GERD Pathophysiology: Motility Conference

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John M. Wo, M.D. Division of Gastroenterology/Hepatology April 15, 2008

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Protection from Acid Reflux

Esophageal clearance

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Lower esophageal sphincter Diaphragm

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Gastric clearance

Significance of Intragastric pH >4 in GERD

Pepsin is inactive at pH >4 Most bile acids and pancreatic enzymes inactive at pH >4 Esophageal mucosa injury is rare at pH >4

Hunt. Arch Intern Med. 1999;159:649-657.

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Three Mechanisms Causing Pathologic Acid Reflux

100

Patients Without Hiatal Hernia (n = 10) Patients With Hiatal Hernia (n = 12)

Reflux Episodes (%)

80 60 40

Van Herwaarden et al. Gastroenterology. 2000;119:1439-1446.

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20 0

Transient LES Relaxations

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*P<0.001 **P0.005

**
Strain + Low LES Pressure

Low LES Pressure

Transient LES Relaxation

Food

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Vagus (transient LES relaxation)

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Vagus (Sensation)

Distension

Hiatal Hernia
Type 1 Sliding hernia Type 2 True paraesophageal hernia

Wo JM et al. Am J Gastroenterol 1996;91:914-916.

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Type 3 Mixed paraesophageal hernia

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GERD Symptoms are Associated with Obesity in Meta-Analysis Study

Adjusted Odds Ratio (95% CI) Andersen and Jensen, 1991 Stanghellini, 1999 Locke et al., 1999 Lagergren et al., 2000 Wu et al., 2003 Nilsson et al., 2003 Murray et al., 2003 Diaz-Rubio et al., 2004 Pooled odds ratio Andersen and Jensen, 1991 Stanghellini, 1999 Locke et al., 1999 Lagergren et al., 2000 Wu et al., 2003 Nilsson et al., 2003 Murray et al., 2003

GERD Symptoms (BMI 25-30 kg/m2)

1.0 (0.7-1.5) 1.8 (1.5-2.3)

Diaz-Rubio et al., 2004

GERD Symptoms (BMI 25 kg/m )

2

Hampel H, et al. Ann Intern Med. 2005;143:199-211.

Pooled odds ratio Pooled odds ratio

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GERD Symptoms (BMI > 30 kg/m2)

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0.2 0.5

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1.3 (1.0-1.7) 1.3 (1.0-1.9) 2.3 (2.1-2.5)

1.0 (0.6-1.4)

2.0 (1.6-2.5)

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1.5 (1.2-1.9)

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1.6 (1.3-1.9)

1.4 (0.8-2.4) 2.9 (2.2-3.8) 2.2 (1.7-3.0) 1.1 (0.6-1.9)

1.4 (1.0-1.9) 4.1 (3.7-4.5) 3.1 (2.5-3.9) 1.9 (1.5-2.5) 2.1(1.5-3.0) 1.7 (1.3-2.2)

0.1

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2.0

5.0

10.0

Increased Intragastric Pressure and BMI

25 Expiratory 20 Intragastric Pressure 15 (mm Hg) 10 5 0 10 20 30 40 50 60 BMI 70

* R = 0.57

Inspiratory Intragastric 15 Pressure 10 (mm Hg) 5

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25

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80 70 80

90

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100 100

* R = 0.55 90

Higher intragastric pressure may increase the chance that gastric contents will ascend into the esophagus

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50 60 BMI

Gastric Acid Buffering by Food

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Acid Pocket After Meals Below the GEJ

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Gastric Acid Buffering is Amplified by Gastroparesis

Hasler et al. Am J Physiol Gastrointest Liver Physiol 2008.

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gastric

Patients undergoing SmartPill transit study

Traditional GERD Iceberg

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GERDA Spectrum of Disease?

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Pro-GERD Epidemiological Study from Germany, Austria, and Switzerland

Kulig M et al. Clin Epidemiol 2004;57:580-9.

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New Conceptual Model for GERD

Fass R et AL. Am J Gastroenterol 2002;97:1901-9.

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Heartburn Severity Does Not Correlation with Erosive Esophagitis

100 80 Patients (%) 60 40

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20 0 Normal
(n = 258)

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A
(n = 105)

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C

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Severe Mild None

Moderate

(n = 144)

(n = 31)

Grade

Heartburn Severity May Not Correlate with Disease Severity in GERD

No hiatal hernia Transient LES relaxation

Heartburn Severity

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Hypersensitive esophagus NERD Functional heartburn

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Large hiatal hernia Low LES pressure

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Barretts esophagus Peptic stricture

No Esophagitis

Severe Esophagitis

GERD Severity

GERD is More Common in Males

Cook et al. Am J Epidemiol 2005;162:1050-1061.

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NERD is More Common in Females

Cook et al. Am J Epidemiol 2005;162:1050-1061.

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Brain-Gut Axis for Non-Erosive Reflux Disease

Acid Hypersensitivity

Fass 2004. J Clin Gastroenterol 2004;38:628.

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Acid Reflux is More Than Just Heartburn

ACID REFLUX
TYPICAL Symptoms Esophagus

- Heartburn - Chest pain - Regurgitation - Dysphagia/odnyphagia - Esophagitis - Peptic stricture - Barrett's esophagus - Adenocarcinoma

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Chest

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ATYPICAL Symptoms Lung

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Ear, Nose, Throat

- Hoarseness - Throat clearing/pain - Voice loss

- Shortness of breath - Cough - Choking

- Mimic angina

- Refractory asthma - Posterior laryngitis - Aspiration - Vocal cord ulcers - Pneumonia - Vocal cord granuloma - Excerbate pul. disease

Typical vs. Atypical GERD

Symptoms Typical consistent

Esophagitis/Barretts common Causes

Treatment response Therapy

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reflux rapid

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Atypical variable

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uncommon

Multifactorial

variable more aggressive + longer duration

step-therapy

u o Why PPI is not Working? L f o y t i s r e v i n U

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Six Most Common Reasons for Why PPI Is Not Working

1. 2. 3. 4. 5. 6. Inadequate acid suppression pH test on meds Not taking medication correctly - history Large hiatal hernia - EGD Impaired esophageal motility - manometry Gastroparesis 4-hr GET Wrong diagnosis pH test off meds & further w/u

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Inadequate Acid Suppression by PPI

Adapted from Tutuian et al. Med Gen Med 6(4), 2004. 1 Hammer et al. Aliment Pharmacol Ther. 2004 15;

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Not Taking the PPT before Meals

75 Time Gastric pH < 4.0 (%)

50

Reprinted with permission from Hatlebakk JG, et al. Aliment Pharmacol Ther. 2000:14;1267-1272.

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With Meal

*P < .01

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Without Meal

PPI Oral Formulation

Delayed-release PPI Tablet Capsule Powder Dissolvable Immediate-release PPI Tablet Powder

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Median Gastric pH During Night PPI Dosing q.h.s. (Day 7)

Katz PO et al. Gastroenterol 2006;130(2):A175.

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Qhs Before Bed Dosing is Not Appropriate with Delayed-Release PPI*

(n=49) Zegerid vs. lansoprazole p-value <0.001 Zegerid vs. esomeprazole p-value <0.001

Katz PO et al. Gastroenterol 2006;130(2):A175.

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*Nighttime Interval (2200-0600) on day 7

Pharmacokinetics of Immediate-release and Delayed-release Omeprazole

40mg

N=31, open label cross-over, after 7 days of study drug

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20mg

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Diagnostic Testing for GERD*

Empiric Trial With a PPI Endoscopy Barium Swallow

Esophageal pH Monitoring Esophageal Manometry

*Depends on clinical suspicion

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Sensitivity Specificity (%) (%) 70-80 40-70 70-90 30-35 15-30 60-85 90-95 80-95 60-75 20-40

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Presentation of Gastroparesis
Vomiting-Predominant Vomiting Dehydration Hospitalizations 48% Weight loss

Regurgitation-Predominant Heartburn Effortless regurgitation

Bizer et al. Gastroenterol 2005; 128 (suppl 2): abstract.

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N=338 patients presenting to University of Louisville

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Dyspepsia-Predominant Epigastric pain Bloating Abdominal distension

Bravo Wireless pH Telemetry

Strength

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Patient friendly 48-hr test Single sensor

Weakness

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Transnasal pH monitoring
Strength

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Most sensitive and specific test for GERD Useful for atypical GERD Patient discomfort Costly

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Weakness

v s All GERD patients are not the same i u o L Causes of GERD are multifactorial f o Six most common y reason for refractory t i typical or atypical GERD are s r e v i n U
NERD vs. EE vs. BE

Conclusion

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