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NX‐PVKA assay, a conventional but refined prognostic biomarker for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide. The recent dramatic increase of HCC cases is associated with chronic hepatitis B and C. Worldwide, there are 300 million people infected with hepatitis B virus and 170 million with hepatitis C virus, respectively. Prothrombin, a 72-kDa plasma protein, is synthesized in hepatocytes as a precursor with 10 glutamic acid (Glu) residues. Under physiological condition, these Glu residues are converted into gamma-carboxy glutamic acid (Gla) by gammaglutamylcarboxylase, which uses vitamin K as a cofactor. However, when gamma-glutamylcarboxylation is impaired, Glu residues of prothrombin remain unconverted, and a des-carboxy prothrombin (DCP) is released into the bloodstream as a result. DCP is elevated in many patients with HCC, as well as those with vitamin K deficiency, so that raised plasma DCP can result from the administration of vitamin K antagonists like warfarin or impaired uptake of vitamin K in cholestasis with hyperbilirubinemia. Plasma level lf DCP is significantly elevated in patients with HCC, and is a clinically established HCC marker. For small tumors, measurement of both alpha fetoprotein (AFP) and DCP is recommended, because DCP is more specific for HCC than AFP. DCP is potentially valuable primarily as a prognostic biomarker, which would be predictive of rapid tumor progression and provide information about a possible poor prognosis. This is because DCP-positive HCCs show aggressive and invasive distinctiveness. A high DCP level implies a poor prognosis, and a slight increase in the DCP concentration after therapy could suggest recurrence. Kiriyama et al. demonstrated significantly poorer prognosis in “triple-positive” HCC patients, who were positive for all three available serum HCC markers, AFP, AFP-L3, and DCP. Besides its significance in serum HCC marker, DCP acts as an autologous mitogen for HCC cell lines. In vitro, DCP stimulates cell proliferation in HCC lines through the activation of cMET-Jak1 signal transducer and an activator of the transcription 3 signaling pathway. Moreover, DCP can induce both cell proliferation and migration of human umbilical vein endothelial cells. DCP has several variants based on the number of Glu residues. It is reported that there are differences in the number of Glu residues in DCP between patients with HCC and those taking warfarin. The conventional DCP assay, which uses the MU-3 antibody, detects DCP with 9–10 Glu residues and has lower affinity for DCP with one to five Glu residues. Toyoda et al. have reported a new DCP assay which specifically detects DCP with fewer Glu residues by using P-11 and P-16 monoclonal antibodies (Fig. 1). They have demonstrated the usefulness of this new test as an HCC marker in patients who were taking warfarin. In this issue of the Journal of Gastroenterology and Hepatology, Takeji et al. have reported an assay to detect DCP variants with fewer Glu residues, named NX-PVKA assay in HCC patients. They included 197 HCC patients and measured NX-PVKA and the NX-PVKA ratio (DCP/NX-PVKA-R), along with conventional DCP, AFP, and AFP-L3 prior to HCC treatment. They demonstrated that NX-PVKA was the strongest independent prognostic marker for overall survival with a hazard ratio of 81.32 by multivariate analysis. NX-PVKA level of greater than 100 mAU/mL correlated with significantly lower survival rates. NX-PVKA level was also significantly associated with platelet count, prothrombin time, C-reactive protein (CRP), sex, maximum tumor size, number of nodules, and portal venous invasion by HCC. With the said results, they established a prognostic model by using parameters; sex, serum albumin, 2 gamma glutamyl transferase, leucin aminopeptidase, CRP, hyaluronic acid, and NX-PVKA. Overall, they have presented a novel PVKA assay that associates with HCC prognosis more precisely than the conventional assays. The authors acknowledge several shortcomings in the present study. Because this is a retrospective study of patients from a single center in Japan, the results, including the prognostic model, should be validated using an independent testing cohort of patients. In addition, the patients enrolled in this study had several etiologies of liver damage and received different treatments. Overall survival is determined by patient and tumor factors, liver cirrhosis and functional reserve, and by the treatment modality. Because treatment was not considered, its influence on the overall survival remains unclear. Additional largescale and multicenter studies are warranted to verify their results. Nonetheless, the combination of NX-DCP and a conventional DCP assay is useful to identify HCC in patients taking the vitamin K antagonist warfarin. Moreover, NX-PVKA, along with their proposed prognostic model, potentially offers an efficient tool to predict longand short-term prognosis and overall survival of HCC patients.