Our study found that elevated GLR has a positive correlation with the recurrence of HCC patients with staging Ⅰ-Ⅱ after adjustment of age, sex, smoking, operation time, lymphovascular invasion, allogeneic blood, HB, AST, ALP, HBsAg, tumor number, tumor size, AFP. To the best of our knowledge, we were the first to discover a nonlinear relationship between GLR and the risk of recurrence in HCC patients at stage I-II, with a cutoff point of 27.5. The nonlinear relationship was as follows: the hazard ratio (95%CI) of incident recurrence was 1.041 (1.014, 1.068) when the GLR was less than 27.5 and 1.001 (1.000, 1.003) when the GLR was beyond 27.5. Moreover, according to the subgroup analysis, the association between GLR and incident recurrence of HCC patients with staging Ⅰ-Ⅱ was modified by HBsAg and AFP.
Inflammatory responses played a vital role in all stages of cancer development and progression [15–17]. In the early stages of cancers, inflammatory cell recruitment created a favorable microenvironment for tumor growth and facilitated the formation of new blood vessel formation[18, 19]. Intrahepatic GGT was chiefly found on the surface of the cell and played a key role in glutathione metabolism. Furthermore, previous studies have shown that increased preoperative increased GGT values were positive relationship with a poor prognosis of hepatocellular carcinoma [21–23]. GGT had pro-oxidant effect and catalyzed the generation of reactive oxygen species (ROS), ROS played proinflammatory function in the the NF-κB signaling pathway [22, 24, 25]. Similarly, lymphocytes inhibited tumor proliferation and migration in the human immune system, and increased lymphocyte count predicted favorable prognosis in patients with various solid tumors [26–28].
In recent years, the prediction model of prognosis of the HCC combined with different inflammation factors has always been a hot issue[9, 10, 29, 30]. Previous studies have examined GLR's prognostic ability in HCC[14, 31], intrahepatic cholangiocarcinoma  and nonfunctional pancreatic neuroendocrine tumors. These studies revealed that increased GLR values had a positive correlation with poor long-term outcomes, which matched our findings. However, building a reliable model required us to understand the true relationship between each predictor and the prognosis of HCC, where a non-linear relationship was important. In this study, we found that the relationship between GLR and the recurrence of HCC with staging Ⅰ-Ⅱ was nonlinear. This would help us build models in the future.
Subsequently, by subgroup analysis, the association between GLR and the recurrence of HCC with staging Ⅰ-Ⅱ was modified by HBsAg and AFP. In HBsAg-negative patients, our study found a significant positive relationship, but this relationship was closely significant (P = 0.0589) in HBsAg- positive patients. The previous study found that in HCC patients with AFP-negative after radical resection, GLR had fair accuracy in predicting the early-recurrence, and our findings persisted .
Noticeably, to our knowledge, the nonlinear relationship between GLR and the recurrence in HCC with staging Ⅰ-Ⅱ was first found. This study, however, has some limitations. First, this study was retrospective and included patients from a single-center hospital. Second, only patients who underwent first resection and with staging Ⅰ-Ⅱ were included in this study. Furthermore, the results of the study were for the Chinese population and may not be applicable to people in other countries. Due to these limitations, multicenter and large-scale studies were warranted to validate our finds.
In conclusion, the increased GLR was independently associated with the recurrence of HCC patients with staging I-II. Furthermore, the relationship between increased GLR and developing recurrence was positive, no-linear and modified by HBsAg and AFP.