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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


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Role of Endoscopy in Management

of GERD: AGA Guidelines

GERD despite therapy

Dysphagia

Obtain > 5 biopsies for eosinophilic

esophagitis


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


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


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


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


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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%


Definition of Failure of PPITherapy: AGA Position Paper

Inadequate response of

heartburn to twice daily PPI

therapy


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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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Documents

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