Cancer Causes Control DOI 10.1007/s10552-015-0615-3
REVIEW ARTICLE
Alcohol consumption and liver cancer risk: a meta-analysis Shu-Chun Chuang1 • Yuan-Chin Amy Lee2 • Guo-Jie Wu1 • Kurt Straif3 Mia Hashibe2
•
Received: 1 December 2014 / Accepted: 9 June 2015 Ó Springer International Publishing Switzerland 2015
Abstract Purpose Alcohol is a confirmed risk factor of liver cancer. Yet, its dose–response function and synergistic effects with other risk factors remain unclear. Methods We performed a meta-analysis on publications up to May 2014. A total of 112 publications were identified. The meta-relative risk (mRR) and the dose–response trend were calculated. Tests for heterogeneity, publication bias, and sensitivity analyses were performed. The synergy index (SI) was recorded or calculated, whenever possible. Results Compared to individuals who never drank or drank at very low frequencies, the mRR for ever drinkers was 1.29 (95 % confidence interval, CI 1.16–1.42) and 1.46 (95 % CI 1.27–1.65) for case–control studies, and 1.07 (95 % CI 0.87–1.27) for cohort studies. Being a current drinker was associated with an increased liver cancer risk in case–control studies (mRR = 1.55, 95 % CI 0.38–2.73), but not in cohort studies (mRR = 0.86, 95 % CI 0.74–0.97). The dose–response relation between alcohol and liver cancer was apparent with RR = 1.08 (95 % CI 1.04–1.11) for 12 g/day (*1 drink), 1.54 (95 % CI 1.36–1.74) for 50 g/day, 2.14 (95 % CI 1.74–2.62) for 75 g/day, 3.21 (95 % CI 2.34–4.40) for 100 g/day, and 5.20 (95 % CI 3.25–8.29) for 125 g/day of alcohol
& Mia Hashibe
[email protected] 1
Institutes of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
2
Division of Public Health, Department of Family and Preventive Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108, USA
3
International Agency for Research on Cancer, Lyon, France
consumption. There were synergistic effects of alcohol consumption with hepatitis (S = 2.14, 95 % CI 1.31–2.98) and with diabetes (S = 3.57, 95 % CI 2.29–4.84) on the risk of liver cancer, although this may be subject to publication bias. Conclusion Overall, one alcoholic drink per day (*12 g/day) may be associated with a 1.1 times higher liver cancer risk. Further studies on the synergistic effects of alcohol consumption and other major risk factors are warranted. Keywords Alcohol Liver cancer Meta-analysis Dose–risk relationship
Introduction Worldwide, liver cancer is the fifth most common cancer in men and the ninth most common cancer in women. The incidence rate of liver cancer varies by sex, with a male-tofemale ratio of 2.8, and by region, with the highest rates observed in eastern and southeastern Asia (in men, agestandardized rates, ASR: 31.9 and 22.2/100,000, respectively) and the lowest rates observed in northern Europe and south-central Asia (ASR: 4.6 and 3.7/100,000, respectively). The ratio of mortality to incidence was 0.95. It was estimated that there would be 746,000 deaths from liver cancer in 2aˆ¤012 [1]. The geographic difference in liver cancer incidence is partly due to the distribution of the risk factors of liver cancer. Hepatitis B and C virus (HBV and HCV) infections and aflatoxin exposure are the major risk factors of liver cancer. The prevalence of chronic HBV infection was the highest in southeastern Asia ([10 %) and the lowest in northern Europe and North America (*5 %) [2]. The HCV
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Cancer Causes Control
infection prevalence ranged from \1 % in northern Europe to [3 % in northern Africa [3]. The relative risks (RR) of liver cancer were 5–30 for HBV and 1.3–134 for HCV [3]. HBV and HCV together were responsible for 50–90 % of liver cancer cases worldwide [4]. Overall, 17 % liver cancer are related to aflatoxin exposure, with higher proportions in the HBV? (21 %) than in the HBV- populations (9 %) [5]. Other established risk factors include aflatoxin exposure, tobacco smoking, and alcohol drinking. Suspected risk factors are diets low in fruit and vegetables, obesity, diabetes and insulin resistance, and use of oral contraceptives [6]. Alcohol has been classified as a human carcinogen for the liver by the International Agency for Research on Cancer (IARC) since 1988 [7]. In areas low in HBV and HCV prevalence, alcohol consumption is probably the most important risk factor of liver cancer. Heavy alcohol consumption confers a RR of 1.5–2.0 [8] and accounts for 32–45 % liver cancers in the USA and southern Europe [9, 10]. Alcohol can directly initiate and promote liver cancer development and is associated with tumor progression. The potential mechanisms of alcohol on liver carcinogenesis include [10–13]: (1) alcohol and its metabolite, acetaldehyde, increase oxidative stress, which damages the DNA and influences its repair; (2) alcohol causes liver injury that results in enhanced fibrogenesis and cirrhosis. Most alcohol-related liver cancer is through the development of liver cirrhosis; (3) alcohol interacts with other environmental carcinogens, e.g., smoking; (4) alcohol interrupts one-carbon metabolism, thus leads to impaired methylation patterns and altered genetic expression enhancing the carcinogenesis; and (5) alcohol exaggerates liver damage by HBV and/or HCV infection and accelerates tumor progression. Previous studies have suggested that regular consumption of 40–60 g of alcohol is associated with an increased liver cancer risk [9, 11, 13]. A lower level of alcohol consumption conferring risk was proposed for women [9]. A recent dose–risk meta-analysis of prospective studies suggested a linear relationship between increasing alcohol consumption and liver cancer risk, with an excess risk of 66 % for 100 g/day [14]. However, data from these original studies did not allow the investigators to provide precise risk estimates for such high alcohol doses [14]. To address the question, we summarized the risk estimates from alcoholism or alcohol misuser cohorts. Moreover, the synergic effect of the emerging risk factors, the diabetes, obesity, and alcohol, was not fully assessed yet. In this study, we attempted to provide a comprehensive picture of the associations between alcohol and liver cancer and the joint effects with other carcinogens.
123
Materials and methods Search strategy and selection criteria We conducted a literature search up to May 2014 through PubMed with a restriction to English language and human studies, using the following search terms, alcohol AND liver cancer, in the abstract and title. We also checked the reference lists of the articles retrieved from PubMed search (Fig. 1). Studies to be included had to provide enough information to estimate the relative risk (RR) and 95 % confidence intervals (CI) for alcohol drinking. The crude and best adjusted odds ratios (OR) from the selected publications were recorded. When several publications were available from the same study, either the most recent publication, the publication with the best adjusted OR, or the relevant analyses, e.g., ever/never, dose–response, or subgroup analyses, was included. Essential characteristics of the cohort studies are shown in Table 1, and those of the case– control studies are shown in Table 2. The cohort studies, in which the participants received more medical attention, are listed in Appendix 1 separately. Statistical analysis Meta-RR (mRR) was calculated with random effect models to combine study-specific risk estimates. Because liver cancer is a rare disease, risk ratio and odds ratio estimates were not differentiated. Since the mortality is almost identical to the incidence, we combined estimates for incidence and mortality. Subgroup analyses were performed by sex (men and women), region (Asia, Europe, North America, and other), study design (cohort and case– control), outcome (incidence and mortality), case number (B200 and [200 cases), year of publication (1966–1990 and 1991–), and specific adjustment (HBV, HCV, or smoking). Whenever possible, synergistic effects of alcohol consumption and other risk factors on the risk of liver cancer were recorded or calculated using the formula: S = (RR11 - 1)/(RR10 ? RR01 - 2) [15], where RR11 is the joint effect of alcohol consumption, and the other risk factors, RR01 and RR10, are the component effects of alcohol consumption and the other risk factor, respectively. The degree of heterogeneity was estimated by using the I2 statistics which represents the percentage of total variation contributed by between-study variance [16]. Begg’s plots and Egger’s tests were used to evaluate publication bias. Sensitivity analyses were performed by removing one study at a time to assess whether the mRR was influenced by a particular study. We used a flexible meta-regression model to estimate the dose–response trend [17, 18]. For each study, the
Cancer Causes Control Fig. 1 Flowchart of the study search and selection
MEDLINE search N=7,755 Limited to English language, published from 1966/1/1 to 2014/5/31, and human studies Search fields: abstract/tle N=890 Exclude: 1. Review, meta-analysis, editorial, leer, etc. (N=255) 2. Exposure is not alcohol intake or outcome is not HCC incidence or mortality (N=539) Include: Retrieved from reference lists (N=204) Full text review N=300 Exclude: 1. No effect esmates on the main associaon between alcohol intake and HCC risk (N=109) 2. Duplicated publicaons (N=45) 3. Crude analysis or frequency only (N=34) A total of 112 studies were included in the meta-analysis
midpoint of alcohol drinking for each category was assigned to each corresponding RR estimate. For the highest alcohol consumption category, a level of 1.2 times the lower cut point of the highest category was applied [19]. The best fitting model is defined as the one with the smallest Akaike’s information criteria (AIC). The alcohol intake was converted into g/day using the following equivalencies: 0.8 g/mL, 12.5 g/drink [18], or the conversion provided by the original article. We also performed sensitivity analyses examining whether the dose–response trend was affected by the factor used for the lower cut point of the highest category, i.e., 1.5 times. All statistical tests were two-sided, and all statistical analyses were carried out with SAS 9.3 and Stata SE12.1.
Results A total of 300 publications were retrieved from the PubMed search, which included 45 duplicate publications (Fig. 1). Overall, 112 independent cohort, case–control, and clinical
studies were included in the analyses. The definition of ever drinking varied by study as shown in the tables. Relative to the reference population, liver cancer incidence/mortality was higher in people with alcohol-related disorders, including alcohol abusers, alcoholism, and alcoholic cirrhosis (Fig. 2). The meta-SIR was 7.87, 95 % CI 4.94–10.8, I2 = 94.9 %, p for heterogeneity \0.001. However, Sorensen et al. [20] appeared to be an influential study. After excluding the Sorenson study, the meta-SIR decreased to 4.60, 95 % CI 2.71–6.49, I2 = 86.64 %, p for heterogeneity \0.001. Similarly, among patients in clinical cohorts with chronic liver diseases, the history of ever drinking was associated with 1.17-fold (95 % CI 1.08–1.26) higher risk than never or low-frequency drinking (Fig. 3). Particularly, alcohol consumption was associated with liver cancer in patients with any cirrhosis (OR 1.15, 95 % CI 1.06–1.25) and in patients with hepatitis-related liver diseases (OR 1.87, 95 % CI 1.32–2.43). Overall, relative to ‘‘never or low-frequency drinking,’’ ever drinking was associated with an increased risk of liver
123
Region
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Europe
Asia
References
Kono et al. [46]
123
Shibata et al. [49]
Kato et al. [22]
Chang et al. [51]
Goodman et al. [52]
London et al. [53]
Yu et al. [55]
Yuan et al. [56]
Yu et al. [57]
Mori et al. [60]
Evans et al. [61]
Jee et al. [62]
Nakaya et al. [63]
Ozasa et al. [64]
Allen et al. [66]
Wang et al. [67]
Taiwan
UK
Japan
Japan
Korea
China
Japan
Taiwan
China
Taiwan
China
Japan
Taiwan
Japan
Japan
Japan
Country
1997–2004
1996–2006
1988–2003
1990–1997
1993–2002
1992–2000
1992–1997
1988–1992
1986–1989
1980–1990
1992–1995
1978–1981
1984–1986
1987–1990
1958–1986
1965–1983
Period of recruitment
40–69
27–89
Age
9,775
5,929
F
Both [35
46,178
21,201
1,283,112
1,280,296
40–79
40–64
[49
Both
M
Both
Both
83,885
3,059
Both [30 25–64
7,342
M
[30
1,506
18,244
60,984
30–64
36,133
[20
30–85
2,225
1,316
5,135
Cohort size
45–64
M
M
M
Both
M
Both [16
M
M
Sex
8
7
12
7
10
8
5
6
6
7
2.5
9
6
3
28
19
Years of followup
Incidence
Incidence
Death
Incidence
Death
Death
Incidence
Incidence
Death
Incidence
Mortality
Incidence
Incidence
Incidence
Death
Death
Outcome
Table 1 Summary characteristics of the cohort studies on alcohol drinking and liver cancer
111
337
463
48
3,807
1,092
22
84
102
16
183
242
38
122
33
51
No. of cases
Yes
Age, residence, and HBV status
Age, smoking, HBV, and diabetes
[0 g/day
Drinkers
[10 g/day in the 6 months before the interview
[2 drinks/week
Age, sex, smoking, BMI, and diabetes
Age, residence, SES, BMI, smoking, physical activity, use of oral contraceptive, and hormone replacement therapy
Age and area of study
Age, smoking, education, daily consumption of orange and other fruit juice, spinach, carrot or pumpkin, and tomato
HBV, history of acute hepatitis, family history of HCC, occupation (nonpeasant/peasant), current tea drinker, drinking well water in 1980s
]4 drinks/week
Current
Age and sex
Age and plasma retinol levels
Age, education, and smoking
Age, AFP (normal/fluctuating/persistent elevated), elevation of serum ALT/ AST for at least 6 months, liver cirrhosis scanning (no/yes), smoking, and education
[1 drink/week regularly
Drinking alcohol at least once a week for [1 year
Once per week for 6 months or more
At least once a week for [1 year
Age, sex, residence, age at the time of bombing, and radiation dose to the liver
Age, residence, and date at recruitment
[50 ml/day Drink regularly
Age and sex
Age
Age and smoking
Potential confounders under consideration
Current
Drinker
Daily in the past 20 years
Definition of ever drinking
[65]
[58, 59]
[54]
[50]
[47, 48]
Other publications from the same population
Cancer Causes Control
Region
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
Asia
North America
Asia
References
Kim et al. [68]
Loomba et al. [31]
Yi et al. [77]
Koh et al. [78]
Shimazu et al. [79]
Joshi et al. [80]
Jung et al. [81]
Yang et al. [82]
Shen et al. [83]
Persson et al. [84]
Michikawa et al. [85]
Table 1 continued
Japan
USA
China
China
Korea
Korea
Japan
Singapore
Korea
Taiwan
Korea
Country
1993–2006
1995–1996
1998–2001
1990–1991
1993–2004
1999–2004
1988–2004
1993–1998
1985–2005
1990–2004
2001–2005
Period of recruitment
30–65
40–69
Age
30–59
40–79
45–74
Both
Both
Both
M
40–69
50–71
C65
40–79
Both [20
M
Both
Both
Both [55
M
Both
Sex
17,654
494,743
66,820
220,000
16,320
548,530
174,719
61,321
6,291
2,260
1,341,393
Cohort size
12.6
10.5
10.5
15
9.3
6
12
12
21
14
5
Years of followup
Incidence
Incidence
Death
Death
Death
Death
Incidence
Incidence
Death
Incidence
Death
Outcome
104
435
590
1,115
85
998
804
394
55
135
1,506
No. of cases Age, residence, smoking, physical activity, BMI, blood pressure, and fasting blood sugar
[1 g/day
Drinker
Drinker
Drinker
At least once a week on a regular basis during the past 12 months
Drinker
Drinker
Current
Any alcoholic beverage on a monthly basis or more often
Yes
Age, sex, area, BMI, diabetes, coffee consumption, HBV, and HCV
Age, sex, race, education, smoking, BMI, and diabetes
Age, sex, education, housing type, monthly expenditure, BMI, exercise, health status, and smoking status
Age, area, smoking, and education
Age, sex, areas, education, smoking, and BMI
Age, BMI, fasting serum glucose, smoking, and HBV
Age, study, history of diabetes, smoking, and coffee intake
Age, sex, year of recruitment, dialect group, education, BMI, diabetes, and cups of coffee per day
Age, history of chronic disease, smoking, ginseng intake, pesticide use, BMI, and education
Age, BMI, smoking, HBV, ALT, Drinking alcohol and cirrhosis [4 days a week for [1 year
Potential confounders under consideration
Definition of ever drinking
Pooled analysis on [63–65]
[69–76]
Other publications from the same population
Cancer Causes Control
123
Region
North America
North America
North America
Asia
Europe
Asia
Asia
Asia
Africa
Europe
Asia
Asia
Asia
Asia
Europe
References
Stemhagen et al. [86]
123
Yu et al. [87]
Austin et al. [88]
Tsukuma et al. [89]
Caporaso et al. [90]
Choi et al. [23]
Srivatanakul et al. [43]
Yu et al. [91]
Mohamed et al. [93]
Simonetti et al. [94]
Tanaka et al. [95]
Cordier et al. [97]
Fukuda et al. [98]
Yamaguchi et al. [99]
Arico et al. [100]
Italy
Japan
Japan
Vietnam
Japan
Italy
South Africa
Taiwan
Thailand
Korea
Italy
Japan
USA
USA
USA
Country
1986–1992
1976–1985
1986–1992
1989–1992
1985–1989
1982–1988
1985–1987
1987–1988
1986–1990
1988–1990
1983–1987
1975–1979
1975–1980
Period of recruitment
18–84
Both
M
Both
M
Both
Both
Both
M
40–69
40–69
20–87
Both \75
Both
Both
Both \74
Both
62
466
368
152
204
197
101
127
65
260
88
221
86
78
Both \70
No. of cases
265
Age
Both [20
Sex
310
466
368
241
410
197
101
127
65
780
224
266
161
78
530
No. of controls
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Outcome
Age and sex
Age, sex, and admission date
Age, sex, residence, and time of hospitalization (±2 months after a case interview)
Age, hospital and residence
Age and sex
Age and sex
Age, sex, and race
Age, sex, race, and residence
Age, sex, and residence
Age, sex, and admission date
Age and sex
Age, sex, and race
Age, sex, race, and residence
Age, sex, race, and residence
Matching variables
Table 2 Summary characteristics of the case–control or cross-sectional studies on alcohol drinking and liver cancer
Matched/paired analysis
[100 serving in the entire life
Hospital
Hospital
Matched/paired analysis Age, sex and HBV
Heavy [25 g/day
HBV, blood transfusion, parental history of hepatic diseases
[1 drink/day, once a week or [1 year
Age and sex
[1 drink/day, once a week for [1 year
Hospital
Matched/paired analysis
]80 g/day
Age, hospital, residence, and HBV
Smoking and HBV
[10 years
Occasional or regular drinkers
Smoking, peanut consumption, HBV, and HCV
HBV, diet, and betel nut chewing
Age, marital status, education, HBV, and smoking
Age, sex, HBV, HCV, and HDV
Drinking alcohol [3 days for [15 years
Regular
Ever
[1 g/kg of ideal body weight for men and 0.7 g/kg for women for [5 years
[3 go/day of sake for Age, HBV, history of blood transfusion, [10 years (1 go smoking, and family *27 ml ethanol) history of liver cancer
Matched/paired analysis
Age and smoking
Covariables in the statistical model
Usual habit
Ever
Definition of ever drinking
Hospital
Hospital
Hospital
Hospital
Population
Hospital
Hospital
Hospital
Hospital
Hospital
Population
Hospital
Sources of controls
[96]
[92]
Other publications from the same population
Cancer Causes Control
Japan
Japan
Japan
Italy
Japan
Greece
Japan
USA
Asia
Asia
Asia
Asia
Asia
Europe
Asia
Asia
Asia
Asia
Europe
Asia
North America
Asia
Pyong et al. [102]
Chiba et al. [103]
Murata et al. [104]
Shin et al. [105]
Wang et al. [106]
Braga et al. [110]
Shibata et al. [115]
Wang et al. [116]
Zhang et al. [38]
Koide et al. [117]
Lagiou et al. [118]
Takeshita et al. [121]
Hassan et al. [122]
Yu et al. [123]
China
Japan
China
Taiwan
Taiwan
Korea
Germany
Europe
Peters et al. [101]
Country
Region
References
Table 2 continued
1995–1997
1994–1995
1993–1994
1995–1998
1994
1994–1995
1984–1995
1992–1995
1984–1996
1991–1995
1993–1993
1984–1993
1991–1993
1989–1992
1986–1993
Period of recruitment
30–65
40–89
Age
Both
Both
Both
Both
Both
Both
Both
Both
25–79
46–79
17–86
40–69
Both \75
Both
Both
M
Both
Both
Both
Sex
248
115
102
333
84
152
105
115
428
56
203
66
128
90
86
No. of cases
248
230
125
360
84
115
37
115
1,502
220
406
132
76
249
86
No. of controls
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Outcome
Age, sex, and residence
Age, sex, and year of diagnosis
Age, sex, and residence
Age, sex, and hospital
Age, sex, and residence
Age and sex
Age and sex
Age, sex, residence, and date of blood collection
Age and sex
Age, sex, and residence
Age
Age and sex
Matching variables
Age, sex, HBV, HCV, and smoking Age, sex, and HBV
[1 go/day of sake for [10 years [80 g/day for [5 years
HBV, HCV, smoking, and diabetes
[100 servings in the entire life Hospital
Population
HBV
Age and smoking
]20 drink-year Hospital
Ever
Age, sex, diabetes, years of schooling, hepatitis virus infection, and smoking
Hospital
]40 glasses/ week
History of liver disease, family history of liver diseases, corn consumption, peanut consumption, psychological stress, HBV
[50 g/day once a week or at least 1 year
Age and sex
Age, sex, and HBV
Matched/paired analysis
Ever
Drinkers
Age, sex, residence, education, smoking, oral contraceptive use, and history of hepatitis
Age, sex. Residence, date of blood collection, and HBV
SES
Current ? former
Population
Hospital
Hospital
Population
[6 drinks/day for men and ]4 drinks/day for women
Drinking alcohol [4 days a week for [6 months
Population
Hospital
Drinker
Smoking
HBV, HCV, smoking
[80 g/day for [10 years
Current habit
Covariables in the statistical model
Definition of ever drinking
Hospital
Population
Hospital
Hospital
Hospital
Sources of controls
[119, 120]
[111–114]
[107–109]
Other publications from the same population
Cancer Causes Control
123
123
Japan
Japan
Italy
USA
China
Japan
Japan
Asia
Asia
Asia
North America
Europe
Europe
North America
Asia
Asia
Asia
Matsuo et al. [125]
Munaka et al. [126]
Tsai et al. [127]
Yuan et al. [128]
Gelatti et al. [131]
Gelatti et al. [133]
Marrero et al. [138]
Zhu et al. [139]
Fukushima et al. [141]
Sakamoto et al. [142]
Italy
USA
Taiwan
Taiwan
Asia
Huang et al. [124]
Country
Region
References
Table 2 continued
2001–2004
2001–2002
1999–2003
2002–2003
1994–2003
1999–2002
1984–2002
1996–1997
1997–1998
1995–2000
1999–2001
Period of recruitment
Both
Both
Both
Both
40–79
209
73
507
210
250
Both \80
295
210
78
222
185
No. of cases
200
18–74
40–75
Age
Both \75
Both
Both
Both
Both
Both
Sex
275
253
541
420
500
400
435
210
138
222
185
No. of controls
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Outcome
Age, sex, and the date of the first visit
Age and sex
Age, sex, date and hospital of admission
Age, sex, date and hospital of admission
Age, sex, and race
Age and sex
Age, sex, race, and residence
Age, sex, and smoking status
Matching variables
Age, sex, smoking, HBV, and HCV
[69 g/day for [10 years Hospital
Years since identification of liver disease, IFN treatment for cirrhosis?, abdominal ultrasonography, platelet, AST, albumin, and fasting blood sugar Once or more per week for at least 1 year
Hospital
Age, sex, smoking, HBV, HCV, and family history of HCC
Smoking and obesity
Yes/no
Current
Age, sex, HBV, HCV, and coffee intake
Age, sex, residence, HBV, and HCV
[60 g/day
Current drinker
Age, sex, race, education, smoking status, and history of diabetes
Matched/paired analysis
Consume alcohol on a weekly basis
Drinking alcohol [4 days a week for [1 year
Age and sex
Hospital
Hospital
Hospital
Hospital
Population
Population
Drinker
Drinker
Population
Hospital
Age, sex, chronic viral hepatitis, stage, family history of HCC, smoking, red meat intake, white meat intake, salt food intake, vegetable consumption, and fruit intake
[30 g/day for [10 years
Hospital
Diabetes, history of blood transfusion, and smoking
Covariables in the statistical model
Definition of ever drinking
Sources of controls
[143]
[140]
[134–137]
[132]
[129, 130]
Other publications from the same population
Cancer Causes Control
Japan
India
Italy
France
Korea
Canada
USA
Asia
Asia
Asia
Europe
Europe
Asia
North America
North America
Asia
Asia
Tanaka et al. [144]
Yuan et al. [145]
Kumar et al. [146]
Polesel et al. [147]
Ferrand et al. [151]
Yoon et al. [152]
Benedetti et al. [153]
Hassan et al. [154]
Jeng et al. [158]
Zaridze et al. [21]
Russia
Taiwan
China
Country
Region
References
Table 2 continued
1990–2001
2003–2004
2000–2008
Mid 1980s
2004–2006
2000–2003
1999–2002
1994–2005
1986–2001
1990–2002
Period of recruitment
Both
Both
Both
M
Both
15–74
35–70
125
\75
43,082
200
420
28
287
185
Both \85
M
213
213
Both
45–64
13
Both [20
M
No. of cases
Age
Sex
5,475
200
1,140
507
296
142
412
254
1,087
61
No. of controls
Death
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Outcome
Age and sex
Age and area
Age and hospital
Age, sex, and residence
Age, sex, race, and time period
Age, residence, and date of sample collection
Matching variables
Population
Hospital
Hospital
Population
Hospital
Hospital
Usual weekly consumption [0.5 bottle of vodka or equivalent
Age, city, and smoking
Matched/paired analysis
Age, sex, race, education. HBV, HCV, smoking, diabetes, and family history of cancer
[4 drinks each month for 6 months Drinking alcohol [4 days a week for [1 year
Age, smoking, respondent status, race, income, education, and time since quitting
Age. Sex. Cirrhosis, HBV, and AFP
]80 g/day for [10 years Daily
Age and hospital
Age, sex, center, place of birth, and education
[4 drinks/day
Former/current
Age and sex
[80 g/day for [5 years
Hospital
Hospital
Serum level of retinol
Age, sex, smoking, history of blood transfusion, history of icterus, liver function, HBV, and HCV
Covariables in the statistical model
Once a week for 6 months or more
]75 g/day for [10 years
Definition of ever drinking
Population
Sources of controls
[155–157]
[148–150]
[37]
Other publications from the same population
Cancer Causes Control
123
Region
Europe
Asia
Asia
Asia
Asia
Asia
Europe
North America
Asia
Asia
Asia
Europe
References
Balbi et al. [159]
Yun et al. [161]
Asim et al. [44]
Li et al. [163]
Liu et al. [165]
Ohishi et al. [166]
Trichopoulos et al. [169]
Ha et al. [170]
Tanaka et al. [171]
Asim et al. [172]
Patil et al. [173]
Kuske et al. [174]
Table 2 continued
123
Switzerland
India
India
Japan
USA
Europe
Japan
China
China
India
Korea
Italy
Country
2000
2009–2011
2006–2009
1985–1989
2001–2009
1992–2006
1970–2002
2008–2010
2000
2005–2009
2002–2006
1994–2006
Period of recruitment
Both
Both
Both
F
Both
Both
Both
18–70
40–69
25–70
130
141
348
120
259
125
224
240
204
Both [20
Both
266
Both
207
Both [30
No. of cases
465
Age
Both
Sex
3,260
240
375
257
781
229
644
240
415
251
828
490
No. of controls
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Incidence
Outcome
Age, sex, and race
Age
Age (±12 months), sex, center, date (±2 months) of blood collection, and time of day (±3 h) of blood collection
Age, sex, city, and time, and method of serum storage, and countermatched on radiation dose
Age, sex, and residence
Age and sex
Age and sex
Age and sex
Matching variables Covariables in the statistical model
Age, sex, and smoking
]80 g/day for [1 year
Hospital
Hospital
Hospital
Hospital
Hospital
Age
[1 drink/ week for [1 year
Age, sex, smoking, and coffee drinking Age and sex
Ever [20 g/day
Yes/no
Age, sex, race, cirrhosis, AFP, smoking, etiology of liver diseases, and diabetes
[50 g/day
HBV, HCV, BMI, Population [10 g/day education, coffee for men and intake, and smoking [5 g/day for women
Radiation dose
Age, sex, education, income, BMI, family history of cancer, smoking, and HBV
Age, sex, smoking, HBV, and HCV
[60 ml/day Occasionally/ often/every day
Age and sex
Former/ current
HCV and diabetes [30 g/day for men and [20 g/day for women
Definition of ever drinking
Population [0 g/day
Hospital
Population
Hospital
Hospital
Hospital
Sources of controls
Pooled analyses among women from [89, 98, 115]
[167, 168]
[164]
[162]
[160]
Other publications from the same population
Cancer Causes Control
Cancer Causes Control Cohort
Sex
SIR (95% CI)
Hakulinen et al., 1974 (172)
Alcohol misusers
M
1.49 (1.15, 1.90)
Hakulinen et al., 1974 (172)
Chronic alcoholics
M
2.60 (0.29, 9.38)
Saieva et al., 2012 (176)
Alcoholism
M
13.90 (9.20, 20.90)
Saieva et al., 2012 (176)
Alcoholism
F
11.20 (3.60, 34.60)
Source
Death
6.02 (0.16, 11.88)
Subtotal (I-squared = 84.1%, p = 0.000) . Incidence Adami et al., 1992 (173)
Alcoholism
M
5.40 (3.40, 8.10)
Adami et al., 1992 (173)
Alcoholism
F
12.50 (3.40, 32.00)
Tonnesen et al., 1994 (174)
Alcohol abusers
M
4.10 (2.90, 5.60)
Tonnesen et al., 1994 (174)
Alcohol abusers
F
1.60 (0.00, 8.90)
Sorensen et al., 1998 (20)
Alcoholic cirrhosis
Both
70.60 (59.50, 83.20)
Thygesen et al., 2009 (175)
Alcohol use disorder
M
4.70 (3.60, 6.00)
Thygesen et al., 2009 (175)
Alcohol use disorder
F
6.00 (2.60, 11.90) 10.46 (5.82, 15.10)
Subtotal (I-squared = 95.1%, p = 0.000) .
7.87 (4.94, 10.80)
Overall (I-squared = 94.9%, p = 0.000) NOTE: Weights are from random effects analysis .51
5
10
50
Fig. 2 Standardized incidence/mortality rate ratio (SIR) (the comparison groups of these studies were the source population of the study population, i.e., the general population) in specific cohorts
cancer (mRR = 1.29, 95 % CI 1.16–1.42, Table 3). There was evidence of heterogeneity among studies (I2 = 46.2 %, p \ 0.001). The estimate was not driven by any single study. Former drinking was also associated with an increased risk of liver cancer (mRR = 2.06, 95 % CI 1.31–2.81). Heterogeneity was evident in the assessment of estimates for former drinkers (p \ 0.001); however, none of the studies were influential. In general, we observed a consistent increased risk of liver cancer in various subgroups in the stratified analyses, although the mRR was not statistically significant in studies with B200 cases. On the other hand, current drinking was marginally associated with a decreased liver cancer risk (mRR = 0.85, 95 % CI 0.68–1.01). Albeit not statistically significant, inverse associations were observed in most strata, except in case–control studies and in studies adjusted for smoking. There were 12 studies that were included in the assessment of joint effects of alcohol consumption and other risk factors on the risk of liver cancer (Table 4). There was a synergistic effect between alcohol consumption with hepatitis and with diabetes on the risk of liver cancer; however, there was marginal publication bias for
the synergistic effect of alcohol consumption and HBV (Egger’s test p = 0.048 and Begg’s test p = 0.089). In fact, restricting to studies that reported synergistic effects yielded higher estimates, e.g., S = 3.10, 95 % CI 1.10–5.10 for alcohol consumption and hepatitis and S = 3.09, 95 % CI 1.06–5.11 for alcohol consumption and smoking. Yet, the overall S of alcohol consumption and smoking was 1.64 (95 % CI 0.58–2.70) when we included the S calculated from two original publications. Overall, 38 studies were in the flexible meta-regression. The random effect model-based mRRs of liver cancer were 1.08 (95 % CI 1.04–1.11) for 12 g/day (*1 drink), 1.19 (95 % CI 1.12–1.27) for 25 g/day (2 drinks), 1.54 (95 % CI 1.36–1.74) for 50 g/day (4 drinks), 2.14 (95 % CI 1.74–2.62) for 75 g/day (6 drinks), 3.21 (95 % CI 2.34–4.40) for 100 g/day (8 drinks), and 5.20 (95 % CI 3.25–8.29) for 125 g/day (10 drinks) alcohol consumption, respectively (Fig. 4). The estimates for high alcohol consumption were sensitive to the factors that were used for the highest category. For example, the mRR was 2.73 (95 % CI 2.14–3.49) for 125 g/day if we used 1.5 times the lower cut point of the highest category. The lower mRR could be due to the fact that the same RRs were assigned to
123
Cancer Causes Control
Fig. 3 Risk ratios of ever drinking in clinical cohorts
higher levels of alcohol consumption for the highest categories. The relative risk functions and the corresponding 95 % CIs of alcohol consumption and liver cancer risk in men, women, and subjects without hepatitis infections are presented in Appendix Figs. 5, 6, and 7. Women tend to have higher RR than men when consuming equal amounts of alcohol; however, the estimates were also imprecise at high concentrations (mRR = 2.29, 95 % CI 1.68–3.11 for men and mRR = 14.4, 95 % CI 2.01–103.4 for women at 100 g/day). There was only one study [21] that reported risk estimates for women who drank more than 100 g/day. Most studies had higher cutoffs of around 50 g/day for women.
Discussion Our meta-analysis supports the inferences that people with alcohol-related disease have a higher risk of liver cancer than the general population, and that alcohol consumption is positively associated with liver cancer risk. The risk
123
seems to be moderate, with a mRR of *1.3 for ever drinkers. The meta-regression model suggested a 1.2 times higher risk of liver cancer for people who drank 25 g/day alcohol (*2 drinks). The inverse association between current drinker and liver cancer risk was counterintuitive and could be driven by the results from the cohort studies. Most of the cohort studies followed up participants for more than 7 years except the Kato et al. [22], which was based on decompensated liver cirrhosis or posttransfusion hepatitis patients with only 3 years of follow-up. Although Kato et al. [22] reported the strongest inverse association (mRR = 0.41, 95 % CI 0.16–1.06), the study result was not influential. The mRR was 0.89, 95 % CI 0.73–1.04 after excluding Kato et al. [22]. There was no major differences for the meta-risk estimates between cohort studies with 5–10 years of follow-up and [10 years of follow-up (Table 3). The results from studies based on mortality cases had stronger associations (mRR = 0.89, 95 % CI 0.80–0.97, three studies), while those based on incident cases usually yielded null associations (mRR = 0.97, 95 % CI 0.46–1.48, six studies). Focusing on studies with incident cases
11
43
5
2
4
1.67
1.41
1.31
21
Positive
1.30
1.45
1.14
1.40
22
6
14
Negative
Stratified by HBV
Yes
No
Adjusted for HBVa
Women
Men
Sex
21
2001–
1.88 1.16
1.50
17
2 20
1.20
1966–1990 1991–2000
Year of publication
[200 cases
B200 cases
1.20
1.39
1.28
1.44
0.98
1.42
1.47
1.13 1.46
1.23
0.71
1.07
1.29
RR
26
5
North America
Case number
7
Europe
Asia
31
Incidence
Region
5
38
Mortality
Outcome
27
[10 years Case–control
Population-based
3 32
5–10 years
Hospital-based
2
6
B5 years
Average/median follow-up
Cohort
Study design
Overall
No. of studies
Ever drinker
(1.06–2.28)
(0.45–2.37)
(1.08–1.54)
(1.14–1.46)
(1.01–1.90)
(0.95–1.34)
(1.20–1.60)
(0.92–2.84) (0.96–1.35)
(1.24–1.75)
(1.03–1.37)
(0.86–1.54)
(0.93–1.85)
(1.13–1.44)
(1.27–1.62)
(0.73–1.12)
(0.98–1.87)
(1.26–1.68)
(0.99–1.27) (1.27–1.65)
(0.91–1.55)
(0.49–0.94)
(0.87–1.27)
(1.16–1.42)
95 % CI
23.9
0.0
60.0
15.9
0.0
41.4
35.6
52.6 43.3
55.1
32.7
18.0
63.3
45.5
44.9
29.1
0.0
54.5
0.0 50.6
0.0
0.0
32.0
46.2
I (%)
2
0.463
1
3
\0.001
0.268
0.553
6
3
6
3
3
4
5
2
7
6
3
1 3
4
0.235
0.928
0.047
0.047
0.121 0.019
0.003
0.047
0.293
0.012
0.003
0.001
0.228
0.597
\0.001
0.399 \0.001
0.872
6
9
\0.001 0.135
No. of studies
Current drinker p
Table 3 Stratified mRR and 95 % CI of alcohol drinking and liver cancer risk
1.04
0.82
0.76
0.98
0.88
1.18
0.93
0.73
0.74
0.86
0.97
0.89
1.55
0.90
0.86
0.85
RR
(0.51–1.57)
(0.65–0.99)
(0.50–1.01)
(0.73–1.24)
(0.80–0.97)
(0.24–2.12)
(0.70–1.17)
(0.49–0.97)
(0.26–1.21)
(0.68–1.05)
(0.46–1.48)
(0.80–0.97)
(0.38–2.73)
(0.80–0.99)
(0.74–0.97)
(0.68–1.01)
95 % CI
66.0
16.2
0.0
53.0
0.0
43.6
60.0
15.9
7.2
52.2
61.3
0.0
73.1
16.1
16.1
43.6
I (%)
2
0.019
0.306
0.633
0.059
0.565
0.053
0.041
0.309
0.340
0.033
0.017
0.531
0.011
0.304
0.304
0.053
p
1
8
3
6
6
1 2
3
6
2
7
5
4
3 2
3
1
7
9
No. of studies
Former drinker
1.98
1.78
2.16
2.26
1.33
2.48
2.03
4.16
1.87
2.38
2.24
2.12 4.16
2.56
1.87
2.06
RR
(1.22–2.74)
(0.66–2.90)
(1.09–3.23)
(1.43–3.10)
(0.00–3.02)
(0.95–4.02)
(0.82–3.25)
(1.55–6.76)
(1.13–2.62)
(0.64–4.12)
(1.16–3.32)
(0.97–3.28) (1.55–6.76)
(1.36–3.76)
(1.13–2.62)
(1.31–2.81)
95 % CI
79.3
30.6
69.5
64.7
83.1
72.5
64.2
0.0
80.0
67.4
74.7
78.9 0.0
0.0
80.0
76.1
I2 (%)
\0.001
0.236
0.006
0.004
0.015
0.003
0.010
0.424
\0.001
0.009
0.003
0.003 0.424
0.661
\0.001
\0.001
p
Cancer Causes Control
123
123
5
2
2
HBV- and HCV?
HBV? and HCV-
11
32 1.50
1.22
1.33
1.29
1.77
1.31
2.00
1.64
1.81
(1.22–1.79)
(1.08–1.37)
(1.15–1.52)
(1.08–1.50)
(1.17–2.38)
(0.37–2.26)
(0.64–3.35)
(1.16–2.11)
(1.26–2.36)
(1.19–1.94)
(1.09–1.37)
95 % CI
b
a
28
Yes
1.35
1.25 (1.18–1.52)
(1.00–1.50) 53.3
34.3
10.5
46.2
24.3
55.6
0.0
0.0
0.0
0.0
0.0
44.0
42.8
I2 (%) p
0.001
0.072
0.344
0.002
0.138
0.001
0.436
0.528
0.581
0.504
0.802
0.065
0.004
4
5
1
8
No. of studies
Current drinker
1.52
0.86
0.84
RR
(0.45–2.58)
(0.77–0.96)
(0.67–1.01)
95 % CI
75.2
5.10
49.8
I2 (%)
0.007
0.391
0.036
p
4
5
1
8
No. of studies
Former drinker
1.32
2.62
1.98
RR
(1.00–1.64)
(1.13–3.70)
(1.22–2.74)
95 % CI
0.0
84.0
79.3
I2 (%)
0.405
\0.001
\0.001
p
Adjust for HCV and smoking in western countries; HBV and smoking in Taiwan and China; HBV, HCV, and smoking in Mediterranean countries; and smoking, HBV, and/or HCV in Japan
Include studies on HBV or HCV carriers
15
No
Ever defined by dose, frequency, and/or duration
Yes
Full adjustment No
21
Yes
b
22
No
Adjust for smoking
2
HBV- and HCV-
Stratified by hepatitis status
2
1.56
10
Positive
1.23
RR
33
No. of studies
Ever drinker
Negative
Stratified by HCV
Yes
No
Adjusted for HCVa
Table 3 continued
Cancer Causes Control
3
4
2
2
HCV
Smoking
Diabetes
Obesity
1,641
410
2,964
593
2,872
4,034
Casesi
1.68
3.04
1.50
2.81
2.55
2.15
(1.06–2.31)
(1.85–4.22)
(1.18–1.85)
(0.95–4.67)
(0.86–4.25)
(1.37–2.94)
1.10
2.46
1.50
12.14
20.91
13.68
RR
RR
95 % CI
RRf10
RRf01
(0.56–1.63)
(1.48–3.45)
(1.31–1.69)
(0.00–28.95)
(10.82–30.99)
(5.40–21.96)
95 % CI
3.75
11.38
3.55
46.31
26.14
25.40
RR
RRf11
(0.075–7.45)
(0.00–27.84)
(1.19–5.91)
(0.00–147.13)
(14.62–37.67)
(9.61–41.19)
95 % CI
2.50
3.57
1.64
1.64
1.14
2.14
RR
(0.86–4.15)
(2.29–4.84)
(0.58–2.70)
(0.30–2.98)
(1.00–1.28)
(1.31–2.98)
95 % CI
Synergistic effectg,h
0.0
18.6
78.1
0.0
0.0
77.9
I2 (%)
0.919
0.268
0.001
0.670 0.276
0.048
0.294
\0.001 0.543
Egger’s test
p
0.806
0.089
0.466
Begg’s test
All studies tested markers for anti-HCV or HBsAg. Two studies included anti-HBc as well [122, 128]
RR01: with alcohol but without the other risk factor; RR10: with the other risk factor but without alcohol; RR11 with both alcohol and risk factor
Both studies defined obesity as BMI C 30
Diabetes was ascertained by reviewing medical records 1 year prior to the cancer onset [122] or by interview [128]
The definitions for smoking include: ever [62], current or recent ex-smoker [128], and C 100 cigarettes lifetime [138, 155]
i
Two publications were missing detailed case number [122, 138]. Replaced with the total case number in the study, respectively
Pooled synergetic effect based on reported values: for hepatitis and alcohol, S = 3.10, 95 % CI 1.10–5.10, n = 4 [122, 128, 158, 161], I2 = 71.9 %, p = 0.014; and for smoking and alcohol, S = 3.09, 95 % CI 1.06–5.11, n = 3 [128, 138, 155], I2 = 70.8 %, p = 0.033. Only one study reported synergetic effects of HBV and alcohol [161]: S = 2.36, 95 % CI 0.99–5.65. The pooled synergetic effects of diabetes and alcohol and obesity and alcohol reported here were based on reported synergetic effects
h
S: synergetic effects; based on reported synergetic effects if available; otherwise, S was calculated from the formula—S = (RR11 - 1)/(RR10 ? RR01 - 2), the confidence interval was calculated from case and control numbers from each stratum [15]
g
f
e
d
c
b
The definition for alcohol varies by study: C3 times/week for 15 years for [91], [60 g/day for [137], C80 mL/day for [122], yes for two studies [70, 76], [4 days/week for 1 year for two studies [71, 158], C25 g/day for [62], [4 drinks/day for [128], [100 drinks/lifetime for [138], [60 mL/day for [155], or C24 g/day for [161]
a
4
10
HBV
Hepatitis
Studies
Table 4 Joint effects of alcohola and hepatitis infectionb, smokingc, diabetesd, or obesitye on the risk of liver cancer
Cancer Causes Control
123
Cancer Causes Control Fig. 4 Relative risk function and the corresponding 95 % confidence interval of alcohol consumption (g/day) and liver cancer. The random effect model-based mRRs of liver cancer were 1.19 (95 % CI 1.12–1.27) for 25, 1.54 (95 % CI 1.36–1.74) for 50, 2.14 (95 % CI 1.74–2.62) for 75, 3.21 (95 % CI 2.34–4.40) for 100, and 5.20 (95 % CI 3.25–8.29) for 125 g/day alcohol consumption, respectively
(Appendix 2), we observed positive associations (not statistically significant) in Asian studies (influenced by Choi et al. [23], a case–control study), studies that had more than 200 cases (both were case–control studies), and studies that adjusted for HBV (case–control studies) and smoking. The potential reason for the observation was that people at a high risk of developing liver cancer (e.g., HBV carrier) may give up drinking or tend not to drink (too much), and this might lead to spurious protective effect. Of note, all of the six cohort studies were conducted in Asia: four in Japan, one in Korea, and one in China, where HCV and HBV are prevalent [3]. The null drinking status may be a marker of the presence of other risk factors, e.g., hepatitis or chronic liver diseases, and may represent distinct populations. The observation is supported by the much higher RR of liver cancer in the former drinkers. It has been suggested that a time period of 23 years is needed for a former drinker to have an equal risk of liver cancer to never drinkers [24]. None of the cohort studies reviewed here has such a long follow-up. Our analyses based on clinical liver diseases suggested that drinking habits at or before the diagnosis of the liver disease were associated with an increased risk of liver cancer (Fig. 3). It is not clear whether stopping drinking after liver disease onset would reduce the liver cancer risk or prolong the disease progression. IARC published a handbook on risk reversal after smoking cessation [25], but there seems to be limited data for alcohol cessation and liver cancer risk. The heterogeneity of the risks observed in ever drinkers was not explained by sex, study design, region, case number, and year of publication; however, the point estimates were relatively stable across study design and region. The studies with full adjustment, i.e., adjusting for HCV
123
and smoking in studies conducted in western countries; HBV and smoking in Taiwan and China; HBV, HCV, and smoking in Mediterranean countries; and HBV and/or HCV and smoking in Japan, yielded stronger point estimates. Furthermore, in studies with relatively clear definitions of ever drinkers, i.e., ever drinking was defined by dose, frequency, and/or duration, the mRR was stronger. These may further strengthen the association between alcohol consumption and liver cancer. A positive dose–response trend was observed for the daily consumption of alcohol (in grams) and liver cancer risk with no safe threshold. Our results were similar to that reported in the previous meta-analyses [14, 26–28], except that we had higher estimated RR in higher consumption groups, e.g., RR = 3.21 for 100 g/day in our report and *1.8 in previous reports. The previous reports [26–28] included publications up to year 2000 and assessed the association with a fixed-effects model. When we repeated our analyses using fixed-effect models, the RRs (95 % CI) of liver cancer were 1.07 (1.04–1.09) for 25 g/day, 1.15 (1.11–1.20) for 50 g/day, and 1.37 (1.30–1.44) for 100 g/day. The corresponding RRs (95 % CI) from a random effect linear model [14] were 1.27 (1.20–1.35), 1.62 (1.44–1.83), and 2.63 (2.06–3.35), respectively. The positive associations were present in both men and women and in participants without hepatitis infection. Among the participants without hepatitis, the lower 95 % CI crossed the null value at *40 g/day (*3 drinks; RR = 1.40, 95 % CI 1.02–1.93). Although the mRRs of liver cancer for 75 g/day and above in women were much higher than that in men (Appendix Figs. 5 and 6), it is noteworthy that the distribution of alcohol consumption from the original publications did not reach such high levels. As a result, the mRR may be unreliable at high levels for women. Nevertheless, it was also reported that women have weaker
Cancer Causes Control
ability to metabolize alcohol [29, 30]. Whether women have higher risk of alcohol-related diseases than men at equal level of alcohol consumption warrants further investigation. We summarized the joint effects of alcohol consumption and other risk factors across studies in Table 4. The mechanism of the synergistic effect of alcohol consumption and hepatitis has been summarized previously [12, 13]. Chronic alcohol consumption may reduce one’s immune response to hepatitis infection, may increase HCV replication and the subsequent damage, may amplify the liver damage by hepatitis and speed up the tumor progression, may result in iron overload when coexisting with HCV infection, and may increases the oxidative stress to the liver. Tobacco smoke contains several carcinogens; alcohol drinking might promote carcinogenesis [11]. However, a significant synergistic effect of alcohol consumption and tobacco smoking was not observed in our analyses. Furthermore, Eggers’ test suggested a marginal publication bias of the reported significant synergistic effects. Obesity and/or diabetes and alcohol consumption are associated with increased oxidative stress and may promote liver injuries via multiple interconnected metabolic pathways [31]. Aflatoxin is a major hepatocarcinogen [32]. However, few studies evaluated the joint effects of alcohol and aflatoxins on the risk of liver cancer. We found an early case–control study in Philippines, suggesting a synergistic and statistically significant effect of aflatoxin exposure and alcohol consumption on the risk of liver cancer [33]. Most reports on aflatoxin were from Africa [34, 35], China [36– 39], Taiwan [40–42], or southeastern Asia [43, 44], where homemade or illegally produced beverages are prevalent [45]. Further investigation on the joint effects of aflatoxins and alcohol consumption on the risk of liver cancer is warranted. A limitation of concern in our meta-analysis was the difference in defining ever drinkers. The analysis restricted to studies which provided a clear definition by dose,
frequency, and/or duration did yield stronger associations. Secondly, the adjustment factors varied across studies. We tried to take the best adjusted estimates, i.e., the estimates that considered the most complete potential confounders. We also conducted the analysis based on the studies that minimally adjusted for HBV, HCV, and smoking, which yielded similar results. Thirdly, publication bias is suggested in the analysis of synergistic effects, implying that the results with evident synergistic effects tend to be published or reported. In addition, the mRR at high levels of alcohol consumption was sensitive to the values we assigned to the highest category. This makes sense because we regressed the same RR on different levels of alcohol consumption. Ideally, the best choice would be to use the median consumption of the highest open-ended category. With the global coverage of our meta-analysis, with heterogeneity this is not straightforward, either. In summary, our meta-analysis supports the conclusions from previous studies that there is a moderate association between alcohol consumption and liver cancer risk. Overall, one drink per day may be associated with a 1.1-fold increase in liver cancer risk. In addition, women had higher liver cancer risk than men at the same level of alcohol consumption. People without hepatitis infections had statistically significant higher liver cancer risk if they drank more than three drinks per day. Acknowledgments
There was no external funding for the project.
Conflict of interest
The authors declare no conflict of interest.
Appendix 1 See Table 5 and Figs. 5, 6, and 7.
Appendix 2 See Table 6.
123
Region
Asia
Asia
Europe
Asia
Asia
Asia
Asia
Europe
Asia
Asia
References
Ikeda et al. [175]
123
Tsukuma et al. [176]
Benvegnu et al. [177]
Aizawa et al. [178]
Ishikawa et al. [179]
Iwasaki et al. [180]
Ohata et al. [181]
Bruno et al. [182]
Ikeda et al. [183]
Chuma et al. [184]
Japan
Japan
Italy
Japan
Japan
Japan
Japan
Italy
Japan
Japan
Country
1987–2002
1995–2005
1989–1990
1980–1999
1986–2000
2000
1981–1990
1986–1993
1987–1991
1974–1989
Period
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Sex
30–69
16–68
20–65
n/a
40–69
19–84
Age
104
872
163
73
792
239
153
290
917
795
Cohort size
14
8
11
7
5
6
8
7
4
17
Years of followup
HCV infection
HCV infection
HCV? cirrhosis
HBV carrier
Chronic HCV
Cirrhosis
Chronic HCV
Cirrhosis
Chronic hepatitis or compensated liver cirrhosis
Viral or alcoholic cirrhosis
Population
Biochemical tests every 1–3 months; ultrasonography or CT every 6 months; 75 patients received IFN treatment
AFP and ultrasonography or CT every 3–6 months; 224 patients received IFN therapy
85 patients received IFN monotherapy
Biochemical tests every 1–3 months and ultrasonography or CT every 3–6 months
All patients received IFN therapy. Patients received regular checkups, including abdominal ultrasonography every 6 months and AFP screening for HCC at start? and after the completion of therapy
Monthly or bimonthly monitoring by ultrasonography and biochemical data (AFP and protein induced by vitamin K antagonists II)
Ultrasound and biochemical tests every 3 or 6 months; 42 patients received IFN treatment
Ultrasound every 6 months
237
35
Incidence
Incidence
21
Incidence
55
23
Incidence
Incidence
133
N?
Incidence
Incidence
32
54
221
No. of cases
Incidence
Incidence
Incidence
Monthly or bimonthly monitoring AFP and other biochemical data AFP and ultrasonography ever 3 or 6 months
Outcome
Follow-up of the patients and treatment
Table 5 Summary characteristics of the special clinical cohorts on alcohol drinking and liver cancer
At the time of liver biopsy; [65 g/day for [5 years
During the 15 years before study entry; [30 g/day
At baseline; [80 g/day for men and [60 g/day for women for at least 5 years
At the time of liver biopsy; [80 g/day for [5 years
Pre-treatment [50 g/day
At recruitment; [80 ml/day for [10 years
At the time of liver biopsy; [65 g/day for [5 years
Previous alcohol abuse, [80 g/day for men and [50 g/day for women
Age, sex, diabetes, ALT, staging (mild or severe fibrosis) and grading (mild or severe activity)
Age, sex, smoking, and history of IFN treatment
Age, sex, HCV genotype, Child class, presence of varices, diabetes, liver functions, IFN treatment, and IFNRBV treatment
Age, sex, ALT, IFN treatment, stage, and grading
Age and fibrosis staging
Sex, ALT, LDH, HCVRNA, and anti-HBc
Age, sex, ALT, IFN treatment, stage, irregular regeneration
Age, sex, duration, AFP, Child’s stage, HBV, and HCV
Age, sex, chronic hepatitis or liver cirrhosis, serum AFP levels, hepatitis virus markers, and smoking habit
Age, HCV, AFP, ICG R15
[500 kg of total alcohol intake before cirrhosis Non/ occasional/former/ current
Covariables in the statistical model
Definition of ever drinking
Cancer Causes Control
Region
Europe
Europe
Asia
Europe
Asia
Europe
Asia
References
Stroffolini et al. [185]
Cavazza et al. [186]
Ikeda et al. [187]
Romeo et al. [188]
Ohki et al. [189]
Di Martino et al. [190]
Takahashi et al. [191]
Table 5 continued
Japan
France
Japan
Italy
Japan
Italy and Spain
Italy
Country
2002–2007
1994–2001
1994–2004
1978–2006
1976–1998
1981–1999
1992–1997
Period
Both
Both
Both
Both
Both
Both
Both
Sex
[15
34–80
883
\70
203
1,159
1,262
299
82
716
Cohort size
Age
4
10
7
19
6
9
8
Years of followup
HCV infection
HCV infection
HCV infection
HDV infection
Non-B and non-C cirrhosis
Primary biliary cirrhosis
Cirrhosis
Population
All patients were treated with IFN. The follow-up started at the end of IFN regimen. Ultrasonography and/or CT were performed every 6 months. AFP was measured at baseline
Patients were obtained from the hepatitis C registry and the clinical data was obtained from the patients’ physicians; anti-viral therapy was filled by the patients; physicians and follow-up data was collected from the medical files. HCC was either histologically proven or defined by hypervascular nodules on CT scan or MRI or high AFP level according to Barcelona criteria
Biochemical tests including tumor markers (incl. AFP?) and ultrasonography at every 3–6 months; 251 received IFN treatment
39
13
Incidence
339
46
Incidence
Incidence
Incidence
16
Incidence
Monthly or bimonthly monitoring the AFP and other biochemical data; none received IFN therapy but some received oral or intravenous administration of medical herbs Ultrasonography and AFP every 6 months
24
129
No. of cases
Incidence
Incidence
Outcome
Clinical and analytical procedures every 4–6 months and ultrasonography every 6 months. AFP was measured at the HCC diagnosis
All patients received IFN treatment and were required to run surveillance program for HCC during and after stopping IFN treatment. The AFP assay and ultrasound scan were repeated at 6-month intervals
Follow-up of the patients and treatment
Age, sex, HBV, and diabetes
Sex, mode of transmission, treatment, and HBV
[500 kg of total alcohol intake until the diagnosis of liver cirrhosis [40 g/day for more than 5 years
Sex, route of infection, treatment, and motive for HCV screening
Age, sex, IFN theatment, fibrosis, AFP, steatosis, and hyperglycemia
Current status at diagnosis; [50 g/day
[50 g/day
Age, sex, diabetes, BMI, albumin, bilirubin, ALT, prothrombin time activity, and platelet counts
Age, sex, smoking, HBV, HCV, and staging
[40 g/day
At first visit; [80 g/day
Age, sex, platelets, AFP, HBV, and HCV
Covariables in the statistical model
[60 g/day for men and [40 g/day for women for at least 10 years
Definition of ever drinking
Cancer Causes Control
123
Cancer Causes Control
Fig. 5 Relative risk function and the corresponding 95 % confidence interval of alcohol consumption (g/day) and liver cancer in men. The model was based on 23 studies, and the random effect mRRs of liver cancer were 1.21 (95 % CI 1.10–1.32) for 25, 1.48 (95 % CI
Fig. 6 Relative risk function and the corresponding 95 % confidence interval of alcohol consumption (g/day) and liver cancer in women. The model was based on 11 studies, and the random effect mRRs of liver cancer were 1.27 (95 % CI 1.05–1.53) for 25, 2.08 (95 % CI 1.22–3.55) for 50, 4.68 (95 % CI 1.51–14.5) for 75, and 14.4 (95 % CI 2.01–103.4) for 100 g/day alcohol consumption, respectively
Fig. 7 Relative risk function and the corresponding 95 % confidence interval of alcohol consumption (g/day) and liver cancer in subjects without hepatitis infection. The model was based on seven studies, and the random effect mRRs of liver cancer were 1.12 (95 % CI 0.82–1.52) for 25, 1.74 (95 % CI 1.25–2.41) for 50, 3.68 (95 % CI 2.15–6.29) for 75, and 10.6 (95 % CI 3.66–30.7) for 100 g/day alcohol consumption, respectively
123
1.25–1.74) for 50, 1.83 (95 % CI 1.45–2.30) for 75, 2.29 (95 % CI 1.68–3.11) for 100, and 2.89 (95 % CI 1.93–4.33) for 125 g/day alcohol consumption, respectively
7
38
1 31
26
5
[10 years Case–control
Hospital-based
Population-based
6
5
Europe
North America
15
18
2001–
20
18
Yes
1.44
1.44
1.72
8
1.48
1.39
1.44
1.30
1.51
1.28
1.88
1.61
1.35
1.20
1.38
No
Adjust for smoking
Yes
No
1.51 1.52
30
17
Adjusted for HCVa
21
Yes
5
No
Adjusted for HBVa
Women
11
18
1991–2000
Sex Men
2
1966–1990
Year of publication
23
B200 cases
[200 cases
Case number
27
Asia
Region
1.52
5
1.42
1.50
1
5–10 years
1.21
1.28
1.44
RR
B5 years
Average/median follow-up
Cohort
Study design
Overall
No. of studies
Ever drinker
(1.21–1.67)
(1.18–1.70)
(1.27–2.16)
(1.19–1.56)
(1.18–1.78)
(1.20–1.58)
(0.99–1.89)
(1.08–1.52)
(1.27–1.75)
(1.04–1.52)
(0.92–2.84)
(1.29–1.93)
(1.14–1.55)
(0.86–1.54)
(0.91–2.12)
(1.29–1.73)
(0.98–1.87)
(1.29–1.75)
(1.30–1.71)
(0.88–1.53)
(1.00–1.56)
(1.27–1.62)
95 % CI
20.8
49.6
39.5
38.5
56.5
8.5
50.4
0.0
31.5
29.7
52.6
55.4
21.9
18.0
66.5
41.5
0.0
56.1
50.2
0.0
0.0
44.9
I (%)
2
0.892
0.923
0.001
0.197
0.005
0.104
0.015
0.002
0.345
0.880
0.631
0.094
0.109
0.121
0.004
0.131
0.293
0.011
0.012
0.597
\0.001
\0.001
p
2
4
1
5
2
4
1
4
3
3
2
4
2
4
3
2
1
3
6
No. of studies
Current drinker
3.45
0.72
0.94
2.23
0.69
2.25
0.75
1.18
3.34
0.70
0.74
1.24
1.55
1.00
0.73
0.97
RR
Table 6 Stratified mRR and 95 % CI of alcohol drinking and liver cancer risk, incidence studies only
(1.77–5.12)
(0.41–1.03)
(0.36–1.53)
(0.30–4.17)
(0.36–1.01)
(0.57–3.93)
(0.31–1.19)
(0.24–2.12)
(1.79–4.88)
(0.43–0.97)
(0.26–1.21)
(0.33–2.15)
(0.38–2.73)
(0.56–1.44)
(0.19–1.28)
(0.46–1.48)
95 % CI
0.0
24.2
70.6
71.4
27.7
66.9
2.3
83.9
0.0
7.4
7.2
77.4
73.1
0.0
50.6
61.3
I (%)
2
0.692
0.260
0.009
0.030
0.246
0.029
0.381
0.002
0.603
0.365
0.340
0.004
0.011
0.408
0.132
0.017
p
1
4
1
4
1
4
1
3
3
2
1
4
2
3
2
2
1
3
5
No. of studies
Former drinker
2.29
2.04
2.04
2.76
4.28
1.33
2.12
4.16
1.44
4.16
2.39
1.44
2.38
RR
(0.52–4.05)
(0.16–3.93)
(0.16–3.93)
(0.68–4.85)
(1.74–6.82)
(0.00–3.02)
(0.45–3.80)
(1.55–6.76)
(0.00–3.12)
(1.55–6.76)
(1.04–3.74)
(0.00–3.12)
(0.64–4.12)
95 % CI
72.0
73.7
73.7
5.0
0.0
83.1
68.7
0.0
71.3
0.0
0.0
71.3
67.4
I2 (%)
0.011
0.010
0.010
0.349
0.596
0.015
0.012
0.424
0.031
0.424
0.458
0.031
0.009
p
Cancer Causes Control
123
Include studies on HBV or HCV carriers a
Adjust for HCV and smoking in western countries; HBV and smoking in Taiwan and China; HBV, HCV, and smoking in Mediterranean countries; and smoking, HBV, and/or HCV in Japan
\0.001
0.797 0.0
56.5 (1.26–1.74)
(1.13–1.58)
26 Yes
1.35 12 No
16.9 (1.20–1.82) 1.51 10 Yes
Ever defined by dose, frequency, and/or duration
1.50
0.288
0.005 43.9 28 Full adjustmentb
No
1.41
(1.21–1.61)
p I2 (%) 95 % CI RR No. of studies
Ever drinker Table 6 continued
123
b
No. of studies No. of studies
Current drinker
RR
95 % CI
I2 (%)
p
Former drinker
RR
95 % CI
I2 (%)
p
Cancer Causes Control
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