Abstract
Background:
Population-based prospective studies on the associations of cigarette smoking, alcohol drinking, and primary liver cancer remain limited in mainland China. Our study was designed to evaluate such relationships in middle-aged Chinese men.
Methods:
Self-reported habits of smoking and alcohol drinking were obtained from all cohort members at the baseline survey. The outcomes were identified through in-person follow-up and annual record linkage to multiple statistics of vital and cancer registration. Age-adjusted and multivariable-adjusted hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were estimated utilizing the Cox regression model.
Results:
After a median follow-up time of 12.31 years, 329 incident cases of primary liver cancer occurred among 45,266 male participants. Compared with never smoker, former smoking was positively associated with liver cancer risk, with a multivariable-adjusted HR of 1.42 (95% CI, 1.02-1.98). Individuals who have smoked for more than 40 years have a 49% increased risk of liver cancer (HR>40 years = 1.49, 95% CI, 1.04-2.14). The association of alcohol drinking with liver cancer showed no statistical significance.
Conclusion:
Our study provided evidence that cigarette smoking was positively associated with an increased liver cancer risk among Chinese men. Attention to such non-viral modifiable risk factors to prevent liver cancer effectively is needed.
Keywords: alcohol drinking, cigarette smoking, men, primary liver cancer, prospective study
Graphical Abstract
Using data from a population-based prospective cohort, we evaluated the associations between cigarette smoking, alcohol drinking and the risk of male liver cancer in Shanghai, China. Comprehensive adjustment for potential confounders was fully considered in this large-scale cohort study. We found that ever smokers and former smokers had 30% and 42% increased risks of primary liver cancer compared with never smokers.
Introduction
Primary liver cancer is the sixth most common malignant tumor and the third leading cause of cancer deaths worldwide, according to the cancer statistics published by the International Agency for Research on Cancer (IARC) [1]. Liver cancer is particularly prevalent in Asia and Africa [2]. In Shanghai, China, the age-standardized incidence and mortality rates of liver cancer in 2017 were 10.42 per 100,000 person-years and 8.73 per 100,000 person-years, respectively ranking sixth and fourth [3].
In the etiology of liver cancer [4], cigarette and alcohol drinking are linked to a key role in the development and prognosis of liver cancer although viral infection, and aflatoxin exposures are well-established risk factors. The role of cigarette smoking and alcohol drinking, as well as their combined effects on hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC), two main histological types of liver cancer, have been extensively studied in Europe, the USA, Japan, and South Korea [2, 5-8], although these studies showed some inconsistencies. A recent pooling project of 14 cohorts in the USA [6] suggested that a long duration of smoking can significantly increase the risk of HCC and ICC, and heavy alcohol drinking had a significant association with HCC. A nested case-control study [8] conducted in Europe showed similar associations between smoking/alcohol drinking and liver cancer. In contrast, studies [5, 9] in Japan did not observe similar associations between smoking or alcohol drinking and HCC risk.
In China, several hospital-based and community-based case-control studies have been conducted to estimate the independent and joint effects of smoking and alcohol drinking on liver cancer risk. A large case-control study in Jiangsu province [10] suggested that these two habits were positively associated with liver cancer risk, whereas a nested case-control study in the Taiwan, China [11] showed null significant results on both habits. However, so far, limited population-based prospective cohort studies, an optimal study design for proving causal associations [12], have been carried out in China to investigate the concrete associations of cigarette smoking and alcohol drinking with the risk of liver cancer.
Therefore, using data from the Shanghai Men's Health Study (SMHS), a population-based prospective cohort study, we aimed to examine the effects of cigarette smoking and alcohol drinking on the risk of liver cancer incidence among Chinese men.
Material and Methods
Study population
The subjects of our study were drawn from the SMHS which ran from 2002 to 2006 and details were fully described previously [13]. Briefly, 83,033 participants aged 40-74 years old were eligible for inclusion, of which 61,478 completed the baseline surveys, with an overall response rate of 74.0%. The baseline information, including sociodemographic characteristics, medical history, personal habits and lifestyles, dietary habits, physical activity, family history of cancer, and occupational history, was obtained by trained interviewers using structured questionnaires. Moreover, anthropometric measurements, such as weight, height, and circumferences of the waist and hip, were measured by trained surveyors following a standard protocol. Exclusion criteria for cohort members included subjects who lack blood samples to determine hepatitis B virus (HBV) infection status, with unconfirmed cancer diagnosis date/site of all types, diagnosis with cancer in situ during follow-up, lost to follow-up, beyond the age range (<40 years or >75 years), with extreme total energy intake (≤ 800 kcal/day or ≥ 4000 kcal/day) [14], and with missing covariate values. After exclusions, a total of 45,266 men were retained in our final analysis (Figure 1). Informed consent was acquired from each participant at baseline. This study was approved by the Renji Hospital Ethics Committee of Shanghai Jiao Tong University School of Medicine (KY2019-197).
Figure 1.
The process of inclusion and exclusion of study subjects
Exposure assessment
Each participant was asked whether they had ever smoked at least one cigarette per day for more than 6 months continuously [13], Participants who answered “no” were defined as “never smokers”. Those who answered “yes” (ever smokers) were further asked about the age they started smoking, the smoking intensity (cigarettes/day), and the present smoking status (former/current). In the same way, for alcohol consumption, subjects who drank at least 3 times per week for more than 6 months continuously were defined as “ever alcohol drinkers” and were required to report their age of starting drinking and their present drinking status (former/current) [13]. Ever drinkers were asked about the frequency (times per week), type, and amount of alcoholic drinks they consumed per week during the past year. We also collected a 10-ml blood sample from each of 45,770 participants (about 75% of the cohort members) willing to donate samples at study enrollment, and the collected samples were kept in the refrigerators at −70 °C. HBV infection status was determined by quantifying the hepatitis B surface antigen (HBsAg) levels with Architect HBsAg QT (Abbott Diagnostics, Abbott Park, IL, USA) according to the manufacturer’s instructions [15, 16].
Specifically, the duration of exposure was defined as years of cigarette smoking and alcohol drinking from initiation of exposure to baseline survey. The cumulative exposure to cigarettes was calculated as pack-years (packs/day × years of smoking; 1 pack = 20 cigarettes). As for alcohol drinking intensity, the amount of pure ethanol was obtained according to the consumption of each type of alcoholic drinks in the questionnaire, and then converted into “drink/day” (1 drink = 14.18 g pure ethanol). The cumulative exposure to alcohol was indicated by the total amount of pure ethanol consumed (equal to the intensity multiplied by the duration, in kilograms).
Follow-up and identification of outcome
In-person follow-up surveys [17] were conducted every 3-4 years and the record linkage to the Shanghai Cancer Registry and the Shanghai Vital Statistics Registry was maintained annually to update the residential information and to track outcome information and vital statistics. To date, three rounds of follow-up were completed in 2004-2008, 2008-2011, and 2012-2017, with response rates of 97.6%, 93.7%, and 93.6%, respectively. The verification of all possible cancer diagnoses was conducted by home visits or reviews of medical records from hospitals. Cancers were coded according to the International Classification of Disease, Ninth Revision (ICD-9). Primary liver cancer, a malignant neoplasm originating in the liver, was coded 155 in ICD-9.
Statistical analyses
Person-years were calculated by entering the cohort to the liver cancer diagnosis, death, loss to follow-up, or December 31, 2016, whichever occurred first. Categorical variables were expressed as numbers and percentages, whereas continuous variables were expressed as median and interquartile range (IQR) after tested for normal distribution. Basic characteristics between participants with and without liver cancer were compared using the Chi-square test for categorical variables and the Mann-Whitney U-test for continuous variables. To evaluate the quantitative associations between cigarette smoking, alcohol drinking and the risk of liver cancer, Cox regression models were established to calculate age-adjusted and multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs), with follow-up time as the underlying time scale. The proportional hazard assumption was tested by examining the correlation between follow-up time and Schoenfeld residuals of covariates in the model, and no variables were found to violate this assumption.
Multivariable-adjusted Cox model included the following potential confounders which were determined based on our previous studies or pre-existing knowledge: age at study enrollment (continuous), education (three categories: elementary school or below, middle school, college or above), income (three categories: low, middle, high), body mass index (BMI, kg/m2, continuous), HBV infection (HBsAg positive or negative), history of cholelithiasis (yes or no), history of type 2 diabetes mellitus (T2DM, yes or no), family history of liver cancer (yes or no), total energy intake (kcal/day, continuous) and total physical activity (MET-hours/week, continuous). Ever alcohol drinking (yes or no) was adjusted when the effect of smoking was analyzed; likewise ever cigarette smoking (yes or no) was adjusted when analyzing the effect of alcohol drinking. A linear trend test was performed by recoding the categorical variables as rank variables (0,1,2,3).
All P-values were two-sided and P<0.05 was considered statistically significant. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, NC, USA).
Results
Of 45,266 participants included in the current analysis, 329 incident cases of primary liver cancer occurred after a median follow-up time of 12.31 years (interquartile range, IQR = 2.17 years). The cumulative incidence and incidence density rates of liver cancer in our cohort were 0.73% and 60.39 per 100,000 person-years.
Table 1 shows the baseline information relevant to this study and specific habits of smoking and alcohol drinking by the presence or absence of liver cancer. The comparison between exposure and non-exposure to smoking and drinking was shown in Table S1. Compared to participants without liver cancer, those who developed liver cancer were more likely to be older and to have a higher HBsAg positive rate, a history of T2DM, a history of cholelithiasis, and a family history of liver cancer. Significant differences were also observed between the two groups of participants in terms of education and income, as more patients with liver cancer had an education level of middle school or below and a lower income than those without liver cancer. Additionally, subjects diagnosed with liver cancer tended to smoke longer, drink longer, and have higher cumulative alcohol drinking consequently. Differences in other information failed to attain statistical significance.
Table 1.
Baseline characteristics and cigarette smoking and alcohol drinking habits by liver cancer status
| Characteristics | All subjects (N=45266) |
Without liver cancer (N=44937) |
With liver cancer (N=329) |
P value‡ |
|---|---|---|---|---|
| Age at study enrollment, years (median [IQR]) | 53.47 (16.58) | 53.44 (16.55) | 57.87 (17.72) | |
| BMI, kg/m2 (median [IQR]) | 23.70 (4.01) | 23.70 (4.00) | 23.70 (4.88) | 0.8067 |
| Total physical activity, MET-h/week (median [IQR]) | 55.31 (45.04) | 55.30 (45.03) | 58.22 (46.31) | 0.1686 |
| Total energy intake, kcal/day (median [IQR]) | 1874.05 (622.51) | 1874.13 (622.40) | 1854.68 (614.98) | 0.7089 |
| Education (n, %) | ||||
| Elementary school or below | 3626 (8.01) | 3585 (7.98) | 41 (12.46) | |
| Middle school | 31758 (70.16) | 31516 (70.13) | 242 (73.56) | |
| College or above | 9882 (21.83) | 9836 (21.89) | 46 (13.98) | |
| Income (n, %)§ | ||||
| Low | 25770 (56.93) | 25551 (56.86) | 219 (66.57) | |
| Middle | 15447 (34.12) | 15361 (34.18) | 86 (26.14) | |
| High | 4049 (8.94) | 4025 (8.96) | 24 (7.29) | |
| Cigarette smoking (n, %) | 0.5705* | |||
| Never smoker | 13719 (30.31) | 13624 (30.32) | 95 (28.88) | |
| Ever smoker | 31547 (69.69) | 31313 (69.68) | 234 (71.12) | |
| Former smoker | 5029 (11.11) | 4972 (11.06) | 57 (17.33) | |
| Current smoker | 26518 (58.58) | 26341 (58.62) | 177 (53.80) | |
| Starting age of cigarette smoking, years (median [IQR]) | 20 (6) | 20 (6) | 20 (8) | 0.2644 |
| Duration of smoking, years (median [IQR]) | 28.87 (10.68) | 28.85 (10.66) | 30.66 (13.01) | |
| Cigarette smoking intensity, cigarette/day (median [IQR]) | 20 (10) | 20 (10) | 15 (10) | 0.1450 |
| Cumulative exposure to cigarettes, pack-year (median [IQR]) | 22.25 (18.99) | 22.26 (18.98) | 22.18 (21.43) | 0.7783 |
| Alcohol drinking (n, %) | 0.4773** | |||
| Never drinker | 29976 (66.22) | 29752 (66.21) | 224 (68.09) | |
| Ever drinker | 15290 (33.78) | 15185 (33.79) | 105 (31.91) | |
| Former drinker | 1821 (4.02) | 1803 (4.01) | 18 (5.47) | |
| Current drinker | 13469 (29.76) | 13382 (29.78) | 87 (26.44) | |
| Age when starting alcohol drinking, years (median [IQR]) | 26 (15) | 26 (15) | 30 (18) | 0.2975 |
| Duration of alcohol drinking, years (median [IQR]) | 24 (16.77) | 24 (16.74) | 26.23 (18.38) | 0.0156 |
| Alcohol drinking intensity, drinks/day (median [IQR]) | 1.84 (2.37) | 1.84 (2.37) | 1.91 (2.59) | 0.3026 |
| Cumulative exposure to alcohol, kg (median [IQR]) | 221.11 (309.69) | 220.83 (309.14) | 254.11 (451.95) | 0.0819 |
| HBsAg positive (n, %) | 3429 (7.58) | 3216 (7.16) | 213 (64.74) | |
| History of T2DM (n, %) | 2964 (6.55) | 2930 (6.52) | 34 (10.33) | |
| History of cholelithiasis (n, %) | 3436 (7.59) | 3388 (7.54) | 48 (14.59) | |
| Family history of liver cancer (n, %) | 1665 (3.68) | 1633 (3.63) | 32 (9.73) |
Continuous variables were compared using Mann-Whitney U-test and categorical variables were compared using Chi-square tests.
Defined as low: <¥1,000 per person per month; middle: ¥1,000–2,999 per person per month; high: ≥¥3,000 per person per month.
Never smoker vs ever smoker.
Never drinker vs ever drinker.
Table 2 presents the results of the age-adjusted and multivariable-adjusted Cox regression models on smoking habits and the risk of liver cancer. Ever and former smokers were associated with a 30% and 42% increased risk of liver cancer, with multivariable-adjusted HR of 1.30 (95% CI, 1.00-1.67), and 1.42 (95% CI, 1.02-1.98), respectively. In comparison with never smokers, smokers whose starting age of smoking was under 20 years old, smoked for 40 years or longer, and whose cumulative exposure to cigarette were more than 40 pack-years have significantly increased risks of liver cancer, with age-adjusted HRs of 1.45 (95% CI, 1.03-2.02), 1.58 (95% CI, 1.11-2.24), and 1.47 (95% CI, 1.02-2.11), respectively. Moreover, significant linear trends in risks were seen for the lengthening duration of smoking exposure (Ptrend = 0.010; Figure S1) and starting smoking at a younger age (P trend = 0.020). However, these previously mentioned significant associations disappeared after multivariable adjustments, except for those who smoked for 40 years or longer, with multivariable-adjusted HR of 1.49 (95% CI, 1.04-2.14).
Table 2.
The associations between cigarette smoking and the risk of male liver cancer
| Cigarette smoking | Cases | Incidence density† | HR‡ | HR§ |
|---|---|---|---|---|
| Never smokers (Ref.) | 95 | 57.21 | 1.00 | 1.00 |
| Ever smokers | 234 | 61.79 | 1.37 (1.07, 1.75) | 1.30 (1.00, 1.67) |
| Former smokers | 57 | 98.31 | 1.58 (1.14, 2.20) | 1.42 (1.02, 1.98) |
| Current smokers | 177 | 55.19 | 1.29 (0.99, 1.67) | 1.24 (0.94, 1.63) |
| Starting age of cigarette smoking (years old) | ||||
| <20.0 | 60 | 58.65 | 1.45 (1.03, 2.02) | 1.27 (0.90, 1.80) |
| 20.0-24.9 | 93 | 58.30 | 1.40 (1.04, 1.89) | 1.36 (0.99, 1.85) |
| 25.0-29.9 | 31 | 57.92 | 1.19 (0.79, 1.79) | 1.12 (0.74, 1.69) |
| ≥30.0 | 50 | 78.93 | 1.37 (0.97, 1.93) | 1.35 (0.95, 1.90) |
| P trend | 0.020 | 0.115 | ||
| Duration of smoking (year) | ||||
| <20.0 | 25 | 49.84 | 1.19 (0.76, 1.88) | 1.17 (0.75, 1.84) |
| 20.0-29.9 | 85 | 50.59 | 1.37 (0.98, 1.92) | 1.33 (0.95, 1.87) |
| 30.0-39.9 | 72 | 61.20 | 1.24 (0.91, 1.70) | 1.16 (0.85, 1.60) |
| ≥40.0 | 52 | 121.35 | 1.58 (1.11, 2.24) | 1.49 (1.04, 2.14) |
| P trend | 0.010 | 0.044 | ||
| Cigarette smoking intensity (cigarette/day) | ||||
| <10.0 | 44 | 73.45 | 1.49 (1.04, 2.13) | 1.43 (0.99, 2.05) |
| 10.0-19.9 | 79 | 60.90 | 1.37 (1.01, 1.86) | 1.28 (0.94, 1.75) |
| 20.0-29.9 | 91 | 60.10 | 1.36 (1.01, 1.82) | 1.28 (0.94, 1.73) |
| ≥30.0 | 20 | 53.13 | 1.16 (0.72, 1.89) | 1.13 (0.69, 1.86) |
| P trend | 0.103 | 0.239 | ||
| Cumulative exposure to cigarettes (pack-year) | ||||
| <10.0 | 41 | 65.77 | 1.48 (1.02, 2.15) | 1.44 (0.99, 2.10) |
| 10.0-19.9 | 66 | 62.01 | 1.45 (1.05, 2.01) | 1.35 (0.97, 1.88) |
| 20.0-39.9 | 85 | 52.76 | 1.21 (0.89, 1.64) | 1.14 (0.83, 1.55) |
| ≥40.0 | 42 | 86.04 | 1.47 (1.02, 2.11) | 1.40 (0.96, 2.03) |
| P trend | 0.070 | 0.191 |
Note: Bold characters represent statistical significance.
per 100,000 person-years.
adjusted for age at study enrollment.
adjusted for age, education, income, BMI, ever alcohol drinking, HBsAg, history of T2DM, history of cholelithiasis, family history of liver cancer, total energy intake, and total physical activity.
The association between alcohol drinking and primary liver cancer is shown in Table 3. Among ever drinkers, a positive association with incidence of liver cancer was observed for those whose lifetime cumulative exposure to alcohol was more than 600 kg, after adjustment for age (HR = 1.62, 95% CI, 1.08-2.43), but such an association disappeared after multivariable adjustments. No significant associations emerged between starting age, duration, intensity of drinking and liver cancer.
Table 3.
The associations between alcohol drinking and the risk of male liver cancer
| Alcohol drinking | Cases | Incidence density† | HR‡ | HR§ |
|---|---|---|---|---|
| Never drinkers (Ref.) | 224 | 61.89 | 1.00 | 1.00 |
| Ever drinkers | 105 | 57.43 | 0.98 (0.77, 1.23) | 0.89 (0.70, 1.12) |
| Former drinkers | 18 | 87.63 | 1.32 (0.82, 2.14) | 0.95 (0.58, 1.55) |
| Current drinkers | 87 | 53.61 | 0.93 (0.72, 1.19) | 0.87 (0.68, 1.13) |
| Starting age of alcohol drinking (years old) | ||||
| <20.0 | 13 | 58.51 | 1.09 (0.62, 1.91) | 0.86 (0.49, 1.52) |
| 20.0-24.9 | 24 | 49.47 | 0.91 (0.60, 1.39) | 0.82 (0.54, 1.26) |
| 25.0-29.9 | 12 | 41.13 | 0.73 (0.41, 1.30) | 0.63 (0.35, 1.13) |
| ≥30.0 | 56 | 67.53 | 1.06 (0.79, 1.42) | 1.01 (0.75, 1.36) |
| P trend | 0.739 | 0.203 | ||
| Duration of drinking (year) | ||||
| <20.0 | 32 | 46.30 | 0.85 (0.59, 1.24) | 0.85 (0.59, 1.24) |
| 20.0-29.9 | 29 | 47.63 | 0.94 (0.63, 1.39) | 0.85 (0.57, 1.27) |
| 30.0-39.9 | 25 | 69.88 | 1.08 (0.72, 1.64) | 0.93 (0.61, 1.41) |
| ≥40.0 | 19 | 111.33 | 1.17 (0.72, 1.90) | 0.95 (0.58, 1.56) |
| P trend | 0.675 | 0.512 | ||
| Alcohol drinking intensity (drink/day) | ||||
| <1.0 | 20 | 55.15 | 0.85 (0.54, 1.34) | 0.89 (0.56, 1.40) |
| 1.0-1.19 | 35 | 47.64 | 0.82 (0.58, 1.17) | 0.75 (0.52, 1.07) |
| 2.0-3.9 | 33 | 68.24 | 1.20 (0.84, 1.74) | 1.04 (0.72, 1.51) |
| ≥4.0 | 17 | 68.73 | 1.23 (0.75, 2.01) | 0.99 (0.60, 1.63) |
| P trend | 0.573 | 0.610 | ||
| Cumulative exposure to alcohol (kg) | ||||
| <200.0 | 46 | 53.55 | 0.93 (0.68, 1.28) | 0.91 (0.66, 1.26) |
| 200.0-399.9 | 24 | 46.88 | 0.82 (0.54, 1.25) | 0.76 (0.50, 1.17) |
| 400.0-599.9 | 9 | 41.64 | 0.70 (0.36, 1.36) | 0.62 (0.32, 1.22) |
| ≥600.0 | 26 | 107.77 | 1.62 (1.08, 2.43) | 1.17 (0.77, 1.78) |
| P trend | 0.429 | 0.635 |
Note: Bold characters represent statistical significance.
per 100,000 person-years.
adjusted for age at study enrollment.
adjusted for age, education, income, BMI, ever cigarette smoking, HBsAg, history of T2DM, history of cholelithiasis, family history of liver cancer, total energy intake, and total physical activity.
Discussion
We conducted a large population-based prospective cohort study and evaluated the associations between cigarette smoking, alcohol drinking and the risk of primary liver cancer in Chinese men. We found that ever smokers and former smokers had 30% and 42% increased liver cancer risks compared with never smokers. A duration of smoking of 40 years or longer can increase the risk of male liver cancer by 49% when compared with never smokers.
Cigarette smoking is a well-established risk factor for primary liver cancer, but the results of epidemiological studies are not consistent in different populations. In the Europe-wide cohort study of the European Prospective Investigation into Cancer and Nutrition (EPIC) [8], male current smokers were 5.37 times more likely to develop HCC than non-smokers, but no association was observed between former smoking and liver cancer risk. There was also a study [9] demonstrating neither former nor current smokers were associated with HCC. However, in our study, we only found an association of ever smoking and former smoking with liver cancer risk, but no current smoking. There were slight differences in the risk of liver cancer between different smoking statuses in different study populations, which may be due to the difference in the proportion of former smokers and current smokers in the study population. In contrast to these two studies, the proportion of current smokers in our study population was higher than that of former smokers regardless of whether liver cancer eventually developed. These differences may also be related to the number and duration of smoking cessation in the study population. A previous study in the USA has shown an inverse association between the duration of smoking cessation and the risk of HCC [6]. Since our original questionnaire did not investigate the duration of smoking cessation, the exact association between the duration of smoking cessation and the risk of liver cancer in the Chinese population could not be determined in this study.
Our estimate for the magnitude of association between duration of smoking and liver cancer risk was lower than previous epidemiological studies [18, 19], and such duration-dependent association persisted after adjustments for potential confounders. In a prospective cohort study based on 11,837 males from seven townships in the Taiwan China [18], researchers reported a 91% increased HCC risk among individuals who smoked over 25 years, and the confounding factors this study adjusted included age at recruitment, residence, and serostatus of HBsAg and anti-HCV. The Singapore-Chinese cohort [19] reported that smoking longer than 20 years was associated with a 53% elevated risk of HCC and reported a duration-dependent association between smoking and HCC after multivariable adjustments for gender, age at recruitment, year of recruitment, dialect group, the level of education, BMI, diabetes mellitus, daily ethanol intake, and cups of coffee per day. The lower HRs obtained in our study compared with these two studies can be attributed to the inclusion of other subtypes of primary liver cancer, such as ICC, in our study follow-up outcomes. Specifically, the association of smoking habits with ICC was not statistically significant in two hospital-based case-control studies conducted in Shanghai and Beijing, China [20,21], so the presence of ICC may have some influence on the HRs in our study, although the specific proportion of ICC among the follow-up outcomes in our study was unknown. Moreover, compared with these two studies our study adjusted for more comprehensive confounders, including not only diabetes, disease history, physical activity, and energy intake, but adjustment for HBV infection status, an important factor causing the occurrence of liver cancer.
Few studies have reported an association between starting age of cigarette smoking, another variable reflecting the time-related patterns, and the risk of liver cancer. The results from a population-based cohort study in Japan [22] showed that the earlier the age at onset of smoking, the higher incidence risk of all types of cancer, which provides support to our report. As for the association of lifetime cumulative exposure to cigarettes with liver cancer, unlike the findings of the Liver Cancer Pooling Project in the USA (HR>17 pack-years = 1.90, 95% CI, 1.42-2.55) [6], a population-based cohort in Japan (relative risk [RR] high pack-years = 3.09, 95% CI, 1.31-7.29) [23], such an association showed no statistical significance in our analysis. These inconsistent observed associations could be ascribed to differences in sample size, gender, and confounding factors that researchers took into consideration.
Despite sufficient evidence to support the effect of alcohol drinking on liver cancer risk, pre-existing epidemiological investigations in the Chinese population still showed some inconsistency. Unlike our findings, a prospective cohort from China Kadoorie Biobank (CKB) of 0.5 million people [24] showed the consuming more than four drinks/day was associated with a 44% elevated liver cancer risk. There were also discordances between the current study and studies in other regions. Results from the Liver Cancer Pooling Project [6] in the USA supported the null association of drinking intensity with liver cancer risk, whereas previous case-control studies in Jiangsu, China, and Italy [10, 25] demonstrated that high-intensity alcohol drinking was associated with a nearly six-fold increased risk of liver cancer. The lack of consistency might be attributed to many elements, including different confounding factors, different study settings, different methods of calculating drinking frequency or intensity, or, most importantly, the wide variation in alcohol consumption patterns across ethnic groups or different regions [26, 27]. To be specific, differences in the type of drinks consumed, time and context of drinking influenced by cultural background, and the quantity and type of other alcoholic beverages consumed can affect the incidence of liver cancer to varying degrees [28]. Moreover, compared to other studies, SMHS participants had a relatively lower level of alcohol consumption. In terms of pure ethanol, approximately 60% of the participants in our study drank no more than 28.36 g (2 drinks) per day, with mean cumulative alcohol consumption of 329.91 kg, much lower than that of a case-control study in Italy [29] (Mean of total lifetime alcohol intake was 776 kg) and a prospective cohort study in Taiwan China [30] (More than 60% of the study participants consumed more than 46.2g of alcohol per day. Apart from the previously mentioned possible attributions, discrepancies in tea drinking habits may also influence the harmful effect of alcohol on cancer incidence, as studies have proved that tea is related to a reduced risk of liver disease [31, 32]. Nevertheless, whatever forms of measurement of alcohol consumption and different cut-offs for each group in different studies, most studies [2, 33] appear to reach an agreement on heavy alcohol drinking with an increased risk of liver cancer in men by 40%-70%, which also accords with our results. Despite many pieces of research reporting a protective effect of light-to-moderate alcohol consumption on multiple diseases, including but not limited to all-cause and cardiovascular-specific mortality as well as type 2 diabetes [34-36], investigations on cancer suggested that light-to-moderate intake of alcohol still contributes to adverse outcomes [37-39].
The chief strengths of our current study included population-based and prospective design, longer follow-up and more incident cases of liver cancer, and a very low proportion of loss to follow-up. In addition, comprehensive adjustment for potential confounders fully considered in data analysis enhanced the dependability of this study, including relevant demographic characteristics, ever cigarette smoking or ever alcohol drinking, HBsAg positive, total energy intake and total physical activity, history of T2DM, history of cholelithiasis, family history of liver cancer. More importantly, the inclusion of HBV infection status in the adjusted confounders took full account of the fact that China has one of the highest rates of hepatitis B infection in Asia, making this study more reliable. However, this study also has non-negligible limitations. First, subsequent changes in cigarette and alcohol drinking habits were ignored because the information was only gathered at baseline, and it might increase the possibility of measurement bias. Such bias might result in an underestimation or overestimation of the observed association. Some researchers treated both factors as time-dependent variables, but this treatment was unnecessary in our study because no covariate violated the proportional hazard assumption. Second, even though we had adjusted for as comprehensive potential confounders as possible in our analysis, there remained residual confounders that we did not measure or know. Finally, the study population was middle-aged men in urban China, and the number of liver cancer cases in our cohort may still be in low and not have sufficient statistical power to test the relationships, so extrapolation needs to be done with caution.
In conclusion, this large population-based, prospective cohort study found that cigarette smoking was positively associated with an increased risk of primary liver cancer, especially from premature exposure and heavy consumption of cigarettes. Long-term lifetime exposure to alcohol may have some effects on the development of liver cancer in Chinese men. Therefore, our findings suggested that these non-viral modifiable risk factors still deserve more special attention in China, to promote the prevention and control of primary liver cancer.
Supplementary Material
Supplementary Table 1 Baseline characteristics of subjects included in the final analysis according to cigarette smoking and alcohol drinking status
Supplementary Figure 1 Age-adjusted and multivariable-adjusted linear trends between duration of smoking and the risk of male liver cancer
Acknowledgments
We would like to thank the participants and the staff from the Shanghai Men’s Health Study for their contribution to this research.
Funding
National Key Project of Research and Development Program of China, Grant/Award Numbers: 2021YFC2500404, 2021YFC2500400; US National Institutes of Health, Grant/Award Number: UM1 CA173640
Abbreviations:
- IARC
International Agency for Research on Cancer
- HCC
Hepatocellular carcinoma
- ICC
Intrahepatic cholangiocarcinoma
- SMHS
Shanghai Men's Health Study
- ICD
International Classification of Disease
- HR
Hazards ratio
- CI
Confidence Interval
- BMI
Body mass index
- T2DM
Type 2 diabetes mellitus
- HBV
Hepatitis B virus
- HBsAg
Hepatitis B surface antigen
- IQR
Interquartile range
Footnotes
Conflicts of Interest
There is no conflict of interest.
Data Availability Statement
The data will be available on request pending approval by the scientific committee of the relevant institutes.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1 Baseline characteristics of subjects included in the final analysis according to cigarette smoking and alcohol drinking status
Supplementary Figure 1 Age-adjusted and multivariable-adjusted linear trends between duration of smoking and the risk of male liver cancer
Data Availability Statement
The data will be available on request pending approval by the scientific committee of the relevant institutes.