SlideShare utilise les cookies pour améliorer les fonctionnalités et les performances, et également pour vous montrer des publicités pertinentes. Si vous continuez à naviguer sur ce site, vous acceptez l’utilisation de cookies. Consultez nos Conditions d’utilisation et notre Politique de confidentialité.
SlideShare utilise les cookies pour améliorer les fonctionnalités et les performances, et également pour vous montrer des publicités pertinentes. Si vous continuez à naviguer sur ce site, vous acceptez l’utilisation de cookies. Consultez notre Politique de confidentialité et nos Conditions d’utilisation pour en savoir plus.
Interplay between H. pylori factors and the host response leads to chronic gastritis and persistent colonization. H. pylori binds to gastric epithelial cells through BabA and other adhesins249. In strains that carry the Cag pathogenicity island (Cag-PAI), a type IV secretory apparatus allows translocation of effector molecules such as CagA into the host cell, resulting in the production of interleukin (IL)-8 and other chemokines by epithelial cells. The secreted chemokines lead to the recruitment of polymorphonuclear cells (PMNs), resulting in inflammation. Injected CagA also associates with tight junctions and targets H. pylori to them. In the long term, CagA might cause disruption of the epithelial barrier and dysplastic alterations in epithelial-cell morphology. Disruption of junctions by CagA might also cause leakage of nutrients into the mucous layer245 and entry of bacterial VacA into the submucosa. VacA induces apoptosis in epithelial cells by reducing the mitochondrial transmembrane potential and inducing cytochrome c release, which might also contribute to the disruption of the epithelial barrier. Tumour-necrosis factor- (TNF-)-mediated apoptosis may also lead to disruption of the epithelial barrier. The chronic phase of H. pylori gastritis links an adaptive lymphocyte response with the initial innate response. Cytokines produced by macrophages, particularly IL-12, activate recruited cells — such as helper T cells (TH0, TH1 and TH2), which respond with a biased TH1 response, and B cells. Cytokines also alter the secretion of mucus, which contributes to H. pylori-induced disruption of the mucous layer, as they induce changes in gastric-acid secretion and homeostasis. H. pylori inhibits the host immune response by blocking the production of nitric oxide (NO) by macrophages and through the ability of VacA to interfere with the IL-2 signalling pathway in T cells (and therefore T-cell activation) by blocking transcription of the genes encoding IL-2 and its receptor, IL-2R (see main text for details). An intracellular pool of H. pylori may repopulate the mucous layer after cycles of extracellular clearance. Ig, immunoglobulin.
(iii) SabA (HopP). SabA mediates binding to sialic acidcontaining glycoconjugates (387, 529). H. pylori-induced gastric inflammation and gastric carcinoma are associated with the replacement of nonsialylated Lewis antigens by sialylated Lex and sialylated Lea (387, 480, 541). Thus, the role of SabA is probably during the chronic inflammatory and atrophic disease stages (387). Human granulocytes also carry sialylated carbohydrates on their surface, and as a consequence these cells are specifically recognized by SabA. In vitro binding of H. pylori to granulocytes results in the nonopsonic activation of these cells (639), potentially allowing the bacterium to control these cells. SabA also seems to be involved in the binding of the extracellular matrix protein laminin (672a).
Peptic ulcer disease
• 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
• Ulcers occur within the stomach and/or duodenum and are often
chronic in nature.
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
agents, or oxidative stress.)
• Trefoil factor family peptides
and cathelicidins, surface
cell protection and
Restitution (epithelial level)
• If the preepithelial barrier were
breached, gastric epithelial cells
bordering a site of injury can migrate
to restore a damaged region (
• This process occurs independent of
cell division and requires
uninterrupted blood flow and an
alkaline pH in the surrounding
• Epidermal (EGF), TGFα and basic
fibroblast growth factor (FGF),
modulate the process of restitution.
• Larger defects - require cell
• Epithelial cell regeneration is
regulated by prostaglandins and
growth factors such as EGF and TGF-
Prostaglandins E and I
• PGE receptors: EP1, 2, 3, 4
• In addition to stimulating
epithelial cells to release
more bicarbonate and
• prostaglandins can reduce
the permeability of the
epithelium and thus reduce
PI2 = Prostacyclin
IP = Prostacyclin receptor
Essentials of gastric secretion
• Basal acid production occurs in a circadian pattern
• Highest – night
• Lowest – morning hours
Why blocking only one receptor type
decreases acid secretion that activate
Regulation of gastric acid secretion
• 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
• Prepyloric area
• 90% of all DUs were associated with H.Pylori
• H.Pylori is present in only 30-60% of individuals
• 50-70% of those with DUs
• Abnormalities in resting and stimulated pyloric sphincter
pressure with a concomitant increase in
• Duodenal gastric reflux
• Bile acids, lysolecithin, and pancreatic enzymes may injure
• Delayed gastric emptying of solids
When GUs develop in the presence of minimal acid levels,
impairment of mucosal defense factors may be present.
Role of H. pylori
1. cag PAI
2. VacA vacuolating factor
3. Acid resistance
4. Adhesins and outer membrane proteins
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
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
1. Directly delivered to cell
2. Secreted VacA binds to
3. Directly taken up by cell
4. Taken up by pinocytosis
5. Form membrane channel
leakage of nutrients to
6. Pass through tight
Nature reviews Microbiology
Acid secretion ↓
3. Acid resistance
• H. pylori is able to colonize acidic gastric
• 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
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.
• 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.
• 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
• 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
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
• 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
• 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
• Complete symptom resolution at 3 months had a 98%
positive predictive value for successful eradication of Hp
• Persisting symptoms had only a 25% positive predictive
value for persisting Hp infection
• ~1/3 of Hp+ ulcer patients 1-3 years symptoms after
• 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
by duodenal ulcers and
normal or high gastric acid
• Type IV are found in the
cardia and low gastric
The surrounding mucosa is edematously swollen and no regenerating epithelium is
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
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
The 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
The 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’’
In several months to a few years, the redness is reduced to the color of the surrounding mucosa. This is
called ‘‘white scar’’
Endoscopic Stage Classification of Gastric Ulcer by Sakita-Miwa
Gastric ulcer stages using
a six-stage system
A1 (active stage 1) Ulcer that contains mucus coating, with marginal elevation because of
A2 (active stage 2) Mucus-coated ulcer with discrete margin and less edema than active
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
S1 (scar stage 1) Red scar with rough epithelialization without mucosal break
S2 (scar stage 2) White scar with complete re-epithelialization
World J Gastrointest Endosc. 2010 January 16; 2(1): 36–40.
Published online 2010 January 16. doi: 10.4253/wjge.v2.i1.36.
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
K25 – Gastric ulcer
K26 – 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
• 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
• 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
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.
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
• 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.
• Clinical algorithm for the
management of peptic ulcer
bleeding adopted at the Prince of
Wales Hospital, Hong Kong.
Management of Patients
with Ulcer Bleeding
American College of Gastroenterology – Practice guideline
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
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.
2015-04-07 79*UGIB – Upper GastroIntestinal Bleeding
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 hemoglobins
targeted 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).
Pre-endoscopicmedicaltherapy 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
8. Nasogastric or orogastric lavage is NOT REQUIRED in patients with UGIB for diagnosis,
prognosis, visualization, or therapeutic effect (Conditional recommendation).
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).
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]
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 they
reduce 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 yield
variable results and currently used clips have not been well studied (Conditional
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).
• 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
13. 14. 15.
Endoscopic hemostatic therapy
• 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
A. Initial endoscopic finding
B. Post state of epinephrine
injection+argon plasma coagulation
C. Re-bleeding occurred 2 days after
the initial endoscopic treatment
D. Second endoscopic therapy with
epinephrine injection+argon plasma
E. Post state of 2nd endoscopic therapy
endoscopy Figure 1, green
22. Routine second-look endoscopy, in which repeat endoscopy is performed 24 h
after initial endoscopic hemostatic therapy, is not recommended. (Conditional
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%
Long-term prevention of
recurrent bleeding ulcers
27, 28, 29, 30
25. Patients with high-risk stigmata (active bleeding, visible vessels, clots) should
generally be hospitalized for 3 days assuming no rebleeding and no other
reason for hospitalization. They may be fed clear liquids soon after endoscopy
26. Patients with clean-based ulcers may receive a regular diet and be discharged
after endoscopy assuming they are hemodynamically stable, their hemoglobin
is 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.
1.6 vs 14.8% recurrent ulcer
H.Pylori erad+PPI : Without PPI
• 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)
• S.J. Konturek et al, Brain-gut and appetite regulating hormones in the control of gastric secretion and mucosal
• Johannes G. Kusters et al, Pathogenesis of Helicobacter pylori Infection, CLINICAL MICROBIOLOGY REVIEWS,
July 2006, p. 449–490 Vol. 19, No. 3, 0893-8512/06/$08.000 doi:10.1128/CMR.00054-05
• Tadataka Yamada et al, Principles of clinical gastroenterology, 2008, chapter 7, pp99-120
• Nicholas J. Talley et al, Practice guidelines, Guidelines for the Management of Dyspepsia, American Journal of
Gastroenterology ISSN 0002-9270, 2005 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2005.00225.x
• Loren Laine, MD and Dennis M. Jensen, MD, Management of Patients With Ulcer Bleeding, Am J Gastroenterol
2012; 107:345–360; doi: 10.1038/ajg.2011.480; published online 7 February 2012
• Guillermo Gutierrez et al, Clinical review: Hemorrhagic shock, Critical Care 2004, 8:373-381 (DOI 10.1186/cc2851)