Alcohol Drinking and Liver Cancer Risk: An Evaluation Based on a Systematic Review of Epidemiologic Evidence among the Japanese Population

Background: Although alcohol consumption has been recognized as a risk factor for primary liver cancer, it will be informative to summarize relevant epidemiologic data in the Japanese who have characteristic environmental determinants (e.g. hepatitis C virus infection) and genetic traits (e.g. presence of poor acetaldehyde metabolizers). Methods: We systematically reviewed epidemiologic studies on alcohol drinking and liver cancer among Japanese populations. Original data were obtained through searches of the MEDLINE (PubMed) and Ichushi databases, 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 assessed by the International Agency for Research on Cancer. Results: Among 22 cohort studies identiﬁed, 14 (64%) reported weak to strong positive associations between alcohol and liver cancer risk, 3 (14%) reported no association and ﬁve (23%) reported weak to moderate inverse associations; such inverse associations were found mostly in follow-up studies of patients with chronic liver disease (particularly, cirrhotic patients), yet recent studies on patients with chronic hepatitis C presented fairly consistent positive associations. Of 24 case–control studies identiﬁed, 19 (79%) showed weak to strong positive associations, whereas the remainder demonstrated no association ( n ¼ 4) or a moderate inverse association ( n ¼ 1). Conclusion: We conclude that there is ‘convincing’ evidence that alcohol drinking increases the risk of primary liver cancer among the Japanese population.


INTRODUCTION
Alcohol has long been viewed as a hepatotoxic agent, and its heavy consumption is known to cause hepatocellular injury that can lead to enhanced fibrosis and eventually to liver cirrhosis through various mechanisms presumed (1). Alcohol drinking has also been implicated in the etiology of primary liver cancer that often develops from cirrhosis (2). In the most recent evaluation by the International Agency for Research on Cancer (IARC), the occurrence of liver cancer has been 'causally' related to the consumption of alcoholic beverages (3). In the second report published by the World Cancer Research Fund and the American Institute for Cancer Research, the Panel has judged that alcohol consumption is 'probably' a direct cause of liver cancer (4).
Primary liver cancer is one of the most common cancers in Japan (5). More than 90% of primary liver cancers in this country are hepatocellular carcinomas (HCCs) that are mostly attributable to chronic infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) (6,7); HCV and HBV infections are estimated to account for 70 and 15%, respectively, of the recent occurrences of HCC in Japan (6). This tendency clearly contrasts with the situation in southeast Asia and sub-Saharan Africa where HBV represents a dominant risk factor of HCC, and with that in Western countries where HCV infection plays an increasingly important role (2,8). The role of alcohol in hepatocarcinogenesis might differ between Japan and such areas. Moreover, 50% of the Japanese are poor metabolizers of acetaldehyde (9), the first metabolite of ethanol, which has been recognized as being possibly carcinogenic to humans (10). Such poor metabolizers have not been found in Africans or Caucasians (9), and thus the Japanese as Mongoloids might be more susceptible to alcohol than other ethnic groups.
The aim of the present study was to review and summarize epidemiologic findings on alcohol drinking and liver cancer among Japanese populations. This work was conducted as part of a project of systematic evaluation of the epidemiologic evidence regarding lifestyles and cancers in Japan (11).

PATIENTS AND METHOD
The details of the evaluation method have been described elsewhere (11). In brief, original data for this review were identified through searches of the MEDLINE (PubMed) and Ichushi (Japana Centra Revuo Medicina) databases, complemented by manual searches of references from relevant articles where necessary. All epidemiologic studies on the association between alcohol drinking and liver cancer incidence/mortality among the Japanese from 1950 (or 1983 for the Ichushi database) to June 2008, including papers in press if available, were identified using the following as keywords: alcohol, liver, hepatocellular, cohort, follow-up, casecontrol, Japan and Japanese. 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 as cohort or case -control studies.
The evaluation was made based on the magnitudes of association and the strength of evidence. First, the former was assessed by classifying the 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 2) when 0.67 RR 1.5 (NS); the RR used in this paper denotes ratio measures of effect, including risk ratios, rate ratios, hazard ratios and odds ratios. 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 data sets, only data from the largest or most updated results were included. Studies that reported RRs for indefinite exposure levels, or did not provide RRs or data necessary for the present authors to calculate relevant RRs, were excluded.
After this process, the strength of evidence was evaluated in a manner similar to that used in the WHO/FAO Expert Consultation Report (12), 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 IARC (3). Despite the use of this quantitative assessment rule, an arbitrary assessment cannot be avoided when considerable variation exists in the magnitudes of association among 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.
Overall, about 60% of the cohort studies identified reported weak to strong positive associations between alcohol drinking and liver cancer risk, although all such studies are done on mostly healthy subjects lacking information on hepatitis virus infection. Since there is no reason to consider that individuals with chronic HCV or HBV infection tend to consume more alcohol than those without, potential confounding by such viral infection is unlikely to explain the positive associations found. Cohort studies of mostly healthy subjects demonstrated fairly consistent positive associations, yet several follow-up studies on CLD patients (particularly, cirrhotic patients) reported no association (18,20) or even inverse associations (15,17,22,33), which may be due to the following reasons.
First, among CLD patients, the severity of liver disease may confound the association with alcohol consumption. If patients with more severe liver disease tend to drink less alcohol at baseline for any reason (e.g. impaired liver

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Alcohol drinking and liver cancer risk        However, it appears difficult to differentiate these possibilities by observational studies.
In some cohort studies based on mostly healthy subjects, former drinkers experienced a higher risk of liver cancer than never drinkers (19,31,32); in all such studies, information on hepatitis virus infection and the presence or absence of CLD was missing. In this regard, a plausible explanation is that former drinkers may have included highrisk individuals such as hepatitis virus carriers and CLD patients who had abstained from alcohol because of illness.
In the case -control studies identified, alcohol consumption was almost consistently associated with increased liver cancer risk. This was the case regardless of the type of controls (mostly healthy subjects vs. CLD patients or hepatitis virus carriers), and only one study on patients with chronic hepatitis C reported an inverse association (57), which somewhat differs from the situation in the cohort studies. A possible change in recent drinking habits among CLD patients can be taken into account in case -control studies, but not usually in cohort studies, and this matter might partly account for the above difference, although the exact reason remains unknown.
Since about 90% of patients with HCC in Japan are known to be chronically infected with HCV or HBV (6), the postulation that heavy alcohol consumption causes alcoholic cirrhosis and thereby leads to the development of HCC does not appear to play a major role. Instead, the potential modifying effect of alcohol on HCC risk among HCV-or HBV-infected individuals is likely to be more important. In this connection, most follow-up studies of patients with chronic hepatitis C over the past decade showed fairly consistent positive associations between alcohol drinking and HCC risk (21,24,27,28,30,34), with few exceptions (33). It remains unclear to what extent alcohol consumption increases the HCC risk among the Japanese general population who are not infected with HCV or HBV because no study exists on this issue.
Potential mechanisms linking the use of alcohol with the development of liver cancer are discussed elsewhere (3). As for the role of alcohol among those with HCV infection, which is the most important risk factor of HCC in Japan, several mechanisms including increased viral replication, enhanced HCV quasispecies complexity, increased liver-cell death, suppression of immune responses, iron overload and increased oxidative stress have been suggested (59,60).
The Japanese may be more susceptible than other ethnic groups, to potential carcinogenic effects of alcohol because about half of them represent heterozygous or homozygous carriers of the inactive aldehyde dehydrogenase (ALDH) 2 allele (ALDH2*2) (9), who have an excessive accumulation of acetaldehyde after alcohol intake; acetaldehyde has been classified as being possibly carcinogenic to humans (10). Epidemiologic data on the role of the ALDH2 genotype in hepatocarcinogenesis has been conflicting (49,51,52,55,56,61). Overall, no material differences have been observed in the ALDH2 genotype distribution between liver cancer patients and control subjects, although two studies of relatively small size reported a significantly increased risk among heterozygous or homozygous carriers of ALDH2*2 (55,61). Two studies suggested a significantly elevated risk of HCC for ALDH2*2 carriers vs. non-carriers among drinkers, but not among non-drinkers (55,56).
The IARC has concluded that there is sufficient evidence for the carcinogenicity of ethanol in experimental animals (3). Taken together, this systematic review confirms a biologically plausible positive association between alcohol drinking and liver cancer risk among the Japanese, and a meta-analysis should be conducted to obtain summary estimates for the overall magnitude of association. However, the studies included in this review employed very different categories of alcohol consumption ( particularly in reference categories), which has made a meaningful meta-analysis unfeasible. A meta-analysis of several largecohort studies using common alcohol consumption categories is now underway, and we hope it will address the above issue.

EVALUATION OF EVIDENCE ON ALCOHOL DRINKING AND LIVER CANCER RISK AMONG JAPANESE
From these results and based on assumed biological plausibility as previously evaluated by the IARC (3), we conclude that there is 'convincing' evidence that alcohol drinking increases the risk of primary liver cancer among the Japanese population. High-risk individuals such as patients with CLD and hepatitis virus carriers are strongly recommended to abstain from alcohol use.

Funding
This work was supported by a Grant-in-Aid for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor and Welfare, Japan.