Can the detection of serum glutathione reductase serve as an effective complement to traditional tumor biomarkers in clinical laboratory medicine for patients with hepatocellular carcinoma?

[BACKGROUND] Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies within the digestive system, characterized by alarmingly high incidence and mortality rates. Early screening and diagnosis play a crucial role in the treatment and prognosis of HCC patients. We investigated whether the detection of serum glutathione reductase (GR) can serve as an effective complement to traditional tumor biomarkers in clinical laboratory medicine for patients with HCC.

[METHODS] We analyzed the positive rates and levels of serum GR, alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in 330 patients with HCC, 160 patients with benign liver tumors (BLT), 260 patients with chronic hepatitis B (CHB), 220 patients with liver cirrhosis (LC), and 280 healthy controls (HCs). The diagnostic performance of five biomarkers and their combinations for HCC patients and AFP-negative HCC patients was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis. Additionally, we investigated the correlation between the levels of GR, PIVKA-Ⅱ or AFP and the clinicopathological parameters of patients with HCC.

[RESULTS] The positive rates and levels of GR, AFP, PIVKA-II, CEA, and CA19-9 were significantly higher in the HCC group, the early HCC group, and the advanced HCC group than in the control group (p < 0.001). In the advanced HCC group, the positivity rates and levels of GR, AFP, and PIVKA-Ⅱ were markedly higher than those in the early HCC group (p < 0.01). PIVKA-Ⅱ exhibited the highest AUC and sensitivity for HCC diagnosis, at 0.873 (95% CI 0.853-0.891) and 72.7%, respectively, with a specificity of 94.9%. GR demonstrated exceptional diagnostic capability for patients with AFP-negative HCC, AFP-negative early HCC, and AFP-negative advanced HCC, with AUC values ranging from 0.864 to 0.881, sensitivity between 46.4% and 71.4%, and specificity of 97.7% (p < 0.001). Among all possible combinations, the combined detection of the five biomarkers yielded the highest AUC and sensitivity for diagnosing HCC, at 0.922 (95% CI 0.906-0.936) and 90.3%, respectively. The levels of GR, AFP, and PIVKA-Ⅱ exhibited varying degrees of correlation with the clinicopathological parameters of HCC patients.

[CONCLUSIONS] The detection of serum GR can serve as an effective complement to traditional tumor biomarkers in clinical laboratory medicine for HCC patients, particularly those with AFP-negative HCC. The combined detection of GR, AFP, PIVKA-Ⅱ, CEA, and CA19-9 can significantly enhance the diagnostic performance of HCC patients.