Transcript Helicobacter pylori and cancer

14th World Congress on Gastrointestinal Cancer
Helicobacter pylori and
gastric cancer
Thomas Seufferlein
Department of Internal Medicine I
Ulm University, Germany
Helicobacter pylori
• Spiral shaped, flagellated
microaerophilic Gram negative
bacteria
• Colonizes the gastric mucosa in
more than 50% of the human
population
• Transmitted within the family in
childhood, likely by fecal-oral
transmission
Helicobacter pylori - prevalence
• world wide 7% - 87%
• highest in developing countries
• Europe up to 30% (depending on
immigration background)
MPI Infektionsbiologie Aachen
H. pylori
• Present in oral cavity ->
reinfection of gastric mucosa?
• Majority of infected population
remains asymptomatic
In some cases development of
• chronic gastritis
• peptic ulcer
• gastric mucosa associated
lymphoid tissue (MALT)
lymphoma
• associated with increased risk of
cancer
H. Pylori is a risk factor for gastric cancer
• H. pylori is recognized as a class I carcinogen
since 1994
Helicobacter and gastric cancer
Maastricht IV:
• H. pylori infection is the most consistent factor
for gastric cancer
• Increase in gastric cancer risk: ≥ 20 fold when
• lesion is gastric in nature
• originates below the cardia
Ekstrom Gastroenterology 2001; Brenner, Am J Epidemiol 2004; GUT, JUNE 2012
Pathological outcome of H pylori:
H. pylori and the mucosal immune system
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H pylori specific Treg in gastric mucosa
suppress mucosal immune responses
contribute to infection persistence
modulate H pylori-induced gastritis
immune response to H pylori infection
and pathological oucome might be
different according to the age of infection
(children – adult)
• role of CagA: CagA-positive, but not CagAnegative bacteria promote CagA
dependent T-cell priming
Szczepanik, JPP 2008
Lundgren Infect Immun 2005; Freire de Melo, Microbes Infect 2012; Kido, BBRC 2011
H. pylori and mutagenesis
• H. pylori has direct mutagenic
effects in mice
– F (duration of infection, gender)
• Causes genetic instability of
chromosmal and mitochondrial
DNA
• Causes preneoplastic lesions and
cancer in experimental models
Touati, Gastroenterology 2003; Helicobacter 2006; Sheh, PNAS 2010; Machade, BBA 2010; CCR 2009
Pathological outcome of H pylori
• Pathological outcome of H pylori infection depends on
– bacterial action
– host response
– susceptibility
• gastric cancer susceptibility <->
inflammation-related gene polymorphisms
– Allele 2 of IL1R antagonist <-> gastric cancer
– > causes high circulating IL-1Ra and IL-1b levels
– > severe and prolonged inflammatory response
Persson, Am J Epidemiol 2011
H. pylori pathophysiology
• Types of pathogen-host interaction
– Type 1:
• H pylori escapes immune system and gets nutrients
from the host tissue
• Asymptomatic gastritis
– Type 2:
• Proinflammatory genetic backgound plus H pylori
strains with dangerous factors ->
• Immune response initiates
– chronic inflammation
– hypochlorhydria
– malignancy
Bacterial action: H- pylori strains
Type I:
• Cag PAI complex
in their genome
• Express CagA protein
• More toxic s1 allele of
VacA
• Most severe
infections
Type II:
• Cag negative
• less toxic s2m2 allele
of VacA
• Mainly asymptomatic
gastritis
H pylori – bacterial action
• cagPAI complex: encodes T4SS –
type IV secretion system
– Molecular syringe that translocates
CagA into eukaryotic cells
• Phosphorylation and nuclear
translocation of CagA
– IL-8 production
– NF-kB production
– remodeling of cytoskeleton by
epithelial cells
Onishi PNAS 2008
CagA– pathogenetic mechanisms
• CagA induces p53
degradation via
binding to and
inactivation of
ASPP2 (activates
p53) -> inhibition of
apoptosis
Buti, PNAS 2011; Ruggiero, Co infectious diseases 2012;
CagA is a bacterial oncogene
• CagA attaches H. pylori near
the intracellular junctional
complex and alters the
differentiation and behaviour
of polarized cells
• Intracellular Cag contributes
to EMT
• CagA-expressing transgenic
mice:
– gastric epithelial hyperplasia
– gastric adenocarcinomas in the
absence of gastritis
Ohnishi, PNAS 2008
• 1526 Japanese with
• duodenal ulcers
• gastric ulcers
• gastric hyperplasia,
• nonulcer dyspepsia
• mean follow up 7.8 Jahre
• gastric cancer
development
•2.9% in infected
(n =36)
•0% in not infected
patients
Uemura, NEJM 2001
H. pylori infection
associated with
• development of
intestinal type and
• diffuse-type gastric
cancer.
Uemura, NEJM 2001
Helicobacter and gastric cancer
• High risk profile for gastric cancer
– active corpus gastritis (34 x risk)
– gastric atrophy und IM (5-6 x risk)
– gastric hypochlorhydria
– lack of ascorbic acid (scavenges
carcinogenic N-nitrosamines and
ROS)
– gastric ulcer
Uemura, NEJM 2001; Sobala, Carcinogenesis 1991
Ekstrom, Gastroenterology 2001
What can be achieved by H pylori eradication?
• H pylori eradication
• abolishes the inflammatory response
• slows or may arrest the progression of atrophy
• may even reverse atrophy to some degree
• Abolishing the active inflammatory process with
infiltration of polymorphonuclear cells takes 4 weeks
• Chronic inflammation with lymphocyte infiltration
persists up to 1 year.
• Metaanalysis:
• corpus atrophy potentially reversible
• antral atrophy most likely irreversible
• IM is irreversible
Tulassy, Scand J Gastroenterol 2010; Rokkas, Helicobacter, 2007
Eradication of H pylori and prevention of gastric
cancer
• Cohort studies show positive
effect of H pylori eradication
on prevention of gastric
cancer
• RCTs show benefit of H pylori
eradication
– on preneoplastic
conditions
– in primary and secondary
gastric cancer prevention
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Multicenter prospective cohort
Yamagata/Japan (high incidence region)
2000-2007, mean f-u 5.6 y; n = 4133
Mean age: 53 years
Patients choice to receive eradication
therapy (3090) or only antacid therapy
(rest)
Annual endoscopy
Eradication rate: 80%
Incidence of gastric cancer decreased by
40% in the eradication group
Correa, JNCI 2000; Leung, GUT 2004; Mera, GUT 2005, Fukase Lancet 2008; Wong, JAMA 204
Take, AJG 2005; Yanaoka, Int J Cancer 2009; Uemra, NEJM 2001; Kosunen, Int J Cancer 2011, Ogura, J Cli
Gastroenterol 2008; Fuccio, Annals Internal Medicine 2009; Mabe, WJG 2009
When should H pylori eradication best be
performed?
Intervention studies in
• Columbia
• China
• Japan
-> H.p. eradication is the most effective strategy
to prevent gastric cancer
-> particularly effctive before IM or gastric
atrophy are present
Mera, GUT, 2005; You JNCI 2006; Take Am J Gastroenterol 2005
When should H pylori eradication be
performed?
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Pooled analysis 6 trials (mostly Asia),
–  7000 participants
– f-u 4-10 years:
– RR for gastric cancer after H pylori eradication: 0.65 (0.43-0.98)
– Significant reduction in gastric cancer incidence only when serum pepsinogen
levels normal
– Cancers originating after eradication related to extensive atrophic gastritis
• The shorter the time between infection and eradication, the
larger the preventive effect with respect to gastric cancer
Fuccio, Ann Int Med 2009
Incidence of gastric cancer following H.pylori
eradication
Effective prophylaxis only in patients
without severe histological changes!
Wong, JAMA 2004
• Since 2004 mass eradication of H pylori for Taiwanese
population with prevalent H pylori infection and age > 30
years
• Endpoint – prevalence of:
– HP
– Premalignant gastric lesions
– Comparison between premalignant lesions and gastric
cancer before (1995-2003) and after (2004-2008) mass
eradication
Lee, GUT 2012
Results:
Reduction
• H pylori infection:
78.7%
• Peptic ulcer:
67.4%
• gastric atrophy
77.2%
• intestinal
metaplasia: n. s.
Reduction of gastric
cancer incidence:
25%
rate ratio: 0.753, 0.372-1.524
When does screening for H. pylori make sense?
Screening
• could prevent 17-25% of all gastric cancers in China
• is sensible in high risk patients (resected early gastric cancer)
and high risk regions
Miki, AJG 2003
Malfertheiner, GUT 2012
Who must / should get eradication
treatment?
• First-degree relatives of family members with a diagnosis of gastric cancer
(2-3 fold)
• Patients with previous gastric neoplasia already treated by endoscopic or
subtotal gastric resection
• Patients with risk of gastric cancer:
– Severe pan-gastritis
– corpus-dominant gastritis
– severe atrophy
• Patients with chronic gastritis and acid inhibition for more than 1 year
• Patients with strong environmental risk factors for gastric cancer (heavy
smoking, high exposure to dust, coal, quartz, cement, and/or work in
quarries
• H pylori postive patients with a fear of gastric cancer
Rokkas, Eur J Gastroenterol Hepatol 2010; Malfertheiner GUT 2012
What is the best eradication therapy
for H pylori?
• Proton pump inhibitor plus 2 antibiotics for 1-2 weeks
(standard triple amoxicillin, clarithromycin, omeprazole)
– efficacy has dropped below 80%
– increasing antibiotic resistance
– poor patient compliance
First line quadruple therapy in Europe recommended
in areas of high clarithromycin resistance
bismuth subcitrate potassium
metronidazole
tetracycline hydrochloride
omeprazole
Eradication: 80% vs. 55% with standard triple (ITT)
Malfertheiner, Lancet 2011
H pylori eradication treatment – open
issues
• Eradication more efficacious in long term aspirin
users?
• Can probiotics increase the efficacy of H pylori
tretament?
– saccharomyces boulardii
– lactoferrin
– Kefir - fermented milk containing probiotics:
• 50% -> 78%
Goturk, Am J Med Sci 2011; Bekar J Med Food 2011; Niv, WJG 2008
What to do in case of high risk (after
eradication)?
Endoscopic follow up in case of
• pernicious anemia with histologically confirmed
diagnosis of type A autoimmune atrophic gastritis
• histological or serological signs of subtotal or total
atrophic gastritis with hypo- or achlorhydria
• intervals:
– Dysplasia:
3-6 months
– Moderate to severe atrophy: 2-3 years
Malfertheiner GUT 2012
Niv, Helicobacter 2008
Reinfection or reoccurence after eradication
About 1% in developed countries
Around 13% in developing countries
-> retesting/rescreening
Helicobacter pylori and gastric cancer conclusion
• H. pylori is an essential factor in 71%-95% of all gastric
cancers
• Eradication makes sense in high risk patients
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corpus-dominant gastritis
first degree relatives of patients with gastric cancer
serum pepsinogen I as marker of atrophy
serological testing for H. pylori
• Prospective trials: Eradication can only prevent gastric cancer if there
are no major histological abnormalities such as atrophy, metaplasia or
dysplasia
• Eradication should therefore take place in early stages of infection to
prevent carcinogenesis