Gastroenterology-Hepatology Division

Internal Medicine Departement

FK-USU/Adam Malik Hospital
INCIDENCE in USA
 10% US population >17 years of age have
peptic ulcer disease at some time.
 White Americans have a 10% prevalence of H.
pylori by age 35 and 80% by age 75.
 Black Americans have a 45% prevalence of H.
pylori by age 25.
Incidens in Western Countries:
Female 4 – 15 % & Male 10 – 15 %
 INCIDENCE IN INDONESIA

Medan Jakarta
Peptic Ulcer 20,01 % 6,93 %

CA Gastro 5,18 % 1,73 %

Dispepsia Non 72,15 % 88,4 %

Ulkus
Esofagitis 1,59 % 1,5 %
 9
Death per 100,000

0
Leukemia AIDS NSAID-GI Melanoma Asthma Cervical
disease cancer

Wolfe et al. NEJM 1999

 Peptic Ulcer: Damage of mucosal
layer/muscularis mucosa or deeper until
submucosa of the stomach/duodenum, ulcer
edge surounded by acute and chronic
inflamatory cells; the diameter ≥ 5 mm

 Erosion: damage < 5 mm and the depth not

over than muscularis mucosa
1. “NO ACID NO ULCER” 1910 SCHWARTZ

2. GANGGUAN KESEIMBANGAN
AGRESIF (Asam Pepsin) & DEFENSIF

3. “NO HP NO ULCER” WARREN AND

MARSHALL 1983
 Ulcer
Healing
Aggressive
Factor

Defensive
Factor BALANCE Acid
Shay & Sun
Pepsin
Mucus, mucin Food
Fosfolipida Alcohol
Ion bicarbonat NSAIDs
Prostaglandin H. pylori
Mucous blood flow
Cell regeneration
 Prostaglandins produce mucous and
bicarbonate ions which protect the tissue in the
stomach by being destroyed with hydrochloric
acid and pepsin.
 Dyspepsia is the imbalance between the
protective mucosa and acid/pepsin.
 Peptic ulcer which is a defect beyond
muscularis mucosa will develop if there is an
imbalance.
 Note -stress ulcers do not extent through the
muscularis mucosa.
 Two types of peptic ulcers
1) Duodenal ulcers which occur
in the first portion of the
duodenum.
2) Gastric ulcers which usually
occur in the lesser curvature of the
stomach.
 H. pylori - a spiral, urease producing
flagellated bacterium which lives between
the mucus gel and mucosa. Its production of
urease, cytotoxins, proteases and other
compounds disturb the gel and increase
tissue exposure to acid and pepsin.
 H. pylori is seen in 95% of patients with
duodenal ulcers and 80% of gastric ulcers.
 Note only 10-20% of patients who are infected
with H. pylori will develop ulcers.
 NSAID’s - inhibit prostaglandins which in
turn increases tissue exposure to acid and pepsin.

 Zollinger-Ellison syndrome - is a gastrin

secreting tumor which creates such a high acid
level it over rides the protective gel.

 Cigarette smoking - inhibits bicarbonate ion

production and increases gastric emptying.
 NSAIDs induced H.pylori
Patients Elderly more than Young more often
demographics young than elderly
Women more often Men more often than
than men woman
Site of damage Gastric more than Duodenal more than
duodenal gastric
Symptoms More often Usually pain and or
asymptomatic dyspepsia
Histology Surrounding mucosa Surrounding mucosa
normal inflammed
(foveolar hyperplasia) (active chronic
gastritis)

Scarpignato,1997
Established Possible

Advanced age Concomitant infection with

History of ulcer H. pylori
Concomitant use of glucocorticoids Cigarette smoking
High-dose NSAIDs Alcohol consumption
Multiple NSAIDs
Concomitant use of anticoagulants
Serious or multisystem disease
 Meta-analysis of 16 studies consisting of 1633 patients

100 OR 3.55

80 OR 3.53 OR 19.4
HP+, NSAID+
60 OR 18.1 HP-, NSAID+
40 HP+, NSAID-
HP-, NSAID-
20

0
HP+, HP-, HP+, HP-,
NSAID+ NSAID+ NSAID- NSAID-

Huang et al. Lancet 2002

HISTORY OF ILLNESS
 None
 Dyspeptic Symptom:
Epigastric Pain, Nausea, Vomiting,anorexia,
epigastric discomfort, etc
 Loss of body weight
 Hematemesis and Melena
 Epigastric Pain
Episodic, Nocturnal, “Pain-Food- Relief”
pattern can be pointed at
 Epigastric pain - (gnawing, aching or
burning) is the main complaint.
 Gastric ulcers usually develop pain shortly
after eating.
 Duodenal ulcers usually develop pain 2-3
hours after eating and awaken patients at
night. Pain can be relieved by food.
 Physical exam of uncomplicated PUD, there
may be a finding of epigastric tenderness.
 Bile salts
 Emotional stress
 Type O blood
 Prolonged use of corticosteriods
 Caffeinated beverages
 Note diet and alcohol are not
predisposing factors to the
development of peptic ulcers.
1. Simptom 25 % mild, 50 % moderate, 25 %
severe with/without complication.
Cardinal simptom epigastric pain or
dyspepsia.
2. Physical Examination and Laboratory tests
are typically normal.
3. Radiology/OMDF (Crater-Niche -->TL)
4. Endoscopy : “gold standard” diagnostic
peptic ulcer
 Definite diagnosis can only be made by
visualization with an upper GI or
endoscopy.
 Endoscopy has the advantage of being
able to take a biopsy which is definitely
needed for gastric ulcers to rule out
malignancy.
 Age over 45 years old
 Alarm signs
 Therapy failure
 History of Peptic ulcer + Complication
 Patient enquery
 The use of aspirin or NSAID
 Abnormality in Upper GI X-Ray (OMD)
 NON-INVASIVE  INVASIVE
 Urea Breath Test (biopsy & endoscopy)
 Serum serology for
– Culture test
Hp antibody test
– Histopatology test
 Whole blood
serology for Hp – Urease test
antibody test – PCR
 Saliva Assay for Hp
antibody test
 Helicobacter Pylori
stool antigent
(HpSA) test
  General/supportif
 Stop/Inhibit aggressive factor
 Increase the defensive factor
 Other treatment

 Threat the complication

 Avoid ulcer relaps/recurrence

 Table 1 : Management of
peptic ulcer
Question: Action taken in the
management of ulcer
What type of ulcer?
- Gastric ulcer Requires biopsy to exclude
malignancy, requires
confirmation of healing by
endoscopy
- Duodenal Ulcer If symptoms resolve after
adequate treatment,
endoscopy generally not
required except for
presentation with bleeding
Yeoh Khay-Guan Kang Jin-Yong, Managemant of Common Gastroenterological Problem, 2006
 Table 2 : Management of peptic ulcer
(Cont…)
Question:
What the cause of ulcer disease?
- Has the patient used NSAID?
- Is H pylory infection present?
Any ulcerogenic risk factor?
- Aspirin or NSAID use
- Smoking
Yeoh Khay-Guan Kang Jin-Yong, Managemant of Common Gastroenterological Problem, 2006
Action taken in the management of
ulcer
Evaluate for NSAID ingestion and H
pylori
If yes, evaluate indication for NSAID;
can this be stoped?
Treat H Pylori
Stop if possible; evaluate indication
and consider non-ulcerogenic
substitutes: eg, ticlopidine instead of
aspirin for cardiovascular prophylaxis;
non-NSAID analgesiscs such as
paracetamol or codein; COX-2
inhibitors
Advice to stop smoking
 Stop any offending agents such as
NSAID’s,steroids etc

 Bland diets with frequent feedings

has not been shown to be effective.
- Non Medicamen : Life style, Diet
- Medicamen
. Antacids
. Cytoproktective agents
Sucralfate, misoprostol, bismuth subsalicylate
. Acid suppresion :
- ARH2 (Antagonis / Reseptor H2)
Cimetidin, Ranitidin, Famotidin
- PPI (Proton Pump Inhibitors)
Omeprazole, Lansoprazole, esomeprazole,
rabeprazole, pantoprazole
 Antacids – neutralize gastric acids.
a) good for acute pain relief and healing
ulcers.
b) poor compliance due frequency of doses.
c) inhibit absorption of some drugs such as
warfarin,digoxin, some anticonvulsants
and antibiotics.
d) aluminum causes constipation and should
not be given with renal failure patients due to
accumulation which can cause osteoporosis and
encephalopathy.
e) magnesium causes diarrhea.
 H2- Antagonists – inhibit gastric acid
secretion
a) equally as effective as antacids with better
compliance due to decreased frequency of
doses.
b) cimetidine inhibits cytochrome p450 system
greater than other H2-antagonists which
will cause an increase in drugs such as
warfarin, phenytoin, diazepam, TCA’s,
propranolol, etc.
c) renal excretion and therefore must adjust doses in
patients with renal disease.
 Proton Pump Inhibitors - inhibit gastric acid
secretion
a) heal ulcers faster then H2-antagonists and
antacids.
b) omeprazole has also been shown to affect
the cytochrome p450 system.
c) lansoprazole does not affect other drug
metabolism.
d) pantoprazole has been shown to decrease
bleeding from peptic ulcers.
e).Esomeprazole has been shown faster and
gastric pH stabilized on 4.
 Sulcralfate – locally binds to the base of the
ulcer and therefore protects it from acid
a) Also has been shown to absorb bile acids,
inhibit pepsin activity, and increase
prostaglandin production.
b) Needs an acidic environment to work
therefore not beneficial to give antacids
c) Causes constipation, dry mouth and
inhibits the absorption of many medications.
 Misoprostol – prostaglandin E1 analogue
which acts as natural prostaglandin in the body
a) Only indicated for prevention of NSAID
-induced gastric ulcers in high risk patients.
b) contraindicated in pregnant women and
women in childbearing age because it
causes spontaneous abortion.
c) can cause diarrhea and crampy abdominal
pain.
 Bismuth compounds
 – Decrease pepsin activity, increase
mucus secretion, form a barrier
protection on ulcers, augment
prostaglandin synthesis, slow hydrogen
ion diffusion across mucosal barrier,
and H. pylori bactericidal effect.
a) Used in triple drug combinations for
the treatment of H. pylori.
 If H. pylori positive then must be given
antibiotics to prevent recurrence of
ulcer.
 Usually done with triple or quadruple
treatment regimens.
 Some antibiotics in regimens are
metronidazole, tetracycline, amoxicillin,
clarithromycin.
Consensus of The Treatment H Pylori Infection
(Maastrich III-2005)

PPI- Clarithromycin – Amoxicillin or metronidazole therapy remains the recommended

first line Therapy In populations with less than 15-20% clarithromycin resistance
prevalence in population in Less than 40% Metronidazole resistance prevalence
PPI – clarithromycin - metronidazole is preferable

Quadriple therapies are alternative first line therapy

In case of failure

Second line therapy

Bismuth – based quadruple therapies remain the best second line therapy, if available,
if not, PPI – Amoxicillin or tetracycline and metronidazole are recommended

Subsequent failures rescue therapy

The rescue therapy should be based on antimicrobial susceptibility testing

Peter Malfertheiner, The 6th western Pasific Helicobacter Congress, 2006

 Tripple therapy (1 or 2 weeks):
 PPI + Amoxicillin + Clarithromycin
 PPI + Metronidazole + Clarithromycin
 PPI + Metronidazole + Tetracyclin (Alergy to
clarithromycin)
 Quadrupple therapy ( 1 or 2 weeks):
 If fail to therapy → combination 3 drugs:
 Bismuth + PPI + Amoxicillin + Clarithromycin
 Bismuth + PPI + Metroniudazole + Clarithromycin
 High resistency area:
 PPI + Bismuth + Tetracyclin + Metronidazole
 PPI 2 x/d: Omeprazole/Esomeprazole 20 mg, Lansoprazole 30
mg, Pantoprazole 40 mg, Rabeprazole 10 mg
 Amoxicillin 2 x 1000 mg/d, Clarithromycin 2 x 500 mg/d,
metronidazole 3 x 500 mg/d, tetracyclin 4 x 250 mg/d, Bismuth 4 x
120 mg/d
Management of Uncomplicated Gastric Ulcer
**Gastric ulcer on endoscopy or barium meal

IS H PYLORI PRESENT?

Yes No

Eradication Treatment Is Patient taking NSAID?

If so, Stop NSAID

Successful *Unsuccessful

ANTI-SECRETORY TREATMENT 4-8 WEEKS

Repeat gastrocopy or barium

meal to asses healing

Healed Not Healed

Follow-Up Continue treatment

Consider repeat Bx To exclude cancer

Consider Surgery
Notes: *Quadriple therapy given for failed triple
**Gastric ulcer should be biopsied to exclude malignancy

Yeoh Khay-Guan Kang Jin-Yong, Managemant of Common Gastroenterological Problem, 2006

 Duodenal Ulcer of Endoscopy or barium meal

Is H pylori Present

Yes No

Is patient taking NSAIDS?

Eradication Treatment
If so, stop NSAIDS

Successful & Unsuccessful* or

Symptoms resolve still symptomatic

optional Anti-secretory treatment 4-6 weeks

Low probability of recurence Review symptomps

No maintenance treatment And follow-up
Yeoh Khay-Guan Kang Jin-Yong, Managemant of Common Gastroenterological Problem, 2006
- HEMORRHAGE
- PERFORATION
- OBSTRUCTION / PYLORIC STENOSIS/
GOO = GASTRIC OUTLET OBSTRUCTION
- PENETRATION
 GI bleeding is the most common
complication of PUD and the most common
cause of upper GI bleeding.

 Please see previous lecture on

management of GI Bleeding.
 Perforation
 Initially a chemical peritonitis develops which then
progresses to a bacterial peritonitis.
 Anterior perforation - patients will have sudden
abdominal pain with guarding and rebound.
60-70% will demonstrate free air of x-rays.
 Posterior perforation - patients will develop
back pain with no free air on x-ray and may
mimic pancreatitis but lipase will be normal or
only slightly elevated.
 No free air on x-rays cannot rule our
perforation.
 IV fluids, electrolyte corrections, NG tube,
broad spectrum antibiotics and surgery.
 Gastric outlet obstruction
 Scaring from healed ulcers or edema from
active ulcer with development of obstruction.
 Obstruction will cause gastric dilation,
vomiting, dehydration, metabolic alkalosis.
 Patients will develop upper abdominal pain
with vomiting, early satiety, weight loss,
succussion splash.
 Abdominal x-ray will show dilated stomach
shadow with large air-fluid level.
 IV fluids, electrolyte corrections, NG tube, and
surgery if needed.
 GI Tract
 Ulcers, perforations, bleeding, obstruction
strictures, enteropathy
 Kidney
 Sodium and fluid retention
 Hyperkalemia
 Acute renal failure
 Hypertension
 Platelet
 Inhibition of aggregation leading to increased
potential for bleeding
Upper GI Small Intestine Colon
• GERD • Ulcers • Colitis
• Subepithelial petechial
• Strictures • Ulcers
hemorrhages
• Erosions • Diaphragms • Strictures
• Ulcers • Enteropathy • Diverticular bleed
– Stomach > duodenum
or perforation
• Bleeding
• Collagenous
– Stomach  duodenum
colitis
• Perforations/obstruction
• Relapse of IBD
 Non-selective NSAIDs account for
approximately 20–25% of all reported drug
adverse events.
 80% of peptic ulcer-related deaths occur in
non-selective NSAID users.
 In the USA, NSAID use accounts for
approximately 107,000 hospitalisations and
16,500 deaths per year.

Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999

 50–60% of NSAID-associated peptic ulcers,
presenting for the first time as a
complication, have been silent previously.
 Most patients with endoscopic lesions do
not develop dyspepsia:
 9% of patients with abnormal endoscopy
had dyspeptic symptoms (n=45).

Larkai et al 1987; Singh 1998

 List of NSAIDs Available by Prescription
NON-SALICYLATES
INHIBITORS
Diclofenac (Voltaren)
Diclofenac/Misoprostol (Arthrotec)b Diflunisal (Dolobid)
Fenoprofen (Nalfon)
Flurbiprofen (Ansaid)
Appreciated
Ibuprofen (Motrin)a
Indomethacin (Indocin)
Ketoprofen (Orudis)a
Meclofenamate
Mefenamic acid (Ponstel)
Nabumetone (Relafen)
Naproxen (Naprosyn, Anaprox)a
Oxaprozin (Daypro)
Piroxicam (Feldene)
Sulindac (Clinoril)
Tolmetin (Tolectin)
2004 Physician’s Desk Reference
SALICYLATES COX-2
Aspirina (Zorprin, Easprin) Celecoxib (Celebrex)
Valdecoxib (Bextra)
Salsalate (Disalcid, Salflex)
Choline salicylate (Trilisate) Not Widely
Magnesium salicylate (Magan) Etodolac (Lodine)
Meloxicam (Mobic)
In Development
Etoricoxib
Parecoxibc
Lumiracoxib
Previously Available
Rofecoxib (Vioxx)
a Also available as over-the-counter preparations in the U.S.
b Combination tablet of NSAID/synthetic prostaglandin E1
c Parenterally administered
 Arachidonic acid

COX-1 COX-2
(constitutive) (induced by inflammatory stimuli)

COX-2 selective NSAIDs 

 Non-selective NSAIDs 
Prostaglandins Prostaglandins

• Gastrointestinal cytoprotection • Inflammation

• Platelet activity • Pain
• Fever
Vane & Botting 1995
 Acidic Gastric
environment NSAIDs acid Pepsin
Ionic gradient
Mucus Surface
layer epithelial cells
Bicarbonate layer
Neutral
environment

Mucosal
blood supply
NSAIDs
Alkaline Prostaglandin Bicarbonate Mucus
environment production production production
 ACID

MUCOSAL DEFENCE
NSAIDs
gastric mucus Smoking
bicarbonate others
prostaglandins H.pylori
mucosal blood
flow ULCER
 Mean Range
NSAID Gastropathy > 90 %
Gastric Ulcer 15 % 10 to 30%
Duodenal Ulcer 5% 4 to 10 %

Wolfe MM et al. N Engl J Med 1999;340:1888-1899

 Mean
Range
Gastric Ulcer 15 % 10 to 30%
Duodenal Ulcer 5% 4 to 10 %
Clinically Significant Ulcers 2% 1 to 4%
Endoscopic Photograph of
Gastropathy
Endoscopic Photograph
of Gastric Ulcer
  Identify risk factors

 Use of gastroprotective drugs

 Safer NSAIDS

Wolfe MM et al. N Engl J Med 1999;340:1888-1899

 Identify risk factors
 Age (>65 years)
 History of GI ulceration
 History of upper GI ulcer complication
 Concomitant drugs (e.g. corticosteroids,
coumadin)
 Multiple NSAIDS • Prescribed + Low-Dose Aspirin
 Cardiovascular disease• Prescribed + OTC NSAIDs

Wolfe MM et al. N Engl J Med 1999;340:1888-1899

Risk factor Relative risk 95% CI
Overall 2.74 2.54-2.97
Age (>60) 5.52 4.63-6.60
Prior GI event 4.76 4.05-5.59
High dosage (>2 X normal) 10.1 4.6-22.0
Concurrent corticosteroids 4.4 2.0-9.7
Concurrent anticoagulants 12.7 6.3-25.7
American College of Gastroenterology
Am J Gastroenterol 1998; 93:2037.
  Identify risk factors
 Use of gastroprotective drugs
 Safer NSAIDS

Wolfe MM et al. N Engl J Med 1999;340:1888-1899

 Useful for the prevention of NSAID-induced ulcers

Lansoprazole versus misoprostol

 a multicenter trial, 537 patients who were long-term NSAID
users were randomly assigned to placebo, misoprostol (200 µg
four times daily), or one of two doses of lansoprazole (15 or 30
mg daily). After 12 weeks, the incidence of endoscopically
detected gastroduodenal ulceration was 49% with placebo vs
7 % with misoprostol , both doses of lansoprazole (20 and 18
%, respectively).
 Graham, DY, Agrawal, NM, Campbell, DR, et al. Ulcer prevention in
long-term users of nonsteroidal anti-inflammatory drugs: Results of a
double-blind, randomized, multicenter, active- and placebo-controlled
study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162:169.
 Standard doses of H2 receptor antagonists are
not effective for the prevention of NSAID-
induced gastric ulcers
 In Hudson et al study, 285 patients with RA or
OA treated with long-term NSAIDs were
randomly assigned to receive two different
doses of famotidine or placebo
 Incidence of gastric ulcers for the 40 mg twice
daily, 20 mg twice daily, and placebo groups
was 8, 13, and 20%,and the incidence of
duodenal ulcers was 2, 4, and 13 %
  Identify risk factors
 Use of gastroprotective drugs

 Safer NSAIDS

Wolfe MM et al. N Engl J Med 1999;340:1888-1899

 Patients with a history of uncomplicated or complicated
peptic ulcers (gastric, duodenal) should be tested for H.
pylori prior to beginning a course of NSAID or low dose
aspirin therapy. If present, H. pylori should be treated
with appropriate therapy, even if it is believed that the
prior ulcer was due to NSAIDs.

 In asymptomatic patients with no history of ulcer and

not currently taking an NSAID, physicians can consider
H. pylori testing prior to beginning long-term therapy
with a NSAID. This "test-and-treat" approach may be
more useful in populations with a relatively high
prevalence of H. pylori infection.
NSAIDS : TREATMENT AND SECONDAR
PREVENTION OF GASTROINTESTINAL E
 If patient develop ulcers while on NSAID
therapy STOP NSAID if possible
 Start with PPI or H2 antagonist therapy
 Assess the H.Pylori status, if positive it should
be treated
 If patient must remain on NSAID therapy PPI
is preferred than H2 antagonist; misoprostol or
sucralflat
 Patients with gastroduodenal ulcers or numerous
erosions who must continue NSAID or aspirin
therapy should be treated with a PPI such as
omeprazole (20 mg/d) or lansoprazole (15 or 30
mg/d) for four to eight weeks followed by
maintenance therapy for as long as the NSAID or
aspirin is used. In addition, H. pylori infection
should be eradicated, if present.
With continue NSAID therapy
 732 patients in whom initial treatment was
successful were randomly assigned to
maintenance therapy with omeprazole (20
mg/day), misoprostol (200 µg twice daily for six
months), or placebo for six months . Patients
remained in remission during maintenance
therapy with omeprazole than with low dose
misoprostol (61 vs 48 %). Omeprazole is better
tolerated than misoprostol.
Hawkey et al. Omeprazole compared with misoprostol for ulcers associated
with nonsteroidal antiinflammatory drugs. N Engl J Med 1998; 338:727.
 Lansoprazole (15 mg or 30 mg daily) and
esomeprazole (20 to 40 mg daily) are approved
by the FDA for prophylaxis against NSAID-
induced ulcers.
 Esomeprazole is also effective in preventing
celecoxib-induced bleeding ulcers.
 Selecting celecoxib (or another COX-2 selective
agent, if available) plus a proton pump
inhibitor will probably be highly effective in
preventing recurrent ulcers, but the
cardiovascular concerns of coxibs and the
higher cost of this regimen are of concern