Primary liver cancer (PLC) is one of the most common cancers. According to the estimation of GLOBOCAN 2012 by the International Agency for Research on Cancer (IARC), approximately 83% of all liver cancer occurred in less developed regions, with China accounting for over 50% of the world's burden (1).

It has been established that chronic infection with hepatitis B virus (HBV), causing chronic hepatic inflammation that may lead to fibrosis and cirrhosis, is the leading cause of PLC (2). With the successful introduction of hepatitis B vaccine into the national immunization program in China, the prevalence of hepatitis B surface antigen (HBsAg) among children under 5 years of age has dramatically declined from 9.67% in 1992 to 0.96% in 2006 (3). Hence, HBV, the dominant risk factor of PLC, is unlikely to be the main risk factor of PLC in the future. Thus, it is necessary to explore other important and potentially modifiable risk factors.

Several meta-analyses based on prospective cohort studies have identified increasing body mass index (BMI), the indicator of general adiposity which is often assumed to represent the degree of body fat, was related to higher risks of PLC (4, 5). However, abdominal fat may vary distinctly within a narrow range of BMI (6). In addition, current evidence suggests that visceral adipose is primarily found in the abdominal cavity, which had been confirmed more metabolically active than subcutaneous adipocytes (7–9). Previous study have suggested that waist circumference was a better predictor of abdominal fat compared with BMI in males (10). Hence, waist circumference, as the index considering both the amount and distribution of adipose, could be an appropriate measurement of abdominal obesity compared with BMI (11).

The recent study reported that the abdominal obesity (waist circumference ≥90 cm for male and ≥80 cm for female) prevalence was approximately quadrupled from 9.53% in 1993 to 36.7% in 2011 among Chinese males (12). Although waist circumference has been identified as an important predictor of several specific cancers such as colorectal cancer (13) and gastroesophageal cancer risk (14) in general, the association between high waist circumference and PLC risk in males has not reached a consensus (15–19). In addition, the effect of low waist circumference has rarely been investigated, leaving evidences to be further strengthened. Therefore, we conducted a large prospective cohort study based on the Kailuan Group to investigate the association between waist circumference and risk of PLC incidence in Chinese males, which might be helpful for identifying a potentially preventable risk factor of PLC.

In this large prospective cohort study among Chinese males, we found a significant U-shaped association between waist circumference and PLC risk. The association was robust even after including BMI in the statistical models, supporting the hypothesis that waist circumference is an independent predictor for PLC. In addition, the subgroup analyses showed that the association between waist circumference and risk of PLC differed across categories of alcohol drinking, tobacco smoking, and status of HBV infection, as there were discrepancies among subgroups. To our knowledge, this is the first prospective cohort study to report on the association of both high and low waist circumference with PLC risk in mainland Chinese males which could be a strong evidence suggesting waist circumference is an independent predictor of PLC.

Waist circumference was one of the earliest means of quantifying body fat distribution, as an approximation of central adiposity (26). Results from several prospective cohort studies have examined the association between high waist circumference and risk of PLC (15–19). European Prospective Investigation into Cancer and Nutrition study identified 177 liver cancer cases and reported that high waist circumference was related to higher risk of liver cancer (highest tertile VS. lowest tertile, HR = 2.60, 95% CI: 1.66–4.07) (17). Similarly, the Liver Cancer Pooling Project also found waist circumference to be an independent risk factor for liver cancer risk in males (waist circumference ≥110 cm VS. < 90 cm, HR = 1.88, 95% CI: 1.42–2.49) (15). A study from Taiwan reported that the association between central obesity (waist circumference >90 cm for men and < 80 cm for women) and PLC was only restricted in subjects with HBsAg negative and antibody to hepatitis C virus (HCV) positive (HR = 2.16, 95% CI: 1.19–3.92) (18). Our results on waist circumference were in line with the previous findings, whereby we consistently observed a significant association between high waist circumference and high liver cancer risk, even after further adjustment for BMI.

However, few studies have explored the association between low waist circumference and risk of PLC. Our study added a new perspective that the statistically U-shaped association between waist circumference and PLC risk, in which that low waist circumference might also play a potential role in PLC incidence. The RCS model showed that PLC risk increased obviously when waist circumference was lower than 75.0 cm. In addition, the present study also found a significant relationship when the first quintile (< 80.0 cm) compared to third quintile (85.0–89.9 cm) in subjects with HBsAg negativity, which support an association between low waist circumference and PLC risk. Perhaps males with low waist circumference were prone to accompany with preclinical disease that can cause weight loss and also increase risk of PLC, which may confuse the association. However, the association between low waist (< 80.0 cm) circumference and PLC risk remained robust with exclusion of participants with BMI < 18.5 kg/m² (HR = 1.51, 95% CI: 1.00–2.28). In addition, for subjects with HBsAg negativity, the association was stronger (HR = 2.29, 95% CI: 1.28–4.08, data was not shown) when excluded the underweight participants (BMI < 18.5 kg/m²). Therefore, the robust findings indicated that low waist circumference might be a risk factor of PLC.

The previous study suggested that waist circumference was a better predictor of abdominal adiposity in males when compared with body weight or BMI (11). In our study, waist circumference conveyed statistically significant association with PLC risk, even after adjusting BMI in the statistical models, supporting the hypothesis that waist circumference is an independent predictor for PLC. Subjects with high waist circumference tend to be diagnosed with PLC maybe due to the following possible mechanisms. Increased release from metabolically active abdominal fat of substantial adipokines, such as tumor-necrosis factor-α, free fatty acids, leptin and inflammatory markers, and reduced release of adiponectin, contribute to development of insulin resistance, compensatory and chronic hyperinsulinaemia (8, 9, 26–28). Increased insulin levels, in turn, lead to reduced insulin-like growth factor (IGF) binding protein 1 synthesis in liver and other tissues, additionally, generally accompany with reduced levels of IGF binding protein 2 in the blood. Both the reduced IGF binding protein 1 and IGF binding protein 2 give rise to facilitate the biological activity of IGF1. Ultimately, insulin and IGF1 signal through the insulin receptors and IGF1 receptor, respectively, to promote cellular proliferation, inhibit apoptosis, and then contribute to tumorigenesis (8, 17). The mechanisms for subjects with low waist circumference also related to high PLC risk is still inconclusive, hence further research to better understand the underlying mechanisms are needed.

In the present study, the association between high waist circumference and risk of PLC differed by status of drinking and smoking. The association was statistically significant in non-drinkers or non-smokers but negative in drinkers or smokers. It is possible owing to the competing risks of tobacco smoking and alcohol drinking. Previous studies have suggested that alcohol drinking may increase 179% (95%CI: 2.00-3.87) risk of liver cancer incidence (29) via the induction of cytochrome P-450 2E1, which potentially leads to activation of procarcinogen (30) and inhibition of phase II enzymes (31), thus affecting the clearance of carcinogens (32). And tobacco smoking (HR = 1.51, 95% CI: 1.37–1.67) was also found to be an independent risk factor for liver cancer (33). Therefore, in the presence of a competing risk, the association may be attenuated among drinkers and smokers. However, for non-drinkers, or non-smokers, high waist circumference showed a significant effect on PLC development which could have key scientific and clinical importance for preventing PLC.

The prevalence of HBsAg was 3.30% in the present study, which was similar to the previous study on HBsAg prevalence (< 4%) among northern Chinese population (34). As it was estimated that hepatitis B viral infections accounts for more than 60% of liver cancer cases in Asia area (2), our study also proved that HBsAg positivity increased 30.74 (95%CI: 24.51–38.55) fold higher risk of PLC when compared with HBsAg negative. Therefore, the effect of waist circumference may be weakened, which explain the finding that increased PLC risk related to higher and lower waist circumference was restricted in subjects with HBsAg negativity. Although the HBV infection currently plays a leading role in the development of PLC (35), it is unlikely to be the main risk factor in the future, as the prevalence of HBsAg among the children under 5 years of age decreasing from 9.67% in 1992 to 0.96% in 2006 (3) with the successful massive hepatitis B vaccination implementation. Whereas, the abdominal obesity prevalence was approximately quadrupled from 9.53% in 1993 to 36.7% in 2011 among Chinese males (13). Thus, the findings of abdominal obesity, related to PLC risk differently depending on HBsAg status may shed some light on preventing PLC in the condition of hepatitis B vaccination application.

One of the main strengths of our study is its prospective design and inclusion of a large population, which gave us high power to detect quite modest associations as well as minimize the potential bias caused by preclinical disease. Furthermore, in our study, anthropometric factors (e.g., waist circumference, weight, and height) at baseline were measured by trained personnel rather than relied on self-reported, which avoid misclassification in analyses. However, there are several limitations that should be discussed when interpreting the results. Firstly, the lack of information on HCV infection is a major limitation of the current study. However, the HCV prevalence rate was only 0.43% in Chinese general population according to a national survey carried in 2006 (36), which attribute little to PLC incidence in China. In subsequent questionnaire interview and health examination, we will complement the HCV infection information to provide more comprehensive results in the future. Secondly, the follow-up time (Median, 8.9 years) was relatively short, which precluded stratified analyses by subtypes of PLC, such as hepatocellular carcinoma and intrahepatic cholangiocarcinoma, owing to limited number of cases. In addition, the subjects focused on male employees from Kailuan Group, it may be difficult in extrapolating to females or general population. So for other population, more studies are warranted to confirm these findings.

In conclusion, our analyses provided convincing evidence that waist circumference might be one of the scientific and important predictor of PLC based on the large-scale prospective study. The findings indicated that both high and low waist circumference could increase the risk of PLC in males, especially for subjects with HBsAg negative. Therefore, controlling waist circumference in an appropriate range might be an effective primary prevention to decrease PLC risk.

The datasets for this manuscript are not publicly available because all our data are under regulation of both the National Cancer Center of China and Kailuan Group. Requests to access the datasets should be directed to Jie He, hejie@cicams.ac.cn and Shouling Wu, drwusl@163.com.

NL, MD, SW, and JH did the study concept and design. GW, XF, YC, HC, and SC carried out the acquisition and quality control of data. LW, ZL, XL, and YW performed statistical analysis, or interpretation of data. LW performed the writing and drafting of the manuscript. NL and MD did the critical revision of the manuscript for important intellectual content. All authors agreed to be accountable for the content of the work.