Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

1The screen versions of these slides have full details of copyright and acknowledgements

Gastric Cancer, Gastritis and the Role of H. pylori

11

Prof. Anthony AxonCentre for Digestive Diseases

The General InfirmaryLeeds

World Organisation of Digestive Endoscopy

1

• Honorary Professor of Gastroenterology University of Leeds UK

Professor Anthony Axon

22

• Past PresidentBSG, ESGE, UEGF, OMED

2

Gastric cancer mortality is second only to lung cancer

333

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

2The screen versions of these slides have full details of copyright and acknowledgements

Scanning EM of Helicobacter pylori colonising the gastric mucosa

444

Aims of this presentation

• Understand the natural history of Hp gastritis

• Review the evidence showing Hp to be an essential risk factor for gastric cancer

55

• Discuss the mechanisms involved in gastric carcinogenesis

• Appreciate why gastric cancer incidence varies

5

Transmission EM of Helicobacter pyloricolonising the gastric mucosa

66h- H. pylori on the apical and intracellular junctions of epithelial layer (arrowhead) L- gastric lumen

6

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

3The screen versions of these slides have full details of copyright and acknowledgements

Acute infection with H. pylori

• Usually occurs in childhood

• 7-10 day incubation

• Epigastric pain, flatulence and halitosis

77

• Anorexia with mucous vomiting

• Achlorhydria

• Symptoms resolve but the infection often persists

• Transmission unknown

7

Acute gastric inflammation immediately after infection with Helicobacter pylori

88Sobala et al., Gut (1991) 32(11) 1415-1418 8

Chronic gastritis with “activity” in the antrum some years following infection

99

Infected antrumNormal, healthy antrum

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

4The screen versions of these slides have full details of copyright and acknowledgements

Helicobacter gastritis before and one month after treatment

1010

Before treatment After treatment

Dixon, Current Diagnostic Pathology (1994) 1, 80-89

H. pylori gastric mucosa interactions

1111Cover and Blaser, Gastroenterology (2009) 136:1863-73

11

Development of atrophy and intestinal metaplasia after many years of infection

1212

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

5The screen versions of these slides have full details of copyright and acknowledgements

H. pylori, gastric atrophy and IM a multicentre study of 2455 patients

1313Asaka et al., Helicobacter (2001) 6 294-29913

Natural history of Hp Gastritis

• Acute infection (days)

• Chronic inflammation (years)

• Atrophy and intestinal metaplasia (severity and time)

1414

• Hypochlorhydria (loss of parietal cells)

• Overgrowth of oral and intestinal bacteria

• Hp disappears and serology reverts

14

Aims of this presentation

• Understand the natural history of Hp gastritis

• Review the evidence showing Hp to be an essential risk factor for gastric cancer

• Discuss the mechanisms involved

1515

• Discuss the mechanisms involved in gastric carcinogenesis

• Appreciate why gastric cancer incidence varies

15

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

6The screen versions of these slides have full details of copyright and acknowledgements

Meta analysis of nested studies showing association between Hp and gastric cancer

1616Helicobacter and cancer collaborative group; Gut (2001) 49: 347-353

Non Cardia (OR; 2.97) Cardia (OR; 0.99)

16

Gastric cancer and infection with H. pylori using IgG ELISA serology

76%

55%• Odds ratio of 3 is not high enough to draw the conclusion that Hp is a necessary factor

• All the nested studies used standard anti Hp ELISA serology80100120140160180200

er o

f pat

ient

s

1717

Cancer cases Normal controls

Odds ratio 2.2 (95% confidence interval 1.4-3.6)

Ekstrom et al., Gastroenterology (2001) 121: 784-791

• The studies may have underestimated the odds ratio

0204060

Hp - Hp + Hp - Hp +

Num

be

17

Gastric cancer and infection with H. pylori (corrected for CagA serology)

96%

57%

80100120140160180200

er o

f pat

ient

s

1818

Cancer cases Normal controls

Odds ratio 21.0 (95% confidence interval 8.3-53.4) Ekstrom et al., Gastroenterology (2001) 121: 784-791

020406080

Hp - Hp + Hp - Hp +

No. of patientsNum

be

18

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

7The screen versions of these slides have full details of copyright and acknowledgements

Helicobacter gastritis and gastric acidity

High acid Low acid

191919

Type of gastritis and cancer risk, an 8 year prospective study of 1526 patients

Gastritis Relative riskAtrophy

None or mild 1.0Moderate 1.7 (0.8-3.7)Severe 4.9 (2.8 - 19.2)

2020

( )Distribution

Antral predominant 1.0Pan gastritis 15.6 (6.5 - 36.8)Corpus predominant 34.5 (7.1-166.7)

Intestinal metaplasiaAbsent 1.0

Present 6.4 (2.6-16.1)

Uemura, N Eng J Med (2001) 345: 784-789 20

Corpus atrophy in gastric cancer,findings in 105 cancers

e of

indi

vidu

als

pus

gast

ritis

2121Komoto et al., Am J Gastroenterol (1998) 93: 1271-6

Nearly all cancer patients have corpus atrophy

Perc

enta

gew

ith c

orp

21

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

8The screen versions of these slides have full details of copyright and acknowledgements

Gastritis

Mild gastritis(No complications)

Severe antral

Duodenalulcer

2222

Gastritis Severe antralgastritis

Severe corpusor pan gastritis

Gastric ulcerAtrophy IM

Cancer

High AcidLow Acid

22

The Mongolian gerbil

232323

H. pylori and gastric cancer

• Nearly all cancer cases have been infected with Hp

• Gastric cancer is associated with corpus predominant atrophy and IM

2424

• These changes are caused by long standing Hp infection

• Corpus gastritis is the main predictor for gastric cancer

• Animal models show that Hp infection leads to cancer

24

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

9The screen versions of these slides have full details of copyright and acknowledgements

Aims of this presentation

• Understand the natural history of Hp gastritis

• Review the evidence that showing Hp to be an essential risk factor for gastric cancer?

• Discuss the mechanisms involved

2525

• Discuss the mechanisms involved in gastric carcinogenesis

• Appreciate why gastric cancer incidence varies

25

Does Hp itself directly cause gastric cancer?

• Antral predominant gastritis does not cause cancer

• Duodenal ulcer doesn’t become neoplastic

• H. pylori does not infect intestinal metaplasia

2626

• 25% of gastric cancer cases develop after H. pylorihas disappeared

• Gastric cancer is common in pernicious anaemia

26

Physiological effects of chronic gastritis, atrophy and intestinal metaplasia

• Hypochlorhydria

• Overgrowth of metabolically active intestinal organisms

The Correa hypothesis

2727

Overgrowth of metabolically active intestinal organisms

• Increase of mutagenic reactive oxygen species in the mucosa

• Absence of luminal ascorbic acid

• Increased cell turnover

• This leads to cancer

27

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

10The screen versions of these slides have full details of copyright and acknowledgements

Epithelial cell proliferation before and after Hp eradication

eoxy

urid

ine

ng in

dex%

2828

Immediately after

treatment

One year later

Lynch et al., Gut (1995) 38; 346-350

Bro

mod

Labe

lli n

Before

28

Intragastric ascorbic acid concentration before and after Hp eradication

Gastric ascorbic acid

scor

bic

acid

er

litr

e)

2929Sobala et al., Gut (1993) 34, 1038-41

Con

cent

ratio

n of

as

(mic

rom

olls

pe

B=Before treatment A=After treatment

29

Reactive oxygen species in H. pylori gastritis

Histology Chemiluminescence cpm/mg

Malondialdehyde nmol/litre

Normal (n=53) 1210 70

3030

Normal (n 53) 1210 70

Reactive gastritis (n=34) 1576 89

H. pylori gastritis (n=77) 23885 112

p<0.0001

Drake et al., Gut (1998) 42: 768-771

30

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

11The screen versions of these slides have full details of copyright and acknowledgements

Effect of treatment

Before (S) After (S) Before (F) After (F)Chemiluminescence 16103 1441*** 30301 10822

Malondialdehyde 122 99** 108 101

Success Failure

3131

Malondialdehyde 122 99 108 101

p<0.001***p<0.01**

Drake et al., Gut (1998) 42: 768-771

31

Stem cells

• Ordinary tissue cells have a limited life span

• Stem cells are long lived and essential for the structural maintenance of the organ

• Embryonic stem cells differentiate into peripheral

3232

stem cells

• Peripheral stem cells are tissue specific

• The bone marrow can provide an emergency team to help in acute injury

• These are the Bone Marrow Derived Cells (BMDCs)

32

Bone marrow derived cells (BMDCs)

• These provide cells for short term repair

• They include stem cells

• Bone marrow stem cells are versatile

3333

• They can take over the role of gastric stem cells

• As in chronic inflammation with atrophy

• They are unstable and produce metaplastic offspring

• These may become dysplastic

33

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

12The screen versions of these slides have full details of copyright and acknowledgements

Bone marrow derived cells and gastric cancer

ControlSham

infected 4/52 20/52 >12/12

3434Houghton and Wang, Gastroenterology (2005) 128: 1567-1578 34

New model for the development of gastric cancer

3535Houghton and Wang, Gastroenterology (2005) 128: 1567-1578

Th1cells

IFNγ

Proliferation and differentiation of stem cells

35

Aims of this presentation

• Understand the natural history of Hp gastritis

• Review the evidence showing Hp to be an essential risk factor for gastric cancer?

Disc ss the mechanisms in ol ed

3636

• Discuss the mechanisms involved in gastric carcinogenesis

• Appreciate why gastric cancer incidence varies

36

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

13The screen versions of these slides have full details of copyright and acknowledgements

World map of gastric cancer mortalityEstimated age-standardised mortality rate per 100,000; Stomach: male, all ages

3737GLOBOCAN 2008 (IARC) 37

Why does gastric cancer vary in incidence?

• Prevalence of H pylori

• Severity of gastritis

3838

• Pattern of gastritis

38

Helicobacter pylori infects those who are socio-economically disadvantaged

• The poverty in the UK during the 19th-20th century

393939

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

14The screen versions of these slides have full details of copyright and acknowledgements

Japanese versus British gastritis

• Japan – very high incidence, UK – relatively low

4040Naylor, Gotoda et al. (2004) 40

Comparison of gastritis in matched populations from Japan and England

• 252 age matched consecutive patients in Tokyo and Leeds/Bradford

• Gastritis assessed histologically

4141

• Gastritis assessed histologically

– Severity

– Pattern

41

Intestinal metaplasia and atrophy in matched populations from Japan and England

tota

l IM

sco

re

n to

tal a

troph

y

4242

Intestinal metaplasia Atrophy

Naylor et al., Gut (2006) 55: 1545-1552

Decennial Decennial

Med

ian

Med

ian

42

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

15The screen versions of these slides have full details of copyright and acknowledgements

Differing patterns of gastritis in Japan and England

4343Naylor et al., Gut (2006) 55: 1545-1552 43

444444

Dietary factors in the development of gastric cancer

• Fruit and vegetables are negatively associated

• Low dietary vitamin C is positively associated

• Vitamins not protective in prospective studies

4545

• Vitamins not protective in prospective studies

• Nitrogenous products may be positively associated

• Salt is strongly associated and also increases risk in animal studies

Riboli and Narat, pub health nutr (2001) 4: 475-484

45

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

16The screen versions of these slides have full details of copyright and acknowledgements

Effects of the CagA pathogenicity island

• Are the H pylori organisms in Japan more virulent than those in the UK?

• CagA positive organisms, which are more virulent, are present in greater numbers in the far east

4646

p g

• But CagA is only one virulence factor, there are many other factors

46

High virulence H. pylori genotypesincrease the risk of non-cardia cancer

221 chronic gastritis222 gastric cancer

Odds ratio

4747

Odds ratioVacAs1 17VacAm1 6.7CagA+ve 15

Figueiredo et al., J Nat Cancer Inst (2002) 94: 1680-1687

47

Genetics and gastric cancer

• Interleukin-1 (IL-1) is an inflammatory cytokine

• IL-1β inhibits gastric acid secretion x 100 PPI

• The IL-1 gene cluster on 2q is polymorphic

4848

The IL 1 gene cluster on 2q is polymorphic

• IL-1B-31T+ and IL-1RN*2/*2 have an odds ratioof 7.5 and 2.1 for gastric cancer

El Omar et al., Nature (2000) 404 (6776): 398-402

48

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

17The screen versions of these slides have full details of copyright and acknowledgements

Proinflammatory cytokine gene polymorphisms increase the risk of non-cardia gastric cancer

Polymorphism Odds RatioIL-1B-511 2.3

IL-1RN 3.6

4949

TNF-A-308 2.2 IL-10 2.5

One polymorphism 2.8Two polymorphisms 5.4

Three or more 27.3

El Omar, Gastroenterology (2003) 124: 1193-1201

49

Proinflammatory cytokine polymorphisms enhance the carcinogenic effect of high

virulence H. pylori genotypes

H. pylori Host Odds RatioIL-1RN 3.3

IL-1B-511 3.3

5050

VacAs1 IL-1B-511 87VacAm1 IL-1B-511 7.4VacAs1 IL-1RN 32VacAm1 IL-1RN 8.8

CagA IL-1B-511 25CagA IL-1RN 7

Figueiredo et al., J Nat Cancer Inst (2002) 94: 1680-1687 50

Helicobacter gastritis and gastric acidity

High acid Low acid

515151

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

18The screen versions of these slides have full details of copyright and acknowledgements

Inflammation in the corpus increases when acid secretion is reduced

• Corpus inflammation increased after 4 weeks omeprazole

– Solcia, Scand J Gastro 1994

• Significant increase in severity after

5252

• Significant increase in severity after 4 weeks ranitidine

– Meining, APT 1997

• Worsened significantly after 1 year PPI Rx

– Stolte, APT 1998

52

Development of corpus atrophy in infected patients treated with acid suppression

• Atrophy increased at a rate of 6.1% per year

– Kuipers N Engl J Med 1996

• Atrophy developed at a rate of 2.7% per year

5353

– Lundell Gastroenterology 1999

• Atrophy occurred at a rate of 4.7% per year

– Klinkenberg-Knol Gastroenterology 2000

• Annual incidence of atrophy 2.5%

– Lamberts Digestion 2001

53

Increasing acid secretion in Japan

5454Kinoshita et al., Gut (1997) 41(4): 452-8 54

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

19The screen versions of these slides have full details of copyright and acknowledgements

Acid secretion is related to lean body mass

5555Baron JH, Gut (1969) 10: 637-642 55

Increasing height of men in Europe 1960-1990

pt o

f hei

ght (

cm)

5656Beard and Blaser, Pers Biol Med (2002) 4: 478-495

Con

scrip

56

Immune experience

• Immune experience may influence the type of inflammatory response to H. pylori

• Animals infected with Helminths develop a Th2 response to Hp infection

5757

develop a Th2 response to Hp infection

• These animals have a reduced degree of gastric atrophy

• This if extrapolated to humans might explain some of the differences in disease prevalence

Fox et al., Nature medicine (2000) 6: 536-542 57

Gastric Cancer, Gastritis and the Role of H. pylori

Prof. Anthony Axon

20The screen versions of these slides have full details of copyright and acknowledgements

Summary

• Helicobacter pylori is a necessary factor in the causation of most non-cardia gastric cancer

• It may not be the direct cause of cancer

Se ere corp s gastritis is the phenot pe

5858

• Severe corpus gastritis is the phenotype that predicts cancer

• This is affected by environmental factors; diet, age and immune experience

• H. pylori and Host genetics and acid secretion

58

5959