Peptic Ulcer Disease in Primary care

Darya Varia : GP Summit

Jakarta 16 – 17 Maret 2019
Definition

A circumscribed ulceration of the gastrointestinal

mucosa occurring in areas exposed to acid and
pepsin and most often caused by Helicobacter
pylori infection. (Uphold & Graham, 2003)
A surface breach of mucosal lining of GI tract occurring as a
result of acid and pepsin attack
Sites:
• Oesophagus
• Stomach (GU)
• Gastro-enterostomy stoma
• Duodenum (DU)
• Related to ectopic gastric mucosa (e.g. in Meckel’s
diverticulum
The acid-peptic diseases
• GERD, and its complications
• normal acid-pepsin secretion, but excessive acid exposure
to the esophageal epithelium
• PUD, and its complications
• DU: acid-pepsin hypersecretion common, but not universal;
heterogeneous disease
• GU: acid-pepsin secretion normal usually, implying impaired
defensive mechanisms
• Zollinger-Ellison syndrome
• acid hypersecretion is massive and pathogenic
PUD Demographics
• Higher prevalence in developing countries
• H. Pylori is sometimes associated with socioeconomic
status and poor hygiene
• In the US:
• Lifetime prevalence is ~10%.
• PUD affects ~4.5 million annually.
• Hospitalization rate is ~30 pts per 100,000 cases.
• Mortality rate has decreased dramatically in the past 20
years
• approximately 1 death per 100,000 cases
Etiology
• A peptic ulcer is a mucosal break, 3 mm or greater, that can involve
the stomach or duodenum.
• The most important contributing factors are H pylori, NSAIDs, acid,
and pepsin.
• Additional aggressive factors include smoking, ethanol, bile acids,
aspirin, steroids, and stress.
• Important protective factors are mucus, bicarbonate, mucosal blood
flow, prostaglandins, hydrophobic layer, and epithelial renewal.
• Increased risk when older than 50 d/t decrease protection
• When an imbalance occurs, PUD might develop.
Comparing Duodenal and Gastric Ulcers
Gastric Ulcers
• Common in late middle age
• incidence increases with age
• Male to female ratio—2:1
• More common in patients with blood group A
• Use of NSAIDs - associated with a three- to four-fold increase in risk of
gastric ulcer
• Less related to H. pylori than duodenal ulcers – about 80%
• 10 - 20% of patients with a gastric ulcer have a concomitant duodenal
ulcer
Symptoms of gastric ulcer disease:

➢epigastric pain after meal or during meal

➢upper dyspeptic syndrome – loss of appetite, nauzea,

vomiting, flatulence

➢vomiting brings relief

➢reduced nutrition

➢loss of weight
Duodenal Ulcers
• Duodenal sites are 4x as common as gastric sites
• Most common in middle age
• peak 30-50 years
• Male to female ratio—4:1
• Genetic link: 3x more common in 1st degree relatives
• More common in patients with blood group O
• Associated with increased serum pepsinogen
• H. pylori infection common
• up to 95%
• Smoking is twice as common
Symptoms of duodenal ulcer disease:

➢epigastric pain 2 hours after meal or on a empty stomach or

during night

➢pyrosis

➢good nutrition

➢obstipation

➢seasonal dependence (spring, autumn)

Subjective Data
• Pain—”gnawing”, “aching”, or “burning”
• Duodenal ulcers: occurs 1-3 hours after a meal and may awaken
patient from sleep. Pain is relieved by food, antacids, or vomiting.
• Gastric ulcers: food may exacerbate the pain while vomiting
relieves it.
• Nausea, vomiting, belching, dyspepsia, bloating, chest
discomfort, anorexia, hematemesis, &/or melena may also
occur.
• Nausea, vomiting, & weight loss more common with Gastric ulcers
Objective Data
• Epigastric tenderness
• Guaiac-positive stool resulting from occult blood loss
• Succussion splash resulting from scaring or edema due to partial or
complete gastric outlet obstruction
• A succussion splash describes the sound obtained by shaking an individual
who has free fluid and air or gas in a hollow organ or body cavity.
• Usually elicited to confirm intestinal or pyloric obstruction.
• Done by gently shaking the abdomen by holding either side of the pelvis. A
positive test occurs when a splashing noise is heard, either with or without a
stethoscope. It is not valid if the pt has eaten or drunk fluid within the last
three hours.
Differential Diagnosis
• Neoplasm of the stomach
• Pancreatitis
• Pancreatic cancer
• Diverticulitis
• Non-ulcer dyspepsia (also called functional dyspepsia)
• Cholecystitis
• Gastritis
• GERD
• MI—not to be missed if having chest pain
Diagnostic Plan
• Stool for fecal occult blood
• Labs: CBC (R/O bleeding), liver function test, amylase, and lipase.
• H. Pylori can be diagnosed by urea breath test, blood test, stool
antigen assays, & rapid urease test on a biopsy sample.
• Upper GI Endoscopy: Any pt >50 yo with new onset of symptoms or
those with alarm markings including anemia, weight loss, or GI
bleeding.
• Preferred diagnostic test b/c its highly sensitive for dx of ulcers and allows
for biopsy to rule out malignancy and rapid urease tests for testing for H.
Pylori.
H.pylori testing

UBT Stool Ag Serology

• Accurate • Acceptsbility • Card test?
• Costly • Dx and F/up • ELISA IgM
• Availability • Rx affect it • Rx no effect
• Dx and F/up • Not for F/up
• Rx affect it
• C13 labeled
•
Peptic Ulcers:
Gastric & Dudodenal
Treatment Plan: H. Pylori
• Medications: Triple therapy for 14 days is considered the treatment of
choice.
• Proton Pump Inhibitor + clarithromycin and amoxicillin
• Omeprazole : 20 mg PO bid for 14 d or
Lansoprazole: 30 mg PO bid for 14 d or
Rabeprazole : 20 mg PO bid for 14 d or
Esomeprazole : 40 mg PO qd for 14 d plus
Clarithromycin : 500 mg PO bid for 14 and
Amoxicillin : 1 g PO bid for 14 d
• Can substitute Metronidazole 500 mg PO bid for 14 d if allergic to PCN
• In the setting of an active ulcer, continue qd proton pump inhibitor
therapy for additional 2 weeks.
• Goal: complete elimination of H. Pylori. Once achieved reinfection rates
are low. Compliance!
Treatment Plan: Not H. Pylori
• Neutralise secreted acid – Antacids
• Drugs that inhibit acid secretion
• Protect mucosa from damage
• Eradicate causative agent (H. pylori)
1. Neutralise secreted acid – Antacids

Bases that raise GI tract pH

Primarily salts of calcium, magnesium and aluminium

• Aluminium hydroxide
• Calcium carbonate
• Magnesium hydroxide or trisilicate
2. Drugs that inhibit acid secretion
Cholinergic nerve Mast-like cell Blood vessel

Acetylcholine Histamine Gastrin 1. H2R antagonists

[Ranitidine]

Parietal cell
3. Arachidonic acid
agonists
[Misoprostol]

2. Proton pump inhibitors

[Omeprazole]
3. Protect mucosa from damage

Agents that coat the mucosa and protect from acid irritation

- Bismuth subcitrate (colloidal suspension)

- Sucralfate (complex of aluminium hydroxide and sucrose)

Peptic Ulcer + sucralfate After 5 days of treatment

4. Eradicate causative agent (H. pylori)

• Most common cause of gastric ulcers.

• Infects ~ 30% population.
• Readily detected with ‘urea breath test’, blood
test (for antibodies).

H. Pylori invades the stomach

and duodenal lining, weakens the
resistance of the lining to acid
and stimulates acid secretion.
Local inflammation can also be
observed.
Lifestyle Changes
• Discontinue NSAIDs and use Acetaminophen for pain control if possible.
• Acid neutralized--Antacids
• Smoking cessation
• No dietary restrictions unless certain foods are associated with problems.
• Alcohol in moderation
• Men under 65: 2 drinks/day
• Men over 65 and all women: 1 drink/day
• Stress reduction
Prevention
• Consider prophylactic therapy for the following patients:
• Pts with NSAID-induced ulcers who require daily NSAID therapy
• Pts older than 60 years
• Pts with a history of PUD or a complication such as GI bleeding
• Pts taking steroids or anticoagulants or patients with significant comorbid
medical illnesses
• Prophylactic regimens that have been shown to dramatically reduce the risk of
NSAID-induced gastric and duodenal ulcers include the use of a prostaglandin
analogue or a proton pump inhibitor.
• Misoprostol 100-200 mcg PO 4 times per day
• Omeprazole 20-40 mg PO every day
• Lansoprazole 15-30 mg PO every day
Result of National NSAID Guideline
 PENGOBATAN DAN PENCEGAHAN GASTROENTEROPATI OAINS

Pasien dengan terapi OAINS atau antiplatelet (ASA atau clopidogrel)

Ya

Evaluasi faktor risiko saluran cerna

Test H. pylori Ya Riwayat ulkus berkomplikasi

(UBT, HpSA) Riwayat ulkus tanpa perdarahan
Bila (+) terapi
Pendarahan saluran cerna
Terapi dual antiplatelet
Terapi antikoagulan

Ya Tidak
Endoskopi SCBA dan atau SCBB
Lebih dari 1 faktor risiko:
(kalau fasilitas tersedia)
Usia ≥ 65 tahun
Penggunaan kortikosteroid
Dispepsia atau GERD
Ulkus di SCBA

Ya Tidak
PPI/Rebamipide/misoprostol***
PPI+Rebamipide//misoprostol*** Rebamipide/misoprostol***
 PENCEGAHAN GASTROENTEROPATI OAINS

Risiko Gastrointestinal
Rendah Sedang Tinggi
Risiko CV OAINS + OAINS + PPI/ Terapi alternatif
rendah* Rebamipide Rebamipide atau COX2 inhibitor
/misoprostol*** /misoprostol*** +PPI/ Rebamipide
/misoprostol***
Risiko CV Naproxen + PPI/ Naproxen + PPI/ Hindari OAINS atau
Rebamipide/ Rebamipide/ COX2 inhibitor
tinggi**
misoprostol*** misoprostol*** Terapi alternatif

* Risiko kardiovaskular (CV) rendah yaitu pasien-pasien yang tidak membutuhkan low dose
aspirin / clopidogrel
** Risiko kardiovaskular (CV) tinggi yaitu pasien-pasien yang membutuhkan low dose aspirin /
clopidogrel
*** Misoprostol sering menimbulkan efek samping berupa diare dan kram perut
Protective Effects of Prostaglandins

⚫ PGE2 and PGI2 synthesized by gastric mucosa

⚫ Acid-reducing effects
• Bind to EP3 receptors on parietal cells
• Decrease acid production
⚫ Cytoprotective effects
• Stimulation of mucin and bicarbonate
• Increase mucosal blood flow
⚫ Contrast with NSAIDS which diminish prostaglandin formation by
inhibition of cycloxygenase and lead to ulcer formation
 Effects of rebamipide on diclofenac-induced small-
intestinal mucosal breaks
Number of subject with mucosal injuries
10 p=0.023*
*Fisher’s exact test

6 Positive finding
multiple erosions
4 ulcer
bleeding
redness mucosa
2

0
Rebamipide placebo
Niwa, Goto, et al. J Gastroenterol 2008;43:270-6
Complications
• Perforation & Penetration—into pancreas, liver and retroperitoneal
space
• Peritonitis
• Bowel obstruction, Gastric outflow obstruction, & Pyloric stenosis
• Bleeding--occurs in 25% to 33% of cases and accounts for 25% of
ulcer deaths.
• Gastric CA
Surgery
• People who do not respond to medication, or who develop
complications:
• Vagotomy - cutting the vagus nerve to interrupt messages sent from the brain
to the stomach to reducing acid secretion.
• Antrectomy - remove the lower part of the stomach (antrum), which
produces a hormone that stimulates the stomach to secrete digestive juices. A
vagotomy is usually done in conjunction with an antrectomy.
• Pyloroplasty - the opening into the duodenum and small intestine (pylorus)
are enlarged, enabling contents to pass more freely from the stomach. May
be performed along with a vagotomy.
Evaluation/Follow-up/Referrals
• H. Pylori Positive: retesting for tx efficacy
• Urea breath test—no sooner than 4 weeks after therapy to avoid false
negative results
• Stool antigen test—an 8 week interval must be allowed after therapy.
• H. Pylori Negative: evaluate symptoms after one month. Patients
who are controlled should cont. 2-4 more weeks.
• If symptoms persist then refer to specialist for additional diagnostic
testing.
 Summary
▪ A peptic ulcer is a break in superficial epithelial cells
penetrating down to muscularis mucosa
▪ Duodenal > gastric ulcers
▪ Can be asymptomatic
▪ H pylori is a predominant risk factor
▪ H pylori diagnosed by c urea breath test, stool antigen or if
validated serology, treated with PAC500 or PMC250 regime
▪ Complications of PUD can lead to acute emergency of upper GI
bleed
 ALGORITME TERAPI
TUKAK PEPTIK BERDARAH
Perdarahan Tukak Peptik

Forest I Forest II a / b Forest IIc / III

PPI – I.V + PPI – I.V + PPI – ORAL tanpa

Endoskopi Terapeutik Endoskopi Terapeutik Endoskopi Terapeutik

Perdarahan berulang

Endoskopi Terapeutik Ulang Bedah

 Rebamipide Mechanisms of Action
↑ prostaglandin synthesis
Kleine A, et al：Dig Dis Sci 1993；38：1441-9
↑ mucus glycoprotein synthesis
Ishihara K, et al：Arzneim-Forsch/Drug Res 1992；42
↓ oxygen free radicals
Naito Y, et al：Free Radical Biol Med 1995；18：117-23
Yoshikawa T, et al：Arzneim-Forsch/Drug Res 1993；43
Han BG, et al：Pharmacol Res 1995；32：201-7
↓ neutrophil activity
Yoshida N, et al：Dig Dis Sci 1996；41：1139-44
Murakami K, et al：Dig Dis Sci 1997；42：319-25
↓ inflammatory cytokines
Aihara M, et al：Dig Dis Sci, in press
Fukuda T, et al：J Gastroenterol Hepatol 1997；12(suppl.)
Tetsuo Arakawa, MD, DMSc, FACG, AGAF. 2008, Professor and Chairman, Dpt. of
Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
 Theoretical Classification of Anti-Ulcer Agents

Offensive Factor Inhibitors Defensive Factor Enhancers

H2 -blocker
Proton-pump inhibitors
Anti-cholinergics
Muscarine antagonists
Cytoprotectants
Tissue repair enhancers
Mucus production/ secretion enhancers
Microcirculation improving agents
Prostaglandin

Anti Free Radicals

Anti Inflammatory Modulator

Mucosta
REBAMIPIDE
Anti Inflammatory Agent
40
T. Yoshikawa. Japan Inflammation Academy 1997
41
 Patofisiologi stress ulcer

Martindale, Robert G. Am J Health-Syst Pharm—Vol 62 May 15, 2005 Suppl 2