Θεόδωοξπ ΡξκκάπMD, PhD(U.K.), FACG, FEBG, AGAF

Δμτής Γαστρεμτερολογικής Κλιμικής

Νοσοκομείο ΄΄Ερρίκος Ντυμάμ΄΄

Τι νεώτερο προτείνει η Συμφωνία Maastricht IV για τοΕλίκοβακτηρίδιο του πυλωρού;

Helicobacter pylori Timeline

• Early 1900’s: Discovery of human gastric bacteria

• 1920-1980: Rediscovery of gastric bacteria

• 1982: Isolation and culture of C.pyloridis by Marshall and Warren

• 1987: Eradication reduces DU reccurence

• 1989: Bacteria are renamed H.pylori

• 1990’s: Association of H.pyloriwith Gastric cancer and MALT lymphoma

• 1997: Complete genome sequence of H.pylori.

Helicobacter PIONEERS

Barry Marshall and Robin Warren in July 1984

The Nobel Prize in Physiology or Medicine 2005

Press Release: The 2005 Nobel Prize in Physiology or Medicine

3 October 2005

The Nobel Assembly at Karolinska Institute has today decided to award

The Nobel Prize in Physiology or Medicine for 2005

jointly to

Barry J. Marshall and J. Robin Warren

for their discovery of

"the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"

The three recent major steps in

Gastroenterology

• Strong antisecretory

factors

• Progress in GI endoscopy

• H.pylori isolation

PPI

CH2

O

S

CH3 OCH2CF3

Number of publications related to

H.pylori

1984

1986

1989

1995

2000 2005

Year

50

1500

Number of papers

EUROPEAN HELICOBACTER STUDY GROUP (EHSG)

Current Concepts in the Management of H.pylori infection.

The Maastricht 1-1996, 2-2000, 3-2005, 4-2010 Consensus Reports.

MAASTRICHT IVMarch 16-18 2010, Florence, Italy

50 participants

25 countries

Gastroenterologists, GPs, Pathologists, Microbiologists

MAASTRICHT IV Consensus Report

ΔΙΑΔΙΚΑΣΙΑ (Ι)

Aλαζθνπήζεθαλ νη πξόζθαηεο γλώζεηο από

εηδηθνύο ζηνπο ζρεηηθνύο ηνµείο έξεπλαο πξηλ ηεζεί

µία ζεηξά νπζηαζηηθώλ εξσηεκάησλ.

Τα δεηήµαηα κειεηήζεθαλ από ηξεηο νµάδεο

εξγαζίαο.

ΔΙΑΔΙΚΑΣΙΑ (ΙΙ)Η θάζε νµάδα εξγαζίαο:

• κειέηεζε µία εηδηθή έλλνηα, ζέµα ή δήηεµα• δηαηύπσζε ηελ νµόθσλε δήισζε ή ζύζηαζή ηεο • δήισζε ηε βαξύηεηα ηεο δήισζεο ή ζύζηαζεο

(ζπληζηάηαη αλεπηθύιαθηα, ζπληζηάηαη, αβέβαηε) • θαηέηαμε ηε βαξύηεηα ησλ ελδείμεσλ πνπ ππνζηήξηδαλ ηε

δήισζε ή ζύζηαζε (αλαµθίβνιε, ππνζηεξηθηηθή ή αζαθήο)

• πεξηέγξαςε ηελ αηηηνινγία ηεο δήισζεο ή ζύζηαζεο.

Κάθε οµάδα εργαζίας παροσζίαζε ηις ζσζηάζεις ηης ζηην ολομέλεια για ζσζήηηζη και ζηη ζσνέτεια με υηθοθορία ζσμθφνήθηκαν οι ηελικές οµόθφνεςζσζηάζεις.

Timer Votes

1. I agree

2. I don’t agree

Question: Is a period of 4-6 weeks sufficient for follow-up after the end of H. pylori treatment?

Statement: The time for follow-up after the end of eradication therapy should be at least 4 weeks.

Evidence Level: 1 Grade of Recommendation: A

ΔΙΑΔΙΚΑΣΙΑ (ΙΙI)

Values in percentages

95,6

4,4

0

25

50

75

100

I agree I don't agree

Question: Is a period of 4-6 weeks sufficient for follow-up after the end of H. pylori treatment?

Statement:The time for

follow-up after the end of eradication

therapy should be at least 4

weeks.

ΔΙΑΔΙΚΑΣΙΑ (ΙV)

Grade of recommendation Evidence level Type of studies

A 1 1a Systematic review of randomized

controlled trials (RCT) of good

methodological quality and with

homogeneity

1b Individual RCT with narrow

confidence interval

1c Non-controlled studies

B 2 2a Systematic review of cohort

studies (with homogeneity)

2b Individual cohort studies

(including low quality RCT, eg ,80%

follow-up)

2c Non-controlled cohort

studies/ecological studies

3 3a Systematic review of case-control

studies (with homogeneity)

3b Individual case-control studies

C 4 Case series/poor quality cohort or

case-control studies

D 5 Expert opinion without explicit

critical appraisal or based on

physiology, bench research or ‘‘first

principles’’

Gut 2012;61:646

Current concepts in the management of Helicobacter pylori infection –The

Maastricht IV Consensus Report

P. MALFERTHEINER, F. MEGRAUD, C. O'MORAIN, F.

BAZZOLI, E. EL-OMAR, D. GRAHAM, R. HUNT,

T. ROKKAS, N. VAKIL, E. KUIPERS

& THE EUROPEAN HELICOBACTER STUDY GROUP (EHSG)

Current concepts in the management of

Helicobacter pylori infection –The

Maastricht IV Consensus Report

60 Statements on:

• Epidemiology

• Diagnosis

• Pathogenesis

• Management

• Carcinogenesis

Diagnosis

Treatment

Carcinogenesis

Diagnosis

Statement : The diagnostic accuracy of the stool

antigen test is equivalent to Urea Breath Test if a

validated laboratory-based monoclonal test is used.

Evidence level: 1a Grade of Recommendation: A

Πεπηηθό έιθνο (ελεξγό ή όρη)

Επηπεπιεγκέλν πεπηηθό έιθνο (αηκνξξαγία)

Χαµειήο θαθνεζείαο γαζηξηθό ιέµθσµα (MALT)

Σνβαξνύ βαζκνύ αηξνθηθή γαζηξίηηδα

Μεηά από αθαίξεζε πξώηµνπ γαζηξηθνύ θαξθίλνπ

Οηθνγελεηαθό ηζηνξηθό γαζηξηθνύ θαξθίλνπ (ζηξαηεγηθή search

and treat ζε πξώηνπ βαζκνύ ζπγγελείο παζρόλησλ)

Επηζπµία ηνπ αζζελνύο (κεηά από πιήξε εμήγεζε από ηνλ

ζεξάπνληα ηαηξό)

Πξνγξαµµαηηδόµελε καθξά ζεξαπεία µε µε ζηεξνεηδή

αληηθιεγµνλώδε θάξµαθα

Ιδηνπαζήο ζξνκβνπεληθή πνξθύξα θαη αλεμήγεηε ζηδεξνπεληθή

αλαηκία

Maastricht IV

Ιρυσοή ρύρςαρη θεοαπείαπ εκοίζωρηπ ςξσ H.pylori

(Level of scientific Evidence1a,1b,1c, Grade of

recommendation A)

Συεςική ρύρςαρη θεοαπείαπ εκοίζωρηπ ςξσ H.pylori

(μεραίξσ βαθμξύ βιβλιξγοατική σπξρςήοινη

Grade of recommendation Β, Evidence level 2,3)

• Δπζπεςία (µεηά από πιήξε δηεξεύλεζε γηα άηνκα >45 εηώλ, θαη εκπεηξηθά γηα ηνπο <45 εηώλ (ζηξαηεγηθή test and treat κεηά από αλίρλεπζε ηνπ κηθξνβίνπ κε κε αηκαηεξή δνθηκαζία)

• Πξνγξαµµαηηδόµελε ή εθαξµνδόµελε καθξά αγσγή µε αλαζηνιείο ηεο αληιίαο πξσηνλίσλ γηα γαζηξννηζνθαγηθή παιηλδξόµεζε

• Εθαξµνδόµελε ζεξαπεία µε µε ζηεξνεηδή αληηθιεγµνλώδε θάξµαθα

Αρθεμήπ ρύρςαρη θεοαπείαπ εκοίζωρηπ ςξσ H.pylori(υαμηλξύ βαθμξύ βιβλιξγοατική σπξρςήοινη

Grade of recommendation C,D, Evidence level 4,5)

• Πξόιεςε γαζηξηθνύ θαξθίλνπ ελ απνπζία παξαγόλησλ

θηλδύλνπ

• Αζπµπησµαηηθά άηνµα

• Νόζνο εθηόο ηνπ πεπηηθνύ (εθηόο ησλ πξναλαθεξζέλησλ

αηκαηνινγηθώλ λνζεκάησλ).

Recommended therapies for Helicobacter pylori eradication

Regions with low ClariR

prevalence (<20%)

Regions with high ClariR

prevalence(>20%)

1st linePPI-Clari-

Amoxicillin/Metronidazole or

non Bismuth quadruple or

Bismuth Quadruple

Bismuth Quadruple

(if not available:

non-Bismuth Quadruple (either

sequential or concomitant)

2nd lineBismuth Quadruple

or

PPI-Levofloxacin/Amoxicillin

PPI-Levofloxacin/Amoxicillin

3rd line Based on susceptibility testing only

H. pylori and MALT lymphoma

Statement : H. pylori eradication is the first line treatment for

low-grade gastric MALT lymphoma.

Evidence Level: 1a Grade of Recommendation: A

H. pylori and Atrophy / Intestinal

Metaplasia

Statement 11: There is accumulating evidence that following H. pylori eradication, corpus function may improve. However, whether this is associated with regression of atrophic gastritis remains equivocal.

Evidence Level: 2a Grade of Recommendation: B

Statement 11b: There is no evidence that H. pylori eradication can lead to regression of intestinal metaplasia.

Evidence Level: 2a Grade of Recommendation: B

Forest plot of studies comparing

corpus gastric atrophy in eradicated versus

non-eradicated patients.

Rokkas et al. 2007Heterogeneity Q value 34. 37, p<0.001

(Random-Effects Model).

Forest plot of studies comparing

corpus intestinal metaplasia in eradicated

versus non-eradicated patients.

Rokkas et al. 2007

(Random-Effects Model)

Heterogeneity Q value 7.378, p=0.194.

Conclusion:

Compared with no eradication, the long-term

eradication histology results showed significant

improvement for GA for both antrum and corpus,

whereas such an improvement was not shown for IM at

both anatomical sites.

It seems that the development of IM in the stomach is

not reversible by H.pylori eradication and represents the

“point of no return”.

Therefore efforts should be directed at preventing the

development of such a lesion by treating the infection

early in life. Rokkas et al. 2007

Gastric cancer

• Statement : The risk of gastric cancer can be

reduced more effectively by employing

eradication therapy before the development of

preneoplastic conditions.

Evidence Level: 1a Grade of Recommendation: A

Natural History of H. pylori

Infection

intestinal metaplasia

dysplasia

gastric cancer

peptic ulcer

MALT lymphoma

Childhood Advanced Age

H. pylori infectionasymptomatic

H. pylori infection

atrophic gastritis

Natural History of H. pylori

Infection

intestinal metaplasia

dysplasia

gastric cancer

peptic ulcer

MALT lymphoma

Childhood Advanced Age

H. pylori infectionasymptomatic

H. pylori infection

atrophic gastritisx

Prevention of gastric cancer

• Statement

a) Preneoplastic high risk conditions require

endoscopic follow up.

b) Prospective studies are needed to determine

the correct timing of follow-up .

• Evidence Level: Grade of Recommendation:

Gastric cancer

• Statement : The risk of gastric cancer is influenced

by host genetic factors (IL-1ß, TNF-, IL-10, IFN-γ,

IL-8) but in clinical practice no specific marker can

be recommended for genetic testing at present.

Evidence Level: 1b Grade of Recommendation: A

Gastric cancer

• Statement : The influence of environmental

factors is subordinate to the effect of H. pylori

infection.

Evidence Level: 1a Grade of Recommendation: A

Gastric

CANCER

Host Genetics

H. pylori infection

Diet

Host genetic factors that make family members of

gastric cancer cases prone to atrophy

Authors Factor• Azuma HLA-DQA1*0102

• Sakai HLA-DQB1*0401

• El-Omar, Machado IL-IB increase

• Fei PTEN decrease

• Ebert Alfa-catenin decrease

• Grady, Saito E-cadherin gene mutation

• Miehlke COX-2 increase

• Miehlke Cyclin D3 increase

• Setiawan GSTT1

Host genetics-Polymorphisms

• Polymorphisms of chronic inflammation mediators may be associated with increased risk of gastric pathology

Diet and Gastric Cancer

• Summarised evidence suggests that raw vegetables and fruits containing vitamins C and E, beta-carotene and some minerals such as selenium, protect against stomach cancer.

• Ascorbic acid protective effect against gastric carcinogenesis is due to its ability to inactivate οxygen free radicals as well as its nitrite scavenging effects.

Multistep model for the progression of gastric cancer

(Wang TC).

Gastric cancer

• Statement : Validated serological tests for H. pylori

and markers of atrophy (i.e.pepsinogens) are the

best available non invasive tests to identify

subjects at high risk of gastric cancer.

Evidence level: 2b Grade of Recommendation: B

Prevention of gastric cancer

• Statement : H. pylori eradication to prevent gastric cancer should be

considered in the following individuals:

-First degree relatives of family members with a diagnosis of gastric

cancer

-Previous gastric neoplasia already treated by endoscopic or subtotal

gastric resection

-Patients with risk gastritis: severe pangastritis, corpus predominant

gastritis, severe atrophy

-Chronic gastric acid inhibition for more than one year

-Strong environmental risk factors for gastric cancer (heavy smoking,

work high exposure to dust, coal, quartz, cement, and/or work in

quarries)

-H. pylori positive patients with fear of gastric cancer

Evidence Level: 1c Grade of Recommendation: A

Σε κίνδσνο οι ζσγγενείς

αζθενών με γαζηρικό

καρκίνο;

Rokkas et al.,EJGH 2010

Meta-analysis

Forest plot (random effects model), concerning H.pylori

prevalence in first degree relatives of gastric cancer patients

and controls.

Rokkas et al.,EJGH 2010

Forest plot (random effects model), concerning gastric

atrophy prevalence in first degree relatives of gastric

cancer patients and controls.

Rokkas et al.,EJGH 2010

Forest plot (random effects model), concerning

intestinal metaplasia (IM) prevalence in first degree

relatives of gastric cancer patients and controls.

Rokkas et al.,EJGH 2010

Prevention of gastric cancer

Statement : H. pylori infection is the most consistent

risk factor for gastric cancer. Its elimination is

therefore the most promising strategy to reduce the

incidence of gastric cancer.

Evidence Level: 1a Grade of Recommendation: A

Gastric cancer

• Statement : H. pylori eradication for gastric

cancer prevention is cost effective in certain

communities with a high risk for gastric cancer.

• Evidence Level: 3b Grade of Recommendation: B

H. pylori Vaccine

Proof of Principle in Animals

Prophylactic

Therapeutic

Prevention of gastric cancer

• Statement : Vaccine would be the best option

for eliminating H. pylori infection in the

population. A major effort to develop one should

be made.

Evidence Level:1b Grade of Recommendation: A

Impact of Prophylactic Vaccination Beginning

in 2000 on the Incidence of H. pylori-

attributable Complications

Rupnow et al, Vaccine 2001;20:789-885

ga

str

ic c

ancer

incid

ence

Developing countries

2010 2060 2150

0

2100

12

24

36