Peptic ulcer disease

Munkhtulga G.

2015

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Introduction

• Burning epigastric pain exacerbated by fasting and improved with meals is a symptom complex associated with peptic ulcer disease (PUD).

• An ulcer is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation.

• Ulcers occur within the stomach and/or duodenum and are often chronic in nature.

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№85 - 3,9

№91 - 3,6

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20th death cause of total

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Mucous

HCl, Intrinsic factor (pepsinogen, mucous)

Histamine

Pepsinogen

Mucosal defense

• 3 level barrier:1. Pre-epithelialPhysicochemical, mucus-HCO3-phospholipid layer

2. Epithelial

3. SubepithelialMicrovascular system, HCO3, micronutrients, oxygen

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Mucosal barrier – epithelial level

• Mucus production, epithelial

cell ionic transporters that

maintain intracellular pH

bicarbonate production, and

intracellular tight junctions.

• Heat shock proteins that

prevent protein denaturation

and protect cells (increased

temperature, cytotoxic

agents, or oxidative stress.)

• Trefoil factor family peptides

and cathelicidins, surface

cell protection and

regeneration.

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Restitution (epithelial level)

• If the preepithelial barrier were

breached, gastric epithelial cells

bordering a site of injury can migrate

to restore a damaged region (

restitution ).

• This process occurs independent of

cell division and requires

uninterrupted blood flow and an

alkaline pH in the surrounding

environment.

• Epidermal (EGF), TGFα and basic

fibroblast growth factor (FGF),

modulate the process of restitution.

• Larger defects - require cell

proliferation.

• Epithelial cell regeneration is

regulated by prostaglandins and

growth factors such as EGF and TGF-

α.

• Angiogenesis

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Prostaglandins (epithelial defence)

• Regulate release of mucosal HCO3, mucus

• Inhibit parietal cell secretion

• Maintain mucosal blood flow, epithelial restitution

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Prostaglandins E and I

• PGE receptors: EP1, 2, 3, 4

• In addition to stimulating epithelial cells to release more bicarbonate and mucus,

• prostaglandins can reduce the permeability of the epithelium and thus reduce acid back-diffusion

PI2 = ProstacyclinIP = Prostacyclin receptor

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Nytric oxide (NO)

• Stimulate gastric mucus

• Increase mucosal blood flow

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Essentials of gastric secretion

• Basal acid production occurs in a circadian pattern• Highest – night

• Lowest – morning hours

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Why blocking only one receptor type decreases acid secretion that activate different ways?

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Regulation of gastric acid secretion

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Ulcer

• Ulcers are defined as breaks in the mucosal surface >5 mm in size, with depth to the submucosa.

• Duodenal ulcers (DU)• 1st portion of duodenum (95%) with ~90% located within

3 cm of pylorus• Usually ≤1 cm (3-6cm, giant ulcer)

• Gastric ulcers (GU)• Distal to junction between antrum and acid secretory

mucosa• Prepyloric area

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H. Pylori

• 90% of all DUs were associated with H.Pylori

• H.Pylori is present in only 30-60% of individuals with GUs

• 50-70% of those with DUs

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Gastric ulcer

• Abnormalities in resting and stimulated pyloric sphincter pressure with a concomitant increase in

• Duodenal gastric reflux

• Bile acids, lysolecithin, and pancreatic enzymes may injure gastric mucosa

• Delayed gastric emptying of solids

When GUs develop in the presence of minimal acid levels, impairment of mucosal defense factors may be present.

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Role of H. pylori Virulence Factors

1. cag PAI

2. VacA vacuolating factor

3. Acid resistance

4. Adhesins and outer membrane proteins

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1. Cytotoxin associated gene A (CagA)

• 140kD, highly immunogenic

• Encoded by cagA gene – 50-70% of H.pylori strains

• CagA+ strains higher inflammatory PUD, G.cancer

• Type-IV secretion apparatus (syringe like structure)• CagA, Peptidoglycan and others

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Src kinasemediates

Lifelong colonization of the hostCagA эсэд транслокацилагдан орсны дараа EPIYA motif /Glu-Pro-Ile-Tyr-Ala/ хэмээх амин хүчлүүдийн дараалалынхаа тирозин а/х дээр Src бүлгийн киназа ферментийн оролцоотойгоор фосфорждог.Гэхдээ эргээд CagA нь Src киназа ферментээ дарангуйлах нөлөө үзүүлснээр сөрөг эргэх холбооны механизм адил байгаа бөгөөд энэ нь яагаад H.Pylori маш удаанаар оршин тогтнодгийг тайлбарлаж байна.

carcinogenesis2015-04-07 23

2. Vac A – vacoulating cytotoxin

• 50% of all H. Pylori strain secrete

• 95 kD

• Membrane channel formation

• Disruption of endosomal and lysosomal activity

• Effect on integrin R-induced cell signaling

• Interference with cytoskeleton-dependent cell function

• Induction of apoptosis

• Immune modulation

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1. Directly delivered to cell

2. Secreted VacA binds to surface R

3. Directly taken up by cell

4. Taken up by pinocytosis

5. Form membrane channel leakage of nutrients to ECS

6. Pass through tight junction

Nature reviews Microbiology

Acid secretion ↓

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3. Acid resistance

• H. pylori is able to colonize acidic gastric environment

• Bacterium is not acidophile

• pH of gastric mucosa 4-6.5

• Growth occurs pH5.5-8.0

• Brief exposure to pH<4

• UREASE Ammonia pH↑ (neutralize)• Also associated with outer membrane

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3. Acid resistance

• Ammonia cytotoxic to epithelium

• HCO3 suppress bactericidal effect of peroxynitrite, nitric oxide metabolite

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4. A

dh

es

ins

OipA - Proinflammatoryresponse-inducing protein

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Pathophysiology – H.pylori

• Chronic active gastritis – 10-15% PUD

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Summary of bacterial factors

• Vac A:

• CD4 T cells inhibiting their proliferation

• disrupt normal function of B cells, CD8 T cells, macrophages and mast cells.

• CagA+ strains higher inflammatory PUD, G.cancer

• Urease NH3 epithelial cell

• Surface factors that are chemotactic for neutrophils and monocytes,

which in turn contribute to epithelial cell injuries.

• H. pylori makes proteases and phospholipases that break down the

glycoprotein lipid complex of the mucous gel, thus reducing the efficacy

of this first line of mucosal defense.

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Host factors

• Genetic predisposition

• Recruitment of neutrophils, lymphocytes (T and B),

macrophages, and plasma cells

• ↑ cytokines in the gastric epithelium: (IL1α/β, IL-2, IL-6, IL-

8, TNFα, and IFN-γ).

• Mucosal and a systemic humoral response, which does not

lead to eradication of the bacteria but further compounds

epithelial cell injury.

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Duodenal ulceration

• The reason - unclear.

• H. pylori - may be more virulent.

• Certain specific bacterial factors such as the duodenal ulcer-

promoting gene A ( dupA ), may be associated

• Gastric metaplasia high acid exposure, permits H. pylori to bind to it

and produce local injury secondary to the host response.

• H. pylori antral infection could lead to increased acid production,

increased duodenal acid, and mucosal injury.

• Basal and stimulated [meal, gastrin-releasing peptide (GRP)] gastrin

release are increased, and somatostatin secreting D cells may be

decreased. 2015-04-07 34

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NSAIDs induced PUD

Risk factors

• Cigarette smoking

• Decrease healing rates, impair response to therapy, and increase

ulcer-related complications such as perforation. The mechanism

responsible for increased ulcer diathesis in smokers is unknown.

• gastric emptying, decreased proximal duodenal bicarbonate

production, increased risk for H. pylori infection, and cigarette-

induced generation of noxious mucosal free radicals

• Genetic predisposition, Increased frequency of blood

group O

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Risk factors

• Psychological stress

• Diet

• Specific chronics:

• Strong association: systemic mastocytosis, chronicpulmonary disease, chronic renal failure, cirrhosis,nephrolithiasis, and α 1 -antitrypsin deficiency.

• Possible association: (1) hyperparathyroidism, (2) coronary artery disease, (3) polycythemia vera, and (4) chronic pancreatitis

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DIAGNOSIS

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Burning epigastric “hunger” pain

tends to occur when acid is secreted in the absence

of food buffer (e.g., 2–3 h after meals) and at night, usually

between 23.00 and 02.00

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• Pain rarely occurs before breakfast.

• Alkali, food, and antisecretory agents produce relief such that “classic” patients tend to “feed” their ulcers.

• Not specific for PUD

• Asymptomatic

• Food relief is more likely to occur with peptic ulcer,

• Food provocation of symptoms (postprandial pain or food intolerance) and nausea have negative predictive value for underlying PUD

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GERD

• Complete symptom resolution at 3 months had a 98% positive predictive value for successful eradication of Hpinfection

• Persisting symptoms had only a 25% positive predictive value for persisting Hp infection

• ~1/3 of Hp+ ulcer patients 1-3 years symptoms after Hp eradication

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Complaints

• Loss of appetite

• Chest heartburn

• Belching

• Acidy regurgitation

• Hematemesis: bloody vomitus

• Melena: tarry stool passage

• Maroon: tarry- bloody stool passage

• Hematochezia: bloody stool passage

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Physical examination:

• Inspection: pale, weight loss, coating of tongue …

• Palpation: left or epigastric tenderness, pain radiation, Vasilenko’s sign

• Percusion: Mendel’s sign

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Laboratory

• CBC: Anemic signs, inflammatory sign ±

• Biochemistry: Gastrin ↑, secretin and somatostatin ↓

• Immunology: H.Pylori +

• Gregerson test +

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Gastric ulcer

• Type I: gastric body, low gastric acid production;

• Type II: antrum and gastric acid can vary from low to normal;

• Type III occur within 3 cm of the pylorus and are commonly accompanied by duodenal ulcers and normal or high gastric acid production

• Type IV are found in the cardia and low gastric acid production.

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Stages Manifestation

Active stage

A1The surrounding mucosa is edematously swollen and no regenerating epithelium isseen endoscopically

A2

The surrounding edema has decreased, the ulcer margin is clear, and a slight amount of regenerating epithelium is seen in the ulcer margin. A red halo in the marginal zone and a white slough circle in the ulcer margin are frequently seen. Usually, converging mucosal folds can be followed right up to the ulcer margin

Healing stage

H1

The white coating is becoming thin and the regenerating epithelium is extending into the ulcer base. The gradient between the ulcer margin and the ulcer floor is becoming flat. The ulcer crater is still evident and the margin of the ulcer is sharp. The diameter of the mucosal defect is about one-half to twothirds that of A1

H2The defect is smaller than in H1 and the regenerating epithelium covers most of the ulcer floor. The area of white coating is about a quarter to one-third that of A1

Scarring stage

S1The regenerating epithelium completely covers the floor of ulcer. The white coating has disappeared. Initially, the regenerating region is markedly red. Upon close observation, many capillaries can be seen. This is called ‘‘red scar’’

S2In several months to a few years, the redness is reduced to the color of the surrounding mucosa. This is called ‘‘white scar’’

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Endoscopic Stage Classification of Gastric Ulcer by Sakita-Miwa

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Gastric ulcer stages using a six-stage system

Stage FindingA1 (active stage 1) Ulcer that contains mucus coating, with marginal elevation because of

edema

A2 (active stage 2) Mucus-coated ulcer with discrete margin and less edema than active stage 1

H1 (healing stage 1) Unhealed ulcer covered by regenerating epithelium < 50%, with or without converging folds

H2 (healing stage 2) Ulcer with a mucosal break but almost covered with regenerating epithelium

S1 (scar stage 1) Red scar with rough epithelialization without mucosal break

S2 (scar stage 2) White scar with complete re-epithelialization

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World J Gastrointest Endosc. 2010 January 16; 2(1): 36–40.

Published online 2010 January 16. doi: 10.4253/wjge.v2.i1.36.

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Forrest classification system with predictive prognosis

Forrest ClassificationRebleeding Incidence

Surgical Requirement

Incidence of Death

Type I: Active BleedIa: Spurting BleedIb: Oozing Bleed

55-100% 35% 11%

Type II: Recent BleedIla: Non-Bleeding Visible Vessel (NBVV)Ilb: Adherent Clot

40-50% 34% 11%

20-30% 10% 7%

Type III: Lesion without BleedingFlat SpotClean Base

10% 6% 3%

5% 0.5% 2%

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Tactic

• AI, Forrest Ia, Ib, IIa Department of surgery

• AII, Forrest IIb, III Department of Gastroenterology

• H-I, H-II, Forrest III Home

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Forrest Ia ulcer bleeding in a small gastric ulcer

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Arterial hemorrhage (Forrest Ia) from

an ulcer on top of a submucous tumor of the gastric body

A: A spurting bleeding of the gastric ulcer (Forrest Ia)

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B. Oozing bleeding of the gastric ulcer (Forrest Ib);

C: Non-bleeding visible vessel of the gastic ulcer (Forrest IIa).

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A. Active pumping

B. Active oozing

C. Vessel exposure

D. Red or black clot

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Radiology of PUD

• http://radiopaedia.org/articles/peptic-ulcer-disease

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gastric ulcer with bull's eye sign

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Benign gastric ulcer

gastric ulcer

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Benign Antral UlcerDuodenal ulcer

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Double-contrast upper gastrointestinal series. Posterior

wall duodenal ulcer.Lateral view of a posterior wall ulcer

in the same patient

Duodenal ulcer in imaging: http://emedicine.medscape.com/article/367878-overview

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• Stomach acid test• Atropine test

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1. Ходоодны шүүрлийн шинжилгээ хийх заалт

Туйлын заалт: Мэс заслын дараах дахисан шарх, залгадас дээрх шархлаа (анастомозын

шарх) (*PAO>15ммол/цаг) Zollinger-Ellison syndrome сэжиглэсэн тохиолдол, G эсийн гиперплази,

гиперпаратиреодизм (**ВАО>15ммол/цаг, ВАҮ/РАО<0.6)Харьцангуй заалт: Мэс заслын хэлбэрийг сонгох Мэс заслын дараах үр дүнг хянах Пернициоз анемиг сэжиглэх

2. Гастрины сорил хийх заалт (секретин судсаар)

• Zollinger-Ellison syndrome сэжиглэсэн тохиолдол (сийвэнгийн гастрин >100% ихсэнэ)

• G эсийн гиперплази сэжиглэсэн тохиолдол (сийвэнгийн гастрин <50% ихсэнэ)

K25 – Gastric ulcerK26 – Duodenal ulcer

.0 Acute with haemorrhage

.1 Acute with perforation

.2 Acute with both haemorrhage and perforation

.3 Acute without haemorrhage or perforation

.4 Chronic or unspecified with haemorrhage

.5 Chronic or unspecified with perforation

.6 Chronic or unspecified with both haemorrhage and perforation

.7 Chronic without haemorrhage or perforation

.9 Unspecified as acute or chronic, without haemorrhage or perforation

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4545

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Ulcer Healing

• Repair of ulcers is that involves inflammation, cell proliferation

(particularly at the ulcer margin), formation of granulation tissue

at the base of the ulcer, and angiogenesis (new blood vessel

growth).

• In response to ulceration, a new type of cell appears in the ulcer

margin which secretes large amounts of epithelial growth factor

(EGF), acting as a potent stimulus for reepithelialization.

• Glandular structure is gradually reestablished, along with the

mucosal microcirculation.

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Ulcer healing - Platelet

• Platelets contribute significantly to ulcer healing, at least in part

through the delivery of numerous growth factors that can

promote angiogenesis and epithelial cell proliferation.

• Of course, platelets are also an important element in hemostasis,

and bleeding of ulcers is a very important clinical concern.

• Some of the clinical benefit of drugs that suppress gastric acid

secretion may be related to a facilitation of platelet

aggregation; thus platelet aggregation will not occur at a pH <5.4.

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Ulcer healing - PGs

• Prostaglandins also trigger the release of vascular endothelial

growth factor (VEGF), which has been shown to make an

important contribution to ulcer healing, likely via stimulation of

angiogenesis.

• Selective COX-2 inhibitors impair gastric ulcer healing, and

mice deficient in COX-2 exhibit impaired ulcer healing. The

beneficial effects of PGE2 on gastric ulcer healing in rodents

appear to be mediated via the EP4 receptor.

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• Clinical algorithm for the management of peptic ulcer bleeding adopted at the Prince of Wales Hospital, Hong Kong.

• 2006

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Management of Patients with Ulcer Bleeding

American College of Gastroenterology – Practice guideline 2012

The American Journal of GASTROENTEROLOGY

2015-04-07 78Am J Gastroenterol 2012; 107:345–360; doi: 10.1038/ajg.2011.480; published online 7 February 2012

Includes:

Initial management of UGIB*

1. Initial assessment and risk stratification,

2. Pre-endoscopic use of medications

3. Gastric lavage

4. Timing of endoscopy.

Endoscopic and medical management of ulcer disease:

5. Endoscopic findings and their prognostic implications,

6. Endoscopic hemostatic therapy

7. Post-endoscopic medical therapy and disposition

8. Prevention of recurrent ulcer bleeding.

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Init

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str

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1. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed (Strong recommendation).

2. Blood transfusions should target hemoglobin ≥ 7 g / dl, with higher hemoglobinstargeted in patients with clinical evidence of intravascular volume depletion or comorbidities, such as coronary artery disease (Conditional recommendation).

3. Risk assessment should be performed to stratify patients into higher and lower risk categories and may assist in initial decisions such as timing of endoscopy, time of discharge, and level of care (Conditional recommendation).

4. Discharge from the emergency department without inpatient endoscopy may be considered in patients with urea nitrogen < 18.2 mg / dl; hemoglobin ≥ 13.0 g / dl for men (12.0 g / dl for women), systolic blood pressure ≥ 110 mm Hg; pulse < 100 beats / min; and absence of melena, syncope, cardiac failure, and liver disease, as they have < 1 % chance of requiring intervention (Conditional recommendation).

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Pre

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5. Intravenous infusion of erythromycin (250 mg ~ 30 min (20-60min) before endoscopy) should be considered to improve diagnostic yield and decrease the need for repeat endoscopy. However, erythromycin has not consistently been shown to improve clinical outcomes (Conditional recommendation). IMPROVE VISUALIZATION AT EGD, ↓ 2ND EGD

6. Pre-endoscopic intravenous PPI (e.g., 80 mg bolus followed by 8 mg / h infusion) may be considered to decrease the proportion of patients who have higher risk stigmata of hemorrhage at endoscopy and who receive endoscopic therapy. However, PPIs do not improve clinical outcomes such as further bleeding, surgery, or death (Conditional recommendation).

7. If endoscopy will be delayed or cannot be performed, intravenous PPI is recommended to reduce further bleeding (Conditional recommendation).

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Gastric lavage

8. Nasogastric or orogastric lavage is NOT REQUIRED in patients with UGIB for diagnosis, prognosis, visualization, or therapeutic effect (Conditional recommendation).

Tim

ing

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9. Patients with UGIB should generally undergo endoscopy within 24 h of admission, following resuscitative efforts to optimize hemodynamic parameters and other medical problems (Conditional recommendation).

10. In patients who are hemodynamically stable and without serious comorbidities endoscopy should be performed as soon as possible in a non-emergent setting to identify the substantial proportion of patients with low-risk endoscopic findings who can be safely discharged (Conditional recommendation).

11. In patients with higher risk clinical features (e.g., tachycardia, hypotension, bloody emesis or nasogastric aspirate in hospital) endoscopy within 12 h may be considered to potentially improve clinical outcomes (Conditional recommendation).

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End

osc

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dia

gno

sis 12. Stigmata of recent hemorrhage should be recorded as they predict risk of further

bleeding and guide management decisions. [active spurting, non-bleeding visible vessel, active oozing, adherent clot, flat pigmented spot, and clean base] (Strong recommendation). [table 3]

End

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16. Epinephrine therapy should not be used alone. If used, it should be combined with a second modality (Strong recommendation).

17. Thermal therapy with bipolar electrocoagulation or heater probe and injection of sclerosant (e.g., absolute alcohol) are recommended because theyreduce further bleeding, need for surgery, and mortality (Strong recommendation).

18. Clips are recommended because they appear to decrease further bleeding and need for surgery. However, comparisons of clips vs. other therapies yieldvariable results and currently used clips have not been well studied (Conditional recommendation).

19. For the subset of patients with actively bleeding ulcers, thermal therapy or epinephrine plus a second modality may be preferred over clips or sclerosant alone to achieve initial hemostasis (Conditional recommendation).

12.

• Serious bleeding does not occur from an erosion due to absence of vessels in the mucosa

• When ulcer erodes into vessels in submucosa or deeper

• Ulcer surface area dimensions or diameter can be estimated with the use of a device of known dimension, such as an open biopsy forceps.

• Ulcers larger than 1 – 2 cm are associated with increased rates of further bleeding with conservative therapy and aft er endoscopic therapy

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12.

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13. 14. 15.

20. 20.

21.

Decrease re-bleeding, surgery and mortality

Endoscopic hemostatic therapy

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• Bipolar accessories complete a circuit without the use of a grounding pad. (a) Schematic of bipolar circuit; (b) Bipolar hemostasis probe with active and return electrodes closely spaced at the probe's tip

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A. Initial endoscopic findingB. Post state of epinephrine

injection+argon plasma coagulationC. Re-bleeding occurred 2 days after

the initial endoscopic treatmentD. Second endoscopic therapy with

epinephrine injection+argon plasma coagulation

E. Post state of 2nd endoscopic therapy

91

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AFT

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Figure 1, greenR

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22. Routine second-look endoscopy, in which repeat endoscopy is performed 24 h after initial endoscopic hemostatic therapy, is not recommended. (Conditional recommendation).

23. Repeat endoscopy should be performed in patients with clinical evidence of recurrent bleeding and hemostatic therapy should be applied in those with higher risk stigmata of hemorrhage (Strong recommendation).

24. If further bleeding occurs after a second endoscopic therapeutic session, surgery or interventional radiology with transcathether arterial embolization is generally employed (Conditional recommendation).

2nd look EGD significant reduction in rebleeding with no significant benefit in reducing SURGERY OR DEATH

Single Endoscopy + high dose IV PPI vs 2nd EGD without PPI rebleeding 8,2 vs 8,7%

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Long-term prevention of recurrent bleeding ulcers

Figure 227, 28, 29, 30

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25. Patients with high-risk stigmata (active bleeding, visible vessels, clots) should generally be hospitalized for 3 days assuming no rebleeding and no otherreason for hospitalization. They may be fed clear liquids soon after endoscopy (Conditional recommendation).

26. Patients with clean-based ulcers may receive a regular diet and be discharged after endoscopy assuming they are hemodynamically stable, their hemoglobinis stable, they have no other medical problems, and they have a residence where they can be observed by a responsible adult (Strong recommendation).

Figure 2 . Recommended management to prevent recurrent ulcer bleeding based on etiology of ulcer bleeding.

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1.6 vs 14.8% recurrent ulcerH.Pylori erad+PPI : Without PPI

Recurrent bleeding risk

• H.Pylori (+) bleeding ulcer 12 months recurrent bleeding 26%

• NSAIDs user + H.Pylori (+) with bleeding ulcer only H.Pylori eradication ulcer healing 6 months recurrent bleeding 19%

• Low dose aspirin + H.pylori (+) 15%

• Idiopathic bleeding ulcers 7 ys 42%

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Recommendation for PPI usage

• PPIs can cause falsely negative H.pylori in 1/3 cases

• PPIs should be discontinued 2 weeks before testing

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NSAIDs ulcer

• Celecoxib vs Diclofenac+PPIs 6 ms 4.8 : 6.4% recurrent bleeding

• Recurrent ulcer 19 : 26%

• [Celecoxib + PPIs bid] vs [Celecoxib+placebo[ 0 vs 8.9%

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Medication Cost Cost for CI x 72 hours

IV pantoprazole (Protonix®)

Bolus: 80 mg

CI: 8 mg/hr

$55.00

$132.00/day

N/A

$396.00

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Table 3: Average Wholesale Price (AWP) of IV Pantoprazole22

• Clinical algorithm for the management of peptic ulcer bleeding adopted at the Prince of Wales Hospital, Hong Kong.

• 2006

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Uncomplicated ulcer

• Regimen (inpatient or outpatient)

• Diet: 3-4 hours apart, 5-7 times/day• Bleeding risk: food denial for 24h

• H.Pylori eradication

• Acid reducing agents and gastroprotector: PPIs, H2RA• 6-8weeks – gastric ulcer

• 4-6 weeks – duodenal ulcer

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Drugs used in Tx of PUD

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Complication of PUDAcute hemorrhage

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Nonshock state

preterminal

event

Blood transfuse!Restoration of IV fluid

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6100₮7800₮

12500₮

13500₮

23100₮

650₮

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4,550 ₮

54,000 ₮

2,300 ₮

1,600 ₮

6,500 ₮

Мизопростол 200мкг – 3500 ₮

Reference:• Г.Энхдолгор, Н.Бира, Х.Оюунцэцэг нар, Хоол боловсруулах эрхтэний эмгэг, 2014 он, ху214-244

• Harrison’s Principles of Internal Medicine, 18th ed, volume 2, part 14, section 1, chapter 293, pp2438-2459

• Watson et al. Gastrin — active participant or bystander in gastric carcinogenesis?, Nature Reviews Cancer 6, 936–

946 (December 2006) | doi:10.1038/nrc2014

• John L. Wallace, Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn't the Stomach Digest Itself?

Physiol Rev 88: 1547–1565, 2008; doi:10.1152/physrev.00004.2008.

• Koji Takeuchi et al, Prostaglandin EP Receptors Involved in Modulating Gastrointestinal Mucosal Integrity, J

Pharmacol Sci 114, 248 – 261 (2010)

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Thank you for your attention!

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