride,
to a proton pump inhibitor.
Genval statement 47, accepted completely
The most effective initial therapy for reflux
disease is also the most cost-effective.
Genval statement 60, accepted with some
reservation
Dent et al 1999
43
PPIs control acid secretion by directly
inhibiting the proton pump
Gastric gland
H
Proton pump
Inhibition of acid secretion
Inhibition of proton pump
Activation
Concentration
Canalicularspace
Parietalcell
PPI(inactive)
Blood
44
The frequency of acid reflux symptoms is
directly related to the time that the
esophageal pH is lt4
Intraesophageal acid exposure ( time pH lt4)
almost continuous symptoms
8
7
daily symptoms
6
occasional symptoms
5
healthy individuals
4
3
n190
2
1
0
69
912
1215
1518
1821
2124
03
36
Time of day (hours)
Joelsson Johnsson 1989
45
The healing of esophagitis is directly related
to the time for which the intragastric pH is gt4
Patients healed after 8 weeks()
100
80
60
40
20
0
2
4
6
8
10
12
14
16
18
20
22
Duration intragastric pH gt4 (hours)
Adapted from Bell et al 1992
46
Omeprazole and ranitidine in maintaining
intraesophageal pH gt4
Normal zone
omeprazole, 20 mg once daily
Pre-treatment
ranitidine, 150 mg twice daily
Omeprazole treatment

Pre-treatment
p lt0.01 versus pre-treatment
ns, not significant versus pre-treatment
Ranitidine treatment
ns
120
0
80
40
200
160
Time pH lt4 (minutes)
Normal zone is defined as intraesophageal pH lt4
for 04.2 of the time over 24 hours
Ruth et al 1988
47
PPIs and H2-receptor antagonists in healing
esophagitis
Esophagitis cases healed()
100
PPIs
80
plt0.0005
H2-receptorantagonists
60
40
placebo
20
0
0
2
4
6
8
10
12
Time (weeks)
Chiba et al 1997
48
Omeprazole and ranitidine in maintaining patients
in remission
omeprazole, 20 mg once daily n366
Patients in endoscopic remisson at 6 months ()

100

omeprazole, 10 mg once daily n225


80

ranitidine, 150 mg twice daily n179
60

placebon149
p0.05 p0.0001
40
20
0
Carlsson et al 1997
49
Long-term Treatment Strategies in GERD
s symptom recurrence
50
Intermittent Treatment in Symptomatic GERD

• Half the patients do not require treatment for at
  least 6 months during the 12 months of the trial
• Relapses are infrequent (93 of the patients had
  three or fewer relapses in the intermittent
  phase)
• Relapses can be managed with short courses of
  repeat treatment
• Results are similar in patients with erosive and
  non-erosive disease

Bardhan et al. BMJ 1999 318502-7
51
Antireflux surgery an alternative to
pharmacological therapy

• The efficacy of antireflux surgery in controlling
  GERD is similar to that of chronic PPI therapy.
• The outcome of antireflux surgery is highly
  dependent on the skill and experience of the
  surgeon.
• Surgery does not always end the need for
  antisecretory therapy to control the symptoms of
  GERD.

Lundell et al 2001 Spechler et al 2001
52
Nissen fundoplication and the Toupet procedure
Nissen fundoplication
Toupet procedure
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Endoscopic Anti-reflux Therapy
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Results of Endoscopic Anti-reflux Therapy
Filipi et al Gastrointest Endosc 2001
53416-22 Triadafilopoulos et al Gastrointest
Endosc 2001 53 407-15 Feretis et al
Gastrointest Endosc 2001 53 423-6
59
Limitations of Studies on Endoscopic Therapy in
GERD

• Exclusion criteria
• Patients with severe oesophagitis
• Obese patients (BMI gt 35 or 40)
• Previous anti-reflux surgery
• GERD refractory to PPI
• Hiatus hernia gt 2 or 3 cm
• Return to physiological level of acid exposure in
  only half the patients
• Lack of long-term evaluation
• Lack of controlled trials versus optimal PPI
  therapy

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61
Surveillance of Barretts esophagus according to
the degree of dysplasia US perspective

• No dysplasia
• surveillance endoscopy with biopsy every 3
  years.
• Low-grade dysplasia
• surveillance endoscopy with biopsy every year
  until no dysplasia.
• High-grade dysplasia
• surveillance endoscopy with biopsy every 3
  months v esophagectomy v PDT v EMR.

Sampliner 2002
62
The goals of therapy for managing Barretts
esophagus are the same as for GERD US
perspective

• The goals of therapy for Barretts esophagus
  are the control of symptoms of GERD and the
  maintenance of healed mucosa.
• All patients with Barretts esophagus, even
  asymptomatic patients, should be treated
  for GERD.
• Patients with Barretts esophagus have
  greater acid exposure than other patients
  with GERD, and control of symptoms may
  require higher than usual doses of PPIs.

American College of Gastroenterology guidelines
Sampliner 2002
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Medical Therapy in GERDThe State of Art

• Control of acid secretion with PPI is, at the
  moment, most effective, practical way to relieve
  symptoms, heal oesophagitis, restore quality of
  life, and keep patient in remission!
• Therapeutic regimens must be adapted to the full
  spectrum of the disease
• Need for further evaluation of new long-term
  strategies (e.g. on-demand) and endoscopic
  anti-reflux therapy

65
What Do We Need Beyond PPI Therapy in GERD?

• Antirelaxation therapy (i.e. eukinetics) drugs
  targeted to the control of TLOSRs (baclofen 40mg,
  Zhang et al Gut 2001)
• Drugs able to modulate sensitivity (especially in
  endoscopy negative GERD and extra-esophageal
  manifestations like NCCP)
• Drugs able to improve defence and repair
  mechanisms of the esophageal mucosa (COX-2
  inhibitors? antioxidants?)

66
GERD--Take Home Points

• In GERD, endoscopy is not indicated in every
  patient but necessary to assess dysphagia and to
  screen for Barretts esophagus
• The most appropriate initial therapy for a
  patient with GERD is proton pump inhibitor
  therapy
• GERD is a chronic disease that requires long term
  therapy to control symptoms and improve quality
  of life
• H.pylori eradication is not indicated for GERD