Epidemiological studies have identified that GSD is one of several GBC risk factors, despite epidemiologic data, definitive evidence for the role of gallstones as a cause for gallbladder cancer is lacking, GSD might associate to the elevated hazard of GBC by 2.4-fold (gallstone diameter= 2.0~2.9 cm) to 9.2-10.1-fold (gallstone > 3 cm) (17, 18). In this clinical case-control study matched for ethnicity, occupation, and drinking conducted in northwestern China, we identified that Female, insulin resistance and hypercholesterolemia were independent risk factor of GBC predicting (8, 19); and DM didn’t associate significant with GBC in GSD patients as the recent report (20). Interestingly, our study revealed initially that TG was the most remarkable independent predicting factor of GBC risk in GSD patients among metabolic/environmental factors; while HTG was in the patients without GSD.
First, our study showed that DM was not significantly correlation to GBC risk in the GSD patients, which HOMA-IR was significant position to GBC risk in the patient without or with GSD. We trend to consider that hyperinsulinemia is an independent predicting factor of GBC risk (21), while DM is a risk factor for gallbladder cancer as a result of synergistic hypertension and hyperlipidemia (20). The recent study reported that insulin might reduce the levels of insulin growth factor binding proteins (IGFBP) 1 and IGFBP2 in the circulation, resulting in the increase of circulating insulin growth factor (IGF); the latter and insulin might stimulate target cells toward malignant transformation (22). In additional, few study has clarified that LDL-c is associated with GBC, while it is undoubled that very low dentine lipid (VLDL) receptor has been reported to be involved in the pathogenesis of GBC by regulating the expression of the components of the fibroblast growth factor receptor signaling pathway through Mitogen-Activated Protein Kinase (MAPK) (23), while high LDL-c levels could interrupt "endogenous lipid pathway" as result of VLDL accumulation because HTG will lead to the formation of large triglyceride-rich VLDL particles due to triglycerides overproduction is disproportionately greater than increasing apoB production, especially as seen in the insulin resistant state (24).
Second, our result revealed that HTG was significant positive correlation to GBC risk in GSD patients, while was not an independent risk factor; yet elevated TG was an independent risk factor of GBC predicting as the most remarkable. We speculate because of the following: there are little data on the role of elevated TG-related biomarkers on gallbladder cancer risk, but HTG, relating to GSD, might decrease sensitivity to cholecystokinin, increase both biliary cholesterol saturation and bile viscosity enhancing mucin production (25, 26), and cholesterol stones and gallbladder infections were associated with increased MUC3 and MUC5B expression (27). Epidemiological data have revealed that gallbladder stone is considered the most important risk factor for GBC, and the large volume or high weight of gallstones could increase further the risk (28). The synergistic effect of the gallbladder stones and infections leads to the thickening of gallbladder mucosa, which leads to the occurrence of gallbladder cancer in symptomatic GSD patients. Even so, it is known that the synthesis of TG requires glycerol and fatty acids, most of which are for glucose metabolism origin; the former is converted from dihydroxyketone phosphate produced by glycolysis; the latter is synthesized from acetyl CoA produced by oxidative decomposition of glucose. In short, consist elevated TG might infer to accumulation of glucose or insulin resistant, which blood glucose accumulation is transformed into TG by hepatocytes and TG is released into blood, resulting in the increase of TG concentration in blood (24). Several prospective epidemiological studies and showed that excess body weight in combination with physical inactivity is a major determinant for the development of insulin resistance with associated hyperglycemia and hyperinsulinemia and further leads to tumor development by several biological pathways, such as chronic low-grade inflammation, glucose toxicity, advanced glycosylated end product metabolism and the adenosine monophosphate kinase pathway (21). Clearly, elevated blood TG is the most remarkable independent predicting factor of GBC risk, possible because elevated TG is association with GSD (24), other indexes of metabolic syndrome (29), yet the effect of the latter is possible interfered constructively or destructively. Speculatively, our result, the observed persistent increase in serum TG, might be considered as the potential of a candidate diagnostic or prognostic biomarker of GBC in the patients with GSD.
Third, our study revealed that HTG is significant predicting factor of GBC risk including in the patients without GSD, the data are revealing that hypertriglyceridemia might increase the risk of prostate cancer (30), hepatocellular cancer (31), endometrial cancer (32), pancreatic cancer (33) and so on, which trended to consider the above correlation between HTG and GBC due to high secretion of bile acids, while bile acid metabolic dysfunction is a causal factor of gallstones (33, 34). Thus, we speculate that obesity and/or insulin resistance should be the main reasons in patients without GSD (35), as our multivariate logistic regression showed that HOMA-IR was the most remarkable independent predicting factor of GBC risk. There is convincing evidence that obesity may disturb lipid and endogenous hormones metabolism, result in gallbladder dysfunction, increase the risk of gallstones, and thus plays a role in GBC (9, 36), while the recent study supported that obesity might be protective factor for several of cancers (for example premenopausal breast cancer, non-small cell lung cancer and head and neck cancers) (35). Undoubtedly, centrally accumulation of body fat is associated with insulin resistance (37), which have a role in the aetiology of biliary tract cancers (including GBC) (38); insulin could stimulate the insulin receptor or the IGF-1R, activate their intrinsic tyrosine kinase activity, induce the production of lipid messengers by the phosphatidylinositol 3-kinase, and then trigger AKT-mammalian target of rapamycin pathway regulating cell growth and differentiation and the Ras-Raf-MEK-MAPK pathway inducing cell proliferation (39). Moreover, insulin might upregulate the metabolic activity of the cell, producing reactive oxygen species causing DNA double strand break or mutation in vitro (40).
Strengths and limitations. We reviewed a large number of participants’ case history with more than ten years, made sure that the patients had been diagnosed by surgery and pathology in the case group and the matched participants come from same occupation, similar environment. However, the present study has several limitations. First, this is not a multicenter and cohort study, statistics may be biased. Secondly, we provided little enlightenment about the cause for the negative correlation between both HBP, SBP, DBP and GBC, even SBP might be an independent protective factor in our study. Maybe elevated neuropeptides vasoactive intestinal peptide levels linking gastrointestinal motility regulation reduce diarrhea, secondary to avoiding HTG, which need the further proof of animal and molecular epidemiological study (41). Third, there might have been errors in the family history of cancer due to the small family units in China and Chinese personality characteristics; therefore, we haven’t completed an accurate data on family history of cancer and matching, as these statistics may be biased.