This prospective analysis of over 0.47 million individuals suggested that MetS, particularly for central obesity and hyperglycaemia, was associated with elevated risk of liver cancer in male participants, but not in females. For individual MetS components, WC and blood glucose were associated with increased liver cancer risk in a dose-dependent manner, while HDL cholesterol showed a U-shaped relationship. The associations of blood pressure and liver cancer risk were modified by gender, with a U-shaped association in women while no association in men. This study highlighted the importance of individualized liver cancer prevention by gender, especially in patients with MetS.
Accumulating literature demonstrated that MetS was associated with increased risk of liver cancer [5,6,7,8]. Our results were in agreement with a recent meta-analysis of six cohort studies, which showed that the presence of MetS was associated with higher incidence of HCC in male participants but not in females [8]. The gender-specific effect could be explained as different components of MetS may confer diverse risk of liver cancer by gender. In the present study, central obesity was associated with increased risk of liver cancer only in men but not in women. This finding was in agreement with two meta-analyses that suggested that sex disparity existed in the obesity and HCC association, with higher risk of HCC in obese men than in obese women [16, 17]. One explanation for this is that gender dimorphisms may occur in adipose homeostasis. Differences in body fat composition rather than BMI were suggested to be true determinants of liver cancer prognosis [18]. Visceral fat, which played a more important role in liver carcinogenesis than total adiposity accounts for a strikingly larger proportion of body fat in men than in women [19, 20]. Previous study has indicated that the body composition difference may be driven by differing sex hormones: higher androgen receptor density increased visceral fat and estrogen promoted the accumulation of subcutaneous fat, which protects against inflammation [21,22,23,24]. Evidence has also suggested the regulatory roles of the estrogen and/or androgen receptors signaling in the key metabolic microRNAs and chromatin-modifying enzymes in the pathogenesis of both type 2 diabetes and HCC [25]. This may explain why pre-diabetes affected liver cancer risk in men, as also reported by Chen et al. [26] Future studies are needed to confirm these findings and further investigate the underlying mechanisms.
With limited evidence concerning the potential contribution of dyslipidemia to the development of liver cancer, our data suggested that either very low or high levels of HDL cholesterol might increase the risk of liver cancer. Liver is a major organ of cholesterol metabolism. A previous study suggested that excess cholesterol intake increased the incidence of cirrhosis, which in turn, increased liver cancer risk in general population [27]. This is in agreement with the beneficial inhibitory effect of statins on liver cancer incidence [28, 29]. However, cholesterol was also reported negatively associated with the risk of liver cancer [30, 31]; Another prospective cohort of 27,724 participants from Japan found a positive association between low levels of HDL cholesterol and HCC [32]. Our finding on HDL cholesterol provided new insights to why dyslipidemia might have opposite effect on liver cancer incidence in aforementioned studies, and further suggested that controlling HDL cholesterol in an appropriate range by gender might be an effective primary prevention for liver cancer.
Hypertension has been reported to either with or without an increased liver cancer risk [30, 31]. In the present study, we did not identify sufficient evidence of association between hypertension and risk of liver cancer, which could be explained by the U-shaped association, especially in female participants. We did not identify sufficient evidence of association between hypertension and risk of liver cancer, which could be explained by the U-shaped association between blood pressure and liver cancer risk, especially in female participants. The mechanisms underlying the association between blood pressure and liver cancer risk remains unknown, although previous study has suggested that hepatocellular mitogenic effect of several hormones which are known to play a role in the development of hypertension [33]. Further studies are needed to clarify the potential mechanisms.
Hyperglycemia may play a role in the pathogenesis of liver cancer. The dose-dependent increase in the risk of liver cancer by blood glucose in our study was supported by several cohort or case–control studies [7, 34]. Indeed, participants with chronic hyperglycemia related to prolonged diabetes had higher risk for developing primary liver cancer [34]. Some medications against diabetes (for example, metformin), on the other side, may be preventative against liver cancer [35]. Several biological mechanisms have been proposed to explain the linkage. First, accelerated glucose metabolism may serve as an energetic supply for cancer cells, thus favoring tumor growth and metabolism [36]. In addition, hyperglycemia might promote hepatocarcinogenesis via stimulation of the insulin-like growth factor pathway, which was known to promote cell proliferation, inhibit apoptosis, and regulate differentiation, invasion and angiogenesis in tumorigenesis [37].
Our findings, consistent with most previous studies, suggested that central obesity was associated with increased risk of liver cancer [30, 38, 39]. Additionally, we found a linear association between WC and liver cancer even after adjusting for other MetS components, which was identical to other study that demonstrated a linear and positive association with liver cancer for BMI [39]. Considering the evidence that WC was strongly correlated with total body fat, especially among elderly individuals [40], our results supported the hypothesis that the development of liver cancer in obese individuals might be mediated through the development of NAFLD and non-alcoholic NASH [41]. Additionally, central obesity is associated with increased adipokines, insulin and reduced levels of adiponectin, which in turn, may increase the formation of reactive oxygen species and facilitate cellular lipid peroxidation and DNA oxidative damage, promoting hepatocarcinogenesis [42].
A key strength in our study is that, based on a nationwide prospective UK Biobank database with up to 9.6 years of follow-up and detailed measurements, we evaluated the gender-specific non-linear associations between individual components of MetS and the liver cancer risk, which was seldom reported in previous epidemiological studies. The observed U-shaped relationship for HDL cholesterol might provide novel insights underlying the pathological changes for liver cancer development. Furthermore, in the UK Biobank, cases were identified at their first diagnosis by cancer registry, therefore information of outcome was verified. Details of histological type of liver cancer were also provided allowing us to include all reported HCC. While alcohol use was based on touchscreen questionnaire, the information was verified by a trained nurse. More importantly, the availability of a wide range of known and putative risk factor data from UK Biobank allowed us to adequately control other potential confounding effects.
Our study had several limitations. First, as an observational study, the causality between MetS and development of liver cancer could not be confirmed, although we capitalized on complimentary analytic methods to robustly assess their epidemiological relationship. Second, although various covariates were controlled in the models, residual confounding effects could not be excluded particularly for hepatitis virus infection and the status of underlying chronic liver disease. However, it is controversial that hepatitis viral infection is related to metabolic risk factors and studies assessing the association between metabolic comorbidities and liver cancer showed no major changes in risk after excluding individuals with HBV or HCV [7, 43]. In the present study, the primary results were also not altered after exclusion of individuals with either hepatitis or liver failure/cirrhosis. Third, in the case of diabetes, liver cancer risk might vary depending on the glucose control status and the disease duration in patients with diabetes. However, our study was unable to assessment of the associations as these information were lacking. Future prospective cohort studies with detailed information on diabetes are needed to investigate the potential effects. Fourth, with limited cases, this study was underpowered to estimate the association between MetS factors and liver cancer by different ages and alcohol use status. Future prospective studies on this field are required to assess these effects in details. Finally, considering UK Biobank participants differed from the general UK population with regard to a range of sociodemographic and health-related characteristics, the possible “healthy volunteer” effect in the UK Biobank might limit the generalization of our findings. However, its large size and the heterogeneity of exposure measures might provide valid scientific inferences of exposure-outcome relationship that are generalizable to other populations [44].
Overall, this large prospective study suggested a gender-specific linear or U-shaped associations between individual MetS components and the risk of liver cancer. The males with MetS, particularly central obesity and hyperglycaemia, were associated with increased risk of liver cancer. Although the casual relationship has not yet been confirmed, approaches to control the recent worldwide epidemic of MetS might benefit for a reduction in the liver cancer burden. Additionally, since the HDL cholesterol in both genders, and blood pressure in females presented U-shaped associations with liver cancer, it’s important to consider the extra liver cancer risk in individuals with high HDL cholesterol and low blood pressure, which are generally regarded as beneficial for cardiovascular health. Controlling the levels of these health indicators in an appropriate range might be an effective primary prevention to decrease liver cancer risk.