Helicobacter pylori infection and gastric cancer: Facing the enigmas

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Publication of the International Union Against Cancer

Int. J. Cancer: 106, 953–960 (2003) © 2003 Wiley-Liss, Inc.

HELICOBACTER PYLORI INFECTION AND GASTRIC CANCER: FACING THE ENIGMAS Nuno LUNET* and Henrique BARROS Department of Hygiene and Epidemiology, Porto Medical School, Porto, Portugal At an individual level Helicobacter pylori was associated with the occurrence of gastric cancer but in some African and Asian countries its prevalence runs with low gastric cancer rates, the so-called African and Asian enigmas. We assessed whether the association between gastric cancer and H. pylori prevalence at an area level is modified by the level of exposure to fruits and vegetables, alcohol or tobacco. Regression models were fitted to data from 58 countries using as dependent variable log transformed gastric cancer rates and as independent covariables the H. pylori prevalence, fruits and vegetables consumption, cigarette smoking, alcohol intake and interaction terms. The levels of alcohol consumption or cigarette smoking modified the association between gastric cancer and H. pylori infection. Models including H. pylori prevalence, alcohol consumption, cigarette smoking and the interaction terms H. pylori ⴛ alcohol or H. pylori ⴛ tobacco were used to compute gastric cancer incidence multiplying regression coefficients by a H. pylori prevalence of 85% (the approximate median in African countries) and the median figures observed in each continent for alcohol and tobacco availability. The expected gastric cancer incidence per 100,000 would be 5.7 assuming the alcohol and tobacco availability in African countries, 7.0 in Asia and Oceania, 16.0 in America and 26.0 in Europe. The interaction between H. pylori and cigarette or alcohol consumption may contribute to further explain the international variation in gastric cancer and the so-called African and Asian enigmas. © 2003 Wiley-Liss, Inc. Key words: Helicobacter pylori; gastric cancer; ecological; arealevel; African enigma; Asian enigma; alcohol; tobacco

The dramatic decline in gastric cancer incidence in industrialized countries,1 the wide variation in incidence rates across geographical areas2 and the change in cancer risk within 2 generations after moving from high risk to low risk areas3 favor a major role for environmental exposures in the occurrence of gastric cancer, i.e., Helicobacter pylori. Although epidemiological studies using individuals as observation unit (case-control and cohort) have show that H. pylori infection increases the risk of gastric cancer, on an area level analysis (ecological) considering the experience from African and many Asian countries, the prevalence of H. pylori infection and the gastric cancer frequency are not correlated. Some countries from Africa and Asia present low gastric cancer rates and high H. pylori prevalence, which has been labeled as the “African” and “Asian” enigmas. Gastric carcinogenesis is a complex, multistep and multifactorial process,16 and the incidence of gastric cancer in the presence of 2 or more risk factors may be different from the incidence expected to occur from their individual effects. Therefore, the association between H. pylori infection and gastric cancer may be modified by the level of exposure to other factors, that is, from interactions between H. pylori and other environmental exposures. Deficiency of dietary antioxidants,17 tobacco smoking18 or alcohol drinking19,20 are also linked with different stages of gastric carcinogenesis. There is biological plausibility to accept that the carcinogenic effect of H. pylori infection21 is not the same at different levels of these environmental exposures. Fruits and vegetables are a rich dietary source of agents that modulate carcinogen activation or stimulate carcinogen detoxification, inhibit cell proliferation, stimulate DNA repair, modulate cell differentiation, stimulate immune modulation and inhibit invasion and metastasis.22 Individuals infected with H. pylori showed a reduction in gastric juice ascorbic acid levels23 and H. pylori may also impair

the protective role of carotenoids in the stomach.24 Numerous carcinogenic substances in smoke might increase gastric cancer risk and the nutrient intakes of smokers are substantially different from those of nonsmokers. Some of these differences may exacerbate the deleterious effects of smoke components on cancer.25 The risk of H. pylori-associated gastric cancer was higher in smokers compared to nonsmokers.26,27 Despite the adverse effects of alcohol on the gastrointestinal mucosa, a causal role in gastric carcinogenesis was considered unlikely.19 Alcohol drinkers may have different dietary habits compared to non-drinkers,28 however, and alcohol may operate as a co-factor for cigarette carcinogens, conceivably acting as a vehicle for carcinogens or breaking protective barriers.19 It was suggested that cigarette smoking may play a main role in initiation and alcohol may promote the development of gastric cancer, especially in the cardia.29 An interaction between H. pylori infection and alcohol consumption was not shown in individual based studies. The observation that alcohol may selectively increase the risk of cancer of the cardia, which, in contrast to distal gastric cancer, seems to be unrelated to H. pylori infection30 –32 is consistent with the hypothesis of interaction between alcohol and H. pylori. The identification of interactions between H. pylori infection and other environmental factors at population level might contribute to explain the high prevalence of H. pylori infection in some countries presenting low gastric cancer rates.14,15 Using data from a large sample of countries in 5 continents we assessed whether fruits and vegetables, alcohol or tobacco modify the association between gastric cancer and H. pylori on the area level. MATERIAL AND METHODS

Country estimates of age-standardized gastric cancer incidence and mortality were obtained from GLOBOCAN 2000,2 and age and gender-standardized rates were computed using the direct method. Data on the H. pylori prevalence were obtained through library search (Pubmed and cross reference search www.ncbi.nih.gov/ entrez/query.fcgi.). We selected studies published as a full paper or abstract written in English, Spanish, French and Portuguese, or in other languages if English abstracts provided enough information. Data on H. pylori prevalence were considered if representing a large age span, and obtained using random samples of the general population, blood donors, patients with no gastrointestinal diseases and people evaluated in health check-ups. Egyptian data available Grant sponsor: Fundac¸a˜ o para a Ciˆencia e a Tecnologia; Grant number: SFRH/BD/3293/2000. *Correspondence to: Servic¸o de Higiene e Epidemiologia, Faculdade de Medicina do Porto, Al. Prof. Hernˆani Monteiro, 4200-319 Porto, Portugal. Fax: ⫹351-225095618. E-mail: [email protected] Received 27 November 2002; Revised 25 April 2003; Accepted 28 April 2003 DOI 10.1002/ijc.11306

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LUNET AND BARROS TABLE I – PREVALENCE OF HELICOBACTER PYLORI INFECTION IN 58 COUNTRIES FROM 5 CONTINENTS Country (reference)

AFRICA Algeria (6) Cˆote d’lvoire (6) Egypt (5) Nigeria (10) South Africa (11) Sudan (13) Zambia (68) AMERICA Argentina (69) Barbados (70) Brazil (71) Canada (72) Chile (41) Colombia (73) Jamaica (74) Mexico (75) USA (76) Venezuela (77) ASIA Bangladesh (12) China (52) India (9) Israel (78) Japan (79) Malaysia (80) Myanmar (81)5 Nepal (82) Republic of Korea (63) Saudi Arabia (7) Thailand (8) Viet Nam (6) EUROPE Albania (84) Austria (85) Belgium (43) Croatia (86)5 Czeck Republic (87)5 Denmark (88) Estonia (89) Finland (90) France (58) Germany (91) Greece (43) Hungary (92)5 Iceland (93) Ireland (94) Italy (55) Lithuania (95)5 Netherlands (96) Norway (97) Poland (98) Portugal (99) Russia (100) Slovenia (43) Spain (101) Sweden (93) Switzerland (102) Turkey (103) United Kingdom (43) OCEANIA Australia (104) New Zealand (105)

Prevalence of infection1

n

Age group (years)

87.72 77.22 88.0 84.0 86.4 73.0 81.0

176 158 169 212 986 89 221

20–59 20–60⫹ 17–42 20–60⫹ 15–64 18–70 ⬎17

Blood donors NA Pregnant women General population General population Volunteers General population, impoverished, urban

49.1 72.0 84.7 37.9 65.52 96.3 72.2 81.3 32.7 92.0

493 230 164 314 416 571 187 5,997 7,465 173

19–80 10–59 20–90 20–72 20–35 18–65 5–45⫹ 20–90 20–70⫹ 35–91

General population, national survey Blood donors General population, rural General population General population, two regions Blood donors, 12 regions General population General population, national survey General population, national survey Neighborhood controls

20–44

Men undergoing a check-up to work as immigrant worker General male population, 46 rural counties Outpatients, low socioeconomic status Individuals undergoing periodic health exams General population Blood donors, general population, five regions NA General population, 2 villages Outpatients, national survey General population Healthy adults, rural Blood donors

91.7

181

Sample

60.4 87.5 65.6 83.7 35.9 80.0 60.42 69.6 75.82 76.42 73.92

1,882 169 311 365 2,381 379 931 3,041 354 100 261

35–64 21–70 20–70 20–89 12–92 13–74 20–93 20–79 21–91 20–75 20–60⫹

74.0 47.0 36.03 60.4 58.8 44.4 89.3 36.0 25.46 39.2 64.33 63.3 39.9

100 100 208 3,082 309 3,608 1,799 500 1,597 1,806 229 NA 332

21–70 26–63 25–643 20–70 20–80 30–60 15–95 18–65 15–92 18–89 25–643 20–60 20–80⫹

43.0 45.1 78.5 36.6 36.07 69.98 82.8 88.0

1,000 930 200 191 310 7,060 970 213

18–60 35–74 18–60 20–59 20–69 18–76 15–70⫹ 20–75

54.83 67.5 29.6 19.09 81.2 29.33

201 922 363 175 271 358

25–643 20–79 20–70⫹ 18–81 19–65 25–643

General population, rural and urban Blood donors and staff working in a congress General population General population, three regions NA General population General population; two rural villages Blood donors Outpatients, national survey General population, national survey General population Blood donors Blood donors, pregnant women, institutionalized elderly, outpatients Blood donors General population, four regions Blood donors Blood donors General population General population Outpatients, 11 cities General population, individuals undergoing routine health exams General population Outpatients General population Volunteers Medical school staff, students, and their relatives General population, two regions

38.0 38.6

273 308

20–80 21–70

General population Blood donors

Year of survey

1987 1987 1992 19924 19944 19984 1999 1996 1990 1993–1994 19944 1990–1991 1998 19994 1987–1988 1988–1991 1991–1997 1995 1983 1988 19934 20004 20014 20014 1996 1998 19904 19904 1987 19994 1990 19934 19974 19984 19944 1990⫹ 19894 1995–1997 1987–1988 19934 1993 1991–1992 19984 1985–1988 20014 19924 19924 1996–1999 19944 19964 19934 1991–1992 1991–1992 20004 19924 19934 1991 1985

1 Data was obtained by blood serology, except when indicated.–2Estimated from the graphs that appeared in the reports.–3Average of prevalence in two age-groups (25–34 and 55– 64) and in males and females.–4Year of publication.–5Data obtained from abstract.–6Saliva serology.–7Culture.–8 13C urea breath test.–9 13C urea breath test, CLO test娂 or histology. NA, not available.

for a sample of pregnant women was included as such. When more than one figure was available for the same country we opted for studies with a national coverage, using random samples of the general

population, with the largest sample size, carried out as close as possible from 1990 and covering the widest adult age span. Selected studies for each country are briefly described in Table I.

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H. PYLORI AND GASTRIC CANCER TABLE II – GASTRIC CANCER INCIDENCE AND AVAILABILITY OF FRUITS AND VEGETABLES, ALCOHOL, AND TOBACCO IN 58 COUNTRIES Country

Africa Algeria Cˆote d’lvoı´re Egypt Nigeria South Africa Sudan Zambia America Argentina Barbados Brazil Canada Chile Colombia Jamaica Mexico USA Venezuela Asia Bangladesh China India Israel Japan Malaysia Myanmar Nepal Republic of Korea Saudi Arabia Thailand Viet Nam Europe Albania Austria Belgium Croatia Czeck Republic Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland Italy Lithuania Netherlands Norway Poland Portugal Russia Slovenia Spain Sweden Switzerland Turkey United Kingdom Oceania Australia New Zealand

Gastric cancer incidence1 (/100000)

Fruits and vegetables2 (Kg/day/capita)

Alcohol3 (1.alcohol/day/adult)

Tobacco4 (cigarettes/day/adult)

6.5 3.6 3.4 4.2 6.3 3.6 9.2

0.31 0.33 0.59 0.31 0.23 0.16 0.11

0.0007 0.0035 0.0015 0.0019 0.0211 0.0007 0.0018

4.4 1.9 3.3 1.0 4.7 0.4 1.2

9.1 13.8 15.7 6.7 27.0 26.9 23.9 14.4 5.6 17.3

0.41 0.33 0.37 0.61 0.39 0.35 0.42 0.41 0.61 0.37

0.0267 0.0248 0.0152 0.0209 0.0204 0.0177 0.0109 0.0140 0.0246 0.0254

4.4 2.98 4.1 7.0 2.8 4.8 2.4 2.7 7.3 5.3

1.3 26.8 4.3 11.1 48.9 9.4 9.8 5.0 47.9 5.3 3.9 17.6

0.06 0.33 0.23 0.91 0.45 0.20 0.19 0.20 0.70 0.67 0.35 0.25

0.00005 0.0142 0.0025 0.0047 0.0216 0.0024 0.0006 0.00045 0.0395 0.00025 0.0229 0.0033

2.77 5.2 3.87 6.3 8.9 4.5 0.4 1.6 8.2 5.8 2.9 2.2

15.0 12.4 8.6 19.5 12.3 6.3 21.2 9.0 7.8 12.7 9.0 18.6 9.9 9.6 15.1 20.6 9.1 8.6 15.9 22.6 30.5 16.3 13.2 6.8 8.8 8.1 9.0

0.34 0.60 0.67 0.32 0.35 0.43 0.23 0.38 0.56 0.57 1.18 0.44 0.33 0.40 0.86 0.26 0.62 0.42 0.43 0.71 0.33 0.32 0.85 0.44 0.58 0.88 0.45

0.0067 0.0326 0.0303 0.03105 0.0391 0.0331 0.02185 0.0227 0.0384 0.0325 0.0291 0.0359 0.0130 0.0324 0.0266 0.01505 0.0267 0.0133 0.0224 0.0366 0.019210 0.03725 0.0312 0.0174 0.0314 0.0039 0.0253

3.3 6.1 6.3 6.46,11 6.810 5.3 4.8 4.8 5.8 6.5 9.8 8.9 7.8 6.6 5.3 4.5 7.7 5.0 9.9 5.5 4.06,9 8.36,12 7.3 4.2 8.0 5.8 6.1

7.3 8.1

0.48 0.58

0.0265 0.0250

7.4 6.9

1 Data was obtained from GLOBOCAN 2000.2–2Data was obtained from the FAO food balance sheets (years 1990 –1992).34–3Data was obtained from the World Health Organization Global Report on Alcohol Consumption (1994 –1996), except when indicated.33–4Data was obtained from the World Health Organization. Tobacco and health: a global status report (1990 –1992), except when indicated.35–5Data obtained from the FAO food balance sheets (1994 –1996).34–6Data was obtained from the National Tobacco Information Online System database.36– 7 Including bidis.–81990.–91992.–101993.–111994.–121996.

Adult per capita alcohol consumption (litre of alcohol/day/ adult) was obtained in World Health Organization Global Report on Alcohol Consumption33 for years 1994 –96. The mean of 3 consecutive years was used to overcome random fluctuation in availability of food items and beverages. When no data

was available for a specific country, apparent alcohol intake was calculated from consumption of beer (5% alcohol), wine (12% alcohol), spirits (40% alcohol) and other fermented beverages (5% alcohol) as supplied by the FAO Food Balance Sheets.34

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The availability of fruits and vegetables (Kg/day/person) was obtained from FAO Food Balance Sheets for years 1990 –92.34 Data on fruits and vegetables were added and used as a single variable. Adult apparent tobacco consumption (cigarettes/day/adult) was obtained in the Tobacco and Health Report35 and expressed as the number of cigarettes available per capita, per year, for 1990 –92. Figures for the nearest available year at the National Tobacco Information Online System database36 were used when no data was available for this period in the Tobacco and Health Report. Gastric cancer incidence and availability of fruits and vegetables, alcohol and tobacco for each of the 58 countries is presented in Table II. Data were analyzed using STATA威. Gastric cancer incidence and mortality rates were log-transformed. Linear regression models were fitted, using gastric cancer incidence or mortality rates as a dependent variable and H. pylori prevalence, fruits and vegetables, tobacco and alcohol, as well as product terms representing interaction between H. pylori and fruits and vegetables, tobacco or alcohol as independent variables. Residual diagnostics and influence statistics were used to verify if the regression assumptions were satisfied.37 Models including the interaction terms were used to compute gastric cancer incidence multiplying regression coefficients by a H. pylori prevalence of 85% (the approximate median in African countries) and the median figures observed in each continent for alcohol and tobacco availability. RESULTS

Median and range values for key variables describing the 58 countries (7 from Africa, 10 from America, 14 from Asia and Oceania and 27 from Europe) are listed in Table III. There is a large intercountry variation, with a rate ratio (highest:lowest) of

about 35 for gastric cancer incidence and 5 for H. pylori prevalence. The widest ranges for most variables were observed in Asia and Oceania. The lowest gastric cancer rates occur in Africa where the highest H. pylori prevalence and the lowest availability of fruits and vegetables, alcohol or tobacco are recorded. Most African as well as some Asian (Bangladesh, India, Saudi Arabia and Thailand) countries presented low cancer rates but high H. pylori prevalence (Fig. 1). There was a positive association between log-gastric cancer incidence and H. pylori prevalence (␤H. pylori ⫽ 0.0055, p ⬍ 0.05) after adjustment for fruits and vegetables consumption, alcohol intake and cigarette smoking. Statistically significant interactions were observed between H. pylori prevalence and alcohol consumption or cigarette smoking (Table IV). Terms considering the interaction between fruits and vegetables and tobacco (␤fruits and vegetables * tobacco ⫽ ⫺0.09, p ⫽ 0.18) or alcohol (␤fruits and vegetables * alcohol ⫽ ⫺10.30, p ⫽ 0.42), and alcohol and tobacco (␤alcohol * tobacco ⫽ ⫺1.68, p ⫽ 0.23) were assessed but neither reached statistical significance nor added further information to explain the international variation in gastric cancer incidence. Considering a H. pylori prevalence of 85% (about the median in African countries) and the median alcohol and tobacco availability in each continent, the expected gastric cancer incidence per 100,000 would be 5.7 assuming the alcohol and tobacco availability in African countries, 7.0 in Asia and Oceania, 16.0 in America and 26.0 in Europe using the coefficients from Model 12 (Table IV), and 5.8 assuming the figures from African countries, 9.6 in Asia and Oceania, 13.3 in America and 22.1 in Europe using the coefficients from Model 13 (Table IV). Similar results (data not shown) were observed using log-gastric cancer mortality rates. The above mentioned interactions are essentially unchanged when sensitivity analysis is carried out in models with H. pylori, alcohol, tobacco and respectively the interaction terms H. pylori * alcohol (Model 12) or H. pylori * tobacco (Model 13) excluding

TABLE III – MEDIAN AND RANGE OF GASTRIC CANCER INCIDENCE AND MORTALITY, HELICOBACTER PYLORI PREVALENCE, AND AVAILABILITY OF FRUITS AND VEGETABLES, ALCOHOL, AND CIGARETTES IN 58 COUNTRIES1 Gastric cancer

Africa America Asia & Oceania Europe Total 1

n

Incidence (/100000)

Mortality (/100000)

7 10 14 27 58

4.2 (3.4–9.2) 15.0 (5.6–27.0) 8.8 (1.3–48.9) 12.3 (6.3–30.5) 9.5 (1.3–48.9)

3.5 (2.8–7.9) 12.0 (3.4–21.4) 6.4 (1.1–30.6) 9.4 (5.5–25.4) 7.8 (1.1–30.6)

Helicobacter pylori (%)

Fruits and vegetables (Kg/day/capita)

Alcohol (I alcohol/day/adult)

Tobacco (cigarettes/day/adult)

84.0 (73.0–88.0) 72.1 (32.7–96.3) 71.7 (35.9–91.7) 47.0 (19.0–89.3) 66.5 (19.0–96.3)

0.31 (0.11–0.59) 0.40 (0.33–0.61) 0.34 (0.06–0.91) 0.44 (0.23–1.18) 0.40 (0.06–1.18)

0.0018 (0.0007–0.0211) 0.0206 (0.0109–0.0267) 0.0040 (0.0000–0.0395) 0.0291 (0.0039–0.0391) 0.0214 (0.0000–0.0395)

1.9 (0.4–4.7) 4.2 (2.4–7.3) 4.8 (0.4–8.9) 6.1 (3.3–9.9) 5.2 (0.4–9.9)

Values are median (range).

FIGURE 1 – Gastric cancer incidence rates as a function of Helicobacter pylori prevalence (semilogarithmic scale).

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1

Values are ␤ (SE) except for Constant and statistical values. Hp, H. pylori.–2Percentage.–3Kg/day/capita.–41 alcohol/day/adult.–5Cigarttes/day/adult.–6p ⬍ 0.05.–7Adjusted–r2.

0.01 0.02 0.17 0.10 0.007 0.257 0.147 0.247 0.027 0.397 0.237 0.397 0.337 0.397 0.45 0.34 ⬍0.01 ⬍0.05 0.36 ⬍0.001 ⬍0.01 ⬍0.01 0.22 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.67 0.93 11.55 6.28 1.12 10.69 5.72 5.57 1.49 13.36 6.65 10.04 8.09 8.30 0.92 0.94 0.83 0.81 0.78 0.43 0.47 0.37 1.34 1.26 1.68 1.19 1.49 1.55 — — — — — — — — — — 0.003 (0.001)6 — 0.003 (0.001)6 0.001 (0.001) 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0.0015 (0.0019) — — — 0.0022 (0.0019) 0.0052 (0.0018)6 0.0041 (0.0019)6 0.0055 (0.0018)6 ⫺0.0058 (0.0057) ⫺0.0063 (0.0035) ⫺0.0126 (0.0065) ⫺0.0058 (0.0036) ⫺0.0102 (0.0061) ⫺0.0108 (0.0058)

— 0.176 (0.183) — — 0.237 (0.190) — — ⫺0.082 (0.195) ⫺0.953 (0.828) — — — — —

— — 9.9 (2.9)6 — — 13.8 (3.1)6 — 11.5 (3.8)6 — ⫺22.8 (10.3)6 — ⫺23.4 (10.3)6 11.0 (3.6)6 ⫺17.0 (11.9)

— — — 0.041 (0.016)6 — — 0.056 (0.017)6 0.025 (0.023) — — ⫺0.149 (0.078) 0.013 (0.018) ⫺0.170 (0.073)6 ⫺0.073 (0.080)

— — — — — — — — 0.018 (0.012) — — — — —

— — — — — — — — — 0.547 (0.148)6 — 0.535 (0.149)6 — 0.433 (0.176)6

Constant Hp* Tobacco Hp* Alcohol Hp* Fruits and vegetables Tobacco5 Alcohol4 Fruits & vegetables3 H. pylori (Hp)2 Model

TABLE IV – REGRESSION MODELS FOR POTENTIAL DETERMINANTS OF GASTRIC CANCER INCIDENCE (LOG-TRANSFORMED) IN 58 COUNTRIES FROM 5 CONTINENTS1

F

p

r2

H. PYLORI AND GASTRIC CANCER

data from African countries (␤alcohol * H. pylori ⫽ 0.503, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0024, p ⬍ 0.05), American (␤alcohol * H. pylori ⫽ 0.499, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0026, p ⬍ 0.05), Asian (␤alcohol * H. pylori⫽ 0.383, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0011, p ⫽ 0.30), and European (␤alcohol * H. pylori⫽ 0.841, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0052, p ⬍ 0.05), whose cancer rates were estimated using data from neighboring countries2 (Albania, Bangladesh, Egypt, Nepal, Nigeria, Saudi Arabia, Sudan and Zambia) (␤alcohol * H. pylori ⫽ 0.347, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0020, p ⫽ 0.06). The interaction coefficients remained approximately the same after excluding countries for which H. pylori prevalence was obtained from blood donors (␤alcohol * H. pylori ⫽ 0.589, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0032, p ⬍ 0.05), outpatients (␤alcohol * H. pylori ⫽ 0.438, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0021, p ⫽ 0.05), samples including ⬍200 subjects (25th centile of the 58 surveys) (␤alcohol * H. pylori ⫽ 0.373, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0021, p ⬍ 0.05) or using methods other than blood serology (␤alcohol * H. pylori ⫽ 0.657, p ⬍ 0.05; ␤tobacco * H. pylori ⫽ 0.0034, p ⬍ 0.05). DISCUSSION

Countries with high H. pylori prevalence may have different gastric cancer rates depending on the alcohol and tobacco consumption. Geographical differences in the occurrence of gastric cancer are due to differences in H. pylori prevalence but may be further explained by exposure to alcohol and tobacco. Our study follows an ecological design and thus has the wellknown advantages and limitations of such methodological approach.38 Some considerations must be done referring the sources of data and the specific analytic methods we used. The accuracy of GLOBOCAN 2000 incidence and mortality estimates depends on the quality and availability of local data and is usually higher for mortality. In our study, however, similar results were obtained regardless of the frequency measure used or removing from analysis data from 8 countries whose cancer rates were estimated from those observed in neighboring countries.2 Although data from many African and Asian countries probably lack accuracy39 and the low gastric cancer rates may be partly attributed to problems in case ascertainment and certification, the incidence of gastric cancer would have to be underestimated by 90 – 480% to bring, for example, Northern Africa incidence to the level of South America or Japan.39 In African and Asian countries involved in our study the median proportion of all cancers attributable to gastric cancer cases is about 50% of that observed in South and Central American countries.2 Assuming a high degree of underestimation of cancer occurrence in African and Asian countries it would have to be much higher in gastric cancer compared to other cancer locations to explain completely the African and Asian enigmas, because not only the gastric cancer incidence and mortality are low in Africa and in part of Asia, compared with South and Central America (with high H. pylori prevalence) but also the proportion of all cancers attributable to gastric cancer. The quality H. pylori prevalence data varies from country to country due to sampling procedures, number and age-range of assessed subjects and the performance of diagnostic tests. We opted for studies providing data on the H. pylori prevalence for a wide adult age span. Age-range differences are not expected to affect our conclusions because the weight of extreme groups is expectedly low. Additionally, ages above 60 or 70 years are not expected to influence overall prevalence in high H. pylori prevalence countries because their populations acquire the infection early in life, resulting in high prevalence across every adult age group.40 As an example, in Chile, represented in our study by a survey involving subjects 20 –35 years of age,41 a prevalence of infection of 60 –70% in people younger than 20 years of age was estimated in another survey.42 With the exception of some countries that had only more recent data available, we included surveys carried out in the late 80s or early 90s. This heterogeneity is not

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expected to be a major influence. Rates of infection in adults estimated recently from countries with high prevalence of H. pylori are probably similar to those present a few years ago because infection is acquired early in life.40 Studies such as EUROGAST,43 based on more standardized methods only covered a limited number of countries and in most cases single regions in each country. Because H. pylori prevalence varies across regions within a country, we favored studies with the most representative geographic coverage available. The sensitivity analysis carried out supports the hypothesis that intercountry differences on the characteristics of surveys for evaluation of H. pylori prevalence concerning the populations evaluated, number of subjects or diagnostic methods had no significant influence in our conclusions. Estimates of fruit and vegetable consumption, alcohol intake and cigarette smoking are not real per capita consumption data but describe the availability of such products (usually derived from production ⫹ imports ⫺ exports) that under certain assumptions may be used as surrogates for consumption. Estimates do not account for stockpiling by consumers, retailers or wholesalers or by smuggling. Informal, home or domestic alcohol production is extremely important and in some cases may account for as much as 80% of the total alcohol available for consumption.33 With these limitations in mind, per capita availability of alcohol is the best for monitoring global trends. It covers more years and more countries than survey-based prevalence of alcohol use estimates33 although it can be affected by underreporting. Quality of data and the correlation between availability and consumption are expected to differ across countries. Similar considerations apply to data on smoking. When analyzing aggregated data in an ecological analysis the ability to extend inferences reliably to less aggregated data is lost. This type of analysis should be limited to the role of hypothesis generation.44 Our attempt to explain the country variation in gastric cancer rates using the exposures to H. pylori, fruits and vegetables, alcohol and tobacco is supported by previous findings from laboratory research and epidemiological studies using individual subjects as the analysis unit. Our results are also compatible with the observation of different gastric cancer rates according to gender despite small gender differences in H. pylori prevalence.45 Alcohol and tobacco consumption are more frequent among men35,46 worldwide. Additionally, the lowest consumptions of alcohol and tobacco are observed in Africa and Asia,35,46 where the median male:female gastric cancer incidence ratio is lower (1.7 and 2.0, respectively) than in America (2.1) or Europe (2.1).2 In a recent study, the overall antioxidant capacity in healthy subjects was related negatively to tobacco smoking, alcohol intake, moderate vegetable and low fruit consumption.47 Whereas low fruit and vegetable intakes are probably related to a decreased individual antioxidant capacity, only a weak relation between high fruit consumption and an increased antioxidant potential was found, suggesting that it is easier to damage the regulated antioxidant defense system by reducing dietary antioxidants than to strengthen this system by increasing dietary antioxidants.47 This may be the basis for the interaction we observed between alcohol or tobacco consumption and H. pylori infection but not with fruits and vegetables. Geographical correlation studies attempting to explain international48,49 or regional variation in gastric cancer incidence or mortality rates showed rather inconsistent results, despite model-

ing European, North and South American and Asian experiences. Analysis was often restricted to regions within a single country,50 –58 mostly with a small range of variation both in the prevalence of infection and cancer rates.53–56,58 Only the studies with wide gastric cancer rates range showed weak but significant positive correlations.48,51,52 In one of these studies, a significant positive correlation between H. pylori prevalence and gastric cancer mortality remained after adjusting for dietary factors but not after adjustment for the blood micronutrient levels.59 Our study extends previous research by modeling the experience of a larger number of countries from 5 continents, with a wide variation in gastric cancer rates, prevalence of H. pylori, fruits and vegetables, alcohol and tobacco consumption, optimizing the chances of detecting effects. The negative regression coefficients in Models 10 –14 (Table IV) could be interpreted as evidence for a protective effect of H. pylori in the absence of alcohol and tobacco consumption. This apparent inconsistency reflects the fact that our models do not fully explain all the variability in the international gastric cancer rates. Information on other factors, including host response,60 genetic profile,61 environmental hazards, lifestyles such as salt consumption, H. pylori pathogenicity or combined bacterial/host genotyping62 would contribute to explain the remaining variation and overcome such unexpected finding after all that is known from individual based studies. Salt intake, measured as 24-hr urine sodium excretion was correlated highly with gastric cancer mortality in an ecological study involving 24 countries.63 In African countries, salt excretions are generally low compared to many European or Eastern Asian countries. H. pylori isolates from stomach cancer in high-risk populations may differ genetically from those in low-risk areas. Although 2 ecological studies49,64 accounting for H. pylori cagA ⫹ prevalence did not yield stronger associations with gastric cancer rates than those observed with H. pylori prevalence. The study of cagA and vacA status of a large collection of H. pylori cultures from patients of diverse geographic origins obtained by endoscopy, showed a heterogeneous distribution of H. pylori genotypes according to their origin.65 A study carried out in South Africa showed no difference in the prevalence of H. pylori infection when comparing gastric cancer cases with matched controls but the risk of gastric cancer depended on the H. pylori genotype.66 In Colombia, higher relative frequencies of cagA positive and vacA s1 and m1 genotypes were found in patients from a population with high risk for gastric cancer as compared to a population from a low risk area.67 In conclusion, our results suggest that the interaction between H. pylori and cigarette consumption may contribute to further explain the international variation in gastric cancer and the so-called African and Asian enigmas. The modification of the H. pylori effect by alcohol, however, requires confirmation at an individual level and it remains too much potential for uncontrolled confounding in the association between H. pylori and gastric cancer on an area level. Further information on the variability in the infecting organism, host response to infection and other environmental factors will allow new insights in this subject. ACKNOWLEDGEMENTS

N. Lunet gratefully acknowledges a grant from Fundac¸a˜o para a Cieˆncia e a Tecnologia (SFRH/BD/3293/2000).

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