Validity and plausibility of the evidence of hazard
Our study involves many more cases than any previous study of smoking and liver cancer. For men, it shows tobacco smoking to be associated with a moderate, but highly significant, proportional increase in the risk of death from liver cancer throughout middle and old age (i.e., from about age 35 onwards). Among adult men the excess risk of death associated with smoking appeared to be greater for cigarette smokers than for smokers of other forms of tobacco and was associated positively with the number of cigarettes smoked daily, with a relative risk of 1.50 for men smoking 20 cigarettes a day. Although far fewer women than men consumed substantial numbers of cigarettes, smoking was also associated with an increased female risk of death from liver cancer, with a relative risk of 1.45 among women who smoked at least 20 cigarettes a day.
The analyses were standardised for age and area of residence, and the observed excess risk of liver cancer associated with smoking is unlikely to have been inflated by any systematic bias or confounding, since the use of cirrhosis deaths as controls not only allows for any extent to which cirrhosis itself (or any causes of cirrhosis, such as chronic HBV infection) can predispose to liver cancer in this population but also ensures that any bias in the retrospective assessment of smoking affects both cases and controls similarly. Smoking information for both cases and controls was provided by family members, and it is unlikely that the informants for the cases who had died of liver cancer would have been more likely to exaggerate the smoking habits than were the informants for the controls who had died of liver cirrhosis, for at the time of the study few people in China were much aware of the effects of smoking even on lung cancer,23 and most would have been still less aware of the possible effects on other types of cancer. Moreover, the original survey did not focus on the effects of smoking on any particular disease, so there is no good reason to expect any material bias between the dead cases and the dead controls in the accuracy of the retrospectively obtained information about smoking. The prevalence of smoking reported for the live informants was almost the same as that reported for the cirrhosis deaths (see Methods). Separate analyses that used the live informants as controls found that in this particular population there is little association between smoking and cirrhosis.19
The liver is a possible site for metastasis from other types of cancer that can be caused by smoking, but at the time of our study the smoker vs. nonsmoker risk ratio for overall cancer mortality in middle age was only about 1.5.19 Hence, even if a moderate proportion of the deaths ascribed to primary liver cancer were in fact due to misdiagnosed metastasis from other types of cancer, the risk ratios in the present case-control comparisons would not be materially distorted. Also, as primary liver cancer is common in China, it is unlikely, particularly for men in early middle age (among whom about 1/2 of all cancer deaths are attributed to primary liver cancer), that a substantial proportion of the deaths attributed to this cause were actually due to metastasis from other smoking-related cancers. Moreover, about 1/4 of the male cases involved pathologically confirmed liver cancer, and restriction of the analysis to these cases still yielded a highly significant excess risk among smokers. The present study involves uniquely large numbers of cases, so its findings are statistically stable and provide strong evidence of an independent association between smoking (particularly of cigarettes) and liver cancer.
The results of this retrospective study are largely compatible with those from other case-control14, 15, 16 and prospective studies24, 25, 26, 27 in Chinese populations, although none of these other studies was nationally representative, and none involved large numbers of cases. In 2 prospective studies in Shanghai,24, 25 each involving just under 100 liver cancer deaths, cigarette smoking was associated (independently of alcohol consumption) with about a 2-fold relative risk of liver cancer. In 2 prospective studies in Taiwan,26, 27 each involving just over 100 liver cancer deaths, smoking was also associated (independently of alcohol drinking and chronic HBV carrier status) with about a 2-fold relative risk of liver cancer.
An association between liver cancer and smoking has also been reported in non-Chinese populations7–10, 28–31 but has been difficult to interpret as most of those studies involved only small numbers of liver cancer cases, or involved populations where cirrhosis is largely due to alcohol, and is therefore also correlated with smoking. In Britain, for example (where cirrhosis mortality is about 1/3 of that in China, and liver cancer mortality is about 1/40 that in China3), a prospective study10 found both diseases to be positively associated with smoking. The relationship between smoking and cirrhosis was, however, attributed almost entirely to the confounding effects of alcohol drinking.10, 13 As cirrhosis can make liver cancer more probable, it is difficult in such populations to determine reliably whether the association between smoking and liver cancer is largely or wholly due to confounding by alcohol, or whether there is also an independent effect of tobacco.32, 33, 34
As cirrhosis and liver cancer in the present population are determined chiefly by chronic HBV infection,35, 36, 37, 38 not by alcohol, there is little reason to expect much confounding with smoking. (Chronic HBV infection in China, although usually acquired in early childhood, is largely asymptomatic in early adult life and should not materially affect the uptake of smoking.) Although no information was available in the present study on alcohol drinking or on chronic HBV infection, the use of those who had died of cirrhosis as controls should ensure that any possible confounding effects from these factors (or any other causes of liver disease) are likely to be minimal. Further evidence to support this is also provided by the elevated risk observed in women, among whom substantial alcohol drinking is rare.3
Cigarette smoke contains chemicals that are directly-acting causes of liver cancer in experimental animals (e.g., methylnitrosourea) and is also a major source of other carcinogens that, after absorption into the bloodstream, can be metabolised and thereby activated as carcinogens by oxidation in the hepatocytes,39, 40 and there is some evidence of an increased incidence of hepatocellular carcinoma in animals exposed to tobacco smoke constituents.41 It is, however, not known whether these experiments reflect the chief mechanisms by which smoking increases the incidence of liver cancer in humans.
Future changes in the relative risk
The 50% excess risk of liver cancer among men in the present study who smoked 20 cigarettes a day is somewhat smaller than the corresponding excess risks in some other studies. This disparity may be due partly to the lack of positive confounding in the present study and partly to differences in patterns of previous tobacco consumption. Both in urban and, particularly, in rural areas, most of those who, in our study, smoked only cigarettes in 1980 would have been born before 1930, and few of them were likely to have smoked cigarettes persistently from early adulthood, given the great fluctuations in Chinese social circumstances (and cigarette consumption) during the decades before 1980. It is, therefore, likely that the observed smoker vs. nonsmoker relative risk of liver cancer under-estimates the relative risk that will eventually be seen in China with prolonged cigarette smoking. Recently there has been a large increase in cigarette consumption in China, involving chiefly an increase in cigarette consumption per smoker rather than an increase in the proportion of smokers.23, 42 As cigarettes continue to replace other forms of tobacco, the relative risk of liver cancer for persistent smokers in China may well become somewhat greater than that in the present study.
Absolute risks: possible interaction with HBV infection
Although, at least at present, the relative risk is modest, the absolute risk is substantial because Chinese men are already at such high risk of the disease, particularly if they are “antigenaemic” carriers of HBV (i.e., they usually have detectable levels of the HBV surface protein in their bloodstream, indicating chronic infection). In a special study of 181 consecutive cases of liver cancer, mostly from Jiangsu province, 94% were found to be antigenaemic and of the 6% who were not, all were found to have part of the HBV genome integrated into the DNA of their cancer cells, but not of their normal liver cells, indicating that the cancer arose from a single cell that had, earlier in the life of host, had its genome mutated by HBV infection.6, 38 Thus, in parts of China, and perhaps in almost all of China, hepatitis B (or perhaps, in a few cases, hepatitis C) virus infection is a cause of virtually all cases of liver cancer. As only 10–12% of adults are chronic antigenaemic carriers of HBV, and they probably account for the large majority of all cases of liver cancer in China, the absolute risk among them must be substantial, and the chief absolute effect of smoking must be to increase it.
At the male death rates seen in the study, the probability of death from liver cancer at ages 35–69 (in the absence of other causes of death), comparing smokers vs. nonsmokers, would be 4% vs. 3% in China as a whole, and 6% vs. 4% in the high-risk counties or in the high-risk cities (such as Fuzhou). In most parts of China almost all of this mortality would be concentrated in the 10–12% of adults who are chronic antigenaemic HBV carriers, for whom the corresponding risks might be about 33% vs. 25% in China as a whole, or about 50% vs. 33% in certain high-risk counties or cities.
Based on the present study, it is estimated that smoking, chiefly by aggravating the hazards of chronic HBV (or, less commonly, HCV) infection, is a cause of almost 1/5 of the male liver cancer deaths in China. (For discussion of the meaning of causality in this context, see Reference 19.) There are about 0.25 million male liver cancer deaths each year in China, and if the observed associations were largely or wholly causal, then (assuming a mix of 30% in urban and 70% rural), the present results indicate that smoking is a cause of about 19% of these deaths, and of a small percentage of the 0.1 million female liver cancer deaths each year. This would mean that smoking is currently responsible for about 50,000 liver cancer deaths a year in China (plus, of course, more than 10 times as many deaths from various other diseases19). Eventually, as a result of the current policy of nationwide HBV vaccination of all Chinese infants (and perhaps substantial decreases in fungal contamination of stored foodstuffs), the other causes of liver cancer will decrease and the disease will become substantially less common. Until then, however, as the relative risks associated with smoking rise and the population in middle and old age grows larger, the absolute annual number of deaths from tobacco-induced liver cancer may well rise substantially, both in China and worldwide.