Case Illustration Seminar

Gastroesophageal reflux disease

Justin Wu

Professor, Department of Medicine & Therapeutics

Assistant Dean (Clinical), Faculty of Medicine

The Chinese University of Hong Kong

Case 1• A 35 y.o. man presents with frequent heartburn

and acid regurgitation for several years. The

symptoms respond to proton pump inhibitor but

they relapse after cessation of PPI. Endoscopy is

normal and H. pylori testing is negative. What is

your diagnosis?

1. Gastroesophageal reflux disease

2. Functional dyspepsia

3. No diagnosis

Esophagus

Stomach

Lower esophageal sphincter

What is GERD?

Gastric acid

Troublesome symptoms

Complications

Typical reflux symptoms

• Acid regurgitation

• Heartburn

• Mostly occur after 1-3 hours after meal

• Occasionally aggravated by lying down,

bending forward and straining

• Belching is NOT a reflux symptom

Spectrum of GERD

Esophageal acid exposure

Reflux esophagitis

Barrett’s esophagus / Adenocarcinoma

Peptic stricture

Endoscopy negative GERD

GERD: An emerging disease in HK

18

15.4

10.4 10.1

8.59.7

7.1

2.3

3.84.9 5.2 5.4 5.6 5.8

0

2

4

6

8

10

12

14

16

18

20

1996 1997 1998 1999 2000 2001 2002

All H. pylori peptic ulcer

All GERD

Annual incidence

/10,000 persons 36,759 endoscopy records

32,807 records analyzable

Wu et al. DDW 2006

GERD: Symptom based diagnosis

Reflux symptom

Alarm symptom

Empirical PPI (PPI Test)

No

Endoscopy

Yes

Dent et al. Genval Report. Gut 1999

Good response

GERD

No response

Symptom relapse

Lower pretest probability of PPI test in Asia

At least weekly reflux symptoms based

on questionnaire / telephone survey

3%

17%

6%

3%2% 2%

4%

7%

5%

18%

8%

15%

8%

10%

18%

15%17%

13%

28%

20%20%

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5%

10%

15%

20%

25%

30%

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Chi

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UK

Finla

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SAU

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Prevalence

460 patients with frequent heartburn/ acid regurgitation as dominant

complaint recruited for OGD (NSAID use and alarm symptoms excluded)

Is symptom based diagnosis reliable?

218 (48%)

148 (32%)

82 (18%)

OGD neg, no response to PPI

OGD neg, clinical response to PPI

Reflux esophagitis

Peptic ulcer (95% H. pylori

positive)

Predictors of PU

Male, H. pylori, age>60

Wu et al. Gastrointest Endosc 2002

Empirical PPI based on reflux symptom may not be

appropriate in population with high prevalence of H. pylori

Case 1• A 35 y.o. man presents with frequent heartburn

and acid regurgitation for several years. The

symptoms respond to proton pump inhibitor but

they relapse after cessation of PPI. Endoscopy is

normal and H. pylori testing is negative. What is

your diagnosis?

1. Gastroesophageal reflux disease

2. Functional dyspepsia

3. No diagnosis

Case 2

• A 35 y.o. male presents with daily reflux

symptoms for years. OGD shows no esophagitis.

The symptoms persist despite successful H.

pylori eradication but they subside after a course

of Lansoprazole. What is your recommendation?

1.Off all medication

2.Step down to famotidine for long-term treatment

3.Continue Lansoprazole

H. pylori eradication cannot cure GERD

X

121086420

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Probability of treatment failure

Months

Duration of follow up

Eradication group, 43.2% (95% CI: 29.9-56.5%)

P=0.043, log rank testPlacebo group, 21.1%

(95% CI: 9.9-32.3%)

Wu. Gut 2004

H. pylori eradication leads to more difficult control of GERD

104 GERD patients randomized to H. pylori

eradication or placebo followed by PPI treatment

GERD is a relapsing disorder

Lundell. Gut 1999

Symptom remission rate after PPI withdrawn (%)

Objectives of treatment

1. Relieve symptom

2. Heal esophagitis

3. Prevent complication

Long-term treatment required

More demanding on acid suppression than

peptic ulcer

EVIDENCE-BASED LIFESTYLE MODIFICATIONS

LIFESTYLE FACTORS THAT MAY CONTRIBUTE TO GERD

• Weight loss

• Head-of-bed elevation

• Avoid night meals

• Alcohol

• Smoking

• Dietary intake(e.g. chocolate, fatty foods, citrus)

Kaltenbach et al. Arch Intern Med. 2006

How useful is lifestyle modification?

There is little clinical evidence that avoidance of

alcohol, smoking, or dietary factors improves

symptoms

PPI Vs H2RA for 4-8 week treatment of esophagitis

26 trials (N=4064)

RR:0.47 (95% CI: 0.41-0.53)

NNT: 3 (95% CI: 2.8-3.6)

Cochrane Database Systemic Review 2004

1st line treatment Step up / down therapy

NICE (UK) PPI Low dose / on-demand PPI

ACG (US) PPI (H2RA for

milder GERD)

Titrate PPI dose for symptom

control

Genval PPI (strongly

preferred) or

H2RA

Titrate PPI dose for symptom

control; step down to H2RA

after low-dose PPI

Asia-Pacific PPI On-demand PPI

Canadian PPI (preferred) or

H2RA

PPI or H2RA for symptom

control

Australian PPI On-demand PPI

PPI is the gold standard treatment for GERD

28 healthy male volunteers given ranitidine 150 mg

q.i.d. for 5 days with 24-hour intragastric pH

monitoring

Lachman L et al. Am J Gastroenterol. 2000

% time gastric pH>4: 54% →→→→ 30%

Rapid tolerance of H2RA Prokinetic

• No proven value for reflux symptoms or

esophagitis

Emerging issues of PPI use

• Fractures

• PPI-clopidogrel interactions

• Clostridium difficile colitis

• Community acquired pneumonia

• Non-Clostridium enteric infections

• ↓ Thyroxine absorption

• Hypomagnesaemia

• Case control study (13556 cases of hip fracture

Vs 135386 controls)

• Odds ratio

Standard dose: 1.44 (95% C.I.:1.30-1.59)

�1-year: 1.22 (95% C.I.: 1.15-1.30)

�2-year: 1.41 (95% C.I.:1.28-1.56)

�3-year: 1.54 (95% C.I.:1.37-1.73)

�4-year: 1.59 (95% C.I.: 1.39-1.80)

High dose: 2.65 (95% C.I.:1.80-3.90)

Yang et al. JAMA 2006

PPI and fractures

Food and Drug Administration, May 2010

• ↑ Risk in 6 out of 7 epidemiological studies

• Age >50, use >1 year, high dose

• ? Ca2+ malabsorption, ↑ Osteoclast activity

PPI & Fractures: Recommendations

• Identify high risk users

�Prior fractures

�Osteoporosis

�Age>50

�Female

• Avoid high dose PPI >1 year

• On demand PPI for mild disease

• Ca2+ and vitamin D suppl., bisphosphonate

PPI use and Clostridium difficile infection

• Pooled data of 39 observational studies (29 case-controls, 10 cohorts) with 313,000 cases of CDI

Pooled odds ratio (95% CI)

PPI alone 2.1 (1.7–2.7)

H2RA alone 1.5 (1.2–1.8)

PPI + antibiotic 3.9 (2.3–6.6)

Kwok et al. Am J Gastroenterol 2012.

How to minimize the risk of CDI?

• Identification of high-risk patients: old age,

immunosuppressant, cancer, IBD, renal

failure

• Temporary withdrawal of PPI

• Once-daily dosing

• Avoid high dose

• Indications of PPI should be justified

• Reflux are often episodic and self-limited

• Symptom-driven → patient friendly

• Better quality of life, less sick role

• Lower drug cost

• Avoid excessive chronic acid suppression

• PPI use in 33–50% of time; 70–93%

willing to continue treatment [Zacny et al. APT 2005]

Intermittent / on-demand PPI Step-down therapy: contraindications

• Severe esophagitis

• GERD complications: bleeding, peptic

stricture, Barrett’s esophagus

Case 2

• A 35 y.o. male presents with daily reflux

symptoms for years. OGD shows no esophagitis.

The symptoms persist despite successful H.

pylori eradication but they subside after a course

of Lansoprazole. What is your recommendation?

1.Off all medication

2.Step down to famotidine for long-term treatment

3.Continue Lansoprazole

New drugs

44 healthy volunteers randomized to Deslansoprazole 60

mg Vs Esomeprazole 40 mg

Pharmacodynamics: Deslansoprazole Vs Esomeprazole

Dual delayed-release delivery system (DDR™) Kukulka . Clin Exp Gastroenterol 2011

Higher serum concentration ⇒Superior acid suppression

Kukulka . Clin Exp Gastroenterol 2011

24-hour intragastric pH monitoring

Reflux inhibitors

• GABAB agonist

• Lesogabaran, arbaclofen

• ↓ transient LES relaxation and reflux

episodes

• Not superior to placebo for symptom

relief

Boeckxstaens et al. Gastroenterol 2010

Vakil et al. Am J Gastroenterol 2011

H+/K+ ATPase in active form

K+

H+

PPI acts slowly

K+K+

H+H+

Lumen

Parietal Cell

PPI

Irreversibly bind to active proton pump

X

Complete acid blockade after 3 days

ProtonationpH<pKa

Sulphenamide

H+/K+ ATPase (Proton pump)

K+

H+

Potassium-competitive acid blocker

K+K+

H+H+

Lumen

Parietal CellX

Complete acid blockade within 30 minutes

P-CAB

• Imidazopyridine compound

• No chemical conversion

• Reversible ionic bond with

proton pump

P-CAB has more potent inhibition of H+,K+ ATPase than PPI

% Inhibition of gastric H+,K+ ATPase

TAK-438 Lansoprazole

pH 6.5

pH 7.5

pH 6.5

pH 7.5

Hori et al. J Pharmacol Exp Ther 2011

Management of GERD

NERD or mild esophagitis

Infrequent mild reflux

Frequent moderate to severe reflux

Severe, complicated esophagitis

Regular PPI

Antireflux surgery

On-demand / intermittent

H2RA

On-demand / intermittent

PPI