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Keitaro Tanaka, Ichiro Tsuji, Kenji Wakai, Chisato Nagata, Tetsuya Mizoue, Manami Inoue, Shoichiro Tsugane, for the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan, Cigarette Smoking and Liver Cancer Risk: An Evaluation Based on a Systematic Review of Epidemiologic Evidence among Japanese, Japanese Journal of Clinical Oncology, Volume 36, Issue 7, July 2006, Pages 445–456, https://doi.org/10.1093/jjco/hyl040
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Abstract
Background: Emerging epidemiologic data suggest that cigarette smoking may increase the risk of primary liver cancer. We evaluated this association based on a systematic review of epidemiologic evidence among Japanese populations.
Methods: Original data were obtained from MEDLINE searches using PubMed, complemented with manual searches. The evaluation was performed in terms of the magnitude of association (‘strong’, ‘moderate’, ‘weak’ or ‘no association’) in each study and the strength of evidence (‘convincing’, ‘probable’, ‘possible’ or ‘insufficient’), together with biological plausibility as previously done by the International Agency for Research on Cancer.
Results: A total of 12 cohort studies and 11 case–control studies were identified. Nine cohort studies (two with adjustment for hepatitis B and C virus infections and seven without it) reported weak to strong positive associations between smoking and liver cancer, with dose–response relationships shown in three studies. Five case–controls studies (three with the virus adjustment and two without it) demonstrated such positive associations, with a dose–response relationship shown in only one study, while in six case–control studies, the observed associations were judged to be of the lowest magnitude or inverse due to the lack of any dose–response relationship.
Conclusion: We conclude that cigarette smoking ‘probably’ increases the risk of primary liver cancer among the Japanese. Potential confounding by hepatitis virus infection and virus–smoking interactions need to be addressed in future studies.
INTRODUCTION
Primary liver cancer is one of the most common cancers in Japan (1). Its primary prevention remains to be a major concern for both clinicians and epidemiologists, since patients with this tumor still present poor prognosis (1,2). More than 90% of primary liver cancers in Japan are known to be hepatocellular carcinomas (2), which are mostly attributable to chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) (2,3). However, emerging evidence suggests that hepatocarcinogenesis is a multistage process, in which environmental factors other than hepatitis viruses may play additional roles (4). One of such candidates is cigarette smoking, which has not yet attracted much attention of clinicians or the public. Recently, the International Agency for Research on Cancer listed liver cancer as a tobacco-related malignancy (5). In this context, the objective of the present study was to review and summarize epidemiological findings on cigarette smoking and liver cancer among Japanese populations. This work was conducted as part of a project of systematic evaluation of the epidemiological evidence regarding lifestyles and cancers in Japan (6).
METHODS
The details of the evaluation method have been described elsewhere (6). In brief, original data for this review were identified by MEDLINE searches using PubMed, complemented by manual searches of references from relevant articles where necessary. All epidemiologic studies on the association between cigarette smoking and liver cancer incidence or mortality among the Japanese from 1963 to 2005, including papers in press if available, were identified using the search terms ‘smoking’, ‘liver’, ‘hepatocellular’, ‘cohort’, ‘follow-up’, ‘case–control’, ‘Japan’ and ‘Japanese’ as keywords. Papers written in either English or Japanese were reviewed, and only studies on Japanese populations living in Japan were included. The individual results were summarized in the tables separately by a study design as cohort or case–control studies.
The evaluation was made based on the magnitude of association and the strength of evidence. First, the former was assessed by classifying relative risk (RR) in each study into the following four categories, while considering statistical significance (SS) or no statistical significance (NS): (i) ‘strong’ (symbol ↓↓↓ or ↑↑↑) when RR < 0.5 (SS) or RR > 2.0 (SS); (ii) ‘moderate’ (symbol ↓↓ or ↑↑) when RR < 0.5 (NS), 0.5 ≤ RR < 0.67 (SS), 1.5 < RR ≤ 2.0 (SS) or RR > 2.0 (NS); (iii) ‘weak’ (symbol ↓ or ↑) when 0.5 ≤ RR < 0.67 (NS), 0.67 ≤ RR ≤ 1.5 (SS) or 1.5 < RR ≤ 2.0 (NS) and (iv) ‘no association’ (symbol −) when 0.67 ≤ RR ≤ 1.5 (NS). When RRs for three or more exposure levels were reported, that for the highest level was employed for this classification. In the case of multiple publications of analyses of the same or overlapping datasets, only data from the largest or most updated results were included. After this process, the strength of evidence was evaluated in a similar manner to that used in the WHO/FAO Expert Consultation Report (7), in which evidence was classified as ‘convincing’, ‘probable’, ‘possible’ and ‘insufficient’. We assumed that biological plausibility corresponded to the judgment of the most recent evaluation from the International Agency for Research on Cancer (5). Notwithstanding the use of this quantitative assessment rule, an arbitrary assessment cannot be avoided when considerable variation exists in the magnitude of association between the results of each study. The final judgment, therefore, was made based on a consensus of the research group members, and it was therefore not necessarily objective. When we reach a conclusion that there is ‘convincing’ or ‘probable’ evidence of an association, we conduct a meta-analysis to obtain summary estimates for the overall magnitude of association.
MAIN FEATURES AND COMMENTS
We identified a total of 12 cohort studies (8–19) (Table 1) and 11 case–control studies (20–30) (Table 2). Of the cohort studies, three presented results by sex (9,14,19), four for men only (8,10,11,18) and five only for men and women combined (12,13,15–17). The respective numbers for the case–control studies are one (29), five (20,24–27) and five (21–23,28,30). One cohort study showed results separately in two different areas (11), and two case–control studies reported results separately based on hospital controls and community controls (25,29).
Reference . | Study period . | Study population . | . | . | . | Category . | Number among cases . | Relative risk (95% CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Number of subjects for analysis . | Source of subjects . | Event followed . | Number of incident cases or deaths . | . | . | . | . | . | . | |||
Kono et al. (8) | 1965–1983 | 5130 men | Male physicians in western Japan | Death | 51 men (primary 9, unspecified 42) | Never/past | 1.00 | Age, drinking | HBsAg and anti- HCV were not tested | |||||
1–19 cigarettes/day | 1.14 (0.59–2.20) | |||||||||||||
≥20 cigarettes/day | 1.04 (0.49–2.23) | |||||||||||||
Akiba and Hirayama(9) | 1966–1981 | 265 118 (122 261 men and 142 857 women) | 95% of the census population in 29 health- center-covered areas in 6 prefectures | Death | 1050 (652 men and 398 women) | For men | Age, prefecture, occupation, observation period | HBsAg and anti- HCV were not tested. Adjustment for alcohol consumption only slightly changed the relative risks | ||||||
Never | 106 | 1.0 | 0.002 | |||||||||||
Daily | 546 | 1.5 (1.2–1.9) | ||||||||||||
1–4/day | 8 | 1.1 (0.5–2.0) | ||||||||||||
5–14/day | 240 | 1.6 (1.3–2.0) | ||||||||||||
15–24/day | 254 | 1.4 (1.2–1.8) | ||||||||||||
25–34/day | 29 | 1.6 (1.1–2.4) | ||||||||||||
≥35/day | 15 | 1.9 (1.1–3.2) | ||||||||||||
For women | ||||||||||||||
Never | 334 | 1.0 | 0.001 | |||||||||||
Daily | 64 | 1.6 (1.2–2.0) | ||||||||||||
1–4 /day | 9 | 1.4 (0.7–2.5) | ||||||||||||
5–14 /day | 42 | 1.4 (1.0–2.0) | ||||||||||||
≥15 /day | 13 | 2.5 (1.3–4.1) | ||||||||||||
Inaba et al. (10) | 1973–1988 | 270 men | Patients with liver cirrhosis at the Juntendo University Hospital | Death | 46 men | Never | 1.00 | Age, HBsAg, histories of transfusion, hepatitis and surgical operation, drinking | Anti-HCV was not tested | |||||
Current/past | 2.57 (0.46–14.24) | |||||||||||||
Shibata et al. (11) | 1958–1986 | 639 men in a farming area and 677 men in a fishing area | Residents in a farming or a fishing area in Kyushu | Death | 11 men (farming area) and 22 men (fishing area) | Farming area | ||||||||
Non-smoker | 2 | 1.0 | >0.1 | Age | HBsAg and anti-HCV were not tested | |||||||||
Ex-smoker | 0 | – | ||||||||||||
Current smoker | 8 | 1.1 (0.2–4.7) | ||||||||||||
1–9/day | 1 | 0.6 (0.1–3.7) | ||||||||||||
10–19/day | 7 | 1.2 (0.2–5.7) | ||||||||||||
20–29/day | 0 | – | ||||||||||||
≥30/day | 0 | – | ||||||||||||
Fishing area | ||||||||||||||
Non-smoker | 1 | 1.0 | >0.1 | Age | ||||||||||
Ex-smoker | 2 | 2.9 (0.3–29.0) | ||||||||||||
Current smoker | 19 | 3.6 (0.6–22.3) | ||||||||||||
1–9/day | 7 | 11.9 (1.5–96.8) | ||||||||||||
10–19/day | 3 | 1.1 (0.1–10.6) | ||||||||||||
20–29/day | 7 | 2.7 (0.4–19.2) | ||||||||||||
≥30 /day | 2 | 3.2 (0.4–23.7) | ||||||||||||
Fishing area | ||||||||||||||
Non/ex-smoker | 3 | 1.00 | Age, drinking | |||||||||||
1–19/day | 10 | 2.10 (0.44–9.95) | ||||||||||||
≥20/day | 9 | 1.86 (0.37–9.40) | ||||||||||||
Kato et al.(12) | 1987–1990 | 1784 | Patients with decompensated liver cirrhosis or post-transfusion hepatitis | Incidence | 122 | Never smoker | 39 | 1.00 | Sex, age | HBsAg and anti- HCV status was unknown | ||||
Past smoker | 10 | 0.94 (0.44–2.02) | ||||||||||||
Current smoker | 23 | 0.96 (0.53–1.75) | ||||||||||||
Smoking index | ||||||||||||||
0 | 39 | 1.00 | 0.82 | |||||||||||
1–599 | 11 | 0.83 (0.40–1.74) | ||||||||||||
≥600 | 14 | 0.94 (0.47–1.89) | ||||||||||||
Tsukuma et al. (13) | 1987–1991 | 917 (548 men and 369 women) | Patients with chronic hepatitis or compensated cirrhosis at the Center for Adult Diseases, Osaka | Incidence | 54 | Among all patients | Age, sex, stage of disease, serum alpha-fetoprotein, HBsAg, anti-HBc, anti-HCV, drinking | HBsAg and anti-HCV status was adjusted for | ||||||
Non-smoker | 1.00 | 0.07 | ||||||||||||
Ex-smoker | 1.68 (0.63–4.47) | |||||||||||||
Current smoker | 2.30 (0.90–5.86) | |||||||||||||
Among patients with liver cirrhosis | ||||||||||||||
Non-smoker | 1.00 | 0.003 | ||||||||||||
Ex-smoker | 3.44 | |||||||||||||
Current smoker | 7.96 | |||||||||||||
Goodman et al. (14) | 1980–1989 | 36 133 | Atomic bomb survivors | Incidence | 242 (156 men and 86 women) | For men | Sex, city, age at the time of bombing, age, radiation dose to the liver | HBsAg and anti-HCV was not tested | ||||||
Never-smoker | 6 | 1.00 | ||||||||||||
Ever-smoker | 146 | 4.36 (1.93–9.86) | ||||||||||||
Ex-smoker | 46 | 4.56 (1.95–10.7) | ||||||||||||
Quit ≥24 years ago | 14 | 4.04 (1.54–10.6) | ||||||||||||
Quit 14–23 years ago | 14 | 4.11 (1.58–10.7) | ||||||||||||
Quit <14 years ago | 14 | 5.60 (2.15–14.6) | ||||||||||||
Present smoker | 100 | 4.26 (1.87–9.72) | ||||||||||||
1–22 pack-years | 38 | 6.47 (2.74–15.3) | ||||||||||||
23–40 pack-years | 39 | 4.43 (1.87–10.5) | ||||||||||||
≥41 pack-years | 41 | 3.09 (1.31–7.29) | ||||||||||||
For women | ||||||||||||||
Never-smoker | 61 | 1.00 | ||||||||||||
Ever-smoker | 20 | 1.60 (0.97–2.66) | ||||||||||||
Ex-smoker | 7 | 1.66 (0.76–3.63) | ||||||||||||
Quit ≥25 years ago | 3 | 2.31 (0.72–7.43) | ||||||||||||
Quit 10–24 years ago | 2 | 1.03 (0.25–4.24) | ||||||||||||
Quit <10 years ago | 2 | 10.4 (2.51–43.5) | ||||||||||||
Present smoker | 13 | 1.58 (0.86–2.88) | ||||||||||||
1–15 pack-years | 8 | 1.81 (0.86–3.78) | ||||||||||||
≥16 pack-years | 8 | 1.51 (0.72–3.16) | ||||||||||||
Chiba et al.(15) | 1977–1993 | 412 (249 men and 163 women) | Patients with HCV-associated chronic hepatitis or compensated cirrhosis at the Tsukuba University Hospital | Incidence | 63 (54 men and 9 women) | Non-smoker | 1.00 | Sex, age, stage of disease, serum alpha-fetoprotein, anti-HBs, anti-HBc, histories of transfusion, surgical procedure and liver cancer in family, drinking | All subjects were anti-HCV-positive and HBsAg- negative | |||||
Smoking index <400 | 1.67 (0.75–3.73) | |||||||||||||
Smoking index ≥ 400 | 2.46 (1.11–5.49) | |||||||||||||
Tanaka et al. (16) | 1985–1995 | 96 (62 men and 34 women) | Patients with liver cirrhosis at the Kyushu University Hospital | Incidence | 37 (27 men and 10 women) | Never smoker | 12 | 1.00 | Sex, age, years since LC diagnosis, department, hospitalization status, serum albumin, AST, alpha-fetoprotein, HBsAg, anti-HCV, drinking | The relative risks were not described in the original paper, and were re-estimated by one of the authors (KT). HBsAg and anti-HCV status was adjusted for | ||||
Past smoker | 12 | 0.44 (0.11–1.79) | ||||||||||||
Current smoker | ||||||||||||||
<20 cigarettes/day | 9 | 1.46 (0.29–7.37) | ||||||||||||
≥20 cigarettes/day | 4 | 1.00 (0.19–5.28) | ||||||||||||
Mori et al.(17) | 1992–1997 | 3052 (974 men and 2078 women) | Residents in a town in Saga prefecture | Incidence | 22 (14 men and 8 women) | History of cigarette smoking | Sex, age | Anti-HCV and HBsAg status was available, but not adjusted for | ||||||
No | 10 | 1.00 | ||||||||||||
Yes | 22 | 2.10 (0.61–7.23) | ||||||||||||
Never-smoker | 10 | 1.00 | 0.30 | |||||||||||
Smoking index <200 | 1 | 3.26 (0.38–28.2) | ||||||||||||
Smoking index ≥200 | 11 | 1.97 (0.57–6.87) | ||||||||||||
Mizoue et al. (18) | 1986–1996 | 4050 men | Residents in 4 municipalities in Fukuoka prefecture | Death | 59 men | Never smoker | 4 | 1.0 | Age, study area, drinking | HBsAg and anti- HCV were not tested | ||||
Ex-smoker | 22 | 2.9 (1.0–8.4) | ||||||||||||
Current smoker | 33 | 3.3 (1.2–9.5) | ||||||||||||
1–24 cigarettes/day | 25 | 3.5 (1.2–10.2) | ||||||||||||
≥25 cigarettes/day | 8 | 2.8 (0.8–9.6) | ||||||||||||
Ogimoto et al. (19) | 1988–1999 | 65 528 (28 287 men and 37 241 women) | Residents in 45 areas throughout Japan | Death | 186 (number by sex not described) | Men (40–59 years) | Collaborating institutes | HBsAg and anti-HCV were not tested | ||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.37 (0.83–6.78) | |||||||||||||
Current smoker | 1.96 (0.75–5.14) | |||||||||||||
Men (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.72 (1.21–6.11) | |||||||||||||
Current smoker | 2.62 (1.18–5.84) | |||||||||||||
Women (40–59 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | – | |||||||||||||
Current smoker | 2.82 (0.61—13.09) | |||||||||||||
Women (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 1.18 (0.16–8.67) | |||||||||||||
Current smoker | 1.49 (0.46–4.87) |
Reference . | Study period . | Study population . | . | . | . | Category . | Number among cases . | Relative risk (95% CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Number of subjects for analysis . | Source of subjects . | Event followed . | Number of incident cases or deaths . | . | . | . | . | . | . | |||
Kono et al. (8) | 1965–1983 | 5130 men | Male physicians in western Japan | Death | 51 men (primary 9, unspecified 42) | Never/past | 1.00 | Age, drinking | HBsAg and anti- HCV were not tested | |||||
1–19 cigarettes/day | 1.14 (0.59–2.20) | |||||||||||||
≥20 cigarettes/day | 1.04 (0.49–2.23) | |||||||||||||
Akiba and Hirayama(9) | 1966–1981 | 265 118 (122 261 men and 142 857 women) | 95% of the census population in 29 health- center-covered areas in 6 prefectures | Death | 1050 (652 men and 398 women) | For men | Age, prefecture, occupation, observation period | HBsAg and anti- HCV were not tested. Adjustment for alcohol consumption only slightly changed the relative risks | ||||||
Never | 106 | 1.0 | 0.002 | |||||||||||
Daily | 546 | 1.5 (1.2–1.9) | ||||||||||||
1–4/day | 8 | 1.1 (0.5–2.0) | ||||||||||||
5–14/day | 240 | 1.6 (1.3–2.0) | ||||||||||||
15–24/day | 254 | 1.4 (1.2–1.8) | ||||||||||||
25–34/day | 29 | 1.6 (1.1–2.4) | ||||||||||||
≥35/day | 15 | 1.9 (1.1–3.2) | ||||||||||||
For women | ||||||||||||||
Never | 334 | 1.0 | 0.001 | |||||||||||
Daily | 64 | 1.6 (1.2–2.0) | ||||||||||||
1–4 /day | 9 | 1.4 (0.7–2.5) | ||||||||||||
5–14 /day | 42 | 1.4 (1.0–2.0) | ||||||||||||
≥15 /day | 13 | 2.5 (1.3–4.1) | ||||||||||||
Inaba et al. (10) | 1973–1988 | 270 men | Patients with liver cirrhosis at the Juntendo University Hospital | Death | 46 men | Never | 1.00 | Age, HBsAg, histories of transfusion, hepatitis and surgical operation, drinking | Anti-HCV was not tested | |||||
Current/past | 2.57 (0.46–14.24) | |||||||||||||
Shibata et al. (11) | 1958–1986 | 639 men in a farming area and 677 men in a fishing area | Residents in a farming or a fishing area in Kyushu | Death | 11 men (farming area) and 22 men (fishing area) | Farming area | ||||||||
Non-smoker | 2 | 1.0 | >0.1 | Age | HBsAg and anti-HCV were not tested | |||||||||
Ex-smoker | 0 | – | ||||||||||||
Current smoker | 8 | 1.1 (0.2–4.7) | ||||||||||||
1–9/day | 1 | 0.6 (0.1–3.7) | ||||||||||||
10–19/day | 7 | 1.2 (0.2–5.7) | ||||||||||||
20–29/day | 0 | – | ||||||||||||
≥30/day | 0 | – | ||||||||||||
Fishing area | ||||||||||||||
Non-smoker | 1 | 1.0 | >0.1 | Age | ||||||||||
Ex-smoker | 2 | 2.9 (0.3–29.0) | ||||||||||||
Current smoker | 19 | 3.6 (0.6–22.3) | ||||||||||||
1–9/day | 7 | 11.9 (1.5–96.8) | ||||||||||||
10–19/day | 3 | 1.1 (0.1–10.6) | ||||||||||||
20–29/day | 7 | 2.7 (0.4–19.2) | ||||||||||||
≥30 /day | 2 | 3.2 (0.4–23.7) | ||||||||||||
Fishing area | ||||||||||||||
Non/ex-smoker | 3 | 1.00 | Age, drinking | |||||||||||
1–19/day | 10 | 2.10 (0.44–9.95) | ||||||||||||
≥20/day | 9 | 1.86 (0.37–9.40) | ||||||||||||
Kato et al.(12) | 1987–1990 | 1784 | Patients with decompensated liver cirrhosis or post-transfusion hepatitis | Incidence | 122 | Never smoker | 39 | 1.00 | Sex, age | HBsAg and anti- HCV status was unknown | ||||
Past smoker | 10 | 0.94 (0.44–2.02) | ||||||||||||
Current smoker | 23 | 0.96 (0.53–1.75) | ||||||||||||
Smoking index | ||||||||||||||
0 | 39 | 1.00 | 0.82 | |||||||||||
1–599 | 11 | 0.83 (0.40–1.74) | ||||||||||||
≥600 | 14 | 0.94 (0.47–1.89) | ||||||||||||
Tsukuma et al. (13) | 1987–1991 | 917 (548 men and 369 women) | Patients with chronic hepatitis or compensated cirrhosis at the Center for Adult Diseases, Osaka | Incidence | 54 | Among all patients | Age, sex, stage of disease, serum alpha-fetoprotein, HBsAg, anti-HBc, anti-HCV, drinking | HBsAg and anti-HCV status was adjusted for | ||||||
Non-smoker | 1.00 | 0.07 | ||||||||||||
Ex-smoker | 1.68 (0.63–4.47) | |||||||||||||
Current smoker | 2.30 (0.90–5.86) | |||||||||||||
Among patients with liver cirrhosis | ||||||||||||||
Non-smoker | 1.00 | 0.003 | ||||||||||||
Ex-smoker | 3.44 | |||||||||||||
Current smoker | 7.96 | |||||||||||||
Goodman et al. (14) | 1980–1989 | 36 133 | Atomic bomb survivors | Incidence | 242 (156 men and 86 women) | For men | Sex, city, age at the time of bombing, age, radiation dose to the liver | HBsAg and anti-HCV was not tested | ||||||
Never-smoker | 6 | 1.00 | ||||||||||||
Ever-smoker | 146 | 4.36 (1.93–9.86) | ||||||||||||
Ex-smoker | 46 | 4.56 (1.95–10.7) | ||||||||||||
Quit ≥24 years ago | 14 | 4.04 (1.54–10.6) | ||||||||||||
Quit 14–23 years ago | 14 | 4.11 (1.58–10.7) | ||||||||||||
Quit <14 years ago | 14 | 5.60 (2.15–14.6) | ||||||||||||
Present smoker | 100 | 4.26 (1.87–9.72) | ||||||||||||
1–22 pack-years | 38 | 6.47 (2.74–15.3) | ||||||||||||
23–40 pack-years | 39 | 4.43 (1.87–10.5) | ||||||||||||
≥41 pack-years | 41 | 3.09 (1.31–7.29) | ||||||||||||
For women | ||||||||||||||
Never-smoker | 61 | 1.00 | ||||||||||||
Ever-smoker | 20 | 1.60 (0.97–2.66) | ||||||||||||
Ex-smoker | 7 | 1.66 (0.76–3.63) | ||||||||||||
Quit ≥25 years ago | 3 | 2.31 (0.72–7.43) | ||||||||||||
Quit 10–24 years ago | 2 | 1.03 (0.25–4.24) | ||||||||||||
Quit <10 years ago | 2 | 10.4 (2.51–43.5) | ||||||||||||
Present smoker | 13 | 1.58 (0.86–2.88) | ||||||||||||
1–15 pack-years | 8 | 1.81 (0.86–3.78) | ||||||||||||
≥16 pack-years | 8 | 1.51 (0.72–3.16) | ||||||||||||
Chiba et al.(15) | 1977–1993 | 412 (249 men and 163 women) | Patients with HCV-associated chronic hepatitis or compensated cirrhosis at the Tsukuba University Hospital | Incidence | 63 (54 men and 9 women) | Non-smoker | 1.00 | Sex, age, stage of disease, serum alpha-fetoprotein, anti-HBs, anti-HBc, histories of transfusion, surgical procedure and liver cancer in family, drinking | All subjects were anti-HCV-positive and HBsAg- negative | |||||
Smoking index <400 | 1.67 (0.75–3.73) | |||||||||||||
Smoking index ≥ 400 | 2.46 (1.11–5.49) | |||||||||||||
Tanaka et al. (16) | 1985–1995 | 96 (62 men and 34 women) | Patients with liver cirrhosis at the Kyushu University Hospital | Incidence | 37 (27 men and 10 women) | Never smoker | 12 | 1.00 | Sex, age, years since LC diagnosis, department, hospitalization status, serum albumin, AST, alpha-fetoprotein, HBsAg, anti-HCV, drinking | The relative risks were not described in the original paper, and were re-estimated by one of the authors (KT). HBsAg and anti-HCV status was adjusted for | ||||
Past smoker | 12 | 0.44 (0.11–1.79) | ||||||||||||
Current smoker | ||||||||||||||
<20 cigarettes/day | 9 | 1.46 (0.29–7.37) | ||||||||||||
≥20 cigarettes/day | 4 | 1.00 (0.19–5.28) | ||||||||||||
Mori et al.(17) | 1992–1997 | 3052 (974 men and 2078 women) | Residents in a town in Saga prefecture | Incidence | 22 (14 men and 8 women) | History of cigarette smoking | Sex, age | Anti-HCV and HBsAg status was available, but not adjusted for | ||||||
No | 10 | 1.00 | ||||||||||||
Yes | 22 | 2.10 (0.61–7.23) | ||||||||||||
Never-smoker | 10 | 1.00 | 0.30 | |||||||||||
Smoking index <200 | 1 | 3.26 (0.38–28.2) | ||||||||||||
Smoking index ≥200 | 11 | 1.97 (0.57–6.87) | ||||||||||||
Mizoue et al. (18) | 1986–1996 | 4050 men | Residents in 4 municipalities in Fukuoka prefecture | Death | 59 men | Never smoker | 4 | 1.0 | Age, study area, drinking | HBsAg and anti- HCV were not tested | ||||
Ex-smoker | 22 | 2.9 (1.0–8.4) | ||||||||||||
Current smoker | 33 | 3.3 (1.2–9.5) | ||||||||||||
1–24 cigarettes/day | 25 | 3.5 (1.2–10.2) | ||||||||||||
≥25 cigarettes/day | 8 | 2.8 (0.8–9.6) | ||||||||||||
Ogimoto et al. (19) | 1988–1999 | 65 528 (28 287 men and 37 241 women) | Residents in 45 areas throughout Japan | Death | 186 (number by sex not described) | Men (40–59 years) | Collaborating institutes | HBsAg and anti-HCV were not tested | ||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.37 (0.83–6.78) | |||||||||||||
Current smoker | 1.96 (0.75–5.14) | |||||||||||||
Men (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.72 (1.21–6.11) | |||||||||||||
Current smoker | 2.62 (1.18–5.84) | |||||||||||||
Women (40–59 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | – | |||||||||||||
Current smoker | 2.82 (0.61—13.09) | |||||||||||||
Women (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 1.18 (0.16–8.67) | |||||||||||||
Current smoker | 1.49 (0.46–4.87) |
CI, confidence interval; HBsAg, hepatitis B surface antigen; anti-HCV, antibody to hepatitis C virus; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; LC, liver cirrhosis; AST, aspartate aminotransferase.
Reference . | Study period . | Study population . | . | . | . | Category . | Number among cases . | Relative risk (95% CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Number of subjects for analysis . | Source of subjects . | Event followed . | Number of incident cases or deaths . | . | . | . | . | . | . | |||
Kono et al. (8) | 1965–1983 | 5130 men | Male physicians in western Japan | Death | 51 men (primary 9, unspecified 42) | Never/past | 1.00 | Age, drinking | HBsAg and anti- HCV were not tested | |||||
1–19 cigarettes/day | 1.14 (0.59–2.20) | |||||||||||||
≥20 cigarettes/day | 1.04 (0.49–2.23) | |||||||||||||
Akiba and Hirayama(9) | 1966–1981 | 265 118 (122 261 men and 142 857 women) | 95% of the census population in 29 health- center-covered areas in 6 prefectures | Death | 1050 (652 men and 398 women) | For men | Age, prefecture, occupation, observation period | HBsAg and anti- HCV were not tested. Adjustment for alcohol consumption only slightly changed the relative risks | ||||||
Never | 106 | 1.0 | 0.002 | |||||||||||
Daily | 546 | 1.5 (1.2–1.9) | ||||||||||||
1–4/day | 8 | 1.1 (0.5–2.0) | ||||||||||||
5–14/day | 240 | 1.6 (1.3–2.0) | ||||||||||||
15–24/day | 254 | 1.4 (1.2–1.8) | ||||||||||||
25–34/day | 29 | 1.6 (1.1–2.4) | ||||||||||||
≥35/day | 15 | 1.9 (1.1–3.2) | ||||||||||||
For women | ||||||||||||||
Never | 334 | 1.0 | 0.001 | |||||||||||
Daily | 64 | 1.6 (1.2–2.0) | ||||||||||||
1–4 /day | 9 | 1.4 (0.7–2.5) | ||||||||||||
5–14 /day | 42 | 1.4 (1.0–2.0) | ||||||||||||
≥15 /day | 13 | 2.5 (1.3–4.1) | ||||||||||||
Inaba et al. (10) | 1973–1988 | 270 men | Patients with liver cirrhosis at the Juntendo University Hospital | Death | 46 men | Never | 1.00 | Age, HBsAg, histories of transfusion, hepatitis and surgical operation, drinking | Anti-HCV was not tested | |||||
Current/past | 2.57 (0.46–14.24) | |||||||||||||
Shibata et al. (11) | 1958–1986 | 639 men in a farming area and 677 men in a fishing area | Residents in a farming or a fishing area in Kyushu | Death | 11 men (farming area) and 22 men (fishing area) | Farming area | ||||||||
Non-smoker | 2 | 1.0 | >0.1 | Age | HBsAg and anti-HCV were not tested | |||||||||
Ex-smoker | 0 | – | ||||||||||||
Current smoker | 8 | 1.1 (0.2–4.7) | ||||||||||||
1–9/day | 1 | 0.6 (0.1–3.7) | ||||||||||||
10–19/day | 7 | 1.2 (0.2–5.7) | ||||||||||||
20–29/day | 0 | – | ||||||||||||
≥30/day | 0 | – | ||||||||||||
Fishing area | ||||||||||||||
Non-smoker | 1 | 1.0 | >0.1 | Age | ||||||||||
Ex-smoker | 2 | 2.9 (0.3–29.0) | ||||||||||||
Current smoker | 19 | 3.6 (0.6–22.3) | ||||||||||||
1–9/day | 7 | 11.9 (1.5–96.8) | ||||||||||||
10–19/day | 3 | 1.1 (0.1–10.6) | ||||||||||||
20–29/day | 7 | 2.7 (0.4–19.2) | ||||||||||||
≥30 /day | 2 | 3.2 (0.4–23.7) | ||||||||||||
Fishing area | ||||||||||||||
Non/ex-smoker | 3 | 1.00 | Age, drinking | |||||||||||
1–19/day | 10 | 2.10 (0.44–9.95) | ||||||||||||
≥20/day | 9 | 1.86 (0.37–9.40) | ||||||||||||
Kato et al.(12) | 1987–1990 | 1784 | Patients with decompensated liver cirrhosis or post-transfusion hepatitis | Incidence | 122 | Never smoker | 39 | 1.00 | Sex, age | HBsAg and anti- HCV status was unknown | ||||
Past smoker | 10 | 0.94 (0.44–2.02) | ||||||||||||
Current smoker | 23 | 0.96 (0.53–1.75) | ||||||||||||
Smoking index | ||||||||||||||
0 | 39 | 1.00 | 0.82 | |||||||||||
1–599 | 11 | 0.83 (0.40–1.74) | ||||||||||||
≥600 | 14 | 0.94 (0.47–1.89) | ||||||||||||
Tsukuma et al. (13) | 1987–1991 | 917 (548 men and 369 women) | Patients with chronic hepatitis or compensated cirrhosis at the Center for Adult Diseases, Osaka | Incidence | 54 | Among all patients | Age, sex, stage of disease, serum alpha-fetoprotein, HBsAg, anti-HBc, anti-HCV, drinking | HBsAg and anti-HCV status was adjusted for | ||||||
Non-smoker | 1.00 | 0.07 | ||||||||||||
Ex-smoker | 1.68 (0.63–4.47) | |||||||||||||
Current smoker | 2.30 (0.90–5.86) | |||||||||||||
Among patients with liver cirrhosis | ||||||||||||||
Non-smoker | 1.00 | 0.003 | ||||||||||||
Ex-smoker | 3.44 | |||||||||||||
Current smoker | 7.96 | |||||||||||||
Goodman et al. (14) | 1980–1989 | 36 133 | Atomic bomb survivors | Incidence | 242 (156 men and 86 women) | For men | Sex, city, age at the time of bombing, age, radiation dose to the liver | HBsAg and anti-HCV was not tested | ||||||
Never-smoker | 6 | 1.00 | ||||||||||||
Ever-smoker | 146 | 4.36 (1.93–9.86) | ||||||||||||
Ex-smoker | 46 | 4.56 (1.95–10.7) | ||||||||||||
Quit ≥24 years ago | 14 | 4.04 (1.54–10.6) | ||||||||||||
Quit 14–23 years ago | 14 | 4.11 (1.58–10.7) | ||||||||||||
Quit <14 years ago | 14 | 5.60 (2.15–14.6) | ||||||||||||
Present smoker | 100 | 4.26 (1.87–9.72) | ||||||||||||
1–22 pack-years | 38 | 6.47 (2.74–15.3) | ||||||||||||
23–40 pack-years | 39 | 4.43 (1.87–10.5) | ||||||||||||
≥41 pack-years | 41 | 3.09 (1.31–7.29) | ||||||||||||
For women | ||||||||||||||
Never-smoker | 61 | 1.00 | ||||||||||||
Ever-smoker | 20 | 1.60 (0.97–2.66) | ||||||||||||
Ex-smoker | 7 | 1.66 (0.76–3.63) | ||||||||||||
Quit ≥25 years ago | 3 | 2.31 (0.72–7.43) | ||||||||||||
Quit 10–24 years ago | 2 | 1.03 (0.25–4.24) | ||||||||||||
Quit <10 years ago | 2 | 10.4 (2.51–43.5) | ||||||||||||
Present smoker | 13 | 1.58 (0.86–2.88) | ||||||||||||
1–15 pack-years | 8 | 1.81 (0.86–3.78) | ||||||||||||
≥16 pack-years | 8 | 1.51 (0.72–3.16) | ||||||||||||
Chiba et al.(15) | 1977–1993 | 412 (249 men and 163 women) | Patients with HCV-associated chronic hepatitis or compensated cirrhosis at the Tsukuba University Hospital | Incidence | 63 (54 men and 9 women) | Non-smoker | 1.00 | Sex, age, stage of disease, serum alpha-fetoprotein, anti-HBs, anti-HBc, histories of transfusion, surgical procedure and liver cancer in family, drinking | All subjects were anti-HCV-positive and HBsAg- negative | |||||
Smoking index <400 | 1.67 (0.75–3.73) | |||||||||||||
Smoking index ≥ 400 | 2.46 (1.11–5.49) | |||||||||||||
Tanaka et al. (16) | 1985–1995 | 96 (62 men and 34 women) | Patients with liver cirrhosis at the Kyushu University Hospital | Incidence | 37 (27 men and 10 women) | Never smoker | 12 | 1.00 | Sex, age, years since LC diagnosis, department, hospitalization status, serum albumin, AST, alpha-fetoprotein, HBsAg, anti-HCV, drinking | The relative risks were not described in the original paper, and were re-estimated by one of the authors (KT). HBsAg and anti-HCV status was adjusted for | ||||
Past smoker | 12 | 0.44 (0.11–1.79) | ||||||||||||
Current smoker | ||||||||||||||
<20 cigarettes/day | 9 | 1.46 (0.29–7.37) | ||||||||||||
≥20 cigarettes/day | 4 | 1.00 (0.19–5.28) | ||||||||||||
Mori et al.(17) | 1992–1997 | 3052 (974 men and 2078 women) | Residents in a town in Saga prefecture | Incidence | 22 (14 men and 8 women) | History of cigarette smoking | Sex, age | Anti-HCV and HBsAg status was available, but not adjusted for | ||||||
No | 10 | 1.00 | ||||||||||||
Yes | 22 | 2.10 (0.61–7.23) | ||||||||||||
Never-smoker | 10 | 1.00 | 0.30 | |||||||||||
Smoking index <200 | 1 | 3.26 (0.38–28.2) | ||||||||||||
Smoking index ≥200 | 11 | 1.97 (0.57–6.87) | ||||||||||||
Mizoue et al. (18) | 1986–1996 | 4050 men | Residents in 4 municipalities in Fukuoka prefecture | Death | 59 men | Never smoker | 4 | 1.0 | Age, study area, drinking | HBsAg and anti- HCV were not tested | ||||
Ex-smoker | 22 | 2.9 (1.0–8.4) | ||||||||||||
Current smoker | 33 | 3.3 (1.2–9.5) | ||||||||||||
1–24 cigarettes/day | 25 | 3.5 (1.2–10.2) | ||||||||||||
≥25 cigarettes/day | 8 | 2.8 (0.8–9.6) | ||||||||||||
Ogimoto et al. (19) | 1988–1999 | 65 528 (28 287 men and 37 241 women) | Residents in 45 areas throughout Japan | Death | 186 (number by sex not described) | Men (40–59 years) | Collaborating institutes | HBsAg and anti-HCV were not tested | ||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.37 (0.83–6.78) | |||||||||||||
Current smoker | 1.96 (0.75–5.14) | |||||||||||||
Men (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.72 (1.21–6.11) | |||||||||||||
Current smoker | 2.62 (1.18–5.84) | |||||||||||||
Women (40–59 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | – | |||||||||||||
Current smoker | 2.82 (0.61—13.09) | |||||||||||||
Women (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 1.18 (0.16–8.67) | |||||||||||||
Current smoker | 1.49 (0.46–4.87) |
Reference . | Study period . | Study population . | . | . | . | Category . | Number among cases . | Relative risk (95% CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Number of subjects for analysis . | Source of subjects . | Event followed . | Number of incident cases or deaths . | . | . | . | . | . | . | |||
Kono et al. (8) | 1965–1983 | 5130 men | Male physicians in western Japan | Death | 51 men (primary 9, unspecified 42) | Never/past | 1.00 | Age, drinking | HBsAg and anti- HCV were not tested | |||||
1–19 cigarettes/day | 1.14 (0.59–2.20) | |||||||||||||
≥20 cigarettes/day | 1.04 (0.49–2.23) | |||||||||||||
Akiba and Hirayama(9) | 1966–1981 | 265 118 (122 261 men and 142 857 women) | 95% of the census population in 29 health- center-covered areas in 6 prefectures | Death | 1050 (652 men and 398 women) | For men | Age, prefecture, occupation, observation period | HBsAg and anti- HCV were not tested. Adjustment for alcohol consumption only slightly changed the relative risks | ||||||
Never | 106 | 1.0 | 0.002 | |||||||||||
Daily | 546 | 1.5 (1.2–1.9) | ||||||||||||
1–4/day | 8 | 1.1 (0.5–2.0) | ||||||||||||
5–14/day | 240 | 1.6 (1.3–2.0) | ||||||||||||
15–24/day | 254 | 1.4 (1.2–1.8) | ||||||||||||
25–34/day | 29 | 1.6 (1.1–2.4) | ||||||||||||
≥35/day | 15 | 1.9 (1.1–3.2) | ||||||||||||
For women | ||||||||||||||
Never | 334 | 1.0 | 0.001 | |||||||||||
Daily | 64 | 1.6 (1.2–2.0) | ||||||||||||
1–4 /day | 9 | 1.4 (0.7–2.5) | ||||||||||||
5–14 /day | 42 | 1.4 (1.0–2.0) | ||||||||||||
≥15 /day | 13 | 2.5 (1.3–4.1) | ||||||||||||
Inaba et al. (10) | 1973–1988 | 270 men | Patients with liver cirrhosis at the Juntendo University Hospital | Death | 46 men | Never | 1.00 | Age, HBsAg, histories of transfusion, hepatitis and surgical operation, drinking | Anti-HCV was not tested | |||||
Current/past | 2.57 (0.46–14.24) | |||||||||||||
Shibata et al. (11) | 1958–1986 | 639 men in a farming area and 677 men in a fishing area | Residents in a farming or a fishing area in Kyushu | Death | 11 men (farming area) and 22 men (fishing area) | Farming area | ||||||||
Non-smoker | 2 | 1.0 | >0.1 | Age | HBsAg and anti-HCV were not tested | |||||||||
Ex-smoker | 0 | – | ||||||||||||
Current smoker | 8 | 1.1 (0.2–4.7) | ||||||||||||
1–9/day | 1 | 0.6 (0.1–3.7) | ||||||||||||
10–19/day | 7 | 1.2 (0.2–5.7) | ||||||||||||
20–29/day | 0 | – | ||||||||||||
≥30/day | 0 | – | ||||||||||||
Fishing area | ||||||||||||||
Non-smoker | 1 | 1.0 | >0.1 | Age | ||||||||||
Ex-smoker | 2 | 2.9 (0.3–29.0) | ||||||||||||
Current smoker | 19 | 3.6 (0.6–22.3) | ||||||||||||
1–9/day | 7 | 11.9 (1.5–96.8) | ||||||||||||
10–19/day | 3 | 1.1 (0.1–10.6) | ||||||||||||
20–29/day | 7 | 2.7 (0.4–19.2) | ||||||||||||
≥30 /day | 2 | 3.2 (0.4–23.7) | ||||||||||||
Fishing area | ||||||||||||||
Non/ex-smoker | 3 | 1.00 | Age, drinking | |||||||||||
1–19/day | 10 | 2.10 (0.44–9.95) | ||||||||||||
≥20/day | 9 | 1.86 (0.37–9.40) | ||||||||||||
Kato et al.(12) | 1987–1990 | 1784 | Patients with decompensated liver cirrhosis or post-transfusion hepatitis | Incidence | 122 | Never smoker | 39 | 1.00 | Sex, age | HBsAg and anti- HCV status was unknown | ||||
Past smoker | 10 | 0.94 (0.44–2.02) | ||||||||||||
Current smoker | 23 | 0.96 (0.53–1.75) | ||||||||||||
Smoking index | ||||||||||||||
0 | 39 | 1.00 | 0.82 | |||||||||||
1–599 | 11 | 0.83 (0.40–1.74) | ||||||||||||
≥600 | 14 | 0.94 (0.47–1.89) | ||||||||||||
Tsukuma et al. (13) | 1987–1991 | 917 (548 men and 369 women) | Patients with chronic hepatitis or compensated cirrhosis at the Center for Adult Diseases, Osaka | Incidence | 54 | Among all patients | Age, sex, stage of disease, serum alpha-fetoprotein, HBsAg, anti-HBc, anti-HCV, drinking | HBsAg and anti-HCV status was adjusted for | ||||||
Non-smoker | 1.00 | 0.07 | ||||||||||||
Ex-smoker | 1.68 (0.63–4.47) | |||||||||||||
Current smoker | 2.30 (0.90–5.86) | |||||||||||||
Among patients with liver cirrhosis | ||||||||||||||
Non-smoker | 1.00 | 0.003 | ||||||||||||
Ex-smoker | 3.44 | |||||||||||||
Current smoker | 7.96 | |||||||||||||
Goodman et al. (14) | 1980–1989 | 36 133 | Atomic bomb survivors | Incidence | 242 (156 men and 86 women) | For men | Sex, city, age at the time of bombing, age, radiation dose to the liver | HBsAg and anti-HCV was not tested | ||||||
Never-smoker | 6 | 1.00 | ||||||||||||
Ever-smoker | 146 | 4.36 (1.93–9.86) | ||||||||||||
Ex-smoker | 46 | 4.56 (1.95–10.7) | ||||||||||||
Quit ≥24 years ago | 14 | 4.04 (1.54–10.6) | ||||||||||||
Quit 14–23 years ago | 14 | 4.11 (1.58–10.7) | ||||||||||||
Quit <14 years ago | 14 | 5.60 (2.15–14.6) | ||||||||||||
Present smoker | 100 | 4.26 (1.87–9.72) | ||||||||||||
1–22 pack-years | 38 | 6.47 (2.74–15.3) | ||||||||||||
23–40 pack-years | 39 | 4.43 (1.87–10.5) | ||||||||||||
≥41 pack-years | 41 | 3.09 (1.31–7.29) | ||||||||||||
For women | ||||||||||||||
Never-smoker | 61 | 1.00 | ||||||||||||
Ever-smoker | 20 | 1.60 (0.97–2.66) | ||||||||||||
Ex-smoker | 7 | 1.66 (0.76–3.63) | ||||||||||||
Quit ≥25 years ago | 3 | 2.31 (0.72–7.43) | ||||||||||||
Quit 10–24 years ago | 2 | 1.03 (0.25–4.24) | ||||||||||||
Quit <10 years ago | 2 | 10.4 (2.51–43.5) | ||||||||||||
Present smoker | 13 | 1.58 (0.86–2.88) | ||||||||||||
1–15 pack-years | 8 | 1.81 (0.86–3.78) | ||||||||||||
≥16 pack-years | 8 | 1.51 (0.72–3.16) | ||||||||||||
Chiba et al.(15) | 1977–1993 | 412 (249 men and 163 women) | Patients with HCV-associated chronic hepatitis or compensated cirrhosis at the Tsukuba University Hospital | Incidence | 63 (54 men and 9 women) | Non-smoker | 1.00 | Sex, age, stage of disease, serum alpha-fetoprotein, anti-HBs, anti-HBc, histories of transfusion, surgical procedure and liver cancer in family, drinking | All subjects were anti-HCV-positive and HBsAg- negative | |||||
Smoking index <400 | 1.67 (0.75–3.73) | |||||||||||||
Smoking index ≥ 400 | 2.46 (1.11–5.49) | |||||||||||||
Tanaka et al. (16) | 1985–1995 | 96 (62 men and 34 women) | Patients with liver cirrhosis at the Kyushu University Hospital | Incidence | 37 (27 men and 10 women) | Never smoker | 12 | 1.00 | Sex, age, years since LC diagnosis, department, hospitalization status, serum albumin, AST, alpha-fetoprotein, HBsAg, anti-HCV, drinking | The relative risks were not described in the original paper, and were re-estimated by one of the authors (KT). HBsAg and anti-HCV status was adjusted for | ||||
Past smoker | 12 | 0.44 (0.11–1.79) | ||||||||||||
Current smoker | ||||||||||||||
<20 cigarettes/day | 9 | 1.46 (0.29–7.37) | ||||||||||||
≥20 cigarettes/day | 4 | 1.00 (0.19–5.28) | ||||||||||||
Mori et al.(17) | 1992–1997 | 3052 (974 men and 2078 women) | Residents in a town in Saga prefecture | Incidence | 22 (14 men and 8 women) | History of cigarette smoking | Sex, age | Anti-HCV and HBsAg status was available, but not adjusted for | ||||||
No | 10 | 1.00 | ||||||||||||
Yes | 22 | 2.10 (0.61–7.23) | ||||||||||||
Never-smoker | 10 | 1.00 | 0.30 | |||||||||||
Smoking index <200 | 1 | 3.26 (0.38–28.2) | ||||||||||||
Smoking index ≥200 | 11 | 1.97 (0.57–6.87) | ||||||||||||
Mizoue et al. (18) | 1986–1996 | 4050 men | Residents in 4 municipalities in Fukuoka prefecture | Death | 59 men | Never smoker | 4 | 1.0 | Age, study area, drinking | HBsAg and anti- HCV were not tested | ||||
Ex-smoker | 22 | 2.9 (1.0–8.4) | ||||||||||||
Current smoker | 33 | 3.3 (1.2–9.5) | ||||||||||||
1–24 cigarettes/day | 25 | 3.5 (1.2–10.2) | ||||||||||||
≥25 cigarettes/day | 8 | 2.8 (0.8–9.6) | ||||||||||||
Ogimoto et al. (19) | 1988–1999 | 65 528 (28 287 men and 37 241 women) | Residents in 45 areas throughout Japan | Death | 186 (number by sex not described) | Men (40–59 years) | Collaborating institutes | HBsAg and anti-HCV were not tested | ||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.37 (0.83–6.78) | |||||||||||||
Current smoker | 1.96 (0.75–5.14) | |||||||||||||
Men (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 2.72 (1.21–6.11) | |||||||||||||
Current smoker | 2.62 (1.18–5.84) | |||||||||||||
Women (40–59 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | – | |||||||||||||
Current smoker | 2.82 (0.61—13.09) | |||||||||||||
Women (60–79 years) | ||||||||||||||
Never smoker | 1.00 | |||||||||||||
Ex-smoker | 1.18 (0.16–8.67) | |||||||||||||
Current smoker | 1.49 (0.46–4.87) |
CI, confidence interval; HBsAg, hepatitis B surface antigen; anti-HCV, antibody to hepatitis C virus; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; LC, liver cirrhosis; AST, aspartate aminotransferase.
Reference . | Study period . | Study subjects . | . | . | . | Category . | Relative risk (95%CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Type and source . | Definition . | Number of cases . | Number of controls . | . | . | . | . | . | |||
Oshima et al. (20) | 1972–1980 | Nested case–control (HBsAg- positive blood donors at the Osaka Red Cross Blood Center) | Cases: confirmed by record linkage with the Osaka Cancer Registry; Controls: healthy HBV carriers | 19 men | 38 men | None or <10/day | 1.0 | >0.10 | Matched (1:2) for birth year Adjusted for drinking | All subjects were HBsAg-positive. Anti-HCV was not tested | |||
10–29/day | 1.2 | ||||||||||||
≥30/day | 6.3 | ||||||||||||
Tsukuma et al. (21) | 1983–1987 | Hospital-based (Center for Adult Diseases, Osaka) | Cases: histologically confirmed as HCC; Controls: inpatients with gastrointestinal disease, or examinees for health checkups or gastroendoscopy; no liver disease, cancer, or smoking/alcohol- related disease | 229 (192 men and 37 women) | 266 (192 men and 74 women) | Never | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of blood transfusion, drinking, and family history of liver cancer | Anti-HCV was not tested | ||||
Ex-smoker | 0.7 (0.3–1.9) | ||||||||||||
Current smoker | 2.5 (1.4–4.5) | ||||||||||||
1–19/day | 4.2 | ||||||||||||
20–39/day | 2.2 | ||||||||||||
≥40/day | 1.1 | ||||||||||||
Cigarette index | |||||||||||||
0–399 | 1.0 | ||||||||||||
400–799 | 1.9 (1.1–3.3) | ||||||||||||
800–1199 | 2.0 (1.1–3.6) | ||||||||||||
≥1200 | 1.0 (0.5–1.9) | ||||||||||||
Tanaka et al. (22) | 1985–1989 | Hospital-based (Kyushu University Hospital) | Cases: 40% were histologically confirmed as HCC; Controls: health examinees at a public health center | 204 (168 men and 36 women) | 410 (291 men and 119 women) | Non-smoker | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of transfusion, drinking, and family history of liver disease | Anti-HCV status was available for part of the subjects, but not adjusted for | ||||
Ex-smoker | 1.5 (0.8–2.8) | ||||||||||||
Current smoker | 1.5 (0.8–2.7) | ||||||||||||
Pack-years | 0.41 | ||||||||||||
0–10.9 | 1.0 | ||||||||||||
11.0–26.2 | 1.4 (0.8–2.4) | ||||||||||||
26.3–35.9 | 1.3 (0.7–2.5) | ||||||||||||
≥36.0 | 1.3 (0.7–2.5) | ||||||||||||
Fukuda et al. (23) | 1986–1992 | Hospital-based (Kurume University Hospital) | Cases: 77% were histologically confirmed as HCC; Controls: inpatients without chronic hepatitis or cirrhosis in two general hospitals in Kurume | 368 (287 men and 81 women) | 485 (287 men and 198 women) | Never | 1.0 | Matched (1:1 for men and 1:4 for women) for sex, age (±5 years), residence, and time of hospitalization. Adjusted for sex | The odds ratios (and 95% CIs) and P value for trend were not described in the original paper, and were estimated by one of the authors (KT), based on the Mantel–Haenszel and Mantel Extension methods | ||||
Ex-smoker | 1.3 (0.8–2.2) | ||||||||||||
Current smoker | 1.8 (1.1–3.1) | ||||||||||||
Cigarette index | |||||||||||||
Non-smoker | 1.0 | 0.48 | |||||||||||
1–499 | 1.7 (1.0–2.8) | ||||||||||||
500–999 | 1.5 (0.9–2.5) | ||||||||||||
≥1000 | 0.6 (0.3–1.4) | ||||||||||||
Murata et al. (24) | 1984–1993 | Nested case–controls (male participants in a gastric mass screening by the Chiba Cancer Association) | Cases: confirmed by record linkage with the Chiba Cancer Registry; Controls: participants in the screening without liver cancer | 66 men | 132 men | Cigarettes/day | Matched (1:2) for sex, birth year (±2 years), and the first digit of the address code. No adjustment | Anti-HCV and HBsAg were not tested | |||||
None | 1.0 | 0.75 | |||||||||||
1–10 | 1.4 | ||||||||||||
11–20 | 2.0 (P < 0.05) | ||||||||||||
≥21 | 0.4 | ||||||||||||
Shibata et al. (25) | 1992–1995 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; Hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 115 men | 115 male HCs and 115 male CCs | Cigarette index, based on HCs | Matched (1:1) for sex, age (±5 years for HCs and ±3 years for CCs), residence (for HCs) and time of hospitalization (for HCs). Adjusted for matching factors | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 1.6 (0.6–4.0) | ||||||||||||
500-999 | 1.2 (0.5–2.9) | ||||||||||||
≥1000 | 0.7 (0.2–2.0) | ||||||||||||
Cigarette index, based on CCs | |||||||||||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 2.1 (0.9–4.7) | ||||||||||||
500-999 | 1.9 (0.8–4.6) | ||||||||||||
≥1000 | 1.2 (0.4–3.5) | ||||||||||||
Mukaiya et al. (26) | 1991–1993 | Hospital-based (Sapporo Medical University Hospital) | Cases: histologically and/or clinically confirmed as HCC; Controls: chronic liver disease (hepatitis or cirrhosis) without HCC | 104 men | 104 men | Non-smoker | 1.00 | Matched (1:1) for age (±3 years). Adjusted for age | Additional adjustment for drinking and HBV and HCV infections did not materially alter the results | ||||
Ever-smoker | 3.50 (1.41–8.70) | ||||||||||||
Period < 5years | 1.00 | ||||||||||||
Period ≥ 5years | 3.33 (1.34–8.30) | ||||||||||||
Cigarette index | |||||||||||||
<200 | 1.00 | ||||||||||||
≥200 | 3.33 (1.34–8.30) | ||||||||||||
Takeshita et al. (27) | 1993–1996 | Hospital-based (20 major hospitals in the southern part of Hyogo prefecture) | Cases: 64% were histologically confirmed as HCC; Controls: outpatients or inpatients with various diseases, but without liver disease positive for HBsAg and/or anti-HCV | 102 (85 men and 17 women) | 125 (101 men and 24 women) | Men | Frequency matched for hospital, sex, age, and living area Adjusted for age and drinking | All the controls were HBsAg-negative and anti-HCV-negative by definition | |||||
Non-smoker | 1.0 | ||||||||||||
Ex-smoker | 0.7 (0.3–1.5) | ||||||||||||
Current smoker | 1.6 (0.7–3.5) | ||||||||||||
Women | |||||||||||||
Not described | |||||||||||||
Koide et al. (28) | 1994 | Hospital-based (Nagoya City University Hospital) | Cases: clinically and/or histologically confirmed as HCC; community controls: selected from the same resident community as cases, with no signs of hepatic diseases or HCC | 84 (64 men and 20 women) | 84 (64 men and 20 women) | Never | 1.00 | Matched (1:1) for sex and age (±2 years) Adjusted for sex, age, history of blood transfusion, anti- HBc, anti-HCV, and CYP2E1 | |||||
Current + former | 5.41 (1.10–26.70) | ||||||||||||
Matsuo et al. (29) | 1995–2000 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 222 (177 men and 45 women) | 326 HCs (177 men and 149 women) and 222 CCs (177 men and 45 women) | Men based on HCs | Matched for sex (1:4 for female HCs and 1:1 for other controls), age (±5 years for HCs and ±3 years for CCs), residence (for HCs), and time of hospitalization (for HCs) Adjusted for matching factors | Anti-HCV and HBsAg status was available except for CCs, but not adjusted for | |||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.95 (P < 0.05) | ||||||||||||
25-49 pack-years | 2.15 (P < 0.05) | ||||||||||||
≥50 pack-years | 1.13 | ||||||||||||
Men based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 4.39 (P < 0.05) | ||||||||||||
25–49 pack-years | 2.75 (P < 0.05) | ||||||||||||
≥50 pack-years | 2.90 (P < 0.05) | ||||||||||||
Women based on HCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 1.69 | ||||||||||||
≥25 pack-years | 0.68 | ||||||||||||
Women based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.00 | ||||||||||||
≥25 pack-years | ∞ | ||||||||||||
Munaka et al. (30) | 1997–1998 | Hospital-based (University of Occupational and Environmental Health Hospital) | Cases: no detailed description; controls: no evidence of cancer in any organ | 78 (61 men and 17 women) | 139 (94 men and 44 women) | Cigarette index | Unmatched. Adjusted for sex and age | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Never | 1.00 | ||||||||||||
1 ≤ 400 | 1.14 (0.58–2.25) | ||||||||||||
400 ≤ 800 | 1.09 (0.56–2.14) | ||||||||||||
≥800 | 1.09 (0.56–2.15) |
Reference . | Study period . | Study subjects . | . | . | . | Category . | Relative risk (95%CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Type and source . | Definition . | Number of cases . | Number of controls . | . | . | . | . | . | |||
Oshima et al. (20) | 1972–1980 | Nested case–control (HBsAg- positive blood donors at the Osaka Red Cross Blood Center) | Cases: confirmed by record linkage with the Osaka Cancer Registry; Controls: healthy HBV carriers | 19 men | 38 men | None or <10/day | 1.0 | >0.10 | Matched (1:2) for birth year Adjusted for drinking | All subjects were HBsAg-positive. Anti-HCV was not tested | |||
10–29/day | 1.2 | ||||||||||||
≥30/day | 6.3 | ||||||||||||
Tsukuma et al. (21) | 1983–1987 | Hospital-based (Center for Adult Diseases, Osaka) | Cases: histologically confirmed as HCC; Controls: inpatients with gastrointestinal disease, or examinees for health checkups or gastroendoscopy; no liver disease, cancer, or smoking/alcohol- related disease | 229 (192 men and 37 women) | 266 (192 men and 74 women) | Never | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of blood transfusion, drinking, and family history of liver cancer | Anti-HCV was not tested | ||||
Ex-smoker | 0.7 (0.3–1.9) | ||||||||||||
Current smoker | 2.5 (1.4–4.5) | ||||||||||||
1–19/day | 4.2 | ||||||||||||
20–39/day | 2.2 | ||||||||||||
≥40/day | 1.1 | ||||||||||||
Cigarette index | |||||||||||||
0–399 | 1.0 | ||||||||||||
400–799 | 1.9 (1.1–3.3) | ||||||||||||
800–1199 | 2.0 (1.1–3.6) | ||||||||||||
≥1200 | 1.0 (0.5–1.9) | ||||||||||||
Tanaka et al. (22) | 1985–1989 | Hospital-based (Kyushu University Hospital) | Cases: 40% were histologically confirmed as HCC; Controls: health examinees at a public health center | 204 (168 men and 36 women) | 410 (291 men and 119 women) | Non-smoker | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of transfusion, drinking, and family history of liver disease | Anti-HCV status was available for part of the subjects, but not adjusted for | ||||
Ex-smoker | 1.5 (0.8–2.8) | ||||||||||||
Current smoker | 1.5 (0.8–2.7) | ||||||||||||
Pack-years | 0.41 | ||||||||||||
0–10.9 | 1.0 | ||||||||||||
11.0–26.2 | 1.4 (0.8–2.4) | ||||||||||||
26.3–35.9 | 1.3 (0.7–2.5) | ||||||||||||
≥36.0 | 1.3 (0.7–2.5) | ||||||||||||
Fukuda et al. (23) | 1986–1992 | Hospital-based (Kurume University Hospital) | Cases: 77% were histologically confirmed as HCC; Controls: inpatients without chronic hepatitis or cirrhosis in two general hospitals in Kurume | 368 (287 men and 81 women) | 485 (287 men and 198 women) | Never | 1.0 | Matched (1:1 for men and 1:4 for women) for sex, age (±5 years), residence, and time of hospitalization. Adjusted for sex | The odds ratios (and 95% CIs) and P value for trend were not described in the original paper, and were estimated by one of the authors (KT), based on the Mantel–Haenszel and Mantel Extension methods | ||||
Ex-smoker | 1.3 (0.8–2.2) | ||||||||||||
Current smoker | 1.8 (1.1–3.1) | ||||||||||||
Cigarette index | |||||||||||||
Non-smoker | 1.0 | 0.48 | |||||||||||
1–499 | 1.7 (1.0–2.8) | ||||||||||||
500–999 | 1.5 (0.9–2.5) | ||||||||||||
≥1000 | 0.6 (0.3–1.4) | ||||||||||||
Murata et al. (24) | 1984–1993 | Nested case–controls (male participants in a gastric mass screening by the Chiba Cancer Association) | Cases: confirmed by record linkage with the Chiba Cancer Registry; Controls: participants in the screening without liver cancer | 66 men | 132 men | Cigarettes/day | Matched (1:2) for sex, birth year (±2 years), and the first digit of the address code. No adjustment | Anti-HCV and HBsAg were not tested | |||||
None | 1.0 | 0.75 | |||||||||||
1–10 | 1.4 | ||||||||||||
11–20 | 2.0 (P < 0.05) | ||||||||||||
≥21 | 0.4 | ||||||||||||
Shibata et al. (25) | 1992–1995 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; Hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 115 men | 115 male HCs and 115 male CCs | Cigarette index, based on HCs | Matched (1:1) for sex, age (±5 years for HCs and ±3 years for CCs), residence (for HCs) and time of hospitalization (for HCs). Adjusted for matching factors | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 1.6 (0.6–4.0) | ||||||||||||
500-999 | 1.2 (0.5–2.9) | ||||||||||||
≥1000 | 0.7 (0.2–2.0) | ||||||||||||
Cigarette index, based on CCs | |||||||||||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 2.1 (0.9–4.7) | ||||||||||||
500-999 | 1.9 (0.8–4.6) | ||||||||||||
≥1000 | 1.2 (0.4–3.5) | ||||||||||||
Mukaiya et al. (26) | 1991–1993 | Hospital-based (Sapporo Medical University Hospital) | Cases: histologically and/or clinically confirmed as HCC; Controls: chronic liver disease (hepatitis or cirrhosis) without HCC | 104 men | 104 men | Non-smoker | 1.00 | Matched (1:1) for age (±3 years). Adjusted for age | Additional adjustment for drinking and HBV and HCV infections did not materially alter the results | ||||
Ever-smoker | 3.50 (1.41–8.70) | ||||||||||||
Period < 5years | 1.00 | ||||||||||||
Period ≥ 5years | 3.33 (1.34–8.30) | ||||||||||||
Cigarette index | |||||||||||||
<200 | 1.00 | ||||||||||||
≥200 | 3.33 (1.34–8.30) | ||||||||||||
Takeshita et al. (27) | 1993–1996 | Hospital-based (20 major hospitals in the southern part of Hyogo prefecture) | Cases: 64% were histologically confirmed as HCC; Controls: outpatients or inpatients with various diseases, but without liver disease positive for HBsAg and/or anti-HCV | 102 (85 men and 17 women) | 125 (101 men and 24 women) | Men | Frequency matched for hospital, sex, age, and living area Adjusted for age and drinking | All the controls were HBsAg-negative and anti-HCV-negative by definition | |||||
Non-smoker | 1.0 | ||||||||||||
Ex-smoker | 0.7 (0.3–1.5) | ||||||||||||
Current smoker | 1.6 (0.7–3.5) | ||||||||||||
Women | |||||||||||||
Not described | |||||||||||||
Koide et al. (28) | 1994 | Hospital-based (Nagoya City University Hospital) | Cases: clinically and/or histologically confirmed as HCC; community controls: selected from the same resident community as cases, with no signs of hepatic diseases or HCC | 84 (64 men and 20 women) | 84 (64 men and 20 women) | Never | 1.00 | Matched (1:1) for sex and age (±2 years) Adjusted for sex, age, history of blood transfusion, anti- HBc, anti-HCV, and CYP2E1 | |||||
Current + former | 5.41 (1.10–26.70) | ||||||||||||
Matsuo et al. (29) | 1995–2000 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 222 (177 men and 45 women) | 326 HCs (177 men and 149 women) and 222 CCs (177 men and 45 women) | Men based on HCs | Matched for sex (1:4 for female HCs and 1:1 for other controls), age (±5 years for HCs and ±3 years for CCs), residence (for HCs), and time of hospitalization (for HCs) Adjusted for matching factors | Anti-HCV and HBsAg status was available except for CCs, but not adjusted for | |||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.95 (P < 0.05) | ||||||||||||
25-49 pack-years | 2.15 (P < 0.05) | ||||||||||||
≥50 pack-years | 1.13 | ||||||||||||
Men based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 4.39 (P < 0.05) | ||||||||||||
25–49 pack-years | 2.75 (P < 0.05) | ||||||||||||
≥50 pack-years | 2.90 (P < 0.05) | ||||||||||||
Women based on HCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 1.69 | ||||||||||||
≥25 pack-years | 0.68 | ||||||||||||
Women based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.00 | ||||||||||||
≥25 pack-years | ∞ | ||||||||||||
Munaka et al. (30) | 1997–1998 | Hospital-based (University of Occupational and Environmental Health Hospital) | Cases: no detailed description; controls: no evidence of cancer in any organ | 78 (61 men and 17 women) | 139 (94 men and 44 women) | Cigarette index | Unmatched. Adjusted for sex and age | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Never | 1.00 | ||||||||||||
1 ≤ 400 | 1.14 (0.58–2.25) | ||||||||||||
400 ≤ 800 | 1.09 (0.56–2.14) | ||||||||||||
≥800 | 1.09 (0.56–2.15) |
CI, confidence interval; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; anti-HCV, antibody to hepatitis C virus; HCC, hepatocellular carcinoma; HCs, hospital controls; CCs, community controls; HCV, hepatitis C virus; anti-HBc, antibody to hepatitis B core antigen; CYP2E1, cytochrome P450 2E1.
Reference . | Study period . | Study subjects . | . | . | . | Category . | Relative risk (95%CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Type and source . | Definition . | Number of cases . | Number of controls . | . | . | . | . | . | |||
Oshima et al. (20) | 1972–1980 | Nested case–control (HBsAg- positive blood donors at the Osaka Red Cross Blood Center) | Cases: confirmed by record linkage with the Osaka Cancer Registry; Controls: healthy HBV carriers | 19 men | 38 men | None or <10/day | 1.0 | >0.10 | Matched (1:2) for birth year Adjusted for drinking | All subjects were HBsAg-positive. Anti-HCV was not tested | |||
10–29/day | 1.2 | ||||||||||||
≥30/day | 6.3 | ||||||||||||
Tsukuma et al. (21) | 1983–1987 | Hospital-based (Center for Adult Diseases, Osaka) | Cases: histologically confirmed as HCC; Controls: inpatients with gastrointestinal disease, or examinees for health checkups or gastroendoscopy; no liver disease, cancer, or smoking/alcohol- related disease | 229 (192 men and 37 women) | 266 (192 men and 74 women) | Never | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of blood transfusion, drinking, and family history of liver cancer | Anti-HCV was not tested | ||||
Ex-smoker | 0.7 (0.3–1.9) | ||||||||||||
Current smoker | 2.5 (1.4–4.5) | ||||||||||||
1–19/day | 4.2 | ||||||||||||
20–39/day | 2.2 | ||||||||||||
≥40/day | 1.1 | ||||||||||||
Cigarette index | |||||||||||||
0–399 | 1.0 | ||||||||||||
400–799 | 1.9 (1.1–3.3) | ||||||||||||
800–1199 | 2.0 (1.1–3.6) | ||||||||||||
≥1200 | 1.0 (0.5–1.9) | ||||||||||||
Tanaka et al. (22) | 1985–1989 | Hospital-based (Kyushu University Hospital) | Cases: 40% were histologically confirmed as HCC; Controls: health examinees at a public health center | 204 (168 men and 36 women) | 410 (291 men and 119 women) | Non-smoker | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of transfusion, drinking, and family history of liver disease | Anti-HCV status was available for part of the subjects, but not adjusted for | ||||
Ex-smoker | 1.5 (0.8–2.8) | ||||||||||||
Current smoker | 1.5 (0.8–2.7) | ||||||||||||
Pack-years | 0.41 | ||||||||||||
0–10.9 | 1.0 | ||||||||||||
11.0–26.2 | 1.4 (0.8–2.4) | ||||||||||||
26.3–35.9 | 1.3 (0.7–2.5) | ||||||||||||
≥36.0 | 1.3 (0.7–2.5) | ||||||||||||
Fukuda et al. (23) | 1986–1992 | Hospital-based (Kurume University Hospital) | Cases: 77% were histologically confirmed as HCC; Controls: inpatients without chronic hepatitis or cirrhosis in two general hospitals in Kurume | 368 (287 men and 81 women) | 485 (287 men and 198 women) | Never | 1.0 | Matched (1:1 for men and 1:4 for women) for sex, age (±5 years), residence, and time of hospitalization. Adjusted for sex | The odds ratios (and 95% CIs) and P value for trend were not described in the original paper, and were estimated by one of the authors (KT), based on the Mantel–Haenszel and Mantel Extension methods | ||||
Ex-smoker | 1.3 (0.8–2.2) | ||||||||||||
Current smoker | 1.8 (1.1–3.1) | ||||||||||||
Cigarette index | |||||||||||||
Non-smoker | 1.0 | 0.48 | |||||||||||
1–499 | 1.7 (1.0–2.8) | ||||||||||||
500–999 | 1.5 (0.9–2.5) | ||||||||||||
≥1000 | 0.6 (0.3–1.4) | ||||||||||||
Murata et al. (24) | 1984–1993 | Nested case–controls (male participants in a gastric mass screening by the Chiba Cancer Association) | Cases: confirmed by record linkage with the Chiba Cancer Registry; Controls: participants in the screening without liver cancer | 66 men | 132 men | Cigarettes/day | Matched (1:2) for sex, birth year (±2 years), and the first digit of the address code. No adjustment | Anti-HCV and HBsAg were not tested | |||||
None | 1.0 | 0.75 | |||||||||||
1–10 | 1.4 | ||||||||||||
11–20 | 2.0 (P < 0.05) | ||||||||||||
≥21 | 0.4 | ||||||||||||
Shibata et al. (25) | 1992–1995 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; Hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 115 men | 115 male HCs and 115 male CCs | Cigarette index, based on HCs | Matched (1:1) for sex, age (±5 years for HCs and ±3 years for CCs), residence (for HCs) and time of hospitalization (for HCs). Adjusted for matching factors | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 1.6 (0.6–4.0) | ||||||||||||
500-999 | 1.2 (0.5–2.9) | ||||||||||||
≥1000 | 0.7 (0.2–2.0) | ||||||||||||
Cigarette index, based on CCs | |||||||||||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 2.1 (0.9–4.7) | ||||||||||||
500-999 | 1.9 (0.8–4.6) | ||||||||||||
≥1000 | 1.2 (0.4–3.5) | ||||||||||||
Mukaiya et al. (26) | 1991–1993 | Hospital-based (Sapporo Medical University Hospital) | Cases: histologically and/or clinically confirmed as HCC; Controls: chronic liver disease (hepatitis or cirrhosis) without HCC | 104 men | 104 men | Non-smoker | 1.00 | Matched (1:1) for age (±3 years). Adjusted for age | Additional adjustment for drinking and HBV and HCV infections did not materially alter the results | ||||
Ever-smoker | 3.50 (1.41–8.70) | ||||||||||||
Period < 5years | 1.00 | ||||||||||||
Period ≥ 5years | 3.33 (1.34–8.30) | ||||||||||||
Cigarette index | |||||||||||||
<200 | 1.00 | ||||||||||||
≥200 | 3.33 (1.34–8.30) | ||||||||||||
Takeshita et al. (27) | 1993–1996 | Hospital-based (20 major hospitals in the southern part of Hyogo prefecture) | Cases: 64% were histologically confirmed as HCC; Controls: outpatients or inpatients with various diseases, but without liver disease positive for HBsAg and/or anti-HCV | 102 (85 men and 17 women) | 125 (101 men and 24 women) | Men | Frequency matched for hospital, sex, age, and living area Adjusted for age and drinking | All the controls were HBsAg-negative and anti-HCV-negative by definition | |||||
Non-smoker | 1.0 | ||||||||||||
Ex-smoker | 0.7 (0.3–1.5) | ||||||||||||
Current smoker | 1.6 (0.7–3.5) | ||||||||||||
Women | |||||||||||||
Not described | |||||||||||||
Koide et al. (28) | 1994 | Hospital-based (Nagoya City University Hospital) | Cases: clinically and/or histologically confirmed as HCC; community controls: selected from the same resident community as cases, with no signs of hepatic diseases or HCC | 84 (64 men and 20 women) | 84 (64 men and 20 women) | Never | 1.00 | Matched (1:1) for sex and age (±2 years) Adjusted for sex, age, history of blood transfusion, anti- HBc, anti-HCV, and CYP2E1 | |||||
Current + former | 5.41 (1.10–26.70) | ||||||||||||
Matsuo et al. (29) | 1995–2000 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 222 (177 men and 45 women) | 326 HCs (177 men and 149 women) and 222 CCs (177 men and 45 women) | Men based on HCs | Matched for sex (1:4 for female HCs and 1:1 for other controls), age (±5 years for HCs and ±3 years for CCs), residence (for HCs), and time of hospitalization (for HCs) Adjusted for matching factors | Anti-HCV and HBsAg status was available except for CCs, but not adjusted for | |||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.95 (P < 0.05) | ||||||||||||
25-49 pack-years | 2.15 (P < 0.05) | ||||||||||||
≥50 pack-years | 1.13 | ||||||||||||
Men based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 4.39 (P < 0.05) | ||||||||||||
25–49 pack-years | 2.75 (P < 0.05) | ||||||||||||
≥50 pack-years | 2.90 (P < 0.05) | ||||||||||||
Women based on HCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 1.69 | ||||||||||||
≥25 pack-years | 0.68 | ||||||||||||
Women based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.00 | ||||||||||||
≥25 pack-years | ∞ | ||||||||||||
Munaka et al. (30) | 1997–1998 | Hospital-based (University of Occupational and Environmental Health Hospital) | Cases: no detailed description; controls: no evidence of cancer in any organ | 78 (61 men and 17 women) | 139 (94 men and 44 women) | Cigarette index | Unmatched. Adjusted for sex and age | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Never | 1.00 | ||||||||||||
1 ≤ 400 | 1.14 (0.58–2.25) | ||||||||||||
400 ≤ 800 | 1.09 (0.56–2.14) | ||||||||||||
≥800 | 1.09 (0.56–2.15) |
Reference . | Study period . | Study subjects . | . | . | . | Category . | Relative risk (95%CI or P) . | P for trend . | Confounding variables considered . | Comments . | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Type and source . | Definition . | Number of cases . | Number of controls . | . | . | . | . | . | |||
Oshima et al. (20) | 1972–1980 | Nested case–control (HBsAg- positive blood donors at the Osaka Red Cross Blood Center) | Cases: confirmed by record linkage with the Osaka Cancer Registry; Controls: healthy HBV carriers | 19 men | 38 men | None or <10/day | 1.0 | >0.10 | Matched (1:2) for birth year Adjusted for drinking | All subjects were HBsAg-positive. Anti-HCV was not tested | |||
10–29/day | 1.2 | ||||||||||||
≥30/day | 6.3 | ||||||||||||
Tsukuma et al. (21) | 1983–1987 | Hospital-based (Center for Adult Diseases, Osaka) | Cases: histologically confirmed as HCC; Controls: inpatients with gastrointestinal disease, or examinees for health checkups or gastroendoscopy; no liver disease, cancer, or smoking/alcohol- related disease | 229 (192 men and 37 women) | 266 (192 men and 74 women) | Never | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of blood transfusion, drinking, and family history of liver cancer | Anti-HCV was not tested | ||||
Ex-smoker | 0.7 (0.3–1.9) | ||||||||||||
Current smoker | 2.5 (1.4–4.5) | ||||||||||||
1–19/day | 4.2 | ||||||||||||
20–39/day | 2.2 | ||||||||||||
≥40/day | 1.1 | ||||||||||||
Cigarette index | |||||||||||||
0–399 | 1.0 | ||||||||||||
400–799 | 1.9 (1.1–3.3) | ||||||||||||
800–1199 | 2.0 (1.1–3.6) | ||||||||||||
≥1200 | 1.0 (0.5–1.9) | ||||||||||||
Tanaka et al. (22) | 1985–1989 | Hospital-based (Kyushu University Hospital) | Cases: 40% were histologically confirmed as HCC; Controls: health examinees at a public health center | 204 (168 men and 36 women) | 410 (291 men and 119 women) | Non-smoker | 1.0 | Frequency matched for sex and age Adjusted for sex, age, HBsAg, history of transfusion, drinking, and family history of liver disease | Anti-HCV status was available for part of the subjects, but not adjusted for | ||||
Ex-smoker | 1.5 (0.8–2.8) | ||||||||||||
Current smoker | 1.5 (0.8–2.7) | ||||||||||||
Pack-years | 0.41 | ||||||||||||
0–10.9 | 1.0 | ||||||||||||
11.0–26.2 | 1.4 (0.8–2.4) | ||||||||||||
26.3–35.9 | 1.3 (0.7–2.5) | ||||||||||||
≥36.0 | 1.3 (0.7–2.5) | ||||||||||||
Fukuda et al. (23) | 1986–1992 | Hospital-based (Kurume University Hospital) | Cases: 77% were histologically confirmed as HCC; Controls: inpatients without chronic hepatitis or cirrhosis in two general hospitals in Kurume | 368 (287 men and 81 women) | 485 (287 men and 198 women) | Never | 1.0 | Matched (1:1 for men and 1:4 for women) for sex, age (±5 years), residence, and time of hospitalization. Adjusted for sex | The odds ratios (and 95% CIs) and P value for trend were not described in the original paper, and were estimated by one of the authors (KT), based on the Mantel–Haenszel and Mantel Extension methods | ||||
Ex-smoker | 1.3 (0.8–2.2) | ||||||||||||
Current smoker | 1.8 (1.1–3.1) | ||||||||||||
Cigarette index | |||||||||||||
Non-smoker | 1.0 | 0.48 | |||||||||||
1–499 | 1.7 (1.0–2.8) | ||||||||||||
500–999 | 1.5 (0.9–2.5) | ||||||||||||
≥1000 | 0.6 (0.3–1.4) | ||||||||||||
Murata et al. (24) | 1984–1993 | Nested case–controls (male participants in a gastric mass screening by the Chiba Cancer Association) | Cases: confirmed by record linkage with the Chiba Cancer Registry; Controls: participants in the screening without liver cancer | 66 men | 132 men | Cigarettes/day | Matched (1:2) for sex, birth year (±2 years), and the first digit of the address code. No adjustment | Anti-HCV and HBsAg were not tested | |||||
None | 1.0 | 0.75 | |||||||||||
1–10 | 1.4 | ||||||||||||
11–20 | 2.0 (P < 0.05) | ||||||||||||
≥21 | 0.4 | ||||||||||||
Shibata et al. (25) | 1992–1995 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; Hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 115 men | 115 male HCs and 115 male CCs | Cigarette index, based on HCs | Matched (1:1) for sex, age (±5 years for HCs and ±3 years for CCs), residence (for HCs) and time of hospitalization (for HCs). Adjusted for matching factors | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 1.6 (0.6–4.0) | ||||||||||||
500-999 | 1.2 (0.5–2.9) | ||||||||||||
≥1000 | 0.7 (0.2–2.0) | ||||||||||||
Cigarette index, based on CCs | |||||||||||||
Non-smoker | 1.0 | ||||||||||||
1-499 | 2.1 (0.9–4.7) | ||||||||||||
500-999 | 1.9 (0.8–4.6) | ||||||||||||
≥1000 | 1.2 (0.4–3.5) | ||||||||||||
Mukaiya et al. (26) | 1991–1993 | Hospital-based (Sapporo Medical University Hospital) | Cases: histologically and/or clinically confirmed as HCC; Controls: chronic liver disease (hepatitis or cirrhosis) without HCC | 104 men | 104 men | Non-smoker | 1.00 | Matched (1:1) for age (±3 years). Adjusted for age | Additional adjustment for drinking and HBV and HCV infections did not materially alter the results | ||||
Ever-smoker | 3.50 (1.41–8.70) | ||||||||||||
Period < 5years | 1.00 | ||||||||||||
Period ≥ 5years | 3.33 (1.34–8.30) | ||||||||||||
Cigarette index | |||||||||||||
<200 | 1.00 | ||||||||||||
≥200 | 3.33 (1.34–8.30) | ||||||||||||
Takeshita et al. (27) | 1993–1996 | Hospital-based (20 major hospitals in the southern part of Hyogo prefecture) | Cases: 64% were histologically confirmed as HCC; Controls: outpatients or inpatients with various diseases, but without liver disease positive for HBsAg and/or anti-HCV | 102 (85 men and 17 women) | 125 (101 men and 24 women) | Men | Frequency matched for hospital, sex, age, and living area Adjusted for age and drinking | All the controls were HBsAg-negative and anti-HCV-negative by definition | |||||
Non-smoker | 1.0 | ||||||||||||
Ex-smoker | 0.7 (0.3–1.5) | ||||||||||||
Current smoker | 1.6 (0.7–3.5) | ||||||||||||
Women | |||||||||||||
Not described | |||||||||||||
Koide et al. (28) | 1994 | Hospital-based (Nagoya City University Hospital) | Cases: clinically and/or histologically confirmed as HCC; community controls: selected from the same resident community as cases, with no signs of hepatic diseases or HCC | 84 (64 men and 20 women) | 84 (64 men and 20 women) | Never | 1.00 | Matched (1:1) for sex and age (±2 years) Adjusted for sex, age, history of blood transfusion, anti- HBc, anti-HCV, and CYP2E1 | |||||
Current + former | 5.41 (1.10–26.70) | ||||||||||||
Matsuo et al. (29) | 1995–2000 | Hospital-based (Kurume University Hospital) | Cases: confirmed as HCC by histological, angiographical, and/or other findings; hospital controls (HCs): inpatients without chronic hepatitis or cirrhosis in 2 general hospitals in Kurume; Community controls (CCs): randomly sampled citizens of Kurume | 222 (177 men and 45 women) | 326 HCs (177 men and 149 women) and 222 CCs (177 men and 45 women) | Men based on HCs | Matched for sex (1:4 for female HCs and 1:1 for other controls), age (±5 years for HCs and ±3 years for CCs), residence (for HCs), and time of hospitalization (for HCs) Adjusted for matching factors | Anti-HCV and HBsAg status was available except for CCs, but not adjusted for | |||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.95 (P < 0.05) | ||||||||||||
25-49 pack-years | 2.15 (P < 0.05) | ||||||||||||
≥50 pack-years | 1.13 | ||||||||||||
Men based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 4.39 (P < 0.05) | ||||||||||||
25–49 pack-years | 2.75 (P < 0.05) | ||||||||||||
≥50 pack-years | 2.90 (P < 0.05) | ||||||||||||
Women based on HCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 1.69 | ||||||||||||
≥25 pack-years | 0.68 | ||||||||||||
Women based on CCs | |||||||||||||
Non-smoker | 1.00 | ||||||||||||
1–24 pack-years | 2.00 | ||||||||||||
≥25 pack-years | ∞ | ||||||||||||
Munaka et al. (30) | 1997–1998 | Hospital-based (University of Occupational and Environmental Health Hospital) | Cases: no detailed description; controls: no evidence of cancer in any organ | 78 (61 men and 17 women) | 139 (94 men and 44 women) | Cigarette index | Unmatched. Adjusted for sex and age | Anti-HCV and HBsAg status was available, but not adjusted for | |||||
Never | 1.00 | ||||||||||||
1 ≤ 400 | 1.14 (0.58–2.25) | ||||||||||||
400 ≤ 800 | 1.09 (0.56–2.14) | ||||||||||||
≥800 | 1.09 (0.56–2.15) |
CI, confidence interval; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; anti-HCV, antibody to hepatitis C virus; HCC, hepatocellular carcinoma; HCs, hospital controls; CCs, community controls; HCV, hepatitis C virus; anti-HBc, antibody to hepatitis B core antigen; CYP2E1, cytochrome P450 2E1.
Study populations in the cohort studies were classified as two different types: mostly healthy subjects (n = 7) such as local residents (9,11,17–19), physicians (8) and atomic bomb survivors (14) versus patients with chronic liver disease (10,12,13,15,16) (n = 5) (Table 1). Chronic infections with both HCV and HBV were taken into account in only three studies, all of which followed patients with chronic liver disease (13,15,16). In the case–control studies, a similar classification was possible based on the type of controls: hospital or community controls (21–25,27–30) (n = 9) versus HBV carriers (20) or patients with chronic liver disease without liver cancer (26) (n = 2) (Table 2). In only two case–control studies, both HCV and HBV infections were controlled for (26,28).
A summary of the magnitude of association for the cohort studies and case–control studies is shown in Tables 3 and 4, respectively. Among all 12 cohort studies, five (9,13–15,19) reported strong positive associations of cigarette smoking with liver cancer in either sex or for both sexes combined (Tables 1 and 3); of the five studies, three (9,13,15) demonstrated clear dose–response relationships. Moderate, but not strong, positive associations were found in three cohort studies (10,11,18), and a weak association in one cohort study (17), without any presentation of dose–response relation. In the remaining three (8,12,16), virtually no association was observed. Among the seven cohort studies in which mostly healthy subjects were followed, six (9,11,14,17–19) revealed at least weak positive associations, whereas three (10,13,15) out of the five follow-up studies of patients with chronic liver disease showed such positive associations.
Reference . | Study period . | Study population . | . | . | . | . | Magnitude of association . | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Number of subjects . | Age range . | Event . | Number of incident cases or deaths . | . | ||||
Kono et al. (8) | 1965–1983 | Men | 5130 | Not specified | Death | 51 | – | ||||
Akiba and Hirayama (9) | 1966–1981 | Men | 122 261 | ≥40 | Death | 652 | ↑↑ | ||||
Women | 142 857 | ≥40 | Death | 398 | ↑↑↑ | ||||||
Inaba et al. (10) | 1973–1988 | Men | 270 (liver cirrhosis) | Not specified | Death | 46 | ↑↑ | ||||
Shibata et al. (11) | 1958–1986 | Men | 639 (farming area) | 40–69 | Death | 11 | – | ||||
677 (fishing area) | 40–69 | Death | 22 | ↑↑ | |||||||
Kato et al. (12) | 1987–1990 | Men and women | 1784 (cirrhosis and post-transfusion hepatitis) | ≥16 | Incidence | 122 | – | ||||
Tsukuma et al. (13) | 1987–1991 | Men and women | 917 (chronic liver disease) | 40–69 | Incidence | 54 | ↑↑↑ | ||||
Goodman et al. (14) | 1980–1989 | Men | 36 133 (men and women) | Not specified | Incidence | 156 | ↑↑↑ | ||||
Women | Not specified | Incidence | 86 | ↑ | |||||||
Chiba et al. (15) | 1977–1993 | Men and women | 412 (HCV-associated chronic liver disease) | 40–72 | Incidence | 63 | ↑↑↑ | ||||
Tanaka et al. (16) | 1985–1995 | Men and women | 96 (liver cirrhosis) | 40–69 | Incidence | 37 | – | ||||
Mori et al. (17) | 1992–1997 | Men and women | 3052 | ≥30 | Incidence | 22 | ↑ | ||||
Mizoue et al. (18) | 1986–1996 | Men | 4050 | ≥40 | Death | 59 | ↑↑ | ||||
Ogimoto et al. (19) | 1988–1999 | Men | 28 287 | 40–79 | Death | 186 (number by sex not described) | ↑↑↑ | ||||
Women | 37 241 | 40–79 | Death | ↑↑ |
Reference . | Study period . | Study population . | . | . | . | . | Magnitude of association . | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Number of subjects . | Age range . | Event . | Number of incident cases or deaths . | . | ||||
Kono et al. (8) | 1965–1983 | Men | 5130 | Not specified | Death | 51 | – | ||||
Akiba and Hirayama (9) | 1966–1981 | Men | 122 261 | ≥40 | Death | 652 | ↑↑ | ||||
Women | 142 857 | ≥40 | Death | 398 | ↑↑↑ | ||||||
Inaba et al. (10) | 1973–1988 | Men | 270 (liver cirrhosis) | Not specified | Death | 46 | ↑↑ | ||||
Shibata et al. (11) | 1958–1986 | Men | 639 (farming area) | 40–69 | Death | 11 | – | ||||
677 (fishing area) | 40–69 | Death | 22 | ↑↑ | |||||||
Kato et al. (12) | 1987–1990 | Men and women | 1784 (cirrhosis and post-transfusion hepatitis) | ≥16 | Incidence | 122 | – | ||||
Tsukuma et al. (13) | 1987–1991 | Men and women | 917 (chronic liver disease) | 40–69 | Incidence | 54 | ↑↑↑ | ||||
Goodman et al. (14) | 1980–1989 | Men | 36 133 (men and women) | Not specified | Incidence | 156 | ↑↑↑ | ||||
Women | Not specified | Incidence | 86 | ↑ | |||||||
Chiba et al. (15) | 1977–1993 | Men and women | 412 (HCV-associated chronic liver disease) | 40–72 | Incidence | 63 | ↑↑↑ | ||||
Tanaka et al. (16) | 1985–1995 | Men and women | 96 (liver cirrhosis) | 40–69 | Incidence | 37 | – | ||||
Mori et al. (17) | 1992–1997 | Men and women | 3052 | ≥30 | Incidence | 22 | ↑ | ||||
Mizoue et al. (18) | 1986–1996 | Men | 4050 | ≥40 | Death | 59 | ↑↑ | ||||
Ogimoto et al. (19) | 1988–1999 | Men | 28 287 | 40–79 | Death | 186 (number by sex not described) | ↑↑↑ | ||||
Women | 37 241 | 40–79 | Death | ↑↑ |
HCV, hepatitis C virus; ↑↑↑, strongly positive; ↑↑, moderately positive; ↑, weakly positive; –, no association.
Reference . | Study period . | Study population . | . | . | . | . | Magnitude of association . | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Number of subjects . | Age range . | Event . | Number of incident cases or deaths . | . | ||||
Kono et al. (8) | 1965–1983 | Men | 5130 | Not specified | Death | 51 | – | ||||
Akiba and Hirayama (9) | 1966–1981 | Men | 122 261 | ≥40 | Death | 652 | ↑↑ | ||||
Women | 142 857 | ≥40 | Death | 398 | ↑↑↑ | ||||||
Inaba et al. (10) | 1973–1988 | Men | 270 (liver cirrhosis) | Not specified | Death | 46 | ↑↑ | ||||
Shibata et al. (11) | 1958–1986 | Men | 639 (farming area) | 40–69 | Death | 11 | – | ||||
677 (fishing area) | 40–69 | Death | 22 | ↑↑ | |||||||
Kato et al. (12) | 1987–1990 | Men and women | 1784 (cirrhosis and post-transfusion hepatitis) | ≥16 | Incidence | 122 | – | ||||
Tsukuma et al. (13) | 1987–1991 | Men and women | 917 (chronic liver disease) | 40–69 | Incidence | 54 | ↑↑↑ | ||||
Goodman et al. (14) | 1980–1989 | Men | 36 133 (men and women) | Not specified | Incidence | 156 | ↑↑↑ | ||||
Women | Not specified | Incidence | 86 | ↑ | |||||||
Chiba et al. (15) | 1977–1993 | Men and women | 412 (HCV-associated chronic liver disease) | 40–72 | Incidence | 63 | ↑↑↑ | ||||
Tanaka et al. (16) | 1985–1995 | Men and women | 96 (liver cirrhosis) | 40–69 | Incidence | 37 | – | ||||
Mori et al. (17) | 1992–1997 | Men and women | 3052 | ≥30 | Incidence | 22 | ↑ | ||||
Mizoue et al. (18) | 1986–1996 | Men | 4050 | ≥40 | Death | 59 | ↑↑ | ||||
Ogimoto et al. (19) | 1988–1999 | Men | 28 287 | 40–79 | Death | 186 (number by sex not described) | ↑↑↑ | ||||
Women | 37 241 | 40–79 | Death | ↑↑ |
Reference . | Study period . | Study population . | . | . | . | . | Magnitude of association . | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Number of subjects . | Age range . | Event . | Number of incident cases or deaths . | . | ||||
Kono et al. (8) | 1965–1983 | Men | 5130 | Not specified | Death | 51 | – | ||||
Akiba and Hirayama (9) | 1966–1981 | Men | 122 261 | ≥40 | Death | 652 | ↑↑ | ||||
Women | 142 857 | ≥40 | Death | 398 | ↑↑↑ | ||||||
Inaba et al. (10) | 1973–1988 | Men | 270 (liver cirrhosis) | Not specified | Death | 46 | ↑↑ | ||||
Shibata et al. (11) | 1958–1986 | Men | 639 (farming area) | 40–69 | Death | 11 | – | ||||
677 (fishing area) | 40–69 | Death | 22 | ↑↑ | |||||||
Kato et al. (12) | 1987–1990 | Men and women | 1784 (cirrhosis and post-transfusion hepatitis) | ≥16 | Incidence | 122 | – | ||||
Tsukuma et al. (13) | 1987–1991 | Men and women | 917 (chronic liver disease) | 40–69 | Incidence | 54 | ↑↑↑ | ||||
Goodman et al. (14) | 1980–1989 | Men | 36 133 (men and women) | Not specified | Incidence | 156 | ↑↑↑ | ||||
Women | Not specified | Incidence | 86 | ↑ | |||||||
Chiba et al. (15) | 1977–1993 | Men and women | 412 (HCV-associated chronic liver disease) | 40–72 | Incidence | 63 | ↑↑↑ | ||||
Tanaka et al. (16) | 1985–1995 | Men and women | 96 (liver cirrhosis) | 40–69 | Incidence | 37 | – | ||||
Mori et al. (17) | 1992–1997 | Men and women | 3052 | ≥30 | Incidence | 22 | ↑ | ||||
Mizoue et al. (18) | 1986–1996 | Men | 4050 | ≥40 | Death | 59 | ↑↑ | ||||
Ogimoto et al. (19) | 1988–1999 | Men | 28 287 | 40–79 | Death | 186 (number by sex not described) | ↑↑↑ | ||||
Women | 37 241 | 40–79 | Death | ↑↑ |
HCV, hepatitis C virus; ↑↑↑, strongly positive; ↑↑, moderately positive; ↑, weakly positive; –, no association.
Reference . | Study period . | Study subjects . | . | . | . | Magnitude of association . | |||
---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Age range . | Number of cases . | Number of controls . | . | |||
Oshima et al. (20) | 1972–1980 | Men | Not specified | 19 | 38 | ↑↑ | |||
Tsukuma et al. (21) | 1983–1987 | Men and women | ≤74 | 229 | 266 | – | |||
Tanaka et al. (22) | 1985–1989 | Men and women | 40–69 | 204 | 410 | – | |||
Fukuda et al. (23) | 1986–1992 | Men and women | 40–69 | 368 | 485 | ↓ | |||
Murata et al. (24) | 1984–1993 | Men | Not specified | 66 | 132 | ↓↓ | |||
Shibata et al. (25) | 1992–1995 | Men | 40–69 | 115 | 115 hospital controls | – | |||
115 community controls | – | ||||||||
Mukaiya et al. (26) | 1991–1993 | Men | Not specified | 104 | 104 (chronic liver disease) | ↑↑↑ | |||
Takeshita et al. (27) | 1993–1996 | Men | Not specified | 85 | 101 | ↑ | |||
Koide et al. (28) | 1994 | Men and women | 46–79 | 84 | 84 | ↑↑↑ | |||
Matsuo et al. (29) | 1995–2000 | Men | 40–75 | 177 | 177 hospital controls | – | |||
177 community controls | ↑↑↑ | ||||||||
Women | 40–75 | 45 | 149 hospital controls | – | |||||
149 community controls | ↑↑ | ||||||||
Munaka et al. (30) | 1997–1998 | Men and women | 34–92 | 78 | 138 | – |
Reference . | Study period . | Study subjects . | . | . | . | Magnitude of association . | |||
---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Age range . | Number of cases . | Number of controls . | . | |||
Oshima et al. (20) | 1972–1980 | Men | Not specified | 19 | 38 | ↑↑ | |||
Tsukuma et al. (21) | 1983–1987 | Men and women | ≤74 | 229 | 266 | – | |||
Tanaka et al. (22) | 1985–1989 | Men and women | 40–69 | 204 | 410 | – | |||
Fukuda et al. (23) | 1986–1992 | Men and women | 40–69 | 368 | 485 | ↓ | |||
Murata et al. (24) | 1984–1993 | Men | Not specified | 66 | 132 | ↓↓ | |||
Shibata et al. (25) | 1992–1995 | Men | 40–69 | 115 | 115 hospital controls | – | |||
115 community controls | – | ||||||||
Mukaiya et al. (26) | 1991–1993 | Men | Not specified | 104 | 104 (chronic liver disease) | ↑↑↑ | |||
Takeshita et al. (27) | 1993–1996 | Men | Not specified | 85 | 101 | ↑ | |||
Koide et al. (28) | 1994 | Men and women | 46–79 | 84 | 84 | ↑↑↑ | |||
Matsuo et al. (29) | 1995–2000 | Men | 40–75 | 177 | 177 hospital controls | – | |||
177 community controls | ↑↑↑ | ||||||||
Women | 40–75 | 45 | 149 hospital controls | – | |||||
149 community controls | ↑↑ | ||||||||
Munaka et al. (30) | 1997–1998 | Men and women | 34–92 | 78 | 138 | – |
↑↑↑, strongly positive; ↑↑, moderately positive; ↑, weakly positive; –, no association; ↓, weakly inverse; ↓↓, moderately inverse.
Reference . | Study period . | Study subjects . | . | . | . | Magnitude of association . | |||
---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Age range . | Number of cases . | Number of controls . | . | |||
Oshima et al. (20) | 1972–1980 | Men | Not specified | 19 | 38 | ↑↑ | |||
Tsukuma et al. (21) | 1983–1987 | Men and women | ≤74 | 229 | 266 | – | |||
Tanaka et al. (22) | 1985–1989 | Men and women | 40–69 | 204 | 410 | – | |||
Fukuda et al. (23) | 1986–1992 | Men and women | 40–69 | 368 | 485 | ↓ | |||
Murata et al. (24) | 1984–1993 | Men | Not specified | 66 | 132 | ↓↓ | |||
Shibata et al. (25) | 1992–1995 | Men | 40–69 | 115 | 115 hospital controls | – | |||
115 community controls | – | ||||||||
Mukaiya et al. (26) | 1991–1993 | Men | Not specified | 104 | 104 (chronic liver disease) | ↑↑↑ | |||
Takeshita et al. (27) | 1993–1996 | Men | Not specified | 85 | 101 | ↑ | |||
Koide et al. (28) | 1994 | Men and women | 46–79 | 84 | 84 | ↑↑↑ | |||
Matsuo et al. (29) | 1995–2000 | Men | 40–75 | 177 | 177 hospital controls | – | |||
177 community controls | ↑↑↑ | ||||||||
Women | 40–75 | 45 | 149 hospital controls | – | |||||
149 community controls | ↑↑ | ||||||||
Munaka et al. (30) | 1997–1998 | Men and women | 34–92 | 78 | 138 | – |
Reference . | Study period . | Study subjects . | . | . | . | Magnitude of association . | |||
---|---|---|---|---|---|---|---|---|---|
. | . | Sex . | Age range . | Number of cases . | Number of controls . | . | |||
Oshima et al. (20) | 1972–1980 | Men | Not specified | 19 | 38 | ↑↑ | |||
Tsukuma et al. (21) | 1983–1987 | Men and women | ≤74 | 229 | 266 | – | |||
Tanaka et al. (22) | 1985–1989 | Men and women | 40–69 | 204 | 410 | – | |||
Fukuda et al. (23) | 1986–1992 | Men and women | 40–69 | 368 | 485 | ↓ | |||
Murata et al. (24) | 1984–1993 | Men | Not specified | 66 | 132 | ↓↓ | |||
Shibata et al. (25) | 1992–1995 | Men | 40–69 | 115 | 115 hospital controls | – | |||
115 community controls | – | ||||||||
Mukaiya et al. (26) | 1991–1993 | Men | Not specified | 104 | 104 (chronic liver disease) | ↑↑↑ | |||
Takeshita et al. (27) | 1993–1996 | Men | Not specified | 85 | 101 | ↑ | |||
Koide et al. (28) | 1994 | Men and women | 46–79 | 84 | 84 | ↑↑↑ | |||
Matsuo et al. (29) | 1995–2000 | Men | 40–75 | 177 | 177 hospital controls | – | |||
177 community controls | ↑↑↑ | ||||||||
Women | 40–75 | 45 | 149 hospital controls | – | |||||
149 community controls | ↑↑ | ||||||||
Munaka et al. (30) | 1997–1998 | Men and women | 34–92 | 78 | 138 | – |
↑↑↑, strongly positive; ↑↑, moderately positive; ↑, weakly positive; –, no association; ↓, weakly inverse; ↓↓, moderately inverse.
Among all 11 case–control studies, five (20,26–29) reported weak to strong positive associations with cigarette smoking, with a dose–response relationship presented in only one study (20) (Tables 2 and 4). In the remaining six studies (21–25,30), the observed associations were judged to be null or inverse due to the lack of dose–response relationship, although around 2- to 4-fold risk excess in light to moderate exposure categories was observed in five of them (21–25). In the nine case–control studies employing hospital or community controls, three (27–29) demonstrated at least weak positive associations, whereas both case–control studies using controls of HBV carriers or patients with chronic liver disease (20,26) afforded such positive associations.
In the cohort studies, cigarette smoking was almost consistently associated with elevated liver cancer risk. Information and selection biases may not be serious issues in those studies. However, potential confounding by chronic HBV and HCV infections was not addressed in most studies. Since, in Japan, individuals with either or both infections may have more than 100 times higher risk than those without either (3,31), only a slight change in smoking habit among such infected individuals could result in a substantial distortion of associated RRs. Alcohol consumption, another potential confounder, was not adequately controlled in some studies. In addition, the lack of dose–response relationship in three-quarters of the cohort studies has made our conclusion more conservative.
As for the case–control studies, the data have been controversial. In some studies, the recruitment of hospital controls, which possibly included those with smoking-related diseases, may have biased the RRs towards unity. Confounding issues by hepatitis virus infection and alcohol drinking were the same as those in the cohort studies. The absence of dose–response relation in majority of the case–control studies appears very perplexing. Among cases, symptoms resulting from pre-existing liver disease or physicians' advice on their health can lead to lifestyle changes including a reduction in number of cigarettes smoked per day. This might be responsible for elevated risks among light to moderate smokers observed in most case–control studies. However, the situation was similar in the cohort studies where smoking habit many years before the development of liver cancer was evaluated. Some unknown biological implications might exist in these non-linear relations.
An interaction issue between hepatitis viruses and cigarette smoking (i.e. possible difference in risk increase due to smoking according to hepatitis virus infection) should also be considered. Since the great majority of patients with hepatocellular carcinoma in Japan is known to be chronically infected with HBV or HCV (2,3), the following question naturally arises: ‘Does smoking increase the risk of hepatocellular carcinoma among people without either HBV or HCV infection?’ This question has not fully been addressed, probably due to the difficulty in conducting epidemiologic studies on this subject and its low practical implication in the prevention of liver cancer. It seems biologically implausible that cigarette smoking, without any hepatitis virus infection or heavy alcohol consumption, causes chronic liver disease, thereby playing a major role in hepatocarcinogenesis. On the other hand, the evaluation of the risk for smoking among people infected with HBV or HCV will be easier to be performed and will provide more practical information. It is noteworthy that, based on such evaluations, a limited number of cohort or case–control studies demonstrated clear dose–response relationships between smoking and liver cancer risk (13,15,20).
Finally, the authors consider that it will be problematic to perform a meta-analysis to obtain a summary estimate for the overall magnitude of association, since such an estimate may not be applicable to general populations of the Japanese due to the above interaction issue. Therefore, the planned meta-analysis was not conducted in this particular evaluation. In addition, the authors cannot exclude the possibility of publication bias and missing relevant epidemiologic studies, although they have long been knowledgeable about the situation of such studies in Japan.
EVALUATION OF THE EVIDENCE ON CIGARETTE SMOKING AND LIVER CANCER RISK AMONG JAPANESE
From these results and based on assumed biological plausibility as previously done by the International Agency for Research on Cancer (5), we conclude that cigarette smoking ‘probably’ increases the risk of primary liver cancer among the Japanese. Potential confounding by hepatitis virus infection and virus–smoking interactions need to be addressed in future studies.
Research group members: Shoichiro Tsugane [principal investigator], Manami Inoue, Shizuka Sasazuki, Motoki Iwasaki, Tetsuya Otani (National Cancer Center, Tokyo); Ichiro Tsuji [since 2004], Yoshitaka Tsubono [in 2003], Taichi Shimazu (Tohoku University, Sendai); Kenji Wakai (Aichi Cancer Center, Nagoya); Chisato Nagata (Gifu University, Gifu); Tetsuya Mizoue (Kyushu University, Fukuoka); Keitaro Tanaka (Saga University, Saga). For reprints and all correspondence: Keitaro Tanaka, MD, Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan; E-mail: tanakake@post.saga-med.ac.jp
The authors gratefully acknowledge the assistance of Ms Izumi Suenega and Mr Tomohiro Shintani in this review. This work was supported by the Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare, Japan.
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Author notes
1Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, 2Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, 3Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 4Department of Epidemiology and Preventive Medicine, Gifu University School of Medicine, Gifu, 5Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka and 6Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan