In this study, we have confirmed previous studies that low TC level is associated with an increase risk of liver cancer. And we also found that normal-high ALT level could increase the risk of PLC. Furthermore, with significantly higher relative risk for PLC would be seen in subject who both keep low TC level and normal-high ALT level.
While the association between low TC level and the risk of liver cancer are rarely reported, our results are basically consistent with the previous studies. A large prospective study including 1,189,719 adults based on NHIC(National Health Insurance Corporation) cohort in Korea had clarified that the inverse association between the concentration of TC and incident liver cancer[13]. Additionally, Tanaka et al. [15] also found that low TC level(TC < 3.59 mmol/L) was significantly inversely associated with the risk of liver cancer(RR = 6.16; 95% CI: 1.39–27.35) based on data of voluntary blood donors in Japan. And our findings agree with this. In our study, we observed that low TC level(TC < 4.24 mmol/L) increased 1.71-fold risk of PLC(HR = 1.71; 95%CI: 1.34–2.19) compared with non-low TC level group. Even after excluding statins in our studies, there were no significant changes in our results (HR = 1.69; 95%CI: 1.32–2.16). Decreased TC concentration is significantly associated with the risk of PLC.
Transaminase has a strong power to predict the risk of liver cancer[10]. Although the JPHC Study(The Japan Public Health Center-based Prospective Study) has confirmed that elevated ALT would increase the risk of liver cancer(HR = 13.5; 95% CI: 8.0–22.0)[29], this slightly different from our research. Indeed, the association between normal-high ALT level and PLC risk is our focus. We found that normal-high ALT level alone increased 1.52-fold risk of PLC(HR = 1.52; 95%CI: 1.18–1.95) compared with normal ALT level after adjustment of potential confounders. This means that ALT in normal range is adverse for development of PLC. And we should paid enough attention to this phenomenon.
More importantly, by using cross-classification method, our study indicated that low TC level and normal-high ALT level have a combined effect on the risk of PLC. After adjusting confounders, we observed that combination of low TC level and normal-high ALT level showed 2.70-fold increased risk of PLC(HR = 2.70; 95%CI: 1.84–3.96) compared with combination of non-low TC level and normal ALT level. Futhermore, the joint effect of the these two factors was greater than their separate risks. To the best of our knowledge, this is the first time to prospectively evaluate the association of joint effect of low TC level and normal-high ALT level with PLC risk to date. These observations actually indicated that low TC level and normal-high ALT level had conjoint impact on PLC risk. This will remind us that in screening for early PLC, besides focusing on chronic liver diseases such as hepatitis, cirrhosis and fatty liver, dyslipidemia and slight increase of transaminase also play roles in PLC risk.
In sensitivity analysis, after excluding HBsAg positive participants, participants in cirrhosis, fatty liver participants, participants who used statins, ALT ≥ 40U/L participants during follow-up, respectively. We found that the results of sensitivity analysis are consistent with the main results. This could speculate that the joint effect of low TC level and normal-high ALT level on the risk of PLC may be independent of chronic liver disease. In consideration of the prediagnostic PLC might influence the level of TC or ALT, thus, this result for PLC was slightly attenuated after excluding participants who occurred PLC within 1 year after entry to the cohort.
The mechanisms that low TC level and normal-high ALT level increased the risk of PLC remain uncertain. Omer F et al.[30] reported that cancer is associated with modulation of cholesterol homeostasis. Several carcinogenic signals, such as PI3K/AKT/mTOR, RTK/RAS and TP53, is associated with cholesterol synthesis in cells. TP53, a key tumor suppressor, could affect the development of cancers via modulating cholesterol homeostasis. As all we know, the major marker of chronic liver inflammation were serum ALT levels. The OhdG, a parameter of genetic risk for hepatocarcinogenesis, acts as a pro-mutagenic DNA lesion produced by oxygen(hydroxy) radicals [31–33]. Shimoda et al.[34] found that the OhdG is positively associated with serum ALT levels in patients without liver cancer, and speculated that oxidative DNA damage is produced by chronic liver tissue inflammation, which would increase the risk of genomic alterations causing liver cancer.
In fact, the interventions for the development of liver cancer can be achieved. Such as effective therapy or lifestyle changes are available to reduce the incidence and mortality for high-risk individuals. Meanwhile, it should be noted that the correct use of cholesterol-lowering drugs is also important for avoiding the potential health risks.
Our study has several limitations. Firstly, HCV is a known independent risk factor for PLC[35]. Around 170 million people worldwide were infected with HCV[36]. Our research lacked this information, and the risk of HCV infection affecting the risk of PLC cannot be verified. Secondly, in this study, there were still a part of potential unmeasured factors which we did not consider, such as Aflatoxin, dietary habit et al. Thirdly, serum TC and ALT levels fluctuate daily, our study needs to be measured several times to ensure the accuracy of the results. Finally, our data did not differentiate between hepatocellular carcinoma and intrahepatic cholangiocarcinoma, the risk factors of both might be different.
In conclusion, based on Kailuan Study, we have confirmed that low TC level is associated with an increase risk of liver cancer. In addition, the novel evidence was provided that normal-high ALT level is associated with the risk of PLC. And individuals with coexistence of low TC level and normal-high ALT level would have an higher risk of PLC.