Serum Des-gamma-carboxy Prothrombin Levels Research Articles

Prognostic Significance of Simultaneous Measurement of Three Tumor Markers in Patients With Hepatocellular Carcinoma

We conducted a prospective study to evaluate the significance of simultaneous measurement of 3 currently used tumor markers in the evaluation of tumor progression and prognosis of patients with hepatocellular carcinoma (HCC). Three tumor markers for HCC, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), were measured in the same serum samples obtained from 685 patients at the time of initial diagnosis of HCC. Positivity for AFP >20 ng/dL, AFP-L3 >10% of total AFP, and/or DCP >40 mAU/mL was determined. In addition, tumor markers were measured after treatment of HCC. Of the 685 patients, 337 (55.8%) were positive for AFP, 206 (34.1%) were positive for AFP-L3, and 371 (54.2%) were positive for DCP. In a comparison of patients positive for only 1 tumor marker, patients positive for AFP-L3 alone had a greater number of tumors, whereas patients positive for DCP alone had larger tumors and a higher prevalence of portal vein invasion. When patients were compared according to the number of tumor markers present, the number of markers present clearly reflected the extent of HCC and patient outcomes. The number of markers present significantly decreased after treatment. Tumor markers AFP-L3 and DCP appear to represent different features of tumor progression in patients with HCC. The number of tumor markers present could be useful for the evaluation of tumor progression, prediction of patient outcome, and treatment efficacy.

Des-γ-carboxyprothrombin expression in cancer and/or non-cancer liver tissues: Association with survival of patients with resectable hepatocellular carcinoma

Des-gamma-carboxyprothrombin (DCP), also known as a protein induced by vitamin K absence or antagonist II, is an abnormal prothrombin. The level of serum DCP is used in clinical diagnosis and prognosis of patients with hepatocellular carcinoma (HCC). Our previous immunohistochemical study showed that DCP is expressed not only in cancer tissues but also in the surrounding non-cancer tissues of HCC patients. However, clinical significance of DCP expression in non-cancer tissues of HCC patients remains unclear. In this study, we examined the relationship between histochemical expression of DCP in cancer and/or non-cancer tissues and the clinical outcome of the HCC patients. A retrospective study was performed of 132 patients each with a single primary HCC nodule. Expression of DCP in tissues was evaluated with immunohistochemical staining using anti-DCP antibody (MU-3). Serum DCP levels were determined using enzyme immunoassay with a double antibody sandwich system. Experimental and clinical data were processed by univariate and multivariate statistical analyses. DCP expression, even if it was observed only in non-cancer tissues, was related to poorer prognosis. Univariate and multivariate analyses showed that DCP expression in cancer and/or non-cancer tissues was a significant prognostic factor. Furthermore, the combined evaluation of tissue DCP expression and serum DCP levels showed that prognosis was poorest for patients showing positive tissue DCP expression and high levels of serum DCP. These results suggest that immunohistochemical evaluation of DCP expression not only in cancer but also in non-cancer tissues serves as a valuable factor in the prognosis of HCC patients and that the combined evaluation of tissue DCP expression and serum DCP level will be more valuable than either factor alone in the effective treatment and prognosis.

Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma.

Des-gamma-carboxy prothrombin (DCP) has been reported to be more sensitive and specific in diagnosing hepatocellular carcinoma (HCC) when compared with alpha-fetoprotein (AFP). However, its ability to identify small HCC still remains unclear. Thus, we conducted a cross-sectional case control study to evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. Serum DCP and AFP levels were determined in 127 patients. Among these patients, 32 were with non-cirrhotic chronic hepatitis, 34 were with compensated cirrhosis, and 61 were with HCC. The cut-off value for the DCP and AFP were set as 40 mAU/mL and 20 ng/mL, respectively. To compare the diagnostic value of DCP and AFP in distinguishing HCC from nonmalignant chronic liver disease, receiver operating characteristic (ROC) curves were constructed for each assay. The accuracy, sensitivity and specificity of DCP were higher than AFP in detecting HCC (81.9%, 77% and 86.4% vs 68.5%, 59% and 77.3%, respectively). The area under the ROC (AUROC) curves revealed that DCP had a better accuracy than AFP in diagnosis of HCC (0.85 [95%CI, 0.78-0.91] vs 0.73 [95%CI, 0.65-0.81], P = 0.013). In 39 patients with solitary HCC, the positive rates of DCP were 100% in patients with tumor size larger than 3 cm, 66.7% in patients with tumor size 2-3 cm and 50% in patients with tumor size less than 2 cm. The positive rates of AFP in patients with tumor size larger than 3 cm, 2-3 cm and less than 2 cm were 55.6%, 50%, and 33.3%, respectively. The median level of DCP in HCC patients with tumor size larger than 3 cm was significantly higher than those with tumor size 2-3 cm and those with the size of less than 2 cm. Our study indicates that DCP has a better diagnostic value than AFP in differentiating HCC from nonmalignant chronic liver disease. DCP has not only a stronger correlation with HCC than AFP in tumor size but also more effectiveness than AFP in detecting small size of HCC.

Measurement of des-gamma-carboxy prothrombin levels in cancer and non-cancer tissue in patients with hepatocellular carcinoma

In a recent experiment, we discovered that liver tissue adjacent to HCC can also produce des-gamma-carboxy prothrombin (DCP). The goal of this study was to advance measurements of DCP levels in hepatocellular carcinoma (HCC) and non-cancer tissues using an electro-chemiluminescence immunoassay (ECLIA) and immunohistochemistry, and to assess their clinical significance. DCP levels in HCC tissues ranged from 0.7 to 209862.4 mAU/0.1 g tissue weight, with a median of 492.6 mAU/0.1 g. DCP levels in non-cancer tissues ranged from 0 to 2329.9 mAU/0.1 g tissue weight, with a median of 88.8 mAU/0.1 g. DCP levels in cell membranes were significantly higher than in the cytoplasm (p<0.001). DCP levels in HCC tissue were significantly higher than in non-cancer tissue (p<0.001). The logarithm of serum DCP levels correlated not only with that of DCP levels in HCC tissues (p=0.019), but also with that in non-cancer tissues (p=0.020), and the total DCP level of liver tissues (p=0.016). The logarithm of DCP levels in HCC tissues correlated with that of DCP levels in non-cancer tissues (p=0.011). DCP levels in HCC tissue with portal vein invasion were significantly greater than in HCC tissues without portal vein invasion (p=0.028). DCP levels in non-cancer tissues with intrahepatic metastatic lesions were significantly higher than in non-cancer tissues without intrahepatic metastatic lesions (p=0.023). Our results suggest that the origin of elevated serum DCP may lie not only in HCC tissue, but in non-cancer tissue. The existence of HCC may influence production of DCP in non-cancer tissue. Tissue DCP may be a prognostic factor, while increased DCP levels in non-cancer tissues may play an important role in hepatocarcinogenesis.

Des-γ-carboxy prothrombin in cancer and non-cancer liver tissue of patients with hepatocellular carcinoma

Des-gamma-carboxy prothrombin (DCP), also known as protein induced by vitamin K absence or antagonist II absence (PIVKA-II), has been considered as a useful serum tumor marker for hepatocellular carcinoma (HCC). However, the underlying mechanism causing the elevation of serum DCP levels in HCC patients remains unclear. This study was undertaken to identify the relationship between serum DCP levels and the expression of DCP in cancer and surrounding non-cancer liver tissues of HCC patients. Serum and tissue samples prepared from 92 patients with a single HCC nodule were subjected to clinicopathological study by measuring serum DCP levels and performing immunohistochemical staining for tissue DCP. Serum DCP levels correlated significantly with clinicopathological factors such as hepatitis markers, tumor differentiation, vascular invasion, intrahepatic metastasis, TNM stage, tumor size, tumor recurrence, and patient survival. DCP immunohistochemical staining was positive in cancer tissues for 68 (68/92, 73.9%) patients and in non-cancer tissues surrounding tumors for 24 (24/92, 26.1%) patients. There was no apparent correlation between serum DCP values and the expression of DCP in HCC tissues; however, there was a significant correlation between serum DCP levels and the expression of DCP in non-HCC tissues (p=0.0398). In conclusion, our results suggest that the origin of elevated serum DCP may lie not only in HCC tissue but also in non-cancer tissues. The HCC lesion itself appears to influence the production of DCP in surrounding non-cancer tissues.

Sequential fluctuation pattern of serum des-γ-carboxy prothrombin levels detected by high-sensitive electrochemiluminescence system as an early predictive marker for hepatocellular carcinoma in patients with cirrhosis

Serum concentration levels of des-gamma-carboxy prothrombin (DCP), alpha-fetoprotein (AFP) and Lens culinaris agglutinin-reactive fraction (AFP-L3) are useful tumor markers for the diagnosis of hepatocellular carcinoma (HCC). Recently, a novel immunoassay using the electrochemiluminescence (ECLIA) was developed to enable measurement of low-concentration of DCP. This study investigated the usefulness of high-sensitive DCP for the early diagnosis of HCC. The subjects consisted of 90 patients with viral cirrhosis who could be followed for at least 24 months from 1992 to 1997. Fifty-six of these patients developed HCC and 34 patients had not by 1998. We measured the serum levels of high-sensitive DCP, AFP and %AFP-L3 every 3 months during 2 years before the detection of tumor in patients with HCC and during 2 years from 1995 to 97 in patients without HCC. Youden's index was calculated for evaluation of the ideal cut-off levels. The patterns of serial changes during 2 years were divided into two types: fluctuating type and non-fluctuating type. Cut-off levels of 40 mAU/ml for high-sensitive DCP (Youden's index = 0.435), 20 ng/ml for AFP (Youden's index = 0.442) and 10% for %AFP-L3 (Youden's index = 0.364) gave the highest index for each marker. When these markers were combined, the combination of high-sensitive DCP, AFP and %AFP-L3 gave the highest accuracy (sensitivity = 82.1%, specificity = 82.4%, accuracy = 82.2%). Fluctuating type of high-sensitive DCP, AFP and %AFP-L3 levels were found in 15 (17%), 29 (32%) and 11 (12%) patients, respectively. The rate of complication with HCC in the patients who showed the fluctuating type of high-sensitive DCP levels was significantly greater than that in the patients who showed non-fluctuating type (P<0.01). These results suggest that periodic measurement of serum DCP levels using ECLIA method is very useful for HCC screening and predicting the development of HCC.

Impairment of clathrin-mediated endocytosis via cytoskeletal change by epithelial to fibroblastoid conversion in HepG2 cells: A possible mechanism of des-γ-carboxy prothrombin production in hepatocellular carcinoma

Des-gamma-carboxy prothrombin (DCP) has been well established as a hepatocellular carcinoma (HCC) tumor marker. However, the precise mechanism by which HCC cells produce DCP remains unknown. Importantly, DCP is not specific for HCC. For example, vitamin K-deficiency or ingestion of a vitamin K antagonist (warfarin) also leads to DCP production. In addition, supplementary administration of vitamin K2 analogues to HCC patients has led to reduce serum DCP levels. From these observations, we hypothesize that DCP might be produced from HCC cells with functional impairment of vitamin K uptake. Because, as previously reported, the down-regulation of E-cadherin or high serum DCP in HCC patients is associated with a high risk of vascular invasion, intra-hepatic metastasis and tumor recurrence, we examined if HCC cells might produce DCP by epithelial to fibroblastoid conversion (EFC) in vitro. HepG2 cells were induced EFC by tumor promoter, 12-O-tetracanoylphorbol-13-acetate (TPA). DCP production was observed in HepG2 cells that had lost E-cadherin expression in a TPA-dose-dependent manner. The DCP production was inhibited by introducing additional vitamin K2 into the treated cells. In addition, LDL uptake as a surrogate of vitamin K uptake was significantly impaired in TPA-treated HepG2 cells. The cells with impairment of LDL uptake produced DCP. Fat soluble vitamins are taken up into cells through clathrin-mediated endocytosis, in which the dynamic polymerization of F-actin plays a crucial role. We found that HepG2 cells with F-actin rearrangement produced DCP. In addition, latrunculin A, an actin depolymerizer, induced naïve HepG2 cells to produce DCP, confirming that impairment of F-actin polymerization is a key mechanism of DCP production. We showed in vitro that cytoskeletal filament change by EFC is crucial for DCP production in HepG2 cells.