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Gary W. Falk, M.D., M.S.
Professor of Medicine
Division of Gastroenterology
Perelman School of Medicine of the
University of Pennsylvania
GERDGERD
CCF Intensive Review of Gastroenterology & Hepatology
GERD: Montreal Definition
A condition which develops when the
reflux of stomach contents causes
troublesome symptoms and/or
complications
> 2 heartburn episodes/week
Adversely affect an individuals well
being
From Vakil N et al. Am J Gastroenterol 2006;101:1900-20.
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Impact of GERD on Quality of Life
In patients with daily or > weekly
symptoms:
Increased time off of work
Decreased work productivity
Low sleep scores
Decrease in physical functioning
Impact on QOL Nocturnal > daytime
From Becher A et al. Aliment Pharmacol Ther 2011;34:618-27.
GERD Epidemiology
Prevalence of at least twice
weekly heartburn and/or acid
regurgitation
10-20% in Western world < 5% in Asia
From Dent J et al. Gut 2005;54:710-7.
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Aging & GERD
No change in symptom frequency
Decreased symptom intensity
Increase in complications
LA C & D esophagitis
Barretts esophagus
Association Of Obesity (BMI >30kg/m2) & GERD Symptoms
From Hampel H et al. Ann Intern Med 2005;143:199-211.
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Dose Dependent Association Between BMI &
Frequent Reflux Symptoms In Women
From Jacobson BC et al. N Engl J Med 2006;354:2340-8.
Pathogenesis of GERD
Impaired Esophageal Clearance
Decreased Salivation
Impaired Tissue Resistance
Decreased LES Resting Tone
Delayed Gastric Emptying
Bile Reflux
Hiatal Hernia
LES
Duodenum
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Vagal Pathways Involved in TLESR:
Importance of GABA Receptors
From Falk GW. Gastroenterology 2010;139:377-86
Different Reflux Mechanisms
With Hiatal Hernia
*P
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Relationship Between BMI & TLESr
From Wu JC et al. Gastroenterology 2007;132:883-9.
Gastroesophageal Pressure Gradients &
GERD: The Importance of Obesity
From de Vries DR et al. Am J Gastroenterol 2008;103:1349-54.
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Acid Exposure Times in
Spectrum of GERD
From Bredenoord AJ et al. Neurogastroenterol Motil 2009;21:807-12.
Rates of Symptomatic & AsymptomaticReflux Episodes With High Proximal Extent
From Zerbib F et al. Gut 2008;57:156-60.
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Sleep Deprivation is
Hyperalgesic in Erosive GERD
From Schey R et al. Gastroenterology 2007;133:1787-95.
GERD As A Cytokine Mediated
Mechanism: Animal Model
Sequence of reflux damage
Lymphocytic infiltration starts in submucosa
Progresses to epithelial surface
Basal cell hyperplasia precedes erosions
Exposure of squamous cells to acidified
bileIL8 &IL1 secretion Bottom line: refluxate stimulates esophagealcytokine productioninflammatory
cellsbottom up inflammatory response
From Souza RF et al. Gastroenterology 2009;137:1776-84.
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GERD Diagnosis
There is no single
diagnostic
gold standard for GERD.
GERD Diagnostic ApproachAGA Technical Review
If history typical for uncomplicated
heartburn, initial trial of empiric PPI
therapy appropriate
Typical symptoms responding to
therapy require no diagnostic testing
From Kahrilas PJ et al. Gastroenterology 2008;135:1392-1413.
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Clarifying Patient Symptoms:
Heartburn
Carlsson et al. Scand J Gastroenterol. 1998;33:1023-1029.
Patients do not reliably
interpret the word
heartburn
For symptom evaluation, a
burning feeling rising from
the stomach or lower chest
up toward the neck is morereliable than heartburn
Alternative Diagnosis in GERD Coronary artery disease
Gallstones
Gastric/esophageal cancer
Peptic ulcer disease
Esophageal motility disorders
Pill induced esophagitis
Eosinophilic esophagitis
From Kahrilas PJ. N Engl J Med 2008;359:1700-7.
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GERD Diagnosis: Menu
Empiric trial
Barium esophagram
Endoscopy
Manometry
pH testing Impedance
Meta-Analysis of PPI Trials as aDiagnostic Test for GERD
Comparator Sensitivity
(95% CI)
Specificity
(95% CI)
24-hr pH 0.78
(0.66-0.86)
0.54
(0.44-0.65)
EGD 0.68
(0.56-0.79)
0.46
(0.34-0.59)
From Numans ME et al. Ann Intern Med 2004;140:518-27.
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Barium Esophagram
Especially sensitive in evaluating dysphagia In pre- and postoperative evaluations,
identifies:
Normal or impaired esophageal emptying
Normal or impaired motility
Presence and type of hiatal hernia
Distal stricture or mucosal ring
Presence of gastroesophageal reflux
Main deficiency is insensitivity for erosive
esophagitis & Barretts esophagus
Diagnostic Testing in GERD
Avert misdiagnosis
Identify complications
Evaluate treatment failures
Priority: identify conditions forwhich effective therapy exists
From Kahrilas PJ. N Engl J Med 2008;359:1700-7.
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Role of Endoscopy in Management
of GERD: AGA Guidelines
GERD despite therapy
Dysphagia
Obtain > 5 biopsies for eosinophilic
esophagitis
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.
Normal Esophagus
From Nakamura T et al. Aliment Pharmacol Ther 2005;21(Suppl 2):19-26.
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Symptoms Do Not Predict the
Presence of Erosive Esophagitis
From Venables et al. Scand J Gastroenterol. 1997;32:965-973.
Mild
Moderate
Severe
Heartburn Grade
68%NERD
(n = 677)
32%EE
(n = 316)
Prevalence of Erosive Esophagitis
NERD: Montreal Classification ofGERD
Nonerosive reflux disease is defined by
the presence of troublesome reflux-
associated symptoms & absence of
mucosal breaks @ endoscopy
Erythema @ GEJ not reliable finding for
diagnosis of reflux esophagitis
From Vakil N et al. Am J Gastroenterol 2006;101:1900-20.
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NERD Pathophysiology
Nonacid reflux
Gas reflux
Proximal distention of esophagus
Neural visceral hypersenstivity
Dilated intercellular spaces
Motility abnormalities
From Modlin IM et al. J Clin Gastroenterol 2007;41:237-41.
LA Classification of Esophagitis
From Nayar DS et al. Gastrointest Endosc 2004;60:253-7.
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Limitations of Endoscopy in
Failure of PPI Therapy Patients
Poor correlation of symptoms and
esophagitis
Resolution of esophagitis with prior
PPI therapy
Poor sensitivity for motility disorders
From Kahrilas PJ. N Engl J Med 2008;359:1700-7.
Eosinophilic Esophagitis:Endoscopy
From Gonsalves N et al. Gastrointest Endosc 2006;64:313-9.
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Eosinophilic Esophagitis: Number of
Biopsies Needed for Diagnosis With
Different Diagnostic Criteria
From Gonsalves N et al. Gastrointest Endosc 2006;64:313-9.
AGA Esophageal GERD Practice
Guidelines: Manometry
GERD despite therapy
Negative endoscopy
Goals:
LES location
Peristaltic function preoperatively
Detection of subtle motility abnormalities High resolution manometry superior to
conventional manometry for achalasia
variants & distal esophageal spasmFrom Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.
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AGA Esophageal GERD Practice
Guidelines: Reflux Monitoring
Failure to respond to PPI
Negative EGD
No major manometric abnormality
Wireless pH studies superior for detection
of abnormal acid exposure
Studies should be done offtherapy On or off therapy remains subject of debate
Impedance-pH best tool to detect symptom
association
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.
NERD Classification NERD-pH posi tive Normal EGD
Abnormal acid exposure off therapy
Hypersensitive esophagus
Normal EGD
Normal acid exposure
[+] symptom association-acid or nonacid
Functional heartburn
Normal EGD
Normal acid exposure
[-] symptom association-acid or nonacid
From Savarino E et al. Gut 2009;58:1185-91
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pH Monitoring Performance
Characteristics Erosive esophagitis
Sensitivity: 77-100%
Specificity: 85-100%
NERD
Sensitivity: 0-71%
Symptom Association in pH
Monitoring
Symptom index > 50%
Sensitivity 80%
Specificity 35%
Symptom association probability > 95%
Sensitivity 73%
Specificity 65%
Neither validated Information needs to be interpreted in
conjunction with other testing & clinical setting
From Vaezi MF. Gastroenterology & Hepatology 2012;8:185-7.
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Short Term (1-12 Week) Treatment of GERD
Symptoms Or Endoscopy Negative GERD
Treatment Heartburn
Remission
RR
95% CI
Empiric Therapy Group
PPI vs. placebo 0.37 0.32-0.44
H2RA vs. placebo 0.77 0.60-0.99
PPI vs. H2RA 0.66 0.60-0.73
Endoscopy Negative Reflux Group
PPI vs. placebo 0.69 0.62-0.78H2RA vs. placebo 0.84 0.74-0.95
PPI vs. H2RA 0.78 0.62-0.97
From Van Pinxteren B et al. Cochrane Database of Systematic Reviews 2006:3:CD002095.
Healing of Erosive Esophagitis:Systematic Review
Pooled Healing Rate
PPIs 84%
H2RA 52%
Placebo 28%
From Khan M et al. Cochrane Database Sys Rev 2007;2CD003244.
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PPIs for GERD
In equivalent doses different PPI
preparations do not show statistically
significant difference in healing effect
Double dose therapy associated with
modest improvement in healing of
erosive esophagitis
NNT-25
From Moayyedi P et al. Cochrane Database of Systematic Reviews 2007;2
Symptom Relief with PPIs inGERD: Systematic Review
Pooled PPI
Symptomatic
Response
95% CI
NERD 36.7% 34.1-39.3
ErosiveGERD
55.5% 51.5-59.5
From Dean BB et al. Clin Gastroenterol Hepatol 2004;2:656-64.
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Adverse Events With Up to 1 Yearof
Esomeprazole TreatmentAdverse Event % Patients (N=807)
Headache 10.3
Diarrhea 9.4
Abdominal pain 9.3
Nausea 6.1
Back pain 5.9
From Maton PN et al. Drug Safety 2001;24:625-35
Patientsinsymptomaticremission(%)
100
80
60
40
20
00 1 2 3 4 5 6
Time after cessation of therapy (months)
No mucosal breaks
LA Grade A
LA Grade B
LA Grade C
GERD Is a Chronic Condition
Likely to Relapse
From Lundell LR, et al. Gut. 1999;45:172-180.
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GERD Maintenance Therapy:
AGA Guidelines
Long term therapy with PPIs
proven clinically effective
Titrate to lowest effective dose
based on symptom control
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.
Safety Profile of PPIs Recent epidemiologic associations
C. difficile
Pneumonia
Hospital
Community acquired
Hip fracture
Bacterial gastroenteritis
No association with osteoporosis/bone mineraldensity loss*
Fundic gland polyps
*From Targownik LE et al. Gastroenterology 2010;138:896-904.
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Pharmacologic Therapy of
GERD: Not Recommended Evidence for use of PPIs @ doses >
standard are weak
Nocturnal H2 blocker
Not supported by clinical endpoints
Rapid tachyphylaxis
Metoclopramide monotherapy oradjunctive therapy
From Kahrilas PJ. Gastroenterology 2008;135:1383-91.
TLESr Inhibitor Therapy Physiologic effects
Decrease TLESr frequency
Increase LESp
Decrease reflux events
Modest clinical efficacy
Industry withdrawal from market Astra Zeneca
Addex
Xenoport
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From Galmiche J. et al. JAMA 2011;305:1969-1977.
RCT of Laparoscopic Antireflux
Surgery Vs. Esomeprazole for GERD92%
85%
AGA GERD Practice Guidelines:Surgery
Patients with esophagitis who are well
maintained on medical therapy have
nothing to gain from surgery
Incur added risk
Should be advised against surgery
Patients likely to benefit from surgery: PPI intolerance
Persistent symptoms especially regurgitation
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.
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Complications of Laparoscopic
Antireflux Surgery
Death: 0.1-0.2%
Life threatening complications:1.2-3.4%
Redo surgery: 1.5-7%
Dysphagia requiring dilation: 3.5-12%
From Kahrilas PJ et al. Gastroenterology 2008;135:1392-1413.
Definition of Failure of PPITherapy: AGA Position Paper
Inadequate response of
heartburn to twice daily PPI
therapy
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.
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PPI Instructions By Primary
Care Physicians
From Chey WD et al. Am J Gastroenterol 2005;100:1237-42.
Possible Causes for Failure of
PPI Therapy
Ongoing reflux/acid exposure
Noncompliance
Incorrect dose timing
Pathologic acid secretion
Rapid PPI metabolism
Hypersecretory state Large hiatal hernia
Nonacid reflux
From Dellon E et al. Gastroenterology 2010;139;7-13.
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Possible Causes for Failure of
PPI Therapy Visceral hypersensitivity
Nonreflux esophageal causes
Dysmotility
Eosinophilic esophagitis
Pill induced esophagitis
Infectious esophagitis
From Dellon E et al. Gastroenterology 2010;139;7-13.
Heartburn Nonspecific symptom
Potential etiologies
Chemoreceptors
Mechanical stimulation
Hyperalgesia
From Kahrilas P. Am J Gastroenterol 2005;100:549-50.
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Summary
Classic GERD symptoms common in
West
Atypical symptoms diagnostic &
therapeutic gray zone
Pathophysiology involves imbalance
between offensive & defective factors
Increasing importance of obesity
Summary
No diagnostic gold standard
Goal of testing is to identify
treatable conditions
pH testing is not the gold
standard All symptom association schemes
problematic
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Summary
Lifestyle measures should be tailored
to specific circumstances
PPIs remain cornerstone of chronic
therapy at lowest dose to control
symptoms
Safety concerns exist for PPIs basedon association studies
Summary
Medical & surgical therapy equivalent
in long term studies
Surgery reserved for;
Volume regurgitation
PPI intolerance Multiple possible causes for GERD
despite therapy
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