core lecture: gerd and barrett’s esophagus

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