Case 1

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

What is GERD?
Esophagus

Troublesome symptoms

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

Typical reflux symptoms

Acid regurgitation
Heartburn

Complications

Lower
esophageal
sphincter

Mostly occur after 1-3 hours after meal

Occasionally aggravated by lying down,
bending forward and straining

Stomach
Gastric
acid

Belching is NOT a reflux symptom

Spectrum of GERD

GERD: An emerging disease in HK

Annual incidence
/10,000 persons

Endoscopy
negative GERD

Barretts esophagus /
Adenocarcinoma

20
18
16

36,759 endoscopy records

32,807 records analyzable

18
15.4

All H. pylori peptic ulcer

14
12

All GERD

10.4

10.1

10
8

7.1

Reflux esophagitis

Peptic stricture

Esophageal acid exposure

9.7
8.5

4.9

3.8

4
2

5.6

5.4

5.2

5.8

2.3

0
1996

GERD: Symptom based diagnosis

30%

1999

2000

Yes

At least weekly reflux symptoms based

on questionnaire / telephone survey

18%

17%

18%

17%
15%
13%

15%

Endoscopy

10%

10%

No response

GERD

Symptom relapse

5% 3%

8%

7%

6%

Good response

28%

20% 20%

20%
15%

Empirical PPI (PPI Test)

2001
2002
Wu et al. DDW 2006

25%

Alarm symptom
No

1998

Lower pretest probability of PPI test in Asia

Prevalence

Reflux symptom

1997

4%
3%

8%

5%

2% 2%

Dent et al. Genval Report. Gut 1999

I ra
n
I ra
n
Is
ra
el
U
K
U
Fi K
nl
a
Sw n d
ed
en
U
SA
U
SA
U
SA
U
SA

C
hi
n
C a
hi
na
H Ch
on in
g a
Si Kon
ng g
ap
or
Ko e
re
a
Ko
re
Ko a
re
Ja a
pa
Ja n
pa
n

0%

Case 1

Is symptom based diagnosis reliable?

Empirical
based
on reflux
symptom
mayasnot
be
460 patients
withPPI
frequent
heartburn/
acid
regurgitation
dominant
complaint
recruited
for OGD (NSAID
andprevalence
alarm symptoms
appropriate
in population
withuse
high
of H.excluded)
pylori
OGD neg, no
response to PPI
OGD neg, clinical
response to PPI

148
(32%)

82
(18%)

218
(48%)

Reflux
esophagitis

Peptic ulcer
(95% H. pylori
positive)

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

Predictors of PU
Male, H. pylori,
age>60

2. Functional dyspepsia
3. No diagnosis

Wu et al. Gastrointest Endosc 2002

Case 2

H. pylori eradication cannot cure GERD

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 leads to more

difficult control of GERD

GERD is a relapsing disorder

Symptom remission rate
after PPI withdrawn (%)

Probability of treatment failure

1.0

104 GERD patients randomized to H. pylori

eradication or placebo followed by PPI treatment

.9
.8
.7

Eradication group, 43.2%

(95% CI: 29.9-56.5%)
P=0.043, log rank test

.6

Placebo group, 21.1%

(95% CI: 9.9-32.3%)

.5
.4
.3
.2
.1
0.0
0

10

Duration of follow up

12

Months
Lundell. Gut 1999

Wu. Gut 2004

Objectives of treatment
1. Relieve symptom
2. Heal esophagitis
3. Prevent complication
Long-term treatment required
More demanding on acid suppression than
peptic ulcer

How useful is lifestyle modification?

EVIDENCE-BASED
LIFESTYLE MODIFICATIONS

Weight loss
Head-of-bed elevation
Avoid night meals

LIFESTYLE FACTORS THAT MAY

CONTRIBUTE TO GERD

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

There is little clinical evidence that avoidance of

alcohol, smoking, or dietary factors improves
symptoms
Kaltenbach et al. Arch Intern Med. 2006

PPI Vs H2RA for 4-8 week treatment of

esophagitis
26 trials (N=4064)
RR:0.47 (95% CI: 0.41-0.53)

PPI is the gold standard treatment for GERD

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

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

Asia-Pacific PPI

Cochrane Database Systemic Review 2004

On-demand PPI

Canadian

PPI (preferred) or PPI or H2RA for symptom

H2RA
control

Australian

PPI

On-demand PPI

Rapid tolerance of H2RA

Prokinetic

28 healthy male volunteers given ranitidine 150 mg

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

No proven value for reflux symptoms or

esophagitis

% time gastric pH>4: 54% 30%

Lachman L et al. Am J Gastroenterol. 2000

PPI and fractures

Emerging issues of PPI use

Fractures
PPI-clopidogrel interactions
Clostridium difficile colitis
Community acquired pneumonia
Non-Clostridium enteric infections
Thyroxine absorption

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)

Hypomagnesaemia

Yang et al. JAMA 2006

PPI & Fractures: Recommendations

Identify high risk users

Prior fractures

Osteoporosis

Age>50

Risk in 6 out of 7 epidemiological studies

Age >50, use >1 year, high dose
?

Ca2+

malabsorption, Osteoclast activity

Food and Drug Administration, May 2010

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

How to minimize the risk of CDI?

Pooled data of 39 observational studies (29 case-controls,

10 cohorts) with 313,000 cases of CDI

Identification of high-risk patients: old age,

immunosuppressant, cancer, IBD, renal
failure

Pooled odds ratio (95% CI)

PPI alone
H2RA alone
PPI + antibiotic

2.1 (1.72.7)
1.5 (1.21.8)
3.9 (2.36.6)

Temporary withdrawal of PPI

Once-daily dosing
Avoid high dose
Indications of PPI should be justified

Kwok et al. Am J Gastroenterol 2012.

Intermittent / on-demand PPI

Step-down therapy: contraindications

Reflux are often episodic and self-limited

Symptom-driven patient friendly

Severe esophagitis

Better quality of life, less sick role

GERD complications: bleeding, peptic

Lower drug cost

Avoid excessive chronic acid suppression
PPI use in 3350% of time; 7093%
willing to continue treatment [Zacny et al. APT 2005]

stricture, Barretts 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.

New drugs

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

Pharmacodynamics:
Deslansoprazole Vs Esomeprazole
44 healthy volunteers randomized to Deslansoprazole 60
mg Vs Esomeprazole 40 mg

Higher serum concentration

Superior acid suppression
24-hour intragastric pH monitoring

Dual delayed-release delivery system (DDR)

Kukulka . Clin Exp Gastroenterol 2011

Kukulka . Clin Exp Gastroenterol 2011

PPI acts slowly

Reflux inhibitors

pH<pKa

Sulphenamide

GABAB agonist
Lesogabaran, arbaclofen
transient LES relaxation and reflux
episodes

Vakil et al. Am J Gastroenterol 2011

Boeckxstaens et al. Gastroenterol 2010

Potassium-competitive acid blocker

H+ H+
H+
H+/K+ ATPase
(Proton pump)

P-CAB

Imidazopyridine compound
No chemical conversion
Reversible ionic bond with

H+/K+ ATPase
in active form

Lumen

Parietal Cell

K+ +
K K+

pH 6.5

pH 6.5
pH 7.5

Parietal Cell

Complete acid blockade

within 30 minutes

Complete acid blockade

after 3 days

% Inhibition of gastric H+,K+ ATPase

Lumen

K+ +
K K+

PPI

P-CAB has more potent inhibition of

H+,K+ ATPase than PPI

proton pump

Irreversibly bind to
active proton pump

H+ H+
H+

Not superior to placebo for symptom

relief

Protonation

TAK-438

pH 7.5

Lansoprazole
Hori et al. J Pharmacol Exp Ther 2011

Management of GERD
NERD or mild
esophagitis

Infrequent
mild reflux

On-demand /
intermittent
H2RA

Frequent
moderate to
severe reflux
On-demand /
intermittent
PPI

Severe, complicated
esophagitis

Regular PPI
Antireflux surgery