Helicobacter pylori and gastric cancer

1
Helicobacter pylori and gastric cancer
14th World Congress on Gastrointestinal Cancer

• Thomas Seufferlein
• Department of Internal Medicine I
• Ulm University, Germany

2
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

3
Helicobacter pylori - prevalence

• world wide 7 - 87
• highest in developing countries
• Europe up to 30 (depending on immigration
  background)

MPI Infektionsbiologie Aachen
4
H. pylori

• Present in oral cavity -gt 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

5
H. Pylori is a risk factor for gastric cancer

• H. pylori is recognized as a class I carcinogen
  since 1994

6
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
7
Pathological outcome of H pylori H. pylori and
the mucosal immune system

• 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
  CagA-negative bacteria promote CagA dependent
  T-cell priming

Szczepanik, JPP 2008
Lundgren Infect Immun 2005 Freire de Melo,
Microbes Infect 2012 Kido, BBRC 2011
8
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
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Pathological outcome of H pylori

• Pathological outcome of H pylori infection
  depends on
• bacterial action
• host response
• susceptibility
• gastric cancer susceptibility lt-gt
• inflammation-related gene polymorphisms
• Allele 2 of IL1R antagonist lt-gt gastric cancer
• gt causes high circulating IL-1Ra and IL-1b levels
• gt severe and prolonged inflammatory response

Persson, Am J Epidemiol 2011
10
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 -gt
• Immune response initiates
• chronic inflammation
• hypochlorhydria
• malignancy

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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

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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
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CagA pathogenetic mechanisms

• CagA induces p53 degradation via binding to and
  inactivation of ASPP2 (activates p53) -gt
  inhibition of apoptosis

Buti, PNAS 2011 Ruggiero, Co infectious diseases
2012
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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
15

• 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
16

• H. pylori infection associated with
• development of intestinal type and
• diffuse-type gastric cancer.

Uemura, NEJM 2001
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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

Ekstrom, Gastroenterology 2001
Uemura, NEJM 2001 Sobala, Carcinogenesis 1991
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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
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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

• 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
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When should H pylori eradication best be
performed?

• Intervention studies in
• Columbia
• China
• Japan
• -gt H.p. eradication is the most effective
  strategy to prevent gastric cancer
• -gt particularly effctive before IM or gastric
  atrophy are present

Mera, GUT, 2005 You JNCI 2006 Take Am J
Gastroenterol 2005
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When should H pylori eradication be performed?

• 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
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Incidence of gastric cancer following H.pylori
eradication
Effective prophylaxis only in patients without
severe histological changes!
Wong, JAMA 2004
23

• Since 2004 mass eradication of H pylori for
  Taiwanese population with prevalent H pylori
  infection and age gt 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
24

• Results
• Reduction
• H pylori infection 78.7
• Peptic ulcer 67.4
• gastric atrophy 77.2
• intestinal metaplasia n. s.

25

• Reduction of gastric
• cancer incidence
• 25
• rate ratio 0.753, 0.372-1.524

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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
27
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
28
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
29
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 -gt 78

Goturk, Am J Med Sci 2011 Bekar J Med Food 2011
Niv, WJG 2008
30
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
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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
• 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