In this study, we evaluated the impact of postoperative hyperglycemia on the early recurrence of HCC. While patients with early HCC are asymptomatic, patients in the intermediate and advanced stages present with liver pain, hepatomegaly, digestive symptoms, and/or systemic symptoms; additionally, some patients may be accompanied by paraneoplastic syndrome[15]. At present, open surgical resection offers the best curative potential for HCC[16, 17]. However, hyperglycemia is common after hepatectomy because of the reduction in liver volume, influence of immune function, and stress caused by the operation[12, 18].
A large number of studies have reported diabetes as a risk factor for the occurrence and prognosis of HCC[7–10, 19–21]. Reportedly, the incidence of HCC in patients with diabetes is 23 times higher than that in patients without diabetes. A meta-analysis of five cohort studies by Tan et al.[21] suggested that people with diabetes have an increased risk of HCC compared to people with normal blood glucose, which was confirmed in a case cohort study by Liu Tong et al. involving 90,000 individuals[22]. Liu Tong’s study showed that although the fasting blood glucose level increased, it did not meet the diagnostic criteria of diabetes; however, the risk of HCC still increased significantly. At present, the relationship between the early postoperative recurrence of HCC and hyperglycemia is still controversial, both at home and abroad[23–27]..
The results of this study showed that the 1- and 2-year recurrence rates in the hyperglycemia group were significantly higher than that in the normal blood glucose group, and the tumor-free survival time was significantly shorter, which was consistent with the conclusions of Yu et al.[27] and Hosokawa T et al.[28]. The results of the univariate and COX multivariate analyses suggested that a postoperative increase in the fasting blood glucose level was an independent risk factor for early recurrence of HCC.
Although the mechanism whereby postoperative hyperglycemia induces a recurrence of HCC is unclear, the following mechanisms have been proposed(1)Vascular endothelial growth factor (VEGF): Hyperglycemia can promote the expression of VEGF, which can promote the growth, invasion ,and metastasis of tumor cells[29];(2)Hyperinsulinemia: Hyperglycemia may lead to hyperinsulinemia. Insulin binds to insulin receptors, which then activates insulin receptor substrate-1, and the downstream mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3 kinase / Akt (PI3K-Akt) pathway, and the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway. The activation of these pathways can promote cell proliferation and protein synthesis, inhibit cell apoptosis, and promote cancer progression[30];(3) Insulin growth factor-1 (IGF-1): A study by Yan et al.[31] using a rat hepatoma model found that IGF-1 receptor (IGF-1R) was overexpressed in hepatoma cells, and IGF-1R may be involved in the occurrence and development of rat hepatoma;(4) Oxidative stress: Hyperglycemia can promote the formation of advanced glycation end products (AGEs), and cause interference between oxidative stress and AGEs or AGEs receptor (RAGE), thus accelerating the occurrence of hepatocellular carcinoma[32];(5)Inflammatory factors: Under the condition of hyperglycemia, metabolic disorders could produce some inflammatory factors, which are conducive to the formation of the tumor microenvironment, lead to excessive immune activation, and promote tumor occurrence and development[33];(6) Glycolysis: Glycolysis is the primary metabolic pathway of cells under aerobic condition. Lactic acid is the main final product of glycolysis, which is beneficial for tumor invasion and inhibition of tumor immunity in an acidic environment, thus promoting the growth and metastasis of cancer cells[34]. The above results suggest that there may be a correlation between hyperglycemia and early recurrence of HCC.
In addition to high blood glucose levels, this study also found that tumor pathology and postoperative adjuvant therapy were independent risk factors for postoperative disease-free survival of HCC. Clinical practice has demonstrated that targeted adjuvant therapy for patients with HCC can effectively improve their postoperative prognosis and quality of life.
In summary, fasting blood glucose level ≥ 6.1 mmol / L, poor differentiation of tumor tissue, and no adjuvant treatment after radical resection of HCC were independent factors affecting DFS after radical resection of HCC.
While some studies have suggested that preoperative AFP concentration, Child-Pugh grade, liver cirrhosis, the number of tumors, and other factors would affect the prognosis of patients with HCC, similar conclusions could not be reached in this study.This may be due to the single-center, retrospective nature of this study and/or its small number of included cases. The effect of elevated blood glucose on early recurrence of HCC after open radical hepatectomy needs to be further confirmed by multicenter studies with larger sample sizes.