Metabolic syndrome is composed of a complex constellation of factors, that namely glucose intolerance and insulin resistance, central obesity, dyslipidemia, hypertension [4, 18, 19]. Over the past decade several researches have produced preliminary clues on the relationship between metabolic syndrome and hepatocellular carcinoma [20, 21]. However, few studies have investigated the association between metabolic factors and HBV-related HCC. As with the development of economy and changing of living behavior, metabolic-related chronic diseases have become more common in China. The present study extended the research on metabolic abnormalities in HBV related HCC in Chinese populations.
Insulin resistance and obesity, the majority components of MS are often revealed to be linked with cancer and now widely recognized as significant risk factors for HCC [22–24]. Our data displayed that with the increasing of BMI, the higher level of GLU, HOMA-IR, Insulin, QUICKI, FFA, TG and LDL-C. (p < 0.05) were found in HCC. Similar study demonstrated that HOMA-IR, a marker of insulin resistance, is elevated with increasing BMI. The link between obesity/diabetes and HCC may be explained by oxidative stress and/or lipid peroxidation that increase the possibility of hepatic injury, fibrosis, and even cirrhosis result from hepatic inflammation [26, 27]. Increased plasma insulin concentration combined with impaired whole-body glucose clearance in the present study was most likely a consequence of decreased insulin sensitivity, a typical phenomenon in patients with malignant diseases [28, 29].
In investigation the existence of oxidative stress and/or lipid peroxidation in HCC, we measured MDA and TAOC in all subjects. MDA is the lipid peroxidation end product and an important player in oxidative stress. Now MDA is widely used as one of the most reliable indices of oxidative stress to evaluate the oxidative damage in diseased status. TAOC is an index of the antioxidative defense system. We found for the first time that elevated levels of oxidative stress(MDA) and decreased antioxidative capacity (TAOC) were revealed in HCC patients. The results were consistent with the finding that HBV infection could increase toxic oxidation products, which lead to oxidative stress and DNA damage [31, 32]. HBV X protein has drawn considerable attention to the generation of HCC via mitochondria-derived reactive oxygen species (ROS). ROS could activate kupffer cells modulating hepatocyte injury and generating ROS, accompanied by lipid peroxidation, further impairment of mitochondrial function, which contributed much to carcinogenesis . In addition, ROS are most potent and can modify DNA methylation [33, 34]. But what predominates the extent of liver injury in HBV-related HCC and how abnormal metabolism accelerates the pathogenesis of HCC remain to be elucidated.
The liver is a critical organ in maintaining glucose and lipid homeostasis. The decreased glucose metabolism, utilization and downregulation of triglyceride synthesis in HCC patients were revealed in this study. ALT as an indicator of liver injury was obviously elevated in HCC in our observation (table 1). The elevation of ALT levels might be the reflection of excess accumulation of fat in the liver because of various metabolic abnormalities and indicated ongoing inflammation which impairs insulin signaling in the liver [35–37]. Our further logistic regression analysis revealed that lower TG and cholesterol levels as well as higher GA were contributing factors to HCC (Table 5). Meanwhile we found that the inverse correlation between serum TG and tumor size, the positive correlation between tumor size and GGT (supplementary Figure 1). These interesting observations indicate the intimate relation between lipid or glucose metabolisms and HBV-related malignancies, The contradicatory associations, ie. the inverse and positive correlations between lipid metabolisms and HCC, as revealed by us and others further demonstrated the complicated process of dyslipidemia involved in the pathogenesis HCC[26, 38, 39]. Though the mechanism how HBV-related diseases were closely related to lipid metabolisms is not clarified up to now, there are several studies supporting our findings: (1) HBV infection disturbs liver lipid metabolism, which was reported by Jan et al and revealed that low serum TG level was also associated with chronic HBV infection . Another independent in vitro study had ever demonstrated that HBX protein could directly inhibit secretion of ApoB, an essential component of LDL-C and very-low-density lipoprotein (VLDL-C), via promoting high expression of N-acetylglucosaminyltransferase III, in cell culture [41, 42]. (2) Lipids and lipoprotein metabolisms could be regulated by cytokines, while tumor cells are known to produce large amounts of pro-inflammatory cytokines. For instance, interleukin-6 (IL-6), tumor necrosis factor (TNF-α), IL-1 may inhibit TG synthesis . (3)The change of general nutritional status in exhaustive malignant diseases is another important factor leading to dyslipidemia. Low levels of TG and cholesterol were also revealed in other malignancies including colorectal cancer, lung cancer and so on [44–47]. Although our findings of inverse relationship between TG level and HCC were also consistent with previous study[26, 48], the possibility that low TG was a consequence of malignant liver diseases (HCC) can not be excluded. Hence further prospective study should be designed to elucidate the causative or consequent effect or even both causative and consequent effects of dyslipidemia in HBV-related HCC in future study.
Another important metabolic indicator which could be linked with obesity is FFA. FFA is normally released from an expanded adipose tissue and produced an increased secretion of VLDL. MDA, the lipid peroxidation end product via fatty acid β-oxidation, was found to be associated with FFA in this study. Our result further confirmed that obesity might be related with liver injury and eventual accelerating the development of HCC [49, 50].
There are some limitations of this study. HBV carrier was used as disease control instead of CLD (fibrosis and cirrhosis). Metabolic abnormality might develop in CLD and abnormal metabolism could accelerate the progress of CLD at the same time. Further validation in CLD groups and in large sample size were required to illustrate the value of metabolic assessment in the prediction and prognosis in HCC. Another limitation is that the research is a cross-sectional study drawn from a clinical series of patients and not from the community. But the cases were carefully matched or stratified by age, gender, BMI, time of hospital admission and etiology to minimize the interferences. A better understanding of the relationship between these metabolic parameters should ultimately lead to improve prediction and treatment options for patients with HBV related HCC. To counteract the adverse effects of metabolic abnormalities, those infected with HBV should first attempt to achieve the metabolic control through changes in diet and life style.