The role of Helicobacter pylori - PowerPoint Presentation

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The role of Helicobacter pylori infection in colorectal carcinogenesis

Vasilios Papastergiou

Gastroenterology Dept.

Konstantopouleio-Patission

General Hospital of

Nea

Ionia,

Athens, Greece

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Disclosures

nothing to disclose

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Colorectal Cancer

3

rd

most common cancer worldwide

4

th

leading cause of cancer-related death1.4 million new cases/700.000 deaths (2012)More that 2/3 in countries with high HDIThe global burden of CRC is expected to increase by 60% (>2.2 million new cases/1.1 million deaths) by year 2030

Global patterns and trends in colorectal cancer incidence and mortality. Arnold M. et al. Gut 2016; 0:1-9.

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Sporadic CRC pathogenesis: multifactorial

Fatty diet

Red meat

Low Physical activity

Obesity

Smoking

Alcohol

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Adenoma to Carcinoma sequence

Amersi

et al.

Clin

Colon Rectal

Surg

, 2005Zauber et al. NEJM, 2012

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CRC pathogenesis: role of infectious agents (?)

Virus

-JC virus

-HPV

-EBV

-CMV

Bacteria

-Streptococcus

bovis

-

Bacteroides

fragilis

-Enterococcus

faecalis

-Escherichia Coli

Helminths

-Schistosoma

japonicum-Schistosoma mansoni

Universal human pathogen (50% of the world population and up to 80% in developing countries)

Recognized class I carcinogen (IARC)

Established role in gastric cancer (ADC, MALT)Studies on its oncogenicity have been extended to examine its role in the development of other gastrointestinal malignancies

-

H. Pylori

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1. H. Pylori infection status and colorectal neoplasia

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Case-control studies: n=18 (1991-2017)Cross-sectional studies, n=6 (2010-2016)

Meta-analyses, n=8 (2006-2016)

Published Studies evaluating a relationship between

H. Pylori

infection status and colorectal neoplasia

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HP infection and colorectal neoplasia: case-control studies (1)

Case/Controls (n)

Matching variables

Measure of H.P. status

Outcome

Adjusted OR

Talley, 1991,USA

80/252

Convenience sample

IgG

Cancer

1.17 (1.03-2.84)

Penman, 1994, UK

42/34

Age, Gender

UBT

Cancer

1.31 (0.52-3.26)Moss, 1995, USA41/41Age, Gender, RaceIgGCancer0.74 (0.30-1.79)Meucci, 1997, Italy94/100Age, GenderIgGAdenoma or Cancer

1.92 (1.08-3.43)Thorburn, 1998, USA233/233Age, Gender, Education, Region, DateIgGCancer1.02 (0.69-1.51)Breuer, 1999, Germany98/98Age, GenderIgGPolyp2.10 (1.12-3.92)Fireman, 2000, Israel51/51Convenience sampleIgGCancer2.43 (1.00-5.59)Hartwitch, 2001, Poland80/160Age, GenderIgG, UBTCancer3.78 (1.89-7.53)Shmuely, 2001, Israel

67/92Convenience sampleIgG, CagACancer1.35 (0.67-2.74)Siddheswar

, 2001, UK189/179Age, Gender, Social ClassIgGCancer

Polyp1.1 (0.7-1.8)1.3 (0.7-2.5)Limburg, 2002, Finland118/236Age, Gender, Centre, Date of serum collectionCagA, whole cell assayCancer0.91 (0.53-1.55)

Fujimori, 2005, Japan

481/188

Age

UBT, RUT, histology

Adenoma

Cancer

1.60 (1.18-2.02)

1.80 (1.28-2.32)

Inoue, 2011, Japan

239/239

Age

IgG

Adenoma

2.52 (1.57-4.05)

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HP infection and colorectal neoplasia: case-control studies (2)

Case/Controls (n)

Matching variables

Measure of H.P. status

Outcome

Adjusted OR (95%CI)

Zhang, 2012, Germany

1712/1669

Age, Gender, CRC risk factors, Former colonoscopy

IgG,

CagA

Cancer

1.22 (1.02-1.45)

Epplein

, 2013, Germany

188/370

Age, Gender, Race, Date blood collection

IgGSeropositivity for 5 H. Pylori proteins (VacA, HP231, HP305, NapA, HcpC)Cancer1.03 (0.59-1.77)2.24 (1.22-4.11) (VacA)Zuniga, 2015, USA216/727Age, Gender, Race, Triple therapy for HP eradication, PPI use

RUT, histology, H. Pylori Ag in serum or stoolAdenoma1.43 (1.04-1.77)Blasé, 2016, USA392/774Cancer site, Age, Stage at diagnosisIgGSeropositivity for 15 H. Pylori specific proteinsCancer1.17 (0.91-1.50)1.32 (1.03-1.70) (GroEl)De Larrea-Baz, Spain, 20172140/4098Age, Gender, ProvinceSeroreactivities against 16 H. Pylori proteins (seropositivity defined as positivity to ≥4 proteins) Cancer0.91 (0.71-1.16)

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HP infection and colorectal neoplasia: cross-sectional studies

N

Measure of HP status

Outcome

Conclusion

Lin, 2010, China

9311

RUT

Adenoma

HP with metabolic syndrome might further increase the risk of colorectal adenoma (

aOR

=1.40)

Hong, 2012, Korea

2195

IgG, UBT

Adenoma

HP is associated with modest increase in the risk of adenoma (

aOR=1.30)Shmuely, 2014, Israel273IgG, CagAAdvanced adenoma or CRCHP is associated with advanced colorectal neoplasia (aOR=9.57) and CRC (aOR=7,98)Brim, 2014, USA1256IgG, CagAPolyps, AdenomaHP is associated with an increased risk of colorectal polyps (aOR=1.5) and adenoma (aOR

=1.5) in African-AmericansPatel, 2014, USA799RUT, histologyAdenomaNo association in US Hispanic populationLee, 2016, Korea316IgG, histologyAdvanced adenoma or CRCHP associated with colorectal neoplasia (aOR=1.34)

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Case-control/Cross-sectional studies: pitfalls

Small sample size/hospital-based design (patient selection bias)

Retrospective design (retrospective recall bias)

Serological testing does not discriminate between current and past infections and may yield positive results for other Helicobacter species (

eg

; H.

Heilmannii)History of prior H. pylori eradication and/or prior polyp removal were not consideredDisparities in factors affecting the cancerogenic risk, as most studies controlled solely for age and gender or relied on a convenience sample. CASE-CONTROL AND CROSS-SECTIONAL STUDIES MAY PROVE A STATISTICAL ASSOCIATION BUT THEY DO NOT PROVE CAUSATION

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HP infection and colorectal neoplasia: meta-analyses

Included studies, N

Outcome

Summary OR (95%CI)

Conclusion

Zumkeller

, 2006, Germany

11*

CRC

1.4 (1.1-1.8)

Possible small increase in the risk of CRC

Zhao, 2008, China

13* (9 using IgG)

CRC

1.47 (1.17-1.91)

1.56 (1.14-2.14) evaluating only IgG

Possible increase in the risk of CRC

Hong, 2012, Korea10Adenoma1.58 (1.32-1.88)Modest increase in the risk of adenomaWu, 2013, China27AdenomaCancer1.66 (1.39-1.97)1.39 (1.18-1.64)Positive association between HP and colorectal neoplasiaRokkas, 2013, Greece28

PolypsCancer1.50 (1.26-1.79)1.30 (1.07-1.59)Modest statistically significant relationship of HP with polyps and CRCChen, 2013, China22CRC1.49 (1.30-1.72)HP increases the risk of CRCGuo, 2014, China9**HyperplasticAdenomaCRC0.72 (0.44-1.18)1.83 (1.35-2.51)1.08 (0.89-1.68)No statistical association between HP and colorectal neoplasm, but HP may increase the risk of adenomaZhao, 2016, China14*CRC1.33 (1.01-1.77)CRC is associated with HP infection*Only case-control studies were included; **included only data on East-Asian population

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2. H. Pylori-related chronic gastritis and colorectal neoplasia

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Nation-scale (USA) histological series of patients who underwent bidirectional endoscopy on the same day (biopsies from both procedures)

N=156.000 (mean age: 58.7 years, 41% males)

Patients with

H. pylori

gastritis (chronic active inflammation in the gastric mucosa with presence of H. pylori demonstrated by IHC) were more likely (than patients without H. Pylori) to have:

-Hyperplastic polyps (

OR=1.24, 95%CI: 1.18-1.30) -Adenomas (OR = 1.52, 95%CI: 1.46-1.57) -Advanced adenomas (OR = 1.80, 95%CI: 1.69-1.92) -Adenocarcinoma (

OR = 2.35

, 95%CI: 1.98-2.80)

Sonnenberg

and

Genta

, Am J

Gastr

, 2013

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3. H. Pylori-related gastric premalignant lesions and colorectal neoplasia

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20.928 males smokers aged 50-69 yrs who were participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) had serum PG-I levels measured.

1665 with low (<25

μ

g/l) PG-I levels were invited for gastroscopy

1059 (63.6%) underwent gastroscopy and atrophic gastritis was histologically confirmed

During a mean follow-up of 11.3 years, 425 incident CRCs were diagnosed

Compared to subjects with normal PG-I, there was no increased risk of CRC among subjects with low PG-I (aHR: 0.71) and among those with histologically confirmed atrophic gastritis (aHR: 0.86). Laiyemo AO et al, Cancer Causes Control, 2010

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Two Japanese case-control studies with 339[1] and 478[2]

subjects found no association between AG diagnosed on the basis PG-I and PG-I/II ratio and colorectal neoplasia

A smaller Japanese study (n=99) identified AG as an independent predictor of recurrence after endoscopic resection of colorectal neoplasia

[3]

In a recent cross-sectional study (n=6.351) from Korea, H. pylori-related AG was significantly associated with the risk of advanced colorectal neoplasm (OR=1.40)

[4]

Atrophic gastritis (AG) and colorectal neoplasia[1] Machida-Montani A et al, Helicobacter, 2007[2] Inoue I et al, Int

J Cancer, 2011

[3]

Inoue I et al,

Mol

Clin

Oncol

, 2013

[4]

Lee JY et al, Gut and Liver, 2016

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Gastric intestinal metaplasia and colorectal neoplasia

Sonnenberg

et al, Am J

Gastr

, 2013

The following conditions were found more frequently in patients with intestinal metaplasia (n=5651) than without intestinal metaplasia:

-colon adenoma (OR: 1.83, 95%CI: 1.71-1.94)-advanced adenoma (OR: 2.02, 95%CI: 1.93-3.37)-CRC (OR: 2.55, 95%CI: 1.93-3.37)*

Data concerning AG was not analyzed due to the absence of multiple mapped gastric biopsy specimens required to diagnose this condition

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Potential Oncogenic actions of H. Pylori

to colorectal mucosa

Hypothesis #1: Trophic/

mitogenic

action of Gastrin on colonic mucosa

Hypothesis #2: Microbial

dysbiosis secondary to reduced acid exposureHypothesis #3: Direct activation of colonic carcinogenesis by H. pyloriHelicobacter pylori and colorectal neoplasia: is there a causal link? Papastergiou V,

Karatapanis

S,

Georgopoulos

SD; WJG, 2016.

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Hypothesis # 1: Gastrin

Persistent H. pylori exposure elicits

hypergastrinemia

Gastrin is a putative trophic factor for the colorectal mucosa

Mitogenic

on colonic cells in vitro

Hyperpropliferation of colonic mucosa in animal models (transgenic mice)

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Georgopoulos

et al, Digestion, 2006

Correlation between high gastrin levels and colorectal neoplasia

Thorburn

et al, Gastroenterology, 1998

2 prospective case-control studies

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Several other studies could not detect any association

(Fireman,

Isr

Med

Assoc

J, 2000; Machida-

Montani, Helicobacter 2007; Penman, Gastroenterology, 1994; Kikendal Am J Gastr, 1992; Selgrad, Int J Cancer, 2014)Human models of long-term hypergastrinemia (PPIs, ZES) showed no effect on the development of CRC (Singh, APT, 2007; Orbuch, DDS, 1996)CRC tumors cells have been shown to produce gastrin themselves (likely act in an autocrine manner )Hypergastrinemia may be simply an epiphenomenon of CRC, as supported by the fact that the gastrin levels fall after surgical resection of the tumor (

Bombski

,

Int

J

Colorctal

Dis, 2003;

Charnley

, Ann R

Coll

Surg Engl, 1992)Evidence against a role of Gastrin in Colorectal neoplasia

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Hypothesis #2:

changes in intestinal microbiota induced by reduced acid secretion

H. pylori-related atrophic gastritis (AG) might contribute to colorectal carcinogenesis by promoting changes in the colorectal microflora.

Microbial

dysbiosis

with selective growth of certain microbial species (

eg; Bacteroides, Prevotella, E. Faecalis), may promote the development of CRC

1)

Sobhani

et al, PLOS ONE, 2011; 2)Compare et al,

Transl

Gastrointest

Cancer, 2014

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Hypothesis #3: H. Pylori is a direct activator of colorectal carcinogenesis (?)

H. pylori is not an invader of the colonic epithelium

However, it moves through the colonic lumen, as indicated by reports of fecal shedding of viable

H. pylori

Several reports of detection (IHC, PCR) of H. pylori in colonic neoplasms (

Soylu

, BMC Gastroenterol 2008; Jones, WJSO 2007; Kapetanakis, J Gastrointes Oncol 2012; Grahn, J Med Microbiol 2005)Potential Mechanisms

Induction of inflammatory responses, with overproduction of cytokines (

eg

; IL-8, a known growth factor for CRC)

Promotion of

neoangiogenesis

CagA

seropositivity

→ positive association with colorectal neoplasia according to some reports , disputed by others

Stimulation of stem cells and recruitment of bone marrow-derived cells (BMDC), similar to animal models of gastric carcinogenesis

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Conclusions (1)

Since more than 2 decades, several studies investigated the potential relationship between

H. pylori

and colorectal neoplasia

However, most investigation relied on relatively small hospital-based samples providing conflicting results

More recently, better designed population-based studies as well as the large-scale histological series by

Sonnenberg and several meta-analyses have become available Nevertheless, results should be interpreted cautiously, as the possibility of bias cannot be excluded.

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Conclusions (2)

Based on a critical analysis of available data, it appears that

H. pylori

infection/gastritis is associated with an increased, although modest, risk of colorectal neoplasia.

However, current evidence supports nothing more than a statistical relationship and a definitive proof of causality remains to be established.

In the future, large-scale prospective studies are awaited to confirm

H. pylori as an infectious contributor in the complex multifactorial process of colorectal carcinogenesis.

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