core lecture: gerd and barrett’s esophagus
TRANSCRIPT
Core Lecture:GERD and Barrett’s Esophagus
John M. Wo, M.D.Director, Swallowing and Motility CenterDivision of Gastroenterology/Hepatology
January 4, 2006University of Louisville
Prevalence of GERD Symptoms: The Olmsted County Study*
58.7(56.1-61.3)
19.8(17.7-21.9)
0
20
40
60
80
100
Per 1
00 P
opul
atio
n
GERD Symptoms
Experienced Within the Past Year
Experienced >1/week
*Data collected by self-report questionnaire.
Locke et al. Gastroenterology. 1997;112:1448-1456.
N = 2,200 residents
University of Louisville
Protection from Acid Reflux
Acid
Esophagealclearance
Gastric clearance
Lower esophageal sphincter
Diaphragm
University of Louisville
Significant of Intragastric pH >4 in GERD
• Pepsin inactive at pH >4• Most bile acids and pancreatic enzymes
inactive at pH >4• Injury rare at pH >4
Hunt. Arch Intern Med. 1999;159:649-657.Smith et al. Gastroenterology. 1989;96:683-689.
University of Louisville
Three Mechanisms Causing Pathologic Acid Reflux
Van Herwaarden et al. Gastroenterology. 2000;119:1439-1446.
**
**
Transient LESRelaxations
Low LES Pressure Strain + Low LESPressure
0
20
40
60
80
100 Patients Without Hiatal Hernia (n = 10)Patients With Hiatal Hernia (n = 12)
Ref
lux
Epi
sode
s (%
)
**
*P<0.001**P≤0.005
University of Louisville
Transient LES Relaxation
Distension
Vagus (Sensation)
Vagus (transient LES relaxation)Food
University of Louisville
Acid Reflux is More Than Just Heartburn
- Esophagitis- Peptic stricture- Barrett's esophagus- Adenocarcinoma
Esophagus- Heartburn- Regurgitation- Dysphagia/odnyphagia
TYPICALSymptoms
- Mimic angina
Chest- Chest pain
- Refractory asthma- Aspiration- Pneumonia- Excerbate pul. disease
Lung- Shortness of breath- Cough- Choking
- Posterior laryngitis- Vocal cord ulcers- Vocal cord granuloma
Ear, Nose, Throat- Hoarseness- Throat clearing/pain- Voice loss
ATYPICALSymptoms
ACIDREFLUX
University of Louisville
Typical vs. Atypical GERDTypical Atypical
Symptoms consistent variable
Esophagitis/Barrett’s common uncommon
Causes reflux reflux + others
Treatment response rapid variable
Therapy step-therapy more aggressive +longer durationUniversity of Louisville
Empiric Therapy is Appropriate in Patients with Typical Heartburn
University of Louisville
Fass R et AL. Am J Gastroenterol 2002;97:1901-9.
New Conceptual Model for GERDOld
University of Louisville
Brain-Gut Axis for Non-Erosive Reflux Disease
Fass 2004. J Clin Gastroenterol 2004;38:628.
AcidHypersensitivity
University of Louisville
Heartburn Severity Does Not Correlation with Erosive Esophagitis
0
20
40
60
80
100
Normal A B C
Grade
Patie
nts
(%)
SevereModerate
MildNone
(n = 105) (n = 144) (n = 31)(n = 258)
Lundell et al. Gut. 1999;45:172-180.
University of Louisville
Heartburn Severity May Not Correlate with Disease Severity in GERD
GERD Severity
Severe EsophagitisNo Esophagitis
Hea
rtbu
rn S
ever
ity
“Hypersensitive” esophagusNERDFunctional heartburn
No hiatal herniaTransient LES relaxation
Large hiatal herniaLow LES pressure
Barrett’s esophagusPeptic stricture
University of Louisville
Eight Reasons Why Acid Suppression Not Working
1. Not taking the medication correctly2. Inadequate acid suppression3. Large hiatal hernia4. Impaired esophageal motility5. Gastroparesis6. Wrong diagnosis7. Non-acidic reflux8. Hypersecretion of acid
University of Louisville
Diagnostic Tests for GERD
Sensitivity (%)
Specificity (%)
Empiric Trial With a PPI 70-80 60-85Endoscopy 40-70 90-95Esophageal pH Monitoring 70-90 80-95Barium Swallow 30-35 60-75Esophageal Manometry 15-30 20-40University of Louisville
When is Upper Endoscopy Indicated?1. Alarm symptoms of GERD
- Dysphagia, odynophagia, GI bleed, weight loss2. Refractory heartburn3. Recurrent disease4. At risk for Barrett’s esophagus
DeVault, Castell. Guidelines for the Diagnosis and Treatment of GERD. Arch Intern Med 1995;155:2165-73
University of Louisville
GERD Complications
• Esophagitis• Esophageal stricture• Barrett’s esophagus• Adenocarcinoma
University of Louisville
LA Classification of Erosive Esophagitis
LA = Los Angeles. Lundell et al. Gut. 1999;45:172-180.
Isolated mucosal breaks >5 mm long
LA Grade B
LA Grade C
Mucosal breaks bridging the tops of folds but involving <75% of the circumference
Isolated mucosal breaks ≤5 mm long
LA Grade A
LA Grade D
Mucosal breaks bridging the tops of folds and involving >75% of the circumferenceUniversity of Louisville
LA Class C Esophagitis
University of Louisville
Esophageal Peptic Stricture
University of Louisville
Prevalence of GERD Complication
616
4134
22
2
48 49
0
20
40
60
80
100
Alarm Symptoms (n=124) Persistent Heartburn (n=82)
% o
f Sub
ject
s
Barrett's esophagus
Erosive esophagitis
GEJ peptic stricture
At least one complication
**
+
+
*p=0.03+p<0.001
Wo et al. Am J Gastroenterol 2004:99; 2304-10.
University of Louisville
Treatment Options for GERD
• Lifestyle and dietary modification• Medical
– Acid suppression– Prokinetic
• Surgical
University of Louisville
Healing of Erosive Esophagitis
Meta-analysis from 23 placebo-controlled trials with grade II to grade IV EE.Chiba et al. Gastroenterology. 1997;112:1798-1810.
0
20
40
60
80
100
Patie
nts
Hea
led
(%)
Placebo
Sucralfate
Cisapride
H RAs
PPIs2
‡
†
28.2 ± 15.6
39.2 ± 22.4
37.9 ± 4.5
51.9 ± 17.1
83.6 ± 11.4
University of Louisville
Formulations for Proton Pump Inhibitors
• Pill & Capsule• Powder• Chewable• Non-coated with bicarbonate• Intravenous injection
University of Louisville
Patie
nts
in S
ympt
omat
icR
emis
sion
(%)
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 that is Likely to Relapse
Lundell LR, et al. Gut. 1999;45:172-180.
University of Louisville
Long-Term PPI for Reflux Esophagitis
Omeprazole ≥20 mg.Klinkenberg-Knol et al. Gastroenterology. 2000;118:661-669.
0
20
40
60
80
100
Patie
nts
(%)
1 2 3 4 5 6 7 8 9 10 11
230 230 215 193 180 158 140 110 70 58 25N =Years
Healed Esophagitis Relapses
University of Louisville
Summary (GERD)
• Pathophysiologic mechanisms of GERD are many
• All GERD patients are not the same– NERD vs. EE vs. BE
• Acid suppression is the first-line of therapy• Reflux complications require maintenance
therapyUniversity of Louisville
Barrett’s Esophagus
University of Louisville
Heartburn Duration and Frequency is Associated with Esophageal Adenocarcinoma
1.0
5.2
16.4
7.5
02468
1012141618
None <12 12-20 >20Symptom Duration (years)
Esop
hage
al A
deno
carc
inom
a R
elat
ive
Ris
k
N = 1,438 (n = 189 with esophageal adenocarcinoma).Lagergren et al. N Engl J Med. 1999;340:825-831.
02468
1012141618
1.0
5.16.3
16.7
Symptom Frequency (weeks)None 1 2-3 >3
University of Louisville
Risk of Adenocarcinoma in Patients with Barrett’s Esophagus
• Spechler (1984) 1/175 pt-yr• Cameron (1985) 1/442 pt-yr• Achkar (1988) 1/166 pt-yr• Robertson (1988) 1/56 pt-yr• Vanderveen (1988) 1/170 pt-yr• Hameetman (1989) 1/52 pt-yr• Ovaska (1989) 1/55 pt-yr• Drewitz (1995) 1/278 pt-yr
Average risk of developing adenocarcinoma: 0.4% per patient-yearUniversity of Louisville
“Natural” History of Barrett’s Esophagus
Sampliner RE. ACG Practice Guideline. Am J Gastroenterol 1998;93: 1028-32.
Published Data From Prospective Registry
Dysplasia Ca / # of pts % progressed to Ca F/U (yrs)
None 5/150 3% 3.4-10
Low grade 8/45 18% 1.5-4.3
High grade 44/161 27% 0.2-9
University of Louisville
Relationship of Acid and Bile Exposure to Barrett’s Esophagus
Vaezi and Richter. Gastroenterology. 1996;111:1192-1199.
1.5
15.4 14.7
22.8
0.4 3.2
14.6
23.0
46.0
7.0
0
10
20
30
40
50
60
70
Controls No Esophagitis Esophagitis UncomplicatedBE
Complicated BE
Tota
l Tim
e pH
<4
and
Bili
rubi
n ≥0
.14
(%) Acid
Bilirubin
University of Louisville
Esophagus Lining is Damaged by Acid Reflux
Jankusz et al. Am J Path 1999;154:965-973University of Louisville
Hyperproliferation Occurs, Esophagus Stem Cells are Damaged
Jankusz et al. Am J Path 1999;154:965-973University of Louisville
Instead of Healing with Squamous Cells, Mucous-Secreting Cells are
Generated
Jankusz et al. Am J Path 1999;154:965-973
University of Louisville
Esophagogastroduodenostomy Esophagoduodenostomy External Esophageal Perfusion
University of Louisville
Comparing Post-Op Stress Among Animal Models of Erosive Esophagitis
380390400410420430440450460470
beforesurgery
1W 2W 3W 4W
Body
wei
ghts
(g)
Normal controlEEPEGDAEDA
Li Y et al. J Surg Res 2005; 129:107-113.
University of Louisville
External Esophageal Perfusion Model (after 7 days)
Li Y et al. J Surg Res 2005; 129:107-113.
University of Louisville
External Esophageal Perfusion Model with Implantation of Bone Marrow Cells
Li Y, Wo JM, Martin R, et al. DDW 2006.
University of Louisville
Metaplasia-Dysplasia-Adenocarcinoma Sequence of Barrett’s Esophagus
Normal epithelium
Hyper-proliferativeepithelium
Barrett’s:intestinalmetaplasia
Barrett’s:withdysplasia
Carcinoma
Acid refluxdamage
Differentiationabnormalities
Regulatoryproblems in
cell progression
Molecular alteration
University of Louisville
Barrett’s Esophagus:Specialized Intestinal Metaplasia (SIM)
• Globlet cells• Resemble cells
from the small intestine
University of Louisville
Barrett’s Esophagus: Indeterminate/Low Grade Dysplasia
• Prominent and crowded nuclei
• Diminished mucus cells
• Preserved architecture
University of Louisville
Barrett’s Esophagus: High Grade Dysplasia
• Hyperchromatic nuclei
• Prominent nucleoli• Diminished mucus
cells• Distorted architecture • No invasion of
lamina propria
University of Louisville
Barrett’s Esophagus: Adenocarcinoma
• Back-to-back glands
• Markedly hyperchromatic nuclei
• Loss of architecture • Invade lamina
propria
University of Louisville
Who should be Screened for Barrett’s Esophagus?
University of Louisville
Prevalence of Barrett’s Esophagus Increases with Age
Cameron et al. Gastroenterol 1992;103:124-45. EGD’s from 1976-1989.
0
2
4
6
8
20-29
30-39
40-49
50-59
60-69
70-79
80-89
Age (years)
BE
Len
gth
(cm
)0
0.2
0.4
0.6
0.8
1
20-29
30-39
40-49
50-59
60-69
70-79
80-89
Age (years)
% P
opul
atio
n w
ith B
E
N=377 with BE
University of Louisville
Prevalence of Barrett’s Esophagus is Associated with Duration of Heartburn
Lieberman et al. Am J Gastroenterol. 1997;92:1293-1297.
4
11
17
21
0
5
10
15
20
25
Prev
alen
ce o
f Pro
babl
e B
arre
tt's
Esop
hagu
s (%
)
<1n = 127
1-5n = 236
5-10n = 81
>10n = 140
Symptom DurationUniversity of Louisville
Screening for Barrett’s Esophagus
• > 10 years of heartburn • > 50 years old• Caucasians• Males • (Patients with long standing heartburn who
require maintenance medications to control symptoms)
Sampliner RE. ACG Practice Guideline. Am J Gastroenterol 1998;93: 1028-32.
University of Louisville
Diagnosing Barrett’s Esophagus and Dysplasia
University of Louisville
Where are the Dysplasia?
University of Louisville
Systematic Mapping of Esophagectomy Specimens
Surface AreaTotal Barrett’s mucosa 32 cm2
Low grade dysplasia 13 cm2
High grade dysplasia 1.3 cm2
Adenocarcinoma 1.1 cm2
Cameron et al. Am J Gastroenterol 1997;92:586-91. (N=30 pts without endoscopic evidence of cancer)University of Louisville
Barrett’s with Ulcer
University of Louisville
Barrett’s with Stricture
University of Louisville
Barrett’s with Nodular Mucosa
University of Louisville
Real-Time Endoscopy to Detect Dysplasia
• Chromoendoscopy– Methylene blue, crystal violet, indo
• Optical devices– Fluorescence spectroscopy– Confocal fluorescence microendoscopy– Light scattering spectroscopy– Raman spectroscopy
• Magnification endoscopy• Blue-light endoscopyUniversity of Louisville
Methylene-Blue Chromoendoscopy
University of Louisville
Results of MB-directed vs. Conventional Biopsy for Barrett’s Esophagus
0
20
40
60
80
100
SIM DysplasiaLong Segment CLE (N=15)
Prev
alen
ce (%
)
MB Bx (n=217)Conventional Bx (n=185)p=NS
p=NS
0
20
40
60
80
100
SIM DysplasiaShort Segment CLE (N=20)
MB Bx (n=70)Conventional Bx (n=82)
p=NS
p=NS
University of Louisville
Crystal Violet and Magnification Endoscopy
University of Louisville
Treatment and Surveillance for Barrett’s Esophagus
University of Louisville
Efficacy of High-Dose PPI Therapyin Regression of Barrett’s Esophagus
N = 13 patients treated with lansoprazole 60 mg daily for a mean of 5.7 years.Sharma et al. Am J Gastroenterol. 1997;92:582-585.
5.6
4.25.0
4.2
0
2
4
6
8
10
Normal Abnormal
Esophageal pH
Mea
n Le
ngth
of
BE
Segm
ent (
cm)*
BaselineFollow-Up
University of Louisville
Does Treatment Alter Barrett’s Esophagus?
• No clear evidence that antireflux therapy reduces the extent of Barrett’s esophagus of risk of adenocarcinoma
University of Louisville
Goals for Surveillance in Barrett’s Esophagus
• Detect dysplasia before becoming cancer• Identify which patient is at high risk for
developing cancer• Early intervention to prolong quality of life
University of Louisville
Management of Barrett’s Esophagus with No Dysplasia
Sampliner. Am J Gastroenterol. 2002;97:1888-1895.
ACG Practice Guidelines for No Dysplasia
New diagnosis Repeat in 1 year* (for long segment)(Repeat in 3 years for short segment)
Confirm on repeat Surveillance every 3 years
*To avoid sampling error
University of Louisville
Management of Barrett’s Esophagus with Low-Grade Dysplasia
• Prescribe aggressive antisecretory therapy to eliminate confounding inflammation
ACG Practice Guidelines for Low Grade DysplasiaNew diagnosis Repeat in 6 months
Confirm on repeat Surveillance every 1 year
University of Louisville
Management of Barrett’s Esophagus with High-Grade Dysplasia
• Difficult to differentiate from cancer; requires intensive biopsy protocol
Sampliner. Am J Gastroenterol. 2002;97:1888-1895.
ACG Practice Guidelines for HGD
Mucosal irregularity Endoscopic mucosal resection
Focal high-grade dysplasia Follow-up EGD every 3 months
Multifocal (diffuse) high-grade dysplasia
a. Surgery orb. Photodynamic therapy orc. EGD every 3 monthsUniversity of Louisville
Endoscopic Mucosal Resection for Barrett’s Esophagus
University of Louisville
Risk of Adenocarcinoma inFocal vs. Diffuse HGD
*P<0.001.Buttar et al. Gastroenterology. 2001;120:1630-1639.
*
*
714
38
56
0
20
40
60
80
1 Year 3 Years
Patie
nts
Prog
ress
ing
to
Ade
noca
rcin
oma
(%)
Diffuse High-Grade DysplasiaFocal High-Grade Dysplasis
University of Louisville
Progression of HGD to Cancer
Buttar et al. Gastroenterology. 2001;120:1630-1639. Reid et al. Am J Gastroenterol. 2000;95:1669-1676.Schnell et al. Gastroenterology. 2001;120:1607-1619.
5.0-Year Follow-Up
2.1-Year Follow-Up(Median) 7.3-Year
Follow-Up(Median)
0
10
20
30
40
50
60
70
Reid et al Buttar et al Schnell et al
Patie
nts
Prog
ress
ing
to E
soph
agea
l Can
cer (
%)
(N = 76) (N = 100) (N = 1099) University of Louisville
Photodynamic Therapy with Porfimer: Randomized Controlled Trail
• Pts with confirmed HGD were randomized (2:1) to – PDT/porfimer sodium (2 mg/kg IV) + Omeprazole
20 bid• Laser exposure at 630 nm wavelength within 40-50 hrs• Max of 3 PDT sessions at least 90 days apart• Single center pathologists blinded to treatment arms
– Omeprazole 20 bid onlyUniversity of Louisville
PDT with Porfimer Sodium: 2-Year Follow-up of RCT
77
39
020406080
100
PDT +Omeprazole
(n=138)
Omeprazole(n=70)%
of p
ts w
ith H
GD
abl
ated
p<0.0001
University of Louisville
1529
020406080
100
PDT +Omeprazole
(n=138)
Omeprazole(n=70)%
of p
ts w
ith p
rogr
essio
n to
Ade
noC
a
p<0.0001
PDT with Porfimer Sodium: 5-Year Follow-up of RCT
University of Louisville
Summary• Screening for Barrett’s
–Caucasian, male, >50 yrs old, heartburn >10 yrs
• Biopsy is inadequate due to sampling error• Progression from intestinal metaplasia to
cancer is uncommon (0.4% per patient-year)• Expert pathologist needed to diagnose HGDUniversity of Louisville